DK153403B - METHOD OF ANALOGUE FOR THE PREPARATION OF 4- (2-TIENYLMETHYLAMINO) -BENZOIC ACID COMPOUNDS - Google Patents
METHOD OF ANALOGUE FOR THE PREPARATION OF 4- (2-TIENYLMETHYLAMINO) -BENZOIC ACID COMPOUNDS Download PDFInfo
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- DK153403B DK153403B DK153178AA DK153178A DK153403B DK 153403 B DK153403 B DK 153403B DK 153178A A DK153178A A DK 153178AA DK 153178 A DK153178 A DK 153178A DK 153403 B DK153403 B DK 153403B
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- dichloro
- thiophenecarboxaldehyde
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
Description
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Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte halogensubstituerede 4-(2-tienylmetylamino)-benzoesyrer, eller til-5 svarende estere eller salte deraf, hvilke forbindelser har hypolipidæmisk virkning.The present invention relates to an analogous process for the preparation of novel halogen-substituted 4- (2-thienylmethylamino) benzoic acids, or corresponding esters or salts thereof, which compounds have hypolipidemic activity.
4-(2-Tienylmetylamino)-benzoesyre og den tilsvarende ætylester er beskrevet i Izo. nauk SSSR, Ser. Khim.4- (2-Thienylmethylamino) benzoic acid and the corresponding ethyl ester are described in Izo. close USSR, Ser. Khim.
1967 (9), 2049-2055 (C.A. 68, 104869K). Der er ikke angi-10 vet nogen anvendelse for disse forbindelser.1967 (9), 2049-2055 (C.A. 68, 104869K). No use is indicated for these compounds.
De ved fremgangsmåden ifølge opfindelsen fremstillede 4-(2-tienylmetylamino)-benzoesyreforbindelser har den almene formel 1 ς io Y-----xThe 4- (2-thienylmethylamino) benzoic acid compounds prepared by the process of the invention have the general formula 1 ς io Y ----- x
z CH2NH-—C00Rz CH2 NH- C00R
20 hvor R er hydrogen eller alkyl og X, Y og Z uafhæn gigt af hinanden er hydrogen, klor eller brom med det forbehold at mindst et af symbolerne X, Y og Z betegner klor eller brom, eller er farmaceutisk acceptable salte med 25 baser af de af forbindelserne hvor R = H.Wherein R is hydrogen or alkyl and X, Y and Z are independently hydrogen, chlorine or bromine with the proviso that at least one of the symbols X, Y and Z represents chlorine or bromine or are pharmaceutically acceptable salts with 25 bases of those of the compounds where R = H.
Farmaceutisk acceptable salte refererer til salte med sådanne baser som danner salte med karboxylsyrer, og som ikke vil fremkalde en skadelig fysiologisk virkning ved indgift til et dyr i doser svarende til god far-30 makologisk virkning. Hensigtsmæssige baser indbefatter således fx alkalimetal- og jordalkalimetal-hydroxyder, -karbonater og -bikarbonater, såsom natriumhydroxyd, kaliumhy-droxyd, kalciumhydroxyd, kaliumkarbonat, natriumbikarbonat eller magniumkarbonat, ammoniak, og primære, sekundære og 35 tertiære aminer. Aluminiumsalte kan også vindes ved behandling af det tilsvarende natriumsalt med et passende aluminiumkompleks såsom aluminiumklorid-hexahydrat.Pharmaceutically acceptable salts refer to salts with bases which form salts with carboxylic acids and which will not produce a deleterious physiological effect when administered to an animal at doses corresponding to good pharmacological action. Thus, suitable bases include, for example, alkali metal and alkaline earth metal hydroxides, carbonates and bicarbonates such as sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, sodium bicarbonate or magnesium carbonate, ammonia, and primary, secondary and tertiary amines. Aluminum salts can also be obtained by treating the corresponding sodium salt with a suitable aluminum complex such as aluminum chloride hexahydrate.
