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
  • A61K31/437—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 five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• the present application relates to novel 6-chloro-substituted imidazo [1,2-a] pyridine-3-carboxamides, processes for their preparation, their use alone or in combinations for the treatment and / or prophylaxis of diseases and their use for the production of medicaments for the treatment and / or prophylaxis of diseases, in particular for the treatment and / or prophylaxis of cardiovascular diseases.
• cGMP cyclic guanosine monophosphate
• NO nitric oxide
• GTP guanosine triphosphate
• the soluble guanylate cyclases consist of two subunits and most likely contain one heme per heterodimer, which is part of the regulatory center. This is central to the activation mechanism. NO can bind to the iron atom of the heme and thus significantly increase the activity of the enzyme. On the other hand, heme-free preparations can not be stimulated by NO. Carbon monoxide (CO) is also able to bind to the central iron atom of the heme, with stimulation by CO being markedly lower than by NO.
• CO Carbon monoxide
• guanylate cyclase plays a crucial role in various physiological processes, in particular in the relaxation and proliferation of smooth muscle cells, platelet aggregation and adhesion, neuronal signaling and diseases based on a disturbance of the above operations.
• the NO / cGMP system may be suppressed, leading, for example, to hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, atherosclerosis, angina pectoris, heart failure, myocardial infarction, thrombosis, stroke and sexual dysfunction.
• a NO-independent treatment option for such diseases which is aimed at influencing the cGMP pathway in organisms, is a promising approach on account of the expected high efficiency and low side effects.
• the object of the present invention was to provide new substances which act as stimulators of soluble guanylate cyclase, and as such are suitable for the treatment and / or prophylaxis of diseases.
• the present invention relates to compounds selected from the group consisting of eni-N- (2-amino-3-fluoro-2-methylpropyl) -6-chloro-8 - [(2,6-difluorobenzyl) oxy] -2- methylimidazo [l, 2-a] pyridine-3-carboxamide (enantiomer B)
• Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.
• Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, Efhansulfon- acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, Malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
• Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and by way of illustration, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
• customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts
• solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
• the compounds of the invention may exist in different stereoisomeric forms, i. in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in atropisomers).
• the present invention therefore includes the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform constituents can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.
• the present invention encompasses all tautomeric forms.
• the present invention also includes all suitable isotopic variants of the compounds according to the invention.
• An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature.
• isotopes used in a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 129 I and 131 I.
• isotopic variants of a compound of the invention such as, in particular, those in which one or more radioactive isotopes are incorporated, may be useful, for example, to study the mechanism of action or drug distribution in the body; Due to the comparatively easy production and detectability, compounds labeled with 3 H or 14 C isotopes are particularly suitable for this purpose.
• isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose;
• modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention.
• Isotopic variants of the compounds according to the invention can be prepared by the processes known to the person skilled in the art, for example by the methods described below and the rules given in the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.
• the present invention also includes prodrugs of the compounds of the invention.
• prodrugs refers to compounds which themselves may be biologically active or inactive, but are converted during their residence time in the body to compounds of the invention (for example metabolically or hydrolytically).
• treatment includes inhibiting, delaying, arresting, alleviating, attenuating, restraining, reducing, suppressing, restraining or curing a disease, a disease, a disease, an injury or a medical condition , the unfolding, the course or progression of such conditions and / or the symptoms of such conditions.
• therapy is understood to be synonymous with the term “treatment”.
• prevention means the avoidance or reduction of the risk, a disease, a disease, a disease, an injury or a health disorder, a development or a Progression of such conditions and / or to get, experience, suffer or have the symptoms of such conditions.
• the treatment or the prevention of a disease, a disease, a disease, an injury or a health disorder can be partial or complete.
• Preferred in the context of the present invention is the compound with the systematic name eni-N- (2-amino-3-fluoro-2-methylpropyl) -6-chloro-8 - [(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxamide (enantiomer B) and the structural formula
• Preferred within the context of the present invention is the compound with the systematic name eni-N- (2-amino-5,5,5-trifluoro-2-methylpentyl) -6-chloro-8 - [(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxamide (enantiomer B) and the structural formula
• the compound with the systematic name eni-N- (2-amino-4,4-difluoro-2-methylbutyl) -6-chloro-8 - [(2,6-difluorobenzyl) oxy] -2 is preferred - methylimidazo [1,2-a] pyridine-3-carboxamide (enantiomer A) and the structural formula
• the compound with the systematic name eni-N- (2-amino-4,4-difluoro-2-methylbutyl) -6-chloro-8 - [(2,6-difluorobenzyl) oxy] -2 is preferred - methylimidazo [1,2-a] pyridine-3-carboxamide (enantiomer B) and the structural formula
• Preferred within the context of the present invention is the compound having the systematic name eni-N- (2-amino-4-fluoro-2-methylbutyl) -6-chloro-8 - [(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxamide (enantiomer A) and the structural formula
• the invention further provides a process for the preparation of the compounds according to the invention which comprises [A] a compound of the formula (I)
• T 1 is (C 1 -C 4 ) -alkyl or benzyl, in an inert solvent in the presence of a suitable base or acid to give a carboxylic acid of the formula (II)
• Inert solvents for the amide coupling are, for example, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichlorethylene or chlorobenzene , or other solvents such as acetone, ethyl acetate, acetonitrile, pyridine, dimethyl sulfoxide, dimethylformamide, / V, / V-dimethylacetamide, ⁇ , ⁇ '-dimethylpropyleneurea (DMPU) or -Methylpyrrolidon (NMP). It is also possible to use
• Suitable condensing agents for amide formation are, for example, carbodiimides such as ⁇ , ⁇ '-diethyl, N, N'-dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide (DCC) or N- (3-dimethylaminopropyl ) - / V'-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as ⁇ , ⁇ '-carbonyldiimidazole (CDI), 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methylisoxazolium perchlorate, acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or isobutylchloroformate, propanephosphonic anhydride
• TBTU is used in conjunction with N-methylmorpholine, HATU in conjunction with -Diisopropylefhylamin or l-chloro- / V, / V, 2-trimethylprop-l-en-lamin.
