EP3717480A1 - Verfahren zur herstellung von (3s)-3-(4-chlor-3-{[(2s,3r)-2-(4-chlorphenyl)-4,4,4-trifluor-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropansäure und dessen kristalline form für die verwendung als pharmazeutischer wirkstoff - Google Patents

Verfahren zur herstellung von (3s)-3-(4-chlor-3-{[(2s,3r)-2-(4-chlorphenyl)-4,4,4-trifluor-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropansäure und dessen kristalline form für die verwendung als pharmazeutischer wirkstoff

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Publication number
EP3717480A1
EP3717480A1 EP18814516.3A EP18814516A EP3717480A1 EP 3717480 A1 EP3717480 A1 EP 3717480A1 EP 18814516 A EP18814516 A EP 18814516A EP 3717480 A1 EP3717480 A1 EP 3717480A1
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Prior art keywords
formula
compound
alkyl
acid
preparation
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EP18814516.3A
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German (de)
English (en)
French (fr)
Inventor
Peter Fey
Philipp Rubenbauer
Kai Lovis
Britta Olenik
Julia KÜSEL
Felix Spindler
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Bayer Pharma AG
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Bayer Pharma AG
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Definitions

  • the present invention relates to a novel and improved process for the preparation of (35) -3- (4-chloro-3 - ⁇ [(25, 3R) -2- (4-chlorophenyl) -4,4,4-trifluoro 3-methylbutanoyl] amino ⁇ phenyl) -3-cyclopropylpropanoic acid of the formula (I)
  • (I-A) denotes the compound of the formula (I) in amorphous form; the crystalline modification 1 is designated (1-1). Without further differentiation, the compound of formula (I) is present in one or more modifications or as a solvate.
  • the compound of the formula (I) and the compound of the formula (I) in crystalline modification 1 (1-1) act as an activator of soluble guanylate cyclase and can be used as agents for the prophylaxis and / or treatment of cardiovascular diseases and in particular diseases of the kidney, as used for example for the treatment of chronic renal failure (CKD).
  • CKD chronic renal failure
  • the compound (I-A) and its production process are basically known.
  • WO 2012/139888 the preparation of the compound (I-A) starting from the compound of formula (II) and the lerl. - Butyl ester (III-A) by amide coupling and subsequent ester cleavage in two stages disclosed.
  • the compound of formula (I) was obtained by concentrating chromatography fractions as an amorphous solid. A defined crystallization process of the final stage polymorphism adjustment has not been described.
  • Scheme 1 shows the known process for preparing the compound (I-A).
  • the resulting reaction product of formula (V) is obtained as an oil and trifluoroacetic acid (TFA) to give (3S) -3- (4-chloro-3-j [(2SJR) -2- (4-chlorophenyl) -4,4,4-trifluoro-3-methylbutanoyl] amino ⁇ phenyl) -3-cyclopropylpropanoic acid of the formula (I).
  • TFA trifluoroacetic acid
  • the purification of the crude product of the compound (IA) is carried out according to the experimental procedure of Example 22 of WO 2012/139888 by preparative RP-HPLC.
  • a disadvantage of this method is that it comes through the epimerization of the stereocenter in addition to the amide function to undesirable by-products.
  • Another disadvantage is the side reaction of the 1-chloro-V, V, 2-trimethylprop-1-en-1-amine (IV) with the nitrogen of compound (III-A).
  • undesirable side reactions in the ester cleavage in process step (V-A) -> (I-A) such as the opening of the cyclopropane ring on.
  • the side reactions as well as the epimerization of the stereocenter in addition to the amide function during these two steps reduce the yield of the desired reaction product.
  • the secondary components with open-ended cyclopropyl ring are scarcely more abundant owing to their similar structure, and are therefore contained in the active ingredient and must be removed by a very complicated chromatographic purification.
  • Suitable solvents are not protic, polar solvents, for example THF (tetrahydrofuran), DCM (dichloromethane), dioxane, toluene, DMF (dimethylformamide), NMP (N-methyl-2-pyrrolidone), DMA (dimethylacetamide) or ethers.
  • THF tetrahydrofuran
  • DCM diichloromethane
  • dioxane dioxane
  • toluene DMF (dimethylformamide)
  • NMP N-methyl-2-pyrrolidone
  • DMA dimethylacetamide
  • the carboxylic acid of formula (II) is converted into the corresponding carboxylic acid chloride or mixed carboxylic acid anhydride.
  • the preparation of the carbonyl chloride is carried out in the usual way by treatment of the carboxylic acid with thionyl chloride or oxalyl chloride. Preference is given to using 0.5eq to 2eq of oxalyl chloride, more preferably 1.1 eq of oxalyl chloride.
  • the preparation of the mixed carboxylic acid anhydride is carried out in a conventional manner by treatment of the carboxylic acid with suitable sulfonyl chlorides. Preferably, methanesulfonyl chloride is used.
  • the reaction is carried out at 0 ° C to 50 ° C, preferably at 0 ° C to 25 ° C, more preferably at 20 ° C. The reaction takes place in the absence of a base.
  • tert-butyl (35) -3- (3-amino-4-chlorophenyl) -3-cyclopropyl-propanoate of the formula (PI-A) is dissolved in a solvent and an amine base.
  • esters known to those skilled in the art, such as methyl, ethyl, propyl, isopropyl, Butyl, sec-butyl, or isobutyl ester. Preference is given to using ferric butyl ester.
  • Suitable solvents are not protic, polar solvents, for example THF, DCM, dioxane, toluene, DMF, NMP, DMA or ether, preferably THF is used.
  • Suitable amine bases are triethylamine, IV-methylmorpholine, V-methylpiperidine, N, / V-diisopropene 1 cthylamine, pyridine, 4 -, V -, V - D imcthy 1-amino-pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or l, 5-diazabicyclo [4.3.0] non-5-ene (DBN).
  • the intermediate acid chloride or the mixed carboxylic acid anhydride at 0 ° C to 50 ° C, preferably 0 ° C to 25 ° C, particularly preferably 20 ° C, is added.
  • the coupling to the compound of the formula (VA) proceeds rapidly (lh), very cleanly and without epimerization.
  • the solvent is evaporated off and the solid is dissolved in a mixture of MTBE and heptane in a volume ratio of 1: 1 to 1: 8, preferably 1: 4.
  • reaction solution is concentrated to half its volume, slowly cooled to room temperature and the compound of formula (VA) is obtained as a crystalline solid in very high purity in good yield.
  • the connec tion of formula (VA) is obtained after crystallization in a yield of 86% in high purity.
  • the compound of formula (V-A) is dissolved in dioxane and reacted by adding HCl to the compound of formula (I).
  • the compound of formula (I) is converted into the formula (1-1) by the following crystallization method:
  • the compound of formula (I), present in one or more modifications or as a solvate is preferably selected in an inert solvent from a list containing heptane, 2-methoxy-2-methylpropane, ethanol, ethyl acetate or Ge mixtures of these solvents, at a temperature of 20 ° C to l20 ° C, preferably from 30 ° C to l00 ° C, more preferably of 40 ° C to 60 ° C, stirred and optionally after cooling the connec tion (1-1) isolated.
  • Preferred inert solvents for the process for preparing the compound (1-1) are heptane, mixtures of ethanol and water in the volume ratio of 1: 4, mixtures of 2-methoxy-2-methylpropane and heptane in the volume ratio 4: 1 to 1:25 and Mixtures of ethyl acetate and heptane, wherein the proportion of ethyl acetate is 2% or less.
  • Particularly preferred inert solvents are mixtures of 2-methoxy-2-methylpropane and heptane in the volume ratio of 1: 1 to 4: 1, very particularly preferably 2.3: 1, which in a subsequent step by adding heptane to a volume ratio of 1: 13 to 1:25, especially before being given 1:18.
  • the solution can be inoculated with the compound (1-1).
  • the inoculation (1-1) for seeding can be obtained, for example, from the compound (IA) by stirring in n-heptane or a mixture of ethanol and water in a ratio of 1: 4, preferably at 25 ° C.
  • the novel synthesis has the advantage over the prior art (WO 2012/139888, Example 99A) that the base-free reaction of the compound of the formula (II) with the corresponding carboxylic acid chloride or carboxylic anhydride surprisingly does not result in the epimerization of the stereocenter besides the amide function. Epimerization is also not observed in the following process step (11) + (111-A) -> (VA).
  • the coupling reaction is therefore carried out with a high yield of the compound of formula (VA) of 86% d. Th. And high purity.
  • Using the reaction (11) + (III-A) -> (VA) on an industrial scale gives a yield of about 70% and additionally 5% contamination of the product by the side reaction of the 1-chloro-V, V, 2- trimethylprop-l-en-1-amine of the formula (IV) with the nitrogen of compound (III-A).
  • the equimolar use of the carcinogenic compound 1 - C h 1 o r- / V, / V, 2-trimethyl prop-1-en-1-amine (IV) is dispensed with.
  • the by-product formation by reaction of the compound of formula (III-A) with compound of formula (IV) is therefore not possible.
  • R is (C 1 -C 4 ) -alkyl, characterized in that the compound of the formula (II)
  • R 1 is (Ci-C i) -alkyl
  • Another object of the present invention is a process for the preparation of the compound of formula (V), in which R 1 is (Ci-C i) -alkyl, characterized in that the compound of formula (II) under base-free conditions to the corresponding intermediate carboxylic acid chloride or to the corresponding intermediate carboxylic acid anhydride and in a coupling reaction with the compound of formula (III)
  • R 1 is (Ci-C i) -alkyl
  • Another object of the present invention is a process for the preparation of the compound of formula (V), in which
  • R 1 is (Ci-C i) -alkyl
  • Another object of the present invention is a process for the preparation of the compound of formula (V), wherein instead of the compound of formula (VI), the compound of formula (VI-A) ci
  • a preferred object of the present invention is the process for the preparation of the connec tion of the formula (V) using catalytic amounts of DMF for the synthesis of the intermediate carbonyl chloride.
