List of phenyltropanes

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).

2-Carboxymethyl esters

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
Tamagnan:[1] pM activity for SERT
Selected Phenyltropanes
Short Name X DA 5HT NE
WIN 35,065-2 (CPT) H 231962920
WIN 35,428 (CFT) F1415685
? NO210.1??
RTI-29[2] NH29.85110151
RTI-31 Cl 1.12 44.537
RTI-32 Me 1.7124060
RTI-51 Br 1.6910.637.4
Iometopane (RTI-55) I 1.26 4.21 36
RTI-83Et5528.44030
RTI-11wcis-propenyl157.128,000
RTI-298[3]–≡–Ph3.746.8347
RTI-436–CH=CHPh3.09335 (31)1960 (1181)
RTI-430–C≡C(CH2)2Ph6.282128 (198)1470 (886)
Tamagnan[1]p-thiophene120.017189
Meta-subsituted 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
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 ± 0.0510.5 ± 0.0536.2 ± 1.013.044.7
17c Cl Cl 0.79 ± 0.083.13 ± 0.3618.0 ± 0.84.022.8
17d Br NH2 3.91 ± 0.59----
17e I NH2 1.35 ± 0.11120 ± 41329 ± 12488.9984
17f I N3 4.93 ± 0.32----

(3,4-Disubstituted phenyl)-tropanes

CompoundX Y 2 Position config 8 DA 5-HT NE
RTI-318 β-naphthyl CO2Me β,β NMe 0.50.8120
Dichloropane (RTI-111) ClCl CO2Me β,β NMe 0.793.1318.0
RTI-88 [recheck] NH2I CO2Me β,β NMe 1.35 1329 320
RTI-97 NH2Br CO2Me β,β NMe 3.91181 282
RTI-112 ClMe CO2Me β,β NMe 0.8210.536.2
RTI-96 FMeCO2Me β,β NMe 2.9576520
RTI-295 EtICO2Me β,β NMe 21.32.961349
RTI-353 (EINT)EtICO2Me β,β NH 3310.69148
RTI-279 MeICO2Me β,β NH 5.981.0674.3
RTI-280 MeICO2Me β,β NMe 3.126.81484
Meltzer[5]catecholCO2Me β,β NMe >100??
Meltzer[5]OAcOAcCO2Me β,β NMe ???
Meta-subsituted 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
23a CH(CH3)2 H 85.1 ± 2.523121 ± 397632047 ± 1491 272 376
23b C6H5 H 76.7 ± 3.6106149 ± 725619262 ± 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 ± 0.10168 ± 1.8235 ± 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 ± 3.91227 ± 176967.6 ± 26.3 37.6 29.7
24e C6H4-3-CH3 Cl 9.37 ± 0.522153 ± 1432744 ± 140 230 293
24f C6H4-4-CH3 Cl 27.4 ± 1.51203 ± 421277 ± 118 43.9 46.6
24g C6H4-2-CH3 Cl 3.91 ± 0.233772 ± 3844783 ± 387 965 1223
24h C6H4-4-Cl Cl 55 ± 2.316914 ± 10564883 ± 288 307 88.8
24i C6H4-4-OCH3 Cl 71 ± 5.619689 ± 18431522 ± 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 ± 0.0815.5 ± 0.72102 ± 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 ± 14499 ± 5573444 ± 44 235 180
26c cyclopropyl CH3 17.8 ± 0.76485 ± 212628 ± 252 27.2 148
26d cyclobutyl CH3 3.74 ± 0.522019 ± 1334738 ± 322 540 1267
26e cyclopentyl CH3 1.68 ± 0.141066 ± 109644 ± 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 ± 0.905237 ± 4532136 ± 208 639 261
26h C6H4-4-CH3 CH3 81.2 ± 1615954 ± 6144096 ± 121 196 50.4
26i C6H4-2-CH3 CH3 23.2 ± 0.9711040 ± 50425695 ± 1394 476 1107
26j C6H4-4-Cl CH3 117 ± 7.942761 ± 23999519 ± 864 365 81.3
26k C6H4-4-OCH3 CH3 95.6 ± 8.882316 ± 78523151 ± 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 ± 2.456371 ± 3744398 ± 271 152 105
29b N(CH2CH3)2 CH3 24.7 ± 1.9333928 ± 21926222 ± 729 1374 252
29c N(OCH3)CH3 CH3 2.55 ± 0.433402 ± 353422 ± 26 1334 165
29d 4-morpholine CH3 11.7 ± 0.87 >100000 23601 ± 1156 >8547 2017

