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WO1997046543A1 - Derives acetyle de thiazoles et analogues - Google Patents

Derives acetyle de thiazoles et analogues Download PDF

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Publication number
WO1997046543A1
WO1997046543A1 PCT/AU1997/000342 AU9700342W WO9746543A1 WO 1997046543 A1 WO1997046543 A1 WO 1997046543A1 AU 9700342 W AU9700342 W AU 9700342W WO 9746543 A1 WO9746543 A1 WO 9746543A1
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WO
WIPO (PCT)
Prior art keywords
acetyl
tetrahydroxybutyl
thiazole
compound
oxazole
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/AU1997/000342
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English (en)
Inventor
Stephen Geoffrey Pyne
Alison Thavary Ung
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University of Wollongong
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University of Wollongong
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Filing date
Publication date
Application filed by University of Wollongong filed Critical University of Wollongong
Priority to AU28817/97A priority Critical patent/AU2881797A/en
Publication of WO1997046543A1 publication Critical patent/WO1997046543A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms

Definitions

  • the present invention relates to novel acetyl derivatives of five-member heterocyclic ring structured compounds and methods of preparation thereof. These compounds have advantageous properties and useful pharmacological activities and may be used in the treatment and diagnosis of disease.
  • the invention is also directed to a method of synthesis of the compounds, pharmaceutical compositions containing such compounds and to derivatives of the compounds incorporating detectable moieties.
  • the compounds of the present invention are novel acetyl derivatives in which a five-member cyclic ring structure is substituted with sulphur, nitrogen or oxygen heteroatoms in different positions of the ring. These compounds have advantageous properties and pharmacological activities, particularly as immunosuppressive agents. Method of synthesis of these compounds, their analogues and stereoisomers is also described and included within the scope of the present invention, as are pharmaceutical compositions containing the compounds and their use in methods of treatment.
  • R is alkyl, alkenyl or alkynyl having from 1 to 6 carbons, phenyl, benzyl or phenethyl;
  • R 2 is H, C, to C 5 alkyl which can optionally be partially hydroxylated or the group
  • n is from 0 to 4.
  • X, Y and Z are independently CH, N, NI 1, O or S, with the proviso that at least one of X, Y or Z is CH, that one and only one of X, Y and Z is NH, O or S and further that when Y is N or NH then Z is not N or NH.
  • a site for stereo or geometric isomerism may exist, eg. asymmetric carbon atom.
  • Any of the optical and/or cis/trans isomers are considered to be within the scope of this invention as are pharmaceutically acceptable esters and acid addition salts.
  • Preferred compounds of the invention are acetyl derivatives of thiazole, oxazole, pyrrole, thiophene, furan, pyrazole, isothiazole and isoxazole. Even more preferred are 2 acetyl derivatives of thiazole and oxazole, and their stereoisomers.
  • the compounds of the invention comprise a detectable marker such as a radionucleotide, a fluorescent marker or an enzyme.
  • a detectable marker need not be covalently coupled to the compounds and may be introduced via a suitable labelled specific binding pair such as biotin/avidin or antibody/antigen pairs wherein one of the binding pair carries a detectable marker.
  • the invention provides a process for the synthesis of a compound according to the first aspect comprising reacting a protected and formylated intermediate compound of the formula:
  • the invention provides a process for the synthesis of a compound of the formula:
  • R j is alkyl, alkenyl or alkynyl having from 1 to 6 carbons, phenyl, benzyl or phenethyl;
  • R 2 is H, C[ to C 5 alkyl which can optionally be partially hydroxylated or the group
  • n is from 0 to 4.
  • X, Y and Z are independently CH, N, NH, O or S, or a stereoisomer or a geometric isomer thereof, with the proviso that at least one of X, Y or Z is CH and that one and only one of X, Y and Z is NH, O or S, comprising reacting a lithiated intermediate compound of the formula:
  • P' and P" are protecting groups which may be same or different and m and n may be same or different and are independently 0 or 1 , to obtain the intermediate compounds of the formula: O ⁇
  • the lithiated intermediate is a 5-lithiated thiazole and the carbohydrate is a carbohydrate lactone.
  • a suitable carbohydrate lactone which may be used 2,3-0- Isopropylidine-£>-erythronolactone.
  • the compounds of the invention preferably synthesised by the above processes are selected from the group consisting of 2-acetyl-4-(l,2,3,4-tetrahydroxybutyl)-thiazole, 2- acetyl-4-( 1 ,2,3,4-tetrahydroxybutyl)-oxazole, 2-acetyl-4-( 1 ,2,3,4-tetrahydroxybutyl)- pyrrole, 2-acetyl-4-(l,2,3,4-tetrahydroxybutyl)-thiophene, 2-acetyl-4-( 1,2,3,4- tetrahydroxybutyl)-furan, 2-acetyl-5-( 1 ,2,3,4-tetrahydroxybutyl)-thiazole, 2-acetyl-5- (l ,2,3,4-tetrahydroxybutyl)-oxazole, 3-acetyl-5-(l,2,3,4-tetrahydroxybutyl)-pyrazole, 3- acetyl-5
  • the compound synthesised by the above processes are selected from the group consisting of 2-acetyl-4-( 1,2,3 ,4-tetrahydroxybutyl)-thiazole, 2-acetyl-4-( 1,2,3,4- tctrahydroxybutyl)-oxazole, 2-acetyl-5-( 1 ,2,3,4-tetrahydroxybutyl)-thiazole.
