WO1999032459A1 - Inhibiteurs de la chymase - Google Patents

Inhibiteurs de la chymase Download PDF

Info

Publication number
WO1999032459A1
WO1999032459A1 PCT/JP1998/005786 JP9805786W WO9932459A1 WO 1999032459 A1 WO1999032459 A1 WO 1999032459A1 JP 9805786 W JP9805786 W JP 9805786W WO 9932459 A1 WO9932459 A1 WO 9932459A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
oxo
dihydro
alkyl
solution
Prior art date
Application number
PCT/JP1998/005786
Other languages
English (en)
Japanese (ja)
Inventor
Takuya Yoshimura
Fumihiko Akahoshi
Masahiro Eda
Hiroshi Sakashita
Atsuyuki Ashimori
Hajime Fukuyama
Masahide Nakajima
Tatsuyuki Ootsuka
Mikio Tanaka
Teruaki Imada
Original Assignee
Yoshitomi Pharmaceutical Industries, 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 Yoshitomi Pharmaceutical Industries, Ltd. filed Critical Yoshitomi Pharmaceutical Industries, Ltd.
Priority to AU16849/99A priority Critical patent/AU1684999A/en
Publication of WO1999032459A1 publication Critical patent/WO1999032459A1/fr

Links

Classifications

    • 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
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/81—Protease inhibitors
    • C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
    • C07K14/811—Serine protease (E.C. 3.4.21) inhibitors

