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EP0824529A1 - Benzothiazoles et benzoxazoles, medicaments les contenant, leur utilisation et procedes permettant de les preparer - Google Patents

Benzothiazoles et benzoxazoles, medicaments les contenant, leur utilisation et procedes permettant de les preparer

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Publication number
EP0824529A1
EP0824529A1 EP96914169A EP96914169A EP0824529A1 EP 0824529 A1 EP0824529 A1 EP 0824529A1 EP 96914169 A EP96914169 A EP 96914169A EP 96914169 A EP96914169 A EP 96914169A EP 0824529 A1 EP0824529 A1 EP 0824529A1
Authority
EP
European Patent Office
Prior art keywords
benzothiazole
group
theory
yield
general formula
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.)
Withdrawn
Application number
EP96914169A
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German (de)
English (en)
Inventor
Peter Müller
Rudolf Hurnaus
Roland Maier
Michael Mark
Bernhard Eisele
Ralph-Michael Budzinski
Leo Thomas
Gerhard Hallermayer
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.)
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Dr Karl Thomae GmbH
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Filing date
Publication date
Application filed by Dr Karl Thomae GmbH filed Critical Dr Karl Thomae GmbH
Publication of EP0824529A1 publication Critical patent/EP0824529A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/116—Heterocyclic compounds
    • A23K20/137—Heterocyclic compounds containing two hetero atoms, of which at least one is nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • 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
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C07D277/66—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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 in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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 in position 2
    • C07D277/70—Sulfur atoms
    • C07D277/74—Sulfur atoms substituted by carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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 in position 2
    • C07D277/70—Sulfur atoms
    • C07D277/76—Sulfur atoms attached to a second hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to new benzothiazoles and benzoxazoles, their salts with physiologically compatible organic and inorganic acids, processes for the preparation of these compounds and medicaments containing them.
  • the compounds according to the invention are inhibitors of cholesterol biosynthesis, in particular inhibitors of the enzyme 2,3-epoxysqualene lanosterol cyclase, a key enzyme in cholesterol biosynthesis.
  • the compounds according to the invention are suitable for the treatment and prophylaxis of hyperlipidemia, hypercholesterolaemia and atherosclerosis. Further possible fields of application arise for the treatment of hyperproliferative skin and vascular diseases, tumors, gallstone disorders and mycoses.
  • Hypercholesterolemias and hyper lipidemias which are risk factors for the development of atherosclerotic vascular changes and their consequential diseases such as, for example, coronary heart disease, cerebral ischemia, intermittent claudication and gangrene, are to be mentioned here in particular.
  • cholesterol biosynthesis inhibitors are the treatment of hyperproliferative skin and vascular diseases and tumor diseases, the treatment and prophylaxis of gallstone disorders and the use in mycoses. In the latter case, this involves an intervention in ergosterol biosynthesis in fungal organisms, which is largely analogous to cholesterol biosynthesis in mammalian cells.
  • the cholesterol or ergosterol biosynthesis proceeds, starting from acetic acid, over a larger number of reaction steps.
  • This multi-stage process offers a number of possible interventions, examples of which are:
  • HMG-CoA 3-hydroxy-3-methylglutaryl-coenzyme A
  • Inhibitors of the enzyme HMG-CoA reductase are 3,5-dihydroxycarboxylic acids of the mevinoline type and their ⁇ -lactones, the representatives of which lovastatin, simvastatin and pravastatin are used in the therapy of hypercholesterolemia. Further possible areas of application of these compounds are fungal infections (US Pat. No. 4,375,475, EP-A-0 113 881, US Pat. No. 5,106,992), skin diseases (EP-A-0 369 263) and gallstone disorders and tumor diseases (US Pat. A-5,106, 992; Lancet 33j9, 1154-1156 [1992]). Inhibition of smooth muscle cell proliferation by Lovastatin is described in Cardiovasc. Drugs. Ther. 5th, Suppl. 3, 354 [1991].
  • Inhibitors of the enzyme squalene synthetase are e.g. Isopronide (phosphinylmethyl) phosphonates, the suitability of which for the treatment of hypercholesterolemia, gallstone disorders and tumor diseases is described in EP-A-0 409 181 and J. Med. Chemistry 24, 1912 [1991], and also the Sgualestatine with cholesterol-lowering and antifungal activity (J. Antibiotics 5th, 639-647 [1992] and J. Biol. Chemistry 2 £ 7, 11705-11708 [1992].
