JP2003524588A - Geminal substituted amine - Google Patents

Abstract

(57) The present invention relates to amines of general formula (I), wherein R ¹ and R ² may be the same or different and are each independently substituted or unsubstituted alkyl, Cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl or trialkylsilyl. R ¹ and R ² together with the nitrogen atom to which they are attached form a substituted or unsubstituted cycloalkyl ring which, in addition to the nitrogen atom, comprises nitrogen, oxygen or sulfur. It is also possible to include at least one further selected heteroatom. R ³ is selected from hydrogen and methyl, but methyl may be optionally substituted by 1 to 3 fluorine atoms, and R ⁴ and R ⁵ may be the same or different and each is independently And is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, or alkynyl. The invention also relates to their salts.

Description

Detailed Description of the Invention

The present invention relates to geminal substituted amines. In particular, the present invention relates to geminally alkylated amines, combinatorial libraries of such amines, and in particular as intermediates for the combinatorial synthesis of active compounds,
Or to the use of those amines as active compounds in medicine.

It is known to synthesize material libraries containing mixtures of various reaction products starting from several different starting materials by combinatorial preparative methods.
On the one hand, it is then possible to identify reaction products with physiological activity by suitable screening of the library and subsequently to identify and synthesize this compound. On the other hand, however, the library can also be used for subsequent combinatorial synthesis. The combination of these two possibilities makes it possible to develop new classes of active compounds.

A prerequisite for the combinatorial synthesis of libraries of active compounds is to obtain the appropriate starting compound which already has a physiologically active structural element or which forms it by combinatorial synthesis.

The object of the present invention is therefore to provide novel compounds which have specific biologically active structural elements and which can be used in the combinatorial synthesis of compounds which are active individually or as a library.

This object is achieved by obtaining the amines of formula (I) below, either in pure form or as a substance library as a mixture of various amines of formula (I). Surprisingly, it has been found that the geminal substitution of preferably tertiary amines not only leads to physiological activity, but at the same time provides advantageous properties for the combinatorial synthesis of active compounds. It has also been found out how many amines of general formula (I) can be synthesized as a substance library.

[Chemical 3] In the formula, R ¹ and R ² may be the same or different, each independently being a 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 form a substituted or unsubstituted cycloalkyl ring, which, in addition to the nitrogen atom, consists of nitrogen, oxygen or sulfur It is also possible for it to contain at least one further heteroatom selected from the group, R ³ is selected from hydrogen or methyl, which may optionally be substituted with 1 to 3 fluorine atoms, R ⁴ And R ⁵ may be the same or different and each independently of each other, a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, cycl Alkenyl, or alkynyl, or a salt, especially a pharmaceutically acceptable salt thereof.

[0006]   The compounds of the present invention are particularly useful as sympathomimetic agents.

Alkyl is preferably C _1-10 alkyl, more preferably C _2-8 alkyl. Cycloalkyl is preferably C _3-8 cycloalkyl, more preferably C _3-7 cycloalkyl. Alkenyl is preferably C _2-10 alkenyl, more preferably C _2-8 alkenyl. Cycloalkenyl is preferably C _3-8 cycloalkenyl, more preferably C _3-7 cycloalkenyl. Alkynyl is preferably C _2-10 alkynyl, more preferably C _2-8 alkynyl. Aryl is preferably phenyl, naphthyl, anthryl, or phenanthryl.

Specific examples of the alkyl radical include methyl, ethyl, propyl, butyl,
Examples include pentyl and hexyl. Specific examples of cycloalkyl radicals include:
Examples include cyclopropyl, cyclobutyl and cyclohexyl. Specific examples of the alkenyl radical include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl and isobutenyl.

Examples of R ¹ and R ² are listed below, wherein halogen is fluorine, chlorine, bromine or iodine: R ¹ and R ² may be the same or different and may be Independently, C _1-8
Alkyl group, C _3-7 cycloalkyl, C _3-7 C _1-6 alkyl group substituted by a cycloalkyl group, C _3-7 cycloalkenyl group, C _3-7 C ₁ which is substituted by a cycloalkenyl group _-6 alkyl group, C _2-8 alkenyl group, C _2-8 alkynyl group, C _1-6 alkyl group substituted by C _1-6 alkoxy group, C _1- substituted by C _2-6 alkenyloxy group ₆ alkyl groups, C _1-6 substituted by C _2-6 alkynyloxy groups
Alkyl group, C _1-6 alkyl group substituted by mono-, di- or polyhalo-C _1-6 alkoxy group, C _1- substituted by mono-, di- or polyhalo-C _2-6 alkenyloxy group ₆ alkyl group, a mono -, di - or polyhalo -C _2-6 C _1-6 alkyl group substituted by alkynyloxy group, C _1-6 alkyl group substituted by a C _1-6 alkylthio group, C _1- C _1-6 substituted by ₆ alkylsulfinyl group
Alkyl group, C _1-6 alkyl group substituted by C _1-6 alkylsulfonyl group, mono-, di- or polyhalo-C _1-6 alkyl group, mono-, di- or polyhalo-
A C _2-8 alkenyl group, a mono-, di- or polyhalo-C _2-8 alkynyl group, a C _1-6 alkyl group substituted by a cyano group, a C _2-6 alkenyl group substituted by a cyano group,

A C _1-6 alkyl group substituted by a nitro group, a C _2-6 alkenyl group substituted by a nitro group, a C _2-6 alkynyl group substituted by a nitro group, a C _1-6 alkylamino group substituted C _1-6 alkyl group, C _1-6 alkoxy amino C _1-6 alkyl group substituted by a group, di (C _1-3 alkyl) C _1-6 alkyl group substituted by an amino group, N -(C _1-3 alkyl) -N- (C _1-3 alkoxy) amino group-substituted C _1-6 alkyl group, N- (C _1-6 alkylsulfonyl) -N- (C _1-6 alkyl) ) C _1-6 alkyl group substituted by an amino group, N-(C _1-6 alkylsulfonyl) -N- (C _1-6 alkoxy) C _1-6 alkyl group substituted by an amino group, tri -C _1-6 alkylsilyl C _1-6 alkyl group substituted by a group, a triarylsilyl group Substituted C _1-6 alkyl group, a phenyl group (provided that such a phenyl group is selected from the group consisting of halogen atom, trifluoromethyl group, nitro group, C _1-6 alkyl and C _1-6 alkoxy groups Optionally substituted by one or more substituents),

[0011] phenyl C _1-6 alkyl group substituted by (provided that such a phenyl group consists of a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 alkyl group and C _{1 -6} alkoxy group Optionally substituted by one or more substituents selected from the group), C _2-7 alkenyl groups substituted by phenyl groups (provided that
Such phenyl group is a halogen atom, a trifluoromethyl group, a nitro group, optionally substituted by one or more substituents selected from C _1-6 alkyl groups and C _1-6 group consisting alkoxy group C _2-6 alkynyl group substituted by a phenyl group (provided that such a phenyl group comprises a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 alkyl group and a C _1-6 alkoxy group) Optionally substituted by one or more substituents selected from the group), C _1-6 alkyl group substituted by a phenoxy group (provided that such a phenoxy group is a halogen atom, a trifluoromethyl group, nitro group, optionally substituted by one or more substituents selected from the group consisting of C _1-6 alkyl and C _1-6 alkoxy group), phenylthio group More substituted C _1-6 alkyl group (provided that such a phenylthio group selected from the group consisting of halogen atom, trifluoromethyl group, nitro group, C _1-6 alkyl and C _1-6 alkoxy groups Optionally substituted by one or more substituents),

[0012] C substituted by a phenylsulfinyl group_1-6Alkyl group (however,
Phenylsulfinyl group is a halogen atom, trifluoromethyl group, nitro group,
C_1-6Alkyl group and C_1-61 or it selected from the group consisting of alkoxy groups
Optionally substituted by the above substituents), substituted by phenylsulfonyl group
C_1-6Alkyl group (however, phenylsulfonyl group is halogen atom, tri
Fluoromethyl group, nitro group, C_1-6Alkyl group and C_1-6More than an alkoxy group
Optionally substituted by one or more substituents selected from the group
C substituted with a benzyloxy group_1-6Alkyl group (However,
The phenyl group of the ruoxy group is a halogen atom, trifluoromethyl group, nitro group, C _1-6 Alkyl group and C_1-61 or more selected from the group consisting of alkoxy groups
Optionally substituted by the above substituents),

[0013] C substituted by a benzylthio group_1-6Alkyl group (However,
The phenyl group of the ruthio group is a halogen atom, trifluoromethyl group, nitro group, C_{1- 6} Alkyl group and C_1-6One or more selected from the group consisting of alkoxy groups
Optionally substituted by a substituent), substituted by a benzylsulfonyl group
C_1-6Alkyl group (however, such phenyl group of benzylsulfinyl group
Is a halogen atom, trifluoromethyl group, nitro group, C_1-6Alkyl group and C_{1 -6} Substituted by one or more substituents selected from the group consisting of alkoxy groups
C) substituted with a benzylsulfinyl group_1-6Alkyl group
(However, the phenyl group of such a benzylsulfonyl group is a halogen atom or a triphenyl group.
Fluoromethyl group, nitro group, C_1-6Alkyl group and C_1-6More than an alkoxy group
Optionally substituted by one or more substituents selected from the group _1-4 C substituted with an amino group substituted with an alkylsulfonyl group_1-6Al
For example, a kill group.