Definitions

  • the present invention relates to a novel heterocyclic amide compound and a pharmacologically acceptable salt thereof, a pharmaceutical composition thereof, and a pharmaceutical use thereof.
  • the present invention relates to pyridone and pyrimidonacetoamide derivatives and pharmacologically acceptable salts thereof, which are useful in pharmacological, diagnostic and disease prevention / treatment.
  • Angiotensin II has physiological activities such as increasing blood pressure by strongly constricting blood vessels and stimulating secretion of aldosterone, which has a sodium-retaining action from the adrenal cortex, and has high blood pressure, cardiac hypertrophy, myocardial infarction, It is considered a causative agent or risk factor for diseases such as arteriosclerosis, diabetic and non-diabetic renal disease, and vascular restenosis after PTCA (percutaneous transluminal coronary angioplasty).
  • PTCA percutaneous transluminal coronary angioplasty
  • This angiotensin 11 is produced by cleavage of two amino acids from angiotensin I, which is a peptide consisting of 10 amino acids present in a living body, and the cleavage involves angiotensin conversion. It is known that an enzyme (ACK) is involved, and many ACE inhibitors have been developed as prophylactic and therapeutic agents for the above diseases.
  • ACK enzyme
  • Chymase has been shown to be involved in the process of angiotensin H formation that is not based on ACE in the above-mentioned conversion of angiotensin I to angiotensin H (Okuni shi et al., Jpn. J. Pharmacol. 1993, 62. p07, etc.), and many other physiologies such as extracellular matrix, site force proteins, substance P, VIP (basoactive 'intestinal' polypeptide), and apoprotein B. It is known that the active substance is used as a substrate, and the activity of other proteases such as collagenase is also known. Involvement in sex has also become apparent (Miyazaki et al., History of Medicine 19 95. 172, p559).
  • chimase inhibitors are expected to be inhibitors of angiotensin II action by suppressing the ACE-independent production of angiotensin II, as well as various diseases caused by chimaze. It is also expected as a therapeutic agent.
  • An object of the present invention is to provide a novel compound having a more excellent chimase inhibitory activity than the above-mentioned compound, a pharmaceutical composition thereof, and a chymase inhibitor.
  • the present inventors have disclosed in the above-mentioned W ⁇ 96 / 339974 to achieve the above object.
  • the structural transformation of the compound was studied in various ways. As a result, it has been surprisingly found that amidation of the terminal carboxyl group can improve the chimase inhibitory activity and impart excellent blood stability, thereby completing the present invention.
  • the present invention provides a compound represented by the formula (I):
  • R is a hydrogen atom, alkyl, one CH0, -C ONH2, — CORl, one C 00R 1 , -C 0NH0R 1 , -C ONHR 1 , one CONRl Rl ', one CONH S 0 2 R 1 , one COSRl, -C 0 C OR2, one COCO oR 2, one C_ ⁇ _NHC 00 R2, one COCONR 3 R4, one C SXRl, - S 0 2 WR], - S O2 N Rl Rl 1 or a SO2 E (the above formula Wherein R 1 and Rl ′ may be the same or different and each independently represents alkyl, cycloalkyl, cycloalkyl, alkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle or heterocyclealkyl.
  • R 2 , R 3 and R 4 may be the same or different and each independently represents a hydrogen atom, an alkyl or an arylalkyl, and one NR 3 R4 together forms a heterocycle.
  • X may represent a single bond, 10 ⁇ , 10 0 or 1S S.
  • W. is a single bond, one ⁇ -, - ⁇ HC0-, shows an NHC00- or a NHC0NH-, E denotes a hydroxyl group or ⁇ amino) indicates,
  • R5, R6, R7 are the same or different or was or hydrogen atom an alkyl and each may independently have, or R 5, R6, 1 Tsu is Ariru of R7, Ari Ruarukiru, ⁇ Li one Ruarukeniru, Heteroa Reel, heteroaryl alkyl Or a heteroarylalkenyl, and the rest are hydrogen atoms,
  • M represents a carbon atom or a nitrogen atom, provided that when M is a nitrogen atom, R6 does not exist;
  • Y represents cycloalkyl, aryl or heteroaryl
  • R 8 represents a hydrogen atom, alkyl or arylalkyl
  • R9 and R1 may be the same or different and each independently represents a hydrogen atom, an alkyl, an alkenyl, a cycloalkyl, a cycloalkylalkyl, a heterocyclealkyl, an aryl, an arylalkyl, an arylalkenyl, a heteroaryl, A heteroarylalkyl or a heteroarylalkenyl, and one NR 9 R10 together may exhibit a heterocycle;
  • R U and R] 2 may be the same or different and are each independently a hydrogen atom.
  • Q represents —0—, one S—, a direct bond or the formula: one NR13— (where R! 3 represents a hydrogen atom, alkyl or arylalkyl), and P and r are the same Or may be different and each independently represents an integer of 0 to 3 ⁇ or formula ( ⁇ )
  • n 0 or J.
  • alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocyclyl, heterocyclylalkyl each have a substituent.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising compound (I) or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable carrier, and a pharmaceutical use, particularly a chymase inhibitor.
  • Alkyl in R, Rl, Rl 'and R2 to R13 preferably has 1 to 6 carbon atoms and may be linear or branched, for example, methyl, ethyl, n-propyl pill, isobutyl pill, n-butyl, isobutyl, sec-butyl, tert-butyl, ⁇ -pentyl, isopentyl, ⁇ -hexyl and the like.
  • the cycloalkyl in Rl, Rl ', R9 and RlO ⁇ preferably has a carbon number of
  • the cycloalkylalkyl in R 1, Rl ⁇ R9, R] 0 is the same as the cycloalkyl portion described above, and the alkyl portion preferably has 1 to 3 carbon atoms and may be linear or branched.
  • the alkyl portion preferably has 1 to 3 carbon atoms and may be linear or branched.
  • Aryl in Rl, Rl ', R5-R7, R9, RlO, ⁇ is preferably phenyl, naphthyl, or ortho-fused; a bicyclic radical having at least one ring atom having at least one ring atom and at least one ring atom.
  • Those in which the ring is an aromatic ring (eg, indenyl and the like) and the like can be mentioned.
  • Arylalkyl in R ⁇ and R 1 R2 to R13 has the same aryl moiety as described above, and the alkyl moiety preferably has 1 to 3 carbon atoms and may be linear or branched.
  • Benzyl, phenyl, 3-phenylpropyl 1-naphthylmethyl, 2-naphthylmethyl, 2- (1-naphthyl) ethyl, 2- (2-naphthyl) ethyl, 3- (1-naphthyl) propyl, 3- (2 —Naphthyl) Probi'nole and the like.
  • Arylalkenyl in R5 to R7 means that the aryl part is the same as described above, and the alkenyl part is preferably C6 to C6 and may be linear or branched, for example, styryl, 3 —Phenyl 1-probenyl, 4-phenyl 3-butenyl, 5-phenyl-1-41-pentenyl, 6-phenyl 5-hexenyl, 3- ( ⁇ -naphthyl) 1-2-pro Benil, 4- (2-naphthyl) 1: Babel and the like.
  • the arylalkenyl in R9 and RlO means that the aryl moiety is the same as described above, and the alkenyl moiety thereof preferably has 3 to 6 carbon atoms and may be linear or branched. 2-ru 1-l-provenil, 4-huen 2-ru 3-butenyl and the like.
  • the heteroaryl in RI, R1, R5 to R7, R9, R ⁇ 0, Y is preferably a heteroaryl having 5 carbon atoms and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen atoms). 6-membered or ortho-fused bicyclic heteroaryls having 8 to 10 ring atoms derived therefrom, especially those derived from Benz, or ⁇ -benylene, trimethylene or tetramethylene groups. Examples include those derived by fusion, and stable ⁇ ⁇ -oxides thereof.
