DE10034623A1 - New heterocyclic substituted pyridine 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

Heterocyclic substituted pyridine derivatives and their salts and s-oxides are new. The heterocyclic substituted pyridine derivatives of formula (I) and their salts and S-oxides: P and Q = S; N; O; or -CH-; R<1> and R<2> = H or hydrocarbyl, e.g. alkyl (optionally substituted with OH, alkoxy or alkoxycarbonyl); or R<1> or R<2> = -CO-O-R<3>; or NR<1>R<2> = R4 of formula: m = 0-1; R<3> = hydrocarbyl, alkyl (optionally monosubstituted with aryl or with 1 or more OH, alkoxy (optionally monosubstituted with aryl) or -O-CO-N(R3,1)(R3,2)) or saturated or partly unsaturated heterocyclyl ( optionally substituted with alkyl); R3,1, R3,2 = H or hydrocarbyl; R4,1 = halo, OH, alkoxy or -X-CO-Y(R4,2,1)(R4,2,2); X, Y = N and/or O; R4,2,1, R4,2,2 = H, alkyl (optionally substituted or alkoxycarbonyl); and R4,2,2 = absent when Y=0.

Description

The present invention relates to new, heterocyclically substituted pyridines, Processes for their production and their use as pharmaceuticals, in particular for the treatment of tumor necrosis factor (TNF) 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, S15-S19, 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, S15-S19, 1997; J. L. Barks et al. J. Immunology 159, 4532-4538, 1997; Iademarco, M.F. et al., 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 the wall (H. Funayama, Cardiovasc. Res. 37, 216-229 (1998); T. B. Rajava shisth, Circulation 99, 3103-3109 (1999).

In addition to its importance for the progression of arteriosclerotic vessels, TNFα is also important ignition (P. T. Kovanen et al., 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 generalized autoimmune disease 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 pyridines of the general formula (I)

in the
a, b can represent a heteroatom selected from S, N, or O, or the group CH,
and in the
R ¹ , R ^{2 can} independently represent hydrogen or a hydrocarbon radical such as alkyl which can be substituted by groups selected from hydroxyl, alkoxy, alkoxycarbonyl,
and in the
one of the radicals R ¹ , R ² for a group

can stand
and in the
R ¹ and R ² together, including the nitrogen atom to which they are attached, form a radical (R4)

can form, in which m can assume the values 0 or 1,
where R ³ can represent a hydrocarbon radical,

• - R ³ can be alkyl which can be mono- or polysubstituted with hydroxy, alkoxy, wherein said alkyl and alkoxy in turn can be substituted with an aromatic hydrocarbon
• - R ³ can be alkyl which in turn can be substituted one or more times with radicals (R3a)
  
• R ³ can represent a saturated or partially unsaturated heterocycle which in turn can be substituted by alkyl,
  where R ^3.1 and R ^{3.2 can} independently represent hydrogen or a hydrocarbon radical, preferably alkyl;
• R ^4.1 can represent halogen, preferably chlorine, hydroxy, alkoxy, a group (R4.2)
  in which X, Y can stand for nitrogen and / or oxygen and if y stands for oxygen, R ^{4,2,2 is} omitted,
  in which R ^4.2.1 and R ^4.2.2 independently of one another are hydrogen, alkyl, alkyl which in turn can be substituted, or alkoxycarbonyl,
  and their salts and S-oxides.

Physiologically acceptable salts are preferred in the context of the invention.

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, apples acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid,  Ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid or naphthalenedisulfone acid.

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 salts (e.g. magnesium or calcium salts) and ammonium salts derived from ammonia or organic Amines, such as ethylamine, di- or triethylamine, di- or triethanol amine, 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 that are either like picture and mirror image (enantiomers), or which do not behave like image and mirror image (diastereomers) hold. The invention relates to both the enantiomers and the diastereomers as well as their respective mixtures. The racemic shapes can be just like that Diastereomers in a known manner into the stereoisomerically uniform constituents separate; for example, separation by chromatography on chiral phases respectively.

The compounds of the invention and their salts can be used in the context of Er invention also exist as solvates. Such connections are meant here under solvates are understood to contain solvents in the crystal in a defined manner. Such compounds can have one or more, typically 1 to 5 equivalents of the solvent by crystallization of the compound from the corresponding Solvent can be obtained. Typical solvates are e.g. B. the hydrates in Contain crystal water.

In the context of the invention, hydrocarbon residues can be saturated or unsaturated, be linear, branched or cyclic and have 1 to 24 carbon atoms.  

Saturated hydrocarbon residues can be linear, branched or cyclic and bis to have 24 carbon atoms.

Unsaturated hydrocarbon residues can be linear, branched or cyclic and contain one or more C-C double and / or triple bonds and up to Have 24 carbon atoms.

Cyclic hydrocarbon radicals can be mono- or polycyclic, saturated or be unsaturated, non-aromatic or aromatic and have up to 14 carbon atoms.

Preferred hydrocarbon radicals in the context of the invention are alkyl radicals.

C ₁ -C ₆ alkyl includes methyl, ethyl, n- and i-propyl, n-, i-, sec- and tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl.

C ₁ -C ₄ alkyl includes methyl, ethyl, n- and i-propyl; n-, i-, sec- and tert-butyl.

