RU2379312C2 - Lysine compounds, pharmaceutical composition containing these compounds, application of said compounds for treatment or prevention of hiv-infection - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: present invention concerns lysine compounds of formula

(I) or its pharmaceutically acceptable salts, a based pharmaceutical compositions and application for treatment or prevention of HIV-infection. The compounds of formula (I) where n is equal to 3 or 4, where X and Y identical or different are chosen from the group consisting of H, F, Cl, Br, I and -NR₄R₅, where R₆ is chosen from the group consisting of unbranched alkyl group, containing 1 to 6 carbon atoms, and branched alkyl group containing 3 to 6 carbon atoms, where R₃ is chosen from the group consisting of the group of formula R_3A-CO-, and R_3a is chosen from the group consisting of unbranched or branched alkyl group containing 1 to 6 carbon atoms, alkyloxygroup containing 1 to 6 carbon atoms, and 4-morpholinyl, where R₄ and R₅ are identical and represent H, where R₂ is chosen from the group consisting of diphenylmethyl group, naphthyl-1-CH₂-group, and naphthyl-2-CH₂-group, where X' and Y' are identical and represent H, and where R₁ is chosen from the group consisting of from (HO)₂P(O) and (MO)₂P(O), where M represents alkaline metal.

EFFECT: lysine compounds representing effective inhibitors of aspartyl-protease.

15 cl, 3 tbl, 1 ex

Description

FIELD OF THE INVENTION

This invention relates to lysine-based compounds that exhibit good solubility and bioavailability. More specifically, the present invention relates to lysine-based compounds containing a physiologically cleavable unit, whereby when the unit is cleaved, the compound is capable of releasing an HIV protease inhibitor. The compounds and pharmaceutical compositions of the present invention are particularly well suited to reduce drug loading and improve patient compliance with treatment regimens and regimens.

BACKGROUND

HIV viral protease inhibitors were developed relatively recently, and their use only began in 1996. They are currently regarded as the most effective anti-HIV drugs. Unfortunately, most of the currently available protease inhibitors are relatively large hydrophobic molecules that have fairly low bioavailability. Therefore, to achieve a therapeutic dose for a patient, a high drug load is required. This is a deterrent, which too often leads to non-compliance with the treatment regimen and regimen and insufficient treatment results. This situation leads to a suboptimal therapeutic concentration of the drug, which in turn leads to the development of resistant strains of HIV.

Therefore, there is an urgent need to improve the solubility and bioavailability of protease inhibitors.

Examples of improved compounds have been developed in the form of prodrugs of aspartyl protease inhibitors, such as those described, for example, in US Pat. No. 6,436,989 to Hale et al. , the full contents of which are incorporated into the description by reference. This patent shows a new class of molecules characterized by suitable solubility in water, high oral bioavailability and easy in vivo generation of the active ingredient. However, it is well known that HIV has the ability to develop resistance to currently available drugs. Thus, there is a need for alternative HIV protease inhibitors active against wild types of viral strains and resistant viral strains. So, to combat resistant viral strains, molecules derived from currently available HIV protease inhibitors showing improved solubility and bioavailability are desirable.

A unique class of aromatic derivatives that are aspartyl protease inhibitors is described in US Pat. No. 6,632,816 to Stranix et al ., The entire contents of which are incorporated herein by reference. More specifically, this patent includes derivatives of L-lysine substituted with N, a synthetic amino acid, having effective inhibitory properties against aspartyl protease. However, it would be beneficial to improve these derivatives by increasing water solubility and bioavailability in order to reduce drug loading and maintain patient compliance with treatment regimen and regimen. Since it is promising to create active protease inhibitors, especially to wild types of strains and resistant strains, the formation of derivatives of the original HIV protease inhibitors, such as those described in US Pat. No. 6,632,816 to Stranix et al ., Which are known to be active in in relation to resistant strains, is a viable path with significant advantages. More specifically, in the development of an effective drug, it is desirable to provide compounds with improved water solubility, bioavailability, duration of action and formulation properties, along with other advantages.

SUMMARY OF THE INVENTION

The present invention provides new compounds based on lysine, the source of which is a class of derivatives that are effective aspartyl protease inhibitors, and their pharmaceutically acceptable derivatives. These compounds can be readily cleaved in vivo , releasing the active ingredient. The active ingredient has an affinity for aspartyl proteases, in particular HIV-1 aspartyl protease (US Pat. No. 6,632,816). The active ingredients also show effective antiviral activity when tested on the non-mutant viral strain of HIV-1 (NL4.3 as the wild-type virus), as well as several mutant strains. Therefore, the compounds of the present invention can be used as a means to increase solubility and improve the bioavailability of the active ingredient (protease inhibitor). The compounds of the present invention can be used alone or in combination with other therapeutic or prophylactic agents for treating or preventing HIV infection. The compounds of the present invention have good solubility and bioavailability and can be administered orally in the form of an aqueous solution.

The main objective of this invention is to provide an improved class of lysine-based compounds that are capable of releasing an aspartyl protease inhibitor and especially HIV aspartyl protease inhibitors. The lysine-based compounds of the present invention may contain a cleavable unit, whereby when the unit is cleaved, the compound is capable of releasing an HIV protease inhibitor. The present invention also provides pharmaceutical compositions comprising the lysine-based compounds described herein.

Therefore, the present invention, in one aspect, provides lysine-based compounds which, under in vivo physiological conditions (e.g., metabolic, intestinal, gastrointestinal, etc.) allow a protease inhibitor (e.g., an aspartyl protease inhibitor) to be released. The compounds of the present invention can serve as a means to improve the solubility and / or bioavailability of protease inhibitors, and, therefore, can reduce the drug load, and may favor patient compliance with the treatment regimen and regimen.

The compounds of the present invention may contain, for example, (for example, physiologically) a cleavable (for example, hydrolyzable) bond or link, which upon cleavage of the cleavable link or link give a protease inhibitor (for example, an active protease inhibitor).

A protease inhibitor can act on HIV-1 aspartyl protease, including mutant or non-mutant HIV-1 viral strains (e.g., NL4.3), or on HIV-2 protease (mutant or non-mutant), or even a protease of related viruses (SIV and t .d.). The compounds of the present invention can be used alone or in combination with other therapeutic or prophylactic agents for the treatment or prophylaxis of, for example, HIV infection.

The compounds and pharmaceutical compositions of the present invention can release a protease inhibitor (active ingredient) in vivo and, thereby, can inhibit (for example, in vivo ) the activity of HIV aspartyl protease, an enzyme essential for the development and infectivity of the virus. The compounds and pharmaceutical compositions of the present invention may have higher bioavailability, and may also be suitable for lowering the dosage required to suppress and, therefore, may improve the treatment of HIV-infected patients.

The present invention, in one aspect, provides a compound (for example, a compound capable of generating an HIV protease inhibitor) of formula I:

and pharmaceutically acceptable salts and derivatives thereof (for example, when the compound of the present invention includes an amino group, the pharmaceutically acceptable salt may be an ammonium salt),

where n may be equal to, for example, 3 or 4,

where X and Y, the same or different, can be selected, for example, from the group consisting of H, an unbranched alkyl group containing from 1 to 6 carbon atoms, a branched alkyl group containing from 3 to 6 carbon atoms, a cycloalkyl group containing from 3 to 6 carbon atoms, F, Cl, Br, I, —CF ₃ , —OCF ₃ , —CN, —NO ₂ , —NR ₄ R ₅ , —NHCOR ₄ , —OR ₄ , —SR ₄ , —COOR ₄ , —COR ₄ and —CH ₂ OH, or X and Y together define an alkylenedioxy group selected from the group consisting of a methylenedioxy group of the formula —OCH ₂ O— and an ethylenedioxy group of the formula —OCH ₂ CH ₂ O—, where R ₆ can be selected, e.g. from gro PP, consisting of an unbranched alkyl group containing from 1 to 6 carbon atoms, a branched alkyl group containing from 3 to 6 carbon atoms, a cycloalkylalkyl group containing from 3 to 6 carbon atoms in its cycloalkyl part and from 1 to 3 carbon atoms in its alkyl part,

where R ₃ can be selected, for example, from the group consisting of H, an unbranched alkyl group containing from 1 to 6 carbon atoms, a branched alkyl group containing from 3 to 6 carbon atoms, a cycloalkyl group containing from 3 to 6 carbon atoms and groups of the formula R _3A —CO—, where R _3A can be selected, for example, from the group consisting of a straight or branched alkyl group containing from 1 to 6 carbon atoms (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, tert- butyl-CH ₂ and t etc.), a cycloalkyl group containing from 3 to 6 carbon atoms (for example, cyclopropyl, cyclohexyl, etc.), a cycloalkylalkyl group containing from 3 to 6 carbon atoms in its cycloalkyl part and from 1 to 3 carbon atoms in its alkyl part (for example, cyclopropyl-CH ₂ -, cyclohexyl-CH ₂ -, etc.), alkyloxy group containing from 1 to 6 carbon atoms (for example, CH ₃ O-, CH ₃ CH ₂ O-, isobutyl- O-, tert- butyl-O- (Boc), etc.), tetrahydro-3-furanyloxy, -CH ₂ OH, -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CF ₃ , pyrrolidinyl, piperidinyl, 4-morpholinyl, CH ₃ O ₂ C-, CH ₃ O ₂ CCH ₂ -, acetyl-OCH ₂ CH ₂ -, HO ₂ CCH ₂ -, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-CH ₃ OC ₆ H ₄ CH ₂ -, CH ₃ NH-, (CH ₃ ) ₂ N-, (CH ₃ CH ₂ ) ₂ N-, ( CH ₃ CH ₂ CH ₂ ) ₂ N-, HOCH ₂ CH ₂ NH-, CH ₃ OCH ₂ O-, CH ₃ OCH ₂ CH ₂ O-, C ₆ H ₅ CH ₂ O-, 2-pyrrolyl, 2-pyridyl , 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of the formula

picolyl group selected from the group consisting of

picolyloxy group selected from the group consisting of

substituted pyridyl group selected from the group consisting of

and groups of the formula

where X 'and Y', the same or different, can be selected, for example, from the group consisting of H, an unbranched alkyl group containing from 1 to 6 carbon atoms, a branched alkyl group containing from 3 to 6 carbon atoms, a cycloalkyl group containing from 3 to 6 carbon atoms, F, Cl, Br, I, —CF ₃ , —NO ₂ , —NR ₄ R ₅ , —NHCOR ₄ , —OR ₄ , —SR ₄ , —COOR ₄ , —COR ₄ and -CH ₂ OH,

where R ₄ and R ₅ , the same or different, can be selected, for example, from the group consisting of H, an unbranched alkyl group containing from 1 to 6 carbon atoms, a branched alkyl group containing from 3 to 6 carbon atoms, a cycloalkyl group containing from 3 to 6 carbon atoms,

where R ₂ can be selected, for example, from the group consisting of diphenylmethyl group of the formula IV

naphthyl-1-CH ₂ groups of formula V

naphthyl-2-CH ₂ groups of formula VI

biphenylmethyl group of formula VII

and antryl-9-CH ₂ groups of formula VIII

and where R ₁ may be a cleavable unit (for example, a physiologically cleavable unit), whereby when the unit is cleaved, the compound releases a protease inhibitor (HIV protease inhibitor), provided that R _{1 is} not H. For example, R ₁ may be an enzyme or metabolically cleavable unit or a hydrolyzable bond that can be cleaved under conditions existing in the intestine and / or gastrointestinal tract (pH) or other physiological conditions.

According to the present invention, R ₁ can be selected, for example, from the group consisting of (HO) ₂ P (O) and (MO) ₂ P (O), where M is an alkali metal (e.g., Na, K, Cs, etc.). e.) or alkaline earth metal (Ca, Mg, etc.).

Further, according to the present invention, R ₁ can be a group of the formula R _1A —CO—, where R _1A can be selected, for example, from the group consisting of a straight or branched alkyl group containing from 1 to 6 carbon atoms (for example, methyl, ethyl propyl, isopropyl, butyl, isobutyl, tert- butyl, tert- butyl-CH ₂ - etc.), a cycloalkyl group containing from 3 to 6 carbon atoms (e.g. cyclopropyl, cyclohexyl, etc.), cycloalkylalkyl group containing from 3 to 6 carbon atoms in its cycloalkyl the second part and from 1 to 3 carbon atoms in its alkyl moiety (e.g. cyclopropyl-CH ₂ -, cyclohexyl-CH ₂ -, etc.), an alkyloxy group containing from 1 to 6 carbon atoms (e.g., CH ₃ O- , CH ₃ CH ₂ O-, isobutyl-O-, tert- butyl-O- (Boc) etc.), -CH ₂ OH, CH ₃ O ₂ C-, CH ₃ O ₂ CCH ₂ -, acetyl -OCH ₂ CH ₂ -, HO ₂ CCH ₂ -, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, (CH ₃ ) ₂ NCH ₂ -, (CH ₃ ) ₂ CHCH (NH ₂ ) -, HOCH ₂ CH ₂ NH-, CH ₃ OCH ₂ O-, CH ₃ OCH ₂ CH ₂ O-, 2-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-1,4-dihydro-3-pyridyl, 2 -pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, phenyl group pp formulas

picolyl group selected from the group consisting of

picolyloxy group selected from the group consisting of

substituted pyridyl group selected from the group consisting of

and groups of the formula

where X ', Y', R ₄ and R ₅ are as defined herein.