  • R] R ⁇ , and the Heteroa reel alkyl in R 5 ⁇ R 7, R 9 ⁇ R 1 2, Teroa re Ichiru portion to that is the same as above, properly favored the alkyl portion is 1 to carbon atoms 3 may be linear or branched, such as 2-pyrrolylmethyl, 1-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-phenylphenyl, 2- (2-pyridyl) ethyl, 1- ( 3- (pyridyl) ethyl, 2- (4-pyridyl) ethyl, 3- (2-pyrrolyl) propyl and the like.
  • the heteroarylalkenyl in R 5 to R 7 has the same meaning as the above, and the alkenyl part thereof is preferably a straight-chain or branched-chain having 6 to 6 carbon atoms.
  • the alkenyl part thereof is preferably a straight-chain or branched-chain having 6 to 6 carbon atoms.
  • heteroarylalkenyl in has the same meaning as the heteroaryl portion described above, and the alkenyl portion preferably has 3 to 6 carbon atoms and may be linear or branched.
  • the heterocycle represented by R l and R! ′ Is a 4- to 6-membered ring group having a carbon atom and 1 to 4 hetero atoms (oxygen atom, sulfur atom or nitrogen atom), for example, azetidinyl, Pyrrolidinyl, Piberidinyl, Piberidino, Piberazinil, Morpho Examples include linyl, morpholino, thiomorpholinyl, oxothiomorpholinyl, dioxothiomorpholinyl, tetrahydroviranyl, and dioxacyclohexyl.
  • - NR 3 R 4, - NR 9 and Heterosai cycle represented by R 10 have the coal ⁇ terminal and at least yet another heteroatom having a single nitrogen atom (oxygen atom or a sulfur atom)
  • a 4- to 7-membered ring group which may be selected, for example, azetidinyl, pyrrolidinyl, biperidino, piperazinyl, hexahi draw I [1-azebine-diyl, morpholino, thiomorpholino, oxothiomorpholino, Oxothiomorpholino.
  • the alkenyl in R 9 and R 10 preferably has 3 to 6 carbon atoms and may be linear or branched, and includes, for example, 2-phenyl-phenyl, 3-butenyl, 4-pentenyl, 5-hexenyl and the like. No.
  • alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylaryl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocycle, heterocyclealkyl are Each may be substituted with one or more substituents shown below.
  • substituent of these S-substituents include, for example, nitrogen, hydroxyl, nitro, cyano, trifluoromethyl, alkyl, alkoxy, alkylthio, formyl, acyloxy, oxo, phenyl, arylalkyl, COORa, -CH 2 C 0 0 Ra, -0 CH 2 C 00 Ra, one C ONRb Rc, -CH 2 CONRb Rc, -OC H 2 C ONRb Rc, one C OO (CH2) 2 Re Rf, one S ⁇ 2 T], -C ONRd SOT 1, -NRe Rf, one NRg CH_ ⁇ , - Rg C OT2, -N Rg C 0 OT2, -NRh CQNRi Rj, -N Rk S O2 T 3, - S O2 N Rl Rm, - S O2 NRn C OT ⁇ And the like.
  • alkyl and arylalkyl are the same as those described above.
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • the alkoxy preferably has 1 to 6 carbon atoms and may be linear or branched and includes, for example, methoxy, ethoxy, ethoxy, butoxy, butoxy, hexoxy and the like.
  • the alkylthio preferably has 1 to 6 carbon atoms and may be linear or branched, and examples thereof include methylthio, ethylthio, propylthio, butylthio, pentylthio, and hexylthio.
  • the acyloxy may preferably be linear or branched having from i to 6 carbon atoms, and includes, for example, formyloxy, acetyloxy, propionyloxy, butyryloxy, valeryloxy, vivaloyloxy, hexanoyloxy and the like.
  • Ra to Rn are a hydrogen atom, alkyl (as described above), arylalkyl
  • ⁇ -44 represent the same groups as Rl described above, which may be substituted by the substituents described above.
  • the compound (I) can exist as an optically active substance and a racemic form by an asymmetric carbon atom to which one (CH 2 ) n one Y group is bonded.
  • Each of the optically active substances can be separated by a known method.
  • the compounds can exist as a mixture of diastereomers or as a single diastereomer, but these may also be present. Each of them can be separated by a method known per se.
  • Compound (I) can exhibit polymorphism, can exist as more than one tautomer, and can have a solvate (eg, ketone solvate). Products, hydrates, etc.).
  • a solvate eg, ketone solvate
  • the present invention includes any stereoisomers, optical isomers, polymorphs, tautomers, solvates, and any mixtures thereof as described above.
  • compound (I) is an acidic compound
  • its pharmacologically acceptable salts include alkali metal salts (eg, salts with lithium, sodium, potassium, etc.), alkaline earth metal salts (eg, Salts with calcium, magnesium, etc.), aluminum salts, ammonium salts, salts with organic bases (eg, salts with triethylamine, morpholin, piperidine, triethanolamine, etc.).
  • compound (I) When compound (I) is a basic compound, its pharmacologically acceptable salts include inorganic acid addition salts (for example, salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.) ), Organic acid addition salts (eg, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoalphaacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipine) Acid, maleic acid, tartaric acid, succinic acid, mandelic acid, linoleic acid and the like), and salts with amino acid (for example, salts with glutamic acid, aspartic acid and the like).
  • inorganic acid addition salts for example, salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,
  • a preferable compound is a compound wherein ⁇ in the formula (() is an aryl which may have a substituent: a compound wherein ⁇ in the formula (I) is a formula (i); A compound in which one of R 5 , R 6 , and R 7 in (I) may have a substituent, and a compound in which the remainder is a hydrogen atom (however, when M is a hydrogen atom, R 6 does not exist) And the like. More preferred compounds include those described in Examples 3, 4, 7, 8, 1K12, 17, 18, 18, 21-38, and 42-48. 55 and 59.
  • the production method of the wood compound (I) is shown in the following scheme 1 (1-0), 1-2, and 1-3).
  • R14 represents a protecting group for a hydroxyl group (for example, tert-butyldimethylsilyl, triisobromovirsilyl, tert-butyldiphenylsilyl group, etc.), cbz represents a benzyloxycarbonyl group, Ru represents a hydrogen atom or Na or Represents an alkali metal such as K, and other symbols are as defined above)
  • Compound (III) is a compound described in the literature (JP-A-6-56785, JP-A-5-286946, Warner et al. J. Med. Chem. 1994. 37, p3O90, Symbolwood et al. Med. Chem. 994 , 37, p3303, Veale et al., Med. Chem. 1995. 38, p98, WO 3/21210, etc.), or prepared by conventional methods based on these documents. It is made. Moreover, ⁇ Mi emissions (A), ⁇ Mi emissions (A '), ⁇ Mi emissions (eight ”) and ⁇ Mi emissions: HNR 8 Preparation of ZC ONR9 R 10 will be described later.
  • Compound (VUb) include dicyclohexylcarbodiimide (DCC) / hydroxybenztriazole (H0BT), N- (3 -Dimethylaminopropyl)- ⁇ '-ethylcarbodiimide (WSC1) or its hydrochloride / HOB, WSC1 or its hydrochloride / 4-dimethylaminopyridine (DMAP), 2-ethoxy-ethoxycarbonyl -1.2 -Dihydroquinoline (EEDQ), carbonyldiimidazole (CDI) / H0BT.
  • DCC dicyclohexylcarbodiimide
  • H0BT hydroxybenztriazole
  • WSC1 N- (3 -Dimethylaminopropyl)- ⁇ '-ethylcarbodiimide
  • WSC1 or its hydrochloride / 4-dimethylaminopyridine
  • EEDQ 2-ethoxy-ethoxycarbonyl -1.2 -D
  • Getyl phosphoryl cyanide benzotriazole-1-yloxytris (dimethylamino) phosphonium hexaoxafluophosphate (B0P) , Phenyl N— Eniruhosuhorami skull Ride one bets, and the like as a preferable example.
  • the reaction is generally carried out in an inert solvent, and the inert solvent used may be any non-protonic solvent, and is preferably acetate nitrile, dichloromethane, or the like. Black form, N, N-dimethylformamide and the like.
