Methods for the synthesis of densely functionalized...

Details Methods for the synthesis of densely functionalized... Methods for the synthesis of densely functionalized...

2002-03-12

2003-01-28

Dentz, Bernard (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S453000, C548S531000, C548S538000, C548S550000, C548S551000, C548S566000, C548S568000, C548S572000

Reexamination Certificate

active

06512120

ABSTRACT:

FIELD OF THE INVENTION
This invention is directed to a method for synthesizing densely functionalized pyrrolidine intermediates. In particular, the invention is directed to a method for synthesizing highly substituted pyrrolidine intermediates both on and off solid supports. More particularly, the invention is directed to highly substituted pyrrolidine intermediates useful for the further in situ and resin-bound synthetic generation of chemical libraries.
BACKGROUND OF THE INVENTION
Compounds having biological activity can be identified by screening diverse collections of compounds (i.e., libraries of compounds) produced through molecular biology techniques or synthetic chemical techniques.
Pharmaceutical drug discovery relies heavily on studies of structure-activity relationships wherein the structure of “lead compounds” is typically altered to determine the effect of the alteration on activity. Alteration of the structure of the lead compound around a core “scaffold” structure creates a plurality of compounds and permits evaluation of the effect of the structural alteration on activity.
The “library” of compounds thus created is derived from a single lead compound. Accordingly, a plurality of scaffolds and libraries can be created and screened by modifying the core of the lead compound and repeating the screening procedures. In this manner, compounds with the best biological profile, i.e. those that are most active and which have the most ideal pharmacologic and pharmacokinetic properties, can be quickly identified from the initial lead compound.
The generation of chemical libraries both on and off solid resins have proven to be a valuable resource for the pharmaceutical industry in their endeavors to discover new drugs using high throughput screening techniques (Wu, Zengru et al,
Beijing Daxue Xuebao, Ziran Kexueban
2000, 36(2), 275-285; Brummer, Oliver et al,
Curr. Opin. Drug Discovery Dev.,
2000, 3(4), 462-473; Roe, Diana C.,
Mol. Diversity Drug Des.,
1999, 141-173; Barnes, Colin et al,
Curr. Opin. Chem. Biol.,
2000, 4(3), 346-350; Weber, Lutz,
Curr. Opin. Chem. Biol.,
2000, 4(3), 295-302).
In creating the libraries, the compounds are ideally synthesized on a solid support (resin-bound) or in solution phase (in situ or off-solid support). Relatively simple synthetic methods to produce a diverse collection of such derivatives in situ, though, are often not available.
The need for large numbers of compounds has led to the synthesis of compounds based on very simple templates. A number of peptidomimetic libraries based on amino acid modules have also been introduced (R. A. Owens et al,
Biochem. Biophys. Res. Comm.,
1991, 181, 402; P. F. Alewood et al,
Tet. Lett.,
1992, 33, 977; E. K. Kick and J. A. Ellman,
J. Med. Chem.,
1995, 38, 1427; G. T. Wang et al,
J. Med. Chem.,
1995, 38, 2995; J. Jiracek et al,
J. Biol. Chem.,
1995, 270 21701). Chiron's peptoid approach led to a number of interesting starting points for analogs early in the library generation era (Zuckermann, Ronald N. et al,
J. Am. Chem. Soc.,
1992, 114(26), 10646-7). Amino acid based libraries have been used to address protein-protein interactions as well (Connolly, P. J. et al,
Bioorg. Med. Chem. Lett.,
2000, 10(17), 1995-1999; Connolly, P. J. et al,
Tetrahedron Lett.,
2000, 41(27), 5187-5191). Unfortunately, some of the more simple libraries have not yielded compounds that demonstrate significant biological activity.
More recently efforts have been made to develop chemistry that is amenable to library generation that produces molecules of considerable complexity for the purpose of creating more diverse chemical libraries. Recently electrocyclic reactions of amino acid derived dienes have been used to produce densely funtionalized octahydroquinolines and hexahydroisoindoles (Sun, Sengen et al,
J. Org. Chem.,
2000, 65(8), 2555-2559; Murray, William V. et al,
J. Org. Chem.,
1999, 64(16), 5930-5940; Sun, Sengen and Murray, William V.,
J. Org. Chem.,
