CA1113006A - Medicine with activity as prostaglandin-synthetase inhibitor - Google Patents
Medicine with activity as prostaglandin-synthetase inhibitorInfo
- Publication number
- CA1113006A CA1113006A CA318,817A CA318817A CA1113006A CA 1113006 A CA1113006 A CA 1113006A CA 318817 A CA318817 A CA 318817A CA 1113006 A CA1113006 A CA 1113006A
- Authority
- CA
- Canada
- Prior art keywords
- glycoside
- pgs
- preparation according
- glycosides
- compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 230000000694 effects Effects 0.000 title abstract description 13
- 239000003814 drug Substances 0.000 title abstract description 5
- 229940079593 drug Drugs 0.000 title 1
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 title 1
- 229930182470 glycoside Natural products 0.000 claims abstract description 21
- 150000002148 esters Chemical class 0.000 claims abstract description 12
- 239000003112 inhibitor Substances 0.000 claims abstract description 11
- -1 sterol glycosides Chemical class 0.000 claims abstract description 7
- 229930182558 Sterol Natural products 0.000 claims abstract description 6
- 235000003702 sterols Nutrition 0.000 claims abstract description 6
- 150000002338 glycosides Chemical class 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 13
- 239000002245 particle Substances 0.000 claims description 11
- OXLGJTRVVNGJRK-UHFFFAOYSA-N Hecogenin Natural products CC1CCC2(CC3CC4C5CCC6CC(O)CCC6(C)C5CC(=O)C4(C)C3C2C)OC1 OXLGJTRVVNGJRK-UHFFFAOYSA-N 0.000 claims description 7
- UVLDESQWQRMYKD-UHFFFAOYSA-N Neobotogenin Natural products CC1C(C2(C(=O)CC3C4(C)CCC(O)CC4=CCC3C2C2)C)C2OC11CCC(C)CO1 UVLDESQWQRMYKD-UHFFFAOYSA-N 0.000 claims description 7
- LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 claims description 7
- WQLVFSAGQJTQCK-UHFFFAOYSA-N diosgenin Natural products CC1C(C2(CCC3C4(C)CCC(O)CC4=CCC3C2C2)C)C2OC11CCC(C)CO1 WQLVFSAGQJTQCK-UHFFFAOYSA-N 0.000 claims description 7
- DWCSNWXARWMZTG-UHFFFAOYSA-N Trigonegenin A Natural products CC1C(C2(CCC3C4(C)CCC(O)C=C4CCC3C2C2)C)C2OC11CCC(C)CO1 DWCSNWXARWMZTG-UHFFFAOYSA-N 0.000 claims description 6
- WQLVFSAGQJTQCK-VKROHFNGSA-N diosgenin Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CC[C@H](O)CC4=CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 WQLVFSAGQJTQCK-VKROHFNGSA-N 0.000 claims description 6
- KZJWDPNRJALLNS-VPUBHVLGSA-N (-)-beta-Sitosterol Natural products O[C@@H]1CC=2[C@@](C)([C@@H]3[C@H]([C@H]4[C@@](C)([C@H]([C@H](CC[C@@H](C(C)C)CC)C)CC4)CC3)CC=2)CC1 KZJWDPNRJALLNS-VPUBHVLGSA-N 0.000 claims description 5
- CSVWWLUMXNHWSU-UHFFFAOYSA-N (22E)-(24xi)-24-ethyl-5alpha-cholest-22-en-3beta-ol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(CC)C(C)C)C1(C)CC2 CSVWWLUMXNHWSU-UHFFFAOYSA-N 0.000 claims description 5
- KLEXDBGYSOIREE-UHFFFAOYSA-N 24xi-n-propylcholesterol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CCC)C(C)C)C1(C)CC2 KLEXDBGYSOIREE-UHFFFAOYSA-N 0.000 claims description 5
- LPZCCMIISIBREI-MTFRKTCUSA-N Citrostadienol Natural products CC=C(CC[C@@H](C)[C@H]1CC[C@H]2C3=CC[C@H]4[C@H](C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C LPZCCMIISIBREI-MTFRKTCUSA-N 0.000 claims description 5
- ARVGMISWLZPBCH-UHFFFAOYSA-N Dehydro-beta-sitosterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)CCC(CC)C(C)C)CCC33)C)C3=CC=C21 ARVGMISWLZPBCH-UHFFFAOYSA-N 0.000 claims description 5
- QOLRLLFJMZLYQJ-LOBDNJQFSA-N Hecogenin Chemical compound O([C@@H]1[C@@H]([C@]2(C(=O)C[C@@H]3[C@@]4(C)CC[C@H](O)C[C@@H]4CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 QOLRLLFJMZLYQJ-LOBDNJQFSA-N 0.000 claims description 5
- MJVXAPPOFPTTCA-UHFFFAOYSA-N beta-Sistosterol Natural products CCC(CCC(C)C1CCC2C3CC=C4C(C)C(O)CCC4(C)C3CCC12C)C(C)C MJVXAPPOFPTTCA-UHFFFAOYSA-N 0.000 claims description 5
- NJKOMDUNNDKEAI-UHFFFAOYSA-N beta-sitosterol Natural products CCC(CCC(C)C1CCC2(C)C3CC=C4CC(O)CCC4C3CCC12C)C(C)C NJKOMDUNNDKEAI-UHFFFAOYSA-N 0.000 claims description 5
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 5
- KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 claims description 5
- 235000015500 sitosterol Nutrition 0.000 claims description 5
- 229950005143 sitosterol Drugs 0.000 claims description 5
- NLQLSVXGSXCXFE-UHFFFAOYSA-N sitosterol Natural products CC=C(/CCC(C)C1CC2C3=CCC4C(C)C(O)CCC4(C)C3CCC2(C)C1)C(C)C NLQLSVXGSXCXFE-UHFFFAOYSA-N 0.000 claims description 5
- RTMWIZOXNKJHRE-UHFFFAOYSA-N Tigogenin Natural products CC1COC2CC(C)(OC12)C3CCC4C5CCC6CC(O)CCC6(C)C5CCC34C RTMWIZOXNKJHRE-UHFFFAOYSA-N 0.000 claims description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 4
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 claims description 3
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 claims description 3
- GMBQZIIUCVWOCD-WWASVFFGSA-N Sarsapogenine Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CC[C@H](O)C[C@H]4CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@H](C)CO1 GMBQZIIUCVWOCD-WWASVFFGSA-N 0.000 claims description 3
- 150000003432 sterols Chemical class 0.000 claims description 3
- BQPPJGMMIYJVBR-UHFFFAOYSA-N (10S)-3c-Acetoxy-4.4.10r.13c.14t-pentamethyl-17c-((R)-1.5-dimethyl-hexen-(4)-yl)-(5tH)-Delta8-tetradecahydro-1H-cyclopenta[a]phenanthren Natural products CC12CCC(OC(C)=O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C BQPPJGMMIYJVBR-UHFFFAOYSA-N 0.000 claims description 2
- CHGIKSSZNBCNDW-UHFFFAOYSA-N (3beta,5alpha)-4,4-Dimethylcholesta-8,24-dien-3-ol Natural products CC12CCC(O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21 CHGIKSSZNBCNDW-UHFFFAOYSA-N 0.000 claims description 2
- XYTLYKGXLMKYMV-UHFFFAOYSA-N 14alpha-methylzymosterol Natural products CC12CCC(O)CC1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C XYTLYKGXLMKYMV-UHFFFAOYSA-N 0.000 claims description 2
- FPTJELQXIUUCEY-UHFFFAOYSA-N 3beta-Hydroxy-lanostan Natural products C1CC2C(C)(C)C(O)CCC2(C)C2C1C1(C)CCC(C(C)CCCC(C)C)C1(C)CC2 FPTJELQXIUUCEY-UHFFFAOYSA-N 0.000 claims description 2
- BKLIAINBCQPSOV-UHFFFAOYSA-N Gluanol Natural products CC(C)CC=CC(C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(O)C(C)(C)C4CC3 BKLIAINBCQPSOV-UHFFFAOYSA-N 0.000 claims description 2
- LOPKHWOTGJIQLC-UHFFFAOYSA-N Lanosterol Natural products CC(CCC=C(C)C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(C)(O)C(C)(C)C4CC3 LOPKHWOTGJIQLC-UHFFFAOYSA-N 0.000 claims description 2
- CAHGCLMLTWQZNJ-UHFFFAOYSA-N Nerifoliol Natural products CC12CCC(O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C CAHGCLMLTWQZNJ-UHFFFAOYSA-N 0.000 claims description 2
- HZYXFRGVBOPPNZ-UHFFFAOYSA-N UNPD88870 Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)=CCC(CC)C(C)C)C1(C)CC2 HZYXFRGVBOPPNZ-UHFFFAOYSA-N 0.000 claims description 2
- 235000012000 cholesterol Nutrition 0.000 claims description 2
- QBSJHOGDIUQWTH-UHFFFAOYSA-N dihydrolanosterol Natural products CC(C)CCCC(C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(C)(O)C(C)(C)C4CC3 QBSJHOGDIUQWTH-UHFFFAOYSA-N 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- CAHGCLMLTWQZNJ-RGEKOYMOSA-N lanosterol Chemical compound C([C@]12C)C[C@@H](O)C(C)(C)[C@H]1CCC1=C2CC[C@]2(C)[C@H]([C@H](CCC=C(C)C)C)CC[C@@]21C CAHGCLMLTWQZNJ-RGEKOYMOSA-N 0.000 claims description 2
- 229940058690 lanosterol Drugs 0.000 claims description 2
- HCXVJBMSMIARIN-PHZDYDNGSA-N stigmasterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)/C=C/[C@@H](CC)C(C)C)[C@@]1(C)CC2 HCXVJBMSMIARIN-PHZDYDNGSA-N 0.000 claims description 2
- 229940032091 stigmasterol Drugs 0.000 claims description 2
- 235000016831 stigmasterol Nutrition 0.000 claims description 2
- BFDNMXAIBMJLBB-UHFFFAOYSA-N stigmasterol Natural products CCC(C=CC(C)C1CCCC2C3CC=C4CC(O)CCC4(C)C3CCC12C)C(C)C BFDNMXAIBMJLBB-UHFFFAOYSA-N 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims 2