In the context of the invention, alkoxy represents a straight-chain or branched Alkoxy radical with 1 to 6 carbon atoms. A straight-chain or ver is preferred branched alkoxy radical with 1 to 4 carbon atoms. Examples include: Methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy. A straight-chain or branched alkoxy radical with 1 to 3 is particularly preferred Carbon atoms, which in turn can be substituted with an aromatic Hydrocarbon, preferably phenyl.

Alkoxycarbonyl stands for a straight-chain or ver in the context of the invention branched alkoxy radical with 1 to 6 carbon atoms, which has a carbonyl group is linked. A straight-chain or branched alkoxycarbonyl radical is preferred with 1 to 4 carbon atoms. Examples include: methoxycarbonyl, Ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl.  

Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Prefers are chlorine or fluorine.

A 5- to 6-membered heterocycle with up to 3 heteroatoms from the S, N series and / or O in the context of the invention generally represents a heterocycle which can contain one or more double bonds and that via a ring carbon atom or a ring nitrogen atom is linked. Examples include: Tetrahy drofur-2-yl, tetrahydrofur-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, Pyrrolin-1-yl, piperidin-1-yl, piperidin-3-yl, 1,2-dihydropyridin-1-yl, 1,4-dihydro pyridin-1-yl, piperazin-1-yl, morpholin-1-yl, azepin-1-yl, 1,4-diazepin-1-yl. before piperidinyl and morpholinyl are added.

Hydroxy protecting group in the context of the above definition is generally NEN for a protective group from the series: trimethylsilyl, triisopropylsilyl, tert-butyl dimethylsilyl, benzyl, benzyloxycarbonyl, 2-nitrobenzyl, 4-nitrobenzyl, tert. butyl oxycarbonyl, allyloxycarbonyl, 4-methoxybenzyl, 4-methoxybenzyloxy carbonyl, tetrahydropyranyl, formyl, acetyl, trichloroacetyl, 2,2,2-trichloroethoxy carbonyl, methoxyethoxymethyl, [2- (trimethylsilyl) ethoxy] methyl, benzoyl, 4- Methylbenzoyl, 4-nitrobenzoyl, 4-fluorobenzoyl, 4-chlorobenzoyl or 4-methoxy benzoyl. Acetyl, tert are preferred. Butyldimethylsilyl or tetrahydropyranyl. in the The tert-butyldimethylsilyl group is particularly preferred in the context of the invention, the benzyl group and the trityl group.

Compounds of the general formula (I) are preferred
in which
a, b can represent nitrogen or CH,
and in those
R ¹ , R ² independently of one another are hydrogen or a hydrocarbon radical, preferably (C ₁ -C ₆ ) -alkyl, which in turn can be substituted one or more times with groups selected from hydroxy, (C ₁ -C ₆ ) -alkoxy, ( C ₁ -C ₆ ) alkoxycarbonyl,
and in those
one of the radicals R ¹ , R ² for a group

can stand
and in those
R ¹ and R ² together, including the nitrogen atom to which they are attached, form a radical (R4)

can form, in which m can assume the values 0 or 1,
in which
R ³ can represent a hydrocarbon radical, preferably (C ₁ -C ₆ ) alkyl, benzyl,

• R ^{3 can} stand for (C ₁ -C ₆ ) alkyl which in turn can be mono- or polysubstituted with hydroxy, alkoxy, wherein said (C ₁ -C ₆ ) alkyl and said (C ₁ -C ₆ ) - Alkoxy in turn can be substituted with an aromatic hydrocarbon, preferably phenyl,
• - R ³ can represent (C ₁ -C ₆ ) alkyl which in turn can be substituted one or more times with radicals (R3a)
• R ³ can represent a saturated or partially unsaturated heterocycle which in turn can be substituted by (C ₁ -C ₆ ) alkyl,

in which
R ^3.1

and R ^3.2

can independently represent hydrogen or a hydrocarbon radical, preferably (C ₁

-C ₆

) Alkyl;

• - R ^{4.1 can} stand for halogen, preferably chlorine, hydroxy, (C ₁ -C ₆ ) alkoxy, a group (R4.2)
  wherein
  X, Y can stand for nitrogen and / or oxygen and if Y stands for oxygen, R ^{4,2,2 is} omitted,
  wherein
  R ^4.2.1 and R ^4.2.2 independently of one another are hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkyl which in turn can be substituted, (C ₁ -C ₆ ) -Alkoxy carbonyl, can stand
  and their salts and S-oxides.

