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WO2008022365A2 - Agent servant à influencer les effets de composés organophosphorés et utilisation de galanthamine, de ses dérivés et analogues pour la fabrication d'un tel agent - Google Patents

Agent servant à influencer les effets de composés organophosphorés et utilisation de galanthamine, de ses dérivés et analogues pour la fabrication d'un tel agent Download PDF

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WO2008022365A2
WO2008022365A2 PCT/AT2007/000404 AT2007000404W WO2008022365A2 WO 2008022365 A2 WO2008022365 A2 WO 2008022365A2 AT 2007000404 W AT2007000404 W AT 2007000404W WO 2008022365 A2 WO2008022365 A2 WO 2008022365A2
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alkyl
group
hydrogen
branched
optionally substituted
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WO2008022365A3 (fr
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Werner Frantsits
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Sanochemia Ltd
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Sanochemia Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes

Definitions

  • the invention relates to a means for influencing the effects of organophosphorus compounds and the use of galanthamine, its derivatives and analogs for producing such agents.
  • Galanthamine its derivatives and analogs are known acetylcholine esterase inhibitors.
  • the invention is based on the object to provide means of the type mentioned.
  • the invention is based on the action of galanthamine and galanthamine derivatives, as well as analogs of galanthamine, to inhibit or completely abolish the effect of organophosphates on the central nervous system.
  • the mechanism is believed to be that galanthamine, galanthamine analogs, and also galanthamine derivatives, which are reversible acetylcholine esterase inhibitors, inhibit irreversible inhibition by organophosphate compounds, such as parathion or sarin, by occupying the receptors to allow coupling through the receptors irreversible Ach ⁇ inhibitors, which are the organophosphates, do not allow them to be degraded or excreted in the body and then slowly release the reversible galanthamine derivatives from the receptor. Since the highly toxic irreversible AchE inhibitors are already eliminated from the body.
  • Organophosphates such as Parathion, Paraxon, used in agriculture, have such high toxicity to inhalation that creatures die quickly if given a large enough amount.
  • organophosphorus compounds such as sarin, soman, tabun, which has developed militarily as a nerve gas and also against humans were used with deadly effect.
  • the compounds contained in the medicaments of the invention may contain the active compounds (galanthamine, its derivatives and analogs) in any suitable chemical, e.g. as acid addition salt, or physical form.
  • active compounds galanthamine, its derivatives and analogs
  • these compounds may be present as the hydrobromide, hydrochloride, methylsulfate or methiodide.
  • the medicaments of the invention may be administered orally or by (preferably) subcutaneous or intravenous injection or intracerebroventricularly by means of an implanted container.
  • Typical dosage rates when administering drugs containing the agents proposed according to the invention depend on the nature of the compound used and on the condition of the patient. For example, typical dosage rates are in the range of 0.01 to 1.0 mg per kilogram of body weight depending on the age, physical condition and other medication of the patient.
  • the medicaments according to the invention can be present in the following specific formulations mentioned as examples:
  • parenteral solution containing 0.1 to 30 mg / ml
  • liquid formulation for oral administration at a concentration of 0.1 to 15 mg / ml.
  • the compounds according to the invention may also be contained in a transdermal system in which 0.1 to 10 mg of active ingredient per day are released.
  • a transdermal dosing system consists of a
  • Storage layer containing 0.1-30 mg of the active substance as the free base or salt, if necessary together with a penetration accelerator, e.g. Dimethyl sulfoxide or a carboxylic acid, e.g. Octanoic acid, and a skin neutral polyacrylate, e.g. Hexyl acrylate / vinyl acetate / acrylic acid copolymer including plasticizer, e.g. Isopropyl myristate.
  • a penetration accelerator e.g. Dimethyl sulfoxide or a carboxylic acid, e.g. Octanoic acid
  • a skin neutral polyacrylate e.g. Hexyl acrylate / vinyl acetate / acrylic acid copolymer including plasticizer, e.g. Isopropyl myristate.
  • the cover is an active ingredient impermeable
  • Outer layer for example a metal-coated, siliconized polyethylene paving with a thickness of, for example, 0.35 mm.
