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WO2002055484A1 - Compose biaryle, procede de production de ce compose, et principe actif - Google Patents

Compose biaryle, procede de production de ce compose, et principe actif Download PDF

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Publication number
WO2002055484A1
WO2002055484A1 PCT/JP2002/000073 JP0200073W WO02055484A1 WO 2002055484 A1 WO2002055484 A1 WO 2002055484A1 JP 0200073 W JP0200073 W JP 0200073W WO 02055484 A1 WO02055484 A1 WO 02055484A1
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Prior art keywords
methyl
biphenyl
group
amino
optionally substituted
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PCT/JP2002/000073
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English (en)
Japanese (ja)
Inventor
Masakuni Kori
Eiichiro Ishikawa
Mikiyo Nakata
Makoto Kobayashi
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Takeda Pharmaceutical Co Ltd
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Takeda Chemical Industries Ltd
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Publication of WO2002055484A1 publication Critical patent/WO2002055484A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/18—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/14—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • 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
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a novel biaryl derivative having excellent properties as a medicament, a method for producing the same, and an agent containing the same.
  • the hepatic low-density lipoprotein (LDL) receptor plays a major role in cholesterol homeostasis. Cholesterol circulating in the form of LDL is cleared from plasma by very specific LDL receptors and is taken up by cells via receptor-mediated cellular uptake. Once taken up into cells, LDL particles are broken down by lysosomes, thereby releasing cholesterol, and intracellular concentrations of free cholesterol. Enhance. Increased free cholesterol levels signal hepatocytes to reduce the rate of transcription of genes for key enzymes in the cholesterol biosynthetic pathway, resulting in reduced de novo cholesterol synthesis. Also, the LDL receptor fflRNA and protein are down-regulated by increased intracellular cholesterol, reducing the liver's ability to remove the increased LDL cholesterol from plasma.
  • LDL receptor fflRNA and protein are down-regulated by increased intracellular cholesterol, reducing the liver's ability to remove the increased LDL cholesterol from plasma.
  • R 4 represents phenyl which may have dialkylamino, protected amino, etc.
  • Y represents a bond
  • R 2 represents lower alkyl, etc.
  • R 3 represents one or more And n represents 0 or 1.] or a salt thereof is disclosed as being useful as an ACAT inhibitor.
  • the present inventors have synthesized, for the first time, a novel biaryl derivative having the following specific substituent, which has an excellent LDL receptor increasing action, a blood lipid lowering action, and And found it useful, and completed this research.
  • ring A and ring B each represent a 5- or 6-membered aromatic ring which may be substituted
  • R 1 and R 2 each represent a hydrogen atom, a hydrocarbon group which may be substituted or
  • X 1 , X 2 , X 3 and X 4 each represent a bond or a divalent hydrocarbon group which may be substituted
  • Y represents one NR 3 —CO— ,
  • 3 and 3 ′ each represent a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group
  • CO- NH-, - CS- NH-, - CO- or _S0 2 - indicates,
  • Ar represents an optional
  • R 1 is a substituted C 3 _ 8 optionally cycloalkyl group (1) Symbol placement compound
  • Y is NR 3 — C ⁇ , CO — NR 3 — or — NR 3 — CH.
  • R 3 The compound according to (1), wherein the compound has the same meaning as defined in claim 1).
  • X 2 is a bond or (: - 6 alkylene group wherein (1) a compound according;
  • X 3 is a bond or C ⁇ - 6 wherein an alkylene group (1)
  • Z gar S0 2 - a is the (.1) Compound according;
  • the ⁇ ring and the ⁇ ring each represent an optionally substituted 5- or 6-membered aromatic ring (provided that the atom adjacent to the ⁇ ring atom bonded to the ⁇ ring is unsubstituted.)
  • R 1 and R 2 each represent a hydrogen atom, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted;
  • X 1 ′ represents a bond;
  • X 2 ′ represents a bond or (: 6 represents an alkylene group, X 3 ′ represents a 6- alkylene group, X 4 ′ represents a bond or an alkylene group, and
  • Y ′ represents one NR 3 —C ⁇ (R 3 is a hydrogen atom, Represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group), and Z represents one CO—NH—, one CS—NH—, one CO— or one S ⁇ 2 —.
  • Ar represents a cyclic hydrocarbon group which may be substituted
  • ring A and ring B each represent a 5- or 6-membered aromatic ring which may be substituted (the atom adjacent to the ring A atom bonded to the ring B is unsubstituted.)
  • R 1 and R 2 each represent a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group
  • X 1 ′ represents a bond
  • X 3 ′ represents an alkylene group
  • X 4 ′ represents a bond or ( ⁇ —6 alkylene group
  • Y ′′ represents one CO—NR 3 — (R 3 represents a hydrogen atom the shown) optionally substituted hydrocarbon group or an optionally substituted heterocyclic group indicates
  • Z is one CO- NH-, one CS- NH-, one CO- or a S 0 2 - are shown
  • a r is expressed by showing the optionally substituted cyclic hydrocarbon group or an
  • R 1 ′ ′′ represents an optionally substituted hydrocarbon group
  • R 2 ′ ′′ represents an optionally substituted heterocyclic group
  • X 2 ''' indicates a bond
  • X 4 ''' indicates Ci_ 6 alkylene group represents a group
  • Z''' is - S0 2 - shows the shows the a r '''is an optionally substituted cyclic hydrocarbon group] Or a salt thereof (hereinafter, sometimes referred to as compound (1 ′ ′′ ′));
  • composition according to (29) which is a low-density lipoprotein receptor enhancer
  • composition according to (29) which is a lipid-lowering agent
  • Y preferably represents one NR 3 —CH 2 — or _CH 2 —NR 3 —, and more preferably represents —NR 3 _CH 2 —], or a salt thereof with an isocyanate,
  • each symbol in the formula has the same meaning as described in the above (1).
  • the compound represented by the formula (Ia) or a salt thereof is subjected to an acylation reaction, a sulfonylation reaction or an alkylation reaction.
  • Ya is one O—CO—NR 3 —, one CO—NR 3 —, _S ⁇ 2 —NR 3 — or —CH 2 —NR 3 _ (R 3 is the same as described in (1) above.) ⁇ indicating significance)), and other symbols have the same meanings as described in (1) above.
  • a method for increasing a low-density lipoprotein receptor in a mammal which comprises administering to the mammal an effective amount of the compound or a salt thereof according to (1);
  • a method for decreasing lipid in a mammal which comprises administering an effective amount of the compound or a salt thereof according to (1) to the mammal;
  • an effective amount of the compound or salt thereof according to (1) is administered to the mammal, (1) hyperlipidemia, (2) arteriosclerosis, (3) hypertension. (4) Prevention and treatment of diabetic complications with lipemia or arteriosclerosis or (4) hypertension with hyperlipidemia or arteriosclerosis;
  • divalent hydrocarbon group refers to, for example, an alkylene group having 1 to 15 carbon atoms (eg, methylene, ethylene, propylene, butylene, pentamethylene, hexamethylene, heptamethylene).
  • Octamethylene, etc . preferably an alkylene group
  • 2 to 16 alkenylene groups eg, vinylene, probenylene, 1-butenylene, 2-butenylene, 1-pentenylene, 2-pentenylene
  • 3-pent two alkylene preferably, C 2 - 6 alkenylene group
  • 2 to 16 alkynylene group e.g., Echiniren, propynylene, 1-Petit two alkylene, 2-butyl two Ren, 1 one pliers two alkylene, 2 one pliers two alkylene, 3-pentylene two alkylene like; preferably, C 2 - 6 alkynylene group) divalent chain hydrocarbon group, such as, And a phenylene group or a combination thereof.
  • substituents which the “divalent hydrocarbon group” may have include, for example, an alkyl group which may be substituted, an aralkyl group which may be substituted, a aryl group which may be substituted, A hydroxyl group which may be substituted (eg, a hydroxyl group which may be substituted with an optionally substituted hydrocarbon group; preferably a hydroxyl group which may be substituted with an optionally substituted alkyl group) , A hydroxyl group, etc.) and the like, and an optionally substituted alkyl group is preferable.
  • the “phenylene group” may have a substituent.
  • the substituent of the "phenylene group” for example, a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), ⁇ - 4 alkyl group (e.g., methyl, Echiru, propyl, isopropyl, butyl, etc.) , an alkoxy group (e.g., methoxyethanol, ethoxy, Purobokishi, isopropoxy etc.), ( ⁇ _ 4 alkylthio group (eg example, methylthio, Echiruchio, propylthio, isopropylthio etc.), hydrin proxy group, the force Rupokishiru group, Shiano group, nitro group, amino group, mono - or di - C i-4 alkylamino group (e.g., Mechiruamino, Echiruamino, dimethylaminopyridine Roh, etc.
  • a halogen atom e.g., fluor
  • Jechiruamino a formyl group, a mercapto group, ( ⁇ _ 4 alkyl - Cal Poniru group (e.g., Asechiru, propionyl, such as Puchiriru),. door 4 Al Key sheet - Power Ruponiru group (e.g., methoxy Cal Poni Le, ethoxy Cal Poni Le, Provo Kishikaruponiru etc.), a sulfo group (_ S_ ⁇ 3 H), C bets 4 alkylsulfonyl group (e.g., methylsulfonyl, Echirusuruhoniru, propylsulfonyl etc.
  • alkyl - Cal Poniru group e.g., Asechiru, propionyl, such as Puchiriru
  • door 4 Al Key sheet - Power Ruponiru group e.g., methoxy Cal Poni Le, ethoxy Cal Poni Le
  • force Rubamoiru group eg, N- methylcarbamoyl, N- E Ji carbamoyl, N, N- dimethyl Cal Bamoiru, N, N - GETS Chi carbamoyl etc.
  • halogen atom refers to, for example, fluorine, chlorine, bromine, iodine and the like.
  • hydrocarbon group in the term “optionally substituted hydrocarbon group” means, for example, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, an aralkyl group, Represents an aryl group, etc.
  • cyclic hydrocarbon group in the term “optionally substituted cyclic hydrocarbon group” refers to, for example, 'a cycloalkyl group, a cycloalkenyl group, an aryl group and the like.
