CS3692A3 - Heterocyclic hydroxylamines, process of their preparation, their use andpharmaceutical preparations comprising said compounds - Google Patents

Description

1

Í I? L o> 4

“O ^ 3) o · - - • 03 * - -1> <~“ -c m -e. ----- to rc

Heterocyclic hydroxylamines, a process for their preparation, their use and pharmaceutical preparations containing them

Technical field

BACKGROUND OF THE INVENTION The present invention relates to novel heterocyclic hydroxylamines, to the preparation of such compounds and to their salts, to pharmaceutical compositions containing such compounds and to the use of such compounds for the therapeutic treatment of nalidas or animals, as well as to a process for the preparation of such pharmaceutical preparations.

SUMMARY OF THE INVENTION

The present invention relates to heterocyclic hydroxylamines of the formula I

X

(1) in which X denotes a methylene group, an imino group, an oxygen atom or a sulfur atom, and the R group '/ CH2 / n' 0 ~ 'wherein n denotes the number 0, 1 or 2, with which women do not denote zero when the substituent R 2 is attached at the 2-position. In the present general description, the ring atoms are numbered starting from the nitrogen atom numbered 1, the atom / group / Σ being recognized by the number 4, while in the exemplary embodiments the numbering follows the IUPAC nomenclature.

Salts of the compounds of the present invention are primarily pharmaceutically acceptable salts with acids such as, for example, inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or suitable organic carboxylic or sulfonic acids, for example acetic acid, octanoic acid - succinic acid, adipic acid, fumaric acid, maleic acid, hydroxymaleic acid, propionic acid, lactic acid, malic acid, citric acid, salicylic acid, p-aminosalicylic acid, ascorbic acid, oxalic acid, benzenesulfonic acid, 1,5-naphthalenedisulfonic acid, methanesulfonic acid, 1,2-ethanedisulfonic acid or U-cyclohexylsulfamic acid, or, for example, amino acids such as glutamic acid or aspartic acid. They can be formed mono- to tris-so, depending on the number of basic groups present.

Pharmaceutically unsuitable salts, for example picrates or chlorates, may also be used for isolation or purification. For therapeutic use, only acceptable salts can be applied, which are therefore preferred.

The compounds of the present invention which contain an asymmetric carbon atom may be present in the form of pure enantiomers or as enantiomeric mixtures (racemates).

The compounds of the present invention exhibit valuable, particularly pharmacologically useful properties. In particular, they have a potent, specific inhibitory effect of the enzyme ornithine decarboxylase (ODC). Ornithindecarboxylase plays a key role in the biamine synthesis of polyamines, which is practiced in virtually all mammalian cells, including humans. The ornithine decarboxylate controls the concentration of polyamines in the cells. Thus, inhibition of ornithindecarboxylase results in a reduction in the concentration of polyamines. Since reducing the concentration of polyamines causes cell growth suppression, ornithindecarboxylase inhibiting / suppressing applications, it can suppress the growth of both eukaryotic and prokaryotic, especially fast or uncontrolled, growing cells and even kill these cells or suppressing the differentiation of cells.

The inhibition of the enzyme ornithindecarboxylase can be determined, for example, by the J.E. Seely and A.E. Pegga, Ornithin Decarboxylase / kidney fly / p.158 - 161, H. Tabor and C. White - Taboi? / Hrsg./: Me-thods in Enzymology, Vol. 94: Polyamines, Academic PressNew York 1983 · When ornithine-decarboxylase from rat liver / isolation is used in this assay: Hayashi, S.-Ia Kameji, T., equiv., P. in the micromolar region, for example in the range of 0.2 to 2 µM. IC 50 is the inhibitor concentration at which the ornithine decarboxylase activity is 50% of the control without inhibitor.

As an ornithindecarboxylase inhibitor, the 1 - 4 - compounds of formula I have antiproliferative properties which can be demonstrated, for example, by demonstrating an inhibitory effect on the growth of human T24 carcinoma cells. The evidence is that these cells are incubated in "Eagle's Minimum Essential Media" to which 5% (v / v) fetal calf serum, in a humidified incubator at 37 ° C and 5% carbon dioxide in air, are added. The carcinoma cells (1000-1,500) are inoculated on a 96-well microtiter plate and incubated under the indicated conditions for the day, and the test substance is added to the first day in serial dilutions and incubated under the conditions for 5 days. At least four cell divisions were performed in control cultures in the control period, cells were fixed with 3.3% w / v solution / glutaraldehyde after washing, washed with water and stained with 0.05% solution / w / v / aqueous methylene blue. eluted with 3% w / v solution of aqueous hydrochloric acid, then the optical density (OD) for each hole, which is directly proportional to b the optical density is measured with 662 nm using a computer-photometer / Titertek multiskan / u

The values ΙΟ ^ θ are calculated by the system using the formula ODg ^ / test / - ODg ^ / start / 0Dz; <c./control/ - OD ^ / -.- / start / x 100

The ΙΟ ^ θ values are defined as those concentrations in which the number of cells in one hole at the end of the incubation period is only 50% of the number of cells in control cultures. - 5 -

For example, the compounds of formula (I) are suitable for use in diseases requiring inhibition of ornithindecarboxylase, for example, in benign amalignant tumors. They can cause tumor regression and further suppress tumor cell proliferation as well as growth micrometastases. In addition, they may serve, for example, for application to protozoal infections such as trypanosomiasis, malaria or pneumonia caused by Pneumocystis carinii.

The selective ornithindecarboxylase inhibitors may be those compounds of formula (I) or else in combination with other pharmacologically active substances. For example, combinations with / inhibitors of other polyamine biosynthesis enzymes such as S-adenosylmethionindecarboxylase inhibitors, b / protein kinase C inhibitors, c / tyrosine protein kinase inhibitors, d / cytokines, e / negative growth regulators, f / aromatase inhibitors, g antiestrogens, or h / classical cytostatic active agents. Preferably, the present invention relates to a compound of formula (I) wherein xaix ± x X is a methylene group, an imino group or an oxygen atom, R is attached at the 2-position or 3-an and 1 or 2 and the compounds of formula (I) are X is a methylene group, R is attached at the 4-position and n is 0 or 1, as well as salts thereof.

It should be pointed out that the compounds of formula (I) in which X is a methylene group or an oxygen atom, R is attached at 2 or 3 and n is 1 or 2, and compounds of formula I wherein X is methylene, R is attached at 4 and the number 0 or 1 as well as the salts thereof.

Particularly preferred are compounds of formula I in which X represents a methylene group or an oxygen atom, the substituent is attached in the 3-position and n is 1, or where X represents a methylene group, R is bonded in the 4-position and the label as well as salts.

In particular, the invention relates to the specific compounds described in the Examples and their salts.

