NO140270B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPHUTICALLY ACTIVE TRIAMCINOLONACETONIDE-4,4`-METHYLENE-BIS- (3-METHOXY-2-NAFTHOATE) - Google Patents
ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPHUTICALLY ACTIVE TRIAMCINOLONACETONIDE-4,4`-METHYLENE-BIS- (3-METHOXY-2-NAFTHOATE) Download PDFInfo
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- NO140270B NO140270B NO740732A NO740732A NO140270B NO 140270 B NO140270 B NO 140270B NO 740732 A NO740732 A NO 740732A NO 740732 A NO740732 A NO 740732A NO 140270 B NO140270 B NO 140270B
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- methoxy
- methylene
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- triamcinolone acetonide
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- 238000000034 method Methods 0.000 title claims description 9
- 238000002360 preparation method Methods 0.000 title description 2
- 229960002117 triamcinolone acetonide Drugs 0.000 claims description 13
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 claims description 13
- BVCDTHYWRLBGTG-YIVOTWLUSA-N 8q5fk6p4bc Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]([C@@H](O)C[C@]23C)(F)[C@@H]1[C@@H]3C[C@H]1OC(C)(C)O[C@]12C(=O)COC(=O)C1=CC2=CC=CC=C2C(CC=2C3=CC=CC=C3C=C(C=2OC)C(=O)OCC(=O)[C@]23[C@H](OC(C)(C)O2)C[C@@H]2[C@@]3(C[C@H](O)[C@]3(F)[C@@]4(C)C=CC(=O)C=C4CC[C@H]32)C)=C1OC BVCDTHYWRLBGTG-YIVOTWLUSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- VGNGFRZTSUWCLT-UHFFFAOYSA-N 4-[(3-carboxy-2-methoxynaphthalen-1-yl)methyl]-3-methoxynaphthalene-2-carboxylic acid Chemical compound C1=CC=C2C(CC3=C4C=CC=CC4=CC(=C3OC)C(O)=O)=C(OC)C(C(O)=O)=CC2=C1 VGNGFRZTSUWCLT-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 description 9
- 239000006071 cream Substances 0.000 description 8
- 229960004618 prednisone Drugs 0.000 description 8
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 201000004624 Dermatitis Diseases 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000003470 adrenal cortex hormone Substances 0.000 description 4
- 230000002927 anti-mitotic effect Effects 0.000 description 4
- 208000010668 atopic eczema Diseases 0.000 description 4
- RKHQGWMMUURILY-UHRZLXHJSA-N cortivazol Chemical compound C([C@H]1[C@@H]2C[C@H]([C@]([C@@]2(C)C[C@H](O)[C@@H]1[C@@]1(C)C2)(O)C(=O)COC(C)=O)C)=C(C)C1=CC1=C2C=NN1C1=CC=CC=C1 RKHQGWMMUURILY-UHRZLXHJSA-N 0.000 description 4
- 210000003491 skin Anatomy 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 210000002615 epidermis Anatomy 0.000 description 3
- 210000000981 epithelium Anatomy 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- RTBQQRFTCVDODF-UHFFFAOYSA-N 3-methoxynaphthalene-2-carboxylic acid Chemical compound C1=CC=C2C=C(C(O)=O)C(OC)=CC2=C1 RTBQQRFTCVDODF-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 206010021531 Impetigo Diseases 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
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- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 229960005294 triamcinolone Drugs 0.000 description 2
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 2
- LNETULKMXZVUST-UHFFFAOYSA-N 1-naphthoic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=CC2=C1 LNETULKMXZVUST-UHFFFAOYSA-N 0.000 description 1
- KGRVJHAUYBGFFP-UHFFFAOYSA-N 2,2'-Methylenebis(4-methyl-6-tert-butylphenol) Chemical compound CC(C)(C)C1=CC(C)=CC(CC=2C(=C(C=C(C)C=2)C(C)(C)C)O)=C1O KGRVJHAUYBGFFP-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
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- 230000037396 body weight Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
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- 231100000321 erythema Toxicity 0.000 description 1
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- 238000002474 experimental method Methods 0.000 description 1
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- 239000012467 final product Substances 0.000 description 1
- 229960001347 fluocinolone acetonide Drugs 0.000 description 1
