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WO1992010510A1 - Peptides inhibiteurs de la renine contenant de la dithiolanoglycine et de la dithianoglycine, leur procede de production et leur utilisation dans des medicaments - Google Patents

Peptides inhibiteurs de la renine contenant de la dithiolanoglycine et de la dithianoglycine, leur procede de production et leur utilisation dans des medicaments Download PDF

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Publication number
WO1992010510A1
WO1992010510A1 PCT/EP1991/002301 EP9102301W WO9210510A1 WO 1992010510 A1 WO1992010510 A1 WO 1992010510A1 EP 9102301 W EP9102301 W EP 9102301W WO 9210510 A1 WO9210510 A1 WO 9210510A1
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Prior art keywords
carbon atoms
chain
straight
branched alkyl
hydrogen
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PCT/EP1991/002301
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German (de)
English (en)
Inventor
Wolfgang Bender
Gunter Schmidt
Andreas Knorr
Johannes-Peter Stasch
Christian Laue
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Bayer Aktiengesellschaft
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Priority to JP4500345A priority Critical patent/JPH06503316A/ja
Publication of WO1992010510A1 publication Critical patent/WO1992010510A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to renin inhibitory peptides containing dithiolano and dithianoglycin, processes for their preparation and their use in
  • Renin is a proteolytic enzyme that is predominantly produced by the kidneys and secreted into the plasma. It is known that renin cleaves the decapeptide angiotensin I from the angiotensinogen in vivo. Angiotensin I in turn is broken down in the lungs, kidneys or other tissues to form the blood pressure-effective octapeptide angiotensin II. The different effects of angiotensin II such as vasoconstriction, Na + retention in the kidney,
  • renin-angiotensin system can be pharmacologically manipulated by inhibiting the activity of renin or the angiotensin conversion enzyme (ACE) and by blocking angiotensin II receptors.
  • ACE angiotensin conversion enzyme
  • a more recent approach is to intervene in the renin-angiotensin cascade at an earlier point in time, namely by inhibiting the highly specific peptidase renin.
  • renin-specific antibodies renin-specific antibodies
  • phospholipids peptides with the N-terminal sequence of prorenin
  • synthetic peptides as substrate analogues
  • modified peptides renin-specific antibodies, phospholipids, peptides with the N-terminal sequence of prorenin, synthetic peptides as substrate analogues and modified peptides.
  • peptides have now been found in which the usual amino acid residue -His (histidine) has been replaced by a 1,3-dithiolane or dithiane residue and which have a renin-inhibitory effect.
  • the invention relates to peptides of the general formula (I)
  • R 1 - represents hydrogen or
  • - represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by aryl having 6 to 10 carbon atoms, which in turn can be substituted by halogen or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms
  • a, a ', b, d and e are the same or different and represent the number 0, 1 or 2
  • h represents the number 0, 1 or 2
  • g di ⁇ represents 1, 2, 3, 4, 5 or 6
  • i is the number 0, 1, 2, 3 or 4
  • c and f are identical or different and are a number 0, 1, 2 or 3
  • R 4 and R 4 are identical or different and are phenyl, quinolyl, indolyl, naphthyl, pyridyl or pyridyl N-oxide,
  • R 5 , R 11 and R 18 are the same or different and
  • Aryl having 6 to 10 carbon atoms which is optionally substituted by halogen or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms
  • R 6 denotes straight-chain or branched alkyl having up to 8 carbon atoms
  • R 7 halogen or straight-chain or branched
  • Alkyl or alkoxy each having up to 6 carbon atoms, m is the —NH group, an oxygen atom, a sulfur atom or the SO 2 group,
  • R 8 and R 9 are the same or different and are hydrogen or straight-chain or branched
  • R 10 is the rest of the formula (CH 3 ) 3 C-CO-CH 2 - or
  • R 12 means via N-linked morpholine or piperidinyl
  • R 13 means aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms or
  • R 19 - is a radical of the formula R 19 -S- (O) 1 - or R 20 -CO-, in which R 19 means morpholino or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by aryl having 6 to 10 carbon atoms
  • 1 means a number 0, 1 or 2
  • R 20 represents morpholino, pyrrolidinyl or the rest or one
  • R 21 and R 22 are the same or different and are hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which may be repeated several times by hydroxyl, phenoxy, a 5- or 6-membered saturated or unsaturated heterocycle with up to 3 heteroatoms from the series N, O or S, alkoxy with up to 6 carbon atoms, (C 1 -C 6 ) dialkylamino, quaternary ammonium salts or by a radical of the formula
  • Carbon atoms mean or
  • R 21 and R 22 together with the nitrogen atom are a 5- to 7-membered, saturated or unsaturated
  • R 14 and R 15 are the same or different and
  • R 16 straight-chain or branched alkoxy having up to 8 carbon atoms or the group
  • R 21 ' and R 22' have the meaning of R 21 and R 22 given above and is the same or different with this,
  • R 17 represents hydrogen or the group -NR 23 R 24 , wherein
  • R 23 and R 24 are the same or different and are hydrogen, an amino protecting group or
