EP0387309A1 - Nouveaux inhibiteurs de la renine, leur procede de fabrication et leur emploi - Google Patents

Nouveaux inhibiteurs de la renine, leur procede de fabrication et leur emploi

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Publication number
EP0387309A1
EP0387309A1 EP89906087A EP89906087A EP0387309A1 EP 0387309 A1 EP0387309 A1 EP 0387309A1 EP 89906087 A EP89906087 A EP 89906087A EP 89906087 A EP89906087 A EP 89906087A EP 0387309 A1 EP0387309 A1 EP 0387309A1
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EP
European Patent Office
Prior art keywords
cyclohexylmethyl
acid amide
hydroxy
butenyl
butyl
Prior art date
Legal status (The legal status 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 status listed.)
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Application number
EP89906087A
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German (de)
English (en)
Inventor
Beat Weidmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sandoz AG
Original Assignee
Sandoz AG
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Filing date
Publication date
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Publication of EP0387309A1 publication Critical patent/EP0387309A1/fr
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/38—Amides of thiocarboxylic acids
    • C07C327/40—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C327/42—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of a saturated carbon skeleton
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    • C07C327/00—Thiocarboxylic acids
    • C07C327/38—Amides of thiocarboxylic acids
    • C07C327/40—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C327/44—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C333/02—Monothiocarbamic acids; Derivatives thereof
    • C07C333/04—Monothiocarbamic acids; Derivatives thereof having nitrogen atoms of thiocarbamic groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • 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
    • 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
    • C07K5/0207—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)4-C(=0), e.g. 'isosters', replacing two 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
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/021—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)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
    • 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
    • C07K5/0212—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -N-C-N-C(=0)-, e.g. retro-inverso peptides
    • 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
    • C07K5/0227—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the (partial) peptide sequence -Phe-His-NH-(X)2-C(=0)-, e.g. Renin-inhibitors with n = 2 - 6; for n > 6 see C07K5/06 - C07K5/10

