WO1999065864A2 - Geminally substituted amines - Google Patents

Abstract

The present invention relates to an amine of the general formula (I) in which R?1 and R2¿ may be the same or different and represent each independently substituted or non-substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkinyl, aryl or trialkylsilyl. R?1 and R2¿ can also form together with the nitrogen atom to which they are bound a substituted or non-substituted cycloalkyl ring which may contain, together with the nitrogen atom, at least one other heteroatom selected from the group comprising nitrogen, oxygen and sulphur. R3 is selected from the group comprising hydrogen and methyl optionally substituted with 1 to 3 fluorine atoms, while R?4 and R5¿ may be the same or different and represent each independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkinyl or substituted or non-substituted aryl. R?4 and R5¿ may also represent alkyl substituted with a substituted or non-substituted aryl, cycloalkyl, alkenyl, cycloalkenyl or alkinyl, with the proviso that at least one of the R?4 and R5¿ radicals comprises an aryl. This invention also relates to a salt thereof.

Description

 GEMINAL SUBSTITUTED AMINE

The present invention relates to geminally substituted amines. In particular, the present invention relates to amines substituted with aryl group-containing substituents, combinatorial libraries of such amines and special uses of these amines as intermediates in combinatorial drug synthesis or as drugs in pharmaceuticals.

It is known by combinatorial synthesis, starting from several different starting compounds, to produce substance libraries which contain a mixture of different reaction products. On the one hand, a suitable screening of a library makes it possible to identify biologically active reaction products that can then be produced in a targeted manner. On the other hand, a library can also be used in another combinatorial synthesis. By combining these two options, new classes of active ingredients can be developed.

A prerequisite for the combinatorial synthesis of active substance libraries is the accessibility of suitable starting compounds which either already contain a biologically active structural element or form this through combinatorial synthesis. Furthermore, the starting compounds must be suitable to provide as many of the reaction products as possible by law in the same possible yield in order to reduce the influence of the concentration of the individual compounds during screening and to create a combinatorial library that is as complete as possible.

The object of the invention is therefore to provide new compounds which contain a special biologically active structural element and which can be used individually or as a library in the combinatorial synthesis of active substances.

This object is achieved by providing an amine of the following formula (I) as a pure substance or in a substance library in a mixture with several different amines of the formula (I). It has been found that, surprisingly, the geminal substitution of a preferably tertiary amine can not only provide biological activity, but at the same time its preparation also has advantageous properties in combinatorial active ingredient synthesis. A process is also proposed in which a large number of amines of the general formula (I) can be prepared as a substance library.

where R ¹ and R ^{2 may be the} same or different and each independently represent substituted or unsubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl or trialkylsilyl or R ¹ and R ² together with the nitrogen atom to which they are attached can form substituted or unsubstituted cycloalkyl ring which, in addition to the nitrogen atom, can also contain at least one further heteroatom which is selected from the group consisting of nitrogen, oxygen or sulfur,

R ^{3 is} selected from hydrogen and methyl, which can optionally be substituted by 1-3 fluorine atoms,

R ⁴ and R ^{5 may be the} same or different and each individually independently of one another represents alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, substituted or unsubstituted aryl or an alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl substituted by substituted or unsubstituted aryl , with the proviso that at least one radical R ⁴ or R ⁵ contains an aryl group; or a salt thereof, especially a pharmaceutically acceptable salt thereof.

The compounds of the present invention are valuable as α-sympathicomimetics with a stimulating effect on the central nervous system, in particular in the treatment of depression, obesity, fatigue, allergic disorders and nasal mucosal inflammation.

Alkyl is preferably C ^ ^ alkyl, more preferably C ₂ . ₈ alkyl. Cycloalkyl is preferably C _3.g -cycloalkyl, more preferably C ₃ . _7- cycloalkyl. Alkenyl is preferably C _2.10 alkenyl, more preferably C ₂ . ₈ alkenyl. Cycloalkenyl is preferably C ₃ . _β- Cycloalkenyi, more preferred for C ₃ _ ₇ -cycloalkenyi. Alkynyl is preferably C ₂ . ₁₀ alkynyl, more preferably for C ₂ _a alkynyl.

Aryl is preferably phenyl, naphthyl, anthryl or phenanthryl.

Specific examples of an aryl radical are phenyl, benzyl, p-tolyl, m-tolyl, 4-fluorophenyl, 4-fluoro-3- Methylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 2,6-dimethylphenyl, 2-methyl-2-phenylethyl, 3-phenylprop-2-ynyl, 4-dimethylaminophenyl, naphthalen-1-yl and 3-aminophenyl.

Specific examples of an alkyl radical are methyl, ethyl, propyl, butyl, pentyl, hexyl. Specific examples of a cycloalkyl radical are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. Specific examples of an alkenyi radical are vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl isobutenyl.

Examples of R ¹ and R ² are described below, where halogen is fluorine, chlorine, bromine or iodine.

R ¹ and R ² can be the same or different and independently of one another for a C ,.

"Alkyl group, a C ₃ . _7- cycloalkyl group, one with a C ₃ . _7- Cycloalkyl group substituted C ..

₆ alkyl group, a C ₃ . _7- cycloalkenyl group, one with a C ₃ . _7- Cycloalkenyl group substituted C ,. _β- alkyl group, a C ₂ . ₈ alkenyl group, a C ₂ . ₈ alkynyl group, one substituted with a C. _.6 alkoxy group

one with a C ₂ . ₆ -Alkenyloxy group substituted C. _.6 -alkyl group, a C ^ -alkyl group substituted with a C _2.6 -alkynyloxy group, one with a mono-, di- or

Polyhalo-C .. ₆ -alkoxy group substituted C ^ alkyl group, one with a mono-, di- or

Poiyhalogen-C _2.6 -alkenyloxy group substituted C ^ alkyl group, one with a mono-, di- and

Polyhalogen C ₂ . ₆ -alkynyloxy group substituted C .. ₆ -alkyl group, one substituted with a C ^ -alkylthio group

one with one

Alkyl group, a mono-, di- or _{Polyhaiogen-C.}

₈ alkyl group, a mono-, di- or polyhalo-C ₂ . ₈ - alkenyl group, a mono-, di- or

Polyhalogen C ₂ . ₈ - alkynyl group, a C .. _β- alkyl group substituted with a cyano group, a C ₂ substituted with a cyano group. ₆ -alkenyl group, a C ₂ -substituted C _{2 e} -alkynyl group, a C 1-4 alkyl group substituted with a nitro group, a C ₂ -substituted with a nitro group. ₆ alkenyl group, a C ₂ substituted by a nitro group. ₆ -alkynyl group, a C, substituted by a C .. ₆ -alkylamino group. ₆ alkyl group, one with a C ,. ₆ - alkoxyamino group substituted C ^ alkyl group, one with a di (C .. ₃ - alkyl) amino group substituted C ^ alkyl group, one with an N- (C .. ₃ - alkyl) -N- (C _{1. 3} . -alkoxy) amino group substituted C .. ₆ alkyl group, one with a

N- (C _{1. 6} alkylsulfonyl) -N- (C _{1. 6} alkyl) amino group substituted C .. ₆ alkyl group, a a N- _(C,.

one with a _{tri-C. 6} -alkylsilyl group substituted C. ^ - alkyl group, a C, substituted with a triaryisilyl group.

₆ alkyl group, a phenyl group (provided that such a phenyl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C. _.6 alkyl group and a

C ^ alkoxy group), a C .. ₆ -alkyl group substituted with a phenyl group (with the proviso that such a phenyl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C,. ^ - alkyl group and a C _{1 6} alkoxy group), a C-substituted by a phenyl group. _{2 7-} alkenyl group (with the proviso that such a phenyl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C. ₆ alkyl group and one

C. ^ - alkoxy group), a C ₂ ^ -alkynyl group substituted by a phenyl group (with the proviso that such a phenyl group can be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C. ₆ alkyl group and a C. ₆ alkoxy group), one with a

Phenoxy group substituted

(provided that such a phenoxy group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C _g alkyl group and a _C. ^ -. alkoxy ), a C, ^ - substituted with a phenylthio group

Alkyl group (with the proviso that such a phenylthio group may be substituted with one or more substituents selected from the group consisting of one

Halogen atom, a trifluoromethyl group, a nitro group, a C ₆ - alkyl group and a _C,.

