IL35047A - Beta-aryl and heteroaryl-2-amino-alkoxy-styrenes,and their preparation - Google Patents

Beta-aryl and heteroaryl-2-amino-alkoxy-styrenes,and their preparation

Info

Publication number
IL35047A
IL35047A IL35047A IL3504770A IL35047A IL 35047 A IL35047 A IL 35047A IL 35047 A IL35047 A IL 35047A IL 3504770 A IL3504770 A IL 3504770A IL 35047 A IL35047 A IL 35047A
Authority
IL
Israel
Prior art keywords
formula
group
reaction
styryl
acid addition
Prior art date
Application number
IL35047A
Other languages
Hebrew (he)
Other versions
IL35047A0 (en
Original Assignee
Thomae Gmbh Dr K
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Thomae Gmbh Dr K filed Critical Thomae Gmbh Dr K
Publication of IL35047A0 publication Critical patent/IL35047A0/en
Publication of IL35047A publication Critical patent/IL35047A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/18—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with unsaturation outside the aromatic ring
    • C07C39/19—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with unsaturation outside the aromatic ring containing carbon-to-carbon double bonds but no carbon-to-carbon triple bonds
    • C07C39/20—Hydroxy-styrenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/42—Singly bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4056—Esters of arylalkanephosphonic acids

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Neurology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Psychiatry (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Anesthesiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Quinoline Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Furan Compounds (AREA)
  • Illuminated Signs And Luminous Advertising (AREA)

