JPS6261591B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a thienooxamate compound having the following general formula and a method for producing the same. Although the compound of the present invention has antiallergic activity by itself,
It is useful as an intermediate in the synthesis of thieno[2,3-d]pyrimidines, which are very useful antiallergic agents. The present invention also provides
It is closely related to the thienoxazines of the formula (which, like the compounds of the present invention, have antiallergic activity in their own right and are likewise useful as intermediates in the synthesis of compounds of the formula).

【formula】

【formula】

These substances are useful in the treatment of allergic diseases characterized by episodes of acute attack induced by inhalation or ingestion of allergens, and in particular asthma, hay fever, as well as food allergies. These compounds have the advantage for long-term prophylactic use of virtually no other pharmacological effects and low toxicity. Preferred members are orally active. In the formula, the symbol R ² refers to a carboxylic acid substituent or a lower alkyl ester thereof or a non-toxic pharmacologically inert metal salt. It is also R ²
is a vinyl substituent of CH=CHCO ₂ R ³ (R ³ is hydrogen, lower alkyl having 1 to 8 carbon atoms, or a non-toxic pharmacologically inert metal cation) carboxylic acids, esters, and salts. The term "non-toxic pharmacologically inert cation" means that the cation has no adverse or noxious pharmacological effect on the host at the doses required for administration of one of the salts containing the cation. It means. Preferred metal cations are the alkali metals sodium and potassium, but other non-toxic pharmacologically inert cations such as calcium, magnesium, aluminum, zinc, and barium are also suitable. R ₂ may also be a methylol group or a formate, or a lower alkyl ester thereof. R ² is also carboxaldehyde, 5-
Tetrazolyl, or N-(tetrazole-5-
yl)carbamyl group. In summary,
R ² is a group having one of the following formulas, in which R ³ has the meaning indicated above and R is lower alkyl having 1 to 8 carbon atoms. −CO ₂ R ³ , −CH=CHCO ₂ R ³ , −CH ₂ OH,

【formula】 【formula】

【formula】

【formula】

[Formula] In the formula, R ³ is the same as above, R ⁵ and
R ⁶ is hydrogen, lower alkyl with 1 to 8 carbon atoms, lower alkenyl with 3 to 6 carbon atoms, lower alkoxy with 1 to 6 carbon atoms, hydroxy, nitro, amino, chlorine, bromine ,
Iodine and halo containing fluorine, phenyl, 2
may be alkanoyl having ~6 carbon atoms or cycloalkene rings having a total of 5 to 7 ring carbon atoms or 5 to 7 ring carbon atoms bonded to each other and fused to a thiophene ring. R-substituted cycloalkene having a carbon atom (wherein R is
with the same meaning as above). In the formula ^, R ³ has the same meaning as above and A is a covalent bond connecting -CO ₂ R ³ to the ring _or a vinyl group, -
CH=CH−. Symbols L and B are R ⁵ and R ⁶
means some of the same groups defined for
Their definition is somewhat limited. L and B may be hydrogen, lower alkyl having 1 to 8 carbon atoms, lower alkenyl having 3 to 6 carbon atoms, phenyl, alkanoyl having 2 to 6 carbon atoms, or a cycloalkene ring fused to a thiophene ring and having 5 to 7 cyclic ring carbon atoms or an R-substituted cycloalkene having 5 to 7 cyclic ring carbon atoms, where R has the same meaning as above. ) may be formed. In the formula, the symbols R ³ L and B have the same meaning as given for the formula and A represents a covalent bond. Compounds of formulas and inhibit granule reduction in sensitized mast cells. Immediate sensitivities such as asthma, hay fever, allergic rhinitis, measles, and food allergies are caused by immunoglobulin E (sometimes called reagin antibodies) reacting with antigens on the cell membrane of mast cells, resulting in the production of gradikinin and histamine. ,
It is thought to be mediated by initiating reactions within mast cells that release mediating agents such as serotonin or slow reactant substance A (SRS-A). Mediators cause changes in end organs such as the respiratory tract, blood vessels, skin, and mucous membranes, resulting in symptoms of allergic attack. This substance is believed to prevent the release of mediators and thereby prevent allergic attacks. However, they are useful in the prophylactic treatment of humans with hypersensitivity of the type mentioned above, preventing acute allergic attacks such as asthma attacks. Suitable compounds are particularly distinguished by the fact that they are orally active, have extremely low toxicity, and are substantially devoid of other types of pharmacological action, including antihistamine action. Therefore, they are not primarily of value in the treatment of acute allergic reactions, but rather are used prophylactically by hypersensitive individuals to prevent the development of allergic reactions when exposed to allergens for hypersensitive conditions. It is especially valuable to be It has been shown in the prior art that the activity of test compounds in the case of passive cutaneous anaphylaxis (PCA) in rats correlates with the usefulness of the active compound in the treatment of immediate hypersensitivity conditions such as asthma. Using a male Sprague Dawley (Carworth Farms) or Wistar (Harlan) rat weighing 100-175 g, substantially
Lactreagin antiserum is prepared according to the method of Immunology 7 , 681-699 (1964). Rats are injected intramuscularly with a solution of egg albumin in saline at a dose of 10 mg per kg and intraperitoneally with 2×10 ¹⁰ Bordetella pertussis bacteria. Twelve days after injection, serum is collected and antibody titers are determined. Sera containing enough antibodies to produce a 10 mm spot on the dorsal skin of rats in the PCA test after 10-fold dilution are pooled. The highest dilution of antiserum that can cause PCA in rats 48-72 hours after injection is usually 50-80. In conducting this test, groups of 5 to 10 male Sprague-Dawleys (Carworth Farms) (each weighing 100 to 150 g) are used. Before exam 48
At time, animals are passively sensitized by intradermal injection of 0.1 ml of diluted antiserum at various locations on the dorsal depilated skin. Use a dilution of the antiserum to obtain spots 20-25 mm in diameter after challenge. A relatively high dilution of the antiserum is injected such that the activity of less potent compounds can be measured relatively sensitively at at least one location. There is usually an incubation period of 48 hours before challenging the animal. According to standard screening procedures, test drugs are administered by intraperitoneal injection, intraperitoneal injection, or oral ingestion 15 minutes before the challenge. The challenge is 25mg/saline solution.
It is carried out by intravenous injection of ovalbumin at a dose of Kg and Evans Blue dye at 25 mg/Kg. The dye simply acts as a marker. The response to the antigen challenge at the previously sensitized skin location causes an increase in capillary permeability at the sensitized location and leakage of blue pigment into the area surrounding the sensitized location. The PCA response is scored by measuring the mean spot diameter on the excised and reversed skin 20-30 minutes after the challenge. A group of non-drug control animals is used in each experiment. Percent inhibition of PCA is determined by measuring the mean diameter of the spots in the control and treated animals, calculating the difference in the square of the mean diameter of the control and treated animals, and expressing this difference as a percentage of the mean diameter of the control animal squared. Calculated by. Results are expressed as percent inhibition. Rats may be injected intradermally with 0.1 ml of a solution containing 1 mg/ml histamine 10 minutes before death. This allows it to be determined whether the test compound exhibits an antihistamine effect on the end organs in blocking PCA rather than interfering with mediator release from mast cells. When dose-response curves are to be constructed for quantitative comparisons of potency between active compounds, different doses of test compounds are used in parallel experiments. 50% of PCA
The dose ID ₅₀ at which inhibition occurs is determined by interpolation. In other variations, various intervals are used between drug treatment and challenge to ensure the durability of the drug's effect. A more complex test reflecting the usefulness of this substance in the treatment of immunologically induced tracheal constriction is the allergic respiratory model in rats, in which each body weight 225 ml as before for the preparation of the Reagen antiserum. ~275
G male Harlan rats are actively sensitized with ovalbumin and B. pertussis vaccine (2 x 10 ¹⁰ bacteria per rat). 13-15 days after sensitization, rats are prepared for intraduodenal administration of compounds by exposing the duodenum through a small intestinal incision, cannulating the cervix, cervix, and trachea. A jugular cannula is used to administer egg albumin challenge, and blood pressure is measured from the jugular cannula through the cannula. The tracheal cannula is connected to a glass T-tube,
One arm is open to the atmosphere, and the other arm is connected to a pressure transducer to measure inspiration and expiration pressures. Changes in inspiratory and expiratory pressures are monitored as a reflection of changes in airway resistance after challenge with egg albumin antigen. The drug was administered into the duodenum 15 minutes before the challenge with egg albumin injection.
Measure the change in airway resistance compared to control animals.
The challenge dose of antigen is approximately 36 cm above the inspiratory and expiratory pressures.
% reduction - which was found to be approximately the maximum the animal could survive. The effect of the drug on this reduction in expiratory and inspiratory pressures is then determined for various doses of the drug. The dose that produces a half-maximal response is determined by interpolation from the dose-response curve (ID = max). The data presented in the following table reflect the oral antiallergic effect of some of the substances of the invention in the above-mentioned tests.

