WO1993002710A2 - Utilisation de radicaux libres persistants en imagerie par resonance magnetique - Google Patents

Utilisation de radicaux libres persistants en imagerie par resonance magnetique Download PDF

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WO1993002710A2
WO1993002710A2 PCT/EP1992/001792 EP9201792W WO9302710A2 WO 1993002710 A2 WO1993002710 A2 WO 1993002710A2 EP 9201792 W EP9201792 W EP 9201792W WO 9302710 A2 WO9302710 A2 WO 9302710A2
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radical
group
radicals
product
added
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WO1993002710A3 (fr
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Sven Andersson
Frode Rise
Lars-Göran Wistrand
Håkan WIKSTRØM
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Nycomed Innovation Ab
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    • C07—ORGANIC CHEMISTRY
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/20—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations containing free radicals, e.g. trityl radical for overhauser
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    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/48—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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    • C07C255/36—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by hydroxy groups
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    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/41—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C07C309/66—Methanesulfonates
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    • C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/20—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
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    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
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    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
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    • C07C46/00—Preparation of quinones
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
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    • C07—ORGANIC CHEMISTRY
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    • C07C50/00—Quinones
    • C07C50/26—Quinones containing groups having oxygen atoms singly bound to carbon atoms
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    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/92—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with etherified hydroxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
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    • C07D339/02—Five-membered rings
    • C07D339/06—Five-membered rings having the hetero atoms in positions 1 and 3, e.g. cyclic dithiocarbonates
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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    • C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates to the use of
  • persistent free radicals in particular persistent aryloxy and arylthio free radicals, as image enhancing agents in magnetic resonance imaging (MRI) as well as to contrast media containing such radicals and to the use of such radicals and their non-radical precursors in the manufacture of MRI contrast media.
  • MRI is a diagnostic technique that has become particularly attractive to physicians as it is non- invasive and does not involve exposing the patient under study to potentially harmful radiation, such as for example the X-radiation of conventional radiography.
  • MR images are generated by manipulation of the MR signals detected from the sample, for example a human or animal body, placed in a magnetic field and exposed to pulses of radiation of a frequency (typically
  • radiofrequency (RF) selected to excite MR transitions in selected non-zero spin nuclei (the "imaging nuclei", which are generally water protons in body fluids) in the sample.
  • the amplitude of the induced MR signals is
  • the strength of the magnetic field experienced by the sample dependent upon various factors such as the strength of the magnetic field experienced by the sample, the temperature of the sample, the density of the imaging nuclei within the sample, the isotopic nature and chemical environment of the imaging nuclei and the local inhomogeneities in magnetic field experienced by the imaging nuclei.
  • enhancing MR image quality for example by increasing MR signal amplitude or by increasing the difference in MR signal amplitude between different tissue types.
  • the imaging parameters may be altered and many
  • MRI contrast agents are paramagnetic they produce significant reduction in the T 1 of the water protons in the body zones into which they are administered or at which they congregate, and where the materials are ferromagnetic or superparamagnetic (for example as suggested by Jacobsen) they produce a significant
  • contrast enhancement achievable by such agents in conventional MRI is relatively limited and it is generally not such as to allow a reduction in the image acquisition period or in the field strength of the primary magnet.
  • This new technique for generating a MR image of the sample which is hereinafter termed electron spin resonance enhanced magnetic resonance imaging (ESREMRI) or Overhauser MRI (OMRI), involves exposing the sample to a first radiation of a frequency selected to excite nuclear spin transitions in selected nuclei in the sample (radiation which is generally of radiofrequency or thereabouts and thus for convenience will be referred to hereinafter as RF radiation) and also exposing the sample to a second radiation of a frequency selected to excite electron spin transitions coupled to nuclear spin transitions for at least some of the selected nuclei (radiation which is generally of microwave frequency or thereabouts and thus for convenience is referred to hereinafter as MW or UHF radiation), the MR images being generated from the resulting amplified MR signals (free induction decay signals) emitted by the sample.
  • RF radiation radiofrequency or thereabouts and thus for convenience will be referred to hereinafter as RF radiation
  • MW or UHF radiation the MR images being generated from the resulting amplified MR
  • the paramagnetic substance which possesses the ESR transition which couples with the NMR transition of the imaging nuclei may be naturally present within the imaging sample or more usually may be administered as an OMRI contrast agent.
  • Hafslund Nycomed Innovation AB proposed the use of deuterated stable free radicals, in particular deuterated nitroxide stable free radicals, as OMRI contrast agents.
  • Organic free radicals however frequently have properties which render them unsuitable for use as OMRI contrast agents.
  • free radicals commonly are unstable in physiological conditions, or have very short half-lives leading to toxicity problems.
  • a further drawback is the low relaxivity exhibited by many free radicals, which results in poor coupling of the electron and nuclear spin transitions and thus a poor enhancement of the magnetic resonance signa.
  • free radicals For such free radicals to be effective, they should be relatively long lived and to distinguish from free radicals which have a momentary existence, those usable as OMRI contrast agents will be referred to herein as being "persistent" free radicals, that is having a half life of at least one minute at ambient temperature.
  • radicals other than perhalo radicals for the manufacture of a contrast medium for use in MRI, and especially for use in OMRI, said radical preferably having an inherent linewidth for the peaks in its esr spectrum of less than 500 mG, especially less than 100 mG, and most especially no more than 50 mG.
  • OMRI contrast agents Since it is generally preferred for OMRI contrast agents that their esr spectra should contain as few lines as possible, it is especially preferred that the number of non-zero spin nuclei in the proximity of high free electron density sites within the radical should be as low as possible. Accordingly proton ( 1 H) substitution of the atoms of the aryl moiety should be minimized and while halogen atoms such as chlorines may (by virtue of their vacant d orbitals) participate in the aryl ⁇ - electron system and so enhance radical stability their presence as substituents is generally to be avoided.
  • Suitable radicals usable according to the invention thus include the following:
  • Ar is a 5-7 membered carbo- or heterocyclic
  • aromatic ring optionally carrying one or more
  • heterocyclic aromatic rings the resultant aryl ring structure preferably containing 0, 1 or 2 heteroatoms selected from O, N and S and optionally being
  • radical skeletons More explicit examples include
  • -0o and -So moieties are generally interchangeable and fused aryl rings may be added on if desired, subject of course to a general preference that the ⁇ -system should preferably contain no more than 4, especially no more than 3, fused rings.
