Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • 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
  • A61P31/12—Antivirals
• • 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
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • 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
  • A61P35/02—Antineoplastic agents specific for leukemia
• • 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

Definitions

• the invention relates to compounds of the formula I.
• R 1 is H, A, - [C (R 6 ) 2 ] n Ar, - [C (R 6 ) 2 ] n Het or - [C (R 6 ) 2 ] n cycloalkyl,
• R 2 is H, A, benzyl or CH 2 CH 2 OR 6 ,
• R 3 , R 4 are each independently H, A, Hal, CN, - [C (R 6 ) 2 ] n Ar, - [C (R 6 ) 2 ] n Het or - [C (R 6 ) 2 ] n cycloalkyl .
• R b is H or alkyl having 1-6 C atoms
• R fc is H or alkyl having 1-6 C atoms
• Cycloalkyl Cyclic alkyl having 3-7 C atoms, which may additionally be substituted by alkyl having 1-6 C atoms,
• Hal is F, Cl, Br or I
• Ar is unsubstituted or mono-, di- or trisubstituted by Hal, A,
• 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 compounds according to the invention can therefore be used for the control and / or treatment of tumors, tumor growth and / or tumor metastases.
• the antiproliferative effect can be tested in a proliferation assay / vitality assay.
• amino-pyrimidinyl derivatives are described in WO 2006/050076.
• Other 4- (pyrrolopyridinyl) -pyrimidinyl-2-amine derivatives are described, for example, by PM Fresneda et al. in Tetrahedron 57 (2001) 2355-2363.
• Other 4- (pyrrolopyridinyl) -pyrimidinyl-2-amine derivatives are also described by A. Karpov in his dissertation, University of Heidelberg, April 2005.
• Other amino-pyrimidine derivatives bearing a 2,2,6,6-tetramethyl-piperidin-4-yl moiety are described for the treatment of inflammatory and autoimmune diseases in WO 2004/089913.
• the compounds of the invention or a pharmaceutically acceptable salt thereof are administered for the treatment of cancer including solid carcinomas such as carcinomas (eg, the lungs, pancreas, thyroid, bladder, or colon), myeloid diseases (eg myeloid leukemia) or adenomas (eg villous colonic adenoma).
• solid carcinomas such as carcinomas (eg, the lungs, pancreas, thyroid, bladder, or colon)
• myeloid diseases eg myeloid leukemia
• adenomas eg villous colonic adenoma
• the tumors further include monocytic leukemia, brain, urogenital, lymphatic, gastric, laryngeal and lung carcinomas, including lung adenocarcinoma and small cell lung carcinoma, pancreatic and / or breast carcinoma.
• the compounds are also useful in the treatment of HIV-1 (human immunodeficiency virus type 1) induced immunodeficiency.
• Cancerous hyperproliferative disorders include brain, lung, squamous, bladder, stomach, pancreatic, liver, kidney, colorectal, breast, head, neck, esophageal, gynecological, thyroid, lymphoma
• cancerous cell growth is a disease that is an object of the present invention.
• the present invention therefore relates to compounds according to the invention as medicaments and / or active pharmaceutical ingredients in the treatment and / or prophylaxis of said diseases and the use of compounds of the invention for the preparation of a Pharrnazeutikums for the treatment and / or
• Treatment of said diseases comprising administration of one or more compounds of the invention to a patient in need of such administration.
• the compounds according to the invention have an antiproliferative action.
• the compounds of the invention are administered to a patient with a hyperproliferative disorder, e.g. To inhibit tumor growth, to reduce inflammation associated with a lymphoproliferative disorder, to inhibit graft rejection or neurological damage due to tissue repair, etc.
• a hyperproliferative disorder e.g. to inhibit tumor growth, to reduce inflammation associated with a lymphoproliferative disorder, to inhibit graft rejection or neurological damage due to tissue repair, etc.
• the present compounds are useful for prophylactic or therapeutic purposes.