If the R ¹ and R ² radicals form a cycloalkyl ring and, in addition to the nitrogen atom, optionally further comprise at least one heteroatom, preferably a nitrogen, oxygen or sulfur atom, Examples of such rings include: 1-pyrrolidinyl, 1-imidazolinyl, 1-pyrazolinyl, 1-piperidyl, 1-piperazinyl, 4-morpholinyl, 4-thiamorpholinyl.

Particularly preferred R ¹ and R ² radicals are in each case, independently of one another, methyl, ethyl, isopropyl, n-butyl, isobutyl, phenyl, benzyl, 2-pyridyl or trimethylsilyl, or a combination thereof. 1-pyrrolidinyl, 1-piperidyl, 4-methylpiperidyl or 4-morpholinyl, together with the nitrogen atom present.

Particularly preferred as R ³ is hydrogen.

[0017]   R^FourAnd R^FiveThe following are examples of halogen, where halogen is fluorine, chlorine, or bromine.
Or is iodine:   R^FourAnd R^FiveMay be the same or different, but independently of each other, C_{1- 8} Alkyl group, C_3-7Cycloalkyl group, C_3-7Substituted by a cycloalkyl group
C_1-6Alkyl group, C_3-7Cycloalkenyl group, C_3-7Cycloalkenyl group
Replaced by C_1-6Alkyl group, C_2-8Alkenyl group, C_2-8Alkynyl group, C_1-6 C substituted by an alkoxy group_1-6Alkyl group, C_2-6By alkenyloxy group
Replaced by C_1-6Alkyl group, C_2-6C substituted by an alkynyloxy group_{1- 6} Alkyl group, mono-, di- or polyhalo-C_1-6Substituted by an alkoxy group
C_1-6Alkyl group, mono-, di- or polyhalo-C_2-6For alkenyloxy groups
More substituted C_1-6Alkyl group, mono-, di- or polyhalo-C_2-6Alkini
C substituted by a ruoxy group_1-6Alkyl group, C_1-6Substituted by alkylthio group
C_1-6Alkyl group, C_1-6C substituted with an alkylsulfinyl group_1-6
Alkyl group, C_1-6C substituted with an alkylsulfonyl group_1-6Alkyl group,
No-, di- or polyhalo-C_1-8Alkyl group, mono-, di- or polyhalo-
C_2-8Alkenyl group, mono-, di- or polyhalo-C_2-8Alkynyl group, cyano
C substituted by a group_1-6C substituted with an alkyl group or a cyano group_2-6Archeni
C substituted with a chloro group or a cyano group_2-6Substituted by alkynyl and nitro groups
C_1-6C substituted with an alkyl group or a nitro group_2-6For alkenyl and nitro groups
More substituted C_2-6Alkynyl group, C_1-6C substituted with an alkylamino group _1-6 Alkyl group, C_1-6C substituted by an alkoxyamino group_1-6An alkyl group,
The (C_1-3C substituted with an alkyl) amino group_1-6Alkyl group, N- (C_1-3
Alkyl) -N- (C_1-3C) substituted with an alkoxy) amino group_1-6Alkyl
Group, N- (C_1-6Alkylsulfonyl) -N- (C_1-6Alkyl) amino group
The substituted C_1-6Alkyl group, N- (C_1-6Alkylsulfonyl) -N- (C_1-6
C) substituted with an alkoxy) amino group_1-6Alkyl group, Tri-C_1-6Alkyl
C substituted by a silyl group_1-6Substituted with alkyl or triarylsilyl group
C_1-6It is an alkyl group.

Particularly preferred as R ⁴ and R ⁵ are methyl, ethyl, isopropyl, n-
Butyl, tert-butyl, ethenyl, ethynyl, allyl, n-hexyl, trimethylsilylmethyl, cyclopropyl, cyclopentyl, cyclohexyl.

[0019]   The present invention also provides the amine of the following general formula (Ia).

[Chemical 4] In the formula, R ¹ , R ² , R ⁴ and R ⁵ have the meanings given above, but preferably,
R ¹ and R ² are in each case independently of one another ethyl or hexyl or, together with the nitrogen atom to which they are bonded, a piperidyl group, and R ⁴ and R ⁵ are In each case hydrogen, methyl, butyl or hexyl, both independently of one another and together.

The combinatorial library contemplated by the present invention comprises at least 5, preferably at least 7 different amines of general formula (I) or (Ia).

[0021]   The synthesis of amines of general formulas (I) and (Ia) is described below.

The method for synthesizing the compound of general formula (I) is not particularly limited. However, it has been found that the compound of general formula (I) can be preferably synthesized by any of the following methods.

In the compounds of the present invention, especially the geminally symmetrically substituted amines of formula (I),
R ⁴ and R ⁵ are the same, but the compound of the general formula (II)

[Chemical 5] In the formula, R ¹ , R ² and R ³ have the meanings given above, but R ³ is particularly preferably hydrogen or a methyl group, which is used in a suitable solvent to give a compound of the general formula (III) during the M-R ⁴ (III) wherein the radical M is a radical MgX (X is Cl, Br or I) is or lithium, but R ⁴ denotes those indicated above, further optionally the general formula (IV compound with R ⁵ TiY in _{^{3-n (oR III) n}} (IV-a) expression -a), Y is F, Cl, Br and I, a radical R ^III is an alkyl radical of C ₁ -C _10, C ₆ -C ₂₀ aryl radical or fluorine, chlorine, aryl radicals of bromine or C ₆ -C ₂₀ which is 1-5-substituted iodine, preferably isopropyl radical, those R ⁵ is as indicated above Means, n is an integer from 1 to 3, That.

The compound suitable for this reaction is preferably carboxamide, and the R ¹ and R ² radicals of the carboxamide may be the same or different, and also include C ₁ -C ₁₀ alkyl radicals and perfluorinated compounds. C ₁ -C ₁₀ alkyl radicals mono- or poly-substituted with fluorine, C ₃ -C ₈ cycloalkyl radicals, C ₆ -C ₂₀ aryl radicals, 1-5 substituted with fluorine, chlorine, bromine, iodine aryl radicals, alkenyl radicals of C ₂ -C _10, alkynyl radical of C ₂ -C _10, cycloalkyl ring of C ₃ -C ₈ formed from R ¹ and R ² radicals, further optionally in addition to the nitrogen heteroatom It contains a nitrogen, oxygen or sulfur atom as an atom.

Particularly preferred compounds for use as the carboxamide of formula (II) are compounds of the formula:

[Chemical 6]

[0026]   The Grignard compound or organolithium compound used in the reaction has the general formula (II
It is a compound of I). In this general formula (III), R^FourThe radical is preferably C₁ ~ C_TenAlkyl radicals, including all-fluorinated compounds
Converted C₁~ C_TenAlkyl radical, C₃~ C₆Cycloalkyl radical, C₂~
C_TenAlkenyl radical, C₂~ C_TenAlkynyl radical, or- (CR ")
(R ') CH₂A radical of the form R, where R ″ is —Si (R)₃, Sn (R) ₃ , -SR, -OR, -NRR ', wherein R and R'are the same or different.
May be present, but C₁~ C_TenFluorine including alkyl radicals and perfluorinated compounds
More mono- or poly-substituted C₁~ C_TenAlkyl radical, C₂~ C_TenArcheni
Luradal, C₂~ C_TenAlkynyl radical, C₃~ C₆Cycloalkyl radical
Is. Particularly preferred R^FourThe radical is a methyl or cyclopropyl radical
R^FourAnd R^FivePreferably has at most one hydrogen atom in its β position
Yes.