The novel compounds of formula (I) can be prepared by methods known per se, for example, from a compound of formula (I) in which:

at least one amino group is protected, for example, compounds of formula II X '/ CHO / - O / 2' n

N

I R,

N

IR, R (11), 7 - or a salt thereof, in which R methy denotes a methylene group, an oxygen atom or a group NR ^ and an integer of 0, 1 or 2, provided that n is different from zero, when the substituent - (CH2) n-NR4R6 is attached at the 2-position and R1, R2, R1 and R4 independently of one another denotes an amino protecting group or a hydrogen atom, with the proviso that at least one of R1, R2, R and R 1 represents a protecting group for an amino group, or wherein R 1 and R 2 independently of one another denote an amine protecting group, a non-hydrocarbon atom, and R 1 together with R 6 forms a divalent protecting group for the amino group, cleaving the protecting group, or amino groups, or amino groups, or b) for the preparation of compounds of formula I

or their salts, in which the imino group denotes a non-methylene group, reduces the compound of formula III (111),

wherein Z is a nitrogen atom or a methine group CH and is as defined above, R 1 or a salt thereof, or c is not used to prepare the compounds of formula I

or a salt thereof in which it denotes an imino group, an oxygen atom or a sulfur atom, R is bonded in the 2 or 3 position and n is 1 or 2, the cyclis compound of formula IV

(IV), in which n * is 1 or 2 and one of Y and Y 'is hydroxyl, amino or sulfhydryl, the other being a leaving group, or a salt thereof, or d / i.

the compound of formula V / 0Η2 / η0 "Μ + / V /, or a salt thereof, is reacted, the ropes being as defined above, with the proviso that n is not zero when the substituent - / CH 2 / n0" M + is bound in position 2, wherein the metal cation is

with a compound of formula VI-9-H2N-A '(VI), or a salt thereof, wherein A' is a nucleofugal leaving group, and the compound of formula (I) obtained is converted to another compound of formula (I) as desired, the enantiomeric mixture obtained is cleaved the salt of the compound of formula (I) is converted to the individual enantiomer and / or the obtained compound of formula (I) is converted to a free compound or other salt.

Salts of starting materials having at least one basic center, for example compounds of Formula III, are the corresponding acid addition salts. In the following, the " lower " prefix used in the present invention denotes a radical having 1 to 7 carbon atoms and in particular 1 to 4 carbon atoms. Thus, the lower alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl and heptyl, the alkyl radical of 3 to 7 carbon atoms being straight-chain or branched.

Process (s): Preferably, the monovalent protecting groups of the amino groups R 1, R 2, R 4 and R 6 are acyl groups, for example lower alkanoyl groups such as formyl group, acetyl group or propionyl group, lower haloalkanoyl group a group such as a 2-haloacetyl group, in particular a 2-chloroacetyl group, a 2-bromoacetyl group, a 2-iodoacetyl group, a 2,2,2-trifluoroacetyl group or a 2,2,2-trichloroacetyl group; pina, benzoyl optionally substituted with halo, lower alkoxy, lower alkoxycarbonyl or nitro such as benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl, 2-methoxycarbonylbenzoyl or 4-nitrobenzoyl an arylmethoxycarbonyl group having one or two aryl radicals, which preferably represents a monosubstituted or poly-substituted phenyl radical which is optionally substituted for example a lower alkyl group, in particular a lower alkyl group such as a tert-butyl group, a lower alkoxy group such as a methoxy group, a hydroxyl group, a halogen atom such as a chloro and / or a nitro group such as for example, a substituted benzyloxycarbonyl group, preferably a 4-nitrobenzyloxycarbonyl group, or a substitutedadiphenylmethoxycarbonyl group, such as a di- (4-methoxyphenyl) -methoxycarbonyl group, a lower 2-haloalkoxycarbonyl group, e.g. a chloroethoxycarbonyl group, a 2-bromomethoxycarbonyl group or a 2-iodoethoxycarbonyl group, or a lower alkoxycarbonyl group branched at the 1-lower alkyl radical or suitably substituted at the 1 or 2 position, especially a lower tert-alkoxycarbonyl group such as tert-butoxycarbonyl or an arylmethyl group such as a monoarylmethyl group, diary a methyl group or especially a triarylmethyl group, wherein the aryl moieties in particular are optionally substituted phenyl moieties such as benzyl, diphenylmethyl or triphenylmethyl (trityl).

Particularly preferred monovalent amino protecting groups, R ^ ^ 3 3 and 3sousou are acyl-11-carbonic acid esters, especially tert-butoxycarbonyl, optionally substituted benzyloxycarbonyl, for example 4-nitro-benzoylcarbonyl a diphenylmethoxycarbonyl group, or a lower 2-haloalphenoxycarbonyl group such as a 2,2,2-trichloroethoxycarbonyl group, a trityl group, a formyl group, or a 2-methoxycarbonylbenzoyl group. Preferred bivalent protecting groups for the amino groups formed by the radicals R a and n are monosubstituted or disubstituted methylidene groups such as 1-lower alkoxy (e.g. methoxy or ethoxy) lower alkylidene (e.g. butylene /, for example = C / CH 2 -, for example = C / CH-j / 2 or = CH-phenyl, and in particular bisacyl residues, for example phthalyl, which together with the protected nitrogen atom form 1 H -isoindole-1,3 (2H) -dione / phthalimido.

The amino protecting groups, their introduction and cleavage are known per se and described, for example, in JPW McOmie, " Protective Groups in Organic Chemistry ", Plenum Press, London, New York, 1973, and TW Greene, &quot; Protective Groups in Organic Synthesis Wiley, New York, 1984

The removal of the protecting group (s) of the amino groups takes place, optionally, sequentially or simultaneously, according to the type of protecting group (s) known per se, for example by reduction or solvolysis, in particular hydrolysis, preferably in acidic medium, alcoholysis, acidolysis or hydrazinolysis. The tert-butyloxycarbonyl or trityl moiety can be liberated, for example, by treatment with an acid such as mineral acid, for example, hydrochloric acid, optionally in the presence of solvents, especially methyl alcohol or tetrahydrofuran, or an organic acid such as formic acid, acetic acid or trifluoroacetic acid, optionally in the presence of water or an organic solvent, for example methylene chloride. The removal of the optionally substituted benzyloxycarbonyl group is carried out, for example, by hydrogenolysis, i.e. by treatment with hydrogen in the presence of a suitable catalyst, for example palladium, or by sodium in liquid ammonia, or by acidolysis, in particular by hydrogen bromide and glacial acetic acid. The lower 2-haloalkoxycarbonyl group may be cleaved off, for example, by treatment with a suitable reducing agent such as zinc in the presence of an organic solvent such as methanol or aqueous acetic acid. The removal of the phthalyl group can be effected, for example, with hydrazine hydrate or with an acid such as a mineral acid such as hydrochloric acid, optionally in the presence of an organic solvent, for example methyl alcohol. The starting compounds of the formula II are known or can be prepared by methods known per se (see, for example, Houben-Weyl, Methoden der Organischen Chemie, 3d X / 1/1971) and Bd E 16a (1990). For example, the starting compounds of formula (II) are prepared such that the compound of general formula Via 13 - X?

/ CH2 / n - A / Via / in which they have X ’, R? and n as defined above and A represents a hydroxyl group or a nucleofugal leaving group, is reacted with hydroxylamine, optionally with nitrogen protected.

For example, when the compound A has a hydroxyl group, an intermolecular dehydration reaction can be carried out. In particular, the Mitsunobo reaction (Synthesis (1976), 682) is reacted therein. to form a compound of formula (VIa) with a nitrogen-protected hydroxylamine derivative, such as N-hydroxyphthalimide, N-hydroxy-5-norbornene-2,3-dicarboxyimide or ethyl acethydroxamic acid and, for example, triphenylphosphine and diethyl ester of Ιί, Ν'-ηζ-dicarboxylic acid.

In the compounds of formula VIa, a cleavable leaving group A is, for example, an aliphatic or aromatic substituted sulfonyloxy group such as methanesulfonyloxy or p-toluolsulfonyloxy / tosyloxy, but also, for example, a halogen atom, in particular chlorine, bromine or iodine. 14 -

The corresponding compounds of formula (VTa) are not reacted by simple nucleophilic substitution with hydroxylamine derivatives, protected at the nitrogen atom, e.g.