• the term "treatment” is used to refer to both the e prevention of diseases and treatment of pre Leiden.
• the prevention of proliferation / vitality is achieved by administering the compounds according to the invention prior to development of overt disease, z. B. to prevent tumor growth.
• the host or patient may be of any mammalian species, e.g. A primate species, especially humans; Rodents, including mice,
• Rats and hamsters Rats and hamsters; Rabbits; Horses, cattle, dogs, cats etc.
• Animal models are for experimental investigations of interest, providing a model for treatment of human disease Q available.
• the susceptibility of a particular cell to treatment with the compounds of the invention can be determined by testing in vitro.
• the dose will vary depending on the specific compound used, the specific disease, the patient status, etc. Typically, one therapeutic dose will be sufficient to target the unwanted cell population
• Treatment is generally continued until there is a significant reduction, e.g. B. at least about 50% reduction in cell load and can be continued until substantially
• the ailments of interest include, but are not limited to, the following conditions.
• Transplant vascular diseases of interest include atherosclerosis, coronary vascular disease after transplantation, vein graft stenosis, peri-anastomotic prosthetic restenosis, restenosis after angioplasty or stent placement, and the like.
• the compounds of the formula I also act as regulators, modulators or inhibitors of protein kinases, in particular of the serine / threonine kinase type.
• the compounds also show activity against TGF-beta kinase, hSGK and / or CDK2.
• Protein kinase-mediated diseases are characterized by abnormal activity or hyperactivity of such protein kinases. Abnormal activity involves either: (1) expression in cells that usually do not express these protein kinases; (2) increased kinase 5
• Hyperactivity refers to either amplification of the gene that
• ⁇ 5 of a protein kinase may also be affected by the presence or absence of a set of binding proteins of this kinase.
• Compound can treat, include colorectal cancer,
• the compounds of the present invention can be used to achieve additive or synergistic effects in certain existing cancer chemotherapies and radiation and / or to inhibit them
• O0 restore efficacy of certain existing cancer chemotherapies and radiation.
• the compounds of the formula I are also understood to mean their pharmaceutically usable derivatives, solvates and all polymorphs
• the invention also relates to the optically active forms (stereoisomers), salts, the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds.
• 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, for example, mono- or dihydrate or alcoholates.
• Pharmaceutically usable derivatives are understood as meaning, for example, the salts of the compounds according to the invention and also what are known as prodrug compounds.
• biodegradable polymer derivatives of the compounds of the invention include biodegradable polymer derivatives of the compounds of the invention, as z. In Int. J. Pharm. 115, 61-67 (1995).
• the term "effective amount” means the amount of a drug or pharmaceutical agent that elicits a biological or medical response in a tissue, system, animal or human, e.g. sought or desired by a researcher or physician.
• the term "therapeutically effective amount” means an amount which, compared to a corresponding subject who has not received this amount, results in: improved curative treatment, cure, prevention or elimination of a disease, a disease, a disease state, a disease Suffering, a disorder or side effects or even the reduction of the progression of a disease, a disease or a disorder.
• therapeutically effective amount also includes the amounts effective to increase normal physiological function.
• the invention also provides the use of mixtures of
• 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 1-13 and their pharmaceutically usable salts,
• R is a protecting group
• R 3 , R 4 and R 5 have the meanings given in claim 1,
• R is a protecting group
• R 3 , R 4 and R 5 have the meanings given in claim 1,
• R 1 is - [C (R 6 ) 2 ] n Ar or - [C (R 6 ) 2 ] n Het, and Ar, Het, R 6 and n have the meanings given in claim 1,
• R is a protective group
• R 3 is trialkylsilyl, wherein alkyl has 1-6 carbon atoms
• R 4 and R 5 have the meanings given in claim 1,
• R 1 substituted guanidine wherein R 1 - [C (R 6 ) 2 ] n is Ar or - [C (R 6 ) 2 ] n Het, and simultaneously or subsequently the protective group R is split off,
• A is alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms.
