DD253817A5 - PROCESS FOR PREPARING A 3 (2H) -PYRIDAZINONE - Google Patents

Abstract

The invention relates to a process for the preparation of a 3 (2H) -pyridazinone for use as a medicament. According to the invention, 3 (2H) -pyridazinones of the formula below are prepared; wherein, for example: R1 is hydrogen or C1-5-alkyl; R 2 is hydrogen, C 1-8 -alkyl, chloro or bromo; A NR3 or O; X (CH 2) n, CH (OR 4), CO or a single bond; if X is (CH 2) n or a single bond, BO, S, NH, OSO 2, OCO or a single bond, if X is CH (OR 4), BO, S, NH or OSO 2 and if X is CO, BO or S; and each of the symbols Y1, Y2 and Y3, which may be the same or different, is hydrogen, C1-8 alkyl, C2-8 alkenyl, halogen and the like. al .; and pharmaceutically acceptable salts thereof. Formula (I)

Description

The invention relates to a method for producing a 3 (2H) -pyridazinone which exhibits antagonism to slow-reacting substance of anaphylaxis (SRS-A) which induces contraction of bronchial smooth muscle. The compounds of the invention are thus useful as an antiallergic agent. The invention further relates to a pharmaceutical composition containing the compounds.

Characteristic of the known state of the art

It is believed that SRS-A is one of the major causative agents that induces acute allergy, such as bronchial asthma or allergic rhinitis. A drug that can control or combat the pharmacological effects of SRS-A, d. H. an SRS-A antagonist, therefore presumably represents a useful anti-allergic agent.

However, there are only a few medicinal substances available which have antagonism to SRS-A, and so far no example of their practical application has been reported.

As an example, a compound which is somewhat similar to the compound of the invention describes, CA-PS 784 639 C hereinafter referred to as "reference (a)"} 2-C-alkyl-4-chloro- or -bromo-5- benzylamino-3 (2H) -pyridazinone derivatives. However, the utility of the compounds described in reference (a) is

• 17.Ϊ? ·

limited to one herbicide. The medical use or pharmacological activities are not mentioned.

As another example of a compound similar to the compound of the present invention, British Patent 917,849 (February 6, 1963) [ reference (b) ] describes J 2-Al! <- yl-4-chloro-5-arylalkyloxy-3 ( 2H) -pyridazinone. However, reference (b) does not contain any examples in which the compounds of the present invention are disclosed, and the usefulness of the compounds described is limited to a herbicide. A medical use or pharmacological activities are not mentioned.

Another example of a compound similar to the compound of the invention is described in DE-OS 1,670,169 (published November 5, 1970). Literature parts (c) J, namely 2-alkyl-4-chloro-5-arylalkylamino -3 (2H) -pyridazinone. This reference (c) describes a method of synthesizing pyridazinones including such compounds, their application to agricultural chemicals, their use as intermediates for medicaments or dyes or their use as intermediates for various compounds. However, their pharmacological activities are not mentioned, and no specific example of such compounds is given. Furthermore, there is no specific description of such compounds.

As another example of a compound similar to the compound of the present invention, Chemical Abstracts, 62, 2773b (Bull. Soc. Chim., France, 1964 (9), pp. 2124-32) [, reference (d) J 2-methyl-4-chloro or

bromo-5-benzylamino-3 (2H) -pyridazinone. However, this reference (d) is silent with respect to medical use or pharmacological activities.

Object of the invention

The aim of the invention is the provision of novel compounds with valuable pharmacological properties, in particular antagonistic activities against SRS-A, which are suitable for the treatment of allergic disease states.

Explanation of the essence of the invention

It is the object of the invention to find new compounds having the desired properties and processes for their preparation.

Various compounds have been synthesized by the inventors and investigated for their antagonistic activities against SRS-A. It has surprisingly been found that 3 (2H) -pyridazinones of the formula I and their pharmaceutically acceptable salts have antagonistic activities against SRS-A and are thus useful as active ingredients of an anti-allergic agent.

Thus, according to the invention, 3 (2H) -pyridazinones of the following formula are provided:

A-CH ₀ XCH ₀ -B - // - -Y ~ ^Y

wherein R. is hydrogen or C alkyl; R _{2 is} hydrogen, C 1-4 alkyl, chloro or bromo; A is -N ^ ₃ - (wherein R is hydrogen or C 1-4 alkyl) or -O-; X is - (CH ₂ ) - (wherein η is an integer from 1 to), -CH (OR) - (wherein R 1 is hydrogen or C ₁ alkyl), -CO- or a single bond; if X is - (CH ₂ ) - (where η is as defined above) or a single bond, B is -O-, -S-, -NH-, -OSO ₂ - or -OCO- or a single bond; if X is -CH (OR.) - (wherein R is as defined above), B is -O-, -S-, -NH- or -OSO ₂ -, and if X is -CO-, B is -O- or -S-; and each of Y ₁ , Y ₂ and Y ₃ , which may be the same or different, is hydrogen, C "alkyl, C ₂ _ ₈ alkenyl, halo, -OR (wherein R, - represents hydrogen or C ₁ alkyl ), -CO ₂ R ₅ (wherein R _{5 is} hydrogen or C ₁ ^ -alkyl), -CH = CHCO ₂ R ₇ (wherein R _{7 is} hydrogen or

C₁ Alkyl), -CN,- ^II, -CON (R._p) (R_Q) ^x "^ ^ N-N · ö y.

(where Ro and R _q are the same or different, is hydrogen or C ₁ alkyl), -COR _Q £ _Q wherein R. is hydrogen, C _1- alkyl or - ^{CH (CH} _{2) m} ^CO 2 ^R ~ i2

K ₁

is (where m is an integer from 0 to 3, hydrogen or C ₁ , alkyl and R _{1 is} Wasse: material or C ₁ A-alkyl)], or two of

Radicals Y 1, Y ₀ and Y, together form the formula

^c Vi3

form (wherein R., is hydrogen or C ₁ ^ alkyl), with the proviso that when A is -NH- and both X and B represent single bonds, Y _1, Y ₂ and Xz not simultaneously hydrogen and a pharmaceutically acceptable salt thereof.

The invention also provides a process for the preparation of the pyridazinones of the formula I:

wherein R _{1 is} hydrogen or Cj c alkyl; R _{2 is} hydrogen, C _1-8 alkyl, chloro or bromo; A is -NR, - (wherein R, hydrogen or C _{1 is} λ-alkyl) or

-0- stands; X is - (CH ₂₎ (where η is an integer from to 4), -CH (OR ^) - (wherein R ^ is hydrogen or C _{1- +} ^ - alkyl) or a single bond; B is -O-, -S- or -NH-; and each of Y _1, Y ₂ and Y ^ and which may be the same or different, are hydrogen, C ^ g alkyl, C ₂ _ _Q alkenyl, halogen, (wherein Rc is hydrogen or C ₁ _ ^ - alkyl (where Rg 'denotes hydrogen or C ₁ _ ^ -alkyl), -CH = CHCO ₂ R ₇ (in which R ₇ denotes hydrogen or C 1 -C 4 -alkyl)

/ NN), -CN, - <.- _N §, -CON (R) (R _g ) (where, each

R ~ \ - ⁸

of R _Q and Rg, which may be identical or different, are hydrogen or C ₁ _ ^ - alkyl ") or is [wherein R ₁₀ is hydrogen, C ₁ C alkyl or j) -CO ₂ R _{111 12} · ( where m is an integer of

0 to 3, R _{11 is} hydrogen or C ₁ , -alkyl and R _{12 is} hydrogen or C ₁ λ-alkyl)], or two of the radicals Y ₁ , Y ₂ and Y together form the formula 0

(Form (in which R "-, hydrogen or C ₁ , -

^ CO ₂ R ₁₃ ^{13 1} ""

Alkyl means

which is characterized in that one has a compound

the formula,

wherein R ₁ and R _{2 are} as defined above and Z is chloro or bromo, with a compound of the formula

HA-CH ₂ XCH ₂ OH (III)

wherein A and X are as defined above, in the presence of a dehydrohalogenating agent, to form a compound of the formula.

(IV)

wherein R ₁ , R ₂ , A and X are as defined above

then reacting the compound of formula IV with p-toluenesulfonyl chloride, methanesulfonyl chloride or a halogenating agent in the presence of a dehydrohalogenating agent to give a compound of formula

^Rn\\ (Ν)

N <= ^ / ^ · A-CH ₂ XCH ₂ -T

wherein R ₁ , R ₂ , A and X are as defined above and T is -OSO ₂ -Z ^ V) -CH ₃ , -OSO ₂ CH ₃ , chlorine, bromine or iodine, and the compound of the formula V with

a compound of formula VI

HB -.._

(VI)

where B, Y ₁ , Y ₂ and Y _{3 have} the above meaning,

In the following the invention will be explained with reference to preferred embodiments.

Specific examples of the substituents R ₁ , R ₂ , A, X, B, Y 1, Y ₂ and Y- are described. It should be noted, however, that the present invention is not limited to the specific examples. In the following substituents "n" = normal, "i" = iso, "sec" = secondary and "t" = tertiary.

R ₁ includes hydrogen, methyl, ethyl, n-propyl, i -propyl, η-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl and cyclopentyl.

R ₂ includes chloro, bromo, methyl, ethyl, n -propyl, i -propyl, η -butyl, i -butyl, sec -butyl, n -pentyl, n -hexyl, n -heptyl and n -octyl.

A includes oxygen, unsubstituted amino (-NH-), methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, sec-butylamino and i-butylamino.

B includes oxygen, sulfur, sulphonyloxy, carbonyloxy, unsubstituted amino (-NH-) and a single bond;

X includes methylene, ethylene, propylene, butylene, a single bond, hydroxymethylene, methoxymethylene, ethoxymethylene, n-propoxymethylene, i-propoxymethylene, n-butoxymethylene, i-3utoxymethylene, sec-butoxymethylene and oxomethylene (C = O).

Each of Y ^, Yp and Y-, which may be the same or different, includes hydrogen, methyl, ethyl, n -propyl, i -propyl, n -butyl, i -butyl, sec -butyl, n -pentyl , i-pentyl, sec-pentyl, n-hexyl, i-hexyl, sec-hexyl, n-heptyl, n-octyl, vinyl, 1-propenyl, allyl, 1-3-n-butyl, 2-butenyl, 1-pentenyl , 1-hexenyl, 1-heptenyl, 1-octenyl, fluorine, chlorine, bromine, iodine, hydroxy, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, carboxy, Methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, i-butoxycarbonyl, sec-butoxycarbonyl, 2-carboxyethenyl, 2-hethoxycarbonylethenyl, 2-ethoxycarbonylethenyl, 2-n-propo: cyclopentylethenyl, 2-n-butoxycarbonylethenyl , Cyano, 1H-tetrazol-5-yl, carbamoyl, N-methylaminocarbonyl, N, N-dimethylaminocarbonyl, N-ethylaminocarbonyl, N, N-diethylaminocarbonyl, Nn-propylaminocarbonyl, N, N-di-n-propylaminocarbonyl, Nn-3-aminocarbonyl , Carboxy-

1-carboxyethylcarbonyl, 1-carboxyethylcarbonyl, 1-methoxycarbonylethylcarbonyl, 1-carboxypropylcarbonyl, Methoxycarbonylpropylcarbonyl, formyl, acetyl, propionyl, butyryl, valeryl and hexyryl. Also, two of the radicals

Il

Y ^, Y ₂ and Y ^ together form the formula / ~ \,

^v ° "^ CO R

wherein R 1, is hydrogen, methyl, ethyl, n-propyl or η-butyl.

The compounds of formula I of the present invention can be prepared according to the following nineteen methods 1 to 19.

Method 1

χ-

(VIII) or its salt

In the above formulas, R 1, R ₂ , A, Y 1, Yp, Y 1 and η are as defined for formula I and Z is chloro or bromo and B is -G, -S or a single bond.

- ¹ O '

In the process 1, a compound of the formula VIII is prepared by reacting a 3 (2H) -pyridazinone compound of the formula II with another starting material compound of the formula VII in an inert solvent in the presence of a dehydrohalogenating agent.

The solvent used may be an ethereal solvent such as isopropyl ether, tetrahydrofuran or 1,4-dioxane, an amide solvent such as N, N-dimethylformamide, N-methylacetamide or N-methylpyrrolidone, dimethyl sulfoxide, an alcohol Solvent such as methanol or ethanol, a hydrocarbon solvent such as toluene or benzene, pyridine or water or a solvent mixture employing two or more solvents selected from such solvents.

If .Rp and Z are the same halogen atoms, good results are obtainable using a high polarity solvent such as water, an alcohol or an ether, or a solvent mixture thereof. The isolation and purification of the desired product can be easily achieved by conventional methods such as crystallization or silica gel chromatography.

As the dehydrohalogenating agent to be used, there can be used an inorganic base such as potassium carbonate or sodium carbonate, and an organic base such as triethylamine or pyridine.

Optionally, one can add an interphase transfer catalyst, such as triethylbenzylammonium chloride, as a catalyst to the reaction system.

The reaction temperature may range from room temperature to the boiling point of the solvent used in the reaction system.

The molar ratio of the starting materials can be adjusted in any manner. However, preferred results are obtained if the compound of the formula VII is used in an amount of 1 to 5 mol, based on 1 mol of the pyridazinone derivative of the formula II.

There are no particular restrictions on the reaction time. Usually, the reaction is carried out for 1 to 20 hours.

Method 2

(IX)

Have along

L η

(VIII)

, Yp,

Y? and η is the formula I

as defined, X 1 is chlorine, bromine or iodine and B is -O-, -S- or a single bond.

In process 2, a compound of formula VIII is prepared by reacting a pyridazinone derivative.

Compound of formula IX with -AH (wherein A is as defined above) in the 5-position with a compound of formula X in the presence of an organic or inorganic base. As the solvent, a common solvent which is inert in the reaction can be used. As the organic base, an amine such as triethylamine or pyridine is usually used. As the inorganic base, sodium carbonate or potassium carbonate may be used. Further, a metal hydride such as sodium hydride may be used, as the case requires. The reaction conditions and the conditions for the isolation and purification of the intended product may be appropriately selected in the same manner as in Method 1.

Process 3 R _r A ^R 2 ^X i- ^CH 2 ^(CH 2 ⁾ n ^CH 2 ^X :

_(IX) Level A

(XII)

^Y l

Level B _r

In this case, R 1, Rp, A, Y 1, Yp, Y 1 and η have the meaning given above for formula I, X 1 and X 2, which may be identical or different, each represent chlorine, bromine or iodine and B is -0-, -S- or -IiH-.

Process 3 comprises steps A and B. A compound of formula IX is reacted with a compound of formula XI in an inert solvent in the presence of a

Base reacted to obtain a compound of formula XII (step A). Then the compound of formula XII is reacted with a phenol, a thiophenol or an aniline of formula VI in the presence of a dehydrohalogenating agent to give a compound of formula XIII (step B).

The reaction conditions for the steps A and B, as well as for the isolation and purification of the intended product may be appropriately selected in the same manner as in the method 1.

Method 4

(ID

Level B

HA-CH ₂ XCH ₂ OH (III)

Level A

R ₁ -N

R ₁ -ϊ

-CH ₂ XCH ₂ -T (V)

A-CH ₂ XCH ₂ OH (IV)

(VI)

Stage C

R ₁ -N

R ₂

A-CH ₀ XCH ₀ -B (XIV)

Have along

and

the above formula

I denotes meaning, Z stands for chlorine or bromine, X means - (CH ₉ V - (wherein η stands for an integer of 1

to 4), -CH (OR ^) - (wherein R ^ is hydrogen or C, ι-alkyl) or a single bond, B is

-O-, -S- or -NH- and T represents -OSO ₂ - ^ Jy-CH ,, -OSO ₂ CH ₃ , chlorine, bromine or iodine.

Process 4 comprises steps A, B and C. In process 4, a compound of formula II is reacted with a compound of formula III in an inert organic solvent in the presence of a dehydrohalogenating agent to give a. Implemented compound of formula IV (step A). Then, this compound is reacted with p-toluenesulfonyl chloride, methanesulfonyl chloride or a halogenating agent as described below in the presence of a dehydrohalogenating agent to form a compound of formula V (step B) and finally this compound is reacted with an Fnenol, a thiophenol or aniline of the formula VI in an inert, organic solvent in the presence of a dehydrohalogenating agent to form a compound of formula XIV reacted (step C).

In Step A, the dehydrohalogenating agent which can be used comprises an inorganic base such as potassium carbonate or sodium carbonate, and an organic base such as triethylamine or pyridine. There is no particular restriction on the reaction temperature and the reaction time. However, it is usual to carry out the reaction at a temperature ranging from room temperature to the boiling point of the solvent for 1 to 24 hours. The kind of the solvent used, the molar ratio of the starting materials, and the isolation and purification of the intended product may be appropriately selected as in the method 1.

