DK153471B - ANALOGY PROCEDURE FOR PREPARING A 4-MET HYLAMINOBENOIC ACID COMPOUND - Google Patents
ANALOGY PROCEDURE FOR PREPARING A 4-MET HYLAMINOBENOIC ACID COMPOUND Download PDFInfo
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Description
DK 153471 BDK 153471 B
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte p-methylaminobenzoesyreforbindelser af den i krav l's indledning angivne art.The present invention relates to an analogous process for the preparation of novel p-methylaminobenzoic acid compounds of the kind set forth in claim 1.
Det -er kendt at cholesterol og triglycerider spiller en større rolle ved dannelsen af artheroschlerotisk plaque ved at fremskynde aflejringen af blodlipider i arterievæggen.It is known that cholesterol and triglycerides play a greater role in the formation of artherosclerotic plaque by accelerating the deposition of blood lipids in the arterial wall.
4-(l,3~ benzodioxol-5-ylmethyl-amino)benzoesyreethylester og 4-((2-naphthylenylmethyl)amino)-benzoesyre er blevet nævnt i litteraturer Se tysk patent nr. 716.668 og Chemical Abstracts 58, 521f. Ingen af forbindelserne er angivet som nyttige til at nedsætte lipidmæng-den i serum hos dyr.4- (1,3-Benzodioxol-5-ylmethylamino) benzoic acid ethyl ester and 4 - ((2-naphthylenylmethyl) amino) benzoic acid have been mentioned in literature See German Patent No. 716,668 and Chemical Abstracts 58, 521f. None of the compounds are listed as useful for reducing the amount of serum lipid in animals.
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DK 153471 BDK 153471 B
De ifølge opfindelsen fremstillede forbindelser har den almene formel hvor R er 9-anthracenyl eller lf3-benzodioxol-5-yl, eller er et farmaceutisk anvendeligt salt deraf.The compounds of the invention have the general formula wherein R is 9-anthracenyl or 1-3-benzodioxol-5-yl, or is a pharmaceutically useful salt thereof.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i krav l's kendetegnende del angivne.The process according to the invention is characterized by the characterizing part of claim 1.
Farmaceutisk anvendelige salte refererer til syreadditionssaltene af de baser, som kan danne et salt med en carboxylsyre, og som ikke forårsager nogen skadelig fysiologisk virkning, når de administreres til et dyr i doser, der er forenelige med god farmakologisk virkning. Egnede baser indbefatter f.eks. alkalimetal og jordålkalimetal= hydroxider, carbonaterne og bicarbonaterne, såsom natriumhydroxid, kaliumhydroxid, calciumhydroxid, kaliumcarbonat, natriumbicarbonat eller magniumcarbonat, ammoniak og primære, sekundære og tertiære aminer. Aluminiumsalte kan også fås ved at behandle det tilsvarende natriumsalt med et egnet aluminiumkompleks, såsom aluminiumchlorid= hexahydrat.Pharmaceutically useful salts refer to the acid addition salts of the bases which can form a salt with a carboxylic acid and which cause no detrimental physiological effect when administered to an animal at doses compatible with good pharmacological action. Suitable bases include e.g. alkali metal and alkaline earth metal = hydroxides, the 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.
Forbindelserne, der fremstilles ifølge opfindelsen, er krystallinske faste stoffer, som er opløselige i mange almindelige organiske opløsningsmidler, som f.eks. acetone, benzen alkoholer eller fly-, dende alkaner.The compounds prepared according to the invention are crystalline solids which are soluble in many common organic solvents such as e.g. acetone, benzene alcohols or liquid alkanes.
De ovenfor beskrevne forbindelser har vist hypolipidemisk virkning hos dyr og især pattedyr. Hypolipidemisk virkning refererer i denThe compounds described above have shown hypolipidemic activity in animals and especially mammals. Hypolipidemic effect refers in it
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foreliggende beskrivelse til den virkning at nedsætte indholdet af lipid i blodet og især cholesterol-og triglyceridindholdet i serum,present description to the effect of reducing the lipid content in the blood and especially the serum cholesterol and triglyceride content,
Forbindelserne fremstillet ifølge opfindelsen er derfor egnede til brug ved behandling af serumhyperlipidemi hos pattedyr og er især nyttige til behandling af hypercholesterolemi og hypertriglyceridemi, dvs. abnormt høje mængder lipider, cholesterol eller triglycerider i serum. Forbindelserne kan administreres oralt eller parenteralt ved subkutan, intravenøs eller intraperitoneal injektion eller ved implantation, idet oral administration foretrækkes.The compounds of the invention are therefore suitable for use in the treatment of serum hyperlipidemia in mammals and are particularly useful in the treatment of hypercholesterolemia and hypertriglyceridemia, i.e. abnormally high amounts of lipids, cholesterol or triglycerides in serum. The compounds may be administered orally or parenterally by subcutaneous, intravenous or intraperitoneal injection or by implantation, with oral administration being preferred.
