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WO1997030075A1 - Pseudopeptides substitues par oxime et nitron a action antivirale - Google Patents

Pseudopeptides substitues par oxime et nitron a action antivirale Download PDF

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Publication number
WO1997030075A1
WO1997030075A1 PCT/EP1997/000470 EP9700470W WO9730075A1 WO 1997030075 A1 WO1997030075 A1 WO 1997030075A1 EP 9700470 W EP9700470 W EP 9700470W WO 9730075 A1 WO9730075 A1 WO 9730075A1
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WO
WIPO (PCT)
Prior art keywords
phenyl
carbon atoms
chain
branched alkyl
straight
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.)
Ceased
Application number
PCT/EP1997/000470
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German (de)
English (en)
Inventor
Siegfried Raddatz
Dieter Häbich
Thomas-Joachim Schulze
Thomas Schenke
Jürgen Reefschläger
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.)
Bayer AG
Original Assignee
Bayer AG
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
Priority claimed from DE19632948A external-priority patent/DE19632948A1/de
Application filed by Bayer AG filed Critical Bayer AG
Priority to AU15994/97A priority Critical patent/AU1599497A/en
Publication of WO1997030075A1 publication Critical patent/WO1997030075A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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 antivirally active oxime- and nitrone-substituted pseudopeptides, processes 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 [US ⁇
  • nucleoside and nucleotide analogs Various nucleoside and nucleotide analogs, anthraquinone derivatives, phosphoric acid salts, cobalt complexes, macrolides and acyl peptides [EP-488 041] are known as classes of compounds with anti-cytomegaly activity.
  • the present invention now relates to new antivirally active oxime- and nitrone-substituted pseudopeptides of the general formula (I)
  • R 1 represents tert-butyloxycarbonyl or a radical of the formula -R 4 -CH 2 -O-CO- or R 5 -CO-, in which R 4 and R 5 are the same or different and phenyl
  • Row S, N and / or O stands, the ring systems optionally being substituted up to 3 times identically or differently 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 3 represents phenyl or straight-chain or branched alkyl having up to 7 carbon atoms, which is optionally substituted by phenyl or cycloalkyl having up to 6 carbon atoms,
  • R 6 is hydrogen or straight-chain or branched alkyl having up to 6
  • R 7 denotes straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl, and their salts
  • 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 such as hydrofluoric acid, hydrochloric acid and Hydrobromic acid, especially hydrofluoric and hydrochloric acids, also phosphoric acid, nitric acid, sulfuric acid, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids, such as acetic acid, maleic acid, malonic acid, oxalic acid, gluconic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, lactic acid and sorbic acid and sorbic acid Sulfonic acids such as p-toluenesulfonic acid, 1,5-naphthalenedisulfonic acid or camphorsulfonic acid.
  • hydrohalic acids such as hydrofluoric acid, hydrochloric acid and Hydrobromic acid, especially hydrofluoric and hydrochloric acids, also phosphoric acid, nitric acid, sulfuric acid, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids
  • 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 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-condensed unsaturated 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. Particularly preferred are: quinolyl, quinoxalinyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl or tetrazolyl.
  • the invention includes both the pure diastereomers, mixtures of several diastereomers and racemates.
  • the 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.
  • Preferred compounds of the general formula (I) according to the invention are those in which
  • R 1 represents tert-butoxycarbonyl or a radical of the formula -R 4 -CH 2 -O-CO- or R 5 -CO-, in which R 4 and R 5 are identical or different and are phenyl, pyridyl, quinolyl,
  • Furyl, thienyl, pyrryl, pyrimidyl or quinoxalinyl which are optionally substituted up to 2 times the same or different by fluorine, chlorine, bromine or by straight-chain or branched alkyl or acyl each having up to 5 carbon atoms, R 2 for hydrogen or methyl stands,
  • R 3 represents phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl or cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,
  • R 6 denotes hydrogen or for straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by phenyl,
  • R 7 denotes straight-chain or branched alkyl having up to 5 carbon atoms or benzyl, and their salts.
  • R 1 is tert-butoxycarbonyl or a radical of the formula -R 4 -CH 2 -O-CO- or R 5 -CO- in which R 4 and R 5 are identical or different and phenyl, pyridyl, quinolyl, or quinoxalinyl mean, which are optionally up to 2 times the same or different by fluorine, chlorine, bromine or by straight-chain or branched alkyl or acyl each having up to 5 carbon atoms, R 2 is hydrogen or methyl,