  • substitution is intended to fulfil a dual or treble function - to stabilize the radical and to reduce esr linewidths and/or reduce the number of lines in the esr spectrum.
  • substitution sites one or more of these functions can be achieved by the same manner of
  • electron donor or withdrawing substituents should preferably be selected to minimize esr line broadening or line
  • splitting effects and sterically hindering or blocking groups should be selected to achieve their steric effect of hindering intermolecular approach with minimal deformation of the delocalizing ⁇ -system as such
  • nitrile and, more preferably, carboxyl groups (and esters, amides and salts thereof) are especially preferred.
  • carboxyl groups and esters, amides and salts thereof.
  • groups of formula R 2 O, R 2 S, R 2 SO 2 , R 2 OCOSO 2 and R 2 2 NCOSO 2 are especially preferred where R 2 is hydrogen or C 1-6 alkyl optionally substituted by hydroxyl, or C 1- 6 alkoxy, amine, C 1-6 alkyl or dialkyl amine, carboxyl (and amides and esters thereof) etc.
  • the invention also provides a method of magnetic resonance
  • investigation of a sample comprising introducing into said sample a persistent aryloxy or arylthio radical as discussed above, exposing said sample to a first radiation of a frequency selected to excite electron spin transitions in said free radical, exposing said sample to a second radiation of a
  • the invention also provides a magnetic resonance imaging contrast medium comprising a physiologically tolerable persistent aryloxy or arylthio free radical together with at least one pharmacologically acceptable carrier or excipient.
  • the free radical should of course preferably be a physiologically tolerable
  • tolerable e.g. encapsulated, form.
  • Preferred free radicals for use according to the invention exhibit high stability to oxygen, to pH, for example in the range pH 5-9, and in aqueous solution, particularly stability up to a concentration of 300 mM. Further desirable characteristics include reduced tendency to dimerization, long half-life, preferably greater than 1 minute, particularly preferably greater than 1 hour and especially preferably 1 year, long relaxation times, both T 1e and T 2e preferably being greater than 1 ⁇ sec, high relaxivity, for example
  • nuclei in all substituents and their positions within the molecule should be selected so as to minimise their effect (line splitting or broadening) on the esr transitions. Substitution of ortho and para and equivalent carbons is desirable in order to minimise dimerisation and oxygen attack on the molecule. Carbons in the orthoposition are preferably substituted by bulky substituents to minimise attack by oxygen and
  • the substituents should be bonded in such a manner that they are capable of free rotation.
  • the carbons of the aryl moiety preferably carry
  • Suitable substituents include groups R 1 which may be the same or different, and independently represent alkyl groups or groups of formula -M, -X 3 M, - X 3 Ar 2 where M represents a water solubilizing group, each group X 3 , which may be the same or different, represents an oxygen or sulphur atom or a NH, CH 2 , CO or SO 2 group; Ar 2 represents a 5 to 10 membered aromatic ring
  • R 6 represents a hydrogen atom, a hydroxyl group, an optionally alkoxylated, optionally hydroxylated acyloxy or alkyl group or a solubilising group M;
  • Z represents an oxygen or sulphur atom or a group NR 5 , CR 7 2 , or SiR 7 2 ;
  • R 5 represents a hydrogen atom or an optionally
  • each R 7 which may be the same or different, represents a hydrogen atom, an alkyl, hydroxyalkyl, alkoxycarbonyl or carbamoyl group or two groups R 7 together with the atom to which they are bound represent a carbonyl group or a 5 to 8 membered
  • cycloalkylidene mono- or di-oxacycloalkylidene, mono- or di-azacycloalkylidene or mono- or di- thiacycloalkylidene group optionally with the ring attachment carbon replaced by a silicon atom (preferably however in any spiro structure the ring linking atom will be bonded to no more than three heteroatoms) and R 7 where it is other than hydrogen, is optionally
  • radicals substituted in this fashion are new and they, their salts and their non-radical precursors (e.g. compounds having a structural unit ArOX 4 or ArSX 4 where X 4 is a leaving group, e.g. hydrogen, hydroxyl, halogen, carboxyl, CO 2 OCO. C(Ar) 3 or NNC(Ar) 3 ) form further aspects of the present invention.
  • solubilizing groups M may be any of the solubilizing groups conventionally used in diagnostic and
  • solubilizing groups M include optionally hydroxylated, optionally alkoxylated alkyl or oxo-alkyl groups and groups of formulae R 5 , COOR 5 , OCOR 5 , CHO, CN, CH 2 S(O)R 5 , CONR 5 2 , NR 5 COR 5 , NR 5 2 , SO 2 NR 5 2 , OR 5 , PO 3 2" , SOR 5 , SO 2 R 5 , SO 3 M 1 , COOM 1 (where M 1 is one equivalent of a physiologically tolerable cation, for example an alkali or alkaline earth metal cation, an ammonium ion or an organic amine cation, for example a meglumine ion), -(O(CH 2 ) p ) m OR 5
  • R 10 is a group R 5 or an alkyl group optionally substituted by one or more, especially two or three groups COOR 5 , OCOR 5 , CHO, CN, CONR 5 2 , NR 5 COR 5 , NR 5 2 , SO 2 NR 5 2 , OR 5 , PO 3 2- , SOR 5 , SO 2 R 5 , SO 3 M 1 , COOM 1 , or - (O(CH 2 ) n ) m OR 5 .
  • solubilizing groups M are groups or formula C(H) 3-p (CH 2 OH) , R 9 , COR 9 , SR 9 , SOR 9 , SO 2 R 9 , CON(R 9 ) 2 , NR 9 2 , NHR 9 and CONHR 9 [where R 9 may
  • R 9 group attached to a sulphur, nitrogen or oxygen atom is preferably not hydroxylated at the ⁇ carbon
  • groups of formula SR 12 where R 12 is a group CH 2 COOR 13 , CH(COOR 13 ) 2 , CH 2 CONHR 9 , CH 2 CONR 9 2 , CR 5 (COOR 13 ) 2 , CH(CN)CO 2 R 13 , (CH 2 ) p SO 3 -M 1 , (CH 2 ) p COR 9 , CH(COR 9 ) CH 2 COR 9 and CH(R 5 )COR 9 where p, M 1 and R 5 are as earlier defined and R 13 is a hydrogen atom, an alkyl group or a group M 1 or R 9 .
