EP3515919A1 - Thiéno-uraciles à substitution n3-cyclique et leur utilisation - Google Patents

Thiéno-uraciles à substitution n3-cyclique et leur utilisation

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Publication number
EP3515919A1
EP3515919A1 EP17765199.9A EP17765199A EP3515919A1 EP 3515919 A1 EP3515919 A1 EP 3515919A1 EP 17765199 A EP17765199 A EP 17765199A EP 3515919 A1 EP3515919 A1 EP 3515919A1
Authority
EP
European Patent Office
Prior art keywords
methyl
mmol
formula
cyclopropyl
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP17765199.9A
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German (de)
English (en)
Inventor
Michael Härter
Dirk Kosemund
Yolanda Cancho Grande
Martina Delbeck
Bernd Kalthof
Klemens Lustig
Frank SÜSSMEIER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Bayer Pharma AG
Original Assignee
Bayer AG
Bayer Pharma AG
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Publication of EP3515919A1 publication Critical patent/EP3515919A1/fr
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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P7/06—Antianaemics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • New combination therapies are one of the most promising future treatment options for the treatment of pulmonary hypertension.
  • the exploration is newer pharmacological mechanisms for the treatment of PH of particular interest [Ghofrani et al., Herz 2005, 30, 296-302; EB Rosenzweig, Expert Opinion. Emerging Drugs 2006, 11, 609-619; T. Ito et al., Curr. Med. Chem. 2007, 14, 719-733].
  • new therapeutic approaches which can be combined with the therapy concepts already on the market, could be the basis of a more efficient treatment and thus bring a great advantage for the patients.
  • PAH also includes persistent pulmonary hypertension in neonates and associated pulmonary arterial hypertension (AP AH), which is associated with collagenosis, congenital systemic pulmonary shunt veins, portal hypertension, HIV infection, use of certain drugs and medications (eg of appetite suppressants), with diseases with a significant venous / capillary involvement such as pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis, or with other diseases such as thyroid disorders, glycogen storage diseases, Gaucher disease, hereditary telangiectasia, hemoglobinopathies, myeloproliferative disorders and splenectomy.
  • AP AH pulmonary arterial hypertension
  • WO 2015/052065-A1 has recently described cyclic thienouracil-6-carboxamides as adenosine A2b receptor antagonists for the treatment of diseases of the lung and the cardiovascular system
  • WO-A-2016/023832-A1 discloses 3- (hydroxyalkyl ) -substituted thieno [2,3-d] pyrimidine-2,4-diones are disclosed as TRPC5 modulators for the treatment of neurological diseases.
  • R 4 is a group of the formula -CH 2 -CH 2 -OR 9 or -CH 2 -CH 2 -SR 10 wherein R 9 is methyl, trifluoromethyl, ethyl or z o -propyl and
  • 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.
  • substituents and radicals have the following meanings: (C 1 -C 4) -alkyl in the context of the invention represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Ethyl, n-propyl, isopropyl, n -butyl, isobutyl, ec-butyl and tert -butyl.
  • R 1A and R 1B independently of one another are hydrogen or deuterium, R 2 is methyl or ethyl,
  • R 8 is cyano, cyclopropyl, cyclobutyl, cyclopentyl, 2-oxetanyl, 3-oxetanyl, 2-tetrahydrofuranyl or 3-tetrahydrofuranyl, where cyclopropyl, cyclobutyl and cyclopentyl may be substituted up to two times by fluorine, or
  • R 7 is cyano or methoxycarbonyl, and R 1B both are hydrogen or both are deuterium, is methyl, cyclopropyl, cyclobutyl, cyclopentyl or spiro [3.3] hept-2-yl, where cyclopropyl, cyclobutyl, cyclopentyl and spiro [ 3.3] hept-2-yl up to twice, identically or differently, may be substituted by a radical selected from fluoro, methyl and methoxy, and
  • R 5A and R 5B are the same or different and are independently hydrogen or methyl
  • R 6 is hydrogen or methyl
  • X is O or N (R 7 ), in which
  • R 7 represents cyano or methoxycarbonyl
  • R 1A and R 1B are both hydrogen or both are deuterium, R 2 is methyl,
  • R 3 is cyclopropyl, cyclobutyl, cyclopentyl or spiro [3.3] hept-2-yl, wherein cyclopropyl, cyclobutyl, cyclopentyl and spiro [3.3] hept-2-yl are up to twice, the same or different, selected from fluoro , Methyl and methoxy, and
  • R 4 is a group of formula -CH 2 -R 8 wherein R 8 is cyclopropyl, cyclobutyl or 2-tetrahydrofuranyl, or
  • R 4 is a group of the formula -CH 2 -CH 2 -OR 9 , wherein R 9 is methyl or trifluoromethyl, and their solvates.