  • the condensation is usually performed at a temperature of -30 to 80 ° C, and preferably at 0 to 25 ° C.
  • the hydroxyl group of the obtained compound (VII) may be protected and converted to the compound (IV). Conversely, the protective group (R 14 ) of the hydroxyl group of compound (! V) may be deprotected to give compound (VII).
  • the compound can be obtained by, for example, converting the amino group bonded to carbon on the heterocycle (pyridone ring or pyrimidone ring) in compound (V) by the following method.
  • R force '-CHO,-C 0 NH 2, C ORl,-COOR 1 ,-C ONH 0 R 1.- CONHR 1 ,-C QNRl R',-C ONH S O2 R 1 ,-COS Rl,
  • R is - synthesizing CS XR 1, compound a (VI), a method of using activated Chiokarubon acid derivatives (e.g., lower alkyl esters such as Chioirukurorai de Ya Jichioikku acid), a Chioi click acid and couplings agent Examples include the method used. Further, for example, dimethyl Bok Li Chio carbonate, an alcohol of the formula R 1 0H, and a method for use with Amin represented by thiols or formula R 1 NH2 formula Rl SH and the like. Further, in the case of synthesizing the compound (VI) in which X is -NH, a method using isothiocyanate and the like can be mentioned.
  • activated Chiokarubon acid derivatives e.g., lower alkyl esters such as Chioirukurorai de Ya Jichioikku acid
  • Examples include the method used. Further, for example, dimethyl Bok Li Chio carbonate, an alcohol of the formula R 1 0
  • compound (VI) has C 00 Ra (carboxyl group) in which Ra is a hydrogen atom as a substituent of each substituent in R, for example, a corresponding compound synthesized using an acid protecting group suitably removed
  • the ester compound (VI) having CO ORa in which Ra is not a hydrogen atom as a substituent of the substituent
  • This decomposition can be performed by any of various methods well known in organic chemistry, for example, basic hydrolysis using lithium hydroxide or sodium hydroxide, or hydrogenolysis of benzyl ester. .
  • Compound (VI) is, C 00 Ra as substituents for each substituent at R, - C ON Rb Rc, if having a -C OO (CH 2) 2 NRe Rf or a C QNRd S 0 2, for example, the formula HORa , HNRb Rc, HO (CH 2 ) 2 NRe Rf or HNRd S 0 the compound represented by the 2 Tl and (if Ra to Ri 'is not hydrogen atom), it is Ra is hydrogen atom as the substituent of the substituted group one
  • the compound (VI) having C 00 Ra (carboxy group) or an activated derivative thereof can be reacted to obtain the compound.
  • the compound (VI) has OCH 2 C OORa or O CH2 C ONRbRc as a substituent of each substituent in R 5 to R 7 and R, for example, the compounds represented by the formulas B r C H2 C OORa, I CH C OORa, B r C H2 CON Rb Rc or I CH 2 C ONRb Rc compound represented by (in the case Ra to Rc is not hydrogen atom), the compound having a hydroxyl group as a substituent of substituent (VI), hydrogenated diisocyanato Li um By reacting in the presence of such a base, the compound can be derived.
  • Compound (VI) is, R5 through R7, the substituent of each substituent in R - NRg COT 2, - NRg C 00 T2, - N Rh CQNRi Rj, - NRk case with S 0 2 T3 or Ashiruokishi group, e.g. , hydroxyl group as the substituent of the substituted group, or is NHRg, - NHRh or - the corresponding compound having an amino group NHRk with (VI), formula HO C OT2, HOC OOT 2, HOC QNRi Rj or H_ ⁇
  • the compound is obtained.
  • Compound (VI) is, R 5 ⁇ R 7, Heteroari Ichiru into R - Okisai a de base case including, R 5 ⁇ R 7, R or the corresponding compounds containing Heteroariru groups in Z (VI) Is oxidized using a common oxidizing agent such as dioxysilane in acetate to obtain the compound.
  • the compound (II) is obtained by removing the protecting group (R 14 ) of the hydroxyl group in the compound (VI).
  • the removal of the hydroxyl-protecting group can be performed using tetrabutylammonium fluoride or the like in an inert solvent such as tetrahydrofuran, and at this time, the reaction solution is buffered with an acid such as acetic acid. Is preferred.
  • a preferable method of this oxidation for example, there is a method of using excess dimethyl sulfoxide and water-soluble carbodiimide at about room temperature in an inert solvent such as toluene and using acetic acid as a catalyst.
  • Other useful methods include, for example, a method using an aqueous solution of potassium permanganate: a method using oxalyl chloride, dimethyl sulfoxide, and a tertiary amine: acetic anhydride and dimethyl.
  • Method using sulfoxide Method using pyridine trioxide complex and dimethyl sulfoxide: Method using chromium oxide (VI) pyridine complex in methylene chloride Method: 1, 1, tritolyacetoxy-1, 1, 2, 3, 4 dihydro-1.2-benzidodotool-3 (1H) -Hypervalent hyperiodine reagents such as perodinane, etc. N-N-dimethylformamide can be used.
  • the compound (1 ⁇ ) is condensed with amine (A) or the compound (HI) is condensed with amine ( ⁇ ')
  • the compound (VI ⁇ ) derived through the hydrolysis compound (VI lb) of the compound (VIla) or obtained by deprotecting the hydroxyl group of the compound (IV) The compound (I) having an amino group protected with a benzyloxycarbonyl group can be obtained by oxidation.
  • benzyloxycarbonyl group of this compound is removed (deprotected) under mild reaction conditions to obtain a compound (I) in which R is a hydrogen atom.
  • deprotection is carried out by an acid decomposition reaction in which trifluoromethanesulfonic acid or trifluoroacetic acid acts in the presence of anisol or thioanisole, or a hydrogenolysis reaction using palladium carbon or the like as a catalyst.
  • the compound (I) in which R is other than a hydrogen atom can also be obtained by performing the above acylation reaction or the like.
  • R15 represents a straight-chain or branched alkyl having i to 6 carbon atoms, or a group forming an ether serving as a protecting group for a carboxyl group, and other symbols are as defined above.
  • compound ( ⁇ ) is condensed with amine (B) (XIV), the compound ( ⁇ ! Is condensed with an amide ( ⁇ ') to form a compound (VI la), and the compound (Vllb) is hydrolyzed to the compound (XIV).
  • the compound (111) is condensed with an amine (C) to give a compound (Vlli).
  • compound (XV) is obtained from compound (1 ⁇ ) via compound (XIV) in the same manner as in Scheme 1-3. This is converted into a compound (XVI) by deprotection of the carboxyl group, and by amidation, a compound (I) (wherein R represents bbz and other symbols are as defined above) is obtained.
  • Scheme 3 shows another method for producing compound UV). In this method, if M is a carbon field Used only when
  • compound (XVII) [Compound described in the literature (Japanese Patent Publication No. 6-56785, Warner et al., J. Med. Chem. 1994, 37, p3090, Symbolood et al., J. Med. Chem. 1994, 37, p3303) or a compound prepared by a conventional method based on these documents] and compound (D) to obtain compound (IV).
  • compound (D) can be.
  • the method for preparing compound (D) will be described later. As described in, for example, JP-A-6-56785 and J. Med. Chem.
  • this reaction is carried out by converting compound (XVII) into a non-protonic solvent, especially N, Inactive solvents such as N-dimethylformamide, tetrahydrofuran, etc., bases such as sodium hydride, hydrogenation power, etc., -30 to 80 ° C, preferably 0 to 30 °
  • N non-protonic solvent
  • bases such as sodium hydride, hydrogenation power, etc.
  • R V represents an amino-protecting group (for example, a benzyloxycarbonyl group (bzz), a tert-hydroxycarbonyl group (B0C), etc.), and Rw represents an alkyl group having 1 to 5 carbon atoms. And other symbols are as defined above.
