公开(公告)号：JPH08277271A

公开(公告)日：1996-10-22

申请号：JP8154495

申请日：1995-04-06

申请人： EISAI CO LTD

发明人： OINUMA HITOSHI ,  SUDA SHINJI ,  YONEDA NAOKI ,  KOTAKE MAKOTO ,  MATSUSHIMA TOMOHIRO ,  SAITO MAMORU ,  MATSUOKA TOSHIYUKI ,  ADACHI HIDEYUKI ,  NAMIKI MASAYUKI ,  SUDO TAKESHI ,  MIYAKE KAZUTOSHI

IPC分类号： C07D223/16 ,  A61K31/55 ,  A61P7/10 ,  A61P9/00 ,  A61P9/12 ,  A61P43/00

摘要： PURPOSE: To obtain a new compound having both NEP inhibiting action and ACE inhibiting action and useful for the prevention and treatment of cardiac insufficiency, hypertension, etc., and as a diuretic hypotensor, etc. CONSTITUTION: This compound is expressed by formula I (R is H or acyl; R is H or a carboxyl-protecting group; R is H, a lower alkyl, etc.; R and R are each H, a lower alkyl, acyl, etc.) or its salt, e.g. ethyl 3-amino-7- methylsulfonuylamino-2,3,4,5-tetrahydro-1H-[1] benzazepin-2-one-1-acetate. The compound of formula I can be produced by condensing a carboxylic acid derivative of formula II (R is a carboxyl-protecting group) with an amide derivative of formula II (R is acyl). The compound can increase the action of ANP on cardiac insufficiency by the inhibiting action on NEP and ACE. It can be administered by oral administration and has good metabolic stability. It has also a vasopressin-antagonistic action and further increases the effect of a treating agent for cardiac insufficiency, a diuretic or a hypotensor.

公开(公告)号：JPH0859672A

公开(公告)日：1996-03-05

申请号：JP19918094

申请日：1994-08-24

申请人： EISAI CO LTD

发明人： YONEDA NAOKI ,  OINUMA HITOSHI ,  SUDA SHINJI ,  KOTAKE MAKOTO ,  MIZUNO MASANORI ,  MIYAKE KAZUTOSHI

IPC分类号： C07D513/04 ,  A61K31/55 ,  A61P9/00 ,  A61P9/12 ,  A61P43/00 ,  C07B53/00

摘要： PURPOSE: To industrially advantageously obtain the subject compound useful as a medicine by hydroxylating L-isoleucine and coupling the product with a specific amine derivative. CONSTITUTION: This method for producing a compound of formula V is to hydroxylate L-isoleucine of formula I, subject the resultant α-hydroxycarboxylic acid of formula II to coupling with an amine derivative of formula III [R to R are each H, a lower alkyl, a (substituted)aryl or a (substituted)arylalkyl; R is a carboxylic acid-protecting group], provide an α-hydroxycarboxylic amide derivative of formula IV and, as necessary hydrolyze the resultant derivative of formula IV.

公开(公告)号：JPH0827156A

公开(公告)日：1996-01-30

申请号：JP16548194

申请日：1994-07-18

申请人： EISAI CO LTD

发明人： SUDA SHINJI ,  OINUMA HITOSHI ,  YONEDA NAOKI ,  KOTAKE MAKOTO ,  MATSUSHIMA TOMOHIRO ,  MIZUNO MASANORI ,  MIYAKE KAZUTOSHI

IPC分类号： C07D277/06 ,  A61K31/55 ,  A61P9/00 ,  A61P9/12 ,  C07D211/60 ,  C07D513/04 ,  C25B3/02

摘要： PURPOSE:To obtain an amino acid derivative useful as a therapeutic agent for cardiac insufficiency industrially and advantageously by a new method for using a hemiacetal substance prepared by electrically oxidizing a pipecolic acid derivative as an intermediate. CONSTITUTION:A pipecolic acid derivative of formula I (R to R are H, OH, etc.; R'' is a carboxylic acid-protecting group; Z is an acyl or carbamate) is electrically oxidized preferably by a method for using platinum or carbon as an electrode and tetraethylammonium perchlorate as a supporting electrolyte and injecting >=2 Faraday s/mol to the compound of formula I to give a hemiacetal substance of formula II (R forms an aldehyde equivalent with an N atom in the ring) and the objective compound is obtained from the hemiacetal substance. The hemiacetal substance is reacted with a cysteine derivative of formula III (R is H or a carboxylic acid protecting group; R and R are each H, a lower alkyl, etc.) to give a thiazolidine derivative. Then, the compound is deprotected and subjected to ring formation to give an amino acid derivative of formula IV.

