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  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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• • A—HUMAN NECESSITIES
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  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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  • A61P35/00—Antineoplastic agents
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  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the invention relates to the use of pyrimidine-4,6-dicarboxylic acid diamides for the selective inhibition of collagenase (MMP 13).
• MMP 13 collagenase
• MMPs matrix metalloproteinases
• CMOS matrix metalloproteinases
• a large number of different inhibitors of MMPs or collagenases are known (EP 0 606 046, WO 94/28888). Disadvantages of the known inhibitors of MMPs are often the lack of specificity of inhibition for only one class of MMPs.
• MMP inhibitors inhibit multiple MMPs simultaneously because the MMP's catalytic domain has a similar structure. Consequently, the inhibitors undesirably affect many enzymes, including those with vital function (Massova I., et al., The FASEB Journal (1998) 12, 1075-1095).
• WO 02/064571 describes pyrimidine-4,6-dicarboxylic acid and pyrimidine-4,6-dicarboxylic acid derivatives and their selective inhibition of MMP 13. Also in EP 0418797 Pyrimidine-4,6-dicarboxylic acid derivatives described and their inhibitory effect on proline hydroxylase. The inhibition of pyrimidine-4,6-dicarboxylic acid could be confirmed in own experiments. Disadvantage of the compounds described in WO 02/064571 and EP 0418797, it is therefore that the collagen biosynthesis is also inhibited by the inhibition of proline hydroxylase and a non-functional, underhydroxylated collagen molecule is formed, which of the cells only in small amount can be discharged into the extracellular space.
• the invention therefore relates to the use of compounds of the formula I.
• R 1 is hydrogen or - (C 1 -C 3) -alkyl
• R 2 is - (C 1 -C 6) -alkyl, where alkyl is monosubstituted, disubstituted or trisubstituted by
• R 14 and R 15 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered saturated ring, wherein one or two further carbon atoms also have a Heteroatom from the series oxygen, sulfur and nitrogen may be and in the case of nitrogen, the nitrogen atoms may be independently unsubstituted or substituted by - (Cj-CgJ-alkyl,
• R10 are the same or different and independently of one another denote 3.41) hydrogen or 3.42) - (C -] - Cs) -alkyl or R9 and R10 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered one form a saturated ring, wherein for one or two further carbon atoms also a heteroatom from the series oxygen, sulfur and nitrogen may be and in the case of nitrogen, the nitrogen atoms may be independently unsubstituted or substituted by (G] -Cö) alkyl, 3.5) -O- (C 2 -C 6 ) -alkyl-N (R 9) -R 10, wherein R 9 and R 10 have the abovementioned meaning,
• Het wherein Het is a saturated or unsaturated monocyclic or bicyclic 3- to 10-membered heterocyclic ring system containing 1, 2 or 3 identical or different ring heteroatoms from the nitrogen, oxygen and sulfur series and unsubstituted or on or is substituted several times by
• alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen,
• Another object of the invention is the use of the compounds of formula I, wherein
• R1 is hydrogen or - (Ci-G-j-alkyl
• R 2 is - (C 1 -C 4) -alkyl, where alkyl is monosubstituted, disubstituted or trisubstituted by
• R 14 and R 15 together with the nitrogen atom to which they are attached, form a 5-, 6- or 7-membered saturated ring, with one or two further carbon atoms as well a heteroatom from the series oxygen, sulfur and nitrogen can be and in the case of
• Nitrogen the nitrogen atoms may be unsubstituted or substituted by - (0] -C4) -alkyl,
• R 9 and R 10 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered saturated ring, it also being possible for one or two further carbon atoms to stand for an oxygen, sulfur and nitrogen heteroatom and Trap of nitrogen, the nitrogen atoms may be independently unsubstituted or substituted by (C -) - C4) -alkyl,
• alkyl is unsubstituted or mono-, di- or trisubstituted by halogen, 4.7) pyridyl or
• phenyl is unsubstituted or monosubstituted and polysubstituted and independently of one another by a radical selected from halogen, - (C -) - C4) -alkoxy and - (G
