WO2002070459A1 - Neuartige aminodicarbonsäurederivate - Google Patents
Neuartige aminodicarbonsäurederivate Download PDFInfo
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- WO2002070459A1 WO2002070459A1 PCT/EP2002/001682 EP0201682W WO02070459A1 WO 2002070459 A1 WO2002070459 A1 WO 2002070459A1 EP 0201682 W EP0201682 W EP 0201682W WO 02070459 A1 WO02070459 A1 WO 02070459A1
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- 0 Cc(c(*)cc(*)c1)c1O Chemical compound Cc(c(*)cc(*)c1)c1O 0.000 description 4
- REXQBEYYHXLNSO-UHFFFAOYSA-N COC(CCCCN(CCc(cccc1)c1O)Cc(cc1)ccc1C(OC)=O)=O Chemical compound COC(CCCCN(CCc(cccc1)c1O)Cc(cc1)ccc1C(OC)=O)=O REXQBEYYHXLNSO-UHFFFAOYSA-N 0.000 description 1
- MKJFJMUAFKMDMN-UHFFFAOYSA-N COC(c1ccc(CNCCc2c(COc3ccc(C4CCCCC4)cc3)ccc(F)c2)cc1)=O Chemical compound COC(c1ccc(CNCCc2c(COc3ccc(C4CCCCC4)cc3)ccc(F)c2)cc1)=O MKJFJMUAFKMDMN-UHFFFAOYSA-N 0.000 description 1
- RASXKKSTQCRUOJ-UHFFFAOYSA-N N#Cc1cccc(Oc2ccc(C3CCCCC3)cc2)c1 Chemical compound N#Cc1cccc(Oc2ccc(C3CCCCC3)cc2)c1 RASXKKSTQCRUOJ-UHFFFAOYSA-N 0.000 description 1
- VFDPQZFQILFRSY-UHFFFAOYSA-N OC(CCCCN(Cc1ccccc1)Cc1ccccc1)=O Chemical compound OC(CCCCN(Cc1ccccc1)Cc1ccccc1)=O VFDPQZFQILFRSY-UHFFFAOYSA-N 0.000 description 1
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Definitions
- the present invention relates to new aminocarboxylic acid derivatives which also stimulate soluble guanylate cyclase via a novel mode of action which does not involve the heme group of the enzyme, their production and their use as medicaments, in particular as medicaments for the treatment of cardiovascular diseases.
- Cyclic guanosine monophosphate is one of the most important cellular transmission systems in mammalian cells. Together with nitrogen monoxide (NO), which is released from the endothelium and transmits hormonal and mechanical signals, it forms the NO / cGMP system.
- the guanylate cyclases catalyze the biosynthesis of cGMP from guanosine triposphate (GTP).
- GTP guanosine triposphate
- the previously known representatives of this family can be divided into two groups according to structural features and the type of ligand: the particulate guanylate cyclases that can be stimulated by natriuretic peptides and the soluble guanylate cyclases that can be stimulated by NO.
- the soluble guanylate cyclases consist of two subunits and most likely contain one heme per heterodimer, which is part of the regulatory center. This is of central importance for the activation mechanism. NO can bind to the iron atom of the heme and thus significantly increase the activity of the enzyme. Hem-free preparations, on the other hand, cannot be stimulated by NO. CO is also able to attack the central iron atom of the heme, whereby the stimulation by CO is significantly less than that by NO.
- guanylate cyclase plays a decisive role in different physiological processes, in particular in the relaxation and proliferation of smooth muscle cells, platelet aggregation and adhesion and neuronal signal transmission as well as in diseases , which before based on a disturbance of the above-mentioned processes.
- the NO / cGMP system can be suppressed, which can lead, for example, to high blood pressure, platelet activation, increased cell proliferation, endothelial dysfunction, atherosclerosis, angina pectoris, heart failure, thrombosis, stroke and myocardial infarction.
- a NO-independent treatment option for such diseases aimed at influencing the cGMP signal path in organisms is a promising approach due to the expected high efficiency and few side effects.