In Step B, the dehydrohalogenating agent to be used together with p-toluenesulfonyl chloride or methanesulfonyl chloride comprises an amine such as triethylamine or pyridine. Such an amine can also be used as a solvent. Further, a solvent inert to the reaction may be used, for example, a hydrocarbon solvent such as hexane, benzene, toluene or petroleum ether; an ether solvent such as ethyl ether, isopropyl ether or tetrahydrofuran; or a ketone solvent such as acetone or methyl ethyl ketone. Regarding the reaction temperature und.der reaction time, it is usual to carry out the reaction at a temperature from -15 to 40 ⁰ C for 30 minutes to 2 hours. After the reaction, the intended product can be isolated by removing the by-product amine salts, drying the separated organic layer, distilling off the solvent, and chromatographing or crystallizing the oily substance or crystals thereby obtained. When using a halogenating agent, thionyl chloride, thionyl bromide, phosphorus trichloride or hydroiodic acid may be suitably used. When using a solvent, it is preferable to use a solvent inert to the reaction, for example, a hydrocarbon solvent such as benzene, hexane or petroleum ether, or an ether solvent such as ethyl ether or isopropyl ether. With respect to the reaction temperature and the reaction time, it is usual to conduct the reaction at a temperature of -10 to 40 ^° C for 30 minutes to 5 hours.

A compound of formula V in which T is iodo can be readily prepared by reacting a compound of formula V wherein T is chloro, bromo, p-toluenesulfonyloxy or

Methanesulfonyloxy is obtained with potassium iodide or sodium iodide in a suitable solvent.

The isolation of the desired product after completion of the reaction can be easily carried out by distilling off the solvent, adding water and an organic solvent such as benzene or ethyl ether to the residue, vigorously shaking the mixture, drying and concentration of the organic layer separated therefrom and chromatography or - Crystallization of the obtained oily substance or crystals take place.

method 5 A-CH ₉ XCH ₉ -OH Ci U Cl-Q (XV) V ^ ^Y 2 ^Y 3 ^R r - / -

(IV)

(XVI)

R 1, R ₂ , A, Y ₁ , Y ₂ and Y- have the meanings given above for formula I, X is - (CH ₂ ) - (where η is an integer from 1 to 4), CH (OR ^) - (wherein R ^ is hydrogen or C, λ-alkyl) or for a single bond and Q for -CO- or -

Process 5 is a process for preparing a compound of formula XVI, wherein a 3 (2H) -pyridazinone compound of formula IV prepared according to process 4 with an acid chloride of formula XV in an inert

Solvent in the presence of a dehydrohalogenating agent, such as triethylamine or pyridine, is reacted. As the solvent, an ether solvent such as isopropyl ether, tetrahydrofuran or 1,4-dioxane, an amide solvent such as N, N-dimethylformamide, Ν, Ν-dimethylacetamide or N-methylpyrrolidone, or the like can be used halogenated alkyl solvents such as chloroform or dichloromethane. The reaction temperature may be within a range of -15 ⁰ C to the boiling point of the solvent used, but is preferably -15 to 30 ⁰ C.

The molar ratio of the starting materials can be arbitrarily selected. However, it is preferred that the acid chloride of the formula XV is used in an amount of 1 to 2 moles based on 1 mole of the 3 (2H) -pyridazinone compound of the formula IV.

The isolation of the desired product after completion of the reaction can be easily carried out by first removing the by-product amine hydrochlorides, adding water to the residue, vigorously shaking the mixture, drying and concentrating the organic layer thus separated and the resulting oily substance or Subjecting crystals to chromatography or crystallization.

Procedure 6 ο

MN.

(XVIII)

Here, FL, Rp ₉ A, X, Y ^ and Y ^ have the meaning given above for formula I and B is -O-, -S-, -NH- or a single bond.

Process 6 is a process for preparing a

S NN

binding of the formula. XVIIi with a - ^., "- group,

, H

in which a compound of the formula XVII having a -CN group is reacted with a salt of hydrazoic acid of the formula MN, (M = alkali metal).

As the hydrazoic acid salt to be used in the reaction, an alkali metal salt of hydrazoic acid such as lithium azide, sodium azide or potassium azide may be used.

These salts of hydrazoic acid can be used alone. On the other hand, however, it is possible to use, for example, sodium azide in combination with a Lewis acid, such as aluminum chloride, tin (IV) chloride, zinc chloride or titanium tetrachloride, or with ammonium chloride. Among these combinations, a combination of sodium azide and ammonium chloride is particularly preferred.

Usually, it is preferable to conduct the reaction in an organic solvent. As such a solvent, mention may be made of a hydrocarbon solvent such as benzene, toluene or petroleum ether, an ether solvent such as tetrahydrofuran, dioxane, ethylene glycol or dimethyl ether, an amide solvent such as dimethylformamide or formamide, and dimethyl sulfoxide. With regard to the reaction conditions, such as reaction temperature

temperature and reaction time, there are no particular restrictions. Im.generally, however, the reaction at a temperature of! performed up to 2 days.

at a temperature of 50 to 150 ° C for 1 hour

If a salt of hydrazoic acid is used as one of the starting materials in the reaction according to the invention, the resulting compound of the formula XVIII is obtained in the form of a salt which corresponds to the salt of the hydrazoic acid used. The reason for this is the acidity of the tetrazole ring. By treating this salt with an acid, e.g. a mineral acid such as hydrochloric acid or sulfuric acid, it is possible to obtain the desired compound of formula XVIII with a free tetrazole ring. By reacting the compound of the formula XVIII with sodium hydroxide, potassium hydroxide, an organic amine such as methylamine or L-lysine, or ammonia in a suitable solvent, an alkali metal salt, an organic amine salt or an ammonium salt can be conventionally used, such as by mixing or heating the compound of the formula XVIII.

Method 7

A τ ,.

t-Bu-N '

A-CH ₂ XCH ₂ -B- ^ JfY ₂

(XIX) ³ O

.yi

' ₂ XCH ₂ -B- _W

^X 3 (XX)

Rp, A, Y.sup.1, Y.sup.p and Y.sup.2 have the abovementioned meaning, X is - (CKp) - (where .eta. Is an integer from 1 to 4), -CH (OR.sup.-) - (where R.sup.1 = 4) Is hydrogen or Cj ^ -alkyl) or a single bond and B is -O-, -S-, -NH- or a single bond.

In Process 7, a compound of Formula XX is prepared by treating a compound of Formula XIX. Having a tertiary butyl group as a protecting group in the 2-position with a mineral acid such as sulfuric, hydrochloric or hydrobromic acid to remove the tertiary butyl group. The solvent used may be an alcohol solvent, a hydrocarbon solvent, a halogenated hydrocarbon solvent, or water or a mixed solvent of said solvents.

In this process, when Y 1, Yp or Y 1 is a -CN group, one can convert the -CN group into an ester or a carboxylic acid group of the formula -COpRr, simultaneously with the deprotection, by using as solvent a compound of the formula R5OH (where Rg is hydrogen or C, λ-alkyl) together with the abovementioned mineral acid. The reaction conditions, such as reaction temperature or reaction time, are not critical. In general, the reaction is carried out at a temperature near the boiling point of the solvent used for 1 hour to 2 days. Isolation of the desired product after completion of the reaction may be carried out by distilling off the solvent, adding an organic solvent such as ethyl acetate or chloroform, and adding water to the residue, shaking the mixture, drying and concentrating

thereby separated organic layer and purification of the obtained substance by recrystallization or chromatography.

If there are substituents which are susceptible to decomposition by a mineral acid, the desired object can also be attained by employing a conventional hydrogenation process, depending on the requirements of the case.

Method 8

₂ ³

A-CH ₂ (CH ₂ ) _n CH ₂ -B - <(^ (XXII)

Here R _{1 is} C ₁ c-alkyl, B is -O-, -S- or a single bond and R ₂ , A, n, Y ₁ , Y ₂ and Y- * have the meaning given above for formula I.

In method 8, a 3 (2H) -pyridazinone of formula XXII with alkylated 2-position is prepared by reacting a compound of formula XXI with an alkyl halide of formula R ₁ X in the presence of a base. The solvent may be an ether solvent such as isopropyl ether, tetrahydrofuran or 1,4-dioxane, an amide solvent such as N, Kf-dimethylformamide, N-methylacetamide or N-methylpyrrolidone, dimethylsulfoxide, an alcohol solvent, such as methanol or ethanol

Hydrocarbon solvents such as toluene or benzene, a ketone solvent such as acetone or methyl ethyl ketone, or use water.

The purification of the desired product can be easily achieved by crystallization or silica gel chromatography.

As the base, an inorganic base such as potassium carbonate or sodium carbonate, or an organic base such as triethylamine or pyridine may be used. Sin interphase transfer catalyst such as triethylbenzyl ammonium chloride may be added as a catalyst to the reaction system if necessary. The reaction temperature may be within a range from room temperature to the boiling point of the solvent present in the reaction system.

The molar ratio of the starting materials can be set arbitrarily. However, good results are obtained when the compound of formula R ₁ X is used in an amount of 1 to 5 moles, based on 1 mole of pyridazinone derivative of formula XXI.

Method 9

C YYTTT ^

A-CH ₉ XCH _n -P "^ - ^Y - 1 * Λ_-,

Here, R ₁ , R ₂ , A, X, Y ^ and Y _{2 have} the meaning given above for formula I, B is -O-, -S-, -NK- or a single bond and R ₁ ^ is -CO ₂ Rg (Rg = C _1-7 , -alkyl) or for -CN.

In process 9, a compound of formula XXIII is converted to the corresponding carboxylic acid or its salt by hydrolysis of R ₁ - (where R 1 is λ as defined above) of the compound of formula XXII under acidic or alkaline conditions. As the solvent for the reaction, one may use water or an organic solvent such as ethanol, methanol, tetrahydrofuran or dioxane, or a mixture of water with such organic solvents. There are no particular restrictions on the reaction temperature, the reaction time or other reaction conditions. In general, however, the reaction is carried out at a temperature of 10 to 100 ⁰ C for 1 to 5 hours.

The isolation of the desired product after completion of the reaction can be carried out by separating and purifying the precipitated crystals or purifying the liberated oily substance by recrystallization or silica gel chromatography.

Method 10 O

Rl-N ^ V ^R 2 cox HN <L

^N ^^ A -CH ₉ XCH ₂ -B

(XXIV)

(XXV)

In this case, FL, Rp, Rg, Rg, Rq, A and X have the meaning given above for formula I and B is -O-, -S-cder a single bond.

In method 10, an amide compound of formula XXV is prepared by reacting a compound of

Formula XXIV with an amine of formula HN ^ ⁸ .

R9

If the starting material of formula XXIV is an ester (Rg = C 1-4 alkyl), the desired product can be readily obtained by conventional aminolysis or ammonolysis by addition of an amine or by addition of ammonia.

In general, it is preferred to carry out the reaction in an organic solvent. Suitable organic solvents are: an alcohol solvent, ie ethanol or methanol, or an ether solvent, such as tetrahydrofuran or dioxane It is also possible to use a mixture of these organic solvents with water Reaction conditions such as reaction temperature or reaction time are not particularly limited, but in general, the reaction is carried out at a temperature of 50 to 150 ^° C. for 1 to 15 hours.

If the starting material is a carboxylic acid (R 1 - = hydrogen), the desired product can be readily obtained by reacting the starting material in the form of an acid halide with an amine or in the presence of a dehydrating condensing agent or by heating an amine salt of the corresponding carboxylic acid.

The isolation of the desired product after completion of the reaction can be easily carried out by separating the crude crystals of the objective product precipitated from the reaction system by filtration, then recrystallized or, in cases where no crystals precipitate, the Distilled solvent, adding an organic solvent, ie a conventional solvent for extraction, such as ethyl acetate or chloroform, and water, the mixture is vigorously shaken, the resulting organic layer is concentrated, and the resulting crude crystals are subjected to recrystallization or silica gel chromatography.

Method 11

Z-CH ₂ CH-CH ₂ R ₂ ν ^R lN

AH

Level B

Level A

(XXVII)

-CH ₀ CH-CH,

(XXVI)

Thereby R.

the above formula

L ₁ , R ₂ , A, Y ₁ , Y ₂ and '^ I given meaning, Z is chlorine or bromine and B is -O-, -S- or -I ¹ TH-.

Process 11 comprises a step of reacting a compound of formula IX as used in process 2 with an epihalohydrin of the formula

 Z-CHpCH-CHp in an inert solvent in the presence of a base to produce an epoxy compound of formula XXVI (step A); and a step of reacting the compound of formula XXVI with a phenol, a thiophenol or an aniline in the presence of a basic Catalyst to obtain a compound of formula XXVII (step B).

The reaction conditions for step A and the isolation of the desired product can be selected in a similar manner to method 1. If A is -NR * - (where FU is as defined for formula I), it is preferred to use aprotic solvent such as dimethylformamide, dimethylacetamide or tetrahydrofuran, as a solvent, and a metal hydride such as sodium hydride as a dehydrohalogenating agent.

Regarding the reaction conditions for the step B, the same solvent as in the step A can be used. However, the reaction may be carried out in the absence of a "solvent." As the basic catalyst, it is preferable to use an ordinary inorganic base such as sodium carbonate or potassium carbonate, or a quaternary ammonium base such as trimethylbenzylammonium hydroxide There are no particular limitations on the reaction temperature and the reaction time. Usually, however, the reaction is carried out at a temperature of 20 ^° C. to the boiling point of the solvent used for 20 minutes to 2 hours.

Method 12

9 D Metal hydride

sr ^^ - R9

2) R ₃ Hal

H ^A (XXVIII)

(XXIX)

Where R is C _1-5 -alkyl, R 1 is C 1-4 -alkyl, X is - (CH 2 P) - (wherein η is an integer from 1 to 4) or -CH (OR 1) - (where R 1 as defined above for formula 1) or for a single bond, B for -O- or -S- and Y ^, Yp and Y ^ have the meaning given above for formula I.

In Method 12, a compound of Formula XXIX is prepared by reacting a compound of Formula XXVIII. an alkyl halide of the formula R, Hal (wherein Hal represents halogen, such as chlorine, bromine or iodine) in the presence of a metal hydride, such as sodium hydride.

In the method 12, in the case of X = -CH (OH) -, the N-alkylation and the O-alkylation are carried out simultaneously by adding at least 2 moles of the respective alkyl halide and the metal hydride, based on 1 mole of the compound of formula XXVIIl , uses. In this case, a compound of formula O

Ν ^ / "Ν-αί-CH-CH -BK / ^ Y ₀ (XXIXa)

I ² I ^W Y ₃ "

R ₃ OR ₃

be obtained in good yield. If at least one of the radicals Y ₁ , Y ₂ and Y ^ for -C-CH ₂ (CH ₂ ) ^ CO ₂ R ₁₂

(wherein R ₁₂ and m have the meaning given above for formula I), the N-alkylation, and alkylation of the active methylene of -C-CH find ₉ (CH ₉₎ -CO R _{0 -1} instead _o the same time to give a

0 compound of the formula

"* ² ^^ v /? - f ^{H (CH} 2'm- ^CO 2 ^R 12

N-CH _n XCH _n -BHf ^, j ^{2 2} \ _V ^ Y, (XXIXb)

^R 3 can receive.

The process can be carried out by first reacting a compound of formula XXVIII with the metal hydride in an organic solvent and then with the alkyl halide of formula R 1 Hal. As the organic solvent, an inert organic solvent such as dimethylformamide, tetrahydrofuran or diethyl ether is preferably used. The reaction with the alkali metal hydride is preferably carried out at a temperature in the range of -15 to 10 ° C and the reaction with the alkyl halide is preferably carried out at a temperature in the range of 0 to 80 ⁰ C. The isolation and purification of the desired product after completion of the Reaction can be carried out in the same manner as in Method 8.

Procedure 13 O

-CH ₉ CH-CH ₉ -I

OR ₄ (XXXI)

In this case, R _{1 is} C _1-5 -AllJyI, R ^ is C, alkyl, B is -0- or -S-, X is chlorine, bromine or iodine and Rp, A, Y ₁ , Yp and Y have the meaning given above for formula I.

In Process 13, a compound of Formula XXXI is prepared by reacting a compound of Formula XXX with an alkyl halide of Formula R, X (wherein R 1 and X are as defined above). The -OH group in the side chain is converted into an -OR ^ group.

The reaction conditions and the isolation of the desired product may be similar to those in processes.

Method 14

oxidation

A-CH ₀ CH-CHo-BK ⁷ -

OH

(XXXII)

A-CH ₉ CCH ₀ -I

and Y up at For

(XXXIII)

R 1, R ₂ , A, Y ₁ ,

mel 1 and B is -O- or -S-.