  • W represents a radical of the formula R 25 -SO 2 , R 22 R 21 N-SO 2 or R 22 R 21 N-CO, in which
  • R 25 denotes straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by aryl having 6 to 10 carbon atoms or a radical of the formula
  • R 21 and R 22 have the meaning given above
  • R 2 - represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, or in the event that A and B simultaneously represent a bond
  • n - stands for the number 1 or 2 «
  • R 3 - represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms or
  • Renin inhibitor chemistry is the usual mimic of the Leu-Val cleavage site in angiotensinogen, ⁇ - depending on the meaning of the substituent X, is either absent or
  • R 26 is hydrogen, straight-chain or branched alkyl, alkoxy or alkoxy- (C 1 -C 6 ) -alkenyl, each with up to to 20 carbon atoms, which are optionally substituted by pyridyl or aryl having 6 to 10 carbon atoms, which in turn can be substituted by straight-chain or branched alkyl or alkoxy having up to 10 carbon atoms, or R 26 denotes the group -NR 32 R 33 , in which
  • R 32 and R 33 are the same or different and
  • Hydrogen, straight-chain or branched alkyl with up to 8 carbon atoms means that is optionally substituted by 5- to 7-membered saturated or unsaturated heterocycle with up to 3 heteroatoms from the series N, S or O, or R 32 or R 33 is cycloalkyl with 3 to 8 carbon atoms, or
  • Form N, S or O or R 26 denotes adamantyl or aryl having 6 to 10 carbon atoms, the latter optionally being substituted by alkyl or alkoxy each having up to 10 carbon atoms
  • R 27 , R 28 and R 29 are identical or different and are hydrogen, Cycloalkyl with 3 to 8 carbon atoms or straight-chain or branched alkyl or alkoxy each with up to 8 carbon atoms, which may be protected several times by hydroxy
  • R 30 is hydrogen, straight-chain or branched
  • R 30 is a 5- to 7-membered saturated heterocycle bonded via N and having up to 3 heteroatoms from the series N, O or S
  • R 31 is hydrogen or straight-chain or branched alkyl having up to 20 carbon atoms, which is optionally substituted by phenyl, which in turn can be substituted by alkoxycarbonyl having up to 8 carbon atoms, halogen or by straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms or
  • R 32 and R 33 are identical or different and are hydrogen, phenyl or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by phenyl, and their physiologically acceptable salts with the proviso that in the event that X is for the rest
  • R 3 may not mean cyclohexyl.
  • Formula (I) have several asymmetric carbon atoms. You can independently in the D or L-shape.
  • the invention includes the optical antipodes as well as the isomer mixtures or racemates.
  • the amino acid residues are preferably present independently of one another in the optically pure, preferably in the L-form.
  • the compounds of the general formula (I) according to the invention can be present in the form of their salts. These can be salts of the compounds according to the invention with inorganic or organic acids or bases.
  • the acid addition products preferably include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, or with carboxylic acids such as acetic acid, propionic acid, oxalic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, adipic acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, Lactic acid,
  • Ascorbic acid Ascorbic acid, salicylic acid, 2-acetoxybenzoic acid, nicotinic acid, isonicotinic acid, or sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalene-2-sulfonic acid or naphthalenedisulfonic acid.
  • Salts of the compounds according to the invention with salt-forming groups can be prepared in a manner known per se, for example by reacting the compounds according to the invention which contain acidic groups with corresponding bases or by reacting the compounds according to the invention which contain basic groups with corresponding acids, in each case preferably with the bases or acids listed above.
  • the amino protective groups customary in peptide chemistry are suitable as the amino protective group.
  • benzyloxycarbonyl 4-bromobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, dichlorobenzyloxycarbonyl, 3,4-dimethyxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzylyloxycarbonyl, nitro-4-benzylyloxycarbonyl 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, isopentoxycarbonyl, hexoxycarbonyl, cyclohexoxycarbonyl, octy
  • amino protecting groups are benzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, propoxycarbonyl, propoxycarbonyl, propoxycarbonyl, propoxycarbonyl, propoxycarbonyl, propoxycarbonyl, propoxycarbonyl, propoxycarbonyl, propoxycarbonyl, propoxycarbonyl, propoxycarbonyl, propoxycarbonyl, propoxycarbonyl, propoxycarbonyl, propoxycarbonyl, propoxycarbonyl, propoxycarbonyl, propoxycarbonyl tert-butoxycarbonyl, cyclohexoxycarbonyl, hexoxycarbonyl, octoxycarbonyl,
  • natural amino acids includes, for example, ⁇ lanin (Ala), aspartic acid (Asp), asparagine (Asn), glutamic acid (Glu), glutamine (Gln), histidine (His), leucine (Leu), methionine (Met), proline (Pro ),
  • Phenylalanine (Phe), serine (Ser), tryptophan (Trp) and
  • unnatural amino acids includes pF-, p-Cl-, p-nitro and pJ substituted phenylalanine, 4-C 1 -C 6 -alkoxyphenylalanine, in particular 4-methoxyphenylalanine, homophenylalanine, O-benzylserine and 1- or 2-naphthylalanine detected.