• A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore 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-,
• A also means 2-5
• Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
• Ar means e.g. Phenyl, o-, m- or p-tolyl, o-, m- or 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,
• Ar is preferably unsubstituted or mono-, di- or trisubstituted by A, Hal, OR 6 and / or CN substituted phenyl.
• Benzisothiazolyl 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, A-, 5-, 6-, 7- or 8-quinolyl, 1-, 3- , 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, A-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo [1,4] oxazinyl, more preferably 1,3-benzodioxole-5 -yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4 or 5-yl or 2,1,3-benzoxadiazol-5-yl.
• the heterocyclic radicals may also be partially or completely hydrogenated.
• Unsubstituted Het can thus z.
• B. also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -A- or 5-furyl, tetrahydro-2 - or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or 3-thienyl, 2,3-dihydro-1, -2, -3, -A- or -5 -pyrrolyl, 2,5-dihydro-1-, 2-, -3-, -A- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4 -imidazolyl, 2,3-dihydro-1-, 2-, -3-, -A- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazo
• Het furthermore preferably denotes an unsubstituted or mono- or di-substituted by one mono- or bicyclic aromatic heterocycle having 1 to 4 N, and / or O and / or S atoms.
• R 1 is preferably H, - [C (R 6 ) 2 ] n Ar or - [C (R 6 ) 2 ] n Het.
• R 1 particularly preferably denotes H, phenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-hydroxyphenyl , o-, m- or p-methoxyphenyl, 4-fluoro-3-chlorophenyl, pyridyl,
• R 2 is preferably H.
• R 3 is preferably H, A, benzyl or CH 2 CH 2 OCH 3 .
• R 3 is preferably H, A, - [C (R 6 ) 2 ] n Het or - [C (R 6 ) 2 ] n Ar.
• R 4 is preferably H.
• R 5 is preferably H.
• R 6 is preferably H or CH 3 .
• n is preferably 0 or 1.
• Hal preferably denotes F, Cl or Br, but also I 1 particularly preferably F or Cl. It is true for the entire invention that all radicals which occur more than once can be the same or different, ie are independent of one another.
• 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 relates in particular to those compounds of the formula I in which at least one of the radicals mentioned
• R 1 is H, - [C (R 6 ) 2 ] n Ar or - [C (R 6 ) 2 ] ⁇ Het;
• R 2 is H, A, benzyl or CH 2 CH 2 OCH 3 ;
• Ic R 3 is H, A, - [C (R 6 ) 2 ] n Het or - [C (R 6 ) 2 ] n Ar;
• N in If A is a straight or branched alkyl having 1-8 C atoms, oil) in which a CH 2 group may be replaced by oxygen and / or also 1-7 H atoms by F, means;
• Ii Het an unsubstituted or mono- or di-substituted by A mono- or binuclear aromatic heterocycle having 1 to 4 N-, and / or O- and / or S-
• R 3 is H, A, - [C (R 6 ) 2 ] n Het or - [C (R 6 ) 2 ] n Ar,
• R 5 is H
• R 6 is H or alkyl having 1-6 C atoms
• A is unbranched or branched alkyl having 1-6 C atoms, in which 1-7 H atoms may be replaced by F,
• Ar is unsubstituted or mono-, di- or trisubstituted by A,
• Compounds of formula I may preferably be obtained by reacting compounds of formula II or formula V with a guanidine salt, e.g. Guanidinium carbonate, reacted.
• a guanidine salt e.g. Guanidinium carbonate
• the compounds of the formula II and of the formula V are generally known. If they are new, they can be produced by methods known per se.
• the reaction takes place in an inert solvent and is generally carried out in the presence of an acid-binding agent, preferably an organic base such as DIPEA, triethylamine, dimethylaniline, pyridine or quinoline.
• an acid-binding agent preferably an organic base such as DIPEA, triethylamine, dimethylaniline, pyridine or quinoline.
• an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or other salt of a weak acid of Alkali or alkaline earth metals preferably potassium, sodium, calcium or cesium may be beneficial.