Compounds of formula (II) may also be prepared by carrying out one of the methods (b), (c) or (d) with protected (protected) amino (amino) groups. Furthermore, compounds of general formula (II) can also be prepared from compounds of general formula (I) for possible purification purposes.

Way / b /:

The compounds of formula (III) are reducted, for example with alkaline earth metals or alkali metals, such as sodium, in a lower alkanol such as ethyl alcohol, by electrolytic reduction, by reduction with metal hydrides, such as sodium aluminum hydride or lithium aluminum hydride, or especially by hydrogen, in the presence of a transition metal catalyst, to the hexahydro-derivatives of formula (I) (see M. Hudlicky, inorganic chemistry reductions, Ellis Horwood Limited, 1984) · Catalytic hydrogenation is carried out, for example, in the presence of palladium, platinum oxide or rhodium, optionally with coal addition preferably in an acidic medium such as glacial acetic acid or in the presence of ruthenium trioxide, Raney nickel or cuprous chromate. The compounds of general formula (III) are known or can be prepared by methods known per se.

Way / c /:

A nucleofugic leaving group Y or Y 15 - is, for example, a hydroxyl group or a reactively esterified hydroxyl group, such as a strong inorganic acid or an organic sulfonic acid esterified hydroxyl group, for example halogen, such as chlorine, bromine or iodine, sulfonyloxy group such as is hydroxy-sulfonyloxy, halo-sulfonyloxy, for example fluoro-sulfonyloxy, optionally halogen-substituted lower alkanesulfonyloxy, for example, methanesulfonyloxy or trifluoromethanesulfonyloxy, cycloalkanesulfonyloxy, e.g. -tolu-sulfonyloxy. Preferably, Y represents a hydroxyl group, an amino group, or a sulfhydryl group, and Y 'represents a nucleophilic leaving group, for example the groups mentioned above.

Compounds of formula (IV) wherein Y or Y * is a hydroxyl group, an amino group or a sulfhydryl group and the other is a nucleofugal cleavable group, for example one of the above, may be converted into the compounds of general formula I. Suitable bases are, for example, inorganic bases such as alkali metal hydroxides, for example sodium hydroxide, or especially organic bases, for example lower alkylamines such as diethylamine or triethylamine, basic heterocyclic compounds, for example pyridine, such as e.g. pyridine alone, or alkali metal alkoxides, for example, tert-butoxide. In a particularly preferred embodiment, for example, a compound of formula (IV) wherein Y is a hydroxyl or sulfhydryl or amino group is reacted and Y * is a hydroxyl group with aliphatic or aromatic substituted sulfoxychloride, such as methanesulfonyl chloride -rid or tosyl chloride (p-toluenesulphochloride) in the presence of an inorganic or organic base, such as pyridine, under the reaction conditions of further reaction to the desired end product of formula (I) or a salt thereof.

Particularly in the latter reaction, it may be necessary to protect the amino groups in the compound of formula IV prior to the reaction with protecting groups, for example, as described in (a). After the reaction, the amino protecting groups are then cleaved off in a manner known per se.

Compounds of formula (IV) wherein Y and Y * are hydroxyl groups may, for example, be cyclized in the presence of strong acids such as sulfuric acid or hydrofluoric acid, optionally in the presence of sulfur tetrafluoride or in the presence of an ion exchanger, to compounds of formula I in which Σ is an oxygen atom. It is furthermore possible for compounds of formula IV wherein one of Y or Y 'is hydroxy or sulfhydryl and the other is hydroxy, for example by reaction with suitable fluorinating agents, for example converting the hydroxyl group to fluorine , for example, with hydrogen fluoride, sulfur tetrafluoride, especially mixtures of hydrogen fluoride and sulfur tetrafluoride, and also with substituted aminotrifluoride, such as sulfur diethylaminotrifluoride (DAST) or sulfur piperidinotrifluoride, are cyclized to the morpholine or thiomorpholine derivatives of formula (I). The starting compounds of formula IV are known or can be prepared by methods known per se. The starting compounds of formula (IV) in which Y and / or Y * are aliphatic or aromatic-substituted sulfonyloxy may be advantageously produced in a manner known per se from compounds of formula IV wherein Y and / or Y * is a hydroxyl group, for example by reaction with lower alkanesulfonyl chlorides or arenesulfonyl chlorides. Further, starting compounds of general formula IV in which Y or Y * denotes an amino or sulfhydryl group can be prepared in situ by, for example, a compound of formula IV * Y &apos;

H in which n 'indicated in formula IVa Y' 'is a nucleofugal leaving group, for example one of the above,

it is reacted with ammonia or sodium sulphide, the primary compound of the formula IV 18 being formed in the reaction conditions being equally reacted.

The amino groups in the compounds of formula (IV ') may optionally be protected from carrying out the reaction with amino protecting groups, for example in the process (a), and may be liberated by known methods at any stage of the process.

The starting compounds of the formula IV, wherein Y is a hydroxyl group or a sulfhydryl group and Y 'is a hydroxyl group, can be produced, for example, by a compound of the formula VII.

(VII) in which n is as defined in formula (IV), W represents an oxygen atom or a sulfur atom, and R 6 represents a protected amino group, for example one of the aforementioned methods (a) and / or a residue (6). wherein, for example, Rg represents a lower alkyl group, a lower alkoxyalkyl group, for example a methoxymethyl group, or an ethoxymethyl group, or a phenyl group, R6; is a hydrogen atom, a lower alkyl group or a lower alkoxy group, for example an n-propoxy group, an isopropoxy group, an n-butoxy group or a tert-butoxy group, preferably a methoxy group and especially an ethoxy group; carbon atoms or a benzoalkylene group having from 4 to about 4 carbon atoms in the alkylene moiety, is reacted with ethanolamine, whereby the protected amino groups are liberated, e.g.

hydrolyses. The group RgRyC = R-, in which Rg and R? collectively, an alkylene radical having from 4 to 6 carbon atoms refers to a cycloalkylidene amino radical having from 5 to 7 ring atoms, such as, for example, cyclopentylideneamino or cyclohexylideneamino.

The term RgRyC = N-, in which Rg and R? together a benzoalkylene group having from 4 to 6 carbon atoms in the alkylene moiety is understood to mean, for example, cyclopentylideneamino or cyclohexylamino-amino, which always bears the fused benzene ring.

The reaction of the compounds of the formula VII with sethanolamine is carried out without solvent or in the presence of a solvent such as, for example, a lower alkanol or an alkyl ether, preferably isopropyl alcohol or tetrahydrofuran. The reaction is optionally carried out at elevated pressure and is selectively selected at the terminal carbon atom of the oxiranyl or thiiranyl moiety. For example, starting compounds of the formula VII in which W is an oxygen atom can be obtained by reacting hydroxylamine, optionally oxime of the formula R 10H with, for example, epichlorohydrine, epibromohydrin or 3-tosyloxy-1,2-epoxypropane. . The starting compounds of the formula VII in which W is sulfur are formed, for example, by reacting hydroxylamine or an oxime of the formula R @ 1 --OH with thioepichlorohydrin. This reaction is preferably carried out in the presence of a base such as sodium hydroxide or a solvent or in the presence of a solvent such as acetone or acetonitrile.

Way / d /:

The metal cation M + is, for example, an alkali metal cation, for example sodium, potassium or lithium, or is a cation 1/2 (M) and is an alkaline earth metal such as magnesium, calcium or barium.