₆ -alkoxy group), a C, ₆ -alkyl group substituted with a phenylsulfinyl group (with the proviso that such a phenylsulfinyl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group , a C .. _β - alkyl group and a C ,. _s -Alkoxygrupp), one with a

Phenylsulfonyl group substituted

Alkyl group (with the proviso that such

Phenylsulfonyl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, one

Nitro group, one

a C, substituted with a benzyloxy group. _β - alkyl group (with the proviso that the phenyl group of such

Benzyloxy group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C ... ₆ alkyl group and one

Alkyl group (with the proviso that the phenyl group of such a benzylthio group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C. ₆ alkyl group and a C. ₆ -alkoxy group), a C, substituted by a benzylsulfinyl group. ₆ -alkyl group (with the Provided that the phenyl group of such a benzylsulfinyl group can be substituted with one or more substituents which are selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C. ₆ alkyl group and a C. _β- alkoxy group), a C, substituted with a benzylsulfonyl group. ₆ -alkyl group (with the proviso that the phenyl group of such a benzylsulfonyl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C 1-4 alkyl group and a C _Lg -Alkoxy group), a substituted with an amino group which is substituted by a C 1-4 alkylsulfonyl group _{. 6} alkyl group.

Examples of rings which are present when the radicals R ¹ and R ^{2 form} a cycloalkyl ring which may optionally contain, in addition to N, at least one further heteroatom, preferably N, 0 or S, are as follows: 1-pyrrolidinyl, 1-imidazolinyl , 1 -pyrazolinyl, 1 -piperidyl, 1 -piperazinyl, 4-morpholinyl, 4-thiamorpholinyl.

The radicals R ¹ and R ² are particularly preferably each independently of one another methyl, ethyl, isopropyl, n-butyl, isobutyl, phenyl, benzyl, 2-pyridyl or trimethylsilyl, or together with the nitrogen atom to which they are attached are for 1-pyrrolidinyl, 1-piperidyl, 4-methylpiperidyl, or 4-morpholinyl.

R ³ particularly preferably represents hydrogen.

Examples of R ⁴ and R ⁵ are described below, where halogen is fluorine, chlorine, bromine or iodine and aryl is phenyl, naphthyl, anthryl or phenanthryl:

R ⁴ and R ⁵ may be the same or different and independently of one another represent alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, which can have the same meaning as described for R ¹ and R ² , or an aryl group (with the proviso that such aryl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C ,. ₆ - alkyl group and a C ,. alkoxy group _β), one with a aryl substituted C ^ _g alkyl group (with the proviso that such an aryl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C .. ₆ - alkyl and a C, .g-alkoxy group), a C ₂ substituted with an aryl group. ₇ alkenyl group (with the proviso that such an aryl group may be substituted with one or more substituents which are selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C,

Alkyl group and a C _ι alkoxy group), a substituted with an aryl group C ₂₆ alkynyl group

(with the proviso that such an aryl group can be substituted with one or more

Substituents selected from the group consisting of a halogen atom, one

Trifluoromethyl group, a nitro group, a C, ₆ -alkyl group and a C, ₆ -alkoxy group), a C 1-4 alkyl group substituted with an aryloxy group (with the proviso that such an aryloxy group may be substituted with one or more substituents selected from the group consisting of a haiogen atom, a trifluoromethyl group, a nitro group, a C,

₆ alkyl group and a C _{1 6} alkoxy group), a C ₆ - substituted with an arylthio group

Alkyl group (with the proviso that such an arylthio group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C ₆ - alkyl group and a C _{1 6} alkoxy group ), a C, _e - alkyl group substituted by an arylsulfmyl group (with the proviso that such an

Arylsulfmyl group can be substituted with one or more substituents which are selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C 1-4 alkyl group and a C ₆ alkoxy group), a C substituted with an arylsulfonyl group, ₆ -

Alkyl group (with the proviso that such an arylsulfonyl group may be substituted with one or more substituents selected from the group consisting of one

Halogen atom, a trifluoromethyl group, a nitro group, a C, ₆ -alkyl group and a C,

₆ -alkoxy group), a C, ₆ -alkyl group substituted by a benzyloxy group (with the proviso that the aryl group of such a benzyloxy group may be substituted by one or more

Substituents selected from the group consisting of a halogen atom, one

Trifluoromethyl group, a nitro group, a C, _6- alkyl group and a C, _6- alkoxy group), a C, ₆ -alkyl group substituted by a benzylthio group (with the proviso that the aryl group of such a benzylthio group may be substituted by one or more substituents, which are selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C, ₆ -alkyl group and a C, _6- alkoxy group), one with a

C, _6- alkyl group substituted by benzylsulfinyl (with the proviso that the aryl group of such a benzylsulfinyl group may be substituted by one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C, _β - Alkyl group and a C, _e -alkoxy group), one with a

C, ₆ -alkyl group substituted by benzylsulfonyl group (with the proviso that the aryl group of such a benzylsulfonyl group may be substituted by one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C.G alkyl group and a C. ₆ alkoxy group), with the proviso that at least one radical R ⁴ or R ⁵ contains an aryl group.

R ⁴ and R ⁵ are particularly preferably phenyl, benzyl, p-tolyl, m-tolyl, 4-fluorophenyl, 4-fluoro-3-methylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 2,6-dimethylphenyl, 2-methyl -2-phenylethyl, 3-phenyl-prop-2-ynyl, 4-dimethylaminophenyl, naphthalene-1-yl and 3-aminophenyl.

A combinatorial library in the sense of the present invention contains at least five, preferably at least seven different amines of the general formula (I).

The preparation of the amines of the general formula (I) is described below.

The preparation of the compounds of the general formula (I) is not particularly restricted. However, it has been found that the compounds of the general formula (I) can preferably be prepared by one of the following processes.

Compounds of the present invention, in particular geminally symmetrically substituted amines of the formula (I) in which R ⁴ and R ^{5 have the} same meaning, are advantageously prepared by reacting a compound of the general formula (II)

wherein R ¹ , R ² and R ^{3 have} the meaning given above and R ³ particularly preferably represents hydrogen or a methyl group, in a suitable solvent with a compound of the general formula (III)

MR ⁴ (III)

wherein the radical M is a radical MgX with X = Cl, Br or J, or Li and R ^{4 has} the meaning given above, and optionally with a compound of the general formula (IV-a) R ⁵ TIY ₃ . _n (0R) _n (IV-a)

where Y for F, Cl, Br and I, the radicals R ¹ "for an alkyl radical with C ^ C. _Q , an aryl radical with C ₆ -C ₂₀ or an aryl radical which is mono- to pentasubstituted by fluorine, chlorine, bromine or iodine with C ₆ -C ₂₀ , preferably an iso-propyl radical, R ^{5 has} the meaning given above and n is an integer from 1 to 3.

For the reaction are preferably carboxylic acid amides are suitable, in which the radicals R ¹ and R ^2, identical or different, represent an alkyl radical with C, - C _10, a one by fluorine or polysubstituted, including perfluorinated alkyl radical with C, - C ₁₀ , a cycloalkyl radical with C ₃ - C ₈ , an aryl radical with C _β - C ₂₀ , an aryl radical which is mono- to pentasubstituted by fluorine, chlorine, bromine, iodine, an alkenyl radical with C ₂ - C ₁₀ , an alkynyl radical with C ₂ - C ₁₀ , a cycloalkyl ring consisting of the radicals R ¹ and R ² with C ₃ - C ₈ , which may contain a nitrogen, oxygen or sulfur atom as a further hetero atom, in addition to nitrogen.

The following compounds are very particularly preferably used as carboxamides of the formula (II):

A compound of the general formula (III) is used as the Grignard compound or organolithium compound for the reaction. In this general formula (III) the radical R ^{4 is} preferably a C, -C ₁₀ alkyl radical, a fluorine or polysubstituted by fluorine, including perfluorinated C, - C ₁₀ alkyl radical, a C ₃ - C ₆ cycloalkyl radical, a C. ₂ - C ₁₀ alkenyirest, a C ₂ - C ₁₀ alkynyl radical, or a radical -C (R ") (R ') CH ₂ R, where R" represents -Si (R) ₃ , Sn (R) ₃ , -SR , -OR, - NRR ', where R or R', the same or different, represent a C, - C ₁₀ alkyl radical, one by fluorine mono- or polysubstituted, including perfluorinated C, - C ₁₀ alkyl radical, an alkenyi radical with C ₂ - C ₁₀ , an alkynyl radical with C ₂ - C ₁₀ , a cycloalkyl radical with C ₃ - C _β . The R ₄ radical is particularly preferably a methyl or cyclopropyl radical. R ⁴ and R ⁵ preferably have at most one hydrogen atom in the β position.

The radical M in the general formula (III) preferably stands for a -MgX radical with X for Cl or Br or the radical M stands for lithium.

The reaction is preferably also carried out with an organotitanium compound.

Suitable organotitanium compounds are preferably compounds of the general formula (IV-a) shown above, where n is an integer from 1 to 3, preferably 3, Y is Cl, Br or I, the radicals R '", the same or different, one Alkyl radical with C, - C ₁₀ or an aryl radical with C ₆ - C ₂₀ , preferably isopropyl, and R ⁵ , identical or different from R \, has the meaning given for R ⁴ .

