JPS6139947B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides certain 2-phenyl-5-(5-1H
-tetrazolyl)pyrimidin-4-(3H)-one derivative and its production method. Compounds of the invention are useful as anti-allergic agents. Various drugs are used to treat allergic reactions such as bronchial asthma and allergic rhinitis, which are believed to be caused primarily by antigen-antibody interactions. For bronchial asthma, one of the most severe allergic diseases, bronchodilators such as theophylline, isoproterenol, epinephrine and atropine are mainly used to relieve symptoms. However, these drugs cause unwanted side effects, such as cardiac stimulation and gastrointestinal distress. Adv.in by JSG Cox et al.
The recent introduction of disodium cromoglycate, described in Drug. the medium being
For example, drugs are used to prevent the production of histamine and SRS-A (a slow-acting substance that causes anaphylaxis). Although great progress has been made in the preventive treatment of bronchial asthma without side effects on the heart and blood vessels, disodium cromoglycate has the major disadvantage that it cannot be absorbed orally and must be administered by inhalation. The 2-phenyl-5-(5-1H-tetrazolyl)pyrimidin-4(3H)-one derivatives of the present invention are illustrated with reference to structurally related compounds known in the art. 1 formula The preparation of unsubstituted acids and esters with the formula R in which R represents hydrogen or ethyl is described by S. Ruhemann in Ber. 30, 821 (1897). 2 formulas (wherein R represents hydrogen or ethyl, and X represents methyl or methoxy, respectively) p-methylphenyl and p-methoxyphenyl substituted esters have been described by Mitter et al. in J. Chem. Soc., 123, 2179 (1923) and Quart.J.Indian Chem.Soc., 2 , 61 (1925)
It is described in. 3. Shen et al., U.S. Patent No. 3,660,403, general formula: (wherein R[-Ar]- is, inter alia, substituted phenyl, Y is hydrogen, and X is any of a variety of substituents including hydroxy, alkoxy, or N-heterocyclic). are doing. Although it has been announced that these compounds have anti-inflammatory, antipyretic and analgesic activities, nothing has been said about their use as anti-allergic agents. 4 U.S. Patent No. 3,883,653 has the formula: (In the formula, m is 0 or 1 and Ar is substituted with pyridyl, thienyl, furyl, phenyl, hydroxy, methyl, methoxy, nitro, chloro, fluoro, 3,4-dimethoxy, 3,4,5-trimethoxy, or alkanoylamino) (representing phenyl). 5 U.S. Patent No. 3,448,107 has the formula: (In the formula, X ¹ and X ² are hydroxy, phenyl, p-
Chlorophenyl, p-methylphenyl and p
It represents various substituents including -aminophenyl, and n is an integer of 0 to 4. ) is described as a lipid regulator. There is no mention of compounds according to the invention in which n is 0 in the above formula and the pyrimidinyl ring system is substituted in the 4-position by hydroxy and in the 2-position by phenyl substituted. The present invention provides novel therapeutically useful 2-(substituted) phenyl-5-(5-1H-tetrazolyl)-
The present invention relates to pyrimidin-4(3H)-one derivatives, methods for producing them, pharmaceutical compositions containing them, and methods for treating diseases caused by allergies by administering these derivatives or pharmaceutical compositions to animals. The compounds and compositions according to the invention are of particular value for the prophylactic treatment of allergic bronchial asthma by oral administration. Compounds of the invention have the formula: [In the formula, R ¹ , R ² and R ³ may be the same or different and each represents hydrogen, lower alkoxy, -O-lower alkenyl, cyclopropylalkyloxy, amino,
nitro or di(lower) alkylamino, but not all of them are the same except when R ¹ , R ² and R ³ all represent lower alkoxy, and their pharmaceutical use It is an acceptable salt. The above R ¹ R ² and R ³ substituents may be located at any position on the phenyl ring, ie, at any position from 2 to 6.
The substituents may be the same or different, but R ¹ =
The only compounds within the scope of this invention where R ² = R ³ are
This is the case where R ¹ , R ² and R ³ are all lower alkoxy. Among the substituents mentioned above, specific examples of lower alkoxy, -O-lower alkenyl, cyclopropylalkyloxy, and di(lower) alkylamino are as follows: (d) C ₁ -C ₁₀ alkoxy group; Lower alkoxy, the alkyl portion of which is as defined in (b) above. For example, methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, n
-pentyloxy, isopentyloxy, n-
Examples include hexyloxy. The preferred one is C _1
-C6 alkoxy and _C1 - _C4 alkoxy groups are most preferred. (b) -O-lower alkenyl group having a _C2 - _C10 alkenyl moiety. Examples include vinyloxy, allyloxy or isopropenyloxy. The best is allyloxy. (c) Cyclopropyl lower alkyloxy, especially a cyclopropyl-(C ₁ -C ₆ )alkyloxy group. Examples of this are cyclopropylmethyloxy and cyclopropylethyloxy. (d) di-C ₁ -C ₁₀ for di(lower)alkylamino;
Alkylamino groups are particularly dimethylamino and diethylamino. A preferred embodiment of the invention has the formula: Pharmaceutically acceptable compounds of the formula (wherein R ¹ and R ² may be the same or different and are as defined in the general formula, but R ¹ must not be hydrogen) and compounds of the formula ' Contains salts. Preferred compounds with the formula ′ and the number of salts are R ¹
is lower alkoxy, i.e. straight or branched C ₁
-C ₁₀ alkoxy, -O-lower alkenyl or cyclopropylalkyloxy.
Preferred types of this group are the following compounds and salts of formula '. (a) Best are those in which R ¹ is -O-C ₁ -C ₆ alkyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or sec-butoxy. (b) R ¹ is -O-C ₂ -C ₆ alkenyl;
Allyloxy is the best. (c) Those in which R ¹ is cyclopropylalkyloxy, cyclopropylmethoxy are the best.
Preferred R ² substituents for compounds with formula ' are hydrogen, lower alkoxy, -O-lower alkenyl, cyclopropylalkyloxy, nitro,
Amino or di(lower) alkylamino.
The most preferred R ² substituents are hydrogen, lower alkoxy, nitro, amino or di(lower)alkylamino. A further preferred embodiment of the present invention has the formula: (In the formula, R ¹ and R ² may be the same or different and each is as defined in the compound of the general formula, but R ¹ must not be hydrogen.) Includes pharmaceutically acceptable salts of the compounds. Preferred compounds and salts with the formula R ¹
is lower alkoxy, -O-lower alkenyl, or cyclopropylalkyloxy. Preferred types from this group are, in the formula "(a) R ¹ is -O-C ₁ -C ₆ alkyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, isobutoxy,
or sec-butoxy is best. (b) R ¹ is -O-C ₂ -C ₆ alkenyl;
Allyloxy is the best. (c) Those in which R ¹ is cyclopropylalkyloxy, cyclopropylmethoxy are the best. These are compounds and salts having the above formula. Preferred ^R substituents of the compounds having the formula are hydrogen, lower alkoxy, -O-lower alkenyl, cyclopropylalkyloxy, nitro, amino, or di( (lower) alkylamino. The most preferred R ² substituents are hydrogen, lower alkoxy, nitro, amino or di(lower)alkylamino. Particularly preferred compounds and salts of the formula ``in which R ¹ is methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, allyloxy or cyclopropylmethoxy, and
Such that R ² is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, allyloxy, cyclopropyl-methoxy, nitro, amino or dimethylamino. Another more preferred embodiment of the present invention has the formula: [In the formula, R ¹ , R ² and R ³ may be the same or different and each represents hydrogen, lower alkoxy, -O-lower alkenyl, cyclopropylalkyloxy, amino,
nitro or di(lower) alkylamino, but not all of them are the same except when R ¹ , R ² and R ³ all represent lower alkoxy, and pharmaceuticals thereof Contains acceptable salts. Preferred compounds and salts have the formula
Such that R ¹ is lower alkoxy, -O-lower alkenyl or cyclopropylalkyloxy. More preferred compounds and salts have the formula
Those in which R ¹ is -O-C ₁ -C ₆ alkyl, and those in which R 1 is -O-C ₂ -C ₆ alkenyl and cyclopropylalkyloxy, most preferably R ¹ or methoxy , ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or sec-butoxy; or allyloxy or cyclopropylmethoxy. The most preferred compounds and salts of the formula are those where R ¹ is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, allyloxy, or cyclopropylmethoxy. Since the compounds of this invention are amphoteric in nature, these compounds may be treated with substantially equimolar amounts of the selected acid or base in aqueous solution or in a suitable organic solvent such as methanol or ethanol. It can be converted into either acid or base salts. When these salts are used in the human body, the acids or salts used to produce pharmaceutically acceptable salts must, of course, form non-toxic salts. Suitable acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, citric acid, tartaric acid, oxalic acid, succinic acid, maleic acid, gluconic acid,
Ascorbic acid and p-toluene sulphonic. Pharmaceutically acceptable salts are ammonia,
It can be generated from bases such as organic amines and metal salts, including metal salts containing sodium, potassium, calcium, magnesium, barium and aluminum cations. Typical examples of such bases are ammonia, n-propylamine, and n-propylamine.
- primary amines such as butylamine, ethanolamine, ethylenediamine, cyclohexylamine, benzylamine, ethylamine, octylamine or tris(hydroxy-methyl)aminomethane; secondary amines such as di-ethanolamine;
tertiary amines such as tri-ethanolamine, N-methylpropyridine, N-methylmorpholine or 1,5-diazabicyclo-[4.3.0]-5-nonene, and sodium hydroxide. , potassium hydroxide, ammonium hydroxide, sodium ethoxide, potassium methoxide, magnesium hydroxide, calcium hydroxide or aluminum hydroxide. Those skilled in the art will recognize that the compounds of the formula have two tautomeric hydrogen atoms and therefore can exist in the following forms 1-6. All types exist to a greater or lesser extent and are in dynamic equilibrium with each other. Although the invention encompasses all of this type, structures are arbitrarily used herein for convenience to describe the compounds of the invention. The compounds of this invention can be prepared in a variety of alternative ways.
A good method is published by WG Finnegan et al. in J.Am.Chem.Soc., 80 , 3908 (1958), and is expressed by the formula: (wherein R ¹ , R ² and R ³ are as defined in the formula) in an inert solvent with an azide selected from the group consisting of ammonium, substituted ammonium, sodium and lithium azide. by reacting with a compound salt.
The nitrile and azide salts are used in approximately equimolar amounts. Examples of suitable azide salts are given by Finnegan in the above reference and include NaN ₃ , LiN ₃ ,
Includes azides _{such as NH4N3} , (n _{- C4H9 ) 2} - _{NH2N3 , C6H5NH3N3 and ( CH3} ) _4NH3 . The azide salt may be added directly or may be generated in situ by a double decomposition reaction between sodium azide and a suitable chloride salt such as LiCl, NH ₄ Cl, (CH ₃ ) ₄ NCl, etc. You may. Although the condensation reaction proceeds over a wide temperature range, in order to shorten the reaction time, it is preferable to use a high temperature, for example, from about 100° C. to the reflux distillation temperature of the solvent system. The inert organic solvent is generally any chemically inert solvent that has good solvent power for the azide salt. Examples of preferred solvents are dimethylformamide, dimethylacetamide, dimethylsulfoxide and hexamethylformamide. The best solvent is dimethylformamide. This condensation reaction is said to be susceptible to general acid catalysis, and the yield can be improved by adding reagents such as hydrazo acids, amine hydroazides, and Lewis acids such as BF ₃ to the sodium azide. . Upon completion of the reaction, the solvent is removed from the reaction mixture, the residue is diluted with water, and the mixture is acidified to recover the desired compound of formula to yield the tetrasol product. The product can be purified, for example by recrystallization from glacial acetic acid, and optionally converted to a pharmaceutically acceptable salt thereof as described above. Following the condensation reaction, the product having the formula can be reacted further, if necessary, in a manner known per se to convert one of the R ¹ , R ² or R ³ substituents into
Or two or more can be converted to other substituents within the formula. Thus, for example, a compound in the formula in which R ¹ , R ² or R ³ is nitro can be catalytically hydrogenated to the corresponding amino-substituted compound or R ¹ , R ² or
Compounds in which R ³ is amino can be alkylated to the corresponding lower alkylamino or di(lower)-alkylamino substituted compounds. An alternative to the above method is to precipitate the nitrile starting material with aluminum azide in tetrahydrofuran followed by acid recovery as described above. This reaction is carried out by reacting the nitrile with aluminum chloride and sodium azide in a molar ratio of about 1:1:3, respectively. The reaction temperature is not critical, but good results are obtained at reflux distillation temperature. Another method for preparing compounds with the formula is to heat a nitrile compound with the desired formula with hydrazoic acid in an inert organic solvent such as benzene, xylene or toluene, or with sodium azide and acetic acid in butanol. It is. This process does not require acidification to recover the desired end product. Yet another good method for preparing compounds with the formula: The acrylate intermediate having the formula R ¹ , R ² and R ³ are as defined above in the formula is reacted with sodium azide and ammonium chloride in an inert organic solvent. This good reaction condition, i.e. molar ratio, temperature range and solvent is
The NaN ₃ /NH ₄ Cl condensation method is as described above. The product having the formula precipitates out as an acid after adding sufficient water to the reaction mixture and can be easily recovered. The best way to prepare a compound with the formula is: (wherein R ¹ , R ² and R ³ are as defined in the above formula) and ethyl ethoxymethylenecyanoacetate with sodium azide and ammonium chloride in an inert solvent. Approximately equimolar amounts of the four reactants are used in an organic solvent that is reactively inert and has good solvent power for the sodium azide. Suitable solvents are dimethylformamide,
They are dimethylacetamide, dimethylsulfoxide and hexamethylphosfluoramide.
The best is dimethylformamide. Best results are obtained if the reaction is heated to a temperature from about 100°C to the reflux distillation temperature of the solvent system. At the end of the reaction, the reaction mixture can be acidified after adding sufficient water to precipitate the product and recover the compound. The above method allows the compound to be prepared in one step directly from the basic benzamidine and ethyl ethoxymethylenecyanoacetate starting materials without the need to first prepare and separate one or more intermediates required for the other methods described above. Therefore, this is the best embodiment of the present invention. The advantages of total yield and ease of operation will be apparent from consideration of the following embodiments. Nitrile starting materials having the formula can be prepared by a variety of known methods. One method [J.Heterocycl.