  • 2-acetyl-5-( 1,2,3 ,4-tetrahydroxybutyl)-thiazole 2-acetyl-4-( 1,2,3,4-tctrahydroxybutyl)-oxazole
  • 2-acetyl-5-( 1 ,2,3,4-tetrahydroxybutyl)-thiazole 2-acetyl-5-
  • the above processes may be used to synthesise compounds 2-acetyl-5-(l ,2,3,4,5-pentahydroxypentyl)-thiazole, 2-acetyl-5-(l,2.3,4-tetrahydroxybutyl)- thiazole, 2-acetyl-4-(l,2,3,4,5-pentahydroxypentyl)-oxazole and 2-acetyl-4-(l,2,3,4- tetrahydroxybutyl)-oxazole.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the first aspect together with a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.
  • the invention provides a method of treating a disorder by immunomodulation in a subject requiring such treatment comprising the step of administering to a subject requiring such treatment an effective amount of a compound according to the first aspect or a pharmaceutical composition according to the fourth aspect in an amount effective to induce said immunomodulation.
  • a non-limiting example of a group of conditions and disorders which may benefit from, or which may be prevented from occurring by, treatment with the compounds of the invention is that which includes autoimmune diseases, inflammatory conditions and transplantation.
  • the compounds of the invention have a broad spectrum of pharmacological activity and may be used for treatment of other diseases and disorders.
  • the treatment is administered therapeutically, however, certain disorders may be advantageously treated prophylactically.
  • the treatment can be administered orally, parenterally or topically, depending on the subject and the disorder to be treated.
  • the invention consists in a method of detecting in a sample an agent capable of binding to the compounds of the invention comprising the steps of contacting said sample with a compound according to the first aspect, wherein the compound comprises a detectable marker and detecting the marker in the sample.
  • the detectable marker is covalently coupled to the compound and includes but is not limited to a radionucleotide or a fluorescent marker.
  • the detectable marker can also be easily introduced via a specific binding pair such as biotin/avidin pair or biotin/antibody pair wherein the avidin or the antibody carry a detectable marker.
  • an enzyme can be coupled to the compound wherein the detectable marker is generated by the enzyme action on its specific substrate to generate a detectable coloured or reactive product.
  • the preferred compounds of the invention have the following general structures:
  • X is NH, S or O.
  • 2-acetyl-4-(l,2,3,4-tetrahydroxybutyl)-thiazole 2-acetyl- 4-( 1 ,2,3,4-tetrahydroxybutyl)-oxazole, 2-acetyl-4-( 1 ,2,3,4-tetrahydroxybutyl)-pyrrole, 2- acetyl-4-( 1,2,3 ,4-tetrahydroxybuty l)-thiophenc, 2-acety l-4-( 1 ,2,3 ,4-tetrahydroxybutyl)- furan, 2-acetyl-5-(l ,2,3,4-te.rahydroxybutyl)-thiazole, 2-acetyl-5-(l ,2,3,4- tetrahydroxybutyl)-oxazole, 3-acetyl-5-(l,2,3,4-tetrahydroxybutyl)-pyrazole, 3-acetyl-5- (l ,2,3,4-tetrahydroxybutyl)
  • the compounds of the invention have been found to have immunosuppressive actions.
  • the compounds can be used for therapeutic or prophylactic treatment and may be administered orally, parenterally or topically.
  • the dosage administered will depend on the subject being treated , the route of administration and the type and severity of the condition being treated.
  • the compounds to be administered can be formulated by admixing with any of a number of suitable pharmaceutical solvents, diluents, excipients, adjuvants or carriers, all of which are well known in the art.
  • the carbonyl group of the starting compound for example 2- acetylthiazole
  • 2- acetylthiazole can be first protected, preferably using slight excess of ethylene glycol in the presence of p-toluenesulfonic acid in refluxing toluene, to give compound 1.
  • Formylation of the heterocyclic ring at the 5-position can be achieved by treating compound 1 with n-butyl lithium at -78°C and then quenching with DMF to afford compound 2.
  • compound 2 can be reduced using NaBH 4 in MeOH to give compound 3 as a crystalline solid.
  • X-ray structure analysis of crystals of compound 3 can be used to ascertain that the formyl group is at the 5-position of the heterocyclic ring structure.
  • the diols can be protected by treatment with 2,2-dimethoxypropane in the presence of catalytic amount of BF 3 .Et 2 O to give protected diols 6a and 6b which could be isolated in pure form.
  • Dihydroxylation of compound 6a can be carried out using AD-mix- ⁇ . This allows the addition of two hydroxy groups to give the protected tctraol 7.
  • the enantiomeric purity of compound 7, a major intermediate in the synthetic protocol, can be determined by H NMR analysis of its Mosher's diester derivative 7a.
  • the diester 7a can be obtained by reacting compound 7 with Mosher's acid chloride in the presence of pyridine.
  • Deprotection of compound 7 to give the final product 9, for example 2-acetyl-5- (l,2,3,4-tetrahydroxybutyl)thiazole (X), can be carried out in two steps. Firstly, the deprotection of the two terminal hydroxy groups can be carried out by acid hydrolysis in acetone and 10% aqueous hydrochloric acid to give compound 8.
  • the cleavage of the cyclic dioxolane can be carried out by reacting compound 8 in wet acetone in the presence of 0.1 equivalent of PdCl 2 (CH 3 CN) 2 under reflex for 18 hrs to give compound 9, for example 2-acetyl-5-(l,2,3,4-tetrahydroxybutyl)thiazole (X), plus ethylene glycol as the by-product.