Carboxyaryl

Compound X 2 Position config 8 DA 5-HT NE
RTI-122 I -CO2Ph β,β NMe1.501843,791
RTI-113 Cl -CO2Ph β,β NMe 1.982,3362,955
RTI-277 NO2 -CO2Ph β,β NMe 5.942,9105,695
RTI-120 [recheck] Me -CO2Ph β,β NMe 3.2624,4715,833
RTI-116 Cl -CO2(p-C6H4I) β,β NMe 33 1,227 968
RTI-203 Cl CO2(m-C6H4Me) β,β NMe 9.3721532744
RTI-204 Cl -CO2(o-C6H4Me) β,β NMe 3.913,7724,783
RTI-205 Me -CO2(m-C6H4Me) β,β NMe 8.195,2372,137
RTI-206Cl-CO2(p-C6H4Me) β,β NMe 27.41,2031,278

Carboxyalkyl

Code X 2 Position config 8 DA 5-HT NE
RTI-77ClCH2C2(3-iodo-p-anilino)β,βNMe2.51—2247
RTI-121 I -CO2Pri β,β NMe0.4366.8285
RTI-153 I -CO2Pri β,β NH1.063.59132
RTI-191 I -CO2Prcyc β,β NMe0.6115.5102
RTI-114 Cl -CO2Pri β,β NMe 1.401,404778
RTI-278 NO2 -CO2Pri β,β NMe 8.142,1474,095
RTI-190 Cl -CO2Prcyc β,β NMe 0.96168235
RTI-193 Me -CO2Prcyc β,β NMe1.681,066644
RTI-117 Me -CO2Pri β,β NMe6.456,0901,926
RTI-150 Me -CO2Bucyc β,β NMe3.742,0204,738
RTI-127 Me -CO2C(H)Et2 β,β NMe1945003444
RTI-338ethyl-CO2C2Ph β,β NMe11047.413366

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

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

Code X 2 Position config 8 DA NE 5-HT
RTI-106 ClCON(H)Me β,β NMe 12.415111312
RTI-118 ClCONH2β,β NMe11.542671621
RTI-222Memorpholinylβ,β NMe11.7—>100K
RTI-129 ClCONMe2β,β NMe 1.389421079
RTI-146 Cl CONHCH2OH β,β NMe 2.0514498
RTI-147 Cl CON(CH2)4 β,β NMe 1.383,94912,394
RTI-156 ClCON(CH2)5β,β NMe 6.6158323468
RTI-170 ClCON(H)CH2C≡CHβ,β NMe16.518394827
RTI-172 ClCON(H)NH2β,β NMe 44.139143815
RTI-174 ClCONHCOMeβ,β NMe 158>43K>125K
RTI-182 ClCONHCH2COPhβ,β NMe 7.791722827
RTI-183 ClCON(OMe)Meβ,β NMe 0.85549724
RTI-186 MeCON(OMe)Meβ,β NMe 2.55442 (266)3400 (309)
RTI-198 ClCON(CH2)3β,β NMe 6.57990813
RTI-196 ClCONHOMeβ,β NMe 10.79907>43K
RTI-201 ClCONHNHCOPhβ,β NMe 91.8>20K>48K
RTI-208 ClCONO(CH2)3β,β NMe 1.479982470
RTI-214 Cl CON(-CH2CH2-)2O β,β NMe 2.908545>88K
RTI-215 ClCONEt2β,β NMe 5.48?9432
RTI-217 ClCONH(m-C6H4OH)β,β NMe 4.78>30K>16K
RTI-218 Cl CON(Me)OMe β,β NMe 1.195201911
RTI-226 ClCONMePhβ,β NMe 45.0?24K
RTI-227 ICONO(CH2)3β,β NMe 0.75446230
RTI-229[6] I CON(CH2)4 β,β NMe 0.379911,728

