JP2002518366A - Preparation of combinatorial amine library - Google Patents

Abstract

(57) Abstract: The present invention relates to a method for preparing a combinatorial library containing an amine compound represented by the general formula (I), which method comprises the steps of preparing a combinatorial library represented by the general formula (II) (wherein R ³ , R ⁴ and R ⁵ Has the meaning described in the specification), and an α component selected from the group consisting of a general formula (IIIa): Z—R ⁴ or a general formula (IIIb): Z—R ⁴ —R ⁵ —Z (formula Wherein R ⁴ and R ⁵ have the meanings described in the description, and in the case of the compound represented by the general formula (IIIb), the groups R ⁴ and R ⁵ are bonded via a bond, and Z is Li or MgX , X represents Hal, and Hal represents Cl, Br or I). Here, α represents a whole number greater than or equal to 1 and β represents a total number greater than or equal to 1, where αβ ² ≧ 5. The reaction is carried out in a solvent in the presence of a titanium, hafnium or zirconium compound, and optionally in the presence of a cocatalyst. Embedded image

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the discovery of new lead structures, starting from combinatorial libraries. In particular, the present invention
The present invention relates to a method for preparing a combinatorial amine library. Lead scaffolds that are not peptides but also have an affinity for receptors or enzymes are routinely found by mass screening of a large number of compounds. Here, mixtures of natural substances or the accumulation of synthetically produced pure substances are traditionally used as sources of chemical structural diversity. However, the use of natural substance mixtures is ethical, as organisms, the source of natural substance mixtures, are often threatened with extinction and the search for new lead scaffolds threatens the maintenance of the target organism. And from an implementation standpoint, are increasingly viewed as problematic. On the other hand, the accumulation of chemicals initiated by pharmaceutical companies imposes limits on the diversity of structures and their scope. Furthermore, since the individual substances are originally produced in terms of a particular biological activity, their accumulation usually only comprises those selected from the possible diversity of structures. Furthermore, the accumulation of such substances can only be handled by a limited group of people.

[0002] It is known to prepare substance libraries containing a mixture of different reaction products, starting from a number of different starting compounds, by combinatorial synthesis. On the other hand, by appropriate selection of the library, a new biologically active lead scaffold can be identified, which can subsequently be specifically prepared, and then optionally , Can be optimized. However, on the other hand, this combinatorial library can also be used for subsequent combinatorial synthesis. By combining these two possibilities, new lead scaffolds can be found. The prerequisites for the combinatorial synthesis of a substance library containing a lead scaffold are:-already equipped with biologically active structural elements or using combinatorial synthesis to form biologically active structural elements, Easy access to simple starting materials-to create as complete a combinatorial library as possible and to eliminate the effect of the concentration of each compound in the screening, Simplicity in order to produce as many of the possible reaction products as possible in parallel with the same possible yield in each case;-separation of the reaction products in a form which can be used for screening The method is easy.

[0003] The lead scaffolds found also are simple, inexpensive, suitable for further development, to drugs that can be administered orally, are biologically stable and can be used clinically. Must be in form. Preparation of combinatorial peptide libraries is known in the art. However, peptides have the disadvantages of poor bioavailability, low in vivo stability and very expensive. Although a large number of peptides can be produced, their structural diversity is limited by the linear structure of natural amino acids or easily produced amino acid units and peptides. The preparation of substance libraries containing compounds composed of small molecules is known from the prior art, but the starting materials must be supported on solids during the synthesis.
That is, US-A 5,786,448 discloses a combinatorial library of cyclic urea or thiourea compounds. However, because these compounds are derived from the peptide structure, it is not possible for the possible structural diversity to deviate significantly from the structural diversity of the peptide.

Accordingly, it is an object of the present invention to contain a non-peptide lead scaffold with specific biologically active structural elements, and to be used for screening active compounds or for subsequent combinatorial synthesis, wherein the compounds are used for peptide synthesis. The object is to make available available methods for the preparation of combinatorial libraries which make it possible to achieve structural diversity that is distinct from structural diversity. This object is achieved by a method for preparing combinatorial libraries, which comprises an amine compound represented by the following general formula (I):

Embedded image

Wherein R ¹ , R ² and R ³ may be the same or different and are hydrogen or substituted or unsubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl or aryl groups , -Si (R) ₃ , -Sn (R) ₃ , -SR,
—OR, NRR ′ or the radicals R ¹ and R ² or R ² and R ³ contain, in addition to N, at least one additional heteroatom, preferably N, O or S Groups R ⁴ and R ⁵ are the same or different and are substituted or unsubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl or aryl groups, —Si (R ) ₃ , —Sn (R) ₃ , —SR, —OR, NRR ′, or the radicals R ⁴ and R ⁵ , in addition to N, at least one additional heteroatom, preferably N, O Or a cycloalkyl ring optionally containing S; R and R ′ in the definition of the groups R ⁴ and R ⁵ are the same or different;
A substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group).

General formula (II):

Embedded image (In the formula, R ¹ , R ² and R ⁵ have the above-mentioned meanings), a compound represented by the general formula: (III-a)
Or (III-b): ZR ⁴ or ZR ⁵ (III-a) ZR ⁴ —R ⁵ —Z (III-b) (wherein R ⁴ and R ⁵ are as defined above) And in the case of formula (III-b), the groups R ⁴ and R ⁵ are linked by a bond, Z is Li or MgX, where X is Hal, and Hal is C
where α is greater than or equal to one, and β is greater than one. Or equal to 1 and αβ ² is ≧ 5, especially ≧ 7.

[0007] The particular cross-links resulting from the use of the method of the present invention provide compounds having particular structural features that have been found to be important for the interaction of the compound with the receptor or enzyme. be able to. That is, these compounds have an amine function whose gem carbon atom carries at least two specific substituents. On the one hand, this results in branching, which is also found, for example, in natural amino acids.
) Is obtained. In this regard, a structurally common ground exists between the compounds obtainable by the method of the invention and the amino acids or peptides used in biological systems involved in the interaction of enzymes and receptors. On the other hand, polar carbonyl functions are not involved in the gem branching of amine compounds obtainable by the process of the invention, as for example when using amino acids. In contrast, the compounds obtainable according to the invention have a simple non-polar hydrophobic group at the corresponding position. In this regard, there are differences in the electronic state between the compounds obtainable according to the invention and naturally occurring amino acids and peptides.

[0008] Regarding the resulting structural features common to the compounds obtainable according to the invention and the importance of the structure and electronic state involved in the interaction with enzymes and receptors, the known active compound cyclizine (1) -Diphenylmethyl-4-methylpiperazine), prolintane (1-benzylbutylpyrrolidine) or methamphetamine. By using the process according to the invention, starting from simple starting compounds, a large number of gem-substituted amine compounds can be prepared simply, inexpensively and effectively simultaneously, most preferably All theoretically possible reaction products can be produced. Thus, the present invention provides a fundamentally different electronic state,
It offers the potential to systematically produce compounds with multiple structural diversity while retaining the structural features typical of amino acids.

Thus, the resulting combinatorial library can be used as a simple and inexpensive source of diverse chemical structure, from which it has the desired ligand affinity or enzyme inhibitory activity New lead scaffolds can be selected and these lead scaffolds can be optimized using combination or conventional methods. In the description herein, alkyl is preferably _C1-10 -alkyl, more preferably _C1-8 -alkyl. Cycloalkyl preferably C _{3 to 8} - cycloalkyl, more preferably C _{3 to 7} - cycloalkyl. Alkenyl is preferably _C2-10 -alkenyl, more preferably _C2-8 -alkenyl. Cycloalkenyl is preferably C _{3 to 8} - cycloalkenyl - cycloalkenyl, more preferably C _{3 to 7.} Alkynyl is preferably _C2-10 -alkynyl, more preferably _C2-8 -alkynyl. Aryl is preferably phenyl, naphthyl, anthranyl or phenanthryl.

