CA2149854A1 - Substituted furoxanes - Google Patents
Substituted furoxanesInfo
- Publication number
- CA2149854A1 CA2149854A1 CA002149854A CA2149854A CA2149854A1 CA 2149854 A1 CA2149854 A1 CA 2149854A1 CA 002149854 A CA002149854 A CA 002149854A CA 2149854 A CA2149854 A CA 2149854A CA 2149854 A1 CA2149854 A1 CA 2149854A1
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- Canada
- Prior art keywords
- alkyl
- general formula
- methyl
- furoxane
- alkoxy
- 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.)
- Abandoned
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/04—1,2,3-Oxadiazoles; Hydrogenated 1,2,3-oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cardiology (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The present invention relates to furoxanes of the general formula I
(I) wherein one of the radicals R1 and R2 is -S(O)n-R3 and the other is (C1-C10)-alkyl, (C3-C7)-cycloalkyl, -CONR4R5, -CN
or -XR6, where R3, R4, R5, R6, X and n are defined as specified in claim 1, to processes for their preparation and their use as pharmaceuticals for treatment of cardiovascular system disorders or treatment of erectile disfunction.
(I) wherein one of the radicals R1 and R2 is -S(O)n-R3 and the other is (C1-C10)-alkyl, (C3-C7)-cycloalkyl, -CONR4R5, -CN
or -XR6, where R3, R4, R5, R6, X and n are defined as specified in claim 1, to processes for their preparation and their use as pharmaceuticals for treatment of cardiovascular system disorders or treatment of erectile disfunction.
Description
3~g 21~9854 I `
Substituted furoY~ne6 The present invention relates to thio-, sulphinyl- or sulphonyl-substituted furoxanes, to processes for their preparation and their use.
Various thio-, sulphinyl- or sulphonyl-sub-stituted furoxanes are already known and described, for example, in J. Chem. Soc. 1964, 904; Synth. Comm. 1, 121 (1971); J. ~eterocyclic Chem. 10, 587 (1973); Synth.
Comm. 4, 311 (1974); Eur. J. Med. Chem. 1977, 157; J.
Hetero~yclic Chem. 14, 1415 (1977); Eur. J. Med. Chem.
1980, 485; J. Heterocyclic Chem. 19, 427 (1982);
Tetrahedron 41, 727 (1985); Heterocycles 24, 889 (1986);
Biochem. Pharm. 43, 1281 (1992); J. Med. Chem. 35, 3296 (1992); J. Chem. Soc. Perkin Trans. 2 1992, 1643; Il Farmaco 48, 321 (1993); EP-A 571 795 and WO 94/01422.
The present in~ention relates to furoxanes of the gene~al formula I
R2 Rl (I) N~o, ~Oe wherein one of the radicals Rl and R2 is -S(o)n-R3 and the other is (Cl-C10)-alkyl, (C3-C7)-cycloalkyl, -CoNR4Rs, -CN
or -XR6, where n i8 O, 1 or 2;
i8 (Cl-Clo)-alkyl, hydroxy-(cl-clo)-alkyl R7R8N-(Cl-C10)-alkyl, (C2-C22)-alkyl which is inter-rupted by one, two or three oxygen atoms, (C3-C7)-cycloalkyl, (C7-C10)-aralkyl, -(CH2)mCOY, pyridyl-methyl, (C6-Cl4)-aryl, 5- to 14-me_bered heteroaryl, (C6-Cl4)-aryl or 5- to 14-membered heteroaryl, each of which i8 su~stituted one or more time6 by one or more groups from the series (Cl-Cs)-alkyl, (C3-C7)-cyclo-alkyl, formyl, (Cl-C4)-alkylcarbonyl, am;no, (Cl-Cs)-alkylam;no, di-(Cl-C5)-alkylamino, hydroxyl, (Cl-C5)-alkoxy, nitro, cyano or halogen, or -CH2CH2SCOO(Cl-C4)-alkyl;
R4 and R5 independently of one another are hydrogen or are defined as R3;
R6 independently of this is defined as R3, where -C~I2CH2SCOO(Cl-C4)-alkyl i8 excluded and where, if X is sulphur, R6 together with R3 can form an ethylene group;
R7 and R8 independently of one another are hydrogen, (Cl-C1O)-alkyl, ( C7-Clo)- aralkyl or (C6-Cl4)-aryl which can be substituted as specified in the definition of R3;
X is oxygen or sulphur;
Y is hydroxyl, (Cl-C4)-alkoxy, ~m;no, (Cl-C4)-alkylamino or di-(Cl- C4)- alkylmino; and m i8 1, 2 or 3;
and their p~rm~cologically acceptable salts, where, if one of the two radicals Rl and R2 is methyl, R3 cannot be phenyl or phe~yl para-substituted by methyl, methoxy, chlorine or fluorine; if one of the two radicals Rl and R2 i8 methyl and n = O or 2, R3 cannot be methyl or ethyl; if one of the two radicals Rl and R2 i8 methyl and n = 2, R3 c~nnot be benzyl; and if one of the two radicals Rl and R2 is ethoxy, the other cannot be -SO2C6~5 or -SO2C6H4- CH3.
Alkyl groups can be straight-chain or branched and are, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl. Alkyl groups preferably have 1 to 4 carbon atoms and are particularly preferably methyl, ethyl, n-propyl, i-propyl, n-butyl and tert-butyl.
(c3-c7)-cycloalkyl i8 preferably cyclopentyl or cyclohexyl. (C2-C22)-alkyl which i8 interrupted by one, two or three oxygen atoms is understood as m~n;n~, for example, alkoxyalkyl groups, such as methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl and propoxypropyl, but also polyethers, for example of the formula ( C~2CH--0--t--~lk wherein z is hydrogen or methyl, x is 1, 2 or 3 and Alk is (C1-C6)-alkyl.
(C7-clO)-aralkyl i8 preferably benzyl or phenethyl. Pyridylmethyl is, for example, pyrid-2-yl-methyl, pyrid-3-yl-methyl or pyrid-4-yl-methyl.
(C6-C14)-aryl is preferably phenyl.
5- to 14-mem~ered heteroaryl contains as hetero me_bers in particular ~0, ~S, ~ or ~ R9, wherein R9 is defined as ~7, but independently of this. If the heterocycle has two hetero members, these can be identical or different. A nitrogen-cont~;n;ng heterocycle can also be bonded via the nitrogen atom and can then 6till contain any desired one of the abovementioned hetero m mhers in addition to the first nitrogen atom which brings about the bo~; ng .
Preferred heteroaryl i8 5- or 6-membered, particu-larly preferred radicals being derived from pyrrole, thiophene, pyrazole, ;m; dazole, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyridazine, pyrimidine and pyrazine.
The aryl and heteroaryl groups mentioned can be mono- or polysubstituted, where fl-n~m~ntally each suitable position can carry one substituent.
The radical -S (o)~R3 i8 preferably -S ()n~ (Cl-C4)-alkyl, -StO)3-hydroxy-(Cl-C4)-alkyl, -S(O)n-cyclohexyl, -S(O)n-C~2COY', wherein Y' is hydroxyl or (Cl-C4)-alkoxy, -S(O)n-phenyl or -S(O)n-C~2CX2SCOO(Cl-C4)-alkyl.
Those of the radicals Rl and R2 which are not -S(o)~R3 are preferably ~Cl-C4)-alkyl, -CoN~R4 , wherein R4 is hydro-gen, (Cl-C4)-alkyl, or phenyl substitutsd by halogen, -CN, cyclohexylthio, phenylthio, (Cl-C4)-alkoxy, a group of the formula .z O ( CH2CII O ) Alk wherein Z, x and Alk are defined as specified above, pyrid-3-yl-methoxy, R7 R8 -N-(Cl-C4)-alkoxy, wherein R7 . and R3 independently of one another are methyl or benzyl, or SC~2COY', wherein Y' is defined as specified above.
The compounds of the general formula I can be prepared, for example, by oxidizing a compound of the general formula II
R2 Rl H ~ ~II) OH OH
wherein one of the radicals Rl and R2 is -SR3 and the other is (Cl-Cl0)-alkyl, (C3-C7)-cycloalkyl, CoNR4R5, -CN
or -XR6, where R3, R4, R5, R6 and X are defined as specified above, and optionally by further oxidizi~g the resulting compound of the general formula I wherein n=0 to the correspon~;ng compound of the general formula I
wherein n=l or 2.
~ or the oxidation of a compound of the general formula II to a compound of the general formula I, wherein n=0, conventional reagents such as, for example, 21~9854 halogens, N-chloro- and N-bromosuccinimide, alkali metal and alkaline earth metal hypochlorites, alkyl hypochlor-ites, such as e.g. tert-butyl hypochlorites, lead (IV) compounds, such as e.g. lead tetraacetate, iron(III) salts, such as e.g. potassium ferricyanide, or nitrous gases, such as e.g. N203 or N204 can be used. A preferred oxidizing agent in this case is N204.
The reaction is preferably carried out in a solvent, such as, for example, water, an alcohol, an ether, ethyl acetate, methylene chloride, cyclo~Y~ne, DMF, DMSO, benzene, toluene or chlorobenzene at temperatures from -10C to 50C, preferably from -5 to 25C. A particularly preferred solvent is diethyl ether.
Oxidizing agents which are suitable for the reaction of compounds of the general formula I in which n=O to compounds of the general formula I in which n=1 or 2 are, for example, hydrogen peroxide in acetic acid or trifluoroacetic acid medium, and also peracids, prefer-ably m-chloroperbenzoic acid, which are employed in an organic solvent, in particular methylene chloride or acetone. The temperature in this reaction is preferably -10 to 50C, particularly preferably 20 to 30C.
If equimolar amounts of oxidizing agents are employed, this results in compounds of the general formula I in which n=1, while the use of excess oxidizing agent under the same conditions leads, without the necessity of isolation of the intermediates, to compounds of the general formula I in which n=2.
In the oxidation of the compounds of the general formula II, the c~o~ds of the general formula I are as a rule obtained in the form of isomer mixtures. ~owever, these can be separated by known methods such as recrystallization or chromatographic methods, in particu-lar col~mn chromatography. Isomer mixtures are also obtained if a pure isomer is heated, in substance or dissolved in an inert solvent, to temperatures of 50 to 200C or photolysed at O to 50C. As a result of separation of the mixture thus obt~; ne~, it is thus possible to convert one isomer to the other.
21~98~4 The compounds of the general formula II are known from the literature or can be prepared in analogy to known processes.
For example, a procedure according to the following scheme can be used:
O O
ll NOHal ll Nt~20H
R '--C--CH3 ) R '~ =N~H >
H~l (III) (IY) R ' H~l R ' - sR3 N~l ~ N~l OH OH OH OH
~ V ) ( I I ~ ) In the general formulae III to IIa, R' in this case is (C~-C10)-alkyl, (C3-C7)-cycloalkyl, -CoNR4R5, -CN
or XR5, where R3, R4, R5 and R6 are defined as specified above, and ~al is halogen, in particular chlorine.
10The reaction of the compound of the general formula III with e.g. nitrosyl chloride is carried out, for example, in carbon tetrachloride or, preferably, in ether at 0 to 20C. The sub6equent oximation with hydroxylamine i8 carried out in alcoholic or preferably 15aqueous solution (Liebigs Ann. Chem. 44, 113 (1925), Tetrahedron 19, 143 (1963~).
The hydroY;m;noyl halides of the general formula V are then reacted with a thiol ~SR3 to give the compound of the formula IIa. The co~ou~d of the general formula V is preferably initially introduced here in an organic solvent, for example a lower alcohol, ether or ester, but preferably in diethyl ether, an auxiliary base, for example alcoholate, inorganic carbonate or hydroxide or a tertiary amine, preferably triethylamine, is added in a 10 to 15 mol% excess and the thiol is added dropwise in 2149~5~
a 5 to 10 mol% excess. The temperature in this case is preferably 0 to 60C, particularly preferably 20 to 40C.
In an alternative procedure, the compound of the general formula IV can also first be reacted with the thiol ~SR3 and then with hydroxyl7~;ne, where the reac-tion conditions specified above are also to be used in this case.
The compounds of the general formula V can moreo~er also be obt~;ne~ according to the following scheme:
N~N02 NH2H ~ 2 HHal V ) R 'FH2~N ) R'--OH - -t V I ~ ( V I I ) The nitriles of the general formula VI can in this case be converted to the ami~nY;me~ of the general formula VII (Che~. ~eterocycl. Compd. 1985, 988), nitrosation of which in 10 - 60% strength mineral acid EXal leads to the compounds of the general formula V
(Synth. C~mmlln. 22, 453 (1992)). If it is intended to prepare compounds of the general formula I in which one of the two radicals Rl and R2 is -CoNR4R5, the corre~pon-ding nitriles of the general formula VIa o R 4 R ~ H 2--~
can be obt~;ne~ by ~;nation of cyanoacetic esters (Aust.