R ⁵ Ti (OiPr) ₃ is particularly preferably used as the organotitanium compound, where iPr stands for an isopropyl radical.

Methyl, phenyl, cyclopropyl or p-fluorophenyl-th-isopropyl titanates are very preferably used.

For the reaction, the compounds of the general formula (III) and (IV) should each be present in amounts of 0.7 to 1.3, preferably 0.9 to 1.1 equivalents, based on the compound of the general formula (II) .

The reaction is preferably carried out in a suitable solvent for the compounds of the general formulas (II) and (III) and (IV-a), preferably in a suitable organic solvent, such as, for. B. an aliphatic or aromatic hydrocarbon or ether, preferably toluene, tetrahydrofuran, n-hexane, cyclohexane, benzene or diethyl ether.

A solution of the compound of the general formula (II) and (IV) and the cocatalyst are very particularly preferably introduced and the compounds of the general formula (III) are metered in slowly. It is advantageous if the addition of the Grignard or lithium compounds is present as a solution in the solvents mentioned and preferably by dropwise addition to the reaction mixture is added. It is also advantageous to stir the reaction mixture during the entire reaction.

The process for the preparation of amino compounds of the general formula (I) is preferably carried out at room temperature, i.e. H. at 20 to 25 ° C, carried out under an inert gas atmosphere.

After the reaction, the symmetrically or asymmetrically substituted amino compounds can be purified and isolated in the usual way.

The products can be used as salts with the help of hydrochloric acid solutions such. B. 1 molar, ethereal hydrochloric acid solutions, precipitated and filtered off, and, if necessary, purified by recrystallization.

It is also possible to extract the products from the organic phase using acid solutions, preferably an aqueous hydrochloric acid solution, to adjust the extract obtained to a pH> 10 using lyes, preferably sodium hydroxide solution, and at least once, preferably several times extract dried diethyl ether. The organic phases obtained in this way, which contain the reaction product, can optionally be dried (over potassium carbonate) and freed from the organic solvent under vacuum.

It is also possible to isolate the reaction product by removing the organic solvent with the aid of a vacuum and separating the remaining residue by column chromatography to isolate the reaction product.

Compounds of the present invention can also be prepared by reacting a compound of the general formula (II) shown above, in which R ¹ , R ² and R ^{3 have} the meanings given for formula (I), with a nucleophilic reagent of the general formula (III), wherein R ^{4 has} the meanings given for formula (I), in the presence of catalytic amounts of a metal oxide selected from the group consisting of titanium dioxide, hafnium dioxide and zirconium dioxide.

The process can also be carried out in the presence of a cocatalyst, where alkylsilyl halides can be used as cocatalysts; namely alkylsilyl halides of the general formula (V)

R ^lv ₃ SiX (V) or the general formula (VI)

R ₀ - (X) _m Si-Y- (Si) _p - (X) ₉ -R ₀ (VI)

wherein

R ^ιv alkyl with 1 to 10 C atoms or aryl with 6 to 20 C atoms,

X F, Ci, Br, I, CN,

Y is (CH ₂ ) _n , 0, NH, bond, m 0.1, n I to 10, o 0.2.3, p 0.1 and q 0.1, with the proviso that o = 3 and Y ≠ (CH ₂ ) _n if m = 0.

Surprisingly, the use of the cocatalyst suppresses the α and / or 3 elimination which is usually observed in titanium alkyls which have α and / or β hydrogen atoms.

Accordingly, the process can also be carried out by

a) a carboxamide of the general formula (II), 1 -15 mol% of a metal oxide selected from the group consisting of titanium dioxide, hafnium dioxide and zirconium dioxide, based on the carboxamide, and optionally a cocatalyst at room temperature under an inert gas atmosphere in a solvent selected from the group Toluene, THF, n-hexane, benzene and diethyl ether,

b) a solution containing a nucleophilic reagent of the general formula (III) is added dropwise and

c) can be reacted with stirring and worked up in the usual manner after the reaction has ended,

or that if Z = MgX a ') Magnesium shavings, a carboxamide of the general formula (II), 1 - 15 mol% of one

Catalyst selected from the group consisting of titanium dioxide, hafnium dioxide and zirconium dioxide, based on the carboxamide, at room temperature under an inert gas atmosphere in a solvent selected from the group consisting of toluene, THF, n-hexane, benzene and diethyl ether,

b ') an alkyl halide of the general formula (III') taken up in a solvent selected from the group consisting of toluene, THF, n-hexane, benzene and diethyl ether

XR ⁴ (III ')

in which R ⁴ and X have the meanings given above,

c ') can be reacted with stirring and worked up in the usual manner after the reaction has ended.

Experiments have shown that with a nucleophilic reagent of the general formula (III), which can be a Grignard reagent and either generated in situ or added as such to the reaction mixture, carboxamides of the general formula (II) in the presence of catalytic amounts of titanium dioxide, hafnium dioxide or Zirconium dioxide can be converted in a simple manner to symmetrically substituted but also unsymmetrically substituted compounds of the general formula (I).

According to the process described here, carboxamides of the general formula (II) can be reacted with good yields, in which R ¹ , R ² independently of one another have the following

Can assume meanings:

H or A ie branched or unbranched alkyl having 1 to 10 carbon atoms, such as methyl, ethyl, n- or i-propyl, n-, sec- or t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and their suitable isomers, or cycloalkyl having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or corresponding methyl- or ethyl-substituted cycloalkyl groups or mono- or polyunsaturated cycloalkyl groups, such as cyclopentenyl or cyclopentadienyl or branched or unbranched alkenyl having 2 to 10 carbon atoms, such as allyl, vinyl, isopropenyl, propenyl or branched or unbranched alkynyl having 2 to 10 C atoms, such as ethynyl, propynyl or aryl with 6 to 20 C atoms, optionally unsubstituted or mono- or polysubstituted, such as phenyl, naphthyl, anthryl, phenanthryl, mono- or polysubstituted by substituents selected from the group NO ₂ , F, Cl, Br, NH ₂ , NHA, NA ₂ , OH, and OA, where A can have the meanings given above, can be simple, multiply or completely halogenated, preferably fluorinated, or aralkyl with 7 to 20 C atoms , such as benzyl, optionally mono- or polysubstituted by substituents selected from the group N0 ₂ , F, Cl, Br, NH ₂ , NHA, NA ^ OH, and OA, where A can assume the abovementioned meanings and, if appropriate, simply, can be halogenated several or completely, preferably fluorinated, or

Aralkenyl or aralkynyl, where in each case the aryl, alkenyl and alkynyl group can assume the meanings given, such as. B. in phenylethynyl, and R ^{3 is} hydrogen or methyl.

Good yields are also achieved in particular with carboxamides in which R ¹ and R ² together form a cyclic ring with 3 to 8 carbon atoms which, in addition to nitrogen, contains further heteroatoms, such as - S -, - O - or - N -. Particularly preferred here are compounds in which R ¹ and R ^{2 form} a simple cyclic ring which includes the nitrogen of the carboxamide or in which R ¹ and R ^{2 form} a cyclic ring which contains an oxygen atom as a further hetero atom.

In this way, high yields are achieved when compounds such as. B.

be used as starting material.

Grignard or lithium compounds of the general formula (III) in which the radicals, R ⁴ preferably represents an alkyl radical having 1 to 10 carbon atoms, such as methyl, ethyl, n- or i-propyl, n-, sec- or t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and the like suitable isomers, or cycloalkyl having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or corresponding methyl- or ethyl-substituted cycloalkyl groups or mono- or polyunsaturated cycloalkyl groups, such as cyclopentenyl or cyclopentadienyl or

for branched or unbranched alkenyl radicals with 2 to 10 carbon atoms, such as allyl, vinyl, isopropenyl, propenyl or

are branched or unbranched alkynyl radicals having 2 to 10 carbon atoms, such as ethynyl or propynyl.

Particularly preferred are Grignard compounds such as methyl magnesium bromide, ethyl magnesium bromide, n- or i-propyl magnesium bromide, i-, sec- or tert-butyl magnesium bromide, n-hexyl magnesium bromide, cyclohexyl mag nesium chloride, alylyl magnesium bromide, vinyl chloride, vinyl bromide, vinyl chloride , Allyl magnesium bromide used for the reactions.

It was found that the geminal symmetrical dialkylation reactions only start at room temperature by adding a cocatalyst and lead to complete conversion of the starting materials in a relatively short reaction time. Alkylsilyl halides are suitable as co-catalysts in this reaction. In particular, these are the alkylsilyl halides of the general formula (V) or of the general formula (VI) described above.