In Method 14, a compound of Formula XXXIII is prepared by reacting a compound of Formula XXXII having an -OH group with an oxidizing agent conventionally used in organic reactions to convert the> CHOH group to a> CO group becomes.

For the oxidation, any oxidation methods conventionally used for the oxidation of alcohols, such as Jone's oxidation, Collin's oxidation, Moffat oxidation (dimethylsulfoxide / N, N'-dicyclohexylcarbodiimide) or a modification of these reactions (dimethylsulfoxide / Acetic anhydride or trifluoroacetic anhydride). However, preference is given to the use of a suitable oxidation process, in which the types of the substituents Y ₁ , Yp and Yz are taken into account.

The isolation and purification of the desired product after completion of the reaction can easily be carried out.

be led by adding water and a conventional organic solvent for the extraction of the reaction solution, the mixture is shaken, the resulting organic layer is dried and concentrated and. subjecting the obtained crude crystals or the oily substance obtained to recrystallization or silica gel chromatography.

method 15 (XXXIV) \ ^ Γ ^Υ 2 ^Υ 3 hydrogenation - ν ^Rl l K χ catalyst

(XXXV)

R ₁ , A, X, B, Y 1, Y ₂ and Y have the meaning given above for formula I and R ₂ is chlorine or bromine.

In Method 15, a compound of Formula XXXV is prepared by subjecting a compound of Formula XXXlV, which has chlorine or bromine in the 4-position of the pyridazinone, to a conventional hydrogenation reaction (ie, an ordinary hydrogenation using palladium or platinum as the catalyst becomes). In this way dehalogenation is carried out.

As the organic solvent, ordinary inert solvents are preferable, but an alcohol solvent such as ethanol or methanol is particularly preferable.

It is possible to facilitate the reaction by adding an organic amine such as triethylamine or pyridine. The reaction temperature may be in the range of 10 ^° C. to the boiling point of the organic solvent used, but is preferably in the range of 20 to 60 ^° C. The isolation of the intended product after completion of the reaction can be easily carried out by first treating the catalyst filtered, the filtrate concentrated, the residue dissolved in a conventional extraction solvent such as ethyl acetate, tat, chloroform or benzene, water or aqueous hydrochloric acid solution (about 10%) added, the mixture is shaken, the organic layer dried and concentrated, subjecting the obtained crude crystals or the oily substance obtained to recrystallization or silica gel chromatography.

Method 16

R ₁ -N

.CO ₂ H

(XXXVI)

basic catalyst

(XXXVII)

Here R ₁ , R ₂ * Ry, A, X, Y ^ and Y _{2 have} the above meaning and B is -O- or -S-.

In process 16, a compound of formula XXXVII is prepared by reacting a compound of formula XXXVI of a condensation reaction with malonic acid or

Malonic acid monoesters of the formula CH ₂ V in the presence

CO ₂ R ₇

an organic amine catalyst such as piperidine or pyrrolidine, or an inorganic basic catalyst such as potassium acetate or sodium acetate, to convert the -CHO group to a -CH = CHCO ₂ R ₇ -GrUpPe.

As the organic solvent, a solvent which is inert in the reaction, for example, a hydrocarbon solvent such as benzene, toluene; an ether solvent such as 1,4-dioxane or tetrahydrofuran; an alcohol solvent such as ethanol or propanol; or an amine solvent such as pyridine or triethylamine. The reaction temperature and the reaction time can be adjusted within wide ranges. The reaction may be carried out at a temperature of 50 to 150 ^° C for 5 to 24 hours.

The isolation and purification of the desired product after completion of the reaction can be easily carried out by first acidifying the reaction solution with a mineral acid such as hydrochloric acid, extracting it with a suitable organic solvent such as Eth.sup.3 L acetate, chloroform or ethyl ether distilled off organic solvent and the resulting residue subjected to crystallization or silica gel chromatography.

(XXXVIII)

Deinethylierung

N ι

R ^,

A-CH ₉ XCH ₉ -BHf 2 2 X =

(XXXIX) j A, X,.

and Y ₂ the above at For

mel I given meaning and B is -O- or -S-.

In method 17, a compound of formula XXXIX is prepared by the reaction of a compound of formula XXXVIII with the conversion of the -OMe group into an -OH group.

It is preferable to use as the demethylating agent a reagent obtained by a combination of a hard acid and a soft base such as aluminum chloride / di-n-propylsulfide.

As the solvent, a solvent inert in the reaction, such as dichloromethane or dichloroethane, is preferable. The reaction temperature and the reaction time can be selected within wide ranges. However, it is usual to carry out the reaction at a temperature of 0 to 30 ° C for 5 to 48 hours.

35 Procedure 18

A-CH ₂ XCH ₂ -B

H esterification

2-SU ^ f

(XL) ^Y 2

'' 1 / T ^ 2 6

(XLI) ^Y 2

Here R ₁ , R ₂ , A, X, B, Y ₁ and Y _{2 have} the meaning given above for formula I and Rg is C, -alkyl.

In Method 18, a compound of Formula XLI is prepared by esterifying a compound of Formula XL with a -CO ₂ H group by various conventional esterification methods. For the esterification, the following methods (a) to (d) can be used.

(a) esterification with an alcohol of the formula RgOH in the presence of an acid catalyst, such as sulfuric acid or hydrochloric acid.

(B) conversion of the -C0 ₂ H group in a COCl group and subsequent reaction with an alcohol of the formula RgOH in the presence of a dehydrochlorinating agent, such as triethylamine or pyridine.

(c) conversion of the -C0 ₂ H group into a metal salt of the formula -CO ₂ M (M = Na, K, Ag, etc.) and subsequent reaction with an alkyl halide of the formula RgHaI (Hai = chlorine, bromine or iodine) ,

(d) If Rg in formula XLI is methyl, reacting a compound of formula XL with diazomethane.

It is possible to a desired product by appropriate selection of the above methods (a) to (d) depending on the chemical or physical properties of X, B, to obtain Y and Y ^. ₂

Method 19 O

A-CH ₂ XCH ₂ -B /

(XLII)

(XLIII)

L, Rp ₅ A, X, B, formula I given meaning

There are FL

and Yp the above at

In Method 19, a compound of Formula XLIII is prepared by conversion of the -CONH ₂ -GrUpPe ^{in the} compound of Formula XLII to a -CN group by various commonly used methods. Various reaction examples are known for the conversion of the amide into the nitrile, for example in Compentium of Organic Synthetic Method (1971), Vol. I, pp. 644-465. The desired product can be obtained by suitably selecting one of the conventional methods, depending on the chemical or physical properties of A, X, B, compound of formula XLII.

and Y ₂ in the

The above-mentioned 3 (2H) -pyridazinone compound of the formula II having a substituent in the 2-position which

is used as starting material, wherein both R ₂ and Z are the same and are chlorine or bromine, ie the compound of formula Ha, can be prepared by known methods, as shown in Reaction Scheme 2 (for example, according to the method 2-1 described in Advances in Heterocyclic Chemistry, Vol. 9, p. 257 (1'9β8), or by Method 2-2, described in Chemical Abstract, 62, 2772g).

Reaction scheme 2 2-1

+ HO R Z R ₁ NHNH ₀ j 2 I 1 Δ ₉ cc = CCHO or of 2 salt

2-2 0

R ₁ HaI ^ (Ha)

Here R _{1 has} the meaning given above for formula I and R ₂ , Z and Hai are chlorine or bromine.

In method 2-1, a compound of the formula Ha 1 is prepared by the cyclization reaction of a hydrazine or its acid salt with a mucochloric acid or mucobromic acid. In method 2-2, the compound of formula Ha is prepared by reacting -4,5- (dichloro or bromo) -3 (2H) -pyridazinone with a compound of formula R ₁ -HaI (R ₁ = alkyl; Hal = Chlorine, bromine or iodine). For the preparation of the compound of the formula Ha, the method 2-1 or 2-2 can be selected in any desired manner. The method 2-1 is preferable in terms of yield and operating efficiency. On the other hand, it is generally advantageous to use the method 2-2 if a hydrazine is commercially available

is not readily available or can not be produced economically.

The compound of formula II wherein R 1 is may be prepared by a process as illustrated in Scheme 3 or 4.

Reaction scheme 3

R ₂ MgX

There are R ,. and Z is the meaning given above for formula Ha, X is bromine or iodine and Rp is C, o-alkyl.

It is easy to prepare such a compound by reacting a 2-alkyl-4,5-di (chloro or bromo) -3 (2H) -pyridazinone of the formula

11

  -α

with a Grignard reagent of the formula R ^ gIi in the presence of an inert gas. As the solvent, a hydrocarbon solvent such as toluene or benzene, and an ether solvent such as tetrahydrofuran or ethyl ether may be used.

The reaction temperature may be within a range of ⁰ ° C to the boiling point of the solvent.

from O ⁰ C to the boiling point of the reaction used.

The molar ratio of the starting materials can be arbitrarily selected. However, it is usual to use 1 to 5 moles, preferably 1 to 3 moles, of Grignard reagent based on 1 mole of 4,5-di (chloro or bromo) -3 (2H) -pyridazinone.

Reaction scheme 4

Stage (a) N ^ X * z Stage (b) (lic) (Hd)

(Hb)

Here, R 1 and R p have the meaning given in Reaction Scheme 3 and Hai is defined as in Process 2-2.

The compound of the formula Hb can also be obtained by reacting 4,5-di (chloro or bromo) -3 (2H) -pyridazinone of the formula Hc which has no substituent in the 2-position, with a Grignard reagent. Reagent of the formula R ₂ MgX to form a compound of the formula Hd and reacting the compound of the formula Hd with an alkyl halide of the formula R ₁ Hai.

Step (a) may be carried out under conditions similar to those of Reaction Scheme-3. Similarly, step (b) can be carried out in the same way as in the reaction scheme 2-2.

The 3 (2H) -pyridazinone compound of the formula He having a hydroxyl group in the 5-position and used as starting material in the processes 2, 3 and 11 can be prepared by a conventional method as shown in Reaction Scheme-5.

Reaction scheme 5

ά alkali metal R hydroxide ² >

(II) (he)

R and Rp have the meanings given above for formula I and Z is chlorine or bromine.

The compound of the formula He can be easily obtained by reacting the 3 (2H) -pyridazinone compound of the formula II which has chlorine or bromine at the 5-position with an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide in water or an alcohol solvent such as ethanol or methanol, or in a solvent mixture thereof at a temperature within a range of 50 ^° C. to the boiling point of the solvent used.

Similarly, the compound of the formula Hf can be prepared with -NHR 1 (wherein R has the meaning given above in formula I) in the 5-position by a conventional method according to the following reaction scheme 6.

Reaction scheme _6

H ₂ NR ₃

(II) - (Hf)

R ₁ , R ₂ and R_ have the meaning given above for formula I and Z is chlorine or bromine.

The compound of the formula Hf can be prepared by reacting a pyridazinone compound of the formula II with a compound of the formula H ₂ NR- ,. As the organic solvent, a polar solvent such as water, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, dimethylformamide or pyridine is particularly preferable. However, it is also possible to use an amine compound of the formula H ₂ NR-Z as solvent. If R ^ is hydrogen, ie H ₂ NR ^ ammonia, the desired product can be easily obtained in good yields by reacting the compound of formula II with ammonia under pressure.

Of the compounds of formulas VII and X used as the other starting materials in processes 1 and 2, those which are not readily available as commercial products may be selected by a suitable method selected from the following conventional methods A to L, depending on the reactivity of Y ^, Y ₂ , Y, X and B are produced. The methods G to L are described with respect to the preparation of the compounds of formula VII wherein B is a single bond. Y ₁ , Y ₂ , Y 1, B, A and η have the meanings given above for formula I, unless stated otherwise.

Method A

HO-CH ₂ (CH ₂ J _n CH ₂ -X> HO-CH ₂ (CH ₂ ) _n CH ₂ -Β - //

A-I A-3

Where X is chlorine, bromine or iodine and B is -O-, -S- or -NH-. Method A is a method of preparing a compound of Formula A-3 by reacting a compound of Formula A-1 with a phenol, a thiophenol or aniline of Formula A-2 in a conventional solvent in the presence of a dehydrohalogenating agent.

Method B

Β-2 ^ -1

X-CH (CH) CH -X - ^ X-CH ₉ (CH ₉₎ CH2-Bf ^ 2

^{1 λ η 2} 2 2η ^ =? "Y ₃

BI. _Β _3. ,

Metal hydroxide / OT ₁

Γ HO-CH "(CH_) CH2-B- ( ^/ '^ -Y

/ λ η \ = £ τ ~ - 2

B-4 ³

X and B have the meaning described in method A. ,

Method B is a method of preparing a compound of Formula B-4 by reacting a compound of Formula B-1 with an Fnenol, a thiophenol or aniline of Formula B-2 in the presence of a dehydrohalogenating agent to form a compound of Formula B-3 and then hydrolysing this compound with an aqueous solution of a metal hydroxide such as sodium hydroxide, if necessary after its reaction with a metal acetate such as sodium acetate, to convert it to an acetate.

43 Method C

X

CH ₀ ) CH2-B- ^ f ^ ^Y 2 ^ NC (CH ₉ ) CH "Bf ^ f 2 η \ =? - γ, 2 η. 2 \ == 7-γ

C-I C-3

} _N H N-CH- (CH.,) CH--

'2 2 2 η 2

x "

C-4 ^ό

X and B have the meaning given in method A and M ₁ is sodium or potassium.

Method C is a method wherein the halide of Formula C-1 obtained in Method B is reacted with a metal cyanide of Formula C-2 to form a cyano compound, which is then converted to a corresponding amino compound by a reducing agent. '. ,

Method D

/ -Y ^Y l NH. OH, .Y ₁

X-CH (CH) CH ₂ -B-Y ₂ ^ ZZ> H ₉ N-CH- (CH-) Lot B ^ Y,

D-I D-2.

X and B have the meaning given in method A. '-

Method D is a method in which a compound of the formula D-1 is subjected to an ammonolysis reaction to convert it to a substituted amine of the formula D-2.

44 Method E

NC-CH ₂ (CH ₂ ) _n CH ₂ -B-f ₂ -Y ₃ -> H ₂ NC-CH ₂ (CH ₂ ) _n Cl

E-I ° - E-2

RaOCl

^Y 3

E-3

Where B is -O- or -S-.

Method Ξ is a method in which a compound of the formula Έ-1 obtained in the same manner as in Method C is subjected to amidation to form a corresponding amide compound of the formula E-2, which is then converted into an amino compound of the formula E-3 by means of a Hoffmann reaction is transferred.

Method F

Y ^NaN0 2

^Y 3 FI F-2

reduction

F-3

₂ ^Y 3

Here, X and B have the meaning given in method A ·.

• ö ·

Method F is a method in which a halide of formula F-1 is reacted with NaNO ₂ to give a corresponding nitro compound of formula F-2 which is then

with a reducing agent, such as Fe / FeSO.sub.2 type, to form a corresponding amine of formula F-3.

Method G

Y, G-2 'v.

AlCl ₃ "3

G-I G-3

Where m is 2 or 3.

Method G is a method for preparing a compound of formula G-3 by reacting a benzene of formula G-1 with a compound of formula G-2 by means of a Friedel-Crafts reaction.

Method H

halogenation

HO- (CH ₀ ) < ^/ <V ' ^Y 2 means _X X- (CH) ^ 3> -γ

H-I H-2

CH ₀ CH ₀

r ~~ ν ^X 3

H-3

H-4

Where X is chlorine or bromine and m has the meaning given in Method G.

Method H is a method in which an alcohol compound of formula H-1 is added with a halogenating agent

a compound of formula H-2 is halogenated. This is then converted to a Grignard reagent of formula H-3, which is subsequently reacted with ethylene oxide to form a compound of formula H-4.

Method I

(CH

1-2

1-3

reducing agent

^: » ^ΗΟ

1-4 ^Y 3

Here, m has the meaning given above in Method G.

Method I is a method in which a benzene of formula 1-1 is reacted with an acid anhydride of formula 1-2 according to a Friedel-Crafts reaction to give a compound of formula 1-3 which is then reacted with a reducing agent to give an alcohol compound of formula 1-4 is reduced.

Method J

γ RO ₉ C- (CH 2) -COCl

XO Δ Δ χ,

I -) R "OC- (CHJ -CoAy

^{Ji Aiül} 3 Y,

J-3 °

Reduction ν

with el. Λ

J-4

47 where 1 is an integer from O to 4 and R

Method J is a method in which a benzene of formula j-1 and an acid chloride of formula J-2 are reacted by a Friedel-Crafts reaction to give a compound of formula J-3, which is then further reduced by means of a reducing agent Alcohol compound of formula J-4 is reduced.

