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. 1-Leucine ethyl ester, HCl
FIGURE 20p) Patent Application Publication Feb. 19, 2004 Sheet 18 of 95 US 2004/0033986A1
176. l-Methionine ethyl ester, HCl CH3 177. D.L O HC3 so re. 177. d.l-a-Amino-n-butyric acid methyl ester, HCI NH2 H3C 178. L- o? O HN
NO 178. 3-Mnitro-l-tyrosine ethyl ester, HCI HO 2
179, L O o-'3CH NH HO 2 179. 1-3,4-Dihydroxyphenylalanine methyl ester, HCl OH NH2
180. L
NH2 o 180. 1-Lysine methyl ester, HCl 181. (S)- O
srsonNH2 181. (S)-Benzyl-l-cysteine ethyle ester, HCl
FIGURE 200) Patent Application Publication Feb. 19, 2004 Sheet 19 of 95 US 2004/0033986 A1
82. L O CH3 H3C YO CH3 182. l-Isoleucine methyl ester, HCI NH2 CH3 183. L- O O H2N
HN )=NH 183. 1-Arginine methyl ester, HCl HN 184. D.L. O. resor-ch, 84. d.l-Norleucine methyl ester, HCl NH2
185. HC1 O Sr NH2 185. b-Alanine ethyle ester, HCl O
186. L O O HC1 No OH 186. l-Glutamic acid ethyl ester, HCl NH2 87. L- O o1 NCH NH2 187. -Phenylalanine ethyl ester, HCl
188. D,L- O -CH3 NH 188. d.l-Phenylalanin methyl ester, HCl
FIGURE 20r) Patent Application Publication Feb. 19, 2004 Sheet 20 of 95 US 2004/0033986 A1
189, L- O8 N O CH3 189, l-Histidine- - - methyl ester, HCl S.N NH2
190. D,L- O Hacs, 1 190. d.l-Alanine ethyl ester, HCl NH2
19. O O1 NCH NH2 191. Tyrosine ethyl ester, HCl HO O CH3 192, L-sole, 192. I-Valine ethyl ester, HCl NH2
193. H.N.'CH 193. tert-Amylamine H3C
194. HN >CH3 CH 194. tert-Butylamine H3C 3
197. L
197. S-Benzyl-L-cysteinol OrrorNH2
198. H O N 1N NH2 198. N-Phenylethyldiamine
FIGURE 20s) Patent Application Publication Feb. 19, 2004 Sheet 21 of 95 US 2004/0033986 A1
201. N,N,2,2-Tetramethyl-1,3-propanediamine
202.
202. Isonipecotamide
2O3. CH3 NH2 203. Isobutylamine CH 204. CH3 ryN rt HN Nulua-CH 204. Hexetidine (mixture of stereosiomers) CH3
26.
206. exo-Aminonorbornane
207. os-o-o: CN 207. Ehtyl 4-amino-1-piperidinecarboxylate NH2
211. D OH NH O
211. D-Glucosamine, HCl OH OH FIGURE 20t) Patent Application Publication Feb. 19, 2004 Sheet 22 of 95 US 2004/0033986 A1
24 NH2 214. Aminodiphenylmethane C C
215 H N | NH2 215. alpha-Methyltryptamine CH3
216 NH2
216. 9-Aminofluorene, HCl
219 NH2
219. 4-Phenylbutylamine
22 CH3
NH2 221. 4-Chloroamphetamine, HCI C O?,
222. H CH3 3C N CH3 H t 222. 4-Amino-2,2,6,6-tetramethylpiperidine NH2
223. 4-(Hexacylamino)benzylamine
223. H H3C-1a1a1a1a1a1a1n-N lulu,
FIGURE 20u) Patent Application Publication Feb. 19, 2004 Sheet 23 of 95 US 2004/0033986 A1
225. -CH3
"ru NH 225. 3-O-Methyldopamine, HCl 2
226.
226. 3-Fluorophenethylamine F
227.
227. 3-Aminopyrrolidine, diHCl NH
229, 2-Thiopheneethylamine \ f
230. mix of cis/trans
230. 2-Methylcyclohexylamine NH2
23. NH
231. 2-Methoxyphenethylamine CC.
232. NH2 232. 2.-Fluoroethylamine, HCl 1N-1
FIGURE 2(v) Patent Application Publication Feb. 19, 2004 Sheet 24 of 95 US 2004/0033986 A1 28: - - 21 NH2 S 233. 2-Chlorobenzylamine C
234. .NH2
234. 2-Aminoindan, HCl
235. 2-Amino-4-phenyl-5-tetradecylthiazole 235.
S CH3
236. OH NH2
236. 2-Amino-1-phenylethanol
238. 2,5-Dimethoxyphenethylamine
240.
240. 2,4-Dichlorophenethylamine
241.
241. 2,2,2-Trifluoroethylamine F
FIGURE 20W) Patent Application Publication Feb. 19, 2004 Sheet 25 of 95 US 2004/0033986 A1
242.
Cr".C 242. 2-(2-Chlorophenyl)ethylamine
243.
S OH
243. 2-(2-Aminomethyl)phenylthio)benzyl alcohol OC.
245. Ol 245. 1-Aminoindan NH2
246, ro ON 246. 1-Amino-4-(2-hydroxyethyl)piperazine
247. NH2 CH
247. 1,3-Dimethylbutylamine e-se 3
249. NH2 CH3 H3C 249. 1,2-Dimethylbutylamine CH3
FIGURE 2(x) Patent Application Publication Feb. 19, 2004 Sheet 26 of 95 US 2004/0033986 A1 253. 49-such-7N, 253. 1-(1-Adamantyl)ethylamine, HCl NH2
H 254 N 254. (S)-(+)-2-(Aminomethyl)pyrrolidine
255. NH2
255. (S)-(–)-2-Cyclohexylethylamine cCH3
256. 21N1Y1OH V 256. (S)-(–)-2-Amino-3-phenyl-1-propanol U H.
257. NH2 CH3 257. (R)-(-)-Cyclohexylethylamine
259. (1S,2S) OH O1 CH3 NH2 259. (1S,2S)-(+)-2-Amino-3-methoxy 1-phenyl-1-propanol
FIGURE 20y) Patent Application Publication Feb. 19, 2004 Sheet 27 of 95 US 2004/0033986 A1 260. (1R,2S) NH
s OH 260. (1R,2S)-(–)-2-Amino-1,2-diphenylethanol
261. (-) CH3
HO NH2 261. (-)-3,4-Dihydroxynorephedrine OH
262. (1S,2R) NH2 IA
262. (1S,2R)-(+)-2-Amino-1,2-diphenylethanol OH
263. 263. Octadecylamine HaC-(CH2) 17-NH2
264. N
264. 3-Aminoquinonuclidine, didCl NH2
265. (R)-(+) C 265. (R)-Cycloserine NH2
266.