- FEBLZLNTKCEFIT-VSXGLTOVSA-N fluocinolone acetonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O FEBLZLNTKCEFIT-VSXGLTOVSA-N 0.000 description 1
- 229960003973 fluocortolone Drugs 0.000 description 1
- GAKMQHDJQHZUTJ-ULHLPKEOSA-N fluocortolone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)CO)[C@@]2(C)C[C@@H]1O GAKMQHDJQHZUTJ-ULHLPKEOSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
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- 210000004400 mucous membrane Anatomy 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 150000003118 prednisones Chemical class 0.000 description 1
- 208000037921 secondary disease Diseases 0.000 description 1
- 238000010517 secondary reaction Methods 0.000 description 1
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- 231100000444 skin lesion Toxicity 0.000 description 1
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- Medicines Containing Plant Substances (AREA)
Description
Foreliggende oppfinnelse angår en analogifremgangsmåte ved fremstilling av terapeutisk aktivt triamcinolon-acetonid-4,41 - methylen-bis-(3-methoxy-2-nafthe at ) . The present invention relates to an analogue method for the production of therapeutically active triamcinolone acetonide-4,41-methylene-bis-(3-methoxy-2-naphtha).
Det er vel kjent at trramcinolon acetonid eller 9a-fluor-lip,21-dihydroxy-l6a,17a-isopropyliden-dioxy-l,^--pregna-dien-3,20-dion har funnet spesiell anvendelse innen dermatologien. Forbindelsen utviser en betydelig effektivitet ved behandling av derraatosis, eczema, neurodermitis, impetigo, psoriasis, pruritis og andre beslektede sykdommer. Ved topisk langtidsbehandling over store områder, spesielt på barn hvor det er hudlesjoner, kan det imidlertid oppstå et stort antall sekundære reaksjoner grunnet percutan absorbsjon av corticoidet. It is well known that triamcinolone acetonide or 9a-fluoro-lip,21-dihydroxy-16a,17a-isopropylidene-dioxy-1,^--pregna-diene-3,20-dione has found special use in dermatology. The compound shows significant effectiveness in the treatment of derraatosis, eczema, neurodermatitis, impetigo, psoriasis, pruritis and other related diseases. However, with long-term topical treatment over large areas, especially in children where there are skin lesions, a large number of secondary reactions may occur due to percutaneous absorption of the corticoid.
Triamcinolon acetonid er et fluorineitt derivat av prednison,hvor fluoratomet i 9a stilling i corticosteroid ring-systemet øker aktiviteten av glucocorticoidet og reduserer virkningen på metabolismen av elektrolytter. Triamcinolone acetonide is a fluorinated derivative of prednisone, where the fluorine atom in the 9a position of the corticosteroid ring system increases the activity of the glucocorticoid and reduces the effect on the metabolism of electrolytes.
I britisk patentskrift 1.332.058 og tysk offentliggjørelses-skrift 2.149.470 er det beskrevet hvordan de uønskede bivirkninger til prednison kan nedsettes eller unngås ved at dette omsettes med en syre (eller spesielt med syrekloridet) under dannelse av en ester som har nedsatt eller ingen absorbsjon i forhold til prednison. Den nevnte ester har prednisonets ønskede anti-inflammatoriske egenskaper men kan administreres uten bivirkninger på grunn av absorbsjon når den administreres oralt eller lokalt, f.eks. intramuskulært eller intravenøst. Syren med hvilken prednison omsettes er 4,4'-methylen-bis-{3-methoxy-2-nafthoin) syre. In British patent document 1,332,058 and German publication document 2,149,470, it is described how the unwanted side effects of prednisone can be reduced or avoided by reacting this with an acid (or especially with the acid chloride) to form an ester that has reduced or no absorption compared to prednisone. Said ester has the desired anti-inflammatory properties of prednisone but can be administered without side effects due to absorption when administered orally or topically, e.g. intramuscularly or intravenously. The acid with which prednisone reacts is 4,4'-methylene-bis-{3-methoxy-2-naphthoic) acid.
