EP0352301A1 - Buttersäure-ester und ihre verwendung als arzneimittel - Google Patents

Buttersäure-ester und ihre verwendung als arzneimittel

Info

Publication number
EP0352301A1
EP0352301A1 EP88908255A EP88908255A EP0352301A1 EP 0352301 A1 EP0352301 A1 EP 0352301A1 EP 88908255 A EP88908255 A EP 88908255A EP 88908255 A EP88908255 A EP 88908255A EP 0352301 A1 EP0352301 A1 EP 0352301A1
Authority
EP
European Patent Office
Prior art keywords
butanoyl
isopropylidene
compound
butyric acid
compound according
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.)
Withdrawn
Application number
EP88908255A
Other languages
English (en)
French (fr)
Inventor
Pierre Joseph Villa
François PIERI
Gino Lino Ronco
Emile Pierre René SEGARD
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.)
Universite de Picardie Jules Verne
Original Assignee
Universite de Picardie Jules Verne
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
Priority claimed from FR8713294A external-priority patent/FR2621039B1/fr
Application filed by Universite de Picardie Jules Verne filed Critical Universite de Picardie Jules Verne
Publication of EP0352301A1 publication Critical patent/EP0352301A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
    • C07D317/24—Radicals substituted by singly bound oxygen or sulfur atoms esterified