  • Examples of the substituent which the “hydrocarbon group” may have include the following “alkyl group”, “cycloalkyl group”, “alkenyl group”, “cycloalkenyl group”, “alkynyl group”, “aralkyl” And the same substituents as the substituents which the "aryl group” and “aryl group” may have.
  • alkyl group includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, pendecyl, dodecyl, tridecyl Rideshiru, tetradecyl, etc. pentadecyl etc.
  • "linear or branched C Bok i 5 alkyl group” preferably C E -. 6 alkyl group is used.
  • cycloalkyl group examples include r c 3 such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Etc. _ 8 cycloalkyl group ", preferably c 5 _ 7 cycloalkyl group is used.
  • substituents which the “alkyl group” and “cycloalkyl group” may have include, for example, (i) a nitro group, (ii) a hydroxy group, an oxo group, (iii) a cyano group, and (iv) rubamoyl.
  • V mono- or di-4-alkyl-l-rubamoyl group (for example, N-methylcarbamoyl, N-ethylcarbamoyl, N, -dimethylcarbamoyl, N, N-getylcarbamoyl, etc.), (vi ) Carbonyl group, (viCi- 4 alkoxy monocarbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl !, etc.)), (Viii) sulfo group,
  • halogen atom eg, fluorine, chlorine, bromine, iodine, etc.
  • X optionally halogenated alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, etc.), halogenated which may C 5 - 7 Shikuroaruko alkoxy group, optionally halogenated and C 5 - 7 cycloalkoxy one C i-e an alkoxy group, (xi) phenyl group, (xi i) an optionally halogenated phenoxy Groups (eg, 0-, m- or p-chlorophenoxy, o-, m- or p-promophenoxy), optionally halogenated phenoxy monoalkyl groups, (xi ii) halogenated Alkyl group, even if halogenated Good 6 alkylthio groups (eg, methylthio, ethylthio, n-propylthio,
  • E chill sulfide El (xvi ii) 6 alkylsulfonyl group (e.g., methylsulfonyl, etc. Echirusuru Honiru), (xix) amino group, aminosulfonyl group, (XX) (: 3 Ashiruamino group (e.g., Asechiruamino propionyloxy, etc. Rua Mino), (xxi) mono - or di - 4 alkylamino group (eg , Mechiruamino, Echiruamino, dimethyl Amino, etc.
  • (xx iv) a benzoyl group, (XXV) a 5- to 10-membered heterocyclic group which may be bonded via a C alkyl or alkoxy group (for example, 2- or 3- phenyl, 2- or 3-furyl, 3 —, 4 _ or 5 — pyrazolyl, 2.—, 4 mono or 5 — thiazolyl, 3 —, 4 _ or 5 — isothiazolyl, 2—, 4— or 5 — year old xazolyl, 1, 2, 3 — or 1, 2,4_triazolyl, 1H- or 2H-tetrazolyl, 2-, 3- or 4-pyridyl, 2-, 4_ or 5-pyrimidyl, 3- or 4-monopyridazinyl, quinolyl, isoquinolyl indolyl And (xxv i) (to 4 alkyl or Optionally linked through an alkoxy group C 3 - 8 cycloalkyl group (e.g.
  • alkyl group examples include linear or branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.
  • substituent which may have the "d _ 6 alkyl group” is, for example, a halogen atom, (4 alkoxy group, hydroxyl group, d-4 alkoxy - carboxymethyl group, carboxy Group, forces Rubamoiru group, mono- or di-C i _ 4 alkyl force Rubamoiru group, 3 to 1, such as pyridinium Jiruchio group are used.
  • alkenyl group for example Biel, Ariru, isoproterenol base alkenyl, three to-butenyl, 3-Okuparu, such as "C 2 _ 1 8 alkenyl group” such as 9 one year old Kutadeseniru, preferably C 2 - 6 alkenyl group Is used.
  • cycloalkenyl group for example Shikuropuro base sulfonyl, Shikurobuteni Le, cyclopentenyl, cyclohexenyl, cycloheptenyl cyclohexane, such Shikurookute two Le: such as "(3 _ 8 cycloalkenyl group", preferably a C 5 - A 7 cycloalkenyl group is used.
  • alkenyl group and the “cycloalkenyl group” may have, the same substituents as those which the “alkyl group” may have are used.
  • alkenyl group include vinyl, Ariru, 2-butenyl, C 2, such as three to butenyl - like 6 alkenyl group.
  • the - The "C 2 6 alkenyl group” substituent optionally have include the ones "alkyl group” is the same even substituent 3 ⁇ 4 that have are used.
  • alkynyl group for example, Echiniru, propynyl, 1 one heptynyl, 2 Buchiniru, 1-pentynyl, 2-pentynyl, "C 2 _ 1 8 alkynyl group” such as three to pentynyl, preferably C 2 - 6 alkynyl groups are used.
  • alkynyl group for example Echiniru, Puropieru, 1 one heptynyl, etc.
  • C 2 _ 6 alkynyl groups such as 2-Bucheru the like.
  • the - The "C 2 6 alkynyl group” may have not have substituent, for example, the intended “alkyl group” is the same as the substituent which may be possessed are used.
  • Ararukiru group such as 6 Ararukiru group is used, specifically, for example, benzyl, phenethyl, 3 one phenylpropyl, phenylene Lou such 4 _ phenylene Rubuchi Le - 6 alkyl group and, for example, (1 one-naphthyl) methyl, 2 - (1 one-naphthyl) Echiru, 2 i (2-naphthyl) Nafuchiru such Echiru C 1 - such as 6 alkyl group.
  • aralkyl group examples include, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a C 4 alkyl group which may be halogenated (eg, methyl, Edjiru, propyl, isopropyl, etc. butyl), optionally halogenated good c 5 _ 7 cycloalkyl group, c 2 _ 6 alkenyl group (e.g., vinyl, Ariru, 2-butenyl, 3-butenyl, etc.), ( : Bok 3 ⁇ Shi Le group (e.g., formyl, etc.
  • a halogen atom eg, fluorine, chlorine, bromine, iodine, etc.
  • C 4 alkyl group which may be halogenated (eg, methyl, Edjiru, propyl, isopropyl, etc. butyl)
  • optionally halogenated alkoxy group e.g., methoxy, ethoxy, Purobokishi, etc. isopropoxy
  • nitro group Shiano group, hydroxy group, hydroxy group - ( ⁇ - 4 alkyl group, a force Rupokishiru group, (Bok 4 alkoxy Ichiriki Ruponiru group (e.g., methoxycarbonyl two Le Ethoxycarponyl, propoxyl-proponyl, isopropoxyl-luponyl, etc.), l-rubamoyl group, mono- or di-alkyl-l-lumbamoyl group (for example, N-methylcarbamoyl, N-ethylcarbamoyl, N, N_dimethylcarbamoyl, N-, N-getylcarbamoyl, etc.), mono- or di-alkenyl radical bamoyl groups (eg, N-vinylcar
  • aryl group examples include phenyl, 1-naphthyl and 2-naphthyl , biphenyl, Fuenantoriru, anthryl (anthryl) aromatic monocyclic such as, bicyclic or tricyclic C 6 _ 4 of ⁇ Li Ichiru Groups are used.
  • Examples of the substituent that the “aryl group” may have include an oxo group and the like, in addition to the substituent that the “aralkyl group” may have, and the “aryl group” is They may have 1 to 4, preferably 1 or 2 of these substituents at substitutable positions.
  • Examples of the aryl group having an oxo group include benzoquinonyl, naphthoquinolyl, and anthraquinonyl.
  • heterocyclic group in the term “optionally substituted heterocyclic group” used in the present specification includes, for example, oxygen atom, sulfur atom and nitrogen atom as atoms (ring atoms) constituting a ring system.
  • aromatic heterocyclic group examples include, for example, furyl, phenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxaziazolyl, 1,2,4-oxaziazolyl, 1,3 1,4-oxaziazolyl, furzanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 5- or 6-membered aromatic monocyclic heterocyclic groups such as pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and, for example, benzofuranyl, isobenzofuranyl, benzo [b.
  • [4,3-] 8- to 12-membered aromatic condensed heterocyclic group such as pyridazinyl (preferably a heterocyclic or condensed 5- or 6-membered aromatic monocyclic heterocyclic group described above with a benzene ring)
  • non-aromatic heterocyclic group examples include 3- to 8-membered groups such as oxilanyl, azetidinyl, oxenyl, ceyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydroviranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like ( (Preferably 5 to 6 members) saturated or unsaturated (preferably saturated)
  • a non-aromatic heterocyclic group aliphatic heterocyclic group) or the above aromatic unit such as 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, etc.
  • a non-aromatic heterocyclic group in which the double bond is partially or entirely saturated in the cyclic heterocyclic group or the aromatic condensed heterocyclic group is exemplified.
  • heterocyclic group in the “optionally substituted heterocyclic group”, a 5- or 6-membered aromatic monocyclic heterocyclic group or the like is preferable, and the “optionally substituted heterocyclic group” is preferred.
  • the substituent which the "heterocyclic group” in “” may have is the same as the substituent which the "hydrocarbon group” in “optionally substituted hydrocarbon group” may have And the like.
  • the A ring and the B ring represent an optionally substituted 5- or 6-membered aromatic ring (the atom adjacent to the A ring atom bonded to the B ring is unsubstituted).
  • the A ring and B ring substituents which may have respectively, For instance a halogen atom (e.g., fluorine, chlorine, bromine, iodine), ( ⁇ - 4 alkyl group (e.g., methyl, Echiru, propyl, isopropyl, and butyl), hydroxy _ C Bok 4 alkyl groups, C i-4 alkoxy primary alkyl groups, mono- or di - ⁇ alkyl or C 5 - 7 cycloalkyl over ⁇ amino groups, C DOO 4 alkoxy groups (e.g., main 'Toxy, ethoxy, propoxy, isopropoxy, etc.), 4 alkylthio groups (eg, methylthio, ethylthio, propylthio, isopropylthio, etc.), hydroxy group, hydroxyl group, cyano group, nitro group, amino group, mono- or di- C Bok 4 alkylamino group (e.
  • the B ring is unsubstituted, and particularly preferable that the A ring and the B ring are unsubstituted.
  • the “5- or 6-membered aromatic ring j” in the “optionally substituted 5- or 6-membered aromatic ring” represented by ring A and ring B is, for example, a benzene ring, a 5- or 6-membered aromatic heterocycle. And the like.
