Bioreversable promoieties for nitrogen-containing and hydroxyl-containing drugs

Abstract

Disclosed are promoieties of the following formula which can be used to form prodrugs of nitrogen-containing or hydroxyl-containing drug or a pharmaceutically active agent: and pharmaceutical compositions comprising the prodrugs.

We claim: 
     
         1 . A prodrug or a pharmaceutically acceptable salt thereof, comprising a nitrogen-containing or hydroxyl-containing drug or a pharmaceutically active agent conjugated to a promoiety via a covalent bond hydrolytically labile at physiological conditions, wherein the promoiety is of the following formula 
       
         
           
           
               
               
           
         
       
       wherein
 X is HN—R 0 , OH, or SH; 
 Y is: 
 (1) N—R O ; 
 (2) C(R p R q ); 
 (3) O or S, provided that X is not OH or SH; or 
 (4) C(R p R q ), when X is HN—R 0 , wherein R 0  and R p  together with the atoms to which they are attached can form a 4, 5, or 6 membered heterocyclic ring; 
 R 0 , R O , R p , R q  are independently selected from hydrogen (H), lower alkyl, lower alkoxy, acyl, alkoxycarbonyl, aryl, phenyl, benzyl, halo, haloformyl, haloloweralkyl, trifluoromethyl, trifluoromethoxy, trichloromethyl, cyanato, isocyano, isocyanate, isothiocyanate, thiocyanate, lower alkylthio, amino, imino, amino lower alkyl, lower alkylamino, lower dialkylamino, hydroxyl, hydroxyl alkyl, nitro, nitrile (—CN), isonitrile (—NC), pyridyl, azido, azo, carboxyl, carboxamido, carbethoxy, thiolalkyl, carbonate, carbamate group, loweralkylcarbamyl, diloweralkylcarbamyl, sulfonic acid group, sulfamide group, sulfonamide group, sulfonate group, sulfonyl, sulfoxide group, sulfide group, disulfide group, mercapto (or sulfhydryl); 
 or R 0 , R O , R p , R q  are independently selected from hydrogen (H), C 1 -C 18  alkyl, C 2 -C 18  alkenyl, (C 1 -C 10  alkyl)OH, (C 1 -C 10  alkyl)SH, (C 2 -C 3  alkyl)SCH 3 , (C 1 -C 4  alkyl)CONH 2 , (C 1 -C 10  alkyl)COOH, (C 1 -C 10  alkyl)NH 2 , (C 1 -C 4  alkyl)NHC(═NH 2   + )NH 2 , (C 0 -C 4  alkyl)(C 3 -C 6  cycloalkyl), (C 0 -C 4  alkyl)(C 2 -C 5  heterocyclic), (C 0 -C 4  alkyl)(C 6 -C 10  aryl), (C 0 -C 4  alkyl)(C 6 -C 10  aryl)R 16 , (C 1 -C 4  alkyl)(C 3 -C 9  heteroaryl), and (C 1 -C 12  alkyl)(W 1 )(C 1 -C 12  alkyl), wherein W 1  is a heteroatom selected from N, S and O; R 16  is selected from H, OH, halo, C 1 -C 7  alkyl, C 2 -C 7  alkenyl, CF 3 , OCF 3 , NO 2 , CN, NC, O(C 1 -C 7  alkyl), CO 2 H, CO 2 (C 1 -C 7  alkyl), NH(C 1 -C 10  alkyl), O(C 1 -C 10  alkyl), aryl, and heteroaryl; 
 or two R groups, which are selected from R 0 , R O , R p , and R q , that are attached to the same atom or attached to two atoms separated by one bond, together with the atom(s) to which they are attached form a C 3 -C 8  cycloalkyl, cycloalkenyl, or cycloalkynyl ring, or saturated or unsaturated heterocyclic ring optionally substituted by the at least one group other than hydrogen (H); or two R groups together with the atom(s) to which they are attached form an aromatic ring optionally substituted by the at least one group other than hydrogen (H), wherein the at least one group is selected from lower alkyl, lower alkoxy, acyl, acyloxy, alkoxycarbonyl, aryl, phenyl, benzyl, halo, haloformyl, haloloweralkyl, trifluoromethyl, trifluoromethoxy, trichloromethyl, cyanato, isocyano, isocyanate, isothiocyanate, thiocyanate, lower alkylthio, amino, imino, amino lower alkyl, lower alkylamino, lower dialkylamino, hydroxyl, hydroxyl alkyl, nitro, nitrile (—CN), isonitrile (—NC), nitroso, pyridyl, azido, azo, carboxyl, carboxamido, carbethoxy, thiolalkyl, carbonate, carbamate group, loweralkylcarbamyl, diloweralkylcarbamyl, sulfonic acid group, sulfamide group, sulfonamide group, sulfonate group, sulfonyl, sulfoxide group, sulfide group, disulfide group, and mercapto (or sulfhydryl); 
 A and B together with the atoms to which they are attached form a C3-C10 cycloalkyl ring (cycloalkane, cycloalkene, and cycloalkyne) optionally substituted by the at least one group; or saturated or unsaturated monocyclic or polycyclic, or fused cyclic ring optionally substituted by the at least one group; or saturated or unsaturated monoheterocyclic or polyheterocyclic, or fused heterocyclic ring optionally substituted by the at least one group; 
 or A and B together with the atoms to which they are attached form an aromatic ring optionally substituted by the at least one group selected from the above; or A and B together with the atoms to which they are attached form a polyaromatic ring; 
 further wherein the prodrug is optionally conjugated to a modifying moiety of the following formula:
   -L-M 
 