Definitions

  • Esters of n-butyric acid and their use as medicaments are also useful as medicaments.
  • the present invention relates to derivatives of n-butyric acid and their use as a medicament.
  • the salts of n-butyric acid, and in particular sodium butyrate have interesting inhibitory actions on the growth of fibroblasts as a result of actions on histones and the structure of chromatin in cell nuclei.
  • This inhibitory action of cell division has proved particularly important to exploit in cancerology, in particular for the treatment of various leukemias or sarcomas and various carcinomas.
  • antiviral actions of sodium butyrate have also been characterized for the herpes virus.
  • n-arginine butyrate gives the following results: 2 min: 1.36 mmol / l; 5 min: 0.23 mmol / l; 30 min: 0.06 mmol / l; 60 min: 0 mmol / l.
  • the Applicant has set itself the goal of synthesizing chemical compounds containing in their structure at least one butanoyl radical linked by a covalent bond to an atoxic carrier compound so that these compounds in vivo under the action of enzyme systems in humans or animals slowly release n-butyric acid, resulting in a longer half-life than that of the above saline derivatives and therefore providing better bioavailability of the biologically active product.
  • W represents a radical of a product having at least one OH group esterifiable by n-butyric acid, n possibly varying from 1 to the total number of esterifiable OH groups in said product.
  • the product, of radical W plays the role of a temporary transporter of n-butyric acid and it is particularly advantageous to choose it from products which are the least toxic possible with respect to organisms. alive, to the extent that this product is released into the body and must therefore be eliminated or metabolized.
  • the ester compounds of the present invention will have a radical W forming part of products chosen from carbohydrates and their acetonide derivatives, hydrogenated carbohydrates and their acetonide derivatives, glyceryl esters of fatty acids, the derivative glycerol acetonide, serine and homoserine.
  • the compounds according to the present invention are intended for use as a medicament alone or in combination with other compounds, intended for use as n-butyric acid and its salts, for example for anti-tumor and / or antiviral use.
  • the collected filtrate is evaporated under reduced pressure.
  • the product obtained (31.69 g) is a yellow pasty liquid with rotary power
  • [ ⁇ ] D 22 - 28o (ethanol).
  • the CPV analysis (OV 17 ; 1 m; 200o C; 1.7 bar; retention time 3 min) indicates a purity of the order of 98%.
  • the entire product is then chromatographed on silica (Kielselgel 60, 150 g) using a heptane / ethyl ether gradient (fraction 90/20 v / v).
  • the mono-isopropylidene derivative is prepared from the di-isopropylidene derivative (compound I) prepared under the conditions of Example 1.
  • the vapor phase chromatography shows the disappearance of the butyrate-3 peak of di-isopropylidene glucose and the solution is neutralized with tripropylamine, the sulfate of which is insoluble in the medium.
  • the solvent is removed under reduced pressure.
  • the crude fraction obtained is purified by liquid chromatography on silica (Kielselgel 60 Merck 9585, 230 - 400 mesh, 150 g) using a heptane / acetone gradient (80/20 v / v fraction).
  • This quantity can be increased when the above acid hydrolysis is carried out at the higher temperature of 80oC and by increasing the contact time (3 hours).
  • This compound is prepared by isomerization of O-butanoyl-3 O-isopropylidene-1,2 ⁇ -D-glucofuranose (II) synthesized under the conditions of Example 2. It is dissolved. 30 g of II in 1 liter of methanol containing 10 ml of triethylamine; the mixture is stirred at room temperature for 2 hours. After evaporation under reduced pressure, the syrup obtained, fractionated by preparative HPLC on a WATERS Prep column. pack P / N 500-41.75 mesh (eluent hexane-acetone, 80/20 v / v), gives:
  • This compound is prepared from di-O-isopropylidene-1,2: 3,4 ⁇ -D galactopyrannose according to the method of Example 1 with a yield of 62% after recrystallization from hexane.
  • This compound is prepared from VIII by deprotection of the hydroxyls in 2 and 3, ie in the homogeneous phase according to the method of Example 2 slightly modified (6 hours at room temperature instead of 1 hour at 70 ° C); either in the heterogeneous phase by passage through a column of 25 ml of Amberlist resin. 15 Wet maintained at 30oC with a flow rate of 0.1 ml / min of VIII in 20% solution in an isopropanol-water mixture 90-10 v / v. The purification is carried out on a column of silica gel with ethyl ether as eluent.
  • This compound is prepared from compound IX according to the method of Example 1 with a yield of 72% after purification on silica gel.
  • This compound is prepared according to the following sequence: a) esterification with palmitoyl chloride of
  • Example 1 leading to O-palmitoyl-1 O-isopropylidene-2,3 propane; b) deprotection of the hydroxyls in 2 and 3 of the compound obtained in a) according to the methods described for the preparation of IX, leading to O-palmitoyl-1 propane diol-2,3; c) esterification with butanoyl chloride of the compound obtained in b) according to the method of Example 1 leading to XI, with a yield of 70% after purification on silica gel. Liquid, n D 20 1.4475.