  • solubilising groups M or X 3 M include groups of formula X 5 C((CH 2 ) COOR 13 ) 2 R 14 , X 5 C((CH 2 ) p CCOR 13 ) 3 and X 5 C((CH 2 ) p COOR 13 )R 14 2 , where R 13 is as defined above, p is an integer from 1 to 3, X 5 is an oxygen or sulphur atom, and R 14 is a hydroxyalkyl group such as a group R 9 as earlier defined.
  • R 1 groups include for example the following structures
  • R 23 is C 1-4 alkyl (e.g.
  • NR 2 21 or OR 21 and R 21 is C 1-4
  • M represents a group containing a moiety NR 5 2
  • this may also represent an optionally substituted nitrogen-attached 5 to 7 membered heterocyclic ring optionally containing at least one further ring
  • heteroatom e.g. N or O, for example a group of formula
  • any aryl moiety will preferably contain 5 to 7 ring atoms in the or any aromatic ring and especially preferably will comprise an aromatic ring with 0, 1 or 2 further aromatic rings fused directly or indirectly thereto.
  • Preferred structures for the radicals include those in which at least one pair of adjacent ring carbons of the aryl moiety carries a fused ring of formula
  • X 3 is oxygen, sulphur, carbonyl or SO 2 and R 7 is hydrogen or optionally hydroxylated methyl.
  • the substituents on the aryl skeleton serve primarily to achieve one or more of the functions of i) steric hindrance (blocking), ii) electron withdrawing (from the ⁇ -system), iii) electron donating (into the ⁇ -system) and iv) enhancing the water solubility of the overall radical.
  • electron donating blocking groups are t-butoxy, t- butylthio, NR 70 2 (where R 70 is as described below), and the -X 7 -CR 7 2 -X 7 - (where X 7 is O or S) bridging groups.
  • the preferred electron withdrawing blocking groups include -X 7 -CR 7 2 -X 7 - (where at least one X 7 is SO or SO 2 ) bridging groups, CHO, CONR 70 2 , COOR 70 , OCOR 70 , SO 2 NR 70 2 , SO 2 CR 70 3 , NR 70 COR 70 , NR 70 COOR 70 , OCONR 70 2 , NR 70 SO 2 R 70 ,
  • NR 70 CONR 70 2 , NR 70 SO 2 NR 70 2 , COCR 70 3 , COCOR 70 , SO 2 R 70 , COCOOR 70 , CN, COSR 70 , SOCR 70 and CR 70 NOR 70
  • R 70 is hydrogen or alkyl or cycloalkyl (preferably C 1-4 alkyl or C 5- 6 cycloalkyl) optionally substituted by one or more groups selected from OH, NH 2 , CONR 71 2 and COOR 71 (preferably 1, 2 or 3 hydroxy groups) and R 71 is hydrogen or optionally hydroxylated C 1.3 alkyl.
  • R 70 is C 1-4 hydroxyalkyl (e.g.
  • each R 31 which may be the same or different, represents a steric hindrance group, e.g. t- butyl or more preferably a -O-t-butyl or -S-t-butyl group, or two groups R 31 on adjacent carbons together represent a steric hindrance bridging group e.g. a group -X 7 -CR 7 2 -X 7 -, or X 7 -NR 5 -X 7 - it being particularly
  • R 37 is alkyl
  • R 31 groups include Ar-O-, Ar-S-, Ar-SO 2 -, Ar-CO-, alkyl-CO-, and other carbon or nitrogen attached homo or heterocyclic rings (preferably 5-7 membered, especially 5-membered and particularly preferably dithiacyclopentanes and derivatives thereof), e.g. P
  • exemplary phenoxy structures include the following
  • R 52 is an electron withdrawing group (e.g. a cyano or carboxyl group or an amide or ester thereof, e.g. a group COOR 54 or CONR 2 54 where R 54 is hydrogen or optionally hydroxylated, alkoxylated or aminated alkyl) or, less preferably, a steric hindrance or solubilizing group, e.g. R 31 or M;
  • R 52 is an electron withdrawing group (e.g. a cyano or carboxyl group or an amide or ester thereof, e.g. a group COOR 54 or CONR 2 54 where R 54 is hydrogen or optionally hydroxylated, alkoxylated or aminated alkyl) or, less preferably, a steric hindrance or solubilizing group, e.g. R 31 or M;
  • each of R 48 , R 49 , R 50 , R 51 and R 53 is a hydrogen or a steric hindrance or solubilizing roup (e.g. R 31 or M), R 50 preferably being hydrogen and the remaining preferably being other than hydrogen, especially R 48 and R 49 which particularly preferably represent steric hindrance groups such as -S-tBu, -O-tBu etc.
  • each of the groups R 50 , R 51 and R 53 which may be the same or different,
  • R 52 represents an electron withdrawing group or a group as defined for R 50 with the exception of hydrogen;
  • each of the groups R 48 and R 49 independently represents a hydrogen atom, a water solubilising group M or an alkyl, alkoxy, alkylthio, acyloxy or aryl group optionally substituted by alkyl, hydroxy, mercapto, alkoxy or optionally alkoxylated, optionally hydroxylated acyloxy groups, or by a water solubilising group M;
  • R 48 and R 49 , R 50 and R 51 , R 51 and R 52 and/or R 52 and R 53 , together with the two intervening carbon atoms may represent groups of formula
  • R 7 represents a hydrogen atom, a hydroxy, or optionally hydroxylated, optionally alkoxylated acyloxy group or a water solubilising group M.
  • Preferred indolizinyl radicals include those wherein R 52 is an electron withdrawing group, especially an ester or amide or a carboxy group or a salt thereof.
  • R 48 and R 49 are identical, and
  • R 48 and R 49 are both solubilizing groups M or optionally substituted alkoxy or alkylthio groups.
  • R 52 and one of R 50 , R 51 and R 53 are alkoxy groups or a group
  • -COOR 54 -OCOR 54 , -CONHR 54 or -CONR 54 2 , e.g. -CON(CH 2 CH 2 OH) 2 .