 
       wherein:
 L is a covalent bond or an optional linker selected from PEG, long chain fatty acids, natural or unnatural amino acids, dipeptides, —(CH 2 ) n —, —(CH 2 CH 2 O) n —, —O—, —S—, —C(O)—, —C(O)O—, —NH—, —NHC(O)CH 2 —, —C(O)NH—, —SO 2 CH 2 CH 2 —, —HNSO 2 —, maleimide, and a combination of two or more of the above thereof, or any structure connecting a modifying moiety to a prodrug through a covalent bond; n is an integer in the range from 1 to 30; 
 M is a modifying moiety selected from hydrophilic moieties, lipophilic moieties, amphiphilic moieties, salt forming moieties, carrier proteins, a targeting agent, a diagnostic label, a fluorophore or enzymatic label, or combinations of two or more of the above thereof with appropriate spacer moieties, linker moieties, and terminating moieties, wherein the various moieties can be covalently coupled to one another by either hydrolyzable or non-hydrolyzable bonds. 
 
     
     
         2 . The prodrug of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the promoiety is of the following formula 
       
         
           
           
               
               
           
         
       
       wherein
 a and b are independently selected from straight or branched chain alkyl having from 1 to 20 carbon atoms; aryl having from 6 to 15 carbon atoms; cycloalkyl having a 3, 4, 5, 6, 7, 8, 9, or 10 membered ring; alkenyl having from 2 to 20 carbon atoms; cycloalkenyl having a 3, 4, 5, 6, 7, 8, 9, or 10 membered ring; alkynyl having from 2 to 20 carbon atoms; cycloalkynyl having a 3, 4, 5, 6, 7, 8, 9, or 10 membered ring; monocyclic or polycyclic; aralkyl, aralkenyl, aralkynyl, alkaryl, alkenylaryl, alkynylaryl, lower acyloxyalkyl, and carboxyalkyl; mono- or poly-substituted derivatives of the above; saturated or unsaturated monoheterocyclic or polyheterocyclic, or fused heterocyclic, containing from 1 to 3 of any one or more of the heteroatoms N, S or O in each heterocyclic ring thereof and each such ring being from 3- to 8-membered; and mono- or poly-substituted derivatives of the above, each of said substituents being selected from lower alkyl, lower alkoxy, acyl, alkoxycarbonyl, aryl, phenyl, benzyl, halo, haloformyl, haloloweralkyl, trifluoromethyl, trifluoromethoxy, trichloromethyl, cyanato, isocyano, isocyanate, isothiocyanate, thiocyanate, lower alkylthio, amino, imino, amino lower alkyl, lower alkylamino, lower dialkylamino, hydroxyl, hydroxyl alkyl, nitro, nitrile (—CN), isonitrile (—NC), pyridyl, azido, azo, carboxyl, carboxamido, carbethoxy, thiolalkyl, carbonate, carbamate group, loweralkylcarbamyl, diloweralkylcarbamyl, sulfonic acid group, sulfamide group, sulfonamide group, sulfonate group, sulfonyl, sulfoxide group, sulfide group, disulfide group, mercapto (or sulfhydryl); 
 or a and b are selected from hydrogen (H), lower alkyl, lower alkoxy, acyl, alkoxycarbonyl, aryl, phenyl, benzyl, halo, haloformyl, haloloweralkyl, trifluoromethyl, trifluoromethoxy, trichloromethyl, cyanato, isocyano, isocyanate, isothiocyanate, thiocyanate, lower alkylthio, amino, imino, amino lower alkyl, lower alkylamino, lower dialkylamino, hydroxyl, hydroxyl alkyl, nitro, nitrile (—CN), isonitrile (—NC), pyridyl, azido, azo, carboxyl, carboxamido, carbethoxy, thiolalkyl, carbonate, carbamate group, loweralkylcarbamyl, diloweralkylcarbamyl, sulfonic acid group, sulfamide group, sulfonamide group, sulfonate group, sulfonyl, sulfoxide group, sulfide group, disulfide group, mercapto (or sulfhydryl); 
 or a and b, together with the atoms to which they are attached form a C3-C10 cycloalkyl ring (cycloalkane, cycloalkene, and cycloalkyne) optionally substituted by the at least one group; or saturated or unsaturated monocyclic or polycyclic, or fused cyclic ring optionally substituted by the at least one group; or saturated or unsaturated monoheterocyclic or polyheterocyclic, or fused heterocyclic ring optionally substituted by the at least one group; and 
 m and n are each an integer independently selected from 0, 1, 2, 3, 4, 5, and 6. 
 