Description

onasm Ο'ΤΡΤΓΠ New β -aryl and h.eteroaryl-2-aminoalkoxy«» styrenes, and their preparation DR. KARL THO AE GmbH.
G: 33202 This invention relates to novel styrenes having interesting physiological properties.
According to one feature of the present invention there are provided compounds of the general formula [wherein Ar represents a phenyl group; a 2-, 3-, or 4- pyridyl group (which may optionally be substituted by a lower alkyl group); a 2-quinolyl or 2-pyrazinyl group (each of which may optionally be substituted by a lower alkyl group) » a/pyrimidyl group optionally substituted by a lower alkyl group; a 2-benzimidazolyl group optionally substituted phenyl by a halogen atom or a lower alky,/or trifluoromethyl group; a 4-isoxazolyl group or a 2-furyl or 2-thienyl group;/a 5-isoxazolyl group optionally substituted by a lower alkyl or phenyl group ;or a 5-(l,2,4- oxadiazolyl )-group optionally substituted by a lower alkyl group; R^, R^* anc ^5> which may be the same or different, each represents a hydrogen atom or lower alkyl group; ^ represents a hydrogen atom or a lower alkoxy group; either R^ and R^, which may be the same or different, each represents a hydrogen atom, a lower alkyl, alkenyl, hydroxyalkyl or alkoxyalkyl group or an aralkyl group, or and R^, together with the nitrogen atom to which they are attached, form a saturated, monocyclic, heterocyclic 5-to 7-membered ring which may optionally be interrupted by an or an N-methylimino group oxygen atom,-©*- a further nitrogen aton/; and n represents 0 or 1] and their acid addition salts.
For use in pharmaceutical compositions the acid addition salts will, of course, be physiologically acceptable acid addition salts.
The compounds of formula I may, for example, be prepared according to the following processes, which processes con¬ stitute further features of the present invention: 1) By elimination of water from compounds of formula (wherein Ar, R^ to R-. and n are as hereinbefore defined).
The elimination of water may, for example, be effected using phosphoric acid, polyphosphoric acids, phosphoric acid with phosphorus pentoxide or sulfuric acid; 85% phosphoric acid has proved to be especially suitable. The reaction takes place at elevated temperatures, and is preferably effected in the range 70 to 130°C. 2) By reaction of a phosphonate of formula Rl Ar- C —H III 0 = P(0Rg)2 (wherein and Ar are as hereinbefore defined and Rg represents a lower alkyl group) with an aldehyde or ketone of formula (wherein R2 to R-. and n are as hereinbefore defined) in the presence of a base, whereby the carbanion of the compound or formula III is formed as an intermediate. Alkali metal hydrides are the preferred bases.
The reaction is conveniently performed in a solvent. Higher-Foiling ethers such as dioxan are especially suitable as solvents. The reaction may also be performed in a solvent containing water, for instance in methanol/water in the presence of an inorganic base. Conveniently, the phosphonic acid ester of formula III is first admixed with an alkali metal hydride. After development of hydrogen has finished, the aldehyde or the ketone of formula IV is added, conveniently without previous isolation of the carbanion formed, The reactions are advantageously carried out at slightly elevated temperatures, preferably at temperatures between and 60°C. 3) By reaction of a phosphonic acid ester of formula (wherein 2 to R^ and n are as hereinbefore defined and Rg represents a lower alkyl group) with an aldehyde or ketone of formula R, Ar - C =0 VI (wherein Ar and R^ are as hereinbefore defined) in the presence of a base, whereby a carbanion of the compound of formula V is formed as an intermediate. Alkali metal hydrides are the preferred bases .
The reaction is conveniently carried out in a solvent.
As solvents are especially suitable higher-boiling ethers, for example dioxan. The reaction may, however, also be performed in solvents containing water, for instance in a methanol water mixture in the presence of inorganic bases.
Conveniently, the phosphonic acid ester of formula V is admixed first with an alkali metal hydride. Then, after development of hydrogen has finished, the aldehyde or ketone of formula VI is added }conveniently without previous isolation of the carbanion formed. The reactions are advantageously carried out at slightly elevated temperatures, preferably at temperatures between 30 and 60 °C. 4) By reaction of a compound of formula VII OX (wherein Ar and R^ to are as hereinbefore defined and X represents a hydrogen atom or an acetyl group) with an amine of formula (wherein R^ to R^ are as hereinbefore defined and Y represents a halogen atom) in the presence of a base.
The reaction is conveniently carried out in an inert solvent such as for exam le benzene chlorobenzene toluene or xylene, advantageously at elevated temperatures, preferably at the boiling point of the solvent used. Preferred bases include alkali metal hydroxides, carbonatesand alcoholates, the latter being especially suitable.
) By reaction of a compound of formula (wherein Ar, R^ to and n are as hereinbefore defined and* Z represents a group replaceable by a basic group, such as for instance a halogen atom or a tosyl group) with an amine of formula / 6 H N \ R7 (wherein and R^ are as hereinbefore defined).
The reaction is performed in a solvent, conveniently in the presence of an acid binding agent. Inorganic or organic bases may be used as acid binding agents alternatively an excess of the amine of formula X may serve simultaneously as solvent and acid binding agent. The reaction is advant¬ ageously carried out at elevated temperatures, generally at temperatures between 60 and 120°C. If an easily volatile amine of formula X is used the reaction is conveniently performed in a closed vessel. 6) By reaction of a phosphorylide of formula Ar C YT P (C6H5)3 (wherein Ar and R^ are as hereinbefore defined) with a basic ketone or aldehyde of formula (wherein to ^ an<^ n are as hereinbefore defined). The phosphorylides of formula XI are conveniently liberated shortly before reaction from the corresponding phosphonium halides by means of bases, for example by means of alkali metal alcoholates. The reaction is preferably carried out in a solvent, for example in an alcohol, such as ethanol. The reaction advantageously takes place at temperatures between 40°C and the boiling point of the solvent used.
The compounds of formula I are generally formed as mixtures of their cis- and trans-isomers . If in processes 1,2,3 and 6 the radicals R^ and are hydrogen atoms, the trans-isomer predominates in the product. The cis- and trans-compounds may be separated from each other by fractional crystallisation, conveniently in the form of their salts, for example their hydrochlorides.
The compounds of formula I may be converted into their acid addition salts by means of inorganic or organic acids in conventional manner. If Ar represents a heterocyclic group containing a nitrogen atom it is possible to protonate the nitrogen atoms of the basic side-chain by means of stepwise neutralization. If the reaction is performed with excess acid, the nitrogen atom(s) of the heterocyclic ring(s) are protonated. The following acids have proved to be especially suitable: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, tartaric acid and p_-toluene- sulfonic acid.
The compounds of formula II which serve as starting materials in process 1) may, for example, be obtained by condensing a compound of formula (wherein Ar and R. are as hereinbefore defined) with an ester of formula XIV (wherein to and n are as hereinbefore defined and RQ represents an alkyl group) to give a ketone of formula for example in the presence of sodium amide in toluene; subsequently, the ketone of formula XV is reduced,e.g. with complex hydrides ( for example with sodium borohydride ) or with catalytically activated hydrogen, to an alcohol of formula II.
The phosphonic acid esters of formula III used in process 2) may be prepared by reacting a halomethyl compound of formula (wherein Ar and R^ are as hereinbefore defined and Hal represents a chlorine, bromine or iodine atom) with a trialkyl phosphite, according to the method of Arbusow - Miehaelis (Houben-Weyl, Methoden der organischen Chemie, 4th edition, vol. XII, part 1, page 433) or with sodium dialkyl phosphite according to the. method of Miehaelis - Becker (Houben- Weyl, Methoden der organischen Chemie, 4th edition, vol. XII, part 1, page 447).
The compounds of formula IV may be prepared by basic alkylation of compounds of formula by means of compounds of formula VIII according to the method described in process 4). Thus, the following compounds have been obtained from the corresponding salicylaldehydes and 2-hydroxyacetophenones : 2- (2-dimethylaminoethoxy)-benzaldehyde b.p.Q Q5 =H0°C 2-(2-dimethylaminoethoxy)-acetophenone 05 = 103 - 105°C 2-(3-dimethylaminopropoxy)-benzaldehyde b.p.^ = 109 - 112 °C 2- (3-dimethylaminopropoxy)-acetophenone b. .Q ^ = 130°C The phosphonic acid esters of formula V used in process 3) may be obtained by basic alkylation of compounds of formula XVII with compounds of general formula VIII to yield ketones and aldehydes of formula IV which may be subsequently reacted with complex hydrides, preferably with sodium borohydride in methanol, to give the corresponding alcohols. The latter may be subsequently reacted with inorganic acid halides, for example with thionyl chloride, to give the coresponding halogen compounds of formula (wherein R to and n are as hereinbefore defined and Hal represents a halogen atom, preferably a chlorine or bromine atom). The compounds of formula XVIII, which are generally crystalline, are present in the form of their hydrohalide salts. These salts are reacted in an inert solvent, such as for instance in benzene, with double the quantity of sodium dialkyl phosphite to give compounds of formula V, according to the method of Michaelis-Becker (Houben-Weyl, Methoden der organischen Chemie, 4th edition, vol. XII, part 1, page 447).
The compounds of formula VII used in process 4) may be prepared according to known processes (cf · L. Horwitz, J.
Org. Chem. 21, 1039 - 1041 (1956)). The compounds of formula VIII are known from the literature or may be obtained analogously to processes known from the literature.
The starting compounds of general formula IX used for process 5 may, for example, be produced by reacting the corresponding 2- (2-acetoxystyryl)-aryls with 2-haloethyl benzene-sulfonates in the presence of potassium methoxide in toluene.
Thus for example, the following starting compounds have been prepared: 2-[2-(2-chloroethoxy)styryl]-pyridine, m.p.: 57 - 59°C, 2-[2-(2-chloroethoxy)styryl]-quinoline, m.p. of the hydrochloride: 200 - 202 °C.