  • the 5- or 6-membered aromatic heterocyclic ring for example, furan, thiophene, pyrrole, imidazole, pyrazole, thiazol, oxazole, isothiazole, isoxazole, oxaziazole, thiadiazol, triazol 5- to 6-membered aromatic heterocycles containing 1 to 2 heteroatoms selected from nitrogen, sulfur and oxygen, such as pyridine, pyrazine, pyrazine, pyrimidine, pyridazine and triazine Among them, a 6-membered nitrogen-containing aromatic heterocycle is preferable, and pyridine, pyrimidine and the like are particularly preferable.
  • Preferred examples of ring A and ring B include
  • a 6-membered nitrogen-containing aromatic heterocyclic ring in which ring A may be substituted (preferably, an optionally substituted pyridine ring or an optionally substituted pyrimidine ring);
  • a 6-membered nitrogen-containing aromatic heterocyclic ring in which ring B may be substituted (preferably, an optionally substituted pyridine ring or an optionally substituted pyrimidine ring);
  • a 6-membered nitrogen-containing aromatic heterocyclic ring in which ring A and ring B may be substituted preferably, a pyridine ring which may be substituted or a pyrimidine ring which may be substituted; Among them, it is preferable that the A ring and the B ring are benzene rings which may be substituted.
  • R 1 represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group.
  • Examples of the optionally substituted hydrocarbon group and the optionally substituted heterocyclic group represented by R 1 include the aforementioned “optionally substituted hydrocarbon group” and “substituted The same heterocyclic group as described above "may be used.
  • R 1 preferably optionally substituted C 3 8 also be a cycloalkyl group, also in the name or, optionally substituted C 3 _ 8 cycloalkyl group is preferable, especially, to a good cycloalkyl substituted Xyl groups are preferred.
  • R 2 represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group.
  • Examples of the optionally substituted hydrocarbon group and the optionally substituted heterocyclic group represented by R 2 include the above-mentioned “optionally substituted hydrocarbon group” and “optionally substituted heterocyclic group”. The same groups as those described above are used.
  • an optionally substituted aromatic hydrocarbon group, an optionally substituted aromatic heterocyclic group, and the like are preferable, and among them, an optionally substituted phenyl group, an optionally substituted phenyl group, Preferred is a 5- or 6-membered aromatic heterocyclic group (preferably, an optionally substituted pyridyl group).
  • R 3 and R 3 ′ each represent a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group.
  • R 3 or R 3 ′ may be bonded to R 1 so that R 3 or R 3 ′ may form a 510-membered cyclic amino group together with an adjacent nitrogen atom.
  • R 3 or R 3 ′ may form a 510-membered cyclic amino group together with an adjacent nitrogen atom.
  • Examples thereof include morpholino, piperidino, piperazine-11-yl, phthalimide and the like.
  • the cyclic amino group may have any substituent at a substitutable position, and such a substituent may be a hydrocarbon group in the optionally substituted hydrocarbon group represented by R 1 And similar substituents (eg, a hydroxy group—a C 4 alkyl group, a carboxyl group, a Ci 4 alkoxy—a carbonyl group).
  • R 3 and R 3 ′ a hydrogen atom, an optionally substituted alkyl group, and the like are preferable, and among them, a hydrogen atom is preferable.
  • X 1 represents a bond or a divalent hydrocarbon group which may be substituted.
  • Examples of the optionally substituted divalent hydrocarbon group represented by X 1 include the aforementioned
  • X 1 is preferably a bond or a -6 alkylene group, particularly preferably a bond.
  • X 2 represents a bond or a divalent hydrocarbon group which may be substituted.
  • the optionally substituted divalent hydrocarbon group represented by X 2 is as described above.
  • X 2 is preferably a bond or an alkylene group, particularly preferably a bond.
  • X 3 represents a bond or a divalent hydrocarbon group which may be substituted.
  • the optionally substituted divalent hydrocarbon group represented by X 3 is as described above.
  • X 3 is preferably a bond or an alkylene group, particularly preferably a methylene group.
  • X 4 represents a bond or a divalent hydrocarbon group which may be substituted.
  • the optionally substituted divalent hydrocarbon group represented by X 4 is as described above.
  • X 4 is preferably a bond or an alkylene group, particularly preferably a methylene group.
  • Y an NR 3 - CO-, one CO- NR 3 -, - NR 3 - S0 2 -, - S0 2 - NR 3 -, - NR 3 - CH 2 -, _CH 2 - NR 3 - , one hundred and one CO - NR 3 or one NR 3 '- NR 3 - CO- (R 3 and R 3' showing a is as defined above).
  • Y is preferably one NR 3 _CO—, one NR 3 —CH 2 — or —CO—NR 3 —.
  • Z represents —CO—NH—, _CS—NH—, one CO— or one S ⁇ 2 —.
  • Ar represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group.
  • the “optionally substituted cyclic hydrocarbon group” and the “optionally substituted heterocyclic group” represented by Ar the aforementioned “optionally substituted cyclic hydrocarbon group” and “optionally substituted The same heterocyclic groups as those described above may be used.
  • Ar is preferably an optionally substituted phenyl group or an optionally substituted 5- to 6-membered aromatic heterocyclic group (preferably, an optionally substituted pyridyl group).
  • ring A and ring B each represent a 5- or 6-membered aromatic ring which may be substituted (provided that the atom adjacent to the ring A atom bonded to the ring B is unsubstituted.)
  • R 1 and R 2 each represent a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;
  • X 1 ′ represents a bond;
  • X 2 ′ represents a bond or an alkylene group
  • X 3 ′ represents a 6 alkylene group;
  • X 4 ′ represents a bond or a Ci- 6 alkylene group;
  • Y ′ represents one NR 3 —CO— (R 3 is a hydrogen atom;
  • Z represents one CO—NH—, one CS—NH—, one C ⁇ or one S ⁇ 2 —, and
  • A represents r represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group] or a salt thereof;
  • ring ⁇ and ring ⁇ ⁇ each represent a 5- or 6-membered aromatic ring which may be substituted (provided that the atom adjacent to the ring A atom bonded to the ring B is unsubstituted.)
  • R 1 and R 2 each represent a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, X 1 ′ represents a bond, X 2 ′ represents a bond or X 3 ′ represents an alkylene group; X 3 ′ represents an alkylene group; X 4 ′ represents a bond or a Ci-e alkylene group; Y ′′ represents —CO—NR 3 — (R 3 represents a hydrogen atom, shows also heterocyclic group is a hydrocarbon group or a substituted may have) was shown, Z is one CO- NH-, one CS- NH-, one CO- or a S0 2 - indicates, a r represents a cyclic hydrocarbon group which may be substituted
  • X 1 ′ ′′ is preferably a bond, a methylene group or the like
  • X 3 ′ is preferably a methylene group or the like
  • X 4 ′′ ′′ is preferably a methylene group or the like.
  • an optionally substituted aromatic heterocyclic group or the like is preferable, and an optionally substituted pyridyl group or the like is more preferable.
  • Ar " optionally substituted An aromatic hydrocarbon group and the like are preferable, and a halogen atom, an optionally halogenated ( ⁇ -alkyl group and an optionally halogenated alkoxy group)
  • the salt of the compound represented by the formula (I) of the present invention is preferably a pharmaceutically acceptable salt or a physiologically acceptable acid addition salt.
  • Such salts include, for example, inorganic acids (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, etc.) or organic acids (eg, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, Tartaric acid, cunic acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, etc.) are used.
  • inorganic acids eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, etc.
  • organic acids eg, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, Tartaric acid, cunic acid, malic acid, oxalic acid, benzoic acid,
  • the compound (I) of the present invention has an acidic group such as a carboxylic acid
  • the compound (I) may be, for example, an inorganic base (eg, an alkali metal such as sodium, potassium, calcium, magnesium, or an alkaline earth metal).
  • an organic base for example, a tree C ⁇ 3 alkylamine such as triethylamine
  • a salt for example, a salt, a salt, a salt.
  • the same salt as described above is used, but is not particularly limited as long as the reaction is not hindered.
  • the prodrug of the compound represented by the formula (I) or a salt thereof (hereinafter may be referred to as compound (I)) of the present invention can be obtained by a reaction with an enzyme, stomach acid or the like under physiological conditions in a living body.
  • Compounds that are converted to (I) that is, compounds that are enzymatically oxidized, reduced, hydrolyzed, etc. to be converted to compound (I), and compounds that are hydrolyzed, for example, to gastric acid, to be converted to compound (I), Say.
  • Prodrugs of compound (I) include compounds in which the amino group of compound (I) is acylated, alkylated, or phosphorylated (for example, the amino group of compound (I) is eicosanoylated, alanylated, pentylamino).
  • a compound in which the hydroxyl group of the compound (I) is acylated, alkylated, phosphorylated, or borated for example, the hydroxyl group of the compound (I) is acetylated, palmitoylated, propanoylated, pivaloyylated, succinylated) , Fumarylation, aranylation, dimethylaminomethylcarbonylated compounds, etc.
  • the lipoxyl group is esterified or amidated (e.g., the lipoxyl group of compound (I) is converted into ethyl ester, phenyl ester, carboxymethyl ester, Methylaminomethyl esterification, Pivaloyloxymethyl esterification, Ethoxycarbonyloxyethyl esterification, Phthalidyl esterification, (5-Methyl-2-oxo-1-1,3-Dioxolen-1-yl) methyl Ester
  • the prodrug of compound (I) changes to compound (I) under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Drugs, Vol. 7, Molecular Design, pp. 163 to 198”. It may be something.
  • Compound (I) may be a hydrate.
  • compound (I) When an optically active form of compound (I) is required, it can be obtained, for example, using an optically active starting material or by resolving the racemic form of the compound using conventional methods. Can be.
  • compound (I) may have an asymmetric carbon in the molecule.
  • two types of stereoisomers of the R-coordination or S-coordination exist each of them or a mixture thereof is used. Included in the invention.
  • an acid addition salt is preferable, and among them, a hydrochloride is preferably used.
  • the compound (I) of the present invention can be synthesized according to a reaction known per se, for example, by the following method. '
  • the compound (I) of the present invention can be synthesized, for example, by the following method.
