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WO1999036408A1 - Nouveaux derives pyrimidine - Google Patents

Nouveaux derives pyrimidine Download PDF

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Publication number
WO1999036408A1
WO1999036408A1 PCT/JP1999/000069 JP9900069W WO9936408A1 WO 1999036408 A1 WO1999036408 A1 WO 1999036408A1 JP 9900069 W JP9900069 W JP 9900069W WO 9936408 A1 WO9936408 A1 WO 9936408A1
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WO
WIPO (PCT)
Prior art keywords
substituent
hydroxy
halogen
amino
acyl
Prior art date
Application number
PCT/JP1999/000069
Other languages
English (en)
Japanese (ja)
Inventor
Yasuyuki Kawanishi
Yoshitaka Araki
Original Assignee
Shionogi & Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shionogi & Co., Ltd. filed Critical Shionogi & Co., Ltd.
Priority to JP2000540124A priority Critical patent/JP4433253B2/ja
Priority to AU17855/99A priority patent/AU1785599A/en
Publication of WO1999036408A1 publication Critical patent/WO1999036408A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/69—Benzenesulfonamido-pyrimidines

Definitions

  • the present invention relates to compounds useful as medicaments and uses thereof. More specifically, it contains a novel pyrimidine derivative having a selective antagonistic activity of endoselin B receptor, and useful for the prevention and / or treatment of diseases involving endoselin receptor or endoselin B receptor, and the novel pyrimidine derivative.
  • Endothelin is a vasoactive peptide derived from endothelial cells consisting of 21 amino acids and is involved in vasculature homeostasis. Endothelin is also involved in some cardiovascular diseases, such as exacerbation of cardiovascular diseases such as hypertension, cerebral vasoconstriction, acute renal failure, acute proliferative nephropathy, acute myocardial infarction, and intimal hyperplasia. It exerts its action via end serine receptor as a factor.
  • Endothelin receptors have two types of sub-ends, endothelin A and endothelin B, and three types of receptor antagonists are known: A-selective, B-selective, and AB-nonselective. It is gradually becoming clear what kind of disease each type of receptor antagonist is involved in, and selective endothelin A receptor antagonists are effective in the acute phase of cardiovascular disease It is expected that the results may not be satisfactory, but no satisfactory results have been obtained. This suggests that not only endothelin A receptor, but also endothelin B receptor may be involved in the development and progression of cardiovascular lesions. It is thought to be involved in the metabolism of intestine, intimal thickening of blood vessels, and development and differentiation of certain cells.
  • the present inventors have found that a compound represented by the following formula (I) has high activity and selectivity as an antagonist. That is, the present invention provides a compound represented by the formula (I):
  • R 1 and R 2 are each independently
  • Aryl which may have a substituent (where the substituent is a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an R 3 is hydrogen, hydrogen, carboxy or lower alkoxycarbonyl)
  • Lower alkyl optionally having substituent (s) (wherein the substituent is lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy or lower alkoxycarbonyl)
  • an aryl which may have a substituent (where the substituent is a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy or a lower alkoxycarbonyl)
  • X is o, S or a single bond;
  • Y is lower alkylene or lower alkenylene
  • R 4 and R 5 are each independently hydrogen, hydroxy
  • a lower alkyl which may have a substituent (where the substituent means a lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy, lower alkoxycarbonyl, cycloalkyl, aryl or hetero ring); ), A lower alkenyl which may have a substituent (where the substituent is a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy or a lower alkoxycarbonyl),
  • Aryl lower alkyl which may have a substituent (here, the substituent means lower alkyl which may be substituted with halogen or hydroxy, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, Lower alkylene dioxy, amino optionally substituted with lower alkyl, asyl, nitro, cyano, carboxy, lower alkoxycarbonyl, aryl, aryl lower alkyl or rubamoyl),
  • Aryl lower alkenyl which may have a substituent (where the substituent means lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydride Oxy, amino, alkyl, carboxy or lower alkoxycarbonyl), lower alkoxy which may have a substituent (substituent means lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acryl, Carboxy, lower alkoxycarbonyl or aryl)),
  • a lower alkenyloxy which may have a substituent (where the substituent is a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy or a lower alkoxycarbonyl),
  • a heterocyclic ring which may have a substituent (where the substituent is a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy or a lower alkoxycarbonyl ),
  • a carbocyclic ring which may have a substituent (where the substituent means a lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy, lower alkoxycarbonyl or aryl) Or an optionally substituted amino (where the substituent means a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino or a heterocyclic ring) Is also a carboxy or lower alkoxycarbonyl) or
  • a lower alkylene which may have a substituent together (where the substituent is a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy, a lower Which is an alkoxycarbonyl or aryl)
  • R 6 and R 7 are each independently hydrogen