266. Undecylamine HC-(CH2) 10 -NH2
FIGURE 20z) Patent Application Publication Feb. 19, 2004 Sheet 28 of 95 US 2004/0033986 A1
- OH Af. CH
HO NH2 267. 3,4-Dihydroxynorephedrine OH
268. NH2
HO 268. 3-Hydroxytyramine OH
269. Sk 269. 4-(Trifluoromethoxy)benzylamine F F Clue,
272. CH3 (H3 272. Geranylamine
H 275. N
275. 5-Methoxytryptamine H3C-O O N1 NH
276 NH2 CH
276, 6-Amino-2-methyl-2-heptanol, HCI H3C--suk. CH
277. 1S-1N1N-O 277. 6-Amino-l-hexanol H2N
FIGURE 20aa) Patent Application Publication Feb. 19, 2004 Sheet 29 of 95 US 2004/0033986 A1
CH3 278. CH3 CH3
HC H 278. Dehydroabietylamine H2N
279. H.C. NH2
279. 1-(1-Naphthyl)ethylamine
28. GH
R l?). A minra.fhvrly-1-mathvlnvirrrli?lina a V . 1 V1 - ...... VW Lily if w vary 1y a W a Y-- a . ra 282, D,L-cro CH3 282. d, 1-Valinol NH2
283. D,L- re 283. d, 1-2-Amino-1-hexanol NH2
284. Or H 284. trans-2-Aminocyclohexanol, HCl OH
FIGURE 20ab) Patent Application Publication Feb. 19, 2004 Sheet 30 of 95 US 2004/0033986 A1
285. (S)- s-n-NH2 285. S-Benzylcysteamine, HCl Or
2.88. NH2 CH
288. 4-Fluoro-a-methylbenzylamine F
FIGURE 20ac) Patent Application Publication Feb. 19, 2004 Sheet 31 of 95 US 2004/0033986 A1 Acyclic Secondary
4. N-Propylcyclopropanemethylamine
H N CH3 15. 2-(Ethylamino)ethanol Ho-1\-1 N-1 20. t CH3 20. N-Methyl-iso-propylamine HC CH3
60. N-Methylpropylamine YCH 3
62. "y-r CH3 62. 2-Methylaminomethyl 1,3-dioxolane KrsO
64. HN
64. Dibenzylamine
H 65. N-Butylbenzylamine N N-1N1
FIGURE 3(a) Patent Application Publication Feb. 19, 2004 Sheet 32 of 95 US 2004/0033986 A1
67.
N CH 3 H 67. N-Benzylethylamine
76. QH N
76. (Methylaminomethyl)benzyl alcohol
81. H N 81. N-Benzyl-2-phenethylamine C
HO 89 21 CH3 r V N H NN 89. Pseudoephedrine CH
10. (1R,2S) HO NCH3 HN 110. (1R,2S)-(-)-Ephedrine CH3
113. Diethanolamine
H 118. N-Benzylethanolamine
FIGURE 3(b) Patent Application Publication Feb. 19, 2004 Sheet 33 of 95 US 2004/0033986 A1
120. H N 120. 2-(Propylamine)-ethanol Hc1N1 N1NOH
H3C
121.
HN V 121. N-methylbutylamine CH3
127. (Hs N H 127. N-Benzyl-n,N-dimethylethylenediamine Crs.
131. H N
3
32.
132. N-Ethylcyclohexylamine
136.
1NCH, 136. 4-(Ethylaminomethyl)pyridine
63. He-O-1N1-S CH3 163. Bis(2-methoxyethyl)amiane
FIGURE 3(c) Patent Application Publication Feb. 19, 2004 Sheet 34 of 95 US 2004/0033986 A1 CH3 183. L- O O HN
HN )=NH 183. l-Arginine methyl ester, HCl H2N
196. OH H NCH
196. Synephrine HO
198. H
198. N-Phenylethyldiamine
199. CH3 HC1
199. N-Methylhomoveratrylamine
200. H NN-s 200. N-Allylcyclopentylamine ("s-se,
208. OH s YCH
HO 208. Epinephrine OH
FIGURE 3(d) Patent Application Publication Feb. 19, 2004 Sheet 35 of 95 US 2004/0033986 A1
209. mix of (+),(-), and Ineso CH3
HN - N-CH
209. Di-sec-butylamine (mix of (+), (-) and meso) H3C 1-c.
CH 210,
210. Diisopropylamine HC1 CHs
212. cis-(1S,2R)-(–)-2-(Benzylamino)cyclohexanemethanol 212. cis-(1S,2R)
H CC,N 213. cis-(1R,2S)-(+)-2-(Benzylamino)cyclohexanemethanol
213. cis-(1R,2S) OCN
223. 4-(Hexacylamino)benzylamine 223. H H3C-1a1a1a1a1a1a1n-N Clue,
258. (3S(3a,4Ab),8A b)-N-t-butyl-D-ecahydro-3-isoquinolinecarboxamide
258.3S
NH H N CH3 N
6H3C YSc,-- FIGURE 3(e) Patent Application Publication Feb. 19, 2004 Sheet 36 of 95 US 2004/0033986 A1
274. H O N n1sch, 274. Allylcyclohexyamine
FIGURE 3(f) Patent Application Publication Feb. 19, 2004 Sheet 37 of 95 US 2004/0033986 A1 Cyclic Secondary Ami
5. 4-Benzylpiperidine
14. H N
14. 3-Piperidinemethanol
25. H C N N1 N 25. Tryptamine NH2
H 26. N
26. Morpholine OO
32 32. 4-Piperidinopiperidine C
40. s N-1
N 40. Ethyl l-piperazine carboxylate H
FIGURE 4(a) Patent Application Publication Feb. 19, 2004 Sheet 38 of 95 US 2004/0033986 A1 1Ninil 41. WI 12
N 41. 1-(2-Aminoethyl)piperazine H
58. H
58. Decahydroquinoline CC)
75.
NH
75. 1,2,3,4-Tetrahydropyridoindole NH
80. 3-Amino-5-phenyl pyrazole
87. 3-Aminopyrazole
H 96a.