  • Isopronide phosphinylmethyl
  • Allylamines such as naftifin and terbinafine are known as inhibitors of the enzyme sgualen epoxidase, which have found use in the treatment of fungal diseases, and the allylamine NB-598 with antihypercholesterolemic activity (J. Biol. Chemistry ______., 18075-18078 , [1990]) and fluorosquale derivatives with hypocholesterolemic activity (US-A-5, 011, 859).
  • piperidines and azadecalines have been described with potential hypocholesterolemic and / or antifungal activity, the mechanism of action of which has not been clearly established and which are squalene epoxidase and / or 2,3-epoxysqualene lanosterol cyclase inhibitors (EP-A -0 420 116, EP-A-0 468 434, US-A-5, 084,461 and EP-A-0 468 457).
  • inhibitors of the enzyme 2,3-epoxysqualene-lanosterol cyclase are diphenyl derivatives (EP-A-0 464 465), aminoalkoxybenzene derivatives (EP-A-0 410 359), aminoalkyl derivatives
  • inhibitors of the enzyme lanosterol-14 ⁇ -demethylase are also steroid derivatives with potential antihyperlapemic activity which simultaneously influence the enzyme HMG-CoA reductase (US Pat. No. 5,041,432, J. Biol. Chemistry 266, 20070-20078 [ 1991], US-A-5, 034,548).
  • this enzyme is inhibited by the azole-type antifungals, which are N-substituted imidazoles and triazoles.
  • This class includes, for example, the antifungals ketoconazole and fluconazole on the market.
  • the compounds of the general formula I below are new. It has surprisingly been found that they are very effective inhibitors of the enzyme 2,3-epoxysqualene lanosterol cyclase (international classification: EC5.4.99.7).
  • the enzyme 2,3-epoxisqualen-lanosterol cyclase catalyzes a key step in cholesterol or ergosterol biosynthesis, namely the conversion of 2,3-epoxis torment into lanosterol, the first compound with a steroid structure in the biosynthesis cascade.
  • inhibitors of this enzyme are expected to have the advantage of higher selectivity, since the inhibition of these early biosynthesis steps leads to a decrease in biosynthetically formed mevalonic acid and thereby can also negatively influence the biosynthesis of the mevalonic acid-dependent substances dolichol, ubiquinone and isopentenyl-t-RNA (cf. J. Biol. Chemistry 265. 18075-18078 [1990]).
  • the invention relates to the provision of antihypercholesterolemic substances which are suitable for the treatment and prophylaxis of atherosclerosis and which, compared to known active substances, are distinguished by a better antihypercholesterolemic effect with increased selectivity and thus increased safety. Since the compounds according to the invention can also inhibit ergosterol biosynthesis in the fungal organism due to their high activity as inhibitors of the enzyme 2,3-epoxysqualene lanosterol cyclase, they are also suitable for the treatment of mycoses.
  • the present invention comprises the new benzothiazoles and benzoxazoles of the general formula
  • n is the number 2, 3, 4, 5 or 6
  • X is an oxygen atom or sulfur atom
  • Z is a bond, an oxygen or sulfur atom, an imino group in which the hydrogen atom can be replaced by an alkyl group having 1 to 3 carbon atoms, or the sulfonyl group,
  • R 1 is a triphenylmethyl, phenyl or pyridyl group, a straight-chain or branched alkyl group with 1 to 8 carbon atoms or a straight-chain alkenyl group with 2 to 6 carbon atoms, optionally with 1 to 3 methyl groups may be substituted, both the alkyl group and the alkenyl group being terminated by a cycloalkyl group having 3 to 7 carbon atoms, by a phenyl or naphthyl group, by a 5-membered heteroaryl group bonded via a carbon atom, which may be by an alkyl group substituted imino group, an oxygen or sulfur atom or a nitrogen atom and an oxygen or sulfur atom or an imino group optionally substituted by an alkyl group, or by a 6-membered heteroaryl group bonded via a carbon atom and containing 1 or 2 nitrogen atoms where the phenyl radicals mentioned above can each be mono- or di-substituted
  • R 2 and R 3 which may be the same or different, each represent a straight-chain or branched alkyl group having 1 to 6 carbon atoms, which may be terminally substituted by a hydroxyl, alkyloxy or alkylcarbonyloxy group, the alkyl parts in each case being straight-chain or branched and can comprise 1 to 6 carbon atoms, a straight-chain or branched alkenyl group having 3 to 6 carbon atoms or
  • R 2 and R 3 together with the intermediate nitrogen atom form a 5-, 6- or 7-membered, saturated, monocyclic ring, wherein in a 6- or 7-membered ring formed in this way a methylene group in the 4-position by an oxygen atom or a -NH group can be replaced and the hydrogen atom in the -NH group can be replaced by an alkyl group and the above-mentioned 5-, 6- or 7-membered rings can additionally be substituted in the carbon skeleton by one or two alkyl groups, mean,
  • halogen atom denotes a fluorine, chlorine, bromine or iodine atom and, unless stated otherwise, an alkyl group can contain 1 to 3 carbon atoms, their enantiomers, diastereomers and their salts, especially their physiologically acceptable acid addition salts.