  • a preferred object of the present invention is the process for the preparation of the connec tion of formula (V) using catalytic amounts of DMF for the synthesis of the intermediate carboxylic acid anhydride.
  • a preferred subject of the present invention is the process for the preparation of the connec tion of the formula (V) at a temperature of 0 ° C to 50 ° C, preferably 0 ° C to 25 ° C, especially before given to 20 ° C.
  • a further subject matter of the present invention is a process for the preparation of the compounds of the formula (I), characterized in that the compound of the formula (V)
  • R 1 is (Ci-C4) -alkyl, in the presence of dioxane and hydrochloric acid to the compound of formula (I) is reacted.
  • An object of the present invention is a process for the preparation of the compound of the formula (I), characterized in that the compound of the formula (II)
  • An object of the present invention is a process for preparing the compound of formula (I), characterized in that the compound of formula (II)
  • a preferred subject of the present invention is the process for the preparation of the connec tion of formula (I) using catalytic amounts of DMF for the synthesis of the intermediate Car bonklarechlorids.
  • a preferred subject of the present invention is the process for the preparation of the connec tion of the formula (I) using catalytic amounts of DMF for the synthesis of the intermediate Car bonklareanhydrids.
  • a preferred subject matter of the present invention is the process for preparing the compound of the formula (I) at a temperature of 0 ° C to 50 ° C, preferably 0 ° C to 25 ° C, particularly preferably 20 ° C.
  • a further subject of the present invention is the compound of formula (I) in crystalline form of modification 1 (1-1)
  • the IR spectrum of the compound shows band maxima at 1709, 1660, 1534, 1491, 1263, 1167, 1131, 1093, 1016 cm 1 .
  • a further subject of the present invention is the compound of formula (I) in crystalline form of modification 1 (1-1)
  • Another object of the present invention is a process for the preparation of the compound (1-1), characterized in that the compound of the formula (I), present in one or more
  • Preferred inert solvents for the process for the preparation of the compound (1-1) are heptane, mixtures of ethanol and water in the volume ratio of 1: 4, mixtures of 2-methoxy-2- methylolpropane and heptane in the volume ratio 4: 1 to 1:25 and mixtures of ethyl acetate and heptane, wherein the proportion of ethyl acetate is 2% or less.
  • Particularly preferred inert solvents are mixtures of 2-methoxy-2-methylpropane and heptane in the volume ratio of 1: 1 to 4: 1, very particularly preferably 2.3: 1, which in a subsequent step by adding heptane to a volume ratio of 1: 13 to 1:25, especially before being given 1:18.
  • the carboxylic acid of formula (II) is converted into the corresponding carboxylic acid chloride or mixed carboxylic acid anhydride.
  • the preparation of the carboxylic acid chloride ge in the usual way by treatment of the carboxylic acid with thionyl chloride or oxalyl chloride, preferably oxalyl chloride, more preferably 1.1 eq oxalyl chloride are used.
  • the preparation of the mixed carboxylic acid anhydride is carried out in the usual way by treatment of the carboxylic acid with suitable sulfonyl chlorides, preferably methanesulfonyl chloride is used.
  • the Reaction takes place at 0 ° C to 50 ° C, preferably at 0 ° C to 25 ° C.
  • the reaction takes place in the absence of a base.
  • (3S) -3- (3-amino-4-chlorophenyl) -3-cyclopropylpropanoic acid (VII) or a salt of this compound is dissolved in a non-protic, polar solvent and an amine base.
  • non-protic, polar solvent for example, THF, DCM, dioxane, toluene, DMF, NMP, DMA or ether, preferably THF is used.
  • Suitable amine bases are, for example, triethylamine, V-methylmorpholine, V-methylpiperidine,, V, / V-diisopropenyl, pyridine, 4-V, IV-dimethylaminopyridine, 1,8-diazabicyclo [5.4.0 ] undec-7-ene (DBU) or l, 5-diazabicyclo [4.3.0] non-5-ene (DBN), preferably N, N-diisopropylethylamine, more preferably 5eq N, N-diisopropylethylamine are used.
  • the carboxylic acid moiety of the compound of formula (VII) must be protected.
  • the carboxylic acid moiety of the compound of formula (VII) is preferably protected at 0 ° C to 50 ° C, more preferably at 20 ° C in the presence of a non-protic, polar solvent and an amine base having a silyl protecting group.
  • silicon organic compound for example chlorotriethylsilane (TESC1), chlorotrimethylsilane or tert-butyl (chloro) dimethylsilane can be used, preferably chlorotriethylsilane (TESC1) is used.
  • TSC1 chlorotriethylsilane
  • chlorotrimethylsilane or tert-butyl (chloro) dimethylsilane preferably chlorotriethylsilane (TESC1) is used.
  • TSC1 chlorotriethylsilane
  • THC1 chlorotriethylsilane
  • carboxylic acid chloride or carboxylic anhydride By aqueous, acidic workup, the silyl group is split off.
  • EtOAc acts as a solubilizer in the reaction and may also be present in small amounts after the redistillation.
  • the novel synthesis has the advantage over the prior art (WO 2012/139888, Example 99A) that the base-free reaction of the compound of the formula (II) with the corresponding carboxylic acid chloride or carboxylic anhydride surprisingly does not result in the epimerization of the stereocenter besides the amide function. Epimerization is also not observed during the coupling reaction.
  • the reaction the compound (1-1) starting from the Kupplungsedukten in a manufactured one-step process. In comparison to the prior art, a solid insulation is eliminated.
  • Another advantage is that the compound of formula (VII) is accessible by racemate resolution.
  • the racemate resolution is shown in Scheme 8 and is significantly more efficient than the separation of the enantiomers via chiral chromatography, which is necessary for the separation of the enantiomers of the compound of formula (III).
  • the equimolar use of the carcinogenic compound 1-chloro-W, 2-trimethylprop-l-en-1-amine of the formula (IV) can be dispensed with.
  • the disadvantageous by-product formation by reaction of the compound of formula (III) with compound of formula (IV) is therefore not possible.
  • Another object of the present invention is a process for the preparation of the compound of formula (I), characterized in that the compound of formula (II)
  • PG is a silyl protective group, is reacted and with elimination of the silyl protective group in aqueous acidic solution to the connec tion of the formula (I)
  • Another object of the present invention is a process for the preparation of the compound of formula (I), characterized in that the compound of formula (II)
  • PG is a silyl protective group, is reacted and with elimination of the silyl protective group in aqueous acidic solution to the connec tion of the formula (I)
  • a preferred subject of the present invention is a process for the preparation of the compound of the formula (I), characterized in that the compound of the formula (II)
  • PG is chlorotriethylsilyl, and with elimination of the silyl protecting group in aqueous acidic solution to the compound of formula (I)
  • Another object of the present invention is a process for the preparation of the compound of formula (I), characterized in that the compound of formula (II),
  • an organosilicon compound preferably chlorotriethylsilane (TESC1), chlorotrimethylsilane or tert-butyl (chloro) dimethylsilane, especially before chlor triethylsilane (TESC1) is added, with the compound of the formula (VII)
  • Another object of the present invention is a process for the preparation of the compound of formula (I), characterized in that the compound of formula (II)
  • a preferred subject of the present invention is a process for the preparation of the compound of the formula (I), characterized in that the compound of the formula (II)
  • chlorotriethylsilane (TESC1), chlorotrimethylsilane or tert-butyl (chloro) dimethylsilane
  • an organosilicon compound preferably chlorotriethylsilane (TESC1), chlorotrimethylsilane or tert-butyl (chloro) dimethylsilane
  • a preferred subject matter of the present invention is the process for preparing the compounds of formula (I) using catalytic amounts of DMF for the synthesis of the intermediate carboyl chloride.
  • a preferred subject of the present invention is the process for the preparation of the connec tion of the formula (I) using catalytic amounts of DMF for the synthesis of the intermediate Car bonklareanhydrids.
  • Another object of the present invention is a process for the preparation of the compound (1-1), characterized in that the compound of formula (I), in this case in one or more modifications or as solvate, is dissolved in ethyl acetate and after redistillation to heptane and optionally after cooling, the compound (1-1) is isolated.
  • Another object of the present invention is the preparation of (2S, 3 /?) - 2- (4-chlorophenyl) - 4,4,4-trifluoro-3-methylbutanoic acid of the formula (II), which is used as starting material for the preparation of the verbin of the formula (I) is used.
  • the preparation of the compound of the formula (II) is known in principle.
  • WO 2012/139888 discloses the preparation of the compound of the formula (II) starting from the compounds of the formula (VIII) and (IX) in eight stages.
  • ethyl (diethoxyphosphoryl) acetate of the formula (VIII) is deprotonated in benzene at 0 ° C with sodium hydride and with trifluoroacetone (IX) to the corresponding ester of the compound 4,4,4-trifluoro-3-methyl-2-butenoic acid ethyl ester of Implemented formula (X).
  • a disadvantage of the process for the preparation of (+) - (25 ', 3R ) -2- (4-chlorophenyl) -4,4,4-trifluoro-3-methylbutanoic acid of the formula (II) is the use of the solid sodium hydride in the reaction step (VIII) + (IX) -> (X).
  • Sodium hydride is unsuitable for large-scale production since, when in contact with water, it forms easily flammable gases which may ignite spontaneously. The handling of sodium hydride requires on a large scale, especially when introduced into the reaction vessel enormous safety precautions and high costs and should be avoided if possible.
  • Another disadvantage of this process step is the low yield of 40%.
  • a disadvantage of the stereoselective hydrogenation to (3R) -4,4,4-trifluoro-3-methylbutanoic acid in the process step (X) -> (XI) is the cost-intensive catalyst with low stereoselectivity, the subsequent enantiomeric enrichment by crystallization as tert. -Butylammoniumsalz neces sary and results in a low overall yield.