The phosphonium halides from which the phosphorylides of formula XI used in process 6) are obtained, may be prepared by the action of triphenylphosphine on halomethyl compounds of formula R In this manner, (3, 5-dimethylisoxazolyl-4)-methyl-triphenyl-phosphonium chloride has been obtained from 3 , 5-dimethyl-4-chloromethylisoxazole and triphenylphosphine in the form of colourless crystals in a yield of 89 % of theory.
The compounds of formula I in general possess valuable pharmacological properties. More particularly, they exhibit an analgesic action without having the side-effects of morphine; moreover they possess sedative and muscle-relaxing activities .
For these physiological activities, the o-position of the basic side-chain at the benzene nucleus is essential. Thus, for example, the known isomeric 4-aminoalkoxystyrenes do not exhibit analgesic activity (compare Cavallini et al . , II Farmaco, Ed. Sci. 9, 405 - 415 [1954] and P. Montegazza et al., Arch, intern, pharmacodyn. 103, 371 - 309). According to the literature these compounds exhibit antinicotinic and antihistaminic activities. .
The analgesic activity of the compounds of formula I was tested according to the hot-plate method of Chen and Beckmann, Science 113, 1951, page 631. Groups of 10 mice each were exposed to heat on a hot-plate of 56 °C. The animals used for the test normally reacted within 20 seconds. The analgesic action was judged according to the percentage of exposed animals which did not react within 50 seconds when administered a certain dose. The ED^ represents the dose on the application of which 50 % of the mice did not react to the heat-pain. The active ingredients were administered perorally.
The new compounds are only slightly toxic. The acute toxicity was determined in mice. To groups of 10 mice each the active ingredient was administered perorally in increased dosage. The the dose after the administration of which 50 % of the mice died within 14 days, was calculated from the values found faccording to the method of Litchfield and Wilcoxon.
The following compounds exhibit especially strong analgesic activity: 2- [2- (2-dime h laminoethoxy)styryl ]-pyrazine monohydrochloride , 2-[2-(2-dimethy1aminoethoxy)styry1 ]-quino1ine monohydroch1or-ide, 2- [2- (2-dimethylaminoethoxy)styryl ]-6-methylpyridine mono-hydrochloride, 2-[2-(2-dimethylaminoethoxy)styry1 ]-pyridine monohydroch1or-ide, -3-methylisoxazole hydrochloride , hydrochloride , 2- [2- (2-dimethylaminoethoxy)-styryl ]-l-methylbenzimidazole dihydrochloride , 2- (2-dimethylaminoethoxy)-stilbene hydrochloride, 2-[2-(2-dimethylaminoethoxy)-styryl]-furan hydrochloride, 2- [2- (2-dimethylaminoethoxy)-styryl]-thiophene hydrochloride, 1- (2-dimethylaminoethoxyphenyl)-2- (pyridyl-2 )-propene-l monohydrochloride , 2- [ 2- ( 2-methylaminoethoxy)-styry1 ]-pyridine dihydrochloride and 2- [2- (2-morpholinoethoxy)-styryl]-pyridine dihydrochloride .
When administered perorally the compounds possess an between 10 and 60 mg/kg mouse. The substances are only slightly toxic the LD^^-values of the following compounds, for instance, lie between 500 and 800 mg/kg mouse: 2- [2- (2-dimethylaminoethoxy)-styryl]-l-methyl-benzimidazole dihydrochloride , 2-(2-dimethylaminoethoxy)-stilbene hydrochloride, 2- [2- (2-morpholinoethoxy)-styryl ]-pyridine dihydrochloride and 2- [2- (2-dimethylaminoethoxy)-styryl ]-6-methylpyridine hydrochloride .
According to a further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient a compound of formula I as hereinbefore defined or a physiologically compatible acid addition salt thereof in association with a pharmacutical carrier or excipient. The compositions may be presented in a form suitable for oral, rectal or parenteral administration.
Thus, for example, compositions for oral administration may be solid or liquid and may take the form of granules, tablets, coated tablets, capsules, syrups, emulsions, suspensions or drops, such compositions comprising carriers or excipients conventionally used in the pharmaceutical art. Thus, for example, suitable tabletting excipients include lactose, potato and soluble starches and magnesium stearate.
For parenteral administration, the carrier may be a sterile, parenterally acceptable liquid such as sterile water, or a parenterally acceptable oil e.g. arachis oil, contained in ampoules. Compositions for rectal administration may take the form of suppositories, the carrier comprising a suppository base.
Advantageously, the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Tablets, coated tablets, capsules, suppositories and ampoules are examples of suitable dosage unit forms. Each dosage unit preferably contains 5 to 100 mg, and especially 20 to 50 mg, of active ingredient .
The following non-limiting Examples further illustrate the preparation of compounds according to the invention and pharmaceutical compositions containing them.
Example 1 .2 g of l-pyrazinyl-2- (2-dimethylaminoethoxyphenyl )- 2 ethanol/^ were admixed with 60 ml of 85% phosphoric acid; the mixture increased its temperature to 70 °C. The mixture was then heated for 1 hour to 110°C, dissolved, after cooling in 300 ml of water, neutralized and saturated with potassium carbonate. The resulting reaction product was extracted three times, each with 50 ml of ether, dried over anhydrous potassium carbonate and filtered over charcoal. The evaporation residue was distilled in vacuo. 13.25 g (corres. to 70.2 % of theory) of a light yellow oil of b.p.Q = 143 150°C were obtained. The oil was dissolved in 250 ml of acetone and was carefully mixed with sufficient of a solution of hydrogen chloride in acetone to just produce a yellow colour. After cooling in an ice-bath, white crystals separated, the quantity of which was increased by stirring 150 ml of ether into it. After suction filtration and drying, 13.9 g (corresponding to 88.2 % of theory referred to the hydrochloride formation) of 2- [ 2- (2-dimethylamino- t ethoxy)-s^yryl ]-pyrazine monohydrochloride were obtained.
M.p. : 194 - 195°C. 2- The 1- ^pyraziny]-½)-2- (2-dimethylaminoethoxyphenyl)- 2 - ethanol required as starting material, a non-distillable yellow oil, uniform to thin- layer chromatography, was obtained from (pyrazinyl-2)- ( 2-dimethylaminoethoxyphenyl )- ketone (non-distillable oil, forms a crystallized lithium enolate) by reduction with sodium borohydride. The ketone required was prepared from 2-methylpyrazine and methyl 2- dimethylaminoethoxy-benzoate by condensation with sodium amide in toluene.
Examples 2 to 7 were effected analogously to Example 1: Example 2 From l-(¾uino 2- (2-dimethylaminoethoxyphenyl ) -2- ethanol-^, a yellow, non-distillable oil, uniform in the thin- layer chromatogram, was prepared 2- [2- (2-dimethylamino- ethoxy)-styryl]-quinoline monohydrochloride .
M.p.: 188°C, yield: 87 %.
Example 3 From 1- (o-dimethylamino-ethoxyphenyl )-^thanoi ^ (light yellow crystals, m.p. 228°C) was obtained 2- [2- (2-dimethylaminoethox )-styryl ] 6-methylpyridine monohydrochloride .
M.p.: 200°C, yield: 20 %.
Example 4 -2- From l-(4,6-dimethytfpyridyl )-2-(o-dimethy1amino- 2-ethoxyphenyl)-ethanol/# (light yellow, non-distillable oil, thin-layer chromatographically uniform) was prepared 2- [2- (2-dimethylaminoethoxy)-styry1 ]-4, 6- dimethylpyridine dihydrochloride .
M.p.: 177°C, yield: 81 % of theory.
Example 5 From 1- (2-pyridyl )-2- ( 2-dimethylaminoethoxyphenyl ) ethanol- , a yellow, non-distillable oil, uniform to thin-layer chromatography was prepared 2- [2- (2-dimethylaminoethoxy)-styryl]-pyridine monohydrochloride .
M.p. : 183°C, yield: 88 %.
Example 6 -2- From l-(5-methy pyrazinyl ^)-2- (2-dimethylaminoethoxyphenyl )Vethanol/ , a colorless, non-distillable 2- [2- (2-dimethylaminoethoxy)-styryl ]-5-methylpyrazine- 2 dihydrochloride, a resinous, white substance, uniform to thin- layer chromatography.
Yield: 65 %.
Example 7 -6- From 1- (4-methy pyrimidyl / )-2- (2-dimethylamino- 2-ethoxyphenyl )/ethanol-/¾, a non-distillable , clear, yellow oil, unifrom to thin- layer chromatography, was prepared 6-[2-(2-dimethyl'aminoethoxy)-styry1 ]-4-methylpyrimidine .
M.p.: 234°C, yield: 87 %.
Example 8 12 g of a 50 % suspension of sodium hydride in paraffin oil were liberated from the adhesive paraffin oil by decanting twice with dioxane.and suspended in 100 ml of absolute dioxane , This solution was added portionwise with stirring to a solution of 54 g of diethyl 3-methylisoxazolyl-5-methylphosphonate in After hydrogen development had finished, stirring was continued for 1 hour at 50°C. After cooling to room temperature, 40 g of 2- (2-dimethylamino)-ethoxybenzaldehyde were added dropwise and the mixture was subsequently heated to 50 °C for one hour. The reaction mixture was poured on ice, acidified with 2N hydrochloric acid and extracted with ether. The ether extract was abandoned and the aqueous phase rendered alkaline with dilute sodium hydroxide solution and extracted with ether. The oily residue, obtained after drying over sodium sulfate and evaporation of the ether, was taken up in ethanol, treated with active charcoal and mixed with ethereal hydrochloric acid. After recrystallizing twice from ethanol/ether, 45 g (70.5 % of theory) of 5-[o- (2-dimethylamino)-ethoxy]styryl-3-methylisoxazolehydrochloride pale were obtained in the form of weakiy yellow crystals of m.p. 150 to 151°C.
The starting product, diethyl 3-methylisoxazolyl-5- methylphosphonate, was obtained in a yield of 84 % of theory from 3-methyl-5-chloromethylisoxazole and triethyl phosphite, as a yellow oil of b.p. 76 - 80°C at 0.0015 mm Hg. 3-Methyl-5-chloromethylisoxazole is known from the literature and can be prepared from acetonitrile oxide and propargyl chloride, according to the method of G. Stagno d'Alcontres and G. Currocrea, Atti soc. peloritana sci. fis. mat. nat. 3, 179 - 186 (1956/57), [CA 52, 1994 c]. 2- (2-Dimethylaminoethoxy)benzaldehyde (b.p.Q Q5 = 110°C) was prepared from salicylaldehyde and dimeth laminoethy1 chloride in chlorobenzene in the presence of potassium methoxide .
Examples 9 to 23 were effected analogously to Example 8: Example 9 - [o- (2-Dimethylamino)ethoxy]styryl-3-phenyl-isoxazole hydrochloride was prepared from diethyl (3-phenyl-isoxazolyl-5)-methylphosphonate and 2- (2-dimethylamino )ethoxybenzaldehyde in a yield of 23.4 % of theory. Melting point: 189 - 190°C.
The phosphonate used as starting material was obtained from 3-phenyl-5-bromomethylisoxazole (H.G. Sen, D. Seth and U.N. Joshi, J. med. chem. 9, page 431 - 433 (1966)) and triethyl phosphite as a yellow, non-distillable oil.
Quantitative yield.
Example 10 - [o- (2-Dimeth lamino)-ethoxy]styryl-3-methyl-oxadiazole-(1,2,4) hydrochloride was prepared from diethyl (3-methyl-oxadiazolyl-(l,2,4)-5)-methyl phosphonate and 2- (2-dimethyl-amino)-ethoxybenzaldehyde as colourless crystals of m.p. 186 -188 °C. Yield 55 % of theory.
