公开(公告)号：EP0974592A4

公开(公告)日：2001-09-19

申请号：EP96931249

申请日：1996-09-18

Applicant: FUJISAWA PHARMACEUTICAL CO

Inventor： KAGARA KOOJI ,  KAWAI NOBUTAKA ,  NAKAMURA TAKASHI ,  IEDA SHIGERU ,  MACHIYA KOJI ,  OHIGASHI ATSUSHI

IPC: C07D471/04 ,  C07B57/00 ,  C07M7/00

CPC classification number: C07D471/04 ,  Y02P20/55

Abstract: A process for producing pyridiondole derivatives represented by general formula (III) or their salts (wherein R1 represents hydrogen, lower alkyl or lower alkenyl; R2 represents hydrogen, lower alkyl or halogeno; and R3 represents optionally substituted imidazolyl), which comprises reacting a compound represented by general formula (I) or its salt (wherein R?1 and R2¿ are each as defined above) with a compound represented by general formula (II) or its salt (wherein R3a represents optionally substituted imidazolyl having an imino protecting group; and X represents halogeno), followed by a reaction for eliminating the imino protecting group); and a process for producing optically active pyridoindole derivatives represented by general formula (IV) or their salts: which comprises reacting a racemic mixture of the pyridoindole derivative represented by general formula (III) or its salt with (1R)-(-)-10-camphorsulfonic acid.

Abstract translation: 通式（Ⅲ）代表的吡啶并吲哚衍生物或其盐（其中R1代表氢，低级烷基或低级链烯基; R2代表氢，低级烷基或卤代; R3代表任意取代的咪唑基）的制备方法，该方法包括使化合物 （I）表示的化合物或其盐（式中，R 1和R 2分别与上述相同）表示的化合物与通式（II）表示的化合物或其盐（式中，R 3a表示任选具有亚氨基保护基的咪唑基。 X代表卤代），然后进行消除亚氨基保护基的反应）。 （IV）表示的光学活性吡啶并吲哚衍生物或其盐的制造方法，其特征在于，使通式（III）表示的吡啶并吲哚衍生物或其盐的外消旋混合物与（1R） - （ - ） - 樟脑磺酸。

公开(公告)号：EP0648747A4

公开(公告)日：1996-07-31

申请号：EP93913599

申请日：1993-06-28

Applicant: FUJISAWA PHARMACEUTICAL CO

Inventor： KAGARA KOOJI ,  KAWAI NOBUTAKA ,  MACHIYA KOJI ,  FURUTERA TETSUO ,  NAKAMURA TAKASHI ,  OMORI HIROKI

IPC: C07D233/54 ,  C07D233/64

CPC classification number: C07D233/64 ,  C07D233/54 ,  Y02P20/55

Abstract: A novel intermediate (II) for use in synthesis which is useful for the production of an amino acid derivative (I) having a renin-inhibiting activity, and a process for producing the derivative (I) which involves the reaction step represented by the figure, wherein R1 represents lower alkyl, etc., which may be substituted by -NR?7-CO-NR8R9¿ (wherein R7 represents hydrogen or lower alkyl, and R?8 and R9¿ may be combined together with the adjacent nitrogen atom to represent an optionally substituted heterocyclic group), etc.; R2 represents hydrogen, lower alkyl, etc.; R3 represents hydrogen or lower alkyl; R4 represents hydrogen or an N-protecting group; R5 represents hydrogen or a carboxyl-protecting group; and R10 represents lower alkyl. This process, proceeding via the intermediate (II), is industrially advantageous because the final product (I) can be obtained in a high yield from an inexpensive starting material as compared with the conventional processes and hence the production cost can be reduced remarkably.

公开(公告)号：HUT70049A

公开(公告)日：1995-09-28

申请号：HU9403793

申请日：1993-06-28

Applicant: FUJISAWA PHARMACEUTICAL CO

Inventor： KAWAI NOBUTAKA ,  KAGARA KOOJI ,  MACHIYA KOJI ,  FURUTERA TETSUO ,  NAKAMURA TAKASHI ,  OMORI HIROKI

IPC: C07D233/54 ,  C07D233/64 ,  C07D413/12

Abstract: A novel intermediate (II) for use in synthesis which is useful for the production of an amino acid derivative (I) having a renin-inhibiting activity, and a process for producing the derivative (I) which involves the reaction step represented by the figure, wherein R represents lower alkyl, etc., which may be substituted by -NR -CO-NR R (wherein R represents hydrogen or lower alkyl, and R and R may be combined together with the adjacent nitrogen atom to represent an optionally substituted heterocyclic group), etc.; R represents hydrogen, lower alkyl, etc., R represents hydrogen or lower alkyl; R represents hydrogen or an N-protecting group; R represents hydrogen or a carboxyl-protecting group; and R represents lower alkyl. This process, proceeding via the intermediate (II), is industrially advantageous because the final product (I) can be obtained in a high yield from an inexpensive starting material as compared with the conventional processes and hence the production cost can be reduced remarkably.