公开(公告)号：JPH07224059A

公开(公告)日：1995-08-22

申请号：JP29938994

申请日：1994-12-02

申请人： EISAI CO LTD

发明人： MIYAKE KAZUTOSHI ,  MATSUKURA MASAYUKI ,  HIROSHIMA OSAMU ,  MORI NOBUYUKI ,  ISHIHARA HIROKI ,  MUSHA TAKASHI ,  HAMANO SUKEYUKI

IPC分类号： C07D235/08 ,  A61K31/00 ,  A61K31/415 ,  A61K31/4184 ,  A61K31/435 ,  A61K31/44 ,  A61K31/496 ,  A61K31/505 ,  A61P9/00 ,  A61P9/12 ,  A61P43/00 ,  C07D221/02 ,  C07D235/02 ,  C07D235/06 ,  C07D235/10 ,  C07D235/12 ,  C07D235/26 ,  C07D235/28 ,  C07D403/10 ,  C07D471/04 ,  C07D487/04

摘要： PURPOSE:To obtain a new biphenylmethane derivative useful as an agent for the treatment of hypertension and/or cardiac insufficiency and its pharmacologically permissible salt. CONSTITUTION:This biphenylmethane derivative is a compound expressed by formula I [R is H, an alkyl, a cycloalkyl, a halogenated alkyl, S-R (R is H, an alkyl, a cycloalkyl, etc.), etc.; R and R each is H, a halogen, a lower alkyl, etc.; R is H or a lower alkyl; R is group of formula II, carboxyl, etc.; R is H, a halogen, hydroxy or a lower alkoxy; A =A --A =A is CH=CH-CH =CH, etc.] or its pharmacologically permissible salt, e.g. 7-methyl-2-eta- propyl-3-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-3H-imidazo[4,5- b]pyridine. The compound of formula I wherein R is group of formula II can be produced by using a compound of formula III as a starting substance, reacting with a nitrile compound and reacting the reaction product with an azide of formula IV.

公开(公告)号：JPH0586059A

公开(公告)日：1993-04-06

申请号：JP2763292

申请日：1992-02-14

申请人： EISAI CO LTD

发明人： YAMANAKA MOTOSUKE ,  MIYAKE KAZUTOSHI ,  SUDA SHINJI ,  OHARA HIDETO ,  OGAWA TOSHIAKI

IPC分类号： A61K31/435 ,  A61K31/44 ,  A61P9/00 ,  A61P9/04 ,  C07D471/04

摘要： PURPOSE:To provide new low toxic and long-acting compounds excellent in cardiotonic effects and safety and useful as a medicine for improving heart failure. CONSTITUTION:Compounds of formula I (X is H or methyl; Y is cyano, carboxamide, H, amino or halogen; Z is H or lower alkyl; W is H or lower alkyl; R is H, lower alkyl, etc.; R is H or halogen; R is H, lower alkyl, halogen, etc.), e.g. 1,2-dihydro-6-methyl-5-(2-methylimidazo [1,2-a]pyridin-6-yl)-2-oxo-3- pyridinecarbonitrile. The compound of formula I is obtained by reacting a compound of formula II (R and R are lower alkyl) with 2-cyanoacetamide under a basic condition.

