DE10034625A1 - New aryl substituted thienyl-oxazolidinone derivatives useful as tumor necrosis factor-alpha inhibitors in treatment of e.g. atherosclerosis, arthritis, Crohn's disease, osteoporosis, transplant rejection and psoriasis - Google Patents

Abstract

Aryl substituted thienyl-oxazolidinone derivatives and their salts and s-oxides are new. Aryl substituted thienyl-oxazolidinone derivatives of formula (I) and their salts and S-oxides: A = NH2, OH (optionally protected), one of 7 linear or cyclic carbamate groups, e.g. (AI)-(AIII) or -N-CO-NRA5RA6; RA1, RA2 = H, alkyl (optionally substituted by alkoxycarbonyl, alkoxy, aryl (optionally substituted by heteroaryl) or CHal3 when only 1 of RA1 and RA2 is alkyl), cycloalkyl, or aryl; RA4 = H, -CO-RAA4,1 or alkyl (optionally substituted); RA4,1 = NH2 or alkoxy (optionally substituted); RA5 and RA6 = H, alkyl (optionally substituted by cycloalkyl), aryl (optionally substituted by aryl or aryloxy), alkoxycarbonyl, -CO-aryl or a group of formula (c); or NRA5RA6 = saturated or partly unsaturated heterocycle (optionally N-substituted by alkyl); RA8 = alkyl (optionally substituted with aryl); RB = heteroaryl (optionally fused by benzene, cycloalkyl or a saturated or partly unsaturated heterocycle (cyclic groups are optionally substituted by RB1, RB2, RB3, RB4 and RB5) via alkyl; RB1 = -CN-CX3, COOH, alkoxycarbonyl or aminocarbonyl (optionally substituted with hydrocarbyl); RB2, RB3 = alkyl, CHO, CH2OH, CN, COOH, alkoxycarbonyl or aminocarbonyl (optionally substituted by hydrocarbyl); and RB4, RB5 = H or hydrocarbyl.

Description

The present invention relates to new, 6-membered nitrogen-containing heteroaryl oxa zolidinones, process for their preparation and their use as medicines, especially for the treatment of tumor necrosis factor (TNF) triggered effects such as B. Atherosclerosis.

Tumor necrosis factor α (TNFα) is a pro-inflammatory cytokine with athero gener effect. Pro-inflammatory cytokines are proteins that are considered inflammatory promotional messenger substances formed after a stimulus in certain tissue cells become.

TNFα is a cytokine that is also used in many pathological inflammatory reactions particularly promotes inflammation progression. In extreme cases, if TNFα is increasingly released into the blood circulation, contributes to TNFα development of life-threatening conditions such as septic shock disseminated intravascular coagulation or cachexia. With locally limited Release of TNFα promotes inflammatory processes that affect the tissue in to which it is formed remain limited.

Recently it has been reported that TNFα is of particular importance in the pro inflammatory processes in the arterial wall. In this together is the arteriosclerosis-promoting (atherogenic) effect of TNFα in several studies have been proven. It could be shown that TNFα is increasingly formed in arteriosclerotic tissue.

(T. J. DeGraba, Neurology 49 Suppl 4, S 15-S 19, 1997; M. Kaartinen et al. Circula tion 94, 2787-2792, 1996; X. Lei et al., Atherosclerosis 125 (1996) 81-89) and the Effect of TNFα on cells of the vascular wall (endothelial cells, smooth muscle cells), and in particular the effect of TNFα on cells of the arteriosclerotic vascular wall,  which additionally monocytes, naive macrophages, foam cells and Contains lymphocytes, has been examined and described in many different ways:

TNFα triggers the formation of cell adhesion molecules, especially on endothelial cells from how B. vascular cell adhesion molecule (VCAM), intercellular adhesion mole cule (ICAM-1) or P-selectin, which in turn is another immigration of Monozy macrophages and lymphocytes for the progression of inflammation of the vascular wall (T. J. DeGraba, Neurology 49 Suppl 4, S 15-S 19, 1997; J. L. Barks et al. J. Immunology 159, 4532-4538, 1997; M.F. Jademarco et al., J. Clin. Invest 95 (1995) 264-271). TNFα triggers the formation of other cytokines in endothelial cells, Monocytes, foam cells and smooth muscle cells. Interleukin 1 (IL- 1) and autocrine TNFα are mentioned here.

TNFα triggers the formation of chemokines such as monocyte chemoattractant protein (MCP-1) and interleukin 8 (IL-8) in the named vascular cells for further Recruitment of monocytes and lymphocytes into the arteriosclerotically altered Vessel wall.

TNFα triggers the formation of growth factors (e.g. platelet derived growth factor) and matrix metalloproteases, which in turn cause inflammatory processes in the vessel promote wall (H. Funayama et al., Cardiovasc. Res. 37 (1998) 216-224; T. B. Rajavashisth, Circulation 24 (1999), 3103-3109).

TNFα is next to the importance for the progression of arteriosclerotic Vascular inflammation (P. T. Kovanen, Circulation 94, 2787-2792, 1996) also from crucial in the pathophysiological progression of others Inflammatory diseases, for which a synthesis inhibition of the pro-inflammatory Cytokins TNFα also a therapeutically useful intervention for weakening which represents disease. Inflammatory and autoimmune diseases can be treated by TNFα synthesis inhibition because TNFα is causative contributes to the clinical picture are arthritis, rheumatoid arthritis, osteoporosis,  Crohn's disease, inflammatory lung diseases like Adult Respiratory Distress Syndrome (ARDS), graft rejection, reperfusion tissue damage after stroke, heart attack or peripheral vascular occlusion, chronic inflammatory fibrotic organ changes such as liver fibrosis, or the genera systemic lupus erythematosus or others Forms of lupus erythematosus as well as dermal inflammatory diseases such as Psoriasis.

From publications EP-A-0 693 491, EP-A-789 026 and EP-A-789 025 Oxazolidinones with antibacterial effects known.

The present invention relates to heterocyclically substituted thienylphenyloxazolidinone compounds of the general formula (I)

wherein
B represents a radical of the formula (II),

wherein
R ^{B stands} for a 5-membered aromatic heterocycle linked via an alkyl group with up to 3 heteroatoms from the series S, N and / or O, which can additionally be fused with benzene, cycloalkyl with 3 to 6 carbon atoms, a saturated or partially unsaturated heterocycle with up to three nitrogen atoms which can also carry up to two oxo flu, said cycles in turn being substituted with the groups R ^B1 , R ^B2 , R ^B3 , R ^B4 , R ^B5
in which
R ^B1 can stand
for -C∼N -CX ₃ , or carbonyl to which in turn groups selected from hydroxy, alkoxy or amino are bonded, which in turn can be substituted by one or more hydrocarbon radicals;
in which
R ^B2 R ^B3 can be alkyl, -COH, -CH ₂ OH, -C∼N, or carbonyl to which, in turn, groups selected from hydroxy, alkoxy or amino are bonded, which in turn can be substituted with one or more carbons;
R ^B4 and R ^B5 can represent hydrogen or a hydrocarbon test,
A can stand for a group selected from -NH ₂ , hydroxy, hydroxy protected by a hydroxy protecting group or one of the residues (AI) - (AVIII)

wherein
R ^A1 , R ^{A2 may be the} same or different and may stand for hydrogen, alkyl, cycloalkyl, aryl,
where in the case that one of the groups R ^A1 , R ^{A2 is} alkyl, this in turn can be substituted with alkoxycarbonyl, alkoxy, aryl, aryl which in turn can be substituted, 5- to 10-membered heteroaryl of the group -CX ₃ wherein X is halogen;
wherein
R ^A3 can stand for

Alkyl or alkyl which in turn is mono- or polysubstituted with radicals selected from aryl, alkoxy, alkanoyl, alkanoyl which in turn is substituted with aryloxy;
or
R ^A3 can represent 5- to 10-membered heteroaryl bonded via a carbon atom,
or
R ^A3 can stand for the rest

wherein
R ^A3.1 can represent hydrogen, 5- to 10-membered heteroaryl, alkoxy, which in turn can be substituted;
wherein
R ^{A3.2 can} stand for alkyl, which in turn can be substituted with aryl;
wherein
R ^{A4 can} stand for hydrogen, a group

Alkyl, which in turn can be substituted;
wherein
R ^A4.1 can represent -NH ₂ , alkoxy, which in turn can be substituted;
U can stand for a heteroatom selected from N, O, S; or
U can stand for the group

wherein
R ^{AIV, 1} , R ^{AIV, 2 can be the} same or different and can stand for hydrogen, hydroxy, alkyl, alkyl, which in turn can be substituted with alkoxycarbonyl or alkoxy, which in turn can be substituted with an aryl radical
or U can stand for the group

R ^A5 and R ^{A6 can be the} same or different and can stand for hydrogen, alkyl or alkyl which in turn is substituted by cycloalkyl, or can stand for aryl or aryl which in turn can be substituted with aryl or aryloxy; or can stand for alkoxycarbonyl, or can stand for an aryl radical attached via a carbonyl group, or can stand for the group

or
R ^A5 and R ^A6 together, including the nitrogen atom to which they are attached, form a 5- to 6-membered, saturated or partially unsaturated heterocycle with up to 3 heteroatoms from the series S, N or O, the nitrogen atoms of which may be substituted can with alkyl;
where D can be nitrogen or oxygen or CH ₂ ,
where E can be nitrogen or CH ₂ ,
with the proviso that if D is oxygen, then R ^{A6 is} absent, E is nitrogen and R ^{A7 is} alkyl, which may be substituted by aryl,
or
R ^A7 can represent an alkoxy radical bonded via a carbonyl group,
R ^A8 can represent alkyl which is optionally substituted by an aryl radical;
and their salts and S-oxides.