  • an adhesive layer is, for example, a dimethylamino-methyl acrylate / methyl acrylate copolymer in an organic solvent.
  • the medicaments of the invention may be used as a precaution, e.g. by injection, when contact with e.g. is expected to be used as neurotoxin organic phosphorus compound.
  • the medicaments according to the invention can also be administered to humans after contact with a (toxic) organic phosphorus compound. Therefore, the invention also extends to preventive treatment of mammals (especially humans), as well as treating mammals after contact (e.g., inhalation) of toxic organic phosphorus compounds.
  • a (toxic) organic phosphorus compound especially humans
  • the invention also extends to preventive treatment of mammals (especially humans), as well as treating mammals after contact (e.g., inhalation) of toxic organic phosphorus compounds.
  • the derivatives and analogs of galanthamine contemplated by the present invention mention may be made, by way of example, of the following (in part known) compounds (and their salts):
  • R 2 , R 4 , Xi and X 2 are either the same or different and are selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, alkoxy, lower alkyl optionally substituted by at least one halogen , lower alkenyl, lower alkynyl, aryl, aralkyl, aryloxyalkyl,
  • A is a benzene nucleus optionally substituted at least simply by lower alkyl, lower alkene, lower alkyne, alkoxy, fluorine, chlorine, bromine, iodine, alkyl substituted by at least one halo, aralkyl, hydroxy, primary amino, secondary amino, tertiary Amino, nitro, nitrile, alkylamino, aldehyde, carboxylic acid and carboxylic acid derivatives;
  • Z is an anion of a pharmaceutically acceptable organic acid or an inorganic anion
  • R 5 is selected from the group consisting of hydrogen, formyl, alkyl, alkenyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, arylsulfonyl and aralkylsulfonyl;
  • Ri, R 2 are either the same or different and are hydrogen, F, Cl, Br, J, CN, NC, OH, SH, NO 2 , SO 3 H, NH 2 ,
  • R 4 , R 5 either both hydrogen or alternatively any combination of hydrogen or an (Ar) alkyl (Ar) alkenyl, (Ar) alkynyl with • SR 8 , wherein R 8 is hydrogen or a lower (Ci-C 10 ) optionally branched, optionally substituted (Ar) alkyl group
  • O-protecting group such as TMS, TBDMS), O-CS-NR 8 (thiourethane),
  • esters with the substitution pattern of amino acids, such as
  • Y 1 , Y 2 O, S, NH or NR 10 (surplus valencies are each -H) • wherein in the event that R 4 ⁇ H R 5 is also OH or for the case that R 5 ⁇ H is R 4 can also be OH.
  • Ri 3 , R J4 is hydrogen, OH, a lower, optionally branched, optionally substituted (Ar) alkyl, aryl, (Ar) alkyloxy or
  • Aryloxy group or together may be an alkyl spiro group (C 3 to C 7 - spiro ring).
  • G 4 satisfies the following definitions:
  • Aromat aryl group, -O-, or -NR 15 - , ie an ortho, meta, or para disubst.
  • Ri7 / Ri ⁇ / Ri9 f and R 2 O are individually or together, the same or different hydrogen
  • G 8 O, S, NH, NR 2I , - (CH 2 J n -,
  • R 2 i CHO, COOR 7 , or an unsubstituted, or by one or more F, Cl, Br, J, NO 2 , NH 2 , OH, alkyl, alkyloxy, CN, NC or CF 3 , CHO, COOH, COOalkyl, SO 3 H, SH, S-alkyl groups of identical or different substituted (hetero) aryl, (with heteroaryl in particular 2-pyridyl, 4-pyridyl, 2-pyrimidinyl) or A methyl group which is substituted by 1-3 unsubstituted or substituted by one or more F, Cl, Br, J, NO 2 , NH 2 , alkyl, alkyloxy, CN, NC or CF 3 groups phenyl group (s) is
  • G 6 can be further:
  • R 7 is equal to R 6 or represents -O ( '(N-oxide) or a lone pair of electrons (e-pair), wherein R 6 and R 7 can also form a common ring of size 3-8, and
  • [X] only exists and represents an ion of a pharmacologically usable inorganic and organic acid when R 5 and R 6 are present and thus the nitrogen carries a positive charge.
