EP1064287A1 - Verwendung von aminophosphonaten als ph-markers in 31 p-mnr - Google Patents

Verwendung von aminophosphonaten als ph-markers in 31 p-mnr

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Publication number
EP1064287A1
EP1064287A1 EP99909041A EP99909041A EP1064287A1 EP 1064287 A1 EP1064287 A1 EP 1064287A1 EP 99909041 A EP99909041 A EP 99909041A EP 99909041 A EP99909041 A EP 99909041A EP 1064287 A1 EP1064287 A1 EP 1064287A1
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Prior art keywords
group
alkyl
nitro
alkoxy
halogen
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EP99909041A
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English (en)
French (fr)
Inventor
Sylvia Pietri
François Résidence Marie-Christine LE MOIGNE
Malvina Miollan
Marcel Culcasi
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Centre National de la Recherche Scientifique CNRS
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Centre National de la Recherche Scientifique CNRS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the invention relates to novel linear or cyclic ammo-phospho ⁇ ates and their use as pH markers in 31 NMR spectroscopy More generally, the invention relates to the use of amino phosphonate derivatives as pH markers in spectroscopy NMR Phosphorus 31 NMR spectroscopy has proven to be an effective means for the measurement, in vivo, of extra- and intracellular pH
  • the advantage of this method is that it does not disturb the medium at all on which the measurement is carried out, an essential condition for an in vivo measurement.
  • a compound can be used as a pH marker when the numerical value of the chemical shift of the resonance peak obtained by NMR of the
  • 31 P varies as a function of the pH of the medium into which the compound has been introduced.
  • the difficulty consists in developing the ideal, non-toxic compound, which can function as a pH marker in a wide pH range, with good sensitivity.
  • An additional requirement is that the measurement must be little, if at all, affected by the other constituents of the physiological medium and react only to a variation, even a very small one, of the pH.
  • the level of Pi is generally low in the cell and varies with the metabolic state of the cell, - the lack of sensitivity of this compound does not make it possible to differentiate between the intra and extra cellular pH
  • REPLACEMENT SHOE (RULE 26) 2 permeability to cell membranes in the case of the tumor cell line studied
  • Phenylphosphonate is another marker of extracellular pH (cf. Circulation Research, vol 60, n ° 4, 1987, 472-477)
  • the disadvantage of this compound is that the chemical displacement of 31 P is influenced by the presence of specific ions in the measurement medium
  • the American Physiological Society, 1994, C195-C203 also points out the possibility of using 3-aminopropylphosphonate as an indicator of extracellular pH
  • the present inventors have discovered a family of molecules, namely linear or cyclic amino-phosphonates, which are particularly advantageous insofar as they lead to improved sensitivity of pH measurement and where they make it possible to cover a whole range of pH different according to the substituents, thus making it possible to have an important precision on the measurement at more acidic or more basic pH These molecules are moreover not very toxic
  • R represents a (C ⁇ -C ⁇ ) alkyl or (C 6 -C ⁇ 0 ) aryl group
  • Ri and R 2 independently represent a deuterium atom, a halogen atom, a (C ⁇ -C ⁇ ) alkyl ⁇ group optionally substituted by one or several radicals chosen from (dC 6 ) alkoxy, (C 3 -Cn) cycloalkyl, halogen, (C 6 -C 10 ) aryl and nitro, a (C 6 -C ⁇ 0 ) aryl group optionally substituted by one or more radicals chosen from (C ⁇ -C ⁇ ) alkyl, (d- C6) alkoxy, halogen, nitro and (C 3 -Cn) cycloalkyl, (C ⁇ -C ⁇ 8) é alkoxy optionally substituted by one or more radicals selected from (d- C 6) alkoxy, halogen, nitro, (C 3 -Cn) cycloalkyl and (
  • R 3 represents a hydrogen or deuterium atom, an n-propyl group or a (C 5 -C ⁇ 8 ) linear alkyl group, optionally substituted by one or more radicals chosen from: nitro, halogen, (C ⁇ -Ce) alkoxy and (C 3 -C ⁇ ) cycloalkyle; a (C 3 -Cn) cycloalkyl group optionally substituted by one or more radicals chosen from (C ⁇ -C 6 ) alkyl, (d- C 6 ) alkoxy, halogen and nitro; and its salts with a pharmaceutically acceptable acid.