- the soluble guanylate cyclase stimulators described above stimulate the enzyme either directly via the heme group (carbon monoxide, nitrogen monoxide or diphenyliodonium hexafluorophosphate) by interaction with the iron center of the heme group and a resultant to increase the enzyme activity-leading conformational change (Gerzer et al., FEBS Lett. 132 (1981), 71), or via a heme-dependent mechanism that is independent of NO but leads to a potentiation of the stimulating effect of NO or CO (e.g. YC- 1, Hoenicka et al., J. Mol. Med. (1999) 14; or the pyrazole derivatives described in WO 98/16223, WO 98/16507 and WO 98/23619).
- NO or CO e.g. YC- 1, Hoenicka et al., J. Mol. Med. (1999) 14; or the pyrazole derivatives described in WO 98
- the enzyme still shows a detectable catalytic basal activity, i.e. cGMP is still formed.
- the remaining catalytic basal activity of the heme-free enzyme cannot be stimulated by any of the known stimulators mentioned above.
- protoporphyrin LX A stimulation of heme-free soluble guanylate cyclase by protoporphyrin LX has been described (Ignarro et al., Adv. Pharmacol. 26 (1994), 35).
- protoporphyrin IX can be regarded as facial expressions for the NO-heme adduct, which is why the addition of protoporphyrin LX to soluble guanylate cyclase should lead to the formation of a structure of the enzyme corresponding to the soluble guanylate cyclase which is stimulated by NO.
- the compounds according to the invention are able to stimulate both the heme-containing and the hani-free form of the soluble guanylate cyclase.
- Enzyme with these new stimulators runs via a heme-independent Way, which is also demonstrated by the fact that the new stimulators on the heme-containing enzyme on the one hand show no synergistic effect with NO and on the other hand the effect of these novel stimulators is not affected by the heme-dependent inhibitor of soluble guanylate cyclase, lH-l, 2,4 -Oxadiazol- (4,3-a) -quinoxalin-l-one (ODQ).
- ODQ soluble guanylate cyclase
- EP-A-0 345 068 describes, inter alia, the aminoalkanecarboxylic acid (1) as an intermediate in the synthesis of GABA antagonists:
- the present invention relates to compounds of the general formula (I)
- R 1 is arranged in the meta or para position to the radical W and denotes a radical from the group consisting of H, halogen or OCF 3 ;
- R 2 represents H or halogen
- R 3 represents H or halogen
- V is arranged in the ortho or meta position to the radical W and represents O, CH 2 O, OCF 2 , or OC ⁇ g-alkyl-O; W represents CH 2 or CH 2 CH 2 ;
- the present invention relates to compounds of the formula (I) in which
- R 1 is arranged in the meta position to the radical W and denotes a radical from the group consisting of H or halogen;
- R 2 represents H or halogen
- R 3 represents H or halogen
- R 4 denotes Ci.g-alkyl, C 3 .g-cycloalkyl or phenyl, where the phenyl radical can additionally carry a substituent from the group consisting of halogen, CN, C ⁇ _g-alkoxy, CF 3 , C g-alkyl;
- V is arranged in the ortho or meta position to the rest W and for O, CH 2 O,
- W represents CH 2 or CH 2 CH 2 ;
- the present invention relates to compounds of the formula (I) in which
- R 1 is arranged in the meta position to the radical W and denotes a radical from the group consisting of H, F, CI or Br;
- R 2 represents H
- R 3 represents H
- R 4 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl, the phenyl radical additionally being a substituent from the group consisting of F, CI, Br, CN, methoxy, ethoxy, n-propoxy, i-propoxy, n-butyloxy, i-butyloxy, t-butyloxy, CF 3 , methyl, ethyl, n-propyl, i-propyl, n-butyl , i-butyl, t-butyl, can wear;
- V is arranged in the ortho or meta position to the radical W and represents O, CH 2 O, OCF 2 or OC ⁇ alkyl-O;
- W represents CH 2 or CH 2 CH 2 ;
- the present invention relates to compounds of the formula (I) in which
- R 1 is arranged in the meta position to the rest W and denotes H;
- R 2 represents H
- R 3 represents H
- R 4 denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl, where the phenyl radical can additionally carry a substituent from the group consisting of F, CI, Br, CF 3 ;
- V is arranged in the meta position to the rest W and stands for O;
- W represents CH 2 ;
