Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
1999-08-04
2002-12-10
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C540S200000, C540S362000, C540S504000, C540S506000, C540S507000, C544S354000, C544S355000, C544S359000, C544S360000, C544S374000, C544S377000, C548S313700, C548S333500, C560S027000, C564S155000, C564S158000, C502S159000, C558S441000
Reexamination Certificate
active
06492553
ABSTRACT:
This invention is directed to a method for preparing an N-[(aliphatic or aromatic)carbonyl)]-2-aminoacetamide compound, and for preparing a cyclized compound therefrom, as well as to the novel resin bound intermediate compounds that are useful for preparing such compounds.
BACKGROUND OF THE INVENTION
1,4-benzodiazepine-2,5-diones are an important class of biologically actives compounds. This class of compounds has been identified as having platelet aggregation inhibitor activity, anticonvulsant activity, anxiolytic activity and activity as anti tumor agents (Mc Dowell, R. S. et al., J. Am. Chem. Soc., 1994, 116, 5077; Cho, N. S. et al., J Heterocycl. Chem., 1989, 26, 1807; Wright, W. B. et al., J. Med. Chem., 1978, 21, 1087; Jones; G. B. et al., Anti-Cancer Drug Des. 1990, 5, 249).
Diketopiperazines are known to be ligands of neurokinin-2 receptors and neurokinin-3 receptors (Gordon, D. W.; Steele, J. Bioorg. Med. Chem. Lett., 1995, 5, 47. (b) Terrett, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J.; Steele, J., Tetrahedron, 1995, 51, 8135) and are useful in the treatment of asthma, inflammation, Parkinsons disease, anxiety, psychosis, epilepsy and pain.
Reports of the biological utility of ketopiperazines have appeared in several areas, including applications as antagonists of the platelet glycoprotein IIb-IIIa (Takada, S.; Kurokawa, T.; Miyazaki, K.; Iwasa, S.; Ogawa, Y. Pharm. Res. 1997, 14, 1146), and substance P (Wright, H. B.; Martin, D. L. J. Med. Chem. 1968, 11, 390) and as hypocholesteremic agents (Piercey, M. F.; Moon, M. W.; Blinn, J. R. Brain Res., 1986, 385, 74).
Reports of the biological utility of dihydroquinoxalinones (also known as benzopiperazinones) have appeared in several areas, including applications as inhibitors of aldose reductase (Sarges, R.; Lyga, J. W. J. Heterocycl. Chem. 1988, 25, 1474), and partial agonists of the gamma-aminobutyric acid (GABA)/benzodiazepine receptor complex (Tenbrink, R. E.; Im, W. B.; Sethy, V. H.; Tang, A. H.; Carter, D. B. J. Med. Chem. 1994, 37, 758), angiotensin II receptor antagonists (Kim, K. S.; Qian, L.; Bird, J. E.; Dickinson, K. E.; Moreland, S.; Schaeffer, T. R.; Waldron, T. L.; Delaney, C. L.; Weller, H. N.; Miller, A. V. J. Med. Chem. 1993, 36, 2335); also they are known to possess antiviral activity as associated with HIV (Meichsner, C.; Riess, G.; Kleim, J. P.; Roesner, M.; Paessens, A.; Blunck, M. Eur. Pat. Appl. EP 657166 A1 950614).
Early work pioneered by Freidinger (Freidinger, R. M.; Perlow, D. S.; Veber, D. F. J. Org. Chem. 1982, 47, 104) showed g-lactams to be a useful new type of conformational constraint in peptides and useful in the synthesis of LHRH (Samenen, J.; Hempel, J. C.; Narindray, D.; Regoli, D. ‘Peptides. Chemistry and Biology’, Proc. 10th Am. Peptide Symp. 1988, 137), angiotensin II (Douglas, A. J.; Mulholland, G.; Walker, B.; Guthrie, D. J. S.; Elmore, D. T.; Murphy, R. F. Biochem. Soc. Trans. 1988, 16, 175), pentagastrin (Piercey, M. F.; Moon, M. W.; Blinn, J. R.; Dobry-Schreur, P. J. K. Brain Res. 1986, 385, 74), and substance P analogues. The lactams described herein, in particular those produced via cyclization of a primary amine, result in potential ATP competitive kinase inhibitors possessing functionality that may mimic the N1-N6 interaction of ATP binding to a relevant kinase (Myers, M. R.; He, W.; Hulme, C. Curr. Pharm. Design. 1997, 3, 473).