Table: Cromolyn sodium is inactive upon oral administration in the above test. This substance is used clinically for the prophylactic treatment of asthmatic patients by oral inhalation, and its activity is reflected in the rat PCA study described above when administered by intravenous or intraperitoneal injection. When chronotropically administered cromolyn sodium simultaneously with antigen, it can show an ID ₅₀ of about 1 mg/Kg in rats in the PCA test. Similarly, the inherent activity of the substances of the invention, which show a reduced level of activity in the PCA test when administered orally, compared to the activity of the substances shown in the table above, is due to the intraperitoneal or intraperitoneal routes. can be demonstrated by administering it to test animals. The activity of the substances in interfering with the release of allergy mediating substances can be demonstrated in vitro by a test consisting of antagonizing antigen-induced histamine release from peritoneal mast cells of passively sensitized rats. The method used is described by Kussner et al., Journal of
Pharmacology and Experimental Therapeutics
184, 41-46 (1973). This test consists of isolation of mast cells from rats by peritoneal lavage and isolation of cellular material from the lavage fluid. Cells are sensitized by shaking in antiserum from rats sensitized as described above for passive cutaneous anaphylaxis.
The sensitized cells are then exposed to ovalbumin antigen and the release of histamine from the cells is measured by automated fluorophotometry. Inhibition of histamine release by the presence of a test compound during challenge of sensitized cells is a measure of the test compound's activity. A dose-response curve is constructed using various concentrations of the test compound, and the concentration that inhibits 50% histamine release (IC ₅₀ ) is determined by interpolation. Cromolyn sodium was found to exhibit an IC ₅₀ of 1 μm in this test system. The compounds of the invention prepared by procedures 2, 3, and 36 were substantially more potent than cromolyn sodium in exhibiting IC ₅₀ values in the range of 0.3-0.8 μm. Thus, the present invention provides a method for suppressing the allergic manifestations of immediate hypersensitivity in susceptible warm-blooded animals upon exposure to an allergen.
Mammals that undergo immediate hypersensitization include humans, mice, rats, hamsters, gerbils, dogs, cats, sheep, goats, horses, cows, and the like. The method comprises administering an effective amount of one of the compounds of the invention by oral, topical, parenteral, or inhalation routes. The effective dose range in rats is about 1-200 mg/kg body weight, with preferred compounds being effective orally in the range of about 1-15 mg/kg body weight. Estimated human doses for the material in Procedure 29 range from 1 to 500 mg orally. Suitable dosage unit forms for the above-mentioned applications of the substance, such as tablets, solutions or suspensions for injection or inhalation, as well as formulas, are determined according to conventional pharmaceutical practice in accordance with established practice in pharmaceutical technology. It can be produced using a carrier. The compound (formula) of the present invention is 2-amino-thiophene-3-carboxyamide or 2-aminothiophene-3-carboxylic acid of the formula shown in the following scheme (in the formula, Z is -OH or _-NH2 ). The compound of formula was previously described by Gewald et al.
Chem. Berichte 98 , 3571 (1965) and the same magazine.
99 , 94 (1966). Compounds of the new formula for use in preparing the compounds of the present invention can be prepared by obvious adaptation of the method of Gewald et al. The symbol L in the formula
and B are independently selected from the group consisting of hydrogen, lower alkyl having 1 to 8 carbon atoms, lower alkenyl having 3 to 6 carbon atoms, phenyl, alkanoyl having 2 to 6 carbon atoms. is,
or a cycloalkene having a total of 5 to 7 cyclic ring carbon atoms or an R-substituted cycloalkene having 5 to 7 cyclic ring carbon atoms (wherein R is 1 to
is a lower alkyl group having 8 carbon atoms)
Configure. The intermediate 2-aminothiophene-3-carboxyamide or 2-aminothiophene-3-carboxylic acid, when reacted with an acylating agent of the formula:
This yields a thiophene derivative of the formula or an oxazine derivative of the formula. R ³ in the formula, , and
is H, lower alkyl having 1 to 8 carbon atoms, or M, where M is a non-toxic pharmacologically usable metal cation. The acylating agent of the formula is oxalic acid or a 1,4-but-2-enedionic acid derivative. That is, A in the above formula is
A covalent bond directly connected to the group shown or a vinyl group (-CH=CH-). X is chloro, bromo, or lower alkoxy having 1 to 8 carbon atoms, preferably an ethoxy group when working with the starting material of formula when Z is -OH, and When working on the starting material of the formula where Z is _-NH2 , it is chloro. For the preparation of substances of the formula and when A is a vinyl group, starting materials of the formula when Z is -OH and 1,4- as acylating agent are used.
It is preferred to use lower alkyl diesters or lower alkyl monoesters of but-2-enedionic acid. For the preparation of compounds of the formula when R ³ is lower alkyl, the 2-aminothiophene-3-carboxamide of the formula when Z is -NH ₂ is combined with pyridine or an acylating reagent of the formula The treatment is carried out in acetonitrile, benzene, or other aprotic solvents such as diisopropyl ether containing at least one molecule of pyridine per molecule of pyridine (which is preferably ethyloxalyl chloride). The acylating agent is carefully mixed with the solution of intermediate at room temperature by adding the acylating agent in portions to the carboxamide intermediate while cooling the reaction vessel, or vice versa. It is undesirable to pre-cool the reactants before starting the reaction. After the reaction has stopped,
The reaction is usually stirred for a period of time at room temperature to ensure completion of the reaction. The reaction mixture is then poured into an aprotic solvent such as isopropanol,
This intermediate is recovered by collecting the intermediate of formula precipitated by filtration. The thienyl intermediate of the formula is a novel compound with antiallergic activity and is the object compound of the present invention. The thienyl compounds of the formula when R ³ is lower alkyl can be prepared at temperatures ranging from about 200 to 265 °C,
It is preferably converted in the latter by heating in the molten state into thienopyrimidines having the formula. The progress of this reaction can be estimated by the foaming caused by the evaporation of water, which is formed as a by-product during the process. In each particular case, the optimal temperature at which the pyrolysis is carried out can be estimated by determining the temperature at which vigorous evolution of water vapor occurs when the melt is heated in a test tube. Oxazines of the formula are also novel compounds with antiallergic activity. Oxazines of the formula when R ³ is lower alkyl can be prepared using 2-aminothiophene- It is prepared by reacting a 3-carboxylic acid with an acylating agent of the formula. In this case, it is preferable to use a bimolecular portion of the acylating agent. When using a single molecule acylating agent, the intermediate 2-carbamylthiophene-3- which is structurally similar to thiophenecarboxamides of formula
Mixtures containing carboxylic acids may be obtained. The 2-carbamylthiophene-3-carboxylic acid may further contain one molecular moiety of an acylating agent or
Cyclization can be achieved by treatment with other cyclodehydrating agents such as SOCl ₂ to give oxazines of formula. Although such stepwise operation is possible, there are no advantages. In the first case, it is preferred to use a bimolecular portion of the acylating agent to obtain the pure oxazine as the reaction product. Oxazines of the formula are converted to thienopyrimidines of the formula by reaction with an amine of the formula RNH ₂ where R is as defined above or an ammonium salt that is soluble in the reaction medium. As reaction medium a protic solvent is used, preferably a lower alkanol such as ethanol or isopropanol. The reaction is carried out at reflux temperature and upon cooling the product usually crystallizes out of the reaction mixture. Suitable ammonium salts are: ammonium fluoride, ammonium fluorosulfonate, ammonium fluorosilicate, ammonium acetate, ammonium iodide, ammonium nitrate, ammonium hypophosphite, and ammonium valerate. It is preferred to use ammonium acetate, optionally in the presence of about 1 chemical equivalent of acetic acid, to form a buffer system to minimize the formation of amide from the 2-carboxyester group. Compounds of formula and when R ³ is H or M are prepared by hydrolysis and neutralization of the corresponding ester (where R ³ is lower alkyl) as exemplified by Steps 3 and 32. Compounds of formula (when R ³ is H or M) are sometimes obtained from compounds of formula as by-products in the preparation of compounds of formula. They can also be obtained by hydrolysis and neutralization of compounds of formula (when R ³ is lower alkyl). A compound of formula (R ³ is H
) can be prepared by selective hydrolysis of the corresponding acid halide, followed by neutralization to form the M salt. Compounds of formula include R ² is CO ₂ R ³ or CH=
CHCO ₂ R ³ constitutes a subgroup of compounds of formula where R ⁵ and R ⁶ of formula partially correspond to L and B of formula, respectively. They are compounds of other formulas (R ⁵ and R ⁶ are hydroxy, alkoxy, nitro, amino, or halogen;
or R ² is CH ₂ OH,

【formula】

[Formula] 5-tetrazolyl, N-(tetrazol-5-yl)carbamyl, or CHO). Conventional aromatic substitution reactions that can be used for substituted thiophenes can be used for compounds of the formula when one of L and B is hydrogen to introduce the R ⁵ and R ⁶ groups. For example, a compound of the formula where R ⁵ or R ⁶ is a nitro group can be prepared by treating the corresponding compound where R ⁵ or R ⁶ is a hydrogen atom, respectively, with a solution of nitric acid in trichloroacetic acid and acetic anhydride. It is produced by its nitration. The reaction is carried out by carefully adding the nitration solution to a solution of the reactants at a temperature of about -15°C. Any convenient temperature from about 0 to -20°C may be used. The nitrothiophene is recovered from the reaction mixture by quenching with water and filtering the resulting precipitate. Next, the obtained compound of the formula in which one of R ⁵ and R ⁶ is a nitro group,
