SE450381B - ESTIMATES OF NICOTIC ACID AND 2- (P-CHLORPHENOXY) -ISOSMORIC ACID FOR USE AS A LIPID SENSITIVE AGENT - Google Patents
ESTIMATES OF NICOTIC ACID AND 2- (P-CHLORPHENOXY) -ISOSMORIC ACID FOR USE AS A LIPID SENSITIVE AGENTInfo
- Publication number
- SE450381B SE450381B SE8000962A SE8000962A SE450381B SE 450381 B SE450381 B SE 450381B SE 8000962 A SE8000962 A SE 8000962A SE 8000962 A SE8000962 A SE 8000962A SE 450381 B SE450381 B SE 450381B
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- nicotinate
- acid addition
- acid
- addition salt
- pharmaceutically usable
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- 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
- C07D213/60—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 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Vascular Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
15 25 30 35 450 381 z Denna förening, som speciellt användes som nikotinat, kan dock med hänsyn till dess höga andel pyridinkomponenter och härav be- tingade biverkningarna användas endast i låg dos och kan därmed knappast användas terapeutiskt. _ Samtliga nämnda ämnen har den egenskapen, att endast signi- fikant sänka en av lipidkomponenterna, exempelvis triglyceriderna, under det att de andra lipidkomponenterna ej eller endast i ringa del påverkas terapeutiskt. Detta uppnås endast genom högre dose- ring. 15 25 30 35 450 381 z However, in view of its high proportion of pyridine components and the consequent side effects thereof, this compound, which is especially used as nicotinate, can only be used in low dose and can thus hardly be used therapeutically. All the substances mentioned have the property of significantly lowering only one of the lipid components, for example the triglycerides, while the other lipid components are not or only slightly affected therapeutically. This is achieved only through higher dosages.
Man har inom detta område därför strävat efter att finna ytterligare föreningar, vilka utan doshöjning utövar en lipid- sänkande verkan på flera lipidkomponenter.Efforts have therefore been made in this field to find additional compounds which, without a dose increase, exert a lipid-lowering effect on several lipid components.
Detta ändamål uppnås överraskande med föreningarna enligt uppfinningen. Dessa föreningar uppvisar stark verkan såväl vid förhöjda triglycerid- som kolesterínnivåer i serum. I jämförelse med níkotinsyra och etylestern av 2-(p-klorfenoxij-isosmörsyra ligger doseringarna ojâmförligt lägre, varigenom risken för bi- verkningar reduceras till ett minimum. Föreningarna är fasw.äm- nen.This object is surprisingly achieved with the compounds according to the invention. These compounds show strong activity in both elevated serum triglyceride and cholesterol levels. In comparison with nicotinic acid and the ethyl ester of 2- (p-chlorophenoxy-isobutyric acid, the dosages are incomparably lower, whereby the risk of side effects is reduced to a minimum. The compounds are phase-specific substances.
Enligt en sida av uppfinningen åstadkommas sålunda föreni- ngar för användning som lipidsänkande medel, vilka har formeln: 2 n1...@ -o-a: 1 _ ___/f' °“'f°“2%r@ z där R ârJf I (EEz¿2"“-_ CHZ vari n är 3-12, m är 0 eller 1 och z är 0 eller 1; ßuzuzylå-í/'të z vari m är 0 eller 1 och Q 2 är 0 eller l, cumyl, p-klorbenzoyl, eller väte, men då endast när R2 är lika med cykloalkyl eller cyklobutylen (-CHZ-Jn; dar Rz ar vana, (-cH2-)4, cl-có-alkyl eller cyxloalkyi; 10 15 25 30 35 /j/X PÛUR QUAUTY 3 450 381 och där Rs är - i) -É eller Z-metyl-Z(p-klørfenoxüpropionyl, N. . och farmaceutiskt användbara syraadditionssalter därav.Thus, according to one aspect of the invention, there are provided compounds for use as lipid lowering agents which have the formula: 2% r @ z where R ârJf I (EEz¿2 "" -_ CHZ where n is 3-12, m is 0 or 1 and z is 0 or 1; ßuzuzylå-í / 'të z where m is 0 or 1 and Q 2 is 0 or 1, cumyl , p-chlorobenzoyl, or hydrogen, but then only when R 2 is cycloalkyl or cyclobutylene (-CH 2 -Jn; where R 2 is used, (-cH 2 -) 4, C 1 -C 6 alkyl or cycloalkyl; and wherein R 5 is -i or Z-methyl-Z (p-chlorophenoxypropionyl, N. and pharmaceutically usable acid addition salts thereof.