J. Chem. 29, 1039 (1976)),.
Cu~u~ds, according to the invention of the general formula I in which one of the radicals Rl and R2 is CON~2 can be obt~; ne~ by alkaline hydrolysis of appropriate nitriles. This reaction is preferably carried out in a sol~ent, in particular water, with the addition of alkali metal hydroxides and addition of hydrogen peroxide. The temperature in this case is preferably 21498a4 0 to 50C.
Compounds, according to the invention of the general formula Ia R3S sR3 ~ (I~) b~ ~Oe wherein R3 is defined as specified above, can be obtained by base-catalysed reaction of dichloroglyoxime with thiols R3S~ or thioglycol and subsequent oxidation.
In the reaction with the thiols R3S~, 2 mol equivalents per mole of dichloroglyoxime are used, and in the reaction with thioglycol the reaction components are employed in the molar ratio 1:1.
The reaction is in general carried out in the presence of a base, preferably in stoichiometric amounts, alkali metal ~lkox;des, such as sodium methoxide, alkali metal hydroxides or carbonates, such as potassium carbonates, or trialkyl~m;ne~, such as triethylamine, being particu-larly preferred.
The compounds of the general formula Ia can be reacted by oxidation to give the correspon~;ng bissul-phonylfuroxanes and subsequent sequential ~xch~nge of the sulphonyl radicals to give compounds according to the invention of the general formula Ib.
R'' R''' ~Ib) N~ ~Nb e wherein R'' i8 -XR5 and R''' is -So2R3 or -SR3. To do this, the bissulphonylfuroxanes mentioned, which can be prepared as specified above or by other processes known from the literature (e.g. J. ~eterocyclic Chem. 14, 1415 (1977)), are dissolved in a solvent, for example an alcohol, water or acetone, and reacted with an alcohol g ~o~6 or a mercaptan HS~6 with addition of a base, for example sodium hydroxide, sodium alkoxide or an al~ali metal carbonate. In this reaction, only the 4-sulphone group is selectively ~Y~h~nged. If desired, the 3-sulphonyl group can then also be ~xrh~nged by freshreaction with a mercaptan ~SR6.
Compounds, according to the invention of the general formula I which contain a basic group can form salts with inorganic or organic acids. Suitable acids for the formation of ph~r~-cologically acceptable acid addition salts are, for example: hydrochloric acid, hydrobromic acid, naphthalenedisulphonic acids, in particular 1, 5-naphthalenedisulphonic acid, phosphoric, nitric, sulphuric, oxalic, lactic, tartaric, acetic, salicylic, benzoic, formic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, maleic, malic, sulphamic, phenylpropionic, gluconic, ascorbic, isonicotinic, methanesulphonic, p-toluene-sulphonic, citric or adipic acid. The acid addition salts can be prepared in the customary ~-nner by combination of the components, expediently in a suitable solvent or diluent. C~o~ds according to the invention which contain an acidic group can form salts with inorganic or organic bases, for example sodium or potassium salts.
The compounds of the general formula I and their pharmacologically acceptable salts have useful pharmaco-logical properties. In the guinea-pig potassium-depolarised plllmon~ry artery model (Godfraind and Raba (Arch. Int. Pharmacodyn. Ther. 196, (Suppl) 35 to 49, 1972), they lead, at low concentrations, to long-lasti~g relaxation. This action can be inhibited with oxyhaemo-globin, which points to an N0-mediated ~?chAnism. Nitro-gen m~noYide leads, a3 an activator of guanylate cyclase, to an increase in cyclic guanosine monophosphate, which causes a relaxation in the smooth muscle and ant;A~he~ive and antiaggregatory actions in the ~lood platelets.
Nitrogen m~no~; de is additionally also crucially involved in learning processes, in the regulation of ~idney function, in ~ -ne defence, in septic shoc~ and in 21498~4 erectile dysfunctions. The c~oh~ds according to the invention can thus be employed in the indications mentioned. Above all, however, N0 donors have proven suitable for the treatment and prophylaxis of angina pectoris.
The compounds of the general formula I and their ph~rm~cologically acceptable salts can therefore be ~m;ni stered to h~ n~ as medicaments by themselves, in mixtures with one another or in the form of ph~rm~ceutical preparations-which ma~e possible enteral or parenteral ~m;n;stration and which, as active consti-tuent contain an effective dose of at least one compound of the general formula I or of a salt thereof, in addi-tion to customary ph~-m~ceutically innocuous excipients and additives.
The medicaments can be ~m;ni stered orally, e.g. in the form of pills, tablets, lacquered tablets, coated tablets, hard and soft gelatin capsules, 801-utions, syrups, emulsions or suspensions or aerosol mixtures. ~m;n; stration, however, can also be carried out rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions, or percutaneously, e.g. in the form of ointments, elastic liquid plasters, trans~r~-l systems or tinctures.
For the production of the pharmaceutical prepara-tions, ph~rm~ceutically inert inorganic or organic excipients can be used. ~or the production of pills, tablets, coated tablets and hard gelatin capsules, use can be made of e.g. lactose, maize starch or derivatives thereof, talc, stearic acid or their salts etc.
Excipients for soft gelatin capsules and suppositories are e.g. fats, waxes, semi-solid and liquid polyols, natural or hardened oils etc. Suitable excipients for the production of solutions and syrups are e.g. water, 3S sucrose, invert sugar, glucose, polyols etc. Suitable excipients for the production of injection solutions are e.g. water, alcohols, glycerol, polyols or vegetable oils.
In addition to the active co~o~d~ and 21498~
excipients, the p-h~rm~ceutical preparations can additionally contain additives, such as e.g. fillers, extenders, disintegrants, binders, glidants, wetting agents, stabilizers, emulsifying agents, preservatives, 6weeteners, colorants, flavourings or aromatizers, buffer substances, and also solvents or solubilizers or agents for obt~;n~ng a depot effect, as well as salts for altering the osmotic pressure, coating agents or antioxi-dants. They can also contain two or more compounds of the general formula I or their ph~r~-cologically acceptable salts and additionally other therapeutically active substances.
Other therapeutically acti~e substances of this type are, for example: ~-receptor blockers, such as e.g.
propranolol, pindolol, metoprolol; vasodilators, such as e.g. carbocromen; tranquilisers, such as e.g. bar~ituric acid derivatives, 1,4-benzodiazepines and meprobamate;
diuretics, such as e.g. chlorothiazide; cardiotonic agents, such as e.g. digitalis preparations; hypertensive agents, such as e.g. hydralazine, dihydralazine, r~ipril, prazosin, clonidine, Rauwolfia alkaloids;
agents which reduce the fatty acid level in the blood, such as e.g. bezafibrate, fenofibrate; agents for thrombosis prophylaxis, such as e.g. phenprocoumon.
The compounds of the general formula I, their ph~rm~cologically acceptable salts and pharmaceutical preparations which contain the compounds of the general formula I or their ph~rm~cologically acceptable salts as active compounds can be used in hllm~nc in the control or pre~ention of disorders of the cardiovascular system, for example as antihypertensive medicaments in the various forms of high blood pressure, in the control or preven-tion of angina pectoris etc. Moreover, they can also be employed for the treatment of erectile dysfunctions. The dose can vary within wide l~;ts and is in each case to be matched to the individual conditions. In general, in the case of oral ~min; stration, a daily dose of about 0.5 to 100 mg, preferably 1 to 20 mg, per human individual is appropriate. Also, in the case of other 21498~ ~
, ~m;n; gtration forms, the daily dose, because of the good absorption of the active compounds, is within similar ranges of amounts, i.e. in general also 0.5 to 100 mg/person. The daily dose is normally divided into two or more, e.g. 2 to 4, part ~m;n;strations.
~xamDle 1 N-I8v~v~yl-3 -PhenYlmercaPtoLu~d~e-4-ca~L~mide a) 3-Amino-3-hydroY;m;no-N-isopropylpropionamide A solution of 93.6 g (0.9 mol) of sodium carbon-ate in 240 ml of water is mixed with a solution of 61.3 g (0.9 mol) of hydroxylamine hydrochloride, stirred for half an hour and _ixed with 100 ml of ethanol.
The solution thus obtained i8 added to a solution of 87 g (0.7 mol) of cyano-N-isopropylacet~m;de and the mixture is heated at 70 for lh. After st~n~ing overnight, the precipitate is filtered off with suction, the filtrate is concentrated, the residue is triturated with 200 ml of water and filtered off with suction again, and the r~m~;n;n~ residue is recrystallized from ethanol.
69.9 g (63%) of 3-amino-3-hydroYim;no-N-isopropylpropion-~m; de are obt~;ne~.
M.p.: 135C
b) 3-Chloro-2,3-bishydroY;m;no-N-isopropylpropionamide 115 g (0.72 mol) of 3-amino-3-hydrox;m;no-N-iso-propylpropionamide are dissolved in 1320 ml of conc. HC1, the solution is cooled to 0C and a solution of 149 g (2.16 mol) of sodium nitrite in 360 ml of water is added dropwise such that the temperature does not exceed 5C.
To wor~ up the _ixture, the solid is filtered off with suction, suspended in 2000 ml of ethyl acetate and stirred with 500 ml f ~2~ and the organic phase is concentrated after drying over Na2SO4.
28 g (18%~ of 3-chloro-2,3-bishydrox;m;no-N-isopropyl-propionamide are obt~;ne~.
The product melts with decomposition H-NMR: 1.04 (d, 6H, C~3), 3.94 (oct, lH, C~-N), 8.17 (d, 1~, N~), 12.08 (8, lH, OH~, 12.80 (8, lH, OH) 21g98S~
c) 2,3-BishydrnY;m;no-N-isopropyl-3-phenylmercaptopropio-namide 22.8 g (0.11 mol) of 3-chloro-2,3-bishydrox;mino-N-isopropylpropion~m;de and 13.3 g (0.12 mol) of thiophenol are initially introduced in 1000 ml of diethyl ether and a solution of 12.6 g (0.12 mol) of triethylamine in 100 ml of diethyl ether is added dropwise.
After stirring at RT for lh, the mixture is washed successi~ely with lN ~2S04, saturated sodium car~onate solution and water, dried with MgS04 and concentrated, and the residue is triturated with hexane/diethyl ether and filtered off with suction.
21.1 g (68%) of 2,3-bishydro~;m;no-N-isopropyl-3-phenyl-mercaptopropiona_ide are obtained.
M.p.: 148.5C
d) N-Isopropyl-3-phenylmercaptofuroxane-4-car~oxamide 21 g (75 _mol) of 2,3-bishydrox;m;nQ-N-isopropyl-3-phenylmercaptopropion~;de are suspended in 500 ml of diethyl ether and 8.24 g (90 _mol) of dinitrogen tetroxide are added dropwise at 0C.
After lh at 0C, the mixture is added to ice-water, the ethereal phase is separated off, dried and concentrated, and the residue i~ recry~tallized from hexane/ether 1:1.
14.6 g (70%) of N-isoproyl-3-phenylmercaptofuroxane-4-car~oxamide are obtained.
M.p.: 81C
k~amPle 2 4-PhenYl - ~vto~u~e-3-~r~n;trile 12.6 g (57 mmol) of 2,3-bis-hydroxim;no-3-phenylmer-captopropionit~ile are initially introduced in 600 ml of diethyl ether and 6.3 g (68 mmol) of dinitrogen tetroxide are added dropwise at 0C. After 3h at 0C, the mixture is added to ice-water, and the ethereal phase is separ-ated off, dried and concentrated. The residue is chromatographed on silica gel using ethyl acetate:hexane = 1:1 and the main fraction is recrystallized from ether/hexane = 1:1.
6.12 g (49%) of 4-phenylmercaptofuroxane-3-carbonitrile 2149~S4 _ are obtained.
M.p.: 59.5C
R--a~le 3 4-Phenylsulphi~ylLu~u~e-3-c~Th~m; trile and 4 -phenYlsn 1 rhr~nylLu~ ~e - 3 - car~oni trile 2 g (9.7 mmol) of 4-phenylmercaptofuroxane-3 -carbonitrile are dissolved in 20 ml of acetone and a solution, pre~riously dried using 6 g of Na2S04, of 7 g 32.5 mmol) of about 80% strength m-chloroper~enzoic acid is added dropwise until the desired degree of reaction is achie~red with continuous TLC checking.
To worlc up the mixture, it is poured onto ice-water and-extracted with methylene chloride, and the organic phase is washed several times with bicarbonate solution, sodium sulphite solution and water. The residue r~-;n;ng after drying and concentrating on a rotary e~raporator is chromatographed on silica gel using C~I2Cl2: hexane = 1: 1 and the respective main fraction is recrystallized from ether:hexane.