• reaction time depending on the conditions used, between a few minutes and 14 days, the reaction temperature between about -15 ° and 150 °, normally between 40 ° and 130 °, particularly preferably between 60 ° and 110 0 C.
• Suitable inert solvents are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers, such as diethyl ether, diisopropyl ether,
• Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene
• chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane
• Alcohols such as methanol, ethanol, isopropanol, n-propano
• Tetrahydrofuran (THF) or dioxane Tetrahydrofuran (THF) or dioxane
• Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides like
• Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of said solvents.
• Nitro compounds such as nitromethane or nitrobenzene
• Esters such as ethyl acetate or mixtures of said solvents.
• glycol ethers such as ethylene glycol monomethyl ether, THF, dichloromethane and / or DMF.
• Preferred protecting groups are e.g. Sulfonyl protecting groups such as tosyl or mesyl, further protecting groups such as e.g. BOC.
• the reaction is carried out in an inert solvent and under
• the compounds of the formula I can furthermore be obtained by liberating them from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenolysis.
• Preferred starting materials for the solvolysis or hydrogenolysis are those which contain, instead of one or more free amino and / or hydroxyl groups, corresponding protected amino and / or hydroxyl groups, preferably those which, instead of an H atom which is substituted by an N- Atom, carry an amino protecting group, z.
• amino protecting group is well known and refers to groups which are capable of protecting (blocking) an amino group from chemical reactions, but which are readily removable after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are in particular unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Moreover, because the amino protecting groups are removed after the desired reaction (or reaction sequence), their type and size is not critical; however, preference is given to those having 1-20, in particular 1-8 C atoms.
• acyl group is to be understood in the broadest sense in the context of the present process.
• acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups.
• acyl groups are alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl such as Mtr, Pbf or Pmc.
• Preferred amino protecting groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl.
• hydroxy protecting group is also well known and refers to groups which are capable of protecting a hydroxy group from chemical reactions, but which are readily removable after the desired chemical reaction at other sites of the invention
• Typical of such groups are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl groups, and also alkyl groups.
• the nature and size of the hydroxy-protecting groups is not critical since they are removed after the desired chemical reaction or reaction sequence; preferred are groups having 1-20, in particular 1-10 C-atoms. Examples of hydroxy protecting groups include i.a. tert-butoxycarbonyl, benzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred.
• the COOH groups in aspartic acid and glutamic acid are preferably protected in the form of their tert-butyl esters (eg, Asp (OBut)).
• Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol, and water. Also suitable are mixtures of the abovementioned solvents. TFA is preferably used in excess without the addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9: 1.
• the reaction temperatures for the cleavage are suitably between about 0 and about 50 °, preferably between 15 and 30 ° (room temperature).
• the groups BOC, OBut, Pbf, Pmc and Mtr can, for. B. preferably cleaved with TFA in dichloromethane or with about 3 to 5n HCl in dioxane at 15-30 °, the FMOC group with an about 5- to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30 °.
• Hydrogenolytically removable protecting groups may e.g. By cleavage with hydrogen in the presence of a catalyst (e.g., a noble metal catalyst such as palladium, conveniently on a support such as carbon).
• a catalyst e.g., a noble metal catalyst such as palladium, conveniently on a support such as carbon.
• Suitable solvents are those given above, in particular z.
• alcohols such as methanol or ethanol or amides such as DMF. Hydrogenolysis is usually included
• the abovementioned compounds according to the invention can be used in their final non-salt form.
• the present invention also encompasses the use of these compounds in the form of theirs pharmaceutically acceptable salts which can be derived from various organic and inorganic acids and bases by art-known procedures.
• 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 base addition salt.
• 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, eg, 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 eg, 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, for example 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,
• 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,
• the base salts of the compounds according to the invention include aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium , Sodium and zinc salts, but this should not be limiting.
• Preferred among the above salts are ammonium; the alkali metal salts sodium and potassium, and the alkaline earth metal salts calcium and magnesium.