  • R ' represents a hydrogen atom, a (C ⁇ -Ci 8 ) alkyl or (C ⁇ - C ⁇ 0 ) aryl group,
  • R'j represents a hydrogen atom; a deuterium atom. a halogen atom, a (d-C ⁇ 8 ) alkyl group optionally substituted by one or more radicals chosen from (dC 6 ) alkoxy, (C 3 -Cn) cycloalkyl, halogen, (C 6 -C 10 ) aryl and nitro ; an (C 6 -C ⁇ 0 ) aryl group optionally substituted by one or more radicals chosen from (C ⁇ -C 6 ) alkyl, (dC 6 ) alkoxy, halogen, nitro and (C 3 -C ⁇ ) cycloalkyl; (C ⁇ -Ci8) alkoxy optionally substituted by one or more radicals chosen from (C ⁇ -C 6 ) alkoxy, halogen, nitro, (C 3 - Cn) cycloalkyl and (C 6 -C ⁇ 0 ) aryl, a nitro group; or a (C 3
  • R ' 2 and R' 3 together form R ' 2 and R' 3 together form the bivalent radical O 99/47527
  • one of L 5 and L 6 represents a hydrogen atom, and the other represents (C 2 -C ⁇ 8 ) alkyl or (C 6 - C ⁇ 0 ) aryl;
  • the compounds of formula (1.1) are linear phosphonates.
  • the compounds of formula (I.2) are cyclic phosphonates.
  • alkyl means a linear or branched saturated hydrocarbon radical such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1 - ethylpropyl , hexyl, isohexyl, neohexyl, 1 -methylpentyle, 3-methylpentyle, 1, 1 -dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1 -methyl-1 -ethylpropyle. 5
  • the alkyl radical comprises 1 to 10 carbon atoms, better still 1 to 6.
  • alkoxy designates the radical -O-alkyl where alkyl is as defined above.
  • Halogen denotes a chlorine, bromine, fluorine or iodine atom, fluorine and chlorine being preferred.
  • cycloalkyl is meant according to the invention saturated, monocyclic or polycyclic carbocycles, preferably monocyclic or bicyciic.
  • cycloalkyls having 3 to 8 endocyclic carbon atoms.
  • cycloalkyl mention may be made of cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyciooctyl, cyclopentyl and cyclohexyfe being preferred.
  • Aryl is understood to mean a monocyclic or polycyclic aromatic hydrocarbon radical, preferably monocyclic or bicyclic, having from 6 to 10 endocyclic carbon atoms, such as phenyl and naphthyl.
  • R 3 is other than a hydrogen atom.
  • RT and R 2 are both distinct from a hydrogen atom.
  • R 3 represents n-propyl or a (C 5 -C 6 ) linear alkyl group, optionally substituted by one or more radicals chosen from nitro, halogen, (C ⁇ -C 6 ) alkoxy and (C 3 -C 8 ) cycloalkyl .
  • R 3 represents n-propyl or a (C 5 -C 6 ) linear alkyl group.
  • R 1 and R 2 independently represent a (dC 6 ) alkyl group optionally substituted by one or more radicals chosen from (C 1 -C 6 ) alkoxy, (C 5 -C 6 ) cycloalkyl, halogen, (C 6 -C ⁇ o) aryl and nitro; or a (C 6 -C ⁇ 0 ) aryl group optionally substituted by one or more radicals chosen from (C ⁇ -C 6 ) alkyl, (dC 6 ) alkoxy, halogen, nitro and (C 5 -C 6 ) cycloalkyl; and R represents a (Ci-Ce) alkyl group or a (Ce-C 1 o) aryl group.
  • Ri and R 2 independently represent (d-Ce) alkyl or (C 6 - C ⁇ o) aryl, for example phenyl
  • At least one of Ri and R 2 represents a deuterium atom, a halogen atom, nitro or (C ⁇ -C ⁇ 8 ) alkoxy optionally substituted
  • cyclic compounds of formula (I 2) those in which R ′ is chosen from (d-C ⁇ 8 ) alkyl and (Ce-C ⁇ o) aryl are preferred.