Preferred examples of R ¹ , R ² and R ³ are described below. Halogen is fluorine, chlorine, bromine or iodine; R ¹ , R ² and R ³ are the same or different. Well, independent of each other,
Hydrogen atom, C _{1 to 8} - alkyl group, C _{3 to 7} - cycloalkyl group, C _{3 to 7} - C _{1 to 6} substituted by a cycloalkyl group - alkyl group, C _{3 to 7} - cycloalkenyl group, C _{3 to 7} - C _{1 to 6} substituted by a cycloalkenyl group - alkyl group, C _{2 to 8} - alkenyl group, C _{2 to 8} - alkynyl group, C _{1 to 6} - C which is substituted by an alkoxy group _1-6 - alkyl group, C _{2 to 6} - C _1-6 substituted by an alkenyloxy group - alkyl group, C _{2 to 6} - C _1-6 substituted by alkynyloxy group - alkyl group, a mono -, di - or polyhalo -C _{1 to 6} -
C _{1 to 6} substituted by an alkoxy group - alkyl group, a mono -, di - or polyhalo -C _{2 to 6} - C _{1 to 6} substituted by an alkenyloxy group - alkyl group, a mono -, di - or polyhalo -C _{2 to 6} - C _{1 to 6} substituted by alkynyloxy group - alkyl group, C _{1 to 6} - C _{1 to 6} substituted by an alkylthio group - alkyl group, C _{1 to 6} - alkylsulfinyl A C _1-6 -alkyl group substituted by a group,

[0011] C _{1 to 6} - C _{1 to 6} substituted by an alkylsulfonyl group - alkyl group, a mono -, di - or polyhalo -C _{1 to 6} - alkyl group, a mono -, di - or polyhalo -C _{2 8} - alkenyl, mono-, - di - or polyhalo -C _{2 to 8} - alkynyl group, C _{1 to 6} substituted by a cyano group - alkyl group, C _{2 to 6} substituted by a cyano group - alkenyl Group, C _2-6 -substituted by a cyano group
An alkynyl 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, C ₁ C ₁ substituted by a ₆ -alkylamino group
₆ - alkyl group, C _{1 to 6} - alkoxy C _{1 to 6} substituted by an amino group - alkyl group, a di (C _{1 to 3} - alkyl) C _{1 to 6} substituted by an amino group - alkyl group _, N- (C 1~3 - _alkyl) -N- (C 1~3 - alkoxy) C _{1 to 6} substituted by an amino group - alkyl _group, N- (C 1~6 - alkylsulfonyl) -N - (C _{1 to 6} - alkyl) C _{1 to 6} substituted by an amino group -
Alkyl group, N-(C _{1 to 6} - _{alkylsulfonyl)} -N- (C 1~6 - alkoxy) C _{1 to 6} substituted by an amino group - alkyl group,

[0012] tri -C _{1 to 6} - C _{1 to 6} substituted by an alkyl silyl group - alkyl group,
A C _1-6 -alkyl group or an aryl group substituted by a triarylsilyl group (provided that the aryl group is one or more halogen atoms, a trifluoromethyl group, a nitro group, a C _1-6- An alkyl group and a C _1-6 -alkoxy group which may be substituted with a substituent selected from the group consisting of an alkyl group and an aryl group (wherein the aryl group is one or more halogen atoms, methyl group, a nitro group, C _{1 to 6} - alkyl and C _{1 to 6} - C ₁ to be substituted by substituents selected from the group consisting of an alkoxy group substituted by may also be)
₆ - alkyl group, an aryl group (provided that the aryl group, one or more halogen atoms, trifluoromethyl group, nitro group, C _{1 to 6} - alkoxy group - alkyl and C _{1 to 6} A C _2-7 -alkenyl group or an aryl group substituted by a substituent selected from the group consisting of one or more halogen atoms, fluoromethyl group, nitro group, C _{1 to 6} - alkyl and C _{1 to 6} - substituted by a substituent selected from the group consisting of an alkoxy group substituted by may also be) C _2
-6 -alkynyl group,

A phenoxy group (provided that the phenoxy group is selected from the group consisting of one or more halogen atoms, trifluoromethyl groups, nitro groups, C _1-6 -alkyl groups and C _1-6 -alkoxy groups) A C _1-6 -alkyl group or an arylthio group substituted by a selected substituent which may be substituted, provided that the arylthio group is one or more halogen atoms, a trifluoromethyl group , nitro group, C _{1 to 6} - alkyl and C _{1 to 6} - C _{1 to 6} substituted by may) be substituted by a substituent selected from the group consisting of alkoxy - alkyl group, an aryl Sulfinyl group (provided that the arylsulfinyl group is 1
Or two or more halogen atoms, trifluoromethyl group, nitro group, C _1-6
- alkyl and C _{1 to 6} - C _{1 to 6,} optionally substituted by a substituent selected from the group consisting of an alkoxy group substituted by may also be) - alkyl group, an arylsulfonyl group (provided that this arylsulfonyl The group is substituted by one or more halogen atoms, trifluoromethyl groups, nitro groups, _C1-6 -alkyl groups and _C1-6 -alkoxy groups. A C _1-6 -alkyl group substituted by

A benzyloxy group (where the aryl group of the benzyloxy group is one or more halogen atoms, a trifluoromethyl group, a nitro group, a C _1-6 -alkyl group and a C _1-6 -alkoxy A C _1-6 -alkyl group or a benzylthio group substituted by a substituent selected from the group consisting of a group consisting of one or more aryl groups _May be substituted with a substituent 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 to 6} substituted by - alkyl group, benzylsulfinyl group (provided that the aryl group of the benzyl sulfinyl group, one or more halogen atoms, trifluoromethyl group, nitro group, C _{1 to 6} -Alkyl group and C _1-6-
A C _1-6 -alkyl group substituted by a substituent selected from the group consisting of an alkoxy group, a benzylsulfonyl group (provided that the aryl group of the benzylsulfonyl group is one or Two or more halogen atoms,
Trifluoromethyl group, nitro group, C _{1 to 6} - alkyl and C _{1 to 6} - substituted by a substituent selected from the group consisting of an alkoxy group substituted by may also be) C _{1 to 6} - an alkyl group - alkyl group, C _{1 to 4} - C _{1 to 6} which is substituted by an amino group substituted by an alkylsulfonyl group.

A group R¹And R^TwoOr R^TwoAnd R^ThreeHas at least one additional head in addition to N
A cycloalkyl ring optionally containing a terrorist atom, preferably N, O or S;
Examples of rings, when formed, include the following rings: 1-pyrrolidinyl, 1
-Imidazolinyl, 1-pyrazolinyl, 1-piperidyl, 1-piperazinyl, 4
-Morpholinyl and 4-thiamorpholinyl. Particularly preferably, the group R¹And R^TwoIs not a hydrogen atom. Particularly preferably, the group R^ThreeIs a hydrogen atom or 1 to 3 fluorine atoms
It is a methyl group which may be more substituted. R^FourAnd R^FiveHalogen is fluorine, chlorine, bromine or
Is iodine: R^FourAnd R^FiveMay be the same or different and independently of one another, a hydrogen atom
, C_1-8-Alkyl group, C_3-7-Cycloalkyl group, C_3-7-Cycloalkyl
C substituted by a_1-6-Alkyl group, C_3-7-Cycloalkenyl group
, C_3-7-C substituted by a cycloalkenyl group_1-6-Alkyl group, C _2-8 -Alkenyl group, C_2-8An alkynyl group,

C_1-6-C substituted by an alkoxy group_1-6-Alkyl group, C_2-6−
C substituted by an alkenyloxy group_1-6-Alkyl group, C_2-6-Al
C substituted by a quinyloxy group_1-6Alkyl groups, mono-, di- and
Is polyhalo-C_1-6-C substituted by an alkoxy group_1-6-Alkyl group
, Mono-, di- or polyhalo-C_2-6-Substituted by an alkynyloxy group
C_1-6-Alkyl group, C_1-6-C substituted by an alkylthio group _1-6 -Alkyl group, C_1-6-C substituted by an alkylsulfinyl group _1-6 -Alkyl group, C_1-6-C substituted by an alkylsulfonyl group_{1
~ 6}-Alkyl groups, mono-, di- or polyhalo-C_1-8-Alkyl groups, mono
-, Di- or polyhalo-C_2-8An alkenyl group, a mono-, di- or polyha
B-C_2-8-C substituted by an alkynyl group or a cyano group_1-6-Alkyl
Group substituted by a cyano group_2-6-Substituted by an alkenyl group or a cyano group
C being replaced_2-6-C substituted by an alkynyl group or a nitro group_1-6−
C substituted by an alkyl group or a nitro group_2-6An alkenyl group,

A C _2-6 -alkynyl group substituted by a nitro group, a C _1-6 -alkyl group substituted by a C _1-6 -alkylamino group, and a C _1-6 -alkoxyamino group substituted by a C _1-6 -alkoxyamino group and are C _{1 to 6} - alkyl group, a di (C _{1 to 3} - alkyl) C _{1 to 6} substituted by an amino group - alkyl group, N-(C _{1 to 3} - alkyl) -N-
A C _1-6 -alkyl group substituted by a (C _1-3 -alkoxy) amino group,
N-(C _{1 to 6} - _{alkylsulfonyl)} -N- (C 1~6 - alkyl) C _{1 to 6} substituted by an amino group - alkyl _group, N- (C 1~6 - alkylsulfonyl) -N - (C _{1 to 6} - alkoxy) C _{1 to 6} substituted by an amino group - alkyl group, tri -C _{1 to 6} - C _{1 to 6} substituted by an alkyl silyl group - alkyl group, triarylsilyl A C _1-6 -alkyl group, an aryl group substituted by a group, provided that the aryl group is one or more halogen atoms, a trifluoromethyl group, a nitro group, a C _1-6 -alkyl group and _May be substituted with a substituent selected from the group consisting of C _1-6 -alkoxy groups),

An aryl group (where the aryl group is one or more halogen atoms,
Trifluoromethyl group, nitro group, C_1-6-Alkyl group and C_1-6−Arco
Which may be substituted with a substituent selected from the group consisting of
C being replaced_1-6An alkyl group, an aryl group (provided that the aryl group is
One or more halogen atoms, trifluoromethyl groups, nitro groups, C_1-6  -Alkyl group and C_1-6-A substituent selected from the group consisting of an alkoxy group
Which may be further substituted by_2-7An alkenyl group, a
A reel group (however, this aryl group is one or more halogen atoms,
Trifluoromethyl group, nitro group, C_1-6-Alkyl group and C_1-6-Alkoki
(Optionally substituted by a substituent selected from the group consisting of
C_2-6Alkynyl group, phenoxy group (provided that the phenoxy group
Represents one or more halogen atoms, a trifluoromethyl group, a nitro group, _1-6 -Alkyl group and C_1-6-Substitution selected from the group consisting of alkoxy groups
Substituted by a group which may be substituted by_1-6An alkyl group,

