WO2008022365A2 - Compositions for influencing the effects of organophosphorus compounds and use of galanthamine, its derivatives and analogues for producing such compositions - Google Patents

Abstract

The use of galanthamine of the formula (I) and derivatives or analogues of galanthamine for controlling the effect of toxic organic phosphorus compounds such as parathion, paraxon, sarin, soman or tabun is described, wherein a composition comprising the said compound or a combination of at least two of the said compounds is administered before and/or after contact of a human with the toxic organic phosphorus compound.

Description

 Means for influencing the effects of

Organophosphorus compounds and use of galanthamine, its derivatives and analogs for making such agents

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.

This object is achieved with an agent having the features of claim 1. Insofar as the invention relates to the use, this object is achieved according to the independent claim directed to the use.

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 AchΞ 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.

This can be used e.g. Protect soldiers from gas attacks with sarin or other toxic phosphorus compounds. But even with rapid intervention, farmers who have been poisoned with parathion or similar insecticides successfully treat.

Organophosphates such as Parathion, Paraxon, used in agriculture, have such high toxicity to inhalation that creatures die quickly if given a large enough amount. The same applies to the 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. For example, 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:

Tablets or capsules containing 0.5 to 50 mg

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. 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. to Production of 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. Among 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):

Derivatives of 4a, 5, 9, 10-11, 12-hexahydro-6H-benzofur [3a, 3, 2-ef] [2] benzazepine having the general formula selected from the group consisting of

and

(II)

or salts thereof, in which

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,

Formyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, aralkylsulfonyl and arylsulfonyl;

Yi and Y _{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, formyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, aralkylsulfonyl and arylsulfonyl or together = 0 (ketone);

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; and

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;

Including in particular a) Bromgalanthamine of the formula

b) Epibromgalanthamine of the formula

c) N-Demethylbromgalanthamine of the formula

OH

d) N-demethyl-epibromgalanthamine of the formula H.

e) bromine N-methyl-narwedin-propylene glycol ketal of the formula

f) Narwedin propylene glycol ketal of the formula

g) bromo-N-formyl-narwedine-ethylene glycol ketal of the formula

h) Narwedine ethylene glycol ketal of the formula

i) O- (2-hydroxyethyl) galanthamine of the formula

j) bromo-N-demethyl-narwedine-ethylene glycol ketal of the formula

k) ^■ Bromo-N-benzyl-narwedine-ethylene glycol ketal of the formula

1) Bromo-N-demethylnarwedine of the formula

Compounds of the general formula (I)

Formula (I)

in which

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 ,

CF ₃ or

• a lower (C ₁ -C ₆ ) optionally branched, optionally substituted (Ar) alkyl or (Ar) alkyl oxy group or • an amino group which is substituted by one or two identical or different lower (Ci-C ₆ ), optionally branched optionally substituted (Ar) alkyl or (Ar) alkyl carbonyl or (Ar) alkyloxycarbonyl groups, or • a COOH, COO (Ar) alkyl, CONH, CON (Ar) alkyl group or

• - (CH ₂ ) _n -Cl, - (CH ₂ ) _n -Br, - (CH ₂ J _n -OH, - (CH ₂ J _n -COOH, - (CH ₂ ) '' - CN, - (CH ₂ J _n -NC, represent

R _r R _{2 may} also together be defined as -CH =CH-CH =CH-, -O- (CH ₂ J _n -O-, with n = 1-3, R ₃ s ^β R ₁ , in particular OH and OCH ₃ , further R ₂ -R ₃ together: -O- (CH ₂ J _n -O- can form, where n = 1 - 3

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

• SO-R ₈ , SO ₂ R ₈

OH, O-protecting group (such as TMS, TBDMS), O-CS-NR ₈ (thiourethane),

• 0-CO-NR ₉ , where R _{9 has} the following meanings:

0-CO-R ₈ (ester, R ₈ see above), in particular also esters with the substitution pattern of amino acids, such as

• furthermore: R ₄ , R ₅ = together hydrazones (= N-NH-R ₁₀ , = NN (R ₁₀ ,

R ₁₁ ), oximes (= N-O-Rn) where R i _{0 is} hydrogen, a lower (C ₁ -Cg) optionally branched, optionally substituted (Ar) alkyl or (Ar) alkylcarbonyl or (Ar) alkylcarbonyloxy group and sulfonic acid such as tosyl and mesyl and R _{11 is} hydrogen, a lower (C ₁ -C ₆ ), optionally branched, optionally substituted (Ar) alkyl or (Ar) alkylcarbonyl group and sulfonic such as tosyl and mesyl. and substituents of the type:

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.

Gi, G ₂ : together or differently have the meaning:

• -C (Ri ₃ , Ri ₄ ) -, where 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).

• Also Gi and G _{2 in} common

with m = 1 to 7 represents.

G _{3 represents} -CH ₂ - or = CO. R _{6 represents} a group - (G ₄ ) _p - (G ₅ ), - - G ₆ with p, q = 0 - 1, in which

G ₄ satisfies the following definitions:

• - (CH ₂ ) _r -, -C (R ₁₅ , R ₁₆ ) - (CH ₂ J _r -, with r = 1-6 and R ₁₅ , R ₁₆ = hydrogen, lower, optionally branched, optionally substituted (Ar ) Alkyl, cycloalkyl,

aryl group, -O-, or -NR ₁₅ -

, ie an ortho, meta, or para disubst. Aromat

O or S represents,

G _{5 may be the} same or different from G ₄ and, in the event that p = 1 is additionally -S-, G ₆ fulfills the following definitions:

Ri7 _/ Riβ _/ Ri9 _f and R ₂ O are individually or together, the same or different hydrogen,

lower, optionally branched, optionally substituted (Ar) alkyl, cycloalkyl, or aryl groups, where Rn and Ri ₈ or R ₁₉ and R ₂ o together may form a cycloalkyl group (ring size 3-8).

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:

• -CHO, COOR ₁₇ , -CONR ₁₇

A lower, optionally branched, optionally substituted (Ar) alkyl, (AR) alkenyl, (AR) alkynyl, cycloalkyl, or aryl group,

• -O-R ₁₇ , -NR ₁₇ R ₁₈ , phthalimido, -CN, or -NC.

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 ^~ .

Further compounds of the general formula (I) are the compounds of the general formula (II)

(Formula (II)

where the radicals have the meanings described for formula (I). This formula is formally derived from formula (I) by breaking the bond of Ci to the "furan" oxygen and instead forming it from C ₁ directly to Z.

Including in particular compounds of the type of the general formula:

Analogs of the galanthamine considered in the context of the invention are starting from galanthamine of the formula

such compounds wherein the hydroxyl group is represented by a methoxy, ethoxy, nied. Alkanyloxy (e.g., acetyloxy) group, 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. Alkylphenyl or substituted lower. Alkylphenol is replaced, wherein the substituents fluorine, chlorine, bromine, nied. Alkoxy, hydroxy, nitro, amino, lower alkyl or acylamino of 1 to 5 carbon atoms or unsubstituted and halogen-substituted benzoyl, nied. Are 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.

In the context of the invention, compounds of the general formula (I)

Formula (I)

considered,

Ri, R _{2 are} either the same or different and

Hydrogen, F, Cl, Br, J, CN, NC, OH, SH, NO ₂ , SO ₃ H, NH ₂ , CF ₃ or a lower (C ₁ -C ₆ ), optionally branched, optionally substituted (Ar) alkyl or (Ar) alkyloxy group or

an amino group which is substituted by one or two identical or different lower (C ₁ -C ₆ ), optionally branched, optionally substituted (Ar) alkyl or (Ar) alkylcarbonyl or (Ar) alkyloxycarbonyl groups, or

a COOH, COO (Ar) alkyl, CONH, CON (Ar) alkyl group or

- (CH ₂ ) _n -Cl, - (CH ₂ J _n -Br, - (CH ₂ J _n -OH, - (CH ₂ ) _n -COOH, - (CH ₂ ) "-CN, - (CH ₂ ) _n - NC, represent

Ri-R _{2 can} also be defined together as -CH = CH-CH = CH-, -O- (CH ₂ ) _n -O-, with n = l-3.

R ₃ = R ₁ , in particular OH and OCH ₃ , further

R ₂ -R ₃ together can form -0- (CH ₂ ) _n -O-, where n = l-3

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 (C ₁ -C ₁₀ ), optionally branched, optionally substituted (Ar) alkyl group

SO-R ₈ , SO ₂ R ₈

OH, O-protecting group (such as TMS, TBDMS),

0-CS-NR ₈ (thiourethanes),

0-CO-NR ₉ , where R _{9 has} the following meanings:

V CH, 0-CO-R ₈ (ester, R ₈ see above), in particular also esters with the substitution pattern of amino acids, such as

furthermore: R ₄ , R ₅ = together hydrazones (= N-NH-R ₁₀ , = N-

N (Rio _/ Rn) i oxime (= N-O-Rn) where R _{10 is} hydrogen, a lower (C ₁ -C ₆ ), optionally branched, optionally substituted (Ar) alkyl or (Ar) alkylcarbonyl or (Ar ) Alkylcarbonyloxygruppe 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 ,

and substituents of the type:

Yi, Y ₂ = O, S, NH or

N-Ri ₀ (surplus valencies are each -H)

where, in the event that R ₄ =, / H, R _{5 is} also OH or in the case where R ₅ =, / H, R _{4 can} also be OH.