For example, the nucleofugal leaving group A 'is a reactively esterified hydroxyl group, such as that described in Method (c). For example, in a preferred embodiment, the metal salt of formula V, in which the M + sodium cation is not reacted, is not reacted with a haloamine such as schloramine or with a sodium salt of hydroxylamine 21-O-sulfonic acid to give a compound of formula I.

For example, the metal salts of formula (V) are formed by treating metals, in particular metal alkali earths or alkali metals, with the corresponding alcohols to produce hydrogen, or by reacting alcohols with suitable bases such as an alkali metal hydride or amide.

In particular, the invention relates to the compounds and methods described in the Examples.

Salts of the compounds of formula (I) may be prepared by methods known per se, for example by treatment with acids such as inorganic acids, for example hydrochloric acid or sulfuric acid, organic carboxylic acids, for example adipic acid, or organic sulfonic acids, for example benzenesulfonic acid, or with a suitable ion exchange reagent which is, for example, saturated with the corresponding acid. Salts can be converted into the free compounds by conventional means, for example, by treatment with suitable basic agents, such as hydroxides in free solutions, for example, alkali metal hydroxides, or ion exchangers saturated with hydroxides such as chromatography or batches.

It is also possible to directly convert the acid addition salt from one of the compounds of the formula I and the one acid with the second acid into the acid addition salt of the compound of the formula I and the other, the new acid. free solution in the presence of a suitable amount of a new acid, for example an excess, or b) on the anion exchange saturated with the new acid anions. All reactions which serve to convert the acidic acid salts and the base of the formula (I) to other acid addition salts or free compounds or free bases to the corresponding acids are also useful methods of gel chromatography. Depending on the course of the process, optionally under-reaction conditions, the compounds of the present invention can be obtained with the salt-forming basic properties in free form or in the form of salts.

The compounds, as well as their salts, can also be obtained in the form of their hydrates, or their crystals can contain, for example, a solvent used for crystallization.

The enantiomeric mixtures obtainable according to the present invention can be separated into their individual enantiomers by methods known per se, for example by formation of salts with optically pure salt-forming compounds and separation of the diastereoisomer mixtures thus obtained, for example by means of fractionated crystallization. The above-mentioned reactions can be carried out under known reaction conditions in the absence or usually in the presence of solvents or diluents, preferably those inert to the reagents used and dissolving them. Furthermore, these reactions can be carried out in the absence or presence of catalysts, condensation agents or neutralizing agents, depending on the type of reaction and / or the participants in the reaction, at reduced, normal or elevated temperatures, e.g. up to about 190 ° C, preferably about -20 to about 150 ° C, for example at room temperature or at -20 to 40 ° C, or at the boiling point of the solvent used, under atmospheric pressure or in a sealed container, respectively pressure and / or in an inert atmosphere, for example under a nitrogen atmosphere. X solvents such as those suitable for the reaction are, for example, water, ethers such as aliphatic ethers, for example diethyl ether, or cyclic ethers such as tetrahydrofuran, liquid aromatic hydrocarbons such as for example benzene or toluene, alcohols such as methyl alcohol, ethyl alcohol, 1-propanol or 2-propanol, nitriles such as acetonitrile, halohydrocarbons such as methylene chloride, acid amides such as dimethylformamide, base, such as heterocyclic nitrogenous bases, for example pyridine, or mixtures of these solvents. As an example, aqueous solutions may be used unless otherwise described in the description of the process. In the processes of the present invention, starting materials which lead to the compounds described as particularly valuable are preferably used. The present invention also relates to such embodiments of the process, starting from a compound obtainable by any process step as an intermediate and performing the remaining steps or interrupting the process at some stage or forming the reaction conditions. the starting material or in which it is used as a derivative, for example in the form of a salt. The present invention also relates to pharmaceutical preparations which contain the pharmacologically active compounds of the formula I as active ingredient. 24 -

Especially preferred are preparations for enteral, especially oral, as well as parenteral administration. The preparations contain the active ingredient alone or, preferably, together with pharmaceutically acceptable carrier materials. Dosage-active substances depend on the disease in which it is applied, as well as on the species, its age, weight and individual status, as well as the mode of administration.

The pharmaceutical preparations contain the active ingredient in the range of about 5 to 95% by weight, with the dosage forms being individually dosed containing about 20 to 90% by weight, and the non-uniformly administered dosage forms preferably containing 5 to 20% by weight of the active ingredient. Individually dosed forms, such as dragees, tablets or capsules, contain about 0.05 g to about 1.0 g of the active ingredient.

The pharmaceutical compositions of the present invention are prepared by methods known per se, for example, by conventional mixing, granulating, draining, dissolving, or lyophilizing processes. Thus, pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with one or more solid carrier substances, optionally granulating the resulting mixture, and then processing the mixture or granulate, if desired, with the addition of additional excipients. or dragees.

Suitable carrier materials are, in particular, fillers such as sugars, for example lactose, sucrose, mannitol, or sorbitol, cellulose preparations and / or calcium phosphates such as calcium phosphate or dibasic calcium phosphate, and binders such as starches such as corn starch , wheat starch, rice starch or potato starch, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and / or, if desired, disintegrants such as the starches mentioned above, carboxymethylated starches, crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof such as sodium jealginate. Additional excipients are, in the first instance, fluid flow control and lubricating agents, such as silicic acid, talc, acid stearate or salts thereof, such as magnesium stearate or calcium stearate and / or polyethylene glycol or derivatives thereof.

The dragees may be provided with suitable coatings, gastric-resistant cases, whereby, in addition, concentrated sugar solutions which optionally contain gum arabic, talc, vinyl vinyl pyrrolidone, polyethylene glycol and / or titanium dioxide may be used, the lacquer solutions in suitable organic solvents not or solvent mixtures, or for the manufacture of gastric resistant coatings of solutions of suitable cellulosic preparations such as acetylsulfonyl phthalate or hydroxypropyl methylcellulose phthalate. Dyes or pigments may be added to the coating for tablets or dragees, for example to identify or mark different amounts of active ingredient.

Orally administrable pharmaceutical compositions are also plug-in capsules of gelatin, as well as soft, sealed capsules of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules may contain the active ingredient in the form of granules, for example in admixtures with fillers such as corn starch, binders and / or glidants such as talc or magnesium stearate, and optionally stabilizers. For example, in soft capsules 2b - and preferably about 10% - of the substance is dissolved or suspended in suitable liquid excipients such as fatty oils, paraffinic or liquid polyethylene glycols, and stabilizers may also be added.

Other oral dosage forms include, for example, conventional syrup formulations containing the active ingredient, for example, in a suspended concentration of about 5 to 20% by weight, preferably in weight, or at a similar concentration which provides a suitable dose for 5 or 10 ml. Furthermore, they also come, for example, in powder or liquid concentrates for the preparation of preparations, for example for mixing in milk. Such concentrates may also be packaged in single-dose quantities.

Suitable rectally administrable pharmaceutical preparations are, for example, suppositories which consist of a combination of the active ingredient with a suppository base. Examples of suitable suppository bases are natural or synthetic triglycerides, paraffinic hydrocarbons, polyethylene glycols or higher alkanols.

For parenteral administration, aqueous solutions of the active ingredient in water-soluble form, for example, water-soluble salts, or aqueous suspensions for injection, which contain viscosity enhancers such as sodium carboxymethylcellulose, sorbitol and / or dextran, are suitable in the first series; optionally also stabilizers. In this case, the active compound, optionally together with the auxiliary substances, can also be used in the form of lyophilisates and can be converted into solution by the addition of a suitable solvent before parenteral administration.

