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CA1173034A - 3,4-disubstituted 1,2,5-oxadiazole 2-oxides, processes for their preparation, their use and pharmaceutical formulations containing them - Google Patents

3,4-disubstituted 1,2,5-oxadiazole 2-oxides, processes for their preparation, their use and pharmaceutical formulations containing them

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Publication number
CA1173034A
CA1173034A CA000392542A CA392542A CA1173034A CA 1173034 A CA1173034 A CA 1173034A CA 000392542 A CA000392542 A CA 000392542A CA 392542 A CA392542 A CA 392542A CA 1173034 A CA1173034 A CA 1173034A
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denotes
atoms
oxadiazole
radical
alkyl
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CA000392542A
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French (fr)
Inventor
Karl Schonafinger
Rudi Beyerle
Anton Mogilev
Helmut Bohn
Melitta Just
Piero A. Martorana
Rolf-Eberhard Nitz
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Sanofi Aventis Deutschland GmbH
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Cassella AG
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61P9/12—Antihypertensives
    • 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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  • Urology & Nephrology (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

ABSTRACT OF THE DISCLOSURE
3,4-Disubstituted 1,2,5-oxadiazole 2-oxides of the formula I

(I) wherein, when R2 represents CH3, R1 denotes -CONHR3NR24, -CONHR3OR7, -CONHCH2CH=CH2, -CONHR8, -CONR9R10, -CONHR11CO2R4, -CONHR11CONH?2, -CONHR11-Het, , -CONHR11CONHR8, and when R2 is other than CH3 and has one of the meanings indicated above for R1, R1 denotes -CH3, R3 denotes an alkylene radical -CnH2n-, wherein ?? 2, 3 or 4, R4 denotes -CH3 or -C2H5, R5 and R6 denote -H, -CH3, -C2H5, -OCH3 or Cl, R7 denotes -H, -CH3 or -C2H5, R8 denotes C1-C6 alkyl or C3-C7 cycloalkyl, R9 and R10 denote C1-C4 alkyl, R11 denotes an alkylene radical -CmH2m wherein m = 1, 2 or 3, Het denotes a pyridyl, pyrimidinyl, thienyl, oxazolyl, imidazolyl, furanoyl or thiazolyl radical, X denotes -(CH2)p-, -(CH2)2-0-(CH2)2- or

Description

t 17~03~

The invention relates to a process :Eor preparing 3,4-disubstit-uted 1,2,5-oxadiazole 2-oxides of formula I Rl R2 (I) N~ o~N~~O

and their pharmaceutically acceptable acid addition compolmds, wherein, when R2 represents CH3 Rl denotes -CONilR3NR24, -CoNHR3-N ~N- ~CH2) ~R6 -CoNHR3NHCo ~ H3 -CO ~ N-(CH2)m ~ RR45 ~O' ~O
-CONHR OR , -CONHCH2CH=CH2~ -CONHR , CoNR9R10 -CONHR lC02R , -CONHR CON112, -CONHR ~ R56 -coNHRll-Het, -CON X -CONHRllCONHR , and, when R2 is other than CH3 and has one of the meanings indicated above for Rl, Rl denotes -CH3, R3 denotes an alkylene radical -CnH2n-, wherein n = 2, 3 or 4, R4 denotes -CH3 or -C2H5, R5 and R6 denote -H, -CH3, -C2H5, -OCH3 or -CL, R denotes -H, -CH3 or -C2H5, R denotes alkyl having 1 to 6 C atoms or cycloalkyl having 3 to 7 C atoms, R9 and R10 denote alkyl with 1 to 4 C atoms, Rll denotes an alkylene radical -CmH2m wherein m = 1, 2 or 3, Het denotes a pyridyl, pyrimidinyl, thienyl, oxazolyl, imidazolyl, furanoyl or thiazolyl radical, X denotes -~CH2)p-, -(CH2)2-0-~CH2)2- or -(CH2)2-N-~CH2)2-, wherein p is 4, 5 or 6, wilich process comprises a) when R2 denotes -CH3, reacting a 3-methyl-1,2,5-oxadiazole 2-oxide-4-carboxylic acid ester of the formula (II) ! 1 7 3 0 3 4 (II) ~0/ ~0 wherein R12 denotes alkyl having 1 to 6 C atoms, with an amine HZ and the amine employed here is selected in such a way that the radical Z, together with the carbonyl group of the ester II, forms the radical Rl, or b) when Rl denotes -CH3, heating a compound of the formula ~Ia) Rl / CH3 ~ ~Ia) ~ 0~ ~0 wherein Rl has a meaning indicated above for R2, at temperatures from 150 to 220~C, and converting to an acid addition compound when required. The present invention also provides the compound of formula (I) prepared by the process defined above.
It can be seen from the above definitions of the radicals and R2 that, in the compounds of the formula I, one of the radicals Rl or R , and indeed only one, always represents -CH3, that is to say the radicals Rl and R2 cannot simultaneously denote -CH3 in a compound; one of them mu~t be -CH3.
The alkyl radicals represented by R8, R9 and R10 (and those represented by R12 mentioned below) and the alkylene radicals represented by R3 and Rll can be straight-chain or branched. R3 preferably denotes -CH2CH2- or -CH2CH2CH2-. Rll preferably denotes -CH2- or -CH2CH2-.