C N F
96a. 1-(2-Fluorophenyl)piperazine Cr
FIGURE 4(b) Patent Application Publication Feb. 19, 2004 Sheet 39 of 95 US 2004/0033986 A1
106. O CH3
106. 1-Proline methyl ester
107. S. OH 107. Histidinol NH2
114.
114. 1-Piperonylpiperazine
15. -v
115. Hexamethyleimine
22.
122. 4-Hydroxypiperidine OH
23. H N
123. 2-Piperidinemethanol Cre
FIGURE 4(c) Patent Application Publication Feb. 19, 2004 Sheet 40 of 95 US 2004/0033986 A1 CH3 A4.
HN CH3 124. 1,3,3-Trimethyl-6-azabicyclo3.2.1]octane CH3 25. (aH 125. 3-Pyrrolidinol OH
128. CH3
()N 128. 1.-Methylpiperazine H
130. (S)-(+) H N 130. (S)-(+)-(2-Pyrolidinylmethyl)pyrrolidine Kyr)
CH3 33.
133. 1.-Methylhomopiperazine C)NH
35. O H N -CH3 135. Methyl pipecolinate, HCl
139. N
139. 2-Ethylpiperidine FIGURE 4(d) Patent Application Publication Feb. 19, 2004 Sheet 41 of 95 US 2004/0033986 A1
53.
153. 1,2,3,4-Tetrahydroisoquinoline
65. H N 165. Piperidine O
168. Nu1NH 168. 1-(4-Fluorophenyl)piperazine O
173. d.l-Tryptophan methyl ester, HCl O
189. L- O H
189. 1-Histidine methyl ester, HCl N f --"NH2
195. tert-Butyl (1S,4S)-(–)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate
195. (1S,4S) HN
202.
202. Isonipecotamide
FIGURE 4(e) Patent Application Publication Feb. 19, 2004 Sheet 42 of 95 US 2004/0033986 A1
H N
205. Heptamethyleneimine
25. H N
215. alpha-Methyltryptamine CH 3
217. H
217. 6-Fluoro-1,2,3,4-tetrahydro-2-methylcquinoline F
218. 6,7-Dimethoxy 1,2,3,4-tetrahydroisoquinoline, HCl 218. 11st- O YCH3 HN Null-Nen21 O CH3
' CHH CH HC N CH
222. 4-Amino-2,2,6,6-tetramethylpiperidine NH2
224.
OH 224. 4-(-4-Chlorophenyl)-4-hydroxypiperidine Cl
FIGURE 4(f) Patent Application Publication Feb. 19, 2004 Sheet 43 of 95 US 2004/0033986 A1 227. ( H 227. 3-Aminopyrrolidine, diHCl NH2
228. H
228. 3,5-Dimethylpiperidine (cis-and trans-) is ICl CH3 ()H 237. 2,6-Dimethylmorpholine H3C O CH3
239. O
239. 1,4-Dioxo-8-azaspiro4.5 decane \ / O
244. 1.-Methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, HBr 244. CH3 HO NH
HO 248. 1,3,4,6,7,8-Hexahydro-2H-pyrido(1,2-A)pyrimidine
H 248. N N CY N
250. H
250. 1,2,3,4-Tetrahydroquinoline OC)
FIGURE 4(g) Patent Application Publication Feb. 19, 2004 Sheet 44 of 95 US 2004/0033986 A1
251. H N
25l. 1-(2-Methoxyphenyl)piperazine XY
OH 252. ro1
C)N 252. 1-(2-(2-Hydroxyethoxy)ethyl)piperazine H
H 254. Kyrle,N 254. (S)-(+)-2-(Aminomethyl)pyrrolidine
258. (3S(3a,4Ab),8A b)-N-t-butyl-D-ecahydro-3-isoquinolinecarboxamide
258.3S
1na Yna
265. (R)-(+)
265. 3-Aminoquinonuclidine, diHCl NH2
H 270. N
270. Homopiperazine HN D
FIGURE 4(h) Patent Application Publication Feb. 19, 2004 Sheet 45 of 95 US 2004/0033986 A1 271. H H3C N t N 271. 2,6-Dimethylpiperazine H
CON 273. Iminodibenzyl H
H 275. N HC ? l Ya 275. 5-Methoxytryptamine YO NH
280.
280. 4,4'-Bipiperidine, HCI
286. rol CN 286. 1-(2-Hydroxyethyl)piperazine H
287.
287. 4-Methylpiperidine CH3
FIGURE 4(i)
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nz = -Susul - itine NH 2-AdamantanineSkyttanyamine Amino-1-propano -kethionino
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Synthesis of the library of 70,000 ethan buto analogs
Screening (HTS) against M.th 2,796 actives identification of actives f70 corponds, Evaluation of SAR AC < 2.5W
Re-synthesis of the best 70 Compounds for in Vitro evaluations
Testing of the best 26 compounds in seconday in Vitro assays
in wwo of studies of 6 compounds Pharmacology 3 Compounds
FIGURE 21 Patent Application Publication Feb. 19, 2004 Sheet 63 of 95 US 2004/0033986 A1
Compound 58
* ------Compound 59
------Compound 109
------Compound 73
Compound 111
FIGURE 22 Patent Application Publication Feb. 19, 2004 Sheet 64 of 95 US 2004/0033986A1 EMB compounds activity (spleen) Chemotherapy EC 1.OE+08 .1 Start UC 1.OE+07
1.OE+06
1.OE+05
1.OE+04
1.OE+03
FIGURE 23 Patent Application Publication Feb. 19, 2004 Sheet 65 of 95 US 2004/0033986A1 EMB compounds activity (lung) Chemotherapy 1.OE+06 start 11 p=0.04 EC
1.OE--O5 UC EMB g INH s 10E--04 73/1 s 73/10 109/1 1.OE+03 109/10
1.OE+O2 20 d ------35 d ------d ------O 65 d ------
FIGURE 24 Patent Application Publication Feb. 19, 2004 Sheet 66 of 95 US 2004/0033986 A1
EMB compounds activit (Spleen)
1.OE+07 A1 StartChemotherapy
EC 1.OE--O6 UC EMB 1.OE--O5 OINH 111/10 1.OE+04 59/1 CD 59/10 59-INH 1.OE+03 EMB-NH
1.OE--O2
FIGURE 25 Patent Application Publication Feb. 19, 2004 Sheet 67 of 95 US 2004/0033986A1 EMB compounds activity (lungs) Chemotherapy
1.OE+06 Start
EC 1.OE+05 EMB g INH s 1.OE+04. 111/10
59/10 INH/59 1.OE+03 EMB/NH
1.OE+02 |
FIGURE 26 Patent Application Publication Feb. 19, 2004 Sheet 68 of 95 US 2004/0033986A1
10E--O9
1.OE-08 p=0.05
c 10E--O7 D Cl2 O Q d 5 1.0E+06
1.OE-05