In another aspect, the present invention further provides a compound of formula II,

and pharmaceutically acceptable salts and derivatives thereof (for example, when the compound of the present invention includes an amino group, the pharmaceutically acceptable salt may be an ammonium salt),

where n may be 3 or 4,

where X and Y, the same or different, can be selected, for example, from the group consisting of H, an unbranched alkyl group containing from 1 to 6 carbon atoms, a branched alkyl group containing from 3 to 6 carbon atoms, a cycloalkyl group containing from 3 to 6 carbon atoms, F, Cl, Br, I, —CF ₃ , —OCF ₃ , —CN, —NO ₂ , —NR ₄ R ₅ , —NHCOR ₄ , —OR ₄ , —SR ₄ , —COOR ₄ , —COR ₄ and —CH ₂ OH, or X and Y together define an alkylenedioxy group selected from the group consisting of a methylenedioxy group of the formula —OCH ₂ O— and an ethylenedioxy group of the formula —OCH ₂ CH ₂ O—,

where R ₆ can be selected, for example, from the group consisting of an unbranched alkyl group containing from 1 to 6 carbon atoms, a branched alkyl group containing from 3 to 6 carbon atoms, a cycloalkylalkyl group containing from 3 to 6 carbon atoms in its cycloalkyl part and from 1 to 3 carbon atoms in its alkyl part,

where R ₃ can be selected, for example, from the group consisting of H, an unbranched alkyl group containing from 1 to 6 carbon atoms, a branched alkyl group containing from 3 to 6 carbon atoms, a cycloalkyl group containing from 3 to 6 carbon atoms and groups of the formula R _3A —CO—, where R _3A can be selected, for example, from the group consisting of a straight or branched alkyl group containing from 1 to 6 carbon atoms (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, tert- butyl-CH ₂ - and etc.), a cycloalkyl group containing from 3 to 6 carbon atoms (e.g., cyclopropyl, cyclohexyl, etc.), a cycloalkylalkyl group containing from 3 to 6 carbon atoms in its cycloalkyl part and from 1 to 3 carbon atoms in its alkyl part (for example, cyclopropyl-CH ₂ -, cyclohexyl-CH ₂ - etc.), an alkyloxy group containing from 1 to 6 carbon atoms (for example, CH ₃ O-, CH ₃ CH ₂ O-, isobutyl -O-, tert- butyl-O- (Boc), etc.), tetrahydro-3-furanyloxy, -CH ₂ OH, -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CF ₃ , pyrrolidinyl , piperidinyl, 4-morpholinyl, CH ₃ O ₂ C-, CH ₃ O ₂ CCH ₂ -, acetyl-OCH ₂ CH ₂ - , HO ₂ CCH ₂ -, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-CH ₃ OC ₆ H ₄ CH ₂ -, CH ₃ NH-, (CH ₃ ) ₂ N-, (CH ₃ CH ₂ ) ₂ N-, (CH ₃ CH ₂ CH ₂ ) ₂ N-, HOCH ₂ CH ₂ NH-, CH ₃ OCH ₂ O-, CH ₃ OCH ₂ CH ₂ O-, C ₆ H ₅ CH ₂ O-, 2-pyrrolyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, phenyl group

picolyl group selected from the group consisting of

picolyloxy group selected from the group consisting of

substituted pyridyl group selected from the group consisting of

and groups of the formula

where X 'and Y', the same or different, can be selected, for example, from the group consisting of H, an unbranched alkyl group containing from 1 to 6 carbon atoms, a branched alkyl group containing from 3 to 6 carbon atoms, a cycloalkyl group containing from 3 to 6 carbon atoms, F, Cl, Br, I, —CF ₃ , —NO ₂ , —NR ₄ R ₅ , —NHCOR ₄ , —OR ₄ , —SR ₄ , —COOR ₄ , —COR ₄ and -CH ₂ OH,

where R ₄ and R ₅ , the same or different, can be selected, for example, from the group consisting of H, an unbranched alkyl group containing from 1 to 6 carbon atoms, a branched alkyl group containing from 3 to 6 carbon atoms, and cycloalkyl a group containing from 3 to 6 carbon atoms,

where R ₂ can be selected, for example, from the group consisting of diphenylmethyl group of the formula IV

naphthyl-1-CH ₂ groups of formula V

naphthyl-2-CH ₂ groups of formula VI

biphenylmethyl group of formula VII

and antryl-9-CH ₂ groups of formula VIII

and where R ₁ may be a physiologically cleavable unit, whereby when the unit is cleaved, the compound may be capable of releasing a protease inhibitor, provided that R _{1 is} not H.

According to the present invention, R ₁ can be selected, for example, from the group consisting of (HO) ₂ P (O) and (MO) ₂ P (O), where M is an alkali metal (e.g., Na, K, Cs, etc.). e.) or alkaline earth metal (Ca, Mg, etc.).

Further, according to the present invention, R ₁ can be a group of the formula R _1A —CO—, where R _1A can be selected from the group consisting of an unbranched or branched alkyl group containing from 1 to 6 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, tert- butyl-CH ₂ - etc.), a cycloalkyl group containing from 3 to 6 carbon atoms (for example, cyclopropyl, cyclohexyl, etc.), cycloalkylalkyl group, containing from 3 to 6 carbon atoms in its cycloalkyl part and from 1 to 3 carbon atoms in its alkyl part (for example, cyclopropyl-CH ₂ -, cyclohexyl-CH ₂ -, etc.), alkyloxy group containing from 1 to 6 carbon atoms (for example, CH ₃ O-, CH ₃ CH ₂ O-, isobutyl-O-, tert- butyl-O- (Boc), etc.), -CH ₂ OH, CH ₃ O ₂ C-, CH ₃ O ₂ CCH ₂ -, acetyl-OCH ₂ CH ₂ -, HO ₂ CCH ₂ -, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, (CH ₃ ) ₂ NCH ₂ -, (CH ₃ ) ₂ CHCH (NH ₂ ) -, HOCH ₂ CH ₂ NH-, CH ₃ OCH ₂ O-, CH ₃ OCH ₂ CH ₂ O-, 2-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-1,4-dihydro-3-pyridyl, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, phenyl group of the formulas s

picolyl group selected from the group consisting of

picolyloxy group selected from the group consisting of

substituted pyridyl group selected from the group consisting of

and groups of the formula

where X ', Y', R ₄ and R ₅ are as defined herein.

In a further aspect, the present invention provides a compound of formula IIa:

its pharmaceutically acceptable salts and derivatives (for example, when the compound of the present invention includes an amino group, the pharmaceutically acceptable salt may be an ammonium salt),

where X and Y, the same or different, can be selected, for example, from the group consisting of H, an unbranched alkyl group containing from 1 to 6 carbon atoms, a branched alkyl group containing from 3 to 6 carbon atoms, a cycloalkyl group containing from 3 to 6 carbon atoms, F, Cl, Br, I, —CF ₃ , —OCF ₃ , —CN, —NO ₂ , —NR ₄ R ₅ , —NHCOR ₄ , —OR ₄ , —SR ₄ , —COOR ₄ , —COR ₄ and —CH ₂ OH, or X and Y together define an alkylenedioxy group selected from the group consisting of a methylenedioxy group of the formula —OCH ₂ O— and an ethylenedioxy group of the formula —OCH ₂ CH ₂ O—,

where X 'and Y', the same or different, can be selected, for example, from the group consisting of H, an unbranched alkyl group containing from 1 to 6 carbon atoms, a branched alkyl group containing from 3 to 6 carbon atoms, a cycloalkyl group containing from 3 to 6 carbon atoms, F, Cl, Br, I, —CF ₃ , —NO ₂ , —NR ₄ R ₅ , —NHCOR ₄ , —OR ₄ , —SR ₄ , —COOR ₄ , —COR ₄ and -CH ₂ OH,

and where n, R ₁ , R ₃ , R ₄ , R ₅ and R ₆ are as defined herein.

In an additional aspect, the present invention provides a compound of formula IIb:

its pharmaceutically acceptable salts and derivatives (for example, when the compound of the present invention includes an amino group, the pharmaceutically acceptable salt may be an ammonium salt),

where X and Y, the same or different, can be selected, for example, from the group consisting of H, an unbranched alkyl group containing from 1 to 6 carbon atoms, a branched alkyl group containing from 3 to 6 carbon atoms, a cycloalkyl group containing from 3 to 6 carbon atoms, F, Cl, Br, I, —CF ₃ , —OCF ₃ , —CN, —NO ₂ , —NR ₄ R ₅ , —NHCOR ₄ , —OR ₄ , —SR ₄ , —COOR ₄ , —COR ₄ and —CH ₂ OH, or X and Y together define an alkylenedioxy group selected from the group consisting of a methylenedioxy group of the formula —OCH ₂ O— and an ethylenedioxy group of the formula —OCH ₂ CH ₂ O—,

where X 'and Y', the same or different, can be selected, for example, from the group consisting of H, an unbranched alkyl group containing from 1 to 6 carbon atoms, a branched alkyl group containing from 3 to 6 carbon atoms, a cycloalkyl group containing from 3 to 6 carbon atoms, F, Cl, Br, I, —CF ₃ , —NO ₂ , —NR ₄ R ₅ , —NHCOR ₄ , —OR ₄ , —SR ₄ , —COOR ₄ , —COR ₄ and -CH ₂ OH,

and where n, R ₁ , R ₃ , R ₄ , R ₅ and R ₆ are as defined herein.

In yet a further aspect, the present invention provides a compound of formula IIc:

its pharmaceutically acceptable salts and derivatives (for example, when the compound of the present invention includes an amino group, the pharmaceutically acceptable salt may be an ammonium salt),

and where n, X, Y, X ', Y', R ₁ , R ₃ , R ₄ , R ₅ and R ₆ are as defined herein.

In another aspect, the present invention relates to a compound of formula IIA

where Y, n, R ₁ , R ₂ , R ₃ , X 'and Y' are as defined herein.

According to the present invention, R ₁ may be, for example, (HO) ₂ P (O) or (NaO) ₂ P (O). Further, in the present invention, n may be 4. Y may, for example, be H. R ₃ may, for example, be CH ₃ O-CO. R ₂ may, for example, be a diphenylmethyl group of formula IV, where X 'and Y' may be, for example, H,

Therefore, the compounds of formula IIA ', as well as their pharmaceutically acceptable salts and derivatives are encompassed by the present invention,

such as, for example, a compound of formula IIA ', where R ₁ is (HO) ₂ P (O), or a compound of formula IIA', where R ₁ is (NaO) ₂ P (O).

In another distinct aspect, the present invention relates to a pharmaceutical composition comprising at least one compound of formula I, II, IIa, IIb, IIc, IIA, IIA 'or a combination of compounds of formula I, II, IIa, IIb, IIc, IIA and / or IIA '. The pharmaceutical composition may include a pharmaceutically acceptable carrier. The pharmaceutical composition may include, for example, a pharmaceutically effective amount of such one or more compounds or, where appropriate, their pharmaceutically acceptable ammonium salts.

For example, the pharmaceutical composition of the present invention may include one or more of the following compounds:

- a compound of formula IIa, where n is 4, R ₁ is (HO) ₂ P (O), X is 4-NH ₂ , Y is H, X 'is H, Y' is H, R ₆ represents isobutyl and R ₃ represents CH ₃ O-CO,

- a compound of formula IIa, where n is 4, R ₁ represents (NaO) ₂ P (O), X represents 4-NH ₂ , Y represents H, X 'represents H, Y' represents H, R ₆ represents isobutyl and R ₃ represents CH ₃ O-CO,

- a compound of formula IIa, where n is 4, R ₁ is (HO) ₂ P (O), X is 4-NH ₂ , Y is H, X 'is H, Y' is H, R ₆ represents isobutyl and R ₃ represents CH ₃ CO,

- a compound of formula IIa, where n is 4, R ₁ is (HO) ₂ P (O), X is 4-NH ₂ , Y is 3-F, X 'is H, Y' is H, R ₆ represents isobutyl and R ₃ represents CH ₃ O-CO,

- a compound of formula IIa, where n is 4, R ₁ represents CH ₃ CO, X represents 4-NH ₂ , Y represents H, X 'represents H, Y' represents H, R ₆ represents isobutyl and R ₃ represents CH ₃ O-CO,

- a compound of formula IIa, where n is 4, R ₁ represents 3-pyridyl-CO, X represents 4-NH ₂ , Y represents H, X 'represents H, Y' represents H, R ₆ represents isobutyl and R ₃ represents CH ₃ O-CO,

- a compound of formula IIa, where n is 4, R ₁ represents (CH ₃ ) ₂ NCH ₂ CO, X represents 4-NH ₂ , Y represents H, X 'represents H, Y' represents H, R ₆ represents isobutyl and R ₃ represents CH ₃ O-CO,

- a compound of formula IIa, where n is 4, R ₁ represents (CH ₃ ) ₂ CHCH (NH ₂ ) CO, X represents 4-NH ₂ , Y represents H, X 'represents H, Y' represents H , R ₆ represents isobutyl and R ₃ represents CH ₃ O-CO,

- a compound of formula IIb, where n is 4, R ₁ is (HO) ₂ P (O), X is 4-NH ₂ , Y is H, X 'is H, Y' is H, R ₆ represents isobutyl and R ₃ represents CH ₃ O-CO, and where the naphthyl group is a naphthyl-2-CH ₂ group,

- a compound of formula IIb, where n is 4, R ₁ is (HO) ₂ P (O), X is 4-NH ₂ , Y is H, X 'is H, Y' is H, R ₆ represents isobutyl and R ₃ represents 4-morpholine-CO, and where the naphthyl group is a naphthyl-1-CH ₂ group, or

- a combination of any of the above compounds.

In an additional aspect, the present invention relates to the use of at least one compound of formula I, II, IIa, IIb, IIc, IIA, IIA 'or a combination of compounds of formula I, II, IIa, IIb, IIc, IIA and / or IIA' or its pharmaceutically acceptable salts or derivatives (and combinations thereof) in the manufacture of a medicament (or pharmaceutical composition) for the treatment or prevention of HIV infection.

In a further aspect, the present invention relates to the use of at least one compound of formula I, II, IIa, IIb, IIc, IIA, IIA 'or a combination of compounds of formula I, II, IIa, IIb, IIc, IIA and / or IIA' or its pharmaceutically acceptable salts or derivatives in the treatment or prevention of HIV infection in mammals in need thereof, or to delay the onset of AIDS.

In yet a further aspect, the present invention relates to a method for treating or preventing HIV infection (or for delaying the onset of AIDS), comprising administering at least one compound of formula I, II, IIa, IIb, IIc, IIA, IIA ', or a combination compounds of formula I, II, IIa, IIb, IIc, IIA and / or IIA 'or its pharmaceutically acceptable salts or derivatives thereof to a mammal in need thereof.

In another aspect, the present invention relates to a compound of formula I, II, IIa, IIb, IIc, IIA or IIA ', its pharmaceutically acceptable salts or derivatives thereof, for use in the treatment or prevention of HIV infection.

In yet a further aspect, the present invention relates to a method for the manufacture of a lysine-based compound using any of the compounds described in US Pat. No. 6,632,816 to Stranix et al. or to a method for manufacturing a compound capable of forming any of the compounds described in US Pat. No. 6,632,816 to Stranix et al. , when cleaving ( in vivo ) cleavable link.

The compounds listed in the present description are illustrative embodiments of the present invention in practice and it should be understood that the present invention is not limited to these compounds.

The term “pharmaceutically effective amount” refers to an amount effective to treat or prevent HIV infection in a patient or to reduce or eliminate the symptoms of AIDS. It is also to be understood here that a “pharmaceutically effective amount” can be interpreted as an amount giving the desired therapeutic effect, taken as a single dose or multiple doses, or in any dosage or route, or taken alone or in combination with other therapeutic agents. In the case of the present invention, a "pharmaceutically effective amount" can be understood as an amount having an inhibitory effect on the HIV infection cycle (HIV-1 and HIV-2, as well as related viruses (e.g., HTLV-I and HTLV-II and simian immunodeficiency virus (SIV ))) (for example, suppression of reproduction, reinfection, maturation, replication, etc.) and on any organism whose life cycle depends on aspartyl proteases. The inhibitory effect in the context of the present description should be understood as a decrease in the body's ability (for example, HIV) to reproduce itself (replicate), reinfect the surrounding cells, etc. or even complete suppression (or destruction) of the body.