- the present invention relates to compounds of the formula (I) in which
- R 1 is arranged in the meta position to the rest W and denotes H;
- R 2 represents H
- R 3 represents H
- R 4 is phenyl, the phenyl radical additionally being a substituent from the
- V is arranged in the ortho position to the rest W and stands for OCF 2 ;
- W represents CH 2 CH 2 ;
- the present invention relates to compounds of the formula (I) in which
- R 1 is arranged in the meta position to the radical W and denotes a radical from the group consisting of H, F, CI or Br;
- R 2 represents H
- R 3 represents H
- R 4 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl, where the
- Phenyl radical additionally a substituent from the group consisting of F,
- V is arranged in the ortho position to the radical W and represents CH 2 O;
- W represents CH 2 CH 2 ;
- the compounds of the general formula (I) according to the invention can also be in the form of their salts.
- salts with organic or inorganic bases or acids may be mentioned here.
- Physiologically acceptable salts are preferred in the context of the present invention.
- Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids.
- Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids.
- particular preference is given to Salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
- Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group.
- Sodium, potassium, magnesium or calcium salts are particularly preferred, and ammonium salts derived from ammonia, or organic amines such as ethylamine, di- or trie ylamine, di- or triemanolamine, dicyclohexylamine, dimemylaminoethanol, arginine, lysine or emylenediamine.
- the compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers).
- the invention relates both to the enantiomers or diastereomers and to their respective mixtures.
- the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner, for example by racemate resolution or chromatographic separation.
- Double bonds present in the compounds according to the invention can be in the eis or trans configuration (Z or E form).
- Alkyl generally represents a straight-chain or branched hydrocarbon radical having 1 to 20 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl,
- Alkoxy generally stands for a straight-chain or branched hydrocarbon radical with 1 to 14 carbon atoms which is bonded via an oxygen atom.
- Cycloalkyl generally represents a cyclic hydrocarbon radical having 3 to 8 carbon atoms. Cyclopropyl, cyclopentyl and cyclohexyl are preferred. Examples include cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
- Halogen in the context of the invention represents fluorine, chlorine, bromine and iodine.
- the definitions for the radical V are to be understood such that the first-mentioned atom is bonded to the phenyl ring which also carries the radical R 1 .
- V OCF 2
- the oxygen atom is bound to the phenyl ring, which also carries the radical R 1 .
- the present invention further relates to a process for the preparation of the compounds of the formula (I), characterized in that
- R 1 , V and W have the meanings given in claim 1, and
- R 1 , V, W and L have the meanings given above and Q represents a Ci.g-alkyl radical
- R 1 , V, W and Q have the meanings given above, Q 'represents a Ci.g-alkyl radical and L represents H - if V is O - or a radical of the formula LT-A,
- R 2 and R 3 have the meaning given in claim 1 and X and X 'each represent halogen
- the bases preferred for the processes according to the invention comprise basic compounds conventionally used for basic reactions.
- Alkali metal hydrides such as, for example, sodium hydride or potassium hydride, or alkali metal alcoholates such as sodium methoxide, sodium ethanolate, potassium methoxide, potassium ethanolate or potassium t-butoxide, or carbonates such as sodium carbonate, cesium carbonate or potassium carbonate or amides such as sodium amide or lithium diisopropyl amide, or organolifids, or organolifices, are preferably used like phenyllithium,
- Butyllithium or methyl lithium or sodium hexamethyldisilazane can be used.
- Preferred solvents for the conversion of the compounds of formula (II) to the compounds of formula (III) are conventional organic solvents which do not change under the reaction conditions.