  • R 48 to R 53 are as follows:
  • R 53 hydrogen, methoxy and carboxy and salts, esters and amides thereof
  • R 52 cyano, carboxy and salts, esters and amides thereof
  • R 51 hydrogen, methoxy and carboxy and salts, esters and amides thereof
  • R 50 hydrogen, methoxy, tri (hydroxymethyl)- methylthio and carboxy and salts, esters and amides thereof
  • R 50 and R 51 together: dimethyl methylenedioxy and di(hydroxymethyl)methylenedioxy
  • R 48 and R 49 phenyl, t-butoxy, t-butylthio, carboxymethylthio, 3,4-dihydroxybutanoyloxy, 2,3- dihydroxypropoxycarbonyl, 2-sulphoethylthio,
  • R 48 and R 49 together: dimethylmethylenedioxy and di (hydroxymethyl) methylenedioxy.
  • indolizinyl radicals for use in accordance with the invention include
  • 2,3-di-t-butoxy-6,7,8-tricarboxy-1-indolizinyl radical More preferred indolizinyl radicals include:
  • Indolizinyl radicals wherein R 53 and R 52 are carboxy groups and R 50 and R 51 together are dimethylmethylenedioxy or di(hydroxymehtyl)methylenedioxy groups or where R 53 and R 51 are methoxy groups, R 52 is a carboxy group and R 50 is a trihydroxymehtyl methylthio group are also.
  • indolizinyl radicals examples include
  • R 54 H, CH 3 , CH 2 CH 3 ,
  • R 61 COOH, CH 3
  • R 62 alkyl, phenyl, alkoxy, alkylthio
  • novel indolizinyl radicals include compounds wherein R 48 to R 53 are as hereinbefore defined
  • R 53 , R 52 or R 51 is cyano, or R 52 is -CHO, -CO 2 CH 3 , -CONH 2 , or -COOH 3
  • R 50 , R 51 , R 52 , R 53 are hydrogen, at least one of R 48 and R 49 is other than a substituted or unsubstituted phenyl group, and that where R 52 is cyano, and R 50 , R 51 , and R 53 are hydrogen, at least one of R 48 and R 49 is other than n-C 3 H 7 .
  • R 69 to R 72 which may be the same or different represent steric hindrance and/or solubilizing groups or more preferably R 69 and R 70 and/or R 71 and R 72 , together with the intervening carbons form fused aryl rings, preferably 5-7 membered rings, which optionally but preferably themselves carry steric hindrance and/or solubilizing (e.g. R 31 and M) groups.
  • R 69 to R 72 which may be the same or different represent steric hindrance and/or solubilizing groups or more preferably R 69 and R 70 and/or R 71 and R 72 , together with the intervening carbons form fused aryl rings, preferably 5-7 membered rings, which optionally but preferably themselves carry steric hindrance and/or solubilizing (e.g. R 31 and M) groups.
  • the mesomeric forms of the semiquinone anion radicals i.e. oO-B-O- and -O-B-Oo (
  • substitution to enhance radical stability should be at or adjacent sites in the aryl system which have high spin density.
  • substitution at high spin density sites should generally be with
  • Substitution at neighbouring sites should generally be by bulky steric hindrance groups which serve to prevent the radical from reacting with other molecules or radicals.
  • the steric hindrance groups can also serve to enhance water solubility of the radical; alternatively separate solubilizing substituents may be included.
  • the particularly preferred substituent groups for the radicals for use according to the invention include the following -tBu, -O-tBu, -S-tBu, -OC(CH 3 ) 2 -O-, I, -CO- CR 7 2 -CO-, -CO-NR 5 -CO-, -SO 3 Na, -COOR 2 , -S-R 2 , -SO 2 R 2 ,
  • Persistent aryloxy and arylthio radicals are widely known from the literature and ones suitable for -use according to the invention may be prepared by the
  • Persistent free radicals which have relatively few transitions, e.g. less than 15, preferably less than 10, in their esr spectra and radicals having narrow
  • linewidth esr transitions e.g. up to 500 mG, preferably less than 150 mG, especially less than 60 mG and
  • the linewidths referred to are conveniently the intrinsic linewidths (full width at half maximum in the absorption spectrum) at ambient conditions).
  • novel radicals of the invention include
  • radicals which surprisingly are stable at physiological pH, have long half lives (at least one minute, and preferably at least one hour), long relaxation times, and exhibit surprisingly good relaxivity.
  • Water-soluble radicals are a particularly important aspect of the invention.
  • the radicals may be coupled to further molecules for example to lipophilic moieties such as long chain fatty acids or to macromolecules, such as polymers, proteins, polysaccharides (e.g. dextrans), polypeptides and polyethyleneimines.
  • the macromolecule may be a tissue-specific biomolecule such as an antibody or a backbone polymer such as polylysine capable of carrying a number of independent radical groups which may itself be attached to a further macromolecule. Coupling to lipophilic groups is particularly useful since it may enhance the relaxivity of the radicals in certain systems such as blood. Such lipophilic and
  • the linkage of a radical to the further molecule may be effected by any of the conventional methods such as the carbodiimide method, the mixed anhydride
  • novel radicals of the invention may also be used as esr spin labels in esr imaging or in
  • the radicals may be prepared from their non-radical precursor compounds by conventional radical generation, methods for example comproportionation, oxidation, reduction or any of the other methods known from the literature or described in PCT/EP91/00285.
  • the invention provides a process for the preparation of the novel radicals of the invention which comprises subjecting a radical precursor therefor to a radical generation step and optionally subsequently modifying the substitution on the aryl moieties, e.g. by oxidation or reduction.
  • sulphide substituents e.g. - SCH 3 or -SCH 2 COOEt
  • lipophilic radicals e.g. - SCH 3 or -SCH 2 COOEt
  • substituents such as -SCH 2 COOEt
  • hydrophilic substituents e.g. -SCH 2 CH 2 OH
  • the non-radical precursors may themselves be prepared by methods conventional in the art or analogous to those described in PCT/EP91/00285.
  • radicals with long half lives in aqueous solution for example at least one hour, preferably ten days, more preferably fifty days and especially
  • At least one year are clearly particularly desirable for use in in vivo imaging, shorter lived inert free radicals may still be utilised in imaging (e.g. of inanimate samples) and these may particularly conveniently be prepared immediately pre-administration.
  • indolizinyl radicals these radicals may be generated from the corresponding indolizinols by oxidation under air or oxygen, or by using a chemical oxidant such as benzoquinone, iodine or chloranil. Oxidation under air or oxygen is preferred.