Amongst the compounds of the formula I, preferred compounds are those in which R2 is -CH3 and also tnose which have an -NH- grouping in the ! 173034 radical Rl. Thc pyridyl radical is preferred for l-let.
The compounds, according to the invention, of the formula I in which R2 = -CH3 can be prepared by reacting 3-methyl-1,2,5-oxdiazole-
2-oxide-4-carboxyli.c acid esters of the formula II with an amine HZ.

R 02C CH3 + HZ ~ R CH3 N\ / ~ -ROH N~

(II) (Ia) whcrein R12 denotes an alkyl radical having 1 to 6 C atoms, in par-- 2a -~ 173~34 ticular 1 to 4 C atoms, preferably me~hyl or ethyl. In this reaction, the amine HZ is selected in such a way that the radical Z, together with the carbonyl group of the ester II forms the radical R in the compound Ia.
Z therefore has the following meanings:

-NHR NR2, -NHR -N ~ N-(CH2)m ~ R

-NHR NHCO ~ 3 , -N ~ N-(CH2)m ~ R

NHR30R7 -NHCH2CH=CH2, -NHR , -NR R

-NHRllC02R , -NHR CONH2, -NHR ~ R6 NHRll-Het, ~ X, -NHR CONHR , The reaction of the compound II with the amine HZ is appropriately carried out in a suitable solvent or dispersing agent. Examples of solvents or dispersing agents of this type which can be used are alcohols, such as methanol, ethanol or i-propanol; and also ethers, such as diethyl ether, dioxane or tetrahydrofuran; ketones such as acetone: hydrocarbons, such as toluene, xylenes or peiroleum ether; halogenated hydrocarbons, such as chloroform or chlorobenzene; polar aprotic solvents, such as, for example, acetonitrile or dimethylformamide, or aqueous solutions of the amine HZ. As a rule, the reaction is carried out at temperatures from 15 to 25 C. It can, however, also be carried out at temperatures from 0C to the reflux tempera-ture of the solvent or dispersing agent.
The compound of the formula II in which R12 = ethyl is described in Berichte der deutschen chemischen Gesellschaft 28, 2681 (1895) as the ester of peroxydiisonitrosobutyric acid. Compounds of the formula II having other R12 radicals can be prepared analogously by choosing suitable starting materials.