G ₁ , G ₂ : together or differently have the meaning:

-C (R ₁₃ , Ri ₄ ) -, where 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).

Furthermore, G ₁ and G ₂ together

with m = 1 to 7 represents.

G _{3 represents} -CH ₂ - or = CO.

R _{6 represents} a group - (G ₄ ) _p - (G ₅ ) _q - G ₆ with p, q = 0-1, in which

G ₄ satisfies the following definition:

- (CH ₂ J _r -, -C (R ₁₅ , Ri ₆ ) - (CH ₂ ) _r -, with r = l-6 and R ₁₅ , R _{16 is} hydrogen, lower, optionally branched, optionally substituted (Ar) alkyl , Cycloalkyl, aryl group,

-0-, or -NR ₁₅ -

, ie an ortho, meta, or para disubst. Aromat

O or S represents,

G _{5 may be the} same or different from G ₄ and in the event that p = 1 is additionally -S-,

G ₆ satisfies the following definition:

With 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:

W

VX / ^■

(CH ₂ ) IR ₁ ,

-CHO, COORJ ₇ , -CONR ₁₇ a lower, optionally branched, optionally substituted (Ar) alkyl, (AR) alkenyl, (AR) alkmyl, cycloalkyl,

or aryl group,

-O-Ri ₇ , -NR ₁₇ R ₁₈ , phthalimido, -CN, or -NC.

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.

Z = N, or N ⁺ in the case that R ₆ and R ₇ are present together and R _{7 is} not equal to O ^~ .

The 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.

wherein the substituents have the meanings explained below: 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 cyclic substitution in the form of an optionally substituted pyrrolidine, piperidine, morpholine, Thiomorpholin-, piperazine, Homopiperazinrestes has d) a COOH, COO (Ar) alkyl, CO-amino, with the definition of the amino group as in the last paragraph c), or a CHOH (Ar) alkyl group; e) a - (CH ₂ J _n X (wherein X = Br, Cl, F or J), - (CH ₂ ) _n OH, - (CH ₂ ) _n CHO, - (CH ₂ ) _n COOH, - (CH _{2) n} CN, - (CH ₂ J _n NC, - (CH ₂₎ "COalkyl, - (CH _{2) n} COAryl group, wherein n is 1-4 alkyl; f) - (CH _{2) n} vinyl, ( CH ₂ ) _n ethynyl group, or (CH ₂ ) "cycloalkyl group in which n is 0, 1 or 2 and cycloalkyl describes an aliphatic ring of the ring size of 3-7 g) a C ₃ -C ₆ substituted alkenyl group (optionally substituted by H, F, Br, Cl, CN, CO ₂ alkyl, COalkyl, COAryl); h) a C ₃ -C ₆ substituted alkynyl group (optionally substituted with H, F, Br, Cl, CN, CO ₂ alkyl, COAlkyl, COAryl); or i) R ₁ and R ₂ together are -CH = CH-CH = CH-, -O (CH ₂ ) _n O- (n

= 1 to 3), -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 α- alkoxyalkyl group such as tetrahydropyranyl, tetra- hydrofuranyl, methoxymethyl, ethoxymethyl, (2-methoxypropyl), ethoxyethyl, phenoxymethyl or (1 Phenoxyethyl); ii) O-CS-NHR ₆ (thiourethanes) in which R _{6 has} the abovementioned meaning iii) O-CO-NHR ₇ with the following meaning:

iv) 0-CO-HR ₆ , wherein R _{6 has} the abovementioned meaning, in particular esters with the substitution pattern of amino acids (both enantiomers), such as

v) 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.

When R _{4 is} hydrogen, 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-π heterocycle (such as imidazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl and substituted variants the same), or imidazolinyl, thiazolinyl or oxazolinyl.

In the event that R _{5 is} not hydrogen, R _{4 may} also be OH.

R ₄ and R ₅ may together be carbonyl (= O), hydrazone (= N-NH-Rg, = N-NR ₉ Rio or oxime (= N-ORi ₀ ) wherein R _{9 is} hydrogen, a lower (Ci-C ₆ ), optionally branched or cyclic, optionally substituted (Ar) alkyl or (Ar) alkylcarbonyl (Ar) alkylcarbonyloxy group or a sulfonic acid group, such as tosyl or mesyl, and R _{10 is} hydrogen, a lower (C ₁ -C ₆ ), optionally branched or cyclic, optionally substituted (Ar) alkyl or (Ar) alkylcarbonyl group, a sulfonic acid group such as a tosyl or mesyl group, R ₄ and R ₅ may together represent substituents of the type

where Y ₁ , Y _{2 are the} same or different and are 0, S, NH or NR ₉ (free valencies are in each case hydrogen), or in the case where Y _{1 is} NH and Y ₂ NR ₉ , R may be ₄ and R _{5 can be joined} by - (CH ₂ J _n - (n = 2, 3 or 4) G ₁ : - (CH ₂ ) _x -, wherein x is 1 or 2; G ₂ j_ - (CH ₂ ) _y -, wherein y is 0 to 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

wherein m is 1 to 7.

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 _7, respectively have the meaning given above; c) one of the substituents reproduced below

where J is not a bond or - (CH ₂ ) _n -, where n = 0 to 3, carbonyl, thiocarbonyl, O, S, -SO- or SO ₂ , R _{6 is} the one given above

And Q is defined as - (CH 2) n M * - (CH 2) m -, where n = 0 to 4 and m = 0 to 4 and M * is alkynyl, alkenyl, disubstituted phenyl, disubstituted thiophene, disubstituted furan, disubstituted pyrazine, disubstituted pydidazine, a pepdid spacer L or a heterocyclic spacer

HS, wherein this definition of the spacer further by the following formula images

Z = CH or N

in which 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;

d) W can also be connected via the spacer Q with a tricyclic substituent (Tr), the tricyclic substituents being defined by the following formula pictures,

and these formulas are to be understood in such a way that the atom N in addition to Q is in each case linked to G2 and G3 of the formula I and Q and Z have the meaning given under c).

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.

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. In particular, 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.

When 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.

Thus, the tricyclic substituent Tr may be a fused benzene ring of the general formula

be. Examples of this are

carbazole,

1, 2, 3, 4-4a, 9a-hexahydrocarbazole, 9,10-dihydroacridine,

1,2,3,4-tetrahydroacridine,

10, ll-dihydro-5H-dibenz [b, f] azepine,

5, 6, 11, 12-tetrahydrodibenz [b, g] azocine, 6, ll-dihydro-5H-dibenz [b, e,] azepine,

6,7-dihydro-5H-dibenzo [c, e] azepine,

5,6,11,12-tetrahydrodibenz [b, f] azocine,

Dibenzofuran, 9H-xanthene,

1-O-dihydrobenz [b, f] oxepin,

6, 11-dihydrobenz [b, e] oxepin,

6,7-Dihydro-5H-dibenz [b, g] oxacin,

Dibenzothiophene, 9H-thioxanthene,

10, 11-dihydrodibenzo [b, f] thiepin,

6, 11-dihydrodibenzo [b, e] thiepin,

6,7-dihydro-5H-dibenzo [b, g] thiocin,

10H-phenothiazine, 10H-phenoxazine,

5,10-dihydrophenazine,

10, ll-dibenzo [b, f] - [l, 4] thiazepine,

2,3,5,6,11,11-hexahydro-1H-pyrrolo [2, 1-b] [3] benzazepine,

1-0, ll-dihydro-5H-dibenzo [b, e] [1,4] diazepine, 5, 11-dihydrodibenz [b, e] [1, 4] oxazepine,

5, 11-dihydrodibenzo [b, f] [1,4] thiazepine,

10, ll-dihydro-5H-dibenzo [b, e] [1,4] diazepine,

1, 2, 3, 3a, 8, 8a-hexahydropyrrolo [2, 3b] indole.