- MBZYKEVPFYHDOH-UHFFFAOYSA-N (10S)-3c-Hydroxy-4.4.10r.13t.14c-pentamethyl-17t-((R)-1.5-dimethyl-hexyl)-(5tH)-Delta8-tetradecahydro-1H-cyclopenta[a]phenanthren Natural products CC12CCC(O)C(C)(C)C1CCC1=C2CCC2(C)C(C(C)CCCC(C)C)CCC21C MBZYKEVPFYHDOH-UHFFFAOYSA-N 0.000 claims 1
- RQOCXCFLRBRBCS-UHFFFAOYSA-N (22E)-cholesta-5,7,22-trien-3beta-ol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CCC(C)C)CCC33)C)C3=CC=C21 RQOCXCFLRBRBCS-UHFFFAOYSA-N 0.000 claims 1
- HVYWMOMLDIMFJA-VEIPTCAHSA-N (3r,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-ol Chemical compound C1C=C2C[C@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-VEIPTCAHSA-N 0.000 claims 1
- MBZYKEVPFYHDOH-BQNIITSRSA-N 24,25-dihydrolanosterol Chemical compound C([C@@]12C)C[C@H](O)C(C)(C)[C@@H]1CCC1=C2CC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@]21C MBZYKEVPFYHDOH-BQNIITSRSA-N 0.000 claims 1
- DNVPQKQSNYMLRS-NXVQYWJNSA-N Ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@]12C DNVPQKQSNYMLRS-NXVQYWJNSA-N 0.000 claims 1
- LWPLEHFGBRFRKI-CQKTXKLZSA-N Ganoderic acid B Natural products C[C@H](CC(=O)C[C@H](C)C(=O)O)[C@H]1CC(=O)[C@@]2(C)C3=C(C(=O)C[C@]12C)[C@@]4(C)CC[C@H](O)C(C)(C)[C@H]4C[C@@H]3O LWPLEHFGBRFRKI-CQKTXKLZSA-N 0.000 claims 1
- DNVPQKQSNYMLRS-SOWFXMKYSA-N ergosterol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H](CC[C@]3([C@H]([C@H](C)/C=C/[C@@H](C)C(C)C)CC[C@H]33)C)C3=CC=C21 DNVPQKQSNYMLRS-SOWFXMKYSA-N 0.000 claims 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 19
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 8
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- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 8
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- PXGPLTODNUVGFL-BRIYLRKRSA-N (E,Z)-(1R,2R,3R,5S)-7-(3,5-Dihydroxy-2-((3S)-(3-hydroxy-1-octenyl))cyclopentyl)-5-heptenoic acid Chemical compound CCCCC[C@H](O)C=C[C@H]1[C@H](O)C[C@H](O)[C@@H]1CC=CCCCC(O)=O PXGPLTODNUVGFL-BRIYLRKRSA-N 0.000 description 4
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- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 3
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
ABSTRACT OF DISCLOSURE
This invention relates to a medicament with activity as PGS inhibitor characterized in that it contains sterol glycosides and/or esters thereof and/or spiroketal-steroid glycosides and/or esters thereof.
This invention relates to a medicament with activity as PGS inhibitor characterized in that it contains sterol glycosides and/or esters thereof and/or spiroketal-steroid glycosides and/or esters thereof.
Description
The invention relates to medicaments with prostaglandin-synthetase (PGS) inhibiting activity.
Prostaglandins (PGs) are widely present in all mammalian organisms. For some years scientific research has been concentrated in intensive efforts for extracting and acknowledging the bio-logical activity of prostaglandins. Arcording to present knowledge multiple PGS or precursors exist which vary somewhat in structure and of which the biological importances are wide spread occurrence,high activities and differences in metabolic actionO These different actions are based on the fact that the intracellular PG synthesis can be induced by irritation or damage of cellular membranes during which in th~ first phase phospho-lipases release PG-precursors from membrane lipids, or that on the other hand several hormones e.g. bradykinines, acetylchlorine or histamine increase the synthesis and release of PGs and that moreover PGs not only stimulate the adenyl-cyclase-system but also the guanyl--cyclase-system and therefore can cause an increase of intracellular APM- and GPM- concentrations.
It had already been known that the PG e~ects vary depending on PG types used and tested organs, e.g. the adenyl-cyclase is stimulated in endocrine organs by PGEl and PGE2 but inhibited in fat tissue. This fact explains why PGs are able to increase or decrease the APM level in a target organ and display an adrenalin- and glucagon antagonistic effect in fat tissue. With smooth muscles PGs in part effect contractions e.g~ in uterus or intestine or dilatation e.g. in blood vessels.
Cl PGs E2 and A2 increase secretion of sodium and potassium in the ~idneys. Furthermore, it had been established already that an increase of PGs E2 and F2 level in the tissue can initiate and maintain inflammatory reactions.
The multiple metabolic effects of PGs are basis for several therapeutic uses. Thus, PGs are used in the treatment of asthma and circulatory diseases because PGs of the E-type have vessel-dilatating activity. On the other hand, PGs induce labor and initiate parturition so that it is possible to use them for inducing abortion.
It was not known until recently that the activity of some medicaments with analgetic and anti-inflammatory action which had already been used for decades is based on an inhibition of the prostaglandin synthetases. This applies for e.g. acetylsalicylic acid, indomethacine or ibuprofen. The strong inhibitory action of these compounds explains the activity against inflammations on one hand and on the other hand the presence of several side e~fects of which only the induction of stomach hemorrhages is referred to.
The biosynthesis of the PGs starts from membrane phospholipides which are converted into arachidonic acid and are reacted into endoperoxide - PGs by oxygen radicals. By further reactions the relatively stable PGs, thromboxanes and the relatively unstable prosta-cyclin are formed from the endoperoxide -PGs.
The synthesis of PGE2 and PGF2~ from arachidonic acid can be shown in a shortened way in the following formula:
f~ I
- ~ , ' :
' ' ' ' ' \ COOH
OH
COOH
~ ",.
OH
~1 ~ .
COQH
OH
OH
The biological residence time of PGs and their precursors is only miniscule. The decomposition starts from oxidation at C-5 and continues via the ~-oxidation of fatty acids.
It had already been established that certain chemical compounds are strong PGS inhibitors. These compounds e.g.
indometacine or acetylsalicylic had been found to be PGE2 -synthetase inhibitors and are used correspondingly in the treatment of rheumatic and arthritic and similar conditions for instance. The strong inhibitor action which is not necessarily restricted to PGE2 - synthetase leads to unwanted side effects ~J~
'~
based on this action e.g. initiation of bleeding in the stomach and intestine, other scattered bleedings,occUrrenCe of allergies or possibilities of influencing gravidity.
Therefore, it is the object of the invention to develop a new medicament with an activity as PGS-inhibitor which does not possess the known disadvantages.
The invention accordingly provides a pharmaceutical preparation in unit dosage form, active as a PGS inhibitor, comprising from about 0.01 to 10 mg. per dosage unit of a glycoside 10 selected from sterol glycosides and esters thereof and spiroketal-steroid glycosides and esters thereof, in a pharmaceutically acceptable carrier.
Surprisingly and completely unexpected it has now been established that sterolglycosides, spiroketal-steroidglycosides and esters thereof are active inhibitors for PGE2 - and PGF2~
synthetases without producing side effects which normally occur in influencing the PG level. Sterolins are compounds occurring frequently though only in small amounts in nature~in plants and microorganisms. Sterolins are chemically glycosides of phyto-sterols including cholesterol and sterol type tetracyclic triterpenes as for example lanosterol and cycloartenol. Some of these compounds occur in various plants in relati~ely larger amounts, e.g., campesterol and stigmasterol and particularly sitosterol. The phytosterols correspond to the following general formula:
, j j . .