  • • Z N, or N + for the case that R 6 and R 7 are present together and R 1 is not equal to O ⁇ .
  • Alkanyloxy e.g., acetyloxy
  • the methoxy group is replaced by hydrogen, the atoxy or a lower.
  • Alkanoyloxy group (such as acetyloxy-), and the methyl group substituted on the nitrogen atom by other straight or branched chain lower alkyl groups, such as ethyl, cyclopropylmethyl or cyclobutylmethyl, allyl, lower.
  • Alkylphenol is replaced, wherein the substituents fluorine, chlorine, bromine, nied.
  • alkyl in which the substituents are on the phenyl ring, and compounds wherein hydrogen atoms in the "ring" structure have been replaced by fluoro or chloro groups are likely to have all or part of these properties.
  • Ri, R 2 are either the same or different and
  • R 3 R 1 , in particular OH and OCH 3 , further
  • R 4 , R 5 either both hydrogen or alternatively any combination of hydrogen or an (Ar) alkyl, (Ar) alkenyl (Ar) alkynyl with
  • R 8 is hydrogen or a lower (C 1 -C 10 ), optionally branched, optionally substituted (Ar) alkyl group
  • O-protecting group such as TMS, TBDMS
  • R 9 has the following meanings:
  • esters with the substitution pattern of amino acids such as
  • R 10 is hydrogen, a lower (C 1 -C 6 ), optionally branched, optionally substituted (Ar) alkyl or (Ar) alkylcarbonyl or (Ar ) Alkylcarbonyloxy devis and sulfonic acid such as tosyl and mesyl group and Ri 1 is hydrogen, a lower (Ci-C 6 ), optionally branched, optionally substituted (Ar) alkyl or (Ar) alkylcarbonyl and sulfonic such as tosyl and mesyl ,
  • G 1 , G 2 together or differently have the meaning:
  • R 137 R 14 is hydrogen, OH, a lower, optionally branched, optionally substituted (Ar) alkyl, aryl, (Ar) alkyloxy or aryloxy group or together an alkyl spiro group ( C 3 to C 7 spiro ring).
  • R 16 is hydrogen, lower, optionally branched, optionally substituted (Ar) alkyl , Cycloalkyl, aryl group,
  • Aromat ie an ortho, meta, or para disubst.
  • R 17 , R 18 , Ri 9 , and R 20 are individually or jointly, identical or different hydrogen, lower, optionally branched, optionally substituted (Ar) alkyl, cycloalkyl, or
  • Aryl groups wherein R 17 and Ri 8 or R 19 and R 2 o may together form a cycloalkyl group (ring size 3-8).
  • G 8 O, S, NH, NR 21 , - (CHz) n - /
  • R 21 CHO, COORi 7 , or an unsubstituted, or by one or more F, Cl, Br, J, NO 2 , NH 2 , OH, alkyl, alkyloxy, CN, NC or CF 3 , CHO, COOH, COOalkyl, SO 3 H, SH, S-alkyl groups identical or differently substituted (hetero) aryl, (with
  • Heteroaryl in particular 2-pyridyl, 4-pyridyl, 2-pyrimidinyl) or
  • a methyl group which is substituted by 1-3 unsubstituted or substituted by one or more F, Cl, Br, J, NO 2 , NH 2 , alkyl, alkyloxy, CN, NC or CF 3 groups the same or different substituted phenyl group (s) .
  • G fi can be further:
  • R 7 is equal to R 6 or represents -O ( ⁇ '(N-oxide) or a lone pair of electrons (e-pair), where R 6 and R 7 can also form a common ring of size 3-8, and
  • [X] only exists and represents an ion of a pharmacologically usable inorganic and organic acid, if R 5 and R 6 are present and thus the nitrogen carries a positive charge.