The substances of the general formula (I) according to the invention can also be used as salts available. Physiologically acceptable salts are within the scope of the invention prefers.

Physiologically acceptable salts can be salts of the compound according to the invention with inorganic or organic acids. Salts are preferred with inorganic acids such as hydrochloric acid, bromine water Substance acid, phosphoric acid or sulfuric acid, or salts with organic carbon or sulfonic acids such as acetic acid, maleic acid, fumaric acid, Malic acid, citric acid, tartaric acid, lactic acid, benzoic acid or methanesulfonic acid,  Ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid or naphtha lindisulfonsäure.

Physiologically acceptable salts can also be metal or ammonium salts compounds of the invention. Alkali metal salts are particularly preferred (e.g. sodium or potassium salts), alkaline earth metal salts (e.g. magnesium or cal cium salts) and ammonium salts derived from ammonia or organic amines, such as ethylamine, di- or triethylamine, di- or Triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, Ethylenediamine or 2-phenylethylamine.

The compounds of general formula (I) according to the invention can be found in ver different stereoisomeric forms occur, which are either like picture and Mirror image (enantiomers), or which are not like image and mirror image (Diastereomers) behave. The invention relates to both the enantiomers and Diastereomers and their respective mixtures. The racemic forms can be as well as the diastereomers in a known manner in the stereoisomerically uniform Separate components.

Furthermore, certain compounds can exist in tautomeric forms. This is known to those skilled in the art, and such compounds are also within the scope of Invention includes.

Hydrocarbon radicals in the context of the invention can be saturated or unsaturated, be linear, branched or cyclic and have 1 to 24 carbon atoms.

Alkyl radicals in the context of the invention are in particular saturated carbons hydrogen radicals.

In the context of the invention, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₄ ) alkyl represent a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms.

Examples include: methyl, ethyl, n-propyl, isopropyl, t-butyl, n-pentyl and n-hexyl.

In the context of the invention, (C ₃ -C ₆ ) cycloalkyl stands for a cycloalkyl group with 3 to 6 carbon atoms. The following may be mentioned as preferred examples: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. Cyclopropyl is particularly preferred.

In the context of the invention, (C ₆ -C ₁₀ ) aryl represents an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are, for example, phenyl and naphthyl. Phenyl is particularly preferred.

The aryl radicals according to the invention, in particular the phenyl radical, can in turn be mono- or polysubstituted with radicals selected from -halogen, -hydroxy, (C ₁ -C ₄ ) -alkoxy, (C ₁ -C ₄ ) -alkyl , Aryl, aryloxy, amino, mono- (C ₁ -C ₆ ) alkyl amino, di (C ₁ -C ₆ ) alkylamino. The aryl radicals according to the invention also include phenyl groups with mutually ortho-standing oxygen atoms which are connected to one another via a methylene bridge.

Alkoxy, in the context of the invention, stands for a straight-chain or branched Alkyl radical which is attached via an oxygen atom.

In the context of the invention, (C ₁ -C ₆ ) -allcoxy, (C ₁ -C ₄ ) -alkoxy stands for a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms. A straight-chain or branched alkoxy radical having 1 to 4 carbon atoms is preferred. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, n-pentoxy, n-hexoxy.

In the context of the invention, (C ₁ -C ₆ ) alkoxycarbonyl represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms, which is linked via a carbonyl group. A straight-chain or branched alkoxy carbonyl radical having 1 to 4 carbon atoms is preferred. Examples include: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and t-butoxy carbonyl.

In the context of the invention, aryloxy stands for an aryl radical which has an oxygen is connected to the atom.

In the context of the invention, mono- (C ₁ -C ₆ ) -alkylamino stands for an amino group with a straight-chain or branched alkyl substituent which has 1 to 6 carbon atoms. Examples include: methylamino, ethylamino, n-propylamino, isopropylamino, t-butylamino, n-pentylamino and n-hexylamino.

In the context of the invention, di- (C ₁ -C ₆ ) -alkylamino stands for an amino group with two identical or different straight-chain or branched alkyl substituents, each having 1 to 6 carbon atoms. Examples include: N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-N-n-propylamino, Nt-butyl-N-methylamino, N- Ethyl-N-n-pentylamino and Nn-hexyl-N-methylamino.

In the context of the invention, 5- to 10-membered heteroaryl is 5- to 10-membered aromatic rings containing 1 to 4 heteroatoms selected from O, S and N. and includes, for example: pyridyl, furyl, thienyl, pyrrolyl, Imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolicenyl, indolyl, Benzo [b] thienyl, benzo [b] furyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl, Quinazolinyl, etc.

Imidazolyl, triazolyl, benzo [b] triazolyl are preferred in the context of the invention.

A 5- to 6-membered saturated or partially unsaturated heterocycle with up to 3 heteroatoms from the series S, N and / or O is within the scope of the invention in general for a heterocycle that has no, one or more double bonds  can contain and via a ring carbon atom or a ring nitrogen atom is linked. Examples include:

Tetrahydrofur-2-yl, tetrahydrofur-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin 3-yl, pyrrolin-1-yl, piperidin-1-yl, piperidin-3-yl, piperazin-1-yl, morpholin-1-yl. Tetrahydrofur-2-yl, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl is preferred.

Hydroxy protective group in the context of the above definition is in general for a protective group from the series: trimethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, benzyl, benzyloxycarbonyl, 2-nitrobenzyl, 4-nitrobenzyl, tert-butyloxycarbonyl, allyloxycarbonyl, 4-methoxybenzyl, 4-methoxybenzyloxy carbonyl, tetrahydropyranyl, formyl, acetyl, trichloroacetyl, 2,2,2-trichlor ethoxycarbonyl, methoxyethoxymethyl, [2- (trimethylsilyl) ethoxy] methyl, benzoyl, 4-methylbenzoyl, 4-nitrobenzoyl, 4-fluorobenzoyl, 4-chlorobenzoyl or 4-meth oxybenzoyl. Acetyl, tert are preferred. Butyldimethylsilyl or tetrahydropyranyl.

Compounds of the general formula (I) in which
B represents a radical of the formula (II),

wherein
R ^B from one of the residues of the formulas BI-BIV

is selected
wherein
R ^B1 can be selected for a remainder

wherein
R ^{B1.1 can} stand for hydrogen, (C ₁ -C ₆ ) alkyl,
R ^B1.2 , R ^{B1.3, independently of} one another, can be hydrogen, (C ₁ -C ₆ ) -alkyl, benzyl, (C ₁ -C ₆ ) -alkyl substituted by an aryl radical, preferably phenyl, and
X represents halogen
wherein
R ^B2 can stand independently of R ^B1 selected for a remainder

wherein
R ^{B2.1 can} stand for hydrogen, (C ₁ -C ₆ ) alkyl,
R ^B2.2 , R ^{B2.3, independently of} one another, can be hydrogen, (C ₁ -C ₆ ) alkyl, benzyl, (C ₁ -C ₆ ) alkyl substituted with aryl, preferably phenyl,
R ^B3 can represent hydrogen or a group

wherein
R ^{B3.1 represents} (C ₁ -C ₆ ) alkyl.

R ^B4 and R ^B5 can be hydrogen or (C ₁ -C ₁₂ ) alkyl,
A can stand for a group selected from -NH ₂ , hydroxy, hydroxy protected by a hydroxy protecting group or one of the residues (AI) - (AVIII)

wherein
R ^A1 , R ^{A2 are the} same or different and can stand for hydrogen, (C ₁ -C ₆ ) alkyl, cycloalkyl, aryl,
in the event that one of the groups R ^A1 , R ^{A2 is} (C ₁ -C ₆ ) alkyl, this in turn can be substituted by alkoxycarbonyl, alkoxy, aryl or aryl which in turn can be substituted, or in the case that one of the groups R ^A1 , R ^{A2 is} (C ₁ -C ₆ ) alkyl, which in turn can be substituted by 5- to 10-membered heteroaryl, or group -CX ₃ in which X is halogen;
wherein
R ^A3 can stand for

or (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkyl, which in turn is mono- or polysubstituted with radicals selected from aryl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) -alkanoyl which in turn can be substituted with aryloxy;
or
R ^A3 can represent 5- to 10-membered heteroaryl bonded via a carbon atom, or
R ^A3 can stand for the rest

wherein
R ^{A3.1 can} stand for hydrogen, 5- to 10-membered heteroaryl, alkoxy, which in turn can be substituted with (C ₆ -C ₁₀ ) aryl, or where R ^{A3.1 can} stand for (C ₁ -C ₁₂ ) Alkyl, which in turn can be substituted with aryloxy;
wherein
R ^{A3.2 can} stand for (C ₁ -C ₆ ) alkyl, which in turn can be substituted with aryl;
wherein
R ^{A4 can} stand for hydrogen, a group

(C ₁ -C ₆ ) alkyl, which in turn can be substituted with groups selected from hydroxy, aryl;
wherein
R ^A4.1 can represent -NH ₂ , alkoxy;
U can represent a heteroatom selected from N, O, S, O is preferred; or
U can stand for the group

wherein
R ^{AIV, 1} , R ^{AVI, 2 can be the} same or different and can stand for hydrogen, hydroxy, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl, which in turn can be substituted with alkoxycarbonyl or Alkoxy, which in turn can be substituted by an aryl radical,
or U can stand for the group

R ^A5 and R ^{A6 can be the} same or different and can stand for hydrogen, an aryl radical attached via a carbonyl group, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl, which in turn is substituted by cycloalkyl, the group

(C ₁ -C ₆ ) alkoxycarbonyl, (C ₆ - C ₁₀ ) aryl or (C ₆ -C ₁₀ ) aryl, which in turn can be substituted with (C ₆ -C ₁₀ ) aryl or (C ₆ - C ₁₀ ) aryloxy;
or
R ^A5 and R ^A6 together, including the nitrogen atom to which they are attached, form a 5- to 6-membered, saturated or partially unsaturated heterocycle with up to 3 heteroatoms from the series S, N and / or O,
or
R ^A5 and R ^A6 together, including the nitrogen atom to which they are attached, form a saturated heterocycle which may contain further nitrogen atoms; piperidine is preferred, the free nitrogen atom of which may be substituted by (C ₁ -C ₁₂ ) -alkyl;
where D can be nitrogen or oxygen or CH ₂ ,
where E can be nitrogen or CH ₂ ,
with the proviso that if D is oxygen, then R ^{A6 is} absent, E is nitrogen and R ^{A7 is} (C ₁ -C ₆ ) alkyl, which can be substituted by (C ₆ -C ₁₀ ) Aryl, preferably phenyl;
or
R ^A7 can represent alkoxycarbonyl,
R ^A8 can represent (C ₁ -C ₁₂ ) -alkyl, which may optionally have an aryl radical; is substituted
and their salts and S-oxides.