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22
De omhandlede forbindelser har vist hypolipidæmisk virkning hos forsøgsdyr og navnlig hos pattedyr. Betegnelsen hypolipidæmisk virkning, som anvendes i nærværen-5 de beskrivelse og krav, henviser til den nedsættende virkning på blodets lipidindhold og navnlig indholdet af kolesterol og triglycerid i serum. Forbindelserne er derfor velegnede til anvendelse ved behandling af serum-hyperlipidæmi hos pattedyr og de er særlig nyttige 10 til behandling af hyperkolesterolæmi og hypertriglyceri-dæmi, dvs. unormale høje niveauer af henholdsvis lipi-der, kolesterol eller triglycerider i serummet. Forbindelserne kan indgives oralt eller parenteralt ved subkutant, intravenøs eller intraperitoneal injektion eller 15 ved implantation, idet oral indgift foretrækkes. En nærmere dokumentation for virkningen findes sidst i beskrivelsen.The compounds of this invention have shown hypolipidemic activity in laboratory animals and in particular in mammals. The term hypolipidemic effect used in the present description and claims refers to the reducing effect on the lipid content of the blood and in particular the serum cholesterol and triglyceride content. Therefore, the compounds are suitable for use in the treatment of serum hyperlipidemia in mammals and are particularly useful in the treatment of hypercholesterolemia and hypertriglyceria, ie. abnormally high levels of serum lipids, cholesterol or triglycerides, respectively. The compounds may be administered orally or parenterally by subcutaneous, intravenous or intraperitoneal injection or by implantation, with oral administration being preferred. A detailed documentation of the effect can be found at the end of the description.
I denne dokumentation viser sammenligning med den i tienylgruppen usubstituerede forbindelse (kendt fra CA 20 68, 104 869K) tydeligt at de ved fremgangsmåden ifølge op findelsen fremstillede forbindelser har overlegen virkning med hensyn til serums indhold af kolesterol og triglycerider og med hensyn til virkningen på legemsvægten.In this documentation, comparison with the unsubstituted compound of the thienyl group (known from CA 20 68, 104 869K) clearly shows that the compounds of the present invention have superior effects on serum cholesterol and triglycerides content and on the effect on body weight. .
Den effektive hypolipidæmiske mængde af p-amino-25 benzoesyreforbindelser som skal indgives til et dyr, dvs. den mængde som er effektiv til på signifikant måde at sænke serum-lipidniveauet, kan variere i afhængighed af sådanne faktorer som det behandlede dyr, den specielt anvendte forbindelse, det lipidniveau som ønskes opnået 30 hvad enten dyret er hyperlipidæmisk eller ikke, indgiftsperioden og indgiftsmetoden. I almindelighed ligger en effektiv daglig dosis fra ca. 1 mg/kg legemsvægt til 200 mg/kg legemsvægt, med et foretrukket dagligt dosisområde fra ca. 10 mg/kg til 100 mg/kg legemsvægt.The effective hypolipidemic amount of β-amino-benzoic acid compounds to be administered to an animal, i.e. the amount effective to significantly lower the serum lipid level may vary depending on such factors as the treated animal, the compound used, the lipid level desired to be achieved, whether the animal is hyperlipidemic or not, the period of administration and the method of administration. In general, an effective daily dose ranges from approx. 1 mg / kg body weight to 200 mg / kg body weight, with a preferred daily dose range of approx. 10 mg / kg to 100 mg / kg body weight.
35 Præparaterne kan tage form af tabletter, linguests, pulvere, kapsler, opslæmninger eller pastiller og sådanne præparater kan fremstilles ved farmaceutiske standardmetoder .The compositions may take the form of tablets, linguests, powders, capsules, slurries or lozenges and such preparations may be prepared by standard pharmaceutical methods.
