Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1997-10-10
2001-12-04
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S026200, C536S026230, C536S026240, C536S026720, C536S026740, C536S027210, C536S027300, C536S027600, C536S027700, C536S028530, C536S029200, C544S276000, C544S277000, C544S265000, C558S087000, C558S155000
Reexamination Certificate
active
06326490
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel bicyclic tris(anhydride)s (BTAS) useful as intermediates in the synthesis of biologically active compounds, and the compounds which may be synthesized from such intermediates.
2. Description of Related Art
P
1
,P
2
-disubstituted pyrophospate derivatives play an important role in a variety of biochemical transformations. For example, nicotinamide adenine dinucleotide (NAD) and flavin adenine dinucleotide (FAD) serve as the major electron carriers in biological dehydrogenations, whereas another pyrophosphate, coenzyme A (CoA), is a universal carrier of acyl groups. Cytidine diphosphodiacylglycerol (CDP-diacylglycerol), cytidine diphosphocholine (CDP-choline) and cytidine diphosphoethanolamine (CDP-ethanolamine) are activated intermediates in the de novo synthesis of various phospholipids. UDP-glucose, UDP-galactose as well as some purine dinucleotide sugars such as GDP-mannose serve as cofactors in many sugar transfer processes. Finally, mono- and poly(ADP-ribose) derivatives which modulate the function of proteins, as well as cyclic ADP-ribose which influences calcium metabolism, also contain the pyrophosphate moiety.
It has long been sought to develop a simple method to synthesize isosteric methylenebis(phosphonate) analogues of the above biologically important P
1
,P
2
-disubstituted pyrophosphates, because such analogues, in which the pyrophosphate oxygen is replaced by a methylene group, preserve the shape, size and electronic charge of the n atural counterpart significantly, and provide derivatives with modified biochemical properties at a particular site. For example, in contrast to the pyrophosphate bond (P
1
—O—P
2
), the P
1
—CH—P
2
linkage o f methylenebis(phosphonate)s cannot be hydrolyzed by the enzymes that cleave the pyrophosphate bond. Another advantage of phosphonates as phosphate mimics is their ability to penetrate cell membranes (Miller and Tso,
Anti
-
Cancer Drug Design
, 1987, 2, 117; Bergstrom, et al.,
Nucleosides, Nucleotides
, 1987, 6, 53; Bergstrom and Shum,
J. Org. Chem
., 1988, 53, 3953).
Currently, no practical method is available for the synthesis of P
1
,P
2
-disubstituted methylenebis(phosphonate) analogues of natural cofactors and ADP-ribose derivatives. only a few such compounds have been synthesized in low yields after lengthy and tedious processes. For example, methylenebis(phosphonate) analogues of ADP-glucose, UDP-galactose, and GDP-mannose were prepared as potential inhibitor s of glycosyl transferase. Activation of the corresponding pyranosyl-1-methylenebis (phosphonate) with 1-(mesitylene-2-sulfonyl)-3-nitro-1,2,4-triazole (MSTN) and coupling with an appropriate nucleoside derivative afforded the desired compounds only in moderate yields (32-48%) which made the isolation of pure compounds a rather difficult and time consuming process (Vaghefi, et al.,
J. Med. Chem
. 1987, 30, 1391). The methylenebis(phosphonate) analogue of tiazole-4-carboxamide adenine dinucleotide, &bgr;-methylene-TAD, was synthesized in 36% yield by dicyclohexylcarbodiimide (DCC) catalyzed coupling of protected tiazofurin with adenosine 5′-methylene bis(phosphonate). Again, purification of this compound from the mixture was quite cumbersome. It was found that &bgr;-methylene TAD is a potent inhibitor of inosine monophosphate dehydrogenase (IMPDH) (Marquez, et al.,
J. Med. Chem
. 1986, 29, 1726).
Inosine monophosphate dehydrogenase (IMPDH) catalyzes the NAD dependent conversion of inosine 5′ monophosphate (IMP) to xanthosine monophosphate. Two forms of the enzyme are found in mammalian cells, each encoded by distinct cDNAs (Natsumeda, Y. et al.,
J. Biol. Chem
., 1990,265, 5292-5295). Type I is expressed constitutively, while the levels of type II are markedly increased in tumor cells and activated lymphocytes. Conversely, when tumor cells are induced to differentiate, transcripts of type II decline to below those of type I.
Mycophenolic acid (MPA) is the most potent inhibitor of IMPDH (Carr, et al.
