KR20060105426A - Antiviral phosphonate analogs - Google Patents

Abstract

The invention is related to phosphorus substituted compounds with antiviral activity, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.

Description

Antiviral phosphonate analogs {ANTIVIRAL PHOSPHONATE ANALOGS}

[Priority of this invention]

This application claims 35 U.S.C. In accordance with § 119 (e), we claim priority to U.S. Provisional Patent Application No. 60/519476, filed on November 12, 2003. The foregoing provisional application is incorporated herein by reference.

The present invention relates generally to compounds containing phosphonates with antiviral activity.

 There has been considerable focus over the years on research to improve the delivery of drugs and other drugs to cells and tissues. Despite many efforts to develop effective methods for introducing biologically active molecules into cells in vivo and in vitro, none have been found to be entirely satisfactory. For example, optimizing the association between inhibitors and their intracellular targets while minimizing drug redistribution between cells to adjacent cells has been very difficult and insufficient.

Most drugs currently parenterally administered to a patient are untargeted and therefore deliver drugs to the cells and tissues of the patient which are either unnecessary or sometimes undesirable. This results in drug side effects, sometimes limiting the dosage of administrable drugs (eg, glucocorticoids and other anti-inflammatory agents). In contrast, although oral administration of drugs is generally recognized as a convenient and economical method of administration, such oral administration may involve (a) cell and tissue barriers resulting in undesirable systemic distribution, such as blood / brain, epithelium. Or the absorption of the drug through cell membranes or the like, or (b) the temporary retention of the drug in the gastrointestinal tract. Therefore, specific targeting of drugs to cells and tissues has been a major challenge. Benefits of such targeting treatment include avoiding the general physiological effects resulting from inappropriate delivery of such agents to other cells and tissues, such as uninfected cells.

Therefore, there was a need for antiviral therapies with improved pharmaceutical properties, such as drugs with improved antiviral activity and pharmacokinetic properties, including improved oral bioavailability, better potential and extended effective in vivo half-life. .

New antiviral compounds should have fewer side effects, less annoying doses, and oral activity. In particular, there has been a need for less annoying dosage regimens, such as, for example, one tablet per day.

Analytical methods that can determine the presence, absence or amount of virus inhibition are practical methods for diagnosing the presence of abnormal symptoms related to infection as well as antiviral screening.

Summary of the invention

Intracellular targeting is achieved by methods and compositions that allow for the accumulation or retention of biologically active agents in cells. The present invention provides phosphonate analogs of the novel antiviral compounds. These compounds contain all the functions of the parent compound and additionally provide for intracellular accumulation as described below.

 In one aspect, the compounds of the present invention can inhibit viral RNA polymerase. For example, hepatitis B, hepatitis C, polio, Coxsackie A and B, Rhino, Echo, small pox, Ebola, and West Nile (West Nile) virus polymerase and the like, but is not limited thereto. The compounds of the present invention can inhibit retroviral RNA dependent RNA polymerase or reverse transcriptase and thus inhibit the replication of the virus. The compounds of the present invention may be useful for the treatment of patients infected with human retroviruses such as hepatitis C and the like. The present invention generally relates to the accumulation or retention of therapeutic compounds in cells. In particular, the present invention relates to maintaining high concentrations of active metabolite molecules in viral infected cells (eg, cells infected with HCV or HIV). Such effective targeting can be applied to a variety of therapeutic formulations and procedures.

Accordingly, in one embodiment of the present invention, there is provided a conjugate comprising an antiviral compound linked to at least one phosphonate group; Or pharmaceutically acceptable salts or solvates thereof.

In another embodiment, the present invention provides a complex of one of Formula 1-108 :

here:

A ⁰ is A ¹ ;

A ¹ is:

이고;

ego;

A ³ is:

이며;

Is;

Y ¹ is independently O, S, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ) or N (N (R ^x ) (R ^x ) )ego;

Y ² is independently one bond, O, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ), N (N (R ^x ) (R ^x )), -S (O) _M2- , or -S (O) _M2 -S (O) _M2- ; Y ² is C (R ² ) (R ² ) if Y ² is bonded to two phosphorus atoms;

R ^x is independently H, R ² , W ³ , a protecting group or formula:

이며;

Is;

R ^y is independently H, W ³ , R ² or a protecting group;

R ¹ is independently H or alkyl having 1 to 18 carbon atoms;

R ² is independently H, R ³ or R ⁴ , wherein each R ⁴ is independently substituted with 0-3 R ³ groups;

R ³ is R ^3a , R ^3b , R ^3c or R ^3d , and if R ³ binds to a heteroatom, R ³ becomes R ^3c or R ^3d ;

R ^3a is F, Cl, Br, I, -CN, N ₃ or -NO ₂ ;

R ^3b is Y ¹ ;

R ^3c is -R ^x , -N (R ^x ) (R ^x ), -SR ^x , -S (O) R ^x , -S (O) ₂ R ^x , -S (O) (OR ^x ),- S (O) ₂ (OR ^x ), -OC (Y ¹ ) R ^x , -OC (Y ¹ ) OR ^x , -OC (Y ¹ ) (N (R ^x ) (R ^x )), -SC (Y ¹ ) R ^x , -SC (Y ¹ ) OR ^x , -SC (Y ¹ ) (N (R ^x ) (R ^x )), -N (R ^x ) C (Y ¹ ) R ^x , -N (R ^x ) C (Y ¹ ) OR ^x or -N (R ^x ) C (Y ¹ ) (N (R ^x ) (R ^x ));

R ^3d is —C (Y ¹ ) R ^x , —C (Y ¹ ) OR ^x or —C (Y ¹ ) (N (R ^x ) (R ^x ));

R ⁴ is alkyl having 1 to 18 carbon atoms, alkenyl having 2 to 18 carbon atoms, or alkynyl having 2 to 18 carbon atoms;

R ⁵ is R ⁴ , wherein each R ⁴ is substituted with 0-3 R ³ groups;

R ^5a is independently an alkylene having 1 to 18 carbon atoms, an alkenylene having 2 to 18 carbon atoms, or one of alkynylene, alkylene, alkenylene or alkynylene having 2 to 18 carbon atoms is 0 to 3 R ³ Substituted with a group;

W ³ is W ⁴ or W ⁵ ;

W ⁴ is R ⁵ , -C (Y ¹ ) R ⁵ , -C (Y ¹ ) W ⁵ , -SO ₂ R ⁵ or -SO ₂ W ⁵ ;

W ⁵ is carbocycle or heterocycle, wherein W ⁵ is independently substituted with 0 to 3 R ² groups;

W ⁶ is independently W ³ substituted with 1, 2, or 3 A ³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M 12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

Mla, Mlc, and Mld are independently 0 or 1;

M 12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

X ⁵¹ is H, a-Br, or b-Br;

X ⁵² is a C ₁ -C ₆ alkyl or C ₇ -C ₁₀ arylalkyl group;

X ⁵³ is H, alkyl or substituted alkyl;

X ⁵⁴ is CH or N;

X ⁵⁵ is thymine, adenine, uracil, 5-halouracil, 5-alkyluracil, guanine, cytosine, 5-halocytosine, 5-alkyl cytosine, or 2,6-diaminopurine;

X ⁵⁶ is H, Me, Et, or i- Pr;

X ⁵⁷ is H or F;

X ⁵⁸ is OH, Cl, NH ₂ , H, Me, or MeO;

X ⁵⁹ is H or NH ₂ ;

X ⁶⁰ is OH, Cl, NH ₂ , or H;

X ⁶¹ is H, NH ₂ , or NH-alkyl;

X ⁶² and X ⁶³ are independently H, alkyl, or cyclopropyl;

X ⁶⁴ is H, N ₃ , NH ₂ , or NHAc;

X ⁶⁵ is halo;

X ⁶⁶ is alkoxy, aryloxy, halo-substituted alkoxy, alkenyloxy, arylalkoxy;

X ⁶⁷ is O or NH;

X ⁶⁸ is H, acetate, benzyl, benzyloxycarbonyl, or an amino protecting group;

X ⁶⁹ is H or alkyl;

X ⁷⁰ is H; Alkyl; Optionally, alkyl substituted with cyclic alkyl having 3 to about 6 carbon atoms substituted with one or more alkyl; Alkenyl; Optionally, alkenyl substituted with cyclic alkyl having 3 to about 6 carbon atoms substituted with one or more alkyl; Hydroxyl-substituted alkyl; Alkoxy-substituted alkyl; Acyloxy-substituted alkyl; Aryl; Substituted aryl; Arylalkyl; Or (substituted aryl) alkyl;

X ⁷¹ and X ⁷² are each independently hydrogen, alkyl, phenyl, or substituted phenyl;

X ⁷³ is alkoxy, substituted alkyl, alkylamido amino, monoalkylamino, dialkylamino, azido, chloro, hydroxy, 1-morpholino, 1-pyrrolidino, and alkylthio;

X ⁷⁴ is aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

X ⁷⁵ and X ⁷⁶ bind to nitrogen or carbon in X ⁷⁴ . Wherein X ⁷⁵ is H, halo, nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, (fluoro-substituted) C ₁ -C ₆ alkyl, (fluoro-substituted) C ₁ -C ₆ alkoxy , C ₂ -C ₈ alkoxyalkyl, (fluoro-substituted) C ₂ -C ₈ alkoxyalkyl, N (R ^a ) (R ^b ), (CH ₂ ) _1-3 N (R ^a ) (R ^b ), (CH ₂ ) _0-3 R ^c , or O (CH ₂ ) _0-3 R ^c ; And X ⁷⁶ is H, halo, nitro, C _{1 - 6} alkyl, C _{1 - 6} alkoxy, (fluoro-substituted) C ₁ (fluoro-substituted) _-6-alkyl, C _1-6 alkoxy, C _{2 - 8} (fluoro-substituted) alkoxy alkyl, C _{2 - 8} ^{alkoxy-alkyl, N (R a) (R} b), (CH 2) 1-3 N (R a) (R b), (CH 2) 0-3 R ^c , O (CH ₂ ) _0-3 R ^c , (CH ₂ ) _0-3 R ^d , O (CH ₂ ) _0-3 R ^d , C (= O) CH ₂ C (= O) R ^e , Or R ^f ; R ^a and R ^b are each independently H, C ₁ -C ₆ alkyl, or (fluoro-substituted) C ₁ -C ₆ alkyl; R ^c is aryl, or substituted aryl; R ^d is heterocycle, or substituted heterocycle; R ^e is heteroaryl or substituted heteroaryl; R ^f is X ¹²⁰ -NH (CH ₂ ) _1-3 X ¹²¹ , wherein X ¹²⁰ is a 5- or 6-membered monocyclic heterocycle, which can be saturated or unsaturated, and has from 1 to 3 carbon atoms May contain nitrogen atoms, halo, cyano, OH, (CH ₂ ) _1-4 OH, oxo, N (R ^a ) (R ^b ), C ₁ -C ₆ alkyl, fluorinated C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkoxy, fluorinated C ₁ -C ₆ alkoxy, (CH ₂ ) _0-4 CO ₂ R ^a , (CH ₂ ) _0-4 C (= 0) N (R ^a ) (R ^b ), (CH ₂ ) _0-4 SO ₂ R ^a , (CH ₂ ) _1-4 N (R ^a ) (R ^b ), (CH ₂ ) _0-4 N (R ^a ) C (= O) R ^b , (CH ₂ ) _0-4 SO ₂ N (R ^a ) (R ^b ), (CH ₂ ) _1-4 N (R ^a ) SO ₂ R ^b , C ₂ -C ₈ alkoxyalkyl, and (fluoro- Substituted or unsubstituted with one or more substituents selected from C ₂ -C ₈ alkoxyalkyl; X ¹²¹ is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, which are halo, cyano, OH, (CH ₂ ) _1-4 OH, oxo, N (R ^a ) (R ^b ), C ₁ -C ₆ alkyl, fluorinated C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, fluorinated C ₁ -C ₆ alkoxy, (CH ₂ ) _0-4 CO ₂ R ^a , (CH ₂ ) _{0- 4} C (= 0) N (R ^a ) (R ^b ), (CH ₂ ) _0-4 SO ₂ R ^a , (CH ₂ ) _1-4 N (R ^a ) (R ^b ), (CH ₂ ) _{0 -4} N (R ^a ) C (= O) R ^b , (CH ₂ ) _0-4 SO ₂ N (R ^a ) (R ^b ), (CH ₂ ) _1-4 N (R ^a ) SO ₂ R ^b Or may be unsubstituted from one or more substituents selected from C ₂ -C ₈ alkoxyalkyl, and (fluoro-substituted) C ₂ -C ₈ alkoxyalkyl;

X ⁷⁷ is H or C _{1 -6} alkyl;

X ⁷⁸ is OH, protected hydroxyl, or N (R ^a ) (R ^b );

X ⁷⁹ is bonded to nitrogen or carbon in X ⁷⁴ ; X ⁷⁹ is H, halo, nitro, oxo, C _1-6 alkyl, C _{3 - 7} cyclic alkyl, C _{3 - 7} cyclic alkyl, C _{1 - 6} alkoxy, (fluoro-substituted) C _{1 -6} alkyl , (fluoro-substituted) C _{1 -6} alkoxy, C ₂ (fluoro-substituted) _-8 alkoxyalkyl, C _{2 -8} alkoxyalkyl, N (R ^a) (R ^b), (CH _{2) 1-4} N (R ^a ) (R ^b ), C (= 0) N (R ^a ) (R ^b ), (CH ₂ ) _1-4 C (= 0) N (R ^a ) (R ^b ), N (R ^a ) C (= 0) R ^b , (CH ₂ ) _1-4 N (R ^a ) C (= 0) R ^b , SO ₂ R ^a (CH ₂ ) _1-4 SO ₂ R ^a , SO ₂ N (R ^a ) (R ^b ), (CH ₂ ) _1-4 SO ₂ N (R ^a ) (R ^b ), (CH ₂ ) _1-4 N (R ^a ) SO ₂ R ^b , (CH ₂ ) _0-3 R ^c , or (CH ₂ ) _0-3 R ^g ;

R ^g is a 5- or 6-membered monocyclic heterocycle, which may be saturated or unsaturated and contain one or more carbon atoms and 1 to 4 nitrogen atoms. The heterocycle is halo, cyano, OH, (CH ₂ ) _1-4 OH, oxo, N (R ^a ) (R ^b ), C ₁ -C ₆ alkyl, (fluoro-substituted) C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkoxy, (fluoro-substituted) C ₁ -C ₆ Alkoxy, (CH ₂ ) _0-4 CO ₂ R ^a , (CH ₂ ) _0-4 C (= 0) N (R ^a ) (R ^b ), (CH ₂ ) _0-4 SO ₂ R ^a , (CH ₂ ) _1-4 N (R ^a ) (R ^b ), (CH ₂ ) _0-4 N (R ^a ) C (= O) R ^b , (CH ₂ ) _0-4 SO ₂ N (R ^a ) ( At least one selected from R ^b ), (CH ₂ ) _1-4 N (R ^a ) SO ₂ R ^b , C ₂ -C ₈ alkoxyalkyl, (fluoro-substituted) C ₂ -C ₈ alkoxyalkyl, phenyl and benzyl May or may not be substituted with a substituent;

X ⁸⁰ is (i) a 5- or 6-membered heteroaromatic ring containing 1 to 4 nitrogen atoms, 0 to 2 sulfur atoms, and at least one carbon atom or (ii) 1 to 4 nitrogen atoms, 0 8- to 10-membered conjugated bicyclic heterocycle containing 2 to 2 sulfur atoms and carbon atoms. Wherein the heterocycle ring bonded to the central dione moiety is a 5- or 6-membered heteroaromatic ring containing at least one nitrogen or sulfur atom, and the other ring of the heterocycle is a saturated or unsaturated ring; Wherein X ⁸⁰ is bonded to the central propenone moiety through a carbon atom and X ⁸⁰ At least one nitrogen or sulfur atom in the neighborhood is adjacent to the bond site;

X ⁸¹ is X ⁸⁰ And in is bound to a nitrogen or carbon, which is, independently, H, _{halo, OH, (CH 2) 1-4} OH, C 1 -C 6 alkyl, C ₁ -C ₆ alkoxy, (fluoro-substituted) C ₁ -C ₆ alkyl, (fluoro-substituted) C ₁ -C ₆ alkoxy, C ₁ -C ₈ alkoxyalkyl, (fluoro-substituted) C ₁ -C ₈ alkoxyalkyl, N (R ^a ) (R ^b ), (CH ₂ ) _1-4 N (R ^a ) (R ^b ), C (= 0) N (R ^a ) (R ^b ), (CH ₂ ) _1-4 C (= 0) N (R ^a ) ( R ^b ), N (R ^a ) C (= O) R ^b , (CH ₂ ) _1-4 N (R ^a ) C (= O) R ^b , SO ₂ R ^a , (CH ₂ ) _1-4 SO ₂ R ^a , SO ₂ N (R ^a ) (R ^b ), (CH ₂ ) _1-4 SO ₂ N (R ^a ) (R ^b ), (CH ₂ ) _1-4 N (R ^a ) SO ₂ R ^b, and it is selected from ^{_{(CH 2) 0 -3 R b}} ;

X ⁸² is OH, F, or cyano;

X ⁸³ is N or CH;

X ⁸⁴ is C is H or trans H;

X ⁸⁵ is C ₈ -C ₁₆ alkyl which may contain from 1 to 5 oxygen atoms in the chain, if necessary;

X ⁸⁶ is H, methyl, hydroxymethyl, or fluoromethyl;

X ⁸⁷ and X ⁸⁸ are each independently H or substituted C _{1 -4} alkyl, wherein alkyl is as required, OH, amino, C _{1 -4} alkoxy, C _{1 -4} alkylthio, or one to three halogen atoms Become;

X ⁸⁹ is -O- or -S (O) n-, wherein n is 0, 1, or 2;

X ⁹⁰ is H, methyl, hydroxymethyl, or fluoromethyl;

X ⁹¹ is H hydroxy, alkyl, azido, cyano, alkenyl, alkynyl, bromovinyl, -C (O) O (alkyl), -O (acyl), alkoxy, alkenyloxy, chloro, bro Parent, fluoro, iodo, NO ₂ , NH ₂ , -NH (lower alkyl), -NH (acyl), -N (lower alkyl) ₂ , -N (acyl) ₂ ;

X ⁹² is H, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, or, as needed, amino, hydroxy or from one to three fluorine atoms and optionally substituted C _{1 -4} alkyl;

X ⁹³ and X ⁹⁴ One is hydroxy or C _{1 -4} alkoxy, the other of X ⁹³ and X ⁹⁴ is H; Hydroxy; Halo; C1-4 alkyl substituted with 1 to 3 fluorine atoms; If necessary, C _{1 -3} alkoxy, or one to three fluorine atoms substituted C _{1 -10} alkoxy; C _{2 -6} alkenyloxy; C _{1 - 4} alkylthio; C _1-8 alkylcarbonyloxy; Aryloxycarbonyl; Azido; Amino; C _{1 -4} alkyl amino; And di (C _1-4 alkyl) amino; or

X ⁹³ is H, C _{2 -4} alkenyl, C _{2 -4} alkenyl or necessary depending on the carbonyl, amino, hydroxy or from one to three fluorine atoms substituted C _{1 -4} alkyl and X ⁹² X ⁹⁴ One is hydroxy or C _{1 - 4} alkoxy and the other of X ⁹² and X ⁹⁴ is H; Hydroxy; Halo; C1-4 alkyl substituted with 1 to 3 fluorine atoms; If necessary, C _{1 -3} alkoxy, or one to three fluorine atoms substituted C _{1 -10} alkoxy; C _{2 -6} alkenyloxy; C _{1 - 4} alkylthio; C _{1 -8-alkyl-carbonyl-oxy;} Aryloxycarbonyl; Azido; Amino; C _{1 -4} alkyl amino; And di (C _1-4 alkyl) amino; or

X ⁹² and X ⁹³ are taken together with the carbon atoms to which they are attached, form a, O, S, and NC _{0 -4} 3- to 6-membered saturated monocyclic type containing heteroatoms selected from alkyl ring system, as needed ;

X ⁹⁵ is H, OH, SH, NH _2, C _{1 -4} alkylamino, di (C _1-4 alkyl) amino, C _{3 - 6} alkyl, cyclic amino, halo, C _{1 - 4} alkyl, C _{1 -4} Alkoxy, or CF ₃ ; Or X ⁹² and X ⁹⁵ may be a bond linked to the two carbons to which they are bonded, if necessary;

X ⁹⁶ is H, methyl, hydroxymethyl, or fluoromethyl;

X ⁹⁷ is

Is selected from the group consisting of;

U, G, and J are each independently CH or N;

D is N, CH, C-CN, C-NO 2, CC 1 -3 _{alkyl, C-NHCONH 2, C-} CONT 11 T 11, C-CSN T 11 T 11, C-COOT 11, CC (= NH ) NH _2, C- hydroxy, CC _{1 -3} alkoxy, C- amino, CC _{1 -4} alkylamino, di-C- (C _l-4 alkyl) amino, C- halogen, C- (1,3- oxazol Zol-2-yl), C- (1,3 thiazol-2-yl), or C- (imidazol-2-yl); Wherein alkyl is independently selected from halogen, amino, hydroxy, carboxy, and C _{1 -3} is not substituted or substituted from 1 to 3 selected from alkoxy groups;

E is N or CT ₅ ;

W ^a is O or S;

T ₁ is H, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, or, as needed, amino, hydroxy, or one to three fluorine atoms substituted with C _{1 -} and _4-alkyl, one of T ₂ and T ₃ is hydroxy or C _{1 -4} alkoxy and the other of T ₂ and T ₃ are H; Hydroxy; Halo; C1-4 alkyl substituted with 1 to 3 fluorine atoms; C1-10 alkoxy or C1-10 alkoxy substituted with 1 to 3 fluorine atoms; C _{2 -6} alkenyloxy; C _1-4 alkylthio; C _{1 -8-alkyl-carbonyl-oxy;} Aryloxycarbonyl; Azido; Amino; C _{1 -4} alkyl amino; And di (C _1-4 alkyl) amino;

T ₂ is H, C _{2 - 4} alkenyl, C _{2 - 4} alkynyl, or, as needed, amino, hydroxy, or 1 to 3 fluorine-substituted C1-4 alkyl, and one T ₁ and T ₃ is hydroxy or C _{1 - 4} alkoxy and the other of T ₁ and T ₃ is H; Hydroxy; Halo; C1-4 alkyl substituted with 1 to 3 fluorine atoms; C1-10 alkoxy or C1-10 alkoxy substituted with 1 to 3 fluorine atoms; C _{2 -6} alkenyloxy; C _1-4 alkylthio; C _{1 -8-alkyl-carbonyl-oxy;} Aryloxycarbonyl; Azido; Amino; C _{1 -4} alkyl amino; And di (C _1-4 alkyl) amino; or

T ₁ and T ₂ are taken together with the carbon atoms to which they are attached, form a, O, S, and NC _{0 -4} 3- to 6-membered saturated monocyclic type containing heteroatoms selected from alkyl ring system, as needed ;

T ₄ and T ₆ are each independently H, OH, SH, NH _2, C _{1 -4} alkylamino, di (C _{1 -4} alkyl) amino, C _{3 -6} cyclic alkyl amino, halo, C _{1 -4} alkyl, C _{1 -4} alkoxy, or CF ₃ and;

T ₅ is H, C _{1 - 6} alkyl, C _{2 - 6} alkenyl, C _{2 - 6} alkynyl, C _{1 - 4} alkylamino, CF _3, or halogen; T ₁₄ is H, CF _3, C _{1 -4} alkyl, amino, C ₁₄ alkylamino, C _{3 - 6} cyclic alkylamino or di (C _1-4 alkyl) amino;

T ₇ is H, amino, C _{1 - 4} alkylamino, C _{3 -6} cyclic alkyl amino, or di (C _1-4 alkyl) amino and;

Each of T ₁₁ are independently H or C _{1 -6} alkyl;

T ₈ is H, halo, CN, carboxy, C _{1 -4} alkyloxycarbonyl, N _3, amino, C _{1 -4} alkylamino, di (C _{1 -4} alkyl) amino, hydroxy, C _{1 -6} alkoxy , C _{1 -6} alkylthio, C _{1 -6} alkyl sulfonyl, or (C _1-4 alkyl) _0-2 amino-methyl;

X ⁹⁸ is methoxy, ethoxy, vinyl, ethyl, methyl, cyclopropyl, N -methylamino, or N -formylamino;

X ⁹⁹ is methyl, chloro, or trifluoromethyl;

X ¹⁰⁰ is H, methyl, ethyl, cyclopropyl, vinyl, or trifluoromethyl;

X ¹⁰¹ is H, methyl, ethyl, cyclopropyl, chloro, vinyl, allyl, 3-methyl-1-buten-yl;

X ¹⁰² is thymine, adenine, guanine, cytosine, uracil, inosine or diaminopurine;

X ¹⁰³ is OH, OR, NR ₂ , CN, NO ₂ , F, Cl, Br, or I;

X ¹⁰⁴ represents adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenin, inosine, nebularin , Nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynyl Cytosine, Isocytosine, Isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine, O ⁴ -methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, or pyrazole [3,4-d] pyrimidine;

X ¹⁰⁵ is selected from O, C (R ^y ) ₂ , OC (R ^y ) ₂ , NR and S;

¹⁰⁶ X is _{^{O, C (R y) 2}} , C = C (R y) 2, is selected from NR, and S;

X ¹⁰⁷ is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenin, inosine, nebularin , Nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynyl Cytosine, Isocytosine, Isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine, O ⁴ -methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazoles, and pyrazole [3,4-D] pyrimidines;

X ¹⁰⁸ is independently selected from H, OH, OR, NR ₂ , CN, NO ₂ , SH, SR, F, Cl, Br, and I;

X ¹⁰⁹ is H, C ₁ -C ₈ alkyl, substituted C ₁ -C ₈ alkyl, C ₁ -C ₈ alkenyl, substituted C ₁ -C ₈ alkenyl, C ₁ -C ₈ alkynyl, and substituted C _1- C ₈ alkynyl;

X ¹¹⁰ is independently O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N-NR ₂ , S, SS, S (O), or S (O) ₂ ;

X ¹¹¹ is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenin, inosine, nebularin , Nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynyl Cytosine, Isocytosine, Isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine, O ⁴ -methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazoles, or pyrazole [3,4-D] pyrimidines;

X ¹¹² is independently selected from H, OH, OR, NR ₂ , CN, NO ₂ , SH, SR, F, Cl, Br and I;

X ¹¹³ is F;

X ¹¹⁴ is independently H, F, Cl, Br, I, OH, R, -C (= Y ¹ ) R, -C (= Y ¹ ) OR, -C (= Y ¹ ) N (R) ₂ , -N (R) ₂ ,- ⁺ N (R) ₃ , -SR, -S (O) R, -S (O) ₂ R, -S (O) (OR), -S (O) ₂ (OR ), -OC (= Y ¹ ) R, -OC (= Y ¹ ) OR, -OC (= Y ¹ ) (N (R) ₂ ), -SC (= Y ¹ ) R, -SC (= Y ¹ ) OR, -SC (= Y ¹ ) (N (R) ₂ ), -N (R) C (= Y ¹ ) R, -N (R) C (= Y ¹ ) OR, or -N (R) C (= Y ¹ ) N (R) ₂ , amino (-NH ₂ ), ammonium (-NH ₃ ⁺ ), alkylamino, dialkylamino, trialkylammonium, C ₁ -C ₈ alkyl, carboxy, sulfate, sulfa Mate, sulfonate, 5-7 membered ring sulfam, C ₁ -C ₈ alkylsulfonate, 4-dialkylaminopyridinium, hydroxyl-substituted C ₁ -C ₈ alkyl, C ₁ -C ₈ alkylthiol, alkylsul Ponyl, arylsulfonyl, arylsulfinyl (-SOAr), arylthio, -SO ₂ NR ₂ , -SOR, -C (= 0) OR, -C (= 0) NR ₂ , 5-7 member cyclic lactam, 5-7 member cyclic lactones, cyano, azido, nitro, C ₁ -C ₈ alkoxy, substituted C ₁ -C ₈ alkyl, C ₁ -C ₈ alkenyl, substituted C ₁ -C ₈ alkenyl, C _1- C ₈ alkynyl, substituted C ₁ -C ₈ alkynyl, aryl, substituted Aryl, heterocycle, substituted heterocycle, polyethylenoxy, protecting group, or W ³ ; Or taken together, two R ^y form a carbocyclic ring of 3 to 7 carbon atoms;

X ¹¹⁵ is independently selected from H, OH, OR, NR ₂ , CN, NO ₂ , SH, SR, F, Cl, Br, and I;

X ¹¹⁶ is H, C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, and C ₁ -C ₈ substituted alkynyl.

The present invention provides a pharmaceutical composition comprising an effective amount of the complex of the present invention or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient.

The present invention relates to a method of increasing cell accumulation and retention of antiviral compounds, including compounds linked to one or more phosphonate groups.

The invention also provides a method of inhibiting viral infection in an animal (eg, a mammal) by administering an effective amount of the complex of the invention to an animal.

The invention is also useful for the treatment of viral infections in animals (eg mammals), as well as the use of the compounds of the invention for medical treatment (preferably for the treatment of viral infections in animals). Provided are methods for preparing the drug.

The invention also provides processes useful for the preparation of the compounds of the invention and the novel intermediates disclosed herein. Some of the compounds of the present invention are useful for the preparation of the compounds of the present invention.

In another embodiment, the present invention provides a method for inhibiting viral infection in a sample comprising treating a sample suspected of containing a virus with a composition of the present invention.

Detailed Description of the Invention to Representative Claims

Reference will be made in order to detail the claims of the invention. In these examples, the structure and formula will be described together. While the invention will be described in conjunction with the enumerated claims, it should be understood that it is not intended to limit the invention to those claims. On the contrary, the invention is intended to cover all alternatives, modifiers and equivalents falling within the scope of the invention as defined by the claims.

Justice

Unless otherwise stated, the following terms and phrases used herein have the following meanings:

If a trade name is used herein, the applicant is intended to include the product of that trade name and the active pharmaceutical ingredient (s) of the product independently.

"Bioavailability" refers to the extent to which a pharmaceutical active is applicable to a target tissue after introduction into the body. Increasing the bioavailability of the pharmaceutically active agent enables more efficient and effective treatment for the patient. This is because more pharmaceutically active agents act on the target tissue site at a given dose.

 The terms " phosphonate " and " phosphonate group " refer to 1) a single bond to carbon, 2) a double bond to heteroatoms, 3) a single bond to heteroatoms, and 4) a single bond to another heteroatom. It includes a functional group or part in the molecule consisting of. Here, each heteroatom may be the same or different. The terms " phosphonate " and " phosphonate group " also refer to a functional group or moiety consisting of a phosphorus in the same oxidation state as the aforementioned phosphorus and a prodrug moiety containing a phosphorus separated from the compound and containing the above characteristics. Include the part. For example, the terms phosphonate and phosphonate groups include phosphonic acid, phosphorous acid monoesters, phosphorous acid diesters, phosphonamidates and phosphonthioic acid functional groups. In one particular embodiment of the invention, the terms "phosphonate" and "phosphonate group" are used to refer to 1) a single bond to carbon, 2) a double bond with oxygen, 3) a single bond with oxygen, and 4) another It includes a functional group or moiety in a molecule consisting of a phosphorus that single bonds with oxygen, and includes a functional group or moiety consisting of a prodrug moiety separated from a phosphorus containing compound having this characteristic. In another particular embodiment of the invention, the terms "phosphonate" and "phosphonate group" are used to refer to 1) a single bond to carbon, 2) a double bond with oxygen, 3) a single bond with oxygen or nitrogen, and 4 ) Includes a functional group or moiety in a molecule composed of phosphorus that is single-bonded with another oxygen or nitrogen, and includes a functional group or moiety consisting of a prodrug moiety that contains a phosphorus that is separated from the compound and that the compound can retain these properties do.