:
, " , ' ' ~ :
., .
HO ,' \
in which R , R2 and R3 are hydrogen atoms or methyl groups and in which R4 can be a hydrogen atom or a methyl, ethyl, methylene or ethylidene groupO Furthermore, there can be present double bonds at various places of the basic structure. This is true also for the side chain.
Phytosterols are present in most plants partially as steroglycosides i.e. therefore as sterolins and sometimes as their esters. The most common sterolins in nature are monoglycosides though a few diglycosides had been described as well. Besides the predominantly occurring D-glucose which is joined to the s-terol by the 3-~-hydroxy group, mostly by equatorial or ~-glycoside bonds, mannose, galactose, arabinose and xylose has been found in the naturally occurring compounds.
As far as esters which occur in nature, these have been identified as esters of monobasic monocarboxylic acids.
C, Spiroketal-steroidglycosides are those steroidsaponins which carry at the steroid basic structure - which is the aglycone -at carbon atoms 16 and 17 a spiroketal group. The aglycones can be classified in being 5-ene-steroid sapogenins or 5~-steroid sapogenins. 5-ene-compounds are for example diosgenin, yamogenin, botogenin and correlogin while representatives of 5-~-compounds are for example tigogenin, neotigonin, hecogenin and sisalagenin.
In nature the aglycones of the saponins exist as glyco-sides which carry in general 3 or more monosaccharide units in the sugar moity.
sased on this fact these compounds which are relatively rich in sugar dissolve rather readily in water and frequently give rise to a soap like froth.
The spiroketal-steroidglycosides correspond to the following general formula , ~\0~
Z--O
~, .
.:, ~ .
where in position 5 a double bond or an ~-hydrogen atom can be present and where Z is a mono- or disaccharide, especially glucose, which can be esterified.
The sterolins and spiroketal-steroidglycosides used according to the invention and their esters can be dispensed as extracts o-f plant material, enriched extracts or compounds produced synthetically.
The synthesis can be carried out in a manner known per se as for example the known Kornigs-Knorr-synthesis for producing glycosides using the corresponding aglyconest a C-l brominated sugar acetate and silver oxide or silver carbonate.
In case of treatment with sterolins or their esters it is to be noted that these compounds are extremely insoluble in water.
Therefore, for administration, sterolins must have an appropriately small particle size which enables resorption. It is absolutely necessary that the sterolins used in the invention are produced and/or prepared and/or incorporated in pharmaceutical preparations in such a manner that liquid or solid solutions, emulsions or solid dispersions are formed which can be made in a known way by adsorption, absorption or grinding with or without auxiliary material. All these methods lead to a reduction of particle size and crystallinity so that the compounds no longer exist as crystalline micro particles but as miniscule amorphous mono- or multilayer aggregates.
The compounds o-f the invention generally are used with a particle size of about 0.1 mm and preferably 0.06 mm and smaller.
The same applies to the spiroketal-steroidglycosides `' ~ 1 s ~
not-withstanding their better solubility in water. Ihese compounds too ar~ used with a particle size of 0.1 mm and preferably 0.06 mm or smaller~
The compounds of the invention are administered in daily doses of about 0.03 to 10 mg. The usual curati~e or protective dosage is about 0.1 to 0.45 mg daily. The doses can be given in 3 single doses or in a single dose with slow release of active material.
According to present knowledge the compounds are suited for treatment of diseases in which a reduction of the PGE2 or PGF2 level is necessary. Among these diseases are the following ones:
1.) Ulcers, especially of stomach and intestine,
Prostaglandins (PGs) are widely present in all mammalian organisms. For some years scientific research has been concentrated in intensive efforts for extracting and acknowledging the bio-logical activity of prostaglandins. Arcording to present knowledge multiple PGS or precursors exist which vary somewhat in structure and of which the biological importances are wide spread occurrence,high activities and differences in metabolic actionO These different actions are based on the fact that the intracellular PG synthesis can be induced by irritation or damage of cellular membranes during which in th~ first phase phospho-lipases release PG-precursors from membrane lipids, or that on the other hand several hormones e.g. bradykinines, acetylchlorine or histamine increase the synthesis and release of PGs and that moreover PGs not only stimulate the adenyl-cyclase-system but also the guanyl--cyclase-system and therefore can cause an increase of intracellular APM- and GPM- concentrations.
It had already been known that the PG e~ects vary depending on PG types used and tested organs, e.g. the adenyl-cyclase is stimulated in endocrine organs by PGEl and PGE2 but inhibited in fat tissue. This fact explains why PGs are able to increase or decrease the APM level in a target organ and display an adrenalin- and glucagon antagonistic effect in fat tissue. With smooth muscles PGs in part effect contractions e.g~ in uterus or intestine or dilatation e.g. in blood vessels.
Cl PGs E2 and A2 increase secretion of sodium and potassium in the ~idneys. Furthermore, it had been established already that an increase of PGs E2 and F2 level in the tissue can initiate and maintain inflammatory reactions.
The multiple metabolic effects of PGs are basis for several therapeutic uses. Thus, PGs are used in the treatment of asthma and circulatory diseases because PGs of the E-type have vessel-dilatating activity. On the other hand, PGs induce labor and initiate parturition so that it is possible to use them for inducing abortion.
It was not known until recently that the activity of some medicaments with analgetic and anti-inflammatory action which had already been used for decades is based on an inhibition of the prostaglandin synthetases. This applies for e.g. acetylsalicylic acid, indomethacine or ibuprofen. The strong inhibitory action of these compounds explains the activity against inflammations on one hand and on the other hand the presence of several side e~fects of which only the induction of stomach hemorrhages is referred to.
The biosynthesis of the PGs starts from membrane phospholipides which are converted into arachidonic acid and are reacted into endoperoxide - PGs by oxygen radicals. By further reactions the relatively stable PGs, thromboxanes and the relatively unstable prosta-cyclin are formed from the endoperoxide -PGs.
The synthesis of PGE2 and PGF2~ from arachidonic acid can be shown in a shortened way in the following formula:
f~ I
- ~ , ' :
' ' ' ' ' \ COOH
OH
COOH
~ ",.
OH
~1 ~ .
COQH
OH
OH
The biological residence time of PGs and their precursors is only miniscule. The decomposition starts from oxidation at C-5 and continues via the ~-oxidation of fatty acids.
It had already been established that certain chemical compounds are strong PGS inhibitors. These compounds e.g.
indometacine or acetylsalicylic had been found to be PGE2 -synthetase inhibitors and are used correspondingly in the treatment of rheumatic and arthritic and similar conditions for instance. The strong inhibitor action which is not necessarily restricted to PGE2 - synthetase leads to unwanted side effects ~J~
'~
based on this action e.g. initiation of bleeding in the stomach and intestine, other scattered bleedings,occUrrenCe of allergies or possibilities of influencing gravidity.
Therefore, it is the object of the invention to develop a new medicament with an activity as PGS-inhibitor which does not possess the known disadvantages.
The invention accordingly provides a pharmaceutical preparation in unit dosage form, active as a PGS inhibitor, comprising from about 0.01 to 10 mg. per dosage unit of a glycoside 10 selected from sterol glycosides and esters thereof and spiroketal-steroid glycosides and esters thereof, in a pharmaceutically acceptable carrier.
Surprisingly and completely unexpected it has now been established that sterolglycosides, spiroketal-steroidglycosides and esters thereof are active inhibitors for PGE2 - and PGF2~
synthetases without producing side effects which normally occur in influencing the PG level. Sterolins are compounds occurring frequently though only in small amounts in nature~in plants and microorganisms. Sterolins are chemically glycosides of phyto-sterols including cholesterol and sterol type tetracyclic triterpenes as for example lanosterol and cycloartenol. Some of these compounds occur in various plants in relati~ely larger amounts, e.g., campesterol and stigmasterol and particularly sitosterol. The phytosterols correspond to the following general formula:
, j j . .
:
, " , ' ' ~ :
., .
HO ,' \
in which R , R2 and R3 are hydrogen atoms or methyl groups and in which R4 can be a hydrogen atom or a methyl, ethyl, methylene or ethylidene groupO Furthermore, there can be present double bonds at various places of the basic structure. This is true also for the side chain.
Phytosterols are present in most plants partially as steroglycosides i.e. therefore as sterolins and sometimes as their esters. The most common sterolins in nature are monoglycosides though a few diglycosides had been described as well. Besides the predominantly occurring D-glucose which is joined to the s-terol by the 3-~-hydroxy group, mostly by equatorial or ~-glycoside bonds, mannose, galactose, arabinose and xylose has been found in the naturally occurring compounds.
