WO1998015541A1 - Novel isoxazol derivatives, pharmaceutical compositions containing the same, and a process for the preparation of the novel compounds - Google Patents

Novel isoxazol derivatives, pharmaceutical compositions containing the same, and a process for the preparation of the novel compounds Download PDF

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Publication number
WO1998015541A1
WO1998015541A1 PCT/HU1997/000059 HU9700059W WO9815541A1 WO 1998015541 A1 WO1998015541 A1 WO 1998015541A1 HU 9700059 W HU9700059 W HU 9700059W WO 9815541 A1 WO9815541 A1 WO 9815541A1
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group
formula
value
atom
isoxazole
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PCT/HU1997/000059
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French (fr)
Inventor
József NYITRAI
József Nagy
Gyula Simig
Zoltán Greff
Gábor BLASKÓ
János WELLMANN
Gábor SZÉNÁSI
István Gacsályi
Tamás Szabados
István Gyertyán
Éva SCHMIDT
Katalin Pallagi
András BILKEI-GORZÓ
Károly TIHANYI
András Egyed
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EGIS Gyógyszergyár Rt.
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Priority to AU48789/97A priority Critical patent/AU4878997A/en
Publication of WO1998015541A1 publication Critical patent/WO1998015541A1/en

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • Novel isoxazol derivatives pharmaceutical compositions containing the same, and a process for the preparation of the novel compounds
  • the invention refers to novel isoxazole and 4 , 5-dihydroisoxazole derivatives, a process for the preparation thereof, pharmaceutical compositions containing a novel isoxazole or 4 , 5-dihydroisoxazole derivative as the active ingredient as well as a medical use process employing such an active ingredient.
  • the invention refers to isoxazole derivatives of the formula I
  • a and B represent, independently, a hydrogen atom, or A forms, together with B, a valence bond
  • Z stands for a hydrogen atom, a halo atom, a C, _ . alkyl group, a trifluoromethyl group or one or two C-, _ . alkoxy group(s)
  • R 1 and R2 mean, independently, a C-, _ fi alkyl group or a C-._ 7 cycloalkyl group, or R 1 and R2 form, together with the nitrogen atom they are attached to and optionally with one or more further nitrogen and/or oxygen atom(s), a 5 to 8-membered heterocyclic ring that can be substituted by a C, .
  • alkyl group a (C-, . alkyl)phenyl group, a ( C-, _. alkoxy ) - phenyl group, a di(C-,_. alkoxy )phenyl group, a halophenyl group, a trifluoromethylphenyl group or a furoyl group, m has a value of 0 or 1, n has a value of 0 or 1, with the proviso that
  • each of R 1 and R2 stands for an ethyl group or R 1 and R2 form, together with the nitrogen atom they are attached to, a piperidin-1-yl or a morfolino group, then Z is other than a hydrogen atom or a chloro atom in position para, and
  • each of R I and R2 stands for a methyl group or R 1 and R2 form, together with the nitrogen atom they are attached to, a pirrolidin-1-yl group, then Z is other than a hydrogen atom, and pharmaceutically acceptable acid addition salts thereof.
  • novel compounds of the formula I influence, significantly, the central and peripheric nervous serotonin neurotransmitter system; have affinity for the central nervous system alpha, and/or 5-HT, receptors; and possess psychotropic and cardiovascular effects .
  • 3-Aryl-5-aminomethylisoxazole derivatives are known from the literature /J. Med. Chem. , 10, 411-418 (1967)/.
  • the known compounds have hypothermic, analgesic and antitussive activities.
  • the aim of the invention is to prepare novel isoxazole derivatives influencing, in the first place, the central nervous system and the peripheric serotonin neurotransmitter system.
  • a halo atom is mainly a fluoro, chloro or bromo atom.
  • a C, _. alkyl group is a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec. -butyl, tert. -butyl or isobutyl group.
  • a C- . alkyl group is a methyl group.
  • a C, alkyl group can be, in addition to the meanings listed in connection with the C, . alkyl group, generally also a n-pentyl group or a n-hexyl group.
  • a ⁇ 1_4 alkoxy group is, in the first place, a methoxy, ethoxy, n-propoxy or n-butoxy group, preferably a methoxy group. If R 1 and R2 form, together with the nitrogen atom they are attached to and optionally together with one or more further nitrogen and/or oxygen atom(s), a 5 to
  • 8-membered heterocyclic ring it is preferably a pyrrolidinyl, piperidinyl, azepanyl, morpholino or piperazinyl group.
  • an acid addition salt formed with a pharmaceutically acceptable inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid etc. or with a pharmaceutically acceptable organic acid such as acetic acid, fumaric acid, lactic acid, malic acid etc. are meant.
  • a preferred subgroup of the isoxazole derivatives of the formula I consists of the 4 , 5-dihydroisoxazole derivatives of the formula
  • each of A and B stands for a hydrogen atom.
  • R 1 and R2 mean, independently, a C-, _ fi alkyl group or a C-s 7 cycloalkyl group, or R 1 and R2 form, together with the nitrogen atom they are attached to and optionally with one or more further nitrogen and/or oxygen atom(s), a 5 to 8-membered heterocyclic ring that can be substituted by a C, _ . alkyl group, a (C, . alkyl)phenyl group, a (C-, .
  • n has a value of 0 or 1.
  • Another preferred subgroup of the isoxazole derivatives of the formula I consists of the isoxazole derivatives of the formula lb
  • formula lb Z stands for a hydrogen atom, a halo atom, a C, , alkyl group, a trifluoromethyl group or one or two C-, , alkoxy group(s),
  • R and R mean, independently, a C-_ fi alkyl group or a C ⁇ 7 cycloalkyl group, or
  • 1 2 R and R form, together with the nitrogen atom they are attached to and optionally with one or more further nitrogen and/or oxygen atom(s), a 5 to 8-membered heterocyclic ring that can be substituted by a C-, 4 alkyl group, a (C-,_ 4 alkyl)phenyl group, a (C-, . alkoxy )phenyl group, a di(C, . alkoxy ) phenyl group, a halophenyl group, a trifluoromethylphenyl group or a furoyl group, m has a value of 0 or 1, n has a value of 0 or 1 , with the proviso that
  • each of R 1 and R2 stands for an ethyl group or R 1 and R2 form, together with the nitrogen atom they are attached to, a piperidin-1-yl or a morfolino group, then Z is other than a hydrogen atom or a chloro atom in position para, and
  • each of R 1 and R2 stands for a methyl group or R 1 and R2 form, together with the nitrogen atom they are attached to, a pirrolidin-1-yl group, then Z is other than a hydrogen atom.
  • a and B represent, independently, a hydrogen atom, or A forms, together with B, a valence bond
  • Z stands for a hydrogen atom, a halo atom, a trifluoromethyl group or one or two methoxy group(s), R 1 and R2' form, together with the nitrogen atom they are attached to and optionally together with further nitrogen and/or oxygen atom(s), a pyrrolidinyl , piperidinyl, azepanyl, morpholino or piperazinyl group which latter can be substituted by a methyl, methylphenyl, methoxyphenyl, dimethoxyphenyl, halophenyl, trifluoromethylphenyl or furoyl group, m has a value of 0 or 1, n has a value of 0 or 1.
  • Z represents a halo atom, a methyl group or a methoxy group
  • R 1 and R2 form, together with the nitrogen atom they are attached to and a further nitrogen atom, a piperazinyl group optionally substituted by a methoxyphenyl group
  • m has a value of 0 or 1
  • n has a value of 0 or 1.
  • the compounds of the formula I may contain one or two chiral carbon atom(s), thus, they can exist in the form of optical isomers.
  • the invention includes the single isomers as well as any mixtures thereof.
  • novel compounds of the invention are prepared as follows:
  • reaction that consists of a dipolar cycloaddition is carried out in organic aprotic solvents such as benzene, toluene, diethyl ether, dichloromethane etc.
  • organic aprotic solvents such as benzene, toluene, diethyl ether, dichloromethane etc.
  • the reaction temperature is, in general, between 0 C and the boiling point of the reaction mixture.
  • the nitril oxide of the formula II is prepared from the compound of the formula
  • Z is as stated in relation to formula I, by methods described in the literature or by suitable modifications thereof: R. Huisgen, W. Mack, E. Anneser, Angew. Chem., 73, 656 (1961); H. Wieland, Ber . der Deutsch. Chem. Ges., O, 1670 (1907); F. Eloy, R. Lenaers , Bull. Soc . Chi . Belg., 7_2_, 719 (1963); R. Lenaers, F. Eloy, Helv. Chim. Acta, 46, 1067 (1963); T. Sasaki, T. Yoshioka, Bull. Chem. Soc. Japan, 0, 2604 (1967); ibid. 4_1, 2206 (1968); ibid. _42_, 258 (1969).
  • a suitably substituted benzaldehyde is used as the starting compound.
  • an oxime is prepared /for example according to the methods described in Houben- -Weyl: Methoden der Organischen Chemie, l ⁇ /4 , 55-58 (1968)/, then the oxime is chlorinated in alpha position.
  • the chlorination is performed by introducing elemental chlorine gas into the solution of the oxime in a chlorinated hydrocarbon e.g.
  • the nitril oxide of the formula II is prepared from the compound of the formula VI in the reaction mixture obtained after the preparation thereof.
  • the allyl derivative of the formula III is prepared by the reaction of an allyl halogenide, preferably allyl bromide, with an amine of the formula IX
  • Hal represents a halo atom
  • R and 2 R are as stated above, with a 4,5-dihydro- isoxazole-5-ylmethanol of the formula IV
  • the propargyl derivative of the formula VII is prepared by means of the reaction of a propargyl halide suitably propargyl bromide and an amine of the formula IX under the conditions given in connection with the preparation of the allyl derivatives of the formula III.
  • Isoxazole derivatives of the formula lb described above can be also prepared by reacting a compound of the formula VIII
  • Hal represents a halo atom preferably a bromo atom
  • Z is as stated in relation to formula I, with an amine of the formula IX.
  • the reaction is carried out preferably in an aromatic hydrocarbon such as benzene or toluene at the boiling point of the reaction mixture.
  • the amine of the formula IX is used in an excess.
  • the compound of the formula VIII is prepared by dipolar cycloaddition of the nitril oxide of the formula II with a propargyl halide preferably propargyl bromide.
  • Isoxazole derivatives of the formula lb, wherein m has a value of 1, n has a value of 1, Z, R 1 and R2 are as stated in relation to formula I, are prepared by reacting an epoxide of the formula X
  • the epoxide of the formula X is prepared from an isoxazole-5-ylmethanol of the formula XII
  • the isoxazole-5-ylmethanol of the formula XII is prepared by the dipolar cycloaddition of the nitril oxide of the formula II and propargyl alcohol.
  • R 1 and R2 are as defined above.
  • a compound of the formula VIII, wherein Hal represents a bromo atom is reacted with an alcoholate of a hydroxyethylamine of the formula XI in an ether type solvent.
  • the epoxide of the formula XIII can be obtained by reacting the corresponding 4 , 5-dihydroisoxazole-5-ylmethanol with epichlorohydrin.
  • optical isomers can be prepared in a manner known per se.
  • an obtained compound of the formula I is converted to an acid addition salt by reacting it with a pharmaceutically suitable inorganic or organic acid.
  • novel isoxazole derivatives of the formula I possess extremely valuable pharmacological activities.
  • 5-HT, receptor assay was performed as described earlier /S.J. Peroutka, J. Neurochem., . 47, 529-540 (1986)/.
  • the binding was determined in membrane fragments prepared from rat frontal cortex using tritium-labeled 8-hydroxy-N,N-dipropyl-2-aminotetraline as specific ligand in a final volume of 250 microliters.
  • Non-specific binding was determined in the presence of 10 microM of serotonine creatinine sulfate /the chemical name of serotonine is 3- ( 2-aminoethyl ) -1H- -indole-5-ol/ .
  • the assay samples were incubated for 30 minutes at 25 C.
  • the compounds found to be effective in receptor binding were further examined both in psychopharmacological and cardiovascular tests .
  • the elevated plus-maze consists of two open and two 40 cm wall enclosed arms of the same size (50 x 15 cm) arranged in the shape of a cross. The arms of the same type are opposite to each other. The junction of the four arms forms a central square area (15 x 15 cm) .
  • the apparatus is made of wooden material elevated to a height of 50 cm and illuminated by a dim light from above- Male Sprague-Dawley rats weighing 220 to 260 g were treated with the test or reference compounds 60 minutes prior to the test. The animals were then placed onto the central square area and were subjected to the test for 5 minutes. The following parameters were determined:
  • MED Minimum Effective Doses
  • novel compounds were more effective in the elevated plus-maze test than the reference compounds.
  • mice were individually placed into the experimental chamber which was a 22 cm x 15.5 cm x 14 cm plexyglass box with 5 cm thick layer of sawdust on the bottom. 24 glass marbles of 1 cm diameter were placed, in close contact with each other, on the sawdust in the middle of the cage. The mice were left in the cage with the marbles for 15 minutes. After the mice were removed, the number of buried marbles (i.e. the marbles covered by sawdust to a height exceeding the two thirds of the diameter) were determined.
  • the novel compounds examined have significant activity on the above model
  • the activity of three novel compounds is higher than that of the buspirone used as reference* compound.
  • test substance was tested in 4 to 5 mongrel dogs of both sexes weighing 11 to 31 kg. Anesthesia was induced i.v. with 30 g/kg of sodium pentobarbital i.e. 5-ethyl-5- ( 1-methylbutyl ) -2 , 4 , 6- ( 1H, 3H, 5H) - pyrimidinetrione sodium salt.
  • the dogs were intubated with cuffed endotracheal tubes and were ventilated with 180 ml/kg of room air enriched in oxygen at a rate of 15/minute (Haeward 55 type ventilator, South Natick, USA) .
  • the right femoral artery and vein were cannulated with PP 90 tubings for determining the arterial blood pressure and for taking arterial blood samples as well as for drug administration.
  • Arterial blood pressure was measured with a Gould Statham P 23 Gb pressure transducer and Hugo Sachs amplifier (HS, Hugo Sachs Elektronik, March, Germany) and was recorded continuously during the experiment (Watanabe Graphtec Linearcorder mark VII, WR 3101, Hugo Sachs Elektronik, March, Germany ) .
  • test substances were administered in cumulative i.v. doses.
  • Mean arterial pressure was estimated from the recording prior to the first drug administration and 15 minutes after injection of each dose. Blood pressure was plotted against the logarithm of the dose, and a regression line was fitted on the linear part of the blood pressure curve. The dose causing 30 percent decrease in blood pressure (ED., ) was calculated from the regression .
  • the novel isoxazole derivatives have remarkable anxiolytic and antihypertensive effect in the test models studied. In some tests, their effectiveness is better than that of the reference substances. Results obtained in receptor binding studies are in line with effects measured in in vivo tests since it has been suggested that the 5HT, receptors have a role in the regulation of several central nervous system processes /Cliffe and Fletchere, Drugs Fut., . 18 . (7), 631-642 (1993)/.
  • the novel compounds of the invention may be useful in antihypertensive , antianginal and vasodilator therapy. Moreover, the novel compounds may also be effective in gastrointestinal disorders.
  • novel isoxazole derivatives of the formula I and pharmaceutically acceptable acid addition salts thereof can be used as active ingredients of pharmaceutical compositions.
  • the pharmaceutical compositions of the invention contain a therapeutically active amount of the compound of the formula I or a pharmaceutically acceptable acid addition salt thereof and one or more conventional carrier ( s ) .
  • compositions of the invention are suitable for peroral, parenteral or rectal administration or for local treatment, and can be solid or liquid.
  • the solid pharmaceutical compositions suitable for peroral administration may be powders, capsules, tablets, film-coated tablets, microcapsules etc., and can comprise binding agents such as gelatine, sorbitol, poly ( vinylpyrrolidone ) etc.; filling agents such as lactose, glucose, starch, calcium phosphate etc.; auxiliary substances for tabletting such as magnesium stearate, talc, poly ( ethyleneglycol ) , silica etc.; wetting agents such as sodium laurylsulfate etc. as the carrier.
  • binding agents such as gelatine, sorbitol, poly ( vinylpyrrolidone ) etc.
  • filling agents such as lactose, glucose, starch, calcium phosphate etc.
  • auxiliary substances for tabletting such as magnesium stearate, talc, poly ( ethyleneglycol ) , silica etc.
  • wetting agents such as sodium laurylsulfate etc. as the carrier.
  • the liquid pharmaceutical compositions suitable for peroral administration may be solutions, suspensions or emulsions and can comprise e.g. suspending agents such as gelatine, carboxymethylcellulose etc.; emulsifiers such as sorbitane monooleate etc.; solvents such as water, oils, glycerol, propyleneglycol , ethanol etc.; preservatives such as methyl p-hydroxybenzoate etc. as the carrier .
  • suspending agents such as gelatine, carboxymethylcellulose etc.
  • emulsifiers such as sorbitane monooleate etc.
  • solvents such as water, oils, glycerol, propyleneglycol , ethanol etc.
  • preservatives such as methyl p-hydroxybenzoate etc. as the carrier .
  • compositions suitable for parenteral administration consist of steril solutions of the active ingredient, in general
  • Dosage forms listed above as well as other dosage forms are known per se, see e.g. Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co., Easton, USA (1990) .
  • compositions of the invention contain, in general, O.l to 95.0 per cent by mass of a compound of the formula I or a pharmaceutically acceptable acid addition salt thereof.
  • a typical dose for adult patients amounts to 0.1 to 20 mg of the compound of the formula I or a pharmaceutically acceptable acid addition salt thereof, daily.
  • the above dose can be administered in one or more portions. The actual dosage depends on many factors and is determined by the doctor.
  • compositions of the invention are prepared by admixing a compound of the formula I or a pharmaceutically acceptable acid addition salt thereof to one or more carrier(s), and converting the mixture obtained to a pharmaceutical composition in a manner known per se.
  • Useful methods are known from the literature, e.g. Remington's Pharmaceutical Sciences.
  • the pharmaceutical compositions of the invention contain an isoxazole derivative of the formula I, wherein ⁇ and B represent, independently, a hydrogen atom, or A forms together with B a valence bond, Z stands for a hydrogen atom, a halo atom, a methyl group, a trifluoromethyl group or one or two methoxy group(s),
  • R and R form together with the nitrogen atom they are attached to and optionally together with a further nitrogen or oxygen atom a pyrrolidinyl , piperidinyl, azepanyl, morpholino or piperazinyl group which latter can be substituted by a methyl, methyl- phenyl, methoxyphenyl, dimethoxyphenyl, halophenyl, trifluoromethylphenyl or furoyl group, m has a value of 0 or 1 , n has a value of 0 or 1, or a pharmaceutically acceptable acid addition salt thereof as the active ingredient.
  • composition of the invention comprise an isoxazole derivative of the formula I, wherein
  • a and B represent, independently, a hydrogen atom, or
  • A forms together with B a valence bond
  • Z stands for a halo atom, a methyl group or a methoxy group
  • R 1 and R2 form together with the nitrogen atom they are attached to and with a further nitrogen atom a piperazinyl group optionally substituted by a methoxyphenyl group
  • m has a value of 0 or 1
  • n has a value of 0 or 1
  • a pharmaceutically acceptable acid addition salt thereof as the active ingredient.
  • the invention refers to a method for the treatment of diseases which comprises administering a therapeutically effective non-toxic amount of an isoxazole derivative of the formula I or a pharmaceutically acceptable acid addition salt thereof to a patient suffering from a pathological alteration of the central nervous system and/or a cardiovascular and/or gastrointestinal disease.
  • a pathological alteration of the central nervous system anxiety, depression, cognitive deficit, trophopathy, dyssomnia etc. are meant in the first place.
  • the invention also refers to the use of an isoxazole derivative of the formula I or a pharmaceutically acceptable acid addition salt thereof for the preparation of a pharmaceutical composition.
  • the title compound is prepared from 50 mmoles of 4-methylbenzhydroxamic chloride as given under the preparation of 5-bromo- methyl-3- ( 4-methoxyphenyl ) isoxazole. Yield: 52.7 %. M.p.: 69-72 °C (ethanol). IR (KBr): 3150, 1610, 1420, 810 cm "1 .
  • the title compound is prepared from 50 mmoles of 4-methoxybenzhydroxamic chloride by the method given under item 4 above. Yield: 36.1 %. M.p. : 99-101 °C.
  • the title compound is prepared from 50 mmoles of 4-fluorobenzhydroxamic acid by the method given under item 7.
  • the title compound is prepared from 50 mmoles of ,4-chlorobenzhydroxamic acid by the method given under item 7. Yield: 35.8 %. M.p. : 105-106 °C.
  • the residue is taken up in 100 ml of water, extracted 3 times using 100 ml of dichloromethane each time, the organic solutions are combined, dried over anhydrous magnesium sulfate, filtered, and evaporated.
  • the residue obtained is purified by chromatography over a 0.063-0.2 mm gel of Kieselgel G or Kieselgel 60 in vacuo using dichloromethane for the elution.
  • the title compound is obtained as an oil. Yield: 48.8 %.
  • the title compound is prepared from 50 mmoles of 3- ( 3 , 4-dimethoxyphenyl ) isoxazole- -5-ylmethanol by the method described under item 11 above.
  • the title compound is obtained as an oil. Yield: 76.1 %.
  • the title compound is prepared from 50 mmoles of 3- ( 4-methoxyphenyl ) isoxazole-5-yl- methanol by the method described under item
  • the title compound is prepared from 50 mmoles of 3- ( -methylphenyl ) isoxazole-5-yl- methanol by the method described under item
  • the title compound is prepared from 50 mmoles of 3- ( 4-fluorophenyl ) isoxazole-5-yl- methanol by the method described under item 11 above. The title compound is obtained as an oil.
  • the title compound is prepared from 50 mmoles of 3- ( 4-chlorophenyl ) isoxazole-5-yl- methanol by the method described under item
  • the title compound is prepared from 50 mmoles of 3- ( 4-bromophenyl ) isoxazole-5-yl- methanol by the method described under item
  • the residue is purified by chromatography over a 0.063-0.2 mm gel of Kieselgel G or Kieselgel 60 in vacuo using gradient elution starting with dichloromethane and finishing with a mixture consisting of 10 volumes of dichloromethane and 1 volume of acetone or 10 volumes of hexane and 1 volume of acetone. Yield: 25.3 %. M.p. : 66-67 °C .
  • the title product is prepared from 50 mmoles of 4-methylbenzhydroxamic chloride and 100 mmoles of Nallylmorpholine using the method described in Example 2, part a).
  • the title compound is prepared from 50 mmoles of 4-trifluoromethylbenzhydroxamic chloride and 100 mmoles of N-allylmorpholine by the method described in Example 1, part a).
  • the title compound is prepared from 50 mmoles of 4-c.hlorobenzhydroxamic chloride and 100 mmoles of N-allylmorpholine by the method described in Example 1, part a).
  • the title compound is prepared from 50 mmoles of 4-methoxybenzhydroxamic chloride and 100 mmoles of N-allylpyrrolidine by the method of Example 2, part a). Yield: 40.7 %. M.p. : 69.5-71 °C.
  • Example 8 3- ( 4-Methylphenyl ) -5- ( pyrrolidine-1-ylmethyl ) - -4 , 5-dihydroisoxazole hydrochloride a) 3- ( 4-Methylphenyl ) -5- ( pyrrolidine-1-yl- methyl ) -4 , 5-dihydroisoxazole
  • the title compound is prepared from 50 mmoles of 4-methylbenzhydroxamic chloride and 100 mmoles of N-allylpyrrolidine by the method described in Example 2, part a). Yield: 62.1 %. M.p. : 62-64 °C.
  • the title compound is prepared from 50 mmoles of 4-methoxybenzhydroxamic chloride and 100 mmoles of N-allylpiperidine by the method described in Example 2, part a). Yield: 50.3 %. M.p. : 88-91 °C.
  • the title compound is prepared from 50 mmoles of 4-methylbenzhydroxamic chloride and 100 mmoles of N-allylpiperidine by the method given in Example 2, part a). Yield: 59.4 %. M.p. : 61 °C.
  • Example 11 5-(Azepane-l-ylmethyl)-3-( 4-methoxyphenyl ) -4 , 5- -dihydroisoxazole hydrochloride a ) 5- ( Azepane-1-ylmethy1 ) -3- ( 4-methoxyphenyl ) -4 , 5-dihydroisoxazole
  • the title compound is prepared from 50 mmoles of 4-methoxybenzhydroxamic chloride and 100 mmoles of N-allylazepane by the method described in Example 2, part a). Yield: 96.1 %. M.p. : 72-73 °C.
  • the title compound is prepared from 50 mmoles of 4-methylbenzhydroxamic chloride and 100 mmoles of N-allylazepane by the method described in Example 2, part a). The title compound is obtained as an oil.
  • the title compound is prepared from 50 mmoles of 4-methoxybenzhydroxamic chloride and 50 mmoles of l-allyl-4- ( 2-methoxy ) - piperazine by the method described in Example
  • Example 14 l-/3-( 4-Methylphenyl ) -4 , 5-dihydroisoxazole-5- -ylmethyl/-4- ( 2-methoxyphenyl ) piperazine dihydrochloride a) l-/3-(4-Methylphenyl)-4, 5-dihydroisoxazole- -5-ylmethyl/-4- ( 2-methoxyphenyl ) piperazine
  • the title compound is prepared from 50 mmoles of 4-methylbenzhydroxamic chloride and 50 mmoles of l-allyl-4- ( 2-methoxyphenyl ) - piperazine by the method given in Example 2 , part a ) . Yield: 64.1 %. M.p. : 84-86 °C.
  • Example 15 1- ( 2-Methoxyphenyl ) -4-/3- ( 4-trifluoromethylphenyl ) -4 , 5-dihydroisoxazole-5-ylmethyl/- piperazine hydrochloride a) l-( 2-Methoxyphenyl ) -4-/3- ( 4-trifluoromethylphenyl ) -4 , 5-dihydroisoxazole-5-yl- methyl/piperazine
  • the title compound is prepared from 50 mitioles of 4- ( trifluoromethyl ) benzhydroxamic chloride and 50 mmoles of l-allyl-4- ( 2- -methoxyphenyl ) piperazine by the method described in Example 1, part a). Yield: 27.6 %. M.p. : 114-117 °C.
  • Example 16 1-/ 3- ( 4-Fluorophenyl ) -4 , 5-dihydroisoxazole-5- -ylmethyl/-4- ( 2-methoxyphenyl ) piperazine dihydrochloride a) l-/3-( 4-Fluorophenyl ) -4 , 5-dihydro- isoxazole-5-ylmethyl/-4-( 2-methoxyphenyl ) - piperazine
  • the title compound is prepared from 50 mmoles of 4-fluorobenzhydroxamic chloride and 50 mmoles of l-allyl-4- ( 2-methoxyphenyl ) - piperazine by the method described in Example 1 , part a ) . Yield: 40.1 %. M.p. : 86-91 °C.
  • Example 17 1-/3- ( 4-Methylphenyl ) -4 , 5-dihydroisoxazole-5- -ylmethyl/-4-( 3 -trifluoromethylphenyl ) - piperazine hydrochloride a) 1-/3- ( 4-Methylphenyl ) -4 , 5-dihydro- isoxazole-5-ylmethyl/-4- ( 3-trifluoromethylphenyl ) piperazine
  • Example 18 1- ( 3-Trifluoromethylphenyl ) -4-/3- ( 4-trifluoromethylphenyl ) -4 , 5-dihydroisoxazole-5-ylmethyl/- piperazine hydrochloride a) l-( 3-Trifluoromethylphenyl ) -4-/3- (4- trifluoromethylphenyl ) -4 , 5-dihydro- isoxazole- 5-ylmethy1/piperazine
  • the title compound is prepared from 50 mmoles of 4-trifluoromethylbenzhydroxamic chloride and 50 mmoles of l-allyl-4- ( 3- -trifluoromethylphenyl ) piperazine by the method described in Example 1, part a). Yield: 20 %. M.p. : 81-83 °C.
  • the title compound is prepared from 50 mmoles of 4-methylbenzhydroxamic chloride and 50 mmoles of l-allyl-4- ( 3-chloro- phenyl ) piperazine by the method described in Example 2, part a).
  • Example 20 1- ( 3-Chlorophenyl ) -4-/3- ( 4-trifluoromethylphenyl ) -4 , 5-dihydroisoxazole-5-ylmethyl/ - piperazine hydrochloride a) l-( 3-Chlorophenyl) -4-/ 3- (4-trifluoromethylphenyl ) -4 , 5-dihydroisoxazole- -5-ylmethyl /piperazine
  • the title compound is prepared from 50 mmoles of 4-trifluoromethylbenzhydroxamic chloride and 50 mmoles of l-allyl-4- ( 3-chloro- phenyl )piperazine by the method described in Example 1, part a). Yield: 35 %. M.p. : 109-111 °C. Analysis: for C 21 H 21 C1F 3 N 3 0 (423.87)
  • Example 21 1- ( 2-Furoyl ) -4-/3- ( 4-methylphenyl ) -4 , 5-dihydro- isoxazole-5-ylmethyl/piperazine hydrochloride
  • the title compound is prepared from 50 mmoles of 4-methylbenzhydroxamic chloride and 50 mmoles of l-allyl-4- ( 2-furoyl ) piperazine by the method described in Example 2, part a) .
  • the title compound is prepared from 50 mmoles of 4-trifluoromethylbenzhydroxamic chloride and 50 mmoles of l-allyl-4- ( 2- -furoyl ) piperazine by the method described in Example 1, part a). Yield: 28 %. M.p. : 86-88 °C. Analysis: for c 2 o H 20 F 3 N 3 0 3 (407 - 38) C H N calculated: 58.97 %, 4.95 %, 10.31 %; found: 58.76 %, 4.75 %, 10.13 %.
  • Example 23 3- ( 4-Methoxyphenyl ) -5- ( 2-morpl ⁇ olinoethoxy- methyl ) -4 , 5-dihydroisoxazole hydrochloride a ) 3- ( 4-Methoxyphenyl ) -5- ( 2-morpholinoethoxy- inethyl ) -4 , 5-dihydroisoxazole
  • the reaction mixture is cooled, ethyl acetate and water are added, the clear phases are separated, the organic phase is washed 3 times using 50 ml of water each time, dried over anhydrous magnesium sulfate, and evaporated.
  • the residue is purified by chromatography over a 0.0630.2 mm gel of Kieselgel G or Kieselgel 60 in vacuo using a mixture consisting of 5 volumes of dichloromethane and 1 volume of acetone as the eluent.
  • N-methylpiperazine are added, then the reaction mixture is boiled for 8 hours.
  • the ammonium bromide separated is filtered, and the reaction product is separated from the organic solution by extraction with a mixture consisting of 9 volumes of water and 1 volume of concentrated hydrochloric acid.
  • the aqueous phase is made alkaline by adding 20 % aqueous sodium hydroxide solution, and the product is extracted with ether.
  • the organic solution is dried over anhydrous magnesium sulfate, and evaporated.
  • the residue is purified by chromatography over a 0.063-0.2 mm gel of Kieselgel 60 in vacuo using gradient elution starting with dichloromethane and finishing with a mixture consisting of 10 volumes of dichloromethane and 1 voJ ume of acetone.
  • the title compound is obtained as an oil. Yield: 42.6 %.
  • the title compound is prepared from 50 mmoles of 5-bromomethyl-3- ( 4-methoxyphenyl ) - isoxazole by the method described in Example 24 , part a) . Yield: 64.6 %.
  • the title compound is prepared from 50 mmoles of 5-bromomethyl-3- ( 4-methylphenyl ) - isoxazole by the method described in Example 24 , part a ) . Yield: 68.9 %.
  • the residue is purified by chromatography over Kieselgel G using a mixture consisting of 10 volumes of hexane and 0.5 volumes of acetone as the eluent.
  • the ratio of 3-aryl-5-bromomethylisoxazole and 3 , 4-diary1-1, 2 , 5-oxadiazol-N-oxide is determined by NMR.
  • fivefold amount of N-methylpiperazine, calculated on the bromomethyl compound, is added to a 10 % solution thereof in toluene.
  • the mixture is boiled while ' following the reaction by thin layer chromatography (hexane/acetone 10:2, UV, FM).
  • the reaction mixture is diluted with toluene to the double of the volume thereof, washed twice with water, dried over anhydrous magnesium sulfate, and evaporated.
  • the residue is purified by chromatography over a 0.0630.2 mm gel of Kieselgel 60 in vacuo using gradient elution starting with hexane and finishing with a maxture consisting of 10 volumes of hexane and 1 volume of acetone. Yield: 60.3 %. M.p. : 72-75 °C.
  • Example 28 bis(l-/3-( 4-Bromophenyl ) isoxazol-5-ylmethyl 1-4- -methylpiperazinium ) L-malate a) 1-/3- ( 4-Bromophenyl ) isoxazole-5-ylmethyl/- 4-methylpiperazine
  • Example 29 1-/ 3- ( 4-Methoxyphenyl ) isoxazole-5-ylmethyl/- piperazine dihydrochloride a ) 1-/3- ( 4-Methoxyphenyl ) isoxazole-5-yl- methyl /piperazine
  • 150 mmoles of piperazine are added to a solution of 50 mmoles of pure 5-bromo- methyl-3- ( 4-methoxyphenyl ) isoxazole in 100 ml of anhydrous toluene, and the reaction mixture is boiled for 8 hours.
  • the ammonium bromide separated is filtered, and the organic solution is extracted with a mixture consisting of 9 volumes of water and 1 volume of concentrated hydrochloric acid to obtain the product.
  • the aqueous phase is made alkaline by adding 20 % sodium hydroxide solution, and the product is extracted with ethyl acetate.
  • the organic solution is dried over anhydrous magnesium sulfate, and evaporated.
  • Example 30 1-/3- ( 4-Methylphenyl ) isoxazole-5-ylmethyl/- piperazine dihydrochloride a ) 1-/3- ( 4-Methylphenyl )isoxazole-5-yl- methy1 /piperazine
  • the title compound is prepared from 50 mmoles of 5-bromomethyl-3- ( 4-methylphenyl ) - isoxazole by the method described in Example 29 , part a ) . Yield: 68.8 %.
  • Example 31 1- ( 2-Methoxyphenyl ) -4-/3- ( 4-methoxyphenyl ) - isoxazole-5-ylmethyl /piperazine dihydrochloride a) l-( 2-Methoxyphenyl ) -4-/3- ( 4-methoxyphenyl ) ⁇ soxazole5-ylmethyl /piperazine
  • Kieselgel 60 in vacuo using a mixture consisting of 10 volumes of hexane and 1 volume of acetone as the eluent.
  • Example 32 l-/3-( 4-Methylphenyl ) isoxazole-5-ylmethyl/-4- - ( 2-methoxyphenyl ) piperazine dihydrochloride a ) 1-/3- ( 4-Methylphenyl )isoxazole-5-yl- methyl/-4- ( 2-methoxyphenyl ) piperazine Either 50 mmoles of N- ( 2-methoxyphenyl ) - piperazine obtained from the hydrochloride thereof through alkalization with sodium hydroxide, extraction with ethyl acetate, drying and evaporation, furthermore 8.46 ml
  • Example 33 l-/3-(4-Methylphenyl) isoxazole-5-ylmethyl/-4- - ( 3-trifluoromethylphenyl ) piperazine hydrochloride a ) 1-/3- ( 4-Methylphenyl ) isoxazole-5-yl- methyl/-4- ( 3-trifluoromethylphenyl ) - piperazine
  • the title compound is prepared from 50 mmoles of 5-bromomethyl-3- ( 4-methylphenyl ) - isoxazole and 50 mmoles of N- ( 3-trifluoromethylphenyl ) piperazine hydrochloride by the method described in Example 32, part a). Yield: 81.2 %. M.p. : 98-99 °C.
  • Example 34 1-/3- ( 4-Bromophenyl ) isoxazole-5-ylmethy1/-4- ( 3- -trifluoromethylphenyl/piperazine hydrochloride a ) 1-/3- ( 4-Bromophenyl ) isoxazole-5-yl- methyl /-4- ( 3-trifluoromethylphenyl /- piperazine
  • the title compound is prepared from 50 mmoles of 3- ( 4-bromophenyl ) -5- (bromomethyl ) - isoxazole and 50 mmoles of N- ( 3-trifluoromethylphenyl ) piperazine hydrochloride by the method described in Example 32, part a). Yield: 99.8 %. M.p. : 55-56 °C.
  • the title compound is prepared from 50 mmoles of 5-bromomethyl-3- ( 4-methoxyphenyl ) - isoxazole and 150 mmoles of azepane by the method described in Example 24, part a).