^{Alkylsilane halides} are preferably used, in which R ^{ιv is} alkyl having 1 to 6 carbon atoms. Particularly preferred are those in which R ^{ιv is} alkyl having 1 to 3 carbon atoms and X is chlorine.

In particular, a. the following silicon compounds are suitable as co-catalysts:

(CH ₃ ) ₃ SiCl,

(CH ₃ ) ₂ CISi (CH ₂ ) ₂ SiCi (CH ₃ ) ₂ (CH ₃ ) ₂ CISi (CH ₂ ) ₃ CN, [(CH ₃ ) ₃ Si] ₂ 0, [(CH ₃ ) ₃ Si] ₂ NH and [(CH ₃ ) ₃ Si] ₂

It has been found that the addition of 0.7 to 1.2 moles, in particular 0.9 to 1.1 moles, of a cocatalyst, based on one mole of starting material, leads to improved results, such as. B. higher yields, lower reaction temperature or shorter reaction times.

As can be shown on the basis of examples, a complete conversion of the carboxamide has already taken place after one hour under favorable conditions.

Dried commercially available metal oxide, selected from the group consisting of titanium dioxide, hafnium dioxide and zirconium dioxide, can be used as the catalyst for carrying out the process. Powdered titanium (IV) oxide (Ti0 ₂ ) is preferably used. In the simplest case, this can be a technical quality. In order to be able to ensure simple separation after the reaction has taken place, it is advantageous to choose a quality which is not too finely divided.

The metal oxide, preferably titanium dioxide, which has been predried by heating, is used as a suspension in a suitable, likewise predried organic solvent. Suitable solvents are e.g. B. aliphatic or aromatic hydrocarbons or ethers. Solvents selected from the group consisting of toluene, tetrahydrofuran, n-hexane, cyciohexane, benzene and diethyl ether are preferably used, which are dried before the reaction by methods known to those skilled in the art. Drying can be done using magnesium sulfate, calcium chloride, sodium, KOH or other methods.

A preferred embodiment of the method is that the titanium (IV) oxide used as catalyst in an amount of 1-15, preferably 1.5 to 14, in particular 2 to 10, and very particularly preferably 3-6 mol%, based on a mole of the amide used as starting material is introduced in the form of a suspension which is set to a temperature of 10-30 ° C., preferably 15-25 ° C., particularly preferably a temperature of approximately 20 ° C. Under an inert gas atmosphere (nitrogen or argon), the starting material is slowly added dropwise either as such in liquid form or dissolved in a solvent selected from the group consisting of toluene, tetrahydrofuran, n-hexane, cyciohexane, benzene and diethyl ether with stirring. Then an amount of cocatalyst corresponding to the amount of starting material to be reacted, if necessary also taken up in a solvent, is added dropwise. The reaction mixture obtained is stirred for a short time, ie for a few minutes, at a constant temperature. To the reaction mixture thus obtained is then added as much nucleophilic reagent of the general formula (IN), in particular one Grignard reagent, slowly added in excess, that the geminal carbonyl carbon atom can be replaced by two identical substituents, ie, a symmetrical substitution of the geminal carbonyl carbon atom. The addition of a nucleophilic reagent according to the invention, produced according to methods well known to the person skilled in the art, should take place so slowly that the temperature of the reaction mixture does not exceed 50 ° C. It is advantageous if the nucleophilic reagent, ie the Grignard reagent or the lithium compound, is added with thorough mixing, preferably with intensive stirring. In order to shift the reaction equilibrium to the side of the desired symmetrically substituted product, the nucleophilic reagent used, preferably a Grignard reagent, is added in an amount of 2.1 to 3 moles per mole of reactant reactant. The Grignard reagent is preferably added in an amount of 2.2 to 2.6 mol based on 1 mol of starting material.

After the addition of the Grignard reagent has ended, the reaction mixture is stirred for a while at a constant temperature until the reaction is complete.

Another variant of this method is that the Grignard reagent is prepared in situ by reacting magnesium with an appropriate halide. When the Grignard compounds are prepared in situ, the amount of magnesium is preferably 2 to 5 times the molar amount, preferably 2.8 to 3.2 times the molar amount, based on the compounds of the general formula (II) used as starting material and the amount of the halide is 2 to 3.8 times the molar amount, preferably 2.2 to 2.6 times the molar amount, based on the compound of the general formula (II).

If no co-catalyst is added to the reaction mixture, the reaction temperature can be adjusted to approximately 80 ° C., preferably 60 to 70 ° C., in particular 75 ° C., after the addition of the nucleophilic reagent has been completed and thorough mixing has taken place.

For example, 5 mmol of educt are added dropwise at 20 ° C. under an inert gas atmosphere to a suspension of 3 mol% of titanium (IV) oxide in 40 ml of dried tetrahydrofuran with stirring. 5 mmol of cocatalyst, likewise taken up in dried tetrahydrofuran, are slowly added to this mixture with stirring. The mixture is stirred for 5 minutes at 20 ° C and then 12 mmol of a Grignard reagent is added so slowly that the temperature of the reaction mixture does not rise above 50 ° C. The mixture is stirred for an hour until the reaction is complete.

After the reaction, the reaction mixture can be worked up in a manner known to the person skilled in the art known way.

The products can be used as salts with the help of hydrochloric acid solutions, e.g. B. 1 molar ethereal hydrochloric acid solutions, precipitated and filtered, and if necessary, purified by recrystallization.

To remove the Lewis acid, a suitable amount of saturated ammonium chloride solution and water can be added, for example, and stirring is continued intensively for several hours (1-3 hours). The resulting precipitate is separated off and washed with a little dried ether, preferably diethyl ether. The filtrate is made basic (pH> 10) by adding a suitable alkali, such as a NaOH, KOH, sodium or potassium carbonate solution, preferably sodium hydroxide solution. The phases that form are then separated and the aqueous phase is extracted several times (eg three times with 30 ml each in the special case given above) with diethyl ether. The combined organic phases are washed with (e.g. 15 ml) saturated sodium chloride solution and can be dried over potassium carbonate, magnesium sulfate or sodium sulfate and filtered.

The products can be purified in various ways according to methods known to the person skilled in the art, such as e.g. B. in the manner described above.

Instead of the general description of the process implementation given in the above, the Grignard reagents can also be replaced by the corresponding lithium compounds. The corresponding lithium compounds, like the Grignard compounds, can be prepared by methods generally known to the person skilled in the art and can be reacted in the same manner as described above.

The reaction takes place in the presence of an organotitanium compound as a catalyst, which is used in an amount of 0.5 to 5 mol%, preferably 1 to 3.5 mol%, based on the compound of the general formula (II).

Compounds of the general formula (IV-b) are also preferably suitable as organotitanium compounds

TiX _4-n (OR ^v ) _n

wherein n is an integer from 1 to 4,

X Cl, Br, I and

R ^{v, the} same or different, is an alkyl radical with 1 to 10 C atoms or an aryl radical with 6 to 20

C atoms mean.

Those organotitanium compounds in which R ^{v is} isopropyl are preferably used.

The organotitanium compound used is particularly preferably Ti (Oi-Pr) ₄ , where i-Pr corresponds to an isopropyl radical. The symmetrically substituted amine compounds of the general formula (I) prepared are preferably not only in the presence of a catalyst, but can also be in the presence of a compound of one of the general formulas (V) or (VI) shown above or a compound of the general formula (VII )

M ' ^{(m +)} (Oi-Pr) m (VII)

where M 'is Al, Ca, Na, K, Si or Mg, preferably Mg or Na, m is an integer from 1 to 4 and the oxidation state of the metal, prepared as a cocatalyst.

The following compounds are very particularly preferably used as cocatalysts:

NaOi-Pr,

Mg (Oi-Pr) ₂ ,

(CH ₃ ) ₃ SiCl

If a cocatalyst is added to the reaction mixture, it should be used in amounts of 0.7 to 1.2, preferably 0.9 to 1.1 equivalents, based on the compound of the general formula (II).

Compounds of the present invention which are geminally asymmetrically substituted are advantageously prepared by reacting a compound of the general formula (II) shown above in which R ¹ , R ² and R ^{3 have} the meanings given for formula (I), by reaction with at least two nucleophilic reagents of the general formula (purple) and (lllb) ZR ⁴ (purple)

ZR ⁵ (lllb)

wherein

R ⁴ and R ^{5 have} the meanings given above, where,

Z Li or MgX with

X shark and

Shark Cl, Br or I mean which are generated in situ or added directly. In particular, this is carried out

Process by it in the presence of catalytic amounts of a metal oxide selected from the

Group of titanium dioxide, hafnium dioxide and zirconium dioxide.

The catalyst is preferably used in the presence of a cocatalyst, in particular in the presence of an alkylsilane halide as cocatalyst.