 As used herein, the term “prodrug drug” means a drug, when administered to the biological system as a result of spontaneous chemical reaction (s), such as enzyme catalyzed chemical reaction (s), photolysis and / or metabolic chemical reaction (s), etc. In other words, all compounds that produce the active ingredient. Prodrugs are therefore latent forms of analogs or therapeutically active compounds that have been covalently modified.

"Prodrug drug moiety" refers to an unstable functional group that is isolated from an active inhibitory compound in cells during systemic metabolism by hydrolysis, enzymatic digestion, or other reaction procedures (Bundgaard, Hans, Design and Application of Prodrugs A Textbook of Drug Design and Develpment (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191). Enzymes that enable enzymatic activation mechanisms using phosphonate prodrug compounds of the present invention include, but are not limited to, amidase, esterase, microbial enzyme, phospholipase, cholinesterase and phosphase. The prodrug moiety enhances solubility, absorption and lipophilicity to optimize drug delivery, bioavailability and efficiency. The prodrug moiety may comprise an active metabolite or the drug body thereof.

Representative prodrug moieties include acyloxymethylesters -CH ₂ OC (= 0) R ⁹ and acyloxymethylcarbonate -CH ₂ OC (= 0) OR ⁹ that are sensitive or unstable to hydrolysis. Wherein R ⁹ is C ₁ -C ₆ alkyl, C ₁ -C ₆ substituted alkyl, C ₆ -C ₂₀ aryl or C ₆ -C ₂₀ substituted aryl. Acyloxyalkylesters were first used as prodrug strategies for carboxylic acids, followed by Farquhar et al. (1983) J. Pharm . Sci . 72: 324; It was also applied to phosphates and phosphonates by US Pat. Nos. 4816570, 4968788, 5631159 and 5792756. Acyloxyalkylesters were then used to deliver phosphonic acid across the cell membrane to enhance oral bioavailability. Alkoxycarbonyloxyalkylesters (carbonates), a similar variant of acyloxy alkyl esters, also enhance oral bioavailability as prodrug moiety in the compounds combined in the present invention. Representative acyloxymethylesters are pivaloyloxymethoxy (POM) -CH ₂ OC (= 0) C (CH ₃ ) ₃ . An exemplary acyloxymethylcarbonate prodrug moiety is pivaloyloxymethylcarbonate (POC) —CH ₂ OC (═O) OC (CH ₃ ) ₃ .

The phosphonate group can be a phosphonate prodrug moiety. Prodrug moieties are sensitive to hydrolysis, such as, but not limited to, pivaloyloxymethyl carbonate (POC) or POM groups. As an alternative, the prodrug moiety may be susceptible to enzymatic potential degradation, such as lactate ester or phosphonamide acid-ester groups.

Aryl esters of phosphorus groups, especially phenyl esters, have been reported to enhance oral bioavailability (De Lombaert et al. (1994) J. Med . Chem . 37: 498). Phenyl esters containing a carboxyl ester at the ortho position for phosphate have also been reported (Khamnei and Torrence, (1996) J. Med . Chem . 39: 4109-4115). Benzyl esters have been reported to produce maternal phosphonic acid. In some cases, substituents in the ortho or para position may promote hydrolysis. Benzyl analogs with acylated phenols or alkylated phenols can produce phenolic compounds, for example, by enzymatic action such as esterases, oxidases, and the like. This in turn decomposes the benzyl CO bond to produce phosphoric acid and quinone metide intermediates. Examples of this class of prodrugs are described in Mitchell et al. (1992) J. Chem . Soc . Perkin Trans. II 2345; Glazier WO 91/19721. Another benzyl-based prodrug comprising a group containing a carboxylic acid ester in the benzyl methylene is described (Glazier WO 91/19721). They are known to be useful for the delivery of phosphonate drugs in cells containing thio groups. Such proesters include ethylthio groups in which thiol groups are esterified with acyl groups or combined with other thiol groups to form disulfides. Free thio intermediates are produced by the ester removal reaction or reduction of disulfide. It is broken down into phosphoric acid and episulfide (Puech et al. (1993) Antiviral Res ., 22: 155-® Benzaria et al. (1996) J. Med . Chem . 39: 4958). Cyclic phosphonate esters have also been described as prodrugs of compounds containing phosphorus (Erion et al., US Pat. No. 6,312,662).

A "protecting group" refers to a compound moiety that blocks or alters the properties of a functional group or the properties of the entire compound. The chemical substructure of the protecting group is very diverse. One function of the protecting group is to serve as an intermediate in the synthesis of the parent drug substance. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See Protective group in Organic Chemistry , Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991.

Protecting groups are often used to block the reactivity of certain functional groups, thereby increasing the efficiency of the desired chemical reaction, eg, to form and break chemical bonds sequentially in a planned manner. When protecting a functional group of a compound, in addition to the reactivity of the protected functional group, other physical properties, such as polarity, lipophilic (hydrophobic), and other properties that can be measured by common analytical instruments, are altered. Chemically protected intermediates are themselves biologically active or inactive.

Protected compounds may also optimize in vitro and in vivo properties such as resistance or sequestration to transport through cell membranes or enzymatic degradation in some cases. In this role, protected compounds with the intended therapeutic effect may be referred to as prodrugs. Another function of the protecting group is to convert the parent drug into the prodrug, thereby releasing the parent drug by conversion of the prodrug in vivo. Since the active prodrug can be absorbed more effectively than the parent drug, the prodrug can have greater viscosity in vivo than the parent drug. The protecting group is removed in vitro for chemical intermediates and in vivo for prodrugs. In the case of chemical intermediates, the resulting product, such as alcohol, after deprotection, although it is more preferred that the product is pharmaceutically harmless, is not very important whether it should be physiologically acceptable.

Any expressions for the compounds of the present invention include those for physiologically acceptable salts thereof. Physiologically acceptable salt thereof Examples of compounds of the invention include alkali metal (e.g., sodium), alkaline earth metal (e.g. magnesium), ammonium and NX ₄ ⁺ (wherein, X is alkyl of C _{1 -4)} with a suitable base such as And salts derived from them. Physiologically acceptable salts of compounds having a hydrogen atom or an amino group include organic carboxylic acids such as acetic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, isethionic acid, lactobionic acid and succinic acid; Organic sulfonates such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; And organic acid solutions such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid. Physiologically acceptable salts of compounds with hydroxy groups include anions of the compounds with suitable cations such as Na ⁺ and NX ₄ ⁺ , where X is independently selected from H or C ₁ -C ₄ alkyl groups do.

For therapeutic use, the salts of the active ingredients of the compounds of the invention should be physiologically acceptable, ie they will be salts derived from physiologically acceptable acids or bases. However, salts of acids or bases that are not physiologically acceptable may also be used, for example, in the manufacture or purification of physiologically acceptable compounds. All salts, whether derived from physiologically acceptable acids or bases, fall within the scope of the present invention.

"Alkyl" is a normal, secondary, tertiary or cyclic carbon atom containing C ₁ -C ₁₈ hydrocarbons. For example, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), 1-propyl ( n -Pr, n -propyl, -CH ₂ CH ₂ CH ₃ ), 2-propyl ( i -Pr, i -propyl, -CH (CH ₃ ) ₂ ), 1-butyl ( n -Bu, n -butyl, -CH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-1-propyl ( i -Bu , i -butyl, -CH ₂ CH (CH ₃ ) ₂ ), 2-butyl ( s -Bu, s -butyl, -CH (CH ₃ ) CH ₂ CH ₃ ), 2-methyl-2-propyl ( t- Bu, t -butyl, -C (CH ₃ ) ₃ ), 1-pentyl ( n -pentyl, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH (CH ₃ ) CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH (CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butyl (-C (CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH (CH ₃ ) CH (CH ₃ ) ₂ ), 3-methyl-1-butyl (-CH ₂ CH ₂ CH (CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH (CH ₃ ) CH ₂ CH ₃ ), 1-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH (CH ₃ ) CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH (CH ₂ CH ₃ ) (CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C (CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH ( CH ₃ ) CH (CH ₃ ) CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH (CH ₃ ) CH ₂ CH (CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C (CH ₃ ) (CH ₂ C H ₃ ) ₂ ), 2-methyl-3-pentyl (-CH (CH ₂ CH ₃ ) CH (CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C (CH ₃ ) ₂ CH (CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH (CH ₃ ) C (CH ₃ ) ₃ .

"Alkenyl" refers to a C ₂ -C ₁₈ hydrocarbon containing a normal, secondary, tertiary or cyclic carbon atom having at least one carbon-carbon unsaturated bond, ie having an sp ² double bond. Examples include ethylene or vinyl (-CH = CH ₂ ), allyl (-CH ₂ CH = CH ₂ ), cyclopentenyl (-C ₅ H ₇ ) and 5-hexenyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH = CH ₂ ), including but not limited to.

"Alkynyl" refers to a C ₂ -C ₁₈ hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms having at least one carbon-carbon unsaturated bond, ie sp triple bonds. Acetylene (-C≡H) and propazyl (-CH ₂ C≡H).

The term "alkylene" refers to a saturated, branched or straight or cyclic hydrocarbon radical of 1 to 18 carbon atoms derived from the removal of two hydrogen atoms from the same or different two carbon atoms of the moalkanes, It is a group having two monovalent radical centers. Typical alkylene radicals include methylene (-CH _2- ) 1,2-ethyl (-CH ₂ CH _2- ), 1,3-propyl (-CH ₂ CH ₂ CH _2- ), 1,4-butyl (-CH ₂ CH ₂ CH ₂ CH _2- ), and the like, and the like.

"Alkenylene" is an unsaturated, branched or straight-chain or cyclic hydrocarbon radical of 2-18 carbon atoms, two of which are derived by removing two hydrogen atoms from the same or different two carbon atoms of the moalkene. Monovalent radical centers, ie groups having a double carbon-carbon bond moiety. Typical alkenylene radicals include, but are not limited to, 1,2-ethylene (-CH = CH-).

"Alkynylene" is an unsaturated, branched or straight-chain or cyclic hydrocarbon radical of 2-18 carbon atoms derived from the removal of two hydrogen atoms from the same or different two carbon atoms of moalkynes. Monovalent radical centers, ie groups having triple carbon-carbon bond moieties. Typical alkynylene radicals include acetylene (-C≡C-), propargyl (-CH ₂ C≡C-), and 4-pentynyl (-CH ₂ CH ₂ CH ₂ C≡CH-) It is not limited to this.

By "aryl" is meant a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms derived by removing one hydrogen atom from a single carbon atom of the parent aromatic ring system. Typical aryl groups include, but are not limited to, radicals derived from benzene, substituted benzenes, naphthalenes, anthracenes, biphenyls, and the like.

"Arylalkyl" refers to an acyclic alkyl radical wherein one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp ³ carbon atom, is replaced by an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl, and the like. It is not limited. The arylalkyl group contains 6 to 20 carbon atoms, for example the alkyl portion of the arylalkyl group is 1 to 6 carbon atoms, including alkanyl, alkenyl or alkynyl groups, and the aryl portion is 5 to 14 carbon atoms.

Substituted substituents such as "substituted alkyl", "substituted aryl" and "substituted arylalkyl" refer to alkyl, aryl and arylalkyl, each of which one or more hydrogen atoms are independently replaced with non-hydrogen substituents. Typical substituents include, but are not limited to: ^{-X, -R, -O -, -OR} , -SR, -S, -NR 2, -NR 3, = NR, -CX 3, -CN, -OCN, -SCN, -N = C = O, _{-NCS, -NO, -NO 2, =} N 2, -N 3, NC (= O) R, -C (= O) R, -C (= O) NRR -S (= O) 2 O -, -S (= O) ₂ OH, -S (= O) ₂ R, -OS (= O) ₂ OR, -S (= O) ₂ NR, -S (= O) R, -OP (= O) O ₂ RR, _{-P (= O) O 2 RR} , -P (= O) (O -) 2, -P (= O) (OH) 2, -C (= O) R, -C (= O) X, - C (s) R, -C (O) OR , -C (O) O -, -C ( s) OR, -C (O) SR , -C ( s) SR, -C (O) NRR , - C (s) NRR, -C (NR) NRR, wherein each X is independently halogen. F, Cl, Br, or I; And each R is independently —H, alkyl, aryl, heterocycle, protecting group or prodrug moiety. Alkylene, alkenylene, and alkynylene groups may likewise be substituted.

As used herein, the term "heterocycle" refers to Paquette, Leo A .; Principles of Modern Heterocyclic Chemistry (WA Benjamin, New York, 1968), in particular Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs (John Wiley & Sons, New York, 1950), especially volumes 13, 14, 16, 19, and 28; And J. Am. Chem . Soc . (1960) 82: 5566, but are not limited to these. In certain embodiments of the invention, the heterocycle includes a carbocycle as defined herein. Here, one or more (eg 1, 2, 3, or 4) carbon atoms have been substituted with heteroatoms (eg O, N, or S).

Heterocycles include, but are not limited to, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidinyl), thiazolyl, tetrahydrothiophenyl, sulfur oxides tetrahydrothiophenyl, pyrimididi Neil, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, cyanaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl , Piperidinyl, 4-piperidoneyl, pyrrolidinyl, 2-pyrrolidoneyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, Octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H, 6H-1,5,2-dithiazinyl, thienyl, thiandrenyl, pyranyl, Isobenzofuranyl, chromenyl, xanthenyl, phenoxatinyl, 2H-pyrrolyl, isothiazolyl Isooxazolyl, pyrazinyl, pyridazinyl, indolinyl, isoindolinyl, 3H-indolyl, 1H-indazole, purinyl, 4H-quinolininyl, phthalazinyl, naphthyridinyl, quinoxalinyl , Quinazolinyl, cynolinyl, pterridinyl, 4aH-carbazolyl, carbazolyl, -carbolinyl, phenantridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenocyaninyl, fuj Lazanyl, phenoxazinyl, isochromenyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholi Nil, oxazolidinyl, benzotriazolyl, benzisooxazolyl, oxindolyl, benzozazolinyl, isatinoyl, and bis-tetrahydrofuranyl:

Heterocycles bonded with carbon are 2, 3, 4, 5 or 6 positions of pyridine, 3, 4, 5 or 6 positions of pyridazine, 2, 4, 5 or 6 positions of pyrimidine and 2, 3 of pyrazine , 5 or 6 position, furan, tetrahydrofuran, thiofuran, thiophene, 2, 3, 4, or 5 position of pyrrole or tetrahydropyrrole, 2, 4, or 5 position of oxazole, imidazole or thiazole , 3, 4, or 5 position of isoxazole, pyrazole, or isothiazole, 2 or 3 position of aziridine, 2, 3, or 4 position of azetidine, 2, 3, 4, 5, 6 of quinoline , 7 or 8, or 1, 3, 4, 5, 6, 7 or 8 of isoquinoline, but is not limited thereto. More generally, heterocycles bonded with carbon include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3- pyridazinyl, 4-pyridazinyl, 5 -Pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5- pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

Heterocycles associated with nitrogen include aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrrolidine, 3-pyrrolidine, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline , Pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indolin, 1 position of 1H-indazole, isoindole, or 2 position of isoindolin, morpholine 4, and carbazole or β-carboline is bound to 9, but is not limited thereto. More generally, heterocycles associated with nitrogen include, but are not limited to, 1-aziridyl, 1-azededyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl and 1-piperidinyl Do not.

"Carbocycle" means a saturated, unsaturated or aromatic ring system having from 3 to 7 carbon atoms as a single ring or from 7 to 12 carbon atoms as a two ring and up to about 20 carbon atoms as a polycyclic ring. Monocyclic carbocycles have 3 to 6 ring atoms, more generally 5 or 6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, for example two [4,5], [5,5], [5,6] or [6,6] or two rings Having 9 or 10 ring atoms disposed as [5,6] or [6,6] systems. Examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclophen-1-tenyl, 1-cyclopent-2-tenyl, 1-cyclophen-3-tenyl, cyclohexyl, 1-cyclo Hex-1-senyl, 1-cyclohex-2-senyl, 1-cyclohex-3-senyl, phenyl, spiryl and naphthyl.

"Connector" or "link" refers to a chemical moiety comprising a covalent bond or a chain or group of atoms that covalently attaches a phosphonate group to a drug. The linkage includes portions of substituents A ¹ and A ³ . These include repeating units of alkyloxy (eg polyethyleneoxy, PEG, polymethyleneoxy) and alkylamino (eg polyethyleneamino, Jeffamine ™); And diacid esters and amides including succinate, succinamide, diglycolate, malonate and caproamide.

The term "chiral" refers to molecules having non-superimposition of the mirror image partner, and the term "bichiral" refers to molecules superimposed on their mirror image partner.

"Stereoisomers" refer to compounds having the same chemical structure but different spatial arrangements of atoms or groups.

A "diastereoisomer" refers to a stereoisomer that has two or more chiral centers and the molecules are not mirror images of each other. Diastereomers differ from one another in physical properties such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereoisomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography.

 The term "enantiomer" refers to two stereoisomers of a compound that have mirror images that do not overlap each other.

The term treatment or treatment within the scope associated with the disease or condition includes preventing or preventing the occurrence of the disease or condition, removing the disease or condition, and / or alleviating one or more disease or condition symptoms. .

Stereochemical definitions and concepts used herein are generally described in SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; And Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of planar polarization. In describing an optically active compound, prefixes such as D and L or R and S are used to indicate the absolute placement of the molecule relative to its chiral center (s). The prefixes d and l or (+) and (-) are used to indicate the rotational signal of planar polarization of the compound, where (-) or l means that the compound is left linear. Compounds with (+) or d are preferred compounds. In a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. Specific stereoisomers may be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to a mixture of the same moles of two enantiomeric species, without optical activity.

Saver

Protecting groups in the context of the present specification include prodrug moieties and chemical protecting groups.

Protecting groups are generally known to be used to prevent side reactions using protected groups during the course of using synthetic procedures, ie, routes or methods for preparing compounds of the present invention. In most cases, when determining which group to protect, the nature of the chemical protecting group “PG” depends on the reaction to be protected (eg acidic, basic, oxidation, reducing or other reaction state) and the direction of the desired synthesis. When a compound is substituted with several PGs, the PG groups do not need to be identical, and generally do not. In general, PG is used to protect functional groups such as carboxyl, hydroxyl, thio, or amino groups to prevent side reactions or promote synthesis efficiency. The order of deprotection to obtain free, deprotected groups depends on the direction of the desired synthesis and the reaction conditions encountered, and can be in any order depending on the intention of the experimenter.

Various functional groups of the compounds of the present invention may be protected. For example, -OH group protecting groups (hydroxyl, carboxylic acid, phosphonic acid or other functional groups) include "ether- or ester forming groups". Ether- or ester formers can act as chemical protecting groups in the synthetic reactions described herein. However, some hydroxyl and thio protecting groups are not ether- or ester forming groups and include the amides discussed below, as understood by those skilled in the art.

Groups forming a large number of hydroxyl protecting groups and amides and corresponding chemical decomposition reactions are described in Protective Groups in Organic synthesis , Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN 0-471-62301 -6) (Greene). Kocienski, Philip J .; See also Protecting Groups (GeOrg Thieme Verlag Stuttgart, New York, 1994), which are incorporated by reference. Especially Chapter 1, protecting groups: overview, p 1-20, Chapter 2, hydroxyl protecting groups, p 21-94, Chapter 3, diol protecting groups, p 95-117, Chapter 4, carboxyl protecting groups, p 118-154, Chapter 5, Carbonyl protecting group, p 155-184. See Greene as described below for carboxylic acids, phosphonic acids, phosphonates, protecting groups for sulfonic acids and other protecting groups for acids. Such groups include, but are not limited to, esters, amides, hydrazides, and the like.

Ether- and ester-forming protecting groups

Ester formers include: (1) phosphonate ester formers such as phosphonamidate esters, phosphorothioate esters, phosphonate esters and phosphon-bis-amidates; (2) carboxyl ester formers, and (3) sulfur ester formers such as sulfonic acid, sulfuric acid, and sulfinate.

The phosphonate moiety of the compound of the invention may or may not be a prodrug moiety. In other words, they may be susceptible to hydrolysis or enzymatic degradation or modification. Certain phosphonate moieties are stable in most or almost all metabolic conditions. For example, dialkylphosphonates wherein the alkyl group is at least two carbons can have significant in vivo stability because of the slow rate of hydrolysis.

Within the scope of the phosphonate prodrug moiety, numerous types of structurally diverse prodrugs for phosphonic acids have been described ( Progress in Medicinal Chemistry 34: 112-147 (1997) by Freeman and Ross, which is within the scope of the present invention). Exemplary phosphonate ester formers are the phenyl carbocycles of substructure A ₃ having the formula:

Wherein R ₁ may be H or C ₁ -C ₁₂ alkyl; m1 is 1, 2, 3, 4, 5, 6, 7 or 8, and the phenyl carbocycle is substituted with 0 to 3 R ₂ groups. Wherein when Y ₁ is O, lactate esters are formed, wherein when Y ₁ is N (R ₂ ), N (OR ₂ ) or N (N (R ₂ ) ₂ , the phosphonamidate ester is Obtained.

In the role of forming their esters, protecting groups typically form CO ₂ R ^x by combining with any acidic group such as, for example, a -CO ₂ H or -C (s) OH group, where R ^x is As defined herein, or R ^x includes, for example, ester groups listed in WO 95/07920, which are by way of example and not limited thereto.

Examples of savers:

C ₃ -C ₁₂ heterocycle (as described above) or aryl. Such aromatic groups are optionally polycyclic or monocyclic. Examples include phenyl, spiryl, 2- and 3-pyrrolyl, 2- and 3-thienyl, 2- and 4-imidazolyl, 2-, 4- and 5-oxazolyl, 3- and 4-iso Oxazolyl, 2-, 4- and 5-thiazolyl, 3-, 4- and 5-isothiazolyl, 3- and 4-pyrazolyl, 1-, 2-, 3- and 4-pyridyl, and 1-, 2-, 4- and 5-pyrimidinyl,

;

;

;C_{4 -} C₈ 2-카복실페닐의 에스테르; 및 할로겐, C₁-C₁₂ 알콕시 (메톡시 및 에톡시를 포함), 시아노, 니트로, OH, C₁-C₁₂ 할로겐화알킬 (1 내지 6개의 할로겐 원자; -CH₂CCl₃을 포함), C₁-C₁₂ 알킬 (메틸 및 에틸을 포함), C₂-C₁₂ 알케닐 또는 C₂-C₁₂ 알키닐이고; 알콕시 에틸 [C₁-C₆ 알킬 -CH₂-CH₂-O-CH₃ (메톡시 에틸)을 포함]; 아릴기에서 설명된 기, 특히 OH에 의해서 또는 1 내지 3 개의 할로겐화 원자에 의해서 치환된 알킬(-CH_{3 ,} -CH(CH₃)₂, -C(CH₃)₃, -CH₂CH₃, -(CH₂)₂CH₃, -(CH₂)₃CH₃, -(CH₂)₄CH₃, -(CH₂)₅CH₃, -CH₂CH₂F, -CH₂CH₂Cl, -CH₂CF₃, 및 -CH₂CCl₃을 포함)이고;

;-N-2-프로필모르폴리노, 2,3-디하이드로-6-하이드록시인덴, 세사몰, 카테콜 모노에스테르, -CH₂-C(O)-N(R¹)₂, -CH₂-S(O)(R¹), -CH₂-S(O)₂(R¹), -CH₂-CH(OC(O)CH₂R¹)-CH₂(OC(O)CH₂R¹), 콜레스테릴, 엔올피루베이트 (HOOC-C(=CH₂)-), 글리세롤 중에서 선택된 기, 3 내지 5개의 할로겐 원자 또는 1 내지 2개의 원자가 아릴부분에 치환된 C₁-C₄ 알킬렌-C₃-C₆ 아릴(벤질, -CH₂-피롤릴, -CH₂-티엔일, -CH₂-이미다졸릴, -CH₂-옥사졸릴, -CH₂-이소옥사졸릴, -CH₂-티아졸릴, -CH₂-이소티아졸릴, -CH₂-파이라졸릴, -CH₂-피리딜 및 -CH₂-피리미디닐을 포함)이고; _{^{Halo, R 1, R 1 -OC 1}} - C 12 alkylene, C ₁ -C ₁₂ alkoxy, CN, NO _2, OH, carboxyl, carboxyl ester, thiol, thioester, C ₁ -C ₁₂ halogenated alkyl (1 to substituted to 6 halogen atoms), C ₂ -C ₁₂ alkenyl or C ₂ -C ₁₂ alkynyl group, etc. C ₃ -C ₁₂ heterocycle or aryl have. Such groups include 2-, 3- and 4-alkoxyphenyl (C ₁ -C ₁₂ alkyl), 2-, 3- and 4-methoxyphenyl, 2-, 3- and 4-ethoxyphenyl, 2,3- , 2,4-, 2,5-, 2,6-, 3,4- and 3,5-diethoxyphenyl, 2- and 3-carboethoxy-4-hydroxyphenyl, 2- and 3- Methoxy-4-hydroxyphenyl, 2- and 3-ethoxy-5-hydroxyphenyl, 2- and 3-ethoxy-6-hydroxyphenyl, 2-, 3- and 4-O-acetylphenyl, 2 -, 3- and 4-dimethylaminophenyl, 2-, 3- and 4-methylmercaptophenyl, 2-, 3- and 4-halogenated phenyl (2-, 3- and 4-fluorophenyl and 2-, 3- and 4-chlorophenyl), 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethylphenyl, 2,3-, 2, 4-, 2,5-, 2,6-, 3,4- and 3,5-biscarboxylethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4 And 3,5-dimethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dihalogenated phenyl (2,4-difluoro Phenyl and 3,5-difluorophenyl), 2-, 3- and 4-halogenatedalkylphenyl (1 to 5 halogen atoms, 4-trifluoromethylphenyl Comprising C ₁ -C ₁₂ alkyl), 2-, 3-, and 4-cyanophenyl, 2-, 3-, and 4-nitrophenyl, 2-, 3-, and 4-halogenated alkylbenzyl (1-5 halogens Atom, 4-trifluoromethylbenzyl and C ₁ -C ₁₂ alkyl comprising 2-, 3- and 4-trichloromethylphenyl and 2-, 3- and 4-trichloromethylphenyl), 4-N-methylpipe Ridinyl, 3-N-methylpiperidinyl, 1-ethylpiperazinyl, benzyl, alkylsalicylphenyl (C ₁ -C ₄ alkyl including 2-, 3- and 4-ethylsalicylphenyl), 2 -, 3- and 4-acetylphenyl, 1,8-dihydroxynaphthyl (-C ₁₀ H ₆ -OH) and aryloxy ethyl [C ₆ -C ₉ aryl (including phenoxy ethyl)], 2, 2'-dihydroxybiphenyl, 2-, 3- and 4-N, N-dialkylaminophenol, -C ₆ H ₄ CH ₂ -N (CH ₃ ) ₂ , trimethoxybenzyl, triethoxybenzyl , 2-alkyl-pyridyl (C _{1 -4} alkyl);

;

;

; Ester of C ₄ -C ₈ 2-carboxyphenyl; And halogen, C ₁ -C ₁₂ alkoxy (including methoxy and ethoxy), cyano, nitro, OH, C ₁ -C ₁₂ alkyl halide (including 1 to 6 halogen atoms; —CH ₂ CCl ₃ ), C ₁ -C ₁₂ alkyl (including methyl and ethyl), C ₂ -C ₁₂ alkenyl or C ₂ -C ₁₂ alkynyl; Alkoxy ethyl [including C ₁ -C ₆ alkyl -CH ₂ -CH ₂ -O-CH ₃ (methoxy ethyl)]; Groups described in the aryl group, in particular alkyl (-CH _{3 ,} -CH (CH ₃ ) ₂ , -C (CH ₃ ) ₃ , -CH ₂ CH ₃ , substituted by OH or by 1 to 3 halogenated atoms; -(CH ₂ ) ₂ CH ₃ ,-(CH ₂ ) ₃ CH ₃ ,-(CH ₂ ) ₄ CH ₃ ,-(CH ₂ ) ₅ CH ₃ , -CH ₂ CH ₂ F, -CH ₂ CH ₂ Cl, -CH ₂ CF ₃ , and -CH ₂ CCl ₃ ;

; -N-2-propylmorpholino, 2,3-dihydro-6-hydroxyindene, sesamol, catechol monoester, -CH ₂ -C (O) -N (R ¹ ) ₂ ,- CH ₂ -S (O) (R ¹ ), -CH ₂ -S (O) ₂ (R ¹ ), -CH ₂ -CH (OC (O) CH ₂ R ¹ ) -CH ₂ (OC (O) CH ₂ R ¹ ), cholesteryl, enolpyruvate (HOOC-C (= CH ₂ )-), a group selected from glycerol, C ₁ -C having 3 to 5 halogen atoms or 1 to 2 atoms substituted at the aryl moiety ₄ alkylene -C ₃ -C ₆ aryl (benzyl, -CH ₂ - pyrrolyl, -CH ₂ - thienyl, -CH ₂ - imidazolyl, -CH ₂ - oxazolyl, -CH ₂ - iso-oxazolyl, -CH ₂ -thiazolyl, -CH ₂ -isothiazolyl, -CH ₂ -pyrazolyl, -CH ₂ -pyridyl and -CH ₂ -pyrimidinyl);

5 or 6 carbon monosaccharides, disaccharides or oligosaccharides (3 to 9 monosaccharide residues);

Triglycerides such as α-D-βdiglycerides bound to the acyl of the parent compound via the glyceryl oxygen of the triglycerides, wherein the fatty acids that make up the glyceride lipids are generally saturated or unsaturated C _{6 -26} , C _6-18 or C _{6 -10} fatty acids, e.g., linoleic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, palmitoleic resan, linolenic acid and any of the like acids), and;

Phospholipids linked to carboxyl groups via phosphates of phospholipids;

Phthalidyl (FIG. 1, Clayton et al . , Antimicrob . Agents Chemo . (1974) 5 (6): 670-671;

를 포함한다.Cyclic carbonates such as (5-R _d -2-oxo-1,3-dioxolen-4-yl) methyl ester (Sakamoto et al . , Chem . Pharm . Bull. (1984) 32 (6) 2241-2248) where , R _d is R ₁ , R ₄ or aryl; And

It includes.

The hydroxyl groups of the compounds of the invention are alternatively substituted with III, IV or V groups or isopropyl as disclosed in WO 94/21604.

