WO2012149093A1 - Dérivés de 2-guanidino-4-oxo-imidazoline en tant qu'agents antipaludiques, synthèse et procédés d'utilisation de ceux-ci - Google Patents

Dérivés de 2-guanidino-4-oxo-imidazoline en tant qu'agents antipaludiques, synthèse et procédés d'utilisation de ceux-ci Download PDF

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WO2012149093A1
WO2012149093A1 PCT/US2012/035099 US2012035099W WO2012149093A1 WO 2012149093 A1 WO2012149093 A1 WO 2012149093A1 US 2012035099 W US2012035099 W US 2012035099W WO 2012149093 A1 WO2012149093 A1 WO 2012149093A1
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compound
substituted
heteroaryl
aryl
alkyl
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PCT/US2012/035099
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English (en)
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Ai J. Lin
Xianjun Liu
Michael P. Kozar
Michael T. O'neil
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THE UNITED STATES OF AMERICA, as represented by THE SECRETARY OF ARMY
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Publication of WO2012149093A1 publication Critical patent/WO2012149093A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/88—Nitrogen atoms, e.g. allantoin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to new 2-guanidino-4-oxo-imidazoline derivatives (deoxo-IZ), methods of making these compounds, compositions containing the same, and methods of using the same to prevent, treat, or inhibit malaria in a subject.
  • the compounds have radical curative antimalarial activity.
  • the present invention relates to the synthesis and antimalarial activity of a series of new 2-guanidino-4-oxo-imidazoline derivates represented by the structural formula 8 and 9, below,
  • A is aryl or heteroaryl, each optionally substituted with one or more A la ; wherein each A la is independently selected from the group consisting of hydroxyl, carboxyl, halo, aralkyl, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkylsulfonyl, heterocycle, aryl, C3-7 cycloalkyl, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy, optionally substituted with up to 5 fluoro; preferably A is 3,4-dichloro- phenyl;
  • Ri is H or a substituted or unsubstituted alkyl as defined herein, but preferably, -CH 3 , -CH(CH 3 ) 2 , or -C(CH 3 ) 3 ;
  • R 2 is H, or a substituted or unsubstituted substituent selected from the group consisting of alkyl, alkoxyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, aminoalkyl, sulfonyl, alkylsulfonyl, -COOR 3 and -COR 3 ; and
  • R 3 is a substituted or unsubstituted substituent selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, aminoalkyl, sulfonyl, and alkylsulfonyl;
  • FIG. 1 depicts an illustration of the chemical structure of
  • FIG. 2 depicts an illustration of new 4-oxo-imidazoline derivates.
  • (A) compound 8, wherein Ri H, or alkyl, but preferably -CH 3 , -CH(CH 3 ) 2 , or -C(CH 3 ) 3 ;
  • R 2 H, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, acyl, aryl, heteroaryl, alkylaryl, aminoalkyl, sulfonyl, alkylsulfonyl, -COOR 3 or -COR 3 ;
  • R 3 alkyl, alkoxy, cycloalkyl, heterocycloalkyl, acyl, aryl, heteroaryl, alkylaryl, aminoalkyl, sulfonyl, or alkylsulfonyl;
  • (B) compound 9, wherein Ri H, or alkyl, but preferably -CH 3 , -CH(CH 3 ) 2
  • the present invention encompasses antimalarial compounds, methods of synthesizing such compounds, and methods of use thereof.
  • One aspect of the present invention encompasses an antimalarial compound, as defined by formulas 8 and 9 below. It is understood that while a compound of the general structural formulas herein may exhibit the phenomenon of tautomerism, the structural formulas within this specification are expressly depicted in only one of the possible tautomeric forms. It is, therefore, to be understood that the structural formulas herein are intended to represent any tautomeric form of the depicted compound and is not to be limited merely to a specific compound form depicted by the structural formulas.
  • the structural formulas are intended to represent any configurational form of the depicted compound (i.e., stereoisomers, etc.) and is not to be limited merely to a specific compound form depicted by the structural formulas.
  • optically active (R) and (S) isomers may be prepared via a stereospecific synthesis, e.g., using chiral synthons and chiral reagents, or racemic mixtures may be resolved using conventional techniques.
  • Some of the compounds of the present invention may exist as single stereoisomers (i.e., essentially free of other stereoisomers), racemates, or mixtures of enantiomers, diastereomers, or both. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention.
  • the inventive compounds that are optically active are used in optically pure form.
  • an optically pure compound having one chiral center is one that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure.
  • the compounds of the present invention are made synthetically, they are used in a form that is at least 90% optically pure, that is, a form that comprises at least 90% of a single isomer (80% enantiomeric excess (e.e.) or diastereomeric excess (d.e.), more preferably at least 95% (90%) e.e. or d.e.), even more preferably at least 97.5% (95% e.e. or d.e.), and most preferably at least 99% (98% e.e. or d.e.).
  • One aspect of the present invention is a compound represented by the structural formula 8:
  • A is aryl or heteroaryl, each optionally substituted with one or more A la ; wherein each A la is independently selected from the group consisting of hydroxyl, carboxyl, halo, aralkyl, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkylsulfonyl, heterocycle, aryl, C3-7 cycloalkyl, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy, optionally substituted with up to 5 fluoro;
  • Ri is selected from the group consisting of H, a substituted alkyl, and an unsubstituted alkyl
  • R 2 is selected from the group consisting of H, and a substituted or unsubstituted substituent selected from the group consisting of alkyl, alkoxyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, sulfonyl, alkylsulfonyl, aminoalkyl, -COOR 3 and -COR 3 ; and
  • R 3 is selected from the group consisting of a substituted or unsubstituted substituent selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, aminoalkyl, sulfonyl, and alkylsulfonyl.
  • a compound of the invention is a tautomer, or pharmaceutically acceptable salt of 8.
  • A is 3,4-dichlorophenyl.
  • Ri is selected from the group consisting of H, a substituted alkyl, and an unsubstituted alkyl
  • R 2 is selected from the group consisting of H, and a substituted or unsubstituted substituent selected from the group consisting of alkyl, alkoxyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, sulfonyl, alkylsulfonyl, aminoalkyl, -COOR 3 and -COR 3
  • R 3 is selected from the group consisting of a substituted or unsubstituted substituent selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, aminoalkyl, sulfonyl
  • A is 3,4-dichlorophenyl
  • Ri is selected from -CH3, -CH(CH 3 ) 2 , and -C(CH 3 ) 3
  • R 2 is selected from the group consisting of H, and a substituted or unsubstituted substituent selected from the group consisting of alkyl, alkoxyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, sulfonyl, alkylsulfonyl, aminoalkyl, -COOR 3 and -COR 3
  • R 3 is selected from the group consisting of a substituted or unsubstituted substituent selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, aminoalkyl, sulfonyl, and alkylsulfonyl.
