3(2H)pyridazinone, and antagonistic agent against SRS-A containing it

The present invention relates to a novel 3(2H)pridazinone which exhibits antagonism against slow reacting substance of anaphylaxis (SRS-A), a process for its preparation and a pharmaceutical composition containing it.
SRS-A is a chemical mediator released together with histamine, etc. by an allergic reaction and has pharmacological activity to contract bronchial smooth muscle strongly and continuously. It has long been known from such a phenomenal aspect. It was found in 1979 that SRS-A itself is a mixture of leukotriene C.sub.4, D.sub.4 and E.sub.4 (generally called peptide leukotriene). Extensive researches have been conducted on SRS-A for its relationship with acosmia. As a result, the relationship of SRS-A with immediate type allergic diseases such as bronchial asthma, allergic rhinitics, urticaria and hay fever, has become clear. Further, the relationship of SRS-A with various inflammatory diseases, ischemic heart diseases, etc., has been suggested. Therefore, a compound which exhibits antagonism against SRS-A, is expected to be useful as a prophylactic or therapeutic drug against the affections caused by either leukotriene C.sub.4, D.sub.4 or E.sub.4, or by a mixture thereof.
As the antagonists against SRS-A, FPL-55712 and its structural analogues as well as some medicinal substances, have been reported (Agents and Actions, vol 9, p. 133-140 (1979), Annual Reports in Medicinal Chemistry, vol. 20, p. 71-81 (1985) and Agents and Actions, vol. 18, p. 332-341 (1986)) However, no instance of their clinical application has been reported.
Now, the relationship of the compounds of the present invention with compounds disclosed in published references will be described.
Canadian Pat. No. 784,639 (hereinafter referred to as reference (a)) discloses 3(2H)pyridazinone derivatives having hydrogen, C.sub.1 -C.sub.8 alkyl, phenyl or C.sub.3 -C.sub.8 cycloalkyl at 2-position, chlorine or bromine at 4-position and benzylamino at 5-position. However, the reference has no Examples corresponding to the compounds of the present invention, and the application of the compounds disclosed in this reference (a) is restricted to a herbicide, and no mention is made as to their medical use or pharmacological activities.
Chemical Abstract, 62, 2773b, (Bull. Soc. Chim, France, 1964 (9) p 2124-32) (reference (b)) discloses 3(2H)pyridazinones having hydrogen or diethylaminoethyl at 2-position, chlorine at 4-position and benzylamino at 5-position. However, this reference (b) has no Examples corresponding to the compounds of the present invention, and it is silent about medical use or pharmacological activities.
German Patent Application No. 1,670,169 published on Nov, 5, 1970 (reference (c)) discloses 3(2)prydazinones having hydrogen or an aliphatic, cycloaliphatic, araliphatic or aromatic group at 2-position, chlorine or bromine at 4-position and aralkylamino at 5-position. This reference (c) discloses a process for the synthesis of pyridazinones including such compounds, their application to agricultural chemicals, their application as intermediates for medicines or dyestuffs, or their application as intermediates for various compounds. However, no mention is made to their pharmacological activities, and no specific examples are given for such compounds. Further, such compounds are not specifically described.
Angew. Chem. International Edition, vol. 4, p. 292-300 (1965) (reference (d)) discloses 3(2H)pyridazinones having hydrogen at 2-position, chlorine at 4-position and N-methyl-benzylamino at 5-position. However, this reference (d) has no Examples corresponding to the compounds of the present invention, and no mention is made as to medical use or pharmacological activities.
The present inventors have conducted extensive researches with an object to find compounds which exhibit antagonism against SRS-A. They have found that 5-substituted benzylamino-3(2H)pyridazinone derivatives having various functional groups and substitution modes, attain the above object, and have already filed patent applications (Japanese Unexamined Patent Publication No. 267560/1986 (reference (e)) and Japanese Unexamined Patent Publication No. 0751/1986 (reference (f)). However, the compounds disclosed in these references (e) and (f) are restricted to 3(2H)pyridazinones having no substituent at 6-position (hydrogen). Further, reference (f) discloses 5-substituted benzylamino-3(2H)pyridazinone derivatives having hydrogen or 2-propenyl at 2-position. However, the amino at 5-position is secondary amino in all cases, and no compound having tertiary amino is included therein.
The present inventors have then conducted extensive researches on compounds having antagonistic activities against SRS-A, and it has been surprisingly found that 3(2H)pyridazinones of the formula I and their pharmacologically acceptable salts are more excellent in the antagonistic activities against SRS-A, and that they are useful as active ingredients for prophylactic or therapeutic drugs against diseases caused by leukotriene C.sub.4, D.sub.4 or E.sub.4, or by a mixture thereof which is a component of SRS-A. The present invention has been accomplished on the basis of this discovery.
The present invention provides a 3(2H)pyridazinone of the formula: ##STR4## wherein R.sub.1 is hydrogen, 2-propenyl or straight chained or branched C.sub.1 -C.sub.4 alkyl; R.sub.2 is hydrogen or C.sub.1 -C.sub.3 alkyl; X is chlorine or bromine; Y is hydrogen, nitro, --NHR.sub.3 wherein R.sub.3 is hydrogen or straight chained or branched C.sub.1 -C.sub.4 alkyl, --AR.sub.4 wherein A is oxygen or sulfur and R.sub.4 is hydrogen, straight chained or branched C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 alkenyl having one double bond, C.sub.3 -C.sub.6 alkynyl having one triple bond, phenyl or ##STR5## wherein R.sub.5 is hydrogen or C.sub.1 -C.sub.4 alkyl, or halogen; Z.sub.1 is hydrogen, C.sub.1 -C.sub.4 alkyl, --OR.sub.6 wherein R.sub.6 is hydrogen, straight chained or branched C.sub.1 -C.sub.8 alkyl or ##STR6## wherein n is an integer of from 1 to 4, --N(R.sub.7).sub.2 wherein R.sub.7 is C.sub.1 -C.sub.4 alkyl, or halogen; Z.sub.2 is C.sub.1 -C.sub.4 alkyl, --OR.sub.6 wherein R.sub.6 is as defined above, --N(R.sub.7).sub.2 wherein R.sub.7 is as defined above, or halogen, provided that when R.sub.1 is straight chained or branched C.sub.2 -C.sub.4 alkyl, Y is not hydrogen and when R.sub.1 is hydrogen, methyl or 2-propenyl, Y and R.sub.2 are not simultaneously hydrogen, or a pharmaceutically acceptable salt thereof.
Now, the present invention will be described with reference to the preferred embodiment. Specific examples of substituents R.sub.1, R.sub.2, X, Y, Z.sub.1 and Z.sub.2 in the formula I will be described. However, it should be understood that the present invention is by no means restricted to such specific examples. In the following substituents, "n" means normal, "i" means iso, "sec" means secondary and "t" means tertiary.
R.sub.1 includes hydrogen, 2-propenyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Among them, preferred is hydrogen, ethyl or i-propyl. More preferred is hydrogen.
R.sub.2 includes hydrogen, methyl, ethyl and n-propyl. Preferred is hydrogen.
X includes chlorine and bromine.
Y includes hydrogen, nitro, amino, --NHR.sub.3 wherein R.sub.3 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or sec-butyl, --AR.sub.4 wherein AR.sub.4 is a combination of A being oxygen or sulfur and R.sub.4 being hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl, sec-pentyl, n-hexyl, i-hexyl, sec-hexyl, 2-propenyl, 2-butenyl, 2-pentenyl, 2-hexenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 2-n-propyl-2-propenyl, 1-methyl-2-propenyl, 2-ethyl-2-propenyl, 2-propynyl(propargyl), 2-butynyl, 2-pentynyl, 1-methyl-2-propynyl, 2-ethyl-2-propynyl, benzyl, .alpha.-methylbenzyl, .alpha.-ethylbenzyl, .alpha.-n-propylbenzyl or .alpha.-n-butylbenzyl), fluorine, chlorine, bromine and iodine. Among them, preferable examples of Y are nitro and --OR.sub.4 wherein R.sub.4 is the alkyl, alkenyl, alkynyl, benzyl or substituted benzyl as specified above in the definition of AR.sub.4.
Z.sub.1 includes hydrogen, methyl, ethyl, n-propyl, n-butyl, hydroxyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, n-pentoxy, n-hexyloxy, n-heptyloxy, n-octyloxy, benzyloxy, 2-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, dimethylamino, diethyamino, di-n-propylamino, di-n-butylamino, fluorine, chlorine, bromine and iodine. Z.sub.2 includes the same substituents as mentioned for Z.sub.1 except that it does not include hydrogen. Among possible combinations of Z.sub.1 and Z.sub.2, preferred is a combination of the above-mentioned alkyl and/or alkoxy groups such as 3,4-dialkoxy or 3-alkyl-4-alkoxy. A more preferable combination of Z.sub.1 and Z.sub.2 is 3-alkoxy-4-methoxy or 3-alkyl-4-methoxy.
Among the compounds of the formula I, preferable compounds are represented by the formula IC: ##STR7## wherein R.sub.1C is hydrogen, ethyl or i-propyl; X is chlorine or bromine; R.sub.4 ' is the same substituent as R.sub.4 as defined in the formula I except that it does not include hydrogen; Z.sub.1C is hydrogen or --OR.sub.6 wherein R.sub.6 is straight chained C.sub.1 -C.sub.8 alkyl or ##STR8## wherein n is an integer of 1 to 4; and Z.sub.2C is --OR.sub.6 wherein R.sub.6 is as defined above.
Among the compounds of the formula IC, particularly preferred are Compound No. 56, 57, 58, 60, 61, 63, 64, 65, 66, 67, 68, 69, 84, 85, 86, 88, 89, 90 and 91 as identified in Table 5.
The compounds of the formula I may have E- and Z-form isomers depending upon the presence of a double bond, and optical isomers or stereoisomers depending upon the presence of 1 to 3 asymmetric carbon. The present invention includes all these isomers and mixtures thereof.
Now, the process for producing the compounds of the present invention will be described. The compounds of the formula I of the present invention can be prepared by the following processes 1 to 5. ##STR9## In the above formulas, R.sub.1, R.sub.2, X, Z.sub.1 and Z.sub.2 are as defined above with respect to the formula I; Ya is hydrogen, nitro, amino or --OR.sub.4 wherein R.sub.4 is as defined above with respect to the formula I, or halogen.
Process 1 comprises reacting a 4,5-dihalo-3(2H)pridazinone compound of the formula II with a benzylamine derivative of the formula III or its acid salt in an inert solvent, if necessary in the presence of a dehydrohalogenating agent to obtain a compound of the formula IA, which is a compound of the formula I having Ya at 6-position wherein Ya is as defined above.
In process 1 compound of the formula VA: ##STR10## wherein all symbols are as defined above, which is a position isomer of the compound of the formula IA having benzyl amino at 4-position, is formed as a by-product.