  • novel derivatives and analogs of galanthamine according to the invention increase the muscle strength and endurance of Alzheimer's patients.
  • the new compounds according to the invention are those of the general formula I.
  • R 1 and R 2 are identical or different and mean: a) hydrogen, F, Cl, Br, J, CN, NC, OH, SH, NO 2 , SO 3 H, PO 3 H, NH 2 , CF 3 , OSO 2 (CH 2 J n CF 3 , wherein n is 0, 1 or 2), 0S0 2 -aryl, -vinyl- or -ethynyl; b) a lower (C 1 -C 6 ), optionally branched, optionally substituted (Ar) alkyl, (Ar) alkoxy group, cycloalkyl or cycloakyloxy group; c) an amino group which is optionally substituted by one or two identical or different lower (Ci-C 6 ), optionally branched, optionally substituted (Ar) alkyl or (Ar) alkylcarbonyl or (Ar) alkoxycarbonyl or an amino group in which a cycl
  • -CH CH-Al or -CH 2 -CH 2-Al- where Al may be NH, O or S;
  • R 3 has the same meaning as R 1 , in particular OH and OCH 3 and further
  • R 2 and R 3 together represent -A 2 (CH 2 ) n A 2 , where n is 1 to 3 and A 2 is two identical or different radicals selected from NH, O or S;
  • R 4 and R 5 are either a) both hydrogen, or b) a combination of hydrogen or an (Ar) alkyl, (Ar) alkenyl, or (Ar) alkynyl group with i) OR 6 , wherein R 6 is hydrogen, a lower (C 1 -C 10 , optionally branched or substituted) alkyl group or cycloalkyl group, a C 3 -C 10 substituted silyl group (for example triethylsilyl, trimethylsilyl, t-butyldimethylsilyl or dimethylphenylsilyl methylsilyl), a C 2 -C 0 ⁇ - alkoxyalkyl group such as tetrahydropyranyl, tetra- hydrofuranyl, methoxymethyl, ethoxymethyl, (2-methoxypropyl), ethoxyethyl, phenoxymethyl or (1 Phenoxyethyl); ii) O-CS-NHR
  • R 6 has the abovementioned meaning, in particular esters with the substitution pattern of amino acids (both enantiomers), such as
  • NR 7 R 7 in which the two substituents R 7 are identical or different and denote hydrogen, a lower (Ci-C 4 ), optionally branched or cyclic alkyl group or the two substituents R 7 are together - (CH 2 J n - wherein n is 3 to 5; vi) NH-COR 6 (amide), wherein R 6 has the meaning given above; vii) SR 6 , wherein R 6 is hydrogen or a lower (C
  • Cio / optionally branched, optionally substituted (Ar) alkyl group, and wherein R 6 has the abovementioned meaning; viii) SO n R 8 , wherein n is 0, 1 or 2, wherein R 8 is a (C 1 -Cio), optionally branched or cyclic, optionally substituted (Ar) alkyl group.
  • R 5 can be OH, CN, CO 2 alkyl, CONR a R b , wherein R a is hydrogen, a lower (Ci - C 6 ), optionally branched, cyclic, at most substituted alkyl group and
  • R b is hydrogen, a lower (Ci - C 6 ), optionally branched, or substituted alkyl group, or R a + R b are together - (CH 2 ) n -, where n is 2 to 6, or - (CH 2 ) n E (CH 2 ) n -, where E is NH, N- Alkyl, O, or S and n is 0 to 5, aryl (phenyl or naphthyl), 6- ⁇ heterocycle (such as imidazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl and substituted variants the same), or imidazolinyl, thiazolinyl or oxazolinyl.
  • R 4 may also be OH.
  • G 1 - (CH 2 ) x -, wherein x is 1 or 2;
  • G 3j _ - (CH 2 ) z -, wherein z is 0 to 3, carbonyl or thiocarbonyl, with the proviso that x + y + z together are at least 2 and at most 4 or wherein G 3 represents -CH (OH) - or -C (OH) .