10E--04 EC 1 2 3 4 4' 4"wk 5 6 7 1 2 3 4. 4* 4t 5 6 7
2 weeks of chemotherapy 4 weeks of chemotherapy
FIGURE 27 Patent Application Publication Feb. 19, 2004 Sheet 69 of 95 US 2004/0033986A1
10E-08 p=0.05
10E-07
O o 10E-06 d O
1OE-05
10E-04 EC 1 2 3 4 4*k 4*Ark 5 6 7. 1 2 3 4 4 4*kA 5 6 7 2 weeks of chemotherapy 4 weeks of chemotherapy
FIGURE 28 Patent Application Publication Feb. 19, 2004 Sheet 70 of 95 US 2004/0033986 A1
TIC of +MRM (4 pairs): from 02/11/2010 a 2000 3.70 0.28 0.84 1461.82 2.673.10 5.80 6.406.82 2 3 4 6 7 Mixture of tested Time, min Compounds XIC of +MRM (4 pairs): for 377.0 1 2240 amu from 02/11/2010 2.12e4 8 at 1000 0.40 106 1.72 2.29 3.11 3.86 581 6.73 Compound 37 1 2 3 4. 5 6 7 RT: 4.48 min Time, min XIC of +MRM (4 pairs): for 3.07.0 1 1540 amu from 02/11/2010 3 1500 70 1000 Compound 59 5" o23 0.96 2.42 5.25 5.80 RT: 3.70 min 3 4 5 6 7 Time, min XIC of +MRM (4 pairs): for 331.01178.0 amu from 02/11/2010 1.71e4 4. Compound 109 1.94 2.53 3.12 5.09 5.92 RT 4.38 min 2 3 4 5 Time, min
6,406.82 7.3; RT 4.99 min
Time, min
FIGURE 29 Patent Application Publication Feb. 19, 2004 Sheet 71 of 95 US 2004/0033986A1
1000 --e-NSC 722039 --NSC-722040 -A-NSC722041
10
O 5 10 15 20 25 time (hr)
FIGURE 30 Patent Application Publication Feb. 19, 2004 Sheet 72 of 95 US 2004/0033986A1
E C S. S. ------e-NSC722039 - NSC-722040 2s -a-NSC722041 8
O 5 10 15 20 25 time (hr)
FIGURE 31
-e-NSC722039 -- NSC-722040 5, -A-NSC722041 -ulu
C
c) O s
O 5 10 15 20 25 time (hr)
FIGURE 32 Patent Application Publication Feb. 19, 2004 Sheet 73 of 95 US 2004/0033986A1
1000 E g e 3 mg/kg, i.V. 5 100 O 25 mg/kg, p.O.
E \ () 3 O -- 10 Q- 92- --- 9 O------. -Q - 1 --- =O 5 10 15 20 25 Time (h) Patent Application Publication Feb. 19, 2004 Sheet 74 of 95 US 2004/0033986 A1
2500
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Fig. 35 Patent Application Publication Feb. 19, 2004 Sheet 75 of 95 US 2004/0033986A1
+O1 MCA (19.Sys). from control u?ine 100-500 Control Ur $fo
4-Q1 MCA (19 scans), froT grp 1 urine scan 300-450
y Group 1 Urine l t 347.0 G C d w
+Q1 MCA (15 scans): from grp 2 urine 300-600 1.47e7 cps Group 2 Urine 3470
330
FIGURE 36 Patent Application Publication Feb. 19, 2004 Sheet 76 of 95 US 2004/0033986 A1
+Q1 MCA (9 scans): from control urine 300-1000 2.76e6 cps Control Urine
+C1 MCA (10 scans): frongp 1 urine 300-1000 9.23e6 cps
V Group 1 Urine (8-24 hr) Cl
2A. E
+Q1 MCA (6 scans): from grp 2 urine 300-1000 II 1.68e6 cps ise Group 2 Urine (4-24 hr)
397.0 718.0 4910 5770
FIGURE 37 Patent Application Publication Feb. 19, 2004 Sheet 77 of 95 US 2004/0033986A1
Table 22 Binding Assays - Summary Results
ASSay CNEompound ClientCompound ConcentrationTest - Control% Inhibition Specific of I.D. I.D. (M) Binding oil or on of so, on o, (non-selective) 6826-1 SQ109 1.OE-05 37 an oil on to oil on to of , o, . tra of so, on is to on to on is crack oil on to , of , on is a son, or i on GABA (no selective 6826-1 sooo top-os io in on to on , in a son, or ; to on to in i Monon-selective 6826-1 solo top.os 3. set on to on you are son, or ; N (neuronal) (o-BGTX-insensitive) 6826-1 SQ109 10E-05 - 0 onal are son, or is on to oil son, or is at on to . surren of so, on is o (non-selective) 6.826-1 SQ109 OE-05 106 a.a.p. oil solo, in v on to on is see all solo to gi one of so, in i 5-HT transporter (h) 6826-1 SQ109 1.OE-05 95
FIGURE 38 Patent Application Publication Feb. 19, 2004 Sheet 78 of 95 US 2004/0033986 A1
Table 23 Binding Assays - Reference Compound Data
ASSay Reference Compound ICso K fl H (M) (M) prox is on to an in
an in so, in an at it - tra, an in al to is to crick spot in on on station on a is no in to an at all annual can on to , in costs to co H (central) in a so so post on to an an an in sea solois, or in , van spy no is in N (neuronal) (o-BGTX-insensitive) nicotine 74Eoo 4ooo to one an at it in -- surren on to it, , , an an in its of glucocorticoid) or dexamethasone 47 00 2.4E00 to v. Irrive a spin-of NE transporter) protriptyline soros astos to ran on to its at , , stransporten) impramine cop-oo or oo
FIGURE 39 Patent Application Publication Feb. 19, 2004 Sheet 79 of 95 US 2004/0033986 A1
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Position on
Reagent #Acids F.W. 1 1-Adamantanecarboxinterested lic acid Tros
a5 || 5 |c clopropanecarboxylic acid
a6 6 3-Methox cyclohexanecarboxylic acid
a8 8
10 Propionic acid 74.08 11 Tetrahydro-2-furoic acid 116.12 12
www.v. www.ww T0.09
b7b6 HE103 (4-Fluorophenyl)acetoneEN
b8 104 Geranylacetone 194.32 b9 105 5-Hydroxy-2-adamantanone 166.22 b11 107 4-(4-Hydroxyphenyl)-2-butanone 16420
b12- 108 4-Meth lcyclohexanone 12.17 Position on tw. Plate Reagent #Aldehydes + Ketones F.W.