The production ratios of the compounds IA and VA depend primarily upon the polarity of the solvent used. Namely, when a solvent of high polarity is used, the production ratio of the compound IA of the present invention tends to be high. Conversely, when a solvent of low polarity such as benzene, toluene or hexane is used, the production ratio of the compound VA tends to be high. Therefore, as a suitable solvent for efficient production of the compound IA of the present invention, an ether solvent such as tetrahydrofuran or 1,4-dioxane, an amide solvent such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone, acetonitrile, dimethylsulfoxide, an alcohol solvent such as methanol, ethanol or propanol, an organic amine solvent such as pyridine or triethylamine, or water, or a solvent mixture thereof, may be mentioned. The desired 5-benzylamino isomer IA can readily be separated and purified from the mixture of the 4- and 5-benzylamino isomers by conventional methods known per se in organic synthesis, such as fractional recrystallization or various silica gel chromatography.
During the reaction, hydrogen chloride or hydrogen bromide is generated. It is usually advantageous to add to the reaction system a dehydrohalogenating agent which traps such a hydrogen halide.
Any dehydrohalogenating agent may be used so long as it does not adversely affect the reaction and is capable of trapping a hydrogen halide. As such a dehydrohalogenating agent, an inorganic base such as potassium carbonate, sodium carbonate, potassium hydrogencarbonate, or sodium hydrogencarbonate, or an organic base such as N,N-dimethylaniline, N,N-diethylaniline, trimethylamine, triethylamine or pyridine, may be mentioned. Otherwise, the benzylamine III starting material itself may be used in an excessive amount as the hydrogen halide trapping agent. This gives preferred results in many cases. The reaction temperature may be within a range of from 10.degree. C. to the boiling point of the solvent used for the reaction.
The molar ratio of the starting materials may optionally be set. However, the benzylamine derivative of the formula III may be used in an amount of from 1 to 10 moles relative to one mole of the 4,5-dihalo-3(2H)pyridazinone derivative of the formula II, and usually, it is enough that from 1.2 to 5 moles thereof is used.
The 4,5-dihalo-3(2H)pyridazinone derivative II as one of the starting materials can be prepared by a conventional process or by an application of a conventional organic reaction as described below. Namely, the compound of the formula IIa or the formula II wherein Ya is hydrogen, can be prepared by the methods disclosed in the above-mentioned references (e) and (f).
Further, the compound of the formula IIb or the formula II wherein Ya is nitro, can be prepared from the compound IIa by the methods disclosed in Japanese Examined Patent Publication Nos. 1299/1967 and 20096/1969 as shown in process 1-(1). ##STR11##
In the above formulas, R.sub.1 and X are as defined above with respect to the formula I.
The compounds of the formulas IIc-1 and IIc-2 wherein Ya is amino can be prepared, respectively, by the method disclosed in Japanese Examined Patent Publication No. 5298/1969 or by a method of treating the 6-amino-4,5-dihalo-3(2H)pyridazinone derivative wherein R.sub.1 is t-butyl, with a mineral acid such as hydrochloric acid or sulfuric acid or an organic acid such as trifluoroacetic acid or methanesulfonic acid, to remove t-butyl at 2-position.
Further, the compounds of the formulas IId-1 and IId-2 wherein Ya is hydroxyl, and the compound of the formula IId-3 wherein Ya is alkoxy, can easily be prepared by the method as shown in Process 1-(2). Namely, the 6-hydroxy-4,5-dihalopyridazinone derivative can usually be prepared by the ring closure condensation reaction of a hydrazine or its acid salt with a dihalomaleic anhydride. Further, the compound having a substituent at 2-position, can be prepared by employing a process using the compound of the formula IId-2 as the intermediate. ##STR12##
In the above formulas, R.sub.1 and X are as defined above with respect to the formula I, R.sub.1 ' is straight chained or branched C.sub.1 -C.sub.4 alkyl or 2-propenyl, R.sub.4 ' is the same substituent as R.sub.4 defined above with respect to the formula I except that it does not include hydrogen, hal is chlorine, bromine or iodine, and M is alkali metal.
With respect to the reaction efficiency or the operation, the former process is usually advantageous. However, it is advantageous to employ the latter process when the hydrazine starting material is not readily available as a commercial product and it can not easily or economically be produced. Next, the 6-alkoxy-4,5-dihalo-3(2H)pyridazinone derivative of the formula IId-3, can be prepared by reacting the 6-hydroxy derivative of the formula IId-1 or IId-2, with a halogeno derivative of the formula R.sub.4 '-hal in the presence of a conventional base. Here, a 2-R.sub.4 ' form (IId-1, R.sub.1 =R.sub.4 ') may be formed as a by-product in addition to the desired O-R.sub.4 ' form (IId-3, R.sub.1 =H) in the reaction of the compound IId-2 with R.sub.4 '-hal. In such a case, good results are often obtained by using a method wherein the reaction is conducted by restricting the ammount of the base to a level of from 1 to 1.2 equivalent, or a method wherein the compound IId-2 is treated with about the same mol of caustic alkali to isolate an alkali metal salt IId-2' and the isolated alkali metal salt is reacted with R.sub.4 '-hal in a nonaqueous solvent system.
Further, compounds of the formula IIe-1 and IIe-2, which are compounds of the formula II wherein Ya is a halogen, can be prepared by using or applying the method disclosed in Monatshefte fur Chemie, vol 99, 15 (1968) or Japanese Examined Patent Publication No. 24029/1972. ##STR13##
In the above formulas, R.sub.1 '-hal and X are as defined above in Process 1-(2), and X, is halogen.
Among the benzylamines of the formula III as another starting material in Process I, those hardly available as commercial products, can readily be prepared by the method disclosed in reference (e). ##STR14##
In the above formulas, R.sub.1, R.sub.2, X, Z.sub.1 and Z.sub.2 are as defined above with respect to the formula I, M is alkali metal, Yb is --NHR or -AR.sub.4 wherein R.sub.3, A and R.sub.4 are as defined above with respect to the formula I, and R.sub.1 " is a protective group.
Process 2 comprises a substitution reaction of nitro between a 6-nitro-5-benzylamino derivative of the formula IB-a or IB-b and an alkali metal salt of the formula IV i.e. M.sup.+ Yb.sup.-, to obtain a 6-substituted-5-benzylamino derivative of the formula IB or IB'.
Among the desired compounds, a compound having hydrogen at 2-position of pyridazinone, can be prepared by the direct route as shown in Process 2-(1), or by a route as shown in Process 2-(2) which comprises converting the 6-nitro derivative of the formula IB-b protected at 2-position with R.sub.1 " as a starting material to a compound of the formula IB-c and then removing the protective group R.sub.1 ", to obtain the desired compound.
As the protective group of R.sub.1 ", 2-trimethylsilylethoxymethyl (Me.sub.3 Si OCH.sub.2), methoxymethyl (MeOCH.sub.2 --) or CO.sub.2 R wherein R is lower alkyl, is preferably used. The removal of the protective group R.sub.1 " can easily be conducted by a conventional method for the removal of such protective groups.
Here, the alkali metal of the formula M includes lithium, sodium and potassium.
Therefore, an alkali metal salt of the formula IV used as a nucleophilic agent in Process 2 includes an alkali metal amide, an alkali metal hydroxide, an alkali metal alkoxide, an alkali metal hydrosulfide and a metal mercaptide.
There is no particular restriction as to the reaction solvent so long as it is inert to the reaction, though it may be suitably selected depending upon the type of the alkali metal salt used for the reaction. For example, in the case of using a metal amide, liquid ammonia or an ether solvent such as diethyl ether, tetrahydrofuran or 1,4-dioxane, is preferably used. In the case of using an alkali metal hydroxide or alkali metal hydrosulfide, good results are often obtained by using an alcohol solvent such as methanol, ethanol, n-propanol or n-butanol, dimethylsulfoxide, an amide solvent such as formamide, N,N-dimethylformamide or N,N-dimethylaceteamide or a polar solvent such as water. In the case of using a metal alkoxide or metal mercaptide, the reaction is usually conducted in the corresponding alcohol or mercaptan. However, the reaction can be conducted in the above-mentioned ether solvent or in a medium including a benzene solvent such as benzene or toluene.
The reaction temperature varies depending upon the reactants used. It is usually within a range of from -78.degree. C. the boiling point of the solvent used for the reaction.
The molar ratio of the starting materials can be optionally determined, and it is sufficient that the alkali metal salt of the formula IV is used in an amount of from 1.2 to 10 mols relative to one mol of the 6-nitro-5-benzylamino derivative of the formula IB-a or IB-b.
The desired compound can readily be isolated and purified by a method known per se in organic syntheses such as recrystallization, various silica gel chromatography or distillation. ##STR15##
In the above formulas, R.sub.2, X, Y, Z.sub.1 and Z.sub.2 are as defined above with respect to the formula I, and R.sub.1 ' and hal are as defined above in Process 1-(2).
Process 3 is a process which comprises reacting a compound of the formula I-a i.e. a compound of the formula I having hydrogen at 2-position of pyridazinone, with a halogeno derivative of the formula R.sub.1 '-hal, to obtain a 2-substituted compound of the formula I-b.
Process 3 is usually conducted in the presence of an inorganic base such as potassium carbonate, sodium carbonate, lithium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate or lithium hydroxide. Further, in the case where R.sub.2 is alkyl in the formula I-a, it is possible to use a metal hydride such as sodium hydride or n-butyl lithium in addition to the above inorganic base.
In the case of using the inorganic base, a ketone solvent such as acetone, methyl ethyl ketone or diethyl ketone, an amide solvent such as formamide, N,N-dimethylformamide or N,N-dimethylaceteamide, an alcohol solvent such as methanol or ethanol, or water, or a mixture thereof, is preferred as the reaction solvent, and in the case of using the metal hydride, an ether solvent is preferably used.
In the case of using the inorganic base, the reaction temperature is usually within a range of from 0.degree. C. to the boiling point of the solvent, and in the case of using the metal hydride, it is usually within a range of from -78.degree. to 60.degree. C.
The molar ratio of the starting materials may optionally be determined. However, the halogen compound of the formula R.sub.1 -hal is used usually in an amount of from 1 to 5 mols relative to one mol of the compound of the formula I-a.
The desired compound can be isolated and purified in accordance with the method as described with respect to Process 2. ##STR16##
In the above formulas, R.sub.1, R.sub.2, X, A, Z.sub.1 and Z.sub.2 are as defined above with respect to the formula I, and R.sub.4 ' and hal are as defined above in Process 1-(2).
Process 4 is a process which comprises reacting a 6-hydroxy or 6-mercapto derivative of the formula IC-a with a halogeno derivative of the formula R.sub.4 '-hal, to obtain a 6-alkoxy or 6-substituted mercapto derivative of the formula IC-b.
For Process 4, it is possible to employ the same reaction condition as in the above Process 1-(2) or Process 3. ##STR17##
In the above formulas, all symbols are as defined above with respect to the formula I.
Process 5 is a process which comprises a reduction reaction of a 6-nitro derivative of the formula ID, to obtain a 6-amino derivative of the formula IE.