  • benzothiazoles of the general formula I above are preferred, in particular the benzothiazoles of the general formula Ia
  • Z is a bond, an N-methylimino group, an oxygen or sulfur atom,
  • R 1 is a phenyl, 2- or 4-pyridyl group, a straight-chain alkyl group with 1 to 5 carbon atoms optionally substituted by 1 to 3 methyl groups, a straight-chain alkyl group with 1 to 3 carbon atoms being additionally terminated by a cycloalkyl ring with 5 or 6 carbon atoms , by a phenyl, 1-naphthyl, 2-naphthyl, 2-thienyl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, 1-methylpyrrol-2-yl, 1-methylpyrrole -3-yl, 2-pyridyl or 4-pyridyl group can be substituted, or a 2-phenylethenyl group, the above-mentioned phenyl groups each having a fluorine or chlorine atom, a methyl, trifluoromethyl, cyano or Ni tro group can be monosubstituted or disubstituted by a
  • R 2 and R 3 which may be the same or different, each have a straight-chain or branched alkyl group with 1 to 3 carbon atoms, which may be terminally substituted by a hydroxyl, alkyloxy or alkylcarbonyloxy group, the alkyl parts in each case being straight-chain or branched and can comprise 1 to 4 carbon atoms, or an allyl group, or R 2 and R 3 together with the nitrogen atom in between are 1-pyrrolidinyl, 1-piperidinyl, 2, 6-dimethyl-l-piperidinyl, 1- Piperazinyl, 4-methyl-1-piperazinyl or 4-morpholine ring mean their enantiomers, diastereomers and their salts,
  • n is the number 2
  • Z is a bond
  • R 1 is a methyl group which is substituted by a phenyl group which is optionally substituted in 4-position by a fluorine or chlorine atom, a methyl or trifluoromethyl group or by a 1-methylpyrrol-3-yl group, or Z is a sulfur atom and
  • R 1 is a 2,2-dimethyl-propyl, 4-chlorophenyl, 4-fluorophenyl, 4-chlorobenzyl or 4-fluorobenzyl group,
  • R 2 and R 3 which may be the same or different, represent a methyl, ethyl or 2-hydroxyethyl group, and their salts.
  • R 2 and R 3 which may be the same or different, represent a methyl, ethyl or 2-hydroxyethyl group, and their salts.
  • the following are mentioned as particularly preferred compounds:
  • n, X, Z and R 1 are as defined at the outset and W 1 is a reactive leaving group, for example a chlorine, bromine or iodine atom or a sulfonic acid ester grouping, for.
  • W 1 is a reactive leaving group, for example a chlorine, bromine or iodine atom or a sulfonic acid ester grouping, for.
  • the methanesulfonyloxy or toluenesulfonyloxy group means with an amine of the general formula
  • R 2 and R 3 have the meanings mentioned above.
  • the reaction is advantageously carried out in a suitable solvent such as ethanol, ethyl acetate, methylene chloride, acetonitrile or dimethylformamide, if appropriate in the presence of a base such as sodium carbonate, potassium carbonate or triethylamine, or in an excess of a compound of the formula III, if appropriate in the presence of a reaction accelerator such as potassium or sodium iodide, at a temperature between 0 ° C and 120 ° C, but preferably at a temperature between 50 ° C and 120 ° C.