  • the residue is purified over a 0.063-0.2 mm gel of Kieselgel G or Kieselgel 60 in vacuo using gradient elution starting with dichloromethane and finishing with a mixture consisting of 10 volumes of dichloromethane and 2 volumes of acetone.
  • the title compound is obtained as an oil. Yield: 65.9 %.
  • Example 38 1-/3- ( 4-Methoxyphenyl ) isoxazole-5-ylmethoxy / - 3 - -morpholinopropane-2-ol hydrochloride a ) 1-/3- ( 4-Methoxyphenyl )isoxazole-5-yl- meth,oxy/-3-morpholinopropane-2-ol
  • the title compound is prepared from 10 mmoles of 5- ( 2 , 3-epoxypropoxymethyl ) -3- ( 4-
  • Example 37 part a).
  • the title compound is obtained as an oil.
  • Example 39 1-/3- (4-Methylphenyl) isoxazole- 5-ylmethoxy/ - -3-morpholinopropane-2-ol hydrochloride a ) 1-/3- ( 4-Methylphenyl ) isoxazole-5-ylmethoxy/-3-morpholinopropane-2-ol
  • the title compound is prepared from 10 mmoles of 5- ( 2 , 3-epoxypropoxymethyl ) -3- ( 4- -methylphenyl ) isoxazole and 15 to 20 mmoles of morpholine by the method described in Example 37, part a). The title compound is obtained as an oil. Yield: 95.2 %.
  • the title compound is prepared from 10 mmoles of 5- ( 2 , 3-epoxypropoxymethyl ) -3- ( 4- -trifluoromethylphenyl ) isoxazole and 15 to 20 mmoles of morpholine by the method described in Example 37, part a).
  • the title compound is obtained as an oil. Yield: 69.1 %.
  • IR film: 3650-3300 (OH), 3190, 3020, 3000, 2920, 2880 ( CH ) , 1620, 1460, 1440, 1310, 1150, 1100, 1050, 820 cm “1 .
  • Example 41 1-/3- ( 4-Chlorophenyl ) isoxazole-5-ylmethoxy /- -3-morpholinopropane-2-ol hydrochloride a ) 1-/3- ( 4-Chlorophenyl ) isoxazole-5-ylmethoxy/-3-morpholinopropane-2-ol
  • the title compound is prepared from 10 mmoles of 5- ( 2 , 3-epoxypropoxymethyl ) -3- ( 4- -chlorophenyl ) isoxazole and 15 to 20 mmoles of morpholine by the method described in Example 37, part a). The title compound is obtained as an oil.

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Abstract

The invention refers to novel isoxazole and 4,5-dihydroisoxazole derivatives of formula (I) being suitable for the treatment of especially a pathological alteration of the central nervous system and/or a cardiovascular and/or gastrointestinal disease, furthermore pharmaceutical compositions containing the above derivatives, and a process for the preparation of the novel compounds. Specifically, the invention refers to isoxazole derivatives of formula (I). In formula (I), A and B represent, independently, a hydrogen atom, or A forms, together with B, a valence bond; Z stands for a hydrogen atom, a halo atom, a C1-4 alkyl group, a trifluoromethyl group or one or two C1-4 alkoxy group(s); R?1 and R2¿ mean, independently, a C¿1-6? alkyl group or a C3-7 cycloalkyl group; or R?1 and R2¿ form, together with the nitrogen atom they are attached to and optionally with one or more further nitrogen and/or oxygen atom(s), a 5 to 8-membered heterocyclic ring that can be substituted by a C¿1-4? alkyl group, a (C1-4 alkyl) phenyl group, a (C1-4 alkoxy) phenyl group, a di(C1-4 alkoxy) phenyl group, a halophenyl group, a trifluoromethylphenyl group or a furoyl group; m has a value of 0 or 1; n has a value of 0 or 1.

Description

Novel isoxazol derivatives, pharmaceutical compositions containing the same, and a process for the preparation of the novel compounds
The invention refers to novel isoxazole and 4 , 5-dihydroisoxazole derivatives, a process for the preparation thereof, pharmaceutical compositions containing a novel isoxazole or 4 , 5-dihydroisoxazole derivative as the active ingredient as well as a medical use process employing such an active ingredient.
Specifically, the invention refers to isoxazole derivatives of the formula I
Figure imgf000003_0001
wherein
A and B represent, independently, a hydrogen atom, or A forms, together with B, a valence bond, Z stands for a hydrogen atom, a halo atom, a C, _ . alkyl group, a trifluoromethyl group or one or two C-, _ . alkoxy group(s), R 1 and R2 mean, independently, a C-, _fi alkyl group or a C-._7 cycloalkyl group, or R 1 and R2 form, together with the nitrogen atom they are attached to and optionally with one or more further nitrogen and/or oxygen atom(s), a 5 to 8-membered heterocyclic ring that can be substituted by a C, . alkyl group, a (C-, . alkyl)phenyl group, a ( C-, _. alkoxy ) - phenyl group, a di(C-,_. alkoxy )phenyl group, a halophenyl group, a trifluoromethylphenyl group or a furoyl group, m has a value of 0 or 1, n has a value of 0 or 1, with the proviso that
1) if A forms, together with B, a valence bond, m has a value of 0, furthermore each of R 1 and R2 stands for an ethyl group or R 1 and R2 form, together with the nitrogen atom they are attached to, a piperidin-1-yl or a morfolino group, then Z is other than a hydrogen atom or a chloro atom in position para, and
2) if A forms, together with B, a valence bond, m has a value of 0, furthermore each of R I and R2 stands for a methyl group or R 1 and R2 form, together with the nitrogen atom they are attached to, a pirrolidin-1-yl group, then Z is other than a hydrogen atom, and pharmaceutically acceptable acid addition salts thereof.
The novel compounds of the formula I influence, significantly, the central and peripheric nervous serotonin neurotransmitter system; have affinity for the central nervous system alpha, and/or 5-HT, receptors; and possess psychotropic and cardiovascular effects .
3-Aryl-5-aminomethylisoxazole derivatives are known from the literature /J. Med. Chem. , 10, 411-418 (1967)/. The known compounds have hypothermic, analgesic and antitussive activities.
The aim of the invention is to prepare novel isoxazole derivatives influencing, in the first place, the central nervous system and the peripheric serotonin neurotransmitter system.
It was found that the above aim is achieved by the novel isoxazole derivatives of the formula I.
In the description, a halo atom is mainly a fluoro, chloro or bromo atom.
A C, _. alkyl group is a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec. -butyl, tert. -butyl or isobutyl group. Preferably, a C- . alkyl group is a methyl group.
A C, alkyl group can be, in addition to the meanings listed in connection with the C, . alkyl group, generally also a n-pentyl group or a n-hexyl group.
A <1_4 alkoxy group is, in the first place, a methoxy, ethoxy, n-propoxy or n-butoxy group, preferably a methoxy group. If R 1 and R2 form, together with the nitrogen atom they are attached to and optionally together with one or more further nitrogen and/or oxygen atom(s), a 5 to
8-membered heterocyclic ring, it is preferably a pyrrolidinyl, piperidinyl, azepanyl, morpholino or piperazinyl group.
Under a pharmaceutically acceptable acid addition salt an acid addition salt formed with a pharmaceutically acceptable inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid etc. or with a pharmaceutically acceptable organic acid such as acetic acid, fumaric acid, lactic acid, malic acid etc. are meant.
A preferred subgroup of the isoxazole derivatives of the formula I consists of the 4 , 5-dihydroisoxazole derivatives of the formula
Figure imgf000006_0001
and pharmaceutically acceptable acid addition salts thereof, wherein, in formula I, each of A and B stands for a hydrogen atom.
In formula la Z stands for a hydrogen atom, a halo atom, a C-, _ . alkyl group, a trifluoromethyl group or one or two C-, , alkoxy group(s), R 1 and R2 mean, independently, a C-, _fi alkyl group or a C-s 7 cycloalkyl group, or R 1 and R2 form, together with the nitrogen atom they are attached to and optionally with one or more further nitrogen and/or oxygen atom(s), a 5 to 8-membered heterocyclic ring that can be substituted by a C, _ . alkyl group, a (C, . alkyl)phenyl group, a (C-, . alkoxy ) phenyl group, a di(C,_4 alkoxy ) phenyl group, a halophenyl group, a trifluoromethylphenyl group or a furoyl group, m has a value of 0 or 1, n has a value of 0 or 1.
Another preferred subgroup of the isoxazole derivatives of the formula I consists of the isoxazole derivatives of the formula lb
Figure imgf000008_0001
and pharmaceutically acceptable acid addition salts thereof, wherein, in formula I, A forms together with B a valence bond.
In formula lb Z stands for a hydrogen atom, a halo atom, a C, , alkyl group, a trifluoromethyl group or one or two C-, , alkoxy group(s),
1 2 R and R mean, independently, a C-_fi alkyl group or a C^ 7 cycloalkyl group, or
1 2 R and R form, together with the nitrogen atom they are attached to and optionally with one or more further nitrogen and/or oxygen atom(s), a 5 to 8-membered heterocyclic ring that can be substituted by a C-, 4 alkyl group, a (C-,_4 alkyl)phenyl group, a (C-, . alkoxy )phenyl group, a di(C, . alkoxy ) phenyl group, a halophenyl group, a trifluoromethylphenyl group or a furoyl group, m has a value of 0 or 1, n has a value of 0 or 1 , with the proviso that
1) if A forms, together with B, a valence bond, has a value of 0, furthermore each of R 1 and R2 stands for an ethyl group or R 1 and R2 form, together with the nitrogen atom they are attached to, a piperidin-1-yl or a morfolino group, then Z is other than a hydrogen atom or a chloro atom in position para, and
2) if A forms, together with B, a valence bond, m has a value of 0, furthermore each of R 1 and R2 stands for a methyl group or R 1 and R2 form, together with the nitrogen atom they are attached to, a pirrolidin-1-yl group, then Z is other than a hydrogen atom.
Suitable compounds of the formula I are wherein
A and B represent, independently, a hydrogen atom, or A forms, together with B, a valence bond, Z stands for a hydrogen atom, a halo atom, a trifluoromethyl group or one or two methoxy group(s), R 1 and R2' form, together with the nitrogen atom they are attached to and optionally together with further nitrogen and/or oxygen atom(s), a pyrrolidinyl , piperidinyl, azepanyl, morpholino or piperazinyl group which latter can be substituted by a methyl, methylphenyl, methoxyphenyl, dimethoxyphenyl, halophenyl, trifluoromethylphenyl or furoyl group, m has a value of 0 or 1, n has a value of 0 or 1.
Especially preferred compounds of the formula I are wherein
Z represents a halo atom, a methyl group or a methoxy group, R 1 and R2 form, together with the nitrogen atom they are attached to and a further nitrogen atom, a piperazinyl group optionally substituted by a methoxyphenyl group, m has a value of 0 or 1, n has a value of 0 or 1.
The compounds of the formula I may contain one or two chiral carbon atom(s), thus, they can exist in the form of optical isomers.
The invention includes the single isomers as well as any mixtures thereof.
The novel compounds of the invention are prepared as follows:
For the preparation of the 4,5-dihydro- isoxazole derivatives of the formula la,
1 2 wherein m has a value of 0, Z, R and R are as stated in connection with the formula I, a nitril oxide of the formula II
≡N O wherein Z is as stated above, is reacted with an allyl derivative of the formula III
Figure imgf000011_0001
wherein R 1 and R2 are as stated above. The reaction that consists of a dipolar cycloaddition is carried out in organic aprotic solvents such as benzene, toluene, diethyl ether, dichloromethane etc. The reaction temperature is, in general, between 0 C and the boiling point of the reaction mixture.
/Similar reactions are described in
Houben-Weyl: Methoden der Organischen Chemie,
10/3, G. Thieme Verlag, Stuttgart, (1965), pages 858-864./
The nitril oxide of the formula II is prepared from the compound of the formula
VI
Figure imgf000011_0002
wherein Z is as stated in relation to formula I, by methods described in the literature or by suitable modifications thereof: R. Huisgen, W. Mack, E. Anneser, Angew. Chem., 73, 656 (1961); H. Wieland, Ber . der Deutsch. Chem. Ges., O, 1670 (1907); F. Eloy, R. Lenaers , Bull. Soc . Chi . Belg., 7_2_, 719 (1963); R. Lenaers, F. Eloy, Helv. Chim. Acta, 46, 1067 (1963); T. Sasaki, T. Yoshioka, Bull. Chem. Soc. Japan, 0, 2604 (1967); ibid. 4_1, 2206 (1968); ibid. _42_, 258 (1969).
For the preparation of the compound of the formula VI, a suitably substituted benzaldehyde is used as the starting compound. At first, an oxime is prepared /for example according to the methods described in Houben- -Weyl: Methoden der Organischen Chemie, lθ/4 , 55-58 (1968)/, then the oxime is chlorinated in alpha position. In case of electron attracting substituents such as a halo atom or a trifluoromethyl group in para position, the chlorination is performed by introducing elemental chlorine gas into the solution of the oxime in a chlorinated hydrocarbon e.g. chloroform /Houben-Weyl: Methoden der Organischen Chemie, £3, 691 (1952)/, while in case of electron sending substituents such as a methyl group or a methoxy group in para position or two methoxy groups, the chlorinating agent is nitrosyl chloride /Houben-Weyl: Methoden der Organischen Chemie, 10/4, 98-100 (1968)/ or tert. -butyl hypochlorite /C.J. Peake, J.H. Strickland, Synth. Commun., 16.(7), 763-765 (1968)/.
Suitably, the nitril oxide of the formula II is prepared from the compound of the formula VI in the reaction mixture obtained after the preparation thereof.
The allyl derivative of the formula III is prepared by the reaction of an allyl halogenide, preferably allyl bromide, with an amine of the formula IX
1
R
HR
Tt wherein R 1 and R2 are as stated in relation to formula I, for example in an aromatic hydrocarbon in the presence of potassium carbonate and sodium iodide /J. Med. Chem.,
25(13), 2369-2364 (1992)/.
4 , 5-Dihydroisoxazol derivatives of the formula la, wherein m has a value of 1 , n has a value of 0, Z, R 1 and R2 are as stated in connection with formula I, are prepared by reacting a halo compound of the formula
V
Figure imgf000013_0001
wherein Hal represents a halo atom, R and 2 R are as stated above, with a 4,5-dihydro- isoxazole-5-ylmethanol of the formula IV
Figure imgf000014_0001
wherein Z is as given above. From the compound of the formula IV an alcoholate is formed for example with sodium hydride, and the reaction is carried out in an ether type organic solvent such as diethyl ether, tetrahydrofuran or dioxane in the presence of sodium iodide. The 4,5-dihydro- isoxazoie-5-ylmethanol of the formula IV is prepared by means of the reaction of a compound of the formula II and allyl alcohol.
Isoxazole derivatives of the formula lb, wherein m has a value of 0, Z, R and
2 R are as stated in relation to formula I, are prepared by reacting a nitril oxide of the formula II with a propargyl derivative of the formula VII
Figure imgf000015_0001
wherein R 1 and R2 are as stated above. The reaction is carried out as usual in dipolar cycloadditions , essentially under the conditions given at the reaction of the compounds of formulae II and III.
The propargyl derivative of the formula VII is prepared by means of the reaction of a propargyl halide suitably propargyl bromide and an amine of the formula IX under the conditions given in connection with the preparation of the allyl derivatives of the formula III.
Isoxazole derivatives of the formula lb described above can be also prepared by reacting a compound of the formula VIII
Figure imgf000015_0002
wherein Hal represents a halo atom preferably a bromo atom, Z is as stated in relation to formula I, with an amine of the formula IX. The reaction is carried out preferably in an aromatic hydrocarbon such as benzene or toluene at the boiling point of the reaction mixture. Suitably, the amine of the formula IX is used in an excess.
The compound of the formula VIII is prepared by dipolar cycloaddition of the nitril oxide of the formula II with a propargyl halide preferably propargyl bromide.
Isoxazole derivatives of the formula lb, wherein m has a value of 1, n has a value of 1, Z, R 1 and R2 are as stated in relation to formula I, are prepared by reacting an epoxide of the formula X
Figure imgf000016_0001
wherein Z is as defined above, with an amine of the formula IX. The amine of the formula IX is used in excess, and, in general, the reaction is performed in an aromatic hydrocarbon at the boiling point.
The epoxide of the formula X is prepared from an isoxazole-5-ylmethanol of the formula XII
Figure imgf000017_0001
wherein Z is as defined in connection with formula I, with epichlorohydrin in an ether type solvent at the boiling point of the reaction mixture. Suitably, the sodium alcoholate of the compound of the formula XII is reacted with the epichlorohydrin.
The isoxazole-5-ylmethanol of the formula XII is prepared by the dipolar cycloaddition of the nitril oxide of the formula II and propargyl alcohol.
Isoxazole derivatives of the formula lb, wherein m has a value of 1 , n has a value
1 2 of 0, Z, R and R are as stated in relation to formula I, are prepared by reacting a compound of the formula VIII with an amine of the formula XI
Figure imgf000018_0001
wherein R 1 and R2 are as defined above.
Suitably, a compound of the formula VIII, wherein Hal represents a bromo atom, is reacted with an alcoholate of a hydroxyethylamine of the formula XI in an ether type solvent.
4 , 5-Dihydroisoxazole derivatives of the formula la, wherein m has a value of 1, n has a value of 1, Z, R 1 and R2 are as stated in connection with formula I, are prepared by reacting an epoxide of the formula XIII
Figure imgf000018_0002
wherein Z is as defined above, with an amine of the formula IX in a similar manner as described relative to the corresponding compounds of the formula lb.
The epoxide of the formula XIII can be obtained by reacting the corresponding 4 , 5-dihydroisoxazole-5-ylmethanol with epichlorohydrin.
The optical isomers can be prepared in a manner known per se.
If desired, an obtained compound of the formula I is converted to an acid addition salt by reacting it with a pharmaceutically suitable inorganic or organic acid.
The novel isoxazole derivatives of the formula I possess extremely valuable pharmacological activities.
-HT, receptor binding assay
5-HT, receptor assay was performed as described earlier /S.J. Peroutka, J. Neurochem., .47, 529-540 (1986)/. The binding was determined in membrane fragments prepared from rat frontal cortex using tritium-labeled 8-hydroxy-N,N-dipropyl-2-aminotetraline as specific ligand in a final volume of 250 microliters. Non-specific binding was determined in the presence of 10 microM of serotonine creatinine sulfate /the chemical name of serotonine is 3- ( 2-aminoethyl ) -1H- -indole-5-ol/ . The assay samples were incubated for 30 minutes at 25 C. The reactions were stopped by the addition of 9 ml of an ice-cold aqueous solution of tris (hydroxymethyl ) amino- methane hydrochloride having a pH value of 7.7 followed by quick filtration under reduced pressure using a Whatman GFIB glass-fibre filter paper. The radioactivity retained on the filters was determined by liquid scintillation counting. The results obtained are summarized in Table I.
Table I Effect of the compounds on alpha, and 5-HT, receptor binding
Compound K. in nM
(No. of Example) alpha, 5-HT,
51 100 60 13 18 16 14 100 16 16 20 6
Some of the compounds examined showed strong binding to central alpha, and 5-HT, receptors .
The compounds found to be effective in receptor binding were further examined both in psychopharmacological and cardiovascular tests .
Anxiolytic effects
Elevated plus-maze
The elevated plus-maze consists of two open and two 40 cm wall enclosed arms of the same size (50 x 15 cm) arranged in the shape of a cross. The arms of the same type are opposite to each other. The junction of the four arms forms a central square area (15 x 15 cm) . The apparatus is made of wooden material elevated to a height of 50 cm and illuminated by a dim light from above- Male Sprague-Dawley rats weighing 220 to 260 g were treated with the test or reference compounds 60 minutes prior to the test. The animals were then placed onto the central square area and were subjected to the test for 5 minutes. The following parameters were determined:
- time spent in the open arms; -
- time spent in the closed arms;
- number of entries into the open arms;
- number of entries into the closed arms. A compound was considered to be effective where significant increase was found either in the time spent in the open arms or in the number of entries into the open arms when compared to the control animals. Minimum Effective Doses (MED) were determined based on the times spent in the open arms for each compound examined /Pelow et al . , J. Neurosci. Methods, l±, 149-169 (1985)/. Ritanserine i.e. 6-{2-/4-bis( 4 -fluorophenyl ) ethylene/- -l-piperidinylethyl'2-7-methyl-5H-thiazolo- /3 , 2-a/pyrimidine-5-one and meprobamate i.e. 2-methyl-2-propylpropane-l , 3-diol dicarbamate were used as reference materials. The results obtained are shown in Table II.
Table II Effect of compounds on the elevated plus-maze
Compound MED in mg/kg
(No. of Example) p.o.
13 1
16 1 ritanserine 5 meprobamate 10
The novel compounds were more effective in the elevated plus-maze test than the reference compounds.
Marble burying
The experiments were performed in separate groups of C57B1 mice weighing 20 to 25 g. Each group consisted of 10 animals treated either with the test compound or vehicle (control group). 60 minutes later, the mice were individually placed into the experimental chamber which was a 22 cm x 15.5 cm x 14 cm plexyglass box with 5 cm thick layer of sawdust on the bottom. 24 glass marbles of 1 cm diameter were placed, in close contact with each other, on the sawdust in the middle of the cage. The mice were left in the cage with the marbles for 15 minutes. After the mice were removed, the number of buried marbles (i.e. the marbles covered by sawdust to a height exceeding the two thirds of the diameter) were determined. The results were expressed as per cent increase in the number of buried marbles as compared to the control group. ID,, values were determined using linear regression analysis of the dose vs. response curves. Buspirone i.e. 8-^4-/4- ( 2-pyrimidinyl ) - -1-piperazinyl/butyljι -8-azaspiro/4 , 5/decane- -7,9-dione was used as the reference compound. The results obtained are shown in Table III.
Table III Effect of compounds on marble burying
Compound ID,-n in mg/kg
(No. of Example) p.o.
51 31 14 10 13 10 16 14 buspirone 23
The novel compounds examined have significant activity on the above model The activity of three novel compounds is higher than that of the buspirone used as reference* compound.
Measurement of antihypertensive effect
Each test substance was tested in 4 to 5 mongrel dogs of both sexes weighing 11 to 31 kg. Anesthesia was induced i.v. with 30 g/kg of sodium pentobarbital i.e. 5-ethyl-5- ( 1-methylbutyl ) -2 , 4 , 6- ( 1H, 3H, 5H) - pyrimidinetrione sodium salt. The dogs were intubated with cuffed endotracheal tubes and were ventilated with 180 ml/kg of room air enriched in oxygen at a rate of 15/minute (Haeward 55 type ventilator, South Natick, USA) . The right femoral artery and vein were cannulated with PP 90 tubings for determining the arterial blood pressure and for taking arterial blood samples as well as for drug administration. Arterial blood pressure was measured with a Gould Statham P 23 Gb pressure transducer and Hugo Sachs amplifier (HS, Hugo Sachs Elektronik, March, Germany) and was recorded continuously during the experiment (Watanabe Graphtec Linearcorder mark VII, WR 3101, Hugo Sachs Elektronik, March, Germany ) .
The test substances were administered in cumulative i.v. doses. Mean arterial pressure was estimated from the recording prior to the first drug administration and 15 minutes after injection of each dose. Blood pressure was plotted against the logarithm of the dose, and a regression line was fitted on the linear part of the blood pressure curve. The dose causing 30 percent decrease in blood pressure (ED., ) was calculated from the regression .
The results obtained are shown in Table IV.
Table IV Blood pressure decreasing effect
Compound EL n "^ mc9/
(No. of Example)
13 46 14 1192 16 165
Two compounds shown in Table IV have strong and one compound has moderate blood pressure descreasing effect.
Results and evaluation
According to our results, the novel isoxazole derivatives have remarkable anxiolytic and antihypertensive effect in the test models studied. In some tests, their effectiveness is better than that of the reference substances. Results obtained in receptor binding studies are in line with effects measured in in vivo tests since it has been suggested that the 5HT, receptors have a role in the regulation of several central nervous system processes /Cliffe and Fletchere, Drugs Fut., .18.(7), 631-642 (1993)/. Among the disorders that may supposedly be influenced by drugs affecting 5-HT, receptors are anxiety, depression, cognitive deficiencies, nociception, hyper- or hypophagia, disorders of sexual activity and disorders of the cyrcadian rhythm /Brain 5-HT, receptors; Behavioral and Neurochemical Pharmacology, Ellis Horwood Ltd., Chichester, (1987), eds. Douris, CT. et al ; Bowen et al., Lancet, 339, 132-133 (1992)/. Based on their receptor binding and blood pressure lowering effects, the novel compounds of the invention may be useful in antihypertensive , antianginal and vasodilator therapy. Moreover, the novel compounds may also be effective in gastrointestinal disorders.
Due to the above test results, the novel isoxazole derivatives of the formula I and pharmaceutically acceptable acid addition salts thereof can be used as active ingredients of pharmaceutical compositions. The pharmaceutical compositions of the invention contain a therapeutically active amount of the compound of the formula I or a pharmaceutically acceptable acid addition salt thereof and one or more conventional carrier ( s ) .
The pharmaceutical compositions of the invention are suitable for peroral, parenteral or rectal administration or for local treatment, and can be solid or liquid.
The solid pharmaceutical compositions suitable for peroral administration may be powders, capsules, tablets, film-coated tablets, microcapsules etc., and can comprise binding agents such as gelatine, sorbitol, poly ( vinylpyrrolidone ) etc.; filling agents such as lactose, glucose, starch, calcium phosphate etc.; auxiliary substances for tabletting such as magnesium stearate, talc, poly ( ethyleneglycol ) , silica etc.; wetting agents such as sodium laurylsulfate etc. as the carrier.
The liquid pharmaceutical compositions suitable for peroral administration may be solutions, suspensions or emulsions and can comprise e.g. suspending agents such as gelatine, carboxymethylcellulose etc.; emulsifiers such as sorbitane monooleate etc.; solvents such as water, oils, glycerol, propyleneglycol , ethanol etc.; preservatives such as methyl p-hydroxybenzoate etc. as the carrier .
Pharmaceutical compositions suitable for parenteral administration consist of steril solutions of the active ingredient, in general
Dosage forms listed above as well as other dosage forms are known per se, see e.g. Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co., Easton, USA (1990) .
The pharmaceutical compositions of the invention contain, in general, O.l to 95.0 per cent by mass of a compound of the formula I or a pharmaceutically acceptable acid addition salt thereof. A typical dose for adult patients amounts to 0.1 to 20 mg of the compound of the formula I or a pharmaceutically acceptable acid addition salt thereof, daily. The above dose can be administered in one or more portions. The actual dosage depends on many factors and is determined by the doctor.
The pharmaceutical compositions of the invention are prepared by admixing a compound of the formula I or a pharmaceutically acceptable acid addition salt thereof to one or more carrier(s), and converting the mixture obtained to a pharmaceutical composition in a manner known per se. Useful methods are known from the literature, e.g. Remington's Pharmaceutical Sciences.
Preferably, the pharmaceutical compositions of the invention contain an isoxazole derivative of the formula I, wherein Λ and B represent, independently, a hydrogen atom, or A forms together with B a valence bond, Z stands for a hydrogen atom, a halo atom, a methyl group, a trifluoromethyl group or one or two methoxy group(s),
1 2 R and R form together with the nitrogen atom they are attached to and optionally together with a further nitrogen or oxygen atom a pyrrolidinyl , piperidinyl, azepanyl, morpholino or piperazinyl group which latter can be substituted by a methyl, methyl- phenyl, methoxyphenyl, dimethoxyphenyl, halophenyl, trifluoromethylphenyl or furoyl group, m has a value of 0 or 1 , n has a value of 0 or 1, or a pharmaceutically acceptable acid addition salt thereof as the active ingredient.
The especially preferred pharmaceutical composition of the invention comprise an isoxazole derivative of the formula I, wherein
A and B represent, independently, a hydrogen atom, or
A forms together with B a valence bond,
Z stands for a halo atom, a methyl group or a methoxy group, R 1 and R2 form together with the nitrogen atom they are attached to and with a further nitrogen atom a piperazinyl group optionally substituted by a methoxyphenyl group, m has a value of 0 or 1 , n has a value of 0 or 1 , or a pharmaceutically acceptable acid addition salt thereof as the active ingredient.
Furthermore, the invention refers to a method for the treatment of diseases which comprises administering a therapeutically effective non-toxic amount of an isoxazole derivative of the formula I or a pharmaceutically acceptable acid addition salt thereof to a patient suffering from a pathological alteration of the central nervous system and/or a cardiovascular and/or gastrointestinal disease. Under the pathological alteration of the central nervous system, anxiety, depression, cognitive deficit, trophopathy, dyssomnia etc. are meant in the first place.
The invention also refers to the use of an isoxazole derivative of the formula I or a pharmaceutically acceptable acid addition salt thereof for the preparation of a pharmaceutical composition.
The invention is further elucidated by means of the following Examples.
Preparation of the starting compounds
1. 3- ( 4-Methoxyphenyl ) -4 , 5-dihydroisoxazole- 5-yl-methanol (the compound corresponds to the formula IV)
To a solution of 50 mmoles of 4-methoxy- hydroxa ic chloride in 100 ml of anhydrous toluene, 8.46 ml (60 mmoles) of triethyl amine, then a solution of 6.8 ml (100 mmoles) of allyl alcohol in 25 ml of anhydrous toluene are added at 0 C, drop by drop. The reaction mixture is stirred at room temperature for
2 days, then 100 ml of water are added. The substance dissolving neither in water, nor in toluene is filtered, washed with water and toluene,, and dried over phosphorus pentoxide in a desiccator under reduced pressure.
Yield: 63.6 %.
M.p.: 141-144 °C (ethanol).
IR (film) : 3400 br (OH), 1600, 1500, 1230,
1030cm"1.
H-NMR (CDCl3 + DMS0-d6): cf 3.2 (2H, m, 4-H2), 3.6 (2H, m, 5-H2), 3.8 (3H, s, CH30), 4.8 (1H, m, 5-H), 4.8 (1H, br. s, OH), 6.95 + 7.55 (4H, AB, JΆ„
AD 9 Hz, ArH ) ppm.
2. 5-Bromomethyl-3- ( 4-methoxyphenyl ) isoxazole (The compound corresponds to the formula VIII)
To a solution of 50 mmoles of 4-methoxy- benzhydroxamic chloride in 100 ml of anhydrous toluene, 8.46 ml (60 mmoles) of triethylamine, then a 80 % solution of 11.1 ml (100 mmoles) of propargyl bromide in toluene diluted with 25 ml of anhydrous toluene are added at 0 C, drop by drop. The reaction mixture is stirred at room temperature for 2 days, then water is added to dissolve the precipitate separated. The substance dissolving neither in water, nor in toluene is filtered, washed with water, and dried over phosphorus pentoxide in a desiccator under reduced pressure. The organic phase is washed 3 times using 50 ml of water each time, dried over anhydrous magnesium sulfate, and evaporated. The residue is combined with the insoluble substance filtered above and purified by chromatography over 0.063-0.2 mm Kieselgel 60 gel in vacuo using a mixture consisting of 1 volume of dichloromethane and 1 volume of hexane.
Yield: 46.2 %.
M.p.: 82-84 °C (ethanol).
IR (KBr): V 1605, 1515, 1415, 1240, 800 cm-1.
1H-NMR (CDC13): ef 3.8 (3H, s, 0CH3), 4.55
(211, m, 5CH2), 6.55 (1H, s, 4-H), 6.95 + 7.7
(4H, AB, JA-τr3i 9 Hz, ArH) ppm.
3. 5-Bromomethyl-3- ( 4-methylphenyl ) isoxazole (The compound corresponds to the formula VIII)
The title compound is prepared from 50 mmoles of 4-methylbenzhydroxamic chloride as given under the preparation of 5-bromo- methyl-3- ( 4-methoxyphenyl ) isoxazole. Yield: 52.7 %. M.p.: 69-72 °C (ethanol). IR (KBr): 3150, 1610, 1420, 810 cm"1.
■H-NMR (CDC13): cf 2.4 (3H, s, CH.-), 4.55
(2H, m, 5CH„), 6.55 (1H, s, 4-H), 7.25 + 7.7 ( 4H , AB , J- 8 Hz , ArH ) ppm .
AB
4. 3- ( 3 , 4-Dimethoxyphenyl ) isoxazole-5-yl ) - methanol
(The compound corresponds to the formula XII)
8.46 ml (60 mmoles) of triethylamine are added to a stirred solution of 50 mmoles of 3 , 4-dimethoxybenzhydroxymic chloride in 50 to 100 ml of anhydrous toluene while the temperature of the solution is maintained at 0 to 10 C. The reaction mixture is stirred for 3 minutes, then a solution of 5.84 ml (100 mmoles) of propargyl alcohol in 25 ml of anhydrous toluene is added. The reaction mixture is left to reach room temperature, then stirred at this temperature for 2 days. 50 ml of water are added to dissolve the precipitate separated, the organic phase is washed 3 times using 50 ml of water each time, dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue is purified by chromatography over a 0.0630.2 mm gel of Kieselgel G or Kieselgel 60 in vacuo using gradient elution starting with dichloromethane and finishing with a mixture consisting of 10 volumes of dichloromethane and 1 volume of acetone. Yield: 36.9 %. M.p. : 88-92 °C. IR (KBr): V 3500-3000 (br OH), 3110, 2925, 2895 (CH), 1600, 1580, 1520, 1460, 1410, 1260, 1225, 1125, 1005, 830, 755 cm"1. XH-NMR (CDC13): *2.95 (IH, br, OH), 3.85 (6H, 2 x s, 2 x CH30), 4.75 (2H, s, 5-CH2), 6.45 (IH, s, 4-H), 6.85 (IH, m, ArH), 7.3-7.4 (2H, m, ArH) ppm.
5. 3- ( 4-Methoxyphenyl ) isoxazole-5-ylmethanol (The compound corresponds to the formula XII)
The title compound is prepared from 50 mmoles of 4-methoxybenzhydroxamic chloride by the method given under item 4 above. Yield: 36.1 %. M.p. : 99-101 °C.
IR (KBr): 3400 br (OH), 1600, 1500, 1230, 1050cm" .
1H-NMR (CDC13 + DMS0-d6): cf 3.8 (3H, s, 0CH3), 4.7 (2H, dd, J 6 Hz, 5-CH2 ) , 5.3 (IH, t, J 6 Hz, OH), 6.55 (IH, s, 4-H), 6.95 + 7.7 (4H, AB, J A,..B, 9 Hz, ArH) ppm.
6. 3- ( -Methylphenyl ) isoxazole-5-ylmethanol (The compound corresponds to the formula XII)
The title compound is prepared from 50 mmoles of 4-methoxybenzhydroxamic chloride by the method given under item 4 above. Yield: 82.9 %. IR (KBr): V 3400 br (OH), 1610, 1420, 1050, -1
810 cm
1II-NMR (CDC1 + DMSO-d6) : cT 2.4 (3H, s, CH3 ) ,
4.7 (2H, m, 5-CH2), 5.3 (IH, br, OH) , 6.55
(IH, s, 4-H) , 7.25 + 7.7 (4H, AB, JΛD 8 Hz,
AB
ArH) ppm.
7. 3- ( 4-Trifluoromethyl ) pheny1isoxazole-5- ylmethanol
(The compound corresponds to the formula XII)
To a stirred solution of 50 mmoles of 4-trifluoromethylbenzhydroxamic chloride in 50 to 100 ml of anhydrous benzene or toluene, 8.76 ml (150 mmoles) of propargyl alcohol, then 8.46 ml (60 mmoles) of triethylamine are added at 0 to 10 C, drop by drop. The reaction mixture is left to reach room temperature, then boiled for an hour. 50 ml of water are added to dissolve the precipitate separated, the organic phase is washed 3 times using 50 ml of water each time, dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue is purified by chromatography over a 0.0630.2 mm gel of Kieselgel G or Kieselgel 60 in vacuo using gradient elution starting with dichloromethane and finishing with a mixture consisting of 10 volumes of dichloromethane and 1 volume of acetone*. Yield: 59.3 %. M.p. : 94-97 °C. Analysis: for C11H8F3N02 (243.19) C H N calculated: 54.33 %, 3.32 %, 5.76 % ; found: 54.05 %, 3.31 %, 6.00 %. IR (KBr): V 3650-3300 br (OH), 3005 (CH), 1620, 1460, 1450, 1320, 1150, 1120, 1110, 1050, 910, 840, 800 cm" .
1H-NMR (CDC13): S 2.4 (IH, br s, OH), 4.80 (2H, s, 5CH2), 6.59 (IH, s, 4-H), 7.66 + 7.87 (4H, AB, J AB 8 Hz, ArH) ppm.