For the reduction, a method of using sodium hydrosulfite, sodium sulfide or the like, or a method of using a metal such as iron, zinc, tin or the like in the presence of acid, may be employed. For this reduction reaction, it is desired to avoid a high temperature or a strong acidic condition with a high concentration of an acid, because a functional group such as halogen or benzyl, in the compound ID, will readily be reduced or eliminated under a strong acidic condition.
A protic solvent such as methanol, ethanol, n-propanol, acetic acid or water, or a mixture thereof, is usually preferably used as the solvent for the reaction. The reaction temperature may be within a range of from -10.degree. to 50.degree. C. In many cases, the reaction proceeds smoothly.
In addition to those described in the Examples given hereinafter, the following compounds (in Table 1) may be mentioned as the compounds of the present invention. In the following compounds, "n" means normal, "i" means iso, "sec" means secondary, "Me" means methyl, "Et" means ethyl, "Pr" means propyl, "Bu" means butyl, "Pen" means pentyl, "Hex" means hexyl, "Hep" means heptyl, "Oct" means octyl, and "Ph" means phenyl.
TABLE 1__________________________________________________________________________ ##STR18##R.sub.1 R.sub.2 X Y Z.sub.1 Z.sub.2__________________________________________________________________________H Me Cl OEt 3-OEt 4-OMeH Me Br OEt 3-OEt 4-OMeH Me Cl OEt 3-O-n-Pr 4-OMeH Me Br OEt 3-O-n-Pr 4-OMeH Me Cl O-i-Pr 3-OEt 4-OMeH Me Br O-i-Pr 3-OEt 4-OMeH Me Cl O-i-Pr 3-Cl 4-OMeH Me Br O-i-Pr 3-Cl 4-OMeH Me Cl Cl 3-OEt 4-OMeH Me Br Cl 3-OEt 4-OMeH Me Cl OEt 3-n-Pr 4-OMeH Me Cl OEt 3-O-n-Bu 4-OMeH Me Br OEt 3-O-n-Bu 4-OMeH Me Cl OEt 3-O-n-Pen 4-OMeH Me Br OEt 3-O-n-Pen 4-OMeH Me Cl OEt 3-O(CH.sub.2).sub.2 Ph 4-OMeH Me Br OEt 3-O(CH.sub.2).sub.2 Ph 4-OMeEt Me Cl OEt 3-OEt 4-OMeEt Me Br OEt 3-OEt 4-OMeEt Me Cl OEt 3-O-n-Pr 4-OMeEt Me Br OEt 3-O-n-Pr 4-OMeH H Cl OMe 3-OMe 4-OMeH H Br OMe 3-OEt 4-OMeH H Cl OMe 3-O-n-Pr 4-OMeH H Br OMe 3-O-n-Pr 4-OMeH H Cl OMe 3-O-n-Bu 4-OMeH H Br OMe 3-O-n-Bu 4-OMeH H Cl OMe H 4-OEtH H Br OMe H 4-OEtH H Cl OMe H 4-EtH H Br OMe H 4-EtH H Cl OMe 3-n-Pr 4-OMeH H Br OMe 3-n-Pr 4-OMeH H Cl OMe 3-OEt 4-ClH H Br OMe 3-OEt 4-ClH H Cl SEt 3-OMe 4-OMeH H Br OEt 3-OMe 4-OMeH H Cl OEt 2-OMe 4-OMeH H Br OEt 2-OMe 4-OMeH H Cl OEt 2-Me 4-MeH H Br OEt 2-Me 4-MeH H Cl OEt 3-Cl 4-ClH H Br OEt 3-Cl 4-ClH H Cl OEt 3-Et HH H Br OEt 3-Et HH H Cl SEt 3-OEt 4-OMeH H Br OEt 3-OEt 4-OMeH H Cl SEt 3-O-n-Pr 4-OMeH H Br OEt 3-O-n-Pr 4-OMeH H Cl SEt 3-O-n-Bu 4-OMeH H Br OEt 3-O-n-Bu 4-OMeH H Cl OEt 3-O-n-Pen 4-OMeH H Br OEt 3-O-n-Pen 4-OMeH H Cl OEt 3-O-n-Hex 4-OMeH H Br OEt 3-O-n-Hex 4-OMeH H Cl OEt 3-O-n-Hep 4-OMeH H Br OEt 3-O-n-Hep 4-OMeH H Cl OEt 3-O-n-Oct 4-OMeH H Br OEt 3-O-n-Oct 4-OMeH H Cl OEt 3-O(CH.sub.2).sub.2 Ph 4-OMeH H Br OEt 3-O(CH.sub.2).sub.2 Ph 4-OMeH H Cl OEt 3-O(CH.sub.2).sub.3 Ph 4-OMeH H Br OEt 3-O(CH.sub.2).sub.3 Ph 4-OMeH H Cl SMe 3-OMe 4-OMeH H Br O-i-Pr 3-OMe 4-OMeH H Cl O-i-Pr 2-OMe 4-OMeH H Br O-i-Pr 2-OMe 4-OMeH H Cl O-i-Pr 2-Me 4-MeH H Br O-i-Pr 2-Me 4-MeH H Cl O-i-Pr 3-Et 4-ClH H Cl O-i-Pr 3-Et 4-N(Me).sub.2H H Cl O-i-Pr 3-Cl 4-ClH H Br O-i-Pr 3-Cl 4-ClH H Cl O-i-Pr H 4-OEtH H Br O-i-Pr H 4-OEtH H Cl SMe 3-OEt 4-OMeH H Br O-i-Pr 3-OEt 4-OMeH H Cl O-i-Pr 3-OEt 4-ClH H Br O-i-Pr 3-OEt 4-ClH H Cl O-i-Pr 3-OEt 4-N(Me).sub.2H H Br O-i-Pr 3-OEt 4-N(Me).sub.2H H Cl SMe 3-O-n-Pr 4-OMeH H Br O-i-Pr 3-O-n-Pr 4-OMeH H Cl SMe 3-O-n-Bu 4-OMeH H Br O-i-Pr 3-O-n-Bu 4-OMeH H Cl O-i-Pr 3-O-n-Pen 4-OMeH H Br O-i-Pr 3-O-n-Pen 4-OMeH H Cl SMe 3-O-n-Hex 4-OMeH H Br O-i-Pr 3-O-n-Hex 4-OMeH H Cl O-i-Pr 3-O-n-Hep 4-OMeH H Br O-i-Pr 3-O-n-Hep 4-OMeH H Cl O-i-Pr 3-O-n-Oct 4-OMeH H Br O-i-Pr 3-O-n-Oct 4-OMeH H Cl O-i-Pr 3-O(CH.sub.2).sub.2 Ph 4-OMeH H Br O-i-Pr 3-O(CH.sub.2).sub.2 Ph 4-OMeH H Cl Cl 3-O(CH.sub.2).sub.2 Ph 4-OMeH H Br Cl 3-OEt 4-OMeH H Cl Br 3-OEt 4-OMeH H Br Br 3-OEt 4-OMeH H Cl F 3-OEt 4-OMeH H Br F 3-OEt 4-OMeH H Cl NHMe 3-OEt 4-OMeH H Br NHMe 3-OEt 4-OMeH H Cl NHEt 3-OEt 4-OMeH H Br NHEt 3-OEt 4-OMeH H Cl Cl 3-OMe 4-OMeH H Br Cl 3-O-n-Pr 4-OMeH H Cl NHMe 3-O-n-Pr 4-OMeH H Br NHMe 3-O-n-Pr 4-OMeH H Cl O-n-Pr 3-OMe 4-OMeH H Br O-n-Pr 3-OMe 4-OMeH H Cl O-i-Bu 3-OMe 4-OMeH H Br O-i-Bu 3-OMe 4-OMeH H Cl O-n-Pr 3-OEt 4-OMeH H Br O-n-Pr 3-OEt 4-OMeH H Cl O-i-Bu 3-OEt 4-OMeH H Br O-i-Bu 3-OEt 4-OMeH H Cl O-n-Pr 3-O-n-Pr 4-OMeH H Br O-sec-Bu 3-OMe 4-OMeH H Br O-sec-Bu 3-OEt 4-OMeH H Cl O-sec-Bu 3-O-n-Pr 4-OMeH H Br O-sec-Bu 3-O-n-Pr 4-OMeH H Cl O-sec-Bu 3-O-n-Bu 4-OMeH H Br O-sec-Bu 3-O-n-Bu 4-OMeH H Br O-n-Pr 3-O-n-Pr 4-OMeH H Cl O-i-Bu 3-O-n-Pr 4-OMeH H Br O-i-Bu 3-O-n-Pr 4-OMeH H Cl O-n-Pr 3-O-n-Bu 4-OMeH H Br O-n-Pr 3-O-n-Bu 4-OMeH H Cl O-i-Bu 3-O-n-Bu 4-OMeH H Br O-i-Bu 3-O-n-Bu 4-OMeH H Cl O-n-Pr 3-O(CH.sub.2).sub.2 Ph 4-OMeEt H Br OMe 3-O-n-Pr 4-OMeEt H Cl OEt 3-OMe 4-OMeEt H Br OEt 3-OMe 4-OMeEt H Br OEt 3-O-n-Pr 4-OMeEt H Cl OEt 3-O-n-Bu 4-OMeEt H Br OEt 3-O-n-Bu 4-OMei-Pr H Cl OEt 2-OMe 4-OMei-Pr H Br OEt 2-OMe 4-OMei-Pr H Cl OEt 3-OMe 4-OMei-Pr H Br OEt 3-OMe 4-OMei-Pr H Cl OEt 3-OEt 4-OMei-Pr H Br OEt 3-OEt 4-OMei-Pr H Cl OEt 3-O-n-Bu 4-OMei-Pr H Br OEt 3-O-n-Pr 4-OMeEt H Cl OEt 2-Me 4-MeEt H Br OEt 2-Me 4-MeCH.sub.2 CHCH.sub.2 H Cl OEt 3-OEt 4-OMeCH.sub.2 CHCH.sub.2 H Br OEt 3-OEt 4-OMei-Pr H Cl O-i-Pr 3-OEt 4-OMei-Pr H Br O-i-Pr 3-OEt 4-OMei-Pr H Cl O-i-Pr 3-O-n-Bu 4-OMei-Pr H Br O-i-Pr 3-O-n-Pr 4-OMeCH.sub.2 CHCH.sub.2 H Cl O-i-Pr 3-OEt 4-OMeCH.sub.2 CHCH.sub.2 H Br O-i-Pr 3-OEt 4-OMeMe H Cl O-i-Pr 3-OEt 4-OMeMe H Br O-i-Pr 3-OEt 4-OMeMe H Cl O-i-Pr 3-O-n-Pr 4-OMeMe H Br O-i-Pr 3-O-n-Pr 4-OMeEt H Cl O-n-Pr 3-OEt 4-OMeEt H Br O-n-Pr 3-OEt 4-OMeEt H Cl O-n-Pr 3-OMe 4-OMeEt H Br O-n-Pr 3-O-n-Pr 4-OMeEt H Cl O-i-Bu 3-OEt 4-OMeEt H Br O-i-Bu 3-OEt 4-OMeEt H Cl Cl 3-OEt 4-OMeEt H Cl Br 3-OEt 4-OMeEt H Br Cl 3-OEt 4-OMeEt H Br Br 3-OEt 4-OMeEt H Cl Cl 3-OMe 4-OMeEt H Br Cl 3-O-n-Pr 4-OMei-Pr H Cl Cl 3-OEt 4-OMei-Pr H Br Cl 3-OEt 4-OMeEt H Cl NHMe 3-OEt 4-OMeEt H Br NHMe 3-OEt 4-OMei-Pr H Cl NHMe 3-OEt 4-OMei-Pr H Br NHMe 3-OEt 4-OMeEt H Cl NHEt 3-OEt 4-OMeEt H Br NHEt 3-OEt 4-OMeEt H Cl NHMe 3-O-n-Pr 4-OMeEt H Br NHMe 3-O-n-Pr 4-OMeH H Cl O-sec-Bu 3-O(CH.sub.2).sub.2 Ph 4-OMeH H Br O-sec-Bu 3-O(CH.sub.2).sub.2 Ph 4-OMeH H Br OCHMePh 3-OMe 4-OMeH H Br OCHMePh 3-OEt 4-OMeH H Cl OCHMePh 3-O-n-Bu 4-OMeH H Br OCHMePh 3-O-n-Bu 4-OMeH H Cl OCHMePh 3-O(CH.sub.2).sub.2 Ph 4-OMeH H Br OCHMePh 3-O(CH.sub.2).sub.2 Ph 4-OMeH H Cl OCHEtPh 3-OMe 4-OMeH H Br OCHEtPh 3-OMe 4-OMeH H Cl ##STR19## 3-OMe 4-OMeH H Br ##STR20## 3-OMe 4-OMeH H Cl ##STR21## 3-OMe 4-OMeH H Br ##STR22## 3-OMe 4-OMeH H Cl ##STR23## 3-OMe 4-OMeH H Br ##STR24## 3-OMe 4-OMeH H Cl ##STR25## 3-OMe 4-OMeH H Br ##STR26## 3-OMe 4-OMe__________________________________________________________________________
As the manner of administration of the compounds of the present invention, there may be mentined a non-oral administration by injection (subcutaneous, intravenous, intramuscular or intraperitoneal injection), an ointment, a suppository or an aerosol, or an oral administration in the form of tablets, capsules, granules, pills, sirups, liquids, emulsions or suspensions.
