Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

• the present invention relates to a medicament, particularly to an N-[(substituted 5-membered heteroaryl) carbonyl] guanidine derivative or a salt thereof, which has an inhibitory effect on Na + / H + exchanger.
• Intracellular reactions are affected by PH, and the H + gradient drives ATP synthesis. Therefore, it is important that the intracellular pH is accurately controlled in order to perform an accurate cell function.
• the Na exchanger is a type of mechanism that controls intracellular pH, but it has recently been shown that it is closely involved in the activation of cells by various physiologically active substances. Furthermore, it has been noticed that the enhanced activity of Na + ZH + exchanger is related to the onset and maintenance of certain pathological conditions, or worsening. For example, myocardial disorder and rebreathing disorder (Scholtz. Et al Br. J. Pharmacol. 109, 562 (1993)), hypertension (Rosskof D. et al Hypertens.
• amyloid As an N a + / ⁇ + exchanger inhibitor, amyloid, a kind of K + -retentive diuretic, has been known for a long time, and it has been reported that amyloid has an antiarrhythmic effect. (Mol. Pharmacol. 25, 131-136 (1984)). However, it has no specificity of action, has antiarrhythmic effects, and also has antihypertensive and salivary effects, which are unfavorable and side effects of arrhythmia treatment.
• a lipide derivative exhibits an Na + / H + exchanger inhibitory activity and an antiarrhythmic effect (for example, J. Membrane Biol. 105, G21 (1988)).
• pyridylcarboxylguanidine derivatives (WO94Z267909), which have Na + ZH + exchanger inhibitory activity and anti-disruption activity, and furyl, chenyl and pyrrolylcarbone Luguanidine derivative (EP 667 695) No., has been reported.
• EP 5 376 96 discloses that heterobiaryl derivatives which may be substituted with a guanidinocarbonyl group are claimed as carboxyl substituents, such as sulfo groups and acyl groups. It has a structural feature in that it always has a group. Further, no specific compound having a thiazolylcarbonylguanidine skeleton has been disclosed. Furthermore, the compounds, mosquitoes disclosed to have anti-coagulation activity, no no description N a + ZH + exchanger inhibitory action.
• N — [(2-phenyl-4-oxazolyl) carbonyl] guanidine has an analgesic and anti-inflammatory effect (JCS, p405 (1961)), and N — [(5—etkin-1— [4—oxazolyl) carbonyl] guanidine is disclosed as a synthetic intermediate (Synthesis, 10, 8379 (1993)). There is no report on the inhibitory effect of these compounds on the Na-exchanger. . Disclosure of the invention
• the present inventors have conducted intensive studies on compounds having an Na +, H + exchanger inhibitory action, and as a result, have found that a carbon dioxide having a 5-membered heteroaryl group having 2 to 3 ring heteroatoms.
• luguanidine derivatives have good Na + / H + exchanger inhibitory activity, have excellent oral absorption, and are useful as preventive, therapeutic or diagnostic agents for diseases involving Na + / H + exchangers.
• the present invention has been completed.
• the present invention provides a compound represented by the following general formula (I), which has a structural [at the point of having a 5-membered heteroarylcarbonylguanidine having 2 to 3 ring heteroatoms as a basic skeleton. — [(Substituted 5-membered heteroaryl) carbonyl] A guanidine derivative or a salt thereof. (I)
• R 1 substituted, may be substituted or substituted !, may be a 5- or 6-membered teloarylene group,
• R 2 H, a halogen atom, a lower alkyl optionally substituted with a halogen atom, a lower alkyl-10-, a lower alkyl-S-, or an optionally protected amino
• R 3 and R 4 a lower alkyl group optionally substituted with H or a halogen atom.
• a group represented by the formula: Z—B—A—R 5 (wherein Z is ⁇ , S, NR 7 C0, NR 8 S0 2 , NR 9 , SO 2 , SO, CO or a bond, B is a phenylene group or a bond
• A is a lower alkylene, lower alkylene- ⁇ lower alkylene, lower alkenylene or lower alkynylene group which may be substituted with one or more groups selected from the group consisting of a halogen atom and an optionally protected hydroxy group.