al c1 255 14,-- Benzodioxan-6-carboxaldehyde 164.16
c3 27 Benzyloxyacetaldehyde
29 4-Chlorobenzaldehyde
CARBONYTL COMPOUNDS USED IN MASTERPLATE TABLE 27. Figure 49 (a) Patent Application Publication Feb. 19, 2004 Sheet 89 of 95 US 2004/0033986A1 c6 109 l-Methyl-4-piperidone 113.16 c/ 3. 2-Chloro-4-fluorobenzaldehyde i58.56- a Y
EEEc 12 36 SERCyclohexanecarboxaldehyde
d1 37 Cyclopropanecarboxaldehyde 7009
d6 42 24-Dihydroxybenzaldehyde 138.12 d8 I 44 4-(Dimethylamino)benzaldehyde 149.19
alod10 110to Neryacetone)erylacetone (Geranylacetone ~35% is194.32 a
d12 48 2-Ethoxybenzaldehyde
e2 50 3-Ethoxysalicylaldehyde 66.18
e6 54 4-Fluorobenzaldehyde 124.11 e8 56 2-Furaldehyde 96.09 e9 112 Norcamphor I 110.16
e12 60 3-Hydroxybenzaldehyde 122. 12
f1 f2 f3 5 fa. 64 f5 f6 66 f7 f8 fS)
Figure 49 (b) Patent Application Publication Feb. 19, 2004 Sheet 90 of 95 US 2004/0033986 A1
2 74 -Methyl-5-imidazolecarboxaldehyde iiO. i2.
152.22 78 3-Methyl-2-thiophenecarboxaldehyde 126.18 (1R)-(-)-Myrtenal 50.22 100. 12 156.18 151.12 5-Norbornene-2-carboxaldehyde 122.17 84 (S)-(-)-Perillaldehyde 150.22
46.19 86.13 h3 87 2-Pyridinecarboxaldehyde 107.11
h5 89 4-P ridinecarboxaldehyde O7. G E. yrrole-2-carboxaldehyde 95.10 h7 91 4-Quinolinecarboxaldehyde 157.7
h8 92 1,2,3,6-Tetrahydrobenzaldehyde 10.16 h9 93 2-Thiophenecarboxaldeh de 12.15 17412 h11 95 2,3,4-Trimethoxybenzaldehyde 196.20 117 Io-Anisaldehyde Figure 49 (c) Patent Application Publication Feb. 19, 2004 Sheet 91 of 95 US 2004/0033986 A1
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A A A A A A Selected carb comp A1 A3 a added to A1-A10 B Selected carb comp, added to B1-B10
C C C C C Selected carb comp, C1 C C added to C1-C10
D D D 7 D2 added to D1-D10 Selected carb comp, added to E1-E10 F Selected carb comp, 1 FE FEB added to F1-F10 3333--- G G 7 G 8 Selected carb Comp, G G 666 added to G1-G10
H 7 H 8 Selected carb comp, H1 H added to H1-H10 "X" selected carbonyl 4.44.44.4.4 H555555 compounds to be added on the step 4
Resin Resin individual resins #1 #9 #10 through 10, pre loaded with proper artine N1
Table 28 Figure 52 Patent Application Publication Feb. 19, 2004 Sheet 94 of 95 US 2004/0033986 A1
Mic 50 Frag. Original mic.I.E. slux logPTPsa
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ANTITUBERCULAR DRUG: COMPOSITIONS patients. Enormous numbers of MAC are found (up to 10' AND METHODS acid-fast bacilli per gram of tissue), and consequently, the prognosis for the infected AIDS patient is poor. CROSS REFERENCE TO RELATED PATENT 0006 The World Health Organization (WHO) continues APPLICATIONS to encourage the battle against TB, recommending preven 0001. The present application is a continuation-in-part tion initiatives Such as the “Expanded Program on Immu application of pending U.S. patent application Ser. No. nization” (EPI), and therapeutic compliance initiatives Such 10/147.587 filed May 17, 2002. The present application also as “Directly Observed Treatment Short-Course” (DOTS). claims priority to U.S. Provisional Patent Application Serial For the eradication of TB, diagnosis, treatment, and preven No. 60/381,220 filed May 17, 2002. tion are equally important. Rapid detection of active TB patients will lead to early treatment by which about 90% FIELD OF INVENTION cure is expected. Therefore, early diagnosis is critical for the 0002 The present invention relates to methods and com battle against TB. In addition, therapeutic compliance will positions for treating disease caused by microorganisms, ensure not only elimination of infection, but also reduction particularly tuberculosis. The present invention also relates in the emergence of drug-resistance Strains. to methods and compositions having improved anti-myco 0007. The emergence of drug-resistant M. tuberculosis is bacterial activity, namely compositions comprising novel an extremely disturbing phenomenon. The rate of new TB Substituted ethylene diamine compounds. cases proven resistant to at least one Standard drug increased from 10 percent in the early 1980s to 23 percent in 1991. BACKGROUND OF THE INVENTION Compliance with therapeutic regimens, therefore, is also a crucial component in efforts to eliminate TB and prevent the 0.003 Mycobacterial infections often manifest as diseases emergence of drug resistant Strains. Equally important is the Such as tuberculosis. Human infections caused by mycobac development of new therapeutic agents that are effective as teria have been widespread since ancient times, and tuber vaccines, and as treatments, for disease caused by drug culosis remains a leading cause of death today. Although the resistant Strains of mycobacteria. incidence of the disease declined, in parallel with advancing Standards of living, Since the mid-nineteenth century, myco 0008 Although over 37 species of mycobacteria have bacterial diseases still constitute a leading cause of morbid been identified, more than 95% of all human infections are ity and mortality in countries with limited medical caused by Six Species of mycobacteria: M. tuberculosis, M. resources. Additionally, mycobacterial diseases can cause avium intracellulare, M. kansasii, M. fortuitum, M. chelo overwhelming, disseminated disease in immunocompro nae, and M. leprae. The most prevalent mycobacterial mised patients. In Spite of the efforts of numerous health disease in humans is tuberculosis (TB) which is predomi organizations worldwide, the eradication of mycobacterial nantly caused by mycobacterial Species comprising M. diseases has never been achieved, nor is eradication immi tuberculosis, M. bovis, or M. africanum (Merck Manual nent. Nearly one third of the world's population is infected 1992). Infection is typically initiated by the inhalation of with mycobacterium tuberculosis complex, commonly infectious particles which are able to reach the terminal referred to as tuberculosis (TB), with approximately 8 pathways in lungs. Following engulfment by alveolar mac million new cases, and two to three million deaths attribut rophages, the bacilli are able to replicate freely, with even able to TB yearly. Tuberculosis (TB) is the cause of the tual destruction of the phagocytic cells. A cascade effect largest number of human deaths attributable to a single ensues wherein destruction of the phagocytic cells causes etiologic agent (see Dye et al., J. Am. Med. ASSociation, 282, additional macrophages and lymphocytes to migrate to the 677-686, (1999); and 2000 WHO/OMS Press Release). Site of infection, where they too are ultimately eliminated. The disease is further disseminated during the initial Stages 0004. After decades of decline, TB is now on the rise. In by the infected macrophages which travel to local lymph the United States, up to 10 million individuals are believed nodes, as well as into the blood Stream and other tissueS Such to be infected. Almost 28,000 new cases were reported in as the bone marrow, Spleen, kidneyS, bone and central 1990, constituting a 9.4 percent increase over 1989. A nervous system. (See Murray et al. Medical Microbiology, Sixteen percent increase in TB cases was observed from The C. V. Mosby Company 219-230 (1990)). 