  • HN is > in which * the linkage to the adjacent C (R 1A ) (R 1B ) group is marked and
  • R 7 represents cyano or methoxycarbonyl, and their solvates.
  • Another particular embodiment of the present invention relates to compounds of the formula (I) in which the ring A is an aza-heterocycle of the formula
  • R 5A and R 5B are each hydrogen, and their solvates.
  • Another particular embodiment of the present invention relates to compound of formula (I) in which ring A is an aza-heterocycle of the formula
  • R 6 is hydrogen, and their solvates.
  • R 1A and R 1B are both hydrogen and their solvates.
  • Another particular embodiment of the present invention relates to compounds of the formula (I) in which
  • R 2 is methyl, and their solvates.
  • a further particular embodiment of the present invention relates to compounds of the formula (I) in which R 3 is cyclopropyl, cyclobutyl or cyclopentyl, where cyclopropyl, cyclobutyl and cyclopentyl are substituted up to twice, identically or differently, by a radical selected from fluorine and methyl and their solvates.
  • R 4 is 3-fluoropropyl, 3,3,3-trifluoropropyl or n-butyl, and their solvates.
  • Another particular embodiment of the present invention relates to compounds of the formula (I) in which
  • R 4 is methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl or n-propyl, and their solvates.
  • Another particular embodiment of the present invention relates to compounds of the formula (I) in which
  • R 4 is a group of formula -CH 2 -R 8 wherein
  • R 8 is cyclopropyl or cyclobutyl, where cyclopropyl and cyclobutyl may be substituted up to two times by fluorine, and their solvates.
  • Another particular embodiment of the present invention relates to compounds of the formula (I) in which
  • R 4 is a group of the formula -CH 2 -CH 2 -OR 9 , wherein R 9 is methyl or trifluoromethyl, and their solvates.
  • R 5A and R 5B are each hydrogen
  • R 6 is hydrogen
  • X is O or N (R 7 ), in which
  • R 7 represents cyano or methoxycarbonyl
  • R 1A and R 1B are both hydrogen or both are deuterium, R 2 is methyl,
  • R 3 is cyclopropyl, cyclobutyl or cyclopentyl, where cyclopropyl, cyclobutyl and cyclopentyl may be substituted up to two times, identically or differently, by a radical selected from fluoro and methyl, and R 4 is methyl, ethyl, 2-fluoroethyl, 2, 2-difluoroethyl, 2,2,2-trifluoroethyl, n-propyl, 3-fluoro-propyl, 3,3,3-trifluoropropyl or n-butyl, or
  • R 4 is a group of formula -CH 2 -R 8 wherein
  • R 4 is a group of formula -CH 2 -CH 2 -OR 9 wherein
  • R 9 is methyl or trifluoromethyl, and their solvates.
  • Another particularly preferred embodiment of the present invention comprises compounds of the formula (I) in which the ring A is an aza-heterocycle of the formula H VN stands,
  • R 5A and R 5B are each hydrogen
  • X is O or N (R 7 ), in which
  • R 7 represents cyano or methoxycarbonyl
  • R 1A and R 1B are both hydrogen or both are deuterium
  • R 2 is methyl
  • R 3 is cyclopropyl, cyclobutyl or cyclopentyl, wherein cyclopropyl, cyclobutyl and cyclopentyl may be substituted up to two times, identically or differently, by a radical selected from fluoro and methyl, and
  • R 4 is 3-fluoropropyl, 3, 3, 3-trifluoropropyl or n-butyl, or
  • R 4 is a group of formula -CH 2 -R 8 wherein R 8 is cyclopropyl or cyclobutyl, or
  • R 4 is a group of the formula -CH 2 -CH 2 -OR 9 , wherein R 9 is methyl or trifluoromethyl, and their solvates.