Enligt en ytterligare sida av uppfinningen åstadkommes nya föreningar även de üypvisande lipidsänkande effektfnämliggn; p-cyklododecylfenyl-nikotinet, 5,6,7,8-tetrahydro-l-naftylníko- tinat, p-(1-adamuntylfenyl)-nikotinet, p-(cyklohexylacetyl)- fenylnikotinat, 2-(p-klorfenoxi)~isosmörsyra~p-(l-adamanty1- acetyl)-fenylester, o-cyklohexylfenylnikotinat eller farmaceu- tiskt acceptabla syraadditionssalter därav, samt o-cyk1ohexyl- fenylnikotinathydroklorid.According to a further aspect of the invention, novel compounds are also provided which exhibit lipid lowering efficiencies; p-Cyclododecylphenyl nicotine, 5,6,7,8-tetrahydro-1-naphthyl nicotinate, p- (1-adamuntylphenyl) nicotine, p- (cyclohexylacetyl) phenyl nicotinate, 2- (p-chlorophenoxy) isobutyric acid p- (1-adamantyl-acetyl) -phenyl ester, o-cyclohexylphenyl nicotinate or pharmaceutically acceptable acid addition salts thereof, and o-cyclohexyl-phenyl nicotinate hydrochloride.
I det följande beskrives framställningen av föreningarna: EXEMPEL 1: Framställning av p-cyklohexylfenylnikotinat- 17,6 g (100 mMol) cyklohexylfenol och 19 g (106 mMol) ni- kotinsyrekloridhydroklorid överföres i 250 ml torkat pyridin och bibehålles där i H timmar\ád40°. Därefter utföres kylning på is- bad och vatten tillsättes portionsvis. Efter tillsats av 10 ml vatten erhålles en klar lösning. Ytterligare vatten tillföres till dess att en stark grumling uppstår (50 ml). Efter långva- rig omröring utkristalliserar produkten på isbad. Fällningen av- Ur fil- tratet erhåller man genom ytterligare vattentillsats (60 ml) en suges, tvättas med vatten till pyridinfrihet och torkas. andra fraktion. Utbyte: 70% av teoretiskt smp. io3° Analys: Beräknad: Erhållenz C 76,86 76,83 H 6,76 6,76 N U,98 5,05 EXEMPEL 2: Framställning av p-(adamantylfenyl)-nikotinat. 11,4 g (50 mMo1) p-l-adamantylfenol och 10 g (56 mMo1) nikotinsyrekloridhydroklorid överföres i 150 ml torkat pyridin och hålles där i M8 timmar vid 450. vatten utfälles prødukten genom omröring på isbad, avskiljes, tvättas med vatten och torkas.The preparation of the compounds is described below: EXAMPLE 1: Preparation of p-cyclohexylphenyl nicotinate - 17.6 g (100 mmol) of cyclohexylphenol and 19 g (106 mmol) of nicotinic acid chloride hydrochloride are transferred to 250 ml of dried pyridine and kept there for 1 hour. °. Then cooling is performed on an ice bath and water is added portionwise. After adding 10 ml of water, a clear solution is obtained. Additional water is added until a strong cloudiness occurs (50 ml). After prolonged stirring, the product crystallizes out on an ice bath. The precipitate from the filtrate is obtained by additional water addition (60 ml), sucked, washed with water to pyridine-free and dried. second faction. Yield: 70% of theoretical m.p. io3 ° Analysis: Calculated: Found C 76.86 76.83 H 6.76 6.76 N U, 98 5.05 EXAMPLE 2: Preparation of p- (adamantylphenyl) -nicotinate. 11.4 g (50 mMo1) of p-1-adamantylphenol and 10 g (56 mMo1) of nicotinic acid chloride hydrochloride are transferred to 150 ml of dried pyridine and kept there for M8 hours at 450. water, the product is precipitated by stirring on an ice bath, separated, washed with water and dried.