In the radical M in the general formula (III), X is preferably Cl or Br.
It is a MgX radical or the radical M is lithium.

Further, this reaction can be suitably carried out by using an organic titanium compound.
As suitable organotitanium compounds, the compounds of general formula (IV-a) shown above are preferred, where n is an integer from 1 to 3, preferably 3, Y is Cl, Br or I and R ^{III May} be the same or different, but is a C ₁ -C ₁₀ alkyl radical or a C ₆ -C ₂₀ aryl radical, preferably isopropyl, and R ⁵ is the same or different as R ^4. However, it means the one shown by R ⁴ .

Particularly preferable as the organic titanium compound used is R ⁵ Ti (OiPr) ₃ ,
Here, iPr is an isopropyl radical.

Particular preference is given to using methyl, phenyl, cyclopropyl or p-fluorophenyltriisopropyl titanate.

In the reaction, the compounds of the general formulas (III) and (IV) are each 0.7 to 1.3 equivalents, preferably 0.9 to 1 based on the compound of the general formula (II).
． An amount of 1 equivalent should be used.

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

Particularly preferably, the compounds of the general formulas (II) and (IV) and the cocatalyst are first brought into solution and the compound (III) is gradually metered into it. Here, it is preferable that the Grignard compound or the lithium compound is added as a solution in which the above-mentioned solvent is dissolved, and the solution is added dropwise to the reaction mixture. It is more preferred if the reaction mixture is always stirred during the reaction.

In order to synthesize the amino compound of the general formula (I), it is preferable to react at room temperature, that is, 20 to 25 ° C. in an inert gas atmosphere.

After completion of the reaction, the symmetrical or asymmetrically substituted amino compound is purified by a conventional method,
It can be isolated.

In this case, the product can be precipitated with a hydrogen chloride solution, for example with a 1 molar ethereal hydrogen chloride solution and then filtered off, and if necessary by recrystallization. It can also be purified.

The product is also extracted from the organic phase with an acid solution, preferably an aqueous hydrochloric acid solution, and then the p of the resulting extract is extracted with an alkali, preferably sodium hydroxide solution.
Adjust H above 10 and then at least once with dry diethyl ether,
It is also possible to extract preferably several times. The organic phase thus obtained contains the reaction product and can optionally be dried (over potassium carbonate) and the organic solvent can be removed under vacuum.

It is also possible to isolate the reaction product by removing the organic solvent by using vacuum and separating the residue by column chromatography to separate the reaction product.

The compound of the present invention is a compound of general formula (II) above (wherein R ¹ , R ² and R ³ are as defined in formula (I)) and a compound of general formula (III) A nucleophile (wherein R ⁴ is as defined in formula (I)) and a catalytic amount of a metal oxide selected from the group consisting of titanium dioxide, hafnium dioxide and zirconium dioxide. It can also be synthesized by reacting with.

It is also possible to carry out the process in the presence of a cocatalyst, in which case an alkylsilyl halide can be used as a cocatalyst; that is to say general formula (V) R ^IV ₃ SiX (V) or general formula (V) _{VI) R 0 - (X)} m Si-Y- (Si) p - ( a alkylsilyl halide _{X) 9 -R 0 (VI)} , the alkyl wherein R ^IV is selected having 1 to 10 carbon atoms Or aryl having 6 to 20 carbon atoms, X is F, Cl, Br, I, CN Y is (CH ₂ ) _n , O, NH, bond m is 0, 1 n is 1 to 10 o is 0 2,3 p is 0,1 and q is 0,1, provided that when m is 0, o is 3 and Y is not (CH ₂ ) _n .

Surprisingly, the use of cocatalysts suppresses the α- and / or β-elimination normally observed with titanium alkyls having α- and / or β-hydrogen atoms.

Accordingly, the process can be carried out as follows: a) 1 on the carboxamide basis of a carboxamide of the general formula (II) and a catalyst selected from the group consisting of titanium dioxide, hafnium dioxide, zirconium dioxide. ~ 15
An amount of mol% and optionally a cocatalyst 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). A solution containing the nucleophile of the general formula (III) is added dropwise, and c) a post-reaction is carried out with stirring, and after completion of the reaction, the reaction mixture is worked up by a conventional method, or when Z is MgX, A ') magnesium pieces, a carboxamide of the general formula (II), and an amount of 1 to 15 mol% based on the carboxamide of the catalyst selected from the group consisting of titanium dioxide, hafnium dioxide and zirconium dioxide. , 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 '). Toluene, THF, n-hexane, 'was added dropwise alkyl halide, X-R ⁴ (III benzene and formula dissolved in a solvent selected from the group consisting of diethyl ether (III)') where, R ⁴ and X have the meanings given above, c ') the post-reaction is carried out with stirring and, after the reaction has ended, the reaction mixture is worked up in a customary manner.

The nucleophile of the general formula (III) may be a Grignard reagent, or may be produced in the reaction field or added to the reaction mixture, but it may be titanium dioxide, hafnium dioxide or dioxide. In the presence of a catalytic amount of zirconium, the general formula (
It has been shown that the carboxamides of II) can be easily reacted with this nucleophile to give not only symmetrically substituted but also asymmetrically substituted compounds of general formula (I). It became clear from.

The process described herein allows the carboxamides of general formula (II) to react to give high yields, where R ¹ and R ² independently of one another mean: Hydrogen or A, i.e. branched or unbranched alkyl having 1 to 10 carbon atoms, e.g. methyl, ethyl, n- or i-propyl, n-, sec- or t-.
Butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and suitable isomers thereof, or cycloalkyl having 3 to 8 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Cyclooctyl, or their methyl- or ethyl-substituted cycloalkyl groups, or mono- or polyunsaturated cycloalkyl groups, such as cyclopentenyl or cyclopentadienyl, or branched or unbranched with 2 to 10 carbon atoms Alkenyl, such as allyl, vinyl, isopropenyl, propenyl, or branched or unbranched alkynyl having 2-10 carbon atoms, such as ethynyl, propynyl, or unsubstituted or mono- or poly-substituted 6- Aryl having 20 carbon atoms, for example phenyl, naphthyl, anthryl, phenanthryl, with a substituent selected from the group consisting of NO ₂ , F, Cl, Br, NH ₂ , NHA, NA ₂ , OH and OA. Mono- or poly-substituted, where A means the same as above, mono- or poly-or all-halogenated, particularly preferred is fluorinated, or 7- An aralkyl radical having 20 carbon atoms, for example benzyl, optionally NO ₂ , F,
Mono- or poly-substituted with a substituent selected from the group consisting of Cl, Br, NH ₂ , NHA, NA ₂ , OH, and OA, where A means the same as above,
Mono- or poly- or wholly halogenated, especially preferred is fluorinated, or aralkenyl or aralkynyl, wherein the aryl, alkenyl and alkynyl groups respectively have the meanings given above. , For example, phenylethynyl, and R ³ is hydrogen or methyl.

R ¹ and R ² are bonded to each other to form a ring having 3 to 8 carbon atoms, which ring optionally has, in addition to nitrogen, further —S—, —O— and — Good yields are also obtained with carboxamides containing heteroatoms such as N-. Especially preferred are R ¹ and R ² form a monocyclic ring containing nitrogen carboxamide, R ¹ and R ² in compounds as to form a ring containing an oxygen atom as another hetero atom is there.

For the above reasons, a high yield can be obtained by using the following compounds as starting materials.

[Chemical 7]

The nucleophiles which may be used may be Grignard or lithium compounds of the general formula (III), in which each radical has the following meaning: R ⁴ has 1 to 10 carbon atoms, It is preferably an alkyl radical,
For example, methyl, ethyl, n- or i-propyl, n-, sec- or t
Butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and suitable isomers thereof, or cycloalkyls having 3 to 8 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Cyclooctyl, or their methyl- or ethyl-substituted cycloalkyl groups, or mono- or polyunsaturated cycloalkyl groups, such as cyclopentenyl or cyclopentadienyl, or branched or unbranched with 2 to 10 carbon atoms. Alkenyl radicals such as allyl, vinyl, isopropenyl, propenyl, or branched or unbranched alkynyl having 2 to 10 carbon atoms, eg,
Ethynyl and propynyl.