  • acyl group (where the substituent means lower alkyl, lower alkenyl, lower alkenylene, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy, lower alkoxycarbonyl or Kiso), Force ropoxy,
  • a lower alkoxycarbonyl optionally having a substituent (where the substituent is a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a sulfoxy, a lower alkoxycarbonyl or an aryl);
  • R 8 and R 9 are each independently hydrogen
  • an optionally substituted acyl group (where the substituent means a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy, a cyano, a lower alkoxycarbonyl, Substitute with lower alkyl
  • aryl, aryloxy, arylthio, lower alkylsulfonyl, arylsulfonyl optionally substituted with lower alkyl and optionally substituted rubamoyl
  • the substituent is a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy, a lower alkoxycarbonyl or an aryl)
  • a thiocarbamoyl which may have a substituent (Where the substituent means
  • a lower alkoxycarbonyl optionally having a substituent (where the substituent is a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a sulfoxy or a lower alkoxycarbonyl),
  • Aryloxycarbonyl optionally having substituent (s) (wherein the substituent is lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy or lower alkoxycarbonyl); is there) ,
  • Lower alkoxy optionally having substituent (s) (wherein substituent is lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy or lower alkoxycarbonyl)
  • Aryloxy (thiol propyl) which may have a substituent (wherein the substituent means lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy or lower alkoxy carboxy) Nil),
  • Cycloalkyloxy (thiocarbonyl) optionally having substituent (s) (where the substituent is lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy or lower) Alkoxy Carbonyl),
  • Optionally substituted rubamoylcarbonyl (where the substituent is a lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy or lower alkoxycarbonyl Or an arylsulfonyl which may have a substituent (here, the substituent means a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy or an alkyl. Is a good amino, acyl, carboxy or lower alkoxycarbonyl)
  • a pharmaceutical composition containing a compound represented by the above formula (I) (hereinafter, referred to as compound (I)) or a pharmaceutically acceptable salt thereof or a hydrate thereof, and selective antagonist of endoselin B receptor
  • the agent is provided.
  • the present invention relates to a method for treating and / or preventing a disease caused by endothelin B, which comprises administering compound (I), a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • the present invention relates to the use of compound (I), a pharmaceutically acceptable salt thereof, or a hydrate thereof for producing an endothelin B receptor selective antagonist.
  • “aryl” specifically includes phenyl, naphthyl, anthracenyl and the like, and is preferably phenyl. The same applies to the aryl portion of "aryl sulfonyl”.
  • “Lower alkyl” means a straight or branched alkyl having 1 to 6 carbon atoms, and specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, pentyl and It includes hexyl and the like, and is preferably alkyl having 1 to 4 carbon atoms. Lower alkyl as a substituent on aryl of R 1 is most preferably tert-butyl.
  • “Lower alkenyl” means two or more carbon atoms having one or more double bonds at any position.
  • alkenyl 6 means a linear or branched alkenyl, specifically, vinyl, aryl, n-propenyl, isopropyl, n-butenyl, isobutenyl, sec-butenyl, tert-butenyl, butenylenyl, n-pentenyl, isopentenyl, neopentenyl, tert-pentenyl, pentenylenyl, n_hexenyl, isohexenyl, hexenyl and the like.
  • the lower alkenyl moiety of "lower alkenyloxy" is the same as described above.
  • “Lower alkoxy” means a straight or branched alkoxy having 1 to 6 carbon atoms, specifically, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, Includes pentyloxy and hexyloxy. Preferably, it is an alkoxy having 1 to 3 carbon atoms, and more preferably, methoxy. The same applies to the lower alkoxy moiety of “lower alkoxycarbonyl”.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • acyl means a chain or branched isyl having 1 to 8 carbon atoms, an alicyclic isyl having 4 to 9 carbon atoms, aroyl and heterocyclic carbonyl. Specifically, formyl, acetyl, propionyl, butyryl, isoptyryl, norrelyl, pivaloyl, hexanoyl, acryloyl, propioloyl, methacryloyl, crotonyl, cyclopropylcarbonyl, cyclohexanecarbonyl, benzoyl, pyridine propylonyl, Chenylcarponyl and furylcarponyl and the like.
  • “Lower alkenylene” refers to a group having 2 to 7 carbon atoms having at least one double bond, and specifically, vinylene, probenylene, butenylene, butenegenylene, pentenylene, pentagenylene. , Hexenylene, hexenenylene, hexatorienylene, heptenylene, heptagenenylene, heptatrienylene and the like. The positions of these double bonds may be arbitrary.
  • Cycloalkyl is cyclic alkyl having 3 to 6 carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • Heterocycle means a heterocycle having at least one heteroatom in the ring arbitrarily selected from 0, S and N, and specifically, pyrrolyl, imidazolyl, virazolyl, pyridyl, pyridazinyl, pyrimidinyl , Pyrazinyl, triazolyl, triazinyl, isoxazolyl, oxazolyl, oxaziazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl and chenyl, etc.
  • heterocyclic carbonyl Imidazolinyl, birazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl and the like. The same applies to the heterocyclic moiety of “heterocyclic carbonyl”.
  • aryl and lower alkyl portions of “aryl lower alkyl” are the same as the above “aryl” and “lower alkyl”, and are preferably benzyl.