As far as esters which occur in nature, these have been identified as esters of monobasic monocarboxylic acids.
C, Spiroketal-steroidglycosides are those steroidsaponins which carry at the steroid basic structure - which is the aglycone -at carbon atoms 16 and 17 a spiroketal group. The aglycones can be classified in being 5-ene-steroid sapogenins or 5~-steroid sapogenins. 5-ene-compounds are for example diosgenin, yamogenin, botogenin and correlogin while representatives of 5-~-compounds are for example tigogenin, neotigonin, hecogenin and sisalagenin.
In nature the aglycones of the saponins exist as glyco-sides which carry in general 3 or more monosaccharide units in the sugar moity.
sased on this fact these compounds which are relatively rich in sugar dissolve rather readily in water and frequently give rise to a soap like froth.
The spiroketal-steroidglycosides correspond to the following general formula , ~\0~
Z--O
~, .
.:, ~ .
where in position 5 a double bond or an ~-hydrogen atom can be present and where Z is a mono- or disaccharide, especially glucose, which can be esterified.
The sterolins and spiroketal-steroidglycosides used according to the invention and their esters can be dispensed as extracts o-f plant material, enriched extracts or compounds produced synthetically.
The synthesis can be carried out in a manner known per se as for example the known Kornigs-Knorr-synthesis for producing glycosides using the corresponding aglyconest a C-l brominated sugar acetate and silver oxide or silver carbonate.
In case of treatment with sterolins or their esters it is to be noted that these compounds are extremely insoluble in water.
Therefore, for administration, sterolins must have an appropriately small particle size which enables resorption. It is absolutely necessary that the sterolins used in the invention are produced and/or prepared and/or incorporated in pharmaceutical preparations in such a manner that liquid or solid solutions, emulsions or solid dispersions are formed which can be made in a known way by adsorption, absorption or grinding with or without auxiliary material. All these methods lead to a reduction of particle size and crystallinity so that the compounds no longer exist as crystalline micro particles but as miniscule amorphous mono- or multilayer aggregates.
The compounds o-f the invention generally are used with a particle size of about 0.1 mm and preferably 0.06 mm and smaller.
The same applies to the spiroketal-steroidglycosides `' ~ 1 s ~
not-withstanding their better solubility in water. Ihese compounds too ar~ used with a particle size of 0.1 mm and preferably 0.06 mm or smaller~
The compounds of the invention are administered in daily doses of about 0.03 to 10 mg. The usual curati~e or protective dosage is about 0.1 to 0.45 mg daily. The doses can be given in 3 single doses or in a single dose with slow release of active material.
According to present knowledge the compounds are suited for treatment of diseases in which a reduction of the PGE2 or PGF2 level is necessary. Among these diseases are the following ones:
1.) Ulcers, especially of stomach and intestine,
2.) endocrine disregulations,
3.) urogenital diseases especially benign prostata hypertrophy and accompanying diseases,
4.) heart illnesses and blood pressure disturbances,
5.) edematose conditions,
6.) blood vessel diseases, thrombosis varicose veins and hemorrhoids,
7.3 dermatitis and reactions based on excess of histamine,
8.) inflammatory reactions,
9.) arthritic and rheumatoid diseases, ;~
10.) allergies including asthma.
The compounds of the invention can be used in corresponding manner to treat animal diseases. The dosage used in animal diseases can be calculated in a known manner by taking 75 kg as the average human weight.
'' ' ~' The compounds can be prepared in usual way known to the expert as pharmaceutical compositions, e.g. powders, pills, tablets, capsules, dragées, emulsions, solutions, injection - or infusion solutions, ointments or creams.
The invention will be further explained in connection with the examples.
Example 1 Production of Sitosterol-~-D-Glucoside.
A mixture of 41,4 grams of sitosterol and 55,2 grams of silver carbonate in toluene were distilled with stirring until the distillate passed over free of water. Then there was added to the stirred, boiling mixture dropwise a solution of 82,2 grams of acetobromoglucose in 100 ml of toluene. The toluene was continuously further distilled so that the total amount of water formed in the reaction was removed azeotropically. The reaction vessel was protected from light during this time. In case it is necessary, the volume of the reaction mixture is held constant by addition of dry toluene. After the addition of the bromo-acetoglucose solution it was maintained at the boiling point until the distillate was water free. Subsequently the reaction mixture was filtered and the residue washed with fresh hot toluene. The united filtrate and washing liquids were then evaporated under reduced pressure. The residue was recrystallized from ethanol or hexane. The yield of sitosterol glucoside tetraacetate was 22~4 grams, corresponding to 30%.
A solution of 1 gram of sodium in 100 ml of ethanol :
under stirring was added quickly to a solution of 10 grams sitosterol glucoside tetraacetate in 600 ml ethanol at a temperature of 45C. The mixture was stirred for one hour before 2 liters of water were added and the mixture was then stirred for another hour. The precipitated sitosterol glucoside was filtered off and washed until neutral with water prior to drying it for 12 hours in a vacuum. The yield was 6,0 grams, corresponding to 95%.
By selection of suitable starting compounds all the remaining mentioned sterolins also can be produced according to the above given process.
_xample 2 S~nthesis of diosgenin-3-~-D-glucoside.
A well stirred mixture of 55,2 g silver carbonate and a solution of 41,4 g diosgenin in 600 ml toluene was distilled unti~
the collecting distillate was free of water. A solution of 82,2 g bromoacetylglucose in 100 ml toluene was then added dropwise to the stirred mixture, boiling continuing all the time with distillation in order to remove the water formed during the glucosidation reaction. At this stage the reaction vessel is protected from light and the volume of the reaction mixture is kept constant at about 500 ml by adding extra dry toluene whenever necessary. After the acetobromoglucose addition has been completed distillation is continued until no further water separates from the condensate. The reaction mixture is then filtered hot and the residue is washed with fresh, hot toluene~ The combined filtrate and wash solutions are evaporated to dryness under vacuum and the reSldUe lS
, .
crystallised from ethanol or hexane. The yield of diosgenin-3-~-D~$1ucoside tetraacetate l~a~ 25,5 g or 3~.3%
To a stirred solution of lo g diosgenîn tetraacetate in 600 ml ethanol At ~5 C i9 rapidly added 15 ml of an ethanolic solution of 1 g sodium in loo ml abs. ethanol~ The stirred mixture is allowed $o react for 1 hour bsfore 2 1 water is added and this mixture i~ then stirred for a further hour. The precipitated diosgenin glucoside i~ then filtered off and washed to neutrality ~ith water before it is dried under vacu~ at looC for 12 hours. The yield was 7 g or 90%.
Similarly the further spiroketal-steroid-glycGsides can be prepared.
. .
~xample 3 The_preparation of .pharmaceutical products.
~a) The preparation of lact:ose-corn starch powders incorpor~ting diosgenirL-~-D-glucoside:
A boiling ho* solut~8.n of 15 g di~sgenin glucoside in 2,25 1 chloroforn~ and 750 ml ethanol i~ mixed with 1 ~g lactose powder of a particle si~e no*
exceedin~ o,15 mm. The resulting slurry is dried ~ith constant stirring and the impregnated lactose is ~educed to its original particle ~ize before it is mixed ~ith 9 kg corn starch and 50 g maglles.ium stearate. Capæules are rcadil~ filled with this mixture. ~hus a capsule containing l~o mg of the ~ixt-lre l~ill ca.rry approximately o,15 mg diosgenin~
D-glucoæi~le, lo ms of lactose, 90 mg of corll starch a~ well as o,5 mg of magneæium stearate.
(b3 The preparation of lacto~e granu~¢es containing diosgenln-~3-D-glucoside:
A boi].ing hot solution of 5 g diosgenin glucoside in 5 1 ethanol is mixed with 3,32 k~ of a particle ~ize not exceeding o,15 mm. The agi.tated slurry i5 dried and the impregnated lactose i5 then r~duced to the original particle size before it is converted into granules of o,7-1-2 mm particle sizes. This granula~ed product i~ al~o suitable ~or filling into capsules, where for example a capsule contain~ng loo mg granulate carries o,15 mg diogenin-~-D-glucoside.
Produc*s as de3cribed under a) and b) can also be prepared using the fol~owing: ~
' i) Glyeo~ide~ of the mentioned ~ydrox~spiroke~al-~teroids and especially the ~-D-gluco.sides of ~`igogenin and Hecosenin, il) gluco~e, ascorbic acid or t~lc as carrier~ for the glycosides or any other inert and pharmace~.ically acceptable carrier, iii) the contents of actiYe glycoside in each cap~ule can be adju~ted to any ~alue between o,ol and more,~
i~) the auxilliary sub~tances described in a) and b) can be altered to accepted pharmaceutical prace~ces, . v) at each stage of the production process described under a3 and b3 other pharmaceutically actiYe ~ubstan^es can be added and incorporated into the iinal product.
, .
.
.
. .