An arylthio group (provided that the arylthio group is selected from the group consisting of one or more halogen atoms, trifluoromethyl groups, nitro groups, C _1-6 -alkyl groups and C _1-6 -alkoxy groups) May be substituted by a selected substituent)
A C _1-6 -alkyl group or an arylsulfinyl group (wherein, the arylsulfinyl group is one or more halogen atoms, a trifluoromethyl group, a nitro group, a C _1-6 -alkyl group and C _{1 to 6} - C _{1 to 6} substituted by an alkoxy group may be substituted by a substituent selected from the group consisting of) - alkyl group, an arylsulfonyl group (provided that the arylsulfonyl group, (It may be substituted by one or more halogen atoms, trifluoromethyl group, nitro group, _C1-6 -alkyl group and _C1-6 -alkoxy group.) A C _1-6 -alkyl group substituted with a benzyloxy group (provided that the aryl group of the benzyloxy group is
One or more halogen atoms, trifluoromethyl groups, nitro groups, C _1-6 - C _{1 to 6} substituted by may) be substituted by a substituent selected from the group consisting of alkoxy - - alkyl group, the alkyl group and C _{1 to 6}

A benzylthio group (provided that the aryl group of the benzylthio group is selected from one or more halogen atoms, trifluoromethyl groups, nitro groups, C _1-6 -alkyl groups and C _1-6 -alkoxy groups) A C _1-6 -alkyl group or a benzylsulfinyl group substituted by a C _1-6 -alkyl group which may be substituted with a substituent selected from the group consisting of one or more aryl groups. Which may be substituted by a substituent 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) _1-6 -alkyl group, benzylsulfonyl group (where the aryl group of the benzylsulfonyl group is one or more halogen atoms , Trifluoromethyl group, nitro group, C _{1 to 6} - alkyl and C _{1 to 6} - C _{1 to 6,} optionally substituted by a substituent selected from the group consisting of an alkoxy group substituted by may also be) An alkyl group, a C _1-6 -alkyl group substituted by an amino group substituted by a C _1-4 -alkylsulfonyl group.

A preferred group of amine compounds that can be prepared using the method of the present invention is
explain. In the first group, the amine compound of the present invention is represented by the general formula (I)¹, R ^Two And R^ThreeAre the same or different and are hydrogen, alkyl, one or more
Alkyl (perhalogen) substituted by fluorine, chlorine, bromine or iodine above
Alkyl), cycloalkyl, one or more fluorines, salts
Cycloalkyl, aryl, 1-5, substituted by nitrogen, bromine or iodine
Aryl, alkenyl, substituted by fluorine, chlorine, bromine or iodine
, Alkynyl, -Si (R)_Three, -Sn (R)_Three, -SR, -OR, -NRR
′ Or a group R¹And R^TwoOr R^TwoAnd R^ThreeMeans a cycloalkyl ring
This ring, in addition to N, at least one additional heteroatom, preferably
Or N, O or S,

The groups R ⁴ and R ⁵ are the same or different and are alkyl, alkyl substituted by one or more fluorine, chlorine, bromine or iodine (including alkyl perhalides), cycloalkyl, one or more fluorine, chlorine, bromine or cycloalkyl substituted by iodine, alkenyl, alkynyl or a group -C (R'') (R') CH 2 R ( where,, R '' Is -S
_{i (R) 3, -Sn (} R) 3, -SR, -OR, a -NRR', R and R'in the definitions of R ¹ to R ⁵ are the same or different and are an alkyl group, Alkyl group, alkenyl group, alkynyl group, aryl group substituted by one or more fluorine, chlorine, bromine or iodine, aryl group substituted by 1 to 5 fluorine, chlorine, bromine or iodine And the radicals R ⁴ and R ⁵ present in the β-position are gem-symmetric or asymmetric alkylated amine compounds which in each case can have at most one hydrogen.

In the second group, the amine compound of the present invention is a compound of the formula (I)^FourYou
And R^FiveIs a compound having the same meaning, and thus a symmetrically alkylated compound.
And in these compounds, R¹, R^TwoAnd R^ThreeAre, independently of each other, H, A, Ar, -Si (R⁶)_Three , -Sn (R⁶)_Three, -SR⁷, -OR⁷, -NR⁸R⁹Or a group R ¹ And R^TwoOr R^TwoAnd R^ThreeOr R⁸And R⁹And may be interconnected
Together form a cyclic ring having from 3 to 8 carbon atoms, the ring comprising a nitrogen
And at least one selected from the group consisting of -S-, -O- and -N-
And may contain additional heteroatoms^FourIs A, Ar, -Si (R⁶)_Three, -Sn (R⁶)_Three, -SR⁷, -O
R⁷, -NR⁸R⁹Where R⁸And R⁹Has the above meaning or
Or R⁸And R⁹Or two groups R^FourAnd R^FiveAre connected to each other
Often, they form together a cyclic ring having 3 to 8 carbon atoms, which ring
Selected from the group consisting of at least one of -S-, -O- and -N- in addition to nitrogen.
May contain additional heteroatoms selected,

R⁶, R⁷, R⁸And R⁹Are, independently of one another, A or Ar; A is a linear or branched alkyl group having 1 to 10 carbon atoms,
A linear or branched alkenyl group having 2 to 10 atoms, or 2 to 2 carbon atoms
A linear or branched alkynyl group having 10 or 3 to 8 carbon atoms
A substituted or unsubstituted cycloalkyl group having 3 to 8 carbon atoms
A saturated or polyunsaturated cycloalkyl group, and Ar is a substituted or unsubstituted aryl group having 6 to 20 carbon atoms. In the third group, the amine compound of the present invention is a compound represented by the general formula (I):^FourYou
And R^FiveAre compounds having the same meaning, thus diem symmetric alkylation amination
A compound of the formula:¹, R^TwoAnd R^ThreeAre, independently of each other, H, A, Ar, -Si (R⁶)_Three , -Sn (R⁶)_Three, -SR⁷, -OR⁷, -NR⁸R⁹Or a group R ¹ And R^TwoOr R^TwoAnd R^ThreeOr R⁸And R⁹May be connected to each other,
Together, they form a cyclic ring with 3 to 8 carbon atoms, which ring is added to the nitrogen.
And at least one selected from the group consisting of -S-, -O- and -N-
May contain additional heteroatoms,

The group R^FourIs A, Ar, -Si (R⁶)_Three, -Sn (R⁶)_Three, -SR⁷, -O
R⁷, -NR⁸R⁹Where R⁸And R⁹Has the above meaning or
Or R⁸And R⁹Is bonded to each other and together have 3 to 8 carbon atoms
Form a cyclic ring, in addition to the nitrogen atom, at least one -S-,
Containing an additional heteroatom selected from the group consisting of -O- and -N-
-C (R^Ten) (R^Three) CH_TwoR⁹Where R⁸, R⁹And R ^Ten Has the above meaning; or two groups R^FourAnd R^FiveAre interconnected and together
To form a cyclic ring having 3 to 8 carbon atoms.
In addition, at least one selected from the group consisting of -S-, -O- and -N-
May contain additional heteroatoms, provided that R^FourAnd R^FiveRespectively
It has at most one hydrogen atom at the β position. R⁶, R⁷, R⁸And R⁹Are, independently of one another, A or Ar;^TenIs -Si (R⁶)_Three, -Sn (R⁶)_Three, -SR⁷, -OR⁷, -NR ⁸ R⁹Where R⁸And R⁹Has the meaning described above, or R⁸When
R⁹Is bonded to each other and together form a cyclic ring having 3 to 8 carbon atoms
The ring has at least one -S-, -O- and
-N- may contain an additional heteroatom selected from the group consisting of:

A is a linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched alkenyl group having 2 to 10 carbon atoms, or 2 to 10 carbon atoms.
A linear or branched alkynyl group having 10 or a substituted or unsubstituted cycloalkyl group having 3 to 8 carbon atoms, a mono- or polyunsaturated cycloalkyl having 3 to 8 carbon atoms An alkyl group, and Ar is a substituted or unsubstituted aryl group having 6 to 20 carbon atoms. In a fourth group, the amine compounds according to the invention are gem asymmetric alkylated amine compounds in which the radicals R ⁴ and R ⁵ are different in the general formula (I), in which the radicals R ¹ , R ^{2 , R 3, R 4, R} 5, R 6, R 7, R 8 and R ⁹ have the same meaning described for the second group of the amine compound of the present invention. In the fifth group, the amine compound of the present invention is a gem asymmetric alkylated amine compound represented by the general formula (I).