- ethers such as diethyl ether, butyl methyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene or petroleum ether, or alcohols such as methanol or ethanol or halogenated hydrocarbons such as carbon tetrachloride, chloromethane or dichloro
- mixtures of the abovementioned solvents According to the invention, preference is given to using ethanol, methanol, dichloromethane or toluene.
- the compounds of formula (II) are first reacted with a 4-formylbenzoic acid Ci- ⁇ -alkyl ester to form a Schiff base and this is then reduced with common reducing agents, such as NaBFL ;, H 2 / Pd / C etc. or directly under the Conditions of a reductive alkylation in the presence of a reducing agent, such as H 2 / Pd / C, NaCNBH 3 , NaH (OAc) 3, are implemented (cf. Patai, Ed., The Chemistry of the Carbon-Nitrogen Double Bond, pp. 276-293 and the literature cited there).
- the reaction can take place at room temperature or must be heated to 50 to 110 ° C for several hours to several days.
- the reaction can be carried out at normal pressure, elevated or reduced pressure (for example in a range from 0.5 to 5 bar). In general, the reaction is carried out at normal pressure.
- 4-Formylbenzoic acid -o-alkyl esters are commercially available, known from the literature, or can be synthesized analogously to processes known from the literature (cf., for example, J. Med. Chem. 1989, 32, 1277; Chem. Ber. 1938, 71, 335 ; Bull. Soc. Chim. Fr.
- the reaction of the compounds of the formula (DI) to the compounds of the formula (IV) can preferably in acetonitrile or butyronitrile in each case by reaction of the compounds (II) and (III), (TV) and (V) or (VI) and (VII ) in the presence of a base such as sodium carbonate, Et 3 N, DABCO, K 2 CO 3 , KOH, NaOH or NaH.
- the reaction can generally be carried out in a temperature range from -20 ° C. to + 90 ° C., preferably from 0 ° C. to + 70 ° C.
- the reaction can be carried out at normal pressure, elevated or reduced pressure (for example in a range from 0.5 to 5 bar). In general, the reaction is carried out at normal pressure.
- the solvents mentioned above for the conversion of the compounds of the formula (II) to the compounds of the formula (III) are suitable as solvents.
- the corresponding ⁇ -bromovaleric acid methyl ester is preferably used as the ⁇ -halovaleric acid alkyl ester.
- ⁇ -Halovaleric acid alkyl esters are commercially available, known from the literature or can be synthesized by processes known from the literature (see, for example, J. Chem. Soc. 1958, 3065).
- the methoxy group present should be converted into the free hydroxyl group before the reaction of the corresponding compound of the formula (TU) with the ⁇ -halovaleric acid alkyl ester.
- This can be done in a known manner (cf. TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, second edition, New York, 1991).
- the methyl group can be split off to form the phenol by boron tribromide in methylene chloride at -70 to 20 ° C, by trimethylsilyl iodide in chloroform at 25-50 ° C or by sodium ethyl thiolate in DMF at 150 ° C.
- the reaction with boron tribromide is preferred.
- the compounds of formula (TV) are then, for example, by adding aqueous solutions of strong acids such as HC1 or H SO 4 , or strong bases such as NaOH, KOH or LiOH in the compounds of formula (I) by hydrolysis of the ester functions to the free carboxyl groups transferred.
- the reaction can be carried out in one of the abovementioned organic solvents, in water or in mixtures of organic solvents or in mixtures of organic solvents with water. According to the invention, it is preferred, for example, to carry out the reaction in a mixture of water and methanol or dioxane.
- the reaction can generally be in one
- the reaction can be carried out under normal pressure, elevated or reduced pressure (for example in a range from 0.5 to 5 bar), generally the reaction is carried out under normal pressure.
- X ' is, for example: halogen, tosylate, mesylate, or a hydroxyl function activated by reagents such as diisopropylazodicarboxylate / PPh 3 (Mitsonobu reaction).
- X ' is preferably halogen, particularly preferably Br.
