US3709911A - ((thenylidene amino)oxy)alkyl carboxylic acids and salts and esters thereof - Google Patents

((thenylidene amino)oxy)alkyl carboxylic acids and salts and esters thereof Download PDF

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Publication number
US3709911A
US3709911A US00026756A US3709911DA US3709911A US 3709911 A US3709911 A US 3709911A US 00026756 A US00026756 A US 00026756A US 3709911D A US3709911D A US 3709911DA US 3709911 A US3709911 A US 3709911A
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Prior art keywords
oxy
thenylidene
amino
acetic acid
salts
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US00026756A
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English (en)
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Dijk J Van
Houtenlaan J Van
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US Philips Corp
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US Philips Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • 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
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
    • 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
    • C07D333/26—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/28—Halogen atoms

Definitions

  • the invention in this case relates to novel [(thenylidene amino) oxy] alkyl-carboxylic acids their salts and esters and to the use of these compounds as anti-inflammatory and analgetic agents.
  • Some compounds are known for the treatment of rheumatic afiiictions and similar illnesses. However, these known compounds are of little value chiefly because of undesirable side effects or of a high toxicity level.
  • R and R are each independently hydrogen, halogen such as fluorine, chlorine, bromine or iodine or meth yl, R is alkylene of 1 to 3 carbon atoms inclusive for example methylene, ethylene and isopropylene, R is hydrogen, alkyl of 1 to 5 carbon atoms inclusive for example methyl, ethyl, isobutyl and pentyl, alkali metal such as K and Na or the group N(H) ,,(R wherein a is an integer of 0 to 3 inclusive and R is an alkyl of 1 to 5 carbon atoms inclusive or a monohydroxylalkyl of l to 5 carbon atoms inclusive preferably of 1 to 2 carbon atoms, examples of this group being NH (C H NH It has been found that these novel compounds of the invention are useful in that they generally have strong anti-inflammatory activities. along with strong analgetic activities accompanied only by a very low level of toxicity.
  • the compounds of the invention are useful in treating such diseases of mammals as rheumatoid arthritis, Bechterews disease, arthritis psoriacta, collagen diseases, osteoarthrosis, acute lumbago, humeroscapular periarthritis, acute sterile noninfected bursitis, thrombophlebitis and acute rheumatic polyarthritis.
  • the dosage which, and the frequencies at which, the compounds are to be administered for treating these atfiictions depends on the seriousness thereof. As a rule, the physician treating the patient Will have no difficulty in arriving at the right treatment. Generally, from 50 to 1000 mg. daily will be administered to the patient, which may be divided into several portions. As a rule, to 500 mg. daily will be sufiicient.
  • the compounds may be administered orally, parenterally or rectally. 7
  • the anti-inflammatory elfect of the compounds was determined by the carragheenin test carried out according to a modification of the method of Winter, Risley and Nuss, Proc. Soc. Exp. Biol. 111-544 (1962).
  • the test was made with male rats, weight about 220 g. The animals were made to fast for the 16 hours preceding the test.
  • the substance to be tested is suspended in 1% tragacanth solution and administered orally. The administration of the substance is immediately followed by water loading up to 5 ml. per animal. 1 hour after the administration of the test substance and the water loading 0.05 ml. of a l /2% carragheenin solution is injected intraplantarly and the thickness of the legs (dorsal plantar distance) is determined by means of a specially constructed micrometer.
  • percent blank-percent test group percent blank100 From the results of a series of dosages an ED value was computed. This is the amount which causes a reduction of 50% relative to the blank percent group.
  • the analgetic activity of the compounds was determined according to a modification of the method of Randall and Sellito (Arch. Int. Pharmacodyn. 109-409 (1957).
  • the decrease of the response to pain due to increasing pressure of a rats leg inflamed by means of yeast serves as a criterion for the analgetic effect.
  • the test is performed on male rats having weights between 100 and g. One hour before the administration of the test preparation the animals are intraplanatarly injected with 0.1 ml. of a 20% yeast suspension. The compounds to be tested are suspended in a 1% tragacanth solution and administered orally. One hour, two hours and four hours after the administration of the test substance, the pain threshold is measured with increasing pressure on the inflamed leg.
  • an ED value was computed, i.e. the dosage which produces a 100% rise of the pain threshold.
  • the compounds of the invention may be prepared according to methods analogous to those known in the art for preparing similar compounds.
  • the compounds according to the invention are obtainable, for example, by reacting a compound of the Formula II which can be produced from the corresponding ketone by means of hydroxyl amine, with a compound of the For mula III in which formulae R to R have the same meanings as in the Formula I, M is a metal atom, for example Na or K, Hal is a halogen atom, for example chlorine or bromine and R is hydrogen, an alkyl containing up to 5 carbon atoms or an alkali metal, and, if desired, by converting the resulting acids into salts.