33
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Forbindelserne kan inkorporeres i et næringsmiddel som fx smør, margarine, spiseolie, kasein eller kulhydrater. Sådanne næringsmiddelpræparater er tilpasset 5 til at blive indgivet som en del af eller som hele kosten eller som et supplement til kosten, sådanne præparater indeholder fortrinsvis fra ca. 0,02 til ca. 2,0 procent af den aktive bestanddel når præparatet indgives som den samlede kost. Præparaterne kan indeholder højere 10 koncentrationer af den aktive bestanddel når de indgives som et supplement til kosten.The compounds can be incorporated into a nutrient such as butter, margarine, edible oil, casein or carbohydrates. Such food preparations are adapted to be administered as part of or as a whole diet or as a supplement to the diet, such preparations preferably containing from 0.02 to approx. 2.0 percent of the active ingredient when administered as the total diet. The compositions may contain higher 10 concentrations of the active ingredient when administered as a supplement to the diet.
Til parenteral anvendelse kan forbindelserne formuleres med sterile ingredienser, sammensat og emballeret aseptisk. De kan indgives intravenøst eller intramusku-15 lært.For parenteral use, the compounds can be formulated with sterile ingredients, compounded and packaged aseptically. They can be administered intravenously or intramuscularly.
De omhandlede forbindelser fremstilles ifølge opfindelsen på den i patentkravets kendetegnende del angivne måde, altså ved omsætning af p-aminobenzoesyre eller en ester deraf, fx i et inaktivt opløsningsmiddel, med et 20 halogensubstitueret 2-tiofenkarboxaldehyd. Den resulterende schiffske base reduceres til fremstilling af det tilsvarende p-aminobenzoesyrederivat. En hensigtsmæssig metode til at gennemføre denne sidstnævnte procedure indbefatter blanding af den schiffske base med et overskud af 25 ætanol og vand. Der kan eventuelt sættes fortyndet vandigt natriumhydroxyd til blandingen. Natriumborhydrid tilsættes ved stuetemperatur og der omrøres indtil det opløses. Derpå opvarmes blandingen, udhældes i is og syr-nes. Produktet kan filtreres fra som et bundfald og yder-30 ligere renses ved kendte metoder. Man kan desuden gå frem som beskrevet i eksempel 1.The present compounds are prepared according to the invention in the manner specified in the characterizing part of the patent, ie by reaction of p-aminobenzoic acid or an ester thereof, for example in an inactive solvent, with a halogen-substituted 2-thiophenecarboxaldehyde. The resulting schiffic base is reduced to prepare the corresponding p-aminobenzoic acid derivative. A convenient method of carrying out this latter procedure involves mixing the Schiff base with an excess of ethanol and water. Optionally, dilute aqueous sodium hydroxide may be added to the mixture. Sodium borohydride is added at room temperature and stirred until dissolved. Then the mixture is heated, poured into ice and acidified. The product can be filtered off as a precipitate and further purified by known methods. In addition, one can proceed as described in Example 1.
Flere af de halogenerede aldehyder er ikke let tilgængelige, men kan fremstilles ved metoder der er kendte fra litteraturen. Fx fremstilledes 4-klor-2-tio-35 fenkarboxaldehyd ved klorinering af 2-tiofenkarboxaldehyd under anvendelse af et stort overskud af aluminiumklorid som katalysator. Se J. Org. Chem., 21, 381, 1956 og J. Heter. Chem., 393, 1976. Ved anvendelse af sammeSeveral of the halogenated aldehydes are not readily available but can be prepared by methods known in the literature. For example, 4-chloro-2-thiophenecarboxaldehyde was prepared by chlorination of 2-thiophenecarboxaldehyde using a large excess of aluminum chloride as catalyst. See J. Org. Chem., 21, 381, 1956 and J. Heter. Chem., 393, 1976. Using the same
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4 metode fremstilledes også 4,5-diklor-2-tiofenkarboxal-dehyd udfra 5-klor-2-tiofenkarboxaldehyd. Se C.A. 57, 16526i.4 method was also prepared 4,5-dichloro-2-thiophenecarboxaldehyde from 5-chloro-2-thiophenecarboxaldehyde. See C.A. 57, 16526i.
5 Fremgangsmåden ifølge opfindelsen belyses nærmere i det følgende ved hjælp af nogle eksempler.The process according to the invention is illustrated in the following by means of some examples.