• the condensations are generally carried out in a temperature range from -20 ° C to + 100 ° C, preferably at 0 ° C to + 60 ° C.
• the reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). In general, one works at normal pressure.
• the carboxylic acid of the formula (II) can also first be converted into the corresponding carboxylic acid chloride and then reacted directly or in a separate reaction with an amine of the formula (III) to form the compounds according to the invention.
• carboxylic acid chlorides from carboxylic acids is carried out by the methods known in the art, for example by treatment with thionyl chloride, sulfuryl chloride or oxalyl chloride in the presence of a suitable base, for example in the presence of pyridine, and optionally with the addition of dimethylformamide, optionally in a suitable inert solvent.
• the hydrolysis of the ester group T 1 of the compounds of the formula (I) is carried out by conventional methods by treating the esters in inert solvents with acids or bases, wherein the latter salts are converted by treatment with acid in the free carboxylic acids ,
• the ester cleavage is preferably carried out with acids.
• the ester cleavage is preferably carried out by hydrogenolysis with palladium on activated carbon or Raney nickel. Suitable inert solvents for this reaction are water or the organic solvents customary for ester cleavage.
• These preferably include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or ethers such as diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane or glycol dimethyl ether, or other solvents such as acetone, dichloromethane, dimethylformamide or dimethyl sulfoxide , It is likewise possible to use mixtures of the solvents mentioned. In the case of basic ester hydrolysis, preference is given to using mixtures of water with dioxane, tetrahydrofuran, methanol and / or ethanol.
• the usual inorganic bases are suitable. These include preferably alkali or alkaline earth hydroxides such as sodium, lithium, potassium or barium hydroxide, or alkali or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate. Particularly preferred are sodium or lithium hydroxide.
• Suitable acids for the ester cleavage are generally sulfuric acid, hydrochloric acid / hydrochloric acid, hydrobromic / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid or mixtures thereof, optionally with the addition of water.
• Hydrogen chloride or trifluoroacetic acid are preferred in the case of the tert-butyl esters and hydrochloric acid in the case of the methyl esters.
• the ester cleavage is generally carried out in a temperature range from 0 ° C to + 100 ° C, preferably at + 0 ° C to + 50 ° C.
• the reactions mentioned can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). In general, one works at normal pressure.
• the amino-protecting group used is preferably ieri-butoxycarbonyl (Boc) or benzyloxycarbonyl (Z).
• a protective group for a hydroxy or carboxyl function tert-butyl or benzyl is preferably used.
• the cleavage of these protecting groups is carried out by conventional methods, preferably by reaction with a strong acid such as hydrogen chloride, hydrogen bromide or trifluoroacetic acid in an inert solvent such as dioxane, diethyl ether, dichloromethane or acetic acid; optionally, the cleavage can also be carried out without an additional inert solvent.
• a strong acid such as hydrogen chloride, hydrogen bromide or trifluoroacetic acid
• an inert solvent such as dioxane, diethyl ether, dichloromethane or acetic acid
• the cleavage can also be carried out without an additional inert solvent.
• benzyl and benzyloxycarbonyl as a protective group
• these can also be removed by hydrogenolysis in the presence of a palladium catalyst.
• the cleavage of the protective groups mentioned can optionally be carried out simultaneously in a one-pot reaction or in separate reaction steps.
• the cleavage of the benzyl group is carried out here by customary methods known from protective group chemistry, preferably by hydrogenolysis in the presence of a palladium catalyst such as, for example, palladium on activated carbon in an inert solvent such as, for example, ethanol or ethyl acetate [see also e.g. T.W. Greene and P.G.M. Wuts, Protective Croups in Organic Synthesis, Wiley, New York, 1999].
• a palladium catalyst such as, for example, palladium on activated carbon
• an inert solvent such as, for example, ethanol or ethyl acetate
• X is a suitable leaving group, in particular chlorine, bromine, iodine, mesylate, triflate or tosylate, to a compound of the formula (VI)
• Inert solvents for ring closure to the imidazo [1,2-a] pyridine backbone are the usual organic solvents. These preferably include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, n-pentanol or tert-butanol, or ethers such as diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane or glycol dimethyl ether, or other solvents such as acetone, dichloromethane , 1,2-dichloroethane, acetonitrile, dimethylformamide or dimethyl sulfoxide.
• alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, n-pentanol or tert-butanol
• ethers such as diethyl ether, tetrahydrofuran
• the ring closure is generally carried out in a temperature range from + 50 ° C to + 150 ° C, preferably at + 50 ° C to + 100 ° C, optionally in a microwave.
• the ring closure (VI) + (VII) -> (I) or (IV) + (VII) -> (VIII) is optionally carried out in the presence of water-withdrawing reaction additives, for example in the presence of molecular sieve (4 ⁇ pore size) or by means of water.
• reaction ((VI) + (VII) -> (I) or (IV) + (VII) -> (VIII) is carried out using an excess of the reagent of the formula (VII), for example with 1 to 20 equivalents of the reagent (VII), optionally with the addition of bases (such as sodium bicarbonate), whereby the addition of this reagent can be carried out once or in several portions
• bases such as sodium bicarbonate
• R 1 represents the compounds of the formulas (III-A), (III-B), (III-C), (III-D) and (III-E), and in which T 1 has the abovementioned meanings.