The groups R ¹ , R ² and R ³ are the same or different and represent hydrogen, alkyl, cycloalkyl, aryl, alkenyl, alkynyl, —Si (R) ₃ , —Sn (R
) ₃ , —SR, —OR, —NRR ′, or the radicals R ¹ and R ² or R ² and R ³ form a cycloalkyl ring, which, in addition to N, And may contain N, O or S additional heteroatoms, the groups R ⁴ and R ⁵ being different, alkyl, cycloalkyl, aryl,
Alkenyl, alkynyl, or a group —C (R ″) (R ′) CH ₂ R, wherein the group R ″ is —Si (R) ₃ , —Sn (R) ₃ , —SR, —OR , -NRR
R and R ′ in the definitions of groups R ^{1 to} R ⁵ may each be the same or different and are alkyl, alkenyl, alkynyl or aryl groups; and groups R ⁴ and R ⁵ are each It can have at most one hydrogen atom at the β position.

In the sixth group, the amine compound of the present invention is a gem represented by the general formula (I)
Asymmetric alkylated amine compounds, wherein R¹, R^TwoAnd R^ThreeAre the same or different and are hydrogen, alkyl, cyclo
Alkyl, aryl, alkenyl, alkynyl, -Si (R)_Three, -Sn (R) _Three , -SR, -OR, -NRR ', or a group R¹And R^TwoOr R^TwoAnd R ^Three Means a cycloalkyl ring which, in addition to N, has at least one
R, which may contain N, O or S additional heteroatoms, preferably N, O or S.^FourAnd R^FiveAre the same or different and are alkyl, cycloalkyl,
Alkylaryl, alkenyl, alkynyl, or a group -C (R) (R) CH_TwoR
Wherein the group R is -Si (R)_Three, -Sn (R)_Three, -SR, -OR,-
NRR 'and the group R¹~ R^FiveR and R ′ in the definition of each may be the same or different
Often an alkyl, alkenyl, alkynyl or aryl group;^FourAnd R^FiveEach have at least two hydrogen atoms in the β position.

In the first to sixth amine compounds, R ³ is particularly preferably hydrogen or a methyl group, or R ¹ and R ² have no hydrogen atom. The present invention can also use an amine compound represented by the following general formula (Ia):

Embedded image

Where R¹, R^Two, R^FourAnd R^FiveHas the meaning defined above or is
Preferably each is, independently of one another, ethyl or hexyl or
Together with the nitrogen atom to which they are attached represent a piperidinyl group; ^Four And R^FiveAre each independently of one another or together, hydrogen, methyl,
Represents butyl or benzyl. The production of the compound represented by the general formula (Ia) is carried out in the method of the present invention.
Is suppressed by the presence of Five or more combinatorial libraries within the meaning of the present invention are preferred.
Or at least seven different compounds represented by the general formula (I) or the formula (Ia).
Contains a min compound. According to the present invention, an amine compound represented by the general formulas (I) and (Ia) is used.
A method for preparing a combinatorial library is described in detail below. The first component used in the reaction according to the present invention is a compound represented by the general formula (II)
Is the thing:

[0031]

Embedded image Where R¹, R^TwoAnd R^ThreeHas the meaning given above and R^ThreeEspecially preferred
Or hydrogen, or substituted by 1 to 3 fluorine atoms
It is a methyl group. In the formula (II), R^ThreeIs hydrogen, or 1-3
The compound which is a methyl group which may be substituted by a fluorine atom according to the present invention
The reaction is slightly inhibited sterically, while hydrolysis with the separation of the amine function is possible.
This has the advantage that a more stable amine is produced. By the process according to the invention, the carboxyamidation of the general formula (II)
The compound can be reacted in good yield. In the formula (II), R¹, R ^Two And R^ThreeCan, independently of one another, have the following meanings:

H or A, ie a branched or straight-chain 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 The corresponding methyl- or ethyl-substituted cycloalkyl groups, or mono- or polyunsaturated cycloalkyl groups, for example cyclopentenyl or cyclopentadienyl; or branched or straight-chain alkenyl having 2 to 10 carbon atoms For example, allyl, vinyl, isopropenyl, Ropeniru or branched or straight chain alkynyl having 2 to 10 carbon atoms, such as ethynyl, propynyl; or

Unsubstituted or aryl having one or more substituents having 6 to 20 carbon atoms, such as unsubstituted or NO ₂ , F, Cl, Br,
One or two or more substituted with one or more substituents selected from NH ₂ , NHA, NA ₂ , OH and OA, wherein A can have the meaning described above; Phenyl, naphthyl, anthryl, which may be substituted with one or more halogens or may be completely halogenated, preferably fluorinated;
Phenanthryl; or an aralkyl group having 7 to 20 carbon atoms, for example benzyl, which is one or more of the groups NO ₂ , F, Cl, Br, NH ₂ , NHA, NA ₂ , O ₂
H and OA, where A can have the meanings described above, and can be substituted with one or more halogens, or completely substituted with one or more halogens. Optionally halogenated, preferably fluorinated; or

Aralkenyl or aralkynyl; wherein the aryl, alkenyl and alkynyl groups each may have the above meaning as in phenylethynyl. R ¹ and R ² or R ² and R ³ together, the annular ring (this ring having 3 to 8 carbon atoms, in addition to the nitrogen, -S -, - O-or -N-, such as Particularly good yields can be obtained with carboxamide compounds forming an additional heteroatom). In this case, R ¹ and R ² or R ¹ and R ³ together form a simple cyclic ring containing the carboxamide nitrogen, or R ¹ and R ² or R ¹ and R ³ Compounds forming a cyclic ring containing an oxygen atom as an additional heteroatom are particularly preferred. Very particular preference is given to using the following compounds as carboxamide compounds of the formula (II):

[0035]

Embedded image Preferably 1 to 10, more preferably 1 to 5, different compounds represented by the general formula (II) are used.

The second component used in the reaction according to the present invention has the general formula (III-a) or (I
A compound represented by II-b): ZR ⁴ or ZR ⁵ (III-a) ZR ⁴ —R ⁵ —Z (III-b) In each formula, R ⁴ and R ⁵ are as defined above. Has the meaning of The group Z is preferably -MgX
(Where X is Cl or Br), or the group Z is lithium. When R ¹ or R ² is —Si (R) ₃ , the —Si (R) ₃ group can be easily hydrolyzed, thereby introducing a hydrogen atom into the corresponding position. When using a Grignard or lithium compound of the general formula (III-a) or (III-b) as nucleophile, the substituents have the following meanings:

R ⁴ is preferably an alkyl group having 1 to 10 carbon atoms, for example methyl,
Ethyl, n- or i-propyl, n-, sec- or i-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the suitable isomers thereof; or cycloalkyl having 3 to 8 carbon atoms For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or the corresponding methyl or ethyl substituted cycloalkyl group, or a mono- or polyunsaturated cycloalkyl group, for example cyclopentenyl or cyclopentadienyl; Or a branched or straight chain alkenyl having 2 to 10 carbon atoms, such as allyl, vinyl, isopropenyl, propenyl; or

[0038] Branched or straight-chain alkynyl having 2 to 10 carbon atoms, such as ethynyl, propynyl; or unsubstituted or having 1 to 2 or more carbon atoms having 6 to 20 carbon atoms aryl having group, or for example unsubstituted or _{NO 2, F, Cl, Br} , NH 2, NHA, NA 2, OH and OA (wherein a
Can have the meaning described above), and is substituted by one or more substituents selected from the group consisting of may be, preferably may be fluorinated, phenyl, naphthyl, anthryl, phenanthryl; or having 7 to 20 carbon atoms, one or more groups NO _2, F, Cl, Br
, NH ₂ , NHA, NA ₂ , OH and OA (where A can have the meaning given above), and one or more halogens Or an aralkyl group which may be substituted or completely halogenated, preferably optionally fluorinated, such as benzyl;

Aralkenyl or aralkynyl; wherein the aryl, alkenyl and alkynyl groups may each have the above meaning as in phenylethynyl. Furthermore, the groups R ⁴ and R ⁵ present in the general formula (III-a) are
(R ⁶ ) ₃ , —Sn (R ⁶ ) ₃ , —SR ⁷ , —OR ⁷ , —NR ⁸ R ⁹ , wherein R ⁶ , R ⁷ , R ⁸ and R ⁹ are each other Independently, it has the above-mentioned meaning, or R ³ and R ⁹ may be bonded to each other, and together form a cyclic ring having 3 to 8 carbon atoms. Is a nitrogen atom, -S-,
-O- and -N- may contain at least one heteroatom selected from the group consisting of; or formula (III-b) 2 radicals R ⁴ present in the
It can be alkyl having 2 to 7 carbon atoms, in which case, by using the reaction according to the invention, in the general formula (I) two radicals R ⁴ are substituted with 3 carbon atoms
A compound forming a cyclic ring having up to 8 is obtained.

Particularly preferably, R ⁴ represents the following meanings: an alkyl group, for example methyl, ethyl, n- or i-propyl, n-, sec- or t-butyl, pentyl,
Hexyl; or a cycloalkyl group such as cyclopropyl, cyclobutyl,
Cyclopentyl, cyclohexyl; or an aryl group such as phenyl; or an aralkyl group such as benzyl. Particularly preferably, the following Grignard compounds are used in the reaction as compounds of the general formula (III-a): methyl magnesium bromide, ethyl magnesium bromide, n- or i-propyl magnesium bromide, i-, sec- or tert -Butyl magnesium bromide, n-hexyl magnesium bromide, cyclohexyl magnesium chloride, allyl magnesium bromide, vinyl magnesium bromide, cyclopropyl magnesium bromide, cyclopentyl magnesium bromide, cyclopentyl magnesium chloride, phenyl magnesium bromide, benzyl magnesium chloride, p-fluorophenyl magnesium bromide .