  • the substituent of “aryl lower alkyl optionally having substituent (s)” may be substituted on the aryl moiety or the lower alkyl moiety.
  • aryl lower alkenyl optionally having substituent (s)
  • substituents may be substituted on either the aryl part or the lower alkenyl part.
  • Carbocycle includes the above “aryl” and non-aromatic carbocycle. Specifically, in addition to those exemplified in the above “aryl” and “cycloalkyl”,
  • cycloalkenyl for example, cyclohexenyl
  • Bicycloalkyl eg, bicyclopentane, bicyclooctane, etc.
  • tricycloalkyl having 4 to 10 carbon atoms eg, tricycloheptane, tricyclodecane, etc.
  • condensed polycyclic hydrocarbon eg, indanyl, indenyl, fluorenyl, dihydronaphthalenyl
  • R is hydrogen, methyl or ethyl
  • the “compound of the present invention” also includes a pharmaceutically acceptable salt of compound (I).
  • salts of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, and hydrobromic acid; formic acid, acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, and methanesulfonic acid Salts of organic acids such as ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid; salts of organic bases such as ammonium, trimethylammonium, and triethylammonium; Examples thereof include salts of alkali metals such as sodium and potassium, and salts of alkaline earth metals such as calcium and magnesium. These salts can be formed by a commonly used method.
  • the compound according to the present invention also includes a hydrate thereof, and one molecule of the compound (I) may be coordinated with an arbitrary number of water molecules.
  • the compound represented by the general formula (I) has a selective endothelin B receptor antagonistic activity. Among them,
  • R 1 is phenyl substituted with lower alkyl (hereinafter, R 1 - and is 1) compounds, Ru preferably phenyl der substituted with alkyl of 3-6 carbon atoms (hereinafter, R A compound, more preferably a phenyl substituted with tert-butyl (hereinafter, referred to as R 1-3 ),
  • R 21 a compound in which R 2 is phenyl substituted with lower alkyloxy (hereinafter referred to as R 21), preferably substituted with alkyloxy having 1 to 3 carbon atoms
  • R 21 a compound that is a phenyl (hereinafter, referred to as R 2 —2), more preferably a compound that is a phenyl substituted with methoxy (hereinafter, referred to as R 2 —3),
  • R 3 is hydrogen or lower alkyl
  • R 3 -1 a compound in which R 3 is hydrogen or lower alkyl
  • R 3 —2 a compound which is hydrogen
  • Y-1 alkylene having 1 to 6 carbon atoms
  • Y-2 alkylene having 1 to 4 carbon atoms
  • Y-3 A compound, more preferably a compound having 2 to 3 carbon atoms
  • R 4 and R 5 are hydrogen and the other is hydroxy, or lower alkyl which may have a substituent (where the substituent means lower alkoxy, lower alkenyl Oxy, halogen, hydroxy, amino, acyl, carboxyl, lower alkoxycarbonyl, cycloalkyl, aryl or heterocycle), aryl lower alkyl which may have a substituent (wherein Is lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, lower alkylenedioxy, lower amino optionally substituted by halogen or hydroxy, amino, acyl, nitro, Ano, alkoxy, lower alkoxycarbonyl, aryl, aryl lower alkyl Is Taha force Rubamoiru),
  • Lower alkoxy which may have a substituent (here, the substituent is lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy, lower alkoxycarbonyl or aryl),
  • a heterocyclic ring which may have a substituent here, the substituent means lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy or lower alkoxycarbonyl; is there) ,
  • a carbocyclic ring which may have a substituent (where the substituent means a lower alkyl, Alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy, lower alkoxycarbonyl or aryl, or an optionally substituted amino (where the substituent is lower) Alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, heterocyclic-substituted acyl, carboxy or lower alkoxycarbonyl), or
  • a lower alkylene which may have a substituent together (where the substituent is a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy, a lower alkoxy, Carbonyl or aryl)
  • R 6 and R 7 are each independently hydrogen or an optionally substituted acyl (where the substituent is lower alkyl, lower alkenyl, lower alkenylene, lower Alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy, lower alkoxycarbonyl or oxo), carboxy, lower alkoxycarbonyl which may have a substituent (where the substituent is lower alkoxy) Lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy, lower alkoxycarbonyl or aryl), optionally substituted rubamoyl (where the substituent means lower alkyl, lower alkenyl, Lower alkoxy, lower alkenyloxy, halogen, hydroxy, a Bruno, Ashiru, carboxy, lower alkoxycarbonyl or Ariru), or a Shiano or two Bok port,
  • R 8 and R 9 are hydrogen, and the other is optionally substituted with a substituent (where the substituent means lower alkyl, lower alkenyl, lower Alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy, cyano, lower alkoxycarbonyl, aryl which may be substituted with lower alkyl, aryloxy, arylthio, lower alkylsulfonyl, lower Arylsulfonyl which may be substituted with alkyl), and rubamoyl which may have a substituent (where the substituent means lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, Halogen, hydroxy, amino, acyl, carboxy, lower alkoxycarbonyl or aryl)), Thiocarbamoyl which may have a substituent (wherein the substituent is lower alkyl, lower alkenyl, lower alkoxy, lower al
  • R 3 is hydrogen
  • Z is CONR 4 R 5
  • one of R 4 and R 5 is hydrogen
  • the other is an alkyl which may have a substituent (wherein Is a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy, a lower alkoxycarbonyl, a cycloalkyl, an aryl or a heterocyclic ring) or an aryl lower alkyl which may have a substituent (
  • the substituent means a lower alkyl which may be substituted with halogen or hydroxy, lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, lower alkylenedioxy or lower alkyl.
