List of phenyltropanes

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Phenyltropanes are a family of chemical compounds originally derived from structural modification of cocaine. These compounds present many different avenues of research into therapeutic applications, particularly in addiction treatment. Uses vary depending on their construction and structure-activity relationship ranging from the treating of cocaine dependency to understanding the dopamine reward system in the human brain to treating Alzheimer's & Parkinson's diseases. More recently there have been continual additions to the list and enumerations of the plethora of types of chemicals that fall into the category of this substance profile. Many of the compounds were first elucidated in published material by the Research Triangle Institute (RTI) and are thus so named. Similarly, a number of others are named for Sterling-Winthrop pharmaceuticals (WIN) & Wake Forest University (WF).

Phenyltropane.gif

2-Carboxymethyl esters[edit]

Certain phenyltropanes can be used as a smoking cessation aid. Blank spacings within tables for omitted data use "no data", "?", "-" or "" interchangeably.

Troparil structure: c.f. U.S. Patent 5,496,953
WIN 35,065-2.svg
RTI-298.svg
RTI-11W.svg
Tamagnan:[1] pM activity for SERT
Selected Phenyltropanes
Short Name X DA 5HT NE
WIN 35,065-2 (CPT) H 23 1962 920
WIN 35,428 (CFT) F 14 156 85
 ? NO2 10.1 ? ?
RTI-29[2] NH2 9.8 5110 151
RTI-31 Cl 1.12 44.5 37
RTI-32 Me 1.71 240 60
RTI-51 Br 1.69 10.6 37.4
Iometopane (RTI-55) I 1.26 4.21 36
RTI-83 Et 55 28.4 4030
RTI-11w cis-propenyl 15 7.1 28,000
RTI-298[3] –≡–Ph 3.7 46.8 347
RTI-436 –CH=CHPh 3.09 335 (31) 1960 (1181)
RTI-430 –C≡C(CH2)2Ph 6.28 2128 (198) 1470 (886)
Tamagnan[1] p-thiophene 12 0.017 189
Meta-substituted 2β-carbomethoxy-3α-(4′-substituted phenyl)tropanes[4]
Compound Short Name
(S. Singh)
Y X DA 5HT NE Selectivity
5-HTT/DAT
Selectivity
NET/DAT
16and17SSinghPhenyltropanes.png
16a F H 23 ± 7.8 - - - -
16b Cl H 10.6 ± 1.8 - - - -
16c Br H 7.93 ± 0.08
IC50 determined in
Cynomolgous monkey
caudate-putamen
- - - -
16d I H 26.1 ± 1.7 - - - -
16e SnBu3 H 1100 ± 170 - - - -
17a CH3 F 2.95 ± 0.58 - - - -
17b CH3 Cl 0.81 ± 0.05 10.5 ± 0.05 36.2 ± 1.0 13.0 44.7
17c Cl Cl 0.79 ± 0.08 3.13 ± 0.36 18.0 ± 0.8 4.0 22.8
17d Br NH2 3.91 ± 0.59 - - - -
17e I NH2 1.35 ± 0.11 120 ± 4 1329 ± 124 88.9 984
17f I N3 4.93 ± 0.32 - - - -

(3,4-Disubstituted phenyl)-tropanes[edit]