Compounds of the general formula (I) are particularly preferred

in which
a, b can represent nitrogen or CH,
and in those
R ¹ , R ² independently of one another represent hydrogen or a hydrocarbon radical, preferably (C ₁ -C ₄ ) -alkyl which in turn can be substituted one or more times with groups selected from hydroxy, (C ₁ -C ₄ ) -alkoxy, ( C ₁ -C ₄ ) alkoxycarbonyl,
and in those
one of the radicals R ¹ , R ² for a group

can stand
and in those
R ¹ and R ² together, including the nitrogen atom to which they are attached, form a radical (R4)

can form, in which m can assume the values 0 or 1,
in which
R ³ can represent a hydrocarbon radical, preferably (C ₁ -C ₄ ) alkyl, benzyl,

• R ^{3 can} stand for (C ₁ -C ₄ ) alkyl which in turn can be mono- or polysubstituted with hydroxy, alkoxy, wherein said (C ₁ -C ₄ ) alkyl and said (C ₁ -C ₄ ) - Alkoxy in turn can be substituted with an aromatic hydrocarbon, preferably phenyl,
• R ^{3 can} stand for (C ₁ -C ₄ ) alkyl which in turn can be substituted one or more times with radicals (R3a)
  
• R ³ can represent a saturated or partially unsaturated heterocycle which in turn can be substituted by (C ₁ -C ₄ ) alkyl,
  in which
  R ^3.1 and R ^{3.2 can} independently represent hydrogen or a hydrocarbon radical, preferably (C ₁ -C ₄ ) alkyl;
• - R ^4.1 can represent halogen, preferably chlorine, hydroxy, (C ₁ -C ₄ ) alkoxy, a group (R4.2)
  wherein
  X, Y can stand for nitrogen and / or oxygen and if Y stands for oxygen, R ^{4,2,2 is} omitted,
  wherein
  R ^4.2.1 and R ^4.2.2 independently of one another are hydrogen, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkyl which in turn can be substituted, (C ₁ -C ₄ ) -Alkoxy carbonyl, can stand

and their salts and S-oxides.

In addition, processes for producing the compounds according to the invention were found, characterized in that

• 1. [A] compounds of the general formula (AI) wherein
  R ^{AI, 1 represents} a leaving group, for example a halogen atom, in particular special bromine,
  R ^{AI, 2 represents} (C ₁ -C ₆ ) alkyl, in particular methyl or an aryl radical,
  in DMF or an equivalent solvent with trialkylstannylpyridines, for example trimethylstannylpyridines, in the presence of reducing agents such as, for example, palladium (II) complexes, for example bis (triphenylphosphine) palladium (II) chloride, and a base, for example triethylamine elevated temperature, preferably 100 ° C, after silence to compounds of the general formula (AII)
  and then the ester (AII) dissolved in a mixture consisting of a polar solvent, for example an alcohol such as methanol and aqueous alkali, for example sodium hydroxide solution, to give compound (AIII)
  saponified
• 2. [B] Compounds of the formula (AIII) dissolved in an aprotic solvent, for example a ketone, preferably acetone, at reduced temperature, preferably -20 ° C. to 0 ° C. in the presence of a base, for example triethylamine, first with alkyl chloroformate , for example chlorine formic acid ethyl ester, and subsequently reacted with alkali azide, for example sodium azide dissolved in water, and the acyl azide thus obtained then in toluene, at elevated temperature, in the presence of a Curtius alcohol to give compounds of the general formula (BI )
  surrounded,
  wherein R ^{BI, 1} can assume one of the meanings of R ³ .
  Two particularly preferred embodiments of (BI) are the compounds (BII) and (BIII)
  which are obtained when, in the preparation of the compounds having the general formula (BI), the alcohols (BII, I) or (BII, II)
  be used;
• 3. [C] compounds of the general formula (BI) in DMF or an equivalent solvent first with a deprotonating agent, for example an alkali hydride, preferably sodium hydride, and then with a (C ₁ -C ₄ ) alkyl halide , preferably methyl iodide, to compounds of the general formula (CI)
  implemented in which R ^{CI, 1} can assume one of the meanings given for R ¹ , R ² and preferably stands for methyl, and in which R ^{BI, 1 has} the meaning of R ³ .
  A particularly preferred embodiment of the compounds having the general formula (CI) is the compound (CII)
  
• 4. [D] Compounds of the general formula (CI) in which R ^{BI, 1 stands} for a radical containing an alkoxy group, preferably the compound (CII), are in an inert solvent, preferably a halogenated hydrocarbon, for example dichloromethane , dissolved, and at temperatures between 0 ° C and -20 ° C, preferably -10 ° C, under the action of Bortribro mid or other ether-cleaving agents of ether cleavage to give compounds of the general formula (DI)
  implemented. Compound (DI) in which R ^{CI, 1 is} methyl is preferred.
• 5. [E] Compounds of the general formula (DI) in DMF or an equivalent solvent in the temperature range between 20 to 100 ° C, preferably 20 to 50 ° C, with (C ₁ -C ₆ ) alkyl isocyanates, preferably Ethyl isocyanate, a base and a deprotonating agent, preferably phosphazene base P ₁ -tBu, to give compounds of the general formula (EI)
  implements.
  Preferred embodiment of (EI) is compound (EII)
  which is obtained by reacting compound (DI), in which R ^{CI, 1 is} methyl, with ethyl isocyanate.
  The method described above can also be applied to polyols. A preferred polyol in the context of the invention is compound (EIII)
  which is obtained by compound (BIII) in a polar, aprotic solvent, preferably an ether, for example 1,4-dioxane, in the presence of an acid, preferably a hydrohalic acid, for example hydrochloric acid, at elevated temperature, preferably at a temperature close to Boiling temperature of the mixture, which is subjected to acetal cleavage to (EIII), and (EIII) is subsequently reacted as described above with (C ₁ -C ₆ ) alkyl isocyanates.
  As preferred embodiments, the compounds (EIV) and (EV) are obtained using ethyl isocyanate.
  