  • Another group of preferred compounds consists of the compounds of formula (I 2) in which R'i represents (d-Ce) alkyl or a hydrogen atom 5 and R ' 2 and R' 3 together form the radical of formula
  • This group of compounds is designated subgroup CP in the following When in this subgroup of preferred compounds, CP, R'i represents 0 (C ⁇ -Ce) alkyl, it is preferred that R ' 2 and R' 3 together form the bivalent radical
  • L 5 represents H and L 6 represents (C 6 -C ⁇ 0 ) aryl, for example phenyl
  • R'i represents a hydrogen atom
  • R ' 2 and R' 3 together form the bivalent radical
  • R ′ represents a C 1 -C 6 alkyl group or a C 1 -C 10 aryl group are particularly preferred.
  • the invention encompasses both the cis and trans isomers of the cyclic derivatives as well as all the enantiomers and diastereoisomers in the case where the compounds of formula (M) or (12) have one or more asymmetric carbon. According to another of its aspects , the invention relates to the use of aminophosphonates as a pH marker in 31 P NMR
  • the invention relates to the use, as pH markers, of compounds of formula (II 1) or (II 2) or of their salts with pharmaceutically acceptable acids Formula (II 1)
  • R represents a group (C ⁇ -C ⁇ 8 ) alkyl or (C 6 -C ⁇ 0 ) aryl
  • Ri and R 2 independently represent a hydrogen atom, a deuterium atom, a halogen atom, a group (C ⁇ -C 18 ) alkyl optionally substituted by one or more radicals chosen from (C 1 -C 6 ) alkoxy, (C 3 -Cn) cycloalkyl, halogen, (C 6 -C ⁇ o) aryl and nitro, a group (C 6 -C ⁇ 0 ) aryl optionally substituted by one or more radicals chosen from (dC 6 ) alkyia, (d-Ce) alkoxy, halogen, nitro and (C 3 - C ⁇ ) cycloalkyle, (C ⁇ -C ⁇ 8 ) alkoxy optionally substituted by one or several radicals chosen from (dC 6 ) alkoxy, halogen nitro, (C 3 - C
  • R 3 represents a hydrogen or deuterium atom, a (Ci- C ⁇ 8 ) alkyl group optionally substituted by one or more radicals chosen from nitro, halogen, (C ⁇ -C 6 ) alkoxy, (C 6 -C ⁇ o) aryl and (C 3 -Cn) cycloalkyle, and, optionally carrying in position 1 a group -P (O) (OR) 2 , a group (C 3 -Cn) cycioalkyle optionally substituted by one or more radicals chosen from (dC 6 ) alkyl , (C ⁇ -C6) alkoxy, halogen and nitro, a (Ce-C ⁇ o) aryl group optionally substituted by one or more radicals chosen from (d-Ce) alkyl, (C 6 -do) aryl, (d-Ce) alkoxy , nitro, halogen and (C 3 -Cn) cycloalkyl, -
  • A represents the bivalent radical -CR 4 R 5 - where R 4 and R 5 have the meanings given above for R-, and R 2 excluding -P (O) (OR) 2 , it being understood that said compound has no more than two groups -P (O) (OR) 2 Formula (Il 2)
  • Ti and T ' 2 independently represent (C ⁇ -C ⁇ ) alkyl, (C 6 -C ⁇ 0 ) aryl, or a group -OR', R 'represents a hydrogen atom, a group (C ⁇ -C 18 ) alkyl or ( C 6 -
  • R'i represents a hydrogen atom, a deuterium atom a halogen atom, a (C C ⁇ 8 ) alkyl group optionally substituted by one or 9 several radicals chosen from (dC 6 ) alkoxy, (C 3 -Cn) cycloalkyl, halogen, (Ce-do) aryl and nitro, a (Ce-Cio) aryl group optionally substituted by one or more radicals chosen from (dC 6 ) alkyl, (Ci- C 6 ) alkoxy, halogen, nitro and (C 3 -Cn) cycioalkyle, (C ⁇ -d 8 ) alkoxy optionally substituted by one or more radicals chosen from (Ci-
  • L 5 and L 6 independently of one another represent a hydrogen atom, a deuterium atom, a (C ⁇ -C ⁇ 8 ) alkyl group optionally substituted by one or more radicals chosen from (C 10
  • a ' represents the divalent radical -CR' R ' 5 - or R' and R ' 5 have the meanings given above for R'i with the exclusion of -P (O) (OR') 2 , it being understood that said compound has no more than two groups
  • R 3 is n-propyl or (C 5 -C ⁇ 8 ) linear alkyl, optionally carrying in position 1 a group -P (O) (OR) 2
