Enolase levels are predictive of the probability that a cancer patient will respond favorably to cancer therapy involving administration of hypoxia-activated achiral phosphoramide mustards.

The present invention relates to a compound of the following general formula (I): R.sub.1NHCH(R.sub.2)P(O)(OR.sub.3)CH.sub.2C(R.sub.4)(R.sub.5)CONHCH(R.sub.6)COOR.sub.7 (I) or a pharmaceutically acceptable salt of the latter, an isomer or a mixture of isomers in any proportions, especially a mixture of enantiomers, and in particular a racemic mixture, for which R.sub.1 represents a C(O)OC(R.sup.8)(R.sup.9)OC(O)R.sup.10 group; R.sub.2 represents an optionally substituted hydrocarbon-based chain, an aryl or heteroaryl group or a methylene group substituted by a heterocycle; R.sub.3 represents a hydrogen atom or a C(R.sup.12)(R.sup.13)OC(O)R.sup.14 group; R.sub.4 and R.sub.5 form, together with the carbon that bears them, a saturated hydrocarbon-based ring or an optionally substituted piperidine ring or R.sub.4 represents a hydrogen atom and R.sub.5 represents a phenyl or a benzyl that is optionally substituted, a heteroaromatic ring or a methylene group substituted by a heterocycle; R.sub.6 represents an optionally substituted hydrocarbon-based chain or a phenyl or a benzyl that is optionally substituted; and R.sub.7 represents a hydrogen atom or a benzyl, alkyl, heteroaryl, alkylheteroaryl, CHMe-COOR.sup.18, CHR.sup.19OC(O)R.sup.20 and CHR.sup.19OC(O)OR.sup.20 group. The present invention also relates to the use of these compounds as a medicinal product, and in particular for the treatment of pain, more advantageously neuropathic and neuroinflammatory pain, to their method of synthesis and also to the compositions containing them.

The invention relates to phosphohistidine analogs. The invention also relates to antibodies that specifically bind to the analogs and methods of generating said antibodies. In one embodiment of the invention there is provided a phosphohistidine analog of Formula V: (V) wherein W is selected from H, CO.sub.2H or CONH.sub.2; and X is selected from CH or N. ##STR00001##

This invention relates to a compound comprising a structure of formula (I): cyclic disulfide moiety-phosphorus coupling group (I). The cyclic disulfide moiety has the structure of (C-I), (C-II), or (C-III). This invention also relates to an oligonucleotide comprising one or more compounds that comprise the structure of formula (I), wherein at least one phosphorus coupling group contains a nucleoside or oligonucleotide. The invention also relates to a pharmaceutical composition comprising the oligonucleotide described herein and a method of reducing or inhibiting the expression of a target gene by administering to the subject a therapeutically effective amount of the oligonucleotide described herein.

##STR00001##

The present invention discloses novel compounds derived from NSAIDs and pharmaceutically acceptable salts thereof. Other aspects of the invention relate to use of the NSAID derivatives in treating inflammatory diseases and pharmaceutical compositions thereof.

The present invention relates to novel compounds and probes which have a common chemical structure necessary to obtain potent inhibitory activity against KLK4 and/or may be used for the detection of KLK4 peptides and their activity. It further relates to the use of these compounds and methods for inhibiting and/or detecting KLK4 activity in vitro and in vivo by making use of said probes or inhibitors. The compounds of the invention differ from prior art compounds at least in the presence of phenyl guanidine (instead of e.g. benzyl guanidine) and/or the presence of a heteroatom in the tail group, their combined presence unexpectedly leading to potent and selective KLK4 inhibitory activity.

The present application relates to a new method for synthesizing isophosphoramide nitrogen mustard (X-IPM) that is suitable for industrialized production, involves fewer types of solvents, and leads to stable products with high yield. This method is charazterized mainly by the batchwise addition of M (e.g., M is R.sub.3N with R being ethyl; i.e., M is triethylamine) and the specific post-reaction treatment, which make it possible for the reaction to fully proceed, lead to products with less impurities, high yield and relatively stable properties, and can lead to stable crystallized substances with specific crystal structures. The present application also relates to stable crystal forms of the isophosphoramide nitrogen mustard (X-IPM) prepared by the aforementioned method, and use of the same as reactants for the synthesis of aziridine structure-containing compounds.