RTI-318 structure.png
RTIthreefivethree.png
Compound X Y 2 Position config 8 DA 5-HT NE
RTI-318 β-naphthyl CO2Me β,β NMe 0.5 0.81 20
Dichloropane (RTI-111) Cl Cl CO2Me β,β NMe 0.79 3.13 18.0
RTI-88 [recheck] NH2 I CO2Me β,β NMe 1.35 1329 320
RTI-97 NH2 Br CO2Me β,β NMe 3.91 181 282
RTI-112 Cl Me CO2Me β,β NMe 0.82 10.5 36.2
RTI-96 F Me CO2Me β,β NMe 2.95 76 520
RTI-295 Et I CO2Me β,β NMe 21.3 2.96 1349
RTI-353 (EINT) Et I CO2Me β,β NH 331 0.69 148
RTI-279 Me I CO2Me β,β NH 5.98 1.06 74.3
RTI-280 Me I CO2Me β,β NMe 3.12 6.81 484
Meltzer[5] catechol CO2Me β,β NMe >100 ? ?
Meltzer[5] OAc OAc CO2Me β,β NMe ? ? ?
Meta-substituted structures of 2β-ester-3β-phenyltropanes[4]
Compound Short Name
(S. Singh)
R X IC50 (nM)
DAT
[3H]WIN 35428
IC50 (nM)
5-HTT
[3H]paroxetine
IC50 (nM)
NET
[3H]nisoxetine
Selectivity
5-HTT/DAT
Selectivity
NET/DAT
2β-ester-3β-phenyltropaneSeries23a—26k.png
23a CH(CH3)2 H 85.1 ± 2.5 23121 ± 3976 32047 ± 1491 272 376
23b C6H5 H 76.7 ± 3.6 106149 ± 7256 19262 ± 593 1384 251
24a CH(CH3)2 Cl 1.4 ± 0.13
6.04 ± 0.31ɑ
1400 ± 7
128 ± 15b
778 ± 21
250 ± 0.9c
1000
21.2d
556
41.4e
24b cyclopropyl Cl 0.96 ± 0.10 168 ± 1.8 235 ± 8.39 175 245
24c C6H5 Cl 1.99 ± 0.05
5.25 ± 0.76ɑ
2340 ± 27
390 ± 34b
2960 ± 220
242 ± 30c
1176
74.3d
1.3
41.6e
24d C6H4-4-I Cl 32.6 ± 3.9 1227 ± 176 967.6 ± 26.3 37.6 29.7
24e C6H4-3-CH3 Cl 9.37 ± 0.52 2153 ± 143 2744 ± 140 230 293
24f C6H4-4-CH3 Cl 27.4 ± 1.5 1203 ± 42 1277 ± 118 43.9 46.6
24g C6H4-2-CH3 Cl 3.91 ± 0.23 3772 ± 384 4783 ± 387 965 1223
24h C6H4-4-Cl Cl 55 ± 2.3 16914 ± 1056 4883 ± 288 307 88.8
24i C6H4-4-OCH3 Cl 71 ± 5.6 19689 ± 1843 1522 ± 94 277 21.4
24j (CH2)2C6H4-4-NO2 Cl 2.71 ± 0.13 - - - -
24k (CH)2C6H4-4-NH2 Cl 2.16 ± 0.25 - - - -
24l (CH2)2C6H3-3-I-4-NH2 Cl 2.51 ± 0.25 - - - -
24m (CH2)2C6H3-3-I-4-N3 Cl 14.5 ± 0.94 - - - -
24n (CH2)2C6H4-4-N3 Cl 6.17 ± 0.57 - - - -
24o (CH2)2C6H4-4-NCS Cl 5.3 ± 0.6 - - - -
24p (CH2)2C6H4-4-NHCOCH2Br Cl 1.73 ± 0.06 - - - -
25a CH(CH3)2 I 0.43 ± 0.05
2.79 ± 0.13ɑ
66.8 ± 6.53
12.5 ± 1.0b
285 ± 7.6
41.2 ± 3.0c
155
4.5d
663
14.8e
25b cyclopropyl I 0.61 ± 0.08 15.5 ± 0.72 102 ± 11 25.4 167
25c C6H5 I 1.51 ± 0.34
6.85 ± 0.93ɑ
184 ± 22
51.6 ± 6.2b
3791 ± 149
32.7 ± 4.4c
122
7.5d
2510
4.8e
26a CH(CH3)2 CH3 6.45 ± 0.85
15.3 ± 2.08ɑ
6090 ± 488
917 ± 54b
1926 ± 38
73.4 ± 11.6c
944
59.9d
299
4.8e
26b CH(C2H5)2 CH3 19.1 ± 1 4499 ± 557 3444 ± 44 235 180
26c cyclopropyl CH3 17.8 ± 0.76 485 ± 21 2628 ± 252 27.2 148
26d cyclobutyl CH3 3.74 ± 0.52 2019 ± 133 4738 ± 322 540 1267
26e cyclopentyl CH3 1.68 ± 0.14 1066 ± 109 644 ± 28 634 383
26f C6H5 CH3 3.27 ± 0.06
9.13 ± 0.79ɑ
24500 ± 1526
1537 ± 101b
5830 ± 370
277 ± 23c
7492
168d
1783
30.3e
26g C6H4-3-CH3 CH3 8.19 ± 0.90 5237 ± 453 2136 ± 208 639 261
26h C6H4-4-CH3 CH3 81.2 ± 16 15954 ± 614 4096 ± 121 196 50.4
26i C6H4-2-CH3 CH3 23.2 ± 0.97 11040 ± 504 25695 ± 1394 476 1107
26j C6H4-4-Cl CH3 117 ± 7.9 42761 ± 2399 9519 ± 864 365 81.3
26k C6H4-4-OCH3 CH3 95.6 ± 8.8 82316 ± 7852 3151 ± 282 861 33.0

ɑKi value for displacement of [3H]DA uptake. bKi value for displacement of [3H]5-HT uptake. cKi value for displacement of [3H]NE uptake. d[3H]5-HT uptake to [3H]DA uptake ratio. e[3H]NE uptake to [3H]DA uptake ratio.

2β-Carboxamide-3β-Phenyltropanes[4]
Compound Short Name
(S. Singh)
R X IC50 (nM)
DAT
[3H]WIN 35428
IC50 (nM)
5-HTT
[3H]Paroxetine
IC50 (nM)
NET
[3H]Nisoxetine
Selectivity
5-HTT/DAT
Selectivity
NET/DAT
29a NH2 CH3 41.8 ± 2.45 6371 ± 374 4398 ± 271 152 105
29b N(CH2CH3)2 CH3 24.7 ± 1.93 33928 ± 2192 6222 ± 729 1374 252
29c N(OCH3)CH3 CH3 2.55 ± 0.43 3402 ± 353 422 ± 26 1334 165
29d 4-morpholine CH3 11.7 ± 0.87 >100000 23601 ± 1156 >8547 2017

Carboxyaryl[edit]

RTI-204 structure.png
Compound X 2 Position config 8 DA 5-HT NE
RTI-122 I -CO2Ph β,β NMe 1.50 184 3,791
RTI-113 Cl -CO2Ph β,β NMe 1.98 2,336 2,955
RTI-277 NO2 -CO2Ph β,β NMe 5.94 2,910 5,695
RTI-120 [recheck] Me -CO2Ph β,β NMe 3.26 24,471 5,833
RTI-116 Cl -CO2(p-C6H4I) β,β NMe 33 1,227 968
RTI-203 Cl CO2(m-C6H4Me) β,β NMe 9.37 2153 2744
RTI-204 Cl -CO2(o-C6H4Me) β,β NMe 3.91 3,772 4,783
RTI-205 Me -CO2(m-C6H4Me) β,β NMe 8.19 5,237 2,137
RTI-206 Cl -CO2(p-C6H4Me) β,β NMe 27.4 1,203 1,278

Carboxyalkyl[edit]

RTI-77 structure.png
Code X 2 Position config 8 DA 5-HT NE
RTI-77 Cl CH2C2(3-iodo-p-anilino) β,β NMe 2.51 2247
RTI-121 I -CO2Pri β,β NMe 0.43 66.8 285
RTI-153 I -CO2Pri β,β NH 1.06 3.59 132
RTI-191 I -CO2Prcyc β,β NMe 0.61 15.5 102
RTI-114 Cl -CO2Pri β,β NMe 1.40 1,404 778
RTI-278 NO2 -CO2Pri β,β NMe 8.14 2,147 4,095
RTI-190 Cl -CO2Prcyc β,β NMe 0.96 168 235
RTI-193 Me -CO2Prcyc β,β NMe 1.68 1,066 644
RTI-117 Me -CO2Pri β,β NMe 6.45 6,090 1,926
RTI-150 Me -CO2Bucyc β,β NMe 3.74 2,020 4,738
RTI-127 Me -CO2C(H)Et2 β,β NMe 19 4500 3444
RTI-338 ethyl -CO2C2Ph β,β NMe 1104 7.41 3366

Use of a cyclopropyl ester appears to enable better MAT retention than does the choice of isopropyl ester.