1985 to 1990. Overcrowded living conditions and shared air Spaces are especially conducive to the spread of TB, con 0009. There is still no clear understanding of the factors tributing to the increase in instances that have been observed which contribute to the virulence of mycobacteria. Many among prison inmates, and among the homeless in larger investigators have implicated lipids of the cell wall and U.S. cities. Approximately half of all patients with bacterial Surface as contributors to colony morphology and “Acquired Immune Deficiency Syndrome' (AIDS) will Virulence. Evidence Suggests that C-mycosides, on the Sur acquire a mycobacterial infection, with TB being an espe face of certain mycobacterial cells, are important in facili cially devastating complication. AIDS patients are at higher tating Survival of the organism within macrophageS. Treha risks of developing clinical TB, and anti-TB treatment seems lose 6,6' dimycolate, a cord factor, has been implicated for to be less effective than in non-AIDS patients. Consequently, other mycobacteria. the infection often progresses to a fatal disseminated disease. 0010. The interrelationship of colony morphology and 0005) Mycobacteria other than M. tuberculosis are Virulence is particularly pronounced in M. avium. M. avium increasingly found in opportunistic infections that plague the bacilli occur in several distinct colony forms. Bacilli which AIDS patient. Organisms from the M. avium-intracellulare grow as transparent, or rough, colonies on conventional complex (MAC), especially Serotypes four and eight, laboratory media are multiplicable within macrophages in account for 68% of the mycobacterial isolates from AIDS tissue culture, are virulent when injected into Susceptible US 2004/0033986 A1 Feb. 19, 2004 mice, and are resistant to antibiotics. Rough or transparent throughout the Six-month course of therapy, are isoniazid bacilli, which are maintained on laboratory culture media, and rifampin. Although the regimen is relatively simple, its often Spontaneously assume an opaque R colony morphol administration is quite complicated. Daily ingestion of eight ogy, at which time they are not multiplicable in macroph or nine pills is often required during the first phase of ages, are avirulent in mice, and are highly Susceptible to therapy; a daunting and confusing prospect. Even Severely antibiotics. The differences in colony morphology between ill patients are often Symptom free within a few weeks, and the transparent, rough and opaque Strains of M. avium are nearly all appear to be cured within a few months. If the almost certainly due to the presence of a glycolipid coating treatment is not continued to completion, however, the on the Surface of transparent and rough organisms which patient may experience a relapse, and the relapse rate for acts as a protective capsule. This capsule, or coating, is patients who do not continue treatment to completion is composed primarily of C-mycosides which apparently high. A variety of forms of patient-centered care are used to Shield the virulent M. avium organisms from lysosomal promote adherence with therapy. The most effective way of enzymes and antibiotics. By contrast, the non-virulent ensuring that patients are taking their medication is to use opaque forms of M. avium have very little C-mycoside on directly observed therapy, which involves having a member their Surface. Both the resistance to antibiotics and the of the health care team observe the patient take each dose of resistance to killing by macrophages have been attributed to each drug. Directly observed therapy can be provided in the the glycolipid barrier on the Surface of M. avium. clinic, the patient's residence, or any mutually agreed upon site. Nearly all patients who have tuberculosis caused by 0.011 Diagnosis of mycobacterial infection is confirmed drug-Sensitive organisms, and who complete therapy will be by the isolation and identification of the pathogen, although cured, and the risk of relapse is very low ("Ending Neglect: conventional diagnosis is based on Sputum Smears, chest The Elimination of Tuberculosis in the United States' ed. L. X-ray examination (CXR), and clinical Symptoms. Isolation Geiter Committee on the Elimination of Tuberculosis in the of mycobacteria on a medium takes as long as four to eight United States Division of Health Promotion and Disease weeks. Species identification takes a further two weeks. There are Several other techniques for detecting mycobac Prevention, Institute of Medicine. Unpublished.) teria Such as the polymerase chain reaction (PCR), myco 0015 What is needed are effective therapeutic regimens bacterium tuberculosis direct test, or amplified mycobacte that include improved vaccination and treatment protocols. rium tuberculosis direct test (MTD), and detection assays Currently available therapeutics are no longer consistently that utilize radioactive labels. effective as a result of the problems with treatment compli ance, and these compliance problems contribute to the 0012 One diagnostic test that is widely used for detecting development of drug resistant mycobacterial Strains. infections caused by M. tuberculosis is the tuberculin skin test. Although numerous versions of the skin test are avail 0016 Ethambutol (EMB) is a widely used antibiotic for able, typically one of two preparations of tuberculin antigens the treatment of TB, with over 300 million doses delivered are used: old tuberculin (OT), or purified protein derivative for tuberculosis therapy in 1988. (PPD). The antigen preparation is either injected into the skin intradermally, or is topically applied and is then inva Sively transported into the Skin with the use of a multiprong OH inoculator (Tine test). Several problems exist with the skin HN test diagnosis method. For example, the Tine test is not n1n NH generally recommended because the amount of antigen injected into the intradermal layer cannot be accurately controlled. (See Murray et al. Medical Microbiology, The C. HO V. Mosby Company 219–230 (1990)). Ethambutol 0013 Although the tuberculin skin tests are widely used, they typically require two to three days to generate results, 0017 Ethambutol, developed by Lederle Laboratories in and many times, the results are inaccurate Since false posi the 1950s, has low toxicity