8. 3- ( 4-Fluorophenyl ) isoxazole-5-ylmethanol (The compound corresponds to the formula XII)
The title compound is prepared from 50 mmoles of 4-fluorobenzhydroxamic acid by the method given under item 7.
Yield: 38.7 %.
M.p. : 79-80 °C.
Analysis: for C10H8FNO2 (193.18)
C H N calculated: 62.18 %, 4.17 %, 7.25 %; found: 62.12 %, 4.11 %, 7.30 %.
IR (KBr): 3500-3000 ( br OH), 3100, 2920,
2890 (CH), 1600, 1520, 1460, 1420, 1395, 1362,
1240, 1160, 1110, 1045, 990, 900, 830, 820,
530 cm" .
1H-NMR (CDC13): 2.40 (IH, t, J 5.3 Hz, OH),
4.75 (2H, d, J 5.3 Hz, 5-CI1.,), 6.42 (IH, s,
4-H), 7.00 + 7.65 (4H, AB , J AB 8 Hz, J AF 5.3 Hz , JΌ „ 8 Hz , ArH ) ppm . or
9. 3- ( 4-Chlorophenyl ) isoxazole-5-ylmethanol (The compound corresponds to the formula XII)
The title compound is prepared from 50 mmoles of ,4-chlorobenzhydroxamic acid by the method given under item 7. Yield: 35.8 %. M.p. : 105-106 °C.
IR (KBr): V 3280 br (OH), 1609, 1422, 1094, 813 cm" .
1H-NMR (CDC13): <f 2.50 (IH, t, 5.3 Hz, OH), 4.70 (2H, d, J 5.3 Hz, 5-CH2), 6.52 (IH, s, 4-H), 7.36 + 7.68 (4H, AB, ;r AB 8.0 Hz, ArH) ppm.
10. 3- ( 4-Bromophenyl ) isoxazole-5-ylmethanol (The compound corresponds to the formula XII)
The title compound is prepared from 50 mmoles of 4-bromobenzhydroxamic acid by the method given under item 7. Yield: 45.2 %. M.p. : 111-113 °C. Analysis: for Cχ HgBr 02 (254.08)
C H N Br calculated: 47.27 %, 3.17 %, 5.51 %, 31.45%; found: 47.45 %, 3.30 %, 5.81 %, 31.72%. IR (KBr): 3420 br (OH), 1620, 1450, 1090,
Figure imgf000038_0001
1 1HH--NNMMRR ((CCDDCC1133 ++ DDMMΣSO-dg): cf 4.70 (2H, d, J
5.9 Hz, 5CH2), 5.10 (IH, t, J 5.9 Hz, OH),
6 6..6600 ((IIHH,, ss,, 44--HH)),, 7.57 + 7.66 (4H, AB, J
AB
10.67 Hz, ArH) ppm.
11. 5- ( 2 , 3-Epoxypropoxy )methyl-3-phenyl- isoxazole
(The compound corresponds to the formula X)
20 mmoles of 3-phenylisoxazole-5-yl- methanol are dissolved in 50 ml of anhydrous tetrahydrofuran or dioxane, and, to the solution obtained, 0.72 g (24 mmoles) of 80 % sodium hydride are added. The mixture is stirred at room temperature or boiled for an hour to precipitate the alcoholate. 4.7 to 7.8 ml (60-100 mmoles) of epichlorohydrin are added to the mixture at room temperature. The reaction mixture is stirred at 80 C for 5 to 9 hours, then cooled, and evaporated to dryness under reduced pressure. The residue is taken up in 100 ml of water, extracted 3 times using 100 ml of dichloromethane each time, the organic solutions are combined, dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue obtained is purified by chromatography over a 0.063-0.2 mm gel of Kieselgel G or Kieselgel 60 in vacuo using dichloromethane for the elution. The title compound is obtained as an oil. Yield: 48.8 %.
H-NMR (CDC13) : J" 2.4-4.0 (5H, m, OCH2CH(0)CH2) , 4.60 (2H, s, 5-CH ) , 6.54 (IH, s, 4-H), 7.20-7.50 (5H, m, ArH) ppm.
12. 3- ( 3 , 4-Dimethoxyphenyl ) -5- ( 2 , 3-epoxy- propoxy ) methylisoxazole
(The compound corresponds to the formula X)
The title compound is prepared from 50 mmoles of 3- ( 3 , 4-dimethoxyphenyl ) isoxazole- -5-ylmethanol by the method described under item 11 above. The title compound is obtained as an oil. Yield: 76.1 %.
IR (film): V 3080, 2950, 2845 (CH), 1605, 1590, 1520, 1480, 1430, 1280, 1230, 1130, 1100, 1020, 860, 805, 740 cm"1. 1II-NMR (CDCl.,): ^ 2.5-3.6 (411, , OCH.2CH(0)CH2) , 3.85 (6H, 2 x s, 2 x CH30), 3.95-4.2 (IH, m, 0CH2CH( 0) CH2 ) , 4.60 (2H, s, 5-CH2), 6.45 (IH, s, 4-H), 6.85 (IH, m, ArH), 7.3-7.4 (2H, m, ArH) ppm.
13. 5-/(2, 3-Epoxypropoxy )methyl/-3-( 4-methoxyphenyl ) isoxazole
(The compound corresponds to the formula X)
The title compound is prepared from 50 mmoles of 3- ( 4-methoxyphenyl ) isoxazole-5-yl- methanol by the method described under item
11 above. The title compound is obtained as an oil.
Yield: 60.1 %.
IR (film): 3050, 2980, 2890 (CH), 1600,
1510, 1410, 1225, 1150, 1060, 1000 cm"1.
1H-NMR (CDC13): S 2.5-4.0 (5H, m,
OCH2CH(0)CH2) , 3.8 (3H, s, CH30), 4.65 (2H, s, 5-CH2), 6.4 (IH, s, 4-H), 6.8 + 7.6 (4H,
AB, AΛBn 9 Hz, ArH) ppm.
14. 5-/(2, 3-Epoxypropoxy ) methyl/-3- ( 4-methyl- phenyl ) isoxazole
(The compound corresponds to the formula X)
The title compound is prepared from 50 mmoles of 3- ( -methylphenyl ) isoxazole-5-yl- methanol by the method described under item
11 above. The title compound is obtained as an oil.
Yield: 66.8 %.
IR (film): 3080, 3000, 2950 (CH), 1610,
1410, 1080, 890 cm"1.
1H-NMR (CDC13): <£ 2.35 (3H, s, CH3 ) , 2.5-4.0
(511, m, OCH2CH(0)CH2) , 4.65 (211, s, 5-CH2 ) ,
6.55 (IH, s, 4-H), 7.25 + 7.65 (4H, AB, ,7
AB
8 Hz, ArH) ppm.
15. 5-/(2, 3-Epoxypropoxy) methyl/-3- ( 4- trifluoromethylphenyl ) isoxazole
(The compound corresponds to the formula X) The title compound is prepared from 50 mmoles of 3- ( 4-trifluoromethylphenyl ) isoxazole- -5-ylmethanol by the method described under item 11 above. Yield: 50.3 %. M.p. : 36-38 °C. Analysis: for 1 H 12 F3N03 (299.25)
C H N calculated: 56.19 %, 4.04 %, 4.68 %; found: 56.03 %, 3.73 %, 4.90 %. IR (KBr): 1620, 1460, 1440, 1380, 1310, 1150, 1100, 1050, 900, 840, 820, 790 cm" .
H-NMR (CDC13): J 2.45-2.90 (2H, m, OCH2CH(0)CH2) , 3.204.05 (3H, m, 0CH2CH ( 0) CH2 ) , 4.67 (2H, s, 5-CH2), 6.60 (IH, s, 4-H), 7.66
+ 7.88 (4H, AB, J AnDD 6.67 Hz, ArH) ppm.
16. 5-/(2, 3-Epoxypropoxy )methyl/-3- ( 4-fluoro- phenyl/isoxazole
(The compound corresponds to the formula X)
The title compound is prepared from 50 mmoles of 3- ( 4-fluorophenyl ) isoxazole-5-yl- methanol by the method described under item 11 above. The title compound is obtained as an oil.
Yield: 54.0 %.
1H-NMR (CDC13): & 2.5-2.9 (2H, m, OCH2CH(0)CH2), 3.03.25 (IH, m, 0CH2CH ( 0 ) CH2 ) , 3.35-4.0 (2H, m, 0CH2CH( 0) CH2 ) , 4.60 (2H, s, 5-CH2), 6.42 (IH, s, 4-H), 7.00 + 7.65 ( 4H , AB , JAB 8 Hz , JAF 5 . 3 Hz , JβF 8 Hz , ArH ) ppm .
17. 5-/(2, 3-Epoxypropoxy ) methyl /-3-( 4-chloro- phenyl ) isoxazole
(The compound corresponds to the formula X)
The title compound is prepared from 50 mmoles of 3- ( 4-chlorophenyl ) isoxazole-5-yl- methanol by the method described under item
11 above. The title compound is obtained as an oil.
Analysis: .for C13H12ClN03 (265.70)
C H N Cl calculated: 58.77 %, 4.55 %, 5.27 %, 13.34%; found: 58.36 %, 4.70 %, 5.26 %, 13.29%.
IR (KBr): 3100, 3050, 2980, 2890 (CH), 1605,
1480, 1110, 1100, 910, 900, 850 cm"1.
1H-NMR (CDC13): cf 2.50-2.90 (2H, m,
OCH2CH(0)CH2) , 3.03.30 (IH, , 0CH2CH ( 0) CH2 ) ,
3.35-4.0 (2H, m, OCH CH( 0) CH2 ) , 4.65 (2H, s, 5-CH ) , 6.55 (IH, s, 4-H), 7.38 + 7.64
(4H, AB, Jnπ 8 Hz, ArH) ppm. AB
18. 3- ( 4-Bromophenyl ) -5-/ ( 2 , 3-epoxypropoxy ) - methyl/isoxazole
(The compound corresponds to the formula X)
The title compound is prepared from 50 mmoles of 3- ( 4-bromophenyl ) isoxazole-5-yl- methanol by the method described under item
11 above.
Yield: 36.7 %.
M.p. : 61-63 °C.
Analysis: for C13H12BrN03 (310.15)
C H N Br calculated: 50.34 %, 3.90 %, 4.52 %, 25.76%; found: 50.60 %, 3.88 %, 4.66 %, 26.20%. IR (KBr): 1610, 1420, 1100, 1060, 900, 890, 840, 800 cm-1.
H-NMR (CDC13): J 2.53-2.95 (2H, m, OCH2CH(0)CH2) , 3.20 (IH, m, 0CH2CH ( 0) CH2 ) , 3.34-4.15 (2H, m, 0CH2CH ( 0) CH2 ) , 4.70 (2H, s, 5-CH2), 6.54 (IH, s, 4-H), 7.58 + 7.62
(411, AB, J AΛBO 9.3 Hz, ArH) ppm.
Preparation of dihydroisoxazole derivatives of the formula la
Example 1 3-Phenyl-5-morpholinomethyl-4 , 5-dihydro- isoxazole hydrochloride a ) 3-Phenyl-5-morpholinomethyl-4 , 5-dihydro- isoxazole
To a stirred solution of 100 mmoles of N-allylmorpholine and 8.4 ml (60 mmoles) of anhydrous triethylamine in 70 ml of anhydrous toluene, a solution of 50 mmoles of benzhydroxamic chloride in 50 ml of anhydrous toluene are added at 0 to 10 C, drop by drop The reaction mixture is left to reach room temperature, then stirred at 80 C for 1 hour. 50 ml of water is added to the reaction mixture at room temperature to dissolve the precipitate formed, the organic phase is washed 3 times using 30 ml of water each time, dried over anhydrous magnesium sulfate, and evaporated. The residue is purified by chromatography over a 0.063-0.2 mm gel of Kieselgel G or Kieselgel 60 in vacuo using gradient elution starting with dichloromethane and finishing with a mixture consisting of 10 volumes of dichloromethane and 1 volume of acetone or 10 volumes of hexane and 1 volume of acetone. Yield: 25.3 %. M.p. : 66-67 °C .
Analysis: for cχ4H;ι8 N202 (246«31)
C H N calculated: 68.27 %, 7.36 %, 11.36 %; found: 68.36 %, 7.33 %, 11.02 %. IR (KBr): 3140, 3120, 2980, 2950, 2920, 2905, 2870 cm"1.
1H-NMR (CDC1 ): 2.30-2.60 (6H, m, N ( CH ) ) , 3.00-3.40 (2H, m, -H2), 3.50-3.85 (4H, m, 0(CH )2), 4.60-5.0 (IH, m, 5-H), 7.20-7.50 (3H, m, ArH), 7.50-7.80 (2H, m, ArH) ppm. 13C-NMR (CDC1 ): J" 38.40 (C-4), 53.89 (N(CH2)2), 61.81 (5-CH2), 66.58 (0(CH2)2), 79.13 (C-5), 126.42, 128.47, 129.83 ( ar . CH), 129.41 (ar. C-l ) , 156.35 (C-3) ppm.
b ) 3-Phenyl-5-morpholinomethyl- , 5-dihydro- isoxazole hydrochloride 10 mmoles of the isoxazole base obtained as described above are dissolved in a mixture of ether and ethanol to obtain a solution having a concentration of 1 mmole/ml. The solution is acidified by introducing anhydrous hydrogen chloride gas or adding 5 ml of 3N solution of hydrogen chloride in ethanol. The reaction mixture is stirred for some minutes, the product separated is filtered, washed with ether, and dried over phosphorus pentoxide at 40 C under reduced pressure. If desired, the product is recrystallized from ethanol. Yield: 97.5 %. M.p. : 198-200 °C. Analysis: for C14HιgClN202 (282.77)
C H N Cl calculated: 59.47 %, 6.77 %, 9.93 %, 12.54%; found: 59.66 %, 6.57 %, 9.67 %, 12.46%. IR (KBr): V 3020, 3000, 2960, 2900 ( CH ) , 2800-2300 br (NH+) cm"1.
1H-NMR (D20): cf 3.0-3.55 (6H, m, N(CH2) ), 3.20-3.70 (2H, m, 4-H2), 3.80-4.05 (4H, m, 0(CH2) ), 5.10-5.60 (IH, , 5-H) , 7.20-7.40 (3H, m, ArH), 7.40-7.80 (2H, m, ArH) ppm.
Example 2 3- ( 4-Methoxyphenyl ) -5-morpholinomethyl ) -4 , 5- -dihydroisoxazole hydrochloride a ) 3- ( 4-Methoxyphenyl ) -5-morpholinomethyl-
4 , 5-dihydroisoxazole To a stirred solution of 50 mmoles of 4-methoxybenzhydroxamic chloride in 100 ml of anhydrous toluene, 8.4 ml (60 mmoles) of anhydrous triethylamine, then, after 3 minutes, a solution of 100 mmoles of N-allylmorpholine in 20 ml of anhydrous toluene are added at 0 to 10 C, drop by drop. The reaction mixture is left to reach room temperature, then stirred for two days at room temperature. 50 ml of water are added to dissolve the precipitate formed, the organic phase is washed 3 times using 30 ml of water each time, dried over anhydrous magnesium sulfate, and evaporated. The residue is purified by chromatography over a 0.063-0.2 mm gel of Kieselgel G or Kieselgel 60 using gradient elution starting with dichloromethane and finishing with a mixture consisting of 10 volumes of dichloromethane and 1 volume of acetone or 10 volumes of hexane and 1 volume of acetone. Yield: 55.1 %. M.p. : 94-95 °C.
Analysis: for c 15 H2oN2°3 (274-36>
C H N calculated: 65.20 %, 7.30 %, 10.14 %; found: 65.35 %, 7.25 %, 10.18 %. IR (KBr): 1610, 1514, 1251, 1112 cm"1. 1H-NMR (CDC13): cf 2.51-2.72 (6H, m, N(CH2)3),
3.17 + 3.36 (2H, ABX , J AπQrS 16.5 Hz, JAAΛV 8.1
Hz, J DoΛv 10.4 Hz, 4-H Δ-), 3.71 (4H, t, J 4.6
Hz, 0(CH2)2), 3.84 (3H, s, CH30), 4.88 (lH, m, 5-H), 6.92 + 7.61 (4H, AB, J AΛrDS 8.8 Hz, ArH ) ppm.
13C-NMR (CDC13): S 38.68 (C-4), 53.85 (N(CH2)2), 54.95 (CH30), 61.85 (5-CH2), 66.56 (0(CH2)2), 78.78 (C-5), 113.85, 127.93 ( ar . CH), 121.92 (ar. C-l), 155.91 (C3), 180.85 (ar. C-4) ppm.
b ) 3- ( 4-Methoxyphenyl ) -5-morpholinomethyl- -4 , 5-dihydroisoxazole hydrochloride
10 mmoles of the isoxazole base obtained as described above are dissolved in a mixture of ether and ethanol to obtain a solution having a concentration of 1 mmole/ml. The solution is acidified by introducing either anhydrous hydrogen chloride gas or adding
5 ml of 3N solution of hydrogen chloride in ethanol. The reaction mixture is stirred for some minutes, the product separated is filtered, washed with ether, and dried over phosphorus pentoxide at 40 C under reduced pressure.. If desired, the product is recrystallized from ethanol.
Yield: 92.1 %.
M.p.: 189-194 °C.
Analysis: for ClrH21ClN203 (312.80)
C H N Cl calculated: 57.60 %, 6.77 %, 8.96 %, 11.33%; found: 57.64 %, 6.77 %, 8.97 %, 11.26%.
^"H-NMR (DMS0-d6): 3.20 (IH, br, NH+) , 3.35
+ 3.67 (2H, ABX, JΛ„ 17.3 Hz, JΛV 7.4 Hz,
Ati AX
Jπv 10.6 Hz, 4-H-), 3.42 (4H, br, N(CH„)„), hSA Z Z 3.52-3.58 (2H, m, 5-CH2), 3.81 (3H, s, CH30),
3.95 (4H, m, 0(CH2)2), 5.34 (IH, m, 5H), 7.03
+ 7.62 (4H, AB, J,,, 8.8 Hz, ArH) ppm.
ArS
Example 3 3- ( 4-Methylphenyl ) -5-morpholinomethyl-4 , 5- dihydroisoxazole hydrochloride a ) 3- ( 4-Methylphenyl ) -5-morpholinomethyl-4 , 5-
-dihydroisoxazole
The title product is prepared from 50 mmoles of 4-methylbenzhydroxamic chloride and 100 mmoles of Nallylmorpholine using the method described in Example 2, part a).
Yield: 45.6 %.
M.p. : 82-84 °C.
IR (KBr): 3030, 2995, 2910, 2875 ( CH ) , 1100,
800 cm .
1H-NMR (CDC13): d 2.36 (3H, s, CH3 ) , 2.48-2.71
(611, , J 6.5 Hz, J 13.2 Hz, N(CII2)3), 3.17
+ 3.36 (2H, ABX, J A.r_S, 16.6 Hz, JΆV Aλ 10.5 Hz,
Jβχ 8.1 Hz, 4-H2), 3.70 (4H, t, J 4.65 Hz),
0(CH2)2), 4.82-4.94 (IH, m, 5-H), 7.20 + 7.56
(4H, AB, JAΛDrS 8.5 Hz, ArH) ppm.
13 C-NMR (CDC13): of 21.06 (CH3), 38.62 (C-4),
53.94 (N(CH2)2), 61.92 (5-CH2), 66.65 0(CH2)2), 78.98 (c-5), 126.44, 129.23 ( ar . CH), 126.62 (ar. C-l), 140.12 (ar. C-4), 156.36 (C-3) ppm,
b) 3- ( 4-=Methylphenyl ) -5-morpholinomethyl-4 , 5- -dihydroisoxazole hydrochloride The title product is prepared by the method described in Example 2, part b). Yield: 87.2 %. M.p. : 212-214 °C.
Analysis: for c 15 H2iClN2°2 (296-80>
C H N Cl calculated: 60.70 %, 7.13 %, 9.44 %, 11.95%; found: 61.00 %, 7.07 %, 9.42 %, 12.11%. IR (KBr): 3100-2900 ( CH ) , 2800-2300 (br, NH+), 1110, 910, 800 cm"1.
1H-NMR (DMSO-d + CDCl ) : <$ 2.35 (3H, s, CH ) , 3.2-3.8 (8H, m, N(CH2)3 + 4-H2), 3.8-4.0 (4H, m, 0(CH )2), 5.2 (IH, m, 5-H), 7.2 + 7.55
(4H, AB, JAΛπB 8.0 Hz, ArH) ppm.
Example 4 5-Morpholinomethyl-3- ( 4-trifluoromethylphenyl ) 4 , -dihydroisoxazole hydrochloride a ) 5-Morpholinomethyl-3- ( 4-trifluoromethylphenyl ) -4 , 5-dihydroisoxazole
The title compound is prepared from 50 mmoles of 4-trifluoromethylbenzhydroxamic chloride and 100 mmoles of N-allylmorpholine by the method described in Example 1, part a).
Yield: 60 %. M.p. : 98-101 °C. Analysis: for C,,-H F.,N202 (314.31)
C H N calculated: 57.32 % 5.45 %, 8.91 %; found: 57.12 %, 5.55 %, 8.94 %. IR (KBr): V 3030, 2990, 2920, 2890 (CH), 1620,
1600, 1320, 1160, 1090, 1050, 910, 900, 820,
800 cm"1.
"""H-NMR (CDCl3): _f 2.50-2.75 (6H, m, N ( CH ) ) ,
3.23 + 3.41 (2H, ABX, J AΛDrS 16.06 Hz, JA_.Λ__ 10.50
Hz, JDBXV 8.23 Hz, 4-H Z_), 3.71 (4H, t, J 4.7
Hz, 0(CH2)2), 4.97 (IH, m, 5-H), 7.65 + 7.79 (4H, AB, J__ 8.2 Hz, ArH) ppm.
C-NMR (CDC13): cT 38.11 (C-4), 54.04 (N(CH2)2), 61.77 (5-CH2), 66.70 (0(CH2)2), 79.92 (C-5), 125.58, 126.79 (ar. CH), 131.57 (q, J__ 33.1 Hz, ar. C-4), 132.99 ( ar . C-l),
Cr 123.74 (q, J C__r 272.5 Hz, CF J. ) , 155.52 (C-3) ppm.
b) 5-Morpholinomethyl-3- ( 4-trifluoromethylphenyl ) -4 , 5-dihydroisoxazole hydrochloride
The title compound is prepared using the method described in Example 1, part b).
Yield: 94.1 %.
M.p. : 236-238 °C.
Analysis: 'for C15H18C1F3N202 (350.77)
C H N Cl calculated: 51.36 %, 5.17 %, 7.99 %, 10.11%; found: 51.58 %, 5.27 %, 7.78 %, 10.27%.
IR (KBr): V 3010 ( CH ) , 2750-2300 (NH+), 1450,
1410, 1320, 1150, 1100, 1050, 880, 830 cm"1.
XH-NMR (DMS0-d6 + CDCl3): r 3.0-4.70 (8H, m, N(CH3)2 + 4-H2), 3.80-4.05 (4H, m, 0(CH2)2),
5.46 (IH, m, 511), 7.69 + 7.84 (411, AB , J AΛTB1
8.0 Hz, ArH) ppm. Example 5 3- ( 4-Chlorophenyl ) -5-morpholinomethyl-4 , 5- -dihydroisoxazole hydrochloride a ) 3- ( 4-Chlorophenyl ) -5-morpholinomethyl-
-4 , 5-dihydroisoxazole
The title compound is prepared from 50 mmoles of 4-c.hlorobenzhydroxamic chloride and 100 mmoles of N-allylmorpholine by the method described in Example 1, part a).
Yield: 46.4 %.
M.p. : 72-74 °C.
Analysis: for C14H17C1N202 (280.75)
C H N Cl calculated: 59.89 %, 6.10 %, 9.98 %, 12.63%; found: 60.17 %, 6.09 %, 9.92 %, 12.30%.
IR (KBr): V 3020, 3005, 2990, 2980, 2920,
2890 (CH), 1600, 1500, 1100, 810 cm"1.
1H-NMR (CDC13): <S 2.48-2.72 (6H, m, (CH2)3),
3.17 + 3.36 (2H, ABX, JAβ 16.6 Hz, JftX 10.5
Hz, j:BXv 8.23 Hz, 4-H Z), 3.70 (4H, t, J 4.7
Hz, 0(CH2)2), 4.92 (IH, m, 5-H) , 7.28 + 7.51
(4H, AB, JAΛBI, 8.4 Hz, ArH) ppm.
XJC-NMR (CDC13): cf 38.19 (C-4), 53.86 (N(CH2)2), 61.70 (5-CH2), 66.55 (0(CH2)2), 79.40 (C-5), 127.65, 128.71 (ar. CH), 127.92 (ar. C-l), 135.67 ( ar . C-4), 155.43 (C-3) ppm.
b) 3-( 4-Chlorophenyl ) -5-morpholinomethyl-4 , 5- dihydroisoxazole hydrochloride The title compound is prepared using the method described in Example 1, part b). Yield: 98.3 %. M.p. : 201-203 °C. Analysis: for C-, 4H 18 cl2N2ϋ2 < 17.22)
C H N Cl calculated: 53.01 %, 5.72 %, 8.83 %, 22.35%; found: 53.23 %, 5.72 %, 8.77 %, 22.01%. IR (KBr): V 3000 (CH), 2900-2500 br (NH+), 1390, 1080, 867, 812 cm"1.
1H-NMR (DMS0-d6 + CDCl3): £ 3.0-3.7 (8H, m, N(CH2) + 4-H2), 3.80-4.00 (4H, m, 0(CH2)2),
5.42 (IH, m, 5H), 7.44 + 7.64 (4H, AB, J AΛTrS
9.3 Hz, ArH) ppm.
Example -6 3- ( 4-Bromophenyl ) -5-morpholinomethyl-4 , 5- dihydroisoxazole hydrochloride a ) 3- ( 4-Bromophenyl ) -5-morpholinomethyl-
-4 , 5-dihydroisoxazole
The title compound is prepared from 50 mmoles of 4-bromobenzhydroxamic chloride and 100 mmoles of N-allylmorpholine by the method described in Example 1, part a). Yield: 69.8 %. M.p. : 104-106 °C. Analysis: for C14II-,7BrN202 (325.21)
C H N Br calculated: 51.71 %, 5.27 %, 8.61 %, 24.57%; found: 52. OO %, 5.34 %, 8.84 %, 24.94%. IR (KBr): V 3050, 3010, 2910, 2890, 2860 ( CH ) , 1620, 1610, 1460, 1440, 1320, 1100, 820 cm"1.
1H-NMR (CDC13): cT 2.48-2.73 (6H, m, N(CH2)3),
3.22 + 3.41 (2H, ABX, JSD 16.2 Hz, J.v 10.6
AB AX
Hz, JDV 8.22 Hz, 4-H„), 3.71 (4H, t, J 4.61 rSX Z
Hz, 0(CH2)2), 4.93 (IH, m, 5-H), 7.53 (4H, s, ArH) ppm.
13C-NMR (CDC13): cf 38.29 (C-4), 53.99
(N(CH2)2), 61.84 (5-CH2), 66.68 (0(CH2) ),
79.56 (C-5), 128.00, 131.82 ( ar . CH), 124.15
(ar. C-4), 128.44 (ar. C-l), 155.56 (C-3) ppm.
b) 3- ( 4-Bromophenyl ) -5-rnorpholinomethyl-4 , 5- dihydroisoxazole hydrochloride
The title compound is prepared using the method described in Example 1, part b). Yield: 95.4 %. M.p. : 223-225 °C. Analysis: for C 1, .Hl,ooBrClN Z_0 Z„ (361.67) C H N Cl calculated: 46.49 %, 5.02 %, 7.75 %, 9.80%; found: 46.30 %, 4.90 %, 7.52 %, 9.51%.
IR (KBr): 3005, 2940 ( CH ) , 2700-2200 ( NH ) ,
1600, 880 cm" .
1H-NMR (DMS0-d6 + CDCl ) : 3.20-3.70 (8H, m, N(CH2)3 es 4-H2), 3.80-4.05 (4H, m,
0(CH2)2), 5.40 (IH, m, 5-H), 7.60 (4H, m,
ArH) ppm. Example 7 3- ( 4-Methoxyphenyl ) -5- ( pyrrolidine-1-ylmethyl ) -4 , 5-dihydroisoxazole hydrochloride a ) 3- ( 4-Methoxyphenyl ) -5- ( pyrrolidine-l-yl~ methyl ) -4 , 5-dihydroisoxazole
The title compound is prepared from 50 mmoles of 4-methoxybenzhydroxamic chloride and 100 mmoles of N-allylpyrrolidine by the method of Example 2, part a). Yield: 40.7 %. M.p. : 69.5-71 °C.
Analysis: for c 15 H 2oN202 f-260-34)
C H N calculated: 69.20 %, 7.74 %, 10.76 %; found: 69.20 %, 7.75 %, 10.62 %. IR (KBr): V 2966, 2804 ( CH ) , 1611, 1597, 1515, 1467, 1423', 1355, 1307, 1252, 1178, 1157, 1130, 1110, 1043, 1003, 926, 886, 827, 811, 601, 552, 512 cm"1.
1H-NMR (CDCl.,): 1.79 (4H, m, pyrrolidine 3- and 4H2 ) , 2.61 (4H, m, N(CH2)2), 2.74 (2H, d, J 6.2 Hz, 5CH2), 3.18 + 3.36 (2H, ABX , J AADrS 16.5 Hz, J AΛΛV 10.3 Hz, J_ Bλv 8.0 Hz, 4-H Z_),
3.83 (3H, s, CH30) , 4.84 (IH, , 5-H), 6.91
+ 7.61 (4H, AB, J^Ώ 9.0 Hz, ArH) ppm.
1 -3, ΔB
C-NMR (CDCl.,) : cf 23.55 (pyrrolidine C-3 and C-4), 39.18 (C-4), 54.78 (N(CH2)2), 55.34
(CH30), 59.78 (5CH2), 80.11 (C-5), 114.08,
128.19 (ar. CH ) , 122.36 (ar. C-l ) , 156.09
(C-3), 160.97 (ar. C-4) ppm. b) 3- ( 4-Methoxyphenyl ) -5- ( pyrrolidine-1-yl- methyl ) -4 , 5-dihydroisoxazole hydrochloride
The title compound is prepared using the method described in Example 2, part b). Yield: 92.9 %. M.p. : 176-178 °C. Analysis: for C15H21C1N202 (296.80)
C H N Cl (ionic) calculated: 60.70 %, 7.13 %, 9.44 %, 11.95%; found: 60.87 %, 6.79 %, 9.28 %, 12.14%. IR (KBr): 2998, 2890, 2850 (CH), 2800-2200 (NH+), 1605, 1580, 1510, 1425, 1360, 1310, 1260, 1197, 1040, 1010, 900, 890, 850, 810, 560 cm
H-NMR (CDC13): S 2.10 (4H, br , pyrrolidine 3- and 4-H2), 2.80-3.60 (8H, , N+(CH2)3 and 4-H2), 3.72 (3H, s, CH30), 5.2-5.65 (IH, m, 5-H), 6.80 + 7.55 (4H, AB, JAβ 9.2 Hz, ArH) ppm.
Example 8 3- ( 4-Methylphenyl ) -5- ( pyrrolidine-1-ylmethyl ) - -4 , 5-dihydroisoxazole hydrochloride a) 3- ( 4-Methylphenyl ) -5- ( pyrrolidine-1-yl- methyl ) -4 , 5-dihydroisoxazole
The title compound is prepared from 50 mmoles of 4-methylbenzhydroxamic chloride and 100 mmoles of N-allylpyrrolidine by the method described in Example 2, part a). Yield: 62.1 %. M.p. : 62-64 °C.
IR (KBr): V 2967, 2791, 1611, 1516, 1432,
1353, 1262, 1155, 1132, 1044, 1011, 901, 820,
788, 552, 499 cm"1.
"""H-NMR (CDC13) : cT 1.75-1.81 (411, m, pyrrolidine
3- and -H2), 2.36 (3H, s, CH ) , 2.57-2.66
(4H, m, N(CH2)2), 2.74 (2H, d, J 6.1 Hz,
5-CH_), 3.18 + 3.38 (2H, ABX, JΛD 16.6 Hz, Z AB
JΛV 10.4 Hz, J_v 8.1 Hz, 4-H„), 4.85 (IH, AX rSλ Z m, 5-H), 7.19 + 7.56 (4H, AB, J__ 8.1 Hz,
AB
ArH) ppm.
13C-NMR (CDCl ): & 21.16 ( CH ) , 23.32 (pyrrolidine C3 and C-4), 38.77 (C-4), 54.50 (N(CH2)2), 59.50 (5-CH2), 79.99 (C-5), 126.34, 129.08 (ar. CH ) , 126.71 (ar. C-l), 139.87 (ar. C-4), 156.19 (C-3) ppm.
b) 3- ( 4-Methylphenyl ) -5- (pyrrolidine-1-yl- methyl ) -4 , 5-dihydroisoxazole hydrochloride
The title compound is prepared using the method described in Example 2, part b).
Yield: 85.1 %.
M.p. : 203-211 °C.
Analysis: for C15H21ClN202 (296.80)
C H N Cl (ionic) calculated: 64.16%, 7.54%, 9.98%, 12.63%; found: 63.83%, 7.66%, 10.01%, 12.96%.
IR (KBr): Y 2800-2400 (NH+), 1450, 1350, 880,
790 cm .
"""H-NMR (DMSO-d6, + CDCl3-.): <_) 1.9 (4H, br, pyrrolidine 3- and 4-H ) , 2.35 (3H, s, CH ) , 3.4 (8H, m, N (CH2)3 and 4-H2), 5.2 (IH, m,
5-H), 7.1 + 7.5 (4H, AB, J ,0 Hz, ArH) ,
AB 11.3 (IH, br, NH+ ) ppm.
Example 9 3- ( 4-Methoxyphenyl ) -5-piperidinomethyl-4 , 5- dihydroisoxazole hydrochloride a ) 3- ( 4-Methoxyphenyl ) -5-piperidinomethyl-
4 , 5-dihydroisoxazole
The title compound is prepared from 50 mmoles of 4-methoxybenzhydroxamic chloride and 100 mmoles of N-allylpiperidine by the method described in Example 2, part a). Yield: 50.3 %. M.p. : 88-91 °C.
IR (KBr): V 2929, 2850, 2777, 1605, 1513, 1435, 1418, 1351, 1304, 1249, 1180, 1156,
1110, 1041, 1018, 990, 834, 604, 554, 509
"""H-NMR (CDCl ): o" 1.43 (2H, m, piperidine
4-H_), 1.541.60 (4H, m, piperidine 3- and
5-H2), 2.43-2.55 (4H, , (CH2)2), 2.49 +
2.64 (2H, ABX, JΛD 13.4 Hz, J 6.4 Hz, J_v
AB AX BX
5.4 Hz, 5-CH2), 3.13 + 3.35 (2H, ABX, JAβ
16.5 Hz, JAΛXV 10.4 Hz, JBnXv 8.0 Hz, 4-H Z„), 3.82
(3H, s, OCH ) , 4.88 (IH, m, 5-H), 6.90 + 7.60 (4H, AB, J-Q 8.75 Hz, ArH) ppm.
13 AB C-NMR. (CDC13): <ζ 23.88 (piperidine C-4),
25.68 (piperidine (C-3 and C-5), 39.08 (C-4), 54.83 (N(CH2)2), 55.02 (0CH3), 62.49 (5-CH2), 79.00 (C-5), 113.75, 127.86 (ar. CH ) , 122.04 (ar. C-l), 155.72 (C-3), 160.64 ( ar . C-4) ppm.
b) 3- ( 4-Methoxyphenyl ) -5-piperidinomethyl- -4 , 5-dihydroisoxazole hydrochloride
The title compound is prepared using the method described in Example 2, part b).
Yield: 90.0 %.
M.p. : 184-185 °C.
Analysis: for C 1,6rH2_3-,ClN2.,02_ (310.82)
Cl H N Cl (ionic) calculated: 61.82 %, 7.46 %, 9.01 %, 11.41%; found: 61.41 %, 7.35 %, 8.78 %, 10.93%.
IR (KBr): J 2800-2400 (NH+), 1605, 1510, 1460,
1350, 1250, 1180, 1160, 1000, 840, 805 cm"1.
"""H-NMR (DMSO-d6, + CDCl3-.): £ 1.8 (6H, br, piperidine 3-, 4- and 5-H_), 3.2 (8H, m,
N+(CH ) and 4-H2), 3.8 (3H, s, 0CH3 ) , 4.2
(IH, br, NH+), 5.2 (IH, m, 5-H), 6.9 + 7.6
(4H, AB, JA,DB 8.5 Hz, ArH) ppm.