Solutions such as those used for parenteral administration can also be used as infusion solutions.

The invention also relates to a method of using the aforementioned pharmaceutical preparations for application in the above-mentioned disease states of warm-blooded animals, that is to say humans and animals, in particular those in need thereof. The compounds of the present invention can be administered prophylactically or therapeutically, and are preferably used in the form of pharmaceutical preparations, for example, in a dose effective and suitable for inhibiting ornithindecarboxylase, prophylactically or therapeutically against said diseases, e.g. protozoal infections. In this case, at a body weight of about 70 kg, a daily dose of about 0.3 g to about 15 g, preferably about 0.5 g to about 5 g, of the compound of the present invention is applied. In particular, the pharmaceutical preparations are those which are suitable for application in animals, for example humans, for the treatment or prophylaxis of some of the aforementioned diseases which correspond to the inhibition of ornithindecarboxylase and contain an effective amount of a compound of the formula I or its inhibition, optionally together at least with one carrier material. The following examples illustrate the present invention. Temperatures are always given in ° C. The following abbreviations have the following meanings: BOC = tert-butyloxycarbonyl

Rp = ratio of product and solvent distance from the old in thin layer chromatography. Example 1 4-Aminooxy-piperidine dihydrochloride 2a 16.1 g (0.04648 mol) of 2- (N-BOC-4-piperidyloxy) -1H-isoindole-1,3 / 2H-dione are suspended. The reaction mixture was heated at 100 ° C for 2 hours, whereupon a clear solution was formed with the evolution of carbon dioxide, from which a crystalline precipitate (phthalic acid) again precipitated out after a short time. The reaction mixture was cooled to 0 ° C and the residue was washed with water and the filtrate was evaporated in vacuo.

The residue is taken up in ethanol and evaporated to dryness in vacuo. Addition of ethanol, evaporation and crystallization from methanol / diethyl ether gave the title compound.

Melting point: 182 DEG C. (decomposition). The starting compound was prepared as follows: [alpha] -2- [N-BOC-4-piperidyloxy] -1H-isoindole-1,3 / 2H-dione To a solution of 16 g (0.07747 mol) of N-BOC-hydroxy -piperidine (see EP No. 0278621), 12.97 g (0.07947 mol) of N-hydroxyphthalide and 20.85 g (0.07947 mol) of triphenylphosphine in 160 ml of tetrahydrofuran are added dropwise under stirring under a nitrogen atmosphere. at a temperature of 30 to 35 ° C, 14.07 ml (0.08415 mol) of azodicarboxylic acid diethyl ester (93%). The reaction mixture is stirred for 2 hours at room temperature and then evaporated in vacuo. To separate 1,2-hydrazinedicarboxylic acid diethyl ester and triphenylphosphine oxide, the oily residue obtained is dissolved in ethyl 29-acetic acid, cooled to 0 ° C, filtered, the filtrate is evaporated and the same procedure is repeated once but using diethyl ether as solvent. The residue after evaporation of the diethyl ether is purified by chromatography on silica gel with a particle size of 0.04 to 0.063 mm using mixtures of ethyl acetate and hexane (1: 2 or 2: 3) after evaporation of the fractions containing. product and crystallization of methylene chloride / hexane residue yield the title compound.

Melting point: 119-121 ° C. 2- (N-EOC-4-piperidyloxy) -1H-isoindole-1,3 / 2H-dione can be prepared as follows starting from 4-hydroxy-piperidine: b / 5.06 g / 0.05 mol / 4-hydroxy-piperidine in 50 ml of toluene is mixed dropwise with a solution of 10.92 g (0.05 mol) of di-tert-butyl dicarbonate in 30 ml of toluene and the resulting mixture is stirred for 4 days at room temperature. -floor room. 8.16 g (0.05 mol) of N-hydroxyphthalimide and 13.11 g (0.05 mol) of triphenylphosphine are added to the N-BOC-4-hydroxy-piperidine in toluene solution thus obtained, under stirring, under a protective nitrogen atmosphere. /. A solution of 8.85 ml (0.0529 mol) of azodicarboxylic acid diethyl ester (93%) in 20 ml of toluene is then added dropwise at 30-35 ° C and the reaction mixture is stirred for 15 hours at room temperature. . The mixture is cooled to 5 ° C, the precipitated hydrazine dicarboxylic acid diester is filtered off, the filtrate is evaporated in vacuo and the residue is purified by chromatography on silica gel using a mixture of ethyl acetate and hexane (1: 3 or 1: 2). /. After evaporation of the product fractions, the title compound is obtained as a crystalline residue.

Melting point: 116-118 ° C. c 4-aminooxy-piperidine dihydrochloride can also be obtained as follows:

A mixture of 1,414 g (0,005 mol) of 2- (4-piperidinyl-oxy) -1H-isoindole-1,3 / 2H-dione hydrochloride and 10 ml of 6N hydrochloric acid is heated for 2 hours at 100 ° C and then worked up. analogously to Example 1 to give the title compound.

Melting point: 182 DEG C. (decomposition). The starting compound was prepared as follows: d 2 - (4-piperidyloxy) -1H-isoindole-1,3 / 2H-dione hydrochloride

To a solution of 3.46 g (0.01 mol) of 2- (N-BOC-4-piperidyloxy) -1H-isoindole-1,3 / 2H-dione in 40 ml of tetrahydrofuran is added ice-cooling with stirring and cooling. hydrogen chloride in the form of a gas, with the formation of a crystalline precipitate for a short time. The crystalline suspension is then allowed to stand for 15 hours at room temperature. Filtration of the crystallisate and washing of the residue with tetrahydrofuran gave the title compound.

Melting point: 242-243 ° C. Example 2 4-aminooxy-piperidine dihydrochloride

A mixture of 1.57 g (0.005 mol) of 2-methoxycarbonyl- (N- (4-piperidyloxy) -benzoic acid amide hydrochloride and 10 ml of 2k hydrochloric acid was heated to 100 ° C and then worked up analogously to the one described. in Example 1. The title compound is thus obtained.

Melting point: 182 DEG C. (decomposition). The starting compound was prepared as follows: a) 2-Methoxycarbonyl- N - (4-piperidyloxy) benzoic acid amide hydrochloride

A mixture of 5 g (0.01443 mol) of 2- (N-BOCC-4-piperidyloxy) -1H-isoindole-1,3 / 2H-dione and 100 ml of a 1.3 h hydrogen chloride / methanol solution is stirred for for 2 hours at room temperature, whereupon the reaction mixture was evaporated in vacuo. In the fractionated crystallization of the ethyl alcohol residue, first the 2- (4-piperidyloxy) -1H-isoindole-1,3 / 2H-dione hydrochloride with a melting point of 240 DEG-241 DEG C. and the following concentration of the mother liquor are precipitated.

179 DEG-180 DEG C. (decomposition). Example 3 3-Aminooxymethyl-piperidine dihydrochloride

Starting from 6 g (0.0166 mol) of 2- (N-BOC-3-piperidylmethoxy) -1H-isoindole-1,3 / 2H-dione 32- and 40 ml of 6N hydrochloric acid, analogously as in Example 1, the title compound with a water content of 1.74%;

Melting point: 191 DEG C. (decomposition). The starting compound was prepared as follows: a / 2- / N-BOC-3-piperidylmethoxy / 1H-isoindole-1,3 / 2H-dione

Analogously to example 1a, 6.46 g (0.03 mol) of N-BOC-3-hydroxymethyl-piperidine (see 3) are not reacted. No. 0 279 681], 4.90 g (0.03 mol) of N-hydroxyphthalimide, 7.87 g (0.03 mol) of triphenylphosphine and 5.3 ml (0.0317 mol) of diethyl azodicarboxylic acid (93%) in 70 ml of tetrahydrofuran.