  • a group -P (O) (OR) 2 By this is meant that the carbon atom of n-propyl group or (C 5 -C 18 ) alkyl group which is directly linked to the nitrogen atom may carry a group -P (O) (OR) 2 as illustrated below
  • R 3 - c - (C 5 -C 18 ) alkyl or - C - nPr
  • a linear phospho ⁇ ate meeting one or more of the following conditions (i) to (xi) 11 i) a compound of formula (Il 1) in which R 3 is other than a hydrogen atom, n) a compound of formula (Il 1) in which R 1 and R 2 are both distinct from an atom hydrogen, ni) a compound of formula (II 1) in which p represents 0 iv) a compound as defined in ni) for which R 3 represents a (C 1 -C 6 ) alkyl group optionally substituted by one or more radicals chosen from halogenated nitro, (C ⁇ -C 6 ) alkoxy, (C 6 -C ⁇ 0 ) aryl and (C 3 -C 8 ) cycloalkyl, and optionally carrying in position 1 a group -P (O) (OR) 2 , v ) a compound as defined in m) for which R 1 and R 2 independently
  • a cyclic phosphonate of formula (II 2) is used which meets one or more of the following conditions (xn) to (xvn)
  • L 5 and L 6 are as defined for formula (II 2), xiv) a compound as defined in xi) in which L and L 6 are independently chosen from a hydrogen atom, a group (dC 6 ) alkyl, a group (C 6 -C ⁇ 0 ) aryl or a group -P (O) (OR ') 2 , R' representing an alkyl group in (Ci-Ce), an aryl group in (C 6 -C ⁇ 0 ) or a hydrogen atom, xv) a compound chosen from
  • T'i represents -OR 'and T' 2 is (C ⁇ -C ⁇ s) alkyl or (C 6 - C ⁇ 0 ) aryle, xvn) a compound of formula (Il 2) in which T'i and T ' 2 represent -OR'
  • Li to L 6 are as defined in formula (II.2) and comprising in their molecule only one function -P (O) (OR ') 2 can be prepared by reacting a compound of formula (III ):
  • the reaction conditions depend on the nature of the reagents of formulas (III) and (IV) and can be easily determined by a person skilled in the art.
  • the reaction is generally carried out in a solvent, for example a polar protic solvent.
  • the solvent is ethanol.
  • MX n represents BF 3 , this acid being generally used in the form of its BF 3 -And 2 O complex
  • the reaction can be carried out at room temperature in a polar aprotic solvent such as an ether and, for example, tetrahydrofuran or diethyl ether. An excess is preferably reacted. from 10 to 50 mol% of the compound of formula (IV) on the pyrroline (V).
  • the pyrrolme of formula (V) can be prepared by following the following reaction scheme 99/47527
  • the compound of formula (III) is reacted with an alkali metal azide of formula M 0 N 3 where M 0 represents an alkali metal
  • M 0 N 3 is NaN 3 and the reaction is carried out in a polar aprotic solvent in the presence of an ammonium chloride such as tetrabutylammonium chloride
  • an ammonium chloride such as tetrabutylammonium chloride
  • reducing agent t ⁇ butyletafn hydride or NaHTe will be used, for example.
  • reducing agent t ⁇ butyletafn hydride or NaHTe
  • a person skilled in the art will refer, in this regard, to D.H.R. Barton et al. (1985), Tetrahedron Letters, 26, 4603.
  • Application FR 93 08 906 describes a general method for preparing the compounds of formula (VIII).
  • the compounds of formula (VIII) in which L 2 , L 4 and L 6 represent a hydrogen atom and R'i is distinct from a hydrogen atom can be prepared by implementing the following succession reactive steps
  • the reaction of the compound (IX) on the compound (X) is advantageously carried out in a polar aprotic solvent of the acetonitrile type in the presence of a base such as triethylamine, py ⁇ dine or 4-dimethylam ⁇ nopy ⁇ d ⁇ ne in catalytic amount.
  • the reaction temperature is generally between room temperature and the reflux temperature of the solvent.
  • This reaction can be carried out in a solvent.
  • a polar protic solvent such as ethanol will preferably be chosen.