     
     
         3 . The prodrug of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein the promoiety is of the following formula 
       
         
           
           
               
               
           
         
       
       wherein
 a and b, together with the atoms to which they are attached form a C3-C10 cycloalkyl ring (cycloalkane, cycloalkene, and cycloalkyne) optionally substituted by the at least one group; or saturated or unsaturated monocyclic or polycyclic, or fused cyclic ring optionally substituted by the at least one group; or saturated or unsaturated monoheterocyclic or polyheterocyclic, or fused heterocyclic ring optionally substituted by the at least one group; and 
 m and n are each an integer independently selected from 0, 1, 2, 3, 4, 5, and 6. 
 
     
     
         4 . The prodrug of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein the promoiety is of a formula selected from 
       
         
           
           
               
               
           
         
       
       R 5  and R 6  are selected from hydrogen (H), lower alkyl, lower alkoxy, acyl, alkoxycarbonyl, aryl, phenyl, benzyl, halo, haloformyl, haloloweralkyl, trifluoromethyl, trifluoromethoxy, trichloromethyl, cyanato, isocyano, isocyanate, isothiocyanate, thiocyanate, lower alkylthio, amino, imino, amino lower alkyl, lower alkylamino, lower dialkylamino, hydroxyl, hydroxyl alkyl, nitro, nitrile (—CN), isonitrile (—NC), pyridyl, azido, azo, carboxyl, carboxamido, carbethoxy, thiolalkyl, carbonate, carbamate group, loweralkylcarbamyl, diloweralkylcarbamyl, sulfonic acid group, sulfamide group, sulfonamide group, sulfonate group, sulfonyl, sulfoxide group, sulfide group, disulfide group, mercapto (or sulfhydryl). 
     
     
         5 . The prodrug of  claim 4 , or a pharmaceutically acceptable salt thereof, wherein the promoiety is of a formula selected from 
       
         
           
           
               
               
           
         
       
       R 5  and R 6  are selected from hydrogen (H), lower alkyl, lower alkoxy, acyl, alkoxycarbonyl, aryl, phenyl, benzyl, halo, haloformyl, haloloweralkyl, trifluoromethyl, trifluoromethoxy, trichloromethyl, cyanato, isocyano, isocyanate, isothiocyanate, thiocyanate, lower alkylthio, amino, imino, amino lower alkyl, lower alkylamino, lower dialkylamino, hydroxyl, hydroxyl alkyl, nitro, nitrile (—CN), isonitrile (—NC), pyridyl, azido, azo, carboxyl, carboxamido, carbethoxy, thiolalkyl, carbonate, carbamate group, loweralkylcarbamyl, diloweralkylcarbamyl, sulfonic acid group, sulfamide group, sulfonamide group, sulfonate group, sulfonyl, sulfoxide group, sulfide group, disulfide group, mercapto (or sulfhydryl). 
     