  • substituent X which together with the rest stands for a mimic of the Leu-Val cleavage site in angiotensinogen which is common in renin inhibitor chemistry, the usual residues which are known, for example, from patent literature such as EP 0 365 992 or from scientific publications are suitable. I. Patents
  • EP 0 310 072 EP 0 310 073; EP 313 847; EP 332 008;
  • EP 0 377-139A EP 0 374 098-A; EP 300 189;
  • Preferred compounds of the general formula (I) are those in which A, B, D and E are the same or different and
  • proline Pro
  • leu leu
  • isoleucine Ile
  • phenylalanine Phe
  • glycine Gly
  • valine Val
  • histidine His
  • alanine Al
  • lysine Lys
  • Trp Tryptophan
  • Trr tyrosine
  • pF-phenylalanine P-Cl-phenylalanine
  • p-nitrophenylalanine 1- or 2-naphthalalanine (1-Nal, 2-Nal)
  • 4-methoxyphenylalanine or homophenylalanine R 1 - for hydrogen stands or
  • R 4 and R 4 are identical or different and represent phenyl, quinolyl, indolyl, naphthyl, pyridyl or pyridyl-N-oxide,
  • R 11 and R 18 are the same or different and
  • m is the —NH group, an oxygen atom, a sulfur atom or the SO 2 group
  • R 8 and R 9 are the same or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms
  • R 12 means via N-linked morpholine or piperidinyl
  • R 13 means phenyl, 1-naphthyl or 2-naphthyl which is optionally substituted by fluorine, chlorine or by straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms or is a radical of the formula R 19 -S (O) 1 - or R 20 -CO-
  • R 19 denotes morpholino or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl, 1-naphthyl or 2-naphthyl,
  • R 20 morpholino, pyrrolidinyl or a radical of the formula
  • R! 4 and R 15 are the same or different and
  • R 16 denotes straight-chain or branched alkoxy having up to 6 carbon atoms or denotes a group -NR 21 ' R 22' , in which R 21 ' and R 22' are the same or different and are hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl, or R 21 ' and R 22' together with the nitrogen atom form a morphole ring
  • R 17 represents the -NH 2 - or -NH-CO-CH 3 group, L and L 'are the same or different and one
  • W is a radical of the formula R 25 -SO 2 , R 22 R 21 N-SO 2
  • R 22 denotes R 21 N-CO, wherein
  • R 25 denotes straight-chain or branched alkyl having up to 6 carbon atoms or benzyl, R 21 and R 22 are identical or different and
  • R 21 and R 22 together with the nitrogen atom form a morpholino, thiomorpholino, thiomorpholinosulfone or thiomorpholine sulfoxide ring
  • R 2 is hydrogen or represents straight-chain or branched alkyl having up to 6 carbon atoms, or in the case, that A and B simultaneously represent a bond R 1 and R 2 together form one of the rings listed above n - represents the number 1 or 2
  • R 3 - represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or
  • - represents hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or cyclopropyl or
  • - represents a radical of the formula -COR 26 , -NHR 27 , -NR 28 R 29 , S (O) k (NH) r R 30 or -OR 31 , in which
  • R 2 ° signifies hydrogen, straight-chain or branched alkyl, alkoxy or alkoxy- (C 1 -C 6 ) -alkenyl, each having up to 16 carbon atoms, which are optionally substituted by pyridyl or phenyl, which in turn by straight-chain or branched alkyl or alkoxy up to 8 carbon atoms can be substituted, or
  • R 26 represents the group -NR 32 R 33 , wherein R 32 and R 33 are the same or different and
  • R 32 or R 33 is cyclopropyl or phenyl or R 32 and R 33 together with the nitrogen atom form a morpholine ring, or R 26 means adamantyl or phenyl, where
  • Alkoxy is each substituted with up to 8 carbon atoms
  • R 27 , R 28 and R 29 are the same or different and are hydrogen, cyclopropyl or straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, which may optionally be protected several times by hydroxyl, hydroxyl, alkoxy or
  • R 28 and R 29 together with the nitrogen atom form a morpholine or piperidinyl ring which are optionally substituted by benzyl, k represents the number 0, 1 or 2, r represents the number 0 or 1,
  • R 30 denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, tolyl, benzyl or phenyl, or in the event that r denotes the number 0,
  • R 30 is an N-bonded morpholine or pyrrolidinyl ring
  • R 31 is hydrogen or straight-chain or branched alkyl having up to 16 carbon atoms, which is optionally substituted by phenyl, which in turn is substituted by