  • G 1 and G 2 may together or separately also be: -C (R 11 R 12 ) -, in which R 11 and R 12 are hydrogen, OH, a lower, optionally branched or cyclic, optionally substituted (Ar) alkyl, aryl , (Ar) alkyloxy or aryloxy group or together an alkylspiro group (C 3 -C 7 -spirormg) or Gi and G 2 mean together
  • W may have the following meanings: a) CR 13 Ri 4 in which R 13 is hydrogen and R 14 is the radicals - (CH 2 J n NR 7 R 7 or -CO-NR 7 R 7 or -COOR 7 , where n is the Can assume values 0 to 2 and R 7 is as defined above, or R 7 R 7 is - (CH 2 ) n - (wherein n is 3 to 5) form a ring, wherein the substituents R 13 and R 14 may be reversed b) N-phenyl (where the phenyl radical is optionally substituted by fluorine, bromine, chlorine, (C 1 -C 4 ) alkyl, CO 2 alkyl, CN, CONH 2 , or alkoxy), or N-thien-2 or 3 -yl, or N-fur-2 or 3-yl or a N, 3, 5-triazinyl, where the triazine residue may be further substituted by Cl, OR 6 or NR 7 R 7 , and R 6 and
  • R 15 denotes the side chain of D, L, D, L-amino acids or unnatural amino acids, and in the case of n> 1 R 15 in the individual radicals in each case an identical or different side chain side chain of D- , L, D, L-amino acids or unnatural amino acids, which formulas are to be understood such that the atom N in addition to Q is in each case connected to G2 and G3 of the formula I;
  • W can also be connected via the spacer Q with a tricyclic substituent (Tr), the tricyclic substituents being defined by the following formula pictures,
  • the tricyclic substituents (Tr) mean a tricyclic ring system having at least one heterocyclic ring as the ring component and a bonding site on a carbon atom of a fused benzene ring thereof, wherein Tr is optionally at least monosubstituted, wherein the ring A is an optionally substituted benzene ring and one of the rings B and C is an optionally substituted heterocyclic ring and the other is a substituted 4-14 membered, preferably 5-7 membered ring which may contain one or more heteroatoms in the ring.
  • the benzene ring is optionally further substituted at least once, these substituents halogens such as fluorine and chlorine, halo-Ci-C 3 - alkyl groups such as trifluoromethyl, Ci-C 3 ⁇ alkyl groups such as methyl, Ci-C 3 alkoxy groups such as methoxy , and may be hydroxy, with halogens such as fluorine being preferred.
  • halogens such as fluorine and chlorine
  • halo-Ci-C 3 - alkyl groups such as trifluoromethyl
  • Ci-C 3 ⁇ alkyl groups such as methyl
  • Ci-C 3 alkoxy groups such as methoxy
  • the optionally substituted heterocyclic ring B or C is, for example, a 4 to 14-membered ring, preferably a 5 to 7-membered ring.
  • the at least one heteroatom of the heterocyclic ring (1 to 3 heteroatoms are possible) can Nitrogen, oxygen, sulfur, be.
  • rings B or C are pyridine, pyrazine, pyrimidine, imidazole, furan, thiophene, pyrrolidine, piperidine, hexamethyleneimine, tetrahydrofuran, piperazine, morpholine and thiomorpholine, with 5 to 7-membered non-aromatic rings containing one or two identical or different heteroatoms can have are preferred.
  • the ring B or C may also be a non-aromatic heterocyclic ring containing 1-3 heteroatoms such as nitrogen, oxygen or sulfur and non-aromatic heterocyclic rings having one nitrogen atom and another heteroatom which is nitrogen, oxygen or sulfur.
  • 5 to 8 membered rings B or C are 5 to 8 membered heterocyclic or alicyclic rings, or carbon rings which are at least monosubstituted. These 5 to 8-membered carbon rings may be a benzene ring or a saturated or unsaturated ring, for example, benzene, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene and cycloheptadiene.
  • the rings B or C contain at least one hetero atom (e.g., 1-3 heteroatoms such as nitrogen, oxygen, sulfur, etc.), that is, when the ring B or C is a heterocyclic ring, it may or may not be aromatic.
