US20130029973A1 - Tetrahydrobenzothiophene compound - Google Patents

Tetrahydrobenzothiophene compound Download PDF

Info

Publication number
US20130029973A1
US20130029973A1 US13/639,260 US201113639260A US2013029973A1 US 20130029973 A1 US20130029973 A1 US 20130029973A1 US 201113639260 A US201113639260 A US 201113639260A US 2013029973 A1 US2013029973 A1 US 2013029973A1
Authority
US
United States
Prior art keywords
compound
amino
phenyl
ethyl
esi
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US13/639,260
Other languages
English (en)
Inventor
Shunichiro Hachiya
Masanori Miura
Yoshimasa Imamura
Daisuke Kaga
Ippei Sato
Hiroyuki Moritomo
Koji Kato
Kazuhiro Terai
Yoh Terada
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Astellas Pharma Inc
Original Assignee
Astellas Pharma Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astellas Pharma Inc filed Critical Astellas Pharma Inc
Assigned to ASTELLAS PHARMA INC. reassignment ASTELLAS PHARMA INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HACHIYA, SHUNICHIRO, IMAMURA, YOSHIMASA, KAGA, DAISUKE, KATO, KOJI, MIURA, MASANORI, MORITOMO, HIROYUKI, SATO, IPPEI, TERADA, YOH, TERAI, KAZUHIRO
Publication of US20130029973A1 publication Critical patent/US20130029973A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/66—Nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a tetrahydrobenzothiophene compound which is useful as an active ingredient of a pharmaceutical composition, for example, a pharmaceutical composition for treating hyperphosphatemia.
  • 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 phosphorous is excreted by incorporation into urine, whereby its total amount in a living body 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 required 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. Thus, an abnormal increment of the serum phosphorus concentration, that is, hyperphosphatemia develops.
  • Hyperphosphatemia induces an concentration increase of FGF-23 in the blood which is a promoting factor for phosphorous excretion in urine, or that of parathyroid hormone (iPTH).
  • An abnormal rise in iPTH is one of the complications of renal failure, called hyperparathyroidism, which also causes ectopic calcification or the like through the activation of bone metabolism.
  • hyperphosphatemia becomes one of the causes or aggravating factors of other complications associated with decreased renal function, through the action of compensatory functions of the body accompanying hyperphosphatemia.
  • hyperphosphatemia inducing various complications of renal failure becomes a cause of decrease in QOL for patients with renal failure due to bone fracture, bone pain, or the like, or the death of patients with renal failure due to cardiovascular diseases caused by calcification of the cardiovascular system.
  • hyperphosphatemia becomes a very significant problem in clinical practice.
  • phosphate binders for example, various calcium salt preparations typically exemplified by precipitated calcium carbonate, a polymer typically exemplified by sevelamer hydrochloride, or metal salt preparations such as lanthanum carbonate, aluminum hydroxide, an iron preparation, and the like are used for the purpose of inhibiting the phosphorus absorption from the gastrointestinal tract.
  • Non-Patent Document 1 a novel agent for treating hyperphosphatemia having modifications of these weak points.
  • NPT-IIb and NPT-IIa play a major role in phosphate absorption in the gastrointestinal tract and phosphate reabsorption in the kidney, respectively.
  • these molecules have also been reported as a sodium and phosphate cotransporter. From this, it is thought that the phosphorus absorption from the gastrointestinal tract can be inhibited by inhibition of the function of NPT-IIb (see, for example, Non-Patent Document 2).
  • an NPT-IIb inhibiting agent is promising as a medicament for treating hyperphosphatemia with novel mechanism of actions which will replace various phosphate binders that have currently been used in clinical practice.
  • Patent Document 1 there is disclosed a compound having an NPT-IIb inhibitory action, which is represented by the general formula (A) and specifically, a compound having a tetrahydrobenzothiophene skeleton is also disclosed, but its substituents at the 2-position and the 3-position are each different from those of the compound of the present invention. That is, from a viewpoint that its substituent at the 3-position is a hydrazinocarbonyl group, it is clearly different from the compound of the present invention in which the substituent at the 3-position is a phenylcarbamoyl group. Further, a substituent at the 2-position is a benzoylamino group, but the substituents of this benzene ring do not include a sulfamoyl group as in the compound of the present invention.
  • A NPT-IIb inhibitory action
  • Patent Documents 2 and 3 there are disclosed compounds having a NPT-IIb inhibitory action, which have a triazole skeleton and a quinazolinone skeleton, respectively, but there is not disclosed a compound having a tetrahydrobenzothiophene skeleton as in the compound of the present invention.
  • Patent Document 4 there is disclosed a compound represented by the general formula (B), but there is not disclosed a compound in which the substituent at the 2-position of a tetrahydrobenzothiophene ring is a sulfamoylbenzoylamino group as in the compound of the present invention.
  • R 2 represents an optionally substituted phenylamino, or the like
  • R 3 represents an optionally substituted phenyl, or the like
  • n represents 1 or the like.
  • Patent Document 5 there is disclosed a compound represented by the formula (C) or the like, but there is neither disclosed a compound having phenyl instead of cyclopropyl as a substituent of carbamoyl, which is a substituent at the 3-position of the tetrahydrobenzothiophene ring nor a compound having a sulfamoyl group as a substituent of a benzene ring of a benzoylamino group, which is a substituent at the 2-position.
  • Patent Document 6 there is disclosed a compound represented by the formula (D) or the like
  • Patent Document 7 there is disclosed a compound represented by the formula (E) or the like
  • Patent Document 8 there is disclosed a compound represented by the formula (F) or the like.
  • a compound having a sulfamoyl group as a substituent of a benzene ring of a benzoylamino group which is a substituent at the 2-position of a tetrahydrobenzothiophene ring.
  • Patent Document 9 there is disclosed a compound represented by the formula (G) or the like, but there is neither disclosed a compound having a benzene ring as a substituent of carbamoyl, which is a substituent at the 3-position of the tetrahydrobenzothiophene ring nor a compound having a sulfamoyl group as a substituent of benzene ring of a benzoylamino group, which is a substituent at the 2-position.
  • Patent Document 10 there is disclosed a compound represented by the formula (H) or the like, but there is neither disclosed a compound having phenyl as a substituent of carbamoyl which is a substituent at the 3-position of the tetrahydrobenzothiophene ring nor a compound having sulfamoylphenyl instead of cyclobutyl of a cyclobutylcarbonylamino group which is a substituent at the 2-position.
  • Patent Document 11 there is disclosed a compound represented by the general formula (K-a), but it is different from the compound of the present invention in that it does not include a tetrahydrobenzothiophene skeleton. There is further disclosed a compound represented by the general formula (K-b), which can include a tetrahydrobenzothiophene skeleton.
  • R 2 represents C 1 -C 10 alkyl, C 3 -C 8 cycloalkyl, phenyl, 5 to 7-membered heteroaryl, or the like
  • k represents an integer of 2 to 4
  • R 3 represents optionally substituted phenyl, or the like
  • n represents an integer of 0 to 4.
  • Patent Document 12 there is disclosed a compound represented by the general formula (L), but such a compound which has a tetrahydrothieno[2,3-c]pyridine skeleton is different from the compound of the present invention which has a tetrahydrobenzothiophene skeleton.
  • the substituent at the 2-position is a phenylaminocarbonyl group.
  • R 2 represents arylaminocarbonyl in which aryl is optionally substituted, or the like.
  • R 2 represents arylaminocarbonyl in which aryl is optionally substituted, or the like.
  • Patent Document 13 there is disclosed a compound represented by the formula (M-a) or the formula (M-b), but there is not disclosed a compound having a benzene ring as a substituent of carbamoyl, which is a substituent at the 3-position of the tetrahydrobenzothiophene ring.
  • Patent Documents 4 to 13 it is neither suggested nor disclosed that the compound has an NPT-IIb inhibitory action or is used for preventing or treating hyperphosphatemia.
  • a compound represented by a formula (N), the formula (O) or the formula (P) as a compound known according to the database.
  • the compound represented by the formula (N) or the formula (O) does not have a benzene ring as a substituent of carbamoyl, which is a substituent at the 3-position of the tetrahydrobenzothiophene ring.
  • the compound represented by the formula (P) is different from the compound of the formula (I).
  • the compound has an NPT-IIb inhibitory action or is used for preventing or treating hyperphosphatemia.