Example 10 3- ( 4-Methylphenyl ) -5-piperidinomethyl-4 , 5- -dihydroisoxazole hydrochloride a ) 3- ( 4-Methylphenyl ) -5-piperidinomethyl-
-4 , 5-dihydroisoxazole
The title compound is prepared from 50 mmoles of 4-methylbenzhydroxamic chloride and 100 mmoles of N-allylpiperidine by the method given in Example 2, part a). Yield: 59.4 %. M.p. : 61 °C.
IR (KBr): 2990, 2905 (CH), 1100, 880, 790 cm -1
"""H-NMR (CDC13): £ 1.44 (2H, q, J 5.4 Hz, piperidine 4-H,,), 1.54-1.63 (4H, m, piperidine
3- and 5-H2), 2.36 (3H, s, CH3 ) , 2.39-2.58
(4H, m, N(CH2)2), 2.53 + 2.66 (2H, ABX, JAβ
13.1 Hz, JAAXV 6.3 Hz, J_r5vX 5.7 Hz, 5-CH Z-), 3.26
+ 3.36 (2H, ABX, J AπDτ3 16.6 Hz, JAΛXV 10.5 Hz,
JBDXV 8.05 Hz, 4-H Z-), 4.83-4.95 (IH, m, 5-H),
7.20 + 7.57 (4H, AB, JΛD 8.25 Hz, ArH) ppm.
C-NMR (CDC13): 21.15 (CH3), 23.89 (piperidine C4 ) , 25.72 (piperidine C-3 and C-5), 39.05 (C-4), 54.93 (N(CH2)2), 62.60 (5-CH2), 79.27 (C-5), 126.55, 129.28 (ar. CH), 126.89 (ar. C-l), 140.11 ( ar . C-4), 156.42 (C-3) ppm.
b) 3-(4-Methylphenyl) -5-piperidinomethyl- -4 , 5-dihydroisoxazole hydrochloride
The title compound is prepared using the method described in Example 2, part b). Yield: 76.5 %. M.p. : 162-163 °C. Analysis: for C16H23ClN20XH20 (312.84)
C H N Cl (ionic) calculated: 61.43 %, 8.05 %, 8.95 %, 11.33%; found: 61.35 %, 8.02 %, 9.04 %, 11.30%.
Il-NMR (CDCl.,): -5 1.7-2.0 (611, , piperidine
3-, 4- and 5-H2), 2.35 (3H, s, CH ) , 3.2-3.8 (8H, m, N+(CH2)3 and 4-H2), 5.2 (IH, m, 5-H),
7.2 + 7.55 (4H, AB, JΛπ 8.0 Hz, ArH) ppm.
AB
Example 11 5-(Azepane-l-ylmethyl)-3-( 4-methoxyphenyl ) -4 , 5- -dihydroisoxazole hydrochloride a ) 5- ( Azepane-1-ylmethy1 ) -3- ( 4-methoxyphenyl ) -4 , 5-dihydroisoxazole
The title compound is prepared from 50 mmoles of 4-methoxybenzhydroxamic chloride and 100 mmoles of N-allylazepane by the method described in Example 2, part a). Yield: 96.1 %. M.p. : 72-73 °C.
Analysis: for C 17 I124N2°2 (288-39> C H N calculated: 70.80 %, 8.39 %, 9.71 %; found: 70.83 %, 8.26 %, 9.75 %. IR (KBr): 2922, 2851 ( CH ) , 1608, 1515, 1456, 1356, 1307, 1255, 1184, 1111, 1043, 1021, 893, 835, 557 cm"1.
"""H-NMR (CDC13): cf 1.59 (8H, br, azepane 3-, 4-, 5- and 6-H2), 2.72-2.77 (4H, m, N(CH2)2), 2.65 + 2.86 (2H, ABX, JAβ 13.3 Hz, JAχ 5.85
Hz, JΛV 6.1 Hz, 5-CH-), 3.19 + 3.33 (2H, ABX, AX £
JAβ 16.5 Hz, JAχ 10.2 Hz, Jβχ 7.8 Hz, 4-H2),
3.83 (3H, s, CH30), 4.80 (III, m, 5-11), 6.91
+ 7.61 (4H, AB, J AΛBD 8.9 Hz, ArH) ppm.
C-NMR (CDCl-.): rξ 26.83 + 27.77 (azepane C-3, C-4, C-5 and C-6), 38.80 (C-4), 55.08 (CII30), 55.74 (N(CH2)2), 60.62 (5-CH2), 79.56 (C-5), 113.81, 127.90 (ar. CH ) , 122.11 ( ar . C-l), 155.83 (C-3), 160.68 (ar. C-4) ppm.
b ) 5- ( Azepane-1-ylmethy1 ) -3- ( 4-methoxyphenyl ) -4 , 5-dihydroisoxazole hydrochloride
The title compound is prepared using the method described in Example 2, part b). Yield: 86.9 %. M.p. : 145-146 °C. Analysis: C17H25C1 202 (324.85)
C H N Cl (ionic) calculated: 62.86 %, 7.76 %, 8.62 %, 10.91%; found: 62.60 %, 8.11 %, 8.49 %, 10.93%. IR (KBr): 2950 ( CH ) , 2800-2400 (NH+), 1605, 1510, 1460, 1380, 1310, 1275, 1190, 1040, 890, 840 cm" .
■""H-NMR (DMS0-d6 + CDC13): cf 1.6-2.20 (8H, br, azepane 3-, 4-, 5- and 6-H~), 3.05-3.80 (911, , NH+(CH2)3 and -H2), 3.85 (3H, s, CH30), 5.30 (IH, m, 5-H), 6.9 + 7.6 (4H, AB , JAβ 9.0 Hz, ArH) ppm.
Example 12 5- (Azepane-1-ylmethy1 ) -3- ( 4-methylphenyl ) -4 , 5- -dihydroisoxazole hydrochloride
a) 5-(Azepane-l-ylmethyl)-3-(4-methyl- phenyl ) -4 , 5-dihydroisoxazole
The title compound is prepared from 50 mmoles of 4-methylbenzhydroxamic chloride and 100 mmoles of N-allylazepane by the method described in Example 2, part a). The title compound is obtained as an oil.
Yield: 52.2 %.
H-NMR (CDC13): £ 1.58-1.69 (8H, m, azepane
3-, 4-, 5- and 6-H2), 2.36 (3H, s, CH3 ) ,
2.84-2.90 (6H, m, N(CH2)3), 3.15 + 3.39 (2H,
ABX, J,„ 16.7 Hz, JΛV 10.5 Hz, JDV 8.0 Hz, ArS AX rSX
4-H2), 4.88 (IH, m, 5-H), 7.18 + 7.54 (4H, AB, JΛr, 8.1 Hz, ArH) ppm.
C-NMR (CDC13): £ 21.30 (CH3), 26.97 + 27.16 (azepane C-3, C-4, C-5 and C-6), 39.03 (C-4), 55.56 (N(CH2)2), 60.58 (5-CH2), 79.42 (C-5), 126.50, 129.23 (ar. CH), 126.71 (ar. C-l), 139.36 (ar. C-4), 156.36 (C-3) ppm.
b) 5-( Azepane-1-ylmethyl ) -3-( 4 -methyl- phenyl ) -4 , 5-dihydroisoxazole hydrochloride
The title compound is prepared using the method described in Example 2, part b). Yield: 83.3 %. M.p. : 155-156 °C. Analysis: for C17H2-.C1N20 (308.85)
C H N Cl (ionic) calculated: 66.11 %, 8.16 %, 9.07 %, 11.48%; found: 65.66 %, 8.20 %, 9.14 %, 11.52%. IR (KBr): V 2800-2400 (NH+), 1610, 1450, 1410, 1350, 850, 790 cm"1.
II-NMR (CDC13 + DMS0-d6): <_T 1.8 (8H, br, azepane 3-, 4-, 5- and 6—II„ ) , 2.35 (3H, s, CH3), 3.4 (8H, m, N+(CH2)2 and 4-H2), 5.3 (1H, m, 5-H), 7.2 + 7.6 (4H, AB, J"AB 8.0 Hz,
Aril), 11.1 (III, br, NH+) ppm.
Example 13
1- ( 2-Methoxyphenyl ) -4-/3- ( 4-methoxyphenyl ) -4 , 5- dihydroisoxazole- 5-ylmethyl /piperazine hydrochloride a) l-( 2-Methoxyphenyl) -4-/3- ( 4-methoxyphenyl ) -4 , 5-dihydroisoxazole-5-ylmethyl/piperazine
The title compound is prepared from 50 mmoles of 4-methoxybenzhydroxamic chloride and 50 mmoles of l-allyl-4- ( 2-methoxy ) - piperazine by the method described in Example
2 , part a ) .
Yield: 65.8 %.
M.p. : 109-112 °c.
Analysis: for C22H27N303 (381.47)
C H N calculated: 69.27 %, 7.13 %, 11.02 %; found: 69.47 %, 6.95 %, 10.81 %.
IR (KBr): V 2997, 2943, 2815, 1609, 1502,
1462, 1421, 1382, 1356, 1306, 1241, 1181,
1136, 1109, 1044, 1027, 934, 898, 832, 734,
604, 555, 514 cm"1.
■""H-NMR (CDC13): £ 2.5-2.9 (6H, m, N(CH2) ),
3.1 (4H, br, (CH2)2NAr), 3.1-3.5 (2H, m, 4-H2),
3.83 + 3.85 (6H, s, 2 x 0CH3), 4.9 (IH, ,
5-H), 6.77-7.00 (4H, m, NArH ) , 6.91 + 7.62
(4H, AB, JΛΏ 8.9 Hz, 3-ArH) ppm. ArS
13 C-NMR (CDC13): £ 39.05 (C-4), 50.38 + 53.82 (N(CH2CH2N), 55.12 (2 x OCH3 ) , 61.81 (5-CH2), 79.02 (C-5), 111.00, 117.95, 120.75, 122.65 (N-ar. CH), 113.87, 127.97 (3-ar. CH ) , 122.04 (3-ar. C-l), 141.09 (N-ar. C-l), 152.05 (N-ar. C-2), 155.82 (C-3), 160.64 (3-ar. C-4) ppm.
b) 1- ( 2-Methoxyphenyl ) -4-/3- ( 4-methoxyphenyl ) -4 , 5-dihydroisoxazole-5-ylmethyl/- piperazine hydrochloride
The title compound is prepared using the method described in Example 2, part b). Yield: 99 %. M.p. : 205-208 °C. Analysis: for C22H28C1N.,03 (417.94)
C H N CM ionic) calculated: 63.23 %, 6.75 %, 10.05 %, 8.48%; found: 63.19 %, 7.03 %, 9.85 %, 8.49%. IR (KBr): Y1 2800-1900 (NH+), 1610, 1480, 1380, 1240, 1180, 1000, 810 cm"1. ■""H-NMR (DMS0-d6): <£ 3.2-3.6 (12H, br m, CH2N+(CH2CH2)2N and 4-H2), 3.8 (6H, s, 2 x OCH ) , 5.3 (IH, m, 5-H), 5.6 (IH, br, NH+ ) , 6.8 (4H, m, N-ArH), 6.9 + 7.6 (4H, AB, JAβ 8.5 Hz, 3-ArH) ppm.
Example 14 l-/3-( 4-Methylphenyl ) -4 , 5-dihydroisoxazole-5- -ylmethyl/-4- ( 2-methoxyphenyl ) piperazine dihydrochloride a) l-/3-(4-Methylphenyl)-4, 5-dihydroisoxazole- -5-ylmethyl/-4- ( 2-methoxyphenyl ) piperazine The title compound is prepared from 50 mmoles of 4-methylbenzhydroxamic chloride and 50 mmoles of l-allyl-4- ( 2-methoxyphenyl ) - piperazine by the method given in Example 2 , part a ) . Yield: 64.1 %. M.p. : 84-86 °C.
Analysis: for C 22H27N3°2 <365-48)
C H N calculated: 72.30 %, 7.45 %, 11.50 %; found: ' 72.00 %, 7.65 %, 11.34 %. IR (KBr): V 2949, 2831 (CH), 1593, 1501, 1462,
1238, 1178, 1142, 1028, 918, 878, 827, 750
II-NMR (CDCl ): £ 2.36 (3H, s, CH ) , 2.66
+ 2.77 (2H,' ABX,' JAΛnB 11.0 Hz,' J"AX 6.8 Hz,'
Jβχ 7.25 Hz, 5-CH2), 2.80 (4H, m, N(CI-2)2), 3.10 (4H, , (CH2)2NAr), 3.21 + 3.40 (2H, ABX, JAβ 16.8 Hz, JAχ 9.6 Hz, Jβχ 7.2 Hz, 4-H2), 3.86 (3H, s, CH30), 4.95 (IH, m, 5-H), 6.85-7.05 (4H, , N-ArH), 7.21 + 7.57 (4H, AB, JΛD 8.3 Hz, 3-ArH) ppm.
"1 "3
C-NMR (CDCl ): £ 21.19 ( CH ) , 38.87 (C-4), 50.36 + 53.79 (N( CH2CH2 ) 2N ) , 55.11 (CH30), 61.77 (5-CH2), 79.13 (C-5), 110.97, 117.91, 120.72, 122.62 (N-ar. CH), 126.36, 129.12 (3-ar. CH), 126.61 (3-ar. C-l), 139.94 (3-ar. C-4), 141.08 (N-ar. C-l), 152.02 (N-ar. C-2), 156.19 (C-3) ppm. b) 1-/3- ( 4-Methylphenyl ) -4 , 5-dihydroisoxazole- -5-ylmethyl/-4-( 2-methoxyphenyl ) piperazine dihydrochloride
The title compound is prepared using the method described in Example 2, part b). Yield: 92.3 %. M.p. : 219-221 °C. Analysis: for C22H2gCl2N302 (438.40)
C H N Cl (ionic) calculated: 60.27 %, 6.67 %, 9.58 %, 16.17%; found: 60.44 %, 6.50 %, 9.68 %, 15.87%. IR (KBr): V 2945 ( CH ) , 2800-1800 (NH+), 1610, 1514, 1501, 1356, 1298, 1265, 1015, 895, 820, 754 cm"1.
XH-NMR (DMS0-d6): £ 2.35 (3H, s, CH3), 3.2-3.8 (12H, m, CH2N+(CH2CH2)2N + -H2), 3.81 (3H, s, CH 0), 5.4 (IH, m, 5-H), 6.8-7.1 (4H, m, N-ArH), 7.20 (IH, br, NH+ ) , 7.29 + 7.58 (4H, AB, J 8.1 Hz, 3-ArH), 11.76 (IH, br, NH+ ) ppm.
Example 15 1- ( 2-Methoxyphenyl ) -4-/3- ( 4-trifluoromethylphenyl ) -4 , 5-dihydroisoxazole-5-ylmethyl/- piperazine hydrochloride a) l-( 2-Methoxyphenyl ) -4-/3- ( 4-trifluoromethylphenyl ) -4 , 5-dihydroisoxazole-5-yl- methyl/piperazine
The title compound is prepared from 50 mitioles of 4- ( trifluoromethyl ) benzhydroxamic chloride and 50 mmoles of l-allyl-4- ( 2- -methoxyphenyl ) piperazine by the method described in Example 1, part a). Yield: 27.6 %. M.p. : 114-117 °C.
Analysis: for C 22H24F3N3°2 <423-87)
C H N calculated: 63.00 %, 5.77 %, 10.02 % ; found: 62.92 %, 5.75 %, 9.85 %. IR (KBr): 2980, 2822 (CH), 1618, 1596, 1501, 1450, 1323, 1298, 1236, 1165, 1109, 1024, 895, 841, 754 cm"1.
"""H-NMR (CDCl ): S 2.75-2.80 (6H, m, N ( CH ) ) , 3.08-3.12 (4H, m, (CH2) NAr), 3.30 + 3.45
(2H, ABX, _τ 18.0 Hz, ,τ 10.2 Hz, J„v 8.2 ' ' AB AX ' BX
Hz, 4-H ) , 3.86 (3H, s, CH30), 5.05 (IH, m,
5-H), 6.87-7.00 (4H, m, N-ArH), 7.66 + 7.80
(4H, AB, J„n 8.9 Hz, 3-ArH) ppm.
C-NMR (CDCl ): £ 38.34 (C-4), 50.41 + 53.90
(N(CH2CH2)2N) , 55.15 (CH30), 61.61 (5-CH2),
80.03 . (C-5), 111.02, 117.97, 120.78, 122.76
(N-ar. CH), 123.66 (q, Jo__r 272.1 Hz, CF J,),
125.46 (q, J* 4.4 Hz, 3-ar. C-3 + C-5), 126.71
Cr
(3-ar. C-2 + C-6), 130.90 (q, J n 32.3 Hz,
Cr
3-ar. C-4), 132.94 (3-ar. C-l), 141.06 (N-ar. C-l), 152.06 (N-ar. C-2), 155.32 (C-3) ppm.
b) l-( 2-Methoxyphenyl)-4-/3- ( 4-trifluoromethylphenyl ) -4, 5-dihydroisoxazole-5-yl- methyl/piperazine hydrochloride
The title compound is prepared using the method described in Example 1, part b). Yield: 97.5 %.
M.p. : 234-236 °C.
Analysis: for C22H25C1F3 302 (455.91)
C H N CM ionic) calculated: 57.96 %, 5.53 %, 9.22 %, 7.78%; found: 57.96 %, 5.50 %, 9.36 %, 7.93%. IR (KBr): 2968 ( CH ) , 2800-1800 (NH+), 1613, 1503, 1457, 1327, 1266, 1169, 1122, 1070, 1016, 971, 900, 844, 757, 466 cm"1. """H-NMR (DMSO-dg): & 3.3-3.8 (12H, m, CH2N+(CH2CH2)2N + 4-H2), 3.83 (3H, s, CH30),
5.5 (IH, m, 5-H), 6.8-7.1 (4H, m, N-ArH),
7.2200 ((IIHH,, bbrr,, NNHH++)) ,, 7.86 + 7.90 (4H, AB, JAβ 5 Hz, 3-ArH) ppm.
Example 16 1-/ 3- ( 4-Fluorophenyl ) -4 , 5-dihydroisoxazole-5- -ylmethyl/-4- ( 2-methoxyphenyl ) piperazine dihydrochloride a) l-/3-( 4-Fluorophenyl ) -4 , 5-dihydro- isoxazole-5-ylmethyl/-4-( 2-methoxyphenyl ) - piperazine
The title compound is prepared from 50 mmoles of 4-fluorobenzhydroxamic chloride and 50 mmoles of l-allyl-4- ( 2-methoxyphenyl ) - piperazine by the method described in Example 1 , part a ) . Yield: 40.1 %. M.p. : 86-91 °C.
Analysis: for 2ιH24FN3°2 <369-44) C H N calculated: 68.27 %, 6.55 %, 11.36 %; found: 68.07 %, 6.81 %, 11.21 %.
IR (KBr): 2594, 2814 ( CH ) , 1603, 1502, 1451,
1411, 1354, 1299, 1244, 1173, 1139, 1119,
1023, 920, 892, 836, 749, 599, 547 cm"1.
H-NMR (CDC13): £ 2.73-2.81 (6H, m, N(CH2)3),
3.10 (4H, m, (CH2)2NAr), 3.20 + 3.39 (2H,
ABX, JAβ 16.6 Hz, JAχ 10.5 Hz, Jβχ 8.2 Hz,
4-H2), 3.85 (3H, s, CH30), 4.95 (IH, m, 5-H) ,
6.92-7.00 (4H, m, N-ArH), 7.07 + 7.66 (4H,
AB, JΛD 8.8 Hz, J__ 5.3 Hz, JD„ 8.7 Hz, 3-ArH) ArS Ar rSr ppm.
13C-NMR (CDC13): £ 38.72 (C-4), 50.29 + 53.75
(N(CH2CH2)2N) , 55.05 (CH30), 61.62 (5-CH2),
79.38 (C5), 110.94, 117.87, 120.68, 122.62
(N-ar. CH), 115.50 (d, JCF 22.5 Hz, 3-ar.
C-3 + C-5), 128.30 (d, JCF 8.6 Hz, 3-ar. C-2
+ C-6), 125.67 (d,
Figure imgf000069_0001
4.1 Hz, 3-ar. Cl ) ,
140.98 (N-ar. C-l), 151.96 (N-ar. C-2), 155.25 (C3), 163.36 (d, JCF 249.2 Hz, 3-ar. C-4) ppm.
b) 1-/3- ( 4-Fluorophenyl ) -4 , 5-dihydro- isoxazole-5-ylmethyl/-4- ( 2-methoxyphenyl ) - piperazine dihydrochloride
The title compound is prepared using the method described in Example 1, part b).
Yield: 70.0 %.
M.p. : 222.5-224 °C.
_-. o-> (442.36) Analysis: for C21H26Cl2 FN3 2 C H N Cl( ionic) calculated: 57.02 %, 5.91 %, 9.50 %, 16.03%; found: 56.83 %, 5.95 %, 9.41 %, 16.15%. IR (KBr): V 3030, 2998, 2850 ( CH ) , 2800-2100 (NH+), 1605, 1510, 1470, 1450, 1415, 1360, 1302, 1285, 1220, 1020, 980, 905, 840, 775, 650, 601, 548 cm"1.
■""H-NMR (CDC13 + DMSO-dg): £ 3.20-3.80 (12H, m, CH2N+(CH2CH2)2N + 4-H2), 3.85 (3H, s, CH30), 5.42 (IH, m, 5-H), 5.80-6.60 (2H, br, NH+), 6.80-7.90 (8H, m, ArH) ppm.
Example 17 1-/3- ( 4-Methylphenyl ) -4 , 5-dihydroisoxazole-5- -ylmethyl/-4-( 3 -trifluoromethylphenyl ) - piperazine hydrochloride a) 1-/3- ( 4-Methylphenyl ) -4 , 5-dihydro- isoxazole-5-ylmethyl/-4- ( 3-trifluoromethylphenyl ) piperazine
The title compound is prepared from 50 mmoles of 4-methylbenzhydroxamic chloride and 50 mmoles of l-allyl-4- ( 3-trifluoromethylphenyl ) piperazine by the method described in Example 2, part a). Yield: 63.8 %. M.p. : 135 °C. Analysis: for C22H2.F3 30 (403.45)
C • H N F calculated: 65.50 %, 6.00 %, 10.42 %, 14.13%; found: 65.42 %, 6.20 % , 10.11 %, 14.19%. IR (KBr): ^ 2833 ( CH ) , 1610, 1450, 1348, 1319, 1236, 1192, 1115, 947, 824, 781, 692 cm"1.
H-NMR (CDC13): 2.38 (CH , 2.62-2.85 (611, m, N(CH2)3), 3.24 (4H, m, (CH2) NAr), 3.21 + 3.41 (2H, ABX, J ΛΛXDJ 14.4 Hz, J"AX 12.0 Hz,
JπBXv 9.6 Hz, 4-H Z_), 4.95 (IH, m, 5-H), 7.05-7.40
(4H, m, N-ArH), 7.24 + 7.57 (4H, AB, J A_,0B 7.9
Hz, 3-ArH) ppm. 13 C-NMR (CDC13): £ 21.23 (CH3), 38.81 (C-4), 48.42 + 53.40 /N ( CH2CH2 ) 2N ) , 61.51 (5-CH2), 79.24 (C-5), 111.85, 115.57, 118.49, 129.34 (N-ar. CH), 126.42, 129.23 (3ar. CH ) , 126.57 (3-ar. C-l), 131.17 (q, J__r 31.7 Hz, N-ar.
C-3), 124.17 (q, _τ 272.6 Hz, CF.) , 140.12
Cr J
(3ar. C-4), 151.16 (N-ar. C-l), 156.33 (C-3) ppm.
b) 1-/3- ( 4-Methylphenyl ) -4 , 5-dihydro- isoxazole-5-ylmethyl/-4- ( 3-trifluoromethylphenyl ) piperazine hydrochloride
The title compound is prepared using the method described in Example 2, part b). Yield: 99.9 %. M.p. : 220-226 °C. Analysis: for C22H25C1F3N30 (439.91)
C H N F Cl" calculated:60.07%, 5.73%, 9.55%, 12.96%, 8.06%; found: 60.20%, 5.40%, 9.68%, 12.86%, 8.47%. IR (KBr): V 2985 (CH), 2800-1800 (NH+), 1610, 1497, 1450, 1356, 1325, 1169, 1126, 1076, 949, 908, 874, 816, 698 cm-1. """H-NMR (DMSO-d.) : £ 2.35 (3H, s, CH-. ) , 3.3-4.1 (12H, m, CH2N+(CH2CH2)2N + 4-H2 ) , 5.4 (IH, m, 5-II), 7.14-7.49 (411, , N-ArH), 7.29 + 7.59 (4H, AB, JAβ 7.9 Hz, 3-ArH), 11.87 (IH, br, NH ) ppm.
Example 18 1- ( 3-Trifluoromethylphenyl ) -4-/3- ( 4-trifluoromethylphenyl ) -4 , 5-dihydroisoxazole-5-ylmethyl/- piperazine hydrochloride a) l-( 3-Trifluoromethylphenyl ) -4-/3- (4- trifluoromethylphenyl ) -4 , 5-dihydro- isoxazole- 5-ylmethy1/piperazine
The title compound is prepared from 50 mmoles of 4-trifluoromethylbenzhydroxamic chloride and 50 mmoles of l-allyl-4- ( 3- -trifluoromethylphenyl ) piperazine by the method described in Example 1, part a). Yield: 20 %. M.p. : 81-83 °C.
Analysis: for C 22H21F6N30 (457-42>
C H N calculated: 57.77 %, 4.63 %, 9.19 %; found: 57.51 %, 4.40 %, 9.15 %. IR (KBr): 2831 ( CH ) , 1614, 1497, 1452, 1360,
1323, 1236, 1167, 1132, 1070, 1013, 951, 843 cm -1
H-NMR (DMSO-d6): i" 2.64-2.67 (611, m , N(CH2)3),
3.22 (4H, br, (CH2)2NAr), 3.30 + 3.56 (2H,
ABX, J_._ 17.6 Hz, JΛV 10.7 Hz, JDV 10.0 Hz, ArS Aλ rSΛ
4-H2), 5.05 (IH, m, 5H), 7.05-7.45 (4H, m, N-ArH), 7.81 + 7.90 (4H, AB , JAβ 8.4 Hz, 3-ArH) ppm.
13C-NMR (DMSO-d6): £ 38.06 (C-4), 47.65 + 53.03 (N(CH2CH2)2N) , 61.09 (5-CH2), 79.98 (C-5), 110.86, 114.60, 118.71, 129.96 (N-ar. CII), 125.71 (q, J__ 4.1 Hz, 3ar. C-3 + C-5), 127.30 (3-ar. C-2 + C-6), 124.05 (q, j C-,r_ 273 Hz, CF-.), 124.49 (q, J τr, 271.3 Hz, CF-.),
129.89 + 129.95 (2 x q, J C_r_ 32.0 Hz, 3-ar.
C-4 + N-ar. C-3), 133.50 (3-ar. C-l), 151.23 (N-ar. C-l), 156.00 (C-3) ppm.
b) l-(3-Trifluoromethylphenyl) -4-/3- ( 4- trifluoromethylphenyl ) -4 , 5-dihydro- isoxazole-5-ylmethy1/piperazine hydrochloride
The title compound is prepared using the method described in Example 1, part b).
Yield: 98.6 %.
M.p. : 254-256 °C.
Analysis: for C^H^ClFg -^O (493.88)
C H N Cl (ionic) calculated: 53.50 %, 4.49 %, 8.51 %, 7.18%; found: 53.39 %, 4.40 %, 8.51 %, 7.54%.
IR (KBr): 2985, 2890 (CH), 2800-2100 (NH+),
1618, 1497, 1450, 1414, 1329, 1256, 1169,
1126, 1072, 953, 916, 839, 793 cm"1.
"""II-NMR (DMS0-d6): £ 3.4-3.6 (10H, br m,
CH2N+(CH2CH2)2 ) , 3.49 + 3.78 (2H, ABX, JAβ
17.4 Hz, JAV 10.8 Hz, Jαv 9.7 Hz, 4-H ), 5.5 Aλ rSΛ Z
(111, m, 5-H), 7.14-7.49 (4H, m, NArH), 7.84
+ 7.90 (4H, JΛD 8.5 Hz, 3-ArH) ppm. ArS Example 19 1- ( 3-Chlorophenyl ) -4-/3- ( 4-methylphenyl ) -4 , 5- dihydroisoxazole- 5-ylmethy1 /piperazine hydrochloride a) l-( 3-Chlorophenyl)-4-/3-(4-methyl- phenyl ) -4 , 5-dihydroisoxazole-5-yl- methy1/piperazine
The title compound is prepared from 50 mmoles of 4-methylbenzhydroxamic chloride and 50 mmoles of l-allyl-4- ( 3-chloro- phenyl ) piperazine by the method described in Example 2, part a).
Yield: 68 %.
M.p. : 135-136 °C.
Analysis: for C21H .ClN30 (369.89)
C H N Cl calculated: 68.19 %, 6.54 %, 11.36 %, 9.58%; found: 68.21 %, 6.75 %, 11.23 %, 9.31%.
IR (KBr): 2953, 2822 (CH), 1596, 1564, 1485,
1453, 1384, 1355, 1276, 1236, 1142, 1107,
1036, 1006, 988, 941, 918, 883, 823, 762,
679, 550, 491 cm"1.
1H-NMR (CDC13): £ 2.36 ( CH ) , 2.66-2.74 (6H, m, N(CH2)3), 3.16-3.21 (4H, m, (CH^NAr),
3.20 + 3.4θ (2H, ABX, J AIDB 19.2 Hz, JAΛXV 9.6
Hz, JnBXΛ7 7.2 Hz, 4-H Z- , 4.95 (IH, m, 5-H),
6.73-6.88 + 7.11-7.23 (4H, m, N-ArH), 7.20 + 7.57 (4H, AB, Jnr, 8.0 Hz, 3-ArH) ppm.
C-NMR (CDC13): £ 21.23 (CH3), 38.77 (C-4), 48.33 + 53.36 (N( CH2CH2 ) 2 ) , 61.48 (5-CH2), 79.19 (C-5), 113.56, 115.36, 118.91, 129.78 (N-ar. CH), 126.38, 129.16 (3ar. CH), 126.53 (3-ar. C-l), 134.64 (N-ar. C-3), 140.01 (3-ar. C-4), 152.05 (N-ar. C-l), 156.25 (C-3) ppm.
b) l-(3-Chlorophenyl)-4-/3-(4-methyl- phenyl ) -4 , 5-dihydroisoxazole-5-yl- methyl/piperazine hydrochloride
The title compound is prepared using the method described in Example 2, part b). Yield: 99.9 %. M.p. : 219-222 °C.
Analysis: for.C2iH25C12N3° (406.36)
C H N Cl Cl" calculated:62.07%, 6.20%, 10.34%, 8.73%, 8.73%; found: 62.18% 6.10%, 10.29%, 8.91%, 8.77%. IR (KBr): V 2950 ( CH ) , 2800-1800 (NH+), 1610, 1497, 1450, 1356, 1325, 1169, 1126, 1076, 949, 908, 874, 816, 698 cm"1.
"""H-NMR (DMS0-d6): 2.35 (3H, s, CH3), 3.2-4.0 (12H, m, CH2N+(CH2CH2)2N + -H2), 5.4 (IH, m, 5-H), 6.8-7.3 (4H, m, N-ArH), 7.29 + 7.58
(4H, AB, JΛD 8.1 Hz, 3-ArH), 11.92 (IH, br, ArS
NH+) ppm. .
Example 20 1- ( 3-Chlorophenyl ) -4-/3- ( 4-trifluoromethylphenyl ) -4 , 5-dihydroisoxazole-5-ylmethyl/ - piperazine hydrochloride a) l-( 3-Chlorophenyl) -4-/ 3- (4-trifluoromethylphenyl ) -4 , 5-dihydroisoxazole- -5-ylmethyl /piperazine The title compound is prepared from 50 mmoles of 4-trifluoromethylbenzhydroxamic chloride and 50 mmoles of l-allyl-4- ( 3-chloro- phenyl )piperazine by the method described in Example 1, part a). Yield: 35 %. M.p. : 109-111 °C. Analysis: for C21H21C1F3N30 (423.87)
C H N calculated: 59.51 %, 4.99 %, 9.91 %; found: 59.40 %, 4.75 %, 9.58 %. IR (KBr): 2835 (CH), 1597, 1564, 1485, 1325,
1242, 1169, 1130, 1070, 943, 924, 843, 771
Figure imgf000076_0001
II-NMR (CDCl3): £ 2.69-2.75 ( 6H , m, N(CH2)3),
3.17-3.22 (4H, m, (CH2)2NAr), 3.21 + 3.38
(2H, ABX, JAβ 17.0 Hz, JAχ 10.5 Hz, Jβχ 8.2
Hz, 4-H2), 5.05 (IH, m, 5-H), 6.77-6.86 +
7.11-7.18 (4H, m, N-ArH), 7.66 + 7.78 (4H,
AB, J.,-, 8.2 Hz, 3-ArH) ppm.
C-NMR (CDC13): £ 38.27 (C-4), 48.46 + 53.50
(N(CH2CH2)2N) , 61.34 (5-CH2), 80.12 (C-5),
113.70, 115.54, 119.13, 129.87 (N-ar. CH ) ,
123.66 (q, Jo__r 271.1 Hz, CFJ. ) , 125.50, 126.72
(3-ar. CH), 131.01 (q, J„-r 32.7 Hz, 3-ar.
C-4), 132.87 (3-ar. C-l), 134.77 (N-ar. C-3), 152.09 (N-ar. C-l), 155.40 (C-3) ppm.
b) l-(3-Chlorophenyl) -4 -13- (4 -trifluoromethylphenyl ) -4 , 5-dihydroisoxazole-5-yl- methyl /piperazine hydrochloride The title compound is prepared using the method described in Example 1, part b). Yield: 76.3 %. M.p. : 224-227 °C. Analysis: for C21II22Cl2F3N30 (460.33)
C H N Cl (ionic) calculated: 54.79 %, 4.82 %, 9.13 %, 7.70%; found: 54.75 %, 4.80 %, 8.78 %, 7.88%. IR (KBr): ■) 2950, 2840 (CH), 2800-2100 (NH+), 1597, 1413, 1328, 1170, 1128, 1072, 1015, 949, 839, 776 cm1.
"""H-NMR (DMSO-d ): £ 3.2-4.2 (12H, , CH2N+(CH2CH2)2N + 4H2), 5.5 (IH, m, 5-H), 6.8-7.3 (4H, m, N-ArH), 7.86 + 7.90 (4H, AB,
ArS 8.2 Hz, 3-ArH), 11.81 (IH, br, NH+) ppm.
Example 21 1- ( 2-Furoyl ) -4-/3- ( 4-methylphenyl ) -4 , 5-dihydro- isoxazole-5-ylmethyl/piperazine hydrochloride
a) l-(2-Furoyl)-4-/3-(4-methylphenyl)-4,5- dihydroisoxazole-5-ylmethyl/piperazine
The title compound is prepared from 50 mmoles of 4-methylbenzhydroxamic chloride and 50 mmoles of l-allyl-4- ( 2-furoyl ) piperazine by the method described in Example 2, part a) .
Yield: 74.5 %. M.p. : 113-115 °C. Analysis: for c 2oH23N3°3 <353-42) C H N calculated: 67.97 %, 6.56 %, 11.89 % ; found: 67.70 %, 6.75 %, 11.76 %.
IR (KBr): V 2814 (CH), 1622 (CO), 1566, 1486,
1438, 1357, 1297, 1183, 1142, 1013, 923, 901,
824, 769,: 597, 551 cm"1.
"""H-NMR (CDC13): £ 2.38 (CH , 2.63-2.72 (6H, m, N(CH Z) J), 3.20 + 3.41 (2H, ABX, JA1DB 16.8
Hz, J Ά V
AX 12.0 Hz, 4-H~), 3.81 (4H, br s,
(CH ) NCO), 4.95 (IH, m, 5-H), 6.47 (IH, dd,
J 1.8 Hz, J34 3.4 Hz, furan-4-H), 6.98 (IH, dd, J 0.9 Hz, J 3.4 Hz, furan-3-H), 7.47
(IH, dd, J45 1.8 Hz, J35 0.9 Hz, furan-5-H),
7.21 + 7.57 (4H, AB, J__ 8.0 Hz, 3-ArH) ppm.