Use of a cycBu resulted in greater DAT selectivity than did the cycPr homologue.

Amides[edit]

U.S. Patent 5,736,123 RTI-183 and RTI-218 have the same structure??

RTI-183 structure.png
RTI-229 structure.png
RTI-227 structure.png
Code X 2 Position config 8 DA NE 5-HT
RTI-106 Cl CON(H)Me β,β NMe 12.4 1511 1312
RTI-118 Cl CONH2 β,β NMe 11.5 4267 1621
RTI-222 Me morpholinyl β,β NMe 11.7 >100K
RTI-129 Cl CONMe2 β,β NMe 1.38 942 1079
RTI-146 Cl CONHCH2OH β,β NMe 2.05 144 98
RTI-147 Cl CON(CH2)4 β,β NMe 1.38 3,949 12,394
RTI-156 Cl CON(CH2)5 β,β NMe 6.61 5832 3468
RTI-170 Cl CON(H)CH2C≡CH β,β NMe 16.5 1839 4827
RTI-172 Cl CON(H)NH2 β,β NMe 44.1 3914 3815
RTI-174 Cl CONHCOMe β,β NMe 158 >43K >125K
RTI-182 Cl CONHCH2COPh β,β NMe 7.79 1722 827
RTI-183 Cl CON(OMe)Me β,β NMe 0.85 549 724
RTI-186 Me CON(OMe)Me β,β NMe 2.55 442 (266) 3400 (309)
RTI-198 Cl CON(CH2)3 β,β NMe 6.57 990 813
RTI-196 Cl CONHOMe β,β NMe 10.7 9907 >43K
RTI-201 Cl CONHNHCOPh β,β NMe 91.8 >20K >48K
RTI-208 Cl CONO(CH2)3 β,β NMe 1.47 998 2470
RTI-214 Cl CON(-CH2CH2-)2O β,β NMe 2.90 8545 >88K
RTI-215 Cl CONEt2 β,β NMe 5.48 ? 9432
RTI-217 Cl CONH(m-C6H4OH) β,β NMe 4.78 >30K >16K
RTI-218 Cl CON(Me)OMe β,β NMe 1.19 520 1911
RTI-226 Cl CONMePh β,β NMe 45.0 ? 24K
RTI-227 I CONO(CH2)3 β,β NMe 0.75 446 230
RTI-229[6] I CON(CH2)4 β,β NMe 0.37 991 1,728

Acyl[edit]

# X Y 2 Position config 8 DA 5-HT NE
WF-23 β-naphthyl C(O)Et β,β NMe 0.115 0.394 No data
WF-31 -Pri H C.O.Et β,β NMe 615 54.5 No data
WF-11 Me H -C.O.Et β,β NMe 8.2 131 No data
WF-25 H H -C.O.Et β,β NMe 48.3 1005 No data
WF-33 6-MeoBN C(O)Et α,β NMe 0.13 2.24 No data

Ester reduction[edit]

Note: p-fluorophenyl is weaker than the others. RTI-145 is not peroxy, it is a methylcarbonate.

RTI-123 structure.png
Code X 2 Position config 8 DA 5-HT NE
RTI-100 F -CH2OH β,β NMe 47 4741 no data
RTI-101 I -CH2OH β,β NMe 2.2 26 no data
RTI-99 Br -CH2OH β,β NMe 1.49 51 no data
RTI-93 Cl -CH2OH β,β NMe 1.53 204 43.8
RTI-105 Cl -CH2OAc β,β NMe 1.60 143 127
RTI-123 Cl -CH2OBz β,β NMe 1.78 3.53 393
RTI-145 Cl -CH2OCO2Me β,β NMe 9.60 2.93 1.48
[125I]IPT:
N-3-iodoprop-(2E)-ene-2β-carbomethoxy-3β-(4′-chlorophenyl)tropane.

A common radio-labeling research compound used as a ligand to map MAT.

β,α Stereochemistry[edit]

RTI-319 structure.png
Compound X 2 Group config 8 DA 5-HT NE
RTI-140 H CO2Me β,α NMe 101 5,701 2,076
RTI-352 U.S. Patent 6,358,492 I CO2Me β,α NMe 2.86 64.9 52.4
RTI-549 Br CO2Me β,α NMe
RTI-319 U.S. Patent 7,011,813 BN CO2Me β,α NMe 1.1 11.4 70.2
RTI-286 U.S. Patent 7,011,813 F CO2Me β,α NMe 21 5062 1231
RTI-274 U.S. Patent 7,291,737 F CH2O(3′,4′-MD-phenyl) β,α NH 3.96 5.62 14.4
RTI-287 Et CO2Me β,α NMe 327 1687 17,819

α,β Stereochemistry[edit]

CA 2112084 

Brasofensine.svg
Compound DA (μM) M.E.D. (mg/kg) Dose(mg/kg) Activity Activity
(2R,3S)-2-(4-chlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane 0.39 <1 50 0 0
(2R,3S)-2-(carboxymethyl)-8-methyl-3-(2-naphthyl)-8-azabicyclo[3.2.1]octane 0.1 1 25 0 0
(2R,3S)-2-(carboxymethyl)-8-methyl-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane 0.016 0.25 50 + +++
Tesofensine chemical structure.png