Genom tillsats av 40 ml Utbyte: 78% av teoretiskt Smp. 1990 Analys: Beräknad: Erhâllenz C 79,2? 78,01 H 6,90 6,82 N U,20 U,5O 15 30 35 EXEMPEL 52 450 381 Framställning av 2-(p-klorfenoxi)-iSOSmÖPSyPa'P“ (l-adamantylacetyl)-fenylesten 6,75 g (25 mMol) p-(l-adamantylacetyl)-fenol och 6 g (25,7 mMol) 2-(p~klorfenoxi)-isosmörsyraklorid äverföres i.6O ml t0P- kat pyridin och hålles i 20 timmar vid H0 . Gen0m fil1lSflL= av H0 ml vatten utfaller en kristallín produkt. tvättas med vatten och torkas sedan.By adding 40 ml Yield: 78% of theory M.p. 1990 Analysis: Calculated: Retention C 79.2? 78.01 H 6.90 6.82 NU, 20 U, 5O EXAMPLE 52 450 381 Preparation of 2- (p-chlorophenoxy) -ISOSMOPYPa'P '(1-adamantylacetyl) -phenyl stone 6.75 g (25 mMol) p- (1-adamantylacetyl) -phenol and 6 g (25.7 mMol) 2- (p-chlorophenoxy) -isobutyric acid chloride are transferred to 60 ml of t0P-cat pyridine and kept for 20 hours at H0. Gen0m fi l1lS fl L = of H0 ml of water precipitates a crystalline product. washed with water and then dried.
Denna avskiljes, Utbyte: 77% av teoretiskt Smp. llüo Analys: Beräknad: Erhållenl c 72,03 72,12 H 6,su 6,61 EXEMPEL _ü: Framställning av p-cyklododecylfenyl-nikotinat 8 g (50,8 mMol) p-cyklododecylfenol och 5,9 g (53,2 mMol) nikotinsyrekloridhydroklorid överföres i lU0 ml torkat pyrídin och hålles 15 timmar vid 300. Därefter tillsättes långsamt H2 ml vatten och kyles till 00. De utfallna kristallerna avsuges, tvättas till pyridinfrihet med vatten och torkas.This is separated, Yield: 77% of theoretical M.p. Analysis: Calculated: Obtained c 72.03 72.12 H 6, su 6.61 EXAMPLE _ü: Preparation of p-cyclododecylphenyl nicotinate 8 g (50.8 mmol) p-cyclododecylphenol and 5.9 g (53.2 The molar nicotinic acid chloride hydrochloride is transferred to 10 ml of dried pyridine and kept for 15 hours at 300. Then H 2 ml of water is slowly added and cooled to 0 DEG C. The precipitated crystals are filtered off with suction, washed to pyridine freedom with water and dried.
Utbyte: 85% av teoretiskt Smp.: 980 Analys: Beräknad: C 78,91 H 8,50 Erhållen: 79,01 8,54 EXEMPEL 5: ll 3 (50 mMol) p-cyklohexylacetylfenol och 9,6 g (54 mMol) nikotinsyrekloridhydroklorid överföres i 160 ml torkat pyridín och omröres i 8 timmar vid N00. Vatten tillsättes därefter dropp- vis (66 ml) till dess att lösningen grumlas och den ställes på isbad. Den utkristalliserade produkten avsuges,tvättas med vatten till pyridinfrihet och torkas.Yield: 85% of theory M.p .: 980 Analysis: Calculated: C 78.91 H 8.50 Obtained: 79.01 8.54 EXAMPLE 5: 11 (50 mmol) p-cyclohexylacetylphenol and 9.6 g (54 mmol) ) nicotinic acid chloride hydrochloride is transferred to 160 ml of dried pyridine and stirred for 8 hours at N00. Water is then added dropwise (66 ml) until the solution is cloudy and placed on an ice bath. The crystallized product is filtered off with suction, washed with water to give pyridine freedom and dried.