  • a suitable solvent such as ethanol, ethyl acetate, methylene chloride, acetonitrile or dimethylformamide
  • a base such as sodium carbonate, potassium carbonate or triethylamine
  • a reaction accelerator such as potassium or sodium iodide
  • n, X, Z and R 1 to R 3 are defined as mentioned at the outset, with the proviso that at least one of the radicals R 2 or R 3 is a straight-chain or branched alkyl group having 1 to 6 carbon atoms which are terminated by a hydroxyl group is substituted, means with an activated acid derivative of the general formula
  • R 4 is a straight-chain or branched alkyl group with 1 to 6
  • W 2 is a reactive leaving group, for example a chlorine,
  • Bromine or iodine atom or the imidazolide group means.
  • the acylation is carried out in a suitable solvent such as, for example, ethyl acetate, tetrahydrofuran or methylene chloride in the presence of a base such as triethylamine or diisopropylethylamine.
  • X, Z and R 1 are as defined in the introduction, with an amine of the general formula
  • n, R 2 and R 3 are as defined above and W 3 is a reactive leaving group, for example a chlorine, bromine or iodine atom or a sulfonic acid ester grouping such as, for. B. the methanesulfonyloxy group means.
  • the reaction is expediently carried out in a solvent such as acetonitrile, acetone, dimethylformamide or dimethyl sulfoxide, optionally in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or sodium hydroxide, optionally in the presence of a reaction accelerator such as potassium or sodium iodide, at a temperature between 20 ° C and 140 ° C, but preferably carried out at a temperature between 50 ° C and 140 ° C.
  • a solvent such as acetonitrile, acetone, dimethylformamide or dimethyl sulfoxide
  • a base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or sodium hydroxide
  • a reaction accelerator such as potassium or sodium iodide
  • radicals R 2 and / or R 3 in a compound of the general formula VII have free hydroxyl groups, it is advisable to protect them in a suitable manner before the reaction, for. B. by silylation with trialkylsilyl chlorides and the protective groups after completion of the reaction using known methods.
  • X is a sulfur atom and Z is an oxygen or sulfur atom
  • n, R 2 and R 3 have the meanings mentioned above and W 4 represents a reactive leaving group such as, for example, a chlorine or bromine atom, with a compound of the general formula
  • the reaction is expediently carried out in a suitable solvent, such as, for example, tetrahydrofuran, acetonitrile or dimethylformamide, in the presence of a base such as sodium or potassium carbonate, potassium tert-butoxide or sodium hydride.
  • a suitable solvent such as, for example, tetrahydrofuran, acetonitrile or dimethylformamide
  • a base such as sodium or potassium carbonate, potassium tert-butoxide or sodium hydride.
  • R 1 , R 2 , X, Z and n are as defined in the introduction, with a compound of the general formula
  • R 3 is as defined at the beginning and
  • W 5 is a reactive leaving group, for example a chlorine,
  • the reaction is expediently carried out in a solvent such as acetonitrile, acetone, dimethylformamide or dimethyl sulfoxide, optionally in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or sodium hydroxide, optionally in the presence of a reaction accelerator such as potassium or sodium iodide, at a temperature between 20 ° C and 140 ° C, but preferably carried out at a temperature between 50 ° C and 140 ° C.
  • a solvent such as acetonitrile, acetone, dimethylformamide or dimethyl sulfoxide
  • a base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or sodium hydroxide
  • a reaction accelerator such as potassium or sodium iodide
  • radicals R 2 and / or R 3 in a compound of the general formula X and / or XI have free hydroxyl groups, it is advisable to protect them appropriately before the reaction, for. B. by silylation with trialkylsilyl chlorides and the protective groups after completion of the reaction by known methods.
  • the starting materials of the general formula II can be obtained from the corresponding hydroxy compounds VI by alkylation with an 1, ⁇ -dihaloalkane or with a 1, ⁇ -haloalkanol according to Mitsunobu in the presence of triphenylphosphine and an azodicarboxylic acid dialkyl ester, or with an alkylene carbonate such as ethylene or propylene carbonate and subsequent transfer tion of an ⁇ -hydroxyalkoxy derivative thus obtained into a chloroalkoxy, bromoalkoxy, alkyl or arylsulfonyloxy derivative.
