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WO1997030071A1 - Pseudopeptides substitues par thiazolidin-2-yle et 1,3-thiazan-2-yle - Google Patents

Pseudopeptides substitues par thiazolidin-2-yle et 1,3-thiazan-2-yle Download PDF

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Publication number
WO1997030071A1
WO1997030071A1 PCT/EP1997/000474 EP9700474W WO9730071A1 WO 1997030071 A1 WO1997030071 A1 WO 1997030071A1 EP 9700474 W EP9700474 W EP 9700474W WO 9730071 A1 WO9730071 A1 WO 9730071A1
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WO
WIPO (PCT)
Prior art keywords
carbon atoms
chain
straight
branched alkyl
general formula
Prior art date
Application number
PCT/EP1997/000474
Other languages
German (de)
English (en)
Inventor
Siegfried Raddatz
Thomas-Joachim Schulze
Dieter Häbich
Wolfgang Kanhai
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 AU15995/97A priority Critical patent/AU1599597A/en
Publication of WO1997030071A1 publication Critical patent/WO1997030071A1/fr

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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
    • C07K5/02—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
    • 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 novel antiviral thiazolidin-2-yl and 1,3-thiazan-2-yl substituted pseudopeptides, processes for their preparation and their use as antiviral agents, in particular against cytomegaloviruses.
  • peptide aldehydes are described as inhibitors of HIV protease or picornavirus proteases. Furthermore, peptide aldehydes have been described as inhibitors of serine proteases [US 5 153 176; EP 516 877].
  • nucleoside and nucleotide analogs Various nucleoside and nucleotide analogs, anthraquinone derivatives, phosphoric acid derivatives, cobalt complexes, macrolides and acyl peptides [EP 488041] are known as classes of compounds with anti-cytomegaly activity.
  • the present invention now relates to novel antiviral thiazolidin-2-yl and 1,2-thiazan-2-yl-substituted pseudopeptides of the general formula (I)
  • R 1 represents tert-butyloxycarbonyl or a radical of the formula -R 8 -CH 2 -O-CO- or R 9 -CO-, wherein
  • R 8 and R 9 are identical or different and are phenyl or a 5- to 7-membered aromatic, optionally benzocondensed heterocycle having up to 4 heteroatoms from the series S, N and / or O, the ring systems optionally up to 3 times the same or different 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 3 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 and R 5 are the same or different and represent hydrogen or methyl
  • a represents a number 1 or 2
  • R 6 represents hydrogen, benzyl or straight-chain or branched alkyl having up to 6 carbon atoms
  • R 7 represents hydrogen or straight-chain or branched alkyl or acyl each having up to 6 carbon atoms
  • the acids which can be added preferably also include hydrohalic acids, such as, for example, the hydrofluoric acid, hydrochloric acid and the hydrobromic acid, in particular the hydrofluoric and chlorine acids
  • 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, sorbic acid and lactic acid as well as sulfonic acids such as p-toluene sulfonic acid, 1,5-naphthalene disulfonic acid or camphorsulfonic acid.
  • Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group.
  • Heterocycle generally represents a 5- to 7-membered, preferably 5- to 6-membered, aromatic, optionally benzo-fused ring, which may contain up to 4 oxygen, sulfur and / or nitrogen atoms as heteroatoms.
  • 5- and 6 are preferred -linked rings with one oxygen, sulfur and / or up to 4 nitrogen atoms. Are particularly preferred.
  • 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 8 -CH 2 -O-CO- or R 9 -CO-,
  • R 8 and R 9 are the same or different and are phenyl, pyridyl, quinolyl,
  • R 2 represents hydrogen or methyl
  • R 3 represents straight-chain or branched alkyl having up to 5 carbon atoms, which may be substituted by phenyl or cyclopropyl, cyclobutyl,
  • R 4 and R 5 are the same or different and represent hydrogen or methyl
  • a represents a number 1 or 2
  • R 6 represents hydrogen, benzyl or straight-chain or branched alkyl having up to 5 carbon atoms
  • R 7 represents hydrogen or straight-chain or branched alkyl or acyl each having up to 5 carbon atoms
  • R 1 represents tert-butyloxycarbonyl or a radical of the formula -R 8 -CH 2 -O-CO- or R 9 -CO-,
  • R 8 and R 9 are the same or different and are phenyl, pyridyl, quinolyl, 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 represents hydrogen or methyl
  • R J represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl or cycl ⁇ pentyl or cyclohexyl,
  • R 4 and R 5 are identical or different and represent hydrogen or methyl
  • a represents a number 1 or 2
  • R 6 represents hydrogen, benzyl or straight-chain or branched alkyl having up to 4 carbon atoms
  • R 7 represents hydrogen or straight-chain or branched alkyl or acyl each having up to 4 carbon atoms, and their salts.
  • the compounds of the general formula (I) according to the invention can be prepared by:
  • R 1 , R 2 and R 3 have the meaning given above,
  • R 4 , R 5 , R 6 and R 7 have the meaning given above,
  • solvents which do not change under the reaction conditions are suitable as solvents for all process steps.
  • 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 dimethylsulfoxide, dimethylformamide, hexamethylphosphoric acid, hexamethylphosphate Ethyl acetate, pyridine, triethylamine or picoline It is also possible to use mixtures of the solvents mentioned, if appropriate also with water. Methylene chloride, tetrahydrofuran, dioxane and dioxane / water 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 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 under normal pressure, but also under elevated or reduced pressure (for example 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.
  • D represents an amino protecting group, preferably Boc, Fmoc or Z,
  • E represents benzyl or C, -C 4 -alkyl, first converted into the free carboxylic acids, then with compounds of the general formula (VII)
  • R 3 has the meaning given above
  • R 1 has the meaning given above
  • L is hydroxy, C j -C 4 - alkoxy, phenoxy or nitrosubstitutechnisches a typical carboxylic acid activating radical such as chlorine,
  • R 1 and R 2 have the meaning given above
  • solvents which do not change under the reaction conditions are suitable as solvents for all process steps.
  • 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 Hexamethylphosphoric triamide, ethyl acetate, pyridine, triethylamine or picoline It is also possible to use mixtures of the solvents mentioned, if appropriate also with water. Methylene chloride, tetrahydrofuran, dioxane and
  • Suitable bases are organic amines, trialkyl (C, -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 (VII) and (IX)
  • the reactions can be carried out under normal pressure, but also under elevated or reduced pressure (for example 0.5 to 3 bar). In general, the reaction is carried out under 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, for example, potassium permanganate, bromine, Jones reagent, pyridinium dichromate, pyridinium chlorochromate,
  • oxidizing agents such as, for example, 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
  • 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 carboxyl group is activated as the anhydride.
  • the usual condensation agents such as carbodiimides such as BN, N'-dimethyl, N, N'-dipropyl, are preferred here -, N, N'-D ⁇ isopropyl-, N, N'-D ⁇ cyclohexylcarbod ⁇ m ⁇ d, N- (3-D ⁇ methylam ⁇ no- ⁇ sopropyl) -N'-ethylcarbodam ⁇ d-Hydrochlo ⁇ d, or carbonyl compounds such as Carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2 ⁇ oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such
  • 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.
  • alkali metal hydroxides or alkaline earth metal 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.
  • alkali metal hydroxides or alkaline earth metal 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 (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 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.
  • T includes the scope of E and E 'listed above
  • X includes the scope of D and R 1 listed above,
  • auxiliary and / or base preferably HOBT and dicyclohexylcarbodiimide
  • amino protective 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 activity against representatives of the Herpetoviridae group, especially against the human cytomegalovirus
  • the anti-HCMV activity was determined in a screening test system in 96-well microplates 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 Reference substance
  • Ganciclovir (Cymevene® sodium), a clinically approved anti-HCMV chemotherapy drug
  • DMSO dimethyl sulfoxide
  • Toxic and cytostatic effects are also included.
  • IC 50 concentration of the compound according to the invention, which has a 50% inhibition
  • 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:
  • 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, that is to say 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.
  • the dosage is about 0.01 to 25 mg / kg, preferably 0.1 to 10 mg / kg body weight.
  • 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.
  • Diastereomer A and diastereomer B and C as a mixture of 50 mg (0.071 mmol) of the compound from Example V and 12 mg (0.08 mmol) of D - (-) - penicillamine in 10 ml of methanol p.a. produced under an argon atmosphere.
  • Diastereomer B and C (B / C 1/2): (40.5% of theory) 24 mg, colorless foam