• R3, R4, R5, R6 and R7 are the same or different and for
• alkyl is unsubstituted or mono-, di- or trihydric
• R 1 is hydrogen
• R 2 is - (O-C 2) -alkyl, wherein alkyl is monosubstituted, disubstituted or trisubstituted by
• phenyl wherein phenyl is mono-, di- or trisubstituted independently of each other
• Het wherein Het is furan, imidazole, isothiazole, isoxazole, oxazole, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, 1,2,3-triazole or 1,2,4-
• Triazole and Het is unsubstituted or mono- or trisubstituted independently of each other is substituted by
• alkyl is unsubstituted or mono-, di- or trisubstituted by halogen
• alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen,
• phenyl is unsubstituted or mono- or polysubstituted and independently of one another by a radical selected from halogen, - (C -) - C4) -alkoxy and - (C-
• R3, R4, R5, R6 and R7 are the same or different and for
• R1 is hydrogen atom or - (C-
• R 2 is - (C 1 -C 4) alkyl, wherein alkyl is mono-, di- or trisubstituted by 1 -C (O) -O-R 8, where R 8
• 2.1) is hydrogen or 2.2) - (G] -C6) -alkyl
• 3.11) is hydrogen or 3.12) - (C 1 -C 6) -alkyl
• R 14 and R 15 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered saturated ring, wherein for one or two Further carbon atoms can also be a heteroatom from the series oxygen, sulfur and nitrogen and in the case of nitrogen, the nitrogen atoms can be independently unsubstituted or substituted by (C -] - Cg) alkyl, 3.4) - (CH) kN (R9 ) - (R10) wherein k is 2, 3, 4 or 5 and R9 and
• R10 are the same or different and are independently of one another 3.41) hydrogen or 3.42) - (G] -C5) -alkyl or
• R 9 and R 10 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered saturated ring, it also being possible for one or two further carbon atoms to stand for an oxygen, sulfur and nitrogen heteroatom and Trap of nitrogen, the nitrogen atoms may be unsubstituted independently or substituted by (Ci-CgJ-alkyl,
• alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by
• Het wherein Het is a saturated or unsaturated monocyclic or bicyclic, 3- to 10-membered heterocyclic ring system containing 1, 2 or 3 identical or different ring heteroatoms from the series nitrogen, Contains oxygen and sulfur and is unsubstituted or mono- or polysubstituted by
• alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen,
• R3, R4, R5, R6 and R7 are the same or different and are each independently of one another the first hydrogen atom, the second halogen,
• alkyl is unsubstituted or mono-, di- or trisubstituted by
• Halogen is substituted, or 5.
• -C) -Alky I stand.
• Another object of the invention is the compound of formula I, wherein R 1 is hydrogen or R 2 is - (C 1 -C 4) -alkyl, where alkyl is monosubstituted, disubstituted or trisubstituted by
• R 14 and R 15 together with the nitrogen atom to which they are attached, form a 5-, 6- or 7-membered saturated ring derived from imidazolidine, isothiazolidine, isoxazolidine, morpholine , Piperazine, piperidine, pyrazine, pyrazolidine, pyrrolidine, tetrazine or thiomorpholine, where the nitrogen atoms may each be unsubstituted or substituted by - (O-C4) -alkyl, 3.4) - (CH 2 ) kN (R 9) - (R10) wherein k is 2, 3 or 4 and R9 and
• R 10 are the same or different and independently of one another denote 3.41) hydrogen or 3.42) - (G] -C 4 ) -alkyl or
• R 9 and R 10 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered saturated ring of imidazolidine, isothiazolidine, isoxazolidine, morpholine, piperazine, piperidine, pyrazine, pyrazolidine, pyrrolidine, tetrazine or Derive thiomorpholine, the Nitrogen atoms may each be unsubstituted or substituted by - (G] - (- 4) -alkyl,
• alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by
• Het wherein Het-azepine, azetidine, aziridine, benzimidazole, benzo [1,4] dioxin, 1, 3-benzodioxole, benzofuran, 4H-benzo [1,4] oxazine, benzoxazole, benzothiazole, benzothiophene, quinazoline, Quinoline, quinoxaline, chroman, cinnoline, oxirane, 1,2-diazepine, 1, 3-diazepine, 1, 4-diazepine, 1,4-dioxin, dioxole, furan, imidazole, indazole, indole, isoquinoline, isochroman, isoindole , Isoxazole, isothiazole, 1,2-
• R3, R4, R5, R6 and R7 are the same or different and represent, for the 1st hydrogen atom, 2nd halogen,
• alkyl is unsubstituted or mono-, di- or trisubstituted by
• Halogen is substituted, or
• alkyl is unsubstituted or mono-, di- or trisubstituted by halogen.