• 6. [F] the compound of formula (EIII) a mixture of polar solvents, preferably a mixture of acetonitrile and an ether, preferably tetrahydrofuran, under Mitsunobu conditions in the presence of an azodicarboxylic acid ester, preferably diethyl azodicarboxylate, and a condensing agent, preferably triphenylphosphine, and a base, preferably DBU, in the temperature range from room temperature to the boiling point of the mixture to (FIII)
  cyclized;
• 7. [G] compounds of the formula (FIII) as described under [E] with (C ₁ -C ₆ ) -alkyl isocyanates to give compounds of the general formula (GI)
  converts, wherein R ^{GI, 1 can represent} (C ₁ -C ₆ ) alkyl;
  in a preferred embodiment of (GI) R ^{GI, 1 represents} the ethyl group;
• 8. [H] compounds of the general formula (HI)
  wherein R ^{HI, 1 is} hydrogen or a hydroxy protecting group, preferably hydrogen and R ^{HI, 2 is} a leaving group, for example a halogen atom, preferably bromine, in DMF or an equivalent solvent with trialkylstannylpyridines, for example tri methylstannylpyridines in the presence of reducing agents such as for example palladium (II) complexes, preferably bis (triphenylphosphine) palladium (II) chloride, and a base, preferably di-isopropylethylamine, (DiPEA) to give compounds of the general formula (HII)
  reacted; a particularly preferred embodiment of the compounds (HII) is the compound (HIII)
  
• 9. [J] compound (HIII) in DMF or an equivalent solvent in the temperature range between 20 to 100 ° C, preferably 20 to 50 ° C, with (C ₁ -C ₆ ) alkyl isocyanates, preferably ethyl isocyanate, a base and a deprotonating agent, preferably phosphazene base P ₁ -tBu, to compounds of the general formula (HIV)
  converts, wherein R is ^{HIV, 1} preferably represents the ethyl group;
  or
  Compound (HIII) dissolved in a mixture of an inert hydrocarbon and an ether, preferably a mixture of benzene and tetrahydrofuran, in the temperature range from room temperature to boiling temperature of the mixture, first reacted with diphosgene, then the solvent was removed and the intermediate product dissolved in a halogenated hydrocarbon , preferably dichloromethane, with (C ₁ -C ₆ -) - alkylamines dissolved in an ether, preferably tetrahydrofuran, to give compounds (HIV), according to this process a particularly preferred embodiment of (HIV), in the RHIV, 1 for the Methyl group is obtained.

The processes for the preparation of the compounds according to the invention are described by the formula scheme below:

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. Dimethylformamide (DMF) is preferred.

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 IFNFα 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, intra muscular or intraperitoneal).

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 to 100% by weight. available; the concentration of the active ingredient should preferably be 0.5 to 90% by weight, i.e. H. in amounts that are sufficient, the indicated dose to achieve scope.

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 to deviate from the quantities mentioned give way, depending on body weight, application route, indi vidual behavior towards the active ingredient, type of preparation and time 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 × 105 cells / well in a 96-well microtiter plate (Falcon / Becton Dickinson, Lincoln Park, NJ 07035, Microtest III, Tissue Culture 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. Subsequently, 150 μl of culture medium, the test substance, are dissolved in 50 μl of culture medium and 50 μl of lipopolysaccharide (LPS) solution (0.5 μg / ml of LPS in culture medium: Escherichia coli Serotype 0111: B4 from Fa. 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 An were determined by the manufacturer. The TNFα synthesis inhibition can in this way depending on the concentration of the test substance used voices. The concentration of the test substance, which is a half-maximum TNFα Synthesis inhibition (ECSO) is caused by the corresponding dose-response 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. That comes from My blood was centrifuged at 1400 rpm for 10 minutes to collect serum.  

Using a TNF ELISA from R, the TNF content determined.

Table 2

LPS mouse: inhibition of TNF release

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

Example No. 10 in the ApoE knockout mouse model

Abbreviations

abs .: absolutely
Ac: acetyl
aq .: watery
Boc: tert-butoxycarbonyl
Bu: butyl
CDI: N, N'-carbonyldiimidazole
TLC: thin layer chromatography
DCC: N, N'-dicyclohexylcarbodiimide
DEAD: diethyl azodicarboxylate
dist .: 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
RF: retention index (for DC)
RT: room temperature
subl .: sublimed
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 = 10: 1
B = cyclohexane: ethyl acetate = 2: 1
C = dichloromethane: methanol = 3: 1
D = dichloromethane: methanol = 30: 1
E = dichloromethane: methanol = 20: 1