I 1 7303 ~
Compounds, accol~ding to the lnvellt;oll, in which R~ = Cl13 and which have the formula Ib N~o ,N~o (Ib) are prepared from the compounds Ia by a rearrangement under the influence of heat. The rearrangement under the influence of heat is appropriately car-ried in the absence of solvents or dispersing agents by heating the sub-stance to temperatures from 150 to 220 C, preferably 180 to 200 C. As a rule, the rearrangement under the influence of heat is complete after 15 to 120 minutes, in most cases after 30 to 60 minutes. The course of the re-arrangement can be followed by means of thin layer chromatography.
The compounds I, according to the invention, which have a basicside chain, form salts with inorganic or organic acids. Examples of such acids are hydrochloric, hydrobromic, phosphoric, sulphuric, oxalic, lactic, tartaric, acetic, salicylic, benzoic, citric, ascorbic, adipic and naphthalenedisulphonic acids. The acid addition compounds are obtained in a known manner by combining the components in a suitable solvent or dispersing agent.
The compounds of the formula I and their pharmacologically accept-able acid addition compounds possess valuable pharmacological properties.
Their action on the heart/circulation system is particularly pronounced. In a low dosage, they lower the blood pressure, reduce the peripheral resist-ance and produce a reduction in the heart action via a lowering of the pulmonary arterial pressure at a pulse rate which is only slightly affected.
The compounds of the formula I and their pharmacologically accept-able acid addition salts can, therefore, be administered to humans as drugs, on their own, as mixtures with one another or in the form of pharmaceutical ~ ~7303~
formn~ t:iolls wl~icll mako po~sil-~lo oll~:or~ll or pclrolltornl udministr(ltion and whicll contain, as tho activo collstitllent, an eEfective dose of at least one compound of the formula I or an acld addition salt thereo-E, together with customary excipients and additive~s which are pharnlaceutically unobjection-able.
The drugs can be administered oralLy, Eor oxample in the -form of pills, tablets, lacquered tablets, dragees, hard and soft geLatine capsules, solutions, syrups, emulsions or suspensions or aerosol mixtures. Administra-tion can, however, also be carried out rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solu-tions, or percutaneously, for example in the form of ointments or tinctures.
Pharmaceutically inert inorganic or organic exc-ipients can he used for the preparation of the pharmaceutical formulations. Pills, tablets, dragees and hard gelatine capsules are prepared by using, for example, lactose, maize starch or derivatives thereof, talc or stearic acid or deriva-tives thereof and the like. Examples of excipients or soft gelatine cap-sules and suppositories are fats, waxes, semi-solid and liquid polyols, natural or hardened oiLs and the like. Fxamples of excipients which are suitable for the preparation of solutions and syrups are water, sucrose, invert sugar, glucose, polyols and the like. Examples of excipients which are sui.table for the preparation of injection solutions are water, alcohols, glycerol, polyols, vegetable oils and the like.
Besides the active compounds and excipients, the phar-~ ~7303~maceutical formulations can also contain additives, such as, for example, fillers, diluents, disintegrants, binders, lubricants, wetting agents, stabilisers, emulsifiers, preservatives, sweete-ners, colourants, flavouring agents, flavourings, thlckeners, thinners, buffer substances, and also solvents or solubilisers or agents for achieving a depot effect, and also salts for alter-ing the osmotic pressure, coating agents or antioxidants.
They can also contain two or more compounds of the formula I or pharmacologically acceptable acid addition salts thereof and also other therapeutically active substances, , Examples of other therapeutically active substances of this type are: ~-receptor blockers, such as, for example, propranolol, pindolol or metoprolol; vasodilators, such as, for example, carbocromen; sedatives, such as, for example, barbituric acid derivatives, l,4-benzodiazepines and meprobamate; diuretics, such as, for example, chlorothiazide; heart tonics, such as, for example, digitalis formulations; hypotensive agents, such as, for example, hydralazine, dihydralazine, prazosin, clonidine,or Rauwolfia alkaloids; agents which lower the level of fatty acid in the blood, such as, for example, bezafibrate or fenofibrate;
and agents for the prophylaxis of thromboses, such as ) for example, phenprocoumon.
The compounds of the formula I, their pharmacologially acceptable acid addition salts and pharmaceutical formulations which contain, as active compounds, the compounds of the formula I or pharmacologically acceptable acid addition salts thereof, can be used on humans in combating or preventing diseases of the cardiovascular system, for example as antihypertensive drugs against the various forms of high blood pressure, and in combating or preventing angina pectoris and the like. The dosage can ~ 6 --! 173034 vary within wlde limits and should be ad~usted to sult the indi-vidual factors in each individual case. In general, a daily dose of about 0.2 to 150 mg, preferably1 to 30mgperhuman indi~i-dual is suitable for oral administration. In the case of other administration forms too, owing to the good absorption of the active compounds, ~he daily dose is wlthin similar quantity ranges, that is to say in general also 0.2 to 150 mg/person. The daily dose is normally subdivided into several, ~or example 2 to 4, part administrations.
The pharmaceutical formulations generally contain~ per dose, 0.1 to 50 mg, preferably 0.5 to 10 mg, of the active com-pounds of the formula I or pharmacologically acceptable acid addition salts thereof.
The investigations into the anti-anginal and antihyper-tensive action of the compounds of the formula I were carried out on mongrel dogs of both sexes under pentobarbital anaesthesia (30 to 40 mg/kg administered intravenously) or under urethane-chloralose anaesthesia (3 ml/kg of urethane-chloralose mixture administered intravenously = 20 mg/kg of chloralose and 250 mg/kg of urethane). The artificial respiration of the animals was effec*ed by means of a Bird Mark 7 respirator. The final ex-piratory content of carbon dioxide (dstermined by means of the Uras) was between 4.5 and 5 % by volume. During the entire ex-periment, the ani~als under pentobarbital anaesthesia received a continuous intravenous infusion of pentobarbital, 4 mg/kg/6ml/hour, in order to ensure a constant depth of anaesthesia; the animals under urethane-chloralose anaesthesia did not receive a continu-ous infusion. The infusion was administered through the cephalic vein. After the experimental animal had been pre-pared, there was a waiting period of approx. 1 hour until all the ! 1 7 3 0 3 4 haemodynamic parameters had become established (steady s-tate).
The actual test was then begun.
The systolic and diasystoliC blood pressure was measured peripherally in the femoral artery via a Statham préssure recorde~.
A Millar tip catheter inserted via the carotid artery into the left ventricle gave the signal for the LVFDP (left ventricular final diastolic pressure) and the pulse ra,te, The average blood pressure in the pulmonary artery was measured using a second tip catheter ins,erted via the ~ugular vein. The results ob-tained are shown in the following table.' ubstance Dose LVFDP PAP BP a PR
mg/kg ~ ~ mm/Hg ~ mmHg Q mmHg a/minute (administered intravenouslv~
.
ISDN 0.05 -2.1 -0.7 -19 ~ O
A 0.05 -3 -2 -~0 ~ 10 B 0.1 -2.5 -1 -25 + O
C 0.05 -2 -1 -35 - O
The symbols in the table have the following meanings:
LVFDP = left ventricular final diastolic pressure PAP = average pulmonary arterial pressure BP a = average peripheral blood pressure PR = pulse rate ISDN = Isosorbidedinitrate (comparison substance) A = 4-methyl-1,2,5-oxadiazole-3-carboxylic acid-methylamide 2-oxide , B = 3-methyl-1,2,5-oxaaiazole-4-carbo,xylic acid methoxy-ethylamide 2-oxide C = 3-methyl-1,2,5-ox~adiazole-4-carboxylic acid pyrid-3-ylmethylamide 2-oxide.
The following examples serve to illustrate the invention in greater detail.