In the reaction, the compound represented by the general formula (III-a) is converted to a compound represented by the general formula (I
1.6 to 2.4, preferably 1.8 to 2.2, relative to the compound represented by I)
It should be present in equivalent amounts, and when using compounds of the general formula (III-b), they should each be used in half the equivalent amount. In the reaction, the compounds represented by the general formulas (III-a) and (III-b) are used in an amount of 0.7 to 1. 2, preferably used in an amount of 0.9 to 1.1 equivalents. When the compounds represented by the general formulas (III-a) and (III-b) are Grignard reagents, these compounds are represented by the formulas (III-a ′) and (III-b ′) It can be formed in situ by reacting the compound with magnesium. In the generation of this situ Magurushiumu the formula (III-a') and the general formula (III-b'): X- R 4 or ^{X-R 5 (III-a'} ) X-R 4 -R 5 - X (III-b ′) (wherein, X, R ⁴ and R ⁵ have the same meaning as described above).

Preferably, in this in-situ formation of the Grignard compound, the amount of magnesium is 2 to 4, preferably 2.8 to 3, based on the compound represented by the general formula (III-a ′). 2 equivalents, and the amount of the compound represented by the general formula (III-a) is 1.8 to 2.8 equivalents with respect to the compound represented by the general formula (II).
Preferably, it is 2.2 to 2.6 equivalents. When both compounds (III-b ') are used, the corresponding amounts of the respective equivalents are used. The titanium, hafnium or zirconium compound reacted according to the invention is preferably a compound of the general formula (IV-a) or (IV-b): R ⁵ TiY _3-n (OR ^III ) _n (IV-a ) R ⁵ TiY _4-n (OR ^III ) _n (IV-b)

In each formula, R ⁵ has the meaning described above, and n is an integer of 1 to 3 in the case of (IV-a), or an integer of 1 to 4 in the case of (IV-b) Y is Cl, Br or I, and R ^III is the same or different and is an alkyl group having 1 to 10 carbon atoms or an aryl group having 6 to 20 carbon atoms. It is preferred to use an organic titanium compound where R ^III is isopropyl. Particularly preferably, the organic titanium compound used is Ti (OiPr) ₄ (where iPr corresponds to an isopropyl group). When this reaction is carried out as a catalyst in the presence of an organic titanium compound, the catalyst is used in an amount of 0.5 to 5 mol% based on the compounds represented by the general formulas (III-a) and (III-b). And preferably in an amount of 1 to 3.5 mol%.

Experimentally, a nucleophile of general formula (III-a) or (III-b), which can be a Grignard reagent, is used to form this compound in situ or to react When added to the mixture, the carboxamide compounds of the general formula (II) can be reacted in a simple manner in the presence of catalytic amounts of titanium dioxide, hafnium dioxide or zirconium dioxide, whereby the symmetrically substituted It has been shown that compounds of the formula (I) which are substituted or asymmetrically substituted can be obtained. Thus, the method can also be performed in the presence of a catalytic amount of a metal oxide selected from titanium dioxide, hafnium dioxide and zirconium dioxide, wherein the catalytically active form of the catalyst is
Can be generated on the fly. The amine compound represented by the general formula (I) is preferably used not only in the presence of a titanium, hafnium or zirconium compound, but also as a catalyst.
It can also be produced in the presence of a compound represented by formula (V), (VI) or (VII).

(R ^IV ) ₃ SiZ (V) wherein the groups R ^IV are the same or different and are alkyl or aryl groups, and Z is F, Cl, Br or I, preferably Cl) (R ^IV ) ₃ ZSi (CH ₂ ) _O SiZ (R ^IV ) ₂ (VI) wherein o is an integer from 1 to 12, and Z and R ^IV are as defined above. A ^{m +} (OiPr) _m (VII) (where m is an integer of 1 to 4 and represents the oxidation state of the metal, iPr is isopropyl, and A is Al, Ca, Na, K , Si or Mg, preferably Mg or Na).

The reaction can be started even at room temperature by the addition of a cocatalyst and has proven to lead to a complete reaction of the starting materials in a relatively short reaction time. A suitable cocatalyst for this reaction is an alkylsilyl halide. In particular, these are the alkylsilyl halides represented by the above formula (V) or (VI). It is preferred to use alkylsilyl halides where R is alkyl having 1 to 6 carbon atoms. In particular, R is alkyl having 1 to 3 carbon atoms;
Alkylsilyl halides in which is chlorine are preferred. The addition of 0.7 to 1.2 mol, in particular 0.9 to 1.1 mol, of cocatalyst, per mol of starting material, improves, for example, high yields, low reaction temperatures or short reaction times. It has been found that results are obtained. Very particular preference is given to using the following compounds as cocatalysts:

NaO-iPr Mg (O-iPr) ₂ (CH ₃ ) ₃ SiCl (CH ₃ ) ₂ ClSi (CH ₂ ) ₂ SiCl (CH ₃ ) ₂ (CH ₃ ) ₂ ClSi (CH ₂ ) ₃ CN [( When CH ₃ ) ₃ Si] ₂ O [(CH ₃ ) ₃ Si] ₂ NH and [(CH ₃ ) ₃ Si] ₂ co-catalysts are added to the reaction mixture, this can lead to compounds of the general formula (II) On the other hand, it should be used in an amount of 0.7 to 1.2, preferably 0.9 to 1.1 equivalents.

The method for producing the substituted amino compound represented by the general formula (I) is preferably performed at room temperature, that is, at 20 to 25 ° C. in an inert gas atmosphere. If no further cocatalyst is used in this reaction, temperatures up to 80 ° C., preferably up to 65 ° C., can also be set as reaction temperatures. As can be demonstrated by example, under suitable conditions the complete reaction of the carboxamide takes place even after 1 hour. The reaction is carried out in a suitable solvent for the general formulas (II), (III-a), (III-b), (IV-a) or (IV-b), preferably aliphatic or aromatic hydrocarbons Alternatively, the reaction is carried out in a suitable organic solvent such as an ether, preferably toluene, tetrahydrofuran, n-hexane, cyclohexane, benzene or diethyl ether.

A solution of the compound represented by the general formula (II) and the compound represented by the formula (IV-a) and the cocatalyst is first introduced, and then the compound represented by the general formula (III) is slowly added by metering. Very particularly preferred. In this case, it is advantageous if the Grignard or lithium compound is present in the solvent as a solution, preferably added dropwise to the reaction mixture. Furthermore, it is advantageous to stir the reaction mixture during the entire reaction. This synthesis makes it possible to produce symmetrically or asymmetrically substituted amino compounds of the formula (I) in a reasonable yield in a reasonable reaction time. Enamine formation with α-elimination or cyclization with β-hydride elimination is largely avoided.

The process can in particular also be carried out as follows: a) Firstly, at least one carboxamide of the general formula (II):
A metal oxide selected from the group consisting of titanium dioxide, hafnium dioxide and zirconium dioxide in an amount of 1 to 15 mol% with respect to the carboxamide, and optionally a cocatalyst at room temperature under an inert gas atmosphere, toluene, Introduced in a solvent selected from the group consisting of THF, n-hexane, benzene and diethyl ether. B) A solution containing a nucleophile represented by the general formula (IIIa) or (IIIb) is added dropwise. C) after-react with stirring, and after the reaction is complete, subject the mixture to conventional work-up;

Alternatively, when Z is MgX: a ′) Consisting of magnesium pieces, carboxamide represented by the general formula (II), 1 to 15 mol% of titanium dioxide, hafnium dioxide and zirconium dioxide based on the carboxamide. A catalyst selected from the group is first introduced at room temperature under an inert gas atmosphere into a solvent selected from the group consisting of toluene, THF, n-hexane, benzene and diethyl ether, b ′) toluene, THF, Formula (IIIa ′) or (III) in a solvent selected from the group consisting of n-hexane, benzene, and diethyl ether.
The alkyl halide represented by b ′) is added dropwise: XR ⁴ (IIIa ′) or XR ⁴ —R ⁴ —X (IIIa ′) wherein R ⁴ and X are C ') after-reacting with stirring, and after the reaction is complete, the mixture is subjected to conventional work-up.

To carry out this method, a dried, commercially available metal oxide selected from the group consisting of titanium dioxide, hafnium dioxide and zirconium dioxide is used as a catalyst. Preferably, a powdered titanium (IV) oxide (TiO ₂ ) is used. In this case, in the simplest case, it can be of industrial quality. It is advantageous to choose a quality that is not too finely ground, since a simple separation after the reaction has taken place can be ensured. The metal oxide, preferably titanium dioxide, which has been pre-dried by heating is also used as a suspension in a suitable pre-dried organic solvent. Suitable solvents include, for example, aliphatic or aromatic hydrocarbons or ethers. It is preferable to use a solvent selected from the group consisting of toluene, tetrahydrofuran, n-hexane, cyclohexane, benzene and diethyl ether. These solvents can also be dried before the reaction by methods known to those skilled in the art. This drying can be performed using magnesium sulfate, calcium chloride, sodium, KOH, or by another method.