Suitable alkylsian halides are the compounds of the general formula (V) or of the general formula (VI) described above. In particular, titanium dioxide is used as the catalyst for carrying out the process.

The process is characterized in that one

a) a carboxamide of the general formula (II), 1-15 mol% of a metal oxide selected from the group titanium (IV) oxide, hafnium dioxide, zirconium dioxide, based on the carboxamide, and optionally the cocatalyst at 10-30 ° C in an inert gas atmosphere in a solvent selected from the group consisting of toluene, THF, hexanes, benzene and diethyl ether, b) a solution containing at least two nucleophilic reagents of the general formulas (purple) and (IIIb), in which R ⁴ and R ⁵ have the meanings given above, or in which the radicals R ⁴ and R ⁵ are bonded to one another and form a group having 2 to 7 C atoms, or in which R ⁴ and R ^{5 are} optionally via a hetero atom from the group -0-, -NH- , -S- are joined together and together form a group with 2 to 6 carbon atoms and X has the meanings given above, added dropwise and c) can be reacted with stirring and after the reaction has ended in a customary manner or that if Z = MgX a ') magnesium shavings, a carboxamide of the general formula (II), 1 -15 mol% of a

Metal oxide, selected from the group titanium (IV) oxide, hafnium dioxide, zirconium dioxide, based on the carboxamide, at a temperature of 10 to 30 ° C. of the group toluene,

THF, hexanes, benzene and diethyl ether, b ') at least two different in a solvent selected from the group toluene,

THF, hexanes, benzene and diethyl ether, alkyl halides of the general uptake

Formulas (purple ') and (lllb')

XR ⁴ (purple ')

XR ⁵ (lllb ')

where each

R ⁴ and R ^{5 have} the meanings given above, added dropwise, c ') can be re-reacted with stirring and, after the reaction has ended, worked up in a conventional manner.

Process step a) or a ') is carried out at a temperature of 15 to 25 ° C, preferably at room temperature.

A catalyst system consisting of a metal oxide selected from the group consisting of titanium dioxide, hafnium dioxide and zirconium dioxide and a co-catalyst of the general formula (V) or (VI) described above has proven particularly advantageous.

This catalyst system preferably contains a compound selected from the group

(CH ₃ ) ₃ SiCl,

(CH ₃ ) ₂ CISi (CH ₂ ) ₂ SiCI (CH ₃ )

t (CH ₃ ) ₃ Si ₂ ] ₂ 0

[(CH ₃ ) ₃ Si ₂ ] ₂ NH and

[(CH ₃ ) ₃ Si ₂ ] ₂ as a co-catalyst.

A catalyst system containing titanium dioxide as the metal oxide is very particularly preferably used.

Experiments have shown that by reaction of carboxylic acid amides with two different Grignard reagents in the presence of titanium (IV) oxide (Ti0 ₂ ), a reaction takes place using catalytic amounts of the titanium reagent. Furthermore, it has also been found that the desired geminal asymmetrical dialkylation reactions start at room temperature only by adding a cocatalyst. Under the reaction conditions according to the invention, the carboxamides are completely converted in very short reaction times. If small quantities of starting material are used, the reaction is complete after one hour at the latest.

To carry out the process, titanium (IV) oxide (Ti0 ₂ ) as a suspension in a suitable, dried solvent is selected from the group of toluene, tetrahydrofuran (THF), hexanes, benzene and diethyl ether in an amount of 1 to 15 mol%, preferably 3-13 mol%, based on the amount of the reacting amide. The suspension is adjusted to a temperature of 15 to 30 ° C, preferably to about 20 ° C. Under an inert gas atmosphere (nitrogen or argon), the starting material, either as such in liquid form or dissolved in a solvent, selected from the group consisting of tetrahydrofuran, toluene, tetrahydrofuran (THF), hexanes, benzene and diethyl ether, is slowly added dropwise with stirring. An amount of cocatalyst corresponding to the amount of starting material to be reacted, likewise taken up in a dried solvent, is added dropwise. The reaction mixture obtained is stirred for a short time, ie for a few minutes, while maintaining the temperature. A mixture consisting of equal amounts of two different Grignard reagents is then added to the reaction mixture obtained so slowly that the temperature of the reaction mixture does not rise above 50.degree. In order to achieve a complete conversion of the starting material, the Grignard reagents are added in excess. The Grignard reagents are preferably used in an amount of at least 1.05 mol to 1.5 mol per 1 mol of starting material. In particular, the Grignard reagents are used in an amount of 1.1 to 1.3 mol, based on 1 mol of starting material. After the addition of the Grignard reagent has ended, the reaction mixture obtained is stirred at constant temperature for some time to complete the reaction.

For example, 5 mmol of educt are added dropwise at 20 ° C. under an inert gas atmosphere to a suspension of 3 mol% of titanium (IV) oxide in 40 ml of dried tetrahydrofuran with stirring. To this 5 mmol of cocatalyst, likewise taken up in dried tetrahydrofuran, are slowly added to the mixture with stirring. The mixture is stirred at 20 ° C. for 5 minutes and then 6 mmol of two different Grignard reagents are added so slowly that the temperature of the reaction mixture does not rise above 50 ° C. The mixture is stirred for an hour until the reaction is complete.

Compounds of the present invention are advantageously prepared by reacting a compound of the general formula (II) shown above, where R \ R ² and R ^{3 have} the meaning given above, in a suitable solvent with at least one compound of the general formula (III- a) and (III-b) in the presence of an organotitanium compound of the general formula (IV-b) as a catalyst.

Carboxylic acid amides in which the radicals R ¹ and R ² , identical or different, for hydrogen, are an alkyl radical with C ¹ -C ₁₀ , a cycloalkyl radical with C ₃ -C ₈ , an aryl radical with C ₆ -C ₄ are preferably suitable for the reaction ₂₀ , an alkenyi radical with C ₂ -C ₁₀ , an alkynyl radical with C ₂ -C ₁₀ , a cycloalkyl ring from the radicals R ¹ and R ² or R ² and R ³ with C ₃ -C ₈ , which, in addition to nitrogen, may also be present can contain a nitrogen, oxygen or sulfur atom as a further heteroatom, and the radicals R and R 'represent an alkyl radical with CC ₁₀ , a cycloalkyl radical with C ₃ -C _β or an aryl radical with C ₆ -C ₂₀ .

The organotitanium compound used is particularly preferably Ti (OiPr) ₄ , where iPr stands for an isopropyl radical.

The asymmetrically substituted amine compounds of the general formula (I) prepared according to the invention are preferably prepared not only in the presence of a catalyst, but also in the presence of a compound according to one of the general formulas (V), (VI) or (VII) as a cocatalyst.

The following compounds are very particularly preferably used as cocatalysts:

NaOiPr, Mg (OiPr) ₂ , (CH ₃ ) ₃ SiCl

The process for the preparation of symmetrically or asymmetrically substituted amino compounds of the general formula (1) is preferably carried out at room temperature, ie at 20 to 25 ° C., under an inert gas atmosphere. According to the synthesis, symmetrically or asymmetrically substituted amino compounds of the general formula (I) can be prepared with sufficient yields within reasonable reaction times, the enamine reaction with α-elimination and the cyclization reaction with β-hydride elimination being largely avoided.

On the other hand, products of the cyclization reaction with β-hydride elimination can be prepared by not using a cocatalyst in the process described above.

After the reaction, the symmetrically or asymmetrically substituted amino compounds can be purified and isolated in a conventional manner, such as. B. described above.

In the combinatorial synthesis of the amines of the general formula (I), one or more different compounds of the general formula (II) and / or more different compounds of the formulas (III) or (IV) are used. It has been found that a combinatorial library can be obtained in this way, which contains several amines of the general formula (I) in a mixture. 1-10 different compounds of the formula (II) are preferably reacted with at least three different compounds of the formula (III).

It has been found that the combinatorial synthesis of the amines of the general formula (I) often provides all reaction products which are possible under the law, so that with one approach an almost complete combinatorial library can be created which can be used as such in a screening. It was also found that the individual reaction products are produced in comparable amounts, so that the influence of the concentration of each individual compound can be neglected in the most favorable case when screening the library.

It is possible to screen the libraries of the amines of the general formula (I) for biological activity in order to isolate and identify those amines which have special active ingredient properties.

The amines of the general formula (I) can be used as pure substances or several different ones can be used as a combinatorial library in a combinatorial synthesis in which the amines are reacted with one or more reactants to create modified amines of the general formula (I). The structural element of the geminal substitution of the amines is preferably obtained. In the combinatorial synthesis to create modified amines of the general formula (I), it is advantageously possible to use those amines which have already been found to be effective in a biological screening process. Through the use of amines of the general formula (I) with biological activity in the creation of modified amines, it is possible to achieve an improved activity by combinatorial synthesis.