The terms "HIV protease" and "HIV aspartyl protease" are used interchangeably and include aspartyl protease encoded by type 1 or 2 human immunodeficiency virus.

The term "prophylactically effective amount" refers to an amount effective to prevent HIV infection in a patient. As used herein, the term “patient” refers to a mammal, including humans.

The terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient" and "physiologically acceptable solvent" refer to a non-toxic carrier or excipient that can be administered to a patient together with one or more compounds of the present invention and which do not destroy their pharmacological activity.

The present invention provides pharmaceutically acceptable derivatives of compounds of formula I (such as compounds of formula II, IIa, IIb, IIc, IIA and IIA ′) and, where applicable, their pharmaceutically acceptable salts, such as, for example, ammonium salts. “Pharmaceutically acceptable derivative” means a pharmaceutically acceptable salt, ester or salt of such an ester, a compound of this invention or any other compound which, when administered to a recipient, is capable of providing (directly or indirectly) a compound of this invention or an antiviral active metabolite thereof or the remainder.

You must understand that the "unbranched alkyl group containing from 1 to 6 carbon atoms ″ includes, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl.

It should be understood that a “branched alkyl group containing from 3 to 6 carbon atoms” includes, for example, without limitation, isobutyl, tert- butyl, 2-pentyl, 3-pentyl, etc.

It should be understood that the “cycloalkyl group containing from 3 to 6 carbon atoms” includes, for example, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclocyclohexyl (i.e., C ₆ H ₁₁ ).

Salts derived from the appropriate bases include salts of alkali metals (e.g. sodium), alkaline earth metals (e.g. magnesium), ammonium and N- (C _1-4 alkyl) ₄ ⁺ .

The compounds of this invention contain one or more asymmetric carbon atoms and, therefore, can be in the form of racemates and racemic mixtures, a single enantiomer, diastereomeric mixtures and individual diastereoisomers. All such isomeric forms of these compounds are specifically included in the present invention. Each stereogenic carbon atom may have an R or S configuration.

Pharmaceutically acceptable salts of the compounds of this invention include salts derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of such acid salts include: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodetsilgidrosulfat, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthyl sulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, perchlorate, persulfosate, 3-phenyl Fat, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate.

The invention also encompasses the quaternization of any groups of compounds containing basic nitrogen disclosed herein. Basic nitrogen can be quaternized with any reagents known to one skilled in the art, including, for example, lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates, including dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, and aralkyl halides, including benzyl and phenethyl bromides. By such quaternization, water- or oil-soluble or dispersible products can be obtained.

It is necessary to understand here that if a ″ range ″ or ″ group of substances ″ is indicated with respect to a specific characteristic (for example, temperature, concentration, time or the like) of the present invention, the present invention relates and expressly includes all and all specific members and combinations of subranges or subgroups in the present description. Thus, any specified range or group must be understood as a shorthand way to refer to all members of the range or group individually, as well as to all possible common subbands or subgroups covered by this description; and similarly with respect to any subbands or subgroups of the present description. So for example

- with respect to the number of carbon atoms, an indication of the range from 1 to 6 carbon atoms in the present description should be understood as including all individual individual amounts of carbon atoms, as well as subranges, such as, for example, 1 carbon atom, 3 carbon atoms, from 4 to 6 carbon atoms, etc .;

- relative to the reaction time, a time of 1 minute or more, it is necessary to understand how specifically including here all the same individual times, as well as a sub-range of more than 1 minute, such as, for example, 1 minute, from 3 to 15 minutes, from 1 minutes to 20 hours, from 1 to 3 hours, 16 hours, from 3 hours to 20 hours, etc .;

- and similarly with respect to other parameters, such as concentrations, elements, etc.

In particular, it is necessary to understand here that each compound formula includes each and every individual compound described in this way, as well as all possible classes or subgroups or subclasses of compounds, regardless of whether such a class or subclass is defined as specifically including specific compounds, as excluding specific compounds or as a combination of this; for example, an exclusive definition for a formula (eg, I) can be read as follows: ″ provided that when one of A and B is —COOH and the other is H, —COOH may not be present at position 4 ′ ″.

You also need to understand that ″ g ″ or ″ um ″ is a reference to gram units of mass, and ″ C ″ or ″ ° C ″ is a reference to a unit temperature Celsius.

The compounds of the present invention can be easily prepared using conventional methods from readily available starting materials. Detailed descriptions of these approaches are presented, for example, in schemes 1-5, discussed below.

Scheme 1 illustrates a typical example of the preparation of a phosphate monoester III obtained from a primary alcohol (see I ), a compound of HIV protease inhibitors (see example 1 (stages G and H) in the experimental part of this document as a specific example of this synthesis).

It should be noted:

a) R ₂ and R ₃ are as defined herein.

When synthesizing a phosphate monoester III , an aspartyl protease inhibitor ( I , see US Pat. No. 6,632,816) can be used as a starting material. The diethylphosphoric ester II was obtained in good yield by treatment with diethyl chlorophosphate and sodium hydride in a mixture of tetrahydrofuran and triethyl phosphate. Then, the addition of trimethylsilyl bromide in dichloromethane (DCM) afforded compound III in good to excellent yields.

Scheme 1A is another representative example of the preparation of a IIIA phosphate monoester derived from a primary alcohol (see IA ), a compound of HIV protease inhibitors.

It should be noted:

a) n, X, Y, R ₂ , R ₃ and R ₆ are as defined herein.

The synthesis of the phosphate monoester IIIA is carried out as described for preparation III (Scheme 1).

Scheme 2 illustrates a typical example of the preparation of a phosphate monoester III , a compound of HIV protease inhibitors, with a different approach, using (3S) -3-isobutylaminoazepan-2-one ( IV ) as the starting material.

It should be noted:

a) R ₂ and R ₃ are as defined herein.

As shown in Scheme 2, the phosphate monoester III derivative was prepared from (3S) -3-isobutylaminoazepan-2-one ( IV ) in a seven-step reaction sequence. At the beginning, (2S) -3-isobutylaminoazepan-2-one ( IV ) was sulfonated with 4-acetamidobenzenesulfonyl chloride in the presence of triethylamine in dichloromethane to give compound V in excellent yields. Derivative VI was obtained quantitatively by treating V with di- tert-butyl pyrocarbonate and DMAP in acetonitrile. The reductive opening of the cycle with sodium borohydride in ethanol leads to key intermediates VII in good yield. The diethylphosphoric ester VIII was obtained in good yield by treatment with diethyl chlorophosphate and sodium hydride in a mixture of tetrahydrofuran and triethyl phosphate. Boc deprotected by treatment with HCl in ethanol to give compound IX quantitatively (TW Greene and PGM Wuts, Protective groups in Organic Synthesis, 3 ^{rd Edition, John Wiley & Sons,} Inc. 1999). Then, the combination of the free amino group present on intermediate IX with a number of synthetic amino acids in the presence of 1-hydroxybenzotriazole (HOBt) and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (EDAC) led to derivative II in good yields to excellent. Finally, the addition of trimethylsilyl bromide in dichloromethane (DCM) afforded compound III in good to excellent yields.

Scheme 3 represents the conversion of a diphenylmethyl derivative; (1S, 5S) methyl ester - (1- {5 - [(4-aminobenzenesulfonyl) isobutylamino] -6-hydroxyhexylcarbamoyl} -2,2-diphenylethyl) carbamic acid ( PL-100 ) in its analogue XI , which is a sodium salt fluorinated phosphate monoester. This reaction sequence can be used to obtain any other similar compounds derived from unsubstituted (or substituted) diphenylmethyl, 1-naphthyl, 2-naphthyl, biphenyl and 9-antryl groups described in this invention.

Thus, treatment of PL-100 with Selectfluor ™ in acetonitrile gave derivative X in 38% yield. The introduction of the phosphate monoester group was carried out as described previously in Schemes 1 and 2. First, an intermediate compound representing diethyl triphosphoric acid ester was obtained in good yield by treatment with diethyl chlorophosphate and sodium hydride in a mixture of tetrahydrofuran and triethyl phosphate. Then, the addition of trimethylsilyl bromide in dichloromethane (DCM) afforded the phosphate monoester compound in good to excellent yields. The final product XI was easily obtained by treating the phosphate monoester with sodium hydroxide solution in good yields.

Scheme 4 illustrates a typical example of the conversion of phosphotriether II to its fluorinated analogue XIII in a two-step reaction sequence. This typical example represents a second approach to the synthesis of fluorinated compounds of this invention. In this case, the fluorine atom is added to the phosphotriether II , and not to the derivative of the general formula I , which is a primary alcohol, or more specifically PL-100 , as shown in Scheme 3. This alternative reaction sequence can be used to synthesize any other similar compounds obtained from unsubstituted (or substituted) diphenylmethyl, 1-naphthyl, 2-naphthyl, biphenyl and 9-antryl groups described in this invention.

It should be noted:

a) R ₂ and R ₃ are as defined herein.

Briefly, treatment of derivative II with Selectfluor ™ in acetonitrile gave derivative XII in good yield. The addition of trimethylsilyl bromide in dichloromethane (DCM) then gave compound XIII , which is a phosphate monoester, in a yield from good to excellent. If desired, the final product XIII can easily be converted into an analogue, which is a sodium salt of a phosphate complex monoester, as described previously in scheme 3.

Scheme 5 illustrates the synthesis of various compounds of esters XVI according to the invention. It is known that ester compounds are readily cleaved in vivo by esterase enzymes and, as a result, can release the active ingredient. In this scheme, R _{2 is} defined as a diphenylmethyl group. However, this reaction sequence can be used to synthesize any other similar compounds derived from unsubstituted (or substituted) diphenylmethyl, 1-naphthyl, 2-naphthyl, biphenyl and 9-antryl groups described in this invention.

It should be noted:

a) R _1A represents a “residue” of an acid molecule that is bound to the free group of a primary alcohol present on intermediate XV and is as defined herein.

Compounds XVI are usually prepared in a three-step reaction sequence in high yields. The esterification of (1S) tert-butyl ester - {4 - [(5-tert-butoxycarbonylamino-1-hydroxymethylpentyl) isobutylsulfamoyl] phenyl} carbamic acid ( VII ) with a different acid in the presence of 1-hydroxybenzotriazole (HOBt) and 1- [3- ( dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (EDAC) yielded the desired esters XIV in excellent yields. Acetic acid ester was quantified using acetic anhydride in the presence of N, N- dimethylaminopyridine (DMAP) in dichloromethane (DCM). Detachment of the Boc protecting group was achieved quantitatively by treatment with trifluoroacetic acid (TFA) in DCM. A second combination with (2S) -2-methoxycarbonylamino-3,3-diphenylpropionic acid is carried out on the primary amino group of intermediate XV with HOBt and EDAC to give the desired compounds XVI in good to excellent yields. If necessary, catalytic hydrogenation of the benzyloxycarbonyl group is carried out using 10% palladium-carbon to give the final compound XVII .

One skilled in the art will understand that the above synthetic schemes are not intended to constitute a complete list of all the means by which the compound described and claimed in this application for synthesis can be synthesized, but are merely an illustration of synthetic methods, among others. Further methods will be apparent to those skilled in the art.

The compounds of this invention can be modified by adding appropriate functionality to enhance selective biological properties. Such modifications are known in the art and include modifications that increase the biological permeability of a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow injection, alter metabolism and alter excretion rate .

As discussed above, the novel compounds can release active ingredients that are excellent ligands for aspartyl proteases, for example, HIV-1 protease. Accordingly, these compounds, by releasing the active ingredient, are able to target and suppress late-phase events during replication, i.e. processing of viral polyproteins by an HIV-encoded protease. The compounds of this invention advantageously inhibit the ability of the HIV-1 virus to infect immortalized human T cells for a period of days, as determined by analysis measuring the amount of extracellular p24 antigen; a specific marker of virus replication (see, Meek et al., Nature, 343, pp.90-92 (1990)).

In addition to their use in the prevention or treatment of HIV or HTLV infection, the compounds of this invention can also be used as inhibitory or interrupting agents for other viruses that use aspartyl proteases similar to HIV or HTLV aspartyl proteases in their life cycle. Such compounds inhibit the proteolytic processing of viral polyprotein precursors by inhibiting aspartyl protease. Since aspartyl protease is essential for the production of mature virions, the inhibition of this processing effectively blocks the spread of the virus, inhibiting the production and reproduction of infectious virions, in particular from acutely and chronically infected cells. The compounds of this invention advantageously inhibit aspartyl proteases, thereby blocking the ability of aspartyl proteases to catalyze the hydrolysis of peptide bonds.

The compounds of this invention can be used in the usual way for the treatment or prevention of HIV, HTLV or other viral infections, which include aspartyl proteases in their life cycle (replication). Such treatment methods, their dosage levels and requirements can be selected by a person skilled in the art from the available methods and techniques. For example, the compound of this invention can be combined with a pharmaceutically acceptable excipient for administration to a virus infected patient in a pharmaceutically acceptable manner and in an amount effective to reduce the severity of the viral infection.

Alternatively, the compounds of this invention can be used in vaccines and methods of protecting individuals from viral infection for an extended period of time. The compounds can be used in such vaccines either alone or together with other compounds of this invention in a manner consistent with the traditional use of protease inhibitors or derived protease inhibitors in vaccines. For example, the compound of this invention can be combined with pharmaceutically acceptable excipients, or delivery systems commonly used in vaccines, and administered in prophylactically effective amounts to protect individuals for an extended period of time from viral infections such as HIV infection. As such, the novel compounds of the present invention (by cleaving a physiologically cleavable unit) can be administered as agents for the treatment or prophylaxis of viral infections, including HIV infection, in mammals.

The compounds of this invention can be administered to a healthy or HIV-infected patient (before or after the onset of AIDS symptoms) as a single agent or in combination with other antiviral agents that interfere with the HIV replication cycle. By administering the compounds of this invention with other antiviral agents that target other events in the life cycle of the virus, the therapeutic effect of these compounds is enhanced. For example, a co-administered antiviral agent may be one that targets early events in the life cycle of a virus, such as attachment to a cell receptor or cell entry, reverse transcription, and integration of viral DNA into cellular DNA. Antiviral agents targeting such early life-cycle events include, but are not limited to, polysulfonated polysaccharides, sT4 (soluble CD4) and other compounds that block the binding of the virus to the CD4 receptor on CD4-bearing T lymphocytes and other CD4 (+) cells, or inhibit the fusion of the envelope of the virus with the cytoplasmic membrane, and didanosine (ddI), zalcitabine (ddC), stavudine (d4T), zidovudine (AZT) and lamivudine (3TC), which inhibit reverse transcription. For example, another protease inhibitor can be used with the compounds of the present invention. Other antiretroviral and antiviral drugs can also be co-administered with the compounds of this invention to provide therapeutic treatment to substantially reduce or eliminate viral infectivity and its associated symptoms. Examples of other antiviral agents include ganciclovir, dideoxycytidine, trisodium phosphonoformate, eflornithine, ribavirin, acyclovir, interferon alpha, and trimenotrexate. In addition, other types of drugs can be used to enhance the effects of the compounds of this invention, such as envelope virus loss inhibitors, Tat or Rev inhibitors of transactivating proteins, antisense molecules, or virus integrase inhibitors. These compounds can also be co-administered with other HIV aspartyl protease inhibitors. In addition, it may be useful to administer the compounds of the present invention with another drug (other antiviral compounds, antibiotics, an analgesic, etc.).

