WO1996022962A1 - Butyryl-tyrosinyl spermine, ses analogues et leurs procedes de preparation et d'utilisation - Google Patents

Butyryl-tyrosinyl spermine, ses analogues et leurs procedes de preparation et d'utilisation Download PDF

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WO1996022962A1
WO1996022962A1 PCT/US1996/001128 US9601128W WO9622962A1 WO 1996022962 A1 WO1996022962 A1 WO 1996022962A1 US 9601128 W US9601128 W US 9601128W WO 9622962 A1 WO9622962 A1 WO 9622962A1
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compound
group
receptor
phtx
linear
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PCT/US1996/001128
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WO1996022962A9 (fr
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Koji Nakanishi
Danwen Huang
Seok-Ki Choi
Aristotle Kalivretenos
Robert Goodnow
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The Trustees Of Columbia University In The City Of New York
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Priority to AU51684/96A priority Critical patent/AU5168496A/en
Publication of WO1996022962A1 publication Critical patent/WO1996022962A1/fr
Publication of WO1996022962A9 publication Critical patent/WO1996022962A9/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
    • C07C245/12—Diazo compounds, i.e. compounds having the free valencies of >N2 groups attached to the same carbon atom
    • C07C245/14—Diazo compounds, i.e. compounds having the free valencies of >N2 groups attached to the same carbon atom having diazo groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C245/18—Diazo compounds, i.e. compounds having the free valencies of >N2 groups attached to the same carbon atom having diazo groups bound to acyclic carbon atoms of a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/16—Compounds containing azido groups with azido groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/16—Compounds containing azido groups with azido groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C247/18—Compounds containing azido groups with azido groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane

Definitions

  • Glutamate receptors are believed to be the principal excitatory neurotransmitter receptors in the central nervous system (CNS). Based on the chemicals that activate glutamate receptors, such receptors are generally divided into three major subtypes: quisqualate (QUIS-R), N-methyl-D-aspartate (NMDA-R), and kainate (KAIN-R).
  • quisqualate quisqualate
  • NMDA-R N-methyl-D-aspartate
  • KAIN-R kainate
  • NMDA receptors are involved in development, learning and neuropathology and likely mediate the neurodegenerative consequences of hypoxemia, epilepsy, Alzheimer's disease, and Huntington's disease (1-5).
  • glutamate receptors particularly antagonists of the NMDA type receptor because of their anticonvulsant action and possible protection from ischemic brain damage (7).
  • NMDA receptors are involved in a variety of neurological and psychiatric disorders, and antagonists of this receptor may be therapeutically valuable in movement disorders, such as epilepsy, and in various acute and chronic neurodegenerative disorders .
  • Studies of glutamate receptors in particular studies employing biochemical techniques, have been made difficult by the relative paucity of potent antagonists for these receptor proteins.
  • ⁇ -philanthotoxin (termed ⁇ -philanthotoxin) which exhibits a number of pharmacological properties including open-channel block of junctional glutamate receptors (18) and extrajunctional glutamate D-receptors (19) of locust leg muscle, most of which are quisqualate-sensitive
  • the present invention concerns the active ingredient contained in venom from the wasp Philanthus triangulum F., the chemical structure of this active ingredient, a method for synthesizing the active ingredient, designated philanthotoxin-433 (PhTX-433), and the use of PhTX-433 as a potent inhibitor of the glutamate receptors.
  • the present invention involves the synthesis of pharmacologically active analogs of PhTX-433, e.g., PhTX-334, PhTX-343 and many others (wherein the numerals denote the number of methylenes between the amino groups of the spermine moiety).
  • the present invention provides a compound having the structure:
  • R 1 is hydrogen or a branched or unbranched, substituted or unsubstituted aminoalkyl having from two to twenty atoms in the chain
  • R 2 is hydrogen, methyl, a branched or unbranched, substituted or unsubstituted alkyl having from two to twenty atoms in the chain or CH 2 R 3
  • R 3 is hydrogen or a substituted or unsubstituted aryl
  • R 4 is methyl, a branched or unbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkenynyl, or cycloalkyl having from two to twenty atoms in the chain, or a substituted or unsubstituted aryl group.
  • the subject invention further provides a compound having the structure:
  • R 1 is a saturated or unsaturated linear or branched chain alkyl group, or a cholestanyl group
  • R 2 is a 2-indolyl, 3-indolyl, 4-indolyl, 5- indolyl, 4 -hydroxyphenyl, 4-(arylalkyloxy)phenyl, 3,4- dihalophenyl, 4-hydroxy-3,5-dihaloph5nyl, 4-azido- phenyl or 4-halophenyl group
  • R 3 is H, a linear or branched chain alkyl or alkenyl group, or a phenyl, 2-azidophenyl, 3-azidophenyl, 4-azidophenyl group, or an alkenylacyl, 3-amino-3-butylpropyl, N-[N-(N- ⁇ 4-azidobenzoyl ⁇ aminopropyl)aminopropyl], cis- or
  • the invention also concerns a method of preparing the compound which comprises treating venom, venom sacs or venom glands or the wasp Philanthus triangulum F. to produce an aqueous extract, and recovering the compound from the resulting aqueous extract. Additionally, the invention provides a method of preparing the compound which comprises contacting a branched- or unbranched-chain alkylamine having from two to twenty atoms in the chain and having hydrogen or a protection group attached to each nitrogen atom of the chain with a compound having the structure:
  • R 3 and R 4 are the same or different and is hydrogen or a lower alkyl group so as to form a product, treating the product to produce the compound and recovering the compound.