Den hypolipidemiske mængde af p-aminobenzoesyreforbindelserne, som skal administrer es til et dyr, dvs. den mængde, som er effektiv til kendeligt at nedsætte lipidmængden i serum, kan variere med sådanne faktorer som det behandlede dyr, den pågældende anvendte p-amino= benzoesyreforbindelse, den ønskede lipidmængde, som skal opnås, hvad enten dyret er hyperlipidemisk eller ej, administrationsperioden og administrationsmetoden. I almindelighed ligger en effektiv daglig dosis på 1-400 mg pr. kg legemsvægt, idet en daglig dosis på 5-30 mg/kg legemsvægt foretrækkes.The hypolipidemic amount of the β-aminobenzoic acid compounds to be administered to an animal, i.e. the amount effective to appreciably reduce the amount of lipid in serum may vary with such factors as the treated animal, the p-amino = benzoic acid compound used, the desired lipid amount to be obtained, whether the animal is hyperlipidemic or not, the period of administration and the method of administration. In general, an effective daily dose is 1-400 mg per day. a daily dose of 5-30 mg / kg body weight is preferred.
Til oral administration kan farmaceutiske præparater af p-aminoben= zoesyrerne fremstilles på sædvanlig måde. Disse måder indebærer granulering og sammentrykning, når det er nødvendigt, eller blanding og opløsning eller suspendering af bestanddelene for at få det ønskede slutprodukt. Der kan anvendes talrige farmaceutiske former til at bære forbindelserne. F.eks. kan den rene forbindelse anvendes, eller den kan blandes med en fast bærer. I almindelighed foretrækkes uorganiske farmaceutiske bærere og især faste uorganiske bærere.For oral administration, pharmaceutical preparations of the β-aminobenzoic acids can be prepared in the usual manner. These ways involve granulation and compression when needed, or mixing and dissolving or suspending the ingredients to obtain the desired final product. Numerous pharmaceutical forms can be used to support the compounds. Eg. For example, the pure compound can be used or it can be mixed with a solid support. In general, inorganic pharmaceutical carriers and especially solid inorganic carriers are preferred.
En grund hertil er det store antal uorganiske materialer, der vides at være farmaceutisk sikre og acceptable samt meget bekvemme til fremstilling af præparater. Midlerne kan være i form af tabletter, sugetabletter, pulvere, kapsler, opslæmninger, pastiller eller bolcher,og disse midler kan fremstilles ved standardteknik. Midler i form af tabletter kan være overtmkne eller uovertrukne, og de kan være brusende eller ikke-brusende. Sædvanlige hjælpestoffer til tabletdannelse kan anvendes. F.eks. kan anvendes indifferente for-One reason for this is the large number of inorganic materials known to be pharmaceutically safe and acceptable as well as very convenient for the preparation of preparations. The agents may be in the form of tablets, lozenges, powders, capsules, slurries, lozenges or bolches, and these agents may be prepared by standard techniques. Tablets may be coated or uncoated and may be effervescent or non-effervescent. Usual auxiliaries for tablet formation may be used. Eg. can be used inert
^ DK 153471 B^ DK 153471 B
tyndingsmidler, såsom magniumcarbonat eller lactose, sprængmidler som majsstivelse eller alginsyre og smøremidler, såsom magnium= stearat.thinners such as magnesium carbonate or lactose, explosives such as corn starch or alginic acid, and lubricants such as magnesium stearate.
Hvis der anvendes en flydende bærer,kan præparatet være i form af en blød gelatinekapsel, en sirup, en væskeopløsning eller suspension.If a liquid carrier is used, the composition may be in the form of a soft gelatin capsule, a syrup, a liquid solution or suspension.