  • the alkylations with an 1, ⁇ -dihaloalkane or an alkylene carbonate are advantageously carried out in a solvent such as acetonitrile or dimethylformamide in the presence of a base such as sodium or potassium carbonate at temperatures between 20 ° C. and 150 ° C., but preferably between 20 ° C. and 80 ° C executed.
  • the Mitsunobu reaction is preferably carried out in glycol dimethyl ether or tetrahydrofuran at 0-20 ° C.
  • the compounds of the general formula VI can be prepared from the corresponding methoxy or ethoxy compounds which are known from the literature or by processes known from the literature [J. Chem. Soc. 1487 (1956), J. Org. Chem. 33, 2858 (1968)], by ether cleavage using boron tribromide, pyridine hydrochloride or aluminum chloride.
  • the compounds of the general formula VIII are obtained by diazotating a compound of the general formula VIII in which W 4 represents an amino group or by alkylating a compound
  • a starting compound of the general formula VIII or XII obtained in this way can be converted into a corresponding compound, by reaction with a compound of the general formula IX the Z is not a bond. If Z in this way means a sulfur atom in a compound obtained in this way, it can be converted by oxidation into a corresponding compound in which Z represents a sulfinyl or sulfonyl group.
  • the compounds of general formula I have interesting biological properties. They are inhibitors of cholesterol biosynthesis, in particular inhibitors of the enzyme 2,3-epoxysqualen-lanosterol cyclase. Because of their biological properties, they are particularly suitable for the treatment and prophylaxis of hypercholesterolemia, hyperlipoproteinemia and hypertriglyceridemia and the resulting atherosclerotic Vascular changes with their secondary diseases such as coronary heart disease, cerebral ischemia, intermittent claudication, gangrene and others.
  • the compounds of the general formula I can either be used alone for monotherapy or in combination with other cholesterol- or lipid-lowering substances, the compounds preferably as an oral formulation, optionally also in the form of suppositories as rectals Formulation can be administered.
  • Possible combination partners include:
  • HMG-CoA reductase inhibitors such as lovastatin, sim-vastatin, pravastatin and others,
  • Squalene epoxidase inhibitors such as NB 598 and analog compounds as well - Squalene synthetase inhibitors such as representatives of the class of isoprenoid (phosphinylmethyl) phosphonates and squalestatin.
  • combination partners are the class of fibrates, such as clofibrate, bezafibrate, gemfibrozil and others, nicotinic acid, its derivatives and analogues such as acipimox and probucol.
  • the compounds of the general formula I are suitable for the treatment of diseases which are associated with excessive cell proliferation.
  • Cholesterol is an essential cell component and must be used for cell proliferation, i.e. H. Cell division, be present in sufficient quantities.
  • the inhibition of cell proliferation by inhibiting cholesterol biosynthesis is described using the example of smooth muscle cells with the HMG-CoA reductase inhibitor of the mevinoline type lovastatin, as mentioned at the beginning.
  • Tumor diseases are first to be mentioned as examples of diseases which are associated with excessive cell proliferation.
  • HMG-CoA reductase inhibitors reduces tumor growth (Lancet 339, 1154-1156 [1992]).
  • the compounds of the formula I according to the invention are therefore potentially suitable for the treatment of tumor diseases on account of their cholesterol biosynthesis-inhibiting action. They can be used alone or to support known therapy principles.
  • Hyperproliferative skin diseases such as psoriasis, basal cell carcinoma, squamous cell carcinoma, keratosis and keratinization disorders are further examples.
  • psoriasis used here denotes a hyperproliferative inflammatory skin disease which affects the regu Mechanism of the skin changes.
  • lesions are formed which contain primary and secondary changes in the proliferation in the epidermis, inflammatory reactions of the skin and the expression of regulatory molecules such as lymphokines and inflammation factors.
  • Psoriatic skin is morphologically characterized by an increased turnover of epidermis cells, thickened epidermis, abnormal keratinization of inflammatory cell infiltrates into the dermis layer and polymorphonuclear leucocyte infiltration into the epidermis, which causes an increase in the basal cell cycle. Hyperkeratotic and parakeratotic cells are also present.
  • the terms "keratosis”, “basal cell carcinomas”, “squamous cell carcinomas” and “keratinization disorders” refer to hyperproliterative skin diseases in which the regulation mechanism for the proliferation and differentiation of the skin cells is interrupted.