Utbyte: 55% av teoretiskt Smp.: 1050 Analys: Beräknad: Erhållen: c 74,36 7u,o7 H 6,50 6,51 EXEMPEL 6: Framställning av o-cyklohexylfenylnikotinat-hydro- klorid. 15 g (85 mMol) o-cyklohexylfenol och 16,5 g (93 mMol) niko- tinsyrekloridhydroklorid överföras i 200 ml torkat pyridin och omröres i 25 timmar vid 500. Efter kylning avsuges utfälld pyri- Framställning av p-(cyklohexylacetyl)-fenyl-nikotinet.Yield: 55% of theory M.p .: 1050 Analysis: Calculated: Obtained: c 74.36 7u, o7 H 6.50 6.51 EXAMPLE 6: Preparation of o-cyclohexylphenyl nicotinate hydrochloride. 15 g (85 mMol) of o-cyclohexylphenol and 16.5 g (93 mMol) of nicotinic acid chloride hydrochloride are transferred to 200 ml of dried pyridine and stirred for 25 hours at 500. After cooling, precipitated pyrimidine is filtered off. Preparation of p- (cyclohexylacetyl) -phenyl -nicotine.
PUOR QUALITY ß 450 581 Den utfällda råprodukten tvättas med vatten 2 gånger 200 ml, över- föres i alkohol och indunstas i rotationsindunstare. Den kvar- vanande viskösa oljan upplöses i 500 ml torkad eter och hydro- 5 kloreras med HCl-gas. Därefter avfiltreras, tvättas med eter och torkas.PUOR QUALITY ß 450 581 The precipitated crude product is washed with water twice 200 ml, transferred to alcohol and evaporated on a rotary evaporator. The residual viscous oil is dissolved in 500 ml of dried ether and hydrochlorinated with HCl gas. It is then filtered off, washed with ether and dried.
Utbyte! 52 % av teoretiskt smp.= 151=2° Analys: Beräknad: Erhållen: 10 C 68,03 68,11 H 6,29 6,30 _ > Cl ll.l8 11.20 EXEMPEL 7: Framställning av 5,6,7,8-tetrahydro-l-naftylniko- tínat. 15 7 g (47 mMol) 5,6,7,8-tetrahydro-l-naftol och 9 g (50 mMol) nikotinsyrahydroklorid blandades med 132 ml torrt pyridín och om- rördes i 24 timmar vid 3200. Efter kylning avsögs utfälld pyri- dinhydroklorid och fíltratet blandades med 300 ml vatten, Den ut- fällda råprodukten tvättades med två 200 ml portioner vatten och 20 återkristalliserades ur metanol.Exchange! 52% of theoretical m.p. = 151 = 2 ° Analysis: Calculated: Obtained: 10 C 68.03 68.11 H 6.29 6.30 _> Cl 11.18 11.20 EXAMPLE 7: Preparation of 5.6.7, 8-tetrahydro-1-naphthyl nicotinate. 7 g (47 mmol) of 5,6,7,8-tetrahydro-1-naphthol and 9 g (50 mmol) of nicotinic acid hydrochloride were mixed with 132 ml of dry pyridine and stirred for 24 hours at 3200 DEG C. After cooling, precipitated pyridine was filtered off. The hydrochloride and the filtrate were mixed with 300 ml of water. The precipitated crude product was washed with two 200 ml portions of water and recrystallized from methanol.