公开(公告)号：JPH07258215A

公开(公告)日：1995-10-09

申请号：JP7789294

申请日：1994-03-25

申请人： EISAI CO LTD

发明人： NEGI SHIGETO ,  MINAMI NORIO ,  MATSUKURA MASAYUKI ,  SATO KEIZO ,  MIYAKE KAZUTOSHI ,  MIZUNO MASANORI

IPC分类号： C07D213/61 ,  A61K31/44 ,  A61K31/4402 ,  A61K31/4418 ,  A61P13/02 ,  A61P15/00 ,  B01D9/02 ,  C07B57/00

摘要： PURPOSE:To perform optical resolution of 1-(4-chloropyridin-2-yl)-2-(pyridin-2-yl) ethylamine by crystallizing the amine in the presence of a salicylaldehyde derivative and an optically active s-2-benzamidocyclohexanecarboxylic acid and treating the crystal with a base. CONSTITUTION:1-(4-Chloropyrldin-2-yl)-2-(pyridin-2-yl) ethylamine (CDPA) of formula l is crystallized in the presence of a salicylaldehyde derivative of formula II (R and R each is H, a halogen or nitro) and an optically active s-2- benzamldocyclohexanecarboxylic acid of formula III and the precipitated crystal is treated with a base to obtain an optically active 1-(4-chloropyridin-2- yl)-2-(pyridin-2-yl)ethylamine of formula IV. The salicylaldehyde derivative is preferably salicylaldehyde, 3,5-dichlorosalicylaldehyde or 5-nitrosalicylaldehyde. The compound of formula IV is useful as an intermediate for a propenic acid derivative having adenosine receptor antagonistic action and effective for the prevention, treatment and improvement of renal insufficiency, etc.

公开(公告)号：JPH06329626A

公开(公告)日：1994-11-29

申请号：JP7020794

申请日：1994-03-16

申请人： EISAI CO LTD

发明人： HOSHIKO TOMONORI ,  SATO KEIZO ,  SUDA SHINJI ,  OINUMA HITOSHI ,  YONEDA NAOKI ,  MIYAKE KAZUTOSHI ,  MINAMI NORIO ,  MATSUOKA TOSHIYUKI ,  ISHIHARA HIROKI ,  MORI NOBUYUKI ,  SHINO MITSUMASA ,  SODA SHIGERU

IPC分类号： A61K31/40 ,  A61P9/00 ,  A61P9/04 ,  A61P9/12 ,  A61P43/00 ,  C07D207/08 ,  C07D207/12 ,  C07D207/14

摘要： PURPOSE:To provide a new pyrrolidine derivative having high affinity to the receptor of dopamine I and useful as an agent for treating and preventing hypertension and cardiac failures. CONSTITUTION:A compound of formula I [Y is -NH-, -(CH2)n- (n is 0-2), -S(O)p- (p is 0-2); R , R are H, OH, -SO2NR R (R , R are H, lower alkyl and acyl, and R , R may be combined to each other together with the bonded N atom to form a ring), -NR R (R , R are H, alkylsulfonyl, acyl, but a case where both R , R are H is excluded, and R , R may form a ring together with the bonded N atom); but a case where both R , R are H or OH, and a case where either of R , R is H and the other is OH are excluded] or its pharmacologically acceptable salt, e.g. (-)-trans-3-(3-aminosulfonyl-2,6-dihydroxyphenyl)methyl-4-(3,4- dihydroxyphenyl)pyrrolidine hydrochloride.

公开(公告)号：JPS62281858A

公开(公告)日：1987-12-07

申请号：JP4236887

申请日：1987-02-25

申请人： EISAI CO LTD

发明人： OINUMA HITOSHI ,  YAMANAKA MOTOSUKE ,  MIYAKE KAZUTOSHI ,  HOSHIKO TOMONORI ,  MINAMI NORIO ,  SHOJI TADAO ,  DAIKU YOSHIHARU ,  SAWADA KOHEI ,  NOMOTO KENICHI

IPC分类号： C07D473/08 ,  A61K31/40 ,  A61K31/44 ,  A61K31/4427 ,  A61K31/443 ,  A61K31/4433 ,  A61K31/445 ,  A61K31/4465 ,  A61K31/451 ,  A61K31/50 ,  A61K31/505 ,  A61P9/06 ,  C07D207/08 ,  C07D207/09 ,  C07D211/22 ,  C07D211/28 ,  C07D211/32 ,  C07D401/04 ,  C07D401/06 ,  C07D401/12 ,  C07D401/14 ,  C07D405/04 ,  C07D405/06 ,  C07D405/12 ,  C07D409/04 ,  C07D409/06 ,  C07D409/12 ,  C07D417/04 ,  C07D417/06 ,  C07D471/04 ,  C07D473/10

摘要： NEW MATERIAL:The compound of formula I {R is alkyl or tolyl; R is H, OH, alkoxy or alkyl; R is H, alkyl, alkenyl or cycloalkylalkyl; X is CO, CH2 or C(OH)H; g is 1 or 2; h is 2 or 3; Y is H, alkyl, CN, CH2COOR (R is H, alkyl, group of formula II (l is 2 or 3) or -A-B [A is (CH2)n (n is 1-5), etc.; B is group of formula III (R is H, alkyl, CN, etc.)], etc.}, its analogous derivative and its salt. EXAMPLE:4-(4-Methylsulfonylaminbenzoyl)-1-[2-(3-pyridyl)ethyl]piperidine. USE:Antiarrythmic agent. PREPARATION:A sulfonanilide derivative of formula IV is mode to react with a compound of formula V (R' is alkyl or phenyl) in the presence of a Lewis acid and the product is hydrolyzed. The obtained compound of formula VI is condensed with a compound of formula Z-Y (Y is Y except for H) to obtain the corresponding compound of formula I.