Benzodiazepines have been to shown to have utility as GPIIb/IIIa receptor antagonists (Ku, T. W.; Miller, W. H.; Bondinell, W. E.; Erhard, K. F.; Keenan, R. M.; Nichols, A. J.; Peishoff, C. E.; Samenen, J. M.; Wong, A. S.; Huffman, W. F. J. Med. Chem. 1995, 38, 9-12) and may be useful for the treatment of acute myocardial infarction, unstable angina, or thrombotic stroke. Recent developments have extended the therapeutic utility of this class of molecule to include integrin antagonists (for example antagonists of the vitronectin receptor), useful for the stimulation of bone formation and treatment of bone fractures, osteoporosis and other bone-related disorders (Drake, F. H. WO98115278-A1, 1997).
Dihydroimidazoles (or imidazolines) have been shown to have biological utility as anti-depressants and additionally imidazoline receptors are widely distributed in both the peripheral and central nervous system playing potential roles in the regulation of several physiological effects (Pigini, M.; Bousquet, P.; Carotti, A.; Dontenwill, M.; Gianella, M.; Moriconi, R.; Piergentili, A.; Quaglia, W.; Tayebati, S. K.; Brasili, L.; Bioorg. Med. Chem. 1997, 5, 833; Harfenist, M.; Heuser, D. J.; Joyner, C. T.; Batchelor, J. F.; White, H. L.; J. Med. Chem. 1996, 39, 1857; Jackson, H. C.; Griffin, I. J.; Nutt, D. J.; Br. J. Pharmacol. 1991, 104, 258; and Tibirica, E.; Feldman, J.; Mermet, C.; Gonon, F.; Bousquet, P. J. Pharmacol. 1987, 134, 1). The imidazoline moiety has also been extensively studied as an amide bond replacement in biologically active peptides (Gilbert, I.; Rees, D. C.; Richardson, R. S. Tetrahedron Lett. 1991, 32, 2277; and Jones, R. C. F.: Ward, G. J. Tetrahedron Lett. 1988, 29, 3853).
Cyclic ureas have recently shown promise as integrin receptor antagonists useful for the treatment and prevention of bone resorption, restenosis, angiogenesis and diabetic retinopathy (see M. E. Duggan et al., WO9931099-A1 and M. E. Duggan et al., WO9930713-A1).
Also, hydantoins have recently shown promise as inhibitors of luekocyte adhesion and migration and VLA-4 receptor inhibitors useful for the treatment and prevention of e.g. rheumatoid arthritis and inflammatory bowel disease (see V. Wehner et al., EP-903353-A1).
Pressures on the pharmaceutical industry have increased significantly to meet new economic challenges. As a consequence, efforts in both industrial and academic sectors are now being directed at new technologies for approaching drug discovery in a more efficient and cost-effective manner. As such, with the recent development of combinatorial chemistry and high speed parallel synthesis within the Lead Discovery arena, the multi-component reaction (MCR) has witnessed a resurgence of interest. From a practical consideration, “one-pot reactions”, such as the Ugi and Passerini reactions, are easily automated, and production of diverse or directed libraries of small organic molecules is thus both facile and high-throughput. Despite this tremendous synthetic potential, the Ugi reaction is limited in that it produces products that are flexible and peptidic-like, often being classified as “non-drug-like” and exhibiting bioavailability problems. Interestingly, several novel intramolecular variations of this versatile reaction have recently been reported, wherein constrained products are achieved by intercepting the intermediate nitrilium ion of the Ugi reaction. An alternative approach, and the one described in this application, is to constrain the Ugi product via a so-called secondary reaction after initial formation of the classical Ugi product. Production of the derivatives described herein is facile and amenable to automated high throughput production, allowing production of vast arrays of biologically relevant molecules (in the range of at least 10,000 molecules/template, revealed in good purity).
SUMMARY OF THE INVENTION
The present invention relates to a method for preparing an N-[(aliphatic or aromatic)carbonyl)]-2-aminoacetamide compound of the formula
wherein
R
aa
is hydrogen, alkoxy, an optionally substituted aliphatic moiety or an optionally substituted aromatic moiety;
R
b
is hydrogen, an optionally substituted aliphatic moiety or an optionally substituted aromatic moiety;
R
ca
and R
cb
are independently hydrogen, optionally substituted aliphatic or optionally substituted aromatic;
R
da
is optionally substituted aliphatic or optionally substituted aromatic; and wherein either
R
aa
is an aliphatic or aromatic moiety that is substituted with a primary or secondary protected amine that, upon deprotection, can react with the *ab or *db carbon, or with at least one R
b
, R
ca
and R
cb
, which is substituted with
Cherrier Marie-Pierre
Hulme Christopher
Labaudiniere Richard F.
Ma Liang
Mason Helen J.
Aventis Pharamaceuticals Inc.
Kumar Shailendra
Newman Irving
Wang George G.
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