  • X 2-acetyl-5-(l,2,3,4-tetrahydroxybutyl)thiazole
  • ethylene glycol as the by-product.
  • Removal of ethylene glycol from the final product requires acidification and washing of the product 9 with appropriate solvent.
  • This purification step may be required when ethylene glycol is present as a contaminant because it can caused interference in the biological activity of compound 9.
  • the stereochemistry of the 1,2,3,4-tetrahydroxybutyl side chain of compound 9 was confirmed by X-ray structure analysis of the precursor compound 7.
  • the above described compounds have the capacity to bind to biological macromolecules and/or whole cells, for example lymphocytes. Such binding may involve specific interaction with cellular receptors or other biological structures. This property of the compounds makes them useful as diagnostic and analytical reagents.
  • the compounds can be derivatised with a detectable marker or a moiety to which an agent carrying a detectable marker can be coupled specifically.
  • directly detectable markers are fluorescent moieties such as fluorescein, rhodamine, phycoerythrin, phycocyanin and other known fluorescent moieties or radipnucleotides such as H, C, I, I, P, Cr, Tc and other commonly use radionucleotides.
  • Non-limiting examples of moieties to which an agent bearing a detectable marker can be coupled are biotin, antibodies or fragments thereof, enzymes and other agents which have corresponding ligands or substrates.
  • the corresponding binding pairs can be chosen from, for example, avidin, specific antigen or an antibody, or a substrate which generates a coloured product and similar agents.
  • the derivatives of the compounds of the invention which can be coupled, directly or indirectly, to detectable markers can be synthesised according to the general protocol outlined in Scheme III below.
  • the example used in Scheme III relates to derivatives which have a side chain of even number of carbon atoms and carry a fluorescent marker or a moiety such as biotin to which a suitably labelled avidin moiety or a specific antibody can be attached.
  • Other derivative may also be synthesised according to the scheme with only minor adaptation of the protocol.
  • Scheme III should be read in conjunction with Example 2.
  • This protected carbohydrate 12 becomes the synthon for, for example, the tetrahydroxybutyl side chain of 2-acety l-5-( 1, 2,3 ,4-tetrahydroxybutyl)thiazole (compound X) or the pentahydroxypentyl side chain of 2-acetyl-5-( 1 ,2,3 ,4,5-pentahydroxypentyl)thiazole (XV).
  • reaction mixture was cooled to room temperature, extracted excessively with a 10% aqueous solution of NaOH (l OOmL x 5) then water (l OOmL x 3) and dried over K 2 C0 3
  • the reaction mixture was left to stir at 0 °C for 1 hr and at room temperature for another hour.
  • the solvent was removed and the residue was taken up in CH 2 C1 2 (20mL).
  • the organic solution was washed with a saturated aqueous solution of NaCl (20 mL) and dried over MgSO 4 The solvent was removed to give a thick oil which solidified upon standing at
  • a mixture of AD mix- ⁇ (4.69g), MeSO 2 NH 2 (0.63g) and (DHQ) 2 -PHAL (0.106g) was added to a cold solution of the dienes 4a and 4b (0.758g, 3.39mmol) in tert- butanol/H 2 O (16mL, 1 :1 ).
  • the reaction mixture was left to stir at 0°C for 18 hr.
  • Solid Na 2 SO 3 (5.16g) was then added to the reaction mixture at 0°C and the mixture was allowed to warm up to room temperature over 1 hr.
  • the mixture was diluted with H 2 O (40mL) and extracted with CH 2 C1 2 (50mL x 2).
  • Trans protected-tetraol 7 (0.2 lg, 0.64mmol) was dissolved in acetone/water (14mL, 1 : 1 ) and concentrated HCl (6.2mL). The resulting solution was left to reflux for 2 hr. The solvent was removed to give a dark brown oil. The oil was dissolved in water (20mL) and the resulting solution was washed with ether (20mL x 3) by extraction. The water was removed under reduced pressure to give a dark brown oil which was dissolved in wet acetone (20mL). To this solution was added PdCl 2 (CH 3 CN) 2 (0.1 equiv., 0.064mmol, 0.016g) and the mixture was refluxed overnight.
  • PdCl 2 CH 3 CN
  • Example 2 Synthesis of the fluorescein and biotin derivatives of (]R.2S.3R )-2 -acetyl - 4f5y ⁇ .2.3.-trihvdroxy-4-amino-hutvnimidazole.
  • the synthesis of the fluoresceinated or biotinylated derivatives involved a palladium catalyzed coupling of the 1 -protected-4-iodoimidazole 5 to the functional ized vinylstannane 4 to produce the (_i)-alkene 6 and the Sharpless catalytic asymmetric dihydroxylation (AD) to introduce the (l_?,2S)-dihydroxy functionality into the butyl side chain of 7.
  • the vinylstanne 4 was prepared by conversion of D-asparaginc to (_.)-isoserine
  • mice were fed either acidified water or drinking water containing 50mg/L or 1 OOmg/L of the acid salt of compound X for 4 days. After treatment the spleens were removed from the animals and analysed for the presence of T and B cells. Splenocytes were prepared and cells labelled with fluorescent monoclonal antibodies specific for markers for T-cells (Thy- 1.2), T helper cells (CD4), cytotoxic T cells (CD8) and B cells (B220). The cells were then analysed by FACS and the relative numbers of each antigen was recorded. Treatment with both concentrations of compound X induced lymphopenia, as shown in Table 1 below.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