4 - Phenylsulphinylfuroxane - 3 - car~oni trile M . p .: 81 C
4-Phenylsulphonylfuroxane-3 -car~onitrile M.p .: 82 C
B~camPle 4 4 -Phenylmercapto~ ~e- 3 _ . ~Th~ ~ ~e l,12 g (5.1 mmol) of 4 -phenylmercaptofuroxane- 3 carbonitrile are suspended in 15 ml of 2N NaO}~ and 1.81 g (5.25 mmol) of 109~ strength hydrogen peroxide solution are added dropwise. Aftr 4h at RT, the solid is filtered off with suction and recrystallized from isopropanol.
O .7 g (5896) of 4 -phenylmercaptofuroxane- 3 - car~oxamide i8 obtained .
M.p.: 139 - 140C
3~le 5 4- (~- (MethosYc~Th~y~mFL ~ o~ ethY~ ,l o) -3-methYlfur-o~cane 35 a) 1 - (2 - (methoxycar~onyl mercapto) ethylmercapto) - 2 -methyl -glyoxime 20.0 g (0.15 mol) of 1-chloro-2 -methylglyoxime are added dropwise together with 24.5 g (0.16 mol) of methyl ~B-mercaptoethylthiocarbonate in 1500 ml of diethyl ether and 16.75 g (0.16 mol) of triethylamine in 60 ml of ether. The mixture is stirred at RT for 18h and heated under reflux for 2h.
To work up the mixture, the solid is filtered off with suction, the ether phase is washed with water, dried and concentrated, and the residue is recrystallized from isopropanol.
12.3 g (33%) of 1-(2-(methoxycarbonylmercapto)ethylmer-capto)-2-methylglyoxime are obtained.
M.p.: 147 - 151C
b) 4-(~-(Met~u~yc~ mcl~Lo)ethylmR~ ~Lo)-3-methyl-Lu~e 12.3 g (48.B mmol) of ~-methoxycarbonylmercapto-ethylmercaptomethylglyoxime are dissolved in 340 ml of diethyl ether and 5.4 g (58.5 mmol) of dinitrogen tetroxide are added dropwise at 0C. After 18h at RT, the mixture is concentrated, the residue is taken up in methylene chloride, the solution is washed with ~2~
dried and concentrated, and the residue is chromatographed on silica gel using h~Y~n~: ethyl acetate = 3:2.
9.9 g (81%) of 4-(~-(methoxycarbonylmercapto)ethylmercap-to)-3-methylfuroxane are obtained as a colourless, viscous oil.
lH-NMR: 2.08 (8, 3~, C~3) ~ 3.25 (t, 2H, a-CH2), 3.45 (t, X, ~-CH2), 3.80 (8, 3~, C~20) Examrle 6 3-Netho~cyca~ ylmethYlmercaPto-4-methYlLu~ ~ e 3.8 g (18.6 mmol) of 4-methoxycarbonylmethylmer-capto-3-methylfuroxane (Example 9) are heated at 140C
under N2 in 50 ml of xylene for 4h. To work up the mix-ture, it i8 concentrated and the residue is chromato-graphed on silica gel using hexane:ethyl acetate 3:1.
0.85 g (22%) of 3-methoxycarbonylmethylmercapto-4-methyl-furoxane ig obt~; ne~ .
Oil, 1~_NMR: 2.38 (8, 3~, C~3), 3.62 (8, 3~, C~30), 4.82 (8, 2~, C~2) The following can be prepared analogously to the above procedures:
21~9854 -~xamPle 7 4-(B-~d~YethYlmercaPto~-3-me~hYl~u~o~e Oil, l~_NMR: 2.08 (8, 1~, C~3) 3.27 (t, 2H, ~-~) 3.72 (~, 2~ ) 5.20 (t, 1~, OE) Precursor: 1-(~-hydroxyethylmercapto)-2-methylglyoxime M.p.: 129C
~xa~le 8 4-((B-MethosYcarbonYl~ to)ethYlsulph~nyl)-3-methyl-~u~e Oil, l~_NMR: 2.24 (8, 1~, C~3) 3.25-3.40 (m, 2~, H-~) 3.55-3.75 (m, 2~-~-a) 3.80 (8, 3~, C~30) R~am~le 9 4-Metho~Y~a-l-..ylmethY~mercaPto-3-methylLulo~d~e M.p.: 49C
Precursor: 1-methoxycarbonylmethylmercapto-2-methyl-glyoxime M.p.: 121 - 126C (d) ~_NMR: 1.95 (8, 3~, C~3) 3.61 (8, 3~, OC~3) 3.88 (s, 2~, CH2) 11.58 (8, 1~, O~) 12.01 (8, 1~, O~) ~-a~rle 10 4-Metho~ycaTh~nylmethYlsulph;nyl-3-methyl-Lul~d~e Oil, l~_NM~: 2.13 (8, 3~, C~3) 3.77 (s, 3~, C~30) 4.59 (AB-d, 2R, C~2) E~amPle 11 S-(3-MethYlfu~-4-yl)mercaPtoacetic acid M.p.: 106 - 108C
~ample 12 3-PhenylmercaptoLulo~d~e-4-p- Chl oroca-L~
M.p.: 159 -160C
Precursor: 2,3-bishydroY; m; n o-3-phenylmercapto-p-chloro-propim~nilide M.p.: 148C
- le 13 35 4-Butyl - c~toLu~ e-3-c~ e M.p.: 95C
2149~5~
le 14 3~ -Metho~Yc~h~Ylm~-l~a~o~ethylm~a~Lo~u~v~e-4 ch l oroc~ ;de M.p.: 97 - 100C
ExamPle 15 3-~-~Ydro~YethYlmercaPto-N-isopropylfuroxane-4 c~ mide Oil, lH-NMR: 1.20 (d, 6X, CH3) 3.12 - 3.20 ~nd 3.55-3.65 (m, 4H, CH2), 4.10 (oct, lH, CH-N), 5.05 (bs, lX, OH), 9.00 (d, lX, N~) Precursor: 3-(~-hydroxyethylmercapto)-2,3-bishydroYim; n~-N-isopropylpropio~am;de Oil, lX-NM~: 1.10 (d, 6X, X iprop-C$3), 3.11 (t, 2X, H-a) 3.52 (q, 2E, H-~), 3.90 (oct, lE, i-propCH), 8.10 (d, lX, NX), 11.79 (s, lX, OX) 12.17 (8, lH, OX) E~amDle 16 3-Buty~mercapto-N-i~ v~yl~ulv~e-4-r~ ;de Oil, lH-NMR: 0.85 (t, 3H, butyl-4), 1.16 (d, 6H, ipropCH3) 1,35 (~ext, 2H, butyl-3), 1.46 (quint 2H, butyl-2), 3 04 (t, 2X, butyl-l), 4.06 (oct, lX, iprop-CX), 9.03 (d, lX, NH) Precursor: 3-butylmercapto-2,3-bishydroximino-N-isopropylpropio~amide Oil, lX-NMR: 0.89 (t, 3H, butyl-4), 1.08 (d, 6H, iprop-CH3), 1.37 (sext, 2H, butyl-3), 1.46 (quart, 2H, butyl-2), 3.05 (t, 2H, butyl-l), 3.95 (o~t, lH, iprop-CX), 8.12 (d, lH, N~), 11.55 (8, lX, OH), 12.26 (5, lX, OX) R~le 17 4-R~tyl - -~toL~o~e-3-c~h~n;trile Oil, lH-NMR: 0.91 (t, 3H, butyl-4), 1.43 (sext., 2H, butyl-3), 1.73 (quint, 2X, butyl-2), 3.25 (t, 2H, butyl-l) 21498~ i E~ample 18 3-ButYlmercaPto~ulo~o~e-4-c~h~n;trile Oil, l~-NM~: O.88 (t, 3~, butyl-4) 1.35 ~sext, 2~, butyl-3), 1.58 (q, 2~, butyl-2), 3.04 (t, 2H, butyl-l) E~amPle 19 3-ButY~ rhonylLulG~ e-4-~h~n;trile Oil, l~_NMR: 0.90 (t, 3~, butyl-4), 1.45 (sext., 2X, butyl-3), 1.75 (quint, 2~, butyl-2), 3.73 - 3.81 (m, 2~, butyl-l) ~sample 20 1,2,5-~a~i ~7010 [3,4-b][1,4]di~h;~n~-N-oxide a) 21.6 g (120 mmol) of a 30% strength sodium methoxide solution are 810wly added dropwise at -40C to a solution of 9.4 g (60 mmol) of dichloroglyoxime (Tetrahedron 19 (1963) 143) and 5.65 g (60 mmol) of dithioglycol in 120 ml of methanol. The mixture i8 allowed to warm to room temperature in the course of 3h, is stirred for a further 2h and is then completely concentrated. The residue i8 stirred with 40 ml of water and filtered off with suction, and 9.3 g (87%) of 2,3-bishydroxyimino-1,4-di~h;~n~ are obtained.
M.p.: 202 - 205C
b) 330 ml of 14% sodium hypochlorite solution are added dropwise at 0C to a solution of 9.3 g of 2,3-bishydroxyimino-1,4-dithiane in 330 ml of 10% strength sodium hydroxide solution. The precipitate which is deposited i8 immediately filtered off with suction, washed with water and dried in vacuo. 6.5 g (71%) of 1,2,5-oxadiazolo[3,4-b~1,4]dithiane-N-oxide are obt~;ne~, M.p.: 78 - 79C
~vle 21 3,4-Biscyclohe~YlmercaPto~ ~A8~e a) 27 g (150 mmol) of a 30% strength sodium methoxide solution are 810wly added dropwise at -40C to a solution of 11.8 g (75 mmol) of dichloroglyoxime and 15 g (150 mmol) of a cyclohexylmercaptan in 150 ml of methanol. The mixture i8 allowed to warm to room temperature in the course of 3h and i8 stirred o~ernight, and the precipitate formed is filtered off with suction.
The filtrate is concentrated in ~acuo, the residue is di6solved in 60 ml of hot isopropanol and the product is precipitated ~y addition of 500 ml of petroleum ether.
15.2 g (64%) of bi6cyclohexylmercaptoglyoxime are o~tained.
M.p.: 160 - 161C
b) 125 ml of 14% sodium hypochlorite solution are added dropwise to a solution of 6.3 g of biscyclohexyl-mercaptoglyoxime in 125 ml of 10% strength sodium hydrox-ide solution. The oily product precipitated is extracted with ethyl acetate and purified by chromatography using cyclohexane/ethyl acetate 90:5. After recrystallization from isopropanol, 1.5 g of 3,4-biscyclohexylmercapto-furoxane are obtained.
M.p.: 80 - 81C
E~amDle 22 3,4-BisphenylmercaPtoLulo~d~e 3,4-Bisphenylmercaptofuroxane is obtained from dichloroglyoxime and thiophenol, analogously to Example 21, as a light yellowish oil, which does not crystallize e~en after chromatographic purification. As proof of structure, the product is converted by oxidation with hydrogen peroxide in glacial acetic acid to the ~nown 3,4-bisphenylsulphonyl-1,2,5-oxadiazole-2-oxide, M.p.: 155C.
Ex~le 23 4-(2-Metho~Yetho~Y)-3-PhenYls~l~h~YlLu~o~e A solution of 6.0 g of 3,4-diphenylsulphonyl-furoxa~e in 70 ml of acetone is treated with a solution of 3.7 g of glycol monomethyl ether in 26 ml of acetone and 1.0 g of sodium hyd~o~ide in 8 ml of water, the reaction mixture w~rm;~g to 40C. After lh, the mixture is cooled to 10C, precipitated sodium phenylsulphinate is filtered off a~d the filtrate is concentrated. The residue is stirred with 500 ml of ethyl acetate and filtered off again. ~he filtrate is concentrated, the residue is recrystallized from 30 ml of ethanol, and 21~9854 3-4 g (68%) of 4-(2-methoxyethoxy)-3-phenyl-sulphonylfuroxane are obtained.
M.p.: 105 - 107C
~amrle 24 4-MethoxY-3-PhenYls~lrh~nylLu~o~e 4-Methoxy-3-phenylsulphonylfuroxane was obtained in 80% yield analogously to Exa_ple 23.
M.p.: 109 - 111C
13C-NMR: ~ = 58.3, 110.7, 128.3, 130.0, 136.1, 137.2, 159.6 ppm.
The signal at 159.6 ppm, which originates from C-4 of the furoxane ring, has a 3.8 Hz coupling to the methoxy group, while the signal at 110.7 pp_, which originates from C-3, is not split. This pro~es the specified substitution in the 4 position.