• Salts of compounds of formula I 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, e.g. Arginine, betaine, caffeine,
• Groups can be, with agents such as (Ci-C 4 ) alkyl halides, such as methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; Di (C 1 -
• alkyl sulfates for example dimethyl, diethyl and diamyl sulfate; (Cio-C18) alkyl halides, for example decyl, dodecyl, lauryl, myristyl and stearyl chloride, - bromide, and iodide; and aryl (C r C 4 ) alkyl halides, eg benzyl chloride and phenethyl bromide, quaternize.
• aryl (C r C 4 ) alkyl halides eg benzyl chloride and phenethyl bromide, quaternize.
• Preferred pharmaceutical salts include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, Stearate, 10 sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine, which is not intended to be limiting.
• the acid addition salts of basic compounds of formula I are,
• 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 a certain sense
• the pharmaceutically acceptable base addition salts of the compounds of formula I are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines.
• Preferred metals are sodium, potassium, magnesium and calcium.
• Preferred organic amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.
• 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 in some sense differ from their corresponding salt forms in terms of certain physical properties such as solubility in polar
• a compound according to the invention contains more than one group which can form such pharmaceutically acceptable salts, the invention also encompasses multiple salts.
• Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium and trihydrochloride, but this is not intended to be limiting.
• An active ingredient is to be understood, which contains a compound of formula I in the form of one of its salts, especially when this salt form the pharmacokinetic properties of the active ingredient compared to the free form of the active ingredient or any other salt form of the active ingredient, which has been used previously improved gives.
• the pharmaceutically acceptable salt form of the active substance may also first impart a desired pharmacokinetic property to this active ingredient which it has not previously possessed, and may even positively influence the pharmacodynamics of this active ingredient in terms of its therapeutic activity in the body.
• the invention furthermore relates to medicaments comprising at least one compound of the formula I and / or pharmaceutically usable compounds thereof
• 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, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound according to the invention, depending on the treatment
• Disease condition the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be in the form of dosage units containing a predetermined amount of active ingredient per
• Preferred unit dosage formulations are those containing a daily or partial dose as indicated above or a corresponding fraction thereof of an active ingredient. Furthermore, such pharmaceutical formulations can be
• ⁇ c produce by any of the methods well known in the pharmaceutical art.
• compositions may be administered for administration by any suitable route, for example, oral (including
• buccalem or sublingual rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) routes.
• Such formulations may 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 contain as separate units, such as 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 can be mixed with an oral, non-toxic and pharmaceutically acceptable inert carrier, such as
• 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 carrier, such as a gum. 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 and .J stearate 5 lubricant such as finely divided silica, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form may be added to the powder mixture before the filling operation.
• a disintegrant or solubilizer such as agar-agar, calcium carbonate or
• suitable bonding, lubricating and disintegrating agents and dyes may also be included in 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, carboxymethylcellulose, polyethylene glycol, waxes,
• lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like Among the disintegrants, without being restricted thereto, starch, methylcellulose, agar, bentonite,
• Xanthan gum and the like The tablets are formulated by, for example
• a powder mixture is prepared by treating the appropriately comminuted compound with a diluent or a base as described above, and optionally with a
• Binders such as e.g. Carboxymethylcellulose, an alginate, gelatin or
• Polyvinylpyrrolidone a dissolution reducer, such as e.g. Paraffin, one
• Absorption enhancer e.g. 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 cellulose or polymer materials wetted and pressed through a sieve.
• a binder e.g. Syrup, starch paste, Acadia slime or solutions of cellulose or polymer materials wetted and pressed through a sieve.
• the powder mixture can be run through a tableting machine to produce non-uniformly shaped lumps which are broken up into granules.
• the granules may be greased by the addition 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 of the invention can also be used with a
• 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.
• Coatings can be added to dyes to distinguish between different dosage units.
• Oral fluids e.g. Solution, syrups and elixirs may be prepared in unit dosage form such that a given quantity contains a predetermined amount of the compound.