La présente invention concerne des composés qui sont représentés par la formule générale (I) et conviennent au traitement d'affections auto-immunes et d'affections inflammatoires. Dans cette formule générale (I), R1 est alkyl, alcényl ou alkynyl en C1-C6, phényl, benzyl ou phénéthyl; R2 est H, un alkyl en C1-C5 pouvant être partiellement hydroxylaté ou le groupe (a) dans lequel n vaut de 0 à 4; X, Y et Z sont indépendamment CH, N, NH, O ou S, un ester acceptable en pharmacie, l'un de ses sels d'addition, l'un de ses stéréoisomères ou l'un de ses isomères géométriques. Toutefois, lorsque l'un au moins de X, Y ou Z est CH, celui et lui seul parmi X, Y et Z doit être NH, O ou S, et en outre lorsque Y est N ou NH, Z ne doit être ni N ni NH. L'invention concerne également un procédé de synthèse des composés ainsi qu'un procédé d'utilisation de ces composés.
PCT/AU1997/000342 1996-05-31 1997-05-30 Derives acetyle de thiazoles et analogues Ceased WO1997046543A1 (fr)

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AU28817/97A AU2881797A (en) 1996-05-31 1997-05-30 Acetyl derivatives of thiazoles and analogues

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US65611296A 1996-05-31 1996-05-31
US08/656,112 1996-05-31