     
         6 . The prodrug of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein X, Y, and C(O) constitute a natural or unnatural amino acid or hydroxyl acid. 
     
     
         7 . The prodrug of  claim 6 , or a pharmaceutically acceptable salt thereof, wherein the natural or unnatural amino acid or hydroxyl acid is alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, proline, glutamine, phenylalanine, serine, threonine, valine, tryptophan, tyrosine, aminoisobutyric acid, sarcosine, glycolic acid, or phenyllactic acid. 
     
     
         8 . The prodrug of  claim 5 , or a pharmaceutically acceptable salt thereof, wherein the promoiety is of a formula selected from 
       
         
           
           
               
               
           
         
       
       wherein R 5 , R 6 , R 7 , and R 8  are independently selected from hydrogen (H), lower alkyl, lower alkoxy, acyl, alkoxycarbonyl, aryl, phenyl, benzyl, halo, haloformyl, haloloweralkyl, trifluoromethyl, trifluoromethoxy, trichloromethyl, cyanato, isocyano, isocyanate, isothiocyanate, thiocyanate, lower alkylthio, amino, imino, amino lower alkyl, lower alkylamino, lower dialkylamino, hydroxyl, hydroxyl alkyl, nitro, nitrile (—CN), isonitrile (—NC), pyridyl, azido, azo, carboxyl, carboxamido, carbethoxy, thiolalkyl, carbonate, carbamate group, loweralkylcarbamyl, diloweralkylcarbamyl, sulfonic acid group, sulfamide group, sulfonamide group, sulfonate group, sulfonyl, sulfoxide group, sulfide group, disulfide group, mercapto (or sulfhydryl). 
     
     
         9 . The prodrug of  claim 5 , or a pharmaceutically acceptable salt thereof, wherein the promoiety is of a formula selected from 
       
         
           
           
               
               
           
         
       
     
     
         10 . The prodrug of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the promoiety is of a formula selected from 
       
         
           
           
               
               
           
         
       
     
     
         11 . The prodrug of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is HN—R 0  or OH. 
     
     
         12 . The prodrug of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is OH. 
     
     
         13 . The prodrug of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is HN—R 0    
     
     
         14 . The prodrug of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is NH 2 . 
     
     
         15 . A prodrug of an insulin receptor binding analog comprises a modified A chain and B chain, wherein the A chain comprises a sequence of Z-X −1 X 0 X 1 IVX 4 X 5 CCX 8 X 9 X 10 CX 12 LX 14 X 15 LEX 18 YCX 21 X 22  (SEQ ID NO:24) and the B chain comprises a sequence of J-X 23-26 X 27 LCGX 31 X 32 LVX 35 X 36 LX 38 X 39 VCX 42 X 43 X 44 GX 46 X 47 X 48 X 49 X 50 X 51 X 52 X 53  (SEQ ID NO:25); 
       Z and J are independently hydrogen (H) or of a formula 
       
         
           
           
               
               
           
         
       