  • Oxidation may conveniently be effected during cyclization to form the indolizinyl skeleton, during work-up or even before or during administration.
  • the non-radical indolizinyl precursors may be any suitable non-radical indolizinyl precursors.
  • oxoindolizine and oxoindilizinium compounds i.e.
  • indolizinyl free radicals according to the invention may be prepared by following reaction schemes such as those suggested below:-
  • the nitro group can then be transformed into an oxygen radical , e. g. folowing the sequence:
  • Hydrogenated indolizinyls for instance indolizinyl alkaloids like castanospermine or similar substances also represent useful reagents in the synthesis of the indolizinyl radicals. These hydrogenated substances can be dehydrogenated and/or dehydrated to the
  • More specific routes to indolizinyl radicals include the following:
  • R 2' CN, CCR 3'
  • R 4' electron-withdrawing group
  • a quinone starting material should be reduced to the hydroquinone form before the alkylation is
  • diacylated hydroquinone may be made either from diacylated hydroquinone by mild hydrolysis of one acyl group or by selective
  • M 3 represents a group which makes the molecule water soluble
  • substituents may be introduced onto individual component substructures before they are put together to form the radical precursor compounds, or they may be introduced directly onto the precursor compound or the actual radical itself. It is also possible to effect the substitution and radical construction steps
  • the radicals are conveniently formulated into contrast media together with
  • Contrast media manufactured or used according to this invention may contain, besides the radicals (or the non- radical precursor where radical formation is to be effected immediately before administration), formulation aids such as are conventional for therapeutic and diagnostic compositions in human or veterinary medicine.
  • the media may for example include solubilizing agents, emulsifiers, viscosity enhancers, buffers, etc.
  • the media may be in forms suitable for parenteral (e.g. intravenous) or enteral (e.g. oral) application, for example for application directly into body cavities having external voidance ducts (such as the
  • Free radicals which are relatively unstable or insoluble in the sample environment may be encapsulated, e.g. in gastric juice resistant capsules containing a medium in which they are stable.
  • the radicals may be presented as an encapsulated freeze dried powder in a soluble capsule. Such formulations might conveniently be dissolved shortly before in vivo use.
  • the medium which preferably will be substantially isotonic, may conveniently be administered at a concentration
  • concentration of the free radical in the imaging zone is a balance between various factors. In general, optimum concentrations would in most cases lie in the range 0.1 to 100 mM, especially 0.2 to 10 mM, more especially 0.5 to 5 mM.
  • Compositions for intravenous administration would preferably contain the free radical in concentrations of 10 to 1000 mM especially 50 to 500 mM.
  • concentration will particularly preferably be in the range 50 to 200 mM, especially 130 to 170 mM and for non-ionic materials 200 to 400 mM, especially 290 to 330 mM.
  • compositions may perhaps be used having concentrations of for example 10 to 100 mM for ionic or 20 to 200 mM for non-ionic materials.
  • concentration may conveniently be 0.1 to 100 mM, preferably 5 to 25 mM, especially preferably 6 to 15 mM.
  • Diphenylcyclopropenone (Aldrich 17,737-7) (0.5000 g 2.424 * 10 -3 mole) and isonicotinic acid (Aldrich I- 1,750-8) (0.2985 g 2.424 * 10 -3 mole) were added in solid form to a carefully dried reaction flask.
  • the flask was equipped with a septum and the flask was evacuated three times with addition of nitrogen after each evacuation.
  • Chlorobenzene (Aldrich 27,064-4) (5 ml) was added with a gastight syringe. The stirred mixture was cooled to 0°C.
  • Triethylamine (Aldrich 23,962-3) (0.3379 ml, 2.42 * 10 -3 mole) was added dropwise with a gastight syringe. The resulting mixture was stirred at ambient temperature for 2 days. The colour of the mixture changed to yellow and then to green. The solvent was removed on a
  • the reaction mixture was stirred at ambient temperature for 2.5 hours, while the title compound precipitated.
  • the mixture was cooled to about 0°C and the product isolated by filtration under N 2 .
  • the product was washed with minute amounts of methanol and some diethylether and dried.
  • the product was identified by mass spectrometry; DCI probe and electron impact conditions identified the heterocyclic part and 1 H NMR identified the ammonium part.
  • the product was further characterized by ESR and OMRI, measurements of the corresponding radical which was generated by treatment with oxygen.
  • 3,4-Pyridinedicarboxylic acid (2.424 * 10 -3 mole, 0.4051 g), diphenylcyclopropenone (2.424 * 10 -3 mole, 0.5000 g) and di(propane-2,3-diol) amine (4.848 * 10 -3 mole, 0.8008 g) were stirred in methanol (10 ml), under an atmosphere of air for 24 hours at ambient temperature. Thin layer chromatography revealed complete consumption of the cyclopropenone and the solvent was removed on high vacuum, yielding the product as a foam.
  • the radical was identified by mass spectrometry (DCI-EI and thermospray) and by the ESR spectrum and the OMRI effect in a water solution (buffer pH 7.4).
  • 3,4-Pyridinedicarboxylic acid (2.424 * 10 -3 mole, 0.4051 g), diphenylcyclopropenone (2.424 * 10 -3 mole, 0.5000 g) and N-methylglucamine (4.848 * 10 -3 mole, 0.9404 g) were stirred in a mixture of tetrahydrofuran (10 ml, degassed with helium) and methanol (3 ml, degassed with helium) at ambient temperature for 24 hours. The solvent was removed and the product triturated with diethyl ether and methanol and dried.
  • Examples 1 to 5 and 7 are converted to their radicals by oxidation in air or with benioquinone.
  • the title compound was synthesized from the product of Example 9 according to the procedure of D H Wadsworth, J. Org. Chem., 1989, 54, 3652.
  • the isolated green to black precipitate was analyzed by HPLC and the radical content was determined to be 20%.
  • Diphenylcylcopropenone (0.250 g, 1.21 mmol) and 3,4- diamidopyridine (0.200 g, 1.21 mmol) were mixed in a dry, argon filled reaction flask. Chlorobenzene (2.5 mL) (oxygen free) was added, and the reaction was heated to 130oC. After 2 h the heating was stopped and the reaction was allowed to reach room temperature.