Repeated screening and synthesis steps make it possible to specifically increase the effectiveness of the amines of the general formula (I).

The method according to the invention for producing synthetic combinatorial libraries offers the following advantages in particular:

1. A large number of different amines can be produced, which are present in the reaction mixture in similar amounts.

2. The process can be carried out catalytically.

3. It is not necessary to support the starting compounds, as is regularly the case in combinatorial synthesis based on amino acids.

4. Easily accessible output connections can be used.

Compounds of the general formula (I) or (la) and their physiologically acceptable salts can therefore be used for the preparation of pharmaceutical preparations by combining them with at least one carrier or auxiliary and, if desired, with one or more further active ingredients in the appropriate Dosage form brings. The preparations thus obtained can be used as pharmaceuticals in human or veterinary medicine. Suitable carrier substances are organic or inorganic substances which are suitable for enteral (e.g. oral or rectal) or parenteral application or for application in the form of an inhalation spray and do not react with the new compounds, for example water, vegetable oils, Benzyl alcohols, polyethylene glycols, glycerin acetate and other fatty acid glycerides, gelatin, soy lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc or cellulose. Tablets, coated tablets, capsules, syrups, juices or drops are used in particular for oral use; of particular interest are coated tablets and capsules with enteric coatings or capsule shells. Suppositories are used for rectal administration, solutions are used for parenteral administration, preferably oily or aqueous solutions, further suspensions, emulsions or implants. For the application as an inhalation spray, sprays can be used which contain the active ingredient either dissolved or suspended in a propellant gas mixture (e.g. chlorofluorocarbons). The active ingredient is expediently used in micronized form, it being possible for one or more additional physiologically acceptable solvents to be present, for. B. ethanol. Inhalation solutions can be administered using standard inhalers. The active ingredients claimed according to the invention can also be lyophilized and the lyophilizates obtained, for. B. can be used for the preparation of injectables. The specified preparations can be sterilized and / or contain auxiliaries such as preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants and / or flavorings. If desired, they can also contain one or more other active ingredients, e.g. B. one or more vitamins, diuretics, anti-inflammatory drugs.

The compounds of the formula (I) or (Ia) according to the invention are generally administered in analogy to other known, commercially available preparations, but in particular in analogy to the compounds described in US Pat. No. 4,880,804, preferably in doses between about 1 mg and 1 g, in particular between 50 and 500 mg per dosage unit. The daily dosage is preferably between about 0.1 and 50 mg / kg, in particular 1 and 10 mg / kg body weight. However, the specific dose for each individual patient depends on a wide variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the administration time and route and on the excretion speed, drug combination and severity of the disease to which the therapy applies. Oral application is preferred.

The invention will now be described by way of examples.

Examples 1-6:

To a solution of 5.5 mmol of the organotitanium compound given in Table 1, in 40 ml of dry tetrahydrofuran, 5 mmol of the amide given in Table 1 are added dropwise at 20 ° C. under a nitrogen atmosphere. The mixture is stirred at 20 ° C for 5 min. 5.5 mmol of the Grignard reagents shown in Table 1 are then added to the reaction mixture so slowly that the reaction mixture is not heated above 50.degree. The mixture is then stirred at the reaction temperature given in Table 1 during the reaction time given in Table 1, until the implementation is complete.

Processing of the reaction products:

To remove the Lewis acid, 15 ml of saturated ammonium chloride solution and 15 ml of water are added with vigorous stirring (1 hour). Any precipitate that forms is suctioned off via a suction filter / suction bottle and the fiIr residue is washed with 2 × 20 ml of dried diethyl ether. The filtrate is made basic (pH> 10) by adding sodium hydroxide solution. The phases are then separated in the separating funnel. The aqueous phase is extracted three times with 30 ml of diethyl ether. The combined organic phases are washed with saturated sodium chloride solution and the separated organic phase is dried over potassium carbonate and filtered. The solvent is spun off on a rotary evaporator. The residue is chromatographed on 20 g of silica gel with an eluent mixture of heptane / tert-butyl methyl ether 50/1.

Table 1

location table 1

Example 7

Titanium (IV) oxide induced symmetric dialkylation of carboxylic acid amides with Grignard reagents.

After the reaction represented by equation 1, the product listed in Table 2 was prepared using one equivalent (CH ₃ ) ₃ SiCl as cocatalyst:

Table 2

Table 2: Ti0 ₂ -inα ^' u∑ierte implementation of carboxylic acid amides with R ^J McX

Examples 8 to 11

To a solution of 3 mol% Ti (0-i-propyl) ₄ , based on the amide given in Table 3, in 40 ml dry tetrahydrofuran, 5 mmol of the amide given in Table 3 and at 20 ° C under a nitrogen atmosphere 5 mmol of C (CH ₃ ) ₃ SiCl ₃ were added dropwise as cocatalyst. The mixture is stirred at 20 ° C for 5 min. 12 mmol of the Grignard reagent shown in Table 3 are then added to the reaction mixture so slowly that the reaction mixture is not heated above 50.degree. The mixture is then stirred at the reaction temperature given in Table 3 during the reaction time given in Table 3 until the reaction is complete. Example 8-a:

Deviating from this, 15 mmol of magnesium shavings in 10 ml of tetrahydrofuran are introduced at 20 ° C. in a nitrogen atmosphere in Example 8-a. 10 mol%, based on the amide given in Table 3, Ti (0-i propyl) ₄ and 5 mmol of the amide given in Table 3 dissolved in tetrahydrofuran are added. 12 mmol of phenyl bromide are slowly added dropwise so that the mixture boils gently. During the reaction time of 1 hour and 25 ° C. reaction temperature, after adding 5 mmol of the above-mentioned cocatalyst after 1 hour, the product set out in Table 3 is obtained with the yield shown in Table 3. The reaction products are worked up as in Examples 1-4.

TABLE 3

Examples 12 to 14

The compounds listed in Table 4 were prepared by titanium (IV) oxide-induced asymmetrical disubstitution of carboxylic acid amides with different Gngnard reagent mixtures.

TABLE 4

[3] Use of an equivalent (CH ₃ ) ₃ SiCI as a cocatalyst From the experimental results it can be extrapolated that in a suspension of Ti0 ₂ in tetrahydrofuran (using 13 mol% of the Ti reagent with respect to the amide) with the addition of one equivalent each of two different Grignard reagents, all carboxamides dialkylated asymmetrically to the corresponding geminal Have tertiary amines reacted.

Working up was carried out as in the preceding examples.

Examples 15 to 17

To a solution of 3 mol% Ti (OiPr) _4> based on the amide given in Table 5, in 40 ml dry tetrahydrofuran, 5 mmol of the amide given in Table 6 and 5 mmol (CH ₃ ) ₃ SiCI added dropwise as cocatalyst. The mixture is stirred at 20 ° C for 5 min. Then 12 mmol or 6 mmol of the Grignard reagents shown in Table 6 are added to the reaction mixture so slowly that the reaction mixture is not heated above 50.degree. The mixture is then stirred at the reaction temperature given in Table 6 during the reaction time given in Table 5 until the reaction is complete.

Deviating from this, 15 mmol of magnesium shavings in 10 ml of tetrahydrofuran are introduced at 20 ° C. in a nitrogen atmosphere in Example 17. 3 mol%, based on the amide given in Table 1, Ti (OiPr) ₄ and 5 mmol of the amide given in Table 5 dissolved in tetrahydrofuran are added. For this purpose, 6 mmol of methyl bromide or phenyl bromide are slowly added dropwise, so that the mixture boils gently. During the reaction time of 1 hour and 25 ° C. reaction temperature, after previously adding 5 mmol of the above-mentioned cocatalyst, the product set out in Table 5 is obtained with the yield shown in Table 5 after 1 hour.

The reaction products are worked up as in Examples 1-8 Table 5

Me = methyl Ph = phenyl iPr = iso-propyl En = benzyl Cokst = (CH ₃ ) ₃ SiCI

Examples 18-105

The following amines of the general formula (I) were prepared according to the following general working procedure and identified by mass spectroscopy.