• Syrups can be prepared by dissolving the compound in an appropriate taste aqueous solution while preparing elixirs using a non-toxic alcoholic vehicle.
• Suspensions may be prepared by dispersing the compound in a non-aqueous solution.
• Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring additives such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, among others, may also be added.
• the unit dosage formulations for oral administration may optionally be encapsulated in microcapsules.
• the formulation may also be prepared to prolong or retard release, such as by coating or embedding particulate material in polymers, wax, and the like.
• the compounds of formula I as well as salts, solvates and physiologically functional derivatives thereof can also be administered in the form of liposome delivery systems, such as e.g. small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
• Liposomes can be prepared from various phospholipids, such as e.g. Cholesterol,
• Stearylamine or phosphatidylcholines are formed.
• 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 can polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamidphenol, or Polyhydroxyethylaspartamidphenol
• Polyethylene oxide polylysine substituted with palmitoyl radicals may be linked to a class of biodegradable polymers which are capable of controlled release of a
• Drugs suitable e.g. Polylactic acid, polyepsilon-caprolactone,
• Formulations can be used as separate patches for longer, narrow
• the drug may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3 (6), 318 (1986).
• Pharmaceutical compounds adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
• the formulations are preferably as a topical ointment or
• the active ingredient 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.
• the pharmaceutical formulations adapted for topical application to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially 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.
• Pharmaceutical formulations adapted for nasal administration in which the vehicle is a solid contain a coarse powder having a particle size, for example in the range of 20-500 microns, which is administered in the manner in which snuff is received, ie by rapid inhalation via the nasal passages from a container held close to the nose with the powder.
• Suitable formulations for administration as a nasal spray or nasal drops with a liquid carrier include drug solutions in water or oil.
• Fine particulate dusts or mists which may be generated by various types of pressurized dosing dispensers with aerosols, foggers or insufflators.
• compositions adapted for vaginal administration may be used as pessaries, tampons, creams, gels, pastes, foams or
• compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions containing anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickeners.
• the formulations may be administered in single or multi-dose containers, e.g. sealed vials and vials, and stored in the freeze-dried (lyophilized) state so that only the addition of the sterile carrier liquid, e.g. Water for injections, needed immediately before use.
• the sterile carrier liquid e.g. Water for injections
• Injection solutions and suspensions may be sterile powders
• 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 flavorings.
• a therapeutically effective amount of a compound of formula I depends on a number of factors, including e.g. The age and weight of the animal, the exact condition of the disease requiring treatment, its severity, the nature of the formulation and the route of administration, are ultimately determined by the attending physician or veterinarian.
• an effective amount of a compound of the invention is useful for the treatment of neoplastic growth, e.g. Colon or breast carcinoma, generally in the range of 0.1 to 100 mg / kg body weight of the recipient (mammal) per day and more typically in the range of 1 to 10 mg / kg body weight per day.
• Amount per day is usually between 70 and 700 mg, which may be given as a single dose per day or more commonly in a number of divided doses (such as two, three, four, five or six) per day such that the
• 25 total daily dose is the same.
• 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 the invention per se. It can be assumed that similar dosages for the
• the invention furthermore relates to medicaments comprising at least one compound of the formula I and / or pharmaceutically usable compounds thereof
• the invention is also a set (kit), consisting of separate packages 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. containing separate ampoules each containing an effective amount of a compound of formula I and / or its pharmaceutically acceptable salts
• ⁇ c and stereoisomers including mixtures thereof in all ratios, and an effective amount of another active pharmaceutical ingredient dissolved or in lyophilized form.
• the instant compounds are useful as pharmaceutical agents for mammals, particularly for humans, in the treatment and control of cancers. 5
• the present invention includes the use of the compounds of
• Formula I and / or its physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment or prevention of cancer.
• Preferred carcinomas for the treatment come from the group brain carcinoma, genitourinary tract carcinoma, carcinoma of the lymphatic system,
• Gastric carcinoma gastric carcinoma, laryngeal carcinoma and lung carcinoma.
