公开(公告)号：DE3334407A1

公开(公告)日：1985-04-04

申请号：DE3334407

申请日：1983-09-23

Applicant: HOECHST AG

Inventor： GRAU ULRICH DR ,  GEIGER ROLF PROF DR ,  OBERMEIER RAINER DR

IPC: C07K14/575 ,  A61K38/00 ,  A61K38/28 ,  A61P5/00 ,  C07K1/113 ,  C07K14/62 ,  C07C103/52 ,  A61K37/26

Abstract: 1. Claims for the Contracting States : BE CH DE FR GB IT LI LU NL SE A medicament having a delayed action for the treatment of diabetes mellitus, comprising at least one insulin derivative of the formula I see diagramm : EP0137361,P16,F1 in which R**1 denotes H or H-Phe R**30 represents the radical of a neutral, genetically codable L-aminoacid whose OH group, where present, can be free or protected by a physiologically acceptable group, and R**31 denotes a physiologically acceptable neutral group blocking the carboxyl group, with the exception of des-B30 human insulin Leu**B30 -NH2 and des-B30 human insulin Gly**B30 -NH2 and des-B30 human insulin Phe**B30 -NH2 and a pharmaceutically acceptable carrier. 1. Claims for the Contracting State : AT A process for the preparation of a medicament having a delayed action for the treatment of diabetes mellitus, which comprises bringing into a suitable dosage form at least one insulin derivative of the formula I see diagramm : EP0137361,P17,F1 in which R**1 denotes H or H-Phe R**30 represents the radical of a neutral, genetically codable L-aminoacid whose OH group, where present, can be free or protected by a physiologically acceptable group, and R**31 denotes a physiologically acceptable neutral group blocking the carboxyl group, with the exception of des-B30 human insulin Leu**B30 -NH2 and des-B30 human insulin Gly**B30 -NH, and des-B30 human insulin Phe**B30 -NH2 Phe**B30 -NH2 and a pharmaceutically acceptable carrier.

公开(公告)号：GR82650B

公开(公告)日：1985-02-07

申请号：GR840173651

申请日：1984-01-30

Applicant: HOECHST AG

Inventor： GEIGER ROLF PROF DR ,  TEETZ VOLKER DR ,  LANGNER DIETRICH ,  LIRBACH HANSJORG DR ,  HONNING RAINER DR

IPC: C07D207/16 ,  C07B57/00 ,  C07D209/42 ,  C07D209/44 ,  C07D209/52 ,  C07D209/54 ,  C07K5/02 ,  C07K5/06 ,  C07K14/81

Abstract: For the Contracting States BE CH DE FR GB IT LI LU NL SE 1. A process for resolving racemic mixtures of bicyclic imino-alpha-carboxylic esters into the components of the formula Ia and Ib see diagramm : EP0115345,P15,F1 in which R represents an aliphatic radical having 1 to 6 carbon atoms, an alicyclic radical having 4 to 10 carbon atoms, an aromatic radical having 6 to 12 carbon atoms or an araliphatic radical having 7 to 15 carbon atoms, a) A and B**1 denote hydrogen, and B**2 and C together form a chain of the formula -[CH2 ]n -, with n being 3, 4, 5 or 6, or a chain of the formula -[CH2 ]p -CH=CH-[CH2 ]q -, with (p+q) being 1, 2, 3 or 4, b) C and B**2 denote hydrogen, and A and B**1 together form a chain of the formula -[CH2 ]n -, with n bein 3, 4, 5 or 6, or a chain of the formula -[CH2 ]p -CH=CH-[CH2 ]q -, with (p+q) being 1, 2, 3 or 4, or c) A and C denote hydrogen, and B**1 and B**2 together form a chain of the formula -[CH2 ]m -, with m being 4, 5, 6 or 7, by crystallization of diastereomeric salts, which process comprises preparing the salts of the racemic esters with optically active N-acylated R- or S-aminocarboxylic acids which contain a phenyl nucleus, from the series phenylalanine, phenylglycine, beta-phenyl-alpha-aminobutyric acid, 3,4-dihydroxyphenylalalin, beta-phenylserine and tyrosine, recrystallizing them form an aprotic organic solvent or an alcohol having up to 6 carbon atoms, decomposing the precipitated, optically homogenous diastereomeric salts in a manner known per se, and isolating the enantiomers of the formula Ia or Ib, respectively, and where appropriate, converting the latter into the free acids by saponification or hydrogenolysis in a manner known per se. For the Contracting State AT 1. A process for resolving racemic mixtures of bicyclic imino-alpha-carboxylic esters into the components of the formula Ia and Ib see diagramm : EP0115345,P17,F1 in which R represents an aliphatic radical having 1 to 6 carbon atoms, an alicyclic radical having 4 to 10 carbon atoms, an aromatic radical having 6 to 12 carbon atoms or an araliphatic radical having 7 to 15 carbon atoms, a) A and B**1 denote hydrogen, and B**2 and C together form a chain of the formula -[CH2 ]n -, with n being 3, 4, 5 or 6, or a chain of the formula -[CH2 ]p -CH=CH-[CH2 ]q -, with (p+q) being 1, 2, 3 or 4, b) C and B**2 denote hydrogen, and A and B**1 together form a chain of the formula -[CH2 ]n -, with n being 3, 4, 5 or 6, or a chain of the formula -[CH2 ]p -CH=CH-[CH2 ]q -, with (p+q) being 1, 2, 3 or 4, or c) A and C denote hydrogen, and B**1 and B**2 together form a chain of the formula -[CH2 ]m -, with m being 4, 5, 6 or 7, by crystallization of diastereomeric salts, which process comprises preparing the salts of the racemic esters with optically active N-acylated R- or S-aminocarboxylic acids which contain a phenyl nucleus, from the series phenylalanine, phenylglycine, beta-phenyl-alpha-aminobutyric acid, 3,4-dihydroxyphenylalanin, beta-phenylserine and tyrosine, recrystallizing them form an aprotic organic solvent or an alcohol having up to 6 carbon atoms, decomposing the precipitated, optically homogenous diastereomeric salts in a manner known per se, and isolating the enantiomers of the formulae Ia or Ib, respectively, and, where appropriate, converting the latter into the free acids by saponification or hydrogenolysis in a manner known per se.