The tricyclic substituent Tr may be a fused benzene ring of the general formula

be and for example mean:

1H, 3H-naphth [l, 8-cd] [l, 2] oxazine,

Naphth [1, 8-de] -1, 3-oxazine,

Naphth [1, 8-de] -1,2, -oxazine,

1, 2, 2a, 3, 4, 5-hexahydrobenz [cd] indole, 2, 3, 3a, 4, 5, 6-hexahydro-1H-benzo [de] quinoline,

4H-pyrrolo [3,2,1-ij] quinoline,

1,2,5,6-tetrahydro-4H-pyrrolo [3,2,1-ij] quinoline, 5, 6-dihydro-4H-pyrrolo [3,2,1-ij] quinoline, IH, 5H-benzo [ij] quinolizine,

2,3,6,7-tetrahydro-1H, 5H-benzo [ij] quinolizine, azepino [3,2, 1-hi] indole, 1,2,4,5,6, 7-hexahydroazepino [3,2, 1-hi] indole, 1H-pyrido [3,2,1-jk] [l] benzazepine,

5,6,7,8-Tetrahydro-1H-pyrido [3, 2, 1-jk] [1] benzazepine, 1,2,5,6,7,8-hexahydro-5H-pyrido [3, 2, 1 -jk] [1] benzazepine, 2, 3-dihydro-1H-benz [de] isoquinoline, 1,2,3,4,4a, 5,6,7-octahydronaphth [1,8-bc] azepine,

2,3,5,6,7,8-hexahydro-1H-pyrido [3, 2, 1-jk] [1] benzazepine.

The tricyclic substituent Tr may be a fused benzene ring of the general formula

be. Examples of these compounds are:

1,2,3,5,6,7-hexahydrobenzo [l, 2-b: 4, 5b '] dipyrrole, 1,2,3,5,6,7-hexahydrocyclopent [f] indole, 1,2,3 , 6,7,8-hexahydrocyclopentane [e] indole or 2,3,4,7,8-hexahydro-1H-cyclopenta [f] quinoline.

The tricyclic substituent Tr may be a fused benzene ring of the general formula

be. Examples of this are:

1,2,3,6,7,8-hexahydrocyclopent [e] indole or 2,3,4,7,8,9-hexahydro-1H-cyclopenta [f] quinoline. Further examples of the tricyclic substituent Tr are condensed benzene rings of the following formulas, where the binding site to Q can take the place of any hydrogen atom:

Further, 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.

e) W can furthermore be -NH-, -S-, -SO- or -SO ₂ -.

In the context of the invention are further considered compounds of the general formula II

wherein 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.

In the context of the invention are further considered compounds of general formula III

wherein 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.

In the context of the invention are further considered compounds of the general formula IV

wherein 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. It is preferred that in the compound of general formula IV, 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. Among these compounds, particularly the compounds mentioned below are considered:

In the table below "AchE" means: acetylcholinesterase, "BchE": butyrylcholinesterase, "hr": human recombinant, "mE": preincubation of the enzyme with inhibitor and "IC50": concentration at which a 50% inhibition occurs.

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code m £, hr) mE, hr)

SPH-1 184 0.2 0.6 LCz 225/1

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code m £, hr) m £, hr)

SPH-1191 0.35 4.4 LCz 205

SPH-1 163 200 0.47 MH 7-1-1

SPH-1200 200 17 MH 30-1

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code mE, hr) mE, hr)

SPH-1202 200 5.2 MH-28-1

SPH-1205 70 2.4 MH 33

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code mE, hr) mE, hr)

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code mE, hr) m £, hr)

SPH-1216 90 200 CB 35

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code mE, hr) niE, hr)

SPH-1221 4,8 200 CB 45

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code mE, hr) niE, hr)

SPH-1230 CB 53

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code mE, hr) mE, hr)

SPH-1235 3.4 11 CB 42

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code mE, hr) mE, hr)

SPH-1244 ⁷ ' ^{6 36 CB 57}

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code niE, hr) mE, hr)

SPH-1249 45 26 MR 13

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code mE, hr) m £, hr)

OH

SPH-1253 60 5.4 MH-75

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code mE, hr) mE, hr)

SPH-1262 54.5 36 MR 14

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code mE, hr) mE, hr)

SPH-1268 44 200 CB 78

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code niE, hr) mE, hr)

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code mE, hr) mE, hr)

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code mE, hr) mE, hr)

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code mE, hr) mE, hr)

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code mE, hr) mE, hr)

200 200 MT 176

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code mE, hr) mE, hr)

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code m £, hr) mE, hr)

SPH-1326 8.4 2.6 CB 171

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code mE, hr) mE, hr)

SPH-1331 50 200 MH 142

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code mE, hr) mE, hr)

SPH-1339 0.3 1.5 HM 264-1

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code inE, hr) m £, hr)

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code mE, hr) m £, hr)

SPH-1372 0.022 UJ-1682-2

SPH-1373 0.043 UJ-1685

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code mE, hr) mE, hr)

0.024 BK-34-2

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code mE, hr) m £, hr)

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code mE, hr) mE, hr)

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code mE, hr) mE, hr)

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code niE, hr) niE, hr)

SPH-1536 CK-32

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code m £, hr) mE, hr)

SPH-1540 CK-41

IC50 IC50

Substance laboratory

Structure (AChE, (BChE, Code Code mE, hr) mE, hr)

IC50 AChEIC50 BChE

SPH number structure μM μM

Among others, the compound (6R) -3-methoxy-5, 6, 9, 10, 11, 12-hexahydro-4a [Hl] benzofuro [3a, 3, 2-ef] has been particularly considered in the context of the invention. 2] benzazepin-6-ol (norgalanethamine), namely racemic norgalanthamine, (-) norgalanthamine, and (+) norgalanthamine. Both racemic norgalanthamine and its (+) - and (-) isomers can be used as active ingredients in medicaments for the treatment of the diseases mentioned at the beginning under a) to m) be used alone or in combination with other active substances.

Galanthamine derivatives of general formula Ia are also contemplated by the invention

Ia

or their salts used, in which

R 1 is H, branched or straight-chain (C 1 -C 6) alkyl, Br, NO 2, NR 5 R 6,

Rs and R _{6 are} identical or different and denote H, branched or straight-chain (C ₁ -C ₆ ) -alkyl,

and in which

• R ₂ is OH, branched or straight chain (Ci-C ₆ ) alkyl, methoxy, phenyloxy or the following group

where 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,

in which further • Y ₁ and Y ₂ alternately H or a group selected

wherein n represents a value of 0, 1 to 15, and Pol has the meaning given above, and wherein further

Y ₁ and Y ₂ together represent a carbonyl group (= 0), = NH, = N-OR ₇ , where R ₇ is H, tosyl or branched or straight-chain (C ₁ -C ₆ ) -alkyl,

• or Yi and Y ₂ together select a group from:

where 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,

and in which

• Zi is H, branched or straight chain (Ci-C ₆ ) alkyl, (C ₂ -C ₇ ) alkenyl (C ₂ -C ₇ ) alkynyl, trifluoroacetyl, formyl, phenyl

or a group selected from:

means, where 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, where 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, and W has the meaning H or 0,

and in what further

• Z ₁ and R _{3 have} a common ring

easy or

double bond

where R ₁₅ and R _{16 are} mutually H, COOCH ₃ , COOCH ₂ CH ₃ , CN, COCH ₃ .

Advantageously, also galanthamine derivatives having the general formula Ib

ib

used in which

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:

wherein n, R ₁₂ , R ₁₃ and R _{14 have} the meaning according to claim 3.

Likewise, advantageously, galanthamine derivatives having the general formula Ic

ic

used in which

• Y ₃ and Y _{4 have} the meanings given above, and

• 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

id

or their salts, in which

Y ₅ and Y _{6 are} mutually H or OH or together form a keto group, and

Rπ _r Riβf ^R i9 alternately for each two substituents H, wherein the third substituent is NH ₂ or CONH ₂ .

Furthermore, according to the invention advantageously galanthamine derivatives having the general formula Ie

Ie

or their salts used, wherein Z _{4 is} a straight-chain or branched (C ₁ -C ₆ ) alkyl or 4-bromobenzyl.

Also considered ^{according to the} invention are galanthamine derivatives of the general formula If

or their salts, wherein Y ₅ and Y _{6 have} the meanings given above, and R ₂ o is H or Br.

Particularly considered according to the invention is the galanthamine derivative having the following structural formula

and designated (4aS, 6R, 8aS) -6-hydroxy-3-methoxy-ll-methyl-4a, 5,9,10-tetrahydro-6H-benzofuro [3a, 3,2-f] [2] benzazepine and its pharmaceutically acceptable salts, hydrates or solvates.

As counterions of the pharmaceutically acceptable salts of (4aS, 6R, 8aS) -6-hydroxy-3-methoxy-ll-methyl-4a, 5, 9, 10-tetrahydro-6H-benzofuro [3a, 3, 2-ef] [ 2] 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.