1999, 64(16), 5941-5945). Diels Alder reactions are useful synthetic methods either on or off solid support and allow for control of facial selectivity, endo versus exo selectivity and stereochemical selectivity at most of the ring positions.
Pyrrolidines are a class of molecules that have demonstrated diverse biological activity. PCT publication WO0056296 (published Sep. 28, 2000) describes substituted pyrrolidine compounds as dipeptidyl peptidase IV inhibitors for use in improving fertility. U.S. Pat. No. 5,935,980 (PCT publication WO9638139, published Dec. 5, 1996) describes substituted pyrrolidine compounds for use in treating alcoholism and associated conditions. U.S. Pat. No. 6,150,387 (PCT publication WO9728798, published Aug. 14, 1997) describes substituted pyrrolidine compounds for use in preventing or reducing drug dependence, pharmacomania or substance abuse and as useful CCK (cholecystokinin) and gastric receptor inhibitors for treating or preventing psychoses, anxiety disorders, Parkinson's disease, tardive dyskinesia, irritable bowel syndrome, acute pancreatitis, ulcers, disorders of intestinal motility and certain CCK-sensitive tumors and as useful appetite regulators and analgesics. European patent application EP 24382 (published Mar. 4, 1981) describes substituted piperidine derivatives for use as local and topical anesthetics or for use as antiarrythmic agents.
Accordingly, in order to develop new pharmaceutical drugs to treat various disease conditions, it would be highly desirable to be able to generate libraries of diverse pyrrolidine derivatives optionally attached to a solid support. An object of the present invention is to provide a facile in situ and resin-bound method for the generation of a multiplicity of densely functionalized pyrrolidine intermediates.
SUMMARY OF THE INVENTION
The present invention is directed to a method for generating densely functionalized pyrrolidine intermediates through the use of intramolecular Diels Alder reactions (via cycloaddition directed remote hydroxylation or amination) both on and off a solid support.
Accordingly, the present invention is directed to a method for generating densely functionalized pyrrolidine intermediates selected from the group consisting of Formula (I) and Formula (II):
wherein
R
1
is selected from the group consisting of a standard, natural (L) and non-natural (D), non-hydrogen amino acid side chain (wherein the amino acid side chain is optionally substituted with a suitable protecting group), hydrogen and —(C
1-8
)alkyl {wherein C
1-8
alkyl is optionally substituted with 1 to 2 substituents selected from the group consisting of —CO
2
H (wherein CO
2
H is optionally substituted with a suitable protecting group), -phenyl-R
6
, -heteroaryl-R
6
and hydroxy (wherein hydroxy is optionally substituted with a suitable protecting group)}; alternatively, R
1
and R
2
may be joined to form a heterocyclyl ring;
R
6
is one to two substituents selected from the group consisting of hydrogen, —(C
1-8
)alkyl, —O—(C
1-8
)alkyl, halogen, hydroxy and nitro;
R
2
is selected from the group consisting of hydrogen (wherein hydrogen is optionally replaced with a suitable protecting group), —(C
1-8
)alkyl, —(C
1-8
)alkyl-Ph—R
6
, —C(O)—(C
1-8
)alkyl, —C(O)—Ph—R
6
, —C(O)O—(C
1-8
)alkyl, —C(O)O—Ph—R
6
, —C(O)O—(C
1-8
)alkyl-Ph—R
6
and —SO
2
—Ph—R
6
;
R
3
is selected from the group consisting of —C(O)—N(R
7
R
8
), —CO
2
H (wherein CO
2
H is optionally substituted with a suitable protecting group), —C(O)—O—(C
1-8
)alkyl and cyano;
R
7
is selected from hydrogen, —(C
1-8
)alkyl, —(C
1-8
)alkyl-Ph—R
6
, hydroxy (wherein hydroxy is optionally substituted with a suitable protecting group) or a suitable protecting group;
R
8
is selected from hydrogen, —(C
1-8
)alkyl, —(C
1-8
)alkyl-Ph—R
6
or a suitable protecting group;
R
4
is selected from the group consisting of hydrogen, —(C
1-8
)alkyl and —(C
1-8
)alkyl-Ph—R
6
;
R
5
is selected from the group consisting of —(C
1-8
)alkyl and —Ph—R
6
;
Y is optionally present and is selected from the group consisting of O

Affiliated with

Also associated with

Rating

Methods for the synthesis of densely functionalized... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Methods for the synthesis of densely functionalized..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methods for the synthesis of densely functionalized... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3056307