  • the residue definitions given in detail in the respective combinations or preferred combinations of residues are also replaced by residue definitions of other combinations, regardless of the particular combinations of the residues indicated.
  • the present invention also includes all suitable isotopic variants of the compounds of 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 which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ⁇ (deuterium), ⁇ (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 C1, 82 Br, 123 I, 124 I, 129 I and 131 I
  • Certain isotopic variants of a compound of the invention, such as those in which one or more radioactive isotopes are incorporated, may be useful, for example, for the study of 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 in particular are 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;
  • isotopic variants of the compounds according to the invention can be prepared by generally customary processes known to the person skilled in the art, for example by the methods described below and the rules reproduced in the exemplary embodiments by using corresponding isotopic modifications of the respective reagents and / or starting compounds.
  • the present invention also comprises prodrugs of the compounds according to the invention.
  • prodrugs here denotes compounds which may themselves be biologically active or inactive, but are converted during their residence time in the body by, for example, metabolic or hydrolytic routes to compounds of the invention.
  • the compounds of the formula (I) according to the invention can be prepared in different, in some cases also alternative ways.
  • R 1A and R 1B are both hydrogen
  • R 2 , R 3 and R 4 have the meanings given above, are prepared by a general method according to the following Reaction Scheme 1:
  • Thienouracil carbaldehydes of the formula (1) are first reacted with 1,2-diaminoethane (2) in a reductive amination to give the diamino compounds of the formula (3).
  • sodium cyanoborohydride or sodium borohydride is suitable in each case as reducing agent. were from acetic acid.
  • a suitable solvent is methanol or ethanol, optionally mixed with dichloromethane, and the reaction is preferably carried out in a temperature range between RT and + 70 ° C.
  • the target compounds of the formulas (I-la) and (I-Ib) are obtained by subsequent reaction of the diamino compounds (3) with NN'-carbonyldiimidazole (4) [for (I-la)] or N, N'-thiocarbonyldiimidazole (5 ) [for (I-lb)].
  • the reactions are preferably carried out at RT and in solvents such as tetrahydrofuran (THF), 1,4-dioxane or dimethyl sulfoxide (DMSO), if appropriate in the presence of a tertiary amine base such as triethylamine.
  • the products of the formula (I-Ic) are obtained by reaction of the diamino compounds (3) with dimethyl N-cyanodithioimino carbonate (6).
  • the reaction is preferably carried out in N, N-dimethylformamide (DMF) as a solvent in the presence of alkali metal carbonates, for example potassium carbonate, as a base at elevated temperatures of + 80 ° C.
  • the products of the formula (I-1d) are obtained by reaction of the diamino compounds (3) with methyl or ethyl (dichloromethylene) carbamate (7).
  • the reaction is preferably carried out in dichloromethane as solvent in the presence of a tertiary amine base, such as triethylamine, at RT.
  • the products of formula (I-le) are obtained by reaction of diamino compounds (3) with diethyl oxalate (8).
  • the reaction is preferably carried out in ethanol as a solvent at elevated temperatures by + 80 ° C.
  • R 1A and R 1B are both hydrogen or both are deuterium
  • an alcohol of formula (9) is first reacted with a chlorinating agent, such as preferably thionyl chloride, in the presence of a tertiary amine base, such as N, N-diisopropylethylamine or triethylamine, into the corresponding chloro compound [corresponding to formula (1 1)]
  • a chlorinating agent such as preferably thionyl chloride
  • a tertiary amine base such as N, N-diisopropylethylamine or triethylamine
  • strong bases are suitable, such as, for example, alkali metal hydrides or alkali metal amides; Preferably, sodium hydride or lithium hexamethyldisilazide is used.