Fremstilling av syren er beskrevet i spansk patentskrift Production of the acid is described in a Spanish patent document
385.254. 385,254.
Foreliggende oppfinnelse angår en analogifremgangsmåte ved fremstilling av terapeutisk aktivt triamcinolon-acetonid-4,4<1->methylen-bis-(3-methoxy-2-nafthoat, hvilken fremgangsmåte er kjennetegnet ved at 4,4<1->methylen-bis-(3-methoxy-2-nafthosyre) The present invention relates to an analogous method for the production of therapeutically active triamcinolone acetonide-4,4<1->methylene-bis-(3-methoxy-2-naphthoate), which method is characterized by the fact that 4,4<1->methylene-bis -(3-methoxy-2-naphthoic acid)
på i og for seg kjent måte omdannes til et reaktivt derivat derav, hvoretter det erholdte reaktive derivat omsettes med triamcinolon-acetonid. in a manner known per se is converted into a reactive derivative thereof, after which the reactive derivative obtained is reacted with triamcinolone acetonide.
Ved fremstilling av nafhthoatet omsettes syren fortrinnsvis med et halogeneringsmiddel slik som thionylklorid under dannelse av to syre-halogenid grupper på molekylet, dvs. When producing the naphthoate, the acid is preferably reacted with a halogenating agent such as thionyl chloride, forming two acid-halide groups on the molecule, i.e.
hvor X fortrinnsvis er klor. Denne reaksjon utfores i vannfritt medium. where X is preferably chlorine. This reaction is carried out in an anhydrous medium.
Det således erholdte syrehålogenid omsettes deretter med triamcinolon acetonid i nærvær av et middel for binding av den syre som dannes under reaksjonen, slik at det erholdes et sluttprodukt tilsvarende formelen: The acid halide thus obtained is then reacted with triamcinolone acetonide in the presence of an agent for binding the acid formed during the reaction, so that a final product corresponding to the formula is obtained:
hvor R er radikalet av triamcinolon acetonid. where R is the radical of triamcinolone acetonide.
Som syrebindende middel kan det anvendes en organisk base. En spesielt egnet forbindelse er pyridin, som virker både som base og som løsningsmiddel for reaksjonen. An organic base can be used as an acid-binding agent. A particularly suitable compound is pyridine, which acts both as a base and as a solvent for the reaction.
Det folgende eksempel illustrerer oppfinnelsen: The following example illustrates the invention:
Eksempel 15 gr. ^,■+'-methylen-bis(3-methoxy-2-nafhthoin) syre ble blandet med 55 ral thionyl klorid. Blandingen ble oppvarmet på et vannbad i to timer, hvoretter overskudd thionylklofid ; ble destil-lert fra inntil det ble erholdt et fast residuum, som ble renset ved omkrystallisering fra vannfri benzen. Example 15 gr. ^,■+'-methylene-bis(3-methoxy-2-naphthoic) acid was mixed with 55 ral of thionyl chloride. The mixture was heated on a water bath for two hours, after which excess thionylclofid ; was distilled from until a solid residue was obtained, which was purified by recrystallization from anhydrous benzene.
h, k'-methylen-bis(3-methoxy-2-nafhthoinlsyEe klorid ble erholdt som et gult, fast materiale. h,k'-methylene-bis(3-methoxy-2-naphthoinyl chloride) was obtained as a yellow solid.