Table A lists examples of ester moieties of protecting groups capable of bonding with —C (O) O— and —P (O) (O—) ₂ groups via oxygen. Also shown are several amidates that are directly bonded to -C (O)-or -P (O) ₂ . Esters of structures 1-5, 8-10 and 16, 17, 19-22 are compounds of the invention having free hydroxyls and corresponding halides (such as chlorides or acyl chlorides) and N, N-dicyclohexyl-N In DMF (or other solvent such as acetonitrile or N-methyl pyrrolidone) of morpholine carboxamidine (or other bases such as DBU, triethylamine, CsCO ₃ , N, N-dimethylaniline, etc.) Reacted and synthesized. When the compound to be protected is a phosphonate, the esters of structures 5-7, 11, 12, 21, and 23-26 are monohydric to alcohols or alkoxide salts (or corresponding amines for compounds such as 13, 14 and 15). It is synthesized by reacting with chlorophosphonate or dichlorophosphonate (or another activated phosphonate).

TABLE A

1.-CH ₂ -C (O) -N (R ₁ ) ₂ * 10. -CH ₂ -OC (O) -C (CH ₃ ) ₃

2.-CH ₂ -S (O) (R ₁ ) 11.-CH ₂ -CCl ₃

3.-CH ₂ -S (O) ₂ (R ₁ ) 12.-C ₆ H ₅

4.-CH ₂ -OC (O) -CH ₂ -C ₆ H ₅ 13. -NH-CH ₂ -C (O) O-CH ₂ CH ₃

5. 3-cholesteryl 14. -N (CH ₃ ) -CH ₂ -C (O) O-CH ₂ CH ₃

6. 3-Pyridyl 15. -NHR ₁

7.N-ethylmorpholino 16. -CH ₂ -OC (O) -C ₁₀ H ₁₅

8.-CH ₂ -OC (O) -C ₆ H ₅ 17. -CH ₂ -OC (O) -CH (CH ₃ ) ₂

9.-CH ₂ -OC (O) -CH ₂ CH ₃ 18.-CH ₂ -C # H (OC (O) CH ₂ R ₁ )-

CH _2- (OC (O) CH ₂ R ₁ ) *

19. 20.

21.21.

23. 24.

25. 26.

#-Chiral center is (R), (S) or racemate.

Other esters suitable for use in the present invention are described in EP 632048.

-CH₂SCOCH₃, -CH₂OCON(CH₃)₂, 또는 (산성기의 산소에 결합된)-CH(R¹ 또는 W⁵)O((CO)R³⁷) 또는 -CH(R¹ 또는 W⁵)((CO)OR³⁸) 구조의 알킬- 또는 아릴-아실옥시알킬기로서, 여기서, R³⁷ 및 R³⁸은 알킬, 아릴 또는 알킬아릴기이다 (미국 특허 제 4968788호 참조). 종종 R³⁷ 및 R³⁸는 벌크 기, 예컨대, 분지형 알킬, 오르토 치환 아릴, 메타 치환 아릴 또는 이들의 조합이며 탄소원자가 1 내지 6개인 노말, 2차, 이소- 및 3차 알킬을 포함한다. 예로는, 피발로일옥시메틸기가 있다. 이들은 경구투여용 전구 약물에 사용된다. 이러한 유용한 보호기의 예에는 알킬아실옥시메틸 에스테르 및 이들의 유도체가 있으며, 여기에는 -CH(CH₂CH₂OCH₃)OC(O)C(CH₃)₃,

-CH₂OC(O)C₁₀H₁₅, -CH₂OC(O)C(CH₃)₃, -CH(CH₂OCH₃)OC(O)C(CH₃)₃, -CH(CH(CH₃)₂)OC(O)C(CH₃)₃, -CH₂OC(O)CH₂CH(CH₃)₂, -CH₂OC(O)C₆H₁₁, -CH₂OC(O)C₆H₅, -CH₂OC(O)C₁₀H₁₅, -CH₂OC(O)CH₂CH₃, -CH₂OC(O)CH(CH₃)₂ , -CH₂OC(O)C(CH₃)₃ 및 -CH₂OC(O)CH₂C₆H₅가 포함된다.Protecting groups also include double esters that form linearity. For example, -CH ₂ OC (O) OCH ₃ ,

-CH ₂ SCOCH ₃ , -CH ₂ OCON (CH ₃ ) ₂ , or -CH (R ¹ or W ⁵ ) O ((CO) R ³⁷ ) or -CH (R ¹ or W ⁵ ) (-(CO) OR ³⁸ ) An alkyl- or aryl-acyloxyalkyl group, wherein R ³⁷ and R ³⁸ are alkyl, aryl or alkylaryl groups (see US Pat. No. 4968788). Often R ³⁷ And R ³⁸ is a bulk group such as branched alkyl, ortho substituted aryl, meta substituted aryl or combinations thereof and includes normal, secondary, iso- and tertiary alkyl having 1 to 6 carbon atoms. An example is a pivaloyloxymethyl group. These are used in prodrugs for oral administration. Examples of such useful protecting groups include alkylacyloxymethyl esters and derivatives thereof, including -CH (CH ₂ CH ₂ OCH ₃ ) OC (O) C (CH ₃ ) ₃ ,

-CH ₂ OC (O) C ₁₀ H ₁₅ , -CH ₂ OC (O) C (CH ₃ ) ₃ , -CH (CH ₂ OCH ₃ ) OC (O) C (CH ₃ ) ₃ , -CH (CH ( CH ₃ ) ₂ ) OC (O) C (CH ₃ ) ₃ , -CH ₂ OC (O) CH ₂ CH (CH ₃ ) ₂ , -CH ₂ OC (O) C ₆ H ₁₁ , -CH ₂ OC (O ) C ₆ H ₅ , -CH ₂ OC (O) C ₁₀ H ₁₅ , -CH ₂ OC (O) CH ₂ CH ₃ , -CH ₂ OC (O) CH (CH ₃ ) ₂ , -CH ₂ OC (O ) C (CH ₃ ) ₃ and -CH ₂ OC (O) CH ₂ C ₆ H ₅ .

In some claims the protected acid groups are esters of acidic groups and residues of hydroxyl containing functional groups. In another claim, amino compounds are used to protect acid functionality. Residues of suitable hydroxyl or amino containing functional groups are described above or can be found in WO 95/07920. Of particular interest are residues of amino acids, amino acid esters, polypeptides or aryl alcohols. Typical amino acid, polypeptide and carboxyl-esterified amino acid residues are described as L1 or L2 groups on pages 11-18 and related parts of WO 95/07920. WO 95/07920 discloses amidates of phosphonic acids, but it is understood that such amidates can be formed by any of the acid groups described herein and the amino acid residues described in WO 95/07920.

Typical esters for acid protecting functional groups are also disclosed in WO 95/07920, where it is understood that the same ester can be formed from the acid groups described herein as well as the phosphonates in WO 95/07920. Typical ester groups are defined as (R) at least on pages 89 to 93 (in R ³¹ or R ³⁵ ) of WO 95/07920, in the table on page 105 and in pages 21-23. Esters of unsubstituted aryl, such as aryl alkyl or hydroxy-, halo-, alkoxy-, carboxy- and / or alkylestercarboxy substituted aryl or alkyl aryl, in particular phenyl, ortho-ethoxyphenyl, such as phenyl or benzyl, Or C ₁ -C ₄ alkylester carboxylphenyl (salicylic acid C ₁ -C ₁₂ alkylester) are of particular interest.

Especially when using the esters or amides of WO 95/07920, protected acidic groups are useful as prodrugs for oral administration. However, it is not necessary to protect the acidic groups in order for the compounds of the present invention to be effectively orally administered. In the case of systemic or oral administration of a compound of the invention having a protected group, in particular a protecting group such as amino acid amidate or substituted and unsubstituted aryl esters, they can be hydrolyzed in vivo to produce free acid.

One or more acidic hydroxyl groups are protected. If one or more acidic hydroxyl groups are protected, the same or different protecting groups are used, for example the esters may be different or identical, or mixed amidates and esters may be used.

Typical hydroxy protecting groups described in Greene (pp. 14-118) include substituted methyl and alkyl ethers, substituted benzyl ethers, silyl ethers, esters including sulfonic acid esters and carbonates. For example:

Ether (methyl, t -butyl, allyl);

Substituted methyl ether (methoxymethyl, methylthiomethyl, t -butylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p -methoxybenzyloxymethyl, (4-methoxyphenoxy) methyl , Guoacolmethyl, t -butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy ) Methyl, 2- (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydropthiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydropthiopyranyl S, S -dioxido, 1-[(2-chloro-4-methyl) phenyl] -4-methoxypiperidine-4 -Yl, 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a, 4,5,6,7,7a-octahydro-7,8,8-trimethyl -4,7-methanobenzofuran-2-yl)) ;

Substituted ethyl ether (1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyl Oxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylselenyl) ethyl,

P -chlorophenyl, p -methoxyphenyl, 2,4-dinitrophenyl, benzyl);

Substituted benzyl ethers ( p -methoxybenzyl, 3,4-dimethoxybenzyl, o -nitrobenzyl, p -nitrobenzyl, p -halobenzyl, 2,6-dichlorobenzyl, p -cyanobenzyl, p- benzyl, 2-and 4-picolyl, 3-methyl-2-picolyl N - oxido, diphenylmethyl, p, p '- dinitro benzhydryl, 5-dibenzo-standing beryl, triphenylmethyl, α-naphthyldiphenylmethyl, p -methoxyphenyldiphenylmethyl, di ( p -methoxyphenyl) phenylmethyl, tri ( p -methoxyphenyl) methyl, 4- (4'-bromophenacryloxy) phenyl Diphenylmethyl, 4,4 ', 4-tris (4,5-dichlorophthalimidophenyl) methyl, 4,4', 4-tris (revulinoyloxyphenyl) methyl, 4,4 ', 4-tris (Benzoyloxyphenyl) methyl, 3- (imidazol-1-ylmethyl) bis (4 ', 4-dimethoxyphenyl) methyl, 1,1-bis (4-methoxyphenyl) -1'-pyrenylmethyl , 9-anthryl, 9- (9-phenyl) xanthenyl, 9- (9-phenyl-10-oxo) anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S, S Dioxydo);

Silyl ether (trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t -butyldimethylsilyl, t -butyldiphenylsilyl, tribenzylsilyl, tri p -xylylsilyl, triphenylsilyl, diphenylmethylsilyl, t -butylmethoxyphenylsilyl);

Ester (formate, benzoylformate, acetate, ultraacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p -chlorophenoxyacetate, p- Poly-phenylacetate, 3-phenylpropionate, 4-oxopentanoate (Levulinate), 4,4- (ethylenedithio) pentanoate, pivaloate, adamantatoate, crotonate, 4- Methoxycrotonate, benzoate, p -phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate));

Carbonates (methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2- (trimethylsilyl) ethyl, 2- (phenylsulfonyl) ethyl, 2- (triphenylphosphonio)) Ethyl, isobutyl, vinyl, allyl, p -nitrophenyl, benzyl, p -methoxybenzyl, 3,4-dimethoxybenzyl, o -nitrobenzyl, p -nitrobenzyl, S -benzyl thiocarbonate, 4-ethoxy -1-naphthyl, methyl dithiocarbonate);

Secondary crackers (2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl) benzoate, 2-formylbenzenesulfonate, 2- (methyl Thiomethoxy) ethyl carbonate, 4- (methylthiomethoxy) butyrate, 2- (methylthiomethoxymethyl) benzoate); Other esters (2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4- (1,1,3,3 tetramethylbutyl) phenoxyacetate, 2,4-bis (1,1- Dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinic acid, ( E ) -2-methyl-2-butenoate (taigroate), o- (methoxycarbonyl) benzoate, p- Poly-benzoate, α-naphthoate, nitrate, alkyl N, N, N ', N' -tetramethylphosphorodiamidate, N -phenylcarbamate, borate, dimethylphosphinothionyl, 2,4 -Dinitrophenyl sulfenate);

Sulfonates (sulfates, methanesulfonates (mesylate), benzylsulfonates, tosylate).

Typical 1,2-diol protecting groups (hence, generally two OH groups are bonded together as protecting groups) are described on pages 118-142 of Greene, which include cyclic acetals and ketals (methylene, ethylidene, 1- t −). Butylethylidene, 1-phenylethylidene, (4-methoxyphenyl) ethylidene, 2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene, cyclohexyl Den, cycloheptylidene, benzylidene, p -methoxybenzylidene, 2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, 2-nitrobenzylidene); Cyclic ortho esters (methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene, 1-ethoxyethylidene, 1,2-dimethoxyethylidene, α-methoxybenzylidene, 1- ( N, N -dimethylamino) ethylidene derivative, α- ( N, N -dimethylamino) benzylidene derivative, 2-oxacyclopentylidene); Silyl derivatives thereof (di- t -butylsilylene groups, 1,3- (1,1,3,3-tetraisopropyldisiloxanilidene), and tetra- t -butoxydisiloxane-1,3- Diylidene), cyclic carbonate, cyclic boronate, ethyl boronate and phenyl boronate.

More typically 1,2-diol protecting groups include those shown in Table B. More typical include epoxides, acetonides, cyclic ketals and aryl acetals.

TABLE B

Where R ⁹ Is C ₁ -C ₆ alkyl.

Amino protecting group

Another group of protecting groups includes the typical amino protecting groups described in Greene, pp. 315-385, including the following.

Carbamate: (methyl and ethyl, 9-fluorenylmethyl, 9 (2-sulfo) fluorenylmethyl, 9- (2,7-dibromo) fluorenylmethyl, 2,7-di- t -Butyl- [9- (10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)] methyl, 4-methoxyphenacryl);

Substituted ethyl: (2,2,2-trichoethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1- (1-adamantyl) -1-methylethyl, 1,1-dimethyl-2- Ethyl halide, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1- (4-biphenylyl) ethyl, 1 -(3,5-di- t -butylphenyl) -1-methylethyl, 2- (2'- and 4'-pyridyl) ethyl, 2- ( N, N -dicyclohexylcarboxamido) ethyl , t -butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamil, 4-nitrocinamyl, 8-quinolyl, N -hydroxypiperidinyl, alkyldithio, benzyl, p Methoxybenzyl, p -nitrobenzyl, p -bromobenzyl, p -chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, diphenylmethyl);

Auxiliary cracker: (2-methylthioethyl, 2-methylsulfonylethyl, 2- ( p -toluenesulfonyl) ethyl, [2- (1,3-dicyanyl)] methyl, 4-methylthiophenyl, 2 , 4-dimethylthiophenyl, 2-phosphonioethyl, 2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl, m -secondary- p -acyloxybenzyl, p- (dihydr Hydroxyboryl) benzyl, 5-benzisooxazolylmethyl, 2- (trifluoromethyl) -6-chromonylmethyl);

Photodegradable groups: ( m -nitrophenyl, 3,5-dimethoxybenzyl, o -nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, phenyl ( o -nitrophenyl) methyl); Urea-type derivatives thereof (phenothiazinyl- (10) -carbonyl, N' - p -toluenesulfonylaminocarbonyl, N' -phenylaminothiocarbonyl);

Other carbamate: ( t -amyl, S -benzyl thiocarbamate, p -cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p -decyloxybenzyl, diisopropylmethyl, 2,2 -Dimethoxycarbonylvinyl, o- ( N, N -dimethylcarboxamido) benzyl, 1,1-dimethyl-3- ( N, N -dimethylcarboxamido) propyl, 1,1-dimethylpropynyl , di (2-pyridyl) methyl, 2-furanyl-methyl, 2-iodo ethyl, isopropyl barley carbonyl, iso-butyl, iso-nicotinyl, p - (p '- methoxy phenyl azo) benzyl, 1-methylcyclohexyl Butyl, 1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl, 1-methyl-1- (3,5-dimethoxyphenyl) ethyl, 1-methyl-1- ( p -phenylazophenyl) ethyl, 1-methyl-1-phenylethyl, 1-methyl-1- (4-pyridyl) ethyl, phenyl, p- (phenylazo) benzyl, 2,4,6-tri- t -butylphenyl, 4- (trimethyl Ammonium) benzyl, 2,4,6-trimethylbenzyl);

● amide: (N - formyl, N - acetyl, N - sec-acetyl, N - tree seconds acetyl, N - trifluoroacetyl, N - phenylacetyl, N -3- phenylpropionyl, N - avoid collision alkanoyl, N -3-pyridylcarboxamide, N -benzoylphenylalanyl, N -benzoyl, N - p -phenylbenzoyl);

Secondary decomposition amides: ( N - o -nitrophenylacetyl, N - o -nitrophenoxyacetyl, N -acetoacetyl, ( N' -dithiobenzyloxycarbonylamino) acetyl, N- 3- ( p -hydride) Oxyphenyl) propionyl, N- 3- ( o -nitrophenyl) propionyl, N -2-methyl-2- ( o -nitrophenoxy) propionyl, N -2-methyl-2- ( o -phenyla Zofenoxy) propionyl, N -4-chlorobutyryl, N -3-methyl-3-nitrobutyryl, N - o -nitrocinnamoyl, N -acetylmethionine, N - o -nitrobenzoyl, N - o -(Benzoyloxymethyl) benzoyl, 4,5-diphenyl-3-oxazolin-2-one);

● cyclic imide derivatives: (N - phthalimide, N - O-dish succinate alkanoyl, N -2,3- diphenyl maleic five days, -2,5- dimethyl-N-pyrrolyl, N -1,1,4, 4-tetramethyldisilylazacyclopentane adduct, 1,3-dimethyl-1,3,5-triazacyclohexan-2-one substituted with 5, 1,3-dibenzyl-1 substituted with 5, 3-5-triazacyclohexan-2-one, 3,5-dinitro-4-pyridonyl substituted with 1);

N -alkyl and N -aryl amines: ( N -methyl, N -allyl, N- [2- (trimethylsilyl) ethoxy] methyl, N- 3-acetoxypropyl, N- (1-isopropyl-4 -Nitro-2-oxo-3-pyrrolin-3-yl), quaternary ammonium salt, N -benzyl, N -di (4-methoxyphenyl) methyl, N -5-dibenzoserveryl, N -tri Phenylmethyl, N- (4-methoxyphenyl) diphenylmethyl, N- 9-phenylfluorenyl, N- 2,7-dichloro-9-fluorenylmethylene, N -peroxenylmethyl, N- 2 Picolylamine N' -oxide);

Imine derivatives: ( N -1,1-dimethylthiomethylene, N -benzylidene, N - p -methoxybenylidene, N -diphenylmethylene, N -[(2-pyridyl) methyl] methylene, N , ( N ', N' -dimethylaminomethylene, N , N' -isopropylidene, N - p -nitrobenzylidene, N -salicylidene, N -5-chlorosalicylidene, N- (5 -Chloro-2-hydroxyphenyl) phenylmethylene, N -cyclohexylidene);

Enamine derivatives: ( N- (5,5-dimethyl-3-oxo-1-cyclohexenyl));

N -metal derivatives ( N -boron derivatives thereof, N -diphenylborinic acid derivatives, N- [phenyl (pentacarbonylchrome- or -tungsten)] carbenyl, N -copper or N -zinc chelates;

NN derivative: ( N -nitro, N -nitroso, N -oxide);

NP derivatives: ( N -diphenylphosphinyl, N -dimethylthiophosphinyl, N -diphenylthiophosphinyl, N -dialkyl phosphoryl, N -dibenzyl phosphoryl, N -diphenyl phosphoryl);

N-Si derivatives, NS derivatives, and N-sulphenyl derivatives: ( N -benzenesulphenyl, No- nitrobenzenesulphenyl, N -2,4-dinitrobenzenesulphenyl, N -pentachlorobenzenesulphenyl, N -2-nitro-4-methoxybenzenesulphenyl, N -triphenylmethylsulphenyl, N- 3-nitropyridinesulphenyl); N -sulfonyl derivatives ( N - p -toluenesulfonyl, N -benzenesulfonyl, N- 2,3,6-trimethyl-4-methoxybenzenesulfonyl, N- 2,4,6-trimethoxybenzene Sulfonyl, N -2,6-dimethyl-4-methoxybenzenesulfonyl, N -pentamethylbenzenesulfonyl, N- 2,3,5,6, -tetramethyl-4-methoxybenzenesulfonyl, N -4-methoxybenzenesulfonyl, N- 2,4,6-trimethylbenzenesulfonyl, N -2,6-dimethoxy-4-methylbenzenesulfonyl, N- 2,2,5,7,8- pentamethyl-chroman-6-sulfonyl, N - methanesulfonyl, N -β-trimethyl silane tanseol sulfonyl, N -9- anthracene sulfonyl, N -4- (4 ', 8'- dimethoxy-naphthylmethyl) benzene Sulfonyl, N -benzylsulfonyl, N -trifluoromethylsulfonyl, N -phenacrylsulfonyl).

More typical protected amino groups include carbamates and amides, and even more typical include -NHC (O) R ¹ or -N = CR ¹ N (R ¹ ) ₂ . Another protecting group useful as a prodrug of amino or -NH (R ⁵ ) is:

이다.

to be.

For example, Alexander, J. et al. (1996) J. Med . Chem . See 39: 480-486.

Amino acids and Polypeptide  Protectors and complexes

The amino acid or polypeptide protecting groups of the compounds of the invention have a R ¹⁵ NHCH (R ¹⁶ ) C (O) -structure, wherein R ¹⁵ is H, an amino acid or polypeptide residue, and R ⁵ and R ¹⁶ are defined below do.

R ¹⁶ is lower alkyl, or amino, carboxyl, amide, carboxyl ester, hydroxyl, C ₆ -C ₇ Lower alkyl (C ₁ -C ₆ ) substituted with aryl, guanidinyl, imidazolyl, indolyl, sulfidyl, sulfoxide, and / or alkylphosphate. R ¹⁰ silver Proline residues along with amino acid αN (R ¹⁰ = -CH ₂ ) _3- ). However, R ¹⁰ is generally, for example, H, —CH ₃ , —CH (CH ₃ ) ₂ , —CH ₂ —CH (CH ₃ ) ₂ , —CHCH ₃ —CH ₂ —CH ₃ , —CH ₂ —C ₆ H ₅ , -CH ₂ CH ₂ -S-CH ₃ , -CH ₂ OH, -CH (OH) -CH ₃ , -CH ₂ -SH, -CH ₂ -C ₆ H ₄ OH, -CH ₂ -CO -NH ₂ , -CH ₂ -CH ₂ -CO-NH ₂ , -CH ₂ -COOH, -CH ₂ -CH ₂ -COOH,-(CH ₂ ) ₄ -NH ₂ and-(CH ₂ ) ₃ -NH- It is a side chain group of natural amino acids, such as C (NH ₂ ) -NH ₂ . R ¹⁰ may also include 1-guanidinoprop-3-yl, benzyl, 4-hydroxybenzyl, imidazol-4-yl, indol-3-yl, methoxyphenyl and ethoxyphenyl.

Another group of protecting groups includes residues of amino containing compounds, especially amino acids, polypeptides, protecting groups, -NHSO ₂ R _, NHC (O) R, -N (R) ₂ , NH ₂ or -NH (R) (H) Thus, here, for example, the carboxylic acid reacts with the amine, i.e., is coupled to form an amide, such as C (O) NR ₂ . Phosphonic acid reacts with the amine to form phosphonamidate, which is -P (O) (OR) (NR ₂ ).

In general, amino acids have the structure R ¹⁷ C (O) CH (R ¹⁶ ) NH—. Wherein R ¹⁷ is —OH, —OR, an amino acid or a P (O) (OR) (NR ₂ ) residue. Amino acids are low molecular weight compounds, less than about 1000 MW, which include at least one amino or imino group and at least one carboxyl group. Generally, amino acids can be found in nature. In other words, it can be detected in biomaterials such as bacteria or other microorganisms, plants, animals or humans. Suitable amino acids are typically compounds characterized by one amino or imino nitrogen atom separated by a single amino acid, ie a single substituted or unsubstituted a carbon atom from the carbon atom of one carboxyl group. Of particular interest are hydrophobic residues such as mono- or di-alkyl or aryl amino acids, cycloalkylamino acids and the like. These residues contribute to cell permeability by increasing the partition coefficient of the parent drug. Typically, such residues do not contain sulfhydryl or guanidino substituents.

Natural amino acid residues are residues that are naturally present in plants, animals or microorganisms, especially their proteins. Most typically, the polypeptide consists essentially of these natural amino acid residues. These amino acids include glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, glutamic acid, aspartic acid, lysine, hydroxylysine, arginine, histidine, phenylalanine, tyrosine, tryptophan, proline, asparagine, glutamine and hydroxy There is proline. In addition, artificial amino acids such as v-alanine, phenylglycine and homoarginine are also included. Amino acids that do not encode the genes encountered in general may also be used in the present invention. All amino acids used in the present invention may be D- or L-type optical isomers. In addition, other peptide structural analogues are also useful in the present invention. For a general overview, see Spatola, AF, Chemistry and Biochemistry of Amino acids, Peptides and Proteins , B. Weinstein, eds., Marcel Dekker, New York, p. 267 (1983).

If the protecting group is a single amino acid residue or polypeptide, they are alternatively substituted at R ³ of substituent A ¹ , A ² or A ³ of the compounds of the invention. Such complexes are produced by the formation of amide bonds between carboxyl groups of amino acids (or, for example, the C-terminal amino acids of a polypeptide). Similarly, the complex is formed between R ³ and amino groups of an amino acid or polypeptide. In general, the introduction of amino acids at one or more possible positions is within the scope of the present invention, but only one of any sites in the parent molecule is amidated with the aforementioned amino acids. In general, the carboxyl group of R ³ is amidated with amino acids. In general, the α-amino or α-carboxyl group of an amino acid or the terminal amino or carboxyl group of a polypeptide is bound to a parent functional group, that is, the carboxyl or amino group in the amino acid side chain, in general, (described further below). Although these groups need to be protected during the synthesis of the complex, they are not used to form amide bonds with the parent compound.

As for the carboxyl group-containing side chain of an amino acid or polypeptide, the carboxyl group is alternatively, for example, R ¹ Blocked or esterified or amidated with R ⁵ . Similarly, amino side chain R ¹⁶ is alternatively blocked by R ¹ or substituted with R ⁵ .

As bound to the parent molecule, such esters or amides bound to side chain amino groups or carboxyl groups can, alternatively, be hydrolyzed under acidic (pH <3) or basic (pH> 10) conditions in vivo or in vitro. . Alternatively, they are substantially stable in the human gastrointestinal tract but enzymatically hydrolyze in the environment in the blood or cells. Ester or amino acid or polypeptide amidates are also useful as intermediates for the preparation of parent molecules containing free amino or carboxyl groups. The free acid or base of the parent compound is readily formed from the ester or amino acid or polypeptide complex of the invention, for example by known hydrolysis methods.

If the amino acid residue has one or more chiral centers, any of D, L, meso, treo or erythro (if appropriate) racemates, scalemates or mixtures thereof may be used. In general, the D isomer is useful if the intermediate is non-enzymatically hydrolyzed (as if the amide is used as a chemical intermediate for free acid or free amine). On the other hand, the L isomer is more general because it is susceptible to both non-enzymatic and enzymatic hydrolysis, and is more efficiently transported by amino acid or dipeptidyl transport systems in the gastrointestinal tract.

Examples of suitable amino acids whose residues are represented by R ^x or R ^y include:

Glycine;

Aminopolycarboxylic acids such as aspartic acid, β-hydroxyaspartic acid, glutamic acid, β-hydroxyglutamic acid, β-methylaspartic acid, β-methylglutamic acid, β, β-dimethylaspartic acid, γ-hydroxyglutamic acid , β, γ-dihydroxyglutamic acid, β-phenylglutamic acid, γ-methyleneglutamic acid, 3-aminoadipic acid, 2-aminopimelic acid, 2-aminosveric acid and 2-aminosebacic acid;

  Amino acid amides such as glutamine and asparagine;

Polyamino- or polybase-monocarboxylic acids such as arginine, lysine, β-aminoalanine, γ-aminobutyrin, ornithine, citrulline, homoarginine, homocitrulline, hydroxylysine, allohydroxylcin and diaminobutyric acid;

 Other base amino acid residues such as histidine;

Diamino dicarboxylic acids such as α, α-diisuccinic acid, α, α-diaminoglutaric acid, α, α-diaminoadipic acid, α, α-diaminopimelic acid, α, α-diamino -β- hydroxypimelic acid, α, α-diaminosveric acid, α, α-diaminoazelaic acid, and α, α-diamino sebacic acid;

Imino acids such as proline, hydroxyproline, allohydroxyproline, g-methylproline, pipecolic acid, 5-hydroxypipecolic acid, and azetidine-2-carboxylic acid;

Mono- or di-alkyl (typical C ₁ -C ₈ branched or normal) amino acids such as alanine, valine, leucine, allylglycine, butyrin, norvaline, norleucine, heptyline, α-methylserine, α- Amino-α-methyl-γ-hydroxy valeric acid, α-amino- α-methyl-δ-hydroxy valeric acid, α-amino-α-methyl-ε-hydroxycaproic acid, isovaline, α-methylglutamic acid α-aminoisobutyric acid, α-aminodiethylacetic acid, α-aminodiisopropylacetic acid, α-aminodi-n-propylacetic acid, α-aminodiisobutylacetic acid, α-aminodi-n-butylacetic acid, α-aminoethylisopropylacetic acid, α-amino-n-propylacetic acid, α-aminodiisoamiacetic acid, α-methylaspartic acid, α-methylglutamic acid, 1-aminocyclopropane-1-carboxylic acid, isoleucine, alloleucine Tert-leucine, β-methyltryptophan and α-amino-β-ethyl-β-phenylpropionic acid;

β-phenylserinyl;

Aliphatic α-amino-β-hydroxy acids such as serine, β-hydroxyleucine, β-hydroxynorleucine, β-hydroxynorvaline, and α-amino-β-hydroxystearic acid;

α-amino, α-, γ-, δ- or ε-hydroxy acids such as homoserine, δ-hydroxynorvaline, γ-hydroxynorvaline and ε-hydroxynorleucine residues; Cannabin and canaryrin; γ-hydroxyornithine;

D-glucosamine acid or D-galactosamic acid, such as 2-hexosamic acid;

α-amino-β-thiols such as penicylamine, β-thiolnorvaline or β-thiolbutyrin;

Sulfur containing amino acid residues comprising cysteine, homocystine, β-phenylmethionine, methionine, S-allyl-L-cysteine sulfoxide, 2-thiol histidine, cystathionine, and thiol ethers of cysteine or homocysteine;

Phenylalanine, tryptophan and ring-substituted α-amino acids such as phenyl- or cyclohexylamino acid α-aminophenylacetic acid, α-aminocyclohexyl acetic acid and α-amino-β-cyclohexylpropionic acid; Aryl substituted with aryl, lower alkyl, hydroxy, guanidino, oxyalkylether, nitro, sulfur or halogen (e.g., tyrosine, methyltyrosine and o-chloro-, p-chloro-, 3,4-dichloro , o- , m- or p -methyl-, 2,4,6-trimethyl-, 2-ethoxy-5-nitro-, 2-hydroxy-5-nitro- and p-nitro-phenylalanine) Phenylalanine analogs and derivatives thereof; Furyl-, thienyl-, pyridyl-, pyrimidinyl-, purinyl- or naphthyl-alanine; And tryptophan analogs and derivatives thereof including kynurenine, 3-hydroxykynurenine, 2-hydroxytryptophan and 4-carboxytryptophan;

Α-amino substitutions including sarcosine (N-methylglycine), N-benzylglycine, N-methylalanine, N-benzylalanine, N-methylphenylalanine, N-benzylphenylalanine, N-methylvaline and N-benzylvaline amino acid; And

Α-hydroxy and substituted α-hydroxy amino acids, including serine, threonine, allothreonine, phosphoserine, and phosphorreonine.