Method K

- Y, halogen! heung HO- (CH _n ), -f% - \ medium> _χ

K-I · Κ-2

C ^Y l reducing agent

Y "

^X 3

Κ-3

Κ-4

Here, X has the meaning given for method A and M, is as defined in method C and 1 stands for an integer from 1 to 5.

Method K is a method in which an alcohol compound of the formula K-1 is halogenated by means of a halogenating agent to give a halide of the formula K-2, which is then reacted with a metal cyanide to form a cyanide of the formula K-3. The -CN group of this cyanide is reduced to form an amine compound of formula K-4.

48 Method "L

L-I L-2

L-3

Here, X has the meanings given for method A and 1 in method K.

Method L is a method in which a compound of formula L-1 and sodium nitrite are reacted to form a nitro compound of formula L-2. This compound is reacted with a reducing agent to form an amine compound of formula L-3.

In addition to the compounds described in the following examples, specific examples of compounds according to the invention are given in Table 1. In the following compounds, the individual abbreviations have the following meaning: i = iso, η = normal, Me = methyl, Et = ethyl, Pr = propyl, Bu = butyl, pen = pentyl, hex = hexyl, Hep = heptyl, Oct = octyl and - = single bond.

Table 1

/ ^ Y- ^R 9

IU

^R l ^R 2 A X - B 2-n-Pr ^Y 2. ^Y 3 i-Pr Cl NH - O 2-n-Pr 4-CO ₂ Me H et Cl NH CH ₂ O 2-n-Pr 4-CO ₂ Me H me Cl O - O 2-OMe 4-CO ₂ Me H · i-Pr Cl NH. - - 2-Me Ή H . et Cl NH CH ₂ - 2-Cl H H et Cl O O / N N H \ j-N H CH ₂ 2-Cl / N N iPr Cl NH O ⁴ <Il H CH ₂ 2-Cl Ni-n H i-Pr Cl O CH ₂ O 4-OEt 4-CO ₂ H H et Cl O CH ₂ O 2-n-Hex H H H Cl NH CH., O 2-n-Hex 4-CO ₂ Me H H br NH - CH ₂ O 2-n-Hep 4-CO ₂ Me H H Cl NH CH ₂ O 2-n-Hep 4-CN H H br NH CH ₂ O 2-n-Hep 4-CN H H Cl NH CH ₂ "O 2-n-Hep 4-CO ₂ H H H br NH CH ₂ O 2-n-Hep 4-CO H H H Cl · NH O 4-CÖNH H

^R l H R ₂ A X B V ^Y 2 - ^Y 3 H br 'NH CH ₂ 0 2-n-Hep 4-CONH ₂ H H Cl NH ' CH ₂ 0 2-n-0ct 4-CO ₂ H H H br NH CH ₂ 0 2-n-0ct 4-CO ₂ H H H Cl NH CH ₂ 0 2-n-Bu 4-OMe H H br NH CH ₂ 0 2-n-Bu 4-OMe H H Cl NH CH ₂ 0 2-n-Pen -4-0H H H br NH CH ₂ ; 0 2-n-Pen 4-OH H H et NH CH ₂ 0 2-n-Bu 4-CO ₂ Me H H et NH CH ₂ 0 2-n-Bu 4-CN H H et NH CH ₂ 0 2-n-Pen 4-CN H H et NH CH ₂ 0 2-n-Hex 4-CO ₂ H H i-Pr et NH CH ₂ 0 2-n-Hex 4-CONH ₂ H et br NH CH (OMe) 0 2-n-Pr 4-CN H- et Cl NH CH (OMe) 0 2-n-Pr 4-CO ₂ Me H et br NH CH (OMe) 0 2-n-Pr 4-CO ₂ Me H et Cl NH CH (OMe) 0 2-n-Bu 4-CN H i-Pr br NH CH (OMe) 0 2-n-Bu 4-CN H i-Pr Cl NH. CH (OMe) 0 2-n-Bu 4-CO ₂ H H et br NH CH (OMe) 0 2-n-Bu 4-CO ₂ H H et Cl NH CH (OMe) 0 2-n-Pen 4-CO ₂ H H et br   NH CH (OMe) 0 2-n-Pen 4-CO ₂ H H et Cl NH CH (OH) 0 2-n-Bu 4-CO ₂ Me H i-Pr br NH CH (OH) 0 2-n-Bu 4-CO ₂ Me •H i - Pr Cl NH CH (OH) 0 2-n-Bu 4-CO ₂ Me H i-Pr br NH CH (OH) 0 2-n-Bu 4-CO ₃ Me H Cl .NH CH (OH) 0 2-n-Bu 4-CN H

^R l R ₂ A X B ^Y l ^Y 2 ^Y 3 i-Pr Br NH CH (OH) 0 2-n-Bu 4-CN H H me NH CH ₂ 0 2-n-Bu 4-CO ₂ Me H H me NH CH ₂ 0 2-n-Bu 4-CO ₂ H H H" me NH CH ₂ 0 2-n-Bu 4-CONH ₂ H H me NH CH ₂ 0 2-n-Pen 4-CO ₂ Me H H me NH CH ₂ 0 2-n-Pen 4-CO ₂ H H H me NH CH ₂ 0 2-n-Pen 4-CONH ₂ H H me NH CH ₂ 0 2-n-Hex 4-CO ₂ H H i-Pr Cl NH - 0 · 2-n-Bu 4-CO ₂ H H i-Pr br NH - 0 2-n-Bu 4-CO ₂ H H i-Pr br NH - 0 2-n-Pen 4-CO ₂ H H H n-Pr O CH ₂ 0 2-n-Pr 4-CO ₂ H .H H n-Pr O' CH ₂ 0 2-n-Bu 4-CO ₂ H H n-Pr br NH CH ₂ 0 2-n-Pr 4-CO ₂ H H n-Pr br NH CH ₂ 0 2-n-Pr 4-CO ₂ Me H n-Pr Cl NH CH ₂ 0 2-n-Bu 4-CO ₂ H H H n-Pr NH CH ₂ 0 2-n-Bu 4-CO ₂ Me H H n-Pr NH CH ₂ 0 2-n-Bu 4-CO ₂ H H H n-Pr NH CH ₂ 0 2-n-Pen 4-CO ₂ H Ή i-Pr br NH ^(CH 2 ⁾ 2 0 2-n-Pr 4-CO ₂ H H i-Pr Cl NH (CH ₂ J ₂ 0 2-n-Pr 4-CO ₂ H H i-Pr br NH (CH ₂ ) ₃ 0 2-n-Pr 4-CO ₂ H H i-Pr Cl NH (CH ₂ ) ₄ 0 2-n-Pr 4-CO ₂ H H i-Pr br NH - - 3-0-n-Pr 4-OMe H i-Pr. Cl NH - - 3-0-n-Pr 4-OMe H

^R l R ₂ A X - B ^Y l ^Y 2 ^Y 3 i-Pr Br ' NH -CH ₂ - 3-0-n-Bu 4-OMe H H n-Pr NMe CH ₂ 0 2-n-Pr 4-CO ₂ K H H br NMe - - o 2-n-Bu 4-CO ₂ H H H Cl NH - - 4-0-n-Bu H H H br NH - - 4-0-n-Bu H H et Cl NH - - 4-0Et - H H et br NH - - 4-0Et H H et Cl NH - - 4-0-n-Pr H , H et br NH. - - 4-0-n-Pr H H i-Pr Cl NH - - 4-0Et H H i-Pr br NH CH ₂ - 4-0Et H H H Cl O CH ₂ 0 2-n-Bu 4-CO ₂ Me H H br O ^CH 2 0 2-n-Bu 4-CO ₂ Me H H Cl O , CH ₂ 0 2-n-Bu 4-CN H H br O CH ₂ 0 2-n-Bu 4-CN H H Cl O CH 0 2-n-Pen 4-CO ₂ H H H br O CH (OH) 0 2-n-Pen 4-CO ₂ H H H Cl O CH (OH) 0 2-n-Bu 4-CO ₂ H H H br O CH (OH) 0 2-n-Bu 4-CO ₂ H H H Cl O CH (OH) 0 2-n-Bu 4-CO ₂ Me H H br O CH (OH) 0 2-n-Bu 4-CO ₂ Me H H Cl O CH (OH) 0 2-n-Pen 4-CO ₂ H H H br O CH (OH) 0 2-n-Pen 4-CO ₂ H H H Cl O CH (OH) 0 2-n-Bu 4-CN H H br O CH (OH) 0 2-n-SSU 4-CN H et Cl NH 0 2-n-Pen 4-CO ₂ Me H

^R l , ^R 2 A X B ^Y l ^Y 2 ^Y 3 et br NH CH (OH) 0 2-n-Pen 4-CO ₂ Me H et Cl NH CH (OH) 0 2-n-Pen 4-CN H et br NH CH (OH) 0 2-n-Pen 4-CN H i-Pr Cl NH CH (OH) 0 2-n-Hex 4-CO ₂ H H i-Pr br NH CH (OH) 0 2-n-Hex 4-CO ₂ H H et Cl NH - S 2-n-Bu 4-CO ₀ H H et br NH - S 2-n-Bu 4-CO ₂ H H i-Pr Cl NH - S 2-n-Bu 4-CO ₂ H H i-Pr br NH - S 2-n-Bu 4-CO ₂ H H i-Pr Cl NH CH ₂ 0 2- (l-butenyl) 4-CO ₂ H H i-Pr br NH CH ₂ 0 2-U-butenyl) 4-CO ₂ H H H n-Pen NH CH ₂ 0 2-ri-Pr 4-CO ₂ H H

The administration of the compounds according to the invention can be carried out as non-oral administration by injection (subcutaneous, intravenous, intramuscular or intraperitoneal injection), as ointment, as suppository or as aerosol. The compound may also be administered orally in the form of tablets, capsules, granules, pills, syrups, liquids, emulsions or suspensions.

The above pharmacological or veterinary compositions contain a compound of the invention in an amount of 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. The compound of the present invention or the agent containing the compound of the invention may further comprise other pharmacologically or veterinarily active compounds. The agent according to the invention may further comprise several of the compounds according to the invention.

The clinical dose of the compound of the invention varies depending on the age, body weight, sensitivity or symptoms of the patient. However, the effective daily dose is generally 0.003 to 1.5 g, preferably 0.01 to 0.6 g, in an adult. However, if necessary, an amount outside the above ranges may be employed.

The compounds of the present invention may be formulated in various suitable formulations, depending on the intended route of administration, according to conventional methods generally used for the preparation of pharmaceutical formulations.

For example, tablets, capsules, granules or pills for oral administration can be prepared using an extender such as sugar, lactose, glucose, starch or mannitol; a binder such as syrup, gum arabic, gelatin, sorbitol, gum tragacanth, methyl cellulose or polyvinylpyrrolidone; a disintegrant, such as starch, carboxymethylcellulose or its calcium salt, crystalline cellulose powder or polyethylene glycol; a brightener such as talc, magnesium or calcium stearate or colloidal silica; or a lubricant such as sodium laurate or glycerin. The injectors

2 5 " ^?

agents, solutions, emulsions, suspensions, syrups or aerosols can be prepared 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 sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene ether of hydrogenated castor 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 gum tragacanth or gum arabic; or a preservative such as paraoxybenzoic acid ester, benzalkonium chloride or a salt of sorbic acid. Suppositories can be similarly prepared by known methods using e.g. As polyethylene glycol, lanolin or cocoa butter.

embodiments

The invention is explained in more detail below with reference to some examples. ·

Test Examples

A. Anti-allergic effect

A major component of SRS-A, which is an important trigger of acute allergy, such as bronchoconstriction in bronchial asthma, is leukotriene C. (hereafter referred to as LTC, leukotriene D (hereinafter referred to as LTD.) Or a similar substance Antagonist activity against SRS-A can thus be assessed by any of the following test methods.

(1) A method in which the antagonistic activity against SRS-A obtained in a sensitized guinea pig is examined.

(2) A method of antagonizing LTC. is examined, and

(3) a method "in which the antagonistic activity against LTD is examined.

The inventors of the present application investigated the antagonistic activity against SRS-A using the test methods (1) to (3).

The following explains the test methods and the results obtained.

Test methods for anti-allergic efficacy and results

(i) LTC ^ and LTD ^ antagonism in guinea pig trachea

The antagonism for LTC and LTD was determined in isolated guinea pig trachea prepared as a spiral strip. The tracheal preparations were suspended under 1 g tension in 10 ml organ baths and incubated 1 h before use. Contraction response to LTCV (2x10 "g / ml) and LTD ^ (2 x 10" g / ml) was obtained after maximal response to histamine (10 "M) Test compounds dissolved in 100% dimethylsulfoxide were added to the organ baths (final concentration from 10 g / ml to 10 "g / ml) 5 min before LTCV and LTD ^ addition. Then, the contraction response to LTC1 and LTDa was compared with a control value obtained from a parallel experiment in the absence of the test compound. LTC ^ and LTD, -induced contractions were expressed as percent of maximal response to histamine. The antagonism was determined as follows:

Antagonism (%) = (1.0 % concentration in the test / % contraction in the control) χ 100.

Table 2 summarizes LTC / antagonisms due to the test compounds (10 g / ml).

Table 2 Test Compound No.

antagonism (%)

20 23 25 FPL-55712

99 95 73 27 53 100

In Table 3, LTD ^ -Antagonismen are due to the test compounds (10 "- ⁵ g / ml) collected.

Table 3

T est connection Antagonism X%) test compound 31 Antagonis No. 49 No. 32 mus {%) 1 15 33 19 2 28 34 29 3 85 35 15 4 33 37 61 5 96 41 72 6 82 42 40 7 32 43 100 8th 14 44 95 9 46 45 63 10 13 47 90 11 35 48 27 12 53 49 99 13 40 50 36 14 40 51 57 15 31 52 35 16 45 53 82 17 20 54 23 18 60 55 59 19 80 56 64 20 31 57 72 , 23 40 58 62 24 24 59, 83 25 15 88 26 65 82 27 61 28 18 29 40 30

Testvero. antagonism 98 Tsstverb. Anta go ni sinus No. (%) 73 No. (SO 60 57 112 100 61 54 113 100 62 87 114 89 63 98 115 94 64 69 116 90 65 99 117 96 66 33 118 91 67 99 119 100 68 65 140 41 69 88 141 54 70 85 142 69 71 48 143 26 72 73 144 84 73 16 145 85 74 57 146 14 75 17. 147 66 76 32 148 17 77 58 149 81 78 98 150 16 79 80 151 47 80 100 152 60 81 46 153 64 82 85 154 20 83 78 155 55 84 59 156 56 85 60 157 62 86 97 158 93 87 52 159 44 88 83 160 70 89 14 J » VJ VJ 161 71 90 100 162 81 91 .79 163 74 92 98 164 71 93 59 165 33 94 77 166 25 95 62 167 30 96 89 168 21 97 51 169 50 98 66 170 17 99 92 171 66 100 93 172 79 101 93 173 35 102 57 174 78 103 89 175 55 104 93 105 85 FPL-55712 97 106 94 107 QQ 108 77 109 87 110th Ill

.59

(ii) LTD / antagonism in guinea pig trachea

Antagonism for LTD ^ was determined in isolated guinea pig trachea, which was prepared as a spiral strip. The trachea preparations were suspended under 1 g tension in 10 ml organ baths containing 5 μmol indomethacin and incubated for 1 hour before use. Contraction response to LTD / (2 × 10 -4 g / ml) was obtained after Maximairespons versus histamine (10 M). The test compounds dissolved in 100 % dimethylsulfoxide were added to the organ baths (final concentration of 10 "g / ml) 30 minutes before LTD ^ addition, then the contraction response to LTDr was compared to a control value obtained from a parallel experiment in FIG Absence of Test Compounds: LTD ^ -induced contractions were expressed as percent of maximal response to histamine. Antagonism was determined as follows:

Antagonism (%) = (1.0 % contraction in the test / % contraction in the control) χ 100.

Table 4 lists the LTD ^ antagonisms of the test compounds (10 g / ml). The values in Table 4 with one asterisk were obtained by the test method (i), the others by the test method (ii).

Table 4

Testverbind. No.

antagonism

Testverbind. No.