  • A is 3,4-dichlorophenyl
  • Ri is selected from - CH 3 , -CH(CH 3 ) 2 , and -C(CH 3 ) 3
  • R 2 is selected from -COOC(CH 3 ) 3 , -COOCH 2 CH 3 , -COC(CH 3 ) 3 , -COCH(CH 2 CH 3 ) 2 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 CH 3 , and -adamantyl.
  • a compound of the invention is a compound of formula 8 listed in Table A.
  • a compound of the invention is a compound of formula 8 listed in Table B.
  • a compound of the invention is a compound of formula 8 listed in Table C.
  • heterocycloalkyl heterocycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl, heteroaryl, alkylaryl, sulfonyl, alkylaryl, alkylsulfonyl, aminoalkyl, aminoalkyl, - sulfonyl, and COOR 3 and -COR 3 alkylsulfonyl aryl optionally H substituted unsubstituted substituted with one substituent selected substituent selected or more A la from the group from the group consisting of alkyl, consisting of alkyl, alkoxyl, cycloalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl, heteroaryl, alkylaryl, sulfonyl, alkylaryl, alkylsulfonyl, aminoalkyl, aminoalkyl, - sulfonyl, and COOR 3 and
  • alkylsulfonyl aminoalkyl, aminoalkyl, - sulfonyl, and COOR 3 and -COR 3 alkylsulfonyl aryl optionally substituted alkyl unsubstituted unsubstituted substituted with one substituent selected substituent selected or more A la from the group from the group consisting of alkyl, consisting of alkyl, alkoxyl, cycloalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl, heteroaryl, alkylaryl, sulfonyl, alkylaryl, alkylsulfonyl, aminoalkyl, aminoalkyl, - sulfonyl, and COOR 3 and -COR 3 alkylsulfonyl aryl optionally unsubstituted alkyl H substituted substituted with one substituent selected or more A la from the group consisting of
  • alkylsulfonyl aryl optionally unsubstituted alkyl substituted unsubstituted substituted with one substituent selected substituent selected or more A la from the group from the group consisting of alkyl, consisting of alkyl, alkoxyl, cycloalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl, heteroaryl, alkylaryl, sulfonyl, alkylaryl, alkylsulfonyl, aminoalkyl, aminoalkyl, - sulfonyl, and COOR 3 and -COR 3 alkylsulfonyl aryl optionally unsubstituted alkyl unsubstituted substituted substituted with one substituent selected substituent selected or more A la from the group from the group consisting of alkyl,
  • alkylsulfonyl heteroaryl H H unsubstituted optionally substituent selected substituted with one from the group or more A la consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, aminoalkyl, sulfonyl, and alkylsulfonyl heteroaryl H substituted substituted optionally substituent selected substituent selected substituted with one from the group from the group or more A la consisting of alkyl, consisting of alkyl, alkoxyl, cycloalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl, heteroaryl, alkylaryl, sulfonyl, alkylaryl, alkylsulfonyl, aminoalkyl, aminoalkyl, - sulfonyl, and COOR 3 and -COR 3 alkylsulfonyl hetero
  • substituent selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, aminoalkyl, sulfonyl, and alkylsulfonyl ,4-dichlorophenyl isopropyl substituted substituted
  • substituent selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, aminoalkyl, sulfonyl, and alkylsulfonyl ,4-dichlorophenyl t-butyl substituted substituted
  • substituted or unsubstituted aryl -CH 3 -COOC(CH 3 ) 3 substituted or unsubstituted aryl -CH 3 -COOCH 2 CH 3 substituted or unsubstituted aryl -CH 3 -COC(CH 3 ) 3 substituted or unsubstituted aryl -CH 3 -COCH(CH 2 CH 3 ) 2 substituted or unsubstituted aryl -CH 3 -CH(CH 3 ) 2
  • a compound of the invention has a formula of compound 8a, 8b, 8c, 8d, 8e, 8f, 8g, 8h, 8j, 8k, 81, 8m or 8n.
  • a compound of the invention is a tautomer or pharmaceutically acceptable salt of compound 8a, 8b, 8c, 8d, 8e, 8f, 8g, 8h, 8j, 8k, 81, 8m or 8n.
  • a compound of the invention has a formula of compound 8e.
  • a compound of the invention is a tautomer or pharmaceutically acceptable salt of compound 8e. (b) compounds of formula 9
  • One aspect of the present invention is a compound represented by the structural formula 9:
  • A is aryl or heteroaryl, each optionally substituted with one or more A la ; wherein each A la is independently selected from the group consisting of hydroxyl, carboxyl, halo, aralkyl, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkylsulfonyl, heterocycle, aryl, C3-7 cycloalkyl, Ci_ 6 alkyl optionally substituted with up to 5 fluoro, and Ci_6 alkoxy, optionally substituted with up to 5 fluoro;
  • Ri is selected from the group consisting of H, a substituted alkyl, and an unsubstituted alkyl
  • R 2 is selected from the group consisting of H, and a substituted or unsubstituted substituent selected from the group consisting of alkyl, alkoxyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, sulfonyl, alkylsulfonyl, aminoalkyl, -COOR 3 and -COR 3 ; and
  • R 3 is selected from the group consisting of a substituted or unsubstituted substituent selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, aminoalkyl, sulfonyl, and alkylsulfonyl.
  • a compound of the invention is a tautomer, or pharmaceutically acceptable salt of 9.
  • A is 3,4-dichlorophenyl.
  • Ri is selected from the group consisting of H, a substituted alkyl, and an unsubstituted alkyl
  • R 2 is selected from the group consisting of H, and a substituted or unsubstituted substituent selected from the group consisting of alkyl, alkoxyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, sulfonyl, alkylsulfonyl, aminoalkyl, -COOR 3 and -COR 3
  • R 3 is selected from the group consisting of a substituted or unsubstituted substituent selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, aminoalkyl, sulfonyl
  • A is 3,4-dichlorophenyl
  • Ri is selected from -CH 3 , -CH(CH 3 ) 2 , and -C(CH 3 ) 3
  • R 2 is selected from the group consisting of H, and a substituted or unsubstituted substituent selected from the group consisting of alkyl, alkoxyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, sulfonyl, alkylsulfonyl, aminoalkyl, -COOR 3 and -COR 3
  • R 3 is selected from the group consisting of a substituted or unsubstituted substituent selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, aminoalkyl, sulfonyl, and alkylsulfonyl.
  • A is 3,4-dichlorophenyl
  • Ri is selected from - CH 3 , -CH(CH 3 ) 2 , and -C(CH 3 ) 3
  • R 2 is selected from H, -COOC(CH 3 ) 3 , - COOCH 2 CH 3 , -COC(CH 3 ) 3 , and -COCH(CH 2 CH 3 ) 2 .