  • Y 1 represents _NR 3 —CH 2 _ or one CH 2 —NR 3 —, and the other symbols have the same meanings as described above. ]
  • Y 2 represents one NP 1 — CH 2 — or one CH 2 — NP 1 —
  • Y 2 ′ represents one NH—CH 2 — or one CH 2 — NH—
  • P 1 represents an amino group
  • the other symbols are as defined above.
  • 1 to 3 equivalents, preferably 1 to 3 equivalents of the isocyanate is used.
  • an inorganic base for example, potassium carbonate, sodium hydrogen carbonate, etc.
  • an organic base for example, triethylamine, pyridine, dimethylamine, 1,8-diazabicyclo [5.4.0]
  • alcohols eg, sodium methylate, sodium ethylate, potassium tert-butoxy
  • organometallic reagents eg, n-butyllithium
  • sodium hydroxide sodium amide, etc. Is also good.
  • the used amount is 1 to a large excess, preferably 1 to 5 equivalents.
  • the reaction temperature is 0 to 200 ° C, preferably 20 to 100 ° C.
  • Solvents used include hydrocarbons (eg, hexane, benzene, toluene, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, dichloroethane, etc.), ethers (eg, tetrahydrofuran, Dioxane, dimethyl ether, esters (eg, ethyl acetate, methyl acetate, etc.), protic polar solvents (eg, methanol, ethanol, etc.), aprotic polar solvents (eg, acetonitrile, N, N-dimethylphos) Lumamide, dimethylsulfoxide, etc.).
  • the reaction time is generally 5 minutes to 24 hours, preferably 1 to 10 hours.
  • the acylation reaction of compound (II) in the method (A) can be synthesized by a usual amide formation reaction. That is, compound (II) and carboxylic acid (Ar-C ⁇ H) are synthesized using an amide-forming reagent, or acid chloride synthesized from compound (II) and carboxylic acid (Ar-COOH) It can be synthesized by reacting a mixed acid anhydride or active ester.
  • Examples of the amide-forming reagent in the reaction of the compound (II) with the carboxylic acid include 1-ethoxy-1,2-dihydroquinoline, dicyclohexylcarbodiimide, 1-cyclohexyl 3- (2-morpholinoethyl) carbodiimide, Meso-P-toluenesulfonate, N, N'-carbonyldiimidazole, diph Getyl phenyl phosphate, azide diphenyl phosphate, getyl cyanophosphate 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and the like are used.
  • the amide forming reagent is used in the amount of 1 to 3 equivalents based on compound (II).
  • a base for example, an inorganic base (for example, potassium carbonate, sodium hydrogen carbonate, etc.), an organic base (for example, triethylamine, pyridine, dimethylamine, 1,8 diazabicyclo [5.4.0]] — 7-pandene, etc. ), Alcoholates (eg, sodium methylate, sodium ethylate, potassium tert-butoxy), organometallic reagents (eg, n-butyllithium), sodium hydroxide, sodium amide, etc.
  • 1 to 5 equivalents may be used.
  • the reaction temperature is 0 to 200 ° C, preferably 0 to 100 ° C.
  • the solvent to be used include hydrocarbons (eg, hexane, benzene, toluene, etc.), octalogenated hydrocarbons (eg, methylene chloride, chloroform, dichloroethane, etc.), and ethers (eg, tetrahydrofuran).
  • the reaction time is generally 10 to 24 hours, preferably 1 to 10 hours.
  • an inorganic base for example, potassium carbonate, sodium hydrogen carbonate, etc.
  • an organic base for example, triethylamine, pyridine, dimethylamine, 1,8-diazabicyclo [5.4.0] -17-decene
  • Alcoholates eg, sodium methylate, sodium ethylate, potassium tert-butoxy
  • organometallic reagents eg, n-butyllithium
  • sodium hydroxide sodium amide, etc.
  • a large excess may be used, preferably 1 to 5 equivalents.
  • the reaction temperature is 0 to 200 ° C, preferably 0 to 60 ° C.
  • Solvents used include hydrocarbons (eg, hexane, benzene, toluene, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, dichloroethane, etc.), ethers (eg, Tetrahydrofuran, dioxane, getyl ether, etc.), esters (eg, ethyl acetate, methyl acetate, etc.), protic polar solvents (eg, methanol, ethanol, etc.), aprotic polar solvents (eg, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, etc.), or a mixture of these solvents with water.
  • the reaction time is usually 10 to 24 hours, preferably 1 to 10 hours.
  • reaction of compound (II) with the mixed acid anhydride can be carried out in the same manner as in the reaction of compound (II) with acid chloride.
  • the reaction between the compound (II) and the active ester is carried out by first reacting a carboxylic acid with, for example, 2,4,5-trichlorophenol, pentachlorophenol, penfluorophenol, 2-nitrophenol, Phenols such as ditrophenol, for example, N-hydroxy compounds such as N-hydroxysuccinimide, 1-hydroxybenztriazole, N-hydroxy xypiperidine, N-hydroxy-5-norpolpolene-2,3-dicarpoimide,
  • the active ester is synthesized by reacting with an amide-forming reagent such as hexylcarposimide, and then reacted with the compound (II).
  • the reaction can be carried out in the same manner as in the reaction between compound (II) and acid chloride, and can be carried out subsequent to the synthesis of the active ester.
  • an inorganic base for example, potassium carbonate, sodium hydrogen carbonate, etc.
  • an organic base for example, triethylamine, pyridine, dimethylamine, 1,8-diazabicyclo [5.4.0] -17-decene
  • Alcoholates for example, sodium methylate, sodium ethylate, potassium tert-butoxy
  • organometallic reagents for example, n-butyllithium
  • sodium hydroxide sodium amide, etc.
  • the reaction temperature is 0 to 200 ° C, preferably 0 to 60 ° C.
  • Examples of the solvent used include hydrocarbons (eg, hexane, benzene, toluene, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, dichloroethane, etc.), ethers (eg, tetrahydrofuran, The Oxane, acetyl ether, etc.), esters (eg, ethyl acetate, methyl acetate, etc.), protic polar solvents (eg, methanol, ethanol, etc.), non-protonic polar solvents (eg, acetonitrile, N, N— Dimethylformamide, dimethylsulfoxide, etc.), or a mixed solution of these solvents and water.
  • the reaction time is generally 10 to 24 hours, preferably 1 to 10 hours.
  • the method (A-1) and the method (A-2) can be performed in the same manner as the method (A).
  • the reaction of the compound (II-ii) with the isocyanate, the reaction with the isothiocyanate, the acylation reaction and the sulfonylation reaction include the reaction of the compound (II) with the isocyanate and the reaction with the isothiocyanate.
  • the reaction can be carried out in the same manner as in the reaction, acylation reaction and sulfonylation reaction.
  • Subsequent deprotection reaction of P 1 can be performed by its Re methods known per se.
  • E represents a leaving group such as halogen (for example, chlorine, bromine, iodine, etc.), methanesulfonyloxy, P-toluenesulfonyloxy, and other symbols have the same meanings as described above. '
  • a ketone or aldehyde is used in an amount of 1 equivalent to a large excess, preferably 1 equivalent to 5 equivalents, based on the compound (V) to form a Schiff base.
  • sodium cyanoborohydride sodium triacetoxyborohydride, sodium borohydride, lithium aluminum hydride or the like in an amount of 1 equivalent to a large excess, preferably 1 equivalent to 3 equivalents.
  • an acid such as acetic acid or hydrochloric acid may be used in an amount of 1 to a large excess, preferably 1 to 3 equivalents as a reaction accelerator.
  • the reaction temperature is 0 to 200 ° C, preferably 0 to 60 ° C.
  • Solvents used include protic polar solvents (eg, methanol, ethanol, etc.), hydrocarbons (eg, hexane, benzene, toluene, etc.), and halogenated hydrocarbons (eg, methylene chloride, chloroform).
  • reaction time is generally 10 to 24 hours, preferably 1 to 10 hours.
  • the reaction of the compound (V) with the compound represented by the formula R 1 — X 1 — CH 2 — E or a salt thereof is performed by reacting the compound (V) with R 1 — X i — CH
  • a base for example, an inorganic base (eg, potassium carbonate, sodium hydrogen carbonate, etc.), an organic base
  • reaction temperature is 0 to 200, preferably 0 to 100 ° C.
  • solvent examples include protic polar solvents (eg, methanol, ethanol, etc.), hydrocarbons (eg, hexane, benzene, toluene, etc.), halogenated hydrocarbons.
  • reaction time is generally 10 to 24 hours, preferably 1 to 10 hours.
  • Y one O- CO- NR 3 -, -CO- NR 3 - or a S0 2 - NR 3 - indicates, the other symbols are as defined above.
  • the acylation or sulfonylation of the compound (V) in the method (C) can be carried out in the same manner as the acylation or sulfonylation of the compound (II) in the method (A).
  • the oxycarbonylation reaction of the compound (V) in the method (C) for example, 1 equivalent to a large excess, preferably 1 equivalent to 3 equivalents, of a carbonate anhydride or a halogenated carbonate is used based on the compound (V).
  • an inorganic base for example, potassium carbonate, sodium hydrogen carbonate, etc.
  • an organic base for example, triethylamine, pyridine, dimethylamine, 1,8-diazabicyclo [5.4.0] -17-decene, etc.
  • Alcohols eg, sodium methylate, sodium ethylate, potassium tert-butoxy
  • organometallic reagents eg, n-butyllithium
  • sodium hydroxide sodium amide, etc.
  • a large excess preferably 1 to 5 equivalents, may be used.
  • the reaction temperature is 0 to 200 ° C, preferably 0 to 100 ° C.
  • Solvents used include hydrocarbons (eg, hexane, benzene, toluene) Octogenated hydrocarbons (eg, methylene chloride, chloroform, dichloroethane, etc.), ethers (eg, tetrahydrofuran, dioxane, getyl ether, etc.), esters (eg, ethyl acetate, methyl acetate) And aprotic polar solvents (eg, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, etc.), or a mixture of these solvents and water.
  • the reaction time is generally 10 to 24 hours, preferably 1 to 10 hours.
  • Y represents —NR 3 —C ⁇ or —NR 3 , 1 NR 3 —CO—, and the other symbols have the same meanings as described above.