  • Such aromatic heterocyclic rings are, for example, pyridine, furan, thiophene.
  • Preferred non-aromatic heterocyclic rings are the examples of rings B or C given above.
  • the tricyclic substituent Tr may be a fused benzene ring of the general formula
  • the tricyclic substituent Tr may be a fused benzene ring of the general formula
  • the tricyclic substituent Tr may be a fused benzene ring of the general formula
  • the tricyclic substituent Tr may be a fused benzene ring of the general formula
  • Tr may be a cyclic or bicyclic hydrocarbon which is represented by the following formula:
  • Each substituent Tr can be further substituted by one or more substituents R 1 , wherein the definition of the substituent R 1 is the same as in formula I.
  • W can furthermore be -NH-, -S-, -SO- or -SO 2 -.
  • D is NH, N-alkyl, N-acyl, oxygen or sulfur and wherein the substituents R 1 to R 5 , G 1 to G 3 and W may have the meanings given above in the general formula I.
  • XR ⁇ is a substituent in which X is oxygen or sulfur and R 16 is hydrogen or a lower (C 1 -C 10 ), optionally branched or cyclic, optionally substituted (Ar) alkyl group, and wherein the substituents R 1 to R 5 , G 1 to G 3 and W may have the meanings given above in the general formula I.
  • W is CH or N and Ri 8 and Ri 9 is hydrogen, alkyl, aryl or aralkyl and in which the substituents Ri 8 and Ri 9 bearing C atoms are linked together via a single or a double bond and in the the substituents R 1 to R 5 and Gi and G 3 have the meanings given in the general formula I above.
  • the substituent W is nitrogen and / or the substituent Gi - (CH 2 ) x , wherein x is 1 or 2 and G 2 - (CH 2 ) y -, wherein y is 0 to 2, with the proviso that x + y together are at least 2 and at most 4.
  • these compounds particularly the compounds mentioned below are considered:
  • AchE means: acetylcholinesterase
  • BchE butyrylcholinesterase
  • hr human recombinant
  • mE preincubation of the enzyme with inhibitor
  • IC50 concentration at which a 50% inhibition occurs.
  • R 1 is H, branched or straight-chain (C 1 -C 6) alkyl, Br, NO 2, NR 5 R 6,
  • R 6 are identical or different and denote H, branched or straight-chain (C 1 -C 6 ) -alkyl
  • R 2 is OH, branched or straight chain (Ci-C 6 ) alkyl, methoxy, phenyloxy or the following group
  • Pol is a polymer, preferably one according to WO-A1-0174820, and wherein
  • R 3 and R 4 denote either simultaneously or alternatively H, D, CN, straight-chain or branched (C 1 -C 6 ) -alkyl or together a carbonyl group,
  • n represents a value of 0, 1 to 15, and Pol has the meaning given above, and wherein further
  • R 8 and R 9 are identical or different and denote H, branched or straight-chain (C 1 -C 6 ) -alkyl, - (CH 2 ) 2 -OH, CHO, CONH 2 , tBOC (tert-butoxycarbonyl), or COCOOH , R i0 is H or CH 3 , and where Y i is -O- (CH 2 ) 2 -OH Y 2 is OH,
  • Zi is H, branched or straight chain (Ci-C 6 ) alkyl, (C 2 -C 7 ) alkenyl (C 2 -C 7 ) alkynyl, trifluoroacetyl, formyl, phenyl
  • Rn is H, straight chain (C 1 -C 6) alkyl, branched (Ci-C 6) alkyl or (C 2 -C 7) alkenyl
  • R 12 and R 13 are identical or different and are H, straight or branched (C 1 -C 6 ) alkyl, phenyl, chlorophenyl, (trifluoromethyl) phenyl or 1-naphthyl
  • R 14 is H, F, CH 3 , NO 2 , Cl, Br, J, CF 3
  • n is the has the meaning given above
  • m is 0 or 1
  • W has the meaning H or 0,
  • R 15 and R 16 are mutually H, COOCH 3 , COOCH 2 CH 3 , CN, COCH 3 .