The above pharmacological or veterinary composition contains a compound of the present invention in an amount of from about 0.1 to about 99.5% by weight, preferably from about 0.5 to about 95% by weight, based on the total weight of the composition. To the compound of the present invention or to the composition containing the compound of the present invention, other pharmacologically or veterinarily active compounds may be incorporated. Further, the composition of the present invention may contain a plurality of compounds of the present invention.
The clinical dose of the compound of the present invention varies depending upon the age, the body weight, the sensitivity or the symptom, etc. of the patient. However, the effective daily dose is usually from 0.003 to 1.5 g, preferably from 0.01 to 0.6 g, for an adult. However, if necessary, an amount outside the above range may be employed.
The compounds of the present invention may be formulated into various suitable formulations depending upon the manner of administration, in accordance with conventional methods commonly employed for the preparation of pharmaceutical formulations.
Namely, tablets, capsules, granules or pills for oral administration, may be prepared by using an excipient such as sugar, lactose, glucose, starch or mannitol; a binder such as sirups, gum arabic, gelatin, sorbitol, tragacant gum, methyl cellulose or polyvinylpyrrolidone; a disintegrant such as starch, carboxymethyl cellulose or its calcium salt, crystal cellulose powder or polyethylene glycol; a glass agent such as talc, magnesium or calcium stearate or colloidal silica; or a lubricant such as sodium laurate or glycerol. The injections, solutions, emulsions, suspensions, sirups or aerosols, may be prepared by using a solvent for the active ingredient such as water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol, or polyethylene glycol; a surfactant such as a sorbitol fatty acid ester, a polyoxyethylene sorbitol fatty acid ester, a polyoxyethylene fatty acid ester, a polyoxyethylene ether of hydrogenated caster oil or lecithin; a suspending agent such as a sodium salt of carboxymethyl, a cellulose derivative such as methyl cellulose, or a natural rubber such as tragacant gum or gum arabic; or a preservative such as a paraoxy benzoic acid ester, benzalkonium chloride or a salt of sorbic acid. Likewise, the suppositories may be prepared by using e.g. polyethylene glycol, lanolin or cocoa butter.

TEST EXAMPLES
A. Antagonistic activity test against SRS-A
SRS-A is a mixture of leukotriene C.sub.4 (hereinafter referred to as LTC.sub.4), leukotriene D.sub.4 (hereinafter referred to as LTD.sub.4), leukotriene E.sub.4 (hereinafter referred to as LTE.sub.4) and the like. Accordingly, antagonistic activities against SRS-A can be evaluated by one of the following two test methods:
(1) A method of examining the antagonistic activities against SRS-A obtained from a sensitized guinea-pig,
(2) A method of examining the antagonistic activities against LTC.sub.4, LTD.sub.4 or LTE.sub.4.
The present inventors examined the antagonistic activities of compounds of the formula I against SRS-A by using the following test methods.
(1) Test methods
(1) in vitro test
LTD.sub.4 antagonism in guinea-pig trachea
Antagonism for LTD.sub.4 was determined in isolated male guinea-pig (300-400 g) trachea prepared as spiral strip. Tracheal preparations were suspended under 1 g tension in 10 ml organ baths containing 5 .mu.M of indomethacin and they were incubated for 1 hr prior to use. Contractile responses to LTD.sub.4 (2.times.10.sup.-8 g/ml) were obtained after the maximal response to histamine (10.sup.- 4 M). Test compounds dissolved in 100% dimethyl sulfoxide were added to the organ baths (final concentration of 10.sup.-6 g/ml or 10.sup.-7 g/ml) 30 min prior to LTD.sub.4 addition, and then contractile responses to LTD.sub.4 were compared with those of control which was obtained from a paired trachea in the absence of test compounds. LTD.sub.4 -induced contractions were expressed as a percentage of the maximal response to histamine. The antagonism was determined as follows:
Antagonism (%)=(1.0 - % contraction in test/% contraction in control).times.100
FPL-55712 (Fisons Limited) approved as a selective SRS-A antagonist, was used as the control. ##STR27##
(2) in vivo test
Effect on anaphylactic bronchoconstriction mediated by endogeneously liberated SRS-A in passively sensitized guinea-pig
Male guinea-pigs (350-450 g) were passively sensitized with intravenous (i.v.) injection of 0.125 ml rabbit anti-EA (egg albumin) serum (Capple Laboratories) 1 to 2 days preceding the experiment. Antigen-induced anaphylactic bronchoconstrictions mediated by endogeneously liberated SRS-A were measured by modified method of Konzett and Rossler (Arch. Exp. Path. Pharmak., 195, 71, 1940). Sensitized guinea-pigs were anaesthetized with intraperitoneal injection of urethane (1.5 g/kg). The right jugular vein was cannulated for the administration of the all agents and trachea was cannulated to record total pulmonary resistance. Guinea-pigs were artificially ventilated by a small animal respirator (Shinano, Model SN-480-7) set at a stroke volume of 4.5 ml and a rate of 50 breaths per min. The change in pulmonary resistance was measured with a pressure transducer (Nihon Kohden, Model TP-602T) connected to a T-tube on the tracheal cannula. The increase in air overflow volume was expressed as a percentage of the maximum bronchoconstriction obtained by clamping off the trachea. Following surgical preparation, the animals were pretreated with indomethacin (2 mg/kg, 10 min), pyrilamine (2 mg/kg, 6 min) and propranolol (0.1 mg/kg, 5 min) prior to the EA challenge (0.2 mg/kg). All test compounds were administered orally 2 hrs before the EA challenge. Inhibition (%) of bronchoconstriction was determined as follows: Inhibition (%)=(1.0 - % maximum bronchoconstriction in test/% maximum bronchoconstriction in control).times.100. The maximum bronchoconstriction was 62.+-.6% (Mean.+-.S.E.M; n=6) and the number of test animals was 5-6.
(2) Test Results
(1) in vitro test
LTD.sub.4 antagonisms by test compounds at a concentration of 10.sup.-6 g/ml are shown in Table 2. In parenthesis in Table 2, LTD.sub.4 antagonisms by test compounds at a concentration of 10.sup.-7 g/ml are shown.
TABLE 2______________________________________Test Testcompound Antagonism compound AntagonismNo. (%) No. (%)______________________________________ 5 54 64 90 7 50 65 9610 66 66 100 (48)22 59 67 100 (82)23 51 68 9227 72 69 100 (83)30 38 70 6633 93 71 6636 70 72 7545 50 73 10046 73 74 10047 79 75 7748 99 77 5050 95 78 5651 94 79 7952 100 80 10053 100 84 5954 95 85 8555 81 86 100 (48)56 100 (51) 89 96 (55)57 100 (37) 90 96 (70)58 100 (40) 91 100 (76)60 100 (38) 92 6361 96 94 6863 92 FPL-55712 94 (48)______________________________________
(2) in vivo test
Each of test compounds No. 68 and 69 as representative compounds of the present invention showed significant inhibitory effects over the control at a dose by oral administration as identified in Table 3 (P<0.05). The results are shown in Table 3.
TABLE 3______________________________________Test compound No. Dose (mg/kg) Inhibition (%)______________________________________68 30 51 10 6369 30 52______________________________________
B. Acute toxicity test
The lethal ratio was determined in CD-1(ICR) strain male mice (5 weeks old) at 7 days after the oral administration of test compounds. The results are shown in Table 4.
TABLE 4______________________________________ Lethal ratioTest compound Death ExperimentalNo. Dose (mg/kg) number number______________________________________68 1200 0 569 1200 0 5______________________________________
From these results, it is evident that the compounds of the present invention exhibit prominent antagonistic activities against SRS-A and its major constituents peptide leukotrienes in vitro and in vivo. Further, the compounds of the present invention show strong pharmacological activities and low toxicity even by oral administration. Therefore, the compounds of the present invention are expected to be useful as prophylactic and therapeutic drugs against various immediate type allergic diseases such as bronchial asthma, allergic rhinitics, urticaria and hay fever, various inflamatory diseases such as rheumatoid arthritis and spondyloarthritis, or ischemic heart diseases such as angina pectoris and myocardial infarction, induced by SRS-A or by one of leukotriene C.sub.4, D.sub.4 and E.sub.4 as its constituents or a mixture thereof.
Now, the present invention will be described in detail with reference to Examples including Reference Examples and Formulation Examples. However, it should be understood that the present invention is by no means restricted by these specific Examples. In specific Examples, in Reference Examples, or in Table 5, the symbols "NMR", "IR" and "MS" indicate "nuclear magnetic resonance spectrum", "Infrared spectrum" and "mass spectrometry", respectively. IR was measured by the potassium bromide disk method and NMR was measured in heavy chloroform, unless otherwise specified. In the MS data, only the principal peaks or typical fragment peaks are given.