  • the compounds of formula I are effective as antagonists of skin hyperproliferation, i.e. H. as agents that inhibit the hyperproliferation of human keratinocytes.
  • the compounds are consequently suitable as agents for the treatment of hyperproliferative skin diseases such as psoriasis, basal cell carcinomas, keratinization disorders and keratosis.
  • the compounds of the formula I can be administered either orally or topically, where they can be used either alone in the form of monotherapy or in combination with known active ingredients.
  • hyperproliferative vascular diseases such as stenoses and vascular occlusions triggered by surgical measures such as PTCA (percutaneous transluminal coronary angioplasty) or bypass operations, which are based on the proliferation of smooth muscle cells.
  • PTCA percutaneous transluminal coronary angioplasty
  • bypass operations which are based on the proliferation of smooth muscle cells.
  • HMG-CoA reductase inhibitors of the mevinoline type such as lovastatin.
  • the compounds of general formula I are also Suitable for the treatment and prophylaxis of these diseases, where they either alone or in combination with known active ingredients, such as.
  • Another possible application of the compounds of the general formula I according to the invention is the prophylaxis and treatment of gallstone disorders.
  • the formation of gallstones is triggered by the fact that the cholesterol concentration in the bile exceeds the maximum solubility of the cholesterol in the bile, which leads to the precipitation of the cholesterol in the form of gallstones.
  • Lipid-lowering agents from the fibrate class lead to an increased excretion of neutral steroids via the bile and increase the tendency to form gallstones.
  • cholesterol biosynthesis inhibitors such as Lovatatin or Pravastatin do not lead to increased gallstone formation, on the contrary they can bring about a reduction in the cholesterol concentration in the bile and thus reduce the so-called lithogenic index, a measure of the probability of gallstone formation . This is described in Gut 31. 348-350 [1990] and in Z. Gastroenterol. ___., 242-245 [1991].
  • the compounds of general formula I are suitable for the therapy of infections by pathogenic fungi such as z. B. Candida albicans, Aspergillus niger, Trichophyton mentagrophytes, Penicillium sp., Cladosporium sp. and other.
  • pathogenic fungi such as z. B. Candida albicans, Aspergillus niger, Trichophyton mentagrophytes, Penicillium sp., Cladosporium sp. and other.
  • the end product of sterol biosynthesis in the fungal organism is not cholesterol, but rather the ergosterol essential for the integrity and function of the fungal cell membranes. The inhibition of ergosterol biosynthesis therefore leads to growth disturbances and possibly to the killing of the fungal organisms.
  • the compounds of general formula I can be administered either orally or topically. They can be used either alone or in combination with known antifungal agents, in particular those which intervene in other stages of sterol biosynthesis, such as, for example, the squalene epoxidase inhibitors terbinafine and naftifine or the lanosterol-14 ⁇ -demethylase inhibitors dated Azole type such as ketoconazole and fluconazole.
  • Another possible use of the compounds of the general formula I relates to their use in poultry farming.
  • the lowering of the cholesterol content of eggs by administration of the HMG-CoA reductase inhibitor lovastatin to laying hens has been described (FASEB Journal 4., A 533, Abstracts 1543 [1990]).
  • the production of low-cholesterol eggs is of interest since the cholesterol load in the body can be reduced by eggs with a reduced cholesterol content without changing the eating habits.
  • the compounds of general formula I can also be used in poultry farming to produce low-cholesterol eggs, the substances preferably being administered as additives to the feed.
  • Human hepatoma cells (HEP-G2) are stimulated after 3 days of cultivation for 16 hours in a cholesterol-free medium.
  • the substances to be tested dissolved in dimethyl sulfoxide, final concentration 0.1%) are added during this stimulation phase. Subsequently, 1 2- 14 continuing incubation after addition of 200 micromoles / C acetate for another two hours at 37 ° C in the incubator.
  • sterols with digitonin are precipitated after extraction.
  • the 14 C-acetate incorporated in sterols that are susceptible to digitons is determined by scintillation measurement.
  • the compounds of general formula I can be incorporated in a manner known per se into the customary pharmaceutical preparation forms for oral, rectal and topical administration.
  • Formulations for oral administration include, for example, tablets, coated tablets and capsules. Suppositories are preferably used for rectal administration.
  • the daily dose is between 0.1 and 200 mg for a person with a body weight of 60 kg, but a daily dose of 1 to 100 mg is preferred for a person with a body weight of 60 kg.