  • Another aspect of the invention concerns a method of treating a subject afflicted by a disorder associated with binding of an etiological agent to a glutamate receptor which comprises administering to the subject an amount of the compound effective to inhibit binding of the etiological agent to the receptor.
  • the invention also concerns a method of treating a subject afflicted by a stroke-related disorder associated with excessive binding of glutamate to glutamate receptors which comprises administering to the subject an amount of the compound effective to inhibit the excessive binding of the glutamate to the receptors.
  • the invention provides an insecticidal composition which comprises an effective amount of the compound and a suitable carrier and a method of combatting insects which comprises administering to the insects an amount of the insecticidal composition effective to produce paralysis in the insects.
  • FIG. 1 Venom sac (VS), gland (VG) and the sting apparatus (Stg) dissected from Philanthus triangulum.
  • Figure 2. Fractionation of Philanthus venom by reverse phase high pressure liquid chromatography (HPLC).
  • A Fractionation of lyophilized venom glands, extracted in 50% (vol/vol) acetonitrile/water. 450 ⁇ L (representing extracts of 225 wasps) were chromatographed on a YMC-ODS 20 ⁇ 280 mm column and developed by a linear gradient of 5% CH 3 CN/0.1% TFA-95% CH 3 CN/0.1% TFA for 30 minutes at a flow rate of 8 mL/min. UV absorption was monitored at 215 nm.
  • B Fractionation of the main toxic fraction (hatched peak in Fig. 2A).
  • FIG. 3 The chemical structures and synthesis of the natural philanthotoxin (PhTX-433) and two isomers PhTX-334 and PhTX-343.
  • the retractor unguis nerve was stimulated with single, brief (0.1 s), supramaximal stimuli applied at a constant, low frequency, before and after toxin application (in locust saline), but during the period of toxin application, the stimulation frequency was sometimes increased temporarily to 0.6 Hz.
  • Figure 7 Method A and Method B for preparing analogs.
  • a p-nitrophenol, DCC, EtOAc; b. TFA, CHCl 3 ; c. Et 3 N, butyryl chloride, CHCl 3 ; d. spermine, CH 3 OH; e. H 2 , 5% Pd/C, CH 3 OH; f. N- ⁇ , ⁇ -di-Cbz-L-lysine p-nitrophenol ester, DMF;
  • Figure 9 Synthesis of compound 7'. a. SOCl 2 , MeOH; b. butyl bromide, KF/Celite ® , CH 3 CN; c. (Boc) 2 O, CH 2 Cl 2 ; d. DIBAL, CH 2 Cl 2 /hexane; e. (CO) 2 Cl 2 , DMSO, Et 3 N, CH 2 Cl 2 ; f. spermine, Na 2 SO 4 , NaBH 4 ; g. TFA, CH 2 Cl 2 .
  • Figure 10 Synthesis of compound 23'. a. acrylonitrile, MeOH; b. (Boc) 2 O, CH 2 Cl 2 ; c.
  • the present invention provides a compound having the structure:
  • R 1 is hydrogen or a branched or unbranched, substituted or unsubstituted aminoalkyl having from two to twenty atoms in the chain
  • R 2 is hydrogen, methyl, a branched or unbranched, substituted or unsubstituted alkyl having from two to twenty atoms in the chain or CH 2 R 3
  • R 3 is hydrogen or a substituted or unsubstituted aryl
  • R 4 is methyl, a branched or unbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkenynyl, or cycloalkyl having from two to twenty atoms in the chain, or a substituted or unsubstituted aryl group.
  • R 1 include but are not intended to be limited to -H,
  • R 2 may be -H, -CH 3 , -CH 2 CH(CH 3 ) 2 or -CH 2 R 3 .
  • R 3 may be a hydroxyphenyl group, a phenyl group, an acetyloxyphenyl group, a benzyloxyphenyl group, 4-hydroxy-3,5-diiodophenyl, an indolyl moiety, 4-nitro-5-hydroxyphenyl, 4-fluoro-5-hydroxyphenyl, 4-hydroxy-3,5-dichlorophenyl, or 4 - hydroxy- 3 , 5 - dibromophenyl.
  • R 4 may be CH 3 (CH 2 ) 2 -, CH 3 -, CH 3 (CH 2 ) 5 - CH 3 (CH 2 :
  • the compound above has the structure:
  • R 1 is -H
  • R-_ is -CH 2 (CH 2 ) 2 NH(CH 2 ) 4 NH(CH 2 ) 3 NH 2 ,
  • the compound above has the structure:
  • R 2 is hydrogen, methyl, -CH 2 CH(CH 3 ) 2 or -CH 2 R 3 ;
  • R 3 is hydrogen, a hydroxyphenyl group, a phenyl group, an acetyloxyphenyl group, a benzyloxyphenyl group, 4-hydroxy-3,5-diiodophenyl, an indolyl moiety, 4-nitro-5- hydroxyphenyl, 4-fluoro-5-hydroxyphenyl, 4-hydroxy-3,5-dichlorophenyl, or 4-hydroxy-3,5-dibromophenyl.
  • R 2 is CH 2 R 3 and R 3 is a phenyl group, 4-hydroxy-3,5-diiodophenyl, or an indolyl moiety.