! 1 73 0 3 ll Example 1 1,2,5-Oxadiazole-3-methyl-4-carboxylic acid 2-hydroxyethylamide 2-oxide 19.2 g of 1,2,5-oxadiazole-3-methyl-4-carboxylic acid ethyl ester 2-oxide are dissolved in 50 ml of e~hanol~ A solution of 6.1 g of ethanolamine in 40 ml of ethanol is added ~ropwise at 20C. The mixture is stirred for 4 hours at 20C and is cooled to 0C. The solid is filtered off, washed with a little cold ethanol and recrystallised from isopropanol:
colourless crystals, melting point 107 to 108C.
The following compounds were prepared analogously to this process:
1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid allylamide (oil), 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid methylamide (melting point 89 to 91C), 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid ethylamide ~melting point 80 to 82C), 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid isopropylamide (melting point 94 to 95C), 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid 2-diethylaminoethylamide ~melting point 216C,NDA salt), 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid 3-diethylaminopropyl-amide (oil), 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid 3-(4-o-methoxy-phenylpiperazin-l-yl)-propylamide (melting p~int 232C, NDA salt), 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid 4-o-methoxy-phenylpiperazide (melting point 152 to 153C), 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid 3-(4-o-chloro-phenylpiperazin-1-yl)-propylamide (melting point 205 to 206C, dec., NDA Salt), _ g _ B~