Eksempel 1 1 g 4-(3,5-Diklor-2-tienylmetylamino)-benzoesyreExample 1 1 g of 4- (3,5-Dichloro-2-thienylmethylamino) -benzoic acid
En 50%'s oliedispersion (5,8 g, 0,12 mol) af natrium-hydrid vaskedes med hexan under nitrogen. Der tilsattes 200 ml tørt dimetylformamid og 29,5 g (0,113 mol) fast ætyl-N-trifluoracetyl-4-aminobenzoat. Reaktionsmassen 15 opvarmedes eksotermt i mild grad. Blandingen afkøledes til 20°C og omrørtes i 15 minutter. Derefter tilsattes 27,7 g 3,5-diklor-2-brommetyltiofen. Reaktionsmassen opvarmedes i 18 timer til 85°C. Efter afslutningen af denne periode udhældtes blandingen i 1 liter koldt vand og 20 ekstraheredes med metylenklorid. Produktet tørredes med vandfrit natrrumsulfat og den tørrede opløsning koncentreredes til en brun olie. Den resulterende olie kogtes under tilbagesvaling i 2 timer med 50 ml ætanol og 200 ml 5N natr iumhy dr oxyd. Den afkølede, brune opløsning.A 50% oil dispersion (5.8 g, 0.12 mol) of sodium hydride was washed with hexane under nitrogen. 200 ml of dry dimethylformamide and 29.5 g (0.113 mol) of solid ethyl N-trifluoroacetyl-4-aminobenzoate were added. The reaction mass was heated exothermally to a mild degree. The mixture was cooled to 20 ° C and stirred for 15 minutes. Then, 27.7 g of 3,5-dichloro-2-bromomethylthiophene were added. The reaction mass was heated to 85 ° C for 18 hours. At the end of this period, the mixture was poured into 1 liter of cold water and extracted with methylene chloride. The product was dried over anhydrous sodium sulfate and the dried solution concentrated to a brown oil. The resulting oil was refluxed for 2 hours with 50 ml of ethanol and 200 ml of 5N sodium hydroxide. The cooled, brown solution.
25 fortyndedes med vand og syrnedes med eddikesyre. Den rå 4-(3,5-diklor-2-tienylmetylamino)-benzoesyre vandtes som en brun olie og omkrystalliseredes fra propylengly-kolmetylæter hvorved der vandtes 17 g brune krystaller med smp. 169-170,5°C.25 was diluted with water and acidified with acetic acid. The crude 4- (3,5-dichloro-2-thienylmethylamino) benzoic acid was obtained as a brown oil and recrystallized from propylene glycarbon methyl ether to give 17 g of brown crystals, m.p. 169 to 170.5 ° C.
30 Beregnet: C 47,71 H 3,00 N 4,63Calculated: C 47.71 H 3.00 N 4.63
Fundet: C 47,8 H 3,06 N 4,74%.Found: C 47.8 H 3.06 N 4.74%.
Eksempel 2 4-(5-Klor-2-tienylmetylamino)-benzoesyre 35Example 2 4- (5-Chloro-2-thienylmethylamino) -benzoic acid 35
En blanding indeholdende 46,6 g (0,34 mol) p-aminobenzoesyre, 50 g (0,34 mol) 5-klor-2-tiofenkarbox-aldehyd og 400 ml toluen opvarmedes under tilbagesvalingA mixture containing 46.6 g (0.34 mol) of p-aminobenzoic acid, 50 g (0.34 mol) of 5-chloro-2-thiophenecarboxaldehyde and 400 ml of toluene was heated at reflux.