The phosphonate used as starting material was obtained from 3-methyl-5-chloromethyloxadiazole- (1,2,4) and triethyl phosphite as a yellowish oil of b.p. 110 - 112 °C at 0.2 mm Hg. Yield: 48.5 % of theory. 3- ethyl-5-chloromethyj/oxadiazole- (-iyS^j^) was known from the literature (Fr. P. Nr. 363235, CA 62, page 5282 b) and may be prepared from acetamido -oxime and chloroacetyl chloride.
Example 11 From diethyl l-methyl-benzimidazolyl-2-methanephosphonate (m.p. 75.5 - 76.5°C) and 2- (2-dimethylaminoethoxy) -benzaldehyde (b.p.Q = 110°C) was obtained 2- [2- (2-dimethylaminoethoxy) -styryl ]-l-methylbenzimidazole dihydrochloride of m.p. 208 °C in a yield of 45 %.
Exam le 12 From diethyl l-phenyl-6-chloro-benzimidazolyl-2-methane phosphonate (m.p. 140°C; hydrochloride) and 2- (2-dimethylaminoethoxy)-benzaldehyde (b.p.Q Q<- = 110°C) was prepared 2-[2-(2-dimethy1aminoethoxy)styryl]-l-pheny1-6-chloro-benzimi-dazole dihydrochloride (m.p. 256°C, yield: 40 %) .
Example 13 From diethyl l-methyl-6-chloro-benzimidazolyl-2-methane-phosphonate (m.p. 103 - 106°C) and 2- (2-dimethylaminoethoxy)-acetophenone (b.p.Q ^ = 103 - 105°C)was obtained 1-(1-methyl-6-chloro-benzimidazole- (2) )-2- (2-dimethylaminoethoxy-phenyl)-propene dihydrochloride (m.p. 121°C; yield: 55 of theory) .
Example 14 From diethyl 1-phenyl- -trifluoromethyl-benzimidazolyl-2- methane-phosphonate (b.p.Q 13 = 189 °C) and 2- (2-diniethyl-aminoethoxy)-benzaldehyde (b.p.Q Q5 = 110°C) was prepared 2- [2- (2-dimethyl-aminoethoxy)-styryl ]-l-phenyl-5-tri-fluoromethyl-benzimidazole (m.p. 225°C; yield: 50 % of theory). Example 15 From diethyl pyridyl-2-methanephosphonate (b.p.^ 118°C) and 2- (2-dimethylaminoethoxy)-acetophenone (b.p.Q 103 - 105°C) was prepared l-(2-pyridyl)-2-(2-dimethylamino-ethoxyphenyl)-propene-l .
On preparing the dihydrochloride , the trans isomer was obtained from acetone in crystalline form (m.p. 196 - 198°C). In thin-layer chromatography (acetone/ethyl acetate = 1 : 1 on basic aluminium oxide; spray reagent: Dragendorffs reagent) the substance possesses an = 0.85. The mother-liquor from the preparation of the trans isomer was evaporated, the residue was dissolved in water, mixed with sodium hydroxide solution and the base was extracted with ether. After evaporation of the ether extract the product was fractionally distilled. The cis compound was obtained as a yellowish-colourless oil (b.p.Q Q7= 122 - 135°C), showing a lower Rf -value in the thin-layer chromatogram than the trans compound (Rf = 0.80).
Example 16 From diethyl pyridyl-2-methanephosphonate (b.p.Q 118°C) and 2-(3-dimethylaminopropoxy)acetophenone (b.p.Q ^= phenyl ]-p.ropene-l dihydrochloride in its trans form, analogous to the trans compound in example 15 (m.p. 196 -197 °C). From the mother liquor of the hydrochloride crystallization the cis compound was isolated as a colour-less oil (b.p.Q ^=143°C). The two compounds differ clearly from each other in the thin-layer chromatogram. Trans compound: R^ = 0.7; cis-compound: R^=0.65 (solvent system: acetone/ethylacetate = 1 : 1 on thin- layer plates of basic aluminium oxide, spray-reagent : Dragendorffs Reagent).
Example 17 From diethyl pyridyl-2-methanephosphonate (b.p.^ 118 °C) and 2- (3-dimethylaminopropoxy)-benzaldehyde was obtained 2-[2-(3-dimethylaminopropoxy)styryl]pyridine as a glassy-brittle dihydrochloride, in a yield of 36 % of theory, Example 18 From diethyl l-methyl-6-chlorobenzimidazolyl-2-methane-phosphonate (m.p. 103 - 106 °C) and 2- (3-dimethylaminopropoxy)-acetophenone (b.p. ^ ^= 130°C) was prepared 1- (l-methyl-6-chlorobenzimidazolyl-2)-2- (3-dimethylaminopropoxyphenyl )-propene/^ dihydrochloride (m.p. 211 °C; yield: 48 % of theory).
Example 19 From diethyl benzylphosphonate (b.p.-^= 148 °C) and 2-(2-dimethylaminoethoxy)benzaldehyde (b.p.Q Q5= 110°C) was prepared 2- (2-dimethylaminoethoxy)-stilbene hydrochloride (m.p. 199°C; yield 58 % of theory).
Example 20 From diethyl pyridyl-2-methanephosphonate (b.p.Q Q^= 118°C) and 2- (2-diethylaminoethoxy)benzaldehyde (b.p.Q Q,-= 110°C) was obtained 2- [2- (2-diethylaminoethoxy)styryl] pyridine dihydrochloride (m.p. 198 °C; yield: 20 % of theory).
Example 21 From diethyl pyridyl-2-methanephosphonate (b.p.Q Q^= 118 °C) and 2- (2-dimethylaminoethoxy)-4-methoxy-benzaldehyde (b.p.Q 03= 121 - 125°C) was obtained 2- [2- (2-dimethylamino- y ~ ethoxy^A-methox^styryl]-pyridine dihydrochloride (m.p. 221°C; yield: 31 % of theory).
Example 22 2- From diethyl/pyridyl-methanephosphonate (b.p.Q Q^= 118°C) and 2- (2-dimethylaminoethoxy)benzaldehyde (b.p.Q Q^= 110°C) was obtained 2- [2- (2-dimethylaminoethoxy)styryl ]-pyridine monohydrochloride (m.p. 183°C, yield: 43 % of theory).
Example 23 From diethyl 2-quinolyl-methanephosphonate (b.p.Q Q35= 138 - 145°C) and 2- (2-dimethylaminoethoxy)benzaldeyde (b.p.Q Q^= 110°C) was prepared 2- [2- (2-dimethylaminoethoxy) styryl ]-quinoline monohydrochloride (m.p. 188 °C; yield: 77 % of theory).
Example 24 2.0 g of sodium hydride were suspended in 50 ml of absolute dioxan and over 15 minutes a solution of 6.3 g of diethyl 2- (2-dimethylaminoethoxy)-benzylphosphonate was dropped in while stirring well at 28 °C; a moderate development of hydrogen was observed. Stirring was continued for one hour and then, over 15 minutes, a solution of 2.14 g of 3-formyl-pyridine p -g .«€--^»aldehyde in 20 ml of absolute dioxan was dropped in, whereupon the development of gas was again observed.
After the mixture had been allowed to rest overnight, it was decomposed with ice and the reaction product was extracted with chloroform. After distilling off the solvent, a light brown oil remained. It was dissolved in ethanol and the hydrochloride was precipitated with ethereal hydrochloric acid, which was recrystallized from ethanol over charcoal. 3.0 g (corresponding to 44 % of theory) of 3- [2- (2-dimethyl- aminoethoxy)styryl]-pyridine dihydrochloride were obtained as light yellow crystals of m.p. 238 °C. The substance was uniform to thin layer chromatography (basic aluminium oxide , (Merck); mobile phase: ethyl acetate; spray reagent: Dragendorffs Reagent) (R^ = 0.75).
The diethyl 2- (2-dimethylaminoethoxy)-benzylphosphonate used as starting material was prepared as follows: 2- (2- dimethy1aminoethoxy)benzaldehyde was reduced with sodium borohydride in methanol to 2- (2-dimethylaminoethoxy)benzyl- alcohol (b.p.Q ^ = 125°C ; yield: 77 %) and this was reacted with thionyl chloride to give 2- (2-dimethylaminoethox )benzyl chloride hydrochloride (m.p. 145 - 147 °C). This compound was reacted in benzene with excess sodium diethyl phosphite to give diethyl 2- (2-dimethylaminoethoxy)benzyl phosphonate (b.p.0 g= 140 - 148°C).
Examples 25 to 30 were effected analogously to Example 24 : Example 25 From diethyl 2- (2-dimethylaminoethoxy)-benzylphosphonate (b.p.0_ .o0 = 140 - 148°C) and furfural was prepared 2-[2-(2-dimethylaminoethoxy)styryl] furan hydrochloride (m.p. 156 - 158°C), yield: 22 % of theory.
Example 26 From diethyl 2- (2-dimethylaminoethoxy)-benzylphosphonate (b.p. was prepared 2- [ 2- (2-dimethylaminoethoxy)styryl ]thiophene hydrochloride (m.p. 187 - 188°C; yield: 60 % of theory).
Example 2-7 27 Example -2-8- From diethyl 2- (2-dimethylaminoethoxy)benzylphosphonate (b.p.rt o was obtained 2- [2- (2-dimethylaminoethoxy)styryl]pyridine monohydrochloride (m.p. 183°C; yield: 52 % of theory). 28 Example -2-9- From diethyl 2- (2-dimethylaminoethoxy)benzylphosphonate 2-formyl- (b.p.~ 0 = 140 - 148 °C) and/quinoline/^-ald^fey e was prepared 2- [ 2- (2-dimethylaminoethoxy)styryl ]quinoline mono-hydrochloride (m.p. 188°C; yield: 48 % of theory).
Example -30- 29 From diethyl 2- (2-dimethylaminoethoxy)benzylphosphonate (b.p.,-, o = 1 0 ~ 148°C) and benzaldehyde was prepared 2- (2-dimethylaminoethoxy) stilbene hydrochloride (m.p. 199°C; yield: 61 % of theory).
Example -34.- 30 A solution of 400 g of 2- (2-acetoxystyryl )pyridine in 1250 ml of chlorobenzene was mixed with 235.5 g of potassium methoxide and heated to 110°C with stirring, whereupon a yellow suspension was formed. 483 g of dimethylaminoethyl chloride hydrochloride were shaken in a shaking funnel with 1000 ml of ice-cold 30 % sodium hydroxide solution and the liberated oily base was separated and dropped into the suspension in six equal portions, each over 15 minutes (the not yet required dimethylaminoethyl chloride was stored at 0°C, in order to avoid a too early reaction).
Stirring was continued for 30 minutes at 110°C, then the reaction mixture was cooled and mixed with ice. After extracting with ether, drying with anhydrous sodium sulfate and evaporating the solvent an oil remained, which was distilled in vacuo; b.P.Q ^ = 156 - 161°C. 376 g of a honey-coloured oil was obtained (yield: 83.9 % of theory). 123 g of the oily reaction product were dissolved in a mixture of 750 ml of ethyl acetate and 330 ml of absolute ethanol. Gradually, and while stirring well, 430 ml of a solution of 132 ml of ethanolic hydrochloric acid (12.72 % weight/vol) in 638 ml of ethyl acetate were added; no yellow colouring was allowed to show at this point. Then 600 ml of ethyl acetate were added and the mixture was cooled to 0°C. The crystals of 2-[2-(2-dimethylaminoethoxy)-styryl] pyridine monohydrochloride which separated were suction filtered, washed with ethyl acetate and dried in a dessicator over concentrated sulfuric acid and potassium hydroxide.
M.p. 186 - 187.5°C; yield with this salt formation: 9.3 g.
Using an excess of ethanolic hydrochloric acid, a total of 300 ml of hydrochloric acid of the above-indicated concentration, the solution obtained a deep-yellow colour and the dihydrochloride of 2- [2-(2-dimethylaminoethoxy)styryl]-pyridine of m.p. 218 - 220°C was isolated. " For the production of the p-toluenesulfonate, 2.68 g of the free base of 2- [2- (2-dimethylaminoethoxy)styryl]pyridine were dissolved in 20 ml of absolute ethyl acetate and, while stirring, 19 ml of a solution of 1.72 g of p-toluenesulfonic acid in 20 ml of ethylacetate were added slowly. After cooling off in ice the mono-p-toluenesulfonate crystallized and was washed in a little ethyl acetate and dried in a dessicator over sulfuric acid.
M.p. 128 - 130°C; yield: 3.1 g.
For the preparation of the phosphoric acid salt, 2.68 g of the free base of 2-[2-(2-dimethylaminoethoxy)styryl] pyridine were dissolved in 40 ml of ethanol and a solution of 0.346 g of 85 % of phosphoric acid was dropped slowly into the mixture with stirring. The colourless solution was evaporated to 25 ml, mixed with 25 ml of ethyl acetate and placed in an ice-bath. After one hour a white precipitate of the phosphate of the above base crystallized. According to the analysis, 1 mole of base corresponds to 1/3 mole of phosphoric acid. M.p. 133 - 134°C; yield: 1.1 g.