Smeltepunkt : 170 - 173°C Melting point: 170 - 173°C
Utbytte : 95$ Dividend : 95$
Elementeranalyse: Elemental analysis:
Beregnet: C = 66.23$ H = h. 02% Cl = l5. 6h% Calculated: C = 66.23$ H = h. 02% Cl = l5. 6h%
Funnet: C = 66.80$ H = h. 10% Cl = 15.66$ Found: C = 66.80$ H = h. 10% Cl = 15.66$
10 gr. av syrekloridet ble behandlet med 19,2 gr. triamcinolon acetonid i 150 ml pyridin. Blandingen ble oppvarmet i 3 timer ved 90°C og den resulterende losning ble tilsatt til 3 1. vann. Produktet ble erholdt ved filtrering og vasket med vann. Det ble deretter vakuumtorket ved mellom hO°C og 50°C og triamcinolon acetonid h,*+' -methylen-bis(3-methoxy-2-nafhthoat) ble erholdt i 90$ utbytte. 10 gr. of the acid chloride was treated with 19.2 gr. triamcinolone acetonide in 150 ml of pyridine. The mixture was heated for 3 hours at 90°C and the resulting solution was added to 3 L of water. The product was obtained by filtration and washed with water. It was then vacuum dried at between h0°C and 50°C and triamcinolone acetonide h,*+' -methylene-bis(3-methoxy-2-naphthoate) was obtained in 90% yield.
Etter omkrystallisering fra en blanding av aceton og vann ble produktet funnet å ha folgende egenskaper: Smeltepunkt : 220°C (spaltning) Elementæranalyse : After recrystallization from a mixture of acetone and water, the product was found to have the following properties: Melting point : 220°C (decomposition) Elemental analysis :
Beregnet: C = 69,5$ H = 6.25$ F = 3.08$ Calculated: C = 69.5$ H = 6.25$ F = 3.08$
Funnet: C = 70,18$ H = 6.29$ F = 3. 0h% Found: C = 70.18$ H = 6.29$ F = 3.0h%
Forskjellige pre-kliniske tester viste at produktet hverken ble absorbert oralt eller topisk (selv over store hudområder). Spesielt ble det funnet at oral administrering av produktet ikke forandret urinekskresjonshastigheten av 17-ketosteroider, natrium eller kalium ioner, hvilke verdier ble betydelig forandret når beslektede corticoider ble administrert. Various pre-clinical tests showed that the product was neither absorbed orally nor topically (even over large areas of skin). In particular, it was found that oral administration of the product did not alter the urinary excretion rate of 17-ketosteroids, sodium or potassium ions, which values were significantly altered when related corticoids were administered.
Andre målinger viste at produktet fremstilt ifølge oppfinnelsen har den samme anti-inflammatoriske aktivitet som triamcinolon acetonid og var ca. 200- ganger mere aktiv enn prednison. Other measurements showed that the product produced according to the invention has the same anti-inflammatory activity as triamcinolone acetonide and was approx. 200 times more active than prednisone.
Forbindelsen kan administreres i en hvilken som helst egnet form sammen med en farmasøytisk akseptabel bærer, for topisk administrering kan den egnet oppgå tiil en konsentrasjon på 0;3$ i en krem eller pomade. Når kremen administreres tre ganger daglig på de angrepne områder, ble hoved saklig total legning rapportert i 100$ av tilfeller av forskjellige dermatologiske sykdommer, f.eks. kontakt dermatitis og beslektede allergier, eksemer av fysikalsk, kjemisk og medisinsk opprinnelse, foldningseksem og husmoreksem, impetigo, psoriasis og erythema, uten fare for sekundære lidelser bevirket av absorbsjon. The compound may be administered in any suitable form together with a pharmaceutically acceptable carrier, for topical administration it may suitably be at a concentration of 0.3% in a cream or ointment. When the cream is administered three times daily on the affected areas, the main factual total cure was reported in 100$ of cases of various dermatological diseases, e.g. contact dermatitis and related allergies, eczema of physical, chemical and medical origin, folding eczema and household eczema, impetigo, psoriasis and erythema, without the risk of secondary disorders caused by absorption.
Manglende absorbsjon tilveiebringer en ytterligere fordel ved forbindelsen, nemlig at det ikke er noen fare for overdosering når den anvendes på hud eller slimhinner, eller selv fra tette forbindinger. Lack of absorption provides a further advantage to the compound, namely that there is no danger of overdose when applied to the skin or mucous membranes, or even from tight dressings.
Biologisk undersøkelse. Biological examination.