  • R 6 and R 7 may each independently have an optionally substituted substituent (here, the substituent means lower alkyl, lower alkenyl, lower alkyl Len, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amino, acyl, carboxy, lower alkoxycarbonyl or oxo), carboxy, lower alkoxycarbonyl optionally having substituent (s) Is a lower alkoxy, a lower alkenyloxy, a halogen, a hydroxy, an amino, an acyl, a carboxy, a lower alkoxycarbonyl or an aryl), an optionally substituted rubamoyl (where the substituent is a lower alkyl, Lower alkenyl, lower alkoxy, lower alkenyloxy, halogen, hydroxy, amine , Acyl, carboxy, lower alkoxycarbonyl or aryl) or a cyano force,
  • substituent means lower alkyl, lower alkenyl, lower
  • Thiocarbamoyl where the substituent is alkyl or aryl
  • alkoxycarbonyl or carbamoylcarbonyl having 1 to 3 carbon atoms or arylsulfonyl which may have a substituent (wherein Substituent is alkyl or aryl.)
  • R 3 is hydrogen
  • Z is C 0 NR 4 R 5
  • one of R 4 and R 5 is hydrogen
  • the other is an aryl lower alkyl which may have a substituent (where The substituent is halogen, alkyl, aryl or carboxy)
  • R 6 and R 7 are each independently substituted with acyl or aryl.
  • R 1 is R 1 — 1
  • R 2 is R 2 — 1
  • R 3 is R 3 — 1
  • R 1 is R 1 — 2
  • R 2 is R 2 _2
  • R 3 is R 3 — 1
  • Z is Z—1, more preferably R 1 is
  • R 1 is R 1-2
  • R 2 is R 2 _ 1
  • R 3 is R 3 - 2
  • R 2 is R 2 - is 1, R 3 is R 3- 2, Y is Y- 1, Z is Z- A compound that is 1,
  • R 1 is R 1 — 2
  • R 2 is R 2 — 1
  • R 3 is R 3 — 1
  • X is ⁇
  • Y is Y—1
  • Z is A compound that is Z — 1 , preferably R 1 is R 1 —3, R 2 is R 2 —1, R 3 is R 3 —1, X is ⁇ , and Y is Y—1
  • Z is Z—1,
  • R 1 is R 1 — 2, R 2 is R 2 — 1, R 3 is R 3 — 1, Y is Y— 2 and Z is Z— 1
  • R 1 is R 1 — 2, R 2 is R 2 — 1, R 3 is R 3 — i, Y is Y— 1, and Z is Z— 2 , preferably R 1 is R 1 - is 3, R 2 is R 2 - is 1, R 3 is R 3 - is 1, Y is Y- 1, compound Z is Z- 2, A compound wherein R 1 is R 1-2 , R 2 is R 2-1, R 3 is R 3-11, Y is Y-1 and Z is Z-3, most preferably A compound wherein R 1 is R ⁇ — 3, R 2 is R 2 — 1, R 3 is R 3 — 1, Y is Y— 1, and Z is Z _ 3,
  • R 1 is R 1 — 1, R 2 is R 2 — 2, R 3 is R 3 — i, X is ⁇ , Y is Y—1, and Z is A compound that is Z—1, preferably R 1 is R 1 —1, R 2 is R 2 —3, R 3 is R 3 —1, X is ⁇ ,
  • R 1 is R 1 —1, R 2 is R 2 —3, R 3 is R 3 —1, Y is Y—2, and Z is Z—1, A compound wherein R 1 is R 1 —1, R 2 is R 2 —2, R 3 is R 3 — 1, Y is Y—3, and Z is Z—1, most preferably A compound wherein R 1 is R ⁇ —1, R 2 is R 2 — 3, R 3 is R 3 — 1, Y is Y—3 and Z is Z— 1,
  • R 1 is R 1 — 1, R 2 is R 2 — 2, R 3 is R 3 — 1, Y is Y — 1, and Z is Z—2
  • R 1 is R 1 —1, R 2 is R 2 —3, R 3 is R 3 —1, Y is Y—1 and Z is Z—2
  • R 1 is R 1 —1, R 2 is R 2 —3, R 3 is R 3 —1, Y is Y-1 and Z is Z—3, most preferably A compound wherein R 1 is R 1 — 1, R 2 is R 2 — 3, R 3 is R 3 — 1, Y is Y—1, and Z is Z—4;
  • R 1 is R 1 — 1
  • R 2 is R 2 -1
  • R 3 is R 3 — 2
  • X is ⁇
  • Y is Y—1
  • Z is A compound that is Z—1