Acyl

#X Y 2 Position config 8 DA 5-HT NE
WF-23β-naphthyl C(O)Et β,β NMe 0.115 0.394 No data
WF-31 -Pri HC.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

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

Code X 2 Position config 8 DA 5-HT NE
RTI-100 F -CH2OH β,β NMe 474741no data
RTI-101 I -CH2OH β,β NMe 2.2 26 no data
RTI-99 Br -CH2OH β,β NMe 1.4951no data
RTI-93 Cl -CH2OH β,β NMe 1.5320443.8
RTI-105 Cl -CH2OAc β,β NMe 1.60143127
RTI-123 Cl -CH2OBz β,β NMe 1.783.53393
RTI-145Cl-CH2OCO2Me β,β NMe9.602.931.48
[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

Compound X 2 Group config 8 DA5-HTNE
RTI-140 H CO2Me β,α NMe 1015,7012,076
RTI-352 U.S. Patent 6,358,492 I CO2Me β,α NMe 2.8664.952.4
RTI-549 Br CO2Me β,α NMe — — —
RTI-319 U.S. Patent 7,011,813 BN CO2Me β,α NMe1.111.470.2
RTI-286 U.S. Patent 7,011,813 F CO2Me β,α NMe2150621231
RTI-274 U.S. Patent 7,291,737FCH2O(3′,4′-MD-phenyl)β,α NH3.965.6214.4
RTI-287 Et CO2Meβ,α NMe327168717,819

α,β Stereochemistry

CA 2112084

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]octane0.39<15000
(2R,3S)-2-(carboxymethyl)-8-methyl-3-(2-naphthyl)-8-azabicyclo[3.2.1]octane0.112500
(2R,3S)-2-(carboxymethyl)-8-methyl-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane0.0160.2550++++

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

Compound X 2 Group config 8 DA5-HTNE
Brasofensine Cl2 methyl aldoxime α,β NMe — — —
Tesofensine Cl2 ethoxymethyl α,β NMe 65111.7
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 salt0.0620.0350.00072
(2R,3S)-2-(Naphthaleneoxymethane)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt0.0620.150.0063
(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-H-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt0.100.0480.0062
(2R,3S)-2-(Naphthlyloxymethane)-8-H-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt0.0880.0510.013

Aryl-Tropenes

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-ene0.260.0280.010
(+)-3-Napthalen-2-yl-8-azabicyclo[3.2.1]oct-2-ene0.0580.0130.00034
(–)-8-Methyl-3-(naphthalen-2-yl)-8-azabicylo[3.2.1]oct-2-ene0.0340.0180.00023
WO 9713770
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-ene0.0790.0260.0047

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-ene184.90.047
(±)-3-(4-nitrophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene1.50.50.016
(±)-3-(4-trifluoromethoxyphenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene22.008.000.0036
LBT-999, a radio-ligand.