In order to carry out this process, titanium (IV) oxide (TiO ₂ ) is first prepared in toluene in an amount of 1 to 15 mol%, preferably 3 to 13 mol%, based on the amount of amide to be reacted. , Tetrahydrofuran (THF), hexane, benzene and diethyl ether as a suspension in a suitable dry solvent. The suspension is adjusted to a temperature of 15 to 30C, preferably about 20C. Under an inert gas atmosphere (nitrogen or argon), the starting materials are dissolved in liquid form or in a suitable solvent selected from the group consisting of toluene, tetrahydrofuran (THF), hexane, benzene and diethyl ether and slowly stirred. Add dropwise. An amount of cocatalyst corresponding to the amount of starting material to be reacted is also added dropwise in dry solvent. While maintaining this temperature, the resulting reaction mixture is stirred for a short time, ie for several minutes. Then, a mixture of the same amounts of the two different Grignard reagents is slowly added to the reaction mixture such that the temperature of the reaction mixture does not rise above 50 ° C.

In order to achieve as complete a reaction as possible of the starting materials, each of these Grignard reagents is added in excess. Preferably, the Grignard reagent is used in an amount of at least 1.05 mole to 1.5 mole per mole of starting material. After the addition of the Grignard reagent is complete, stirring is continued for several hours at a constant temperature to obtain a complete reaction of the reaction mixture. As an example, 3 mmol% of titanium (IV) oxide in 40 ml of dry tetrahydrofuran, while stirring 5 mmol of the starting material at 20 ° C. under an inert gas atmosphere
Is added dropwise to the suspension. 5 mmol of cocatalyst, also in dry tetrahydrofuran, are added slowly with stirring to this mixture. Then
Stir at 20 ° C. for 5 minutes and then add 6 mmol of the two different Grignard reagents
Add slowly so that the temperature of the reaction mixture does not rise above 50 ° C.
Stir further for 1 hour until the reaction is complete.

In a preferred embodiment for carrying out the process, the titanium (IV) oxide used as catalyst is firstly used in an amount of 1 to 15 mol, preferably 1.5 to 14 mol, per mol of amide used as starting material. Of a suspension which is adjusted to a temperature of 10 to 30 ° C., preferably 15 to 25 ° C., particularly preferably about 20 ° C. Introduce in form. Under an inert gas atmosphere (nitrogen or argon), the starting materials are in liquid form or toluene, tetrahydrofuran, n-
Dissolve in a solvent selected from the group consisting of hexane, cyclohexane, benzene and diethyl ether and slowly add dropwise with stirring. An amount of cocatalyst corresponding to the amount of starting material to be reacted is then taken up in the solvent, if necessary, and slowly added dropwise. While maintaining this temperature, the resulting reaction mixture is stirred for a short time, ie for several minutes. The reaction mixture thus obtained is then substituted with a compound of the general formula (II-a) or (II-a) sufficient to effect substitution of gemcarbonyl C by two identical substituents, ie symmetric substitution of gemcarbonyl C. III-b
Sufficiently add the nucleophile represented by) in excess.

The nucleophiles according to the invention, which are prepared by methods generally known to the person skilled in the art, should be carried out slowly, so that the temperature of the reaction mixture does not exceed 50 ° C. Advantageously, the addition of the nucleophile, ie the Grignard reagent or the lithium compound, is carried out with thorough mixing, preferably with vigorous stirring. To shift the reaction equilibrium towards the desired symmetrically displaced product, the nucleophile used, preferably the Grignard reagent, is present in an amount of from 2.1 to 2.1 moles per mole of starting material reacted.
Add in an amount of 3 mol. Preferably, the Grignard reagent is added in an amount of 2.2 to 2.6 moles per mole of starting material. If a nucleophile or a Grignard reagent of the general formula (IIIb) is used in the reaction, it is added to the reaction mixture according to twice the number of reactive groups and only in equimolar amounts relative to the starting materials used. After the addition of the Grignard reagent is completed, the reaction mixture is subsequently stirred at a constant temperature for several hours until the reaction is completed.

Another variant of the method is that magnesium is converted to a compound of general formula (III-a ′) or
The Grignard reagent is produced in situ by reacting with a compound represented by (III-b ′) (wherein R ⁴ and X have the meanings described above). Preferably, the amount of magnesium in the in situ production of this Grignard reagent is 2 to 5 times, preferably 2.8 to 3 times, the molar amount of the compound of the general formula (II) used as starting material. 2 times the molar amount, and the general formula
The amount of the compound represented by (III-b ′) is 2 to 3.8 times, preferably 2.2 to 2.6 times, the molar amount of the compound represented by the general formula (II). As a surrogate in the general description for carrying out the above method, instead of Grignard reagents, lithium compounds can also be used. The corresponding lithium compounds can be prepared in a similar manner to Grignard reagents by methods generally known to those skilled in the art and can be reacted in a manner similar to that described above.

After the reaction, the symmetrically or asymmetrically substituted amino compound can be purified and isolated by a conventional method. In this case, the product can be precipitated as a salt with a hydrochloric acid solution, for example a 1 molar ethereal hydrochloric acid solution, filtered off and then, if necessary, purified by recrystallization. This product is extracted from the organic phase using an acid solution, preferably an aqueous hydrochloric acid solution,
The pH of the resulting extract is adjusted to> 1 with an alkali, preferably sodium hydroxide solution.
It can be adjusted to zero and then extracted at least once, preferably several times, with dry diethyl ether. The organic phase containing the reaction product obtained here can, if desired, be dried (over potassium carbonate) and then separated from the organic solvent under reduced pressure. Furthermore, the reaction product can be isolated by separating the organic solvent with the aid of pressure and then separating the remaining residue by column chromatography.

On the other hand, the compound represented by the general formula (Ia) can also be produced by the above-mentioned method using a co-catalyst. After the reaction, the symmetrically or asymmetrically substituted amino compound can be purified and isolated by a conventional method as described above. In the combinatorial synthesis of amine compounds of the general formula (I), a number of different compounds of the general formula (III-a) and, if appropriate, of the general formula (III-b) or (III-c) Compounds are used. It has been found that combinatorial libraries containing a large number of amine compounds of the general formula (I) as a mixture can be obtained in this way. One to ten different compounds of the general formula (II) are converted into at least two compounds of the general formula (I)
It is preferable to react with the compound represented by II-a) or (III-b). The library of amine compounds represented by the general formula (I) can be subjected to selection relating to biological activity to isolate and identify amine compounds having specific properties of the active compound.

The amine compounds of the general formula (I) can be used as pure substances or a number of different amine compounds can be used as combinatorial libraries in combinatorial synthesis. In the latter case, the amine compound can be reacted with one or more reactants to create a modified amine compound of the general formula (I). Preferably, the gem-substituted structural element of the amine compound is carried here. In the combinatorial synthesis for creating modified amine compounds of the general formula (I), amine compounds having an activity which has already been proven by biological screening methods can be used advantageously. By using a biologically active amine compound of the general formula (I) in the creation of a modified amine compound, the possibility of achieving an improved activity by combinatorial synthesis is obtained.

By repeating the selection and synthesis steps, the possibility of significantly increasing the activity of the amine compound of the general formula (I) is obtained. Synthetic combinatorial libraries according to the invention offer the following advantages: they contain a large number of different amine compounds which are present in similar amounts in the library. They can be produced by methods which can be carried out catalytically. Support for starting compounds for library preparation, which is customary in combinatorial synthesis, for example starting from amino acids, is unnecessary. -Readily available starting compounds can be used. The invention will now be described by way of example.

Examples 1-3 Libraries containing amine compounds of general formula (I) were prepared according to the following general procedure and then identified by mass spectrometry. Starting material (II) 5 as a liquid or as a solution in tetrahydrofuran
Millimoles at 20 ° C. under an inert gas atmosphere (nitrogen or argon) at 3 mol% or 100 mol% of organic titanium Ti (O
A solution of (ioR) ₄ in 40 ml of dry tetrahydrofuran was added dropwise. In the case of the substances of the general formula (I), 5 mmol of cocatalyst (CH ₃ ) ₃ SiCl are additionally added to the reaction mixture. Stir at 20 ° C. for 5 minutes. Then, 12 mmol of Grignard reagent (III) are slowly added to the reaction mixture, as simultaneously as possible, so that the mixture is not heated above 50 ° C. 1 at room temperature
Stir for hours. 15 ml of saturated ammonium chloride solution and 15 ml of water are added and the mixture is stirred vigorously for a further 1 to 3 hours.

The resulting precipitate is separated off and washed with a small amount of dry diethyl ether. The filtrate is made basic (pH> 10) by the addition of a 15% sodium hydroxide solution. The phases were then separated and the aqueous phase was extracted with 30 ml of diethyl ether each time.
Extract twice. The organic phases are collected, washed with 15 ml of a saturated sodium chloride solution, then dried over potassium carbonate and then filtered. This product can be purified by one of the following methods: These are precipitated as hydrochlorides with a 1M ethereal hydrochloric acid solution and then filtered off (the product obtained is purified, if necessary, by recrystallization). 2. The organic phase is extracted twice with 40 ml of a 0.5 M HCl solution. P of this extract
h is adjusted to> 10 using 2M NaOH solution and then diethyl ether 3
Re-extract three times with 0 ml. The organic phases are collected, dried over potassium carbonate and the solvent is distilled off under reduced pressure. 3. The solvent is distilled off under reduced pressure, and the residue is isolated by column chromatography. 4. The solvent is distilled off under reduced pressure, and the residue is distilled under reduced pressure. The results are shown in Tables 1 to 3. In each of these tables, the production percentage of the product found in the finished product mixture is indicated.