A polypeptide is a polymer of amino acids in which the carboxyl group of one amino acid monomer is bonded to an amino or imino group of an adjacent amino acid monomer by an amide bond. Polypeptides include dipeptides, low molecular weight polypeptides (about 1500-5000 MW) and proteins. The protein alternatively contains 3, 5, 10, 50, 75, 100 or more residues and is suitably substantially identical in sequence to human, animal, plant or microbial protein. These include enzymes (eg, hydrogen peroxidase) and immunogens that elicit an immune response, such as KLH, or the type of antibody or protein, and the like. The nature and identity of polypeptides vary widely.

Polypeptide amidates are useful as immunogens to form antibodies against polypeptides (if they are not immunogens in administered animals) or against epitopes on the remainder of the compounds of the invention.

Antibodies that can bind to the parent bipeptidyl compound are used to separate the parent compound from the mixture, for example in the diagnosis or preparation of the parent compound. Complexes of the parent compound and polypeptide are generally more immunogenic than polypeptides of similar species of animals, thus making the polypeptide more immunogenic by promoting antibody formation against it. Thus, the polypeptide or protein need not be an immunogen in the body of an animal, such as a rabbit, mouse, horse, or rat, typically used to form an antibody. However, the final product complex must be immunogenic in at least one of said animals. The polypeptide may alternatively comprise a peptidase cleavage site at the peptide bond between the first and second residues adjacent to the acidic heteroatoms. This cleavage site is flanked by an enzyme recognition structure. For example, certain sequences of residues are recognized by peptide degrading enzymes.

Peptide degrading enzymes for the degradation of polypeptide complexes of the present invention are well known and in particular include carboxyl peptidase.

Carboxypeptidase degrades polypeptides by removing C-terminal residues and is specific in many cases for certain C-terminus sequences. Conditions for these enzymes and their substrates are generally known. For example, dipeptides (with given pairs of residues and free carboxyl termini) are covalently bonded to their α-amino groups and the phosphorus or carbon atoms of the compounds of the invention. In the claims, if W ₁ is a phosphonate, the peptide is expected to cleave the phosphonoamidate bonds by automatic catalysis by leaving the carboxyl of adjacent amino acid residues by an appropriate peptide degrading enzyme.

Suitable dipeptidyl groups (designated by their single letter codes) are AA, AR, AN, AD, AC, AE, AQ, AG, AH, AI, AL, AK, AM, AF, AP, AS, AT, AW, AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, RI, RL, RK, RM, RF, RP, RS, RT, RW, RY, RV, NA, NR, NN, ND, NC, NE, NQ, NG, NH, NI, NL, NK, NM, NF, NP, NS, NT, NW, NY, NV, DA, DR, DN, DD, DC, DE, DQ, DG, DH, DI, DL, DK, DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC, CE, CQ, CG, CH, CI, CL, CK, CM, CF, CP, CS, CT, CW, CY, CV, EA, ER, EN, ED, EC, EE, EQ, EG, EH, EI, EL, EK, EM, EF, EP, ES, ET, EW, EY, EV, QA, QR, QN, QD, QC, QE, QQ, QG, QH, QI, QL, QK, QM, QF, QP, QS, QT, QW, QY, QV, GA, GR, GN, GD, GC, GE, GQ, GG, GH, GI, GL, GK, GM, GF, GP, GS, GT, GW, GY, GV, HA, HR, HN, HD, HC, HE, HQ, HG, HH, HI, HL, HK, HM, HF, HP, HS, HT, HW, HY, HV, IA, IR, IN, ID, IC, IE, IQ, IG, IH, II, IL, IK, IM, IF, IP, IS, IT, IW, IY, IV, LA, LR, LN, LD, LC, LE, LQ, LG, LH, LI, LL, LK, LM, LF, LP, LS, LT, LW, LY, LV, KA, KR, KN, KD, KC, KE, KQ, KG, KH, KI, KL, KK , KM, KF, KP, KS, KT, KW, KY, KV, MA, MR, MN, MD, MC, ME, MQ, MG, MH, MI, ML, MK, MM, MF, MP, MS, MT , MW, MY, MV, FA, FR, FN, FD, FC, FE, FQ, FG, FH, FI, FL, FK, FM, FF, FP, FS, FT, FW, FY, FV, PA, PR , PN, PD, PC, PE, PQ, PG, PH, PI, PL, PK, PM, PF, PP, PS, PT, PW, PY, PV, SA, SR, SN, SD, SC, SE, SQ , SG, SH, SI, SL, SK, SM, SF, SP, SS, ST, SW, SY, SV, TA, TR, TN, TD, TC, TE, TQ, TG, TH, TI, TL, TK , TM, TF, TP, TS, TT, TW, TY, TV, WA, WR, WN, WD, WC, WE, WQ, WG, WH, WI, WL, WK, WM, WF, WP, WS, WT , WW, WY, WV, YA, YR, YN, YD, YC, YE, YQ, YG, YH, YI, YL, YK, YM, YF, YP, YS, YT, YW, YY, YV, VA, VR , VN, VD, VC, VE, VQ, VG, VH, VI, VL, VK, VM, VF, VP, VS, VT, VW, VY and VV.

Tripeptide residues are also useful as protecting groups. When the phosphonate group is protected, the sequence -X ²⁰⁰ -pro-X ^201- (where X ²⁰⁰ can be any of amino acid residues and X ²⁰¹ is an amino acid residue, a carboxyl ester of proline, or hydrogen) Cleavage by the raw carboxypeptidase results in X ²⁰⁰ with free carboxyl groups, which in turn cleaves the phosphonoamidate bond by an automatic catalytic reaction. The carboxyl group of X ²⁰¹ is, alternatively, esterified with benzyl.

Dipeptides or tripeptides can be selected based on known transport properties and / or susceptibility to peptidase, which can affect delivery to intestinal mucosa or other cell types. Dipeptides and tripeptides without α-amino groups serve as transport substrates for peptide transporters found in the chorionic membranes of intestinal mucosal cells (Bai, JPF, (1992) Pharm Res . 9: 969-978). Peptides with transport capacity can therefore be used to enhance the bioavailability of amidate compounds. Di- or tripeptides having one or more amino acids in the D configuration are also compatible with peptide delivery and may be utilized in the amidate compounds of the invention. The amino acids of the D configuration can be used to reduce the susceptibility to hydrolysis by proteases common to the villi boundaries, such as aminopeptidase N of di- or tripeptides. In addition, di- or tripeptides are alternatively selected based on their relative resistance to hydrolysis by proteases found in the intestinal lining. For example, tripeptides or polypeptides lacking asp and / or glu are poor substrates for aminopeptidase A, and have no amino acid residues at the N-terminal portion of the hydrophobic amino acids (leu, tyr, phe, val, trp). Or tripeptides are poor substrates for endopeptidase and peptides without the precursor residue at the second position at the end of the free carboxyl termini are poor substrates for carboxypeptidase P. Similar considerations can be applied to select peptides that are relatively resistant or relatively sensitive to hydrolysis by cytoplasm, kidney, liver, serum or other peptidase. Such poorly cleaved polypeptide amidates are useful for binding to proteins to become immunogens or generate immunogens.

Specific Embodiments of the Invention

Certain values of radicals, substituents, and ranges, and the particular embodiments of the invention described herein, are illustrative only; They do not exclude other defined values or other values within the defined range.

In certain embodiments of the invention, the complex or pharmaceutically acceptable salt thereof is a compound substituted with one or more phosphonate groups either directly or indirectly through a linker; This may be substituted with one or more groups A ⁰ as necessary. here:

A ⁰ is A ¹ , A ² or W ³ ;

A ¹ is:

이고,

ego,

A ² is:

이며,

Is,

A ³ is:

인데,

Is

Y ¹ is independently O, S, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ) or N (N (R ^x ) (R ^x ) )ego;

Y ² is independently bonded, O, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ), N (N (R ^x ) (R ^x ) ), -S (O) _M2 -or -S (O) _M2 -S (O) _M2- ;

R ^x is independently represented by H, R ¹ , W ³ , a protecting group or the following formula.

;

;

here:

R ^y is independently H, W ³ , R ² or a protecting group;

R ¹ is independently H or alkyl having 1 to 18 carbon atoms;

R ² is independently H, R ¹ , R ³ or R ⁴ , wherein each R ⁴ is independently substituted with 0 to 3 R ³ groups or is bonded together at a carbon atom such that two R ² groups are 3 To 8 carbon rings, which ring may be substituted with 0 to 3 R ³ groups;

R ³ is R ^3a , R ^3b , R ^3c or R ^3d , if R ³ is bonded to a heteroatom, then R ³ Is R ^3c or R ^3d ;

R ^3a is F, Cl, Br, I, -CN, N ₃ or -NO ₂ ;

R ^3b is Y ¹ ;

R ^3c is -R ^x , -N (R ^x ) (R ^x ), -SR ^x , -S (O) R ^x , -S (O) ₂ R ^x , -S (O) (OR ^x ),- S (O) ₂ (OR ^x ), -OC (Y ¹ ) R ^x , -OC (Y ¹ ) OR ^x , -OC (Y ¹ ) (N (R ^x ) (R ^x )), -SC (Y ¹ ) R ^x , -SC (Y ¹ ) OR ^x , -SC (Y ¹ ) (N (R ^x ) (R ^x )), -N (R ^x ) C (Y ¹ ) R ^x , -N (R ^x ) C (Y ¹ ) OR ^x , or —N (R ^x ) C (Y ¹ ) (N (R ^x ) (R ^x ));

R ^3d is —C (Y ¹ ) R ^x , —C (Y ¹ ) OR ^x or —C (Y ¹ ) (N (R ^x ) (R ^x ));

R ⁴ is alkyl having 1 to 18 carbon atoms, alkenyl having 2 to 18 carbon atoms, or alkynyl having 2 to 18 carbon atoms;

R ⁵ is R ⁴ , wherein each R ⁴ is substituted with 0-3 R ³ groups;

R ^5a Is independently alkylene having 1 to 18 carbon atoms, alkenylene having 2 to 18 carbon atoms, or alkynylene having 2 to 18 carbon atoms, and any one of alkylene, alkenylene or alkynylene is 0 to 3 R ³ Substituted with a group;

W ³ is W ⁴ or W ⁵ ;

W ⁴ is R ⁵ , -C (Y ¹ ) R ⁵ , -C (Y ¹ ) W ⁵ , -SO ₂ R ⁵ or -SO ₂ W ⁵ ;

W _⁵ is a carbocycle or heterocycle, wherein W ⁵ is independently substituted with 0 to 3 R _² groups;

W ⁶ is independently W ³ substituted with 1, 2 or 3 A ³ groups;

M 2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M 12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

Mla, Mlc, and Mld are independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In another specific embodiment of the present invention, A ¹ is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ¹ is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ¹ is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ¹ is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ¹ is represented by the following formula.

;

;

W ^5a is a carbocycle or heterocycle, wherein W ^5a is independently substituted with 0 or 1 R ² groups. The specific value of M12a is 1.

In another specific embodiment of the present invention, A ¹ is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ¹ is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ¹ is represented by the following formula.

;

;

Wherein W ^5a is a carbocycle and is independently substituted with 0 or 1 R ² groups;

In another specific embodiment of the present invention, A ¹ is represented by the following formula.

;

;

Wherein Y ^2b is O or N (R 2); M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the present invention, A ¹ is represented by the following formula.

;

;

Wherein W ^5a is a carbocycle and is independently substituted with 0 or 1 R ² groups.

In another specific embodiment of the present invention, A ¹ is represented by the following formula.

;

;

Wherein W ^5a is a carbocycle or heterocycle, where W ^5a is independently substituted with 0 or 1 R ² groups.

In another specific embodiment of the present invention, A ¹ is represented by the following formula.

;

;

Wherein Y ^2b is O or N (R 2); M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In certain embodiments of the present invention, A ² is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ² is represented by the following formula.

;

;

In another specific embodiment of the present invention, M12b is one.

In another specific embodiment of the invention, M12b is 0, Y ² is a bond and W ⁵ is a carbocycle or heterocycle, wherein W ⁵ is, alternatively, independently 1, 2 or 3 R Substituted with ² groups.

In another specific embodiment of the present invention, A ² is represented by the following formula.

;

;

Wherein W ^5a is a carbocycle or heterocycle, where W ^5a is alternatively and independently substituted with 1, 2 or 3 R ² groups.

In another specific embodiment of the present invention, M12a is one.

In another specific embodiment of the present invention, A ² is selected from phenyl, substituted phenyl, benzyl, substituted benzyl, pyridyl and substituted pyridyl.

In another specific embodiment of the present invention, A ² is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ² is represented by the following formula.

;

;

In another specific embodiment of the present invention, M12b is one.

In certain embodiments of the present invention, A ³ is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^1a is O or S; Y ^2a is O, N (R ^x ) or S.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^2b is O or N (R ^x ).

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^2b is O or N (Rx); M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^2b is O or N (Rx); M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the present invention, M12d is one.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

In another particular embodiment of the invention, W ⁵ is carbocycle.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

In another particular embodiment of the invention, W ⁵ is phenyl.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^1a is O or S; Y ^2a is O, N (R ^x ) or S.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^2b is O or N (R ^x ).

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^2b is O or N (Rx); M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another particular embodiment of the invention, R ¹ is H.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein the phenyl carbocycle is substituted with 0, 1, 2 or 3 R ² groups.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^1a is O or S; Y ^2a is O, N (R ² ) or S.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^1a is O or S; Y ^2b is O or N (R 2); Y ^2c is O, N (R ^y ) or S.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^1a is O or S; Y ^2b is O or N (R 2); Y ^2d is O or N (Ry); M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^2b is O or N (R 2); M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

Wherein Y ^2b is O or N (R ² ).

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^1a is O or S; Y ^2a is O, N (R ² ) or S.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^1a is O or S; Y ^2b is O or N (R 2); Y ^2c is O, N (R ^y ) or S.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^1a is O or S; Y ^2b is O or N (R 2); Y ^2d is O or N (Ry); M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^2b is O or N (R 2); M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^2b is O or N (R ² ).

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein: Y ^2b is O or N (Rx); M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein the phenyl carbocycle is substituted with 0, 1, 2 or 3 R ² groups.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein the phenyl carbocycle is substituted with 0, 1, 2 or 3 R ² groups.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

In certain embodiments of the invention, A ⁰ is represented by the formula:

;

;

Wherein each R is independently (C ₁ -C ₆ ) alkyl.

In certain embodiments of the invention, R ^x is independently represented by H, R ¹ , W ³ , a protecting group or the following formula:

here:

R ^y is independently H, W ³ , R ² or a protecting group;

R ¹ is independently H or alkyl having 1 to 18 carbon atoms;

R ² is independently H, R ¹ , R ³ or R ⁴ , wherein each R ⁴ is independently substituted with 0 to 3 R ³ groups or is bonded together at a carbon atom such that two R ² groups are 3 To 8 carbon rings, which ring is substituted with 0 to 3 R ³ groups.

In certain embodiments of the invention, R ^x is represented by the formula:

;

;

Wherein Y ^1a is O or S; Y ^2c is O, N (R ^y ) or S.

In certain embodiments of the invention, R ^x is represented by the formula:

;

;

Wherein Y ^1a is O or S; Y ^2d is O or N (R ^y ).

In certain embodiments of the invention, R ^x is represented by the formula:

;

;

In certain embodiments of the invention, R ^y is hydrogen or alkyl of 1 to 10 carbons.

In certain embodiments of the invention, R ^x is represented by the formula:

;

;

In certain embodiments of the invention, R ^x is represented by the formula:

In certain embodiments of the invention, R ^x is represented by the formula:

;

;

In certain embodiments of the invention, Y ¹ is O or S.

In certain embodiments of the invention, Y ² is O, N (R ^y ) or S.

In certain embodiments of the invention, R ^x is a group of formula:

;

;

here:

m1a, m1b, m1c, m1d and m1e are independently 0 or 1;

m12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

R ^y is H, W ³ , R ² or a protecting group;

only,

if m1a, m12c, and m1d are zero, m1b, m1c and m1e are zero;

if m1a and m12c are zero and m1d is nonzero, m1b and m1c are zero;

if m1a and m1d are zero and m12c is not zero, then m1b and at least one of m1c and m1e is zero;

 if m1a is zero and m12c and m1d are not zero, m1b is zero;

 if m12c and m1d are zero and m1a is not zero, at least two of m1b, m1c and m1e are zero;

if m12c is 0 and m1a and m1d are not zero, at least one of m1b and m1c is 0; If m1d is zero and m1a and m12c are not zero, at least one of m1c and m1e is zero.

In another particular embodiment, the present invention provides a compound of Formula 1-108 . here:

A ⁰ is A ¹ ;

A ¹ is:

이고,

ego,

A ³ is:

인데,

Is

here:

Y ¹ is independently O, S, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ), or N (N (R ^x ) (R ^x ))ego;

Y ² is independently one bond, O, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ), N (N (R ^x ) (R ^x )), -S (O) _M2- , or -S (O) _M2 -S (O) _M2- ;

R ^x is independently H, W ³ , a protecting group, or formula:

이며;

Is;

R ^y is independently H, W ³ , R ² or a protecting group;

R ¹ is independently H or alkyl having 1 to 18 carbon atoms;

R ² is independently H, R ³ or R ⁴ , wherein each R ⁴ is independently substituted with 0-3 R ³ groups;

R ³ is R ^3a , R ^3b , R ^3c or R ^3d , but if R ³ is bonded to a heteroatom, R ³ is R ^3c or R ^3d ;

R ^3a is F, Cl, Br, I, -CN, N ₃ or -NO ₂ ;

R ^3b is Y ¹ ;

R ^3c is -R ^x , -N (R ^x ) (R ^x ), -SR ^x , -S (O) R ^x , -S (O) ₂ R ^x , -S (O) (OR ^x ),- S (O) ₂ (OR ^x ), -OC (Y ¹ ) R ^x , -OC (Y ¹ ) OR ^x , -OC (Y ¹ ) (N (R ^x ) (R ^x )), -SC (Y ¹ ) R ^x , -SC (Y ¹ ) OR ^x , -SC (Y ¹ ) (N (R ^x ) (R ^x )), -N (R ^x ) C (Y ¹ ) R ^x , -N (R ^x ) C (Y ¹ ) OR ^x or -N (R ^x ) C (Y ¹ ) (N (R ^x ) (R ^x ));

R ^3d is —C (Y ¹ ) R ^x , —C (Y ¹ ) OR ^x or —C (Y ¹ ) (N (R ^x ) (R ^x ));

R ⁴ is alkyl having 1 to 18 carbon atoms, alkenyl having 2 to 18 carbon atoms, or alkynyl having 2 to 18 carbon atoms;

R ⁵ is R ⁴ , wherein each R ⁴ is substituted with 0-3 R ³ groups;

R ^5a is independently alkylene having 1 to 18 carbon atoms, alkenylene having 2 to 18 carbon atoms, or alkynylene having 2 to 18 carbon atoms, wherein one of alkylene, alkenylene or alkynylene is 0 to 3 R Substituted with ³ groups;

W ³ is W ⁴ or W ⁵ ;

W ⁴ is R ⁵ , -C (Y ¹ ) R ⁵ , -C (Y ¹ ) W ⁵ , -SO ₂ R ⁵ or -SO ₂ W ⁵ ;

W ⁵ is carbocycle or heterocycle, where W ⁵ is independently substituted with 0 to 3 R ² groups;

W ⁶ is independently W ³ substituted with 1, 2, or 3 A ³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

Mla, Mlc, and Mld are independently 0 or 1;

M 12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In the compounds of the present invention, the W ⁵ carbocycle and W ⁵ heterocycle may be independently substituted with 0 to 3 R ² groups. W ⁵ may be an aromatic ring comprising a saturated, unsaturated or mono- or bicyclic carbocycle or heterocycle. W ⁵ may have 3 to 10 ring atoms, such as 3 to 7 ring atoms. The W ⁵ ring is saturated if it contains 3 ring atoms, saturated if it contains 4 ring atoms or saturated if it is a mono-unsaturated 5 ring atom, or mono- or di-unsaturated, and saturated if it is a 6 ring atom, Mono- or di-unsaturated, or aromatic.

W ⁵ heterocycle is a monocyclic having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or a ring having 4 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S). W ⁵ heterocycle monocyclic is 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S); 5 or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms selected from N and S). W ⁵ heterocycle bicyclic is a 7-10 ring atom (6-9 carbon atoms) arranged as a bicyclic [4,5], [5,5], [5,6], or [6,6] system And 1 to 2 heteroatoms selected from N, O, and S); Or 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2 hetero atoms selected from N and S) arranged as bicyclic [5,6] or [6,6] systems. W ⁵ above Heterocycles may be bonded to Y ² via carbon, nitrogen, sulfur or other atoms by stable covalent bonds.

W ⁵ heterocycles are, for example, pyridyl, dihydropyridyl isomers, piperidine, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxa Zolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, and pyrrolyl. W ⁵ also includes, but is not limited to, the following examples:

W ⁵ carbocycles and heterocycles may be independently substituted with 0 to 3 R ² groups as described above. For example, substitution W ⁵ Carbocycles include:

Examples of substituted phenyl carbocycles include:

Formula III complex

In certain embodiments, the present invention provides a complex of formula III:

III

III

Or pharmaceutically acceptable salts or solvates thereof;

here:

B is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebularin, Nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcyto Sin, isocytocin, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine, O ⁴ -Methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazoles, and pyrazole [3,4-d] pyrimidines;

X is selected from O, C (R ^y ) ₂ , OC (R ^y ) ₂ , NR and S;

Z is independently selected from H, OH, OR, NR ₂ , CN, NO ₂ , SH, SR, F, Cl, Br and I;

Y ¹ is independently O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR) or N-NR ₂ ;

Y ² is independently O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N-NR ₂ , S, SS, S (O) or S (O) ₂ ;

M2 is 0, 1 or 2;

R ^y is independently H, F, Cl, Br, I, OH, -C (= Y ¹ ) R, -C (= Y ¹ ) OR, -C (= Y ¹ ) N (R) ₂ , -N (R) ₂ ,- ⁺ N (R) ₃ , -SR, -S (O) R, -S (O) ₂ R, -S (O) (OR), -S (O) ₂ (OR), -OC (= Y ¹ ) R, -OC (= Y ¹ ) OR, -OC (= Y ¹ ) (N (R) ₂ ), -SC (= Y ¹ ) R, -SC (= Y ¹ ) OR , -SC (= Y ¹ ) (N (R) ₂ ), -N (R) C (= Y ¹ ) R, -N (R) C (= Y ¹ ) OR, or -N (R) C ( = Y ¹ ) N (R) ₂ , amino (-NH ₂ ), ammonium (-NH ₃ ⁺ ), alkylamino, dialkylamino, trialkylammonium, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkylhalide , Carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sulfam, C ₁ -C ₈ alkylsulfonate, C ₁ -C ₈ alkylamino, 4-dialkylaminopyridinium, C ₁ -C ₈ alkyl Hydroxyl, C ₁ -C ₈ alkylthiol, alkylsulfone (-SO ₂ R), arylsulfone (-SO ₂ Ar), arylsulfoxide (-SOAr), arylthio (-SAr), sulfonamide (-SO ₂ NR ₂ ), alkylsulfoxide (-SOR), ester (-C (= O) OR), amido (-C (= O) NR ₂ ), 5-7 member cyclic lactam, 5-7 member cyclic lactone, Nitrile (-CN), Azido (-N ₃ ), Ni Tro (-NO ₂ ), C ₁ -C ₈ alkoxy (-OR), C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl, C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle, C ₂ -C ₂₀ substituted heterocycle, poly Ethylenoxy or W ³ ; Or combine together, R ^y forms a carbocyclic ring having 3 to 7 carbon atoms;

R ^x is independently R ^y , a protecting group or formula:

here:

Mla, Mlc, and Mld are independently 0 or 1;

M 12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

R is C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl , C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle, C ₂ -C ₂₀ substituted heterocycle or a protecting group;

W ³ is W ⁴ or W ⁵ , wherein W ⁴ is R, —C (Y ¹ ) R ^y , —C (Y ¹ ) W ⁵ , —SO ₂ R ^y , or —SO ₂ W ⁵ ; W ⁵ is carbocycle or heterocycle, where W ⁵ is independently substituted with 0 to 3 R ^y groups.

In one specific embodiment of the complex of Formula III, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ substituted alkynyl, C ₆ -C ₂₀ substituted aryl and C ₂ -C ₂₀ substituted heterocycles are independently F, Cl, Br, I, OH, -NH ₂ , -NH ₃ ⁺ , -NHR, -NR ₂ , -NR ₃ ⁺ , C ₁ -C ₈ alkylhalide, carboxylate, sulfate , Sulfamate, sulfonate, 5-7 membered ring sulfam, C ₁ -C ₈ alkylsulfonate, C ₁ -C ₈ alkylamino, 4-dialkylaminopyridinium, C ₁ -C ₈ alkylhydroxyl, C ₁ -C ₈ alkylthiol, -SO ₂ R, -SO ₂ Ar, -SOAr, -SAr, -SO ₂ NR ₂ , -SOR, -CO ₂ R, -C (= O) NR ₂ , 5-7 membered ring Lactam, 5-7 member cyclic lactone, -CN, -N ₃ , -NO ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ trifluoroalkyl, C ₁ -C ₈ alkyl, C ₃ -C ₁₂ carbo Cycle, C ₆ -C ₂₀ aryl, C ₂ -C ₂₀ heterocycle, polyethylenoxy, phosphonate, phosphate and prodrug moieties.

In one particular embodiment of the complex of formula III, the protecting group is selected from carboxyl esters, carboxamides, aryl ethers, alkyl ethers, trialkylsilyl ethers, sulfonic acid esters, carbonates and carbamates.

In one specific embodiment of the complex of Formula III, W ⁵ is selected from the following formula:

In one particular embodiment, in the complex of Formula III, X is O and each R ^y is H.

In one specific embodiment, the complex of Formula III is a dissolved enantiomer having the formula:

;

;

In one specific embodiment, the complex of Formula III is a dissolved enantiomer having the formula:

;

;

In one specific embodiment, the complex of Formula III has the formula:

;

;

In one specific embodiment, the complex of Formula III has the formula:

;

;

In one specific embodiment, the complex of Formula III has the formula:

;

;

In one specific embodiment, the complex of Formula III has the formula:

;

;

In one specific embodiment, the complex of Formula III has the formula:

;

;

In one specific embodiment, the complex of Formula III has the formula:

;

;

Wherein R ² is H or C ₁ -C ₈ alkyl.

In one specific embodiment, the complex of Formula III has the formula:

;

;

In one specific embodiment, the complex of Formula III has the formula:

;

;

In certain embodiments, Z is H and B is adenine.

In one specific embodiment, the complex of Formula III has the formula:

;

;

Where Y ^2c is O, N (R ^y ) or S.

In one specific embodiment, the complex of Formula III has the formula:

;

;

In certain embodiments, Y ^2c is O or N (CH ₃ ).

In one specific embodiment, the complex of formula III, the substituted triazole, has the structure:

;

;

In one specific embodiment, the complex of Formula III has the formula:

;

;

here:

B is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebularin, Nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcyto Sin, isocytocin, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine, O ⁴ -Methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazoles and pyrazole [3,4-D] pyrimidines;

X is selected from O, C (R ^y ) ₂ , OC (R ^y ) ₂ , NR and S;

Z is independently selected from H, OH, OR, NR ₂ , CN, NO ₂ , SH, SR, F, Cl, Br and I;

Y ² is independently O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N-NR ₂ , S, SS, S (O) or S (O) ₂ ;

R ^y is independently H, F, Cl, Br, I, OH, -C (= Y ¹ ) R, -C (= Y ¹ ) OR, -C (= Y ¹ ) N (R) ₂ , -N (R) ₂ ,- ⁺ N (R) ₃ , -SR, -S (O) R, -S (O) ₂ R, -S (O) (OR), -S (O) ₂ (OR), -OC (= Y ¹ ) R, -OC (= Y ¹ ) OR, -OC (= Y ¹ ) (N (R) ₂ ), -SC (= Y ¹ ) R, -SC (= Y ¹ ) OR , -SC (= Y ¹ ) (N (R) ₂ ), -N (R) C (= Y ¹ ) R, -N (R) C (= Y ¹ ) OR, or -N (R) C ( = Y ¹ ) N (R) ₂ , amino (-NH ₂ ), ammonium (-NH ₃ ⁺ ), alkylamino, dialkylamino, trialkylammonium, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkylhalide , Carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sulfam, C ₁ -C ₈ alkylsulfonate, C ₁ -C ₈ alkylamino, 4-dialkylaminopyridinium, C ₁ -C ₈ alkyl Hydroxyl, C ₁ -C ₈ alkylthiol, alkylsulfone (-SO ₂ R), arylsulfone (-SO ₂ Ar), arylsulfoxide (-SOAr), arylthio (-SAr), sulfonamide (-SO ₂ NR ₂ ), alkylsulfoxide (-SOR), ester (-C (= O) OR), amido (-C (= O) NR ₂ ), 5-7 member cyclic lactam, 5-7 member cyclic lactone, Nitrile (-CN), Azido (-N ₃ ), Ni Tro (-NO ₂ ), C ₁ -C ₈ alkoxy (-OR), C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl, C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle, C ₂ -C ₂₀ substituted heterocycle, poly Ethylenoxy or W ³ ; Or combine together, R ^y forms a carbocyclic ring having 3 to 7 carbon atoms;

R is C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl , C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle, C ₂ -C ₂₀ substituted heterocycle or a protecting group;

PG is a protecting group selected from ether-forming groups, ester-forming groups, silyl-ether forming groups, amide-forming groups, acetal-forming groups, ketal-forming groups, carbonate-forming groups, carbamate-forming groups, amino acids, and polypeptides.

In certain embodiments, the present invention provides a virus of an animal infected with a virus comprising administering to a said animal the pharmaceutical composition or formulation comprising an effective amount of a complex of formula (III) or a pharmaceutically acceptable salt or solvate thereof. Provided are methods for treating or preventing infection effects and symptoms.

In certain embodiments, the present invention provides a viral infection effect of an infected animal consisting of administering a pharmaceutical composition or formulation comprising a complex of formula (III) or a pharmaceutically acceptable salt or solvate thereof to an animal infected with the virus and Provides a way to treat or prevent symptoms.

In certain embodiments, the invention also provides a pharmaceutical combination composition or formulation comprising an effective amount of a complex of formula (III) or a pharmaceutically acceptable salt or solvate thereof and a secondary compound having antiviral properties. A method of treating or preventing a viral infection effect or symptom in an infected animal consisting of administering to the animal is provided.

In certain embodiments, the invention also provides pharmaceutical compositions comprising an effective amount of a complex or pharmaceutically acceptable salt of formula III or a solvate thereof and a pharmaceutically acceptable excipient.