Disclosed are compounds of Formulas (I), (II), (III), (IV), and (V):

##STR00001##

and/or a salt thereof, wherein R.sub.1 is OH or OP(O)(OH).sub.2, and X.sub.1, X.sub.2, X.sub.3, R.sub.2, R.sub.2a, R.sub.a, R.sub.b, and R.sub.c are defined herein. Also disclosed are methods of using such compounds as selective agonists for G protein-coupled receptor S1P.sub.1, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.

Disclosed are compounds of Formulas (I), (II), (III), (IV), and (V): ##STR00001##
and/or a salt thereof, wherein R.sub.1 is OH or OP(O)(OH).sub.2, and X.sub.1, X.sub.2, X.sub.3, R.sub.2, R.sub.2a, R.sub.a, R.sub.b, and R.sub.c are defined herein. Also disclosed are methods of using such compounds as selective agonists for G protein-coupled receptor S1P.sub.1, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.

The invention relates to compounds of formula (I) ##STR00001## where m and n are each independently 0 or 1; R.sup.1, R.sup.2, R.sup.3, R.sup.4 are each independently selected from (C.sub.1-C.sub.12)-alkyl, (C.sub.3-C.sub.12)-cycloalkyl, (C.sub.3-C.sub.12)-heterocycloalkyl, (C.sub.6-C.sub.20)-aryl, (C.sub.3-C.sub.20)-heteroaryl; at least one of the R.sup.1, R.sup.2, R.sup.3, R.sup.4 radicals is a (C.sub.3-C.sub.20)-heteroaryl radical; and R.sup.1, R.sup.2, R.sup.3, R.sup.4, if they are (C.sub.1-C.sub.12)-alkyl, (C.sub.3-C.sub.12)-cycloalkyl, (C.sub.3-C.sub.12)-heterocycloalkyl, (C.sub.6-C.sub.20)-aryl or (C.sub.3-C.sub.20)-heteroaryl, may each independently be substituted by one or more substituents selected from (C.sub.1-C.sub.12)-alkyl, (C.sub.3-C.sub.12)-cycloalkyl, (C.sub.3-C.sub.12)-heterocycloalkyl, O(C.sub.1-C.sub.12)-alkyl, O(C.sub.1-C.sub.12)-alkyl-(C.sub.6-C.sub.20)-aryl, O(C.sub.3-C.sub.12)-cycloalkyl, S(C.sub.1-C.sub.12)-alkyl, S(C.sub.3-C.sub.12)-cycloalkyl, COO(C.sub.1-C.sub.12)-alkyl, COO(C.sub.3-C.sub.12)-cycloalkyl, CONH(C.sub.1-C.sub.12)-alkyl, CONH(C.sub.3-C.sub.12)-cycloalkyl, CO(C.sub.1-C.sub.12)-alkyl, CO(C.sub.3-C.sub.12)-cycloalkyl, N[(C.sub.1-C.sub.12)-alkyl].sub.2, (C.sub.6-C.sub.20)-aryl, (C.sub.6-C.sub.20)-aryl-(C.sub.1-C.sub.12)-alkyl, (C.sub.6-C.sub.20)-aryl-O(C.sub.1-C.sub.12)-alkyl, (C.sub.3-C.sub.20)-heteroaryl, (C.sub.3-C.sub.20)-heteroaryl-(C.sub.1-C.sub.12)-alkyl, (C.sub.3-C.sub.20)-heteroaryl-O(C.sub.1-C.sub.12)-alkyl, COOH, OH, SO.sub.3H, NH.sub.2, halogen; and to the use thereof as ligands in alkoxycarbonylation.