US 2004.0033986A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0033986 A1 Protopopova et al. (43) Pub. Date: Feb. 19, 2004 (54) ANTI TUBERCULAR DRUG: Related U.S. Application Data COMPOSITIONS AND METHODS (63) Continuation-in-part of application No. 10/147.587, (76) Inventors: Marina Nikolaevna Protopopova, filed on May 17, 2002. Silver Springs, MD (US); Richard Edward Lee, Cordova, TN (US); (60) Provisional application No. 60/381,220, filed on May Richard Allan Slayden, Ft. Collins, 17, 2002. CO (US); Clifton E. Barry III, Washington, DC (US); Elena Publication Classification Bogatcheva, Bethesda, MD (US); Leo (51) Int. Cl." ....................... A61K 31/695; A61K 31/44; Einck, McLean, VA (US) A61K 31/137 Correspondence Address: (52) U.S. Cl. ............................. 514/63; 514/357; 514/649 JOHN S. PRATT, ESQ (57) ABSTRACT KILPATRICK STOCKTON, LLP 1100 PEACHTREE STREET Methods and compositions for treating disease caused by SUTE 2800 infectious agents, particularly tuberculosis. In particular, ATLANTA, GA 30309 (US) methods and compositions comprising Substituted ethylene diamines for the treatment of infectious diseases are pro (21) Appl. No.: 10/440,017 Vided. In one embodiment, these methods and compositions are used for the treatment of mycobacterial infections, (22) Filed: May 16, 2003 including, but not limited to, tuberculosis. Patent Application Publication Feb. 19, 2004 Sheet 1 of 95 US 2004/0033986 A1 (Pol\ ystyr SVene C2Cl6/PPh3 / A RNH2/EING-P). (1 HR MeO of Ti, RTV'cch.ch.c. Rift V l ( \ O u-1 1. X O MeO - s" x -- PyTHF. R./ Y Me PyBroP X,Y = Cl, Br Rink-acidO resin X= Cl, Br y EtN(so-Pr). R=H, Me, Et, Bu DMF, 70°C 10% TFACHCl2 FIGURE 1 Patent Application Publication Feb. 19, 2004 Sheet 2 of 95 US 2004/0033986 A1 Primary Amines 1. 1. 4-Methylbenzylamine H3C 2. 2. Cyclopentylamine 3. N 3. 2-(Aminomethylo)pyridine 21 6. O 6. Furfurylamine CH3 7 O H3C-o-, Ys --"NH 7. 3,4,5-Trimethoxybenzylamine CH3 NH 2 8. 8. 1-Methyl-3-phenylproplyamine 9. NH2 9. Cyclobutylamine 10. NH2 0. 1,2,3,4-Trimethoxybenzylamine FIGURE 20a) Patent Application Publication Feb. 19, 2004 Sheet 3 of 95 US 2004/0033986 A1 NH2 11. o 1. 2,3-Dimethylcyclohexylamine CH3 12. Tyramine HO 3. 13. 2-Fluorobenzylamine F (R) H3Crol 16. (R)-2-Amino-1-butanol NH2 17. -CH3 HC1 O Clu 17. 3,4-Dimethoxyphenethylamine N H2 18 N H2 8. 3,3-Diphenylpropylamine . NH2 19. 19. Propylamine CH3 21. r NH, N 21. 1-(2-Aminoethyl)piperidine O FIGURE 2(b) Patent Application Publication Feb. 19, 2004 Sheet 4 of 95 US 2004/0033986 A1 22. 22. Phenethylamine 23. re, 23. 4-(2-Aminoethyl)morpholine (...) NH 24. (S)-Phenylglycinol 24. (S)or " 25. H c N N1 N 25. Tryptamine NH2 27. NH 27. Cyclohexylamine O CH 28a. ()i? 3 NH 28a. (+)-Isopinocampheylamine H3C 29. 29. Benzylamine 30. 3-Amino-1-propanol HN1 N1)-oh 3. 3. 