• Typical reaction conditions for such Mitsunobu condensations of phenols with alcohols can be found in the literature, eg Hughes, DL Org. Read. 1992, 42, 335; Dembinski, R. Eur. J. Org. Chem. 2004, 2763.
• an activating reagent eg diethylazodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD)
• a phosphine reagent eg triphenylphosphine or tributylphosphine
• an inert solvent eg THF, Dichloromethane, toluene or DMF
• the compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.
• the compounds according to the invention open up a further treatment alternative and thus represent an enrichment of pharmacy.
• the compounds of the invention cause vasorelaxation and inhibition of platelet aggregation and lead to a reduction in blood pressure and to an increase in coronary blood flow. These effects are mediated by direct stimulation of soluble guanylate cyclase and intracellular cGMP increase.
• the compounds according to the invention enhance the action of substances which increase cGMP levels, such as, for example, endothelium-derived relaxing factor (EDRF), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.
• EDRF endothelium-derived relaxing factor
• NO donors NO donors
• protoporphyrin IX arachidonic acid or phenylhydrazine derivatives.
• the compounds according to the invention are suitable for the treatment and / or prophylaxis of cardiovascular, pulmonary, thromboembolic and fibrotic disorders.
• the compounds according to the invention can therefore be used in medicaments for the treatment and / or prophylaxis of cardiovascular diseases such as hypertension, resistant hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, arrhythmias, rhythm disorders Atrio-ventricular blockades grade ⁇ - ⁇ (AB block I-III), supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular tachyarrhythmia, torsades de pointes tachycardia, extrasystoles of atrial and ventricular atresia Ventricles, AV junctional extrasystoles, sick sinus syndrome, syncope, AV nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute
• cardiac failure includes both acute and chronic manifestations of cardiac insufficiency, as well as more specific or related forms of disease such as acute decompensated heart failure, right heart failure, left heart failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects.
• Heart failure in heart valve defects mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valvular insufficiency, combined valvular heart failure, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders, diastolic heart failure as well as systolic heart failure and acute phases de w worsening of heart failure.
• the compounds according to the invention may also be used for the treatment and / or prophylaxis of arteriosclerosis, lipid metabolism disorders, hypolipoproteinemias, dyslipidaemias, hypertriglyceridemias, hyperlipidemias, hypercholesterolemias, abetelipoproteinemia, sitosterolemia, xanthomatosis, Tangier's disease, obesity (obesity) and obesity combined hyperlipidaemias and the metabolic syndrome.
• the compounds according to the invention can be used for the treatment and / or prophylaxis of primary and secondary Raynaud's phenomenon, microcirculatory disorders, claudication, peripheral and autonomic neuropathies, diabetic microangiopathies, diabetic retinopathy, diabetic ulcers on the extremities, gangrenous, CREST syndrome, erythematosis, onychomycosis, rheumatic diseases and to promote wound healing.
• the compounds according to the invention are furthermore suitable for the treatment of urological diseases such as, for example, benign prostate syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic hyperplasia (BPE), bladder emptying disorder (BOO), lower urinary tract syndromes (LUTS, including Feiine's urological syndrome ( FUS)), diseases of the urogenital system including neurogenic overactive bladder (OAB) and (IC), incontinence (UI) such as mixed, urge, stress, or overflow incontinence (MUI, UUI, SUI, OUI), Pelvic pain, benign and malignant diseases of the organs of the male and female urogenital system.
• BPS benign prostate syndrome
• BPH benign prostatic hyperplasia
• BPE benign prostatic hyperplasia
• BOO bladder emptying disorder
• LUTS lower urinary tract syndromes
• FUS Feiine's urological syndrome
• diseases of the urogenital system including neurogenic overactive bladder (OAB) and (IC), incon
• kidney diseases in particular of acute and chronic renal insufficiency, as well as of acute and chronic renal failure.
• renal insufficiency includes both acute and chronic manifestations of renal insufficiency, as well as underlying or related renal diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial disorders, nephropathic disorders such as primary and congenital kidney disease, nephritis, renal immunological diseases such as renal transplant rejection, immune complex-induced renal disease, toxicant-induced nephropathy, contrast agent-induced nephropathy, diabetic and nondiabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive
• the present invention also encompasses the use of the compounds of the invention for the treatment and / or prophylaxis of sequelae of renal insufficiency, such as pulmonary edema, cardiac insufficiency, uremia, anemia, electrolyte disorders (eg, hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metabolism.
• sequelae of renal insufficiency such as pulmonary edema, cardiac insufficiency, uremia, anemia, electrolyte disorders (eg, hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metabolism.
• the compounds according to the invention are also suitable for the treatment and / or prophylaxis of asthmatic diseases, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), including left heart disease, HIV, sickle cell disease, thromboembolism (CTEPH), sarcoidosis, COPD or pulmonary fibrosis-associated pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute respiratory tract syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (eg, cigarette smoke induced emphysema) and cystic fibrosis (CF).
• PAH pulmonary arterial hypertension
• PH pulmonary hypertension
• COPD chronic obstructive pulmonary disease
• ARDS acute respiratory tract syndrome
• ALI acute lung injury
• AATD alpha-1-antitrypsin deficiency
• CF cystic fibros
• the compounds described in the present invention are also agents for controlling diseases in the central nervous system, which are characterized by disorders of the NO / cGMP system.