Compounds of the general formula (I) are particularly preferred
in which
B represents a radical of the formula (II),

wherein
R ^B from one of the residues of the formulas BI-BIV

is selected
wherein
R ^B1 can be selected for a remainder

wherein
R ^{B1.1 can} stand for hydrogen, (C ₁ -C ₄ ) -alkyl,
R ^B1.2 , R ^{B1.3, independently of} one another, can be hydrogen, (C ₁ -C ₄ ) alkyl, benzyl, (C ₁ -C ₄ ) alkyl substituted with a (C ₆ -C ₁₀ ) aryl Balance, preferably phenyl, and
X represents halogen, preferably fluorine,
wherein
R ^B2 can stand independently of R ^B1 selected for a remainder

wherein
R ^{B2.1 can} stand for hydrogen, (C ₁ -C ₄ ) -alkyl,
R ^B2.2 , R ^{B2.3 can} independently represent hydrogen, (C ₁ -C ₄ ) alkyl, benzyl, (C ₁ -C ₄ ) alkyl substituted with (C ₆ -C ₁₀ ) aryl, preferably phenyl,
R ^B3 can represent hydrogen or a group

wherein
R ^{B3.1 represents} (C ₁ -C ₄ ) -alkyl, preferably methyl,
R ^B4 and R ^B5 can be hydrogen or (C ₁ -C ₆ ) alkyl,
A can stand for a group selected from -NH ₂ , hydroxy, hydroxy protected by a hydroxy protecting group or one of the residues (AI) - (AVIII)

wherein
R ^A1 , R ^{A2 are the} same or different and can stand for hydrogen, (C ₁ -C ₄ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl,
in the event that one of the groups R ^A1 , R ^{A2 represents} (C ₁ -C ₄ ) alkyl, this in turn can be substituted by (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) - Alkoxy, (C ₆ -C ₁₀ ) aryl, which in turn can be substituted, 5- to 10-membered heteroaryl, of the group -CX ₃ where X is halogen, preferably fluorine;
wherein
R ^A3 can stand for

or (C ₁ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkyl, which in turn is mono- or polysubstituted with radicals selected from (C ₆ -C ₁₀ ) aryl, (C ₁ -C ₄ ) Alkoxy, (C ₁ -C ₄ ) alkanoyl which in turn can be substituted with aryloxy;
or
R ^A3 can represent 5- to 10-membered heteroaryl, in particular pyridyl, pyrimidyl, or bonded via a carbon atom
R ^A3 can stand for the rest

wherein
R ^A3.1 can represent hydrogen, 5- to 10-membered heteroaryl, especially furanyl, (C ₁ -C ₆ ) alkoxy, which in turn can be substituted by (C ₆ -C ₁₀ ) aryl, (C ₁ - C ₆ ) alkyl, which in turn can be substituted with aryloxy;
wherein
R ^{A3.2 can} stand for (C ₁ -C ₄ ) alkyl, which in turn can be substituted with aryl;
wherein
R ^{A4 can} stand for hydrogen, a group

(C ₁ -C ₄ ) alkyl, which in turn can be substituted with groups selected from hydroxy, aryl;
wherein
R ^A4.1 can represent -NH ₂ , alkoxy;
U can represent a heteroatom selected from N, O, S, O is preferred; or
U can stand for the group

wherein
R ^{AIV, 1} , R ^{AIV, 2 can be the} same or different and can stand for hydrogen, hydroxy, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkyl, which in turn can be substituted with (C ₁ -C ₆ ) alkoxycarbonyl or (C ₁ -C ₆ ) alkoxy, which in turn can be substituted with (C ₆ -C ₁₀ ) aryl,
or U can stand for the group

R ^A5 and R ^{A6 can be the} same or different and can represent benzoyl, hydrogen, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkyl, which in turn is substituted by cycloalkyl, the group

(C ₁ -C ₆ ) alkoxycarbonyl, (C ₆ -C ₁₀ ) aryl or (C ₆ -C ₁₀ ) aryl, which in turn can be substituted with (C ₆ -C ₁₀ ) aryl or (C ₆ - C ₁₀ ) aryloxy;
or
R ^A5 and R ^A6 together, including the nitrogen atom to which they are attached, form a 5- to 6-membered, saturated or partially unsaturated heterocycle with up to 3 heteroatoms from the series S, N and / or O, preference being given to tetrahydrofuran -2-yl, or
Together with the nitrogen atom to which they are attached, R ^A5 and R ^A6 form a saturated heterocycle, which may contain further nitrogen atoms. Piperidine, whose free nitrogen atom can be substituted by (C ₁ -C ₆ ) -alkyl, is particularly preferred.

D can stand for nitrogen or oxygen or CH ₂ , E can stand for nitrogen or CH ₂ ,
with the proviso that if D is oxygen, then R ^{A6 is} absent, E is nitrogen and R ^{A7 is} (C ₁ -C ₆ ) alkyl, which can be substituted by (C ₆ -C ₁₀ ) Aryl, preferably phenyl;
or
R ^A7 can represent (C ₁ -C ₆ ) alkoxycarbonyl,
R ^{A8 can} stand for (C ₁ -C ₆ ) alkyl, optionally substituted with (C ₆ -C ₁₀ ) aryl; preferably phenyl,
and their salts and S-oxides.

In addition, processes for the preparation of the compounds of the general formula (I) according to the invention were found, characterized in that

• 1. [a] compounds of the general formula (aI)
  wherein
  R ^{a1 represents} a hydroxyl protective group, preferably TBDMS, which is stable under the conditions of the Mitsunobu reaction, or can have one of the meanings given for Al,
  and
  R ^{a2 stands} for a group - (CH ₂ ) _p -OH, which is preferably meta or para, and in which
  p can assume the values 1 to 3,
  in the presence of an azodicarboxylic acid diester, preferably dimethyl azo dicarboxylic acid and a condensing agent, preferably triphenylphosphine, in an inert solvent, preferably an ether, in particular tetrahydrofuran, in the temperature range from -20 to + 20 ° C. with one of the heterocyclic amines BIa or BIIa or BIIIa
  and, if necessary, the hydroxyl protective group is split off and the compounds of the general formula (aII)
  receives what
  R ^{B is} preferably meta or para and
  R ^a3 can stand for hydrogen or (AI),
  and in the event that R ^{a3 is} hydrogen, optionally converted to further compounds of the general formula (I);
  or
• 2. [b] the compound (bI) described in EP 693 491
  according to Suzuki with compounds of the general formula (bII)
  wherein
  R ^{B is} preferably meta or para;
  in the presence of palladium complexes in inert solvents such as, for example, open-chain or cyclic ethers, preferably tetrahydrofuran, at the boiling point of the solvent to give compounds of the general formula (bIII)
  implement, which are optionally converted into further compounds of general formula (I);
  or
• 3. [c] compounds of the general formula (aII) in which
  R ^{a3 is} hydrogen, in the presence of a base, for example phosphazene base P ₁ -t-Bu, first reacted with an alkyl or aryl isocyanate in a solvent which is inert under the conditions, for example dimethylformamide,
  or
• 4. [d] compounds of the general formula (aII) in which R ^{a3 represents} hydrogen, in the presence of a base, for example dimethylaminopyridine, first reacted with 4-nitrophenyl chloroformate in a solvent which is inert under the conditions, for example dichloromethane, and subsequently reacting the intermediate product with a primary or secondary amine,
  or
• 5. [e] Compounds of the general formula (aII), in which R ^{a3 represents} hydrogen, in a solvent which is inert under the reaction conditions, preferably an open-chain or cyclic ether, for example dioxane, optionally in the presence of a base, first with phosgene or a Phosgene equivalent, for example diphosgene, and subsequently reacting the intermediate with a primary or secondary amine.

The processes according to the invention are illustrated by the formula scheme below exemplified.  

Depending on the individual process steps, suitable solvents are suitable the usual solvents that do not change under the reaction conditions. These include non-polar solvents, polar aprotic solvents and protic solvents medium.

Examples of non-polar solvents are: aliphatic and aromatic Hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum petroleum tions; aliphatic and aromatic halogenated hydrocarbons such as dichloromethane, Trichloromethane, carbon tetrachloride, trichloroethane, carbon tetrachloride, 1,2-dichloroethane or trichlorethylene, dichlorobenzene; Ethers such as diethyl ether, tert-butyldimethyl ether, dioxane, tetrahydrofuran (THF), glycol dimethyl ether (1,2-dimethoxyethane, "glyme" or "DME") or diethylene glycol dimethyl ether ("diglyme").