  • M is a metal atom, for example Na or K
  • Hal is a halogen atom, for example chlorine or bromine
  • R is hydrogen, an alkyl containing up to 5 carbon atoms or an alkali metal, and, if desired, by converting the resulting acids into salts.
  • the reaction is preferably performed in a polar solvent such as dimethyl formamine, dimethyl sulphoxide, alcohols and the like, at temperatures between room temperature and the boiling temperature of the reaction mixture and in the presence of an acid binder, such, for example, as an ethanolate.
  • a polar solvent such as dimethyl formamine, dimethyl sulphoxide, alcohols and the like
  • the resulting acids may be esterified or converted into their salts.
  • the reaction is preferably performed in an inert solvent such, for example, as N-methyl-Z-pyrrolidon, benzene and the like, at temperatures between room temperature and the boiling point of the solvent.
  • an inert solvent such, for example, as N-methyl-Z-pyrrolidon, benzene and the like, at temperatures between room temperature and the boiling point of the solvent.
  • the compounds of the Formula VI may alternatively be produced by reacting a compound of the Formula II with a compound of the Formula VIII,
  • R is an ethylene group of a propenyl 1, -2 or -3 group.
  • the reaction is preferably performed in an inert solvent, for example in an alcohol, for example ethanol.
  • the reaction temperature as a rule lies between 0 C. and the boiling point of the reaction mixture.
  • the compounds of the Formula I may also be obtained by saponifying a nitrile of the Formula IX S&
  • R represents an alkyl group containing up to 5 carbon atoms and R to R have the same meanings as in the Formula I
  • RJOH an alcohol
  • the reaction is preferably carried out in an inert solvent, for example an ether, such as diisopropyl ether.
  • the reaction temperature lies between 0 C. and 40 C.
  • Acids of the Formula I may be converted into the corresponding esters of the Formula I with alcohols, if required via the acid chlorides. From esters of the Formula I the acids of the Formula I are obtainable by saponification.
  • the compound according to the invention may be made up into pharmaceutical preparations such as, for example, tablets, pills, powders, injection liquids, salves, suppositories, dragees and the like, by known methods.
  • the invention also relates to the production of pharmaceutical preparations and to the preparations themselves.
  • carrier materials the substances commonly used in pharmaceutics may be employed.
  • carrier materials Water, corn starch, gelatine, lactulose, sucrose, talc, vegetable gums, propylene glycol, polyalkylene glycols, white petroleum jelly and other known pharmaceutical carriers.
  • the pharmaceutical composition of the invention is useful in treating many mammals including dogs, horses as well as humans.
  • the solid substance filtered off was dissolved, together with the obtained residue, in 100 ml. of water, 20 ml. of 2 N solution of caustic soda and 30 ml. of ether.
  • the ethereal layer was separated as and the alkaline layer was extracted 2 times with 40 ml. of ether.
  • the alkaline water layer was then acidified with 10 ml. of concentrated hydrochloric acid and again extracted 3 times with ether.
  • the latter ethereal extract was dried over anhydrous sodium sulfate, and subsequently the solvent was removed.
  • the resulting [(a-methyl-4-bromo-2-thenylidene amino)- oxy] acetic acid was crystallized from a small amount of benzene (2 g. from 10 ml.) and melted at 140141 C.
  • the filtrate was acidified with acetic acid and the solid precipitate was drawn off. This solid substance was dissolved in acetone, the acetonic solution was treated with activated carbon and, after filtration, evaporated to dryness. The residue was crystallized from 30% acetic acid, the 4-[(a-methy1- 5 chloro 2 thenylidene amino)oxy] butyric acid being obtained, melting point 92 C.-96 C.
  • R1 C N-O-R3COOR4 wherein R is a moiety selected from the group consisting of chlorine and bromine, R is a moiety selected from the group consisting of hydrogen, chlorine and bromine, R is methylene and R is a moiety selected from the group consisting of hydrogen, alkyl of l to 5 carbon atoms inclusive, alkali metal and an ammonium group of the formula N(H) (R wherein a is an integer of 0 to 3 inclusive and R is a moiety selected from the group consisting of alkyl of 1 to 5 carbon atoms inclusive and monohydroxyalkyl of 1 to 5 carbon atoms inclusive.
  • a 2-thenylidene derivative selected from the group consisting of [a-methyI-S- bromo-2-thenylidene amino)oxy] acetic acid and its alkali metal salts.
  • a 2-thenylidene derivative selected from the group consisting of [methyl-5- chloro-Z-thenylidene amino)oxy] acetic acid and its alkali metal salts.
  • a Z-thenylidene derivative selected from the group consisting of [m-methyl-3,4- dibromo-Z-thenylidene amino)oxy] acetic acid and its alkali metal salts.
  • a Z-thenylidene derivative selected from the group consisting of [u-methyI-LS- dichloro-thenylidene amino)oxy] acetic acid and its alkali metal salts.
  • a Z-thenylidene derivative selected from the group consisting of [a-methyl-S- its References Cited Richardson, J. Med. Chem. 7(6): 824-6 (1964). Und heim et aL, Acta Chem. Scand. .19(2):317- 24(1965).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US00026756A 1969-04-10 1970-04-08 ((thenylidene amino)oxy)alkyl carboxylic acids and salts and esters thereof Expired - Lifetime US3709911A (en)