• Another object of the invention is the compound of formula I, wherein
• R1 is hydrogen
• R 2 is - (C -) - C 2) -alkyl, where alkyl is monosubstituted, disubstituted or trisubstituted by 1-phenyl in which phenyl is monosubstituted, disubstituted or trisubstituted independently of one another
• R 9 and R 10 together with the nitrogen atom to which they are attached form a radical derived from imidazolidine, isothiazolidine, isoxazolidine, morpholine, piperazine, piperidine, pyrazine, pyrazolidine,
• Pyrrolidine, tetrazine or thiomorpholine derived can and in the case of nitrogen, the nitrogen atoms are unsubstituted or independently of one another by - may be substituted (C j -G ⁇ alkyl,
• alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by
• Het wherein Het is furan, imidazole, isothiazole, isoxazole, oxazole, pyrazole,
• R3, R4, R5, R6 and R7 are the same or different and for
• halogen is meant fluorine, chlorine, bromine or iodine.
• linear and branched hydrocarbon radicals may be methyl, ethyl, propyl, i-propyl, butyl, tert-butyl, pentyl or hexyl
• cyclic groups may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl
• a combination of linear and cyclic radicals may cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl.
• R4 and R5 or R5 and R6 together with the carbon atoms to which they are respectively attached form a 5- or 6-membered ring which is aromatic or saturated and zero, one or two heteroatoms selected from oxygen, nitrogen or Sulfur contains "radicals are understood, for example, of dioxolane, pyrrole, pyrrolidine, pyridine, piperidine, dioxane, tetrahydropyridine, pyrazole, imidazole, pyrazoline, imidazoline, pyrazolidine, imidazolidine, pyridazine, pyrimidine, pyrazine, piperazine, pyran, furan, dihydrofuran , Tetra hydrofuran, oxazole, isoxazole, 2-isoxazoline, isoxazolidine, morpholine, oxothiolane, thiopyran, thiazole, isothiazole, 2-isothiazoline, isothia
• Biphenylyl radicals, naphthyl radicals and, in particular, phenyl radicals are preferred aryl radicals.
• Het is understood to mean a saturated or unsaturated monocyclic or bicyclic, 3- to 10-membered heterocyclic ring system which contains 1, 2 or 3 identical or different ring heteroatoms from the series consisting of nitrogen, oxygen and sulfur monocyclic or bicyclic
• Ring system may be a 3-, 4-, 5-, 6- or 7-membered ring.
• bicyclic Het two rings may be linked together, one of which may be a 5-membered or 6-membered heterocyclic ring and the other may be a 5- or 6-membered heterocyclic or carbocyclic ring.
• a bicyclic Het group may be selected from 8, 9 or
• Het includes saturated heterocyclic ring systems which do not have a double bond in the rings and also unsaturated heterocyclic ring systems including monounsaturated and polyunsaturated heterocyclic ring systems which have one or more double bonds and form a stable ring system.
• Unsaturated rings can be
• Het group are identical or different heteroatoms from the series nitrogen, oxygen and sulfur.
• heterocycles from which the het group can be derived are the radicals acridinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,
• pyridyl such as 2-pyridyl, 3-pyridyl or 4-pyridyl
• pyrrolyl such as 2-pyrrolyl and 3-pyrrolyl
• furyl such as 2-furyl and 3-furyl
• thienyl such as 2-thienyl and 3-thienyl
• Suitable nitrogen heterocycles may also be present as N-oxides or as quaternary salts in which a suitable nitrogen atom is alkylated by - (C 1 -C 4) -alkyl radicals.
• het groups may be unsubstituted or substituted according to the definitions given.
• osteoarthrosis is understood to mean a disease that arises predominantly in the case of a mismatch between the stress and load capacity of the individual joint parts and joint tissue, which is associated with an increasing cartilaginous destruction and is predominantly non-inflammatory , Demarcation or hyalinization, followed by reactive changes in the subchondral bone as well as capsular changes
• pondylosis is understood to mean arthrosis of the vertebral bodies, which is characterized by a noninflammatory loss of cartilage in the vertebral bodies and intervertebral discs.
• the compounds of the formula I can be prepared, for example, by reacting a compound of the formula II
• R1, R2, R3, R4, R5, R6 and R7 are those indicated in formula I.
• Y is halogen, hydroxyl or G
• Carbonyl group forms an active ester or a mixed anhydride and the compound of formula IVa or IVb optionally purifies and then converted with a compound of formula IIIa or IIIb in a compound of formula I.