  • esterification method examples include a method in which Rw is reacted with an alkyl halide corresponding to Rw in the presence of a base such as hydrogen carbonate and a reaction method with a diazoalkane.
  • the amino group-protected ⁇ -amino acid represented by the formula (XV111) is commercially available in many cases, but the other one is obtained by the method of Strecker synthesis from aldehyde ⁇ — (C ⁇ 2) nCHO or other methods. After obtaining an amino acid by the obvious method described above, the amino acid can be protected and protected.
  • the compound (XIX) is reduced with, for example, sodium borohydride Z to give compound 00, and then described in the conversion of compound ( ⁇ ) to compound ([).
  • Compound (XX) can also be obtained by oxidizing compound (XX) by an oxidation method.
  • compound (XXI) was prepared by the method described in (i) Hal 1 inan and Fried (Tetrahedron Lett. 1984, 25. p2301) and Thai rivongs et al. U. Med. Chem. 1986, 29, ⁇ 2 ⁇ 80). (2) reacting with chlorodifluoroacetate in the presence of zinc powder according to the method of ang and Schaub (Tetrahedron Lett. 1988, 29, p2943), or (3) According to the method of Hoover (US Pat. No. 4,855,303), compound (XXU) is synthesized by reacting with ethyl promodifluoroacetate, zinc dust and titanium tetrachloride. can do.
  • the amide (A) is obtained by removing the protecting group Rv of the amino group.
  • Amines ( ⁇ ') can be obtained by removing the protecting group Rv of the compound (XXH).
  • ⁇ Amin (A ") can be obtained by converting the hydroxyl group of the compound (XXIV) to a protecting group (R 14 ), followed by removal of the protecting group Rv of the amino group.
  • HN R 8 ZC 0 2 R 15 is greater commercially available, otherwise it is synthesized as follows.
  • this compound (D) is carried out, for example, according to the report of impliedwood et al. U. Med. Chem. 1994. 37, P3303).
  • the amine (A) is reacted with N-methylmorpholine or the like in an inert solvent such as tetrahydrofuran.
  • Reaction with chloroacetyl chloride at ⁇ 20 to 60 ° C., preferably at 0 to 30 ° C. in the presence of an organic base gives compound (XXVI II).
  • the compound (XXIX) is obtained by protecting the hydroxyl group of this compound (XXV1H) with the above-mentioned protected amino group (Ri4), preferably a silyl group such as a tert-butyldimethylsilyl group. This, for example, When reacted with sodium iodide or lithium iodide in an inert solvent such as acetone at -20 to 60 ° C, preferably at 0 to 30, the desired compound (D) is obtained.
  • the resulting Scheme 8 shows a method for synthesizing compound (E).
  • Compound (E) can be obtained by using compound (XXX) and then compound ( ⁇ ) in the same procedure as starting compound (D) from compound (A), starting from compound (B). Can be.
  • the compound (I) of the present invention thus synthesized can be purified to any desired purity by appropriately performing known separation and purification means, for example, concentration, extraction, chromatography, reprecipitation, and recrystallization. Can be collected as
  • a pharmacologically acceptable salt of the compound (I) can be produced by a known method.
  • various isomers of the compound (I) and the like can also be produced by a known method.
  • the compound (I) of the present invention and a pharmacologically acceptable salt thereof have excellent inhibitory activity against a mammal (for example, human, dog, cat, etc.) against the chimaze group.
  • the compound (I) of the present invention and a pharmacologically acceptable salt thereof are ffl as inhibitors of the chymase group including human heart chymase, and it is considered that angiotensin 11 is present.
  • Prevention of possible diseases eg, hypertension, cardiac hypertrophy, myocardial infarction, arteriosclerosis, diabetic and non-diabetic renal disease, vascular restenosis after PTCA, etc.
  • Useful for prevention and treatment Useful for prevention and treatment.
  • a pharmacologically acceptable carrier or the like may be used, and granules, tablets, capsules, injections, ointments, creams, aerosols and the like may be used. And can be administered orally or parenterally. An effective amount of compound (I) or a pharmacologically acceptable salt thereof is incorporated into the above preparation.
  • the administration site of the compound (e) and a pharmacologically acceptable salt thereof varies depending on the administration route, the patient's symptoms, rest, age, and the like, and can be appropriately set depending on the purpose of administration.
  • 0.01 to l OOOmg / kg body weight /, preferably 0.05 to 500 mg / kg rest / day should be administered in 1 to several times a day. preferable.
  • FIG. 1 is a graph showing the change in the concentration of the unchanged compound in plasma when the compound of the present invention and the conventional compound were orally administered to rats in Experimental Example 2, respectively.
  • FIG. 1 shows plasma in the case where the compound of the present invention was orally administered to dogs in Experimental Example 3. It is a graph showing the transition of the unchanged substance concentration of n
  • NMR spectrum of each product was measured using a Bruker AMX-500 nuclear magnetic resonance apparatus (500 MHz) or a Bruker DPX-300 nuclear magnetic resonance apparatus (300 MHz) using tetramethylsilane (TMS) as an internal standard.
  • IR spectra were measured using a Shimadzu IR-420 infrared spectrophotometer or a Perkin Elmer FT-IR 1725X infrared spectrophotometer.
  • the mass spectrum was measured using a Hitachi M-2000 double focusing mass spectrometer or PE Sciex API165 liquid chromatograph mass spectrometer, and the melting point was measured using a Yanagimoto MP-S3 trace melting point analyzer. It was measured.
  • Silica gel 60 230 to 400 mesh
  • Reagents and solvents used were JIS special grade or primary grade.
  • Lithium iodide (49.0 g, 0.366 mol) was added to a solution of the target compound (55.0 g, 0.145 mol) in pyridine (200 ml) in step (3), and the mixture was heated to 100 and stirred for 16 hours. After evaporating the organic solvent under reduced pressure, toluene (200 ml) was added and the remaining traces of pyridine were distilled off under reduced pressure. The residue was added to a saturated aqueous sodium hydrogen carbonate solution (500 ml), and ethyl acetate was added. The organic substances other than carboxylic acid were extracted with.
  • step (6) The target compound of step (6) (mixture with benzyl alcohol, 20.2 g, 42.3 mmol). 2-Methyl-2-propanol (300 ml) and 2-methyl-2-butene (50 ml.
  • Ethyl 3-methylbenzimid hydrochloride was synthesized in the same manner as in Reference Example I. That is, m-tolunitrile (25.2 g, 0.1 ⁇ ) is treated with hydrogen chloride in a solution of ethanol (250 ml) to give the target compound as colorless crystals, 41.7 g (97%)
  • the target compound (32.5 g, 7.5 mmol) of the step (4) was dissolved in 1,4-dioxane (250 ml) solution in the presence of triethylamine (27 tn and 0.19 mol) in the presence of diphenylphosphoryl azide 6 Then, it was reacted with benzyl alcohol (15 ml, 0.14 mol) to obtain 30.8 g (72%) of the target compound as colorless crystals.