Antagoni sinus

FPL-55712 "~ 76 *, 94 125 91 * 84 6 78 * 126 17 * 90 41 82 127 33 * 42 76 128 26 * 44 63 131 27 * 69 66 * 132 80 59 * 133 98 80 135 53 * 57 105 52 137 53 109 69 158 111 79 178 69 112 62 * 179 63 113 54 180 88 114 66 * 181 70 115 61 197 82 116 82 * 198 86 117 67 * 199 65 118 69 * 200 81 120 82 * 202 89 121 43 * 203 94 122 94 204 95 123 65 * 205 96 124 92 218 84

(iii) Effect on anaphylactic bronchoconstriction in passively sensitized guinea pigs

Male guinea pigs (350-450 g) are passively sensitized by intravenous (iV) injection of 0.125 ml of rabbit anti-EA (egg albumin) serum (Cappel Laboratories) 1 day before the experiment. Antigen-induced anaphylactic bronchoconstrictions were measured by a modified method of Konzett and Rossler (Arch. Expp. Phys. Pharmac., 195 , 71, 1940). Sensitized guinea pigs were anesthetized by intraperitoneal injection of urethane (1.5 g / kg). The right jugular vein was cannulated for administration of the anti-allergic agents and the trachea was cannulated to remove the

Total Pulmonary Resistant to be able to register. The guinea pigs were artificially ventilated using a small animal ventilator (Shinano, Model SN-480-7) .The device was set to a volume of 5 ml and a rate of 50 breaths / min. The change in pulmonary resistance became measured by a pressure transducer (Nihon Kohden Model TP-602T) attached to a T-tube on the traclieal cannula The increase in airflow volume was expressed as a percentage of the maximum bronchoconstriction obtained by clamping the trachea The animals were pretreated with indomethacin (1.0 mg / kg, 10 min), pyrilamine (2 mg / kg, β min) and propranolol (0.1 mg / kg, 5 min) before EA administration (0, 1 or 10 mg / kg) All test compounds, 2 mg / kg in 3% Tween 80 or 3% PEG-400, are administered 1 min each prior to EA administration The inhibition (%) of bronchoconstriction is determined as follows : Inhibition (%) = (1.0% - maximum bronchoconstriction at the test /% maximum bronchoconstriction at the control) χ 100.

The maximum bronchoconstriction is obtained within 20 min after the EA administration. The number of test animals is 4 and the average inhibition is compared with that of FPL-55712 (Fisons Limited) of the following formula

n-Pr

The effect of the test compounds (2 mg / kg, i.v.) is given in Tables 5-0) and 5- (2).

Table 5- (i)

Test compound: No.

inhibition: (%)

7 25 27 23

43 47 51 55 60 FPL-55712

27 31

18

23 17 24 28

15 26 15 27

In the table, the dose is EA 1, each compound is suspended in 3% Tween 80.

Table 5- (2)

0 mg / kg and the - "^ dissolved or

Testverb. No. Solution or suspension of the test verb, Inhi test verb, no. 85 Solution or suspension d.Testverb. Inhi beer. (90 6 PEG-400 44 101 Tween 80 23 41 Tween 80 31 102 PEG-400 51 42 PEG-400 • 31 103 PEG-400 73 64 Tween 80 56 161 PEG-400 69 65 Tween 80 27 162 Tween 80 20 67 Tween 80 62 163 Tween 80 49 69 Tween 80 51 164 Tween 80 32 71 Tween 80 26 50 FPL-55712 Tween 80 40 74 Tween 80 Tween 80 60

The dose of EA is 0.1 mg / kg.

B. Acute Toxicity Study (i) Test Method- (1)

The lethal ratio is determined in ddY strain male mice (4 weeks old) 7 days after the oral administration of the test compounds. The results are shown in Table 6.

Test compound No. Dose (mg / kg) Lethal ratio

72 400 0/2

80 400 0/2

800 0/2

82,400. 0/2

800 0/2

94 400 0/2

800 0/2

101 400. 0/2

800 0/2

(ii) Test Method- ( Z) '

The lethal ratio is determined in ddY-Stainm male mice (4 weeks old) 7 days after the intraperitoneal injection of the test compounds. The results are shown in Table 7.

Table 7 Test Compound No.

Dose (mg / kg) Lethal ratio (number of deaths / number of trial participants)

1 200 400 0/2 0/1 4 200 400 0/2 0/1 7 200 400 0/2 0/1 10 200 400 0/2 o / i 13 200 400 0/2 0/1 14 200 400 0/2 0/1 27 10 0 200 0/2 0/2 28 200 "400 0/2. 0/1 29 200 400 0/2 0/1 35 200 400 0/2 0/1 42 200 400 0/2. 0/1 44 200 400 0/1 0/1 45 200 40 0 0/2 0/1 41 200 0/2 47 200 400 0/2 0/2 142 200 400 , 0/2 0/1 145 - 200 400 0/2 0/1

From these results, it is apparent that the compounds of the present invention produce excellent effects on the antagonism of SRS-A and its major components LTCλ and LTD, both in vitro and in vivo. The compounds of the present invention have therefore been found to be useful for prophylactic and therapeutic drugs against various SRS-A-induced allergic diseases, e.g. Bronchial asthma, allergic rhinitis and urticaria.

In the following the invention will be explained by way of examples. It is to be understood, however, that the invention is not limited by these specific examples. In the examples or reference examples, the symbols "NMR" and "MS" mean "nuclear magnetic resonance spectrum" and "mass spectrometry", respectively. The NMR data ( 6 ) show only the characteristic absorptions. Similarly, only the main signals or typical fragment signals are indicated in the MS data.

In the present specification, "He" means a methyl group, "Et" an ethyl group, "Pr" a propyl group, "Ac" an acetyl group, "Bu" a butyl group, and "Pen" a pentyl group; "n" stands for normal, "i" for iso, "sec" for secondary and "t" for tertiary.

Reference Example 1

Among the phenols used in the examples, those not available as commercial products were prepared according to the following methods 1- (i) to 1- (viii).

.1- (i) 2-ethyl-4-methoxycarbonyl-phenol

A mixture comprising 24.4 g of 2-ethylphenol, 40 g of carbon tetrachloride, 120 ml of a 50% aqueous sodium hydroxide solution and 1.0 g of copper powder is refluxed for 8 hours with stirring. After cooling, the brown reaction mixture is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The extract is treated with charcoal (5 g) and silica gel (30 g) and the filtrate is extracted with a saturated sodium bicarbonate aqueous solution. The extract is acidified by gradually adding an aqueous hydrochloric acid solution to the extract under ice-cooling. Then it is extracted with ethyl acetate. The extract is washed successively with water and a saturated sodium chloride aqueous solution and dried over sodium sulfate. Subsequently, the solvent is distilled off; 12.38 g of 2-ethyl-4-carboxyphenol are obtained as a reddish-purple solid.

3.50 g of this product are dissolved in 60 ml of a 10% hydrochloric acid-methanol solution and the solution is stirred for 2 days at room temperature. The solvent is distilled off and the oily residue is extracted with ethyl acetate. The extract is washed successively with aqueous sodium bicarbonate solution, water and a saturated sodium chloride aqueous solution and dried over sodium sulfate. The solvent is then distilled off to give a dark reddish purple oily substance. This substance is dissolved in chloroform and then treated with charcoal (5 g) and silica gel (20 g). Subsequently, the solvent of the filtrate is distilled off; 2.70 g of the above-identified compound are obtained as a bright reddish purple solid.

NMR _(CDCl3): 7.84 (1H, d), 7.79 (1H, dd), 6.83 (1H, d),

6.6-5.8 (1H, brs, disappears "on addition of D ₂ O), 3.87 (3H, s), 2.63 (2H, q) x, 1.23 (3H, t) ,

In the same manner as above, 2-i-propyl-4-methoxycarbonylphenol, 2-ethoxy-4-methoxycarbonylphenol and 2-sec-butyl-4-methoxycarbonylphenol are prepared from 2-i-propyl-. phenol, 2-ethoxyphenol. 2-sec-buty! Phenol.

1- (ii) 2-Alvl-4-canoano-phenol

A mixture comprising 29.75 g of 4-cyanophenol, 33.27 g of allyl bromide, 41.46 g of potassium carbonate and 350 ml of acetone is refluxed for 4 hours with stirring. Acetone is distilled off and the residue is mixed with water. The mixture is extracted with benzene. The benzene layer is washed successively with a 5% sodium hydroxide aqueous solution and water and dried over sodium sulfate. Then, the solvent is distilled off to obtain a pale yellow, oily substance. The residual substance is recrystallized from n-hexane / ethyl ether, obtaining 38.16 g of 4-Allyloxybenzonitril as colorless crystals, Fp.40,5 to 41 ⁰ C.

38.16 g of this allyloxy compound are stirred for 15 h at a temperature of 195 to 200 ⁰ C. After cooling, the dark orange, oily reaction product is extracted with a 5% sodium hydroxide aqueous solution. The extract is washed with benzene and acidified to a pH of about 2 with concentrated hydrochloric acid and then extracted with ethyl ether. The ethyl ether extract is washed successively with water and saturated sodium chloride-aqueous solution. Subsequently, the solvent is distilled off, wherein

you get a dark orange substance. The residue is dissolved in 200 ml of heated benzene and treated with silica gel (50 g). The solvent of the filtrate is distilled off and the resulting pale yellow oily substance is crystallized from ethyl ether / n-hexane. This gives 24.90 g of the title compound as colorless crystals, 83.5 Fp.83 to ⁰ C.

MR (CDCl _3): 7.5-7.2 (2H, m), 6.80 (1H, d), 6.9 to 6.3 (1H, brs, disappeared by addition of DPO), 6.3 -5.6 (1H, m), 5.3-4.8 (2H, m), 3.35 (2H, d).

In the same way 2-allyl-4-methoxyphenol (oily substance), 2-allyl-4-methoxycarbonylphenol (crystals, mp. 85-88 ⁰ C) and 2-allyl-4-ethoxycarbonylphenol from 4-methoxyphenol, - p- hydroxybenzoic acid methylester. or p-hydroxybenzoic acid ethyl ester prepared.

( 2-n-propyl-4-cyano-olefin

A mixture of 8.15 g of 2-allyl-4-cyanophenol prepared in Reference Example 1- (ii), 1.5 g of 5% palladium on carbon and 100 ml of methanol is stirred for 2.5 hours in a hydrogen stream. The catalyst is filtered off and the solvent is distilled off from the filtrate, giving 7.30 g of the abovementioned compound as a colorless, oily substance.

NMR _(CDCl3) :. 7.4-7.2 (2H, m), 6.76 (1H, d), 6.36 (1H,

brs), 2.58 (2H, t), 1.95-1.25 (2H, m), 0.95 (3H, t)

Similarly, 2-n-propyl-4-methoxyphenol (oily substance), 2-n-propyl-4-methoxycarbonylphenol (crystals) and 2-n-propyl-4-ethoxycarbonylphenol are prepared from 2-allyl-4-methoxyphenol, 2 Allyl-4-methoxycarbo nylphenol or 2-allyl-4-ethoxycarbonylphenol prepared according to Reference Example 1- (ii).

1- (iv) 2-ethyl-4-formylphenol

45.5 g of titanium tetrachloride are added dropwise while stirring with ice to a solution obtained by dissolving 14.64 g of 2-ethylphenol in 200 ml of dichloromethane. After completion of the dropwise addition, 22.76 g of α, α-dichloromethyl methyl ether are added dropwise. The ice bath is removed and the reaction solution is stirred for 2 h at room temperature. Then, the reaction solution is poured into a 10% hydrochloric acid aqueous solution, and the mixture is stirred for 2 hours. The reaction mixture is extracted with chloroform. The chloroform layer is washed with water and then extracted with a 10% sodium hydroxide aqueous solution. The alkali extract layer is washed twice with chloroform and then acidified to a pH of about 2 by the addition of concentrated hydrochloric acid. Then the mixture is extracted with ethyl acetate, the extract washed successively with water and saturated sodium chloride-aqueous solution and dried over sodium sulfate. The solvent is distilled off to obtain a dark reddish purple, oily substance. This product is purified by silica gel column chromatography using benzene / ethyl acetate (16/1, v / v) as a developer. This gives 6.90 g of the compound indicated above as a pale yellow, oily substance.

NMR _(CDCl3): 9.74 (1H, s), 7.65 to 7.49 (2H, m), 7.57 (1H, s, disappears on addition of DPO), 6.88 (IH, d ), 2.69 (2H, q), 1.25 (3H, t).

2-n-butyryl-4-bronrphenol

25.0 g of n-butyryl chloride are added dropwise to a mixture of 38.06 g of 4-bromophenol, 19.75 g of pyridine and 500 ml of benzene with stirring and ice cooling. To

After completion of the dropwise addition, the mixture is stirred for 1 h at room temperature. Water is added to the reaction mixture and the benzene layer separated. The benzene layer is washed successively with water, 2% dilute hydrochloric acid, water and aqueous sodium bicarbonate solution and dried over sodium sulfate. Then, the solvent is distilled off to obtain 53.5 g of 4-bromo-n-butyrylphenolate as a pale yellow, oily substance.

A mixture of 53 »5 g of the above ester and 38.1 g of aluminum chloride is heated with stirring, whereupon a vigorous exothermic reaction begins. The oil bath is removed and stirring continued until the foaming settles. Subsequently, the reaction system is stirred at 160 ^° C. for 1 h. After cooling, the formed, dark brown solid is decomposed by 10% diluted hydrochloric acid and extracted with benzene. The benzene layer is washed twice with water and dried over sodium sulfate. Then, the solvent is distilled off to obtain a brown oily substance. This substance is dissolved in 1 l of an n-hexane / benzene mixture (10/1, vol / vol) and treated with 100 g of silica gel. Then, the solvent is distilled off from the filtrate to give a pale yellow oily substance which is recrystallized from η-hexane. One gets 30.29 g of the title compound as colorless crystals, Fp.50,5 to 51 ⁰ C.

NMR (CDCl 3): 12.30 (1H, s, disappears upon addition of D ₂ O), 7.78 (1H, d), 7.43 (1H, dd), 6.81 (1H, d), 2.43 (2H, t), 2.1-1.5 (2H, m), 1.02 (3H, t).

In the same way, 2-n-valeryl-4-bromophenol (oily substance) is prepared.

1- (vi) 2-n-butyl-4-methoxycarbonylphenol

14.84 g of ethyl chloroformate are added dropwise over 30 minutes with stirring and ice cooling to a mixture of 27.69 g of 2-n-butyryl-4-bromophenol prepared in accordance with Reference Example 1- (v), 13.94 g of triethylamine and 200 ml of tetrahydrofuran. After completion of the dropping, the reaction mixture is stirred at 0 ° C for 30 minutes. The triethylammonium chloride crystals formed are filtered off and washed with 100 ml of tetrahydrofuran. The filtrate and the washing solution are combined. The resulting solution is added dropwise to a mixture of 17.25 g of sodium borohydride and 300 ml of water with stirring and ice cooling to maintain the internal temperature in the range of 5 to 15 ⁰ C. After completion of the dropwise addition, the reaction mixture is stirred for 1.5 hours at room temperature. After completion of the reaction, the reaction mixture is diluted with 200 ml of water and acidified by the gradual addition of concentrated hydrochloric acid. Then the mixture is extracted with ethyl ether. The extract is washed successively with water and saturated sodium chloride-aqueous solution and then dried over sodium sulfate. After distilling off the solvent, 31.12 g of 2-n-butyl-4-bromophenol are obtained as a pale yellow, oily substance.

A mixture comprising 31.12 g of the above phenol, 18.81 g of benzyl bromide, 18.24 g of potassium carbonate and 300 ml of acetone is stirred for 2 days at room temperature. Acetone is distilled off and water is added to the residue. The mixture is extracted with benzene. The benzene layer is washed with saturated sodium chloride-aqueous solution and dried over sodium sulfate. After distilling off the solvent to give a pale yellow, oily substance. This substance is added to the silica

gel column chromatography using benzene / n-hexane (1/9, v / v) as a developer to give a colorless, oily substance.

A solution obtained by dissolving 20.30 g of the obtained bromobenzene derivative and 13.85 g of ethylbroinide in 20 ml of dried ethyl ether is added dropwise to a mixture of 5.41 g of magnesia chips and 100 ml of dried ethyl ether with stirring. During the dropping occurs heat development and the reflux begins. After completion of the dropwise addition, the reaction mixture is refluxed for 30 minutes on an oil bath with stirring. After cooling, excess magnesium is removed by decantation and washed with 2 × 25 ml of dried ethyl ether. The Grignard reagent thus prepared is added dropwise to a mixture of 50 g of powdered dry ice and 300 ml of dried tetrahydrofuran with stirring. During the dropwise addition, another 100 g of dry ice are added. After completion of the dropwise addition, the reaction mixture is stirred for a further 2 h. The reaction mixture is acidified by the gradual addition of a cooled 10% hydrochloric acid aqueous solution and extracted with ethyl acetate. The extract is washed successively with water and saturated sodium chloride-aqueous solution and dried over sodium sulfate. Then the solvent is distilled off, giving a pale yellow solid. This is washed with ethyl ether / n-hexane (1/1, v / v); 3.01 g of 3-n-3-butyl-4-benzyloxybenzoic acid are obtained as a colorless solid.