• R 5 is H; halogen; nitro; cyano; cycloalkyl; optionally protected hydroxy; optionally protected amino; optionally protected mono-lower alkyl-amino; di-lower alkyl-amino; Di-lower alkyl-lower alkyl which may be substituted with an amino group, protected or unprotected hydroxy, lower alkyl- ⁇ -, optionally protected amino, optionally protected mono-lower alkylamino, And at least one group selected from the group consisting of di-lower alkyl-amino groups A nitrogen-containing saturated heterocyclic ring which may be substituted and the ring nitrogen atom may be protected with a protecting group for an amino group; or a lower alkyl which may be substituted with a di-lower alkyl-amino group.
• R 5 is from H, halogen, 0 or N atom, and A and B are both bonds, Z represents a bond.
• R 1 force, 'group (wherein the formula one Z- B- A- R 5, Z is 0, NHCO, the NHS 0 2, S 0 2 or a bond, B is a Fuweniren groups or bonds, A Is a lower alkylene, lower alkylene-0-lower alkylene, lower alkenylene group, or a bond;
• R 5 is H, a halogen atom, nitro, an optionally protected hydroxy, an optionally protected amino, or a protected Mono-lower alkyl-amino, di-lower alkyl-amino, optionally substituted with lower alkyl
• N— [(substituted to 5-membered) is a aryl group which may be substituted with one or more substituents selected from the group consisting of or an unsubstituted 5- to 6-membered heteroaryl group.
• Terrolyl) carbonyl is a aryl group which may be substituted with one or more substituents selected from the group consisting of or an unsubstituted 5- to 6-membered heteroaryl group.
• Terrolyl) carbonyl is guanidine derivative or a pharmaceutically acceptable salt thereof;
• More preferred compounds include R 1 , amino-lower alkylene-0—, mono-lower alkylamino-lower alkylene—0—, di-lower alkylamino—lower alkylene—0—, HO—lower alkylene—0—, di-lower Alkylamino primary alkylene-CONH-, a nitrogen-containing saturated heterocycle which may be substituted on the ring nitrogen atom with a lower alkyl group-CONH-, and a lower alkyl group on a ring nitrogen atom which may be substituted with a lower alkyl group , Substituted with one substituent selected from the group consisting of nitrogen-containing saturated heterocycle—lower alkylene-1 0—, and further substituted with one or more substituents selected from the group consisting of lower alkyl and halogen atoms.
• the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising a ⁇ -[(substituted 5-membered heteroaryl) potassium rubonyl] guanidine derivative or a salt thereof represented by the general formula (I) and a pharmaceutically acceptable carrier, It also relates to Na + / ⁇ + exchanger inhibitors.
• the present invention relates to a pharmaceutical composition which is an agent for preventing or treating a disease.
• a pharmaceutical composition which is an agent for preventing or treating a disease.
• lower means a straight or branched hydrocarbon chain having 1 to 6 carbon atoms, unless otherwise specified.
• the “lower alkyl group” is preferably an alkyl group having 1 to 3 carbon atoms, particularly preferably a methyl and ethyl group.
• the "lower alkenyl group” is preferably a vinyl, aryl, 1-propenyl, isopropenyl, 1-buteninole, 2-butenyl or 3-butenyl group.
• the “lower alkynyl group” is preferably an ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl and 1-methyl-2-propynyl group.
• the "5- to 6-membered heteroaryl group” is a 5- to 6-membered monocyclic heteroaryl group containing 1 to 4 heteroatoms selected from 0, S and N, and preferably furyl. , Cenyl, pyrrolyl, imidazolinole, virazolinole, thiazolinole, isotizazolinole, oxazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, birazinyl groups, and more preferably the thienyl and tetramidyl groups.
• aryl group means an aromatic hydrocarbon ring group, preferably an aryl group having 6 to 14 carbon atoms, more preferably a phenyl and naphthyl group.
• Halogen atoms include F, C 1, Br and I.