Kulbrinteopløseligheden af de fleste af forbindelserne fremstillet ifølge opfindelsen er stor nok til at muliggøre anvendelse af farmaceutisk anvendelige olier som bærestoffer. F.eks. kan anvendes vegetabilske eller animalske olier, såsom solsikkeolie, safflorolie, majsolie eller torskeleverolie. Glycerin kan også anvendes. Med sidstnævnte opløsningsmiddel kan der tilsættes 2 30% vand. Når vand alene er bæreren, eller når opløseligheden af forbindelsen i olie er lav, kan præparaterne administreres i form af en opslæmning.The hydrocarbon solubility of most of the compounds of the invention is large enough to allow the use of pharmaceutically useful oils as carriers. Eg. vegetable or animal oils such as sunflower oil, safflower oil, corn oil or cod liver oil may be used. Glycerin can also be used. With the latter solvent, 2 30% water can be added. When water alone is the carrier or when the solubility of the compound in oil is low, the compositions may be administered in the form of a slurry.
Emulsionsmidler kan fremstilles ved anvendelse af emulgeringsmidler, såsom sorbitantrioleat, polyoxyethylensorbitanmonooleat, lecithin, acaciegummi eller tragant. Suspensioner på vandig basis kan fremstilles ved hjælp af befugtningsmidler, såsom polyethylen= oxidkondensationsprodukter af alkylphenoler, fedtalkoholer eller fedtsyrer med suspenderingsmidlet, f.eks. et hydrofilt colloid, såsom polyvinylpyrrolidon. Emulsionerne og suspensionerne kan indeholde sædvanlige hjælpestoffer, såsom sødemidler, strømningsmidler, farvende materialer eller konserveringsmidler.Emulsifiers may be prepared using emulsifiers such as sorbitan trioleate, polyoxyethylene sorbitan monooleate, lecithin, acacia gum or tragacanth. Aqueous suspensions may be prepared by wetting agents such as polyethylene = oxide condensation products of alkyl phenols, fatty alcohols or fatty acids with the suspending agent, e.g. a hydrophilic colloid such as polyvinylpyrrolidone. The emulsions and suspensions may contain usual adjuvants, such as sweeteners, flowing agents, coloring materials or preservatives.
p-aminobenzoesyrerne kan også inkorporeres i foder eller næringsmidler, som f.eks. smør, margarine, spiseolier, kasein eller kulhydrater. Disse næringsmidler er egnede til at administreres som hel eller delvis kost eller som et supplement til kosten. Disse midler indeholder fortrinsvis fra 0,02 til 2,0 vægt% af den aktive bestanddel, når de administreres som den samlede kost. Midlerne kan indeholde højere koncentrationer af den aktive bestanddel, når de administreres som et supplement.The β-amino benzoic acids may also be incorporated into feed or foodstuffs, such as e.g. butter, margarine, edible oils, casein or carbohydrates. These foods are suitable for administration as a whole or partial diet or as a supplement to the diet. These agents preferably contain from 0.02 to 2.0% by weight of the active ingredient when administered as the total diet. The agents may contain higher concentrations of the active ingredient when administered as a supplement.
Til parenteral brug kan forbindelserne oparbejdes med sterile bestanddele, sammenblandes og pakkes aseptisk. De kan administreres intravenøst eller intramuskulært. Nyttige opløsningsmidler til sammensætning ved sådan anvendelse er de .polyvalente alifatiskeFor parenteral use, the compounds can be worked up with sterile ingredients, mixed together and packed aseptically. They can be administered intravenously or intramuscularly. Useful solvents for composition in such use are the polyhydric aliphatic
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alkoholer og blandinger deraf. Særligt tilfredsstillende er de farmaceutisk anvendelige glycoler, såsom propylenglycol og blandinger deraf. Glycerin er særlig nyttig. Op til 25-30 rumfangsprocent vand kan inkorporeres i bæreren, hvis det ønskes. En 80% vandig propylenglycolopløsning er et særlig bekvemt opløsningsmiddelsystem. En pH-værdi på ca. 7>4 og isotonicitet, der er forenelig med legemsisotonicitetenfer ønskelig. Basicitet kan reguleres ved tilsætning af en base efter behov, og en særlig bekvem base er monoethanolamin. Det kan ofte være ønskeligt at inkorporere et lokalanæstetikum, således som det er velkendt for fagfolk.alcohols and mixtures thereof. Particularly satisfactory are the pharmaceutically useful glycols, such as propylene glycol and mixtures thereof. Glycerin is particularly useful. Up to 25-30% by volume of water can be incorporated into the carrier if desired. An 80% aqueous propylene glycol solution is a particularly convenient solvent system. A pH of approx. 7> 4 and isotonicity compatible with body isotonicity is desirable. Basicity can be adjusted by adding a base as needed, and a particularly convenient base is monoethanolamine. It may often be desirable to incorporate a local anesthetic, as is well known to those skilled in the art.
