[go: up one dir, main page]

WO1997030076A1 - Nouveaux pseudopeptides a action antivirale a fonction mercaptal ou thioether - Google Patents

Nouveaux pseudopeptides a action antivirale a fonction mercaptal ou thioether Download PDF

Info

Publication number
WO1997030076A1
WO1997030076A1 PCT/EP1997/000471 EP9700471W WO9730076A1 WO 1997030076 A1 WO1997030076 A1 WO 1997030076A1 EP 9700471 W EP9700471 W EP 9700471W WO 9730076 A1 WO9730076 A1 WO 9730076A1
Authority
WO
WIPO (PCT)
Prior art keywords
carbon atoms
chain
branched alkyl
straight
phenyl
Prior art date
Application number
PCT/EP1997/000471
Other languages
German (de)
English (en)
Inventor
Siegfried Raddatz
Thomas-Joachim Schulze
Dieter Häbich
Jürgen Reefschläger
Original Assignee
Bayer Aktiengesellschaft
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Bayer Aktiengesellschaft filed Critical Bayer Aktiengesellschaft
Priority to AU15464/97A priority Critical patent/AU1546497A/en
Publication of WO1997030076A1 publication Critical patent/WO1997030076A1/fr

Links

Classifications

    • 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
    • C07K5/06086—Dipeptides with the first amino acid being basic
    • C07K5/06095—Arg-amino acid
    • 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 new antiviral pseudopeptides
  • Mercaptal or thioether function process for their preparation and their use as antiviral agents, in particular against cytomegaloviruses.
  • peptide aldehydes are described as inhibitors of the HIV protease or of picornavirus proteases. Furthermore, peptide aldehydes have been described as inhibitors of serine proteases
  • nucleoside and nucleotide analogs Various nucleoside and nucleotide analogs, anthraquinone derivatives, phosphoric acid salts, cobalt complexes, macrolides and acyl peptides [EP 488041] are known as classes of compounds with anti-cytomegaly activity.
  • the present invention now relates to new antiviral pseudopeptides with mercaptal or thioether function of the general formula (I)
  • R 1 represents tert-butyloxycarbonyl or a radical of the formula -R 6 -CH 2 -O-CO- or R 7 -CO-,
  • R and R are the same or different and are phenyl or a 5- to 7-membered aromatic, optionally benzo-fused heterocycle with up to 4 heteroatoms from the series S, N and / or O, the ring systems optionally up to 3 times are identical or different and are substituted by halogen or by straight-chain or branched alkyl or acyl each having up to 6 carbon atoms,
  • R »2 represents hydrogen or methyl
  • R represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl or cycloalkyl having up to 6 carbon atoms,
  • R 4 represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by phenyl,
  • R 5 represents a radical of the formula -OCO-R 8 ,
  • R 8 is straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or aryl having 6 to 10 carbon atoms,
  • R 4 and R 5 together with the sulfur atom represent a heterocyclic radical
  • R 9 and R 10 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms, a represents a number 1, 2 or 3,
  • the compounds of the general formula (I) according to the invention can also be present in the form of their salts.
  • salts with organic and inorganic bases or acids may be mentioned here.
  • the acids that can be added preferably include hydrohalic acids, e.g. hydrofluoric acid, hydrochloric acid and hydrobromic acid, especially hydrofluoric acid and hydrochloric acid, also phosphoric acid, nitric acid, sulfuric acid, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids, e.g. Acetic acid, maleic acid, malonic acid, oxalic acid, gluconic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid and lactic acid as well as sulfonic acids such as e.g. p-toluenesulfonic acid, 1,5-naphthalenedisulfonic acid or camphorsulfonic acid.
  • hydrohalic acids e.g. hydrofluoric acid, hydrochloric acid and hydrobromic acid, especially hydrofluoric acid and hydrochloric acid, also phosphoric acid, nitric acid, sulfuric acid, mono-
  • Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group.
  • metal or ammonium salts of the compounds according to the invention which have a free carboxyl group.
  • Sodium, potassium, magnesium or calcium salts and ammonium salts derived from ammonia, or organic amines such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.