In certain embodiments, the invention also provides a method of inhibiting a viral enzyme comprising contacting a complex suspected of containing a virus infected cell or tissue or a pharmaceutically acceptable salt or solvate thereof. To provide.

In certain embodiments, the invention also relates to the effect of viral infection in an animal consisting of administering a formulation comprising a therapeutically effective amount of a complex of formula (III) or a pharmaceutically acceptable salt or solvate thereof to an animal infected with the virus or Provides a way to treat or prevent symptoms.

In certain embodiments, the invention also provides the use of a complex of formula (III) or a pharmaceutically acceptable salt or solvate thereof for the preparation of a therapeutic for a viral infection.

In certain embodiments, the invention also provides complexes or pharmaceutically acceptable salts or solvates thereof of Formula III capable of accumulating in human PBMCs.

In certain embodiments, the present invention also provides a complex (eg, formula III). Wherein the bioavailability of the intracellular metabolites of the complex or complex in human PBMCs was improved compared to corresponding analogs without phosphonate groups. For example, in certain embodiments, half-life has been improved by at least about 50%; In another embodiment, the half life is at least about 100%; And in another embodiment, the half-life has improved at least 100%.

In certain embodiments, the present invention also provides an effective amount of a complex of formula (III) or a pharmaceutically acceptable salt or solvate thereof; Pharmaceutically acceptable excipients; And a therapeutically effective amount of an AIDS therapeutic agent selected from HIV inhibitors, anti-infective agents, and immunomodulators.

In certain embodiments, the present invention also provides an effective amount of a complex of formula (III) or a pharmaceutically acceptable salt or solvate thereof; Pharmaceutically acceptable excipients; And a therapeutically effective amount of an HIV-protease inhibitor.

In certain embodiments, the present invention also provides an effective amount of a complex of formula (III) or a pharmaceutically acceptable salt or solvate thereof; Pharmaceutically acceptable excipients; And a therapeutically effective amount of a reverse transcriptase inhibitor.

In certain embodiments, the present invention also provides an effective amount of a complex of formula (III) or a pharmaceutically acceptable salt or solvate thereof; Pharmaceutically acceptable excipients; And a therapeutically effective amount of a non nucleoside reverse transcriptase inhibitor.

In certain embodiments, the present invention also provides an effective amount of a complex of formula (III) or a pharmaceutically acceptable salt or solvate thereof; Pharmaceutically acceptable excipients; And a therapeutically effective amount of an HIV integrase inhibitor.

In certain embodiments, the present invention also provides a method of preparing a pharmaceutical composition comprising combining a complex of formula (III) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient.

In certain embodiments, the invention also provides for the administration of an RNA-dependent RNA polymerase comprising administering to a mammal in need of such treatment a therapeutically effective amount of a complex or pharmaceutically acceptable salt or solvate thereof. Provide a method of inhibition.

In certain embodiments, the invention also provides a method of treating HCV infection comprising administering to a mammal in need thereof a therapeutically effective amount of a complex or pharmaceutically acceptable salt of formula III or a solvate thereof. do.

In certain embodiments, the invention also treats a disease affecting leukocyte cells comprising administering a complex of formula III or a pharmaceutically acceptable salt or solvate thereof to a patient in need thereof. Provide a way to.

In certain embodiments, the present invention also provides a method of preparing an HCV inhibitor complex having selectivity and desired pharmaceutical activity against white blood cells, including a chemically synthesized complex of Formula III (as described herein). do. Wherein the complex is a secondary structure of a compound known to have the desired pharmacological activity as described above since at least one hydrogen atom of the secondary structure has been replaced by an organic substituent comprising a prodrug moiety or an initial prodrug moiety. Is different from

In certain embodiments, the invention also relates to RNA-dependent RNA polymerase inhibitors in leukocyte cells comprising administering to a sample a composition comprising a complex of formula III or a pharmaceutically acceptable salt or solvate thereof. Provided are methods for accumulating compounds. In one particular embodiment, the sample is a patient.

coupler  And Connection

The present invention provides a complex composed of antiviral compounds linked to one or more phosphonate groups either directly (eg covalent bonds) or via linkages (linkers). The nature of the linker should not inhibit the action of the compound containing phosphonate as a therapeutic agent. The phosphonate or linker removes hydrogen or any portion of the compound to provide an open valence for linking to the phosphonate or linker, thereby removing the compound (eg, Formula 501-569 at any synthesizable position on the compound). Compound).

In one embodiment of the present invention, the linking group or linking group (designated L) may comprise all or part of the aforementioned A ⁰ , A ¹ , A ² or W ³ groups.

In another embodiment of the present invention, the linking group or linking group may have a molecular weight of about 20 Daltons to about 400 Daltons.

In another embodiment of the invention the linker or linker has a length of about 5 angstroms to about 300 angstroms

In another embodiment of the invention, the linking group or linker separates the DRUG and P (= Y ¹ ) residues from about 5 angstroms to about 200 angstroms in length.

In another embodiment of the present invention the linking group or linking group is a hydrocarbon chain having 2 to 25 carbon atoms which is divalent, branched or straight chain, saturated or unsaturated. Wherein one or more carbon atoms (eg . 1, 2, 3, or 4) is, alternatively, substituted with (—O—), wherein the chain is, alternatively, on the carbon (C ₁ − C ₆ ) alkoxy, (C ₃ -C ₆ ) cycloalkyl, (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkanoyloxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆₎ alkylthio, azido, cyano, for nitro, halide, hydroxy, oxo (= O), carboxyl, aryl, aryloxy, at least one selected from heteroaryl, and heteroaryloxy (e 1, 2, 3, or 4) substituents.

In another embodiment of the invention the linking group or linking group is represented by the formula WA wherein A is (C ₁ -C ₂₄ ) alkyl, (C ₂ -C ₂₄ ) alkenyl, (C ₂ -C ₂₄ ) alkynyl, (C ₃ -C ₈ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl, or a combination thereof, wherein W is -N (R) C (= 0)-, -C (= 0) N (R)-, -OC (= O)-, -C (= O) O-, -O-, -S-, -S (O)-, -S (O) _2- , -N (R)-, -C ( = O)-or a direct bond; Wherein each R is independently H or (C ₁ -C ₆ ) alkyl.

In another embodiment of the invention the linking group or linking group is a divalent radical formed of a peptide.

In another embodiment of the present invention, the linking group or linking group becomes a divalent radical formed of amino acid.

In another embodiment of the present invention, the linking group or linking group is poly-L-glutamic acid, poly-L-aspartic acid, poly-L-histidine, poly-L-ornithine, poly-L-serine, poly-L-threonine , A divalent radical formed of poly-L-tyrosine, poly-L-leucine, poly-L-lysine-L-phenylalanine, poly-L-lysine or poly-L-lysine-L-tyrosine.

In another embodiment of the invention the linking group or linking group is of the formula W— (CH ₂ ) _n wherein n is between about 1 and about 10; W is -N (R) C (= O)-, -C (= O) N (R)-, -OC (= O)-, -C (= O) O-, -O-, -S- , -S (O)-, -S (O) _2- , -C (= O)-, -N (R)-, or a direct bond; Wherein each R is independently H or (C ₁ -C ₆ ) alkyl.

In another embodiment of the invention the linking group or linking group is methylene, ethylene or propylene.

In another embodiment of the present invention, the linking group or linking group is bonded to the phosphonate group through the carbon atom of the linking group.

Intracellular Targeting

The phosphonate groups of the compounds of the invention can be degraded in vivo, ie in cells, after reaching the desired site of the reaction. Intracellular reaction mechanisms may involve initial degradation. For example, esterases give an electrically negative locked-in intermediate. Decomposition of the terminal ester groups of the compounds of the present invention yields unstable intermediates that release electrically negative fixed intermediates.

After penetrating into cells, intracellular enzymatic degradation or modification of the phosphonate or prodrug compound may result in intracellular accumulation of the compound degraded or modified by the capture mechanism. Decomposed or modified compounds can fix cells by significantly changing charge, polarity, or other physical properties. This change reduces the rate at which degraded or modified compounds escape cells compared to the rate at which the phosphonate prodrug is introduced. Other mechanisms by which the therapeutic effect can be achieved may also work together. Enzymes that enable the activation mechanism of the phosphonate prodrugs of the compounds of the present invention include, but are not limited to, amidase, esterase, microbial enzyme, phospholipase, cholinesterase, and phosphatase.

As mentioned above, it is clear that many other drugs can be induced to be consistent with the present invention. Numerous such drugs are specifically mentioned herein. It is to be understood that this is by way of example only and not intended to exclude pharmacies and modifications thereof for the modifications according to the invention.

Antiviral compounds

Compounds of the present invention include those having antiviral activity. Compounds of the present invention comprise one or more (eg, 1, 2, 3, or 4) phosphonate groups that may be prodrug moieties.

 Antiviral Compounds Includes compounds with antiviral activity. In particular, the compounds include dehydroepiandrosterone, LY-582563, L-Fd4C, L-FddC, telbivudine, clevudine, macrocyclic protease inhibitors, dOTCP, dOTC, DDL DDLP, ddcP, ddC, DADP, DAPD, d4TP, D4T, 3TC, 3TCP FTCP, ABCP, AZT, IsoddAP, FTC, HCV polymerase inhibitors, ribavirin, viramidine, vivavirin and viramidine L-enantiomer, levovirin, alkovirs, imiquimod, resquimod, 4- (3-benzyl-phenyl) -2-hydroxy-4-oxo -But-2-enoic acid, propenone derivatives with HIV inhibitory activity, aza, polyazanaphthalenyl carboxamide, betulinic acid, dihydrobetulinic acid, isdd a, UT-231B, VX-148, gemcitabine ( gemcitabine, merimepodib, levamisole, mycophenolate, entecavir, foscanet rnet), carbovir, abacavir, and BCX-1777.

Typical compounds of the present invention have a molecular weight of about 400 amu to about 10,000 amu; In certain embodiments of the invention, the compound has a molecular weight of less than about 5000 amu; In another particular embodiment of the invention, the compound has a molecular weight of less than about 2500 amu; In another particular embodiment of the invention, the compound has a molecular weight of less than about 1000 amu; In another particular embodiment of the invention, the compound has a molecular weight of less than about 800 amu; In another particular embodiment of the invention, the compound has a molecular weight of less than about 600 amu; And in another particular embodiment of the invention, the compound has a molecular weight of less than about 600 amu and a molecular weight of at least about 400 amu.

Compounds of the invention also typically have a logD (polar) of less than about 5. In some embodiments, the present invention provides compounds with a logD of less than about 4; In another embodiment of the invention, there is provided a compound having a logD of less than about 3; In another embodiment of the invention, there is provided a compound having a logD of at least about −5; In another embodiment of the invention provides compounds having a logD of about −3 or greater; And another embodiment of the present invention provides compounds having a logD of about 0 or greater and less than about 3.

In some embodiments, the invention belongs to the general definition of an antiviral compound and further includes a phosphonate group such as a phosphonate diester, phosphonamidate-ester prodrug or phosphondiamidate-ester (Jiang And US Patent 2002/0173490 A1).

Substituents selected from the scope of the compounds of the invention are provided in the circulation. As used herein, "cyclic substituent" means that the substituent can repeat the vehicle body again. Because of the cyclic nature of these substituents, in theory, many of the given claims may be provided. For example, R ^x Includes a R ^y substituent. R ^y may be R ² , which in turn may be R ³ .

R ³ may be selected as R ^3c and secondly R ^x may be selected. Those skilled in the art of medical chemistry understand that the total number of such substituents is suitably limited by the desired properties of the intended compound. Such properties include physical properties such as molecular weight, solubility or log P, application properties such as activity for the intended purpose, and practical properties such as ease of synthesis. This is an example only and not a limitation.

The following is only an example and is not limited thereto. W ³ , R ^y and R ³ are all cyclic substituents in certain claims. Typically, these are each independently given 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, Can occur 1 or 0 times. More typically, this may occur 12 or fewer times each independently within a given claim. More typically, W ³ can occur 0 to 8 times, R ^y can occur 0 to 6 times and R ³ can occur within a given claim 0 to 10 times. Even more typically, W ³ may occur from 0 to 6 times, R ^y from 0 to 4 times and R ³ from 0 to 8 times within a given claim.

Cyclic substituents are intended by the present invention. Those of ordinary skill in the medical chemistry community understand the currency of such substituents, and to some extent cyclic substituents are provided in the claims of the present invention. The total number will be determined as described above.

When a compound herein is substituted with one or more identically designated groups, such as R ¹ or R ^6a , it is to be understood that the groups are the same or different. In other words, each group is selected independently. The dashed line indicates the position of the covalent bond to an adjacent group, part, or atom.

The phosphonate group can be a phosphonate prodrug moiety. The prodrug moiety is sensitive to hydrolysis but is not limited to pivaloyloxymethyl carbonate (POC) or POM groups. Alternatively, the prodrug moiety may be sensitive to enzymatic potential degradation such as lactate ester or phosphonamidate-ester groups and the like.

In one embodiment of the invention, the compound is not an anti-inflammatory compound; In another embodiment it is not a compound anti-infective; In another embodiment, the compound is not a compound that is active against immune mediated diseases; In another embodiment, the compound is not an anticancer compound; In another embodiment, the compound is not a compound active against metabolic disease; In another embodiment, the compound is not a nucleoside; In another embodiment, the compound is not an IMPDH inhibitor; In another embodiment, the compound is not an anti metabolite; In another embodiment, the compound is not a PNP inhibitor; In another embodiment compounds of the formula 509 - is not a substituted compound of any of 510, 556-557, and 559-562; In another embodiment , the compound is not one of Formulas 13-18, 72, 77-83, and 90-102 .

In one embodiment of the present invention, the compound is present in isolated and purified form. In general, the term "isolated and purified" means that the compound is substantially the biological material (e. G. Blood, tissue, cells, etc.) is glass. In certain embodiments of the invention, the term means that at least about 50% by weight of the compounds or complexes of the invention are free from the biological material; In another particular embodiment, the term means that at least about 75% by weight of the compounds or complexes of the invention are free from the biological material; In another particular embodiment, the term means that at least about 90% by weight of the compounds or complexes of the invention are free from the biological material; In another particular embodiment, the term means that at least about 98% by weight of the compounds or complexes of the invention are free from the biological material; And in yet another embodiment, the term means that at least about 99% by weight of the compounds or complexes of the invention are free from the biological material. In another particular embodiment of the invention, there is provided a compound or complex of the invention, prepared synthetically (eg, in vitro).

Cell accumulation

In some embodiments, the present invention provides compounds that can accumulate in human PBMCs (peripheral blood mononuclear cells). PBMC means blood cells with circular lymphocytes and monocytes. Physiologically, PBMC is an essential component of the anti-inflammatory mechanism. PBMC may be isolated by the addition of heparin from the standard density gradient centrifugation in a normal healthy donors or whole blood of white blood cell yeoncheung keep the material taken from the top surface is washed (e. G. Phosphate buffered saline) to the freezing medium. PBMCs can be cultured in multiwall plates. In several cultures, the supernatant can be removed for measurement and the cells can be captured and analyzed (Smith R. etal (2003) Blood 102 (7) 2532-2540). The compounds of this claim may further comprise phosphonates or phosphonate prodrugs. More typically, as described herein, the phosphonate or phosphonate prodrug may have an A ³ structure.

Typically, the compounds of the present invention show enhanced intracellular half-life or intracellular metabolites of the compound in human PBMCs compared to analogs of compounds that do not contain phosphonates or phosphonate prodrugs. Typically, the half life is improved by at least about 50%, more typically in the range of at least 50 to 100%, more typically at least about 100%, more typically at least about 100%.

In one embodiment of the present invention, the intracellular half-life of the metabolite of the compound in human PBMC is improved over an analog of a compound that does not contain a phosphonate or phosphonate prodrug. In this claim, metabolites can be made in cells. For example, it can be made in human PBMC. Metabolites can be degradation products of phosphonate prodrugs in human PBMCs. Phosphonate prodrugs can degrade to form metabolites with at least one negative charge at physiological pH. Phosphonate prodrugs can be enzymatically digested in human PBMCs to form phosphonates with one active hydrogen atom of the P-OH type.

Structural isomer

The compound of the present invention may have a chiral center, for example, chiral carbon or phosphorus atom. The compounds of the present invention include racemic mixtures of all structural isomers, including enantiomers, diastereomers, and atropisomers. In addition, the compounds of the present invention include concentrated or dissolved optical isomers at any or all asymmetric chiral atoms. In other words, the chiral center represented by the above description serves as a chiral isomer or racemic mixture. Both racemic and diastereomeric mixtures, and the individual optical isomers separated or synthesized, substantially free from enantiomers or diastereomeric pairs, are all within the scope of the present invention. The racemic mixture is separated into individual substantially optically pure isomers through well known techniques such as separation of diastereomeric salts formed from optically active adducts. For example, the acid or base is converted back to the optically active material. In most cases, the desired optical isomer is synthesized from the structure specific reaction starting from the appropriate structural isomer of the desired starting material.

The compounds of the present invention may also exist in some cases as tautomers. Although only one potential resonance structure is described, all such forms are contemplated within the scope of the present invention. For example, en-amine tautomers can exist in purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems, and all possible tautomeric forms are included within the scope of the present invention.

Salts and hydrates

The composition of the present invention alternatively provides salts of the compounds herein, in particular pharmaceutically acceptable non-toxic salts containing, for example, Na ⁺ , Li ⁺ , K ^+, Ca ⁺² and Mg ⁺² . It may include. Such salts may include those derived by a combination of tetravalent amino ions, typically carboxylic acids, with appropriate cation and acid anion moieties such as alkali and alkaline earth metal ions or ammonium. Monovalent salts are preferred if water-soluble salts are desired.

Metal salts can typically be prepared by reacting a metal hydroxide with a compound of the present invention. Examples of metal salts prepared in this way are salts containing Li ⁺ , Na ⁺ and K ⁺ . Poorly soluble metal salts can be precipitated into solutions of more soluble salts by the addition of suitable metal compounds.

In addition, salts may be formulated to certain organic and inorganic acids, such as HCl, HBr, H ₂ SO _{4 ,} H ₃ PO ₄ Or organic sulfonic acids can be formed by addition to base centers, typically amines, or acidic groups. Finally, it is to be understood that the compositions of the present invention comprise compounds of the present invention in combination of deionized or zwitterionic forms and stoichiometric amounts of water in hydrates.

Also within the scope of the present invention are salts of the parent compound having one or more amino acids. All of these amino acids are suitable, in particular such natural amino acids found as protein components, typically base or acidic groups such as lysine, arginine or glutamic acid, or glycine, serine, threonine, alanine, isoleucine, or leucine and the like. It is an amino acid containing a side chain having a natural group.

How to suppress viral infections

Another aspect of the present invention relates to a method for inhibiting viral infection comprising treating a sample or a target suspected of requiring such inhibition with a composition of the present invention.

The compositions of the present invention can act as viral infection inhibitors or inhibitors or intermediates having the following other functions. The inhibitor can bind to the empty space of the cell having the location or specific structure of the surface. Compositions that bind to cells bind with varying reversibility. Such compounds that are substantially irreversibly bound are ideal candidates for use in the methods of the present invention. Once labeled, the substantially irreversibly bound composition is a very useful probe for detecting viruses. Accordingly, the present invention relates to a method for detecting a virus in a sample or an object suspected of containing a virus. Such methods include: treating a sample or object with a composition comprising a compound of the invention labeled; And observing the activation effect on the sample of the label. Suitable labels are well known in the diagnostic arts, including stable free radicals, fluoropores, radioisotopes, enzymes, chemiluminators and chromogens. The compounds herein are labeled by conventional methods using functional groups such as hydroxyl or amino.

In the context of the present invention, samples suspected of containing viruses include natural or artificial substances such as organisms; Tissue or cell culture; Biological samples such as biological material samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples and the like); Laboratory samples; Food, water, or air samples; Biological product samples such as cell extracts, particularly recombinant cells that synthesize desired glycoproteins; And the like and the like. Typically, the sample will be suspected of containing an organism that induces a viral infection. Samples can be included in a medium comprising a water and organic solvent / water mixture. The sample contains an organism such as human, and an artificial substance such as cell culture.

The treatment step of the present invention consists in adding a composition or a precursor of the composition to the sample. The addition step includes any method of administration as described above.

If desired, antiviral activity of the compounds of the present invention can be observed by methods of detection of kinase activity, both directly and indirectly after application of the composition. All methods, quantitative, qualitative and semiquantitative, for measuring kinase activity can be considered. Typically one of the above sorting methods is applied. However, any other method that can observe the physiological properties of the organism is applicable.

Antiviral Screening of Compounds

Compositions of the present invention are selected according to antiviral activity by conventional techniques for assessing enzyme activity. In the context of the present invention, typically, the composition is first selected by ex vivo kinase inhibition and the composition exhibiting inhibitory activity is selected by in vivo activity. Compositions having a Ki (inhibition constant) of less than about 5 X 10 ^-6 M, typically less than about 1 X 10 ^-7 M, and preferably less than about 5 X 10 ^-8 M are preferred for use in vivo.

Useful in vitro screening methods are described in detail but have not been described in detail here.

Pharmaceutical formulation

The compounds of the present invention are formulated with conventional carriers and excipients. These were chosen for general use. Tablets include excipients, lubricants, fillers, binders and the like. Aqueous formulations are prepared in steril form and will generally be isotonic if intended for delivery methods other than oral administration. All formulations alternatively include excipients as described in Hand book of Pharmaceutical Excipients (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. The pH range of the formulation is about 3 to about 11, but generally about 7 to 10.

If the active ingredient can be administered alone, it is preferably provided in a pharmaceutical formulation. Formulations of the present invention for use in humans or animals comprise at least one active ingredient as defined above together with one or more acceptable carriers and, alternatively, other therapeutic ingredients. The carrier (s) should be acceptable in the sense of being compatible with other ingredient formulations and as being physiologically harmless to their recipients.

Such formulations include the suitable routes of administration described above. The formulations may conveniently be presented in unit dosage form and may be prepared by methods well known in the art of pharmacy. Such methods and formulations may generally be found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methods include the step of bringing into association the active ingredient with a carrier consisting of one or more accessory ingredients. Generally, the formulations are made uniformly, directly, by associating the active ingredient with a liquid carrier or a precisely divided solid carrier, or in the form of both. If necessary, it may be in the form of the product.

Formulations of the present invention suitable for oral administration include secretion units such as capsules, cachets or tablets predominantly containing the active ingredient; Powder or granules; Aqueous or non-aqueous liquid solutions of solution or suspension; Or as an oil-in-water solution emulsion or a water-in-oil solution emulsion. The active ingredient may also be a pill, soft or paste.

The tablet is alternatively made by compression or molding with one or more additional ingredients. Compressed tablets may be prepared by mixing and compressing free fluids, such as powders or granules, in a suitable machine, alternatively with binders, lubricants, inert diluents, preservatives, surface active or dispersants. Molded tablets may be prepared by molding a mixture of the powdered active ingredient moistened with an inert liquid diluent in a suitable machine. The tablets may alternatively be coated or scored and formulated as necessary so that the active ingredients therefrom are at slow or controlled release.

For administration to the eye or other external tissue, such as the oral cavity and skin, the formulation is preferably applied in the form of a topical ointment or cream containing the active ingredient. These amounts include, for example, the active ingredient (s) in increments of 0.1% w / w in the range of 0.075 to 20% w / w (0.1% to 20%) 0.6% w / w, 0.7% w / w, etc.), preferably 0.2 to 15% w / w and most preferably 0.5 to 10% w / w. When formulated in the form of ointments, the active ingredients can be used in paraffinic or water soluble ointments. Alternatively, the active ingredient may be formulated as an oil-in-water cream system.

If desired, a creamy aqueous phase may be included. For example, polyhydric alcohols, ie alcohols having two or more hydroxyl groups, such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof, etc. This at least 30% w / w may be included. The topical formulation may comprise a compound that enhances the absorption or penetration of the active ingredient into the skin or other site of infection. Such subcutaneous penetration enhancers include dimethyl sulfoxide and related analogs.

The oil phase of the emulsion of the present invention consists of ingredients known by known methods. If the phase consists simply of an emulsifier (or known as an emulsifier), they preferably consist of a fat or oil, or a mixture of both fat and oil with at least one emulsifier. Specifically, hydrophilic emulsifiers are included along with lipophilic emulsifiers used as stabilizers. It also preferably includes both oils and fats. All of the emulsifier (s) with or without stabilizer (s) constitute so-called emulsifying waxes. The wax together with fats or oils constitutes a so-called emulsified ointment system. These form the oil dispersion phase of the cream formulation.

Emulsifiers and emulsion stabilizers suitable for the formulations of the invention include Tween ^® 60, Span ^® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.

Selecting a suitable oil or fat for the formulation depends on achieving the desired molding properties. The cream should have a suitable hardness, be free from grease, stains, and well-polished products to prevent leakage from tubes or other containers. Straight or branched, mono- or dibasic alkyl esters such as di-isoadiate, isocetyl stearate, propylene glycol diesters of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butylstea Branched esters known as latex, 2-ethylhexyl palmitate or Crodamol CAP can be used. The last three are the preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils are used.

Pharmaceutical formulations according to the invention consist of one or more pharmaceutically acceptable carriers or excipients and, alternatively, one or more compounds of the invention together with other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be any administration method intended, as long as it is suitable. When used in the oral cavity, for example, it may be prepared in tablets, troches, rhombic tablets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Compositions intended for oral use may be prepared according to methods known in the art for preparing pharmaceutical compositions, which compositions may include one or more excipients, such as sweeteners, flavoring agents, colorants, and preservatives, for the manufacture of easy-to-eat medicines. have. Tablets containing the active ingredient are acceptable in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; Granulating and disintegrating agents such as corn starch or arginic acid; Binders such as cellulose, microcrystalline cellulose, starch, gelatin or gum arabic; And lubricants such as magnesium stearate, stearic acid or mica. The tablet may not be coated, or may be coated by known microencapsulation techniques to delay degradation and absorption in the gastrointestinal tract so that long term action is sustained. For example, time delay materials such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with waxes.

Formulations for oral administration may also be presented as hard gelatin capsules. Here, the active ingredient is mixed with an inert solid diluent such as, for example, calcium phosphate or kaolin. Or as a soft gelatin capsule, wherein the active ingredient is mixed with an oil medium such as water or peanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the present invention comprise the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium arginate, polyvinylpyrrolidone, tragacanth gum and gum arabic gum, and natural phosphates such as dispersing or wetting agents. Tide (eg lecithin), condensation products of alkylene oxides and fatty acids (eg polyoxyethylene stearate), condensation products of ethylene oxide and long chain aliphatic alcohols (eg heptadecaethyleneoxycetanol ), Condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (eg polyoxyethylene sorbitan monooleate). The aqueous suspension also includes one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more colorants, one or more flavoring agents and one or more sweeteners such as sucrose or saccharin.

The oil suspension may be formulated with the active ingredient suspended in rapeseed oil such as peanut oil, olive oil, sesame oil or coconut oil, or mineral oil such as liquid paraffin. The oral suspension may include a thickener such as beeswax, hard paraffin or cetyl alcohol. The sweetener and flavoring agent mentioned above are added, and the oral drug which is easy to eat is prepared. Such compositions can be preserved with the addition of antioxidants such as ascorbic acid.

Dispersible powders and granules of the invention suitable for the manufacture of aqueous suspensions by addition of water provide the active ingredient mixed with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified in those mentioned above. Further excipients such as sweeteners, flavoring and coloring agents are also provided.

The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a rapeseed oil such as olive oil or peanut oil, mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include natural gums such as gum arabic gum and tragacanth gum, natural phosphides such as soy lecithin, esters or partial esters derived from fatty acids such as sorbitan monooleate and hexitol anhydride, and polyoxyethylene Condensation products of partial esters such as sorbitan monooleate and ethylene oxide. The emulsion may also include sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents such as glycerol, sorbitol or sucrose. Such formulations may also include emollients, preservatives, flavors or colorants.

The pharmaceutical composition of the present invention may be in the form of a sterile injectable medicament, such as an aqueous or oily suspension for sterile injectable. Such suspensions may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable medicament may also be prepared as a sterile injectable solution or suspension or lyophilized powder of a solution such as a parenterally acceptable non-toxic diluent or solvent such as 1,3-butane-diol. Among the acceptable carriers and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can likewise be used as medicaments for injection.

The amount of the active ingredient combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the respective dosage form. For example, a time-release formulation for oral administration of humans intended for oral administration in humans varies from about 5 to about 95% (weight: weight) of the total composition, with about 1 incorporating an appropriate amount of carrier material. To 1000 mg of active substance. The pharmaceutical composition may be prepared so that the dosage is easily measurable. For example, an aqueous solution for intravenous injection may contain about 3 to 500 mg of active ingredient per milliliter so that an appropriate volume of injection is made at a rate of about 30 mL / hr.

Formulations suitable for ocular administration include eye drops. Here, the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent of the active ingredient. The active ingredient is preferably provided in such formulations at 0.5 to 20%, more preferably at 0.5 to 10%, in particular about 1.5% w / w.

Formulations suitable for oral topical administration generally include rhombic tablets comprising the active ingredient in a flavor system such as sucrose and gum arabic or tragacanth; Pastilles containing the active ingredient in an inert system such as gelatin and glycerin or sucrose and gum arabic; There is a potion for tooth preparation comprising the active ingredient in a suitable liquid carrier.

Formulations for rectal administration may be provided as suppositories with suitable bases including, for example, cocoa butter or salicylic acid.

Suitable formulations for pulmonary or nasal administration include particle size, for example 0.1 to 500 microns (including particle size increasing by 1 micron between 0.1 to 500 microns, such as 0.5, 1, 30 microns, 35 microns, etc.) It may have a rapid inhalation or nasal passage through the nasal canal to reach the alveolar cysts. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and delivered with other therapeutic agents, such as compounds used to prevent or treat abnormalities related to kinase activity.

Formulations suitable for vaginal administration can be pessary, tampon, cream, gel, paste, foam or spray formulations containing the active ingredient or a suitable carrier known to those skilled in the art.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions containing antioxidants, buffers, bacteriostatic agents and solutes of the intended recipient's blood and isotonic formulations; And aqueous and non-aqueous sterile suspensions comprising suspending agents and viscosity sensitizers.

The formulations are provided in unit dose or multi-dose containers such as sealed ampoules and vials and stored in lyophilized form as required for the addition of sterile liquid carriers such as, for example, water injected immediately before use. Instant injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind described above. A preferred unit dosage form is a daily dose or unit daily minor dose, or appropriate portion thereof, of the active ingredient.

The ingredients added to the formulations of the invention described above may include other conventional agents. For example, suitable for oral administration include flavoring agents.

The present invention further provides at least one active ingredient as described above in combination with their veterinary carrier in a veterinary composition.

Veterinary carriers are substances useful for the administration of the composition, are inert or acceptable in the veterinary art, and may be solid, liquid or gaseous substances which are compatible with the active ingredient. Such veterinary compositions can be administered orally, parenterally or by other desired routes.

The compounds of the present invention may also be formulated to provide controlled release for less frequent administration of the active ingredient and to enhance the pharmacokinetic or toxicological properties of the active ingredient. Accordingly, the present invention also provides compositions comprising one or more compound formulas of the present invention formulated to have sustained or controlled release.