Den procentmængde af forbindelsen, der skal anvendes i den farmaceutiske bærer kan varieres. Det er nødvendigt, at forbindelsen udgør en sådan mængde, at der fås en egnet dosering, og det foretrækkes at anvende farmaceutiske midler indeholdende mindst 10 vægt$ af forbindelsen. Aktiviteten vokser med koncentrationen af det aktive stof i bæreren, men de midler, der indeholder en endelig mængde bærer, f.eks. mindst 1% og fortrinsvis mindst 5%,foretrækkes, da de muliggør lettere administration af forbindelsen.The percentage of the compound to be used in the pharmaceutical carrier may be varied. It is necessary that the compound be of such amount as to obtain a suitable dosage and it is preferred to use pharmaceutical agents containing at least 10% by weight of the compound. The activity grows with the concentration of the active substance in the carrier, but the agents containing a finite amount of carrier, e.g. at least 1% and preferably at least 5% are preferred as they allow easier administration of the compound.
I almindelighed gennemføres fremgangsmåden ifølge opfindelsen ved at bringe p-aminobenzoesyre i et indifferent opløsningsmiddel til at reagere med et aldehyd af det organiske radikal, som man søger at fremstille. Den fremkomne Schiffske base reduceres for at fremstille det tilsvarende p-aminobenzoesyrederivat. En bekvem fremgangsmåde til udførelse af sidstnævnte metode indebærer blanding af den Schiffske base med et overskud af ethanol og vand. Fortyndet vandig natriumhydroxid, f.eks. et molært ækvivalent af den Schiffske base,kan eventuelt sættes til blandingen. Natriumborhydrid NaBH^ (1 molært ækvivalent) tilsættes ved stuetemperatur og omrøres, indtil det opløses. Blandingen opvarmes så under tilbagesvaling i 1 til 2 timer. Blandingen hældes på is og syrnes. Produktet kan frafiltreres som et bundfald og renses yderligere på kendte måder.In general, the process according to the invention is carried out by reacting p-aminobenzoic acid in an inert solvent to react with an aldehyde of the organic radical which one seeks to prepare. The resulting Schiff base is reduced to produce the corresponding p-aminobenzoic acid derivative. A convenient method for carrying out the latter method involves mixing the Schiff base with an excess of ethanol and water. Diluted aqueous sodium hydroxide, e.g. a molar equivalent of the Schiff base may optionally be added to the mixture. Sodium borohydride NaBH 2 (1 molar equivalent) is added at room temperature and stirred until dissolved. The mixture is then heated at reflux for 1 to 2 hours. The mixture is poured on ice and acidified. The product can be filtered off as a precipitate and further purified in known ways.
De følgende eksempler illustrerer fremstillingen af nogle forbindelser.The following examples illustrate the preparation of some compounds.
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Eksempel 1 4~(1t3-benzodioxol-5-ylmethylamino)benzoesyreEXAMPLE 14 (1-3-Benzodioxol-5-ylmethylamino) benzoic acid
En blanding af 22,5 g (0,15 mol) piperonal og 24,8 g (0,15 mol) ethyl-p-aminobenzoat i 500 ml benzen blev opvarmet under tilbagesvaling, indtil der var opsamlet 0,15 mol vand i en vandlås. Reaktionen blev afkølet, og der dannedes gule krystaller. Blandingen blev filtreret, og det krystallinske produkt blev vasket med benzen og vakuumtørret. Den Schiffske base vejede 31,97 g (0,107 mol).A mixture of 22.5 g (0.15 mole) of piperonal and 24.8 g (0.15 mole) of ethyl p-aminobenzoate in 500 ml of benzene was heated at reflux until 0.15 mole of water was collected in a trap. The reaction was cooled and yellow crystals formed. The mixture was filtered and the crystalline product was washed with benzene and vacuum dried. The Schiff base was weighed 31.97 g (0.107 mol).