  • ethyl (4-chlorophenyl) acetate of the formula (XV) is radically brominated with benzoyl peroxide and N-bromosuccinimide (NBS) in carbon tetrachloride to give ethyl 2- (4-chlorophenyl) -2-bromoethanoate of the formula (XVI) and obtained the product after distillation in 76.6% yield.
  • the bromoester (XVI) is converted to ethyl 2- (4-chlorophenyl) -4,4,4-trifluoro-3-hydroxy-3-methylbutanoate (XVII) in the presence of zinc, copper bromide and diethylaluminum chloride with trifluoroacetone of the formula (XIII) reacted and obtained after chromatography in 81% yield. Subsequently, (XVII) is dehydrated with phosphorus oxychloride in pyridine to yield ethyl 2- (4-chlorophenyl) -4,4,4-trifluoro-3-methylbut-2-enoate (XVIII) in 98% yield.
  • (XVIII) is deprotonated with lithium diisopropylamide (LDA) and methyl 2- (4-chlorophenyl) -4,4,4-trifluoro-3-methylbut-3-enoate (XIX) after reaction with ammonium chloride and aqueous workup and chromatographic purification with a yield of 83%.
  • the ester (XIX) is completely saponified with sodium hydroxide solution to the corresponding acid (XX) and kata lytically to a diastereomeric mixture of racemic 4, 4, 4-trifluoro-3-methylbutanoic acid (II-rac) in hydrogenated in quantitative yield.
  • 4, 4, 4-trifluoro-3-methylbutanoic acid (II-rac) is obtained as a racemic Dias tereomerengemisch according to this method with an overall yield of 50%.
  • a disadvantage of the process of GB-A 2179941 is that reagents such as benzoyl peroxide, N-bromosuccinimide, zinc and copper salts and aluminum alkyl compounds are used which are either explosive or cause a tremendous amount of waste.
  • benzoyl peroxide undergoes a dangerous decomposition reaction when heated, diethylaluminum chloride is self-igniting on contact with air and forms flammable gases with water.
  • costly and costly measures for safe handling must be taken.
  • Zinc is dangerous to the environment and the resulting zinc bromide and copper bromide are very toxic to aquatic organisms and may cause long-term adverse effects in the aquatic environment.
  • Another disadvantage is that by the use of palladium a large amount of dechlorination takes place.
  • the process according to the invention for the preparation of the compound of the formula (II) is described in detail below.
  • the compound of formula (XXII) is metallated at -30 ° C to -78 ° C, preferably -65 ° C to -78 ° C with a lithium thium amide base in an inert solvent and reacted with trifluoroacetone.
  • a lithium thium amide base in an inert solvent and reacted with trifluoroacetone.
  • lithium hexamethyldisilazide or lithium diisopropylamide (LDA) are suitable as lithium amide base.
  • Lithium hexamethyl disilazide is therefore preferably used as lithium amide base.
  • Suitable inert solvents are ethers such as, for example, ethylene glycol dimethyl ether (DME), dioxane, tetrahydrofuran (THF), methyl tetrahydrofuran or methyl phenyl ether (anisole).
  • DME ethylene glycol dimethyl ether
  • THF tetrahydrofuran
  • anisole methyl tetrahydrofuran
  • THF methyl tetrahydrofuran
  • anisole methyl tetrahydrofuran
  • Suitable acids are mineral acids known to the person skilled in the art. Preference is given to using hydrochloric acid, particularly preferably dilute hydrochloric acid (5N). This gives a diastereomer mixture with 0.2% starting material and 99% product with a yield of 94%.
  • Another object of the present invention is a process for the preparation of the compound of formula (XXIII), characterized in that the compound of formula (XXII)
  • R 2 is (Ci-C i) -alkyl, at a temperature of -30 ° C to -78 ° C, preferably from -65 ° C to -78 ° C, in an inert solvent, preferably tetrahydrofuran, with a lithium amide base, preferably lithium hexamethyldisilazide, and trifluoroacetone to the compound of the formula (XXIII)
  • the reaction is preferably carried out at reflux temperature.
  • pyridine or more were used for the reaction 9eq, preferably 9eq to 15eq pyridine, more preferably 10eq to 12eq pyridine, most preferably 11 eq pyridine.
  • 9eq preferably 9eq to 15eq pyridine, more preferably 10eq to 12eq pyridine, most preferably 11 eq pyridine.
  • This resulted in an increased hydrolyzability, stirrability and phase separation.
  • These properties are particularly on an industrial scale for a more efficient reaction procedure of advantage.
  • the compound of formula (XXIII) is reacted in pyridine with 1 to 3eq of phosphorus oxychloride, preferably 1, 8eq of phosphorus oxychloride at reflux to the compound of formula (XXIV).
  • ethyl acetate is added, washed with dilute hydrochloric acid and water, the solution is concentrated and the resulting oil is used as THF solution in
  • Another object of the present invention is a process for the preparation of the compound of formula (XXIV), characterized in that the compound of formula (XXIII)
  • R 2 is (C 1 -C 4) -alkyl, with phosphorus oxychloride and pyridine, preferably 9 to 15 equivalents of pyridine, particularly preferably 10 to 12 equivalents of pyridine, very particularly preferably 11 equivalents of pyridine to the compound of formula (XXIV)
  • R 2 is (Ci-C i) -alkyl, is reacted.
  • Preferred amounts of phosphorus oxychloride for use in the reaction of the compound of formula (XXIII) to the compound of formula (XXIV) are 1 to 5 equivalents. Particularly preferred amounts of phosphorus oxychloride for use in the reaction of the compound of formula (XXIII) to the compound of formula (XXIV) are 1 to 3 equivalents. Most particularly preferred amounts of phosphorus oxychloride for use in the reaction of the compound of formula (XXIII) to give the compound of formula (XXIV) are 1.8 equivalents.
  • the compound of formula (XXIV) is metallated at -30 ° C to -75 ° C, preferably at -65 to -75 ° C with lithium diisopropylamide (LDA) and protonated with acetic acid in THF.
  • LDA lithium diisopropylamide
  • the product is diluted with polyethylene glycol 400 and distilled on a thin film evaporator at a jacket temperature of 45 ° C and a pressure of 1 to 10 mbar.
  • the yield increases when first acidified at -30 ° C to - 75 ° C, preferably at -65 to -75 ° C with an organic acid in an inert solvent and then carried out the aqueous work-up with a mineral acid at pH 4 becomes.
  • Suitable organic acids are those skilled in the art organic acids, preferably It is used acetic acid.
  • Suitable inert solvents are, for example, ethylene glycol dimethyl ether (DME), dioxane, tetrahydrofuran (THF), methyl tetrahydrofuran or methyl phenyl ether (anisole).
  • THF ethylene glycol dimethyl ether
  • Suitable mineral acids are mineral acids known to those skilled in the art, such as, for example, hydrochloric acid or sulfuric acid, hydrochloric acid is preferably used.
  • Another object of the present invention is a process for the preparation of the compound of formula (XXV), characterized in that the compound of formula (XXIV)
  • R 2 is (C 1 -C 4) -alkyl
  • a lithium amide base preferably lithium diisopropylamide
  • R 2 is (Ci-C i) alkyl, by addition of an organic acid, preferably acetic acid, in an inert solvent, preferably THF, and in a second step by adding a mineral acid, preferably hydrochloric acid, before.
  • organic acid preferably acetic acid
  • inert solvent preferably THF
  • mineral acid preferably hydrochloric acid
  • the hydrolysis is preferably carried out at a temperature of from -30 ° C to -75 ° C, preferably at -65 to -75 ° C.
  • the compound of the formula (XXV) is hydrogenated in an organic solvent with a platinum catalyst.
  • Suitable organic solvents are alcohols, esters and ethers known to the person skilled in the art as solvents. Preference is given to using methanol.
  • the prior art (GB 2179941) discloses a hydrogenation reaction with palladium. Surprisingly, it has been shown that hydrogenation with platinum results in a higher yield, since the dechlorination of the aromatic compound is less pronounced.
  • Another object of the present invention is a process for the preparation of the compound of formula (II), characterized in that the compound of formula (XXV)
  • R 2 is (Ci-C i) -alkyl, in a hydrogenation reaction to the compound of formula (XXVI) in which
  • R 2 is (Ci-C4) -alkyl, is reacted.
  • Another object of the present invention is a process for the preparation of the compound of formula (XXVI), characterized in that the compound of formula (XXIV)
  • R 2 is (Ci-C i) -alkyl, with a lithium amide base, preferably lithium diisopropylamide, is reacted and the hydrolysis to the compound of formula (XXV)
  • R 2 (Ci-C i) -alkyl by addition of an organic acid, preferably acetic acid, in an inert solvent, preferably THF, and in a further step by adding a mineral acid vorgenom men and in a further step in a Hydrogenation reaction to the compound of the formula (XXVI) in which
  • R 2 is (Ci-C4) -alkyl, is reacted.
  • the hydrogenation reaction of the compound of formula (XXVI) to the compound of formula (XXVI) is preferably carried out under platinum catalysis with 5% platinum on carbon.
  • the hydrogenation reaction of the compound of the formula (XXVI) to give the compound of the formula (XXVI) is particularly preferably carried out under platinum catalysis with 5% platinum on carbon, 50% of water at 20 ° C to 70 ° C and a pressure of 5 bar to 100 bar , carried out.
  • the hydrogenation reaction of the compound of the formula (XXVI) to give the compound of the formula (XXVI) is very particularly preferably carried out using platinum catalysis with 5% platinum on carbon, 50% water-moist at 50 ° C. and a pressure of from 5 bar to 100 bar.
  • the hydrogenation reaction of the compound of the formula (XXVI) to give the compound of the formula (XXVI) is very particularly preferably carried out using platinum catalysis with 5% platinum on carbon, 50% water-moist at 50 ° C. and a pressure of 80 bar.