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5 i ca. 3 1/2 time. Det dannede vand opsamledes i en Dean-Stark-fælde. Reaktionsmassen afkøledes ved slutningen af denne periode og den schiffske base opsamledes som 5 et læderbrunt fast stof. Til en blanding af den som mellemprodukt vundne schiffske base og 1,2 liter iseddikesyre sattes 21,2 g (0,35 mol) dimetylaminoboran. Reaktionsmassen opvarmedes til 40°C i ca. 30 minutter og udhældtes i 2 liter isvand. Det hvide bundfald af 4—(5— .j q klor-2-tienylmetylamino)-benzoesyre vaskedes i vand, tørredes og omkrystalliseredes fra toluen. Udbytte 60 g (70%), smp. 177-178°C.5 for approx. 3 1/2 hours. The formed water was collected in a Dean-Stark trap. The reaction mass was cooled at the end of this period and the schiffic base was collected as a leather brown solid. To a mixture of the Schiffen base obtained as an intermediate and 1.2 liters of glacial acetic acid was added 21.2 g (0.35 mole) of dimethylaminoborane. The reaction mass was heated to 40 ° C for approx. 30 minutes and poured into 2 liters of ice water. The white precipitate of 4- (5'-chloro-2-thienylmethylamino) -benzoic acid was washed in water, dried and recrystallized from toluene. Yield 60 g (70%), m.p. 177-178 ° C.
Eksempel 3 15 4-(4,5-Diklor-2-tienylmetylamino)-benzoesyre Trin 1: 4,5-Diklor-2-tiofenkarboxaldehyd.Example 3 4- (4,5-Dichloro-2-thienylmethylamino) -benzoic acid Step 1: 4,5-Dichloro-2-thiophenecarboxaldehyde.
Til en mekanisk omrørt opløsning af 31,8 g (0,217 mol) 5-klor-2-tiofenkarboxaldehyd i 150 ml metylenklorid sattes i små portioner 65 g (0,487 mol) vandfrit 20 aluminiumklorid. Blandingen opvarmedes exotermt og blev purpurfarvet. Til denne blanding sattes dråbevis 20,6 g (0,29 mol) klor i 250 ml kulstoftetraklorid.To a mechanically stirred solution of 31.8 g (0.217 mol) of 5-chloro-2-thiophenecarboxaldehyde in 150 ml of methylene chloride was added in small portions 65 g (0.487 mol) of anhydrous aluminum chloride. The mixture was heated exothermically and purple. To this mixture was added dropwise 20.6 g (0.29 mole) of chlorine in 250 ml of carbon tetrachloride.
Reaktionsmassen kogtes under tilbagesvaling i ca.The reaction mass was refluxed for approx.
15 timer og der tilsattes yderligere 15 g (0,21 mol) 25 klor i 200 ml kulstoftetraklorid. Blandingen kogtes under tilbagesvaling i yderligere 7 timer. Reaktionen standsedes brat ved udhældning af 1 liter isvand. Det vandige lag ekstraherede med kloroform. Kloroformopløsningen vaskedes med vand og natriumkarbonat. Efter tørring med 30 vandfrit natriumsulfat og koncentrering under vakuum vandtes en gulbrun olie. Det rå 4,5-diklor-2-tiofenkar-boxaldehyd krystalliserede ved henstand og omkrystalliseredes fra hexan.15 hours and an additional 15 g (0.21 mol) of chlorine was added in 200 ml of carbon tetrachloride. The mixture was refluxed for an additional 7 hours. The reaction was stopped abruptly by pouring 1 liter of ice water. The aqueous layer was extracted with chloroform. The chloroform solution was washed with water and sodium carbonate. After drying with 30 anhydrous sodium sulfate and concentration in vacuo, a tan oil was obtained. The crude 4,5-dichloro-2-thiophenecarboxaldehyde crystallized on standing and recrystallized from hexane.
Trin 2: Produktet 4-(4,5-diklor-2-tienylmetylamino)-Step 2: The product 4- (4,5-dichloro-2-thienylmethylamino) -
T C QT C Q
benzoesyre med smp. 225-227 C fremstilledes ud fra det som mellemprodukt vundne 4,5-diklor-2-tiofenkarboxaldehyd på i det væsentlige samme måde som beskrevet i eksempel 2 ovenfor. Udbytte: 88%.benzoic acid, m.p. 225-227 ° C was prepared from the 4,5-dichloro-2-thiophenecarboxaldehyde obtained as an intermediate in substantially the same manner as described in Example 2 above. Yield: 88%.