  • the chlorination step is usually carried out in a halogenated hydrocarbon as inert solvent - preferably dichloromethane here - in the temperature range around 0 ° C.
  • the solution of the deprotonated heterocycle (10) is added.
  • the substitution reaction to (1-2) then takes place preferably at RT.
  • Suitable solvents for the preparation of the deprotonated heterocycle (10) are in particular N, N-dimethylformamide (DMF), tetrahydrofuran (THF) or mixtures thereof.
  • the deprotonation itself is preferably carried out in a temperature range between 0 ° C and + 60 ° C.
  • hydrolysis-sensitive chlorine compounds of formula (11) can be prepared and also isolated by reacting alcohols of formula (9) with a chlorinating agent, preferably thionyl chloride, in an inert solvent such as chloroform or dichloromethane, as before become.
  • a chlorinating agent preferably thionyl chloride
  • an inert solvent such as chloroform or dichloromethane
  • the reaction is preferably carried out in a temperature range between RT and + 80 ° C, wherein for the heating above the boiling point of the particular solvent, the use of a microwave oven, using sealed reaction vessels, has proven to be particularly advantageous.
  • the isolated chlorine compounds of the formula (11) are then reacted under similar conditions, as explained above, with a solution of the deprotonated heterocycle (10).
  • the subject aza-heterocycles of formula (10) can also be used in protected form using a suitable amide protecting group which masks one of the two NH groups, if appropriate or necessary to avoid side reactions .
  • amide-protecting groups are familiar to the person skilled in the art [for the suitability, introduction and removal of amide-protecting groups see, for example, US Pat. T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999].
  • R 1A and R 1B both represent hydrogen
  • aldehydes of the formula (1) are first converted with hydroxylamine into the corresponding oximes of the formula (12).
  • the reaction is preferably carried out at RT using an aqueous hydroxylamine solution in a water-miscible ether, such as tetrahydrofuran (THF), as solvent.
  • THF tetrahydrofuran
  • the subsequent reduction to the aminomethyl compounds (13) can be achieved by hydrogenation in the presence of a noble metal catalyst.
  • Preferred reaction conditions are 1 bar hydrogen pressure at RT in the presence of a catalytic amount of palladium (5-10% on carbon) in methanol or ethanol as solvent.
  • the hydrogenation is preferably carried out in the presence of aqueous mineral acid, for example concentrated hydrochloric acid.
  • the reduction to the aminomethyl compounds (13) can also be carried out with sodium borohydride in the presence of suitable metal salts, such as nickel or cobalt chloride.
  • suitable metal salts such as nickel or cobalt chloride.
  • Preferred reaction conditions here are the use of sodium borohydride in combination with nickel (II) chloride hexahydrate in methanol as solvent at RT.
  • Another route to the aminomethyl compounds of the formula (13) starts from the alcohols of the formula (9a).
  • the aminomethyl compounds of the formula (13) obtained in one of these ways are then reacted in a one-pot process with chloroethyl isocyanate (15), initially forming an open-chain urea derivative.
  • the reaction is preferably carried out at RT in a solvent mixture of N, N-dimethylformamide (DMF) and tetrahydrofuran (THF), or in toluene in the temperature range between + 60 ° C and the boiling point of the solvent.
  • a strong base such as, for example, potassium tert-butoxide
  • R 1A and R 1B are both hydrogen
  • Aldehydes of the formula (1) are heated here with aminoacetals or aminoketals of the formula (16) in the sense of a reductive amination first in a suitable solvent, such as methanol or dichloromethane, to reflux and then at RT with sodium triacetoxyborohydride to the compounds of formula (17) reduced. These are then converted with potassium cyanate and aqueous perchloric acid in methanol at RT into the urea derivatives of the formula (18). In the last reaction step acid-catalyzed simultaneous acetal or ketal cleavage and ring closure to the target compounds of formula (1-4). The reaction is carried out in methanol at RT with hydrochloric acid of different concentration (from 0.5 mol / L to concentrated hydrochloric acid).