- This reaction can preferably be carried out in dimethylformamide (DMF) by reaction of the compounds (TV) and (IV-
- A) in the presence of a base such as sodium carbonate, potassium carbonate, Et 3 N, DABCO, K 2 CO 3 , KOH, NaOH or preferably NaH can be carried out.
- the reaction can generally be carried out in a temperature range from -20 ° C. to + 90 ° C., preferably from 0 ° C. to + 90 ° C.
- the reaction can be carried out at normal pressure, elevated or reduced pressure (for example in a range from 0.5 to 5 bar). In general, the reaction is carried out at normal pressure.
- the compounds of the formula (IV-A) can be obtained from commercially available compounds which are known from the literature or can be synthesized analogously to processes known from the literature (see, for example, J. Prakt. Chem. 1960, 341; Farmaco Ed. Sei. 1956, 378; Eur.
- the reaction formally represents a reductive coupling, as described, for example, in LS Hegedus, Organometallics in Synthesis, M. Schlosser, Ed., Wiley & Sons, 1994.
- a halogen group such as Br or I or a conventional leaving group such as a triflate group can be used as the substitutable group X.
- a halogen radical, in particular Br, is preferred according to the invention.
- a palladium ( ⁇ ) compound such as Cl 2 Pd (PPh 3 ) 2 or Pd (OAc) 2 or a palladium (0) compound such as Pd (PPh 3 ) can be used as the palladium compound. 4 or Pd 2 (dba) 3 can be used.
- the reaction mixture can additionally contain a reducing agent such as triphenylphosphine or other additives such as
- the reaction is carried out in the presence of a conventional base such as Na 2 CO 3 , NaOH or triethylamine
- a conventional base such as Na 2 CO 3 , NaOH or triethylamine
- the solvents mentioned are the organic solvents mentioned above, with ethers such as 1,2-dimethoxyethane being particularly preferred
- the reaction can generally be carried out in a temperature range from -20 ° C. to + 90 ° C., preferably from 0 ° C. to + 90 ° C.
- the reaction can be carried out under normal pressure, elevated or reduced pressure (for example in a range from 0.5 to 5 bar)
- reaction is carried out at normal pressure.
- Benzene boronic acids are commercially available, known from the literature, or can be synthesized in analogy to processes known from the literature (see, e.g., J.Chem.Soc.C 1966, 566. J.Org.Chem., 38, 1973, 4016).
- halogenbenzonitriles can be obtained starting from commercially available, known from the literature or synthesized analogously to processes known from the literature (cf. for example Chem. Pharm. Bull. 31, 10, 1983, 3424-3445; Bull. Chem. Soc. Fr. ⁇ ü>, 1979, 241-248; Chem. Ber. 80, 1947, 469-472, J. Chem.
- cardiovascular diseases such as, for example, for the treatment of high blood pressure and heart failure, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, of arrhythmias, for the treatment of thromboembolic disorders and ischemia such as myocardial infarction, stroke, transistoristic and ischemic
- the compounds of the general formula (I) described in the present invention also represent active compounds for combating diseases in the central nervous system which are characterized by disorders of the NO / cGMP system.
- they are suitable for eliminating cognitive deficits, for improving learning and memory and for treating Alzheimer's disease. They are also suitable for the treatment of diseases of the central nervous system such as anxiety, tension and depression, central nervous system-related sexual dysfunctions and sleep disorders, and for the regulation of pathological disorders of the central nervous system
- the active ingredients are also suitable for regulating cerebral blood flow and are therefore effective means of combating migraines.
- the compounds of the general formula (I) according to the invention can also be used to combat painful conditions.
- the compounds according to the invention have anti-inflammatory activity and can therefore be used as anti-inflammatory agents.
- the compounds of the present invention have an unexpectedly long duration of action.
- Vascular relaxant effect in vitro is unexpectedly long duration of action.
- Rabbits are anesthetized or killed by intravenous injection of thiopental sodium (approx. 50 mg / kg) and exsanguinated.
- the saphenous artery is removed and divided into 3 mm wide rings.
- the rings are individually mounted on a triangular pair of hooks made of 0.3 mm special wire (Remanium ® ) that is open at the end.