• they are suitable for improving the perception, concentration performance, learning performance or memory performance after cognitive disorders such as occur in situations / diseases / syndromes such as mild cognitive impairment, age-associated learning and memory disorders, age-associated memory loss, vascular dementia, cranial brain Trauma, post-stroke dementia, post-traumatic traumatic brain injury, generalized concentration disorders, impaired concentration in children with learning and memory problems, Alzheimer's disease, dementia with Lewy bodies, dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, demyelinization, multiple sclerosis, thalamic degeneration, Creutzfeld's disease Jacob-Deme nz, HIV dementia, schizophrenia with dementia or Korsakoff's psychosis.
• cognitive disorders such as occur in situations
• the compounds according to the invention are also suitable for the treatment and / or prophylaxis of diseases of the central nervous system such as states of anxiety, tension and depression, central nervous conditional sexual dysfunctions and sleep disorders as well as for the regulation of pathological disorders of food, consumption and addiction.
• the compounds according to the invention are also suitable for regulating cerebral perfusion and are effective agents for combating migraine. They are also suitable for the prophylaxis and control of the consequences of cerebral infarct events (Apoplexia cerebri) such as stroke, cerebral ischaemias and craniocerebral trauma , Likewise, the compounds of the invention can be used to combat pain and tinnitus.
• the compounds of the invention have anti-inflammatory action and can therefore be used as anti-inflammatory agents for the treatment and / or prophylaxis of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory diseases of the kidney, chronic inflammatory bowel disease (IBD, Crohn's Disease, UC), pancreatitis , Peritonitis, rheumatoid diseases, inflammatory skin diseases and inflammatory ocular diseases.
• SIRS sepsis
• MODS multiple organ failure
• IBD chronic inflammatory bowel disease
• UC chronic inflammatory bowel disease
• pancreatitis e.g., Peritonitis, rheumatoid diseases, inflammatory skin diseases and inflammatory ocular diseases.
• the compounds of the invention can also be used for the treatment and / or prophylaxis of autoimmune diseases.
• the compounds according to the invention are suitable for the treatment and / or prophylaxis of fibrotic disorders of the internal organs such as, for example, the lung, the heart, the kidney, the bone marrow and in particular the liver, as well as dermatological fibroses and fibrotic disorders of the eye.
• fibrotic disorders includes in particular the following terms: liver fibrosis, cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage due to diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring (also after surgical interventions), nevi, diabetic retinopathy, proliferative vitroretinopathy and connective tissue disorders (eg sarcoidosis).
• the compounds of the invention are useful for controlling postoperative scarring, e.g. as a result of glaucoma surgery.
• the compounds according to the invention can likewise be used cosmetically for aging and keratinizing skin.
• the compounds according to the invention are suitable for the treatment and / or prophylaxis of hepatitis, neoplasm, osteoporosis, glaucoma and gastroparesis.
• Another object of the present invention is the use of compounds according to the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
• the present invention further relates to the use of the compounds according to the invention for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders and atherosclerosis.
• the present invention furthermore relates to the compounds according to the invention for use in a method for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders and atherosclerosis.
• Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
• the present invention further relates to the use of the compounds according to the invention for the production of a medicament for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders and arteriosclerosis.
• Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.
• the present invention further provides a method for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular diseases, renal insufficiency, thromboembolic disorders, fibrotic diseases and atherosclerosis, using an effective amount of at least one of the compounds according to the invention ,
• the compounds of the invention may be used alone or as needed in combination with other agents.
• Another object of the present invention are pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases.
• suitable combination active ingredients may be mentioned by way of example and preferably:
• organic nitrates and NO donors such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;
• cGMP cyclic guanosine monophosphate
• PDE phosphodiesterases
• Inhibitors such as sildenafil, vardenafil and tadalafil;
• Antithrombotic agents by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances;
• Antihypertensive agents by way of example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticid Receptor antagonists and diuretics; and or Lipid metabolism-altering agents, by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR inhibitors alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, and lipoprotein (a) antagonists.
• Lipid metabolism-altering agents by way of example and preferably from the group of thyroid
• Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.
• the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
• the compounds according to the invention are administered in combination with a thrombin inhibitor, such as, by way of example and by way of preference, ximelagatran, dabigatran, melagatran, bivalirudin or Clexane.
• a thrombin inhibitor such as, by way of example and by way of preference, ximelagatran, dabigatran, melagatran, bivalirudin or Clexane.
• the compounds according to the invention are administered in combination with a GPIIb / IIIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.
• a GPIIb / IIIa antagonist such as, by way of example and by way of preference, tirofiban or abciximab.
• the compounds according to the invention are administered in combination with a factor Xa inhibitor, such as by way of example and preferably rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux , PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
• a factor Xa inhibitor such as by way of example and preferably rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux , PMD-3112, YM-150, KFA-1982, EMD-503982, MCM
• the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
• LMW low molecular weight
• the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.
• a vitamin K antagonist such as by way of example and preferably coumarin.
• the antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, Renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists and diuretics understood.
• the compounds according to the invention are administered in combination with a calcium antagonist, such as by way of example and preferably nifedipine, amlodipine, verapamil or diltiazem.
• a calcium antagonist such as by way of example and preferably nifedipine, amlodipine, verapamil or diltiazem.
• the compounds according to the invention are administered in combination with an alpha-1-receptor blocker, such as by way of example and preferably prazosin.
• the compounds according to the invention are used in combination with a beta-receptor blocker such as, by way of example and by way of preference, propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipropanol, nadolol, mepindolol, Caroteneol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucinolol.
• a beta-receptor blocker such as, by way of example and by way of preference, propranolol, atenolol,
• the compounds according to the invention are administered in combination with an angiotensin all-antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.
• an angiotensin all-antagonist such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.