Among the abovementioned compounds, the following are considered according to the invention:

1Q6

According to the invention are also considered derivatives of 4a, 5, 9, 10, 11, 12-hexahydro-benzofuro [3a, 3, 2] [2] benzazepine having the general formula Ia or Ib

Ia Ib

and their salts are considered, in which

• Ia optically active (-) derivatives of galanthamine and Ib are optically active (+) derivatives of galanthamine, which are in a mirror-image spatial arrangement, and wherein

Yi and Y ₂ alternatively H or OH,

• X = H or Br are and

• Z ₁ = a group with the following formula representation

i st, in which

• 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,

• R ₂ = R ₃ = H, straight or branched (C ₁ -C ₆ ) alkyl

• W = H, 0, S

• n = 0, 1-6,

and in which

• Zi equals H exclusively for connections 1, 3, 13 and 24

13 24

wherein compounds 1 and 13 are (-) derivatives of 6-epi-norgalanthamine and compounds 3 and 24 are (+) derivatives of 6-epi-norgalanthamine, and wherein

• Zi exclusively for the compound 29 is hydroxypropyl

29 and

• Z ₁ exclusively for compound 26 is ethyl

26

and

• Zi only for the following connections

28 31 Level 1 31 Level 2 56 55

is methyl, and wherein the compounds are 29, 31 and 55 (+) derivatives of galanthamine and the compounds 26, 28 and 56 are (+) -Epi derivatives of galanthamine.

Including the following connections:

, 12-

10,11,12-

] Benzofuro [3a, 3,2

Bromo

- -

, 12-

, 12-

] benzofuro [3a, 3,2-methyl-1 - (3

] Benzofuro [3a, 3,2

(-4- Hydrochlorothiazine - (2-pypenyl) -

] Benzofuro [3a, 3,2

, 12-hexahydro-

acid

To study the effect of Galanthamindeπvaten rats were placed over two (2) and five (5) minutes in a Parathion aerosol filled gas container.

Three different types of test were performed with 0.5 mg, 1 mg and 2 mg substance to be tested per kg body weight:

Trial Type 1:

Ten minutes before introduction, the rat was treated with 0.5 mg, 1 mg and 2 mg intramuscularly with the compound to be tested.

Trial Type 2:

The rat was not previously treated and also not treated after the exposure time.

Trial Type 3:

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.

Substances used:

Molgew AchEHemm. SPH-1088 C16H19NO3 273.33473 0, 16 200

SPH-1150 C19H25Br2NO3 475,224 0, 15 2,7

C17H20BrNO3 366.25785 0.74 100

SPH-1486 C15H17NO3 259,30764 0,8 37

SPH-1549 C20H25NO7 391.42475 0.014 13.4

SPH-1562 C17H19NO2 269.34648 0.008 62.3

SPH-1612 C16H22C12N2O3 361.27134 0.004 200

SPH-1285 C17H20BrNO3 366.25785 0.74 100

Results :

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. At 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. However, parathion intoxication was prevented in all cases.

Rats treated according to test type (2.) survived massive neuronal damage at 2 minutes exposure time; after 5 minutes exposure, the rat died 15 to 45 minutes after exposure.

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.

After 5 minutes exposure occurred at 1 mg / kg SPH 1285, SPH 1088, SPH 1486, SPH 1150, SPH 1562 neuronal disorders, with varying degrees of strength, which subsided in part after a day, the majority but also did not decrease after a day, it must permanent neuronal damage is assumed in these cases. At 2 mg / kg SPH 1285, SPH 1088, mild reversible neuronal disorders were observed a few minutes after treatment. The use of the other substances in 2 mg dosage was omitted since only an increase in intoxication was to be expected.

It has been found that all tested compounds are capable, in the properly selected dosage, in pre-treatment or even rapid post-treatment, of the toxic effects of organophosphates such as Parathion, Paraxon and related molecules such as sarin, also called military nerve gases be used to cancel or prevent. The inhibitory effect obviously applies to all those derivatives crossing the blood-brain barrier.

In summary, one embodiment of the invention can be described as follows: The use of galanthamine of the formula is described

and derivatives or analogs of galanthamine for controlling the

Effect of toxic organic phosphorus compounds, such as

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.

Claims

Claims :

1. A composition for controlling the action of organic phosphorus compounds, characterized by an effective content of galanthamine and / or at least one derivative or analog of galanthamine.

2. Composition according to claim 1, characterized in that the phosphorus compound is an organophosphate.

3. Composition according to claim 1 or 2, characterized in that the organic phosphorus compound is parathion, paraxone, sarin, soman or tabun.

4. Composition according to one of claims 1 to 3, characterized in that the derivative is a compound of general formula (I)

and

5 or salts thereof, wherein

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 , 0 lower alkenyl, lower alkynyl, aryl, aralkyl, aryloxyalkyl, Formyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, aralkylsulfonyl and arylsulfonyl;

Yi and Y _{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, formyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, aralkylsulfonyl and arylsulfonyl or together = 0 (ketone);

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; and

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.

5. Composition according to one of claims 1 to 3, characterized in that the derivative is a compound of the general

Formula (I)

Formula (I)

wherein R _1, 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 , CF ₃ or a lower one

(C ₁ -Ce) i optionally branched, optionally substituted (Ar) alkyl or (Ar) alkoxy group or an amino group by one or two identical or different lower (Cχ-C ₆ ) optionally branched, optionally substituted (Ar) alkyl or (Ar) alkylcarbonyl or (Ar) alkyloxycarbonyl groups or a COOH, COO (Ar) alkyl, CONH, CON (Ar) alkyl group or

- (CH ₂ J _n -Cl, - (CH ₂ J _n -Br, - (CH ₂ J _n -OH, - (CH ₂ ) "-COOH, - (CH ₂ J _n -CN,

- represent (CH ₂ J _n -NC, where

Ri-R _{2 can} also be defined together as -CH = CH-CH = CH-, -O- (CH ₂ ) _n -O-, with n = 1-3,

R ₃ = R ₁ , in particular OH and OCH ₃ , further

R ₂ -R ₃ together can form -O- (CH ₂ J _n -O-, where n = 1-3

R <, R ₅ either both hydrogen or alternatively each

Combination of hydrogen or an (Ar) alkyl, (Ar) alkenyl, (Ar) alkynyl with

SR ₈ , wherein R _{8 is} hydrogen or a lower (C ₁ -C ₁₀ ), optionally branched, optionally substituted (Ar) alkyl group

SO-R ₈ , SO ₂ R ₈

OH, O-protecting group (such as TMS, TBDMS),

0-CS-NR ₈ (thiourethanes),

0-CO-NR ₉ , where R _{9 has} the following meanings:

0-CO-R ₈ (ester, R ₈ see above), in particular also esters with the substitution pattern of amino acids, such as

further: R ₄ , R ₅ = together hydrazones (= N-NH-Ri ₀ , = NN (Ri ₀ , Rn), oximes (= NO-Rn) where Ri ₀ hydrogen, a lower

(Ci-C ₆ ), optionally branched, optionally substituted (Ar) alkyl or (Ar) alkylcarbonyl or

(Ar) Alkylcarbonyloxygruppe and sulfonic acid such as tosyl and mesyl and Rn is hydrogen, a lower (Ci-C ₆ ), optionally branched, optionally substituted (Ar) alkyl or (Ar) alkylcarbonyl and sulfonic such as tosyl and mesyl is. and substituents of the type:

Yi, Y ₂ = 0, S, NH or NR ₁₀ (surplus valencies are each -H)

in the case where R ₄ = H, R _{5 is} also OH or in the case where R ₅ = H, R _{4 can} also be OH.

Gi, G ₂ : together or differently have the meaning:

-C (Ri ₃ , Ri ₄ ) -, wherein Ri ₃ , R _{i4 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).

Furthermore Gi and G ₂ together

1 to 7 represents.

represents a group - (G ₄ ) _p - (G ₅ ) _q - G ₆ with p, q = 0-1, in which G ₄ satisfies the following definitions: - (CH ₂ ) _r -, -C (R ₁₅ , Ri ₆ ) - (CH ₂ Jr-, with r = 1-6 and Ri ₅ , Ri ₆ =

Hydrogen, lower, optionally branched, optionally substituted (Ar) alkyl, cycloalkyl, aryl group,

-O-, or -NR ₁₅ -

, ie an ortho, meta, or para disubst. Aromat

where G ₇ = NRi represents ₅ , O or S,

G _{5 may be the} same or different from G ₄ and in the event that p = 1 is additionally -S-, G ₆ fulfills the following definitions:

RI7, Ri _B / R19 and _R20 are individually or collectively, the same or different hydrogen, lower, optionally branched, optionally substituted (Ar) alkyl, cycloalkyl, or aryl groups, wherein R _i7 and R ₁₈ or R ₁₉ and R ₂₀ together can form a cycloalkyl group (ring size 3-8). G ₈ = O, S, NH, NR ₂₁ , - (CHA) _n -,

R ₂ i = CHO, COORi ₇ , or an unsubstituted, or by one or more more F, Cl, Br, J, NO ₂ , OH, alkyl, alkyloxy, CN, NC or CF ₃ , CHO, COOH, COOalkyl, SO ₃ H, SH, S-alkyl groups are the same or different substituted (hetero) aryl, (with heteroaryl, in particular 2-pyridyl, 4-pyridyl, 2-pyrimidinyl) or a methyl group which is unsubstituted by 1-3, or by an or a plurality of F, Cl, Br, J, NO ₂ , NH ₂ , alkyl, alkyloxy, CN, NC or CF ₃ groups is the same or different substituted phenyl group (s),

G _ß can be further:

• -CHO, COOR _n , -CONR ₁₇

a lower, optionally branched, optionally substituted (Ar) alkyl, (AR) alkenyl, (AR) alkynyl, cycloalkyl, or aryl group, -O-Ri ₇ , -NRi ₇ Ri ₈ , phthalimido, -CN, or -NC. 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 the 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.