  • R 32 and R 33 are identical or different and are hydrogen, phenyl or straight-chain or branched alkyl with up to 6
  • A, B, D and E are the same or different and
  • R 1 - represents hydrogen or
  • - represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl or naphthyl, which in turn can be substituted by fluorine, chlorine, methyl or methoxy
  • a a 'is the number 0, 1 or 2
  • g is the number 1, 2, 3, 4 or 5
  • h is the number 0, 1 or 2
  • i is the number 0, 1 or 2
  • R 4 and R 4 are the same or different and are pyridyl, quinolyl, indolyl, phenyl, naphthyl or pyridyl-N-oxide,
  • R 11 and R 18 are the same or different and
  • phenyl, 1-naphthyl or 2-naphthyl which are optionally substituted by fluorine, chlorine, methyl or methoxy,
  • R 7 is fluorine or chlorine m denotes the NH group or an oxygen atom
  • R 8 and R 9 are identical or different and are hydrogen or methyl
  • R 12 means via N-linked morpholino or piperidinyl
  • R 13 denotes phenyl, 1-naphthyl or 2-naphthyl, which are optionally substituted by fluorine, chlorine, methyl or methoxy or denotes a radical of the formula R 19 -S (O) 1 or R 20 -CO, where R 19 is morpholino or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl or 1-naphthyl 1 is a number 0, 1 or 2, R 20 morpholino, pyrrolidinyl or a radical of the formula (CH 3 ) 2 N- (CH 2 ) 2 -NH-
  • R 14 and R 15 are the same or different and
  • R 16 denotes straight-chain or branched alkoxy having up to z u 4 carbon atoms or an N-bonded morpholine ring
  • R 17 denotes the NH 2 - or the -NH-CO-CH 3 group
  • L and L ' are identical or different and are one
  • W represents a radical of the formula R 25 -SO 2 , R 22 R 21 N-SO 2 , R 22 R 21 N-CO, in which
  • R 25 denotes straight-chain or branched alkyl having up to 4 carbon atoms or benzyl
  • R 21 and R 22 are identical or different and are hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which may be repeated several times by hydroxy, pyridyl, morpholino, piperidinyl, alkoxy with up to 4 carbon atoms, (C 1 -C 4 ) - Dialkylamino, quaternary ammonium salts or through a reed of the formula
  • R 21 and R 22 together with the nitrogen atom form a morpholino, thiomorpholino, thiomorphol insulfone or thiomorpholine sulfoxide ring,
  • R 2 - represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or in the event that A and B simultaneously represent a bond
  • R 1 and R 2 together form one of the rings listed above, n - represents the number 1 or 2, R 3 - represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms or
  • G denotes methyl, isopropyl, butyl, isobutyl, benzyl, - (CH 2 ) 2 -C 6 H 5 ,
  • M is a group of the formula
  • M 'de notes ethyl, vinyl, isopropyl, 1,3-dithian-2-yl, 2-alkylthioethyl or 2-dialkylaminoethyl
  • Q is methyl, isopropyl, benzyl or - (CH 2 ) 2 -C 6 H 5 ,
  • R denotes hydrogen, methyl, isopropyl, isobutyl or benzyl
  • T denotes methyl, isopropyl or isobutyl
  • U is methyl, isopropyl, isobutyl or benzyl
  • T 'and T are the same or different and
  • - represents hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, benzyl or cyclopropyl, or - stands for one of the amino protective groups listed above or
  • R 26 is hydrogen, straight-chain or branched alkyl, alkoxy or alkoxy- (C 1 -C 4 ) -alkenyl each having up to 10 carbon atoms, which are optionally substituted by pyridyl or phenyl, or R 26 is the group -NR 32 R 33 , in which
  • R 32 and R 33 are the same or different and is hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally by
  • R 32 or R 33 is cyclopropyl or phenyl, or
  • R 26 denotes adamantyl or phenyl
  • R 27 , R 28 and R 29 are the same or different and are hydrogen, cyclopropyl or straight chain or branched alkyl or alkoxy each having up to 6 carbon atoms, optionally with hydroxy, phenyl, morpholino, piperidinyl, pyrrolidinyl, thiomorpholino, pyridyl, thiomorphol insulfone or sulfoxide, pyridine-N-oxide, carboxy, sulfo, alkoxy or alkoxycarbonyl each up to 4 carbon atoms, amino or by a radical of the formula
  • R 30 is hydrogen, straight-chain or branched
  • R 30 is an N-linked morpholine
  • R 31 represents hydrogen or straight-chain or branched alkyl having up to 16 carbon atoms or benzyl or
  • R 32 and R 33 are the same or different and are hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or benzyl, and their physiologically acceptable salts with the proviso that in the event that X is for the rest
  • R 3 may not mean cyclohexyl.