Definitions

  • the invention relates to renin inhibitors, processes for their preparation and their use according to claims 1 to 10.
  • IR 1 is a straight-chain or branched alkyl having 1 to 10 carbon atoms, it is in particular methyl, ethyl, propyl, isopropyl, butyl, tert. Butyl, 2, 2-dimethylethyl, pentyl, hexyl etc., especially methyl, tert. Butyl and 2,2-dimethyl-ethyl. If it is substituted by aryloxy, it stands in particular for phenoxymethyl or 1- or 2-naphthyloxymethyl, preferably 1-naphthyloxymethyl. Heteroaryl means in particular. Pyridyl, thienyl or furyl.
  • heteroarylalkyl radical the heteroaryl part and the alkyl part preferably have the abovementioned meanings; a straight-chain or branched alkoxy radical means in particular ethoxy or tert. Butoxy and a (C 6- 10) aryl (C 1-5) alkoxy radical having in particular The specified above for aryl and alkyl as defined and is preferably benzyloxy.
  • R 4 represents a straight-chain or branched alkyl, it means in particular alkyl having 1 to 5 carbon atoms, preferably ethyl, propyl or isobutyl, the glycosidically bonded sugar radical, for example glucopyranosyl, which can optionally be O-acylated, for example tetra-O-acetylglucopyranosyl an optionally substituted or unsaturated saturated (C 2-30 ) alkylcarbonyl group stands in particular for a corresponding (C 4-20 ) alkylcarbonyl group, for example for a palmitoyl, an oleyl, linoyl, stearoyl or pivaloyl radical where the alkylcarbonyl group is substituted by a cyclopentaphe ⁇ anthrene radical and can represent a cholyl radical, a (C 3-6 ) polyhydroxyalkylcarbonyl radical is, for example a glycerinoyl or a
  • R 5 a side chain of a D- or L-amino acid, in particular methyl, isopropyl, isobutyl, benzyl, hydroxy (C 1 - 5) alkyl, 4-aminobutyl or 2-carboxyethyl.
  • a hydrophilic or hydrophobic amino acid side chain in the meaning of R 2 can preferably be cyclohexylmethyl, phenylmethyl, trimethylsilylmethyl, p-methoxyphenylmethyl, 1-adamantylmethyl or isobutyl.
  • the hydrophilic or lipophilic amino acid side chain in the meaning of R 8 can preferably be an n-butyl, isobutyl, (E-2-butenyl), benzyl, 4-imidazolylmethyl, 2-methylthioethyl or methyl, trimethylsilylmethyl -, Cyclohexylmethyl-, an azido or a pyridylmethyl radical.
  • Preferred compounds of the compounds according to the invention have the formula I Y
  • W Y is -CH 2 -CH 2 - or a group of the formula stands, wherein
  • X Y has the meaning of X, but particularly preferably denotes sulfur
  • V Y is oxygen, NR 3 Y wherein R 3 Y is hydrogen or a straight-chain or branched (C 1 _ 5 ) alkyl radical, but especially hydrogen or methyl, or is a bond, Ri Y is tert-butyl, benzyloxy, ⁇ -Aminopentyl or isopropyl or R 1 Y is a group of the formula
  • R 4 Y represents hydrogen, methyl, pyridinoyl or 3,4,5-trimethoxy
  • n Y is an integer from 2-7 and
  • n Y is an integer from 0-2,
  • R 2 Y cyclohexylmethyl, phenylmethyl, trimethylsilylmethyl, p-Met hoxyphenylmethyl, ⁇ -adamantylmethyl or isobutyl means Z has the meaning given in claim 1, A has Y groups of the formulas
  • R 3 Y represents hydrogen or methyl
  • R 8 Y represents n-butyl, isobutyl, E-2-butenyl, benzyl, 4-imidazolylmethyl, pyridylmethyl, trimethylsilylmethyl or an azido radical.
  • B Y is a group of the formula
  • R 9 Y is isobutyl, benzyl or cyclohexylmethyl and either R 10 Y is a hydroxyl radical and
  • R 11 Y is hydrogen if R 12 Y and R 1 3 Y are each hydrogen, or
  • R 10 Y and R 11 Y together form the oxo group, especially if
  • R 12 Y and R 13 Y each represent fluorine.
  • R 14 Y and R 1 5 Y are the same or different and each represent hydrogen, methyl, i-propyl, i-butyl, 2-butyl or a group of the formula
  • R 16 Y for i-butyl or 2-butyl
  • R 17 Y represent aminomethylpyridyl.
  • R 18 Y and R 19 Y independently of one another are hydrogen, fluorine, chlorine, an azido group, n-butyl, isobutyl, E-2-butenyl, methylthiomethyl, methyl, benzyl or isopropyl.
  • the process according to process step a) of claim 3 is preferably carried out in such a way that an amine of the formula II with an acid of the formula III, using methods known in peptide chemistry, e.g. in the presence of N, N'-dicyclohexyl-carbodiimide (with the addition of 1-hydroxybenzotriazole) in a suitable solvent such as e.g. Reacts methylene chloride at temperatures between 0 ° and room temperature.
  • a suitable solvent such as e.g. Reacts methylene chloride at temperatures between 0 ° and room temperature.
  • the compounds of the formula Ia obtained here are a special case of compounds of the formula I in which W is
  • process stage b) of claim 3 is preferably carried out in such a way that an amine of the formula II is directly reacted with an activated acid derivative of the formula IV in which Q is, for example, a p-nitro-phenyl or an alkoxy radical, optionally with the addition of dimethylaminopyridine at 20 ° -80 ° in a suitable solvent such as Dimethylformamide implemented.
  • Q is, for example, a p-nitro-phenyl or an alkoxy radical
  • the process according to process stage c) is a reductive alkylation of the primary amino group of the compounds of the formula II, which is expediently carried out in a solvent such as methanol at a pH of the solution from 6 to 7 and a temperature of 20 ° to 30 ° C, where NaBH 3 CN is preferred as reducing agent.
  • the compounds of the formula Ic obtained in this way are a special case of compounds of the formula I in which W is -CH 2 -CH 2 -.
  • process stage d) of claim 3 is carried out in such a way that compounds of the formula Ie are reacted with a chromium trioxide-dipyridine complex (Collin's reagent) in a solvent such as methylene chloride or dirnethylformamide to give the corresponding ketone.
  • a chromium trioxide-dipyridine complex Cold's reagent
  • a solvent such as methylene chloride or dirnethylformamide
  • X S
  • suitable methods such as Oxidation with / in dimethyl sulfoxide in the presence of dicyclohexylcarbodiimide and a catalytic amount of dichloroacetic acid can be used.
  • R 9 , R 12 to R 15 , Y and X have the meaning given in claim 1 and Rio and Rn together represent an oxo group.
  • the starting compounds used in the above processes are either known or can be prepared by processes known per se, for example as described in the examples below. getting produced.
  • the compounds of the formula I prepared according to the invention can be isolated and purified by methods known per se. Racemic and / or diastereomeric mixtures can be separated in a manner known per se.
  • the compounds of the formula I contain acidic or basic groups, they can optionally also form salts, for example metal salts such as sodium salts or acid addition salts such as hydrochlorides.