  • ring A 5 is a 2,4-dihydro-l, 2,4-triazol-3-one derivative of the formula
  • R 1A and R are both hydrogen, and R 2 , R 3 and R 4 have the meanings given above can be prepared in the general way according to Scheme 5: Scheme 5
  • Aldehydes of formula (1) are converted by reaction with BOC-protected hydrazine in ethanol and in the presence of a catalytic amount of concentrated hydrochloric acid at RT in the hydrazones of formula (19), which then with sodium cyanoborohydride in methanol at + 65 ° C to the hydra - Zinc derivatives of the formula (20) can be reduced.
  • precise control of the pH value plays a major role: in the presence of bromocresol green as an indicator, a pH of about 3-4 is maintained throughout the reaction time by addition of acetic acid in portions.
  • the compounds of formula (20) are then reacted with trimethylsilyl isocyanate to form urea derivatives of formula (21).
  • the reaction is carried out in an alcohol as a solvent, preferably in isopropanol, at elevated temperature, preferably at about + 50 ° C. At the same time, cleavage of the trimethylsilyl group takes place under these conditions. Ring closure to the target compounds of formula (1-5) is achieved by acid-mediated reaction with trimethyl orthoformate.
  • the compounds of formula (21) in the presence of hydrogen chloride with an excess of trimethyl orthoformate in methanol. This reaction is preferably carried out at room temperature.
  • ring A 6 is a 2,4-dihydro-l, 2,4-triazol-3-one of the formula
  • R 1A and R 1B are both hydrogen
  • R 2 , R 3 and R 4 have the meanings given above can be prepared according to the following Reaction Scheme 6:
  • the protected hydrazine derivative of the formula (20) (see Scheme 5) is first converted with trifluoroacetic acid in dichloromethane into the free hydrazine of the formula (22).
  • the BOC cleavage takes place in a temperature range between 0 ° C and RT, preferably at 0 ° C.
  • no longer reaction time should be selected here than necessary, in addition, subsequent work-up and cleaning operations should be carried out at maximum at RT.
  • two-stage process [see US Pat. No.
  • the reaction is carried out in water in the presence of hydrochloric acid in a temperature range between 0 ° C and RT, preferably at + 10 ° C to + 20 ° C.
  • the hydrazonocarboxylic acid (24) is converted with diphenylphosphoryl azide (DPPA) into the corresponding carboxylic acid azide, which then yields the corresponding isocyanate in situ in the sense of a Curtius rearrangement, which spontaneously cyclizes to the triazolone derivative of the formula (1-6).
  • the reaction is carried out in an inert solvent such as toluene and in the presence of a tertiary amine base such as triethylamine.
  • the reaction is initially carried out in a temperature range between about + 40 ° C and + 80 ° C; in the further course, the reaction temperature is then raised to + 100 ° C to + 110 ° C.
  • 2-oxocarboxylic acids (23) in principle those compounds of the formula (1-6) according to the invention in which R 6 is (C 1 -C 4 ) -alkyl can also be prepared by this process.
  • R 1A and R 1B are both hydrogen or both are deuterium
  • Alcohols of the formula (9) are reacted here in the sense of a Mitsunobu reaction directly with an aza heterocycle of the formula (25) to give the target compounds of the formula (1-7).
  • Suitable reagents for this transformation are, for example, triphenylphosphine, polymer-bound triphenylphosphine, tributylphosphine or trimethylphosphine, in each case in combination with diethyl azodicarboxylate (DEAD), diisopropyldiazodicarboxylate (DIAD) or azodicarboxylic acid dipiperidide (ADDP) [cf. z. BDL Hughes, Org. Reactions 42, 335 (1992); DL Hughes, Org. Prep.
  • DEAD diethyl azodicarboxylate
  • DIAD diisopropyldiazodicarboxylate
  • ADDP azodicarboxylic acid dipiperidide
  • the reaction is preferably carried out in tetrahydrofuran (THF) or dichloromethane as solvent in a temperature range between 0 ° C and RT.