  • the compound above has the following structure:
  • the present invention also provides a compound wherein R 1 is
  • R 3 is 4-hydroxy-3,5-diiodophenyl, a hydroxyphenyl group, or an indolyl moiety; and R 4 is CH 3 (CH 2 ) 8 -, CH 3 (CH 2 )-, or an N 3 -benzyl group.
  • the compound above has one of the following structures:
  • the present invention provides for a compound having the structure:
  • R 4 is CH 3 -, CH 3 (CH 2 ) 2 -, CH 3 (CH 2 ) 5 -, CH 3 (CH 2 ) 7 CH 2 - , or a benzyl group.
  • the present invention also provides a compound having the structure:
  • R is CH 3 (CH 2 ) 2 -, CH 3 (CH 2 ) 5 or CH 3 (CH 2 ) 8 -
  • the present invention also provides a compound having the structure:
  • R i CH 3 ( CH 2 ) 2 - , CH 3 ( CH 2 ) 5 - , or CH 3 ( CH 2 ) 8 - .
  • the invention also provides a method of preparing or isolating the compound above.
  • the method comprises treating venom, venom sacs or venom glands or the wasp Philanthus triangulum F. to produce an aqueous extract, and recovering the compound from the resulting aqueous extract.
  • the recovery may be effected by a variety of separation techniques known to those skilled in the art to which the invention pertains, such as filtration, centrifugation, and chromatography.
  • the treating of the venom, venom sacs, or venom glands may be effective by extraction with numerous organic solvents, such as 50%
  • the invention also provides a method of synthesizing the compound described hereinabove which comprises contacting a branched- or unbranched-chain alkylamine, having from two to twenty atoms in the chain and having hydrogen or a protection group attached to each nitrogen atom of the chain, with a compound having the structure-.
  • R 3 and R 4 are the same or different and is hydrogen or a lower alkyl group, so as to form a product, treating the product to produce the compound and recovering the compound.
  • the treating of the product may comprise deprotection with trifluoroacetic acid or hydrogen.
  • the alkylamine has the formula: wherein each of x, y, z is the same or different and is an integer from 1 to 6 and each of R 5 , R 6 and R 7 is the same or different and is hydrogen or a protection group.
  • protection groups may be used in the practice of the present invention and these protection groups are well-known to those skilled in the art to which the invention pertains. Examples of useful protection groups include tert-butoxycarbonyl and carbobenzoxy groups and derivatives thereof.
  • the alkylamine has the structure:
  • Boc is a tert-butoxycarbonyl group and Cbz is a carbobenzoxy group.
  • Such an alkylamine may be obtained by contacting acrylonitrile with a spermidine derivative having the structure:
  • the alkylamine has the structure:
  • the present invention provides a compound having the structure:
  • R 1 is a saturated or unsaturated linear or branched chain alkyl group, or a cholestanyl group
  • R 2 is a 2 -indolyl, 3 -indolyl, 4 -indolyl, 5- indolyl, 4-hydroxyphenyl, 4-(arylalkyloxy)phenyl, 3,4-dihalophenyl, 4-hydroxy-3,5-dihalophenyl, 4-azidophenyl or 4-halophenyl group
  • R 3 is H, a linear or branched chain alkyl or alkenyl group, or a phenyl, 2-azidophenyl, 3-azidophenyl, 4-azidophenyl group, or an alkenylacyl, 3-amino-3-butylpropyl, N-[N-(N- ⁇ 4-azido-benzoyl ⁇ aminopropyl)aminopropyl], c
  • the present invention also provides a compound having the structure:
  • R is selected from a group consisting of H, linear alkyl, linear acyl, arylalkyl, phenyl,
  • R 1 is a C 9 or C 10 linear alkyl group.
  • the present invention provides a compound having the above structure wherein R is H and R 1 is C 9 H 19 .
  • the present invention provides a compound having the structure:
  • the present invention also provides a compound having the structure:
  • R is selected from a group consisting of H
  • R 1 is a C 9 or C 10 linear alkyl group.
  • the invention provides a compound having the above structure wherein R is H and R 1 is C 9 H 19 .
  • the present invention provides a compound having the above structure wherein R is
  • R 1 is C 9 H 19
  • the present invention further provides a compound having the following structure:
  • R 1 is a C 9 or C 10 linear saturated or unsaturated alkyl group; wherein R 2 is selected from a
  • R 3 is selected from a group consisting of F, OH and N 3 .
  • the present invention provides a compound having the above structure wherein R 1 is C 9 H 19 ;
  • R is or
  • the present invention provides a compound having the above structure wherein R 1 is
  • the present invention also provides a compound having the structure:
  • R 1 is a C 9 or C 10 linear saturated or unsaturated alkyl group; wherein R 2 is selected from a
  • R 3 is selected from a group consisting of F, OH and N 3 .
  • the invention provides a compound having the structure:
  • the present invention provides a compound having the structure:
  • the present invention provides a compound having the structure:
  • the present invention also provides a compound having the structure:
  • the present invention provides a compound having the structure:
  • the present invention provides a compound having the structure:
  • the present invention also provides a compound having the structure:
  • any of the compounds of the present invention may be radioactively labelled or be formulated into a pharmaceutical composition or an insecticidal composition comprising an effective amount of any one of the compounds and a suitable carrier.
  • the compounds may also be mixed with glutamate to form an admixture which in turn may be mixed with a carrier to provide a pharmaceutical composition.