Heterocycles

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

N-methylphenyltropanes with 1R β,β stereochemistry.
Code X R DA NE 5HT
RTI-165 Cl 3-methylisoxazol-5-yl0.59181572
RTI-171 Me3-methylisoxazol-5-yl0.932543818
RTI-180 I 3-methylisoxazol-5-yl0.7367.936.4
RTI-177 Cl3-phenylisoxazol-5-yl1.285042418
RTI-176 Me3-phenylisoxazol-5-yl1.583985110
RTI-181 I3-phenylisoxazol-5-yl2.57868100
RTI-184 Hmethyl43.3—6208
RTI-185 HPh285—>12K
RTI-334 Cl 3-ethylisoxazol-5-yl0.501203086
RTI-335 Cl isopropyl 1.199542318
RTI-336 Cl 3-(4-methylphenyl)isoxazol-5-yl4.0917145741
RTI-337 Cl 3-t-butyl-isoxazol-5-yl7.31632137K
RTI-345 Cl p-chlorophenyl6.425290>76K
RTI-346 Cl p-anisyl1.577625880
RTI-347 Cl p-fluorophenyl1.869187257
RTI-354 Me 3-ethylisoxazol-5-yl1.622996400
RTI-366MeR = isopropyl4.52523 (1550)42,900 (3900)
RTI-371Mep-chlorophenyl8.74>100K (60,200)>100K (9090)
RTI-386Mep-anisyl3.93756 (450)4027 (380)
RTI-387Mep-fluorophenyl6.45917 (546)>100K (9400)

3-Substituted-1,2,4-oxadiazole

Heterocyclic (N-methyl)phenyltropanes with 1R stereochemistry.
Code X R DA NE 5HT
ααRTI-87 H3-methyl-1,2,4-oxadiazole20436K30K
βαRTI-119 H3-methyl-1,2,4-oxadiazole1677K41K
αβRTI-124 H3-methyl-1,2,4-oxadiazole102871K33K
RTI-125 Cl 3-methyl-1,2,4-oxadiazole4.053632584
ββRTI-126[8] H 3-methyl-1,2,4-oxadiazole10078763824
RTI-130 Cl 3-phenyl-1,2,4-oxadiazole1.62245195
RTI-141Cl3-(p-anisyl)-1,2,4-oxadiazole1.81835357
RTI-143Cl3-(p-chlorophenyl)-1,2,4-oxadiazole4.14069404
RTI-144Cl3-(p-bromophenyl)-1,2,4-oxadiazole3.441825106
βRTI-151 Me 3-phenyl-1,2,4-oxadiazole2.33601074
αRTI-152 Me 3-phenyl-1,2,4-oxadiazole494—1995
RTI-154Cl3-isopropyl-1,2,4-oxadiazole61353460
RTI-155Cl3-cyclopropyl-1,2,4-oxadiazole3.411774362
RTI-470 structure:[9]
N-methylphenyltropanes with 1R β,β stereochemistry.
Code X 2 Group DA NE 5HT
RTI-157Metetrazole1557>37K>43K
RTI-163 Cl tetrazole911—5456
RTI-178 Me 5-phenyl-oxazol-2-yl35.46771699
RTI-188 Cl 5-phenyl-1,3,4-oxadiazol-2-yl12.69303304
RTI-189 Cl 5-phenyl-oxazol-2-yl19.74961116
RTI-194 Me 5-methyl-1,3,4-oxadiazol-2-yl4.452534885
RTI-195 Me 5-phenyl-1,3,4-oxadiazol-2-yl47.51310>22,000
RTI-199 Me 5-phenyl-1,3,4-thiadiazol-2-yl35.9>24,000>51,000
RTI-200 Cl 5-phenyl-1,3,4-thiadiazol-2-yl15.34142>18,000
RTI-202 Cl benzothiazol-2-yl1.374031119
RTI-219 Cl 5-phenylthiazol-2-yl5.71851610,342
RTI-262Cl
RTI-370 Me 3-(p-cresyl)isoxazol-5-yl8.746980>100K
RTI-371 Cl 3-(p-chlorophenyl)isoxazol-5-yl13>100K>100K
RTI-436Me-CH=CHPh[10]3.091960 (1181)335 (31)
RTI-470Clo-Cl-benzothiazol-2-yl0.0941590 (994)1080 (98)
RTI-451Mebenzothiazol-2-yl1.53476 (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