  • R 1 is R 1 — 1, R 2 is R 2 — 1, R 3 is R 3 — 2, Y is Y—2, and Z is Z—1
  • R 1 is R 1 —1, R 2 is R 2 —1, R 3 is R 3-12, Y is Y—3, and Z is Z— 1
  • R 1 is R 1 -1, R 2 is R 2 — 1, R 3 is R 3 — 2, Y is Y—3, and Z is Z—1;
  • R 1 is R l — 1, R 2 is R 2 — 1, R 3 is R 3 — 2, Y is Y—1, and Z is Z—2
  • R 1 is R 1 —1
  • R 1 is R 1 — 1, R 2 is R 2 — 1, R 3 is R 3 — 1, X is O, Y is Y—2, and Z is A compound that is Z—1, preferably R 1 is R 1 —1, R 2 is R 2 —1, R 3 is R 3 —1, X is O, and Y is Y—3 Wherein Z is Z—1, R 1 is R 1 — 1, R 2 is R 2 — 1, R 3 is R 3 — 1, X is ⁇ , and Y is A compound wherein Y is 3 and Z is Z-1 1;
  • R l is R 1 — 1, R 2 is R 2 — 1, R 3 is R 3 — 1, X is ⁇ , Y is Y—1, and Z is A compound that is Z—2, preferably R 1 is R 1 —1, R 2 is R 2 —1, R 3 is R 3 —1, X is ⁇ , and Y is Y—1 A compound wherein Z is Z—3, most preferably R 1 is R 1 —1, R 2 is R 2 —1, R 3 is R 3 —1, and X is ⁇ Wherein Y is Y—1 and Z is Z—4,
  • R 1 is R 1 — 1, R 2 is R 2 — 1, R 3 is R 3 — 1, Y is Y—2, and Z is Z—2
  • R 1 is R 1 — 1, R 2 is R 2 — 1, R 3 is R 3 — 1, Y is Y—2, and Z is Z—3.
  • R 2 is R 2 - is 1
  • R 3 is R 3 - is 1
  • Y is the Y- 3
  • compound Z is Z- 3, most preferably R 1 A compound wherein R 1 — 1, R 2 is R 2-1, R 3 is R 3 — 1, Y is Y — 3 and Z is Z — 4;
  • R 1 is R 1 — 2, R 2 is R 2 — 2, R 3 is R 3 — 1, Y is Y—1, and Z is Z—2
  • R 1 is R 1-3, R 2 is R 2 — 3, R 3 is R 3 — 1, Y is Y — 1, and Z is Z—3;
  • R 1 is R 1 —3, R 2 is R 2 —3, R 3 is R 3 —1, Y is Y—1, and Z is Z—4;
  • R l is R l—2, R 2 is R 2—1, R 3 is R 3-2, X is O, Y is Y—1, and Z is A compound that is Z—1, preferably R 1 is R 1 — 3, R 2 is R 2 — I, R 3 is R 3 — 2, X is ⁇ , and Y is Y—1 Wherein Z is Z—1,
  • R 1 is 1? ⁇ _2, R 2 is R 2 — 1, R 3 is R 3 — 2,
  • R 2 is R 2 —1, R 3 is R 3 —2, Y is Y—1 and Z is Z—3, most preferably R 1 is R 1—3; R 2 is R 2 1 1;
  • R i is R l—2, R 2 force R 2 — 1, and R 3 is R 3— i
  • X is ⁇ , Y is Y—2, and Z is Z—1, preferably R
  • R 1 is R 1 — 2, R 2 is R 2 — l, R 3 is R 3 — 1, X is O, Y is Y—1, and Z is A compound that is Z—2, preferably R 1 is R 1 —3, R 2 is R 2 —1, R 3 is R 3 —1, X is O, and Y is Y—1 And Z is Z—3, most preferably R 1 is R 1 —3, R 2 is R 2 —1, R 3 is R 3 — 1, X is O A compound wherein Y is Y—1 and Z is Z—4;
  • R 1 is R 1 — 1, R 2 is R 2 — 2, R 3 is R 3 — 2, X is ⁇ , Y is Y—1, and Z is compound is a Z _ 1, preferably R 1 is R 1 - is 1, R 2 is R 2 one 3, R 3 is R 3 - is 3, a ⁇ is o, Y is Y- 1 Wherein Z is Z—1,
  • R 1 is R 1 — 1
  • R 2 is R 2 — 2
  • R 3 is R 3 — 2
  • R 3 is R 3 — 3, Y is Y—1 and Z is Z—4; [3 6] R 1 is R 1 — 1, R 2 is R 2 — 2, R 3 is R 3 — 1, X is ⁇ , Y is Y — 2, and ⁇ is A compound that is ⁇ —1, preferably R 1 is R i — l, R 2 is R 2 — 3 , R 3 is R 3 — 1, X is ⁇ , and Y is Y— 3 Wherein Z is Z—1,
  • R 1 is R 1 — 1, R 2 is R 2 — 2, R 3 is R 3 — i, X is ⁇ , Y is Y—1, and Z is A compound that is Z—2, preferably R 1 is R 1 —1, R 2 is R 2 —3, R 3 is R 3 — l, X is ⁇ , and Y is Y— 1 And Z is Z—3,
  • R 1 is R 1 — 1, R 2 is R 2 — 2, R 3 is R 3 i, Y is Y—2, and Z is Z — 2.
