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WO1993009129A1 - Composes de triterpene presentant une activite anti-inflammatoire - Google Patents

Composes de triterpene presentant une activite anti-inflammatoire Download PDF

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Publication number
WO1993009129A1
WO1993009129A1 PCT/AU1992/000590 AU9200590W WO9309129A1 WO 1993009129 A1 WO1993009129 A1 WO 1993009129A1 AU 9200590 W AU9200590 W AU 9200590W WO 9309129 A1 WO9309129 A1 WO 9309129A1
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WO
WIPO (PCT)
Prior art keywords
amyrin
compound
adjuvant
rats
general formula
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.)
Ceased
Application number
PCT/AU1992/000590
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English (en)
Inventor
George Kweifio-Okai
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
RMIT University
Melbourne Institute of Technology
Original Assignee
Royal Melbourne Institute of Technology Ltd
Melbourne Institute of Technology
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Royal Melbourne Institute of Technology Ltd, Melbourne Institute of Technology filed Critical Royal Melbourne Institute of Technology Ltd
Priority to AU39101/93A priority Critical patent/AU670583B2/en
Publication of WO1993009129A1 publication Critical patent/WO1993009129A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids

Definitions

  • This invention relates to triterpene compounds having antiinflammatory activity. More specifically, this invention relates to novel derivatives of the triterpene, ⁇ -amyrin, which have been found to have useful antiinflammatory activity, particularly antiarthritic activity, and to the use of ⁇ -amyrin itself and of these novel derivatives in antiinflammatory and more especially antiarthritic treatment of human or animal patients.
  • a water or alcoholic extract of Alstonia boonei root barks, Rauvolfia vomitoria root barks and Elaies guineensis nuts without pericarp is used as a herbal cure for arthritis in Ghana, and previous studies have shown that the extract was effective in reducing swelling in acute and chronic models of inflammation (Kweifio-Okai, 1991 a and b).
  • Alstonia boonei is the major plant constituent of the herbal preparation responsible for the antiarthritic effect (Dalziel, 1937) and some of the triterpene constituents of the root barks (Faparusi and Bassir, 1972) have been shown to be antiinflammatory, antiarthritic and antiproteolytic (Gupta et.al. 1969 and 1971; Chaudhari et. ⁇ l, 1974; Chaturvedi et.al 1914).
  • CFA complete Freund's adjuvant
  • pannus a granulomatous outgrowth of synovia! tissue called pannus invades and destroys joints in adjuvant rats.
  • pannus formation occurs 5-10 days after adjuvant inoculation (Pearson and Wood, 1963), and therefore testing was performed from days 11 to 19 postadjuvant, i.e. therapeutically rather than prior to or during the induction of arthritis. It was considered that this mode of testing was more practical and would eliminate drugs which could well inhibit arthritis in the developmental stages but without effect on established arthritis (Glenn et.al, 1977).
  • R represents an acyl group derived from a long chain fatty acid.
  • the compounds of general formula I are provided in substantially pure form.
  • substantially pure is meant at least 75%, preferably at least 85%, and more preferably at least 95%, pure.
  • the acyl group is derived from a fatty acid having 10 or more carbon atoms. Such fatty acids include both saturated and unsaturated acids,
  • acyl group of the invention is derived from palmitic acid.
  • this invention extends to a method of antiinflammatory and more especially antiarthritic treatment of a human or animal patient, which comprises administering to said patient an effective amount of a compound of the general formula II in substantially pure form:
  • R 1 represents hydrogen or an acyl group derived from a long chain fatty acid, preferably a fatty acid having 10 or more carbon atoms as described above.
  • the invention further extends to the use of a compound of the general formula II in substantially pure form in the manufacture of a medicament for antiinflammatory and more especially antiarthritic use.
  • the present invention also provides a pharmaceutical composition for antiinflammatory and more especially antiarthritic use, comprising a compound of the general formula II in substantially pure form, together with a pharmaceutically acceptable carrier or diluent.