- 13 ~ 3~ ~
(c) The preparation of tablets containing diosgenin B-D-glucoside:
A slurry, prepared by mixing 9co g lactose with a hot solutioll of 1,25 g diosgenin glucoside in 1 1 chloroform, i9 dried at room temperature and under a vacuum with constant agitation. The powdered product is then thoroughly mixed with 2,1 kg potato starchO The impregnated lactose-starGh mixt~re i~ granulated by treating it with 2,5 1 of an aqueous solution containing 250 g geiatine and 5 g glycerine. The granulate, dried under reduced pressure at room temperature is converted by kno~n methods into ~oo mg *ablets~ Each table* then con~ainq o,15 mg diosgenin ~-D-glucoside, llo,56 mg lac-tose, 257~97 mg potato starch, 30,31 mg gelatine ~nd o,61 mg glycerine.
(d) The preparation of hecog~enin ~-D_~lucoside con~aining dragee~.
A slurry prepared by mixing 1850 S lactose, 300 g ~ucrose and a hot ~olution of 450 mg hecogenin gluooside in 2 1 chloroform is dricd under a vacuum at 30C.
The powdered product is granulated by knol~n me*hods by adding 1,6 1 of an aqueous solution of 40 g gelatineO The granulate, dried under reduced pressure at ~C and thoroughly l~ixed with lo g magnesium ; stearate, is con~erted into 3000 pressed Xernels which are finally coated to produce drasees.
Every dragée th0n contains o,l5 mg hecogenin ~-D-$1ucoside, 616,67 mg lactose, loo,oo mg sucrose, 13,33 mg gelatine and 3,33 mg magneslwn stearate.
(e) Preparation o~ an ointment containing hecogenin ~-D glucoside:
~ ~ .
' , To a mixture of 1 g hecogenin glucoside worked into emulsifying 90 g cetyl alcohol is added 105 g viscous paraffin and 105 g white Vaseline* before melting the complete mi~ture on a 60C waterbath. Into this melt is stirred 699 g water in small portions at a time. The final mixture is stirred until cold to provide an ointment containing 0,1% glucoside.
(f) Preparation of a cream containing tigogenin ~-D-glucoside:
500 g woolwax alcohol into which 1 g tigogenin glucoside has been incorporated is heated to about 50C on a water bath. To the resulting melt 499 g water is added in small portions with constant stirring. The final cream is stirred until it reaches room temperature; during this process sufficient water is added to replace evaporation losses. This cream contains 0,1% glucoside.
Similarly the other compounds mentioned may be incorporated into pharmaceutical preparations.
E~ample 4 Production of pharmaceutically acceptable solutions (a) Solution having a content of semisynthetic Soya Sterol-~ D-Glucoside There was added to a boiling solution of 600 mg of semi-synthetic soya sterol-~-D-~lucoside in 6 liters of absolute ethanol a solution of 10 grams o~ polyvinyl pyrrolidone in 4 liters of distilled water having a temperature of 65C. The cooled 60%
ethanolic solution was filled with 250 ml flasks. The patients were directed .
*Trade mark ~ Cl .
.
, .~ . .
.
3~
to receive one-half teaspoon corresponding to 2,5 ml of this mixture 3 times a day.
The total solution yielded 40 250 ml flasks, each of ~hich held about lvo dose~ of 2,5 ~1 and therefore w~s sufficient fo~ a treatment of about 33 day~.
Each teaspoon having a content of 2,5 ml had a content of o,15 mg sterolins, 2,5 mg PYP and 1,5 ml ethanol.
It should be obser~ed that concentrations of over o,o75 ~g of sterolins and 1 mg of PVP for each loo ~1 of 60% aqueous ethanol should not be exceeded if clear sslutions are decired~ i.e., that about o,l875 mg of sterolins per 2,5 ml of aqueou~ 60fi ethanol is the maximum dose for a clear solution.
According to the described proce~s the~e c~. also be produced solutions of sterol monoglycosides or ~onoglu~osides. Of course, all of these compounds ha~e low ~olubilities so that these solu*ions according to the described method~ should n~t be expoced to low temperature~ to pre~ent turbidity.
(b) Solutions containing semisynthetic sit~s~erol-¢-U-Maltoside.
800 mS of sitocterol-~-D-maltoside uere dissol~ed in a mi~ture of 3 liters of ethanol and 7 liters of water at gentle reflllx. The cooled 30% aqueous ethanvl solu~ion was then filled into 250 ml flasks. The patients were directed to receiYe 2,5 ml o~ this solution 3 times ~ail~ (accordin$ to the size thereof of one-half or an entire teaspoon full).
. , .
':
' . ': ,. ': , : ' .: :
. . . : :
. .
:
-~ - 16 The total solution yielded 40 250 ml flasks, each of ~ic~ held about loo doses of 2, 5 ml, so that ths total amount wa~3 sufficien* for a trea*m~nt of about 33 days. 2,5 ml of the s<,lution contained o,2 mg sterolins and o,75 ml of ethanol.
According to the de~cribed process there can also be procluced solutions of other ~terol dis~ccharides.
The water solubility of the ~-D-maltoside, the ~-D-lactoside, and the ~-D-celIobioside of sitosterol are respectively o,38 mg, o~21 mg and o, 75 mg psr ml of ~ater at a temperatuxe of 24 C. This soIubility is a~ove the preferred individual do~es employed of the compounds.
p~ e~, recA, The ~IY~ Y~i~ i~dividual dose employed for st~rol disaccharides is o,2 mg, therefore o,'~ m~ per day.
It-is therefore indicated that o*her pharmaceutically e~fecti~e co~pounds can ~lso be worked into the solution~
together with the ~terol disaccharides. Furthermore, the ; alcohol content of these sterolin solutions can be changed; in a given case alqo other pharmaceutically unobjectionable solvent~ can be used. Furthermore, ~
there can also be used pure water as the sole solvent.
.
According to the described method the spiroketal-steroidglycosides can also be wor~ed up into pharma cautical'y acceptabl~ solutions.
_xample_5 ; Pharmacological testin~ o~ sterolins and spiroketal-stero d5lycosides.
(a) Toxicit,~ testin~_of s~erolins.
In the testi11$ of the ac~te toxicity with rats, mice, , , . . . : , . : :
, : .. . . : ~ :
:
:
rabbits, dogs and primates by oral administration of e.g., sitosterol-~-3-glucoside even in doses of 1 to 2 grams/kg of body weight no toxic effects were ascertained. Also, in administration over a long period of time of daily doses of 100 to 200 mg/kg of body weight with these animal species there could not be detected toxicity and also no gout-like appearances so that the tolerance can be designated as good.
Example 6 Proof of activity of PGS inhibitor The activity of the compounds as PGS inhibitor was proved according to the method described by A.L. Willis. Conditions of trial are described for example in Proceedings of a Workshop held during the VIIIth European Dermatology Congress Helsinki 1975.
Siliconized cuvettes of the aggregometer are used at a temperature of 37C as incubation vessels in which an arachidonate solution was rapidly stirred with a PG synthetase enzyme system, usually from sheep vesicular gland. To this solution in the cuvette there is added anticoagulated platelet-rich plasma, previously warmed to 37C. Light trarlsmission through the cuvet-te was recorded immediately after addition. The comparison sample showed a significant peak in the platelet aggregation after 45 seconds of incubation time which proved the formation of PGE2 and PGF2 and the corresponding platelet aggregation.
In the test samples containing 0,00001~ sterolglycoside , , .
. ~
~ ~ .
;.' . , , ~:
' :
~ $
or spiroketal-steroidglycoside no platelet aggre$ation occurred. This clearly shows that the formation of PGs via endo-peroxide compotmds from arachidonate was inhibited.
Example 7 It had previously been established that PGs, PGE2 and PG~2~ as t~ell as the endoperoxide precursors play an important role in the initiating of rheumatoid arthritis.
Therefore, the activity of the compoullds of the invention as PGS inhibitors had been tested in pharmacological trials.
When comparing arthritis based on experim~n~al erysipeloid of for example r~ts with human rheun~ati~ arthr:itis an extensi~e correspondence of the morphological c~anges can be observedO The tests had been ~ade according to the publication of Schulz et al. BeitrOPath. 154, 1-26, 27-51 (1975). The a~t'hritis of rats caused by erysipeloid can be reproducl~d with nearly loo ~ercent ; effectiveness ~ith a single injection. In case of arthritis caused by erysipeloid always more than 6 joints of the limbs are ~ransforlned and namely big and small joints of the limbs in the sam manner.
~ith experimental erysipeloid all animals exhibit extensively proliferati~e transfo~mations eYen after 3 months.
. , In the test of the compounds the following parameters of the mani~`estation~hase had been ~sed for estimating the actlvity oi the compound:
.~ ;d ' .
'' ''' ' ~ ' .' ' '' " ,' ' ' ' .
. ~ , .
''.
