2-aminotetralin derivatives

Extremely active compounds are found among 2-aminotetralines. 6,7-Dihydroxy-2-aminotetraline (4.85, ADTN) and its A-(n-propyl) derivative are well-studied 2-aminotetraline derivatives. Nomifensine (4.83) is related to these aminotetralines and is used as an antidepressant drug. The catechol analog of nomifensine (with two hydroxyls on the 4-phenyl ring) is also a potent inhibitor of NE and DA uptake. 

Homan, E.J. (1998) The medicinal chemistry of 2-aminotetralin-derived henzamides A novel class of potential atypical antipsychotic agents. PhD thesis, Groningen University. 

Cannon, J.G. Lee, T. Goldman, H.D. Costall, B. Naylor, R.J. (1977) Cerebral dopamine agonist properties of some 2-aminotetralin derivatives after peripheral and intracerebral administration. J. Med. Chem 20,1111-1116. 

Seiler, M.P. Stoll, A. Closse, A. Frick, W. Jaton, A Vigouret, J.M. (1986) Structure-activity relationships of dopaminergic 5-hydroxy-2-aminotetralin derivatives with functionalized N-alkyl substituents. J. Med. Chem. 29, 912-917. 

Timmerman, W. Tepper, P.G. Dijkstra, D. Stoelwinder, H. Grol, C.J. Westerink, B.H. Horn, A.S. (1991) Enantiomers of monohydroxy-2-aminotetralin derivatives and their activity at dopamine autoreceptors as studied by brain dialysis. Eur. J. Pharmacol. 199, 145-151. 

In continuing studies on aminotetralin derivatives the best compound, (12), was found to possess slightly more than half of the oral analgesic potency of morphine as measured by the acetic acid writhing test.13 ... 

S Cascade reactions implementing the Ritter reaction Recent examples of the Ritter reaction have combined this useful synthetic tool with other reactions and rearrangements to produce complex reaction sequences. For example, Bishop has reported the combination of the Ritter reaction with the Wagner-Meerwein rearrangement, which can result in complex and sometimes unpredictable reaction sequences.17 The use of the Ritter reaction to trap cationic intermediates in the CAN-mediated dimerization of alkoxystyrenes has recently allowed the synthesis of a-aminotetralin derivatives by Nair.18... 

Fig. 5.10 Aminotetralin-derived hit 2 yields the optimized Y5 receptor antagonist 8i. Note the replacement of the benzyl side chain by an ally side chain.

Numerous tryptamines bind with high affinity at 5-HTia receptors, but most are notoriously nonselective. One of the most selective 5-HTia receptor agonists is the aminotetralin derivative 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH DPAT), and its early discovery was significant in advancing an understanding of 5-HTia receptors. Furthermore, because the structure of 8-OH DPAT is similar to that of 5-HT (8-OH DPAT/serotonin), its activity indicated that an intact indole nucleus was not required for 5-HT ia actions. Although numerous 8-OH DPAT derivatives have been reported, none is used therapeutically because of low oral bioavailability. This has led to efforts to develop novel aminotetralins with greater oral availability. 

Ethonam (99), an imidazole derivative with a very different substitution pattern, is also reported to possess antifungal activity. To prepare it, alkylation of aminotetralin 94 with methylchloro-acetate gives the glycine derivative 95. Heating with formic acid then affords the amide 96 this compound is then reacted with ethyl formate to yield hydroxymethylene ester 97. Reaction with isothio-cyanic acid gives the imidazole-2-thiol 98. (The... 

An interesting comparison can be made looking at the a- and (5-tetralin derivatives entries—15/16 and —17 in Table 1 which can be regarded as cyclic confor-mationally constrained analogues of phenylglycine and phenylalanine. In an interesting study, 6-hydroxy-2-aminotetralin-2-carboxylic acid 12 (Hat) has been incorporated as a conformationally constrained tyrosine analogue into S-opioid receptor selective tetrapeptides.114 15 Whereas entry 15, the (S)-a-tetralin deriva-... 

Some of the earliest and most complete efforts at structural dissection have been carried through by Cannon and his co-workers at the University of Iowa. These studies were initially directed toward elucidation of the pharmacophoric element within the structure of the emetic agent apomorphine, I. The suggestion by Pinder et al. (2) that the 5,6-dihydroxy-2-aminotetralin fragment was the active moiety was followed in short order by the report of Cannon et al. (3) that the N,N-dimethyl derivative ("M-7") II was a potent emetic in the dog. Additional pharmacology on M-7 provided by Long et al. (4) further illustrated the similarity between I and II. Both... 

Holmberg P, Sohn D, Leideborg R, et al. Novel 2-aminotetralin and 3-aminochro-man derivatives as selective serotonin 5-HT7 receptor agonists and antagonists. J Med Chem 2004 47 3927-3930. 

The 2-aminotetralin skeleton has attracted several groups as a basis for potential analgesics. Martin ef a/.(44) succeeded in obtaining several derivatives... 

Since it was found that the thienylethylamine moiety might act as a dopamine receptor pharmacophore, we tested whether a thiophene moiety may act as a bioisostere for a phenol in 2-aminotetralins and hexahydronaphthoxazines. Therefore, thiophene analogues of the 2-aminotetralins and hexahydronaphthoxazines, 34-39 were synthesised. All the compounds synthesised were tested in vitro for their affinity at dopamine D2L and D3 receptors. The derivatives with interesting properties were further investigated for their in vivo dopamine receptor activity and bioavailability using the microdialysis technique in freely moving rats.215... 

Conformationally Constrained Analogs. Local constraints have been incorporated into dynorphin A. The conformational ly constrained phenylalanine derivative Ate (2-aminotetralin-2-carboxylicacid. Fig. 7.43) has been incorporated in [D-Ala ]dynorphin A-(l-... 

V,iV-Di-n-propyl derivatives of 5- or 7-hy-dro3 -2-aminotetralin, e.g., (i )-(+)-7-OH-DPAT (122) and (S)-(-)-5-OH-DPAT, and the corresponding indane derivatives, exemplified by U 99194 (123), were identified as potent and relatively selective Dg agonists (575). However,... 

Another report on ion-pair chromatography, where computed molecular descriptors from molecular modeling were nicely correlated with experimental separation factors, was published by Karlsson, Luthman, Pettersson and Hacksell [81]. They examined factors responsible for separation of aminotetralins on achiral stationary phases in the presence of the chiral additive N-benzyloxycarbonylglycyl-L-proline (L-ZGP), a protected peptide derivative. 

An early example of the use of discriminant analysis in QSAR involved inhibition of the enzyme monoamine oxidase (MAO) by derivatives of aminotetralins and aminoindans shown in Fig. 7.2 (Martin et al. 1974, see also Section 5.5). These compounds inhibited the enzyme in vitro, and it... 

The reaction tolerates the presence of a phenyl group at the carbon atom that forms the bond with the aryl ring well, and can be stopped before decarboxylation or proceeds further to monocarboxylic acids derivatives of tetralin. As an example, cyclization of malonate 28 at room temperature with the use of anyhydrous hydrogen fluoride gives dicarboxylate 29." The anhydrous pyridinium poly(hydrogen fluoride) is more efficient in the same reaction. Compound 29 is obtained with almost quantitative yield with purity sufficient to use a crude product for the follow-up synthetic transformations, which lead to derivatives of l-phenyl-3-aminotetralins 30 that exhibit potential for the treatment of Parkinson disease. ... 

The reaction has been extended to synthesis of tetralone derivatives. Thus treatement of 31 with polyphosphoric acid leads to the substituted 3-tetralone 32, which can be also converted to l-phenyl-3-aminotetraline 33 providing a complementary synthetic route to that one for 30 illustrated above. 

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