  • Non-Patent Document 2 Journal of the American Society of Nephrology, 20: p. 2348-2358 (2009)
  • a compound which has an NPT-IIb inhibitory action is useful as an active ingredient of a pharmaceutical composition for preventing or treating hyperphosphatemia.
  • the present inventors have extensively studied a compound having an NPT-IIb inhibitory action, and as a result, they have found that the tetrahydrobenzothiophene compound of the present invention is useful as a compound having an NPT-IIb inhibitory action, thereby completing the present invention.
  • the present invention relates to a compound of the formula (I) or a salt thereof, and a pharmaceutical composition comprising a compound of formula (I) or a salt thereof and an excipient:
  • R 1 represents —O-lower alkyl, -lower alkylene-phenyl, or -lower alkylene-pyridyl (in which phenyl or pyridyl may be substituted with carboxy or protected carboxy),
  • R 2 and R 3 are the same as or different from each other and represent H, lower alkyl, cycloalkyl, aryl, heteroaryl, nitrogen-containing saturated hetero ring, -lower alkylene-aryl, or -lower alkylene-heteroaryl (in which lower alkyl, cycloalkyl, aryl, heteroaryl, and nitrogen-containing saturated hetero ring may be substituted), or
  • R 2 and R 3 may be combined with a nitrogen atom to which they bind to form 5- to 7-membered saturated cyclic amino (in which the 5- to 7-membered saturated cyclic amino may be substituted),
  • R 4 's are the same as or different from each other and represent halogen, lower alkyl, —OH, —O-lower alkyl, —NO 2 , or a group represented by the formula (II):
  • R 41 and R 42 are the same as or different from each other and represent H or lower alkyl which may be substituted, or R 41 and R 42 may be combined with a nitrogen atom to which they bind to form 5- to 7-membered saturated cyclic amino), and
  • n 0 to 2
  • N-(4-methoxyphenyl)-2-( ⁇ 3-[(4-methylpiperazin-1-yl)sulfonyl]benzoyl ⁇ amino)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide is excluded].
  • the present invention also relates to a compound of the formula (Ia) or a salt thereof, and a pharmaceutical composition comprising a compound of the formula (Ia) or a salt thereof and an excipient:
  • R 1a represents —O-lower alkyl, -lower alkylene-phenyl, or -lower alkylene-pyridyl (in which phenyl or pyridyl may be substituted with carboxy or protected carboxy),
  • R 2a and R 3a are the same as or different from each other and represent H, lower alkyl, cycloalkyl, phenyl, pyridyl, -lower alkylene-phenyl, or -lower alkylene-pyridyl (in which the cycloalkyl, phenyl, or pyridyl may be substituted with carboxy or protected carboxy and the lower alkyl may be substituted with —O-lower alkyl, —[CH(—OH)] m —H, carboxy, or protected carboxy), or
  • R 2a and R 3a may be combined with an N atom to which they bind to form a 5- to 7-membered saturated cyclic amino (in which the 5- to 7-membered saturated cyclic amino may have substituent(s)),
  • R 4a represents halogen, lower alkyl, —OH, —O-lower alkyl, —NO 2 , or a group represented by the formula (IIa):
  • R 41a and R 42a are the same as or different from each other and represent H, or lower alkyl which may be substituted, or R 41a and R 42a may be combined with an N atom to which they bind to form 5- to 7-membered saturated cyclic amino),
  • n 1 to 5
  • n a 0 to 2
  • N-(4-methoxyphenyl)-2-( ⁇ 3-[(4-methylpiperazin-1-yl)sulfonyl]benzoyl ⁇ amino)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide is excluded].
  • the present invention relates to a pharmaceutical composition for treating hyperphosphatemia, which includes a compound of the formula (I) or a salt thereof, or a compound of the formula (Ia) or a salt thereof.
  • the composition includes an agent for treating hyperphosphatemia, which includes a compound of the formula (I) or a salt thereof, or a compound of the formula (Ia) or a salt thereof.
  • the present invention further relates to use of the compound of the formula (I) or a salt thereof, or the compound of the formula (Ia) or a salt thereof, for preparation of a pharmaceutical composition for treating hyperphosphatemia, use of the compound of the formula (I) or a salt thereof, or the compound of the formula (Ia) or a salt thereof for treatment of hyperphosphatemia, a compound of the formula (I) or a salt thereof, or a compound of the formula (Ia) or a salt thereof for treating hyperphosphatemia, and a method for treating hyperphosphatemia, including administering to a subject an effective amount of the compound of the formula (I) or a salt thereof, or the compound of the formula (Ia) or a salt thereof.
  • the “subjects” refer to humans or other animals in need of the prevention or treatment thereof, and in a certain embodiment, humans in need of the prevention or treatment thereof
  • the compound of the formula (Ia) or a salt thereof is included in the compound of the formula (I) or a salt thereof. Accordingly, in the present specification, the description of the compound of the formula (I) also includes that of the compound of the formula (Ia).
  • the compound of the formula (I), or a salt thereof, or the compound of the formula (Ia) or a salt thereof has an NPT-IIb inhibitory action and can be used as an agent for preventing and/or treating hyperphosphatemia or the like.
  • the “lower alkyl” refers to a straight or branched alkyl having 1 to 6 carbon atoms (hereinafter simply referred to as C 1-6 ), for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or the like, in another embodiment, methyl, ethyl, n-propyl, isopropyl, n-butyl, or isobutyl, in a further embodiment, methyl, or ethyl, and in a further embodiment, methyl.
  • lower alkylene refers to a straight or branched C 1-6 alkylene, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methylmethylene, dimethylmethylene, ethylethylene, 1,2-dimethylethylene, 1,1,2,2-tetramethylethylene, or the like, in another embodiment, C 1-4 alkylene, in a further embodiment, ethylene or propylene, in a further embodiment methylene.
  • halogen means F, Cl, Br, or I.
  • cycloalkyl refers to a C 3-10 saturated hydrocarbon ring group, which may have bridge(s), and is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, or the like, in another embodiment, C 3-8 cycloalkyl, in a further embodiment, C 3-6 cycloalkyl, in a further embodiment, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and in a further embodiment, cyclopropyl or cyclohexyl.
  • aryl refers to a C 6-14 monocyclic to tricyclic aromatic hydrocarbon ring group, and includes a ring group fused with C 5-8 cycloalkene at its double bond site. It is, for example, phenyl, naphthyl, 5-tetrahydronaphthyl, 4-indenyl, 1-fluorenyl, or the like, and in another embodiment, phenyl.
  • the “hetero ring” means a ring group containing i) a monocyclic 3- to 8-membered, and in another embodiment, a 5- to 7-membered hetero ring, containing 1 to 4 hetero atoms selected from oxygen, sulfur, and nitrogen, and ii) a bi- to tricyclic hetero ring containing 1 to 5 hetero atoms selected from oxygen, sulfur, and nitrogen, formed by ring-fusion of said monocyclic hetero ring with one or two rings which is selected from a monocyclic hetero ring, a benzene ring, C 5-8 cycloalkane, and C 5-8 cycloalkene.
  • the ring atom, sulfur or nitrogen may be oxidized to form an oxide or a dioxide.
  • hetero ring examples include the following embodiments:
  • cyclic amino means a monovalent group of a 3- to 8-membered cyclic amine ring, which may contain a partially unsaturated bond and may contain nitrogen, oxygen, or sulfur. Specific examples thereof include those in which a nitrogen atom in (1) “Monocyclic saturated hetero ring group” and (2) “Monocyclic unsaturated hetero ring group” as described for the “hetero ring” forms a monovalent group.
  • the ring atom, sulfur or nitrogen, may be oxidized to form an oxide or a dioxide.
  • saturated cyclic amino examples include aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, pyrazolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, and azepan-1-yl
  • unsaturated cyclic amino examples include pyrrol-1-yl, imidazol-1-yl, pyrazol-1-yl, pyrrolin-1-yl, imidazolin-1-yl, 1,2-dihydropyrimidin-1-yl, 1,4-dihydropyridin-1-yl, 1,4,5,6-tetrahydropyridazin-1-yl, and azepin-1-yl.
  • Examples of the 5- to 7-membered saturated cyclic amino formed when R 2 and R 3 are combined with a nitrogen atom to which they bind include pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, and azepan-1-yl, in another embodiment, pyrrolidin-1-yl, piperidin-1-yl, and piperazin-1-yl, in a further embodiment, piperazin-1-yl and morpholin-4-yl, and in a further embodiment, piperazin-1-yl.
  • Examples of the 5- to 7-membered saturated cyclic amino formed when R 41 and R 42 are combined with a nitrogen atom to which they bind include pyrrolidin-1-yl and morpholin-4-yl.
  • heteroaryl refers to an aromatic ring group within the formally described “hetero ring” (2), or hetero ring group within the formally described “hetero ring” (4) which comprises at least one aromatic group.
  • examples thereof include a monocyclic heteroaryl such as pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, triazolyl, triazinyl, tetrazolyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl, furyl, and the like, a bicyclic heteroaryl such as indolyl, isoindolyl, benzoimidazolyl, indazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl
  • heteroaryl examples include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, triazolyl, triazinyl, tetrazolyl, and pyrazolyl, and in another embodiment, pyridyl.
  • the “nitrogen-containing saturated hetero ring” refers to a monocyclic saturated hetero ring or a fused polycyclic saturated hetero ring, which includes at least one nitrogen atom and may further include a heteroatom selected from oxygen and sulfur, as described in (1) (a), (1) (b), (3) (a), and (3) (b) of the “hetero ring” above.
  • the ring atom, sulfur or nitrogen may be oxidized to form an oxide or a dioxide.
  • Examples of the “nitrogen-containing saturated hetero ring” in R 2 and R 3 include azepanyl, diazepanyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidyl, pyrazolidinyl, piperazinyl, and azocanyl, and in another embodiment, piperidyl.
  • Examples of the “protected carboxy” group can include the following groups
  • Esterified carboxy group include —CO—O-lower alkyl, —CO—O-lower alkenyl, —CO—O-lower alkynyl, —CO—O-lower alkylene-O-lower alkyl, —CO—O-lower alkylene-aryl, —CO—O-lower alkylene-O-aryl, and the like.
  • the expression “which may be substituted” represents “which is not substituted” or “which is substituted with 1 to 5 substituents”. Further, if it has a plurality of substituents, the substituents may be the same as or different from each other.
  • Examples of the substituent in the “lower alkyl, cycloalkyl, aryl, heteroaryl, and nitrogen-containing saturated hetero ring” in R 2 and R 3 include halogen; lower alkyl; pyridyl; carboxy; protected carboxy; amino which may be substituted with one alkyl, or the same or different two or more lower alkyls; —O-lower alkyl; —[CH(—OH)] m —H; and —OH, in another embodiment, carboxy; and protected carboxy, and in a further embodiment, carboxy.
  • Examples of the substituent in the “lower alkyl which may be substituted” in R 41 or R 42 include —OH.
  • Embodiments of the compound of the formula (I) or a salt thereof are shown below.
  • R 2 is lower alkyl which may be substituted with at least one substituent selected from the group consisting of carboxy, protected carboxy, —OH, pyridyl, carboxyphenyl, and methoxycarbonylphenyl, in another embodiment, the compound or a salt thereof, wherein R 2 is C 2-4 alkyl substituted with carboxy, and in a further embodiment, the compound or a salt thereof, wherein R 2 is 2-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, or 2-carboxypropan-2-yl.
  • R 2 is a cycloalkyl which may be substituted with at least one substituent selected from the group consisting of carboxy and protected carboxy, in another embodiment, the compound or a salt thereof, wherein R 2 is C 3-6 cycloalkyl substituted with carboxy, and in a further embodiment, the compound or a salt thereof, wherein R 2 is 1-carboxycyclopropyl or 4-carboxycyclohexyl.
  • R 2 is 2-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 2-carboxypropan-2-yl, 1-carboxycyclopropyl, 4-carboxycyclohexyl, or 4-carboxyphenyl.
  • R 3 is a lower alkyl which may be substituted with at least one substituent selected from the group consisting of —O-lower alkyl, and amino which may be substituted with one alkyl, or the same or different two lower alkyls, in another embodiment, the compound or a salt thereof, wherein R 3 is methyl, ethyl, isopropyl, n-propyl, 2-methoxyethyl, or 2-(diisopropylamino)ethyl, and in a further embodiment, the compound or a salt thereof, wherein R 3 is methyl, ethyl, isopropyl, or n-propyl.
  • the compound of the formula (I) may exist in the form of tautomers or geometrical isomers depending on the kind of substituents.
  • the compound of the formula (I) shall be described in only one form of isomer, yet the present invention includes the other isomers, isolated forms of the isomers, or a mixture thereof.
  • the compound of the formula (I) may have asymmetric carbon atoms or axial asymmetry in some cases, and correspondingly, it may exist in the form of optical isomers.
  • the present invention includes both an isolated form of the optical isomers of the compound of the formula (I) or a mixture thereof
  • the present invention also includes a pharmaceutically acceptable prodrug of the compound of the formula (I).
  • the pharmaceutically acceptable prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like through solvolysis or under physiological conditions. Examples of the group forming the prodrug include the groups described in Prog. Med., 5, 2157-2161 (1985) and Pharmaceutical Research and Development, Drug Design, Hirokawa Publishing Company (1990), Vol. 7, 163-198.
  • the salt of the compound of the formula (I) is a pharmaceutically acceptable salt of the compound of the formula (I) and may form an acid addition salt or a salt with a base depending on the kind of substituents.
  • Specific examples thereof include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditolyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, and the like, and salts with inorganic
  • the present invention also includes various hydrates or solvates, and polymorphic crystal substances of the compound of the formula (I) and a salt thereof.
  • the present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.
  • the compound of the formula (I) and a salt thereof can be prepared using the characteristics based on the basic structure or the type of substituents thereof and by applying various known synthesis methods.
  • a suitable protective group a group that can be easily converted into the functional group
  • the protective group for such a functional group may include, for example, the protective groups described in “Greene's Protective Groups in Organic Synthesis (4 th Ed., 2006)” written by P. G. M. Wuts and T. W. Greene, and one of these may be selected and used as necessary depending on the reaction conditions.
  • a desired compound can be obtained by introducing the protective group and carrying out the reaction before eliminating the protective group as necessary.
  • the prodrug of the compound of the formula (I) can be produced by introducing a specific group or by carrying out the reaction using the obtained compound of the formula (I) at the stage from a starting material to an intermediate, just as in the case of the above-mentioned protective group.
  • the reaction can be carried out using methods known to those skilled in the art, such as ordinary esterification, amidation, dehydration, and the like.
  • the compound of the formula (I) can be obtained by an amidation reaction of a compound (1-1a) with a compound (1-1b) or a sulfonamidation reaction of a compound (1-2a) with a compound (1-2b).
  • the compound (1-1a) and the compound (1-1b) or the compound (1-2a) and the compound (1-2b) in an equivalent amount or in an excess amount are used, and a mixture thereof is stirred under any temperature condition from cooling to heating, preferably at ⁇ 20° C. to 120° C., usually for 0.1 hours to 5 days, in a solvent which is inert to the reaction, in the presence of a condensing agent.
  • solvents examples include aromatic hydrocarbons such as benzene, toluene, xylene, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, ethers such as diethyl ether, tetrahydrofuran (THF), dioxane, dimethoxyethane, and the like, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), ethyl acetate, acetonitrile, N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), or water, and a mixture thereof.
  • aromatic hydrocarbons such as benzene, toluene, xylene, and the like
  • halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like
  • ethers such as diethyl ether,
  • condensing agent examples include 1-(3-dimethylamino propyl)-3-ethylcarbodiimide (EDCI), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), bromo(tripyrrolidin-1-yl)phosphonium hexafluorophosphate, 1,1′-carbonyldiimidazole, diphenylphosphoric azide, phosphoryl chloride, N,N′-dicyclohexylcarbodiimide (DCC), 1,1′-carbonylbisimidazole (CDI), N,N′-disuccinimidyl carbonate, a BOP reagent (Aldrich, U.S.A
  • a condensing agent-carrying polystyrene resin for example, a PS-Carbodiimide (Biotage AB, Sweden), may also be used.
  • an additive for example, 1-hydroxybenzotriazole
  • use of a microwave reactor (Biotage AB) makes it possible to advance the reaction smoothly in some cases.
  • an isocyanate-carrying polystyrene resin for example, PS-Isocyanate (Biotage AB, Sweden) and the like, in order to remove an excessive amount of amine after completion of the reaction, or to use a quaternary ammonium salt-carrying polystyrene resin, for example, MP-Carbonate (Biotage AB, Sweden) and the like, in order to remove excessive amounts of carboxylic acid and the above-mentioned additives after completion of the reaction.
  • a carboxylic acid of the compound (1-1b) or a sulfonic acid of the compound (1-2a) is reacted with an amine after conversion to its reactive derivative.
  • the reactive derivative include acid halides that can be obtained by the reaction of a carboxylic acid or sulfonic acid with a halogenating agent such as oxalyl chloride, phosphorus oxychloride, thionyl chloride, and the like, mixed acid anhydrides that can be obtained by the reaction with isobutyl chloroformate or the like, active esters that can be obtained by condensation with 1-hydroxybenzotriazole or the like, etc.