Utbyte: 65% av teoretiskt värde Smältpunkt: 8600 Analys: Beräknad: Erhållen: C 75,88 75,81 35 H 5,93 5,07 Toxicitetsförsök: Tabell l .. . 1 30 Forâïlng R R2 R3 LD50 Human- Tera- Mus dosering peutiskt I (mg/kg peïmäag lndex 2 cyklohexyl H pyridinoyl-(3) 2200 300 0,13 35 l ll-adamantyll H J pyridinoyl-(3) 3200 J 300 J 0,093 (standard) l500 1500 1,0 Nikotinsyra (standard) 4000 3000 0,75 10 15 30 b) kr 450 381 6 Som framgår av tabell l ligger toxicitetsvärdena inom ett gynnsamt omrâde, varigenom mycket goda värden på terpeutiskt index erhålles. vEáKNINGssÄTT= Försök utfördes vidare på hon-wistar-råttor. höll under 5 veckor en starkt fetthaltig specialdiet. av den andra veckan behandlades hälften av råttorna med en dos av 100 ml/kg kroppsvikt. 18 timmar efter den första dosen togs efter den tredje veckan blodprov på djuren, och koncentrationen av triglycerider och kolesterin jämfördes med värdena för de obe- handlade råttorna. Som testmetod för bestämning av kolesterin Råttorna er- Vid början och triglycerider tjänar det enzymatiska Boehringer-testet.Yield: 65% of theory Value Melting point: 8600 Analysis: Calculated: Obtained: C 75.88 75.81 35 H 5.93 5.07 Toxicity test: Table 1 ... 1 30 Preparation R R2 R3 LD50 Human- Tera- Mouse Dosage Peutic I (mg / kg peimage index 2 cyclohexyl H pyridinoyl- (3) 2200 300 0.13 35 l ll-adamantyl HJ pyridinoyl- (3) 3200 J 300 J 0.093 (standard) l500 1500 1.0 Nicotinic acid (standard) 4000 3000 0.75 10 15 30 b) SEK 450 381 6 As can be seen from Table 1, the toxicity values are within a favorable range, whereby very good values for therapeutic index are obtained. WAKING METHOD = Experiments were further performed on female Wistar rats. kept for 5 weeks a high-fat special diet. by the second week, half of the rats were treated with a dose of 100 ml / kg body weight. 18 hours after the first dose, blood samples were taken from the animals after the third week, and the concentration of triglycerides and cholesterol was compared with the values of the untreated rats. At the beginning and triglycerides serve the enzymatic Boehringer test.
Enligt tabell 2 uppträdde högsígnifikanta sänkningar av de båda parametrarna. I förhållande härtill erhölls med Clofibrat och nikontinsyra åtskilda mycket mindre effekt, såsom även framgår av tabell 2. _ Tabell 2 I 1 F" . 1 (Jšfimng R H2 H3 ker-rea. Tr-igiy- - 1 % cerid-red. 1 z I l l-adamantyl H pyridinoyl-(3) 28 47 ; «"Ü 2 Cyklohexyl H pyridinoyl-(3) H5 19 § ”*í 4 Cumyl H pyridinoyl-(3) 2H 1 I 7 p-klor- ? benzoyl H pyridinoyl-(3) 29 - i 8 1-adamantyl- 27 55 flßefiyl H 2-metyl-2-(p- klorfenoxyl) propionyl I ! Nikocin- I syra " (100 mg/kg) 7 _ 2-(p-klor- I fenoxiis - , ' smörsyraf (100 mg/kg) - 8 ! etylester I ü 10 15 20 25 30 WW uuAuTv 450 581 Föreningarna kan framställas genom att man använder i och för sig kända förestringsförfaranden, exempelvis omsätter 1 mol nikotinsyraklorid med l mol utgångsfenol i närvaro av minst 1 mol av ett syrabindande ämne, exempelvis pyridín.According to Table 2, highly significant reductions of the two parameters occurred. In relation to this, much less effect was obtained with Clofibrat and nicotinic acid, as is also shown in Table 2. _ Table 2 I 1 F ". 1 (Jš fi mng R H2 H3 ker-rea. Tr-igiy- - 1% cerid-red. 1 z I l l-adamantyl H pyridinoyl- (3) 28 47; «" Ü 2 Cyclohexyl H pyridinoyl- (3) H5 19 § ”* í 4 Cumyl H pyridinoyl- (3) 2H 1 I 7 p-chloro-? benzoyl H pyridinoyl- (3) 29 - i 8 1-adamantyl- 27 55 ßßeyl H 2-methyl-2- (p-chlorophenoxyl) propionyl II Nicocin-I acid "(100 mg / kg) 7- 2- (p- chloro- I phenoxyis, butyric acid (100 mg / kg) - 8 ethyl ester I u 10 15 20 25 30 WW uuAuTv 450 581 The compounds can be prepared by using per se known esterification methods, for example reacting 1 mole of nicotinic acid chloride with 1 moles of starting phenol in the presence of at least 1 mole of an acid-binding substance, for example pyridine.
' Föreningarna enligt uppfinningen kan överföras till farma- ceutiska preparat, vilka vid sidan av det aktiva ämnet innehåller en bärare eller ett utspädningsmedel. oralt som parenteralt.The compounds of the invention may be converted into pharmaceutical preparations which, in addition to the active substance, contain a carrier or diluent. orally as well as parenterally.