Examples of polar aprotic solvents are: ketones such as acetone or butanone, acetic acid esters such as ethyl acetate or butyl acetate. [which?], amides such as dimethylformamide or hexamethylphosphoric triamide, N-methylpyrrolidone ("NMP"), nitriles such as acetonitrile, nitro compounds such as nitromethane, dimethyl sulfate oxide (DMSO), basic solvents such as pyridine, picoline, N-methylpiperidine.

Examples of protic solvents are: water or alcohols such as Methanol, ethanol, n-propanol, iso-propanol, n-butanol or tert-butanol.

The solvents can also be used in the form of mixtures.

All implementations are generally in normal, elevated or in ernie third pressure carried out (e.g. 0.5 to 5 bar). Generally one works at Normal pressure. Unless otherwise stated, the reactions are at room temperature temperature carried out.

The compounds described above can be used to prepare medicinal products be used for the treatment of diseases in humans and animals.  

The compounds described above are inhibitors of TNFα biosynthesis. They can be used in the prevention and treatment of Cardiovascular diseases, such as B. atherosclerosis and arthritis, rheumatoid arthritis, osteoporosis, Crohn's disease, chronic inflammatory Lung diseases such as Adult Respiratory Distress Syndrome (ARDS), graft Rejection, reperfusion tissue damage after stroke, heart attack or peripheral vascular occlusions, chronic inflammatory fibrotic organ ver Changes such as liver fibrosis or generalized autoimmune disease systemic lupus erythematosus or other forms of lupus erythematosus as well as dermal inflammatory diseases such as psoriasis.

The inhibition of TNFα biosynthesis by the verb described above dungs can be demonstrated in biological tests in vitro and in vivo.

The active ingredient can be administered orally or parenterally to achieve a systemic effect, can be applied locally for an external effect.

Application forms on the are particularly suitable for parenteral administration Mucous membranes (buccal / lingual / sublingual, rectal, nasal, pulmonal, conjunctival or intravaginal) or inside the body. This can be done by bypassing absorption happen (intracardially, intraarterially, intravenously, intraspinally or intralumbally) or with absorption activated (intracutaneous, subcutaneous, percutaneous, intramuscularly or intraperitoneally).

The active ingredients can be administered alone or in the form of administration forms be enough.

For oral application are suitable as forms of application u. a. normal and enteric-coated tablets, capsules, dragees, pills, granules, pellets, powders, solid and liquid aerosols, syrups, emulsions, suspensions and solutions.  

For parenteral administration, injection and administration forms are suitable Infusion solutions.

Suppositories are suitable for local application with systemic distribution and aerosols, if no systemic distribution is desired, vaginal are suitable capsules, nose, ear, eye drops, aqueous suspensions (lotions, shakes mixtures), lipophilic suspensions, ointments, creams, milk, pastes, powder or Sprays.

In the application forms, the active ingredient can be used in a concentration of 0-100% by weight are present; preferably the concentration of the active ingredient 0.5-90 wt%, i.e. H. in amounts that are sufficient Achieve dosage range.

The active substances can be added to the applications listed in a manner known per se forms are transferred. This is done using inert non-toxic, pharmaceutically suitable excipients, e.g. B. carriers, solvents, vehicles, Emulsifiers and / or dispersants.

Examples of auxiliaries include: water, solid carriers such as natural Liche or synthetic stone powder (e.g. talc or silicates), sugar (e.g. Milk sugar), non-toxic organic solvents such as paraffins, vegetable oils (e.g. sesame oil), alcohols (e.g. ethanol, glycerin), glycols (e.g. polyethylene glycol), Emulsifiers, dispersants (e.g. polyvinylpyrrolidone) and lubricants (e.g. Magnesium sulfate).

In the case of oral administration, tablets can of course also contain additives like sodium citrate along with additives like starch, gelatin and the like Chen included. Aqueous preparations for oral administration can continue with flavor enhancers or colorants.  

In general, it has proven to be advantageous for parenteral administration Amounts from about 0.001 to 25 mg / kg, preferably about 0.001 to 10 mg / kg Give body weight for effective results. With oral Application, the amount is about 0.001 to 50 mg / kg, preferably about 0.01 to 20 mg / kg body weight.

Nevertheless, it may be necessary from the amounts mentioned deviate, depending on body weight, application route, individual behavior towards the active ingredient, type of preparation and time point or interval at which the application takes place.

1. Detection of TNFα biosynthesis inhibition in human blood monocytes

Peripheral blood monocytes are made from 150 ml of blood from healthy volunteers as follows isolated:

The blood is in Vacutainer tubes (Becton-Dickinson GmbH, Heidelberg, Order No. 362753) centrifuged for 20 minutes at 1500 g at room temperature. The Monocytes are removed from a zone above the cell according to the manufacturer's instructions Aspirated separating gel and in a 50 ml Falcon centrifuge tube in 50 ml phos phat-buffered saline suspended and centrifuged again at 300 g for 20 minutes.

The cell pellet is dissolved in 10 ml of Versene solution (Life-Technologies GmbH, Karls rest, order no. 15040-033) and centrifuged again at 300 g for 5 minutes. The cells are then placed in culture medium RPMI 1640 (from Life-Technolo gies GmbH, Karlsruhe, order no. 21875-059) added. For the culture medium 1% (vol / vol) of the following solutions are used as additives: 200 mM L-glutamine; 5000 U / ml penicillin G and 5 mg / ml steptomycin sulfate; 1.0 M HEPES buffer solution; 100 mM sodium pyruvate; Solution of non-essential amino acids  (Fa. Life-Technologies GmbH, Karlsruhe, Order No. 11140-035) Furthermore 10% (vol / vol) fetal calf serum was added to the culture medium.

The monocytes are sown in 100 μl in this culture medium with a cell density of 2.5 × 10 ⁵ cells / well in a 96-well microtiter plate (Falcon / Becton Dickinson, Lincoln Park, NJ 07035, Microtest III, Tissue Gulture Plate) , After 1 to 2 hours, the monocytes adhere to the surface. The medium is suctioned off and the monocytes are washed with 100 ul culture medium. Then 150 μl culture medium, the test substance, dissolved in 50 μl culture medium and 50 μl lipopolysaccharide (LPS) solution (0.5 μg / ml LPS dissolved in culture medium: Escherichia coli Serotype 0111: B4 from Sigma, St. Louis, MO 63178, USA, Order No. L-3012) was added and incubated for 18 hours in a cell culture incubator at 37 ° C. and 5% CO ₂ atmosphere.

The amount of TNFα formed is in 100 µl supernatant of the test batches with a commercially available enzyme-linked immunosorbent test (ELISA), e.g. B. from from R Systems GmbH, 65205 Wiesbaden, order no. DTA50, according to the Manufacturer's data determined quantitatively. The TNFα synthesis inhibition in this way depends on the concentration of the test substance used determine. The concentration of the test substance, which is a half-maximum TNFα Synthesis inhibition (EC50) causes is from the corresponding dose Effect curve determined.  

Table 1

TNF ELISA: Effective data

2. Evidence of inhibition of TNF release in vivo

Female Balb / c or OF- were used to determine the TNF release in vivo. 1 mice (Iffa creed) used. These were checked 4 hours before the start of the experiment sober.

The substances to be tested were administered by os, intraperitoneally or intravenously enough. The application volume was peroral and intraperitoneal 10 ml / kg, whereas only 5 ml / kg were administered with intravenous administration.

The TNF release in the mice was characterized by the application of LPS S. minnesota (4 mg / kg) induced the intraperitoneally in a volume of 25 ml / kg was administered in 0.9% NaCl. LPS administration was routinely 30 minutes later the oral administration of substance. For the analysis of kinetic questions or after intravenous administration, LPS was injected 15 to 120 minutes after substance administration.

In all studies, the mice were administered retro-orbi 1.5 hours after LPS administration tale puncture blood was taken and sent for further analysis. The removed  Blood was centrifuged at 1400 rpm for 10 minutes to collect serum. Using a TNF ELISA from R, the TNF content determined.

LPS-MOUSE: selected active data

3. Evidence of the anti-atherosclerotic effects of the above described compounds and TNF synthesis inhibitors in the model the ApoE knockout mouse

To determine the anti-atherosclerotic activity of the compounds, the Model of the ApoE deficient mouse used. This model is mice that have a disturbed gene due to a gene defect in apolipoprotein E. Have lipid metabolism and within 3 months in the heart valve area develop a form of atherosclerosis, that of advanced atherosclerosis of humans is very similar. This model has become one in recent years Standard model of atherosclerosis research developed.

To quantify atherosclerosis, the area of interest is the heart flap removed and fixed in paraffin. Then in histological Cut the cross-sectional area of the atherosclerotic deposits with the help of a computer-based morphometry system.  