  • the condensation reaction of the compound (IV) with the compound represented by the formula R 1 — X 1 — NH—R 3 or R 1 — X 1 — NR 3 '—NH—R 3 or a salt thereof is carried out by The reaction can be carried out under the same conditions as the reaction of compound (II) with a carboxylic acid using an amide-forming reagent, or the reaction of compound (II) with an acid chloride or a mixed acid anhydride.
  • Compound (II) can be synthesized from the compound represented by (VI) in the same manner as in the reductive alkylation reaction of compound (V) in method (II).
  • the compound (II-ii) can be synthesized from the compound represented by (VI-ii) by the same method as the reductive alkylation reaction of the compound (V) in the method (B).
  • W 02
  • E 2 represents halogen (eg, chlorine, bromine, iodine, etc.), and other symbols have the same meanings as described above. ]
  • Compound (VI) can be synthesized from compound (VI) using a Suzuki coupling reaction known per se.
  • Compound (VI-ii) can be synthesized from compound (VI-ii) using a Suzuki coupling reaction known per se.
  • the compound (VII-i) in which Y is -NR 3 —CH 2 — can be synthesized by the following methods (E), (F), (G), E)
  • reaction between (VIII) and the compound represented by the formula R 1 — X 1 NH—R 3 or a salt thereof is represented by the reaction of the compound (V) in the method (B) with the formula R 1 — Xi_E
  • the reaction can be carried out in the same manner as in the reaction with the compound or a salt thereof.
  • the reductive alkylation reaction of compound (IX) in method (G) can be carried out in the same manner as the reductive alkylation reaction of compound (V) in method (B).
  • the compound (VII-ii) wherein Y 2 is — NP 1 —CH 2 — is synthesized by, for example, the following method (H), (I) or (J) be able to.
  • the reaction of the compound (X) with the compound represented by the formula R 1 — X 1 — ⁇ ⁇ ⁇ or a salt thereof is carried out by the compound (V) in the method ( ⁇ ) and the formula R 1 — X 1 — ⁇
  • the reaction can be carried out in the same manner as in the reaction with the represented compound or a salt thereof.
  • Subsequent protection of the amino group can be carried out by a method known per se.
  • the reductive alkylation reaction of the compound (X) in the method (J) can be carried out by the same method as the reductive alkylation reaction of the compound (V) in the method (B).
  • the subsequent protection of the amino group can be carried out by a method known per se.
  • p 2 represents a protecting group for an amino group, and other symbols have the same meanings as described above.
  • Compound (V) in method (B) can be synthesized from compound (XI) by a method similar to the synthesis of compound (I) in method (A).
  • Compound (XI) can be synthesized by subjecting compound (XII) to a reductive alkylation reaction by the same method as the reduction alkylation reaction of compound (V) in method (B).
  • Compound (XII) can be synthesized from compound (XIII) using a Suzuki coupling reaction known per se.
  • the protection of the amino group of compound (XIV) can be carried out by a method known per se.
  • R 4 represents a lower (C ⁇ e) alkyl group, and the other symbols have the same meanings as described above. ]
  • Compound (IV) can be synthesized from compound (XV) in the same manner as in the synthesis of compound (I) in method (A).
  • the subsequent hydrolysis of the ester can be carried out by treating the ester with an acid or a base. That is, the ester form is converted to an acid (eg, hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, iodic acid, etc.) or a base (eg, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, etc.).
  • an acid eg, hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, iodic acid, etc.
  • a base eg, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, etc.
  • the strength of the acid or base is preferably 1 to 10N, more preferably 2 to 5N.
  • Compound (XV) can be synthesized from compound (XVI) by a method similar to the reduction alkylation reaction of compound (V) in method (B).
  • Compound (XVI) can be synthesized from compound (XVII) using a Suzuki coupling reaction known per se.
  • Compound (VI) can be synthesized by oxidizing a compound represented by the formula (1) or a salt thereof (compound (1)).
  • oxidizing agent in the oxidation reaction of compound (1) to an aldehyde compound, for example, 1 to 20 equivalents of an oxidizing agent is used for 1 equivalent of the alcohol compound.
  • oxidizing agents include activated manganese dioxide, pyridinium chromate (PCC), pyridinium dichromate (PDC), dimethyl sulfoxide anhydride (acetic anhydride, trifluoroacetic anhydride, etc.), dimethyl sulfoxide chloride and the like.
  • the solvent used at this time can be appropriately selected depending on the type of the oxidizing agent, and examples thereof include ethers (eg, tetrahydrofuran, dioxane, getyl ether, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform) Form, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), aprotic polar solvents (eg, N, N-dimethylformamide, dimethyl sulfoxide, etc.).
  • the reaction time is 0.5 to 48 hours, preferably 1 to 24 hours.
  • the reaction temperature is appropriately selected according to the type of the oxidizing agent, and the reaction is carried out at a temperature of from 80 to + 100 ° C, preferably from -7 to +30 Can,
  • the compound (1) can be synthesized by reducing the compound represented by the formula (2) or a salt thereof.
  • the reducing agent is used in an amount of 1 equivalent to a large excess, preferably 2 to 10 equivalents, based on compound (2).
  • the reducing agent include metal hydride complex compounds such as lithium aluminum hydride, diisobutylaluminum hydride, sodium borohydride and sodium cyanoborodiamine, and dipolane.
  • the solvent used at this time can be appropriately selected according to the type of the reducing agent, and examples thereof include alcohols (eg, methanol and ethanol), ethers (eg, tetrahydrofuran, dioxane, getyl ether, etc.), halogenated hydrocarbons (Eg, methylene chloride, chloroform, etc.), aprotic polar solvents (eg, N, N-dimethylformamide, dimethylsulfoxide, etc.).
  • the reaction time is 0.5 to 72 hours, preferably 1 to 24 hours.
  • the reaction can be carried out at 180 to + 100 ° C., preferably at ⁇ 80 to +3 O :.
  • reaction between the compound (3) and the compound represented by the formula R 1 — X 1 — NH—R 3 or a salt thereof is represented by the compound (IV) in the method D and the formula R 1 — X 1 — NH—R 3 It can be synthesized by a method similar to the reaction with the represented compound or a salt thereof.
  • Compound (4) reacts with the compound represented by the formula R 1 — X 1 — NH—R 3 or a salt thereof.
  • the reaction can be carried out in the same manner as in the reaction of the compound (IV) with the compound represented by the formula R 1 —X 1 —NH—R 3 or a salt thereof in Method D.
  • Compound (3) can be synthesized by reacting compound (5) with boronic acid using Suzuki coupling known per se.
  • Compound (4) can be synthesized by hydrolyzing compound (6) with one equivalent of a base. That is, 0.5 to 1.5 equivalents of compound (4), preferably 1 equivalent of a base (eg, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, etc.) water or a lower alcohol (eg, methanol) , Ethanol, propanol, etc.) It can be synthesized by reacting in a solution at 0 to 100, preferably at 10 ° C. to 50 for 1 to 48 hours, preferably for 1 to 12 hours.
  • a base eg, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, etc.
  • a lower alcohol eg, methanol
  • Compound (XV) can also be synthesized by halogenating compound (7) and reacting it with amine.
  • the halogenation reaction of the compound (7) is carried out in an amount of 1 to large excess, preferably 1 to 10 equivalents of the halogenating agent, for example, N-halogenimide (for example, N-promosuccinimide, N- —Chlorosuccinimide, N-halogenolactam (eg, N-bromocaprolactam), N-halogenophthalimide (eg, N-bromophthalimide), 1,3-difluoro-5,5-dimethylhydantoin, and the like.
  • N-halogenimide for example, N-promosuccinimide, N- —Chlorosuccinimide, N-halogenolactam (eg, N-bromocaprolactam), N-halogenophthalimide (eg, N-bromophthalimide), 1,3-difluoro-5,5-dimethylhydantoin, and the like.
  • Solvents used in this case are halogenated hydrocarbons (eg, carbon tetrachloride, methylene chloride, chloroform, etc.), aromatic hydrocarbons Element (eg, benzene, etc.) and esters (eg, ethyl acetate, methyl acetate, etc.).
  • the reaction can be promoted by adding, for example, 2,2-azobis (isobutyronitrile), perbenzoic acid, or the like as a catalyst, or by irradiating light.
  • the reaction time is between 0.5 and 48 hours, preferably between 1 and 12 hours.
  • the reaction can be carried out at a temperature of from 120 ° C. to + 200 ° C., preferably from 0 ° C. to + 100 ° C.
  • the compound (I) obtained by the above method can be isolated and purified by a common separation means such as recrystallization, distillation, chromatography and the like.
  • a common separation means such as recrystallization, distillation, chromatography and the like.
  • the compound (I) thus obtained is obtained in a free form, it can be converted into a salt by a method known per se or a method analogous thereto (for example, neutralization, etc.), and conversely, the compound obtained in the salt In this case, it can be converted into a free form or another salt by a method known per se or a method analogous thereto.
  • compound (I) when compound (I) is an optically active form, it can be separated into d-form and 1-form by ordinary optical resolution means.
  • the compound (I) of the present invention has excellent LDL receptor increasing action and lipid lowering action, and has low toxicity. Therefore, these compounds and salts thereof can be used in mammals (eg, mice, rats, eight-stars, puppies, cats, dogs, puppies, puppies, higgins, monkeys, humans, etc.), for example, in arteriosclerotic diseases. It can be safely used as a prophylactic / therapeutic agent, a preventive / therapeutic agent for hyperlipidemia, a preventive / therapeutic agent for diabetes, hypertension and renal disease complications.
  • Compound (I) may be used in the form of bulk powder, but is usually used as a carrier for pharmaceutical preparations, for example, excipients (for example, calcium carbonate, kaolin, sodium bicarbonate, lactose, starches, crystalline cellulose, talc, granulated sugar, Porous materials, etc., binders (eg, dextrin, rubbers, alcoholized starch, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, pullulan, etc.), disintegrants (eg, carboxymethylcellulose calcium, croscarmellose sodium) , Crospopidone, low-substituted hydroxypropyl cell mouth, partially alpha starch, etc.), lubricants (eg, magnesium stearate, calcium stearate, talc, starch, sodium benzoate, etc.), coloring agents (eg, , Tar dye, mosquito Mel, thirty-two Iron oxide, titanium oxide, riboflavin, etc.), flavoring agents (eg, sweet
  • the prophylactic / therapeutic agent of the present invention containing the above-mentioned preparation suitably contains Compound (I) in an amount effective for treating and preventing a disease.