5 mmol of educt (1), either as a liquid or as a solution, were added to a solution of a titanium organyl Ti (0iPr) ₄ (3 mol% based on the amide used) in 40 ml of dry tetrahydrofuran at 20 ° C. under an inert gas atmosphere (nitrogen or argon) added dropwise in tetrahydrofuran. An additional 5 mmol of the cocatalyst CH ₃ SiCl is added to the reaction mixture and the mixture is stirred at 20 ° C. for 5 min. Then 12 mmol of an aryl Grignard reagent (in the case of asymmetrical dialkylation, a mixture of 6 mmol of two different Grignard reagents (2a and 2b), at least one of the Grignard reagents containing an aryl residue) being added so slowly that the mixture does not exceed 50 ° C warmed. 15 ml of saturated ammonium chloride solution and 15 ml of water are added and the mixture is stirred vigorously for 1-3 hours. The resulting precipitate is separated off and washed with a little dried diethyl ether. The filtrate is made basic (pH> 10) by adding 15% sodium hydroxide solution. The phases are then separated and the aqueous phase is extracted three times with 30 ml of diethyl ether each time. The combined organic phases are washed with 15 ml of saturated sodium chloride solution and dried over potassium carbonate and filtered.

The products can be cleaned in various ways (see Table 6):

1. The organic phase is extracted twice with 40 ml of a 0.5 M HCl solution. This extract is adjusted to pH> 10 with 2 M NaOH solution and extracted again with three times 30 ml of dried diethyl ether. The combined organic phases are dried over potassium carbonate and the solvent is removed under vacuum.

2. The solvent is removed in vacuo and the residue is isolated by column chromatography.

3. The solvent is removed in vacuo and the residue is distilled under vacuum. TABLE 6

125

- CA], 139

Examples 154 to 156

Creation of a combinatorial library

Various libraries were presented using the following general instructions: The amides shown in Tables 7 to 9 below are introduced in THF under argon with the catalyst (for example Ti (OiPr) ₄ ) and the cocatalyst (for example (CH ₃ ) ₃ SiCl). The various Grignard reagents are then added simultaneously if possible. The mixture is stirred further and worked up as described above. The synthesis conditions correspond to the individual syntheses described above, except that several amides are initially introduced and several different Grignard reagents are added simultaneously if possible. The amounts of substance were chosen so that the addition of all amides corresponds to the molar amount of the addition of all Grignard reagents. This ensures that all conceivable products can be preserved. The results are shown in Tables 7-9.

Table 7

possible product:

Table 8

possible products

Find

Table 9

possible products:

r, e IC%

Claims

claims

1. amine of the following general formula (I)

where R ¹ and R ^{2 may be the} same or different and each independently represent substituted or unsubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl or trialkylsilyl or R ¹ and R ² together with the nitrogen atom to which they are attached can form substituted or unsubstituted cycloalkyl ring which, in addition to the nitrogen atom, can also contain at least one further heteroatom which is selected from the group consisting of nitrogen, oxygen or sulfur,

R ^{3 is} selected from hydrogen and methyl, which may be substituted with 1 -3 fluorine atoms,

R ⁴ and R ^{5 may be the} same or different and each individually independently of one another represents alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, substituted or unsubstituted aryl or an alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl substituted by substituted or unsubstituted aryl , with the proviso that at least one radical R ⁴ or R ^{5 contains} an aryl group, or a salt thereof

2. Amine according to claim 1, wherein R ^{3 is} hydrogen or methyl

3 amine according to claim 1 or 2, wherein R ⁴ and R ^{5 are} different

4 amine according to one of claims 1 to 3, wherein R ¹ and R ² independently of one another for a C, ₈ -alkyl group, a C ₃₇ cycloalkyl group, a C _{3 7} -cycloalkyl group substituted with C, ₆ -alkyl group, a C ₃₇ -Cycloalkenyl group, one with a C _{3 7-} cycloalkenylene group substituted C, ₆ -alkyl group, a C _{2 a} -alkenyl group, a C _{2 8} -alkionyl group, a C, ₆ -alkoxy group substituted C, ₆ -alkyl group, a C ₂ -C -alkenyloxy group substituted C, _β alkyl group, a C substituted with a C _a 6-Alkιnyloxygruppe, ₆ alkyl group, a with a mono-, di- or Poiyhalogen-C, ₆ alkoxy-substituted C, ₆ alkyl group, a with a mono-, di- or polyhalo-C ₂₆ alkenyloxy group substituted C, ₆ alkyl group, a C substituted with mono-, di- and polyhaloC _{2 6} -Aikιnyloxygruppe, ₆ alkyl group, a with a C, ₆ -Alkyithιogruppe substituted C ^ alkyl group , a substituted with a C, ₆ - alkylsulfinyl group C ^ alkyl group, a substituted with a C, ₆ - alkylsulfonyl group C, ₆ - alkyl group, a mono-, di- or polyhalogen-C, _8- alkyl group, a mono-, di - or polyhalo-C _{2 8} alkenyl group, a mono-, di- or polyhalo-C ₂₈ alkynyl group, a m it a cyano-substituted C, ₆ alkyl group, a with a cyano group-substituted C _{2 e} alkenyl group, a having a cyano group-substituted C ₂ 6-Alkιnylgruppe, a C substituted with a nitro group, ₆ - alkyl group, substituted with a nitro group C ₂₆ alkenyl group, a nitro group substituted with a C _{2 6} -Alkιnylgruppe, a C substituted with C, _e -Alkylamιnogruppe, ₆ alkyl group, one having a C ₆ - C substituted Alkoxyammogruppe, ₆ alkyl group, one with a D ^ C , ₃ -alkyl) amino group substituted C, ₆ -alkyl group, one with an N-fC, ₃ -alkyl) -N- (C, ₃ -alkoxy) amino group-substituted C, _6- alkyl group, one with an N- (C, 6-alkyl) amιnogruppe substituted C, ₆ alkyl group, a, with a N- (C

6- alkoxy) amιnogruppe substituted C, _β alkyl group, a C substituted with a Tπ-C, ₆ -Alkylsιlylgruppe, ₆ alkyl group, a C substituted with a Tπarylsilylgruppe, ₆ alkyl group, a phenyl group (provided that such a phenyl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group and a C ₆ - alkyl group, a C _{1 6} alkoxy group), a C-substituted by a phenyl group, 6-alkyl group (with the proviso that such a phenyl group can be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group and a C, ₆ -aikyl group, a C _{1 s} -Alkoxy group), a C _{2 7} -alkenyl group substituted with a phenyl group (with the proviso that such a phenyl group may be substituted with one or m other substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C, ₆ -alkyl group and a C, ₆ -alkoxy group), a C _{2 6} -alkynyl group substituted by a phenyl group (with the proviso that such a phenyl group can be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C, ^ - alkyl group and a C, ^ - alkoxy group), a C, substituted with a phenoxy group. _6- alkyl group (with the proviso that such a phenoxy group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C,. 6-alkyl group and a C ^ -Alkoxy group), an alkyl group substituted with a phenylthio group (with the proviso that such a phenylthio group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C ,. ₆ - alkyl group and one

a C 1-4 alkyl group substituted with a phenylsulfinyl group (with the proviso that such a phenylsulfinyl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C, _.6 - alkyl group and a C ^ alkoxy group), a C ^ - alkyl group substituted with a phenylsulfonyl group (with the proviso that such a phenylsulfonyl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, one Trifluoromethyl group, a nitro group, a C, ^ alkyl group and a C ^ alkoxy group), a C ^ alkyl group substituted with a benzyloxy group (provided that the phenyl group of such a benzyloxy group may be substituted with one or more substituents selected) are from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C 1-4 alkyl group and a C ,. ₆ - alkoxy group), a C, substituted with a benzylthio group. ₆ -alkyl group (provided that the phenyl group of such a benzylthio group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C, _.6 -alkyl group and one C ^ alkoxy group), a C, substituted with a benzylsulfinyl group _. 6-alkyl group (with the proviso that the phenyl group of such a benzylsulfinyl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a

and one

a C, substituted with a benzylsulfonyl group. ₆ - alkyl group (with the proviso that the phenyl group of such a benzylsulfonyl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, one Trifluoromethyl group, a nitro group, a C, _β -alkyl group and a C, 6-alkoxy group), a C ^ -alkyl group substituted by an amino group which is substituted by a C, _4- alkylsulfonyl group, or together with the nitrogen atom on the they are bound to form a ring which is selected from the group consisting of 1-pyrrolidinyl, 1-imdazolionnyl, 1-pyrazolinyl, 1-pirperolny, 1-pirazolnyl, 4-morpholinyl, 4-thyramololnyl