  • A is 3,4-dichlorophenyl
  • Ri is -CH(CH 3 ) 2
  • R 2 is selected from H, -COOC(CH 3 ) 3 , - COOCH 2 CH 3 , -COC(CH 3 ) 3 , and -COCH(CH 2 CH 3 ) 2 .
  • a compound of the invention is a compound of formula 9 listed in Table D.
  • a compound of the invention is a compound of formula 9 listed in Table E.
  • a compound of the invention is a compound of formula 9 listed in Table F.
  • aryl optionally H H unsubstituted substituted with one substituent selected or more A la from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, aminoalkyl, sulfonyl, and alkylsulfonyl aryl optionally H substituted substituted substituted with one substituent selected substituent selected or more A la from the group from the group consisting of alkyl, consisting of alkyl, alkoxyl, cycloalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl, heteroaryl, alkylaryl, sulfonyl, alkylaryl, alkylsulfonyl, aminoalkyl, aminoalkyl, - sulfonyl, and COOR 3 and -COR 3 alkylsulfonyl aryl optionally H substituted unsub
  • heterocycloalkyl heterocycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl, heteroaryl, alkylaryl, sulfonyl, alkylaryl, alkylsulfonyl, aminoalkyl, aminoalkyl, - sulfonyl, and COOR 3 and -COR 3 alkylsulfonyl heteroaryl H H substituted optionally substituent selected substituted with one from the group or more A la consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, aminoalkyl, sulfonyl, and alkylsulfonyl heteroaryl H H unsubstituted optionally substituent selected substituted with one from the group or more A la consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, aminoalkyl, sulfon
  • alkylsulfonyl aminoalkyl, aminoalkyl, - sulfonyl, and COOR 3 and -COR 3 alkylsulfonyl heteroaryl unsubstituted alkyl H substituted optionally substituent selected substituted with one from the group or more A la consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, aminoalkyl, sulfonyl, and alkylsulfonyl heteroaryl unsubstituted alkyl H unsubstituted optionally substituent selected substituted with one from the group or more A la consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, aminoalkyl, sulfonyl, and alkylsulfonyl heteroaryl unsubstituted alkyl substituted substituted optionally substituent selected substituted with one from
  • alkylsulfonyl heteroaryl unsubstituted alkyl unsubstituted substituted optionally substituent selected substituent selected substituted with one from the group from the group or more
  • alkylsulfonyl heteroaryl unsubstituted alkyl unsubstituted unsubstituted optionally substituent selected substituent selected substituted with one from the group from the group or more
  • substituents selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, aminoalkyl, sulfonyl, and alkylsulfonyl
  • heterocycloalkyl aryl, heteroaryl, alkylaryl, aminoalkyl, sulfonyl, and alkylsulfonyl ,4-dichlorophenyl methyl substituted substituted
  • substituent selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, aminoalkyl, sulfonyl, and alkylsulfonyl ,4-dichlorophenyl isopropyl substituted substituted
  • substituent selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl,
  • substituted or unsubstituted heteroaryl -CH 3 -COOC(CH 3 ) 3 substituted or unsubstituted heteroaryl -CH 3 -COOCH 2 CH 3 substituted or unsubstituted heteroaryl -CH 3 -COC(CH 3 ) 3 substituted or unsubstituted heteroaryl -CH 3 -COCH(CH 2 CH 3 ) 2 substituted or unsubstituted heteroaryl -CH 3 -CH(CH 3 ) 2 substituted or unsubstituted heteroaryl -CH 3 -C(CH 3 ) 3 substituted or unsubstituted heteroaryl -CH 3 -CH 2 CH 3 substituted or unsubstituted heteroaryl -CH 3 -adamantyl substituted or unsubstituted heteroaryl -CH(CH 3 ) 2 H
  • a compound of the invention has a formula of compound 9a, 9b, 9c, 9d, or 9e.
  • a compound of the invention is a tautomer or pharmaceutically acceptable salt of compound 9a, 9b, 9c, 9d, or 9e.
  • the compounds of the invention may include pharmaceutically acceptable salts, multimeric forms, prodrugs, active metabolites, precursors and salts of such metabolites of the compounds of the present invention.
  • salts refers to salt forms that are pharmacologically acceptable and substantially non-toxic to the subject being treated with the compound of the invention.
  • Pharmaceutically acceptable salts include
  • acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, methanesulfonic acid, ethane-disulfonic acid, isethionic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, 2-acetoxybenzoic acid, acetic acid, phenylacetic acid, propionic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, ascorbic acid, maleic acid, hydroxymaleic acid, glutamic acid, sal
  • Exemplary base-addition salts include those derived from ammonium hydroxides (e.g., a quaternary ammonium hydroxide such as tetramethylammonium hydroxide), those derived from inorganic bases such as alkali or alkaline earth-metal (e.g., sodium, potassium, lithium, calcium, or magnesium) hydroxides, and those derived from non-toxic organic bases such as basic amino acids.
  • ammonium hydroxides e.g., a quaternary ammonium hydroxide such as tetramethylammonium hydroxide
  • inorganic bases such as alkali or alkaline earth-metal (e.g., sodium, potassium, lithium, calcium, or magnesium) hydroxides
  • non-toxic organic bases such as basic amino acids.
  • multimer refers to multivalent or multimeric forms of active forms of the compounds of the invention. Such “multimers” may be made by linking or placing multiple copies of an active compound in close proximity to each other, e.g., using a scaffolding provided by a carrier moiety. Multimers of various dimensions (i.e., bearing varying numbers of copies of an active compound) may be tested to arrive at a multimer of optimum size with respect to receptor binding. Provision of such
  • multivalent forms of active receptor-binding compounds with optimal spacing between the receptor-binding moieties may enhance receptor binding. See, for example, Lee et al., (1984) Biochem. 23:4255. The artisan may control the multivalency and spacing by selection of a suitable carrier moiety or linker units.
  • Useful moieties may include molecular supports comprising a multiplicity of functional groups that can be reacted with functional groups associated with the active compounds of the invention.
  • carrier moieties may be used to build highly active multimers, including proteins such as BSA (bovine serum albumin) or peptides such as pentapeptides, decapeptides, pentadecapeptides, and the like, as well as non-biological compounds selected for their beneficial effects on absorbability, transport, and persistence within the target organism.
  • Functional groups on the carrier moiety such as amino, sulfhydryl, hydroxyl, and alkylamino groups, may be selected to obtain stable linkages to the compounds of the invention, optimal spacing between the immobilized compounds, and optimal biological properties.
  • a pharmaceutically acceptable prodrug is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such compound.