公开(公告)号：HU9403793D0

公开(公告)日：1995-02-28

申请号：HU9403793

申请日：1993-06-28

Applicant: FUJISAWA PHARMACEUTICAL CO

Inventor： KAWAI NOBUTAKA ,  KAGARA KOOJI ,  MACHIYA KOJI ,  FURUTERA TETSUO ,  NAKAMURA TAKASHI ,  OMORI HIROKI

IPC: C07D233/54 ,  C07D233/64

Abstract: A novel intermediate (II) for use in synthesis which is useful for the production of an amino acid derivative (I) having a renin-inhibiting activity, and a process for producing the derivative (I) which involves the reaction step represented by the figure, wherein R represents lower alkyl, etc., which may be substituted by -NR -CO-NR R (wherein R represents hydrogen or lower alkyl, and R and R may be combined together with the adjacent nitrogen atom to represent an optionally substituted heterocyclic group), etc.; R represents hydrogen, lower alkyl, etc., R represents hydrogen or lower alkyl; R represents hydrogen or an N-protecting group; R represents hydrogen or a carboxyl-protecting group; and R represents lower alkyl. This process, proceeding via the intermediate (II), is industrially advantageous because the final product (I) can be obtained in a high yield from an inexpensive starting material as compared with the conventional processes and hence the production cost can be reduced remarkably.

公开(公告)号：AU7000696A

公开(公告)日：1997-04-09

申请号：AU7000696

申请日：1996-09-18

Applicant: FUJISAWA PHARMACEUTICAL CO

Inventor： KAGARA KOOJI ,  KAWAI NOBUTAKA ,  NAKAMURA TAKASHI ,  IEDA SHIGERU ,  MACHIYA KOJI ,  OHIGASHI ATSUSHI

IPC: C07D471/04 ,  C07B57/00

Abstract: A process for producing pyridiondole derivatives represented by general formula (III) or their salts (wherein R represents hydrogen, lower alkyl or lower alkenyl; R represents hydrogen, lower alkyl or halogeno; and R represents optionally substituted imidazolyl), which comprises reacting a compound represented by general formula (I) or its salt (wherein R and R are each as defined above) with a compound represented by general formula (II) or its salt (wherein R a represents optionally substituted imidazolyl having an imino protecting group; and X represents halogeno), followed by a reaction for eliminating the imino protecting group); and a process for producing optically active pyridoindole derivatives represented by general formula (IV) or their salts: which comprises reacting a racemic mixture of the pyridoindole derivative represented by general formula (III) or its salt with (1R)-(-)-10-camphorsulfonic acid.

公开(公告)号：JP2000001486A

公开(公告)日：2000-01-07

申请号：JP12937699

申请日：1999-05-11

Applicant: FUJISAWA PHARMACEUTICAL CO

Inventor： TAKENAKA KOHEI ,  INOUE ZENICHI ,  AKAHA ATSUSHI ,  MACHITANI KOJI ,  NAKAMURA TAKASHI

IPC: C07D333/28 ,  A61K31/00 ,  A61K31/165 ,  A61K31/166 ,  A61K31/38 ,  A61K31/381 ,  A61P3/00 ,  A61P3/06 ,  A61P9/00 ,  A61P9/10 ,  A61P13/00 ,  A61P13/12 ,  A61P43/00

Abstract: PROBLEM TO BE SOLVED: To obtain a new compound having strong inhibiting action on Na+/H+ exchange in a human or animal cell and having further high effect as a medicine such as preventing and therapeutic agent for cardiovascular diseases. SOLUTION: This compound is represented by formula I [R1 is a group of formula II or III (R5 and R6 are each H, a lower alkyl or the like; X is carbonyl or sulfonyl); R2 is an arylyl or heterocycle; (n) is 1-6] and its salt, e.g. [3-(2,5-dichlorothiophen-3-yl)-5-[2-(methylaminoethyl)- aminocarbonyl]benzoyl]guanidine dihydrochloride. The compound of formula I is obtained by reacting a compound of formula IV, its derivative or a salt thereof with a compound of formula V, its derivative or a salt thereof. The reaction is usually carried out in water and an organic solvent under cooling or under heating. Furthermore, when the compound of formula V is used in a form of a free acid or its salt, the reaction is preferably carried out in the presence of a condensing agent.