The combination therapies of this invention have a synergistic effect in suppressing HIV replication, as each component combination agent acts on different sites of HIV replication. The use of such combinations also advantageously reduces the dosage of a given conventional antiretroviral agent that would be required for the desired therapeutic or prophylactic action, compared with the case when such an agent is administered as monotherapy. These combinations can reduce or eliminate the side effects of conventional therapies with a single antiretroviral agent, while not interfering with the antiretroviral activity of these agents. These combinations reduce the potential for resistance to single-agent therapies, while minimizing concomitant toxicity. These combinations can also increase the effectiveness of a traditional product without increasing concomitant toxicity. Combination therapies encompassed by the present invention include, for example, administering a compound of the invention with AZT, 3TC, ddI, ddC, d4T or other reverse transcriptase inhibitors.

Alternatively, the compounds of this invention can also be co-administered with other HIV protease inhibitors, such as Ro 31-8959 (Squinavir; Roche), L-735,524 (Indinavir; Merck), AG-1343 (Nelfinavir; Agouron), A-84538 (Ritonavir; Abbott), ABT-378 / r (Lopinavir; Abbott) and VX-478 (Amprenavir; Glaxo), to increase the effect of therapy or prophylaxis against various viral mutants or members of other HIV quasivids.

The administration of the compounds of the present invention can be carried out, for example, in the form of single agents or in combination with retroviral reverse transcriptase inhibitors or other HIV aspartyl protease inhibitors. Co-administration of the compounds of this invention with retroviral reverse transcriptase inhibitors or HIV aspartyl protease inhibitors can have a significant synergistic effect, thereby preventing, substantially reducing or completely eliminating viral infectivity and associated symptoms.

The compounds of the present invention can be administered in this way or in a form that can allow cleavage of the R ¹ unit to release a protease inhibitor. The compounds of this invention can also be administered, for example, in combination with immunomodulators (e.g., bropirimine, anti-human antibodies to alpha interferon, IL-2, GM-CSF, methionine encephalin, interferon alpha , sodium diethyldithiocarbamate, tumor necrosis factor, naltrexone and rEPO), antibiotics (e.g., pentamidine isothionate) or vaccines for the prevention or control of an infection or illness associated with HIV infection, such as AIDS and the AIDS-associated complex.

When the compounds of this invention are administered in combination therapies with other agents, they can be administered to a patient sequentially or in parallel. Alternatively, the pharmaceutical or prophylactic compositions of this invention may comprise a combination of one or more compounds of this invention and another therapeutic or prophylactic agent.

Although the invention focuses on the use of the compounds disclosed herein, for the prevention and treatment of HIV infection, the compounds of this invention can also be used as inhibitory agents for other viruses that depend on similar aspartyl proteases for binding events in their life cycle. These viruses include, but are not limited to, retroviruses that cause AIDS-like diseases, such as monkey immunodeficiency viruses, HIV-2, HTLV-I, and HTLV-II. In addition, the compounds of this invention can also be used to inhibit other aspartyl proteases and, in particular, other human aspartyl proteases, including renin and aspartyl proteases, which are involved in the processing of endothelin precursors.

The pharmaceutical compositions of this invention include any compound of the present invention and its pharmaceutically acceptable salts with any pharmaceutically acceptable carrier, excipient or solvent. Pharmaceutically acceptable carriers, excipients, and solvents that can be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, whey proteins such as human albumin, buffering agents such as phosphates , glycine, sorbic acid, potassium sorbate, mixtures of incomplete glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, acid phosphate SFAT dipotassium, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, block copolymers of polyethylene-polyoxypropylene, polyethylene glycol and wool fat.

The pharmaceutical compositions of this invention can be administered orally, parenterally with an aerosol for inhalation, topically, rectally, nasally, buccally, vaginally or through an implanted reservoir. Therefore, it is understood that oral administration or injection is encompassed by the present invention. For example, the compounds of the present invention can be administered, for example, orally in an aqueous solution. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically acceptable carriers, excipients or solvents. The term “parenteral” as used herein includes the technique of subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarticular, epigastric, intrathecal, directly into the affected tissue, intracrinal injection or infusion.

The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, in the form of a sterile injectable aqueous and oily suspension. The formulation of this suspension can be formulated according to methods known in the art using suitable dispersing or moisturizing agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable carriers and solvents that can be used are amino acids, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are usually used as a solvent or suspending medium. For this purpose, you can use any light non-volatile oil, including synthetic mono - and diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the manufacture of injectable preparations, such as, for example, natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylene versions. These oil solutions or suspensions may also contain diluents or dispersants, which are long chain alcohols, such as Ph. Helv. or similar alcohol.

The pharmaceutical compositions of this invention can be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, and aqueous suspensions and solutions. In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dry corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening agents and / or flavoring agents and / or coloring agents may be added.

The pharmaceutical compositions of this invention can also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compound of the invention with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum, releasing the active components. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.

Topical administration of the pharmaceutical compositions of this invention is particularly applicable when the desired therapy includes areas or organs readily accessible by topical application. For topical application to the skin, the pharmaceutical composition must be formulated as a suitable ointment containing the active ingredients suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid oil, white petrolatum, propylene glycol, a polyoxyethylene or polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition may be formulated as a suitable lotion or cream containing the active compound, suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitol monostearate, polysorbate 60, cetyl ethers, wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention can also be applied topically to the lower intestine with a rectal suppository formulation or in a suitable, pure formulation. Topical transdermal patches are also included in this invention.

The pharmaceutical compositions of this invention can be administered by nasal aerosol or inhalation. Such compositions are prepared by methods well known in the art of pharmaceutical procedures and can be prepared as solutions in saturated salt solutions using benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, fluorocarbons and / or other solubilizers or dispersing agents, known from the prior art.

Dosage levels of from about 0.01 to 25 mg / kg body weight per day, for example from about 0.5 to 25 mg / kg body weight per day of compounding of the active ingredient, are suitable for the prophylaxis or treatment of viral infection, including HIV infection. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to 5 times per day, or, alternatively, as a continuous infusion. Such an introduction can be used in the form of chronic or acute therapy. The amount of active ingredient that can be combined with carrier materials to form a monolithic dosage form will vary depending on the patient being treated and the particular mode of administration. A typical preparation will contain from about 5% to 95% of the active ingredient (w / w). For example, such preparations may contain from about 20% to 80% of the active ingredient.

If the patient's condition improves, a maintenance dose of the compound, composition or combination of this invention may be administered, if necessary. Then, the dosage or frequency of administration, or both, can be reduced as a function of symptoms to a level at which an improved condition persists. When symptoms have eased to the desired level, treatment is stopped. However, patients may require periodic treatment on a long-term basis for relapse of the symptoms of the disease.

One skilled in the art will recognize that lower or higher doses than those set forth above may be desirable. The specific dosage and treatment regimen for a particular patient may depend on a variety of factors, including the activity of the particular compound used, age, body weight, general health, gender, diet, time of administration, excretion rate, combination of drugs, severity and course of infection, tendency patient to infection and the opinion of the attending physician.

The following abbreviations are used in this description:

Abbreviation Designation Ac Acetyl AcOH Acetic acid APCI Chemical ionization at atmospheric pressure AIDS Acquired Immunodeficiency Syndrome AZT 3-azido-3-deoxythymine (zidovudine) Boc Benzyloxycarbonyl t-butyl Tert -Butyl Cam Ammonium Cerium Molybdate

DXM Dichloromethane DMAP N, N- dimethylaminopyridine DMSO Dimethyl sulfoxide DMF Dimethylformamide DNA Deoxyribonucleic acid EDAC 1- [3- (Dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride EtOAc Ethyl acetate EtOH Ethanol g Gram hour Hour HIV-1, -2 Human Immunodeficiency Virus Type 1, Type 2 Hobt 1-hydroxybenzotriazole HPLC High Performance Liquid Chromatography HTLV-I, -II T-cell lymphotropic human virus type I, type II IL-2 Interleukin-2 kg Kilogram l Liter LC-MS Liquid Chromatography - Mass Spectrometry M Molar Meoh Methyl alcohol mg Milligram T _pl. Melting temperature min Minute Moc Methoxycarbonyl

mole Mole ml Milliliter mmol Millimole nm Nanometer nM Nanomole po Orally rEPO Recombinant erythropoietin TLC Thin layer chromatography 3TC 2 ', 3'-Dideoxy-3-thiacytidine Tfu Trifluoroacetic acid THF Tetrahydrofuran

EXAMPLES

This section describes the synthesis of lysine-based compounds capable of releasing HIV aspartyl protease inhibitors as described herein. These examples are given for illustrative purposes only and should not be construed as limiting in any way the scope of the invention. This section provides a detailed synthesis of compounds No. 1-10 of this invention.

Substances and Methods

Analytical thin layer chromatography (TLC) was performed on 0.25 mm silica gel plates of E. Merck 60 F ₂₅₄ and was eluted with the solvent systems shown. Preparative chromatography was performed by flash chromatography using silica gel 60 (EM Science) with the solvent systems shown and excess air pressure to ensure proper elution rate. The compounds were determined by exposing the eluted (analytical or preparative) plates to iodine, UV radiation and / or treating the analytical plates with a 2% solution of p-anisaldehyde in ethanol containing 3% sulfuric acid and 1% acetic acid, followed by heating. Alternatively, assay plates can be treated with a 0.3% solution of ninhydrin in ethanol containing 3% acetic acid and / or a CAM solution made from 20 g (NH ₄ ) ₆ Mo ₇ O ₂₄ and 8.3 g Ce (SO ₄ ) ₂ polyhydrates in water (750 ml) containing concentrated sulfuric acid (90 ml).

Preparative HPLC was performed on a Gilson instrument equipped with a C18 column, a 215 fluid delivery module and pressure pumps with a capacity of 25 ml / min. HPLC works with the Gilson UniPoint System software.

Semi-preparative HPLC conditions for purification of test compounds

HPLC system: 2 Gilson # 305-25 ml pumps, Gilson # 215 liquid inlet and collector, and Gilson # 155 UV-Vis detector, all devices are monitored by Gilson UniPoint V1.91 software.

Column: Alltech (# 96053) Hyperprep PEP, C-18, 100 Еα, 8 μm, 22x250 mm

Flow rate: 15 ml / min

Solvents: A: H ₂ O, B: CH ₃ CN

Gradient: 25% to 80% B for 40 min

Detector: absorption; λ: 210 & 265 nm

The crude substance, dissolved in acetonitrile to a concentration of about 50 to 80 mg / 2 ml, was injected in each cycle. Fractions were collected in an amount of 9 ml, the relevant absorption was determined by a UV detector.

Unless otherwise indicated, all starting materials were obtained from commercial sources such as Aldrich Co. or Sigma Co.

Melting points _(mp.) Were determined on the device 530 for measuring Bϋchi melting point capillary tubes and are uncorrected.

Mass spectra were recorded on a Hewlett Packard LC / MSD 1100 system using an APCI source or an electrospray source in negative or positive mode.

Nuclear Magnetic Resonance Spectra (NMR) were recorded on a Bruker AMX-II-500 equipped with a reversible or QNP probe. Samples were dissolved in deuterated chloroform (CDCl ₃ ), deuterated acetone (acetone-d ₆ ), deuterated methanol (CD ₃ OD), or deuterated dimethyl sulfoxide (DMSO-d ₆ ) using tetramethylsilane as the internal standard for obtaining data. Chemical shifts (*) are expressed in parts per million (ppm), interaction constants ( J ) are expressed in Hertz (Hz), while the multiplicities are denoted as c for singlet, d for doublet, 2d for two doublets, dd for doublet of doublets , t for triplet, q for quartet, quint for quintet, m for multiplet and broad. with for an extended singlet.

DETAILED DESCRIPTION OF THE INVENTION

EXAMPLES

Specific Examples of Derivatives of General Formula I

The following compounds are prepared from L-lysine derivatives using the procedures summarized in Schemes 1, 1A, 2, 3, 4, and 5 of the present invention.

Example 1. Preparation of (1S, 5S) - (1- {5 - [(4-aminobenzenesulfonyl) isobutylamino] -6-phosphonoxyhexylcarbamoyl} -2,2-diphenylethyl) carbamic acid methyl ester (PL-461)

The preparation of the title compound is based on Schemes 1 and 2 of the present invention.

Stage A. Obtaining (3S) -3-isobutylaminoazepan-2-one ( IV )

L-α-amino -, - caprolactam (22.0 g) was dissolved in cold dichloroethane (DCM, 200 ml). Isobutyraldehyde (12.6 g) is added slowly and stirred until the heat released is dissipated (water forms on the surface). A cold solution is added to 46.5 g of powdered NaBH (OAc) ₃ in DCM (0.5 L). AcOH (70 ml) was added to this solution. The slightly turbid mixture was stirred at 20 ° C for 4 hours. 500 ml of a 2M NaOH solution was slowly added to the turbid mixture, the pH was adjusted to 11 using a concentrated NaOH solution, and then the mixture was stirred for an additional 20 minutes. After extraction, the DCM layer was dried over MgSO ₄ , filtered and evaporated. The oily substance thus obtained was slowly crystallized in a stationary state (27.8 g, 85%) and was used without further purification in the next step.

¹ H NMR (CDCl ₃ ): ¹ H NMR (CDCl ₃ ): δ 0.93 (d, J = 6.5, 3H), 0.97 (d, J = 6.5, 3H), 1.39 (t, J = 9.8, 1H), 1.47 (m, 1H), 1.78-1.65 (m, 2H), 2.00-1.93 (m, 2H), 2.32 -2.2 (m, 2H), 2.38 (t, J = 9.7, 1H), 3.16 (m, 3H), 6.62 (s, 1H (NH)). T _pl. 52-54 ° C (hexane).

A small sample is converted to S-methylbenzylurea by adding a solid to a solution of S-methylbenzylisocyanate in MeCN. NMR gives 98% ee.