Z = N, or N ⁺ in the event that R ₆ and R ₇ are present together and R _{7 is} not equal to O ^" .

6. Composition according to one of claims 1 to 3, characterized in that the derivative is a compound of general formula (I),

wherein the substituents have the meanings explained below: A) R ₁ and R ₂ are identical or different and denote:

Aa) 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 , where n is 0, 1 or 2, -OSO ₂ -aryl,

Vinyl or ethinyl;

Ab) a lower (C ₁ -C ₆ ), optionally branched alkyl, aralkyl, alkoxyl, aralkoxy, cycloalkyl or cycloalkoxy group, Ac) an amino group which is optionally substituted by one or two identical or different lower (C ₁ -C ₆ ) C ₆ ), optionally branched alkyl, aralkyl, or alkylcarbonyl,

Aralkylcarbonyl, or alkoxycarbonyl, Aralkoxycarbonylgruppen or by a group selected from a pyrrolidine,

Piperidine, morpholine, thiomorpholine, piperazine or

Homopiperazine radical is substituted;

Ad) a -COOH, -COOalkyl, -COOAralkyl, CO-amino group, which is optionally substituted as indicated above under Ac), or a COH-alkyl group or COH-aralkyl group; Ae) is a - (CH ₂ ) _n X (in which X = Br, Cl, F or J), - (CH ₂ ) _n OH, - (CH ₂ J _n CHO-, - (CH ₂ ) _n COOH-, - (CH ₂ J _n CN, - (CH ₂ J _n NC, (CH ₂ ) _n COalkyl or - (CH ₂ ) _n COAryl group, wherein n is 1-4;

Af) a - (CH ₂ ) _n vinyl, - (CH ₂ ) "ethynyl, - (CH ₂ ) _n cycloalkyl group, wherein n is 0, 1 or 2, wherein cycloalkyl is an aliphatic ring having 3 to 7 C -Atomen is;

Ag) a C ₃ -C ₆ substituted alkenyl group (optionally substituted with H, F, Br, Cl, CN, CO ₂ alkyl, COAlkyl, COAryl); Ah) a C ₃ -C ₆ substituted alkynyl group (optionally substituted with H, F, Br, Cl, CN, CO ₂ alkyl, COAlkyl, COAryl); or

Ai) R ₁ and R ₂ together are -CH = CH-CH = CH-, -O (CH ₂ ) _n O- (n = 1 to 3), -CH = CHA ₁ - (A ₁ is NH, O or S), or -CH ₂ CH ₂ A ₁ - (A ₁ is NH, O or S);

B) R _{3 has the} same meaning as R ₁ , in particular OH and OCH ₃ , or

C) R ₂ and R ₃ together represent -A ₂ (CH ₂ J _n A ₂ -, wherein n is 1 to 3 and the substituents A _{2 are} identical or different and denote NH, O or S;

D) R ₄ and R ₅ are either Da) both hydrogen, or

Db) one of R ₄ and R ₅ is hydrogen, an alkyl, aralkyl, alkenyl, aralkenyl, alkynyl or aralkinyl group and the other of R ₄ and R ₅ is Dbi) OR ₆ , wherein R _{6 is} hydrogen, a lower (C ₁ -C ₁₀ ) optionally branched alkyl group, or cycloalkyl group, a C ₃ -C ₁₀ substituted silyl group (e.g. triethylsilyl, trimethylsilyl, t-butyldimethylsilyl or dimethylphenylsilyl), a C ₂ -C ₁₀ alpha-alkoxyalkyl group for example tetrahydropyranyl, tetrahydrofuranyl, methoxymethyl, ethoxymethyl, 2-methoxypropyl, ethoxyethyl, phenoxymethyl or 1-phenoxyethyl;

Dbii) 0-CS-NHR ₆ (thiourethanes), wherein R _{6 has} the meanings given above under Dbi);

Dbiii) O-CO-NHR ' ₇ with the following meaning:

Dbiv) 0-CO-HR ₆ , wherein R _{6 has} the meanings mentioned above under Dbi), in particular esters with the substitution pattern of amino acids (both enantiomers), such as

Dbv) NR ₇ R ₇ , in which the two substituents R _{7 are} identical or different and denote hydrogen, a lower (C ₁ -C ₄ ), optionally branched, alkyl group or cycloalkyl group, or the substituents R ₇ are in common - (CH ₂ ) _n ~ # where n is 3 to 5;

Dbvi) NH-COR ₆ (amide), wherein R _{6 has} the meanings mentioned above under Dbi);

Dbvii) SR ₆ , wherein R _{6 has} the meaning given above under Dbi);

Dbviii) _n SO Re, wherein n is 0, 1 or 2 and wherein R ₈ is a (C ₁ - C _0), optionally branched or cyclic, optionally substituted alkyl or aralkyl group;

Dbix) R ₄ is hydrogen and R _{5 is} OH, CN, CO ₂ alkyl, CONR _a R _b , wherein R _{a is} hydrogen, a lower (Ci - C ₆ ), optionally branched or cyclic substituted alkyl group and R _b

Is hydrogen, a lower (Ci - C ₆ ), optionally branched or substituted alkyl group, or Ra + Rb are common -

(CH ₂ I _n -, wherein n is 2 to 6, or - (CH ₂ ) _n E (CH ₂ ) _n -, wherein E is NH, N-alkyl, O, or S and n is 0 to 5, aryl (Phenyl or

Naphthyl), or a 6- II heterocycle;

Dbx) R ₄ and R ₅ are, together carbonyl (= 0), hydrazone (= N-)

NH-R ₉ , = N-NR ₉ R ₁₀ ) or oxime (= N-OR ₁₀ ) where R _{9 is} hydrogen, a lower (C ₁ -C ₆ ), optionally branched or cyclic, optionally substituted alkyl, aralkyl, alkylcarbonyl,

Aralkylcarbonyl, alkylcarbonyloxy or aralkylcarbonyloxy group or a sulfonic acid group such as tosyl or mesyl, and R ₁₀

Is hydrogen, a lower (Ci-C ₆ ), optionally branched or cyclic, optionally substituted alkyl, aralkyl, alkylcarbonyl, or Aralkylcarbonylgruppe, a

Sulfonic acid group such as a tosyl or mesyl group;

Dbxi) R ₄ and R ₅ are, together, substituents of the type

wherein Y ₁ , Y _{2 are the} same or different and are O, S, NH or NR ₉ (free valencies are in each case hydrogen), wherein R _{9 has} the meanings mentioned above in Dbx); EJ G ₁ j_ - (CH ₂ ), -, wherein x is 1 or 2;

F) G ₂ : - (CH ₂ ) _y -, wherein y is 0 to 2;

E / Fa: G ₁ and G ₂ mean together or separately:

-C (R ₁₁ R ₁₂ ) -, wherein R ₁₁ and R _{12 are} hydrogen, OH, a lower, optionally branched or cyclic, optionally substituted alkyl, aralkyl, aryl, alkyloxy, arakyloxy, or

Aryloxy group or together an alkylspiro group (C ₃ -C ₇ -

Spiroring);

E / Fb: G ₁ and G ₂ mean together

wherein m is 1 to 7;

E / Fc: G ₁ and G ₂ together or separately mean -CRnR ₁₂ - in which R ₁₁ and R _{12 are} hydrogen, hydroxy, a lower, optionally branched or cyclic, optionally substituted alkyl, aralkyl, aryl, alkoxy, Aralkoxy, or

Aryloxy group;

E / Fd: G ₁ and G ₂ are together alkyl-spiro group (C ₃ -C ₇ -

Spiroring); G) G ₃ : - (CH ₂ ) _z -, wherein z is 0 to 3, with the proviso that the sum of x + y + z is at least 2 and at most 4, or wherein

G _{3 is} carbonyl or thiocarbonyl,

-CH (OH) - or -C (OH) = is;

H) W is: Ha) CR ₁₃ R ₁₄ , wherein R _{13 is} hydrogen and R _{14 is} - (CH ₂ J _n NR ₇ R ₇ , -CO-NR ₇ R ₇ or -COOR ₇ where n is 0 to 2 and R ₇ the above

Has meanings, or R ₇ and R ₇ form over - (CH ₂ ) _n -, where n is 3 to

5 is a ring wherein the substituents R ₁₃ and R ₁₄ may be reversed. Hb) N-phenyl (optionally substituted with fluorine, bromine,