  • a pharmaceutically active metabolite is intended to mean a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. Prodrugs and active metabolites of a compound may be identified using routine techniques known in the art See, e.g., Bertolini, G. et al, (1997) J. Med. Chem. 40:2011 2016; Shan, D. et al, J.
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyrvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an a-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
  • an inorganic acid such as hydrochloric acid,
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include organic salts derived from basic amino acids, such as lysine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • compositions of the invention may further comprise supplementary active compounds.
  • Supplementary active compounds may include antimalarials, antiproliferative agents, antibacterials, antiprotozoal agents, antifungal agents, anti-inflammatory agents, and other compounds commonly used to treat diseases and disorders related to cell proliferation, inflammation, and bacterial, protozoal, and fungal infections.
  • Non- limiting examples of suitable antimalarials may include chloroquine, quinine, mefloquine, amodiaquin, primaquine, pyrimethamine, sulfonamides, sulfones, dihydrofolate reductase inhibitors, tetrandine, derivatives thereof, and the like.
  • antimalarial refers to compounds that show activity against Plasmodium parasites using assays known in the art.
  • the suitable antimalarial is chloroquine.
  • Non- limiting examples of suitable antibiotics may include penicillin, cloxacillin, dicloxacillin, methicillin, nafcillin, oxacillin, ampicillin, amoxicillin, bacampicillin, azlocillin, carbenicillin, mezlocillin, piperacillin, ticarcillin, azithromycin, clarithromycin, clindamycin, erythromycin, lincomycin, demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, quinolone, cinoxacin, nalidixic acid, fluoroquinolone, ciprofloxacin, enoxacin, grepafloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, sparfloxacin, trovafloxacin, bacitracin, colistin, polymyxin B, s
  • Non-limiting examples of antiprotozoal agents may include
  • trimethoprim-sulfamethoxazole pyrimethamine, sulfadiazine, and the like.
  • Non- limiting examples of antifungal agents may include amphotericin B, fluconazole, itraconazole, ketoconazole, potassium iodide, flucytosine, and the like.
  • Non-limiting examples of antiproliferative agents may include altretamine, amifostine, anastrozole, arsenic trioxide, bexarotene, bleomycin, busulfan, capecitabine, carboplatin, carmustine, celecoxib, chlorambucil, cisplatin, cisplatin- epinephrine gel, cladribine, cytarabine liposomal, daunorubicin liposomal, daunorubicin daunomycin, dexrazoxane, docetaxel, doxorubicin, doxorubicin liposomal, epirubicin, estramustine, etoposide phosphate, etoposide VP- 16, exemestane, fludarabine, fluorouracil 5-FU, fulvestrant, gemicitabine, gemtuzumab-ozogamicin, goserelin acetate, hydroxyurea,
  • Non- limiting examples of anti-inflammatory agents may include steroids such as predinsolone, corticosteroid, and the like.
  • compositions within the scope of the present invention comprise a therapeutically effective amount of at least one compound of the present invention, and a pharmaceutically acceptable carrier.
  • Pharmaceutical compositions within the scope of the present invention may further comprise a supplementary active compound such as an antimalarial agent, an antiproliferative agent, an antifungal agent, an antibacterial agent, an anti-inflammatory agent, etc.
  • a supplementary active compound such as an antimalarial agent, an antiproliferative agent, an antifungal agent, an antibacterial agent, an anti-inflammatory agent, etc.
  • a pharmaceutical formulation of the present invention comprises at least one compound of the present invention and may be prepared in a unit-dosage form appropriate for the desired mode of administration.
  • a pharmaceutical formulation of the present invention may be administered for therapy by any suitable route including oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal). It will be appreciated that the preferred route will vary with the condition and age of the recipient, the nature of the condition to be treated, and the chosen compound of the present invention.
  • Administration of prodrugs may be dosed at weight levels that are chemically equivalent to the weight levels of the fully active forms.
  • a compound of the present invention can be incorporated into pharmaceutical formulations suitable for administration.
  • a pharmaceutical formulation of this invention comprises a therapeutically effective amount of at least one compound of the present invention, and an inert, pharmaceutically or cosmetically acceptable carrier or diluent.
  • pharmaceutically or cosmetically acceptable carrier is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical or cosmetic administration.
  • the pharmaceutical or cosmetic carrier employed may be either a solid or liquid.
  • Exemplary of solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like.
  • the carrier or diluent may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate and the like. The use of such media and agents for pharmaceutically or cosmetically active substances is well known in the art.
  • compositions within the scope of the present invention may be employed in any suitable pharmaceutically acceptable carrier.
  • suitable pharmaceutically acceptable carriers include but not limited to, benzyl alcohol, benzyl ether, benzyl ether, benzyl ether, benzyl ether, benzyl ether sulfonylurea, benzyl ether sulfonylurea, benzyl ether sulfonylurea, sulfonylureadiol, sulfonyl, sulfate, a suitable pharmaceutically acceptable carrier, benzylureasulfate, benzyl ether sulfonylurea sulfonylurea sulfonylurea sulfonylurea sulfonylurea sulfonylurea sulfonylurea sulfonylurea sulfonylurea sulf
  • compounds and compositions within the scope of the present invention may be administered to a patient via any suitable pharmaceutically acceptable routes of administration.
  • routes of administration For example, they may be administered orally, intramuscularly, transdermally, via nasal inhalation or via suppository.
  • suitable routes of administration which may be employed in use of the compounds and compositions herein.
  • selection of a suitable pharmaceutically acceptable carrier to employ to facilitate the route of administration sought is within the skill of the art.
  • a pharmaceutical or cosmetic formulation of the invention is formulated to be compatible with its intended route of administration.
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • a variety of pharmaceutical forms can be employed.
  • the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
  • the amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g.
  • a liquid carrier is used, the preparation will be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension.
  • a pharmaceutically acceptable salt of an inventive agent is dissolved in an aqueous solution of an organic or inorganic acid, such as 0.3M solution of succinic acid or citric acid.
  • an organic or inorganic acid such as 0.3M solution of succinic acid or citric acid.
  • the agent may be dissolved in a suitable co-solvent or combinations of co-solvents.
  • suitable co-solvents include, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from about 0% to about 60% of the total volume.
  • the pharmaceutical formulation may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.
  • compositions of the invention may be any pharmaceutical formulations of the invention.
  • compositions manufactured in manners generally known for preparing pharmaceutical compositions, e.g., using conventional techniques such as mixing, dissolving, granulating, dragee- making, levigating, emulsifying, encapsulating, entrapping or lyophilizing.
  • compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, which may be selected from excipients and auxiliaries that facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • the agents of the invention may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds of the present invention can be formulated readily by combining with pharmaceutically acceptable carriers known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (compound), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium
  • polyvinylpyrrolidone PVP
  • disintegrating agents such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally comprise gum horoi, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can comprise the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and, optionally, stabilizers.
