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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/10—Drugs for disorders of the urinary system of the bladder
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • 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
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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 and the use of
• compositions containing these compounds are provided.
• the present invention relates to compounds of the formula I 1 which preferably inhibit one or more enzymes which contain the
• Lysophosphate acid (/ phosphositate / d / c ac / d or LPA for short) regulate and / or modulate levels, compositions containing these
• Retinopathy inflammatory diseases, arthritis, neurodegeneration, restenosis, wound healing or graft rejection.
• the compounds according to the invention are suitable for the therapy or prophylaxis of cancerous diseases.
• ATX Autotaxin
• LPA lysophatidylcholine
• LPA is found in increased concentrations in plasma and ascites fluid of ovarian cancer patients of early and late stage, LPA plays a role in tumor cell proliferation and its invasion into adjacent tissues, which can lead to metastasis (Xu et al., 1995, Clinical Cancer Research Vol 1, page 1223 and Xu et al., 1995, Biochem., J. VoI-309, page 933).
• LPA G protein-coupled receptors
• Autotaxin belongs to the enzyme family of nucleotides pyrophosphatases and phosphodiesterases (Goding et al., 1998, Immunol., Rev. Vol. 161, page 11) and is an important starting point for antitumor therapy (Mills et al., 2003, Nat. Rev. Cancer Vol.
• Angiogenesis is an important process in tumor growth, which ensures the supply of nutrients to the tumor. For this reason, the inhibition of angiogenesis is an important starting point of cancer and tumor therapy, with which the tumor can be starved to some extent (Folkman, 2007, Nature Reviews Drug Discovery Vol. 6, page 273-286).
• Nucleotide pyrophosphatases and phosphodiesterases in particular autotaxine effect.
• the compounds of the invention preferably exhibit a beneficial biological activity that is readily detectable in the assay described, for example, herein.
• the compounds of the invention preferably exhibit and effect an inhibiting effect, which is usually documented by IC 50 sites in a suitable range, preferably in the micromolar range, and more preferably in the nanomolar range.
• all solid and non-solid tumors can be treated with the compounds of formula I, e.g. monocytic leukemia, brain, urogenital, lymphatic, gastric, laryngeal, ovarian and lung carcinomas, including lung adenocarcinoma and small cell lung carcinoma.
• Other examples include prostate, pancreatic and breast carcinoma.
• the compounds of the invention are useful in the prophylaxis and / or treatment of diseases which are affected by inhibition of one or more nucleotide pyrophosphatases and / or phosphodiesterases, particularly autotaxin.
• 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
• the compounds according to the invention have a beneficial effect in a xenograft tumor model.
• the host or patient may be of any mammalian species, e.g. B. one
• the sensitivity of a particular cell to treatment with the compounds of the invention can be determined by testing in vitro.
• a culture of the cell is combined with a compound of the invention at various concentrations for a period of time sufficient to allow the active agents to induce cell death or to inhibit cell migration or to block the cellular secretion of angiogenesis promoting substances, usually between about an hour and a week.
• cultured cells from a biopsy sample can be used.
• the dose will vary depending on the specific compound used, the specific disease, the patient status, etc. Typically, a therapeutic dose will be sufficient to substantially reduce the unwanted cell population in the target tissue while maintaining the patient's viability. 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 essentially no unwanted cells can be detected in the body.
• the invention relates to compounds of the formula I.
• R 1 are each independently H, Hal, OA, OH 1 A, phenyl, Het 2 or CN monosubstituted or polysubstituted,
• Het 2 is a mononuclear, saturated heterocycle with 1 - 3N- and / or
• R 4 each independently of one another H 1 Hal, OA, OH, A, monosubstituted or polysubstituted,
• X, Y are each independently absent, -CH 2 -, - (CH 2 ) 2 -, -CO- or
• R 2 , R 3 are each independently R; R 2 and R 3 together also form an alkylene chain with 2-6 C atoms, in which also a CH 2 -
• R 5 is H, Hal, NH 2 , OH 1 OA or A 1
• Ar is unsubstituted or mono-, di-, tri-, tetra- or quintuple
• Compounds of the formula I also mean pharmaceutically usable derivatives thereof, optically active forms (stereoisomers), tautomers, polymorphs, enantiomers, racemates, diastereomers and the hydrates and solvates of these compounds.