  • the compounds may also be useful as an anticonvulsant.
  • Another aspect of the invention concerns a method of inhibiting binding to a glutamate receptor which comprises contacting the receptor with a binding-inhibiting amount of any of the compounds described hereinabove or the admixture of the compounds with glutamate.
  • Such methods of inhibiting binding to a glutamate receptor may prove useful in medical applications, agricultural applications or as research tools for the study of humans and animals.
  • the invention provides a method of treating a subject afflicted by a disorder associated with binding of an etiological agent to a glutamate receptor which comprises administering to the subject an amount of any one of the compounds or the admixture effective to inhibit binding of the etiological agent to the receptor.
  • the present invention may have therapeutic value in epilepsy, in movement disorders, in protection from ischemic brain damage and in various other neurodegenerative disorders.
  • the method may be useful where the neurodegenerative disorder is Huntington's disease, Parkinson's disease or Alzheimer's disease.
  • Another embodiment provides a method of treating a subject afflicted by a stroke-related disorder associated with excessive binding of glutamate to glutamate receptors which comprises administering to the subject an amount of any one of the compounds or admixture effective to inhibit the excessive binding of the glutamate to the receptors.
  • the compounds may be mixed with a suitable carrier to form an insecticidal composition and the insecticidal composition may be used in a method of combatting insects which comprising administering to the insects an amount of the insecticidal composition effective to induce paralysis in the insects.
  • Honey bee workers (1-3 weeks old) were restrained by chilling at 4°C then placed on their backs in a Lucite holder (16 bees to a holder) and injected in the ventral thorax behind the first pair of legs with 1 ⁇ L of water extract of the venom glands and immediately transferred to holding cages supplied with 40% sucrose solution. Controls received phosphate buffered Ringer's solution.
  • Schistocerca gregaria was dissected and mounted in a small Perspex ® bath as described previously (21).
  • the muscle apodeme was attached to a Grass FT 10-strain gauge with a short strand of terylene and the muscle stretched to maximal body length.
  • the total volume of the bath, including inlet and outlet reservoirs, was about 2.2 mL and the contents could be replaced within 1 s.
  • the dissection and setting up procedure were performed in continuously flowing saline.
  • the muscles were stimulated indirectly through fine (40-80 ⁇ m) platinum wire electrodes, insulated to their tips and placed on the retractor unguis nerve.
  • the venom fractions were dissolved in locust saline of the following composition: NaCl, 140 mM; KCl, 10 mM; CaCl 2 , 2 mM; NaH 2 PO 4 , 4 mM; NaH 2 PO 4 , 6 mM, and buffered at pH 6.8.
  • the nerve muscle preparation was perfused with this saline at a flow rate of 5-10 mL/min. at 19°C.
  • the extract of each batch of 1000 venom glands was fractionated by reverse-phase HPLC and 30 fractions were collected. Each of the 30 fractions was tested for pharmacological activity on the locust nerve muscle preparation, using reduction in neurally evoked twitch amplitude as the measure of activity. Ten fractions were pharmacologically active. The most active fraction was the one collected at retention time 13 min. (hatched peak in Fig. 2A). Further purification of this fraction by reverse-phase HPLC gave four peaks (Fig. 2B) , the most pharmacologically active was in the major peak (hatched Fig. 2B). This fraction gave 1.1 mg of toxin as amorphous powder.
  • PhTX-433 the chemical structure of the major naturally-occurring philanthotoxin is 1, which is designated PhTX-433, the numerals denoting the number of methylene groups between the amino groups of the spermine moiety. All three of the synthetic end-products were biologically active, PhTX-334 having a higher potency than the natural PhTX-433 toxin, while PhTX-343 w&s somewhat less active. Preliminary pharmacological studies with PhTX-433 suggested that its action on a locust nerve-muscle preparation was both time- and concentration-dependent.
  • PhTX-433 at 10 ⁇ M concentration also reduced the response of the retractor unguis muscle to L-glutamate (0.1 mM; bath applied), which suggests that at least part of the reduction in twitch amplitude was due to the antagonism of post junctional, quisqualate-sensitive glutamate receptors.
  • PhTX-334 (Fig. 4B) and PhTX-343 influenced the twitch contraction in the same qualitative fashion as PhTX-433.
  • the physiological activity of PhTX-343 and PhTX-334 were, respectively, 80% and 125% that of PhTX-433 as measured by the locust muscle twitch inhibition concentration.
  • the neutral philanthotoxin and its synthetic counterpart PhTX-433 and analogs PhTX-334 and PhTX-334 and PhTX-343 represent a new class of chemicals that are active biologically and inhibit allosterically the quisqualate-sensitive glutamate receptor in insect skeletal muscle (Fig. 4). They are smaller in molecular weight (435 daltons) than the toxins isolated from orb web spider venoms, the argiotoxins (>600 daltons), and easier to synthesize. (14, 15, 17, 25).
  • NMDA receptor Binding PhTX-433 to NMDA Receptor.
  • the NMDA receptor is identified by its high affinity for the compound (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801).
  • MK-801 This compound is an anticonvulsant introduced by Merck Sharp & Dohme Co. and is a potent non-competitive antagonist of the NMDA receptor. Binding of [ 3 H]MK-801 to synaptic membranes from rat brain after thorough washing is extremely poor.
  • Analog 11 was obtained by treating N-Boc-tyrosine with acetic anhydride and triethylamine before proceeding with Method A.