• the “lower alkyl group substituted with a halogen atom” is a group in which one or more of the above halogen atoms are substituted at any position of the above lower alkyl group, and is preferably CH 1 F or CHF. 2, one CF 3, one CH 2 C 1, - CHC 1 2, one CF 2 CF 3, one CH 2 CF 3, and - a CH 2 CH 2 C 1.
• Cycloalkyl group is preferably a cycloalkyl group having 3 to 8 carbon atoms, particularly preferably cyclopropyl, cyclopentyl and cyclohexyl groups. You.
• the “nitrogen-containing saturated heterocyclic group” is a 5- to 8-membered nitrogen-containing saturated heterocyclic group having at least one ring nitrogen atom, and may further have 0 or S as a ring atom. It may have a crosslink. Preference is given to pyrrolidinyl, piperidinole, morpholinyl, piperazinyl, pyrazolidinyl, imidazolidinyl and homopiperazinyl groups, in which the ring nitrogen atom may be protected by a protecting group for an amino group.
• the bond may be a ring carbon atom or a ring nitrogen atom, and may be out of alignment.
• the group having a cross-link is preferably a quinuclidinyl, a 1-azabicyclo mouth [2.2.1] heptyl, and a 1-azabicyclo [3.2.1] octyl group.
• Particularly preferred are piperidyl, morpholinyl, pyrrolidinyl and quinuclidinyl groups.
• the "mono-lower alkylamino group” is preferably a methylamino, ethylamino or propylamino group.
• the “di-lower alkylamino group” is preferably a dimethylamino, getylamino, dipropylamino, methylethylamino and methylpropinoleamino group, and among them, a dimethylamino group is particularly preferred.
• the “phenylene group” is a divalent group in which an arbitrary hydrogen atom of the phenyl group is a bond, and includes 1,4-1,1,3- and 1,2-phenylene groups. It is preferably a 1,4-fuunylene group. "Bond” means that the groups are not present and the groups on both sides are directly bonded.
• the “lower alkylene group” in A is a divalent group in which an arbitrary hydrogen atom of the lower alkyl group has a bond, and is preferably a methylene, ethylene, propylene, tetramethylene, pentamethylene or hexamethylene group. It is.
• the lower alkylene group in A is particularly preferably a propylene group or a tetramethylene group.
• the “lower alkenylene group” and “lower alkynylene group” are divalent groups in which any hydrogen atom of lower alkenyl and lower alkynyl groups is a bond, and preferably, probenylene, It is a group having 3 to 4 carbon atoms such as butenylene, propynylene, and petynylene.
• Protecting groups for “optionally protected hydroxy group”, “optionally protected amino group” and “optionally protected mono-lower alkyl-amino group” include, for example, green And Wuts 3 ⁇ 4 ⁇ “Protective Group Organic Synthesis”, 2nd edition, etc., as long as it is a protecting group used by those skilled in the art, but is preferably protected by a hydroxy group.
• Examples of the group include acetyl, benzoyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, and tetrahydroviranyl groups.
• Protecttecting groups for the amino and mono-lower alkylamino groups include formyl, trifluoroacetyl, t 1-butoxycarbonyl, benzyloxycarbonyl, triflenylmethyl, benzyl and phthalimid groups.
• the protecting group for an amino group on the ring nitrogen atom of the nitrogen-containing saturated heterocyclic ring may also be the same as the base described above.
• the compounds of the present invention include those in which a cis-trans (or (E) -form or (Z) -form) geometric isomer is present based on a double bond.
• the present invention includes those isolated ((E) -form or (Z) -form) or mixtures thereof.
• the compounds of the present invention exist as tautomers based on the presence of a guanidinocarbonyl group, and the present invention encompasses those separated or mixtures thereof.
• geometric isomers and tautomers may exist depending on the types of substituents.
• the present invention encompasses separated or mixed forms of these isomers.
• the compound of the present invention may have an asymmetric carbon atom, and an (R) -form or (S) -form optical isomer based on this may exist.
• the present invention embraces all mixtures and isolated forms of these optical isomers.
• the compounds of the present invention may form acid addition salts.