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66
Beregnet: C 47,71 H 3,00 N 4,63 Fundet: C 47,6 H 3,09 N 4,80%Calculated: C 47.71 H 3.00 N 4.63 Found: C 47.6 H 3.09 N 4.80%
Foruden de forbindelser der er beskrevet i eksempler-5 ne ovenfor fremstilledes andre forbindelser under anvendelse i det væsentlige samme teknik. Disse forbindelser er vist som eksempel 4, 5 og 6:In addition to the compounds described in Examples 5, other compounds were prepared using essentially the same technique. These compounds are shown as Examples 4, 5 and 6:
Eksempel 4 10 __________ 4-(5-Klor-2-tienylmetylamino)-benzoesyre-ætylester med smp. 108-109°C fremstilledes ud fra ætyl-p-amino-benzoat og 5-klor-2-tiofenkarboxaldehyd. Udbytte 87%. Beregnet: C 56,86 H 4,77 N 4,73 15 Fundet: C 56,7 H 4,87 N 4,85%Example 4 4- (5-Chloro-2-thienylmethylamino) -benzoic acid ethyl ester, m.p. 108-109 ° C was prepared from ethyl p-amino-benzoate and 5-chloro-2-thiophenecarboxaldehyde. Yield 87%. Calculated: C 56.86 H 4.77 N 4.73 Found: C 56.7 H 4.87 N 4.85%
Eksempel 5 4-(5-Brom-2-tienylmetylamino)-benzoesyre, smp. 188-20 190°C, udbytte 61%.Example 5 4- (5-Bromo-2-thienylmethylamino) -benzoic acid, m.p. 188-20 190 ° C, yield 61%.
Beregnet: C 46,18 H 3,23 N 4,49Calculated: C 46.18 H 3.23 N 4.49
Fundet: C 46,1 H 3,29 N 4,65%.Found: C 46.1 H 3.29 N 4.65%.
Eksempel 6 25 4-(4-Klor-2-tienylmetylamino)-benzoesyre, smp. 165-168°C, udbytte 96%.Example 6 4- (4-Chloro-2-thienylmethylamino) -benzoic acid, m.p. 165-168 ° C, yield 96%.
Beregnet: C 53,85 H 3,77 N 5,23Calculated: C, 53.85; H, 3.77; N, 5.23
Fundet: C 53,6 H 3,80 N 5,38% 30Found: C 53.6 H 3.80 N 5.38% 30
Eksempel 7Example 7
De omhandlede forbindelsers hypolipidæmiske virkning demonstreredes illustrativt på rotter. Ved denne procedure opløstes en forbindelse i acetone, blev optaget 35 på en silikagel og blandedes med normalt formalet foder til opnåelse af koncentrationerne på 0,125% af forbindelsen i dyrefoderet. Det behandlede foder blev indgivet til hanrotter med en vægt på 150-160 g over en 14 dagesThe hypolipidemic effect of the compounds of this invention was illustratively illustrated in rats. In this procedure, a compound was dissolved in acetone, taken up on a silica gel, and mixed with normally ground feed to give the concentrations of 0.125% of the compound in the animal feed. The treated feed was administered to male rats weighing 150-160 g over a 14 day period
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7 periode. Efter foderperioden blev rotterne aflivet og der opsamledes blodprøver. Leveren fjernedes, vejedes og blev frosset ned til senere analyse. De relative ni-5 veauer af serumkolesterol i blodprøverne bestemtes ved Henly's metode. A.A. Henley, Analyst, 82, 286, 1957. Leverkolesterol bestemtes med Sperry-Webb-metoden. Journal og Biological Chemistry 187, 97, 1950. De relative niveauer af triglycerider i blodprøverne og leverprøverne 10 bestemtes ved Von Handel og Zilversmit's metode. J. Lab.7 period. After the feeding period, the rats were sacrificed and blood samples were collected. The liver was removed, weighed and frozen for later analysis. The relative nine levels of serum cholesterol in the blood samples were determined by Henly's method. A.A. Henley, Analyst, 82, 286, 1957. Liver cholesterol was determined by the Sperry-Webb method. Journal and Biological Chemistry 187, 97, 1950. The relative levels of triglycerides in the blood and liver samples 10 were determined by Von Handel and Zilversmit's method. J. Lab.