C-NMR (CDC13): J* 21.23 (CH3), 38,75 (C-4),
53.67 (N(CH2CH2)2N) , 61.41 (5-CH2), 79.89
(C-5), 111.04 (furanC-4), 116.08 (furan-C-3),
126.41, 129.20 (3-ar. CH ) , 126.49 (3-ar. C-l),
140.15 (3-ar. C-4), 143.44 (furanC-5), 147.71
(furan-C-2), 156.29 (C-3), 158.84 (C=0) ppm.
b ) 1- ( 2-Furoyl ) -4-/3- ( 4-methylphenyl ) -4 , 5- dihydro isoxazole-5-ylmethyl /piperazine hydrochloride
The title compound is prepared using the method described in Example 2, part b) . Yield: 98.3 %. M.p. : 208-210 °C . Analysis: for C2 H2.ClN30., (389.88): C H N Cl (ionic) calculated: 61.61%, 6.20%, 10.78%, 9.09%; found: 61.58%, 6.40%, 10.69%, 8.71%.
IR (KBr): V 2951 (CH), 2800-1800 (NH+), 1595
(CO), 1568, 1485, 1445, 1356, 1263, 1103,
945, 903, 872, 816 cm"1.
"""H-NMR (DMSO-dg): cT 2.35 (3H, s, CH3), 3.0-3.1
+ 4.4 (12H, m + br, 4-H2 + CH2N+ ( CH2CH2 ) 2N) ,
5.4 (IH, m, 5H), 6.67 (IH, dd, J54 1.7 Hz,
J34 3.3 Hz, furan-4-H), 7.13 (IH, dd J 3.3
Hz, J 3 0.8 Hz, furan-3-H), 7.28 + 7.57 (4H,
AB, JAπBr, 8.1 Hz, 3-ArH), 7.90 (IH, dd, J -. t-i
1.7 Hz, J,j- 0.8 Hz, furan-5-H) ppm.
Example 22
1- ( 2-Furoyl ) -4-/3- ( 4-trifluoromethylphenyl ) -
-4 , 5-dihydroisoxazole-5-ylmethyl/piperazine hydrochloride a) l-(2-Furoyl) -4-/ 3- (4-trifluoromethylphenyl ) -4 , 5-dihydroisoxazole-5-ylmethyl/piperazine
The title compound is prepared from 50 mmoles of 4-trifluoromethylbenzhydroxamic chloride and 50 mmoles of l-allyl-4- ( 2- -furoyl ) piperazine by the method described in Example 1, part a). Yield: 28 %. M.p. : 86-88 °C. Analysis: for c 2oH20F3N303 (407-38) C H N calculated: 58.97 %, 4.95 %, 10.31 %; found: 58.76 %, 4.75 %, 10.13 %.
IR (KBr): > 2920, 2808 (CH), 1630 (CO), 1485,
1436, 1333, 1300, 1182, 1157, 1072, 1016,
879, 845, 758 cm"1.
H-NMR (CDC13): £ 2.62-2.74 (6H, m, N(CH2)3),
3.24 + 3.44 (2H, ABX, J AΛDrS 16.6 Hz, JAΛXV 10.6
Hz, Jβχ 8.1 Hz, 4-H2), 3.81 (4H, br s, (CH2)2NCO), 5.05 (IH, m, 5-H), 6.48 (IH, dd, J54 1.6 Hz, J34 3.4 Hz, furan-4-H), 6.99 (lH, dd, J53 0.8 Hz, J43 3.4 Hz, furan-3-H), 7.48 (IH, dd, J45 1.6 Hz, J35 0.8 Hz, furan-5-H), 7.67 + 7.79 (4H, AB, J.D 8.4 Hz, 3-ArH) ppm.
C-NMR (CDC13): £ 38.15 (C-4), 53.66 (N(CH2CH2)2N) , 61.19 (5-CH2), 79.92 (C-5), 111.04 (furan-C-4), 116.12 (furan-C-3), 123.59 (q, JCF 272.3 Hz, CF3 ) , 125.45 (q, JCF 3.8 Hz, 3-ar. C-3 + C-5), 126.68 (3-ar. C-2 + C6), 131.44 (q, J O_r_ 32.8 Hz, 3-ar. C-4), 132.77
(3-ar. C-l), 143.47 (furan-C-5), 147.63 (furan-C-2), 155.36 (C-3), 158.81 (C=0) ppm.
b) l-(2-Furoyl) -4-/ 3- (4-trifluoromethylphenyl ) -4 , 5-dihydroisoxazole-5-yl- methy1 /piperazine hydrochloride
The title compound is prepared using the method described in Example 1, part a). Yield: 95.2 %. M.p. : 215-217 °C. Analysis: for C2oH21ClF3N303 (443.85) C H N Cl (ionic) calculated: 54.12 %, 4.77 %, 9.47 %, 7.99%; found: 54.47 %, 4.70 %, 9.27 %, 8.09%. IR (KBr): 2932 ( CH ) , 2800-2200 (NH+), 1624 (CO), 1486, 1430, 1328, 1291, 1171, 1114, 1071, 1015, 971, 843, 757, 467 cm"1. 1H-NMR (DMSO-d6): ^ 3.4-4.0 + 4.5 (12H, m + br, CH2N+(CH2CH2)2N + 4-H2), 5.5 (IH, m, 5-H), 6.68 (IH, dd, J 1.8 Hz, J34 3.4 Hz, furan-4-H), 7.13 (IH, d, J43 3.4 Hz, furan-3-H), 7.82-7.91 (5H, furan-5-H + 3ArH) ppm.
Example 23 3- ( 4-Methoxyphenyl ) -5- ( 2-morplιolinoethoxy- methyl ) -4 , 5-dihydroisoxazole hydrochloride a ) 3- ( 4-Methoxyphenyl ) -5- ( 2-morpholinoethoxy- inethyl ) -4 , 5-dihydroisoxazole
20 mmoles of 3- ( 4-methoxyphenyl ) -4 , 5- -dihydro-5-isoxazolemethanol are dissolved in 50 ml of anhydrous dioxane, then, 4.49 g (40 mmoles) of potassium tert . -butoxide , 0.6 g (4 mmoles) of anhydrous sodium iodide and 20 mmoles of N- ( 2-chloroethyl )morpholine hydrochloride are added. The reaction mixture is boiled for 3 days, while adding further 1.12 g (10 mmoles) of potassium tert . -butoxide to the mixture every day. The reaction mixture is cooled, ethyl acetate and water are added, the clear phases are separated, the organic phase is washed 3 times using 50 ml of water each time, dried over anhydrous magnesium sulfate, and evaporated. The residue is purified by chromatography over a 0.0630.2 mm gel of Kieselgel G or Kieselgel 60 in vacuo using a mixture consisting of 5 volumes of dichloromethane and 1 volume of acetone as the eluent.
Yield: 22 to 40 %.
While determining the melting point, the sample decomposes continuously.
IR (film): V 3000, 2910 ( CH ) , 1610, 1510,
1360, 1250, 1105 cm" .
"""H-NMR (CDCl ): £ 2.47 (4H, t, J 4.7 Hz,
N(CH2)2), 2.57 (2H, t, J 5.6 Hz, CH2N), 3.23
+ 3.35 (2H, ABX, J AAnB 16.55 Hz, JAΛXV 10.6 Hz,
J-BX 7.5 Hz, 4-H Z„), 3.57-3.71 (8H, m, 5-CH Z0CH Z
+ 0(CH2)2), 3.83 (CH30), 4.81-4.92 (IH, m,
5-H), 6.91 + 7.60 (4H, AB , J" 8.8 Hz, ArH)
AB ppm.
13C-NMR (CDC13): £ 36.07 (C-4), 53.77
(N(CH ) ), 55.09 (CH30), 57.97 (CH J), 66.61
(0(CH2)2), 69.09 + 71.84 (5-CH2OCH2), 79.49
(C-5), 113.96, 128.06 ( ar . CH ) , 121.94 (ar.
C-l), 155.90 (C-3), 161.00 ( ar . C-4) ppm.
b) 3- ( 4 -Methoxyphenyl ) -5- ( 2-morpholino- ethoxymethyl ) -4 , 5-dihydroisoxazole hydrochloride
To a mixture of 10 mmoles of the isoxazole base obtained as described above in part a) and 5 ml of 3N solution of hydrogen chloride in ethanol, after stirring for some minutes, anhydrous ether is added in an amount to precipitate the salt formed. The salt is filtered, washed with ether, and dried over phosphorus pentoxide under reduced pressure. Yield: 72.4 %. M.p. : 138-140 °C. Analysis: for C17H25C1N204 (356.85)
C H N Cl calculated: 57.22 %, 7.06 %, 7.85 %, 9.94%; found: 57.17 %, 6.91 %, 8.07 %, 9.58%. IR (KBr): s> 3050-2800 ( CH ) , 2700-2400 ( br NH+), 1590, 1505, 1240, 1120 cm"1. """H-NMR (CDCl ): £ 2.95-3.4 (8H, m, N(CH2) + 4-II2), 3.65 (311, s, 0CI'3 ) , 3.45-4.3 (8H, m , 5-CH2OCH2 + 0(CH2)2) , 4.75 (IH, m, 5-H]
6.75 + 7.45 (4H, AB, JAβ 8 Hz, ArH) ppm
Preparation of isoxazole derivatives of the formula lb
Example 24 1- ( 3-Phenylisoxazole-5-ylmethyl ) -4-methy1- piperazinium L-malate a ) 1- ( 3-Phenylisoxazole-5-ylmethyl ) -4- - ethylpiperazine
To a solution of 50 mmoles of pure 5-bromomethyl3-phenylisoxazole in 100 ml of anhydrous toluene, 150 mmoles of
N-methylpiperazine are added, then the reaction mixture is boiled for 8 hours. The ammonium bromide separated is filtered, and the reaction product is separated from the organic solution by extraction with a mixture consisting of 9 volumes of water and 1 volume of concentrated hydrochloric acid. The aqueous phase is made alkaline by adding 20 % aqueous sodium hydroxide solution, and the product is extracted with ether. The organic solution is dried over anhydrous magnesium sulfate, and evaporated. The residue is purified by chromatography over a 0.063-0.2 mm gel of Kieselgel 60 in vacuo using gradient elution starting with dichloromethane and finishing with a mixture consisting of 10 volumes of dichloromethane and 1 voJ ume of acetone. The title compound is obtained as an oil. Yield: 42.6 %.
IR (film): 3200, 3110, 3000, 2940, 2900, 2850, 2730 ( CH ) , 1600, 1580, 730, 660 cm"1.
H-NMR (CDC13): £ 2.28 (3H, s, NCH3 ) , 2.47 (4H, br, N(CH2)2), 2.60 (4H, m, (CH2)2), 3.72 (2H, s, 5-CH2), 6.49 (IH, s, 4-H), 7.40-7.50 (3H, m, ArH), 7.70-7.90 (2H, m,
ArH) ppm. '
13 r
C-NMR (CDCl3): ci 45.50 (NCH3), 52.44
(N(CH2)2), 52.92 (5-CH2), 54.47 (N(CH2)2),
100.98 (C-4), 126.45, 128.57, 129.63 ( ar .
CH), 128.84 (ar. C-l), 162.04 (C-3), 169.71
(C-5) ppm.
b) 1- ( 3-Phenylisoxazole-5-ylmethyl ) -
-4-methylpiperazine dihydrochloride 10 m oles of the isoxazole base obtained as described above in part a) are dissolved in ether or a mixture of ether and ethanol or pure ethanol to obtain a solution having a concentration of 1 mmole/ml. The solution is acidified by introducing anhydrous hydrogen chloride gas or adding 5 ml of 3N solution of hydrogen chloride in ethanol. The reaction mixture is stirred for some minutes, the product separated is filtered, washed with ether, and dried over phosphorus pentoxide at 40 C under reduced pressure. If desired, the product is recrystallized from ethanol. Yield: 87.4 %. M.p.: 200-202 °C (ethanol). Analysis: for C15H21C12N30XH20 (348.27)
C H N Cl calculated: 51.73 %, 6.66 %, 12.07 %, 20.36%; found: 51.87 %, 6.41 %, 12.22 %, 20.26%. IR (KBr): V 3200, 3030 (CH), 2800-2000 br (NH+) cm"1.
H-NMR (D20): £ 3.25 (3H, s, NCH3), 3.60-4.00 (8H, m, N(CH2CH2)2 ) , 4.85 (2H, s, 5-CH2), 7.30 (IH, s, 4-H), 7.45-7.80 (3H, m, ArH), 7.80-8.10 (2H, m, ArH) ppm.
c ) 1- ( 3-Phenylisoxazole-5-ylmethyl ) -4 -methyl- piperaziniu L-malate
10 mmoles of the isoxazole base obtained as described above in part a) are dissolved in 10 ml of pure ethanol. To the solution obtained, a solution of 1.4 g (10.4 mmoles) of L-malic acid in 10 ml of pure ethanol are added. The reaction mixture is stirred for an hour, the product separated is filtered, washed with ether, and dried over phosphorus pentoxide at 40 C under reduced pressure. Yield: 94.3 %. M.p.: 133-134 °C. Analysis: for C 19 H 25N3°6 (391-42)
C H N calculated: 58.30 %, 6.44 %, 10.74 %; found: 58.39 %, 6.45 %, 10.44 %. IR (KBr): 3400-3200 (NH+), 2880 ( CH ) , 1710 (C00H), 1600 br ( COO" ) cm"1. ""•H-NMR (DMSO-dg): £ 2.42 (3H, s, NCH3 ) , 2.38
+ 2.56 (2H, ABX, J A_._r,S 15.6 Hz, JAΛλV 7.2 Hz,
JπBX7 6.0 Hz, CH Z-C00), 2.50-2.60 (4H, m,
N(CH2)2), 2.71 (4H, m, N(CH2)2), 3.78 (2H, s, 5-CH2), 4.08 (IH, dd, J 7.2 Hz, J 6.0 Hz, CHOH), 7.0 (IH, s, 4-H), 7.50-7.55 (3H, m, ArH), 7.858.00 (2H, , ArH) ppm.
Example 25 l-Methyl-4-/3- ( 4-methoxyphenyl ) isoxazole-5-yl- methyl/piperazinium L-malate a) l-Methyl-4-/3- ( 4-methoxyphenyl ) - isoxazole-5-ylmethyl /piperazine
The title compound is prepared from 50 mmoles of 5-bromomethyl-3- ( 4-methoxyphenyl ) - isoxazole by the method described in Example 24 , part a) . Yield: 64.6 %.
M.p. : 95-101 °C.
Analysis: for C16H21N202 (287.36)
C H N calculated: 66.88 %, 7.36 %, 14.62 %; found: 66.69 %, 7.36 %, 14.21 %. IR (KBr): 1614, 1527, 1429, 1250, 1170 cm"1 """H-NMR (DMS0-d6): <£ 2.15 (3H, s, NCH3 ) , 2.47 (4H, br, N(CH2)2), 2.49 (4H, br, N(CH2)2), 3.69 (2H, s, 5-CH2), 3.82 (3H, s, CH30), 6.88 (IH, s, 4-H), 7.06 + 7.82 (4H, AB, JAβ 8.8 Hz, ArH) ppm.
13C-NMR (DMSO-dg): £ 45.74 (NCH3), 52.36 (N(CH2)2), 52.57 (5-CH2), 54.66 ( (CH2)2), 55.36 (C1I30), 101.55 (C-4), 114.66, 128.30 (ar. CH), 121.33 (ar. C-l), 160.97 (ar. C-4), 161.66 (C-3), 170.27 (C-5) ppm.
b) l-Methyl-4-/3-( 4-methoxyphenyl ) - isoxazole-5-ylmethyl/piperazine dihydrochloride
The title compound is prepared using the method described in Example 24, part b). Yield: 94.6 %. M.p. : 216-230 °C .
"""H-NMR (DMSO-d + D20): <_J' 3.05 (3H, s, NCHO, 3.60 (8H, br, N ( CH2CH2 ) 2N ) , 3.90 (3H, s, CH30), 4.55 (2H, s, 5CH2), 7.2 (IH, s, 4-H), 7.20 + 7.80 (4H, AB, J 9.0 Hz, ArH) ppm. c ) l-Methyl-4-/3- ( 4-methoxyphenyl ) isoxazole- 5-ylmethyl/piperazinium L-malate
The title compound is prepared using the method described in Example 24, part c). Yield: 86.0 %. M.p. : 113-115 °C. Analysis: for C20H2_N307 X0.5H20 (430.46)
C H N calculated: 55.81 %, 6.56 %, 9.76 %; found: 55.65 %, 6.47 %, 9.73 %. """H-NMR (DMS0-d6): £ 2.44 (3H, s, NCH3), 2.38 + 2.57 (2H, ABX, J AΑrB, 15.6 Hz, JA_.X__ 7.2 Hz,
Jβχ 6.1 Hz, CH2C00), 2.59 (4H, br, (CH2)2), 2.75 (4H, br, N(CH2)2), 3.75 (2H, s, 5-CH2), 3.82 (3H, s, CH30), 4.08 (IH, dd, J 7.2 Hz, J 6.1 Hz, CH-OH), 6.91 (IH, s, 4-H), 7.06 + 7.81 (411, AB, Jx - 8.8 Hz, ArH) ppm.
Example 26 l-Methyl-4-/3-( 4-methylphenyl ) isoxazole- 5-yl- methyl /piperazine dihydrochloride a) l-Methyl-4-/3-( 4-methylphenyl ) isoxazole-
-5-ylmethyl /piperazine
The title compound is prepared from 50 mmoles of 5-bromomethyl-3- ( 4-methylphenyl ) - isoxazole by the method described in Example 24 , part a ) . Yield: 68.9 %.
IR (KBr): V 2920, 2795 ( CH ) , 1470, 1465, 1170, 1125, 810., 795 cm"1. H-NMR (CDCl3): £ 2.29 (3H, s, NCH3 ) , 2.39 (3H, s, CH3), 2.49 (411, br, (CH2)2), 2.61 (4H, br, N(CH2)2), 3.73 (2H, s, 5-CH2), 6.47 (IH, s, 4-H), 7.25 + 7.69 (4H, AB, JAβ 8.2 Hz, ArH) ppm.
C-NMR (CDCl3): cT 21.17 (CH3), 45.77 (NCH3), 52.75 (N(CH2)2), 53.24 ( 5-CH2 ) , 54.75 (N(CH2)2), 101.19 (C4), 126.23 ( ar . C-l), 126.64, 129.55 ( ar . CH ) , 140.03 (ar. C-4), 162.34 (C-3), 169.73 (C-5) ppm.
b ) l-Methyl-4-/3- ( 4-methylphenyl )isoxazole- -5-ylmethyl/ piperazine dihydrochloride
The title compound is prepared using the method described in Example 24, part b).
Yield: 87.2 %.
M.p. : 222-225 °C.
Analysis: for C16H23C12N30 (344.28)
C H N Cl calculated: 55.82 %, 6.73 %, 12.21 %, 20.60%; found: 55.53 %, 6.72 %, 11.86 %, 20.27%.
IR (KBr): γ> 3050-2900 ( CH ) , 2800-2200 ( br
NH+), 1605, 1450, 1410, 910, 780 cm"1.
H-NMR (DMS0-d6 + CDC13): £ 2.35 (3H, s, CH3)
2.8 (3H, s, NCH3), 3.0-3.7 (811, m,
N(CH2CH2)2N) , 4.4 (2H, s, 5-CH2), 7.1 (IH, s, 4-H), 7.3 + 7.7 (4H, AB, J AΛDrS 8.0 Hz, ArH) ppm. Example 27 1-Methy1-4-/ 3- ( 4-trifluoro ethy1 ) phenyl- isoxazol-5-ylmethyl/piperazine dihydrochloride a) l-Methyl-4-/3- ( 4-trifluoro ethyl ) phenyl- isoxazole-5-ylmethyl/piperazine
50 mmoles of 4-trifluoro ethylbenz- hydroxamic chloride are dissolved in 90 to 100 ml of absolute benzene, and 6.13 ml (55 mmoles) of a 80 % solution of propargyl bromide in toluene are added. To the mixture, 8.46 ml (J60 mmoles) of triethylamine are added at 10 C, drop by drop. The reaction mixture is left to reach room temperature, then it in boiled for J hour. After cooling, the organic phase is washed 3 times using 50 ml of water each time, dried over anhydrous magnesium sulfate, and evaporated. The residue is purified by chromatography over Kieselgel G using a mixture consisting of 10 volumes of hexane and 0.5 volumes of acetone as the eluent. In the mixed product obtained, the ratio of 3-aryl-5-bromomethylisoxazole and 3 , 4-diary1-1, 2 , 5-oxadiazol-N-oxide is determined by NMR. Then fivefold amount of N-methylpiperazine, calculated on the bromomethyl compound, is added to a 10 % solution thereof in toluene. The mixture is boiled while' following the reaction by thin layer chromatography (hexane/acetone 10:2, UV, FM). When the bromomethyl compound is consumed, the reaction mixture is diluted with toluene to the double of the volume thereof, washed twice with water, dried over anhydrous magnesium sulfate, and evaporated. The residue is purified by chromatography over a 0.0630.2 mm gel of Kieselgel 60 in vacuo using gradient elution starting with hexane and finishing with a maxture consisting of 10 volumes of hexane and 1 volume of acetone. Yield: 60.3 %. M.p. : 72-75 °C.
Analysis: for C 16 H 18 F3N3° <325-33)
C H N calculated: 59.07 %, 5.58 %, 12.92 %; found: 58.85 %, 5.60 %, 12.75 %.
IR (KBr): 3150, 3020, 2990, 2910, 2890 ( CH ) ,
1600, 1100, 1000, 840, 800 cm-1.
■""II-NMR (CDCl.,): £ 2.30 (311, s, NCI^), 2.49
(4H, br, N(CH2)2), 2.62 (4H, br, N(CH2)2),
3.76 (2H, s, 5-CH2), 6.56 (IH, s, 4-H), 7.70
+ 7.92 (4H, AB, J__ 8.27 Hz, ArH) ppm. , AB
C-NMR (CDC13): £ 45.57 (NCH-j), 52.59
(N(CH2)2), 53.02 (5-CH2), 54.56 (N(CH2)2),
101.06 (Q-4), 123.69 (q, J__ 272.9 Hz, CF,), or -J
125.67 (d,
Figure imgf000091_0001
3.7 Hz, ar. C-3 + C-5), 126.91
(ar. C-2 + C-6), 131.54 (q, „ 0-_, 32.7 Hz ar .
C4), 132.44 (ar. C-l), 161.05 (C-3), 170.61 (C-5) ppm.
b) l-Methyl-4-/3- ( 4-trifluoromethyl ) phenyl- isoxazole- 5-ylmethyl /piperazine dihydrochloride 10 mmoles of the isoxazole base obtained as described above in part a) are dissolved in ether or in a mixture of ether and ethanol or in pure ethanol to obtain a solution having a concentration of 1 mmole/ml. The solution is acidified by introducing either anhydrous hydrogen chloride gas or adding 5 ml of 3N solution of hydrogen chloride in ethanol. The reaction mixture is stirred for some minutes, the product separated is filtered, washed with ether, and dried over phosphorus pentoxide at 40 °C under reduced pressure. If desired, the product is recrystallized from ethanol. Yield: 98 %. M.p. : 155-157 °C. Analysis:_ for C16H20Cl2F3N30 (398.26)
C H N Cl calculated: 48.25 %, 5.06 %, 10.55 %, 17.80%; found: 48.29 %, 5.38 %, 10.43 %, 17.75%. IR (KBr): 3050, 3005, 2980 (CH), 2800-2100 (br NH+), 1620, 1460, 1430, 1310, 1150, 1110, 1100, 1050, 930, 830, 800 cm"1.
"""H-NMR (DMSO-dg + CDCl3): £ 2.80 (3H, s, CH3 ) , 2.903.92 (8H, m, N( CH2CH2 ) 2N) , 4.05 (2H, s, 5-CH2), 7.13 (IH, s, 4-H), 7.81 + 8.06 (4H, AB, J AΛTBD 8.0 Hz, ArH) ppm.
Example 28 bis(l-/3-( 4-Bromophenyl ) isoxazol-5-ylmethyl 1-4- -methylpiperazinium ) L-malate a) 1-/3- ( 4-Bromophenyl ) isoxazole-5-ylmethyl/- 4-methylpiperazine
The title product is prepared from 50 mmoles of 4-bromobenzhydroxamic chloride by the method described in Example 27, part a). Yield: 78.2 %. M.p.: 115-117 °C. Analysis: for C15H18BrN30 (336.23)
C H N Br calculated: 53.58 %, 5.40 %, 12.50 %, 23.76%; found: 53.25 %, 5.24 %, 12.40 %, 23.94%. IR (KBr): 3150, 2980, 2890, 2850 ( CH ) , 1610, 1600, 1420, 900, 800 cm" .
H-NMR (CDC13): J" 2.41 (311, s, NCH3 ) , 2.69 (8H, br, N(CH2CH2)2N) , 3.76 (2H, s, 5-CH2), 6.49 (IH, s, 4-H), 7.57 + 7.67 (4H, AB , JftB 8.54 Hz, ArH) ppm.
13C-NMR (CDC13): £ 45.13 (NCH.-), 51.87 (N(CH2)2), 52.90 (5-CH2), 54.35 (N(CH2)2), 101.16 (C-4), 124.15 ( ar . C-4), 127.88 ( ar . C-l), 128.18, 132.04 (ar. CH ) , 161.42 (C-3), 169.93 (C-5) ppm.
b) bis(l-/3-( 4-Bromophenyl ) isoxazole-5-ylmethyl /-4-methylpiperaziniurn) L-malate
10 mmoles of the isoxazole base obtained as described above in part a) are dissolved in 10 ml of pure ethanol, and, to the solution obtained, a solution of 1.4 g (10.4 mmoles) of L-malic acid in 10 ml of pure ethanol are added. The reaction mixture is stirred for 1 hour, the product separated is filtered, washed with ether, and dried over phosphorus pentoxide at 40 C under reduced pressure.
Yield: 85.7 %.
M.p.: 184-185 °C (ethanol).
Analysis: for C34H42Br2Ng07 (806.55)
C H N Br calculated: 50.63 %, 5.25 %, 10.42 %, 19.81%; found: 50.40 %, 5.18 %, 10.26 %, 19.25%. IR (KBr): V 3020, 3010, 2900 (CH), 2600-2000 (br NH+) , 1620 cm" .
H-NMR (CDC13 + DMSO-dg): £ 2.35 (6H, s, 2 x NCH3), 2.42-2.80 (18H, m, CH2C00 + 2 x N(CH2CH2)2N) , 3.73 (4H, s, 2 x 5-CH2), 4.05 (IH, m, CHOH), 5.30 ( r XH), 6.82 (2H, s, 2 x 4-H), 7.64 + 7.76 (8H, AB, JAβ 8.0 Hz, 2 x ArH) ppm.
Example 29 1-/ 3- ( 4-Methoxyphenyl ) isoxazole-5-ylmethyl/- piperazine dihydrochloride a ) 1-/3- ( 4-Methoxyphenyl ) isoxazole-5-yl- methyl /piperazine
150 mmoles of piperazine are added to a solution of 50 mmoles of pure 5-bromo- methyl-3- ( 4-methoxyphenyl ) isoxazole in 100 ml of anhydrous toluene, and the reaction mixture is boiled for 8 hours. The ammonium bromide separated is filtered, and the organic solution is extracted with a mixture consisting of 9 volumes of water and 1 volume of concentrated hydrochloric acid to obtain the product. The aqueous phase is made alkaline by adding 20 % sodium hydroxide solution, and the product is extracted with ethyl acetate. The organic solution is dried over anhydrous magnesium sulfate, and evaporated. From the residual crude product, the main part of piperazine is removed by sublimation under reduced pressure (10 mm Hg, 110 C). The residue is boiled in 50 ml of 3N solution of hydrpgen chloride in ethanol to obtain the hydrochloride. After cooling, the product separated is filtered, 25 ml of ethanol are added and the mixture is boiled again. After cooling, the product separated is filtered, and dried over phosphorus pentoxide at 40
C under reduced pressure. Over the hydrochloride obtained - being free from piperazinium dichloride - 50 ml of ethyl acetate are added, and the stirred mixture is made alkaline by adding 20 % aqueous sodium hydroxide, solution . The organic phase is separated, washed with water, dried over anhydrous magnesium sulfate, and evaporated. Yield: 66.6 %.
IR (KBr): l613, 1529, 1463, 1431, 1255, 1179 cm"1.
"""H-NMR (DMS0-d6): £ 2.39 (4H, m, (CH2)2), 2.73 (IH, br NH ) , 3.67 (4H, br, N(CH2)2), 3.68 (2H, s, 5-CH2), 3.82 (3H, s, CH30), 6.88 (IH, s, 4-H), 7.06 + 7.81 (4H, AB, J AΛDrS 8.8 Hz, ArH) ppm.
13C-NMR (DMSO-d6): £ 45.36 ( UN ( CI_2 ) 2 ) , 53.18 (5-CH2), 53.65 (N(CH2)2), 55.40 (CH30), 101.63 (C-4), 114.69, 128.30 ( ar . CH), 121.32 ( ar . C-l), 160.97 (ar. C-4), 161.62 (C-3), 170.26 (C-5) ppm.
b) 1-/3- ( 4-Methoxyphenyl ) isoxazole-5-ylmethyl/piperazine dihydrochloride
10 mmoles of the isoxazole base obtained as described above in part a) are dissolved in ether or a mixture of ether and ethanol or in pure ethanol to obtain a solution having a concentration of 1 mmole/ml. The solution is acidified by introducing either anhydrous hydrogen chloride gas or adding 5 ml of 3N solution of hydrogen chloride in ethanol. The reaction mixture is stirred for some minutes, the product separated is filtered, washed with ether, and dried over phosphorus pentoxide at 40 C under reduced pressure. If desired, the product is recrystallized from ethanol. Yield: 94.5 %. M.p. : 216-230 °C. Analysis: for C1 -.H21Cl2N.,02 X0.5H20 (355.27)
C II N Cl calculated: 50.71 %, 6.24 %, 11.83 %, 19.96%; found: 50.94 %, 6.16 %, 11.86 %, 19.99%. """H-NMR (DMS0-d6): ^ 3.42 (8H, br, N ( CH2CH2 ) 2N) , 3.83 (3H, s, CH30), 4.61 (2H, s, 5-CH2), 7.29 (1H, s, 4-H), 7.10 + 7.83 (4H, AB, JAβ 8.8 Hz, ArH), 9.92 (2H, br, NH+ ) ppm.
Example 30 1-/3- ( 4-Methylphenyl ) isoxazole-5-ylmethyl/- piperazine dihydrochloride a ) 1-/3- ( 4-Methylphenyl )isoxazole-5-yl- methy1 /piperazine
The title compound is prepared from 50 mmoles of 5-bromomethyl-3- ( 4-methylphenyl ) - isoxazole by the method described in Example 29 , part a ) . Yield: 68.8 %.
IR (KBr): 3000-2500 (NH), 1625, 1440, 1280, 810 cm" .
H-NMR (CDC13): £ 2.21 (IH, s, NH), 2.39 (3H, s, CH3), 2.53 (4H, t, J 4.6 Hz, N(CH2)2), 2.90-2.93 (4H, br , N(CH2)2), 3.71 (2H, s, 5-CH2), 6.47 (III, s, 4-H), 7.25 + 7.69 (4H, AB, JπD 8.1 Hz, ArH) ppm.
C-NMR (CDCl3): <£ 21.23 (CH3), 45.74 (HN(CH2)2), 53.81 (5-CH2), 53.99 (N(CH2)2), 101.10 (C-4), 125.01 (ar. C-l), 126.50, 129.39 (ar. CH), 139.87 (ar. C-4), 162.11 (C-3), 169.52 (C-5) ppm.
b) 1-/ 3- (4 -Methylphenyl) isoxazole-5-yl- methyl/piperazine dihydrochloride
The title compound is prepared using the method described in Example 29, part b). Yield: 80.1 %.
M.p. : 235-236 °C.
Analysis: for C15H21Cl2N30 (330.26)
C H N Cl calculated: 54.55 %, 6.41 %, 12.72 %, 21.47%; found: 54.36 %, 6.45 %, 12.52 %, 21.36%. IR (KBr): 3100-2000 ( br NH+), 1610, 1590, 1460, 1430, 950, 790 cm"1.
"""H-NMR (DMSO-dg + CDC13): £ 2.35 (3H, s, CH-j), 3.25 (4H, m, N(CH2>2), 4.0 (4H, m, N(CH2)2), 4.4 (2H, s, 5-CH2), 7.1 (IH, s, 4-H), 7.3 + 7.7 (4H, AB, JAβ 8 Hz, ArH) ppm.
Example 31 1- ( 2-Methoxyphenyl ) -4-/3- ( 4-methoxyphenyl ) - isoxazole-5-ylmethyl /piperazine dihydrochloride a) l-( 2-Methoxyphenyl ) -4-/3- ( 4-methoxyphenyl )ιsoxazole5-ylmethyl /piperazine
To a solution of 50 mmoles of 4-methoxy- benzhydroxamic chloride in 100 ml of anhydrous toluene, 8.46 ml (60 mmoles) of triethylamine, then a solution of 75 mmoles of 1- ( 2-methoxy- phenyl ) -4-propargylpιperazιne in 100 ml of anhydrous toluene are added at 0 C, drop by drop. The reaction mixture is stirred at room temperature for 2 days, then the mixture is diluted with water to dissolve the precipitate formed. The organic phase is washed 3 times using 50 ml of water each time, dried over anhydrous magnesium sulfate, and evaporated. The residue is purified by chromatography over a 0.063-0.2 mm gel of
Kieselgel 60 in vacuo using a mixture consisting of 10 volumes of hexane and 1 volume of acetone as the eluent.
Yield: 49.2 %.
M.p. : 104-105 °C.
Analysis: for C22H25N303 (369.46)
C H N calculated: 69.64 %, 6.64 %, 11.07 %; found: 69.30 %, 6.67 %, 10.96 %.
IR (KBr): > 2933, 2823 (CH), 1612, 1529, 1500,
1460, 1431, 1394, 1347, 1307, 1240, 1181,
1140, 1121, 1028, 1003, 948, 925, 905, 836,
821, 755, 528 cm"1.
"""H-NMR (CDC13): £ 2.8 (4H, br, N(CH2).2), 3.2
(4H, br, (CH2)2NAr), 3.8 (2H, s, 5-CH2), 3.85
(6H, s, 2 x 0CH3), 6.50 (IH, s, 4-H), 6.7-7.0
(4H, m, N-ArH), 6.97 + 7.75 (4H, AB, J A_B_ 8.8
Hz, 3-ArH) ppm.
13C-NMR (CDC13): 50.17 + 52.88 ( ( CH2CH2 ) 2N ) , 53.12 (5-CH2), 55.07 (2 x 0CH3 ) , 101.15 (C-4), 110.96, 117.98, 120.74, 122.80 (N-ar. CH ) , 114.03, 127.93 (3-ar. CH ) , 121.32 (3-ar. C-l), 140.78 (N-ar. C-l), 151.98 (N-ar. C-2), 160.68 (3-ar. C-4), 161.72 (C-3), 169.05 (C-5) ppm.
b) l-( 2-Methoxyphenyl)-4-/3-(4-methoxy- phenyl )isoxazole-5-ylmethyl/piperazine dihydrochloride
10 mmoles of the isoxazole base obtained as described above in part a) are dissolved in ether or a mixture of ether and ethanol or pure ethanol to obtain a solution having a concentration of 1 mmole/ml. The solution is acidified by introducing anhydrous hydrogen chloride gas or adding 5 ml of 3N solution of hydrogen chloride in ethanol. The reaction mixture is stirred for some minutes, the product separated is filtered, washed with ether, and dried over phosphorus pentoxide at 40 C under reduced pressure. If desired, the product obtained is recrystallized from ethanol . Yield: 95.3 %. M.p. : 207-210 °C.
Analysis: for C22π27C12N3°3 (452-38)
C H N Cl (ionic) calculated: 58.41 %, 6.02 %, 9.29 %, 15.67%; found: 58.29 %, 5.86 %, 9.13 %, 15.61%. IR (KBr): V 3010, 2980 ( CH ) , 2700-2000 (NH+), 1605, 1515, 1495, 1450, 1430, 1260, 1180, 1105, 1005, 845, 805, 780, 670 cm"1.
H-NMR (DMS0-d6): £ 3.40 (8H, m, N+(CH2CH2)2N+) , 3.85 (3H, s, CH-^0), 3.90 (3H, s, CH30), 4.65 (2H, s, 5-CH2), 5.5 (2H, br, NH+), 6.80-7.20 (6H, AB + m, ArH), 7.35 (IH, s, 4-H), 7.7 (2H, AB, 9.0 Hz, 3-ArH) ppm.