公开(公告)号：DE3303112A1

公开(公告)日：1984-08-09

申请号：DE3303112

申请日：1983-01-31

Applicant: HOECHST AG

Inventor： GEIGER ROLF PROF DR ,  TEETZ VOLKER DR ,  LANGNER DIETRICH

IPC: A61K38/55 ,  A61P9/12 ,  A61P43/00 ,  C07B57/00 ,  C07D207/16 ,  C07D209/42 ,  C07D209/44 ,  C07D209/52 ,  C07D209/54 ,  C07K1/14 ,  C07K5/02 ,  C07K5/06 ,  C07K5/065 ,  C07K14/81

Abstract: The invention relates to a process for resolving racemic mixtures of bicyclic imino- alpha -carboxylic esters into the components by crystallization of diastereomeric salts, which comprises preparing the salts of the racemic esters with optically active N-acylated R- or S-amino carboxylic acids which contain a phenyl nucleus, recrystallizing them from an organic solvent, decomposing the precipitated, optically homogeneous diastereomeric salts in a manner known per se, and isolating the enantiomers and, where appropriate, converting the latter into the free acids by hydrolysis in a manner known per se. The invention also relates to optically pure compounds of the formula and to diastereomeric salts of these compounds, in which two of the radicals A, B1, B2 and C form a carbon chain and the others denote hydrogen, and R is an esterifying group.

公开(公告)号：DE3211676A1

公开(公告)日：1983-10-06

申请号：DE3211676

申请日：1982-03-30

Applicant: HOECHST AG

Inventor： HENNING RAINER DR ,  URBACH HANSJOERG DR ,  GEIGER ROLF PROF DR ,  TEETZ VOLKER DR ,  BECKER REINHARD DR

IPC: A61K31/40 ,  A61K31/403 ,  A61K31/4035 ,  A61K31/405 ,  A61K38/00 ,  A61P9/12 ,  C07D209/44 ,  C07D209/52 ,  C07D217/24 ,  C07K1/113 ,  C07K5/02 ,  C07K5/06 ,  C07K14/81 ,  C07D207/34 ,  C07D401/06 ,  C07D401/14 ,  C07D403/06 ,  C07D403/14 ,  C07D405/06 ,  C07D405/14 ,  C07D217/26 ,  C07D207/325

Abstract: Compounds of the formula I in which n = 1, 2 or 3, R is hydrogen, unsubstituted or amino-, acylamino- or benzoylamino-substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl or partially hydrogenated aryl each of which can be substituted by alkyl, alkoxy or halogen, arylalkyl which as defined above can be substituted in the aryl radical, a mono- or bicyclic heterocyclic radical having up to 10 ring atoms, 1 to 2 ring atoms of which can be sulphur or oxygen atoms and/or 1 to 4 ring atoms of which represent nitrogen atoms or an amino acid side chain, R is hydrogen, alkyl, alkenyl or arylalkyl, Y is hydrogen or hydroxyl, Z is hydrogen or Y and Z together are oxygen and X is alkyl, alkenyl, cycloalkyl, aryl which can be mono-, di- or trisubstituted by alkyl, alkoxy, hydroxyl, halogen, nitro, amino, alkylamino, dialkylamino or methylenedioxy, or indol-3-yl, a process for their preparation, agents containing them, their use as well as intermediates and a process for their preparation.