  • step (3) To a solution of the desired compound (57.7 g, 0.160 mol) in step (3) in tetrahydrofuran (THF) (500 ml) was added a 0.5N aqueous sodium hydroxide solution (360 ml), and the mixture was stirred at room temperature for 1 hour. After the reaction solution was washed with chloroform, IN hydrochloric acid (200 ml) was added to the aqueous layer, and the oil was extracted with chloroform.
  • THF tetrahydrofuran
  • step (6) The target compound of step (6) (crude product obtained in the above reaction, 22.4 g), 2-methyl-2-propanol (300 ml) and 2-methyl-2-butene (50 ml, 0.47 g) mol), a solution of sodium dihydrogen phosphate dihydrate (51.4 g, 0.329 mol) and sodium chlorite (containing 85! 3 ⁇ 4, 36.6 g, 0.344 mol) in water (130 ml) was added to the mixture at room temperature. Stir for 3 hours. The organic solvent was distilled off under reduced pressure, and 3N hydrochloric acid was added to adjust the pH to 3, followed by extraction with chloroform.
  • the extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain crystals.
  • the crystals were washed with hexane-ether (1: 1) and dried under vacuum to give 16.0 g of the title compound as colorless crystals.
  • Ethyl 4-methylbenzimidyl hydrochloride was synthesized in the same manner as in Reference Example 1. That is, P-tolutritril (25.6 g, 0.219 mol) is treated with hydrogen chloride in an ethanol (250 ml) solution, and the target compound is converted to colorless crystals as 42.3 g (97%). Obtained.
  • the target compound of the step (6) (the crude product obtained in the above reaction, 25.3 g) was mixed with 2-methyl-2-propanol (350 ml) and water (150 ml) in a mixed solvent of 2-methyl-2 -In the presence of butene (60tnl, 0.57 mol) and sodium dihydrogen phosphate dihydrate (61.0 g, 0.391 mol), sodium chlorite (85% content, 43 g, 0.408 mol) ) To give 17.5 g of the title compound as colorless crystals.
  • the target compound (33.0 g. 84.5 mmol) of (3) was reacted with lithium iodide (27.1 g, 202 mmol) in a solution of pyridine (120 ml) to give the target compound as colorless crystals. %)Obtained.
  • step (4) 87.8 mmol of the step (4) was dissolved in 1,4-dioxane (260 ml) solution in the presence of triethylamine (24.5 id, 176 mmol) in the presence of diphenylphosphoryl azide (21.5 ml, 95.9 mmol) and further reacted with benzyl alcohol (12 ml, 0.16 mol) to obtain 39.3 g (85%) of a mixture of the target compound and benzyl alcohol as a colorless solid.
  • the target compound of Step (6) (crude product obtained in the above reaction; 36.8 g) was added to a mixed solvent of 2-methyl-2-butanol (460 ml) and water (190 ml), In the presence of methyl-2-butene (78 m !, 0.74 mol) and sodium dihydrogen phosphate dihydrate (34.2 g, 540 mmol), sodium chlorite (containing 803 ⁇ 4; 58.5 g) , 517) to give 26.6 g of the title compound as colorless crystals.
  • 6-Dihydropyrimidinyl] acetaldehyde dodecyl acetal was synthesized in the same manner as in Reference Example 1. That is, the target compound (22 g, B9.4 ol) of the step (4) was dissolved in 1,4-dioxane (220 ml) solution in the presence of triethylamine (19 ml, 0.14 mol) in the presence of diphenylphosphoryl. It was reacted with azide (17, 9 ml. 79.8 mmol) and further reacted with benzyl alcohol (10.5 ml. 0.101 mol) to obtain 24.5 g (73%) of the target compound as pale yellow crystals.
  • 6-Dihydropyrimidinyl] acetaldehyde was synthesized in the same manner as in Reference Example i. That is, the target compound (24.0 g, 49.7 ol) in Step (5) was treated with 1N hydrochloric acid (40 ml) in a THF (] 85 ml) solution to give 20.4 g (100 mg) of the target compound as pale yellow crystals. Obtained.
  • the aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed successively with a saturated aqueous solution of sodium hydrogencarbonate (20 ml ⁇ 3) and a saturated aqueous solution of sodium chloride (20 ml). After drying over magnesium, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (2: 1, chloroform-ethyl acetate) to give 2--benzyloquincarbonylamino-2- (4-fluorophenyl) -1,6-dihydroxyl.
  • Dro-6-oxo-pyrimidinyl-N- [1-benzyl-3,3-difluoro-2-oxo-3- [N- (te rt-butoxycarbonylmethyl) rubamoyl] propyl 1.61 g (933 ⁇ 4) was obtained as brown morphus.
  • Example 3 Using the title compound of Example 3 and reacting in the same manner as in Example 2, 133 mg (94%) of the title compound was obtained as a yellow powder.
  • the aqueous layer was extracted with ethyl acetate (20 ml ⁇ 2), and the combined organic layers were combined with a 10% aqueous solution of citric acid (20 ml), an aqueous solution of sodium hydrogencarbonate (20 ml), and a saturated aqueous solution of sodium chloride (20 ml). ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (39: 1, chloroform-methanol) to obtain 198 mg (68%) of the title compound as a white powder.
  • Example 7 The same reaction as in Example 2 was carried out using the title compound of Example 7 to obtain 103 mg (80%) of the title compound as a white powder.
  • Example 9 The same reaction as in Example 2 was carried out using the title compound of Example 9 to give 151 mg (805) of the title compound as a white powder.
  • the title compound was obtained as a white powder in the same manner as in Example 2 using the title compound of Example U as a white powder (1 M mg, 76%).
  • Example 9- (3) Using the compound obtained in Example 9- (3), and in the same reaction as in Example 5, 471 mg (71%) of the title compound was obtained as a white solid.
  • Example 2 The same reaction as in Example 2 was carried out using the title compound of Example 13 to give 153 mg (81%) of the title compound as a white powder.
  • Example 14 (1) Using the compound shown in Table 3 of Reference Example 3 and the title compound of Reference Example 14, the same reaction as in Example (2) was carried out to give 2- [5-benzyloxycarbonylamino-1,6-dihydroxy. -2-(3-Methylphenyl) -6-oxo-pyrimidinyl]-N- [1-benzyl-3,3-difluoro-2--2-hydroxy-3- [N- (tert-butoxy There was obtained 3,55 g (66%) of carbonylmethyl) lebamoyl] propyl] acetamide as a light brown solid.
  • the title compound was obtained as a pale-yellow powder (M3 mg, 7 mg) by the same reaction as in Example 2 using the title compound of Example).
  • Example 15 The same reaction as in Example 3 was carried out using the compound obtained in Example 15 (3) to obtain 238 mg (40 mg) of the title compound as a pale yellow powder.
  • Example 17 The same reaction as in Example 1 was carried out using the compound shown in Example 17 to give 114 mg (83%) of the title compound as a pale yellow powder.
  • Example 2 The same reaction as in Example 2 was carried out using the title compound of Example 19 to obtain 133 mg (74 mg) of the title compound as a pale yellow powder.
  • Example 15- (3) Using the compound obtained in Example 15- (3) and in the same reaction as in Example 3, 573 mg (73%) of the title compound was obtained as a pale yellow powder.
  • Example 21 The title compound was obtained in the same manner as in Example 2 using the title compound of Example 21. 241 mg (69 mg) was obtained as a pale yellow powder.
  • Example 15- (3) The same reaction as in Example 3 was carried out using the compound obtained in Example 15- (3) to obtain 563 mg (73 mg) of a compound as a pale yellow powder.
  • the title compound was obtained as a pale-yellow powder (553 mg, 73%) by the same reaction as in Example 3 using the compound obtained in Example 15- (3).
  • Example 25 The title compound of Example 25 was reacted in the same manner as in Example 2 to obtain 309 mg (88 mg) of the title compound as a pale yellow powder.