Stage B. Obtaining N α-isobutyl- N α- (4-acetamidobenzenesulfonyl) -L-α-amino -, - caprolactam ( V )

N α-isobutyl-L-α-amino -, - caprolactam ( IV ) (4.1 g of the free base) was dissolved in DCM (200 ml) and treated with 4.0 g of triethylamine, followed by 4-acetamidobenzenesulfonyl chloride (5.2 g ) 0.1 g of dimethylaminopyridine is added and the mixture is stirred for 5 hours. The resulting viscous suspension was poured into 500 ml of 0.5 M HCl and shaken vigorously. The solid in a two-phase solution is filtered off and washed with cold acetone to give 7.3 g (87%) of pure product.

¹ H NMR (DMSO-d ₆ ): * 0.93 (d, J = 6.0, 3H), 0.96 (d, J = 6.0, 3H), 1.39 (t, J = 12 , 0, 1H), 1.85-1.65 (m, 3H), 2.08-2.18 (m s, 6H), 2.90-2.97 (m, 1H), 3.00 -3.06 (m, 2H), 3.35 (dd, J = 14.2, 8.5, 1H), 4.65 (d, J = 8.7, 1H), 6.3 (s, 1H), 7.42 (d, J = 8.8, 2H), 7.6 (d, J = 8.8, 2H). T _pl. 230-233 ° C (EtOH).

Step C. Preparation of (3S) -3 - {[4-acetyl-tert-butoxycarbonylamino) benzenesulfonyl] isobutylamino} -2-oxoazepane-1-carboxylic acid tert-butyl ester (Boc activation) ( VI )

4.2 g of N α-isobutyl- N α- (4-acetamidobenzenesulfonyl) -L-α-amino -, - caprolactam ( V ) are suspended in 30 ml of MeCN and sonicated briefly to grind large pieces. To this white suspension was added 6.7 g (3 equiv.) Of di- tert-butyl pyrocarbonate in 10 ml of MeCN. The suspension is stirred with a magnetic stirrer and a 120 mg portion of DMAP is added. The solution turns bright yellow after a few minutes. TLC (EtOAc) detects 1 product Rf 0.9 (starting material Rf 0.4). The solution was poured into 20 ml of distilled water and extracted with ether, dried over Na ₂ SO ₄ and evaporated to give 6.90 g. A sample was recrystallized from hexane.

¹ H NMR (DMSO-d ₆ ): * 0.68 (d, J = 6.0, 3H), 0.85 (d, J = 6.0, 3H), 1.39 (s, 10H), 1.47 (s, 9H), 1.85-1.65 (m, 3H), 2.15 (s, 3H), 2.80 (q, J = 4, 1H), 3.10-3, 36 (m, 2H), 4.01 (d, J = 8.0, 1H), 4.85 (d, J = 8.7, 1H), 7.32 (d, J = 8.8, 2H ), 7.87 (d, J = 8.8, 2H) T _pl. 123-124 ° C.

Step D. Preparation of (1S) -4-amino- N - (5-amino-1-gidroksimetilpentil) - N -izobutilbenzolsulfonamida (VII- no protection) (reductive ring opening and deprotection)

A 3.0 g portion of (3S) -3 - {[4-acetyl-tert-butoxycarbonylamino) benzenesulfonyl] isobutylamino} -2-oxoazepan-1-carboxylic acid tert-butyl ester ( VI , step C) is dissolved in 40 ml of EtOH, then add 750 mg of NaBH ₄ . Short-term heating with a hairdryer gives a clear solution. TLC only detected a streaky spot after 20 minutes (EtOAc). The solution is concentrated to a paste, poured into 40 ml of 1 N. NaOH and extracted with ethyl acetate, the organic phase is dried over Na ₂ SO ₄ and evaporated, obtaining 2.8 g of intermediate ( VII ); (1S) tert-butyl ester - {4 - [(5-tert-butoxycarbonylamino-1-hydroxymethylpentyl) isobutylsulfamoyl] phenyl} carbamic acid ( VII )

The above intermediate was dissolved in 5 ml EtOH and 5 ml 12 N was added. HCl. Vigorous gas evolution is observed for several minutes. After 2 hours, the solution was evaporated, concentrated alkaline KOH was made and extracted with EtOAc to obtain 1.75 g of a white powder.

¹ H NMR (DMSO-d ₆ ): * 0.82 (m, 6H), 0.97-1.12 (m, 2H), 1.15-1.30 (m, 3H), 1.57 ( m, 1H), 1.84 (m, 1H), 2.40 (t, J = 7.8, 2H), 2.75 (m, 1H), 2.85 (m, 1H), 3.21 (m, 1H), 3.44 (d, J = 6.4, 2H), 5.92 (br s, 2H), 6.59 (d, J = 8.0, 2H), 7.39 (d, J = 8.0, 2H).

Stage E. Obtaining (2S) -2-methoxycarbonylamino-3,3-diphenylpropionic acid

To a solution of L-diphenylalanine (241 mg, 1.0 mmol) (Peptech Corp.) in 5 ml of 1 N. NaOH and 0.5 ml saturated Na ₂ CO ₃ (the resulting solution at pH 10) add methoxycarbonyloxysuccinimide ((2,5-dioxopyrrolidin-1-yl) carbonic acid methyl ester) (180 mg, 1.1 mmol) dissolved in 5 ml After that, the reaction mixture was stirred at room temperature for 2 hours. The alkaline solution is extracted once with ether (10 ml) and the aqueous phase is acidified with 1 N. HCl. This phase is extracted twice with 20 ml of EtOAc and the combined organic phases are washed with 50 ml of 1 N. HCl. The organic phase was dried over Na ₂ SO ₄ , filtered and evaporated to an oily substance, which was solidified, yielding 250 mg (83%) of the desired substance. This derivative is used without further processing in the next step.

Step F. Preparation of (1S, 5S) - (1- {5 - [(4-aminobenzenesulfonyl) isobutylamino] -6-hydroxyhexylcarbamoyl} -2,2-diphenylethyl) carbamic acid methyl ester (PL-100)

The title compound was prepared from (1S) -4-amino- N - (5-amino-1-gidroksimetilpentil) - N -izobutilbenzolsulfonamida (VII- no protection) (step D) and (2S) -2-methoxycarbonylamino-3, 3-diphenylpropionic acid (step E) using the coupling procedure with HOBt and EDAC described in Example 3 (step D). The final product was obtained in 67% yield (121 mg).

LC-MS: 625.3 (M + H) ⁺ , 95% pure.

¹ H NMR (CD ₃ OD): δ 0.71-0.85 (m, 2H), 0.88 (d, J = 6.3, 5H), 0.91-0.96 (m, 2H) , 1.29-1.34 5 (m, 1H), 1.41-1.52 (m, 1H) 1.82-1.92 (m, 1H), 2.61-2.68 (m, 1H), 2.81-2.85 (m, 2H), 2.94-3.05 (m, 2H), 3.38-3.40 (t, J = 5.0, 1H), 3, 50-3.51 (m, 1H), 3.52 (s, 3H), 4.28 (d, J = 11.0 1H), 4.87 (d, J = 11.0, 1H), 6 69 (d, J = 8.0, 2H), 7.15-718 (m, 2H), 7.20-7.31 (m, 6H), 7.33 (d, J = 7.9, 2H), 7.47 (d, J = 7.5, 1H).

¹³ C NMR (CD ₃ OD): δ 20.0, 20.1, 23.3, 25.4, 28.1, 28.5, 28.9, 38.1, 40.0, 51.2, 51.6, 53.1, 57.2, 57.4, 59.5, 61.9, 62.4, 112.6, 125.7, 126.2, 126.3, 127.9, 128, 1, 128.15, 128.2, 128.4, 128.7, 141.3, 141.9, 152.4, 155.9, 169.9, 172.5.

Step G. Preparation of (1S, 5S) - {1- [5 - [(4-aminobenzenesulfonyl) isobutylamino] -6- (diethoxyphosphoryloxy) hexylcarbamoyl] -2,2-diphenylethyl} carbamic acid methyl ester

Compound PL-100 (product of step F, 203 mg, 0.325 mmol) was dissolved in a mixture of dry tetrahydrofuran (3 ml) and 0.2 ml of triethyl phosphate under an atmosphere of N ₂ . The mixture was stirred at this temperature for 15 minutes, after which diethyl chlorophosphate (0.061 ml, 0.423 mmol) was added. Sodium hydride (60% in mineral oil) (17 mg, 0.423 mmol) was added at 0 ° C. The solution was stirred for 1 hour at 0 ° C and 12 hours at room temperature. To this solution, 20 ml of Amberlite XAD-2 is added and the granules are thoroughly mixed with the solvent. 2 ml of ice-water was added to the mixture, and THF was evaporated. Then the granules are washed 6 times with distilled water 100 ml, then extracted three times with ethyl acetate (30 ml). The combined phase was evaporated and the residue was dried under high vacuum. The crude product was purified by flash chromatography using ethyl acetate / hexane (8/2), then EtOAc 100% as eluent. The yield of this reaction is 152 mg 61%.

LC-MS: 761.2 (M + H) ⁺ , 90% pure.

¹ H NMR (CD ₃ OD): δ 0.68-0.75 (m, 1H), 0.75-0.84 (m, 1H), 0.84-1.10 (m, 9H), 1 , 21-1.50 (m, 8H), 1.88 (m, 1H), 2.58-2.71 (m, 1H), 2.80-2.89 (m, 1H), 2.89 -3.08 (m, 2H), 3.49-3.60 (s, 3H), 3.65-3.74 (m, 1H), 3.85-3.95 (m, 1H), 3 97-4.02 (m, 1H), 4.07-4.21 (m, 4H), 4.29 (d, J = 10.8, 1H), 6.71 (d, J = 8, 0, 2H), 7.10-7.20 (m, 2H), 7.20-7.32 (m, 5H), 7.32-7.45 (m, 3H), 7.50 (d, J = 7.5.2H), 7.86 (br s, 1H).

³¹ P NMR (CD ₃ OD): δ 1.62.

Step H. Preparation of (1S, 5S) - (1- {5 - [(4-aminobenzenesulfonyl) isobutylamino] -6-phosphonoxyhexylcarbamoyl} -2,2-diphenylethyl) carbamic acid methyl ester (PL-461)

The product from step G prepared above (152 mg) was dissolved in anhydrous dichloromethane (3.0 ml). Trimethylsilyl bromide (0.5 ml) was added at 0 ° C. The mixture was stirred for 1 h at this temperature and overnight at room temperature. The solvent was evaporated and 0.2 ml of water was added to the residue. Add 3 ml EtOH, mix and evaporate. This step is repeated three times and the residue is dried under vacuum. Yield 98 mg, 70% of the title derivatives of this first example.

LC-MS: 705.2 (M + H) ⁺ , 95% pure.

¹ H NMR (CD ₃ OD): δ 0.65-0.73 (m, 1H), 0.75-0.83 (m, 1H), 0.89 (d, J = 5.6, 8H) , 1.27-1.38, (m, 1H), 1.42-4.55 (m, 1H), 1.82-1.94 (m, 1H), 2.57-2.68 (m , 1H), 2.78-2.90 (m, 1H), 2.91-20 3.09 (m, 2H), 3.54 (s, 3H), 3.60-3.72 (m, 1H), 3.87-4.05 (m, 1H), 4.00 (m, 1H), 4.29 (d, J = 11.3, 1H), 4.90 (d, J = 11, 4, 1H), 6.73 (d, J = 8.0, 2H), 7.13-7.22 (m, 2H), 7.22-7.33 (m, 6H), 7.33- 7.45 (m, 2H); 7.51 (d, J = 7.5, 2H).

³¹ P NMR (CD ₃ OD): δ 2.80.

Example 2. Obtaining the sodium salt of methyl ester (1S, 5S) - (1- {5 - [(4-aminobenzenesulfonyl) isobutylamino] -6-phosphonoxyhexylcarbamoyl} -2,2-diphenylethyl) carbamic acid (PL-462)

70.7 mg of the final product from example 1 is added to 1 ml of 0.1 N. NaOH and diluted with 1 ml of distilled water. This solution is then frozen and lyophilized. Yield 67.2 mg (92%) of the desired substance with a purity of 95%.

¹ H NMR (CD ₃ OD): δ 0.72-0.83 (m, 1H), 0.90 (d, J = 5.8, 9H), 1.26-1.38 (m, 1H) 1.53-1.65 (m, 1H), 1.88-2.00 (m, 1H), 2.60-2.70 (m, 1H), 2.79-2.89 (m, 1H), 2.98-3.00 (m, 1H), 3.00-3.08 (m, 1H), 3.54 (s, 3H), 3.58-3.71 (m, 1H) 3.72-3.83 (m, 1H); 3.84-3.95 (m, 1H); 4.28 (d, J = 11.1; 1H); 4.91 (d, J = 11.0, 1H), 6.70 (d, J = 7.6, 2H), 7.12-7.22 (m, 2H), 7.22-7.32 (m, 6H), 7, 33-7.40 (m, 2H); 7.50 (d, J = 7.7, 2H).

³¹ P NMR (CD ₃ OD): δ 3.13.

Example 3. Getting (1S, 5S) methyl ester - (1- {5 - [(4-aminobenzenesulfonyl) isobutylamino] -6-phosphonoxyhexylcarbamoyl} -2-naphthalen-2-yl-ethyl) carbamic acid (PL-507)

The preparation of the title compound is based on Scheme 2 of the present invention.

Scheme A. Preparation of (1S) - (4 - {[5-tert-butoxycarbonylamino-1- (diethoxyphosphoryloxymethyl) pentyl] isobutylsulfamoyl} phenyl) carbamic acid tert-butyl ester ( VIII )

2.00 g (3.7 mmol) of (1S) tert-butyl ether - {4 - [(5-tert-butoxycarbonylamino-1-hydroxymethylpentyl) isobutylsulfamoyl] phenyl} carbamic acid ( VII ) (Example 1, step D) are dissolved in a mixture of 0.63 ml of triethyl phosphate and 10 ml of THF at 0 ° C in an inert atmosphere of argon. 0.63 ml (4.44 mmol) of diethyl chlorophosphate is added and then 0.25 g (6.2 mmol) of 60% NaH in oil is added portionwise. The mixture was allowed to warm to room temperature and allowed to mix for 2 hours (LC-MS shows completion after 1 hour). To this solution, 20 ml of Amberlite XAD-2 resin is added, the suspension is thoroughly mixed and added to 200 ml of ice water. After stirring for 15 minutes, the resin suspension is filtered off and the resin washed several times with distilled water (500 ml). The desired product is stripped from the resin with acetone (5 X 50 ml), EtOAc (5 X 50 ml), then the organic phase is dried over Na ₂ SO ₄ . After evaporation of the solvent, 2.66 g (89%) of a clear oily substance are obtained. The crude product contains a fraction with two diethyl phosphates and is used without further processing in the next step.