• Solvates of the compounds are understood as meaning additions of inert solvent molecules to the compounds, which are due to their mutual attraction
• Solvates are, for example, mono- or dihydrate or alcoholates.
• 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, for example, sought or sought by a researcher or physician. 35
• therapeutically effective amount means an amount that, as compared to a corresponding subject that does not receive that amount, results in: improved healing, healing, prevention or elimination of one
• terapéuticaally effective amount also includes the amounts effective to increase normal physiological function.
• the invention also provides for the use of mixtures of the compounds of the formula I 1, 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: 1000.
• Particularly preferred are mixtures of stereoisomeric
• the invention relates to the compounds of formula I and their salts and to a process for the preparation of compounds of formula I according to the claims and their pharmaceutically acceptable salts, and stereoisomers, characterized in that for the preparation of compounds of formula I, is a compound the formula Il
• R 1 , m, D, Z, X and Y have the meanings given in claim 1 and L is a halogen, tosylate, mesylate or triflate,
• A is alkyl and is preferably unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C-atoms.
• Alkyl 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-, 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, more preferably, for example Trifluoromethyl.
• Alkyl very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or 1, 1, 1
• Alkyl also means cycloalkyl.
• Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl,
• Alk preferably denotes unbranched or branched alkylene with 1,
• Ar is preferably 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-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino) -phenyl, o-, m- or p- (N-methylaminocarbonyl) -phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-
• 6-methoxyphenyl 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3 Amino-6-methylphenyl, 3-chloro-4-acetamidophenyl, 2,5-dimethyl-4-chlorophenyl, naphthyl or biphenyl.
• Ar is preferably 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-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino) -phenyl, o-, m- or p- (N-methylaminocarbonyl) -phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-
• Ar furthermore preferably denotes unsubstituted or mono-, di-, tri-, tetra- or quintuple phenyl which is substituted by Hal, A and / or (CF 2) n OR,
• Ar 2 is preferably phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, , m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, more preferably 2,3-, 2,4-, 2,
• Het 1 means, notwithstanding further substitutions, for example 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
• Pyrimidinyl furthermore preferably 1, 2,3-triazoM-, -A- or -5-yl, 1, 2,4-triazol-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-
• Benz-2,1,3-oxadiazolyl 2-, 3-, A-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, A-, 5-, 6-, 7- or 8-isoquinolyl, 3-, A-, 5-, 6-, 7- or 8-cinnolinyl, 2-, A-, 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-benzodioxol-5-yl, 1, A-
• heterocyclic radicals may also be partially or completely hydrogenated.
• Het 1 further preferably means a mononuclear aromatic
• Het 1 particularly preferably denotes unsubstituted or mono-, di- or trisubstituted by A and / or (CH 2 ) n Ar-substituted piperazyl, morpholinyl,
• Het 1 further means a saturated or aromatic heterocycle which may be substituted with piperazine, morpholine, piperidine and pyrrolidine.
• Het can thus z. B. also represent 2,3-dihydro-2-, -3-, -A- or -5-furyl, 2,5-dihydro-2-, -3-, -A- or 5-furyl,
• Het furthermore preferably denotes a monocyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms which is unsubstituted or mono-, di- or trisubstituted by A, Ar 2 , (CR 2 ) n Het 2 and / or (CR 2 ) n OR may be substituted.
• Het very particularly preferably denotes piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl which is unsubstituted or mono- or disubstituted by A, Ar 2 , (CR 2 ) n Het 2 and / or (CR 2 ) n OR, Pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl or pyrazinyl.