• the compounds according to the invention are administered in combination with an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
• an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
• the compounds according to the invention are administered in combination with an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
• an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
• the compounds of the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
• the compounds of the invention are administered in combination with a mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone or eplerenone.
• a mineralocorticoid receptor antagonist such as by way of example and preferably spironolactone or eplerenone.
• the compounds according to the invention are used in combination with a loop diuretic, such as, for example, furosemide, Torasemide, bumetanide and piretanide, with potassium-sparing diuretics such as amiloride and triamterene, with aldosterone antagonists such as spironolactone, potassium canrenoate and eplerenone, and thiazide diuretics such as hydrochlorothiazide, chlorthalidone, xipamide, and indapamide.
• a loop diuretic such as, for example, furosemide, Torasemide, bumetanide and piretanide
• potassium-sparing diuretics such as amiloride and triamterene
• aldosterone antagonists such as spironolactone
• potassium canrenoate and eplerenone potassium canrenoate and eplerenone
• thiazide diuretics such as hydrochlorothiazide
• lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR alpha- , PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) - understood antagonists.
• CETP inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
• ACAT inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
• MTP inhibitors MTP inhibitors
• PPAR alpha- , PPAR gamma and / or PPAR delta agonists cholesterol absorption inhibitors
• polymeric bile acid adsorbers bile acid
• the compounds according to the invention are administered in combination with a CETP inhibitor, such as by way of example and preferably dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-1).
• a CETP inhibitor such as by way of example and preferably dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-1).
• the compounds according to the invention are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214) ,
• a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214) ,
• the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
• statins such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
• the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.
• a squalene synthesis inhibitor such as by way of example and preferably BMS-188494 or TAK-475.
• the compounds according to the invention are administered in combination with an ACAT inhibitor, such as, for example and preferably, avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
• an ACAT inhibitor such as, for example and preferably, avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
• the compounds according to the invention are administered in combination with an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
• an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
• the compounds of the invention are administered in combination with a PPAR-gamma agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
• a PPAR delta agonist such as by way of example and preferably GW 501516 or BAY 68-5042.
• the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor such as, for example and preferably, ezetimibe, tiqueside or pamaqueside.
• a cholesterol absorption inhibitor such as, for example and preferably, ezetimibe, tiqueside or pamaqueside.
• the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.
• a lipase inhibitor such as, for example and preferably, orlistat.
• the compounds of the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
• ASBT IBAT
• the compounds of the invention are administered in combination with a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
• a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
• Another object of the present invention are pharmaceutical compositions containing at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
• the compounds according to the invention can act systemically and / or locally.
• they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
• the compounds according to the invention can be administered in suitable administration forms.
• the compounds of the invention rapidly and / or modified donating application forms, the compounds of the invention in crystalline and / or amorphized and / or dissolved form such as tablets (uncoated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings which control the release of the compound of the invention), orally disintegrating tablets or films / wafers, films / lyophilisates, capsules ( hard or soft gelatin capsules, for example), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
• Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
• a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
• absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
• suitable as application forms i.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
• Inhalation medicaments including powder inhalers, nebulizers
• nasal drops solutions or sprays
• lingual, sublingual or buccal tablets films / wafers or capsules
• suppositories ear or ophthalmic preparations
• vaginal capsules aqueous suspensions (lotions, shake mixtures)
• lipophilic suspensions ointments
• creams transdermal therapeutic systems (eg plasters)
• milk pastes, foams, powdered powders, implants or stents.
• the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
• excipients for example microcrystalline cellulose, lactose, mannitol
• solvents for example liquid polyethylene glycols
• emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitanoleate
• binders for example polyvinylpyrrolidone
• synthetic and natural polymers for example albumin
• Stabilizers eg, antioxidants such as ascorbic acid
• dyes eg, inorganic pigments such as iron oxides
• flavor and / or odoriferous include, among others.
• Excipients for example microcrystalline cellulose, lactose, mannitol
• solvents for example liquid polyethylene glycols
• emulsifiers and dispersants or wetting agents for example sodium dodecy
• the dosage is about 0.001 to 2 mg / kg, preferably about 0.001 to 1 mg kg of body weight.
• the multiplicities of proton signals in ⁇ -NMR spectra given in the following paragraphs represent the respective observed signal form and do not take into account higher-order signal phenomena. All data in ⁇ -NMR spectra indicate the chemical shifts ⁇ in ppm.
• the starting compounds, intermediates and embodiments may be present as hydrates. A quantitative determination of the water content was not. The hydrates may have an influence on the ⁇ -NMR spectrum and possibly shift and / or greatly broaden the water signal in ⁇ -NMR.
• the compounds of the invention may be in salt form, for example as trifluoroacetate, formate or ammonium salt, if the Compounds according to the invention contain a sufficiently basic or acidic functionality.
• a salt can be converted into the corresponding free base or acid by various methods known to those skilled in the art.
• a compound in the form of a salt of the corresponding base or acid is listed in the synthesis intermediates and embodiments of the invention described below, the exact stoichiometric composition of such a salt, as according to the respective preparation and / or purification process was received, usually unknown.
• salt-forming components such as “hydrochloride”, “trifluoroacetate”, “sodium salt” or “x HCl”, “x CF 3 COOH”, “x Na +” are not included in such salts stoichiometrically, but are solely descriptive of the salt-forming components contained.
• Enantiomer A Yield: 1.18 g (> 99% ee)
• Enantiomer B yield: 1.18 g (> 99% ee)
• the reaction solution was admixed first with water at 0 ° C. and then with ethyl acetate and washed with saturated aqueous sodium chloride solution.
• the aqueous phase was extracted twice with ethyl acetate.