Purification of the crude product by silica gel chromatography using ethyl acetate-hexane mixtures (1: 3 or 1: 2) and evaporation of the product fractions afforded the title compound as a crystalline residue.

Melting point: 92-94 ° C. Example 4 2- (2-Aminooxyethyl) piperidine dihydrochloride

A mixture of 6 g (0.01602 mol) of 2- (N-BOC-2-piperidylethoxy) -1H-isoindole-1,3 / 2H-dione and 40 ml of 6N hydrochloric acid is reacted analogously to Example 1. After crystallization of ethyl alcohol / diethyl ether twice, the title compound is obtained. Melting point: 129-132 ° C (decomposition). 33 - The starting compound is prepared as follows: a / 2- / N-BOCC-2-piperidylethoxy / -1H-isoindole-1,3 / 2H / dione

In analogy to Example 1a, 6.9 g (0.03 mol) of K-BOC-2- (2-hydroxyethyl) -piperidine (see 3) are allowed to react. No. 0 289 842], 4.9 g (0.03 mol) of N -hydroxyphthalimide, 7.87 g (0.03 mol) of triphenylphosphine and 5.3 ml (0.0317 mol) of diethyl azodicarboxylate xylic acid (93%) in 70 ml tetrahydrofuran. The separated products (1,2-hydrazine dicarboxylic acid diethyl ester and triphenylphosphine oxide) and the etheric filtrate were concentrated to give the title compound as a crystalline residue.

M.p .: 108 ° C. Example 5 4-aminooxymethyl-piperidine dihydro chloride

A mixture of 0.5 g (0.00217 mol) of N-BOC-4-aminooxymethyl-piperidine and 10 ml of 1.3 N methanolic hydrochloric acid was stirred at room temperature for one hour and then evaporated in vacuo. Crystallization of the residue from methanol / diethyl ether gave the title compound.

Melting point: 199 DEG-200 DEG C. (decomposition). The starting compound is obtained as follows: a / KT-BOCC-4-aminooxymethyl-piperidine

A mixture of 3.5 g (0.00971 mol) of 2- (N-BOC-4-piperidinylmethoxy) -1H-isoindole-1,3 / 2H-dione and 20 ml of hydrazine zinc hydrate is stirred for a period of time. For 2 hours at room temperature, then 75 ml of diethyl ether are added and the mixture is stirred for an additional 2 hours. The organic phase is then separated and the hydrazine hydrate phase is extracted twice with 50 ml of diethyl ether each time. The combined ether extracts are washed with water and brine, dried over sodium sulphate and evaporated in vacuo. The title compound was obtained as a colorless oil. Rf = 0.60 / thin-layer chromatography plates silica gel 60 ^ 254 * mobile phase: methylene chloride-methyl alcohol 9: 1 / b / 2- (N-30C-4-piperidylmethoxy) -1H-isoindole-1,3 / 2H / -dione

Analogously to Example 1a / but maintaining the reaction time for 17 hours when starting from 6.46 g (0.03 mol) of K-BOC-4-hydroxymethylpiperidine (see E?). No. 0 317 997], 4.9 g (0.03 mol) of N-hydroxyphthalimide, 7.87 g (0.03 mol) of triphenylphosphine, 5.3 ml (0.0317 mol) of diethyl azo- dicarboxylic acid (93%) and 120 ml tetrahydrofuran, the title compound is obtained.

Melting point: 109-110 ° C. Example 6 2-Aminooxymethyl-piperazine trihydrochloride

A mixture of 2 g (0.00433 mol) of 2- (1,4-di-Boc-2-piperazinylmethoxy) -1H-isoindole-1,3 / 2H-dione and 20 ml of 6N hydrochloric acid is heated for 2.5 hours. refluxing and further processed analogously to Example 1. After twice crystallization from a mixture of methanol, water and diethyl ether, the title compound is obtained with a water content of 5% 82%. Melting point: 130 DEG-135 DEG C. (decomposition). The starting compounds are prepared as follows: a) 2- [1,4-di-BOC-2-piperazinylmethoxy] -1H-isoindole-1,3- (2H) -dione

Analogously to Example 4b), when starting from 15.82 g (0.05 mol) of 1,4-di-BOC-2-hydroxymethylpiperazine, β 8.16 g (0.05 mol) is obtained. K-hydroxyphthalimide, 13.11 g (0.05 mol) of triphenylphosphine, 8.85 ml (0.0529 mol) of diethyl 1,2-azodicarboxylic acid (93%) and 100 ml of tetrahydrofuran, the title compound.

Melting point: 154-155 ° C. b) 1,4-di-BOC-2-hydroxymethyl-piperazine

A mixture of 8.71 g (0.075 mol) of 2-hydroxymethyl-piperazine (see J. Med. Chem., 33, 142-146 (1990), 100 ml of acetonitrile and 50 ml of water are mixed dropwise with a solution of 34.4 g (0.1576 mol) of di-tert. -butyl dicarbonate in 100 mL of acetonitrile. The reaction mixture is stirred for a further 15 hours at room temperature and then evaporated in vacuo. After recrystallization of the residue from a mixture of ethyl acetate and hexane, the title compound is obtained.

Melting point: 120-121 ° C. Example 7 2-aminooxymethyl-morpholine dihydrochloride - 36 -

A solution of 0.9 g (2.7 mmol) of KT, N * -di-30C-2-aminooxymethyl-morpholine in 10 mL of ethanol is mixed with 10 mL of 2.2 N ethanolic hydrochloric acid and stirred for 16 h. hours at room temperature. The precipitated title compound is collected, washed with a small amount of ethanol and diethyl ether and dried.

185 DEG C. (decomposition). The starting compounds are prepared as follows: α 1 - 2-hydroxyethyl-3- (1-ethoxyethylideneaminooxy) -2-hydroxy-propylamine

A solution of 6.4 g (49.6 mmol) of 0-2,3-epoxypropyl acetic hydroxamic acid ethyl ester in 30 ml of isopropanol is mixed with 8 ml (131 mmol) of ethanolamine and stirred for 16 hours at room temperature. C. The reaction mixture is then evaporated and the residue is purified by chromatography on 250 g of silica gel using methylene chloride / methanol 10: 1 and then methylene chloride / methanol / concentrated ammonia (300: 50: 1). The starting product is obtained in the form of a yellow oil.

R f = 0.12 (silica gel / methylene chloride: methanol: concentrated ammonia 300: 50: 1). b / N, K'-BOC-N-2-hydroxyethyl-3-aminooxy-2-hydroxy-propylamine

The starting product (5.2 g, 23.6 mmol) was refluxed in 2N hydrochloric acid (100 mL) for 4 h. After cooling, 100 ml of 2N sodium hydroxide, 200 ml of tetrahydrofuran, 2 g of sodium carbonate and a solution of 11 g of di-tert-butyl dicarbonate in 100 ml of tetrahydrofuran are added and the reaction mixture is allowed to react for 24 hours at a temperature of room. The biphasic reaction mixture was then diluted with 500 mL of diethyl ether. The organic phase was separated, washed with water, dried over magnesium sulfate, filtered and evaporated. The residual oily liquid is chromatographed using 250 g of silica gel and a 1: 1 mixture of hexane and ethyl acetate to give the starting compound b as a yellow oil.

