ATC code none PubChem CID 104180 UNII 440C8K5Y5K Molar mass 237.339 g/mol | CAS Number 52760-47-1 ChemSpider 143316 Formula C17H19N | |
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Tametraline (CP-24,441) is the parent of a series of chemical compounds investigated at Pfizer that eventually led to the development of sertraline (CP-51,974-1).
Contents
- Chemistry
- cis trans Ratio
- CAN radical induced dimerization of styrene
- Structure activity relationship
- Enantiopurified trans and cis aminotetraline derivatives
- Racemic cis and trans aminotetraline derivatives
- References
Sertraline has been called "3,4-dichloro-tametraline". This is correct but it is an oversimplification in the sense that sertraline is the S,S-isomer whereas tametraline is the 1R,4S-stereoisomer.
1R-Methylamino-4S-phenyl-tetralin is a potent inhibitor of norepinephrine uptake in rat brain synaptosomes, reverses reserpine induced hypothermia in mice, and blocks uptake of 3H into rat heart.
Tametraline is a norepinephrine-dopamine reuptake inhibitor.
Indatraline is an indanamine homolog of tetralin-based tametraline, although in the case of indatraline the product is pm-dichlorinated.
Chemistry
Two routes have been previously described, one for aryl moieties containing electron withdrawing groups, and one for electron donating groups:
Sarges, R. . (1975). "Synthesis of phenyl-substituted 1-aminotetralines". The Journal of Organic Chemistry. 40 (9): 1216–1224. doi:10.1021/jo00897a008.
"As expected, Friedel-Crafts cyclization of the diarylbutyric acid derivatives # to the most reactive ring was observed with little or none of the alternative isomer being detected."
"The KMnO4 oxidation of the 1-aryl-tetralins # was observed to give 4-hydroxy-4-aryltetralones # instead of the expected tetralone # previously reported. As a result of this finding, direct oxidation of Grignard reaction product # was attempted and found to be a more efficient route."
See also: U.S. Patent 4,045,488 (and refs therein: doi:10.1021/ja01193a020 doi:10.1021/ja01183a058 doi:10.1021/ja01157a130 doi:10.1021/ja01635a052)
cis-/trans-Ratio
In the case of 3,4-dichloro product, approximately 50:50 cis-/trans- ratio was achieved, according to the reference.
CAN radical induced dimerization of styrene
"A facile one-pot synthesis of 1-amino-4-aryl-tetralin derivatives by the CAN-induced (see also: CAN) cyclodimerization of various styrenes in acetonitrile and acrylonitrile is described." [1] [2] doi:10.1021/ol0257934
Structure-activity relationship
Certain aromatic substitutients have a potentiating effect (e.g., p-Br), whereas others negate the compound's intrinsic activity.
It is not right to think of the dimethyl analogs as a "prodrug" to the monomethylated drugs (cf. indatraline, "31,345"), but it is correct that it is a "latentiated" form of the drug. This word is from the salsalate page. This was the reason why sertraline was made only as monomethylated because apparently according to the orders the 1° amine is inactive therefore the drug would have a shorter duration of activity.
Enantiopurified trans- and cis-aminotetraline derivatives
Interestingly, (±)-sertraline is not entirely SERT selective until it has been resolved into the S,S-enantiomer.
In terms of the trans- isomers there is relatively marked separation in the activity between the R,S- and S,R-enantiomers. This stands in contrast to what has been observed in the homologous indamine class where both of the trans- enantiomers possessed significant TRI activity at all three of the monoamine transporters.
Racemic cis- and trans-aminotetraline derivatives
The primary amines are claimed to completely lack any affinity for the transporters.