- Each ring is placed in 5 ml organ baths with 37 ° C warm, carbogen-gassed Krebs-Henseleit solution of the following composition (mM): NaCl: 119; KC1: 4.8; CaCl 2 x 2 H 2 O: 1; MgSO 4 x 7 H 2 O: 1.4; KH 2 PO 4 : 1.2; NaHCO3: 25; Glucose: 10; Bovine serum albumin: 0.001%.
- the contraction force is recorded with Statham UC2 cells, amplified and digitized via A / D converter (DAS-1802 HC, Keithley Instruments Munich), and recorded in parallel on line recorders. Contractions are induced by adding phenylephrine.
- the substance to be examined is added in increasing doses in each further run and the level of the contraction achieved under the influence of the test substance is compared with the level of the contraction achieved in the last previous run. From this, the concentration is calculated which is required to reduce the contraction achieved in the pre-control to 50% (IC5 0 ).
- the standard application volume is 5 ⁇ l.
- DMSO content in the bath solution corresponds to 0.1%.
- Stasch Purified soluble guanylyl cyclase expressed in a baculovirus / Sf9 System: Stimulation by YC-1, nitric oxide, and carbon oxide. J. Mol. Med. 77 (1999): 14-23.
- the heme-free guanylate cyclase was obtained by adding Tween 20 to the sample buffer (0.5% in the final concentration).
- Serum e.g. Pig serum in rats is a method frequently used in the literature for triggering liver fibrosis followed by cirrhosis, which, in contrast to other models, causes minimal damage and inflammation of the liver parenchyma cells (Bhunchet, E. and Wake, K. (1992): Role of mesenchymal cell populations in porcine serum-induced rat liver fibrosis.
- mice Female Sprague Dawley rats were treated twice a week with 0.5 ml / animal sterile porcine serum (Sigma) ip, control animals with sterile physiological saline (twice a week 0.5 ml / animal ip). Treatment with test substance (once a day in 5 ml / kg po solvent consisting of 20% Cremophor, 10% Transcutol and 70% H 2 O) was carried out in parallel with the pig serum treatment. After seven weeks of treatment, the animals were sacrificed and the livers were removed to quantify the collagen content.
- test substance once a day in 5 ml / kg po solvent consisting of 20% Cremophor, 10% Transcutol and 70% H 2 O
- transverse tissue cylinders (approx. 10 x 2 mm) were punched out of the right anterior lobe of the liver. Frozen sections were stained with 0.1% picrosirius red solution for the detection of scar collagen caused by liver fibrosis.
- the OH-proline values agree very well with the results of the morphometric fibrosis measurement:
- the pig serum treatment leads to a pronounced collagen accumulation in the liver without simultaneous administration of substances.
- the formation of this collagen deposition is reduced by substance treatment depending on the dose.
- the present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain the compounds according to the invention, in particular the compounds of the general formula (I), and processes for the preparation of these preparations.
- the active ingredient can optionally also be present in microencapsulated form in one or more of the carriers mentioned above.
- the therapeutically active compounds in particular the compounds of the general formula (I), should be present in the pharmaceutical preparations listed above in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture to be available.
- the pharmaceutical preparations listed above can also contain further active pharmaceutical ingredients.
- the active ingredient (s) according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg, kg body weight per 24 hours, optionally in the form of several Single doses to be administered to achieve the desired results.
- An individual guest contains the active ingredient (s) according to the invention preferably in amounts of about 1 to about 80, in particular 3 to
- BABA n-butyl acetate / n-butanol / glacial acetic acid / phosphate buffer pH 6
- Example II and 312 mg (1.90 mmol) of methyl 4-formylbenzoate in 5 ml of dichloromethane are mixed with 806 mg (3.80 mmol) of sodium triacetoxyborohydride under argon and stirred overnight at room temperature.
- the reaction mixture is then carefully saturated with 10 ml. NaHCO 3 solution added, diluted with dichloromethane and the organic phase separated. The organic phase is dried over MgSO 4 and evaporated.