  • Analogs 4 and 5 of Moiety A were obtained through coupling of polyamine intermediates with the appropriate intermediate ester shown in Method A of Fig. 7 and then hydrogenolysis; mixing ammonium acetate and hydrogenolysis yielded 6.
  • Analogs 7 and 8 with branchings were prepared in order to examine the effects of alternating hydrophobic and hydrophilic regions and branching in the polyamine moiety; if active, a group suited for affinity binding to a solid support could be linked to the terminal of the branching.
  • Arginine and other amino acids were linked to Moiety D, since in the spider toxins argiopine (28), NSTX-3 (29), argiotoxin 659 (25), and argiotoxin 673 (25), which show similar inhibition of locust muscle contraction (27), the polyamine moiety contains an additional arginine residue.
  • analogs 33-37 were synthesized by coupling O-benzyl-PhTX-343 with the p-nitrophenol esters of the corresponding amino acids, or in the case of 36, with commercially available (Cbz) 3 -arginine N-hydroxysuccinimide ester followed by deprotection under hydrogenolysis conditions.
  • Analogs 25, 26, 28, 30, 40, and 41 were prepared to check the possibility of converting Moiety C into groups that could be used for photoaffinity labelling: 26, 40, 41; or affinity labelling: 28, 30.
  • these functionalities are sensitive to the hydrogenolysis conditions employed for O-benzyl deprotection, they were synthesized according to Method B shown in Fig. 7.
  • N-carbonbenzyloxylation (Method B) instead of N-butoxycarbonylation (Method A) allowed hydrogenolysis to be performed prior to attachment of the functionality sensitive to reduction.
  • N-tyrosyl acylation was achieved with either the free acid and diphenylphosphoryl azide or with the N-hydroxysuccinimide ester, depending on availability; in all cases the N-tyrosyl acylation proceeded the Boc deprotection step.
  • radiolabelled analogs are necessary both for use in direct pharmacological characterization of receptors as well as for isolation of the glutamate receptor by photoaffinity labelling or affinity labelling. It was fortunate that introduction of iodine, which we had hoped to use for radiolabelling of the tryosyl moiety, also increased the biological activity approximately ten- fold.
  • Cold iodinated analogs 13, 38, 39, 41
  • radioactive 125 I analogs were prepared with Na 125 I and chloramine T in buffered solution on a micro-scale and purified by reverse phase HPLC.
  • CI-MS (NH 3 ) spectra were obtained on a Nermag-10 while FAB-MS (3-nitrobenzyl alcohol matrix) spectra were obtained with a JOEL DX-303.
  • Proton NMR spectra were recorded on a Brucker WM-250 instrument using residual proton solvent peaks of either CDCl 3 at 7.24 ppm or CD 3 OD at 4.68 ppm as an internal standard. NMR spectra were measured in CD 3 OD and as free bases unless otherwise specified.
  • the solvents DMF and i-PrNH 2 and the reagents Et 3 N and pyridine were distilled neat at atmospheric pressure. HPLC was used to identify the correct isomer of the natural product with the following column and conditions.
  • Tri-Boc-polyamine-34-ethylnitrile To a 20 mL CH 3 OH solution of the above di-Boc-polyamine- 34-ethylnitrile 2.47 g (6.21 mmol) was added 1.62 g (7.45 mmol) of Boc anhydride. This mixture was stirred for 12 hours. The reaction was worked up on the same manner as for 3-(di-N,N'-Boc-diaminobutyl)ethylnitrile, yielding 3.06 g (98%).
  • PhTX-343 (compound 1) To a 15 mL CH 3 OH solution containing 0.20 of the previously made N-butyryl-O-benzyl-L-tyrosine-spermineamide was added 0.2 g of 5% Pd/C. This solution was purged several times with hydrogen. The starting material was usually consumed after 2 to 3 hours. The reaction was terminated by filtration through Celite ® and careful washing of the carbon with copious volumes of CH 3 OH. After evaporation of the solvent, the clear oil was chromatographed on 10 g of silica with 10:1 CHCl 3 /CH 3 OH and 4:4:1 CHCl 3 /CH 3 OH/i-PrNH 2 .
  • This pure free amine was dissolved in 3 mL of CH 3 OH and this solution was stirred with 0.07 g of 5% Pd/C under hydrogen atmosphere at room temperature for 12 hours.
  • the reaction was terminated by filtration and washing through Celite- with CH 3 OH followed by removal of solvent in vacuo and then loading onto a silica flash column, eluting with a step gradient of 15:5:1 and 3:3:1 CHCl 3 /CH 3 OH/i-PrNH 2 yielding 0.045 g (75%) of the desired product as a clear oil.
  • N-butyryl-L-glycine-spermine-amide (compound 16) To a 7 mL CH 3 OH solution of spermine 0.171 g (0.848 mmol) was added dropwise a 7 mL CH 3 OH solution of N-butyryl-L-glycine-p-nitrophenol ester 0.188 g (0.71 mmol) with stirring at room temperature. This mixture was stirred for 30 minutes before evaporation of the solvent to a yellow, semi-crystalline oil. Roughly 10 mL of CHCl 3 /CH 3 OH (1:1) was added to enhance crystallization of the p-nitrophenol.
  • PhTX-43 (compound 4) The corresponding O-benzyl-tyrosyl-amine was deprotected in the same manner as for PhTX-343 in 89% yield from 0.189 g of starting material.
