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Patent US5525735 - Methods for synthesizing diverse collections of pyrrolidine compounds - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign in<nobr>Advanced Patent Search</nobr>PatentsDisclosed are methods for synthesizing very large collections of diverse pyrrolidine compounds and derivatives thereof on solid supports and synthetic compound libraries comprising pyrrolidine groups and derivatives thereof prepared by such methods....http://www.google.com/patents/US5525735?utm_source=gb-gplus-sharePatent US5525735 - Methods for synthesizing diverse collections of pyrrolidine compoundsAdvanced Patent SearchPublication numberUS5525735 APublication typeGrantApplication numberUS 08/354,309Publication dateJun 11, 1996Filing dateDec 12, 1994Priority dateJun 22, 1994Fee statusLapsedAlso published asWO1995035278A1Publication number08354309, 354309, US 5525735 A, US 5525735A, US-A-5525735, US5525735 A, US5525735AInventorsMark A. Gallop, Martin A. MurphyOriginal AssigneeAffymax Technologies NvExport CitationBiBTeX, EndNote, RefManPatent Citations (7), Non-Patent Citations (62), Referenced by (125), Classifications (23), Legal Events (5) External Links: USPTO, USPTO Assignment, EspacenetMethods for synthesizing diverse collections of pyrrolidine compoundsUS 5525735 AAbstract Disclosed are methods for synthesizing very large collections of diverse pyrrolidine compounds and derivatives thereof on solid supports and synthetic compound libraries comprising pyrrolidine groups and derivatives thereof prepared by such methods.
What is claimed is: 1. A synthetic compound library comprising a plurality of different compounds each compound covalently linked to a solid support wherein each of said compounds comprise at least one pyrrolidinyl group which group is prepared by the method which comprises(a) selecting a solid support comprising at least one compound attached thereto which compound comprises a moiety selected from the group consisting of a complementary group having at least one site of carbon-carbon unsaturation and an azomethine ylide precursor; and (b) converting said moiety to a pyrrolidinyl group. 2. The synthetic compound library according to claim 1 wherein each compound of said plurality of different compounds is covalently linked to the same solid support.
CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of Ser. No. 08/264,136, filed Jun. 22, 1994, which is expressly incorporated herein by reference for all purposes.
STATE OF THE ART Ligands for macromolecular receptors can be identified by screening diverse collections of compounds, e.g., peptides, produced through either molecular biological or synthetic chemical techniques. For example, recombinant peptide libraries have been generated by inserting degenerate oligonucleotides into genes encoding capsid proteins of filamentous bacteriophage and the DNA-binding protein Lac I.2-8 These random libraries contain more than 109 different peptides, each fused to a larger protein sequence that is physically linked to the genetic material encoding it. Such libraries are efficiently screened for interaction with a receptor by several rounds of affinity purification, the selected exposition or display vectors being amplified in E. coli and the DNA of individual clones sequenced to reveal the identity of the peptide responsible for receptor binding.9,10
SUMMARY OF THE INVENTION This invention is directed to general synthetic methods for incorporating a pyrrolidinyl group on a solid support which methods can be employed in conjunction with known stochastic methods for preparing libraries of compounds comprising one or more pyrrolidinyl groups.
BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 illustrates the synthesis of an azomethine ylide precursor 3 on a solid support A, conversion of precursor 3 to azomethine ylide 6 and subsequent formation of pyrrolidinyl group 8.
DETAILED DESCRIPTION OF THE INVENTION This invention is directed to synthetic methods for preparing pyrrolidinyl groups in situ on solid supports and the use of these methods to incorporate pyrrolidinyl groups in large synthetic compound libraries.
The term "substrate" or "solid support" refers to a material having a rigid or semi-rigid surface which contain or can be derivatized to contain reactive functionality which covalently links a compound to the surface thereof. Such materials are well known in the art and include, by way of example, silicon dioxide supports containing reactive Si--OH groups, polyacrylamide supports, polystyrene supports, polyethyleneglycol supports, and the like. Such supports will preferably take the form of small beads, pellets, disks, or other conventional forms, although other forms may be used. In some embodiments, at least one surface of the substrate will be substantially flat. Preferred substrates include polystyrene resins preloaded with protected amino acids. More preferably, the amino acids will be protected with the Fmoc group. Particularly preferred substrates include TentaGel� pre-loaded with Fmoc-protected amino acids at a loading of about 0.5 grams/loading 0.20-0.26 mmol.
A 13 C label typically is incorporated into at least one of the components or building blocks. The label typically will be incorporated into the amine or carbonyl component because of the commercial availability of these compounds. However, one of skill in the art will readily appreciate that the other components could also be labeled. For example, the aldehyde can be 13 C labeled and then treated with a mixture of resin-bound (TentaGel� resin with a PEG-linker) amino acids to yield the corresponding Schiff bases. When benzaldehyde which has been labeled at the carbonyl carbon (Ph13 CHO) is used, the 13 C NMR exhibits a singlet resonance for each of the different imine carbon around 160-165 ppm. Upon cycloaddition, these resonances are replaced by resonances for the C-5 of the pyrrolidine ring at about 60-70 ppm.
Alternatively, the>NH group of the pyrrolidinyl compound can be acylated via conventional means to provide for acylated pyrrolidinyl compounds. A particularly preferred class of acylating reagents comprise the formula HSCH2 CHR3 C(O)-- which, when reacted with the pyrrolidinyl compound form a class of Captopril� derivatives which are then screened for anti-hypertensive activity as described in greater detail below. R3 being a substituent having the same values as recited above for the substituents listed for the pyrrolidinyl group. Typically, the acylating reagent will comprise an acyl halide having the formula HSCH2 CHR3 C(O)X wherein X is bromine or chlorine. One of skill in the art will readily appreciate that other compounds having activated carboxyl groups can also be used as the acylating reagent.