Det er foretatt en sammenlignende undersøkelse under anvendelse av den metode som er beskrevet av A. Jarret i Lawrence og R. Bacharach: Evaluation of Drug Activities; Pharmacometrics, New York Acad. Press, Vol II, side 649, 1964. Denne metode er velegnet til enkel sammenligning av corticoidstyrke. A comparative study has been carried out using the method described by A. Jarret in Lawrence and R. Bacharach: Evaluation of Drug Activities; Pharmacometrics, New York Acad. Press, Vol II, page 649, 1964. This method is suitable for simple comparison of corticoid strength.
Undersøkelsen omfattet flupameson, det vil si det ifølge oppfinnelsen fremstilte triamcilonon-acetonid-4,4'-methylen-bis-(3-methoxy-2-nafthoat) rmepason, det vil si forbindelsen prednison-4,4'-methylen-bis-(3-methoxy-2-nafthoat som er kjent fra tysk offentliggjørelsesskrift 2.149.470, samt ytterligere seks alminne-lige kjente topisk anvendbare corticoider. The investigation included flupamesone, i.e. the triamcilonone-acetonide-4,4'-methylene-bis-(3-methoxy-2-naphthoate) rmepason produced according to the invention, i.e. the compound prednisone-4,4'-methylene-bis- (3-methoxy-2-naphthoate which is known from German publication 2,149,470, as well as six further commonly known topically usable corticoids.
Metode. Method.
Metoden går ut på at ensartede grupper av mus påføres en daglig dose av corticoidkrem i 18 dager i trekk. Den 19. dag avlives dyrene og deres halehud tørkes og prepareres til histo-logisk bedømmelse. The method involves applying a daily dose of corticoid cream to uniform groups of mice for 18 days in a row. On the 19th day, the animals are euthanized and their tail skin is dried and prepared for histological assessment.
Hudsnittene farges med hæmatoxilin-eosin og epitelets karakter iakttages. Epitelets tykkelse sammenlignes (under anvendelse av en mikrometerskala i det optiske mikroskop) med epi-teltykkelsen hos mus behandlet med bærestoffet alene (kremgrunn-lag) eller med andre referansecorticoider. Bestemmelsen av tyk-kelsen foretas ved halens skalare område og til den numeriske sammenligning anvendes gjennomsnittet av adskillige avlesninger. The skin sections are stained with hematoxylin-eosin and the character of the epithelium is observed. The thickness of the epithelium is compared (using a micrometer scale in the optical microscope) with the thickness of the epithelium in mice treated with the carrier substance alone (cream base layer) or with other reference corticoids. The determination of the thickness is made at the scalar area of the tail and the average of several readings is used for the numerical comparison.
Ved forsøket ble det anvendt 8 corticoidkremer bergenet til klinisk anvendelse. Disse kremer ble påført daglig i 18 dager på halene av hunn-albinomus av Swiss-stammen med en kroppsvekt på 25-30 g. Det ble anvendt 8 grupper med 9 dyr i hver gruppe. En kontrollgruppe av ubehandlede dyr tjente som referanse. In the experiment, 8 corticoid creams were used, designed for clinical use. These creams were applied daily for 18 days to the tails of female albino mice of the Swiss strain with a body weight of 25-30 g. Eight groups of 9 animals in each group were used. A control group of untreated animals served as a reference.
Resultater. Results.
De 8 kremer fremkalte en nedsettelse av haleoverhudens tykkelse. Påføring av triamcinolon-acetonid, fluocortolon, fluo-cinolon-acetonid, mepason og flupameson bevirket et fall i den mitotiske virkning i forhold til de ubehandlede dyr. Flupameson-kremen fremkalte en minskning av overhudens tykkelse i større grad enn alle de andre undersøkte corticoider. The 8 creams induced a reduction in the thickness of the tail epidermis. Application of triamcinolone acetonide, fluocortolone, fluocinolone acetonide, mepason and flupameson caused a fall in the mitotic activity compared to the untreated animals. The flupameson cream induced a reduction in the thickness of the epidermis to a greater extent than all the other corticoids examined.