Abbreviations

abs .: Absolutely
Ac: acetyl
aq .: watery
Boc: tert-butoxycarbonyl
Bu: butyl
CDI: N, N'-carbonyldumidazole
TLC: thin layer chromatography
DCC: N, N'-dicyclohexylcarbodiimide
DEAD: diethyl azodicarboxylate
dest .: distilled
DIBAH: diisobutyl aluminum hydride
DMAP: 4-N, N-dimethylaminopyridine
DME: 1,2-dimethoxyethane
DMF: N, N-dimethylformamide
DMPU: N, N'-dimethylpropyleneurea
DMSO: dimethyl sulfoxide
DPPA: diphenylphosphoryl azide
EDC: N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide × HCl
eq: equivalent (s)
Et: ethyl
fl .: liquid
Mp .: melting point
Fr .: fraction
GC: gas chromatography
sat .: saturated
HMPT: hexamethylphosphoric triamide
HOBt: 1-hydroxy-1H-benzotriazole × H ₂

O
HOSu: N-hydroxysuccinimide
HPLC: high pressure, high performance liquid chromatography
conc .: concentrated
Kp .: boiling point
krist .: crystalline / crystallized
LAH: lithium aluminum hydride
LDA: Lithium-N, N-diisopropylamide
LiHMDS: Lithium-N, N-bistrimethylsilylamide
Lit .: literature (place)
Solution: solution
MCPBA: meta-chloroperbenzoic acid
Me: methyl
MEK: methyl ethyl ketone
MPLC: medium pressure liquid chromatography
MS: mass spectroscopy
MTBE: methyl tert-butyl ether
Nd .: precipitation
NBS: N-bromine succinimide
NMM: N-methylmorpholine
NMR: nuclear magnetic resonance spectroscopy
p. A .: pro analysi
Ph: phenyl
Pr: propyl
RF: reflux
R _F

: Retention index (for DC)
RT: room temperature
subl .: sublimated
TBAF: tetrabutylammonium fluoride
TBDMS: tert-butyldimethylsilyl
TEA: triethylamine
techn .: technical
TFA: trifluoroacetic acid
TFAA: trifluoroacetic anhydride
THF: tetrahydrofuran
titr .: Titrated
TMS: trimethylsilyl
TPP: triphenylphosphine
TPPO: triphenylphosphine oxide
dil .: diluted
Vol .: volume
watery: watery
Z: benzyloxycarbonyl
Decomposition: decomposition

The eluents used for thin layer chromatography are:
A = dichloromethane: methanol = 4: 1
B = dichloromethane: methanol = 4: 1
C = cyclohexane: ethyl acetate = 30: 1
D = dichloromethane: methanol = 20: 1
E = cyclohexane: ethyl acetate = 1: 2
F = cyclohexane: ethyl acetate = 2: 1
G = toluene: ethanol = 10: 1
H = cyclohexane: ethanol = 5: 1
I = cyclohexane: ethyl acetate = 1: 1
J = cyclohexane: ethyl acetate = 1: 3
K = cyclohexane: ethyl acetate = 1:10
L = cyclohexane: ethyl acetate = 1: 8
M = toluene: ethyl acetate = 1: 1
N = dichloromethane: methanol = 9: 1
O = toluene: ethyl acetate = 1: 4
P = dichloromethane
Q = toluene: ethyl acetate = 4: 1

starting compounds

Example I

1H-imidazole-4,5-dicarboxylic acid diethyl ester

3.00 g (19.2 mmol) of 1H-imidazole-4,5-dicarboxylic acid are stirred in 120 ml of ethanol with 2 ml of concentrated sulfuric acid under reflux for 18 hours. Then 8.7 g (103.6 mmol) of sodium hydrogen carbonate are added to the reaction mixture in portions and, after the evolution of gas has ended, the solvent is largely evaporated at a temperature below 25.degree. The residue is mixed with a buffer solution of pH = 7 and extracted with dichloromethane. This produces a precipitate that is suctioned off. The aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated;
Yield: 0.51 g (12%).
R _f = 0.34 (A).
¹ H NMR (d ₆ -DMSO, 300 MHz, TMS): δ = 1.28 (6H), 4, .27 (4H), 7.89 (1H), 13.52 (1H) ppm.
MS (DCI, NH ₃ ): m / z = 425 (41%, [2M + H] ⁺ ), 230 (74%, [M + NH ₄ ] ⁺ ), 213 (100%, [M + H] ⁺ ).

Example II

5,6-dimethyl-5,6-dihydro-1H-imidazo [4,5-d] pyridazine-4,7-dione

4.88 g (15.6 mmol) 5,10-dioxo-5H, 10H-diimidazo [1,5-a; 1 ', 5'-d] pyrazine-1,6-dicar bonyl dichloride (synthesis instructions: N. Yasuda , H. Iwagami, E. Nakanishi, T. Nakamiya, Y. Sasaki and T. Murata, J. Antibiot. 36, 242 (1983).) Are placed in 200 mL DMF, with 8.3 g (62.4 mmol ) N, N'-dimethylhydrazine dihydrochloride, 1.91 g (15.6 mmol) DMAP and 15.79 g (156.0 mmol) triethylamine were added and the mixture was stirred at 130 ° C. for 45 minutes. The reaction mixture is shaken with buffer solution of pH = 4 and dichloromethane. The aqueous phase is then adjusted to pH = 7 with 1 M sodium hydroxide solution and extracted several times with ethyl acetate. The aqueous phase is extracted continuously.
R _f = 0.48 (B).
¹ H NMR (d ₆ -DMSO, 300 MHz, TMS): δ = 3.71 (S, 6H), 8.12 (S, 1H), 13.88 (1H) ppm.
MS (DCI, NH ₃ ): m / z = 361 (15%, [2M + H] ⁺ ), 198 (100%, [M + NH ₄ ] ⁺ ), 181 (21%, [M + H] ⁺ ).

Example III

1- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzyl] -1H-imidazole-4,5- dicarboxylic acid dimethyl ester

10.50 g (57.0 mmol) of dimethyl 1H-imidazole-4,5-dicarboxylate are reacted with stirring at 23 ° C in 300 mL DMF with 2.28 g (57.0 mmol) of 60% sodium hydride (in paraffin) , 15 minutes after the evolution of gas has ended, 22.3 g (57.0 mmol / corresponds to 16.93 g of pure material) of crude 1- (4-bromomethyl-phenyl) -4,4,5,5-tetramethyl- [1,3 , 2] dioxaborolan (synthesis instructions: K. Ramalingam and DP Nowotnik, Org. Prep. Proced. Int. 23, 729 (1991); H.-W. Kleemann, HJ Lang, J.-R. Schwark, A. Weichen, S. Faber and H.-W. Jansen, page 35 in EP 855 392./ and stirred for 16 hours, the procedure provides a material which is not completely brominated, but as such can be introduced into the synthesis.) The reaction mixture is largely freed of DMF in vacuo and the residue obtained is distributed between diethyl ether and buffer solution of pH = 7. The aqueous phase is extracted several times with diethyl ether, and the combined organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. Since the aqueous phase contains by product, it is salted out with solid sodium chloride and extracted with ethyl acetate. The combined organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The two batches obtained in this way are combined and purified by chromatography (Kieselgel 60, Merck, cyclohexane: ethyl acetate = 3: 1 to 1: 2); Yield: 11.81 g (52%).
R _f = 0.16 (E).
¹ H-NMR (d ₆ -DMSO, 200 MHz, TMS): δ = 1.28 (12H), 3.72 (3H), 3.78 (3H), 5.47 (2H), 7.16 ( 2H),
7.67 (2H), 8.18 (1H) ppm.
MS (ESI): m / z = 423 (19%, [M + Na] ⁺ ), 401 (100%, [M + H] ⁺ ), 341 (19%, [M- CO ₂ CH ₃ ] ⁺ ) ,

Example IV

(5-R, S) -5- [dimethyl (1,1-dimethyl-ethyl) silyloxy-methyl] -3- (thien-2-yl) - oxazolidin-2-one

2.00 g (10.0 mmol) (5-R, S) -5-hydroxymethyl-3- (thien-2-yl) -oxazolidin-2-one (synthesis of the starting material: analogous to EP 693 491, there Ex No. 9) are dissolved in 15 mL DMF, 1.71 g (25.1 mmol) imidazole and 1.82 g (12.0 mmol) tert-butyldimethylsilyl chloride are added and the mixture is stirred at 40 ° C. for 16 hours. The reaction mixture is diluted with 350 mL diethyl ether and washed several times with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate, evaporated and freed from residual solvent in a high vacuum; Yield: 2.98 g (95%).
R _f = 0.51 (F).
¹ H-NMR (d ₆ -DMSO, 200 MHz, TMS): δ = 0.01 (6H), 0.73 (9H), 3.67-3.89 (3H), 4.06 (1H), 4.82 (1H),
6.51 (1H), 6.84 (1H), 7.02 (1H) ppm.

Example V

(5-R, S) -3- (5-bromo-thien-2-yl) -5- [dimethyl- (1,1-dimethyl-ethyl) silyloxy-methyl] - oxazolidin-2-one

15.0 g (47.8 mmol) (5-R, S) -5- [dimethyl- (1,1-dimethyl-ethyl) -silyloxy-methyl] -3- (thien-2-yl) -oxazolidine 2-one (Example IV) are dissolved in 400 mL of a mixture of trichloromethane and acetic acid (1: 1), 8.52 g (47.8 mmol) of NBS are added and the mixture is stirred at 23 ° C. for 30 minutes. The reaction mixture is stirred with dichloromethane and water and the aqueous phase is subsequently extracted with dichloromethane. The combined organic phases are washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, evaporated and freed from residual solvent in a high vacuum; Yield: 18.4 g (98%).
R _f = 0.50 (P).
¹ H-NMR (d ₆ -DMSO, 300 MHz, TMS): δ = 0.01 (6H), 0.73 (9H), 3.68-3.88 (3H), 4.03 (1H), 4.85 (1H),
6.33 (1H), 6.98 (1H) ppm.