  • Y 3 and Y 4 are mutually H and OH
  • X is Cl, Br or I
  • Z 2 is oxygen (N-oxide and no counter ion), branched or straight chain (C 1 -C 6) alkyl, or (C 2 - C 7) alkenyl or (C 2 -C 7) alkynyl or a group selected from:
  • n, R 12 , R 13 and R 14 have the meaning according to claim 3.
  • Z 3 is oxygen (N-oxide and no counterion) or a methyl group.
  • Galanthamine derivatives used according to the invention are furthermore compounds having the general formula Id
  • Y 5 and Y 6 are mutually H or OH or together form a keto group
  • R ⁇ r Ri ⁇ f R i9 alternately for each two substituents H, wherein the third substituent is NH 2 or CONH 2 .
  • Z 4 is a straight-chain or branched (C 1 -C 6 ) alkyl or 4-bromobenzyl.
  • benzazepinium are advantageously halides, preferably bromide, and also carboxylic acids having 1 to 3 carboxyl groups, with tartrates, malonates, fumarates and succinates being particularly preferred, as well as sulfonic acids, preferably methanesulfonic acid.
  • Ia optically active (-) derivatives of galanthamine and Ib are optically active (+) derivatives of galanthamine, which are in a mirror-image spatial arrangement, and wherein
  • R 1 H, Cl, Br, I, F, OH, straight or branched (Ci-C 6) alkyl, straight or branched (Ci-C 6) alkyloxy, NO 2, NR 2 R 3,
  • compounds 1 and 13 are (-) derivatives of 6-epi-norgalanthamine and compounds 3 and 24 are (+) derivatives of 6-epi-norgalanthamine, and wherein
  • the rat was treated with 0.5 mg, 1 mg and 2 mg intramuscularly with the compound to be tested.
  • the rat was not previously treated and also not treated after the exposure time.
  • the rat was not previously treated, but was immediately treated intramuscularly with 0.5 mg, 1 mg or 2 mg of the compound to be tested after removal from the gas container.
  • Rats treated according to test type (1) did not show any signs of toxicity with both 0.5 mg, 1 mg and 2 mg SPH 1285, SPH 1088, SPH 1486 and had no abnormalities even after hours.
  • doses of 2 mg SPH 1562, SPH 1150, SPH 1549 and SPH 1612 side effects occurred but were reversible, apparently due to overdosage of the substances to be tested.
  • parathion intoxication was prevented in all cases.
  • Rats of experiment type 3 and an exposure time of 2 minutes showed slight disorders after treatment of 0.5 mg, 1 mg / kg body weight SPH 1285, SPH 1088, but disappeared after about 30 minutes. With 2 mg / kg body weight SPH 1285, SPH 1088 they showed no disturbances. With 0.5 mg and 1 mg of SPH 1486, SPH 1150, SPH 1549, SPH 1562, SPH 1612, only mild neurological disorders occurred, which disappeared after a short time. With 2 mg SPH 1562 and SPH 1612, the rat died after 50 and 66 minutes respectively, obviously the dosage was too high.
  • Parathion, paraxon, sarin, soman or tabun by administering an agent containing said compound or a combination of at least two of said compounds before and / or after contact of a human with the toxic organic phosphorus compound.

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Abstract

L'invention concerne l'utilisation de galanthamine de formule (I) et de dérivés ou d'analogues de galanthamine pour lutter contre les effets de composés de phosphore organiques toxiques, tels que la parathione, la paraxone, le sarin, le soman ou le tabun. Selon l'invention, un agent contenant ledit composé ou une combinaison d'au moins deux desdits composés est administré avant et/ou après le contact d'un humain avec le composé de phosphore organique toxique.