De kan användas såväl Fasta preparat för oral användning är kapslar, tabletter, piller, pulver, granulat. I sådana fasta beredningar är det ak- tiva ämnet blandat med minst ett inert utspädningsmedel, såsom rörsocker, laktos eller stärkelse. Även ytterligare ämnen, så- som smörjmedel eller buffertar, kan vara närvarande. Tabletter- na och pillerna kan vara försedda med ett i tarmen löslígt över- dragsskikt.They can be used as well Solid preparations for oral use are capsules, tablets, pills, powders, granules. In such solid preparations, the active substance is mixed with at least one inert diluent, such as cane sugar, lactose or starch. Additional substances, such as lubricants or buffers, may also be present. The tablets and pills may be provided with a coating layer which is soluble in the intestine.
Vätskor för oral användning utgöres av emulsioner, lösning- ar, suspensioner, vilka på vanligt sätt innehåller utspädnings- medel, såsom vatten. Dessutom kan sådana flytande medel även in- nehålla fuktmedel, emulgermedel och suspendermedel, såväl som sötnings-, smak- och luktmedel.Liquids for oral use consist of emulsions, solutions, suspensions, which usually contain diluents, such as water. In addition, such liquids may also contain wetting agents, emulsifying agents and suspending agents, as well as sweetening, flavoring and perfuming agents.
Preparat för parenteral administration är bl.a. sterila, vattenhaltiga eller vattenfria lösningar, suspensioner eller emulsioner. Som bärare användes de för denna beredningsform kända ämnena.Preparations for parenteral administration include sterile, aqueous or anhydrous solutions, suspensions or emulsions. The carriers known for this formulation are used as carriers.
Doseringen av de aktiva ämnena i beredningarna kan vari- era alltefter administrationssättet och behandlingens varaktig- het.The dosage of the active substances in the preparations may vary according to the method of administration and the duration of the treatment.
Claims (11)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2904757 | 1979-02-08 |
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| Publication Number | Publication Date |
|---|---|
| SE8000962L SE8000962L (en) | 1980-08-09 |
| SE450381B true SE450381B (en) | 1987-06-22 |
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| Application Number | Title | Priority Date | Filing Date |
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| SE8000962A SE450381B (en) | 1979-02-08 | 1980-02-06 | ESTIMATES OF NICOTIC ACID AND 2- (P-CHLORPHENOXY) -ISOSMORIC ACID FOR USE AS A LIPID SENSITIVE AGENT |
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|---|---|
| JP (1) | JPS55129245A (en) |
| AR (1) | AR228251A1 (en) |
| AT (1) | AT374797B (en) |
| AU (1) | AU532208B2 (en) |
| BE (1) | BE881626A (en) |
| CA (1) | CA1135689A (en) |
| CH (1) | CH644092A5 (en) |
| DK (1) | DK152360C (en) |
| ES (1) | ES8101552A1 (en) |
| FR (1) | FR2448532A1 (en) |
| GB (1) | GB2041937B (en) |
| GR (1) | GR73905B (en) |
| HU (1) | HU182099B (en) |
| IE (1) | IE49385B1 (en) |
| IL (1) | IL59337A (en) |
| IT (1) | IT1141197B (en) |
| MX (1) | MX6377E (en) |
| NL (1) | NL8000826A (en) |
| PL (1) | PL123379B1 (en) |
| SE (1) | SE450381B (en) |
| SG (1) | SG51185G (en) |