and is a good pharmacokinetic. tives are Sometimes Seen in Subjects who have been exposed However, ethambutol has a relatively high Minimum Inhi to mycobacteria, but are healthy. In addition, instances of bition Concentration (MIC) of about 5ug/ml, and can cause mis-diagnosis are frequent Since a positive result is observed optic neuritis. Thus, there is an increasing need for new, and not only in active TB patients, but also in perSons vaccinated more effective, therapeutic compositions (See for example, with Bacille Calmette-Guerin (BCG), and those who had U.S. Pat. No. 3,176,040, U.S. Pat. No. 4,262,122; U.S. Pat. been infected with mycobacteria, but have not developed the No. 4,006,234; U.S. Pat. No. 3,931,157; U.S. Pat. No. disease. It is hard therefore, to distinguish active TB patients 3,931,152; U.S. Pat. No. Re. 29.358; and Häusler et al., from the others, such as household TB contacts, by the Bioorganic & Medicinal Chemistry Letters 11 (2001) 1679 tuberculin skin test. Additionally, the tuberculin test often 1681). In the decoder years since the discovery of the produces a croSS-reaction in those individuals who were beneficial effects of ethambutol, few pharmacological infected with mycobacteria other than M. tuberculosis advances in TB treatment have been developed. Moreover, (MOTT). Therefore, diagnosis using the skin tests currently with the combined emergence of drug resistant Strains, and available is frequently Subject to error and inaccuracies. the more prevalent spread of mycobacterial disease, it is 0.014. The standard treatment for tuberculosis caused by becoming Seriously apparent that new therapeutic composi drug-Sensitive organisms is a six-month regimen consisting tions are crucial in the fight against tuberculosis. of four drugs given for two months, followed by two drugs 0018 Clearly effective therapeutic regimens that include given for four months. The two most important drugs, given improved vaccination and treatment protocols are needed. A US 2004/0033986 A1 Feb. 19, 2004 therapeutic Vaccine that would prevent the onset of tuber tion, the methods and compositions comprise Substituted culosis, and therefore eliminate the need for therapy is ethylene diamines with HTS Luc activity of 10% or greater. desirable. Although currently available therapeutics Such as In yet another embodiment of the present invention, the ethambutol are effective, the emergence of drug resistant methods and compositions comprise Substituted ethylene Strains has necessitated new formulations and compositions diamines, wherein one amine group is derived from a that are more versatile than ethambutol. Currently available primary amine, and wherein the other amine group is therapeutics are no longer consistently effective as a result of derived from a primary or Secondary amine. In another the problems with treatment compliance, lending to the embodiment of the present invention, the methods and development of drug resistant mycobacterial Strains. What is compositions comprise Substituted ethylene diamines, needed are new anti-tubercular drugs that provide highly wherein one amine is derived from cis-(-)myrtanylamine, effective treatment, and shorten or Simplify tuberculosis cyclooctylamine, 2,2-diphenylethylamine, 3,3-diphenylpro chemotherapy. pylamine, (+)-bornylamine, 1-adamantanemethylamine, (+)-isopinocampheylamine; or (-)-isopinocampheylamine. SUMMARY OF THE INVENTION 0023 The present invention contemplates various salt 0019. The present invention comprises methods and complexes and other substituted derivatives of the substi compositions comprising ethylene diamine compounds tuted ethylene diamines. The present invention also contem effective for the treatment of infectious disease. The present plates enantiomers and other Stereoisomers of the Substituted invention also provides methods and compositions compris ethylene diamines and their substituted derivatives. The ing Substituted ethylene diamines having improved anti present invention further contemplates treatment for ani mycobacterial activity, including Substituted ethylene mals, including, but not limited to, humans. diamines having improved anti-tuberculosis activity. 0024. Accordingly, it is an object of the present invention 0020. The present invention contemplates substituted to provide methods and compositions for the treatment and ethylene diamines, which can derive from a variety of amine prevention of diseases caused by microorganisms. compounds. In the present invention, the Substituted ethyl 0025. Accordingly, it is an object of the present invention ene diamines are based on the following structure. to provide methods and compositions for the treatment and prevention of infectious diseases. 0026. Another object of the present invention is to pro vide methods and compositions for the treatment and pre RN-N NR2R3 vention of mycobacterial disease, including but not limited to, tuberculosis. Substituted Ethylene Diamine 0027 Yet another object of the present invention is to provide methods and compositions for the treatment and 0021. The Substituted ethylene diamine compounds prevention of infectious diseases using compositions com described herein are Synthesized and Screened for activity as prising Substituted ethylene diamines. follows. A chemical library of substituted ethylene diamines 0028. Another object of the present invention is to pro is prepared on a Solid polystyrene Support using Split and vide methods and compositions for the treatment and pre pool technologies. This technique allows for the Synthesis of vention of mycobacterial disease using compositions com a diverse set of Substituted ethylene diamines. These prising Substituted ethylene diamines. diamines are Screened for anti-TB activity using in vitro, 0029 Still another object of the present invention is to biological assays, including a High-Throughput Screening provide methods and compositions for the treatment and (HTS) assay, based on the recently completed genomic prevention of tuberculosis using compositions comprising sequence of M. tuberculosis, and a Minimum Inhibition Concentration (MIC) assay. Substituted ethylene diamines. 