Constrained tropane:[11][12]

N-alkyl

Compound X 2 Group config 8 DATSERTNET
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 5,736,123I CO2Me β,β N-Prn 1.17 - -
RTI-311 I CO2Me β,β NCH2CH=CH2 1.79 - -
RTI-312 U.S. Patent 5,736,123I 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 10.1114
RTI-252 Cl CO2Me β,β NCH2CH2CO2Et 2.5635.2125
RTI-242 Cl β,β (bridged) -C(O)CH(CO2Me)CH2N 7.67227510

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

Tricyclic Tropanes

Tricyclic tropanes[13]
CompoundXYRSERT Ki (nM)DAT Ki (nM)NET Ki (nM)
1ClClCH2OCOMe1.61870638
2BrClCO2Me2.35420459
3IClCH2OCOPh0.06>10K>10K

Kozikowski Fused

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
cocaine37542315583.3
(–)-4054.360.31.765.24
(+)-40791141.484.62
(±)4061.760.32.322.69
29β62014208030 —
30β18649297.7 —
31β47.021128.5 —
29α4140201003920 —
30α396088506961150
456.8624.01.771.06
42a4.002.2314.02.99
41a17.210.278.915.0
42b3.6111.325.74.43
50a14914981051.7
49a13.714.26183.84
(–)-41050016500189070900
(+)-41850027600463038300
(–)-597409050119004650
(+)-5677010500251004530

Fused

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
CodeCompound 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-oxime0.0120.00200.0033
2(1 S,2S,4S,7R)-2-(3,4-Dichloro- phenyl)-8-azatricyclo[5.4.0.04,8]- undecan-11-one0.180.0350.0075
3(1 S,3S,4S,8R)-3-(3,4-Dichloro-phenyl)-7-azatricyclo[5.3.0.04,8]- decan-5-one O-methyl-oxime 0.01600.00090.0032
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 0.250.00740.0018
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 0.0220.00140.0001
  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)

U.S. Patent 7,247,643

CodeCompound 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 salt0.300.00190.00052
2(2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt0.360.00360.00042
3(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt0.310.000900.00036
4(2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt0.920.00300.00053
5(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane fumaric acid salt0.0740.00180.00074
6(2R,3S)-2-(1-Naphthyloxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane fumaric acid salt0.190.00160.00054

N-replaced (S,O,C)

Compound X 2 Group config 8 DA5-HTNE
Tropoxane Cl,Cl CO2Me (racemic) β,β O 3.36.5No data

Diaryl

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

Radiolabel Tropane

Radiolabel Tropane:[16] Page 64. G.A. Whitlock et al. Table 1 Potential SRI PET and SPECT ligands.
CodeSERT Ki (nM)NET Ki (nM)DAT Ki (nM)RadiolabelIn vivo studyRefs.
1 0.2 102.2 29.9 11C Non-human primate [17]
2 0.2 31.7 32.6 11C Non-human primate [18]
30.05243.47 123I Rat [19]
40.082813 18F Non-human primate [20]
50.1145022 11CRat, monkey[21]

Irreversible


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)

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 4.3968.618.8
RTI-98 I 0.69 0.36 11.0
RTI-110 Cl0.624.135.45
RTI-173 Et49.98.13122
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

Select annotations of above

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

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.