The effective dosage of the active ingredient depends on the condition to be treated, the toxicity, whether the ingredient is used prophylactically (taken less), the method of delivery, the pharmaceutical formulation, and is determined by the clinician using a conventional method of escalating doses. .

It can be expected from about 0.0001 to about 100 mg / kg body weight / day, and typically, from about 0.01 to about 10 mg / kg body weight / day. More typically, from about 0.01 to about 5 mg / kg body weight / day. More typically, from about 0.05 to about 0.5 mg / kg body weight / day. For example, the desired daily dose for an adult weighing about 70 kg is 1 mg to 1000 mg, preferably 5 mg to 500 mg and may be taken in the form of a single or multiple dose.

Route of administration

One or more compounds of the invention (referred to as active ingredients) are administered by a route suitable for the abnormal condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous tissue, intramuscular, vein, dermis, epidural and epidural), and the like. Preferred routes may vary depending, for example, on the symptoms of the receptor. An advantage of the compounds of the present invention is that oral bioavailability and administration are possible.

Complex therapy

The active ingredients of the present invention are also used in combination with other active ingredients. Such a combination is selected based on the condition to be treated, the cross reactivity of the components and the pharmaceutical properties of the combination.

It may also be combined with one or more other active ingredients of the compounds of the invention in a single dosage form for simultaneous or sequential administration to a patient. The combination treatment may be administered concurrent or as sequential therapy. When administered sequentially, the combination may be administered in two or more administrations.

The combination treatment can provide synergistic and synergistic effects. In other words, the above effects are obtained when the active ingredients are used together in a greater effect than the sum of the results of using each compound. The synergistic effect is that the active ingredient is: (1) simultaneous formulation and administration or delivery in combination formulation; (2) delivered in parallel or alternately as separate formulations; Or (3) by other therapies. When delivered in alternation treatment, the synergistic effect may be achieved when the compounds are administered or delivered sequentially, eg, by different injections by separate tablets, pills or capsules, or separate syringes. Generally, in the course of alternation treatment, effective administration of each active ingredient takes place sequentially. In other words, it means to be continuous. In the case of combination therapy, on the other hand, effective administration of two or more active ingredients takes place together.

Of the compounds of the present invention Metabolite

Also within the scope of this invention are the in vivo metabolic products of the compounds described above. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, esterification, and the like, of the administered compound, primarily due to enzymatic reaction procedures. Accordingly, the present invention includes compounds prepared using reaction procedures for inoculating a compound of the invention into a mammal for a time sufficient to obtain their metabolic products. Such products typically contain radiolabelled (eg, C ¹⁴ or H ³ ) compounds of the invention in amounts detectable to animals (eg, rats, mice, guinea pigs, monkeys, or humans) (eg, Parenteral administration, at least about 0.5 mg / kg, to allow metabolism to occur for a sufficient time period (typically from about 30 seconds to 30 hours) and then to separate their conversion products from urine, blood or other biological samples. You will get These products can be easily separated because they are labeled (others are separated using antibodies capable of binding epitopes remaining in the metabolite). Metabolite structures are determined by conventional techniques. For example, by MS or NMR analysis. In general, the analysis of metabolites is performed in the same way as is well known to those of skill in the art for conventional drug metabolism studies. Unless otherwise found in vivo, these conversion products are useful for diagnostic analysis of therapeutic doses of compounds of the invention, even if they do not have their own kinase inhibitory activity.

Prescriptions and methods are known for determining the stability of surrogate gastrointestinal secretion compounds. The compound is defined herein as being stable in the gastrointestinal tract, wherein less than about 50 mole% of the protected groups in one hour of incubation at 37 ° C. are deprotected in the large intestine or gastric juice. The stability of the compound to the gastrointestinal tract does not mean that it cannot be hydrolyzed in vivo. Phosphonate prodrugs of the invention will typically be stable in the digestive system, but substantially the parent drug is generally hydrolyzed in the digestive lumen, liver or other metabolic organs, or cells.

Antiviral activity

Antiviral activity of the compounds of the invention is measured using known standard screening procedures. For example, the antiviral activity of the compounds is measured in a cell culture assay using the following general procedure.

Antiviral Cell Culture Assay

The assay is based on the quantification of the antiviral effect by colorimetrically detecting the viability of virus infected cells in the presence or absence of a test inhibitor. The compound induced cell death is converted into products with specific uptake by healthy cells as described in Weislow OS, Kiser R, Fine DL, Bader J, Shoemaker RH and Boyd MR (1989) J Natl Cancer Inst 81, 577 Metabolite substrate 2,3-bis (2-methoxy-4-nitro-5-sulfophenyl) -2H-tetrazolium-5-carboxanilide (XTT).

Analytical Procedures for EC50 Measurements :

1. Incubate MT2 cells in RPMI-1640 medium fed 5% bovine placental serum and antibiotics.

1. Infect cells at 37 ° C. with viral agents for 3 hours using a viral infectious agent with a multiplicity of infection of 0.01.

3. Infected cells are distributed into 96 well plates (20,000 cells per 100 ml / well), and various concentrations of test inhibitor are added to three plates (100 ml / well in culture medium). This includes untreated infection and uninfected control cells.

4. Incubate the cells at 37 ° C. for 5 days.

5. Prepare a phosphate buffered salt of a compound solution (6 ml per assay plate) at a concentration of 2 mg / ml, pH 7.4, and heat the solution to 55 ° C. for 5 minutes in a water bath. 50 ml of N-methylphenazonium metasulfate (5 mg / ml) is added per 6 ml of XTT solution.

6. Remove 100 ml of medium from each well on the assay plate.

7. Add 100 ml of XTT substrate solution per well and incubate in CO ₂ incubator at 37 ° C. for 45-60 minutes.

8. Add 20 ml of 2% Triton X-100 per well to inactivate the virus.

9. Read the absorbance at 450 nm except for the background absorbance at 650 nm.

10. EC50 values are measured as drug concentrations showing percentage absorbance for untreated controls and protecting 50% of infected cells.

Cytotoxicity of the compounds of the present invention can be measured using routine procedures.

Cytotoxic Cell Culture Assay ( CC50 Measurement):

This assay is based on the evaluation of test compounds using metabolic substrates.

Analytical Procedures for CC50 Measurements:

1. Incubate MT-2 cells in RPMI-1640 medium fed 5% bovine placental serum and antibiotics.

2. Infected cells are distributed into 96 well plates (20,000 cells per 100 ml / well) and various concentrations of test compound are added to three plates (100 ml / well in culture medium). This includes untreated controls.

3. Incubate the cells at 37 ° C. for 5 days.

4. Prepare phosphate buffered salts of XTT solution (6 ml per assay plate) at a concentration of 2 mg / ml at pH 7.4 in the dark. The solution is heated in a water bath to 55 ° C. for 5 minutes. 50 ml of N-methylphenazonium metasulfate (5 mg / ml) is added per 6 ml of XTT solution.

5. Remove 100 ml of medium from each well on the assay plate and add 100 ml of XTT substrate solution per well. Incubate in CO ₂ incubator at 37 ° C. for 45-60 minutes.

6. Add 20 ml of 2% Triton X-100 per well to stop metabolic conversion of XTT.

7. Read the absorbance at 450 nm except for the background absorbance at 650 nm.

8. Absorbance percentages for untreated controls are plotted and EC50 values are determined as drug concentrations that inhibit cell growth by 50%. Consider absorbance directly proportional to cell growth.

Exemplary Methods of Making Compounds of the Invention .

The invention also relates to a process for preparing the composition of the invention. The composition may be prepared by any applicable organic synthesis method. Many of these techniques are known in the art. However, many known techniques are described in Compendium of Organic Synthetic Methods (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; And Vol. 6, Michael B. Smith; As well as March, J., Advanced Organic Chemistry, Third Edition , (John Wiley & Sons, New York, 1985), Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency in Modern Organic Chemistry. In 9 Volumes , Barry M. Trost, Editor-in-Chief (Pergamon Press, New York, 1993 printing).

Some exemplary methods for preparing the compositions of the present invention are provided below. These methods are intended to illustrate the nature of the manufacturing method and do not limit the scope of the applicable method.

In general, reaction conditions, such as temperature, reaction time, solvent, finishing procedure, etc., are those commonly used in the industry of the particular reaction being performed.

The above-mentioned reference materials together with the materials mentioned herein include detailed descriptions of these reaction conditions. Typically, the temperature will be between -100 ° C and 200 ° C. The solvent will be aprotic or protonic and the reaction time will be 10 seconds to 10 days. The finishing procedure typically consists of pouring water into the unreacted reactant to terminate the reaction, dividing the water / organic system (extraction) and separating the layer containing the product.

In the reduction of metal hydrides often the temperature is reduced from 0 ° C. to −100 ° C., and the solvents are typically aprotic at reduction and proton or aprotic at oxidation, but oxidation and reduction reactions are typically at room temperature ( At a temperature close to about 20 ° C.). The reaction time is adjusted so that the desired conversion is achieved.

Although the non-equilibrium, kinetic governing condensation reaction generally lowers the temperature (0 ° C. to −100 ° C.), the condensation reaction is typically carried out at temperatures close to room temperature. The solvent may be protonic (common for equilibrium reactions) or aprotic (common for kinetic dominant reactions).

Basic synthesis techniques such as azeotropic reactions by products and anhydrous reaction conditions (eg, inert gas environments) are commonly used in the industry and can be applied in the application function.

Schemes and Example

General aspects of this representative method are detailed below and in the Examples herein. Each product of the following process may alternatively be separated, isolated and / or purified before being used in the next process.

In general, the reaction conditions such as temperature, reaction time, solvent, reaction finishing procedure, etc. for carrying out a specific reaction are those commonly used in the art. The above-mentioned reference materials together with the materials mentioned herein include detailed descriptions of these reaction conditions. Typically, the temperature will be between -100 ° C and 200 ° C. The solvent will be aprotic or protonic and the reaction time will be 10 seconds to 10 days. The finishing procedure typically consists of pouring water into the unreacted reactant to terminate the reaction, dividing the water / organic system (extraction) and separating the layer containing the product.

In the reduction of metal hydrides often the temperature is reduced from 0 ° C. to −100 ° C., and the solvents are typically aprotic at reduction and proton or aprotic at oxidation, but oxidation and reduction reactions are typically at room temperature ( At a temperature close to about 20 ° C.). The reaction time is adjusted to achieve the desired conversion.

Although the non-equilibrium, kinetic governing condensation reaction generally lowers the temperature (0 ° C. to −100 ° C.), the condensation reaction is typically carried out at temperatures close to room temperature. The solvent may be protonic (common for equilibrium reactions) or aprotic (common for kinetic dominant reactions).

Basic synthesis techniques, such as azeotrope reactions by products and anhydrous reaction conditions (eg, inert gas environments), are commonly used in the art and can be applied where applicable.

When used in conjunction with chemical synthesis operations, the terms treated, treated, treated, etc., refer to a reaction that causes contact by contacting, mixing, and reacting, while other terms mean that one or more chemicals are treated in such a way that one or more other Commonly used in the art to refer to the conversion to chemicals.

 Treating compound 1 with compound 2 is the same meaning as reacting compound 1 with compound 2, and contacting compound 1 with compound 2 means reacting compound 1 with compound 2, compound 1 with compound 2 Other expressions referring to furnace treatment, reactions, allowing reactions, and the like are commonly used in the organic synthesis industry. For example, the term treatment refers to a suitable, general method of reacting organic chemicals. Unless otherwise specified, normal concentrations (0.01 M to 10 M, typically 0.1 M to 1 M), temperature (-100 ° C. to 250 ° C., typically −78 ° C. to 150 ° C., more typically −78 ° C.) To 100 ° C., more typically 0 ° C. to 100 ° C., reaction vessel (typically glass, plastic, metal), solvent, pressure, atmosphere (typically air for reactions that do not react with oxygen and water, or Nitrogen or argon for reaction with oxygen or water). The above knowledge of analogous reactions known in the organic synthesis art is used to select reaction conditions and apparatus for treatment within a given reaction. In particular, the general techniques of the organic synthesis industry will select the reaction conditions and apparatus for successfully performing the above-described chemical reactions.

Each representative scheme and example (hereinafter referred to as the representative scheme) is modified to produce various analogs of certain exemplary materials.

The above cited references describing suitable methods for organic synthesis are applicable for this modification.

In each representative scheme, it is desirable to separate the reaction products from each other and / or from the starting material. The desired product of each stage or successive stages is separated and / or purified (hereinafter referred to as separation) by techniques commonly used in the industry to achieve the desired degree of homogeneity. Typically, such separation involves multiphase extraction, crystallization from solvents or solvent mixtures, the like, distillation, sublimation, chromatography or the like. Chromatography includes, for example: reverse phase and pure phase; Exclusion by size; Ion exchange; High speed, medium, and low pressure liquid chromatography methods and apparatus; Small scale analysis; There are many methods, including simulated moving bed (SMB) and preparative thin or thick layer chromatography, and small scale thin layer and flash chromatography techniques.

Another class of separation methods involves treating a mixture of reactants and unreacted starting materials selected such that the separable becomes the desired product or binds the desired product, or is related to the reaction by the product or the like. Such reactants include adsorbents or activated carbons, molecular sieves, ion exchange media or adsorbents of this kind. Alternatively, the reactants may be acidic in the case of basic substances such as antibodies that bind to the reactants, binding proteins, selective chelators such as crown ethers, liquid / liquid ion exchangers (LIX), and the like. In some cases it may be basic.

Choosing the appropriate method of separation depends on the properties of the material involved. For example, the boiling point and molecular weight in distillation and sublimation, the presence or absence of polar functional groups in chromatography, the acidity in multiphase extraction and the stability of the material in the base medium, and the like. One skilled in the art can apply the most suitable technique to achieve the desired separation.

Single isomers, such as enantiomers, substantially free from the isomers can be obtained from solutions of racemic mixtures using methods of forming diastereomers using optically active solubilities ( Stereochemistry of Carbon Compounds , (1962) EL Eliel, McGraw Hill; Lochmuller, CH, (1975) J. Chromatogr ., 113: (3) 283-302). Racemic mixtures of chiral compounds can be separated and isolated by suitable methods, including: (1) formation of ions, diastereomeric salts of chiral compounds and separation or other methods by partial crystallization, ( 2) formation of diastereomeric compounds with chiral inducing reactants, separation of diastereomers and conversion to pure structural isomers, and (3) direct separation of substantially pure or concentrated structural isomers under chiral reaction conditions.

Under method (1), diastereomeric salts can be formed by enantiomeric reactions. Pure chiral bases, such as those which have asymmetric compounds with acidic functional groups, such as burucine, quinine, ephedrine, strynnin, a-methyl-b-phenylethylamine (amphetamine), and carboxylic acids and sulfonic acids. The diastereomeric salts can be induced to separate by partial crystallization or ion chromatography. For the separation of the optical isomers of amino compounds, chiral carboxylic acids or sulfonic acids such as camphorsulfonic acid, tartaric acid, mandelic acid or lactic acid may be added to form diastereomeric salts.

Alternatively, by method (2), the dissolved substrate is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds , John Wiley & Sons, Inc., p. 322). Diastereomeric compounds may be formed by reacting an asymmetric compound with an enantiomerically pure chiral derivative reactant, such as menthyl derivative. Subsequently, xanthan was concentrated to enantiomer, which was liberated by separation and hydrolysis of diastereomers. Methods for determining optical purity include chiral esters such as menthyl esters of racemic mixtures in the presence of a base such as (-) menthyl chloroformate or mosher esters, a-methoxy-a- (trifluoromethyl) phenyl Making an acetate (Jacob III. (1982) J. org . Chem . 47: 4165) and NMR spectral analysis for the presence of two atropisomer diastereomers. Stable diastereomers of atropisomer compounds can be separated or isolated by normal- and reverse phase chromatography by separation of naphthyl-isoquinolines by atropisomers (Hoye, T., WO 96/15111). . By method (3), the racemic mixture of the two enantiomers can be separated by chromatography using chiral stationary phases ( Chiral Liquid Chromatography (1989) WJ Lough, Ed. Chapman and Hall, New York; Okamoto, ( 1990) J. of Chromatogr . 513: 375-378). Enriched or purified enantiomers can be determined by a method of distinguishing other chiral molecules from asymmetric carbon atoms by optical rotation and circular dichroism.

Example  General part

Representative methods for preparing compounds of the invention are provided in the specification, for example, in the examples below. These methods are intended to illustrate the nature of these manufacturing methods and are not intended to limit the scope of the applicable methods. Certain compounds of the invention can be used as intermediates for the preparation of other compounds of the invention. For example, the interconversion of various phosphonate compounds of the invention is illustrated below.

Phosphonate R- link ^{-P (O) (OR 1)} 2, R- link ^{-P (O) (OR 1)} (OH) and R- link -P (O) (OH) interconversion of ₂

The following reaction schemes 32 - the general structure R- link eseo 38 and ^{-P (O) (OR 1)} 2, R 1 groups are the same or have been described process for producing a phosphonate ester, which may be different from each other. The R ¹ groups bonded to the phosphonate esters or their precursors can be altered using established chemical conversion methods. The interconversion reaction of phosphonates is illustrated in Scheme S32 . In the compounds of the present invention, or precursors thereof, the R group in Scheme 32 represents a substructure, ie, a drug support having a substituent link-P (O) (OR ¹ ) ₂ attached thereto. At certain points in the synthetic pathway to effect phosphonate interconversion, certain functional groups can be protected. The method using a given phosphonate substitution depends on the nature of the substrate to which the substituent R ¹ and the phosphonate group are bound. Methods for the preparation and hydrolysis of phosphonate esters are described in Organic Phosphrous Compounds , GM Kosolapoff, L. Maeir, eds, Wiley, 1976, p. Described in 9ff.

In general, the synthesis of phosphonate esters is accomplished by coupling the nucleophile amine or alcohol with the corresponding active phosphonate electrophilic precursor. For example, the addition of chlorophosphonate to the 5'-hydroxy of nucleosides is a well known method of preparing nucleoside phosphate monoesters. The active precursors can be prepared by several well known methods. Chlorophosphonates useful for the synthesis of prodrugs are synthesized from substituted-1,3-propanediol (Wissner, et al., (1992) J. Med Chem . 35: 1650). Chlorophosphonates are prepared by oxidizing the corresponding chlorophospholane obtained by reacting substituted diols with phosphorus trichloride (anderson, et al . (1984) J. org . Chem . 49: 1304). Alternatively, the chlorophosphonate reagent is obtained by treating substituted 1,3-diol with phosphorus oxychloride (Patois, et al . (1990) J. Chem . Soc. Perkin Trans. I , 1577). Chlorophosphonate species are also produced instantly from the corresponding cyclic phosphites (Silverburg, et al. (1996) Tetrahedron lett ., 37: 771-774). It is in turn made from chlorophospholane or phosphoramidate intermediates. Phosphorofluorate intermediates prepared from pyrophosphate or phosphoric acid may also serve as precursors in the preparation of cyclic prodrugs (Watanabe et al. (1988) Tetrahedron lett ., 29: 5763-66).

The phosphonate prodrugs of the present invention are also described by the carbodiimide (Alexander, et al. (1994) by Mitsnobu, (1981) Synthesis , 1; Campbell, (1992) J. org . Chem . 57: 6331). ....) Collect Czech Chem Commun 59:.... 1853; Casara et al, (1992) BioOrg Med Chem Lett 2:. 145; Ohashi et al, (1988) Tetrahedron Lett, 29 : 1189) and a benzotriazolyl-oxy It can be prepared from free acids by other acid coupling agents, including but not limited to tris- (dimethylamino) phosphonium salt (Campagne et al. (1993) Tetrahedron Lett . 34: 6743).

Halogenated aryl was subjected to a Ni ⁺² catalytic reaction with a phosphite derivative to obtain an aryl phosphonate containing compound (Balthazar, et al . (1980) J. org . Chem . 45: 5425). Phosphonates can also be obtained from chlorophosphonates using aromatic triflate in the presence of a palladium catalyst (Petrakis et al . (1987) J. Am. Chem . Soc . 109: 2831; Lu et al. (1987) Synthesis 726 ). Alternatively, aryl phosphonate esters can be prepared from aryl phosphates under anion rearrangement reaction conditions (Melvin (1981) Tetrahedron Lett . 22: 3375; Casteel et al. (1991) Synthesis , 691). N-alkoxy aryl salts with alkali metal derivatives of cyclic alkyl phosphonates provide a general method for the synthesis of heteroaryl-2-phosphonate linkages (Redmore (1970) J. org. Chem . 35: 4114) . This aforementioned method can be extended to compounds in which the W ⁵ group is heterocycle. Cyclic-1,3-propaneyl prodrugs of phosphonates can also be prepared using a coupling agent such as 1,3-dicyclohexylcarbodiimide (DCC) in the presence of a base (e.g., pyridine). Is prepared from phosphorous acid and substituted propane-1,3-diol. Other carbodiimides based on coupling agents such as 1,3-diisopropylcarbodiimide or water-soluble reagents, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) are also cyclic phos. It can be utilized in the synthesis of phonate prodrugs.

Phosphonate diester S32 . The conversion of 1 to the corresponding phosphonate monoester S32.2 (Scheme 32 , Reaction 1 ) is carried out by several methods. For example, R ¹ such as benzyl The ester S32 .1 which is this aralkyl group is J. org . Chem . (1995) by the reaction with a tertiary organic base such as diazabicyclooctane (DABCO) or quinuclidin and the like, as described in (60) 29: 2946), to the monoester compound S32 .2 . The reaction is carried out at about 110 ° C. in an inert hydrocarbon solvent such as toluene or xylene. R ¹ Is an aryl group, e.g., phenyl, or alkenyl group diester S32 .1 alkenyl, such as allyl is treated with a base such as lithium hydroxide, in hydro-ester .1 S32 in the aqueous solution of sodium hydroxide and acetonitrile or tetra-furan monoester Switch to S32 .2 . R ¹ One group is aralkyl such as benzyl and the other is converted to an alkyl phosphonate diester S32 .1 is a monoester S32 .2 R ¹ by hydrogenation using a catalyst such as palladium on carbon alkyl. Two R ¹ Phosphonate diesters in which the group is alkenyl, such as allyl, are described, for example, for the decomposition of allyl carboxylates, for example in J. org . Chem . (1973) using the procedure described in 38: 3224, alternatively, by refluxing with an aqueous ethanol solution of chlorotris (triphenylphosphine) rhodium (Wilkinson catalyst) in the presence of diazabicyclooctane R ¹ This egg is a switch to the monoester S32 .2 alkenyl. Phosphonate diester S32 .1 or monoester S32 .2 .3 the corresponding phosphonic acid S32 (Scheme 32, Reaction 2, and 3) conversion to the J. Chem. Soc , Chem . As described in Comm ., (1979) 739, diesters or monoesters can be made by reacting with trimethylsilyl bromide. The reaction is alternatively performed at room temperature, in the presence of a silylating agent such as bis (trimethylsilyl) trifluoroacetamide, for example in an inert solvent such as dichloromethane. R ¹ Yi aralkyl of force S32 .2 monoester such as benzyl is converted in a ethereal solvent such as dioxane, or by the hydrogenation of the palladium catalyst to the corresponding acid by treatment with hydrogen chloride to S32 .3. R ¹ It is alkenyl, such as allyl of monoester S32 .2, for example, Helv. Chim . Acta . (1985) using the reaction procedure described in 68: 618, is converted to phosphonic acid S32.3 by reaction with a Wilkinson catalyst in an aqueous 15% acetonitrile solution or an organic solvent solution such as an ethanol solution. Hydrogen degradation by the palladium catalyst of phosphonate ester S32 .1 wherein R ¹ is benzyl is described in J. org . Chem . (1959) 24: 434. R ¹ The hydrogenolysis by the palladium catalyst of the phenyl phosphonate ester S32 .1 is described in J. Am. Chem . Soc . (1956) 78: 2336.

Substrate S32 . 2 in the presence of a coupling agent by a large number of reaction for reacting with the hydroxy compound R ¹ OH wherein the monoester S32 .2 is R ¹ is introduced Group is converted to an alkyl, an aralkyl, an alkyl halide such as chloroethyl, or aralkyl is phosphonate diester .1 S32 (Scheme 32, Reaction 4). Typically, the second phosphonate ester group is different from the first introduced phosphonate ester group. That is, R ¹ is introduced after the introduction of R ² , where R ¹ and R ² are each haloalkyl, such as alkyl, aralkyl, chloroethyl, or aralkyl (Scheme 32 , Reaction 4a ), and accordingly, S32.2 is converted to S32 .1a . Suitable coupling agents used in the preparation of the carboxylate esters include carbodiimides such as dicyclohexylcarbodiimide when the reaction is carried out in a basic organic solvent such as pyridine, or the reaction is tertiary such as diisopropylethylamine In the presence of an organic base, (benzotriazole-1-oxy) tripyrrolidinophosphonium hexafluorophosphate (PYBOP, Sigma) or also the reaction when carried out in a polar solvent solution such as dimethylformamide or triphenylphosphate Aldritol-2 (Aldrich) and the like when carried out with a basic solvent solution such as pyridine in the presence of triaryl phosphine such as pin. Alternatively, the phosphonate monoester S32 .2 can be converted to the diester S32 .1 using the Mitsunobu reaction by the above reaction (Scheme 7 ). The substrate can be reacted with the hydroxy compound R ¹ OH in the presence of triarylphosphine, such as diethylazodicarboxylate and triphenyl phosphine. As an alternative, the phosphonate monoester S32.2 is a phosphonate diester S32 wherein the R ¹ group introduced by reacting the monoester with the halide R ¹ Br (R ¹ is alkenyl or aralkyl) is alkenyl or aralkyl. Can be converted to .1 . The alkylation reaction is in the presence of a base such as cesium carbonate, in a polar organic solvent such as dimethylformamide or acetonitrile, as an alternative, the phosphonate monoester is converted to the phosphonate diester by a two step procedure. In the first step, phosphonate monoester S32 .2 is prepared by Organic Phosphorus Compounds , GM Kosolapoff, L. Maeir, eds, Wiley, 1976, p. As described in 17, it is converted to the chloro analog RP (O) (OR ¹ ) Cl by reaction with thionyl chloride or oxalyl chloride and the like. The product RP (O) (OR ¹ ) Cl thus obtained is reacted with the hydroxy compound R ¹ OH in the presence of a base such as triethylamine to obtain phosphonate diester S32 .1 .

Phosphonic acid R-link-P (O) (OH) ₂ is the aforementioned phosphonate diester R-link-P (O) (except that only ¹ mole of component R ¹ OH or R ¹ Br is used. OR ¹ ) _{2 is} converted to phosphonate monoester RP (O) (OR ¹ ) (OH) (Scheme 32 , Reaction 5 ) by the method described in the preparation of S32 .1 . Dialkyl phosphonates are disclosed in Quast et al. (1974) Synthesis 490; Stowell et al. (1990) Tetrahedron Lett . 3261; It can be prepared according to the method of US 5663159.

Phosphonic acid R-link-P (O) (OH) ₂ S32 .3 is subjected to a coupling reaction with the hydroxy compound R ¹ OH in the presence of a coupling agent such as aldritol-2 (Aldrich) and triphenylphosphine. Phosphonate diester R-link-P (O) (OR ¹ ) ₂ S32 .1 (Scheme 32 , Reaction 6 ). The reaction is carried out in a basic solvent such as pyridine. Alternatively, phosphonic acid S32.3 was converted to phosphorous ester S32 .1 , wherein R ¹ is aryl by a coupling reaction with dicyclohexylcarbodiimide at about 70 ° C., for example in pyridine. Alternatively, the phosphorous acid 0.3 S32 has been converted to S32 .1 of phosphite ester R ¹ is alkenyl, by alkylation. The phosphonic acid is reacted with alkenyl bromide R ¹ Br in a polar organic solvent such as acetonitrile at reflux in the presence of a base such as cesium carbonate to give phosphorus ester S32 . Get 1

Phosphonates Carbamate  Produce

The phosphonate esters may contain carbamate bonds. Methods for preparing carbamate are described in Comprehensive Organic Functional Group Transformations , AR Katritzky, ed., Pergamon, 1995, Vol. 6, p. 416ff, and Organic Functional Group Preparations , SR Sandler and W. Karo, Academic Press, 1986, p. Described in 260ff. Such carbamoyl groups may be formed by the reaction of hydroxy groups by methods known in the art by Ellis, US 2002/0103378 A1 and Hajima, US 6018049.

Scheme 33 illustrates various ways in which carbamate bonds are synthesized. According to Scheme 33, in a typical reaction to produce a carbamate, an alcohol .1 S33, as described herein, it is converted to a leaving group Lv is active derivatives S33 such as a halogen, imidazolyl, triazolyl benzamide 0.2. That by following the reaction of the activated derivative with an amine S33 S33 .2 .3 .4 S33 cava to obtain the formate product. Examples 1 to 7 of Scheme 33 describe methods for causing a general reaction. In Examples 8 to 10 illustrate an alternative process for producing a carbamate.

Scheme 33 , Example 1 illustrates the preparation of carbamate using a chloroformyl derivative of alcohol S33 .5 . In this reaction procedure, alcohol S33 .5 was added to Org . Syn . Coll . Vol. 3 , 167, 1965 at about 0 ° C. with an inert solvent solution such as a toluene solution of phosgene, or Org . Syn . Coll . Vol. Reaction with an equivalent reagent such as trichloromethoxy chloroformate as described in 6 , 715, 1988 yields chloroformate S33.6 . Amine compounds of the latter in the presence of an organic or inorganic base component .3 S33 and S33 to carbamate reaction. Get 7 For example, the chloroformyl compound S33.6 is substituted with Org . Syn . Coll . Vol. 3167, in the presence of aqueous sodium hydroxide solution as described in 1965, it is reacted in a water-miscible solvent such as tetrahydrofuran to give the amine S33 .3 cover mate S33 .7. As an alternative, the reaction is carried out in dichloromethane in the presence of an organic base such as diisopropylethylamine or dimethylaminopyridine.

In Scheme 33 , Example 2 , the chloroformate compound S33 . Already by reacting imidazole with 6 de S33 imidazolidine. The reaction to obtain 8 is illustrated. The imidazole by reaction of sleepy de product with an amine to obtain a cover S33 .3 .7 mate S33. The preparation of imidazolide is carried out with an aprotic solvent such as dichloromethane at 0 ° C., and the preparation of carbamate is described in J. Med . Alternatively at room temperature, as described in Chem ., 1989, 32, 357, it is carried out in a similar solvent in the presence of a base such as dimethylaminopyridine.

Scheme 33 , Example 3 is mixed carbonate ester S33 . It illustrates a chloroformate and S33 .6 activated hydroxyl compound R "OH in the reaction to 10. The reaction is dicyclohexylamine or in the presence of a base such as triethylamine in an inert organic solvent such as dichloromethane is performed. the hydroxyl component R "OH is selected from the group of compounds S33 to S33 .19 .24 and similar compounds as shown in Scheme 33. Inde for example, if the component R "OH if two hydroxy benztriazole S33 .19, N- hydroxy succinimide or pentachlorophenol S33 S33 .20 .21, mixed carbonate S33. 10 is Can. J. As described in Chem ., 1982, 60, 976, obtained by reaction of chloroformate and hydroxyl compound in an ethereal solvent in the presence of dicyclohexylamine. Component R "OH is pentafluorophenol S33 .22 or 2-hydroxypyridine S33 . Similar reactions of 23 , Syn ., 1986, 303, and Chem . Ber . As described in 118, 468, 1985, it is carried out in an ethereal solvent in the presence of triethylamine.