  • the compound of formula (XXVI) is at 5 ° C to 40 ° C, preferably 20 ° C, with sodium methylate, preferably be l, 8eq sodium methylate, isomerized in methanol and the ester saponified by the addition of water to the sodium salt.
  • the sodium salt is isolated by filtration and purified by washing with water.
  • the free acid of the compounds of the formula (II) and (II-A) is obtained by acidification with dilute acids, preferably with hydrochloric acid, especially preferred. obtained with 20% hydrochloric acid.
  • a mixture of the two compounds of the formula (II) and (PA) is referred to hereinafter as rel- (2R, 3S) -2- (4-chlorophenyl) -4,4,4-trifluoro-3-methylbutanoic acid.
  • a further subject of the present invention is a process for the preparation of the compounds of the formulas (II-Na) and (II-A-Na), characterized in that the compound of the formula (XXVI)
  • R 2 is (Ci-C i) -alkyl, with sodium methylate in methanol and subsequent addition of water to the compounds of formula (II-Na) and (II-A-Na)
  • a preferred subject of the present invention is a process for the preparation of the compound of the formula (II) and (P-A), characterized in that the compound of the formula (XXVI)
  • R 2 is (Ci-C i) -alkyl, with sodium methylate in methanol and subsequent addition of water to the compounds of the formula (II-Na) and (II-A-Na)
  • quinine means the compound designated (3alpha, 4beta, 8alpha, 9R) -6'-methoxycinchonan-9-ol (CAS number: 130-95-0), moreover, the quinine salt of the compound (2S, 3R) -2- (4-chlorophenyl) -4,4,4-trifluoro-3-methylbutanoic acid (II), the quinine salt of the compound (2R, 3S) -2- (4-chlorophenyl) -4,4,4
  • trifluoro-3-methylbutanoic acid (II-A) remains in solution, so that this method is suitable for the purification of the desired compound of formula (II)
  • the resolutions used include dilutions of from 5 kg to 30 kg of ethanol, preferably 13 kg up to 17 kg of ethanol per Kilograms of the compound of formula (II) required.
  • the solid is then isolated and washed with ethanol and water.
  • the mixture is then dissolved in a mixture of water and methanol in a ratio of 1: 1 to 1: 5, preferably 1: 2 to 1: 3, particularly preferably 1: 2.7 and cooled.
  • the mixture is then dissolved in a mixture of water and ethanol in a ratio of 1: 1 to 1:10, preferably 1: 4 to 1: 5, more preferably 1: 4.9 and cooled.
  • These Steps preferably take place at a temperature of 20 ° C to reflux temperature, more preferably at a temperature of 50 ° C to reflux temperature.
  • the suspended quinine salt of the formula (II-CH) is treated with a dilute mineral acid, preferably hydrochloric acid, more preferably 25% hydrochloric acid, the solid is isolated, washed with water and dried. Due to the low solubility of quinine hydrochloride (62.5 g / l water) in water, the release must be carried out in appropriate dilution.
  • a dilute mineral acid preferably hydrochloric acid, more preferably 25% hydrochloric acid
  • Another object of the present invention is the compound of the formula (II-Ch)
  • Another object of the present invention is a mixture of substances containing compound of formula (II) and quinine.
  • Another object of the invention is a process for the purification of the compound of formula (II), characterized in that the compound of formula (II) is isolated in the present case as the quinine salt of the formula (II-Ch) in an inert solvent.
  • Another object of the present invention is a process for the preparation of the compound of formula (II-CH), characterized in that the compounds of formula (II)
  • Another object of the present invention is a process for the preparation of the compound of formula (Il-Ch) as described above and the purification of the compound of formula (Il-Ch) in a first step by crystallization in a mixture of water and methanol in ratio 1: 1 to 1: 5, preferably 1: 2 to 1: 3, particularly preferably 1: 2.7 and in a second step by crystallization tion in a mixture of water and ethanol in the ratio 1: 1 to 1:10, preferably 1: 4 to 1: 5, more preferably 1: 4.9 is made.
  • Another object of the present invention is a process for the preparation of the compound of formula (II), characterized in that a mixture of the compounds of formula (II) and (II-A)
  • Another object of the present invention is a process for the preparation of the compound of formula (II), characterized in that the compound of formula (XXVI)
  • R 2 is (Ci-C i) -alkyl, with sodium methylate in methanol and subsequent addition of water to the compounds of formula (II-Na) and (II-A-Na)
  • Another advantage is that by the use of platinum in step (XV) -> (XVI) less dechlorination takes place compared to the hydrogenation conditions in GB 2179941.
  • Another advantage is that effective purification takes place by crystallization of the compounds (II) and (II-A) as the sodium salt. Since all intermediates are used in the form of an oil or a solution in the subsequent stage up to this reaction step, all byproduct can be separated thereby. This eliminates a chromatographic purification, which is technically very complicated and expensive due to the high consumption of solvents.
  • the crystallization of the compound of the formula (II) as a quinine salt surprisingly found a method for obtaining the compound of the formula (II) in high diastereomeric purity and enantiomeric purity, so that the separation on a chiral column can be dispensed with. the tech nically very complex and cost-intensive due to the high consumption of solvents.
  • Ci-C i-alkyl denotes a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3 or 4 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, scA.-butyl, isobutyl or fer / -butyl group.
  • Another object of the present invention is the preparation of (3S) -3- (3-amino-4-chlorophenyl) -3-cyclopropylpropanoic acid of the formula (VII), which serves as starting material for the preparation of the compound of formula (I).
  • the compound of formula (III) represents the corresponding Ierl. Butyl ester of the compound of formula (VII).
  • the preparation of the compound of formula (III) is basically known.
  • WO 2012/139888 describes the preparation of the compound of the formula (III) in the following way (Scheme 7). Scheme 7:
  • the resulting reaction product of the formula (XXX) is isolated and tert with sodium hydride and tert-butyl (diethoxyphosphoryl) acetate of the formula (XXXI-A) to tert-butyl (2E / Z) -3- (4-chloro) 3-nitrophenyl) -3-cyclopropyl acrylate of the formula (XXXII).
  • Catalytic hydrogenation of the isolated and purified reaction product under a hydrogen atmosphere gives the racemic compound ferric butyl-3- (3-amino-4-chlorophenyl) -3-cyclopropylpropanoate of the formula (III-A-rac).
  • the (5) -enantiomer of the formula (III-A) is obtained by preparative HPLC on a chiral phase.
  • a disadvantage of the synthesis of the compound of formula (PI-A) is the simultaneous catalytic Hydrie tion of the double bond and nitro group in the connecting step (XXXII) -> (III-A-rac), leading to some undesirable reactions, such as for the opening of the cyclopropane ring or leads to dechlorination of the aromatic.
  • the compound of formula (XXXIV) is obtained by reacting cyclopropylaldehyde (XXXIII) with fer / -butyldiethylphosphonoacetate (XXXI) in toluene with KOtBu at 0 ° C to 30 ° C. After aqueous acidic workup, the product can be obtained via distillation or crystallization.
  • Another object of the present invention is a process for the preparation of the compound of formula (XXXIV), characterized in that the compound of formula (XXXIII) at 0 to 30 ° C. in toluene, potassium fer-.-butoxide and a compound of the formula (XXXI)
  • R 1 is (Ci-C i) -alkyl, to the compound of formula (XXXIV)
  • R 1 is (Ci-C i) -alkyl, is reacted.
  • the compound of the formula (III-rac) is prepared in a rhodium-catalyzed 1,4-addition of a boronic acid or a boronic ester using a base, a protic solvent, cyclooctadiene (COD) in THF or toluene at preferably 50 ° C to 80 ° C received.
  • the compounds (XXXIV) are presented with the boronic acid ester of the formula (XXXV-BA) in THF, a protic solvent and a base with exclusion of air.
  • Suitable bases are customary inorganic bases. These include in particular alkali metal or alkaline earth metal hydroxides such as, for example, lithium, sodium, potassium or barium hydroxide, or alkali metal or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate.
  • Another object of the present invention is a process for the preparation of the compound of formula (III-rac), characterized in that the compound of formula (XXXIV)
  • R 1 (Ci-C i) -alkyl, with a base, a protic solvent, l, 5-cyclooctadiene, [Rh (COD) Cl] 2 and a compound of the formula (XXXV-A) or (XXXV-) B)
  • R 4 , R 5 , R 6 , R 7 , R 8 and R 9 independently of one another denote hydrogen or (Ci-Gi) -alkyl represent the compound of the formula (III-rac)
  • R 1 is (Ci-C i) -alkyl, is reacted.
  • Another object of the present invention is a process for the preparation of the compound of formula (III-rac), characterized in that the compound of formula (XXXIV)
  • R 1 (Ci-C i) -alkyl, with a base, l, 5-cyclooctadiene, (+, -) - BINAP, [Rh (COD) Cl] 2 in the absence of an inert gas with a compound of formula (XXXV-) A) or (XXXV-B)
  • R 4 , R 5 , R 6 , R 7 , R 8 and R 9 independently of one another denote hydrogen or (C 1 -C 4) -alkyl, to give the compound of the formula (III -rac)
  • R 1 is (Ci-C4) -alkyl, is reacted.
  • Another object of the present invention is a process for the preparation of the compound of formula (VII), characterized in that the compound of formula (XXXIV)
  • R 1 is (Ci-C i) -alkyl, with a base, a protic solvent, l, 5-cyclooctadiene, [Rh (COD) Cl] 2 and a compound of formula (XXXV-A) or (XXXV-B)
  • R 4 , R 5 , R 6 , R 7 , R 8 and R 9 independently of one another denote hydrogen or (Ci-Gi) -alkyl be the compound of formula (III -rac)
  • R 1 is (Ci-C i) -alkyl, is reacted and after ester cleavage to the compound of formula (VII-rac),
  • reaction of the compound of the formula (XXXIV) with a compound of the formula (XXXV-A) or (XXXV-B) preferably takes place in the presence of (+, -) -BINAP and in the absence of an inert gas.