U.S. Patent 2,001,047,028

Compound X 2 Group config 8 DA 5-HT NE
Brasofensine Cl2 methyl aldoxime α,β NMe
Tesofensine Cl2 ethoxymethyl α,β NMe 65 11 1.7
NS-2359 (GSK-372,475) Cl2 Methoxymethyl α,β NH

A1 WO 2004072075 A1 

Test Compound DA uptake IC50(μM) NA uptake IC50(μM) 5-HT uptake IC50(μM)
(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt 0.062 0.035 0.00072
(2R,3S)-2-(Naphthaleneoxymethane)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt 0.062 0.15 0.0063
(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-H-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt 0.10 0.048 0.0062
(2R,3S)-2-(Naphthlyloxymethane)-8-H-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt 0.088 0.051 0.013

Aryl-Tropenes[edit]

WO2004113297 

Test compound DA-uptake IC50(μM) NA-uptake IC50(μM) 5-HT-uptake IC50(μM)
(+)-3-(4-Chlorophenyl)-8-H-aza-bicyclo[3.2.1]oct-2-ene 0.26 0.028 0.010
(+)-3-Napthalen-2-yl-8-azabicyclo[3.2.1]oct-2-ene 0.058 0.013 0.00034
(–)-8-Methyl-3-(naphthalen-2-yl)-8-azabicylo[3.2.1]oct-2-ene 0.034 0.018 0.00023
8-AZABICYCLO[3.2.1]OCT-2-ENE DERIVATIVES
Test Compound DA uptake IC50(μM) NA uptake IC50(μM) 5-HT uptake IC50(μM)
(±)-3-(3,4-Dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene 0.079 0.026 0.0047

U.S. Patent 2,001,047,028

Test Compound DA uptake IC50(μM) NA uptake IC50(μM) 5-HT uptake IC50(μM)
(±)-3-(4-cyanophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene 18 4.9 0.047
(±)-3-(4-nitrophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene 1.5 0.5 0.016
(±)-3-(4-trifluoromethoxyphenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene 22.00 8.00 0.0036
LBT-999, a radio-ligand.

Heterocycles[edit]

These heterocycles are sometimes referred to as the "bioisosteric equivalent" of the simpler esters from which they are derived. A potential disadvantage of leaving the ββ-ester unreacted is that in addition to being hydrolyzable, it can also epimerize[7] to the energetically more favorable trans configuration. This can happen to cocaine also.

3-Substituted-isoxazol-5-yl[edit]

3-R-isoxazol-5-yl.svg

N-methylphenyltropanes with 1R β,β stereochemistry.
Code X R DA NE 5HT
RTI-165 Cl 3-methylisoxazol-5-yl 0.59 181 572
RTI-171 Me 3-methylisoxazol-5-yl 0.93 254 3818
RTI-180 I 3-methylisoxazol-5-yl 0.73 67.9 36.4
RTI-177 Cl 3-phenylisoxazol-5-yl 1.28 504 2418
RTI-176 Me 3-phenylisoxazol-5-yl 1.58 398 5110
RTI-181 I 3-phenylisoxazol-5-yl 2.57 868 100
RTI-184 H methyl 43.3 6208
RTI-185 H Ph 285 >12K
RTI-334 Cl 3-ethylisoxazol-5-yl 0.50 120 3086
RTI-335 Cl isopropyl 1.19 954 2318
RTI-336 Cl 3-(4-methylphenyl)isoxazol-5-yl 4.09 1714 5741
RTI-337 Cl 3-t-butyl-isoxazol-5-yl 7.31 6321 37K
RTI-345 Cl p-chlorophenyl 6.42 5290 >76K
RTI-346 Cl p-anisyl 1.57 762 5880
RTI-347 Cl p-fluorophenyl 1.86 918 7257
RTI-354 Me 3-ethylisoxazol-5-yl 1.62 299 6400
RTI-366 Me R = isopropyl 4.5 2523 (1550) 42,900 (3900)
RTI-371 Me p-chlorophenyl 8.74 >100K (60,200) >100K (9090)
RTI-386 Me p-anisyl 3.93 756 (450) 4027 (380)
RTI-387 Me p-fluorophenyl 6.45 917 (546) >100K (9400)

3-Substituted-1,2,4-oxadiazole[edit]

RTI-130 structure.png
Heterocyclic (N-methyl)phenyltropanes with 1R stereochemistry.
Code X R DA NE 5HT
ααRTI-87 H 3-methyl-1,2,4-oxadiazole 204 36K 30K
βαRTI-119 H 3-methyl-1,2,4-oxadiazole 167 7K 41K
αβRTI-124 H 3-methyl-1,2,4-oxadiazole 1028 71K 33K
RTI-125 Cl 3-methyl-1,2,4-oxadiazole 4.05 363 2584
ββRTI-126[8] H 3-methyl-1,2,4-oxadiazole 100 7876 3824
RTI-130 Cl 3-phenyl-1,2,4-oxadiazole 1.62 245 195
RTI-141 Cl 3-(p-anisyl)-1,2,4-oxadiazole 1.81 835 357
RTI-143 Cl 3-(p-chlorophenyl)-1,2,4-oxadiazole 4.1 4069 404
RTI-144 Cl 3-(p-bromophenyl)-1,2,4-oxadiazole 3.44 1825 106
βRTI-151 Me 3-phenyl-1,2,4-oxadiazole 2.33 60 1074
αRTI-152 Me 3-phenyl-1,2,4-oxadiazole 494 1995
RTI-154 Cl 3-isopropyl-1,2,4-oxadiazole 6 135 3460
RTI-155 Cl 3-cyclopropyl-1,2,4-oxadiazole 3.41 177 4362
RTI-470 structure:[9]
Heterocyclic tropanes.png
N-methylphenyltropanes with 1R β,β stereochemistry.
Code X 2 Group DA NE 5HT
RTI-157 Me tetrazole 1557 >37K >43K
RTI-163 Cl tetrazole 911 5456
RTI-178 Me 5-phenyl-oxazol-2-yl 35.4 677 1699
RTI-188 Cl 5-phenyl-1,3,4-oxadiazol-2-yl 12.6 930 3304
RTI-189 Cl 5-phenyl-oxazol-2-yl 19.7 496 1116
RTI-194 Me 5-methyl-1,3,4-oxadiazol-2-yl 4.45 253 4885
RTI-195 Me 5-phenyl-1,3,4-oxadiazol-2-yl 47.5 1310 >22,000
RTI-199 Me 5-phenyl-1,3,4-thiadiazol-2-yl 35.9 >24,000 >51,000
RTI-200 Cl 5-phenyl-1,3,4-thiadiazol-2-yl 15.3 4142 >18,000
RTI-202 Cl benzothiazol-2-yl 1.37 403 1119
RTI-219 Cl 5-phenylthiazol-2-yl 5.71 8516 10,342
RTI-262 Cl
RTI-370 Me 3-(p-cresyl)isoxazol-5-yl 8.74 6980 >100K
RTI-371 Cl 3-(p-chlorophenyl)isoxazol-5-yl 13 >100K >100K
RTI-436 Me -CH=CHPh[10] 3.09 1960 (1181) 335 (31)
RTI-470 Cl o-Cl-benzothiazol-2-yl 0.094 1590 (994) 1080 (98)
RTI-451 Me benzothiazol-2-yl 1.53 476 (287) 7120 (647)
Above is taken from: RTI, Kuhar, et al. U.S. Patent 5,935,953 (1999).