[0064]

[Table 1] Table 1

[0065]

[Table 2] Table 2

[0066]

[Table 3] Table 3

[Procedural Amendment] Submission of translation of Article 34 Amendment of the Patent Cooperation Treaty

[Submission date] August 16, 2000 (2000.8.16)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claims

[Correction method] Change

[Correction contents]

[Claims]

Embedded image (Wherein R ¹ , R ² and R ³ may be the same or different and are hydrogen or substituted or unsubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl or aryl groups, —Si (R) ₃ , -Sn (R) ₃ , -SR
, —OR, NRR ′, or groups R ¹ and R ² or R ² and R ³ form a cycloalkyl ring which, in addition to N, may contain at least one additional heteroatom. The groups R ⁴ and R ⁵ are the same or different and are substituted or unsubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl or aryl groups, —Si (R) ₃ , —Sn (R) _3, -SR, -OR, a NRR', or the group R ⁴ and R ^5, in addition to the N, form a good cycloalkyl ring optionally containing at least one additional heteroatom cage, each of R and R'in the definition of the group R ⁴ and R ^5, same or are different from a substituted or unsubstituted alkyl or substituted or unsubstituted aryl group), combinatorial Lai comprising A method of adjusting Rarii the general formula (II):

Embedded image (Wherein R ¹ , R ² and R ⁵ have the above-mentioned meanings). III-a) or (III-b): in Z-R ⁴ or ^{Z-R 5 (III-a} ) Z-R 4 -R 5 -Z (III-b) ( the formulas, R ⁴ and R ³ is As defined above, and in the case of formula (III-b), the groups R ⁴ and R ⁵ are linked by a bond, Z is Li or MgX, where X is Hal, and Hal is C
where α is an integer greater than or equal to 1 and β is greater than 1 Big or
Or an integer equal to 1 and αβ ² ≧ 5.

────────────────────────────────────────────────── ─── Continued on the front page (31) Priority claim number 198 27 164.6 (32) Priority date June 18, 1998 (June 18, 1998) (33) Priority claim country Germany (DE) ( 31) Priority claim number 198 27 165.4 (32) Priority date June 18, 1998 (June 18, 1998) (33) Priority claim country Germany (DE) (31) Priority claim number 198 27 166.2 (32) Priority Date June 18, 1998 (June 18, 1998) (33) Priority Country Germany (DE) (31) Priority Number 198 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) Country of priority claim Germany (DE) (81) Designated country EP (AT) BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE), JP, KR, U S (71) the applicant Frankfurter Str. 250, D-64293 Darmstadt, Federal Republic of Germany (72) Inventor Welz-Bielmann, Urs Germany Day-68164 Manheim, Sperzenstraße 14 F-term (reference) 4H006 AA02 AA05 AC10 BA10 BA10 CA40 CA41 CD40

Claims (6)