• the salt is not particularly limited as long as it is a pharmaceutically acceptable salt.
• inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, Acid addition with organic acids such as acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, and glutamic acid And the like. Particularly preferably It is a salt with hydrochloric acid or methanesulfonic acid.
• the present invention provides a compound of the present invention
• the compounds of the present invention and salts thereof can be produced by applying various known synthetic methods by utilizing the characteristics based on the basic skeleton or the type of the substituent.
• the typical manufacturing method is described below.
• the compound (I) of the present invention can be produced by reacting a carboxylic acid represented by the general formula (II) or a reactive derivative thereof with guanidine.
• a carboxylic acid represented by the general formula (II) or a reactive derivative thereof with guanidine.
• the carboxylic acid derivative (II) has functional groups active in the reaction, such as an immobilized droxy group or an amino group, these functional groups are protected with a protecting group in advance, and this reaction is carried out.
• the compound (I) of the present invention can be obtained by removing the protecting group.
• examples of the reactive derivative of a carboxylic acid include acid halides (acid chloride, acid bromide, etc.), acid anhydrides, active esters, lower alkyl esters, aryl lower alkyl esters, acid azides, and the like.
• the acid anhydride a symmetric acid anhydride or a mixed acid anhydride is used.
• the mixed acid anhydride include ethyl ethyl carbonate, benzyl carbonate, funicyl carbonate, and isovaleric acid. And the like.
• active esters examples include p-nitrophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimid ester, N-hydroxypiperidine ester, 2-hydroxyphenyl ester, 2-pyridyl Commonly used products such as thiol ester and 1-benzotriazolyl ester are exemplified.
• Such a reactive derivative of a carboxylic acid can be easily obtained from the corresponding carboxylic acid according to a commonly used general method.
• reaction When reacting with an acid halide or an acid anhydride, the reaction can be carried out in a solvent under cooling or at room temperature in the presence of a base or an excess of guanidine.
• an inorganic base such as sodium hydroxide, or triethylamine
• organic bases such as diisopropylethylamine, N-methylmorpholine and pyridine.
• the solvent examples include aromatic hydrocarbon solvents such as benzene and toluene; ether solvents such as tetrahydrofuran (THF) and 1,4-dioxane; halogenated hydrocarbon solvents such as dichloromethane and chloroform; Examples include amide solvents such as N-dimethylformamide (DMF) and basic solvents such as pyridine. These solvents are used alone or in combination of two or more. The solvent should be appropriately selected according to the type of the starting compound and the like.
• the reaction can be carried out in a solvent in the presence of an equimolar or excess guanidine under cooling or at room temperature or under heating. In some cases, after the solvent is distilled off, heating at about 130 ° C. for a short time can also be performed.
• the solvent include the above-mentioned ether solvents and amide solvents.
• an alcoholic solvent may be further used.
• the reaction is preferably carried out in the presence of a condensing agent.
• the condensing agent include dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC), benzotriazo-l-luyl tris (dimethylamino) phosphonium 'hexafluorophosphoride salt (BOP), diphenylphosphonyl azide (DPPA), 1,1′-carbonylbis-1H-imidazole (CDI) and the like.
• N-hydroxysuccinimide Additives such as (HONS u) and 1-hydroxybenzotriazole (HOB t) may be added.
• solvent examples include the aromatic hydrocarbon solvents, ether solvents, halogenated hydrocarbon solvents, amide solvents, and basic solvents. These solvents are used alone or in combination of two or more.
