EP0925280A1 - N-geschützte alpha-aminosulfinsäuresalze, verfahren zu ihrer herstellung sowie die daraus abgeleiteten sulfonopeptiden - Google Patents

N-geschützte alpha-aminosulfinsäuresalze, verfahren zu ihrer herstellung sowie die daraus abgeleiteten sulfonopeptiden

Info

Publication number
EP0925280A1
EP0925280A1 EP97931852A EP97931852A EP0925280A1 EP 0925280 A1 EP0925280 A1 EP 0925280A1 EP 97931852 A EP97931852 A EP 97931852A EP 97931852 A EP97931852 A EP 97931852A EP 0925280 A1 EP0925280 A1 EP 0925280A1
Authority
EP
European Patent Office
Prior art keywords
group
salt
carbon
chosen
intermediate compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP97931852A
Other languages
English (en)
French (fr)
Inventor
Michel Mulliez
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Universite Toulouse III Paul Sabatier
Original Assignee
Universite Toulouse III Paul Sabatier
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Universite Toulouse III Paul Sabatier filed Critical Universite Toulouse III Paul Sabatier
Publication of EP0925280A1 publication Critical patent/EP0925280A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/31—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms
    • C07C311/32—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/47—Y being a hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C313/02—Sulfinic acids; Derivatives thereof
    • C07C313/04—Sulfinic acids; Esters thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C313/02—Sulfinic acids; Derivatives thereof
    • C07C313/06—Sulfinamides