Chem., 8 , 715-719, (1971)] dehydrates the corresponding amide with the formula shown in the following reaction formula with phosphorus oxychloride. Although the dehydration reaction is carried out at high temperatures, reflux distillation conditions are best. An amide compound with the formula is: (wherein R represents C ₁ -C ₆ alkyl) are treated with liquid ammonia, ammonium hydroxide or aqueous ammonia in a lower alkanol (e.g. methanol or ethanol) containing excess sodium methoxide. It can be obtained by
This reaction can easily be carried out in a closed vessel at steam bath temperature. When concentrated ammonium hydroxide is used, good results have been obtained in which the reaction can be carried out at room temperature for 2 to 3 days without the need for heating or a closed container. An ester intermediate with the formula has the formula: (wherein R ¹ , R ² and R ³ are as defined in the above formula) or an acid addition salt thereof in an inert organic solvent and in the presence of a condensing agent of the formula: (In the formula, R ¹ is C ₁ -C ₆ alkyl, X is carb-lower alkoxy, and Y is -OC ₂ H ₅ , -CH
(COOC ₂ H ₅ ) ₂ ,

[Formula] or

Each represents a suitable leaving group such as: ) can be produced by condensation with a compound having The condensation reaction with the reactants is carried out in an inert solvent, e.g.
It can be easily prepared by heating to high temperature in C ₁ -C ₆ alcohol, acetonitrile, or tetrahydrofuran. Good results have been obtained by distilling the reactants under reflux in ethanol. The compounds are generally reacted together in the presence of at least a several-fold molar excess of the contact amount of a suitable condensing agent. Alkali metal alkoxides (generally formed in situ by addition of an alkali metal to a _C1 - _C6 alcohol), such as sodium methoxide, are good condensing agents. When benzamidine or benzamidine salts are condensed with diethyl ethoxymethylene malonate, the alkali metal alkoxide condensing agent can be replaced with alkali metal carbonates or even omitted as shown in the examples below. The benzamidine starting material can be either the free base or its salt, such as the hydrochloride, fluorozulfonate or methyl sulfate. When using the free base, it is advisable to use molar equivalents of the alkali metal alkoxide or a slight excess thereof. If a benzamidine salt is used, good results can be obtained with 2 moles of alkoxide per mole of compound. A preferred condensation method is to react benzamidine or a benzamidine salt (e.g. methyl sulfate) with diethyl ethoxymethylene malate in an inert organic solvent (ethanol is preferred) in the presence of about 1 mole of potassium carbonate per mole of benzamidine or its salt. nate and condensate by heating to reflux distillation temperature. Good results have been obtained with the above method when benzamidine free base is condensed with diethyl ethoxymethylene malonate without a condensing agent. It is used in approximately equimolar amounts with the compound. Diagram -
exemplifies a condensation reaction method that is an embodiment of the general method described above. Scheme Substituted benzamidines can be condensed with alkyl dicarboxyglutaconates by the general method of S. Ruhemann, Ber. 30 , 821 (1897). This method relies on the following reaction: Scheme Substituted benzamidine is PC Mizter
Reaction with dialkylethoxymethylene malonate by the general method described by Mitter et al., J.Chem.Soc., 123 , 2179 (1923). The method is as follows: The reaction scheme shows a good method for preparing the intermediates of the invention. Other preferred methods include the following reactions as described above. Schematic J.Med.Chem. by Santilli et al.
A third condensation method, described in J.D., 7 , 68, (1964), condenses benzamidines with dialkylmorpholinomethylene-malonates or dialkylpiperidinomethylene-malonates. The reaction of this method is as follows. This method uses an alkali metal condensing agent, e.g. K ₂ CO ₃
Or use NaOC ₂ H ₅ to produce soluble alkali metal salts. Acidifying the reaction mixture with an organic acid such as boronic acid or acetic acid causes the desired ester to precipitate from the solution. The starting materials are known and prepared by methods known in the art. A preferred method for producing substituted benzamidines is as follows. (R ¹ = −OC ₂ H ₅
The case is shown below. ) U.S. Patent No. 3,819,631 and J.Org.Chem.
33 , 1679 (1968), in which the triethyloxonium fluoroborate reactant is an alkylfluorozulfonic acid,
Salts (eg methyl fluorozulfonate), dimethyl sulfate or other alkyl oxonium fluoroborates can be substituted. The best method is to use the relatively inexpensive diethyl sulfate [(CH ₃ O) ₂ SO ₂ ] in place of the more expensive alkylfluorosulfonate or triethyloxonium fluoroborate as the alkylating agent. This method, shown below, results in the production of benzamidine methyl sulfate. Another method for preparing the compound benzamidine having the formula is as follows. (The case of R ¹ = −OC ₂ H ₅ is shown.) Another method for preparing nitriles having the formula is as follows: (a) A substituted benzamidine is prepared in an inert organic solvent, such as a C ₁ -C ₆ alcohol (ethanol is preferred) or dimethylformamide, preferably about After cooling to 0℃, the formula: When condensed with an equimolar amount of ethoxymethylene cyanoacetate having the formula: and (b) heating the intermediate in an inert organic solvent, such as dimethyl sulfoxide, toluene or dimethyl formamide, from room temperature to slightly below the reflux distillation temperature of the solvent. temperature range) to form the desired nitrile. A general method for preparing an intermediate having the formula is Chem.Parm.Bull., 18, when R ¹ , R ² and R ³ are all hydrogen.
1003 (1970), Nishigashi et al. The above method is based on Quart.J.Indian.Chem.Soc. 2 ,
61 (1925) and the desired nitrile and formula as described in U.S. Patent No. 3,660,403: It has been found to be significantly superior to the base-catalyzed condensation of benzamidines with ethyl ethoxymethylenecyanoacetate, which yields a mixture of unwanted amino esters with . The acrylate intermediate produced as described above can also be converted directly to the product having the formula by reaction with sodium azide and ammonium chloride in an inert solvent. A further method that can be used to prepare nitrile compounds having the formula is disclosed in US Pat. No. 2,235,638. The method is as follows: Compounds in which R ¹ , R ² or R ³ in the formula have a free hydroxy, amino or carboxyl group can of course be prepared by appropriately protecting this group during the reaction steps starting with the benzamide starting material and up to the formation of the final tetrazole. It is protected by a group. The protecting group is subsequently removed in a manner well known per se to obtain a product with unprotected substituents. The preparation of compounds in which R ¹ , R ² or R ³ is lower alkyl-amino or di(lower) alkylamino can be prepared by first preparing the corresponding amino-substituted compound and then alkylating it in a manner known per se. That's what I do. Alternatively, dialkyl-amino substituted compounds can be prepared directly from the appropriate benzamide starting material. It has been discovered that compounds having the formula as described above prevent the generation of toxic products, ie, mediators that result from certain combinations of antibodies and specific antigens. This class of compounds is particularly valuable for administering to a mammal a vector-suppressing dose of a compound having the formula to prevent the symptoms of allergic bronchial asthma in that animal. They are also useful in eliminating and preventing other allergic reactions such as allergic rhinitis. The compounds of this invention can be administered either as sole therapeutic agents or in combination with other therapeutic agents. Although these can be administered alone, they are generally used as pharmaceutical compositions,
Thus, the active agent is administered in a mixture with a suitable pharmaceutical carrier or diluent. Examples of such compositions are tablets, buccal tablets, capsules, powders, aerosol sprays, aqueous suspensions, oil suspensions, syrups, elixirs and aqueous solutions for injection. Most preferably, the compounds are administered orally. The nature of the pharmaceutical composition and the pharmaceutical carrier or diluent will, of course, depend on the desired mode of administration, oral, parenteral or inhalation. Oral compositions are often in the form of tablets or capsules containing binders (e.g. syrup, acacia, gelatin, sorbitol, tragacanth or polyvinyl-pyrrolidone), fillers (e.g. lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine). ), lubricants (eg, magnesium stearate, talc, polyethylene glycol, or silica), disintegrants (eg, starch), or wetting agents (eg, sodium lauryl sulfate). Oral liquid formulations include water suspensions, oil suspensions, solutions, emulsions,
It may be in the form of syrup, irixir, etc. or as a dry product for reconstitution with water or other suitable excipients immediately before use. This liquid product contains conventional additives such as suspending agents, flavoring agents, diluents or emulsifying agents. For parenteral administration or inhalation, solutions or suspensions of the compound with the formula and common pharmaceutical excipients, such as nebulized aerosols for inhalation, aqueous solutions for intravenous injection;
Alternatively, an oil suspension for intramuscular injection can be used. The compounds can also be administered by means of an inhaler or other device, such that the active compound in dry powder form enters and directly contacts the lungs. The compounds of the present invention or pharmaceutical compositions thereof can be administered to asthma patients in a single dose of about 1 to 500 mg of active ingredient, or up to several oral doses totaling about 1000 mg of active ingredient per day. When administered by inhalation, the dose is generally small, at a level of about 0.1 of the normal oral dose of a particular compound of the invention. These values are merely examples and, of course, the physician will ultimately determine the most appropriate dosage for a particular patient based on factors such as age, weight, severity of symptoms, and the drug being administered. The animal experiments described below demonstrate the efficacy of compounds having the formula against allergic reactions. Biological Activity Data The reagin-mediated murine passive cutaneous anaphylaxis (PCA) screening test used to evaluate the compounds of the present invention is the best method used to predict the antiallergic activity of test compounds in humans. It is generally considered to be a type of animal test. Briefly, this method consists of passive sensitization of the test animal's skin with reaginic antibodies 24 hours after administration of the test drug and antigen challenge. Allergic responses are measured using Evans blue dye and determined by diameter at the point of injection. The details are as follows. Materials Egg albumin (5 times crystallized) Dinitrobenzenesulfonic acid, Na ⁺ salt Bordetella partathus smallpox seedlings - Phase 10-2 x 10 ⁹ organisms killed/ml Aluminum hydroxide gel - 10 mg/ml Potassium carbonate Male Sprague-Ude Ray Mouse 200g Female Sprague-Do Ray (S/D) Mouse
100g Tris buffered saline (TBS) 0.02M2-amino-2-
Hydroxymethyl-1,3-propanediol (Tris), 0.15M NaCl, PH8.2. Antigen Preparation Method - DNP-dEA A substituted egg albumin antigen was used as both an immunogen and a challenge antigen. The antigen is made as follows: egg albumin (EA) 500
Dissolve 500 mg of K ₂ CO ₃ in 25 ml of distilled water and store at room temperature for 50 minutes.
Stir for a minute. Then, with stirring, 500 mg of dinitrobenzenezulfonic acid Na ⁺ salt (previously acid crystallized from hot absolute ethanol) are added gently. The reaction mixture is then placed in the dark and allowed to react for 2 hours with continued stirring. After 2 hours, the mixture is placed in a suitable dialysis tube and dialyzed 5 times against 4 portions of distilled water at 5°C. The product is then made lyophilized and stored in brown containers at room temperature.
The antigen obtained is a pale yellow amorphous solid that dissolves well in water or saline. This is called DNP-denatured egg albumin (DNP-dEA). Immunization method for IgE production Adult male Sprague-Dawley rats
It was used as a source of reagin-rich antiserum for the PCA model. Immunization with DNP-dEA on Al(OH) ₃ gel
and B. partathusis by a combination of smallpox seedlings.
The preparation method of DNP-dEA-gel immunogen is as follows: DNP-dEA is dissolved in TBS at a concentration of 10 mg/ml.
shall be. 1 ml of this solution is gradually added to 10 ml of Al(OH) ₃ gel (10 mg, solid/ml) at room temperature with stirring. The mixture is stirred for an additional 30 minutes to ensure uniform adsorption of the antigen onto the gel. The resulting preparation was used to immunize male S/D mice with phase B. partathusis smallpox seedlings as follows. 0.1 of DNP-dEA-gel suspension for each mouse
ml was administered intramuscularly into each hindlimb. (Total amount DNP−
This injection (200 μg of dEA and 2 mg of gel) was followed by intraperitoneal administration of 1.0 ml of B. partathusis smallpox seedlings (10−20×10 ⁹ organisms). Light ether anesthesia is preferred during this procedure to ensure normal intramuscular and intraperitoneal injection. On day 9 (not longer than 10 days) after immunization, animals were anesthetized with ether or pentobarbital and blood was collected by cardiac puncture or abdominal aortic cannulation. All collected blood was coagulated, serum was centrifuged, and individual serum samples were stored frozen until analysis of IgE content. Selection of Titer Serum Samples for Combination Since mice do not respond to all immunization methods by producing reagin, individual serum samples need to be screened for reagin antibody concentration before being combined with other sera. A 1:50 dilution of the serum of each immunized mouse in saline was used for this purpose. 2 fish 100-120g
0.05 ml of the diluted serum was injected intradermally onto the shaved back of female mice. Several serum samples were tested simultaneously on recipient animals. After 24-48 hours, each mouse was given 0.5 ml of salt water.
Antigen challenge was performed by intravenously administering 1 mg of DNP-dEA in 0.5 ml of % Evans blue dye. Sera that showed a positive PCA reaction when examined 20 to 30 minutes after the challenge were divided into small portions and stored at -70°C or lower until use. Those that showed negative reactions were discarded. Next, it is necessary to test the IgE titer of the antiserum combination solution. Serial 2-fold dilutions (1:5 to 1:160) of unheated serum and serum heated for 1 hour at 56°C were made in saline and 0.05 ml of each dilution was injected intradermally into the back of female recipient rats. did. At least four animals should be used for each heated and unheated serum test. After 24 hours each group was treated with 0.5% Evans blue dye.
The challenge was with 1 mg of DNP-dEA in 0.5 ml. 20 to 30 minutes after the challenge, the skin was photographed and the reaction was read.
It is necessary to check and record the intensity (blueness) and spot diameter. The titer of the combined fluid is determined by a measurable PCA response in at least half of the recipient animals (>6 mm diameter).
was determined by the reciprocal of the maximum dilution rate of unheated serum resulting in Antiserum complications with a titer of 50 or higher can be used in the PCA screen. These combined solutions must be sterilized and stored at -70°C or below until use. Alternatively, a method of making a small amount lyophilic can be used. PCA Screening Method 1 Animals - 90-110 g of young female Sprague-Dawley mice should be used. Mice must be acclimatized to food and water ad libitum for at least 5 days prior to use. 2. Passive sensitization - Test animals are prepared for passive sensitization by carefully trimming both sides of the back with thin-bladed scissors. Inject the antiserum dilution in saline intradermally using a 27 gauge 5/8 inch needle fitted with a 1 ml tuberculin syringe. 4 dilutions (2 on each side)
use. The actual dilution used will depend on the potency of the combined solution. For example, if the antiserum combination has a titer of 50, use dilutions of 1:10, 1:20, 1:30 and 1:40. If the combined solution titer is 100, the dilutions are 1:20, 1:40, 1:60 and 1:80.
The position order of each dilution level should be either clockwise or vice versa for ease of recording. Latency time shall be at least 24 hours and no more than 48 hours. 3 Drug Administration - Standard and Unknown - Four animals are used for each test compound. Disodium chromosol soluble in salt water
Glycate (DSCG) is administered intravenously (iv) at the time of antigen challenge. Tetrazole test compounds are soluble in aqueous sodium bicarbonate solution.
Test compounds are administered either iv or po for 1-5 or 10 minutes, respectively, before antigen challenge. 4. Antigen Challenge and Dosing Evaluation - Each test mouse was given 0.5 ml of 0.5% Evans' blue dye in saline.