• the carboxylic acid of (substituted 5-membered heteroaryl) carboxylic acid or its reactive derivative (II) as the starting compound in the above-mentioned production method or its reactive derivative can be easily synthesized by a method known to those skilled in the art. .
• R 1 has the above-mentioned meaning
• R 2 is an alkyl group optionally substituted by H or F
• M is a halogen atom
• R 6 is a lower alkyl group, aryl-lower alkyl
• a carboxylic acid protecting group such as a group.
• a thioamide represented by the general formula (III) and a 3-oxocarboxylic acid ester represented by the general formula (IV) or a 2-oxocarboxylic acid ester represented by the general formula (VII) are converted into an alcohol solvent, other acetonitrile, dioxane, or the like.
• an inert solvent such as benzene, toluene, etc.
• a thiazolylcarboxylic acid ester of the general formula (V) or (VIII) can be obtained.
• compounds of the general formula (X) or (XI) may be produced depending on the conditions, and these compounds should be subjected to heat treatment in acetic acid or toluene in the presence of organic sulfonic acid at room temperature or higher.
• the thiazolyl carboxylate of the formula (V) or (VIII) can be obtained. Further, the thiazolyl carboxylate of the formula (V) or (VIII) can be subjected to hydrolysis or the like to obtain the compound of the formula (VI) Alternatively, the thiazolyl carboxylic acid of (IX) can be obtained. In the reaction, protection and deprotection are required depending on the types of substituents of the starting compound, and the method is easily understood by those skilled in the art. Subsequent to this reaction, addition and substitution of a substituent can be carried out by a conventional method to introduce a desired substituent.
• the carboxylic acid ester can be converted to a carboxylic acid by a conventional method.
• Fhe Chem istryof He terocyclic and ompounds (E d) tors: A. We issbergerand EC Ta ylor), and John Wiley & Sons) can be easily synthesized according to the method described in the literature.
• the reaction product obtained by each of the above processes is a free compound, its salt, Is isolated and purified as various solvates.
• the salt can be produced by subjecting it to a usual salt formation reaction. Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography.
• Various isomers can be isolated by a conventional method utilizing the physicochemical difference between the isomers.
• the optical isomers can be separated by a general racemic resolution method, for example, fractional crystallization or close chromatography.
• Optical isomers can also be synthesized from appropriate optically active starting compounds. Industrial applicability
• the compounds of the present invention are useful as active ingredients in pharmaceutical preparations.
• it has an inhibitory activity on the cellular sodium-proton alternating transport mechanism (Na + ZH + exchanger), and thus prevents various physiological activities involving Na + / H + exchangers and diseases related to pathological conditions. It is useful as a therapeutic or diagnostic agent.
• diseases caused by increased Na + ZIT exchangers such as hypertension (eg, essential hypertension, or renal failure, primary aldosteronism, adrenal oxygen deficiency, Liddle disease, Gordon disease) Key, renal tubular acidosis (RTA) type IV, low renin hypoaldosteronism, secondary hypertension associated with primary diseases such as bilateral renal vascular hypertension), arrhythmia, angina pectoris, cardiac hypertrophy, ischemic relapse Organ damage due to perfusion (eg, damage due to reperfusion of cardiac ischemia, damage due to surgical procedures (eg, transplantation or PTCA)), damage due to decreased blood flow during transplantation, myocardial infarction, prevention of myocardial infarction recurrence (eg, Secondary prevention of myocardial infarction, prevention of cardiac accident recurrence), protection of organs during ischemia and improvement of symptoms (eg, heart, brain, kidney, gastrointestinal, lung, liver, skeletal muscle ischemia-related disorders, especially
• N a + / ⁇ + exchanger when loaded with acid platelet H + ions to drain out of the cells occurs.