Clin. Med. 50, 152, 1957 og Clin. Chem. 7, 249, 1961.Clin. With. 50, 152, 1957 and Clin. Chem. 7, 249, 1961.
Ved at tage gennemsnitlige niveauer fra kontrolrotter som standard blev middelresultaterne vundet i de behandlede grupper fastslået. De i tabel 1 opstillede data 15 sammenfatter resultaterne fra de ovennævnte studier.Taking mean levels from control rats by default, mean results obtained in the treated groups were determined. The data 15 presented in Table 1 summarize the results of the above studies.
I tabel 1 betegner alle resultaterne den procentuelle forandring af værdierne for de behandlede dyr sammenlignet med resultaterne for kontrolgruppen.In Table 1, all the results represent the percentage change in the values of the treated animals compared to the results for the control group.
20 25 30 3520 25 30 35
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VO ® H U1 to U O ro 3 tn < 8VO ® H U1 to U O ro 3 tn <8
iDiD
r+s +
Ir1 ro + + + + + + + *s H to H Η H ro ej o o to Η oo σι li <!Ir1 ro + + + + + + + * s H to H Η H ro not o o to Η oo σι li <!
PiPi
cQcQ
c+c +
DK 153403 BDK 153403 B
99
Resultaterne i tabel 1 viser at forbindelser fremstillet ved fremgangsmåden ifølge opfindelsen er højeffektive som hypolipidæmiské midler til sænkning af serumkole-5 sterol og serumtriglycerider mens de kun fremkalder minimale ændringer i levervægt og den samlede legemsvægt. Forbindelserne 4-(4,5-diklor-2-tienylmetylamino)-benzoesyre (eksempel 3) og 4-(5-klor-2-tienylmetylamino)-benzoesyre -ætyles ter (eksempel 4) ses at være særligt nyt-10 tige tilsænkning af kolesterolniveauer hos pattedyr.The results in Table 1 show that compounds prepared by the process of the invention are highly effective as hypolipidemic agents for lowering serum cholesterol and serum triglycerides while only causing minimal changes in liver weight and total body weight. The compounds 4- (4,5-dichloro-2-thienylmethylamino) -benzoic acid (Example 3) and 4- (5-chloro-2-thienylmethylamino) -benzoic acid ethyl ester (Example 4) are seen to be particularly useful in lowering of cholesterol levels in mammals.
Ligeledes viste det sig at forbindelserne 4-(5-klor-2-tienylmetylamino)-benzoesyre-metylester (eksempel 4) og 4-(4-klor-2-tienylmetylamino)-benzoesyre (eksempel 6) er særligt effektive til sænkning af serumtriglyceridniveau- 15 et· 20 25 30 35Similarly, the compounds 4- (5-chloro-2-thienylmethylamino) -benzoic acid methyl ester (Example 4) and 4- (4-chloro-2-thienylmethylamino) -benzoic acid (Example 6) were found to be particularly effective in lowering serum triglyceride levels. - 15 et · 20 25 30 35
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US78546777A | 1977-04-07 | 1977-04-07 | |
| US78546777 | 1977-04-07 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK153178A DK153178A (en) | 1978-10-08 |
| DK153403B true DK153403B (en) | 1988-07-11 |
| DK153403C DK153403C (en) | 1988-11-28 |
Family
ID=25135597
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK153178A DK153403C (en) | 1977-04-07 | 1978-04-06 | METHOD OF ANALOGUE FOR THE PREPARATION OF 4- (2-TIENYLMETHYLAMINO) -BENZOIC ACID COMPOUNDS |
Country Status (14)
| Country | Link |
|---|---|
| JP (1) | JPS53149968A (en) |
| BE (1) | BE865809A (en) |
| CA (1) | CA1108159A (en) |