The 2-(2-acetoxystyryl)pyridine (b.p.Q Q6 = 162 - 175°C) used as starting material was produced from 2-picoline and salicylaldehyde in the presence of acetic acid anhydride at 170°C. 51 33 Examples ·32 to -34 were effected analogously to Example -3Ί : 31 Example -¾τ. 2- -1- From 1- (2-acetoxyphenyl)-2- ('pyridyl-2)-propene (b.p. nc. = 140°C) and dimethylaminoethyl chloride was prepared 1- (2-dimethylaminoethoxypheny1)-2- (pyridy1/2*)- 1- monohydrochloride . M.p. 128 - 133 °C. Yield: 85 % of theory.
Example -3-3- 32 From 2-(2-acetoxystyryl)pyridine (b.p.Q Q6 = 162 - 175°C) and 2-chloro-N,N-dimethylpropylamine was prepared 2-[2-(3-dimethylaminoprop-2-oxy)-styryl Jpyridine (b.p.^ ^5 = 158 -159°C; yield: 86 % of theory).
Example -34- 33 From 2-(2-hydroxystyryl)quinoline (m.p. 274 - 278 °C) and dimethylaminoethyl chloride was prepared 2- [2- (2-dimethyl-aminoethoxy)styryl ]-quinoline-monohydrochloride (m.p. 188°C; yield: 86 % of theory).
Example -3-5- 34 16 g of 2- [2- (2-chloroethoxy)styryl Jpyridine (m.p. 57 -59 °C) were dissolved in 50 ml of methanol and mixed at -15°C with 120 ml of liquid methylamine, taken freshly from a steel container and heated in an autoclave for 4 hours to 80°C.
After cooling and releasing the pressure the contents of the autoclave were evaporated and the residue was dissolved in dilute acetic acid and shaken twice with ether in order to remove weakly basic products. Then, while cooling, it was rendered alkaline with 2N sodium hydroxide solution and the reaction product was extracted with ethyl acetate. After drying with sodium sulfate, on distillation an oily residue remained, which crystalized through on standing overnight (13.8 g, corresponding to 88.2 % of theory). The substance was dissolved in 200 ml of acetone, filtered with active charcoal and mixed with 20 ml of ethanol . Hereto was added carefully a solution of 15.3 ml of ethanolic, 12.72 % hydrochloric acid (weight/vol) in 50 ml of acetone until the yellow colouring was just beginning, for which purpose were required approx. 59 ml of acid precipitating solution. Then the mixture was mixed with ether until turbidity began and stirred with cooling in the icebath. Over one hour a pale yellow substance crystallized, which was suction filtered and dried in a dessicator .9.3 g (corresponding to 52 % of theory) of 2- [2- (2-methylaminoethoxy)styryl]pyridine monohydrochloride were obtained of m.p. 178 - 18p°C.
The 2- [2- (2-chloroethoxy)styryl ]-pyridine '(m.p. 57 - 59 °C) used as starting material was prepared from 2-(2- acetoxystyryl)-pyridine (see example 32) and 2-chloroethyl benzenesulfonate in the presence of potassium methoxide in toluene . 47 Examples to ϋ were effected analogously to 34 Example fyfy From 2-[2-(2-chloroethoxy)styryl]pyridine (m.p. 57 - 59°C) and ammonia was prepared 2- [2- (2-aminoethoxy)styryl]pyridine dihydrochloride (m.p. 269°C; yield: 49 % of theory). 36 Example lifl From 2-[2-(2-chloroethoxy)styryl]quinoline hydrochloride (m.p. 214 - 220°C) and methylamine was prepared 2-[2-(2- methylaminoethoxy)styryl Jquinoline monohydrochloride (m.p. 170°C; yield: 12.0 % of theory).
Example ¾¾ 37 From 2- [2- (2-chloroethoxy)styryl Jpyridine (m.p. 57 -58 °C) and ethylamine was prepared 2- [2- (ethylaminoethoxy) styryl]pyridine dihydrochloride (m.p. 211°C; yield: 48.3 % of theory) .
Example 39 38 From 2-[2-(2-chloroethoxy)styryl]pyridine (m.p. 57 - 58 °C) and piperidine was prepared 2-[2-(2-piperidinoethoxy)styryl]-pyridine dihydrochloride (m.p. 176 °C; yield: 31 % of theory). Example 40 39 From 2-[2-(2-chloroethoxy)styryl]pyridine (m.p. 57 - 58°C) and morpholine was prepared 2-[2-(2-morpholinoethoxy)styryl]-pyridine dihydrochloride (m.p. 248°C; yield: 53 % of theory).
Example ·4. 40 From 2- [2- (2-chloroethoxy)styryl Jpyridine (m.p. 57 -58 °C) and N-methylpiperazine was produced 2- [ 2- (2-methyl-piperazinoethoxy)-styryl ]pyridine trihydrochloride (m.p.. 268°C; yield: 45 % of theory).
Example ·4·¾ 41 From 2-[2-(2-chloroethoxy)styryl]pyridine (m.p. 57 - 58°C) and allylamine was prepared 2-[2-(2-allylaminoethoxy)styryl]-pyridine dihydrochloride (m.p. 201°C; yield: 18 % of theory).
Example 3 42 From 2-[2-(2-chloroethoxy)styrylJpyridine (m.p. 57 -58°C) and 2-phenylethylamine was prepared 2- [2- (2- -phenyl-ethylaminoethoxy)-styryl Jpyridine dihydrochloride (m.p. 263°C; yield: 54 % of theory).
Example 44 43 From 2- [ 2- (2-chloroethoxy)styryl ]pyridine (m.p. 57 -58 °C) and 2-methoxyethylamine was prepared 2- [2- (2- -methoxy-ethylaminoethoxy)styryl Jpyridine monohydrochloride (m.p. 147 °C; yield: 45 % of theory).
Example 5 44 From 2- [2- (2-chloroethoxy) styryl Jpyridine (m.p. 57 - 58°C) and di- (2-hydroxyethyl)amine was prepared 2- [2- (2-dihydroxy-ethylaminoethoxy)styryl Jpyridine dihydrochloride (m.p. 140°C; yield: 22 % of theory).
Example 4& 45 From 2-[2-(2-chloroethoxy)styryl]pyridine (m.p. 57 - 58°C) and methyl-2-hydroxyethylamine was prepared 2-[2-(2-N-methyl-N-hydroxyethylaminoethoxy)styryl Jpyridine dihydrochloride (m.p. 190°C; yield: 42 % of theory).
Example 46 From 2- [2- (2-chloroethoxy)styryl Jpyridine (m.p. 57 - 59°C) and dimethylamine was prepared 2- [ 2- (2-dimethylaminoethoxy) styryl]-pyridine monohydrochloride (m.p. 183°C, yield: 68 % of theory).
Example 48- 47 From 2- [2- (2-chloroethoxy)styryl]quitioline (m.p. 214 -220°C) and dimethylamine was obtained 2- [2- (2-dimethy1amino-ethoxy)-styryl]quinoline monohydrochloride (m.p. 188°C; yield: 74 % of theory).
Example 4-9- 48 -4- 24.5 g of (3, 5-dimethyVisoxazoly]/y4/)-methyl-triphenyl-phosphonium chloride in 150 ml of absolute ethanol were added to 1.4 g of sodium in 50 ml of absolute ethanol. While stirring, 7.8 g of 2- (2-dimethylamino)ethoxy-benzaldehyde were dropped into the reaction mixture heated to 40°C and which was then heated to boiling for 15 minutes. After evaporation of the solvent, the residue was taken up in dilute hydrochloric acid and, to remove the triphenylphosphine oxide formed, it was extracted with benzene. The aqueous phase was rendered alkaline with 2N sodium hydroxide and extracted with ether several times. The oily residue, obtained after drying with sodium sulfate and evaporation of the ether was dissolved in acetone and the hydrochloride was precipitated with ethereal hydrochloric acid. After recrystallizing twice from acetone, 6 g (70 % of theory) of ^ 4-[|-(2-dimethylamin@thox3iityryl]-3>¾-dlmethyliSoxaMle hydrochloride were obtained as colourless crystals of m.p. 180 - 181°C.
The phosphonium chloride used as starting material was obtained in the form of colourless crystals from 3 , 5-dimethyl-4- chloromethylisoxazole and triphenyl phosphite in a yield of 89% of theory. 3, 5-dimethyl-4-chloromethylisoxazole may be prepared according to the method of N.K. Kochetkov, E.E. Khomutova and M.V. Basilevsky, J. Gen. Chem. (USSR) 28, 2736 (1958) by chloromethylation of 3 , 5-dimethylisoxazole . 49 50 Examples 50- and 5-1- were effected analogously to 48 Example -49-: Example -50- 49 From benzyl chloride and triphenyl phosphine was pre¬ pared benzyltriphenylphosphonium chloride [Wittig and Schollkopf, Chem.Ber. 88, 1662 (1955)] and this was reacted with 2- (dimethylaminoethoxy)-benzaldehyde (b.p.Q = 110°C) to give 2- (dimethy1aminoethoxy)- stilbene . The compound was isolated as its hydrochloride (m.p. 199°C; yield: 73 % of theory).
Example ■¾- 50 From 2-chloro-methylpyridine (b.p.^ = 42 - 45 °C) and triphenylphosphine was prepared picolyl-2-triphenylphosphonium chloride and this was reacted with 2- (dimethy1aminoethoxy) benzaldehyde (b.p.Q Q5 = 110°C) to give 2- [2- (2-dimethyl- aminoethoxy)styryl]-pyridine which was isolated as its monohydrochloride (m.p. 186 - 187°C; yield: 66 % of theory).
Example ■½ 51 Tablets containing 25 mg of 2-[2-(2-dimethylaminoethoxy) styry1 ]-pyridine monohydrochloride Composition: 1 tablet comprises: 2-[2-(2-dimethy1aminoethoxy)styry1 ]-pyridine monohydrochloride 25.0 mg anhydrous secondary calcium phosphate 125.0 mg Aerosil 10.0 mg corn starch 30.0 mg polyvinylpyrrolidone 5.0 mg maleic acid 3.0 mg potato starch 20.0 mg magnesium stearate 2.0 mg 220.0 mg Preparation: A mixture of the active ingredient with calcium phosphate Aerosil and corn starch was granulated with a 10 % solution of the polyvinylpyrrolidone in ethanol, containing dissolved therein maleic acid, through a screen of 1.5 mm mesh-size, dried at 45°C and rubbed once more through the above screen. The granulate thus obtained was mixed with potato starch and magnesium stearate and pressed into tablets.
Example 5-3- 52 Coated Tablets containing 25 mg of 2- [2- (2-dimethylamino-ethoxy)-styryl]pyridine monohydrochloride 51 The tablets produced according to Example -55- were coated with a shell in conventional manner. The finished coated tablets were polished with beeswax.
Weight of coated tablet: 330 mg.
Example 54- 53 Suppositories containing 50 mg of 2- [ 2- (2-dimethylaminoethoxy)- styryl ]pyridine monohydrochloride Composition: 1 suppository comprises: 2- [2- (2-dimethylaminoethox )styryl ]- pyridine monohydrochloride 50.0 mg suppository mass (e.g. Witepsol W 45) 1 650.0 mg 1 700.0 mg Preparation: The finely pulverized active ingredient was stirred with the aid of an immersion homogenizer into the molten suppository mass cooled to 40°C. The suppository mass was poured into slightly precooled moulds.
Weight of suppository: 1.7 g.
Example -55- 54 Tablets containing 20 mg of 2- [2- (methylaminoethoxy)styryl]- pyridine monohydrochloride Composition: 1 tablet comprises: 2- [2- (methylaminoethoxy )styryl Jpyridine monohydrochloride 20.0 mg lactose 33.0 mg potato starch 20.0 mg soluble starch 5.0 mg Aerosil 1.0 mg magnesium stearate 1.0 mg 4-2-Θ-.-Θ mg 80.0 Preparation: A mixture of the active ingredient with lactose and potato starch was moistened with a 20 % aqueous solution of the soluble starch, granulated through a screen of 1.5 mm mesh- size, dried at 45 °C and triturated through a screen of 1 mm mesh-size. Aerosil and magnesium stearate were mixed into the dried granulate. Tablets were pressed from the mixture.
Weight of tablet: 120 mg Punch: 7 mm.
Example -56 55 Coated tablets with 2- [ 2- (methylaminoethoxy)styryl ]- pyridine monohydrochloride (20 mg) 54 Tablets produced according to Example §§'were coated with a shell in conventional manner, the shell consisting essentially of talcum and sugar. The finished coated tablets were polished with beeswax.
Weight of coated tablet: 200 mg Example -57- 6 Suppositories with 40 mg of 2-[2-(methylaminoethoxy)styryl]- pyridine monohydrochloride Composition: 1 suppository comprises: 2- [2- (methylaminoethoxy)styryl]pyridine monohydrochloride 40.0 mg suppository mass (e.g. Witepsol W 5) 1 660.0 mg 1 700.0 mg Preparation: The finely pulverized active ingredient was mixed homogeneously into the suppository mass cooled to 40°C.
The mass was cooled to 37 °C and poured into slightly precooled moulds.
Weight of suppository: 1.7 g.