  • R 3 , X, D, E and Y have the meaning given above, and
  • Z ' has the meaning of Z given above and is the same or different with this with activation of the carboxylic acid by customary methods in inert reading media to give compounds of the general formula (IV)
  • the protective group Z' is split off by a customary method and in a further step with compounds of the general formula (V) R 1 - A - B - OH (V) in which
  • R 1 , A and B have the meaning given above, optionally condensed under the above-mentioned carboxylic acid activation, or
  • R 1 , A, B, R 2 , n, R 3 , X, D and E have the meaning given above and Y 'in this case together with X, D and / or E simulates a C 1 -C 6 alkoxycarbonyl radical usual method to the corresponding acids saponified and in a further step, optionally in the presence of auxiliary substances, after
  • R 26 has the meaning given above of R 26 but does not represent hydrogen to the corresponding acids and saponifies
  • Bodanszky in Principles of Peptide Synthesis ", Springer Verlag, Berlin-Heidelberg-New York-Tokyo, 1984; R, Uhmann and K. Radscheit, published specification, DE 3 411 244 AI) or also according to the "solid phase method", as described, for example, by M. Bodanszky, A, Bodanszky in "The Practice of Peptide Synthesis", Springer-Verlag, Berlin, 1984, or
  • Suitable solvents for process variants [A], [B] and [C] are the customary inert solvents which do not change under the reaction conditions chosen in each case. These include water or organic solvents
  • Solvents such as diethyl ether, glycol mono- or dimethyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, toluene, xylene, cyclohexane or petroleum fractions or halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride or Acetone, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, ethyl acetate, pyridine, triethylamine or picoline,
  • hydrocarbons such as benzene, toluene, xylene, cyclohexane or petroleum fractions or halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride or Acetone, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, ethyl acetate, pyridine, trieth
  • Tetrahydrofuran, methylene chloride, dimethylformamide and ethyl acetate are preferred.
  • Process variants [A], CB] and [C] are usually carried out in the presence of suitable solvents or diluents, if appropriate in the presence of an auxiliary or catalyst, in a temperature range from -80 ° C. to 300 ° C., preferably from -30 ° C. to + 30 ° C at normal pressure. It is also possible to work at elevated or reduced pressure.
  • carboxylic acid azides which can be obtained, for example, by the reaction of protected ones
  • carboxylic acid hydrazides are suitable as activated carboxyl groups or unprotected carboxylic acid hydrazides with nitrous acid, its salts or alkyl nitrites (eg isoamyl nitrite),
  • esters especially vinyl esters (obtainable e.g. by reacting a corresponding unsaturated esters
  • Esters with vinyl acetate carbamoyl vinyl esters (obtainable e.g. by reacting an appropriate acid with an isoxazolium reagent), alkoxy vinyl esters (obtainable e.g. by reacting the corresponding acids with alkoxyacetylenes, preferably ethoxyacetylene),
  • N, N'- or N, N-disubstituted amidino esters for example N, N'- or N, N-disubstituted amidino esters (obtainable for example by reacting the ent speaking acid with an N, N'-disubstituted carbodiimide (preferably dicyclohexylcarbodiimide, diisopropylcarbodiimide or N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride) or with an N, N-disubstituted cyanamide,
  • N, N'-disubstituted carbodiimide preferably dicyclohexylcarbodiimide, diisopropylcarbodiimide or N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride
  • N, N-disubstituted cyanamide for example N, N
  • phenyl esters substituted by electron-withdrawing substituents, for example 4-nitrophenyl, 4-methylsulfonylphenyl, 2,4,5-trichlorophenyl, 2,3,4,5,6-pentachlorophenyl, 4-phenyldiazophenyl esters ( obtainable, for example, by reacting the corresponding acid with a correspondingly substituted phenol, if appropriate in the presence of a condensing agent such as, for example, N, N'-dicyclohexylcarbodiimide, diisopropylcarbodiimide, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, isobutylchloroformate, propanephosphonic acid triazole anhydride) ) -phosphonium hexafluorophosphate,
  • a condensing agent such as, for example, N, N'-dicyclohexylcarbodiimi
  • nitrophenylthioesters obtained, for example, by reacting the corresponding acid with nitrothiophenols, if appropriate in the presence of condensing agents such as N, N'-dicyclohexylcarbodiimide, diisopropylcarbodiimide, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, isobutylphosphonate, isobutylchloroformate Benzotriazolyloxytris