Example 32 l-/3-( 4-Methylphenyl ) isoxazole-5-ylmethyl/-4- - ( 2-methoxyphenyl ) piperazine dihydrochloride a ) 1-/3- ( 4-Methylphenyl )isoxazole-5-yl- methyl/-4- ( 2-methoxyphenyl ) piperazine Either 50 mmoles of N- ( 2-methoxyphenyl ) - piperazine obtained from the hydrochloride thereof through alkalization with sodium hydroxide, extraction with ethyl acetate, drying and evaporation, furthermore 8.46 ml
(60 mmoles) of triethylamine, or 50 mmoles of N- ( 2methoxyphenyl ) piperazine hydrochloride and 16.9 ml (120 mmoles) of triethylamine are added to a solution of 50 mmoles of pure
5-bromomethyl-3- ( 4-methylphenyl ) isoxazole in 100 ml of anhydrous toluene. The reaction mixture is boiled for 8 hours, then diluted with toluene to double volume, washed twice with water, dried over anhydrous magnesium su Ifcite, and evaporated. The residue is purified by chromatography over a 0.062-0.2 mm gel of Kieselgel 60 in vacuo using gradient elution starting with hexane and finishing with a mixture consisting of 10 volumes of hexane and 1 volume of acetone.
Yield: 78.2 %.
M.p. : 125-126 °C.
IR (KBr): V 3141 (4-H), 2998, 2923, 2814,
1614, 1594, 1501, 1449, 1432, 1389, 1346,
1304, 1244, 1181, 1145, 1125, 1060, 1027,
949, 927, 901, 817, 749, 512 cm"1.
■""H-NMR (CDC13): £ 2.39 (3H, s, CHj), 2.78
(4H, m, N(CH2)2), 3.13 (411, ra, (CH^N r),
3.79 (2H, s,.5-CH2), 3.84 (3H, s, OCH ) , 6.50
(IH, s, 4-H), 6.77-7.00 (4H, m, N-ArH), 7.25
+ 7.70 (411, AB, J AABt3 8.2 Hz, 3-ArH) ppm.
13C-NMR (CDCl3>: d 21.16 (CH3 ), 50.29 + 52.93 (N(CH2CH2)2N) , 53.25 (5-CH2), 55.10 (0CH3), 101.12 (C4), 110.99, 117.98, 120.75, 122.76 (N-ar. CH), 126.07 (3-ar. C-l), 126.43, 129.34 (3-ar. CH), 139.76 (3-ar. C-4), 140.89 (N-ar. C-l), 152.02 (N-ar. C-2), 162.05 (C-3), 169.41 (C-5) ppm.
b) 1-/3- ( 4-Methylphenyl ) isoxazole-5-yl- methyl/-4- ( 2-methoxyphenyl ) piperazine dihydrochloride
10 mmoles of the isoxazole base obtained as described above in part a) are dissolved in ether or a mixture of ether and ethanol or pure ethanol to obtain a solution having a concentration of 1 mmole/ml. The solution is acidified by introducing anhydrous hydrogen chloride gas or adding 5 ml of 3N solution of hydrogen chloride in ethanol. The reaction mixture is stirred for some minutes, the product separated is filtered, washed with ether, and dried over phosphorus pentoxide at 40 C under reduced pressure. If desired, the product obtained is recrystallized from ethanol . Yield: 92.3 %. M.p. : 224-228 °C. Analysis: for C22 II27C12N3°2 (436.38)
C H N Cl (ionic) calculated: 60.55 %, 6.24 %, 9.63 %, 16.25%; found: 59.96 %, 6.47 %, 9.57 %, 15.93%. IR (KBr): 2800-2200 (NH+), 1610, 1500, 1450, 1430, 1280, 1240, 795 cm-1.
"""H-NMR (DMS0-d6) : £ 2.4 (311, s, CII3 ) , 3.4
(8H, m, N+(CH2CH2)2N+) , 4.0 (3H, OCH3)., 4.;
(2H, s, 5-CH2) , 6.9 (IH, s, 4-H) , 6.8-7.5
( (44HH,, mm,, NN--AArrHH)),, 7.2 + 7.7 (4H, AB, JΛD 8.0
AB
Hz, 3-ArH) ppm.
Example 33 l-/3-(4-Methylphenyl) isoxazole-5-ylmethyl/-4- - ( 3-trifluoromethylphenyl ) piperazine hydrochloride a ) 1-/3- ( 4-Methylphenyl ) isoxazole-5-yl- methyl/-4- ( 3-trifluoromethylphenyl ) - piperazine
The title compound is prepared from 50 mmoles of 5-bromomethyl-3- ( 4-methylphenyl ) - isoxazole and 50 mmoles of N- ( 3-trifluoromethylphenyl ) piperazine hydrochloride by the method described in Example 32, part a). Yield: 81.2 %. M.p. : 98-99 °C.
IR (KBr): V 3131 (4-H), 2834, 2770, 1612, 1501, 1450, 1427, 1390, 1351, 1323, 1241, 1171, 1116, 1004, 945, 925, 890, 862, 812, 787, 722, 695, 670, 652, 517, 466 cm"1. •""H-NMR (CDC13): £ 2.38 (3H, s, CH3), 2.69-2.73 (411, m, N(CH2) ), 3.23-3.27 (4H, , (CI-2)2NAr), 3.77 (2H, s, 5-CH2), 6.50 (lH, s, 4-H), 7.00-7.10 (3H, m, N-ArH), 7.29-7.35 (lH, m, N-ArH), 7.25 + 7.70 (4H, AB, JAβ 8.2 Hz, 3-ArH) ppm. 13C-NMR (CDCl3): £ 21.24 (CHj), 48.47 + 53.21
(N(CH2CH2)2N) , 52.57 (5-CH2), 101.23 (C-4),
112.05, 115.80, 118.66 (N-ar. CH), 124.16
(q, JO__r 272.8 Hz, CFJ, ) , 126.03 (3-ar. C-l),
126.53, 129.44 (3-ar. CH), 129.44 (N-ar. CH), 131.25 (q, J O__r 32.0 Hz, N-ar. C-3), 140.01 (3-ar. C-4), 151.08 (N-ar. C-l), 162.22 (C-3),
169.28 (C-5) ppm.
b ) 1-/3- ( 4-Methylphenyl ) isoxazole-5-yl- methyl/-4- ( 3-trifluoromethylphenyl ) - piperazine hydrochloride
The title compound is prepared using the method described in Example 32, part b). Yield: 96.1 %. M.p. : 192-195 °C. Analysis: for C^H^CIF^O (436.89)
C H N Cl (ionic) calculated: 60.34 %, 5.29 %, 9.60 %, 8.10%; found: 60.20 %, 5.48 %, 9.39 %,'8.59%. IR (KBr): 2800-2200 (NH+), 1620, 1600, 1450, 1320, 1305, 1160, 1100, 920, 805 cm"1. """H-NMR (DMS0-d6): 2.3 (3H, s, CH3), 3.2-3.8 (8H, m, N+(CH2CH2)2N) , 4.7 (2H, s, 5-CH2),
7.1 (IH, s, 4-H), 7.0-7.5 (4H, m, N-ArH),
7.2 + 7.7 (4H, AB, J AΛπB 8.0 Hz, 3-ArH) ppm.
Example 34 1-/3- ( 4-Bromophenyl ) isoxazole-5-ylmethy1/-4- ( 3- -trifluoromethylphenyl/piperazine hydrochloride a ) 1-/3- ( 4-Bromophenyl ) isoxazole-5-yl- methyl /-4- ( 3-trifluoromethylphenyl /- piperazine
The title compound is prepared from 50 mmoles of 3- ( 4-bromophenyl ) -5- (bromomethyl ) - isoxazole and 50 mmoles of N- ( 3-trifluoromethylphenyl ) piperazine hydrochloride by the method described in Example 32, part a). Yield: 99.8 %. M.p. : 55-56 °C.
IR (film): 3120 (4-H), 2920, 2880, 2830, 1600, 1563, 1501, 1450, 1426, 1351, 1320, 1240, 1172, 1122, 1075, 1012, 946, 892, 863, 814, 788, 729, 695, 516 cm"1.
"""H-NMR (CDC13): £ 2.70-2.80 (4H, m, N(CH2)2), 3.20-3.30 (4H, m, (CH2)2NAr), 3.81 (2H, s, 5-C1I ) , 6.52 (111, s, 4-H), 6.95-7.10 (3H, m, N-ArH), 7.20-7.45 (IH, m, NArH), 7.60 + 7.68 (4H, AB, J AATBD 8.6 Hz, 3-ArH) ppm. C-NMR (CDC13): £ 48.53 + 52.64 ( N ( CH2CH2 ) 2N ) ,
53.22 (5-CH2), 101.15 (C-4), 112.16 (q, JCF
4.3 Hz), 115.93 (q, J C_r_ 4.1 Hz), 118.73 (N-ar.
CH), 124.16 (q, j"or 273.0 Hz, CFJ,), 124.20
(3-ar. C-4), 128.16 (3-ar. CH ) , 129.08 (3-ar. C-l), 129.46 (N-ar. CH), 131.32 (q, JCF 31.6 Hz, N-ar. C-3), 132.04 (3-ar. CH), 151.08 (N-ar. C-l), 161.40 (C-3), 169.95 (C-5) ppm.
b) 1-/3- ( 4-Bromophenyl )isoxazole-5-yl- methyl/ -4- ( trifluoromethylphenyl/- piperazine hydrochloride The title compound is prepared using the method described in Example 32,- part b). Yield: 60.7 %. M.p.: 190-191 °C (ethanol). Analysis: for C21H2 BrF.3ClN.3O (502.76)
C H N Cl (ionic) calculated: 50.16 %, 4.21 %, 8.36 %, 7.05%; found: 49.90 %, 4.33 %, 8.02 %, 7.50%. IR (KBr): v* 2800-2300 (NH+), 1620, 1600, 1450,
1420, 1350, 1300, 1160, 1090, 1055, 910, 670
Figure imgf000106_0001
"""H-NMR (DMS0-d6 + CDCl3): £ 3.30-3.80 (8H, m, N+(CH2CH2)2N) , 4.75 (2H, s, 5-CH2>, 7.09
(IH, s, 4-H), 6.90-7.50 (4H, m, N-ArH), 7.63
+ 7.72 (4H, AB, J AΛOB 8.0 Hz, 3-ArH) ppm.
Example 35
3- ( 4-Methoxyphenyl ) -5- ( pyrrolidine-1 -ylmethyl ) - isoxazole hydrochloride a ) 3- ( 4-Methoxyphenyl ) -5- ( pyrrolidine-1-ylmethyl ) isoxazole
The title compound is prepared from 50 mmoles of 5-bromomethyl-3- ( 4-methoxyphenyl ) - isoxazole and 150 mmoles of pyrrolidine by the method described in Example 24, part a). Yield: 99.2 %. M.p. : 33-36 °C . Analysis: for 15 H 18 N 2°2 <258.32)
C H N calculated: 69.74 %, 7.02 %, 10.84 %; found: 69.63 %, 7.19 %, 10.51 %. IR (KBr): 2963, 2794 ( CH ) , 1613, 1575, 1529, 1460, 1432, 1365, 1351, 1296, 1254, 1178, 1116, 1030, 949, 905, 836, 804, 602, 535 cm"1. """H-NMR (CDC13): •£ 1.81 (4H, m, pyrrolidine 3- and 4H2), 2.63 (4H, m, N(CH2)2), 3.80 (2H, s, 5-CH2), 3.82 (3H, s, CH30) , 6.44 (IH, s, 4-H), 6.95 + 7.73 (4H, AB, JAβ 9.0 Hz, ArH) ppm.
C-NMR (CDC13): cf 23.27 (pyrrolidine C-3 and C-4), 50.34 (N(CH2)2), 53.70 (5-CH2), 54.94 (CH30), 100.09 (C-4), 113.91, 127.79 (ar. CH), 121.33 (ar. C-l), 160.57 (ar. C-4), 161.55 (C-3), 170.31 (C-5) ppm. b) 3- ( 4-Methoxyphenyl ) -5- ( pyrrolidine-1-ylmethyl ) isoxazole hydrochloride
The title compound is prepared using the method described in Example 24, part b). Yield: 97.9 %. M.p.: 181-184 °C. Analysis: for C15HlgClN202 (294.78)
C H N Cl (ionic) calculated: 61.12 %, 6.50 %, 9.50 %, 12.03%; found: 60.67 %, 6.26 %, 9.36 %, 12.26%. IR (KBr): 2950 (CH), 2700-2200 (NH+), 1610,
1515, 1465, 1430, 1260, 1180, 1010, 895, 805
-1 cm
H-NMR (CDC13): cJ 2.10 (4H, br, pyrrolidine
3- and 4H2 ) , 3.40 (5H, br , NH+(CH2)2), 3.85
(3H, s, CH30), 4.60 (2H, s, 5-CH2), 7.35 (lH, s, 4-H), 6.90 + 7.7 (2H, AB , JAβ 9.0 Hz, ArH) ppm. Example 36
5- ( Azepane-1 -ylmethyl ) -3- ( 4-methoxyphenyl ) - isoxazole hydrochloride a ) 5- (Azepane-1-ylmethy1 ) -3- ( 4-methoxyphenyl ) isoxazole
The title compound is prepared from 50 mmoles of 5-bromomethyl-3- ( 4-methoxyphenyl ) - isoxazole and 150 mmoles of azepane by the method described in Example 24, part a).
Yield: 69.6 %o •
M.p. : 41-42 °C.
Analysis: for C 17 H22N2°2 <286*36) C H N calculated: 71.30 %, 7.74 %, 9.78 %; found: 71.45 %, 7.70 %, 9.59 %. IR (KBr): 3110, 2925, 2841 (CH), 1614, 1574, 1528, 1432, 1393, 1354, 1297, 1254, 1177, 1029, 951, 907, 835, 602, 534 cm"1.
H-NMR (CDCl ): £ 1.62 (8H, br, azepane 3-, 4-, 5- and 6-H2), 2.69-2.74 (4H, m, N(CH2)2), 3.83 (3 + 2H, s, CH30 + 5-CH2), 6.41 (lH, s, 4-H), 6.96 + 7.74 (4H, AB, J" 9.0 Hz,
AB
ArH) ppm.
13C-NMR (CDCl 3 ) ■ ' £ 26.60 + 27.98 (azepane C-3, C-4, C-5 and C-6), 53.53 (5-CII2), 55.04 (CH 0), 55.23 (N(CH2)2), 100.21 (C-4), 113.99, 127.89 (ar. CH), 121.50 ( ar . C-l), 160.64 (ar. C-4), 161.55 (C-3), 171.04 (C5) ppm.
b) 5-( Azepane-1-ylmethyl ) -3- ( 4-methoxyphenyl ) isoxazole hydrochloride The title compound is prepared using the method described in Example 24, part b).
Yield: 88.5 %.
M.p. : 190-193 °C.
Analysis: for C17H23C1 202 (322.83)
C H N Cl (ionic) calculated: 63.33 %, 7.20 %, 8.69 %, 10.86%; found: 63.06 %, 6.89 %, 8.77 %, 11.12%.
IR (KBr): y1 2940 ( CH ) , 2700-2200 (NH+), 1610,
1520, 1465, 1430, 1260, 1180, 1015, 905, 820,
805 cm"1.
•""H-NMR (DMSO-dg + CDCl.,): £ 1.60-2.20 (8H, br, azepane 3-, 4-, 5- and 6-H~), 3.35 (5H, br, HN+(CH2)2), 3.85 (3H, s, CH30), 4.60 (2H, s, 5-CH2), 7.30 (III, s, 4-II), 6.95 + 7.75
(2H, AB JAΛtr,S 9.0 Hz, ArH) ppm.
Example 37 1- ( 3-Phenylisoxazole-5-ylmethoxy ) -3-morpholino- propane-2-ol hydrochloride a ) 1- ( 3-Phenylisoxazole-5-ylmethoxy ) -3-
-morpholinopropane-2-ol
10 mmoles of 5- ( 2 , 3-epoxypropoxymethyl ) - 3-phenylisoxazole are dissolved in 30 ml of absolute toluene, and, to the solution obtained, 15 to 20 mmoles of morpholine are added. The reaction mixture is boiled for 5 to 10 hours, and the course of the reaction is followed by thin layer chromatography (dichloromethane: acetone 10:2, FM). After cooling, the mixture is washed 3 times using 10 ml of water each time, dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue is purified over a 0.063-0.2 mm gel of Kieselgel G or Kieselgel 60 in vacuo using gradient elution starting with dichloromethane and finishing with a mixture consisting of 10 volumes of dichloromethane and 2 volumes of acetone. The title compound is obtained as an oil. Yield: 65.9 %.
Analysis: for C,--H 2N20. (318-36) C H N calculated: 64.13 %, 6.97 %, 8.80 % ; found: 63.88 %, 7.04 %, 8.59 %. IR (film): 3650-3300 br (OH), 3190, 3110, 3000, 2980, 2960, 2905, 2860 ( CH ) , 1605, 1580, 740, 660 cm"1.
1H-NMR (CDCl ): 2.36-2.51 (4H, m, N(CH )2), 2.56-2.65 (2H, m, CH2N), 3.35 (IH, brs, OH),
3.55 + 3.63 (2H, ' ABX, JAΛπB 9.9 Hz,' JAΛX, 3.8
Hz, J_v 5.7 Hz, 0CH CH(0H) ) , 3.69 (4H, m, BX Z
(CH2)20), 3.93 (IH, m, CHOH), 4.70 (2H, s, 5-CH ) , 6.60 (IH, s, 4-H), 7.42-7.47 (3H, m, ArH), 7.77-7.82 (2H, m, ArH) ppm. 13C-NMR (CDC13): ^ 53.85 (N(CH2)2), 54.95 (CH N), 61.85 + 66.56 (5-CH2OCH + ( CH ) 0 ) , 78.78 (CHOH), 113.84 (C-4), 127.92 (ar. C-l), 127.93 (ar. CH ) , 155.91 (C3), 160.85 (C-5) ppm.
b) 1- ( 3-Phenylisoxazole- 5-ylmethoxy ) -3- -morpholinopropane-2-ol hydrochloride 10 mmoles of the isoxazole base obtained as described above in part a) are dissolved in ether, or a mixture of ether and ethanol or pure ethanol to obtain a solution having a concentration of 1 mmole/ml. The solution is acidified by introducing anhydrous hydrogen chloride gas. The reaction mixture is stirred for some minutes, the product separated is filtered, washed with ether, and dried over phosphorus pentoxide at 40 C under reduced pressure. If desired, the product is recrystallized from ethanol. Yield: 91.6 %. M.p. : 83-84 °C. Analysis: for C17H23C1N204 (354.83)
C H N Cl calculated: 57.54 %, 6.53 %, 7.89 %, 9.99%; found: 57.46 %, 6.41 %, 7.83 %, 9.75%. IR (KBr): V 3650-3100 br (OH and NH), 2980, 2930 (CH), 1610, 740, 670 cm"1.
"""H-NMR (DMS0-d6): £ 3.00-3.60 (8H, m, N(CH2)3 + 0CH2CH(0H)), 3.75-4.05 (4H, ra, (CH2)20), 4.25 (IH, m, CHOH), 4.73 (211, s, 5-CH2), 5.82 (IH, brs, OH), 7.12 (lH, s, 4-H), 7.49-7.56 (3H, m, ArH), 7.85-7.91 (2H, m, ArH), 10.62 (IH, brs, NH) ppm.
Example 38 1-/3- ( 4-Methoxyphenyl ) isoxazole-5-ylmethoxy / - 3 - -morpholinopropane-2-ol hydrochloride a ) 1-/3- ( 4-Methoxyphenyl )isoxazole-5-yl- meth,oxy/-3-morpholinopropane-2-ol The title compound is prepared from 10 mmoles of 5- ( 2 , 3-epoxypropoxymethyl ) -3- ( 4-
-methoxyphenyl ) isoxazole and 15 to 20 mmoles of morpholine by the method described in
Example 37, part a). The title compound is obtained as an oil.
Yield: 75.0 %.
IR (film): 3650-3300 (OH), 3000, 2910 (CH),
1610, 1420, 1230, 1100 cm"1.
"""H-NMR (CDC13): £ 2.37-2.54 (411, m, N(CII2)2),
2.60-2.68 (2H, m, CH2N), 2.93 (lH, brs, OH),
3.56 + 3.64 (2H, ABX, J A-.r,S 9.9 Hz, JA,.Λ.. 3.8
Hz, JnBvX 5.45 Hz, 0C—H ZCH(0H) ) , 3.69-3.84 (4H, m, (CH2)20), 3.85 (3H, s, 0CH3), 3.903.99 (IH, m, CHOH), 4.70 (2H, s, 5-CH2), 6.54 (IH, s, 4-H), 6.97 + 7.74 (4H, AB, J AABτ3 8.8 Hz,
ArH) ppm.
13 -NMR (CDC13): £ 53.47 (N(CH2)2), 55.14
(CH 0), 60.62 (CH2N), 64.08 + 65.70 (5-CH2OCH2), 66.74 ((CH^O), 73.08 (CHOH), 100.86 (C-4), 114.24, 128.14 (ar. CH)., 121.30 (ar. C-l), 161.13 ( ar . C-4), 162.00 (C-3), 169.32 (C-5) ppm.
b ) 1-/3- ( 4-Methoxyphenyl )isoxazole-5-yl- methoxy/-3-morpholinopropane-2-ol hydrochloride
The title compound is prepared by using the method described in Example 37, part b). Yield: 83.3 %. M.p. : 147-150 °C . -Ill- Analysis: for cι8 H25ClN2°5 (38 -86)
C H N Cl calculated: 56.18 %, 6.55 %, 7.28 %, 9.21%; found: 55.87 %, 6.50 %, 7.66 %, 9.42%. """H-NMR (CDCl3 + DMSO-dg): £ 3.0-3.70 (8H, m, N(CH2)3 + 0CH2CH(0H)), 3.85 (3H, s, 0CH3 ) , 3.75-4.1 (4H, m, (CH2)20), 4.15 (IH, m, CHOH), 4.7 (2H, s, 5-CH2), 6.7 (IH, s, 4-H), 6.95 + 7.65 (4H, AB, J A,DrS 8 Hz, ArH) ppm.
Example 39 1-/3- (4-Methylphenyl) isoxazole- 5-ylmethoxy/ - -3-morpholinopropane-2-ol hydrochloride a ) 1-/3- ( 4-Methylphenyl ) isoxazole-5-ylmethoxy/-3-morpholinopropane-2-ol
The title compound is prepared from 10 mmoles of 5- ( 2 , 3-epoxypropoxymethyl ) -3- ( 4- -methylphenyl ) isoxazole and 15 to 20 mmoles of morpholine by the method described in Example 37, part a). The title compound is obtained as an oil. Yield: 95.2 %.
IR (film): V 3600-3200 (OH), 3120 (4-H), 2859, 1614, 1431, 1363, 1297, 1118, 1009, 950, 911, 867, 821, 722, 517 cm"1.
"""H-NMR (CDC13) : £ 2.38 (3H, s, CH3 ) , 2.39-2.47 (411, m, N(CH2)2), 2.58-2.62 (2H, m, CH2N), 3.30 (IH, br, OH) , 3.56 + 3.61 (2H, ABX, JAβ
9.9 Hz, J AπXv 3.8 Hz, J_ ri,λv 5.6 Hz, 0C —H ZCH(0H) ) ,
3.65-3.80 (4H, m, (CH2)20), 3.90 (IH, m, CHOH), 4.69 (2H, s, 5-CH2), 6.56 (lH, s, 4-H) , 7.25 + 7.68 (4H, AB, J-D 8.1 Hz, ArH) ppm.
13 JC-NMR (CDC13) : 20.94 (CH3), 55.32
(N(CH2)2), 60.51 (CH2N), 63.75 + 65.66
(5-CH2OCH2), 66.44 ((CH2)20) , 72.99 (CHOH) ,
100.67 (C-4), 125.57 (ar. C-l), 126.21, 129.16
(ar. CH), 139.69 (ar. C-4), 161.79 (C-3),
169.02 (C-5) ppm.
b) 1-/3- ( 4-Methylphenyl ) isoxazole-5-ylmethoxy/-3-morpholinopropane-2-ol hydrochloride
The title compound is prepared using the method described in Example 37, part b). Yield: 86.6 %. M.p. : 107-109 °C.
Analysis: for c 18 H25ClN2°4 (368.86)
C H N Cl (ionic calculated: 58.61 %, 6.83 %, 7.60 %, 9.61%; found: 58.22 %, 6.97 %, 7.49 %, 9.24%. IR (KBr): 3600-3300 (OH), 3150 (4-H), 2900-2400 (NH), 1605, 1420, 1110 cm"1. """H-NMR (DMSO-dg + CDCl3): £ 2.4 (311, s, CH-j), 3.0-3.7 (6H, m, (CH^N), 3.7-4.0 (6H, m, (CH2)20 + 0CH2CH(0H)), 4.3 (lH, m, CHOH), 4.75 (2H, s, 5-CH2), 6.95 (III, s, 4-II), 7.3
+ 7.7 (4H, AB, J A__rS 8.0 Hz, ArH), 10.95 (IH, br, NH) ppm. Example 40 l-Morpholino-3-/3- ( 4-trifluoromethylphenyl ) - isoxazole-5-ylmethoxy/propane-2-ol hydrochloride a ) l-Morpholino-3-/3- ( 4-trifluoromethylphenyl ) isoxazole-5-ylmethoxy/- propane-2-ol
The title compound is prepared from 10 mmoles of 5- ( 2 , 3-epoxypropoxymethyl ) -3- ( 4- -trifluoromethylphenyl ) isoxazole and 15 to 20 mmoles of morpholine by the method described in Example 37, part a). The title compound is obtained as an oil. Yield: 69.1 %.
IR (film): 3650-3300 (OH), 3190, 3020, 3000, 2920, 2880 ( CH ) , 1620, 1460, 1440, 1310, 1150, 1100, 1050, 820 cm"1.
H-NMR (CDC13): £ 2.37-2.50 (4H, m, N(CH2)2), 2.60-2.68 (2H, m, CH2N), 3.14 (IH, br, OH),
3.58 + 3.67 (2H, ABX, J A,DrS 10.0 Hz, JAAV 3.7
Hz, Jβχ 5.55 Hz, 0CH2CH(0H)), 3.693.77 (4H, m, (CH2)20), 3.95 (IH, m , CHOH), 4.75 (2H, s, 5-CH2), 6.65 (IH, s, 4-H), 7.72 + 7.93
(411, AB, J,D 8.4 Hz, ArH) ppm.
13
C-NMR (CDC13): £ 53.46 (N(CH2)2), 60.58
(CH2N), 64.08 + 65.74 (5-CH2OCH2), 66.75
((CH2)20), 73.26 (CHOH), 101.01 (C-4), 123.76
(q, JCF 273.8 Hz, CF3), 125.82, 127.06 ( ar .
CH), 131.79 (q, Jcp 31.4 Hz, ar. C-4), 132.29
(ar. C-l), 161.24 (C-3), 170.36 (C-5) ppm. b) l-Morpholino-3-/3- ( 4-trifluoromethylphenyl ) isoxazole-5-ylmethoxy/propane-2-ol hydrochloride
The title compound is prepared using the method described in Example 37, part b. Yield: 62.8 %. M.p. : 129-130 °C.
Analysis: for 18 H 22ClF3N2°4 (422.83)
C H N Cl (ionic) calculated: 51.13 %, 5.24 %, 6.63 %, 8.38%; found: 50.92 %, 5.11 %, 6.83 %, 8.57%. IR (KBr): V 3650-3200 (OH), 3050-2900 (CH), 2900-2400 (br, NH), 1310, 1160, 1120, 1100, 1050 cm" .
H-NMR (DMSO-d + CDCl.,): ^ 3.0-3.5 (6H, m, (CH2)3N), 3.8-4.0 (6H, m, (CH^O + OCH CH(OH)), 4.2 (IH, m, CHOH), 4.75 (2H, s, 5-CH ) , 7.0 (IH, s, 4-H), 7.76 + 8.04 (4H,
AB, JAΛrBj 8.0 Hz, ArH) ppm.
Example 41 1-/3- ( 4-Chlorophenyl ) isoxazole-5-ylmethoxy /- -3-morpholinopropane-2-ol hydrochloride a ) 1-/3- ( 4-Chlorophenyl ) isoxazole-5-ylmethoxy/-3-morpholinopropane-2-ol
The title compound is prepared from 10 mmoles of 5- ( 2 , 3-epoxypropoxymethyl ) -3- ( 4- -chlorophenyl ) isoxazole and 15 to 20 mmoles of morpholine by the method described in Example 37, part a). The title compound is obtained as an oil.
Yield: 72.2 %.
IR (film): Y* 3600-3200 (OH), 3120 (4-H), 2920,
2858, 2765, 1608, 1571, 1511, 1430, 1364,
1297, 1117, 1093, 1014, 950, 913, 866, 838,
732, 516 cm"1.
•""H-NMR (CDC13): £ 2.40-2.50 (4H, m, N(CH2) ),
2.55-2.70 (2H, m, CH2N), 3.56 + 3.63 (2H,
ABX, Js_ 10.0 Hz, v 3.8 Hz, J_v 5.7 Hz,
ArS AΛ SX
0CH2CH(0II) , 3.65-3.75 (411, m, (CII2)20), 3.95
(IH, , CHOH) , 4.70 (2H, s, 5-CH2), 6.57 (lH, s, 4-H), 7.41 + 7.70 (4H, AB, r 8.5 Hz,
AB
ArH) ppm.
13C-NMR (CDC13) : £ 53.32 (N(CH2)2), 60.50
(CH2N), 63.78 + 65.60 (5-CH2OCH2) , 66.43
((CH ) 0), 73.05 (CHOH), 100.61 (C-4), 126.97
(ar. C-l), 127.65, 128.76 (ar. CH ) , 135.56
(ar. C-4), 160.90 (C-3), 169.57 (C-5) ppm.
b) 1-/3- ( 4-Chlorophenyl ) isoxazole-5-ylmethoxy/-3-morpholinopropane-2-ol hydrochloride
The title compound is prepared using the method described in Example 37, part b). Yield: 77.7 %. M.p. : 111-113 °C. Analysis: for C17H22CL2N204 (389.28)
C H N Cl (ionic) calculated: 52.45 %, 5.70 %, 7.20 %, 9.11%; found: 52.46 %, 5.92 %, 7.25 %, 9.35%. IR (KBr): V 3600-3260 (OH), 3070 (4-H), 2990, 2950, 2940, 2850-2300 ( NH ) , 1610, 1420, 1105, 765, 595 cm"1.
""•H-NMR (DMSO-dg + CDCl.3): £ 2.90-3.70 (6H, m, (CH2)3N), 3.70-4.05 (6H, m, (CH2)20 + OCH2CH(OH)), 4.20-4.50 (IH, m, CHOH), 4.72 (IH, t, J 4 Hz, 5-CH2), 6.95 (IH, t, J 4 Hz, 4-H), 7.30-8.20 (4H, m, ArH), 10.95 (br NH) ppm.
Example 42 1-/3- ( 4-Bromophenyl ) isoxazole-5-ylmethoxy/- -3-morpholinopropane-2-ol hydrochloride a ) 1- ( 3- ( 4-Bromophenyl ) isoxazole-5-ylmethoxy ) -3-morpholinopropane-2-ol
The title compound is prepared from 10 mmoles of 5- ( 2 , 3-epoxypropoxymethyl ) -3- ( 4-
-bromophenyl ) isoxazole and 15 to 20 mmoles of morpholine by the method described in
Example 37, part a). The title compound is obtained as an oil.
Yield: 76.1 %.
IR (film): 3650-3300 (OH), 3210, 3050, 3020,
3000, 2980, 2950 (CH), 1620, 1460, 1420, 1360, llOO, 1068, 890, 800 cm"1.
"""H-NMR (CDC13): £ 2.36-2.58 (4H, m, N(CH2)2),
2.60-2.67 (2H, m, CH2N), 3.29 (lH, br s, OH),
3.56 + 3.64 (211, ABX, J AΛ hni 10.0 Hz, JΛVX 3.8
Hz, JDBXV 5.55 Hz, OCH/-CH(OH) ) , 3.65-3.76 (4H, m, (CH2)20), 3.91 (IH, m, CHOH), 4.71 (2H, s, 5-CH2), 6.57 (IH, s, 4-H), 7.58 + 7.67
(4H, AB, JΛ-:, 8.7 Hz, ArH) ppm. AB 13C-NMR (CDC13): cf 53.40 (N(CH2)2), 60.53 (CII2N), 63.99 + 65.67 (5-CH2OCH2), 66.68 ((CH2)20), 73.14 (CHOH), 100.80 (C-4), 124.20 (ar. C-4), 127.68 (ar. C-l), 128.16, 132.03 (ar. CH), 161.38 (C-3), 169.95 (C-5) ppm.
b ) 1- ( 3- ( 4-Bromophenyl ) isoxazole-5-yl- methoxy ) -3-morpholinopropane-2-ol hydrochloride
The title compound is prepared using the method described in Example 37, part b).
Yield: 82.9 %.
M.p. : 113-116 °C.
Analysis: for C17H22BrClN204 (433.73)
C H N Cl (ionic) calculated: 47.08 %, 5.11 %, 6.46 %, 8.17%; found: 47.29 %, 5.19 %, 6.42 %, 8.61%.
IR (KBr): V 3650-3300 (OH), 3080-2900 ( CH ) ,
2850-2400 (br NH), 1620, 1430, 1360, 1120,
1110, 1070, 900, 860 cm"1.
"""H-NMR (DMS0-d6 + CDCl3): £ 3.0-3.70 (6H, m, (CH2)3N), 3.75-4.20 (6H, m, (CH^O) +
0CH_2CH(0H)), 4.27 (IH, m, CHOH), 4.75 (IH, s, 5-CH2), 6.98 (IH, s, 4-H) , 7.63 + 7.77
(4H, AB, JA..r.S 8.0 Hz, ArH) ppm.
Example 43 1-/3- ( 4-Methoxyphenyl ) isoxazole-5-ylmethoxy/-3- -(pyrrolidine-1-yl) propane-2-ol hydrochloride a) 1-/3- ( 4-Methoxyphenyl ) isoxazole-5-ylmethoxy/ -3- (pyrrolidine-1-yl) propane-2-ol ' The title compound is prepared from 10 mmoles of 5- ( 2 , 3-epoxypropoxymethyl ) -3- ( 4- -methoxyphenyl ) isoxazole and 15 to 20 mmoles of pyrrolidine by the method described in Example 3.7, part a). The title compound is obtained as an oil. Yield: 87.0 %.
IR (film): 3600-3200 (OH), 3120 (4-H), 2934, 1614, 1531, 1462, 1433, 1363, 1297, 1255, 1179, 1116, 1030, 950, 906, 838, 534 cm"1. """H-NMR (CDC13): 1.74-1.80 (4H, m, pyrrolidine 3- and 4-I_2), 2.35-2.76 (6H, m, (CH2)3), 3.40 (IH, br, OH), 3.57 + 3.62 (2H, ABX, JAβ 10.0 Hz, JAχ 3.8 Hz, Jβχ 5.9 Hz, 0CH2CH(0H)), 3.84 (3H, s, 0CII3), 3.90 (III, m, CHOH), 4.70 (2H, s, 5-CH2), 6.54 (lH, s, 4-H), 6.96 + 7 , -.,74 (4H, AB, JAΛDB 8.9 Hz, ArH) ppm.
C-NMR (CDC13): £ 23.42 (pyrrolidine C-3 and C-4), 53.94 (N(CH2)2), 55.12 (0CH3), 58.14 (CH2N), 64.10 + 61 . 10 (5-CH20CH2), 73.46 (CHOH), 100.69 (C-4), 114.10, 127.96 ( ar . CH), 121.25 (ar. C-l), 160.79 ( ar . C-4), 161.76 (C-3), 169.27 (C-5) ppm.
b) 1-/3- ( 4-Methoxyphenyl ) isoxazole-5-ylmethoxy/- 3- (pyrrolidine-1-yl) propane- 2-ol hydrochloride
The title compound is prepared using the method described in Example 37, part b). Yield: 78.6 %. M.p. : 106-110 °C. Analysis: for C18H25C1N204 (368.86)
C H N Cl (ionic) calculated: 58.61 %, 6.83 %, 7.60 %, 9.61%; found: 58.67 %, 6.84 %, 7.40 %, 9.90%.
IR (KBr): Ϋ 3600-3300 (OH), 3150 (4-H),
2900-2400 (NH), 1605, 1520, 1450, 1420, 1240,
1160, 1110 cm"1.