  • the content of compound (I) in the preparation of the present invention is usually 0.1 to 100% by weight of the whole preparation.
  • the preparation used in the present invention may contain other active ingredients other than the compound (I) as the active ingredient. These ingredients are not particularly limited as long as the object of the present invention is achieved, and may be appropriately determined. It is possible to use it with a proper mixing ratio.
  • dosage forms include tablets (including sugar-coated tablets and film-coated tablets), pills, capsules, granules, fine granules, powders, syrups, emulsions, suspensions, injections, inhalants Agents, ointments and the like are used. These preparations are prepared according to a conventional method (for example, a method described in the Japanese Pharmacopoeia).
  • the tablet is prepared by mixing the compound (I) as it is, adding excipients, binders, disintegrants or other suitable additives, and mixing them uniformly. After forming the granules, add a lubricant etc. and compress and mold, or leave compound (I) as it is, or add excipients, binders, disintegrants or other suitable additives and evenly add
  • the mixture can be produced by directly compression-molding, or can be produced by compression-molding the granules prepared in advance as they are, or after adding an appropriate additive and mixing uniformly.
  • the present agent can contain a coloring agent, a flavoring agent, and the like, if necessary.
  • the agent can be coated with an appropriate coating agent.
  • Injectable preparations can be prepared by using a certain amount of compound (I), and in the case of aqueous solvents, water for injection, physiological saline, Ringer's solution, etc.
  • aqueous solvent it can be usually prepared by dissolving, suspending or emulsifying in vegetable oil or the like to make a fixed amount, or by preparing a fixed amount of the compound (I) and sealing it in a container for injection.
  • the pharmaceutical carrier for oral use substances commonly used in the pharmaceutical field such as starch, mannitol, crystalline cellulose and sodium carboxymethylcellulose are used.
  • the carrier for injection for example, distilled water, physiological saline, glucose solution, infusion agent and the like are used.
  • additives generally used in pharmaceutical preparations can be appropriately added.
  • the preparation of the present invention can be used as a sustained-release preparation.
  • the sustained-release preparation of the present invention can be prepared, for example, by microcapsules (eg, microcapsules) produced by an underwater drying method (o / w method, w / o / w method, etc.), a phase separation method, a spray drying method or a method analogous thereto.
  • Spheres, microcapsules, microparticles, etc. as they are, or these microcapsules or spherical, needle-like, pellet-like, film-like, or cream-like pharmaceutical compositions are formulated into various dosage forms as raw materials and administered. be able to.
  • the dosage form include parenteral preparations (for example, injection or implant preparations for intramuscular, subcutaneous, organ, etc .; transmucosal preparations for nasal cavity, rectum, uterus, etc.), oral preparations (for example, hard capsule preparations) , Soft capsules, granules, powders, suspensions, etc.).
  • a microcapsule is used as a dispersant (for example, a surfactant such as Tween 80, HC-160 or the like; carboxymethylcellulose, sodium alginate, Polysaccharides such as sodium hyaluronate; propylene sulfate, polyethylene glycol, etc.), preservatives (eg, methylparaben, propylparaben, etc.), tonicity agents (eg, sodium chloride, mannitol, sorbitol, glucose, etc.), An aqueous suspension with a local anesthetic (eg, xylocaine hydrochloride, chlorobutanol, etc.) or vegetable oil (eg, sesame oil, corn oil, etc.) or a mixture of this with a phospholipid (eg, lecithin), Alternatively, it is dispersed together with a medium-chain fatty acid triglyceride (for example, miglyceride), e.
  • a surfactant
  • the average particle size is about 0.3.
  • Methods for making the microcapsules into aseptic preparations include a method of sterilizing the entire production process, a method of sterilizing with gamma rays, and a method of adding a preservative, but are not particularly limited.
  • the formulation of the present invention has low toxicity, is useful as a pharmaceutical, and has an excellent LDL receptor-enhancing action and a lipid-lowering action. Therefore, the preparation of the present invention is useful as a preventive or therapeutic drug for diseases based on these pharmacological actions.
  • Atherosclerotic diseases hyperlipidemia, complications associated with hyperlipidemia or arteriosclerosis (eg, hyperlipidemia or arterial Diabetic complications with hyperplasia, hyperlipidemia or hypertension with arteriosclerosis), diabetes, diabetic complications, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, obesity , Renal disease, chronic renal failure, nephrotic syndrome, renal failure and complications of renal dialysis, myocardial infarction, angina, heart failure, arrhythmia, valvular heart disease, sequelae of myocardial infarction, stroke, cerebral infarction, transient cerebral ischemia It can be used for the treatment or prevention of Alzheimer's disease, osteoporosis, peripheral vascular disease, thrombosis, ⁇ disorder and the like. Above all, hyperlipidemia; arteriosclerosis; complications with hyperlipidemia or arteriosclerosis (eg, diabetic complications with hyperlipidemia or arteriosclerosis, hyperlipidemia or arteriosclerosis). Associated with hypertension complications
  • Compound (I) and salts thereof have a cholesterol and triglyceride lowering action.
  • hyperlipidemia especially hypertriglyceridemia, hyperlipoproteinemia and hypercholesterolemia and the atherosclerotic vascular lesions resulting therefrom and their sequelae, for example It is particularly suitable for treatment and prevention of coronary artery disease, myocardial infarction, ischemic brain disease, cerebral ischemia, aneurysm, cerebral arteriosclerosis, peripheral arteriosclerosis, intermittent claudication, gangrene, etc.
  • compound (I) may be used alone for prophylaxis and Z or treatment, and may be used in combination with other lipid-lowering or cholesterol-lowering drugs, in which case These compounds are preferably administered as an oral preparation, and if necessary, may be administered as a rectal preparation in the form of a suppository.
  • the components that can be combined include, for example, (1) fibrates (eg, clofibrate, bezafibrate, gemfibu-gill, fenofibrate, etc.), nicotinic acid, derivatives and analogs thereof (eg, acipimox, probucol) ), (2) bile acid binding resins (eg, cholestyramine, colestipol, etc.), compounds that inhibit cholesterol absorption (eg, sitosterol, neomycin, etc.), (3) compounds that inhibit cholesterol biosynthesis, eg, HMG _ CoA reductase inhibitors (Mouth bath evening tin, Simbas evening tin, Pravas evening tin, Seripastatin, At mouth bath evening tin, Full bath evening tin, etc.), squalene synthase inhibitors, squalene epoxidase inhibitors (eg, NB — 5 9 8 and related compounds ), O dimethyls
  • MTP microsomal triglyceride transfer protein
  • imp1 itapide etc.
  • compound (I) is suitable for the prophylactic treatment of diseases associated with hyperchylomicronemia, for example, acute acute inflammation.
  • diseases associated with hyperchylomicronemia for example, acute acute inflammation.
  • microembolism occurs in capillaries due to chylomicron, or due to hyperchylomicronemia.
  • the amount of free fatty acids generated by the decomposition of triglycerides by lipase increases It is said that it happens to stimulate strong. Therefore, the compounds of the present invention
  • (I) Since (I) has a triglyceride lowering effect, it can be used alone or in combination with known therapies for the prophylactic treatment of inflammation. Compounds for prevention and treatment of this disease
  • t- compounds (I) can be administered orally or topically, and they can be used alone or in combination with known active compounds, for example, aprotinin, gabexate methanesulfonate, nafamostate methanesulfonate, citicoline perinastin, etc.
  • active compounds for example, aprotinin, gabexate methanesulfonate, nafamostate methanesulfonate, citicoline perinastin, etc.
  • t- compounds (I) include secondary hyperlipidemia ⁇ including hypertension, diabetes, insulin resistance (syndrome X), hypothyroidism
  • These diseases include nephrotic syndrome or chronic renal failure, and hyperlipidemia is caused by these diseases.In many cases, hypolipidemia exacerbates these diseases and forms a so-called vicious cycle. It is said that there is.
  • compound (I) is also suitable for the treatment and prevention of the progress of these diseases, in which case compound (I) alone or in combination with known active compounds, preferably orally Can be used.
  • antihypertensive drugs for example, (1) diuretics (eg, furosemide, spironolactone, etc.), (2) sympathomimetic agents (eg, atenolol, etc.),
  • angiotensin II antagonist for example, oral sultan, candesartan, etc.
  • Angiotensin I converting enzyme inhibitors eg, enalapril maleate, delapril hydrochloride, etc.
  • Calcium antagonists eg, difludipine, manidipine hydrochloride, etc.
  • an insulin preparation for example, human insulin etc.
  • a sulfonylprea agent for example, dalibenclamide, daliclazide etc.
  • a hyaldarukosidase inhibitor for example, poglipoise, acarpoose etc.
  • insulin Sensitivity enhancers for example, pioglitazone, troglitazone, oral diglyuzone, etc.
  • aldose reductase inhibitors for example, epalrestat, tolresuyose, etc.
  • darcasion inhibitors for example, aminoguanidine, etc.
  • prednisolone methylprednisolone sodium succinate furosemide, bumetanide, azosemide, etc. It may be used in combination, preferably for oral administration.
  • Further possible uses of the compound (I) of the present invention include suppression of thrombus formation.
  • Blood triglyceride levels are positively correlated with factor VII involved in blood coagulation, and ingestion of ⁇ -13 fatty acids lowers tridaliceride and suppresses coagulation, so hypertriglyceridemia causes thrombus formation. It is also thought to promote.
  • VLDL in hyperlipidemic patients increased plasmino-enactivate inhibitory secretion from vascular endothelial cells more strongly than in normolipidemic patients, triglyceride decreased fibrinolytic ability. Conceivable. Therefore, in view of the triglyceride lowering effect, compound (I) is suitable for preventing and treating thrombus formation.
  • the compound may be used alone or with known therapeutic agents such as dipyridamole, dilazep hydrochloride, thrombolytic agents (eg, sodium heparin, perokinase, etc.), antiplatelet agents (eg, aspirin, sulfinvirazone, ticlopidine hydrochloride, sylos
  • the compound can be used preferably for oral administration in combination with a sol.
  • a further notable indication of the compounds of formula (I) is osteoporosis associated with elevated blood cholesterol.
  • the excellent lipid-lowering effect of the compound of formula (I) can be used for the treatment and prevention of osteoporosis associated with an increase in blood cholesterol.
