WO2009143475A1 - Procédés et compositions associés à l’esculentoside aglycosidique a - Google Patents

Procédés et compositions associés à l’esculentoside aglycosidique a Download PDF

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Publication number
WO2009143475A1
WO2009143475A1 PCT/US2009/045056 US2009045056W WO2009143475A1 WO 2009143475 A1 WO2009143475 A1 WO 2009143475A1 US 2009045056 W US2009045056 W US 2009045056W WO 2009143475 A1 WO2009143475 A1 WO 2009143475A1
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WO
WIPO (PCT)
Prior art keywords
esa
radiation
och
cancer
subject
Prior art date
Application number
PCT/US2009/045056
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English (en)
Other versions
WO2009143475A9 (fr
Inventor
Paul Okunieff
Zhang Lurong
Yang Shanmin
Zhang Mei
Chaomei Liu
Original Assignee
University Of Rochester
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 University Of Rochester filed Critical University Of Rochester
Publication of WO2009143475A1 publication Critical patent/WO2009143475A1/fr
Publication of WO2009143475A9 publication Critical patent/WO2009143475A9/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid

Definitions

  • Figure 7 shows h-EsA inhibits CIA relapsing.
  • Figure 58 shows CIA model in DBA/1 J mouse treated with h-ESA. It was shown that most of the cartilage was normal, but there was a foci of erosions in bone and cartilage
  • Disclosed herein and useful in the methods described are the components to be used to prepare the disclosed compositions as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that, while specific reference of each various individual and collective combinations and permutation of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular molecule, such as EsA, is disclosed and discussed and a number of modifications that can be made to a number of places within the molecule can be made, specifically contemplated is each and every combination and permutation of the molecule unless specifically indicated to the contrary.
  • the alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxamate, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described below.
  • groups including, but not limited to, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxamate, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfox
  • amine or “amino” as used herein are represented by the formula NAA 1 A 2 , where A, A 1 , and A 2 can be, independently, hydrogen, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • sulfonyl is used herein to refer to the sulfo-oxo group represented by the formula -S(O) 2 A, where A can be hydrogen, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • sulfoxide as used herein is represented by the formula AS(O)A 1 , where A and A 1 can be, independently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above. 162.
  • thiol as used herein is represented by the formula -SH.
  • compositions may potentially be administered as a pharmaceutically acceptable acid- or base- addition salt, formed by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, or by reaction with an inorganic base such as sodium hydroxide, ammonium hydroxide, potassium hydroxide, and organic bases such as mono-, di-, trialkyl and aryl amines and substituted ethanolamines.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid
  • organic acids such as formic acid, acetic acid, propionic acid, glyco
  • Implantable or injectable protein depot compositions can also be employed, providing long-term delivery of, e.g., an aglycosidic EsA or derivatives thereof.
  • an injectable depot gel composition which includes a biocompatible polymer, a solvent that dissolves the polymer and forms a viscous gel, and an emulsifying agent in the form of a dispersed droplet phase in the viscous gel.
  • a gel composition can provide a relatively continuous rate of dispersion of the agent to be delivered, thereby avoiding an initial burst of the agent to be delivered. 193.
  • COX-2 inhibitors have dominated the market for nonsteroidal anti-inflammatory agents (NSAIDs).
  • NSAIDs nonsteroidal anti-inflammatory agents
  • Vioxx® a major COX-2 inhibitor, was removed from the marketplace due to cardiac toxicity.
  • Celebrex® the other major COX-2 inhibitor, now has almost no competition and therefore can remain inhibitively expensive.
  • Celebrex® has a lower but still measurable rate of thromboembolic complications. There is therefore a powerful need for a new NSAID.
  • the third device measures a deformed ankle at late stage.
  • the progression of CIA disease in the mouse is characterized by an increasing stiffness of the ankle joint that limits the extension of the joint to values below the normal extension range of 135 degrees.
  • the extension of ankle joint is gauged against a circular rule that measures the extension angle of the joint.
  • Acute toxicities of EsA and its derivative h-EsA Once the administration path (p.o.) was determined, an acute toxicity test was conducted to see the dose limitation. Mice (6 groups) were fed with different doses of EsA once and the number of lethal events was recorded daily for 2 weeks. The LD 50 was about 55 mg/kg, which seems too low for an anti-CI agent (unless effective dose can be lowered to 1 mg/kg). It was speculated that this unexpectedly low LD 50 was due to the sugar function on EsA that confers a saponin (surfactant) property to the compound. This surfactant- like property can cause disruption of cell membranes as was evidenced by the occurrence of hemolysis in the toxicity study.
  • saponin saponin
  • h-EsA is equally effective as Celebrex® at early stage of CIA and can maintain its effectiveness for a longer period of time; 2) the triterpenoid portion of EsA is the functional element of EsA; and 3) h-EsA may be safer than EsA due to elimination of the surfactant sugar group. It has been shown that h-EsA can effectively reduce the effects of CIA during peak inflammation (second boost) as a mitigation/treatment agent. It is also believed that it can also act to reduce or prevent its occurrence of CIA from time of onset (first immunization period). 209.
  • IL-I can better account for EsA-related IR protection than COX-2 inhibition.
  • IL- l ⁇ induced by 2 or 4 Gy IR in A431 human epidermoid carcinoma cells was also completely inhibited by 0.1 ug/ml EsA (P ⁇ .01, Fig 16B and 16C).
  • other proinflammatory cytokines were also studied in a panel of normal cell lines including macrophages, epithelial cells, and fibroblasts from human and mouse origins.
  • mice were anesthetized and the trachea was surgically exposed and incised. A 16-gauge, 1 cm stainless steel tube was inserted into the trachea and then secured with surgical silk. The animal was then connected to a Harvard rodent ventilator. For the studies a respiratory rate of 150 breaths per minute was used, and a tidal volume calculated based on the weight of the mouse.
  • CBCT Cone Beam Computed Tomography