  • Petroleum ether 40-60oC (2.5 mL) was added in order to obtain a complete precipitate of the product. The solvent was filtered off and the precipitate was washed with petroleum ether. Acetone (30 mL) was added to the crude product, and the mixture was stirred for lh. The dark acetone solution was filtered off leaving a yellow precipitate. The precipitate was analyzed by HPLC
  • Example 11 1-Hydroxy-2,3-diphenyl-6,7-diamidoindolizine (Example 11) was dissolved in THF and 4-benzoquinone was added. The reaction was stirred for 15 min at 50oC. The colour changed during the reaction from yellow to dark red. The product was analyzed and the formation of the radical was determined by an OMRI experiment.
  • Diphenylcyclopropenone (0.319 g, 1.55 mmol) and 3,4- dicyanopyridine (0.200 g, 1.55 mmol) were mixed in a dry, argon filled reaction flask.
  • Chlorobenzene (2.5 mL) (oxygen free) was added, and the reaction was heated to 130oC. After 2 h the heating was stopped and. the reaction was allowed to reach room temperature.
  • Petroleum ether 40-60oC (2.5 mL) was added in order to obtain a complete precipitate of the product. The solvent was filtered off and the precipitate was washed with petroleum ether. The crude product was stirred with chloroform (30 mL) for lh. The dark chloroform solution was filtered off leaving the title product as a yellow precipitate.
  • Example 13 1-Hydroxy-2,3-diphenyl-6,7-dicyanoindolizine (10 mg, 0.03 mmol) was dissolved in DMSO (5 mL) and 4-benzoquinone (13.0 mg, 0.12 mmol) was added. The reaction was stirred for 15 min at 700. The colour of the reaction became dark. The product was analyzed and the formation of the radical was determined by an OMRI experiment.
  • OMRI signal enhancement (5 Watts) 80.
  • 1,1'-(2,2',3,3'-tetra-t-butylthio-6,6',7,7'-tetracyano- diindolizine)-disulfide is treated with a reducing agent in an appropriate solvent until all disulfide is
  • the reaction is stopped and the product is isolated by chromatography or recrystallization, or by a combination thereof.
  • the radical is produced by
  • 1,1'-(2,2',3,3'-tetra-t-butylthio-7,7',8,8'-tetracyano- diindolizine)-disulfide is treated with a reducing agent in an appropriate solvent until all disulfide is
  • the reaction is stopped and the product is isolated by chromatography or recrystallization, or by a combination thereof.
  • the radical is produced by conventional techniques .
  • Example 18 The title product and the resulting radical are synthesized analogously to Example 15.
  • Example 18 The title product and the resulting radical are synthesized analogously to Example 15.
  • the radical is generated by conventional techniques.
  • the radical is generated by conventional techniques.
  • 1,2-Di-tert-butoxycyclobutenedione is dissolved in ether and photolyzed under nitrogen by a mercury high pressure lamp through quartz glass for 2-8h depending on the quality of the mercury lamp.
  • 2,3-Di-tert-butoxycyclopropenone and 3,4-dicyanopyridine are mixed in a dry, argon filled flask.
  • a solvent such as chlorobenzene (oxygen free) is used.
  • the product is purified by chromatography or recrystallization, or by a combination of these techniques.
  • the radical is then generated by conventional techniques.
  • PCT/EP91/00285) is dissolved with stirring in dry THF in a dry, argon filled reaction flask.
  • the solution is cooled to (-25) - (-30) oC.
  • Butyllithium in hexane is added dropwise with a syringe.
  • the reaction is stirred for 0.5 h.
  • a large excess of paraformaldehyde is depolymerized by heating.
  • the formaldehyde formed is distilled, by means of an argon stream, into the reaction via a glass tube. When the reaction is complete, the product is hydrolyzed.
  • the crude product is collected and is purified by
  • Triethylamine is dissolved in CH 2 Cl 2 with stirring.
  • 1,1- Dibromo-1,3-bis (8-methylthio-2,2,6,6- tetramethylbenzol [1,2-d:4,5-d']bis (1,3) dioxole-4-yl) acetone in CH 2 Cl 2 is slowly added. After completion, the reaction mixture is worked up. The product is isolated by ctiromatography or recrystallization, or by a
  • the radical is generated by conventional techniques.
  • Phenol 502.1 mg, 5.335 mmol was dissolved in DMF (4 mL, dry Aldrich sureseal).
  • Sodium hydride (159.9 mg, 5.330 mmol, 80% in white oil) was washed twice with dry petroleum ether (decanting most of the petroleum ether after settling of the NaH), dired with argon gas and added to the phenolic solution.
  • the resulting solution was stirred under argon while hydrogen evolved.
  • tetrafluoroquinone (199.0 mg, 1.105 mmol) was added in portions, while cooling the mixture with an ice-water bath.
  • the resulting solution was stirred 48 h, acidified with dilute HCl and
  • the semiquinone anion radicals are generated by
  • PhSO 2 Na (1.6579 g., 0.0101 mol) was dissolved in water (100 mL), while keeping an atmosphere of N 2 .
  • HCl (12 M, 0.84 mL, 0.0101 mol) was added in order to produce PhSO 2 H.
  • Phenylsulfonylhydroquinone (0.0250 g, 0.1 mmol) was dissolved in CH 2 Cl 2 (4 mL). Silicagel (0.5 g) and NalO 4 (0.65 M in H 2 O, 0.5 mL) were added. The clear solution turned yellow quickly and the solution was filtered throug a short plug of silica after 15 min stirring. The product was eluted with CH 2 Cl 2 . Yield 0.0218 g.
  • the product was identified by 1 H and 13 CNMR spectroscopy.
  • the radical is generated using conventional techniques.
  • the product was identified by 1 H NMR spectroscopy.
  • the radical is generated using conventional techniques.
  • hydroquinone is synthesized according to the procedure of Can. J. Chem. 1962, 40, page 1235. If desired the solvent may be changed to DMF and the reaction may be run at a higher temperature. The radical may be generated by conventional techniques.
  • the radical may be generated by conventional techniques.
  • the radical may be generated by conventional techniques.
  • Tetraphenoxy benzoquinone is reduced with Na 2 S 2 O 4 to the tetraphehoxy hydroquinone, as described. by L Feiser et al., JACS 70, 1948, p 3165.
  • the product is purified by crystallization or
  • Tetraphenoxy benzoquinone is reduced with excess NaBH 4 in a mixture of EtOH and water.