4.19 g of the resulting benzoic acid derivative are dissolved with heating in a mixture of 50 ml of ethyl acetate and 100 ml of methanol. Then diazomethan gas is introduced into this solution until the solution becomes a pale yellow

Takes on color. The reaction solution is allowed to stand overnight. After distilling off the solvent, 4.38 g of methyl 3-n-butyl-4-benzyloxybenzoate are obtained as a colorless, oily substance.

A mixture comprising 4.38 g of the obtained benzoate, 500 mg of 5% palladium on carbon and 60 ml of methanol is stirred for 3 hours in a stream of hydrogen. The catalyst is separated by filtration and the solvent distilled off from the filtrate to give a pale yellow solid which is crystallized from ethyl ether / n-hexane. Is recovered 2.69 g of the title compound as colorless crystals, Fp.78 to 81 ⁰ C.

NMR _(CDCl3): 7.8-7.6 (2H, m), 6.76 (1H, d), 6.22 (1H, s, disappears on addition of DPO), 3.85 (3H, s ), 2.62 (1H, collapsed t), 2.1-1.0 (4H, m), 0.91 (3H, collapsed t).

In the same manner 2-n-pentyl-4-methoxycarbonylphenol (crystals, Fp.82,5-83,5 ⁰ C) obtained from the in Reference Example 1- (v) 2-n-valeryl-4-bromophenol is prepared.

2-n-ProT3yl-4-cyanothiophenol

3.28 g of the 2-n-propyl-4-cyanophenol prepared in Reference Example 1- (iii) are dissolved in 40 ml of N, N-dimethylformamide. Then, with stirring and ice cooling, 1.07 g of sodium hydride and the mixture is stirred for 30 min. Then, 2.65 g of dimethylthiocarbamoyl chloride are added gradually, and the mixture is stirred at ⁰ ° C. for 1.5 hours. 50 ml of ice-water are added to the reaction mixture, and the mixture is extracted with ethyl acetate. The extract is washed with saturated sodium chloride aqueous solution and dried over sodium sulfate.

net. After distilling off the solvent gives a pale yellow solid. This is purified by silica gel column chromatography using benzene as a developer to give 4.14 g of 2-n-propyl-4-cyanodimethylthiocarbanioyl phenolate as a pale yellow, oily substance.

4.00 g of the resulting carbamate are stirred at 205 ⁰ C for 13 h. After cooling, the formed, dark brown solid is extracted with ethyl acetate and the solvent is distilled off from the extract. The resulting dark brown solid is treated with ethyl ether under ice-cooling to give 2.90 g of 2-n-propyl-4-cyano-dimethylcarbamoyl-thiophenolate as a pale brown powder. , ,

A mixture comprising 2.86 g of the obtained thiophenolate, 30 ml of dried methanol and 3.0 ml of a 28% sodium methoxide-methanol solution is stirred for 15 hours at room temperature. Then, 1.5 ml of a 28% sodium methoxide-methanol solution is added and the mixture is stirred for a further 5 hours. The reaction mixture is acidified to a pH of about 2 by the gradual addition of concentrated hydrochloric acid and the solvent distilled off. Water is poured to the resulting dark brown oily residue and the mixture is extracted with benzene. The benzene layer is washed successively with water and saturated sodium chloride aqueous solution and dried over sodium sulfate. After distilling off the solvent gives a dark brown, oily substance. This is purified by silica gel column chromatography using benzene / n-hexane (2/1, v / v) as a developer. , 1.13 g of the above-identified compound are obtained as a colorless, oily substance.

NMR _(CDCl3): 7.4-7.2 (3NC, m), 3.51 (1H, s, disappears on addition of D _£ 0), 2.61 (2Η, t), 2.0 to 1 , 3 (2H, m), 0.99 (3Η, t).

1- (viii) 2-ethyl-4-methoxypheriol

This compound is prepared from 2,5-dimethoxyacetophenone according to a method described in the literature [J. Chem. Soc., 1922 (1939), and J. Chem. Soc., (C), Vol. 24, 2274 (1966)].

2-chloro-4-methoxycarbonylphenol, 2-chloro-4-ethoxycarbonylphenol and 2-methoxy-4-ethoxycarbonylphenol:

These compounds are prepared from commercially available 2-chloro-4-carboxyphenol and 3-methoxy-4-hydroxybenzoic acid according to a method similar to the esterification method described in Reference Example 1- (i).

Ethyl ^ -hydroxy-S-n-propyl ^ -oxo ^ H-i-benzopyran ^ - carboxylate and 2-hydroxy-3-n-propyl-4-hydroxyacetophen-

These compounds are prepared according to a method described in the literature [J.Med.Chem., Vol

20, 371 (1977)].

Methyl-4-hydroxy-y-oxobenzolbutanoat:

This compound is obtained according to a method described in Example 1 of Japanese Laid-Open Publication No. 139342/1984.

Reference Example 2 4-Ethyl-5-chloro-2-t-butyl-3 (2H) -pyridazino n

t-Bu-N ¹

In a 1 1 four-necked flask is charged 43 g of ethyl magnesium bromide (3 mol / l of an ether solution) and 200 ml of dry toluene. Stir well at room temperature. 22.1 g (0.1 mol) of 2-t-butyl-4,5-dichloro-3 (2H) -pyridazinone in three parts. The reaction temperature is raised to about 60 ⁰ C and stirring continued for about 30 min. The disappearance of the starting material dichloropyridazinone is confirmed by thin layer chromatography (TLC) (developer: hexane / acetone = 20/1, v / v), whereupon the reaction is terminated. After adding about 300 ml of chilled water, the mixture is stirred vigorously and transferred to a separating funnel. Then the aqueous layer is removed. The organic layer is washed with about 200 ml of water and dried over anhydrous sodium sulfate, and then the solvent is distilled off. The substance thus obtained, a pale brown, oily is purified by silica gel column chromatography (developer: benzene) to give one 14.5 g (yield 67.6%) of pale yellow crystals, m.p. 61.5 to 62.5 ⁰ C, obtained..

NMR _(CDCl3): 7.62 (1H, s), 2.72 (2H, q), 1.61 (9H, s), 1.14 (3H, t).

In the same way, the following compounds are prepared from the corresponding 2-alkyl-4,5-dichloro-3 (2H) -pyridazinones and alkylmagnesium halides: 4-methyl-5-chloro-2-t-butyl-3 (2H) -pyridazinone [oily substance, b.p.60-62 ° C (0.22 mmHg)], 4-n-propyl-5-chloro-2-t-butyl-3 (2H) -pyridazinone (oily substance), 4-n- Butyl-5-chloro-2-t-butyl-3 (2H) -pyridazinone (oily substance) and 4-n-pentyl-5-chloro-2-t-butyl-3 (2H) -pyridazinone (oily substance).

Reference Example 3 4-Chloro-5- (5-chloropropoxy) -2-t-butyl-5 (2H) -pyridazinone

-CH ₂ CH ₂ CH ₂ Cl

A mixture comprising 5.0 g of 4-chloro-5-hydroxy-2-t-butyl-3 (2H) -pyridazinone, 4.2 g of i-bromo-3-chloropropane, 3.7 g of anhydrous potassium carbonate and 30 ml Dimethylformamide, is stirred at 70 to 80 ⁰ C for 3 h. The reaction mixture is transferred to a separatory funnel and 100 ml of water and 50 ml of benzene are added. The mixture is shaken vigorously and the benzene layer washed with water and dried over anhydrous sodium sulfate. Then, the solvent is distilled off. And the resulting oily substance is dissolved in hexane / ethyl ether (3/1, vol / vol). The precipitated crystals were collected by filtration and dried. To give 5.7 g of the title compound, Fp.51 to 52 ⁰ C.

NMR _(CDCl3): 7.79 (1H, s), 4.39 (2H, t), 3.77 (2H, t), 2.28 (2H, m), 1.62 (9H, s) ,

In the same way, the following compounds are prepared from the corresponding 4-chloro-5-hydroxy-2-alkyl-3 (2H) -pyridazinones:

4-Chloro-5- (3-chloropropyloxy) -2-i-propyl-3 (2H) -pyridazinone (crystals, mp. 88-9O ⁰ C) and 4-chloro-5- (3-chloro-prp-p-cyxy) -2- ethyl-3 (2H) -pyridazinone (crystals, mp 73 ⁰ C).

Further, using 1-bromo-2-chloroethane in place of, 1-3 -romo-3-chloropropane gives 4-chloro-5- (2-chloroethyloxy) -2-i-propyl-3 (2H) -pyridazinone (crystals, mp. 100-103 ⁰ C)-chloro-5-hydroxy-2-i-propyl-3 4 (2H) -pyridazinone prepared. , .

Reference Example 4 4-Chloro-5- (3-hydroxypropylamino) -2-t-butyl-3 (2H) -pyridine

Azmon

NHCH ₂ CH ₂ CH ₂ OH

A mixture of 4.42 g of 4,5-dichloro-2-t-butyl-3 (2H) -pyridazinone, 4.50 g of 3-amino-i-propanol, 4.15 g of potassium carbonate, 25 ml of 1,4- Dioxane and 80 ml of water are refluxed for 18 hours with stirring. 1,4-dioxane is distilled off under reduced pressure and the residue obtained is extracted with ethyl acetate. The extract is washed successively with dilute hydrochloric acid, water and saturated sodium chloride-aqueous solution and dried over sodium sulfate. After distilling off the solvent gives a pale yellow, viscous, oily substance. This is purified by silica gel column chromatography; 3.54 g of the above-identified compound are obtained from the chloroform-methanol (20/1, v / v) eluate as a pale yellow, orange, viscous, oily substance.

NMR _(CDCl3): 7.52 (1H, s), 5.25 (1H, brs), 3.79 (2H, t),

3.45 (2H, m), 1.88 (2H, m), 1.60 (9H, s) MS (m / e): 259 (M ⁺ ), 203, 158 (100%).

In the same way, the following compounds are prepared from the corresponding 4,5-dichloro and 4,5-dibromo-2-alkylpyridazinones:

4-bromo-5- (3-hydroxypropylamino) -2-t-butyl-3 (2H) -pyridazinone (viscous, oily substance), 4-chloro-5- (3-hydroxypropylamino) -2-i-propyl-3 (2H) -pyridazinone (viscous, oily substance), 4-3romo-5- (3-hydroxypropylamino) -2-i-propyl-3 (2H) -pyridazinone (viscous, oily substance), 4-chloro

5- (3-hydroxypropylamino) -2-ethyl-3 (2H) -pyridazinone (crystals, m.p. 86-87 ° C) and 4-3romo-5- (3-hydroxypropylamino) -2-ethyl-3 (2H) -pyridazinone (crystals, mp. 83 ⁰ C).

Furthermore obtained using 2-aminoethanol instead of 3-amino-1-propanol 4-Bromo-5- (2-hydroxyethylamino) -3 (2H) -pyridazinone (crystals Fp.121-123 ⁰ C) solution of 4, 5-dibromo-2-i-propyl-3 (2H) -pyridazinone.

Reference Example 5 4-Chloro-5- (2-oxiranylmethoxy) -2-i-propyl-3 (2H) -pyridine

i-Pr-N - ^ \ - Cl.

^1: ^ - ^ 0 -CH "CH-CH ₉ ·

² X / ² o

1.3 g of potassium hydroxide are dissolved in a mixed solvent of 6 ml of ethanol and 0.12 ml of water. To this solution is added 4.0 g of 2-1-PrOPyI-Ch-Or-S-hydroxy-3 (2H) -pyridazinone. Subsequently, a solution obtained by dissolving 5.9 g of epichlorohydrin in 3.4 ml of ethanol is added and the mixture is refluxed for about 3 to 5 hours. After completion of the reaction, the solvent is distilled off and the residue is added with water and ethyl ether in an amount of 30 ml each. The mixture is shaken vigorously. The organic layer is washed once with water and dried over anhydrous sodium sulfate. The solvent is distilled and the residue obtained is extracted three times with 30 ml of n-hexane / ethyl ether (1/1, vol / vol). The extract is concentrated, obtaining 2.3 g of the above-identified compound as colorless crystals, Fp.92 to 95 ⁰ C MS (m / e): 244 (M ⁺⁾ ', 202, 57 (? 100 -a) ,

Similarly, 4-chloro-5- (2-oxiranylmethoxy) -2-ethyl-3 (2H) -pyridazinone (crystals) is prepared from 4-chloro-5-hydroxy-2-ethyl-3 (2H) -pyridazinone ,

Reference Example 6

4-chloro-5- (2,3-dihydroxypropylamino) -2-i-propyl-3 (2H) -

• pyridazinone

i-Pr-N

^ CH ₂ CHCH ₂ OH ⁿ OH

A mixture comprising 5.18 g of 4,5-dichloro-2-i-propyl-3 (2H) -pyridazinone, 7.97 g of 2,3-dihydroxypropylamine, 8 ml of 1,4-dioxane and 80 ml of water 17 h at. a temperature of 75 to 80 ⁰ C stirred. Most of the 1,4-dioxane is distilled off under reduced pressure and the reaction mixture acidified to a pH of about 2 by the addition of dilute hydrochloric acid and sodium chloride added to saturation. Then the mixture is extracted with 2 × 200 ml of tetrahydrofuran. The extract is washed with saturated sodium chloride-aqueous solution and dried over sodium sulfate. After distilling off the solvent to obtain a colorless solid. This is crystallized from ethyl acetate / ethyl ether to give 5.30 g of the above-identified compound as colorless crystals, mp. 137-139 ° C.

NMR (CDCl ₃ + DMSO-d ₆ ): 7.74 (1H, s), 5.75-4, SO (2H, m), 4.62 (1H, d, disappears upon addition of D ₂ O), 4.4-4.0 (1K, brt, disappears upon addition of D ₂ O), 4.0-3.2 (5K, m), 1.29 (6H, d)

MS (m / e): 261 (M ⁺ ), 219, 200, 158 (10054).

In the same way 4-CTilor-5- (2,3-dihydroxypropylamino) -2-ethyl-3 (2H) -pyridazinone (crystals, mp. 120 to 124 ⁰ C) from 4,5-dichloro-2-ethyl 3 (2K) -pyridazinone.

Reference Example 7

2-t-butyl-4-n-propyl-5- (3-hydroxypropylamino) -3 (2H) -

pyridazinone

'NHCH ₂ CH ₂ CH ₂ OH

A mixture of 14.0 g of 2-t-butyl-4-n-propyl-5-chloro-3 (2H) -pyridazinone, 44 g of 3-hydroxypropylamine and 14.8 g of anhydrous potassium carbonate is added 1.2, 5 h at. 145 to 155 ⁰ C stirred. The reaction solution is allowed to come to room temperature and treated with about 200 ml of cold water; then the mixture is stirred. The precipitated white crystals are collected by filtration and dried; 12.1 g of the above-identified compound are obtained, mp 167 to 169 ^° C.

NMR _(CDCl3): 7.49 (1H, s), 4.91 (1H, brs), 4.13 (1H, t), 3.73 (2H, t), 3.33 (2H, m) , 2.41 (2H, t), 2.15-1.20 (4H, m), 1.59 (9H, s), 0.94 (3H, t).

Similarly, 2-t-butyl-4-n-butyl-5- (3-hydroxypropylamino) are -3 (2H) -pyridazinone (crystals Fp.106 to 108 ⁰ C) and 2-t-butyl-4- n-pentyl-5- (3-hydroxypropylamino) -3 (2H) -pyridazinone '(oily substance) from the corresponding 2-t-butyl-4-alkyl-5-chloro-3 (2H) obtained in Reference Example 2 prepared pyridazinones.

Reference 8

3- (2-Ethoxycarbonyl-8-n-propyl-4-oxo-4H-1-benzopyran-7- yl-oxy) -

Br-CH ₂ CH ₉ CH ₂ -O

n-Pr

A mixture of 5.52 g of ethyl 7-hydroxy-8-n-propyl-4-oxo-4H-1-benzopyran-2-carboxylate [J.Med. Chem., 20, 371 (1977 (], 2 , 76 g of potassium carbonate, 12.12 g of 1,3-dibromopropane and 30 ml of dimethylformamide is stirred for 4 h at a temperature of ⁰ to 70 βθ C. the reaction mixture is placed in 60 ml of ethyl acetate and 70 ml of water and the mixture shaken vigorously. The organic layer is washed with water and dried over anhydrous sodium sulfate, the solvent is filtered off and the resulting crude crystals are recrystallised from benzyl / ethyl acetate (2/1, v / v) to give 5.4 g of the above compound

NMR _(CDCl3): 8.02 (1H, d, J = 9.0Hz), 7.01 (1H, d, J = 9.0Hz), 4.42 (2H, q), 4.24 (2H , t), 3.12 (2H, t), 2.90 (2H, t), 2.48 (2H, t), 1.9O-i, 50 (2H, m), 1.42 (3H, t), 0.96 (3H, t).

