Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
  • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
  • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
  • C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • 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

Definitions

• the invention relates to compounds of the general formula
• R, R each independently of one another H, A, OH, OA, arylalkyl, shark, -CO-A, CN, N0 2 , NHR 3 , COOA, COOH, S0 2 A, CF 3 or OCF 3 ,
• R each independently of one another H or A
• R, R each independently of one another H, A, -CO-A, N0 2 or CN,
• n, p independently of one another are 1, 2 or 3,
• the object of the invention was to find new compounds with valuable properties, in particular those which are used for the production of medicaments.
• the compounds of the formula I and their salts have very valuable pharmacological properties with good tolerability. Above all, they act as integrin inhibitors, in particular inhibiting the interactions of the ⁇ v, ⁇ 3, ⁇ 5 or ⁇ 6 integrin receptors with ligands, such as e.g. the binding of fibrinogen to the integrin receptor.
• Integrins belong to the family of heterodimeric class I transmembrane receptors, which play an important role in numerous cell matrix or cell-cell adhesion processes (Tuckwell et al., 1996, Symp. Soc. Exp. Biol. 47) , They can be roughly divided into three classes: the ⁇ 1 integrins, which are receptors for the extracellular matrix, the ⁇ 2 integrins, which can be activated on leukocytes and are "triggered” during inflammatory processes, and the ⁇ v integrins, which are the cell response in wound healing and other pathological processes (Marshall and Hart, 1996, Semin. Cancer
• the relative affinity and specificity for ligand binding is determined by combining the different ⁇ and ⁇ subunits.
• ⁇ vß6 is a relatively rare integrin (Busk et al., J. Biol. Chem. 1992, 267 (9), 5790), which is increasingly formed in repair processes in epithelial tissue and which preferentially binds the natural matrix molecules fibronectin and tenascin (Wang et al. , Am. J. Respir. Cell Mol. Biol. 1996, 75 (5), 664).
• the physiological and pathological functions of ⁇ vß6 are not yet exactly known, but it is suspected that this integrin is associated with physiological processes and diseases (e.g. inflammation,
• ⁇ vß6 is expressed on keratinocytes in wounds (Haapasalmi et al., J. Invest. Dermatol. 1996, 106 (1), 42).
• Fibrous, endometriosis, cirrhosis of the liver or periodontitis can be influenced by agonists or antagonists of said integrin.
• ⁇ vß ⁇ plays a role in the respiratory epithelium (Weinacker et al., Am. J. Respir. Cell Mol. Biol. 1995, 12 (5), 547), so that corresponding agonists / antagonists of this integrin in respiratory diseases such as bronchitis, asthma, Lung fibrosis and respiratory tumors could be used successfully.
• ⁇ v ⁇ also plays a role in the intestinal epithelium, so that corresponding integrin agonists / antagonists could be used in the treatment of inflammation, tumors and wounds of the gastrointestinal tract.
• the compounds of the formula I according to the invention and their salts act as soluble molecules on cells which carry the receptor mentioned, or, if they are bound to surfaces, are artificial ligands for ⁇ v ⁇ -mediated cell attachment. Above all, they act as ⁇ v ⁇ integrin inhibitors, in particular inhibiting the interactions of the receptor with other ligands, e.g. the binding of fibronectin.
• the compounds of the invention are particularly potent
• Inhibitors of the vitronectin receptor ⁇ vß3 and / or potent inhibitors of the ⁇ vß ⁇ receptor are included in the vitronectin receptor ⁇ vß3 and / or potent inhibitors of the ⁇ vß ⁇ receptor.
• the ⁇ vß3 integrin is grown on a number of cells, e.g. Endothelial cells, cells of the smooth vascular muscles, for example of the aorta, cells for
• Antibodies against ⁇ vß3 are described which cause tumor shrinkage by inducing apoptosis.
• the compounds can inhibit the binding of metal proteinases to integrins and thus prevent the cells from the enzymatic activity of the
• An example can be found in the inhibition of the binding of MMP-2- (matrix metallo-proteinase-2) to the vitronectin receptor ⁇ vß3 by a cyclo-RGD peptide, as in PC Brooks et al., Cell 1996, 85, 683-693.
• the compounds of the formula I according to the invention can therefore be used as active pharmaceutical ingredients, in particular for the treatment of tumor diseases, osteoporoses, osteolytic diseases and for suppressing angiogenesis.
• micro-aggregates microthrombi
• the spread of tumor cells from a local tumor into the vascular system occurs through the formation of micro-aggregates (microthrombi) through the interaction of the tumor cells with platelets.
• the tumor cells are shielded by the protection in the micro-aggregate and are not recognized by the cells of the immune system.
• the micro-aggregates can attach themselves to the vessel walls, which facilitates further penetration of tumor cells into the tissue. Since the formation of the microthrombi is mediated by fibrinogen binding to the fibrinogen receptors on activated platelets, the GPIIb / llla antagonists can be regarded as effective metastasis inhibitors.
• compounds of the formula I In addition to the binding of fibrinogen, fibronectin and von Willebrand factor to the fibrinogen receptor of the platelets, compounds of the formula I also inhibit the binding of other adhesive proteins, such as
• Vitronectin, collagen and laminin to the appropriate receptors on the surface of different cell types. In particular, they prevent the formation of platelet thrombi and can therefore be used to treat thrombosis, apoplexy, heart attack, inflammation and arteriosclerosis.
• the antiplatelet effect can be demonstrated in vitro by the method of Born (Nature 1962, 4832, 927-929).
• Organism is its bioavailability. If the active pharmaceutical ingredient is added intravenously to the organism in the form of a solution for injection, its absolute bioavailability, ie the proportion of the drug that remains unchanged in the systemic blood, ie in the large circulation, is 100%.
• the agent When a therapeutic agent is administered orally, the agent is usually present as a solid in the formulation and must therefore first dissolve so that it can overcome the entry barriers, for example the gastrointestinal tract, the oral mucosa, nasal membranes or the skin, in particular the stratum corneum or can be absorbed by the body.
• Pharmacokinetic data ie
• Bioavailability can be obtained analogously to the method of J. Shaffer et al, J. Pharm. Sciences, 1999, 88, 313-318.
• the invention relates to compounds of the formula I as claimed in claim 1 and their physiologically acceptable salts and / or solvates as active therapeutic substances.
• the invention accordingly relates to compounds of the formula I as claimed in claim 1 and their physiologically acceptable salts and / or solvates as integrin inhibitors.
• the invention relates to compounds of the formula I according to claim 1 and their physiologically acceptable salts and / or solvates for use in combating diseases.
• the compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine, in particular for the prophylaxis and / or therapy of diseases of the circulatory system, thrombosis, heart attack, arteriosclerosis, apoplexy, angina pectoris, tumor diseases such as tumor growth or tumor metastasis, osteolytic diseases such as Osteoporosis, pathologically angiogenic diseases such as inflammation, ophthalmological diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, Crohn's disease, atherosclerosis, erythematosus, psoriasis sores, psoriasem sebioma, psoriasis sebiitis, psoriasem sebioma, psoriasis inflammation, psoriasem sebi
• the compounds of formula I can be used as antimicrobial substances in operations where biomaterials, implants, catheters or pacemakers are used. They have an antiseptic effect.
• the effectiveness of the antimicrobial activity can be determined by the P. Valentin-Weigund et al. in Infection and
• the compounds of the formula I are inhibitors of fibrinogen binding and thus ligands of the fibrinogen receptors on platelets, they can be used as diagnostics for the detection and localization of thrombi in the vascular system in vivo, provided that they are substituted, for example, by a radioactive or UV-detectable residue.
• the compounds of formula I can act as inhibitors of
• Fibrinogen binding can also be used as an effective tool for studying the metabolism of platelets in different stages of activation or intracellular signaling mechanisms of the fibrinogen receptor.
• the detectable unit of a "label" to be incorporated for example isotope labeling by 3 H, allows the mechanisms mentioned to be investigated after binding to the receptor.
• Trt trityl (triphenylmethyl).
• the compounds of formula I have at least one chiral center and can therefore occur in several stereoisomeric forms. All of these forms (e.g. D and L forms) and their mixtures (e.g. the DL forms) are included in Formula I.
• prodrug derivatives are also included in the compounds according to the invention, i.e. with e.g. Alkyl or acyl groups, sugars or oligopeptides modified compounds of formula I, which are quickly cleaved in the organism to the active compounds of the invention.
• Carboxyl group is converted into a pharmaceutically acceptable metabolically labile ester or an amide thereof. Furthermore, free amino groups or free hydroxyl groups as substituents of compounds of the formula I can be provided with corresponding protective groups.
• Solvates of the compounds of the formula I are understood to mean additions of inert solvent molecules to the compounds of the formula I which are formed on account of their mutual attraction. Solvates are e.g. Mono- or dihydrates or
• Addition compounds with alcohols e.g. with methanol or ethanol.
• the invention further relates to a process for the preparation of compounds of the formula I according to claim 1 and their salts, characterized in that a) a compound of the formula II, in which Z, R 1 and n have the meaning given above and W denotes a customary protective group or a solid phase used in peptide chemistry,
• guanyl compound e.g. N, N'- bis-BOC-1-guanylpyrazole reacted and, if appropriate, the remaining protective groups and / or the solid phase are split off or
• A means alkyl, is linear or branched, and has 1 to 6, preferably 1, 2, 3, 4, 5 or 6 carbon atoms.
• A is preferably methyl, furthermore ethyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl or tert-butyl, further also n-pentyl, 1-, 2- or 3-methylbutyl, 1, 1- , 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1, 1-, 1, 2-, 1,3-, 2,2- , 2,3- or 3,3-dimethylbutyl, 1- or 2-
• Ethyl butyl 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 1, 2- or 1, 2,2-trimethylpropyl. Methyl is particularly preferred for A.
• protecting group preferably means acetyl, propionyl,
• Arylalkyl preferably means benzyl, phenylethyl, phenylpropyl or naphthylmethyl, particularly preferably benzyl.
• Shark is preferably F, Cl or Br.
• Het means a mono- or bicyclic aromatic or saturated radical with up to three heteroatoms, preferably a saturated, partially or completely unsaturated mono- or bicyclic heterocyclic radical with 5 to 10 ring members, where 1 or 2 N- and / or 1 or 2 S - Or O atoms can be present and the heterocyclic radical can be substituted once or twice by CN, shark, OH, OA, CF 3 , A, N0 2 or OCF 3 .
• Het is preferably substituted or unsubstituted 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, further preferably 1, 2,3-triazol-1-, -4- or -5-yl, 1, 2,4-triazol-1- , -4- or -5-yl, 1- or 5-tetrazolyl, 1, 2,3-oxadiazol-4- or -5-yl 1, 2,4-oxadiazol-3- or -5-yl, 1, 3,4-thiadiazol-2- or -5-yl, 1, 2,4-
• heterocyclic radicals can also be partially or completely hydrogenated.
• Het can also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro -2- or -3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl,
• Het methylpyridyl in particular 4-methylpyridin-2-yl, pyridin-2-yl, pyrimidin-2-yl, imidazol-2-yl, benzimidazol-2-yl and their hydrogenated derivatives, is particularly preferred.
• OA preferably means methoxy, ethoxy, propoxy or butoxy, further also pentyloxy or hexyloxy.
• R 1 and R 5 independently of one another are preferably H, A, CN, NO 2 , shark or -COA-, where A has one of the meanings given above; in particular R 1 and R 5 mean H.
• R 2 is preferably H or A, where A has one of the meanings given above; especially H.
• R 3 and R 4 independently of one another preferably mean H or -COA-, in particular H.
• Y means - (CH 2 ) m- or in particular - (CH 2 ) - or
• n and p independently of one another are preferably 1 or 2, in particular 1.
• n preferably denotes 0, 2 or 4, in particular 0 or 4.
• Radicals has one of the preferred meanings given above. Some preferred groups of compounds can be expressed by the following sub-formulas 11 to I36:
• the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I.
• Compounds of formula I can preferably be obtained under the conditions of peptide synthesis. The procedure is advantageously carried out according to customary methods of peptide synthesis, as described, for example, in Houben-Weyl, 1.c, volume 15/11, pages 1 to 806 (1974).
• the direct precursors of the compounds of formula I can also e.g. according to Merrifield (Angew. Chem. 97, 801-812, 1985) on a solid phase, e.g. a swellable polystyrene resin.
• a solid phase e.g. a swellable polystyrene resin.
• all carriers e.g. from the
• Solid phase peptide chemistry or nucleic acid synthesis are known to be used.
• Suitable polymeric carrier materials are polymeric solid phases with preferably hydrophilic properties, for example cross-linked poly sugars such as cellulose, Sepharose or Sephadex R , acrylamides,
• Polyethylene glycol-based polymer or tentacle polymers R Polyethylene glycol-based polymer or tentacle polymers R.
• the solid phase is trityl chloride polystyrene resin, 4-
• Methoxytritylchloride resin Merrifield resin. And Wang resin used.
• the compounds of formula I can also be obtained by reacting a compound of formula IV with a compound of formula V and then removing the protecting groups.
• the coupling reaction is preferably accomplished in the presence of a dehydrating agent, e.g. a carbodiimide such as DCCI or EDCI, further e.g. Propanephosphonic anhydride (cf. Angew. Chem. 1980, 92,
• diphenylphosphoryl azide or 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline in an inert solvent, e.g. a halogenated hydrocarbon such as dichloromethane, an ether such as tetrahydrofuran or dioxane, an amide such as DMF or dimethylacetamide, a nitrile such as acetonitrile, in dimethyl sulfoxide or in the presence of these solvents
• an inert solvent e.g. a halogenated hydrocarbon such as dichloromethane, an ether such as tetrahydrofuran or dioxane, an amide such as DMF or dimethylacetamide, a nitrile such as acetonitrile, in dimethyl sulfoxide or in the presence of these solvents
• the reaction time is between a few minutes and 14 days depending on the conditions used.
• derivatives of compounds of the formula II and / or IV preferably a preactivated carboxylic acid, or a carboxylic acid halide, a symmetrical or mixed anhydride or an active ester can also be used.
• residues for activating the carboxy group in typical acylation reactions are described in the literature (e.g. in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart).
• Activated esters are conveniently formed in situ, e.g. B. by adding
• reaction is usually carried out in an inert solvent, when using a carboxylic acid halide in the presence of an acid-binding agent, preferably an organic base such as
• Triethylamine dimethylaniline, pyridine or quinoline.
• an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali metal or alkaline earth metal preferably of potassium, sodium, calcium or cesium, can also be favorable.
• the compounds of formula I can also be obtained by liberating them from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenolysis.
• Preferred starting materials for solvolysis or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more free amino and / or hydroxyl groups contain corresponding protected amino and / or hydroxyl groups, in particular those which have a instead of an HN group Carry SG 1 -N group, wherein
• SG 1 means an amino protecting group and / or those which replace the H atoms of a hydroxyl group carry a hydroxyl protective group, for example those which correspond to the formula I, but instead of a group -COOH carry a group -COOSG 2 , in which SG 2 denotes a hydroxyl protective group.
• amino protecting group is generally known and refers to groups which are suitable for protecting (blocking) an amino group against chemical reactions. Unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups are particularly typical of such groups. Since the amino protective groups are removed after the desired reaction (or reaction sequence), their type and size is otherwise not critical; however, those with 1-20 C atoms are preferred.
• acyl group is to be understood in the broadest sense in connection with the present process.
• acyl groups derived from aliphatic, araliphatic, alicyclic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxy-carbonyl, alkenyloxycarbonyl, aryloxycarbonyl and especially aralkoxy-carbonyl groups.
• alkanoyl such as acetyl, propionyl, butyryl
• Aralkanoyl such as phenylacetyl
• Aroyl such as benzoyl or toluyl
• benzoyl or toluyl
• Aryloxyalkanoyl such as phenoxyacetyl
• Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, Boc, 2-iodoethoxycarbonyl
• Alkenyloxycarbonyl such as allyloxycarbonyl (aloe), aralkyloxycarbonyl such as CBZ (synonymous with Z), 4-methoxybenzyloxycarbonyl (MOZ), 4-nitrobenzyloxycarbonyl or 9-fluorenylmethoxycarbonyl (Fmoc); 2
• Phenylsulfonyl ethoxycarbonyl; Trimethylsilylethoxycarbonyl (Teoc) or Arylsulfonyl such as 4-methoxy-2,3,6-trimethylphenylsulfonyl (Mtr).
• Preferred amino protecting groups are Boc, Fmoc and aloe, furthermore Z, benzyl and acetyl.
• hydroxyl protecting group is also generally known and refers to groups which are suitable for protecting a hydroxyl group against chemical reactions. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl, aroyl or acyl groups, furthermore also alkyl groups, alkyl, aryl or aralkylsilyl groups or 0.0- or 0, S-acetals. The nature and size of the
• Hydroxy protective groups are not critical since they are removed again after the desired chemical reaction or reaction sequence; groups with 1-20, in particular 1-10, carbon atoms are preferred.
• hydroxy protecting groups include Aralkyl groups such as benzyl, 4-methoxybenzyl or 2,4-dimethoxybenzyl, aroyl groups such as benzoyl or p-nitrobenzoyl, acyl groups such as acetyl or pivaloyl, p-toluenesulfonyl, alkyl groups such as methyl or tert-butyl, but also allyl, alkylsilyl groups such as trimethylsilyl (TMS ), Triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS) or triethylsilyl, trimethylsilylethyl, aralkylsilyl groups such as tert.-butyldiphenylsilyl (TBDPS), cycl
• Particularly preferred hydroxyl protecting groups are benzyl, acetyl, tert-butyl or
• a base of the formula I can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation.
• acids that provide physiologically acceptable salts are suitable for this implementation.
• inorganic acids can be used, for example sulfuric acid, sulfurous acid, dithionic acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or poly-based carbon.
• Sulfonic or sulfuric acids for example formic acid, acetic acid, propionic acid, hexanoic acid, octanoic acid, decanoic acid, hexadecanoic acid, octadecanoic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid,
• Lactic acid tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfonic acid, benzenesulfonic acid, trimethoxybenzoic acid, adamantane carboxylic acid, p-toluenesulfonic acid, glycolic acid, embonic acid, chlorophenoxyacetic acid, aspartic acid, proline acid, glutamic acid
• Glyoxylic acid palmitic acid, parachlorophenoxyisobutyric acid, cyclohexane carboxylic acid, glucose-1-phosphate, naphthalene mono- and disulfonic acids or lauryl sulfuric acid. Salts with physiologically unacceptable acids, e.g. Picrates can be used for the isolation and / or purification of the compounds of the formula I.
• compounds of the formula I with bases can be converted into the corresponding metal, in particular alkali metal or alkaline earth metal or into the corresponding ammonium salts.
• bases for example sodium or potassium hydroxide or carbonate
• Substituted ammonium salts for example the dimethyl, diethyl or diisopropylammonium salts, monoethanol, diethanol or diisopropylammonium salts, cyclohexyl, dicyclohexylammonium salts, dibenzylethylenediammonium salts, furthermore, for example, salts with arginine or lysine.
• the invention further relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of a pharmaceutical preparation.
• the invention further relates to pharmaceutical preparations containing at least one compound of the formula I and / or one of its physiologically acceptable salts or solvates, which are prepared in particular by a non-chemical route.
• the compounds of the formula I can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active compounds.
• Suitable carriers are organic or inorganic substances which are suitable for enteral (e.g. oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc,
• Vaseline Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for topical use for parenteral use
• the new compounds can also be lyophilized and the resulting lyophilisates e.g. can be used for the production of injectables.
• the specified preparations can be sterilized and / or contain auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, taste and / or several other active substances, e.g. one or more vitamins.
• sprays can be used which either dissolved or suspended in a propellant or the active ingredient
• Propellant mixture e.g. C0 2 or chlorofluorocarbons
• the active ingredient is expediently used in micronized form, it being possible for one or more additional physiologically compatible solvents to be present, for example ethanol.
• Inhalation solutions can be administered using standard inhalers.
• the compounds of the formula I and their physiologically acceptable salts can be used as integrin inhibitors in combating diseases, in particular thromboses, heart attacks, coronary heart diseases, arteriosclerosis, tumors, osteoporosis, inflammations and infections.
• the compounds of formula I according to claim 1 and / or their physiologically acceptable salts are also used in pathological processes which are maintained or propagated by angiogenesis, in particular in tumors or rheumatoid arthritis.
• the substances according to the invention are generally administered in analogy to other known, commercially available peptides, but in particular in analogy to the compounds described in US Pat. No. 4-472,305, preferably in doses between about 0.05 and 500 mg , in particular between 0.5 and 100 mg per dosage unit.
• the daily dosage is preferably between about 0.01 and 2 mg / kg body weight.
• the specific dose for each patient depends on a wide variety of factors, for example on the effectiveness of the specific ones used
• the compounds of the formula I can be used as integrin ligands for the preparation of columns for affinity chromatography for the purification of integrins.
• the ligand ie a compound of the formula I, is covalently coupled to a polymeric support via an anchor function, for example the carboxy group of Asp.
• Integrin purification takes place under conditions which are customary and known per se for the condensation of amino acids.
• the compounds of the formula I contain one or more chiral centers and can therefore be present in racemic or in optically active form.
• Racemates obtained can be separated mechanically or chemically into the enantiomers by methods known per se.
• Diastereomers are preferably formed from the racemic mixture by reaction with an optically active release agent.
• Suitable release agents are e.g. optically active acids, such as the D and L forms of tartaric acid,
• Enantiomer separation using a column filled with an optically active separating agent e.g. dinitrobenzoylphenylglycine
• a suitable solvent is e.g. a mixture
• Hexane / isopropanol / acetonitrile e.g. in the volume ratio 82: 15: 3.
• optically active compounds of the formula I by the methods described above by using starting materials which are already optically active.
• customary work-up means: if necessary, water is added and, if necessary, the pH is adjusted to between 2 and 10, depending on the constitution of the end product, extracted with
• the diastereomers are preferably separated under the stated conditions.
• Fmoc-protected amino acids were purchased from Novabiochem, Advanced ChemTech, MultiSynTech or PepTech Corporation (Cambridge, USA).
• PE syringes from Becton-Dickinson (Fraga, Spain) or Braun (Melsungen) with PE frits from Roland Vetter Labor bin (Ammerbuch) were used for manual solid-phase synthesis.
• the syringes were rotated at about 30 rpm to mix the resin suspension.
• the resin was loaded in glass shaking vessels.
• Hygroscopic and / or absolute solvents were transferred in syringes under argon.
• Mass spectra were recorded using electron impact (El) and chemical ionization (Cl) technology on a Finnigan MAT 8200 instrument.
• Electrospray ionization (ESI) mass spectra were recorded on a Finnigan LCQ mass spectrometer in combination with a
• the compounds were eluted with a linear gradient (15 min) of acetonitrile (solvent B) in water (solvent A) and 0.1% (v / v) formic acid.
• Mass spectra are in the form "X
• Lyophilization was carried out using the Alpha 2-4 device from Christ
• AAV 2 The Fmoc protecting group is split off
• the resin (100 mg) is pre-swollen in NMP (5 mL, 10 min.).
• the Fmoc protective group is removed by treatment with a freshly prepared 20% piperidine solution (v / v) in NMP (5 mL) for 15 min. cleaved. Then the resin is washed with NMP (5 x 5 mL, 3 min. Each) and again with a 20 % Piperidine solution (v / v) in NMP (5 mL, 15 min.) Added. Finally the resin is washed with NMP (5 5 mL, 3 min each).
• AAV 3 Coupling of 5- (9H-fluoren-9-ylmethoxy) -3H- [1, 3,4] oxadiazol-2-one (142) to resin-bound, free amines according to Gibson
• AAV 4 coupling with HATU / HOAt
• connection from the TCP resin is split off according to the following flow diagram:
• N - [(9H-Fluoren-9-ylmethoxy) carbonyl] hydrazine (141) Boc hydrazine (10.0 g, 75.6 mmol) and DIPEA (12.95 mL, 75.6 mmol) were dissolved in dry CH 2 CI 2 (200 mL) and cooled to 0 ° C. Then FmocCI (19.6 g, 75.8 mmol), dissolved in dry CH 2 CI 2 (100 mL), was dissolved within 30 min. added and the mixture was stirred at room temperature overnight. The organic phase was extracted with water (200 mL) and concentrated to a volume of about 100 mL.
• Amine is mixed with an approx. 0.1 M solution from 2.5 equiv. (based on resin coverage, 0.09 mmol) Fmoc-3-aminobenzoic acid, 2.4 equiv. (0.086) HATU and 30 equiv. (1.08) sym-collidine added in dry DMF and shaken for 90 min at room temperature. It is washed with DMF (6 x 1 ml) and deprotected as described.
• the resin is then washed with anhydrous chloroform (3 ⁇ 1 ml) and mixed with a solution of 0.36 mmol of N, N'-bis-BOC-1-guanylpyrazole in 0.4 ml of anhydrous chloroform and reacted at 50 ° C. in a heated shaker. After 20 hours the resin is washed with DCM (6 x 1 ml).
• Example A Injection glasses
• a solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection glass contains 5 mg of active ingredient.
• a mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
• a solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g
• Example D ointment 500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
• a mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient.
• Example F coated tablets
• Example E tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
• Example G capsules
• each capsule contains 20 mg of the active ingredient.

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