  • the amount of zinc is advantageously between 1 and 5 molar equivalents relative to the compound (IX), preferably between 1 and 3 equivalents
  • the compound of formula (X) is easily prepared (i) by reaction of acetyl chloride on a trialkyl phosphite of formula P (OR ') 3 according to the Arbuzov method, then (ii) reaction of oxo-2-ethylphopho ⁇ ate resulting dialkych with hydroxylamine and (iii) oxidation of the resulting oxime to n ⁇ tro-1- ethylphosphonate (X). This last oxidation reaction is notably described 99/47527
  • Li a L 6 are as defined in formula (Il 2), and R 'represents -P (O) (OR'), can be prepared from the corresponding 2-oxopyrrol ⁇ d ⁇ nes of formula (XII)
  • the 2-oxo-pyrrol ⁇ d ⁇ ne (XII) is successively reacted with the appropriate t ⁇ alkylphosphite of formula P (OR ') 3 where R' is as defined for formula (II), under an inert atmosphere, at a temperature varying between -10 ° C and room temperature, then with a phosphoryl halide of formula P (O) X 3 in which X represents a halogen atom at this same temperature.
  • the mixture is maintained reaction with stirring, optionally allowing the temperature to rise to ambient temperature for 1 to 10 hours
  • the reaction mixture is then treated in a second step with hydroxide ,. - _, _ PCT / FR99 / 00631 99/47527
  • Li to L 5 and R'i are as defined in formula (Il 2), and L 6 represents -P (O) (OR ') 2 can be prepared by following the following reaction scheme
  • the reaction of (XIII) on (IV) is carried out in the presence of a large excess of the compound (XIII) of 5 to 20 molar equivalents of the compound (XIII) lead to satisfactory yields
  • the reaction has place in the presence of ammonia at a temperature between room temperature and 100 ° C, preferably between 20 and 70 ° C.
  • the resulting compound of formula (XIV) is reacted with the compound (IV) preferably with an excess of the compound of formula (IV)
  • the average ratio of the compound (XIV) to the compound (IV) is generally between 10 1 and 2 1, preferably between 5 1 and 2 1
  • XVII preferably varies between 0.2 and 2, better still between 0.8 and 1.8
  • the molar ratio of phosphite (IV) to ketone (XVII) preferably varies between 0.2 and 2, better still between 0.8 and 1.8
  • the reaction can be carried out without solvent or in the presence of a solvent.
  • the reagents are used as solvents.
  • the temperature is maintained between 20 ° C. and 50 ° C.
  • the reaction is advantageously carried out at ambient temperature.
  • the amine (XVI) is reacted at room temperature with the ketone (XVII) in the presence of an alkali metal sulfate and a strong acid, such as the Na 2 SO 4 system / HCI
  • a strong acid such as the Na 2 SO 4 system / HCI
  • we 21 prepares a mixture of the ketone (XVII) and famine (XVI) to which the Na 2 SO / HCl system is added. After a reaction time of between 1 and 72 hours, the phosphite (IV) is added to the reaction mixture.
  • alkali metal sulfate Preferably 0.5 to 2 equivalents of the alkali metal sulfate and a catalytic amount of the strong acid are used.
  • the alkali metal is chosen from sodium, potassium, lithium and cesium, sodium being preferred.
  • R is as defined for formula (11.1) and R a , R b independently represent a (C ⁇ -C ⁇ 8 ) alkyl group optionally substituted by one or more radicals chosen from nitro, halogen, (C ⁇ -C 6 ) alkoxy, (C 6 -C ⁇ 0 ) aryl and (C 3 -C 8 ) cycloaikyle; or R a and R b together form with the carbon atom which carries them a (C 3 -C 8 ) cycioalkyl.
  • an aldehyde of formula is treated with ammonia.