  • Heterocycle generally represents a 5- to 7-membered, preferably 5- to 6-membered, aromatic, optionally benzo-fused ring which can contain up to 4 oxygen, sulfur and / or nitrogen atoms as heteroatoms.
  • 5- and 6-membered rings with one oxygen, sulfur and / or up to 4 nitrogen atoms are preferred. The following are particularly preferred:
  • the compounds of the general formula (I) according to the invention like the rest of the general formula (II) shows up to 4 asymmetric carbon atoms (*). They can exist independently of one another in the D or L form, or R or S configuration.
  • the invention includes both the pure diastereomers, mixtures of several diastereomers and racemates.
  • stereoisomer mixtures and racemates can be separated into the pure stereoisomers by known methods. Mixtures of stereoisomers can be separated either by chromatography or by fractional crystallization. Racemates can be separated, for example, by chromatography on chiral phases.
  • R 1 represents tert-butyloxycarbonyl or a radical of the formula -R 6 -CH 2 -O-CO- or R 7 -CO-,
  • R 6 and R 7 are the same or different and are phenyl, pyridyl, quinolyl, quinoxalinyl, furyl, thienyl, pyrryl or pyrimidyl, which are optionally up to 2 times the same or different by fluorine, chlorine, bromine or by straight-chain or branched alkyl or Acyl are each substituted with up to 5 carbon atoms, R 2 represents hydrogen or methyl,
  • R 3 represents straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by phenyl or cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,
  • R 4 represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl,
  • R 5 represents a radical of the formula -OCO-R 8 ,
  • R 8 is straight-chain or branched alkyl having up to 4 carbon atoms, benzyl, phenyl or naphthyl,
  • R 4 and R 5 together with the sulfur atom represent a heterocyclic radical
  • R 9 and R are the same or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
  • a represents a number 1, 2 or 3
  • R 1 represents tert-butyloxycarbonyl or a radical of the formula -R 6 -CH 2 -O-CO- or R 7 -CO-,
  • R and R are the same or different and are phenyl, pyridyl, quinolyl, quinoxalinyl, furyl, thienyl, pyrryl or pyrimidyl, which are optionally up to 2 times identical or different by fluorine, chlorine, bromine or by straight-chain or branched alkyl or acyl up to 4 carbon atoms are substituted,
  • R »2 represents hydrogen or methyl
  • R represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl or cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,
  • R 4 represents straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by phenyl,
  • R 5 represents a radical of the formula -OCO-R 8 ,
  • R 8 is straight-chain or branched alkyl having up to 3 carbon atoms
  • R 4 and R 5 together with the sulfur atom represent a heterocyclic radical
  • R 9 and R 10 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
  • a represents a number 1, 2 or 3
  • R> 4 R D 9, r R> 10 and a have the meaning given above,
  • inert organic solvents such as ethers, e.g. Diethyl ether, glycol mono- or dimethyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, p-cresol, toluene, xylene, cyclohexane or petroleum fractions or halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, or dimethyl sulfoxide, dimethylformamide, hexamethylidium phosphorus, phosphorus methyl amide, Triethylamine or picoline. It is also possible to use mixtures of the solvents mentioned. Methylene chloride, tetrahydrofuran and dioxane are particularly preferred.
  • Suitable bases are organic amines, trialkyl (C 1 -C 6 ) amines such as triethylamine or heterocycles such as pyridine, methylpiperidine, piperidine or
  • N-methylmorpholine Triethylamine and N-methylmorpholine are preferred.
  • the bases are generally used in an amount of 0.1 mol to 5 mol, preferably from 1 mol to 3 mol, in each case based on 1 mol of the compounds of the general formulas (IV) or (IVa).
  • the compounds of the general formulas (IV) and (IVa) are known per se or can be prepared by customary methods.
  • the compounds of the general formula (ED) are new as species and can be prepared by