  • H-Cha (OH) CH (OH) CH 2 N 3 (2S, 3R, 4S) -4-amino-l-azido-5-cyclohexyl-2,3-dihydroxy-pentane.
  • Example 8 4-pyridyl-CH 2 O (CS) -Tmsal-Nle-F 2 -Chatin-NHiBu
  • Example 2 Analogously to Example 1, 1 g of Me-PegS-SMe is reacted with 400 mg of H-Cha-Nle-Cha (OH) Nle-NHBu with the addition of 20 mg of dimethylaminopyridine for 24 hours. The crude product is chromatographed with methanol in methylene chloride (2-5%). You get that. Title compound as a mixture of different oligomers.
  • Example 12 4-Pyridyl-CH 2 O (CS) -Tmsal-Nle-F 2 Chaton-NHiBu
  • Example 13 28 mg of the title compound from Example 13 are oxidized analogously to Example 12 with dimethyl sulfoxide in the presence of 35 mg of dicyclohexylcarbodiimide and 2 mg of dichloroacetic acid.
  • the title compound obtained has a
  • Tmpac-2egS-SMe 500 mg are reacted analogously to Example 1 with 610 mg of H-Tmsal-Nle-F 2 Chatin-NHiBu with the addition of 100 mg of dimethylaminopyridine for 15 hours.
  • the crude product is chromatographed with methanol in methylene chloride (0-5%).
  • the title compound obtained has a
  • Example 15 30 mg of the title compound of Example 15 are analogous to Example 12 with dimethyl sulfoxide in the presence of 33 mg of dicyclohexylcar Bodiimid and 2 mg of dichloroacetic acid oxidized.
  • the title compound obtained has a
  • Example 19 Niacin-2egS-Tmsal-Nle-Cha (OH) -CF 2 -CF 2 -CF 3
  • niacin-2egs-SMe and 225 mg of H-Cha (OH) Bly-Cha (OH) -CF 2 CF 2 CF 3 are reacted with the addition of 20 mg of dimethylaminopyridine in 1 ml of dimethylformamide for 5 hours at room temperature.
  • the mixture is distributed between ethyl acetate and 10% KH 2 PO 4 , the org. Phase dried and evaporated.
  • the crude product is chromatographed with ether / hexane 25 to 100%.
  • the title compound obtained has a
  • Example 28 7EGS-Cha (O) Bly-Chatin-Leu- (S) - ⁇ -Picolin
  • niacin-2egs-SMe and 100 mg of H-Cha (O) Bly-F 2 -Chaton-NH-i-Bu are reacted analogously to Example 1 for 16 hours in methylene chloride with the addition of dimethylaminopyridine.
  • the crude product is chromatographed with alcohol / methylene chloride 1.5%.
  • Example 30 Niacin-2eg-Cha (0H) Bly-Cha (0H) CF 2 CF 2 CF 3
  • Example 31 Niacin-2eg-Cha ⁇ Bly-Cha-CF 2 CF 2 CF 3
  • the starting compound 6-dimethylaminodithiocaproic acid methyl ester is slowly added by 4.9 g of 2,4-bis (methylthio) 1,3,2,4-dithiadiphosphetane -2,4-disulfide to a suspension of 5.0 g 6-dimethylaminoeapronic acid in 40 ml chlorobenzene, then heating to reflux temperature for 10 minutes, decanting chlorobenzene, filtering a solution of the residue in methylene chloride containing 10% ethanol, neutral over aluminum oxide and then Chromatography with methylene chloride, containing 10% ethanol and 1% conc. Ammonia solution made on silica gel.
  • the compounds according to the invention have pharmacological activity. They can be used as a medicine. As can be seen from the results of standard tests, they have typical effects, particularly for enzyme inhibitors. The inhibitory effect in relation to a specific enzyme naturally depends on the peptide structure as a whole.
  • the above compounds, which are particularly suitable as inhibitors of renin activity bring about a 50% inhibition of the enzyme activity of pure human renin by the method of F. Cumin et al. On the human synthetic tetradecapeptide substrate at a concentration of 10 -5 M to 10 -11 M. (Bioch. Biophys. Acta 913, 10-19 (1987)) or by means of the Renin Binding Assay (Fundamental and Clin. Pharmacol in Press).
  • the compounds according to the invention are therefore suitable for use for the prophylaxis and treatment of conditions which are characterized by an enzymatic dysfunction and for which an inhibition of the enzymatic activity is indicated.
  • renin inhibitors they are e.g. suitable for use in the prophylaxis and treatment of hypertension and heart failure ("congestive heart failure").
  • Preferred for the prophylaxis and treatment of hypertension and cardiac insufficiency are the title compounds of Examples 4.35 and 36, in particular of Examples 35 and 36 and very particularly of Example 36.
  • the compounds according to the invention also have an antiretroviral activity and can therefore be used for the treatment of diseases caused by retroviruses, including HTLV-I and III-viruses. This effect can be seen in the FeLV cat model [Cerny and Essex, CPC Press IN 1979, pages 233256; Cockerell et al. J. Natl. Cancer Inst. 57, pages 1095-1099 (1976); Cotter et al. J. AM.VET.MED.ASSOC. 166, pp.
  • the doses required to achieve the antiviral effect correspond to those which are usually used and are, for example, in the order of 5 to 20 mg / kg / day.
  • the dose to be administered depends on the particular compound used, the type of administration and the desired treatment. In general, satisfactory results are obtained if the compounds are administered in a daily dose of 0.02 mg / kg to approximately 20 mg / kg of animal body weight. For larger mammals, the recommended daily dose is from about 1 mg to about 500 mg, more appropriate administered orally, for example, in doses of 0.25 mg to about 500 mg 1-4 times a day or in sustained release form.
  • the compounds according to the invention can be administered in free form or, if acidic or basic groups are present, in pharmacologically acceptable salt form. Such salt forms have an effect of the same order of magnitude as the free forms and can be produced in a known manner.
  • the present invention also relates to pharmaceutical preparations containing a compound according to the invention in free form or in pharmaceutically acceptable salt form, optionally together with pharmaceutically acceptable auxiliaries and / or carriers. Such pharmaceutical preparations can be formulated for use in enteral, preferably oral, administration, e.g. as tablets, or for use in parenteral administration, e.g. as an injectable solution or suspension.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Composé de formule (I), où R1, W, R2, Z, A et B ont la notation donnée dans la revendication 1, procédé pour le fabriquer, et son emploi comme inhibiteur de la rénine dans le traitement de l'hypertension et de l'insuffisance cardiaque chronique ainsi que des maladies d'origine rétrovirale.
EP89906087A 1988-05-10 1989-05-09 Nouveaux inhibiteurs de la renine, leur procede de fabrication et leur emploi Withdrawn EP0387309A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3815913A DE3815913A1 (de) 1988-05-10 1988-05-10 Neue reninhemmer, verfahren zu deren herstellung und deren verwendung
DE3815913 1988-05-10