  • the compounds of formula (XVIII) are especially prepared in which R a and R b are independently chosen from (d-Ce) alkyl or else form together with the carbon atom which carries them a group (C 5 - C 8 ) cycloalkyl
  • T, and T 2 represent -OR, and one of Ri or R 2 represents -P (O) (OR) 2 can be prepared by the action of two molar equivalents of an appropriate trialkylphosphite of formula P (OR) 3 in which R is as defined for (11 1) on a formamide of formula (XIX)
  • the molar ratio of t ⁇ alkyl phosphite to compound (XIX) preferably varies between 2.5 and 2, preferably between 2.2 and 2
  • the reaction is generally carried out by adding POCI 3 to a solution consisting of the mixture of t ⁇ alkyl phosphite and formamide, maintained at -5 ° C
  • the molar quantity of POCI 3 involved in this reaction varies between 2 and 2.5 moles per 1 mole of the compound (XIX)
  • the molar ratio of POCI 3 to the tnalkyl phosphite varies between 1 and 1, 3
  • (XXI) is reacted with an amine of formula R 3 -NH 2 in the presence of a hydride, preferably in the presence of NaBH (OAc) 3 and of a C ⁇ -C alkylcarboxylic acid such as acetic acid
  • a hydride preferably in the presence of NaBH (OAc) 3 and of a C ⁇ -C alkylcarboxylic acid such as acetic acid
  • This reaction is preferably carried out in the presence of a halogenated hydrocarbon solvent (such as dichloroethane) at a temperature between 15 and 35 ° C, for example at room temperature (22 ° C)
  • a halogenated hydrocarbon solvent such as dichloroethane
  • the reactions involved in these two stages are stoichiometric.
  • the molar ratio of alkylcarboxylic acid to compound (XXI) may vary between 1 and 5, preferably between 1 and 2
  • the molar ratio of hydride to compound (XXI) will be adjusted between 1 and 1 , 5, preferably between 1 and 1, 2
  • L, to L 6 are as defined in formula (II.2) and comprising in their molecule only one function -P (O) (OR ') 2 , can be prepared: (i) by reacting a compound of formula (XXII)
  • Li to L 6 , R'i, R ' 4 and R' 5 are as defined above and Pro represents a protecting group for an amino function, for example a benzyloxycarbo ⁇ yle group, with a phosphorus derivative of formula P (OR ') 3 where R' is as defined for formula (II.2); and (ii) by deprotecting the secondary amino function of the product resulting from the first step (i).
  • Pro represents a protecting group for an amino function, for example a benzyloxycarbo ⁇ yle group, with a phosphorus derivative of formula P (OR ') 3 where R' is as defined for formula (II.2); and (ii) by deprotecting the secondary amino function of the product resulting from the first step (i).
  • the protective functions which can be used for the protection of the endocyclic nitrogen of the pyrrolidine nucleus are those conventionally used in organic chemistry.
  • a person skilled in the art will refer for example to Protective Groups in Organic Synthesis, Geeene T.W. and Wuts P.G.M., ed. John Wiley and Sons, 1991. This book also describes the corresponding deprotection methods.
  • the compounds of formula (XXII) can be prepared in two stages starting from the compounds of formula (XXIII)
  • T ',, T' 2 , R'i and Li to L 6 are as defined in formula (II.2) above; alk represents (dC 6 ) alkyl and GP represents a leaving group, preferably a halogen atom, such as chlorine.
  • the reaction of phosphinate XXXa on the silylated derivative XXXI is stoichiometric.
  • the molar ratio of compound XXXI to compound XXXa therefore generally varies between 1 and 1, 5, preferably between 1 and 1, 2.
  • a base preferably an organic base of the tertiary amine type.
  • Suitable bases are N-methylmorpholine, triethylamine, tributylamine, diisopropylamine, dicyclohexylami ⁇ e, N-methylpiperidine, pyridine, 4- (1- pyrrolidinyl) pyridine, N, N-dimethylaniline and N, N -diethylaniline.
  • reaction of XXXa with XXXI is preferably carried out in a polar solvent of the halogenated aliphatic hydrocarbon type such as dichloroethafia, carbon tetrachloride or dichloroethane.
  • a polar solvent of the halogenated aliphatic hydrocarbon type such as dichloroethafia, carbon tetrachloride or dichloroethane.