Den Schiffske base blev opløst i 500 ml vandfri ethanol og opvarmet til 40°C. 4,5 g natriumborhydrid blev tilsat, og den fremkomne opslæmning blev opvarmet under tilbagesvaling i 45 minutter. Reaktionsmassen blev afkølet, hældt over 800 ml isvand, og den rå 4-(1,3-benzodioxol-5-ylmethylamino)benzoesyreethylester fældede ud. Bundfaldet blev opsamlet og vasket med vand. Efter vakuumtørring fremkom 30,4 g af den hvide krystallinske ester.The Schiff base was dissolved in 500 ml of anhydrous ethanol and heated to 40 ° C. 4.5 g of sodium borohydride was added and the resulting slurry was heated under reflux for 45 minutes. The reaction mass was cooled, poured over 800 ml of ice water and the crude 4- (1,3-benzodioxol-5-ylmethylamino) benzoic acid ethyl ester precipitated. The precipitate was collected and washed with water. After vacuum drying, 30.4 g of the white crystalline ester was obtained.
Esteren havde et smeltepunkt på 120-122°C. Elementaranalysen var:The ester had a melting point of 120-122 ° C. The elemental analysis was:
C Η NC Η N
Beregnet 68,21 5,72 4,68Calcd 68.21 5.72 4.68
Fundet 68,1 5,82 4,74 15 g af esteren blev blandet med 15Q ml 20% natriumhydroxid og 15Q ml ethylalkohol. Den fremkomne opslæmning blev opvarmet under tilbagesvaling i 4 timer og derefter afkølet. Den klare opløsning, som fremkom, blev hældt på 800 g is. Reaktionsmassen blev syrnet med koncentreret HC1. Der dannedes krystallinsk 4-(l,3-benzodioxol-5-ylmethylamino)benzoesyre, som blev frafiltreret, vasket med vand og tørret. Produktet blev omkrystalliseret af acetonitril. Forbindelsen havde et smeltepunkt på 193-196°C. Elementaranalysen var;Found 68.1 5.82 4.74 15 g of the ester were mixed with 15Q ml of 20% sodium hydroxide and 15Q ml of ethyl alcohol. The resulting slurry was heated at reflux for 4 hours and then cooled. The resulting clear solution was poured onto 800 g of ice. The reaction mass was acidified with concentrated HCl. Crystalline 4- (1,3-benzodioxol-5-ylmethylamino) benzoic acid was formed which was filtered off, washed with water and dried. The product was recrystallized from acetonitrile. The compound had a melting point of 193-196 ° C. The elemental analysis was;
C Η NC Η N
Beregnet 66,42 4,83 5,16Calculated 66.42 4.83 5.16
Fundet 66,7 4,90 5,50Found 66.7 4.90 5.50
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Eksempel 2 4-(9-anthracenylmethylamino)benzoesyreExample 2 4- (9-Anthracenylmethylamino) benzoic acid
Ved at følge den almene fremgangsmåde, der er beskrevet i eksempel 1, blev fremstillet 4-(9-anthracenylmethylamino)benzoesyre. Som omkrystallisationsopløsningsmiddel anvendtes CH^CN.Following the general procedure described in Example 1, 4- (9-anthracenylmethylamino) benzoic acid was prepared. CH 2 CN was used as recrystallization solvent.