Particularly preferred Grignard compounds for use in the reaction include, for example, methyl magnesium bromide, ethyl magnesium bromide, n- or i-propyl magnesium bromide, i-, sec- or tert-butyl magnesium bromide, n-hexyl magnesium. Examples include bromide, cyclohexylmagnesium chloride, vinylmagnesium bromide, cyclopentylmagnesium bromide, cyclopentylmagnesium chloride and allylmagnesium bromide.

It has been found that the geminal symmetrical dialkylation reaction is initiated by the addition of cocatalyst, even at room temperature, to complete the reaction of the starting materials in a relatively short time. A suitable cocatalyst for this reaction is an alkylsilyl halide. In particular, these are alkylsilyl halides of general formula (V) or general formula (VI) above.

The alkylsilane halide is preferably an alkyl having R ^IV having 1 to 6 carbon atoms. Particularly preferred are alkyls in which R ^IV has from 1 to 3 carbon atoms and X is chlorine.

[0051]   Among these, the following silicone compounds are particularly preferable as the cocatalyst.

[Chemical 8]

0.7 to 1.2 mol of cocatalyst, preferably 0.9 per mol of starting material
It was found that the addition of ˜1.1 mol gives favorable results such as an improvement in yield, a decrease in reaction temperature, and a reduction in reaction time.

As seen in the examples, if the conditions are chosen appropriately, the carboxamide reaction is complete after 1 hour.

To carry out this method, a commercially available metal oxide selected from the group consisting of titanium dioxide, hafnium dioxide and zirconium dioxide can be dried and used as a catalyst. It is preferred to use powdered titanium (IV) oxide (TiO ₂ ). In the simplest case, this may be industrial grade. It is better to select a grade that is not extremely refined so that it can be easily separated after the reaction.

A metal oxide, preferably titanium dioxide, which has been dried in advance by heating,
Similarly, it is used by suspending it in a suitable organic solvent which has been dried in advance. Suitable solvents are, for example, aliphatic or aromatic hydrocarbons or ethers. Preferably, a solvent is selected from the group consisting of toluene, tetrahydrofuran, n-hexane, cyclohexane, benzene and diethyl ether and dried by a method known to those skilled in the art prior to the reaction. For drying magnesium sulfate, calcium chloride, sodium, KOH or other methods are used.

A preferred method of carrying out this reaction consists of the following: First, 1 to 15, preferably 1.5 to 14, more preferably 2 to 10 and most preferably 3 to 6 mol% of titanium oxide (as a catalyst) based on 1 mol of an amide used as a starting material. IV) in the form of a suspension, which is 10-30 ° C, preferably 15-25 ° C.
Particularly preferably, the temperature is adjusted to about 20 ° C. Under an inert gas (nitrogen or argon) atmosphere, the starting material is liquid or dissolved in a solvent selected from the group consisting of toluene, tetrahydrofuran, n-hexane, cyclohexane, benzene and diethyl ether, and the solution is added dropwise with stirring. Add slowly. Then, a reaction amount of the cocatalyst, if necessary dissolved in a solvent as well, is added dropwise. The reaction mixture obtained is stirred for a short time, that is for a few minutes, and the temperature is kept constant.
A sufficient amount of the nucleophile of the general formula (III), preferably the Grignard reagent, is then slowly added to the reaction mixture thus obtained in such a way that the geminal carbonyl carbon atom has two identical substituents. To allow symmetric substitution of the geminal carbonyl carbon atom. The nucleophile in the present invention is prepared by a method generally known to those skilled in the art, but the addition thereof should be carried out gradually so that the temperature of the reaction mixture does not exceed 50 ° C. The addition of the nucleophile, ie the Grignard reagent or the lithium compound, should be carried out with good stirring, preferably with vigorous stirring. In order to shift the equilibrium of the reaction towards the desired symmetrical displacement product, the nucleophile used, preferably the Grignard reagent, is added in an amount of 2.1 to 3 mol per mol of starting material reacted. It is preferable to add the Grignard reagent in an amount of 2.2 to 2.6 mol based on 1 mol of the starting material.

Even after the addition of the Grignard reagent, the reaction mixture is continuously stirred at a constant temperature for a while to complete the reaction.

As a modification of this reaction, there is a method of producing a Grignard reagent by reacting magnesium with an appropriate halide in situ. When the Grignard compound is prepared in situ, the amount of magnesium is 2 to 5 times, preferably 2 times the molar amount of the compound of the general formula (II) used as a starting material.
． The amount of the halide is 8-3.2 times, and the amount of the halide is 2-3.8 times, preferably 2.2-2.6 times the molar amount of the compound of the general formula (II).

When the co-catalyst is not added to the reaction mixture, the reaction temperature is about 80 ° C., preferably 60 to 70 ° C., particularly preferably 75 ° C., after sufficient addition of the nucleophile with sufficient stirring. Adjust to.

To give an example, 3 mol% of titanium (IV) oxide is suspended in 40 ml of dry tetrahydrofuran and stirred at 20 ° C. in an inert gas atmosphere at 5 ° C. for 5 mmo.
1 of starting material is added dropwise. To this mixture is slowly added with stirring 5 mmol of the cocatalyst, also dissolved in dry tetrahydrofuran. Stir for 5 minutes at 20 ° C. and then gradually add 12 mmol of Grignard reagent, taking care not to raise the temperature of the reaction mixture to 50 ° C. or higher. The mixture is stirred for an additional hour and the reaction is complete.

[0061]   After the reaction is complete, the reaction mixture is worked up by methods known to those skilled in the art.

It is also possible to salt using a hydrogen chloride solution, for example a 1 molar ethereal hydrogen chloride solution, to precipitate the product which is filtered off and, if necessary, to purify by recrystallization.

To remove the Lewis acid, it is possible, for example, to add an appropriate amount of saturated ammonium chloride solution and water, and then vigorously stir for several hours (1 to 3 hours). The precipitate that forms is separated and washed with a small amount of dry ether, preferably diethyl ether. To the filtrate is added a suitable alkali, eg NaOH, KOH, sodium carbonate, or potassium carbonate solution, preferably sodium hydroxide solution, to make it basic (pH
> 10). The phases that are formed are separated and the aqueous phase is repeatedly extracted with diethyl ether (eg in some cases more than 3 times using 30 ml each). The combined organic phases are washed with saturated sodium chloride solution (for example 15 ml), dried over potassium carbonate, magnesium sulphate or sodium sulphate and filtered.

The product can be purified in various ways using methods known to the person skilled in the art, eg as described above.

Although generally described for carrying out the method, it is also possible to replace the Grignard reagent with the corresponding lithium compound. The corresponding lithium compound, like the Grignard reagent, can be prepared by methods commonly known to those skilled in the art and reacted in the same manner as described above.

[0066]   This reaction can also be carried out in the presence of an organotitanium compound.

This reaction is carried out in the presence of an organotitanium compound as a catalyst, and the amount of the catalyst used is 0.5 to 5 mol%, preferably 1 to 3.5, based on the compound of the general formula (II).
Mol%.

Suitable organotitanium compounds are preferably compounds of general formula (IV-b). TiX _4-n (OR ^V ) _n (IV-b) Here, n is an integer of 1 to 4 Cl, Br, I, and R ^V may be the same or different, but 1 to Alkyl radicals having 10 carbon atoms or aryl radicals having 6 to 20 carbon atoms.

Preference is given to using organotitanium compounds in which R ^V is isopropyl.

Particularly preferred is the use of Ti (Oi—Pr) ₄ as the organotitanium compound, where i-Pr is an isopropyl radical. The general formula (I
The symmetric substituted amine compounds of) can be preferably synthesized not only in the presence of a catalyst, but also as a cocatalyst of the compounds of general formula (V) or (VI) or compounds of general formula (VII) described above. . M ' ^{(m +)} (Oi-Pr) m (VII) Here, M'is Al, Ca, Na, K, Si or Mg, preferably Mg.
Alternatively, in Na, m is an integer of 1 to 4 and is a metal oxidation state.

It is very particularly preferred to use the following compounds as cocatalysts: NaOi-Pr, Mg (Oi-Pr) ₂ , (CH ₃ ) ₃ SiCl.

When a cocatalyst is added to the reaction mixture, for the compound of general formula (II)
It should be used in an amount of 0.7 to 1.2 equivalents, preferably 0.9 to 1.1 equivalents.