Code X 2 Position config 8 DA 5-HT NE
RTI-102ICO2Hβ,β NMe 474192843,400
RTI-103BrCO2Hβ,β NMe 278307017,400
RTI-104FCO2Hβ,β NMe 2744>100K>100K
RTI-108 Cl -CH2Cl β,β NMe 2.6498129.8
RTI-241 Me -CH2CO2Me β,β NMe1.02619124
RTI-139 Cl -CH3 β,β NMe 1.678557
RTI-161 Cl -C≡N β,β NMe 13.118872516
RTI-230 Cl H3C–C=CH2 β,β NMe 1.2857141
RTI-240 Cl -CHMe2 β,β NMe 1.3838.484.5
RTI-145 Cl -CH2OCO2Me β,β NMe 9.602,9321,478
RTI-158 Me -C≡N β,β NMe5750951624
RTI-131 Me -CH2NH2 β,β NMe10.5855120
RTI-164 Me -CH2NHMe β,β NMe13.62246280
RTI-132 Me -CH2NMe2 β,β NMe3.48206137
RTI-239 Me -CHMe2 β,β NMe0.6111435.6
RTI-338 Et -CO2CH2Ph β,β NMe11047.413366
RTI-348 H -Ph β,β NMe28.2>34,0002670

Phenyltropane based Benztropines

Benztropine phenyltropane:[27]

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

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

Code X 2 Position config DA NE 5-HT
RTI-224 MeF1c β,β 4.49—155.6
RTI-233 MeF2 β,β 4.3851673.6
RTI-235 MeF3 d β,β 1.7540272.4
RTI-236 MeB1 d β,β 1.6386.8138
RTI-237 MeB2 d β,β 7.27258363
RTI-244 MeB3 d β,β 15.6180933.7
RTI-245 ClF4 c β,β 77.3——
RTI-246 MeF4 c β,β 50.33000—
RTI-248 ClF6 c β,β 9.7346746.96
RTI-249 ClF1 c β,β 8.32502381.6
RTI-266 MeF2 β,β 4.80836842
RTI-267 MeF7 wrong β,β 2.52324455
RTI-268 MeF7 right β,β 3.891014382
RTI-269 MeF8 β,β 5.55788986

Biotin

See also

References

  1. ↑ 1.0 1.1 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.
  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. ↑ 4.0 4.1 4.2 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. ↑ 5.0 5.1 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.
  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. ↑ 8.0 8.1 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.
  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.
  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.
  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.
  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.
  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.
  16. ↑ "Transporters as Targets for Drugs". Topics in Medicinal Chemistry. 2009. doi:10.1007/978-3-540-87912-1.
  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.
  18. ↑ Deskus, Jeffrey A. (2007). "Conformationally restricted homotryptamines 3. Indole tetrahydropyridines and cyclohexenylamines as selective serotonin reuptake inhibitors". Bioorganic 17 (11): 3099–3104. doi:10.1016/j.bmcl.2007.03.040.
  19. ↑ Schmitz, William D. (2005). "Homotryptamines as potent and selective serotonin reuptake inhibitors (SSRIs)". Bioorganic 15 (6): 1619–1621. doi:10.1016/j.bmcl.2005.01.059.
  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.
  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.
  24. ↑ Blough, B.; Abraham, P.; Lewin, A.; Kuhar, M.; Boja, J.; Carroll, F. (1996). "Synthesis and transporter binding properties of 3β-(4′-alkyl-, 4′-alkenyl-, and 4′-alkynylphenyl)nortropane-2β-carboxylic acid methyl esters: serotonin transporter selective analogs". Journal of Medicinal Chemistry 39 (20): 4027–4035. doi:10.1021/jm960409s. PMID 8831768.
  25. ↑ Spealman, R. D.; Kelleher, R. T. (Mar 1981). "Self-administration of cocaine derivatives by squirrel monkeys". The Journal of Pharmacology and Experimental Therapeutics 216 (3): 532–536. ISSN 0022-3565. PMID 7205634.
  26. ↑ Carroll, F.; Tyagi, S.; Blough, B.; Kuhar, M.; Navarro, H. (2005). "Synthesis and monoamine transporter binding properties of 3alpha-(substituted phenyl)nortropane-2beta-carboxylic acid methyl esters. Norepinephrine transporter selective compounds". Journal of Medicinal Chemistry 48 (11): 3852–3857. doi:10.1021/jm058164j. PMID 15916437.
  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.

External links