N.B There are some alternative ways of making the tetrazole ring though. C.f. the sartan drugs synthesis schemes. Bu3SnN3 is a milder choice of reagent than hydrogen azide (c.f. Irbesartan).

N-constrained[edit]

Constrained tropane:[11][12]

N-alkyl[edit]

RTI-242 structure.png
Compound X 2 Group config 8 DAT SERT NET
FP-β-CPPIT Cl 3′-phenylisoxazol-5′-yl β,β NCH2CH2CH2F - - -
FE-β-CPPIT Cl (3′-phenylisoxazol-5′-yl) β,β NCH2CH2F - - -
Altropane F CO2Me β,β NCH2CH=CHF - - -
RTI-310 U.S. Patent 5,736,123 I CO2Me β,β N-Prn 1.17 - -
RTI-311 I CO2Me β,β NCH2CH=CH2 1.79 - -
RTI-312 U.S. Patent 5,736,123 I CO2Me β,β NBun 0.76 - -
RTI-313 U.S. Patent 5,736,123 I CO2Me β,β NCH2CH2CH2F 1.67 - -
Ioflupane ¹²³I CO2Me β,β NCH2CH2CH2F - - -
RTI-251 Cl CO2Me β,β NCH2CO2Et 1.93 10.1 114
RTI-252 Cl CO2Me β,β NCH2CH2CO2Et 2.56 35.2 125
RTI-242 Cl β,β (bridged) -C(O)CH(CO2Me)CH2N 7.67 227 510

Bi- and tri-cyclic aza compounds and their uses U.S. Patent 6,150,376 WO 0007994 

Tricyclic Tropanes[edit]

Tricyclic tropanes[13]
Compound X Y R SERT Ki (nM) DAT Ki (nM) NET Ki (nM)
1 Cl Cl CH2OCOMe 1.6 1870 638
2 Br Cl CO2Me 2.3 5420 459
3 I Cl CH2OCOPh 0.06 >10K >10K

Kozikowski Fused[edit]

U.S. Patent 6,150,376

Structures mentioned in US6150376 table of Ki data.
Activity at monoamine transporters (nM)
Compound Mazindol DA 5-HT NE
cocaine 375 423 155 83.3
(–)-40 54.3 60.3 1.76 5.24
(+)-40 79 114 1.48 4.62
(±)40 61.7 60.3 2.32 2.69
29β 620 1420 8030
30β 186 492 97.7
31β 47.0 211 28.5
29α 4140 20100 3920
30α 3960 8850 696 1150
45 6.86 24.0 1.77 1.06
42a 4.00 2.23 14.0 2.99
41a 17.2 10.2 78.9 15.0
42b 3.61 11.3 25.7 4.43
50a 149 149 810 51.7
49a 13.7 14.2 618 3.84
(–)-4 10500 16500 1890 70900
(+)-4 18500 27600 4630 38300
(–)-5 9740 9050 11900 4650
(+)-5 6770 10500 25100 4530

Fused[edit]

Fused tropane-derivatives as neurotransmitter reuptake inhibitors. U.S. Patent 5,998,405

Fused Tropane: NeuroSearch A/S, Scheel-Krüger et al. U.S. Patent 5,998,405
Code Compound DA (μM) NA (μM) (μM)5-HT
1 (1 S,2S,4S,7R)-2-(3,4-Dichloro- phenyl)-8-azatricyclo[5.4.0.04,8]- undecan-11 -one O-methyl-oxime 0.012 0.0020 0.0033
2 (1 S,2S,4S,7R)-2-(3,4-Dichloro- phenyl)-8-azatricyclo[5.4.0.04,8]- undecan-11-one 0.18 0.035 0.0075
3 (1 S,3S,4S,8R)-3-(3,4-Dichloro-phenyl)-7-azatricyclo[5.3.0.04,8]- decan-5-one O-methyl-oxime 0.0160 0.0009 0.0032
4 (1 S,2S,4S,7R)-2-(3,4-Dichloro-phenyl)-8-azatricyclo[5.4.0.04,8]- undecan-11-ol 0.0750 0.0041 0.0028
5 (1 S,3S,4S,8R)-3-(3,4-Dichloro-phenyl)-7-azatricyclo[5.3.0.04,8]- decan-5-one 0.12 0.0052 0.0026
6 (1 S,3S,4S,8R)-3-(3,4-Dichloro- phenyl)-7-azatricyclo[5.3.0.04,8]-decan-5-ol 0.25 0.0074 0.0018
7 (1S,3S,4S,8R)-3- (3,4-Dichloro- phenyl)-7-azatricyclo[5.3.0.04,8]dec- 5-yl acetate 0.21 0.0061 0.0075
8 (1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-5-methoxy-7- azatricyclo[5.3.0.04,8]decane 0.022 0.0014 0.0001
  1. 1-Chloroethyl chloroformate is used to remove N-methyl of trans-aryltropanes.
  2. 2° amine is reacted with Br(CH2)nCO2Et.
  3. Base used to abstract proton α- to CO2Et group and complete the tricyclic ring closure step (Dieckmann cyclization).