Chlorine, (C ₁ -C ₄ ) alkyl, C0 ₂ alkyl, CN, CONH ₂ , or alkoxy), N-thien-2 or 3-yl, or N-fur-2- or 3-yl, or NI, 3, 5-triazinyl, where the triazine residue may be further substituted with Cl, OR ₆ or NR ₇ R ₇ , and R ₆ and R _{7 have} the meaning given above;

Hc) one of the substituents reproduced below

wherein J is not a bond or - (CH ₂ ) _n ~ / where n = 0 to 3, carbonyl, thiocarbonyl, O, S -SO or SO ₂ , R _{6 has} the meanings given above, and wherein

Q is - (CH ₂ ) _n - M * - (CH ₂ ) _m -, where n = 0 to 4 and m = 0 to 4 and M * alkynyl, alkenyl, disubstituted phenyl, disubstituted thiophene, disubstituted furan, disubstituted pyrazine, disubstituted pydidazine, a spacer of one of the formulas given below, a peptide spacer L or a heterocyclic spacer HS of the following formulas,

o _the

P = CH or N T = CH or N

X = NR ₆ , 0 or S Z = CH or N

wherein Ri _{5 is} the side chain of D, L, D, L-amino acids or unnatural amino acids, and in the case of n> l R ₁₅ in the individual radicals each have a same or different side chain of D-, L-, D , L-amino acids or unnatural amino acids, with the proviso that the atom N in addition to Q is in each case connected to the group G2 and G3 of the formula I; Hdi), optionally at least monosubstituted, tricyclic substituent (Tr) having at least one heterocyclic ring as the ring component and a binding site on a carbon atom of a fused benzene ring thereof, via a spacer Q and the Q adjacent nitrogen each with G ₂ and G ₃ of Compound of formula I is connected, wherein Q has the meaning given above under Hc);

Hdii) is a cyclic hydrocarbon of the formulas below:

or

He) -NH-, -O-, -S-, -SO- or -SO ₂ -;

Hf) when W is -NH-, z in the group G _{3 is} 0, 2 or 3, with the proviso that z in the group G _{3 is} 1 when the substituent R _{1 is} a lower alkyl group such as methyl or Ethyl, means.

7. Composition according to one of claims 1 to 3, characterized in that the derivatives compounds of the general formula (Ia)

Ia

or their salts are, in which

R ₁ is H, branched or straight chain (C ₁ -C ₆ ) alkyl, Br, NO ₂ , NR ₅ R ₆ ,

R ₅ and R _{6 are} identical or different and denote H, branched or straight-chain (C ₁ -C ₆ ) alkyl,

and in which R ₂ is OH, branched or straight chain (C ₁ -C ₆ ) alkyl, methoxy, phenyloxy or the following group

where 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,

in which further

• Yi and Y ₂ alternately H or a group selected from:

wherein n represents a value of 0, 1 to 15, and Pol has the meaning given above, and wherein further

Yi and Y ₂ together represent a carbonyl group (= O), = NH, = N-OR _{7 /} , where R ₇ is H, tosyl or branched or straight-chain (C ₁ -C ₆ ) alkyl,

• or Yj and Y ₂ together select a group from:

where Ra and R _{9 are} identical or different and denote H, branched or straight-chain (C ₁ -C ₆ ) -alkyl, - (CH ₂ J ₂ -OH, CHO, CONH ₂ , tBOC (tert-butoxycarbonyl), or -COCOOH , R ₁₀ is H or CH ₃ , and where Y ₁ is -O- (CH ₂ ) ₂ -OH Y ₂ is OH,

and in which

• Z ₁ is H, branched or straight chain (C ₁ -C ₆ ) alkyl, (C ₂ -C ₇ ) alkenyl (C ₂ -C ₇ ) alkynyl, trifluoroacetyl, formyl, phenyl

or a group selected from:

means, where Rn is H, straight chain (Ci-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, where R ₁₄ is H, F, CH ₃ , NO ₂ , Cl, Br, J, CF ₃ , n has the meaning given above, m is 0 or 1, and W has the meaning H or O,

and in what further

• Z ₁ and R _{3 have} a common ring

easy or

double bond

where R ₁₅ and R _{16 are} mutually H, COOCH ₃ , COOCH ₂ CH ₃ , CN, COCH ₃ . 8. Composition according to one of claims 1 to 3, characterized in that the derivatives of compounds of the general formula Ia or Ib

Ia Ib

and their salts are where

• Ia optically active (-) derivatives of galanthamine and Ib are optically active (+) derivatives of galanthamine, which are in a mirror-image spatial arrangement, and wherein 14

Y ₁ and Y ₂ alternately H or OH,

• X = H or Br are and

• Z ₁ = a group with the following formula representation

is in which

• R ₁ = H, Cl, Br, I, F, OH, straight or branched (Ci-C ₆₎ alkyl, straight or branched (C ₁ -C ₆₎ alkyloxy, NO _2, NR ₂ R _3,

• R ₂ = R ₃ = H, straight or branched (C ₁ -C ₆ ) alkyl

• W = H, 0, S

• n = 0, 1-6,

and in which Z ₁ equals H exclusively for the compounds 1, 3, 13 and 24

13 24

wherein compounds 1 and 13 are (-) derivatives of 6-epi-norgalanthamine and compounds 3 and 24 are (+) derivatives of 6-epi-norgalanthamine, and wherein

Z ₁ exclusively for the compound 29 is hydroxypropyl

29

and

• Z ₁ exclusively for compound 26 is ethyl

26 and

Z ₁ exclusively for the following connections

28 31 Level 1 31 Level 2 56 55

is methyl, and wherein the compounds are 29, 31 and 55 (+) derivatives of galanthamine and the compounds 26, 28 and 56 are (+) -Epi derivatives of galanthamine.

9. Use of galanthamine and / or at least one derivative or analog of galanthamine for preparing agents for controlling the action of organic phosphorus compounds.

10. Use according to claim 9, characterized in that the phosphorus compound is an organophosphate.

11. Use according to claim 9, characterized in that the organic phosphorus compound is parathion, paraxone, sarin, soman or tabun.

12. Use according to one of claims 9 to 11, characterized in that the compound used is one of the general formula (I),

and

or salts thereof, wherein

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, which is optionally substituted by at least one halogen, lower alkenyl, lower alkynyl, aryl, aralkyl, aryloxyalkyl,

Formyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl,

Alkylsulfonyl, aralkylsulfonyl and arylsulfonyl;

Y ₁ and Y _{2 are} either the same or different and are selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, alkoxy, lower alkyl which is optionally substituted by at least one halogen, lower alkenyl, lower alkynyl, Aryl, aralkyl, aryloxyalkyl, formyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, aralkylsulfonyl and arylsulfonyl or together = 0 (ketone);

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; and 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.

13. Use according to one of claims 9 to 11, characterized in that the compound used is one of the general formula (I),

Formula (I)

wherein R ₁ , 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 , CF ₃ or a lower (C ₁ -C ₆ ), optionally branched, optionally substituted (Ar) alkyl or (Ar) alkoxy group or an amino group optionally substituted by one or two identical or different lower (C ₁ -Ce) optionally branched, optionally substituted (Ar) alkyl or (Ar ) Alkylcarbonyl or (ar) alkyloxycarbonyl groups or a COOH, COO (Ar) alkyl, CONH, CON (Ar) alkyl group or - (CH ₂ J _n -Cl, - (CH ₂ J _n -Br, - (CH ₂ J _n -OH, - (CH ₂ J _n -COOH, - (CH _{2) »-CN,} - (CH ₂ J _n - NC, showing, wherein R ₁ -R _{2 may} also together as -CH = CH-CH = CH-, -O- (CH ₂ J _n -O-, with n = 1-3 may be defined, R ₃ = Ri / in particular OH and OCH ₃ , further

R ₂ -R ₃ together can form -O- (CH ₂ J _n -O-, where n = 1-3

R ₄ , R ₅ either hydrogen or alternatively any combination of hydrogen or an (Ar) alkyl, (Ar) alkenyl, (Ar) alkynyl with S-Re, where Re is hydrogen or a lower (Ci-C ₁₀ ), optionally branched, optionally substituted

(Ar) is alkyl group

SO-R ₈ , SO ₂ R ₈

OH, O-protecting group (such as TMS, TBDMS),

0-CS-NR ₈ (thiourethanes),

0-CO-NR ₉ , where R _{9 has} the following meanings:

0-CO-R ₈ (ester, Re see above), in particular also esters with the substitution pattern of amino acids, such as

Furthermore: _{R4, R5} = jointly hydrazone (= N-NH-Ri _0, = NN (Ri _0, Rn), oximes (= NO-Rn) where R ₀ is hydrogen, a lower (C ₁ -C _6), optionally branched, optionally substituted (Ar) alkyl or (Ar) alkylcarbonyl or (Ar) alkylcarbonyloxy group and sulfonic acid such as tosyl and mesyl group and R _{11 is} hydrogen, a lower (C ₁ -C ₆ ), optionally branched, optionally substituted (Ar) is alkyl or (Ar) alkylcarbonyl group and sulfonic acid such as tosyl and mesyl group, and substituents of the type:

Y ₁ , Y ₂ = 0, S, NH or NR ₁₀ (surplus valencies are each -H) in the case where R ₄ = H, R _{5 is} also OH or, in the case where R ₅ = H, R _{4 can} also be OH.