  • condensing agents such as N, N'-dicyclohexylcarbodiimide, diisopropylcarbodiimide, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, isobutylphosphonate, isobutylchloroformate Benzotriazolyloxytris
  • N-hydroxyamino or N-hydroxyamido compound in particular N- Hydroxy-succinimide, N-hydroxypiperidine, N-hydroxy-phthalimide, N-hydroxy-5-norbornene-2,3-dicarboximide or 1-hydroxybenzotriazole, optionally in the presence of condensing agents such as N, N'-dicyclohexylcarbodiimide, diisopropylcarbodiimide or N- ( 3-dimethylaminopropyl) - N'-ethylcarbodiimide hydrochloride, isobutylchloroformate or n-propanephosphonic anhydride),
  • condensing agents such as N, N'-dicyclohexylcarbodiimide, diisopropylcarbodiimide or N- ( 3-dimethylaminopropyl) - N'-ethylcarbodiimide hydrochloride, isobutylchloroformate or n
  • anhydrides of acids preferably symmetrical or asymmetrical anhydrides of the corresponding acids, in particular anhydrides with inorganic acids (obtainable, for example, by reacting the corresponding acid with thionyl chloride, phosphorus pentoxide or oxalyl chloride), or anhydrides with carbonic acid semi-derivatives e.g. Carbonic acid lower alkyl half-ester (obtainable, for example, by reacting the corresponding acid with lower alkyl haloformates, e.g.
  • phosphoric acid derivatives or phosphoric acid derivatives e.g. propanephosphonic anhydride, H, Wissmann and H.J. Kleiner, Angew. Chem. Int. Ed. 19, 133 (1980)
  • organic carboxylic acids obtainable, for example, by reacting the corresponding acids with a substituted lower alkane or, if appropriate
  • Phenylalkanecarboxylic acid halide especially phenyl acetic acid, pivalic acid or trifluoroacetic acid chloride
  • organic sulfonic acids obtainable, for example, by reacting an alkali salt of a corresponding acid with a sulfonic acid halide, in particular methane, ethane, benzene or toluenesulfonic acid chloride),
  • Condensation of appropriate acids optionally in the presence of condensing agents such as N, N'-dicyclohexylcarbodiimide, diisopropylcarbodiimide, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride
  • condensing agents such as N, N'-dicyclohexylcarbodiimide, diisopropylcarbodiimide, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride
  • Reactive cyclic amides are in particular amides with five-membered heterocycles with 2 nitrogen atoms and optionally aromatic character, preferably amides with imidazoles or pyrazoles (obtainable, for example, by reacting the corresponding acids with N, N'-carbonyldiimidazole or - optionally in the presence of condensing agents such as, for example, N'-dicyclohexylcarbodiimide, N, N'-diisopropylcarbodiimide, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, isobutylchloroformate, propanephosphonic anhydride, benzotria ⁇ zolyloxy-tris (dimethylamino)
  • auxiliary substances which can also be bases, especially if the carboxyl group is activated as an anhydride
  • the usual condensing agents such as carbodiimides, e.g. N, N'-diethyl, N, N-'dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride, or carbonyl compounds such as carbonyldiimidazole , or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl -1,2-dihydroquinoline, or propanephosphonic anhydride, or isobutylchloroformate, or benzotriazolyloxy-tris (dimethylamino)
  • the amino protective group is split off in a manner known per se under acidic or basic conditions, or reductively by catalytic hydrogenation, for example with Pd / C in organic solvents such as ethers, for example Tetrahydrofuran or dioxane, or alcohols e.g. Methanol, ethanol or isopropanol,
  • the saponification of the carboxylic acid esters is carried out by customary methods in one of the solvents listed above, by treating the esters with customary bases, the salts initially formed by Be act with acid in the free carboxylic acids can be converted,
  • the usual inorganic bases are suitable as bases for the saponification.
  • bases preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates such as sodium or potassium carbonate or sodium hydrogen carbonate, or alkali metal alcoholates such as sodium ethanolate, sodium methoxide, potassium ethoxide, potassium methoxide or potassium tert-butoxide.
  • alkali metal hydroxides or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide or barium hydroxide
  • alkali metal carbonates such as sodium or potassium carbonate or sodium hydrogen carbonate
  • alkali metal alcoholates such as sodium ethanolate, sodium methoxide, potassium ethoxide, potassium methoxide or potassium tert-butoxide.
  • Sodium hydroxide or potassium hydroxide are particularly preferably used.
