Tametraline

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Tametraline
Tametraline.svg
Clinical data
ATC code
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Chemical and physical data
FormulaC17H19N
Molar mass237.339 g/mol g·mol−1
3D model (JSmol)
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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).[1]

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,[2] reverses reserpine induced hypothermia in mice, and blocks uptake of 3H-Norepinephrine into rat heart.[3]

Tametraline is a norepinephrine-dopamine reuptake inhibitor.[4]

Indatraline is an indanamine homolog of tetralin-based tametraline, although in the case of indatraline the product is pm-dichlorinated.

Chemistry[edit]

Two routes have been previously described,[5] one for aryl moieties containing electron withdrawing groups, and one for electron donating groups:

Preparation of tametraline[6]

"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."

Tametraline synthesis.png

"The KMnO4 oxidation of the 1-aryl-tetralins # was observed to give 4-hydroxy-4-aryltetralones # instead of the expected tetralone # previously reported.[5] As a result of this finding, direct oxidation of Grignard reaction product # was attempted and found to be a more efficient route."

See also [6][7][8][9][10].

cis-/trans-Ratio[edit]

In the case of 3,4-dichloro product, approximately 50:50 cis-/trans- ratio was achieved, according to the reference.[4]

CAN radical induced dimerization of styrene[edit]

"A facile one-pot synthesis of 1-amino-4-aryl-tetralin derivatives by the CAN-induced cyclodimerization of various styrenes in acetonitrile and acrylonitrile is described."[11][12]

one-pot synthesis of 1-amino-4-aryl-tetralin derivatives by the CAN-induced cyclodimerization of various styrenes in acetonitrile and acrylonitrile

Structure-activity relationship[edit]

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[edit]

"31,345" structure:[13]
Enantiopurified 4-aryl-aminotetralins IC50 (μM)
Stereo X Y NE DA 5-HT
RS H H 0.018 0.15 0.84
SR H H 0.37 1.40 14.00
RS Cl H 0.019 0.052 0.084
SR Cl H 0.46 1.40 3.50
RS Cl Cl 0.01 0.044 0.039
SR Cl Cl 0.044 0.27 0.47
SS Cl Cl 1.20 1.30 0.06
RR Cl Cl 0.30 0.32 0.46

(±)-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[edit]

The primary amines are claimed to completely lack any affinity for the transporters.

See also[edit]

References[edit]

  1. ^ Koe, B. Kenneth; Weissman, Albert; Welch, Willard M.; Browne, Ronald G. (1983). "Sertraline, 1S,4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine, a new uptake inhibitor with selectivity for serotonin". The Journal of Pharmacology and Experimental Therapeutics. 226 (3): 686–700. PMID 6310078.
  2. ^ Koe, B. Kenneth (1976). "Molecular geometry of inhibitors of the uptake of catecholamines and serotonin in synaptosomal preparations of rat brain". The Journal of Pharmacology and Experimental Therapeutics. 199 (3): 649–661. PMID 994022.
  3. ^ Sarges, Reinhard; Koe, B. Kenneth; Weissman, Albert; Schaefer, John P. (1974). "Blockade of heart 3H-norepinephrine uptake by 4-phenyl-1-aminotetralines: Implications for the active conformation of imipramine-like drugs". The Journal of Pharmacology and Experimental Therapeutics. 191 (3): 393–402. PMID 4427286.
  4. ^ a b Welch, Willard M.; Kraska, Allen R.; Sarges, Reinhard; Koe, B. Kenneth (1984). "Nontricyclic antidepressant agents derived from cis- and trans-1-amino-4-aryltetralins". Journal of Medicinal Chemistry. 27 (11): 1508–1515. doi:10.1021/jm00377a021. PMID 6492080.
  5. ^ a b Sarges, Reinhard (1975). "Synthesis of phenyl-substituted 1-aminotetralines". The Journal of Organic Chemistry. 40 (9): 1216–1224. doi:10.1021/jo00897a008.
  6. ^ a b US patent 4045488, Sarges, Reinhard, "Aminophenyltetralin compounds", issued 1977-08-30, assigned to Pfizer Inc. 
  7. ^ Johnson, William S.; Petersen, Jack W.; Schneider, William P. (1947). "Extension of the modified Stobbe condensation. Acid-catalyzed decomposition of the products and a lacto–enoic tautomerism". Journal of the American Chemical Society. 69 (1): 74–79. doi:10.1021/ja01193a020.
  8. ^ Riegel, Byron; Burr, John G., Jr. (1948). "Carcinogenic hydrocarbons. 9,11-Dimethylbenz[a]anthracene and 8,9,11-trimethylbenz[a]anthracene". Journal of the American Chemical Society. 70 (3): 1070–1073. doi:10.1021/ja01183a058. PMID 18909174.
  9. ^ Daub, Guido H.; Johnson, William S. (1950). "The Stobbe condensation with sodium hydride". Journal of the American Chemical Society. 72 (1): 501–504. doi:10.1021/ja01157a130.
  10. ^ Wawzonek, Stanley; Kozikowski, John (1954). "2-Substituted amino- and aminomethyl-4-phenyl-1-tetralones". Journal of the American Chemical Society. 76 (6): 1641–1643. doi:10.1021/ja01635a052.
  11. ^ Nair, Vijay; Rajan, Roshini; Rath, Nigam P. (2002). "A CAN-induced cyclodimerization–Ritter trapping strategy for the one-pot synthesis of 1-amino-4-aryltetralins from styrenes". Organic Letters. 4 (9): 1575–1577. doi:10.1021/ol0257934. PMID 11975632.
  12. ^ "A CAN-induced cyclodimerization–Ritter trapping strategy for the one-pot synthesis of 1-amino-4-aryltetralins from styrenes: Vijay Nair, Roshini Rajan and Nigam P. Rath". Abstract. Organic Chemistry Portal. Reto Müller. n.d. Retrieved November 10, 2019.
  13. ^ Peng, Xiao-Qing; Xi, Zheng-Xiong; Li, Xia; Spiller, Krista; Li, Jie; Chun, Lauren; Wu, Kuo-Ming; Froimowitz, Mark; Gardner, Eliot L. (2010). "Is slow-onset long-acting monoamine transport blockade to cocaine as methadone is to heroin? Implication for anti-addiction medications". Neuropsychopharmacology. 35 (13): 2564–2578. doi:10.1038/npp.2010.133. PMC 2978747. PMID 20827272.