It can be converted to the corresponding amino compound by conventional hydrogenation methods such as atmospheric pressure hydrogenation over charcoal-supported palladium using a solvent for contacting the hydrogen with the catalyst and reactants. Compounds of the formula when one of R ⁵ and R ⁶ is an amino group can be converted by diazotization and substitution of the diazonium group with a halogen according to known reaction conditions. For example, the amino compound can be dissolved in fluoboric acid and treated with sodium nitrite at ice temperature to yield the corresponding diazonium fluoborate. When the latter is treated with cuprous chloride, bromide or iodide, R ⁵ or R ⁶ becomes chloro,
Compounds of the corresponding formula which are bromo or iodo are obtained. Diazonium fluoroborate salts can also be converted to the corresponding fluoro derivatives in which one of R ⁵ and R ⁶ is a fluoro group by heating just above the melting point (standard Schaiman reaction conditions). These iodo compounds can also be prepared by mercurylation of compounds of the formula when L or B is hydrogen by reaction with mercuric acetate and treatment of this mercury compound with iodine and potassium iodide. Compounds of the formula when one of R ⁵ and R ⁶ is hydroxy are prepared by hydrolysis of the intermediate diazonium fluoborate salt, preferably with potassium trichloroacetate in trichloroacetic acid and then treatment of the reaction product with water. and then manufactured. The hydroxy compound is converted to an alkoxy compound under conventional alkylation conditions such as reaction with a diazoalkane, alkyl iodide, or dialkyl sulfate. Compounds of the formula when R ² is a hydroxymethyl group or an ester thereof can be prepared by reduction using a borohydride derivative such as lithium borohydride or sodium iodohydride when R ² is CO ₂ R ² It is produced from a compound of the formula. Again, conventional conditions consisting of contacting the reactants in a reaction-inert solvent are used. Compounds of formula when R ² is carboxaldehyde are prepared from the corresponding hydroxymethyl compound by oxidation, for example using manganese dioxide or dimethyl sulfoxide in dicyclohexylcarbodiimide under known conditions. In summary, compounds of formula are prepared using a process consisting of reacting a compound of formula with an acylating agent of formula to obtain a compound of formula or formula. The compound of formula is then converted to a compound of formula by heating in the molten state for 5 to 15 minutes at a temperature in the range of 200 to 265°C. A compound of formula can be treated in solution with an amine of formula R ³ NH ₂ or a soluble ammonium salt using a protic solvent such as a lower alkanol having 1 to 4 carbon atoms as the reaction medium at reflux temperature. is converted to a compound of formula by The compounds of the formula thus prepared correspond to the subgroup defined by the above formula. If desired, compounds of the formula in which one hydrogen of L or B can be prepared by nitration under conditions which can be used for the preparation of titro-substituted thiophene compounds by direct nitration of the corresponding unsubstituted thiophene compounds. It can be converted to the corresponding nitro compound. The resulting compound of formula where R ⁵ or R ⁶ is nitro is then converted by catalytic hydrogenation of the nitro group to obtain a compound of formula where R ⁵ or R ⁶ is amino. The latter can then be diazotized to form the corresponding diazonium salt, such as fluoborate, which is then reacted with cuprous halides such that R ⁵ or R ⁶ is Cl, Br, Alternatively, compounds of formula I can be obtained, or the diazonium salt can be hydrolyzed to obtain compounds of formula where one of R ⁵ or R ⁶ is hydroxyl.
This fluoroboric acid diazonium salt can also be heated to its decomposition point to obtain compounds of formula where R ⁵ or R ⁶ is fluoro. Hydroxy derivatives are
Etherification under customary conditions for the formation of aromatic ethers can give compounds of the formula in which R ⁵ or R ⁶ is a lower alkoxy group having 1 to 6 carbon atoms. Furthermore, compounds of the formula when R ⁵ or R ⁶ are hydrogen can be converted into mercuric acetate derivatives by known methods and thus by treatment of this mercuric acetate derivative with I ₂ and KI to form R ⁵ or It can be converted to the corresponding compound where R ⁶ is iodo. This is illustrated in the following flowchart.

[Table] Any compound of the above formula in which A is a covalent bond linking the CO ₂ R group to the ring can be prepared according to the following reaction scheme in which R, R ⁵ and R ⁶ have the same meanings as before. can then be converted into compounds of the formula in which R ² is 5-tetrazoyl or N-(tetrazol-5-yl)carbamoyl. <Examples and Reference Examples> The present invention and related matters will be explained in more detail with the following operations 1 to 100. Runs 1, 6-12, 77 and 83 are examples showing the preparation of target compounds of the formula of the present invention. Steps 2, 3, 5, 13~19, 27~58, 60, 62~
71, 73, 75, 76, 78-82, and 88-100 are reference examples showing the production and use of the final compounds of the formula,
The remaining operations are illustrative examples illustrating the preparation of compounds of formula (which are relevant to the present invention in that they are intermediates of compounds of formula). The nuclear magnetic resonance spectral characteristics reported in these operations are chemical shifts (δ) expressed as parts per million (ppm) relative to tetramethylsilane as a reference standard (D ₂ O is shown as the solvent). , except when HDO at 4.70 ppm was used). The relative areas reported for the various shifts correspond to the number of hydrogen atoms in the substituents involved, and the nature of the shifts with respect to multiplicity is broad singlet (bs), singlet (s),
Reported as multiplets (m), doublets (d), triplets (t), or quartets (q), and coupling constants (J values) are reported where appropriate. The composition is NMR (solvent): δ (multiple precision,
relative area, J value). Abbreviations for solvents are CDCl ₃ (deuterochloroform), DMSO
−d ₆ (deuterodimethyl sulfoxide),
CF ₃ CO ₂ H (trifluoroacetic acid), and D ₂ O (deuterium oxide). Infrared spectrum data displays the wavelength of maximum absorption (in cm ^-1 units). This indicates the properties of the functional group. The infrared spectrum is
Measurements were made on potassium bromide pellets containing 0.5% of the experimental substance. Operation 1 N-[3-aminocarbonyl)-4,5,
6,7-tetrahydrobenzo[b]thiene-2
-yl]ethyl oxamate -2-amino-4,5, in 200 ml of dry pyridine
6,7-tetrahydrobenzo[b]thiophene-
72.92 grams (0.41 moles) of 3-carboxamide
The suspension is stirred at 25° C. during the addition (dropwise) of 55.25 grams (0.41 mol) of oxalylethyl chloride dissolved in 50 ml of dry acetonitrile. cooling the reaction vessel by immersing it in ice;
Place the flask in an ice bath for 30 minutes after the addition is complete. The reaction vessel should not be pre-cooled before beginning the addition of oxalylethyl chloride. After the reaction is complete and the ice bath is removed, 150 ml of acetonitrile is added to the reaction mixture to facilitate stirring and the mixture is kept stirring overnight. Then pour into isopropanol and collect the precipitated product on a filter. The product was air-dried, yellow solid 58.80g (49%), mp204.0~205.0℃
get. A sample of this is recrystallized from isopropanol and shows the same melting point. NMR (DMSO- _d6 ): 12.88 (s, 1), 7.30
(s, 2), 4.37 (q, 2), 2.70 (m, 4), 1.75
(m, 4), 1.37 (t, 3). Infrared (KBr):
1635, 1680, and 1720 cm ⁻¹ analysis Experimental values: C, 52.68; H, 5.34; N, 9.42. Step 2 Ethyl 3,4,5,6,7,8-hexahydro-4-oxobenzothieno[2,3-d]pyrimidine-2-carboxylate - 8.89 g (0.030 mol) of the product of Step 1,
Melt in a round bottom flask with a magnetic stirring bar immersed in an oil bath at 261°C. The melt is heated with stirring until the evolution of water, indicated by foaming of the reaction mixture, is no longer evident. Approximately 5-15 minutes is sufficient. The melt is then dissolved in dimethylformamide and the hot solution is poured into a larger volume of methanol than the reaction mixture. The precipitate was collected and recrystallized from a mixture of dimethylformamide and methanol to give 4.92 g of the desired product as yellow needles, mp 207.0-209.0°C.
(48%). Operation 3 3,4,5,6,7,8-hexahydro-4-oxobenzothieno[2,3-d]pyrimidine-2-carboxylic acid disodium salt dihydrate
C ₁₁ H ₁₀ N ₂ O ₃・2Na・2H ₂ O - Dissolve 12.0 g (0.043 mol) of the product of step 2 and 4.0 g (0.10 mol) of caustic soda in a mixture of 440 ml of water and 160 ml of ethanol. Heat on a steam bath until warm. After dissolution of the starting material, the monosodium salt of the product precipitates temporarily. This redissolves as heating continues until a clear solution is finally obtained. The solution is stirred at room temperature for 6 hours, during which time the desired disodium salt precipitates. The product is collected on a filter and air dried to yield 10.4 g (73%). The product did not melt at 355°C when heated in a capillary tube. Procedure 4 Ethyl 5-methyl-6-octyl-4-oxo-4H-thieno[2,3-d][1,3]oxazine-2-carboxylate - 2- in 25 ml of dry pyridine (initially cooled to 0°C)
Amino-4-methyl-5-(n-octyl)thiophene-3-carboxylic acid hydrate (1/ _4H2O ), 6.88
6.92 g (0.051 mol) of oxalylethyl chloride are added dropwise to the suspension of 0.025 g (0.025 mol). The mixture is stirred for 1 hour at 25° C. after the addition is complete and then poured into 1 liter of cold water. The product precipitates and is recovered by extraction with octane; yield 6.4 g (73%).