  • the saponification is generally carried out in a temperature range from 0 ° C. to + 100 ° C., preferably from + 20 ° C. to + 80 ° C.
  • the saponification is generally carried out at normal pressure. But it is also possible to work under negative pressure or overpressure (e.g. from 0.5 to 5 bar).
  • the base is generally used in an amount of 1 to 3 mol, preferably 1 to 1.5 mol, based on 1 mol of the ester. Molar amounts of the reactants are particularly preferably used.
  • esters can also be split off using customary methods using acids, such as, for example, hydrochloric acid or trifluoroacetic acid in the case of tert-butyl esters or by hydrogenolysis in the case of benzyl esters.
  • acids such as, for example, hydrochloric acid or trifluoroacetic acid in the case of tert-butyl esters or by hydrogenolysis in the case of benzyl esters.
  • the compounds of the general formulas (II) and (V) are known per se or can be built up by customary methods of peptide chemistry by reacting a corresponding fragment consisting of one or more amino acid groups with a free carboxyl group which may be present in activated form with a complementary fragment, consisting of one or more amino acid groups, with an amino group, optionally in activated form, and this process may be repeated with appropriate fragments until the desired peptides of the general formulas (II) and (V ), subsequently split off protective groups or replace them with other protective groups *
  • Additional reactive groups e.g. Amino or hydroxyl groups in the side chains of the fragments may be protected by conventional protective groups [cf. Houben-Weyl, Eugen Müller,
  • reaction with amines of the formulas (VII) and (VIIa) is generally carried out in one of the inert solvents listed above, in the presence one of the bases listed above, preferably in triethylamine and
  • Methylene chloride at a temperature of -40 ° C to 0 ° C at, preferably at -20 ° C and normal pressure In general, 1 to 5, preferably 1.5 to 1, mol of amine, based on 1 mol of the reactant, are used.
  • Mixtures of stereoisomers in particular mixtures of diastereomers, can be prepared in a manner known per se, e.g. be separated into the individual isomers by fractional crystallization or chromatography.
  • Racemates can be used in a manner known per se, e.g. can be split into diastereomers by converting the optical antipodes.
  • the compounds according to the invention have a circulatory effect and can therefore be used in medicaments for the treatment of blood pressure and heart failure.
  • In vitro test
  • the inhibitory strength of the peptides according to the invention against endogenous renin from human plasma is determined in vitro. Pooled human plasma is obtained with the addition of ethylenediaminetetraacetic acid (EDTA) as an anticoagulant and stored at -20 ° C. Plasma renin activity (PRA) is determined as the rate of formation of angiotensin I from endogenous angiotensinogen and renin after incubation at 37 ° C.
  • EDTA ethylenediaminetetraacetic acid
  • the reaction solution contains 150 ° 1 plasma, 3 ⁇ l 6.6% 8-hydroxyquinoline sulfate solution, 3 ⁇ l 10% dimercaprol solution and 144 ⁇ l sodium phosphate buffer (0.2 M; 0.1% EDTA; pH 5.6) with or without the substances according to the invention in various concentrations.
  • the angiotensin I formed per unit of time is determined using a radioimmunoassay (Sorin Biomedica, Italy).
  • the percentage inhibition of plasma renin activity is calculated by comparing the substances claimed here.
  • the concentration range in which the substances claimed here show 50% inhibition of plasma renin activity are between 10 -6 to 10 -10 M.
  • the new active compounds can be converted in a known manner into the customary formulations, such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
  • the therapeutically active compound should be present in each case in a concentration of about 0.5 to 90% by weight of the total mixture, that is to say in amounts which are sufficient to achieve the stated dosage range.
  • the formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, if appropriate using emulsifiers and / or dispersants, where, for example if organic water is used as the diluent, if appropriate organic solvents
  • Auxiliary solvents can be used.
  • auxiliary substances are: water, non-toxic organic solvents, such as
  • Paraffins e.g. petroleum fractions
  • vegetable oils e.g. peanut / sesame oil
  • alcohols e.g.: ethyl alcohol, glycerin
  • carriers e.g. natural stone flours (e.g. kaolins, clays, talc, chalk), synthetic stone flours (e.g. highly disperse silica, silicates),
  • Sugar e.g., cane, milk and dextrose
  • emulsifier e.g. polyoxyethylene fatty acid ester
  • polyoxyethylene fatty alcohol ether e.g., lignin, sulfite liquor, methyl cellulose, starch and polyvinylpyrrolidone
  • lubricants e.g. magnesium stearate, Talc, stearic acid and sodium sulfate.
  • the application is carried out in the usual way, preferably orally or parenterally, in particular perlingually or intravenously.
  • tablets can of course also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatin and the like, in addition to the carrier substances mentioned. Can continue
  • Lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting.