公开(公告)号：DE3118191A1

公开(公告)日：1982-11-25

申请号：DE3118191

申请日：1981-05-08

Applicant: HOECHST AG

Inventor： GEIGER ROLF PROF DR ,  TEETZ VOLKER DR ,  HENNING RAINER DR ,  URBACH HANSJOERG DR ,  SCHOELKENS BERNWARD DR

IPC: A61K38/00 ,  C07D217/26 ,  C07K5/078 ,  A61K31/40 ,  A61K31/47 ,  C07D209/42

Abstract: The invention relates to compounds of the formula I in which n denotes 0 or 1, R1 and R2, which can be identical or different and also can in turn be substituted, each denotes - alkyl or alkenyl, having up to 6 C-atoms, - cycloalkyl or cycloalkenyl each having 5-7 C-atoms, or aralkyl having 7-12 C-atoms, - aryl or partly hydrogenated aryl having 6-10 C-atoms, - aralkyl having 7-14 C-atoms, - a mono- or bicyclic heterocycle having 5-7 or 8-10 members respectively, of which 1-2 are -S- or -O- and/or up to 4 are -N- atoms, and COOR3 is a carboxyl or carboxylic acid ester group, which can be used as medicines, in particular as antihypertensives, a process for their preparation, compositions containing them, and their use.

公开(公告)号：CZ9104162A3

公开(公告)日：1993-09-15

申请号：CS416291

申请日：1991-12-30

Applicant: HOECHST AG

Inventor： TEETZ VOLKER DR ,  GEIGER ROLF PROF DR ,  URBACH HANSJORG DR ,  BECKER REINHARD DR ,  SCHOLKENS BERNWARD DR

IPC: C07C227/08 ,  A61K31/40 ,  A61K31/403 ,  A61K38/00 ,  A61P9/12 ,  C07C227/10 ,  C07C227/16 ,  C07C229/36 ,  C07C237/06 ,  C07D209/52 ,  C07D451/04 ,  C07K5/02 ,  C07K5/06

CPC classification number: C07K5/0222 ,  A61K38/00 ,  C07D209/52

公开(公告)号：DE3783657D1

公开(公告)日：1993-03-04

申请号：DE3783657

申请日：1987-06-05

Applicant: HOECHST AG

Inventor： KOENIG WOLFGANG DR ,  BREIPOHL GERHARD DR ,  GEIGER ROLF PROF DR ,  KNOLLE JOCHEN DR ,  HROPOT MAX DR

IPC: C07K5/10 ,  A61K38/00 ,  A61P7/10 ,  C07K1/06 ,  C07K5/02 ,  C07K5/083 ,  C07K5/11 ,  C07K5/117 ,  C07K7/06 ,  C07K7/64 ,  C07K14/58 ,  A61K37/02

Abstract: Peptide derivs. of formula (I) and their salts are new: R2 = H or NH(A)nR; R3 = NH2, guanidino or mono- or di(1-3C alkyl)amino; m = 1-6; A = NH-CR4R5-CO; R = H, 1-6C alkanoyl, 7-11C aroyl (opt. mono- or disubstd. by 1-4C alkyl, 1-4C alkoxy, 1-4C alkylthio, halogen, CONH2, 2-5C alkoxycarbonyl and/or SO2NH2 or monosubstd. by methylenedioxy), (5-7C)cycloalkyl(1-3C)alkanoyl or (6-14C)aryl(1-3C)alkanoyl, where one CH2 gp. in R may be replaced by O or S; n = 0 or 1; R4 and R5 = H, 1-6C alkyl or 7-11C aralkanoyl; L = Pro, D-Pro or NHCH(R6)CO; R6= (a) 1-6C alkyl opt. monosubstd. by OH, 1-6C alkoxy, 2-7C alkoxycarbonyl, CONH2 or NHR, provided that R is not H, (b) 7-11C aralkyl opt. monosubstd. in the ring by 1-6C alkoxy, or (c) indol-3-ylmethyl; M = Pro, D-Pro or NHCH(R7)CO; R7 is as defined for R6; B = NHCH((CH2)mR3)CO; R8, R6 in which any CH, CH2 or CH3 gps. beta to NH are opt. monohydroxylated; R9 = H; or R8+R9 = (CH2)3 or (CH2)4; R1 = H, OH, 1-6C alkoxy, COOR10 or CONR10R11; or R1+R = CO; R10 and R11 = H, 1-6C alkyl or 7-11C aralkyl, or NR10R11 = pyrrolidino, piperidino or morpholino.