Recrystallized from low-boiling petroleum ether, white crystals,
mp66.0~69.0℃. Step 4 uses 2-[[(ethoxycarbonyl)carbonyl]amino]-4-methyl- as the starting material.
It can be modified by using 5-octylthiophene-3-carboxylic acid and carrying out the cyclization using 1 equivalent of oxalylethyl chloride. Step 5 Ethyl 3,4-dihydro-5-methyl-6-octyl-4-oxothieno[2,3-d]pyrimidine-2-carboxylate - 5.54 g of the product of Step 4 in 50 ml of absolute ethanol
(0.016 mol), 1.10 g (0.0143 mol) of ammonium acetate, and 0.385 g (0.0064 mol) of acetic acid are heated on a steam bath for 40 minutes. On cooling, the desired product crystallizes in the form of needles, which are collected on a filter and dried to yield 4.39 g (79%). This was obtained as off-white needles after recrystallization from isopropanol. mp136.0~137.0℃. Operations 6 to 12 Supplementary thienyl oxamates - appropriately substituted 2-aminothiophene-3
-carboxamide, the following correspondingly substituted ethyl N-[3-(aminocarbonyl)thien-2-yl]oxamate is prepared. In the table, the physical properties and recrystallization solvent are added after the name of each of these substances. Table Thienoxamates Operation number Name 6 [3-(aminocarbonyl)-5-phenylthien-2-yl]-ethyl oxamate - Recrystallization from ethanol-isopropanol,
mp198-200℃ Analysis Experimental values: C, 56.70; H, 4.56; N, 8.87. 7 Ethyl N-[3-(aminocarbonyl)-4-methyl-5-phenylthien-2-yl]oxamate-dimethylformamide-recrystallized from ethanol, mp 175-176°C. 8 Ethyl N-[3-(aminocarbonyl)-5-hexyl-4-methylthien-2-yl]oxamate-isopropyl acetate-recrystallized from isopropyl ether, mp 147-149°C. Analysis Experimental values: C, 56.31; H, 7.24; N, 8.25. Hydrolysis of this substance results in N-[3-aminocarbonyl)-5-hexyl-4-methylthien-2
-yl]oxamic acid sodium salt. C ₁₄ H ₂₀ N ₂ O ₄ S.Na salt, mp > 350°C is obtained. 9 Ethyl N-[3-(aminocarbonyl)-4-methylthien-2-yl]oxamate-dimethylformamide-recrystallized from absolute ethanol, mp 196-198°C. Analysis Experimental values: C, 46.86; H, 4.78; N, 10.76. 10 Ethyl N-[3-(aminocarbonyl)-4-methyl-5-pentylthien-2-yl]oxamate - recrystallized from isopropanol, mp153-154
℃. 11 N-[3-(aminocarbonyl)-4-methyl-5-(3-methyl-2-butenyl)thiene-
2-yl]ethyl oxamate - Recrystallized from isopropanol, mp199-200
℃. 12 Ethyl N-[3-(aminocarbonyl)-6-tert-butyl-4,5,6,7-tetrahydrobenzo[b]thien-2-yl]oxamate -Recrystallized from chloroform-ethanol,
mp228.5~231.5℃. Analysis Experimental values: C, 58.28; H, 7.03; N, 7.80. Steps 13-19 Supplementary Thienopyrimidine-2-Carboxylates by Cyclization of Thienyloxamates - These products are shown in the table and the molten thienyloxamates shown in the table according to the method of Step 2 above. produced by heating. The number in brackets after the operation number in the table is the operation number for the preparation of the starting material used. Table Thienopyrimidine-2-carboxylates Operation number Name 13(6) 3,4-dihydro-4-oxo-6-phenylthieno[2,3-d]ethyl pyrimidine-2-carboxylate - Recrystallized from acetonitrile, yellow Crystalline solid, mp228.0~232.0℃. 14(7) Ethyl 3,4-dihydro-5-methyl-4-oxo-6-phenylthieno[2,3-d]pyrimidine-2-carboxylate-dimethylformamide-recrystallized from ethanol, mp225.5-227.5℃ , yellow crystalline solid. 15(8) Ethyl 3,4-dihydro-6-hexyl-5-methyl-4-oxothieno[2,3-d]pyrimidine-2-carboxylate - Recrystallized from isopropanol, yellow needles,
mp134.0~135.0℃. 16(9) Ethyl 3,4-dihydro-5-methyl-4-oxothieno[2,3-d]pyrimidine-2-carboxylate - Recrystallized from ethanol, pale yellow crystals,
mp151.5~162.0℃. 17(10) Ethyl 3,4-dihydro-5-methyl-4-oxo-6-pentylthieno[2,3-d]pyrimidine-2-carboxylate - Recrystallized from isopropanol, olive green crystals, mp 152.5-153.5 ℃. 18(11) 3,4-dihydro-3-methyl-6-(3
- Ethyl (methyl-2-butenyl)-4-oxothieno[2,3-d]pyrimidine-2-carboxylate - Chromatograph on silica gel, eluting with chloroform. Evaporation of the solvent gave an oil without crystallization.
Nuclear magnetic resonance spectroscopy showed that the product was a mixture of the above compound and the -6-(-methyl-1-butyl) isomer. 19(12) 7-t-butyl-3,4,5,6,7,8
- ethyl hexahydro-4-oxobenzothieno[2,3-d]pyrimidine-2-carboxylate - chromatography on silica gel (hexane),
Elute with ether. Recrystallized from isopropanol,
Pale yellow powder, mp180.0~103.0℃. Operations 20 to 26 Thienooxazine-2-carboxylic acids - The following thienooxazines are prepared by substitution of appropriately substituted 2-aminothiophene-3-carboxylic acids in Operation 4. These thienoxazines are listed in the table, along with physical properties and modifications of operation if necessary. Table Thienooxazine-2-carboxylic acids Operation number name 20 5,6,7,8,-tetrahydro-4-oxo-4H-benzothieno[2,3-d][1,
3] Ethyl oxazine-2-carboxylate - Recrystallized as a hydrate from isopropyl acetate (1/2H ₂ O), yellow solid, mp 148.5-180.5°C. 21 6-ethyl-5-methyl-4-oxo-4H
-ethyl thieno[2,3-d][1,3]oxazine-2-carboxylate -1:1 pyridineacetonitrile as reaction medium; chromatograph on silica gel ( _CHCl3 ): recrystallized from isopropyl ether, pale yellow Needle crystals, mp97.5-99.5℃. 22 5-methyl-6-(2-methylpropyl)-4
-oxo-4H-thieno[2,3-d][1,
3] Ethyl oxazine-2-carboxylate - Recrystallized from hexane, mp 78.5-79.5°C. 23 Ethyl 6-ethyl-4-oxo-4H-thieno[2,3-d][1,3]oxazine-2-carboxylate -13:1 acetonitrile-pyridine used as reaction medium; ethyl acetate-low boiling petroleum Recrystallized from ether, pale yellow needles, mp 109.0-111.0°C. 24 6-acetyl-5-methyl-4-oxo-
Ethyl 4H-thieno[2,3-d][1,2]oxazine-2-carboxylate -3:8 using pyridine-acetonitrile as reaction medium; chromatography on silica gel (CHCl ₃ ), recrystallization from chloroform-hexane , pale yellow platelet crystals, mp102.0-103.0℃. 25 3,4-dihydro-5,6-dimethyl-4-
Ethyl oxothieno[2,3-d][1,2]oxazine-2-carboxylate-2:1 pyridine-acetonitrile was used as reaction medium; ethanol recrystallization, dark brown crystals,
mp129~130℃. 26 6-hexyl-5-methyl-4-oxo-
Ethyl 4H-thieno[2,3-d][1,3]oxazine-2-carboxylate using 5:1 acetonitrile-pyridine as reaction medium; recrystallized from low boiling petroleum ether, light tan solid, mp56. 5-57.0℃. Operations 27-31 Supplementary thienopyrimidine-2-carboxylates from thieno-oxazine-2-carboxylate - Preparation of the compounds listed in the table by substitution of suitably substituted thienooxazine-2-carboxylate as starting material , apply the method in step 5. The products obtained are shown in the table together with information regarding purification and fixation. The number in brackets following the operation number indicates the manufacturing operation of the starting material. Starting materials are listed in the table. Table Thienopyrimidine-2-carboxylates Operation number name 27 (21) 6-ethyl-3,4-dihydro-5-
Methyl-4-oxothieno[2,3-d]pyrimidine-carboxylate - Recrystallized from absolute ethanol, white flaky crystals, mp 148.5-173.5°C. 28(22) 3,4-dihydro-5-methyl-6-
Recrystallized from ethyl (2-methylpropyl)-4-oxoethino[2,3-d]pyrimidine-2-carboxylate isopropanol, grayish white crystals,
mp175-176℃. 29(23) 6-ethyl-3,4-dihydro-4-
Oxothieno[2,3-d]pyrimidine-2-
Ethyl carboxylate - recrystallized from ethanol, pale yellow needles,
mp163.0~168.0℃. 30(24) 6-acetyl-3,4-dihydro-5