  • the active ingredients can be mixed with various flavor enhancers or colorants.
  • solutions of the active ingredients can be used using suitable liquid carrier materials.
  • 1 mg / kg preferably about 0.01 to 0.5 mg / kg body weight to achieve effective results
  • oral administration the dosage is about 0.01 to 30 mg / kg, preferably 0.1 to 10 mg / kg body weight.
  • Stationary phase Merck DC pre-fabricated plates silica gel 60 F-254, 5 ⁇ 10 cm, layer thickness 0.25 mm, item no. 5719.
  • HPLC system I column Merck LiChrosorb ® RP-8, 250-4,
  • HPLC system II column Merck LiChrosorb ® RP-18, 250-4,
  • a / B as 1/1, flow: 2 ml / min, isocratic,
  • the configuration is designated by prefixing an L or D in front of the amino Acid abbreviation, in the case of the racemate by a D, L - whereby for simplification in the case of L-amino acids the configuration name can be omitted and then only in the case of the D form or the D, L mixture is an explicit name given.
  • D- or L-pyr (2) ß- (2-pyridyl) -D- or -L-alanine D- or L-pyr (3) ß- (3-pyridyl) -D- or -L-alanine D- or L-pyr (4) ß- (4-pyridyl) -D- or -L-alanine D- or L-Trz (1) ß- (1-triazolyl) -D- or -L-alanine
  • the basic aqueous phase is adjusted to pH 3 with hydrochloric acid and extracted several times with methylene chloride.
  • the combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. Yield: 18.1 g (60.6% of theory)
  • Detection takes place at 214 nm, the fraction control by thin layer and high pressure liquid chromatography.
  • the title compound is obtained by chromatographic separation (analogously to Example 1) of the crude product synthesized analogously to Example 1 from the compound of Example 2 and N-tert-butoxycarbonyl-L- (4-methoxy) phenylalanine (Bissendorf Biochemicals).
  • the IR and GC / MS spectrum are identical to those of the epimer 42a.

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Abstract

L'invention concerne des peptides inhibiteurs de la rénine contenant de la dithiolanoglycine et de la dithianoglycine, répondant à la formule générale (I), dans laquelle A, B, D, E, R?1, R2, R3¿, n, X et Y ont la signification donnée dans la description, leur procédé de production et leur utilisation dans des médicaments, notamment dans des médicaments affectant la circulation sanguine.
PCT/EP1991/002301 1990-12-06 1991-12-03 Peptides inhibiteurs de la renine contenant de la dithiolanoglycine et de la dithianoglycine, leur procede de production et leur utilisation dans des medicaments WO1992010510A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP4500345A JPH06503316A (ja) 1990-12-06 1991-12-03 ジチオラノ−およびジチアノグリシン−を含有しているレニン−抑制性ペプチド類、それらの製造方法および薬品中におけるそれらの使用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4038947.2 1990-12-06
DE4038947A DE4038947A1 (de) 1990-12-06 1990-12-06 Dithiolano- und dithianoglycin-haltige renininhibitorische peptide, verfahren zu ihrer herstellung und ihre verwendung in arzneimitteln

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WO1992010510A1 true WO1992010510A1 (fr) 1992-06-25

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AU (1) AU9040191A (fr)
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0569811A1 (fr) * 1992-05-14 1993-11-18 Bayer Ag Inhibiteurs de la HIV-protéase du type isostère hydroxyéthylène contenant dithiolanylglycine
US6555542B1 (en) 2001-01-30 2003-04-29 Bristol-Myers Squibb Company Sulfonamide lactam inhibitors of FXa and method

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0403828A1 (fr) * 1989-06-09 1990-12-27 Bayer Ag Peptides inhibitant de la rénine, procédé pour leur préparation et leur utilisation comme médicaments

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0403828A1 (fr) * 1989-06-09 1990-12-27 Bayer Ag Peptides inhibitant de la rénine, procédé pour leur préparation et leur utilisation comme médicaments

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0569811A1 (fr) * 1992-05-14 1993-11-18 Bayer Ag Inhibiteurs de la HIV-protéase du type isostère hydroxyéthylène contenant dithiolanylglycine
US5424426A (en) * 1992-05-14 1995-06-13 Bayer Aktiengesellschaft Dithiolanylglycine-containing HIV protease inhibitors of the hydroxyethylene isostere type
US6555542B1 (en) 2001-01-30 2003-04-29 Bristol-Myers Squibb Company Sulfonamide lactam inhibitors of FXa and method
US7166586B2 (en) 2001-01-30 2007-01-23 Bristol Myers Squibb Co. Sulfonamide lactam inhibitors of FXa and method

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AU9040191A (en) 1992-07-08
JPH06503316A (ja) 1994-04-14

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