• Hal preferably denotes F, Cl or Br, but also I 1 particularly preferably Br or Cl.
• indices have the following preferred meanings m 1, or 2, n 0, 1, 2, 3, 4, or 5 or, p 1, 2, 3 or 4.
• R 1 is H, Hal, CN, phenyl, OA or OH;
• R 2 , R 3 together are morpholinyl, piperazinyl, 1-methyl-piperazinyl, 1-ethyl-4-methyl-piperazinyl, 2- (4-methylpiperazin-1-yl) -ethyl, 1 Methyl 4-propyl-piperazinyl, 1-cyclopentyl-4-methyl-piperazinyl, 1-benzyl-4-methyl- [1,4] diazepanyl or 1-benzyl-4-methyl-piperazinyl;
• Het more preferably means unsubstituted or mono-, di- or trisubstituted by A and / or (CHh) n Ar piperazyl, morpholinyl, piperidinyl, pyrrolidinyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl , Isothiazolyl, pyridyl, pyrimidinyl, triazolyl,
• Benzotriazinyl benzofuranyl, 2,3-dihydro-benzoxazolyl, benzoxazolyl, dihydrobenzofuranyl or tetrazolyl.
• Ig R1 is H, Hal, CN, phenyl, OA or OH;
• R 4 is H, Hal, A or OH
• R 2 , R 3 together are morpholinyl, piperazinyl, 1-methyl-piperazinyl, 1-ethyl-4-methyl-piperazinyl, 2- (4-methylpiperazin-1-yl) -ethyl, 1-methyl-4-propyl piperazinyl, 1-cyclopentyl-4-methylpiperazinyl, 1-benzyl-4-methyl- [1,4] diazepanyl or 1-benzyl-4-methyl-piperazinyl,
• Het 1 particularly preferably denotes unsubstituted or monosubstituted, disubstituted or trisubstituted by A and / or (CH 2 ) n Ar
• Het 2 particularly preferably represents pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl which is unsubstituted or mono- or di-substituted by Hal, OH, OA 1 A and / or OO,
• the compounds of the formula I and also the starting materials for their preparation are prepared by methods known per se, as described in the literature (eg in the standard works such as Houben-Wey !, Methoden der organischen Chemie, Georg-Thieme-Verlag , Stuttgart), under reaction conditions which are known and suitable for the aforementioned reactions.
• 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 formula I.
• Compounds of the formula I can preferably be obtained by reacting a compound of the formula II with a compound of the formula III.
• the reaction time is between a few minutes and 14 days, the reaction temperature between about -30 ° and 140 °, normally between -10 ° and 90 °, in particular between about 0 ° and about 70 °.
• Suitable inert solvents are e.g. Hydrocarbons such as hexane,
• dichloromethane Dichloromethane
• Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol
• Ethers such as diethyl ether, diisopropyl ether, 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 such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles like
• acetonitrile Sulfoxides such as dimethylsulfoxide (DMSO); Carbon disulphide; 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.
• Sulfoxides such as dimethylsulfoxide (DMSO); Carbon disulphide
• 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.
• pyridine acetonitrile
• dichloromethane a compound selected from the group consisting of pyridine, acetonitrile, dichloromethane and / or DMF.
• the starting compounds of formulas II, IM and IV are known in the rule. If they are new, they can be produced by methods known per se. The starting materials are generally also commercially available.
• the invention also relates to 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 according to methods 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-methyl-glutamine N-methyl-glutamine.
• the aluminum salts of the compounds of the formula I count as well.
• 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.
• monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate, as well as 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),
• base salts of the invention include
• Alkali metal salts sodium and potassium, as well as the alkaline earth metal salts sodium and potassium, as well as the alkaline earth metal salts
• salts of the compounds of the formula I which derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted ones
• Amines, cyclic amines, and basic ion exchange resins e.g.
• Benzathine dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine.