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

Abstract

L'invention concerne de nouveaux pseudopeptides à action antivirale de la formule générale (I) substitués par thiazolidin-2-yle et 1,3-thiazan-2-yle. 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/EP1997/000474 1996-02-16 1997-02-03 Pseudopeptides substitues par thiazolidin-2-yle et 1,3-thiazan-2-yle WO1997030071A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU15995/97A AU1599597A (en) 1996-02-16 1997-02-03 Triazolidin-2-yl- and 1,3-thiazan-2-yl-substituted pseudopeptides

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19605767.1 1996-02-16
DE1996105767 DE19605767A1 (de) 1996-02-16 1996-02-16 Thiazolidin-2-yl-und 1,3-Thiazan-2-yl-substituierte Pseudopeptide

Publications (1)

Publication Number Publication Date
WO1997030071A1 true WO1997030071A1 (fr) 1997-08-21

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Application Number Title Priority Date Filing Date
PCT/EP1997/000474 WO1997030071A1 (fr) 1996-02-16 1997-02-03 Pseudopeptides substitues par thiazolidin-2-yle et 1,3-thiazan-2-yle

Country Status (3)

Country Link
AU (1) AU1599597A (fr)
DE (1) DE19605767A1 (fr)
WO (1) WO1997030071A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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 (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

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DE19605767A1 (de) 1997-08-21
AU1599597A (en) 1997-09-02

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