A PCA response can be elicited by intravenous administration of 1 mg of DNP-dEA. The reaction should be recorded by looking at the color intensity at each antiserum dilution position and the mean diameter of the spots should be measured. Both operations should be performed on the skin. The number of control groups (untreated) for ratios should be at least 5%, and usually 10%, of the total number of animals tested on a particular day. The measured inhibitory power of the drug is reported as the percent reduction in effective antiserum titer of the treated group relative to the control group. Results The results of testing compounds of the invention by the iv and po methods of administration are presented below along with the data for DSCG. Results are expressed as ID ₅₀ values, ie, the dose of compound that inhibits 50% of the response.

【table】

TABLE The following examples are intended to illustrate the starting materials and methods of making the compounds of the invention and are not to be construed as limiting the invention. All temperatures below are in degrees Celsius, and "Skelsorb B" is essentially n
- Boiling point of petroleum ether consisting of hexane 60-68°C
It is a distillate. (Trade name of Skelly Oil Company) Method for Preparation of Starting Material The substituted benzamidine (or benzamidine salt) starting material can be prepared by the following method. Preparation 1: 2-Ethoxybenzamidine Hydrochloride A chilled (ice water) solution of triethyloxonium fluoroborate (100 g, 0.53 mol) in 226 ml of methylene chloride is added to 2-ethoxybenzamidine hydrochloride in 915 ml of methylene chloride.
A suspension of ethoxybenzamide (87 g, 0.53 mol) was added in one portion. The resulting liquid was stirred at room temperature for 36 hours. This solution was concentrated to 1/3 volume and diluted with about 600 ml of diethyl ether, resulting in crude ethyl 2-ethoxybenzimidate fluoroborate (130
g, melting point 116-133°) was precipitated. Add this salt to 500ml of cold 10% ethanolic ammonia.
and stirred at room temperature for 36 hours. This liquid was concentrated to dryness and partitioned between ethyl acetate and 5N NaOH. The ethyl acetate layer was dried to obtain a sticky oil. Approximately 200 ml of acetonitrile was added to the oil and the solid separated was collected to yield 36 g of material with a melting point of 180-183°. Approximately 60ml of solid
of methanol, acidified with hydrochloric acid and added about 1 g of dry ether to obtain the desired hydrochloride precipitate (31.2 g, melting point
198−199°) was obtained. Production method 2: 2-ethoxybenzamidine hydrochloride (alternative method) Methyl fluorozulfonate (14.5g, 0.127
mol) was added to a solution of 2-ethoxybenzamide (20.0 g, 0.121 mol) in 324 ml of methylene chloride. After 3 hours, the solvent was removed under reduced pressure, the residue was triturated with diethyl ether, and the mixture was collected by filtration.
Crude ethyl 2-ethoxybenzimidate fluorosulfonate (28.5 g, mp 83-110°) was added to 120 ml of saturated ammoniacal ethanol and the mixture was stirred at room temperature for 4 days. The mixture was filtered, the liquid was concentrated, and the residue was triturated with 2N sodium hydroxide. The resulting mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated. The remaining oil was dissolved in 50 ml of acetonitrile, acidified with hydrochloric acid, and 700 ml of diethyl ether was added to precipitate 2-ethoxybenzamidine hydrochloride (11.0 g, melting point 193-
196°) was obtained. Preparation 3: 2-Ethoxybenzamidine Suspension of triethyloxonium fluoroborate (15.0 g, 0.0785 mol) in 137 ml of methylene chloride in a solution of 2-ethoxybenzamide (13.0 g, 0.0785 mol) in 34 ml of dry methylene chloride. The liquid was added all at once. Immediately after the addition, the resulting solution was stirred at room temperature for 19 hours. Concentrate this liquid to about 1/3 volume to about 100ml.
Ethyl 2- precipitated diluted with diethyl ether
Ethoxybenzimidate fluoroborate was collected and dried to obtain 19.2 g. Melting point 113-116°. The above product was then added to 100 ml of ethanol containing 1.4 g of _NH3 . The resulting liquid was stirred in a sealed flask at room temperature for 78 hours. The colorless solid obtained by removing the solvent under reduced pressure was dissolved in a small amount of water and made alkaline with 6N NaOH. Extraction with ethyl acetate and dry removal of the solvent gave the product (7.4 g, mp 78-84°). The 2-ethoxybenzamide used above was replaced with an equimolar amount of 2-isopropoxybenzamide or 2-ethoxybenzamide.
2-isopropoxybenzamidine or 2-n- respectively in place of n-propoxybenzamide
Propoxybenzamidine is obtained. Preparation 4: 2-Ethoxybenzamidine fluorodulphonate (Method A) To a suspension of 2-ethoxybenzamide (500 g, 3.03 mol) in dry methylene chloride (8 ml) was added methyl fluorosulfonate (256 ml, 3.17 mol). ) was added. After stirring the resulting liquid at room temperature for 3 hours, the solvent was removed under reduced pressure, the residue was triturated with diethyl ether, and the mixture was filtered. After washing the collected solid with ether, add 500 g of ammonia in 3 ethanol.
into a cold (ice water) solution of Cool the mixture at 30
The mixture was stirred for 16 hours at room temperature. The liquid was concentrated and the residue was crystallized from 1,2-dichloro-ethane to give 2-ethoxybenzamidine fluorosulfonate (517 g, 65%). Melting point 98-99°C ₉ H ₁₂ N ₂ O. Analytical values for HFSO ₃ : Calculated: C, 40.90; H, 4.96; N, 10.60 Measured: C, 40.95; H, 4.83; N, 10.73. Preparation 5: 2-Ethoxybenzamidine fluorosulfonate (Method B) A suspension of 2-ethoxybenzamide (1 Kg, 6.05 mol) in methylene chloride (12.5) was added with methyl fluorosulfonate (538 ml, 6.66 mol). ) was added. After the mixture was stirred at room temperature for 18.5 hours, ammonia gas was bubbled through the mixture while keeping the temperature below 26°. The mixture was further stirred at room temperature for 16 hours. The solvent was removed in vacuo to yield 1.7Kg of 2-ethoxybenzamidine fluorosulfonate. Process 6: Methyl 2-ethoxybenzamidine sulfate A solution of 2-ethoxybenzamide (16.5 g, 0.1 mol) and dimethyl sulfate (19.0 ml, 0.2 mol) in 60 ml of 1,2-dichloroethane was stirred for 17 hours. Heat to reflux. The solvent was removed under reduced pressure and the remaining oil was stirred with 200 ml of diethyl ether for 30 minutes. Methyl 2-ethoxybenzimidate methyl sulfate was filtered, dried and then added to 150 ml of stirred saturated ethanolic ammonia. The solution was allowed to stand at room temperature for 18 hours, and then filtered and concentrated. The residue was triturated with diethyl ether and filtered to give methyl 2-ethoxybenzamidine sulfate (19.9
g, 72 based on 2-ethoxybenzamide
%) was collected. Preparation 7: 2-n-Propoxybenzamidine Hydrochloride A Ethyl 2-n-Propoxybenzimidate Fluoroborate A solution of 2-n-propoxybenzamide (31.3 g, 0.175 mol) in 150 ml of methylene chloride is dissolved in methylene chloride with stirring. Triethyloxonium fluoroborate (33.0g,
0.175 mol) was added over 10 minutes. The solution was stirred for an additional 18 hours at room temperature. Concentrate the solution to about 1/5 volume, dilute with diethyl ether, and dilute with ethyl 2-n-
Propoxybenzimidate fluoroborate (44.0 g, 85% yield) was precipitated. Melting point 108−
112°B 2-n-propoxybenzamidine hydrochloride Ethyl 2-n-propoxybenzimidate fluoroborate (44.0
g) for 5 minutes with stirring.
100 ml of ethanol containing 6.5 g of ammonia was added. The resulting solution was stirred at 25° for 20 hours, concentrated to dryness, and the residue was partitioned between diethyl ether and 5N NaOH. The ether layer was washed with brine, dried over sodium sulfate, concentrated, and the residue was purified with ether.
The mixture was dissolved in 500 ml of ethanol and treated with hydrogen chloride to obtain 2-n-propoxybenzamidine hydrochloride precipitate (28.8 g, yield 76.6%). melting point
184-186.5゜Production 8: 2-n-Propoxybenzamidine Methyl Sulfate A solution of 2-n-propoxybenzamide (896 g, 5.0 mol) in 1,2-dichloroethane 5 was heated and stirred in dimethyl sulfate for about 30 minutes. (960ml, 10.0mol) was added. Stir the mixture 17
Heated at reflux for an hour. After removing the solvent, the remaining oily solid was filtered, washed with ethyl acetate, and dried to obtain methyl 2
-n-propoxybenzimidate methyl sulfate (403 g, melting point 79-82°) was obtained. The solution and washing solution were combined and left at 0° for 18 hours, followed by benzimidate.
Obtained 503g. Melting point 81-83°. A slurry of 906 g of methyl 2-n-propoxybenzimidate sulfate in ethanol 1 was added to ethanol 4, which had been saturated with ammonia gas. The mixture was left at room temperature for 17 hours and then filtered. The liquid was evaporated to dryness to give 2-n-propoxybenzamidine methyl sulfate (872 g, 60%). Melting point 86-88°. Preparation 9: 2-Isopropoxybenzamidine Hydrochloride A stirred solution of 2-isopropoxybenzamide (36.2 g, 0.202 mol) in 100 ml of methylene chloride was added with triethyloxonium fluoroporate (38.4 g, 0.202 mol) in 75 ml of methylene chloride. mol) was added over 15 minutes. After stirring the mixture at room temperature for 18 hours, the liquid was concentrated to about 1/5 volume and diluted with diethyl ether to give colorless crystals of crude ethyl 2-
Isopropoxybenzimidate fluoroborate (60 g, melting point 90-110°) was obtained. This was crystallized from methylene chloride-diethyl ether to give 55 g of colorless product. Melting point 114-120° 55g of the above fluoroborate in 50ml of ethanol
Suspend the 8% ethanol solution while stirring.
150ml of _NH3 was added. After stirring the mixture at 25° for 64 hours, the liquid was evaporated to dryness and the residue was dissolved in 100 ml of 5N NaOH.
It was made alkaline. This mixture was extracted with ether and the extract was dried. The residue was dissolved in 500 ml of ether and 50 ml of ethanol and treated with hydrochloric acid to form a colorless precipitate, 2-isopropoxybenzamidine hydrochloride.
24.1g was obtained. Melting point 162-164° Preparation 10: 2-n-Butoxybenzamidine hydrochloride 2-n-Butoxybenzamide in 200 ml of methylene chloride [J.Pharm.Pharmacol., 4 , 872
(1952)] (33.0 g, 0.171 mol) was added to 75 ml of methylene chloride with stirring at 25°.
0.171 mol) of the solution was added. After the mixture was stirred at 25° for 20 hours, the solution was concentrated to about 1/5 of its original volume and diluted with diethyl ether. The precipitated solid was recrystallized from methylene chloride-diethyl ether to give ethyl 2
28.7 g of -n-butoxybenzimidate fluoroborate was obtained. Melting point 82-88°. To a suspension of 28.7 g of fluoroborate in 75 ml of ethanol was added 150 ml of 8% ethanolic ammonia with stirring while cooling (ice water). Mixture at 25°
After stirring for 20 hours, the ethanol was removed and the residue was partitioned between ether and 100 ml of 5N NaOH. The ether layer was washed with brine, dried over sodium sulfate, and concentrated. The remaining oil was dissolved in ether and treated with hydrogen chloride to give 16.8 g of the title compound as a precipitate. Melting point 150-155°. Production method 11: (±)-2-sec-butoxybenzamidine hydrochloride J.Pharm.Pharmacol., 9 in the same manner as described for the production of 2-n-butoxybenzamidine hydrochloride in production method 10 above. (±)-2-sec-butoxybenzamidine hydrochloride (melting point 142-144°) was prepared from (±)-2-sec-butoxy-benzamide as described in J. K., 855 (1957). Preparation 12: 2-Isobutoxybenzamidine A cooled (ice-water) solution of 2-isobutoxybenzamide ¹ (70.1 g, 0.363 mol) in 800 ml of methylene chloride is dissolved in triethyloxonium fluoroborate (69.0 g, 0.363 mol). Mix the mixture at room temperature for 16
After stirring for an hour, about 2/3 of the solvent was removed, the residue was diluted with 500 ml of diethyl ether, and the mixture was filtered.
Collected ethyl 2-isobutoxybenzimidate fluoroborate ¹ (76.5 g, melting point 110-112
゜) ethanol saturated with ammonia gas
Added to 350ml. The solution was left at room temperature for 67 hours, then evaporated to dryness and the residue was treated with 160 ml of 5N sodium hydroxide. The mixture was extracted with methylene chloride (3 x 200ml) and the combined extracts were washed with water, dried (sodium sulfate) and concentrated. The residue was recrystallized from cyclohexane to give 2-isobutoxybenzamidine ^1.
(429 g, total yield 615%) was obtained. Melting point 49-51°. Analytical values for C ₁₁ H ₁₆ N ₂ O: Calculated values: C, 68.72; H, 8.39; N, 14.57 Measured values: C, 68.60; H, 8.42; N, 14.28 References: 1: U.S. Patent No. 3819631 (1974 ) Process 13: 2-isobutoxybenzamidine fluorosulfonate A solution of 2-isobutoxybenzamide ¹ (8.6 g, 0.0445 mol) in 100 ml of methylene chloride was stirred under nitrogen, and methyl fluorosulfonate was added to the solution. nate (5.65 g, 0.0495 mol) was added. The liquid was stirred at room temperature for 18 hours, and then stirred while blowing in ammonia gas for 3 hours. The liquid was concentrated and the residue was recrystallized from 1,2-dichloroethane to give the title compound (1.1
g, yield 8.5%). Reference 1: Same as manufacturing method 12-1. Process 14: 2-ethoxy-5-methoxybenzamidine hydrochloride A 2-ethoxy-5-methoxybenzamide Sodium (6.37 g,
5-methoxysalicylamide (41.8 g, 0.250 moles) was dissolved in a solution containing 0.277-atoms). The resulting liquid was cooled (ice water) and iodoethane (38.9 g, 0.250 mol) was added over 20 minutes. The reaction mixture was allowed to come to room temperature for 0.75 hours and then heated to reflux for 19 hours. The mixture was concentrated and the residue was triturated with water. The solid collected by filtering the mixture was recrystallized from acetonitrile to give 2-ethoxy-5-methoxybenzamide (34.5
g, 70.7%). Melting point 128-130°C ₁₀ H ₁₃ Analytical values for NO ₃ : Calculated value: C, 61.52; H, 6.71; N, 7.18 Measured value: C, 61.45; H, 6.51; N, 6.93 B 2-Ethoxy-5- Methoxybenzamidine hydrochloride 2-ethoxy-5 in 450 ml of methylene chloride
- Methoxybenzamide (33.5 g, 0.172 mol) was cooled (ice water) and methylfluorozulfonate (28.4 g, 0.248 mol) was added to it for 20 minutes.