Geminally asymmetrically substituted compounds according to the present invention include compounds of general formula (II), wherein R ¹ , R ² and R ³ are as defined above in formula (I). ,
It is suitably synthesized by reacting with at least two nucleophiles of general formula (IIIa) and (IIIb). Z—R ⁴ (IIIa) Z—R ⁵ (IIIb) where R ⁴ and R ⁵ mean as indicated above, wherein Z is Li or MgX, where X is Hal, Hal is Cl, Br or I, which are either generated in situ or added directly. This method is preferably carried out by reacting in the presence of a catalytic amount of a metal oxide selected from the group consisting of titanium dioxide, hafnium dioxide and zirconium dioxide.

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

Suitable alkylsilane halides include the above general formula (V) or the general formula (V
There is a compound of IV). Titanium dioxide is preferably used as a catalyst for promoting this reaction.

The characteristics of this reaction are as follows. a) 1 to 1 of the carboxamide of the general formula (II) and a metal oxide selected from titanium (IV) oxide, hafnium dioxide, and zirconium dioxide with respect to the carboxamide.
5 mol% and optionally a cocatalyst are first added to a solvent selected from the group consisting of toluene, THF, hexane, benzene, and diethyl ether at 10-30 ° C. under an inert gas atmosphere, and b) general. A solution containing at least two nucleophiles of formulas (IIIa) and (IIIb) is added dropwise, where R ⁴ and R ⁵ are as defined above or R ⁴ and R ⁵ radicals. Are bonded to each other to form a group having 2 to 7 carbon atoms, or R ⁴ and R ⁵ are optionally intercalated with a heteroatom from the group consisting of —O—, —NH—, —S—. Bind to each other and jointly form a group having 2 to 6 carbon atoms, and X is as defined above, c) the post-reaction is carried out with stirring, and after completion of the reaction, according to a conventional method. Finish this mixture or if Z is MgX Lava, a ') magnesium pieces, carboxamide of the general formula (II), and titanium oxide (I
V), hafnium dioxide, zirconium dioxide, and a metal oxide selected from the group consisting of 1 to 15 mol% based on carboxamide, at a temperature of 10 to 30 ° C. [missing], toluene, THF, n-hexane. , Benzene and diethyl ether [absent] first, and b ') dissolved in a solvent selected from the group consisting of toluene, THF, n-hexane, benzene and diethyl ether, represented by the general formulas (IIIa') and ( IIIb '
) At least two alkyl halides are added dropwise, X—R ⁴ (IIIa ′) X—R ⁵ (IIIb ′) where in each case R ⁴ and R ⁵ are those indicated above. I.e., c ') post-reacting with stirring, and after the reaction is complete, the mixture is worked up in a conventional manner.

The reaction steps a) and a ′) are carried out at a temperature of 15 to 25 ° C., preferably room temperature.

A catalyst system comprising a metal oxide selected from the group consisting of titanium dioxide, hafnium dioxide and zirconium dioxide and a cocatalyst of the general formula (V) or (VI) described above is particularly effective. Has been proven.

This catalyst system preferably contains a compound selected from the following group as a cocatalyst.

[Chemical 9]

[0080]   It is particularly preferred to use a catalyst system containing titanium dioxide as the metal oxide.

Experiments have shown that when a carboxamide is reacted with two different Grignard reagents in the presence of titanium (IV) oxide (TiO ₂ ), the reaction proceeds only by using a catalytic amount of the titanium reagent. It was Furthermore, it was also found that the desired geminal asymmetric dialkylation reaction was initiated even at room temperature simply by adding a cocatalyst. Under the reaction conditions of the invention, the carboxamide completes the reaction in a very short time. If the reaction is carried out using a small amount of starting material, the reaction will be completed after 1 hour at the longest.

In order to promote the reaction, first, titanium (IV) oxide (TiO ₂ ) is added in an amount of 1 to 15 mol%, preferably 3 to 13 mol%, based on the amount of the amide to be reacted, with toluene or tetrahydrofuran. Suspend in a suitable dry solvent selected from the group consisting of (THF), hexane, benzene and diethyl ether. Suspension is 15 to 3
Adjust the temperature to 0 ° C, preferably about 20 ° C. Under an inert gas (nitrogen or argon) atmosphere, the starting materials are liquid, or toluene, tetrahydrofuran (T
HF), hexane, benzene and diethyl ether, in the form of being dissolved in a solvent selected from the group, and gradually added dropwise with stirring. An amount of cocatalyst corresponding to the amount of starting materials to be reacted is likewise prepared in dry solvent and added dropwise. The reaction mixture obtained is stirred for a short time, that is to say for a few minutes, during which the temperature is kept constant. To the resulting reaction mixture is slowly added a mixture containing equal amounts of two different Grignard reagents, keeping the temperature of the reaction mixture below 50 ° C. An excess of each of the Grignard reagents is used in order to react the starting materials as completely as possible. The Grignard reagents are each used in an amount of at least 1.05 mol to 1.5 mol per mol of starting material. Particularly preferably, the Grignard reagent is used in an amount of 1.1 to 1.3 mol per mol of starting material. When the addition of Grignard reagent is complete, the reaction mixture obtained is stirred for a while at constant temperature to complete the reaction.

As an example, 3 mol% of titanium (IV) oxide is suspended in 40 ml of dry tetrahydrofuran and stirred at 20 ° C. in an inert gas atmosphere at 5 ° C. for 5 mmo.
1 of starting material is added dropwise. To this mixture is slowly added with stirring 5 mmol of the cocatalyst, also dissolved in dry tetrahydrofuran. After continuous stirring for 5 minutes at 20 ° C., 6 mmol of the two Grignard reagents are added slowly, taking care that the temperature of the reaction mixture does not rise above 50 ° C. The mixture is stirred for an additional hour and the reaction is complete.

A compound of the general formula (II) as described above, wherein R ¹ , R ² and R ³ are as indicated above, and a compound of the general formula shown above in a suitable solvent. The compounds of the invention are obtained by reacting at least one compound from each of (IIIa) and (IIIb) in the presence of an organotitanium compound of general formula (IV-b) as catalyst.

Suitable carboxamides for this reaction are hydrogen, C ₁ -C ₁₀ alkyl radicals, C ₃ -C ₈ cycloalkyl radicals, although the R ¹ and R ² radicals may be the same or different. , A C ₆ -C ₂₀ aryl radical, a C ₂ -C ₁₀ alkenyl radical, a C ₂ -C ₁₀ alkynyl radical, R ¹ and R ² , or R ² and R ³
A cycloalkyl ring C ₃ -C ₈ formed from radicals, nitrogen optionally in addition to the nitrogen in the ring may contain an oxygen or sulfur atom as a further heteroatom, further wherein R and R ' The radicals are preferably C _{1 to} C ₁₀ alkyl radicals, C _{3 to} C ₆ cycloalkyl radicals or C _{6 to} C ₂₀ aryl radicals.

As the organic titanium compound used, Ti (OiPr) ₄ is particularly preferable, where iPr is an isopropyl radical.

The asymmetrically substituted amine compounds of general formula (I) synthesized according to the present invention are not only present in the presence of a catalyst, but also of the general formula (V), (VI) or (VII) which are cocatalysts.
It is preferable that the compound is synthesized in the presence of any one of the above compounds.

Particularly preferred cocatalysts for use are the following compounds: NaOiPr, Mg (OiPr) ₂ , (CH ₃ ) ₃ SiCl

The method for synthesizing the symmetrical or asymmetrically substituted amino compound of the general formula (I) is preferably carried out at room temperature, that is, at 20 to 25 ° C., under an inert gas atmosphere.

In this synthetic method, a symmetrical or asymmetrically substituted amino compound represented by the general formula (I) can be synthesized in a high yield in a reasonable reaction time, and an enamine reaction accompanied by α elimination and β hydride can be performed. The cyclization reaction with elimination is significantly suppressed.

On the other hand, the compound of the general formula (Ia) can be synthesized in the above reaction without using a cocatalyst.

After completion of the reaction, the symmetrical or asymmetrically substituted amino compound is purified and isolated according to a conventional method as described above.

In the combinatorial synthesis of amines of general formula (I), a single compound of general formula (II) or a plurality of different compounds and / or formulas (III) and (IV)
Of several different compounds are used. It was found that in this way a combinatorial library containing a plurality of amines of general formula (I) as a mixture can be obtained. Preference is given to reacting 1 to 10 different compounds of the formula (II) with at least 3 different compounds of the formula (III).