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NL6905499A NL6905499A (de) 1969-04-10 1969-04-10

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US (1) US3709911A (de)
AT (3) AT301534B (de)
AU (1) AU1349970A (de)
BE (1) BE748682A (de)
CH (4) CH542225A (de)
ES (2) ES378348A1 (de)
FR (1) FR2042318B1 (de)
GB (1) GB1245549A (de)
IL (1) IL34255A0 (de)
NL (1) NL6905499A (de)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2808317A1 (de) * 1977-03-02 1978-09-07 Ciba Geigy Ag Pflanzenwuchsfoerdernde und pflanzenschuetzende mittel auf basis von oximaethern und -estern
US4116974A (en) * 1975-09-11 1978-09-26 Philagro Herbicidal and phytohormonal amidoximes
US4451286A (en) * 1977-03-02 1984-05-29 Ciba-Geigy Corporation Compositions, which influence plant growth and protect plants based on oxime ethers and oxime esters
US4467698A (en) * 1981-11-16 1984-08-28 Perrine Walter E Angular shape firing pin for use with a collapsible toggle recoil in a hand held weapon

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR205682A1 (es) * 1970-06-11 1976-05-31 Philips Nv Metodo de produccion de ester (2-dimetilaminoetil) de acido (4-cloro-alfa - metilbenciliden) amino-oxiacetico y sus sales de adicion de acido formadas con acidos farmacologicamente aceptables
DE3528753A1 (de) * 1985-08-10 1987-02-19 Bayer Ag Substituierte pyrazolin-5-one

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH368169A (de) * 1957-11-11 1963-03-31 Ciba Geigy Verfahren zur Herstellung neuer Aminoalkoxyverbindungen

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4116974A (en) * 1975-09-11 1978-09-26 Philagro Herbicidal and phytohormonal amidoximes
DE2808317A1 (de) * 1977-03-02 1978-09-07 Ciba Geigy Ag Pflanzenwuchsfoerdernde und pflanzenschuetzende mittel auf basis von oximaethern und -estern
US4451286A (en) * 1977-03-02 1984-05-29 Ciba-Geigy Corporation Compositions, which influence plant growth and protect plants based on oxime ethers and oxime esters
US4467698A (en) * 1981-11-16 1984-08-28 Perrine Walter E Angular shape firing pin for use with a collapsible toggle recoil in a hand held weapon

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ES378348A1 (es) 1973-02-01
CH542226A (de) 1973-11-15
AU1349970A (en) 1971-10-14
GB1245549A (en) 1971-09-08
AT299185B (de) 1972-06-12
DE2016057B2 (de) 1976-12-23
NL6905499A (de) 1970-10-13
CH551435A (de) 1974-07-15
BE748682A (fr) 1970-10-08
CH549591A (de) 1974-05-31
CH542225A (de) 1973-11-15
DE2016057A1 (de) 1970-10-15
ES405385A1 (es) 1975-09-01
FR2042318A1 (de) 1971-02-12
AT296278B (de) 1972-02-10
FR2042318B1 (de) 1973-06-08
IL34255A0 (en) 1970-06-17
AT301534B (de) 1972-09-11

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