  • examples of the reactive derivative of the compound (1-2a) include a compound (1-2a-1), and by a sulfonamidation reaction of the compound (1-2a-1) with the compound (1-2b), the compound (I) of the present invention can be obtained.
  • the reactive derivative (1-2a-1) can be derived even though it is not via sulfonic acid (1-2a), as shown below (Starting Material Synthesis 2).
  • the compound of the formula (I), wherein R 3 is lower alkyl, cycloalkyl, a nitrogen-containing saturated hetero ring, -lower alkylene-aryl, or -lower alkylene-heteroaryl (in which lower alkyl, cycloalkyl, aryl, heteroaryl, and the nitrogen-containing saturated hetero ring may be substituted) can be obtained by an alkylation reaction of an amine with the compound (2-1a) and the compound (2-1b).
  • the compound of the formula (I), wherein R 2 is lower alkyl, cycloalkyl, a nitrogen-containing saturated hetero ring, -lower alkylene-aryl, or -lower alkylene-heteroaryl (in which lower alkyl, cycloalkyl, aryl, heteroaryl, and the nitrogen-containing saturated hetero ring may be substituted) can be obtained by an alkylation reaction of an amine with the compound (2-2a) and the compound (2-2b).
  • examples of the leaving group include halogen, methanesulfonyloxy, p-toluenesulfonyloxy groups, and the like.
  • the compound (2-1a) and the compound (2-1b), or the compound (2-2a) and the compound (2-2b) in an equivalent amount or in an excess amount are used, and a mixture thereof is stirred under any temperature condition from cooling to heating under reflux, preferably at 0° C. to 80° C., usually for 0.1 hours to 5 days, in a solvent which is inert to the reaction or without a solvent.
  • solvents examples include aromatic hydrocarbons such as benzene, toluene, xylene, pyridine, and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, N,N-dimethylformamide, dimethylsulfoxide, ethyl acetate, acetonitrile, or a mixture thereof.
  • aromatic hydrocarbons such as benzene, toluene, xylene, pyridine, and the like
  • ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like
  • halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, N,N
  • an organic base such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, and the like
  • an inorganic base such as potassium carbonate, sodium carbonate, potassium hydroxide, and the like.
  • a 1 represents phenylene or pyridinediyl
  • a 2 represents lower alkylene, cycloalkanediyl, phenylene, or pyridinediyl
  • k represents 1 to 6
  • R a and R b represent lower alkyl, which are the same as or different from each other).
  • the compound represented by the general formula (I-1b) or the general formula (I-2b) can be prepared by hydrolysis of the compound of the general formula (I-1 a) or the general formula (I-2a).
  • the hydrolysis reaction can be carried out in accordance with the aforementioned “Protective Groups in Organic Synthesis”.
  • the compound (I) of the present invention having various functional groups for example, a carboxyl group, an amide group, a hydroxyl group, an alkylamino group, and the like, can be prepared from the compound (I) of the present invention, by any combination of the steps that can usually be employed by a person skilled in the art, such as alkylation, acylation, a substitution reaction, oxidation, reduction, hydrolysis, deprotection, halogenation, and the like (see the aforementioned “Courses in Experimental Chemistry (5 th edition)”, “Greene's Protective Groups in Organic Synthesis”, or the like.
  • the processes that can usually be employed by a person skilled in the art may be used in the application for the preparation of intermediates.
  • the step represented by Step 1-1 is a step in which a compound (3-3) is obtained by an esterification using a compound (3-1) and a compound (3-2).
  • the esterification reaction can be carried out in accordance with the aforementioned “Protective Groups in Organic Synthesis”.
  • Each of the steps represented by Step 1-2, Step 1-3, and Step 1-4 is a step in which a compound (3-5), a compound (3-7), and a compound (3-9) are obtained by a sulfonamidation reaction using the compound (3-3) and a compound (3-4), the compound (3-3) and a compound (3-6), and the compound (3-3) and a compound (3-8), respectively.
  • the sulfonamidation reaction can be carried out in accordance with 2 of the Production Process 1.
  • Step 1-5 and Step 1-6 are steps in which a compound (3-9) is obtained by an alkylation reaction of an amine using the compound (3-5) and the compound (2-1b), or the compound (3-7) and the compound (2-2b).
  • the alkylation reaction of an amine can be carried out in accordance with Production Process 2.
  • the step represented by Step 1-7 is a step in which a compound (1-1b) is obtained by deprotection of the compound (3-9).
  • the condition for deprotection usually used by a person skilled in the art can be applied.
  • the deprotection can be carried out in accordance with the aforementioned “Protective Groups in Organic Synthesis”, p. 573-575, or the like.
  • the deprotection can also be carried out by hydrolysis in accordance with Production Process 3.
  • the step represented by Step 1-8 is a step in which a compound (1-1b) is obtained by a sulfonamidation reaction using a compound (3-10) and a compound (3-11).
  • the sulfonamidation reaction can be carried out in accordance with 2 of the Production Process 1.
  • the step represented by Step 2-1 is a step in which a compound (4-3) is obtained by an amidation reaction using a compound (4-1) and a compound (4-2).
  • the amidation reaction can be carried out in accordance with 1 of the Production Process 1.
  • the step represented by Step 2-2 is a step in which a compound (4-5) which is an intermediate for the Gewald reaction is obtained by a reaction of the compound (4-3) with a compound (4-4) by a Gewald reaction.
  • the step represented by Step 2-3 is a step in which a compound (1-1a) which is a thiophene derivative is obtained by a reaction by a reaction of the compound (4-5) with sulfur. This reaction is carried out by stirring a mixture of the compound (4-3) and the compound (4-4), or a mixture of the compound (4-5) and sulfur under any temperature condition from room temperature to heating, usually for 0.1 hours to 5 days, in a solvent which is inert to the reaction, in the presence of a base.
  • Step 2-2 and Step 2-3 simultaneously. That is, the reaction can also be carried out by stirring a mixture of the compound (4-3), the compound (4-4), and sulfur under any temperature condition from room temperature to heating, usually for 0.1 hours to 5 days, in a solvent which is inert to the reaction, in the presence of a base. Further, it is also possible to carry out Step 2-2 and Step 2-3 simultaneously.
  • Examples of the solvent as used herein are not particularly limited, but include aromatic hydrocarbons such as benzene, toluene, xylene, pyridine, and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, dimethylsulfoxide, and a mixed solvent thereof.
  • the base is not particularly limited, but examples thereof include organic bases such as morpholine and the like. For this process, reference may be made to, for example, the method described in McKibben, B. P., et al., Tetrahedron Lett., 40:5471, (1999).
  • the step represented by Step 2-4 is a step in which a compound (1-2a-1) is obtained by an amidation reaction using the compound (1-1a) and the compound (4-6).
  • the amidation reaction can be carried out in accordance with 1 of the Production Process 1.
  • the compound (2-1a) or the compound (2-2a) can be obtained by a sulfonamidation reaction using the compound (1-2a-1) and the compound (3-4), or the compound (1-2a-1) and the compound (3-6).
  • the sulfonamidation reaction can be carried out in accordance with 2 of the Production Process 1.
  • R c represents a substituent which is acceptable for aryl or cycloalkyl in R 2 or R 2
  • Boc represents tert-butyl-O—CO—
  • the step represented by Step 3-1 is a step in which a compound (1-2b-1) is obtained by an alkylation reaction of an amine of the compound (5-1) and the compound (5-2).
  • the alkylation reaction of an amine can be carried out in accordance with the Production Process 2.
  • the step represented by Step 3-2 is a step in which a compound (1-2b-2) is obtained by a reductive amination reaction of the compound (5-3) and the compound (5-2).
  • the reductive amination reaction can be carried out in accordance with A. R. Katritzky and R. J. K. Taylor, “Comprehensive Organic Functional Group Transformations II”, Vol. 2, Elsevier Pergamon, 2005, or the aforementioned “Courses in Experimental Chemistry (5th edition)”.
  • the step represented by Step 3-3 is a step in which a compound (5-5) is obtained by a reductive amination reaction of the compound (5-4) and then a subsequent Boc-addition reaction thereof.
  • the Boc-addition reaction can be carried out in accordance with the aforementioned “Protective Groups in Organic Synthesis”.
  • the step represented by Step 3-4 is a step in which a compound (1-2b-3) is obtained by eliminating Boc of the compound (5-5).
  • the elimination of Boc can be carried out in accordance with the afore-mentioned “Protective Groups in Organic Synthesis”.