• the combined organic phases were dried over sodium sulfate, filtered and concentrated.
• Enantiomer A Yield: 2.64 g (> 99% ee)
• Enantiomer B Yield: 2.76 g (93% ee)
• Enantiomer A Yield: 5.7 g (> 99% ee)
• Enantiomer B Yield: 5.0 g (> 99% ee)
• the residue was purified twice by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with the addition of 0.1% TFA). The product fractions were combined and concentrated. The residue was then taken up in dichloromethane and a little methanol and washed twice with a little saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered, concentrated and lyophilized. 53 mg of the target compound (43% of theory) were obtained.
• the residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient with the addition of 0.1% TFA). The product fractions were combined and concentrated. The residue was then taken up in dichloromethane and a little methanol and washed twice with a little saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered, concentrated and lyophilized. 105 mg of the target compound (59% of theory) were obtained.
• the residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient with the addition of 0.1% TFA). The product fractions were combined and concentrated. The residue was then taken up in dichloromethane and a little methanol and washed twice with a little saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered, concentrated and lyophilized. 133 mg of the target compound (55% of theory) were obtained.
• Trifluoroacetate (enantiomer B) from Example 43A were dissolved in 11.1 ml of ethanol, treated with 14 mg of palladium on activated carbon (10%) and hydrogenated at atmospheric pressure for 3 hours.
• the reaction solution was filtered through celite, washed with ethanol, and the filtrate was concentrated.
• the residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient with the addition of 0.1% TFA).
• the product fractions were combined and concentrated.
• the residue was then taken up in dichloromethane and a little methanol and washed twice with a little saturated aqueous sodium bicarbonate solution.
• the aqueous phase was extracted twice with dichloromethane.
• the combined organic phases were dried over sodium sulfate, filtered, concentrated and lyophilized. 133 mg of the target compound (63% of theory) were obtained.
• Trifluoroacetate (enantiomer A) from Example 44A was dissolved in 15.6 ml of ethanol, treated with 19 mg of palladium on activated carbon (10%) and 75 min hydrogenated at atmospheric pressure. The reaction solution was filtered through a Millipore filter and the filtrate was concentrated.
• the residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with the addition of 0.1% TFA). The product fractions were combined and concentrated. The residue was then taken up in dichloromethane and a little methanol and washed twice with a little saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered, concentrated and lyophilized. 152 mg of the target compound (52% of theory) were obtained.
• the residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient with the addition of 0.1% TFA). The product fractions were combined and concentrated. The residue was then taken up in dichloromethane and a little methanol and washed twice with a little saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered, concentrated and lyophilized. 149 mg of the target compound (53% of theory) were obtained.
• Enantiomer A Yield: 50 mg (> 99% ee)
• the product fractions were collected on dry ice, concentrated (bath temperature: 30 ° C) and lyophilized.
• Soluble guanylyl cyclase converts GTP to cGMP and pyrophosphate (PPi) upon stimulation.
• PPi is detected by the method described in WO 2008/061626.
• the signal generated in the test increases as the reaction progresses and serves as a measure of the sGC enzyme activity.
• the enzyme can be characterized in a known manner, e.g. in terms of turnover rate, stimulability or Michaelis constant.
• 29 ⁇ M enzyme solution (0-10 nM soluble guanylyl cyclase (prepared according to Hönicka et al., Journal of Molecular Medicine 77 (1999) 14-23), in 50 mM TEA, 2 mM magnesium chloride, 0.1% BSA (fraction V), 0.005% Brij 35, pH 7.5) in the microplate and 1 ⁇ of the stimulator solution (0-10 ⁇ 3-Morpholinosydnonimine, SIN-1, Merck in DMSO) added. It was incubated at RT for 10 min.
• the enzyme reaction was started by the addition of 20 .mu. ⁇ substrate solution (1.25 mM guanosine 5 'triphosphate (Sigma) in 50 mM TEA, 2 mM magnesium chloride, 0.1% BSA (fraction V), 0.005% Brij 35, pH 7.5) and continuously luminometric measured.
• 20 .mu. ⁇ substrate solution (1.25 mM guanosine 5 'triphosphate (Sigma) in 50 mM TEA, 2 mM magnesium chloride, 0.1% BSA (fraction V), 0.005% Brij 35, pH 7.5) and continuously luminometric measured.
• B-2 Effect on recombinant guanylate cyclase reporter cell line
• MEC minimum effective concentration
• aorta Rabbits are stunned and bled by a stroke of the neck.
• the aorta is harvested, detached from adherent tissue, divided into 1.5 mm wide rings and placed individually under bias in 5 ml organ baths with 37 ° C warm, carbogen-gassed Krebs-Henseleit solution of the following composition (in each case mM): Sodium chloride: 119; Potassium chloride: 4.8; Calcium chloride dihydrate: 1; Magnesium sulfate heptahydrate: 1.4; Potassium dihydrogen phosphate: 1.2; Sodium hydrogencarbonate: 25; Glucose: 10.
• the force of contraction is detected with Statham UC2 cells, amplified and digitized via A / D converters (DAS-1802 HC, Keithley Instruments Munich) and registered in parallel on chart recorders.
• DAS-1802 HC A / D converters
• phenylephrine is added cumulatively to the bath in increasing concentration.
• the substance to be examined is added in each subsequent course in increasing dosages and the height of the contraction is compared with the height of the contraction achieved in the last predistortion. This is used to calculate the concentration required to reduce the level of the control value by 50% (IC50 value).
• the standard application volume is 5 ⁇ , the DMSO content in the bath solution corresponds to 0.1%.