Added over a period of minutes. After stirring the mixture at room temperature for 4 hours, 2/3 of the solvent was removed and the residue was diluted with diethyl ether. Precipitated crude methyl 2-ethoxy-5-methoxybenzimidate fluorosulfonate (50.0 g, mp 144-152
) was dissolved in 300 ml of cold ethanol saturated with ammonia. This mixture was stirred in the cold (ice-cooled) for 2 hours and further stirred at room temperature for 17 hours. The ethanol was removed under reduced pressure and the semi-solid was treated with 5N sodium hydroxide (200ml). The mixture was extracted with ethyl acetate, and the extract was dried (sodium sulfate) and concentrated. The residue was dissolved in acetonitrile-acetone (2:5) and treated with hydrogen chloride gas to give 2-ethoxy-5-methoxybenzamidine hydrochloride (10.5 g, 26.5%) as a precipitate. Melting point 166-167゜Production method 15: 5-carbomethoxy-2-ethoxy-benzamidine A 5-carbomethoxy-2-ethoxybenzamide Same as described for the production of 2-ethoxy-5-methoxybenzamide in Production method 14A. 5-Carbomethoxy-2 from 5-carbomethoxysalicylamide, iodoethane and sodium methoxide in methanol by the method
-Ethoxybenzamide (melting point 159-161°)
I made it. B 5-Carbomethoxy-2-ethoxybenzamidine 5-carbomethoxy-2-ethoxybenzamidine was prepared from 5-carbomethoxy-2-ethoxybenzamide in the same manner as described for the production of 2-isobutoxybenzamidine in Process 12. -2-Ethoxybenzamidine was prepared. Melting point 133−135
゜. Process 16: 5-chloro-2-ethoxybenzamidine hydrochloride A 5-chloro-2-ethoxybenzamide 5-chlorosalicylamide (16.0 g, 0.093 mol), iodoethane (31.8 g, 0.204 mol) in 225 ml of ethanol. and potassium carbonate (13.1 g, 0.095 mol) was heated at reflux for 20 hours. The hot mixture was filtered and the liquid was evaporated to dryness. The residue was triturated with water, the mixture was filtered and the solid collected was recrystallized from acetonitrile.
-chloro-2-ethoxybenzamide (6.8
g, 36.6%). Melting point 136-139°. Analytical values for C ₉ H ₁₀ ClNO ₂ : Calculated values:
C, 54.15; H, 5.05; Cl, 17.76; N, 7.02 Measured value:
C, 54.25; H, 4.85; Cl, 17.42; N, 6.89 B 5-chloro-2-ethoxybenzamidine hydrochloride An equimolar amount of 5-chloro in place of 2-n-butoxybenzamide used in Preparation Method −
Repeating Preparation 10 using 2-ethoxybenzamide produces the title compound. melting point 227
Decomposed at °. Analytical values _{for C9H11ClN2O.HCl} : Calculated: C, 45.97; H, 5.15; _N , 11.91 Measured: C, 46.23; H, 5.20; N, 11.87. Process 17: 2,5-dimethoxybenzamidine hydrochloride Repeat the process of process 10 using an equimolar amount of 2,5-dimethoxybenzamide in place of the 2-n-butoxybenzamide used in process 10. Then we get the title product. Melting point 170-172゜Production method 18: 2-Cyclopropylmethoxybenzamidine hydrochloride A 2-cyclopropylmethoxybenzamide Salicylamide (10.02
g, 0.074 mol), potassium carbonate (10.24 g,
0.074 mol) and bromomethylcyclopropane (10.0 g, 0.074 mol) was stirred and heated to reflux for 19 hours. The mixture was concentrated, water was added to the residue, and the collected solid was recrystallized from benzene-Scherisorb B to obtain 2-cyclopropylmethoxybenzamide (10.0 g, 71.6%). Melting point 102-105°B 2-Cyclopropylmethoxybenzamidine hydrochloride A solution of 2-cyclopropyl-methoxybenzamide (99.2 g, 0.518 mol) in 450 ml of methylene chloride with stirring was dissolved in triethyloxonium in 225 ml of methylene chloride. A solution of fluoroborate (99.1 g, 0.522 mol) was added. mixture
After stirring at 22° for 18 hours, the mixture was concentrated to about 1/3 volume and diluted with diethyl ether. The precipitated solid was recrystallized from methylene chloride-diethyl ether to give ethyl 2-cyclopropylmethoxybenzimidate fluoroborate (104.7 g, 65.7
%) was obtained. Melting point 120-121゜Ethanol 100ml
104.7 g of fluoroborate was cooled (ice-cooled) and stirred with 6% ethanolic ammonia.
Added 100ml. The mixture was stirred at 20° for 18 hours, then concentrated and the residue was partitioned between diethyl ether and 3N sodium hydroxide. The ether layer was washed with brine, dried over sodium sulfate, and the solution was treated with hydrogen chloride. Precipitate with methylene chloride
Recrystallization from diethyl ether gave 2-cyclopropylmethoxybenzamidine hydrochloride (71.5 g, 92.5% from fluoroborate). Melting point 166-171°. Process 19: 5-methoxy-2-n-propoxybenzamidine hydrochloride A: 5-methoxy-2-n-propoxybenzamide Sodium (8.55 g,
5-Methoxysalicylamide (56.0 g,
0.335 mol) was added. To the resulting suspension was added 1-bromopropane (41.3 g, 0.335 mol) dropwise over 20 minutes. The mixture was stirred at room temperature for 1 hour and then heated under reflux for 19 hours. The solvent was removed under reduced pressure, the residue was treated with 500 ml of cold water, and the collected solid was recrystallized from acetonitrile to give 5-methoxy-2-n-propoxybenzamide (29.0
g, 41.4%). Melting point 83-87°. Analytical values for C ₁₁ H ₁₅ NO ₃ : Calculated: C, 63.14; H, 7.23; N, 6.69 Measured: C, 63.28; H, 7.43; N, 6.47 B: 5-Methoxy-2-n-propoxybenz Amidine hydrochloride 5-methoxy-2 in 200ml of methylene chloride
-n-propoxybenzamide (29.0g,
0.139 mol) was brought to 5° and methyl fluorosulfonate (15.8 g, 0.139 mol) was added. After stirring the solution at room temperature for 5 hours, most of the solvent was removed and the remaining solution was diluted with 500 ml of diethyl ether. Precipitated methyl 5-methoxy-2
-n-Propoxybenzimidate fluorosulfonate (33.4 g, melting point 117-126°) was collected and added to 220 ml of cold saturated ethanolic ammonia. After stirring the mixture at room temperature for 19 hours, the liquid was concentrated and the remaining oil was dissolved in a mixture of acetonitrile and ether. The resulting solution was treated with hydrogen chloride to obtain an oily 5-methoxy-2-n-propoxybenzamidine hydrochloride (31.5 g) precipitate, which was separated from the solvent. Production method 20-1: 2-methoxybenzamidine hydrochloride 2-methoxybenzamidine hydrochloride was produced from 2-methoxybenzamide in the same manner as described for the production of 2-n-propoxybenzamidine hydrochloride in Production method 7. Tsukutsuta. Melting point 150−
152°. Preparation 20-2: 2-ethylthiobenzamidine hydrochloride A 2-ethyloxybenzamidoxime 2-ethylthiobenzonitrile (29.0 g, 0.178 mol) in 284 ml of ethanol [J.Prakt.Chem. by K. Brand et al. 108, 19 (published in 1924) was added over 30 minutes to a solution of hydroxylamine hydrochloride (4.47 g, 0.64 mol) and sodium carbonate (31.2 g, 0.29 mol) in 474 ml of water. The mixture After heating at reflux for 1.75 hours, the coolant was reduced to 1/3 volume.The residue was partitioned between diethyl ether and 1N hydrochloric acid.The aqueous and ether layers were separated and the ether layer was extracted twice with fresh 1N RCl. Combine the aqueous layers and pH with sodium bicarbonate.
Adjusted to 5.5. This mixture was mixed with ether (3x
The combined extracts were dried (sodium sulfate) and concentrated to give 2-ethyl-thiobenzamidoxime (12.5 g, 36%). melting point
72−78°. This was recrystallized from 2-propanol-ether to give analytical material. Melting point 79−
83°. Analytical values _{for C9H12N2OS} : Calculated _: C, 55.09; H, 6.17; N, 14.28. Measured values: C, 54.92; H, 6.27; N, 14.08. B 2-Ethylthiobenzamidine hydrochloride Raney Nickel was added to a solution of 2-ethylthiobenz-amidoxime (6.0 g, 30.6 mmol) in 200 ml of ethanol at an initial pressure of 3.5 Kg/
It was shaken for 3 hours in a cm ² hydrogen atmosphere. Filter the mixture and concentrate the resulting oil with 30 ml of ethanol.
and 400 ml of diethyl ether. This solution was treated with hydrogen chloride to precipitate 2-ethylthiobenzamidine hydrochloride (2.4 g, 36.2
%, mp 290-291°) was recrystallized from 2-propanol-ether to give analytical material. Melting point 296-297°. Manufacturing method 21: Ethyl 1,6-dihydro-6-oxo-
2-(2-ethoxyphenyl)-pyrimidine-
5-carboxylate (example of use of benzamidine free base) Sodium (1.04 g,
The solution containing 0.045 g-atoms was cooled and 2-ethoxybenzamidine (7.4 g, 45 mmol) was added in one portion. To this suspension was added diethyl ethoxymethylene malonate (9.7 g, 45 g) in 20 ml of ethanol.
A pale yellow precipitate was formed after 5 minutes of addition of 5 mmol of the solution. An additional 25 ml of ethanol was added to the reaction mixture, which was then heated under reflux for 21/4 hours. Cool this solution, pour it into 500 ml of ice water, and add 6 N
Acidification with HCl produced a pale yellow solid. The solid was dried to obtain 102 g of the title compound. Melting point 144−
149° This was recrystallized from acetonitrile to obtain 9.8 g of pure compound. Melting point 147-150°. Analytical values _{for C15H15N2O4} : Calculated: C, 62.49; _H , 5.60; _N , 9.72. Measured values: C, 62.23; H, 5.57; N, 9.63. Manufacturing method 22: Ethyl 1,6-dihydro-6-oxo-
2-(2-ethoxyphenyl)pyrimidine-
5-carboxylate (example of use of benzamidine hydrochloride) Sodium (8.2 g,
2-ethoxybenzamidine hydrochloride (35.7 g, 0.178
mol) were added all at once. Ethanol to this suspension
Add diethyl ethoxymethylene malonate (38.4 g, 0.178 mol) to 80 ml and dilute the mixture.
Heated at reflux for 1/4 hour. Cool the liquid and cool it to about 2800
ml of ice water and the mixture was brought to pH 5 with glacial acetic acid.
The precipitate was dried to obtain 47 g of the title compound as an off-white solid. Melting point 147-150゜Production method 23: Ethyl 1,6-dihydro-6-oxo-
2-(2-ethoxyphenyl)pyrimidine-
5-carboxylate (example of use of benzamidine fluorosulfonate) Sodium (41 g, 1.78 g
The sodium ethoxide solution prepared by adding 2-ethoxybenzamidine fluorosulfonate (206.5 g, 0.78 mol) was added to 500 ml of ethanol at 18°. 13 times this liquid
The mixture was cooled to 0.degree. and a solution of diethyl ethoxymethylene malonate (180 ml, 0.89 mol) in 400 ml of ethanol was added. The mixture was heated under reflux for 2.25 hours, then cooled to 10°, poured into cold water 5, and stirred well. Ice was added if necessary to keep the mixture below 20°. The mixture was adjusted to pH 5 with glacial acetic acid, and the precipitate was filtered, washed with water, and dried to give the title compound (218.7 g, 97%). This was recrystallized from acetonitrile to obtain a product. Melting point 144-147゜Production method 24: Ethyl 1,6-dihydro-6-oxo-
2-(2-ethoxyphenyl)pyrimidine-
5-carboxylate (example of best method using methyl benzamidine sulfate) Sodium (3.3 g,
2-Ethoxybenzamidine methyl sulfate (19.9 g, 0.072
mol) was added followed by diethyl ethoxymethylene malonate (17.0 g, 0.079 mol). After heating the mixture under reflux for 2.25 hours, the mixture was cooled, poured into 250 ml of ice water, and acidified with glacial acetic acid. The precipitate was supercollected, washed with water, and dried to obtain the title compound (16.0 g,
77%). Melting point 138-140゜Production method 25: Ethyl 1,6-dihydro-6-oxo-
2-(2-n-propoxyphenyl)pyrimidine-5-carboxylate (benzamidine hydrochloride) Sodium (2.57 g,
While cooling (ice water) and stirring, 2-n-propoxybenzamidine hydrochloride (12.0 g, 0.0558 mol) was added. To this cooled stirred solution was added 10 g of diethyl ethoxymethylene malonate (12.1 g, 0.0558 mol) in 50 ml of ethanol.
Added over a period of minutes. The mixture was heated under reflux for 2.5 hours, then cooled, poured onto ice, and acidified with 6N hydrochloric acid. Precipitated ethyl 1,6-dihydro-6-oxo-2-(2-n-propoxyphenyl)-pyrimidine-5-carboxylate (16.2 g, yield 96
%) had a melting point of 111-113°. Two recrystallizations from cyclohexane gave the title product. melting point
112−113°. Analytical values _{for C16H18N2O4} : Calculated _: C, 63.56; _H , 6.00; N, 9.27. Measured values: C, 63.59; H, 6.15; N, 9.47. Manufacturing method 26: Ethyl 1,6-dihydro-6-oxo-
2-(2-n-propoxyphenyl)pyrimidine-5-carboxylate (methyl benzamidine sulfate and sodium ethoxide) Sodium (181.7 g, 7.9
A slurry containing methyl 2-n-propoxybenzamidine sulfate (1146.7 g, 3.95 mol) in 1.6 g of ethanol was added to the solution containing 2-n-propoxybenzamidine methyl sulfate (1146.7 g, 3.95 mol) while heating and stirring the solution. After a few minutes, diethyl ethoxymethylene malonate (854 g, 3.95 mol) was added and the mixture was stirred and heated at reflux for 2.25 hours. The mixture was cooled, poured into cold water and brought to pH 5-6 with glacial acetic acid. The resulting solid was filtered, washed with water, and dried to obtain 937.8 g of the title compound. Melting point 102-104°. Further product (101.6 g, melting point 105-107
゜) was obtained. Total yield 1039.4g (87%). Manufacturing method 27: Ethyl 1,6-dihydro-6-oxo-
2-(2-n-propoxyphenyl)pyrimidine-5-carboxylate (methyl benzamidine sulfate and _K2CO3 ) Methyl 2-n-propoxybenzamidine sulfate (7.4 g, _0.0255 mol), potassium carbonate in 80 ml of ethanol. (3.53 g, 0.025 mol) and diethyl ethoxymethylene malonate (5.99 g, 0.0277
The mixture was heated to reflux with stirring for 17 hours. The mixture was cooled, poured into 160 ml of ice water, and acidified with glacial acetic acid. The precipitate was filtered, washed with water, and dried to obtain the title compound (6.55 g, 89%). Melting point 106−
107°. Manufacturing method 28: Ethyl 1,6-dihydro-6-oxo-
2-(2-isopropoxyphenyl)pyrimidine-5-carboxylate (benzamidine hydrochloride) Sodium (2.14 g,
2-isopropoxybenzamidine hydrochloride (10.0 g, 0.0465 mol) was added to the cooled (ice water) solution with stirring. To this cooled stirred solution was added a solution of diethyl ethoxymethylene malonate (10.1 g, 0.0465 mol) in 30 ml of ethanol.