-Ethyl methyl-4-oxothieno[2,3-d]pyrimidine-2-carboxylate -dimethylformamide - Recrystallized from ethanol, off-white needles, mp 236.0-242.0°C. 31(25) Ethyl 3,4-dihydro-5,6-dimethyl-4-oxothieno[2,3-d]pyrimidine-2-carboxylate - Recrystallized from acetonitrile, brown crystalline solid, mp 211.5-212.5°C . Step 32 3,4,5,6,7,8-hexahydro-4-oxobenzothieno[2,3-d]pyrimidine-2-carboxylic acid hydrate - Dissolve 5.0 g of the product of Step 3 in warm water. death,
The solution was made clear by filtration. The filtrate was acidified with glacial acetic acid and the solution was frozen. The precipitate was collected, washed with water on a filter, and dried. Cream solid, mp254.5~
256.5℃. Operations 33 to 45 Supplementary Thienopyrimidine-2-Carboxylic Acid Metal Salts - The method of Operation 3 was applied to various other thienopyrimidine-2-carboxylic acid ethers to produce various salts. the source of the starting material indicated by the operation number shown in the box next to the operation number;
and the analytical information of these products are listed in the table with reference. Table Salts Operation Number Name 33(5) 3,4-dihydro-5-methyl-6-octyl-4-oxothieno[2,3-d]pyrimidine-2-carboxylic acid disodium salt hydrate
C ₁₆ H ₂₂ N ₂ O ₃ S・2Na・H ₂ O Does not melt at -300℃. 34(13) 3,4-dihydro-4-oxo-6-
Phenylthieno[2,3-d]pyrimidine-2
-Carboxylic acid sodium salt hemihydrate
C ₁₃ H ₈ N ₂ O ₃ S・2Na・1/2H ₂ O - Dissolve the crude disodium salt prepared as in step 3 in warm water and carefully acidify with acetic acid until a precipitate forms; white powder, mp292.0~294.0℃ (decomposition). 35(14) 3,4-dihydro-5-methyl-4-
Oxo-6- _phenylthieno [2,3 _- d]pyrimidine-2 _- carboxylic acid disodium salt hydrate _{C14H10N2O3S.2Na.H2O} Does not melt at _-350 °C. 36(15) 6-hexyl-3,4-dihydro-5
-Methyl-4-oxothieno[2,3-d]pyrimidine-2-carboxylic acid disodium salt hydrate C ₁₄ H ₁₈ N ₂ O ₃ S・2Na・1/4H ₂ O - Addition of isopropanol to induce precipitation recrystallized from hot water; pale yellow solid, does not melt at 360°C. 37(16) 3,4-dihydro-5-methyl-4-
Oxothieno[2,3-d]pyrimidine-2-
Carboxylic acid disodium salt hydrate
_{C8H6N2O3S.2Na.2H2O} - _{Product recovered} by evaporation of the solvent and trituration of the residue with methanol; off _- white _powder , does not melt at 300<0>C. 38(17) 3,4-dihydro-5-methyl-4-
Oxo-6-pentylthieno[2,3-d]pyrimidine-2 _- carboxylic acid disodium salt sesquihydrate C13H16N2O3S_{・ 2Na}・1-1/ _2H2O - _pale yellow solid, 350 Does not decompose at ℃. 39(18) 3,4-dihydro-5-methyl-6-
(3-Methyl-2-butenyl)-4-oxothieno[2,3-d]pyrimidine-2-carboxylic acid disodium salt sesquihydrate C ₁₃ H ₁₄ N ₂ O ₃ S・
Precipitates from the reaction after evaporation of the alcohol by addition of 2Na.1-1/ _2H2O -isopropanol; yellow solid, does not melt at 350<0>C. 40(19) 7-t-butyl 3,4,5,6,7,
8-hexahydro-4-osasobenzothieno[2,3-d]pyrimidine-2-carboxylic acid disodium salt dihydrate C ₁₅ H ₁₆ N ₂ O ₃ S・2Na・2H ₂ O - Reaction for solubilization Addition of dimethylformamide to the mixture; precipitation of the product with isopropanol;
Does not melt at 300℃. 41(25) 3,4-dihydro-5,6-dimethyl-4-oxothieno[2,3-d]pyrimidine-2-carboxylic acid disodium salt sesquihydrate
_{C9H8N2O3S.2Na.1-1 / 2H2O} - Product precipitates from _the aqueous reaction mixture with isopropanol; _gray solid, does not melt at 350<0>C. 42(27) 6-ethyl-3,4-dihydro-5-
Methyl-4-oxothieno[2,3-d]pyrimidine-2-carboxylic acid disodium salt dihydrate
_{C10H10N2O3S.2Na.2H2O} - _Isopropanol was added to the _{reaction mixture} to induce crystallization of _the product; white solid, not melting at 360<0>C. 43(28) 3,4-dihydro-5-methyl-6-
(2-Methylpropyl)-4-oxothieno[2,3-d]pyrimidine-2-carboxylic acid disodium salt sesquihydrate C ₁₂ H ₁₄ N ₂ O ₃ S・
The product precipitates from the reaction mixture upon addition of 2Na.1-1/ _2H2O -isopropanol; white solid, does not melt at 350<0>C. 44(29) 6-ethyl-3,4-dihydro-4-
Oxothieno[2,3-d]pyrimidine-2-
Carboxylic acid disodium salt dihydrate
C ₉ H ₈ N ₂ O ₃ S・2Na・2H ₂ O - Methanol used as reaction solvent; white powder,
No melting at 360℃. 45(30) 6-acetyl-3,4-dihydro-5
-Methyl-4-oxothieno _[ 2,3-d]pyrimidine-2 _- carboxylic acid disodium _salt sesquihydrate _{C10H8N2O4S.2Na.1-1} / _2H2O - as a yellow solid, No melting at 360℃. 46(58) E-3-(3,4,5,6,7,8-
Hexahydro-4-oxobenzothieno [2,
3-d]pyrimidin-2-yl]-2-propenoic acid disodium hydrate C ₁₃ H ₁₀ N ₂ O ₃ S・2Na・
_3.5H2O - Product precipitated by treatment of the reaction mixture with isopropanol; tan solid, not melting at 300<0>C. 47 ₍ 51) 5-amino-6-ethyl-3,4 _- dihydro-4-oxothieno[2,3-d]pyrimidine-2-carboxylic acid disodium salt sesquihydrate _{C9H7N3O3 ・}2Na.1.5H ₂ O - methanol used as reaction medium; product precipitates with isopropanol; yellow powder, does not melt at 250<0>C. Step 48 Ethyl 3,4-dihydro-5-methyl-6-nitro-4-oxothieno[2,3-d]pyrimidine-2-carboxylate - Dissolve 1.0 g of the product of Step 16 in trifluoroacetic acid and - 5 ml of acetic anhydride were added to this mixture while cooling to 15°C. Next, 4ml of trifluoroacetic acid
A solution of 1.2 ml of medium concentrated nitric acid was added dropwise to this solution at a temperature of -12 to -15°C under stirring. After the formation of a fine yellow precipitate, add 100 ml of water to the reaction mixture and collect the precipitate on the filter. This is the desired product and is recrystallized from ethanol.
mp229~229.5℃. Operation 49 Ethyl 6-amino 3,4-disidro-5-methyl-4-oxothieno[2,3-d]pyrimidine-2-carboxylate - 2.10 g of the product of Operation 48 was dissolved in 100 ml of dry dimethylformamide; 1 g of a 10% suspension of palladium on charcoal is hydrogenated at atmospheric pressure. It takes about 5 minutes for the reaction solution to absorb the calculated amount of hydrogen.
Remove the catalyst by filtration and pour the liquid into 1 liter of cold water. The product is recovered from the aqueous solution by extraction with chloroform, and the orange solid remaining upon evaporation of the solvent is triturated with isopropanol and recrystallized from methanol. Yellow needles, mp199.5-215℃. Operation 50 Ethyl 6-ethyl-3,4-dihydro-5-nitro-4-oxothieno[2,3-d]pyrimidine-2-carboxylate - By the method of Operation 48, the product of Operation 29, 5
g to the desired product. The product is a pale yellow solid and is recrystallized from a mixture of chloroform and ethanol. White crystal, mp200.0~212.0℃. Operation 51 Ethyl 5-amino-6-ethyl-3,4-dihydro-4-oxothieno[2,3-d]pyrimidine-2-carboxylate - Hydrogenation of the product of Operation 50 by the method of Operation 49 do. It takes about 3 to absorb the calculated amount of hydrogen.
It takes time. The catalyst is removed by filtration, and the product is recovered by concentrating the liquid to dryness. The residue is recrystallized from a mixture of methanol and isopropanol to give a yellow powder, mp 181.5-184.5°C. Operation 52 Ethyl 3,4-dihydro-6-ethyl-5-iodo-4-oxothieno[2,3-d]pyrimidine-2-carboxylate - 2.65 g (0.0105 mol) of the product of Operation 29 and mercuric acetate 10.60 g (0.034 mol) are dissolved in 35 ml of glacial acetic acid and heated on a steam bath for 1 hour. This mixture is then poured into 400 ml of saturated saline to precipitate the 5-chloromercury intermediate, mp 237°C (decomposed). 4.10 g of this intermediate are then added to a solution of 4 g of iodine and 10 g of potassium iodide in 150 ml of water. The mixture was kept at room temperature for 3 days under stirring, then the reddish-black solid was collected on a filter and washed with ethanol to give a tanned solid.