starting compounds Example I

(5-R, S) -5-hydroxymethyl-3- (5-pyridin-4-yl-thiophen-2-yl) oxazolidin-2-one

3.56 g (12.8 mmol) of 3- (5-bromo-thiophene-2-yl) - (5-R, S) -5-hydroxymethyl-oxazolidin- 2-one (synthesis of the corresponding enantiomerically pure (5R) - Starting material: B. Riedl, D. Häbich, A. Stolle, H. Wild, R. Endermann, K.-D. Bremm, H.-P. Kroll, H. Labischinski, K. Schauer and H.-O. Werling , EP 693 491.) are made under argon in 30 mL of anhydrous DMF with 4.03 g (16.6 mmol) of freshly prepared 4-trimethylstannyl-pyridine (synthesis: JE Phillips, RH Herber, J. Organomet. Chem. 268, 39 (1984).), 0.72 g (1.0 mmol) of bis (triphenylphosphine) palladium (II) chloride and 2.48 g (19.2 mmol) of di-isopropylethylamine (DiPEA) and Stirred at 100 ° C for 6 hours. The DMF is then evaporated in a high vacuum, the residue is taken up twice in toluene and evaporated again and the material thus obtained is separated into its components by chromatography (silica gel 60, Merck, dichloromethane: methanol = 200: 1 to 30: 1); 2.58 g (73%) of product are obtained.
Rf = 0.24 (A).
MS (ESI positive): m / z = 277 (100%, [M + H] +).

Example II

3- (5-pyridin-4-yl-thiophen-2-yl) - (5-R, S) -5-trityloxymethyl-oxazolidin-2-one

1.40 g (5.1 mmol) of the compound of Example I are dissolved in 25 ml of anhydrous DMF, mixed with 0.62 g (6.1 mmol) of TEA and 1.55 g (5.6 mmol) of trityl chloride and Stirred at 80 ° C for 18 hours. Due to incomplete conversion, 0.5 mL TEA was added and stirring was continued at 80 ° C for 92 hours. The solvent is then evaporated in a high vacuum, the residue is taken up with buffer solution of pH = 7 and dichloromethane and extracted. The aqueous phase is extracted several times with dichloromethane and the undissolved material is sucked off (re-insulated starting material). The combined organic phases are washed with saturated sodium chloride solution, dried with sodium sulfate and evaporated. The material thus obtained is purified by chromatography (silica gel 60, Merck, dichloromethane: methanol = 120: 1); 0.73 g (28%) of product are obtained.
Rf = 0.52 (A).
MS (ESI positive): m / z = 519 (100%, [M + H] +).

Analogously to the procedure of Example II, the compounds of Table 1 manufactured.  

Table 1

Example IV

5- (pyridin-4-yl) -thiophene-2-carboxylic acid methylester

20.78 g (94.0 mmol) of 5-bromo-thiophene-2-carboxylic acid are mixed under argon in 170 mL of anhydrous DMF with 22.74 g (94.0 mmol) of 4-trimethylstannyl-pyridine (synthesis: JE Phillips, RH Herber, J. Organomet. Chem. 268, 39 (1984).), 5.28 g (7.5 mmol) bis (triphenylphosphine) palladium (II) chloride and 18.22 g (141.0 mmol) DiPEA was added and the mixture was stirred at 100 ° C. for 93 hours. The DMF is then removed in a high vacuum and the residue is taken up in toluene and evaporated again under the same conditions. The material thus obtained is separated into its components by chromatography (silica gel 60, Merck, cyclohexane: ethyl acetate = 12: 1 to 1: 1); 7.3 g (35%) of product are obtained.
Rf = 0.09 (B).
MS (ESI positive): m / z = 220 (100%, [M + H] +).

Example V

5- (pyridin-4-yl) -thiophene-2-carboxylic acid

7.2 g (32.8 mmol) of the compound from Example IV are dissolved in 420 mL of methanol, mixed with 164 mL (164 mmol) of 1 M aqueous sodium hydroxide solution and stirred at 24 ° C. for 1.5 hours. The reaction mixture is sucked through a glass frit and the filtrate is evaporated in vacuo. The evaporation residue in water is mixed with 160 ml of 1 M hydrochloric acid and the mixture is then diluted with an aqueous buffer solution of pH = 4. The resulting precipitate is filtered off, washed several times with water and dried over Sicapent in a high vacuum; Yield: 5.7 g (85%).
Rf = 0.11 (C).
MS (ESI positive): m / z = 206 (100%, [M + H] +).

Example VI

(Curtius rearrangement via activation with chloroformic acid ester) [5- (pyridin-4-yl) -thiophene-2-yl] -carbamic acid-2-benzyloxy-ethyl ester

0.92 g (4.5 mmol) of the compound of Example V are anhydrous in 35 mL Acetone submitted and mixed with 1.22 g (12.1 mmol) TEA. The mixture is on -18 ° C cooled and dropwise with a solution of 1.70 g (15.7 mmol) of chlorine ethyl formate stirred in 5 mL acetone. After the addition, 15 minutes stirred at 0 ° C. At this temperature, a solution is pre-cooled to 0 ° C 1.31 g (10.2 mmol) of sodium azide were added dropwise in 5 ml of water and a further 30 Minutes stirred. The reaction mixture thus obtained is made up to 200 mL  Mix the mixture of ice water and buffer solution (pH = 7) and pour it several times Toluene extracted. The aqueous phase is mixed with saturated sodium chloride solution sets and extracted again with toluene. The combined organic phases are dried with magnesium sulfate, filtered (acyl azide solution) and without Ein vapor further implemented.