Claims (9)

1. Compounds of the general formula [wherein Ar represents a phenyl group; a 2-, 3-, or 4- pyridyl group (which may optionally be substituted by a lower alkyl group); a 2-quinolyl or 2-pyrazinyl group (each of which may optionally be substituted by a lower alkyl 6-group); a/pyrimidyl group optionally substituted by a lower alkyl group; a 2-benzimidazolyl group optionally sub- phenyl stituted by a halogen atom or a lower alky], /or trifluoro- a 4-isoxazolyl group or methyl group; a 2-furyl or 2-thienyl group; /a 5-isoxazolyl group optionally substituted by a lower alkyl or phenyl group; or a 5- (1 , 2,4-oxadiazolyl)-group optionally substi¬ tuted by a lower alkyl group; R^, R^ and R.., which may be the same or different, each represents a hydrogen atom or lower alkyl group; R^ represents a hydrogen atom or a lower alkoxy group; either R^ and R^, which may be the same or different, each represents a hydrogen atom, a lower alkyl, alkenyl, hydroxy- alkyl or alkoxyalkyl group or an aralkyl group, or and R^, together with the nitrogen atom to which they are attached, form a saturated, monocyclic, heterocyclic 5- to 7-membered ring which may optionally be interrupted by or an N-methylimino group an oxygen atom,-©*1 a further nitrogen aton; and n represents 0 or 1] and their acid addition salts.
2. Compounds as claimed in claim 1 wherein the acid addition salts are physiologically acceptable acid addition salts .
3. 2-[2-(2-Dimethylaminoethoxy)styryl]pyrazine and its physiologically acceptable acid addition salts.
4. 2- [2- (2-Dimethylaminoethoxy)styryl]quinoline and its physiologically acceptable acid addition salts.
5. 2- [2- (2-Dimethylaminoethoxy)styryl ]-6-methyl-pyridine and its physiologically acceptable acid addition salts.
6. 2- [ 2- (2-Dimethylaminoethoxy )styryl Jpyridine and its physiologically acceptable acid addition salts.
7. 5-^[e- (2-Dimethylamino^ethoxy] styryll -3-methyl-s^Loxazole and its physiologically acceptable acid addition salts. .2 -- ((22--DDiimmeetthhvyllaammiinn0c^^feetthhooxxvyHjssttvyrrvy_I^f - 3-pheny1- isoxazo1e and its physiologically acceptable acid addition salts. 9. 2-[2-(2-Dimethylaminoethoxy) styry1 ]- 1-methy1-benzimidazole and its physiologically acceptable acid addition salts. 10. 2- (2-Dimethylaminoethoxy)-stilbene and its physiologically acceptable acid addition salts. 11. 2- [2- (2-Dimethylaminoethoxy)styryl]-furan and its physiologically acceptable acid addition salts. 12. 2-[2-(2-Methylaminoethoxy)styryl]pyridine and its physiologically acceptable acid addition salts. 13. 2-[2-(2-Morpholinoethoxy)styryl]pyridine and its physiologically acceptable acid addition salts. 14. A process for the preparation of compounds as claimed in claim 1 which comprises eliminating water from a compound of formula (wherein Ar, ^ to R-. and n are as defined in claim 1) . 15. A process as claimed in claim 14 wherein the elimination of water is effected by means of phosphoric acid, a poly-phosphoric acid, phosphoric acid and phosphorus pentoxide, or sulfuric acid. 16. A process as claimed in claim 14 or claim 15 wherein the elimination is effected at a temperature within the range 70 to 130°C. 17. A process for the preparation of compounds as claimed in claim 1 wherein a phosphonate of formula (wherein R^ and Ar are as defined in claim 1 and Rg represents a lower alkyl group) is reacted with an aldehyde or ketone of formula (wherein R2 to R^ and n are as defined in claim 1) in the presence of a base, whereby a carbanion of the compound of formula III is formed as a reaction intermediate. 1
8. A process for the preparation of compounds as claimed in claim 1 wherein a phosphonate of formula (wherein 2 to R7 and n are as defined in claim 1 and Rg ■ψ represents a lower alkyl group) is reacted with an aldehyde or ketone of formula Ar - C = 0 ■ VI (wherein Ar and R^ are as defined in claim 1) in the presence of a base, whereby a carbanion of the compound of formula V is formed as a reaction intermediate. 1
9. A process as claimed in claim 17 or 18 wherein the base is an alkali metal hydride. 20. A process as claimed in any of claims 17 to 19 wherein the reaction is effected in the presence of a solvent. 21. A process as claimed in any of claims 17 to 20 wherein the reaction is effected at a temperature of from 30 to 60°C. 22. A process for the preparation of compounds as claimed in claim 1 wherein a compound of formula (wherein Ar and R^ to R^ are as defined in claim 1 and X represents a hydrogen atom or an acetyl group) is reacted with an amine of formula f (wherein to are as defined in claim 1 and Y represents a halogen atom. 23. A process as claimed in claim 22 wherein the reaction is effected in the presence of a base. 24. A process as claimed in claim 23 wherein the base is an alkali metal hydroxide, carbonate or alcoholate. 25. A process as claimed in any of claims 22 to 24 wherein the reaction is effected in the presence of a solvent. 26. A process as claimed in claim 25 wherein the solvent is benzene, chlorobenzene, toluene or xylene. 27. A process as claimed in claim 25 or claim 26 wherein the reaction is effected at temperatures up to the boiling point of the solvent used. 28. A process for the preparation of compounds as claimed in claim 1 wherein a compound of formula (wherin Ar, R. to Rj. and n are as defined in claim 1 and Z represents a group replaceable by a basic group) is reacted with an amine of formula H - N X \ R7 (wherein and R-. are as defined in claim 1). 29. A process as claimed in claim 28 wherein a compound of formula IX in which Z represents a halogen atom or a tosyl group is used. 30 A process as claimed in claim 28 or claim 29 wherein the reaction is effected in the presence of a solvent. 31. A process as claimed in any of claims 28 to 30 wherein the reaction is effected in the presence of an acid-binding agent . 32. A process as claimed in claim 28 or claim 29 wherein the reaction is effected in the presence of an excess of the amine of formula X, the latter serving as a solvent and an acid-binding agent. 33. A process as claimed in any of claims 28 to 32 wherein the reaction is effected at a temperature of from 60 to 120°C. 34. A process as claimed in any of claims 28 to 33 wherein an easily volatile amine of formula X is used and the reaction is effected in a closed vessel. 35. A process for the preparation of compounds as claimed in claim 1 wherein a compound of formula R Ar. XI P (C6H5)3 (wherein Ar and R^ are as defined in claim 1) is reacted with a basic ketone or aldehyde of formula (wherein R to are as defined in claim 1). 36. A process as claimed in claim 35 wherein the phosphorylide of formula XI is formed from a corresponding phosphonium halide in situ by reaction of the phosphonium halide with a base . 37. A process as claimed in claim 36 wherein the base is an alkali metal alcoholate. 38. A process as claimed in any of claims 35 to 37 wherein the reaction of the compound of formula XI with the compound of formula IV is effected in the presence of a solvent. 39. A process as claimed in claim 38 wherein the solvent is an alcohol. 40. A process as claimed in claim 38 or claim 39 wherein the reaction is effected at a temperature of from 40°C to the boiling point of the solvent used. 41. A process as claimed in any of claims 14 to 40 wherein a compound of formula I is first obtained and is subsequently converted into an acid addition salt thereof. 42. A process as claimed in any of claims 14 to 41 wherein a mixture of cis and trans isomers of a compound of formula I or an acid addition salt thereof is obtained and the cis and trans compounds are subsequently separated by fractional crystallisation . 43. A process as claimed in any of claims 14 to 42 substantially as herein described. 44. A process for the preparation of compounds as claimed in claim 1 substantially as herein described with reference to any of Examples 1 to 51. 45. Compounds as claimed in claim 1 when prepared by a process as claimed in any of claims 14 to 44. 46. Pharmaceutical compositions comprising as active ingredients a compound of formula I, as defined in claim 1, or a physiologically acceptable acid addition salt thereof in association with a pharmaceutical carrier or excipient. 47. Compositions as claimed in claim 46 in a form suitable for oral, rectal or parenteral administration. .J 35047/2 48. Compositions as claimed in claim 46 or claim 47 in the form of dosage units. 49. Compositions as claimed in claim 48 containing from 5 to 100 mg of active ingredient per dosage unit. 50. Compositions as -claimed in claim 49 containing from 20 to 50 mg of active ingredient per dosage unit. 51. Compositions as claimed in claim 46 substantially as herein described. 52. Pharmaceutical composition substantially as herein described with reference to any of Examples 52 to 57. 53. Compositions of the formula II, III, IV, V and VII as herein defined. *
IL35047A 1969-08-05 1970-08-04 Beta-aryl and heteroaryl-2-amino-alkoxy-styrenes,and their preparation IL35047A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE1939809A DE1939809B2 (en) 1969-08-05 1969-08-05 β-Aryl-2-aminoalkoxy-styrenes and process for their preparation