  • the reaction temperature is preferably maintained between -20 and 10 ° C, better still between -5 and 5 ° C
  • the compound XXXII obtained is reacted with the pyrrolme of appropriate formula XXXIII This reaction is preferably carried out in situ, without intermediate isolation of the compound XXXII obtained previously
  • a molar ratio of the pyrrolme XXXIII to the silylated derivative XXXII from 1 to 1 , 5, preferably 1 to 1, 2, is generally suitable
  • reaction of XXXIII with XXXII is generally carried out in a polar solvent of the halogenated aliphatic hydrocarbon type as defined above. This process is particularly suitable for the preparation of the compounds
  • T'i represents - (C ⁇ -C ⁇ 8 ) alkyl or (C 6 -d 0 ) aryl and T ' 2 represents -OR'
  • This reaction can be carried out in the absence of solvent or in the presence of an inert solvent capable of dissolving the reagents XXXb and XXXIV
  • a suitable temperature is a temperature between 15 and 80 ° C, preferably between 30 and 50 ° C 99/47527
  • the phosphinate XXXa [in which Ti (respectively T 'represents -OR (respectively OR') and T 2 (respectively T ' 2 ) represents R (respectively (C ⁇ -C ⁇ 8 ) alkyl or (C 6 - C ⁇ o) aryle]
  • Ti (respectively T 'represents -OR (respectively OR') and T 2 (respectively T ' 2 ) represents R (respectively (C ⁇ -C ⁇ 8 ) alkyl or (C 6 - C ⁇ o) aryle]
  • a halophosphite of formula (alk ⁇ ) (T ⁇ ) Phal ⁇ (respectively (alko) (T' ⁇ ) Phal ⁇ ) in which ha represents a halogen atom, preferably chlorine and alko represents (d-Ce) alkoxy
  • a magnesium of formula T 2 Mghal 2 (respectively T ' 2 Mghal 2 ) where hal 2 is
  • the imine XXXIV is prepared in a conventional manner by following the known methods of organic chemistry and, for example, by the action of an amine on an aldehyde
  • the compounds of formula (11 1) and (II 2) can be isolated in the form of their salts with an organic or mineral acid, for example pic ⁇ que acid, the acid oxalic, tartaric acid, mandelic acid or camphosulfonic acid Physiologically acceptable salts are nevertheless preferred such as the hydrochloride, hydrobromide, 99/47527
  • the originality of the phosphonates of formula (11.2) lies mainly in their rigid cyclic structure.
  • R 'in formula (II.2) and R in formula (11.1) is other than a hydrogen atom
  • the function (s) -P (O) (OR') 2 , respectively -P (O) (OR) 2 are in the form of phosphonate groups.
  • the chemical displacement of phosphorus depends on the pH. More precisely, the chemical displacement of phosphorus varies greatly for pH values close to the pKa of the compound of formula (11.1) or (II.2) studied. For pH values far from the pKa value, the chemical shift of phosphorus tends towards a constant.
  • the pKa value of the compound of formula (Il 1) (respectively (Il 2)) varies pKa depends on the electron-withdrawing or electron-donating effect of these substituents
  • the family of compounds of formula (II 2) has a rather narrow distribution of pKa, compared to the distribution of pKa obtained from the family of corresponding compounds of formula (II 2) for which R ' ⁇ H
  • the compounds of the invention of formula (II 1) have a wide distribution of pKa values, by comparison with the corresponding family of compounds grouping together the compounds of formula (II 3) below.
  • the compounds of the invention have pKa values of between 2 and 9 31
  • diphosphorylated compounds also lead to a greater variation ⁇ , and in particular the cyclic diphosphorylated compounds of formula (II 2)
  • Figures 1 to 8 attached are titration curves obtained from the following compounds Figure 1 titration curve of 2-methyl-2-d ⁇ ethoxyphosphoryl- pyrrolidine compound 1
  • the measured pKa values show that the compounds 1 to 7 allow pH measurements in a very wide pH range More generally, by modifying the nature of the substituents R, R 1 t R 2 , R 3 , RN, R ' 2 , R ' 3 and R' of the compounds of formulas (I 1), (I 2) (Il 1) and (Il 2), it is possible to have particularly sensitive pH markers in different pH zones, up to the most acids, a given compound ensuring good measurement accuracy only in the pH zone surrounding its pKa This has a definite advantage over known pH markers, the known compounds not allowing the study of the acid compartments of the cell
  • the compounds of formulas (M), (1 2), (11 1) and (Il 2) are therefore particularly advantageous pH markers offering greater precision in the measurement of intracellular pH.
  • the phosphorus oxychloride (40 ml; 0.44 mol) is added in 1 h 15 min at -5 ° C to a solution of pyrrol ⁇ din-2-one (18.5 g; 0.22 mol) and t ⁇ ethyl phosphite (9.42 mol).