  • the preferred compound of the present invention, ⁇ -amyrin palmitate has been shown to reduce ankle swelling caused by the subplantar injection of complete Freund's adjuvant.
  • the drug was given orally daily at 56mg/kg body weight from days 11 to 19 postadjuvant and therefore the effect observed was that on established arthritis.
  • the reduction in ankle swelling was about 32% whether the ankle diameters were compared after 6 days of administration or over the entire period of administration using regression analyses.
  • Pannus would have been present by day 11 of adjuvant (Pearson and Wood, 1963) after the compound was administered, after which the compound caused no further increases in ankle diameter. There is histological evidence that this compound prevented further pannus growth, infiltration and destruction of the joints in adjuvant rats.
  • ⁇ -amyrin and lipid esters of ⁇ -amyrin are specific inhibitors of 5-HETE synthesis. Coupled with the knowledge that 5HETE levels increase in the synovial fluid and tissue of patients with rheumatoid arthritis and spondyloarthritis, this finding also suggests that these compounds may be beneficial in antiarthritic therapy.
  • the demonstration of inhibition of 5lipoxygenase activity in human neutrophils is unique in antiarthritic activity - there is no antiarthritic drug in current usage which relies on the inhibition of lipoxygenase activity for antiarthritic effect. Drugs that inhibit only cycloxygenase products of arachidonic acid (the prostaglandins) are limited in their effects because the more potent pro-inflammatory substances are found in lipoxygenase pathways.
  • Antiarthritic agents are often limited by their deleterious effects (Bonta et.al, 1980).
  • liver, kidney and spleen weight changes were followed together with circulating RBC levels to identify possible toxicity of the preferred compound for future studies.
  • the observations that liver and kidney weights did not increase in the presence of this compound would suggest an absence of toxicity.
  • Barritt and Whitehouse (1977) have shown that liver weight could remain unchanged in the presence of functional impairment.
  • Spleen weight increase may primarily account for the moderate anaemia of adjuvant arthritis because the anaemia was normocytic in the absence of liver and kidney weight increases.
  • Figure 1 Percent change in right ankle diameter after 11 days of adjuvant (CFA) and in the presence of the triterpene Iipid ester, ⁇ -amyrin palmitate. Significance of difference of slope from adjuvant control: *P ⁇ 0.05; **P ⁇ 0.001.
  • the triterpenes, ⁇ -amyrin acetate, ⁇ -amyrin acetate, ⁇ -amyrin and lupeol acetate were isolated from the petroleum ether extract of Alstonia boonei de Wild root bark.
  • the crude petroleum ether extract (8g) obtained from a batch of powdered root bark (300g) was separated by vacuum liquid chromatography on silica using petroleum ether/ethyl acetate (9:1).
  • the terpene acetate fraction (4.5g) was further purified by reverse phase h.p.l.c.
  • Control rats did not show any significant changes in injected (ipsilateral) limb ankle diameters during the 19 days of the experiment (Table 1). Similarly there were no changes in contralateral ankle diameters. Adjuvant increased ipsilateral ankle diameters to 94% of preinjection values by day 19 but there was no transfer of adjuvant swelling to the contralateral ankle. The use of older Wistar rats ensured a stable ankle diameter from the beginning of this experiment and a greater response to adjuvant at the ipsilateral limb but as previously (Kweifio-Okai, 1991b) contralateral limb was not nearly as responsive.
  • ankle swelling was statistically similar in the two adjuvant groups, 67 ⁇ 6% in the adjuvant control group and 50+6% in the group which subsequently received the triterpene (Table 1). Histological sections would show that in the range of adjuvant swellings observed in the 2 groups, there was pannus formation and the infiltration of joint (Kweifio-Okai and Bird, unpublished observations).
  • CK091 reduced adjuvant swelling by 20% after 2 days of administration and then after 6 days by an average of 32%.
  • Regression analyses of the rate of ankle diameter change from days 11 to 19 postadjuvant (Fig.1) showed that only in the absence of CK091 was statistical significance of change observed (P ⁇ 0.001) and the slopes were significantly different (P ⁇ 0.05). From the regression analyses, ankle diameter increased by 34% in adjuvant rats and by 3% in the presence of CK091 - reduction of 31 % by CK091.