Biological assay of the individual diastereomers after deacetylation facilitated assignment of the absolute configurations at C-2 of the prolines in these compounds. The earlier eluting isomer displayed very weak ACE-inhibitory activity (Ki >1 μM), and on the basis of extensive structure-activity date36 is consistent with a 2-R configuration. By contrast, the later eluting isomer provided an exceedingly potent ACE inhibitor (Ki �160 pm), approximately 3-fold more active than captopril in this assay37 and among the highest affinity thiol-containing ACE inhibitors yet described.
Example 1 By following the procedures set forth above, 4-cyano-5-phenyl-L-proline was prepared as shown below: ##STR5##
Example 2 By following the procedures set forth above, 4-cyano-5-phenyl-L-proline was prepared as shown below: ##STR6##
Example 3 By following the procedures set forth above, 4-cyano-5-phenyl-L-proline was prepared as shown below: ##STR7##
Example 4 By following the procedures set forth above, 2-amido-4-cyano-5-phenyl-L-pyrrolidine was prepared as shown below: ##STR8##
Example 5 By following the procedures set forth above, 4-carboxymethyl-4-methyl-5-phenyl-L-proline was prepared as shown below: ##STR9##
Example 6 By following the procedures set forth above, 4-carboxymethyl-4-methyl-5-phenyl-L-proline was prepared as shown below: ##STR10##
Example 7 By following the procedures set forth above, 2-amido-4-carboxymethyl-4-methyl-5-phenyl-L-pyrrolidine was prepared as shown below: ##STR11##
TentaGel� AC pre-loaded with an Fmoc-protected amino acid (0.50 g/loading 0.20-0.26 mmol) was added to a 20% solution of piperidine in dimethylformamide (3 mL) and gently vortexed every 5 minutes for 20 minutes to remove the Fmoc protecting group. The resin was filtered using a fine buchner funnel, washed with dimethylformamide (1�3 mL) and dichloromethane (2�3 mL). The resin was added to a 1.0M solution of aromatic aldehyde in trimethyl orthoformate (4 mL), vortexed gently and left for 4 hours. The resin was again filtered using a fine buchner funnel and washed with dichloromethane (2�3 mL). The resin was then added to a solution of silver(I) nitrate and the appropriate olefin, each at 1.0M. To the solution was added a one molar equivalence of triethylamine and the resulting solution gently vortexed and left for 4-8 hours. The solution turned black after 5-10 minutes with plating of silver upon the walls of the vessel occurring after 2 hours. The resin was filtered using a fine buchner funnel, washed with saturated ammonium chloride (2�3 mL), methanol (2�3 mL) and dichloromethane (2�3 mL). The product was cleaved from the resin by treatment with a 10% solution of trifluoroacetic acid in dichloromethane (2 mL) for 30 minutes. The solution was filtered and evaporated to dryness leaving 19-27 mg of product.
Example 8 By following the procedures set forth above, 4-cyano-5-phenyl-2-pyrrolidinecarboxylic acid was prepared as shown below: ##STR12##
Example 9 By following the procedures set forth above, 5-phenyl-2,3,4-pyrrolidinetricarboxylic acid-3,4-dimethyl ester was prepared as shown below: ##STR13##
Example 10 By following the procedures set forth above, 4-methyl-5-phenyl-2,4-pyrrolidinedicarboxylic acid-4-methyl ester was prepared as shown below: ##STR14##
TentaGel� AC resins loaded with Fmoc-protected glycine (0.24 g, 0.0625 mmol)), alanine (0.28 g, 0.0625 mmol), leucine (0.26 g, 0.0625 mmol), and phenylalanine (0.25 g, 0.0625 mmol) resins were pooled and added to a 20 % solution of piperidine in dimethylformamide (3 mL), and gently vortexed every 5 minutes for 20 minutes to remove the Fmoc protecting group. See FIG. 3. The resin was filtered using a fine buchner funnel, washed with dimethylformamide (1-�3 mL) and dichloromethane (2�3 mL). The resin was separated into four equal (by weight) amounts and placed into separate vials.
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MiamiPerforin 2 defense against invasive and multidrug resistant pathogens* Cited by examinerClassifications U.S. Classification548/533, 436/518, 548/565, 435/7.92, 548/577, 548/453, 548/400, 548/560, 548/518, 548/537, 548/406, 548/570, 548/532, 548/517, 530/323, 548/541, 548/566, 548/536International ClassificationC07D207/16Cooperative ClassificationC07D207/16, B01J2219/00592, B01J2219/0072European ClassificationC07D207/16Legal EventsDateCodeEventDescriptionAug 10, 2004FPExpired due to failure to pay maintenance feeEffective date: 20040611Jun 14, 2004LAPSLapse for failure to pay maintenance feesDec 31, 2003REMIMaintenance fee reminder mailedNov 30, 1999FPAYFee paymentYear of fee payment: 4Mar 6, 1995ASAssignmentOwner name: AFFYMAX TECHNOLOGIES N.V., NETHERLANDS ANTILLESFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:GALLOP, MARK A.;MURPHY, MARTIN;REEL/FRAME:007487/0160Effective date: 19950227RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy 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