1.02 g (6.7 mmol) of 2-benzyloxyethanol are refluxed in 100 ml of toluene is heated and the acyl azide solution is added dropwise while stirring. After finished Addition and gas evolution, the reaction mixture is another 3 hours boiled under reflux and then evaporated. The material obtained becomes chromatographic purification in a mixture of dichloromethane and methanol (60: 1) dissolved, with undissolved material suctioned off, with dichlor methane: methanol = 60: 1 washed and be in a high vacuum of residual solvents is freed; Yield: 0.39 g (25%) product.

The dissolved material is separated into its components by chromatography (Kieselgel 60, Merck, dichloromethane: methanol = 60: 1); there are a further 0.55 g (35%) of product.
Rf = 0.16 (D).
MS (DCI, NH3): m / z = 355 (100%, [M + H] +).

Analogously to the procedure of Example VI, the compounds of Table 2 manufactured.  

Table 2

Example VIII

Methyl [5- (pyridin-4-yl) -thiophene-2-yl] -carbamic acid 2-benzyloxy-ethyl ester

0.35 g (1.0 mmol) of the compound of Example VI are dissolved in 10 mL of anhydrous DMF, 0.03 g (1.0 mmol) of 80% sodium hydride are added at 23 ° C. and the mixture is stirred 15 minutes after the evolution of gas has ended , 0.17 g (1.2 mmol) of iodomethane are then added and the mixture is stirred at 23 ° C. for one hour. After the reaction mixture has been evaporated under high vacuum, the residue is partitioned between water and dichloromethane and the aqueous phase is extracted twice more with dichloromethane. The combined organic extracts are washed with saturated aqueous sodium chloride solution, dried with sodium sulfate and evaporated. The material obtained is purified by chromatography (silica gel 60, Merck, dichloromethane: methanol = 300: 1 to 60: 1); 0.158 g (43%) of product are obtained.
Rf = 0.40 (D).
MS (DCI, NH3): m / z = 369 (100%, [M + H] +).

Example IX

[5- (pyridin-4-yl) -thiophene-2-yl] -carbamic acid 2-hydroxy-ethyl ester

0.41 g (1.1 mmol) of the compound of Example VI are dissolved in 60 ml of dichloromethane and stirred at -10 ° C. with 5.73 ml (5.7 mmol) of a 1 M boron tribromide solution in dichloromethane. After 30 minutes, buffer solution of pH = 7 is slowly added dropwise at 0 ° C. and saturated sodium chloride solution is added. The aqueous phase (pH = 3) is extracted with dichloromethane and the organic phase 1 obtained is discarded. The aqueous phase is neutralized with 1 M sodium hydroxide solution and buffer solution of pH = 7 and extracted with dichloromethane (organic phase 2). The aqueous phase is then salted out with sodium chloride and extracted again with dichloromethane (organic phase 3). The organic phases 2 and 3 are dried separately with sodium sulfate, evaporated and freed from residual solvent in a high vacuum; the yields are: 0.11 g (36%) from the organic phase 2 and 0.12 g (39%) from the organic phase 1. Both batches prove to be products.
Rf = 0.19 (A).
1H-NMR (d6-DMSO, 200 MHz, TMS): = 3.64 (2H), 4.18 (2H), 4.88 (1H), 6.60 (1H), 7.49-7.57 (3H), 8.48 (2H), 11.09 (1H ) ppm.

The compounds of Table 3 are prepared analogously to the procedure of Example IX posed.  

Table 3

Example XI

[5- (Pyridin-4-yl) thiophene-2-yl] carbamic acid 3-hydroxy-2-hydroxymethyl propyl ester hydrochloride

1.60 g (4.4 mmol) of the compound of Example VII are stirred in 60 ml of 1,4-dioxane with 2 ml of 6 M hydrochloric acid at 90 ° C. for 16 hours. The reaction mixture is cooled and the precipitate obtained is suction filtered, washed with 1,4-dioxane and dried over Sicapent in a high vacuum; Yield: 1.33 g (86%).
Rf = 0.10 (A).
MS (ESI positive): m / z = 309 (100%, [M + H] +).

To determine the HCl content twice, 3.86 mg and 1.74 mg of the Product each in a mixture of 2 mL ethanol and 3 mL Milli Q water dissolves and titrated with 0.01 M aqueous sodium hydroxide solution. The volume consumed Alkali is 1.17 mL and 0.538 mL, which results in an HCl content of 105% and 106% calculated.  

Example XII

(5-R, S) -5-hydroxymethyl-3- [5- (pyridin-4-yl) -thiophene-2-yl] - [1,3] oxazinan-2-one

1.23 g (3.6 mmol) of the compound of Example XI are preformed in 60 mL acetonitrile placed with stirring with 0.65 g (3.7 mmol) DEAD, 0.98 g (3.7 mmol) triphenyl phosphine and 0.54 g (3.6 mmol) of DBU and for better dissolution with 60 mL THF stirred. After stirring for 64 hours at 24 ° C again 60 mL THF added and stirred for a further 5 hours at 70 ° C; on it another 0.33 g (1.9 mmol) of DEAD and 0.49 g (1.9 mmol) of triphenylphosphine added give and stirred at 70 ° C for 22 hours. The reaction mixture is evaporated, taken up with water and extracted several times with ethyl acetate. The ver United organic extracts are made with saturated sodium chloride solution extracted, dried with sodium sulfate and evaporated. The material thus obtained is purified by chromatography (Kieselgel 60, Merck, dichloromethane: methanol 150: 1 to 10: 1); Fraction 1 (0.383 g, 37%) and fraction 2 (0.448 g, 41%) fall on.