  • Tabular values represent mean ⁇ S.E.M. changes from 0 time readings, N-5/group.
  • Tabular values represent mean ⁇ S.E.M. Data at day 19 of adjuvant, 8 days after administration of triterpene
  • both treated and untreated arthritic rats had identical serum alkaline phosphatase and Ca + + .
  • serum inorganic phosphate was 17% greater in treated arthritic rats than in control rats and 11% greater than in untreated arthritic rats.
  • Serum hyaluronate increased by 77% in untreated arthritic rats but the 47% increase in treated rats did not reach statistical significance.
  • Table 7 shows that by day 50 of adjuvant arthritis, liver and kidney function were preserved both in the treated and untreated arthritic rats. Serum urea was however reduced by 14% in both treated and untreated arthritic rats but only the decrease in treated rats reached statistical significance. Spleen weight increased in both treated and untreated arthritic rats to about the same extent (30-35%).
  • Biochemical indices of bone metabolism suggested reduced joint inflammation and osteoclastic activity in treated arthritic rats. It has been shown that blood leucocytes, agents for adjuvant joint destruction, and serum hyaluronate which result from articular cartilage degradation increase in clinical and experimental arthritis and are reduced by antiarthritic agents. In the present experiment significant joint inflammation or destruction is implied by the 77% increase in serum hyaluronate on day 50 postadjuvant. Treated rats however, showed reduced and insignificant increases in serum hyaluronate. Blood granulocytes also increased in arthritic rats but the increase in treated rats was not statistically significant.
  • Values are mean ⁇ SEM of 8 rats except where indicated in parenthesis. Significance of difference from normal rats was calculated by students t-test for unpaired variates and given as: x p ⁇ 0.05; xx p ⁇ 0.02; xxx p ⁇ 0.01 ; xxxx p ⁇ 0.002; xxxx x p ⁇ 0.001. Treated rats were orally administered with 66mg/Kg body weight of ⁇ -amyrin palmitate every 48 hrs from days 32 to 40 postadjuvant and assessed on day 50.
  • Kidney weight (g%) 0.66 ⁇ 0.01 0.70 ⁇ 0.02 0.71 ⁇ 0.03
  • ⁇ -amyrin was purchased from ICN (USA) and the chlorides of lauric, myristic, palmitic, stearic, oleic and linoleic acids were purchased from Sigma (USA).
  • DCM dichloromethane
  • pyridine equivalent moles of pyridine
  • the DCM extract was dried over anhydrous sodium sulphate, concentrated to the oil and the oil applied to a SiO 2 preparative plate run on petroleum ether spirit. The appropriate band was then separated and identified by NMR spectroscopic analysis.
  • the 5-lipoxygenase enzyme in human neutrophils catalyses the oxidation of membrane arachidonic acid to 5-HPETE from which 5-HETE and the unstable precursor of the leukotrienes, LTA 4 , are formed (Lewis et al. , 1990; Samuelsson and Funk, 1989). Inhibition of 5-lipoxygenase would be expected to inhibit all the 5-lipoxygenase products measured here. In the present study, inhibition of 5- HETE synthesis was observed to varying degrees without inhibition of LTB 4 synthesis. As shown in Table 8, ⁇ -amyrin and ⁇ -amyrin linoleate showed the greatest and most significant reductions in 5-HETE synthesis (-27% and -63% respectively).
  • LTB 4 but not 5-HETE would suggest that inhibition of LTB 4 is more important in the curtailment of chronic inflammation.
  • 5- HETE primes neutrophils for the expression of cellular functions associated with inflammation such as by augmenting cytosolic calcium and mobilising protein kinase C from cytosol to membrane (Lewis et al., 1990; Samuelsson and Funk, 1989). Therefore, it is suggested that inhibition of 5-HETE synthesis may be relevant in antiarthritic therapy.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Un procédé de traitement anti-inflammatoire, en particulier anti-arthritique, d'un patient humain ou animal consiste à administrer à ce patient une quantité efficace d'un composé de formule générale (II), sous une forme pratiquement pure, formule dans laquelle R1 représente hydrogène ou un groupe acyle dérivé d'un acide gras à chaîne longue, de préférence un acide gras contenant au moins 10 atomes de carbone. Les composés idéalement utilisés sont l'α-amyrine et le palmitate d'α-amyrine.
PCT/AU1992/000590 1991-10-30 1992-10-30 Composes de triterpene presentant une activite anti-inflammatoire Ceased WO1993009129A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU39101/93A AU670583B2 (en) 1991-10-30 1992-10-30 Triterpene compound having antiinflammatory activity

