The present invention provides a novel benzene derivative or thiophene derivative useful as a VAP-1 inhibitor, or a medicament for the prophylaxis or treatment of a VAP-1 associated disease and the like, namely, a compound represented by the formula (I): ##STR00001##
wherein each symbol is as defined in the present specification, or a pharmaceutically acceptable salt thereof.

The present invention provides diacylhydrazine ligands and chiral diacylhydrazine ligands for use with ecdysone receptor-based inducible gene expression systems. Thus, the present invention is useful for applications such as gene therapy, large scale production of proteins and antibodies, cell-based screening assays, functional genomics, proteomics, metabolomics, and regulation of traits in transgenic organisms, where control of gene expression levels is desirable. An advantage of the present invention is that it provides a means to regulate gene expression and to tailor expression levels to suit the user's requirements.

The present invention provides diacylhydrazine ligands and chiral diacylhydrazine ligands for use with ecdysone receptor-based inducible gene expression systems. Thus, the present invention is useful for applications such as gene therapy, large scale production of proteins and antibodies, cell-based screening assays, functional genomics, proteomics, metabolomics, and regulation of traits in transgenic organisms, where control of gene expression levels is desirable. An advantage of the present invention is that it provides a means to regulate gene expression and to tailor expression levels to suit the user's requirements.

A substituted alkenylbenzene compound of formula (4):

##STR00001##

wherein X.sup.1 is selected from the group consisting of halogen atom, SF.sub.5, C.sub.1-C.sub.6halo alkyl, hydroxy C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy C.sub.1-C.sub.6haloalkyl, C.sub.3-C.sub.8halocycloalkyl, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.3haloalkoxy C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.6haloalkylthio, C.sub.1-C.sub.6haloalkylsulfinyl and C.sub.1-C.sub.6haloalkylsulfonyl; X.sup.3 is selected from the group consisting of a hydrogen atom, halogen atom, cyano, nitro, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy and C.sub.1-C.sub.6 alkylthio; X.sup.4 is selected from the group consisting of a hydrogen atom, halogen atom, cyano, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy and C.sub.1-C.sub.4haloalkoxy; R.sup.3 is C(R.sup.3a)(R.sup.3b)R.sup.3c, where R.sup.3a and R.sup.3b independently of each other are a halogen atom, or R.sup.3a and R.sup.3b together form 3- to 6-membered ring together with the carbon atom bonding them by forming a C.sub.2-C.sub.5haloalkylene chain, and R.sup.3c is selected from the group consisting of a hydrogen atom, halogen atom, C.sub.1-C.sub.5alkyl, C.sub.1-C.sub.5haloalkyl, C.sub.1-C.sub.4haloalkoxy and C.sub.1-C.sub.4haloalkylthio, with a proviso that in case where X.sup.1 is a fluorine atom, chlorine atom or trifluoromethyl, and both X.sup.2 and X.sup.3 are a hydrogen atom, in case where both X.sup.1 and X.sup.2 are fluorine atom and X.sup.3 is a hydrogen atom, and in case where both X.sup.1 and X.sup.2 are trifluoromethyl and X.sup.3 is a hydrogen atom, R.sup.3c is a hydrogen atom, chlorine atom, bromine atom, iodine atom, C.sub.1-C.sub.5alkyl, C.sub.1-C.sub.5haloalkyl, C.sub.1-C.sub.4haloalkoxy or C.sub.1-C.sub.4haloalkylthio.

In one aspect, the invention relates to compounds having the formula: ##STR00001##
where R.sup.1-R.sup.6, a, b, and X are as defined in the specification, or a pharmaceutically acceptable salt thereof. These compounds have neprilysin inhibition activity. In another aspect, the invention relates to pharmaceutical compositions comprising such compounds; methods of using such compounds; and processes and intermediates for preparing such compounds.

In one aspect, the invention relates to compounds having the formula: ##STR00001##
where R.sup.1-R.sup.6, a, b, and X are as defined in the specification, or a pharmaceutically acceptable salt thereof. These compounds have neprilysin inhibition activity. In another aspect, the invention relates to pharmaceutical compositions comprising such compounds; methods of using such compounds; and processes and intermediates for preparing such compounds.

Provided is a production method comprising step A of reacting a compound represented by Formula (2):

##STR00001##

wherein R.sup.1, R.sup.2, and R.sup.3 are the same or different, R.sup.1 represents COR, R.sup.2 and R.sup.3 each represent a hydrogen atom or COR, and R.sup.4 represents a C.sub.1-C.sub.12 alkyl group or a C.sub.6-C.sub.12 aryl group; with a fluorinating agent containing IF.sub.5, an amine, and HF at 80 C. or lower throughout the reaction from the start to the end. This production method is capable of synthesizing a compound (N-fluoroalkylated hydrazine derivative) represented by formula (1):

##STR00002##

wherein R.sup.1, R.sup.2, and R.sup.3 are as defined above, wherein Rs are the same or different and each represents a C.sub.1-C.sub.12 alkoxy group optionally substituted with one or more substituents or a C.sub.6-C.sub.12 aryloxy group optionally substituted with one or more substituents.

Provided is a production method comprising step A of reacting a compound represented by Formula (2):

##STR00001##

wherein R.sup.1, R.sup.2, and R.sup.3 are the same or different, R.sup.1 represents COR, R.sup.2 and R.sup.3 each represent a hydrogen atom or COR, and R.sup.4 represents a C.sub.1-C.sub.12 alkyl group or a C.sub.6-C.sub.12 aryl group; with a fluorinating agent containing IF.sub.5, an amine, and HF at 80 C. or lower throughout the reaction from the start to the end. This production method is capable of synthesizing a compound (N-fluoroalkylated hydrazine derivative) represented by formula (1):

##STR00002##

wherein R.sup.1, R.sup.2, and R.sup.3 are as defined above, wherein Rs are the same or different and each represents a C.sub.1-C.sub.12 alkoxy group optionally substituted with one or more substituents or a C.sub.6-C.sub.12 aryloxy group optionally substituted with one or more substituents.