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L’invention concerne des compositions associées à des inhibiteurs de COX-2 sélectifs solubles dans l’eau et des procédés d’utilisation des inhibiteurs (y compris h-EsA et ses dérivés).
PCT/US2009/045056 2008-05-23 2009-05-22 Procédés et compositions associés à l’esculentoside aglycosidique a WO2009143475A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US5575508P 2008-05-23 2008-05-23
US61/055,755 2008-05-23

Publications (2)

Publication Number Publication Date
WO2009143475A1 true WO2009143475A1 (fr) 2009-11-26
WO2009143475A9 WO2009143475A9 (fr) 2010-02-25

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102218073A (zh) * 2011-04-21 2011-10-19 中国人民解放军第二军医大学 商陆皂苷甲在制备防治肝纤维化或肝硬化药物中的应用
CN105037483A (zh) * 2015-08-18 2015-11-11 苏州求是本草健康科技有限公司 一种细梗香草皂苷a的制备方法及其用途
CN111018943A (zh) * 2019-12-31 2020-04-17 深圳太太药业有限公司 一种高含量商陆皂苷甲的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5017562A (en) * 1987-02-11 1991-05-21 Regents Of The University Of Minnesota Crystalline saponin-containing complex
WO2006055875A2 (fr) * 2004-11-18 2006-05-26 University Of Rochester Procedes et compositions concernant l'esculentoside a

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5017562A (en) * 1987-02-11 1991-05-21 Regents Of The University Of Minnesota Crystalline saponin-containing complex
WO2006055875A2 (fr) * 2004-11-18 2006-05-26 University Of Rochester Procedes et compositions concernant l'esculentoside a

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102218073A (zh) * 2011-04-21 2011-10-19 中国人民解放军第二军医大学 商陆皂苷甲在制备防治肝纤维化或肝硬化药物中的应用
CN102218073B (zh) * 2011-04-21 2012-05-30 中国人民解放军第二军医大学 商陆皂苷甲在制备防治肝纤维化或肝硬化药物中的应用
CN105037483A (zh) * 2015-08-18 2015-11-11 苏州求是本草健康科技有限公司 一种细梗香草皂苷a的制备方法及其用途
CN111018943A (zh) * 2019-12-31 2020-04-17 深圳太太药业有限公司 一种高含量商陆皂苷甲的制备方法
CN111018943B (zh) * 2019-12-31 2021-01-05 深圳太太药业有限公司 一种高含量商陆皂苷甲的制备方法

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Publication number Publication date
WO2009143475A9 (fr) 2010-02-25

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