REFERENCE EXAMPLE 1
2-ethyl-4,5-dichloro-6-hydroxy-3(2H)pyridazinone
A mixture comprising 5.00 g of 3,6-dihydroxy-4,5-dichloropyridazine, 2.21 g of sodium hydroxide, 5.60 g of ethyl iodide, 40 ml of ethanol and water, was stirred at a temperature of from 60.degree. to 70.degree. C. for 4 hours. Most ethanol was distilled off under reduced pressure. Then, dilute hydrochrolic acid and chloroform were added to the residue, and the mixture was vigorously shaked. The chloroform layer was separated and washed with water, followed by drying over sodium sulfate. Then, the solvent was distilled off to obtain a light orange solid substance. The solid substance was treated with benzene to obtain 3.56 g of the above identified compound as colorless crystals.
NMR (CDCl.sub.3 +DMSO-d.sub.6) .delta.: 4.05(2H, q), 1.33(3H, t).
IR (.upsilon.max cm.sup.-1): 3150, 1635, 1620, 1560, 1510,
MS (m/e): 208(M.sup.+), 193, 180(100%), 166, 148.
REFERENCE EXAMPLE 2
4,5-dichloro-6-ethoxy-3(2H)pyridazinone
27.15 g of 3,6-dihydroxy-4,5-dichloropyridazine was dissolved in a solution prepared by dissolving 6.43 g of sodium hydroxide in 200 ml of water, and the solution was subjected to freeze-drying to obtain 32.80 g of sodium salt of 3,6-dihydroxy-4,5-dichloropyridazine as a light yellow powder. A mixture comprising 14.21 g of the sodium salt, 13.10 g of ethyl iodide and 200 ml of N,N-dimethylformamide was stirred at a temperature of from 70.degree. to 80.degree. C. for 4 hours. The solvent was distilled off under reduced pressure, and water was added to the residue thereby obtained. The mixture was extracted with chloroform. The extract was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. Then, the solvent was distilled off to obtain a light orange solid substance. The solid substance was washed with 250 ml of a solvent mixture of benzene-ethyl acetate (3:1 v/v) to obtain 2.83 g of the above identified compound having a melting point of from 212.degree. to 212.5.degree. C. as colorless crystals. The residual washing solvent was treated with 10 g of silica gel, and then the solvent was distilled off to obtain a light yellow solid substance. The solid substance was washed with diethyl ether to obtain additional 2.37 g of the above identified compound. (Total yield: 5.20 g)
NMR (CDCl.sub.3 +DMSO-d.sub.6): 4.20(2H, q), 1.38(3H, t).
IR (.upsilon.max cm.sup.-1): 2975, 2850, 1645, 1585, 1380.
MS (m/e): 208(M.sup.+), 180(100%), 150.
In the same manner as above, by using isopropyl iodide, benzyl bromide and .alpha.-phenylethyl bromide instead of ethyl iodide, 4,5-dichloro-6-i-propoxy-3(2H)pyridazinone having a melting point of from 210.degree. to 211.degree. C., 4,5-dichloro-6-benzyloxy-3(2H)pyridazinone having a melting point of from 111.degree. to 113.degree. C. and 4,5-dichloro-6 -(.alpha.-methylbenzyloxy)-3(2H)pyridazinone having a melting point of from 160.degree. to 161.degree. C. were prepared, respectively.
REFERENCE EXAMPLE 3
2-(2-trimethylsilylethoxymethyl)-4-chloro-5-(3-ethoxy-4-methoxybenzylamino)-6-nitro-3(2H)pyridazinone
587 mg of trimethysilylethoxymethyl chloride was added to a mixture comprising 500 mg of 4-chloro-5-(3-ethoxy-4-methoxybenzylamino)-6-nitro-3(2H)pyridazinone (Compound No. 17), 911 mg of di-i-propylethylamine and 15 ml of dichloromethane, and the mixture was stirred at room temperature for 10 minutes. The solvent was distilled off and the residue thereby obtained was extracted with chloroform. The extract was washed twice with a saturated copper sulfate solution and once with water in this order and dried over sodium sulfate. Then, the solvent was distilled off to obtain a yellow oily substance. The oily substance was purified by silica gel thin layer chromatography by using diethyl ether as the developper, to obtain 600 mg of the above identified compound as a yellow oily substance. This oily substance was allowed to stand to gradually change to crystals having a melting point of from 56.degree. to 57.5.degree. C.
NMR .delta.: 6.85(3H, s), 6.69(1H, m), 5.48(2H, s), 4.78, 4.68(2H, d), 4.10(2H, q), 3.88(3H, s), 3.80(2H, t), 1.49(3H, t), 1.00(3H, t), 0.0(9H, s).
MS (m/e): 484(M.sup.+), 483(100%), 353, 319
In the same manner as above, 2-(2-trimethylsilylethoxymethyl)-4-chloro-5-(3,4-dimethoxybenzylamino)-6-nitro-3(2H)pyridazinone (yellow oily substance) was prepared from 4-chloro-5-(3,4-dimethoxybenzylamino)-6-nitro-3(2H)pyridazinone (Compound No. 87).
REFERENCE EXAMPLE 4
2-(2-trimethylsilylethoxymethy)-4-chloro-5-(3-ethoxy-4-methoxybenzylamino)-6-methoxy-3(2H)pyridazinone
A mixture comprising 250 mg of 2-(2-trimethylsilylethoxymethyl)-4-chloro-5-(3-ethoxy-4-methoxybenzylamino)-6-nitro-3(2H)pyridazinone prepared in Reference Example 3, 42 mg of sodium methoxide and methanol, was stirred at room temperature for 10 minutes. Water was added to the reaction mixture and the solvent was distilled off, and the residue thereby obtained was extracted with chloroform. The extract was washed with water and dried over sodium sulfate. Then, the solvent was distilled off to obtain a yellow oily substance. The oily substance was purified by silica gel thin layer chromatography by using diethyl ether as the developer, to obtain 220 mg of the above identified compound as a light yellow oily substance.
NMR .delta.: 6.78(3H, s), 5.30(2H, s), 5.10(1H, m), 4.82, 4.74(2H, d), 4.10(2H, q), 3.85(6H, s), 3.72(2H, t), 1.48(3H, t), 1.00(3H, t), 0.0(9H, s).
MS (m/e): 469(M.sup.+), 468(100%), 304, 188
In the same manner as above, by using sec-butoxide instead of sodium methoxide, 2-(2-trimethylsilylethoxymethy)-4-chloro-5-(3-ethoxy-4-methoxybenzylamino)-6-sec-butoxy-3(2H)pyridazinone (oily substance) and 2-(2-trimethylsilylethoxymethyl)-4-chloro-5-(3,4-dimethoxybenzylamino)-6-sec-butoxy-3(2H)pyridazinone (oily substance), were prepared from the corresponding 2-(2-trimethylsilylethoxymethyl)-4-chloro-5-(3-alkoxy-4-methoxybenzylamino)-6-nitro-3(2H)pyridazinones.
REFERENCE EXAMPLE 5
2-(2-trimethylsilylethoxymethyl)-4-chloro-5-(3,4-dimethoxybenzylamino)-6-n-propylmercapto-3(2H)pyridazinone
A solution prepared by dissolving 916 mg of 2-(2-trimethylsilylethoxymethyl)-4-chloro-5-(3,4-dimethoxybenzylamino)-6-nitro-3(2H)pyridazinone prepared in Reference Example 4 in 2 ml of toluene, was dropwise added under cooling with ice and stirring to a mixture comprising of 1 ml of n-propyl mercaptan, 166 mg of sodium amide and 6 ml of toluene. After dropwise addition, the reaction mixture was stirred at the same temperature for further 20 minutes. A saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with water and dried over sodium sulfate. Then, the solvent was distilled off and the residue thereby obtained was purified by silica gel column chromatography by using benzene-ethyl acetate (12:1 v/v) as the eluent, to obtain 500 mg of the above identified compound as a light yellow oily susbtance.
NMR .delta.: 6.72(3H, s), 5.33(2H, s), 5.0-4.6(3H, m), 3.81(6H, s), 3.67(2H, t), 2.08(2H, t), 1.9-0.8(7H, m), 0.00(9H, s)
MS (m/e): 499(M.sup.+), 456, 398, 383, 164, 151(100%).
In the same manner as above, by using i-propyl mercaptan, i-buthyl mercaptan and sec-buthyl mercaptan instead of n-propyl mercaptan, the respective 6-alkylmercapto forms i.e. 2-(2-trimethylsilylethoxymethyl)-4-chloro-5-(3,4-dimethoxybenzylamino)-6-i-propylmercapto, -6-i-butylmercapto and -6-sec-butylmercapto-3(2H)pyridazinones (each being a light yellow oily substance), were prepared.
EXAMPLE 1
4-bromo-5-(3-n-propoxy-4-methoxy-N-methylbenzylamino)-3(2H)pyridazinone (Compound No. 6) ##STR28##
A mixture comprising 300 mg of 4,5-dibromo-3(2H)pyridazinone, 740 mg of 3-n-propoxy-4-methoxy-N-methylbenzylamine and 10 ml of ethanol, was refluxed under stirring for 7 hours. Then, ethanol was distilled off under reduced pressure, dilute hydrochloric acid was added to the residue thereby obtained, and the mixture was extracted with ethyl acetate. The extract was washed twice with water and dried over sodium sulfate. Then, the solvent was distilled off to obtain a yellow solid substance. The product was crystallized from ethyl acetate, to obtain 310 mg of the above identified compound having a melting point of from 149.degree. to 150.degree. C. as light yellow crystals.
NMR .delta.: 7.53(1H, s), 6.75(3H, s), 4.53(2H, s), 3.91(2H, t), 3.81(3H, s), 3.01(3H, s), 1.84(2H, hexalet), 1.01(3H, t).
MS (m/e): 302(M.sup.+ -Br,100%), 179, 137.
EXAMPLE 2
4-chloro-5-(3-n-propoxy-4-methoxybenzylamino)-6-nitro-3(2H)pyridazinone (Compound No. 22) ##STR29##
A mixture comprising 8.0 g of 4,5-dichloro-6-nitro-3(2H)pyridazinone, 29.75 g of 3-n-propoxy-4-methoxybenzylamine and 160 ml of ethanol, was refluxed under stirring for 15 hours. Ethanol was distilled off under reduced pressure, and water was added to the residue thereby obtained. The mixture was extracted with chloroform. The extract was washed with water and dried over sodium sulfate. Then, the solvent was distilled off to obtain an orange solid substance. This product was crystallized from a solvent mixture of methanol-water, to obtain 6.50 g of the above identified compound having a melting point of from 169.degree. to 171.degree. C. as orange crystals.
NMR (CDCl.sub.3 +DMSO-d.sub.6) .delta.: 7.01(1H, t), 6.77 (3H, s), 4.62(2H, d), 3.90(2H, t), 3.77(3H, s), 1.78(2H, hexalet), 1.00(3H, t).