  • R 1 is R 1 -1, R 2 is R 2 _ 3, R 3 is R 3 — 1, Y is Y—3 and Z is Z— 3,
  • R 1 is R 1 —1, R 2 is R 2 —3, R 3 is R 3 —1, Y is Y—3 and Z is Z _4
  • R 1 is R 1 — 1, R 2 is R 2 — 1, R 3 is R 3 _2, X is 2, Y is Y—2, and Z is A compound that is Z—1, preferably R 1 is R 1 —, R 2 is R 2 — 1, R 3 is R 3 — 3, X is O, Y is Y—3 There is a compound wherein Z is Z—1,
  • R 1 is R 1 — 1, R 2 is R 2 — 1, R 3 is R 3 — 2, X is O, is Y—1, and Z is Z — A compound that is —2, preferably R 1 is R 1 — 1, R 2 is R 2 — 1, R 3 is R 3 — 3, X is —, Y is Y— 1 A compound wherein Z is Z—3, most preferably R 1 is R 1 —1, R 2 is R 2 —1, R 3 is R 3 —3, X is ⁇ , A compound wherein Y is Y—1 and Z is Z—4,
  • R 1 is R 1 — 1, R 2 is R 2 — 1, R 3 is R 3-1, Y is Y—2, and Z is Z—2
  • R 1 is R 1 —1
  • R 2 is R 2-1, R 3 is R 3 _ 3 , ⁇ is ⁇ _ 3, Z is Z— 3, most preferably R 1 is R 1 — 1, R 2 is R 2 — 1; A compound wherein R 3 is R 3 — 3, Y is Y—3, and ⁇ is ⁇ — 4,
  • R 1 is R 1- 1, R 2 is R 2 - is 1, R 3 is R 3- iota, X is O, Y is Y- 2, Z is Z _2, preferably R 1 is R 1 — 1, R 2 is R 2 — 1, R 3 is R 3 _l, X is O, Y is Y—3 A compound wherein Z is Z—3, most preferably R 1 is R 1 —1, R 2 is R 2 —1, R 3 is R 3 —1, X is ⁇ , A compound wherein Y is Y—3 and Z is Z—4,
  • R 1 is R 1 — 2
  • R 2 is R 2 _2
  • R 3 is R 3 — 2
  • X is O
  • Y is Y—2
  • Z is Z
  • Z is Z—1
  • R 1 is R 1 — 2
  • R 2 is R 2 — 2
  • R 3 is R 3 — 2
  • X is ⁇
  • Y is Y—2
  • Z is Z — A compound that is 2,
  • R 1 is R i _3, R 2 is R 2 —3, R 3 is R 3 —2, X is O, Y is Y—3, and Z is Z — A compound that is 2,
  • R 1 is R 1 — 3
  • R 2 is R 2 — 3
  • R 3 is R 3 — 2
  • X is O
  • Y is Y—3
  • Z is Z — A compound that is 3,
  • R 1 is R 1 — 3
  • R 2 is R 2 _ 3
  • R 3 is R 3-1
  • X is ⁇
  • Y is Y—3
  • Z is Z — A compound that is 4,
  • the compound of the present invention can be synthesized, for example, according to the following reaction scheme.
  • compound b and amidine or a salt thereof are added to a suitable solvent in the presence of a base such as alkali metal alcoholate. Condensation gives compound c.
  • compound c is reacted with a halogenating agent or the like in the presence or absence of an organic base to obtain compound d.
  • the solvent in this case may be any organic solvent that does not react with the halogenating agent, but when the organic base or the haptic agent is in a liquid state, it can be used as a solvent.
  • Compound e is obtained by reacting compound d with compound g (R 1 S ⁇ 2 NHM; M is a metal salt).
  • Compound g is preferably 1.5 to 2 mol with respect to compound d, and may be reacted in a solution such as dimethylsulfoxide or dimethylformamide.
  • compound e and a diol such as ethylene glycol, propylene glycol, 1,4-butanediol, 1,5-pentanediol, and 1,6-hexanediol in the presence of a base such as sodium hydride and butyllithium. (HO—Y—CH 2 OH) to give compound f.
  • a base such as sodium hydride and butyllithium.
  • a known compound may be used.
  • it can be synthesized from a known compound by the following method.
  • a known compound h is reacted with aqueous ammonia in an appropriate solvent such as toluene to obtain a compound i, and then the compound i is dissolved in a solvent such as methanol or ethanol in an alkali such as potassium hydroxide or sodium hydroxide.
