Amide compound libraries

Details Amide compound libraries Amide compound libraries

1999-03-19

2002-03-19

Celsa, Bennett (Department: 1627)

Synthetic resins or natural rubbers -- part of the class 520 ser

Synthetic resins

Mixing of two or more solid polymers; mixing of solid...

C514S579000, C546S316000, C548S228000, C548S229000, C548S316400, C548S336100, C548S338100, C548S338500, C548S477000, C548S497000, C558S390000, C558S430000, C558S438000, C558S442000, C540S145000, C540S132000, C564S001000, C564S050000, C564S105000, C544S358000

Reexamination Certificate

active

06359061

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to diverse combinatorial libraries, processes and apparatus, in particular to diverse libraries of compounds incorporating amide scaffolds.
BACKGROUND OF THE INVENTION
Discovery of new therapeutic compounds for treating diseases has typically involved screening individual compounds against targets representative of a particular disease of interest. The iterative process relies upon finding a compound having at least a minimal level of activity in an assay and then synthesizing as many derivatives of the lead compound as possible. The derivatives tested would form the basis of a “structure-activity relationship” (SAR) which would hopefully provide insight for designing a lead compound. Often the process is repeated time and again before any lead is uncovered. The obvious and major drawback in this drug discovery process is the generation of compounds on a one-at-a-time basis requiring much labor, time and expense.
Advances in robotics and solid-phase chemical synthesis has spawned the combinatorial approach for preparing libraries of compounds which makes synthesizing thousands of diverse compounds feasible. What once took months or even years by the traditional approach has become possible in a matter of weeks and even days through combinatorial chemistry, thereby drastically reducing the time, labor and expense involved in drug discovery.
The combinatorial approach has been adapted for preparing vast libraries of oligomeric compounds such as peptides and non-oligomeric small organic molecules on the order of 10
2
to 10
6
discreet compounds. Theoretically the total number of compounds in a library is limited only by the number of available reagents for forming substituents on a central scaffold.
SUMMARY OF THE INVENTION
The present invention provides amide compounds of formula (I):
wherein:
each R
1
, R
1′
, R
4
, R
5
and R
5′
is, independently, H, an amino protecting group, or CH
2
, CH(R
2
), C═O, C═S, S(═O)
2
, C(═O)NH, C(═S)NH or C(═O)O substituted with H or a hydrocarbyl group selected from C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
20
alkynyl, C
6
-C
14
aryl, C
6
-C
14
aralkyl, C
3
-C
14
cycloalkyl, C
5
-C
14
fused cycloalkyl, C
4
-C
14
heterocycle, C
4
-C
14
heterocyclylalkyl, C
4
-C
14
heteroaryl, C
4
-C
14
heteroarylalkyl and CH(R
2
)—NH—R
2
; wherein said hydrocarbyl group is optionally substituted with oxo, acyl, alkoxy, alkoxycarbonyl, alkyl, alkenyl, alkynyl, amino, amido, azido, aryl, heteroaryl, carboxylic acid, cyano, guanidino, halo, haloalkyl, haloalkoxy, hydrazino, hydroxyl, alkylsulfonyl, nitro, sulfide, sulfone, sulfonate, sulfonamide, thiol, and thioalkoxy, provided that R
1′
may also be a solid support and R
4
is not H; and
each R
2
and R
3
is, independently, H or a hydrocarbyl group selected from C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
20
alkynyl, C
6
-C
14
aryl, C
6
-C
14
aralkyl, C
3
-C
14
cycloalkyl, C
5
-C
14
fused cycloalkyl, C
4
-C
14
heterocyclyl, C
4
-C
14
heterocycloalkyl, C
4
-C
14
heteroaryl and C
4
-C
14
heteroarylalkyl; wherein said hydrocarbyl group is optionally substituted with acyl, alkoxy, alkoxycarbonyl, alkyl, alkenyl, alkynyl, amino, amido, azido, aryl, heteroaryl, carboxylic acid, cyano, guanidino, halo, haloalkyl, haloalkoxy, hydrazino, hydroxyl, alkylsulfonyl, nitro, sulfide, sulfone, sulfonate, sulfonamide, thiol or thioalkoxy, provided that R
2
is not H.
The present invention also provides combinatorial libraries comprising a plurality of amide compounds of formula
In another aspect of the present invention there are provided methods for preparing amide compounds of formula (I) comprising:
attaching an amine to a solid support to form a solid support-bound amine of formula (II) wherein SS is a solid support;
 reacting compound (II) with an FMOC-protected amino acid to form an amide compound of formula (III);
 replacing the FMOC protecting group on the amino acid with a sulfonyl protecting group to form an amide compound of formula (IV);
 reacting the secondary amine moiety of the compound of formula (IV) with a protected aminohydroxy compound of formula (V) wherein Pg is a protecting group;
to form an amide compound of formula (VI);
 removing the sulfonyl protecting group of the compound of formula (VI) to form an amide compound of formula (VII) bearing a protected terminal primary amine moiety and a secondary amine moiety;
 reacting the secondary amine of the compound of formula (VII) with an R
4
building block to form an amide compound of formula (VIII) bearing a protected terminal primary amine moiety;
 removing the protecting group on the terminal primary amine moiety to form an amide compound of formula (IX); and
 reacting the deprotected primary amine moiety with an R
5
building block to form an amide compound of formula (X).
Also provided, in accordance with the present invention, are methods further comprising cleaving amide compounds of formula (X) from the solid support to form amide compounds of formula (I).
The present invention also provides pharmaceutical compositions of amide compounds of formula (I).