ExamPle 25 4-(3-PYridylmetho~Y)-3-phenYls~l~honylLul~d~e 26.7 g of 3-hydro~y~cthylpyridine dissolved in 100 ml of acetone and 4.9 g of sodium hydroxide dissolved in 40 ml of water are added successi~ely to a solution of g of 3,4-diphenylsulphonylfuroxane in 360 ml of acetone. After 30 _in, the precipitated sodium phenyl-sulphinate i8 filtered off with suction, and the filtrate is concentrated. The residue is purified ~y chromatog-raphy on silica gel (eluent: ethyl acetate) followed byrecrystallization from ethanol.
20.2g (74%) of 4-(3-pyridylmethoxy)-3-phenylsulphonyl-furoxane are obtained.
~.p.: 121C
ExæmPle 26 4-(Me~hoxY-tri(eth~leno~Y))-3-phenYls~lrh~ylLu~e Analogously to Example 25, starting from 6.0 g of 3,4-diphenylsulphonylfuroxane, 5.8 g of triethylene glycol mon~mqthyl ether and 1.0 g of sodium hydroxide, 4.3 g (68%) of 4-(methoxytri(ethylenoxy))-3-phenyl-sulpho~ylL~ o~ane were obtained, which could not be crystallized.
Elemental analysis:
Fou~d: 46.4% C, 5.4% ~, 7.1% N, 32.5% 0, 9.1~ S
21~9~4 Calculated: 46.4% C, 5.2% ~, 7.2% N, 33.0% 0, 8.3% S
R--a~rle 27 4-~2-(N-Benzyl-N-methYl~m;no)etho~y]-3-PhenYls ~ul~e Lyd~ochloride 10.0 g of 3,4-diphenylsulphonylfuroxane, 13.5 g of N-benzyl-N-methylethanolamine and 2.0 g of sodium hydroxide are reacted analogously to Example 25. The crude product is chromatographed on a column using C~2Cl2/MeOH 99:1 and then converted to the hydrochloride using ethereal hydrochloric acid.
2.4 g (20%) of 4-[2-(N-benzyl-N-methylamino)ethoxy]-3-pheylsulphonylfuroxane hydrochloride are obtained.
M.p.: 171C
k~ample 28 4-[2-(N,N-dimet~ylamino)etho~Y]-3-PhenYl~llrh~nyl~uloA~ue hydLochloride Preparation was carried out analogously to Example 27.
M.p.: 142 - 144C
~amPle 29 4-Metho~nrc:-~h~ nyl~n~thyl~nGl~;d~Lo-3-phenyls~lrhnnylL~u~e A solution of 2.0 g (5.5 mmol) of 3,4-diphenyl-sulphonylfuroxane in 10 ml of acetone is treated with 20 ml of methanol, 0.6 g (5.7 mmol) of methyl thioglycol-ate and 0.6 g (5.9 mmol) of triethylamine and stirredunder nitrogen for 2h. The reaction mixture is poured onto 50 ml of water, and the precipitated product is filtered off with suction and purified by chromatography.
0.75 g (42%) of 4-methoxycArhonylmethylmercapto-3-phenyl-sulphonylLu-oxane is obtained.
M.p.: 118 - 120C
~ample 30 3-ButYlmercaPto-4-(3-PYridYlmethoxY)furo~ane L~lko-~hlo~ide A solution of 5.0 g of 4-(3-pyridylmethoxy)-3-phenylsulphonylfuroxane (Ex ~ple 25) and 1.6 g of butyl-mercaptan in 500 ml of methanol is treated with 3.15 g of a 30% sodium methoxide solution and stirred at room temperature for 15 min. The reaction mixture i8 21498~4 completely concentrated and the residue is chromatographed. The resulting oil is dissolved in 100 ml of ether and the hydrochloride is precipitated by addition of ethereal hydrochloric acid.
2.3 g (48%) of 3-butylmercapto-4-(3-pyridylmethoxy)furox-ane hydrochloride are obt~; ne~ .
M.p.: 111 - 113C
ExamPle 31 4-tert-ButYl-3-(PhenYlmercaPto)~ul~e a) S-Phenyl 3,3-dimethyl-2-oxobutanethiohyd,o~d~ate A solution of 9.8 g (89 mmol) of thiophenol in 30 ml of ether and then a solution of 9.3 g (92 mmol) of triethylamine in 50 ml of ether are added dropwise to a solution of 12.2 g (89 mmol~ of chloroisonitrosopinacol-one (Liebigs Ann. Chem. 444 (1925) 113) in 200 ml of ether. After 2h, the precipitate which is deposited is filtered off with suction, the filtrate is concentrated and the residue is crystallized by stirring with petro-leum ether.
12 g (56%) of S-phenyl 3,3-dimethyl-2-oxobutanethiohy-droxamate are obt~; n~ .
M.p.: 110 - 111C
b) S-phenyl 3,3-dimethyl-2-hydroxyi m;nnhutanethio-hydroxamate A mixture of 60 g (0.25 mol) of S-phenyl 3,3-di-methyl-2-oxobutanethiohydroxamate, 52.7 g (0.76 mol) of hydroxyl~mm~n;um chloride and 62.2 g (0.76 mol) of sodium acetate in 250 ml of water and 250 ml of ethanol is heated at 80C for 18h. The reaction mixture is treated with 1500 ml of water and is stirred overnight, and the precipitated product is filtered off with suction. After recrystallization from isopropanol, 35 g (55%) of S-phenyl 3,3-dimethyl-2-hyd.oxy; m; n~hutanethiohyd~o~d~ate are obt~; n~ .
M.p.: 178 - 180C
c) 12.0 g (0.13 mol) of dinitrogen tetroxide are added dropwise to a suspension of 33.0 g (0.13 mol) of S-phenyl 3,3-dimethyl-2-hydroxy; m; n~hutanethiohydlo~d~ate 21~98~
in 400 ml of ether. After 2h at room temperature, the mixture is concentrated on a rotary e~aporator, and the residue is recrystallized from isopropanol.
24.0 g (73%) of 4-tert-butyl-3-(phenylmercapto)furoxane are obtained.
M.p.: SSC
Example 32 4-tert-~utYl-3-phenYlslllrh;nylLu~v~e 4.7 g (48 mmol) of a 35% strength hydrogen peroxide solution are added dropwise to a solution of 3.0 g (12 mmol) of 4-tert-butyl-3-(phenylmercapto)furox-ane in 30 ml of trifluoroacetic acid. After exactly 7 min, the reaction mixture is poured onto 90 g of ice-water and the precipitated product is filtered off with suction. After recrystallization from ethanol/water 3:2, 2.9 g (91%) of 4-tert-butyl-3-phenylsulphinyl-furoxane are obt~;ne~.
M.p.: 89 - 91C
~amPle 33 4- tert-ButYl- 3-PhenYl~ rh~Yl~u~A~e A solution of 14.8 g (59 mmol) of 4-tert-butyl-3-(phenylmercapto)furoxane in 140 ml of trifluoroacetic acid and 25 g (257 mmol) of 35% hydrogen peroxide i8 stirred at room temperature for 24h. The mixture is 2S poured onto 3S0 g of ice-water, the precipitate i8 filtered off with suction and crystallized from ethanol, and lS.l g (90%) of 4-tert-butyl-3-phenylsulphonyl-furoxane are obt~; ne~ .
M.p.: 90 - 92C
~ample 34 4-tert-ButYl -3 -~utYl~erca~toru~ e 3.7 g (41 mmol) of butylmercaptan and 7.4 g (41 mmol) of 30~ strength sodium methoxide solu-tion are added successi~ely to a suspension of 10.0 g 3S (35 mmol) of 4-tert-butyl-3-phenylsulphonylfuroxane in lS0 ml of methanol. The mixture is stirred at room temperature for 3h under nitrogen and the sol~ent is then distilled off. The residue is taken up in 300 ml of cyclohexane and 100 ml of water, the aqueous phase is . _ 2119854 extracted 1 x with cycloh~y~ne and the combined organic phases are concentrated. After chromatographic purifica-tion, 5.5 g (67%) of 4-tert-butyl-3-butylmercaptofuroxane are ob~; ne~ .
~a~rle 35 4 - tert -Butyl - 3 -bUtyl8~ h; nY~ .CL~e 4-tert-Butyl-3-butylsulphinylfuroxane was obt~i n ~ from 4-tert-butyl-3-butylmercaptofuroxane, analogously to Example 32, as an oil.
l3C-NMR: ~ = 163.8 (8), 116.6 (8), 47.9 (t), 33.4 (8), 28.0 (q), 24.2 ~t), 21.1 (t), 13.3 (g).
E~ample 36 4-tert-Butyl-3-butylg~l~h~nylr~., ~ e 4-tert-Butyl-3-butylsulphonylfuroxane was obtained from 4-tert-butyl-3-butylmercaptofuroxane analogously to Example 33.
M.p.: 77 - 79C
Substituted furoY~ne6 The present invention relates to thio-, sulphinyl- or sulphonyl-substituted furoxanes, to processes for their preparation and their use.
Various thio-, sulphinyl- or sulphonyl-sub-stituted furoxanes are already known and described, for example, in J. Chem. Soc. 1964, 904; Synth. Comm. 1, 121 (1971); J. ~eterocyclic Chem. 10, 587 (1973); Synth.
Comm. 4, 311 (1974); Eur. J. Med. Chem. 1977, 157; J.
Hetero~yclic Chem. 14, 1415 (1977); Eur. J. Med. Chem.
1980, 485; J. Heterocyclic Chem. 19, 427 (1982);
Tetrahedron 41, 727 (1985); Heterocycles 24, 889 (1986);
Biochem. Pharm. 43, 1281 (1992); J. Med. Chem. 35, 3296 (1992); J. Chem. Soc. Perkin Trans. 2 1992, 1643; Il Farmaco 48, 321 (1993); EP-A 571 795 and WO 94/01422.
The present in~ention relates to furoxanes of the gene~al formula I
R2 Rl (I) N~o, ~Oe wherein one of the radicals Rl and R2 is -S(o)n-R3 and the other is (Cl-C10)-alkyl, (C3-C7)-cycloalkyl, -CoNR4Rs, -CN
or -XR6, where n i8 O, 1 or 2;
i8 (Cl-Clo)-alkyl, hydroxy-(cl-clo)-alkyl R7R8N-(Cl-C10)-alkyl, (C2-C22)-alkyl which is inter-rupted by one, two or three oxygen atoms, (C3-C7)-cycloalkyl, (C7-C10)-aralkyl, -(CH2)mCOY, pyridyl-methyl, (C6-Cl4)-aryl, 5- to 14-me_bered heteroaryl, (C6-Cl4)-aryl or 5- to 14-membered heteroaryl, each of which i8 su~stituted one or more time6 by one or more groups from the series (Cl-Cs)-alkyl, (C3-C7)-cyclo-alkyl, formyl, (Cl-C4)-alkylcarbonyl, am;no, (Cl-Cs)-alkylam;no, di-(Cl-C5)-alkylamino, hydroxyl, (Cl-C5)-alkoxy, nitro, cyano or halogen, or -CH2CH2SCOO(Cl-C4)-alkyl;
R4 and R5 independently of one another are hydrogen or are defined as R3;
R6 independently of this is defined as R3, where -C~I2CH2SCOO(Cl-C4)-alkyl i8 excluded and where, if X is sulphur, R6 together with R3 can form an ethylene group;
R7 and R8 independently of one another are hydrogen, (Cl-C1O)-alkyl, ( C7-Clo)- aralkyl or (C6-Cl4)-aryl which can be substituted as specified in the definition of R3;
X is oxygen or sulphur;
Y is hydroxyl, (Cl-C4)-alkoxy, ~m;no, (Cl-C4)-alkylamino or di-(Cl- C4)- alkylmino; and m i8 1, 2 or 3;
and their p~rm~cologically acceptable salts, where, if one of the two radicals Rl and R2 is methyl, R3 cannot be phenyl or phe~yl para-substituted by methyl, methoxy, chlorine or fluorine; if one of the two radicals Rl and R2 i8 methyl and n = O or 2, R3 cannot be methyl or ethyl; if one of the two radicals Rl and R2 i8 methyl and n = 2, R3 c~nnot be benzyl; and if one of the two radicals Rl and R2 is ethoxy, the other cannot be -SO2C6~5 or -SO2C6H4- CH3.
Alkyl groups can be straight-chain or branched and are, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl. Alkyl groups preferably have 1 to 4 carbon atoms and are particularly preferably methyl, ethyl, n-propyl, i-propyl, n-butyl and tert-butyl.
(c3-c7)-cycloalkyl i8 preferably cyclopentyl or cyclohexyl. (C2-C22)-alkyl which i8 interrupted by one, two or three oxygen atoms is understood as m~n;n~, for example, alkoxyalkyl groups, such as methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl and propoxypropyl, but also polyethers, for example of the formula ( C~2CH--0--t--~lk wherein z is hydrogen or methyl, x is 1, 2 or 3 and Alk is (C1-C6)-alkyl.