Fraction 1 turns out to be example XII.
Rf = 0.21 (A).
MS (DCI, NH3): m / z = 291 (100%, [M + H] +).

Fraction 1 turns out to be the starting material.  

Preparation Examples Example 1, 2 (Diphosgene method)

(5-R, S) -5-chloromethyl-3- (5-pyridin-4-yl-thiophen-2-yl) -oxazolidin-2-one (Example 1) and methyl-carbamic acid-2-oxo-3- (5-pyridin-4-yl-thiophene-2-yl) oxazolidin (5- R, S) -5-yl methyl ester (Example 2)

0.33 g (1.2 mmol) of the compound of Example I are in 15 mL of benzene and 15 mL THF mixed with 0.24 g (1.2 mmol) diphosgene and first at 3 hours 26 ° C, then stirred at 60 ° C for 8 hours. The reaction mixture is evaporated, the material obtained was taken up in dichloromethane, at 0 ° C. with 6 ml (12.0 mmol) 2 M methylamine solution in THF and ge for 18 hours at 26 ° C. stir. After the addition of dichloromethane is successively with buffer solution from pH = 4, extracted with water and with saturated sodium chloride solution. The organic phase is dried with sodium sulfate and evaporated. So he held material is cleaned chromatographically (silica gel 60, Merck, dichlor methane: methanol = 60: 1 to 20: 1); fraction 1 (0.053 g, 15%), fraction 2 falls (0.126 g, 32%) and fraction 3 (0.058 g, 18%).

Fraction 1 proves to be a chlorine compound, example 1.
Rf = 0.40 (A).
MS (DCI, NH3): m / z = 295, 297 (100%, 42%, [M + H] +).

Fraction 2 proves to be carbamate, example 2.
Rf = 0.28 (A).
MS (DCI, NH3): m / z = 351 (21%, [M + NH4] +), 334 (100%, [M + H] +).

Fraction 3 proves to be the starting material.

The compounds in Table 4 are prepared analogously to the instructions in Example 1 posed.

Table 4

Example 4 (Isocyanate method)

Ethyl carbamic acid 2-oxo-3- (5-pyridin-4-yl-thiophene-2-yl) oxazolidine (5-R, S) -5-yl methyl ester

0.20 g (0.7 mmol) of the compound of Example I are dissolved in 5 mL DMF, with 0.06 g (0.9 mmol) of ethyl isocyanate and g (mmol) of N '''- tert-butyl-N, N, N ', N', N ", N" - hexamethylphosphorimidic acid triamide (phosphazene base P1-tBu) were added and the mixture was stirred at 23 ° C. for 5 hours. Then g (mmol) of phosphazene base P1-tBu are added and the mixture is stirred at 40 ° C. for a further 1.5 hours. The reaction mixture is poured into water and dichloromethane and the aqueous phase is subsequently extracted with dichloromethane. The combined organic phases are dried with sodium sulfate and evaporated. The material obtained in this way is purified by chromatography (silica gel 60, Merck, dichloromethane: methanol = 60: 1); 0.12 g (47%) of product are obtained.
Rf = 0.29 (A).
MS (DCI, NH ₃ ): m / z = 365 (39%, [M + NH4] +), 348 (100%, [M + H] +),

Analogously to the instructions in Example 4, the compounds in Table 5 are obtained provides.

Table 5

Example 10, 11

Methyl-carbamic acid-2-oxo-3- (5-pyridin-4-yl-thiophene-2-yl) -oxazolidin (5-R) -5-yl-methyl ester (enantiomer A / example 10) and methyl-carbamic acid -2-oxo-3- (5-pyridin-4-yl-thiophene-2-yl) oxazolidin (5-S) -5-yl methyl ester (enantiomer B / example 11)

0.11 g (0.3 mmol) of the compound of Example 2 are dissolved in 20 mL ethanol and via the following preparative HPLC system (Table 6) into the enantiomers separates. The purity is checked using the analytical HPLC system (Table 7).  

Table 6

Preparative HPLC parameters

Table 7

Analytical HPLC parameters

45 mg (mmol) of enantiomer A (Example 10) and 52 mg (mmol) Enantiomer B (Example 11). Enantiomer A is compared to a Sample prepared from enantiomerically pure precursors as the R enantiomer identified.  

Enantiomer A (Example 12)

Content <98.5%.

Enantiomer B (Example 13)

Content <97.0%.

Analogous to the regulation of the enantiomer separation of Examples 10, 11, the Obtain compounds of Table 8.