  • the reaction of the compound of the formula (XXXIV) with a compound of the formula (XXXV-A) or (XXXV-B) preferably takes place at a temperature of 50.degree. C. to 80.degree. C., more preferably at 60.degree.
  • reaction of the compound of the formula (XXXIV) with a compound of the formula (XXXV-A) or (XXXV-B) preferably takes place with potassium hydroxide as the base.
  • Preferred amounts of 1, 5-cyclooctadiene for use in the preparation of the compound (III-rac) are 0.0 leq.
  • (+, -) - BINAP for use in the preparation of the compound (III-rac) are 0.006eq.
  • Another object of the present invention is a process for the preparation of the compound of formula (III-rac), characterized in that the compound of formula (XXXIV)
  • R 1 is (C 1 -C 4) -alkyl.
  • the compound of the formula (VII-rac) can be converted into the enantiomerically pure compound of the formula (VII-C) by racemate resolution via a corresponding indanol salt of the formula (VII-I).
  • compound of the formula (VII-rac) in acetonitrile and water is dissolved with heating and (1S, 2R) - (-) - cis-1-amino-2-indanol of the formula (XXXVI) is added.
  • the reaction mixture is seeded on and slowly cooled.
  • the product is isolated, resuspended in acetonitrile and water, dissolved with warming and crystallized.
  • the indanol salt of formula (VII-I) may be converted to the corresponding salt of formula (VII-S) of the compound of formula (VII) by suspending the indanol salt in EtOAc and water and adding HCl. After aqueous workup, the crude solution is concentrated. This crude product is reacted in EtOAc with HCl in dioxane to give the corresponding compound of formula (VII) HCl salt (VII-S). Compound of formula (VII-S) is obtained with an enantiomeric purity of 99.4% in a yield of 37%. Another object of the present invention is the compound of formula (VII-I)
  • Another object of the present invention is a mixture of substances containing compound of formula (VII) and (lS, 2R) - (-) - cis-l-amino-2-indanol.
  • Another object of the invention is a process for the purification of the compound of formula (VII), characterized in that the compound of formula (VII) is isolated here as indanol salt of the formula (VII-I) in an inert solvent.
  • Another object of the present invention is a process for the preparation of the compound of formula (VII-I), characterized in that the compound of formula (VII-rac)
  • Another object of the present invention is a process for the preparation of the compound of formula (VII-I), characterized in that the compound of formula (VII-rac)
  • reaction of the compound of the formula (VII-rac) to give the compound of the formula (VII-I) preferably takes place at a temperature of 30 ° C. to reflux temperature, more preferably at a temperature of 50 ° C. to 80 ° C.
  • Preferred solvent for the preparation of the compound (VII-I) is a mixture of acetonitrile and water in a ratio of 10: 1 to 20: 1.
  • a particularly preferred solvent for the preparation of the compound (VII-I) is a mixture of acetonitrile and water in the ratio 15: 1.
  • Another object of the present invention is a process for the preparation of the compound of formula (VII), characterized in that the compound of formula (VII-rac)
  • the construction of the cyclopropylpropanoate derivative of the formula (XXXIV) is effected by rhodium-catalyzed addition of the boric acid ters of the formula (XXXV-BA).
  • the present alternative process has the advantage that, in contrast to the prior art, a catalytic hydrogenation ((XXXII) -> (III-A-rac)) can be dispensed with. This results in an overall lower by-product formation, such as opening of the cyclopropane ring or dechlorination of the aromatic, whereby a higher purity and yield is obtained.
  • the catalyst consisting of a suitable metal precursor and a suitable diene ligand are stirred under exclusion of air in a solvent.
  • the ratio between metal precursor and diene ligand may be between 1: 1 to 1: 3, preferably 1: 1 or 1: 2 is used.
  • Suitable diene ligands are (1S, 4S) -2,5-diphenylbicyclo [2.2.2] octa-2,5-diene (XXXVII); ((3aR, 6aR) -3,6-diphenyl-l, 3a, 4,6a-tetrahydropentalene (XXXVIII); (1S, 4S, 7S) -a, a, 5-trimethyl-7- (1-methylethyl) bicyclo [2.2.2] octa-2,5-diene-2-methanol (XXXIX); 2-naphthyl
  • Suitable solvents are methanol, dioxane, isopropanol, THF, water or mixtures thereof. Preferably, methanol is used.
  • a suspension of the compounds of formula (XXXIV) and a boronic ester of formula (XXXV-B-A) in a solvent and a suitable base is heated to 40 ° C to 10 ° C, preferably 50 ° C.
  • the pinacol ester of the formula (XXXV-B-A) it is possible to use further esters of boronic acid known to the person skilled in the art and the free boronic acid.
  • Suitable solvents are methanol, dioxane, isopropanol, THF, water or mixtures thereof.
  • Suitable bases are KOH, K 2 CO 3, NaHCO 3 or triethylamine, preferably KOH is used. After aqueous workup, the corresponding tosylate can be isolated in good yield and high enantiomeric purity.
  • WO 2007/057643 describes the reaction of fluorinated phenylboronic acids or their esters with a, b-unsaturated propenoic acid ester derivatives in the presence of chiral rhodium (I) catalyst complexes and a base.
  • the selection of the desired enantiomer takes place in the prior art by a racemate resolution, so that more than half of the product must be discarded in the separation of the enantiomers. The maximum yield in this step is therefore 50%.
  • the desired enantiomer is formed directly by an enantioselective reaction step with a yield of 77% and an enantiomeric purity of 97.1%.
  • Another object of the present invention is a process for the preparation of the compound of formula (III), characterized in that the compound of formula (XXXIV)
  • R 1 is (Ci-C i) -alkyl, with the exclusion of oxygen, preferably at a temperature of 40 ° C to 1 10 ° C, with a appro Neten metal precursor, a suitable diene ligand, a suitable Base and a compound of formula (XXXV-A) or (XXXV-B)
  • R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently of one another hydrogen or (Ci-Gi) -alkyl, to the compound of formula (III)
  • R 1 is (Ci-C i) -alkyl, is reacted.
  • the disclosure also includes all combinations of said metal precursors and diene ligands for the preparation of the compound of the formula (III).
  • Another object of the present invention is a process for the preparation of the compound of formula (III), characterized in that the compound of formula (XXXIV)
  • R 4 , R 5 , R 6 , R 7 , R 8 and R 9 independently of one another denote hydrogen or (C 1 -C 12) -alkyl, to give the compound of the formula (III)
  • R 1 is (Ci-C4) -alkyl, is reacted.
  • the reaction of the compound of the formula (XXXIV) to the compound of the formula (III) preferably takes place with a compound of the formula (XXXV-BA).
  • the indication of equivalents (eq) for reactants refers to the molar ratio of this substance relative to the educt to be reacted.
  • An object of the present invention are also combinations of the previously presented partial reactions for the preparation of the compound of formula (I) in crystalline modification 1 (1-1).
  • WO 2012/139888 discloses the compound of formula (I) as an amorphous solid.
  • Figure 1 shows an X-ray diffractogram of the compound of formula (I), which was prepared according to the synthesis described in WO 2012/139888 be.
  • the compound of formula (1) could be isolated in crystalline form of modification 1 (1-1) by the methods described above.
  • the crystalline form of modification 1 (1-1) shows a reproducible bioavailability, better properties for the formulation of drug forms and shows a higher thermodynamic stability.
  • the compound (1) in the crystalline modification 1 (1-1) is characterized by a higher stability and, in particular, by being stable in the micronization process and thus without conversion and recrystallization.
  • Modification 1 (1-1) has a characteristic X-ray diffractogram characterized by the reflections (2 theta) 7.0; 8.2; 11.1; 14.7; 17.2; 17.5; 18.7 and 19.8 and a characteristic IR spectrum by the peak maxima (in cm 1 ) 1709, 1660, 1534, 1491, 1263, 1167, 1131, 1093 and 1016 (Tables 1 and 2, Figures 1 and 2).
  • Figure 1 X-ray diffractogram of the compound of formula (I) in amorphous form
  • FIG. 2 X-ray diffractogram of the compound of the formula (I) in the modification 1 (1-1).
  • FIG. 3 IR spectrum of the compound of the formula (I) in the modification 1 (1-1)
  • the compounds of the invention, the compound of formula (1) and its compound of formula (1) in crystalline form of the modification 1 (1-1) act as an activator of soluble guanylate cyclase and show an unpredictable, valuable pharmacological activity spectrum. They are therefore suitable for use as medicaments for the treatment and / or prophylaxis of diseases in humans and animals.
  • the term “treatment” or “treating” includes inhibiting, delaying, arresting, alleviating, attenuating, restraining, reducing, suppressing, restraining or curing a disease, disorder, disorder, injury or health Disruption, development, progression or progression of such conditions and / or the symptoms of such conditions.
  • the term “therapy” is hereby understood to be synonymous with the term “treatment”.
  • prevention means prevention or prevention of the risk, a disease, a disease, a disease, an injury or a health disorder, a development or to get, to drive, to suffer, or to have the progression of such conditions and / or 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.
  • the compounds according to the invention are potent activators of soluble guanylate cyclase. They lead to vasorelaxation, antiplatelet inhibition and blood pressure reduction and to an increase in coronary blood flow and microcirculation. These effects are mediated by a direct, heme-independent activation of soluble guanylate cyclase and an intracellular cGMP increase.
  • the compounds according to the invention are particularly suitable for the treatment and / or prevention of cardiovascular, cardiopulmonary, cardiorenal, thromboembolic, fibrotic and pulmonary diseases.