       wherein X is HNR 0 , NH 2 , or OH;
 R 0 , R p , and R q  are independently selected from hydrogen (H), lower alkyl, lower alkoxy, acyl, alkoxycarbonyl, aryl, phenyl, benzyl, halo, haloformyl, haloloweralkyl, trifluoromethyl, trifluoromethoxy, trichloromethyl, cyanato, isocyano, isocyanate, isothiocyanate, thiocyanate, lower alkylthio, amino, imino, amino lower alkyl, lower alkylamino, lower dialkylamino, hydroxyl, hydroxyl alkyl, nitro, nitrile (—CN), isonitrile (—NC), nitroso, pyridyl, azido, azo, carboxyl, carboxamido, carbethoxy, thiolalkyl, carbonate, carbamate group, loweralkylcarbamyl, diloweralkylcarbamyl, sulfonic acid group, sulfamide group, sulfonamide group, sulfonate group, sulfonyl, sulfoxide group, sulfide group, disulfide group, and mercapto (or sulfhydryl); 
 R 5 -R 8  are independently selected from hydrogen (H), lower alkyl, lower alkoxy, acyl, hydroxyl, amino, halogen, trifluoromethyl, trifloromethoxy, nitrile, nitro, carboxylic acid, —SO 2 —OH, —SO 2 —NR m1 R m2 , —SO 2 —R m3 , —O—R m4 , —S—R m5 , —N—R m6 R m7 , —C(O)R m8 , —C(O)OR m9 , —OC(O)R m10 , —NHC(O)R m11 , —C(O)NR m12 R m13 , and —NHC(O)NR m14 R m15 , wherein R m1 , R m2 , R m3 , R m4 , R m5 , R m6 , R m7 , R m8 , R m9 , R m10 , R m11 , R m12 , R m13 , R m14 , and R m15  are independently selected from hydrogen (H), (C 1 -C 18 ) alkyl, aryl, (C 1 -C 18  alkyl)OH, (C 1 -C 18  alkyl)SH, (C 1 -C 18  alkyl)COOH, (C 1 -C 18  alkyl)NH 2 , (C 0 -C 4  alkyl)(C 3 -C 6  cycloalkyl), (C 0 -C 10  alkyl)(C 2 -C 5  heterocyclic), (C 0 -C 4  alkyl)(C 6 -C 10  aryl), and (C 1 -C 4  alkyl)(C 3 -C 9  heteroaryl); 
 X 1  is lysine, arginine, or deleted; 
 X 0  is lysine, arginine, or deleted; 
 X 1  is selected from sarcosine, D-alanine, D-leucine, D-lysine, D-glutamic acid, D-tryptophan, p-benzoyl-L-phenylalanine (Bpa), and glycine; 
 X 4  is aspartic acid or glutamic acid; 
 X 5  is aspartic acid, glutamic acid, asparagine, or glutamine; 
 X 8  is selected from 2,4-diaminobutyric acid (DAB), leucine, isoleucine, threonine, histidine, arginine, lysine, asparagine, glutamine, tryptophan, tyrosine, alanine, phenylalanine, valine, and methionine; 
 X 9  is alanine, serine, arginine, or lysine; 
 X 10  is isoleucine, serine, lysine, or arginine; 
 X 12  is aspartic acid or serine; 
 X 14  is tyrosine, phenylalanine, tryptophan, arginine, alanine, glutamic acid, histidine, or lysine; 
 X 15  is glutamine, leucine, arginine, or lysine; 
 X 18  is asparagine, methionine, or threonine; 
 X 21  is asparagine, aspartic acid, alanine, glycine, lysine, or arginine; 
 X 22  is lysine, arginine, lysine-lysine dipeptide, arginine-arginine dipeptide, or deleted; 
 X 23-26  is any codable amino acid except cysteine, a dipeptide or tripeptide comprising no cysteine, a tripeptide GPE, a tetrapeptide FVNQ, or deleted; 
 X 27  is histidine, threonine, arginine, or lysine; 
 X 31  is selected from threonine, alanine, serine, glycine, and α-aminoisobutyric acid; 
 X 32  is selected from histidine, aspartic acid, glutamic acid, homoglutamic acid, homocysteic acid, cysteic acid, arginine, and phenylalanine; 
 X 35  is glutamic acid or aspartic acid; 
 X 36  is alanine, threonine, or α-aminoisobutyric acid; 
 X 38  is selected from tyrosine, phenylalanine, and tryptophan; 
 X 39  is phenylalanine, tryptophan, or leucine; 
 X 42  is glycine, or alanine; 
 X 43  is glutamic acid, aspartic acid, or alanine; 
 X 44  is selected from arginine, lysine, aspartic acid, glutamic acid, and alanine; 
 X 46  is selected from phenylalaine, D-phenylalaine, D-tyrosine, D-alanine, and glycine; 
 X 47  is selected from tyrosine, phenylalanine, asparagine, and histidine; 
 X 48  is selected from tyrosine, D-tyrosine, phenylalanine, alanine, serine, histidine, D-alanine, D-tyrosine, glutamic acid, sarcosine, or deleted; 
 X 49  is selected from threonine, asparagine, arginine, glutamic acid, aspartic acid, lysine, serine, proline, or deleted; 
 X 50  is selected from proline, arginine, lysine, orthonine, glutamic acid, aspartic acid, or deleted; 
 X 51  is selected from proline, lysine, glutamic acid, aspartic acid, or deleted; 
 X 52  is threonine, alanine, glutamic acid, aspartic acid, or deleted; 
 X 53  is an arginine-arginine dipeptide, glutamic acid-glutamic acid dipeptide, aspartic acid-aspartic acid dipeptide, or deleted. 
 
