Tametraline

Tametraline

Clinical data
ATC code	none
Identifiers
IUPAC name (1R,4S)-N-methyl-4-phenyl-1,2,3,4-tetrahydronaphthalen-1-amine
CAS Number	52760-47-1 Y
PubChem (CID)	104180
ChemSpider	143316 N
UNII	440C8K5Y5K Y
Chemical and physical data
Formula	C17H19N
Molar mass	237.339 g/mol
3D model (Jmol)	Interactive image
SMILES CN[C@H](CC1)C(C=CC=C2)=C2[C@H]1C3=CC=CC=C3
InChI InChI=1S/C17H19N/c1-18-17-12-11-14(13-7-3-2-4-8-13)15-9-5-6-10-16(15)17/h2-10,14,17-18H,11-12H2,1H3/t14-,17+/m0/s1 N Key:NVXPZMLRGBVYQV-WMLDXEAASA-N N
NY (what is this?)  (verify)

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).

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:

Preparation of Tametraline: U.S. Patent 4,045,488 Reinhard Sarges; Pfizer Inc.

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

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

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

"31,345" structure:

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 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

Racemic trans 4-aryl-aminotetralins IC50 (μM)
R1	R2	X	Y	NE	DA	5-HT
H	CH3	H	H	0.04	0.21	1.48
H	CH3	F	H	0.03	0.22	0.58
H	CH3	Cl	H	0.03	0.10	0.12
H	CH3	Br	H	0.03	0.08	0.09
H	CH3	CF3	H	0.69	4.4	0.43
H	CH3	H	CF3	0.26	2.60	0.39
H	CH3	OCH3	H	0.15	0.40	0.38
H	CH3	Cl	Cl	0.02	0.06	0.05
CH3	CH3	H	H	0.14	0.84	0.46
CH3	CH3	Cl	H	0.13	0.38	0.12
CH3	CH3	Cl	Cl	0.04	0.17	0.04

Racemic cis 4-aryl-aminotetralins IC50 (μM)
R1	R2	X	Y	5-HT	DA	NE
H	CH3	H	H	3.50	5.10	1.86
H	CH3	F	H	1.70	4.70	2.30
H	CH3	Cl	H	0.26	1.38	1.41
H	CH3	Br	H	0.19	1.60	1.40
H	CH3	CF3	H	0.82	7.80	9.80
H	CH3	H	CF3	0.25	2.54	2.55
H	CH3	OCH3	H	0.70	4.20	3.00
H	CH3	Cl	Cl	0.07	0.52	0.72
CH3	CH3	H	H	1.6	10.0	0.31
CH3	CH3	Cl	H	0.24	5.60	1.16
CH3	CH3	Cl	Cl	0.07	2.00	0.40
H	H	Cl	Cl	0.40	1.25	0.25

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

See also

Dimefadane	Indriline

• 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)
• Cyproheptadine [4-(5H-dibenz-[a,d]cyclohepten-5-ylidine)-1-methylpiperidine]
• Dasotraline
• Desmethylsertraline
• EXP-561 (1-amino-4-phenylbicyclo[2.2.2]octane)
• JNJ-7925476
• Lometraline
• Nefopam
• Sertraline

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

External links

• http://www.healyprozac.com/Book/Introduction.doc
• http://www.zoominfo.com/people/Koe_Ken_594418650.aspx

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.