Publications (2)

Publication Number Publication Date
IL35047A0 IL35047A0 (en) 1970-10-30
IL35047A true IL35047A (en) 1973-05-31

Family

ID=5741970

Family Applications (1)

Application Number Title Priority Date Filing Date
IL35047A IL35047A (en) 1969-08-05 1970-08-04 Beta-aryl and heteroaryl-2-amino-alkoxy-styrenes,and their preparation

Country Status (25)

Country Link
JP (6) JPS4941433B1 (en)
KR (1) KR780000113B1 (en)
AT (5) AT303055B (en)
BE (1) BE754405A (en)
BG (6) BG17950A3 (en)
CH (6) CH548367A (en)
CS (6) CS170537B2 (en)
DE (1) DE1939809B2 (en)
DK (1) DK139717B (en)
ES (6) ES382430A1 (en)
FI (1) FI54912C (en)
FR (1) FR2068463B1 (en)
GB (1) GB1307436A (en)
HU (1) HU163185B (en)
IE (1) IE34634B1 (en)
IL (1) IL35047A (en)
NL (1) NL7011590A (en)
NO (1) NO135243C (en)
PH (1) PH9520A (en)
PL (2) PL93130B1 (en)
RO (5) RO57794A (en)
SE (1) SE382211B (en)
SU (5) SU439965A3 (en)
YU (2) YU198170A (en)
ZA (1) ZA705411B (en)