(C7-clO)-aralkyl i8 preferably benzyl or phenethyl. Pyridylmethyl is, for example, pyrid-2-yl-methyl, pyrid-3-yl-methyl or pyrid-4-yl-methyl.
(C6-C14)-aryl is preferably phenyl.
5- to 14-mem~ered heteroaryl contains as hetero me_bers in particular ~0, ~S, ~ or ~ R9, wherein R9 is defined as ~7, but independently of this. If the heterocycle has two hetero members, these can be identical or different. A nitrogen-cont~;n;ng heterocycle can also be bonded via the nitrogen atom and can then 6till contain any desired one of the abovementioned hetero m mhers in addition to the first nitrogen atom which brings about the bo~; ng .
Preferred heteroaryl i8 5- or 6-membered, particu-larly preferred radicals being derived from pyrrole, thiophene, pyrazole, ;m; dazole, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyridazine, pyrimidine and pyrazine.
The aryl and heteroaryl groups mentioned can be mono- or polysubstituted, where fl-n~m~ntally each suitable position can carry one substituent.
The radical -S (o)~R3 i8 preferably -S ()n~ (Cl-C4)-alkyl, -StO)3-hydroxy-(Cl-C4)-alkyl, -S(O)n-cyclohexyl, -S(O)n-C~2COY', wherein Y' is hydroxyl or (Cl-C4)-alkoxy, -S(O)n-phenyl or -S(O)n-C~2CX2SCOO(Cl-C4)-alkyl.
Those of the radicals Rl and R2 which are not -S(o)~R3 are preferably ~Cl-C4)-alkyl, -CoN~R4 , wherein R4 is hydro-gen, (Cl-C4)-alkyl, or phenyl substitutsd by halogen, -CN, cyclohexylthio, phenylthio, (Cl-C4)-alkoxy, a group of the formula .z O ( CH2CII O ) Alk wherein Z, x and Alk are defined as specified above, pyrid-3-yl-methoxy, R7 R8 -N-(Cl-C4)-alkoxy, wherein R7 . and R3 independently of one another are methyl or benzyl, or SC~2COY', wherein Y' is defined as specified above.
The compounds of the general formula I can be prepared, for example, by oxidizing a compound of the general formula II
R2 Rl H ~ ~II) OH OH
wherein one of the radicals Rl and R2 is -SR3 and the other is (Cl-Cl0)-alkyl, (C3-C7)-cycloalkyl, CoNR4R5, -CN
or -XR6, where R3, R4, R5, R6 and X are defined as specified above, and optionally by further oxidizi~g the resulting compound of the general formula I wherein n=0 to the correspon~;ng compound of the general formula I
wherein n=l or 2.
~ or the oxidation of a compound of the general formula II to a compound of the general formula I, wherein n=0, conventional reagents such as, for example, 21~9854 halogens, N-chloro- and N-bromosuccinimide, alkali metal and alkaline earth metal hypochlorites, alkyl hypochlor-ites, such as e.g. tert-butyl hypochlorites, lead (IV) compounds, such as e.g. lead tetraacetate, iron(III) salts, such as e.g. potassium ferricyanide, or nitrous gases, such as e.g. N203 or N204 can be used. A preferred oxidizing agent in this case is N204.
The reaction is preferably carried out in a solvent, such as, for example, water, an alcohol, an ether, ethyl acetate, methylene chloride, cyclo~Y~ne, DMF, DMSO, benzene, toluene or chlorobenzene at temperatures from -10C to 50C, preferably from -5 to 25C. A particularly preferred solvent is diethyl ether.
Oxidizing agents which are suitable for the reaction of compounds of the general formula I in which n=O to compounds of the general formula I in which n=1 or 2 are, for example, hydrogen peroxide in acetic acid or trifluoroacetic acid medium, and also peracids, prefer-ably m-chloroperbenzoic acid, which are employed in an organic solvent, in particular methylene chloride or acetone. The temperature in this reaction is preferably -10 to 50C, particularly preferably 20 to 30C.
If equimolar amounts of oxidizing agents are employed, this results in compounds of the general formula I in which n=1, while the use of excess oxidizing agent under the same conditions leads, without the necessity of isolation of the intermediates, to compounds of the general formula I in which n=2.
In the oxidation of the compounds of the general formula II, the c~o~ds of the general formula I are as a rule obtained in the form of isomer mixtures. ~owever, these can be separated by known methods such as recrystallization or chromatographic methods, in particu-lar col~mn chromatography. Isomer mixtures are also obtained if a pure isomer is heated, in substance or dissolved in an inert solvent, to temperatures of 50 to 200C or photolysed at O to 50C. As a result of separation of the mixture thus obt~; ne~, it is thus possible to convert one isomer to the other.
21~98~4 The compounds of the general formula II are known from the literature or can be prepared in analogy to known processes.
For example, a procedure according to the following scheme can be used:
O O
ll NOHal ll Nt~20H
R '--C--CH3 ) R '~ =N~H >
H~l (III) (IY) R ' H~l R ' - sR3 N~l ~ N~l OH OH OH OH
~ V ) ( I I ~ ) In the general formulae III to IIa, R' in this case is (C~-C10)-alkyl, (C3-C7)-cycloalkyl, -CoNR4R5, -CN
or XR5, where R3, R4, R5 and R6 are defined as specified above, and ~al is halogen, in particular chlorine.
10The reaction of the compound of the general formula III with e.g. nitrosyl chloride is carried out, for example, in carbon tetrachloride or, preferably, in ether at 0 to 20C. The sub6equent oximation with hydroxylamine i8 carried out in alcoholic or preferably 15aqueous solution (Liebigs Ann. Chem. 44, 113 (1925), Tetrahedron 19, 143 (1963~).
The hydroY;m;noyl halides of the general formula V are then reacted with a thiol ~SR3 to give the compound of the formula IIa. The co~ou~d of the general formula V is preferably initially introduced here in an organic solvent, for example a lower alcohol, ether or ester, but preferably in diethyl ether, an auxiliary base, for example alcoholate, inorganic carbonate or hydroxide or a tertiary amine, preferably triethylamine, is added in a 10 to 15 mol% excess and the thiol is added dropwise in 2149~5~
a 5 to 10 mol% excess. The temperature in this case is preferably 0 to 60C, particularly preferably 20 to 40C.
In an alternative procedure, the compound of the general formula IV can also first be reacted with the thiol ~SR3 and then with hydroxyl7~;ne, where the reac-tion conditions specified above are also to be used in this case.
The compounds of the general formula V can moreo~er also be obt~;ne~ according to the following scheme:
N~N02 NH2H ~ 2 HHal V ) R 'FH2~N ) R'--OH - -t V I ~ ( V I I ) The nitriles of the general formula VI can in this case be converted to the ami~nY;me~ of the general formula VII (Che~. ~eterocycl. Compd. 1985, 988), nitrosation of which in 10 - 60% strength mineral acid EXal leads to the compounds of the general formula V
(Synth. C~mmlln. 22, 453 (1992)). If it is intended to prepare compounds of the general formula I in which one of the two radicals Rl and R2 is -CoNR4R5, the corre~pon-ding nitriles of the general formula VIa o R 4 R ~ H 2--~
can be obt~;ne~ by ~;nation of cyanoacetic esters (Aust.
J. Chem. 29, 1039 (1976)),.
Cu~u~ds, according to the invention of the general formula I in which one of the radicals Rl and R2 is CON~2 can be obt~; ne~ by alkaline hydrolysis of appropriate nitriles. This reaction is preferably carried out in a sol~ent, in particular water, with the addition of alkali metal hydroxides and addition of hydrogen peroxide. The temperature in this case is preferably 21498a4 0 to 50C.
Compounds, according to the invention of the general formula Ia R3S sR3 ~ (I~) b~ ~Oe wherein R3 is defined as specified above, can be obtained by base-catalysed reaction of dichloroglyoxime with thiols R3S~ or thioglycol and subsequent oxidation.
In the reaction with the thiols R3S~, 2 mol equivalents per mole of dichloroglyoxime are used, and in the reaction with thioglycol the reaction components are employed in the molar ratio 1:1.
The reaction is in general carried out in the presence of a base, preferably in stoichiometric amounts, alkali metal ~lkox;des, such as sodium methoxide, alkali metal hydroxides or carbonates, such as potassium carbonates, or trialkyl~m;ne~, such as triethylamine, being particu-larly preferred.
The compounds of the general formula Ia can be reacted by oxidation to give the correspon~;ng bissul-phonylfuroxanes and subsequent sequential ~xch~nge of the sulphonyl radicals to give compounds according to the invention of the general formula Ib.
R'' R''' ~Ib) N~ ~Nb e wherein R'' i8 -XR5 and R''' is -So2R3 or -SR3. To do this, the bissulphonylfuroxanes mentioned, which can be prepared as specified above or by other processes known from the literature (e.g. J. ~eterocyclic Chem. 14, 1415 (1977)), are dissolved in a solvent, for example an alcohol, water or acetone, and reacted with an alcohol g ~o~6 or a mercaptan HS~6 with addition of a base, for example sodium hydroxide, sodium alkoxide or an al~ali metal carbonate. In this reaction, only the 4-sulphone group is selectively ~Y~h~nged. If desired, the 3-sulphonyl group can then also be ~xrh~nged by freshreaction with a mercaptan ~SR6.
Compounds, according to the invention of the general formula I which contain a basic group can form salts with inorganic or organic acids. Suitable acids for the formation of ph~r~-cologically acceptable acid addition salts are, for example: hydrochloric acid, hydrobromic acid, naphthalenedisulphonic acids, in particular 1, 5-naphthalenedisulphonic acid, phosphoric, nitric, sulphuric, oxalic, lactic, tartaric, acetic, salicylic, benzoic, formic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, maleic, malic, sulphamic, phenylpropionic, gluconic, ascorbic, isonicotinic, methanesulphonic, p-toluene-sulphonic, citric or adipic acid. The acid addition salts can be prepared in the customary ~-nner by combination of the components, expediently in a suitable solvent or diluent. C~o~ds according to the invention which contain an acidic group can form salts with inorganic or organic bases, for example sodium or potassium salts.
The compounds of the general formula I and their pharmacologically acceptable salts have useful pharmaco-logical properties. In the guinea-pig potassium-depolarised plllmon~ry artery model (Godfraind and Raba (Arch. Int. Pharmacodyn. Ther. 196, (Suppl) 35 to 49, 1972), they lead, at low concentrations, to long-lasti~g relaxation. This action can be inhibited with oxyhaemo-globin, which points to an N0-mediated ~?chAnism. Nitro-gen m~noYide leads, a3 an activator of guanylate cyclase, to an increase in cyclic guanosine monophosphate, which causes a relaxation in the smooth muscle and ant;A~he~ive and antiaggregatory actions in the ~lood platelets.
Nitrogen m~no~; de is additionally also crucially involved in learning processes, in the regulation of ~idney function, in ~ -ne defence, in septic shoc~ and in 21498~4 erectile dysfunctions. The c~oh~ds according to the invention can thus be employed in the indications mentioned. Above all, however, N0 donors have proven suitable for the treatment and prophylaxis of angina pectoris.
The compounds of the general formula I and their ph~rm~cologically acceptable salts can therefore be ~m;ni stered to h~ n~ as medicaments by themselves, in mixtures with one another or in the form of ph~rm~ceutical preparations-which ma~e possible enteral or parenteral ~m;n;stration and which, as active consti-tuent contain an effective dose of at least one compound of the general formula I or of a salt thereof, in addi-tion to customary ph~-m~ceutically innocuous excipients and additives.
The medicaments can be ~m;ni stered orally, e.g. in the form of pills, tablets, lacquered tablets, coated tablets, hard and soft gelatin capsules, 801-utions, syrups, emulsions or suspensions or aerosol mixtures. ~m;n; stration, however, can also be carried out rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions, or percutaneously, e.g. in the form of ointments, elastic liquid plasters, trans~r~-l systems or tinctures.
For the production of the pharmaceutical prepara-tions, ph~rm~ceutically inert inorganic or organic excipients can be used. ~or the production of pills, tablets, coated tablets and hard gelatin capsules, use can be made of e.g. lactose, maize starch or derivatives thereof, talc, stearic acid or their salts etc.
Excipients for soft gelatin capsules and suppositories are e.g. fats, waxes, semi-solid and liquid polyols, natural or hardened oils etc. Suitable excipients for the production of solutions and syrups are e.g. water, 3S sucrose, invert sugar, glucose, polyols etc. Suitable excipients for the production of injection solutions are e.g. water, alcohols, glycerol, polyols or vegetable oils.