In a preferred embodiment, the amide of general formula (II) is first treated with a catalyst (eg Ti).
(OiPr) ₄ ) and cocatalyst (eg (CH ₃ ) ₃ SiCl) are added to THF under argon atmosphere. Then, as many different types of Grignard reagents as possible are added simultaneously. The mixture is kept stirring and finished as above. This reaction is a known reaction individually, but the only difference is
Multiple amides are present and / or as many types of Grignard reagents as possible are added simultaneously. In this case, the amounts of reactants have to be chosen such that the additions of all amides correspond to the additions of all Grignard reagents in moles. That would surely yield all of the logically possible products.

In order to isolate and identify amines with specially active compound properties, libraries of amines of general formula (I) can be subjected to a bioactivity screen.

As a combinatorial library in a combinatorial synthesis in which these amines are reacted with one or more reactive substances to create a modified form of the amine of the general formula (I), the amine of the general formula (I) is used as a pure product. It may be used, or it may be used as several different amines. It is preferred that the geminally substituted amine structural elements are retained here as well.

In the combinatorial synthesis to create the modified amines of general formula (I), it is preferred to use amines that have been confirmed to be active by biological screening methods. The use of bioactive amines of general formula (I) to create modified amines may lead to more active ones by combinatorial synthesis.

By repeating the screening and synthesis steps, it will be possible in particular to improve the activity of the amines of general formula (I).

The method of the invention for synthetically producing combinatorial libraries is particularly advantageous in the following points: Many types of different amines can be synthesized and they are present in similar amounts in the reaction mixture. 2. The reaction can be catalytically promoted. 3. In the case of combinatorial synthesis starting from amino acids, it is usually necessary to carry the starting compounds, but this is not necessary. 4. Simple and readily available starting materials can be used.

Accordingly, the compounds of general formula (I) or (Ia) and their physiologically acceptable salts may comprise at least one base or additive and optionally one or more further It can be used for the production of a pharmaceutical preparation by adding the active compound of 1. to a suitable dosage form. The preparation thus obtained can be used as a medicine for humans or animals. Suitable bases include organic or inorganic substances, which are suitable for enteral (eg oral or rectal) or parenteral administration, or in the form of inhalation sprays and which do not react with these novel compounds,
Examples include water, vegetable oils, benzyl alcohol, polyethylene glycol, glycerine triacetate and other fatty acid glycerides, gelatin, soy lecithin, carbohydrates such as lactose and starch, magnesium stearate, talc or cellulose. In particular, tablets, dragees, capsules, syrups, juices and drops are used for oral administration, and coated lacquer tablets and capsule shells for enteral administration are of particular interest.

For rectal administration, suppositories are used, and for parenteral administration, solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions or implants are used. When administered as an inhalation spray, one containing the active compound dissolved or suspended in a propellant mixture (eg chlorofluorohydrocarbons) is used.
In this case, for the sake of convenience, the active compounds are used in micronized form in the presence of one or more further physiologically acceptable solvents, for example ethanol. The inhalation liquid is administered using a commonly used inhaler. The active compounds claimed in the invention can be lyophilized and the lyophilizates obtained are used, for example, for the preparation of injectable formulations. The formulations presented here can also be sterilized, and / or
Alternatively, additives may be included. Additives include, for example, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for adjusting the osmotic pressure, buffers, colorants and / or fragrances. If desired, one or more further active substances can be included, for example one or more vitamins, diuretics, antiphlogistics and the like.

The compounds of formula (I) or (Ia) of the present invention are generally administered in analogy to other known, commercially available formulations, but in particular US Pat. No. 4,880. 80
Administered in a manner similar to the compound described in No. 4, with a dose of about 1 mg to 1
Particularly preferred is between 50 and 500 mg per dosage unit. The daily dose is preferably about 0.1-50 mg / kg of body weight, more preferably 1-
It is 10 mg / kg. However, the appropriate dose for each individual patient will depend upon various factors, such as the efficacy of the particular compound used, age,
It depends on body weight, general health, sex, diet, duration and mode of administration, excretion rate, concomitant use of drugs, and severity of the disease involved in the treatment. Oral administration is preferred.

The invention will now be described by way of example. Example 1-2: 5 mmol of the amides shown in Table 1 are added dropwise at 20 ° C. under nitrogen atmosphere into a solution of 5.5 mmol of the organotitanium compound in dry tetrahydrofuran (40 ml). The mixture is stirred at 20 ° C. for 5 minutes, then 5.5 mmol of Grignard reagent shown in Table 1 is added slowly, while keeping the temperature of the reaction mixture above 50 ° C. The mixture is stirred at the reaction temperature shown in Table 1 for the reaction time shown in Table 1 to complete the reaction.

Finishing of the reaction product To remove the Lewis acid, 15 ml of saturated ammonium chloride solution and 15 ml
Water is added and the mixture is stirred vigorously (1 hour). All the formed precipitates were filtered by vacuum filtration using a suction bottle and a suction filter, and the residue on the filter was 20 ml.
Wash twice with dry diethyl ether. The filtrate is made basic (pH> 10) by adding sodium hydroxide solution. Separate the phases with a separating funnel. Water phase 30m each time
Extract 3 times with 1 of diethyl ether. The organic phases are combined and washed with saturated sodium chloride solution, the separated organic phases are dried over potassium carbonate and then
Filter. The solvent is removed by rotary evaporation. The residue is chromatographed on a 20 g silica gel column using an eluent of heptane / t-butyl methyl ether (50/1).

[0105]

[Table 1]

Examples 3 and 4 Titanium (IV) Oxide-Derived Symmetric Alkylation of Carboxamides with Grignard Reagent Using the reaction shown in Formula 1 using 1 equivalent of (CH ₃ ) ₃ SiCl as a cocatalyst, The products shown in Table 2 were synthesized.

[0107]

[Chemical 10]

[0108]

[Table 2]

Example 5 The compound shown is an asymmetric disubstitution of a carboxamide derivatized with titanium (IV) oxide.

[0110] Table 3

[Table 3]

Reaction of TiO ₂ Derived Carboxamide with R ⁴ MgX / R ⁵ MgX From the results of this experiment, a suspension of TiO ₂ in tetrahydrofuran (T vs. amide)
i reagent at 13 mol%) and two different Grignard reagents each
It is speculated that the equivalent geminal asymmetric dialkylated tertiary amines can be obtained from the reaction from any carboxamide by adding in equivalent amounts.

Examples 6-10 5 mm of 5 mmol of amide shown in Table 4 and (CH ₃ ) ₃ SiCl as cocatalyst
40 ml of 3 mol% Ti (OiPr) ₄ with respect to the amides shown in Table 4.
Was added dropwise at 20 ° C. under nitrogen atmosphere to the solution dissolved in dry tetrahydrofuran. The mixture is stirred at 20 ° C. for 5 minutes and then 12 mmol, 6 mmol each of the Grignard reagents shown in Table 6 are added at a reaction mixture temperature of 5
Gradually add to the reaction mixture, keeping it above 0 ° C. The mixture is stirred at the reaction temperature shown in Table 6 for the reaction time shown in Table 1 to complete the reaction.

[0113]   The reaction product is worked up as in Examples 1-5.

[0114]

[Table 4]

Examples 11-49 The amines of general formula (I) shown below were synthesized according to the general procedure shown below and identified by mass spectrometry.

5 mmol of the starting material (1) as a liquid or a tetrahydrofuran solution,
Into an organic titanium Ti (OiPr) ₄ solution (3 or 100 mol% with respect to the amide used (see Table 5)) dissolved in 40 ml of dry tetrahydrofuran at 20 ° C. under an inert gas (nitrogen or argon) atmosphere. Added by. For substances of general formula (I), 5 mmol of cocatalyst (CH ₃ ) ₃ SiCl are added to the reaction mixture.
Stir for 5 minutes at 20 ° C. Then 12 mmol of Grignard reagent (6 mmol each of two different Grignard reagents in case of asymmetric dialkylation)
Is gradually added dropwise to the reaction mixture while the temperature of the reaction mixture is kept above 50 ° C. Continue stirring at room temperature for 1 hour. Add 15 ml of saturated ammonium chloride solution and 15 ml of water and stir vigorously for another 1-3 hours. The precipitate formed is removed and washed with a little dry diethyl ether. The filtrate is made basic (pH> 10) by adding 15% sodium hydroxide solution. After phase separation,
The aqueous phase is extracted 3 times with 30 ml of diethyl ether each time. 1 after combining the organic phases
Wash with 5 ml of saturated sodium chloride solution, dry over potassium carbonate and filter.