• the preparation of the compounds according to the invention is most simply achieved by combining the two components, the pyrimidine derivative of the formula (II) and the amine of the formula IIIa or IIIb, in equimolar amounts and at temperatures from -30.degree. C. to 150.degree. preferably be reacted at 20 ° C to 100 ° C to give compound of formula IVa or IVb and then the compounds of formula IVa or IVb are reacted with up to an equimolar amount of the amine of formula IIIb or IIIa in an analogous manner.
• the termination of the reaction can be determined, for example, by thin-layer chromatography or HPLC-MS.
• a variant of this method is that in a suitable solvent, such as diethyl ether, dimethoxyethane or tetrahydrofuran, chlorinated hydrocarbons such as methylene chloride, chloroform, tri-nor tetrachlorethylene ,.
• chlorinated hydrocarbons such as methylene chloride, chloroform, tri-nor tetrachlorethylene
• Benzene, toluene or polar solvents such as dimethylformamide, acetone or dimethyl sulfoxide works.
• the reaction temperatures are between room temperature and the boiling point of the solvent, with temperatures in the range from room temperature to 130 ° C being particularly preferred.
• Such coupling reagents are, for example, carbodiimides such as dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide (DCI) or N, N'-carbonyldiazoles such as N, N'-carbonyldiimidazole or a uronium salt such as 0 - ((cyano (ethoxycarbonyl) methylene) amino) -1, 1,3,3-tetramethyluronium tetrafluoroborate (TOTU) or 0- (7-azabenzotriazol-1-yl) -1,3,3,3-tetramethyluronium hexafluorophosphate (HATU).
• amines of the formula IIIa or IIIb are not commercially available, they can be prepared from corresponding commercially available starting compounds by methods known from the literature. Suitable starting compounds for amines are, for example, nitriles, nitro compounds,
• the reaction can also be carried out in the presence of bases.
• bases are, for example, carbonates or bicarbonates, such as sodium or potassium carbonate or sodium or potassium bicarbonate, or tertiary amines, such as triethylamine, tributylamine, ethyldiisopropylamine or heterocyclic amines, such as N-alkylmorpholine, pyridine, quinoline or dialkylanilines.
• the workup of the products for example by extraction or chromatography z. B. on silica gel.
• the isolated product can be recrystallized and optionally with a suitable Acid be converted to a physiologically acceptable salt.
• suitable acids include, for example:
• Mineral acids such as hydrochloric and hydrobromic acid and sulfuric, phosphoric, nitric or perchloric acid or organic acids such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, maleic -, fumaric, phenylacetic, benzoic, methanesulfonic, toluenesulfonic, oxalic, 4-aminobenzoic, naphthalene-1,5-disulfonic or ascorbic acid.
• organic acids such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, maleic -, fumaric, phenylacetic, benzoic, methanesulfonic, toluenesulfonic, oxalic, 4-aminobenzoic, naphthalene-1,5-disulfonic or ascorbic acid.
• the starting compounds of the formula IIIa or IIIb can, insofar as they are not commercially available, be easily synthesized (eg Organikum, Organisch Chemisches Grundpraktikum, 15th ed., VEB Deutscher Verlag dermaschineen, 1976, an overview of the various possibilities can be found in the Methods Register, p. 822).
• the starting compounds of the formula (II) are obtained, for example, by reacting pyrimidine-4,6-dicarboxylic acid or pyridine-2,4-dicarboxylic acid to give the corresponding pyrimidine-4,6-dicarboxylic acid halide or pyridine-2,4-dicarboxylic acid halide , preferably - chloride (according to literature methods), preferably in the presence of a catalyst such as dimethylformamide.
• This acid halide can then be added, for example, either with a suitable alcohol, e.g. B. paranitrobenzyl alcohol to the corresponding active ester, or be reacted with lower alcohols such as methanol or ethanol to the corresponding esters.
• the pyrimidine-4,6-dicarboxylic acid can also be initially converted with the addition of a suitable carboxylic acid or a carboxylic acid ester such as ethyl chloroformate in a mixed anhydride, which then with the amines of the compounds of formulas IIIa or IIIb and (IVa or IVb to the products of the invention
• a suitable carboxylic acid or a carboxylic acid ester such as ethyl chloroformate in a mixed anhydride
• pyrimidine-4,6-dicarboxylic acid is carried out by literature methods, for example by oxidation of 4,6-dimethylpyrimidine, which in turn is obtainable, for example, by catalytic hydrogenation of commercially available 2-mercapto-4,6-dimethylpyrimidine.
• Suitable chiral stationary phases for the thin-layer or column chromatographic separation of enantiomers are, for example, modified silica gel carriers (so-called Pirkle phases) and high molecular weight carbohydrates such as triacetylcellulose.