•"•H-NMR (DMS0-d6 + CDC13): £ 1.9 (4H, s, pyrrolidine 3- and 4-H?), 2.8-3.4 (4H, m,
(CII )2N), 3.4-3.8 (411, m, 0CH2CH ( OH ) CH2N ) ,
3.8 (3H, s, 0CH3), 4.2 (IH, m, CHOH), 4.75
(2H, s, 5-CH2), 6.95 (IH, s, 4-H), 7.0 + 7.7
(4H, AB, JAΛDB 8.5 Hz, ArH), 10.6 (lH, br , NH ) ppm.
Example 44 1-/3- ( 4-Methoxyphenyl ) isoxazole-5-ylmethoxy/ -3- -piperidinopropane-2-ol hydrochloride a ) 1-/3- ( 4-Methoxyphenyl ) isoxazole- 5-ylmethoxy/-3-piperidinopropane-2-ol
The title compound is prepared from 10 mmoles of 5- ( 2 , 3-epoxypropoxymethyl ) -3- ( 4- -methoxyphenyl ) isoxazole and 15 to 20 mmoles of piperidine by the method described in Example 37, part a). The title product is obtained as an oil. Yield: 95.0 %.
IR (film): V 3600-3200 (OH), 3120 (4-H), 2935, 1614, 1577, 1531, 1433, 1363, 1301, 1254, 1179, 1115, 1031, 950, 905, 838, 808, 601, 535 cm """H-NMR (CDC13): £ 1.42-1.45 (2H, m, piperidine 4-H~), 1.54-1.60 (4H, m, piperidine 3- and 5-H2), 2.30-2.40 (4H, m, N(CH2)2), 2.54-2.57 (2H, m, CH2N), 3.50 (IH, br, OH), 3.55 + 3.59 (2H, ABX, J AnDB 10.0 Hz, JAnΛv 3.8 Hz, JnDΛv 5.5
Hz, OCH2CH(OH)), 3.84 (3H, s, 0CH3), 3.90 (IH, m, CHOH), 4.69 (2H, s, 5-CH2), 6.54 (IH, s, 4-H), 6.96 + 7.73 (4H, AB, j A-_B 8.8 Hz,
ArH) ppm.
13C-NMR (CDC13): £ 23.95 (piperidine C-3 and C-5), 25.80 (piperidine C-4), 54.40 (N(CH2)2), 55.07 (OCH3), 60.65 (CH2N), 64.07 + 65.68 (5-CH2OCH2), 73.35 (CHOH), 100.63 (C-4), 114.06, 127.94 ( ar . CH), 121.27 ( ar . C-l), 160.75 (ar. C-4), 161.76 (C-3), 169.27 (C-5) ppm.
b ) 1-13- ( 4-Methoxyphenyl ) isoxazole-5-ylmethoxy/-3-piperidinopropane-2-ol hydrochloride
The title compound is prepared using the method described in Example 37, part b). Yield: 82.4 %. M.p. : 108-110 °C. Analysis: for C19II27ClN2ϋ4 (382.89)
C H N Cl (ionic; calculated: 59.60 %, 7.11 %, 7.32 %, 9.26%; found: ' 59.42 %, 7.23 %, 7.30 %, 9.64%. IR (KBr): 3600-3300 (OH), 3150 (4-H), 2900-2400 (NH), 1605, 1520, 1450, 1420, 1240, 1160, 1110 cm"1. """H-NMR (DMSO-dg + CDCl3): £ 1.8 (6H, br, piperidine 3-, 4- and 5-H2), 2.8-3.4 (4H, m, (CH2)2N), 3.4-3.8 (4H, m, OCH_2CH(OH) CH2N ) , 3.8 (3H, s, OCH3), 4.3 (IH, m, CHOH), 4.75 (2H, s, 5-CH2), 6.95 (IH, s, 4-H), 7.0 + 7.7 (4H, AB, JAβ 8.5 Hz, ArH), 10.2 (lH, br, NH ) ppm.
Example 45 1- ( Azepane-1-yl ) -3-/3- ( 4-methoxyphenyl ) - isoxazole-5-ylmethoxy/propane-2-ol hydrochloride a ) 1- (Azepane-1-yl ) -3-/3- ( 4-methoxyphenyl ) - isoxazole-5-ylmethoxy/propane-2-ol
The title compound is prepared from 10 mmoles of 5- ( 2 , 3-epoxypropoxymethyl ) -3- ( 4- -methoxyphenyl ) isoxazole and 15 to 20 mmoles of azepane by the method described in Example 37, part a). The title product is obtained as an oil. Yield: 94.0 %.
IR (film): \> 3600-3200 (OH), 3120 (4-H), 2934, 1614, 1531, 1462, 1433, 1363, 1297, 1255, 1179, 1116, 1030, 950, 906, 838, 634 cm"1.
H-NMR (CDCl3): £ 1.60 (811, br , azepane 3-, 4-, 5- and 6-H2), 2.39-2.80 (6H, m, (CH2)3), 3.60 (IH, br, OH), 3.55 + 3.62 (2H, ABX, JAβ 10.0 Hz, JAχ 3.8 Hz, Jβχ 5.5 Hz, 0CH2CH ( OH) ) , 3.80 (IH, m, CHOH), 3.84 (3H, s, 0CH3), 4.70 (2H, s, 5-CH2), 6.54 (IH, s, 4-H), 6.97 + 7.74 (4H, AB, JAβ 8.9 Hz, ArH) ppm. 13C-NMR (CDC13): < 26.72 + 28.24 (azepane C-3, C-4, C-5 and C-6), 55.16 (OCII ), 55.58 (N(CH2)2), 59.93 (CH2N), 64.18 + 66.40 (5-CH OCH2), 73.31 (CHOH), 100.71 (C-4), 114.13, 128.03 ( ar . CH), 121.32 (ar. C-l), 160.82 (ar. C-4), 161.79 (C-3), 169.38 (C-5) ppm.
b) l-( Azepane-1-yl ) -3-/3- ( 4-methoxyphenyl ) - isoxazole-5-ylmethoxy/propane-2-ol hydrochloride
The title compound is prepared using the method described in Example 37, part b).
Yield: 90.8 %.
M.p. : 91-94 °C.
Analysis: for C20H2gClN204 (396.91)
C H N Cl (ionic) calculated: 60.52 %, 7.36 %, 7.06 %, 8.93%; found: 60.63 %, 7.38 %, 7.09 %, 8.55%.
IR (KBr): Y1 3600-3300 (OH), 3150 (4-H),
2900-2400 (NH), 1605, 1520, 1450, 1420, 1240,
1160, 1100 cm-1.
"""H-NMR (DMSO- + CDC13>: £ 1.8 (8H, br, azepane 3-, 4-, 5- and 6-H2), 2.8-3.4 (4H, m, (CH2)2N), 3.4-3.8 (4H, m, 0CH2CH ( OH ) CH2N ) ,
3.8 (3H, s, 0CH3), 4.2 (lH, m, CHOH), 4.75
(2H, s, 5-CH2), 6.95 (IH, s, 4-H), 7.0 + 7.7
(4H, AB, JΛ_, 8.5 Hz, ArH), 10.2 (IH, br , NH ) AB ppm. Example 46 1- ( 3-Phenylisoxazole-5-ylmethoxy )-3-(4-methyl- piperazine-1-yl )propane-2-ol dihydrochloride a ) 1- ( 3-Phenylisoxazole-5-ylmethoxy ) -3-
- ( 4-methylpiperazine-l-yl ) propane-2-ol
The title compound is prepared from 10 mmoles of 5- ( 2 , 3-epoxypropoxymethyl ) -3-
-phenylisoxazole and 15 to 20 mmoles of
N-methylpiperazine by the method described in Example 37, part a). The title product is obtained as an oil.
Yield: 49.6 %.
IR (film): 3600-3200 (OH), 3120 (4-H), 2938,
2801, 1612, 1581, 1444, 1407, 1363, 1294,
1167, 1109, 1012, 950, 912, 816, 770, 735,
695 cm
H-NMR (CDC13): cT 2.26 (3H, s, NCH3 ) , 2.30-2.55
(8H, m, N(CH2CH2)2N) , 2.60-2.80 (2H, ra, CH2N),
3.54 + 3.62 (2H, ABX, JAβ 9.9 Hz, JAχ 3.7
Hz, JBDXV 5.6 Hz, 0C—H ZCH(0H) ) , 3.80-3.95 (2H, m, CHOH), 4.69 (2H, s, 5CH2), 6.59 (IH, s, 4-H), 7.41-7.45 (311, m, ArH), 7.777.82 (2H, m, ArH) ppm.
13C-NMR (CDC13): £ 45.45 (NCH3), 52.67 + 54.55 (N(CH2CII2)2N), 59.86 (CH2N), 63.73 + 65.74 (5-CH2OCH2), 73.09 (CHOH), 100.66 (C-4), 126.28, 128.41, 129.52 (ar. CH), 128.69 ( ar . C-l), 161.79 (C-3), 169.26 (C-5) ppm. b) 1- ( 3-Phenylisoxazole-5-ylmethoxy) -3-
- ( 4-methylpiperazine-l-yl ) propane-2-ol hydrochloride
The title compound is prepared using the method described in Example 37, part b). Yield: 77.9 %. M.p. : 191-193 °C.
Analysis: for ι 8H27Cl2N3°3 (404.34)
C II N Cl( ionic) calculated: 53.47 %, 6.73 %, 10.39 %, 17.54%; found: 53.06 %, 6.88 %, 10.19 %, 17.61%. IR (KBr): -J 3600-3200 (OH), 3190 (4-H), 2990, 2980, 2800-2200 (NH), 1610, 1350, 1120, 1095, 880, 725, 665 cm"1.
H-NMR (DMSO-dg + CDCl3): £ 2.80 (3H, s, NCH3), 3.30 (2H, m, CH2N), 3.40-3.85 (10H, m, N(CH2CH2)2N + 0CH2CH(0H)), 4.30 (lH, m, CHOH), 4.65 (2H, s, 5-CH2), 6.95 (lH, s, 4-H), 7.35-7.60 (3H, m, ArH), 7.70-8.0 (2H, m, ArH) ppm.
Example 47 1- ( 4-Methylpiperazine-l-yl ) -3-/3- ( 4-methoxyphenyl ) isoxazole-5-ylmethoxy/propane-2-ol dihydrochloride a) l-( 4-Methylpiperazine-l-yl)-3-/3-( 4- meth'oxyphenyl ) isoxazole-5-ylmethoxy/- propane-2-ol
The title compound is prepared from 10 mmoles of 5- ( 2 , 3-epoxypropoxymethyl ) -3- ( 4- -methoxyphenyl ) isoxazole and 15 to 20 mmoles of N-methylpiperazine by the method described in Example 37, part a). The title product is obtained as an oil.
Yield: 79.0 %.
IR (film): 3000, 2870 (CH), 1610, 1420,
1230, 1100 cm" .
H-NMR (CDC13): £ 2.27 (3H, s, NCH3 ) , 2.39
+ 2.47 (8H, ABX, JAβ 12.5 Hz, JAχ 9.6 Hz,
Jβχ 4.1 Hz, N(CH2CH2)2N) , 2.66 (2H, m, CH2N),
3.44 (IH, br OH), 3.54 + 3.62 (2H, ABX, J AABπ
9.9 Hz, JΛχ 3.8 Hz, Jβχ 5.6 Hz, 0CH2CH ( OH) ) , 3.84 (3H, s,.0CH3), 3.87-3.97 (IH, m, CHOH), 4.69 (2H, s, 5-CH2), 6.54 (IH, s, 4-H), 6.96 + 7.73 (4H, AB, JAβ 8.9 Hz, ArH) ppm. 13C-NMR (CDC13): <f 45.61 (NCH3), 52.83 + 54.76 (N(CH2CH2)2N) , 55.01 (0CH3), 59.94 (CH2N), 64.00 + 65.81 (5-CH2OCH2), 73.16 (CHOH), 100.71 (C-4), 114.11, 128.02 ( ar . CH) , 121.22 ( ar . C-l), 160.92 (ar. C-4), 161.86 (C-3), 169.32 (C-5) ppm.
b) l-( 4-Methylpiperazine-l-yl )-3-/3-(4-
-methoxyphenyl ) isoxazole-5-ylmethoxy/- propane-2-ol dihydrochloride monohydrate
The title compound is prepared using the method described in Example 37, part b). Yield: 80.0 %. M.p. : 179-182 °C. Analysis: for C19H29C12N304 XH20 (452.38) C H N Cl (ionic) calculated: 50.45 %, 6.91 %, 9.29 %, 15.67%; found: 50.38 %, 6.71 %, 9.38 %, 15.83%. IR (KBr): V 3650-3200 (OH), 3100-2900 ( CH ) , 2800-2400 (br, NH) , 1620, 1430, 1260 cm"1.
H-NMR (DMSO-dg + CDCl3): £ 2.95 (3H, s, NCH3 ) , 3.3 (2H, m, CH2N), 3.6-4.0 (10H, m, N(CH2CH2)2N + 0CH2CH(0H) ) , 3.90 (3H, s, OCH3), 4.1 (lH, m, CHOH), 4.75 (2H, s, 5-CH2), 6.85 (IH, s, 4-H), 7.0 + 7.75 (4H, AB, JAβ 8 Hz, ArH) ppm.
Example 48 1- ( 4-Methylpiperazine-l-yl ) -3-/3- ( 4-trifluoromethylphenyl ) isoxazole-5-ylmethoxy/propane-2-ol dihydrochloride
a ) l-( 4-Methylpiperazine-l-yl )-3-/3-(4-
-trifluoromethylphenyl ) isoxazole-5-yl- methoxy/propane-2-ol
The title compound is prepared from 10 mmoles of 5- ( 2 , 3-epoxypropoxymethyl ) -3- ( 4- -trifluoromethylphenyl ) isoxazole and 15 to 20 mmoles of N-methylpiperazine by the method described in Example 37, part a). The title product is obtained as an oil. Yield: 55.43 %.
IR (film): V 3600-3240 (OH), 3120 (4-H), 2940, 2803, 1611, 1461, 1438, 1327, 1294, 1168, 1126, 1072, 1015, 952, 919, 851, 813, 687, 598 cm"1. """H-NMR (CDC13): <$ 2.28 (3H, s, NCH3), 2.30-2.60 (8H, m, N(CH2CH2)2N), 2.70 (2H, m, CH2N), 3.50-3.80 (3H, m, 0CH2CH(0H)), 3.95 (lH, m, CHOH), 4.74 (2H, s, 5-CH2), 6.65 (IH, s, 4-H), 7.71 + 7.92 (4H, AB, J 8.3 Hz, ArH) ppm. 13C-NMR (CDC13): cf 45.67 (NCH3), 52.88 + 54.80 (N(CH2CH2)2N) , 59.93 (CH2N), 63.99 + 65.83 (5-CH2OCH2), 73.33 (CHOH), 100.82 (C-4), 123.56 (q, JCF 272.5 Hz, CF3 ) , 125.60 (q, JCF 4.4 Hz, ar. C-3 and C-5), 126.65 (ar. C-2 and C-6), 131.51 (q, JCF 34.1 Hz, ar. C-4), 132.11 (ar. C-l), 160.93 (C-3), 170.06 (C-5) ppm.
b) l-(4-Methylpiperazine-l-yl)-3-/3-(4-
-trifluoromethylphenyl ) isoxazole-5-yl- methoxy/propane-2-ol dihydrochloride monohydrate
The title compound is prepared using the method described in Example 37, part b). Yield: 81.4 %. M.p. : 197-198 °C. Analysis: for ClgH26F3Cl2N303 XH20 (490.35)
C H N Cl (ionic) calculated: 46.54 %, 5.76 %, 8.57 %, 14.46%; found: 46.19 %, 5.73 %, 8.49 %, 14.35%. IR (KBr): V 3600-3300 (OH), 3180 (4-H), 2990, 2850-2200 (NH), 1475, 1420, 1310, 1150, 1090, 810, 650, 570 cm"1.
"""H-NMR (DMS0-d6 + CDC13): £ 2.95 (3H, s, NCH3 ) , 3.30 (2H, m, CH2N), 3.40-3.90 (10H, m, N(CH2CH2)2N + 0CH2CH(0H)), 4.30 (IH, m, CHOH),
4.75 (2H, s, 5-CH2>' 7 • 20 (lH' s' 4"H)' 7 . 60- 8 . 20 ( 4H , m , ArH ) ppm .
Example.49 1-/3- ( 4-Chlorophenyl ) isoxazole-5-ylmethoxy/- -3- ( 4-methylpiperazine-l-yl ) propane-2-ol dihydrochloride a ) 1-/3- ( 4-Chlorophenyl ) isoxazole-5-yl- methoxy/-3- ( 4-methylpiperazine-l-yl ) - propane-2-ol
The title compound is prepared from 10 mmoles of 5- ( 2 , 3-epoxypropoxymethyl ) -3- ( 4- -chlorophenyl ) isoxazole and 15 to 20 mmoles of N-methylpiperazine by the method described in Example 37, part a). The title product is obtained as an oil. Yield: 76.9 %.
IR (film): V 3600-3240 (OH), 3120 (4-H), 2938, 2803, 1608, 1511, 1459, 1430, 1363, 1294, 1167, 1013, 950, 913, 837, 732, 517 cm"1. 1H-NMR (CDC13): f 2.27 (3H, s, NCH3 ) , 2.30-2.60 (8H, m, N(CH2CH2) 2N) , 2.60-2.80 (2H, m, CII2N), 3.55 + 3.63 (211, ABX, JAβ 10.0 Hz, J" Aχ 3.7 Hz, Jβχ 5.6 Hz, 0CH2CH(0H)), 3.80 (lH, br s, OH), 3.85-3.97 (IH, m, CHOH), 4.70 (2H, s, 5-CH2), 6.57 (III, s, 4-H), 7.41 + 7.70 (4H, AB, JΛTJ 8.5 Hz, ArH) ppm.
C-NMR (CDC13): £ 45.59 (NCH3), 52.72 + 54.73 (N(CH2CH2)2N), 59.89 (CH2N), 63.89 + 65.73 (5-CH2OCH2), 73.20 (CHOH), 100.61 (C-4), 127.04 (ar. C-l), 127.71, 128.79 (ar. CH), 135.63 (ar. C-4), 160.97 (C-3), 169.70 (C-5) ppm. b) 1-/3- ( 4-Chlorophenyl ) isoxazole-5-yl- methoxy/-3- ( 4-methylpiperazine-l-yl ) - propane-2-ol dihydrochloride
The title compound is prepared using the method described in Example 37, part b). Yield: 91.1 %. M.p.: 230-233 °C (ethanol).
Analysis: for cι8 H26Cl3N3°3 (438.78)
C H N Cl (ionic) calculated: 49.27 %, 5.97 %, 9.58 %, 16.16%; found: 49.30 %, 6.03 %, 9.40 %, 16.32%. IR (KBr): 3600-3200 (OH), 3120 (4-H), 2990, 2830, 2830-2200 (NH), 1610, 1450, 1410, 1090, 1080, 1070, 910, 880, 800, 760 cm" .
H-NMR (DMS0-d6 + CDCl3): £ 2.80 (3H, s, NCH3 ) , 3.103.40 (2H, m, CH2N) , 3.50-4.00 (10H, m, N(CH2CH2)2N and 0CH2CH(0H)), 4.10-4.40 (IH, m, CHOH), 4.77 (2H, s, 5CH2), 7.00 (lH, s, 4-H), 7.55 + 7.92 (4H, AB, JAβ 9.4 Hz, ArH) ppm.
Example 50 1-/3- ( 4-Bromophenyl ) isoxazole-5-ylmethoxy/-3- -( 4-methylpiperazine-l-yl ) propane-2-ol dihydrochloride a) 1-/3- ( 4-Bromophenyl ) isoxazole-5-yl- methoxy/-3- ( 4-methylpiperazine-l-yl ) - propane-2-ol
The title compound is prepared from 10 mmoles of 3- ( 4-bromophenyl ) -5- ( 2 , 3-epoxy- propoxymethyl ) isoxazole and 15 to 20 mmoles of N-methylpiperazine by the method described in Example 37, part a). The title product is obtained as an oil.
Yield: 52.0 %.
IR (film): 3600-3200 (OH), 3120 (4-H), 2938,
2802, 1609, 1568, 1507, 1458, 1428, 1363,
1293, 1167, 1111, 1073, 1012, 950, 915, 817,
735, 515 cm" .
•""H-NMR (CDC13): £ 2.26 (311, s, NCI^ ) , 2.30-2.55
(8H, m, N(.CH2CH2)2N) , 2.6-2.80 (2H, m, CH2N),
3.54 + 3.62 (2H, ABX, J AΛnB 9.9 Hz, JAXV 3.7
Hz, J_Bv 5.6 Hz, 0CH Δ„CH(0H)), 3.80-3.97 (2H, m, CHOH), 4.69 (2H, s, 5CH2 ) , 6.58 (IH, s, 4-H), 7.30-7.80 (4H, m, ArH) ppm. 13C-NMR (CDCl ): £ 45.48 (NCH3), 52.67 + 54.55 (N(CH2CH2)2N) , 59.83 (CH2N), 63.71 + 65.71 (5-CH2OCH2), 73.16 (CHOH), 100.45 (C-4), 123.77 (ar. C-4), 128.65 (ar. C-l), 127.79, 131.60 (ar. CH), 160.82 (C-3), 169.61 (C-5) ppm.
b) 1-/3- ( 4-Bromophenyl ) isoxazole-5-ylmethoxy/ -3- ( 4-methylpiperazine-l-yl ) - propane-2-ol dihydrochloride
The title compound is prepared using the method described in Example 37, part b). Yield: 94.4 %. M.p.: 217-220 °C (ethanol). Analysis: for C18H26BrCl2N303 (483..23) C H N Cl (ionic) calculated: 44.74 %, 5.42 %, 8.70 %, 14.67%; found: 44.53 %, 5.64 %, 8.59 %, 14.77%. IR (KBr): 3650-3200 (OH), 3170 (4-H), 2990, 2985, 2800-2300 (NH), 1610, 1460, 1410, 1090, 1050, 790, 775 cm"1.
"""H-NMR (DMSO-dg + CDCl3): £ 2.75 (3H, s, NCH3 ) , 3.30 (2H, m, CH2N), 3.40-4.00 (10H, m, N(CH2CH2)2N) es 0CH2CH(0H)), 3.90-4.20 (lH, m, CHOH), 4.65 (2H, s, 5CH2 ) , 7.00 (IH, s, 4-H), 7.40-7.90 (4H, m, ArH) ppm.
Example 51 1-/3- ( 3 , 4-Dimethoxyphenyl )isoxazole-5-yl- methoxy/-3-/4- ( 2-methoxyphenyl ) piperazine- -1-yl /propane-2-ol dihydrochloride a) 1-/3- ( 3 , 4-Dimethoxyphenyl ) isoxazole-5- ylmethoxy/-3-/4- ( 2-methoxyphenyl ) - piperazine-1-yl/propane-2-ol
10 mmoles of 3- ( 3 , 4-dimethoxyphenyl ) -5- - ( 2 , 3-epoxypropoxymethyl ) isoxazole are dissolved in 30 ml of anhydrous toluene. To the solution obtained, either 11 mmoles of N- ( 2-methoxyphenyl ) piperazine - obtained from the hydrochloride thereof through alkalization with an aqueous sodium hydroxide solution, extraction with ethyl acetate, drying and evaporation - as well as 11 mmoles of triethylamine, or 11 mmoles of N- ( 2-methoxyphenyl ) piperazine hydrochloride and 22 mmoles of triethylamine are added. The reaction mixture is boiled for 5 to 10 hours, and the reaction is followed by thin layer chromatography (dichloromethane: acetone 10:2). After cooling, the mixture is washed three times using 10 ml of water each time, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue is purified by chromatography over a 0.063-0.2 mm gel of Kieselgel G or Kieselgel 60 in vacuo using gradient elution starting with dichloromethane and finishing with a mixture consisting of 10 volumes of dichloromethane and 2 volumes of acetone. The title compound is obtained as an oil that crystalizes. Yield: 38.0 %.
IR (KBr): 3600-3200 (br OH), 2934, 2813 (CH), 1603, 1502, 1451, 1411, 1354, 1299, 1244, 1183, 1139, 1030, 986, 948, 899, 937, 811, 780, 759, 532 cm"1.
H-NMR (CDC13): £ 2.43-2.67 (4H, m, N(CH2)2), 2.81-2.90 (2H, m, CH2N), 3.09 (4H, br, (CH2)2NAr), 3.59 + 3.67 (2H, ABX, JAβ 9.9 Hz, JAχ 3.7 Hz, Jβχ 5.6 Hz, 0CH2CH(0H)), 3.86 + 3.93 + 3.95 (3 x 3H, s, 3 x 0CH3), 3.96 (IH, m, CHOH), 4.72 (2H, s, 5-CH2), 6.57 (IH, s, 4-H), 6.70-7.00 (5H, m, ArH), 7.27-7.32 (IH, m, 3ArH), 7.42 (lH, d, J 1.9 Hz, 3-ArH) ppm.
13C-NMR (CDC13): < 50.55 + 53.29 (N ( CH2CH2 ) 2N) , 55.19 + 55.83 (3 x 0CH3 ) , 60.12 (CH2N), 64.20 + 65.87 (5-CH2OCH2), 73.24 (CHOH), 100.84 (C-4), 111.03, 118.02, 120.81, 122.87 (N-ar. CH), 109.14, 110.90, 119.78 (3ar. CH), 121.47 (3-ar. C-l), 140.95 (N-ar. C-l), 149.14 + 150.47 (3-ar. C-3 + C-4), 152.06 (N-ar. C-2), 161.97 (C-3), 169.34 (C-5) ppm.
b) 1-/3- ( 3 , 4-Dimethoxyphenyl ) isoxazole-5- ylmethoxy/-3-/4- ( 2-methoxyphenyl ) - piperazine-1-yl/propane-2-ol dihydrochloride
10 mmoles of the isoxazole base obtained as described above in part a) are dissolved in ether, or a mixture of ether and ethanol or pure ethanol to obtain a solution having a concentration of 1 mmole/ml. The solution is acidified by introducing anhydrous hydrogen chloride gas. The reaction mixture is stirred for some minutes, the product separated is filtered, washed with ether, and dried over phosphorus pentoxide at 40 C under reduced pressure. If desired, the product is recrystallized from ethanol.
Yield: 78.5 %.
M.p. : 136-138 °C.
Analysis: for C 2-6,H3,5CC12-N3_0C6 (555.19)
C H N Cl (ionic) calculated: 56.20 %, 6.35 %, 7.57 %, 12.60%; found: 56.38 %, 6.47 %, 7.63 %, 12.82%. IR (KBr):
Figure imgf000135_0001
3600-3300 (OH), 3150 (4-H), 2900-2400 (NH), 1605, 1520, 1500, 1450, 1420, 1240, 1180, 1100, 1010 cm"1. """H-NMR (DMS0-dc + CDCl-.): £ 3.20-4.20 (12H, m, CH2N(CH2CH2)2N and OCH2CH(OH)), 3.80 + 3.82 + 3.85 (3 x 3H, 3 x s, 3 x OCH ) , 4.20-4.40 (IH, m, CHOH), 4.75 (2H, s, 5-CH ) , 5.05-5.80 (2H, br, 2 x NH) , 6.75-7.60 (8H, m, ArH + 4H) ppm.
Example 52
1-/4- ( 2-Methoxyphenyl ) piperazine-l-yl/-3-/3-
- ( 4-methoxyphenyl ) isoxazole-5-ylmethoxy/- propane-2-ol dihydrochloride a) 1-/4- ( 2-Methoxyphenyl ) piperazine-1-yl /- -3-/3- ( 4-methoxyphenyl ) isoxazole-5-ylmethoxy/propane-2-ol
The title compound is prepared from 10 mmoles of 5- ( 2 , 3-epoxypropoxymethyl ) -3- ( 4- -methoxyphenyl ) isoxazole and 11 mmoles of N- ( 2-methoxyphenyl ) piperazine by the method described in Example 51, part a). Yield: 60.5 %.
IR (KBr): 3600-3200 (OH), 3110 (4-H), 2938, 2813, 1613, 1529, 1500, 1432, 1392, 1338, 1308, 1243, 1176, 1106, 1075, 1027, 1007, 939, 908, 832, 753, 529 cm"1.
"""H-NMR (CDC13): c 2.38-2.77 (4H, m, N ( CH ) ) , 2.86 (IH, br, CH2N), 3.09 (4H, br , ( CH ) NAr ) , 3.60 (IH, br, OH), 3.50-3.70 (2H, , OCH CH(OH)), 3.85 (6H, s, 2 x OCH ) , 4.00 (IH, m, CHOH), 4.71 (2H, s, 5-CH2), 6.54 (IH, s, 4-H), 6.77-7.0 (4H, m, N-ArH), 6.96 + 7.74 (4H, AB, J AΛTB, 8.6 Hz, 3-ArH) ppm. b) 1-/4- ( 2-Methoxyphenyl ) piperazine-1-yl/ - -3-/3- ( 4-methoxyphenyl ) isoxazole-5-ylmethoxy/propane-2-ol dihydrochloride
The title compound is prepared using the method described in Example 51, part b).
Yield: 82.5 %.
M.p.: 176-177 °C.
Analysis: for C2-.H33C12 30-. (526.44 )
C H N Cl (ionic) calculated: 57.03 %, 6.32 %, 7.98 %, 13.47%; found: 56.76 %, 6.37 %, 7.91 %, 13.24%.
IR (KBr): V" 3600-3300 (OH), 3150 (4-H),
2900-2400 (NH), 1605, 1520, 1500, 1450, 1420,
1240, 1180, 1100, 1010 cm"1.
"""H-NMR (DMSO-dg + CDCl3): £ 3.2-3.8 (12H, m, CH N(CH2CH?) N and 0CH2CH( OH) ) , 3.8 (6H, s, 2 x OCH ) , 4.3 (IH, m, CHOH), 4.75 (2H, s, 5-CH ) , 6.95 (IH, s, 4-H), 6.8-7.0 (4H, m, N-ArH), 7.0 + 7.7 (4H, AB, jr AB 8.5 Hz,
3-ArH) ppm.
Example 53 1-/4- ( 2-Methoxyphenyl ) piperazine-1-yl 1 - 3- 13- - ( 4-trifluoromethylphenyl ) isoxazole-5-yl- methoxy/propane-2-ol dihydrochloride a) 1-/4- ( 2-Methoxyphenyl )piperazine-l-yl/- -3-/3- ( 4-trifluoromethylphenyl ) - isoxazole-5-ylmethox /propane-2-ol
The title compound is prepared from 10 mmoles of 5- ( 2 , 3-epoxypropoxymethyl ) -3- ( 4- trifluoromethylphenyl ) isoxazole and 11 mmoles of N- ( 2-methoxyphenyl ) piperazine by the method described in Example 51, part a). The title product is obtained as an oil. Yield: 39.3 %.
IR (film): 3600-3000 (OH), 3120 (4-H), 2880, 2838, 1500, 1453, 1436, 1332, 1236, 1160, 1111, 1065, 1024, 951, 919, 849, 811, 755, 682, 595 cm"1.
■""H-NMR (CDC13): £ 2.40-2.75 (4H, m, (CH2)2), 2.75-2.95 (2H, m, CH2N), 3.0-3.20 (4H, m, (CH2)2NAr), 3.52 (IH, br s, OH), 3.55-3.70 (2H, m, 0CH2CH(0H)), 3.84 (3H, s, 0CH3), 3.90-4.05 (lH, m, CHOH), 4.74 (2H, s, 5-CH2), 6.65 (IH, s, 4-H), 6.75-7.00 (4H, m, ArH), 7.70 + 7.91 (4H, AB, JΛC 8.35 Hz, ArH) ppm.
"1 "5
C-NMR (CDCl-j): £ 50.53 + 53.30 (N ( CH2CH2 ) 2N ) ,
55.18 (CH2N), 60.08 (0CH3), 64.22 + 65.88
(5-CH2OCH2), 73.43 (CHOH), 101.03 (C-4),
111.19, 118.17, 120.97, 123.03 (N-ar. CH) ,
125.91, 127.14 (3-ar. CH ) , 131.51 (3-ar. C-4),
132.39 (3-ar. C-l), 141.12 (N-ar. C-l), 152.27
(N-ar. C-2), 161.32 (C-3), 170.51 (C-5) ppm.
b) 1-/4- ( 2-Methoxyphenyl) piperazine-1-yl/-
-3-/3- ( 4-trifluoromethylphenyl ) isoxazole- -5-ylmethoxypropane-2-ol dihydrochloride
The title compound is prepared using the method described in Example 51, part b). Yield: 81.1 %. M.p. : 193-194 °C. Analysis: for C25H30 C12F3°4 (564-43)
C H N Cl (ionic) calculated: 53.20 %, 5.36 %, 7.44 %, 12.56%; found: 53.10 %, 5.61 %, 7.62 %, 12.79%. IR (KBr): 3600-3400 (OH), 2800-2300 (NH), 1620, 1500, 1320, 1250, 1160, 1095,' 1050, 1000, 840, 720 cm .
"""H-NMR (DMSO-dg + CDCl3): < 3.0-3.40 (8H, m, N(CH2CH2)2N) , 3.40-3.60 (2H, m, CH2N),
3.70-3.90 (2H, m, 0CH2CH(0H)), 3.76 (3H, s, OCH ) , 4.10-4.45 (lH, , CHOH), 4.70 (2H, s, 5-CH2), 7.15 (IH, s, 4-H), 6.807.00 (4H, m,, NN--AArrHH)),, 7.80 + 8.00 (4H, AB, J„D 8 Hz,
AB 3-ArH) ppm,
Example 54
1-/3- ( 4-Fluorophenyl) isoxazole-5-ylmethoxy/-
-3-/4- ( 2-methoxyphenyl ) piperazine-1-yl/propane-
-2-ol dihydrochloride a) 1-/3- ( 4-Fluorophenyl ) isoxazole-5-ylmethoxy 1-3-14- ( 2-methoxyphenyl ) piperazine- -1-yl/ ropane-2-ol
The title compound is prepared from 10 mmoles of 5- ( 2, 3-epoxypropoxymethyl ) -3- ( 4- -fluorophenyl ) isoxazole and 11 mmoles of N- ( 2-methoxyphenyl) piperazine by the method described in Example 51, part a). The title product is obtained as an oil. Yield: 38.2 %.
IR (film): *V 2940, 2823 (CH), 1611, 1526, 1501, 1434, 1382, 1302, 1241, 1116, 1027, 919, 844, 811, 752, 595, 528 cm"1.
"""H-NMR (CDC13): £ 2.42-2.67 (4H, m, (CH2)2),
2.81-2.89 (2H, m, CH N) , 3.09 (4H, m,
(CH Z„) Z_NAr), 3.58 + 3.67 (2H, ABX, JA.,B, 10.0
Hz, .7 AX 3.7 Hz, J_BvA 5.5 Hz, OC—H Z-CH(OH)), 3.85
(3H, s, OCH3), 4.05 (IH, m, CHOH), ~4.73 (2H, s, 5-CH2), 6.57 (IH, s, 4-H), 6.87-6.92 (4H, m, N-ArH), 7.14 + 7.79 (4H, AB , J A_._B 8.9 Hz,
JA-,r, 5.3 Hz, J_B,_r 8.7 Hz, 3-ArH) ppm.
C-NMR (CDC13): £ 50.48 + 53.28 (N( CH2CH ) ?N) ,
55.15 (OCH3), 60.11 (CH2N), 64.12 + 65.86
(5-CH2OCH2), 73.29 (CHOH), 101.81 (C-4),
111.03, 118.01, 120.79, 122.86 (N-ar. CH),
115.84 (J 21.2 Hz, 3-ar. C-3 + C-5), 128.55 Cr
(Jo_r„ 8.9 Hz, 3-ar. C-2 + C-6), 124.95 ( JC__r
3.9 Hz, 3ar. C-l), 140.91 (N-ar. C-l), 152.05
(N-ar. C-2), 161.26 (C-3), 163.60 (
Figure imgf000140_0001
250.8
Hz, 3-ar. C-4), 169.74 (C-5) ppm.
b ) 1-/3- ( 4-Fluorophenyl ) isoxazole-5-yl- methoxy/-3-/4- ( 2-methoxyphenyl )piperazine- -1-yl /propane-2-ol dihydrochloride
The title compound is prepared using the method described in Example 51, part b). Yield: 76.3 %. M.p.: 168-169 °C (ethanol). Analysis: for C24H Cl2FN 04 (514.43)
C H N Cl (ionic) calculated: 56.03 %, 5.88 %, 8.17 %, 13.78%; found: 56.36 %, 5.64 %, 7.96 %, 13.88%. IR (KBr): V 3110, 3050, 2940, 2870 (CH), 2700-2100 (NH), 1650, 1605, 1520, 1500, 1470, 1450, 1390, 1280, 1240, 1165, 1105, 1020, 1005, 850, 840, 760 cm"1.