Example VI

(5-R, S) -3- [5- (4-formyl-phenyl) thien-2-yl] -5- [dimethyl- (1,1-dimethyl-ethyl) - silyloxy-methyl] oxazolidin-2-one

17.5 g of (5-R, S) -3- (5-bromothien-2-yl) -5- [dimethyl- (1,1-dimethylethyl) silyloxymethyl] oxazolidin-2 -one (Example V), (44.6 mmol) and 8.7 g of 4-formylphenyl boronic acid (58.0 mmol) and 1.6 g of tetrakis (triphenylphosphine) palladium (0) (1.3 mmol ) are stirred in 450 ml of tetrahydrofuran under argon under reflux for one hour. 81 ml of an aqueous 2N sodium carbonate solution are added dropwise to this solution at this temperature within 5 minutes. The reaction mixture is refluxed for a further 24 hours. The reaction solution is then allowed to cool and evaporated under reduced pressure. The material obtained is purified by chromatography (Kieselgel 60, Merck, eluent: toluene, toluene / ethyl acetate 9: 1). Yield: 14.5 g (78%).
R _f = 0.50 (Q).
¹ H-NMR (d ₆ -DMSO, 400 MHz, TMS): δ = 0.02 (3H), 0, .03 (3H), 0.69 (9H), 3.74-3.95 (3H) , 4.16 (1H), 4.92 (1H), 6.64 (1H), 7.58 (1H), 7.82 (2H), 7.91 (2H), 9.97 (1H) ppm ,

Example VII

((5-R, S) -3- [5- (4-hydroxymethyl-phenyl) thien-2-yl] -5- [dimethyl- (1,1-dimethyl ethyl) silyloxy-methyl] oxazolidin-2-one

14.2 g (5-R, S) -3- [5- (4-formylphenyl) thien-2-yl] -5- [dimethyl- (1,1-dimethyl-ethyl) - silyloxy-methyl] -oxazolidin-2-one (Example VI), (34.0 mmol) are in 1000 ml Dissolved ethanol and in portions at 23 ° C with 0.51 g sodium borohydride (13.6 mmol) added. The reaction mixture is stirred at 23 ° C. for 18 hours and then slowly added 200 ml of water. The reaction mixture is with 500 ml Extracted ethyl acetate. The organic phase becomes saturated with 100 ml aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The oily material obtained is chromatographed in its Components separated (Kieselgel 60, Merck, toluene: ethyl acetate = 4: 1); it fraction 1 (0.4 g / 3%) and fraction 2 (12.6 g / 88%) are obtained.

Fraction 2 turns out to be the desired product.
R _f = 0.56 (E).
MS (ESI): m / z = 420 (100%, [M + H] ⁺ ).

Fraction 1 turns out to be re-isolated starting material.

Preparation Examples

example 1

Mitsunobu reaction

1- (4- {5 - [(1R, S) -1-hydroxymethyl-2-oxo-oxazolidin-3-yl] -thiophene-2-yl} benzyl) - 1H-imidazole-4,5-dicarboxylic acid dimethyl ester

10.4 g (25.0 mmol) ((5-R, S) -3- [5- (4-hydroxymethylphenyl) thien-2-yl] -5- [dimethyl- (1,1-dimethyl -ethyl) -silyloxy-methyl] -oxazolidin-2-one (Example VI), and 4.4 g (24.0 mmol) of 1H-imidazole-4,5-dicarboxylic acid dimethyl ester are dissolved in 100 ml of THF and at 0 C. 4.3 g (25.0 mmol) of diethyl azodicarboxylic acid and 6.5 g (25.0 mmol) of triphenylphosphine were added in succession in ° C. The reaction mixture was stirred for 18 hours at 23 ° C. and then 50 ml of water were added slowly is extracted with 200 ml of ethyl acetate. The organic phase is washed with 100 ml of saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The residue obtained is stirred with 200 ml of diethyl ether. The solid which has precipitated is filtered off with suction, washed with 20 ml of diethyl ether and in The residual solvent is removed under high vacuum, and 9.2 g (63%) of 1- (4- {5 - [(1R, S) -1- [dimethyl- (1,1-dimethyl-ethyl) -silyloxy-methyl] - 2-oxo-oxazolidine -3-yl] -thiophene-2-yl} benzyl) -1H-imidazole-4,5-dicarboxylic acid dimethyl ester obtained.
R _f = 0.21 (M).
MS (ESI): m / z = 586 (8% [M + H] ⁺ ), 608 (8% [M + Na] ⁺ ), 402 (100%)

9.1 g (15.5 mmol) 1- (4- {5 - [(1R, S) -1- [dimethyl- (1,1-dimethyl-ethyl) -silyloxymethyl] -2-oxo- oxazolidin-3-yl] -thiophene-2-yl} -benzyl) -1H-imidazole-4,5-dicarboxylic acid dimethyl ester are dissolved in 270 ml of MeOH and 45.5 ml of concentrated hydrochloric acid are added at 23 ° C. and the mixture is stirred for 2 hours this temperature stirred. The reaction mixture is mixed with 500 ml of water and extracted with 500 ml of dichloromethane. The organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The residue is purified by chromatography (Kieselgel 60, Merck, toluene: ethyl acetate = 4: 1 to 1: 1); 7.01 g (97%) of the product are obtained.
R _f = 0.48 (N).
MS (ESI): m / z = 472 (8%, [M + H] ⁺ ), 494 (53%, [M + Na] ⁺ ), 288 (100%).

Analogously to the instructions in Example 1, the compounds in Table 1 manufactured.  

Table 1

Example 7

Suzuki Coupling

1- (4- {5 - [(1R) -1-hydroxymethyl-2-oxo-oxazolidin-3-yl] -thiophene-2-yl} benzyl) - 1H-imidazole-4,5-dicarboxylic acid dimethyl ester

Under argon, 0.1 g (0.36 mmol) of (5-R) -3- (5-bromothien-2-yl) -5-hydroxy methyl-oxazolidin-2-one (preparation instructions analogous to EP 693 491, Example 7), 0.18 g of 1- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzyl] -1H-imidazole- 4,5-dicarboxylic acid dimethyl ester (0.45 mmol) and 0.03 g [1,1'-bis (diphenyl phosphino) ferrocene] palladium (II) chloride-methylene chloride complex (1: 1) ( 0.036 mmol) in 40 ml degassed tetrahydrofuran heated under reflux for 20 min. The reaction mixture is mixed with 0.5 ml of 2N sodium carbonate solution and heated under reflux for a further 6 hours. For working up, the mixture is cooled to 23 ° C. and mixed with 20 ml of water and 20 ml of ethyl acetate. After the phases have been separated, the aqueous phase is extracted once with 20 ml of ethyl acetate and the combined organic phases are dried over sodium sulfate. It is filtered through 5 g of silica gel and the solvent is removed under reduced pressure. The residue obtained is purified by chromatography (silica gel 60, Merck, elution with dichloromethane and dichloromethane / methanol 100: 3). 0.035 g (21%) of the product are obtained.
R _f = 0.48 (N).
MS (ESI): m / z = 472 (8%, [M + H] ⁺ ), 494 (53%, [M + Na] ⁺ ), 288 (100%).

Analogously to the instructions in Example 7, the compounds in Table 2 manufactured.

Table 2

Example 10

1- (4- {5 - ((1R, S) -1- (aminophenyl-carbonyl-oxymethyl) -2-oxo-oxazolidin-3-yl] - thiophen-2-yl} -benzyl) -1H-imidazole-4,5-dicarboxylic acid dimethyl ester

40 mg (0.084 mmol) 1- (4- {5 - [(1R, S) -1-hydroxymethyl-2-oxo-oxazolidin-3-yl] thio phen-2-yl} benzyl) -1H-imidazole -4,5-dicarboxylic acid dimethyl ester (Example 1), who is dissolved in 5 ml of DMF and 13 mg (0.11 mmol) of phenyl isocyanate and a drop of phosphazene base P ₁ -t-Bu are added at 23 ° C. The mixture is stirred at this temperature for 16 h. Then the reaction mixture is mixed with 20 ml of water and extracted with 20 ml of dichloromethane. The organic phase is dried over sodium sulfate, filtered and evaporated. The residue is purified by chromatography (silica gel 60, Merck, elution with dichloromethane and dichloromethane / methanol 20: 1). 10 mg (20%) of the product are obtained.
R _f = 0.28 (D).

Analogously to the instructions in Example 10, the compounds in Table 3 manufactured.

Table 3

Example 17

Carbamate synthesis via nitrophenyl ester

1- (4- {5- [5- (4-methyl-piperazine (1R, S) -1-carbonyloxymethyl) -2-oxo-oxazolidin-3- yl] -thiophene-2-yl} -benzyl) -1H-imidazole-4,5-dicarboxylic acid dimethyl ester

170 mg (0.36 mmol) 1- (4- {5 - ((1R, S) -1-hydroxymethyl-2-oxo-oxazolidin-3-yl] thio phen-2-yl} benzyl) - 1H-imidazole-4,5-dicarboxylic acid dimethyl ester (Example 1), who dissolved in 20 ml dichloromethane and at 23 ° C with 93 mg (0.76 mmol) Di methylaminopyridine added. This solution is added dropwise with stirring 2 h at 23 ° C to a solution of 109 mg (0.54 mmol) chloroformic acid 4- nitrophenyl ester in 20 ml dichloromethane. Then the reaction mixture with 20 ml of aqueous phosphate buffer solution (pH 7), the organic phase separated and the aqueous phase extracted with 20 ml dichloromethane. The combined organic phases are dried over sodium sulfate, filtered and evaporated. 157 mg of a yellow solid are obtained.

30 mg of the solid are dissolved in 1 ml of dichloromethane and added dropwise at 23 ° C. to a solution of 10 mg (0.10 mmol) of 4-methyl-piperazine in 2 ml of dichloromethane. The mixture is stirred at 23 ° C. for 18 h and 0.5 ml of 1 N sodium hydroxide solution are added for working up. The reaction mixture is poured onto a frit filled with 3 g of silica gel (below), 1 g of Extrelut (middle) and 0.5 g of basic ion exchanger (Amberlite IRA-410, above). It is eluted with 20 ml of dichloromethane and ethyl acetate. The product is then eluted with 10 ml dichloromethane / methanol (90:10). 15 mg (49%) of the product are obtained.
R _f = 0.22 (D).
MS (ESI positive): m / z = 598 (93%, [M + H] ⁺ ).