In addition to the active co~o~d~ and 21498~
excipients, the p-h~rm~ceutical preparations can additionally contain additives, such as e.g. fillers, extenders, disintegrants, binders, glidants, wetting agents, stabilizers, emulsifying agents, preservatives, 6weeteners, colorants, flavourings or aromatizers, buffer substances, and also solvents or solubilizers or agents for obt~;n~ng a depot effect, as well as salts for altering the osmotic pressure, coating agents or antioxi-dants. They can also contain two or more compounds of the general formula I or their ph~r~-cologically acceptable salts and additionally other therapeutically active substances.
Other therapeutically acti~e substances of this type are, for example: ~-receptor blockers, such as e.g.
propranolol, pindolol, metoprolol; vasodilators, such as e.g. carbocromen; tranquilisers, such as e.g. bar~ituric acid derivatives, 1,4-benzodiazepines and meprobamate;
diuretics, such as e.g. chlorothiazide; cardiotonic agents, such as e.g. digitalis preparations; hypertensive agents, such as e.g. hydralazine, dihydralazine, r~ipril, prazosin, clonidine, Rauwolfia alkaloids;
agents which reduce the fatty acid level in the blood, such as e.g. bezafibrate, fenofibrate; agents for thrombosis prophylaxis, such as e.g. phenprocoumon.
The compounds of the general formula I, their ph~rm~cologically acceptable salts and pharmaceutical preparations which contain the compounds of the general formula I or their ph~rm~cologically acceptable salts as active compounds can be used in hllm~nc in the control or pre~ention of disorders of the cardiovascular system, for example as antihypertensive medicaments in the various forms of high blood pressure, in the control or preven-tion of angina pectoris etc. Moreover, they can also be employed for the treatment of erectile dysfunctions. The dose can vary within wide l~;ts and is in each case to be matched to the individual conditions. In general, in the case of oral ~min; stration, a daily dose of about 0.5 to 100 mg, preferably 1 to 20 mg, per human individual is appropriate. Also, in the case of other 21498~ ~
, ~m;n; gtration forms, the daily dose, because of the good absorption of the active compounds, is within similar ranges of amounts, i.e. in general also 0.5 to 100 mg/person. The daily dose is normally divided into two or more, e.g. 2 to 4, part ~m;n;strations.
~xamDle 1 N-I8v~v~yl-3 -PhenYlmercaPtoLu~d~e-4-ca~L~mide a) 3-Amino-3-hydroY;m;no-N-isopropylpropionamide A solution of 93.6 g (0.9 mol) of sodium carbon-ate in 240 ml of water is mixed with a solution of 61.3 g (0.9 mol) of hydroxylamine hydrochloride, stirred for half an hour and _ixed with 100 ml of ethanol.
The solution thus obtained i8 added to a solution of 87 g (0.7 mol) of cyano-N-isopropylacet~m;de and the mixture is heated at 70 for lh. After st~n~ing overnight, the precipitate is filtered off with suction, the filtrate is concentrated, the residue is triturated with 200 ml of water and filtered off with suction again, and the r~m~;n;n~ residue is recrystallized from ethanol.
69.9 g (63%) of 3-amino-3-hydroYim;no-N-isopropylpropion-~m; de are obt~;ne~.
M.p.: 135C
b) 3-Chloro-2,3-bishydroY;m;no-N-isopropylpropionamide 115 g (0.72 mol) of 3-amino-3-hydrox;m;no-N-iso-propylpropionamide are dissolved in 1320 ml of conc. HC1, the solution is cooled to 0C and a solution of 149 g (2.16 mol) of sodium nitrite in 360 ml of water is added dropwise such that the temperature does not exceed 5C.
To wor~ up the _ixture, the solid is filtered off with suction, suspended in 2000 ml of ethyl acetate and stirred with 500 ml f ~2~ and the organic phase is concentrated after drying over Na2SO4.
28 g (18%~ of 3-chloro-2,3-bishydrox;m;no-N-isopropyl-propionamide are obt~;ne~.
The product melts with decomposition H-NMR: 1.04 (d, 6H, C~3), 3.94 (oct, lH, C~-N), 8.17 (d, 1~, N~), 12.08 (8, lH, OH~, 12.80 (8, lH, OH) 21g98S~
c) 2,3-BishydrnY;m;no-N-isopropyl-3-phenylmercaptopropio-namide 22.8 g (0.11 mol) of 3-chloro-2,3-bishydrox;mino-N-isopropylpropion~m;de and 13.3 g (0.12 mol) of thiophenol are initially introduced in 1000 ml of diethyl ether and a solution of 12.6 g (0.12 mol) of triethylamine in 100 ml of diethyl ether is added dropwise.
After stirring at RT for lh, the mixture is washed successi~ely with lN ~2S04, saturated sodium car~onate solution and water, dried with MgS04 and concentrated, and the residue is triturated with hexane/diethyl ether and filtered off with suction.
21.1 g (68%) of 2,3-bishydro~;m;no-N-isopropyl-3-phenyl-mercaptopropiona_ide are obtained.
M.p.: 148.5C
d) N-Isopropyl-3-phenylmercaptofuroxane-4-car~oxamide 21 g (75 _mol) of 2,3-bishydrox;m;nQ-N-isopropyl-3-phenylmercaptopropion~;de are suspended in 500 ml of diethyl ether and 8.24 g (90 _mol) of dinitrogen tetroxide are added dropwise at 0C.
After lh at 0C, the mixture is added to ice-water, the ethereal phase is separated off, dried and concentrated, and the residue i~ recry~tallized from hexane/ether 1:1.
14.6 g (70%) of N-isoproyl-3-phenylmercaptofuroxane-4-car~oxamide are obtained.
M.p.: 81C
k~amPle 2 4-PhenYl - ~vto~u~e-3-~r~n;trile 12.6 g (57 mmol) of 2,3-bis-hydroxim;no-3-phenylmer-captopropionit~ile are initially introduced in 600 ml of diethyl ether and 6.3 g (68 mmol) of dinitrogen tetroxide are added dropwise at 0C. After 3h at 0C, the mixture is added to ice-water, and the ethereal phase is separ-ated off, dried and concentrated. The residue is chromatographed on silica gel using ethyl acetate:hexane = 1:1 and the main fraction is recrystallized from ether/hexane = 1:1.
6.12 g (49%) of 4-phenylmercaptofuroxane-3-carbonitrile 2149~S4 _ are obtained.
M.p.: 59.5C
R--a~le 3 4-Phenylsulphi~ylLu~u~e-3-c~Th~m; trile and 4 -phenYlsn 1 rhr~nylLu~ ~e - 3 - car~oni trile 2 g (9.7 mmol) of 4-phenylmercaptofuroxane-3 -carbonitrile are dissolved in 20 ml of acetone and a solution, pre~riously dried using 6 g of Na2S04, of 7 g 32.5 mmol) of about 80% strength m-chloroper~enzoic acid is added dropwise until the desired degree of reaction is achie~red with continuous TLC checking.
To worlc up the mixture, it is poured onto ice-water and-extracted with methylene chloride, and the organic phase is washed several times with bicarbonate solution, sodium sulphite solution and water. The residue r~-;n;ng after drying and concentrating on a rotary e~raporator is chromatographed on silica gel using C~I2Cl2: hexane = 1: 1 and the respective main fraction is recrystallized from ether:hexane.
4 - Phenylsulphinylfuroxane - 3 - car~oni trile M . p .: 81 C
4-Phenylsulphonylfuroxane-3 -car~onitrile M.p .: 82 C
B~camPle 4 4 -Phenylmercapto~ ~e- 3 _ . ~Th~ ~ ~e l,12 g (5.1 mmol) of 4 -phenylmercaptofuroxane- 3 carbonitrile are suspended in 15 ml of 2N NaO}~ and 1.81 g (5.25 mmol) of 109~ strength hydrogen peroxide solution are added dropwise. Aftr 4h at RT, the solid is filtered off with suction and recrystallized from isopropanol.
O .7 g (5896) of 4 -phenylmercaptofuroxane- 3 - car~oxamide i8 obtained .
M.p.: 139 - 140C
3~le 5 4- (~- (MethosYc~Th~y~mFL ~ o~ ethY~ ,l o) -3-methYlfur-o~cane 35 a) 1 - (2 - (methoxycar~onyl mercapto) ethylmercapto) - 2 -methyl -glyoxime 20.0 g (0.15 mol) of 1-chloro-2 -methylglyoxime are added dropwise together with 24.5 g (0.16 mol) of methyl ~B-mercaptoethylthiocarbonate in 1500 ml of diethyl ether and 16.75 g (0.16 mol) of triethylamine in 60 ml of ether. The mixture is stirred at RT for 18h and heated under reflux for 2h.
To work up the mixture, the solid is filtered off with suction, the ether phase is washed with water, dried and concentrated, and the residue is recrystallized from isopropanol.
12.3 g (33%) of 1-(2-(methoxycarbonylmercapto)ethylmer-capto)-2-methylglyoxime are obtained.
M.p.: 147 - 151C
b) 4-(~-(Met~u~yc~ mcl~Lo)ethylmR~ ~Lo)-3-methyl-Lu~e 12.3 g (48.B mmol) of ~-methoxycarbonylmercapto-ethylmercaptomethylglyoxime are dissolved in 340 ml of diethyl ether and 5.4 g (58.5 mmol) of dinitrogen tetroxide are added dropwise at 0C. After 18h at RT, the mixture is concentrated, the residue is taken up in methylene chloride, the solution is washed with ~2~
dried and concentrated, and the residue is chromatographed on silica gel using h~Y~n~: ethyl acetate = 3:2.
9.9 g (81%) of 4-(~-(methoxycarbonylmercapto)ethylmercap-to)-3-methylfuroxane are obtained as a colourless, viscous oil.
lH-NMR: 2.08 (8, 3~, C~3) ~ 3.25 (t, 2H, a-CH2), 3.45 (t, X, ~-CH2), 3.80 (8, 3~, C~20) Examrle 6 3-Netho~cyca~ ylmethYlmercaPto-4-methYlLu~ ~ e 3.8 g (18.6 mmol) of 4-methoxycarbonylmethylmer-capto-3-methylfuroxane (Example 9) are heated at 140C
under N2 in 50 ml of xylene for 4h. To work up the mix-ture, it i8 concentrated and the residue is chromato-graphed on silica gel using hexane:ethyl acetate 3:1.
0.85 g (22%) of 3-methoxycarbonylmethylmercapto-4-methyl-furoxane ig obt~; ne~ .