  • a solvent such as methanol or ethanol in an alkali such as potassium hydroxide or sodium hydroxide.
  • M ⁇ H M is a metal atom, such as potassium and sodium
  • Compound f is oxidized by a conventional method to obtain compound k.
  • the oxidizing agent those usually used for an oxidation reaction from alcohol to carboxylic acid may be used.
  • pyridinium dichromate Collins reagent, Johns reagent, manganese dioxide, potassium permanganate, ruthenium tetroxide and the like can be mentioned.
  • the solvent for example, dimethylformamide, tetrahydrofuran, methylene chloride, benzene, acetate, etc. can be used, and the reaction may be performed at 0 ° C. to under heating, preferably around room temperature for several hours to several tens hours. .
  • the obtained compound k is amidated to obtain compound (la).
  • compound (la) For example, using methylene chloride, tetrahydrofuran, dimethylformamide, getyl ether, or the like as a solvent, under nitrogen atmosphere, at 0 ° C. to under heating, preferably at around room temperature, the number of amine compounds corresponding to the number of amine compounds is reduced.
  • the reaction may be performed for a period of time to several tens of hours. If necessary, the reaction can be suitably promoted by activating with a suitable activator (eg, thionyl chloride, acid halide, acid anhydride, activated ester, etc.).
  • a suitable activator eg, thionyl chloride, acid halide, acid anhydride, activated ester, etc.
  • Compound f is oxidized by a conventional method.
  • the oxidizing agent used in the oxidation reaction of alcohols to aldehydes may be a commonly used one (eg, pyridinium dichromate, chromic anhydride, sodium chlorite, dimethyl sulfoxide oxalyl chloride, etc.).
  • the reaction may be carried out in an active solvent (methylene chloride, dimethylformamide, tetrahydrofuran, etc.) at 0 ° C to heating under heating for several ten minutes to several hours.
  • the obtained compound 1 is reacted with a malonic ester derivative or an active methylene compound corresponding to the target compound.
  • the reaction is ethanol, methanol, methylene chloride,
  • the reaction may be carried out in a solvent such as ethylene glycol dimethyl ether or tetrahydrofuran in the presence of a base such as piperidine, pyridine or pyrrolidine at 0 ° C. to under heating, preferably at room temperature to under heating for several tens to ten hours.
  • a compound in which one of R 6 and R 7 is hydrogen can be obtained by first obtaining a compound in which both R 6 and R 7 are carboxy and decarboxylating it by a conventional method.
  • the compound 1 obtained above is reacted with a hydrazine derivative corresponding to the target compound to obtain a compound (Ic).
  • This reaction may be carried out in a solvent such as ethanol, methanol, methylene chloride or tetrahydrofuran at 0 ° C. to under heating, preferably at about room temperature for several tens minutes to several hours.
  • each substituent of the compound can be converted to another substituent by an ordinary method at an appropriate stage.
  • a compound in which the substituent of any of the obtained compounds is alkoxycarbonyl is reacted with an amine compound such as ammonia or dimethylamine using a lower alcohol such as methanol or an appropriate solvent such as tetrahydrofuran to obtain a substituent.
  • an amine compound such as ammonia or dimethylamine using a lower alcohol such as methanol or an appropriate solvent such as tetrahydrofuran to obtain a substituent.
  • a lower alcohol such as methanol
  • an appropriate solvent such as tetrahydrofuran
  • a compound having a substituent of hydroxyalkyl can be obtained by using a reducing agent such as lithium aluminum hydride or sodium borohydride, or by performing catalytic reduction.
  • the compound (I) of the present invention has high activity and selectivity as an endothelin B receptor selective antagonist, and can be used as a medicament.
  • Endothelin B receptor together with endothelin A receptor, is involved in the development of cardiovascular diseases such as hypertension, acute renal failure, heart failure, renal ischemia, cerebral ischemia, cerebral infarction, cerebral edema, migraine, etc. It is considered.
  • endothelin B receptor is considered to be involved in the metabolism of blood endothelin and intimal hyperplasia of blood vessels, and is therefore very useful as an agent for treating and preventing these diseases. It is also useful as a reagent for elucidating the function of endothelin B receptor.
  • the compound of the present invention When the compound of the present invention is administered as a medicament, it can be administered safely orally or parenterally. Oral administration may be carried out in a usual dosage form such as tablets, granules, powders, capsules, pills, liquids, suspensions, syrups, buccals or sublinguals according to a conventional method.
  • a usual dosage form such as tablets, granules, powders, capsules, pills, liquids, suspensions, syrups, buccals or sublinguals according to a conventional method.
  • any commonly used dosage form such as injections such as intramuscular administration, suppositories, transdermal absorbents, and inhalants, can be suitably administered, but oral administration is particularly preferred.
  • the pharmaceutical composition of the present invention requires various pharmaceutical additives such as a pill, a binder, a wetting agent, a disintegrant, a lubricant and a diluent suitable for the final dosage form in an effective amount of the active ingredient.