  • R 3 represents phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by phenyl or cyclopentyl or cyclohexyl, A for a radical of the formula N-OR 6 or
  • R 6 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl,
  • R 7 straight-chain or branched alkyl having up to 4 carbon atoms or
  • R 3 represents isobutyl, benzyl, phenyl or cyclohexylmethyl.
  • R 1 , R 2 and R 3 have the meaning given above, with compounds of the general formulas (IV) or (IVa) H 2 NOR 6 (IV) R 7 -NH-OH (IVa) in which
  • R 6 and R 7 have the meaning given above, in inert solvents and in the presence of a base.
  • the usual inert solvents which do not change under the reaction conditions are suitable as solvents for all process steps.
  • These preferably include organic solvents such as ethers.
  • organic solvents such as ethers.
  • Suitable bases are organic amines, trialkyl (C 1 -C 6 ) amines such as, for example, triethylamine or heterocycles such as pyridine, methylpiperidine, piperidine or N-methylmorphohn. Triethylamine and N-methylmorpholine are preferred.
  • the bases are generally used in an amount of 0.1 mol to 5 mol, preferably 1 mol to 3 mol, based in each case on 1 mol of the compounds of the general formula (III).
  • the reactions can be carried out at normal pressure, but also at elevated or reduced pressure (e.g. 0.5 to 3 bar). Generally one works at normal pressure.
  • the compounds of general formula (III) are partially new as species and can be prepared by
  • R 2 has the meaning given above
  • D represents an amino protecting group, preferably Boc, Fmoc and Z
  • E represents benzyl or C 1 -C 4 alkyl, first converted into the free carboxylic acids, then with compounds of the general formula (VI)
  • R 3 has the meaning given above, after removal of the protective group D in a last step, with compounds of the general formula (VII)
  • R 1 has the meaning given above and
  • L represents hydroxyl, C 1 -C 4 -alkoxy, nitro-substituted phenoxy or a typical carboxylic acid-activating radical such as chlorine, in inert solvents and optionally in the presence of a base and / or auxiliary, and finally oxidizes the alcohol group, or
  • R 1 and R 2 have the meaning given above and
  • E ' has the meaning of E given above and is the same or different with it, first splits off the protective group E' as described under [A] and then with compounds of the general formula (V) in inert solvents, if appropriate in the presence of a base and / or an auxiliary, and the oxidation is carried out as described above.
  • the usual inert solvents which do not change under the reaction conditions are suitable as solvents for all process steps.
  • 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, hexamethylidium triethyl aminophosphate, triamethylphosphinate, triamethylphosphinate, triamethylphosphinate, triamethylphosphinate, triamethylphosphinate, triamethylphosphinate, triamethylphosphinate, triamethylphosphinate, triamethylphosphinate.
  • 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 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 normal pressure, but also at elevated or reduced pressure (e.g. 0.5 to 3 bar). Generally one works at normal pressure.
  • the reactions are carried out in a temperature range from 0 ° C to 100 ° C, preferably at 0 ° C to 30 ° C and at 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 potassium permanganate, bromine, Jones reagent, pyridinium dichromate, pyridinium chlorochromate,
  • the oxidation generally takes place in a temperature range from 0 ° C. to + 50 ° C., preferably at room temperature and normal pressure.
  • Condensation agents which can also be bases, are preferably used as auxiliaries for the respective peptide couplings, in particular if the carboxyl group is present as an activated anhydride.
  • the usual condensing agents such as carbodiimides, for example N, N'-diethyl, N, N'-dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylaminopropyl) -N ', are preferred here.
  • ethyl carbodiimide hydrochloride or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazoium 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 bis- (2-oxo-3-oxazolidinyl) phosphoryl chloride or benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphate, or 1-hydroxybenzotriazole (HOBT) and as a base, e.g.
  • organic bases such as trialkylamines, for example triethylamine, N-ethylmorpholine, N-methylpiperidine or diisopropylethylamine.
  • Dicyclohexylcarbodiimide, N-methylmorpholine and 1-hydroxybenzotriazole are particularly preferred.
  • 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 to convert the salts initially formed into the free carboxylic acids by treatment with acid.
