USRE42462E1 - Carboxylic acid derivatives, their preparation and use - Google Patents

Carboxylic acid derivatives, their preparation and use Download PDF

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Publication number
USRE42462E1
USRE42462E1 US12/481,594 US48159497A USRE42462E US RE42462 E1 USRE42462 E1 US RE42462E1 US 48159497 A US48159497 A US 48159497A US RE42462 E USRE42462 E US RE42462E
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phenyl
alkyl
group
alkoxy
alkylthio
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Hartmut Riechers
Dagmar Klinge
Wilhelm Amberg
Andreas Kling
Stefan Muller
Ernst Baumann
Joachim Rheinheimer
Uwe Josef Vogelbacher
Wolfgang Wernet
Liliane Unger
Manfred Raschack
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Royalty Pharma Collection Trust
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Abbott GmbH and Co KG
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Definitions

  • the present invention relates to novel carboxylic acid derivatives, their preparation and use.
  • Endothelin is a peptide which is composed of 21 amino acids and is synthesized and released by the vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. In the following text, “endothelin” or “ET” signifies one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a potent effect on vessel tone. It is known that this vasoconstriction is caused by binding of endothelin to its receptor (Nature, 332, (1988) 411-415; FEBS Letters, 231, (1988) 440-444 and Biochem. Biophys. Res. Commun., 154, (1988) 868-875).
  • endothelin causes persistent vasoconstruction in the peripheral, renal and cerebral blood vessels, which may lead to illnesses. It has been reported in the literature that elevated plasma levels of endothelin were found in patients with hypertension, acute myocardial infarct, pulmonary hypertension, Raynaud's syndrome, atherosclerosis and in the airways of asthmatics (Japan J. Hypertension, 12, (1989) 79, J. Vascular Med. Biology 2, (1990) 207, J. Am. Med. Association 264, (1990) 2868).
  • the invention relates to carboxylic acid derivatives of the formula I
  • R is formyl, tetrazole [sic], nitrile [sic], a COOH group —COOH or a radical which can be hydrolyzed to —COOH, and the other substituents have the following meanings:
  • the compounds, and the intermediates for preparing them, such as IV and VI, may have one or more asymmetrical substituted carbon atoms.
  • Such compounds may be in the form of the pure enantiomers or pure diastereomers or a mixture thereof.
  • the use of an enantiomerically pure compound as active substance is preferred.
  • the invention furthermore relates to the use of the above-mentioned carboxylic acid derivatives for producing drugs, in particular for producing endothelin receptor inhibitors.
  • the invention furthermore relates to the preparation of the compounds of the formula IV in enantiomerically pure form.
  • Enantioselective epoxidation of an olefin with two phenyl substituents is known (J. Org. Chem. 59, 1994, 4378-4380).
  • ester groups in these systems permit epoxidation in high optical purity.
  • Carboxylic acid derivatives of the general formula VI can be prepared by reacting the epoxides of the general formula IV (eg. e.g., with R ⁇ ROOR 10 [sic]) with alcohols or thiols of the general formula V where R 6 and Z have the meanings stated in claim 1 .
  • compounds of the general formula IV are heated with compounds of the formula V, in the molar ratio of about 1:1 to 1:7, preferably 1 to 3 mole equivalents, to 50-200° C., preferably 80-150° C.
  • the reaction can also take place in the presence of a diluent. All solvents which are inert toward the reagents used can be used for this purpose.
  • solvents or diluents are water, aliphatic, alicyclic and aromatic hydrocarbons, which may in each case be chlorinated, such as hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichloroethylene, ethers such as diisopropyl ether, dibutyl ether, methyl tert-butyl ether, propylene oxide, dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, alcohols, such as methanol, ethanol, isopropanol, butanol and ethylene glyco
  • the reaction is preferably carried out at a temperature in the range from 0° C. to the boiling point of the solvent or mixture of solvents.
  • Suitable catalysts are strong organic and inorganic acids, and Lewis acids. Examples thereof are, inter alia, sulfuric acid, hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, boron trifluoride etherate and titanium(IV) alcoholates.
  • enantiomerically pure compounds of the formula VI by carrying out a classical racemate resolution on racemic or diastereomeric compounds of the formula VI using suitable enantiomerically pure bases such as brucine, strychnine, quinine, quinidine, chinchonidine [sic], chinchonine [sic], yohimbine, morphine, dehydroabietylamine, ephedrine ( ⁇ ), (+), deoxyephedrine (+), ( ⁇ ), threo-2-amino-1-(p-nitrophenyl)-1,3-propanediol (+), ( ⁇ ), threo-2-(N,N-dimethylamino)-1-(p-nitrophenyl)-1,3-propanediol (+), ( ⁇ ) threo-2-amino-1-phenyl-1,3-propanediol (+), ( ⁇ ), ⁇ -methylbenzylamine (+), ( ⁇ ), ⁇ -(