! 1 7303 4 1,2,5-oxadiazole-2-oxide-3-methyl-~-carboxylic acid 3-(~-o-methoxy-phenyl-piperazin-l-yl)-2-methylpropylamide (melting point 114 to 115C), 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid cyclopentylamide (melting point lQ4 to 106C), 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid cyclohexylamide (melting point 95 to 96.5C), 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid 2-methoxyethylamide (melting point 69 to 70C), 1,2-bis-[1,2,5-oxadiazole-2-oxide-3-methyl-4-carbonylamino]-ethane (melting point 195 to 200Cj dec.), 1,3-bis-[1,2,5-oxadiazole-2-oxide-3-methyl-4-carbonylamino]-propane (melting point 183 to 186C), 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid morpholide (melting point 75 to 78C), 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid benzylamide (melting point 91 to 93C), 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid pyrrolidide (melting point 65 to 67C), 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid 4-methyl-piperazide hydrochloride (melting point 278 to 280C dec). and 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid dimethylamide (melting point 70 to 72C).
Example 2 1,2J5-oxadidzole-2-oxide-4-methyl-3-carboxylic acid methylamide 5 g of 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid methylamide are warmed, in the absence of a solvent, at 190C for 30 minutes. After the melt has cooled, the mixture of products is separated by means of column chromatography (migrating agent: methylene chloride; column packing: silica gel). The fraction which migrates more rapidly is con-~ 173034 centrated and triturated with ligroin. The white solid is filtered off and, after drying in vacuo, is analytically pure: melting point 57 to 59C.
The following compounds were prepared analogously to this process:
1,2,5-oxadiazole-2-oxide-4-methyl-3-carboxylic acid ethylamide (oil) and 1,2J5-oxadizole-2-oxide-4-methyl-3-carboxylic acid 2-methoxy-ethylamide ~oil).
The ab4re~iation "dec." means decomposition. The indication "NDA salt" in connection with the melting point in the case of some of the above-mentioned compounds means that this is the melting point of the addition compound with naphthalene-1,5-disulphonic acid.
The structures of the compounds synthesised were confirmed by elementary analysis and by their IR and NMR spectra.

Claims (16)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of 3,4-disubstituted 1,2,5-oxadiazole 2-oxides of the formula (I) (I) wherein, when R2 represents CH3, R1 denotes -CONHR3NR24, , , -CONHR3OR7, -CONHCH2CH=CH2, -CONHR8, -CONHR9R10, -CONHR11CO2R4, -CONHR11CONH2, , -CONHR11-Het, -CONHR11CONHR8, and, when R2 is other than CH3 and has one of the meanings indicated above for R1, R1 denotes -CH3, R3 denotes an alkylene radical -CnH2n-, wherein n = 2, 3 or 4, R4 denotes -CH3 or -C2H5, R5 and R6 denote -H, -CH3, -C2H5, -OCH3 or -Cl, R7 denotes -H, -CH3 or -C2H5, R8 denotes alkyl having 1 to 6 C atoms or cycloalkyl having 3 to 7 C atoms, R9 and R10 denote alkyl with 1 to 4 C atoms, R11 denotes an alkylene radical -CmH2m wherein m = 1, 2 or 3, Het denotes a pyridyl, pyrimidinyl, thienyl, oxazolyl, imidazolyl, furanoyl or thiazolyl radical, X denotes -(CH2)p-, -(CH2)2-0-(CH2)2- or (CH2)2-, wherein p = 4, 5 or 6 or pharmaceutically acceptable acid addition compounds thereof, which process comprises a) when R2 denotes -CH3, reacting a 3-methyl-1,2,5-oxadiazole 2-oxide-4-carboxylic acid ester of the formula (II) (II) wherein R12 clenotes alkyl having 1 to 6 C atoms, with an amine HZ and the amine employed here is selected in such a way that the radical Z, together with the carbonyl group of the ester II, forms the radical R1, or b) when R1 denotes -CH3. heating a compound of the formula (Ia) (Ia) wherein R1 has a meaning indicated above for R2, at temperatures from 150 to 220°C, and converting to an acid addition compound when required.
2. 3,4-Disubstituted 1,2,5-oxadiazole 2-oxides of the formula I