• activation of the Na + ZH + exchanger will simultaneously take up Na + ions into the cell.
• the influx of Na + ions into cells draws in water molecules due to osmotic pressure gradients, and as a result, platelet infiltration.
• the platelet swelling reaction is detected by absorption using a powerfully attached spectrophotometer (u-3000, Nisshosho) with a personal computer (PC-9821 Xe, NEC). That is, a plastic cuvette containing a propionic acid solution (940-1) as an acid load is attached, and PRP (141) is added to the cuvette, and the absorbance is measured immediately. The measurement wavelength is 680 nm. The absorbance change appears as an exponential decrease that reaches a plateau in 3-4 minutes. Study drug is 1 OmM in DMSO After dissolving in water, dilute to the optimal concentration with propionic acid solution and use as the propionic acid solution containing the test drug. Swelling reaction by reduction of the external solution Na + ion concentration, or an increase in the concentration of N a + / H + test drug with exchanger inhibitory action, it is suppressed.
• the composition of the peptic acid solution is as follows.
• HE PES N- (2-hydroxyethyl) piperazine-N'-2-ethanesulfonic acid
• the change per unit time is calculated from the obtained absorbance change and expressed in logarithm.
• the rate constant of the swelling reaction is determined from the initial gradient of this graph. It has been confirmed that this rate constant does not depend on platelet count.
• K i value the drug-specific inhibition constant (K i value) is calculated by performing a Dickson plot (X-axis: drug concentration, Y-axis: reciprocal of the rate constant) of the rate constant at each concentration of the test drug.
• a pharmaceutical composition comprising the compound (I) of the present invention or a salt thereof and a pharmaceutically acceptable carrier is a compound of the formula (I) or a salt thereof; It can be prepared by a commonly used method using pharmaceutical carriers, excipients and other additives usually used for formulation. Administration may be oral, such as tablets, pills, capsules, granules, powders, or liquids, or parenteral, such as injections such as intravenous and intramuscular injections, suppositories, and transdermals. It may be hot.
• Tablets, powders, granules and the like are used as the solid composition for oral administration according to the present invention.
• one or more active substances may be used, and at least one inert diluent, such as lactose, mannitol, glucose It is mixed with hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylidene, and magnesium aluminate metasilicate.
• the composition may be formulated in a conventional manner with additives other than inert diluents, such as lubricating agents such as magnesium stearate, disintegrating agents such as calcium cellulose monoglyconate, and stabilizing agents such as lactose.
• solubilizing agents such as glutamic acid or aspartic acid. If necessary, tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropyl cellulose, hydroxypropinolemethylcellulose phthalate, or a film of a gastric or enteric substance.
• Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and are commonly used inert diluents, eg, purified. Contains water and ethanol.
• the composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, flavoring agents, and preservatives.
• Injections for parenteral administration include sterile aqueous or non-aqueous solutions and suspensions
• Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline.
• water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysonolate 80 and the like.
• Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, and stabilizing agents (eg, lactose) and solubilizing agents (eg, glutamic acid, aspartic acid). But you can. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. They can also be used in the manufacture of sterile solid compositions which are dissolved in sterile water or sterile injectable solvents before use.
• the daily dose is about 0.001 to 10111 ⁇ Z kg per body weight, which is administered once or in 2 to 4 doses.