     
     
         16 . A prodrug comprising a GLP-1 receptor binding peptide having a sequence J-Xg 7 Xg 8 Xg 9 GTXg 12 TSDXg 16 SXg 18 Xg 19 Xg 20 EXg 22 Xg 23 Xg 24 Xg 25 Xg 26 Xg 27 F Xg 29 Xg 30  WLXg 33 Xg 34 Xg 35 Xg 36 Xg 37 Xg 38 Xg 39 Xg 40 Xg 41 Xg 42 Xg 43 Xg 44 Xg 45 Xg 46 Xg 47  Xg 48 Xg 49  (SEQ ID NO:49),
 wherein J is hydrogen (H) or of a formula   
       
         
           
           
               
               
           
         
         X is HNR 0 , NH 2 , or OH; 
         R 0 , R p , and R q  are independently selected from hydrogen (H), lower alkyl, lower alkoxy, acyl, acyloxy, alkoxycarbonyl, aryl, phenyl, benzyl, halo, haloformyl, haloloweralkyl, trifluoromethyl, trifluoromethoxy, trichloromethyl, cyanato, isocyano, isocyanate, isothiocyanate, thiocyanate, lower alkylthio, amino, imino, amino lower alkyl, lower alkylamino, lower dialkylamino, hydroxyl, hydroxyl alkyl, nitro, nitrile (—CN), isonitrile (—NC), nitroso, pyridyl, azido, azo, carboxyl, carboxamido, carbethoxy, thiolalkyl, carbonate, carbamate group, loweralkylcarbamyl, diloweralkylcarbamyl, sulfonic acid group, sulfamide group, sulfonamide group, sulfonate group, sulfonyl, sulfoxide group, sulfide group, disulfide group, and mercapto (or sulfhydryl); 
         R 5 -R 8  are independently selected from hydrogen (H), lower alkyl, lower alkoxy, acyl, hydroxyl, amino, halogen, trifluoromethyl, trifloromethoxy, nitrile, nitro, carboxylic acid, —SO 2 —OH, —SO 2 —NR m1 R m2 , —SO 2 —R m3 , —O—R m4 , —S—R m5 , —N—R m6 R m7 , —C(O)R m8 , —C(O)OR m9 , —OC(O)R m10 , —NHC(O)R m11 , —C(O)NR m12 R m13 , and —NHC(O)NR m14 R m15 , wherein R m1 , R m2 , R m3 , R m4 , R m5 , R m6 , R m7 , R m8 , R m9 , R m10 , R m11 , R m12 , R m13 , R m14 , and R m15  are independently selected from hydrogen (H), (C 1 -C 18 ) alkyl, aryl, (C 1 -C 18  alkyl)OH, (C 1 -C 18  alkyl)SH, (C 1 -C 18  alkyl)COOH, (C 1 -C 18  alkyl)NH 2 , (C 0 -C 4  alkyl)(C 3 -C 6  cycloalkyl), (C 0 -C 10  alkyl)(C 2 -C 5  heterocyclic), (C 0 -C 4  alkyl)(C 6 -C 10  aryl), and (C 1 -C 4  alkyl)(C 3 -C 9  heteroaryl); 
         Xg 7  is selected from L-histidine, D-histidine, desamino-histidine, 2-amino-histidine, β-hydroxy-histidine, homohistidine, α-fluoromethyl-histidine, α-methyl-histidine, imidazopropionyl, arginine, and tyrosine; 
         Xg 8  is serine, D-serine, alanine, glycine, 2-aminoisobutyric acid, or valine; 
         Xg 9  is glutamic acid, glutamine, or proline; 
         Xg 12  is phenylalanine, tryptophan, tyrosine, or alanine; 
         Xg 16  is valine, tryptophan, isoleucine, leucine, phenylalanine, tyrosine, lysine, or cysteine; 
         Xg 18  is serine, tryptophan, tyrosine, phenylalanine, lysine, isoleucine, leucine, valine, or cysteine; 
         Xg 19  is tyrosine, tryptophan, or phenylalanine, glutamine, or alanine; 
         Xg 20  is leucine, phenylalanine, tyrosine, tryptophan, lysine, cysteine, or methione; 
         Xg 22  is glycine, glutamic acid, aspartic acid, serine, cysteine, or lysine; 
         Xg 23  is glutamine, glutamic acid, arginine, isoleucine, lysine, or cysteine; 
         Xg 24  is alanine, histidine, or arginine; 
         Xg 25  is alanine, glutamine, valine, isoleucine, or leucine; 
         Xg 26  is lysine, cysteine, arginine, or glutamine; 
         Xg 27  is glutamic acid, aspartic acid, leucine, lysine, cysteine, or alanine; 
         Xg 29  is isoleucine or valine; 
         Xg 30  is alanine, asparagine, aspartic acid, glutamic acid, or glutamine; 
         Xg 33  is valine, leucine, lysine, cysteine, or methionine; 
         Xg 34  is lysine, alanine, asparagine, aspartic acid, arginine, cysteine, or glutamic acid; 
         Xg 35  is glycine, threonine, lysine, cysteine, or glutamine; 
         Xg 36  is glycine, lysine, cysteine, proline, or arginine; 
         Xg 37  is glycine, proline, serine, lysine, cysteine, NH 2 , or deleted; 
         Xg 38  is serine, proline, histidine, cysteine, lysine, or deleted; 
         Xg 39  is serine, arginine, threonine, tryptophan, lysine, cysteine, or deleted; 
         Xg 40  is serine, glycine, asparagine, lysine, cysteine, or deleted; 
         Xg 41  is alanine, aspartic acid, arginine, glutamic acid, lysine, cysteine, glycine, or deleted; 
         Xg 42  is proline, alanine, tryptophan, NH 2 , or deleted; 
         Xg 43  is proline, alanine, lysine, NH 2 , or deleted; 
         Xg 44  is proline, alanine, arginine, lysine, histidine, NH 2 , or deleted; 
         Xg 45  is serine, histidine, proline, lysine, arginine, cysteine, asparagine, NH 2  or deleted; 
         Xg 46  is histidine, serine, arginine, lysine, cysteine, isoleucine, NH 2  or deleted; 
         Xg 47  is histidine, serine, arginine, lysine, threonine, NH 2  or deleted; 
         Xg 48  is glutamine or deleted; 
         Xg 49  is NH 2  or deleted. 
       