Definitions

  • the analogues of the transition state of the hydrolysis of the peptide bond (falling into the class of pseudopeptides) can act as false non-degradable substrates or as protease inhibitors, and therefore have great therapeutic interest, in particular for obtaining antibiotics, antihypertensives, analgesics, HIV protease inhibitors ...
  • the rare derivatives of ⁇ -sulfinic amino acids described are not protected on nitrogen by an acyl protecting group, are not substituted at ⁇ , and are unstable.
  • the invention therefore aims to overcome these drawbacks by proposing protected N acid salts ⁇ , amino sulfinic synthesized, stable, isolated or capable of being isolated, and the process for obtaining them.
  • stable we mean that we can keep them at least 8 hours - notably several days - without alteration.
  • the invention aims to propose a process making it possible to obtain said salts, the nitrogen substituent of which can be freely chosen, in particular from traditional acyl protective groups (Cbz, Boc, acetyl, etc.), and by particular distinct from the tosyle (PCH3C5H4SO2) and mesyl (CH3SO2) groups, so that the said salts can serve as precursors of ⁇ sulfonopeptides.
  • the invention aims more particularly to provide salts as mentioned above in which the ⁇ carbon is substituted, in particular by a halogenated carbon group, and their process for obtaining.
  • the invention thus aims to propose these salts which are precursors of sulfonopeptides, or even of sulfinopeptides, but which can also be isolated and used as such, in particular as N acylated analogs of natural ⁇ -amino carboxylic acids.
  • the invention further aims to provide stable sulfonopeptics, namely, the stable synthesized ⁇ -sulfonopeptides, isolated or capable of being isolated, derived from these salts according to the invention.
  • - sulfonopeptide any chain of amino acids comprising at least one ⁇ -amino sulfonamide residue
  • - acyl any group or function of acyl type derived from an oxoacid in general, that is to say not only a carboxylic or thiocarboxylic acyl stricto sensu, but also groups or functions of acyl type derived from mineral acids such that sulfonic, phosphoric, thiophosphoric, phosphonic, or phosphinic acids, - ester: esters derived from acyls as mentioned above,
  • - amide the aids originating from acyls as mentioned above, - CBz or Z: Benzyloxycarbonyl,
  • - halogenated carbon group any group comprising at least one carbon atom and at least one halogen atom.
  • the invention therefore relates to a process for obtaining protected N salts of ⁇ -amino sulfinic acid of formula:
  • Y is an acyl - in particular a protective group adapted to be able to be substituted by a peptide group, and / or a peptide or pseudopeptide peptide group (for example sulfonopeptide) itself protected N
  • R and R ′ may be chosen from hydrogen, a halogenated carbon group directly linked by a carbon atom to the ⁇ carbon of the salt, an alkyl or an aryl,
  • M + is a cation, characterized in that:. an intermediate compound corresponding to the linear formula is chosen or prepared:
  • R1 is an electron-withdrawing group, or to cyclic analogs of this formula, such as:
  • R1 is chosen from:
  • an -0-acyl ester function originating from an acyl as defined above, in particular a carboxylic ester function such as: O // -O- C or -O-SO3-, especially when R is -CF3,
  • R is a fluorinated or chlorinated carbon group, in particular -CF3.
  • R ' is hydrogen.
  • said intermediate compound is added dropwise to an aqueous solution of HO - CH - SO2 Na rongalite.
  • R2 is an organic group chosen from an alkyl; aryl; or a halogenated carbon group, in particular a fluorinated or chlorinated carbon group, more particularly a halogenated carbon group linked by a carbon to the carbon of the sulfinic hydroxyacid salt, advantageously -CF3.
  • said intermediate compound is reacted in an anhydrous organic medium with a salt of sulfinic hydroxy acid of formula: HO - CH - S0 2 ⁇ , B +
  • B is an organic base such as an amine.
  • B is an aliphatic amine, such as NH (CgH- * -
  • the aldehyde or the ketone is first reacted: 0 // R - C with the amide Y - NH2.
  • R ' is preferably hydrogen, the aldehyde being generally more reactive than the ketone.
  • the carbinolamine is activated by reacting it on a sulfonic acyl so as to obtain said intermediate compound where R1 is a sulfonic ester, in particular - O - SO3H or the corresponding anion - O - SO3-.
  • the SO3 - Py complex is used where Py represents Pyridine.
  • the protected salt N is separated from ⁇ -amino sulfinic acid by adding a water-soluble salt of dicyclohexylamrnoniurn (in particular a citrate), selective extraction in an organic solvent and evaporation.
  • the dicyclohexylamrnoniurn salt formed with the aminosulfinate is selectively extracted in an organic extraction solvent (such as chloroform), while the other salts remain in the aqueous phase.
  • This first situation and the corresponding variants of the process according to the invention are particularly applicable when Y is a protective group, distinct from tosyl and mesyl groups, and chosen to be able to be eliminated at least in part subsequently (and substituted by a peptide group) without destroying the sulfonamide function which can be formed from the salt, in particular under milder conditions than the tosyl and mesyl groups, and in particular when Y is chosen from benzyloxycarbonyl or tert-butyloxycarbonyl.
  • Y is an acyl group, distinct from R ' 1 S0 2 , R''being methyl or PCH3C6H4,
  • R is a halogenated carbon group directly linked by a carbon atom to the carbon ⁇ of the salt, or an alkyl or an aryl,