  • the compound of (I) can be administered alone or in combination with the drugs exemplified below. Possible combinations in this case include, for example, sex hormones and related drugs
  • estrogen preparations ibriflavone (osten), raloxifene, osaterone, tipolone, etc.
  • calcitonins vitamin D preparations (e.g., alfacalci Dol, calcitriol, etc.), bone resorption inhibitors such as bisphosphonic acids (eg, etidronate, clodronate, etc.), fluorine compounds, bone formation promoters such as PTH and the like.
  • vitamin D preparations e.g., alfacalci Dol, calcitriol, etc.
  • bone resorption inhibitors such as bisphosphonic acids (eg, etidronate, clodronate, etc.), fluorine compounds, bone formation promoters such as PTH and the like.
  • the compounds of the formula (I) include the prevention and treatment of Alzheimer's disease. Elevated blood cholesterol is known to be a risk factor for Alzheimer's disease.
  • the compound represented by the formula (I) or a salt thereof, or a prodrug thereof can be used for the prevention and treatment of Alzheimer's disease due to its excellent lipid-lowering effect.
  • the compound represented by the formula (I) Alternatively, the salt thereof can be administered alone or in combination with the drugs exemplified below.
  • Possible combinations in this case include, for example, acetylcholinesterase inhibitors (eg, alicebut, exerone, etc.), amyloid j8 production / secretion inhibitors (eg, such as JT-52 and LY-374973 or i3 secretase inhibitors, Or SIB-1848), amyloid aggregation inhibitors (eg, ⁇ ⁇ ⁇ -00703 and BETABL0C (AN-1792), etc.), and amyloid) 3 vaccine.
  • acetylcholinesterase inhibitors eg, alicebut, exerone, etc.
  • amyloid j8 production / secretion inhibitors eg, such as JT-52 and LY-374973 or i3 secretase inhibitors, Or SIB-1848
  • amyloid aggregation inhibitors eg, ⁇ ⁇ ⁇ -00703 and BETABL0C (AN-1792), etc.
  • amyloid 3 vaccine e
  • Antibodies and vaccine preparations include, for example, vaccine preparations for angiotensin II, vaccine preparations for CETP, CETP antibodies, antibodies to TNFa antibody and other cytodynamics, amyloid) 3 vaccine preparations, etc.
  • Examples of gene therapy include cytotherapy, therapy using genes related to renin'angiotensin enzymes and their products, and genes related to enzymes and proteins involved in blood lipid metabolism. Therapies used include those using genes related to proteins involved in glucose metabolism and insulin resistance.
  • the dosage of the preparation of the present invention varies depending on the administration route, symptoms, age, weight, etc. of the patient.
  • a therapeutic agent for hyperlipidemia or a therapeutic agent for arteriosclerotic disease When administered orally to adult patients, 0.2 to 20 mg / day, preferably 0.2 to 5 mg / day, more preferably 1.5 to 30 mg / day of Compound (I) is divided into one or several doses. It is desirable to administer.
  • the route of administration may be oral or parenteral.
  • the dosage of the sustained-release preparation of the present invention may vary depending on the route of administration, symptoms, age, weight, etc. of the patient, as well as the duration of release, but the compound (I) as an active ingredient There is no particular limitation as long as the effective concentration is maintained in the body, and the number of administrations can be appropriately selected depending on the situation, such as once a day to three days, or once a week to three months.
  • Test Example 1 Transcriptional promotion of LDL receptor gene in HepG2 cells (Reporter Atsui)
  • HepG2 cells purchased from ATCC (American Type Culture Collection) in RPMI1640 iedium (containing 103 ⁇ 4 FCS, no phenol red) in 1.6X
  • the cells were seeded on a 96-well luminescence plate (Corning Costar). After culturing for 24 hours, add GL3 basic / LDLRP 0.3 g / welK lipid (Superfect transfection reagent (QI AGEN)) 1 1 / welK RPMI1640 medium (FCS, phenol red, no antibiotics) 20 1 / wel 1 mixture Then, the mixture was reacted in a 37 ° C. carbon dioxide incubator, and the reporter gene was transiently introduced.
  • Test example 2 LDL binding increase effect in HepG2 cells [Test method]
  • HepG2 cells purchased from ATCC were dispersed in MEM [Eagle's minimum essential Medium] (10% FBS) according to the method of JLGoldstein et al. Then, the cells were seeded on a collagen-coated 6-well plate (Sumitomo Belite) for 4 days. The cells were cultured in 37 CO2 incubators. After washing the cells, use 25-hydroxycholesterol (2.3 M) as a standard compound in MEM (10% FBS), add 5 M of each test compound, and incubate in a carbon dioxide incubator for 20 hours. did. After washing with PBS, MEM (25 mM HEPBS, 1% BSA-FAF) containing 125 1-human LDL (4 ⁇ g / ml) was added.
  • MEM 25 mM HEPBS, 1% BSA-FAF
  • non-specific binding ability LDL300; g / ml was added, and binding was performed at 4 ° C for 2 hours. It measured 125 1 by dissociating dextran sulfate, and the total binding capacity. The protein amount was measured by dissolving the cells with 0.5N NaOH according to the Lowry method. The specific binding ability (LDL-Binding value) was calculated by subtracting the non-specific binding ability from the total binding ability and correcting for the amount of protein, and expressed as a percentage of the control group. The result
  • ⁇ NMR spectra were measured with Varian Di200 (200 MHz) using tetramethylsilane as an internal standard, and all ⁇ values were shown in ppm.
  • the numerical values shown for the mixed solvents are volume mixing ratios of each solvent unless otherwise specified. % Means% by weight unless otherwise specified.
  • the elution solvent in silica gel chromatography indicates a volume ratio unless otherwise specified.
  • room temperature normal temperature refers to a temperature from about 20 ° C to about 30 ° C.
  • each symbol in an Example and a reference example has the following meaning.
  • S singlet
  • d doublet
  • t triplet
  • q Kuarutetsuto
  • br broad
  • J a coupling constant
  • dd Daburudaburetsuto
  • m Maruchipuretsu Bok
  • Hz Hertz
  • CDC 1 3 Heavy black port Holm,% :weight%.
  • N-4-bromobenzyl-N-1ert-butoxycarbonyl cycle hexylamine (11.0 g, 30 mmol), 4_formylbenzeneporonic acid (5.40 g, 36 mmol), tetrakistriphenylphosphine palladium (1.04 g, 0.9 mmol) mmol), sodium carbonate (6.36 g, 60 mmol), toluene (100 ml), and water (100 ml) were stirred at 70 ° C for 13:00.
  • Ethyl acetate 50 ml was added to the reaction solution for extraction. The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.
  • 3-Bromo-N-teri-butoxycarboelbenzylamine (23.8 g, 83.4 ol), 3-formyl-benzeneboronic acid (15 g, 0.1 mol), tetrakistriphenylphosphine palladium (2.89 g, 2.5 mmol), sodium carbonate (17.7 g, 0.167 mol), toluene (200 ml), and water (200 ml) were stirred at 70 ° C. for 24 hours under a nitrogen atmosphere. Ethyl acetate (100 ml) was added, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and distilled under reduced pressure.
  • Di-tert-butyl dicarbonate (12.68 g, 58.lmmol) was added to a solution of P-promorediline (10 g, 58. limol) in ethyl acetate (200 ml), and the mixture was stirred at room temperature for 2 hours.
  • Di-tert-butyl dicarbonate (6.0 g, 27.5 mmol) was added, and triethylamine (9.7 ml, 69.7 imol) was further added. The mixture was stirred at room temperature for 2 hours, and further refluxed for 25 hours.
  • reaction solution was concentrated under reduced pressure, adjusted to pH 5-6 with 6N hydrochloric acid, water (50 ml) was added, and the precipitated crystals were collected by filtration to give 4 '-[(2-pyridyl ⁇ [4- (trifluoromethyl) phenyl] [Sulfonyl ⁇ amino) methyl] [1 ,,-biphenyl] -4-carboxylic acid (1.23 g, 91) was obtained as crystals.
  • Tetrahydropyran-4-one (4.5 g, 45 mmol), benzylamine (5.90 ml, 54.0 ol), acetic acid (3.86 ml, 67.4 gang. 1), sodium chloride (30 g) and ethanol
  • reaction solution was diluted with saturated aqueous sodium hydrogen carbonate (50 ml) and ethyl acetate (50 ml), and ditert-butyl dicarbonate (0.32 g, 1.44 mmol) was added, followed by stirring for 1 hour.
  • the ethyl acetate layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.

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Abstract

L'invention concerne un composé représenté par la formule (I): dans laquelle les cycles A et B représentent chacun un cycle aromatique à cinq ou six membres, éventuellement substitués, R1 et R2 représentent chacun un hydrogène, un groupe hydrocarboné éventuellement substitué, ou un groupe hétérocyclique éventuellement substitué, X?1, X2, X3 et X4¿ représentent chacun une liaison ou un groupe hydrocarboné divalent éventuellement substitué, Y représente un groupe -NR3-CO-, -CO-NR?3-, -NR3-SO¿2-, -SO2-NR?3-, -NR3-CH¿2- (R3 représentant un hydrogène, un groupe hydrocarboné éventuellement substitué, ou un groupe hétérocyclique éventuellement substitué), Z représente un groupe CO-NH-, -CS-NH-, -CO-, ou SO¿2?-, et Ar représente un groupe hydrocarboné cyclique éventuellement substitué ou un groupe hétérocyclique éventuellement substitué. L'invention concerne aussi un sel de ce composé. Le composé ou son sel permet d'augmenter la quantité d'un récepteur de lipoprotéine de basse densité (LDL) et est utile dans la diminution de lipides sanguins. L'invention concerne aussi un médicament ou analogue contenant le composé ou son sel.