"""H-NMR (DMSO-dg + CDCl3): £ 3.10-3.40 (8H, m, N(CH2CH2)2N) , 3.40-3.60 (2H, m, CH2N), 3.80 (2H, m, OCH2CH(OH)), 4.20-4.30 (IH, m, CHOH), 4.55 (2H, s, 5CH2>, 6.80-7.10 (5H, m, N-ArH + 4-H), 7.10-7.40 + 7.808.05 (4H, m, 3-ArH) ppm.
Example 55
1 - 13- ( 4-Methoxyphenyl ) isoxazole-5-ylmethoxy/-3-
- 14 - ( 3-trifluoromethylphenyl ) piperazine-1-yl/- propane-2-ol dihydrochloride a) 1-/3- ( 4-Methoxyphenyl ) isoxazole-5-ylmethoxy 1 - 3 - 1 - ( 3-trifluoromethylphenyl ) - piperazine-1-yl /propane-2-ol
The title compound is prepared from 10 mmoles of 5- ( 2 , 3-epoxypropoxymethyl ) 3- ( 4- -methoxyphenyl ) isoxazole and 11 mmoles of N- ( 3-trifluoromethylphenyl ) piperazine by the method described in Example 51, part a). The title product is obtained as an oil. Yield: 68.0 %.
IR (film): V 3600-3200 (br OH), 2834 (CH), 1613, 1530, 1496, 1451, 1433, 1357, 1319, 1255, 1164, 1122, 1030, 994, 950, 838, 757, 696, 535 cm" .
1H-NMR (CDC13): £ 2.42-2.64 (4H, m, N(CH2)2), 2.76-2.84 (2H, m, CH2N), 3.23 (4H, m, (CH2)2NAr), 3.59 + 3.66 (2H, ABX, JAβ 9.9 Hz, AA 3.8 Hz, J_BvA 5.5 Hz, OCH Z_CH(OH)), 3.85
(3H, s, OCH3), 3.97 (lH, m, CHOH), 4.71 (2H, s, 5-CH2), 6.54 (ΪH, s, 4-H), 6.95-7.10 (3H, m, N-ArH), 7.30-7.34 (IH, m, N-ArH), 6.97-7.74 (4H, AB, J,._ 8.8 Hz, 3-ArH) ppm.
13
C-NMR (CDC13): £ 48.54-52.90 (N ( CH2CH2 ) N) ,
55.17 (OCH3), 60.12 (CHj ), 64.11 + 66.05
(5-CH20CH2), 73.06 (CHOH), 100.87 (C-4),
112.02, 115.80, 118.62, 129.41 (N-ar. CH ) ,
114.17, 128.05 (3-ar. CH) , 121.21 (3-ar. C-l),
124.14 (q, Cr 273.0 Hz, CF 3, ) , 131.24 (q, 31.4 Hz, N-ar. C-3), 151.06 (N-ar. C-l),
160.90 (3-ar. C-4), 161.86 (C-3), 169.13 (C-5) ppm.
b) 1-/3- ( 4-Methoxyphenyl ) isoxazole-5-ylmethoxy/ -3-/ 4- ( 3-trifluoromethylphenyl ) - piperazine-1-yl/propane-2-ol dihydrochloride
The title compound is prepared using the method described in Example 51, part b). Yield: 76.6 %. M.p. : 120-124 °C. Analysis: for C25H30C12F3N304 (563.16)
.C H N Cl (ionic) calculated: 53.27 %, 5.37 %, 7.46 %, 12.42%; found: 53.34 %, 5.48 %, 7.66 %, 12.76%. IR (KBr): V 3400-3200 (OH), 2940 (CH), 2700-200 (NH), 1605, 1515, 1435, 1320, 1310, 1265,
1180, 1105, 1080, 1010, 900, 840, 800, 700 cm -1 H-NMR (DMSO-dg): ζ 3.0-3.40 (8H, m, N(CH2CH2)2 ) , 3.40-3.65 (2H, m, CH2N), 3.70-3.90 (2H, m, OCH_2CH(OH) ), 3.80 (3H, s, OCH3), 4.10-4.45 (lH, m, CHOH), 4.55 (2H, s, 2 x NH), 4.85 (2H, s, 5-CH2), 6.80-7.50 (7H, m, ArH + 4-H), 7.80 (2H, AB, j' 9.0
AB
Hz, 3-ArH) ppm.
Example 56 1-/3- ( 4-Chlorophenyl) isoxazole-5-yl-methoxy/- -3-/4- ( 3-trifluoromethylphenyl ) piperazine- -1-yl/propane-2-ol dihydrochloride a) 1-/3- ( 4-Chlorophenyl ) isoxazole-5-yl- methoxy/-3-/4- ( 3-trifluoromethylphenyl ) - piperazine-1-yl /propane-2-ol
The title compound is prepared from 10 mmoles of 5- ( 2 , 3-epoxypropoxymethyl ) -3- ( 4- -chlorophenyl ) isoxazole and 11 mmoles of N- ( 3-trifluoromethylphenyl )piperazine by the method described in Example 51, part a). The title product is obtained as an oil. Yield: 67.2 %.
IR (film): V 3438 br (OH), 3120 (4-H), 2920, 2880, 2829, 1611, 1497, 1451, 1430, 1357, 1319, 1236, 1165, 1124, 1014, 994, 950, 837, 730, 696, 517 cm"1.
XH-NMR (CDC13): £ 2.40-2.60 (4H, m, N(CH2)2), 2.70-2.85 (2H, m, CH2N), 3.00 (lH, br s, OH), 3.20-3.30 (4H, m, (CH^NAr), 3.59 + 3.66 (2H, ABX, Aβ 9.9 Hz, JAχ 3.8 Hz, Jβχ 5.5 Hz, 0CH_2CH(0H)), 3.9-4.05 (lH, m, CHOH), 4.73 (2H, s, 5-CH2), 6.58 (IH, s, 4-H), 6.95-7.05 (3H, m, N-ArH), 7.20-7.40 (lH, m, N-ArH), 7 - ,.44 + 7.72 (4H, AB, JAπtBD 6.7 Hz, 3-ArH) ppm.
C-NMR (CDC13): £ 48.48 + 52.85 ( N ( CH2CH2 ) 2N ) ,
60.05 (CH-2N), 64.06 + 66.05 (5-CH2OCH2), 73.17
(CHOH), 100.84 (C-4), 111.94 (q, JCF 4.2 Hz
N-ar. C-2 and C-4), 118.55, 129.36 (N-ar.
CH), 124.13 (q, Jcp 272.8 Hz, CF3), 127.18
(3-ar. C-l), 127.87, 129.02 (3-ar. CH ) , 131.17
(q, J__ 31.6 Hz, N-ar. C-3), 135.88 (3-ar. Cr
C-4), 151.05 (N-ar. C-l), 161.22 (C-3), 169.77 (C-5) ppm.
b) 1-/3- ( 4-Chlorophenyl ) isoxazole-5-ylmethoxy/ - 3 -14- ( 3-trifluoromethylphenyl ) - piperazine-1-yl/propane-2-ol dihydrochloride
The title compound is prepared using the method described in Example 51, part b). Yield: 83.9 %. M.p. : 176.178 °C. Analysis: for C24H27C13F3N303 (568.85)
C H N Cl (ionic) calculated: 50.67 %, 4.79 %, 7.39 %, 12.47%; found: 50.66 %, 5.12 %, 7.56 %, 12.68%. IR (KBr) 3600-3300 (OH), 285O-2300 ( H ) , 1610, 1550, 1520, 1320, 1150, 1105, 1097, 920, 890, 810, 680 cm"1.
1H-NMR (DMSO-dg + CDCl3): 2.80-3.35 (8H, m, N(CH2CH2)2N) , 3.40-3.55 (2H, m, CH2N), 3.70-4.00 (2H, m, 0CH_2CH(0H)), 4.10-4.40 (IH, m, CHOH), 4.70 (2H, s, 5-CH2 ) , 7.0 (IH, s, 4-H), 7.05-7.40 (4H, m, N-ArH) , 7.55 + 7.80 (4H, AB, JΛD 8 Hz, 3-ArH) ppm.
AB
Example 57 l-/3-( 4-Methoxyphenyl ) isoxazole-5-ylmethoxy/- -3-/4- ( 3-chlorophenyl ) piperazine-1-yl/propane- -2-ol dihydrochloride a ) 1-/3- ( 4-Methoxyphenyl )isoxazole-5-yl- methoxy/-3-/4- ( 3-chlorophenyl.) - piperazine-1-yl /propane-2-ol
The title compound is prepared from 10 mmoles of 5- ( 2 , 3-epoxypropoxymethyl ) -3- ( 4- methoxyphenyl ) isoxazole and 11 mmoles of
N-( 3-chlorophenyl ) piperazine by the method described in Example 51, part a).
Yield: 68.0 %.
M.p. : 92-95 °C.
Analysis: for C24H2gClN304 (457.96)
C H N Cl calculated: 62.95 %, 6.16 %, 9.18 %, 7.74%; found: 63.05 %, 5.90 %, 9.21 %, 8.06%.
IR (KBr): 3600-3200 (br OH), 2823 (CH),
1612, 1595, 1562, 1529, 1486, 1454, 1430,
1392, 1362, 1305, 1259, 1176, 1102, 1030,
986, 948, 899, 837, 811, 780, 759, 679, 532 cm- .
"""H-NMR (CDC13): £ 2.41-2.61 (4H, m, (CH2)2),
2.73-2.82 (2H, m, CH2N), 3.19 (4H, m,
(CH2)2NAr), 3.58 + 3.66 (2H, ABX, JAβ 9.9
Hz, JAΛVA 3•.8 Hz, JBDAV 5.4 Hz, 0CH Z„CH(0H)), 3.85 (3H, s, 0CH3), 3.96 (IH, m, CHOH), 4.71 (2H, s, 5-CH2), 6.54 (IH, s, 4-H), 6.75-7.00 (3H, m, N-ArH), 7.12-7.19 (IH, m, N-ArH), 6.97
+ 7.74 (4H, AB, JΛD 8.9 Hz, 3-ArH) ppm.
13 C-NMR (CDC13): 48.51 + 52.88 (N( CH2CH2 ) 2N) ,
55 . 15 ( OCH3 ) , 60.08 ( CH2N ) , 64 .09 + 66 .01
(5-CH2OCH2), 73.06 (CHOH), 100.82 (C-4),
113.70, 115.58, 119.20, 129.84 (N-ar. CH),
114.14, 128.01 (3-ar. CH), 121.18 (3-ar. C-l),
134.73 (N-ar. C-3), 151.98 (N-ar. C-l), 160.86
(3-ar. C-4), 161.79 (C-3), 169.12 (C-5) ppm.
b ) 1-/3- ( 4-Methoxyphenyl ) isoxazole-5-yl- methoxy/-3-/4- ( 3-chlorophenyl )piperazine- -1-yl/propane-2-ol dihydrochloride
The title compound is prepared using the method described in Example 51, part b). Yield: 78.1 %. M.p. : 135-138 °C. Analysis: for C24H30C13N304 (529.13)
C H N Cl Cl calculated:54.43%, 5.71%, 7.94%, 6.61%, 13.22%; found: 54.10%, 5.69%, 8.14%, 6.50%, 13.56%. IR (KBr): 3400-3200 (OH), 2940 (CH), 2700-2000 (NH), 1605, 1515, 1450, 1435, 1375, 1310, 1300, 1250, 1180, 1105, 1020, 900, 840, 810, 780, 680 cm"1.
1H-NMR (DMSO-dg + CDCl3): <£ 3.03-3.40 (8H, m, N(CH2CH2)2N) , 3.40-3.65 (2H, m, CH2 ), 3.70-3.90 (2H, m, 0CH2CH (OH) ) , 3.85 (3H, s, OCH ) , 4.10-4.45 (IH, m, CHOH), 4.65 (2H, s, 5-CH2), 5.05 (2H, s, 2 x NH), 6.70-7.20 ( (77HH,, ,, AArrHH ++ 4-H), 7.80 (2H, AB, O
AB Hz, 3 ArH) ppm.
Example 58 3-Phenyl-5- ( 2-morpholinoethoxymethyl ) isoxazole hydrochloride a ) 3-Phenyl-5- ( 2-morpholinoethoxymethyl ) - isoxazole
0.33 g (11 mmoles) of sodium hydride are added to a solution of 1.33 ml (11 mmoles) of N- ( 2-hydroxyethyl )morpholine in 45 ml of anhydrous tetrahydrofuran. The mixture is boiled for 0.5 hours to achieve complete salt forming. To the cooled suspension, 10 mmoles of 5-bromomethyl-3-phenylisoxazole are added, and the reaction mixture is boiled for about 4 hours. The reaction is followed by thin layer chromatography ( hexane : acetone 10:2, UV, FM) . If desired, a further portion of alcoholate prepared from 5.5 moles of N-(2- -hydroxyethyl )morpholine as described above is added to the reaction mixture, and boiling is continued until the starting isoxazole compound is disappeared. The reaction mixture is evaporated, the residue is rubbed with 30 ml of water, and the product is extracted 3 times using 30 ml of dichloromethane each time. The organic phases are combined, dried over anhydrous magnesium sulfate, and evaporated. The residue is purified by chromatography over Kieselgel G using gradient elution starting with hexane and finishing with a mixture consisting of 10 volumes of hexane and 2 volumes of acetone. The title compound is obtained as an oil. Yield: 55.7 %.
"""H-NMR (CDC13): £ 2.52 (4H, t, J 4.6 Hz, N(CH2)2), 2.64 (2H, t, J 5.6 Hz, CH2N), 3.65-3.80 (6H, m, OCH2CH2 and (CH2)20), 4.67 (211, s, 5-CH-,), 6.57 (III, s, 4-11), 7.40-7.50 (3H, m, Ph), 7.75-7.80 (2H, m, Ph ) ppm.
b) 3-Phenyl-5-( 2-morpholinoethoxymethyl ) - isoxazole hydrochloride
The isoxazole base obtained as described above in part a) is dissolved in a tenfold amount of ether, and the solution is saturated with anhydrous hydrogen chloride gas under cooling with ice water. The product separated is filtered, washed with anhydrous ether, and dried over phosphorus pentoxide at 40
C under reduced pressure. Yield: 72.3 %. M.p.: 107-109 °C. Analysis: for C161121C1N203 (324.81)
C H N Cl (ionic) calculated: 59.17 %, 6.52 %, 8.62 %, 10.92%; found: 58.87 %, 6.37 %, 8.65 %, 10.95%. IR (KBr): V 2800-2300 (NH), 1610, 1440, 1090, 890, 760, 670 cm"1. VNMR (DMS0-d6 + CDC13) : " 2.9-3.6 (6H, m. N(CH2)3), 3.7-4.05 (6H, m, (CH2)20 + OCH2CH2), 4.70 (2H, s, 5CH2), 7.09 (lH, s, 4-H), 7.30-7.60 (3H, m, Ph), 7.65-8.00 (2H, m, Ph ) ppm.
Example 59 3- ( 4-Chlorophenyl ) -5- ( 2-morpholinoethoxy- methyl ) isoxazole hydrochloride a ) 3- ( 4-Chlorophenyl ) -5- ( 2-morpholino- ethoxymethyl ) isoxazole
The title compound is prepared from 10 mmoles of 5-bromomethyl-3- ( 4-chlorophenyl ) - isoxazole by the method described in Example 58 , part a) . Yield: 43.0 %. M.p. : 69-71 °C. Analysis: for C10HιgClN203 (322.79)
C H N Cl calculated: 59.54 %, 5.93 %, 8.68 %, 10.98%; found: 59.22 %, 5.78 %, 8.40 %, 10.71%. IR (KBr): 3112 (4-H), 3046, 2961, 2861, 2827, 1686, 1605, 1568, 1510, 1455, 1432, 1356, 1302, 1278, 1211, 1169, 1115, 1016,
974, 949, 917, 845, 772, 723, 684, 628, 720,
-1
463 cm
•""H-NMR (CDC13): 2.45-2.55 (4H, in, N(C1_2)2), 2.63 (2H, t, J 5.6 Hz, CH2N) , 3.65-3.75 (6H, m, OCH2CH2 and (CH2)20), 4.67 (2H, s, 5-CH2), 6.55 (IH, s, 4-H), 7.43 + 7.73 (4H, AB, JAβ 8.5 Hz, A'rH) ppm.
13
IR (CDC13) : £ 53.89 (N(CH2)2), 58.1(
(CH2 N , 63.78 + 68.36 (5-CH2 OCH2)' 66-73 ((CH2)20), 100.78 (C-4), 127.25 (ar. C-l), 127.93, 129.09 ( ar . CH), 135.96 ( ar . C-4), 161.29 (C-3), 170.09 (C-5) ppm.
b) 3-( 4-Chlorophenyl ) -5- ( 2-morpholino- ethoxymethyl ) isoxazole hydrochloride
The title compound is prepared using the method described in Example 58, part b). Yield: 95.9 %. M.p. : 148-150 °C.
Analysis: for cι6 H20C12N203 (359-25)
C H N Cl (ionic) calculated: 53.49 %, 5.61 %, 7.80 %, 9.87%; found: 53.26 %, 5.65 %, 7.84 %, 9.95%. IR (KBr): 2800-2300 (NH), 1610, 1410, 1360, 1110, 1070, 890, 810, 760 cm"1. """H-NMR (DMSO-dg + CDCl3): <£ 2.80-3.60 (6H, m, N(CH2)3), 3.70-4.00 (6H, m, (CH^O and OCH2OCH2), 4.75 (2H, s, 5-CH2), 7.00 (lH, s, 4-H), 7.50 + 7.82 (4H, AB, JAβ 8 Hz, ArH) ppm.
Example 60 3- ( 4-Bromophenyl ) -5-( 2-morpholinoethoxy- methyl ) isoxazole hydrochloride a ) 3- ( 4-Bromophenyl ) -5- ( 2-morpholino- ethoxymethyl ) isoxazole
The title compound is prepared from 10 mmoles of 3- ( 4-bromophenyl ) -5-bromomethyl- isoxazole by the method described in Example 58 , part a) .
Yield: 54.5 %.
M.p. : 83-85 °C.
IR (KBr): 3113 (4-H), 2962, 2862, 2812,
1619, 1507, 1480, 1454, 1431, 1363, 1325,
1294, 1262, 1211, 1172, 1115, 1070, 1013,
995, 949-, 914, 842, 798, 773, 723, 520, 464
"""H-NMR (CDCl3): £ 2.45-2.55 (4H, m, N(CH2)2),
2.63 (2H, t, J 5.6 Hz, CII2N), 3.65-3.75 (6H, m, OCH2CH2 and (CH2)20), 4.67 (2H, s, 5-CH2),
6.55 (IH, s, 4-H), 7.59 + 7.67 (4H, AB , JAβ
7.6 Hz, ArH) ppm.
13C-NMR (CDC13): £ 53.86 ( (CH2)2), 58.04
(CH2N), 63.74 + 68.32 (5-CH2OCH2), 66.70
((CH2)20), 100.71 (C-4), 124.20 ( ar . C-4),
128.12, 131.99 (ar. CH), 129.05 ( ar . C-l),
161.33 (C-3), 170.10 (C-5) ppm.
b) 3-( 4-Bromophenyl ) -5- ( 2-morpholino- ethoxymethyl ) isoxazole hydrochloride
The title compound is prepared using the method described in Example 58, part b). Yield: 79.6 %. M.p.: 166-169 °C. Analysis: for C16H20BrCl 203 (403.70)
C H N Cl (ionic) calculated: 47.60 %, 4.99 %, 6.94 %, 8.78%; found: 47.59 %, 5.19 %, 6.88 %, 9.03%. IR (KBr): V 2800-2300 (NH), 1650, 1610, 1450, 1410, 1100, 1075, 780 cm" . 1 H-NMR (DMSO-d6 + CDCl3): δ 3.00-3.45 (6H, m, N(CH2)3), 3.70-4.00 (6H, m, OCH2CH2 and (CH2)20), 4.70 (2H, s, 5-CH2), 7.07 (1H, s, 4-H), 7.5-7.95 (4H, m, ArH) ppm.

Claims

Claims :
1. Isoxazole derivatives of the formula
Figure imgf000153_0001
wherein
A and B represent, independently, a hydrogen atom, or A forms, together with B, a valence bond, Z stands for a hydrogen atom, a halo atom, a C-, . alkyl group, a trifluoromethyl group or one or two C-, _ Δ alkoxy group(s), R 1 and R2 mean, independently, a C, _fi alkyl group or a C, 7 cycloalkyl group, or R 1 and R2 form, together with the nitrogen atom they are attached to and optionally with one or more further nitrogen and/or oxygen atom(s), a 5 to 8-membered heterocyclic ring that can be substituted by a C- . alkyl group, a (C,_. alkyl )phenyl group, a (C,_. alkoxy ) phenyl group, a di(C, . alkoxy )phenyl group, a halophenyl group, a trifluoromethylphenyl group or a furoyl group, m has a value of 0 or 1, n has a value of 0 or 1, with the proviso that
1) if A forms, together with B, a valence bond, m has a value of 0, furthermore each of R 1 and R2 stands for an ethyl group or R 1 and R2 form, together with the nitrogen atom they are attached to, a piperidin-1-yl or a morfolino group, then Z is other than a hydrogen atom or a chloro atom in position para, and
2) if A forms, together with B, a. valence bond, m has a value of 0, furthermore each of R 1 and R2 stands for a methyl group or R 1 and R2 form, together with the nitrogen atom they are attached to, a pirrolidin-1-yl group, then Z is other than a hydrogen atom, and pharmaceutically acceptable acid addition salts thereof.
2. 4 , 5-Dihydroisoxazole derivatives of the formula la
Figure imgf000155_0001
being a narrower group of the compounds claimed in Claim 1, wherein
Z stands for a hydrogen atom, a halo atom, a C-, _ . alkyl group, a trifluoromethyl group or one or two C-, Δ alkoxy group(s), ι 2
R and R mean, independently, a C, β alkyl group or a C,_7 cycloalkyl group, or
RJ 2 and R form, together with the nitrogen atom they are attached to and optionally with one or more further nitrogen and/or oxygen atom(s), a 5 to 8-membered heterocyclic ring that can be substituted by a C-|_4 alkyl group, a (C,_4 alkyl)phenyl group, a (C-, , alkoxy ) phenyl group, a di(C,_4 alkoxy ) phenyl group, a halophenyl group, a trifluoromethylphenyl group or a furoyl group, m has a value of 0 or 1, n has a value of 0 or 1, and pharmaceutically acceptable acid addition salts thereof.
3. Isoxazole derivatives of the formula lb
Figure imgf000156_0001
being a narrower group of the compounds claimed in Claim 1, wherein
Z stands for a hydrogen atom, a halo atom, a C-,_4 alkyl group, a trifluoromethyl group or one or two C, . alkoxy group(s),
R and R 2 mean, independently, a C, fi alkyl group or a C, 7 cycloalkyl group, or
RJ and R 2 form, together with the nitrogen atom they are attached to and optionally with one or more further nitrogen and/or oxygen atom(s), a 5 to 8-membered heterocyclic ring that can be substituted by a C, _4 alkyl group, a (C, . alkyl) phenyl group, a (C,_. alkoxy )phenyl group, a di(C, 4 alkoxy ) phenyl group, a halophenyl group, a trifluoromethylphenyl group or a furoyl group, m has a value of 0 or 1 , n has a. value of 0 or 1, with the proviso that
1) if m has a value of 0, furthermore each of R 1 and R2 stands for an ethyl group or R 1 and R2 form, together with the nitrogen atom they are attached to, a piperidin-1-yl or a morfolino group, then Z is other than a hydrogen atom or a chloro atom in position para, and
2) if m has a value of 0, furthermore each of R 1 and R2' stands for a methyl group or R 1 and R2 form, together with the nitrogen atom they are attached to, a pirrolidin-1-yl group, then Z is other than a hydrogen atom, and pharmaceutically acceptable acid addition salts thereof.
4. Compounds as claimed in Claim 1, wherein in formula I
A and B represent, independently, a hydrogen atom, or A forms, together with B, a valence bond, Z stands for a hydrogen atom, a halo atom, a methyl group, a trifluoromethyl group or one or two methoxy group(s), R 1 and R2 form, together with the nitrogen atom they are attached to and optionally with a further nitrogen or oxygen atom, a pyrrolidinyl , piperidinyl, azepanyl, morpholino or piperazinyl group which latter can be substituted by a methyl, methylphenyl, methoxyphenyl, di ethoxy phenyl, halophenyl, trifluoromethylphenyl or furoyl group, m has a value of 0 or 1, n has a value of 0 or 1, and pharmaceutically acceptable acid addition salts thereof.
5. Compounds as claimed in Claim 4, wherein in formula I
A and B represent, independently, a hydrogen atom, or A forms, together with B, a valence bond,
Z stands for a halo atom, a methyl group or a methoxy group, R 1 and R2 form together with the nitrogen atom they are attached to and with a further nitrogen atom a piperazinyl group optionally substituted by a methoxyphenyl group, m has a value of 0 or 1, n has a value of 0 or 1, and pharmaceutically acceptable acid addition salts thereof.
6. A process for preparing isoxazole derivatives of the formula I, wherein A, B, Z, R 1 , R2 , m and n are as defined in Claim
1, and pharmaceutically acceptable acid addition salts thereof, in which a) for the preparation of 4,5-dihydro- isoxazole derivatives of the formula la being a narrower group of the compounds of the formula I, wherein m has a value of 0, Z, RR 1 1 aanndd RR22 aarree aass ddeeffiinneecd in the scope, a nitril oxide of the formula II
Figure imgf000159_0001
wherein Z is as stated above, is reacted with an allyl derivative of the formula III
R
Figure imgf000159_0002
wherein R 1 and R2 are as defined above; or b) for the preparation of 4,5-dihydro- isoxazole derivatives of the formula la being a narrower group of the compounds of the formula I, wherein m has a value of 1, n has a value of 0, Z, R 1 and R2 are as stated in the scope, a 4 , 5-dihydroisoxazole-5-ylmethanol of the formula IV
Figure imgf000160_0001
wherein Z is as stated above, is reacted with a halo compound of the formula V
Figure imgf000160_0002
wherein Hal represents a halo atom, R and
2 R are as stated above; or c) for the preparation of 4,5-dihydro- isoxazole derivatives of the formula la being a narrower group of the compounds of the formula I, wherein m has a value of 1, n has a value of 1, Z, R 1 and R2 are as stated in the scope, an epoxide of the formula XIII
Figure imgf000161_0001
wherein Z is as defined above, is reacted with an amine of the formula IX
1
R
HN.
R wherein R 1 and R2 are as defined above; or d) for the preparation of isoxazole derivatives of the formula lb being a narrower group of the compounds of the formula I,
1 2 wherein m has a value of 0, Z, R and R are as stated in the scope, a nitril oxide of the formula II, wherein Z is as defined above, is reacted with a propargyl derivative of the formula VII
Figure imgf000161_0002
wherein R1 and R2 are as stated above; or e) for the preparation of isoxazole derivatives of the formula lb being a narrower group of the compounds of the formula I, wherein m has a value of 0, Z, R 1 and R2 are as stated in the scope, a halomethylisoxazole derivative of the formula VIII
Figure imgf000162_0001
wherein Hal represents a halo atom, Z is as defined above, is reacted with an amine of the formula IX, wherein R 1 and R2 are as defined above; or f) for the preparation of isoxazole derivatives of the formula lb being a narrower group of the compounds of the formula I, wherein m has a value of 1 , n has a value of 1, Z, R 1 and R2 are as defined in the scope, an epoxide of the formula X
Figure imgf000163_0001
wherein Z is as defined above, is reacted with an amine of the formula IX, wherein R
2 and R are as defined above; or g) for the preparation of isoxazole derivatives of the formula lb being a narrower group of the compounds of the formula I, wherein m has a value of 1, n has a value
1 2 of 0, Z, R and R are as stated above, a halomethylisoxazole derivative of the formula
VIII, wherein Hal represents a halo atom,
Z is as defined above, is reacted with an amine of the formula XI
Figure imgf000163_0002
wherein R 1 and R2 are as defined above; and, if desired, a compound of the formula
I obtained is converted to a pharmaceutically acceptable inorganic or organic acid addition salt .
7. A pharmaceutical composition comprising an isoxazole derivative of the formula I
Figure imgf000164_0001
wherein
A and B represent, independently, a hydrogen atom, or A forms, together with B, a valence bond, Z stands for a hydrogen atom, a halo atom, a C- _Δ alkyl group, a trifluoromethyl group or one or two C, _ . alkoxy group(s), R 1 and R2 mean, independently, a C-, _fi alkyl group or a C,_7 cycloalkyl group, or R 1 and R2 form, together with the nitrogen atom they are attached to and optionally with one or more further nitrogen and/or oxygen atom(s), a 5 to 8-membere heterocyclic ring that can be substituted by a C-, . alkyl group, a (C-, . alkyl) phenyl group, a (C-, , alkoxy ) phenyl group, a di(C,_4 alkoxy ) phenyl group, a halophenyl group, a trifluoromethylphenyl group or a furoyl group, m has a value of 0 or 1, n has a value of 0 or 1, with the proviso that
1) if A forms, together with B, a valence bond, m has a value of 0, furthermore each
1 2 of R and R stands for an ethyl group or R 1 and R2 form, together with the nitrogen atom they are attached to, a piperidin-1-yl or a morfolino group, then Z is other than a hydrogen atom or a chloro atom in position para, and
2) if A forms, together with B, a valence bond, m has a value of 0, furthermore each
1 2 of R and R stands for a methyl group or R 1 and R2 form, together with the nitrogen atom they are attached to, a pirrolidin-1-yl group, then Z is other than a hydrogen atom, or a pharmaceutically acceptable acid addition salt thereof as the active ingredient and one or more conventional carrier (s).
8. A pharmaceutical composition as claimed in Claim 7, comprising an isoxazole derivative of the formula I, wherein
A and B represent, independently, a hydrogen atom, or A forms, together with B, a valence bond, Z stands for a hydrogen atom, a halo atom, a methyl group, a trifluoromethyl group or one or two methoxy group(s), R 1 and R2 form, together with the nitrogen atom they are attached to and optionally with a further nitrogen or oxygen atom, a pyrrolidinyl , piperidinyl, azepanyl, morpholino or piperazinyl group which latter can be substituted by a methyl, methylphenyl, methoxyphenyl, dimethoxyphenyl, halophenyl, trifluoromethylphenyl or furoyl group, m has a value of 0 or 1, n has a value of 0 or 1, or a pharmaceutically acceptable acid addition salt thereof as the active ingredient and one or more conventional carrier (s).
9. A pharmaceutical composition as claimed in Claim 7 or 8 comprising an isoxazole derivative of the formula I, wherein A and B represent, independently, a hydrogen atom, or A forms, together with B, a valence bond, Z stands for a halo atom, a methyl group or a methoxy group, R 1 and R2 form together with the nitrogen atom they are attached to and with a further nitrogen atom a piperazinyl group optionally. substituted by a methoxyphenyl group, m has a value of 0 or 1, n has a value of 0 or 1, or a pharmaceutically acceptable acid addition salt thereof as the active ingredient and one or more conventional carrier(s).
10. A method of treatment in which a patient suffering especially from a pathological alteration of the central nervous system and/or cardiovascular and/or gastrointestinal diseases is treated with a nontoxic' dose of an isoxazole derivative of the formula I
Figure imgf000167_0001
wherein
A and B represent, independently, a hydrogen atom, or A forms, together with B, a valence bond, Z stands for a hydrogen atom, a halo atom, a C-, . alkyl group, a trifluoromethyl group or one or two C, , alkoxy group(s), R 1 and R2 mean, independently, a C, _fi alkyl group or a C, ' cycloalkyl group, or R1 and R2 form, together with the nitrogen atom they are attached to and optionally with one or more further nitrogen and/or oxygen atom(s), a 5 to 8-membered heterocyclic ring that can be substituted by a C, . alkyl group, a (C, . alkyDphenyl group, a (C, . alkoxy ) phenyl group, a di(C,_4 alkoxy )phenyl group, a halophenyl group, a trifluoromethylphenyl group or a furoyl group, m has a value of 0 or 1, n has a value of 0 or 1, with the proviso that
1) if A forms, together with B, a valence bond, m has a value of 0, furthermore each of R 1 and R2 stands for an ethyl group or R 1 and R2 • form, together with the nitrogen atom they are attached to, a piperidin-1-yl or a morfolino group, then Z is other than a hydrogen atom or a chloro atom in position para, and
2) if A forms, together with B, a valence bond, m has a value of 0, furthermore each of R 1 and R2 stands for a methyl group or R 1 and R2 form, together with the nitrogen atom they are attached to, a pirrolidin-1-yl group, then Z is other than a hydrogen atom, or a pharmaceutically acceptable acid addition salt thereof.
11. The use of the compounds as claimed in Claim 1 for the preparation of a pharmaceutical composition suitable for the treatment of especially a pathological alteration of the central nervous system and/or a cardiovascular and/or gastrointestinal disease.
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US6723724B2 (en) * 2000-12-04 2004-04-20 Korea Institute Of Science And Technology Isoxazolylalkylpiperazine derivatives having selective biological activity at dopamine D3 or D4 receptor, and preparation thereof
US6673800B2 (en) * 2000-12-04 2004-01-06 Korea Institute Of Science And Technology 4,5,-dihydroisoxazolylakylpiperazine derivatives having selective biological activity at dopamine D3 or D4 receptor, and preparation thereof
CN100400540C (en) * 2001-02-21 2008-07-09 詹森药业有限公司 Isoxazoline derivatives as anti-depressants
US7022705B2 (en) 2001-10-25 2006-04-04 Astrazeneca Ab Isoxazoline derivatives useful as antimicrobials
US7728009B1 (en) 2005-02-18 2010-06-01 Neurogen Corporation Thiazole amides, imidazole amides and related analogues
US8318743B2 (en) 2006-07-03 2012-11-27 Egis Gyogyszergyar Nyilvanosan Mukodo Reszvenytarsasag Medicament for the enhancement of cognitive function and neuroprotection
WO2008004013A2 (en) * 2006-07-03 2008-01-10 EGIS GYÓGYSZERGYÁR Nyilvánosan Müködö Részvénytársaság Medicament for the enhancement of cognitive function and neuroprotection
WO2008004013A3 (en) * 2006-07-03 2008-04-03 Egyt Gyogyszervegyeszeti Gyar Medicament for the enhancement of cognitive function and neuroprotection
EA016142B1 (en) * 2006-07-03 2012-02-28 Эгиш Дьёдьсердьяр Ньильваношан Мюкёдё Ресвеньтаршашаг USE OF 4-CHLORO-5-{2-[4-(6-FLUORO-1,2- BENZ[d]ISOXAZOLE-3-YL)PIPERIDIN-1-YL]ETHYL-AMINO}-2-METHYL-3- (2H) PYRIDAZINONE OR PHARMACEUTICALLY ACCEPTABLE SALTS FOR NEUROPROTECTION (EMBODIMENTS) MEDICAMENT (EMBODIMENTS) AND METHOD FOR TREATMENT (EMBODIMENTS)
WO2008033513A1 (en) * 2006-09-15 2008-03-20 Janssen Pharmaceutica N.V. ISOXAZOLINE ALPHA 1a/1d ADRENORECEPTOR ANTAGONISTS
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JP2012518683A (en) * 2009-02-25 2012-08-16 エスケー バイオファーマスティカルズ カンパニー リミテッド Substituted azole derivatives, pharmaceutical compositions containing the derivatives, and methods of treating Parkinson's disease using the same
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US8828992B2 (en) 2009-02-25 2014-09-09 Sk Biopharmaceuticals Co., Ltd. Substituted azole derivatives, pharmaceutical composition containing the derivatives, and method for treating Parkinson's disease using the same
AU2010218584B2 (en) * 2009-02-25 2015-12-03 Sk Biopharmaceuticals Co., Ltd. Substituted azole derivatives, pharmaceutical composition containing the derivatives, and method for treating Parkinson's disease using the same
US8765735B2 (en) 2009-05-18 2014-07-01 Infinity Pharmaceuticals, Inc. Isoxazolines as inhibitors of fatty acid amide hydrolase
US8927551B2 (en) 2009-05-18 2015-01-06 Infinity Pharmaceuticals, Inc. Isoxazolines as inhibitors of fatty acid amide hydrolase
US9149465B2 (en) 2009-05-18 2015-10-06 Infinity Pharmaceuticals, Inc. Isoxazolines as inhibitors of fatty acid amide hydrolase

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