  • the step represented by Step 4-1 is a reaction in which a compound (6-3) is obtained by a reaction of a compound (6-1) and a compound (6-2) by a Horner-Wadsworth-Emmons reaction.
  • a mixture of the compound (6-1) and the compound (6-2) are stirred under any temperature condition from room temperature to heating under reflux, preferably at a temperature from 0° C. to 80° C., usually for 0.1 hours to 5 days, in a solvent which is inert to the reaction, in the presence of a base.
  • solvents examples include aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, N,N-dimethylformamide, dimethylsulfoxide, ethyl acetate, acetonitrile and a mixture thereof.
  • aromatic hydrocarbons such as benzene, toluene, xylene, and the like
  • ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like
  • halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, N,N-dimethylformamide, dimethyl
  • the base examples include organic bases such as sodium methoxide, potassium-tert-butoxide, n-butyl lithium, lithium hexamethyldisilazide, and the like, and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydride, and the like.
  • organic bases such as sodium methoxide, potassium-tert-butoxide, n-butyl lithium, lithium hexamethyldisilazide, and the like
  • inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydride, and the like.
  • the step represented by Step 4-2 is a reaction in which a compound (6-4) is obtained by a hydrogenation reaction of the compound (6-3).
  • a hydrogenation reaction reference may be made to, for example, the method described in M. Hudlicky, “Reductions in Organic Chemistry, 2 nd ed. (ACS Monograph: 188)”, ACS, 1996, and the aforementioned “Courses in Experimental Chemistry (5 th edition)”, Vol. 19 (2005).
  • the step represented by Step 4-3 is a reaction in which a compound (6-7) is obtained by a Claisen-Schmidt reaction of the compound (6-5) with the compound (6-6).
  • a Claisen-Schmidt reaction reference may be made to, for example, the method described in J. March, “Advanced Organic Chemistry, 4 th ed.” Wiley Interscience, 1992.
  • the step represented by Step 4-4 is a reaction in which a compound (6-8) is obtained by a hydrogenation reaction of the compound (6-7).
  • a hydrogenation reaction reference may be made to, for example, the method described in C. W. Jefford, Tetrahedron Letter, 1994, 35:4759.
  • the compound of the formula (I) can be isolated and purified as their free compounds, salts, hydrates, solvates, or polymorphic crystal substances thereof.
  • the salts of the compound of the formula (I) can be prepared by carrying out the treatment of a conventional salt forming reaction.
  • Isolation and purification are carried out by employing ordinary chemical operations such as extraction, fractional crystallization, various types of fractional chromatography, and the like.
  • Various isomers can be prepared by selecting an appropriate starting compound or separated by using the difference in the physicochemical properties between the isomers.
  • the optical isomers can be obtained by means of a general method for designing optical resolution of racemic products (for example, fractional crystallization for inducing diastereomer salts with optically active bases or acids, chromatography using a chiral column or the like, and others), and further, the isomers can also be prepared from an appropriate optically active starting compound.
  • Test Example 1 33 P Phosphate Uptake Inhibiting Action of Rat NPT-IIb Expressing Cell
  • rat NPT-IIb ORF was cloned into p3 ⁇ FLAG-CMV-10 by PCR according to a standard method. Then, the cloned rat NPT-IIb expressing plasmid was transfected into 293 cells, and G418 was used to obtain a rat NPT-11b-stably expressing cell line.
  • the rat NPT-Hb expressing cells were seeded into a 96-well plate and incubated overnight. The medium was taken out and washed with buffer A (137 mM N-methyl-D-glucamine, 5.4 mM KCl, 2.8 mM CaCl 2 , 1.2 mM MgCl 2 , 10 mM HEPES (adjusted to pH 7.4 with HCl)), and then buffer B (137 mM NaCl, 5.4 mM KCl, 2.8 mM CaCl 2 , 1.2 mM MgCl 2 , 0.1 mM KH 2 PO 4 , 10 mM HEPES (adjusted to pH 7.4 with KOH)) was added thereto.
  • buffer A 137 mM N-methyl-D-glucamine, 5.4 mM KCl, 2.8 mM CaCl 2 , 1.2 mM MgCl 2 , 10 mM HEPES (
  • a compound having 10-fold higher concentration relative to the evaluation concentration was prepared by dilution with the buffer B and added thereto, followed by incubation in CO 2 incubator.
  • Buffer B supplemented 50 ⁇ Ci/mL 33 P was added thereto, followed by further incubation in a CO 2 incubator.
  • the buffer was taken out and the cells were washed with buffer C (137 mM NaCl, 10 mM Tris/HCl pH 7.2).
  • Microscint-20 was added thereto and 33 P uptake was measured by using TopCount.
  • the inhibitory rate was determined according to the following equation.
  • Inhibitory rate (%) (1 ⁇ ( 33 P uptake of drug-treated well)/( 33 P uptake of DMSO-added well)) ⁇ 100
  • rat NPT-11b inhibitory activity at a pharmacological evaluation concentration of 1 ⁇ M is shown in Table 1.
  • Ex represents Example No. as denoted below (this shall apply hereinafter).
  • mice Male Wistar rats (6 to 7 weeks old) were fasted for 24 hours and used as experimental animals.
  • the compound was dissolved or suspended with a solvent, and was used at a concentration of 0.6 mg/mL.
  • the compound-administered animals were forcibly orally administered with the compound at a dose of 3 mg/kg.
  • Control-group animals were administered a solvent containing no compound at a dose of 5 mL/kg.
  • a 32 P-containing phosphate solution (8.3 mM NaH 2 PO 4 ) was orally administered thereto at a dose of 7.2 mL/kg. After 15 minutes and 30 minutes, the blood was taken from the orbital venous plexus and the serum was collected.
  • Radioactivity in 0.1 mL of the serum was measured by a liquid scintillation counter.
  • AUC 0-30min calculated from the measured counts was considered as a phosphate absorption amount.
  • the phosphate absorption inhibitory rate was determined from the AUC 0-30min value according to the following equation.
  • Phosphate absorption inhibitory rate (%) (1 ⁇ Phosphate absorption count of compound-administered group/Phosphate absorption count of control group) ⁇ 100
  • the compound of the formula (I) can be used to treat hyperphosphatemia or the like.
  • a pharmaceutical composition containing one or two or more kinds of the compound of the formula (I) or a salt thereof as an active ingredient can be prepared using excipients that are usually used in the art, that is, excipients for pharmaceutical preparation, carriers for pharmaceutical preparation, and the like according to the methods usually used.
  • Administration can be accomplished either by oral administration via tablets, pills, capsules, granules, powders, solutions, and the like, or parenteral administration injections, such as intraarticular, intravenous, or intramuscular injections, and the like, suppositories, ophthalmic solutions, eye ointments, transdermal liquid preparations, ointments, transdermal patches, transmucosal liquid preparations, transmucosal patches, inhalers, and the like.
  • parenteral administration injections such as intraarticular, intravenous, or intramuscular injections, and the like, suppositories, ophthalmic solutions, eye ointments, transdermal liquid preparations, ointments, transdermal patches, transmucosal liquid preparations, transmucosal patches, inhalers, and the like.
  • the solid composition for use in the oral administration according to the present invention is used in the form of tablets, powders, granules, or the like.
  • one or more active ingredient(s) are mixed with at least one inactive excipient, such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, and/or magnesium aluminometasilicate.
  • the composition may contain inactive additives, such as a lubricant such as magnesium stearate, a disintegrating agent such as carboxymethyl starch sodium and the like, a stabilizer, or a solubilization assisting agent. If necessary, tablets or pills may be coated with sugar or a film of a gastric or enteric coating substance.
  • the liquid composition for oral administration contains pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, or the like, and also contains generally used inert diluents, for example, purified water or ethanol.
  • the liquid composition may also contain auxiliary agents, such as a solubilization assisting agent, a moistening agent, and a suspending agent, sweeteners, flavors, aromatics, and antiseptics.
  • the injections for parenteral administration include sterile aqueous or non-aqueous solution preparations, suspensions and emulsions.
  • the aqueous solvent includes, for example, distilled water for injection and physiological saline.
  • the non-aqueous solvent include propylene glycol, polyethylene glycol, plant oils such as olive oil, alcohols such as ethanol, polysorbate 80 (Japanese Pharmacopeia), and the like.
  • Such a composition may further contain a tonicity agent, an antiseptic, a moistening agent, an emulsifying agent, a dispersing agent, a stabilizing agent, or a solubilizing aid.
  • These are sterilized, for example, by filtration through a bacteria retaining filter, blending of a bactericide, or irradiation.
  • these can also be used by preparing a sterile solid composition, and dissolving or suspending it in sterile water or a sterile solvent for injection prior to its use.