  • the daily dose is preferably divided into 1 to 3 single doses.
  • the compounds When used topically, the compounds can be administered in preparations which contain about 1 to 1000 mg, in particular 10 to 300 mg, of active ingredient per day.
  • the daily dose is preferably divided into 1 to 3 single doses.
  • Topical formulations include gels, creams, lotions, ointments, powders, aerosols and other conventional formulation rings for the application of medicinal products to the skin.
  • the amount of active ingredient for topical use is 1 to 50 mg per gram of formulation, but preferably 5 to 20 mg per gram of formulation.
  • the topical formulations of the present invention can also be used in the treatment of mucous membranes which are accessible to topical treatment.
  • the topical formulations can be applied to the mucous membranes of the mouth, the lower colon and others.
  • the active compounds of the general formula I are administered to the animals by the customary methods as an additive to suitable feeds.
  • concentration of the active substances in the finished feed is normally 0.01 to 1%, but preferably 0.05 to 0.5%.
  • the active ingredients can be added to the feed as such.
  • the feeds according to the invention for laying hens contain, for example, corn, soybean meal, meat meal, feed fat and soybean oil.
  • One of the compounds of the formula I mentioned at the beginning is added to this feed as an active ingredient in a concentration of 0.01 to 1%, but preferably 0.05 to 0.5%.
  • 6-ethoxy-2- [4- (trifluoromethyl) phenylmercapto] benzothiazole yield: 89.4% of theory.
  • 6-ethoxy-2- (4-nitrophenylmercapto) benzothiazole yield: 70.8% of theory, melting point: 103-104 ° C.
  • Example 0 6- (2-bromoethoxy) -2- (4-chlorobenzylmercapto) benzothiazole, yield: 51.4% of theory, melting point: 91-92 ° C.
  • Oxalate (from acetone / ether): melting point: 128-130 ° C.
  • ⁇ -N R spectrum (200 MHz, DMSO-dg / CD 3 OD, signals at ppm): 2.28 (S, 3H); 2.5 (t, 2H); 2.78 (t, 2H); 3.5 (t, 2H); 4.08 (t. 2H); 7.05 (dd, IH); 7.3-7.47 (m, 2H); 7.5 (d, IH); 7.73 (d, IH); 7.78-7.92 (m, 2H).
  • Composition 1 tablet contains:
  • a 10% slime is made from potato starch by heating.
  • the active substance, lactose and the remaining potato starch are mixed and granulated with the above mucus through a sieve with a mesh size of 1.5 mm.
  • the granules are dried at 45 ° C., rubbed again through the above sieve, mixed with magnesium stearate and pressed into tablets.
  • Example 8 The tablets produced according to Example I are coated according to the known method with a casing which essentially consists of sugar and talc. The finished coated tablets are polished with the help of beeswax. Drage weight: 300 mg Example 8
  • Composition 1 suppository contains:
  • Suppository mass (e.g. Witepsol W 45 (R) ) 1 695.0 mg
  • the finely powdered active substance is suspended in the molten suppository mass, which has been cooled to 40 ° C.
  • the mass is poured into slightly pre-cooled suppository molds at 37 ° C.
  • Suppository weight 1.7 g.
  • Composition 1 capsule contains:
  • Example 10 The powder mixture is mixed intensively and filled into size 3 hard gelatin capsules on a capsule filling machine, the final weight being continuously checked.
  • Example 10 The powder mixture is mixed intensively and filled into size 3 hard gelatin capsules on a capsule filling machine, the final weight being continuously checked.
  • Cream for topical administration with 1 g of active ingredient
  • a formulation for the topical administration of the compounds of the formula I can have the following composition
  • the components 2-6 are heated to 80 ° C. until everything has melted. Then component 1 is dissolved in the oily phase. Constituents 7 and 10 are heated to 90 ° C. and constituents 8 and 9 are dissolved in the aqueous phase thus obtained. The aqueous phase is then added to the oil phase and stirred rapidly, so that an emulsion is obtained. Then allowed to cool slowly to 50 ° C to solidify the emulsion. With further stirring, the preparation is cooled to room temperature.