Similarly, 3- (3-methoxyphenoxy) -propylbromide [oily substance, Bp.102-105 ° C (1.0 mmHg)] and 3- (2-chloro-4-ethoxycarbonylphenoxy) -propylbromide (oily substance ) from 3-methoxyphenol or 2-chloro-4-ethoxycarbonylphenol.

Further, using 1,4-dibromobutane instead of 1,3-dibromopropane, 4- (2-bromophenoxy) -butyl bromide (oily substance) is prepared from 2-bromophenol.

example 1

4-Chloro-5- [2- (4-methoxyphenyl) ethylamino] -2-ethyl-3 (2H) pyridazinone (Compound; No. 20)

i HC H ₂ CH ₂ - ^ V-OMe

A mixture comprising 0.5 g of 4,5-dichloro-2-ethyl-3 (2H) -pyridazinone, 1.18 g of 4-methoxyphenylethylamine, 0.36 g of potassium carbonate, 18 ml of water and 6 ml of 1,4-dioxane , is refluxed for 8 h with stirring. Then, 1,4-dioxane is distilled off under reduced pressure and the residue obtained is extracted with ethyl acetate. The extract is washed successively with dilute hydrochloric acid and water, and dried over sodium sulfate, and then the solvent is distilled off. The residue is purified by silica gel column chromatography using benzene / ethyl acetate (1/1, v / v) as a developer, wherein one, 400 mg of the above identified compound as colorless crystals, Fp.135-135,5 ⁰ C.

NMR _(CDCl3): 7.54 (1H, s), 7.15, 6.86 (each 2H, ABq), 4.78 (1H, brs), 4.18 (2H, q), 3.80 (3H, s), 3.55 (2H, q), 2.90 (2H, t), 1.35 (3H, t)

MS (m / e): 307 (M ⁺ ), 186, 121 (100%).

Example 2

4-Chloro-5- [3- (2-chloro-4-ethoxycarbonylphenoxy) propoxy] -

2-ethyl-3 (2H) -pyridazinone (compound, No. 50)

0-CH ₂ CH ₂ CH ₂ O

A mixture of 1.36 g of 3- (2-chloro-4-ethoxycarbonylphenoxy) propyl bromide prepared from 2-chloro-4-ethoxycarbonylphenol and 1,3-dibromopropane in Reference Example 8, 0.74 g of 2-ethyl-4- Chloro-5-hydroxy-3 (2H) -pyridazinone, 0.64 g of anhydrous potassium carbonate and 5 ml of Ν, Ν-dimethylfonaamide. is stirred for about 4 h at a temperature of 70 to 80 ⁰ C. The reaction mixture is mixed with 50 ml of water and the mixture is stirred vigorously and then transferred to a separating funnel. Then, the mixture is extracted with 50 ml of benzene, washed once with 2% hydrochloric acid aqueous solution and once with water, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the resulting crystals are recrystallized from hexane / ethyl acetate; to obtain 1.14 g of the above-identified compound as colorless crystals, Fp.101 to 103 ⁰ C.

1639, 1598, 1310, 1265

NMR _(CDCl3): 8.04 (1H, d), 7.92 (1H, -dd), 6.96 (1H, d), 7.86 (1H, s), 4.60 to 4.06 (8H, m), 2.40 (2H, t), 1.38 (3H, t), 1.35 (3H, t)

MS (m / e): 414 (M ⁺ , 100%), 342, 187.

Example 3

4-Chloro-5- [3- (2-n-propyl-3-hydroxy-4-acetylphenoxy) -propoxy ] -1-2-t-butyl-3 (2H) -pyridazinone (Compound No. 37)

Cl

0-CH ₀ CH ₀ CH ₀ O ^ f Vi-Me

ύ Δ Δ \ /

Pr-n OH

A mixture comprising 1.0 g of 4-chloro-5- (3-chloropropyloxy) -2-t-butyl-3 (2H) -pyridazinone obtained in reference

Example 3, 0.7 g of 2,4-dihydroxy-3-n-propylacetophenone, 1.0 g of anhydrous potassium carbonate, 0.6 g of potassium iodide and 5 ml of dimethylformamide is stirred at 70 to 80 ⁰ C for 3 h. The reaction mixture is treated with 20 ml of water and 20 ml of benzene and the mixture shaken vigorously. The benzene layer is washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off and the resulting oily substance is separated and purified by silica gel column chromatography (developer: hexane / ethyl acetate = 2/1, v / v). 0.92 g of the above-identified compound are obtained as a pale yellow, oily substance.

NMR (CDCl ₃ ): 8.79 (1H, 's), 7.63 (1H, d), 6.48 (1H, d), 4.45 (2H, t), 4.26 (2H, t), 2.64 (2H, t), 2.35 (2H, t), ... 2.5-4 (3Ή, s), 1.65 - (9H, -s)

MS (m / e): 401 (M ⁺ -Cl), 345 (100%), 205.

Example 4

4-Chloro-5- [3- (4-methylphenylsulfonyloxy) -propylamino] 2-t-butyl-3 (2H) -pyridazinone (Compound No. 15)

t-Bu-N

-Cl

CH ₉ CHOCH- ^ ^H 0

2.55 g of .p-toluenesulfonyl chloride are added. A mixture of 3.16 g of the 4-chloro-5- (3-hydroxypropylamino) -2-t-butyl-3 (2H) -pyridazinone prepared in Reference Example 4, 1 , 44 g of pyridine and 50 ml of dichloromethane with stirring and ice cooling and the mixture is stirred for 2 h at the same temperature. Then, 2.0 g of pyridine and 2.5 g of p-toluenesulfonyl chloride are added to the reaction mixture in this order. The mixture is stirred for a further 2 hours under ice-cooling and then overnight in

a cold chamber left. The solvent is distilled off and the obtained, pale yellow, oily substance extracted with benzene. The extract is washed successively with dilute hydrochloric acid, water (twice) and saturated sodium chloride-aqueous solution and dried over sodium sulfate. After distilling off the solvent gives a pale yellow, oily substance. This is purified by silica gel column chromatography using benzene / ethyl acetate (1 / i, vol / vol) as a developer; 4.67 g of the above-identified compound are obtained as a pale yellow, viscous, oily substance.

NMR _(CDCl3): 7.72, 7.26 (each 2H, ABq), 7.37 (1H, s), 4.60 (1H, brs), 4.10 (2H, t), 3,3.8 (2H, m), 2.41 (3H _r S), 1.96 (2H, -m), -1, 60 - (9H, s)

MS (m / e): 413 (M ⁺ ), 357 (100%), 322, 158, 150.

Example 5

4-Chloro-5- [3- (2-n-propyl-4-cyanophenoxy) -propylamino] -2 -t-butyl-3 (2H) -pyridazinone (Compound No. 1)

t-Bu-i

HCH ₂ CH ₂ CH ₂ o / V ^CN

Pr η

A mixture comprising 1.24 g of Compound No. 15 prepared in Example 4, 0.53 g of 2-n-propyl-4-cyanophenol, 150 mg of sodium iodide, 1.04 g of potassium carbonate and 30 ml of 2-butanone becomes 5 h refluxed with stirring. The solvent is distilled off and the residue obtained is mixed with water. The mixture is extracted with chloroform. The extract is successively with 5% sodium hydroxide aqueous solution and saturated

Sodium chloride-aqueous solution and dried over sodium sulfate. After distilling off the solvent gives a pale yellowish-orange, viscous, oily substance. The remaining oily substance is crystallized from ethyl ether / benzene / hexane to give to 97 ⁰ C, obtained 0.83 g of the title compound as colorless crystals, Fp.96.

IR (^ Si) cm ^-1 : 3345, 2225, 1630 (Sch), 1605-1615

dcwi

NMR _(CDCl3): 7.53 (1H, s), 7.42 (1H, dd), 7.36 (1H, d), 6.82 (1H, d), 4.80 (1H, brs) , 4.12 (2H, t), 3.57 (2H, m), 2.62 (2H, t), 2.38-1.45 (4H, m), 1.61 (9H, s), 0.95 (3H, t)

MS (m / e): 402 (M ⁺ ), 346, 311 (100 ° / o), 159.

Example 6

4-Chloro-5- [3- [2-n-propyl-4- (1H-tetrazol-5-yl-phenoxy)] propylamino] -2-t-butyl-3 (2H) -pyridazinone (Comp

No. 2) ;

NH-CH ₉ CH ₉ CH ₀ Of ^

Δ Δ Δ \

A mixture of 483 mg of Compound No. 1 prepared in Example 5, 390 mg of sodium azide, 385 mg of ammonium chloride and 5 ml of dimethylformamide is stirred at 120 ^° C. for 5 hours. The solvent is distilled off and the residue obtained is treated with dilute hydrochloric acid. The mixture is extracted with ethyl acetate. The extract is washed successively with water and saturated sodium chloride-aqueous solution and dried over sodium sulfate. After distilling off the solvent

The pale yellow solid obtained by elution with chloroform / methanol (20/1, v / vl) is crystallized from methanol / ethyl ether to give 263 g of a pale yellow, viscous, oily substance which is subjected to silica gel column chromatography mg of the title compound as colorless crystals, Fp.189 to 19O ⁰ C.

IR (J ¹ ^ tI) cm ^-1 : 3300, 1615, 1590

NMR (CDCl ₃ + DMSO-dg): 7.95-7.70 (2H, m), 7.61 (1H, s), '6.92 (1H, d), 4.12 (2H, t) , 3.80 (2H, m), 2.68 (2H, t), 2.4-2.0, 1.9-1.4 (2H, m each), 0.98 (3K, t)

MS (m / e): 445 (M ⁺ ), 41.0, 354, 159, 143 (10050

BeisOiel 7

4-chloro-5- [3-n-propyl-methoxycarbonylphenoxy) propylamino] -3 (2H) n-pyridazinone (Compound No. 4)

H-N

Pr η

A mixture of 2.015 g of Compound No. 1 prepared in Example 5, 7.5 ml of sulfuric acid and 30 ml of methanol is refluxed for 9.5 hours while stirring. Methanol is distilled off and the resulting, pale brown residue is added gradually with ice cooling with sodium bicarbonate and water for neutralization. Then the mixture is extracted with ethyl acetate, the extract is washed successively with water and saturated sodium chloride aqueous solution and dried over sodium sulfate. After distilling off the solvent gives a pale yellow, oily substance. The residue will be

subjected to silica gel column chromatography. The eluting with chloroform / methanol (3/1, v / v) obtained, colorless, viscous oily substance is crystallized / hexane from chloroform to give 666 mg of colorless crystals, Fp.164 to 166 ⁰ C, is obtained.

IR (^ S) cm " ¹ : 3260, 1705, 1665, 1595

NMR _(CDCl3): 7.78 (1H, dd), 7.76 (1H, d), 7.59 (1H, s), 6.76 (1H, d), 4.99 (1H, brs) , 4.12 (2H, t), 3.84 (3H, s), 3.59 (2H, m), 2.63 (2H, t), 2.45-1.40 (4H, m), 0.95 (3H, t)

MS (m / e): 379 (M ⁺ , 100%), 190.

BeisOiel 8

4-Chloro-5- [3- (2-n-propyl-4-methoxycarbonylphenoxy) -propylamine] -2-ethyl-5 (2H) -pyridazinone (Compound; No. 6)

Pr-n

A mixture of 456 mg of Compound No. 4 prepared in Example 7, 207 mg of potassium carbonate, 0.5 ml of ethyl iodide and 5 ml of Ν, Ν-dimethylformamide is stirred at 60 ^° C. for 2 hours. The solvent is distilled off and the resulting, pale brown, oily substance is mixed with water. The mixture is extracted with ethyl acetate, the extract washed with water and dried over sodium sulfate. After distilling off the solvent, a pale yellow oily substance is obtained, which is subjected to silica gel column chromatography. From the eluate with chloroform / methanol (30/1, v / v), the above-identified compound is obtained as a pale yellow, semi-solid substance.

(CDCl ₃ ): 7.83 (1H, dd), 7.77 (1H, d), 7.55 (1H, s), 6.78 (1H, d), 4.80 (brs), 4, 40-3.90 (4H, m), 3.84 (3H, s), 3.80-3.45 (2H, m), 2.63 (2H, t), 2.40-2.00, 1.90-1.45 (2H, m each), 1.32 (3Ή, t), 0.96 (3H, t) MS (m / e): 407 (M ⁺ ), 372, 340, 187

Example 9

4-Chloro-5- [3- (2-n-propyl-4-carboxyphenoxy) -propylamino] -2-ethyl-5 (2H) -pyridazinone (Compound No. 7)

EtVSr ⁰¹ ^ _co , h

* ^ V-Nm-

NH-CH ₂ CH ₂ CH ₂ O

Pr-n

A mixture of 370 mg of Compound No. 6 prepared in Example 8, 1.0 ml of methanol and 1.0 ml of a 2N sodium hydroxide aqueous solution is refluxed for 1.5 hours. Then another 0.5 ml of a 2N sodium hydroxide aqueous solution is added and refluxing is continued for 30 minutes. After cooling, the reaction mixture is acidified to a pH of about 7.0 by the addition of dilute hydrochloric acid, and then the solvent is distilled off. Dilute hydrochloric acid is poured into the obtained residue, and the mixture is extracted with ethyl acetate. The extract is washed with water and a saturated sodium chloride aqueous solution and dried over sodium sulfate. Then the solvent is distilled off to give a pale yellow solid. This is recrystallized twice from methanol / ether; is obtained Ί60 mg of the above compound as colorless crystals, mp. 164-165 ⁰ C.

MR (CDCl _3): 8.0 to 7.7 (2H, m), 7.52 (1H, s), 6.75 (1H, d), 4.90 (1H, brs), 4.4 -3.9 (4H, m), 3.8-3.3 (2H, m), 2.63 (2H, t), 2.3-1.5 (4H, m), 1.32 (3H , ~ t), 0.97 (3H, t)

MS (m / e): 393 (M ⁺ ), 358, 187 (100%).

Example 10

4-Chloro-5- [3- (2-n-propyl-4-carbamoyl-phenoxy) -propyl- amino] -2-i-propyl-5 (2K) -i3yridazinone (Compound No. 42)

^ Cl i-Pr-N "

A mixture of 130 mg Compound No. 41, i. 4-Chloro-5- [3- (2-n-propyl-4-carboxyphenoxy) -propylamino] -2-ipropyl-3 (2H) -pyridazinone, 62 mg N, N'-carbonyldiimidazole and 20 ml N, N- Dimethy! Formamide is stirred for 1 h at room temperature. Then, ammonia gas is blown into the mixture for 10 minutes under ice-cooling, and the system is sealed and allowed to stand at room temperature for 2 hours. Then, the solvent is distilled off under reduced pressure. The residue is extracted with chloroform and the chloroform layer is washed successively with aqueous sodium hydroxide solution and dilute hydrochloric acid aqueous solution and dried over sodium sulfate. Then, chloroform is distilled off and the residue is treated with ethyl ether. 20 mg of the above-identified compound are obtained as a white powder.

NMR _(CDCl3): 7.89, 6.78 (each 1 H, .ABq), 7.69 (2H, s),

6.46 (2H, brs), 5.50-5.00 (2H, m), 4.21 (2H, ΐ), 3.80-3.35 (2H, m), 2.63 (2H, t), 1.85-1.15 (2H, m), 1.50 (6H, d), 0.93 (3H, t)

IR (£ * £) cm " ¹ : 3350, 2950, 1610

IUcLA

MS / m / e): 406 (M ⁺ ), 312, 201 (100%)

Example 11

4-chloro-5r [3- (2-n-propyl-4-cyanophenoxy) -2-hydroxypropoxy- 2-iT} roOVl-3 (2H) -i3yridazinone (Compound No. 171)

O-CH ₂ CHCH ₂ OOH

A mixture comprising 2.0 g of the 4-chloro-5- (2-oxiranylmethoxy) -2-i-propyl-3 (2H) -pyridazinone ε prepared in Reference Example 5, 1.5 g of 2-n-propyl-4 cyanophenol, 1.35 g of potassium carbonate and 80 ml of diethyl ketone is refluxed for 8 hours with stirring. Then diethylene ketone is distilled off (under reduced pressure) and the residue obtained is extracted with ethyl acetate. The extract is washed with water and dried over sodium sulfate. The solvent is distilled off and the residue is purified by silica gel column chromatography using benzene / ethyl acetate (1/1, v / v) as a developer. The resulting colorless crystals are recrystallized from ethyl ether; obtained 1.3 g of the above-identified compound as colorless crystals, Fp.118,5 to 121 ⁰ C.

NMR _(CDCl3): 7.92 (1H, d), 7.46 (1H, dd) (, 7.40 (1H, s), 6.90 (1H, d), 5.58 to 4.95 1H, m), 4.62-4.06 (5H, m), 3.72-3.46 (1H, m), 2.59 (2H, t), 2.00-1.26 (2H, m), 1.42 (6H, d), 0.92 (3H, t)

MS (m / e): 405 (M ⁺ ), 328, 189 (10050, 147.