Added dropwise over 10 minutes. The mixture was distilled under reflux for 2 hours and then left at 22° for 18 hours. The mixture was then poured into ice water containing 10 ml of acetic acid and 10 ml of concentrated hydrochloric acid to precipitate the desired product. The precipitate was washed with water and dried to obtain 15.5 g of the title product. Melting point 123-124°. Crystallization from ethyl acetate followed by cyclohexane gave a colorless crystalline ester. Melting point 128-130°C ₁₆ H ₁₈ N ₂ O ₄ Analysis values: Calculated value: C, 63.56; H, 6.00; N, 9.27 Measured value: C, 63.60; H, 5.98; N, 9.29 Manufacturing method 29: Ethyl 1・6-dihydro-6-oxo-
2-(2-allyloxyphenyl)pyrimidine-5-carboxylate (benzamidine hydrochloride) A solution of sodium ethoxide (12.25 g, 0.18 mol) in 100 ml of ethanol was cooled (ice water) and added to 2-allyloxy with stirring. Benzamidine hydrochloride
¹ (19.07 g, 0.0896 mol) was added. To this cooled stirred solution was added a solution of diethyl ethoxymethylene malonate (19.4 g, 0.0896 mol) in 15 ml of ethanol. The mixture was heated under reflux for 2.5 hours and then left at room temperature for 18 hours. The mixture was poured into ice water containing acetic acid, and the precipitated solid was collected and recrystallized from cyclohexane to give the title compound (24.0 g, 89%). Melting point 118-120°. The melting point of the product recrystallized from cyclohexane was 118.5-120.5°. Analytical values for C ₁₆ H ₁₆ N ₂ O ₄ : Calculated values: C, 63.99; H, 5.37; N, 9.33 Measured values: C, 63.93; H, 5.42; N, 9.36 Reference 1. US Patent No. 3,819,631. Production method 30: Ethyl-1,6-dihydro-6-oxo-2-(2-n-butoxyphenyl)pyrimidine-5-carboxylate (benzamidine hydrochloride) 2-allyloxy-benzamidine hydrochloride used in Production method 29 instead of an equimolar amount of 2-n-
Manufacturing method using butoxybenzamidine hydrochloride
The title compound was produced by the method of 29. melting point
123−125°. Analytical values for C ₁₇ H ₂₀ N ₂ O ₄ : Calculated values: C, 64.54; H, 6.37; N, 8.86 Measured values: C, 64.41; H, 6.29; N, 9.07 Manufacturing method 31: Ethyl (±)-1. 6-dihydro-6-
Oxo-2-(2-sec-butoxyphenyl)
Pyrimidine-5-carboxylate (benzamidine hydrochloride) Ethyl 1,6-dihydro-6-
(±)-2-sec- by a method similar to that described for the preparation of oxo-2-(2-n-butoxyphenyl)pyrimidine-5-carboxylate.
Butoxybenzamidine hydrochloride to ethyl (±)-1,6-dihydro-6-oxo-2-(2
-sec-butoxyphenyl)pyrimidine-5-
A carboxylate was produced. Melting point 134-136°C ₁₇ H ₂₀ N ₂ O ₄ Analysis values: Calculated value: C, 64.54; H, 6.37; N, 8.86 Measured value: C, 64.31; H, 6.12; N, 8.82 Manufacturing method 32: Ethyl 1・6-dihydro-6-oxo-
2-(2-isobutoxyphenyl)pyrimidine-5-carboxylate (benzamidine hydrochloride) Sodium (3.15 g,
While stirring, add 2-
Isobutoxyoxy-benzamidine (26.3g,
0.137 mol) followed by diethyl ethoxymethylene malonate (29.6 g, 0.137 mol).
The mixture was heated under reflux for 3 hours, then cooled and poured with 300 ml of ice water.
The pH was adjusted to 5 with glacial acetic acid. Collect the crystals (36.4 g, 85%, melting point 89-91°) formed by cooling.
The title compound was obtained by recrystallization from a 50% aqueous ethanol solution. Melting point 92-93°. Analytical values for C ₁₇ H ₂₀ N ₂ O ₄ : Calculated values: C, 64.54; H, 6.37; N, 8.86 Measured values: C, 64.66; H, 6.64; N, 8.69 Manufacturing method 33: Ethyl 1,6-dihydro- 6-Oxo-
2-(2-isobutoxyphenyl)pyrimidine-5-carboxylate (benzamidine fluorozulfonate) Sodium (161 mg, 7 mg
2-isobutoxybenzamidine fluorosulfonate (1.02 g, 3.5 mmol) was added to the solution containing - atoms). The mixture was warmed to a clear liquid, to which diethyl ethoxymethylene malonate (756 mg, 3.5 mmol) in 2 ml of ethanol was added and the liquid was heated under reflux for 3 hours. Cool the mixture with ice water 50 ml
ml and acidified the pH to 5 with glacial acetic acid. After stirring for a while, the solid was collected, washed with water, and dried to obtain the title compound (0.94 g, 86%). Melting point 90-91°. Production method 34: Ethyl 1,6-dihydro-6-oxo-
2-(2-isobutoxyphenyl)pyrimidine-5-carboxylate (Usage of _K2CO3 instead of alkali metal alkoxide) 2-isobutoxybenzamidine (5.76 g, 0.03 mol) in 70 ml _of ethanol ) and potassium carbonate (4.14 g, 0.03 mol) to which diethyl ethoxymethylene malonate (6.42 g, 0.03 mol) was added. The mixture was heated under reflux for 4 hours, cooled, poured into 100 ml of water, acidified to pH 8 with 6N hydrochloric acid, and then adjusted to pH 5 with glacial acetic acid.
The precipitate was filtered, washed with water, and dried to obtain the title compound (6.76 g, 71%). Melting point 88-90°. Production method 35: Ethyl 1,6-dihydro-6-oxo-
2-(2-isobutoxyphenyl)pyrimidine-5-carboxylate (coupling reaction without base condensing agent) The experiment described in Preparation 34 above was repeated, but this time without using potassium carbonate. The title compound was obtained in a yield of 69%. Melting point 89-91°. Production method 36: The following ethyl 1,6-
Dihydro-6-oxo-2-phenyl-pyrimidine-5-carboxylates were prepared from the corresponding benzamidine hydrochloride: A Ethyl 1,6-dihydro-6-oxo-2-
(2,5-dimethoxyphenyl)pyrimidine-5-carboxylate Melting point 149-150°C Analysis value for ₁₅ H ₁₆ N ₂ O ₅ : Calculated value: C, 59.20; H, 5.30; N, 9.21 Measured value :C, 59.07;H, 5.27;N, 9.23B Ethyl 1,6-dihydro-6-oxo-2-
(5-Chloro-2-ethoxyphenyl)pyrimidine-5-carboxylate Melting point 209-212°. Analytical values for C ₁₅ H ₁₅ ClN ₂ O ₄ : Calculated values:
C, 55.82; H, 4.68; Cl, 10.99; N, 8.68 Measured value:
C, 55.66; H, 4.76; Cl, 10.87; N, 8.78 C Ethyl 1,6-dihydro-6-oxo-2-
(2-ethoxy-5-methoxyphenyl)
Pyrimidine-5-carboxylate Melting point 149-152°. Analytical values for C ₁₆ H ₁₈ N ₂ O ₆ : Calculated: C, 60.37; H, 5.70; H, 8.80 Measured: C, 60.31; H, 5.68; N, 9.09 D Ethyl 1,6-dihydro-6- Oxo-2-
(2-methoxyphenyl)pyrimidine-5-
Carboxylate Melting point 148-150°. Analytical values for C ₁₄ H ₁₄ N ₂ O ₄ : Calculated: C, 61.31; H, 5.14; N, 10.21 Measured: C, 61.38; H, 5.05; N, 10.28 E Ethyl 1,6-dihydro-6- Oxo-2-
(2-Chloro-phenyl)pyrimidine-5-carboxylate Melting point 139-141°. Analytical values for C ₁₃ H ₁₁ ClN ₂ O ₃ : Calculated values:
C, 56.02; H, 3.98; Cl, 12.72; N, 10.05 Measured value:
C, 55.90; H, 3.83; Cl, 12.34; N, 10.16 F Ethyl 1,6-dihydro-6-oxo-2-
(3-methoxyphenyl)pyrimidine-5-
Carboxylate Melting point 169-170°C ₁₄ H ₁₄ N ₂ O ₄ Analysis: Calculated: C, 61.31; H, 5.14; N, 10.21 Measured: C, 60.96; H, 5.13; N, 10.16 G Ethyl 1・6-dihydro-6-oxo-2-
(3-Trifluoromethylphenyl)pyrimidine-5-carboxylate Melting point 151-152°C Analytical values for ₁₄ H ₁₁ N ₂ O ₃ : Calculated: C, 53.85; H, 3.55; N, 8.97 Measured: C , 53.84; H, 3.70; N, 8.71 H Ethyl 1,6-dihydro-6-oxo-2-
(4-methoxyphenyl)pyrimidine-5-
Carboxylate Melting point 230-232゜I Ethyl 1,6-dihydro-6-oxo-2-
(4-Chlorophenyl)pyrimidine-5-carboxylate Melting point 245-247°C Analytical values for ₁₃ H ₁₁ ClN ₂ O ₃ : Calculated values:
C, 56.02; H, 3.98; Cl, 12.72; N, 10.05 Measured value:
C, 55.94; H, 4.06; Cl, 12.46; N, 9.86 J Ethyl 1,6-dihydro-6-oxo-2-
Analytical values for (4-trifluoromethylphenyl)pyrimidine-5-carboxylate _C14H11F3N2O3 : Calculated: C, _53.85 ; H, _3.55 ; N, _8.97 Measured: C, 54.00 _; H, 3.62; N, 9.05 Production method 37: Ethyl 1,6-dihydro-6-oxo-
2-(5-Carbethoxy-2-ethoxyphenyl)pyrimidine-5-carboxylate (benzamidine free base) Sodium ethoxide (0.37 g, 5.45 mmol) and 5-carbomethoxy-2-ethoxy- in 15 ml of ethanol. Benzamidine (1.21g,
The mixture was cooled and stirred and diethyl ethoxymethylene malonate (1.18 g, 5.45 mmol) was added. The mixture was heated under reflux for 0.5 h, then cooled, poured into ice water, and acidified with acetic acid. The precipitate was recrystallized from ethanol to give colorless crystals of the title compound (1.49 g, 76%). Melting point 180−181.5
゜. Note that during the coupling reaction of carbomethoxybenzamidine and ethoxymethylene malonate, the ester changes (under the influence of NaOC ₂ H ₅ /C ₂ H ₅ OH) to form the 5′-carbethoxy product. Manufacturing method 38: Ethyl 1,6-dihydro-6-oxo-
2-(5-amino-2-ethoxyphenyl)
Pyrimidine-5-carboxylate A Ethyl 1,6-dihydro-6-oxo-2-
(2-Ethoxy-5-nitrophenyl)pyrimidine-5-carboxylate A mixture of 70% nitric acid (1.7ml, d=1.42) and 96% sulfuric acid (0.29ml, d=1.84) was cooled (ice water).
Add ethyl 1,6-dihydro- to this while stirring.
6-oxo-2-(2-ethoxyphenyl)
Pyrimidine-5-carboxylate (1.0g,
3.46 mmol) was added. The mixture was stirred at room temperature for 19 hours, poured into 300 ml of ice water, ground and filtered. The collected solid was recrystallized from acetonitrile to give the title compound (0.64 g, 55
%) was obtained. Melting point 222-224°. Analytical values for C ₁₅ H ₁₅ N ₃ O ₆ : Calculated: C 54.05; H, 4.54; N, 12.61 Measured: C, 54.32; H, 4.71; N, 12.56 B Ethyl 1,6-dihydro-6-oxo -2-
(5-amino-2-ethoxyphenyl)pyrimidine-5-carboxylate Ethyl 1,6-dihydro-6-oxo-2-(2-ethoxy-5
-Nitrophenyl)-pyrimidine-5-carboxylate (0.42 g, 1.26 mmol) and a mixture of 10% palladium on carbon (0.07 g) to approx.
It was treated with hydrogen at Kg/cm ² pressure until the absorption stopped. The mixture was filtered and the liquid was evaporated to dryness. The residue was recrystallized from water and then from aqueous ethanol to give the title compound (0.12g, 31.6%). melting point
107−110°. Analysis value for C ₁₅ H ₁₇ N ₃ O ₄・H ₂ O: Calculated value:
C, 56.07; H, 5.96; N, 13.08; _H2O , 5.62 Measured value:
C, 56.37; H, 5.70; N, 13.32; _H2O , 5.82 Process 39: Ethyl 1,6-dihydro-6-oxo-
2-(2-cyclopropylmethoxyphenyl)pyrimidine-5-carboxylate In Process 29, ethyl 1,6-dihydro-6-
The title compound was prepared from 2-cyclopropylmethoxybenzamidine hydrochloride by the same method described for the preparation of oxo-2-(2-allyloxyphenyl)pyrimidine-5-carboxylate. Melting point 104-105°C ₁₇ H ₁₈ N ₂ O ₄ Analysis values: Calculated value: C, 64.95; H, 5.77; N, 8.91 Measured value: C, 64.66; H, 5.93; N, 8.87 Manufacturing method 40: Ethyl 1・6-dihydro-6-oxo-
2-(5-methoxy-2-n-propoxyphenyl)pyrimidine-5-carboxylate In Process 29, ethyl 1,6-dihydro-6-
The title compound was prepared from 5-methoxy-2-n-propoxybenzamidine hydrochloride by the same method described for the preparation of oxo-2-(2-allyloxyphenyl)pyrimidine-5-carboxylate. Melting point 124-126゜Production method 41: Ethyl 1,6-dihydro-6-oxo-
2-(2,4-dimethoxyphenyl)pyrimidine-5-carboxylate 2,4-dimethoxybenzamidine (7.0 g, 0.0388 mol) and sodium (0.89 g, 0.0388 g-atom) in 50 ml of ethanol. A solution of diethyl ethoxymethylene malonate (8.4 g, 0.0388 mol) in 20 ml of ethanol was added dropwise to the mixture containing the following.