To make a different type of analog (see Kozikowski patent above)

  1. Remove N-Me
  2. Add ɣ-bromo-chloropropane
  3. Allow for cyclization with K2CO3 base and KI cat.

3-(2-thiophene) and 3-(2-furan)[edit]

U.S. Patent 7,247,643

Code Compound DA (μM) NA (μM) (μM)5-HT
1 (2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt 0.30 0.0019 0.00052
2 (2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt 0.36 0.0036 0.00042
3 (2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt 0.31 0.00090 0.00036
4 (2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt 0.92 0.0030 0.00053
5 (2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane fumaric acid salt 0.074 0.0018 0.00074
6 (2R,3S)-2-(1-Naphthyloxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane fumaric acid salt 0.19 0.0016 0.00054

N-replaced (S,O,C)[edit]

Thia.png
Compound X 2 Group config 8 DA 5-HT NE
Tropoxane Cl,Cl CO2Me (racemic) β,β O 3.3 6.5 No data
Meltzer.png

Diaryl[edit]

Hanna et al. (2007)[14]
ZIENT:[15]

Radiolabel Tropane[edit]

Radiolabel Tropane:[16] Page 64. G.A. Whitlock et al. Table 1 Potential SRI PET and SPECT ligands.
Code SERT Ki (nM) NET Ki (nM) DAT Ki (nM) Radiolabel In vivo study Refs.
1 0.2 102.2 29.9 11C Non-human primate [17]
2 0.2 31.7 32.6 11C Non-human primate [18]
3 0.05 24 3.47 123I Rat [19]
4 0.08 28 13 18F Non-human primate [20]
5 0.11 450 22 11C Rat, monkey [21]

Irreversible[edit]

RTI-76 structure.png
Irreversible (phenylisothiocyanate) binding ligand (Murthy, V.; Martin, T. J.; Kim, S.; Davies, H. M. L.; Childers, S. R. (2008). "In Vivo Characterization of a Novel Phenylisothiocyanate Tropane Analog at Monoamine Transporters in Rat Brain". Journal of Pharmacology and Experimental Therapeutics 326 (2): 587–595. doi:10.1124/jpet.108.138842. PMID 18492949. )[22] RTI-76:[23] 4′-isothiocyanatophenyl (1R,2S,3S,5S)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate. Also known as: 3β-(p-chlorophenyl)tropan-2β-carboxylic acid p-isothiocyanatophenylmethyl ester.

Note the contrast to the phenylisothiocyanate covalent binding site location as compared to the one on p-Isococ, a non-phenyltropane cocaine analogue.

Nortropanes (N-demethylated)[edit]

NS2359 (GSK-372,475)

It is well established that electrostatic potential around the para position tends to improve MAT binding. This is believed to also be the case for the meta position, although it is less studied. N-demethylation dramatically potentiates NET and SERT affinity, but the effects of this on DAT binding are insignificant.[24] Of course, this is not always the case. For an interesting exception to this trend, see the Taxil document. There is ample evidence suggesting that N-demethylation of alkaloids occurs naturally in vivo via a biological enzyme. The fact that hydrolysis of the ester leads to inactive metabolites means that this is still the main mode of deactivation for analogues that have an easily metabolised 2-ester substituent. The attached table provides good illustration of the effect of this chemical transformation on MAT binding affinities. N.B. In the case of both nocaine and pethidine, N-demethyl compounds are more toxic and have a decreased seizure threshold.[25]

Selected ββ Nortropanes
Code X DA 5HT NE
RTI-142 F 4.39 68.6 18.8
RTI-98 I 0.69 0.36 11.0
RTI-110 Cl 0.62 4.13 5.45
RTI-173 Et 49.9 8.13 122
N-demethylating various β,β p-HC-phenyltropanes
X [3H]Paroxetine [3H]WIN 35,428 [3H]Nisoxetine
Ethyl 28.4 → 8.13 55 → 49.9 4,029 → 122
vinyl 9.5 → 2.25 1.24 → 1.73 78 → 14.9
Ethynyl 4.4 → 1.59 1.2 → 1.24 83.2 → 21.8
1-Propyl 70.4 → 26 68.5 → 212 3,920 → 532
trans-propenyl 11.4 → 1.3 5.29 → 28.6 1,590 → 54
cis-propenyl 7.09 → 1.15 15 → 31.6 2,800 → 147
Allyl 28.4 → 6.2 32.8 → 56.5 2,480 → 89.7
1-Propynyl 15.7 → 3.16 2.37 → 6.11 820 → 116
i-Propyl 191 → 15.1 597 → 310 75,000 → ?
2-Propenyl 3.13 → 0.6 14.4 → 23 1,330? → 144
N-Demethylating phenyltropanes to find a NRI
Isomer 4′ 3′ NE DA 5HT
β,β Me H 60 → 7.2 1.7 → 0.84 240 → 135
β,β F H 835 → 18.8 15.7 → 4.4 760 → 68.6
β,β Cl H 37 → 5.45 1.12 → 0.62 45 → 4.13
β,α Me H 270 → 9 10.2 → 33.6 4250 → 500
β,α F H 1200 → 9.8 21 → 32.6 5060 → 92.4
β,α Cl H 60 → 5.41 2.4 → 3.1 998 → 53.3
β,α F Me 148 → 4.23 13.7 → 9.38 1161 → 69.8
β,α Me F 44.7 → 0.86 7.38 → 9 1150 → 97.4