  • the product is purified by extractions and chromatography, or by a combination of these techniques.
  • the product is then monoalkylated or monoetherified to yield a phenoxy radical precursor as follows:
  • Tetraphenoxyhydroquinone is monomesylated in pyridine with one equivalent of MeSO 2 Cl for 2-3 days at ambient temperature. The product is isolated in low to moderate yield by extractions and chromatography. (See Annalen 551:235 (1942)).
  • 2,6-Diphenylsulfonyl hydroquinone is monomesylated in pyridine with one equivalent of MeSO 2 Cl for 2-3 days at ambient to high temperature.
  • the product is isolated and purified by extractions and chromatography.
  • Tetraethylthiohydroquinone is monomesylated with MeSO 2 Cl in pyridine at room temperature for 2-4 days. The product is isolated by extractions and chromatography.
  • Radicals may be generated from the compounds of Examples 34-37 by conventional techniques.
  • Tetraethylthiohydroquinone monomesylate is stirred with lead dioxide (excess) in the dark under an atomosphere of N 2 .
  • Small samples are taken, centrifuged or filtered through oxygen-free silica and analysed by ESR, or by OMRI signal enhancement measurements.
  • the product is purified by centrifugation, filtration and
  • 2,6-Dichlorohydroquinone monomethyl ether is stirred with an excess of K 3 Fe(CN) 6 in benzene until samples taken show high conversion to the radical.
  • the product is purified as described in Example 38.
  • a phenoxy radical precursor is prepared by a
  • the phenol end product can be transformed into a radical directly or after oxidation of the sulphurs in the steric hindrance groups according to the reaction scheme below:
  • step (b) 2-hydroxy-1,3,5-tripivaloyl benzene
  • trisethylenethioketal is dissolved in CH 2 Cl 2 at ambient temperature.
  • Magnesium monoperphtalic acid (MMPA) and tetra-n-butylammonium hydrogensulphate (Q+HSO 4- dissolved in water are added dropwise.
  • the reaction is complete after several hours.
  • the phases are separated and the organic phase is washed with a saturated solution of NaHCO 3 .
  • the ether phase is dried (Na 2 SO 4 ) and the solvent evaporated leaving the product, which can be purified via distillation,
  • voluminous red precipitate is formed and filtered off.
  • the product can be crystallized and the two isomeric products (the 2,6- and 2,4-isomers, respectively) can be separated by chromatography.
  • the O-alkylation of the product (2,6-bisphenylthio hydroquinone) can be performed in dry dioxane with isobutylene, condensed into the solution, and a
  • 2,6-Diphenylthio-4-t-butoxyphenole is dissolved in CH 2 Cl 2 and mixed with metachloroperbenzoic acid (MCPBA) and Q+HSO- 4 , dissolved in water. Efficient stirring is maintained at reflux for 20 h. Sodium sulphite is added to reduce the excess MCPBA. After concentration in high vacuum, the reaction mixture is worked up to give the product, which is purified via distillation,
  • reaction is performed according to the method of Ullman et al. Chem. Ber. 42: 2539-2548 (1909). If another oxidant is selected the same reaction sequence can be used to give the corresponding 5-COOH derivative.
  • the product of the first reaction step is dissolved in dry acetone and active MnO 2 is added.
  • the mixture is stirred for 24 h at room temperature.
  • the mixture is filtered, and the filtrate treated with an acidic ion exchanger (e.g. Dowex 50 x B) and filtered again.
  • an acidic ion exchanger e.g. Dowex 50 x B
  • ethanedithiole and a few drops of BF 3 ⁇ OEt 2 are added. Stirring is maintained for 20 h.
  • the acetic acid is evaporated at reduced pressure (1-2 torr) and the residue is the desired product, compound (A).
  • the oxidation of the compound (A) takes place in glacial acetic acid with H 2 O 2 (35%). Stirring is continued at room temperature for 48 h. The excess peroxide is destroyed by the careful addition of a saturated
  • Compound (B) can then be purified via distillation, crystallization or
  • p-Hydroxymethyl phenol is etherified by dissolving it in dioxane, condensing isobutylene into the solution and adding a catalytic amount of mineral acid.
  • This product can be converted to the di-hydroxymethyl derivative by addition to a solution of NaOH (50%) adn then adding, at room temperature, a solution of formaldehyde (37%). The oxidation of this product takes place with active MnO 2 (20 equivalents) in acetone.
  • the starting product is dissolved in glacial acetic acid, and ethanedithiol (2.5 equivalents), and a few drops or BF 3 ⁇ OEt 2 are added. After stirring overnight, the reaction mixture is worked up by evaporation of the solvent. The residue is then purified by crystallization, distillation or
  • the phenol function can, by use of diazomethane, be
  • the methyl ether is cleaved to the phenol with hydrogen iodide in acetone.
  • the mixture is evaporated to dryness at high vacuum, and the phenol can be converted to its radical by anion formation and oxidation. S-oxidation can take place without prior phenol protection.
  • the starting compound is dissolved in dry Et 2 O, and t-BuLi is added via a syringe. Stirring is continued for several hours at room temperature. After quenching with water, the phases are separated and the organic phase is worked up. The product is used directly in the next reaction step. In this it is dissolved in acetone and oxidized with active MnO 2 . After stirring at room temperature for 24 h, the mixture is filtered and the solvent is evaporated under reduced pressure. The product is then purified by
  • thioketal product is then purified by crystallization, distillation or chromatography, or combinations thereof.
  • the thioketal is dissolved in acetone and MnO 2 is added.
  • After work up the aldehyde product is used directly in next step.
  • the aldehyde compound is mixed with diethylmalonate and pyridine, according to the procedure given by Mullet et al. (see above).
  • the product is then purified by
  • the product can then be purified by crystallization, distillation or
  • 3,5-Di-tert-butyl-4-hydroxyanisole (0.1 g, 0.4 mmol) was dissolved in diethylether (80 mL), and into the mixture was bubbled argon for 30 minutes.
  • Potassiumferricyanide (0.29 g) was dissolved in water (100 mL), which had been made alkaline with potassiumhydroxide and bubbled with argon for 30 minutes. The solutions were mixed and after 10 minutes the organic phase was red and the presence of the radical was established with ESR measurements.