公开(公告)号：JPH06172318A

公开(公告)日：1994-06-21

申请号：JP32348392

申请日：1992-12-02

Applicant: FUJISAWA PHARMACEUTICAL CO

Inventor： KAGARA KOUJI ,  KAWAI NOBUTAKA ,  MACHITANI KOJI ,  KODERA TETSUO ,  NAKAMURA TAKASHI ,  OMORI HIROKI

IPC: A61K31/415 ,  A61P9/04 ,  A61P35/00 ,  A61P43/00 ,  C07D233/64

Abstract: PURPOSE:To industrially advantageously produce a amino acid derivative having a renin-inhibiting activity in high yield from inexpensive starting raw materials through a new synthetic intermediate. CONSTITUTION:The compound of formula I [R is alkyl or aryl which may be substituted with one or more substituents selected from acyl, OH, alkoxy, aryl, alkylthio, and group of formula II (R is H, acyl; R is H, alkyl), amino which may be substituted with alkyl or acyl; R and R form a substitutable heterocyclic group together with the adjacent nitrogen atom; R , R are H, alkyl; R is H, N-protected group; R'' is H, carboxy-protecting group], e.g. Nalpha-[2(S)-[N-methyl-N-[2-{N-(morpholinocarbonyl)-N- methylamino}ethyl]aminocarbonyloxy]-3-phenylpropionyl]-N -trityl-L- histidine. The compound is produced by reacting a compound of formula III with a compound of formula IV, and can be converted into an amino acid derivative of formula VI by reacting the compound of formula I with a compound of formula V (R is alkyl) and, if necessary, releasing the N-protecting group.

公开(公告)号：JPH0616645A

公开(公告)日：1994-01-25

申请号：JP17580692

申请日：1992-07-02

Applicant: FUJISAWA PHARMACEUTICAL CO

Inventor： KAGARA KOUJI ,  KAWAI NOBUTAKA ,  MACHITANI KOJI ,  KODERA TETSUO ,  NAKAMURA TAKASHI

IPC: C07D233/64

Abstract: PURPOSE:To obtain a new synthetic intermediate useful for producing an amino acid derivative having renin inhibiting activity in good yield at a reduced cost. CONSTITUTION:The compound of formula I [R is lower alkyl which may be substituted with a substituent group selected from acyl, OH, lower alkoxy, aryl, lower alkylthio and formula II (R is H or acyl; R is H or lower alkyl), aryl or amino which may be substituted with lower alkyl or acyl; R is H or lower alkyl or R and R , together with the adjacent N atom, form a heterocyclic group which may be substituted (with alkyl, hydroxyalkyl, acyl, etc.); R is H or lower alkyl; R is H or N-protecting group; R is H or carboxy- protecting group]. This compound is obtained by reacting a compound of formula III with a compound of formula IV. The objective amino acid derivative of formula VI is prepared by reacting the compound of formula I or a reactive derivative at the carboxyl group thereof with a compound of formula V (R is lower alkyl) and, as necessary, releasing the N-protecting group.

公开(公告)号：MX9303933A

公开(公告)日：1994-02-28

申请号：MX9303933

申请日：1993-06-30

Applicant: FUJISAWA PHARMACEUTICAL CO

Inventor： FURUTERA TETSUO ,  NAKAMURA TAKASHI ,  OMORI HIROKI ,  KAGARA KOOJI ,  KAWAI NOBUTAKA ,  MACHIVA KOJI

IPC: C07D233/54 ,  C07D233/64 ,  C07C229/00

Abstract: A novel intermediate (II) for use in synthesis which is useful for the production of an amino acid derivative (I) having a renin-inhibiting activity, and a process for producing the derivative (I) which involves the reaction step represented by the figure, wherein R represents lower alkyl, etc., which may be substituted by -NR -CO-NR R (wherein R represents hydrogen or lower alkyl, and R and R may be combined together with the adjacent nitrogen atom to represent an optionally substituted heterocyclic group), etc.; R represents hydrogen, lower alkyl, etc., R represents hydrogen or lower alkyl; R represents hydrogen or an N-protecting group; R represents hydrogen or a carboxyl-protecting group; and R represents lower alkyl. This process, proceeding via the intermediate (II), is industrially advantageous because the final product (I) can be obtained in a high yield from an inexpensive starting material as compared with the conventional processes and hence the production cost can be reduced remarkably.

公开(公告)号：CA2139362A1

公开(公告)日：1994-01-20

申请号：CA2139362

申请日：1993-06-28

Applicant: FUJISAWA PHARMACEUTICAL CO

Inventor： KAGARA KOOJI ,  KAWAI NOBUTAKA ,  MACHIYA KOJI ,  FURUTERA TETSUO ,  NAKAMURA TAKASHI ,  OMORI HIROKI

IPC: C07D233/54 ,  C07D233/64 ,  C07D413/12 ,  C07D401/12 ,  C07D403/12 ,  C07D417/12

Abstract: A novel synthetic intermediate (II) useful for preparation of compound (I) possessing renin-inhibitory activity, and processes for preparing the compound (I) using said intermediate (II), which is schematically shown in the following: + (II) (III) Elimination of the N-protective group if necessary (I) wherein R1 is lower alkyl which may be substituted by a group of the formula -N(R7)-CO-N(R8)(R9) (wherein R7 is hydrogen or lower alkyl, and R8 and R9 together with the attached nitrogen atom form a heterocyclic group optionally substituted), or the like; R2 is hydrogen, lower alkyl, or the like; R3 is hydrogen or lower alkyl; R4 is hydrogen or an N-protective group; R5 is hydrogen or a carboxy-protective group; and R10 is lower alkyl. The process via the intermediate (II) of the present invention is industrially advantageous in that it affords the final product (I) at high yields from cheaper starting materials as compared with the conventional methods, and that a remarkable reduction of preparation cost can be achieved.