• Another group of preferred forms of cancer are monocyte leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma and breast carcinoma.
• Also included is the use of the compounds of formula I and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment and / or control of a tumorigenic disease in a mammal, comprising:
• a method of administering to a diseased mammal in need of such treatment a therapeutically effective amount of a compound of the invention.
• the therapeutic amount depends on the particular disease and can be determined by the skilled person without great effort.
• a disease wherein the disease is a solid tumor.
• the solid tumor is preferably selected from the group of squamous cell tumors, bladder, stomach, kidney, head and neck, esophagus, cervix, thyroid, intestine, and the like
• the solid tumor is furthermore preferably selected from the group of lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma, colon carcinoma and breast carcinoma.
• a tumor of the blood and immune system preferably for the treatment of a tumor selected from the group of acute myelotic leukemia, chronic myelotic leukemia, acute lymphoblastic leukemia and / or chronic lymphocytic leukemia.
• the invention further relates to the use of the compounds according to the invention for the treatment of bone pathologies, wherein Bone pathology originates from the group osteosarcoma, osteoarthritis and rickets.
• the compounds of formula I may also be coadministered with other well-known therapeutics selected for their particular suitability for the condition being treated.
• the present compounds are also useful for combination with known anticancer agents. These include known anticancer agents
• estrogen receptor modulators androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors and others
• Estrogen receptor modulators refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of how this occurs.
• modulators include, for example, tamoxifen, raloxifene, idoxifen, LY353381,
• Androgen receptor modulators refers to compounds that interfere with or inhibit the binding of androgens to the receptor, and
• Androgen receptor modulators include, for example, finasteride and other 5 ⁇ -reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.
• Retinoid receptor modulators refers to compounds that
• retinoids Disrupt or inhibit retinoids to the receptor, regardless of how this happens.
• retinoid receptor modulatory include, for example, bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, ⁇ -difluoromethylornithine, ILX23-7553, trans-N- (4'-hydroxyphenyl) -retinamide and N-4-carboxyphenylretinamide.
• Cytotoxic agents refers to compounds that are primarily derived from direct
• cytotoxic agents include, for example, tirapazimine, Sertenef, cachectin, ifosfamide, tasonermine, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcite, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improvisulfan-tosylate, trofosfamide, nimustine, dibrosylamine.
• microtubulin inhibitors include, for example, paclitaxel, vindesine sulfate, S '' '- dideshydro' '- desoxy- ⁇ '-norvincaleukoblastin, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin,
• RPR109881, BMS184476 vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) benzenesulfonamide, anhydrovinblastine, N 1 N-dimethyl-L-valyl-L-valyl-N methyl-L-valyl-L-prolyl-L-proline-t-butylamide,
• Topoisomerase inhibitors are for example topotecan, hycaptamine,
• Antiproliferative agents include antisense RNA and DNA
• Oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabinecofosfate, fosteabic sodium hydrate, raltitrexed, paltitrexide, emitefur, tiazo furin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'-methylidenecytidine, 2 l -fluoromethylene-2'-deoxycytidine, N- [5- (2,3-dihydrobenzofuryl) sulfonyl] -N '- (3 , 4-dichlorophenyl) urea, N6- [4-deoxy-4-Q [
• antiproliferative agents also include other monoclonal antibodies to growth factors than those already known under the "angiogenesis"
• Inhibitors such as trastuzumab, as well
• Tumor suppressor genes such as p53, recombinantly mediated by virus
• Tumor cell proliferation / tumor cell vitality described by drugs are seeded in suitable cell density in microtiter plates (96-well format) and the test substances are in the form of a
• tumor cell proliferation / tumor cell vitality can be determined by an Alamarblue test system.