公开(公告)号：CS9104094A3

公开(公告)日：1992-05-13

申请号：CS409491

申请日：1991-12-27

Applicant: HOECHST AG

Inventor： GEIGER ROLF PROF DR ,  TEETZ VOLKER DR ,  URBACH HANSJORG DR ,  SCHOLKENS BERNWARD DR ,  HENNING RAINER DR

IPC: A61K38/00 ,  A61K31/40 ,  A61K31/403 ,  A61K31/404 ,  A61K31/47 ,  A61K31/472 ,  A61P9/12 ,  C07D209/42 ,  C07D217/26 ,  C07D233/64 ,  C07D241/20 ,  C07D307/54 ,  C07D309/10 ,  C07D317/66 ,  C07D333/24 ,  C07D335/02 ,  C07D339/08 ,  C07D401/06 ,  C07D401/12 ,  C07D403/06 ,  C07D403/12 ,  C07D405/12 ,  C07D409/12 ,  C07D413/12 ,  C07D417/12 ,  C07K1/02 ,  C07K1/113 ,  C07K5/02 ,  C07K5/06 ,  C07K5/062 ,  C07K5/065 ,  C07K5/078 ,  C07K14/81 ,  C07D405/06

CPC classification number: C07K5/0222 ,  A61K38/00 ,  C07D217/26

公开(公告)号：DE3280196D1

公开(公告)日：1990-07-26

申请号：DE3280196

申请日：1982-11-02

Applicant: HOECHST AG

Inventor： TEETZ VOLKER DR ,  GEIGER ROLF PROF DR ,  URBACH HANSJOERG DR ,  BECKER REINHARD DR ,  SCHOELKENS BERNWARD DR

IPC: C07C227/08 ,  A61K31/40 ,  A61K31/403 ,  A61K38/00 ,  A61P9/12 ,  C07C227/10 ,  C07C227/16 ,  C07C229/28 ,  C07C229/36 ,  C07C237/06 ,  C07D209/52 ,  C07D451/04 ,  C07K5/02 ,  C07K5/06

Abstract: Compounds of the formula I (I) in which the carboxyl group on carbon atom 3 is orientated in the endo-position relative to the bicyclic ring system of cis-configuration, and in which R1 denotes hydrogen, allyl, vinyl or a side-chain of a naturally occurring alpha -aminoacid, which may be protected, R2 denotes hydrogen, alkyl, alkenyl or aralkyl, Y denotes hydrogen or hydroxyl and Z denotes hydrogen, or Y and Z together denote oxygen, and X denotes alkyl, alkenyl or cycloalkyl, or aryl which is optionally mono-, di- or tri-substituted by alkyl, alkoxy, hydroxyl, halogen, nitro, amino, alkylamino, dialkylamino or methylenedioxy, or denotes indol-3-yl, a process for their preparation, agents containing these compounds and their use.

公开(公告)号：DE3482470D1

公开(公告)日：1990-07-19

申请号：DE3482470

申请日：1984-09-11

Applicant: HOECHST AG

Inventor： OBERMEIER RAINER DR ,  GEIGER ROLF PROF DR ,  GRAU ULRICH DR

IPC: C07K14/575 ,  A61K38/00 ,  A61K38/28 ,  A61P5/00 ,  C07K14/62 ,  C12P21/02 ,  C07K7/40 ,  A61K37/26

Abstract: 1. A process for the preparation of an insulin derivative of the formula I, see diagramm : EP0140084,P8,F1 in which R**1 denotes H or H-Phe, a) R**30 represents the radical of a neutral, naturally occurring L-aminoacid and R**31 represents a physiologically acceptable organic group of basic character, comprising up to 3 alpha-aminoacids in which the terminal carboxyl function is in the free form, or b) R**30 represents the radical of a basic, naturally occurring L-aminoacid and R**31 represents a physiologically acceptable organic group of neutral or basic character, comprising up to 3 alpha-aminoacids in which the terminal carboxyl function is in the free from and which insuline derivative has an isoelectric point above 5.8, which comprises reacting an insulin of the formula I in which R**1 denotes H or H-Phe, R**30 denotes the radical of a genetically codable L-aminoacid and R**31 represents OH or a protective group of the carboxy function, with a peptide of the formula III in which a) R**30 represents the radical of a neutral, naturally occurring L-aminoacid and R**31 represents a physiologically acceptable organic group of basic character, comprising up to 3 alpha-aminoacids in which the terminal carboxyl function is in the free from, or b) R**30 represents the radical of a basic, naturally occurring L-aminoacid and R**31 represents a physiologically acceptable organic group of neutral or basic character, comprising up to 3 alpha-aminoacids in which the terminal carboxyl function is in the free form, in the presence of trypsin-like endopeptidase in water, if appropriate with the addition or a suitable organic solvent at a pH value below the isoelectric point of the insulin, and splitting off any protective groups introduced into the side chains.