:
$
aw volume The arthriti~ of rats i~ characterized in animals with a body weight of 150 g after the third day, with a body weight of 200 g after the 5 h day by an extensi~e periarticular edema.
Xidney (protein secrection) Nephro~es caused by r.licrothrombes can occur in 30 to 40 percent of the animals during 7 to 8 day.
( Inflammations of the cornea ~turbidity~ about 8th day ;
xternal genital~, tip o~ tail Necro~e-~ cau~ed by thrombes about 6th to 8th day.
Aorta With rats fibrine-rich thrombes occur about 6 h to
The compounds of the invention can be used in corresponding manner to treat animal diseases. The dosage used in animal diseases can be calculated in a known manner by taking 75 kg as the average human weight.
'' ' ~' The compounds can be prepared in usual way known to the expert as pharmaceutical compositions, e.g. powders, pills, tablets, capsules, dragées, emulsions, solutions, injection - or infusion solutions, ointments or creams.
The invention will be further explained in connection with the examples.
Example 1 Production of Sitosterol-~-D-Glucoside.
A mixture of 41,4 grams of sitosterol and 55,2 grams of silver carbonate in toluene were distilled with stirring until the distillate passed over free of water. Then there was added to the stirred, boiling mixture dropwise a solution of 82,2 grams of acetobromoglucose in 100 ml of toluene. The toluene was continuously further distilled so that the total amount of water formed in the reaction was removed azeotropically. The reaction vessel was protected from light during this time. In case it is necessary, the volume of the reaction mixture is held constant by addition of dry toluene. After the addition of the bromo-acetoglucose solution it was maintained at the boiling point until the distillate was water free. Subsequently the reaction mixture was filtered and the residue washed with fresh hot toluene. The united filtrate and washing liquids were then evaporated under reduced pressure. The residue was recrystallized from ethanol or hexane. The yield of sitosterol glucoside tetraacetate was 22~4 grams, corresponding to 30%.
A solution of 1 gram of sodium in 100 ml of ethanol :
under stirring was added quickly to a solution of 10 grams sitosterol glucoside tetraacetate in 600 ml ethanol at a temperature of 45C. The mixture was stirred for one hour before 2 liters of water were added and the mixture was then stirred for another hour. The precipitated sitosterol glucoside was filtered off and washed until neutral with water prior to drying it for 12 hours in a vacuum. The yield was 6,0 grams, corresponding to 95%.
By selection of suitable starting compounds all the remaining mentioned sterolins also can be produced according to the above given process.
_xample 2 S~nthesis of diosgenin-3-~-D-glucoside.
A well stirred mixture of 55,2 g silver carbonate and a solution of 41,4 g diosgenin in 600 ml toluene was distilled unti~
the collecting distillate was free of water. A solution of 82,2 g bromoacetylglucose in 100 ml toluene was then added dropwise to the stirred mixture, boiling continuing all the time with distillation in order to remove the water formed during the glucosidation reaction. At this stage the reaction vessel is protected from light and the volume of the reaction mixture is kept constant at about 500 ml by adding extra dry toluene whenever necessary. After the acetobromoglucose addition has been completed distillation is continued until no further water separates from the condensate. The reaction mixture is then filtered hot and the residue is washed with fresh, hot toluene~ The combined filtrate and wash solutions are evaporated to dryness under vacuum and the reSldUe lS
, .
crystallised from ethanol or hexane. The yield of diosgenin-3-~-D~$1ucoside tetraacetate l~a~ 25,5 g or 3~.3%
To a stirred solution of lo g diosgenîn tetraacetate in 600 ml ethanol At ~5 C i9 rapidly added 15 ml of an ethanolic solution of 1 g sodium in loo ml abs. ethanol~ The stirred mixture is allowed $o react for 1 hour bsfore 2 1 water is added and this mixture i~ then stirred for a further hour. The precipitated diosgenin glucoside i~ then filtered off and washed to neutrality ~ith water before it is dried under vacu~ at looC for 12 hours. The yield was 7 g or 90%.
Similarly the further spiroketal-steroid-glycGsides can be prepared.
. .
~xample 3 The_preparation of .pharmaceutical products.
~a) The preparation of lact:ose-corn starch powders incorpor~ting diosgenirL-~-D-glucoside:
A boiling ho* solut~8.n of 15 g di~sgenin glucoside in 2,25 1 chloroforn~ and 750 ml ethanol i~ mixed with 1 ~g lactose powder of a particle si~e no*
exceedin~ o,15 mm. The resulting slurry is dried ~ith constant stirring and the impregnated lactose is ~educed to its original particle ~ize before it is mixed ~ith 9 kg corn starch and 50 g maglles.ium stearate. Capæules are rcadil~ filled with this mixture. ~hus a capsule containing l~o mg of the ~ixt-lre l~ill ca.rry approximately o,15 mg diosgenin~
D-glucoæi~le, lo ms of lactose, 90 mg of corll starch a~ well as o,5 mg of magneæium stearate.
(b3 The preparation of lacto~e granu~¢es containing diosgenln-~3-D-glucoside:
A boi].ing hot solution of 5 g diosgenin glucoside in 5 1 ethanol is mixed with 3,32 k~ of a particle ~ize not exceeding o,15 mm. The agi.tated slurry i5 dried and the impregnated lactose i5 then r~duced to the original particle size before it is converted into granules of o,7-1-2 mm particle sizes. This granula~ed product i~ al~o suitable ~or filling into capsules, where for example a capsule contain~ng loo mg granulate carries o,15 mg diogenin-~-D-glucoside.
Produc*s as de3cribed under a) and b) can also be prepared using the fol~owing: ~
' i) Glyeo~ide~ of the mentioned ~ydrox~spiroke~al-~teroids and especially the ~-D-gluco.sides of ~`igogenin and Hecosenin, il) gluco~e, ascorbic acid or t~lc as carrier~ for the glycosides or any other inert and pharmace~.ically acceptable carrier, iii) the contents of actiYe glycoside in each cap~ule can be adju~ted to any ~alue between o,ol and more,~
i~) the auxilliary sub~tances described in a) and b) can be altered to accepted pharmaceutical prace~ces, . v) at each stage of the production process described under a3 and b3 other pharmaceutically actiYe ~ubstan^es can be added and incorporated into the iinal product.
, .
.
.
. .
- 13 ~ 3~ ~
(c) The preparation of tablets containing diosgenin B-D-glucoside:
A slurry, prepared by mixing 9co g lactose with a hot solutioll of 1,25 g diosgenin glucoside in 1 1 chloroform, i9 dried at room temperature and under a vacuum with constant agitation. The powdered product is then thoroughly mixed with 2,1 kg potato starchO The impregnated lactose-starGh mixt~re i~ granulated by treating it with 2,5 1 of an aqueous solution containing 250 g geiatine and 5 g glycerine. The granulate, dried under reduced pressure at room temperature is converted by kno~n methods into ~oo mg *ablets~ Each table* then con~ainq o,15 mg diosgenin ~-D-glucoside, llo,56 mg lac-tose, 257~97 mg potato starch, 30,31 mg gelatine ~nd o,61 mg glycerine.
(d) The preparation of hecog~enin ~-D_~lucoside con~aining dragee~.
A slurry prepared by mixing 1850 S lactose, 300 g ~ucrose and a hot ~olution of 450 mg hecogenin gluooside in 2 1 chloroform is dricd under a vacuum at 30C.
The powdered product is granulated by knol~n me*hods by adding 1,6 1 of an aqueous solution of 40 g gelatineO The granulate, dried under reduced pressure at ~C and thoroughly l~ixed with lo g magnesium ; stearate, is con~erted into 3000 pressed Xernels which are finally coated to produce drasees.
Every dragée th0n contains o,l5 mg hecogenin ~-D-$1ucoside, 616,67 mg lactose, loo,oo mg sucrose, 13,33 mg gelatine and 3,33 mg magneslwn stearate.
(e) Preparation o~ an ointment containing hecogenin ~-D glucoside:
~ ~ .
' , To a mixture of 1 g hecogenin glucoside worked into emulsifying 90 g cetyl alcohol is added 105 g viscous paraffin and 105 g white Vaseline* before melting the complete mi~ture on a 60C waterbath. Into this melt is stirred 699 g water in small portions at a time. The final mixture is stirred until cold to provide an ointment containing 0,1% glucoside.
(f) Preparation of a cream containing tigogenin ~-D-glucoside:
500 g woolwax alcohol into which 1 g tigogenin glucoside has been incorporated is heated to about 50C on a water bath. To the resulting melt 499 g water is added in small portions with constant stirring. The final cream is stirred until it reaches room temperature; during this process sufficient water is added to replace evaporation losses. This cream contains 0,1% glucoside.
Similarly the other compounds mentioned may be incorporated into pharmaceutical preparations.