G ₁ , G ₂ : together or differently have the meaning:

-C (Ri ₃ , Ri ₄ ) -, wherein Ri ₃ , R _{14 is} hydrogen, OH, a lower, optionally branched, optionally substituted (Ar) alkyl, aryl, (Ar) alkyloxy or aryloxy group or together an alkylspiro group (C ₃ to C ₇ spiro ring). Furthermore Gi and G ₂ together

with m = 1 to 7 represents.

R _{6 represents} a group - (G ₄ ) _p - (G ₅ ) _q - G ₆ where p, q = 0-1, in which G ₄ satisfies the following definitions:

- (CH ₂ J _r - _/ -C (Ri ₅ , R ₁₆ ) - (CH ₂ ) _r -, where r = 1-6 and R ₁₅ , R _i6 = hydrogen, lower, optionally branched, optionally substituted

(Ar) alkyl, cycloalkyl, aryl group, -O-, or -NRi ₅ -

, ie an ortho, meta, or para disubst. Aromat

0 or S represents, G _{5 may be the} same or different from G ₄ and, in the event that p = 1 is additionally -S-, G ₆ fulfills the following definitions:

Ri ₇ , Ri ₈ , Ri ₉ and R ₂ o are individually or jointly, identical or different hydrogen, lower, optionally branched, optionally substituted (Ar) alkyl, cycloalkyl, or aryl groups, wherein Ri ₇ 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 ₂ I, - (CHA) _n -,

R ₂ i = CHO, COORi ₇ , or an unsubstituted, or by one or more more F, Cl, Br, J, NO ₂ , OH, alkyl, alkyloxy, CN, NC or CF ₃ , CHO, COOH, COOalkyl, SO ₃ H, SH, S-alkyl groups are the same or different substituted (hetero) aryl, (with heteroaryl, in particular 2-pyridyl, 4-pyridyl, 2-pyrimidinyl) or a methyl group which is unsubstituted by 1-3, or by an or several F, Cl, Br, J, NO ₂ , NH ₂ , alkyl, alkyloxy, CN, NC or CF ₃ groups is the same or different substituted phenyl group (s) substituted, G ₆ may be further:

respectively.

-CHO, COOR ₁₇ , -CONRi _{7 is} a lower, optionally branched, optionally substituted (Ar) alkyl, (AR) alkenyl, (AR) alkynyl, cycloalkyl, or aryl group, -O-R ₁₇ , -NR ₁₇ R _18, phthalimido, -CN or -NC.

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 the 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.

Z = N, or N ⁺ in the case that R ₆ and R ₇ are present together and R _{7 is} not equal to 0 ^~ .

14. Use according to one of claims 9 to 11, characterized in that the compound used is one of the general formula (I),

wherein the substituents have the meanings explained below:

A) R ₁ and R ₂ are identical or different and mean: Aa) 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 ) _n CF ₃ , wherein n is 0, 1 or 2, -OSO ₂ -aryl, -vinyl or -ethynyl;

Ab) a lower (C ₁ -C ₆ ), optionally branched alkyl, aralkyl, alkoxyl, aralkoxy, cycloalkyl or cycloalkoxy group,

Ac) an amino group optionally substituted by one or two identical or different lower (C ₁ -C ₆ ), optionally branched alkyl, aralkyl, or alkylcarbonyl,

Aralkylcarbonyl, or alkoxycarbonyl, Aralkoxycarbonylgruppen or by a group selected from a pyrrolidine,

Piperidine, morpholine, Thiomorpholin-, piperazine or Homopiperazinrest is substituted;

Ad) a -COOH, -COOalkyl, -COOAralkyl, CO-amino group, which is optionally substituted as indicated above under Ac), or a COH-alkyl group or COH-aralkyl group;

Ae) is a - (CH ₂ J _n X (in which X = Br, Cl, F or J), - (CH ₂ J _n OH-, - (CH ₂ J _n CHO-, - (CH ₂ J _n COOH-) , - (CH ₂ J _n CN, - (CH ₂ J _n NC, (CH ₂ ) _n COalkyl or - (CH ₂ ) _n COAryl group, wherein n is 1-4;

Af) a - (CH ₂ ) _n vinyl, - (CH ₂ ) _n ethynyl, - (CH ₂ ) _n cycloalkyl group, wherein n is 0, 1 or 2, wherein cycloalkyl is an aliphatic ring having 3 to 7 C -Atomen is; Ag) a C ₃ -C ₆ substituted alkenyl group (optionally substituted with H, F, Br, Cl, CN, CO ₂ alkyl, COAlkyl, COAryl);

Ah) a C ₃ -C ₆ substituted alkynyl group (optionally substituted with H, F, Br, Cl, CN, CO ₂ alkyl, COAlkyl, COAryl); or

Ai) R ₁ and R ₂ together are -CH = CH-CH = CH-, -O (CH ₂ J _n O- (n = 1 to 3), -CH = CHA ₁ - (A ₁ is NH, O or S), or -CH ₂ CH ₂ A ₁ - (A ₁ is NH, O or S);

BJ R _{3 has the} same meaning as R ₁ , in particular OH and OCH ₃ , or

CJ R ₂ and R ₃ together are -A ₂ (CH ₂ J _n A ₂ -, wherein n is 1 to 3 and the substituents A _{2 are the} same or different and are NH, O or S;

D) R ₄ and R ₅ are either

Since) both hydrogen, or Db) one of R ₄ and R ₅ is hydrogen, an alkyl, aralkyl, alkenyl, aralkenyl, alkynyl, or aralkinyl group and the other of R ₄ and R ₅

Dbi) OR ₆ , wherein R _{6 is} hydrogen, a lower (Ci-C ₁₀ ), optionally branched alkyl group, or cycloalkyl group, a

C ₃ -C ₁₀ substituted silyl group (for example triethylsilyl,

Trimethylsilyl, t-butyldimethylsilyl or dimethylphenylsilyl), a C ₂ -C ₁₀ alpha-alkoxyalkyl group, for example

Tetrahydropyranyl, tetrahydrofuranyl, methoxymethyl, ethoxymethyl, 2-methoxypropyl, ethoxyethyl, phenoxymethyl or 1-phenoxyethyl;

Dbii) 0-CS-NHR ₆ (thiourethanes), wherein R _{6 has} the meanings given above under Dbi);

Dbiii) O-CO-NHR ' ₇ with the following meaning:

Dbiv) 0-CO-HR ₆ , where R _{6 is} that mentioned above under Dbi)

Has meanings, especially esters with the substitution pattern of amino acids (both enantiomers), such as

Dbv) NR ₇ R ₇ , in which the two substituents R _{7 are} identical or different and denote hydrogen, a lower (C ₁ -C ₄ ), optionally branched, alkyl group or cycloalkyl group, or the substituents R ₇ are in common - (CH ₂ ) _n -, wherein n is 3 to 5;

Dbvi) NH-COR ₆ (amide), wherein R _{6 has} the meanings mentioned above under Dbi); Dbvii) SR ₆ , wherein R _{6 has} the meaning given above under Dbi);

Dbviii) SO _n R ₈ , wherein n is 0, 1 or 2 and R _{8 is} a (Ci-Cio) i optionally branched or cyclic, optionally substituted alkyl or aralkyl group; Dbix) R ₄ is hydrogen and R _{5 is} OH, CN, CO ₂ alkyl, CONR _a R _{b /} where R _{a is} hydrogen, a lower (C ₁ - C ₆ ), optionally branched or cyclic substituted alkyl group and R _{b is} hydrogen, a lower (C ₁ -C ₆ ), optionally branched or substituted alkyl group, or Ra + Rb are together - (CH ₂ J _n -, wherein n is 2 to 6, or - (CH ₂ ) _n E (CH ₂ ) _n - wherein E is NH, N-alkyl, O, or S and n is 0 to 5, aryl (phenyl or naphthyl), or a 6- II heterocycle;

Dbx) R ^ and R ₅ are together carbonyl (= 0), hydrazone (= N-NH-R ₉ , = N-NR ₉ Ri ₀ ) or oxime (= N-OR ₁₀ ) where R _{9 is} hydrogen, a lower (C ₁ -C ₆ ), optionally branched or cyclic, optionally substituted alkyl, aralkyl, alkylcarbonyl, aralkylcarbonyl, alkylcarbonyloxy or aralkylcarbonyloxy group or a sulfonic acid group, such as tosyl or mesyl, and R _{10 is} hydrogen, a lower (C ₁ -C ₆ ), optionally branched or cyclic, optionally substituted alkyl, aralkyl, alkylcarbonyl, or aralkylcarbonyl group, a sulfonic acid group such as a tosyl or mesyl group;