  • the agent for external use includes ointments, plasters, creams, jellies, cataplasm, sprays, lotions, eye drops, eye ointments, and the like.
  • the agents contain generally used ointment bases, lotion bases, aqueous or non-aqueous liquid preparations, suspensions, emulsions, and the like.
  • the ointment bases or the lotion bases include polyethylene glycol, propylene glycol, white vaseline, bleached bee wax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, and the like.
  • transmucosal agents such as an inhaler, a transnasal agent, and the like, those in the form of a solid, liquid, or semi-solid state are used, and can be prepared in accordance with a conventionally known method.
  • a known excipient and also a pH adjusting agent, an antiseptic, a surfactant, a lubricant, a stabilizing agent, a thickening agent, or the like may be appropriately added thereto.
  • an appropriate device for inhalation or blowing can be used.
  • a compound may be administered alone or as a powder of formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier, using a conventionally known device or sprayer, such as a measured administration inhalation device, and the like.
  • a dry powder inhaler or the like may be for single or multiple administration use, and a dry powder or a powder-containing capsule may be used.
  • this may be in a form such as a pressurized aerosol spray which uses an appropriate ejection agent, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane, carbon dioxide, and the like, or other forms.
  • the daily dose is generally from about 0.001 to 100 mg/kg, preferably from 0.1 to 30 mg/kg, and more preferably 0.1 to 10 mg/kg, per body weight, administered in one portion or in two or more divided portions.
  • the daily dose is suitably administered from about 0.0001 to 10 mg/kg per body weight, once a day or two or more times a day.
  • a transmucosal agent is administered at a dose from about 0.001 to 100 mg/kg per body weight, once a day or two or more times a day. The dose is appropriately decided in response to the individual case by taking the symptoms, the age, and the gender, and the like into consideration.
  • the compound of the formula (I) can be used in combination with various therapeutic or prophylactic agents for the diseases for which the compound of the formula (I) is considered to be effective.
  • the combined preparation may be administered simultaneously, or separately and continuously, or at a desired time interval.
  • the preparations to be co-administered may be a blend, or may be prepared individually.
  • the preparation methods for the compound of the formula (I) will be described in more detail with reference to Examples. Further, the present invention is not limited to the compounds described in the Examples as described below. Furthermore, the production processes for the starting compounds will be described in Preparation Examples. Further, the preparation methods for the compound of the formula (I) are not limited to the preparation methods of the specific Examples as below, but the compound of the formula (I) can be prepared by any combination of the preparation methods or the methods that are apparent to a person skilled in the art.
  • HCl in the structural formula indicates that the Example compound is isolated as a hydrochloride.
  • a concentration mol/l is expressed as M.
  • a 1 M aqueous sodium hydroxide solution means a 1 mol/l aqueous sodium hydroxide solution.
  • the resultant was concentrated under reduced pressure, and to a mixture of the obtained residue and 10 mL of THF was added a solution of TBAF in THF (1.0 M, 4.0 mL), followed by stirring at room temperature for 3 hours. A solution of TBAF in THF (1.0 M, 2.0 mL) was further added thereto, followed by stirring at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate, and then washed with 0.2 M hydrochloric acid, water, and saturated brine in this order.
  • the obtained residue was purified by silica gel column chromatography (aqueous ammonia-methanol-chloroform) to obtain 0.47 g of ethyl 4-[(1-isopropylpiperidin-4-yl)amino]butyrate as a yellow oily substance.
  • a mixture of the obtained crude product and 50 mL of dichloromethane was added to a mixture of 80 mL of a 1 M aqueous sodium hydroxide solution, 300 mL of dichloromethane, and 14.3 g of 4-(pyridin-4-ylmethyl)aniline under ice-cooling.
  • a 1 M aqueous sodium hydroxide solution was added on time to adjust the reaction solution to be kept alkaline.
  • the organic layer was collected by separation and the aqueous layer was extracted with dichloromethane.
  • the combined organic layer was dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure.
  • the obtained residue was recrystallized from ethanol to obtain 10.2 g of 2-cyano-N-[4-(pyridin-4-ylmethyl)phenyl]acetamide as a pale yellow solid.
  • the compound of Preparation Example 9-1 was prepared; in the same manner as in the method of Preparation Example 15, the compounds of Preparation Examples 15-1 and 15-2 were prepared; in the same manner as in the method of Preparation Example 18, the compound of Preparation Example 18-1 was prepared; in the same manner as in the method of Preparation Example 19, the compounds of Preparation Examples 19-1 to 19-3 were prepared; in the same manner as in the method of Preparation Example 22, the compound of Preparation Example 22-1 was prepared; in the same manner as in the method of Preparation Example 23, the compound of Preparation Example 23-1 was prepared; in the same manner as in the method of Preparation Example 25, the compounds of Preparation Examples 25-1 to 25-3 were prepared; in the same manner as in the method of Preparation Example 26, the compounds of Preparation Examples 26-1 to 26-3 were prepared; and in the same manner as in the method of Preparation Example 27, the compound of Preparation Example 27-1 was prepared by using corresponding starting materials, respectively.
  • reaction mixture was purified by silica gel column chromatography (hexane-chloroform) to obtain 320 mg of methyl 4-(2- ⁇ 4-[( ⁇ 2-[(3- ⁇ ethyl[trans-4-(methoxycarbonyl)cyclohexyl]sulfamoyl ⁇ benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl ⁇ carbonyl)amino]phenyl ⁇ ethyl)benzoate as a yellow foamed solid.
  • reaction mixture was purified by silica gel column chromatography (hexane-chloroform) to obtain 279 mg of methyl 4-(2- ⁇ 4-[( ⁇ 2-[(3- ⁇ [1-(ethoxycarbonyl)cyclopropyl](isopropyl)sulfamoyl ⁇ benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl ⁇ carbonyl)amino]phenyl ⁇ ethyl)benzoate as a yellow foamed solid.
  • reaction mixture was purified by silica gel column chromatography (hexane-chloroform) to obtain 505 mg of methyl 4-( ⁇ [3-( ⁇ 3-[(4- ⁇ 2-[4-(methoxycarbonyl)phenyl]ethyl ⁇ phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl ⁇ carbamoyl)phenyl]sulfonyl ⁇ amino)benzoate as a yellow foamed solid.
  • ESI+ 752
  • reaction mixture was concentrated under reduced pressure, and then to a mixture of the obtained crude product and 3 mL of dichloromethane were added 0.11 mL of pyridine and 300 mg of methyl 4-[3-(4- ⁇ [(2-amino-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino ⁇ phenyl)propyl]benzoate, followed by stirring at room temperature overnight.
  • reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (methanol-chloroform) to obtain 164 mg of 1- ⁇ [3-( ⁇ 3-[(4- ⁇ 2-[4-(methoxycarbonyl)phenyl]ethyl ⁇ phenyl)carbonyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl ⁇ carbamoyl)phenyl]sulfonyl ⁇ -2-methylproline as a yellow powder solid.
  • the product was lyophilized to obtain 33 mg of sodium 1- ⁇ [(3- ⁇ [3-( ⁇ 4-[2-(4-carboxylatophenyl)ethyl]phenyl ⁇ carbamoyl)-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]carbamoyl ⁇ phenyl)sulfonyl](methyl)amino ⁇ -1-deoxy-D-glucitol as a yellow foamed solid.
  • reaction mixture was purified by silica gel column chromatography (hexane-chloroform) to obtain 850 mg of methyl 4-[2-(4- ⁇ [(2- ⁇ [3-(cyclopropylsulfamoyl)benzoyl]amino ⁇ -4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino ⁇ phenyl)ethyl]benzoate as a pale yellow solid.
  • reaction mixture was purified by silica gel column chromatography (hexane-chloroform) to obtain 442 mg of methyl 4- ⁇ 2-[4-( ⁇ [2-( ⁇ 3-[(4-ethoxy-4-oxobutyl)sulfamoyl]benzoyl ⁇ amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl ⁇ amino)phenyl]ethyl ⁇ benzoate as a pale yellow solid.
  • the reaction mixture was concentrated under reduced pressure, and then to the obtained residue were added water, 300 mg of citric acid, dichloromethane, and THF in this order, and the organic layer was separated and concentrated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (chloroform-methanol).
  • the compound of the formula (I) or a salt thereof, or the compound of the formula (I) or a salt thereof has an NPT-IIb inhibitory action and can be used as an agent for preventing or treating hyperphosphatemia.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Molecular Biology (AREA)
  • Obesity (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
US13/639,260 2010-04-28 2011-04-27 Tetrahydrobenzothiophene compound Abandoned US20130029973A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP2010104044 2010-04-28
JP2010-104044 2010-04-28
PCT/JP2011/060261 WO2011136269A1 (ja) 2010-04-28 2011-04-27 テトラヒドロベンゾチオフェン化合物