  • THF tetrahydrofuran
  • dichloromethane dichloromethane
  • the aza heterocycle (25) may also be used in protected form using a suitable amide protecting group which masks the N 4 atom of the l, 2,4-triazol-3-one, if desired for avoidance of side reactions is appropriate or necessary.
  • amide-protecting groups are familiar to the person skilled in the art [for the suitability, introduction and removal of amide-protecting groups see, for example, US Pat. BTW Greene and PGM Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999].
  • the reaction of the hydrazine derivatives of the formula (20) (see Scheme 5) with the acrylic acid chlorides of the formula (26) is carried out under customary conditions, for example in dichloromethane as solvent in a temperature range between 0 ° C. and RT and in the presence of a tertiary amine base such as N, N-diisopropylethylamine.
  • the final acid catalyzed removal of the Boc protecting group and subsequent ring closure to the target compounds of formula (1-8) is carried out at RT in either pure concentrated sulfuric acid or in dichloromethane to which is added a catalytic amount of concentrated sulfuric acid.
  • the reaction takes place in an inert solvent, for example and preferably in dichloromethane or chloroform, in the temperature range between about 0 ° C. and room temperature.
  • the alkylation of the compounds (36) to the compounds (37) takes place under the same conditions as described above [see Scheme 9: Reaction of (35) to (1) or from (32) to (34)].
  • the metallation of 6-Bromthienouracile (37) is preferably carried out with tert. Butyllithium in an ethereal solvent, such as preferably tetrahydrofuran, at low temperature of about -78 ° C. At the same temperature, by adding a formamide, preferably N, N-dimethylformamide (DMF), the aldehydes of the formula (1) are obtained.
  • a formamide preferably N, N-dimethylformamide (DMF)
  • the compounds of the invention may also be used for the treatment and / or prevention of cardiovascular diseases, such as hypertension, heart failure, coronary heart disease, stable and unstable angina, renal hypertension, peripheral and cardial vascular diseases, arrhythmias, atrial arrhythmia and of the ventricles as well as conduction disorders such as atrio-ventricular blockades of grade I-III, supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, torsades de pointes tachycardia, extrasystoles of the atrium and ventricle, atrioventricular extrasystoles, Sick sinus syndrome, syncope, AV nodal reentry tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune heart disease (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathy),
  • the compounds according to the invention are furthermore suitable for the treatment and / or prevention of fibrous diseases 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 fibroid diseases of the eye .
  • the term fibrotic disorders includes in particular such diseases as liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial kidney fibrosis, fibrotic damage as a result of diabetes, bone marrow fibrosis, peritoneal fibrosis and similar fibrotic disorders, scleroderma, Morphaea, keloids, hypertrophic scarring, nevi, diabetic retinopathy, proliferative vitroretinopathy and connective tissue diseases (eg sarcoidosis).
  • the compounds of the invention may also be used to promote wound healing, to
  • Rho kinase inhibiting compounds such as by way of example and preferably Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049;
  • Chemotherapeutic agents such as those used for the treatment of neoplasms (neoplasms) of the lungs or other organs.
  • Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants and profibrinolytic substances.
  • 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 calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • a calcium antagonist such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • the compounds according to the invention are administered in combination with an ACE inhibitor, such as by way of example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an ACE inhibitor such as by way of example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • 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.
  • the compounds according to the invention are administered in combination with 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 by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • a cholesterol absorption inhibitor such as by way of 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.
  • compositions containing at least one compound of the invention are pharmaceutical compositions containing at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, as well as their use for the purposes mentioned above.
  • the eriindungssieen compounds rapidly and / or modified donating application forms containing the compounds according to the invention in crystalline and / or amorphized and / or dissolved form, such as.
  • 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 / wafers rapidly breaking down in the oral cavity, films / lyophilisates
  • capsules e.g. Soft gelatin capsules
  • dragees granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • inhalant medicines including powder inhalers, nebulizers, metered aerosols
  • nasal drops solutions or sprays, throat sprays, lingual, sublingual or buccal tablets to be applied
  • films / wafers or capsules suppositories, eye drops, ointments or baths, ocular inserts, ear drops, sprays, powders, rinses or tampons, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, emulsions, microemulsions, ointments, creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, powdered powders, implants or stents.