Scheme 33 , Example 4 illustrates a method for preparing carbamate in which alkyloxycarbonylimidazole S33 .8 is used. In this reaction procedure, alcohol S33 .5 is reacted with the same molar number of carbonyl diimidazole S33 .11 to give intermediate S33 .8 . The reaction is carried out with an aprotic organic solvent such as dichloromethane or tetrahydrofuran. Acyloxyimidazole S33 .8 is reacted with the same moles of amine R'NH ₂ to give carbamate S33 .7 . The reaction is Tet . As described in Lett ., 42, 2001, 5227, it is carried out in an aprotic organic solvent such as dichloromethane to give carbamate S33 .7 .

Scheme 33, Example 5 illustrates the preparation of carbamates by S33 .13 Intermediate alkoxycarbonyl benztriazole. In this reaction procedure, an alcohol ROH is reacted with benzamide S33 .12 triazol-carbonyl chloride in the same molar amount at room temperature to obtain the alkoxycarbonyl product S33.13. The reaction is carried out in an organic solvent such as benzene or toluene in the presence of a tertiary organic amine such as triethylamine, as described in Synthesis ., 1977, 704. The product is reacted with amine R'NH ₂ to give carbamate S33 .7 . The reaction is carried out in toluene or ethanol at about 80 ° C. at room temperature, as described in Synthesis ., 1977, 704.

Scheme 33 and Example 6 illustrate a method for preparing carbamate by reacting carbonate (R ″ O) ₂ CO, S33 .14 with alcohol S33 .5 to obtain intermediate alkyloxycarbonyl intermediate S33 .15 . the amine R'NH ₂ to cover the reaction to obtain a reaction mate S33 .7 33. the reaction procedure 15 is derived from the S33 .19 hydroxy benztriazole are Synthesis, 1993, has been described in 908;.. reactants S33 15 is a N- hydroxy-succinimide the reaction sequence derived from the mid-S33.20 Tet Lett, 1992, was described in 2781;... reactants S33 15 the reaction sequence is derived from 2-hydroxy-pyridine-S33 .23 the Tet Lett, 1991, was described in 4251;..... reactants S33 15 the reaction sequence which is derived from 4-nitrophenol .24 S33 has been described in Synthesis 1993, 103 molar equivalents of an alcohol ROH and the carbonate S33 .14 The reaction of the liver at room temperature, Carried out by an inert organic solvent.

Scheme 33 , Example 7 illustrates a process for preparing carbamate from alkoxycarbonyl azide S33 .16 . In this reaction procedure, alkyl chloroformate S33 . 6 is reacted with an azide, for example sodium azide, to give alkoxycarbonyl azide S33 .16 . The latter compound is reacted with the same molar number of amines R'NH ₂ to give carbamate S33 .7 . The reaction is carried out with a polar aprotic solvent, such as dimethylsulfoxide, at room temperature, as described, for example, in Synthesis ., 1982, 404.

Scheme 33, Example 8 illustrates the method for producing carbamates by the reaction between an alcohol ROH and chloro-formyl derivative of the amine .17 S33. Synthetic Organic Chemistry , RB Wagner, HD Zook, Wiley, 1953, p. Described in 647, in the reaction sequence, in the presence of a base such as triethylamine to the reaction at room temperature, to obtain a formate S33 .7 cava was coupled within an aprotic solvent such as acetonitrile.

Scheme 33, Example 9 illustrates the preparation of carbamates by the reaction between an alcohol ROH and an isocyanate S33 .18. Synthetic Organic Chemistry , RB Wagner, HD Zook, Wiley, 1953, p. In this reaction procedure described at 645, the reactants are combined at room temperature in an aprotic solvent such as ether or dichloromethane to form carbamate S33 . Get 7

Scheme 33 , Example 10 illustrates a method for preparing carbamate by reaction between alcohol ROH and amine R'NH ₂ . Chem . Lett . In this reaction procedure described in 1972, 373, the reaction is bound at room temperature in the presence of a tertiary base such as triethylamine and selenium in an aprotic organic solvent such as tetrahydrofuran. Carbamate S33 . Carbon monoxide was passed through the solution to proceed with the reaction . Get 7

Carboalkoxy Substituted Phosphonate Preparation of bis amidate, mono amidate, diesters and monoesters.

Many methods of converting phosphonic acids to amidates and esters are available. In one group of methods, phosphonic acid can be converted to isolated active intermediates such as phosphoryl chloride or activated on the fly to react with amines or hydroxy compounds.

The conversion of the phosphonic acid to phosphoryl chloride is described, for example, in J. Gen. Chem . USSR , 1983, 53, 480, Zh . Obschei Khim ., 1958, 28, 1063, or J. org . By reaction with thionyl chloride described in Chem ., 1994, 59, 6144, or in J. Am. Chem . Soc ., 1994, 116, 3251, or J. org . Reaction with oxalyl chloride as described in Chem ., 1994, 59, 6144, or J. org . Chem ., 2001, 66, 329, or J. Med . By reaction of phosphorus pentachloride as described in Chem ., 1995, 38, 1372. The resulting phosphoryl chloride is then reacted with an amine or hydroxy compound in the presence of a base to give an amidate or ester product.

Phosphonic acid is described by J. Chem . Soc , Chem . Comm . (1991) 312, or as described in Nucleosides & Nucleotides (2000) 19: 1885, which are converted to active imidazolyl derivatives by reaction with carbonyl diimidazole. Active sulfonyloxy derivatives are described in Tet . Lett . (1996) 7857 or BioOrg . Med . Chem . Lett . (1998) As described at 8: 663, phosphonic acid is obtained by reaction with trichloromethylsulfonyl chloride or triisopropylbenzenesulfonyl chloride. The active sulfonyloxy derivatives are reacted with amines or hydroxy compounds to yield amidates or esters.

Alternatively, the phosphonic acid and the amine or hydroxy reactant are bound in the presence of the diimide coupling agent. Processes for the preparation of phosphite amidate and esters by coupling reactions in the presence of dicyclohexyl carbodiimide are described, for example, in J. Chem . Soc , Chem . Comm . (1991) 312 or Coll . Czech. Chem . Comm . (1987) 52: 2792. The use of said ethyl dimethylaminopropyl carbodiimide for the activation and coupling of phosphonic acids is described in Tet . Lett ., (2001) 42: 8841 or Nucleosides & Nucleotides (2000) 19: 1885.

Several additional coupling agents have been disclosed for the preparation of amidates and esters from phosphonic acids. The coupling agent is J. org . Chem ., 1995, 60, 5214, and J. Med . Chem . (1997) 40: 3842 alditiol-2, and PYBOP and BOP, as described in J. Med . Chem . (1996) 39: 4958 Mesitylene-2-sulfonyl-3-nitro-1,2,4-triazole (MSNT), J. org . Chem . (1984) Diphenylphosphoryl azide, Bioorg. Med . Chem . Lett . (1998) 1- (2,4,6-triisopropylbenzenesulfonyl-3-nitro-1,2,4-triazole (TPSNT) described in 8: 1013, Tet . Lett ., (1996) 37 Bromotris (dimethylamino) phosphonium fluorophosphate (BroP) described in: 3997, 2-chloro-5,5-dimethyl-2-oxo-1,3,2 described in Nucleosides Nucleotides 1995, 14, 871 Dioxaphosphinane and diphenyl chlorophosphate as described in J. Med . Chem ., 1988, 31, 1305, and the like.

Phosphonic acid is converted to amidates and esters by a Mitsunobu reaction in which phosphonic acid and amine or hydroxy reactant bind in the presence of triaryl phosphine and dialkyl azodicarboxylate. The reaction procedure is described in Org . Lett ., 2001, 3, 643, or J. Med . Chem ., 1997, 40, 3842.

Phosphoric acid esters are also obtained by reaction between phosphonic acid and halogenated compounds in the presence of a suitable base. The method is, for example, Anal. Chem ., 1987, 59, 1056, or J. Chem. Soc . Perkin Trans., I , 1993, 19, 2303, or J. Med . Chem ., 1995, 38, 1372, or Tet . Lett ., 2002, 43, 1161.

Schemes 34-37 include phosphonbisamidates (Scheme 34 ), phosphonamidates (Scheme 35 ), phosphonate monoesters (Scheme 36 ) and phosphonates with phosphonate esters and phosphonic acids substituted with carboalkoxy. Conversion to diesters (Scheme 37 ) is illustrated. Scheme 38 illustrates the synthesis of a gem-dialkyl amino phosphonate reactant.

Scheme 34 illustrates various ways in which phosphonate diester S34 .1 is converted to phosphonbisamidate S34.5 . Diester S34 prepared by the above-described method . 1 is hydrolyzed to monoester S34 .2 or phosphonic acid S34 .6 . The above methods for such substitutions are those described above. Monoester S34 . 2 reacts with aminoester S34 .9 to monoamidate S34 . Switch to 3 Wherein said group R ² is H or alkyl; The group R ^4b is a divalent alkylene moiety, for example CHCH ₃ , CHCH ₂ CH ₃ , CH (CH (CH ₃ ) ₂ ), CH (CH ₂ Ph), and the like, or natural or modified Side chain groups present in amino acids; And the group R ^5b is C ₁ -C ₁₂ alkyl, such as methyl, ethyl, propyl, isopropyl or isobutyl; C ₆ -C ₂₀ aryl, such as phenyl or substituted phenyl; Or C ₆ -C ₂₀ arylalkyl, such as benzyl or benzhydryl. The reaction was performed by J. Am. Chem . Soc . (1957) amidate products by binding in the presence of a coupling agent such as carbodiimide, for example dicyclohexyl carbodiimide, described in 79: 3575, alternatively in the presence of an active agent such as hydroxybenztriazole, etc. S34 .3 was obtained. The reaction to form the amidate is also described in J. org . Chem . (1995) Reacts in the presence of a coupling agent such as BOP, aldithiol, PYBOP and the similar coupling agents used in the preparation of amides and esters described in 60: 5214. Alternatively, the reactants S34 .2 and S34 . 9 is transformed into monoamidate S34.3 by Mitsunobu reaction. The method for preparing amidate by Mitsunobu reaction is described in J. Med . Chem . (1995) 38: 2742. The same molar number of reactants are bound in an inert solvent such as tetrahydrofuran in the presence of triaryl phosphine and dialkyl azodicarboxylate. The obtained mono ester amidate S34 .3 the amidate phosphonic acid S34 again. Transform it to 4 The reaction conditions of the hydrolysis reaction depend on the characteristics of the R ¹ group as described above. The phosphonic acid amidate S34.4 was reacted with the aforementioned aminoester S34 .9 to give the bisamidate product S34 . 5 was obtained. Their amino substituents are the same or different. Alternatively, phosphonic acid S34 .6 can be treated simultaneously with two different amino ester reactants. In other words, R ² , R ^4b, or R ^5b are different According to S34 .9 . The mixed product of bisamidate product S34 .5 can be separated, for example, by chromatography or the like.

Examples of reaction procedures are shown in Scheme 34 , Example 1 . In this reaction sequence, dibenzyl phosphonate S34 .14 the J. org. Chem., 1995, 60, as described in 2946, by refluxing with octane (DABCO) in toluene solution to the reaction diazabicyclo, monobenzyl phosphonate to obtain the S34 .15. The product was reacted with a pyridine solution of the same molar number of ethyl alanate S34 .16 and dicyclohexyl carbodiimide to give the amidate product S34 .17 . The benzyl group is removed by, for example, hydrogenolysis using a palladium catalyst, thereby degrading the J. Med. Chem. (1997) 40 (23): 3842 to give the unstable monoacid product S34.18 . This compound S34 .18 , J. Med . Chem., 1995, 38, as described in 2742, Mitsunobu reaction with ethyl ryusi S34 .19 carbonate, triphenylphosphine and diethyl azodicarbonyl reacted with a carboxylate to give the bis S34 .20 amidate product.

Instead of ethyl leucinate S34 .19 or ethyl alanate S34 .16 , the reaction procedure using another aminoester S34 .9 was used to obtain the corresponding product S34 .5 .

Alternatively, S34 .6 acid is converted to the bis amidate S34.5 by the above-described coupling reactions. The reaction is carried out in one stage where the nitrogen-based substituents in the product S34 .5 are the same or in two stages where the nitrogen-based substituents are different.

Examples of the methods are shown in Scheme 34, Example 2. In this reaction procedure, phosphonic acid S34.6 is described, for example, in J. Chem . Soc , Chem . The bisamidate product S34 . Was reacted with excess ethyl phenylalanineate S34 .21 and dicyclohexylcarbodiimide on pyridine solution as described in Comm ., 1991, 1063 . 22 was obtained.

Instead of ethyl phenylalanineate, using the above reaction procedure using another aminoester S34 .9 , the corresponding product S34 .5 was obtained.

By further alternative, phosphonic acid S34 .6 is converted to mono or bis-active derivative S34.7 . Here, Lv is a leaving group such as chloro, imidazolyl, triisopropylbenzenesulfonyloxy and the like. Conversion of the chloride acid S34 .7 (Lv = Cl) is, Organic Phosphorus Compounds, GM Kosolapoff, L. Maeir, eds, Wiley, 1976, p. As described in 17, by reaction with thionyl chloride or oxalyl chloride and the like. The conversion of monoimidazolide S34 .7 (Lv = imidazolyl) of the phosphonic acid is described in J. Med . Chem ., 2002, 45, 1284 and J. Chem . Soc . Chem . Comm ., 1991, 312. Alternatively, phosphonic acid is reacted with triisopropylbenzenesulfonyl chloride as described in Nucleosides and Nucleotides , 2000, 10, 1885. The active product was reacted with aminoester S34 .9 in the presence of a base to give bisamidate S34.5 . The reaction is carried out in one step in which the nitrogen substituents of the product S34 .5 are identical, or the nitrogen substituents are different, and the intermediate S34 . This can be done in two steps.

Examples of such methods are shown in Scheme 34, Examples 3 and 5. In the reaction procedure illustrated in Scheme 34, Example 3, phosphonic acid S34 .6 was converted to Zh . Obschei Reaction with 10 molar equivalents of thionyl chloride as described in Khim ., 1958, 28, 1063 afforded the dichloro compound S34.23 . The product was reacted with butyl serinate S34 .24 at reflux temperature in the presence of an aprotic solvent such as polar acetonitrile and a base such as triethylamine to give the bisamidate product S34 . Get 25

Butyl serinate S34 . Instead of 24 , using the above reaction procedure using another aminoester S34 .9 , the corresponding product S34 . 5 was obtained.

Using the reaction procedure illustrated in Scheme 34, Example 5, phosphonic acid S34 .6 was prepared by J. Chem . Soc. Chem . Comm., 1991, as described in 312, carbonyl di-imidazole to the reaction to give the imidazole Id Jolla S34 .32. The product was subjected to 1 molar equivalent of ethyl alanate S34 in acetonitrile at room temperature . It was reacted with 33 neunda obtain the monosubstituted product S34 .34. The compound of the latter carbonyl di reacted with imidazol to obtain an active intermediate .35 S34, to the product under the same reaction conditions, ethyl N- methylal by reaction with Raney carbonate S34.33a bis amidate product S34 .36 Got it.

Ethyl carbonate instead of the Raney Al S34 .33 or ethyl N- methylal Raney carbonate .33a S34, using the general procedure with different amino ester .9 S34, to obtain the corresponding products S34.5 to.

Intermediate mono amidate S34 .3 also was converted to the mono-ester using the general procedure described above primarily as Lv is a leaving group such as halo, imidazolyl etc, activated derivative S34.8 prepared by the monoester S34 .2 It became. The product S34 .8 was reacted with aminoester S34 .9 in the presence of a base such as pyridine to give the intermediate monoamidate product S34 .3 . The latter compound was converted to bisamidate S34 .5 by removal of the R ¹ group and coupling of the product with aminoester S34 .9 as described above.

Is converted to a phosphonic acid S34 .26 chloro derivative shows an example of the general procedure that is activated in Scheme 34, Example 4. In this reaction procedure, Tet . As described in Letters ., 1994, 35, 4097, phosphorous acid monobenzyl ester S34 .15 was reacted with thionyl chloride in dichloromethane solution to phosphoryl chloride S34 . 26 was obtained. The product was dissolved in acetonitrile solution at room temperature in 1 molar equivalent of ethyl 3-amino-2-methylpropionate S34 . 27 and the reaction to obtain a mono amidate product S34 .28. By the hydrogenation of the latter compounds with 5% palladium on carbon catalyst in ethyl acetate solution it turned out to S34 .29 mono acid product. The product was subjected to the same molar number of butylalanininate S34.30 , triphenyl phosphine, in tetrahydrofuran by the Mitsunobu coupling reaction procedure, Treatment with diethylazodicarboxylate and triethylamine afforded bisamidate product S34 .31 .

Ethyl 3-amino-2-methylpropionate S34 .27 or Butylalanine S34 . Instead of 30 , using the above reaction procedure using another aminoester S34 .9 , the corresponding product S34 .5 was obtained.

Said active phosphonic acid derivatives S34 . 7 is also converted to bisamidate S34 .5 via diamino compound S34 .10 . A method of switching to the active amino acid yudocheeul analogs corresponding to react with ammonia, such as phosphoryl chloride, S34 .10 been described in Organic Phosphorus Compounds, GM Kosolapoff, L. Maeir, eds, Wiley, 1976. In the presence of a base such as 4, 4-dimethylaminopyridine (DMAP) or potassium carbonate while heating the bisamino compound S34 .10 , halogenated ester S34 .12 (Hal = halogen, That is, reacted with F, Cl, Br, I) to make bisamidate S34 . 5 was obtained. Alternatively, S34.6 can be treated simultaneously with two different amino ester reactants. In other words, R ^4b or R ^5b of S34 .12 is different from each other. The resultant mixture of the bisamidate product S34 .5 can be separated, for example, by chromatography.

Examples of such reaction procedures are shown in Scheme 34, Example 6. In this method, dichlorophosphonate S34 . 23 is reacted with ammonia to diamide S34 . Get 37 The reaction is carried out in aqueous, aqueous alcoholic solution or alcohol at reflux temperature. The diamino compound is prepared in a polar organic solvent such as N-methylpyrrolidinone, in the presence of a base such as potassium carbonate, or alternatively in the presence of potassium iodide, 2 molar equivalents of ethyl 2-bromo-3 -Methylbutyrate S34 . And allowed to react at 38 to about 150 ℃, gets S34 .39 bis amidate product.

Instead of ethyl 2-bromo-3-methylbutyrate S34 .38 , using the reaction procedure above with another halogenated ester S34.12 , the corresponding product S34 .5 was obtained.

The reaction procedure shown in Scheme 34 is also applicable to a method for preparing bisamidate in which the aminoester moiety includes other functional groups. Scheme 34, Example 7 illustrates the preparation of bisamidate derived from tyrosine. In this reaction sequence, as described in Example 5, when the mono-imidazole Jolla Id S34 .32 to profile tie carbonate S34. React with 40 to give monoamidate S34 . 41 was obtained. The product was reacted with carbonyl diimidazole to afford imidazolide S34 .42 . And it reacted with the carbonate when the material to the profile of the tie added one molar equivalent of the obtained bis amidate product S34 .43.

Instead of propyl tyrosinate S34 .40 , using the above reaction procedure using another aminoester S34 .9 , the corresponding product S34 . 5 was obtained. The aminoesters used in the two steps of the reaction procedure may be the same or different, and thus bisamidates having the same or different amino substituents may be prepared.

Scheme 35 illustrates a method for preparing phosphonate monoamidate.

Within one reaction procedure, phosphonate monoester S34 .1 is converted to active derivative S34 .8 , as described in Scheme 34. As it described above this compound, in the presence of a base, and reacting the amino ester S34 .9 to obtain a mono amidate product S35 .1.

The reaction procedure is illustrated in Scheme 35, Example 1. By this method, monophenyl phosphonate S35 . 7 to J. Gen. Chem . USSR., 1983, 32, for example, such as described in 367, was reacted with thionyl chloride to give the chloride product .8 S35. The product was reacted with ethyl alaninate, as described in Scheme 34, to provide amidate S35 . 10 was obtained.

Instead of ethyl alanate S35 .9 , the reaction procedure using another aminoester S34 .9 was used to give the corresponding product S35 .1 .

Alternatively, phosphonate monoester S34 .1 is coupled with aminoester S34 .9 as described in Scheme 34 to amidate S35 . Produced 1 If necessary, the R ¹ substituent is modified by initial decomposition to obtain phosphonic acid S35 .2 . The reaction procedure for this substitution depends on the properties of the R ¹ group and the like. The phosphonic acid and the amine coupling reaction the same procedures described in Scheme 34 for the coupling of the acid (carbodiimide, Al -2 give thiol, PYBOP, Mitsunobu reaction etc) by using the R ³ group is an aryl, heteroaryl, Ester amidate product S35 by reacting with hydroxy compound R ³ OH which is cycle, alkyl, cycloalkyl, alkyl halide and the like . Transformed to 3

Examples of such methods are shown in Scheme 35, Examples 1-3. In the reaction sequence shown in Example 2, monobenzyl phosphonate S35 . 11 is reacted with Raney Al ethyl carbonate by the above-mentioned method is modified to mono amidate S35 .12. The benzyl group was phosphonic acid amidate S35 by hydrogenation with a 5% carbonaceous palladium catalyst in ethyl acetate solution . Get 13 The product is, for example, Tet . Amidate esters by reacting with the same moles of 1- (dimethylaminopropyl) -3-ethylcarbodiimide and trifluoroethanol S35 .14 at room temperature as described in Lett ., 2001, 42, 8841 S35 . 15 was obtained.

In the reaction sequence shown in Scheme 35, Example 3, the monoamidate S35 . 13 was coupled with the same molar number of dicyclohexyl carbodiimide and 4-hydroxy-N-methylpiperidine S35 .16 at tetrahydrofuran at room temperature to yield the amidate ester product S35.17 .

Instead of ethyl alanate product S35 .12 , other monoacids S35 .2 , and instead trifluoroethanol S35 .14 or 4-hydroxy-N-methylpiperidine S35 .16 , other hydroxy compounds R ³ Using the above reaction procedure with OH, the corresponding product S35 . 3 was obtained.

Alternatively, the active phosphonate ester S34 . 8 was reacted with amidate S35 .4 to give ammonia. The product was reacted with halogenated ester S35 .5 in the presence of a base, as described in Scheme 34, to yield the amidate product S35 .6 . If necessary, the properties of the R ¹ groups can be changed using the reaction procedure described above to give the product S35 . 3 was obtained. The method is illustrated in Scheme 35, Example 4 . In this reaction sequence, as the monophenyl phosphoryl chloride .18 S35 described in Scheme 34, by reaction with ammonia to give the amino product S35.19. This material in N- methylpyrrolidinone solution of butyl 2-bromo-3-phenyl propionate S35 .20 and potassium carbonate were reacted at 170 ℃ and gets amidate product S35 .21.

Instead of butyl2 -bromo-3-phenylpropionate S35 .20 , this reaction procedure using another halogenated ester S35.5 was used to obtain the corresponding product S35 .6 .

The mono S35 .3 amidate product was also prepared from a dual-active phosphonate derivatives S34.7. In this reaction procedure, as described in Synlett ., 1998, 1, 73, the intermediate S34 . 7 is reacted with a limited amount of aminoester S34 .9 to give the mono-substituted product S34 . 11 was obtained. The latter compound was reacted with a hydroxy compound R ³ OH in a polar organic solvent such as dimethylformamide in the presence of a base such as diisopropylethylamine to obtain monoamidate ester S35 .3 .

The method is illustrated in Scheme 35, Example 5. In this method, the phosphoryl dichloride S35 .22 was reacted with 1 molar equivalent of ethyl N-methyl tyrosinate S35.23 and dimethylaminopyridine in dichloromethane solution to give monoamidate S35 .24 . Was reacted with the product-dimethylformamide solution of phenol .25 S35 containing potassium carbonate to give the ester amidate product S35 .26.

Instead of ethyl N-methyl tyrosinate S35 .23 or phenol S35 .25 , this reaction procedure using aminoester S34 .9 and / or hydroxy compound R ³ OH was used to obtain the corresponding product S35 .3 . .

Scheme 36 illustrates a process for the preparation of phosphonate diesters in which one of the ester groups is substituted with carboalkoxy contained in a carboalkoxy substituent. In one reaction procedure, phosphonate monoester S34 prepared as described above . 1 by the method described above, the R ^4b and R ^5b groups are hydroxyester S36 . Coupling with 1 For example, an equivalent molar amount of reactant is Aust . Dimethylaminopyridine, as described in Tet ., 1999, 55, 12997, alternatively in the presence of carbodiimides such as dicyclohexyl carbodiimide, as described in J. Chem ., 1963, 609. Coupling in the presence of The reaction is carried out in an inert solvent at room temperature.

The reaction procedure is illustrated in Scheme 36, Example 1. In this way, Monophenyl phosphonate S36 . 9 is ethyl 3-hydroxy-2-methylpropionate S36 . In dichloromethane solution in the presence of dicyclohexyl carbodiimide . Coupled with 10 to give diester S36 .11 mixed with phosphonate.

Instead of ethyl 3-hydroxy-2-methylpropionate S36 .10 , other hydroxyester S33 . Using the reaction procedure with 1 , the corresponding product S33 . 2 was obtained.

The conversion of the phosphonate monoester S34 .1 to mixed diester S36 .2 is also described in Org . As described in Lett ., 2001, 643, it is carried out with hydroxyester S36 .1 by a Mitsunobu coupling reaction. In this method, the reactants S34 .1 and in the presence of a triaryl phosphine and a dialkyl azodicarboxylate S36.1, tetrahydro combined in a polar solvent such as THF to yield the mixed diester S36 .2. By the method described above, wherein the R ¹ substituent is decomposed to obtain a deformation by being .3 S36 mono acid product. By the above method, the product was coupled with the hydroxy compound R ³ OH to give diester product S36 .4 .

The reaction procedure is illustrated in Scheme 36, Example 2. In this method, a monoallyl phosphonate S36 .12 triphenylphosphine and diethyl azo dicarboxylate in the presence of the rate and, tetrahydrofuran ring by ethyl lactate S36 .13 and couple in the mixed diester S36.14 Got. To remove the allyl product (triphenylphosphine) acetonitrile to the solution and the reaction to obtain a nitrile S36 .15 mono acid product of rhodium chloride (Wilkinson's catalyst). The latter compound was coupled to 1 molar equivalent of 3-hydroxypyridine S36 .16 on pyridine solution in the presence of dicyclohexyl carbodiimide at room temperature to produce mixed diester S36 . 17 was obtained.

Instead of ethyl lactate S36 .13 or 3-hydroxypyridine, using the above reaction procedure using other hydroxyester S36 .1 and / or other hydroxy compound R ³ OH, the corresponding product S36 .4 was obtained.

From the above mixed diester S36 .2 and monoester S34 .1 Obtained through the mediation of active monoester S36.5 . In this reaction procedure, the monoester S34 . 1 is converted to the active compound S36.5 . This is described, for example, in J. org . Reaction with phosphorus pentachloride, as described in Chem ., 2001, 66, 329, or thionyl chloride or oxalyl chloride (Lv = Cl), or as described in Nucleosides and Nucleotides , 2000, 19, 1885, or By reaction with a pyridine solution of triisopropylbenzenesulfonyl chloride, or by J. Med . As described in Chem ., 2002, 45, 1284, it occurs in reaction with carbonyl diimidazole. As mentioned above, the active monoester resultant was converted to hydroxyester S36 . It is reacted with 1 to obtain the mixed diester S36 .2.

The reaction procedure is illustrated in Scheme 36, Example 3. In this reaction sequence, mono phenyl phosphonate S36 .9 is reacted with 10 equivalents of thionyl chloride on a acetonitrile solution of 70 ℃ turned out to S36 .19 phosphoryl chloride. The product was reacted with a dichloromethane solution of ethyl 4-carbamoyl-2-hydroxybutyrate S36 .20 containing triethylamine to give mixed diester S36 . 21 was obtained.

Instead of ethyl 4-carbamoyl-2-hydroxybutyrate S36 .20 , other hydroxyester S36 . Using the reaction procedure above using 1 , the corresponding product S36 .2 was obtained.

The mixed phosphonate diesters or R ³ O groups can be obtained by alternative reaction routes for inclusion in intermediate S36 .3 already containing a hydroxyester moiety. In this reaction procedure, as described above, the monoacid intermediate S36 . Lv 3 is chloro, it is already converted into a leaving group S36 .6 active derivatives such as imidazole. The active intermediate was reacted with the hydroxy compound R ³ OH in the presence of a base to produce a mixed diester product S36 . 4 was obtained.

The method is illustrated in Scheme 36, Example 4. In this reaction sequence, J. Med . Phosphonate monoacid S36 , as described in Chem ., 1995, 38, 4648 . 22 was reacted with a tetrahydrofuran solution of trichloromethanesulfonyl chloride containing collidine to give the trichloromethanesulfonyloxy product S36 . 23 was created. The compound was reacted with a dichloromethane solution of 3- (morpholinomethyl) phenol S36 .24 containing triethylamine to give mixed diester product S36 . 25 was obtained.

Instead of 3- (morpholinomethyl) phenol S36 .24 , using the above reaction procedure using another alcohol R ³ OH, the corresponding product S36 . 4 was obtained.

Phosphonate ester S36 .4 is also obtained by alkylation with monoester S34 .1 . Between acid S34 .1 and halogenated ester S36 .7 The reaction was Anal. Diisopropylethylamine, described in Chem ., 1987, 59, 1056, J. Med . In the presence of a base such as triethylamine as described in Chem ., 1995, 38, 1372, a polar solvent or Syn . In the presence of 18-crown-6 described in Comm ., 1995, 25, 3565, in a polar solvent such as benzene.

The method is illustrated in Scheme 36, Example 5. In this reaction procedure, the monoacid S36 .26 to 80 ℃ ethyl 2-bromo-3-phenyl propionate S36 .27 and diisopropylethylamine in dimethylformamide solution to yield a mixed diester product at S36. Get 28

Instead of ethyl 2-bromo-3-phenylpropionate S36 .27 , using the above reaction procedure using another halogenated ester S36.7 , the corresponding product S36 .4 was obtained.

Scheme 37 illustrates a process for preparing phosphonate diesters in which two ester substituents are bonded to a carboalkoxy group.

The compound was prepared directly or indirectly from phosphonic acid S34 .6 . Alternatively, the phosphonic acid is coupled with hydroxyester S37 .2 using the reaction conditions of Scheme 34-36, such as a coupling reaction using the aforementioned dicyclohexyl carbodiimide or similar reactants, or under Mitsunobu reaction conditions . Ring to diester product S37 . Get 3 Here, the ester substituents are the same as each other.