  • a solution containing 0.600 g of the compound according to the invention is prepared in 2 ml of formal glycerol (mixture of dioxane - 1.3 ol-5 and dioxolane - 1.3 methanol-4).
  • formal glycerol mixture of dioxane - 1.3 ol-5 and dioxolane - 1.3 methanol-4.
  • a prior injection 0.1 ml / kg
  • a heparin solution at a concentration of 5000 IU / ml is carried out in the marginal vein of the ear; the needle is left in place allowing administration, two minutes later, of a dose of 0.1 ml / kg (i.e. 23 mg / kg) of the solution prepared above.
  • Blood samples of 1 cm3 spread over time are taken from the marginal vein of the other ear. The blood is centrifuged (2,000 rpm for 3 min) and the serum is collected.
  • the concentration of potential serum butyric acid is determined by gas chromatography using a column of CHROMOSORB 101 or CARBOPACK C.
  • the sample to be analyzed by chromatography is prepared by the following treatment: - 80 ⁇ l of serum - 10 ⁇ l of pure formic acid
  • This treatment before chromatography has the effect of hydrolyzing the compound or its metabolites and releasing n-butyric acid.
  • the quantification is done by comparison of the respective surfaces of butyric acid and valeric acid, the response coefficients having been determined beforehand.
  • the serum concentration (in mmoles) of potential or releasable n-butyric acid is thus measured from the compound or its metabolites contained in the serum. These measurements make it possible to determine the apparent serum half-life of the injected ester compound.
  • the compounds according to the invention have a duration of
  • mice 3o In-vivo anti-tumor tests in mice.
  • the anti-tumor properties studies were carried out in mice, according to the protocol of CHANY and CERUTTI (Int. J. Cancer, 1982, 30, 489) on the compounds I to V above.
  • the TG 180 strain is used (ip injection of 10 6 cells for a 25 g male mouse and 0.1 ml of a solution of Corynebacterium Parvum Mérieux (CP)).
  • CP Corynebacterium Parvum Mérieux
  • mice 9 lots of 15 mice each. After injection on day D O of TG 180 cells and of CP, the procedure is as follows: The control batch No. 1 is. treated daily with a placebo injection. Control batch 2 is treated daily with an injection of CP (0.1 ml).
  • Control batch 4 is treated daily with CP and then interferon at the same doses as above.
  • the experimental batches are treated, alternately on D + 1 with the compound according to the invention (0.5 ml of an 8 mmolar solution in compound I to V), on D + 2 with interferon, on D + 3 by CP and this for three weeks.
  • Table 4 shows the very good therapeutic anti-tumor efficacy of the compounds I, II, III according to the invention, compared with the control batches 1, 2, 3 and 4.
  • the amount of potential n-butyric acid which can be released in the mouse body is in this protocol for compounds I, II, III of 14 mg per kilogram of mouse, which corresponds in theory to the optimal dose recommended for arginine butyrate for a 25 g mouse. Second experience.
  • Tests according to the same protocol as above to determine the dose-effect of the compounds according to the invention were carried out by keeping constant the amount of CP and of interferon from the previous experiment, but by varying the concentration of 0.25 to 50 millimoles of compound II per liter of solution for injection (0.5 ml of this solution being injected), ie the potential equivalent of 0.44 to 88 mg of n-butyric acid per kg of mouse.
  • the survival at 100 days is 1 mouse out of 45 for CP alone, 0 out of 45 for interferon alone, 30 out of 45 for compound II, whatever its concentration between 0.25 and 50 mmol / l, the compound II being administered alternately with CP and interferon according to the above protocol.
  • Another trial according to another protocol in which the interferon has been suppressed but in which one continues to administer alternately 0.1 ml of CP and 0.5 ml of a solution of compound II at a concentration varying from 0, 25 to 50 millimoles / l, shows that the number of mice surviving to 100 days is constant whatever the concentration of compound II and amounts on average to 20 out of 45 mice.
  • compositions are prepared for therapeutic use in humans or animals comprising 100 to 2000 mg of a compound according to the invention and any pharmaceutically acceptable excipient.
  • compound II is placed in isotonic solution with physiological serum or glucose to form an injectable drug dosed unitarily between 100 to 500 mg of compound II.
  • Compound II is optionally mixed with an excipient such as a polyethylene glycol (PEG) to form a medicament which can be administered orally or rectally and dosed individually between 1 and 2 g of compound II.
  • PEG polyethylene glycol
  • gastro-resistant capsules are provided to avoid acid hydrolysis in the stomach.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP88908255A 1987-09-25 1988-09-26 Buttersäure-ester und ihre verwendung als arzneimittel Withdrawn EP0352301A1 (de)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
FR8713294A FR2621039B1 (fr) 1987-09-25 1987-09-25 Derives non toxiques de l'acide n-butyrique, presentant des actions therapeutiques retardees
FR8713294 1987-09-25
FR8809092 1988-07-05
FR8809092A FR2633929B2 (fr) 1987-09-25 1988-07-05 Derives non toxiques de l'acide n-butyrique, presentant des actions therapeutiques retardees