  • the usual inorganic bases are suitable as bases for the saponification. These preferably include alkali hydroxides or alkaline earth hydroxides such as sodium hydroxide, lithium hydroxide, potassium hydroxide or barium hydroxide, or alkali 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 generally carried out at normal pressure. However, it is also possible to work under negative pressure or overpressure (for example 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 such as hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid or phosphoric acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid or phosphoric acid.
  • carboxylic acids it has proven advantageous to acidify the basic reaction mixture of the saponification in a second step without isolating the salts. The acids can then be isolated in the usual way.
  • R 2 has the meaning given above and
  • T includes the scope of E and E 'given above, with amino acid derivatives of the general formula (X)
  • X includes the above-mentioned scope of D and R 1 , in one of the abovementioned solvents, preferably methylene chloride, in the presence of an auxiliary and / or base, preferably HOBT and dicyclohexylcarbodiimide, and then, likewise by customary methods, cleaves the amino protecting group, specifically 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.
  • solvents preferably methylene chloride
  • an auxiliary and / or base preferably HOBT and dicyclohexylcarbodiimide
  • the compounds show an antiviral activity against representatives of the group of the Herpetoviridae, especially against the human cytomegalovirus (HCMV).
  • HCMV human cytomegalovirus
  • the anti-HCMV activity was determined in a screening test system in 96-well microtiter plates with the aid of human embryonic pulmonary fibroblasts (HELF) cell cultures.
  • the influence of the substances on the spread of the cytopathogenic effect was compared to that of the reference substance Ganciclovir (Cymevene ® sodium), a clinically approved anti-HCMV chemotherapy drug.
  • the compounds according to the invention are therefore valuable active substances for the treatment and prophylaxis of diseases caused by the human cytomegalovirus. Examples of indications which may be mentioned are:
  • HCMV infections Treatment and prophylaxis of HCMV infections in AIDS patients (retinitis, pneumonitis, gastrointestinal infections).
  • the new active ingredient can be converted in a known manner into the customary formulations, such as tablets, dragées, 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, i.e. in amounts sufficient to achieve the dosage range indicated.
  • the formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. if water is used as the diluent, organic solvents can optionally be used as auxiliary solvents.
  • the application is carried out in the usual way, preferably orally, parenterally or topically, in particular perlingually or intravenously.
  • solutions of the active ingredient can be used using suitable liquid carrier materials.
  • Application is about 0.01 to 25 mg / kg, preferably 0.1 to 10 mg / kg body weight.
  • Example XI In analogy to the procedure of Example XI, the title compound is prepared from 1.4 g (2.19 mmol) of the compound from Example XII and 1.32 g (4.38 mmol) of 2,5-dimethylbenzyl-4-nitrophenyl carbonate.
  • the mixture is stirred for 3 hours at room temperature, extracted three times with 100 ml of dichloromethane, the combined dichloromethane solution is shaken twice with 50 ml of saturated sodium chloride solution, dried with sodium sulfate and evaporated to dryness.
  • Example II In analogy to the procedure of Example I, the title compound is prepared from 2.0 g (2.82 mmol) of the compound from Example XXII and 2.1 g (13.2 mmol) of sulfur trioxide-pyridine complex.
  • Example (XX) Analogously to Example (XX), the title compound is prepared from 2.6 g (3.6 mmol) of the substance from Example (XXV) and 2.46 g (8.18 mmol) of the substance from Example (XI).
  • Example (XXI) Analogously to Example (XXI), the title compound is prepared from 2.13 g (2.95 mmol) of substance from Example (XXVI) with 2.21 g (13.9 mmol) of sulfur trioxide-pyridine complex in 20 ml each of dichloromethane and dimethyl sulfoxide.
  • Diastereomer A, R or S, E or Z product, R f 0.43 (dichloromethane / methanol 9/1)
  • Diastereomer B, R or S, Z or E product, R f 0.39 (dichloromethane / methanol 9/1)
  • the title compounds are prepared from 80 mg (0.11 mol) of the compound from Example XIV, 0.4 ml (5.28 mmol) of pyridine and 9 mg (0.13 mmol) of hydroxylamine hydrochloride .
  • the title compound is prepared from 100 mg (0.146 mg) of the compound from Example XXI, 0.6 ml (6.99 mmol) of pyridine and 12 mg (0.175 mmol) of hydroxylamine hydrochloride.
  • Example XXII 1.1 ml (13.56 mmol) of pyridine and 24 mg (0.34 mmol) of hydroxylamine hydrochloride.
  • the title compound is prepared from 200 mg (0.283 mmol) of the compound from Example VIII, 30 mg (0.426 mmol) of hydroxylamine hydrochloride and 3.5 ml (0.43 mmol) of pyridine. There is an E / Z mixture that is not separated.