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS50139537A (en) * 1974-04-25 1975-11-07
US4220603A (en) * 1977-10-07 1980-09-02 Mitsubishi Chemical Industries, Limited Pharmaceutically active (omega-aminoalkoxy)bibenzyls
JPS6045632B2 (en) * 1978-03-09 1985-10-11 三菱化学株式会社 ω-aminoalkoxystilbenes and their acid addition salts
DE2818765A1 (en) 1978-04-28 1979-11-08 Basf Ag AMINO DERIVATIVES OF 2-METHYL-5- (2-HYDROXYSTYRENE) -1,3,4-THIADIAZOLE
DE2818999A1 (en) * 1978-04-29 1979-11-15 Basf Ag AMINO DERIVATIVES OF 3-ALKYL-5- (2-HYDROXYSTYRYL) -ISOXAZOLES
DE2818998A1 (en) * 1978-04-29 1979-11-15 Basf Ag 3-ALKYL-5- (2-HYDROXY-STYRYL) -ISOXAZOLES AND METHOD FOR THE PRODUCTION THEREOF
JPS5629548A (en) * 1979-08-16 1981-03-24 Mitsubishi Chem Ind Ltd Omega-aminoalkoxystilbenes and their acid addition salts
DE2943405A1 (en) * 1979-10-26 1981-05-07 Basf Ag, 6700 Ludwigshafen NEW AMINO DERIVATIVES OF 5- (2-HYDROXYSTYRYL) -ISOXAZOLE
DE2943406A1 (en) 1979-10-26 1981-05-07 Basf Ag, 6700 Ludwigshafen AMINO DERIVATIVES OF 2-METHYL-5- (2-HYDROXYSTYRYL) -1,3,4-THIADIAZOL
DE3006809A1 (en) * 1980-02-23 1981-09-24 Basf Ag, 6700 Ludwigshafen 2 - ((3-AMINO-2-HYDROXY-PROPOXY) -STYRYL) -ISOXAZOLES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM
JPS5874379U (en) * 1981-11-16 1983-05-19 富士通株式会社 electronic equipment
NO174506B (en) * 1984-10-30 1994-02-07 Usv Pharma Corp Analogous procedure for the preparation of therapeutically active compounds
JP5940655B2 (en) 2011-06-10 2016-06-29 ザ プロクター アンド ギャンブル カンパニー Absorbent core for disposable absorbent articles
EP3284449B1 (en) 2011-06-10 2019-10-02 The Procter & Gamble Company Disposable diapers
BR112013030593B1 (en) 2011-06-10 2021-02-17 The Procter & Gamble Company absorbent structure for absorbent articles
PL2740449T3 (en) 2012-12-10 2019-07-31 The Procter & Gamble Company Absorbent article with high absorbent material content
EP2813201B1 (en) 2013-06-14 2017-11-01 The Procter and Gamble Company Absorbent article and absorbent core forming channels when wet
US9987176B2 (en) 2013-08-27 2018-06-05 The Procter & Gamble Company Absorbent articles with channels
EP3351225B1 (en) 2013-09-19 2021-12-29 The Procter & Gamble Company Absorbent cores having material free areas
PL2886092T3 (en) 2013-12-19 2017-03-31 The Procter And Gamble Company Absorbent cores having channel-forming areas and c-wrap seals

Also Published As

Publication number Publication date
JPS5113147B1 (en) 1976-04-26
DE1939809C3 (en) 1979-01-11
KR780000113B1 (en) 1978-04-15
ES382426A1 (en) 1972-11-16
ES382427A1 (en) 1972-11-16
YU37478A (en) 1979-07-10
CH548366A (en) 1974-04-30
BG18600A3 (en) 1975-02-25
BE754405A (en) 1971-02-04
IE34634B1 (en) 1975-07-09
DE1939809B2 (en) 1978-04-13
ES382425A1 (en) 1972-11-16
FI54912C (en) 1979-04-10
GB1307436A (en) 1973-02-21
JPS5113146B1 (en) 1976-04-26
CH548982A (en) 1974-05-15
BG17952A3 (en) 1974-03-05
SU428597A3 (en) 1974-05-15
DK139717B (en) 1979-04-02
PH9520A (en) 1976-01-09
ES382429A1 (en) 1972-11-16
JPS5113150B1 (en) 1976-04-26
PL78370B1 (en) 1975-06-30
IE34634L (en) 1971-02-05
AT302346B (en) 1972-10-10
ES382430A1 (en) 1972-12-01
BG18599A3 (en) 1975-02-25
RO58861A2 (en) 1975-06-30
FR2068463A1 (en) 1971-08-27
RO57794A (en) 1975-06-15
CH548368A (en) 1974-04-30
SE382211B (en) 1976-01-19
JPS5113149B1 (en) 1976-04-26
CS170533B2 (en) 1976-08-27
CH548367A (en) 1974-04-30
CS170537B2 (en) 1976-08-27
JPS4941433B1 (en) 1974-11-08
BG20095A3 (en) 1975-10-30
HU163185B (en) 1973-06-28
SU439965A3 (en) 1974-08-15
SU439966A3 (en) 1974-08-15
IL35047A0 (en) 1970-10-30
AT302345B (en) 1972-10-10
AT302344B (en) 1972-10-10
FR2068463B1 (en) 1974-08-30
BG17950A3 (en) 1974-03-05
NO135243C (en) 1977-03-09
AT301565B (en) 1972-09-11
NL7011590A (en) 1971-02-09
CS170534B2 (en) 1976-08-27
NO135243B (en) 1976-11-29
YU198170A (en) 1979-07-10
FI54912B (en) 1978-12-29
CH548983A (en) 1974-05-15
SU432712A3 (en) 1974-06-15
CS170535B2 (en) 1976-08-27
AT303055B (en) 1972-11-10
DE1939809A1 (en) 1971-02-18
BG17951A3 (en) 1974-03-05
RO57548A (en) 1975-02-15
RO58837A (en) 1975-09-15
ZA705411B (en) 1971-05-27
DK139717C (en) 1979-09-17
SU450398A3 (en) 1974-11-15
RO57793A (en) 1975-03-15
ES382428A1 (en) 1972-11-16
PL93130B1 (en) 1977-05-30
CH548981A (en) 1974-05-15
CS170536B2 (en) 1976-08-27
CS170538B2 (en) 1976-08-27
JPS5113148B1 (en) 1976-04-26

Similar Documents

Publication Publication Date Title
IL35047A (en) Beta-aryl and heteroaryl-2-amino-alkoxy-styrenes,and their preparation
US3644353A (en) 4 hydroxy-alpha&#39;aminomethyl-m-xylene-alpha&#39; alpha**3-diols
US4451476A (en) Isoxazoles as antiviral agents
US4110337A (en) Triazolobenzodiazepines
US7005432B2 (en) Substituted imidazol-pyridazine derivatives
DK160610B (en) METHOD OF ANALOGUE FOR THE PREPARATION OF 4-PHENYLALKYL OR 4-PHENYLALKENYLIMIDAZOLD DERIVATIVES OR PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS THEREOF
SI9210305A (en) Indole derivatives, processes for their preparation and medicaments containing them
CS216544B2 (en) Method of preparation of basic ethers
IL31246A (en) Phenylethanolamines,their preparation and pharmaceutical and veterinary compositions containing them
SU439966A1 (en) The method of obtaining aryl-2-aminoalkoxystyrenes
CS229938B2 (en) Production method imidazoline derivative
US4323707A (en) Antifertility compounds
NO811630L (en) IMIDAZOAZOLYLIC ACID AMOIDS, NEW INTERMEDIATE PRODUCTS FOR THEIR PREPARATION, THEIR PREPARATION AND THEIR USE AS A MEDICINE
US4077999A (en) Novel oxime ethers
US3708482A (en) 4-morpholinoethoxy-benzophenones
US3655743A (en) Substituted 4 - biphenyl-4-hydroxy crotonic acids and salts thereof
US4315006A (en) Benzoxocin derivatives having anxiolytic and anti-convulsant activities
Meanwell et al. Nonprostanoid prostacyclin mimetics. 4. Derivatives of 2-[3-[2-(4, 5-diphenyl-2-oxazolyl) ethyl] phenoxy] acetic acid substituted. alpha. to the oxazole ring
EP0005299A1 (en) Substituted 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines, process for the preparation thereof, and pharmaceutical compositions containing them
US3127401A (en) Z-benzyl-j
CS217979B2 (en) Method of making the cycloalcanonoximether
US4157399A (en) Benzo(B)thiophenes
DK159435B (en) METHOD OF ANALOGUE FOR PREPARING 2-HYDROXY-5- (1-HYDROXY-2-PIPERAZINYLETHYL) BENZOIC ACID DERIVATIVES OR A PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALT
US4075223A (en) Novel antifertility agents
US4251539A (en) Amino derivatives of 3-alkyl-5-(2-hydroxystyryl)-isoxazoles