  • the reaction medium is stirred for 5 hours at room temperature and then poured onto a mixture of ice (300 g) and 32% ammonia (300 ml).
  • the aqueous phase is extracted with dichloromethane (4 times 100 ml) and the latter is evaporated under reduced pressure to obtain a yellow oil.
  • the oil is dissolved in 100 ml of dichloromethane, 200 ml of water are added and then hydrochloric acid 37% up to pH 1.
  • the aqueous phase is washed with dichloromethane (4 times 50 ml) Soda and sodium carbonate are added to pH 10 and the aqueous phase is extracted with dichloromethane (4 50 ml).
  • the organic phase is dried over sodium sulfate, filtered and then evaporated under reduced pressure to obtain the gem-bisphophonate.
  • the reaction mixture is treated with a 0.1N hydrochloric acid solution until a pH 1 is obtained.
  • the aqueous phase thus obtained is treated with a sodium hydroxide solution until a pH 8 is obtained.
  • the treatment is terminated by addition of Na 2 CO 3 then saturated with NaCl It is extracted again with dichloromethane (4 x 30 ml)
  • the organic phase is dried over MgSO 4 After evaporation of the solvents under reduced pressure, 9.8 g of crude product are obtained (yield 45%) in the form of a yellow oil
  • the phosphite is evaporated under reduced pressure
  • the pyrrolidine is purified by chromatography on silica with the eluent acetone / pentane (1/3) with 60% yield 31 P (C 6 D 6 ) ⁇ 26.9 ppm
  • T ⁇ ethyl phosphite (23 g, 0.14 mole) and N-tertiobutylformamide (7.5 g, 0.073 mole) are placed in a 250 ml two-necked flask.
  • the compounds are mixed at room temperature for a few minutes.
  • an ice bath with salt and 23 g of POCI 3 (i.e. 0.15 mole) are added at -5 ° C. The addition lasts 1 hour Then the reaction is allowed to stir at ambient temperature for 5 hours The solution is gradually colors o in orange
  • the crude mixture is then poured into a beaker containing 150 g of ice and 150 ml of 32% ammonia solution.

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EP99909041A 1998-03-18 1999-03-18 Verwendung von aminophosphonaten als ph-markers in 31 p-mnr Withdrawn EP1064287A1 (de)

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FR9803317 1998-03-18
FR9803317A FR2776293B1 (fr) 1998-03-18 1998-03-18 Nouveaux aminophosphonates et utilisation d'aminophosphonates comme marqueurs de ph et rmn du 31p
PCT/FR1999/000631 WO1999047527A1 (fr) 1998-03-18 1999-03-18 UTILISATION D'AMINOPHOSPHONATES COMME MARQUEURS DE pH EN RMN DU 31P

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US2635112A (en) * 1949-07-28 1953-04-14 Research Corp Process for producing aminomethylphosphonic acid compounds
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US3907652A (en) * 1974-10-30 1975-09-23 Monsanto Co Electrooxidation of phosphonomethyl amines
US4005160A (en) * 1975-05-05 1977-01-25 Petrolite Corporation Preparation of α-amino phosphonic acid derivatives
PL112289B2 (en) * 1978-11-30 1980-10-31 Process for preparing novel dipeptides of aminophosphonic acids
SE455259B (sv) * 1984-01-30 1988-07-04 Kenogard Ab Anvendning av vissa aminoalkanfosfonsyror for bekempning av svampsjukdomar hos vexter
DE3445300A1 (de) * 1984-12-12 1986-06-12 Hoechst Ag, 6230 Frankfurt Verfahren zur herstellung von (alpha)-aminoalkylphosphon- und (alpha)-aminoalkylphosphinsaeuren
PL148859B1 (en) * 1987-04-23 1989-12-30 Method of obtaining aminophosphonic esters
FR2639350B1 (fr) * 1988-11-21 1990-12-21 Commissariat Energie Atomique Radical nitroxyde, son procede de fabrication et son application en magnetometrie
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FR2707990B1 (fr) * 1993-07-20 1995-10-20 Centre Nat Rech Scient Nouvelles nitrones utilisables pour le piégeage des radicaux libres.
US5508463A (en) * 1994-03-17 1996-04-16 Trustees Of The University Of Pennsylvania α-aminophosphonates

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FR2776293A1 (fr) 1999-09-24

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