  • the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • the formulations may take the form of tablets or lozenges formulated in conventional manner.
  • Oral formulations generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral formulations can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can comprise any of the following ingredients, or compounds of a similar nature: a binder such as
  • microcrystalline cellulose, gum tragacanth or gelatin an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • Preferred formulations for oral formulations include microcrystalline tablets, gelatin capsules, or the like.
  • the compounds of the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas
  • the compounds of the present invention may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit-dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the formulations may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may comprise formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • Aqueous injection suspensions may comprise substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also comprise suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • suspensions of the active agents may be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor EL.TM. (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
  • the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium comprising, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid horoidsene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the formulation.
  • Prolonged absorption of the injectable compositions can be brought about by including in the formulation an agent which delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating a therapeutically effective amount of at least one compound of the present invention in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the compound of the present invention into a sterile vehicle which comprises a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active compound plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active compounds are formulated into ointments, salves, gels, foams, powders, sprays, aerosols or creams as generally known in the art.
  • pharmaceutically acceptable excipients or cosmetically acceptable carriers and additives include solvents, emollients, humectants, preservatives, emulsifiers, and pH agents.
  • Suitable solvents include ethanol, acetone, glycols, polyurethanes, and others known in the art.
  • Suitable emollients include petrolatum, mineral oil, propylene glycol dicaprylate, lower fatty acid esters, lower alkyl ethers of propylene glycol, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, stearic acid, wax, and others known in the art.
  • Suitable humectants include glycerin, sorbitol, and others known in the art.
  • Suitable emulsifiers include glyceryl monostearate, glyceryl monoleate, stearic acid, polyoxyethylene cetyl ether, polyoxyethylene cetostearyl ether, polyoxyethylene stearyl ether, polyethylene glycol stearate, propylene glycol stearate, and others known in the art.
  • Suitable pH agents include hydrochloric acid, phosphoric acid, diethanolamine, triethanolamine, sodium hydroxide, monobasic sodium phosphate, dibasic sodium phosphate, and others known in the art.
  • Suitable preservatives include benzyl alcohol, sodium benzoate, parabens, and others known in the art.
  • the compounds of the present invention may be delivered in a pharmaceutically acceptable ophthalmic vehicle such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the corneal and internal regions of the eye, including, for example, the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/cilary, lens, horoids/retina and selera.
  • the pharmaceutically acceptable ophthalmic vehicle may be an ointment, vegetable oil, or an encapsulating material.
  • Compounds of the present invention may also be injected directly into the vitreous and aqueous humor.
  • compounds of the present invention may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., comprising conventional suppository bases such as cocoa butter or other glycerides.
  • compounds of the present invention may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds of the present invention may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • the cosolvent system may be a VPD co-solvent system.
  • VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the VPD co-solvent system (VPD:5W) comprises VPD diluted 1 : 1 with a 5% dextrose in water solution.
  • This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
  • the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • identity of the co-solvent components may be varied, for example: other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose.
  • other delivery systems for hydrophobic pharmaceutical formulations may be employed.
  • Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs and cosmetics. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers comprising the therapeutic agent. Various sustained-release materials have been established and are known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.
  • the pharmaceutical formulations also may comprise suitable solid- or gel-phase carriers or excipients.
  • suitable solid- or gel-phase carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • Some of the compounds of the invention may be provided as salts with pharmaceutically compatible counter ions.
  • Pharmaceutically compatible salts may be formed with many acids, including hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, and the like. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free-base forms.
  • the compounds of the present invention are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • the materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
  • Liposomal suspensions can also be used as pharmaceutically or cosmetically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit comprising a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 / ED 50
  • Compounds which exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.
  • the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC 50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture.
  • IC 50 i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms
  • levels in plasma may be measured, for example, by high performance liquid chromatography. f) solvates
  • solvates are intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound.
  • examples of solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or acetone.
  • miscible formulations of solvate mixtures such as a compound of the invention in combination with an acetone and ethanol mixture.
  • the solvate includes a compound of the invention in combination with about 20% ethanol and about 80% acetone.
  • the structural formulas include compounds having the indicated structure, including the hydrated as well as the non-hydrated forms.
  • the compounds of the present invention in accordance with the present invention are useful in the treatment of malaria and diseases and disorders associated with malaria or a Plasmodium parasite.
  • the antimalarial activity of the compounds of the present invention may be measured by any of the methods available to those skilled in the art, including in vitro and in vivo assays. Examples of suitable assays for activity measurements are provided herein. Properties of the compounds of the present invention may be assessed, for example, by using one or more of the assays set out in the Examples below. Other pharmacological methods may also be used to determine the efficacy of the compounds as antimalarial agents.
  • the compounds of the present invention may be used in combination with or as a substitution for treatments of the above conditions.
  • the compounds of the present invention may also be used alone or combination with antimalarial agents known in the art.
  • the compounds of the present invention may be used alone or in combination with supplementary active compounds including antibiotics, antiprotozoal agents, antifungal agents, and antiproliferative agents, and analgesics known in the art. (For instance, see section 1(d) above.)
  • a compound of the present invention may be administered in a therapeutically effective amount to a mammal such as a human.
  • Therapeutically effective amounts of the compounds of the present invention may be used to treat, modulate, attenuate, reverse, or affect malaria in a mammal.
  • An "effective amount" is intended to mean that amount of an agent that is sufficient to treat, prevent, or inhibit malaria or a disease or disorder associated with malaria.
  • malaria or the disease or disorder associated with malaria is caused by a Plasmodium parasite, preferably, P. falciparum, P. vivax, P. ovale, or P. malariae.
  • a "therapeutically effective amount" of a compound of the present invention, a prodrug, an active metabolite, or a salt thereof is a quantity sufficient to, when administered to a mammal, treat, prevent, or inhibit malaria or a disease or disorder associated with malaria or a Plasmodium parasite.
  • the amount of a given compound of the present invention that will correspond to such an amount will vary depending upon factors such as the given drug or compound, the pharmaceutical formulation and route of administration, the type of disease or disorder, the identity of the subject or host being treated, and the like, but can nevertheless be routinely determined by one skilled in the art.
  • a "therapeutically effective amount" of a compound of the present invention is an amount which prevents, inhibits, suppresses, or reduces malaria (as determined by clinical symptoms or the amount of Plasmodium organisms) in a subject as compared to a control.
  • a therapeutically effective amount of a compound of the present invention may be readily determined by one of ordinary skill by routine methods known in the art. [0078]
  • a therapeutically effective amount of a compound of the invention ranges from about 0.1 to about 1,000 mg/kg body weight, preferably about 0.1 to about 500 mg/kg body weight, and more preferably about 0.1 to about 100 mg/kg body weight.