  • R 15 is halogen or R 16 —SO 2 —
  • R 16 can be C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl or phenyl.
  • the reaction preferably takes place in one of the abovementioned inert diluents with the addition of a suitable base, ie. i.e., of a base which deprotonates the intermediate VI, in a temperature range from room temperature to the boiling point of the solvent.
  • alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride
  • a carbonate such as an alkali metal carbonate, eg. e.g., sodium or potassium carbonate
  • an alkali metal or alkaline earth metal hydroxide such as sodium or potassium hydroxide
  • an organometallic compound such as butyllithium
  • an alkali metal amide such as lithium diisopropylamide.
  • the reaction preferably takes place in one of the above-mentioned inert diluents with the addition of a suitable base, ie. i.e., a base which deprotonates the intermediate IX, in a temperature range from room temperature to the boiling point of the solvent.
  • a suitable base ie. i.e., a base which deprotonates the intermediate IX
  • organic bases such as triethylamine, pyridine, imidazole or diazabicycloundecane [sic].
  • cuprates can be prepared as described in Tetrahedron Letters 23, (1982) 3755.
  • Compounds of the formula I can also be prepared by starting from the corresponding carboxylic acids, ie. i.e., compounds of the formula I where R is COOH, and initially converting these in a conventional manner into an activated form, such as a halide, an anhydride or imidazolide, and then reacting the latter with an appropriate hydroxy compound HOR 10 .
  • This reaction can be carried out in the usual solvents and often requires addition of a base, in which case those mentioned above are suitable.
  • These two steps can also be simplified, for example, by allowing the carboxylic acid to act on the hydroxy compound in the presence of a dehydrating agent such as a carbodiimide.
  • compounds of the formula I can be prepared by starting from the salts of the corresponding carboxylic acids, ie. i.e., from compounds of the formula I where R is COR 1 and R 1 is OM, where M can be an alkali metal cation or the equivalent of an alkaline earth metal cation.
  • salts can be reacted with many compounds of the formula R 1 -A where A is a conventional nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or aryl- or alkylsulfonyl which is unsubstituted or substituted by halogen, alkyl or haloalkyl, such as toluenesulfonyl and methylsulfonyl, or another equivalent leaving group.
  • A is a conventional nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or aryl- or alkylsulfonyl which is unsubstituted or substituted by halogen, alkyl or haloalkyl, such as toluenesulfonyl and methylsulfonyl, or another equivalent leaving group.
  • Compounds of the formula R 1 -A with a reactive substituent A are known or can be easily obtained with general expert knowledge
  • R in formula I may vary widely.
  • R is a group
  • R 1 has the following meanings:
  • carboxylic acid derivatives of the general formula I both as pure enantiomers and pure diastereomers or as mixture thereof, are those where the substituents have the following meanings:
  • the ET A receptor-expressing CHO cells were grown in F 12 medium containing 10% fetal calf serum, 1% glutamine, 100 U/ml penicillin and 0.2% streptomycin (Gibco BRL, Gaithersburg, Md., USA).
  • the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS for 5 min. Neutralization was then carried out with F 12 medium, and the cells were collected by centrifugation at 300 ⁇ g. To lyze lyse the cells, the pellet was briefly washed with lysis buffer (5 mM Tris-IICl, pII 7.4 with 10% glycerol) and then incubated at a concentration of 107 cells/ml of lysis buffer at 4° C. for 30 min. The membranes were centrifuged at 20,000 ⁇ g for 10 min, and the pellet was stored in liquid nitrogen.
  • lysis buffer 5 mM Tris-IICl, pII 7.4 with 10% glycerol
  • Guinea pig cerebella were homogenized in a Potter-Elvejhem homogenizer and [lacuna] obtained by differential centrifugation at 1000 ⁇ g for 10 min and repeated centrifugation of the supernatant at 20,000 ⁇ g for 10 min.
  • the membranes were suspended in incubation buffer (50 mM Tris-HCl, pH 7.4 with 5 mM MnCl 2 , 40 ⁇ g/ml bacitracin and 0.2% BSA) at a concentration of 50 ⁇ g of protein per assay mixture and incubated with 25 pM [125I] [ 125 I]-ET 1 (ET A receptor assay) or 25 pM [125I] [ 125 I]-RZ 3 (ET B receptor assay) in the presence and absence of test substance at 25° C.
  • the nonspecific binding was determined using 10 --7 10 ⁇ 7 M ET 1 .
  • the free and bound radioligand were separated by filtration through GF/B glass fiber filters (Whatman, England) on a Skatron cell collector (Skatron, Lier, Norway) and the filters were washed with ice-cold Tris-HCl buffer, pH 7.4 with 0.2% BSA. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.