• Piperazine Piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris (hydroxymethyl) methylamine (tromethamine), but this is not intended to be limiting.
• Compounds of the present invention containing basic nitrogen-containing groups can be reacted with agents such as (C 1 -C 4 ) alkyl halides, eg, methyl, ethyl, isopropyl, and tert-butyl chloride, bromide, and iodide;
• agents such as (C 1 -C 4 ) alkyl halides, eg, methyl, ethyl, isopropyl, and tert-butyl chloride, bromide, and iodide;
• C 18) alkyl halides for example decyl, dodecyl, lauryl, myristyl and stearyl chloride, bromide and iodide; and aryl (C 1 -C 4 ) alkyl halides, eg benzyl chloride and phenethyl bromide, quaternize.
• aryl (C 1 -C 4 ) alkyl halides eg benzyl chloride and phenethyl bromide, quaternize.
• compositions 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 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 in some sense differ from their corresponding salt forms in terms of certain physical properties such as solubility in polar solvents; however, in the context of the invention, the salts otherwise correspond to their respective free base forms.
• 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.
• metals are sodium, potassium, magnesium and calcium.
• Preferred organic amines are N, N'-dibenzylethylenediamine, chloroprocaine,
• the base addition salts of acidic compounds of this invention are prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt in a 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 in some sense differ from their corresponding salt forms in terms of certain physical properties such as solubility in polar solvents; However, in the context of the invention, the salts otherwise correspond to their respective free acid forms.
• Invention also multiple salts.
• multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium and trihydrochloride, but this is not intended to be limiting.
• pharmaceutically acceptable salt as used herein means an active ingredient containing a compound of formula I in the form of one of its salts, particularly when that salt form is the active ingredient compared to the free form of the active ingredient or any other salt form of the active ingredient that has been used earlier confers improved pharmacokinetic properties.
• 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 salts 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 moiety 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 of the invention, depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations can be used in
• dosage unit formulations are those containing a daily or partial dose, such as above, or a corresponding fraction thereof, of an active ingredient.
• pharmaceutical formulations can be prepared by any of the methods well known in the pharmaceutical art.
• compositions 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 entities, 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 combined with an oral, non-toxic and pharmaceutically acceptable inert carrier, such as, for example, ethanol, glycerol, water and the like.
• an oral, non-toxic and pharmaceutically acceptable inert carrier such as, for example, ethanol, glycerol, water and the like.
• Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a similarly comminuted pharmaceutical carrier such as 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 e.g. 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 lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate,
• 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 mix, granulating or dry pressing, adding a lubricant and a disintegrant, and compressing the whole into tablets.
• 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 carboxymethyl cellulose, an alginate, gelatin or polyvinylpyrrolidone, a Wegsverlangsamer such as paraffin, a absorption accelerator such as a quaternary salt and / or an absorbent, such as bentonite, kaolin or dicalcium phosphate.
• the powder mixture can be granulated by adding it with a binder such as 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 form non-uniformly shaped lumps which are broken up into granules 5.
• the granules can be added by adding
• Stearic acid, a stearate salt, talc or mineral oil are greased to prevent sticking to the tablet molds. The greased mixture is then compressed into tablets.
• a transparent or opaque protective layer consisting of a
• c Shellac sealant a layer of sugar or polymer 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 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 adding the compound in an aqueous solution
• elixirs are prepared using a non-toxic alcoholic vehicle.
• Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
• Solubilizers and emulsifiers
• OQ 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 can also be prepared so that the release is prolonged or retarded, such as by coating or embedding particulate material in polymers, wax, etc.
• 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 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, polyhydroxyethylaspartamidophenol or polyethyleneoxidepolylysine substituted with palmitoyl radicals.
• the compounds can be attached to a class of biodegradable polymers suitable for the controlled release of a drug, e.g. Polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates, and crosslinked or amphipathic block copolymers of hydrogels.