PCT/JP2002/000073 2001-01-12 2002-01-10 Compose biaryle, procede de production de ce compose, et principe actif Ceased WO2002055484A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2001005823 2001-01-12
JP2001-5823 2001-01-12
JP2001-174901 2001-06-08
JP2001174901 2001-06-08

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WO2004096771A1 (fr) * 2003-04-29 2004-11-11 Glaxo Group Limited Composes biaryle exerçant une activite sur le recepteur de 5ht5a
US7235560B2 (en) 2002-08-19 2007-06-26 Glaxo Group Limited Pyrimidine derivative as selective COX-2 inhibitors
WO2007126957A2 (fr) 2006-03-31 2007-11-08 Novartis Ag Nouveaux composés
US7446117B2 (en) 2002-09-16 2008-11-04 Glaxo Group Limited Cox-2 inhibiting pyridine derivatives
EP2129218A4 (fr) * 2007-02-16 2011-11-30 Emisphere Tech Inc Composés à fraction cyclique et compositions d'administration d'agents actifs
EP1848430A4 (fr) * 2004-12-31 2011-12-28 Reddys Lab Ltd Dr Nouveaux dérivés de benzylamine en tant qu'inhibiteurs de cetp
WO2012069428A1 (fr) 2010-11-22 2012-05-31 Noscira, S.A. Dérivés de bipyridine-sulfonamide pour le traitement de maladies et d'affections neurodégénératives
US8362017B2 (en) 2003-08-29 2013-01-29 Exelixis, Inc. C-kit modulators and methods of use
US20130183252A1 (en) * 2007-08-21 2013-07-18 Senomyx, Inc. Compounds that inhibit (block) bitter taste in composition and methods of making same
US8895776B2 (en) 2008-03-18 2014-11-25 Arena Pharmaceuticals, Inc. Modulators of the prostacyclin (PGI2) receptor useful for the treatment of disorders related thereto
US8912184B1 (en) 2010-03-01 2014-12-16 Alzheimer's Institute Of America, Inc. Therapeutic and diagnostic methods
US8940891B2 (en) 2008-12-08 2015-01-27 Arena Pharmaceuticals, Inc. Modulators of the prostacyclin (PGI2) receptor useful for the treatment of disorders related thereto
US9012478B2 (en) 2008-11-26 2015-04-21 Arena Pharmaceuticals, Inc. Pyrazolyl substituted carbonic acid derivatives as modulators of the prostacyclin (PGI2) receptor useful for the treatment of disorders related thereto
WO2018188795A1 (fr) 2017-04-10 2018-10-18 Phenex-Fxr Gmbh Modulateurs des récepteurs hépatiques x (lxr)
WO2019016269A1 (fr) 2017-07-18 2019-01-24 Phenex-Fxr Gmbh Modulateurs de lxr à base d'amine ou de (thio) amide
US10537546B2 (en) 2014-10-23 2020-01-21 Arena Pharmaceuticals, Inc. Method of treating conditions related to the PGI2 receptor
WO2020148325A1 (fr) 2019-01-15 2020-07-23 Phenex-Fxr Gmbh Modulateurs de lxr neutres
US11123298B2 (en) 2017-03-01 2021-09-21 Arena Pharmaceuticals, Inc. Compositions comprising PGI2-receptor agonists and processes for the preparation thereof
US12098116B2 (en) 2022-02-15 2024-09-24 United Therapeutics Corporation Crystalline prostacyclin (IP) receptor agonist and uses thereof
US12377067B2 (en) 2016-11-10 2025-08-05 Arena Pharmaceuticals, Inc. Methods of treating PAH with combinations of ralinepag and other agents
US12433865B2 (en) 2018-05-16 2025-10-07 Arena Pharmaceuticals, Inc. Compositions comprising PGI2-receptor agonists and processes for the preparation thereof
US12441707B2 (en) 2019-12-30 2025-10-14 Tyra Biosciences, Inc. Indazole compounds

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Publication number Priority date Publication date Assignee Title
US7235560B2 (en) 2002-08-19 2007-06-26 Glaxo Group Limited Pyrimidine derivative as selective COX-2 inhibitors
US7446117B2 (en) 2002-09-16 2008-11-04 Glaxo Group Limited Cox-2 inhibiting pyridine derivatives
WO2004096771A1 (fr) * 2003-04-29 2004-11-11 Glaxo Group Limited Composes biaryle exerçant une activite sur le recepteur de 5ht5a
EP1663204B1 (fr) * 2003-08-29 2014-05-07 Exelixis, Inc. Modulateurs c-kit et leurs procedes d'utilisation
US8362017B2 (en) 2003-08-29 2013-01-29 Exelixis, Inc. C-kit modulators and methods of use
EP1848430A4 (fr) * 2004-12-31 2011-12-28 Reddys Lab Ltd Dr Nouveaux dérivés de benzylamine en tant qu'inhibiteurs de cetp
EP2402319A1 (fr) 2006-03-31 2012-01-04 Novartis AG Inhibiteurs de la DGAT
EP2402318A1 (fr) 2006-03-31 2012-01-04 Novartis AG Inhibiteurs de la DGAT
EP2404905A1 (fr) 2006-03-31 2012-01-11 Novartis AG Nouveaux composés
EP2301923A1 (fr) 2006-03-31 2011-03-30 Novartis AG Nouveaux composés
WO2007126957A2 (fr) 2006-03-31 2007-11-08 Novartis Ag Nouveaux composés
EP2129218A4 (fr) * 2007-02-16 2011-11-30 Emisphere Tech Inc Composés à fraction cyclique et compositions d'administration d'agents actifs
US20130183252A1 (en) * 2007-08-21 2013-07-18 Senomyx, Inc. Compounds that inhibit (block) bitter taste in composition and methods of making same
USRE50267E1 (en) 2008-03-18 2025-01-14 Arena Pharmaceuticals, Inc. Modulators of the prostacyclin (PGI2) receptor useful for the treatment of disorders related thereto
US8895776B2 (en) 2008-03-18 2014-11-25 Arena Pharmaceuticals, Inc. Modulators of the prostacyclin (PGI2) receptor useful for the treatment of disorders related thereto
US10668033B2 (en) 2008-03-18 2020-06-02 Arena Pharmaceuticals, Inc. Modulators of the prostacyclin (PGI2) receptor useful for the treatment of disorders related thereto
US11098034B2 (en) 2008-11-26 2021-08-24 Arena Pharmaceuticals, Inc. Pyrazolyl substituted carbonic acid derivatives as modulators of the prostacyclin (PGI2) receptor useful for the treatment of disorders related thereto
US10689372B2 (en) 2008-11-26 2020-06-23 Arena Pharmaceuticals, Inc. Pyrazolyl substituted carbonic acid derivatives as modulators of the prostacyclin (PGI2) receptor useful for the treatment of disorders related thereto
US9012478B2 (en) 2008-11-26 2015-04-21 Arena Pharmaceuticals, Inc. Pyrazolyl substituted carbonic acid derivatives as modulators of the prostacyclin (PGI2) receptor useful for the treatment of disorders related thereto
US9663500B2 (en) 2008-11-26 2017-05-30 Arena Pharmaceuticals, Inc. Pyrazolyl substituted carbonic acid derivatives as modulators of the prostacyclin (PGI2) receptor useful for the treatment of disorders related thereto
US10214518B2 (en) 2008-11-26 2019-02-26 Arena Pharmaceuticals, Inc. Pyrazolyl substituted carbonic acid derivatives as modulators of the prostacyclin (PGI2) receptor useful for the treatment of disorders related thereto
US10138210B2 (en) 2008-12-08 2018-11-27 Arena Pharmaceuticals, Inc. Substituted pyridazines as prostacyclin receptor modulators
US10793529B2 (en) 2008-12-08 2020-10-06 Arena Pharmaceuticals, Inc. Substituted pyridazines and 1,2,4-triazines as prostacyclin receptor modulators
US8940891B2 (en) 2008-12-08 2015-01-27 Arena Pharmaceuticals, Inc. Modulators of the prostacyclin (PGI2) receptor useful for the treatment of disorders related thereto
US8912184B1 (en) 2010-03-01 2014-12-16 Alzheimer's Institute Of America, Inc. Therapeutic and diagnostic methods
WO2012069428A1 (fr) 2010-11-22 2012-05-31 Noscira, S.A. Dérivés de bipyridine-sulfonamide pour le traitement de maladies et d'affections neurodégénératives
US10688076B2 (en) 2014-10-23 2020-06-23 Arena Pharmaceuticals, Inc. Method of treating conditions related to the PGI2 receptor
US11826337B2 (en) 2014-10-23 2023-11-28 Arena Pharmaceuticals, Inc. Method of treating conditions related to the PGI2 receptor
US11000500B2 (en) 2014-10-23 2021-05-11 Arena Pharmaceuticals, Inc. Method of treating conditions related to the PGI2 receptor
US12239627B2 (en) 2014-10-23 2025-03-04 Arena Pharmaceuticals, Inc. Method of treating conditions related to the PGI2 receptor
US10537546B2 (en) 2014-10-23 2020-01-21 Arena Pharmaceuticals, Inc. Method of treating conditions related to the PGI2 receptor
US11426377B2 (en) 2014-10-23 2022-08-30 Arena Pharmaceuticals, Inc. Method of treating conditions related to the PGI2 receptor
US12377067B2 (en) 2016-11-10 2025-08-05 Arena Pharmaceuticals, Inc. Methods of treating PAH with combinations of ralinepag and other agents
US11826471B2 (en) 2017-03-01 2023-11-28 Arena Pharmaceuticals, Inc. Compositions comprising PGI2-receptor agonists and processes for the preparation thereof
US11123298B2 (en) 2017-03-01 2021-09-21 Arena Pharmaceuticals, Inc. Compositions comprising PGI2-receptor agonists and processes for the preparation thereof
WO2018188795A1 (fr) 2017-04-10 2018-10-18 Phenex-Fxr Gmbh Modulateurs des récepteurs hépatiques x (lxr)
WO2019016269A1 (fr) 2017-07-18 2019-01-24 Phenex-Fxr Gmbh Modulateurs de lxr à base d'amine ou de (thio) amide
US12433865B2 (en) 2018-05-16 2025-10-07 Arena Pharmaceuticals, Inc. Compositions comprising PGI2-receptor agonists and processes for the preparation thereof
WO2020148325A1 (fr) 2019-01-15 2020-07-23 Phenex-Fxr Gmbh Modulateurs de lxr neutres
US12441707B2 (en) 2019-12-30 2025-10-14 Tyra Biosciences, Inc. Indazole compounds
US12098116B2 (en) 2022-02-15 2024-09-24 United Therapeutics Corporation Crystalline prostacyclin (IP) receptor agonist and uses thereof

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