  • N-Cbz-L-tyrosyl-spermine-Na,Ne-di-Boc-L-lysine-diamide To a 5 mL DMF solution of 0.62 g (1.2 mmol) of N-Cbz-L- tyrosyl-spermine amide was added dropwise a 4 mL DMF solution of 0.39 g (1.2 mmol) of Na, Ne-di-Boc-L-lysine p- nitrophenol ester. This solution was stirred at room temperature for 30 minutes.
  • N-Cbz-O-Boc-L-tyrosyl-di-Boc-spermine-Na,Ne-di-Boc-L-lysine-diamide To a 10 mL CH 3 OH solution containing 0.59 g (0.88 mmol) of the above diamide was added 0.81 mL (3.51 mmol) of Boc anhydride an 0.07 mL (0.88 mmol) of pyridine, and this mixture was stirred at room temperature for 12 hours. The clear oil was purified by evaporation of the solvent and by elution from 10.5 g of silica with 2% CH 3 OH/CHCl 3 .
  • Boc deprotection of the above per-BOC-azido-triamide, 0.12 g (0.129 mmol) was effected in 4 mL CHCl 3 with 3 mL of repetitive evaporations of CHCl 3 , the crude oil was chromatographed on silica with 15:5:1 CHCl 3 /CH 3 OH/i-PrNH 2 and 5:5:1 CHCl 3 /CH 3 OH/i-PrNH 2 .
  • the desired product was obtained in 70% yield.
  • N-bromosuccinimide N-bromosuccinimide
  • This compound was prepared as described above for N-Boc-L-tyrosine p-nitrophenyl ester.
  • the filtrate was concentrated to a clear yellow oil and then purified by silica gel flash column chromatography using a step gradient of CH 2 Cl 2 /MeOH (9:1) and CH 2 Cl 2 /MeOH/i-PrNH 2 (15:5:1) eluting bis [N-decanoyl-L- tryptophan] spermine diamide.
  • the column elution was continued with CH 2 Cl 2 /MeOH/i-PrNH 2 (4:4:1) which yielded
  • PhTX-3X3 (compound 13'). To a stirred suspension of 137 mg (0.37 mmole) N-butyryl-L-tyrosine p-nitrophenyl ester in 5 mL MeOH was added a 5 mL MeOH solution of 260 mg (0.37 mmole) of polyamine-3X3 TFA salt and 59 mg (1.5 mmole) of NaOH. The reaction mixture was stirred for 12 hours at room temperature. MeOH was evaporated to yield a yellow oily residue. The crude product was purified by silica gel flash chromatography using 16:4:1 CH 2 Cl 2 /MeOH/i-PrNH 2 .
  • N-cyanoethyl-1,4-diaminobutane (compound 14').
  • a methanol solution containing 10 mL MeOH
  • 1,4- diaminobutane (3 mL) was added acrylonitrile by syringe pump over 5 hours.
  • the mixture was stirred overnight, and then concentrated in vacuo .
  • the residue was purified by column chromatography.
  • the retractor unguis muscle and its nerve were dissected from the metathoracic legs of adult, female locusts
  • the muscle was stretched to maximal body length and attached at its tendon or apodeme to a Grass FT 10-strain gauge by a short length of nylon thread.
  • the volume of the muscle bath was about 0.5 mL and its contents could be exchanged within 1 s.
  • the preparation was perfused continuously at the rate of 5-10 mL/min. (except during the application of toxin (see below) with standard locust saline of the following composition (mM) : NaCl, 180; KCl, 10; CaCl 2 , 2; HEPES, 10; buffered to pH 6.8.
  • the retractor unguis muscle is innervated by two excitatory motoneurons (30) and an inhibitory motoneuron (19,32), but the influence of the latter on the responsiveness of the muscle is slight.
  • Maximal stimulation of the retractor unguis nerve at 0.2 Hz produced a series of twitch contractions of constant amplitude, which were maintained for many hours in good preparations.
  • the test compounds were kept at -20°C. They were dissolved in locust saline on the day of the assay and tested at room temperature. The compounds were applied by pipette to a nerve-muscle preparation such that the contents of the perfusion bath were completely replaced by the test solution. Exposure to the test compound lasted 20 minutes.
  • the preparation was not perfused during this period.
  • the amplitude of the retractor unguis muscle twitch rarely changed by more than 5-10% over a 20 minute period.
  • the stimulation frequency was raised to 0.6 Hz for brief periods to test for stimulus frequency-dependent effects on twitch amplitude (31,37).
  • Dose-inhibition data were obtained by testing the effects, on single retractor unguis muscle preparations, of a range of concentrations of the test compounds. Each concentration of the respective samples was tested at least three times, and each compound was assayed usually over a 100 -fold con- centration range (a total of 7-10 concentrations) .
  • PhTX-343 was assayed at a variety of concentrations on eight retractor unguis nerve-muscle preparations to give a cumulative dose-inhibition relationship for this toxin.
  • PhTX-343 Chemical modifications of PhTX-343 were performed at four regions: (A), spermine or polyamine moiety; (B), tyrosyl moiety; (C), butyryl moiety; and (D), spermine terminal amino group (Fig. 8).
  • the structures of such compounds and their pharmacological activities are given in Tables 1-9.