MS (m/e): 368(M.sup.+), 333, 179(100%), 137.
EXAMPLE 3
4-chloro-5-(3-n-propoxy-4-methoxybenzylamino)-6-amino-3(2H)pyridazinone (Compound No. 23) ##STR30##
1.00 g of 4-chloro-5-(3-n-propoxy-4-methoxybenzylamino)-6-nitro-3(2H)pyridazinone (Compound No. 22) prepared in Example 2, was dissolved in a solvent mixture of 20 ml of ethanol and 20 ml of a 10% sodium carbonate aqueous solution, 3.30 g of sodium hydrosulfite was gradually added thereto at room temperature under stirring. The mixture was stirred at room temperature for 1 hour, and was neutralized with glacial acetic acid. Then, ethanol was distilled off under reduced pressure, and water was added to the residue thereby obtained. The mixture was extracted with chloroform. The extract was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. Then, the solvent was distilled off to obtain light yellow crystals This product was crystallized from a solvent mixture of methanol-diethyl ether, to obtain 634 mg of the above identified compound having a melting point of from 187.5.degree. to 189.5.degree. C. as colorless crystals
MS (m/e): 338(M.sup.+), 303, 179(100%), 137.
EXAMPLE 4
2-ethyl-4-chloro-5-(3-n-propoxy-4-methoxybenzylamino)-6-nitro-3(2H)pyridazinone (Compound No. 24) ##STR31##
A mixture comprising 500 mg of 4-chloro-5-(3-n-propoxy-4-methoxybenzylamino)-6-nitro-3(2H)pyridazinone (Compound No. 22) prepared in Example 2, 634 mg of ethyl iodide, 562 mg of anhydrous potassium carbonate and 25 ml of methyl ethyl ketone, was refluxed under stirring for 1.5 hours. The solvent was distilled off under reduced pressure, and water was added to the residue thereby obtained and the mixture was extracted with diethyl ether. The extract was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. Then, the solvent was distilled off, and the residual oily substance thereby obtained was crystallized from a solvent mixture of diethyl ether-n-hexane, to obtain 473 mg of the above identified compound having a melting point of from 76.degree. to 77.degree. C. as yellow crystals.
NMR .delta.: 6.79(3H, s), 6.60(1H, broad t), 4.68(2H, d), 4.30(2H, q), 3.93(2H, t), 3.82(3H, s), 1.84(2H, hexalet), 1.39(3H, t), 1.03(3H, t).
MS (m/e): 396(M.sup.+), 361, 179(100%), 137.
EXAMPLE 5
2-i-propyl-4-chloro-5-(3-n-propoxy-4-methoxybenzylamino)-6-nitro-3(2H)pyridazinone (Compound No. 25) ##STR32##
A mixture comprising 500 mg of 4-chloro-5-(3-n-propoxy-4-methoxybenzylamino)-6-nitro-3(2H)pyridazinone (Compound No. 22) prepared in Example 2, 691 mg of isopropyl iodide, 562 mg of anhydrous potassium carbonate and 25 ml of methyl ethyl ketone, was refluxed under stirring for 1.5 hours. The solvent was distilled off under reduced pressure, and water was added to the residue thereby obtained. The mixture was extracted with diethyl ether. The extract was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. Then, the solvent was distilled off. The residual oily substance thereby obtained was crystallized from a solvent mixture of diethyl ether-n-hexane, to obtain 435 mg of the above identified compound having a melting point of from 82.5.degree. to 84.degree. C. as yellow crystals.
NMR .delta.: 6.80(3H, s), 6.63(1H, broad t), 5.25 (1H, heptalet), 4.69(2H, d), 3.94(2H, t), 3.83(3H, s), 1.85(2H, hexalet), 1.38(6H, d), 1.04(3H, t).
MS (m/e): 410(M.sup.+), 375, 179(100%), 137.
EXAMPLE 6
2-(2-propenyl)-4-chloro-5-(3-n-propoxy-4-methoxybenzylamino)-6-nitro-3(2H)pyridazinone (Compound No. 26) ##STR33##
A mixture comprising 500 mg of 4-chloro-5-(3-n-propoxy-4-methoxybenzylamino)-6-nitro-3(2H)pyridazinone (Compound No. 22) prepared in Example 2, 820 mg of allyl bromide, 937 mg of anhydrous potassium carbonate and 25 ml of methyl ethyl ketone, was refluxed under stirring for 1.5 hours. The solvent was distilled off under reduced pressure, water was added to the residue thereby obtained, the mixture was extracted with diethyl ether. The extract was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. Then, the solvent was distilled off, and the residue was purified by silica gel column chromatography by using a solvent mixture of benzene: ethyl acetate (85:15 v/v) as the eluent, to obtain 394 mg of the above identified compound having a melting point of from 62.5.degree. to 64.degree. C. as yellow crystals.
NMR .delta.: 6.81(3H, s), 6.59(1H, broad t), 6.1-4.4(7H, m), 3.95(2H, t), 3.85(3H, s), 1.84(2H, hexalet), 1.02(3H, t).
MS (m/e): 408(M.sup.+), 373, 179(100%), 137.
EXAMPLE 7
2-ethyl-4-bromo-5-(3-n-butoxy-4-methoxybenzylamino)-6-amino-3(2H)pyridazinone (Compound No. 32) ##STR34##
A mixture comprising 280 mg of 4-bromo-5-(3-n-butoxy-4-methoxybenzylamino)-6-amino-3(2H)pyridazinone (Compound No. 30) prepared according to the process of Example 3 from 4-bromo-5-(3-n-butoxy-4-methoxybenzylamino)-6-nitro-3(2H)pyridazinone (Compound No. 29) as the starting material, 0.29 ml of ethyl iodide, 487 mg of anhydrous potassium carbonate and 15 ml of methyl ethyl ketone, was refluxed under stirring for 2 hours. The solvent was distilled off under reduced pressure, and water was added to the residue thereby obtained. The mixture was extracted with chloroform. The extract was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. Then, the solvent was distilled off, the residue thereby obtained was subjected to silica gel thin layer chromatography by using a solvent mixture of chloroform:methanol (9:1 v/v) as the developer, the oily substance thereby obtained was crystallized from a solvent mixture of diethyl ether-n-hexane, to obtain 180 mg of the above identified compound having a melting point of from 108.degree. to 110.5.degree. C. as light yellow crystals.
NMR .delta.: 6.78(3H, s), 5.1-3.8(9H, m), 3.80 (3H, s), 2.0-1.4(4H, m), 1.25, 0.95(each 3H,t).
MS (m/e): 424(M.sup.+), 345, 193(100%), 137.
Further, the above identified compound was prepared also by subjecting 2-ethyl-4-bromo-S-(3-n-butoxy-4-methoxybenzylamino)-6-nitro-3(2H)pyridazinone (Compound No. 31) to the same reduction as in Example 3.
EXAMPLE 8
2-ethyl-4-chloro-5-(3-n-propoxy-4-methoxybenzylamino)-6-hydroxy-3(2H)pyridazinone (Compound No. 43) ##STR35##
A mixture comprising 523 mg of 2-ethyl-4,5-dichloro-6-hydroxy-3(2H)pyridazinone prepared in Reference Example 1, 1.71 g of 3-n-propoxy-4-methoxybenzylamine, 15 ml of 1,4-dioxane and 15 ml of water, was refluxed under stirring for 24 hours, and 1.71 g of 3-n-propoxy-4-methoxybenzylamine was further added thereto, and the reaction was conducted under the same condition for 2 days. The solvent was distilled off under reduced pressure, and dilute hydrochloric acid was added to the residue thereby obtained. The mixture was extracted with ethyl acetate. The extract was washed with water and a saturated sodium chloride aqueous solution in this order, and dried over sodium sulfate. Then, the solvent was distilled off to obtain a yellow oily substance. The oily substance was purified by silica gel column chromatography, and the slightly yellow oily substance obtained by eluting with a solvent mixture of benzene-ethyl acetate (1:2 v/v) was crystallized from ethyl acetate-diethyl ether, to obtain 418 mg of the above identified compound having a melting point of from 73.degree. to 74.degree. C. as colorless crystals.
NMR .delta.: 7.79(1H, broad s), 6.79(3H, s), 5.4-5.0(1H, m), 6.9-6.4(2H, m), 3.92(2H, t), 3.81(3H, s), 1.82(2H, hexalet), 1.17, 1.0l(each 3H,t).
MS (m/e): 367(M.sup.+), 332, 179(100%), 137.
EXAMPLE 9
2-ethyl-4-chloro-5-(3-n-propoxy-4-methoxybenzylamino)-6-ethoxy-3(2H)pyridazinone (Compound No. 50) ##STR36##
(1) A mixture comprising 184 mg of 2-ethyl-4-chloro-5-(3-n-propoxy-4-methoxybenzylamino)-6-hydroxy-3(2H)pyridazinone (Compound No. 43) prepared in Example 8, 156 mg of ethyl iodide, 207 mg of anhydrous potassium carbonate and 15 ml of methyl ethyl ketone, was refluxed under stirring for 2 hours. The solvent was distilled off under reduced pressure, and water was added to the residue thereby obtained and the mixture was extracted with ethyl acetate. The extract was washed with water and a saturated sodium chloride aqueous solution in this order and dried over sodium sulfate. Then, the solvent was distilled off to obtain a slightly yellow viscous oily substance. The oily substance was crystallized from diethyl ether-n-hexane, to obtain 158 mg of the above identified compound having a melting point of from 77.5.degree. to 78.degree. C. as colorless crystals.
NMR .delta.: 6.75(3H, s), 5.0-4.6(3H, m), 4.60, 4.40(each 2H, q), 3.93(2H, t), 3.81(3H, s), 1.84(2H, hexalet), 1.35, 1.29, 1.04(each 3H, t).
IR (.kappa.max cm.sup.-1): 3280, 1625, 1605, 1530. MS (m/e): 395(M.sup.+), 360, 179(100%), 137.
(2) 300 mg of 2-ethyl-4-chloro-5-(3-n-propoxy-4-methoxybenzylamino)-6-nitro-3(2H)pyridazinone (Compound No. 24) prepared in Example 4, was dissolved in 6 ml of dried ethanol, and 160 mg of sodium ethoxide was added thereto. The mixture was gently refluxed under stirring for 10 minutes. After cooling, ice water was poured into the reaction solution, and then most ethanol was distilled off under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, water and a saturated sodium chloride aqueous solution in this order and dried over sodium sulfate. The solvent was distilled off and the residual oily substance thereby obtained was purified by silica gel thin layer chromatography by using benzene:ethyl acetate (7:3 v/v) as the developer, to obtain 300 mg of the above identified compound. The physical properties and the spectrum data of NMR, IR and MS of the compound completely agreed to those of the compound prepared by the above method (1).