• a commercially available telemetry system from DATA SCIENCES INTERNATIONAL DSI, USA is used for the blood pressure measurement on awake rats described below.
• the system consists of 3 main components:
• Implantable transmitters Physiotel® telemetry transmitters
• Physiotel® receivers connected to a data acquisition computer through a multiplexer (DSI Data Exchange Matrix).
• the telemetry system allows a continuous recording of blood pressure heart rate and body movement on awake animals in their habitual habitat.
• the experimental animals are kept individually in macroion cages type 3 after transmitter implantation. You have free access to standard food and water.
• the day - night rhythm in the experimental laboratory is changed by room lighting at 6:00 in the morning and at 19:00 in the evening.
• the TAH PA - C40 telemetry transmitters are surgically implanted into the experimental animals under aseptic conditions at least 14 days before the first trial.
• the animals so instrumented are repeatedly used after healing of the wound and ingrowth of the implant.
• the fasting animals are anaesthetized with pentobabital (Nembutal, Sanofi: 50 mg / kg ip) and shaved and disinfected on the ventral side.
• the system's liquid-filled measuring catheter above the bifurcation is inserted cranially into the descending aorta and secured with tissue adhesive (VetBonD TM, 3M).
• the transmitter housing is fixed intraperitoneally to the abdominal wall musculature and the wound is closed in layers.
• an antibiotic is administered for infection prevention (Tardomyocel COMP Bayer 1ml / kg s.c.)
• a solvent-treated group of animals is used as a control.
• Experimental procedure The existing telemetry measuring device is configured for 24 animals. Each trial is registered under a trial number (VYear month day).
• the instrumented rats living in the plant each have their own receiving antenna (1010 receivers, DSI).
• the implanted transmitters can be activated externally via a built-in magnetic switch. They will be put on the air during the trial run.
• the emitted signals can be recorded online by a data acquisition system (Dataquest TM A.R.T. for Windows, DSI) and processed accordingly. The storage of the data takes place in each case in a folder opened for this purpose which carries the test number.
• SBP Systolic blood pressure
• DBP Diastolic blood pressure
• MAP Heart rate
• HR Heart rate
• ACT Activity
• SBP Systolic blood pressure
• DBP Diastolic blood pressure
• MAP Mean arterial pressure
• HR Heart rate
• ACT Activity
• the data acquisition is repeated computer-controlled at 5-minute intervals.
• the absolute value of the source data is corrected in the diagram with the currently measured barometric pressure (Ambient Pressure Reference Monitor, APR-1) and stored in individual data. Further technical details can be found in the extensive documentation of the manufacturer (DSI). Unless otherwise stated, administration of the test substances will take place on the day of the experiment at 9.00. Following the application, the parameters described above are measured for 24 hours.
• the collected individual data are sorted with the analysis software (DATAQUEST TM A.RT. TM ANALYSIS).
• the blank value is assumed here 2 hours before application, so that the selected data record covers the period from 7:00 am on the day of the experiment to 9:00 am on the following day.
• the data is smoothed over a presettable time by means of value determination (15 minutes average) and transferred as a text file to a data medium.
• value determination 15 minutes average
• the presorted and compressed measured values are transferred to Excel templates and displayed in tabular form.
• the filing of the collected data takes place per experiment day in a separate folder that bears the test number. Results and test reports are sorted in folders and sorted by paper.
• the pharmacokinetic parameters of the compounds of the invention are determined in male CD-1 mice, male Wistar rats and female beagle dogs.
• Intravenous administration is in mice and rats using a species-specific plasma / DMSO formulation and in dogs using a water / PEG400 / ethanol formulation.
• Oral administration of the solute by gavage is performed in all species based on a water / PEG400 / ethanol formulation. Rats are placed in the right external jugular vein for ease of blood sampling prior to drug administration. The operation is carried out at least one day before the experiment under isoflurane anesthesia and with the administration of an analgesic (atropine / rimadyl (3/1) 0.1 mL s.c.).
• an analgesic atropine / rimadyl (3/1) 0.1 mL s.c.
• the blood collection (usually more than 10 times) takes place in a time window, which includes terminal times of at least 24 to a maximum of 72 hours after substance administration.
• the blood is transferred to heparinized tubes at collection. So then the blood plasma is recovered by centrifugation and optionally stored at -20 ° C until further processing.
• An internal standard is added to the samples of the compounds according to the invention, calibration samples and qualifiers (this may also be a chemically unrelated substance) and protein precipitation by means of acetonitrile follows in excess.
• the supernatant is measured by LC-MS / MS using C18 reversed-phase columns and variable eluent mixtures.
• the quantification of the substances is based on the peak heights or areas of extracted ion chromatograms of specific selected ion monitoring experiments.
• the pharmacokinetic parameters such as AUC, C ma x (terminal half-life), F (bioavailability), MRT (Mean Residence Time) and CL hn (clearance) by means of a validated pharmacokinetic computer program calculated.
• the blood / plasma distribution of the substance must be determined in order to adjust the pharmacokinetic parameters accordingly.
• a defined amount of substance is incubated in heparinized whole blood of the corresponding species for 20 min in a tumble roll mixer. After centrifugation at 1000 g, the concentration in the plasma is measured (by means of LC-MS / MS, see above) and the quotient formation of the C ⁇ iut / Cpiasma value is determined.
• CYP cytochrome P450
• the compounds of the invention were incubated at a concentration of about 0.1-10 ⁇ .
• stock solutions of the compounds according to the invention with a concentration of 0.01-1 mM in acetonitrile were prepared, and then pipetted with a 1: 100 dilution into the incubation mixture.