Publications (1)

Publication Number Publication Date
EP0387309A1 true EP0387309A1 (fr) 1990-09-19

Family

ID=6354052

Family Applications (1)

Application Number Title Priority Date Filing Date
EP89906087A Withdrawn EP0387309A1 (fr) 1988-05-10 1989-05-09 Nouveaux inhibiteurs de la renine, leur procede de fabrication et leur emploi

Country Status (4)

Country Link
EP (1) EP0387309A1 (fr)
JP (1) JPH02504152A (fr)
DE (1) DE3815913A1 (fr)
WO (1) WO1989010917A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5527114A (en) * 1994-03-23 1996-06-18 Nsk Ltd. Tapered roller bearing with rotational speed detection unit

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3839128A1 (de) * 1988-11-19 1990-05-31 Hoechst Ag Renin-hemmende dipeptide, verfahren zu ihrer herstellung, diese enthaltende mittel und deren verwendung
IT1244983B (it) * 1991-04-29 1994-09-13 Raggio Italgene Spa Procedimento per rivelare sequenze di acidi nucleici e kit per la sua utilizzazione.

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4613676A (en) * 1983-11-23 1986-09-23 Ciba-Geigy Corporation Substituted 5-amino-4-hydroxyvaleryl derivatives
FI88400C (fi) * 1984-08-06 1993-05-10 Upjohn Co Foerfarande foer framstaellning av renin inhiberande peptider
IT1177379B (it) * 1984-12-11 1987-08-26 Anic Spa Derivati della sostanza p e di suoi frammenti
FR2585708B1 (fr) * 1985-07-31 1989-07-07 Sanofi Sa Derives aminoalcools peptidiques inhibiteurs de la resine et des proteases acides, leur procede de preparation et leur application en therapeutique
KR870005013A (ko) * 1985-11-29 1987-06-04 가와무라 요시부미 레닌-억제 올리고펩티드, 그의 제조방법 및 용도

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5527114A (en) * 1994-03-23 1996-06-18 Nsk Ltd. Tapered roller bearing with rotational speed detection unit

Also Published As

Publication number Publication date
WO1989010917A2 (fr) 1989-11-16
JPH02504152A (ja) 1990-11-29
WO1989010917A3 (fr) 1989-12-28
DE3815913A1 (de) 1989-11-23

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