The mixture was heated under reflux for 2 hours, cooled, poured into ice water, and acidified with dilute hydrochloric acid. The precipitate was recrystallized from 95% ethanol to give ethyl 1,6-dihydro-6-
Oxo-2-(2,4-dimethoxy-phenyl)pyrimidine-5-carboxylate (9.0
g, 63.5%). Melting point 190-192°. Analytical values for C ₁₅ H ₁₆ N ₂ O ₅ : Calculated values: C, 59.20; H, 5.30; N, 9.21 Measured values: C, 59.15; H, 5.22; N, 9.19 Manufacturing method 42-1: General method of Manufacturing method 41 The following ethyl 1,6-dihydro-6-oxo-2-phenyl-pyrimidine-5-carboxylates were prepared from the reaction of the appropriate benzamidine with diethylethoxymethylene malonate. Ethyl 1,6-dihydro-6-oxo-2-(2
-Fluorophenyl-5-carboxylate Melting point 151-153°C ₁₃ H ₁₁ Analytical values for FN ₂ O ₃ : Calculated: C, 59.54; H, 4.23; H, 10.68 Measured: C, 59.69; H, 4.15 ;N, 11.05 Ethyl 1,6-dihydro-6-oxo-2-benzoyl-oxyphenyl)pyrimidine-5-carboxylate Melting point 156.5-157.5°. Analytical values for C ₂₀ H ₁₈ N ₂ O ₄ : Calculated value: C, 68.56; H, 5.18; N, 8.00 Measured value: C, 68.27; H, 4.99; N, 8.01 Manufacturing method 42-2: Ethyl 1,6- Dihydro-6-oxo-2-(2-ethylthiophenyl)pyrimidine-5-carboxylate Sodium (0.46 g, 20 mg in 12 ml ethanol)
- atoms) in chilled (ice water) 2-ethyl-thiobenzamidine hydrochloride (2.12 g, 10.0 mmol)
added. A solution of diethyl ethoxymethylene malonate (2.16 g, 10.0 mmol) in 4 ml of ethanol was added to the mixture and heated under reflux for 3.5 hours. The mixture was cooled, poured into 400 ml of ice water, and acidified to pH 6 with glacial acetic acid. The precipitate was collected and recrystallized from acetonitrile to give the title compound (2.04 g, 64.6%). melting point
117~120°. Analytical values for C ₁₅ H ₁₆ N ₂ O ₃ S: Calculated values: C, 59.19; H, 5.30; N, 9.20 Measured values: C, 59.42; H, 5.31; N, 9.37 Manufacturing method 42-3: Ethyl 1.6 -Dihydro-6-oxo-2-(2-methylthiophenyl)pyrimidine-5-carboxylate The title compound was prepared from 2-methylthiobenzamidine hydrochloride in the same manner as described in Preparation 42-2. (Published in U.S. Pat. No. 3,819,631.) The product recrystallized from benzene has a melting point of 155
It was -156°. Analytical value for C ₁₄ H ₁₄ N ₂ O ₃ S: Calculated value:
C, 57.92; H, 4.86; N, 9.65; S, 11.04 Measured values:
C, 57.93; H, 4.76; N, 9.71; S, 11.01 Manufacturing method 42-4: Ethyl 1,6-dihydro-6-oxo-2-(2-nitrophenyl)pyrimidine-
5-Carboxylate diethyl ethoxymethylene malonate (0.73
g, 3.44 mmol), potassium carbonate (0.95 g, 6.88
mmol) and ethanol (11 ml) were added to 2-nitrobenzamidine hydrochloride (0.69 g, 3.44 mmol) (prepared by the general method described in US Pat. No. 2,450,386). The mixture was heated under reflux for 3.5 hours, then cooled, and the filtrate was poured into 150 ml of ice water to adjust the acetic acid concentration to 6.0. The precipitate was collected and dried to give the title compound (0.20 g, 20.2%). Melting point 171-175°. Analytical material was prepared by recrystallization from acetonitrile. Melting point 175-177°. Analytical values for C ₁₃ H ₁₁ N ₃ O ₅ : Calculated value: C, 53.98; H3.83; N.14.53 Measured value: C, 53.62; H, 3.90; N, 14.35 Manufacturing method 42-5: Ethyl 1,6- Dihydro-6-oxo-2-(2-aminophenyl)pyrimidine-
5-carboxylate ethyl 1,6-dihydro-6-oxo-2-
(2-nitrophenyl)pyrimidine-5-carboxylate (0.91 g, 3.14 mmol), carbon (0.34
g) Top 10% palladium and 200ml of ethanol
The mixture was shaken in a hydrogen atmosphere with an initial pressure of 3.5 Kg/cm ² . After hydrogen absorption had ceased, the mixture was filtered and the liquid was concentrated. The residue was recrystallized from acetonitrile to give the title compound (0.455g, 54.5%). melting point
228-230° (decomposition) Analysis values for C ₁₃ H ₁₃ N ₃ O ₃ : Calculated value: C, 60.22; H, 5.05; N, 16.21 Measured value: C, 59.89; H, 4.98; N, 16.51 1.6 -Dihydro-6-oxo-2-phenyl-pyrimidine-5-carboxamides (general formula) can be produced as follows. Manufacturing method 43: 1,6-dihydro-6-oxo-2-
(2-Ethoxyphenyl)pyrimidine-5-carboxamide In a sealed container, 0.0 g of ethyl 1,6-dihydro-6-oxo-2-(2-ethoxyphenyl)pyrimidine-5-carboxylate and aqueous ammonia ( 120 ml, d=0.90) was heated on a steam bath for 4.5 hours. After partially evaporating this liquid, it was acidified to pH 3 with 6N hydrochloric acid. The collected solid was washed with water, dried, and N・N−
Recrystallization from dimethyl formamide gave the title compound (69.3 g, 77%). Melting point 236-238°. Analytical values for C ₁₃ H ₁₃ N ₃ O ₃ : Calculated values: C, 60.22; H, 5.05; N, 16.21 Measured values: C, 60.15; H, 5.11; N, 15.77 Manufacturing method 44: The method described in Manufacturing method 43 above The following carboxamides can be converted to the corresponding ethyl 1,6-dihydro-
Manufactured from 6-oxo-2-phenylpyrimidine-5-carboxylates. A 1,6-dihydro-6-oxo-2-(2-
n-propoxyphenyl)pyrimidine-5-carboxamide melting point 225-226°. Analytical values for C ₁₄ H ₁₅ N ₃ O ₃ : Calculated: C, 61.53; H, 5.53; N, 15.38 Measured: C, 61.76; H, 5.56; N, 15.14 B 1,6-dihydro-6-oxo -2-(2-
methoxyphenyl)pyrimidine-5-carboxamide melting point 218-219°. Analytical values for C ₁₂ H ₁₁ N ₃ O ₃ : Calculated: C, 58.77; H, 4.52; N, 17.14 Measured: C, 59.17; H, 4.48; N, 16.87 C 1,6-dihydro-6-oxo -2-(2-
isoproboxyphenyl)pyrimidine-5-carboxamide melting point 200-201°. Analytical values for C ₁₄ H ₁₅ N ₃ O ₃ : Calculated: C, 61.53; H, 5.53; N, 15.38 Measured: C, 61.42; H, 5.53; N, 14.99 D 1,6-dihydro-6-oxo -2-(2-
n-butoxyphenyl)pyrimidine-5-carboxamide melting point 181-183°. Analytical values for C ₁₅ H ₁₇ N ₃ O ₃ : Calculated values: C, 62.70; H, 5.96; N, 14.63 Measured values: C, 62.71; H, 5.94; N, 14.61 Manufacturing method 45: (±) -1・6 -dihydro-6-oxo-2-(2-sec-butoxyphenyl)pyrimidine-5-carboxamido ethyl (±)-1,6-dihydro-6-oxo-2-(2-sec-butoxyphenyl)pyrimidine-5 - 3.76 g of carboxylate and liquid ammonia (approximately 45 ml) are placed in a steel cylinder on a steam bath for 4 hours.
heated for an hour. Ammonia was removed, and the residue was dissolved in ice water and acidified with concentrated hydrochloric acid. The precipitate was recrystallized from methanol to give the title compound (2.99 g, 87.7%). Melting point 183-185゜C ₁₅ H ₁₇ N ₃ O ₃ Analytical values: Calculated value: C, 62.70; H, 5.96; N, 14.63 Measured value: C, 62.37; H, 5.95; N, 14.50 Manufacturing method 46:1. 6-dihydro-6-oxo-2-
(2-isobutoxyphenyl)pyrimidine-5
-carboxamide ethyl 1,6-dihydro-6-oxo-2-
(2-isobutoxyphenyl)pyrimidine-5-
Carboxylate (10.0 g, 0.0316 mol) and ammonium hydroxide (110 ml, d=0.9) were heated in a steel bomb for 4.5 hours. Part of the liquid was evaporated and the remainder was acidified with 6N hydrochloric acid. The mixture was filtered and the collected solid was recrystallized from N.N-dimethylformamide to give the title compound (7.5 g, 83%). melting point
230−231°. Analytical values for C ₁₅ H ₁₇ N ₃ O ₃ : Calculated value: C, 62.70; H, 5.96; N, 14.63 Measured value: C, 62.58; H, 5.91; N, 14.23 Manufacturing method 47: 1,6-dihydro-6 -Oxo-2-
(2-n-propoxyphenyl)pyrimidine-
5-carboxamide (at room temperature)
Example of using NH ₄ OH) Ethyl 1,6-dihydro-6-oxo-2-(2-
To a slurry of n-propoxyphenyl)pyrimidine-5-carboxylate (1811.4 g) was added 800 ml of tetrahydrofuran. After the solution was allowed to stand at room temperature for 64 hours, a portion of the solvent was evaporated and the resulting thick slurry was cooled and acidified to PH3 or less with 6N hydrochloric acid. The precipitate was filtered, washed with water, dried, and recrystallized from N.N-dimethyl-formamide to obtain the title compound (1407.7
mg, 86%). Melting point 227-229°. Preparation 48: The following carboxamides were prepared from the appropriate ethyl 1,6-dihydro-6-oxo-2-phenylpyrimidine-5-carboxylate by the general method of Preparations 43-47 above: A 1. 6-dihydro-6-oxo-2-(2-
Chlorophenyl)-pyrimidine-5-carboxamide, B 1,6-dihydro-6-oxo-2-(3-
methoxyphenyl)pyrimidine-5-carboxamide, C 1,6-dihydro-6-oxo-2-(3-
trifluoromethyl)pyrimidine-5-carboxamide D 1,6-dihydro-6-oxo-2-(4-
methoxyphenyl)pyrimidine-5-carboxamide, E 1,6-dihydro-6-oxo-2-(4-
trifluoromethyl)pyrimidine-5-carboxamide, F 1,6-dihydro-6-oxo-2-(2,
4-dimethoxyphenyl)pyrimidine-5-
Carboxamide, G 1,6-dihydro-6-oxo-2-(2-
fluorophenyl)-pyrimidine-5-carboxamide, H 1,6-dihydro-6-oxo-2-(2-
benzyloxyphenyl)pyrimidine-5-carboxamide, I 1,6-dihydro-6-oxo-2-(2-
ethylthiophenyl)pyrimidine-5-carboxamide, J 1,6-dihydro-6-oxo-2-(2-
methylthiophenyl)pyrimidine-5-carboxamide, K 1,6-dihydro-6-oxo-2-(2-
Aminophenyl) pyrimidine-5-carboxamide, Process 49: 1,6-dihydro-6-oxo-2-
(2-allyloxyphenyl)pyrimidine-5
-carboxamide ethyl 1,6-dihydro-6-oxo-2-
(2-allyloxyphenyl)pyrimidine-5-
50g carboxylate and 50ml liquid ammonia
The mixture was kept at 25° in a steel bomb for 18 hours and then heated on a steam bath for 2.5 hours. Ammonia was removed, the residue was dissolved in water, and the solution was acidified with acetic acid. The precipitated title compound (4.4 g, 97%) had a melting point of 202-204
The analytical material, which re-solidified at 275-280° and remelted again at 275-280°, had a melting point of 205-280°.
It was 207°. Analytical values for C ₁₄ H ₁₃ N ₃ O ₃ : Calculated value: C, 61.98; H, 4.83; N, 15.49 Measured value: C, 61.97; H, 4.79; N, 15.30 Manufacturing method 50: 1,6-dihydro-6 -Oxo-2-
(2-Cyclopropylmethoxyphenyl)pyrimidine-5-carboxamide Production of 1,6-dihydro-6-oxo-2-(2-allyloxyphenyl)pyrimidine-5-carboxamide in Process 49 The title compound was prepared from ethyl 1,6-dihydro-6-oxo-2-(2-cyclopropylmethoxyphenyl)-pyrimidine-5-carboxylate in the same manner as described for. The product recrystallized from ethanol (100%) had a melting point of 215-217°. Analytical values for C ₁₅ H ₁₅ N ₃ O ₃ : Calculated value: C, 63.15; H, 5.30; N, 14.73 Measured value: C, 63.00; H, 5.46; N, 14.62 Manufacturing method 51: 1,6-dihydro-6 -Oxo-2-
(5-methoxy-2-n-propoxyphenyl)pyrimidine-5-carboxamido ethyl 1,6-dihydro-6-oxo-2-
(5-methoxy-2-n-propoxyphenyl)
A mixture of pyrimidine-5-carboxylate (10.0 g) and concentrated ammonium hydroxide (100 ml) was heated on a steam bath in a sealed steel bomb for 4.5 hours. The reaction mixture was taken out and concentrated, and the pH was adjusted to 3 with 6N hydrochloric acid.
The collected solid was dried and recrystallized from acetonitrile to give the title compound (3.8 g, 41.6%). Melting point 206-207°. Analytical values for C ₁₅ H ₁₇ N ₃ O ₃ : Calculated: C, 59.39; H, 5.65; N, 13.86 Measured: C, 59.17; H, 5.81; N, 13.69 1,6-dihydro-6-oxo- 2-phenylpyrimidine-5-carbonitrile (general formula)
can be manufactured by the following method. Method A (via carboxamides) Process 52: 1,6-dihydro-6-oxo-2-
(2-ethoxyphenyl)pyrimidine-5-
Carbonitrile 1,6-dihydro-6 in 160ml of phosphorus oxyoxide
A solution containing 5.5 g of -oxo-2-(2-ethoxyphenyl)pyrimidine-5-carboxamide was heated under reflux for 3.5 hours. 150 ml of water was added to the viscous oil obtained by evaporating the liquid under reduced pressure, and the mixture was stirred vigorously and filtered. The collected solid was washed with water, dried and recrystallized from glacial acetic acid to give the title compound (3.48g, 68%).