EXAMPLE 10
4,6-dichloro-5-(3-n-propoxy-4-methoxybenzylamino)-3(2H)pyridazinone (Compound No. 71) ##STR37##
A mixture comprising 997 mg of 4,5,6-trichloro-3(2H)pyridazinone, 3.20 g of 3-n-propoxy-4-methoxybenzylamine and 30 ml of ethanol, was refluxed under stirring for 2 hours. Ethanol was distilled off under reduced pressure, and dilute hydrochloric acid was poured into the residue thereby obtained. The mixture was extracted with ethyl acetate. The extract was washed with water and dried over sodium sulfate. Then, the solvent was distilled off to obtain a light brown viscous oily substance. The residue was subjected to silica gel column chromatography, and the second fraction obtained by eluting with a solvent mixture of benzene-ethyl acetate (2.5:1 v/v) was separated to obtain a colorless solid substance. The product was crystallized from a solvent solution of methanol-diethyl ether, to obtain 513 mg of the above identified compound having a melting point of from 181.degree. to 183.degree. C. as colorless crystals.
NMR (CDCl.sub.3 +DMSO-d.sub.6) .delta.: 12.72(1H, broad s), 6.79(3H, s), 6.0-5.6(1H, m), 4.78(2H, d), 3.91(2H,t), 3.79(3H, s), 1.80(2H, hexalet), 1.02(3H, t).
MS (m/e): 357(M.sup.+), 322, 179(100%), 137.
EXAMPLE 11
2-ethyl-4,6-dichloro-5-(3-n-propoxy-4-methoxybenzylamino)-3(2H)pyridazinone (Compound No. 62) ##STR38##
(1) A mixture comprising 150 mg of 4,6-dichloro-5-(3-n-propoxy-4-methoxybenzylamino)-3(2H)pyridazinone (Compound No. 71) prepared in Example 10, 0.2 ml of ethyl iodide, 116 mg of anhydrous potassium carbonate and 10 ml of methyl ethyl ketone, was refluxed under stirring for 1 hour. The reaction mixture was subjected to distillation under reduced pressure, and water was poured into the residue thereby obtained. The mixture was extracted with ethyl acetate. The extract was washed with water and dried over sodium sulfate. Then, the solvent was distilled off to obtain a light yellow viscous oily substance. The product was crystallized from a solvent mixture of diethyl ether-n-hexane, to obtain 139 mg of the above identified compound having a melting point of from 101.degree. to 103.degree. C. as colorless crystals.
NMR .delta.: 6.83(3H, s), 4.80(3H, broad s), 4.12(2H, q), 3.96(2H, t), 3.84(3H, s), 1.86(2H, hexalet), 1.34, 1.05(each 3H, t).
MS (m/e): 385(M.sup.+), 350, 179(100%), 137.
(2) A mixture comprising 455 mg of 2-ethyl-4,5,6-trichloro-3(2H)pyridazinone, 1.20 g of 3-n-propoxy-4-methoxybenzylamine and 20 ml of ethanol, was refluxed under stirring for 3.5 hours. Ethanol was distilled off under reduced pressure, and water was poured into the residue thereby obtained. The mixture was extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and water in this order and dried over sodium sulfate. Then, the solvent was distilled off to obtain a light brown viscous oily substance. The product was purified by silica gel column chromatography by using a solvent mixture of benzene-ethyl acetate (15:1 v/v) as the eluent, to obtain 277 mg of the above identified compound. The physical properties and the spectrum data of NMR and MS of the compound completely agreed to those of the compound prepared by the method (1).
EXAMPLE 12
4-chloro-5-(3-n-butoxy-4-methoxybenzylamino)-6-ethoxy-3(2H)pyridazinone (Compound No. 68) ##STR39##
A mixture comprising 7.32 g of 4,5-dichIoro-6-ethoxy-3(2H)pyridazinone prepared in Reference Example 2, 21.95 g of 3-n-butoxy-4-methoxybenzylamine, 60 ml of 1,4-dioxane and 60 ml of water, was refluxed under stirring for 15 hours. Then, most 1,4-dioxane was distilled off under reduced pressure, and dilute hydrochloric acid was added for acidification. Then, chloroform was added thereto, and the mixture was vigorously shaked. The precipitated crystals were separated by filtration, and the chloroform layer of the filtrate was subjected to liquid separation and washed with water and dried over sodium sulfate. Then, the solvent was distilled off to obtain a light yellow oily substance. The product was crystallized from n-propanol-di-i-propyl ether (1:9 v/v), to obtain 10.48 g of the above identified compound having a melting point of from 117.degree. to 118.degree. C. as colorless crystals.
NMR .delta.: 11.79(1H, broad s), 6.76(3H, s), 5.2-4.8 (1H, m), 4.80, 4.71(2H, d), 4.19(2H, q), 3.96(2H, t), 3.81(3H, s), 2.1-1.3(4H, m), 1.32, 0.97(each 3H, t).
MS (m/e): 381(M.sup.+), 346, 193(100%), 137.
EXAMPLE 13
4-chloro-5-(3-ethoxy-4-methoxybenzylamino)-6-sec-butoxy-3(2H)pyridazinone (Compound No. 88) ##STR40##
A mixture comprising 150 mg of 2-(2-trimethylsilylethoxymethyl)-4-chloro-5-(3-ethoxy-4-methoxybenzylamino)-6-sec-butoxy-3(2H)pyridazinone prepared in Reference Example 4, 1.46 ml of tetra-n-butylammonium fluoride (1M tetrahydrofuran solution) and 5 ml of 1,2-dimethoxyethane, was refluxed under stirring for 3 hours. The solvent was distilled off under reduced pressure, and the residue thereby obtained was extracted with chloroform. The extract was washed twice with 1N hydrochloric acid and once with water in this order and dried over sodium sulfate. Then, the solvent was distilled off to obtain a dark brown oily substance. The oily substance was purified by silica gel preparative thin layer chromatography by using ethyl acetate as the developer, to obtain a light yellow solid substance. The product was crystallized from chloroform-diethyl ether, to obtain 50 mg of the above identified compound having a melting point of from 130.5.degree. to 132.degree. C. as slightly yellow crystals.
NMR (CDCl.sub.3 +DMSO-d.sub.6) .delta.: 11.70(1H, s), 6.70(3H, s), 5.02(2H, m), 4.81, 4.74 (2H, d), 4.05(2H, q), 3.82(3H, s), 1.50(9H,m), 1.00(2H, m).
MS (m/e): 381(M.sup.+), 346, 165(100%).
EXAMPLE 14
4-chloro-5-(3,4-dimethoxybenzylamino)-6-n-propylmercapto-3(2H)pyridazinone (Compound No. 92) ##STR41##
A mixture comprising 256 mg of 2-(2-trimethylsilylethoxymethyl)-4-chloro-5-(3,4-dimethoxybenzylamino)-6-n-propylmercapto-3(2H)pyridazinone prepared in Reference Example 5, 3 ml of tetra-n-butylammonium fluoride (1M tetrahydrofuran solution) and 1.5 ml of N,N-dimethylformamide, was stirred at a temperature of 150.degree. C. for 3 hours. A 1N hydrochloric acid aqueous solution was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with water and a sodium hydrogencarbonate aqueous solution in this order, and dried over sodium sulfate. The solvent was distilled off and the residue thereby obtained was purified by silica gel thin layer chromatography by using benzene-ethyl acetate (1:1 v/v) as the developer, to obtain 39 mg of the above identified compound as a light yellow solid substance. The product was changed into slightly yellow crystals having a melting point of from 129.degree. to 130.degree. C. by the recrystallization thereof from a solvent mixture of ethyl acetate-diethyl ether-n-hexane.
NMR .delta.: 6.73(3H, s), 5.1-4.4(3H, m), 3.81(6H, s), 2.97(2H, t), 2.1-1.4(2H, m), 0.98(3H, t).
MS (m/e): 369(M.sup.+), 334, 165, 151(100%).
The compounds prepared in the same manner as in Examples are shown in Table 5. The Example No. in the right hand side column is the number of the Example in accordance with which the particular compound was prepared.