  • certain factors may influence the dosage required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present.
  • Preferred topical concentrations include about 0.1% to about 10% of at least one compound of the present invention in a formulated salve.
  • the skilled artisan will appreciate that certain factors may influence the dosage required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present.
  • treatment of a subject with a therapeutically effective amount of the compound of the present invention may consist of a single administration, or alternatively comprise a series of applications.
  • a subject may be treated with a compound of the present invention at least once.
  • the subject may be treated with the compound from about one time per week to about once daily for a given treatment period.
  • the length of the treatment period will depend on a variety of factors such as the severity of inflammation, the concentration and activity of the compounds of the present invention, or a combination thereof.
  • the effective dosage of the compound used for treatment may increase or decrease over the course of a particular treatment. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances chronic administration may be required.
  • the compounds of the present invention may be administered before exposure, during exposure, after exposure, or a combination thereof to malaria or a Plasmodium parasite.
  • kits of the invention comprises a compound described in section I above, packaged together with instructional material.
  • the compound may be part of a pharmaceutical formulation.
  • the kit may further comprise a supplementary active compound.
  • alkyl is intended to mean a straight or branched chain
  • a "lower alkyl group” is intended to mean an alkyl group having from 1 to 8 carbon atoms in its chain.
  • a "cycloalkyl” is intended to mean a non-aromatic monovalent monocyclic, bicyclic, or tricyclic radical comprising 3-14 carbon ring atoms, each of which may be saturated or unsaturated, and which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more heterocycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more substituents.
  • Illustrative examples of cycloalkyl groups include the following moieties:
  • heterocycloalkyl is intended to mean a non-aromatic monovalent monocyclic, bicyclic, or tricyclic radical, which is saturated or unsaturated, comprising 3- 18 ring members, which includes 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur, where the radical is unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents.
  • suitable substituents as defined below
  • Illustrative examples of heterocycloalkyl groups include the following moieties:
  • aryl is intended to mean an aromatic monovalent monocyclic, bicyclic, or tricyclic radical comprising 6, 10, 14, or 18 carbon ring members, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents.
  • aryl group includes a benzyl group (Bzl).
  • aryl groups include the following moieties:
  • heteroaryl is intended to mean an aromatic monovalent monocyclic, bicyclic, or tricyclic radical comprising 4-18 ring members, including 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or aryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents.
  • suitable substituents as defined below
  • heterocycle is intended to mean a heteroaryl or heterocycloalkyl group (each of which, as defined above, are optionally substituted).
  • aryl (Ar) and “heteroaryl” refer to monocyclic and polycyclic unsaturated or aromatic ring structures, with “aryl” referring to those that are carbocycles and “heteroaryl” referring to those that are heterocycles.
  • aromatic ring structures include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, furyl, thienyl, pyrrolyl, pyridyl, pyridinyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, 1,2,3- triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, l-H-tetrazol-5-yl, indolyl, quinolinyl, benzofuranyl, benzothiophenyl (thianaphthenyl), and the like.
  • acyl is intended to mean a -C(0)-R a radical, where R a is a suitable substituent as defined below.
  • a "thioacyl” is intended to mean a -C(S)-R a radical, where R a is a suitable substituent as defined below.
  • a "sulfonyl” is intended to mean a -S0 2 R a radical, where R a is a suitable substituent as defined below.
  • a "hydroxyl” is intended to mean the radical -OH.
  • amino is intended to mean the radical -NH 2 .
  • alkylamino is intended to mean the radical -NHR a , where R a is an alkyl group.
  • dialkylamino is intended to mean the radical -NR a R b , where R a and R b are each independently an alkyl group.
  • alkoxyl is intended to mean the radical -OR a , where R a is an alkyl group.
  • alkoxyl groups include methoxyl, ethoxyl, propoxyl, and the like.
  • alkoxycarbonyl is intended to mean the radical -C(0)OR a , where R a is an alkyl group.
  • alkylsulfonyl is intended to mean the radical -S0 2 R a , where R a is an alkyl group.
  • alkylaminocarbonyl is intended to mean the radical -C(0)NHR a , where R a is an alkyl group.
  • a "dialkylaminocarbonyl” is intended to mean the radical -C(0)NR a R b , where R a and R b are each independently an alkyl group.
  • a "mercapto" is intended to mean the radical -SH.
  • alkylthio is intended to mean the radical -SR a , where R a is an alkyl group.
  • a "carboxyl” is intended to mean the radical -C(0)OH.
  • a "carbamoyl” is intended to mean the radical -C(0)NH 2 .
  • aryloxyl is intended to mean the radical -OR c , where R c is an aryl group.
  • a "heteroaryloxyl” is intended to mean the radical -OR d , where
  • R.sup.d is a heteroaryl group.
  • arylthio is intended to mean the radical -SR C , where R c is an aryl group.
  • heteroarylthio is intended to mean the radical -SR d , where R d is a heteroaryl group.
  • heterocycloalkyl which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl); carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic aryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); amino (primary, secondary
  • Such moieties may also be optionally substituted by a fused-ring structure or bridge, for example OCH 2 -O. All of these substituents may optionally be further substituted with a substituent selected from groups such as hydroxyl groups, halogens, oxo groups, alkyl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkyloxyl groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, carboxyl groups, amino groups, alkylamino groups, dialkylamino groups, carbamoyl groups, aryloxyl groups, heteroaryloxyl groups, arylthio groups, heteroarylthio groups, and the like.
  • groups such as hydroxyl groups, halogens, oxo groups, alkyl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkyloxyl
  • optionally substituted is intended to expressly indicate that the specified group is unsubstituted or substituted by one or more suitable substituents, unless the optional substituents are expressly specified, in which case the term indicates that the group is unsubstituted or substituted with the specified substituents.
  • various groups may be unsubstituted or substituted (i.e., they are optionally substituted) unless indicated otherwise herein (e.g., by indicating that the specified group is unsubstituted).
  • Carbamate 3 the most active compound of this class, protect(s) monkeys infected with P. cynomolgi sporozoites at a dose of 10 mg/kg x 3 days by im dosing. Nevertheless, the IZ derivatives showed very weak or no in vitro cell growth inhibition against blood stage malaria P. falciparum and are inactive in Thompson mouse test against P. berghei, a blood stage rodent malaria 17"18 . This is believed to be the first class of antimalarial agents possessing activity against the liver stage malaria exclusively. From the view point of drug resistant development, drugs used exclusively for prophylaxis have a significantly decreased chance of exposure to parasites than those used for treatment, and thus there is less concern with developing drug resistance. However, carbamate 3 showed poor activities by oral administration; it protects the treated monkeys for only 3 days vs.