• Formulations may be presented as discrete plasters 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).
• Pharmaceutical compounds 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 can be used with either a paraffinic or water miscible cream base.
• 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 or suspended in a suitable carrier, especially an aqueous solvent.
• compositions adapted for topical application in the mouth include lozenges, lozenges and mouthwashes.
• compositions adapted for rectal administration may be presented in the form of suppositories or enemas.
• compositions 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, i. 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 containing 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, nebulisers or insufflators.
• Formulations can be used as pessaries, tampons, creams, gels 1 pastes. Foams or spray formulations are presented.
• compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions containing the antioxidants, buffers, bacteriostats and solutes, which render the formulation isotonic with the blood of the subject
• Recipient is included; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickeners.
• the formulations may be administered in single or multiple dose containers, e.g. sealed ampoules and vials, and stored in the freeze-dried (lyophilized) state, such that only the addition of the sterile carrier liquid, e.g. Water for
• Injection solutions and suspensions prepared by formulation can be prepared from sterile powders, granules and tablets.
• formulations in addition to the above particularly mentioned ingredients, may contain other conventional agents in the art with respect to the particular type of formulation; for example, formulations suitable for oral administration
• a therapeutically effective amount of a compound of formula I depends on a number of factors including, but not limited to, the age and weight of the animal, the exact condition requiring treatment, as well as its severity, nature of the formulation and route of administration determined by the attending physician or veterinarian.
• an effective amount of a compound of the invention for the treatment of neoplastic growth, eg, colon or breast carcinoma will generally range from 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.
• the actual amount per day would usually be between 70 and 700 mg, this amount 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 can be given so that the total daily dose is the same.
• Derivatives thereof can be determined as a proportion of the effective amount of the compound according to the invention per se. It can be assumed that similar dosages are suitable for the treatment of the other, above-mentioned disease states.
• 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 at least one further active pharmaceutical ingredient.
• the invention is also a set (kit), consisting of separate
• the kit contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules.
• the set may e.g. containing separate ampoules in each of which an effective amount of a compound of formula I and / or its pharmaceutically acceptable derivatives, solvates and stereoisomers, including mixtures thereof in all proportions, and an effective amount of another drug substance is dissolved or in lyophilized form.
• the medicaments of Table 1 are combined with the compounds of the formula I.
• a combination of Formula I and Drugs of Table I can also be combined with compounds of Formula VI.
• Mitoxantrone diflomotecan (Beaufourrinotecan (CPT-11) Ipsen)
• Rhizoxin (Fujisawa) LU 223651 (BASF)
• Epothilone B Novartis
• ZD 6126 AstraZeneca
• Auristatin PE (Teikoku NeuroPharma)
• Taxoprexin (Protarga) CA-4 (OXiGENE)
• TNF-alpha-virulizine (Lorus Revimid (Celgene)
• CapCell TM CYP450-N-acetylcysteine Stimulant, Bavarian (reducing agent,
• Antagonist kappaB inhibitor, Encore
• Efaproxiral oxygenator, receptor agonist, Leo
• PI-88 heparanase antagonist
• TLK-286 glutthione-S-CHS-828 (cytotoxic)
• PT-100 growth factor (differentiator, NIH)
• Point MX6 apoptosis promoter
• CDA-II apoptosis-Ro-31-7453 (apoptosis
• SDX-101 apoptosis-brostallicin (apoptosis)
• Rhizoxin (Fujisawa) LU 223651 (BASF)
• Auristatin PE (Teikoku NeuroPharma)
• Taxoprexin (Protarga) CA-4 (OXiGENE)
• TNF-alpha-virulizine (Lorus Revimid (Celgene)
• RNA cyclic stimulant, Alfacell
• AMP AMP agonist
• ribapharm galarubicin
• CapCell TM CYP450-R flurbiprofen (NF-1)
• GCS-IOO gal3 inhibitor, Active Biotech
• SR-31747 (IL-1 PG2 (hematopoietic)
• SRL-172 T-cell (differentiator, NIH)
• TLK-286 (glutathione-S-MAXIA)
• PLC-brostallicin apoptosis
• CDA-Ii apoptosis
• the compounds of the formula I are combined with those with known anticancer agents:
• estrogen receptor modulators include the following: 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 other angiogenesis inhibitors.