公开(公告)号：JPH07233073A

公开(公告)日：1995-09-05

申请号：JP4515094

申请日：1994-02-18

申请人： EISAI CO LTD

发明人： OINUMA HITOSHI ,  SUDA SHINJI ,  YONEDA NAOKI ,  KOTAKE MAKOTO ,  HAYASHI KENJI ,  MIYAKE KAZUTOSHI ,  MORI NOBUYUKI ,  SAITO MAMORU ,  MATSUOKA TOSHIYUKI ,  NAMIKI MASAYUKI ,  SUDO TAKESHI ,  SODA SHIGERU

IPC分类号： C07D223/16 ,  A61K31/55 ,  A61K31/554 ,  A61P9/00 ,  A61P9/12 ,  A61P13/02 ,  A61P15/00 ,  A61P43/00 ,  C07D281/10 ,  C07D471/04 ,  C07D487/04 ,  C07D495/14 ,  C07D513/04 ,  C07K5/06

摘要： PURPOSE:To obtain a vasopressin antagonist useful as a preventive and therapeutic agent for edema, ascites, renal function disorder, hepatocirrhosis, etc., having excellent vasopressin antagonism, capable of being orally administered, having no effect on vasopressin in a body. CONSTITUTION:This vasopressin antagonist comprises a compound of formula I [A is a group of the formula SR (R is H or an acyl) or a group of the formula COOR (R is a protecting group); R is H or a protecting group; R is H, an alkyl, a (substituted) (hetero)aryl, etc.; n, m and p are 0 to 2; q is 0 or 1, when q=1, Y , Y and Z are H, Q and Z form an (S or O-containing) ring, X , X , Y and Y are H or, together with carbons to which they are bonded form a (substituted) aromatic ring and when q=0, Y , Y , Z and Z , together with carbons to which they are bonded, form an (S or O-containing) aromatic ring] or its salt such as a compound of formula II as an active ingredient. A dose of the objective antagonist is preferably 0.1-1,000mg calculated as the amount of the active ingredient per adult daily.

公开(公告)号：JPH07165722A

公开(公告)日：1995-06-27

申请号：JP30335693

申请日：1993-11-09

申请人： EISAI CO LTD

发明人： OINUMA HITOSHI ,  SUDA SHINJI ,  YONEDA NAOKI ,  KOTAKE MAKOTO ,  MIYAKE KAZUTOSHI ,  MORI NOBUYUKI ,  SAITO MAMORU ,  MATSUOKA TOSHIYUKI ,  NAMIKI MASAYUKI ,  SUDO TAKESHI ,  SODA SHIGERU

IPC分类号： C12N9/99 ,  A61K31/55 ,  A61P9/00 ,  A61P9/04 ,  A61P9/12 ,  A61P43/00 ,  C07D223/16 ,  C07K5/06 ,  C07K14/81

摘要： PURPOSE:To obtain a new compound useful as a therapeutic agent for cardiac insufficiency widely usable for a patient having complication, capable of being orally administered, having excellent metabolic stability and high effectiveness. CONSTITUTION:A compound of the formula (R is II or an acyl; R is H or an alkyl; R is H, an alkyl, an alkoxy, OH, a halogen, a substitutable aryl or a substitutable heteroaryl; R is H, an alkyl, a substitutable aryl or a substitutable heteroaryl; (n) is 1 or 2; (l) and (m) are 0-2) or its pharmaceutically permissible salt, such as (RS)-3-[(2S)-acetylthio-phenylpropionylamino]-1- ethoxycarbonylmethyl-8-phenyl-1H-[1]-benzazepin-2-one. This compound has both inhibitory action on ACE and inhibitory action on NEP, enhances ANP action as a metabolic mechanism of disease state in cardiac insufficiency suppresses formation of AT-II as an exacerbation factor of cardiac insufficiency and is expected to have multiple treating effect on cardiac insufficiency.