  • PhTX-343 compound 1
  • PhTX-433 natural, compound 2
  • PhTX-334 compound 3
  • PhTX-0 compound 6 which is not protonated was slightly more active than PhTX-4 (compound 5), which has a single protonated group. Addition of a methyl group to the middle carbon of the central C-3 moiety of spermine
  • insertion of a double bond between the aromatic ring and the carbonyl moiety (compound 25) led to a greatly increased potency.
  • Substitution of an azido moiety on the aromatic ring (compound 26) which nominally produces a photosensitive affinity label, produced reasonably active compounds compared with PhTX-343, whereas the diazo analog 27 was only weakly active.
  • the potencies of the two dinitrophenyl analogs 28 and 29 were similar to PhTX-343. Introduction of hydrophilic groups in region C reduces activity.
  • the enhanced potency of the arginine analog 36 could be accounted for if the guanidinium group were able to delocalize its positive charge over a wider area than a single point charge such as that associated with a primary amino group. In this way the guanidinium group may be better able to accommodate to the distribution of anionic centers on the wall of the receptor channel.
  • the results with compound 36 indicate that a terminal guanidine is better than a terminal amine (compare 36 with 35).
  • the mono- and bis-spermine analogs 47-52 (Table 7) were prepared in order to check whether chain analogs with a hydrophobic end and a polyamine chain would have activity.
  • the low potencies of the mono- and bis- spermine analogs (48, 49, 50) suggest that geometric constraints and the presence of both hydrophobic and hydrophilic moieties are essential for activity.
  • compound 52, bis-C 10 -spermine is as active as PhTX-343.
  • the assay does not unequivocally differentiate between presynaptic and postsynaptic sites of action, both of which could, in principle, be influenced by stimulation frequency.
  • PhTX-343 binds to the QUIS-R channel, possible at a site located within its selectively filter (35, 36) .
  • Other studies in our laboratories have shown that antagonism of locust muscle QUIS-R by PhTX-343 and compound 13, the diiodo analog, is voltage-dependent, as one might expect for open channel blockers carrying a net positive charge.
  • polyamine amide toxins that they interact exclusively with cation-selective channels of specific transmitter receptors (6, 8, 35).
  • the polyamine, spermine which is also a non-competitive antagonist of locust muscle QUIS-R
  • PhTX-343 and analogs might also bind thereby reducing membrane fluidity.
  • the increased potency seen with increasing hydrophobicity of the PhTX-343 analogs could arise through the closer association of toxin molecule with the cell membrane lipid.
  • the number and disposition of positive charges on the toxin relative to those on the membrane phospholipids would also play a role in determining the affinity of the toxin.
  • the presence of proteins could, in principle, enable these compounds to bridge across the lipid-protein interface.
  • membrane stabilization reduces the capacity of receptor molecules to undergo conformational changed for required for channel gating, then one could envisage non-competitive antagonism of QUIS-R arising through relatively non-specific binding of PhTX-343 to membrane phospholipids, but it is difficult to understand how this model could account for the open channel block and the striking voltage dependencies associated with PhTX-343 antagonism.
  • Clark, R.B. Donaldson, P.L., Gration K.A.F., Lambert, J.J., Piek, T., Ramsey, R.L., Spanjer, W. and Usherwood, P.N.R., Brain Res. 1979; 171:360-364.

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Abstract

La présente invention décrit un composé de structure (I): où R1 est un groupe alkyle saturé ou insaturé linéaire ou à chaîne ramifiée ou un groupe cholestanyle; où R2 est un groupe 2-indolyle, 3-indolyle, 4-indolyle, 5-indolyle, 4-hydroxyphényle, 4-(arylalkyloxy)phényle, 3,4-dihalophényle, 4-hydroxy-3,5-dihalophényle, 4-azidophényle ou 4-halophényle; où R3 est H, un groupe alkyle ou alcényle linéaire ou à chaîne ramifiée, ou un groupe phényle, 2-azidophényle, 3-azidophényle, 4-azidophényle, ou un groupe alcényacyle, 3-amino-3-butylpropyle, N-[N-(N-{4-azidobenzoyl}aminopropyl)aminopropyle], cis- ou trans-cinnamyle, 2-amino-2-[(4'-azidophényl)acétyle], (trifluorométhyl)-aminoacétyle ou un groupe arginyle D ou L liés par la fraction α-carbonyle dudit composé; R4 est H, ou un groupe alkyle linéaire ou à chaîne ramifiée; où R5, R6 et R7 sont indépendamment identiques ou différents et sont H, un groupe alkyle linéaire ou à chaîne ramifiée, un groupe aryle ou un groupe arylalkyle; où n, j et t sont chacun égaux à 0 ou à 1; où m, o, p, q, r et s sont indépendamment identiques ou différents et sont égaux à 0, 1 ou 2; où r+s et m+o sont chacun égaux à 2; où, si j égale 0, p+q égale 2; où, si j égale 1, alors p égale 1, q égale 0 et R6 est H; et où * dénote une configuration D ou L. La présente invention décrit également un procédé pour synthétiser ledit composé. Un autre aspect de l'invention concerne un procédé de traitement d'un sujet souffrant d'un trouble lié à la fixation d'un agent étiologique sur un récepteur du glutamate.