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

Abstract

L'invention concerne de nouveaux pseudopeptides de la formule générale (I) substitués par oxime et nitron, à action antivirale. Dans cette formule, les substituants ont la notation mentionnée dans la description. L'invention concerne par ailleurs des procédés permettant de les préparer et leur utilisation comme agents antiviraux, notamment pour lutter contre des cytomégalovirus.
PCT/EP1997/000470 1996-02-16 1997-02-03 Pseudopeptides substitues par oxime et nitron a action antivirale Ceased WO1997030075A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU15994/97A AU1599497A (en) 1996-02-16 1997-02-03 Oxime- and nitron-substituted pseudopeptides with an anti-viral action

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE19605770 1996-02-16
DE19605770.1 1996-02-16
DE19632948A DE19632948A1 (de) 1996-02-16 1996-08-16 Neue antiviral wirksame oxim- und nitronsubstituierte Pseudopeptide
DE19632948.5 1996-08-16

Publications (1)

Publication Number Publication Date
WO1997030075A1 true WO1997030075A1 (fr) 1997-08-21

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Application Number Title Priority Date Filing Date
PCT/EP1997/000470 Ceased WO1997030075A1 (fr) 1996-02-16 1997-02-03 Pseudopeptides substitues par oxime et nitron a action antivirale

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AU (1) AU1599497A (fr)
WO (1) WO1997030075A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012004554A1 (fr) 2010-07-06 2012-01-12 St George's Hospital Medical School Composés aldéhyde comme inhibiteurs de l'allergène peptidique de groupe 1 de l'acarien détriticole et leur utilisation
US8541363B2 (en) 2010-01-22 2013-09-24 St George's Hosptial Medical School Pyruvamide compounds as inhibitors of dust mite group 1 peptidase allergen and their use

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4307438A1 (de) * 1993-02-15 1994-08-18 Bayer Ag Neue antiviral wirksame Pseudopeptide
DE4331134A1 (de) * 1993-09-14 1995-03-16 Bayer Ag Neue antiviral wirksame Pseudopeptide
DE4331135A1 (de) * 1993-09-14 1995-03-16 Bayer Ag Neue antiviral wirksame valinhaltige Pseudopeptide

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4307438A1 (de) * 1993-02-15 1994-08-18 Bayer Ag Neue antiviral wirksame Pseudopeptide
DE4331134A1 (de) * 1993-09-14 1995-03-16 Bayer Ag Neue antiviral wirksame Pseudopeptide
DE4331135A1 (de) * 1993-09-14 1995-03-16 Bayer Ag Neue antiviral wirksame valinhaltige Pseudopeptide

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8541363B2 (en) 2010-01-22 2013-09-24 St George's Hosptial Medical School Pyruvamide compounds as inhibitors of dust mite group 1 peptidase allergen and their use
US8637453B2 (en) 2010-01-22 2014-01-28 St George's Hospital Medical School Pyruvamide compounds as inhibitors of dust mite group 1 peptidase allergen and their use
WO2012004554A1 (fr) 2010-07-06 2012-01-12 St George's Hospital Medical School Composés aldéhyde comme inhibiteurs de l'allergène peptidique de groupe 1 de l'acarien détriticole et leur utilisation

Also Published As

Publication number Publication date
AU1599497A (en) 1997-09-02

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