Table 8

Claims (7)

1. Compounds of the general formula (I)
in the
a, b can represent a heteroatom selected from S, N, or O, or the group CH,
and in the
R ¹ , R ^{2 can} independently represent hydrogen or a hydrocarbon radical such as alkyl which can be substituted by groups selected from hydroxyl, alkoxy, alkoxycarbonyl,
and in the
one of the radicals R ¹ , R ² for a group
can stand
and in the
R ¹ and R ² together, including the nitrogen atom to which they are bound, form a radical (R4)
can form, in which m can assume the values 0 or 1,
in which
R ^{3 can} stand for a hydrocarbon residue,

• - R ³ can be alkyl which can be mono- or polysubstituted with hydroxy, alkoxy, wherein said alkyl and alkoxy in turn can be substituted with an aromatic hydrocarbon
• - R ³ can be alkyl which in turn can be substituted one or more times with radicals (R3a)
  
• R ³ can represent a saturated or partially unsaturated heterocycle which in turn can be substituted by alkyl,

in which
R ^3.1 and R ^{3.2 can} independently represent hydrogen or a hydrocarbon radical, preferably alkyl;

• R ^4.1 can represent halogen, preferably chlorine, hydroxy, alkoxy, a group (R4.2)
  

wherein
X, Y can stand for nitrogen and / or oxygen and if Y stands for oxygen, R ^{4,2,2 is} omitted,
wherein
R ^4.2.1 and R ^4.2.2 independently of one another are hydrogen, alkyl, alkyl which in turn can be substituted, or alkoxycarbonyl,
and their salts and S-oxides. 2. Compounds of the general formula (I),) in which
a, b can represent nitrogen or CH,
and in those
R ¹ , R ² independently of one another are hydrogen or a hydrocarbon radical, preferably (C ₁ -C ₆ ) -alkyl, which in turn can be substituted one or more times with groups selected from hydroxy, (C ₁ -C ₆ ) -alkoxy, (C ₁ -C ₆ ) alkoxycarbonyl,
and in those
one of the radicals R ¹ , R ² for a group
can stand
and in those
R ¹ and R ² together, including the nitrogen atom to which they are bound, form a radical (R4)
can form, in which m can assume the values 0 or 1,
in which
R ³ can represent a hydrocarbon radical, preferably (C ₁ -C ₆ ) alkyl, benzyl,

• R ^{3 can} stand for (C ₁ -C ₆ ) alkyl which in turn can be mono- or polysubstituted with hydroxy, alkoxy, said (C ₁ -C ₆ ) alkyl and said (C ₁ -C ₆ ) - Alkoxy in turn can be substituted with an aromatic hydrocarbon, preferably phenyl,
• - R ³ can represent (C ₁ -C ₆ ) alkyl which in turn can be substituted one or more times with radicals (R3a)
  
• R ³ can represent a saturated or partially unsaturated heterocycle which in turn can be substituted by (C ₁ -C ₆ ) alkyl,

in which
R ^3.1 and R ^{3.2 can} independently represent hydrogen or a hydrocarbon radical, preferably (C ₁ -C ₆ ) alkyl;

• R ^{4.1 can} stand for halogen, preferably chlorine, hydroxy, (C ₁ -C ₆ ) alkoxy, a group (R4.2)
  

wherein
X, Y can stand for nitrogen and / or oxygen and if Y stands for oxygen, R ^{4,2,2 is} omitted,
wherein
P ^4.2.1 and R ^4.2.2 independently of one another for hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkyl which in turn can be substituted, (C ₁ -C ₆ ) -Alkoxy carbonyl, can stand
and their salts and S-oxides. 3. Compounds of the general formula (I) in which
a, b can represent nitrogen or CH,
and in those
R ¹ , R ² independently of one another represent hydrogen or a hydrocarbon radical, preferably (C ₁ -C ₄ ) -alkyl, which in turn can be substituted one or more times with groups selected from hydroxy, (C ₁ -C ₄ ) -alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl,
and in those
one of the radicals R ¹ , R ² for a group can stand
and in those
R ¹ and R ² together, including the nitrogen atom to which they are bound, form a radical (R4)
can form, in which m can assume the values 0 or 1,
in which
R ³ can represent a hydrocarbon radical, preferably (C ₁ -C ₄ ) alkyl, benzyl,

• R ^{3 can} stand for (C ₁ -C ₄ ) alkyl which in turn can be substituted one or more times with hydroxy, alkoxy, said (C ₁ -C ₄ ) alkyl and said (C ₁ -C ₄ ) Alkoxy in turn can be substituted with an aromatic hydrocarbon, preferably phenyl,
• - R ³ can represent (C ₁ -C ₄ ) alkyl which in turn can be substituted one or more times with radicals (R3a)
  
• R ³ can represent a saturated or partially unsaturated heterocycle which in turn can be substituted by (C ₁ -C ₄ ) alkyl,

in which
R ^3.1 and R ^{3.2 can} independently represent hydrogen or a hydrocarbon radical, preferably (C ₁ -C ₄ ) alkyl;

• R ^{4.1 can} stand for halogen, preferably chlorine, hydroxy, (C ₁ -C ₄ ) alkoxy, a group (R4.2)
  

wherein
X, Y can stand for nitrogen and / or oxygen and if y stands for oxygen, R ^{4,2,2 is} omitted,
wherein
R ^4.2.1 and R ^4.2.2 independently of one another for hydrogen, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkyl which in turn can be substituted, (C ₁ -C ₄ ) -Alkoxy carbonyl, can stand
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 Her provision of medicines. 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 ver Changes such as liver fibrosis or generalized autoimmune disease 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.