Oil, 1~_NMR: 2.38 (8, 3~, C~3), 3.62 (8, 3~, C~30), 4.82 (8, 2~, C~2) The following can be prepared analogously to the above procedures:
21~9854 -~xamPle 7 4-(B-~d~YethYlmercaPto~-3-me~hYl~u~o~e Oil, l~_NMR: 2.08 (8, 1~, C~3) 3.27 (t, 2H, ~-~) 3.72 (~, 2~ ) 5.20 (t, 1~, OE) Precursor: 1-(~-hydroxyethylmercapto)-2-methylglyoxime M.p.: 129C
~xa~le 8 4-((B-MethosYcarbonYl~ to)ethYlsulph~nyl)-3-methyl-~u~e Oil, l~_NMR: 2.24 (8, 1~, C~3) 3.25-3.40 (m, 2~, H-~) 3.55-3.75 (m, 2~-~-a) 3.80 (8, 3~, C~30) R~am~le 9 4-Metho~Y~a-l-..ylmethY~mercaPto-3-methylLulo~d~e M.p.: 49C
Precursor: 1-methoxycarbonylmethylmercapto-2-methyl-glyoxime M.p.: 121 - 126C (d) ~_NMR: 1.95 (8, 3~, C~3) 3.61 (8, 3~, OC~3) 3.88 (s, 2~, CH2) 11.58 (8, 1~, O~) 12.01 (8, 1~, O~) ~-a~rle 10 4-Metho~ycaTh~nylmethYlsulph;nyl-3-methyl-Lul~d~e Oil, l~_NM~: 2.13 (8, 3~, C~3) 3.77 (s, 3~, C~30) 4.59 (AB-d, 2R, C~2) E~amPle 11 S-(3-MethYlfu~-4-yl)mercaPtoacetic acid M.p.: 106 - 108C
~ample 12 3-PhenylmercaptoLulo~d~e-4-p- Chl oroca-L~
M.p.: 159 -160C
Precursor: 2,3-bishydroY; m; n o-3-phenylmercapto-p-chloro-propim~nilide M.p.: 148C
- le 13 35 4-Butyl - c~toLu~ e-3-c~ e M.p.: 95C
2149~5~
le 14 3~ -Metho~Yc~h~Ylm~-l~a~o~ethylm~a~Lo~u~v~e-4 ch l oroc~ ;de M.p.: 97 - 100C
ExamPle 15 3-~-~Ydro~YethYlmercaPto-N-isopropylfuroxane-4 c~ mide Oil, lH-NMR: 1.20 (d, 6X, CH3) 3.12 - 3.20 ~nd 3.55-3.65 (m, 4H, CH2), 4.10 (oct, lH, CH-N), 5.05 (bs, lX, OH), 9.00 (d, lX, N~) Precursor: 3-(~-hydroxyethylmercapto)-2,3-bishydroYim; n~-N-isopropylpropio~am;de Oil, lX-NM~: 1.10 (d, 6X, X iprop-C$3), 3.11 (t, 2X, H-a) 3.52 (q, 2E, H-~), 3.90 (oct, lE, i-propCH), 8.10 (d, lX, NX), 11.79 (s, lX, OX) 12.17 (8, lH, OX) E~amDle 16 3-Buty~mercapto-N-i~ v~yl~ulv~e-4-r~ ;de Oil, lH-NMR: 0.85 (t, 3H, butyl-4), 1.16 (d, 6H, ipropCH3) 1,35 (~ext, 2H, butyl-3), 1.46 (quint 2H, butyl-2), 3 04 (t, 2X, butyl-l), 4.06 (oct, lX, iprop-CX), 9.03 (d, lX, NH) Precursor: 3-butylmercapto-2,3-bishydroximino-N-isopropylpropio~amide Oil, lX-NMR: 0.89 (t, 3H, butyl-4), 1.08 (d, 6H, iprop-CH3), 1.37 (sext, 2H, butyl-3), 1.46 (quart, 2H, butyl-2), 3.05 (t, 2H, butyl-l), 3.95 (o~t, lH, iprop-CX), 8.12 (d, lH, N~), 11.55 (8, lX, OH), 12.26 (5, lX, OX) R~le 17 4-R~tyl - -~toL~o~e-3-c~h~n;trile Oil, lH-NMR: 0.91 (t, 3H, butyl-4), 1.43 (sext., 2H, butyl-3), 1.73 (quint, 2X, butyl-2), 3.25 (t, 2H, butyl-l) 21498~ i E~ample 18 3-ButYlmercaPto~ulo~o~e-4-c~h~n;trile Oil, l~-NM~: O.88 (t, 3~, butyl-4) 1.35 ~sext, 2~, butyl-3), 1.58 (q, 2~, butyl-2), 3.04 (t, 2H, butyl-l) E~amPle 19 3-ButY~ rhonylLulG~ e-4-~h~n;trile Oil, l~_NMR: 0.90 (t, 3~, butyl-4), 1.45 (sext., 2X, butyl-3), 1.75 (quint, 2~, butyl-2), 3.73 - 3.81 (m, 2~, butyl-l) ~sample 20 1,2,5-~a~i ~7010 [3,4-b][1,4]di~h;~n~-N-oxide a) 21.6 g (120 mmol) of a 30% strength sodium methoxide solution are 810wly added dropwise at -40C to a solution of 9.4 g (60 mmol) of dichloroglyoxime (Tetrahedron 19 (1963) 143) and 5.65 g (60 mmol) of dithioglycol in 120 ml of methanol. The mixture i8 allowed to warm to room temperature in the course of 3h, is stirred for a further 2h and is then completely concentrated. The residue i8 stirred with 40 ml of water and filtered off with suction, and 9.3 g (87%) of 2,3-bishydroxyimino-1,4-di~h;~n~ are obtained.
M.p.: 202 - 205C
b) 330 ml of 14% sodium hypochlorite solution are added dropwise at 0C to a solution of 9.3 g of 2,3-bishydroxyimino-1,4-dithiane in 330 ml of 10% strength sodium hydroxide solution. The precipitate which is deposited i8 immediately filtered off with suction, washed with water and dried in vacuo. 6.5 g (71%) of 1,2,5-oxadiazolo[3,4-b~1,4]dithiane-N-oxide are obt~;ne~, M.p.: 78 - 79C
~vle 21 3,4-Biscyclohe~YlmercaPto~ ~A8~e a) 27 g (150 mmol) of a 30% strength sodium methoxide solution are 810wly added dropwise at -40C to a solution of 11.8 g (75 mmol) of dichloroglyoxime and 15 g (150 mmol) of a cyclohexylmercaptan in 150 ml of methanol. The mixture i8 allowed to warm to room temperature in the course of 3h and i8 stirred o~ernight, and the precipitate formed is filtered off with suction.
The filtrate is concentrated in ~acuo, the residue is di6solved in 60 ml of hot isopropanol and the product is precipitated ~y addition of 500 ml of petroleum ether.
15.2 g (64%) of bi6cyclohexylmercaptoglyoxime are o~tained.
M.p.: 160 - 161C
b) 125 ml of 14% sodium hypochlorite solution are added dropwise to a solution of 6.3 g of biscyclohexyl-mercaptoglyoxime in 125 ml of 10% strength sodium hydrox-ide solution. The oily product precipitated is extracted with ethyl acetate and purified by chromatography using cyclohexane/ethyl acetate 90:5. After recrystallization from isopropanol, 1.5 g of 3,4-biscyclohexylmercapto-furoxane are obtained.
M.p.: 80 - 81C
E~amDle 22 3,4-BisphenylmercaPtoLulo~d~e 3,4-Bisphenylmercaptofuroxane is obtained from dichloroglyoxime and thiophenol, analogously to Example 21, as a light yellowish oil, which does not crystallize e~en after chromatographic purification. As proof of structure, the product is converted by oxidation with hydrogen peroxide in glacial acetic acid to the ~nown 3,4-bisphenylsulphonyl-1,2,5-oxadiazole-2-oxide, M.p.: 155C.
Ex~le 23 4-(2-Metho~Yetho~Y)-3-PhenYls~l~h~YlLu~o~e A solution of 6.0 g of 3,4-diphenylsulphonyl-furoxa~e in 70 ml of acetone is treated with a solution of 3.7 g of glycol monomethyl ether in 26 ml of acetone and 1.0 g of sodium hyd~o~ide in 8 ml of water, the reaction mixture w~rm;~g to 40C. After lh, the mixture is cooled to 10C, precipitated sodium phenylsulphinate is filtered off a~d the filtrate is concentrated. The residue is stirred with 500 ml of ethyl acetate and filtered off again. ~he filtrate is concentrated, the residue is recrystallized from 30 ml of ethanol, and 21~9854 3-4 g (68%) of 4-(2-methoxyethoxy)-3-phenyl-sulphonylfuroxane are obtained.
M.p.: 105 - 107C
~amrle 24 4-MethoxY-3-PhenYls~lrh~nylLu~o~e 4-Methoxy-3-phenylsulphonylfuroxane was obtained in 80% yield analogously to Exa_ple 23.
M.p.: 109 - 111C
13C-NMR: ~ = 58.3, 110.7, 128.3, 130.0, 136.1, 137.2, 159.6 ppm.
The signal at 159.6 ppm, which originates from C-4 of the furoxane ring, has a 3.8 Hz coupling to the methoxy group, while the signal at 110.7 pp_, which originates from C-3, is not split. This pro~es the specified substitution in the 4 position.
ExamPle 25 4-(3-PYridylmetho~Y)-3-phenYls~l~honylLul~d~e 26.7 g of 3-hydro~y~cthylpyridine dissolved in 100 ml of acetone and 4.9 g of sodium hydroxide dissolved in 40 ml of water are added successi~ely to a solution of g of 3,4-diphenylsulphonylfuroxane in 360 ml of acetone. After 30 _in, the precipitated sodium phenyl-sulphinate i8 filtered off with suction, and the filtrate is concentrated. The residue is purified ~y chromatog-raphy on silica gel (eluent: ethyl acetate) followed byrecrystallization from ethanol.
20.2g (74%) of 4-(3-pyridylmethoxy)-3-phenylsulphonyl-furoxane are obtained.
~.p.: 121C
ExæmPle 26 4-(Me~hoxY-tri(eth~leno~Y))-3-phenYls~lrh~ylLu~e Analogously to Example 25, starting from 6.0 g of 3,4-diphenylsulphonylfuroxane, 5.8 g of triethylene glycol mon~mqthyl ether and 1.0 g of sodium hydroxide, 4.3 g (68%) of 4-(methoxytri(ethylenoxy))-3-phenyl-sulpho~ylL~ o~ane were obtained, which could not be crystallized.
Elemental analysis:
Fou~d: 46.4% C, 5.4% ~, 7.1% N, 32.5% 0, 9.1~ S
21~9~4 Calculated: 46.4% C, 5.2% ~, 7.2% N, 33.0% 0, 8.3% S
R--a~rle 27 4-~2-(N-Benzyl-N-methYl~m;no)etho~y]-3-PhenYls ~ul~e Lyd~ochloride 10.0 g of 3,4-diphenylsulphonylfuroxane, 13.5 g of N-benzyl-N-methylethanolamine and 2.0 g of sodium hydroxide are reacted analogously to Example 25. The crude product is chromatographed on a column using C~2Cl2/MeOH 99:1 and then converted to the hydrochloride using ethereal hydrochloric acid.
2.4 g (20%) of 4-[2-(N-benzyl-N-methylamino)ethoxy]-3-pheylsulphonylfuroxane hydrochloride are obtained.
M.p.: 171C
k~ample 28 4-[2-(N,N-dimet~ylamino)etho~Y]-3-PhenYl~llrh~nyl~uloA~ue hydLochloride Preparation was carried out analogously to Example 27.
M.p.: 142 - 144C
~amPle 29 4-Metho~nrc:-~h~ nyl~n~thyl~nGl~;d~Lo-3-phenyls~lrhnnylL~u~e A solution of 2.0 g (5.5 mmol) of 3,4-diphenyl-sulphonylfuroxane in 10 ml of acetone is treated with 20 ml of methanol, 0.6 g (5.7 mmol) of methyl thioglycol-ate and 0.6 g (5.9 mmol) of triethylamine and stirredunder nitrogen for 2h. The reaction mixture is poured onto 50 ml of water, and the precipitated product is filtered off with suction and purified by chromatography.
0.75 g (42%) of 4-methoxycArhonylmethylmercapto-3-phenyl-sulphonylLu-oxane is obtained.
M.p.: 118 - 120C
~ample 30 3-ButYlmercaPto-4-(3-PYridYlmethoxY)furo~ane L~lko-~hlo~ide A solution of 5.0 g of 4-(3-pyridylmethoxy)-3-phenylsulphonylfuroxane (Ex ~ple 25) and 1.6 g of butyl-mercaptan in 500 ml of methanol is treated with 3.15 g of a 30% sodium methoxide solution and stirred at room temperature for 15 min. The reaction mixture i8 21498~4 completely concentrated and the residue is chromatographed. The resulting oil is dissolved in 100 ml of ether and the hydrochloride is precipitated by addition of ethereal hydrochloric acid.
2.3 g (48%) of 3-butylmercapto-4-(3-pyridylmethoxy)furox-ane hydrochloride are obt~; ne~ .
M.p.: 111 - 113C
ExamPle 31 4-tert-ButYl-3-(PhenYlmercaPto)~ul~e a) S-Phenyl 3,3-dimethyl-2-oxobutanethiohyd,o~d~ate A solution of 9.8 g (89 mmol) of thiophenol in 30 ml of ether and then a solution of 9.3 g (92 mmol) of triethylamine in 50 ml of ether are added dropwise to a solution of 12.2 g (89 mmol~ of chloroisonitrosopinacol-one (Liebigs Ann. Chem. 444 (1925) 113) in 200 ml of ether. After 2h, the precipitate which is deposited is filtered off with suction, the filtrate is concentrated and the residue is crystallized by stirring with petro-leum ether.
12 g (56%) of S-phenyl 3,3-dimethyl-2-oxobutanethiohy-droxamate are obt~; n~ .
M.p.: 110 - 111C
b) S-phenyl 3,3-dimethyl-2-hydroxyi m;nnhutanethio-hydroxamate A mixture of 60 g (0.25 mol) of S-phenyl 3,3-di-methyl-2-oxobutanethiohydroxamate, 52.7 g (0.76 mol) of hydroxyl~mm~n;um chloride and 62.2 g (0.76 mol) of sodium acetate in 250 ml of water and 250 ml of ethanol is heated at 80C for 18h. The reaction mixture is treated with 1500 ml of water and is stirred overnight, and the precipitated product is filtered off with suction. After recrystallization from isopropanol, 35 g (55%) of S-phenyl 3,3-dimethyl-2-hyd.oxy; m; n~hutanethiohyd~o~d~ate are obt~; n~ .
M.p.: 178 - 180C
c) 12.0 g (0.13 mol) of dinitrogen tetroxide are added dropwise to a suspension of 33.0 g (0.13 mol) of S-phenyl 3,3-dimethyl-2-hydroxy; m; n~hutanethiohydlo~d~ate 21~98~
in 400 ml of ether. After 2h at room temperature, the mixture is concentrated on a rotary e~aporator, and the residue is recrystallized from isopropanol.