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WO2007100617A3 (fr) * 2006-02-24 2008-01-17 Lexicon Genetics Inc Composés à base d'imidazole, compositions les comprenant et leurs méthodes d'utilisation
WO2008109314A1 (fr) * 2007-03-01 2008-09-12 Lexicon Pharmaceuticals, Inc. Composés hétérocycliques, compositions les comprenant et leurs procédés d'utilisation
WO2008128045A1 (fr) * 2007-04-12 2008-10-23 Lexicon Pharmaceuticals, Inc. Formes solide de (e) -1- (4- ( (ir, 2s, 3r) -1, 2, 3, 4-tetrahydroxybutyl) -1h-imidaz0l-2-yl) ethanone oxime
CN101619060A (zh) * 2008-06-30 2010-01-06 莱西肯医药有限公司 杂环化合物、包括其的组合物和它们的使用方法
US7825150B2 (en) 2007-09-06 2010-11-02 Lexicon Pharmaceuticals, Inc. Compositions and methods for treating immunological and inflammatory diseases and disorders
US7968726B2 (en) 2008-06-18 2011-06-28 Lexicon Pharmaceuticals, Inc. Methods of preparing imidazole-based bicyclic compounds
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WO2011102404A1 (fr) 2010-02-18 2011-08-25 第一三共株式会社 Dérivé d'imidazole
WO2013002248A1 (fr) 2011-06-28 2013-01-03 第一三共株式会社 Dérivé ester de l'acide phosphorique
US9200309B2 (en) 2010-06-28 2015-12-01 Daiichi Sankyo Company, Limited Method for screening for S1P lyase inhibitors using cultured cells
CN110698441A (zh) * 2019-10-31 2020-01-17 浙江大学 一类2-甲基-4-(1-丙三醇)-呋喃类化合物及其制备方法和应用

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WO2007100617A3 (fr) * 2006-02-24 2008-01-17 Lexicon Genetics Inc Composés à base d'imidazole, compositions les comprenant et leurs méthodes d'utilisation
JP2009527564A (ja) * 2006-02-24 2009-07-30 レクシコン ファーマシューティカルズ インコーポレイテッド イミダゾール系化合物、それらを含む組成物、及びそれらの使用方法
EP2090334A2 (fr) 2006-02-24 2009-08-19 Lexicon Pharmaceuticals, Inc. Composés à base d'imidazole, compositions les comportant et procédés de leur utilisation
AU2007221265B2 (en) * 2006-02-24 2012-08-02 Lexicon Pharmaceuticals, Inc. Imidazole-based compounds, compositions comprising them and methods of their use
US7649098B2 (en) 2006-02-24 2010-01-19 Lexicon Pharmaceuticals, Inc. Imidazole-based compounds, compositions comprising them and methods of their use
US8093267B2 (en) 2006-02-24 2012-01-10 Lexicon Pharmaceuticals, Inc. Methods of treating rheumatoid arthritis
WO2008109314A1 (fr) * 2007-03-01 2008-09-12 Lexicon Pharmaceuticals, Inc. Composés hétérocycliques, compositions les comprenant et leurs procédés d'utilisation
JP2010520214A (ja) * 2007-03-01 2010-06-10 レクシコン ファーマシューティカルズ インコーポレイテッド 複素環式化合物、それらを含む組成物、及びそれらの使用方法
US7825142B2 (en) 2007-03-01 2010-11-02 Lexicon Pharmaceuticals, Inc. Heterocyclic compounds, compositions comprising them and methods of their use
EA016495B1 (ru) * 2007-03-01 2012-05-30 Лексикон Фармасьютикалз, Инк. Гетероциклические соединения, содержащие их композиции и способы их применения
EA017042B1 (ru) * 2007-04-12 2012-09-28 Лексикон Фармасьютикалз, Инк. Твердые формы (e)-1-(4-((1r,2s,3r)-1,2,3,4-тетрагидроксибутил)-1h-имидазол-2-ил)этаноноксима
TWI412362B (zh) * 2007-04-12 2013-10-21 Lexicon Pharmaceuticals Inc （ｅ）-１-（４-（（１ｒ，２ｓ，３ｒ）-１，２，３，４-四羥丁基）-１ｈ-咪唑-２-基）乙酮肟的固體形式
CN101284818B (zh) * 2007-04-12 2012-10-03 莱西肯医药有限公司 (e)-1-(4-((1r,2s,3r)-1,2,3,4-四羟基丁基)-1h-咪唑-2-基)乙酮肟的固体形式
WO2008128045A1 (fr) * 2007-04-12 2008-10-23 Lexicon Pharmaceuticals, Inc. Formes solide de (e) -1- (4- ( (ir, 2s, 3r) -1, 2, 3, 4-tetrahydroxybutyl) -1h-imidaz0l-2-yl) ethanone oxime
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