Pharmaceutically relevant aromatic-cationic peptides

1. A process comprising combining a compound of formula VIII

with a hydrogen source and a transition metal catalyst to form a compound of formula I

or a pharmaceutically acceptable salt thereof, wherein

R 1 and R 2 are each independently hydrogen

R 3 and R 7 are each independently methyl;

R 4 and R 6 are each independently hydrogen;

R 5 is hydrogen

R 8 is

 where R 10 , R 11 , R 12 , R 13 , and R 14 are each independently hydrogen;

R 9 is NH 2 ;

n is 4;

m is 3;

X 1 is H on the residue with Z 6 and is 2-chlorobenzyloxycarbonyl on the residue with Z 5 ;

X 3 is benzyloxycarbonyl;

Z 1 is hydrogen;

Z 2 is —C(NH)—NH 2 ;

Z 5 is hydrogen; and

Z 6 is —C(N—X 4 )—NH—X 2 wherein X 2 and X 4 are each independently benzyloxycarbonly.

2. The process of claim 1 , wherein the compound of formula VIII is formed by a process comprising combining a compound of formula VI

with a compound of formula VII

under conditions to form the compound of formula VIII.

3. The process according to claim 2 , wherein forming a compound of formula VI comprises

combining a compound of formula III

with a compound of formula IV

under conditions to form a compound of formula V,

 and

combining the compound of formula V

with a cleaving acid to produce a compound of formula VI

wherein

Y 1 is tert-butoxycarbonyl.

4. The process of claim 1 , wherein

the hydrogen source comprises hydrogen gas, formic acid, formate salts, diimide, cyclohexene, cyclohexadiene, or combinations of any two or more thereof; and

the transition metal catalyst comprises Co, Ir, Mo, Ni, Pt, Pd, Rh, Ru, W, or combinations of any two or more thereof.

5. The process of claim 4 , wherein the transition metal catalyst further comprises a support material, optionally wherein the support material comprises carbon, carbonate salts, silica, silicon, silicates, alumina, clay, or mixtures of any two or more thereof.

6. The process of claim 5 , wherein the transition metal catalyst comprises Pd on carbon or Pd on silicon.

7. The process of claim 4 , further comprising a solvent, optionally wherein the solvent comprises methanol (CH 3 OH), ethanol (EtOH), isopropanol (iPrOH), trifluorethanol (TFE), butanol (BuOH), methylene chloride (CH 2 Cl 2 ), chloroform (CHCl 3 ), benzotrifluoride (BTF; PhCF 3 ), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2Me-THF), dimethoxyethane (DME), dioxane, ethyl acetate, isopropyl acetate, acetone, methylethyl ketone, methyl isobutyl ketone, dimethylformamide (DMF), dimethylacetamide (DMA), acetonitrile (CH 3 CN), proprionitrile (CH 3 CH 2 CN), benzonitrile (PhCN), dimethyl sulfoxide, sulfolane, water, or mixtures of any two or more thereof.