  • excipients such as lactose, sucrose, glucose, starch, calcium carbonate or crystalline cellulose
  • binders such as methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, gelatin or polyvinylpyrrolidone, etc.
  • the agent include carboxymethylcellulose, sodium carboxymethylcellulose, starch, sodium alginate, powdered agar or sodium lauryl sulfate
  • the lubricant include talc, magnesium stearate, and macrogol.
  • cocoa butter, macrogol, methylcellulose, or the like can be used.
  • additives when it is prepared as a liquid or emulsion or suspension injection, it is usually used as a solubilizing agent or suspension.
  • Additives, emulsifiers, stabilizers, preservatives, isotonic agents, and the like may be added as appropriate.
  • a flavoring agent, a fragrance, and the like may be added.
  • the dose of the endothelin B receptor selective antagonist should be set in consideration of the patient's age, weight, administration route, type and degree of disease, etc., but was orally administered to humans.
  • the dose may be administered to an adult in a daily dose of 1 g to 20 Omg / kgZ once to several times.
  • parenteral administration it varies depending on the administration route, but it is usually sufficient to administer 0.1 g to 2 OmgZkg gZ once or several times a day.
  • Rat aortic smooth muscle A 7 r 5 1 2 5 I-labeled endothelin to the cell - 1 was determined from the intensity of inhibiting binding. Specifically, 48 after washing the cells with buffer cultured in well plates, 125 I-labeled endothelin 8. 3 X 1 0- 12 M - HE PES buffer containing 1 and various proteolytic enzyme inhibitors Hanks' solution (0.3 ml) was added, and the mixture was incubated at 37 ° C for 1 hour in the presence or absence of the compound of the present invention. After completion of the reaction, the reaction solution was removed by suction, and the cells were washed with a Hank's solution buffered with HE PES.
  • granules for tableting were prepared by wet granulation using an aqueous solution of 8% (w / w) hydroxypropylmethylcellulose as a binder. After mixing with magnesium stearate, it was formed into a tablet with a diameter of 7 mm and a tablet weight of 13 Omg using a tableting machine.
  • the compound of the present invention has a strong endothelin B receptor antagonistic action and its selectivity is very high, and thus is useful as an endothelin B receptor selective antagonist.

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Abstract

L'invention concerne des composés représentés par la formule générale (I), des sels pharmaceutiquement acceptables de ces composés ou des hydrates de ces composés ou de leurs sels, ainsi que des antagonistes sélectifs vis à vis des récepteurs de l'endothéline B et contenant ces composés. Dans la formule (I), R1 et R2 sont chacun indépendamment un groupe aryle éventuellement substitué; R3 est hydrogène ou analogue; X est O, S ou analogue; Y est alcylène inférieur ou analogue; Z est CONR?4R5, CH=CR6R7¿ ou CH=NNR?8R9; R4 et R5¿ sont chacun indépendamment hydrogène, alkyle inférieur ou analogue; R6 et R7 sont chacun indépendamment acyle, alcoxycarbonyle ou analogue; et R8 et R9 sont chacun hydrogène, acyle ou analogue.
PCT/JP1999/000069 1998-01-19 1999-01-12 Nouveaux derives pyrimidine WO1999036408A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2000540124A JP4433253B2 (ja) 1998-01-19 1999-01-12 新規ピリミジン誘導体
AU17855/99A AU1785599A (en) 1998-01-19 1999-01-12 Novel pyrimidine derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP10/7445 1998-01-19
JP744598 1998-01-19

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WO1999036408A1 true WO1999036408A1 (fr) 1999-07-22

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001046156A1 (fr) * 1999-12-22 2001-06-28 Actelion Pharmaceuticals Ltd. Derives de butynediol
WO2001081335A1 (fr) * 2000-04-20 2001-11-01 Actelion Pharmaceuticals Ltd Pyrimidine-sulfonamides agissant comme antagonistes de l'endotheline
US6387915B2 (en) 2000-05-31 2002-05-14 Pfizer Inc. Isoxazole-sulfonamide endothelin antagonists

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0971570A (ja) * 1994-12-28 1997-03-18 Kowa Co ピリミジン誘導体及びこれを含有する医薬
JPH09132568A (ja) * 1995-09-06 1997-05-20 Kowa Co ピリミジン誘導体

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0971570A (ja) * 1994-12-28 1997-03-18 Kowa Co ピリミジン誘導体及びこれを含有する医薬
JPH09132568A (ja) * 1995-09-06 1997-05-20 Kowa Co ピリミジン誘導体

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001046156A1 (fr) * 1999-12-22 2001-06-28 Actelion Pharmaceuticals Ltd. Derives de butynediol
WO2001081335A1 (fr) * 2000-04-20 2001-11-01 Actelion Pharmaceuticals Ltd Pyrimidine-sulfonamides agissant comme antagonistes de l'endotheline
US6387915B2 (en) 2000-05-31 2002-05-14 Pfizer Inc. Isoxazole-sulfonamide endothelin antagonists

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AU1785599A (en) 1999-08-02

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