| YU (1) | YU33880A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1989006643A1 (en) * | 1988-01-22 | 1989-07-27 | Kharkovsky Nauchno-Issledovatelsky Institut Endokr | UNDECYLIC ETHER n-CHLOROPHENOXYISOBUTYRIC ACID AND A PHARMACEUTICAL PREPARATION FOR TREATING HYPERLIPEMIA BASED ON IT |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR3175M (en) * | 1963-06-25 | 1965-03-08 | Analyses Et De Rech S Biolog M | New chemical compounds with peripheral vasodilating action. |
| DE2352012A1 (en) * | 1972-11-01 | 1974-05-09 | Ciba Geigy Ag | NEW ALIPHATICALLY SUBSTITUTED ARYLCHALCOGENO-HYDROCARBON DERIVATIVES AND THE PROCESS FOR THEIR PRODUCTION |
| ES438246A1 (en) * | 1975-06-04 | 1977-01-16 | Alter Sa | Process for purifying the mixed ester, ethylene glycol 1-(2-p-chlorophenoxy)-2-methylpropionate nicotinate |
| JPS57102866A (en) * | 1980-12-19 | 1982-06-26 | Kyorin Pharmaceut Co Ltd | Nicotinic acid derivative and its preparation |
-
1980
- 1980-02-06 SE SE8000962A patent/SE450381B/en not_active IP Right Cessation
- 1980-02-07 ES ES488345A patent/ES8101552A1/en not_active Expired
- 1980-02-07 IL IL59337A patent/IL59337A/en not_active IP Right Cessation
- 1980-02-07 IE IE236/80A patent/IE49385B1/en not_active IP Right Cessation
- 1980-02-07 MX MX808635U patent/MX6377E/en unknown
- 1980-02-07 DK DK053680A patent/DK152360C/en not_active IP Right Cessation
- 1980-02-08 AT AT0070380A patent/AT374797B/en not_active IP Right Cessation
- 1980-02-08 GR GR61163A patent/GR73905B/el unknown
- 1980-02-08 AU AU55355/80A patent/AU532208B2/en not_active Ceased
- 1980-02-08 JP JP1374980A patent/JPS55129245A/en active Granted
- 1980-02-08 CA CA000345303A patent/CA1135689A/en not_active Expired
- 1980-02-08 YU YU00338/80A patent/YU33880A/en unknown
- 1980-02-08 PL PL1980221888A patent/PL123379B1/en unknown
- 1980-02-08 GB GB8004310A patent/GB2041937B/en not_active Expired
- 1980-02-08 NL NL8000826A patent/NL8000826A/en not_active Application Discontinuation
- 1980-02-08 AR AR279916A patent/AR228251A1/en active
- 1980-02-08 BE BE0/199326A patent/BE881626A/en not_active IP Right Cessation
- 1980-02-08 HU HU80289A patent/HU182099B/en not_active IP Right Cessation
- 1980-02-08 FR FR8002783A patent/FR2448532A1/en active Granted
- 1980-02-08 CH CH106380A patent/CH644092A5/en active IP Right Maintenance
- 1980-02-08 IT IT19782/80A patent/IT1141197B/en active
-
1985
- 1985-06-27 SG SG511/85A patent/SG51185G/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK152360B (en) | 1988-02-22 |
| GR73905B (en) | 1984-05-21 |
| JPS6126993B2 (en) | 1986-06-23 |
| AT374797B (en) | 1984-05-25 |
| GB2041937B (en) | 1983-04-13 |
| AR228251A1 (en) | 1983-02-15 |
| GB2041937A (en) | 1980-09-17 |
| IE800236L (en) | 1980-08-08 |
| ES488345A0 (en) | 1980-12-16 |
| IL59337A (en) | 1984-10-31 |
| MX6377E (en) | 1985-05-23 |
| NL8000826A (en) | 1980-08-12 |
| ES8101552A1 (en) | 1980-12-16 |
| ATA70380A (en) | 1983-10-15 |
| SG51185G (en) | 1986-01-24 |
| AU5535580A (en) | 1980-08-14 |
| CA1135689A (en) | 1982-11-16 |
| JPS55129245A (en) | 1980-10-06 |
| IE49385B1 (en) | 1985-10-02 |
| FR2448532B1 (en) | 1984-12-14 |
| CH644092A5 (en) | 1984-07-13 |
| PL123379B1 (en) | 1982-10-30 |
| YU33880A (en) | 1983-06-30 |
| BE881626A (en) | 1980-08-08 |
| DK53680A (en) | 1980-08-09 |
| IT8019782A0 (en) | 1980-02-08 |
| AU532208B2 (en) | 1983-09-22 |
| HU182099B (en) | 1983-12-28 |
| SE8000962L (en) | 1980-08-09 |
| FR2448532A1 (en) | 1980-09-05 |
| IT1141197B (en) | 1986-10-01 |
| DK152360C (en) | 1988-08-01 |
| PL221888A1 (en) | 1980-10-20 |
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