Obtain 2.70g. It did not melt at 240°C. Operation 53 2-(hydroxymethyl)-5-methyl-
6-(2-methylpropyl)thieno[2,3-
d] Pyrimidin-4-(3H)-one - 2.0 g of the product of step 28 in a solution of 2.0 g (0.052 mol) of sodium borohydride in 150 ml of absolute ethanol
g (0.0069 mol) is added in small portions. Foaming occurs during the addition and the solution turns yellow in color. The mixture is kept at room temperature for 2 hours under stirring. It is then poured into ice water with stirring and the mixture is acidified with glacial acetic acid. This acidic solution is then extracted with chloroform and the solvent is evaporated from the extract to yield a yellow solid. Recrystallization from ethyl acetate gives white crystalline solid, mp182-183
The product is obtained as ℃. Operation 54 2-(hydroxymethyl)-5-methyl-
6-Pentylthieno[2,3-d]pyrimidin-4-(3H)-one - This material was prepared by the method of Procedure 53 using the product of Procedure 17 as the starting material. Recrystallized from ethyl acetate, pale yellow crystalline solid, mp158.5
~159.5℃. Operation 55 5,6,7,8-tetrahydro-2-
(Hydroxymethyl)benzothieno[2,3-
d]-4-(3H)-pyrimidinone - Step 2 1.0 g of the product is suspended in 50 ml of absolute ethanol, and 2.0 g of lithium borohydride is added in small portions. Gas evolution occurs and the mixture is stirred for 1-1/2 hours at room temperature and then refluxed for 20 minutes. The mixture is poured into 300 ml of water and the aqueous mixture is then acidified with glacial acetic acid. The desired product precipitates out and is collected on a filter as slightly yellow needles and recrystallized from a mixture of dimethylformamide and ethanol. mp262.5~268.5℃. Operation 56 6-Hexyl-2-(hydroxymethyl)-5-methylthieno[2,3-d]pyrimidin-4-(3H)-one - For the preparation of this material, the product of Operation 15 was added to the product of Operation 53. Apply the method; recrystallized from ethyl acetate; light tan powder, mp 136.0-140.0°C. Operation 57 Acetic acid (3,4,5,6,7,8-hexahydro-4-oxobenzothieno[2,3-
d] pyrimidin-2-yl)methyl-0.68 ml of the product of step 55 in 30 ml of acetonitrile containing 5 ml of acetic anhydride and 5 ml of pyridine.
(0.00288 mol) and heated at 100°C for 30 minutes. The mixture is then poured into 150 ml of cold water to give the desired product as a pale yellow solid, which is recrystallized from ethyl acetate; pale yellow needles, mp202.0~
204.0℃. Operation 58 3-(3,4,5,6,7,8-hexahydro-4-oxobenzothieno[2,3-
d] A solution of sodium ethoxylate in ethanol is prepared from 3.05 g of sodium ethyl pyrimidin-2-yl)-2-propenoate and 100 ml of ethanol. Next, the product of step 1 in 300 ml of ethanol
24.5g (0.125mol) and diethyl fumarate 21.6g
(0.125 mol) of the mixture produces a red solution, which is stirred overnight at reflux temperature. The mixture is then allowed to cool to room temperature and poured into 1 liter of water containing 9 g of acetic acid. A yellow precipitate forms during stirring at room temperature for 1.5 hours, which is collected by filtration;
Rinse with water on a filter and dry. yellow solid,
mp285~287℃. Operation 59 (E)-3-(3,4,5,6,7,8-hexahydro-4-oxobenzothieno[2,3
-d]ethyl oxazin-2-yl)-2-propenoate -acetonitrile containing 1.2 ml of pyridine 10
2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid in ml 0.985
1.63 g (0.010 mol) of fumarylethyl chloride are added to a suspension (cooled to 0° C.) of 1.63 g (0.010 mol) of fumarylethyl chloride. Upon completion of the fumarylethyl chloride addition a clear solution forms and the reaction mixture is stirred for an additional 1.5 hours at ice bath temperature. Stirring is continued overnight at room temperature, then the precipitated solid is collected by filtration and washed with ether and finally aqueous hydrochloric acid, aqueous potassium bicarbonate, and water. This is purified by recrystallization from isopropanol and washed on a filter with isopropyl ether and low-boiling petroleum ether. Yellow crystalline solid, mp147.5-148.5℃. Operation 60 6-ethyl-2-(hydroxymethyl)
Thieno[2,3-d]pyrimidine-4-(3H)
-On - The method of Operation 53 is applied to the product of Operation 29 to give the desired product, which is recrystallized from 3:1 ethyl acetate:ethanol. mp201.5~202.5℃. Operation 61 6-hexyl-4-oxo-4H-thieno[2,3-d][1,3]oxazine-2-
Ethyl carboxylate - This product can be converted to 2-amino-
It is obtained by applying it to 5-(n-hexyl)thiophene-3-carboxylic acid. The oxalylethyl chloride is dissolved in acetonitrile prior to the addition of the aminothiophene carboxylic acid dissolved in pyridine. The product is collected as a pale green solid and recrystallized from ethanol. mp80~81℃. Operation 62 3,4-dihydro-6-hexyl-4-
Oxothieno[2,3-d]pyrimidine-2-
The product of ethyl carboxylate - Step 61 - is treated with ammonium acetate and acetic acid in ethanol as described in Step 5 to give this product, mp 114-115°C. Operation 63 Ethyl 6-chloro-3,4-dihydro-5-methyl-4-oxothieno[2,3-d]pyrimidine-2-carboxylate - Dissolve 0.01 mole of the product of Operation 49 in 20 ml of 10% aqueous fluoboric acid. and cool to 0°C. A solution of 0.01 mol of sodium nitrite in 5 ml of water is added dropwise. The mixture was stirred for 30 minutes at 0°C and then the bulky diazonium 2-carbetoxy-3,4-dihydro-5-methyl-4-oxothieno[2,3-d]pyrimidin-6-ylfluoroborate was precipitated. Collect on a filter and air dry. The latter is then added in portions to a solution containing a stoichiometric excess of cuprous chloride in concentrated hydrochloric acid at 0.degree. When all the diazonium salt has been added, the temperature is raised to 20°C, then the mixture is poured into ice water and the product is filtered to give the desired 6-chloro compound. Operation 64 Ethyl 6-ethyl-3,4-dihydro-5-hydroxy-4-oxothieno[2,3-d]pyrimidine-2-carboxylate - Manipulate diazonium fluoborate from the amino compound obtained in Operation 51 63 to obtain 0.03 mol of the required diazonium fluoborate. The latter was added at once to trifluoroacetic acid at 0 °C.
Add to a solution of 0.03 mol of potassium trifluoroacetate in 13 ml. The mixture was stirred at 25°C for 1 hour,
Then reflux overnight. The trifluoroacetic acid is evaporated in vacuo to give a residue, which is triturated with water and filtered to give the desired product. Operation 65 Ethyl 6-ethyl-3,4-dihydro-5-methoxy-4-oxothieno[2,3-d]pyrimidine-2-carboxylate - 0.01 mole of the product of Operation 64 and its chemical equivalent trifluoride The boron etherate is dissolved in 100 ml of ether and the solution is cooled to 0° C. with stirring. A solution of 0.011 mol of diazomethane in 50 ml of ether is then added in portions and the solution is stirred at 0° C. until the yellow color disappears. Evaporation of the solvent yields the desired 5-methoxypyrimidine compound. Operation 66 5,6,7,8-tetrahydro-2-
(5-tetrazolyl)benzothieno[2,3-
d] Pyrimidin-4-(3H)-one - 1.0 g of the product from step 2 in 30 ml of concentrated ammonia water
(0.0036 mol) is added. Enough ethanol is then added to form a clear solution and the mixture is cleared by filtering out a small amount of insoluble material. The solution is kept at room temperature for 4 hours, during which time a pale yellow precipitate forms.
Collect the latter by filtration and air dry it.
0.80 g of 6,7,8-hexahydro-4-oxobenzothieno[2,3-d]pyrimidine-2-carboxamide, pale yellow solid, mp 278.0-281.0°C (decomposition) is obtained. 0.01 mol of the latter is then added to a mixture of 5 g of phosphorus pentachloride in 10 ml of phosphorus oxychloride. After the initial exothermic reaction had stopped, the mixture was heated to 120°C for 1 hour,
Then pour into ice water and collect the insoluble matter on a filter. The collected material was air-dried to give 4-chloro-2-
Cyano-5,6,7,8-tetrahydro-4-oxobenzothieno[2,3- d ]pyrimidine-4
-(3H)-one is obtained. The latter is dissolved in 100 ml of dimethylformamide containing 1.5 g of sodium azide and 1.0 g of ammonium chloride. this mixture
Heat at 105-110°C for 24 hours. Pour this mixture onto ice water and precipitate 4-azido-2-(5-
tetrazoyl)-5,6,7,8-tetrahydrobenzothieno[2,3- d ]pyrimidine-4-
Collect (3H)-on. Hydrolysis of the latter with two chemical equivalents of caustic soda dissolved in ethanol gives the desired product as the sodium salt. Operation 67 5,6,7,8-tetrahydro-2-N
-(tetrazol-5-yl)carbamylbenzothieno[2,3-d]pyrimidine-4-
(3H)-one - The product of step 32 is treated with 20 ml of thionyl chloride at room temperature until gas evolution ceases. The excess thionyl chloride is then evaporated in vacuo and the remaining acid chloride is dissolved in 25 ml of dry dimethylformamide. 0.01 mol of 5-aminotetrazole is then added to the mixture, which is stirred for 1 hour at room temperature and then heated on a steam bath for 2 hours. Then pour this mixture into water,
to obtain the desired product. Operation 68 3-Butyl-3,4,5,6,7,8-
Hexahydro-4-oxobenzothieno [2,
3-d] Pyrimidine-2-carboxylic acid sodium salt hemihydrate C ₁₅ H ₁₈ N ₂ O ₃ S・Na・1/2H ₂ O - 2.79 g of the product of step 20 in 50 ml of absolute ethanol
(0.01 mol) and 0.73 g (0.01 mol) of n -butylamine are heated to reflux temperature over a steam bath for 4 hours. This mixture is then poured into 500 ml of cold water and extracted with chloroform. The extract was dried over magnesium sulfate and concentrated in vacuo to give 2.83 g of a brown oil, which crystallized. The crystal mass was triturated with 1:1 ether low boiling petroleum ether and the crystalline material was removed by filtration. The mother liquor was then concentrated in vacuo to obtain a brown oil;
This is chromatographed using 1:1 ether-low boiling petroleum ether for development on silica gel to give 1.52 g of the desired product as ethyl ether. The latter was saponified according to the method in Step 3, and the resulting sodium salt was recrystallized from isopropanol-ether to give an off-white powder, mp 265.0-285.0.