Rf = 0.06 (silica gel / hexane: ethyl acetate 1: 2). c / N, J &apos; -di-BOCC-2-aminooxymethyl-morpholine

A solution of 1.2 g (3.4 mmol) of starting material b in 10 ml of pyridine is mixed dropwise with 10 ml of 0.67 g (3.5 mmol) of tosyl chloride with stirring and at 0 ° C. -thylene chloride. The reaction mixture is stirred for one hour in an ice bath and then for 16 hours at room temperature, then 1 ml of water is added and the reaction mixture is evaporated to dryness. The residue was partitioned between 100 mL of diethyl ether and 50 mL of water. The organic phase is separated and washed with water, saturated sodium bicarbonate solution and water, then dried over magnesium sulfate, filtered and evaporated. The residue is chromatographed on 400 g of silica gel with a 2: 1 mixture of hexane and ethyl acetate to give the starting product c as white crystals. R f = 0.16 (silica gel / hexane: ethyl acetate 2: 1), m.p .: 106-108 ° C, 33-1 H-NMR (CDCl 3) δ = 1.46 (s, 18H); 2.62-2.81 / t, 1K / 2.82-3.05 / t, 1H7; 3.46-3.61 (m, 1H); 3.64-3.77 (m, 1H); 3.80-4.00 (m, 5H); 7.3 (s, 1H). d / N, K'-di-BOCC-2-aminooxymethyl-morpholine can also be produced as follows: 2.2 g (14 mmol) of N-2-hydroxyethyl-3-aminooxy-2-hydroxy-propylamine dihydrochloride in a Teflon reactor dissolved in 25 ml of dry hydrogen fluoride at -78 ° C. Sulfur tetrafluoride (5.4 g, 50 mmol) was introduced into the solution, the reactor was sealed and the reaction mixture was stirred at 0 DEG C. for 24 hours. The reactor was then degassed and the residue was dissolved in 20 ml of 2N hydrochloric acid. The solution was filtered and successively diluted with 100 ml of tetrahydrofuran, neutralized with solid sodium bicarbonate and mixed dropwise with a solution of 7.6 g of di-tert-butyl dicarbonate in 100 ml of tetrahydrofuran. The reaction mixture was stirred for 16 hours at room temperature and then diluted with 100 billion ether. The organic phase is separated, washed with water, saturated sodium bicarbonate solution and again, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on 400 g silica gel using 2: 1 hexane / ethyl acetate to give the starting product c as white crystals.

Rf = 0.16 (silica gel / hexane: acetic acid ethyl ester 2: 1), m.p. 106-108 ° C, 1H-N, R R GHDCCliy: δ = 1.46 (s, 18H); 2.62-2.81 (t, 1H); 2.82-3.05 (t, 1H); 3.46-3.61 (m, 1H); 3.64-3.77 (m, 1H); 39 3.80-4.00 (m, 5H); 7.3 (s, 1H). Example 8 2-Aminooxymethyl-morpholine dihydrochloride 3.2 g (14 mmol) of k-2-hydroxyethyl-3-amino-oxy-2-hydroxy-propylamine dihydrochloride was dissolved in 25 ml of dry hydrogen fluoride at -78 ° C in a Teflon reactor. . To this solution was introduced 5.4 g (50 mmol) of sulfur tetrafluoride, the reactor was sealed and stirred at 0 ° C for 24 hours. Then the reactor was degassed and the residue was dissolved in 20 ml of 2N hydrochloric acid. The solution obtained is filtered and the dryness is evaporated. The oily residue is taken up in a small amount of water and chromatographed over 200 ml of Dowex 1/01-form. The fractions containing the title compound were pooled and evaporated. The residue is recrystallized from ethyl alcohol and diethyl ether.

Melting point: 185 ° C. Example 9 2-Aminooxymethyl-morpholine dihydrochloride

A solution of 2.5 g (20 mmol) of sodium acetic acid ethyl ester salt and 10.8 g (21 mmol) of 4-triphenylmethyl-2- (p-toluenesulfonyloxymethyl) -morpholine / Chem. Pharm. Bull. 33> 3766 (1985) in 50 ml of N, U-dimethylformamide was stirred for 16 hours at 100 ° C. After cooling, the reaction mixture was poured into 400 ml of water. The precipitated product is filtered off with suction, washed with water and taken up in 100 ml of ethanol. This solution was mixed with 100 ml of 2N hydrochloric acid, refluxed for 4 hours, cooled, filtered and the filtrate was evaporated. The residue is crystallized from ethyl alcohol and diethyl ether to give the title compound.

Melting point: 185 ° C. Example 10 2-Aminooxymethyl-piperazine hydrochloride

A mixture of 0.45 g (1.35 mmol) of 2- (N-OC-amino-oxa-oxymethyl) -4-E-BOC-piperazine in 10 ml of ethyl alcohol is treated with 10 ml of 2.211 ethanolic hydrochloric acid and the reaction mixture is stirred at room temperature. stirring for 16 hours at room temperature and then evaporating in vacuo. Crystallization of the residue from methanol, water and diethyl ether gave the title compound.

130 DEG-135 DEG C. (decomposition). The starting compounds are prepared as follows: a / N, N'-di-BOC-N-2-ylsyloxyethyl-3-aminooxy-2-tosyloxy-propylamine

A solution of 1.2 g (3.4 mmol) of N, N * -di-Boc-N-2-hydroxyethyl-3-aminooxy-2-hydroxy-propylamine in 10 ml of pyridine is stirred at 0 ° C with no humidity. ° C with a solution of tosyl chloride (1.34 g, 7.0 mmol) in methylene chloride (10 mL) dropwise. The reaction mixture was then stirred for 16 hours in an ice bath, poured into ice water and extracted with diethyl ether. The ether phase is washed with water (41), diluted with ice-cold hydrochloric acid, saturated sodium bicarbonate solution and recirculated, dried over anhydrous magnesium sulfate, filtered and evaporated. The starting compound a is obtained. b) 2- (E-Boc-aminooxymethyl) -4-N-Boc-piperazine

A mixture of N, N-di-Boc-N-2-tosyloxyethyl-3-amino-oxy-2-tosyloxy-propylamine in 12% ethanolic ammonia was heated in an autoclave for 5 hours at 100 ° C. Then the reaction mixture is filtered, evaporated and the residue is taken up in diethyl ether, the ether solution is washed with dilute sodium hydroxide and water, dried over sodium sulphate and evaporated in vacuo. The starting compound b is obtained (see Archivder Pharmazie 291, 3/1958). Example 11 2-Aminooxymethyl-thiomorpholine dihydrochloride

Analogously to Example 10, 2- (N-BOC-aminooxymethyl) -4-P-BOC-thiomorpholine was treated with ethanolic hydrochloric acid to give the title compound. The starting compound is prepared as follows: a) 2- [N-BOC-amino oxyme thy] -4-N-BO C-thi omo rfoin;

The mixture of N, N'-di-BOC-N-2-yloxyethyl-3-amino-oxy-2-tosyloxy-propylamine and sodium sulfide hydrate in ethyl alcohol is refluxed for 4 hours. The reaction mixture is filtered, evaporated and the residue 42 is taken up in diethyl ether. The ether solution was washed, dried over sodium sulfate, and concentrated in vacuo. The starting compound and / or Austral are obtained. J. Chem. 9.397 (1956). Example 12 4-Aminooxy-piperidine dihydrochloride

A mixture of 1.08 g (0.005 mol) of N-BOC-4-aminooxy-piperidine and 25 ml of 1.3N methanolic hydrochloric acid is stirred for 8 hours at room temperature and then evaporated in vacuo. After crystallization of the residue of alcohol and diethyl ether, the title compound is obtained.