24.0 g (73%) of 4-tert-butyl-3-(phenylmercapto)furoxane are obtained.
M.p.: SSC
Example 32 4-tert-~utYl-3-phenYlslllrh;nylLu~v~e 4.7 g (48 mmol) of a 35% strength hydrogen peroxide solution are added dropwise to a solution of 3.0 g (12 mmol) of 4-tert-butyl-3-(phenylmercapto)furox-ane in 30 ml of trifluoroacetic acid. After exactly 7 min, the reaction mixture is poured onto 90 g of ice-water and the precipitated product is filtered off with suction. After recrystallization from ethanol/water 3:2, 2.9 g (91%) of 4-tert-butyl-3-phenylsulphinyl-furoxane are obt~;ne~.
M.p.: 89 - 91C
~amPle 33 4- tert-ButYl- 3-PhenYl~ rh~Yl~u~A~e A solution of 14.8 g (59 mmol) of 4-tert-butyl-3-(phenylmercapto)furoxane in 140 ml of trifluoroacetic acid and 25 g (257 mmol) of 35% hydrogen peroxide i8 stirred at room temperature for 24h. The mixture is 2S poured onto 3S0 g of ice-water, the precipitate i8 filtered off with suction and crystallized from ethanol, and lS.l g (90%) of 4-tert-butyl-3-phenylsulphonyl-furoxane are obt~; ne~ .
M.p.: 90 - 92C
~ample 34 4-tert-ButYl -3 -~utYl~erca~toru~ e 3.7 g (41 mmol) of butylmercaptan and 7.4 g (41 mmol) of 30~ strength sodium methoxide solu-tion are added successi~ely to a suspension of 10.0 g 3S (35 mmol) of 4-tert-butyl-3-phenylsulphonylfuroxane in lS0 ml of methanol. The mixture is stirred at room temperature for 3h under nitrogen and the sol~ent is then distilled off. The residue is taken up in 300 ml of cyclohexane and 100 ml of water, the aqueous phase is . _ 2119854 extracted 1 x with cycloh~y~ne and the combined organic phases are concentrated. After chromatographic purifica-tion, 5.5 g (67%) of 4-tert-butyl-3-butylmercaptofuroxane are ob~; ne~ .
~a~rle 35 4 - tert -Butyl - 3 -bUtyl8~ h; nY~ .CL~e 4-tert-Butyl-3-butylsulphinylfuroxane was obt~i n ~ from 4-tert-butyl-3-butylmercaptofuroxane, analogously to Example 32, as an oil.
l3C-NMR: ~ = 163.8 (8), 116.6 (8), 47.9 (t), 33.4 (8), 28.0 (q), 24.2 ~t), 21.1 (t), 13.3 (g).
E~ample 36 4-tert-Butyl-3-butylg~l~h~nylr~., ~ e 4-tert-Butyl-3-butylsulphonylfuroxane was obtained from 4-tert-butyl-3-butylmercaptofuroxane analogously to Example 33.
M.p.: 77 - 79C
Claims (7)
1. A furoxane of the general formula I
(I) wherein one of the radicals R1 and R2 is -S(O)n-R3 and the other is (C1-C10)-alkyl, (C3-C7)-cycloalkyl, -CONR4R5, -CN
or -XR6, where n is 0, 1 or 2;
R3 is (C1-C10)-alkyl, hydroxy-(C1-C10)-alkyl, R7R8N-(C1-C10)-alkyl, (C2-C22)-alkyl which is interrupted by one, two or three oxygen atoms, (C3-C7)-cycloalkyl, (C7-C10)-aralkyl, -(CH2)mCOY, pyridylmethyl, (C6-C14)-aryl, 5- to 14-membered heteroaryl, (C6-C14)-aryl or 5- to 14-membered heteroaryl, each of which is substituted one or more times by one or more groups from the series (C1-C5)-alkyl, (C3-C7)-cycloalkyl, formyl, (C1-C4)-alkylcarbonyl, amino, (C1-C5)-alkylamino, di-(C1-C5)-alkylamino, hydroxyl, (C1-C5)-alkoxy, nitro, cyano or halogen, or -CH2CH2SCOO(C1-C4)-alkyl;
R4 and R5 independently of one another are hydrogen or are defined as R3;
R6 independently of this is defined as R3, where -CH2CH2SCOO(C1-C4)-alkyl is excluded and where, if X is sulphur, R6 together with R3 can form an ethylene group;
R7 and R8 independently of one another are hydrogen, (C1-C10)-alkyl, (C7-C10)-aralkyl or (C6-C14)-aryl which can be substituted as specified in the definition of R3;
X is oxygen or sulphur;
Y is hydroxyl, (C1-C4)-alkoxy, amino, (C1-C4)-alkyl-amino or di-(C1-C4)-alkylamino; and m is 1, 2 or 3;
or a pharmacologically acceptable salt thereof, where, if one of the two radicals R1 and R2 is methyl, R3 cannot be phenyl or phenyl para-substituted by methyl, methoxy, chlorine or fluorine; if one of the two radicals R1 and R2 is methyl and n = 0 or 2, R3 cannot be methyl or ethyl; if one of the two radicals R1 and R2 is methyl and n = 2, R3 cannot be benzyl;
and if one of the two radicals R1 and R2 is ethoxy, the other cannot be -SO2C6H5 or -SO2C6H4-CH3.
(I) wherein one of the radicals R1 and R2 is -S(O)n-R3 and the other is (C1-C10)-alkyl, (C3-C7)-cycloalkyl, -CONR4R5, -CN
or -XR6, where n is 0, 1 or 2;
R3 is (C1-C10)-alkyl, hydroxy-(C1-C10)-alkyl, R7R8N-(C1-C10)-alkyl, (C2-C22)-alkyl which is interrupted by one, two or three oxygen atoms, (C3-C7)-cycloalkyl, (C7-C10)-aralkyl, -(CH2)mCOY, pyridylmethyl, (C6-C14)-aryl, 5- to 14-membered heteroaryl, (C6-C14)-aryl or 5- to 14-membered heteroaryl, each of which is substituted one or more times by one or more groups from the series (C1-C5)-alkyl, (C3-C7)-cycloalkyl, formyl, (C1-C4)-alkylcarbonyl, amino, (C1-C5)-alkylamino, di-(C1-C5)-alkylamino, hydroxyl, (C1-C5)-alkoxy, nitro, cyano or halogen, or -CH2CH2SCOO(C1-C4)-alkyl;
R4 and R5 independently of one another are hydrogen or are defined as R3;
R6 independently of this is defined as R3, where -CH2CH2SCOO(C1-C4)-alkyl is excluded and where, if X is sulphur, R6 together with R3 can form an ethylene group;
R7 and R8 independently of one another are hydrogen, (C1-C10)-alkyl, (C7-C10)-aralkyl or (C6-C14)-aryl which can be substituted as specified in the definition of R3;
X is oxygen or sulphur;
Y is hydroxyl, (C1-C4)-alkoxy, amino, (C1-C4)-alkyl-amino or di-(C1-C4)-alkylamino; and m is 1, 2 or 3;
or a pharmacologically acceptable salt thereof, where, if one of the two radicals R1 and R2 is methyl, R3 cannot be phenyl or phenyl para-substituted by methyl, methoxy, chlorine or fluorine; if one of the two radicals R1 and R2 is methyl and n = 0 or 2, R3 cannot be methyl or ethyl; if one of the two radicals R1 and R2 is methyl and n = 2, R3 cannot be benzyl;
and if one of the two radicals R1 and R2 is ethoxy, the other cannot be -SO2C6H5 or -SO2C6H4-CH3.
2. A furoxane according to claim 1, wherein the radical -S(O)nR3 is -S(O)n-(C1-C4)-alkyl, -S(O)n-hydroxy-(C1-C4)-alkyl, -S(O)n-cyclohexyl, -S(O)nCH2COY' (wherein Y' is hydroxyl or (C1-C4)-alkoxy), -S(O)n-phenyl or -S(O)n-CH2CH2SCOO(C1-C4)-alkyl.
3. A furoxane according to claim 1, wherein R1 or R2 which is not -S(O)nR3 is (C1-C4)-alkyl, -CONHR4', wherein R4' is hydrogen, (C1-C4)-alkyl or phenyl substituted by halogen, -CN, cyclohexylthio, phenylthio, (C1-C4)-alkoxy, a group of the formula wherein Z is hydrogen or methyl, x is 1, 2 or 3 and Alk is (C1-C6)-alkyl, pyrid-3-yl-methoxy, R7'R8'-N-(C1-C4)-alkoxy, wherein R7' and R8' independently of one another are methyl or benzyl, or SCH2COY', wherein Y' is hydroxyl or (C1-C4)-alkoxy.
4. Process for preparing a furoxane of the general formula I according to any one of claims 1 to 3, which process comprises oxidizing a compound of the general formula II
(II) wherein R1 and R2 are defined as specified in any one of claims 1 to 3.
(II) wherein R1 and R2 are defined as specified in any one of claims 1 to 3.
5. Use of a furoxane of the general formula I according to any one of claims 1 to 3 for control and prevention of a disorder of the cardiovascular system.
6. Use of a furoxane of the general formula I according to any one of claims 1 to 3 for the treatment of an erectile disfunction.
7. Pharmaceutical preparation, comprising a pharma-ceutically effective amount of a furoxane of the general formula I according to any one of claims 1 to 3, or a pharma-cologically acceptable salt thereof as active ingredient together with a pharmaceutically acceptable excipient or additive and, if required, additionally one or more other pharmacological active compounds.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4417705A DE4417705A1 (en) | 1994-05-20 | 1994-05-20 | Substituted furoxanes |
| DEP4417705.4 | 1994-05-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2149854A1 true CA2149854A1 (en) | 1995-11-21 |
Family
ID=6518580
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002149854A Abandoned CA2149854A1 (en) | 1994-05-20 | 1995-05-19 | Substituted furoxanes |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0683159A1 (en) |
| JP (1) | JPH0841039A (en) |
| KR (1) | KR950032155A (en) |
| CA (1) | CA2149854A1 (en) |
| DE (1) | DE4417705A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2009266408B2 (en) * | 2008-07-02 | 2014-08-28 | The University Of Queensland | Pain-relieving compositions of furoxan NO donors and uses thereof |
| US8822509B2 (en) | 2006-12-29 | 2014-09-02 | The University Of Queensland | Pain-relieving compositions and uses therefor |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080306041A1 (en) * | 2005-01-21 | 2008-12-11 | Garvey David S | Cardiovascular Compounds Comprising Heterocyclic Nitric Oxide Donor Groups, Compositions and Methods of Use |
| US20090018091A1 (en) | 2005-08-02 | 2009-01-15 | Nitromed, Inc. | Nitric Oxide Enhancing Antimicrobial Compounds, Compositions and Methods of Use |
| US7838023B2 (en) | 2005-11-16 | 2010-11-23 | Nitromed, Inc. | Furoxan compounds, compositions and methods of use |
| WO2007126609A1 (en) | 2006-03-29 | 2007-11-08 | Nitromed, Inc. | Nitric oxide enhancing prostaglandin compounds, compositions and methods of use |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4217794A1 (en) * | 1992-05-29 | 1993-12-02 | Cassella Ag | Phenylfuroxane |
| IT1255207B (en) * | 1992-07-03 | 1995-10-20 | Chiesi Farma Spa | PHARMACEUTICAL COMPOSITIONS WITH ANTI-AGGREGATING AND VASODILATING ACTIVITY |
-
1994
- 1994-05-20 DE DE4417705A patent/DE4417705A1/en not_active Withdrawn
-
1995
- 1995-05-06 EP EP95106885A patent/EP0683159A1/en not_active Withdrawn
- 1995-05-18 JP JP7119782A patent/JPH0841039A/en not_active Withdrawn
- 1995-05-19 KR KR1019950012502A patent/KR950032155A/en not_active Application Discontinuation
- 1995-05-19 CA CA002149854A patent/CA2149854A1/en not_active Abandoned
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8822509B2 (en) | 2006-12-29 | 2014-09-02 | The University Of Queensland | Pain-relieving compositions and uses therefor |
| US9994534B2 (en) | 2006-12-29 | 2018-06-12 | The University Of Queensland | Pain-relieving compositions and uses therefor |
| AU2009266408B2 (en) * | 2008-07-02 | 2014-08-28 | The University Of Queensland | Pain-relieving compositions of furoxan NO donors and uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| DE4417705A1 (en) | 1995-11-23 |
| EP0683159A1 (en) | 1995-11-22 |
| KR950032155A (en) | 1995-12-20 |
| JPH0841039A (en) | 1996-02-13 |
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