  • the S-methylated di-ketal (500 mg, 1.87 mmol) was dissolved in THF (50 mL, distilled over Na) under argon. The mixture was cooled to -70oC. n-Butyllithium (0.8 mL, 2.0 mmol) was added through a syringe. The mixture was stirred at -70oC for 2 hours. The Dewar flask was removed, and O 2 was bubbled through the mixture for 3 h. Diethylether (50 mL) was added, and a solid precipitated. This was filtered off and dissolved in 1 N NaOH and washed with Et 2 O. The organic phase was extracted twice with 1 N NaOH (10 mL).
  • the alkaline water phase was acidified with concentrated HCl to pH 2 and then extracted with CH 2 Cl 2 (2 x 50 mL). After drying, filtering and evaporation the product was isolated (130 mg, 0.46 mmol; 25%). Radical formation is performed with KOH and K 3 Fe(CN) 6 , as described above.
  • N,N-bis-(2,3-dihydroxypropyl)-2,6-bis-(1,1-dimethylethyl)- benzene-4-carboxamide-1-oxy radical To a saturated solution of N,N-bis-(2,3-dihydroxypropyl)- 3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzenecarboxamide in redistilled. Argon-flushed water (50 mg in 50 ml) was added in one portion while flushing with argon, 0.5 g of lead dioxide. The flask was sealed with an ordinary stopper and teflon tape and thoroughly shaken. The dark green solution thus obtained was used directly for ESR-measurements.
  • aqueous phase was extracted three times with ether and the combined organic phases were washed with aqueous NaHSO 3 , 2 M NaOH, dried (MgSO 4 ) and evaporated.
  • the product was purified by preparative HPLC (RP-18, CH 3 CN: H 2 O 80:20).
  • tetrabutylammonium hydrogensulfate (163 mg, 0.48 mmol), 1M aqueous NaOH (20 mL) and methyl iodide (2.4 mmol, 0.15 mL). The mixture was stirred vigorously for 15 hours, the organic phase was evaporated and triturated with ether.
  • the radical is prepared from 4-hydroxy-3,3,5,5-tetroxo-8- methoxy-2,2,6,6-tetramethylbenzo[1,2-d;5,4-d']bis- (1,3) oxathiole using either PbO 2 or K 3 Fe(CN) 6 as the
  • N,N-bis (2 ,3-dihydroxypropyl)-1-hydroxy-2,4,6-triodo- benzene-3,5-dicarboxylic acid diamide (13.1 g, 40 mmol) was dissolved in water (160 mL) and pH was adjusted to 3.9 using aqueous HCl. To this solution, NaICl 2 (42.6 g, 50.3%, 40 mmol) was added dropwise during a period of 30 minutes. After standing overnight, the reaction mixture was
  • N,N-bis(2,3-dihydroxypropyl)-1-hydroxy-2,4,6-triodo- benzene-3,5-dicarboxylic acid diamide (100 mg, 0.14 mmol) was dissolved in water (7 mL) under an atmosphere of argon.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Radiology & Medical Imaging (AREA)
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Abstract

On a prévu l'utilisation de radicaux libres d'aryloxy ou d'arylthio, à l'exclusion des radicaux perhalo, dans la fabrication d'un agent de contraste destiné à l'imagerie par résonance magnétique. On a également prévu des compositions de milieu de contraste et des procédés d'imagerie par résonance magnétique contenant ou utilisant ces radicaux.
PCT/EP1992/001792 1991-08-09 1992-08-06 Utilisation de radicaux libres persistants en imagerie par resonance magnetique WO1993002710A2 (fr)

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GB919117258A GB9117258D0 (en) 1991-08-09 1991-08-09 Use of radicals
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FR2742550A1 (fr) * 1995-12-19 1997-06-20 Commissariat Energie Atomique Solution radicalaire pour magnetometre a resonance magnetique nucleaire
US5728370A (en) * 1993-04-02 1998-03-17 Nycomed Imaging As Free Radicals
CN100458316C (zh) * 1999-05-12 2009-02-04 大金工业株式会社 冷冻回路用电动针阀及其具有该针阀的冷冻装置
CN103922977A (zh) * 2014-05-07 2014-07-16 江南大学 一种制备磺酰基醌类的新方法

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Publication number Priority date Publication date Assignee Title
US20070155738A1 (en) 2005-05-20 2007-07-05 Alantos Pharmaceuticals, Inc. Heterobicyclic metalloprotease inhibitors

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WO1991012024A1 (fr) * 1990-02-12 1991-08-22 Hafslund Nycomed Innovation Ab Radicaux de triarylmethyle et utilisation de radicaux exempts de carbone inerte en irm

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WO1991012024A1 (fr) * 1990-02-12 1991-08-22 Hafslund Nycomed Innovation Ab Radicaux de triarylmethyle et utilisation de radicaux exempts de carbone inerte en irm

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J. Org. Chem., vol. 51, no. 24, 1986, American Chemical Society, D.H. WADSWORTH et al.: "Indolizines. 2. Preparation of 1- and 3-indolizinols and their esters", pages 4639-4644, see page 4639, column 2, last 6 lines (cited in the application) *
Journal of Magnetic Resonance, vol. 76, 1988, Academic Press, Inc., D.J. LURIE et al.: "Communications, proton-electron double magnetic resonance imaging of free radical solutions", pages 366-370, see paragraph 1; page 369, last paragraph *
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5728370A (en) * 1993-04-02 1998-03-17 Nycomed Imaging As Free Radicals
FR2742550A1 (fr) * 1995-12-19 1997-06-20 Commissariat Energie Atomique Solution radicalaire pour magnetometre a resonance magnetique nucleaire
EP0780697A1 (fr) * 1995-12-19 1997-06-25 Commissariat A L'energie Atomique Solution radicalaire pour magnétomètre à résonance magnétique nucléaire
US5952826A (en) * 1995-12-19 1999-09-14 Commissariat A L'energie Atomique Radical solution for nuclear magnetic resonance magnetometer
CN100458316C (zh) * 1999-05-12 2009-02-04 大金工业株式会社 冷冻回路用电动针阀及其具有该针阀的冷冻装置
CN103922977A (zh) * 2014-05-07 2014-07-16 江南大学 一种制备磺酰基醌类的新方法

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AU2396492A (en) 1993-03-02
GB9117258D0 (en) 1991-09-25

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