Melting point: 182 DEG C. (decomposition). The starting compound was obtained as follows: a / N-BOCC-4-aminooxy-piperidine

A mixture of 3 g (0.00866 mol) of 2- (N-BOCC-4-piperidloxy) -1H-isoindole-1,3 (2H) -dione (Example 1a) and 17 ml of hydrazine hydrate is stirred for one hour at a temperature of room. Then, the reaction mixture is mixed with 15 ml of water and 70 ml of diethyl ether and further stirred for 1.5 hours. After analogous treatment to Example 5a /, the title compound is obtained as a crystalline residue.

Melting point: 51-52 ° C. Example 13 4-Amino-oxy-piperidine sulfate

A solution of 2.32 g (0.02 mol) of 4-aminooxypiperidine in 50 ml of ethyl alcohol is mixed with 20 ml of 2W sulfuric acid (0.02mol) at room temperature and stirred, and the reaction mixture is then cooled to 5 ° C.

Filtration and washing of the precipitate with ethanol and diethyl ether gave the title compound.

Melting point: 245 DEG-247 DEG C. (decomposition). The starting compound was prepared as follows: α / 4-9minooxy-piperidine

A solution of 16 g (0.0846 mol) of 4-aminooxy-piperidine dihydrochloride (Example 1, 2, 12) in 10 ml of water is applied to a column packed with Amberlite IRA-400 / anion exchange in a hydroxyl cycle and eluted with water . Evaporation of the product-containing fractions under vacuum and a temperature of 40 ° C gave the title compound as a colorless oil.

Rf = 0.11 thin layer chromatography on silica gel, mobile phase methylene chloride: methanol: concentrated 40: 10: 1 / v / v ammonia. Example 14 4-Aminooxo-5-piperidine-benzenesulfonate To a solution of 2.32 g (0.02 mol) of 4-sminooxy-piperidine in 20 ml of ethanol is added a solution of 3.16 g (0.02 mol) of benzenesulfonic acid in 30 ml of ethyl alcohol. After concentration to about 25 ml, 30 ml of diethyl ether are added dropwise. A crystalline precipitate is formed which is filtered off and washed with diethyl ether to give the title compound.

Melting point: 110-112 ° C. 44 - Example 15 4-aminooxy-piperidine adipate

To a 35 ° C solution of 2.32 g (0.02 mol) of 4-aminooxy-piperidine and 2.92 g (0.02 mol) of adipic acid in 70 ml of ethanol was added 50 ml of diethyl ether with stirring. After cooling to room temperature, the crystalline precipitate formed is filtered off and washed with diethyl ether to give the title compound. Melting point: 97-98 ° C. Example 16

Capsules containing 0.25 g of active ingredient, for example one of the compounds of Examples 1 to 15

Composition / for 5000 capsules / active ingredient 1250 gmastek 180 gpstarch 120 gstagnesium 80 glactose 20 g

The powdery substances are sieved to a mesh size of 0.6 mm and mixed together. One dose of 0.33 g of the mixture is filled with the filling into gelatin capsules.

Claims (11)

Claims i. Heterocyclic hydroxylamines of Formula I (1) in which X represents a methylene group, an imino group, an oxygen atom, or a sulfur atom and R represents a group - (CHg) nO-NH2 - in which n is 0, 1 or 2, where n is not 0, when R is bound in position 2, as well as salts thereof. Compounds of formula (I) according to claim 1, wherein X represents a methylene group, an imino group or an oxygen atom, R is attached at the 2-position or 3a, and n is 1 or 2, and salts thereof. Compounds of formula I according to claim 1, wherein X represents a methylene group or an oxygen atom, R is attached at the 2-position or 46-3a and n is 1 or 2, as well as salts thereof. Compounds of formula I according to claim 1, wherein X represents a methylene group or an oxygen atom, R is attached at the 3-position and n is 1, as well as salts thereof. The compounds of formula (I) according to claim 1, wherein X represents a methylene group, R is bonded at the 4-position and n is 0 or 1, and salts thereof. Pharmaceutically acceptable salts of the compounds of general formula I according to one of claims 1 to 5 · A compound of formula (I) according to claim 1, wherein X is methylene and R is n, wherein R is 4-aminooxy-piperidine at the 4-position of the ring, and pharmaceutically acceptable salts thereof. A compound of formula (I) according to claim 1, wherein X is an oxygen atom and R is n 1, wherein R is attached to the 3-position of the ring, 2-aminooxymethyl-morpholine, as well as pharmaceutically acceptable salts. 9. A compound of formula (I) according to claim 1, wherein X is methylene and R is n1, wherein R is in the 3-position of the ring, the 3-aminooxymethenyl-piperidine, and the R-group thereof. pharmaceutically acceptable salts. - 47 - A pharmaceutical composition comprising a compound of formula I or a salt thereof according to claim 1 and at least one pharmaceutically acceptable carrier material. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 and 7 to 9 or a pharmaceutically acceptable salt thereof. together with at least one pharmaceutically acceptable carrier material; 13. The method of claim 1, wherein the compound of formula (I) is selected from the group consisting of a compound of formula (I) in which at least one amino group is protected, that is, a compound of formula (I). the formula II 7.Λ3Γ9 ° ji V ('JU IGV'40 _J • f'3 - 48 - Or a salt thereof in which X 'is a methylene group, an oxygen atom or a group NR 1 an is 0, 1 or 2, provided that n is different from zero when the substituent is - / CH 2 / n -O-NR 4 R 4 is attached at the 2-position and R 4, R 6, R 6 and R 6 independently of one another denotes an amino or hydrogen atom protecting group, with the proviso that at least one of R 4, R 6, R5 and R6 represent an amino-protecting group or, independently of one another, R6 and R6 represent an amino-protecting group or a hydrogen atom and R1 together with R6 forms a bivalent amine protecting group, cleaving the protecting group or for the preparation of compounds of formula (I) or salts thereof, in which X represents a non-methylene group, a compound of formula (III) 49 - (111), in which Z represents a nitrogen atom or a methine group, is reduced -pine CH and R are as defined above, or a salt thereof, or for the preparation of compounds of formula I or salts thereof, wherein X is imino, oxygen or sulfur, R is bonded at the 2-position or 3 and n is 1 or 2, cyclic to the general compound wherein IV is 1 or 2 and one of Y and Y 'is hydroxyl, amino or sulfhydryl, the other being a leaving group or a salt thereof or d / reacting a compound of formula V 50 - (CH 2) n O "M + (V), or a salt thereof, wherein X and n are as defined above, provided that n is not zero when it is tent - (CH 2) 2 M + is bonded at the 2-position, wherein M + is a metal cation, with a compound of formula (VI) H 2 N - A '(VI), or a salt thereof, wherein A' is a nucleofugal leaving group and converting a compound of formula I into another compound of formula I, z Channel for the S-enantiomeric mixture was separated into the individual enantiomers, and / or the resulting compound of formula Ipřevede a salt or a resulting salt of a compound obecnéhovzorce I into the free compound or another salt. 4