Produktet har et smeltepunkt på 255 - 259°C, og elementaranalysen var:The product has a melting point of 255 - 259 ° C and the elemental analysis was:
C Η NC Η N
Beregnet 80,71 5,24 4,28Calculated 80.71 5.24 4.28
Fundet 80,43 5,36 4,68Found 80.43 5.36 4.68
Den hypolipidemiske virkning af de aktive forbindelser, der fremstilles ifølge opfindelsen, demonstreres i rotter. Ved denne metode opløses en forbindelse i acetone, optages på en silicagel og blandes med formalet føde til at give koncentrationer på 0,125 vægt% af forbindelsen i dyrefoderet. Det behandlede foder blev administreret til hanrotter, der vejede 150-160 g, gennem en periode på 14 dage. Efter fodringsperioden blev rotterne dræbt, og der blev opsamlet blodprøver. Leveren blev fjernet, vejet og frosset med henblik på fremtidig analyse. De relative koncentrationer af serum-cholesterol i blodprøverne blev bestemt ved Henly's metode, A. A. Henly, Analyst, 82, 286 (1957). Levercholesterolet blev målt ved Sperry-Webb’s metode, Journal of Biological Chemistry, 187» 97 (1950). De relative mængder af triglycerider i blodet og leverprøverne blev bestemt ved metoden ifølge Van Handel og Zilversmit J. Lab. Clin. Med, 50, 152 (1957) og Clin. Chem., 7, 249 (1961).The hypolipidemic effect of the active compounds prepared according to the invention is demonstrated in rats. In this method, a compound is dissolved in acetone, taken up on a silica gel and mixed with ground food to give concentrations of 0.125% by weight of the compound in the animal feed. The treated feed was administered to male rats weighing 150-160 g over a period of 14 days. After the feeding period, the rats were killed and blood samples were collected. The liver was removed, weighed and frozen for future analysis. The relative concentrations of serum cholesterol in the blood samples were determined by Henly's method, A. A. Henly, Analyst, 82, 286 (1957). Liver cholesterol was measured by Sperry-Webb's method, Journal of Biological Chemistry, 187 »97 (1950). The relative amounts of triglycerides in the blood and liver samples were determined by the method of Van Handel and Zilversmit J. Lab. Clin. Med., 50, 152 (1957) and Clin. Chem., 7, 249 (1961).
Idet gennemsnitsniveauet hos kontrolrotter blev taget som standard, konstateredes derved gennemsnitsresultaterne, som fremkom i de behandlede grupper.Taking the average level of control rats by default, the average results obtained in the treated groups were thus established.
Dataene i følgende tabel 1 opsummerer resultaterne af ovenstående undersøgelser.The data in the following Table 1 summarizes the results of the above studies.
8 DK 153471 B8 DK 153471 B
% M Φ% M Φ
- Φ +> E- Φ +> E
> tr> m m a) fB + i +> J > φ d in> tr> m m a) fB + i +> J> φ d in
HH
i—1 ai — 1 a
CDCD
κ. sκ. p
M EM E
a) m rd cna) m rd cn
HH
L) ML) M
Μ Φ H >i a> o cm i Td > >1 1' φ h <dΜ Φ H> i a> o cm i Td>> 1 1 'φ h <d
J tr> 'OJ tr> 'O
H CDH CD
M HM H
.μ >d d cd Λ CD Λ.µ> d d cd Λ CD Λ
* CD* CD
H ΌH Ό
OISLAND
μ to CD 0 μ +1 m xi CD Cfl Hiµ to CD 0 µ +1 m xi CD Cfl Hi
> CD + I M> CD + I M
CD H CDCD H CD
JOJO
xi dxi d
ϋ -Hϋ -H
MM
Η Ό d h d CD 5-1 Λ ΟH Ό d h d CD 5-1 Λ Ο
Cd »! Ή E-l Μ ·Η CD Ό Ό ΜCd »! Ή E-l Μ · Η CD Ό Ό Μ
Η fBΗ fB
Μ > CD r·· inCD> CD r ·· in
go Γ" η CDgo Γ "η CD
d >ι ii > ΜΗ Η φ tP +> CO H cd Μ Ηd> ι ii> ΜΗ Η φ tP +> CO H cd Μ Η
•μ CD• μ CD
Μ Μ (ϋ Μ Φ κ -μ η d ο Φ μ £ Φ fB · S +) CM Η Μ d 3 cfl η Η ft Φ Μ Φ II Φ ft φ Η Μ ft CO Ο d Λ «β ϋ ϋ -μ ίη cd Η Ό Ο Μ φ -μ Η dΜ Μ (ϋ Μ κ -μ η d ο Φ μ £ Φ fB · S +) CM Η Μ d 3 cfl η Η ft Φ Μ Φ II Φ ft φ Η Μ ft CO Ο d Λ «β ϋ ϋ -μ ίη cd Η Ό Ο Μ φ -μ Η d
• HO• HO
CO rfj Μ Μ m η cm κCO rfj Μ Μ m η cm κ
Claims (4)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US65009076A | 1976-01-19 | 1976-01-19 | |