  • the compounds according to the invention can therefore be used for the treatment and / or prevention of cardiovascular and cardiopulmonary disorders such as hypertension, heart failure, coronary heart disease, and unstable angina pectoris, pulmonary arterial hypertension (PAH) and secondary forms of pulmonary hypertension (PH ), renal hypertension, peripheral and cardiovascular diseases, arrhythmias, arrhythmias, arrhythmias of the atria and the chambers and conduction disorders such as atrio-ventricular blockades of grade I-III, supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular tachyarrhythmia, torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV junctional extrasystoles, sick sinus syndrome, syncope, AV grade reentry tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune heart disease (Perikardi tis,
  • the compounds of the invention are also suitable for the prophylaxis and / or treatment of various diseases and disease-related conditions, in particular for the treatment and / or prophylaxis of primary and secondary forms of pulmonary hypertension, acute pulmonary hypertension, in particular acute respiratory distress syndrome acute respiratory distress syndrome (ARDS), acute lung injury (AL1) and neonatal respiratory distress syndrome (1RDS), heart failure, angina pectoris, hypertension, thromboembolic disorders, ischaemia, vascular disease, microcirculum lungs disorders, renal insufficiency, fibrotic diseases and arteriosclerosis.
  • ARDS acute respiratory distress syndrome acute respiratory distress syndrome
  • AL1 acute lung injury
  • RDS neonatal respiratory distress syndrome
  • heart failure angina pectoris
  • hypertension thromboembolic disorders
  • ischaemia vascular disease
  • microcirculum lungs disorders renal insufficiency
  • fibrotic diseases and arteriosclerosis arteriosclerosis.
  • pulmonary hypertension includes both primary and secondary subforms thereof, as defined by the Dana Point classification according to their respective etiology (D. Montana and G. Simonneau et al .: AJ Peacock et al Eds., Pulmonary Circulation, Diseases and their Treatment, 3 rd edition, Hodder Arnold Publ., 2011, pp. 197-206, Hoeper MM et al., 2009).
  • group 1 includes pulmonary arterial hypertension (PAH), which includes idiopathic and familial forms (1PAH and FPAH, respectively).
  • PAH pulmonary arterial hypertension
  • PAH also includes persistent pulmonary hypertension in neonates and associated pulmonary arterial hypertension (APAH), which is associated with collagenosis, congenital systemic pulmonary shunt veins, portal hypertension, HIV infection, the use of certain drugs and medications (eg of appetite suppressants), with diseases with significant venous / capillary involvement, such as pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis, or with other diseases such as thyroid disorders, glycogen storage disorders, Gaucher disease, hereditary telangiectasia, hemoglobinopathies, myeloproliferative disorders and splenectomy.
  • APAH pulmonary arterial hypertension
  • diseases with significant venous / capillary involvement such as pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis
  • other diseases such as thyroid disorders, glycogen storage disorders, Gaucher disease, hereditary telangiectasia, hemoglobinopathies, myeloproliferative disorders and splen
  • Group 2 of the Dana Point classification the PH patients are summarized with causative left ventricular disease, such as ventricular, atrial or valvular disorders.
  • Group 3 includes forms of pulmonary hypertension associated with a lung disease such as chronic obstructive pulmonary disease (COPD), interstitial lung disease (1LD), pulmonary fibrosis (1PF), and / or hypoxemia (eg sleep apnea syndrome, alveolar disease). oliv hypoventilation, chronic altitude sickness, plant-related malformations) are associated.
  • COPD chronic obstructive pulmonary disease
  • 1LD interstitial lung disease
  • PF pulmonary fibrosis
  • hypoxemia eg sleep apnea syndrome, alveolar disease
  • Group 4 includes PH patients with chronic thrombotic and / or embolic diseases, eg in thromboembolic obstruction of proximal and distal pulmonary arteries (CTEPH) or in non-thrombotic embolizations (eg due to tumors, parasites, foreign bodies).
  • CTEPH proximal and distal pulmonary arteries
  • non-thrombotic embolizations eg due to tumors, parasites, foreign bodies.
  • Rarer forms of pulmonary hypertension such as in patients with sarcoidosis, histiocytosis X or lymphangiomatosis, are group 5 summarized.
  • heart failure encompasses both acute and chronic manifestations of heart failure as well as specific or related forms of the 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, valvular heart failure, heart failure in valvular heart failure, 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 ciency, alcoholic cardiomyopathy, cardiac storage disorders and diasto
  • the compounds according to the invention can also be used for the treatment and / or prevention of atherosclerosis, lipid metabolism disorders, hypolipoproteinemias, dyslipidemias, hyperpiglyceridemias, hyperlipidemias, combined hyperlipidemias, hypercholesterolemias, abetaliproteinemia, sitosterolemia, xanthomatosis, Tangier's disease, obesity (adiposity) , Obesity and the metabolic syndrome.
  • the compounds according to the invention can be used for the treatment and / or prevention of primary and secondary Raynaud's phenomenon, microcirculatory disorders, claudication, hearing disorders, tinnitus, peripheral and autonomic neuropathies, diabetic microangiopathies, diabetic neuropathies, diabetic retinopathy, diabetic ulcers on the extremities, diabetic foot syndrome, gangrene, CREST syndrome, erythematosis, onychomycosis, as well as rheumatic diseases.
  • the compounds according to the invention can be used to prevent ischemia- and / or reperfusion-related damage to organs or tissues and as additives for perfusion and preservation solutions of organs, organ parts, tissues or tissue parts of human or animal origin, in particular in surgical interventions or in the field the transplant onstechnik, find use.
  • the compounds according to the invention are also suitable for the treatment and / or prevention of kidney diseases, in particular renal insufficiency and kidney failure.
  • renal insufficiency and renal failure include both chronic kidney disease (CKD) thereof as well as underlying or related renal diseases such as renal hypoperfusion, intradialytic hypotension, whether structural uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomeruloskle rose, tubulointerstitial diseases, nephropathic disorders such as primary and congenital kidney disease, nephritis, immunological kidney diseases such as renal transplant rejection and immune complex-induced renal disease, toxicology-induced nephropathy, contrast agent-induced nephropathy, diabetic and non-diabetic nephropathy, diabetic Kidney disease (DKD), proteinuric kidney disease, acute renal failure-induced chronic renal failure, pyelonephritis, renal cysts, nephrosclerosis, focal seg mental glomerulosclerosis (FSGS), hypertensive nephrosclerosis and nephrotic syndrome,
  • CKD chronic kidney disease
  • the present invention also encompasses the use of the compounds of the invention for the treatment and / or prevention of sequelae of renal insufficiency, for example hyperplasia, pulmonary edema, cardiac insufficiency, uremia, anemia, electrolyte disorders (for example hypercalemia, hyponatremia) and carbohydrate metabolism disorders.
  • sequelae of renal insufficiency for example hyperplasia, pulmonary edema, cardiac insufficiency, uremia, anemia, electrolyte disorders (for example hypercalemia, hyponatremia) and carbohydrate metabolism disorders.
  • the compounds according to the invention are suitable for the treatment and / or prevention of diseases of the urogenital system, for example benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostate enlargement (BPE), bladder emptying disorders (BOO), lower hamster syndromes (LUTS).
  • BPS benign prostatic syndrome
  • BPH benign prostatic hyperplasia
  • BPE benign prostate enlargement
  • BOO bladder emptying disorders
  • LUTS lower hamster syndromes
  • the compounds according to the invention are also suitable for the treatment and / or prevention of asthmatic diseases, chronic obstructive pulmonary diseases (COPD), acute respiratory syndrome (ARDS) and acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD).
  • COPD chronic obstructive pulmonary diseases
  • ARDS acute respiratory syndrome
  • ALI acute lung injury
  • AATD alpha-1-antitrypsin deficiency
  • Pulmonary fibrosis idiopathic pulmonary fibrosis (IPF), pulmonary emphysema (for example, CSF-induced pulmonary emphysema) and cystic fibrosis (CF).
  • IPF idiopathic pulmonary fibrosis
  • CF cystic fibrosis
  • the compounds described in the present invention are also agents for combating diseases in the central nervous system which are characterized by disorders of the NO / cGMP system.
  • tuationen / diseases / syndromes such as "mild cognitive impairment", age-associated Lem- and memory disorders, age-associated memory loss, vascular dementia, skull Trauma, stroke, post-stroke dementia, post-traumatic craniocerebral trauma, generalized concentration disorders, impaired concentration in children with learning and memory problems, Alzheimer's disease, dementia with Lewy Corpuscles, dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyolaryngeal sclerosis (ALS), Huntington's disease, demyelination, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV Dementia, schizophrenia with dementia or Korsakoff's psychosis. They are also suitable for the treatment and / or prevention of diseases of the central nervous system such as anxiety, tension and depression, central nervous system, and the central nervous system.
  • the compounds of the invention are also suitable for the regulation of cerebral blood flow and thus represent effective means of combating migraine. Also, they are suitable for the prophylaxis and control of the consequences of cerebral infarction (Apoplexia cerebri) such as stroke, cerebral ischemia and the skull Him -Traumas. Likewise, the compounds according to the invention can be used to combat pain.
  • cerebral infarction Apoplexia cerebri
  • the compounds according to the invention can be used to combat pain.
  • the compounds according to the invention have anti-inflammatory action and can therefore be used as anti-inflammatory agents for the treatment and / or prevention of sepsis (SIRS), multi-plem organ failure (MODS, MOF), inflammatory diseases of the kidney, chronic intestinal inflammation (IBD, Crohn's disease , UC), pancreatitis, peritonitis, rheumatoid diseases, inflammatory skin diseases and inflammatory eye diseases.
  • SIRS sepsis
  • MODS multi-plem organ failure
  • IBD chronic intestinal inflammation
  • Crohn's disease UC
  • pancreatitis peritonitis
  • rheumatoid diseases inflammatory skin diseases and inflammatory eye diseases.
  • the compounds according to the invention are also suitable for the treatment and / or prevention of fibro-genetic diseases of the internal organs, such as the lung, heart, kidneys, bone marrow and especially the liver, as well as dermatological fibroses and fibrotic Erkran diseases of the eye.