Melting point 186-187°. Analytical values for C ₁₃ H ₁₁ N ₃ O ₂ : Calculated values: C, 64.72; H, 4.60; N, 17.42 Measured values: C, 65.09; H, 4.84; N, 17.75 Manufacturing method 53: The method described in Manufacturing method 52 above A 1,6-dihydro-6-oxo-2-( 2-
n-propoxyphenyl)pyrimidine-5-carbonitrile melting point 171-172°. Analytical values for C ₁₄ H ₁₃ N ₃ O ₂ : Calculated: C, 65.87; H, 5.13 Measured: C, 65.82; H, 5.22 B 1,6-dihydro-6-oxo-2-(2-
methoxyphenyl)pyrimidine-5-carbonitrile melting point 245-246°. Analytical values for C ₁₂ H ₉ N ₃ O ₂ : Calculated: C, 63.43; H, 3.99; N, 18.49 Measured: C, 63.09; H, 4.09; N, 18.22 C 1,6-dihydro-6-oxo -2-(2-
isopropoxyphenyl)pyrimidine-5-carbonitrile melting point 174-175°. Calculated N for C ₁₄ H ₁₃ N ₃ O ₂ : 16.46 Measured N: 16.53 D 1,6-dihydro-6-oxo-2-(2-
n-butoxyphenyl)pyrimidine-5-carbonitrile melting point 171.5-176.5°. Analytical values for C ₁₅ H ₁₅ N ₃ O ₂ : Calculated value: C, 66.90; H, 5.61; N, 15.61 Measured value: C, 66.58; H, 5.62; N, 15.46 E (±)-1,6-dihydro -6-oxo-2
-(2-sec-butoxyphenyl)pyrimidine-5-carbonitrile melting point 152-158°. Analytical values for C ₁₂ H ₁₅ N ₃ O ₂ : Calculated value: C, 66.90; H, 5.61; N, 15.61 Measured value: C, 66.59; H, 5.43; N, 15.77 Manufacturing method 54: 1,6-dihydro-6 -Oxo-2-
(2-isobutoxyphenyl)pyrimidine-
A mixture of 7.4 g of 5-carbonitrile 1,6-dihydro-6-oxo-2-(2-isobutoxyphenyl)pyrimidine-5-carboxamide and 150 ml of phosphorus oxychloride was heated under reflux for 3.5 hours. Excess phosphorus oxychloride was removed under reduced pressure, the residue was treated with 150 ml of water, stirred, cooled,
passed. The collected solid was crystallized from 50% aqueous acetic acid to give the title compound (3.9 g, 53%). Melting point 186-187°. Production method 55: 1,6-dihydro-6-oxo- by preparing the following carbonitrile by the general method of 52-54 above.
Prepared from 2-phenylpyrimidine-5-carboxamide. . A 1,6-dihydro-6-oxo-2-(2-
chlorophenyl)pyrimidine-5-carbonitrile, B 1,6-dihydro-6-oxo-2-(3-
methoxyphenyl)pyrimidine-5-carbonitrile, C 1,6-dihydro-6-oxo-2-(3-
trifluoromethylphenyl)pyrimidine-5
-carbonitrile, D 1,6-dihydro-6-oxo-2-(4-
methoxyphenyl)pyrimidine-5-carbonitrile, E 1,6-dihydro-6-oxo-2-(4-
trifluoromethyl)pyrimidine-5-carbonitrile, F 1,6-dihydro-6-oxo-2-(2,
4-dimethoxyphenyl)pyrimidine-5-
Carbonitrile, G 1,6-dihydro-6-oxo-2-(2-
fluorophenyl)pyrimidine-5-carbonitrile, H 1,6-dihydro-6-oxo-2-(2-
benzyloxyphenyl)pyrimidine-5-carbonitrile, I 1,6-dihydro-6-oxo-2-(2-
ethylthiophenyl)pyrimidine-5-carbonitrile, J 1,6-dihydro-6-oxo-2-(2-
methylthiophenyl)pyrimidine-5-carbonitrile, K 1,6-dihydro-6-oxo-2-(2-
Aminophenyl)pyrimidine-5-carbonitrile, Process 56: 1,6-dihydro-6-oxo-2-
(2-allyloxyphenyl)pyrimidine-5
-Carbonitrile 1,6-dihydro-6- in 60 ml of phosphorus oxychloride
Add 3.58 g of oxo-2-(2-allyloxyphenyl)pyrimidine-5-carboxamide to 2
After heating under reflux for an hour, it was evaporated to dryness. The residue was cooled with ice and then carefully treated with ice water. The mixture was warmed to 25° and then heated on a steam bath for 15 minutes. Wash the collected solid with cold water and add benzene-Skerisorb B.
The title compound (2.3 g, 69%) was obtained by recrystallization from . Melting point 162-164°. Analytical values for C ₁₄ H ₁₁ N ₃ O ₂ : Calculated values: C, 66.39; H, 4.38; N, 16.59 Measured values: C, 66.36; H, 4.45; N, 16.53 Manufacturing method 57: 1,6-dihydro-6 -Oxo-2-
(2-Cyclopropylmethoxyphenyl)pyrimidine-5-carbonitrile Pyrimidine (18.9 g,
0.24 mol) of the liquid was cooled and stirred, and 1.6
-dihydro-6-oxo-2-(2-cyclopropylmethoxyphenyl)pyrimidine-5-carboxamide (13.6 g, 0.0476 mol) was added.
Heated at reflux for 15 minutes. The mixture was evaporated to dryness and the residue was added to a mixture of ice and methylene chloride. The mixture was neutralized with sodium bicarbonate and the methylene chloride layer was dried (sodium sulfate) and concentrated. 1 N to the remaining oil
15ml sodium hydroxide and 10ml tetrahydrofuran
In addition, the mixture was left at 25° for 18 hours. The mixture was washed with diethyl ether and the solution was made acidic with acetic acid.
The precipitate was recrystallized from toluene to give the title compound (7.6 g, 59.6%). Melting point 188-190°. Analytical material was obtained by recrystallization from ethyl acetate. melting point
187−189°. Analytical values for C ₁₅ H ₁₃ N ₃ O ₂ : Calculated values: C, 67.40; H, 4.90; N, 15.72 Measured values: C, 67.00; H, 4.96; N, 15.50 Manufacturing method 58: 1,6-dihydro-6 -Oxo-2-
(5-methoxy-2-n-propoxyphenyl)pyrimidine-5-carbonitrile 1,6-dihydro-6-oxo-2-(5-methoxy-2-n
The title compound was prepared from -propoxyphenyl)pyrimidine-5-carboxamide and recrystallized from 2-propanol. (82.5%) Melting point 192−
194°. Analytical values for C ₁₅ H ₁₅ N ₃ O ₃ : Calculated: C, 63.15; H, 5.30; N, 14.73 Measured: C, 62.87; H, 52.8; N, 14.74 via) Manufacturing method 59: 1,6-dihydro-6-oxo-2-
(2-isopropoxyphenyl)pyrimidine-
Ethyl 2-cyano-3-(2-isopropoxybenzamidino)acrylate (0.60 g, 1.99 mmol) (prepared according to Preparation 60) in 15 ml of 5-carbonitrile dimethyl sulfoxide was dissolved in an oil bath at 100 ml of 5-carbonitrile dimethyl sulfoxide. Heated at ℃ for 18 hours. The cooled mixture was poured into 400 ml of ice water to give the title compound (0.40 g, 78.7%).
Melting point 182-184°. When toluene was used in place of dimethylsulfoxide in the above method, the yield of the crude product was 81.7%. Similarly, if N.N-dimethylformamide was used in place of dimethylsulfoxide, the yield of the product (melting point 184-188°) was 74%. Acrylate intermediates with the general formula can be prepared as follows: Process 60: Ethyl 2-cyano-3-(2-isopropoxybenzamino)acrylate Ethyl ethoxymethylenecyanoacetate (0.95
g, 5.61 mmol) in 7.1 ml of ethanol.
Isopropoxybenzamidodine (1.0g, 5.61
mmol) of ice-cold liquid. Mixture at 5°
After stirring for 1.5 hours, the title compound (1.2 g,
71%). The melting point is 118-122°, and the melting point of the analytical sample is 123-124° (decomposition). Analytical values for C ₁₆ H ₁₉ N ₃ O ₃ : Calculated values: C, 63.77; H, 6.36; N, 13.95 Measured values: C, 63.57; H, 6.25; N, 14.02 In the above method, N・N was used instead of ethanol. −
A similar operation using dimethylformamide yields ethyl 2-cyano-3-(2-isopropoxybenzamidino)acrylate (melting point 118-120).
) was obtained with a yield of 76.2%. Example 1 2-(2-ethoxyphenyl)-5-(5-1H
-tetrazolyl)-pyrimidine-4-(3H)-one 1,6-dihydro-6-oxo-2-(2-ethoxyphenyl)-pyrimidine-5-carbo in 18 ml of dry N.N-dimethylformamide. A mixture of nitrile (2.17 g, 9.0 mmol), sodium azide (0.645 g, 9.9 mmol) and ammonium chloride (0.53 g, 9.9 mmol) was heated at 125° for 16
Stir for hours. The solvent was removed under reduced pressure, water was added to the residue, and the resulting slurry was acidified with 1N hydrochloric acid. The solid collected by filtering the mixture was washed with water, dried and recrystallized from glacial acetic acid to give the title compound (1.28 g, 50%). The melting point of the analytical sample was 289-290° (decomposed). Analysis value of C ₁₃ H ₁₂ N ₆ O ₂ : Calculated value: C, 54.92; H, 4.26; N, 29.57 Measured value: C, 55.09; H, 4.32; N, 29.29 Example 2 2-(2-n- propoxyphenyl)-5-(5
-1H-tetrazolyl)pyrimidine-4(3H)
-one 1,6-dihydro- used in Example 1
Instead of 6-oxo-2-(2-ethoxyphenyl)pyrimidine-5-carbonitrile, an equimolar amount of 1,6-dihydro-6-oxo-2-(2-n
The title compound was produced in a similar manner using -propoxyphenyl)pyrimidine-5-carbonyl. Melting point 247-248°. Calculated N for C ₁₄ H ₁₄ N ₆ O ₂ : 28.17 Measured N: 28.27 Example 3 2-(2-isopropoxyphenyl)-5-(5
-(1H-tetrazolyl)pyrimidine-4
(3H)-one 1,6-dihydro- used in Example 1
Instead of 6-oxo-2-(2-ethoxyphenyl)pyrimidine-5-carbonitrile, an equimolar amount of 1,6-dihydro-6-oxo-2-(2-isopropoxyphenyl)pyrimidine-5- A similar method was repeated using carbonitrile to produce the title compound. Melting point 275-276 (decomposed). Analytical values for C ₁₄ C ₁₄ N ₆ O ₂ : Calculated values: C, 56.37; H, 4.73; N, 28.17 Measured values: C, 56.22; H, 4.75; N, 28.13 Example 4 2-(2-n- butoxyphenyl)-5-(5
-1H-tetrazolyl)-pyrimidine-4
(3H)-one 1,6-dihydro- used in Example 1
Instead of 6-oxo-2-(2-ethoxyphenyl)pyrimidine-5-carbonitrile, an equimolar amount of 1,6-dihydro-6-oxo-2-(2-n
A similar procedure was repeated using -butoxyphenyl)pyrimidine-5-carbonitrile to produce the title compound. Melting point 244-247° (decomposition). Analytical values for C ₁₅ H ₁₆ N ₆ O ₂ : Calculated value: C, 57.68; H, 5.16; N, 26.91 Measured value: C, 57.41; H, 5.13; N, 27.09 Example 5 (±)-2-( 2-sec-butoxyphenyl)-
5-(5-1H-tetrazolyl)pyrimidine-4
(3H)-one in equimolar amounts (±) in place of 1,6-dihydro-6-oxo-2-(2-ethoxyphenyl)-pyrimidine-5-carbonitrile used in the method of Example 1. A similar procedure was repeated using -1,6-dihydro-6-oxo-2-(2-sec-butoxyphenyl)pyrimidine-5-carbonitrile to produce the title compound. Melting point: 240-242° (decomposition) It is important to note that because the product of this example has an asymmetric carbon atom, it exists as a racemate, that is, it is a mixture of equal amounts of (+) and (-) optical isomers. If dissolved in a manner known per se, the individual (+) and (-) isomers will be obtained. Analytical values for C ₁₅ H ₁₆ N ₆ O ₂ : Calculated value: C, 57.68; H, 5.16; N, 26.91 Measured value: C, 57.49; H, 5.09; N, 26.66 Example 6 2-(2-methoxy phenyl)-5-(5-1H
-Tetrazolyl)-pyrimidin-4(3H)-one To a solution of aluminum chloride (193 mg, 1.45 mmol) in 8 ml of tetrahydrofuran was added sodium azide (283 mg, 4.35 mmol). 0.5 mixture
After stirring at reflux for an hour, 1,6-dihydro-6-oxo-2-(2-methoxyphenyl)pyrimidine-5-carbonitrile (300 mg, 1.32 mmol) was added and the mixture was stirred at reflux for 24 hours. The mixture was cooled, diluted with 15 ml of water, acidified with 6N hydrochloric acid, the mixture was filtered and the solid was recrystallized from glacial acetic acid to give the title compound (130 mg, 36.4%). Melting point 282−
283 (decomposition). Analytical values for C ₁₂ H ₁₀ N ₆ O ₂ : Calculated value: C, 53.33; H, 3.73; N, 31.10 Measured value: C, 53.20; H, 3.74; N, 31.50 Example 7 2-(2-isobut oxyphenyl)-5-(5
-1H-tetrazolyl)pyrimidine-4(3H)
-one 1,6-dihydro-6-oxo-2-(2-isobutoxyphenyl)pyrimidine-5-carbonitrile (3.78 g, 0.014 mol), sodium azide (1 ,
A mixture of 0 g, 0.0154 mol) and ammonium chloride (0.824 g, 0.0154 mol) was heated and stirred at 125° for 19 hours. Remove the solvent under reduced pressure and add the residue to 40 ml of water.
and treatment 6 It was made acidic with N hydrochloric acid. The mixture was filtered and the solid collected was recrystallized from glacial acetic acid to give the title compound (2.4 g, 55%). Melting point 230-231°. Analytical values for C ₁₅ H ₁₆ N ₆ O ₂ : Calculated value: C, 57.68; H, 5.16; N, 26.91 Measured value: C, 57.52; H, 5.27; N, 26.72 Example 8 2-(2-allyloxy phenyl)-5-(5-
1H-tetrazolyl)pyrimidine-4(3H)-
Aluminum chloride (1.71 g, 0.0128 mol) and then sodium azide (2.5 g, 0.0384 mol) were added slowly to 100 ml of tetrahydrofuran with stirring. The mixture was heated under reflux for 30 minutes and then 1,6-dihydro-6-oxo-2-(2-allyloxyphenyl)pyrimidine-5-carbonitrile (3.23
g, 0.0128 mol) and further heated under reflux for 18 hours. The reaction mixture was cooled, diluted with water, and acidified with 6N hydrochloric acid. The precipitate was collected and recrystallized from 95% ethanol to give the title compound (1.4 g, 37%). Melting point 221-225°. An analytical sample was obtained by recrystallization twice from acetic acid. Melting point: 230.5-232° (decomposed). Analytical values for C ₁₄ H ₁₂ N ₆ O ₂ : Calculated values: C, 56.75; H, 4.08; N, 28.37 Measured values: C, 56.71; H, 4.24; N, 28.40 Example 9 2-(2-cyclopropyl methoxyphenyl)-5-(5-1H-tetrazolyl)pyrimidin-4(3H)-one 1.