• the daily dose is preferably about 0.001 to lmgZkg per body weight, and it is administered once or several times a day. The dose is determined as appropriate for each individual case, taking into account symptoms, age, sex, and the like.
• SCG silica gel gel chromatography
• S01B saturated aqueous sodium hydrogen carbonate solution
• S-Mg anhydrous magnesium sulfate
• S-Na anhydrous sodium sulfate.
• o-Methylbenzoic acid is treated with potassium hydroxide in methanol, then 2-ethyl chloroacetoacetate is added, and the mixture is reacted under heating to reflux to obtain 1-ethoxycarbonyl 2-oxopropyl 2-methylbenzoate as a colorless oil. I got it. This is dissolved in acetic acid, treated with ammonium acetate, and the product is subjected to SCG. 4-Methyl-2-0-tolyloxazol-5-ethyl carboxylate and 4-methyl-2-0-tolylimidazo 1-ethyl 5-carboxylate was obtained as a colorless oil.
• Each of these compounds is treated with an aqueous solution of 1 N—NaOH in ethanol to give a) 4-methyl-2-o_tolyloxazol-5-colorless crystals of carboxylic acid and b) 4—methyl-2- A colorless oil of 0-tolylmidazolu-5-potassium rubonic acid was obtained.
• Example 7 49 mg of imidazole was dissolved in 3 ml of DMF, and 28 mg of 60% sodium hydride was added, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added 240 mg of 2- [3- (2-bromoethoxy) phenyl] -14-methylthiazo-1-yl 5-carboxylate, and the mixture was stirred at 70 ° C. for 3 hours while heating. After dissolving 61 mg of guanidine hydrochloride in 3 ml of DMF, adding 26 mg of sodium hydride, and stirring at room temperature for 1 hour, the solution was added to the above reaction solution, and heated at 80 ° C. Stirred for hours.
• Example 2 The same treatment as in Example 1 was carried out using 20 mg of 3-tert-butoxycarbonylamino-1-monophenyl-1H-virazo-roux-carboxylic acid, and an excess amount of 4 N-hydrogen chloride in ethyl acetate. A solution of -ethyl acetate was added, and 154 mg of the precipitated solid was collected by filtration. 74 mg of this solid was added to a mixed solvent of methanol-chloroform (1:19, v / v), and the mixture was washed successively with a 1N—NaOH aqueous solution and a saturated saline solution.
• the organic layer was dried over S—Mg and concentrated under reduced pressure to obtain 15 mg of N — [(3-amino-1-phenyl-1 fi-pyrazol-1-yl-4-carbonyl) carbonyl] guanidine.
• the compounds of Examples 14 to 45, 49 to 65, 67 to 82 and 85 to 91 shown in Tables 5 to 9 were prepared in the same manner as in Example 1, 3 or 4, and 6 ⁇ 4 8, 6 6,
• the compounds of 83 and 84 were produced in the same manner as in Example 11 or 12. If desired, after the reaction, the product was treated with methanesulfonic acid or a 4N-hydrogen chloride / ethyl acetate solution to obtain a product as a salt.
• Tables 10 to 17 specifically show other compounds included in the present invention. These compounds can be easily prepared in a manner similar to that described in the above Examples or in the preparation methods, or by applying some modifications obvious to those skilled in the art.
• Table 1 shows the physicochemical properties of the reference compound
• Tables 2 to 4 show the structure and physicochemical properties
• Tables 5 to 9 show the structure and physicochemical properties of the example compound.
• the symbols in the table have the following meanings.
• TBDMS0 tert-butyldimethylsilyloxy
• Sul methanesulfone
• NMR-1 2.22 (63 ⁇ 4s), 2.36-2.52 (4H, m), 5.81 (IH, dt), 6.45 (IH, d), 7.39-7.59 (4H, m) .7-b) NMR-1: 2.27 (6H, s), 2.37-2.51 (4H, m), 6.24-6.36 (IH, m), 6.42 (IH, d), 7.38 (IH, t), 7.47

Priority Applications (1)

Applications Claiming Priority (2)

Publications (1)

Family

ID=18290844

Family Applications (1)

Country Status (4)

Cited By (10)

Citations (4)

• 1997
  • 1997-12-10 ZA ZA9711102A patent/ZA9711102B/xx unknown
  • 1997-12-10 AR ARP970105802 patent/AR009435A1/es unknown
  • 1997-12-15 AU AU54119/98A patent/AU5411998A/en not_active Abandoned
  • 1997-12-15 WO PCT/JP1997/004605 patent/WO1998027061A1/ja active Application Filing

Patent Citations (4)

Also Published As

Similar Documents

Legal Events