(I) wherein, when R2 represents CH3, R1 denotes -CONHR3NR24, , , , -CONHR3OR7, -CONHCH2CH=CH2, -CONHR8, -CONR9R10, -CONHR11CO2R4, -CONHR11CONH2, , -CONHR11-Het, , -CONHR11CONHR8, and, when R2 is other than CH3 and has one of the meanings indicated above for R1, R1 denotes -CH3, R3 denotes an alkylene radical -CnH2n-, wherein n = 2, 3 or 4, R4 denotes -CH3 or -C2H5, R5 and R6 denote -H, -CH3, -C2H5, -OCH3 or -Cl, R7 denotes -H, -CH3 or -C2H5, R8 denotes alkyl having 1 to 6 C atoms or cycloalkyl having 3 to 7 C atoms, R9 and R10 denote alkyl with 1 to 4 C atoms, R11 denotes an alkylene radical -CmH2m wherein m = 1, 2 or 3, Het denotes a pyridyl, pyrimidinyl, thienyl, oxazolyl, imidazolyl, furanoyl or thiazolyl radical, X denotes -(CH2)p-, -(CH2)2-O-(CH2)2- or , wherein p is 4, 5 or 6 and pharmaceutically acceptable acid addition compounds thereof, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
3. A process for the preparation of 3,4-disubstituted 1,2,5-oxa-diazole 2-oxides according to claim 1, characterised in that R2 denotes -CH3 and R1 denotes R1 = -CONHR3NR24, , -CONHR3OR7, -CONHCH2CH=CH2, -CONHR8, -CONR9R10, -CONHR11CO2R4, -CONHR11CONH2, , -CONHR11CO2R4-Het, , -CONHR11CONHR8, R3 denotes an alkylene radical -CnH2n- wherein n denotes 2, 3 or 4, R4 denotes -CH3 or -C2H5, R5 and R6 denote -H, -CH3, -C2H5, -OCH3 or -Cl, R7 denotes -H, -CH3 or -C2H5, R8 denotes alkyl having 1 to 6 C atoms or cycloalkyl having 3 to 7 C atoms, R9 and R10 denotes alkyl having 1 to 4 C atoms, R11 denotes an alkylene radical -CmH2m- wherein m denotes 1, 2 or 3, Het denotes a pyridyl, pyrimidinyl, thienyl, oxazolyl, imid-azolyl, furanoyl or thiazolyl radical and X denotes -(CH2)p-, -(CH2)2-O-(CH2)2- or wherein p is 4, 5 or 6 characterised in that a 3-methyl-1,2,5-oxadiazole 2-oxide-4-carboxylic acid ester of the formula II
(II) wherein R12 denotes alkyl having 1 to 6 C atoms, is reacted with an amine HZ and the amine employed here is selected in such a way that the radical Z, together with the carbonyl group of the ester II, forms the radical R1, and the resulting compound is, if appropriate, converted into an acid addition compound.
4. A process according to claim 3, characterised in that the reaction is carried out in a solvent or dispersing agent at temperatures from 0°C to the reflux temperature of the solvent or dispersing agent.
5. 3,4-Disubstituted 1,2,5-oxadiazole 2-oxides according to claim 2, characterised in that R2 denotes -CH3 and R1 denotes R1 = -CONHR3NR24,, , , , -CONHR3OR7, -CONHCH2CH=CH2, -CONHR8, -CONR9R10 , -CONHR11CO2R4, -CONHR11CONH2, -CONHR11-Het, , -CONHR11CONHR8 , R3 denotes an alkylene radical -CnH2n- wherein n denotes 2, 3 or 4, R4 denotes -CH3 or -C2H5, R5 and R6 denote -H, -CH3, -C2H5, -OCH3 or -Cl, R7 denotes -H, -CH3 or -C2H5, R8 denotes alkyl having 1 to 6 C atoms or cycloalkyl having 3 to 7 C atoms, R9 and R10 denote alkyl having 1 to 4 C atoms, R11 denotes an alkylene radical -CmH2m- wherein m denotes 1, 2 or 3, Het denotes a pyridyl, pyrimidinyl, thienyl, oxazolyl, imid-azolyl, furanoyl or thiazolyl radical and X denotes -(CH2)p-, -(CH2)2-O-(CH2)2- wherein p is 4, 5 or 6 or , whenever pre-pared by the process of claim 3 or 4 or by an obvious chemical equiv-alent thereof.
6. A process according to claim 3 in which the radical Z in the amine HZ denotes -NHR3NR24, , -NHR3OR7, wherein R3 is -CH2CH2 or -CH2CH2CH2-.
7. 3,4-Disubstituted 1,2,5-oxadiazole 2-oxides according to claim 2, characterised in that R3 denotes -CH2CH2- or -CH2CH2CH2-, whenever prepared by the process of claim 6 or by an obvious chemical equivalent thereof.
8. A process according to claim 3 in which the radical Z in the amine HZ denotes -NHR11CO2R4, -NHR11CONH2, -NHR11-Met, -NHR11CONHR8, wherein R11 is -CH2- or -CH2CH2-.