| CH (1) | CH629796A5 (en) |
| DE (1) | DE2814798A1 (en) |
| DK (1) | DK153403C (en) |
| FR (1) | FR2386542A1 (en) |
| GB (1) | GB1565936A (en) |
| IE (1) | IE46713B1 (en) |
| IT (1) | IT1094318B (en) |
| NL (1) | NL7803669A (en) |
| NO (1) | NO149241C (en) |
| NZ (1) | NZ186886A (en) |
| SE (1) | SE446734B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4143151A (en) * | 1978-07-03 | 1979-03-06 | The Dow Chemical Company | Method for treating hyperglycemia in mammals using arylamino benzoic acids |
| JPS6421196A (en) * | 1987-07-15 | 1989-01-24 | Nippon Concrete Ind Co Ltd | Auger screw |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2609962A1 (en) * | 1975-03-12 | 1976-09-30 | American Cyanamid Co | PARA-SQUARE BRACKETS ON ARYL (ALKYL- OR ALKENYL) AMINO SQUARE BRACKETS FOR BENZOIC ACID DERIVATIVES AND THE PROCESS FOR THEIR PRODUCTION |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2983729A (en) * | 1958-04-30 | 1961-05-09 | Monsanto Chemicals | Preparation of 5-halothienyl amines |
| US3859440A (en) * | 1971-10-08 | 1975-01-07 | Ici Australia Ltd | Certain thienyl compounds used to control acarina |
-
1978
- 1978-04-03 CH CH355178A patent/CH629796A5/en not_active IP Right Cessation
- 1978-04-04 IT IT21941/78A patent/IT1094318B/en active
- 1978-04-05 DE DE19782814798 patent/DE2814798A1/en active Granted
- 1978-04-05 IE IE678/78A patent/IE46713B1/en not_active IP Right Cessation
- 1978-04-05 FR FR7810111A patent/FR2386542A1/en active Granted
- 1978-04-05 NZ NZ186886A patent/NZ186886A/en unknown
- 1978-04-06 CA CA300,577A patent/CA1108159A/en not_active Expired
- 1978-04-06 GB GB13449/78A patent/GB1565936A/en not_active Expired
- 1978-04-06 JP JP4075978A patent/JPS53149968A/en active Granted
- 1978-04-06 NL NL7803669A patent/NL7803669A/en not_active Application Discontinuation
- 1978-04-06 DK DK153178A patent/DK153403C/en not_active IP Right Cessation
- 1978-04-06 SE SE7803910A patent/SE446734B/en not_active IP Right Cessation
- 1978-04-06 NO NO781214A patent/NO149241C/en unknown
- 1978-04-07 BE BE186657A patent/BE865809A/en not_active IP Right Cessation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2609962A1 (en) * | 1975-03-12 | 1976-09-30 | American Cyanamid Co | PARA-SQUARE BRACKETS ON ARYL (ALKYL- OR ALKENYL) AMINO SQUARE BRACKETS FOR BENZOIC ACID DERIVATIVES AND THE PROCESS FOR THEIR PRODUCTION |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2386542B1 (en) | 1981-07-10 |
| CA1108159A (en) | 1981-09-01 |
| GB1565936A (en) | 1980-04-23 |
| CH629796A5 (en) | 1982-05-14 |
| NO781214L (en) | 1978-10-10 |
| BE865809A (en) | 1978-10-09 |
| NZ186886A (en) | 1980-02-21 |
| JPS53149968A (en) | 1978-12-27 |
| DK153178A (en) | 1978-10-08 |
| IE46713B1 (en) | 1983-09-07 |
| DE2814798A1 (en) | 1978-10-19 |
| IT7821941A0 (en) | 1978-04-04 |
| SE446734B (en) | 1986-10-06 |
| SE7803910L (en) | 1978-10-08 |
| NO149241B (en) | 1983-12-05 |
| DK153403C (en) | 1988-11-28 |
| NL7803669A (en) | 1978-10-10 |
| DE2814798C2 (en) | 1988-05-26 |
| IE780678L (en) | 1978-10-07 |
| NO149241C (en) | 1984-03-14 |
| FR2386542A1 (en) | 1978-11-03 |
| JPS6126790B2 (en) | 1986-06-21 |
| IT1094318B (en) | 1985-07-26 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed | ||
| PUP | Patent expired |