E~ample 4 Production of pharmaceutically acceptable solutions (a) Solution having a content of semisynthetic Soya Sterol-~ D-Glucoside There was added to a boiling solution of 600 mg of semi-synthetic soya sterol-~-D-~lucoside in 6 liters of absolute ethanol a solution of 10 grams o~ polyvinyl pyrrolidone in 4 liters of distilled water having a temperature of 65C. The cooled 60%
ethanolic solution was filled with 250 ml flasks. The patients were directed .
*Trade mark ~ Cl .
.
, .~ . .
.
3~
to receive one-half teaspoon corresponding to 2,5 ml of this mixture 3 times a day.
The total solution yielded 40 250 ml flasks, each of ~hich held about lvo dose~ of 2,5 ~1 and therefore w~s sufficient fo~ a treatment of about 33 day~.
Each teaspoon having a content of 2,5 ml had a content of o,15 mg sterolins, 2,5 mg PYP and 1,5 ml ethanol.
It should be obser~ed that concentrations of over o,o75 ~g of sterolins and 1 mg of PVP for each loo ~1 of 60% aqueous ethanol should not be exceeded if clear sslutions are decired~ i.e., that about o,l875 mg of sterolins per 2,5 ml of aqueou~ 60fi ethanol is the maximum dose for a clear solution.
According to the described proce~s the~e c~. also be produced solutions of sterol monoglycosides or ~onoglu~osides. Of course, all of these compounds ha~e low ~olubilities so that these solu*ions according to the described method~ should n~t be expoced to low temperature~ to pre~ent turbidity.
(b) Solutions containing semisynthetic sit~s~erol-¢-U-Maltoside.
800 mS of sitocterol-~-D-maltoside uere dissol~ed in a mi~ture of 3 liters of ethanol and 7 liters of water at gentle reflllx. The cooled 30% aqueous ethanvl solu~ion was then filled into 250 ml flasks. The patients were directed to receiYe 2,5 ml o~ this solution 3 times ~ail~ (accordin$ to the size thereof of one-half or an entire teaspoon full).
. , .
':
' . ': ,. ': , : ' .: :
. . . : :
. .
:
-~ - 16 The total solution yielded 40 250 ml flasks, each of ~ic~ held about loo doses of 2, 5 ml, so that ths total amount wa~3 sufficien* for a trea*m~nt of about 33 days. 2,5 ml of the s<,lution contained o,2 mg sterolins and o,75 ml of ethanol.
According to the de~cribed process there can also be procluced solutions of other ~terol dis~ccharides.
The water solubility of the ~-D-maltoside, the ~-D-lactoside, and the ~-D-celIobioside of sitosterol are respectively o,38 mg, o~21 mg and o, 75 mg psr ml of ~ater at a temperatuxe of 24 C. This soIubility is a~ove the preferred individual do~es employed of the compounds.
p~ e~, recA, The ~IY~ Y~i~ i~dividual dose employed for st~rol disaccharides is o,2 mg, therefore o,'~ m~ per day.
It-is therefore indicated that o*her pharmaceutically e~fecti~e co~pounds can ~lso be worked into the solution~
together with the ~terol disaccharides. Furthermore, the ; alcohol content of these sterolin solutions can be changed; in a given case alqo other pharmaceutically unobjectionable solvent~ can be used. Furthermore, ~
there can also be used pure water as the sole solvent.
.
According to the described method the spiroketal-steroidglycosides can also be wor~ed up into pharma cautical'y acceptabl~ solutions.
_xample_5 ; Pharmacological testin~ o~ sterolins and spiroketal-stero d5lycosides.
(a) Toxicit,~ testin~_of s~erolins.
In the testi11$ of the ac~te toxicity with rats, mice, , , . . . : , . : :
, : .. . . : ~ :
:
:
rabbits, dogs and primates by oral administration of e.g., sitosterol-~-3-glucoside even in doses of 1 to 2 grams/kg of body weight no toxic effects were ascertained. Also, in administration over a long period of time of daily doses of 100 to 200 mg/kg of body weight with these animal species there could not be detected toxicity and also no gout-like appearances so that the tolerance can be designated as good.
Example 6 Proof of activity of PGS inhibitor The activity of the compounds as PGS inhibitor was proved according to the method described by A.L. Willis. Conditions of trial are described for example in Proceedings of a Workshop held during the VIIIth European Dermatology Congress Helsinki 1975.
Siliconized cuvettes of the aggregometer are used at a temperature of 37C as incubation vessels in which an arachidonate solution was rapidly stirred with a PG synthetase enzyme system, usually from sheep vesicular gland. To this solution in the cuvette there is added anticoagulated platelet-rich plasma, previously warmed to 37C. Light trarlsmission through the cuvet-te was recorded immediately after addition. The comparison sample showed a significant peak in the platelet aggregation after 45 seconds of incubation time which proved the formation of PGE2 and PGF2 and the corresponding platelet aggregation.
In the test samples containing 0,00001~ sterolglycoside , , .
. ~
~ ~ .
;.' . , , ~:
' :
~ $
or spiroketal-steroidglycoside no platelet aggre$ation occurred. This clearly shows that the formation of PGs via endo-peroxide compotmds from arachidonate was inhibited.
Example 7 It had previously been established that PGs, PGE2 and PG~2~ as t~ell as the endoperoxide precursors play an important role in the initiating of rheumatoid arthritis.
Therefore, the activity of the compoullds of the invention as PGS inhibitors had been tested in pharmacological trials.
When comparing arthritis based on experim~n~al erysipeloid of for example r~ts with human rheun~ati~ arthr:itis an extensi~e correspondence of the morphological c~anges can be observedO The tests had been ~ade according to the publication of Schulz et al. BeitrOPath. 154, 1-26, 27-51 (1975). The a~t'hritis of rats caused by erysipeloid can be reproducl~d with nearly loo ~ercent ; effectiveness ~ith a single injection. In case of arthritis caused by erysipeloid always more than 6 joints of the limbs are ~ransforlned and namely big and small joints of the limbs in the sam manner.
~ith experimental erysipeloid all animals exhibit extensively proliferati~e transfo~mations eYen after 3 months.
. , In the test of the compounds the following parameters of the mani~`estation~hase had been ~sed for estimating the actlvity oi the compound:
.~ ;d ' .
'' ''' ' ~ ' .' ' '' " ,' ' ' ' .
. ~ , .
''.
:
$
aw volume The arthriti~ of rats i~ characterized in animals with a body weight of 150 g after the third day, with a body weight of 200 g after the 5 h day by an extensi~e periarticular edema.
Xidney (protein secrection) Nephro~es caused by r.licrothrombes can occur in 30 to 40 percent of the animals during 7 to 8 day.
( Inflammations of the cornea ~turbidity~ about 8th day ;
xternal genital~, tip o~ tail Necro~e-~ cau~ed by thrombes about 6th to 8th day.
Aorta With rats fibrine-rich thrombes occur about 6 h to
11 day at the intima of the aorta. The largest spac~ covered i~ about 8~h day.
: ., ... . .
: : .. .. ., .. : . .
:
,. . :,:
Male wistar rats with a body weight of 150 to 180 g were used for the tests. The animals had been kept in single cages and received a rat standard diet (Ssniff R) and water ad libitum.
The room temperature was constantly 22C, the relative air humidity 50-60%. The daily illumination time was 12 hours.
Prior to the beginning of the tests the animals had an acclimatization period of 10 days.
The infection was carried out with the erysipeloid strain T 28. The dosage was 2 ml s.c. (about 100 200 millions germs).
The compounds to be tested had been suspended in sterile saline solution and had been injected i.p. in a dosage of 5 mg/kg body ; weight. The treatment was 5 times per week from infection day to end of test or death of animal.
The evaluation of the characterizing aorta thrombes showed the following results sitosterolglucoside: 2,00 hecogeninglucoside : 1,38 diosgeninglucoside : 1,33.
.
. , ' : ` '
: ., ... . .
: : .. .. ., .. : . .
:
,. . :,:
Male wistar rats with a body weight of 150 to 180 g were used for the tests. The animals had been kept in single cages and received a rat standard diet (Ssniff R) and water ad libitum.
The room temperature was constantly 22C, the relative air humidity 50-60%. The daily illumination time was 12 hours.
Prior to the beginning of the tests the animals had an acclimatization period of 10 days.
The infection was carried out with the erysipeloid strain T 28. The dosage was 2 ml s.c. (about 100 200 millions germs).
The compounds to be tested had been suspended in sterile saline solution and had been injected i.p. in a dosage of 5 mg/kg body ; weight. The treatment was 5 times per week from infection day to end of test or death of animal.
The evaluation of the characterizing aorta thrombes showed the following results sitosterolglucoside: 2,00 hecogeninglucoside : 1,38 diosgeninglucoside : 1,33.
.
. , ' : ` '
Claims (7)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A pharmaceutical preparation in unit dosage form, active as a PGS inhibitor, comprising from about 0.01 to 10 mg. per dosage unit of a glycoside selected from sterol glycosides and esters thereof and spiroketal-steroid glycosides and esters thereof, in a pharmaceutically acceptable carrier.