Analogously to the instructions in Example 17, the compounds in Table 4 manufactured.  

Table 4

Example 28

1- (4- {5- [5- (4-methyl-piperazine (1S) -1-carbonyloxymethyl) -2-oxo-oxazolidin-3- yl] -thiophene-2-yl} -benzyl) -1H-imidazole-4,5-dicarboxylic acid dimethyl ester

In a solution of 0.59 ml of diphosgene (3.0 mmol) in 40 ml of dioxane heated to 80 ° C., 1.4 g of 1- (4- {5 - [(15) -1-hydroxymethyl-2 - oxo-oxazolidin-3-yl] -thiophene-2-yl} -benzyl) -1H-imidazole-4,5-dicarboxylic acid dimethyl ester (Example 8), (3.0 mmol). The reaction mixture is stirred at 80 ° C for one hour. A vigorous stream of argon is then passed through the solution for 30 minutes in order to drive off excess diphosgene from the solution. The reaction mixture is cooled to 23 ° C. and 0.89 g of 4-methyl-piperazine is added (9.0 mmol). At this temperature, stirring is continued for 3 h and then 40 ml of saturated sodium hydrogen carbonate solution are added. The mixture is extracted twice with 50 ml dichloromethane each time, the organic phases are combined, dried over sodium sulfate and filtered. The product obtained after evaporation under reduced pressure is purified by chromatography (silica gel 60, Merck, dichloromethane: methanol = 100: 3 for elution of the starting material, then dichloromethane: methanol = 95: 5 for elution of the product); Yield: 1.60 g (90%).
R _f = 0.22 (D).
MS (ESI positive): m / z = 598 (93%, [M + H] ⁺ ).

Analogously to the instructions in Example 28, the compounds in Table 5 manufactured.

Table 5

The carbamates listed in Table 6 (Examples 35-74) are characterized by automated parallel synthesis from 1- (4- {5 - [(1R, S) -1-hydroxymethyl-2-oxo oxazolidin-3-yl] -thiophene-2-yl} -benzyl) -1H-imidazole-4,5-dicarboxylic acid dimethyl ester (Example 1), and the corresponding amines according to the following general Working procedure produced. The purity of the compounds produced is determined by HPLC determined. The compounds are characterized by LC-MS. The The percentage of the desired compounds in the table is in the column "HPLC" indicated.

General procedure for the synthesis of those listed in Table 6 Links:

In a heated to 80 ° C solution of 0.66 ml diphosgene (5.4 mmol) in 300 ml Dioxane are added in portions under argon 1.8 g 1- (4- {5 - [(1R, S) -1-hydroxymethyl-2- oxo-oxazolidin-3-yl] -thiophene-2-yl} -benzyl) -1H-imidazole-4,5-dicarboxylic acid di- methyl ester (3.6 mmol). The reaction mixture is 1.5 hours at 80 ° C. touched. Then a strong stream of argon is passed through the solution for 30 minutes directed to drive off excess diphosgene from the solution. The received Solution of 1- (4- {5 - [(1R, S) -1-chlorocarbonyl-oxymethyl-2-oxo-oxazolidin-3-yl] - thiophene-2-yl} benzyl) -1H-imidazole-4,5-dicarboxylic acid dimethyl ester is 0.01 molar and is implemented without further cleaning.  

3.2 molar equivalents of the amine are placed in the reaction vessel. At 23 ° C 0.1 mmol of the chlorocarbonyl compound are added with stirring. The The reaction mixture is stirred at 23 ° C. for 24 hours. To work up with 0.5 ml of 1N hydrochloric acid are added and the mixture is stirred at 23 ° C. for a further 5 minutes. The Reaction mixture is passed through a 1.0 g extrelut (upper phase) and 2.0 g Filtered silica gel 60 (under phase) cartridge (elution with 8 ml dichlor methane). The product obtained after evaporation under reduced pressure chromatographically cleaned (cartridges, 1.5 g silica gel 60, Machery-Nagel, Di chloromethane: methanol = 100: 1 to 1: 1).  

Table 6

Examples 75 and 76

1- (4- {5- [5- (4-methyl-piperazine (1S) -1-carbonyloxymethyl) -2-oxo-oxazolidin-3- yl] -thiophene-2-yl} -benzyl) -1H-imidazole-4,5-dicarboxylic acid 4-methyl ester and 1- (4- {5- [5- (4-methyl-piperazine (1S) -1-carbonyloxymethyl) -2-oxo-oxazolidin-3- yl] -thiophene-2-yl} -benzyl) -1H-imidazole-4,5-dicarboxylic acid-5-methylester

The compounds in the table are analogous to the instructions in Examples 75 and 76 7 manufactured.  

Table 7

Claims (7)