• gas chromatographic methods can also be used on chiral stationary phases according to appropriate derivatization known to the person skilled in the art.
• an optically active, usually commercially available base such as (-) - nicotine, (+) - and (-) - phenylethylamine, quinine bases, L-lysine or L- and D-arginine which have different solubility formed diastereomeric salts, the less soluble component as a solid isolated, the more readily soluble diastereomer from the mother liquor deposited, and obtained from the thus obtained diastereomeric salts, the pure enantiomers.
• racemic compounds of the formula I which contain a basic group such as an amino group
• optically active acids such as (+) - camphor-10-sulfonic acid, D- and L-tartaric acid, D- and L- Convert lactic acid and (+) and (-) - mandelic acid into the pure enantiomers.
• the chirality of introduced in enantiomerically pure form amino acid or alcohol residue can be used to separate the isomers by performing a separation of the diastereomers now present by crystallization or chromatography at suitable stationary phases and then splits off the entrained chiral moiety by suitable methods again.
• Acidic or basic products of the compound of formula I may be in the form of their salts or in free form. Preference is given to pharmacologically acceptable salts, for. As alkali or alkaline earth metal salts or hydrochlorides, hydrobromides, sulfates, hemisulfates, all sorts of phosphates and salts of amino acids, natural bases or carboxylic acids. The preparation of physiologically acceptable salts of compounds capable of salt formation of the formula I, including their stereoisomeric forms, takes place in a manner known per se.
• the carboxylic acids form with basic reagents such as hydroxides, carbonates, bicarbonates, alcoholates and ammonia or organic bases, for example trimethyl- or triethylamine, ethanolamine or triethanolamine or basic amino acids, such as lysine, ornithine or arginine, stable alkali, alkaline earth or optionally substituted ammonium salts , If the compounds of the formula I have basic groups, it is also possible to prepare stable acid addition salts with strong acids.
• basic reagents such as hydroxides, carbonates, bicarbonates, alcoholates and ammonia or organic bases, for example trimethyl- or triethylamine, ethanolamine or triethanolamine or basic amino acids, such as lysine, ornithine or arginine, stable alkali, alkaline earth or optionally substituted ammonium salts , If the compounds of the formula I have basic groups, it is also possible to prepare stable acid addition salts with strong acids.
• both inorganic and organic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, 4-bromobenzenesulfone, Cyclohexylamidosulfon-, trifluoromethylsulfone, acetic, oxal come -, wine, succinic or trifluoroacetic acid in question.
• the compounds of the formula I are suitable for the prophylaxis and therapy of all such diseases, in whose course increased activity of matrix metalloproteinase 13 is involved.
• degenerative joint diseases such as osteoarthrosis, spondylosis, loss of cartilage after joint trauma or prolonged joint restraint after meniscal or patella injuries or torn ligaments. It also includes connective tissue disorders such as collagenosis, periodontal disease, wound healing disorders and chronic musculoskeletal disorders such as inflammatory, immunological or metabolic acute and chronic arthritides, arthropathies, myalgia and bone metabolism disorders or cancers such as breast cancer.
• the application of the medicaments according to the invention can be effected by subcutaneous, intraarticular, intraperitoneal or intravenous injection. Preference is given to intra-articular injection. Rectal, oral, inhalation or transdermal administration is also possible.
• the invention also relates to a process for the preparation of a medicament, which comprises at least one compound of the formula I with a pharmaceutically suitable and physiologically tolerated carrier and optionally brings further suitable active ingredients, additives or excipients in a suitable dosage form.
• the compounds of the formula I are mixed with the appropriate additives such as carriers, stabilizers or inert diluents and brought by the usual methods into suitable dosage forms, such as tablets, dragees, capsules, aqueous alcoholic or oily suspensions or aqueous or oily solutions.
• suitable dosage forms such as tablets, dragees, capsules, aqueous alcoholic or oily suspensions or aqueous or oily solutions.
• inert carriers z. Gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch.
• the preparation can be carried out both as a dry and as a wet granules.
• Suitable oily carriers or solvents are, for example, vegetable or animal oils, such as sunflower oil or cod liver oil.
• the active compounds are, if desired, brought into solution, suspension or emulsion with the substances suitable therefor, such as solubilizers, emulsifiers or other excipients.
• substances suitable therefor such as solubilizers, emulsifiers or other excipients.
• physiological saline or alcohols eg. For example, ethanol, propanol, glycerol, besides sugar solutions such as glucose or mannitol solutions, or ⁇ a mixture of the various solvents mentioned.
• auxiliaries such as carriers, disintegrants, binders, coatings, swelling agents, lubricants or lubricants, flavorings, sweeteners and solubilizers are used.
• Commonly used adjuvants are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycol and solvents such as sterile Water and mono- or polyhydric alcohols such as glycerol, called.
• Dosage units are prepared and administered, each unit containing as active ingredient a certain dose of the compound of formula I.
• they may be administered orally at doses of 0.01 mg / kg / day to 25.0 mg / kg / day, preferably 0.01 mg / kg / day to 5.0 mg / kg / day or parenterally at doses of 0.001 mg / kg / day to 5 mg / kg / day, preferably 0.001 mg / kg / day to 2.5 mg / kg / day.
• the dosage can also be increased in severe cases. In many cases, however, smaller doses are sufficient. This information refers to the treatment of an adult.
• Example 1 [4 - ( ⁇ [6- (4-Fluoro-3-methyl-benzylcarbamoyl) -pyrimidine-4-carbonyl] -amino ⁇ -methyl) -phenoxy-acetic acid tert-butyl ester
• 6- (4-Fluoro-3-methyl-benzylcarbamoyl) -pyrimidine-4-carboxylic acid methyl ester The compound was prepared analogously to methyl 6-benzylcarbamoyl-pyrimidine-4-carboxylate.
• 6- (4-fluoro-3-methyl-benzylcarbamoyl) -pyrimidine-4-carboxylic acid 8.75 g (0.0202 mol) of methyl 6- (4-fluoro-3-methyl-benzylcarbamoyl) -pyrimidine-4-carboxylate
• To 80 ml of methanol were added 0.889 g (0.0222 mol) of sodium hydroxide in 6 ml of water and stirred at room temperature (RT).
• Example 2 [4 - ( ⁇ [6- (4-Fluoro-3-methyl-benzylcarbamoyl) -pyrimidine-4-carbonyl-1-amino ⁇ -methyl) -phenoxy-acetic acid 83.6 mg (0.16 mmol) [4 Tert-butyl ( ⁇ [6- (4-fluoro-3-methyl-benzylcarbamoyl) -pyrimidine-4-carbonyl] -amino ⁇ -methyl) -phenoxy-acetic acid (Example 31) was reacted in 90% for 4 hours.
• Trifluoroacetic acid stirred at RT. Subsequently, it was mixed with acetonitrile / water, the
• This protein is obtained as an inactive pro-enzyme from INVITEK, Berlin (catalog no. 30 100 803). Activation of the proenzyme:
• the APMA solution is prepared from a 10 mmol / L p-aminophenyl-mercuric acetate solution in 0.1 mmol / L NaOH by dilution with 3 volumes of Tris / HCl buffer pH7.5 (see below). The pH is adjusted by adding 1 mmol / L HCl between 7.0 and 7.5. After activation of the enzyme, it is diluted with the Tris / HCl buffer to a concentration of 1.67 ⁇ g / ml.
• Enzyme inhibitor activity will be 10 ⁇ L enzyme solution with 10 ⁇ L of a 3% (v / v) buffered
• reaction 1 Both in reaction 1 and in reaction 2, the enzyme reaction is monitored by fluorescence spectroscopy after addition of 10 ⁇ L of a 3% (v / v) aqueous dimethylsulfoxide solution containing 0.75 mmol / L of the substrate (328 nm (absorbance)). / 393 nm (emission)).
• the enzyme activity is expressed as the increase in absorbance / minute.
• the inhibitor activity is calculated as percent inhibition according to the following formula:
• the enzyme solution contains 1.67 ⁇ g / mL of the enzyme domain.
• the substrate solution contains 0.75 mmol / L of the fluorogenic substrate (7-methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly-Leu-3- (2 ', 4'-dinitrophenyl) -L-2,3-diaminopropionyl -Ala-Arg-NH 2 (Bachern, Heidelberg, Germany).
• the enzymes human neutrophil collagenase and human stromelysin were prepared as active catalytic domains as described in Weithmann et al Inflamm Res, 46 (1997), pages 246-252. The measurement of the enzyme activity and the determination of the inhibitory effect of inhibitors on the enzyme activity was also carried out as described there.
• the compounds according to the above examples each showed IC50 values of. In the determination of human neutrophil collagenase and human stromelysin more than 100000 nM. Thus, these compounds are virtually ineffective in inhibiting MMP 3 and 8.

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