¹ H NMR (CD ₃ OD): δ 0.91 (d, J = 6.3, 6H), 1.11-1.21 (m, 2H), 1.33 (t, J = 6.9, 10H), 1.43 (s, 9H), 1.53 (s, 10H), 1.90-1.97 (m, 1H), 2.88-2.96 (m, 3H), 2.96 -3.04 (m, 1H), 3.81-3.90 (m, 1H), 3.91-3.99 (m, 1H), 4.01-4.14 (m, 4H), 7 61 (d, J = 8.3, 2H); 7.72 (d, J = 8.4.2H).

³¹ P NMR (CD ₃ OD): δ 1.59.

Stage B. Obtaining (diethyl) (6-amino-2 - [(4-aminobenzenesulfonyl) isobutylamino] hexyl) ether (2S) -phosphoric acid ( IX )

The crude product obtained in the previous step ( VIII , 2.66 g) was dissolved in 12 ml of EtOH. 4 ml of HCl _conc. and briefly heated to 70 ° C, then left at room temperature for 3 hours. The solvent was evaporated and the residue was triturated with 50 ml of ether. Then the viscous residue is dissolved in 3 ml of ice water and the pH is adjusted to 12 to 50% NaOH. The resulting viscous suspension was extracted with EtOAc (3 X 50 ml) and the organic phase was dried over Na ₂ SO ₄ . After filtering off the drying agent, the organic phase is evacuated, yielding 1.84 g (98%) of the desired product ( IX ).

LC-MS: 480.2 (M + H) ⁺ , 95% pure.

¹ H NMR (CD ₃ OD): δ 0.91 (s, 6H), 1.11-1.26 (m, 3H), 1.28-1.43 (m, 8H), 1.45-1 51 (m, 1H), 1.52-1.61 (m, 1H), 1.89-1.96 (m, 1H), 2.56 (t, J = 6.7, 2H), 2 85-2.91 (m, 1H), 2.98-3.11 (m, 1H), 3.79-3.99 (m, 1H), 3.94 (d, J = 5.3, 1H), 4.09-4.11 (m, 4H), 6.69 (d, J = 7.9, 2H), 7.50 (d, J = 7.9, 2H).

³¹ P NMR (CD ₃ OD): δ 1.61

Step C. Preparation of (2S) -2-methoxycarbonylamino-3-naphthalen-2-yl-propionic acid (or L-Moc-2-naphthylalanine)

To a solution of L-2-naphthylalanine (215 mg, 1 mmol) (Peptech Corp.) in 5 ml of 1 N. NaOH and 0.5 ml of saturated Na ₂ CO ₃ (pH of the resulting solution 10) add methoxycarbonyloxysuccinimide (187 mg, 1.1 mmol) dissolved in 5 ml. After that, the reaction mixture was stirred at room temperature for 2 hours. The alkaline solution was extracted once with ether (10 ml) and the aqueous phase was acidified with 1N HCl. This phase is extracted twice with 20 ml of EtOAc and the combined organic phases are washed with 50 ml of 1 N. HCl. The organic phase was dried over Na ₂ SO ₄ , filtered and evaporated to an oily substance, which was solidified, yielding 200 mg (73%) of the desired substance. This intermediate (called an N- substituted amino acid) is used without further processing in the next step.

Step D. Preparation of (1S, 5S) - (1- {5 - [(4-aminobenzenesulfonyl) isobutylamino] -6-phosphonoxyhexylcarbamoyl} -2-naphthalen-2-yl-ethylcarbamic acid methyl ester (PL-507)

100 mg of L-Moc-2-naphthylalanine (step C) activate 100 mg of EDAC and 57 mg of HOBt in 1.5 ml of DMF for 30 minutes. Then, 100 mg of (6-amino-2 - [(4-aminobenzenesulfonyl) isobutylamino] hexyl) (diethyl) phosphoric acid ester (step B) was added and allowed to stir at room temperature for 1 h. 40 ml of 1M K was added to the DMF solution ₂ CO ₃ and left for 10 minutes Then add 50 ml EtOAc and then the mixture is vigorously stirred. The EtOAc phase is separated, followed by extraction once with 5% citric acid (50 ml), then 3 times with water (50 ml) and, finally, with brine. The organic phase is separated and evaporated. The residue was taken up in 50 ml of DCM and re-evaporated. The residue was again taken up in 50 ml of DCM and 0.5 ml of TMSBr was added. The solution was left overnight (16 hours). DXM is pumped out and a solution of MeOH: Water 1: 1 cooled in an ice bath is added, it is briefly mixed and pumped out. The residue is triturated in ether, then dissolved in 1 N. NaOH. The clear solution was extracted with ether and the aqueous phase was acidified with 6 N HCl. Then a white precipitate was collected by filtration and dried in vacuo overnight. Yield 88 mg of the title compound.

LC-MS: 679.8 (M + H) ⁺ , 95% pure.

¹ H NMR (CD ₃ OD): δ 0.89-0.98 (m, 8H), 1.15 (m, 2H), 1.35 (m, 1H), 1.45 (m, 1H), 1.88 (m, 1H), 2.84 (m, 2H), 2.98 (m, 1H), 3.01 (m, 2H), 3.24 (m, 1H), 3.56 (s , 3H), 3.60 (m, 1H), 3.81 (m, 1H), 3.99 (m, 1H), 4.39 (t, J = 6.8, 1H), 6.91 ( d, J = 8.0, 2H), 7.34 (d, J = 8.0, 1H), 7.45 (m, 2H), 7.58 (d, J = 8.0.2H), 7.66 (s, 1H); 7.70-7.82 (m, 3H).

³¹ P NMR (CD ₃ OD): δ 2.56

Example 4. Obtaining mono- (2 - [(4-aminobenzenesulfonyl) isobutylamino] -6- {2 - [(morpholine-4-carbonyl) amino] -3-naphthalene-1-ylpropionylamino} hexyl ester (2S, 2S) phosphoric acids (PL-498)

Step A. Preparation of (2S) -2 - [(morpholine-4-carbonyl) amino] -3-naphthalene-1-yl-propionic acid

To a solution of L-1-naphthylalanine (215 mg, 1 mmol) (Peptech Corp.) in 5 ml of 1 N. NaOH and 0.5 ml of saturated Na ₂ CO ₃ (pH of the resulting solution 10) add morpholine-4-carbonyl chloride (150 mg, 1.0 mmol) dissolved in 5 ml. After that, the reaction mixture was stirred at room temperature for 2 hours. The alkaline solution was extracted once with ether (10 ml) and the aqueous phase was acidified with 1N HCl. This phase is extracted twice with 20 ml of EtOAc and the combined organic phases are washed with 50 ml of 1 N. HCl. The organic phase was dried over Na ₂ SO ₄ , filtered and evaporated to an oily substance, which was solidified, yielding 125 mg (38%) of the desired substance. This intermediate is used without further processing in the next step.

Step B. Preparation of Mono- (2 - [(4-aminobenzenesulfonyl) isobutylamino] -6- {2 - [(morpholine-4-carbonyl) amino] -3-naphthalene-1-ylpropionylamino} hexyl ester (2S, 2S) phosphoric acids (PL-498)

This compound is synthesized in the same way as in the method of obtaining the product from example 3 (stage D) using 100 mg of (2S) -2 - [(morpholine-4-carbonyl) amino] -3-naphthalene-1-yl-propionic acid (stage A of this example). The resulting precipitated residue was further purified by preparative reverse phase HPLC. Yield 41 mg of the final compound.

LC-MS: 734.8 (M + H) ⁺ , 95% pure.

¹ H NMR (CD ₃ OD): δ 0.83-0.98 (m, 8H), 1.00-1.25 (m, 4H), 1.45-1.52 (m, 1H), 1 52-1.66 (m, 1H), 1.88-1.99 (m, 1H), 2.77-2.92 (m, 2H), 2.98-3.16 (m, 3H) 3.40-3.49 (m, 1H), 3.50-3.56 (m, 6H), 3.67-3.69 (m, 1H), 3.81-3.89 (m, 1H), 3.99-4.05 (m, 1H), 4.59 (t, J = 6.0, 1H), 6.75 (d, J = 8.0, 2H), 7.30- 7.60 (m, 7H), 7.75 (d, J = 8.0, 1H), 7.90 (d, J = 7.8, 1H), 8.23 (d, J = 7.8 2H).

³¹ P NMR (CD ₃ OD): δ 2.71

Example 5. Obtaining mono {6- (2-acetylamino-3,3-diphenylpropionylamino) -2 - [(4-aminobenzenesulfonyl) isobutylamino] hexyl} ether (2S, 2S) -phosphoric acid (PL-504)

Step A. Preparation of (2S) -2-acetylamino-3,3-diphenylpropionic acid

To a solution of L-diphenylalanine (100 mg, 0.4 mmol) (Peptech Corp.) in 5 ml of 1 N. NaOH and 0.5 ml saturated Na ₂ CO ₃ (pH of the resulting solution 10) add acetyl chloride (0.5 mmol) dissolved in 5 ml. After that, the reaction mixture was stirred at room temperature for 2 hours. The alkaline solution was extracted once with ether (10 ml) and the aqueous phase was acidified with 1N HCl. This phase is extracted twice with 20 ml of EtOAc and the combined organic phases are washed with 50 ml of 1 N. HCl. The organic phase was dried over Na ₂ SO ₄ , filtered and evaporated to an oily substance, which was solidified, yielding 70 mg (60%) of the desired substance. This crude intermediate is used without further processing in the next step.

Stage B. Obtaining mono {6- (2-acetylamino-3,3-diphenylpropionylamino) -2 - [(4-aminobenzenesulfonyl) isobutylamino] hexyl} ether (2S, 2S) -phosphoric acid (PL-504)

This compound is synthesized in the same way as in the method of obtaining the product from example 3 (step D) using 100 mg of (2S) -2-acetylamino-3,3-diphenylpropionic acid (step A of this example). The final product is obtained in 30% yield (30 mg).

LC-MS: 689.3 (M + H) ⁺ , 95% pure.

¹ H NMR (CD ₃ OD): δ 0.77-1.04 (m, 9H), 1.10-1.17 (m, 1H), 1.23-1.49 (m, 1H), 1 46-1.57 (m, 1H), 1.78 (s, 3H), 1.88-1.99 (m, 1H), 2.80-2.92 (m, 2H), 2.92 -3.08 (m, 2H), 3.63-3.75 (m, 1H), 3.79-3.95 (m, 1H), 4.00 (m, 1H), 4.34 (d , J = 11.3, 1H), 5.19-5.28 (m, 1H), 6.77-6.85 (m, 2H), 7.10-7.20 (m, 2H), 7 27-7.33 (m, 6H); 7.32-7.41 (m, 2H); 7.49-7.62 (m, 2H).

³¹ P NMR (CD ₃ OD): δ 2.70

Example 6. Preparation of (1S, 5S) - (1- {5 - [(4-amino-3-fluorobenzenesulfonyl) isobutylamino] -6-phosphonoxyhexylcarbamoyl} -2,2-diphenylethyl) carbamic acid methyl ester (PL-515)

First Procedure: The preparation of the title compound is based on Scheme 3 of the present invention.

Step A. Preparation of (1- {5 - [(4-amino-3-fluorobenzenesulfonyl) isobutylamino] -6-hydroxyhexylcarbamoyl} -2,2-diphenylethyl) carbamic acid methyl ester ( X ) (PL-337)

The product from example 1, step F (0.624 g, 1 mmol) was dissolved in 5 ml of MeCN at 24 ° C. 0.35 g (1 mmol) of SelectFluor was added in one portion and stirred for 1 h. 1 ml of water was added and the solution was injected directly into preparative reverse phase HPLC. The product was collected and lyophilized to give a white solid yield of 250 mg (38%).

LC-MS: 643.3 (M + H) ⁺ , 99% pure.

¹ H NMR (MeOD): δ 0.71-0.85 (m 2H), 0.88 (d, J = 6.3, 6H), 0.91-0.96 (m, 2H), 1, 21-1.29 (m, 1H), 1.41-1.52 (m, 1H) 1.82-1.92 (m, 1H), 2.61-2.68 (m, 1H), 2 81-2.85 (m, 2H), 2.94-3.05 (m, 2H), 3.38-3.40 (t, J = 5, 1H), 3.49-3.52 ( m, 5H), 4.28 (d, J = 10, 1H), 4.87 (d, J = 10, 1H) 6.90 (t, J = 8.3, 1H), 7.20 (m , 2H), 7.28 (m, 3H), 7.33 (m, 3H), 7.39 (m, 4H).

Step B. Preparation of (1S, 5S) - {1- [5 - [(4-amino-3-fluorobenzenesulfonyl) isobutylamino] -6- (diethoxyphosphoryloxy) hexylcarbamoyl] -2,2-diphenylethyl} carbamic acid methyl ester

The product from step A is phosphorylated with chlordiethyl phosphate following the procedure described in example 1, step G. Yields 157 mg, 68%.

LC-MS: 779.3 (M + H) ⁺ , 95% pure.

¹ H NMR (CD ₃ OD): δ 0.82 (m, 1H), 0.92 (d, J = 6.2, 8H), 0.96 (m, 3H), 1.36 (d, J = 3.7, 6H), 1.90 (m, 1H), 2.69 (m, 1H), 2.89 (m, 1H), 2.98 (m, 2H), 3.56 (s, 3H), 3.74 (m, 1H), 3.93 (m, 1H), 4.03 (m, 1H), 4.12 (q, J = 7.5 and 14.8.4H), 4 32 (d, J = 11.4, 1H), 4.92 (d, J = 11.4, 1H), 6.90 (t, J = 8.3, 1H), 7.20 (m, 2H), 7.28 (m, 3H), 7.33 (m, 3H), 7.39 (m, 4H).

³¹ P NMR (CD ₃ OD): δ 1.65

Step C. Preparation of (1S, 5S) - (1- {5 - [(4-amino-3-fluorobenzenesulfonyl) isobutylamino] -6-phosphonoxyhexylcarbamoyl} -2,2-diphenylethyl) carbamic acid methyl ester ( XI ) (PL- 515)

Deprotection is carried out using the procedure described in example 1, step G. Yields 101 mg.

LC-MS: 723.2 (M + H) ⁺ , 95% pure.

¹ H NMR (CD ₃ OD): 0.65-0.77 (m, 1H), 0.77-0.85 (m, 1H), 0.85-1.05 (m, 9H), 1, 25-1.39 (m, 1H), 1.40-1.52 (m, 1H), 1.82-1.98 (m, 1H), 2.58-2.72 (m, 1H), 2.82-2.92 (m, 1H), 2.92-3.05 (m, 2H), 3.54 (s, 3H), 3.64-3.75 (m, 1H), 3, 80-3.92 (m, 1H), 3.91-4.04 (m, 1H), 4.29 (d, J = 11.4, 1H), 7.19 (t, J = 6.6 , 1H), 7.13-7.21 (m, 2H), 7.22-7.33 (m, 6H), 7.34-7.38 (m, 2H), 7.39-7.48 (m, 2H)

³¹ P NMR (CD ₃ OD): δ 2.74

Second method: The preparation of the title compound is based on Scheme 4 of the present invention.