The product was purified by one of the following methods (see Table 5). It is precipitated as the hydrochloride salt with a 1.1 molar ethereal hydrogen chloride solution and filtered off (the product obtained is purified by recrystallization if necessary). 2. The organic phase is extracted twice with 40 ml of a 0.5 molar hydrochloric acid solution. The extract is adjusted to pH> 10 with a 2 molar NaOH solution and extracted 3 times with 30 ml of dry diethyl ether each time. The organic phases are combined, dried over potassium carbonate and the solvent removed in vacuo. 3. The solvent is removed in vacuo and the residue is isolated by column chromatography. 4. The solvent is removed in vacuo and the residue is vacuum distilled.

[0118]

[Table 5]

[0119]

[Table 6]

[0120]

[Table 7]

[0121]

[Table 8]

[0122]

[Table 9]

[0123]

[Table 10]

[0124]

[Table 11]

[0125]

[Table 12]

[0126]

[Table 13]

[0127]

[Table 14]

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) C07C 211/22 C07C 211/22 211/27 211/27 211/35 211/35 211/48 211/48 C07D 295/02 ZCC C07D 295/02 ZCC C07F 7/10 C07F 7/10 Q // C07B 61/00 300 C07B 61/00 300 (31) Priority claim number 198 27 164.6 (32) Priority date 1998 June 18 (June 18, 1998) (33) Priority claiming country Germany (DE) (31) Priority claim number 198 27 165.4 (32) Priority date June 18, 1998 (June 18, 1998) 18) (33) Priority claim Germany (DE) (31) Priority claim number 198 27 166.2 (32) Priority date June 18, 1998 (June 18, 1998) (33) Priority Claiming country Germany (DE) (31) Priority claim number 19 27 167.0 (32) Priority date June 18, 1998 (June 18, 1998) (33) Priority claim country Germany (DE) (31) Priority claim number 198 44 194.0 (32) Priority Date September 26, 1998 (September 26, 1998) (33) Priority claiming country Germany (DE) (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR) , GB, GR, IE, IT, LU, MC, NL, PT, SE), JP, KR, US (71) Applicant Frankfurter Str. 250, D-64293 Darmstadt, Federal Republish of Germany (72) Inventor Buchholz, Helwick Germany Day-60599 Franckfurt am Main, Aufdem Muhlberg 75 (72) Inventor Werz-Wielmann, Urs Germany Day 68164 Mannheim, Sperzenstraße 14F Term (Reference) 4H006 AA01 AA02 AA03 AB84 AC25 BA10 BA30 BA32 BA53 BB15 BB23 BB61 BE10 4H039 CA10 CD40 4H049 VN01 VP02 VQ35 VQ84 VR24 VU36 VW01

Claims (13)