  • Example 15-(: 3) Using the compound obtained in Example 15-(: 3), the title compound was obtained as a pale-yellow powder (570 mg, 74%) by the same reaction as in Example 3.
  • Example 27 The same reaction as in Example 2 was performed using the title compound of Example 27 to give the title compound (320 mg, 88%) as a pale-yellow powder.
  • WSCI hydrochloride (1.10 g, 5.75 mmol) was added to a mixed solution of the compound obtained in Reference Example 15- (4) (564 mg, 1.15 nraol) in DMSO (10 ml) and toluene (10 ml). Then, acetic acid (0.190 ml, 2.30 mmol) was added dropwise under ice cooling, and the mixture was stirred at 0 "C for 40 minutes. After further stirring at room temperature for 3 hours, the reaction mixture was poured into 1M hydrochloric acid (50 ml).
  • the mixture was extracted with ethyl acetate (50 ml x 2)
  • the organic layer was extracted with water (50 ml), saturated aqueous sodium hydrogen carbonate solution (50 ml x 2), water (50 ml), and saturated sodium chloride.
  • the extract was washed with an aqueous solution (50 ml), dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (7: 5, gel-form-ethyl acetate).
  • Example 31 The title compound of Example 31 was reacted in the same manner as in Example 2 to obtain 21 mg (51%) of the title compound as a pale yellow powder.
  • the title compound was obtained as a pale yellow powder by the same reaction as in Example 35 using the title compound of Example 35 as a pale yellow powder (55 mg, 77%).
  • Example 39 The same reaction as in Example 2 was carried out using the title compound of Example 39 to obtain 67 mg (45 mg) of the title compound as a pale yellow powder.
  • Example 38 The same reaction as in Example 38 was carried out using the title compound of Example 42 to obtain 700 mg (82%) of the title compound as a white solid.
  • Example 38 The same procedures as in Example 38 were carried out except for using the title compound of Example 46, to give 770 mg (71%) of the title compound as a white solid.
  • Example 48 Using the title compound of Example 48 and performing the same reaction as in Example 2, 680 mg (86 ⁇ l) of the title compound was obtained as a white solid.
  • Example 2 The same reaction as in Example 1- (1) was carried out using the above compound and the compound of Reference Example 2.
  • 2-L5-benzyloquincarbonylamino-1,6-dihydro-2- (3-methylphenyl) -6-oxo-1-pyrimidinyl N-U-benzyl-3,3-difluoro- 2.39 g (90%) of 2-hydroxy-3-ethoxycarbonylpropyl] acetamide was obtained as a white solid.
  • the inhibitory activity of the compound (I) of the present invention was measured as the inhibitory activity on the amidase activity of human cardiac chimase, and its effectiveness was evaluated as follows.
  • the inhibitory activity was evaluated based on the apparent inhibition constant (Kiapp) obtained by this analysis and the inhibition constant (Ki) calculated from the final concentration of the reaction solution substrate and the Km value separately determined.
  • the initial rate of the enzymatic reaction is determined spectrophotometrically by increasing the absorbance at 405 nm by subtracting the absorbance at 650 nm light from the amount of p-ditroaniline produced by hydrolysis of the substrate. did.
  • the chimase inhibitory activity of the compound of the present invention is calculated as the fraction of the activity remaining in the presence of the inhibitor relative to the enzyme activity in the absence of the inhibitor, and is measured below the initial rate guaranteed absorbance at the substrate concentration used for the enzyme. After capturing the values, analysis was performed.
  • the composition of the reaction solution was the compound of the present invention dissolved in 10 ⁇ l dimethyl sulfoxide (DMS0) at a concentration of 20 / il in 140 ⁇ l of a buffer solution (pH 7.5) of Tris-HC1 (100 m) -KCI (2). , The substrate dissolved in DMS ⁇ , and 20 l of chimase were added to a total volume of 200/1.
  • DMS0 dimethyl sulfoxide
  • the inhibitory activity against human leukocyte elastase was measured by using N-methoxysuccinyl-aralanyl-aralanyl-prolyl-valin-p-nitroanilide as a substrate and using 20 tnM CaCl2 and 0.1 0.1 0.1M Tris-HCl (pH 8.0) containing Twecn 80 was used, and the other composition was the same as above.
  • Table 7 shows the results of the human cardiac chimase inhibitory activity test for the obtained compound together with the results of the comparative compound shown in Table 6.
  • the compound ( ⁇ ) of the present invention does not inhibit human leukocyte elastase at all and strongly inhibits human cardiac chimase.
  • Example 18 Using an SD male rat, under fasting conditions, the compound obtained in Example 18 was orally administered at a dose of ⁇ Omg / kg and administered for 10 and 30 minutes and I, 1, 3, and 6 hours after administration. Blood was collected at the point. Pretreatment of plasma was performed by a general solid-phase extraction method, and the obtained sample was analyzed by HP-C using a DS column (solvent: acetonitrile / The reaction was carried out using a dihydrogen oxygen solution (aqueous aqueous solution).
  • the compound of the present invention showed the maximum concentration at about 30 minutes after administration, and after this, the plasma concentration decreased over 2 hours after administration, and then disappeared moderately over 6 hours after administration. Was. The half-life during the period of this mild disappearance was more than 10 hours. On the other hand, with respect to Comparative Compound 1, after 3 hours, the unchanged rest in plasma was below the detection limit.
  • Example 45 Using a male beagle dog, the compound obtained in Example 45 was orally administered at a ffl amount of 1 OmgZkg under fasting conditions, and blood was collected at 30 minutes and at i, 2, 4, and 7 hours after the administration.
  • the pretreatment of the plasma was performed by a general solid phase extraction method, and the analysis of the obtained sample was performed by HPLC using an ODS column (solvent: acetonitrile / hydrogen potassium dihydrogen phosphate). Aqueous solution).
  • Fine particles for direct hit No.209 (Fuji Chemical Co., Ltd.) 46 mg Magnesium aluminate metasilicate 20% Tropical starch 30%
  • (1), (3) and (4) are all passed through a 10 () 0 mesh sieve in advance. These (1), (3), (4) and (2) were each dried to reduce the water content to a certain level, and then mixed at the above weight ratio using a mixer. (5) is added to the mixed powder of uniform quality and mixed for a short time (30 seconds), and the mixed powder is tabletted (punch: 6.3 mm0, 6.0 mmR) to obtain .1 tablet 8 5 mg tablets were obtained.
  • the tablet may be coated with a commonly used gastrosoluble film coating (eg, polyvinyl acetal getylamino acetate) or an edible colorant, if necessary.
  • a commonly used gastrosoluble film coating eg, polyvinyl acetal getylamino acetate
  • an edible colorant if necessary.
  • the heterocyclic amide compound of the present invention and a pharmacologically acceptable salt thereof have excellent chymase group inhibitory activity against mammals including human, and can be administered orally and parenterally. . Therefore, it is useful as a chimase inhibitor and is useful for the prevention and treatment of various diseases caused by chimase, including various diseases caused by angiotensin II.
  • This application is based on Japanese Patent Application No. 3535572 filed in Japan and its contents are incorporated in full herein.