Step A. Preparation of (1S, 5S) - (1- {5 - [(4-aminobenzenesulfonyl) isobutylamino] -6-phosphonoxyhexylcarbamoyl} -2,2-diphenylethyl) carbamic acid methyl ester (PL-461).

(2S) -2-methoxycarbonylamino-3,3-diphenylpropionic acid ((example 1, step E) 0.9 g, 3 mmol) is activated in DMF (5 ml) by EDAC (1.7 g, 9 mmol) and HOBt (1.2 g, 9 mmol). To this solution was added 1.17 g of (diethyl) (6-amino-2 - [(4-aminobenzenesulfonyl) isobutylamino] hexyl) ether (2S) -phosphoric acid ( IX ) (Example 3, step B) and the mixture was stirred for 3 hours. Then add 20 g of Amberlite XAD-2 and the granules are left to wet for 10 minutes. The resin was transferred to a glass filter and washed thoroughly with distilled water (400 ml) and 200 ml of 1M NaHCO ₃ . Then the granules are washed with 4 x 50 ml portions of MeOH, then EtOAc 200 ml. The organic phase is evaporated. The residue was adsorbed onto silica gel and passed through a short silica gel column (EtOAc) to give 2.4 g (83%) of a white solid after evaporation.

¹ H NMR identical to Example 1, step H.

Step B. Preparation of (1S, 5S) - {1- [5 - [(4-amino-3-fluorobenzenesulfonyl) isobutylamino] -6- (diethoxyphosphoryloxy) hexylcarbamoyl] -2,2-diphenylethyl} carbamic acid methyl ester ( XII )

Product from Step A above, (1S, 5S) - (1- {5 - [(4-aminobenzenesulfonyl) isobutylamino] -6-phosphonoxyhexylcarbamoyl} -2,2-diphenylethyl) carbamic acid methyl ester (0.555 g, 0.73 mmol) is dissolved in 5 ml of MeCN. Selectfluor (0.26 g, 0.7 mmol) was added and the mixture was stirred for 30 minutes. The mixture was purified by reverse phase preparative HPLC and lyophilized to obtain 278 mg (48% yield) of a white solid.

¹ H NMR identical to the previous description, see first procedure above.

Step C. Preparation of (1S, 5S) - (1- {5 - [(4-amino-3-fluorobenzenesulfonyl) isobutylamino] -6-phosphonoxyhexylcarbamoyl} -2,2-diphenylethyl) carbamic acid methyl ester ( XIII , in this particular case is a compound XI ) (PL-515)

The procedure giving this derivative is as described in the deprotection step for the above procedure. Yields 139 mg 70% after reverse phase HPLC.

¹ H NMR identical to the previous description, see first procedure above.

Example 7. Obtaining 2 - [(4-aminobenzenesulfonyl) isobutylamino] -6- (2-methoxycarbonylamino-3,3-diphenylpropionylamino) hexyl ester (2S, 2S) acetic acid (PL-521)

The preparation of the title derivative is based on Scheme 5 of the present invention.

Step A. Preparation of 6-tert-butoxycarbonylamino-2 - [(4-tert-butoxycarbonylaminobenzenesulfonyl) isobutylamino] hexyl ester (2S) acetic acid ( XIV , R _1A = CH ₃ )

To a stirred solution of (1S) tert-butyl ether - {4 - [(5-tert-butoxycarbonylamino-1-hydroxymethylpentyl) isobutylsulfamoyl] phenyl} carbamic acid (intermediate ( VII ) from Example 1, step D, 97 mg, 0, 18 mmol) in anhydrous CH ₂ Cl ₂ (3 ml) add N, N- dimethylaminopyridine (22 mg, 0.18 mmol) and acetic anhydride (0.014 ml, 0.18 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was evaporated. Ethyl acetate (50 ml) was added and the organic layer was washed with water (30 ml), then dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography, eluting with ethyl acetate. The resulting yield is quantitative (100 mg).

LC-MS: 586.2 (M + H) ⁺ , 95% pure.

Step B. Preparation of 6-amino-2 - [(4-aminobenzenesulfonyl) isobutylamino] hexyl ester of (2S) -acetic acid ( XV , R _1A = CH ₃ )

This derivative is prepared from 6-tert-butoxycarbonylamino-2 - [(4-tert-butoxycarbonylaminobenzenesulfonyl) isobutylamino] hexyl ether (2S) -acetic acid as described in Example 15, step B. A yellow solid (66 mg) was used in next reaction without purification.

LC-MS: 386.2 (M + H) ⁺ , 95% pure.

Step C. Preparation of 2 - [(4-aminobenzenesulfonyl) isobutylamino] -6- (2-methoxycarbonylamino-3,3-diphenylpropionylamino) hexyl ester (2S, 2S) -acetic acid ( XVI, R _1A = CH ₃ ) (PL- 521)

This derivative is prepared from 6-amino-2 - [(4-aminobenzenesulfonyl) isobutylamino] hexyl ester of (2S) -acetic acid (product from step B) as described in Example 15, step B. The final product is purified by flash chromatography using a mixture of eluents hexane / ethyl acetate (2/8). A yellow solid is obtained with a yield of 70% (70 mg).

LC-MS: 667.3 (M + H) ⁺ , 95% pure.

¹ H NMR (acetone-d ₆ ): δ 0.85-0.97 (m, 12H), 1.21-1.41 (m, 2H), 1.88-2.00 (s, 3H), 2.59-2.69 (m, 1H), 2.83-2.90 (m, 1H), 2.90-3.01 (m, 1H), 3.01-3.10 (br s , 1H), 3.45-3.60 (s, 3H), 3.70-3.80 (m, 1H), 3.93-4.00 (m, 1H), 4.00-4.11 (m, 1H), 4.38-4.45 (d, J = 11.0, 1H), 4.89-4.98 (t, J = 10.0, 1H), 5.43-5, 58 (br s, 1H), 6.28-6.48 (d, J = 8.9, 1H), 6.72-6.83 (d, J = 8.0, 2H), 6.85 -6.93 (br s, 1H), 7.12-7.22 (t, J = 7.4, 1H), 7.21-7.31 (d, J = 7.0, 4H), 7.31-7.45 (m, 5H); 7.48-7.57 (d, J = 8.0, 2H).

Example 8. Obtaining 2 - [(4-aminobenzenesulfonyl) isobutylamino] -6- (2-methoxycarbonylamino-3,3-diphenylpropionylamino) hexyl ester (2S, 2S) -nicotinic acid (PL-520)

Step A. Preparation of 6-tert-butoxycarbonylamino-2 - [(4-tert-butoxycarbonylaminobenzenesulfonyl) isobutylamino] hexyl ester (2S) -nicotinic acid ( XIV , R _1A = 3-pyridyl)

(1S) tert-butyl ether - {4 - [(5-tert-butoxycarbonylamino-1-hydroxymethylpentyl) isobutylsulfamoyl] phenyl} carbamic acid (intermediate ( VII ) from Example 1, step D, 130 mg, 0.24 mmol) dissolved in anhydrous DMF (1 ml) and treated with 0.066 ml (0.48 mmol) of triethylamine, the field of which is EDC (120 mg, 0.65 mmol), HOBt (88 mg, 0.65 mmol) and nicotinic acid (27 mg, 0.22 mmol). The mixture was stirred overnight at room temperature. The product was extracted with a mixture of ethyl acetate (40 ml) and water (40 ml). The organic phase was separated and dried over Na ₂ SO ₄ , then evaporated to give 200 mg of a crude product. This compound was purified by flash chromatography with ethyl acetate as eluent. A clear oily substance is obtained in a yield of 100% (150 mg).

LC-MS: 649.3 (M + H) ⁺ , 95% pure.

¹ H NMR (acetone-d ₆ ): δ 0.90-1.14 (d, J = 5.9, 6H), 1.31-1.42 (m, 2H), 1.48 (s, 9H ), 1.51-1.55 (m, 2H), 1.59 (s, 9H), 1.62-1.69 (m, 1H), 1.72-1.83 (m, 1H), 3.00-3.11 (m, 2H), 3.11-30 3.17 (m, 1H), 3.19-3.27 (m, 1H), 4.15-4.24 (m, 1H), 4.35-4.44 (t, J = 9.1, 1H), 4.50-4.58 (dd, J = 4.4 and 11.5, 1H), 5.89-5 99 (br s, 1H), 7.53-7.60 (m, 1H), 7.70-7.77 (d, J = 8.2, 2H), 7.80-7.87 ( d, J = 8.2, 2H), 8.24-8.31 (d, J = 7.3, 1H), 8.75-8.82 (m, 1H), 8.82-8.88 (m, 1H), 9.12-9.18 (br s, 1H).

Step B. Preparation of 6-amino-2 - [(4-aminobenzenesulfonyl) isobutylamino] hexyl ester of (2S) -nicotinic acid ( XV , R _1A = 3-pyridyl)

The product from step A, 6-tert-butoxycarbonylamino-2 - [(4-tert-butoxycarbonylaminobenzenesulfonyl) isobutylamino] hexyl ether (2S) -nicotinic acid (150 mg, 0.23 mmol) was dissolved in CH ₂ Cl ₂ (5 ml) and trifluoroacetic acid (1 ml) was added. The mixture was stirred for 2 hours at room temperature. The solvent was evaporated and the residue was extracted with a mixture of ethyl acetate (40 ml) and NaOH 1M (40 ml) (pH 10). The organic portion was separated, dried over Na ₂ SO ₄ and then evaporated. The residue (100 mg) was used for the next reaction without further purification. The output is quantitative.

LC-MS: 449.3 (M + H) ⁺ , 95% pure.

Step C. Preparation of 2 - [(4-aminobenzenesulfonyl) isobutylamino] -6- (2-methoxycarbonylamino-3,3-diphenylpropionylamino) hexyl ester (2S, 2S) -nicotinic acid (PL-520)

The product from stage B, 6-amino-2 - [(4-aminobenzenesulfonyl) isobutylamino] hexyl ether (2S) -nicotinic acid (100 mg, 0.22 mmol) was dissolved in anhydrous DMF (2 ml) and treated with 0.062 ml (0 , 45 mmol) of triethylamine, followed by EDC (100 mg, 0.56 mmol), HOBt (75 mg, 0.56 mmol) and (2S) -2-methoxycarbonylamino-3,3-diphenylpropionic acid (56 mg, 0, 19 mmol). This mixture was stirred overnight at room temperature. The product was extracted with a mixture of ethyl acetate (40 ml) and water (40 ml). The organic layer was separated, dried over Na ₂ SO ₄ and then evaporated to give 160 mg of a crude oily substance. The residue was purified by flash chromatography with hexanes / ethyl acetate (2/8). The title compound was obtained as a clear oily substance in 20% yield (25 mg).

LC-MS: 730.2 (M + H) ⁺ , 95% pure.

¹ H NMR (acetone-d ₆ ): δ 0.80-0.97 (m, 9H), 0.97-1.13 (m, 2H), 1.26-1.40 (m, 1H), 1.40-1.57 (m, 1H), 2.61-2.73 (m, 1H), 2.86-2.98 (m, 2H), 3.00-3.17 (m, 2H) ), 3.45-3.59 (s, 3H), 3.91-4.00 (m, 1H), 4.24-4.34 (m, 1H), 4.34-4.47 (m , 2H), 4.90-4.99 (t, J = 9.7, 1H), 6.35-6.44 (m, 1H), 6.68-6.79 (d, J = 7, 9, 1H), 6.91-7.00 (br s, 1H), 7.13-7.22 (m, 2H), 7.22-7.31 (m, 3H), 7.35- 7.48 (m, 4H), 7.49-7.64 (m, 2H), 7.75-7.84 (m, 1H), 8.25-8.36 (m, 1H), 8, 76-8.88 (br s, 1H); 9.12 - 9.26 (br s, 1H).

Example 9. Obtaining 2 - [(4-aminobenzenesulfonyl) isobutylamino] -6- (2-methoxycarbonylamino-3,3-diphenylpropionylamino) hexyl ester (2S, 2S) -dimethylaminoacetic acid (PL-534)

Step A. Preparation of 6-tert-butoxycarbonylamino-2 - [(4-tert-butoxycarbonylaminobenzenesulfonyl) isobutylamino] hexyl ester (2S) -dimethylaminoacetic acid ( XIV , R _1A = (CH ₃ ) ₂ NCH ₂ -)

The title compound was prepared from (1S) - {4 - [(5-tert-butoxycarbonylamino-1-hydroxymethylpentyl) isobutylsulfamoyl] phenyl} carbamic acid tert-butyl ester (intermediate ( VII ) from Example 1, step D), as described in example 15, step A, using N, N- dimethylglycine. Get a clear oil with a yield of 100% (150 mg).

LC-MS: 629.3 (M + H) ⁺ , 95% pure.

¹ H NMR (acetone-d ₆ ): δ 0.81-0.95 (d, J = 6.1, 6H), 1.18-1.30 (m, 2H), 1.32-1.43 (s, 9H), 1.43-1.52 (s, 8H), 1.52-1.62 (m, 1H), 1.93-2.00 (m, 1H), 2.19-2 29 (s, 4H), 2.69-2.80 (m, 4H), 2.90-3.05 (m, 6H), 3.60-3.65 (m, 1H), 3, 85-3.97 (m, 1H), 3.98-4.08 (m, 1H), 4.08-4.14 (m, 1H), 5.78-5.88 (m, 1H), 7.68-7.80 (m, 3H); 8.80-8.88 (br s, 1H).

Step B. Preparation of 6-amino-2 - [(4-aminobenzenesulfonyl) isobutylamino] hexyl ester of (2S) -dimethylaminoacetic acid ( XV , R _1A = (CH ₃ ) ₂ NCH ₂ -)

The title derivative was prepared from 6-tert-butoxycarbonylamino-2 - [(4-tert-butoxycarbonylaminobenzenesulfonyl) isobutylamino] hexyl ester of (2S) -dimethylaminoacetic acid as described in Example 15, step B. The final product (100 mg) was used without additional processing in the next stage.

LC-MS: 429.3 (M + H) ⁺ , 90% pure.

Step C. Preparation of 2 - [(4-aminobenzenesulfonyl) isobutylamino] -6- (2-methoxycarbonylamino-3,3-diphenylpropionylamino) hexyl ester (2S, 2S) -dimethylaminoacetic acid (PL-534)

The title compound was prepared from 6-amino-2 - [(4-aminobenzenesulfonyl) isobutylamino] hexyl ester of (2S) dimethylaminoacetic acid as described in Example 15, Step C. The crude product was purified by preparative LC. The final compound was obtained in 10% yield (10 mg).