  • R ' is chosen from hydrogen, a halogenated carbon group directly linked by a carbon atom to the carbon ⁇ of the salt, an alkyl or an aryl, M + is a cation. It should be noted that R is distinct from hydrogen.
  • R is a fluorinated or chlorinated carbon group, in particular -CF3.
  • R ' is hydrogen.
  • Y is a protective group distinct from the tosyl and mesyl groups.
  • Y is chosen so that it can be eliminated at least in part (and subsequently substituted by a peptide group) without destruction of the sulfonamide function which can be formed from the salt, in particular under milder conditions than the tosyl and mesyl groups.
  • Y is in particular a group chosen from benzyloxycarbonyl or tert-butyloxycarbonyl.
  • Y is an acyl group which can itself incorporate an ⁇ -amino acid residue N protected, in particular by an acyl function, or even a protected peptide or pseudo-peptide chain (for example sulfonopeptide) N, in particular by an acyl function. In this case, only the protective part of Y is eliminated.
  • the salts according to the invention are then already themselves of sulfonopeptide nature.
  • the new salts according to the invention are stable and can be isolated. They constitute analogs N acyls of the natural ⁇ -amino carboxylic acids and have in themselves the properties, in particular therapeutic, corresponding to this structure.
  • the new salts according to the invention also make it possible to obtain particularly stable synthesized sulfonopeptides.
  • the stable salts according to the invention are subjected to an electrophilic amination of the type: Y-NH-CR'R-S0 2 ⁇ , M + + H 2 N-0-S0 2 -0H -> Y-NH -CR'R-S0 2 -NH2 + HS0 - ⁇ , M « protest +
  • Y-NH-CR'R-S02-NH2 is then used in conventional peptide synthesis reactions.
  • the invention thus makes it possible to obtain the synthesized stable sulfonopeptides incorporating at least one residue of ⁇ -amino sulfonamide:
  • R is a halogenated carbon group linked directly by a carbon atom to the carbon ⁇ of the residue; and R 'is chosen among hydrogen, a halogenated carbon group directly linked by a carbon atom to the carbon ⁇ of the residue, an alkyl or an aryl.
  • R is a fluorinated or chlorinated carbon group, in particular -CF3.
  • R ′ is in particular hydrogen, so that the sulfonopeptide is a natural peptide analog.
  • the sulfonopeptides according to the invention are easy to isolate. The invention therefore also extends to these isolated sulfonopeptides.
  • a fluorinated carbon group R such as -CF3 provides numerous advantages: it does not disturb the steric hindrance of the salt or of the sulfonopeptide; it can be easily followed by nuclear magnetic resonance and therefore constitutes a tracer element; it gives the molecule an ability to cross cell membranes and improves its therapeutic effectiveness ...
  • the invention also relates to a process for obtaining the new salts and the sulfonopeptides comprising in combination all or part of the characteristics mentioned above or below.
  • Y is Z
  • R is CF3
  • R ' is H
  • M + is H 2 N + (C 6 H-
  • Y is Tos; R is CF3; R 'is H; M + is H 2 N + (C 6 H- ⁇ - * ) 2 * A 0.41 g (1.19 mmol, 1.5 eq.) Of the sulfinic hydroxyacid HOCHCF 3 S ⁇ 2 ⁇ H2N + (C6H-- - *) 2 (R2 is - -CF3 and M 'is identical to M; Tetrahedron 1993, 2469) and 0.29 g (0.75 mmol) of the diacylaminal (TosNH) 2 CHCF3 (Chem. Ber.
  • the product can be recrystallized, without heating, from a MeCN-CHCl3 mixture.
  • MeCN-H 0 mixture the product is hydrolyzed in less than an hour and after addition of dicyclohexylamine, it is isolated with an almost quantitative yield, TosNHCH2S03 _ H2N (C5H-
  • the product is stable in MeCN-H2 ⁇ solution and is recognized quantitatively after 24 h by adding an excess of water.
  • the protective group Z is easy to remove, for example by catalytic hydrogenation, to obtain the new sulfonopeptide according to the invention in salt form: N + H 3 - CH CF 3 - SO2 - NH 2 - A ⁇
  • This alanine analog is of major therapeutic interest, in particular as an antibiotic.
  • the new monosulfonopeptides of the invention are stable, in particular when one chooses -CF3 for the group R.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Peptides Or Proteins (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP97931852A 1996-07-31 1997-07-03 N-geschützte alpha-aminosulfinsäuresalze, verfahren zu ihrer herstellung sowie die daraus abgeleiteten sulfonopeptiden Withdrawn EP0925280A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9609845 1996-07-31
FR9609845A FR2751973B1 (fr) 1996-07-31 1996-07-31 Nouveaux sels n proteges d'acide alfa-amino sulfinique, leur procede d'obtention, et les sulfonopeptides qui en derivent
PCT/FR1997/001185 WO1998004522A1 (fr) 1996-07-31 1997-07-03 NOUVEAUX SELS N PROTEGES D'ACIDE α-AMINO SULFINIQUE, LEUR PROCEDE D'OBTENTION, ET LES SULFONOPEPTIDES QUI EN DERIVENT

Publications (1)

Publication Number Publication Date
EP0925280A1 true EP0925280A1 (de) 1999-06-30

Family

ID=9494811

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97931852A Withdrawn EP0925280A1 (de) 1996-07-31 1997-07-03 N-geschützte alpha-aminosulfinsäuresalze, verfahren zu ihrer herstellung sowie die daraus abgeleiteten sulfonopeptiden

Country Status (3)

Country Link
EP (1) EP0925280A1 (de)
FR (1) FR2751973B1 (de)
WO (1) WO1998004522A1 (de)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5387671A (en) * 1990-12-27 1995-02-07 Abbott Laboratories Hexa- and heptapeptide anaphylatoxin-receptor ligands

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9804522A1 *

Also Published As

Publication number Publication date
WO1998004522A1 (fr) 1998-02-05
FR2751973B1 (fr) 1998-09-11
FR2751973A1 (fr) 1998-02-06

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