  • imidazolinedione ring of the IZ molecules (1-6) were replaced with a chemically more stable 4-oxo-imidazoline ring (see compounds 8 and 9) as shown in FIG. 2.
  • Deoxo-IZ (8a-c), N-carbamates (8d-g) and N-carboxamides (8h-i) were prepared according to Scheme 1.
  • the starting material N-alkylaminoacetic acid (lOa-c) and l-alkyl-2-thiohydantoin (lla-c) were prepared according to the reported procedures 21"22 .
  • the starting material lOa-c was obtained in over 90% yield by treatment of hydroxyacetonitrile with primary amine at room temperature for 1 h, followed by NaOH hydrolysis. Fusion of N-alkylaminoacetic acid lOa-b with NH 4 SCN at 140 °C gave compound lla-b in 65% yields.
  • guanidine derivatives (8a-c) were readily prepared in good yield by coupling of l-alkyl-2- methylsulfanyl-imidazolin-4-one (13a-c) with 3,4-dichlorophenyl-guanidine.
  • Carbamates 8d-g was prepared by treatment of 8a, 8b or 8c with 1 equiv of di-t-butyl dicarbonate or alkyl chloroformate under basic condition.
  • treatment of compound 8b with 1 equiv. of trimethylacetyl chloride or 2-ethylbutyryl chloride resulted in the formation of carboxamides 8h and 8i, respectively.
  • Isopropyl group was considered an essential substituent at Ni-position of imidazolinedione ring of IZ antimalarials 1-6 in previous studies.
  • a number of N-CH 3 and N-C(CH 3 ) 3 analogs 8a and 8c and their carbamates 8d and 8f were designed and prepared as shown in Scheme 1.
  • R 1 -C(CH 3 ) 3
  • R 2 -COOC(CH 3 ) 3 ClCH 2 CONH 2 + RNCN
  • R 1 -CH(CH 3 ) 2
  • R 2 -COCH(CH 2 CH 3 ) 2
  • the free base, 2-methylisothiourea (18a-d) were prepared via the reaction of 3,4- dichlorophenylisothiocyanate (16) with a variety of primary amines to form thiourea derivatives (17a-d) followed by methylation with CH 3 I 25 .
  • the desired N-alkyl guanidine derivatives (8j-n) were readily prepared by coupling of the free base (18a-d) with 2- aminoimidazoline 15a-c. After heating at 100 °C for 24 hours, the substituted guanidine derivatives (8j-n) were obtained in moderate to good yields (50-75%). It was noted that the coupling reaction required base as catalysis to give good yields.
  • Reagents and Conditions (i): RNH 2 , CH 2 C1 2 , 25°C, 2h; (ii): CH 3 I, Acetone, reflux, 2h; (iii): Na 2 C0 3 , H 2 0, 25°C; (iv) 15a-c, K 2 C0 3 , CH 3 CH 2 CH 2 OH, reflux, 24h; (v) RRNH, CH 2 C1 2 , 25°C, 2h.
  • N-alkyl-N'-(3,4-dichlorophenyl) biguanidine analogs 25a-c were prepared by coupling of 2-amino-3-(3,4-dichlorophenyl)-imidazolin-4-one (24) with compound 18a-d in the presence of K 2 C0 3 .
  • the system consisted of an Agilent 1100 Series LC-UV7VIS system online with a ThermoFinnigan (now Thermo Scientific; Waltham, MA) LCQ MS equipped with electro spray ionization (ESI) source. Samples were analyzed using shallow CH 3 CN: 1% HCOOH/H 2 0 gradients at low flow rate.
  • Method A 2-Methylthioimidazolin-4-one 13b (0.86 g, 5 mmol) in MeOH was added to 8 mL of 7.0 M ammonia in MeOH. The reaction was refiuxed at 65 °C for 5 hours. The MeOH was removed under reduced pressure. The crude product was purified by first suspending in 20 mL of CH 2 C1 2 . The product was collected by filtration, washed twice with CH 2 C1 2 and dried to give the white product in 80-88 % yield.
  • N-(3,4-Dichlorophenyl)-N'-(l-methyl-4-oxo-4,5-dihydro-lH- imidazol-2-yl)-guanidine (8a): Yield 70%, mp 256.6-258.5 °C, white solid.
  • Compound 8i was prepared by treatment of 8b with 2-ethylbutyryl chloride. Yield: 32%, white solid, mp 142.6-143.8 °C.
  • the title compound was prepared from 15b and 18a. Yield: 75%, mp 195-196°C, white crystal.
  • a reaction mixture consisting 2-amino-imidazolin-4-one (15b, l .Og, 7.08 mmol), 2-methylisourea 20 (10.6 mmol), K 2 CO 3 (1.0 g, 7.08 mmol) and 1-propanol (50 mL) was refluxed for 12 h and, after cooling to rt, was filtered to remove the K 2 CO 3 . The filtrate was evaporated to dryness under the reduced pressure.
  • the metabolic stability assay was performed in a 96-well plate on a TECAN Genesis robotic sample processor following WRAIR SOP SP 01-02. Samples were analyzed by LC-MS/MS using fast LC gradient or isocratic methods. Parent drug was quantified using external calibration and plots of parent drug response v. amount. The results are shown in Table 1.
  • the in vitro assays were conducted by using a modification of the semiautomated microdilution techniques of Desjardins et al and Chulay et al 27-28 .
  • Three P. falciparum malaria parasite clones, from CDC Indochina III (W-2), CDC Sierra Leone I (D-6), and Southeast Asia Isolates (TM91C235) were utilized in susceptibility testing. They were derived by direct visualization and micromanipulation from patient isolates 29 . The results are shown in Table 1.
  • New compounds were assessed for their causal prophylactic activity in exoerythrocytic (EE) mouse model using sporozoites of P. berghei.
  • the procedures have been previously described 18"20 . Briefly, each compound was ground with a mortar and pestle and suspended in hydroxyethylcellulose and Tween 80 for compounds to be administered PO and those given SC were suspended in peanut oil. Each compound was prepared at different dose levels. Compounds were administered either PO or SC to mice once a day for three consecutive days as follows: on the day before being inoculated with sporozoites of P. berghei intravenously, 4 hours before the inoculation on the day of inoculation, and the day after the inoculation.
  • the causal prophylactic and radical curative antimalarial activity of the new derivatives 8e, 8h and 8j were assessed in P. cynomolgi sporozoites challenged Rhesus monkey model. Detailed procedure of sporozoites harvest and drug tests are described in the previous reports 16 . The results are shown in Table 2. Assessment of radical curative activity of the test compounds were carried out using the monkeys that developed parasitemia during the causal prophylactic experiments when the test compounds showed no or weak activity. Monkeys were treated with chloroquine (10 mg/kg/day) by oral for 7 consecutive days and the test compounds by im for 3 consecutive days after the parasitemia level reached 5,000 parasites/mm 3 . Chloroquine at 10 mg/kg/day x 7 days eliminates the blood stage parasites, but not the liver stage hypnozoites. Compounds with antihypnozoite activity will delay the relapse or radically cure the infection.