"Interest in NET selective drugs continues as evidenced by the development of atomoxetine, manifaxine, and reboxetine as new NET selective compounds for treating ADHD and other CNS disorders such as depression" (FIC, et al. 2005).[26]

Thiophenyltropanes[edit]

Thiophenyltropanes.png

Select annotations of above[edit]

Phenyltropanes can be grouped by "N substitution" "Stereochemistry" "2-substitution" & by the nature of the 3-phenyl group substituent X.
Often this has dramatic effects on selectivity, potency, and duration, also toxicity, since phenyltropanes are highly versatile. For more examples of interesting phenyltropanes, see some of the more recent patents, e.g. U.S. Patent 6,329,520, U.S. Patent 7,011,813, U.S. Patent 6,531,483, and U.S. Patent 7,291,737.

Potency in vitro should not be confused with the actual dosage, as pharmacokinetic factors can have a dramatic influence on what proportion of an administered dose actually gets to the target binding sites in the brain, and so a drug that is very potent at binding to the target may nevertheless have only moderate potency in vivo. For example, RTI-336 requires a higher dosage than cocaine. Accordingly, the active dosage of RTI-386 is exceedingly poor despite the relatively high ex vivo DAT binding affinity.

Sister substances[edit]

Many molecular drug structures have exceedingly similar pharmarcology to phenyltropanes, yet by certain technicalities do not fit the phenyltropane moniker. These are namely classes of dopaminergic cocaine analogues that are in the piperidine class (a category that includes methylphenidate) or benztropine class (such as Difluoropine: which is extremely close to fitting the criteria of being a phenyltropane.) Whereas other potent DRIs are far removed from being in the phenyltropane structural family, such as Benocyclidine or Vanoxerine.

Misc.[edit]

RTI-241 structure.png
RTI-239 structure.png
Code X 2 Position config 8 DA 5-HT NE
RTI-102 I CO2H β,β NMe 474 1928 43,400
RTI-103 Br CO2H β,β NMe 278 3070 17,400
RTI-104 F CO2H β,β NMe 2744 >100K >100K
RTI-108 Cl -CH2Cl β,β NMe 2.64 98 129.8
RTI-241 Me -CH2CO2Me β,β NMe 1.02 619 124
RTI-139 Cl -CH3 β,β NMe 1.67 85 57
RTI-161 Cl -C≡N β,β NMe 13.1 1887 2516
RTI-230 Cl H3C–C=CH2 β,β NMe 1.28 57 141
RTI-240 Cl -CHMe2 β,β NMe 1.38 38.4 84.5
RTI-145 Cl -CH2OCO2Me β,β NMe 9.60 2,932 1,478
RTI-158 Me -C≡N β,β NMe 57 5095 1624
RTI-131 Me -CH2NH2 β,β NMe 10.5 855 120
RTI-164 Me -CH2NHMe β,β NMe 13.6 2246 280
RTI-132 Me -CH2NMe2 β,β NMe 3.48 206 137
RTI-239 Me -CHMe2 β,β NMe 0.61 114 35.6
RTI-338 Et -CO2CH2Ph β,β NMe 1104 7.41 3366
RTI-348 H -Ph β,β NMe 28.2 >34,000 2670

Phenyltropane based Benztropines[edit]

Benztropine phenyltropane:[27]

F&B series (Biotin side-chains etc.)[edit]

The compound of the present invention are useful pesticides.[8]

Code X 2 Position config DA NE 5-HT
RTI-224 Me F1c β,β 4.49 155.6
RTI-233 Me F2 β,β 4.38 516 73.6
RTI-235 Me F3 d β,β 1.75 402 72.4
RTI-236 Me B1 d β,β 1.63 86.8 138
RTI-237 Me B2 d β,β 7.27 258 363
RTI-244 Me B3 d β,β 15.6 1809 33.7
RTI-245 Cl F4 c β,β 77.3
RTI-246 Me F4 c β,β 50.3 3000
RTI-248 Cl F6 c β,β 9.73 4674 6.96
RTI-249 Cl F1 c β,β 8.32 5023 81.6
RTI-266 Me F2 β,β 4.80 836 842
RTI-267 Me F7 wrong β,β 2.52 324 455
RTI-268 Me F7 right β,β 3.89 1014 382
RTI-269 Me F8 β,β 5.55 788 986

F series.png B series.png Biotin

See also[edit]

References[edit]