9. 3,4-Disubstituted 1,2,5-oxadiazole 2-oxides according to claim 2, characterised in that R11 denotes -CH2- or -CH2CH2-, whenever pre-pared by the process of claim 8 or by an obvious chemical equivalent thereof.
10. A process according to claim 3 in which the radical Z in the amine HZ denotes -NHR3NR24, , -NHR3OR7, -NHCH2CH=CH2, -NHR8, -NHR11CO2R4, -NHR11CONH2, , -NHR11-Met, -NHR11CONHR8.
11. 3,4-Disubstituted 1,2,5-oxadiazole 2-oxides according to claim 2, characterised in that they contain an -NH- grouping, whenever prepared by the process of claim 10 or by an obvious chemical equivalent thereof.
12. A process for the preparation of the compounds of the formula Ib (Ib) wherein R2 denotes -CONHR3NR24, -CONHR3OR7, -CONHCH2CH-CH2, -CONHR8, -CONR9R10, -CONHR11CO2R4, -CONHR11CONH2, -CONHR11-Het, , -CONHR11CONR8, R3 denotes an alkylene radical -CnH2n- wherein n denotes 2,3 or 4, R4 denotes -CH3 or -C2H5, R5 and R6 denote -H, -CH3, -C2H5, -OCH3 or Cl, R7 denotes -H, -CH3 or -C2H5, R8 denotes alkyl having 1 to 6 C atoms or cycloalkyl having 3 to 7 C atoms, R9 and R10 denote alkyl having 1 to 4 C atoms, R11 denotes an alkylene radical -CmH2m- wherein m denotes 1, 2 or 3, Het denotes a pyridyl, pyrimidinyl, thienyl, oxazolyl, imidazolyl, furanoyl or thiazolyl radical and X denotes -(CH2)p-, -(CH2)2-O-(CH2)2- or wherein p is 4, 5 or 6, characterised in that a compound of the formula (Ia) (Ia) wherein R1 has a meaning indicated above for R2, is heated at temper-atures from 150 to 220 °C and the resulting compound is, if appropriate, converted into an acid addition compound.
13. 3,4-Disubstituted 1,2,5-oxadiazole 2-oxides having the formula (Ib) (Ib) wherein R2 denotes -CONHR3NR24, , -CONHR3OR7, -CONHCH2CH=CH2, -CONHR8, -CONR9R10 , -CONHR11CO2R4, -CONHR11CONH2, -CONHR11-Het , , -CONHR11CONR8 , R3 denotes an alkylene radical -CnH2n- wherein n denotes 2, 3 or 4, R4 denotes -CH3 or -C2H5, R5 and R6 denote -H, -CH3, -C2H5, -OCH3 or Cl, R7 denotes -H, -CH3 or -C2H5, R8 denotes alkyl having 1 to 6 C atoms or cycloalkyl having 3 to 7 C atoms, R9 and R10 denote alkyl having 1 to 4 C atoms, R11 denotes an alkylene radical -CmH2m- wherein m denotes 1, 2 or 3, Het denotes a pyridyl, pyrimidinyl, thienyl, oxazolyl, imidazolyl, furanoyl or thiazolyl radical and X denotes -(CH2)p-, -(CH2)2-O-(CH2)2-or , whenever prepared by the process of claim 12 or by an obvious chemical equivalent thereof.
14. A process for preparing 4-methyl-1,2,5-oxadiazole-3-carboxylic acid methylamide 2-oxide, which process comprises:
heating 3-methyl-1,2,5-oxadiazole-4-carboxylic acid methyl amide 2-oxide at temperatures at 150 to 220°C.
15. A process for preparing 3-methyl-1,2,5-oxadiazole-4-carboxylic acid methoxyethylamide 2-oxide, which process comprises:
reacting 3-methyl-1,2,5-oxadiazole-4-carboxylic acid alkyl ester 2-oxide having 1 to 6 carbon atoms in the alkyl moiety, with methoxyethylamine.
16. A process for preparing 3-methyl-1,2,5-oxadiazole-4-carboxylc acid pyrid-3-ylmethylamide 2-oxide, or a pharmaceutically acceptable acid addition salt thereof, which process comprises:
reacting 3-methyl-1,2,5-oxadiazole-4-carboxylic acid alkyl ester 2-oxide having 1 to 6 carbon atoms in the alkyl moiety, with pyrid-3-ylmethylamine, and when required, converting to a pharmaceutically acceptable acid addition salt thereof.
CA000392542A 1980-12-18 1981-12-17 3,4-disubstituted 1,2,5-oxadiazole 2-oxides, processes for their preparation, their use and pharmaceutical formulations containing them Expired CA1173034A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5374640A (en) * 1992-06-05 1994-12-20 Cassella Aktiengesellschaft Pyridyl-1,2,5-oxadiazolecarboxamide-2-oxides
US5389655A (en) * 1992-05-29 1995-02-14 Cassella Ag Phenylfuroxans
US5424326A (en) * 1992-06-20 1995-06-13 Cassella Aktiengesellschaft Phenyl-1,2,5-oxadiazolecarboxamide-2-oxides, their preparation and their use