Amine according to one of claims 1 to 3, wherein R ¹ and R ² independently of one another represent a C ₈ alkyl group, a C ₃₇ cycloalkyl group, a C ₆ alkyl group substituted by a C _{3 7} cycloalkyl group, a C ₃₇ - Cycloalkenyl group, a C ₃ 7 -cycloalkenyl group substituted C, ₆ alkyl group, a C _{2 8} alkenyl group, a C _{2 g} alkynyl group, a C, _6- alkoxy group substituted C, _β- alkyl group, one with a C. _{2 e} -Alkenyloxy group substituted C, _6- alkyl group, a substituted with a C ₂ 6-alkιnyloxy group C, _6- alkyl group, a substituted with a mono-, di- or polyhalo-C, _6- alkoxy group, C, _6- alkyl group, one with a mono-, di- or polyhalo-C _{2 β} -alkenyloxy group substituted C, _e -alkyl group, one with a mono-, di- and polyhalo-C _{2 6} -alkionyloxy group substituted C, ₆ -alkyl group, one with a C, _e -Alkylthιogruppe substituted C, ₆ -alkyl group, one with a C, ₆ - Alkylsulfinylgruppe substiti erte C, ₆ -alkyl group, a C, _β -alkylsuifonyl group substituted by C, ₆ -alkyl group, a mono-, di- or polyhalo-C, _8- alkyl group, a mono-, di- or polyhalo-C ₂₈ -alkenyl group , a mono-, di- or polyhalo-C ₂₈ alkynyl group, a C, _β- alkyl group substituted with a cyano group, a C _{2 6} -alkenyl group substituted with a cyano group, a C ₂ g -alkionyl group substituted with a cyano group, one with a nitro group-substituted C ₆ - alkyl group, a nitro group with a substituted C _{2 6} alkenyl group, a nitro group substituted with a C _{2 g} -Alkιnylgruppe, substituted with a C, ₆ -Alkylamιnogruppe C, ₆ alkyl group, a with a C , ₆ - Alkoxyamino group substituted C ^ alkyl group, one with a Dι (C, ₃ - alkyl) amino group substituted C, ₆ alkyl group, one with an N- (C, ₃ - alkyl) -N- (C, ₃ - alkoxy ) amino group substituted C, _β- alkyl group, one with an N- C, ₆ -alkylsulfonyl) -N- (C _{1 6} -alkyl) amino group substituted C, ₆ -alkyl group, one with an N- (C, _6- alkylsulfonyl) -N- (C _{1 6} -alkoxy) amino group-substituted C, _e -alkyl group, one with a Tπ-C, _6th -Alkylsιlylgruppe substituted C, ₆ -alkyl group, a C, ₆ -alkyl group substituted with a tπarylsilyl group or a C, _e -alkyl group substituted with an amino group which is substituted with a C, ₄ -alkylsulfonyl group

6. Amine according to one of claims 1 to 3, wherein R ¹ and R ² together with the nitrogen atom to which they are attached form a ring which is selected from the group of 1-pyrrolidinyl, 1-imidazolinyi, 1 -pyrazolinyl, 1 -Piperidyl, 1-piperazinyl, 4-morpholinyl, 4-thiamorpholinyl.

7. Amine according to one of claims 1 to 6, wherein R ¹ and R ² independently of one another for a phenyl group (with the proviso that such a phenyl group may be substituted with one or more substituents selected from the group consisting of a Halogen atom, a trifluoromethyl group, a nitro group, a C, _.6 - alkyl group and a C, .g-alkoxy group), a C,. Substituted with a phenyl group _. g-aikyl group (with the proviso that such a phenyl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C 1-4 alkyl group and one

a C _2.7 alkenyl group substituted with a phenyl group (with the proviso that such a phenyl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C 1-4 alkyl group and a C ^ _g alkoxy group), a substituted phenyl group having a C _{2nd 6} -alkynyl group (with the proviso that such a phenyl group can be substituted with one or more substituents which are selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C ^ - alkyl group and a C, ^ - Alkoxy group), a C 1-4 alkyl group substituted with a phenoxy group (with the proviso that such a phenoxy group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C ^ Alkyl group and a C _L g alkoxy group), a C, ^ - alkyl group substituted with a phenylthio group (with the proviso that such a phenylthio group may be substituted with one or more substituents selected from the group consisting of a Halogen atom, a trifluoromethyl group, a nitro group, a C ^ - alkyl group and a C ^ alkoxy group), one with a Ph enylsulfinyl group substituted C, ^ - alkyl group (with the proviso that such a phenylsulfinyl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C ,. ₆ -alkyl group and a C, _.6- alkoxy group), a C ^ - alkyl group substituted by a phenylsulfonyl group (with the proviso that such a phenylsulfonyl group may be substituted by a or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C 1-4 alkyl group and one

a C, substituted with a benzyloxy group. ₆ - alkyl group (with the proviso that the phenyl group of such a benzyloxy group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C 6 alkyl group and one

a C, substituted with a benzylthio group _{. 6} -alkyl group (with the proviso that the phenyl group of such a benzylthio group can be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C, ^ - alkyl group and a C ^ -Alkoxy group), a C ^ -alkyl group substituted with a benzylsulfinyl group (with the proviso that the phenyl group of such a benzylsulfinyl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, one _. nitro group, a C ,. ₆ alkyl group and a C, 6 alkoxy group), a substituted benzylsulfonyl group with a C, ^ - alkyl group (with the proviso that the phenyl group of such a benzylsulfonyl group may be substituted with one or more substituents are selected from the group consisting of a halogen atom, a trifluoromethyl group, egg a nitro group, a C ,. _e - alkyl group and one

stand

8. Amine according to one of claims 1 to 6, wherein at least one radical from R ⁴ or R ⁵ for an aryl group (with the proviso that such an aryl group may be substituted with one or more substituents selected from the group consisting of from a halogen atom, a trifluoromethyl group, a nitro group, a C, _.6 -alkyl group and a C, _.β- alkoxy group), a C, substituted with an aryl group. ₆ -alkyl group (with the proviso that such an aryl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C, _.beta. -alkyl group and a C, _e. alkoxy group), an aryl group substituted with a _{C2. 7-} alkenyl group (with the proviso that such an aryl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C,. ₆ -alkyl group and a C, _. β-alkoxy group), an aryl group substituted with a _{C2. 6} -alkynyl group (with the proviso that such an aryl group can be substituted with one or more Substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C, .g alkyl group and a C ^ - alkoxy group), a C ^ alkyl group substituted with an aryloxy group (with the proviso that such an aryloxy group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C. ₆ alkyl group and a C 6 alkoxy group), one substituted with an arylthio group C, ^ - alkyl group (with the proviso that such an arylthio group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C,. ₆ -alkyl group and one _. C, 6-alkoxy group), a C-substituted with an arylsulfinyl group ,. ₆ -alkyl group (with the proviso that such an arylsulfinyl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C 1-4 alkyl group and one

Alkyl group (with the proviso that such an arylsulfonyl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, one

Alkyl group and one

a C, substituted with a benzyloxy group. ₆ - alkyl group (with the proviso that the aryl group of such a benzyloxy group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C g alkyl group and a C, ₆ -Aikoxygruppe), a C substituted with a benzylthio group _{. 6} - alkyl group (with the proviso that the aryl group of such a benzylthio group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a

a C, _.e alkyl group substituted with a benzylsulfinyl group (provided that the aryl group of such a benzylsulfinyl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, one

and a _C,. β-alkoxy group), or a C, substituted with a benzylsulfonyl group. _s - alkyl group (with the proviso that the aryl group of such a benzylsulfonyl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C ,. ₆ - alkyl group and one

stands.

9. Amine according to one of claims 1 to 3, wherein R ¹ and R ^{2 are} each independently of one another for methyl, ethyl, isopropyl, n-butyl, isobutyl, phenyl, benzyl, 2-pyridyl or trimethylsilyl, or together with the nitrogen atom to which they are attached represent 1-pyrrolidinyl, 1-piperidyl, 4-methylpiperidyl, or 4-morpholinyl.

10. Amine according to one of claims 1 to 3, wherein at least one radical from R ⁴ and R ^{5 is} phenyl, benzyl, p-tolyl, m-tolyl, 4-fluorophenyl, 4-fluoro-3-methylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 2,6-dimethylphenyl, 2-methyl-2-phenylethyl, 3-phenyl-prop-2-ynyl, 4-dimethylaminophenyl, naphthalen-1-yl or 3-aminophenyl.

11. Combinatorial library comprising amines of the general formula (I) as defined in one or more of claims 1 to 10.

12. A process for the preparation of a combinatorial library comprising amines as claimed in claim 1, which comprises reacting one or more compounds of the general formula (II)

wherein R ³ , R ⁴ and R ^{5 have} the meanings given in claim 1, with at least one compound of the general formula (purple) or (IIIb)

ZR ⁴ (purple)

ZR ⁵ (lllb)

in which

R ⁴ and R ^{5 have} the meanings given above, where, Z Li or MgX with

X shark and

Hai Cl, Br or I mean in a solvent in the presence of a titanium, hafnium, or

Zirconium compound and optionally a cocatalyst to a combinatorial

Create a library with at least 5 different amines.

13. Use of an amine according to one of claims 1 to 10 or a combinatorial library according to claim 11 as an intermediate in the production of active ingredients.