Publications (1)

Publication Number Publication Date
EP0352301A1 true EP0352301A1 (de) 1990-01-31

Family

ID=26226229

Family Applications (1)

Application Number Title Priority Date Filing Date
EP88908255A Withdrawn EP0352301A1 (de) 1987-09-25 1988-09-26 Buttersäure-ester und ihre verwendung als arzneimittel

Country Status (4)

Country Link
US (1) US5185436A (de)
EP (1) EP0352301A1 (de)
FR (1) FR2633929B2 (de)
WO (1) WO1989002895A1 (de)

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US7910624B1 (en) 1995-03-03 2011-03-22 The Trustees Of Boston University Compositions for the treatment of blood disorders
WO1995011699A1 (en) * 1993-10-29 1995-05-04 The Trustees Of Boston University Physiologically stable compositions of butyric acid, and butyric acid salts and derivatives as anti-neoplastic agents
EP0727989A4 (de) * 1993-11-10 1998-08-19 Sloan Kettering Inst Cancer Buttersäureester als zelldifferenzierende wirkstoffe
FR2723096B1 (fr) * 1994-07-28 1996-10-18 Univ Picardie Esters associant les acides phenylacetique,3-phenyl-propionique, 4-phenyl-butyrique et n-butyrique au d-mannose, au xylitol et a leurs derives. applications comme medicaments
US6011000A (en) * 1995-03-03 2000-01-04 Perrine; Susan P. Compositions for the treatment of blood disorders
US5763488A (en) * 1995-10-30 1998-06-09 Vertex Pharmaceuticals Incorporated Methods and compositions using butyrate esters of threitol
IT1286510B1 (it) * 1996-11-29 1998-07-15 Cooperativa Centro Ricerche Po Esteri butirrici ad attivita' antiproliferativa e composizioni farmaceutiche che li contengono
US6130248A (en) * 1996-12-30 2000-10-10 Bar-Ilan University Tricarboxylic acid-containing oxyalkyl esters and uses thereof
US6030961A (en) * 1997-03-11 2000-02-29 Bar-Ilan Research & Development Co., Ltd. Oxyalkylene phosphate compounds and uses thereof
US6110955A (en) * 1997-03-11 2000-08-29 Beacon Laboratories, Inc. Metabolically stabilized oxyalkylene esters and uses thereof
US6124495A (en) * 1997-03-11 2000-09-26 Beacon Laboratories, Inc. Unsaturated oxyalkylene esters and uses thereof
US6043389A (en) 1997-03-11 2000-03-28 Mor Research Applications, Ltd. Hydroxy and ether-containing oxyalkylene esters and uses thereof
US5939455A (en) * 1997-03-11 1999-08-17 Beacon Laboratories, Inc. Therapeutic augmentation of oxyalkylene diesters and butyric acid derivatives
US6110970A (en) * 1997-03-11 2000-08-29 Beacon Laboratories, Inc. Nitrogen-containing oxyalkylene esters and uses thereof
AU9258798A (en) * 1997-08-08 1999-03-01 Hoechst Marion Roussel Deutschland Gmbh Substituted tetrahydropyrane derivatives, method for producing same, the ir use as medicine or diagnostic agent, as well as medicine containing same
AU774861B2 (en) * 1998-02-11 2004-07-08 Douglas V Faller Compositions and methods for the treatment of cystic fibrosis
KR20030020482A (ko) * 2001-08-29 2003-03-10 대한민국(서울대학교) 소디움부티레이트를 유효성분으로 하는 항암제
WO2003033678A2 (en) * 2001-10-18 2003-04-24 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Methods of using deacetylase inhibitors to promote cell differentiation and regeneration
DE102005046237A1 (de) * 2005-09-28 2007-04-05 Südzucker Aktiengesellschaft Mannheim/Ochsenfurt Buttersäureester von Kohlenhydraten und Kohlenhydratpolyolen
WO2010105112A1 (en) * 2009-03-11 2010-09-16 Hemaquest Pharmaceuticals, Inc. Detection of short-chain fatty acids in biological samples
US20110086869A1 (en) 2009-09-24 2011-04-14 The Trustees Of Boston University Methods for treating viral disorders
WO2011072086A1 (en) 2009-12-08 2011-06-16 Hemaquest Pharmaceuticals, Inc. Methods and low dose regimens for treating red blood cell disorders
US20110245154A1 (en) 2010-03-11 2011-10-06 Hemaquest Pharmaceuticals, Inc. Methods and Compositions for Treating Viral or Virally-Induced Conditions
GB2567093A (en) 2016-07-15 2019-04-03 Viracta Therapeutics Inc Histone deacetylase inhibitors for use in immunotherapy
KR102054401B1 (ko) * 2018-03-26 2019-12-10 주식회사 엔지켐생명과학 1,2-디아실글리세롤 화합물, 그 제조방법 및 이를 유효성분으로 함유하는 면역조절제
CA3142142A1 (en) 2019-05-31 2020-12-03 Viracta Subsidiary, Inc. Methods of treating virally associated cancers with histone deacetylase inhibitors

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Also Published As

Publication number Publication date
FR2633929A2 (fr) 1990-01-12
US5185436A (en) 1993-02-09
FR2633929B2 (fr) 1995-05-24
WO1989002895A1 (fr) 1989-04-06

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