  • PQ Primaquine
  • TQ Tafenoquine
  • DP Delayed Parasitemia Patency
  • Malarone® Atovaquone (lOmg/kg) + Proguanil (4 mg/kg).
  • the deoxo-IZ analogs (8-9) prepared in this study exhibited only weak in vitro activity against blood stage malaria, P. falciparum, except 8j, 8h, 9b and 9c, which showed moderate activity with IC 50 less than 1 ⁇ g/mL.
  • deoxo-IZ compounds (8-9) are, in general, metabolically unstable, especially analogs with good prophylactic activity, such as 8d, 8e, 8f, 8i, and 8j.
  • To identify the active metabolites extensive metabolic studies of the most active compounds 8e and 8f in mice were conducted. Preliminary results indicated that these compounds were metabolized extensively to yield a host of metabolites in mice. The major metabolites 31 , however, were identified as the
  • deoxo-IZ 8e and 8j are metabolically vulnerable and their major metabolites (8e' and 8j') are potent antimalarials
  • the new class of deoxo-IZ (I) may act as the pro-drugs of the IZ compounds (III) as shown in scheme 4.
  • the nine compounds (8b, 8e, 8g, 8h, 8i, 8j, 8k, 81, and 8m) with Ri being isopropyl six (8e, 8g, 8h, 8i, 8j, and 81) showed curative activity in the prophylactic test in mice.
  • the tafenoquine dose of 0.316 mg/kg was based on the report of Puri 30 .
  • the Malarone dose (14 mg/kg) was derived from the recommended human dose.
  • the results showed that both 8e and 8j showed comparable activity with that of primaquine, tafenoquine and Malarone, delaying patency of the treated monkeys 2-5 days longer than the untreated control by oral administration (Table 2).
  • the IZ class of compounds (1, 3, and 5) showed good casual prophylactic activity in Rhesus by IM but not by oral dosing. Although 2-3 days of delay in patency is far from impressive, it is the first time significant oral activity of this class of compounds was observed in Rhesus monkeys.
  • compound 3 was well absorbed by oral route; peak absorption of a 60 mg/kg dose given orally was nearly 10 fold higher than 30 mg/kg dose by IM route.
  • the Rhesus PK and the efficacy data suggested that long plasma half-life of the drug are critical for its activity against liver stage malaria.
  • analysis of the relative presence of metabolites indicated that compound 3 is the major species, comprising 86%> and 96%> of measurable analytes at 24 hours via the oral and IM routes, respectively.
  • a small amount (4-10%) of the metabolites is the original lead compound 1 and very small amount ( ⁇ 0.5%>) is metabolized to s-triazenes (7) at 24 hours, suggesting that the parent compound 3 is the active species 31 .
  • the deoxo-IZ (I) analogs prepared in this study may act as pro-drugs of the corresponding IZ derivative (III).

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Abstract

La présente invention a trait à de nouveaux dérivés de 2-guanidino-4-oxo-imidazoline (deoxo-IZ), à des procédés permettant de réaliser ces composés, à des compositions contenant ces derniers, et à des procédés d'utilisation de ces derniers afin de prévenir, traiter ou inhiber le paludisme chez un sujet.
PCT/US2012/035099 2011-04-26 2012-04-26 Dérivés de 2-guanidino-4-oxo-imidazoline en tant qu'agents antipaludiques, synthèse et procédés d'utilisation de ceux-ci WO2012149093A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103922952A (zh) * 2014-05-07 2014-07-16 宁夏宝马药业有限公司 用羟基乙腈制取环丙基甘氨酸的方法
CN104230744A (zh) * 2014-09-01 2014-12-24 湖南尔康制药股份有限公司 一种替加环素原料药的生产方法
WO2019008027A1 (fr) * 2017-07-04 2019-01-10 Sanofi Composés éthynyle, leur préparation et leur utilisation thérapeutique dans le traitement du paludisme
CN111533694A (zh) * 2020-06-05 2020-08-14 河南牧业经济学院 一种2-亚胺基乙内酰脲化合物的合成方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7101902B2 (en) * 2003-11-21 2006-09-05 The United States Of America As Represented By The Secretary Of The Army 2-guanidinylimidazolidinedione compounds and methods of making and using thereof
WO2007074171A1 (fr) * 2005-12-29 2007-07-05 Immupharma France Sa Heterocycles aza destines au traitement du paludisme ou du sida
US20100160321A1 (en) * 2005-06-23 2010-06-24 Peter Ten Holte Imidazolinone and hydantoine derivatives as novel inhibitors of histone deacetylase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7101902B2 (en) * 2003-11-21 2006-09-05 The United States Of America As Represented By The Secretary Of The Army 2-guanidinylimidazolidinedione compounds and methods of making and using thereof
US20100160321A1 (en) * 2005-06-23 2010-06-24 Peter Ten Holte Imidazolinone and hydantoine derivatives as novel inhibitors of histone deacetylase
WO2007074171A1 (fr) * 2005-12-29 2007-07-05 Immupharma France Sa Heterocycles aza destines au traitement du paludisme ou du sida

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103922952A (zh) * 2014-05-07 2014-07-16 宁夏宝马药业有限公司 用羟基乙腈制取环丙基甘氨酸的方法
CN104230744A (zh) * 2014-09-01 2014-12-24 湖南尔康制药股份有限公司 一种替加环素原料药的生产方法
CN104230744B (zh) * 2014-09-01 2016-06-08 湖南尔康制药股份有限公司 一种替加环素原料药的生产方法
WO2019008027A1 (fr) * 2017-07-04 2019-01-10 Sanofi Composés éthynyle, leur préparation et leur utilisation thérapeutique dans le traitement du paludisme
CN110869350A (zh) * 2017-07-04 2020-03-06 赛诺菲 炔基化合物，其制备及其治疗用途
US11078160B2 (en) 2017-07-04 2021-08-03 Sanofi Ethynyl compounds, their preparation and their therapeutic use for the treatment of malaria
CN110869350B (zh) * 2017-07-04 2023-05-02 赛诺菲 炔基化合物，其制备及其治疗用途
CN111533694A (zh) * 2020-06-05 2020-08-14 河南牧业经济学院 一种2-亚胺基乙内酰脲化合物的合成方法
CN111533694B (zh) * 2020-06-05 2023-03-14 河南牧业经济学院 一种2-亚胺基乙内酰脲化合物的合成方法

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