  • R> 2 has the meaning given above
  • D represents an amino protecting group, preferably tert-butoxycarbonyl, benzyloxycarbonyl or FMOC,
  • E represents benzyl or C r C 4 alkyl
  • R 1 has the meaning given above
  • L represents hydroxy, C 1 -C 4 -alkoxy, nitro-substituted phenoxy or a typical carboxylic acid-activating radical such as chlorine,
  • E 1 has the meaning of E given above and is the same or different with it
  • Suitable solvents for all processes are the customary inert solvents which do not change under the reaction conditions. These preferably include organic solvents such as ethers, for example diethyl ether, glycol mono- or dimethyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, p- Cresol, toluene, xylene, cyclohexane or petroleum fractions or halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, or dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric acid triamide, ethyl acetate, pyridine, triethylamine or picoline. It is also possible to use mixtures of the named sols, if appropriate to be used with water. Methylene chloride, tetrahydrofuran, dioxane and dioxane / water are particularly preferred
  • Suitable bases are organic amines, T ⁇ alkyl (C ] -C 6 ) amme such as
  • T ⁇ ethylamine or heterocycles such as Py ⁇ din, Methylpipe ⁇ din, Pipendm or N-methylmorpholine are preferred T ⁇ ethylamin and N-methylmorpholine
  • the bases are generally used in an amount of 0.1 mol to 5 mol, preferably from 1 mol to 3 mol, in each case based on 1 mol of the compounds of the general formulas (V) and (VIII)
  • the reactions can be carried out at atmospheric pressure, but also at elevated or reduced pressure (for example 0.5 to 3 bar). In general, atmospheric pressure is used
  • the reactions are carried out in a temperature range from 0 ° C. to 100 ° C., preferably at 0 ° C. to 30 ° C. and under normal pressure.
  • oxidation of alcohol groups to the corresponding aldehydes is generally carried out in one of the solvents listed above in the presence of one of the bases listed above with oxidizing agents, such as, for example, potassium permanganate, bromine, Jones reagent, pyridine dichromate, pyridinium chlorochromate, pyridine -Sulfur trioxide complex or with chlorine solution and 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) [Org. Synth. 69, 212 (1990)] or oxalyl chloride [Swern oxidation (C1COCOC1 / DMSO / CH 2 C1 2 / NEt 3 ), for example according to RE Ireland et al., J. Org. Chem. 50, 2199 (1985)]. Oxidation is preferably carried out using pyridine
  • the Oxidaüon is generally carried out in a temperature range from 0 C to +50 C, preferably at room temperature and normal pressure.
  • the amino protective groups are split off in a manner known per se.
  • Condensation agents which can also be bases, are preferably used as auxiliaries for the respective peptide couplings, in particular if the carboxy group is activated as the anhydride.
  • the usual condensing agents such as carbodiimides, for example N, N'-diethyl, N, N'-dipropyl, NN 1 -diisopropyl, N, N * -dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N'-, are preferred here.
  • ethyl carbodiimide hydrochloride or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-l-ethoxycarbonyl-l, 2-dihydroquinoline, or propanephosphonic anhydride, or isobutylchloroformate, or bis (2-oxo-3-oxazolidinyl) phosphoryl chloride or benzotriazolyloxytri (dimethylamino) phosphonium hexafluorophosphobot, or 1-hydroxy benzotriazole and as bases alkali metal carbonates, for example sodium or potassium carbonate, or hydrogen carbonate, or organic bases such as trialkylamines, for example triethylamine, N-ethylmorph
  • N-methylmorpholine and 1-hydroxybenzotriazole N-methylmorpholine and 1-hydroxybenzotriazole.
  • the saponification of the carboxylic acid esters is carried out by customary methods by treating the esters with customary bases in inert solvents, it being possible for the salts initially formed to be converted into the free carboxylic acids by treatment with acid.
  • Suitable bases for the saponification are the customary inorganic bases. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as sodium hydroxide, lithium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates such as sodium or potassium carbonate or sodium hydrogen carbonate. Sodium hydroxide or lithium hydroxide are particularly preferably used