Publications (1)

Publication Number Publication Date
US20130029973A1 true US20130029973A1 (en) 2013-01-31

Family

ID=44861567

Family Applications (3)

Application Number Title Priority Date Filing Date
US13/639,260 Abandoned US20130029973A1 (en) 2010-04-28 2011-04-27 Tetrahydrobenzothiophene compound
US13/661,545 Active US8729068B2 (en) 2010-04-28 2012-10-26 Tetrahydrobenzothiophene compound
US14/229,146 Expired - Fee Related US9284295B2 (en) 2010-04-28 2014-03-28 Tetrahydrobenzothiophene compound

Family Applications After (2)

Application Number Title Priority Date Filing Date
US13/661,545 Active US8729068B2 (en) 2010-04-28 2012-10-26 Tetrahydrobenzothiophene compound
US14/229,146 Expired - Fee Related US9284295B2 (en) 2010-04-28 2014-03-28 Tetrahydrobenzothiophene compound

Country Status (14)

Country Link
US (3) US20130029973A1 (zh)
EP (1) EP2565190B1 (zh)
JP (1) JP5617919B2 (zh)
KR (1) KR101721025B1 (zh)
CN (1) CN102869656B (zh)
AU (1) AU2011246072B2 (zh)
BR (1) BR112012025390B8 (zh)
CA (1) CA2793856C (zh)
EA (1) EA022521B1 (zh)
ES (1) ES2539722T3 (zh)
MX (1) MX2012012421A (zh)
PL (1) PL2565190T3 (zh)
PT (1) PT2565190E (zh)
WO (1) WO2011136269A1 (zh)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9062032B2 (en) 2011-10-27 2015-06-23 Astellas Pharma Inc. Aminoalkyl-substituted N-thienylbenzamide derivative
US9284295B2 (en) 2010-04-28 2016-03-15 Astellas Pharma Inc. Tetrahydrobenzothiophene compound
US9499553B2 (en) 2013-03-13 2016-11-22 Chugai Seiyaku Kabushiki Kaisha Dihydropyridazine-3,5-dione derivative and pharmaceuticals containing the same
US9617232B2 (en) 2013-04-24 2017-04-11 Daiichi Sankyo Company, Limited Dicarboxylic acid compound
US10053437B2 (en) 2014-09-26 2018-08-21 Daiichi Sankyo Company, Limited Salt of dicarboxylic acid compound
EP3287448A4 (en) * 2015-04-24 2019-01-23 Daiichi Sankyo Company, Limited PROCESS FOR PREPARING A DICARBOXYLIC ACID COMPOUND