This method is illustrated in Scheme 37, Example 1. In this reaction procedure, the phosphonic acid S34 .6 is reacted with 3 equivalents of butyl lactate S37 .5 at about 70 ° C. in the presence of a pyridine solution of aldritol-2 and triphenyl phosphine . Diester S37 . Get 6

Using the above reaction procedure using another hydroxyester S37 .2 instead of butyl lactate S37 .5 , the product S37 . 3 was obtained.

Alternatively, the diester S37 . 3 is obtained by alkylating phosphonic acid S34 .6 with halogenated ester S37 .1 . The alkylation reaction is carried out according to Scheme 36 for the preparation of ester S36 .4 .

This method is illustrated in Scheme 37, Example 2. In this reaction procedure, the phosphonic acid S34 .6 was analyzed by Anal. Excess at about 80 ° C. as described in Chem ., 1987, 59, 1056 Reacting with ethyl 3-bromo-2-methylpropionate S37 .7 and dimethylformamide of diisopropylethylamine to yield diester S37 . Get 8

Instead of ethyl 3-bromo-2-methylpropionate S37 .7 , the above reaction procedure using another halogenated ester S37.1 was used to obtain the corresponding product S37 .3 .

Diester S37 . 3 is the active derivative of phosphonic acid S34 . It is obtained by substitution-reacting 7 with hydroxyester S37 .2 . The substitution reaction is carried out in a polar solvent in the presence of a suitable base as described in Scheme 36. The substitution reaction gives the diester product S37 .3 in which the ester substituents are identical to each other in the presence of an excess of hydroxyester, or a diester S37 having different ester substituents using sequentially limited amounts of other hydroxyesters . Get 3

The method is illustrated in Scheme 37, Examples 3 and 4. As seen in Example 3, the phosphoryl dichloride S35 .22 in a tetrahydrofuran solution containing potassium carbonate, 3 equivalent moles of ethyl 3-hydroxy-2- (hydroxymethyl) propionate S37 Reaction with .9 gave the diester product S37 .10

Instead of ethyl 3-hydroxy-2- (hydroxymethyl) propionate S37 .9 , using the above reaction procedure using another hydroxyester S37 .2 , the corresponding product S37.3 was obtained.

In Scheme 37, Example 4, the monoester product S37 . Was substituted by a substitution reaction between phosphoryl dichloride S35 .22 equal moles of ethyl 2-methyl-3-hydroxypropionate S37 .11 . 12 was obtained. The reaction was carried out with acetonitrile solution at 70 ° C. in the presence of diisopropylethylamine. Product S37 . 12 was reacted with 1 equivalent mol of ethyl lactate S37 .13 under the same reaction conditions to obtain diester product S37 .14 .

Instead of ethyl 2-methyl-3-hydroxypropionate S37 .11 and ethyl lactate S37 .13 , the corresponding product S37 .3 was prepared using the above reaction procedure which was sequentially reacted with other hydroxyester S37 .2. Got it.

The 2,2-dimethyl-2-aminoethylphosphonic acid intermediate can be prepared by the route of Scheme 5. 2-methyl-2-propane-sulfinamide by condensation of acetone and sulfinyl imine S38 .11 (J. org. Chem. 1999, 64, 12) by the addition of a S38.11 in dimethyl methyl phosphonate lithium S38 .12 was obtained. S38 .12 by the acidic decomposition of methane to give the amine .13 S38. The amine was protected with a Cbz group and the methyl group was removed to give phosphonic acid.

S38. 14 is intended by the method already known S38. 15 (Scheme 38a). An alternative method of synthesizing Compound S38 .14 is also shown in Scheme 38b. Commercially available 2-amino-2-methyl-aziridine was converted to S38 .16 by the literature method (J. org Chem 1992, 57, 5813;.... Syn Lett 1997, 8, 893) . The aziridine is opened by phosphite to yield S38 .17 ( Tetrahedron Lett . 1980 , 21 , 1623). Reprotect S38 .17 to obtain S38 .14 .

The invention will be illustrated by the following non-limiting examples.

Example  One   Illustrative Synthesis of Compounds of the Invention

The following scheme illustrates the general process for the preparation of the compounds of the invention, 2'fluoro, 2'3'didehydronucleoside supports.

Methods for introducing fluorine at the 2 'position of ribonucleoside and nucleoside analogues are described in US Pat. US 5859233; Journal of Medicinal ChemistryJournal of the Chemical Society, Perkintransactions 1 Journal of Medicinal ChemistryNucleosides & NucleotidesJournal of Medicinal Chemistry Tetrahedron LettersBioorganic & Medicinal Chemistry Letters Tetrahedron LettersNucleic acids Symposium SeriesJournal of Medicinal ChemistryJournal of Medicinal ChemistryJournal of Medicinal ChemistryJournal of Medicinal described ChemistryJournal of the American Chemical Society It is.

Scheme 556 (A-F) represents a synthetic route that can be utilized to prepare the exemplary embodiments shown herein.

The (-) enantiomer of adenosine 556-A.1 was subjected to excess trityl (Tr, triphenylmethyl, Ph ₃ C-) containing dimethylaminopyridine in N-6 and 5 'hydroxyls of adenine exocyclic amines. Bis-trityl 556-A by tritylation with a pyridine solution of . 2 was obtained. This was treated with trichloromethane anhydrous dichloromethane and DMAP to give 556-A.3 (Scheme 556-A). The 2'triplate group was substituted with fluoride at room temperature by THF solution of tetra-butylammonium fluoride to obtain 556-A.4 .

All of the above references and cited inventions are incorporated herein by reference in their place. In particular, the cited portions or pages of the cited documents cited above are incorporated as specialized references. The invention has been described in sufficient detail to enable those skilled in the art to make or use the subject matter of the following claims. It is evident that modifications can be made to the compositions and methods of the following claims within the spirit and scope of the invention.

In the claims of this specification, the superscript and subscript of a given variable are different. For example, R ₁ is R ¹ Is different.

Claims (134)

Complexes comprising antiviral compounds linked to one or more phosphonate groups; Or a pharmaceutically acceptable salt or solvate thereof. The method of claim 1, wherein the complex is represented by Formula 105 or 106 ; Or a pharmaceutically acceptable salt or solvate thereof, here; A ⁰ is A ¹ , A ² or W ³ , provided that the complex contains at least one A ¹ , A ¹ is

ego; A ² is

Is; A ³ is

Is, Y ¹ is independently O, S, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ) or N (N (R ^x ) (R ^x ) )ego, Y ² is independently one bond, O, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ), N (N (R ^x ) (R ^x )), -S (O) _M2- , or -S (O) _M2 -S (O) _M2 -and when Y ² is bonded to two phosphorus atoms, Y ² is C (R ² ) (R ² ); R ^x is independently H, R ¹ , R ² , W ³ , a protecting group or the following formula:

Is here: R ^y is independently H, W ³ , R ² or a protecting group; R ¹ is independently H or alkyl having 1 to 18 carbon atoms; R ² is independently H, R ¹ , R ³ or R ⁴ , wherein each R ⁴ is independently substituted with 0 to 3 R ³ groups or is bonded together to a carbon atom such that two R ² groups are carbon 3 to 8 Two rings, which ring is substituted with from 0 to 3 R ³ groups; R ³ is R ^3a , R ^3b , R ^3c or R ^3d , and if R ³ is bonded to a heteroatom, R ³ is R ^3c or R ^3d ; R ^3a is F, Cl, Br, I, -CN, N ₃ or -NO ₂ ; R ^3b is Y ¹ ; R ^3c is -R ^x , -N (R ^x ) (R ^x ), -SR ^x , -S (O) R ^x , -S (O) ₂ R ^x , -S (O) (OR ^x ),- S (O) ₂ (OR ^x ), -OC (Y ¹ ) R ^x , -OC (Y ¹ ) OR ^x , -OC (Y ¹ ) (N (R ^x ) (R ^x )), -SC (Y ¹ ) R ^x , -SC (Y ¹ ) OR ^x , -SC (Y ¹ ) (N (R ^x ) (R ^x )), -N (R ^x ) C (Y ¹ ) R ^x , -N (R ^x ) C (Y ¹ ) OR ^x or -N (R ^x ) C (Y ¹ ) (N (R ^x ) (R ^x )); R ^3d is —C (Y ¹ ) R ^x , —C (Y ¹ ) OR ^x or —C (Y ¹ ) (N (R ^x ) (R ^x )); R ⁴ is alkyl having 1 to 18 carbon atoms, alkenyl having 2 to 18 carbon atoms or alkynyl having 2 to 18 carbon atoms; R ⁵ is R ⁴ , wherein each R ⁴ may be substituted with 0 to 3 R ³ groups; W ³ is W ⁴ or W ⁵ ; W ⁴ is R ⁵ , -C (Y ¹ ) R ⁵ , -C (Y ¹ ) W ⁵ , -SO _M2 R ⁵ or -SO _M2 W ⁵ ; W _⁵ is carbocycle or heterocycle, wherein W ⁵ may be independently substituted with 0 to 3 R _² groups; W ⁶ is independently a W ³ group substituted with 1, 2, or 3 A ³ ; M2 is 0, 1 or 2; M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; M 12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; Mla, Mlc, and Mld are independently 0 or 1; M 12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; X ¹⁰⁵ is selected from O, C (R ^y ) ₂ , OC (R ^y ) ₂ , NR and S; X ¹¹⁰ is independently O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N-NR ₂ , S, SS, S (O) or S (O) ₂ ; X ¹¹¹ is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deaza guanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenin, inosine, nebularin , Nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynyl Cytosine, Isocytosine, Isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine, O ⁴ -methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazole or pyrazole [3,4-D] pyrimidine; X ¹¹² is independently selected from H, OH, OR, NR ₂ , CN, NO ₂ , SH, SR, F, Cl, Br and I; X ¹¹³ is F; X ¹¹⁴ is independently H, F, Cl, Br, I, OH, R, -C (= Y ¹ ) R, -C (= Y ¹ ) OR, -C (= Y ¹ ) N (R) ₂ , -N (R) ₂ ,- ⁺ N (R) ₃ , -SR, -S (O) R, -S (O) ₂ R, -S (O) (OR), -S (O) ₂ (OR ), -OC (= Y ¹ ) R, -OC (= Y ¹ ) OR, -OC (= Y ¹ ) (N (R) ₂ ), -SC (= Y ¹ ) R, -SC (= Y ¹ ) OR, -SC (= Y ¹ ) (N (R) ₂ ), -N (R) C (= Y ¹ ) R, -N (R) C (= Y ¹ ) OR, or -N (R) C (= Y ¹ ) N (R) ₂ , amino (-NH ₂ ), ammonium (-NH ₃ ⁺ ), alkylamino, dialkylamino, trialkylammonium, C ₁ -C ₈ alkyl, carboxy, sulfate, sulfa Mate, sulfonate, 5-7 membered ring sulfam, C ₁ -C ₈ alkylsulfonate, 4-dialkylaminopyridinium, hydroxyl-substituted C ₁ -C ₈ alkyl, C ₁ -C ₈ alkylthiol, alkylsul Ponyl, arylsulfonyl, arylsulfinyl (-SOAr), arylthio, -SO ₂ NR ₂ , -SOR, -C (= 0) OR, -C (= 0) NR ₂ , 5-7 member cyclic lactam, 5-7 member cyclic lactones, cyano, azido, nitro, C ₁ -C ₈ alkoxy, substituted C ₁ -C ₈ alkyl, C ₁ -C ₈ alkenyl, substituted C ₁ -C ₈ alkenyl, C _1- C ₈ alkynyl, substituted C ₁ -C ₈ alkynyl, aryl, substituted Aryl, heterocycle, substituted heterocycle, polyethylenoxy, protecting group or W ³ ; Or combine together to form two R ^y carbocyclic rings of 3 to 7 carbon atoms. The complex of claim 2, wherein each A ¹ is represented by the formula:

. The complex of claim 2, wherein each A ¹ is represented by the formula:

. The complex of claim 2, wherein each A ¹ is represented by the formula:

. The complex of claim 2, wherein each A ¹ is represented by the formula:

. The complex of claim 2, wherein each A ¹ is represented by the formula:

. Wherein W ^5a is a carbocycle or heterocycle, wherein W ^5a is independently substituted with 0 or 1 R ² groups. The complex of claim 2, wherein M 12a is 1. 4. The complex of claim 2, wherein each A ¹ is represented by the formula:

. The complex of claim 2, wherein each A ¹ is represented by the formula:

. The complex of claim 2, wherein each A ¹ is represented by the formula:

; In the above formula, W ^5a is independently a carbocycle substituted with 0 or 1 R ² groups. The complex of claim 2, wherein each A ¹ is represented by the formula:

; In the above formula, Y ^2b is O or N (R ² ) and M 12d is 1, 2, 3, 4, 5, 6, 7 or 8. The complex of claim 2, wherein each A ¹ is represented by the formula:

; In the above formula, W ^5a is independently a carbocycle substituted with 0 or 1 R ² groups. The complex of claim 2, wherein each A ¹ is represented by the formula:

; Wherein W ^5a is a carbocycle or heterocycle, wherein W ^5a is independently substituted with 0 or 1 R ² groups. The complex of claim 2, wherein each A ¹ is represented by the formula:

; In the above formula, Y ^2b is O or N (R ² ) and M 12d is 1, 2, 3, 4, 5, 6, 7 or 8. The complex according to any one of claims 2 to 15, wherein each A ² is represented by the formula:

. The complex according to any one of claims 2 to 15, wherein each A ² is represented by the formula:

. 16. The complex of any one of claims 2-15, wherein each M12b is one. The compound of claim 18, wherein M 12b is 0, Y ² is a bond, and W ⁵ is a carbocycle or heterocycle, wherein W ⁵ is optionally and independently substituted with 1, 2 or 3 R ² groups It is complex). The complex according to any one of claims 2 to 15, wherein each A ² is represented by the formula:

; Wherein W ^5a is a carbocycle or heterocycle, wherein W ^5a is optionally and independently substituted with 1, 2 or 3 R ² groups. The complex of claim 20 wherein M12a is 1. The complex of any one of claims 2-15, wherein each A ² is selected from phenyl, substituted phenyl, benzyl, substituted benzyl, pyridyl and substituted pyridyl. The complex according to any one of claims 2 to 15, wherein each A ² is represented by the formula:

. The complex according to any one of claims 2 to 15, wherein each A ² is represented by the formula:

. 25. The complex of claim 24, wherein said M12b is one. The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

. The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

. The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

; In the above formula, Y ^1a is O or S, and Y ^2a is O, N (R ^x ) or S. The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

; In the above formula, Y ^2b is O or N (R ^x ). The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

; In the above formula, Y ^2b is O or N (R ^x ) and M 12d is 1, 2, 3, 4, 5, 6, 7 or 8. The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

; In the above formula, Y ^2b is O or N (R ^x ) and M 12d is 1, 2, 3, 4, 5, 6, 7 or 8. 32. The complex of claim 31, wherein M12d is 1. The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

; The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

; The complex of claim 34, wherein W ⁵ is carbocycle. The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

. The complex of claim 38 wherein W ⁵ is phenyl. 40. The complex of claim 39, wherein M12b is 1. The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

; In the above formula, Y ^1a is O or S, and Y ^2a is O, N (R ^x ) or S. The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

; In the above formula, Y ^2b is O or N (R ^x ). The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

; In the above formula, Y ^2b is O or N (R ^x ) and M 12d is 1, 2, 3, 4, 5, 6, 7 or 8. 44. The complex of claim 43, wherein R ¹ is H. 45. The complex of claim 44, wherein M12d is one. The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

; Wherein the phenyl carbocycle is substituted with 0, 1, 2 or 3 R ² groups. The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

; Wherein the phenyl carbocycle is substituted with 0, 1, 2 or 3 R ² groups. The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

. The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

. The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

. The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

; In the above formula, Y ^1a is O or S, and Y ^2a is O, N (R ² ) or S. The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

; In the above formula, Y ^1a is O or S, Y ^2b is O or N (R ² ), and Y ^2c is O, N (R ^y ) or S. The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

; Wherein Y ^1a is O or S, Y ^2b is O or N (R ² ), Y ^2d is O or N (R ^y ), and M12d is 1, 2, 3, 4, 5, 6, 7 or 8. The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

; In the above formula, Y ^2b is O or N (R ² ) and M 12d is 1, 2, 3, 4, 5, 6, 7 or 8. The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

; In the above formula, Y ^2b is O or N (R ² ). The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

. The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

. The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

; In the above formula, Y ^1a is O or S, and Y ^2a is O, N (R ² ) or S. The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

; In the above formula, Y ^1a is O or S, Y ^2b is O or N (R ² ), and Y ^2c is O, N (R ^y ) or S. The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

; Wherein Y ^1a is O or S, Y ^2b is O or N (R ² ), Y ^2d is O or N (R ^y ), and M12d is 1, 2, 3, 4, 5, 6, 7 or 8. The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

; In the above formula, Y ^2b is O or N (R ² ) and M 12d is 1, 2, 3, 4, 5, 6, 7 or 8. The complex according to any one of claims 2 to 25, wherein each A ³ is represented by the formula:

; In the above formula, Y ^2b is O or N (R ² ). The complex of claim 2 wherein A ⁰ is represented by the formula:

; Wherein each R is independently alkyl. 62. The complex according to any one of claims 1 to 61, isolated and purified. 62. The complex of any one of claims 1-61, which is not a compound with anti-inflammatory action. 62. The complex of any one of claims 1-61, which is not an anti-infective compound. 62. The complex according to any one of claims 1 to 61, which is not a compound which is active against immune mediated diseases. 62. The complex according to any one of claims 1 to 61, which is not a compound having activity against metabolic diseases. 62. The complex of any one of the preceding claims, wherein the complex is not a kinase inhibitor. 62. The complex of any one of claims 1-61, which is not an IMPDH inhibitor. 62. The complex of any one of claims 1-61, which is not an anti-metabolic agent. 62. The complex of any one of claims 1-61, which is not a PNP inhibitor. Antiviral complexes described herein. A pharmaceutical composition comprising the pharmaceutically acceptable excipients and complexes or pharmaceutically acceptable salts or solvates thereof described in any one of claims 1-71. A unit dosage form comprising the complex or pharmaceutically acceptable salt or solvate thereof and pharmaceutically acceptable excipient described in any one of claims 1 to 71. An antiviral effect in vitro or in vivo, comprising contacting a sample in need of treatment with the complex or pharmaceutically acceptable salts or solvates thereof described in any one of claims 1-71. How to promote. 75. The method of claim 74, wherein said contact occurs in vivo. 72. A method of inhibiting viral infection in an animal comprising administering an effective amount of said complex or pharmaceutically acceptable salt or solvate thereof as described in any one of claims 1-71. The method of claim 76, wherein the complex or compound is formulated with a pharmaceutically acceptable carrier. 119. The method of claim 110, wherein a second active ingredient is added to the formulation. The complex as described in any one of claims 1 to 71 for use in medical treatment. Use of said complex as described in any one of claims 1 to 71 for the preparation of a therapeutic agent for viral infection in an animal. Phosphonate substituted antiviral compounds described herein. Process for the preparation of the complexes described in the schemes and examples herein. A complex according to claim 1 having the formula

Or pharmaceutically acceptable salts or solvates thereof; here: B is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebularin, Nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcyto Sin, isocytocin, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine, O ⁴ -Methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazoles and pyrazole [3,4-d] pyrimidines; X is selected from O, C (R ^y ) ₂ , OC (R ^y ) ₂ , NR and S; Z is independently selected from H, OH, OR, NR ₂ , CN, NO ₂ , SH, SR, F, Cl, Br and I; Y ¹ is independently O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), or N-NR ₂ ; Y ² is independently O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N-NR ₂ , S, SS, S (O) or S (O) ₂ ; M2 is 0, 1 or 2; R ^y is independently H, F, Cl, Br, I, OH, -C (= Y ¹ ) R, -C (= Y ¹ ) OR, -C (= Y ¹ ) N (R) ₂ , -N (R) ₂ ,- ⁺ N (R) ₃ , -SR, -S (O) R, -S (O) ₂ R, -S (O) (OR), -S (O) ₂ (OR), -OC (= Y ¹ ) R, -OC (= Y ¹ ) OR, -OC (= Y ¹ ) (N (R) ₂ ), -SC (= Y ¹ ) R, -SC (= Y ¹ ) OR , -SC (= Y ¹ ) (N (R) ₂ ), -N (R) C (= Y ¹ ) R, -N (R) C (= Y ¹ ) OR, or -N (R) C ( = Y ¹ ) N (R) ₂ , amino (-NH ₂ ), ammonium (-NH ₃ ⁺ ), alkylamino, dialkylamino, trialkylammonium, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkylhalide , Carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sulfam, C ₁ -C ₈ alkylsulfonate, C ₁ -C ₈ alkylamino, 4-dialkylaminopyridinium, C ₁ -C ₈ alkyl Hydroxyl, C ₁ -C ₈ alkylthiol, alkylsulfone (-SO ₂ R), arylsulfone (-SO ₂ Ar), arylsulfoxide (-SOAr), arylthio (-SAr), sulfonamide (-SO ₂ NR ₂ ), alkylsulfoxide (-SOR), ester (-C (= O) OR), amido (-C (= O) NR ₂ ), 5-7 member cyclic lactam, 5-7 member cyclic lactone, Nitrile (-CN), Azido (-N ₃ ), Ni Tro (-NO ₂ ), C ₁ -C ₈ alkoxy (-OR), C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl, C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle, C ₂ -C ₂₀ substituted heterocycle, poly Ethylenoxy or W ³ ; Or combine together, R ^y forms a carbocyclic ring having 3 to 7 carbon atoms; R ^x is independently R ^y , a protecting group or formula:

here: Mla, Mlc, and Mld are independently 0 or 1; M 12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; R is C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl , C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle, C ₂ -C ₂₀ substituted heterocycle or a protecting group; W ³ is W ⁴ or W ⁵ , wherein W ⁴ is R, —C (Y ¹ ) R ^y , —C (Y ¹ ) W ⁵ , —SO ₂ R ^y , or —SO ₂ W ⁵ ; W ⁵ is a carbocycle or heterocycle, wherein W ⁵ is independently substituted with 0 to 3 R ^y groups. 84. The method of claim 83, wherein the C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ substituted alkynyl, C ₆ -C ₂₀ substituted aryl and C ₂ -C ₂₀ substituted heterocycle Independently F, Cl, Br, I, OH, -NH ₂ , -NH ₃ ⁺ , -NHR, -NR ₂ , -NR ₃ ⁺ , C ₁ -C ₈ alkylhalide, carboxylate, sulfate, sulfamate, sulfo Nate, 5-7 membered ring sulfam, C ₁ -C ₈ alkylsulfonate, C ₁ -C ₈ alkylamino, 4-dialkylaminopyridinium, C ₁ -C ₈ alkylhydroxyl, C ₁ -C ₈ alkylthiol , -SO ₂ R, -SO ₂ Ar, -SOAr, -SAr, -SO ₂ NR ₂ , -SOR, -CO ₂ R, -C (= O) NR ₂ , 5-7 member cyclic lactam, 5-7 Ring cyclic lactone, -CN, -N ₃ , -NO ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ trifluoroalkyl, C ₁ -C ₈ alkyl, C ₃ -C ₁₂ carbocycle, C _6- A complex that is one or more substituents selected from C ₂₀ aryl, C ₂ -C ₂₀ heterocycle, polyethylenoxy, phosphonate, phosphate and prodrug moieties. 84. The complex of claim 83, wherein said protecting group is selected from carboxyl esters, carboxamides, aryl ethers, alkyl ethers, trialkylsilylethers, sulfonic acid esters, carbonates, and carbamates. 84. The method of claim 83, wherein W ⁵ is structure:

The complex is selected from. 84. The complex of claim 83, wherein X is O and each R ^y is H. 84. The dissolved enantiomer of claim 83, wherein the complex has the structure:

. 84. The dissolved enantiomer of claim 83, wherein the complex has the structure:

89. The complex of claim 88 having the structure:

. 89. The complex of claim 88 having the structure:

. 92. The complex of claim 91 having the structure:

. 92. The complex of claim 92 having the structure:

. 93. The complex of claim 93 having the structure:

95. The complex of claim 94 having the structure:

Wherein R ² is H or C ₁ -C ₈ alkyl. 95. The complex of claim 95 having the structure:

96. The complex of claim 96 having the structure:

97. The complex of claim 96, wherein Z is H. 97. The complex of claim 96, wherein B is adenine. 96. The complex of claim 96 having the structure:

; Where Y ^2c is O, N (R ^y ) or S. 100. The complex of claim 100 having the structure:

. 102. The complex of claim 101, wherein said Y ^2c is O. 102. The complex of claim 101, wherein said Y ^2c is N (CH ₃ ). 84. The complex of claim 83, wherein said substituted triazole has the structure:

The complex of claim 1 having the formula:

here: B is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebularin, Nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcyto Sin, isocytocin, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine, O ⁴ -Methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazoles and pyrazole [3,4-d] pyrimidines; X is selected from O, C (R ^y ) ₂ , OC (R ^y ) ₂ , NR and S; Z is independently selected from H, OH, OR, NR ₂ , CN, NO ₂ , SH, SR, F, Cl, Br and I; Y ² is independently O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N-NR ₂ , S, SS, S (O) or S (O) ₂ ; R ^y is independently H, F, Cl, Br, I, OH, -C (= Y ¹ ) R, -C (= Y ¹ ) OR, -C (= Y ¹ ) N (R) ₂ , -N (R) ₂ ,- ⁺ N (R) ₃ , -SR, -S (O) R, -S (O) ₂ R, -S (O) (OR), -S (O) ₂ (OR), -OC (= Y ¹ ) R, -OC (= Y ¹ ) OR, -OC (= Y ¹ ) (N (R) ₂ ), -SC (= Y ¹ ) R, -SC (= Y ¹ ) OR , -SC (= Y ¹ ) (N (R) ₂ ), -N (R) C (= Y ¹ ) R, -N (R) C (= Y ¹ ) OR, or -N (R) C ( = Y ¹ ) N (R) ₂ , amino (-NH ₂ ), ammonium (-NH ₃ ⁺ ), alkylamino, dialkylamino, trialkylammonium, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkylhalide , Carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sulfam, C ₁ -C ₈ alkylsulfonate, C ₁ -C ₈ alkylamino, 4-dialkylaminopyridinium, C ₁ -C ₈ alkyl Hydroxyl, C ₁ -C ₈ alkylthiol, alkylsulfone (-SO ₂ R), arylsulfone (-SO ₂ Ar), arylsulfoxide (-SOAr), arylthio (-SAr), sulfonamide (-SO ₂ NR ₂ ), alkylsulfoxide (-SOR), ester (-C (= O) OR), amido (-C (= O) NR ₂ ), 5-7 member cyclic lactam, 5-7 member cyclic lactone, Nitrile (-CN), Azido (-N ₃ ), Ni Tro (-NO ₂ ), C ₁ -C ₈ alkoxy (-OR), C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl, C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle, C ₂ -C ₂₀ substituted heterocycle, poly Ethylenoxy or W ³ ; Joined together, R ^y forms a carbocyclic ring having 3 to 7 carbon atoms; R is C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl , C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle, C ₂ -C ₂₀ substituted heterocycle or a protecting group; PG is a protecting group selected from ether-forming groups, ester-forming groups, silyl-ether forming groups, amide-forming groups, acetal-forming groups, ketal-forming groups, carbonate-forming groups, carbamate-forming groups, amino acids, and polypeptides. 84. A method of treating or preventing viral infection symptoms and effects comprising administering to a virus infected animal a pharmaceutical composition or formulation comprising an effective amount of the complex of claim 83 or a pharmaceutically acceptable salt or solvate thereof. 84. A method of treating or preventing HCV infection symptoms and effects comprising administering to an animal infected with HCV a pharmaceutical composition or formulation comprising an effective amount of the complex of claim 83 or a pharmaceutically acceptable salt or solvate thereof. 84. A method of treating or preventing viral infection symptoms and effects comprising administering to a virus infected animal a pharmaceutical complex composition or formulation comprising an effective amount of the complex of claim 83 and a secondary compound having antiviral properties. 84. The complex or pharmaceutically acceptable salt of claim 83; Pharmaceutically acceptable excipients; And an effective amount of a secondary compound having antiviral properties. A method of inhibiting a viral enzyme comprising contacting a sample suspected of containing a virus or infected cell or tissue with the complex of claim 83 or a pharmaceutically acceptable salt or solvate thereof. 84. A method of treating or preventing a viral infection symptom or effect comprising administering to a virally infected animal a formulation comprising a therapeutically effective amount of the complex of claim 83 or a pharmaceutically acceptable salt or solvate thereof. 112. The complex of claim 111, wherein the complex is formulated in a pharmaceutically acceptable carrier. Use of a pharmaceutically acceptable salt or solvate thereof for the manufacture of a virus therapeutic or. The complex of claim 83 or a pharmaceutically acceptable salt or solvate thereof, capable of accumulating in human PBMC. 119. The complex of claim 114, wherein the bioavailability of the intracellular metabolites of the complex or complex in human PBMCs is improved over an analog of the complex that does not contain a prodrug moiety. 119. The complex of claim 114, wherein said intracellular half-life of the intracellular metabolite of the complex or complex in human PBMC is enhanced compared to an analog of said complex that does not contain a prodrug moiety. 119. The complex of claim 116, wherein the half life is improved by at least about 50%. 119. The complex of claim 116, wherein the half life is improved by at least about 100%. 119. The complex of claim 114, wherein said intracellular half-life of the intracellular metabolite of the complex in human PBMCs is improved over an analog of said metabolite that does not contain a prodrug moiety. 119. The complex of claim 119, wherein the half life is improved by at least about 50%. 119. The complex of claim 119, wherein the half life is improved by at least about 100%. 119. The complex of claim 119, wherein the half life is improved by at least about 100% or more. 84. The complex of claim 83, wherein the compound of formula 556-E.5 or 556-E.6

84. A pharmaceutical composition comprising a complex or pharmaceutically acceptable salt of claim 83 or a solvate thereof and a therapeutically effective amount of a pharmaceutically acceptable excipient. 126. The pharmaceutical composition of claim 124, further comprising a therapeutically effective amount of an AIDS therapeutic agent selected from HIV inhibitors, anti-infectives, and immunomodulators. 126. The pharmaceutical composition of claim 125, wherein the HIV inhibitor is an HIV-protease inhibitor. 126. The pharmaceutical composition of claim 125, wherein the HIV inhibitor is a nucleoside reverse transcriptase inhibitor. 126. The pharmaceutical composition of claim 125, wherein the HIV inhibitor is a non nucleoside reverse transcriptase inhibitor. 84. A method of preparing a pharmaceutical composition comprising combining the complex of claim 83 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient. 84. A method of inhibiting an RNA-dependent RNA polymerase comprising administering to a mammal in need thereof a therapeutically effective amount of the complex of claim 83 or a pharmaceutically acceptable salt or solvate thereof. 83. A method of treating a viral infection comprising administering to a mammal in need thereof a therapeutically effective amount of the complex of claim 83 or a pharmaceutically acceptable salt or solvate thereof. 83. A method for treating a disease affecting white blood cells comprising administering the complex of claim 83 to a patient in need thereof. 84. A method of accumulating an RNA-dependent RNA polymerase inhibitor compound in white blood cells comprising administering a composition comprising the complex of claim 83 to a sample. 134. The method of claim 133, wherein said sample is a patient.