REFERENCES:
patent: 5539083 (1996-07-01), Cook et al.
patent: 5831014 (1998-11-01), Cook et al.
Dueholm et al., Bioorg. Med. Chem. Lett. vol. 4(8) pp 1077-1080 and RN 159411-09-3, Apr. 1994.*
Achari, A. et al., “Facing up to Membranes: Structure / Function Relationships in Phospholipases”,Cold Spring Harbor Symp. Quant. Biol., 1987, vol. 52, Cold Spring Harbor Laboratory, 441-452.
Atherton, E. et al., “The Fluorenylmethoxycarbonyl Amino Protecting Group”,The Peptides, 1987, 9, 1-39.
Bomalaski, J.S. et al., “Human Extracellular Recombinant Phospholipase A2Induces an Inflamatory response in Rabbit Joints”,J. Immunol., 1991, 146, 3904-3910.
Brennen, T. et al., “Two-Dimensional Parallel Array Technology as a New Approach to Automated Combinatorial Solid Phase Organic Synthesis”,Biotech.&Bioengin., 1998, 61, 33-45.
Burack, W.R. et al., “Role of Lateral Phase Separation in the Modulation of Phospholipase A2Activity”,Biochemistry, 1993, 32, 583-589.
Campbell, M.M. et al., “Inhibition of Phospholipase A2; a Molecular Recognition Study”,J. Chem. Soc. Chem. Comm., 1988, 1560-1562.
Cho, W. et al., “The Chemical Basis for Interfacial Activation of Monomeric Phospholipases A2”,J. Biol. Chem., 1988, 263, 11237-11241.
Davidson, F.F. et al., “1-Stearyl,2-Stearoylaminodeoxyphosphatidylcholine, A Potent Reversible Inhibitor of Phospholipase A2”,Biochem. Biophys. Res. Comm., 1986, 137, 587-592.
Davidson, F.F. et al., “Inhibition of Phospholipase A2by ‘Lipocortins’ and Calpactins”,J. Biol. Chem., 1987, 262, 1698-1705.
Dennis, E.A., “Phospholipases”,The Enzymes, Boyer, P.D. (ed.), Academic Press, New York, 1983, vol. 16, 307-353.
Franson, R. et al., “Phospholipid metabolism by phagocytic cells. Phospholipase A2associated with rabbit polymorphonuclear leukocyte granules”,J. Lipid Res., 1974, 15, 380-388.
Glaser, K.B. et al., “Phospholipase A2enzymes: regulation and inhibition”,TiPS, 1993, 14, 92-98.
Grainger, D.W. et al., “An enzyme caught in action: direct imaging of hydrolytic function and domain formation of phospholipase A2in phosphatidylcholine monolayers”,FEBS Letts., 1989, 252, 73-82.
Lombardo, D. et al., “Cobra Venom Phospholipase A2Inhibition by Manoalide”,J. Biol. Chem., 1985, 260, 7234-7240.
Märki, F. et al., “Differential inhibition of human secreory and cytosolic phospholipase A2”,Agents Actions, 1993, 38, 202-211.
Miyake, A. et al., “The Novel Natural Product YM-26567-1 [(+)-trans-4-(3-dodecanoyl-2,3,6-trihydroxyphenyl)-7-hydroxy2-(4-hydroxyphenyl)chroman]: A Competitive Inhibitor of Group II Phospholipase A2”,J. Pharm. Exp. Therap., 1992, 263, 1302-1307.
Noel, J.P. et al., “Phospholipase A2Engineering. 3. Replacement of Lysine-56 by Neutral Residues Improves Catalytic Potency Significantly, Alters Substrate Specificity, and Clarifies the Mechanism of Interfacial Recognition”,J. Am. Chem. Soc., 1990, 112, 3704-3706.
Oinuma, H.

Affiliated with

Also associated with

Rating

Amide compound libraries does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Amide compound libraries, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Amide compound libraries will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2840181