  • fibrotic disorders includes in particular such diseases as liver fibrosis, liver cirrhosis, pulmonary fibrosis, endocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage as a consequence of diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, sys - temic sclerosis, morphea, keloids, hypertrophic scarring, nevi, diabetic retinopathy, proliferative vitroretinopathy and connective tissue disorders (eg sarcoidosis).
  • the compounds of the invention may also be used to promote wound healing, to combat postoperative scarring, for example, after glaucoma surgery, and for cosmetic purposes in the case of aging and calloused skin.
  • the compounds according to the invention are suitable for the treatment and / or prevention of ophthalmological disorders, which are to be understood as meaning, for example, the following diseases: age-related macular degeneration (AMD) including dry (non-exudative) and moist (exudative, neovascular) AMD , choroidal neovascularization (CNV), choroidal neovascular membranes (CNVM), cystoid macular edema (CME), epiretinal membranes (ERM) and macular perforations, myopia-associated choroidal neovascularization, angioid and vascular strips, retinal detachment, diabetic Retinopathy, diabetic macular edema (DME), atrophic and hypertrophic changes of the retinal pigment epithelium, retinal venous occlusion, choroidal retinal venous occlusion, macular edema, macular edema associated with retinal vein occlusion, reti
  • the compounds of the invention are particularly suitable for treatment and / or prevention of cardiovascular and cardiopulmonary diseases such as primary and secondary forms of pulmonary hypertension, heart failure, angina and hypertension as well as thromboembolic diseases, ischemia, vascular diseases, Mikrozirkulationsstörun conditions, renal insufficiency , fibrotic diseases and arteriosclerosis.
  • cardiovascular and cardiopulmonary diseases such as primary and secondary forms of pulmonary hypertension, heart failure, angina and hypertension as well as thromboembolic diseases, ischemia, vascular diseases, Mikrozirkulationsstörun conditions, renal insufficiency , fibrotic diseases and arteriosclerosis.
  • Another object of the present invention is the use of the compounds of the invention Ver for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of Ver compounds of the invention for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is a pharmaceutical composition containing at least one of the compounds of the invention, for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention Ver in a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.
  • Another object of the present invention is a method for the treatment and / or prevention of sickle cell disease in which traumatized patients receive a synthetic blood substitute, and for the preservation of blood substitutes.
  • Another object of the present invention is the use of the compounds according to the invention Ver for the treatment and / or prevention of diseases, in particular the aforementioned diseases, wherein the production of a liquid aerosol is carried out with the aid of an aerosol generator.
  • Another object of the present invention is the use of Ver compounds of the invention for the treatment and / or prevention of diseases, in particular the aforementioned diseases, wherein the addition of ß-cyclodextrin selected from a list containing unsubstituted ß-cyclodextrin, methyl-ß cyclodextrin and (2-hydroxypropyl) - ⁇ -cyclodextrin, in the pharmaceutical formulation does not alter systemic blood pressure.
  • Another object of the present invention is the use of Ver compounds of the invention for the treatment and / or prevention of diseases, in particular the aforementioned diseases, wherein the addition of ß-cyclodextrin selected from a list containing unsubstituted ß-cyclodextrin, methyl-ß cyclodextrin and (2-hydroxypropyl) - ⁇ -cyclodextrin, in the pharmaceutical formulation does not alter the pharmacokinetic profile of the compound of formula (I).
  • the compounds of the invention can be used alone or as needed in combination with other active substances.
  • Another object of the present invention are medicaments ent holding at least one of the compounds of the invention and one or more other active substances, in particular for the treatment and / or prophylaxis of the aforementioned diseases.
  • ge suitable combination active ingredients are exemplary and preferably mentioned: • organic nitrates and NO donors, for example sodium nitroprusside, nitroglycerin, isosor bidmononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;
  • cGMP cyclic guanosine monophosphate
  • cAMP cyclic adenosine monophosphate
  • PDE phosphodiesterases
  • PDE-4 inhibitors such as roflumilast or Revamilast
  • PDE-5 inhibitors such as sildenafil, vardenafil, tadalafil, uddenafil, dasantafil, avanafil, mirodenafil or lodenafil;
  • Prostacyclin analogs and IP receptor agonists by way of example and preferably iloprost, beraprost, treprostinil, epoprostenol, NS-304, selexipag or raline pag;
  • Endothelin receptor antagonists by way of example and preferably bosentan, darusentan, ambrisentan, macicentan or sitaxsentan;
  • HNE human neutrophil elastase
  • Sivelestat Sivelestat
  • DX-890 Reltran
  • Rho kinase inhibitors by way of example and preferably Fasudil, Y-27632, SLx-21 19, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049;
  • anti-obstructive agents such as those used for the treatment of chronic obstructive pulmonary disease (COPD) or bronchial asthma, exemplary and preferably before inhalatively or systemically applied beta-receptor mimetics (eg bedoradrine) or inhaled anti-muscarinerge substances;
  • COPD chronic obstructive pulmonary disease
  • bronchial asthma exemplary and preferably before inhalatively or systemically applied beta-receptor mimetics (eg bedoradrine) or inhaled anti-muscarinerge substances;
  • Antiinflammatory and / or immunosuppressive agents such as are used for the treatment of chronic obstructive pulmonary disease (COPD), bronchial asthma or pulmonary fibrosis, corticosteroids, flutiform, pirfenidone, acetylcysteine, azathioprine or, preferably, systemically or by inhalation BIBF-I 120; • chemotherapeutic agents, such as those used for the treatment of neoplasms of the lungs or other organs;
  • active substances used for the systemic and / or inhalative treatment of lung diseases for example in cystic fibrosis (alpha-1-antitrypsin, aztreonam, ivacaftor, lu-macaftor, ataluren, amikacin, levofloxacin), chronic obstructive pulmonary disease (COPD) (LAS40464, PT003, SUN-101), acute respiratory tract syndrome (ARDS) and acute lung injury (ALI) (interferon-beta-la, trauma), obstructive sleep apnea (VI-0521), bronchiectasis (mannitol, ciprofloxacin), bronchiolitis obliterans (Cyclosporine, aztreonam) and sepsis (pagibaximab, voluven, ART-123);
  • cystic fibrosis alpha-1-antitrypsin, aztreonam, ivacaftor,
  • Antithrombotic agents by way of example and preferably from the group of thrombocytogenesis 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, mineralocorticoid receptor Antagonists and diuretics; and or
  • Thyroid receptor agonists by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and / or PPAR-inhibitors. delta agonists, cholesterol
  • Absorption inhibitors lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, and lipoprotein (a) antagonists;
  • agents that inhibit neoangiogenesis by way of example and preferably, inhibitors of VEGF and / or PDGF signaling pathways, inhibitors of integrin signaling pathways, inhibitors of angiopoietin signaling pathways, inhibitors of PI3K-Akt-mTor signaling pathways, inhibitors of Ras Raf-Mek-Erk signaling pathways, MAPK signaling pathway inhibitors, FGF signaling pathway inhibitors, sphingosine-1-phosphate signaling inhibitors, endothelial cell proliferation inhibitors or apoptosis-inducing agents;
  • Agents that reduce the vascular wall permeability by way of example and preferably, corticosteroids, inhibitors of ALKl-Smadl / 5 signaling, inhibitors of VEGF and / or PDGF signaling pathways, cyclooxygenase inhibitors, inhibitors of kallikrein-kinin system or Inhibitors of sphingosine-l-phosphate signaling pathways; and or • active ingredients that reduce the damage to the retina in oxidative stress, for example and preferably before inhibitors of the complement system, in particular antagonists of the complement C5a receptor or agonists of the 5-HTi A receptor;
  • the active substances lowering the blood pressure by way of example and preferably from the group of the calcium
  • Antagonists angiotensin AII antagonists, ACE inhibitors, beta-receptor blockers, alpha-receptor blockers, diuretics, phosphodiesterase inhibitors, sGC stimulators, cGMP level enhancers, aldosterone antagonists, mineralocorticoid receptor antagonists, ECE inhibitors and vasopeptidase inhibitors;
  • Antidiabetics by way of example and preferably from the group of insulins and insulin derivatives, sulfonylureas, biguanides, meglitinide derivatives, glucosidase inhibitors, PPAR-gamma agonists, GLP 1 receptor agonists, glucagon antagonists, insulin sensitizers, CCK1 receptor agonists, leptin receptor agonists, potassium channel antagonists and the inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and / or glycogenolysis;
  • Anti-infective agents by way of example and preferably from the group of
  • Antithrombotic agents are preferably compounds from the group of platelet aggregation inhibitors, the anticoagulants or the profibrinolytic substances were ver.
  • the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, by way of example and preferably aspirin, clopidogrel, ticlopidine or dipyridamole.
  • a platelet aggregation inhibitor by way of example and preferably aspirin, clopidogrel, ticlopidine or dipyridamole.
  • the compounds according to the invention are administered in combination with a thrombin inhibitor, by way of example and preferably ximelagatran, melagatran, dabigatran, bivalirudin or Clexane.
  • a thrombin inhibitor by way of example and preferably ximelagatran, melagatran, dabigatran, bivalirudin or Clexane.
  • the compounds according to the invention are administered in combination with a GPIIb / IIIa antagonist, by way of example and preferably tirofiban or abciximab.
  • the compounds according to the invention are used in combination with a factor Xa inhibitor, by way of example and preferably rivaroxaban, apixaban, fidxaban, razaxaban, fondaparinux, ldraparinux, DU-l76b, 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 by way of example and preferably rivaroxaban, apixaban, fidxaban, razaxaban, fondaparinux, ldraparinux, DU-l76b, PMD-3112, YM-150, KFA- 1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • 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, by way of example and preferably coumarin.
  • antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin all-antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blocker, mineralocorticoid receptor Understood antagonists and diuretics.
  • the compounds according to the invention are administered in combination with a calcium antagonist, by way of example and preferably nifedipine, amlodipine, verapamil or diltiazem.
  • a calcium antagonist by way of example and preferably nifedipine, amlodipine, verapamil or diltiazem.