2. A preparation according to claim 1 wherein the amount of said glycoside per dosage unit is from about 0.033 to 0.45 mg.
3. A preparation according to claim 1 wherein the dosage units contain said glycoside in solid particulate form having a particle size of less than 0.1 mm in diameter.
4. A preparation according to claim 2 wherein the dosage units contain said glycoside in solid particulate form having a particle size of less than 0.06 mm in diameter.
5. A preparation according to claims 2, 3 or 4 wherein the glycoside is selected from the glycosides of tall oil sterols, sito-sterol, ergosterol, cholesterol, 5.alpha.-cholesterol, lanosterol, 24,25-dihydrolanosterol, stigmasterol and/or soybeansterols.
6. A preparation according to claims 2, 3 or 4 wherein the glycoside is selected from sitosterol .beta.-D-galactoside, .beta.-D-maltoside, .beta.-D-lactoside and .beta.-D-cellobioside.
7. A preparation according to claims 2, 3 or 4 wherein the glycoside is selected from the glycosides of diosgenin, hecogenin and tigogenin.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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DE19772759171 DE2759171A1 (en) | 1977-12-31 | 1977-12-31 | MEDICINAL PRODUCTS WITH EFFECT AS PROSTAGLANDIN SYNTHETASE INHIBITOR |
DEP2759171 | 1977-12-31 |
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CA318,817A Expired CA1113006A (en) | 1977-12-31 | 1978-12-29 | Medicine with activity as prostaglandin-synthetase inhibitor |
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JP (1) | JPS54101436A (en) |
AR (1) | AR223334A1 (en) |
AU (1) | AU516933B2 (en) |
BE (1) | BE873222A (en) |
CA (1) | CA1113006A (en) |
CH (1) | CH637829A5 (en) |
DE (1) | DE2759171A1 (en) |
DK (1) | DK587778A (en) |
ES (1) | ES476443A1 (en) |
FR (1) | FR2425859A1 (en) |
GB (1) | GB2039217B (en) |
IL (1) | IL56345A (en) |
IT (1) | IT1109336B (en) |
LU (1) | LU80739A1 (en) |
NL (1) | NL7812656A (en) |
NZ (1) | NZ189297A (en) |
PT (1) | PT69012A (en) |
SE (1) | SE466683B (en) |
ZA (1) | ZA787399B (en) |
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DE2926463A1 (en) * | 1978-07-05 | 1980-01-24 | Roecar Holdings Nv | SPIROKETALINE AND THEIR USE |
JPS5874619A (en) * | 1981-10-29 | 1983-05-06 | Nippon Shinyaku Co Ltd | Liposome and its preparation |
IE54837B1 (en) | 1982-04-19 | 1990-02-28 | Roecar Holdings Nv | Extract of plants of the family of hypoxidaceae for treatment of cancer |
US4602003A (en) * | 1982-05-17 | 1986-07-22 | Medical Research Foundation Of Oregon | Synthetic compounds to inhibit intestinal absorption of cholesterol in the treatment of hypercholesterolemia |
US4602005A (en) * | 1982-05-17 | 1986-07-22 | Medical Research Foundation Of Oregon | Tigogenin cellobioside for treating hypercholesterolemia and atherosclerosis |
DE3401178A1 (en) * | 1984-01-14 | 1985-07-18 | Roecar Holdings (Netherlands Antilles) N.V., Willemstad, Curacao, Niederländische Antillen | USE OF PHYTOSTEROL GLYCOSIDES FOR TREATING INCREASED 5 (6) (ALPHA) EPOXICHOLESTEROL LEVELS |
DE3416112A1 (en) * | 1984-04-30 | 1985-10-31 | Roecar Holdings (Netherlands Antilles) N.V., Willemstad, Curacao, Niederländische Antillen | USE OF STEROLINES AND SPIROKETALINES AS LIPOXYGENAS REGULATORS |
DE3829641A1 (en) * | 1988-09-01 | 1990-03-15 | Roecar Holdings Nv | TRANSDERMAL APPLICABLE PHARMACEUTICAL PREPARATIONS WITH STEROLINES AND / OR SPIROKETALINES |
US5166194A (en) * | 1988-09-01 | 1992-11-24 | Roecar Holdings | Transdermally applicable pharmaceutical preparations having a pharmaceutically usable glycoside content |
DE3829643A1 (en) * | 1988-09-01 | 1990-03-15 | Roecar Holdings Nv | PHYTO AND ZOOSTEROLS AND THEIR DERIVATIVES WITH IMPROVED WATER SOLUBILITY |
DE3829640C1 (en) * | 1988-09-01 | 1990-04-26 | Roecar Holdings (Netherlands Antilles) N.V., Willemstad, Curacao, Niederlaendische Antillen, Nl | |
DE3838716A1 (en) * | 1988-11-15 | 1990-05-17 | Kanoldt Arzneimittel Gmbh | MEDICINAL PRODUCTION OF ESTER DERIVATIVES OF HECOGENINE AND ITS USE FOR THE TREATMENT OF BENIGNER PROSTATE HYPERPLASIA |
US5502038A (en) * | 1993-06-21 | 1996-03-26 | Medical Research Foundation Of Oregon | Cholesterol sequestrant glycosides that inhibit intestinal cholesterol absorption |
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IE35018B1 (en) * | 1970-03-18 | 1975-10-15 | Liebenberg R W | Therapeutic agent |
US3966918A (en) * | 1973-12-12 | 1976-06-29 | Nippon Shinyaku Co., Ltd. | Method of preparing aqueous solutions of sterol glycosides and their ester derivatives |
JPS51118817A (en) * | 1975-04-08 | 1976-10-19 | Nippon Shinyaku Co Ltd | A process for preparing absorbable steroid glycoside pharmaceutical |
-
1977
- 1977-12-31 DE DE19772759171 patent/DE2759171A1/en active Granted
-
1978
- 1978-12-28 AR AR274988A patent/AR223334A1/en active
- 1978-12-28 ES ES476443A patent/ES476443A1/en not_active Expired
- 1978-12-28 ZA ZA787399A patent/ZA787399B/en unknown
- 1978-12-29 GB GB7850259A patent/GB2039217B/en not_active Expired
- 1978-12-29 CA CA318,817A patent/CA1113006A/en not_active Expired
- 1978-12-29 IL IL56345A patent/IL56345A/en not_active IP Right Cessation
- 1978-12-29 AU AU43024/78A patent/AU516933B2/en not_active Expired
- 1978-12-29 DK DK587778A patent/DK587778A/en not_active Application Discontinuation
- 1978-12-29 PT PT69012A patent/PT69012A/en unknown
- 1978-12-29 BE BE192687A patent/BE873222A/en not_active IP Right Cessation
- 1978-12-29 JP JP16443078A patent/JPS54101436A/en active Pending
- 1978-12-29 LU LU80739A patent/LU80739A1/en unknown
- 1978-12-29 CH CH1330878A patent/CH637829A5/en not_active IP Right Cessation
- 1978-12-29 FR FR7836823A patent/FR2425859A1/en active Granted
- 1978-12-29 IT IT52493/78A patent/IT1109336B/en active
- 1978-12-29 NL NL7812656A patent/NL7812656A/en not_active Application Discontinuation
- 1978-12-29 SE SE7813443A patent/SE466683B/en not_active IP Right Cessation
-
1979
- 1979-01-04 NZ NZ189297A patent/NZ189297A/en unknown
Also Published As
Publication number | Publication date |
---|---|
JPS54101436A (en) | 1979-08-10 |
GB2039217B (en) | 1982-08-04 |
IL56345A (en) | 1984-11-30 |
LU80739A1 (en) | 1980-01-22 |
AU516933B2 (en) | 1981-07-02 |
ZA787399B (en) | 1980-01-30 |
IT7852493A0 (en) | 1978-12-29 |
AU4302478A (en) | 1979-07-05 |
SE466683B (en) | 1992-03-23 |
AR223334A1 (en) | 1981-08-14 |
ES476443A1 (en) | 1979-10-16 |
NZ189297A (en) | 1984-10-19 |
BE873222A (en) | 1979-06-29 |
IT1109336B (en) | 1985-12-16 |
DE2759171C2 (en) | 1990-10-25 |
FR2425859A1 (en) | 1979-12-14 |
SE7813443L (en) | 1979-07-01 |
DK587778A (en) | 1979-07-01 |
NL7812656A (en) | 1979-07-03 |
IL56345A0 (en) | 1979-03-12 |
DE2759171A1 (en) | 1979-07-12 |
GB2039217A (en) | 1980-08-06 |
CH637829A5 (en) | 1983-08-31 |
FR2425859B1 (en) | 1983-04-08 |
PT69012A (en) | 1979-01-01 |
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MKEX | Expiry |