2-Fluorophenethylamine F FIGURE 20c) Patent Application Publication Feb. 19, 2004 Sheet 5 of 95 US 2004/0033986 A1 CH3 33. NH2 33. b-Methylphenethylamine 34. O H.C1 Olus 34. 4-Methoxyphenethylamine NH2 35 t N 35. N,N-Dimethylethylenediamine HC 1. N-1N NH2 36. L - S H3 c1 Y-rro H 36. L-Methioninol NH2 37. O 37. Tetrahydrofurfurylamine 38, 1N1,N1 NH 38. Amylamine HC NH2 39. Aminomethylcyclopropane 39. A 41. r NH2 C N 41. 1-(2-Aminoethyl)piperazine H FIGURE 20d) Patent Application Publication Feb. 19, 2004 Sheet 6 of 95 US 2004/0033986 A1 42a. CH3 HN CH 42a. (+)-Bornylamine 2 ():3 ' CH, CH, HN >luk 43. tert-Octylamine H3C CH3 44. 44. 1-Adamantanemethylamine t > y 4S. H3C Yo: 45. 2-Amino-1-propanol, d.l NH2 46 NH2 2Y ~/ 46. 3-Phenyl-1-propylamine CJN 47 47. 2,2-Diphenylamine " NH2 N O 48. 1-(3-Aminopropyl)-2-pyrrolidinone (- (tech) FIGURE 2Ce) Patent Application Publication Feb. 19, 2004 Sheet 7 of 95 US 2004/0033986 A1 49. HN F 49. 4-(Trifluoromethyl)benzylamine F re, 50. N 50. 1-(2-Aminoehtyl)-pyrrolidine K) 51. -CH3 HC1 O NH2 51. Veratryl amine 52. 1\1\1\ 52. 5-Amino-1-pentanol H2N OH 53. O 53. 2-(1-Cylcohexenyl)ethylamine NH2 n 54. 21 54. 5-Aminoquinoline NH2 HN 55. 2 OH 55. 1-Aminomethyl-1-cylcohexanol, HCl 56. H. N 56. 1-Aminopiperidine O FIGURE 20?) Patent Application Publication Feb. 19, 2004 Sheet 8 of 95 US 2004/0033986 A1 57. Yn 1N F 57. 3-Fluorobenzylamine 2 59. (1S,2R)- c r 59. (1S,2R)-cis-1-Amino-2-indanol NH2 61. 61. 4-Amino-1-butanol H2N 1N1,N1OH 63. (S)- terror 63. (S)-2-Amino-1-butanol NH2 66. NH2 e CH, N O 66. 2,4-Dimethoxybenzylamine CH 68. H3C NH2 68. 1-(1-Naphthyl)ethylamine 69. O 69. 2-(2-Aminoethyoxy)ethanol HN1 Y1 N1 Noh 70. N NH2 reN 70. 3-Amino-1,2,4-triazine N FIGURE 20g) Patent Application Publication Feb. 19, 2004 Sheet 9 of 95 US 2004/0033986 A1 71. NH2 71. 2-Ethoxybenzylamine --- 72. NH 72. 4-(3-Aminopropyl)morpholine C)O 73. NH2 O 73. 2-Amino-1-methoxypropane -- YOH 3. 74a. CH3 74a. cis-(-)-Myrtanylamine 77 a. 77a. Cyclooctylamine 78a.H2N ) C 78a. 2-Adamantamine, HCl 79. NH2 79. trans-2-Aminocyclohexanol, HCl OH 80. NH2 80. 3.Amino-5-phenyl pyrazole FIGURE 2(h) Patent Application Publication Feb. 19, 2004 Sheet 10 of 95 US 2004/0033986 A1 82. N p 2 NH 2 CH3 O. 82. 2,3-Dimethoxybenzylamine CH3 83a. 83a. Noradamantamine, HCl () 84. 4-Amino-1-benzylpiperidine NH 85. re 85. 4-Methylcyclohexylamine H2N 1N1 86. (1R,2S) OH 86. (1R,2S)-l-Amino-2-indanol NH2 87.7 N 87. 3-Aminopyrazole 8 8. F 88. 4-Fluorobenzylamine NH2 90a. trans-2-Phenylcyclopropylamine, HCI FIGURE 20i) Patent Application Publication Feb. 19, 2004 Sheet 11 of 95 US 2004/0033986 A1 1a-NH2 91. 91. 1-(3-Aminopropyl)pipecoline O 92. to-rrison 92. 2-Amino-1,3-propanediol NH2 93. OH HC NH2 93. Thiomicamine 3 NS Cre 94. (R) OH NH2 94. (R)-1-Amino-2-propanol H3C 95. 1N1 Y1,V YOH 95. (S)-2-Amino-3-cyclohexyl-1-propanol, HCI lu NH2 97. HO NH2 97. 