- 429 mg (1 mmol) of 4 - ( ⁇ [3- (4-cyclohexylphenoxy) benzyl] amino ⁇ methyl) benzoic acid methyl ester are obtained as a colorless oil.
- the aqueous solution obtained is first washed with ether and then adjusted to pH 4 to 5 with 1 molar hydrochloric acid. It is extracted with ethyl acetate. The organic phase is dried over Na 2 SO 4 . After filtration and evaporation, 107 mg of crude product are obtained, which are purified by HPLC. The product fractions are combined and it is recrystallized from methanol. It will
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002439939A CA2439939A1 (en) | 2001-03-01 | 2002-02-18 | Novel aminodicarboxylic acid derivatives |
EP02718141A EP1368302B1 (de) | 2001-03-01 | 2002-02-18 | Neuartige aminodicarbonsäurederivate |
US10/469,557 US6939990B2 (en) | 2001-03-01 | 2002-02-18 | Derivatives of dicarboxylic acid having pharmaceutical properties |
DE50212761T DE50212761D1 (de) | 2001-03-01 | 2002-02-18 | Neuartige aminodicarbonsäurederivate |
JP2002569780A JP4074520B2 (ja) | 2001-03-01 | 2002-02-18 | 新規なアミノジカルボン酸誘導体 |
US11/209,517 US7329777B2 (en) | 2001-03-01 | 2005-08-22 | Methods for treating heart failure, thromboembolic disorders, and pulmonary fibrosis |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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DE10109859.6 | 2001-03-01 | ||
DE10109859A DE10109859A1 (de) | 2001-03-01 | 2001-03-01 | Neuartige Aminodicarbonsäurederivate |
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US10469557 A-371-Of-International | 2002-02-18 | ||
US11/209,517 Continuation US7329777B2 (en) | 2001-03-01 | 2005-08-22 | Methods for treating heart failure, thromboembolic disorders, and pulmonary fibrosis |
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WO2002070459A1 true WO2002070459A1 (de) | 2002-09-12 |
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PCT/EP2002/001682 WO2002070459A1 (de) | 2001-03-01 | 2002-02-18 | Neuartige aminodicarbonsäurederivate |
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US (2) | US6939990B2 (de) |
EP (1) | EP1368302B1 (de) |
JP (1) | JP4074520B2 (de) |
CA (1) | CA2439939A1 (de) |
DE (2) | DE10109859A1 (de) |
ES (1) | ES2312556T3 (de) |
WO (1) | WO2002070459A1 (de) |
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- 2002-02-18 JP JP2002569780A patent/JP4074520B2/ja not_active Expired - Fee Related
- 2002-02-18 CA CA002439939A patent/CA2439939A1/en not_active Abandoned
- 2002-02-18 DE DE50212761T patent/DE50212761D1/de not_active Expired - Lifetime
- 2002-02-18 US US10/469,557 patent/US6939990B2/en not_active Expired - Fee Related
- 2002-02-18 WO PCT/EP2002/001682 patent/WO2002070459A1/de active IP Right Grant
- 2002-02-18 ES ES02718141T patent/ES2312556T3/es not_active Expired - Lifetime
- 2002-02-18 EP EP02718141A patent/EP1368302B1/de not_active Expired - Lifetime
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Also Published As
Publication number | Publication date |
---|---|
US7329777B2 (en) | 2008-02-12 |
US20040110840A1 (en) | 2004-06-10 |
US6939990B2 (en) | 2005-09-06 |
JP4074520B2 (ja) | 2008-04-09 |
JP2004529896A (ja) | 2004-09-30 |
DE10109859A1 (de) | 2002-09-05 |
ES2312556T3 (es) | 2009-03-01 |
EP1368302A1 (de) | 2003-12-10 |
CA2439939A1 (en) | 2002-09-12 |
EP1368302B1 (de) | 2008-09-10 |
US20050288366A1 (en) | 2005-12-29 |
DE50212761D1 (de) | 2008-10-23 |
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