     
     
         17 . A pharmaceutical composition comprising a prodrug of  claim 1  and a pharmaceutically acceptable excipient thereof. 
     
     
         18 . The prodrug of  claim 1 , wherein a nitrogen-containing or hydroxyl-containing drug or a pharmaceutically active agent is selected from the group of agents falling into the following therapeutic categories: ACE-inhibitors; anti-anginal drugs; anti-arrhythmias; anti-asthmatics; anti-cholesterolemics; anti-convulsants; anti-depressants; anti-diarrhea preparations; anti-histamines; antihypertensive drugs; anti-infectives; anti-inflammatory agents; anti-lipid agents; anti-manics; anti-nauseants; antistroke agents; anti-thyroid preparations; anti-tumor drugs; anti-tussives; anti-uricemic drugs; anti-viral agents; acne drugs; alkaloids; amino acid preparations; anabolic drugs; analgesics; anesthetics; angiogenesis inhibitors; antacids; anti-arthritics; antibiotics; anticoagulants; antiemetics; antiobesity drugs; antiparasitics; antipsychotics; antipyretics; antispasmodics; antithrombotic drugs; anxiolytic agents; appetite stimulants; appetite suppressants; beta blocking agents; bronchodilators; cardiovascular agents; cerebral dilators; chelating agents; cholecystokinin antagonists; chemotherapeutic agents; cognition activators; contraceptives; coronary dilators; cough suppressants; decongestants; deodorants; dermatological agents; diabetes agents; diuretics; emollients; enzymes; erythropoietic drugs; expectorants; fertility agents; fungicides; gastrointestinal agents; growth regulators; hormone replacement agents; hyperglycemic agents; hypnotics; hypoglycemic agents; laxatives; migraine treatments; mucolytics; narcotics; neuroleptics; neuromuscular drugs; NSAIDS; peripheral vasodilators; prostaglandins; psychotropics; renin inhibitors; respiratory stimulants; steroids; stimulants; sympatholytics; thyroid preparations; tranquilizers; uterine relaxants; vaginal preparations; vasoconstrictors; vasodilators; vertigo agents; vitamins; and wound healing agents.