1-Amino-1-cyclopentane methanol 98. NH2 OH HC 98. (S)-Isoleucinol CH C 99. S-OH 99. 4-Clorophenylalaniol NH2 FIGURE 20) Patent Application Publication Feb. 19, 2004 Sheet 12 of 95 US 2004/0033986 A1 100. CH NH2 100. l-Leucinol H3C luluoh OH 101. NH2 OH 101. (1S,2S)-(+)-2-Amino-1-phenyl-1,3-propanediol 102. (S)-(+) OH 102. (S)-(+)-1-Amino-2-propanol H3C --- NH2 OH 103. CH3 H2N 103. 2-Amino-2-methyl-1,3-propanediol OH NH2 104. (d,l) HC1 O N OH 104. d, 1-Serine methyl ester, HCl O O5a. H3 H3C CH3H 105a. (-)-Isopinocampheylamine NH2 107. H N 107. Histidinol FIGURE 2(k) Patent Application Publication Feb. 19, 2004 Sheet 13 of 95 US 2004/0033986 A1 108. M M 108. 2-Amino-5-cyclopropyl-1,3,4-thiadiazol 2N 109. CH3 H2N OH 109. 2-Amino-2-methyl-1-propanol H3C 111. 111. Allylamine H2C an-NH2 112. 112. 3-Amino-1,2-propanediol to-rrs,OH 1S. NH N-F 115. Hexamethyleimine H2N NH 117. ss,oS 17. 3-Aminorhodamine CH NH2 119. OH 119. (R)-(–)-2-Phenylglycinol 126. NH O 126. Methyl-3-aminocrotonate FIGURE 201) Patent Application Publication Feb. 19, 2004 Sheet 14 of 95 US 2004/0033986 A1 129, CS 129. d, 1-Homocysteine, thiolactone, HCl NH2 F F 137. 2-Amino-5trifluoromethyl-1,3,4-thiadiazol HN E38. Racemic; "test' well c-rriso 138. d, 1-2-Amino-1-butanol (test, making EMB) NH2 140. 140. 3-Etoxypropylamine HN1\-1No11N NCH, 141. Herr CH3 141. Sec-Butylamine NH2 142. 142. 2-Aminoheptane HC -->CH, 143. CH3 H2N OH 143. 2-Amino-2-methyl-1-propanol H3C 144. NH2 144. (S)-1-Amino-2-(Methoxymethyl)pyrrolidine FIGURE 20m) Patent Application Publication Feb. 19, 2004 Sheet 15 of 95 US 2004/0033986 A1 145a. ANH2 145a. trans-1,2-Diaminocyclohexane 147. 3-Amino-2-methoxydibenzofuran 148. A 148. 2-Amino-4-methoxybenzothiazole NH 49. f 149. 1-Aminohomopiperidine C) 150. N-NH2 150. 2-Amino-3-hydroxypyridine OH 151. UN 151. 1-Aminopyrrolidine, HCl NH2 152. orr CH3 152. d, 1-2-Amino-1-pentanol NH2 S4. OH 154. Ethanolamine HN FIGURE 20n) Patent Application Publication Feb. 19, 2004 Sheet 16 of 95 US 2004/0033986 A1 155. t- Nr12 S. 155. 3-Methylbenzylamine CH3 56. terra, 156. 3-(Dibutylamino)propylamine NH2 157. HO CH3 NH2 157. Norephedrine, HCl 58. Piperonylamine 59. 1 n 159. 2-Methoxyethylamine HN CH3 160. c-rrsch, 160. 1-Ethylpropylamine NH2 6. S N 61. 1-(3-Aminopropyl)imidazol N.N-N-NH2 162. HN C 62. 1-Aminoadamantamine 164. NH2 CH3 64. Dimethyl aminomalonate, HCl FIGURE 200) Patent Application Publication Feb. 19, 2004 Sheet 17 of 95 US 2004/0033986 A1 166. NH2 166. Isopropylamine H3C CH3 167. fl. 1. N-N-NH2 167. 3-(Dimethylamino)propylamine H3C 169. NH2 169. 4-Fluorophenethylamine Or 70. NH2 170. 2-(4-Aminophenyl)ethylamine 171. NH2 w N 171 3-Aminoisoxazole O 172. NH, 1N- NH2 172. 1,2-Diaminopropane HC 173. D.L. H N | NH2 O YCH 173. d, 1-Tryptophan methyl ester, HCl O 174. D- O HaC O 174. d-Aspartic acid, dimethyl ester, HCl NH2O 175.