Abstract

L'invention concerne des composés d'amides hétérocycliques représentés par la formule générale (I) (chaque symbole étant défini dans le descriptif), ou leurs sels pharmaceutiquement acceptables. L'invention concerne également des compositions contenant ces composés et leur utilisation comme médicaments. Ces composés présentent une excellente activité d'inhibition de la chymase chez des mammifères, y compris l'Homo sapiens, et sont, par conséquent, utiles comme inhibiteurs de la chymase administrés par voie orale ou parentérale. Dès lors, ils sont efficaces pour la prévention ou le traitement de diverses maladies induites par l'angiotensine II ou d'autres maladies induites par la chymase.
PCT/JP1998/005786 1997-12-22 1998-12-21 Inhibiteurs de la chymase WO1999032459A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU16849/99A AU1684999A (en) 1997-12-22 1998-12-21 Chymase inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP35357297 1997-12-22
JP9/353572 1997-12-22

Publications (1)

Publication Number Publication Date
WO1999032459A1 true WO1999032459A1 (fr) 1999-07-01

Family

ID=18431753

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1998/005786 WO1999032459A1 (fr) 1997-12-22 1998-12-21 Inhibiteurs de la chymase

Country Status (2)

Country Link
AU (1) AU1684999A (fr)
WO (1) WO1999032459A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002006242A2 (fr) * 2000-07-18 2002-01-24 Neurogen Corporation 2-aryl-4-pyrimidinones 5-substituees
WO2002051815A1 (fr) * 2000-12-26 2002-07-04 Ono Pharmaceutical Co., Ltd. Derives de pyrimidine et procede de preparation de ceux-ci
EP1224945A4 (fr) * 1999-10-25 2004-08-18 Senju Pharma Co Agents permettant de soulager la tension d'un muscle ciliaire
US7812038B2 (en) 1999-05-07 2010-10-12 Encysive Pharmaceuticals, Inc. Carboxylic acid derivatives that inhibit the binding of integrins to their receptors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996033974A1 (fr) * 1995-04-27 1996-10-31 The Green Cross Corporation Composes heterocycliques amides et leur utilisation medicinale
JPH107661A (ja) * 1996-06-20 1998-01-13 Green Cross Corp:The 新規複素環式アミド化合物およびその医薬用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996033974A1 (fr) * 1995-04-27 1996-10-31 The Green Cross Corporation Composes heterocycliques amides et leur utilisation medicinale
JPH107661A (ja) * 1996-06-20 1998-01-13 Green Cross Corp:The 新規複素環式アミド化合物およびその医薬用途

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7812038B2 (en) 1999-05-07 2010-10-12 Encysive Pharmaceuticals, Inc. Carboxylic acid derivatives that inhibit the binding of integrins to their receptors
EP1224945A4 (fr) * 1999-10-25 2004-08-18 Senju Pharma Co Agents permettant de soulager la tension d'un muscle ciliaire
WO2002006242A2 (fr) * 2000-07-18 2002-01-24 Neurogen Corporation 2-aryl-4-pyrimidinones 5-substituees
WO2002006242A3 (fr) * 2000-07-18 2002-07-18 Neurogen Corp 2-aryl-4-pyrimidinones 5-substituees
US6943173B2 (en) 2000-07-18 2005-09-13 Neurogen Corporation 5-substituted 2-aryl-4-pyrimidinones
US7169790B2 (en) 2000-07-18 2007-01-30 Neurogen Corporation 5-substituted 2-aryl-4-pyrimidinones
WO2002051815A1 (fr) * 2000-12-26 2002-07-04 Ono Pharmaceutical Co., Ltd. Derives de pyrimidine et procede de preparation de ceux-ci

Also Published As

Publication number Publication date
AU1684999A (en) 1999-07-12

Similar Documents

Publication Publication Date Title
AU2021240103B2 (en) Substituted pyrrolizine compounds and uses thereof
US5948785A (en) Heterocyclic amide compounds and pharmaceutical use of the same
CN113286794B (zh) Kras突变蛋白抑制剂
WO1998018794A1 (fr) Nouveaux composes d'amide heterocycliques et leur utilisation a des fins medicinales
CN112218859A (zh) 蛋白水解调节剂及相关使用方法
WO2004096806A1 (fr) Derive d'imidazole condense
KR20180081584A (ko) Il-12, il-23 및/또는 ifn 알파 반응의 조정제로서 유용한 이미다조피리다진 화합물
KR102205914B1 (ko) IL-12, IL-23 및/또는 IFNα의 조절에 유용한 알킬 아미드-치환된 피리미딘 화합물
CN110191887B (zh) IL-12、IL-23和/或IFN-α的咪唑并哒嗪调节剂
CN112552295A (zh) Kras突变蛋白抑制剂
JPWO2002062775A1 (ja) ２−アシルアミノチアゾール誘導体又はその塩
JP2005535702A (ja) 新規化合物
WO2001027105A1 (fr) Composes de pyrimidine-5-carboxamide, procede de preparation et d'utilisation desdits composes
JP2009502922A (ja) カスパーゼ阻害剤プロドラッグ
KR20140059164A (ko) 트라이사이클릭 자이라제 억제제
AU2018236290A1 (en) MK2 inhibitors, synthesis thereof, and intermediates thereto
KR102602558B1 (ko) Il-12, il-23 및/또는 ifn 알파 반응의 조정제로서의 포스핀 옥시드 알킬 아미드 치환된 헤테로아릴 화합물
KR20200089706A (ko) 술폰 피리딘 알킬 아미드-치환된 헤테로아릴 화합물
JPH0820597A (ja) トロンビン阻害作用を有する複素環カルボニル化合物
CN111801100B (zh) 用于治疗和预防肝癌的7-取代的磺亚氨酰基嘌呤酮化合物和衍生物
KR101133959B1 (ko) 면역조절 헤테로고리 화합물
JPH0826037B2 (ja) 生理活性物質ｋ−２５２の誘導体
WO2005021550A1 (fr) Derive de pyrazole bicyclique
JP2005255675A (ja) 医薬組成物
JP2007291050A (ja) ピログルタミン酸誘導体の合成および用途

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: KR

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA