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  • 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 had the object of finding new compounds with valuable properties, in particular those that can be used for the production of medicaments.
• the present invention relates to compounds in which the inhibition, regulation and / or modulation of HSP90 plays a role, as well as pharmaceutical compositions containing these compounds, as well as the use of the compounds for the treatment of
• HSPs Heat shock proteins
• the cells of a tissue are responsive to external stress, e.g. Heat, hypoxia, oxidative stress, or toxins such as heavy metals or alcohols with the activation of a number of chaperones known as "heat shock proteins” (HSPs) .
• HSPs heat shock proteins
• the activation of HSPs protects the cell against injuries caused by such stressors triggers the restoration of the physiological state and leads to a stress-tolerant state of the cell.
• HSPs mediated protective mechanism of external stress have been over time.
• HSPs regulate the correct folding, intracellular localization and function, or the regulated degradation of a number of biologically important proteins of cells.
• HSPs constitute a gene family of individual gene products whose cellular expression, function and localization differ in different cells. The designation and classification within the family is due to their molecular weight e.g. HSP27, HSP70, and HSP90.
• HSPs are also considered of great importance in tumor diseases. There are e.g. Evidence that the expression of certain
• HSPs are related to the stage of tumor progression (Martin et al., 2000; Conroy et al., 1996; Kawanishi et al., 1999;
• HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17AAG), a derivative of geldanamycin, is currently undergoing clinical trials.
• HSP90 represents about 1-2% of the total cellular protein mass. It is usually present in the cell as a dimer and is associated with a variety of proteins, so-called co-chaperones (see, e.g., Pratt, 1997). HSP90 is essential for the vitality of cells (Young et al., 2001) and plays a key role in the response to cellular stress by interacting with many proteins whose native folding by external stress, e.g. Heat shock, was changed to restore the original folding or the aggregation of
• HSP90 is important as a buffer against the effects of mutations, presumably by correcting for incorrect protein folding induced by the mutation (Rutherford and Lindquist, 1998).
• HSP90 also has a regulatory significance. Under physiological conditions, HSP90, along with its endoplasmic reticulum homolog, GRP94, plays a role in the cell balance to ensure the stability of the conformation and maturation of various "serving" key proteins, which can be divided into three groups: steroid hormone receptors, sera / Thr or tyrosine kinases (eg ERBB2, RAF-1, CDK4 and LCK) and a
• HSP90 human immunoglobulin sequence
• cytosolic HSP90 ⁇ the inducible HSP90 ⁇ isoform
• GRP94 the endoplasmic reticulum
• HSP75 / TRAP1 the mitochondrial matrix
• ERBB2 is a specific "serving" protein of GRP94 (Argon et al., 1999 ), while the Type 1 receptor of tumor necrosis factor (TNFR1) or the retinoblastoma protein (Rb) were detected as "clients” of TRAP1 (Song et al., 1995; Chen et al., 1996).
• TNFR1 tumor necrosis factor
• Rb retinoblastoma protein
• HSP90 is involved in a number of complex interactions with a large number of "serve” proteins and regulatory proteins (Smith, 2001). Although precise molecular details have not yet been elucidated, biochemical experiments and X-ray crystallographic examinations are recent For many years, HSP90 has been able to decipher details of the chaperone function of HSP90 (Prodromou et al., 1997, Stebbins et al., 1997)., According to this, HSP90 is an ATP-dependent molecular chaperone (Prodromou et al, 1997) ATP hydrolysis is the binding of ATP results in the
• HSP90 inhibitors were benzoquinone ansamycins with the compounds herbimycin A and geldanamycin. Originally, they were used to detect the reversion of the malignant phenotype in fibroblasts induced by transformation with the v-Src oncogene (Uehara et al., 1985).
• geldanamycin derivative 17-allylamino-17-demethoxygeldanamycin (17AAG) showed an unchanged property in the inhibition of HSP90, the degradation of "serving" proteins and antitumoral activity in
• Radicicol a macrocyclic antibiotic, also demonstrated a revision of the v-Src and v-Ha-Ras-induced malignant phenotype of fibroblasts (Kwon et al 1992, Zhao et al, 1995). Radicicol downgrades one
• Coumarin-type antibiotics are known to bind to the ATP binding site of the HSP90 homolog DNA gyrase in bacteria.
• the coumarin, novobiocin binds to the carboxy-terminal end of HSP90, which is another site in HSP90 than the benzoquinone Ansamycins and Radicicol, which bind to the N-terminal end of HSP90 (Marcu et al., 2000b).
• PU3 a purine-derived HSP90 inhibitor, the degradation of signaling proteins, e.g. ERBB2, are shown. PU3 causes cell cycle arrest and differentiation in breast cancer cell lines (Chiosis et al., 2001).
• HSP90 By including HSP90 in the regulation of a large number of signaling pathways that are critically important to the phenotype of a tumor, and the discovery that certain natural products exert their biological effect by inhibiting the activity of HSP90, HSP90 is currently a new target for development of a tumor therapeutic (Neckers et al., 1999).
• the main mechanism of action of geldanamycin, 17AAG, and radicicol involves the inhibition of binding of ATP to the ATP binding site at the N-terminal end of the protein and the consequent inhibition of the intrinsic ATPase activity of HSP90 (see, eg, Prodromou et al. 1997; Stebbins et al., 1997; Panaretou et al., 1998).
• the inhibition of ATPase activity of HSP90 prevents the
• Heterocomplexes that "serve" proteins via the ubiquitin-proteasome pathway of degradation see, eg, Neckers et al., 1999; Kelland et al., 1999) .Treating tumor cells with HSP90 inhibitors leads to the selective degradation of important proteins fundamental for processes such as cell proliferation, cell cycle regulation and apoptosis. These processes are often deregulated in tumors (see, eg, Hostein et al., 2001).
• the present invention relates to compounds which inhibit, regulate and / or modulate HSP90, compositions containing these compounds, and methods for their use in the treatment of HSP90-related diseases, such as tumor diseases, viral diseases, e.g. Hepatitis B (Waxman, 2002); Immunosuppression in transplantations (Bijlmakers, 2000 and Yorgin, 2000); Inflammatory Diseases (Bucci, 2000) such as Rheumatoid Arthritis, Asthma, Multiple Sclerosis, Type 1 Diabetes, Lupus Erythematosus, Psoriasis and Inflammatory Bowel Disease; cystic
• HSP90-related diseases such as tumor diseases, viral diseases, e.g. Hepatitis B (Waxman, 2002); Immunosuppression in transplantations (Bijlmakers, 2000 and Yorgin, 2000); Inflammatory Diseases (Bucci, 2000) such as Rheumatoid Arthritis, Asthma, Multiple Sclerosis, Type 1 Diabetes,
• Hemangiomas, endometriosis and tumor angiogenesis Hemangiomas, endometriosis and tumor angiogenesis; infectious diseases; Autoimmune diseases; ischemia; Promotion of nerve regeneration (Rosen et al., WO 02/09696, Degranco et al., WO 99/51223, Gold, US 6,210,974 B1); fibrogenetic diseases, e.g. Scleroderma, polymyositis, systemic lupus, liver cirrhosis, keloid formation, interstitial nephritis and pulmonary fibrosis (Strehlow, WO 02/02123).
• fibrogenetic diseases e.g. Scleroderma, polymyositis, systemic lupus, liver cirrhosis, keloid formation, interstitial nephritis and pulmonary fibrosis
• the invention also relates to the use of the compounds of the invention for the protection of normal cells against toxicity caused by chemotherapy, as well as for use in diseases where protein misfolding or aggregation is a major causative factor, e.g. Scrapie, Creutzfeldt-Jakob Disease, Huntington or Alzheimer's
• the present invention therefore relates to compounds of the formula I as medicaments and / or active pharmaceutical ingredients in the
• the host or patient may be of any mammalian species, e.g. A primate species, especially humans; Including rodents
• mice Mice, rats and hamsters; Rabbits; Horses, cattle, dogs, cats, etc. Animal models are of interest for experimental studies, being a model for the treatment of a disease of the
• WO 03/041643 A2 discloses HSP90-inhibiting zearalanol derivatives.
• HSP90-inhibiting pyrazole derivatives which are in the 3- or 5-position by a
• Aromatic substituted are known from WO 2004/050087 A1 and WO
• GRP94 homologue or paralogue to HSP90
• the cancerous tissue comprises a sarcoma or carcinoma selected from the group consisting of fibrosarcoma, myxosarcoma, liposarcoma,
• Chondrosarcoma osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer,
• Squamous cell carcinoma basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, bone marrow carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma,
• WO 01/72779 furthermore discloses the use of the compounds mentioned there for the treatment of viral diseases, wherein the viral pathogen is selected from the group consisting of hepatitis type A, type B hepatitis, type C hepatitis, influenza, varicella, Adenovirus, herpes simplex type I (HSV-I), herpes simplex type II (HSV- * c II), rinderpest, rhinovirus, echovirus, rotavirus, respiratory syncytial virus (RSV), papillomavirus, papovavirus, cytomegalovirus, echinovirus, arbovirus, huntavirus , Coxsackie virus, mumps virus, measles virus, rotten virus, poliovirus, human immunodeficiency virus
• the viral pathogen is selected from the group consisting of hepatitis type A, type B hepatitis, type C hepatitis, influenza, varicella, Adenovirus, herpes simple
• HIV-I Human Immunodeficiency Virus Type II
• HAV-II Human Immunodeficiency Virus Type II
• GRP94 modulation wherein the modulated GRP94 biological activity elicits an immune response in an individual, endoplasmic reticulum protein transport, recovery from hypoxic / anoxic stress, recovery from malnutrition, recovery from heat stress, or combinations thereof, and / or wherein the disorder is a type of cancer, an infectious disease, a disorder involving disrupted protein transport from the endo- Q plasmatic reticulum, a disorder associated with ischemia / reperfusion, or combinations thereof, wherein the ischemia / reperfusion-associated disorder comprises Consequences of cardiac arrest, asystole and delayed ventricular arrhythmias, cardiac surgery, cardiopulmonary bypass surgery, organ transplantation, spinal cord 5
• WO 01/72779 describes the use of an effective amount of a GRP94 protein modulator for the manufacture of a medicament, for modifying a subsequent one
• Tissue site in an individual by treating the cells at the tissue site with the GRP94 protein modulator to enhance the GRP94 activity in cells to a subsequent level
• ⁇ , C is varied cellular response to an ischemic state where the subsequent ischemic condition is preferably the result of cardiac arrest, asystole and delayed ventricular arrhythmia, heart surgery, cardiopulmonary bypass surgery, organ transplantation,
• hypoglycemia hypoglycemia
• status epilepticus epileptic seizure
• anxiety schizophrenia
• neurodegenerative disorder Alzheimer's disease
• Huntington's chorea amyotrophic lateral sclerosis (ALS)
• ALS amyotrophic lateral sclerosis
• the invention relates to compounds of the formula wherein
• R 1 Hal, OH, OA, SH, SA, H or A
• R 2 , R 3 are each independently -O- (X) S -Q, -S- (X) 5 -Q,
• R 4 , R 5 are each independently H, Hal, CN, NO 2 , A, OH, OA,
• A, A 'each independently of one another are unbranched or branched alkyl having 1-10 C atoms, in which 1-5 H atoms may be replaced by F, Cl and / or Br,
• Atoms in which one or two CH 2 groups can be replaced by O, S, SO, SO 2 , NH, NA and / or N-COOA,
• Q is H, carb, Ar or Het
• Carb is unsubstituted or mono-, di-, tri-, tetra- or quintuple by A, OA, OH, SH, SA, Hal, NO 2 , CN, (CHz) n Ar 1 ,
• Ar is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by A 1 OA, OH, SH, SA, Hal, NO 2 , CN, (CH 2 ) n Ar ', (CH 2 ) n COOH, ( CH 2 ) n COOA, CHO, COA, SO 2 A, CONH 2 ,
• NHSO 2 OA NASO 2 OA, NHCONH 2 , NACONH 2 , NHCONHA, NACONHA, NHCONAA 1 and / or NACONAA 1 substituted phenyl, naphthyl or biphenyl, Het a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N- , O and / or S atoms which are mono-, di- or trisubstituted by A, OA, OH, SH, SA, Hal, NO 2 , CN, (CH 2 JnAr 1 , (CH 2 ) n COOH, ( CH 2 ) n COOA, CHO, COA, SO 2 A, CONH 2 , SO 2 NH 2 , CONHA, CONAA 1 ,
• Carbonyl oxygen may be substituted
• Het 1 is a monocyclic saturated, unsaturated or aromatic heterocycle having 1 to 2 N and / or O atoms, which may be monosubstituted or disubstituted by A, OA, OH, Hal, and / or 0O (carbonyl oxygen),
• Hal is F, Cl, Br or I 1 n O, 1, 2, 3 or 4, o is 1, 2 or 3, s is O, 1 or 2, and their pharmaceutically usable derivatives, salts, solvates,
• the invention relates to the compounds of the formula I and their salts and to a process for the preparation of compounds of the formula I according to claims 1-15 and their pharmaceutically usable
• the invention also relates to the hydrates and solvates of these
• Solvates of the compounds are understood to mean additions of inert solvent molecules to the compounds which form due to their mutual attraction. Solvates are e.g. 20 mono- or dihydrate or alcoholates.
• the compounds of the formula I according to the invention can also be present in tautomeric forms.
• Formula I includes all of these tautomeric O1 _ forms.
• Sugars or oligopeptides modified compounds of formula I which are rapidly cleaved in the organism to the active compounds of the invention. 35 These include biodegradable polymer derivatives of the compounds of the invention, as z. In Int. J. Pharm. 115, 61-67 (1995).
• an effective amount means the amount of a drug or pharmaceutical agent which elicits a biological or medical response in a tissue, system, animal or human, e.g. wanted or searched by a researcher or physician
• terapéuticaally effective amount means an amount that, as compared to a corresponding subject who has not received that amount, results in:
• ⁇ C improved treatment, healing, prevention or elimination of a disease, a disease condition, a disease condition, complaint, disorder or side effects or also the reduction in the progress of a disease, condition or disorder.
• terapéuticaally effective amount also includes the
• the invention also provides mixtures of the compounds of the formula I according to the invention, for example mixtures of two diastereomers, for example in a ratio of 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 10, 1: 100 or 1 : 1000th Particularly preferred are mixtures of stereoisomeric Q isomeric compounds.
• a or A ' is preferably alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C-atoms.
• a or A 1 is more preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and also 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-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl.
• Alk represents alkenyl having 2-6 C atoms, such as e.g. Vinyl or propenyl.
• Cycloalkylalkylene means e.g. Cyclohexylmethyl, cyclohexylethyl,
• C 1 -C 10 alkylene is preferably methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene or decylene, isopropylene, isobutylene, sec.
• Alkenylene means a hydrocarbon chain with 2-10 C atoms, with 2 free valencies and containing at least one double bond.
• Ac is acetyl
• BzI is benzyl
• Ms is -SO 2 CH 3 .
• R 1 is preferably OH or OA, such as methoxy; furthermore H or
• R 2 , R 3 are preferably each independently -O- (X) 3 -Q 1
• R 4 , R 5 are preferably each independently H, Hal, A,
• R 4 is preferably H, Hal, OH or OA.
• R 5 is preferably H, Hal, A, OH, OA, COOA, O (CH 2) 0 CONH 2,
• X is preferably unsubstituted or mono- or disubstituted by
• Ar is, for example, phenyl, o-, m- or p-tolyl, 0-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, 0-, m- or p-hydroxyphenyl, 0-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino ) -phenyl, o-, m- or p- (N-methylaminocarbonyl) -phenyl, 0-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-e
• Carboxymethoxy-phenyl more preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 5
• Ar is preferably, for example, unsubstituted or mono-, di-, tri-, tetra- or quintuple phenyl substituted by A, Hal, OA, (CH 2 ) n COOH, (CH 2 ) n COOA and / or tetrazole.
• Ar is particularly preferably phenyl, o-, m- or p-tolyl, o-, m- or 5-p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-trifluoromethylphenyl, o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- or p-carboxyphenyl.
• Ar ' preferably means e.g. unsubstituted or mono-, di- or trisubstituted by Hal substituted phenyl.
• the heterocyclic radicals may also be partially or completely hydrogenated.
• B. also mean 2,3-dihydro-2-, -3-, -A- or -5-furyl,
• Het is preferably a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms, which are mono-, di- or trisubstituted by A, OH, OA and / or Hal can.
• Het preferably denotes a mono- or binuclear aromatic heterocycle having 1 to 2 N, O and / or S atoms which may be monosubstituted, disubstituted or trisubstituted by A, OH, OA and / or Hal where A is preferably methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl or trifluoromethyl.
• Het particularly preferably denotes unsubstituted or monohydric-substituted 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, A- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5 -lsothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1, 2,3-triazoM-, -4- or -5-yl, 1, 2, 4-triazole-1, -3- 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-thiadiazol-3
• Het very particularly preferably denotes unsubstituted or monohydric-substituted imidazolyl, pyridyl, pyrimidinyl, indolyl, benzimidazolyl or indazolyl.
• Het 1 preferably denotes a monocyclic saturated heterocycle having 1 to 2 N and / or O atoms, such as, for example, piperazinyl, piperidinyl,
• Het 1 very particularly preferably means 4-A-piperazinyl, where A is alkyl having 1-6 C atoms.
• the compounds of the formula I can possess one or more chiral centers and therefore occur in different stereoisomeric forms.
• Formula I encompasses all these forms.
• the invention are in particular those compounds of formula I 1 where at least one of said radicals has one of the preferred meanings indicated above.
• Some preferred groups of compounds can be expressed by the following partial formulas Ia to II, which correspond to the formula I and in which the unspecified radicals have the meaning given in the formula I, in which however
• R 1 is Hal, OH, OA or H
• R 3 are each independently of one another -O- (X) S -Q,
• R 5 are each independently H, Hal, A, OH, OA,
• R 5 is H, Hal, A, OH, OA, COOA, O (CH 2) 0 CONH 2l
• Alkylene wherein one, two or three C groups may be replaced by O, NHCO 1 CONH and / or replaced by NH groups, means;
• Ih Het a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N-, O- and / or S atoms which may be mono-, di- or trisubstituted by A, OH, OA and / or Hal;
• Ik A is unbranched or branched alkyl having 1-6 C atoms, wherein 1-5 H atoms may be replaced by F and / or Cl, means;
• R 1 Hal, OH, OA or H R 2 , R 3 are each, independently of one another, -O- (X) S -Q,
• R 4, R 5 are each independently H, Hal, A, OH, OA, COOA, O (CH 2) 0 2l CONH NHCO (CH 2) n NH 2 or
• Ar is unsubstituted or mono-, di-, tri-, tetra- or quintuple by A, Hal, OA, (CH 2 ) "COOH, (CH 2 ) n COOA and / or Tetrazo! substituted phenyl, Het a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms, which is mono-, di- or trisubstituted by A, OH, OA and / or Hal Het 1 is a mononuclear saturated heterocycle containing 1 to 2
• A, A ' are each independently of one another unbranched or branched alkyl having 1-6 C atoms, in which 1- 5 H atoms can be replaced by F and / or Cl,
• Hal is F, Cl, Br or I, n is 0, 1, 2, 3 or 4, o is 1, 2 or 3, s is 0, 1 or 2;
• R 1 Hal, OH, OA or H, R 2 , R 3 are each independently of one another -O- (X) S -Q,
• R 4 is H, Hal, OH or OA
• R 5 is H, Hal, A, OH, OA, COOA, O (CH 2 ) O CONH 2 ,
• Ar is unsubstituted or mono-, di-, tri-, tetra- or pentaphenyl substituted by A, Hal, OA, (CH 2 ) n COOH, (CH 2 ) n COOA and / or tetrazole, Het is a mononuclear or binuclear aromatic
• Heterocycle having 1 to 4 N, O and / or S atoms which may be mono-, di- or trisubstituted by A, OH, OA and / or Hal,
• Het 1 is a mononuclear saturated heterocycle containing 1 to 2
• A is unbranched or branched alkyl having 1-6 C atoms, in which 1-5 H atoms are replaced by F and / or Cl can be replaced,
• Hal is F, Cl, Br or I, n is O, 1, 2, 3 or 4, o is 1, 2 or 3, s is O, 1 or 2;
• the starting materials can, if desired, also be formed in situ, so that they are not isolated from the reaction mixture, but immediately further reacted to the compounds of the invention.
• the starting compounds are generally known. If they are new, they can be produced by methods known per se.
• the reactions are carried out in a suitable inert solvent.
• Suitable inert solvents are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as
• the reaction times are between a few minutes and 14 days depending on the conditions used, the reaction temperature between about -30 ° and 140 °, normally between -10 ° and 130 °, in particular between about 30 ° and about 125 °.
• Free amino groups are, for example, acylated in the usual way with an acid chloride or anhydride or alkylated with an unsubstituted or substituted alkyl halide, suitably in an inert solvent such as dichloromethane or THF and / or in the presence of a base such as triethylamine or pyridine at temperatures between -60 and + 30 °.
• compositions according to the invention can be used in their final non-salt form.
• present invention also encompasses the use of these compounds in the form of their pharmaceutically acceptable salts, which can be derived from various organic and inorganic acids and bases by procedures known in the art.
• Pharmaceutically acceptable salt forms of the compounds of formula I are for the most part prepared conventionally. If the compound of the formula I contains a carboxylic acid group, one of its suitable salts can be formed by reacting the compound with a suitable base to give the corresponding
• Such bases include, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; Alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; Alkali metal alcoholates, e.g. Potassium ethanolate and sodium propanolate; and various organic bases such as piperidine, diethanolamine and N-methylglutamine.
• alkali metal hydroxides including potassium hydroxide, sodium hydroxide and lithium hydroxide
• Alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide
• Alkali metal alcoholates e.g. Potassium ethanolate and sodium propanolate
• various organic bases such as piperidine, diethanolamine and N-methylglutamine.
• acid addition salts can be formed by reacting these compounds with pharmaceutically acceptable organic and inorganic acids, e.g. Hydrogen halides such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and their corresponding
• Salts such as sulfate, nitrate or phosphate and the like, and alkyl and
• Monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate, and other organic acids and their corresponding salts such as Acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate and the like.
• pharmaceutically acceptable acid addition salts of the compounds of formula I include the following: acetate, adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate , Cyclopentaneproprionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulphate, ethanesulphonate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate,
• base salts of the invention include
• Salts of compounds of formula I 1 derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, eg arginine, betaine, Caffeine, chloroprocaine, choline, N, N'-dibenzylethylenediamine
• Compounds of the present invention containing basic nitrogen-containing groups can be formulated with agents such as (C 1 -C 4 ) alkyl halides,
• APyI (C 1 -C 4 ) alkyl halides eg
• pharmaceutical salts which are preferred, include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,
• the acid addition salts of basic compounds of formula I are prepared by contacting the free base form with a sufficient Q amount of the desired acid to form the salt in a conventional manner.
• the free base can be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner.
• the free base forms differ in some sense from their corresponding salt forms with respect to certain physical properties such as solubility in polar solvents; in the However, the salts of the invention otherwise correspond to their respective free base forms.
• metals or amines such as alkali metals and alkaline earth metals or organic amines formed.
• metals are sodium, potassium, magnesium and calcium.
• Preferred organic amines are N, N'-dibenzylethylenediamine, chloroprocaine,
• the base addition salts of acidic compounds according to the invention are prepared by bringing the free acid form with a sufficient amount of C ,, the desired base, causing the formation of the salt in the conventional manner.
• the free acid can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.
• the free acid forms differ in some sense from their corresponding salt forms in
• a compound of the invention contains more than one group capable of forming such pharmaceutically acceptable salts, the invention also encompasses multiple salts.
• Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine,
• 35 is an active ingredient which is a compound of the formula I in the
• the pharmaceutically acceptable salt form of the active ingredient may also be this
• the active ingredient first conferred a desired pharmacokinetic property that it did not previously possess, and may even positively affect the pharmacodynamics of that agent in terms of its therapeutic efficacy in the body.
• Compounds of the formula I according to the invention may be chiral due to their molecular structure and may accordingly occur in different enantiomeric forms. They may therefore be in racemic or optically active form.
• the pharmaceutical activity of the racemates or stereoisomers of the compounds of formula I may differ, it may be desirable to use the enantiomers.
• the end product or else the intermediates may already be separated into enantiomeric compounds, chemical or physical measures known to those skilled in the art, or already be used as such in the synthesis.
• diastereomers are formed from the mixture by reaction with an optically active release agent.
• Suitable release agents are e.g. optically active acids such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline) or the various optically active camphorsulfonic acids.
• an optically active resolving agent e.g., dinitrobenzoylphenylglycine, cellulose triacetate, or others
• eluents for this purpose are aqueous or alcoholic solvent mixtures such as hexane / isopropanol / acetonitrile, for example in the ratio 82: 15: 3.
• the invention further provides the use of the compounds and / or their physiologically acceptable salts for the preparation of a pharmaceutical preparation (pharmaceutical preparation), in particular by a non-chemical route.
• a pharmaceutical preparation pharmaceutical preparation
• they can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or excipient and optionally in combination with one or more further active ingredients.
• the invention furthermore relates to medicaments comprising at least one compound of the formula I and / or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and / or adjuvants.
• compositions may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose.
• a unit may contain, for example, 0.1 mg to 3 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound of the invention, depending on the treatment
• compositions may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose.
• Preferred dosage unit formulations are those containing a daily or partial dose as indicated above or a corresponding fraction of an active ingredient.
• pharmaceutical formulations can be prepared by any of the methods well known in the pharmaceutical art.
• Pharmaceutical formulations may be administered by any suitable route, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) Ways, adapt.
• Such formulations can be prepared by any method known in the pharmaceutical art, for example, by bringing the active ingredient together with the carrier (s) or excipient (s).
• compositions adapted for oral administration may be administered as separate units, e.g. Capsules or tablets; Powder or granules; Solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
• the active ingredient component in the case of oral administration in the form of a tablet or capsule, can be mixed with an oral, non-toxic and pharmaceutically acceptable inert carrier, e.g. Ethanol, glycerin, water and the like. combine. Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a similarly comminuted pharmaceutical excipient, e.g. an edible carbohydrate such as starch or mannitol. A flavor, preservative, dispersant and dye may also be present.
• an oral, non-toxic and pharmaceutically acceptable inert carrier e.g. Ethanol, glycerin, water and the like.
• Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a similarly comminuted pharmaceutical excipient, e.g. an edible carbohydrate such as starch or mannitol.
• a flavor, preservative, dispersant and dye may also be present.
• Capsules are made by preparing a powder mix as described above and filling shaped gelatin casings therewith.
• Lubricants such as e.g. fumed silica, talc,
• Magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling process.
• a disintegrants or solubilizers such as agar-agar, calcium carbonate or sodium carbonate may also be added to improve the availability of the drug after ingestion of the capsule.
• suitable binding, lubricating and disintegrants as well as dyes can also be incorporated into the mixture.
• suitable binders include starch, gelatin, natural sugars, e.g. Glucose or beta-lactose, corn sweeteners, natural and synthetic gums, e.g. Acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, and the like.
• the lubricating agents used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
• the disintegrating agents include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
• the tablets are formulated by, for example, preparing a powder mixture, granulating or dry-pressing, adding a lubricant and a disintegrating agent and pressing the whole into tablets.
• a powder mixture is prepared by dissolving the appropriately comminuted compound with a diluent or a base as described above, and optionally with a binder, e.g. Carboxymethylcellulose, an alginate, gelatin or polyvinylpyrrolidone, a dissolution reducer, such as e.g.
• Paraffin Paraffin, a resorption accelerator, such as a quaternary salt and / or an absorbent, e.g. Bentonite, kaolin or dicalcium phosphate is mixed.
• the powder mixture can be granulated by mixing it with a binder, e.g. Syrup, starch paste, Acadia slime or solutions of cellulosic or polymer materials is wetted and pressed through a sieve.
• a binder e.g. Syrup, starch paste, Acadia slime or solutions of cellulosic or polymer materials is wetted and pressed through a sieve.
• Granulation can be run through the powder mixture through a tabletting machine, resulting in irregularly shaped lumps in
• Granules are broken up.
• the granules can be added by adding of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet molds.
• the greased mixture is then compressed into tablets.
• the compounds according to the invention can also be combined with a free-flowing inert carrier and then pressed directly into tablets without carrying out the granulation or dry-pressing steps.
• a transparent or opaque protective layer consisting of a shellac sealant, a layer of sugar or polymeric material and a glossy layer of wax may be present. Dyes can be added to these coatings in order to differentiate between different dosage units.
• Oral fluids such as solution, syrups and elixirs can be prepared in the form of dosage units so that a given quantity contains a predetermined amount of the compound.
• Syrups can be made by dissolving the compound in an appropriate taste aqueous solution while using elixirs
• Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
• Solubilizers and emulsifiers e.g. ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring additives, e.g. Peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, i.a. can also be added.
• the dosage unit formulations for oral administration may optionally be encapsulated in microcapsules.
• the formulation can also be prepared so that the release is prolonged or retarded, such as by coating or embedding particulate material in polymers, wax, etc. 35
• the compounds of the formula I and salts, solvates and physiologically functional derivatives thereof can also be administered in the form of liposome delivery systems, such as, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
• Liposomes can be prepared from various phospholipids, such as e.g.
• Cholesterol, stearylamine or phosphatidylcholines Cholesterol, stearylamine or phosphatidylcholines.
• the compounds of formula I as well as the salts, solvates and physiologically functional derivatives thereof can also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are coupled.
• the compounds can also be coupled with soluble polymers as targeted drug carriers.
• Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol or polyethyleneoxidepolylysine substituted with palmitoyl radicals.
• the compounds can be attached to a class of biodegradable polymers that are controlled to achieve
• compositions adapted for transdermal administration may be presented as discrete patches for prolonged, intimate contact with the epidermis of the recipient.
• the drug may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3 (6), 318 (1986).
• compositions adapted for topical administration may be used as ointments, creams, suspensions, lotions, powders, solutions,
• the formulations are preferably applied as a topical ointment or cream.
• the active ingredient 5 may be either paraffinic or water-miscible
• Cream base can be used.
• the active ingredient can be formulated into a cream with an oil-in-water cream base or a water-in-oil base.
• eye drops wherein the active ingredient is dissolved in a suitable carrier, in particular an aqueous solvent,
• compositions adapted for topical application in the mouth include lozenges, troches and mouthwashes.
• compositions adapted for rectal administration may be presented in the form of suppositories or enemas.
• Adapted for nasal administration pharmaceutical 5 formulations in which the carrier substance is a solid comprise a coarse powder having a particle size for example in the range 20-500 microns, which is received in the manner in which snuff is administered, ie by Quick inhalation over the
• Powder Suitable formulations for administration as a nasal spray or
• Nasal drops containing a liquid carrier include drug solutions in water or oil.
• Formulations include fine particulate dusts or mists, which by means of various types of pressurized dispensers with aerosols, nebulizers or insufflators can be produced.
• Formulations can be used as pessaries, tampons, creams, gels, pastes,
• Foams or spray formulations are presented.
• compositions adapted for parenteral administration include aqueous and nonaqueous sterile injection solutions containing antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the recipient to be treated; and aqueous and nonaqueous e sterile suspensions which may contain suspending agents and thickeners.
• the formulations may be presented in single or multi-dose containers, eg, sealed vials and vials, and stored in freeze-dried (lyophilized) condition such that only the addition of the sterile carrier liquid, eg, water for 0
• Injection solutions and suspensions prepared by formulation can be prepared from sterile powders, granules and tablets.
• formulations may include other means conventional in the art with respect to the particular type of formulation; for example, formulations suitable for oral administration may contain Q flavors.
• a therapeutically effective amount of a compound of formula I depends on a number of factors, including, for example, the age and weight of the human or animal, the exact disease state requiring treatment, as well as its severity, the nature of the formulation, and the route of administration. and ultimately determined by the attending physician or veterinarian.
• an effective amount of a compound of the invention for treatment is generally in the range of 0.1 to 100 mg / kg of body weight of the recipient (mammal) per day, and more typically in the range of 1 to 10 mg / kg of body weight per day.
• the actual amount per day would usually be between 70 and 700 mg, this amount being administered as a single dose per day or more commonly in a number of divided doses (such as two, three,
• An effective amount of a salt or solvate or a physiologically functional derivative thereof can be determined as a proportion of the effective amount of the compound of Formula I per se
• Treatment of the other, above-mentioned disease states are suitable.
• the invention further relates to medicaments containing at least
• chemotherapeutic agents are preferred, in particular those which inhibit angiogenesis and thereby inhibit the growth and spread of tumor cells; preferred are VEGF receptor inhibitors, including robozymes and antisense,
• O0 directed to VEGF receptors, as well as angiostatin and endostatin.
• antineoplastic agents examples include but not limited to
• Antineoplastic agents are preferably selected from the following five classes:
• Anthracyclines vinca drugs, mitomycins, bleomycins, cytotoxic agents, and others.
• Particularly preferred in the mentioned classes are e.g. Carminomycin, daunorubicin, aminopterin, methotrexate, methopterine, dichloromethotrexate, mitomycin C, porfiromycin, 5-fluorouracil, 5-fluorodeoxyuridine monophosphate, cytarabines, 5-azacytidine, thioguanine, azathioprines,
• Mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podophyllotoxin derivatives e.g. Etoposide, Etoposide Phosphate or Teniposide, Melphalan, Vinblastine, Vinorelbine, Vincristine, Leurosidine,
• antineoplastic agents are selected from the group consisting of:
• O0 Antibiotics are preferred as further active pharmaceutical ingredients .
• Preferred antibiotics are selected from the group dactinomycin, daunorubicin, idarubicin, epirubicin, mitoxantrone, bleomycin, plicamycin, mitomycin.
• enzyme inhibitors are preferred.
• Preferred enzyme inhibitors are selected from the group the histone deacetylation inhibitors (eg suberoylanilide hydroxamic acid [SAHA]) and the tyrosine kinase inhibitors (eg ZD 1839 [Iressa]).
• SAHA suberoylanilide hydroxamic acid
• tyrosine kinase inhibitors eg ZD 1839 [Iressa]
• nuclear export inhibitors 5 are preferred. Nuclear export inhibitors prevent the discharge of
• Biopolymers e.g., RNA from the nucleus.
• Preferred nuclear export inhibitors are selected from the group Callystatin, Leptomycin B, Ratjadone.
• nuclear export inhibitors prevent the removal of biopolymers (e.g., RNA) from the nucleus.
• biopolymers e.g., RNA
• ⁇ . c Inhibitors are selected from the group Callystatin, Leptomycin B, Ratjadone.
• immunosuppressants are preferred.
• Preferred immunosuppressants are selected from group 20 rapamycin, CCI-779 (Wyeth), RAD001 (Novartis), AP23573 (Ariad Pharmaceuticals).
• the invention is also a set (kit), consisting of separate 5 packs of
• the kit contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules.
• suitable containers such as boxes or boxes, individual bottles, bags or ampoules.
• the set may e.g. separate 5
• the present compounds are useful as pharmaceutical
• the invention thus relates to the use of compounds of formula I 1 and their pharmaceutically usable derivatives, solvates and stereoisomers, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment of diseases in which the inhibition, regulation and / or modulation of HSP90 plays a role.
• the present invention comprises the use of the compounds of the formula I and / or their physiologically acceptable salts and solvates for the preparation of a medicament for the treatment of tumorous diseases, such as, for example, Fibrosarcoma, myxosarcoma, liposarcoma,
• Chondrosarcoma osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer,
• Squamous cell carcinoma basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, bone marrow carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, Cervix cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangio- blastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma,
• Neuroblastoma retinoblastoma, leukemia, lymphoma, multiple myeloma,
• hepatitis type A hepatitis type A
• type B hepatitis
• type C hepatitis
• influenza varicella
• adenovirus herpes simplex type I
• HSV -I herpes simplex type II
• rinderpest rhinovirus, echovirus, rotavirus, respiratory syncytial virus (RSV)
• papillomavirus papovavirus, cytomegalovirus, echinovirus, arbovirus, huntavirus, coxsackievirus, mumpsvirus, measles virus, rotten virus, poliovirus, human immunodeficiency virus type I (HIV-I) and human immunodeficiency virus type II (HIV-II); for immunosuppression in transplantations; inflammation-related
• Cystic fibrosis Diseases associated with angiogenesis, e.g. diabetic retinopathy, hemangiomas, endometriosis, tumor angiogenesis; infectious diseases; Autoimmune diseases; ischemia; Promotion of nerve regeneration; fibrogenetic disorders, such as Scleroderma, polymyositis, systemic lupus, liver cirrhosis, keloid formation, interstitial nephritis and pulmonary fibrosis;
• the compounds of the formula I can in particular the growth of
• tumor cells and tumor metastases inhibit and are therefore suitable for tumor therapy.
• the present invention further includes the use of
• the invention also relates to the use of the compounds of the formula I and / or their physiologically acceptable salts and solvates for the preparation of a medicament for the treatment of central nervous system diseases, cardiovascular diseases and cachexia.
• the invention also relates in a further embodiment to the use of the compounds of the formula I and / or their physiologically acceptable salts and solvates for the production of a medicament for HSP90 modulation, where the modulated biological HSP90 activity is an immune reaction in an individual, Protein transport from endoplasmic reticulum, recovery from hypoxic / anoxic stress,
• the disorder is a type of cancer, an infectious disease, a disorder associated with impaired protein transport from the endoplasmic reticulum, a disorder associated with
• Ischemia / reperfusion or combinations thereof, wherein the ischemia / reperfusion-associated disorder is a result of cardiac arrest, asystole and delayed ventricular arrhythmias, cardiac surgery, cardiopulmonary bypass surgery, organ transplantation,
• the invention also relates to the use of the compounds of the formula I and / or their physiologically acceptable salts and solvates for the preparation of a medicament for
• geldanamycin or 17-allylamino-17-demethoxy-geldanamycin (17AAG) and their competitive inhibition to HSP90 can be used to assess the inhibitory activity of the present invention
• radioligand filter binding test is used.
• the radioligand used is tritium-labeled 17-allylamino-geldanamycin, [3H] 17AAG. This filter binding assay allows a targeted search for inhibitors that interfere with the ATP binding site.
• HEPES filter buffer 50 mM HEPES 1 pH 7.0, 5 mM MgCl 2, BSA 0.01%
• Multiscreen FB (1 ⁇ m) filter plate (Millipore, MAFBNOB 50).
• the 96 well microtiter filter plates are first watered and coated with 0.1% polyethyleneimine.
• Vacuum Manifolds Multiscreen Separation System, Millipore aspirated and the filter washed twice.
• the filter plates are then measured in a beta counter (Microbeta, Wallac) with scintillator (Microscint 20, Packard).
• Hewlett Packard HP 1100 series system with the following features: Ion source: electrospray (positive mode); Scan: 100-1000 m / z; Fragmentation voltage: 60 V; Gas temperature: 300 0 C, DAD: 220 nm.
• Flow rate 2.4 ml / min.
• the splitter used reduced the flow rate for the MS to O, 75 ml / min after the DAD.
• Solvent LiChrosolv grade from Merck KGaA
• Solvent A H2O (0.01% TFA)
• Solvent B ACN (0.008% TFA)
• a solution of 2.0 kg of methyl 2-aminobenzoate in 15 liters of dichloromethane 10 is mixed with 1 liter of glacial acetic acid and 10 liters of ice water. With vigorous stirring is added at 10 ° 1, 9 kg calcium hypochlorite, the temperature should not rise above 15 °. It is stirred for 6 hours and allowed to stand for 16 hours.
• the dichloromethane is separated off, the aqueous phase is washed with dichloromethane and the combined organic phases are washed with a 10% Na 2 SO 3 solution (heating!).
• the combined dichloromethane phases are stirred with 2 kg of silica gel, 200 g of activated charcoal and 2 kg of sodium sulfate.
• reaction mixture is poured onto 10 liters of ice and stirred 3
• BOC-GABA-OH BOC- ⁇ -aminobutyric acid
• BOC-Ala-OH BOC- (S) -alanine
• Example 1.4 Analogously to Example 1.4, the compound is obtained by reacting "3" with 5-fluoro-4-methoxy-2-nitrophenylboronic acid 2,6-dichloro-4- (5-fluoro-4-methoxy-2-nitro-phenyl) -quinazoline; and from this analogously to Example 1.5 and 1.6 the compound
• the compound is obtained by reacting 2-amino-6-chloro-4- (2-hydroxy-4-methoxyphenyl) quinazoline with 4-chloro-butyric acid methyl ester and ester hydrolysis
• the compound is obtained by reacting 2-amino-6-chloro-4- (3-hydroxy-5-methoxyphenyl) quinazoline with 4-chloro-butyric acid methyl ester and ester hydrolysis
• the compound is obtained by reacting 2-amino-6-aminomethylcarbonylamino-4- (2-hydroxyphenyl) quinazoline with 4-chlorobutyric acid amide
• the compound is obtained by reacting 2-amino-4- (2-amino-4-chlorophenyl) -quinazoline with methoxycarbonyl-methoxy-acetic acid, after ester cleavage and after customary work-up
• Example 12 Analogously to Example 12 is obtained by reacting 2-amino-6-chloro-4- (3-hydroxy-4-methoxyphenyl) quinazoline with 4-chloro-butyric acid ethyl ester the compound 2-amino-6-chloro-4- [3- (3-ethoxycarbonyl-propoxy) -4-methoxy-phenyl] -quinazoline ("A98"), MW 416.88
• a solution of 94.36 g of BOC-L-Asn and 62.22 g of 1-hydroxybenzotriazole hydrate in 1 ml of DMF is treated with 106.2 mg of N- (dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (DAPECI) and 56.04 mg 4-methylmorpholine (NMM) and stirred for 4 hours at room temperature. You give 100 mg "6" and stirred for 16 hours. You give everything in 10 ml of water and separates the precipitated material. It is dissolved in 2 ml of dichloromethane, treated with 1 ml of TFA and stirred for 16 hours at room temperature.
• DAPECI N- (dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride
• NMM 4-methylmorpholine
• Example A Injection glasses
• a solution of 100 g of an active ingredient according to the invention and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 2 l of twice-distilled water with 2N hydrochloric acid, filtered sterile, filled into injection vials, lyophilized under sterile conditions and closed under sterile conditions. Each injection jar contains 5 mg of active ingredient.
• a mixture of 20 g of an active ingredient according to the invention is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
• a solution of 1 g of an active ingredient is prepared according to the invention, 9.38 g of NaH 2 PO 4 ⁇ 2 H 2 O, 28.48 g Na 2 HPO 4 12 ⁇ H 2 O and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water , Adjust to pH 6.8, make up to 1 liter and sterilize by irradiation.
• This solution can be used in the form of eye drops.
• Example E Tablets
• a mixture of 1 kg of active ingredient, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in the usual way into tablets, such that each tablet contains 10 mg of active ingredient.
• Tablets are pressed analogously to Example E, which are then coated in the usual way with a coating of sucrose, potato starch, talc, tragacanth and dye.
• a solution of 1 kg of an active ingredient according to the invention in 60 l of bidistilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each vial contains 10 mg of active ingredient.

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