0.90 g (59%) of the desired product is obtained as °C (decomposition). Operation 69 6-Ethyl-3,4-dihydro-3-methyl-4-oxothieno[2,3-d]pyrimidine-2-carboxylic acid sodium salt - Applying the method of Operation 68 to the oxazine obtained in Operation 23 and replacing the butylamine used during step 68 with methylamine to give the desired product. Operation 70 Ethyl 3,4-dihydro-6-fluoro-5-methyl-4-oxothieno[2,3-d]pyrimidine-2-carboxylate - 2-carbetoxy- as described in Operation 63
0.03 mol of diazonium 3,4-dihydro-5-methyl-4-oxothieno[2,3-d]pyrimidin-6-ylfluoroborate is prepared. The latter is then heated in an oil bath with appropriate aeration to carry off the boron trifluoride liberated by this treatment. A temperature of about 150°C is sufficient and heating is continued until no gas evolution is evident. The residue is cooled, triturated with water and filtered to obtain the desired compound. Operation 71 3,4,5,6,7,8-hexahydro-4-oxobenzothieno[2,3-d]pyrimidine-2-carboxaldehyde - 0.01 mol of the product of Operation 55 in 100 ml of dimethyl sulfoxide and dicyclohexylcarbodiimide
Add 0.01 mol of orthophosphoric anhydride to the 0.3 mol solution. The mixture is stirred at room temperature for 4 hours, then 250 ml of ethyl acetate and then a solution of 25 g of oxalic acid in methanol are added. Insoluble by-product dicyclohexylurea is removed by filtration. The liquid is washed with dilute aqueous sodium bicarbonate solution, the organic layer is separated and dried over magnesium sulfate. The solvent is evaporated in vacuo to yield the desired product. Operation 72 5,6-dihydro-4-oxo-4H-
cyclopenta[b]thienyl[2,3-d]
[1,3]Ethyl oxazine-2-carboxylate - Step 4 was followed in the preparation of this product by using 2-amino-4,5-dihydrocyclopenta[b]thiophene-3-carboxylic acid as the starting material. Apply. Operation 73 3,4,5,6-tetrahydro-4-oxocyclopenta[b]thieno[2,3-d]
Ethyl pyrimidine-2-carboxylate - The oxazine obtained during Procedure 72 is converted to this product by the method of Procedure 5. Operation 74 3,4,5,6-tetrahydro-4-oxocyclohepta[b]thieno[2,3-d]
Ethyl oxazine-2-carboxylate - The method of Procedure 4 is applied to the preparation of this material by substitution of 2-amino-4,5,6,7-tetrahydrocyclohepta[ b ]thiophene-3-carboxylic acid as starting material. do. Operation 75 3,4,5,6,7,8-hexahydro-4-oxocyclohepta[b]thieno[2,
3-d] Ethyl pyrimidine-2-carboxylate - Convert the product of Step 74 to this material by the method of Step 5. Operation 76 (3,4,5,6,7,8-hexahydro-4-oxobenzothieno[2,3-d]pyrimidin-2-yl]methylformate 30 ml of acetic anhydride and 15 ml of 100% formic acid at -0°C
Dissolve 0.01 mol of the product of step 55 in the mixture with The mixture is then warmed to room temperature over the course of 1 hour while stirring. Then pour into 200 ml of ice to collect the formate ester. Operation 77 N-[3(aminocarbonyl)-4,5,
6,7-tetrahydrobenzo[b]thiene-2
-yl]oxamic acid -2-amino- in 5 liters of absolute ethanol
4,5,6,7-tetrahydrobenzo[ b ]thiophene-3-carboxamide 392 g (2.0 mol)
A suspension of 321.2 g (2.2 moles) and diethyl oxylate is added to a solution of sodium ethoxylate prepared from 50.6 g (2.2 moles) of sodium in 2 liters of absolute ethanol under a stream of nitrogen. The mixture is stirred under heating at reflux temperature for 6 hours and then refrigerated overnight. A fine precipitate forms and is removed by filtration. Acetic acid 150 dissolved in 350ml of water
g (2.5 mol) and the resulting precipitated product was collected on a filter, washed with water, and air-dried to yield 194.6 g (0.7 mol) of the product from step 2.
get. The solution is acidified to pH 2 with concentrated hydrochloric acid and the resulting precipitate is collected on a filter, washed with water and air dried to yield 264.8 g (0.99 mol) of the desired product. A portion of 25 g is recrystallized from 1.4 liters of dioxane to yield 18.2 g, mp 223.5-224.5°C (decomposed). NMR (DMSO-d ₆ ): 7.45 (s, 2), 1.79 (s,
8). Infrared (KBr): 3520, 3360, 3190, 2950,
2860, 1730, 1640, 1565, 1530, 1460, 1410,
1360, as well as 1290cm ^-1 . Analysis Experimental values: C, 49.04; H, 4.47; N, 10.25. Operation 78 Tablets for Oral Ingestion - Blend the following ingredients dry in a twin shell blender and compress on a tablet press using an 11/32 inch die and concave punch. Product of Operation 29 50.0 g Pregranulated sucrose for direct compression 210.0 g Corn starch 6.0 g Microcrystalline cellulose 40.0 g Magnesium stearate 1.0 g This batch size is for 1000 tablets;
This yields tablets weighing 307 ml providing 50 mg of active ingredient per tablet. By using the same ingredients but adjusting the weight and tablet size accordingly, tablets containing 25-200 mg can be made. Procedure 79 Solution for injection - Dissolve the following ingredients in 1 liter of water for injection and pass the solution through a membrane filter with a pore size of 0.45 μm. Product of step 44 0.250 g Common salt (to make isotonic) Sufficient amount Sodium phosphate (to buffer) pH 7.5 Fill the strained solution into clean sterile ampoules, seal with flame, and then sterilize in an autoclave. Procedure 80 Powder for Inhalation - The following ingredients are mixed aseptically and packed into hard gelatin capsules, each containing 50 mg of the mixture to provide 25 mg of active ingredient. Product of step 36, micronized 25.0g Lactose powder 25.0g The above is for 1000 capsules. These capsules are suitable for dispensing the powder into the inhaled air stream using a breath-propelling device. The composition can be suitably adjusted to obtain capsules containing 0.5 to 40 mg of active ingredient. Operation 81 3,4-dihydro-6-hexyl-4-
Oxothieno[2,3-d]pyrimidine-2-
Carboxylic acid disodium salt hydrate
_{C13H14N2O3S.2Na.2-1 / 2H2O} - Apply the method _of Step 3 to the product of Step ₆₂ .
At the end of the reaction period, the product is precipitated by adding isopropanol to the reaction mixture. A white gelatin-like precipitate forms, which is collected on a filter and dried. Operation 82 2-(hydroxymethyl)-6-hexylthieno[2,3-d]-pyrimidine-4-
(3H)-one - The product of Operation 62 is converted to the title compound by the method of Operation 53. The product is a tan solid. The compounds of Step 28, as well as the corresponding disodium salts of the carboxylic acids described in Step 43, are of the preferred class as inhibitors of immediate hypersensitivity reactions.
The corresponding dipotassium salt is described in Operation 97 below and is particularly suitable for preventing immediate hypersensitivity reactions in mammals when allergic rhinitis is an episode. Due to its potency and water solubility, the latter is suitable for use as a nasal solution for application as drops, spray or aerosol to the nasal mucosa. A powder composition for deposition on the nasal mucosa after insufflation can be used, similar to the composition of step 80, except for micronization. For deposition on the nasal mucosa, approx.
A relatively large particle size of 100μ is preferred. Systemic routes of administration may be used, including oral, rectal, parenteral and oral. This dipotassium salt (operation 97)
is the PCA described on page 79 in rats.