J. Biol. Chem
. 1993, 268, 27286-27290). It blocks B and T lymphocyte proliferation and has been used as an immunosuppressant (Wu, J. C.
In Perspectives in Drug Discovery and Design
, Wyvratt, M. J.; Sigal, N. H., Eds.; ESCOM Science Publ., Leiden, 1994, Vol. 2, pp 185-204), although it is inactive against tumors due to its quick conversion into the inactive &bgr;-glucuronide after administration (Franklin, et al.
Cancer Res
., 1996, 56, 984-987). MPA inhibits IMPDH with even better specificity against the type II isoform dominant in cancer cells (K
i
=6-10 nM) than type I expressed in normal cells (K
i
=33-37 nM) (Carr, et al., loc cit.). When the MPA binds to the cofactor moiety of IMPDH, it resembles that of nicotinamide mononucleotide (NMN) with a carboxyl group positioned at the space occupied by the phosphoryl group of NMN (Sintchak, et al.,
Cell
, 1996, 85, 921-930).
SUMMARY OF THE INVENTION
In one aspect, the present invention relates to a compound having the following structure:
wherein
Z and Z
1
are the same or different and are alkyl, aralkyl, aryl, aminoalkyl, alkyloxy, aralkyloxy, alkylamino, aralkylamino, arylamino, alkylmercaptan, aralkylmercaptan, arylmercaptan, carbohydrate, nucleoside, a mycophenolic acid residue or derivative, steroid, or substituted glyceride; and
X is methylene (—CH
2
—), mono- or di-halo methylene, or —NR—, where R is H or alkyl.
In another aspect, the present invention provides a method for the preparation of a compound having the following structure:
wherein
Z and Z
1
are the same or different and are alkyl, aralkyl, aryl, aminoalkyl, alkyloxy, aralkyloxy, alkylamino, aralkylamino, arylamino, alkylmercaptan, aralkylmercaptan, arylmercaptan, carbohydrate, nucleoside, a mycophenolic acid residue or derivative, steroid, or substituted glyceride; and
X is methylene (—CH
2
—), mono- or di-halo methylene, or —NR—, where R is H or alkyl; which method comprises reacting a compound having the following structure:
wherein Z and X are as described, with a dehydrating agent.
In another aspect, the present invention provides a method for the preparation of a compound having the following structure:
wherein
Z and Z
1
are the same or different and are alkyl, aralkyl, aryl, aminoalkyl, alkyloxy, aralkyloxy, alkylamino, aralkylamino, arylamino, alkylmercaptan, aralkylmercaptan, arylmercaptan, carbohydrate, nucleoside, a mycophenolic acid residue or derivative, steroid, or substituted glyceride; and
X is methylene (—CH
2
—), mono- or di-halo methylene, or —NR—, where R is H or alkyl; which method comprises reacting a compound having the following structure:
wherein Z, Z
1
and X are as defined above, with a dehydrating agent.
In another aspect, the present invention provides a method for the preparation of a compound having the following structure:
wherein
Z and Z
1
are the same or different and are alkyl, aralkyl, aryl, aminoalkyl, alkyloxy, aralkyloxy, alkylamino, aralkylamino, arylamino, alkylmercaptan, aralkylmercaptan, arylmercaptan, carbohydrate, nucleoside, steroid, a mycophenolic acid residue or derivative or substituted glyceride; and
X is methylene (—CH
2
—), mono- or di-halo methylene, or —NR—, where R is H or alkyl; which method comprises reacting a compound having the following structure:
wherein Z, Z
1
and X are as defined above, with a nucleophilic agent.
In another aspect, the present invention provides compounds having the following structure:
wherein
Z and Z
1
are the same or different and are alkyl, aralkyl, aryl, aminoalkyl, alkyloxy, aralkyloxy, alkylamino, aralkylamino, arylamino, alkylmercaptan, aralkylmercaptan, arylmercaptan, carbohydrate, nuc leos ide, steroid, a mycophenolic acid residue or derivative, or substituted glyceride; and
X is methylene (—CH
2
—), mono- or di-halo methylene, or —NR—, where R is H or alkyl.
In another aspect, the present invention provides compounds having the following structure:
wherein
each of R
1
, R
2
, R
3
, and R
4
is independently H, OH or F;
X is
Lesiak Krystyna
Pankiewicz Krzysztof W.
Watanabe Kyoichi A.
King & Spalding
Knowles Sherry M.
Pharmasset, Ltd.
Sullivan Clark G.
Trinh Ba K.
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