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US4507485A (en) * 1984-01-23 1985-03-26 Bristol-Myers Company 3,4-Disubstituted-1,2,5-oxadiazoles having histamine H2 -receptor antagonist activity
DE4218979A1 (en) * 1992-06-10 1993-12-16 Cassella Ag Pyrimidofuroxanes
DE4223800A1 (en) * 1992-07-20 1994-01-27 Cassella Farbwerke Mainkur Ag Use of 1.2.5-oxadiazole-2-oxides for the treatment of erectile dysfunctions
DE4401150A1 (en) * 1994-01-17 1995-07-20 Cassella Ag Furazancarbonsäurederivate
US6957741B2 (en) 2001-08-07 2005-10-25 Manfred Franz Axel Freissle Screening arrangement

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CH498856A (en) * 1968-02-06 1970-11-15 Geigy Ag J R Pharmaceutical furazan derivatives prodn
GB1474692A (en) * 1973-05-21 1977-05-25 Ici Ltd Furoxan production

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5389655A (en) * 1992-05-29 1995-02-14 Cassella Ag Phenylfuroxans
US5374640A (en) * 1992-06-05 1994-12-20 Cassella Aktiengesellschaft Pyridyl-1,2,5-oxadiazolecarboxamide-2-oxides
US5424326A (en) * 1992-06-20 1995-06-13 Cassella Aktiengesellschaft Phenyl-1,2,5-oxadiazolecarboxamide-2-oxides, their preparation and their use

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