PCT/US1996/001128 1995-01-23 1996-01-23 Butyryl-tyrosinyl spermine, ses analogues et leurs procedes de preparation et d'utilisation WO1996022962A1 (fr)

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997046877A1 (fr) * 1996-06-04 1997-12-11 The University Of Edinburgh Neurotransmetteurs
WO1999003823A2 (fr) * 1997-07-15 1999-01-28 Oridigm Corporation Nouveaux analogues de polyamine utilises comme agents therapeutiques et diagnostiques
WO2000066587A2 (fr) * 1999-04-30 2000-11-09 Slil Biomedical Corporation Analogues de polyamine a conformation restreinte utilises pour traiter des maladies
WO2002016314A1 (fr) * 2000-08-18 2002-02-28 H. Lundbeck A/S Composes polyamines substitues
US6646149B1 (en) 1997-07-15 2003-11-11 Nicolaas M. J. Vermeulin Polyamine analogues as therapeutic and diagnostic agents
US6649587B1 (en) 1999-04-30 2003-11-18 Slil Biomedical Corporation Polyamine analog conjugates and quinone conjugates as therapies for cancers and prostate diseases
US6809176B2 (en) 1999-04-30 2004-10-26 Slil Biomedical, Corporation Quinones as disease therapies
AU781525B2 (en) * 1999-09-15 2005-05-26 Mediquest Therapeutics, Inc. Novel polyamine analogues as therapeutic and diagnostic agents
US6914079B2 (en) 2002-09-23 2005-07-05 Mediquest Therapeutics, Inc. Polyamine analogs that activate antizyme frameshifting
AU2003200048B2 (en) * 1997-07-15 2005-12-15 Mediquest Therapeutics, Inc. Novel polyamine analogues as therapeutic and diagnostic agents
US6982351B2 (en) 2001-12-07 2006-01-03 Cellgate, Inc. Cycloalkyl substituted polyamines for cancer therapy and methods of synthesis therefor
US7208528B1 (en) 1997-07-15 2007-04-24 Mediquest Therapeutics, Inc. Polyamine analogues as therapeutic and diagnostic agents

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
PURE & APPL. CHEM., Volume 62, No. 7, issued 1990, K. NAKANISHI et al., "Philanthotoxin-433(PhTX-433), a Non-Competitive Glutamate Receptor Inhibitor", pages 1223-1230. *
TETRAHEDRON, Volume 46, No. 9, issued 1990, R. GOODNOW et al., "Synthesis of Glutamate Receptor Antagonist Philanthotoxin-433(PhTX-433) and its Analogs", pages 3270-3286. *
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, Volume 254, No. 3, issued September 1990, N. ANIS et al., "Structure-Activity Relationship of Philanthotoxin Analogs and Polyamines on N-Methyl-D-Aspartate and Nicotinic Acetylcholine Receptors", pages 764-773. *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997046877A1 (fr) * 1996-06-04 1997-12-11 The University Of Edinburgh Neurotransmetteurs
AU2003200048B2 (en) * 1997-07-15 2005-12-15 Mediquest Therapeutics, Inc. Novel polyamine analogues as therapeutic and diagnostic agents
WO1999003823A2 (fr) * 1997-07-15 1999-01-28 Oridigm Corporation Nouveaux analogues de polyamine utilises comme agents therapeutiques et diagnostiques
WO1999003823A3 (fr) * 1997-07-15 1999-04-08 Oridigm Corp Nouveaux analogues de polyamine utilises comme agents therapeutiques et diagnostiques
US7208528B1 (en) 1997-07-15 2007-04-24 Mediquest Therapeutics, Inc. Polyamine analogues as therapeutic and diagnostic agents
US7160923B1 (en) 1997-07-15 2007-01-09 Mediquest Therapeutics, Inc. Polyamine analogues as therapeutic and diagnostic agents
US6646149B1 (en) 1997-07-15 2003-11-11 Nicolaas M. J. Vermeulin Polyamine analogues as therapeutic and diagnostic agents
WO2000066587A3 (fr) * 1999-04-30 2001-01-25 Slil Biomedical Corp Analogues de polyamine a conformation restreinte utilises pour traiter des maladies
US6794545B1 (en) 1999-04-30 2004-09-21 Slil Biomedical Corporation Conformationally restricted polyamine analogs as disease therapies
US6809176B2 (en) 1999-04-30 2004-10-26 Slil Biomedical, Corporation Quinones as disease therapies
US6649587B1 (en) 1999-04-30 2003-11-18 Slil Biomedical Corporation Polyamine analog conjugates and quinone conjugates as therapies for cancers and prostate diseases
WO2000066587A2 (fr) * 1999-04-30 2000-11-09 Slil Biomedical Corporation Analogues de polyamine a conformation restreinte utilises pour traiter des maladies
AU781525B2 (en) * 1999-09-15 2005-05-26 Mediquest Therapeutics, Inc. Novel polyamine analogues as therapeutic and diagnostic agents
WO2002016314A1 (fr) * 2000-08-18 2002-02-28 H. Lundbeck A/S Composes polyamines substitues
US6982351B2 (en) 2001-12-07 2006-01-03 Cellgate, Inc. Cycloalkyl substituted polyamines for cancer therapy and methods of synthesis therefor
US7235695B2 (en) 2001-12-07 2007-06-26 Benjamin Frydman Cycloalkyl substituted polyamines for cancer therapy and methods of synthesis therefor
US7453011B2 (en) 2001-12-07 2008-11-18 Progen Pharmaceuticals, Inc. Cycloalkyl substituted polyamines for cancer therapy and methods of synthesis therefor
US6914079B2 (en) 2002-09-23 2005-07-05 Mediquest Therapeutics, Inc. Polyamine analogs that activate antizyme frameshifting

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