[Claims] An amine compound represented by the general formula (I): (Wherein R ¹ , R ² and R ³ may be the same or different and are hydrogen or substituted or unsubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl or aryl groups, —Si (R) ₃ , -Sn (R) ₃ , -SR
, —OR, NRR ′ or the radicals R ¹ and R ² or R ² and R ³ contain, in addition to N, at least one additional heteroatom, preferably N, O or S Groups R ⁴ and R ⁵ are the same or different and are substituted or unsubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl or aryl groups, —Si (R ) ₃ , —Sn (R) ₃ , —SR, —OR, NRR ′, or the radicals R ⁴ and R ⁵ , in addition to N, at least one additional heteroatom, preferably N, O Or a cycloalkyl ring optionally containing S; R and R ′ in the definitions of groups R ⁴ and R ⁵ are the same or different, respectively, and are a substituted or unsubstituted alkyl group or substituted Or unplaced A method for preparing a combinatorial library comprising: (Wherein R ¹ , R ² and R ⁵ have the above-mentioned meanings). III-a) or (III-b): in Z-R ⁴ or ^{Z-R 5 (III-a} ) Z-R 4 -R 5 -Z (III-b) ( the formulas, R ⁴ and R ⁵ are As defined above, and in the case of formula (III-b), the groups R ⁴ and R ⁵ are linked by a bond, Z is Li or MgX, wherein X is Hal, and Hal is C
where α is an integer greater than or equal to 1 and β is greater than 1 Big or
Or an integer equal to 1 and αβ ² ≧ 5. 2. The method according to claim 1, wherein the groups R ¹ and R ² are not hydrogen atoms. 3. The method according to claim 1, wherein the group R ³ is a hydrogen atom or a methyl group optionally substituted by 1 to 3 fluorine atoms. 4. R ¹ , R ² and R ³ may be the same or different and each independently represents a hydrogen atom, a C _1-8 -alkyl group, a C _3-7 -cycloalkyl group, a C _3-7 -cycloalkyl group, _Three
A C _1-6 -alkyl group substituted by a ₇₇ -cycloalkyl group, a C _3-7-
Cycloalkenyl _group, C 3~7 - C 1~ ₆ which is substituted by a cycloalkenyl group - alkyl group, C _{2 to 8} - alkenyl group, C _{2 to 8} - alkynyl group, C _{1 to 6} -
C _{1 to 6} substituted by an alkoxy group - alkyl group, C _{2 to 6} - C _{1 to 6} substituted by an alkenyloxy group - alkyl group, C _{2 to 6} - C which is substituted by an alkynyloxy group _1-6 - alkyl group, a mono -, di - or polyhalo -C _1-6 - C _1-6 substituted by alkoxy - alkyl group, a mono -,
Di - or polyhalo -C _{2 to 6} - _{C. 1 to 6} substituted by an alkenyloxy group - alkyl group, a mono -, di - or polyhalo -C _{2 to 6} - _{C. 1 to} which is substituted by an alkynyloxy group ₆ - alkyl group, C _{1 to 6} - C _{1 to 6} substituted by an alkylthio group - alkyl group, C _{1 to 6} - C _{1 to 6} substituted by an alkylsulfinyl group - alkyl group, C _{1 to 6} A C _1-6 -alkyl group substituted by an alkylsulfonyl group, a mono-, di- or polyhalo-C _1-6 -alkyl group, a mono-, di- or polyhalo-C _2-8 -alkenyl group, a mono -, Ji-
Or polyhalo -C _{2 to 8} - C _{2 to 6} substituted alkyl group, a cyano group - - C ₂ alkenyl group, substituted by a cyano group an alkynyl group, _{C. 1 to 6} substituted by a cyano group ₆ - alkynyl group, C _{1 to 6} substituted by nitro group - alkyl group, C _{2 to 6} which is substituted by nitro group - alkenyl group, C _{2 to 6} which is substituted by nitro group - alkynyl , C _{1 to 6} - C _{1 to 6} substituted by an alkyl amino group - alkyl group, C _{1 to 6} - alkoxy C _{1 to 6} substituted by an amino group - alkyl group, a di (C _{1 to 3} - C _{1 to 6} substituted by alkyl) amino group - alkyl _group, N- (C 1~3 - alkyl) -
By a _C1-6 -alkyl group substituted by an N- ( _C1-3 -alkoxy) amino group, an N- ( _C1-6 -alkylsulfonyl) -N- ( _C1-6 -alkyl) amino group C _{1 to 6} substituted - alkyl _group, N- (C 1~6 - alkylsulfonyl) -N- _(C 1~6 - alkoxy) C _{1 to 6} substituted by an amino group -
Alkyl group, tri -C _{1 to 6} - C _{1 to 6} substituted by an alkyl silyl group -
A C _1-6 -alkyl group or an aryl group substituted by an alkyl group or a triarylsilyl group (provided that the aryl group is one or more halogen atoms, a trifluoromethyl group, a nitro group, a C _{1 A 6} -alkyl group and a C _1-6 -alkoxy group, which may be substituted with a substituent selected from the group consisting of a C _1-6 -alkoxy group and an aryl group (wherein the aryl group is one or more halogen atoms , trifluoromethyl group, nitro group, C _{1 to 6} - alkyl and C _{1 to 6} - C _{1 to 6,} optionally substituted by a substituent selected from the group consisting of an alkoxy group substituted by may also be) An alkyl group, an aryl group (provided that the aryl group is one or more halogen atoms, a trifluoromethyl group, a nitro group, a C _1-6-
A C _2-7 -alkenyl group substituted by an alkyl group and a substituent selected from the group consisting of a C _1-6 -alkoxy group, and an aryl group (provided that the aryl group is (It may be substituted by one or more halogen atoms, trifluoromethyl group, nitro group, _C1-6 -alkyl group and _C1-6 -alkoxy group.) A C _1-6 -alkyl group, a phenoxy group (provided that the phenoxy group is
One or more halogen atoms, trifluoromethyl groups, nitro groups, C _1-6 A C _1-6 -alkyl group or an arylthio group substituted by a substituent selected from the group consisting of an alkyl group and a C _1-6 -alkoxy group, provided that the arylthio group is One or more halogen atoms, a trifluoromethyl group, a nitro group, a C _1-6 -alkyl group and a C _1-6 -alkoxy group which may be substituted by a substituent selected from the group consisting of ) _-Substituted C _1-6 -alkyl group, arylsulfinyl group (where the arylsulfinyl group is one or more halogen atoms, a trifluoromethyl group, a nitro group, a C _1-6 -alkyl groups and C _{1 to 6} - C _{1 to 6,} optionally substituted by a substituent selected from the group consisting of an alkoxy group substituted by may also be) - alkyl group, Reel sulfonyl group (provided that the arylsulfonyl group, one or more halogen atoms, trifluoromethyl group, nitro group, C _{1 to 6} - selected from the group consisting of alkoxy - alkyl and C _{1 to 6} A C _1-6 -alkyl group substituted by a substituted benzyloxy group, wherein the aryl group of the benzyloxy group is one or more halogen atoms, Trifluoromethyl group, nitro group, C _1-6-
Alkyl and C _{1 to 6} - C _{1 to 6} substituted by an alkoxy group may be substituted by a substituent selected from the group consisting of) - alkyl group, benzylthio group (provided that the aryl of the benzylthio group The group is substituted by one or more halogen atoms, trifluoromethyl groups, nitro groups, _C1-6 -alkyl groups and _C1-6 -alkoxy groups. A benzylsulfinyl group substituted by a C _1-6 -alkyl group or a benzylsulfinyl group (provided that the aryl group of the benzylsulfinyl group is one or more halogen atoms, a trifluoromethyl group, a nitro group, ₆ - which is substituted by may be substituted by a substituent selected from the group consisting of an alkoxy group) - alkyl and C _{1-6 C1-6} -alkyl group, benzylsulfonyl group (
However, aryl groups of this benzylsulfonyl group, one or more halogen atoms, trifluoromethyl group, nitro group, C _{1 to 6} - is selected from the group consisting of alkoxy - alkyl and _{C. 1 to 6} C _1-6 substituted by may) be substituted by a substituent that - alkyl group, C _{1 to 4} - alkylsulfonyl C which is substituted by an amino group substituted by a group _1-6 - alkyl A group or a group R ¹ and R ² or R ² and R ³ is a cycloalkyl ring which, in addition to N, may contain at least one additional heteroatom, preferably N, O or S Wherein the ring is 1-pyrrolidinyl, 1-imidazolinyl, 1-
Pyrazolinyl, 1-piperidyl, 1-piperazinyl, 4-morpholinyl and 4
4. The method according to claim 1, wherein the method is selected from thiamorpholinyl. 5. R ⁴ and R ⁵ may be the same or different and each independently represents a hydrogen atom, a C _1-8 -alkyl group, a C _3-7 -cycloalkyl group, a C _3-7 −
C _{1 to 6} substituted by a cycloalkyl group - alkyl group, C _{3 to 7} - cycloalkenyl groups, C _{3 to 7} - C _{1 to 6} substituted by a cycloalkenyl group - alkyl group, C _{2 to 8} - alkenyl, C _{2 to 8} - alkynyl group, C _{1 to 6} - C _{1 to 6} substituted by an alkoxy group - alkyl group, C _{2 to 6} - C _{1 to 6} substituted by an alkenyloxy group - alkyl group, C _{2 to 6} - C _{1 to 6} substituted by alkynyloxy group - alkyl group, a mono -, di - or polyhalo _{-C. 1 to 6} - C _{1 to 6} substituted by an alkoxy group - alkyl Group, a C _1-6 -alkyl group substituted by a mono-, di- or polyhalo-C _2-6 -alkenyloxy group, substituted by a mono-, di- or polyhalo-C _2-6 -alkynyloxy group _C1-6 -Al A C _1-6 -alkyl group substituted by a C _1-6 -alkylthio group, a C _1-6 -alkyl group substituted by a C _{1-6 -alkylsulfinyl} group, a C _1-6 -alkyl A C _1-6 -alkyl group, mono-, di- or polyhalo-C _1-8 -alkyl group, mono-, di- or polyhalo-C _2-8 -alkenyl group, mono-, di - or polyhalo -C _{2 to 8} - alkynyl group, C _{1 to 6} substituted by a cyano group - alkyl group, C _{2 to 6} substituted by a cyano group - alkenyl group is substituted by a cyano group C _{2 to 6} - alkynyl group, C _{1 to 6} substituted by nitro group - alkyl group, C _{2 to 6} which is substituted by nitro group - alkenyl group, C _{2 to 6} which is substituted by nitro group - alkynyl group, C _{1 6} - C _{1 to 6} substituted by an alkyl amino group - alkyl group, C _{1 to 6} - alkoxy C _{1 to 6} substituted by an amino group - alkyl group, a di (C _{1 to 3} - alkyl) amino group A C _1-6 -alkyl group substituted by N- (C _1-3 -alkyl) -N- (
_C1-6 -alkyl substituted by _C1-3 -alkoxy) amino, N
- (C _{1 to 6} - alkylsulfonyl)-N-(C _{1 to 6} - alkyl) C _{1 to 6} substituted by an amino group - alkyl _group, N- (C 1~6 - alkylsulfonyl)
A _C1-6 -alkyl group substituted by an -N- ( _C1-6 -alkoxy) amino group, a _C1-6 -alkyl group substituted by a tri- _C1-6 -alkylsilyl group, A C _1-6 -alkyl group or an aryl group substituted by a reelsilyl group (provided that the aryl group is one or more halogen atoms, a trifluoromethyl group, a nitro group, a C _1-6 -alkyl An aryl group, which may be substituted with a substituent selected from the group consisting of a group and a _C1-6 -alkoxy group, provided that the aryl group is one or more halogen atoms, trifluoromethyl group, nitro group, C _{1 to 6} - alkyl and C _{1 to 6} - C _{1 to 6,} optionally substituted by a substituent selected from the group consisting of an alkoxy group substituted by may also be) - alkyl group, Aryl group (where the aryl group is selected from the group consisting of one or more halogen atoms, trifluoromethyl group, nitro group, _C1-6 -alkyl group and _C1-6 -alkoxy group) A _C2-7 -alkenyl group or an aryl group substituted by a substituent, which may be substituted with one or more halogen atoms, a trifluoromethyl group, a nitro group, A C _2-6 -alkynyl group or a phenoxy group substituted by a C _1-6 -alkyl group and a C _1-6 -alkoxy group which may be substituted with a substituent selected from the group consisting of The phenoxy group may have one or more halogen atoms, a trifluoromethyl group, a nitro group, a C _1-6-
A C _1-6 -alkyl group or an arylthio group substituted by an alkyl group and a substituent selected from the group consisting of a C _1-6 -alkoxy group, provided that the arylthio group is (It may be substituted by one or more halogen atoms, trifluoromethyl group, nitro group, _C1-6 -alkyl group and _C1-6 -alkoxy group.) A C _1-6 -alkyl group or an arylsulfinyl group (wherein, the arylsulfinyl group is one or more halogen atoms, a trifluoromethyl group, a nitro group, a C _1-6 -alkyl group and C _{1 to 6} - C _{1 to 6,} optionally substituted by a substituent selected from the group consisting of an alkoxy group substituted by may also be) - alkyl group, a Rusuruhoniru group (provided that the arylsulfonyl group, one or more halogen atoms, trifluoromethyl group, nitro group, C _{1 to 6} - is selected from the group consisting of alkoxy - alkyl and C _{1 to 6} A C _1-6 -alkyl group or a benzyloxy group substituted by a benzyloxy group which may be substituted with one or more halogen atoms, fluoromethyl group, nitro group, C _{1 to 6} - alkyl and C _{1 to 6} - C _{1 to 6,} optionally substituted by a substituent selected from the group consisting of an alkoxy group substituted by may also be) - alkyl Group, benzylthio group (provided that the aryl group of the benzylthio group is one or more halogen atoms, a trifluoromethyl group, a nitro group, a C _1-6 - alkyl and C _{1 to 6} - C _{1 to 6} substituted by an alkoxy group may be substituted by a substituent selected from the group consisting of) - alkyl group, benzylsulfinyl group (provided that this benzylsulfinyl aryl groups, one or more halogen atoms, trifluoromethyl group, nitro group, C _{1 to 6} - substituted by a substituent selected from the group consisting of alkoxy - alkyl and _{C. 1 to 6} which may also be) C substituted by _1-6 - alkyl groups, benzylsulfonyl group (provided that the aryl group of the benzylsulfonyl group, one or more halogen atoms, a trifluoromethyl group, a nitro A C _1-6 -alkyl group and a C _1-6 -alkoxy group, which may be substituted by a substituent selected from the group consisting of C _{1 to 6} substituted Ri - alkyl group, C _1-4 - C _{1 to 6} which is substituted by an amino group substituted with an alkylsulfonyl group - alkyl group, either of claims 1 to 4 The method described in Crab. 6. .alpha..beta ² is a> 7 A method according to any one of claims 1 to 5.