  • Vitamin-mineral mixture 5 g / kg

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Abstract

L'invention concerne des benzothiazoles et des benzoxazoles de la formule générale (I) dans laquelle R<1> à R<3>, X, Z et n correspondent à la définition donnée dans la revendication 1, leurs énantiomères, leurs diastéréomères et leurs sels, notamment leurs sels d'addition d'acide physiologiquement tolérables, qui possèdent des propriétés précieuses et ont notamment un effet inhibiteur sur la biosynthèse du cholestérol. L'invention concerne par ailleurs des médicaments contenant lesdits composés, leur utilisation et des procédés permettant de les préparer.
EP96914169A 1995-05-12 1996-05-02 Benzothiazoles et benzoxazoles, medicaments les contenant, leur utilisation et procedes permettant de les preparer Withdrawn EP0824529A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19517448 1995-05-12
DE19517448A DE19517448A1 (de) 1995-05-12 1995-05-12 Neue Benzothiazole und Benzoxazole, diese Verbindungen enthaltende Arzneimittel und deren Verwendung sowie Verfahren zu ihrer Herstellung
PCT/EP1996/001827 WO1996035681A1 (fr) 1995-05-12 1996-05-02 Benzothiazoles et benzoxazoles, medicaments les contenant, leur utilisation et procedes permettant de les preparer

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EP0824529A1 true EP0824529A1 (fr) 1998-02-25

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EP (1) EP0824529A1 (fr)
JP (1) JPH11504928A (fr)
AU (1) AU5763396A (fr)
CA (1) CA2217860A1 (fr)
DE (1) DE19517448A1 (fr)
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WO (1) WO1996035681A1 (fr)

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JP2894445B2 (ja) * 1997-02-12 1999-05-24 日本たばこ産業株式会社 Ｃｅｔｐ活性阻害剤として有効な化合物
JP2003501418A (ja) * 1999-06-04 2003-01-14 エラン ファーマ インターナショナル，リミティド 細胞死を阻害するための組成物および方法
AUPR213700A0 (en) 2000-12-18 2001-01-25 Biota Scientific Management Pty Ltd Antiviral agents
US7531553B2 (en) 2003-03-21 2009-05-12 Amgen Inc. Heterocyclic compounds and methods of use
US7144907B2 (en) * 2003-09-03 2006-12-05 Array Biopharma Inc. Heterocyclic inhibitors of MEK and methods of use thereof
JP4986485B2 (ja) * 2006-03-28 2012-07-25 株式会社Ａｄｅｋａ エポキシ樹脂硬化性組成物
US8173688B2 (en) * 2008-06-13 2012-05-08 Nexmed Holdings, Inc. Thiazole compounds, and compositions and methods using same
CN102112129A (zh) * 2008-06-13 2011-06-29 生物量子股份有限公司 噻唑化合物、组合物及其使用方法
JP2010095522A (ja) * 2008-09-19 2010-04-30 Sumitomo Chemical Co Ltd 植物病原菌による植物病害を防除又は予防するための農業用組成物
US9409904B2 (en) 2011-08-01 2016-08-09 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd Compounds and compositions for use in augmentation of glucose
CN109337821B (zh) * 2018-09-29 2022-06-24 中国海洋大学 一种产甾醇酯酶的枝孢菌及产酶方法

Citations (1)

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US2578757A (en) * 1949-03-02 1951-12-18 Hoffmann La Roche 2-tertiaryamino-6-(dialkylaminoalkoxy)-benzothiazoles and process for their manufacture

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Publication number Priority date Publication date Assignee Title
GB825016A (en) * 1956-11-02 1959-12-09 Crookes Lab Ltd Therapeutic derivatives of aryl-benzthiazoles
DE2950095A1 (de) * 1979-12-13 1981-06-19 Merck Patent Gmbh, 6100 Darmstadt Benzothiazolderivate, diese enthaltende pharmazeutische zubereitungen und verfahren zu ihrer herstellung

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2578757A (en) * 1949-03-02 1951-12-18 Hoffmann La Roche 2-tertiaryamino-6-(dialkylaminoalkoxy)-benzothiazoles and process for their manufacture

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MX9708735A (es) 1997-12-31
CA2217860A1 (fr) 1996-11-14
US5919807A (en) 1999-07-06
AU5763396A (en) 1996-11-29
DE19517448A1 (de) 1996-11-14
WO1996035681A1 (fr) 1996-11-14

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