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013129435A1 (ja) * 2012-02-28 2013-09-06 協和発酵キリン株式会社 縮環チオフェン誘導体
WO2014003153A1 (ja) * 2012-06-28 2014-01-03 協和発酵キリン株式会社 置換アミド化合物
CA2901868C (en) 2013-03-13 2022-05-03 Chugai Seiyaku Kabushiki Kaisha Dihydropyridazine-3,5-dione derivative
WO2015064532A1 (ja) * 2013-10-30 2015-05-07 第一三共株式会社 モルホリン化合物
CN105658635B (zh) * 2014-08-22 2019-03-08 江苏恒瑞医药股份有限公司 噻吩并环烷基或噻吩并杂环基类衍生物、其制备方法及其在医药上的应用
AU2015316425B2 (en) * 2014-09-12 2019-11-21 Chugai Seiyaku Kabushiki Kaisha Pharmaceutical containing sodium-dependent phosphate transporter inhibitor
CN105524053B (zh) * 2014-10-19 2020-06-05 广东东阳光药业有限公司 四氢苯并噻吩化合物
AU2017312783B2 (en) * 2016-08-15 2020-02-06 Eli Lilly And Company Condensed thiophene derivatives useful as NaPi-IIb inhibitors
AR126060A1 (es) 2021-06-08 2023-09-06 Chugai Pharmaceutical Co Ltd Método para producir derivado de dihidropiridazin-3,5-diona
TW202317118A (zh) 2021-06-08 2023-05-01 日商中外製藥股份有限公司 含有二氫嗒-3，5-二酮衍生物的製劑
WO2023219127A1 (ja) * 2022-05-11 2023-11-16 中外製薬株式会社 嚢胞性疾患を治療または予防するための医薬組成物

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007131532A (ja) * 2001-09-28 2007-05-31 Kirin Brewery Co Ltd 生体内リン輸送を阻害する化合物およびそれを含んでなる医薬
JPWO2003048134A1 (ja) * 2001-12-05 2005-04-14 日本たばこ産業株式会社 トリアゾール化合物及びその医薬用途
IL154306A0 (en) 2003-02-05 2003-09-17 Rimonyx Pharmaceuticals Ltd Pharmaceutical compositions comprising thieno [2,3-c] pyridine derivatives and use thereof
US8134015B2 (en) 2003-03-27 2012-03-13 Kyowa Hakko Kirin Co., Ltd. Compound inhibiting in vivo phosphorous transport and medicine containing the same
AU2004270394A1 (en) 2003-09-10 2005-03-17 Gpc Biotech Ag Heterobicyclic compounds as pharmaceutically active agents
US20050085531A1 (en) 2003-10-03 2005-04-21 Hodge Carl N. Thiophene-based compounds exhibiting ATP-utilizing enzyme inhibitory activity, and compositions, and uses thereof
WO2006093518A2 (en) 2004-06-25 2006-09-08 Apath, Llc Thienyl compounds for treating virus-related conditions
EP1796662A2 (en) 2004-08-30 2007-06-20 The Government of the U.S.A., as repr. by the Secretary, Dept. of Health & Human Services, the Nat. Inst. of Health Inhibition of viruses using rnase h inhibitors
WO2006044826A2 (en) 2004-10-20 2006-04-27 Compass Pharmaceuticals Llc Thiophens and their use as anti-tumor agents
GB0514652D0 (en) 2005-07-15 2005-08-24 Syngenta Ltd Pesticidal mixtures
US20110015239A1 (en) 2007-12-14 2011-01-20 The Regents Of The University Of California Inhibitors of calcium-activated chloride channels
CA2709784A1 (en) 2007-12-21 2009-07-09 University Of Rochester Method for altering the lifespan of eukaryotic organisms
EP2240443B1 (en) 2008-01-08 2013-11-20 Purdue Pharma LP Proline analogs as ligands for cannabinoid receptors for the treatment of pain
CN102105470B (zh) 2008-06-17 2014-06-04 韩国巴斯德研究所 作为抗结核病药的吡啶并嘧啶化合物
ES2539722T3 (es) 2010-04-28 2015-07-03 Astellas Pharma Inc. Compuesto de tetrahidrobenzotiofeno
EP2591354B1 (en) 2010-07-07 2016-09-07 Ardelyx, Inc. Compounds and methods for inhibiting phosphate transport

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9284295B2 (en) 2010-04-28 2016-03-15 Astellas Pharma Inc. Tetrahydrobenzothiophene compound
US9062032B2 (en) 2011-10-27 2015-06-23 Astellas Pharma Inc. Aminoalkyl-substituted N-thienylbenzamide derivative
US9499553B2 (en) 2013-03-13 2016-11-22 Chugai Seiyaku Kabushiki Kaisha Dihydropyridazine-3,5-dione derivative and pharmaceuticals containing the same
US9617232B2 (en) 2013-04-24 2017-04-11 Daiichi Sankyo Company, Limited Dicarboxylic acid compound
US9670173B2 (en) 2013-04-24 2017-06-06 Daiichi Sankyo Company, Limited Dicarboxylic acid compound
US10053437B2 (en) 2014-09-26 2018-08-21 Daiichi Sankyo Company, Limited Salt of dicarboxylic acid compound
EP3287448A4 (en) * 2015-04-24 2019-01-23 Daiichi Sankyo Company, Limited PROCESS FOR PREPARING A DICARBOXYLIC ACID COMPOUND
US10189804B2 (en) 2015-04-24 2019-01-29 Daiichi Sankyo Company, Limited Method for producing dicarboxylic acid compound

Also Published As

Publication number Publication date
AU2011246072A1 (en) 2012-10-11
PL2565190T3 (pl) 2015-10-30
CN102869656B (zh) 2014-03-12
EP2565190A1 (en) 2013-03-06
AU2011246072B2 (en) 2014-06-26
EA201291121A1 (ru) 2013-04-30
KR20130073908A (ko) 2013-07-03
EA022521B1 (ru) 2016-01-29
KR101721025B1 (ko) 2017-03-29
MX2012012421A (es) 2012-12-17
CA2793856C (en) 2018-07-17
BR112012025390B1 (pt) 2021-10-13
EP2565190B1 (en) 2015-06-03
US9284295B2 (en) 2016-03-15
JP5617919B2 (ja) 2014-11-05
US8729068B2 (en) 2014-05-20
ES2539722T3 (es) 2015-07-03
BR112012025390B8 (pt) 2022-11-22
BR112012025390A2 (pt) 2016-06-28
US20130053369A1 (en) 2013-02-28
PT2565190E (pt) 2015-08-24
CN102869656A (zh) 2013-01-09
JPWO2011136269A1 (ja) 2013-07-22
EP2565190A4 (en) 2013-08-21
WO2011136269A1 (ja) 2011-11-03
CA2793856A1 (en) 2011-11-03
US20140329802A1 (en) 2014-11-06

Similar Documents

Publication Publication Date Title
US9284295B2 (en) Tetrahydrobenzothiophene compound
US9062032B2 (en) Aminoalkyl-substituted N-thienylbenzamide derivative
US8802679B2 (en) Glycine compound
JP4732354B2 (ja) グリシン輸送阻害薬としての二環式［３．１．０］誘導体
AU2016202010A1 (en) Guanidine compound
US8765750B2 (en) Piperazine compound having a PGDS inhibitory effect
JP2008531679A (ja) オキシトシンアンタゴニストとしての１，２，４−トリアゾール誘導体とその使用
JPWO2010058846A1 (ja) ４，６−ジアミノニコチンアミド化合物
KR20090114439A (ko) 아실구아니딘 유도체
MX2011004704A (es) Compuesto de carbamato o sal del mismo.
US9951060B2 (en) 2-acylaminothiazole derivative or salt thereof
US20150315208A1 (en) Benzazepine compound
CN101611005B (zh) 用作pde4抑制剂的取代的苯乙酮类
JP5673676B2 (ja) イミダゾ［１，２−ａ］ピリジン誘導体
KR102253721B1 (ko) 벤조티오펜 화합물
WO2012115066A1 (ja) グリシントランスポーター阻害物質

Legal Events

Date Code Title Description
AS Assignment

Owner name: ASTELLAS PHARMA INC., JAPAN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:HACHIYA, SHUNICHIRO;MIURA, MASANORI;IMAMURA, YOSHIMASA;AND OTHERS;REEL/FRAME:029090/0614

Effective date: 20120906

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION