Cyclic amidines as benzamide bioisosteres: EPC synthesis and SAR studies leading to the selective dopamine D4 receptor agonist FAUC 312

Bioorganic and Medicinal Chemistry Letters

Volumn 13, Issue 5, 2003, Pages 851-854

  Einsiedel, Jürgen ^a   Hübner, Harald ^a   Gmeiner, Peter ^a  

^a UNIVERSITY OF ERLANGEN NUREMBERG   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

8 CHLORO 2,3,4,5 TETRAHYDRO 3 METHYL 5 PHENYL 1H 3 BENZAZEPIN 7 OL HYDROGEN MALEATE; AMIDINE; ASPARAGINE; BENZAMIDE DERIVATIVE; CLOZAPINE; DOPAMINE 4 RECEPTOR; DOPAMINE RECEPTOR STIMULATING AGENT; FAUC 312; LIGAND; PYRIMIDINE DERIVATIVE; QUINPIROLE; UNCLASSIFIED DRUG;

ANIMAL TISSUE; ARTICLE; CATTLE; CHIRALITY; CONFORMATION; CONTROLLED STUDY; DRUG EFFICACY; DRUG POTENCY; DRUG PURITY; DRUG RECEPTOR BINDING; DRUG SELECTIVITY; DRUG SYNTHESIS; ENANTIOMER; MITOGENESIS; NONHUMAN; RECEPTOR AFFINITY; STRUCTURE ACTIVITY RELATION;

EID: 0037430568     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(03)00004-0     Document Type: Article

References (30)

1. Einsiedel J., Hübner H., Gmeiner P. Bioorg. Med. Chem. Lett. 11:2001;2533. and references cited therein.
2. McCracken J.T., Smalley S.L., McGough J.J., Crawford L., Del'Homme M., Cantor R.M., Liu A., Nelson S.F. Mol. Psychiatry. 5:2000;531 Lichter J.B., Barr C.L., Kennedy J.L., Van Tol H.H.M., Kidd K.K., Livak K.J. Hum. Mol. Genet. 2:1993;767.
3. McCracken J.T., Smalley S.L., McGough J.J., Crawford L., Del'Homme M., Cantor R.M., Liu A., Nelson S.F. Mol. Psychiatry. 5:2000;531 Lichter J.B., Barr C.L., Kennedy J.L., Van Tol H.H.M., Kidd K.K., Livak K.J. Hum. Mol. Genet. 2:1993;767.
4. Löber S., Hübner H., Utz W., Gmeiner P. J. Med. Chem. 44:2001;2691 Bettinetti L., Schlotter K., Hübner H., Gmeiner P. J. Med. Chem. 45:2002;4594.
5. Löber S., Hübner H., Utz W., Gmeiner P. J. Med. Chem. 44:2001;2691 Bettinetti L., Schlotter K., Hübner H., Gmeiner P. J. Med. Chem. 45:2002;4594.
6. Gmeiner P., Hummel E., Haubmann C., Höfner G. Arch. Pharm (Weinheim Ger.). 328:1995;265.
7. 1%,pH4 98:2; 1 mL/min; 250 nm): SR (rt=25.01 min): RR (rt=22.35 min)=98:2.
8. Thomas C., Orecher F., Gmeiner P. Synthesis. 1998;1491.
9. Wang C.-L.J., Taylor T.L., Mical A.J., Spitz S., Reilly T.M. Tetrahedron Lett. 33:1992;7667.
10. Speicher A., Bomm V., Eicher T. J. Prakt. Chem. 338:1996;588.
11. Weber K., Kuklinski S., Gmeiner P. Org. Lett. 2:2000;647.
12. ent10a synthesized from 9a was reacted with (R)-PEI (according to ref 5). HPLC analysis showed no (SR)-diastereomer.
13. Djerassi C., Scholz C.R. J. Am. Chem. Soc. 49:1947;1688.
14. +): 334.21576; found: 334.21690.
15. Wheeler Am. Chem. J. 17:1895;358. Release of the free imidate base according to: Glickman S.A., Cope A.C. J. Am. Chem. Soc. 67:1945;1017.
16. Wheeler Am. Chem. J. 17:1895;358. Release of the free imidate base according to: Glickman S.A., Cope A.C. J. Am. Chem. Soc. 67:1945;1017.
17. Hirwe N.W., Patil B.V. J. Indian Chem. Sect. A. 1937;321.
18. Meyers A.I., Flisak J.R., Aitken R.A. J. Am. Chem. Soc. 109:1987;5446.
19. 3, resulting in a complete and clean formation of the amide.
20. Boksiner E.I., Golubyatnikova A.A., Fel'dman I.Kh. Zh. Obshch. Khim. 38:1968;999 Kato T., Takada A., Ueda T. Chem. Pharm. Bull. 20:1972;901 Weis A.L., Frolow F., Zamir D., Bernstein M. Heterocycles. 22:1984;657.
21. Boksiner E.I., Golubyatnikova A.A., Fel'dman I.Kh. Zh. Obshch. Khim. 38:1968;999 Kato T., Takada A., Ueda T. Chem. Pharm. Bull. 20:1972;901 Weis A.L., Frolow F., Zamir D., Bernstein M. Heterocycles. 22:1984;657.
22. Boksiner E.I., Golubyatnikova A.A., Fel'dman I.Kh. Zh. Obshch. Khim. 38:1968;999 Kato T., Takada A., Ueda T. Chem. Pharm. Bull. 20:1972;901 Weis A.L., Frolow F., Zamir D., Bernstein M. Heterocycles. 22:1984;657.
23. The structure of 15 and its tautomer were preminimized at the MM-level with MAXIMIN2, using the Tripos force field implemented in Sybyl 6.6. Employing the 6-31G* basis set and the ab initio program Gamess (version of 25.03.2000), a geometry optimization of both tautomers was performed, resulting in a significant energy difference of 5.3 kcal/mol in favour of tautomer 15.
24. Michel D., Waibel R., Gmeiner P. Heterocycles. 51:1999;365.
25. 3 and ent3 were investigated by performing chiral HPLC (Chiralcel OD; petroleum ether/iPrOH 1:1; 1 mL/min; 250 nm): 3: S (rt=16.1 min): R (rt=13.0 min):=96:4. ent3: R:S=99.4:0.6.
26. Hayes G., Biden T.J., Selbie L.A., Shine J. Mol. Endocrinol. 6:1992;920.
27. Sokoloff P., Andrieux M., Besancon R., Pilon C., Martres M.-P., Giros B., Schwartz J.-C. Eur. J. Pharmacol. 225:1992;331.
28. Agashari V., Sanyal S., Buchwaldt S., Paterson A., Jovanovic V., Van Tol H.H.M. J. Neurochem. 65:1995;1157.
29. Hübner H., Haubmann C., Utz W., Gmeiner P. J. Med. Chem. 43:2000;756.
30. Hübner H., Kraxner J., Gmeiner P. J. Med. Chem. 43:2000;4563.