[Claims] 1. The following general formula (I): In the formula, R ¹ and R ² may be the same or different, each independently being a 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 form a substituted or unsubstituted cycloalkyl ring, which, in addition to the nitrogen atom, consists of nitrogen, oxygen or sulfur It is also possible to include at least one further heteroatom selected from the group, R ³ is selected from hydrogen or methyl, which may optionally be substituted with 1 to 3 fluorine atoms, R ⁴ and R ⁵ may be the same or different and each independently of each other, may be substituted or unsubstituted alkyl, cycloalkyl, alkenyl, silane. An amine represented by chloroalkenyl or alkynyl or a salt thereof. 2. The amine according to claim 1, wherein R ³ is hydrogen or methyl. 3. The amine according to claim 1, wherein R ⁴ and R ⁵ are different. 4. R¹And R²Independently of each other, C_1-8Alkyl group, C_3-7Shi
Chloroalkyl group, C_3-7C substituted with a cycloalkyl group_1-6Alkyl group, C _3-7 Cycloalkenyl group, C_3-7C substituted with a cycloalkenyl group_1-6Al
Kill group, C_2-8Alkenyl group, C_2-8Alkynyl group, C_1-6Positioned by an alkoxy group
Converted C_1-6Alkyl group, C_2-6C substituted with an alkenyloxy group_1-6A
Rukiru group, C_2-6C substituted by an alkynyloxy group_1-6Alkyl group, mono-
, Di- or polyhalo-C_1-6C substituted by an alkoxy group_1-6An alkyl group,
Mono-, di- or halogen atom, trifluoromethyl group, nitro group, C_1-6A
Rukiru group and C_1-6By one or more substituents selected from the group consisting of alkoxy groups
R), C substituted with a phenylthio group_1-6Alkyl groups (but like this
Phenylthio group is a halogen atom, trifluoromethyl group, nitro group, C_1-6Al
Kill group and C_1-6One or more units selected from the group consisting of alkoxy groups
Optionally substituted by a substituent), substituted by a phenylsulfinyl group
C_1-6Alkyl group (however, such a phenylsulfinyl group is a halogen atom
, Trifluoromethyl group, nitro group, C_1-6Alkyl group and C_1-6Alkoxy group
May be substituted with one or more substituents selected from the group consisting of
), C substituted with a phenylsulfonyl group_1-6Alkyl group (however, phenyl
Lesulfonyl group is a halogen atom, trifluoromethyl group, nitro group, C_1-6Al
Kill group and C_1-6One or more units selected from the group consisting of alkoxy groups
Optionally substituted by a substituent), C substituted by a benzyloxy group_1-6
Alkyl group (However, the phenyl group of such benzyloxy group is a halogen atom.
, Trifluoromethyl group, nitro group, C_1-6Alkyl group and C_1-6Alkoxy group
May be substituted with one or more substituents selected from the group consisting of
), C substituted with a benzylthio group_1-6Alkyl group (however,
The phenyl group of the benzyl group is a halogen atom, trifluoromethyl group, nitro group,
C_1-6Alkyl group and C_1-61 or it selected from the group consisting of alkoxy groups
Optionally substituted by the above substituents), substituted by benzylsulfonyl group
C_1-6Alkyl group (however, such a phenylsulfinyl group
Group is a halogen atom, trifluoromethyl group, nitro group, C_1-6Alkyl groups and
And C_1-6By one or more substituents selected from the group consisting of alkoxy groups
C) substituted with a benzylsulfinyl group_1-6Al
Kill group (however, the phenyl group of such a benzylsulfonyl group is a halogen atom)
, Trifluoromethyl group, nitro group, C_1-6Alkyl group and C_1-6Alkoxy group
May be substituted with one or more substituents selected from the group consisting of
), C_1-4C substituted with an amino group substituted with an alkylsulfonyl group_{1 -6} Is an alkyl group, Or, together with the nitrogen atom to which they are attached, 1-pyrrolidinyl, 1-imid
Dazolinyl, 1-pyrazolinyl, 1-piperidyl, 1-piperazinyl, 4-mol
Forming a ring selected from the group consisting of folinyl and 4-thiamorpholinyl, The amine according to any one of claims 1 to 3. 5. R ⁴ and R ⁵ may be the same or different, but independently of each other, a C _1-8 alkyl group, a C _3-7 cycloalkyl group, a C _3-7 cycloalkyl group. C _1-6 alkyl group substituted by, C _3-7 cycloalkenyl group, C _3-7 C _1-6 alkyl group substituted by a cycloalkenyl group, C _2-8 alkenyl, C _2-8 alkynyl group , C _1-6 C _1-6 alkyl group substituted by alkoxy group, C _1-6 alkyl group substituted by a C _2-6 alkenyloxy group, C _2-6 C substituted by alkynyloxy _{1- 6} alkyl group, C _1-6 alkyl group substituted by mono-, di- or polyhalo-C _1-6 alkoxy group, C ₁ substituted by mono-, di- or polyhalo-C _2-6 alkenyloxy group _-6 alkyl groups, mono-, di- or polyhalo-C _2-6 alkynyloxy groups Substituted C _1-6 alkyl group, C _1-6 C _1-6 alkyl group substituted by an alkylthio group, C _1-6 alkylsulfinyl C _1-6 alkyl group substituted by a group, C _1-6 alkyl C _1-6 alkyl group substituted by sulfonyl group, mono-, di- or polyhalo-C _1-6 alkyl group, mono-, di- or polyhalo-C _2-8 alkenyl group, mono-, di- or polyhalo A C _2-8 alkynyl group, a C _1-6 alkyl group substituted with a cyano group, a C _2-6 alkenyl group substituted with a cyano group, a C _2-6 alkynyl group substituted with a cyano group, a nitro group A substituted C _1-6 alkyl group, a C _2-6 alkenyl group substituted by a nitro group, a C _2-6 alkynyl group substituted by a nitro group, a C _1- substituted by a C _1-6 alkylamino group ₆ alkyl group, C _1-6 alkoxyamino group Substituted C _1-6 alkyl group, a di (C _1-3 alkyl) C _1-6 alkyl group substituted by an amino group, N-(C _1-3 alkyl)-N-(C _1-3 alkoxy) C _1-6 alkyl group substituted by an amino group, N-(C _1-6 alkylsulfonyl)-N-(C _1-6 alkyl) C _1-6 alkyl group substituted by an amino group, N-(C _1-6 alkylsulfonyl) -N- (C _1-6 alkoxy) amino group-substituted C _1-6 alkyl group, tri-C _1-6 alkylsilyl group-substituted C _1-6 alkyl group, tria The amine according to any one of claims 1 to 4, which is a C _1-6 alkyl group substituted with a reel silyl group. 6. R¹And R², But independently of each other, C_1-8Alkyl group, C_3-7 Cycloalkyl group, C_3-7C substituted with a cycloalkyl group_1-6An alkyl group,
C_3-7Cycloalkenyl group, C_3-7C substituted with a cycloalkenyl group_1-6A
Rukiru group, C_2-8Alkenyl group, C_2-8Alkynyl group, C_1-6By an alkoxy group
The substituted C_1-6Alkyl group, C_2-6C substituted with an alkenyloxy group_1-6
Alkyl group, C_2-6C substituted by an alkynyloxy group_1-6Alkyl group, mono
-, Di- or polyhalo-C_1-6C substituted by an alkoxy group_1-6Alkyl group
, Mono-, di- or polyhalo-C_2-6C substituted with an alkenyloxy group_{1 -6} Alkyl group, mono-, di- or polyhalo-C_2-6By an alkynyloxy group
The substituted C_1-6Alkyl group, C_1-6C substituted with an alkylthio group_1-6Al
Kill group, C_1-6C substituted with an alkylsulfinyl group_1-6Alkyl group, C_{1- 6} C substituted with an alkylsulfonyl group_1-6Alkyl group, mono-, di- or
Polyhalo-C_1-6Alkyl group, mono-, di- or polyhalo-C_2-8Alkenyl group
, Mono-, di- or polyhalo-C_2-8Substituted by alkynyl group, cyano group
C_1-6C substituted with an alkyl group or a cyano group_2-6For alkenyl and cyano groups
More substituted C_2-6C substituted by alkynyl group or nitro group_1-6Alkyl group
, C substituted by a nitro group_2-6C substituted with an alkenyl group or a nitro group_{2 -6} Alkynyl group, C_1-6C substituted with an alkylamino group_1-6Alkyl group, C _1-6 C substituted by an alkoxyamino group_1-6Alkyl group, di (C_1-3Alkyl
) C substituted with an amino group_1-6Alkyl group, N- (C_1-3Alkyl) -N- (
C_1-3C) substituted with an alkoxy) amino group_1-6Alkyl group, N- (C_1-6A
Rukylsulphonyl) -N- (C_1-6C substituted with an alkyl) amino group_1-6A
Rukyi group, N- (C_1-6Alkylsulfonyl) -N- (C_1-6Alkoxy) amino
C substituted by a group_1-6Alkyl group, Tri-C_1-6Substituted with alkylsilyl group
C_1-6C substituted with an alkyl group or a triarylsilyl group_1-6A
The amine according to any one of claims 1 to 5, which is a rualkyl group. 7. R ¹ and R ² are each independently of each other a phenyl group (provided that such a phenyl group is a halogen atom, a trifluoromethyl group, a nitro group,
_Optionally substituted with one or more substituents selected from the group consisting of C _1-6 alkyl group, C _1-6 alkoxy group and C _2-7 alkoxycarbonyl group),
C _1-6 alkyl group substituted by a phenyl group (provided that such a phenyl group is a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 alkyl group, a C _1-6 alkoxy group and a C _2-7 group). Optionally substituted by one or more substituents selected from the group consisting of alkoxycarbonyl groups), C _2-7 alkenyl groups substituted by phenyl groups (provided such phenyl groups are halogen atoms, Optionally substituted with one or more substituents selected from the group consisting of trifluoromethyl group, nitro group, C _1-6 alkyl group and C _1-6 alkoxy group), substituted with phenyl group A C _2-6 alkynyl group (however, such a phenyl group is selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 alkyl group and a C _1-6 alkoxy group) Optionally substituted by one or more selected substituents, C _1-6 alkyl group substituted by phenoxy group (provided that such phenoxy group is a halogen atom, a trifluoromethyl group, a nitro group, C _1-6 may be substituted by one or more substituents selected from alkyl groups and C _1-6 group consisting alkoxy group), C _1-6 alkyl group substituted by a phenylthio group (provided that Such a phenylthio group may be substituted with one or more substituents selected from the group consisting of halogen atom, trifluoromethyl group, nitro group, C _1-6 alkyl group and C _1-6 alkoxy group. C _1-6 alkyl group substituted by a phenylsulfinyl group (provided that such a phenylsulfinyl group is a halogen atom, a trifluoromethyl group, a nitro group). Group, a C _1-6 alkyl group and a C _1-6 alkoxy group, which may be substituted with one or more substituents), a C _1-6 alkyl substituted with a phenylsulfonyl group Group (however, the phenylsulfonyl group of such a benzyloxy group is one or more selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 alkyl group and a C _1-6 alkoxy group. C _1-6 alkyl group substituted by a benzyloxy group (provided that the phenyl group is a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 alkyl group and C _{1-6 1-6} may be substituted by one or more substituents selected from the group consisting of alkoxy groups), C _1-6 alkyl group substituted by a benzylthio group (only Substituted phenyl group is a halogen atom such benzylthio group, a trifluoromethyl group, a nitro group, by one or more substituents selected from the group consisting of C _1-6 alkyl and C _1-6 alkoxy groups C _1-6 alkyl group substituted by a benzylsulfinyl group (provided that the phenyl group of such a benzylsulfonyl group is a halogen atom, a trifluoromethyl group, a nitro group, a C _1-6 alkyl group) and may be substituted by one or more substituents selected from the group consisting of C _1-6 alkoxy groups), C _1-6 alkyl group substituted by a benzylsulfonyl group (provided that such a benzyl Is the phenyl group of the sulfonyl group a group consisting of halogen atom, trifluoromethyl group, nitro group, C _1-6 alkyl group and C _1-6 alkoxy group? Al may be substituted by one or more substituents selected), a C _1-6 alkyl group substituted by an amino group substituted by C _1-4 alkylsulfonyl group, claim 1 The amine according to any one of 5 above. 8. R ¹ and R ² share the nitrogen atom to which they are attached, 1-pyrrolidinyl, 1-imidazolinyl, 1-pyrazolinyl, 1-piperidyl, 1-piperazinyl, 4-morpholinyl and 4 -The amine according to any one of claims 1 to 5, which forms a ring selected from the group consisting of thiamorpholinyl. 9. R ¹ and R ² are each, independently of one another, methyl, ethyl, isopropyl, n-butyl, isobutyl, phenyl, benzyl, 2-pyridyl or trimethylsilyl, or a nitrogen atom to which they are bonded. Incorporate,
The amine according to any one of claims 1 to 5, which is 1-pyrrolidinyl, 1-piperidyl, 4-methylpiperidyl or 4-morpholinyl. 10. R ⁴ and R ⁵ independently of one another are methyl, ethyl, isopropyl, n-butyl, tert-butyl, ethenyl, ethynyl, allyl, n-hexyl, trimethylsilylmethyl, cyclopropyl, cyclopentyl or cyclohexyl. The amine according to any one of claims 1 to 6. 11. A combinatorial library comprising amines of general formula (I) as defined in any of claims 1-10. 12. A method for preparing a combinatorial library comprising amines according to claim 1, comprising one or more compounds of general formula (II) and In the formula, R ¹ , R ² and R ³ have the same meanings as defined in claim 1, and at least one compound represented by the general formula (IIIa) or (IIIb) is used as Z—R ⁴ (IIIa) Z. —R ⁵ (IIIb) In the formula, R ⁴ and R ⁵ are as defined in claim 1, wherein Z is Li or MgX, and X is Hal and Hal. Is Cl, Br or I, and reacting in a solvent in the presence of a titanium, hafnium or zirconium compound and optionally a cocatalyst to form a combinatorial library having at least 5 different amines. Law. 13. Use of the amine according to any of claims 1 to 10 and the combinatorial library according to claim 11 as an intermediate step in the synthesis of active compounds.