De erholdte resultater er vist i tabel 1. The results obtained are shown in table 1.
Gjennomsnittlig tykkelse av halens overhud i y . Average thickness of the tail's epidermis in y .
Hver verdi er gjennomsnittet ay 15 avlesninger for 9 mus pr. behandling, det vil si 135 bestemmelser pr. behandling. Each value is the average of 15 readings for 9 mice per treatment, i.e. 135 provisions per treatment.
W Antimitotisk indeks i forhold til et 5 % hydrocortison-pre-parat (100). W Antimitotic index in relation to a 5% hydrocortisone preparation (100).
Bedømmelse. Judgment.
Prednison og mepason har ifølge de erholdte resultater samme antimitotiske indeks (henholdsvis 120 og 121). Derimot har triamcinolon-acetonid en indeks på 240 sammenlignet med 300 for flupameson. According to the results obtained, prednisone and mepasone have the same antimitotic index (120 and 121 respectively). In contrast, triamcinolone acetonide has an index of 240 compared to 300 for flupameson.
Det fremgår således at forestringen av triamcinolon-acetonid med 4,4'-methylen-bis-(3-methoxy-2-nafthosyre under dannelse av flupameson gir en uventet økning av den antimitotiske indeks (fra 240 til 300), mens forestringen av prednison med den samme syre under dannelse av mepason ikke gir noen økning av denne indeks (fra 120 til 121). It thus appears that the esterification of triamcinolone acetonide with 4,4'-methylene-bis-(3-methoxy-2-naphthoic acid) to form flupamesone gives an unexpected increase in the antimitotic index (from 240 to 300), while the esterification of prednisone with the same acid during the formation of mepason does not give any increase of this index (from 120 to 121).
Det ifølge oppfinnelsen fremstilte flupamesons egenskaper The properties of the flupameson produced according to the invention
er således overraskende på bakgrunn av egenskapene hos de kjente forbindelser prednison og mepason. is thus surprising on the basis of the properties of the known compounds prednisone and mepason.
Flere forfattere har fastslått at topikale corticoiders antimitotiske virkning har relasjon til deres terapeutiske effekt. Dessuten er det ved en dobbelt-blindundersøkelse vist at flupameson er bedre enn triamcinolon-acetonid ved klinisk anvendelse. Det ifølge oppfinnelsen fremstilte flupameson er således et lege-middel som har vesentlig bedre terapeutisk virkning enn de hittil kjente , beslektede legemidler. Several authors have determined that the antimitotic effect of topical corticoids is related to their therapeutic effect. In addition, it has been shown in a double-blind study that flupameson is better than triamcinolone acetonide in clinical use. The flupamesone produced according to the invention is thus a drug that has a significantly better therapeutic effect than the hitherto known, related drugs.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO740732A NO140270C (en) | 1974-03-04 | 1974-03-04 | ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPHUTICALLY ACTIVE TRIAMCINOLONACETONIDE-4,4`-METHYLENE-BIS- (3-METHOXY-2-NAFTHOATE) |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO740732A NO140270C (en) | 1974-03-04 | 1974-03-04 | ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPHUTICALLY ACTIVE TRIAMCINOLONACETONIDE-4,4`-METHYLENE-BIS- (3-METHOXY-2-NAFTHOATE) |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO740732L NO740732L (en) | 1975-09-05 |
| NO140270B true NO140270B (en) | 1979-04-23 |
| NO140270C NO140270C (en) | 1979-08-01 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO740732A NO140270C (en) | 1974-03-04 | 1974-03-04 | ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPHUTICALLY ACTIVE TRIAMCINOLONACETONIDE-4,4`-METHYLENE-BIS- (3-METHOXY-2-NAFTHOATE) |
Country Status (1)
| Country | Link |
|---|---|
| NO (1) | NO140270C (en) |
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1974
- 1974-03-04 NO NO740732A patent/NO140270C/en unknown
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| Publication number | Publication date |
|---|---|
| NO740732L (en) | 1975-09-05 |
| NO140270C (en) | 1979-08-01 |
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