LC-MS: 710.3 (M + H) ⁺ , 92% pure.

¹ H NMR (acetone-d ₆ ): δ 0.81-0.98 (m, 12H), 1.14-1.30 (m, 2H), 1.31-1.45 (m, 1H), 2.58-2.77 (m, 2H), 2.79-2.90 (m, 2H), 3.42-3.56 (s, 3H), 3.75-3.85 (m, 1H ), 3.99-4.17 (m, 3H), 4.23-4.35 (m, 1H), 4.36-4.45 (m, 1H), 4.86-4.96 (m , 1H), 6.33-6.42 (m, 1H), 6.74-6.83 (m, 1H), 6.85-6.90 (m, 1H), 7.12-7.22 (m, 3H), 7.23-7.31 (m, 4H), 7.31-7.44 (m, 5H), 7.47-7.55 (m, 1H), 7.73-7 80 (m, 1H).

Example 10. Obtaining 2 - [(4-aminobenzenesulfonyl) isobutylamino] -6- (2-methoxycarbonylamino-3,3-diphenylpropionylamino) hexyl ester (2S, 2S) -2-amino-3-methylbutyric acid (PL-530)

Step A. Preparation of 6-tert-butoxycarbonylamino-2 - [(4-tert-butoxycarbonylaminobenzenesulfonyl) isobutylamino] hexyl ester (2S) -2-benzyloxycarbonylamino-3-methylbutyric acid ( XIV , R _1A = (CH ₃ ) ₂ CHCH (NH ₂ ) -)

The title compound was prepared from (1S) - {4 - [(5-tert-butoxycarbonylamino-1-hydroxymethylpentyl) isobutylsulfamoyl] phenyl} carbamic acid tert-butyl ester (intermediate ( VII ) from Example 1, step D), as described in example 15, step A using (2S) -2-benzyloxycarbonylamino-3-methylbutyric acid. The crude product was purified by flash chromatography, eluting with hexane / ethyl acetate (1/1). The resulting yield is 100% (150 mg).

LC-MS: 777.3 (M + H) ⁺ , 95% pure.

¹ H NMR (acetone-d ₆ ): δ 0.80-1.00 (m, 14), 1.13-1.28 (s, 2H), 1.30-1.44 (s, 11H), 1.45-1.56 (s, 10), 1.58-1.67 (m, 1H), 2.87-3.04 (m, 4H), 3.84-3.97 (m, 1H) ), 3.97-4.12 (m, 2H), 4.12-4.21 (m, 1H), 4.99-5.14 (m, 2H), 5.78-5.89 (m , 1H), 6.38-6.52 (m, 1H), 7.24-7.34 (m, 1H), 7.34-7.41 (m, 2H), 7.65-7.83 (m, 4H), 8.77-8.86 (m, 1H).

Step B. Preparation of 6-amino-2 - [(4-aminobenzenesulfonyl) isobutylamino] hexyl ester of (2S) benzyloxycarbonylamino-3-methylbutyric acid ( XV , R _1A = (CH ₃ ) ₂ CHCH (NH ₂ ) -)

This derivative is prepared from 6-tert-butoxycarbonylamino-2 - [(4-tert-butoxycarbonylaminobenzenesulfonyl) isobutylamino] hexyl ester (2S) -2-benzyloxycarbonylamino-3-methylbutyric acid (the product from Step A) as described in Example 15, step B. The final compound is obtained in quantitative yield (110 mg) and used in the next step without purification.

LC-MS: 577.3 (M + H) ⁺ , 90% pure.

Step C. Preparation of 2 - [(4-aminobenzenesulfonyl) isobutylamino] -6- (2-methoxycarbonylamino-3,3-diphenylpropionylamino) hexyl ester (2S, 2S) -2-benzyloxycarbonylamino-3-methylbutyric acid

The title compound was prepared from 6-amino-2 - [(4-aminobenzenesulfonyl) isobutylamino] hexyl ester of (2S) -benzyloxycarbonylamino-3-methylbutyric acid (product from step B) as described in Example 15, step C. Transparent oily the substance is obtained in 86% yield (120 mg).

LC-MS: 858.3 (M + H) ⁺ , 95% pure.

Step D. Preparation of 2 - [(4-aminobenzenesulfonyl) isobutylamino] -6- (2-methoxycarbonylamino-3,3-diphenylpropionylamino) hexyl ester (2S, 2S) -2-amino-3-methylbutyric acid (PL-530)

To a stirred solution of 2 - [(4-aminobenzenesulfonyl) isobutylamino] -6- (2-methoxycarbonylamino-3,3-diphenylpropionylamino) hexyl ester (2S, 2S) -2-benzyloxycarbonylamino-3-methylbutyric acid (step C, 120 mg, 0.14 mmol) in anhydrous THF (8 ml) in a nitrogen atmosphere add palladium 10% wt. on activated carbon (160 mg). The mixture is reacted in an atmosphere of hydrogen overnight at room temperature. The solution was filtered and the palladium-carbon was washed with THF (50 mg). The solvent was evaporated and the residue (110 mg) was purified by flash chromatography using ethyl acetate as an eluent. A clear oily substance is obtained with a yield of 47% (47 mg).

LC-MS: 796.4 (M + H) ⁺ , 95% pure.

¹ H NMR (acetone-d ₆ ): 0.84-0.97 (m, 12H), 0.97-1.08 (m, 2H), 1.27-1.43 (m, 3H), 1 49-1.62 (m, 4H), 1.80-1.93 (m, 1H), 1.94-2.00 (m, 1H), 2.36-2.46 (m, 1H) 2.58-2.74 (m, 2H), 2.86-2.96 (m, 3H), 2.99-3.10 (m, 2H), 3.46-3.52 (s, 3H), 3.52-3.60 (m, 2H), 3.75-3.87 (m, 2H), 3.95-4.04 (m, 1H), 4.10-4.18 ( m, 1H), 4.37-4.44 (m, 1H), 4.89-4.97 (m, 1H), 5.40-5.48 (m, 1H), 6.30-6, 40 (m, 1H), 6.76-6.83 (d, J = 8.2, 1H), 6.87-7.03 (m, 2H), 7.14-7.22 (m, 1H ), 7.23-7.34 (m, 3H), 7.35-7.45 (m, 4H), 7.50-7.56 (m, 1H), 7.57-7.65 (m , 1H).

The bioavailability of compounds

In order to evaluate the degree of in vivo removal of the phosphate group from the intended compounds, compounds PL-100, PL-462 (based on PL-100), PL-337 and PL-515 (based on PL-337) are orally administered (50 mg / kg) male Sprague-Dawley rats and their plasma concentrations are measured at various time intervals after administration.

PL-100 is an active ingredient (protease inhibitor) of the following formula:

PL-337 is an active ingredient (protease inhibitor) of the following formula:

This active ingredient has been shown to be effective against HIV-1 aspartyl protease (US Pat. No. 6,632,816). The active ingredients also show effective antiviral activity when tested on a non-mutant HIV-1 virus strain (NL4.3 as wild-type virus), as well as on several mutant strains.

All test products (PL-100, PL-462, PL-337 and PL-515) are prepared in various solvents with a final concentration of 25 mg / ml. The solvent composition is as follows: (1) 20% ethanol, 50% propylene glycol, 0.05% w / v. Tween 20 and water (Mixture); (2) phosphate buffered saline (PBS).

Test products are administered to male Sprague-Dawley rats at a single oral dose of 50 mg / kg. Each product is tested for three rats. Blood samples (0.2-0.3 ml) are collected 10, 20, 40, 60, 120, 180 and 360 minutes after the dose. The collected blood is centrifuged to isolate the plasma. The resulting plasma is separated and stored at -70 ° C.

Plasma samples, together with standards and quality control samples, are processed to precipitate the proteins, then HPLC-MS is analyzed for the presence of PL-462, PL-100, PL-515 and PL-337.

Table 1 Compound PL-462
(Note No. 2) PL-100
(Note No. 1-F) PL-515
(Note No. 13) PL-337
(Note No. 13-A) Solvent Pbs Mixture Pbs Mixture Number of rats 3 3 3 3 Dose (mg / kg) 50 orally 50 orally 50 orally 50 orally AUC (mg / h * ml) 0.816 ± 0.295
(PL-100 detected) 0.675 ± 0.171 1,075 ± 0,625
(PL-337, detected) 1,180 ± 0,196 C _max (nM) 330 ± 109 498 ± 203 545 ± 215 681 ± 131 T _max (min) 93 ± 60 40 ± 16 87 ± 60 60 ± 15 50 mg / kg PL-462 = 43 mg / kg PL-100
50 mg / kg PL-515 = 43 mg / kg PL-337

The results demonstrate that compounds PL-462 and PL-515 can be delivered orally in aqueous solutions. None of the compounds PL-462 and PL-515, delivered in the form of an aqueous solution, are detected in blood samples, which indicates a rapid metabolism of the starting drugs in PL-100 and PL-337.

It was found that aqueous dosages of PL-462 and PL-515 solutions slightly exceed the delivery of PL-100 and PL-337 compared to non-aqueous formulations of PL-100 and PL-337.

Based on these results, all phosphorylated compounds described in the present invention will exhibit similar pharmacokinetic properties.

Distribution coefficients (LogP) of selected compounds and corresponding HIV protease inhibitors (drugs) are as follows:

table 2 Connections Logp Appropriate medicines Logp PL-461 (or PL-462) -1.2 PL-100 3.6 PL-515 0.72 PL-337 3.8

LogP is measured standardly by dissolving 1 mg of the compound in 0.8 ml of octanol or phosphate buffer pH 7.4 (0.04 M KHPO ₄ ). The concentration of compounds in the phases is determined by LC-MS. This test demonstrates the solubility of the compounds at physiological pH. The resulting LogPs show that the compounds are readily soluble in comparison with the corresponding drugs.

The compounds listed in table 3 are prepared according to the following schemes 1, 1A, 2, 3, 4, or 5; and more specifically, as described in each example listed above. The numbers of the compounds listed in table 3 (Note No.) correspond to the numbers of the examples presented above.

Table 3

Structures of lysine-based compounds of the present invention

Claims (15)

1. The compound of formula I

or a pharmaceutically acceptable salt thereof,
where n is 3 or 4,
where X and Y, identical or different, are selected from the group consisting of H, F, Cl, Br, I and —NR ₄ R ₅ ,
where R ₆ selected from the group consisting of an unbranched alkyl group containing from 1 to 6 carbon atoms, and a branched alkyl group containing from 3 to 6 carbon atoms,
where R ₃ selected from the group consisting of a group of the formula R _3A -CO-, and R _3A selected from the group consisting of a straight or branched alkyl group containing from 1 to 6 carbon atoms, alkyloxy group containing from 1 to 6 carbon atoms, and 4-morpholinyl,
where R ₄ and R ₅ are the same, represent H,
where R ₂ selected from the group consisting of diphenylmethyl group of formula IV

naphthyl-1-CH ₂ groups of formula V

and naphthyl-2-CH ₂ groups of formula VI

where X 'and Y' are the same, represent H,
and where R _{1 is} selected from the group consisting of (HO) ₂ P (O) and (MO) ₂ P (O), where M is an alkali metal. 2. The compound according to claim 1, which is a compound of formula II,

or a pharmaceutically acceptable salt thereof,
where the values of R ₁ , R ₂ , R ₃ , R ₆ , n, X and Y are defined in claim 1. 3. The compound of claim 2, wherein R ₆ is isobutyl and n is 4. 4. The compound according to claim 3, where R ₁ represents (HO) ₂ P (O) or (NaO) ₂ P (O). 5. The compound according to claim 4, where R ₃ selected from the group consisting of CH ₃ CO, CH ₃ O-CO and 4-morpholine-CO. 6. The compound according to claim 5, where X represents 4-NH ₂ , a Y represents H or F. 7. The compound according to claim 6, where R _{2 is} selected from the group consisting of a diphenylmethyl group of formula IV, naphthyl-1-CH ₂ is a group of formula V and naphthyl-2-CH ₂ is a group of formula VI. 8. The compound according to claim 2, which is a compound of formula IIa

or a pharmaceutically acceptable salt thereof,
where the values of R ₁ , R ₃ , R ₆ , n, X, Y, X 'and Y' are defined in claim 1. 9. The compound of claim 8, where R ₆ is isobutyl; n is 4; R ₁ represents (HO) ₂ P (O) or (NaO) ₂ P (O); R ₃ selected from the group consisting of CH ₃ CO, CH ₃ O-CO and 4-morpholine-CO; X represents NH ₂ and Y represents H or F. 10. The compound according to claim 1, which is selected from the group consisting of the following compounds and salts:

Example X Y n R ₁ R ₂ R ₃ R ₆ X '/ D, L, No. (PL- #) Y ' DL R, S, RS 1 (PL-461) 4-NH ₂ H four (BUT) ₂ P (O) (C ₆ H ₅ ) ₂ CH CH ₃ O-CO Isobutyl N / A S 2 (PL-462) 4-NH ₂ H four (NaO) ₂ P (O) (C ₆ H ₅ ) ₂ CH CH ₃ O-CO Isobutyl N / A S 3 (PL-507) 4-NH ₂ H four (BUT) ₂ P (O) Naphthyl-2-CH ₂ CH ₃ O-CO Isobutyl N / A S 4-morpholine CO - 4 (PL-498) 4-NH ₂ H four (BUT) ₂ P (O) Naphthyl-2-CH ₂ Isobutyl N / A S 5 (PL-504) 4-NH ₂ H four (HO) ₂ P (o) (C ₆ H ₅ ) ₂ CH CH ₃ CO Isobutyl N / A S 6 (PL-515) 4-NH ₂ 3-f four (BUT) ₂ P (O) (C ₆ H ₅ ) ₂ CH CH ₃ O-CO Isobutyl N / A S 11. The compound of claim 10, which is the sodium salt of methyl ester (1S, 5S) - (1- {5 - [(4-aminobenzenesulfonyl) isobutylamino] -6-phosphonoxyhexacarbamoyl} -2,2-diphenylethyl) carbamic acid. 12. The compound of claim 10, which is a methyl ester of (1S, 5S) - (1- {5 - [(4-amino-3-fluorobenzenesulfonyl) isobutylamino] -6-phosphonoxyhexacarbamoyl} -2,2-diphenylethyl) carbamic acids. 13. A pharmaceutical composition having an aspartyl protease inhibitory activity against HIV, comprising at least one compound as defined in any one of claims 1-12, in a pharmaceutically effective amount or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 14. Compounds as defined in any one of claims 1-12, or a pharmaceutically acceptable salt thereof, which are effective aspartyl protease inhibitors. 15. A method of treating or preventing HIV infection, comprising administering at least one compound as defined in any one of claims 1-12, or a pharmaceutically acceptable salt thereof, to a mammal in need thereof.