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Tametraline
Systematic (IUPAC) name
(1R,4S)-N-methyl-4-phenyl-1,2,3,4-tetrahydronaphthalen-1-amine
Identifiers
CAS number 52760-47-1
ATC code none
PubChem 104180
Chemical data
Formula C 17H19N 
Mol. mass 237.339 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability  ?
Metabolism  ?
Half life  ?
Excretion  ?
Therapeutic considerations
Pregnancy cat.  ?
Legal status Legal
Routes  ?

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". In the case of tametraline the cis diastereomers are totally impotent and are separated from the product because they are an unneeded contaminant (depressing the crystals melting point, etc).

1R-Methylamino-4S-phenyl-tetralin is a potent inhibitor of NE uptake in rat brain synaptosomes,[2] reverses reserpine induced hypothermia in mice, and blocks uptake of [3H] into rat heart.[3]

Tametraline is a catecholamine reuptake inhibitor that possesses certain properties that are mandatory for a psychostimulant.[4] The benzhydryl moiety is an eminent feature and will remind viewers of related molecules such as desoxypipradrol. Indatraline is an indanamine analog of tetralin-based tametraline.

Contents

Chemistry

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)

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

"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."

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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

Tam. Mech.png

SAR

Certain aromatic substitutients have a potentiating effect (e.g. p-Br), whereas others negate the compounds intrinsic activity.

Enantiopurified Trans and Cis Aminotetraline Derivatives

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

Interestingly, (±)-sertraline is not entirely SERT selective until it has been resolved into the SS enantiomer.

C.f. "book" values:

In terms of the trans isomers there is relatively marked separation in the activity between the RS and SR 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 MA transporters.

Racemic Cis and Trans Aminotetraline Derivatives

Racemic trans 4-aryl-aminotetralins IC50 (μM)
R1 R2 X Y NE DA 5-HT
H Me H H 0.04 0.21 1.48
H Me F H 0.03 0.22 0.58
H Me Cl H 0.03 0.10 0.12
H Me Br H 0.03 0.08 0.09
H Me CF3 H 0.69 4.4 0.43
H Me H CF3 0.26 2.60 0.39
H Me OMe H 0.15 0.40 0.38
H Me Cl Cl 0.02 0.06 0.05
Me Me H H 0.14 0.84 0.46
Me Me Cl H 0.13 0.38 0.12
Me Me Cl Cl 0.04 0.17 0.04
Racemic cis 4-aryl-aminotetralins IC50 (μM)
R1 R2 X Y 5-HT DA NE
H Me H H 3.50 5.10 1.86
H Me F H 1.70 4.70 2.30
H Me Cl H 0.26 1.38 1.41
H Me Br H 0.19 1.60 1.40
H Me CF3 H 0.82 7.80 9.80
H Me H CF3 0.25 2.54 2.55
H Me OMe H 0.70 4.20 3.00
H Me Cl Cl 0.07 0.52 0.72
Me Me H H 1.6 10.0 0.31
Me Me Cl H 0.24 5.60 1.16
Me Me Cl Cl 0.07 2.00 0.40
H H Cl Cl 0.40 1.25 0.25

Figures in brackets are for the N-dimethyl congeners. The primary amines are claimed to completely lack any affinity for the transporters.

c.f. "This property can be perceived as a potential advantage in that enhanced synaptosomal DA levels may be equated with undesirable stimulant properties of certain compounds in the trans series.[6]"

See also

EXP-561 (1-amino-4-phenylbicyclo[2.2.2]octane)
  • EXP-561 (1-amino-4-phenylbicyclo[2.2.2]octane)
  • cyproheptadine [4-(5H-dibenz-[a,d]cyclohepten-5-ylidine)-1-methylpiperidine]
  • Nefopam
  • CP-24,441 (1R, 4S-N-methyl- 4-phenyl-1,2,3,4-tetrahydro-1-naphthylamine)
  • CP-39,332 (N-methyl-4-phenyl-1,2,3,4-tetrahydro-2- naphthylamine)
  • JNJ-7925476

Sepracor has tried to patent the trans dichloro analog U.S. Patent 7,105,699

External links

During his 40 years at Pfizer, Koe authored more than 100 articles and papers. ... Koe learned to review previous studies and to build on findings that had failed to lead to successful products. In his early work with serotonin, for example, he studied the chemical tametraline, which proved ineffective as an anti-depressant.

Tests showed the chemical functioned more as a stimulant, a use Pfizer was not interested in pursuing. Although his research had failed to yield the desired result, Koe was convinced that the development of a viable anti-depressant was within reach.

References

  1. ^ Koe, BK; Weissman; Welch; Browne (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.   edit
  2. ^ Koe, BK (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): 649–61. PMID 994022.   edit
  3. ^ Sarges, R; Koe; Weissman; Schaefer (1974). "Blockade of heart 3H-norepinephrine up-take 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.   edit
  4. ^ Welch, WM; Kraska; Sarges; Koe (1984). "Nontricyclic antidepressant agents derived from cis- and trans-1-amino-4-aryltetralins". Journal of medicinal chemistry 27 (11): 1508–15. doi:10.1021/jm00377a021. PMID 6492080.   edit
  5. ^ a b Sarges, R. (1975). "Synthesis of phenyl-substituted 1-aminotetralines". The Journal of Organic Chemistry 40: 1216–1224. doi:10.1021/jo00897a008.   edit
  6. ^ Spyraki, C; Fibiger (1981). "Intravenous self-administration of nomifensine in rats: implications for abuse potential in humans". Science (New York, N.Y.) 212 (4499): 1167–8. PMID 7195072.   edit

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