  • This assay system is a functional, cell-based assay for endothelin receptors.
  • endothelin 1 When certain cells are stimulated with endothelin 1 (ET1) they show an increase in the intracellular calcium concentration. This increase can be measured in intact cells loaded with calcium-sensitive dyes.
  • test animals received an i.v. injection of the test compounds (1 ml/kg) 5 min before the administration of ET1.
  • the rise in blood pressure in the test animals was compared with that in the control animals.
  • the principle of the test is the inhibition of the sudden heart death caused in mice by endothelin, which is probably induced by constriction of the coronary vessels, by pretreatment with endothelin receptor antagonists.
  • Intravenous injection of 10 nmol/kg endothelin in a volume of 5 ml/kg of body weight results in death of the animals within a few minutes.
  • the lethal endothelin-1 dose is checked in each case on a small group of animals. If the test substance is administered intravenously, the endothelin-1 injection which was lethal in the reference group usually takes place 5 min thereafter. With other modes of administration, the times before administration are extended, where appropriate up to several hours.
  • the survival rate is recorded, and effective doses which protect 50% of the animals (ED 50) from endothelin-induced heart death for 24 h or longer are determined.
  • Segments of rabbit aorta are, after an initial tension of 2 g and a relaxation time of 1 h in Krebs-Henseleit solution at 37° C. and pH 7.3-7.4, first induced to contract with K + . After washing out, an endothelin dose-effect plot up to the maximum is constructed.
  • Potential endothelin antagonists are administered to other preparations of the same vessel 15 min before starting the endothelin dose-effect plot.
  • the effects of the endothelin are calibrated as a % of the K + -induced contraction. Effective endothelin antagonists result in a shift to the right in the endothelin dose-effect plot.
  • the compounds according to the invention can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperotoneally intraperitoneally) in a conventional way. Administration can also take place with vapors or sprays through the nasopharyngeal space.
  • the dosage depends on the age, condition and weight of the patient and on the mode of administration.
  • the daily dose of active substance is, as a rule, about 0.5-50 mg/kg of body weight on oral administration and about 0.1-10 mg/kg of body weight on parenteral administration.
  • 91.11 g (0.5 mol) of benzophenone and 45.92 g (0.85 mol) of sodium methoxide were suspended in 150 ml of methyl tert-butyl ether (MTB) at room temperature. After cooling to ⁇ 100° C., 92.24 g (0.85 mol) of methyl chloroacetate were added in such a way that the internal temperature rose to 40° C. while continuing to cool in a bath at ⁇ 10° C. The mixture was then stirred without cooling at the autogenous temperature for one hour. After addition of 250 ml of water and brief stirring, the aqueous phase was separated off. The MTB phase was washed with 250 ml of dilute sodium chloride solution.
  • MTB methyl tert-butyl ether
  • the residue was suspended in 500 ml of water and 350 ml of MTB and then the pH was adjusted to 1.2 with concentrated hydrochloric acid at room temperature, and, after stirring and phase separation, the aqueous phase was separated off and extracted with 150 ml of MTB.
  • the combined organic phases were extracted with 100 ml of water. 370 ml of MTB were distilled out and then 390 ml of n-heptane were added under reflux, and the mixture was slowly cooled to room temperature while the product crystallized.
  • the contents of the flask were diluted with about 600 ml of H 2 O and cautiously acidified with concentrated HCl, and 250 ml of ethyl acetate were added. 31.4 g of pure product precipitated and were filtered off.
  • the ethyl acetate phase was separated from the mother liquor, the aqueous phase was extracted again with ethyl acetate, and the combined organic phases were concentrated.
  • reaction mixture was stirred at ⁇ 10° C. for about 2 h, then poured into water and extracted several times with ethyl acetate. The combined organic phases were dried over Na 2 SO 4 and concentrated, and the residue was purified by chromatography on silica gel (n-heptane/ethyl acetate).
  • Electrospray-MS 435 (M+H + ) 1 H-NMR (CDCl 3 ): ⁇ (ppm) 3.28 (s, 3H), 3.85 (s, 6H), 5.75 (s, 1H), 7.25-7.40 (m, 10H), 7.50 (s, 1H).
  • Receptor binding data were measured by the binding assay described above for the compounds listed below. The results are shown in Table 2 [sic].

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Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ABBVIE DEUTSCHLAND GMBH & CO. KG;REEL/FRAME:035007/0817

Effective date: 20140115

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