  • inhalant medicines including powder inhalers, nebulizers, metered aerosols
  • nasal drops solutions or sprays
  • throat sprays lingual, sublingual or buccal tablets to be applied
  • films / wafers or capsules suppositories
  • eye drops oint
  • oral and parenteral administration in particular oral, intravenous and intrapulmonary (inhalative) administration.
  • Ointment bases for example Vaseline, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols);
  • Suppository bases for example, polyethylene glycols, cocoa butter, hard fat;
  • Solvents e.g., water, ethanol, isopropanol, glycerol, propylene glycol, medium chain triglycerides, fatty oils, liquid polyethylene glycols, paraffins;
  • surfactants for example sodium dodecyl sulphate, lecithin, phospholipids, fatty alcohols such as Lanette ®, sorbitan fatty acid esters such as clamping ®, polyoxyethylene sorbitan fatty acid ester such as Tween ®, polyoxyethylene fatty acid glycerides such as Cremophor ®, polyoxyethylene fatty acid ester, polyoxyethylene fatty alcohol ethers, glycerol fatty acid ester, poloxamers such as Pluronic ®);
  • surfactants for example sodium dodecyl sulphate, lecithin, phospholipids, fatty alcohols such as Lanette ®, sorbitan fatty acid esters such as clamping ®, polyoxyethylene sorbitan fatty acid ester such as Tween ®, polyoxyethylene fatty acid glycerides such as Cremophor ®, polyoxyethylene fatty acid ester, polyoxyethylene fatty alcohol ethers, glycerol
  • Buffer substances and acids and bases for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine
  • ⁇ Isotonizing agents for example, glucose, sodium chloride
  • Adsorbents for example highly dispersed silicas
  • flow regulators for example magnesium stearate, stearic acid, talc, colloidal silicas such as Aerosil ®);
  • Dyes e.g., inorganic pigments such as iron oxides, titanium dioxide
  • Flavors e.g., sweeteners, flavor and / or smell remedies.
  • the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.
  • the amount of active ingredient is generally about 0.1 to 50 mg per inhalation. Nevertheless, it may be necessary to deviate from the stated amounts of active ingredient, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. Thus, in some cases it may be sufficient to manage with less than the aforementioned minimum amount, while in other cases, the said upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.
  • Instrament MS Thermo Scientific FT-MS; UHPLC device: Thermo Scientific UltiMate 3000; Column: Waters HSST3 C18 1.8 ⁇ , 75 mm x 2.1 mm; 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; Temperature: 50 ° C; Flow: 0.90 ml / min; UV detection: 210-300 nm.
  • Instrument Waters Prep LC / MS system; Column: Phenomenex Kinetex C18, 5 ⁇ m, 100 mm ⁇ 30 mm; Eluent A: water with 5 ml of 2% formic acid per 1 L of water, eluent B: acetonitrile; Flow: 65 ml / min; Gradient profile: 0 to 2 minutes 10% B, 2 to 2.2 minutes to 20% B, 2.2 to 7 minutes to 60% B, 7 to 7.5 minutes to 92% B, 7.5 to 9 minutes 92% B; Room temperature; Wavelength: 200-400 nm.
  • Instrument Waters Prep LC / MS system; Column: XBridge C18, 5 ⁇ m, 100 mm ⁇ 30 mm; Eluent A: water with 5 ml of 2% formic acid per 1 L of water, eluent B: acetonitrile; Flow: 65 ml / min; Gradient profile: 0 to 2 minutes 10% B, 2 to 2.2 minutes to 20% B, 2.2 to 7 minutes to 60% B, 7 to 7.5 minutes to 92% B, 7.5 to 9 minutes 92% B; Room temperature; Wavelength: 200-400 nm.