PCT/AT2007/000404 2006-08-24 2007-08-23 Agent servant à influencer les effets de composés organophosphorés et utilisation de galanthamine, de ses dérivés et analogues pour la fabrication d'un tel agent Ceased WO2008022365A2 (fr)

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ATA1417/2006 2006-08-24
AT14172006 2006-08-24

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Cited By (6)

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EP2123328A1 (fr) * 2008-05-23 2009-11-25 Sopharma AD Dérivés de galanthamine, procédés pour leur obtention et utilisation
RU2404160C1 (ru) * 2009-06-01 2010-11-20 Федеральное государственное учреждение "33 Центральный научно-исследовательский испытательный институт Министерства обороны Российской Федерации"(ФГУ "33 ЦНИИИ МО РФ") Применение n,n-диэтиланилина в качестве имитатора зомана в водной среде
WO2013160728A1 (fr) 2012-04-26 2013-10-31 Alma Mater Studiorum - Universita' Di Bologna Composés à double ciblage pour le traitement de la maladie d'alzheimer
EP2334182A4 (fr) * 2008-08-27 2014-04-23 Univ Maryland Procédé de traitement d une intoxication par des composés organophosphorés
CN104860955A (zh) * 2015-04-22 2015-08-26 华东理工大学 加兰他敏类似物及其用途
CN118908968A (zh) * 2024-10-09 2024-11-08 威胜生物医药(苏州)股份有限公司 一种加兰他敏中间体衍生物及其催化氧化制备方法

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DE4342174C1 (de) * 1993-12-10 1995-05-11 Lohmann Therapie Syst Lts Transdermales therapeutisches System sowie ein Verfahren zur Herstellung eines transdermalen therapeutischen Systems zur kombinierten transdermalen Anwendung von Physostigmin und Scopolamin für die Prophylaxe und zur Vorbehandlung einer Vergiftung durch hochtoxische phosphororganische Nervengifte, insbesondere Soman und seine Verwendung
MXPA01012275A (es) * 2000-03-31 2003-06-24 Sanochemia Pharmazeutika Ag Derivados y analogos novedosos de galantamina.
US20050013869A1 (en) * 2003-07-18 2005-01-20 Chaw Cheng Shu Sustained release formulation for carbamates and a method therefor
MXPA05005570A (es) * 2003-09-29 2005-10-18 Sanochemia Pharmazeutika Ag Uso de galantamina y los derivados de la misma en la produccion de medicamentos.
AT414125B (de) * 2003-09-29 2006-09-15 Sanochemia Pharmazeutika Ag Neue derivate des 4a,5,9,10,11,12-hexahydro- benzofuro(3a,3,2)(2) benzazepin, verfahren zu deren herstellung sowie deren verwendung zur herstellung von arzneimitteln
ES2662868T3 (es) * 2004-09-24 2018-04-10 University Of Maryland, Baltimore Procedimiento para el tratamiento de una intoxicación por una sustancia organofosforada

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9132135B2 (en) 2004-09-24 2015-09-15 University Of Maryland, Baltimore Method of treating organophosphorous poisoning
EP2123328A1 (fr) * 2008-05-23 2009-11-25 Sopharma AD Dérivés de galanthamine, procédés pour leur obtention et utilisation
EP2334182A4 (fr) * 2008-08-27 2014-04-23 Univ Maryland Procédé de traitement d une intoxication par des composés organophosphorés
RU2404160C1 (ru) * 2009-06-01 2010-11-20 Федеральное государственное учреждение "33 Центральный научно-исследовательский испытательный институт Министерства обороны Российской Федерации"(ФГУ "33 ЦНИИИ МО РФ") Применение n,n-диэтиланилина в качестве имитатора зомана в водной среде
WO2013160728A1 (fr) 2012-04-26 2013-10-31 Alma Mater Studiorum - Universita' Di Bologna Composés à double ciblage pour le traitement de la maladie d'alzheimer
CN104860955A (zh) * 2015-04-22 2015-08-26 华东理工大学 加兰他敏类似物及其用途
CN118908968A (zh) * 2024-10-09 2024-11-08 威胜生物医药(苏州)股份有限公司 一种加兰他敏中间体衍生物及其催化氧化制备方法
CN118908968B (zh) * 2024-10-09 2025-03-04 威胜生物医药(苏州)股份有限公司 一种加兰他敏中间体衍生物及其催化氧化制备方法

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