  • Suitable solvents for the saponification are water or the organic solvents customary for saponification. These preferably include alcohols such as methanol, ethanol, propanol, isopropanol or butanol, or ethers such as tetrahydrofuran or dioxane, or dimethylformamide or dimethyl sulfoxide. Alcohols such as methanol, ethanol, propanol or isopropanol are particularly preferably used.
  • the saponification is generally carried out in a temperature range from 0 ° C. to + 100 ° C., preferably from 0 ° C. to + 40 ° C.
  • the saponification is carried out at normal pressure.
  • negative pressure or overpressure e.g. from 0.5 to 5 bar
  • the base or the acid 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
  • the salts of the compounds according to the invention are formed in the first step as intermediates which can be isolated.
  • the acids according to the invention are obtained by treating the salts with customary inorganic acids. These preferably include mineral acids, for example
  • T includes the scope of E and E 'listed above,
  • auxiliary and / or base preferably HOBT and dicyclohexylcarbodiimide
  • the amino protecting group is split off, preferably Boc with hydrochloric acid in dioxane, Fmoc with piperidine and Z with HBr / HOAc or by hydrogenolysis.
  • All process steps take place at normal pressure and in a temperature range from 0 ° C to room temperature, preferably at room temperature.
  • the compounds show an antiviral effect against representatives of the Herpetoviridae group, especially against the human cytomegalovirus (HCMV).
  • the anti-HCMV activity was tested in a screening test system in 96-well
  • Microtiter plates determined with the aid of human embryonic pulmonary fibroblasts (HELF) cell cultures. The influence of the substances on the spread of the cytopathogenic effect was determined in comparison to the reference substance ganciclovir (Cymevene® sodium), a clinically approved anti-HCMV chemotherapeutic agent.
  • HELF human embryonic pulmonary fibroblasts
  • CIC50 highest concentration that shows no obvious anti-cellular effects.
  • IC50 concentration of the compound according to the invention which effects a 50% inhibition of the CPE.
  • the compounds according to the invention are therefore valuable active ingredients for the treatment and prophylaxis of diseases caused by the human cytomegalovirus.
  • the new active ingredient 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 in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, ie in amounts which are sufficient to achieve the dosage range indicated
  • 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 water is used as a diluent, organic solvents can optionally be used as auxiliary solvents
  • solutions of the active ingredient can be used using suitable liquid carrier materials.
  • Type of formulation and the time or interval at which the administration takes place. In some cases it may be sufficient to make do with less than the aforementioned minimum quantity, while in other cases the above-mentioned upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several individual doses over the day.
  • Example 2 The title compound is prepared analogously to the procedure of Example 1 from 80 mg (0.1 1 mmol) of the compound from Example XXIII, 17 ⁇ l (0.132 mmol) of 3-methyl-1-butanethiol, 4 ⁇ l of triethylamine in 10 ml of acetonitrile.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux pseudopeptides à action antivirale à fonction mercaptal ou thioéther de formule générale (I) dans laquelle les substituants ont la notation mentionnée dans la description. L'invention concerne en outre des procédés permettant de les préparer et leur utilisation comme agents antiviraux, notamment pour lutter contre des cytomégalovirus.
PCT/EP1997/000471 1996-02-16 1997-02-03 Nouveaux pseudopeptides a action antivirale a fonction mercaptal ou thioether WO1997030076A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU15464/97A AU1546497A (en) 1996-02-16 1997-02-03 Pseudopeptides with an anti-viral action and containing a mercaptal or thioether group