  • the compounds according to the invention in combination with an alpha-1-receptor B are loosely, by way of example and preferably prazosin, administered.
  • the compounds according to the invention are used in combination with a beta-receptor blocker, by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol , Betaxolol, Celiprolol, Bisoprolol, Carteolol, Esmolol, Labetalol, Carvedilol, Adaprolol, Landiolol, Nebivolol, Epanolol or Bucindolol.
  • a beta-receptor blocker by way of example and preferably propranolol, atenolol, timolol, pindolol, al
  • the compounds according to the invention are administered in combination with an angiotensin all-antagonist, by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.
  • an ACE inhibitor by way of example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • the compounds according to the invention are administered in combination with an endothelin antagonist, by way of example and preferably bosentan, darusentan, ambrisentan or sitaxsentan.
  • an endothelin antagonist by way of example and preferably bosentan, darusentan, ambrisentan or sitaxsentan.
  • the compounds of the invention are administered in combination with a renin inhibitor, by way of example and preferably aliskiren, SPP-600 or SPP-800.
  • a renin inhibitor by way of example and preferably aliskiren, SPP-600 or SPP-800.
  • the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, by way of example and preferably spironolactone, eplerenone or finerenone.
  • a mineralocorticoid receptor antagonist by way of example and preferably spironolactone, eplerenone or finerenone.
  • the compounds according to the invention are used in combination with a diuretic, by way of example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichloromethiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, dichlorophenamide , Methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.
  • a diuretic by way of example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichloromethiazide,
  • Natriuretic peptides e.g. "atrial natriuretic peptide” (ANP, anaritide), "B-type natriuretic peptide” or “brain natriuretic peptide” (BNP, nesiritide), "C-type natriuretic peptide” (CNP) and urodilatin;
  • NEP inhibitors e.g. Sacubitril, omapatrilat or AVE-7688
  • 'ARNls' angiotensin receptor blockers
  • valsartan e.g. LCZ696
  • the 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, 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 antagonists understood.
  • the compounds according to the invention are administered in combination with a CETP inhibitor, by way of example and with preference torcetrapib (CP-5294/4), JJT-705 or CETP -vaccine (Avant).
  • the compounds of the invention are administered in combination with a thyroid receptor agonist, by way of example and preferably D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • a thyroid receptor agonist by way of example and preferably 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, by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavas tatin.
  • an HMG-CoA reductase inhibitor from the class of statins, by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavas tatin.
  • the compounds of the invention are administered in combination with a squalene synthesis inhibitor, by way of example and preferably BMS-1 88494 or TAK-475.
  • the compounds according to the invention are administered in combination with an ACAT inhibitor, by way of example and preferably avasimibe, melinamide, pactimibe, eflucimib or SMP-797.
  • an ACAT inhibitor by way of example and preferably avasimibe, melinamide, pactimibe, eflucimib or SMP-797.
  • the compounds of the invention are administered in combination with an MTP inhibitor, by way of example and preferably implitapid, BMS-201038, R-103757 or JTT-130.
  • the compounds according to the invention are administered in combination with a PPAR-gamma agonist, by way of example and preferably pioglitazone or rosiglitazone.
  • the compounds according to the invention are administered in combination with a PPAR-delta agonist, 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, by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • the compounds according to the invention are administered in combination with a lipase inhibitor, by way of example and preferably orlistat.
  • the compounds according to the invention are administered in combination with a polymeric bile acid adsorbent, by way of example and preferably cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • ASBT 1BAT
  • the compounds according to the invention are administered in combination with a lipoprotein (a) antagonist, by way of example and preferably gemcabene calci um (CI-1027) or nicotinic acid.
  • a lipoprotein (a) antagonist by way of example and preferably gemcabene calci um (CI-1027) or nicotinic acid.
  • compositions containing at least one inven tion proper compound 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.
  • suitable, fast and / or modified delivery forms which contain the compounds according to the invention in crystalline and / or amorphized and / or dissolved form are suitable, e.g. Tablets (uncoated or coated tablets, for example, with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention), tablets or films rapidly breaking down in the oral cavity, films / lyophilisates, capsules (e.g. Hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Tablets uncoated or coated tablets, for example, with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention
  • tablets or films rapidly breaking down in the oral cavity films / lyophilisates
  • capsules e.g. Hard or soft gelatin capsules
  • dragees granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can be done bypassing a resorption step (eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or with involvement of resorption (eg, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • a resorption step eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
  • involvement of resorption eg, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal.
  • inhalation medicaments including powder inhalers, nebulizers
  • nasal drops solutions or sprays
  • Tab letten films / wafers or capsules
  • suppositories films / wafers or capsules
  • suppositories films / wafers or capsules
  • suppositories films / wafers or capsules
  • suppositories films / wafers or capsules
  • suppositories ear or eye 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.
  • transdermal therapeutic systems eg plasters
  • 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 appro Neten excipients.
  • adjuvants include, among others.
  • Carriers for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecylsulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example Al bumin
  • stabilizers for example, antioxidants such as ascorbic acid
  • dyes eg Anorga African pigments such as iron oxides
  • flavor and / or odoriferous include, among others.
  • Carriers for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • parenterally administered amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg of body weight to achieve effective results.
  • the dosage is about 0.01 to 100 mg / kg, preferably before about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg body weight.
  • LiHMDS lithium bis (trimethylsilyl) amide
  • Instrument Thermo Fisher-Scientific DSQ; chemical ionization; Reactant gas NH3; Source temperature: 200 ° C; Ionization energy 70eV.
  • Method D Device Type MS: Thermo Scientific FT-MS; Device type UHPLC +: Thermo Scientific UltiMate 3000; Column: Waters, HSST3, 2.1 x 75 mm, C18 1.8 pm; Eluent A: 1 liter of water + 0.01% of formic acid; eluent B: 1 liter acetonitrile + 0.01% formic acid; Gradient: 0.0 min 10% B-> 2.5 min 95% B-> 3.5 min 95% B; Oven: 50 ° C; Flow: 0.90 ml / min; UV detection: 210 nm / Optimum Integration Path 210-300 nm
  • Stationary phase Zorbax SB-AQ (length 100 mm, ID 2.1 mm, grain size 1.8 pm); mobile phase A: 2 mL 70% perchloric acid / 1 L water; mobile phase B: acetonitrile; UV detection at 210 nm; Oven temperature: 45 ° C, injection volume: 1.5 pL; Flow rate: 1.0 mL / min; linear gradient in 4 steps: 8% B -> 15% B (0.70 min), 15% B -> 42% B (0.30 min), 42% B -> 57% B (2.20 min) , 57% B-> 100% B (1.80 min), 1.00 min isocratic at 100% B;
  • Method B 59.5 kg (0.140 kmol) of n-butyllithium (1.6 M in hexane) were cooled to 0 ° C. in a stirred kettle and 23.6 kg (0.146 kmol) of hexamethyldisilazane were added. The mixture was stirred for 10 min and added 21.4 kg of tetrahydrofuran. At -70 ° C., 24.0 kg (0.127 kmol) of methyl chlorophenyl acetate were added and the reaction mixture was stirred for 3 h.
  • (+, -) - BINAP (29g, 0.00575eq) and [Rh (COD) Cl] 2 (9.8g, 0.0025eq) were stirred in air for 1 1/2 hr in THF.
  • aqueous hydrochloric acid (32%) was added to the aqueous solution and 3.5 L of DCM was added. The phases were separated and the organic phase was washed with 0.8 l of water. The crude solution was used in the subsequent crystallization. For crystallization, three crude solutions were combined. The DCM was stripped off and 2.9 L of methylcyclohexane was added. The suspension was concentrated and treated with 2.9 1 methylcyclohexane ver. This operation was repeated, with methylcyclohexane being removed and a further 2.9 l added.
  • methylcyclohexane was removed in vacuo, and 0.6 liter of DCM and 0.6 liter of methylcyclohexane were added. The solution was seeded at 45 ° C with 2 g of crystalline product. The suspension was cooled to 0 ° C, washed with methyl cyclohexane and dried in vacuo to give 2.23 kg (78% of theory) of a solid.
  • the free amino acid 860g was dissolved in 1.9 L of EtOAc and treated with 900 mL HCl in dioxane (4 M). The product was filtered off, washed with EtOAc and dried to give 936 g (94% of theory) of a solid having an enantiomeric purity of 99.4%.
  • the TES-protected amino acid was slowly added to the acid chloride at 0 ° C and the empty vessel was washed with 1 kg of THF. After stirring for 1.5 h, EtOAc (6.2 kg) and 2N HCl (7.4 kg) were added and the phases were separated. The organic phase was washed with another 7.4 kg of 2N HCl solution and twice with 7.4 kg of 10% NaCl solution in water. The solution was filtered and washed with EtOAc. The EtOAc was removed in vacuo and 13.6 kg of heptane was added. The distillation was continued and an additional 5.5 kg of heptane were added. The reaction mixture was seeded at 55 ° C and slowly cooled to 0 ° C.
  • the aqueous phase was extracted with a mixture of 228 g of heptane and 495 g of MTBE.
  • the organic phases were combined, washed with 1.3 kg of water and dried with sodium sulfate. Two of these approaches were combined and the solvent was evaporated.
  • the crude product was dissolved at 40 ° C in 220 g of MTBE and 96 g of heptane. This solution was slowly added at 50 ° C to 3897 g of heptane.
  • the mixture was seeded with 1.5 g of product and slowly cooled to 0 ° C.
  • the product was filtered off, washed with heptane and dried in vacuo to give 250 g (88% of theory) as a solid.

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EP18814516.3A 2017-12-01 2018-11-26 Verfahren zur herstellung von (3s)-3-(4-chlor-3-{[(2s,3r)-2-(4-chlorphenyl)-4,4,4-trifluor-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropansäure und dessen kristalline form für die verwendung als pharmazeutischer wirkstoff Withdrawn EP3717480A1 (de)

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