Dbxi) R ₄ and R ₅ are, together, substituents of the type

wherein Y ₁ , Y _{2 are the} same or different and are O, S, NH or NR ₉ (free valencies are in each case hydrogen), wherein R _{9 has} the meanings mentioned above in Dbx);

EJ Gi _j _ - (CH ₂ J _x -, where x is 1 or 2;

.F] G ₂ j - (CH ₂ ) _y -, wherein y is 0 to 2; E / Fa: G ₁ and G ₂ mean together or separately:

-C (R ₁₁ R ₁₂ ) -, wherein R ₁₁ and R _{12 are} hydrogen, OH, a lower, optionally branched or cyclic, optionally substituted alkyl, aralkyl, aryl, alkyloxy, arakyloxy, or aryloxy group or together a Alkyl spiro group (C ₃ -C ₇ - spiro ring);

E / Fb: G ₁ and G ₂ mean together

wherein m is 1 to 7; E / Fc: G ₁ and G ₂ together or separately mean -CR ₁₁ R ₁₂ -, wherein R ₁₁ and R _{12 are} hydrogen, hydroxy, a lower, jo

optionally branched or cyclic, optionally substituted alkyl, aralkyl, aryl, alkoxy, aralkoxy, or aryloxy group;

E / Fd: Gi and G ₂ are together alkyl spiro group (C ₃ -C ₇ - spiro ring);

G) G ₃ : - (CH ₂ J ₂ -, wherein z is 0 to 3, with the proviso that the sum of x + y + z is at least 2 and at most 4, or wherein G _{3 is} carbonyl or thiocarbonyl, -CH (OH) - or -C (OH) = is; H) W is:

Ha) CR ₁₃ Ri ₄ in which R _{13 is} hydrogen and R _{14 is} - (CH ₂ J _n NR ₇ R ₇ , -CO-NR ₇ R ₇ or -COOR ₇ , where n is 0 to 2 and R _{7 is} the abovementioned

Has meanings, or R ₇ and R ₇ form over - (CH ₂ ) _n -, where n is 3 to

5 is a ring wherein the substituents R ₁₃ and R ₁₄ may be reversed.

Hb) N-phenyl (optionally substituted with fluoro, bromo, chloro, (C ₁ -C ₄ ) alkyl, CO ₂ alkyl, CN, CONH ₂ , or alkoxy), N-thieno-2 or 3-yl, or N -Fur-2-or 3-yl, or NI, 3, 5-triazinyl, wherein the triazine residue may be further substituted with Cl, OR ₆ or NR ₇ R ₇ , and R ₆ and R _{7 have} the meaning given above;

Hc) one of the substituents reproduced below

wherein J is not a bond or - (CH ₂ J _n - _/ wherein n = 0 to 3, carbonyl, thiocarbonyl, O, S -SO or SO ₂ , R _{6 has} the meanings given above, and wherein

Q is - (CH ₂ ) _n - M * - (CH ₂ ) _ra -, where n = 0 to 4 and m = 0 to 4 and M * alkynyl, alkenyl, disubstituted phenyl, disubstituted thiophene, disubstituted furan, disubstituted pyrazine, disubstituted pydidazine, a spacer of one of the formulas given below, a peptide spacer L or a heterocyclic spacer HS of the following formulas,

HS = P = CH or N T = CH or N

X = NR ₆ , 0 or S Z = CH or N

wherein Ri _{5 is} the side chain of D, L, D, L-ammosauric or unnatural amino acids, and in the case of n> l R ₁₅ in the individual radicals each have a same or different side chain of D-, L-, D , L-amino acids or unnatural amino acids, with the proviso that the atom N in addition to Q is in each case connected to the group G2 and G3 of the formula I; Hdi), optionally at least monosubstituted, tricyclic substituent (Tr) having at least one heterocyclic ring as the ring component and a binding site on a carbon atom of a fused benzene ring thereof, via a spacer Q and the Q adjacent nitrogen each with G ₂ and G ₃ of Compound of formula I is connected, wherein Q has the meaning given above under Hc);

Hdii) is a cyclic hydrocarbon of the formulas below:

or

He) -NH-, -O-, -S-, -SO- or -SO ₂ -;

Hf) when W is -NH-, z in the group G _{3 is} 0, 2 or 3, with the proviso that z in the group G _{3 is} 1 when the substituent R _{1 is} a lower alkyl group such as methyl or Ethyl, means.

15. Use according to one of claims 9 to 11, characterized in that the compound used is one of the general formula (Ia),

Ia

or their salts are, in which

Ri is H, branched or straight chain (Ci-C ₆ ) alkyl, Br, NO ₂ , NR ₅ R ₆ ,

R ₅ and R _{6 are} identical or different and denote H, branched or straight-chain (C ₁ -C ₆ ) alkyl,

and in which

R ₂ is OH, branched or straight chain (Ci-C ₆ ) alkyl, methoxy, phenyloxy or the following group

where 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,

in which further

• Y ₁ and Y ₂ alternately H or a group selected from:

wherein n represents a value of O, 1 to 15, and Pol has the meaning given above, and wherein further

Y ₁ and Y ₂ together represent a carbonyl group (= 0), = NH, = N-OR _{7 /} , where R ₇ is H, tosyl or branched or straight-chain (C ₁ -C ₆ ) -alkyl,

• or Y ₁ and Y ₂ together have a group selected from:

where R ₈ and R _{9 are} identical or different and are H, branched or straight-chain (C ₁ -C ₆ ) -alkyl, - (CH ₂ J ₂ -

OH, CHO, CONH ₂ , tBOC (tert-butoxycarbonyl), or -COCOOH, Ri ₀ is H or CH ₃ , and where Yi is -O- (CH ₂ ) ₂ -OH Y ₂ is OH,

and in which

• Z ₁ is H, branched or straight chain (C ₁ -C ₆ ) alkyl, (C ₂ -C ₇ ) alkenyl (C ₂ -C ₇ ) alkynyl, trifluoroacetyl, formyl, phenyl

or a group selected from:

where R ₁₁ is H, straight-chain (C ₁ -C ₆ ) -alkyl, branched (C ₁ -C ₆ ) -alkyl or (C ₂ -C ₇ ) -alkenyl, R ₁₂ and R _{13 are} identical or different and H, straight-chain or branched (C ₁ -C ₆ ) alkyl, phenyl, chlorophenyl, (trifluoromethyl) phenyl or 1-naphthyl, where R ₁₄ is H, F, CH ₃ , NO ₂ , Cl, Br, J, CF ₃ , n has the meaning given above, m is 0 or 1, and W has the meaning H or O,

and in what further

• Z ₁ and R _{3 have} a common ring

easy or

double bond

where Ri ₅ and R _{16 are} mutually H, COOCH ₃ , COOCH ₂ CH ₃ , CN, COCH ₃ .

16. Use according to one of claims 9 to 11, characterized in that the compounds used one of the general formula Ia or Ib

Ia Ib

and their salts are where

• Ia optically active (-) derivatives of galanthamine and Ib are optically active (+) derivatives of galanthamine, which are in a mirror-image spatial arrangement, and wherein

Y ₁ and Y ₂ alternately H or OH, • X = H or Br are and

• Z ₁ = a group with the following formula representation

is in which

R ₁ = H, Cl, Br, J, F, OH, straight-chain or branched (C ₁ -C ₆ ) -alkyl, straight-chain or branched (C ₁ -C ₆ ) -alkyloxy, NO ₂ , NR ₂ R ₃ ,

• R ₂ = R ₃ = H, straight or branched (C ₁ -C ₆ ) alkyl

• W = H, 0, S

• n = 0, 1-6,

and in which

• Z ₁ equals H exclusively for connections 1, 3, 13 and 24

13 24

wherein the compounds 1 and 13 are (-) derivatives of 6-epi-norgalanthamine and the compounds 3 and 24 are (+) derivatives of 6-epi-norgalantham, and wherein

Z ₁ exclusively for the compound 29 is hydroxypropyl

29

and

• Z ₁ exclusively for compound 26 is ethyl

26 and

Z ₁ exclusively for the following connections 7

28 31 Level 1 31 Level 2 56 55

is methyl, and wherein the compounds are 29, 31 and 55 (+) derivatives of galanthamine and the compounds 26, 28 and 56 are (+) -Epi derivatives of galanthamine.

17. A method of treating mammals, especially humans, in contact with an organic

Phosphorus compound or expected to contact with an organic phosphorus compound, characterized by administering a therapeutically effective amount of galanthamine and / or at least one derivative and / or analog of galanthamine.

18. The method according to claim 17, characterized in that the organic phosphorus compound is at least one of the compounds mentioned in claims 2 and 3.

A method according to claim 17 or 18, characterized in that a derivative defined in any one of claims 4 to 15 or a combination of at least two such derivatives is administered.