| US65009076 | 1976-01-19 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK8177A DK8177A (en) | 1977-07-20 |
| DK153471B true DK153471B (en) | 1988-07-18 |
| DK153471C DK153471C (en) | 1988-11-21 |
Family
ID=24607411
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK008177A DK153471C (en) | 1976-01-19 | 1977-01-10 | ANALOGY PROCEDURE FOR PREPARING A 4-METHYLAMINOBENOIC ACID COMPOUND |
Country Status (14)
| Country | Link |
|---|---|
| JP (1) | JPS5289660A (en) |
| AT (1) | AT347923B (en) |
| AU (1) | AU500881B2 (en) |
| BE (1) | BE850516A (en) |
| CA (1) | CA1072969A (en) |
| CH (1) | CH628340A5 (en) |
| DE (1) | DE2702058C2 (en) |
| DK (1) | DK153471C (en) |
| FR (1) | FR2338040A1 (en) |
| GB (2) | GB1521458A (en) |
| IE (1) | IE44858B1 (en) |
| NL (1) | NL7700480A (en) |
| NO (1) | NO145839C (en) |
| SE (1) | SE435175B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0424904Y2 (en) * | 1987-09-18 | 1992-06-12 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE716668C (en) * | 1938-02-15 | 1942-01-27 | Dr Aladar Skita | Process for the preparation of derivatives of substituted aminobenzoic acids |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2080069A5 (en) * | 1970-02-23 | 1971-11-12 | Commissariat Energie Atomique | |
| US3868416A (en) * | 1973-10-01 | 1975-02-25 | American Cyanamid Co | Hypolipidemic 4-(monoalkylamino)benzoic acid derivatives |
-
1977
- 1977-01-07 AU AU21140/77A patent/AU500881B2/en not_active Expired
- 1977-01-10 DK DK008177A patent/DK153471C/en not_active IP Right Cessation
- 1977-01-11 CA CA269,483A patent/CA1072969A/en not_active Expired
- 1977-01-17 JP JP384477A patent/JPS5289660A/en active Granted
- 1977-01-17 GB GB1803/77A patent/GB1521458A/en not_active Expired
- 1977-01-17 GB GB52242/77A patent/GB1521459A/en not_active Expired
- 1977-01-18 NO NO770151A patent/NO145839C/en unknown
- 1977-01-18 FR FR7701296A patent/FR2338040A1/en active Granted
- 1977-01-18 SE SE7700490A patent/SE435175B/en not_active IP Right Cessation
- 1977-01-18 NL NL7700480A patent/NL7700480A/en active Search and Examination
- 1977-01-19 IE IE104/77A patent/IE44858B1/en not_active IP Right Cessation
- 1977-01-19 BE BE174188A patent/BE850516A/en not_active IP Right Cessation
- 1977-01-19 DE DE2702058A patent/DE2702058C2/en not_active Expired
- 1977-01-19 AT AT31277A patent/AT347923B/en not_active IP Right Cessation
- 1977-01-19 CH CH65877A patent/CH628340A5/en not_active IP Right Cessation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE716668C (en) * | 1938-02-15 | 1942-01-27 | Dr Aladar Skita | Process for the preparation of derivatives of substituted aminobenzoic acids |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2338040B1 (en) | 1980-04-30 |
| AT347923B (en) | 1979-01-25 |
| IE44858B1 (en) | 1982-04-21 |
| IE44858L (en) | 1977-07-19 |
| AU500881B2 (en) | 1979-06-07 |
| SE435175B (en) | 1984-09-10 |
| SE7700490L (en) | 1977-07-20 |
| DK8177A (en) | 1977-07-20 |
| NO145839B (en) | 1982-03-01 |
| FR2338040A1 (en) | 1977-08-12 |
| NO145839C (en) | 1982-06-09 |
| NL7700480A (en) | 1977-07-21 |
| NO770151L (en) | 1977-07-20 |
| CH628340A5 (en) | 1982-02-26 |
| BE850516A (en) | 1977-07-19 |
| ATA31277A (en) | 1978-06-15 |
| JPS6233230B2 (en) | 1987-07-20 |
| GB1521458A (en) | 1978-08-16 |
| CA1072969A (en) | 1980-03-04 |
| JPS5289660A (en) | 1977-07-27 |
| DK153471C (en) | 1988-11-21 |
| DE2702058A1 (en) | 1977-07-28 |
| AU2114077A (en) | 1978-07-13 |
| GB1521459A (en) | 1978-08-16 |
| DE2702058C2 (en) | 1985-09-19 |
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| Date | Code | Title | Description |
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| PBP | Patent lapsed |