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19605769.8 1996-02-16
DE1996105769 DE19605769A1 (de) 1996-02-16 1996-02-16 Neue antiviral wirksame Pseudopeptide mit Mercaptal- oder Thioetherfunktion

Publications (1)

Publication Number Publication Date
WO1997030076A1 true WO1997030076A1 (fr) 1997-08-21

Family

ID=7785584

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1997/000471 WO1997030076A1 (fr) 1996-02-16 1997-02-03 Nouveaux pseudopeptides a action antivirale a fonction mercaptal ou thioether

Country Status (3)

Country Link
AU (1) AU1546497A (fr)
DE (1) DE19605769A1 (fr)
WO (1) WO1997030076A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0611776A2 (fr) * 1993-02-15 1994-08-24 Bayer Ag Nouveaux pseudopeptides à activité antivirale
EP0646598A1 (fr) * 1993-09-14 1995-04-05 Bayer Ag Nouveaux pseudopeptides à activité antivirale contenant de la valine
EP0646597A1 (fr) * 1993-09-14 1995-04-05 Bayer Ag Nouveaux pseudopeptides à activité antivirale contenant de la valine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0611776A2 (fr) * 1993-02-15 1994-08-24 Bayer Ag Nouveaux pseudopeptides à activité antivirale
EP0646598A1 (fr) * 1993-09-14 1995-04-05 Bayer Ag Nouveaux pseudopeptides à activité antivirale contenant de la valine
EP0646597A1 (fr) * 1993-09-14 1995-04-05 Bayer Ag Nouveaux pseudopeptides à activité antivirale contenant de la valine

Also Published As

Publication number Publication date
AU1546497A (en) 1997-09-02
DE19605769A1 (de) 1997-08-21

Similar Documents

Publication Publication Date Title
DE69034202T2 (de) Zwischenprodukte zur Herstellung von non-peptiden retroviralproteasehemmenden Verbindungen
EP0608759B1 (fr) Dérivés de pipérazines
EP0412350A2 (fr) Inhibiteurs de la rénine, procedure de leur préparation de leur utilisation comme médicament
DE69929669T2 (de) Zyklische Amidderivate die Cathepsin K hemmen
CH677672A5 (fr)
CH676988A5 (fr)
EP0656348A2 (fr) Dérivés d'acide acérique comme médicaments
DE69602940T2 (de) Derivate von bernsteinsäure als protease-inhibitoren
WO2001010845A1 (fr) Nouvelles diketo-piperazines
DE4003574A1 (de) Neue dipeptide, verfahren zu ihrer herstellung und ihre verwendung als renininhibitoren in arzneimitteln
EP0646598A1 (fr) Nouveaux pseudopeptides à activité antivirale contenant de la valine
DE4331134A1 (de) Neue antiviral wirksame Pseudopeptide
CH676003A5 (fr)
EP0432595A1 (fr) Nouveaux peptides, leur préparation et leur utilisation dans des médicaments
EP1165601A2 (fr) Promedicaments d'inhibiteurs de la thrombine
DE3000628A1 (de) Neue epoxybernsteinsaeurederivate
EP0611776A2 (fr) Nouveaux pseudopeptides à activité antivirale
DE3506307C2 (fr)
DE19838998A1 (de) Neue Naturstoffderivate
DE19930075A1 (de) Neue Amino- und Amidosulfonamide als antivirale Mittel
DE3017684A1 (de) Epoxysuccinylaminosaeurederivate und arzneimittel, welche diese enthalten
WO1997030076A1 (fr) Nouveaux pseudopeptides a action antivirale a fonction mercaptal ou thioether
EP0403828A1 (fr) Peptides inhibitant de la rénine, procédé pour leur préparation et leur utilisation comme médicaments
WO1997030075A1 (fr) Pseudopeptides substitues par oxime et nitron a action antivirale
WO1997030071A1 (fr) Pseudopeptides substitues par thiazolidin-2-yle et 1,3-thiazan-2-yle

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BG BR BY CA CN CZ EE HU IL IS JP KE KP KR LT LV MX NO NZ PL RO RU SG SI SK UA US VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: JP

Ref document number: 97528933

Format of ref document f/p: F

122 Ep: pct application non-entry in european phase