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPK919991 1991-10-30
AUPK9199 1991-10-30

Publications (1)

Publication Number Publication Date
WO1993009129A1 true WO1993009129A1 (fr) 1993-05-13

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994024145A1 (fr) * 1993-04-16 1994-10-27 Glycomed Incorporated Derives d'acides triterpenoides et leurs utilisations
CN105456275A (zh) * 2015-12-14 2016-04-06 深圳市神秘果实业有限公司 一种治疗糖尿病或高血脂症的药物组合物或功能性保健品
KR20190025168A (ko) * 2017-08-31 2019-03-11 단국대학교 천안캠퍼스 산학협력단 목진피 추출물을 유효성분으로 포함하는 자가면역질환 예방 또는 치료용 약제학적 조성물

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1405681A (en) * 1973-03-14 1975-09-10 Biorex Laboratories Ltd Amyrin derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1405681A (en) * 1973-03-14 1975-09-10 Biorex Laboratories Ltd Amyrin derivatives

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
AGNIHOTRI, V.K. et al., "Constituents from the Seeds of Cordia Obliqua as Potential Anti-Inflammatory Agents", INDIAN J. PHARMACEUTICAL SCIENCES, V49, No. 62, 1987, pages 66-69. *
CHAUDHARI, A. et al., "Antiproteolytic Activity of Amyrin-Acetates", RESEARCH COMMS. IN CHEM. PATHOLOGY AND PHARMACOLOGY, 7(1), Jan. 1974. *
ERCIYAS, E. et al., "Alpha-Amyrin Tetratriacontanoate, a New Triterpene from Scolymus Hispanicus L", DIE PHARMAZIE, v44(8), 1989, page 580. *
GUELZ, P-G et al., "Epicuticular Leaf Waxes of Citrus Halimii Stone", J. AGRIC. FOOD CHEM., 1987, 35, 716-720. *
GUELZ, P-G et al., "Epicuticular Wax of Euphorbia Aphylla Brouss Ex Willd, Euphorbiaceae", Z. NATURFORSCH, 43c, 19-23, (1988). *
GUPTA, M.B. et al., "Anti-Inflammatory Activity of Natural Products (1) Triterpenoids", EUROPEAN JOURNAL OF PHARMACOLOGY, 6, (1969), 67-70. *
GUPTA, M.B. et al., "Biochemical Study of the Anti-Inflammatory Activity of Alpha- and Beta-Amyrin Acetate", BIOCHEMICAL PHARMACOLOGY, V20, pp. 401-405. *
HEMMERS, H. et al., "Tetra and Pentacyclic Triterpenoids from Epicuticular Wax of Euphorbia Cyparissias L., Eurphorbiaceae", Z. NATURFORSCH, 44c, 563-567, (1989). *
HEMMERS, H. et al., "Triterpenoids in Epicuticular Waxes of Three European Euphorbia Species", Z. NATURFORSCH, 43c, 799-805, (1988). *
KWEIFIO-OKAI, G., "Antiinflammatory Activity of a Ghanaian Antiarhritic Herbal Preparation: II", JOURNAL OF ETHNOPHARMACOLOGY, 33, (1991), 129-133. *
KWEIFIO-OKAI, G., "Antiinflammatory Activity of a Ghanaian Antiarthritic Herbal Preparation: 1", JOURNAL OF ETHNOPHARMACOLOGY, 33, (1991), 263-267. *
LIN, C-N, et al., "Antihepatoxic Principles of Sambucus Formosana", PLANTA MEDICA, V54, No. 3, 1988, pp. 223-224. *
NIEMANN, G.J. et al., "Biosynthesis and Accumulation of Triterpenoids in Epidermis and Mesophyll of Ilex Aquifolium Leaves in Relation to the Age of the Leaf", J. PLANT. PHYSIOL., Vol. 129, 395-405, (1987). *
YASUKAWA, K. et al., "Sterol and Triterpene Derivatives from Plants Inhibit the Effects of a Tumor Promoter, and Sitosterol and Betulinic Acid Inhibit Tumor Formation in Mouse Skin Two-Stage Carcinogenesis", ONCOLOGY, 1991: 48:72-76. *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994024145A1 (fr) * 1993-04-16 1994-10-27 Glycomed Incorporated Derives d'acides triterpenoides et leurs utilisations
US5527890A (en) * 1993-04-16 1996-06-18 Glycomed Incorporated Derivatives of triterpenoid acids and uses thereof
US5679644A (en) * 1993-04-16 1997-10-21 Glycomed Incorporated Methods of treating diseases using triterpenoid acid derivatives
US5688922A (en) * 1993-04-16 1997-11-18 Glycomed Incorporated Substituted fucopyranosides
US5763582A (en) * 1993-04-16 1998-06-09 Glycomed Incorporated Derivatives of triterpenoid acids and uses thereof
US5837690A (en) * 1993-04-16 1998-11-17 Glycomed Incorporated Derivatives of triterpenoid acids and uses thereof.
CN105456275A (zh) * 2015-12-14 2016-04-06 深圳市神秘果实业有限公司 一种治疗糖尿病或高血脂症的药物组合物或功能性保健品
CN105456275B (zh) * 2015-12-14 2019-01-04 深圳市神秘果实业有限公司 一种治疗糖尿病或高血脂症的药物组合物或功能性保健品
KR20190025168A (ko) * 2017-08-31 2019-03-11 단국대학교 천안캠퍼스 산학협력단 목진피 추출물을 유효성분으로 포함하는 자가면역질환 예방 또는 치료용 약제학적 조성물
KR101970457B1 (ko) 2017-08-31 2019-04-19 단국대학교 천안캠퍼스 산학협력단 목진피 추출물을 유효성분으로 포함하는 자가면역질환 예방 또는 치료용 약제학적 조성물

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