8. The process of claim 2 , wherein the conditions to form the compound of formula VIII comprise a coupling agent, where the coupling agent comprises (7-azabenzotriazol -1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), O-benzotriazol-1-yl -N,N,N′,N′-bis(pentamethylene)uronium hexafluorophosphate, O-(benzotriazol-1-yl) -N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate, (benzotriazol-1-yloxy)dipiperidinocarbenium hexafluorophosphate, (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), bromotripyrrolidinophosphonium hexafluorophosphate, Bromotris(dimethylamino)phosphonium hexafluorophosphate, O-(6-chlorobenzotriazol -1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TCTU), O-(6-chlorobenzotriazol -1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HCTU), 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate, 2-chloro-1,3-dimethylimidazolidinium tetrafluoroborate, 2-chloro-1,3-dimethylimidazolidinium chloride, chlorodipyrrolidinocarbenium hexafluorophosphate, chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate, chlorotripyrrolidinophosphonium hexafluorophosphate, (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino -morpholino-carbenium hexafluorophosphate (COMU), dipyrrolidino(N-succinimidyloxy)carbenium hexafluorophosphate, O -[(ethoxycarbonyl)cyanomethylenamino]-N,N,N′,N′-tetramethyluronium hexafluorophosphate, fluoro-N,N,N′,N′-bis(tetramethylene)formamidinium hexafluorophosphate, fluoro-N,N,N′,N′-bis(tetramethylene)formamidinium hexafluorophosphate, 1-hydroxybenzotriazole (HOBT), 1-hydroxy-7-azabenzotriazole (HOAT), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uranium hexafluorophosphate (HBTU), 1-[(dimethylamino)(morpholino)methylene]-1H -[1,2,3]triazolo[4,5-b]pyridine-1-ium 3-oxide hexafluorophosphate (HDMA), O-(5-norbornene-2,3-dicarboximido)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, S-(1-oxido-2-pyridyl)-N,N,N′,N′-tetramethylthiuronium hexafluorophosphate, O-(2-oxo -1(2H)pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, N,N,N′,N′-tetramethyl -O—(N-succinimidyl)uronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide (DCC), N,N′-diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (EDC-MeI), propane phosphonic acid anhydride (T3P), N,N′-di-tert-butylcarbodiimide, N-cyclohexyl -N′-(2-morpholinoethyl)carbodiimide methyl-p-toluenesulfonate, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, 1,1′-carbonyldiimidazole, 1,1′-carbonyldi(1,2,4-triazole), bis(4-nitrophenyl) carbonate, 4-nitrophenyl chloroformate, di(N-succinimidyl) carbonate, 1-(2-mesitylenesulfonyl)-3-nitro-1H-1,2,4-triazole, or a combination of any two or more thereof.

9. The process of any of claims 8 , wherein the conditions to form the compound of formula VIII further comprise a solvent.

10. The process of claim 9 , wherein the solvent comprises methanol (CH 3 OH), ethanol (EtOH), isopropanol (iPrOH), trifluorethanol (TFE), butanol (BuOH), methylene chloride (CH 2 Cl 2 ), chloroform (CHCl 3 ), benzotrifluoride (BTF; PhCF 3 ), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2Me-THF), dimethoxyethane (DME), dioxane, ethyl acetate, isopropyl acetate, acetone, methylethyl ketone, methyl isobutyl ketone, dimethylformamide (DMF), dimethylacetamide (DMA), acetonitrile (CH 3 CN), propionitrile (CH 3 CH 2 CN), benzonitrile (PhCN), dimethyl sulfoxide, sulfolane, water, or a mixture of any two or more thereof.

11. The process of claim 3 , wherein the conditions to form the compound of formula V comprise a coupling agent, where the coupling agent comprises (7-azabenzotriazol -1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), O-benzotriazol-1-yl -N,N,N′,N′-bis(pentamethylene)uronium hexafluorophosphate, O-(benzotriazol-1-yl) -N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate, (benzotriazol-1-yloxy)dipiperidinocarbenium hexafluorophosphate, (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), bromotripyrrolidinophosphonium hexafluorophosphate, Bromotris(dimethylamino)phosphonium hexafluorophosphate, O-(6-chlorobenzotriazol -1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TCTU), O-(6-chlorobenzotriazol -1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HCTU), 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate, 2-chloro-1,3-dimethylimidazolidinium tetrafluoroborate, 2-chloro-1,3-dimethylimidazolidinium chloride, chlorodipyrrolidinocarbenium hexafluorophosphate, chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate, chlorotripyrrolidinophosphonium hexafluorophosphate, (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), dipyrrolidino(N-succinimidyloxy)carbenium hexafluorophosphate, O -[(ethoxycarbonyl)cyanomethylenamino]-N,N,N′,N′-tetramethyluronium hexafluorophosphate, fluoro-N,N,N′,N′-bis(tetramethylene)formamidinium hexafluorophosphate, fluoro-N,N,N′,N′-bis(tetramethylene)formamidinium hexafluorophosphate, 1-hydroxybenzotriazole (HOBT), 1-hydroxy-7-azabenzotriazole (HOAT), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), 1-[(dimethylamino)(morpholino)methylene]-1H -[1,2,3]triazolo[4,5-b]pyridine-1-ium 3-oxide hexafluorophosphate (HDMA), O-(5-norbornene-2,3-dicarboximido)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, S-(1-oxido-2-pyridyl)-N,N,N′,N′-tetramethylthiuronium hexafluorophosphate, 0-(2-oxo -1(2H)pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, N,N,N′,N′-tetramethyl -O—(N-succinimidyl)uronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide (DCC), N,N′-diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (EDC-MeI), propane phosphonic acid anhydride (T3P), N,N′-di-tert-butylcarbodiimide, N-cyclohexyl -N′-(2-morpholinoethyl)carbodiimide methyl-p-toluenesulfonate, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, 1,1′-carbonyldiimidazole, 1,1′-carbonyldi(1,2,4-triazole), bis(4-nitrophenyl) carbonate, 4-nitrophenyl chloroformate, di(N-succinimidyl) carbonate, 1-(2-mesitylenesulfonyl)-3-nitro-1H-1,2,4-triazole, or combinations of any two or more thereof.