  • Example 1A Ethyl 2 - [(cyclopropylcarbamoyl) amino] -4-methylthiophene-3-carboxylate
  • Example 3A Ethyl 4-methyl-2- ( ⁇ [1- (trifluoromethyl) cyclopropyl] carbamoyl ⁇ amino) thiophene-3-carboxylate
  • Example 4A Ethyl 4-methyl-2- ⁇ [(2-methylcyclopropyl) carbamoyl] amino ⁇ thiophene-3-carboxylate
  • the crude product was purified by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, silica gel, eluent cyclohexane / ethyl acetate 2: 1). After combining the product fractions, concentrating and drying in a high vacuum, 4.96 g (62% of theory) of the title compound were obtained.
  • Example 16A Analogously to the process described in Example 16A, from 6.23 g (21.0 mmol) of the compound from Example 10A, 4.51 g (86% of theory) of the title compound were prepared.
  • Example 38A 3- (3,3-Difluorocyclobutyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde
  • Example 42A 3- (3,3-Dimethylcyclobutyl) -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde
  • Example 52A 1- (Cyclobutylmethyl) -3-cyclopropyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde
  • the product was isolated by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 100 g silica gel, eluent cyclohexane / ethyl acetate 2: 1). After evaporation of the product fractions and drying in a high vacuum, a first fraction of 942 mg of the title compound was obtained. A likewise obtained mixed fraction was concentrated and the residue was purified by preparative HPLC (Method 11). This gave, after evaporation of the product fractions and drying under high vacuum, a second fraction of 120 mg of the title compound. Overall, 1.06 g (86% of theory) of the title compound were thus obtained.
  • Example 62A 1, 5-Dimethyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde
  • the product was isolated therefrom by means of MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 340 g of silica gel, mobile phase cyclohexane / ethyl acetate 2: 1). After evaporation, a first fraction of the title compound (13.2 g) was obtained in pure form and a second, contaminated fraction. The contaminated fraction was stirred at RT for 16 h with ethyl acetate. The solid was filtered off with suction to give, after drying, a second fraction of the title compound (11.0 g) in pure form. In total, 24.2 g (66% of theory) of the title compound were thus obtained.
  • MPLC Biotage Isolera One, cartridge SNAP KP-Sil, 340 g of silica gel, mobile phase cyclohexane / ethyl acetate 2: 1).
  • Example 70A (2-Ethoxyethyl) -5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde
  • Example 71A (2-Isopropoxyethyl) -5-methyl-3- (1-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde
  • reaction mixture was admixed with water after cooling to RT and stirred at RT for 30 min.
  • the precipitated product was filtered off, washed with water and dried under high vacuum. 485 mg (73% of theory) of the title compound were obtained.
  • Example 74A 1- (2-methoxyethyl) -5-methyl-2,4-dioxo-3- [1- (trifluoromethyl) cyclopropyl] -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine -6-carbaldehyde
  • the organic extract was washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated.
  • the product was isolated by MPLC (Biotage Isolera One, cartridge SNAP KP-Sil, 100 g silica gel, eluent cyclohexane / ethyl acetate 2: 1). After evaporation of the product fractions and drying in a high vacuum, 1.50 g (70% of theory) of the title compound were obtained.
  • Example 75A 1- (3-fluoropropyl) -5-methyl-3- (2-methylcyclopropyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carbaldehyde (trans-racemate)

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Abstract

La présente invention concerne de nouveaux dérivés de thiéno[2,3-d]pyrimidin-2,4-dione ("thiéno-uracile") à substitution cyclique en position 3, des procédés de production desdits dérivés, leur utilisation seuls ou en associations pour le traitement et/ou la prévention de maladies, ainsi que leur utilisation pour la fabrication de médicaments destinés au traitement et/ou à la prévention de maladies, en particulier au traitement et/ou à la prévention de maladies des poumons et du système cardiovasculaire, ainsi que de cancers.
EP17765199.9A 2016-09-23 2017-09-18 Thiéno-uraciles à substitution n3-cyclique et leur utilisation Withdrawn EP3515919A1 (fr)

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