TABLE 5__________________________________________________________________________ ##STR42##Compound Melting ExampleNo. R.sub.1 R.sub.2 X Y Z.sub.1 Z.sub.2 point (.degree.C.) MS(m/e) No.__________________________________________________________________________1 H Me Cl H 3-OMe 4-OMe 169.about.178 309(M.sup.+), 151(100%)2 H Me Br H 3-OMe 4-OMe 160.about.165.5 274(M.sup.+Br), 151(100%)3 H Me Cl H 3-OEt 4-OMe 161.about.162 323(M.sup.+), 165(100%)4 H Me Br H 3-OEt 4-OMe 166.about.167 288(M.sup.+Br, 100%), 1655 H Me Cl H 3-O-n-Pr 4-OMe 144.5.about.155.5 337(M.sup.+), 179(100%)6 H Me Br H 3-O-n-Pr 4-OMe 149.about.150 see Example 17 H Me Cl H 3-O-n-Bu 4-OMe 158.about.159.5 351(M.sup.+), 193(100%)8 H Me Br H 3-O-n-Bu 4-OMe 153.about.157 316(M.sup.+Br), 193(100%)9 H Me Cl H 3-O(CH.sub.2).sub.2 Ph 4-OMe 170.about.173 399(M.sup.+), 141(100%)10 H Me Br H 3-O(CH.sub.2).sub.2 Ph 4-OMe 158.about.159 443(M.sup.+), 164(100%)11 H Me Cl H H 4-Cl 179.about.180 283(M.sup.+), 125(100%)12 H Me Br H H 4-Cl 171.about.173 327(M.sup.+), 148(100%)13 H Me Cl H 2-Me 4-Me 230.about.235 277(M.sup.+), 119(100%)14 H Me Br H 2-Me 4-Me 210.about.218 242(M.sup.+Br), 119(100%)15 H Et Cl H 3-OEt 4-OMe 130.about.131.5 337(M.sup.+), 165(100%)16 H Et Br H 3-OEt 4-OMe 130.about.131.5 302(M.sup.+Br, 100%), 16517 H H Cl NO.sub.2 3-OEt 4-OMe 187.about.188.5 354(M.sup.+), 265(100%)18 H H Br NO.sub.2 3-OEt 4-OMe 172.about.174 319(M.sup.+Br), 265(100%)19 Et H Cl NO.sub.2 3-OEt 4-OMe 122.about.123 382(M.sup.+), 265(100%)20 Et H Br NO.sub.2 3-OEt 4-OMe 122.about.123 426(M.sup.+), 265(100%)21 Et Me Br NO.sub.2 3-OEt 4-OMe 97.about.98 440(M.sup.+), 265(100%)22 H H Cl NO.sub.2 3-O-n-Pr 4-OMe 169.about.171 see Example 223 H H Cl NH.sub.2 3-O-n-Pr 4-OMe 187.5.about.189.5 see Example 324 Et H Cl NO.sub.2 3-O-n-Pr 4-OMe 76.about.77 see Example 425 iPr H Cl NO.sub.2 3-O-n-Pr 4-OMe 82.5.about.84 see Example 526 Allyl H Cl NO.sub.2 3-O-n-Pr 4-OMe 62.5.about.64 see Example 627 H H Br NO.sub.2 3-O-n-Pr 4-OMe 165.about.166.5 412(M.sup.+), 279(100%)28 Et H Br NO.sub.2 3-O-n-Pr 4-OMe 84.about.84.5 440(M.sup.+), 479(100%)29 H H Br NO.sub.2 3-O-n-Bu 4-OMe 130.about.132 426(M.sup.+), 293(100%)30 H H Br NH.sub.2 3-O-n-Bu 4-OMe 155.about.159 396(M.sup.+), 393(100%)31 Et H Br NO.sub.2 3-O-n-Bu 4-OMe 55.about.56 454(M.sup.+), 493(100%)32 Et H Br NH.sub.2 3-O-n-Bu 4-OMe 108.about.110.5 see Example 7,333 H H Br NO.sub.2 3-O-n-Hex 4-OMe 138.about.141 454(M.sup.+), 221(100%)34 H H Br NH.sub.2 3-O-n-Hex 4-OMe 171.about.173 424(M.sup.+), 321(100%)35 iPr H Br NO.sub.2 3-O-n-Hex 4-OMe 57.about.58.5 496(M.sup.+), 517(100%)36 H H Cl NO.sub.2 3-O(CH.sub.2).sub.2 Ph 4-OMe 149.about.150.5 430(M.sup.+), 205(100%)37 H H Cl NH.sub.2 3-O(CH.sub.2).sub.2 Ph 4-OMe 192.about.194.5 400(M.sup.+), 341(100%)38 Et H Cl NO.sub.2 3-O(CH.sub.2).sub.2 Ph 4-OMe oily 458(M.sup.+), 405(100%) substance39 H H Cl NO.sub.2 H 4-NMe.sub.2 147.5.about.149.5 323(M.sup.+), 234(100%)40 H H Cl NH.sub.2 H 4-NMe.sub.2 118.about.123 293(M.sup.+), 334(100%)41 H Me Br NO.sub.2 H 4-Cl 215.about.219 372(M.sup.+), 225(100%)42 Et Me Br NO.sub.2 H 4-Cl Oily 400(M.sup.+), 425(100%) substance43 Et H Cl OH 3-O-n-Pr 4-OMe 73.about.74 see Example 844 Et H Cl OH 3-O-n-Bu 4-OMe 77.about.78 381(M.sup.+), 893(100%)45 Et H Cl OMe 3-OEt 4-OMe 103.about.105 367(M.sup.+), 9-(ii)0%)46 Et H Cl OEt 3-OEt 4-OMe 80.5.about.81.5 381(M.sup.+), 9-(ii)0%)47 Et H Br OMe 3-OEt 4-OMe 88.about.89 411(M.sup.+), 9-(ii)0%)48 Et H Br OEt 3-OEt 4-OMe 67.5.about.69 425(M.sup.+), 9-(ii)0%)49 Et H Cl OMe 3-O-n-Pr 4-OMe 92.about.93 381(M.sup.+), 9-(i)00%)50 Et H Cl OEt 3-O-n-Pr 4-OMe 77.5.about.78 see Example 9-(i),(ii)51 Et H Cl O-i-Pr 3-OEt 4-OMe Oily 395(M.sup.+), 9-(ii)0%) substance52 Et H Br O-i-Pr 3-OEt 4-OMe Oily 439(M.sup.+), 9-(ii)0%) substance53 Et H Cl O-i-Pr 3-O-n-Pr 4-OMe Oily 409(M.sup.+), 9-(ii)0%) substance54 Et H Cl ##STR43## 3-O-n-Pr 4-OMe Oily substance 407(M.sup.+), 9-(ii)0%)55 Et H Cl ##STR44## 3-OEt 4-OMe Oily substance 395(M.sup.+), 9-(ii)0%)56 Et H Br ##STR45## 3-OEt 4-OMe Oily substance 439(M.sup.+), 9-(ii)0%)57 Et H Cl O-n-Pr 3-O-n-Pr 4-OMe Oily 409(M.sup.+), 9-(ii)0%) substance58 Et H Br ##STR46## 3-OEt 4-OMe 98.5.about.100 435(M.sup.+), 9-(ii)0%)59 Et H Br O-n-Hex 3-OEt 4-OMe 89.about.91.5 481(M.sup.+), 9-(ii)0%)60 Et H Br ##STR47## 3-OEt 4-OMe Oily substance 451(M.sup.+), 9-(ii)0%)61 Et H Br ##STR48## 3-OEt 4-OMe Oily substance 451(M.sup.+), 9-(ii)0%)62 Et H Cl Cl 3-O-n-Pr 4-OMe 101.about.103 see Example 1163 H H Cl O-i-Pr 3-OMe 4-OMe 173.about.174 353(M.sup.+), 121(100%)64 H H Cl OEt 3-OEt 4-OMe 186.5.about.188 353(M.sup. +), 125(100%)65 H H Cl O-i-Pr 3-OEt 4-OMe 149.5.about.150 367(M.sup.+), 125(100%)66 H H Cl OEt 3-O-n-Pr 4-OMe 145.about.146 367(M.sup.+), 129(100%)67 H H Cl O-i-Pr 3-O-n-Pr 4-OMe 103.about.104 381(M.sup.+), 129(100%)68 H H Cl OEt 3-O-n-Bu 4-OMe 117.about.118 see Example 1269 H H Cl O-i-Pr 3-O-n-Bu 4-OMe 105.about.106 395(M.sup.+), 123(100%)70 H H Cl Cl 3-OEt 4-OMe 155.about.156 343(M.sup.+), 105(100%)71 H H Cl Cl 3-O-n-Pr 4-OMe 181.about.183 see Example 1072 H H Cl O-i-Pr 3-O-n-Hex 4-OMe 84.about.87 423(M.sup.+), 101(100%)73 Et Me Br OMe 3-OEt 4-OMe Oily 425(M.sup.+), 9-(ii)0%) substance74 Et Me Br OEt 3-OEt 4-OMe 81.5.about.84 439(M.sup.+), 9-(ii)0%)75 Et H Cl OCH.sub.2 Ph 3-O-n-Pr 4-OMe Oily 457(M.sup.+), 9-(i)00%) substance76 iPr H Cl OMe 3-O-n-Pr 4-OMe 108.about.110 395(M.sup.+), 9-(ii)0%)77 iPr H Cl OEt 3-O-n-Pr 4-OMe Oily 409(M.sup.+, 9-(ii) substance78 iPr H Cl O-i-Pr 3-O-n-Pr 4-OMe Oily 423(M.sup.+), 9-(ii)0%) substance79 iPr H Cl ##STR49## 3-O-n-Pr 4-OMe Oily substance 421(M.sup.+, 9-(ii)80 H H Cl OMe 3-OEt 4-OMe 184.about.186.5 339(M.sup.+), 135(100%)81 Et H Cl OPh 3-OEt 4-OMe 77.about.82 429(M.sup.+, 9-(ii)82 H H Cl O-i-Pr 2-O-n-Pr H 138.about.144 351(M.sup.+), 129(100%)83 H H Cl O-i-Pr 2-O-n-Pr 4-OMe 126.about.127.5 381(M.sup.+), 129(100%)84 H H Cl OEt 3-OMe 4-OMe 182.about.185 339(M.sup.+), 121(100%)85 H H Cl OCH.sub.2 Ph 3-OMe 4-OMe 179.about.180 401(M.sup.+), 12(100%)86 H H Cl OCH.sub.2 Ph 3-OEt 4-OMe 182.about.185 415(M.sup.+), 125(100%)87 H H Cl NO.sub.2 3-OMe 4-OMe 205.about.208 340(M.sup.+), 251(100%)88 H H Cl O-sec-Bu 3-OEt 4-OMe 130.5.about. 132 see Example 1389 H H Cl O-sec-Bu 3-OMe 4-OMe 151.about.153 367(M.sup.+), 131(100%)90 H H Cl ##STR50## 3-OMe 4-OMe 126.about.127 415(M.sup.+), 125(100%)91 H H Cl ##STR51## 3-OEt 4-OMe 95.about.96 429(M.sup.+), 125(100%)92 H H Cl S-n-Pr 3-OMe 4-OMe 129.about.130 see Example 1493 H H Cl S-i-Pr 3-OMe 4-OMe 179.about.180 369(M.sup.+), 141(100%)94 H H Cl S-i-Bu 3-OMe 4-OMe 154.5.about.155 383(M.sup.+), 141(100%)95 H H Cl O-sec-Bu 3-OMe 4-OMe 169.about.170 383(M.sup.+), 141(100%)__________________________________________________________________________
Now, Formulation Examples of the compounds of the formula I will be given.
______________________________________FORMULATION EXAMPLES 1 and 2 (Tablets)Compound No. 53 (Formulation Example 1) 10 gor Compound No. 68 (Formulation Example 2)Lactose 20 gStarch 4 gStarch for paste 1 gMagnesium stearate 100 mgCarboxymethyl cellulose calcium 7 gTotal 42 1 g______________________________________
The above components were mixed in a usual manner, and formulated into sugar-coated tablets each containing 50 mg of an active ingredient.
______________________________________FORMULATION EXAMPLES 3 and 4 (Capsules)Compound No. 52 (Formulation Example 3) 10 gor Compound No. 69 (Formulation Example 4)Lactose 20 gCrystal cellulose powder 10 gMagnesium stearate 1 gTotal 41 g______________________________________
The above components were mixed in a usual manner, and filled into gelatin capsules to obtain capsules each containing 50 mg of an active ingredient.
______________________________________FORMULATION EXAMPLES 5 and 6 (Soft capsules)Compound No. 48 (Formulation Example 5) 10 gor Compound No. 91 (Formulation Example 6)Corn Oil 35 gTotal 45 g______________________________________
The above components were mixed and formulated in a usual manner to obtain soft capsules.
______________________________________FORMULATION EXAMPLES 7 and 8 (Ointment)Compound No. 51 (Formulation Example 7) 1.0 gor Compound No. 89 (Formulation Example 8)Olive Oil 20 gWhite vaseline 79 gTotal 100 g______________________________________
The above components were mixed in a usual manner to obtain 1% ointment.
______________________________________FORMUALTION EXAMPLES 9 and 10 (Aerosol suspension)(A) Compound No. 33 (Formulation Example 9) 0.25(%) or Compound No. 67 (Formulation Example 10) Isopropyl myristate 0.10 Ethanol 26.40(B) A 60-40% mixture of 1,2-di- 73.25 chlorotetrafluoroethane and 1-chloropentafluoroethane 73.25______________________________________
The above composition (A) was mixed. The solution mixture thereby obtained was charged in a container equipped with a valve, and the propellant (B) was injected from a valve nozzle to a gauge pressure of from about 2.46 to 2.81 mg/cm.sup.2 to obtain an aerosol suspension.

Number	Name	Date	Kind
4296120	Kadin	Oct 1981
4892947	Mutsukado et al.	Jan 1990

Number	Date	Country
784639	May 1968	CAX
186817	Sep 1985	EPX
193853	Feb 1986	EPX
1441438	Nov 1964	FRX
1413955	Sep 1965	FRX

3(2H)pyridazinone, and antagonistic agent against SRS-A containing it

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