• Q Cells are cultured in medium. At intervals of several days, the cells are detached from the culture dishes with the aid of trypsin solution and seeded in fresh medium at a suitable dilution. The cells are cultured at 37 ° C and 10% CO 2 . 5
• a defined number of cells (eg 2000 cells) are seeded per culture / well in a volume of 180 ⁇ l culture medium in microtiter plates (96 well cell culture plates) with a multichannel pipette. The cells are then cultured in a CO2 incubator (37 ° C and 10% CO2).
• test substances are dissolved, for example, in DMSO and then used in the cell culture medium in appropriate concentration (optionally a dilution series).
• concentration optionally a dilution series
• the dilution levels can be adjusted depending on the efficiency of the active ingredients and the desired spread of the concentrations.
• the test substances are mixed in appropriate concentrations with cell culture medium.
• the addition of the test substances to the cells can take place on the same day as the sowing out of the cells. For this purpose, 20 ⁇ l of substance solution is added to the cultures / wells from the predilution plate.
• the cells are cultured for a further 4 days at 37 ° C and 10% CO 2 .
• microtiter plates are kept in one for another seven hours
• CO2 incubator at 37 ° C and 10% CO2.
• the plates are measured on a reader with a fluorescence filter at a wavelength of 540 nm.
• the plates can be easily shaken just before the measurement.
• the absorbance value of the medium control (no use of cells and test substances) is subtracted from all other extinction values.
• the Controls (cells without test substance) are set equal to 100 percent and all other absorbance values related thereto (expressed as% of control, for example):
• APCI-MS atmospheric pressure chemical ionization - mass spectrometry (M + H) + . - -
• Chromolith Performance RP-18e Merck KGaA, Cat 1.02129.0001
• 25 solution is introduced in an autoclave apparatus carbon monoxide and stirred for 50 minutes at a pressure of about 5 bar.
• the apparatus is depressurised and 0.18 ml (1.50 mmol) of 1-hexyne and 0.28 ml (2.00 mmol) of triethylamine are added under nitrogen.
• the apparatus is again under a pressure of
• Residue is on a silica gel column with petroleum ether / ethyl acetate as
• the apparatus is decompressed and 2.45 g (24.9 mmol) of trimethylsilylacetylene and 1.68 g (16.6 mmol) of triethylamine are added under nitrogen.
• the apparatus is again placed under a pressure of 5 bar carbon monoxide and the reaction mixture is stirred for 41 hours at room temperature.
• the reaction mixture becomes saturated Sodium chloride solution and extracted with dichloromethane.
• the organic phase is dried over sodium sulfate and evaporated.
• the residue is chromatographed on a silica gel column with petroleum ether / ethyl acetate as
• reaction mixture is heated rapidly to 80 ° C and stirred for 5 min at this temperature.
• the reaction mixture is cooled rapidly to room temperature, diluted with 5 ml of water and extracted several times with dichloromethane.
• the combined organic phases are dried over sodium sulfate, evaporated and chromatographed on a silica gel column with petroleum ether / ethyl acetate / triethylamine (5: 1: 0.1) as the eluent.
• 3- [3- (4-fluorophenyl) -propinoyl] -pyrrolo [2,3-c] pyridine-1-carboxylic acid tert-butyl ester is obtained as an orange solid; ESI 365.
• Example A Injection glasses
• a solution of 100 g of an active compound of the formula I and 5 g of disodium hydrogen phosphate is adjusted to pH 6.5 in 3 l of bidistilled water with 2N hydrochloric acid, filtered sterile, filled into injection jars, lyophilized under sterile conditions and sealed under sterile conditions. Each injection jar contains 5 mg of active ingredient.
• Betspiel B Suppositories
• a mixture of 20 g of an active compound of the formula I 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 is prepared from 1 g of an active compound of the formula I, 9.38 g
• 500 mg of an active compound of the formula I are mixed with 99.5 g of Vaseline under aseptic conditions.
• a mixture of 1 kg of active ingredient of the formula I 1 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is added in the usual manner
• Example E tablets are pressed, which are then in the usual
• a solution of 1 kg of active compound of the formula I 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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