  1. ^ a b Tamagnan, Gilles (2005). "Synthesis and monoamine transporter affinity of new 2β-carbomethoxy-3β-[4-(substituted thiophenyl)]phenyltropanes: discovery of a selective SERT antagonist with picomolar potency". Bioorganic 15 (4): 1131–1133. doi:10.1016/j.bmcl.2004.12.014. PMID 15686927.  edit
  2. ^ U.S. Patent 6,479,509 Method of promoting smoking cessation.
  3. ^ Blough, B. E.; Keverline, K. I.; Nie, Z.; Navarro, H.; Kuhar, M. J.; Carroll, F. I. (2002). "Synthesis and transporter binding properties of 3beta-4′-(phenylalkyl, -phenylalkenyl, and -phenylalkynyl)phenyltropane-2β-carboxylic acid methyl esters: evidence of a remote phenyl binding domain on the dopamine transporter". Journal of Medicinal Chemistry 45 (18): 4029–4037. doi:10.1021/jm020098n. PMID 12190324. 
  4. ^ a b c Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists. Satendra Singh et al. Chem. Rev. 2000, 100. 925-1024. PubMed; Chemical Reviews (Impact Factor: 45.66). 04/2000; 100(3):925-1024 American Chemical Society; 2000, ISSN: 0009-2665 ChemInform; May, 16th 2000, Volume 31, Issue 20, DOI: 10.1002/chin.200020238. Mirror hotlink.
  5. ^ a b Meltzer, P. C.; McPhee, M.; Madras, B. K. (2003). "Synthesis and biological activity of 2-Carbomethoxy-3-catechol-8-azabicyclo[3.2.1]octanes". Bioorganic & Medicinal Chemistry Letters 13 (22): 4133. doi:10.1016/j.bmcl.2003.07.014.  edit
  6. ^ http://www3.interscience.wiley.com/journal/55001898/abstract
  7. ^ Carroll, F. I.; Gray; Abraham; Kuzemko; Lewin; Boja; Kuhar (1993). "3-Aryl-2-(3′-substituted-1′,2′,4'-oxadiazol-5′-yl)tropane analogues of cocaine: affinities at the cocaine binding site at the dopamine, serotonin, and norepinephrine transporters". Journal of Medicinal Chemistry 36 (20): 2886–2890. doi:10.1021/jm00072a007. PMID 8411004. 
  8. ^ a b Methods for controlling invertebrate pests using cocaine receptor binding ligands. U.S. Patent 5,935,953
  9. ^ Carroll, F.; Howard, J.; Howell, L.; Fox, B.; Kuhar, M. (2006). "Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse". The AAPS journal 8 (1): E196–E203. doi:10.1208/aapsj080124. PMC 2751440. PMID 16584128.  edit
  10. ^ Carroll, F.; Howard, J.; Howell, L.; Fox, B.; Kuhar, M. (2006). "Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse". The AAPS journal 8 (1): E196–E203. doi:10.1208/aapsj080124. PMC 2751440. PMID 16584128. 
  11. ^ Hoepping, Alexander (2000). "Novel Conformationally Constrained Tropane Analogues by 6- e ndo-trig Radical Cyclization and Stille Coupling − Switch of Activity toward the Serotonin and/or Norepinephrine Transporter". Journal of Medicinal Chemistry 43 (10): 2064–2071. doi:10.1021/jm0001121.  edit
  12. ^ Zhang, Ao (2002). "Thiophene derivatives: a new series of potent norepinephrine and serotonin reuptake inhibitors". Bioorganic 12 (7): 993–995. doi:10.1016/S0960-894X(02)00103-8.  edit
  13. ^ Zhang, Ao (2002). "Further Studies on Conformationally Constrained Tricyclic Tropane Analogues and Their Uptake Inhibition at Monoamine Transporter Sites:  Synthesis of ( Z )-9-(Substituted arylmethylene)-7-azatricyclo[4.3.1.0 3,7 ]decanes as a Novel Class of Serotonin Transporter Inhibitors". Journal of Medicinal Chemistry 45 (9): 1930–1941. doi:10.1021/jm0105373.  edit
  14. ^ Hanna, Mona M. (2007). "Synthesis of some tropane derivatives of anticipated activity on the reuptake of norepinephrine and/or serotonin". Bioorganic 15 (24): 7765–7772. doi:10.1016/j.bmc.2007.08.055.  edit
  15. ^ Goodman, Mark M. (2003). "Synthesis and Characterization of Iodine-123 Labeled 2β-Carbomethoxy-3β-(4′-(( Z )-2-iodoethenyl)phenyl)nortropane. A Ligand for in Vivo Imaging of Serotonin Transporters by Single-Photon-Emission Tomography". Journal of Medicinal Chemistry 46 (6): 925–935. doi:10.1021/jm0100180.  edit
  16. ^ "Transporters as Targets for Drugs". Topics in Medicinal Chemistry. 2009. doi:10.1007/978-3-540-87912-1.  edit
  17. ^ Stehouwer, Jeffrey S. (2006). "Synthesis, Radiosynthesis, and Biological Evaluation of Carbon-11 Labeled 2β-Carbomethoxy-3β-(3′-(( Z )-2-haloethenyl)phenyl)nortropanes:  Candidate Radioligands for in Vivo Imaging of the Serotonin Transporter with Positron Emission Tomography". Journal of Medicinal Chemistry 49 (23): 6760–6767. doi:10.1021/jm060641q.  edit
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  20. ^ Plisson, Christophe (2007). "Synthesis and in Vivo Evaluation of Fluorine-18 and Iodine-123 Labeled 2β-Carbo(2-fluoroethoxy)-3β-(4′-(( Z )-2-iodoethenyl)phenyl)nortropane as a Candidate Serotonin Transporter Imaging Agent". Journal of Medicinal Chemistry 50 (19): 4553–4560. doi:10.1021/jm061303s.  edit
  21. ^ PMC 2671940
  22. ^ Carroll, F. I.; Gao; Abraham; Lewin; Lew; Patel; Boja; Kuhar (1992). "Probes for the cocaine receptor. Potentially irreversible ligands for the dopamine transporter". Journal of Medical Chemistry 35 (10): 1813–1817. doi:10.1021/jm00088a017. PMID 1588560. 
  23. ^ Wu; Reith, M.; Walker, Q.; Kuhn, C.; Carroll, F.; Garris, P. (2002). "Concurrent autoreceptor-mediated control of dopamine release and uptake during neurotransmission: an in vivo voltammetric study". Journal of Neuroscience 22 (14): 6272–6281. PMID 12122086. 
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  27. ^ Xu, L.; Kulkarni, S. S.; Izenwasser, S.; Katz, J. L.; Kopajtic, T.; Lomenzo, S. A.; Newman, A. H.; Trudell, M. L. (2004). "Synthesis and Monoamine Transporter Binding of 2-(Diarylmethoxymethyl)-3β-aryltropane Derivatives". Journal of Medicinal Chemistry 47 (7): 1676. doi:10.1021/jm030430a.  edit

External links[edit]