6-dihydro-6-oxo-2-(2-cyclopropylmethoxyphenyl)pyrimidine-5-carbonitrile (4.5 g, 0.0168 mol), sodium azide (1.2 g, 0.0184 mol) and ammonium chloride (0.99 g, 0.0185 mol) was stirred on an oil bath for 20 hours while maintaining the temperature at 125°. The residue was diluted with water and the mixture was made acidic with concentrated hydrochloric acid. The resulting precipitate was the title compound (4.7 g, 90%, mp 237-
243 (decomposition)) from acetic acid to obtain a sample for analysis. Melting point 252-254° (decomposed). Analytical values for C ₁₅ H ₁₄ N ₆ O ₂ : Calculated value: C, 58.05; H, 4.55; N, 27.09 Measured value: C, 58.16; H, 4.66; N, 27.04 Example 10 2-(5-methoxy- 2-n-propoxyphenyl)-5-(5-1H-tetrazolyl)pyrimidin-4(3H)-one In Example 9, 2-(2-cyclopropylmethoxyphenyl)-5-(5-1H- The title compound was prepared in the same manner as described for the preparation of 1,6-dihydro-6-oxo-2-(5-methoxy-2
-n-propoxyphenyl)pyrimidine-5-carbonitrile. The crude product was recrystallized from 2-methoxyethanol to obtain an analytical sample. (65%) Melting point 257-260°. Analytical values for C ₁₅ H ₁₆ N ₆ O ₃ : Calculated value: C, 54.87; H, 4.91; N, 25.60 Measured value: C, 54.92; H, 4.90; N, 25.69 Example 11 2-(2-isopropoxy Phenyl-5-(5-
1H-tetrazolyl)pyrimidine-4(3H)-
(via acrylate intermediate) A solution of ethyl 2-cyano-3-(2-isopropoxybenzamidino)-acrylate (0.60 g, 1.99 mmol) in 15 ml of N.N-dimethylformamide was dissolved in sodium azide (0.159 mmol). g, 2.44 mmol) and ammonium chloride (0.131 g, 2.44 mmol) were added. The mixture was heated at 127° for 21 hours, cooled, poured into 400 ml of ice water, and pHed with 6N hydrochloric acid.
It was set as 2. The mixture was filtered and the collected solid was recrystallized from 2-methoxyethanol to give the title compound (0.06 g, 10%). Melting point 274-277°. Example 12 2-(2-n-propoxyphenyl)-5-(5
-1H-tetrazolyl)pyrimidine-4(3H)
-one (single step method example) 2-n-propoxybenzamidine (1.00 g,
5.61 mmol) was cooled (ice water), and ethyl ethoxymethylene cyanoacetate (0.94
g, 5.61 mmol) were added. After 20 minutes, additional sodium azide (0.447 g, 6.88 mmol) and ammonium chloride (0.368 g, 6.88 mmol) were added. Remove the ice bath and keep the mixture at 127° in an oil bath.
Heated for 30 hours. The mixture was cooled, poured into 400 ml of ice water, and acidified with 6N hydrochloric acid. The resulting solid was collected (0.93 g, mp 245-248° (decomposed)) and recrystallized from 2-methoxyethanol to give the title compound. (0.69g, 41%) Melting point 256-257°. (Decomposition) Example 13 2-(2-isopropoxyphenyl)-5-(5
-1H-tetrazolyl)pyrimidine-4(3H)
-one (single step method) The title compound was made in a similar manner using 2-isopropoxybenzamidine in place of 2-n-propoxybenzamidine in Example 12.
The recrystallized product (38%) has a melting point of 282-283° (decomposed)
It was hot. Example 14 2-(5-nitro-2-n-propoxyphenyl)-5-(5-1H-tetrazolyl)pyrimidin-4(3H)-one 70% nitric acid (1.7 ml, 26.9 mmol) and concentrated sulfuric acid 2
ml of the mixture was cooled to 5° and 2-(2-n-
propoxyphenyl)-5-(5-1H-tetrazolyl)pyrimidin-4(3H)-one (1.03 g,
3.46 mmol) was added over 20 minutes. The mixture was left at room temperature for 2 hours, then poured into 200 ml of ice water, and the resulting precipitate was recrystallized from 2-methoxyethanol to obtain the title compound (0.73 g, 61.3%). Melting point 251-252° (decomposition). Analytical values for C ₁₄ H ₁₃ N ₇ O ₄ : Calculated: C, 48.98; H, 3.82; N, 28.56 Measured: C, 48.76; H, 3.71; N, 28.47 Example 15 2-(5-amino- 2-n-Propoxyphenyl)-5-(5-1H-tetrazolyl)pyrimidin-4(3H)-one 2-(5-
Nitro-2-n-propoxyphenyl)-5-(5
-1H-tetrazolyl)pyrimidine-4(3H)-
A mixture of 5.0 g of 10% palladium on carbon and 4.0 g of carbon was shaken for 19 hours in a hydrogen atmosphere with an initial pressure of 3.5 Kg/cm ² .
The mixture was filtered and the liquid was evaporated to dryness to give the title compound (3.6 g, 79%). Melting point 250-253° (decomposition). A sample for analysis was obtained by recrystallization from 2-methoxyethanol. Melting point 261-262°. Analytical values for C ₁₄ H ₁₅ N ₇ O ₂ : Calculated value: C, 53.66; H, 4.83 Measured value: C, 53.92; H, 5.04 Example 16 2-(5-dimethylamino-2-n-propoxyphenyl )-5-(5-1H-tetrazolyl)
Pyrimidin-4(3H)-one 2-(5-amino-2
-n-propoxyphenyl)-5-(5-1H-tetrazolyl)pyrimidin-4(3H)-one (0.50
A 37% aqueous formaldehyde solution (1.32 ml, 16.0 mmol) was added to a suspension of 37% aqueous formaldehyde (1.32 ml, 16.0 mmol). Then sodium cyanoborohydride (0.302
g, 4.8 mmol) and then glacial acetic acid (1.67 ml) were added. The suspension was stirred at room temperature for 15 hours and then heated under reflux for 3 hours. The mixture was cooled in an ice bath and the resulting precipitate was recrystallized from acetonitrile to give the title compound (0.19 g, 35%). Melting point 258-259°. Analytical values for C ₁₆ H ₁₉ N ₇ O ₂ : Calculated values: C, 56.29; H, 5.61; N, 28.73 Measured values: C, 55.92; H, 5.42; N, 28.63 Example 17 2-(2-n- propoxyphenyl)-5-(5
-1H-tetrazolyl)pyrimidine-4(3H)
-one sodium salt A slurry of 2-(2-n-propoxyphenyl)-5-(5-1H-tetrazolyl)pyrimidin-4(3H)-one (298 mg, 1 mmol) in 10 ml of water with 1N sodium hydroxide 1 ml was added. The obtained liquid was filtered, the liquid was concentrated, acetone was added, and the mixture was stirred for 20 minutes. Sodium salts were over-collected, washed with acetone, dried, and left in the air for one week. Analytical values for C ₁₄ H ₁₃ N ₆ NaO ₂・2H ₂ O: Calculated values: C, 47.19; H, 4.81; N, 23.59;
H ₂ O, 10.11 Measured value: C, 47.37; H, 4.55; N, 24.54;
H ₂ O, 11.70 2-(2-n-propoxy-
Instead of phenyl)-5-(5-1H-tetrazolyl)pyrimidin-4(3H)-one, an equimolar amount of other 5-(5-1H-tetrazolyl)pyrimidin-4
(3H)-one compounds (Examples 1, 3-11 and 13
-17) can be used to obtain the sodium salt of each compound. If other bases such as KOH, Ca(OH) ₂ , Mg(OH) ₂ or NH ₄ OH are used in place of sodium hydroxide in the above process, the corresponding base addition salts are obtained. 5-(5-1H-) produced in Example 1-16
Tetrazolyl)pyrimidin-4(3H)-one compounds are prepared by adding a methanolic solution of the desired pyrimidin-4(3H)-one compound to a suitable acid, such as HCl,
The acid addition temperature can be converted by adding stoichiometric equivalents of HBr, HI, CH ₃ COOH or H ₃ PO ₄ . Example 18 2-(2-n-propoxyphenyl)-5-(5
-1H-tetrazolyl)pyrimidine-4(3H)
Ethanolamine monohydrate salt of 2-(2-n-propoxyphenyl)-5-(5-1H-tetrazolyl) finely ground in distilled water 7
Freshly distilled ethanolamine (141.6 g, 2.32 moles) was added to a stirring suspension of pyrimidin-4-(3H)-one (671.4 g, 2.25 moles).
Stir at 40° until almost all of the mixture is in solution. The mixture was filtered to make the liquid lyophilic and the title compound (831.4 g, 98
%) produced. Melting point 145-148°. Analytical values for C ₁₄ H ₁₄ N ₆ O ₂・C ₂ H ₇ NO・H ₂ O: Calculated values: C, 50.92; H, 6.14; N, 25.98;
H ₂ O, 4.77 Measured value: C, 50.71; H, 6.09; N, 26.18;
H ₂ O, 5.64 Example 19 2-(2-n-propoxyphenyl)-5-(5
-1H-tetrazolyl)pyrimidine-4(3H)
Ethylenediamine dihydrate salt of 2-(2-n-propoxyphenyl)-5-(5-1H-tetrazolyl)pyrimidin-4(3H)-one (2.98 g, 0.010 mol) in 30 ml of water. Ethylenediamine (0.625g,
0.0104 mol) was added. Gentle warming brought the whole into solution which made it lyophilic to produce a quantitative yield of the title compound and was allowed to equilibrate in air for one month. Melting point 177−180
Analysis values for ゜C ₁₄ H ₁₄ N ₆ O ₂・C ₂ H ₈ N ₂・2H ₂ O: Calculated values: C, 48.72; H, 6.64; N, 28.41;
H ₂ O, 9.13 Measured value: C, 48.98; H, 6.21; N, 29.25;
H ₂ O, 8.75 Example 21 The following 2-(2-
A water _- soluble salt _of n-propoxyphenyl)-5-(5-1H _- tetrazolyl)pyrimidin-4(3H)-one was prepared: _{diethanolamine salt C14H14N6O2.C4H11NO2 ,} Melting point 138-143゜ Triethanolamine salt C ₁₄ H ₁₄ N ₆ O ₂・C ₆ H ₁₅ NO ₃ , Melting point 146-199゜ Tris(hydroxymethyl)aminomethane salt C ₁₄ H ₁₄ N ₆ O ₂・C ₄ H ₁₁ NO ₃ , melting point 180-195° instead of 2-(2-n-propoxyphenyl)-5-(5-1H-tetrazolyl)pyrimidin-4(3H)-one in the method of Examples 18-20 Corresponding salts of each compound using equimolar amounts of other 5-(5-1H-tetrazolyl)pyrimidin-4(3H)-one compounds (prepared in Examples 1, 3-11 and 13-16) is obtained. Example 21 2-(2-n-pentyloxyphenyl)-5-
(5-1H-tetrazolyl)pyrimidine-4
(3H)-3H)-one 70 ml of a solution of ethyl ethoxymethylene cyanoacetate (24.6 g, 0.145 mol) in 50 ml of N-N-dimethylformamide (DMF).
2-n-pentyloxybenzamidine (30.0 g, 0.145 mol) was added to DMF and cooled (ice water).
Added dropwise to the stirring solution over 10 minutes. Stir for an additional 20 minutes and add sodium azide (11.5 g, 0.178 mole) and ammonium chloride (9.5 g, 0.178 mole). The mixture was heated for 24 hours using an oil bath maintained at 123-127°C. The mixture was poured into cold water and acidified with 50 ml of concentrated hydrochloric acid. The solid content was collected and recrystallized using 2-methoxyethanol to obtain the title compound (18.1 g, 38%, decomposed). Recrystallization using 2-methoxyethanol followed by 2-propanol gave colorless needles. melting point
236-238℃ (decomposition). Analytical values _{for C16H18N6O2} : Calculated: C, 58.88; _H , 5.56; N, 25.75 _. Measured values: C, 58.77; H, 5.69; N, 25.55. The title compound was tested orally in a rat PCA screen and showed an ID _{50 of} 0.4 mg/Kg. The compound was solubilized with aqueous sodium bicarbonate 10 minutes before administration.

Claims (1)

[Claims] 1 Formula: [In the formula, R ¹ , R ² and R ³ may be the same or different and each represents hydrogen, lower alkoxy, -O-lower alkenyl, cyclopropylalkyloxy, amino,
nitro or di(lower) alkylamino, but are not all the same except when R ¹ , R ² and R ³ all represent lower alkoxy. Compounds and their pharmaceutically acceptable salts. 2 formula: [In the formula, R ¹ is lower alkoxy, -O-lower alkenyl or cyclopropylalkyloxy, and R ² is hydrogen, lower alkoxy, nitro, amino or di(lower)alkylamino] A compound according to scope 1 or a pharmaceutically acceptable salt thereof. 3 R ¹ is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, allyloxy or cyclopropyl-methoxy, and R ² is hydrogen, methoxy, ethoxy, n-propoxy,
The compound according to claim 2, or a pharmaceutically acceptable salt thereof, which is isopropoxy, n-butoxy, isobutoxy, sec-butoxy, amino, nitro, or dimethylamino. 4. The compound or a pharmaceutically acceptable salt thereof according to claim 2 or 3, wherein R ¹ is n-propoxy and R ² is hydrogen. 5. Sodium salt of the compound according to claim 4. 6. Ethanolamine salt of the compound according to claim 4. 7. Ethylenediamine salt of the compound according to claim 4. 8 Formula: [In the formula, R ¹ , R ² and R ³ may be the same or different and each represents hydrogen, lower alkoxy, -O-lower alkenyl, cyclopropylalkyloxy, amino,
nitro, or di(lower) alkylamino, but are not all the same except when R ¹ , R ² and R ³ all represent lower alkoxy. characterized in that ethyl ethoxymethylene cyanoacetate is reacted with equimolar amounts of sodium azide and ammonium chloride in an inert organic solvent and, if necessary, the compound thus formed is converted into the corresponding pharmaceutically acceptable salt. Formula to: (In the formula, R ¹ , R ² and R ³ are as defined above.) A method for producing a compound represented by the formula and pharmaceutically acceptable salts thereof. 9. The method of claim 8, wherein the inert solvent is selected from the group consisting of dimethylformamide, dimethylacetamide, dimethylsulfoxide and hexamethylphosphoramide. 10. The method of claim 8 or 9, wherein the reaction is carried out at a temperature of about 100°C to the reflux temperature of the solvent system.