Phosphorus is an essential element in the maintenance of life and plays very important roles in various physiological functions. Phosphorus is taken up in the form of phosphate through the gastrointestinal tract from food, and most of the phosphorus is excreted by incorporation into urine, whereby its total amount in a living is maintained and regulated. It is known that in the process of formation of urine, substantially most of phosphate is filtered at the glomerulus and only a necessary amount thereof is reabsorbed in the tubules. Accordingly, if the filtration ability of the glomerulus decreases as renal failure progresses, excretion of phosphorus becomes insufficient, and abnormal increase in the serum phosphorus level, that is, hyperphosphatemia is caused. Thus, hyperphosphatemia that induces various complications of renal failure is considered to be a factor for reducing the QOL of a patient with renal failure through fractures and bone pain, or a factor of death of a patient with renal failure through cardiovascular diseases resulting from cardiovascular calcification. Consequently, hyperphosphatemia is a very major issue in clinical practice (“KDIGO Clinical Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD))”, Kidney International, 76, Supplement 113 (2009)).
Currently, for the treatment of hyperphosphatemia, phosphate binders are used, for example, various calcium salt preparations represented by precipitated calcium carbonate, polymers represented by sevelamer hydrochloride, or metal salt preparations such as lanthanum carbonate, aluminum hydroxide, and iron preparations. However, these drugs have various problems, such as poor dose adherence due to the requirement for several grams per day, gastrointestinal symptoms such as constipation and diarrhea, increase in serum calcium levels, and accumulation of various metals. Therefore, development of a novel agent for treating hyperphosphatemia that improves the above factors is required (ibid).
Phosphate transporters present in the brush-border membrane of the gastrointestinal tract and renal tubules are considered to be involved in the absorption and excretion of phosphorus. So far, a large number of phosphate transporters have been reported. Among these, NPT-IIb plays a main role in phosphate absorption in the gastrointestinal tract, and NPT-IIa plays a main role in phosphate reabsorption in the kidneys. In addition, these molecules have been reported to be cotransporters of sodium and phosphate. In this respect, it has been pointed out that if the function of the NPT-IIb is inhibited, phosphorus absorption from the gastrointestinal tract can be suppressed (Journal of the American Society of Nephrology, 20: p 2348-2358 (2009)).
A drug for treating hyperphosphatemia based on this mechanism of action is being studied, and for example, a compound represented by the following general formula has been reported to be a compound having NPT-IIb inhibitory action (Patent Document 1).
(In the formula, A represents a 5- to 9-membered unsaturated carbocycle portion or unsaturated heterocycle portion; when the carbocycle portion or the heterocycle portion represented by A is substituted with two C1-6alkyl groups or C2-6alkenyl groups, these alkyl groups or alkenyl groups may form a 5- to 7-membered unsaturated carbocycle in combination with the carbon atoms to which these groups bind; R5 represents an aryl group or the like which may be substituted; R101 and R102 in combination represent ═O, R103 and R104 represent a hydrogen atom or the like; and Z represents the following Formula (A), (B), or (C) in which R6 and R7 may be the same as or different from each other and represent a hydrogen atom, an aryl group, or the like, and R17 represents a hydrogen atom. Regarding other symbols in the formula, see the corresponding gazette.)

In addition, as compounds that have the NPT-IIb inhibitory action and are used for preventing or treating hyperphosphatemia, a triazole compound (Patent Document 2) and a quinazolone compound (Patent Document 3) have been disclosed.
Moreover, a tetrahydrobenzothiophene derivative that has a carbonylamino group at a 2-position and a carbamoyl group at a 3-position has been reported. For example, a tetrahydrobenzothiophene compound represented by the following general formula is reported to have an antiviral action (Patent Document 4).
(In the formula, X represents N(R′) or an oxygen atom, R1 and R2 form a ring in combination with atoms bonded thereto, y represents 0 to 3, R3 represents a substituted carbocycle or heterocycle, or the like, R4 represents —N(R′)—C(O)—R7 or the like, R7 represents a substituted carbocycle or heterocycle, or the like, and R′ represents a hydrogen atom or lower alkyl. Regarding other symbols in the formula, see the corresponding gazette.)
A tetrahydrobenzothiophene compound represented by the following general formula is reported to have an antiviral action (Patent Document 5).

(In the formula, Ra represents a hydrogen atom, an alkyl group, or the like which may be substituted, Rb represents —C(O)—Rb1 or the like which may be substituted, Rb1 represents amino, aminoalkyl, a carbocycle, a heterocycle, or the like which may be substituted, Rc represents —C(O)—Rb1 or the like which may be substituted, and Rd and Rc represent a carbocycle, a heterocycle, formed in combination with atoms bonded thereto or the like which may be substituted. Regarding other symbols in the formula, see the corresponding gazette.)
A tetrahydrobenzothiophene compound represented by the following general formula is reported to have an antitumor action (Patent Document 6).
(In the formula, W represents a carbon atom or a nitrogen atom, A represents 5- to 14-membered cycloalkyl, heteroaryl, or the like which may be substituted, Y represents —NR1R2 or the like, X represents —C(O)NR5R6 or the like, R1 represents a hydrogen atom or lower alkyl, R2 represents —C(O)R10 or the like, R10 represents aryl, heteroaryl, or the like which may be substituted, R5 represents aryl, heteroaryl, or the like which may be substituted, and R6 represents a hydrogen atom or the like. Regarding other symbols in the formula, see the corresponding gazette.)
However, none of Patent Documents 4 to 6 disclose or suggest that these compounds have an NPT-IIb inhibitory action or can be used for preventing or treating hyperphosphatemia.
USPTO Backgrounds
USPTO Backgrounds