• the liver microsomes and recombinant enzymes were incubated in 50 mM potassium phosphate buffer pH 7.4 with and without NADPH-generating system consisting of 1 mM NADP + , 10 mM glucose-6-phosphate and 1 unit glucose-6-phosphate dehydrogenase at 37 ° C.
• Primary hepatocytes were also incubated in suspension in Williams E medium also at 37 ° C.
• the incubation mixtures were stopped with acetonitrile (final concentration about 30%) and the protein was centrifuged off at about 15,000 ⁇ g. The samples thus stopped were either analyzed directly or stored at -20 ° C until analysis.
• the analysis is carried out by high performance liquid chromatography with ultraviolet and mass spectrometric detection (HPLC-UV-MS / MS).
• HPLC-UV-MS / MS ultraviolet and mass spectrometric detection
• the supernatants of the incubation samples are chromatographed with suitable C18-reversed-phase columns and variable eluent mixtures of acetonitrile and 10 mM aqueous ammonium formate solution or 0.05% formic acid.
• the UV chromatograms in combination with mass spectrometry data serve to identify, structure elucidate and quantitatively estimate the metabolites, and quantitative metabolic decrease of the compound of the invention in the incubation approaches.
• the permeability of a test substance was determined using the Caco-2 cell line, an established in vitro model for permeability predictions at the gastrointestinal barrier (Artursson, P. and Karlsson, J. (1991) Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells, Biochem., Biophys. 175 (3), 880-885).
• the Caco-2 cells (ACC No. 169, DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany) were seeded in 24-well plates with use and cultured for 14 to 16 days.
• test substance was dissolved in DMSO and diluted to the final test concentration with transport buffer (Hanks Buffered Salt Solution, Gibco / Invitrogen, with 19.9 mM glucose and 9.8 mM HEPES).
• transport buffer Hanks Buffered Salt Solution, Gibco / Invitrogen, with 19.9 mM glucose and 9.8 mM HEPES.
• P app AB the solution containing the test substance was added to the apical side of the Caco-2 cell monolayer and transport buffer to the basolateral side.
• P app BA the solution containing the test substance was added to the basolateral side of the Caco-2 cell monolayer and transport buffer to the apical side.
• hERG human ether-a-go-go related gene
• the functional hERG assay used here is based on a recombinant HEK293 cell line stably expressing the KCNH2 (HERG) gene (Zhou et al., 1998). These cells are assayed by the whole-cell voltage-clamp technique (Hamill et al., 1981) in an automated system (Patchliner TM, Nanion, Kunststoff, D) which controls membrane voltage and hERG potassium current at room temperature measures.
• the PatchControlHT TM software (Nanion) controls patchliner system, data acquisition and data analysis. The voltage is controlled by 2 EPC-10 quadro amplifiers under the control of the PatchMasterPro TM software (both: HEKA Elektronik, Lambrecht, D).
• NPC-16 medium resistance chips ( ⁇ 2 ⁇ , Nanion) serve as a planar substrate for the voltage-clamp experiments.
• NPC-16 chips are filled with intra- and extracellular solution (see Himmel, 2007) as well as with cell suspension.
• the cell membrane After formation of a giga-ohm seal and production of the whole cell mode (including several automated quality control steps), the cell membrane is clamped to the hold potential -80 mV.
• the following voltage logic protocol changes the command voltage to +20 mV (duration 1000 ms), -120 mV (duration 500 ms), and back to the holding potential -80 mV; this is repeated every 12 seconds.
• an initial stabilization phase about 5-6 minutes
• test substance solution in ascending concentrations (eg, 0.1, 1, and 10 ⁇ / L) (exposure about 5-6 minutes per concentration), followed by several washout steps.
• the amplitude of the inward TaiF current generated by a potential change from +20 mV to -120 mV serves to quantify the hERG potassium current and is plotted as a function of time (IgorPro TM software)
• Periods of time eg, stabilization phase before test substance, first / second / third concentration of test substance serve to produce a concentration-effect curve from which the half-maximal inhibitory concentration IC50 of the test substance is calculated.
• the compounds according to the invention can be converted into pharmaceutical preparations as follows:
• the mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
• the granules are mixed after drying with the magnesium stearate for 5 minutes.
• This mixture is compressed with a conventional tablet press (for the tablet format see above).
• a pressing force of 15 kN is used as a guideline for the compression.
• Composition 1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel ® (xanthan gum of the firm FMC, Pennsylvania, USA) and 99 g of water.
• a single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension.
• the compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention.
• i.v. solution The compound of the invention is dissolved at a concentration below saturation in a physiologically acceptable solvent (e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%). The resulting solution is sterile filtered and filled into sterile and pyrogen-free injection containers.
• a physiologically acceptable solvent e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Epidemiology (AREA)
• Urology & Nephrology (AREA)
• Hematology (AREA)
• Diabetes (AREA)
• Vascular Medicine (AREA)
• Obesity (AREA)
• Hospice & Palliative Care (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=50693467

Family Applications (1)

Country Status (6)

Families Citing this family (4)

Family Cites Families (5)

• 2015
  • 2015-04-29 EP EP15721635.9A patent/EP3137465A1/de not_active Withdrawn
  • 2015-04-29 CA CA2947372A patent/CA2947372A1/en not_active Abandoned
  • 2015-04-29 JP JP2017508756A patent/JP2017514901A/ja active Pending
  • 2015-04-29 CN CN201580034595.5A patent/CN106507673A/zh active Pending
  • 2015-04-29 WO PCT/EP2015/059350 patent/WO2015165970A1/de active Application Filing
  • 2015-04-29 US US15/308,200 patent/US20170101407A1/en not_active Abandoned

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events