0022. The methods and compositions described herein 0030. Another object of the present invention is to pro comprise Substituted ethylene diamines that are effective vide methods and compositions for the treatment and pre against disease caused by infectious organisms, including, vention of tuberculosis using compositions comprising Sub but not limited to, bacteria and viruses. One embodiment of stituted ethylene diamines, wherein the diamine has an MIC the invention provides methods and compositions compris of 50 uM, or less. ing Substituted ethylene diamines that are effective against 0031) Another object of the present invention is to pro mycobacterial disease. Another embodiment of the inven vide methods and compositions for the treatment and pre tion provides methods and compositions comprising Substi vention of tuberculosis using compositions comprising Sub tuted ethylene diamines that have MIC of 50 uM or lower for stituted ethylene diamines, wherein the diamine has an MIC mycobacterial disease. Another embodiment of the present of 25 uM, or less. invention comprises Substituted ethylene diamines that have an MIC of 25 uM or lower for mycobacterial disease. Yet 0032) Another object of the present invention is to pro another embodiment of the present invention comprises vide methods and compositions for the treatment and pre substituted ethylene diamines that have an MIC of 12.5 uM vention of tuberculosis using compositions comprising Sub or lower for mycobacterial disease. Another embodiment of stituted ethylene diamines, wherein the diamine has an MIC the present invention comprises Substituted ethylene of 12.5 uM, or less. diamines that have an MIC of 5 uM or lower for mycobac 0033 Yet another object of the present invention is to terial disease In another embodiment of the present inven provide methods and compositions for the treatment and US 2004/0033986 A1 Feb. 19, 2004 prevention of tuberculosis using compositions comprising 0048 FIG. 9 is a bar graph providing a summary of MIC Substituted ethylene diamines, wherein the diamine has an activities for discrete Substituted ethylene diamines. MIC of 5 uM, or less. 0049 FIG. 10 is a bar graph providing a summary of 0034). Yet another object of the present invention is to Luciferase activity of discrete Substituted ethylene diamines provide methods and compositions for the treatment and with at least 10% activity in reference to ethambutol at 3.1 prevention of tuberculosis using compositions comprising luM. Substituted ethylene diamines, wherein the diamine has 0050 FIG. 11 is a bar graph showing the frequency of HTS/Luc activity of 10% or greater. occurrences of the Selected amine monomers in the Substi 0.035 Another object of the present invention is to pro tuted ethylene diamine compounds that were active against vide methods and compositions for the treatment and pre TB. Amine monomers are represented by their numerical vention of tuberculosis using compositions comprising Sub designations. Stituted ethylene diamines, wherein one amine group is 0051 FIG. 12 represents a flow schematic showing a derived from a primary amine, and the other amine group is synthesis of N-Geranyl-N'-(2-adamanthyl)ethane-1,2-di derived from a primary or Secondary amine. amine (compound 109). 0.036 Yet another object of the present invention is to provide methods and compositions for the treatment and/or 0052 FIG. 13 is a flow schematic showing a synthesis of prevention of tuberculosis using compositions comprising N-(Cyclooctyl)-N'-(1R, 2R, 3R, 5S)-(–)-isopinocamphey Substituted ethylene diamines, wherein one amine is derived letbane-1,2-diamine as hydrochloride (compound 59). from cis-(-)myrtanylamine, cyclooctylamine, 2,2-diphenyl 0053 FIG. 14 is a mass spec profile for one representa ethylamine, 3,3-diphenylpropylamine, (+)-bornylamine, tive Sample well containing pooled Substituted ethylene 1-adamantanemethylamine, (+)-isopinocampheylamine; or diamine compounds. (-)-isopinocampheylamine. 0054 FIG. 15 is a mass spec profile for compound 109, 0037 Yet another object of the present invention is to N-Geranyl-N'-(2-adamanthyl)ethane-1,2-diamine. provide composition for the therapeutic formulation for the 0055 FIG. 16 is a proton NMR profile for compound treatment and prevention of mycobacterial disease. 109, N-Geranyl-N'-(2-adamanthyl) ethane-1,2-diamine. 0.038 Another object of the present invention is to pro vide compositions for therapeutic formulations for the treat 0056 FIG. 17 is a bar graph of data from a Colony ment and prevention of mycobacterial disease caused by Forming Units/Lung (CFU/Lung) study showing CFU/Lung mycobacterial Species comprising M. tuberculosis complex, growth over time in days for various compounds. M. avium intracellulare, M. kansarii, M. fortuitum, M. 0057 FIG. 18 is a bar graph of data from a CFU/Lung chelonoe, M. leprae, M. africanum, M. microti, or M. bovis. study showing CFU/Lung growth over time in days for 0.039 These and other objects, features and advantages of various compounds. the present invention will become apparent after a review of 0.058 FIG. 19 is a bar graph of data from a CFU/Lung the following detailed description of the disclosed embodi study showing CFU/Lung growth over time in days for ments and the appended claims. various compounds. BRIEF DESCRIPTION OF THE FIGURES 0059 FIG. 20 is a bar graph of data from a lesion study 0040 FIG. 1 represents a flow chart schematic showing showing visible lesions over time after treatment with vari various Solid Support Syntheses used to prepare Substituted ous compounds. ethylene diamines. 0060 FIG. 21 provides a schematic demonstrating the 0041 FIGS. 2(a)-2(ac) provide chemical structures of a identification of a drug candidate variety of primary amines. 0061 FIG.22 provides the compounds tested for in vivo 0.042 FIGS. 3(a)-3(f) provide chemical structures of a efficacy. variety of acyclic Secondary amines. 0062 FIG. 23 is a graph showing the results of in vivo 0043 FIGS. 4(a)-4(i) provide chemical structures of a studies of compounds 73 and 109 at 1 and 10 mg/kg doses variety of cyclic Secondary amines. (spleen). 0044 FIG. 5 represents a flow schematic for a represen 0063 FIG. 24 is a graph showing the results of in vivo tative reaction pool of ten Substituted ethylene diamines. studies of compounds 73 and 109 at 1 and 10 mg/kg doses (lungs). 004.5 FIG. 6 is a graph of Luminescence Count per Second (LCPS) versus concentration showing HTS Luc 0064 FIG. 25 is a graph showing in vivo studies of assay results for pooled Substituted ethylene diamine com compounds 59 and 111 at 1 and 10 mg/kg doses (spleen). pounds. 0065 FIG. 26 is a graph showing in vivo studies of 0046 FIG. 7 is a graph of LCPS versus concentration compounds 59 and 111 at 1 and 10 mg/kg doses (lungs). showing HTS Luc assay results for individual substituted 0066 FIG. 27 is a graph showing the results of efficacy ethylene diamine compounds. testing of the compounds 58, 73, 109, and 111 in C57BL.6 0047 FIG. 8 is a graph of LCPS versus concentration mice infected with M. tuberculosis H37RV (spleen). Mice showing HTS Luc assay results for individual substituted were infected i.v. with 5x10 CFU M. tuberculosis H37Rv; ethylene diamine compounds. treatment with drugs started 18 days following infection. EC