12. The process of claim 11 , wherein the conditions to form the compound of formula VIII further comprise a solvent, optionally wherein the solvent comprises methanol (CH 3 OH), ethanol (EtOH), isopropanol (iPrOH), trifluorethanol (TFE), butanol (BuOH), methylene chloride (CH 2 Cl 2 ), chloroform (CHCl 3 ), benzotrifluoride (BTF; PhCF 3 ), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2Me -THF), dimethoxyethane (DME), dioxane, ethyl acetate, isopropyl acetate, acetone, methylethyl ketone, methyl isobutyl ketone, dimethylformamide (DMF), dimethylacetamide (DMA), acetonitrile (CH 3 CN), proprionitrile (CH 3 CH 2 CN), benzonitrile (PhCN), dimethyl sulfoxide, sulfolane, water, or a mixture of any two or more thereof.

13. The process of claim 3 , wherein the cleaving acid used to produce a compound of formula VI comprises a halogen acid, a carboxylic acid, a phosphonic acid, a phosphoric acid, a sulfinic acid, a sulfonic acid, a sulfuric acid, a sulfamic acid, a boric acid, a boronic acid, an acid resin, or combinations of any two or more thereof.

14. The process of claim 3 , wherein the cleaving acid used to produce a compound of formula VI comprises hydrofluoric acid, hydrochloric acid (HCl), hydrobromic acid, hydroiodic acid, acetic acid (AcOH), fluoroacetic acid, trifluoroacetic acid (TFA), chloroacetic acid, benzoic acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid, trifluoromethanesulfonic acid, sulfuric acid, or combinations of any two or more thereof.

15. The process of claim 3 , wherein combining with the cleaving acid occurs at a temperature from about −40° C. to about 150° C.

16. The process of claim 3 , wherein combining with the cleaving acid further comprises a protic solvent, a polar aprotic solvent, or a mixture of the two.

17. The process of claim 3 , wherein combining with the cleaving acid further comprises methanol (CH 3 OH), ethanol (EtOH), isopropanol (iPrOH), trifluorethanol (TFE), butanol (BuOH), methylene chloride (CH 2 Cl 2 ), chloroform (CHCl 3 ), benzotrifluoride (BTF; PhCF 3 ), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2Me -THF), dimethoxyethane (DME), dioxane, ethyl acetate, isopropyl acetate, acetone, methylethyl ketone, methyl isobutyl ketone, dimethylformamide (DMF), dimethylacetamide (DMA), acetonitrile (CH 3 CN), proprionitrile (CH 3 CH 2 CN), benzonitrile (PhCN), dimethyl sulfoxide, sulfolane, water, or mixtures of any two or more thereof.