The test shows the following ID ₅₀ values: oral, 2.7mg/Kg; intravenous, 0.14mg/Kg. Publications describing work chemically related to this disclosure include Arya, VP, Indian Journal of
Chemistry, 10, 1141-1150 (1972), which discloses the materials described above in Operation 2. The following procedure describes additional compounds and compositions that fall within the scope of this invention. Operation 83 N-[3-(aminocarbonyl)thiene-
2-yl]ethyl oxamate-2-aminothiophene-3-carboxyamide by applying the method of Step 1 to obtain the desired product,
This is recrystallized from acetonitrile. mp186.0
~187.0℃. Analysis Experimental values: C, 44.52; H, 4.16; N, 11.56. NMR (DMSO- _d6 ): 1.34 (t, 3, 7.0Hz),
4.48 (q, 2, 7.0Hz), 7.26 (d, 1, 6.0Hz),
7.65 (d, 1, 6.0Hz), 7.80 (bs, 1), 8.19
(bs, 1), and 1.36 (bs, 1). IR (KBr): 3415, 3390, 3180, 1730, 1685,
1650, 1590, 1550, and 1280cm ^-1 . This substance has an oral ED ₅₀ =4.5 mg/
Indicates weight in Kg. Operation 84 4-oxo-6-pentyl-4H-thieno[2,3-d][1,3]oxazine-2-
Ethyl carboxylate -2-amino-5-pentylthiophene-3-
Applying the method of Procedure 4 to the carboxylic acid gives the desired product as a crystalline solid; recrystallized from di-isopropyl ether, mp 69.6-70.5°C. Operation 85 4-oxo-6-propyl-4H-thieno[2,3-d][1,3-oxazine-2-
Ethyl carboxylate -2-amino-5-propylthiophene-3-
Apply the method of Step 4 to carboxylic acid. The product obtained is recrystallized from diisopylether.
mp90.5~91.5℃. Operation 86 6-isopropyl-4-oxo-4H-
Thieno[2,3,-d][1,3]oxazine-
Ethyl 2-carboxylate-2-amino-5-isopropylthiophene-3-
The desired product is prepared by applying the method of Procedure 4 to the carboxylic acid and recrystallized from di-isopropyl ether. mp87.5~88.5℃. Operation 87 Ethyl 6-butyl-4-oxo-4H-thieno[2,3-d][1,3]oxazine-2-carboxylate-2-amino-5-( n -butyl)thiophene-3-carboxylic acid Apply the method in step 4 to The product obtained is recrystallized from di-isopropyl ether. mp76.0~77.5℃. Operation 88 Ethyl 6-ethyl-3,4-dihydro-4-oxothieno[2,3-d]pyrimidine-2-carboxylate - Dissolve 5.0 g (0.019 mol) of the product of Operation 29 in 20 ml of butanol and prepare P - Toluenesulfonic acid 0.5
Add g to it. The mixture is refluxed for 3 hours, heated, and the product (which crystallizes on cooling) is collected and recrystallized from butanol.
mp116.0~118.0℃. Operation 89 Ethyl 3,4-dihydro-4-oxothieno[2,3-d]pyrimidine-2-carboxylate - The product of Operation 83 is converted to this material by application of the method of Operation 2. The product is purified by chromatography on silica gel using chloroform for elution and recrystallized from isopropanol. mp191.0~192.0℃. Operation 90 6-Ethyl-3,4-dihydro-3-methyl-4-oxothieno[2,3-d]pyrimidine-2-carboxylate - The method of Operation 69 is repeated by omitting the post-chromatography saponification step and Step 69 is repeated except that 2 molecular equivalents of acetic acid are added to the reaction system for the oxazine starting material obtained in Step 23. The desired product is obtained as a dark oil. Procedure 91 Ethyl 3,4-dihydro-6-methyl-4-oxothieno[2,3-d]pyrimidine-2-carboxylate - Using ethyl acetate as the solvent, 6-methyl-
4-oxo-4H-thieno[2,3- d ][1,
3] Step 5 to ethyl oxazine-2-carboxylate
Apply the method. The product is recovered as a crystalline solid, which can be recrystallized from 95% ethanol. mp204.0~208.0℃. Operation 92 Ethyl 3,4-dihydro-6-(1-methylethyl)-4-oxothieno[2,3-d]pyrimidine-2-carboxylate - Ethanolization of the product of Operation 86 according to the method of Operation 5 Convert to the desired product by refluxing with ammonium acetate and acetic acid.
This product is recrystallized from ethanol.
mp182~183℃. Operation 93 3,4-dihydro-6-(1-methylethyl)-4-oxothieno[2,3-d]pyrimidine-2-carboxylic acid disodium salt - The product of Operation 92 was prepared according to the method of Operation 3. Then, hydrolyze with ethanolic caustic soda. Dilute the cooled reaction mixture with isopropanol and collect the product on a filter. Air dry and grind in mortar. Does not melt when heated to 350°C in a capillary tube. Elemental analysis is based on water per mole of disodium salt.
Corresponds to a hydrate containing 1.75 mol. Operation 94 Ethyl 6-butyl-3,4-dihydro-4-oxothieno[2,3-d]pyrimidine-2-carboxylate - The product of Operation 87 was dissolved in an ethanolic solution containing acetic acid according to the method of Operation 5. Treat with ammonium acetate. The product is recrystallized from ethanol-isopropanol. mp144~145℃. Operation 95 3,4-dihydro-4-oxo-6-propylthieno[2,3-d]pyrimidine-2-
Ethyl Carboxylate - The product of Step 85 is converted to the desired product by treatment with ethanolic ammonium acetate according to the method of Step 5 except that the acetic acid is omitted. The product is recrystallized from ethanol. mp169
~170℃. Operation 96 3,4-dihydro-4-oxo-6-pentylthieno[2,3-d]pyrimidine-2-
Ethyl Carboxylate - The oxazine obtained in Step 84 is converted to this product by treatment with ethanolic ammonium acetate containing acetic acid according to the method of Step 5. The product is recrystallized from a mixture of ethanol and isopropanol at 124-125 °C. Operation 97 3,4-dihydro-5-methyl-6-
(2-Methylpropyl)-4-oxothieno[2,3-d]pyrimidine-2-carboxylic acid dipotassium salt - 150 ml of isopropanol
Hydrolyze by treating 1.91 g of it with 0.86 g of caustic potash dissolved in . The mixture is heated under reflux for 4 hours while stirring. It is then allowed to cool and the product is collected on a filter. Grind in mortar and air dry. It did not melt when heated to 350°C in a capillary tube. Elemental analysis shows that the product contains water per mole of salt.
It was shown that it could be obtained as a hydrate containing 1.75 mol. Operation 98 3,4-dihydro-3,5-dimethyl-
6-octyl-4-oxothieno[2,3-
d] Pyrimidine-2-carboxylic acid sodium salt - 2.34 g of oxazine obtained in Step 4 (0.0064
A mixture of 4.47 g (0.0576 mol) of 40% aqueous methylamine, and 5.00 g (0.0832 mol) of glacial acetic acid is heated on a steam bath in 40 ml of absolute ethanol for 40 minutes. This mixture is then processed substantially as described in Step 5 to yield the desired product, mp310.0~
Obtain 315.5℃ (decomposition). This is obtained as a hydrate containing 0.25 mol of water per mol of salt. Operation 99 6-hexyl-2-(hydroxymethyl)thieno[2,3-d]pyrimidine-4-
(3H)-one - The product of Step 61 is reduced with sodium borohydride according to the method of Step 53. The product is recrystallized from ethyl acetate. mp141~143℃. Operation 100 Nasal Solution A 1% solution of the product of Operation 97 is prepared by dissolving a 1% solution of the product of Operation 97 in a suitable amount of water with a pharmaceutically acceptable microbial inhibitor and enough common salt to produce an isotonic solution. Adjust the pH to 9.0 with hydrochloric acid and bottle with nasal drop or spray attachment.

Claims (1)

[Claims] 1 formula [wherein R ³ is selected from the group consisting of hydrogen, lower alkyl having 1 to 8 carbon atoms, and M, where M is a non-toxic pharmacologically inert metal cation] , A is a covalent bond, and L and B are hydrogen, lower alkyl having 1 to 8 carbon atoms, lower alkenyl having 3 to 6 carbon atoms, phenyl, and 2 to 6 carbon atoms. independently selected from the group consisting of alkanoyl having carbon atoms, or L and B taken together
constitutes a cycloalkene having ~7 carbon atoms, or an R-substituted cycloalkene having 5 to 7 carbon atoms, where R is lower alkyl having 1 to 8 carbon atoms ] A compound having 2 formulas [wherein R ³ is selected from the group consisting of hydrogen, lower alkyl having 1 to 8 carbon atoms, and M, where M is a non-toxic pharmacologically inert metal cation] , A is a covalent bond, and L and B are hydrogen, lower alkyl having 1 to 8 carbon atoms, lower alkenyl having 3 to 6 carbon atoms, phenyl, and 2 to 6 carbon atoms. independently selected from the group consisting of alkanoyl having carbon atoms, or L and B taken together
constitutes a cycloalkene having ~7 carbon atoms, or an R-substituted cycloalkene having 5 to 7 carbon atoms, where R is lower alkyl having 1 to 8 carbon atoms ] In the method for producing a compound having the formula (wherein Z is _-NH2 , and L and B
is as defined above) with the formula [wherein X is chloro, bromo or lower alkoxy having 1 to 8 carbon atoms, R is 1
lower alkyl having ~8 carbon atoms;
and A is as defined above to obtain a compound of the above formula.