• the present compounds are particularly suitable for co-administration with radiotherapy.
• the synergistic effects of inhibiting VEGF in combination with radiotherapy have been described in the art (see WO 00/61186).
• Estrogen receptor modulators refers to compounds that disrupt or inhibit the binding of estrogen to the receptor, regardless of how this occurs.
• Estrogen receptor modulators include, for example, tamoxifen, raloxifene, idoxifen, " LY353381, LY 117081, toremifene, fulvestrant, 4- [7- (2,2-dimethyl-1-oxopropoxy-4-methyl-2- [4- [2- (1-piperidinyl) ethoxy] phenyl] -2H-1 - Benzopyran-3-yl] phenyl-2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone and SH646, but this is not intended to be limiting.
• Androgen receptor modulators refers to compounds that interfere with or inhibit the binding of androgens to the receptor, regardless of how this occurs, and the 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 interfere with or inhibit the binding of retinoids to the receptor, regardless of how this occurs.
• Such retinoid receptor modulators 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
• Cell death or cell myosis inhibiting or interfering with cell function including alkylating agents, tumor necrosis factors, intercalators, microtubulin inhibitors and topoisomerase inhibitors.
• the 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, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulvene, dexifosfamide, cis -amino-dichloro (2-methylpyridine) -platinum, benzylguanine, glufosfamide, GPX100,
• MEN10755 and 4-desmethoxy-3-desamino-3-aziridinyl-4-methylsulfonyl-5 daunorubicin see WO 00/50032, but this is not intended to be limiting.
• microtubulin inhibitors include, for example, paclitaxel, vindesine sulfate, S '' '- dideshydro' '- deoxy- ⁇ '-norvincaleukoblastin, docetaxol,
• 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, irinotecan, rubitecane, 6-ethoxypropionyl-3 ', 4'-O-exo-benzylidene-chartreusine, 9-methoxy-N, N-dimethyl-5-nitropyrazolo [3,4; 5-kl] acridine-2
• Antiproliferative agents include antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001, as well as antimetabolites such as enocitabine, carmofur, tegafur, pentostatin,
• Angiogenesis inhibitors such as trastuzumab, as well as tumor suppressor genes such as p53, can be delivered via recombinant virus-mediated gene transfer (see, e.g., U.S. Patent No. 5,6,069,134).
• the compound of the invention for the treatment and prophylaxis of tumor diseases.
• the tumor is preferably selected from the group of squamous cell tumors, bladder, stomach, kidney, head and neck,
• Esophagus Esophagus, cervix, thyroid, intestine, liver, 5 of the brain, prostate, genitourinary tract, lymphoid
• the tumor is furthermore preferably selected from the group of lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, ovarian carcinoma, glioblastoma, colon carcinoma and
• a tumor of the blood and immune system preferably for the treatment of a tumor selected from the group of acute myeloid leukemia, chronic myelotic leukemia, acute lymphoblastic leukemia and / or chronic lymphocytic leukemia.
• the invention includes a treatment of a patient having a neoplasm such as a cancer by administering a compound of the formula (I) in combination with an antiproliferative agent.
• a neoplasm such as a cancer
• an antiproliferative agent include those described in U.S. Pat
• “usual work-up” means adding water if necessary, if necessary, adjusting to pH values between 2 and 10, depending on the constitution of the final product, extracted with
• Solvent B acetonitrile + 0.1% HCOOH flow: 2.4 ml / min
• Solvent A water + 0.1% HCOOH solvent B: acetonitrile + 0.08% HCOOH

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