1. Compounds of the general formula (I)
wherein
B represents a radical of the formula (II),
wherein
R ^{B stands} for a 5-membered aromatic heterocycle bonded via an alkyl group with up to 3 heteroatoms from the series S, N and / or O, which can additionally be fused with benzene, cycloalkyl with 3 to 6 carbon atoms, a saturated or partially unsaturated heterocycle with up to three nitrogen atoms which can also carry up to two oxo groups, where the cycles in turn can be substituted with the groups R ^B1 , R ^B2 , R ^B3 , R ^B4 , R ^B5
where R ^B1 can stand
for -C∼N -CX ₃ , or carbonyl to which in turn groups selected from hydroxy, alkoxy or amino are bonded, which in turn can be substituted by one or more hydrocarbon radicals;
where R ^B2 R ^B3 can be alkyl, -COH, -CH ₂ OH, -C∼N, or carbonyl to which groups selected from hydroxy, alkoxy or amino are bonded, which in turn can be substituted with one or more hydrocarbon radicals;
R ^B4 and R ^B5 can represent hydrogen or a hydrocarbon residue,
A can stand for a group selected from -NH ₂ , hydroxy, hydroxy protected by a hydroxy protecting group or one of the residues (AI) - (AVIII)
wherein
R ^A1 , R ^{A2 may be the} same or different and may stand for hydrogen, alkyl, cycloalkyl, aryl,
where in the case that one of the groups R ^A1 , R ^{A2 is} alkyl, this in turn can be substituted with alkoxycarbonyl, alkoxy, aryl, aryl which in turn can be substituted, 5- to 10-membered heteroaryl of the group -CX ₃ wherein X is halogen;
wherein
R ^A3 can stand for
Alkyl or alkyl which in turn is mono- or polysubstituted with radicals selected from aryl, alkoxy, alkanoyl, alkanoyl which in turn is substituted with aryloxy;
or
R ^A3 can represent 5- to 10-membered heteroaryl bonded via a carbon atom,
or
R ^A3 can stand for the rest
wherein
R ^A3.1 can represent hydrogen, 5- to 10-membered heteroaryl, alkoxy, which in turn can be substituted;
wherein
R ^{A3.2 can} stand for alkyl, which in turn can be substituted with aryl;
wherein
R ^{A4 can} stand for hydrogen, a group
Alkyl, which in turn can be substituted;
wherein
R ^A4.1 can represent -NH ₂ , alkoxy, which in turn can be substituted;
U can stand for a heteroatom selected from N, O, S; or
U can stand for the group
wherein
R ^{AIV, 1} , R ^{AIV, 2 can be the} same or different and can stand for hydrogen, hydroxy, alkyl, alkyl, which in turn can be substituted with alkoxycarbonyl or alkoxy, which in turn can be substituted with an aryl radical
or U can stand for the group
R ^A5 and R ^{A6 can be the} same or different and can stand for hydrogen, alkyl or alkyl which in turn is substituted by cycloalkyl, or can stand for aryl or aryl which in turn can be substituted with aryl or aryloxy; or can stand for alkoxycarbonyl, or can stand for an aryl radical attached via a carbonyl group, or can stand for the group
or
R ^A5 and R ^A6 together, including the nitrogen atom to which they are attached, form a 5- to 6-membered, saturated or partially unsaturated heterocycle with up to 3 hetero atoms from the series S, N or O, the nitrogen atoms of which are optionally substituted can be with alkyl;
wherein
D can represent nitrogen or oxygen or CH ₂ ,
wherein
E can stand for nitrogen or CH ₂ ,
with the proviso that if D is oxygen, then R ^{A6 is} absent, E is nitrogen and R ^{A7 is} alkyl, which may be substituted by aryl,
or
R ^A7 can represent an alkoxy radical bonded via a carbonyl group,
R ^A8 can represent alkyl which is optionally substituted by an aryl group;
and their salts and S-oxides. 2. Compounds of the general formula (I),
in which
B represents a radical of the formula (II),
wherein
R ^B from one of the residues of the formulas BI-BIV
is selected
wherein
R ^B1 can be selected for a remainder
wherein
R ^{B1.1 can} stand for hydrogen, (C ₁ -C ₆ ) alkyl,
R ^{B1,2 B1,3} R may each independently represent hydrogen, (C ₁ - C ₆₎ alkyl, benzyl, (C ₁ -C ₆₎ alkyl substituted with one aryl radical, preferably phenyl, and
X represents halogen
wherein
R ^B2 can stand independently of R ^B1 selected for a remainder
wherein
R ^{B2.1 can} stand for hydrogen, (C ₁ -C ₆ ) alkyl,
R ^B2.2 , R ^{B2.3, independently of} one another, can be hydrogen, (C ₁ -C ₆ ) -alkyl, benzyl, (C ₁ -C ₆ ) -alkyl substituted with aryl, preferably phenyl,
R ^B3 can represent hydrogen or a group
wherein
R ^{B3.1 represents} (C ₁ -C ₆ ) alkyl.
R ^B4 and R ^B5 can be hydrogen or (C ₁ -C ₁₂ ) alkyl,
A can stand for a group selected from -NH ₂ , hydroxy, hydroxy protected by a hydroxy protecting group or one of the residues (AI) - (AVIII)
wherein
R ^A1 , R ^{A2 are the} same or different and can stand for hydrogen, (C ₁ -C ₆ ) alkyl, cycloalkyl, aryl,
in the event that one of the groups R ^A1 , R ^{A2 is} (C ₁ -C ₆ ) alkyl, this in turn can be substituted by alkoxycarbonyl, alkoxy, aryl or aryl which in turn can be substituted, or in the case that one of the groups R ^A1 , R ^{A2 is} (C ₁ -C ₆ ) alkyl, which in turn can be substituted by 5- to 10-membered heteroaryl, or group -CX ₃ in which X is halogen;
wherein
R ^A3 can stand for
or (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkyl, which in turn is mono- or polysubstituted with radicals selected from aryl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) -alkanoyl which in turn can be substituted with aryloxy;
or
R ^A3 can represent 5- to 10-membered heteroaryl bonded via a carbon atom, or
R ^A3 can stand for the rest
wherein
R ^A3.1 can represent hydrogen, 5- to 10-membered heteroaryl, alkoxy, which in turn can be substituted by (C ₆ -C ₁₀ ) aryl, or in which
R ^{A3.1 can} stand for (C ₁ -C ₁₂ ) alkyl, which in turn can be substituted with aryloxy;
wherein
R ^{A3.2 can} stand for (C ₁ -C ₆ ) alkyl, which in turn can be substituted with aryl;
wherein
R ^{A4 can} stand for hydrogen, a group
(C ₁ -C ₆ ) alkyl, which in turn can be substituted with groups selected from hydroxy, aryl;
wherein
R ^A4.1 can represent -NH ₂ , alkoxy;
U can represent a heteroatom selected from N, O, S, O is preferred; or
U can stand for the group
wherein
R ^{AIV, 1} , R ^{AIV, 2 can be the} same or different and can stand for hydrogen, hydroxy, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl, which in turn can be substituted with alkoxycarbonyl or Alkoxy, which in turn can be substituted with an aryl radical,
or U can stand for the group
R ^A5 and R ^{A6 can be the} same or different and can stand for hydrogen, an aryl radical attached via a carbonyl group, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl, which in turn is substituted by cycloalkyl, the group
(C ₁ -C ₆ ) alkoxycarbonyl, (C ₆ -C ₁₀ ) aryl or (C ₆ -C ₁₀ ) aryl, which in turn can be substituted with (C ₆ -C ₁₀ ) aryl or (C ₆ - C ₁₀ ) aryloxy;
or
R ^A5 and R ^A6 together, including the nitrogen atom to which they are attached, form a 5- to 6-membered, saturated or partially unsaturated heterocycle with up to 3 hetero atoms from the series S, N and / or O,
or
R ^A5 and R ^A6 together, including the nitrogen atom to which they are attached, form a saturated heterocycle which may contain further nitrogen atoms; piperidine is preferred, the free nitrogen atom of which may be substituted by (C ₁ -C ₁₂ ) -alkyl;
where D can represent nitrogen or oxygen or CH ₂ ,
where E can be nitrogen or CH ₂
with the proviso that if D is oxygen, then R ^{A6 is} absent, E is nitrogen and R ^{A7 is} (C ₁ -C ₆ ) alkyl, which can be substituted by (C ₆ -C ₁₀ ) Aryl, preferably phenyl;
or
R ^{A7 can} stand for alkoxycarbonyl,
R ^A8 can represent (C ₁ -C ₁₂ ) -alkyl, which may optionally have an aryl radical; is substituted
and their salts and S-oxides. 3. Compounds of the general formula (I),
in which
B represents a radical of the formula (II),
wherein
R ^B from one of the residues of the formulas BI-BIV
is selected
wherein
R ^B1 can be selected for a remainder
wherein
R ^{B1.1 can} stand for hydrogen, (C ₁ -C ₄ ) -alkyl,
R ^{B1,2, B1,3} R may each independently represent hydrogen, (C ₁ - C ₄₎ alkyl, benzyl, (C ₁ -C ₄₎ alkyl substituted by a (C ₆ -C ₁₀₎ -aryl Balance, preferably phenyl, and
X represents halogen, preferably fluorine.
wherein
R ^B2 can stand independently of R ^B1 selected for a remainder
wherein
R ^{B2.1 can} stand for hydrogen, (C ₁ -C ₄ ) -alkyl,
R ^B2.2 , R ^{B2.3 can} independently represent hydrogen, (C ₁ -C ₄ ) alkyl, benzyl, (C ₁ -C ₄ ) alkyl substituted with (C ₆ -C ₁₀ ) aryl, preferably phenyl,
R ^B3 can represent hydrogen or a group
wherein
R ^{B3.1 is} (C ₁ -C ₄ ) alkyl, preferably methyl.
R ^B4 and R ^B5 can be hydrogen or (C ₁ -C ₆ ) alkyl,
A can stand for a group selected from -NH ₂ , hydroxy, hydroxy protected by a hydroxy protecting group or one of the residues (AI) - (AVIII)
wherein
R ^A1 , R ^{A2 are the} same or different and can stand for hydrogen, (C ₁ -C ₄ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl,
in the event that one of the groups R ^A1 , R ^{A2 represents} (C ₁ -C ₄ ) alkyl, this in turn can be substituted by (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) - Alkoxy, (C ₆ -C ₁₀ ) aryl, which in turn can be substituted, 5- to 10-membered heteroaryl, of the group -CX ₃ where X is halogen, preferably fluorine;
wherein
R _A3 can stand for
or (C ₁ -C ₄ ) alkyl
or (C ₁ -C ₄ ) alkyl, which in turn is mono- or polysubstituted with radicals selected from (C ₆ -C ₁₀ ) aryl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) Alkanoyl which in turn can be substituted with aryloxy;
or
R ^A3 can represent 5- to 10-membered heteroaryl, in particular pyridyl, pyrimidyl, or bonded via a carbon atom
R ^A3 can stand for the rest
wherein
R ^A3.1 can represent hydrogen, 5- to 10-membered heteroaryl, especially furanyl, (C ₁ -C ₆ ) alkoxy, which in turn can be substituted by (C ₆ -C ₁₀ ) aryl, (C ₁ - C ₆ ) alkyl, which in turn can be substituted with aryloxy;
wherein
R ^{A3.2 can} stand for (C ₁ -C ₄ ) alkyl, which in turn can be substituted with aryl;
wherein
R ^{A4 can} stand for hydrogen, a group
(C ₁ -C ₄ ) alkyl, which in turn can be substituted with groups selected from hydroxy, aryl;
wherein
R ^A4.1 can represent -NH ₂ , alkoxy;
U can represent a heteroatom selected from N, O, S, O is preferred; or
U can stand for the group
wherein
R ^{AIV, 1} , R ^{AIV, 2 can be} identical or different and can stand for hydrogen, hydroxy, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkyl, which in turn can be substituted with (C ₁ - C ₆ ) alkoxycarbonyl or (C ₁ -C ₆ ) alkoxy, which in turn can be substituted with (C ₆ -C ₁₀ ) aryl,
or U can stand for the group
R ^A5 and R ^{A6 can be the} same or different and can represent benzoyl, hydrogen, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkyl, which in turn is substituted by cycloalkyl, the group
(C ₁ -C ₆ ) alkoxycarbonyl, (C ₆ -C ₁₀ ) aryl or (C ₆ -C ₁₀ ) aryl, which in turn can be substituted with (C ₆ - C ₁₀ ) aryl or (C ₆ - C ₁₀ ) aryloxy;
or
R _A5 and R _A6 together, including the nitrogen atom to which they are attached, form a 5- to 6-membered, saturated or partially unsaturated heterocycle with up to 3 heteroatoms from the series S, N and / or O, preference being given to tetrahydrofuran -2-yl, or
R _A5 and R _A6 together, including the nitrogen atom to which they are attached, form a saturated heterocycle, which may contain further nitrogen atoms. Piperidine, whose free nitrogen atom can be substituted by (C ₁ -C ₆ ) -alkyl, is particularly preferred.
D can stand for nitrogen or oxygen or CH ₂ , E can stand for nitrogen or CH ₂ ,
with the proviso that if D is oxygen, then R ^{A6 is} absent, E is nitrogen and R ^{A7 is} (C ₁ -C ₆ ) alkyl, which can be substituted by (C ₆ -C ₁₀ ) Aryl, preferably phenyl;
or
R ^A7 can represent (C ₁ -C ₆ ) alkoxycarbonyl,
R ^{A8 can} stand for (C ₁ -C ₆ ) alkyl, optionally substituted with (C ₆ - C ₁₀ ) aryl; preferably phenyl,
and their salts and S-oxides. 4. Compounds according to any one of claims 1 to 3 for use in the Fighting disease. 5. Use of compounds according to one of claims 1 to 3 for Manufacture of drugs.   6. Use of compounds according to one of claims 1 to 3 for Her Provision of medicines that have a preventive, soothing or healing effect disease patterns mediated by TNFα such as arthritis, rheumatoid Arthritis, osteoporosis, Crohn's disease, chronic inflammatory lungs diseases such as Adult Respiratory Distress Syndrome (ARDS), graft Rejection, reperfusion tissue damage after stroke, heart attack or peripheral vascular occlusions, chronic inflammatory fibrotic organ changes such as liver fibrosis, or generalized autoimmune systemic lupus erythematosus or other forms of Lupus erythematosus and dermal inflammatory diseases such as psoriasis. 7. Medicament containing a compound according to any one of claims 1 to 3 and a pharmaceutically acceptable auxiliary.