Example 12

4-Chloro-5- [3- (4-methylphenylsulfonyloxy) -2-hydroxypropylamino] -2-i-propyl-3 (2H) -pyridazinone (Compound No. 143) ; :

NCH ₀ CHCH ₀ OS H 2, 2 η

OH 0

1.60 g of p-toluenesulfonyl chloride are added under ice-cooling to a mixture containing 2.09 g of the 4-chloro-5- (2,3-dihydroxypropylamino) -2-i-propyl-3 (2H) prepared in Reference Example. Pyridazinons, 12 ml of pyridine and 20 ml Di chlorine than included. The mixture is stirred for 6 hours and then allowed to stand for 2 days in a cooling chamber. The reaction mixture is acidified to a pH of about 2 by addition of cooled, dilute hydrochloric acid and the mixture is extracted with ethyl acetate. The extract is washed successively with water, saturated sodium bicarbonate-aqueous solution and saturated sodium chloride-aqueous solution and dried over sodium sulfate. After distilling off the solvent, a colorless, oily substance is obtained. This is purified by silica gel column chromatography to obtain 2.45 g of the above-identified compound as a colorless, viscous, oily substance from the eluate with chloroform / methanol (25/1, v / v).

NMR (CDCl ₃ ): 7.72, 7.27 (2H each, ABq), 7.60 (1H, s),

5.5-4.9 (2H, m), 4.44 (1H, brs), 4.2-3.8 (3H, m), 3.7-3.1 (2H, m), 2, 42 (3H, s), 1.29 (6H, d)

MS (m / e): 415 (M ⁺ ), 373, 200, 158

94 Example 15

Example 15 4-Chloro-5- [3- (2-n-propyl-4-cyanothiophenoxy) -2-hydroxypropylamino] -2-i-propyl-3 (2H) -pyridazinone (Compound

* T JK t- T \

No. 155)

1-.pr-N

-CH ₀ CHCH S

OH Pr-n

A mixture of 1.62 g of Compound No. 143 prepared in Example 12, ie, the tosyloxy product, 690 mg of the 2-n-propyl-4-cyanothiophenol prepared in Reference Example 1- (vii), 585 mg of sodium iodide, 1, 35 g of potassium carbonate and 40 ml of diethyl ketone is refluxed for 18 hours with stirring. The solvent is distilled off and the residue obtained is mixed with water. The mixture is extracted with chloroform, the extract washed successively with 5% sodium hydroxide aqueous solution, water and saturated sodium chloride-aqueous solution and dried over sodium sulfate. After distilling off the solvent, a pale yellow, oily substance is obtained, which is crystallized from a mixture of ethyl acetate / ethyl ether / benzene. This gives the title compound as colorless crystals, mp. 151.5 to 152.5 ⁰ C.

MMR (CDCl ₃ + DMSO-d ₆ + D _£ 0): 7.67 (1H, s), 7.34 (3H, s), 5.5 to 4.9 (1H, m), 4,3 3.1 (5H, m), 2.69 (2H, t), 1.9-1.2 (2H, m), 1.28 (6H, d); 0.98 (3H, t)

MS (m / e): 420 (M ⁺ ), 343, 200, 177, 148 (10050.

Example 14

4-Chloro-5- [3- (2-n-propyl-4-carboxythiophenoxy) -2-hydroxypropylamino] -2-i-propyl-3 (2H) -pyridazinone (Compound No. 154)

i-Pr

NCH CHCH.S.-H I

Oh

Pr-n

A mixture comprising 1.00 g of Compound No. 153 prepared in Example 13, 10 ml of 10N sodium hydroxide and 10 ml of methanol is refluxed for 5.5 hours with stirring. Most of the methanol is distilled off and the residue is acidified to a pH of about 2 by the gradual addition of concentrated hydrochloric acid under ice-cooling. The precipitated solid is collected by filtration and recrystallized from methanol / ethyl ether. This gives 950 mg of the title compound "as colorless crystals, Fp.174 to 174.5 ⁰ C

NMR (CDGl ₃ + DMSO-d ₆ + D _£ 0): 7.9-7.6 (3H, m), 7.27 (1H, d), 5.5 to 4.8 (1H, m), 4.2-3.0 (5H, m), 2.70 (2H, t), 1.9-1.2 (2H, m), 1.28 (6H, d), 0.97 (3H, t)

MS (m / e): 439 (M ⁺ ), 404, 362, 200 (100%), 196, 167

ice

-1

i e 1

3340, 3270, 1680, 1625 (Sch), 1600.

15

4-Chloro-5- [3- (2-n-propyl-4-methoxycarbonylthiophenoxy) 2-hydroxypropylamino] -2-i-propyl-3 (2K) -pyridazinone (Compound No. 155)

CO ₂ Me

Dissolve 730 mg of prepared in Example 14 compound No. 154 in a mixture of 10 ml of methanol and

10 ml of ethyl acetate and introduce Diazomethangas until the solution becomes a pale yellow color. The reaction solution is allowed to stand overnight and the solvent is distilled off. The resulting residual solid is subjected to silica gel column chromatography. The colorless crystals obtained from the eluate with benzene / ethyl acetate (1/1, v / v) are recrystallized from ethyl ether / n-hexane. 420 mg of the above-identified compound are obtained as colorless crystals, mp. 155 to 156 ^° C.

NMR _(CDCl3): 7.9-7.7 (2H, m), 7.68 (1H, s), 7.33 (1H, d), 5.4 to 4.8 (2H, m), 4.2-3.0 (6H, m), 3.88 (3H, s), 2.76 (2H, t), 1.9-1.3 (2H, m), 1.30 (6H, d), 1.00 (3H, t)

MS (m / e): -453 (M ⁺ ), 418, 376, 210, 200 (10054) »131 IR (v ⁷ J? J) cm" * ¹ : 3340, 3280, 1710, 1630 (Sch), 1605th

Π13Λ '"

Example 16

4-Chloro-5- [3- (2-n-propyl-4-methoxycarbonylphenoxy) -propyl-N-methylamino] -2-i-propyl-3 (2H) -pyridazinone ( Compound No. 73) ·

^C1

-N-CH ₀ CH ₀ CH ₀ O ι LLL

Me p _r . _n

350 mg of 4-chloro-5- [3- (2-n-propyl-4-methoxycarbonylphenoxy) -propylamino] -2-i-propyl-3 (2H) -pyridazinone (Compound No. 44) is used in 20 ml of dry tetrahydrofuran. Dissolved and 43 mg of sodium hydride (55% mineral oil suspension) and then added 0.2 ml of methyl iodide with ice cooling. The mixture is stirred for 15 minutes. Ice-water is poured into the reaction mixture and

hydrochloric acid is added to acidify the mixture to a pH of about 2. Then the mixture is extracted with ethyl acetate, the extract is washed successively with water and saturated sodium chloride aqueous solution and dried over sodium sulfate. After distilling off the solvent, 365 mg of the above-identified compound are obtained as a pale yellowish-orange, viscous, oily substance.

NMR _(CDCl3): 7.9-7.7 (2H, m), 7.63 (1H, s), 6.75 (1H, d), 5.28 (1H, 7 Heptaplett), 4.03 (2H, t), 3.81 (3H, s), 3.64 (2H, t), 3.08 (£ H, s), 2.60 (2H, t), 2.5-1.2 (4K, m), 1.27 (6H, d), 0.92 (3H, t)

MS (m / e): 435 (H ⁺ ), 400, 214, 206 (100%).

Example 17

4-Chloro-5- [3- (2-n-propyl-4-cyanophenoxy) -2-methoxypropoxy- 2-i-propyl-3 (2H) -pyridazinone (Compound; No. 172)

i-Pr -N

0-CH ₀ CHCH ₀ -O ^ /

OMe

0.036 g of sodium hydride (55% mineral oil suspension) is added to a mixture of 300 mg of the 4-chloro-5- [3- (2-n-propyl-4-cyanophenoxy) -2-hydroxy-propoxy prepared in Example 11]. 2-i-propyl-3 (2K) -pyridazinone (Compound No. 171), 0.13 g of methyl iodide and 15 ml of tetrahydrofuran under ice-cooling, and the mixture is stirred at room temperature for 2 hours. Then another 0.13 g of methyl iodide and 0.036 g of sodium hydride are added and the mixture is stirred for 2 hours. To decompose excess sodium hydride, ice pieces are gradually added to the reaction solution under ice-cooling. Then the reaction

acidified with dilute hydrochloric acid and distilled off tetrahydrofuran under reduced pressure. The residue is extracted with ethyl acetate, and the extract is washed with water and dried over sodium sulfate. The solvent is distilled off and the resulting oily substance is isolated and purified by silica gel column chromatography (developer: benzene / ethyl acetate = 2/1, v / v). 0.17 g of the above-identified compound are obtained as a yellow, oily substance.

NMR _(CDCl3): 7.85 ,. (1H, d), 7.44 (1H, dd), 7.37. (1H, s), 6.87 (1H, d), 5.54-5.51. (1H, m), 4,43 (2H, d), 4,21 (2H, d), 4,34-3 ^, 84 (1H, m), 3,55 (3H, s), 2,69 (2H, t), 2.04-1.14 (2H, m), 1.34 (6H, d), 0.93 (3K, t) -.

MS (m / e): 419 (M ⁺ ), 384, 189 (100? Q.

example

18

4-Chloro-5- [3- (2-n-propyl-4-cyanophenoxy) -2-methoxypropyl-N-methylamino] j-2-i-propyl-3 (2H) -pyridazinone ( Compound No. 157)

Ale O

n-Pr

Dissolve 122 mg of 4-chloro-5- [3- (2-n-propyl 1-4-cyanophenoxy) -2-hydroxypropylamino] -2-i-propyl-3 (2H) -pyridazinone (Compound No. 145). in 5 ml of dry tetrahydrofuran and 30 mg of sodium hydride (55 ° oige mineral oil suspension) and then 0.2 ml of methyl iodide with stirring and ice cooling. The mixture is stirred at ⁰ ° C. for 15 minutes, ice-water is poured into the reaction solution, and the reaction mixture is stirred.

extracted with ethyl acetate. The extract is washed with water and saturated sodium chloride-aqueous solution and dried over sodium sulfate. After distilling off the solvent, a pale yellow oily substance is obtained, which is isolated and purified by silica gel column chromatography. 69 mg of the above-identified compound are obtained as a pale yellow, viscous, oily substance from the eluate with benzene / ethyl acetate (3/2, v / v).

NMR _(CDCl3): 7.70 (1H, s), 7.5-7.3 (2H, m), 6.79 (1H, d), 5,7O "(1H, 7 Heptaplett) · 4 , 1-3.2 (5H, m), 3.43 (3H, s), 2.58 (2H, t), 1.9-1.3 (2H, m), 1.30 (6H, d ), 0.94 (3H, t)

MS (m / e): 432 (M ⁺ ), 2.14 (10050.

Example '19

4-Chloro-5- [3- (2-n-propyl-4-cyanophenoxy) -2-methoxypropylamino] -2-i-propyl-3 (2H) -pyridazinone (Compound No.

158) ; ;

CN

NCH _{0 0} O ^ CHCH ² H I ² I OMe ⁿ '

n-Pr

In the separation process of the crude product by silica gel column chromatography in Example 18, the fraction obtained with a benzene / ethyl acetate mixture (1/1, v / v) as in Compound No. 157 is obtained and the solvent is distilled off from the fraction. 35 mg of the above-identified compound are obtained as a pale yellow, viscous, oily substance.

NMR _(CDCl3): 7.65 (1H, s), 7.6-7.3 (2H, m), 6.84 (1H, d), 5.5 to 4.8 (2H, m), 4.2-3.3 (5H, mZ, 3.50 (3H, s), 2.60 (2H, t), 2.0-1.3 (2H, m), 1.30 (6H, d ), 0.96 (3H, t)

MS (m / e): 418 (M ⁺ ), 383, 341, 200 (100%), 161, 158, 132.

Example 20

4-Chloro-5- [3- [4- (β-methoxycarbonyl-α-methyl-propionyl) -phenoxy] -2-methoxy-propyl-N-methylamino] -2-i-propyl- 3 (2H) -pyridazinone (Compound; 167)

N-CH ₀ CHCH ₀ O Me OMe

600 mg of 4-chloro-5- [3- [4- (β-methoxycarbonylpropionyl) -phenoxy] -2-hydroxypropylamino] -2-i-propyl-3 (2H) -pyridazinone (Compound No. 166) are dissolved in 10 ml dissolved dry tetrahydrofuran and 0.12 g of sodium hydride (55% mineral oil suspension) and then added 0.47 g of methyl iodide with stirring and ice cooling. The mixture is stirred for 1 hour on an ice bath, ice-water is added to the reaction solution, and then dilute hydrochloric acid is added to bring the pH to about 7. Then, tetrahydrofuran is distilled off, water is poured to the residue, and the mixture is extracted with ethyl acetate. The extract is washed successively with water and saturated sodium chloride-aqueous solution and dried over sodium sulfate. After distilling off the solvent to obtain a yellow, oily substance. This is subjected to silica gel column chromatography to obtain 100 mg of the above-identified compound as a pale yellow, viscous, oily substance from the eluate with benzene / ethyl acetate (1/1 vol / vol).

NMR _(CDCl3): 7.92, 6.91 (de 2H, ABq), 7.73 (1H, s),

5.19 (1H, 7 heptaplett), 4.2-2.4 (8H, m), 3.60, 3.45, 3.18 (3H, s), 1.28 (6H, d), 1.20 (3H, d)

MS (m / e): 494 (M + 1; 100%), 460.

Example 21

4-Chloro-5- [3- (2-n-propyl-4-methoxycarbonylphenoxy) -2-oxypropylamino] -2-i-propyl-3 (2H) -pyridazinone (Compound No. 161)

i-Pr ->

n-Pr

A mixture of 1.11 g of dimethylsulfoxide and 20 ml of tetrahydrofuran is cooled with dry ice / acetone, gradually dropping a mixture of 2.24 g of trifluoroacetic anhydride and 3.67 ml of tetrahydrofuran. The mixture is stirred for 20 minutes and then one by dissolving 0.93 g of 4-chloro-5- [3- (2-n-propyl-4-methoxycarbonylphenoxy) -2-hydroxypropylamino] -2-i-propyl-3 ( 2H) -pyridazinone (Compound No. 44) in 8 ml of tetrahydrofuran was added dropwise. The mixture is stirred for 30 minutes. Subsequently, 1.26 g of triethylamine are added dropwise. The mixture is stirred for 30 minutes under ice-cooling and then for 1 hour at room temperature. Sodium bicarbonate is added and tetrahydrofuran is distilled off under reduced pressure. The residue is extracted with chloroform and the extract is washed with water and dried over sodium sulfate. Finally, the solvent is distilled off and the resulting residue is purified by silica gel column chromatography using benzene / ethyl acetate (1/1, v / v) as

Developer cleaned. The solvent is distilled off. The resulting colorless crystals are further recrystallized from ethyl acetate / ethyl ether, giving 0.52 g of the above-identified compound as colorless crystals, mp. 133 ⁰ C.

NMR _(CDCl3): 8.09 to 7 »74 (2H, m), 7.43 '(1H, s), 6.72 (1H, d), 5.71 to 4.99 (2H, m) , 4.77 (2H, s), 4.53, 4.46 (total 2H, each s), 3.85 (3H, s), 2.72 (2H, t), 2.09-1.49 (2H, in), 1, 30 (6H, d), 1.01 (3H, t)

MS (m / e): 435 (M ⁺ ), 392, 200, 165 (100%).

Example 22

5- [3- (2-n-propyl-4-ethoxycarbonylphenoxy) -propylamine] -2 -i-propyl-3 (2H) -pyridazinone (Compound Mr. 63)

A mixture comprising 0.82 g of 4-chloro-5- [3- (2-n-propyl-4-ethoxycarbonylphenoxy) -propylamino] -2-i-propyl-3 (2H) -pyridazinone (Compound nr. 64), 50 ml ethanol, 1.5 ml of triethylamine and 150 mg of 5% palladium-on-carbon is hydrogenated for 3 h at a temperature of 40 to 5O ⁰ C with stirring. The reaction mixture is filtered and the filtrate concentrated. The resulting crude crystals are recrystallized from ethyl ether to give 0.58 g of the above-identified compound as colorless crystals, mp. 111-116 ⁰ C.

NMR _(CDCl3): 7.89 to 7.72 (2H, m), 7.50 (1H, d, J = 3.0 Hz), 6.75 (1H, d), 5.97 (1H, brs ), 5.63 (1H, d, J = 3.0Hz), 5.18 (1K, m), 4.50-4.00 (4H, m),

3.25 (2H, t), 2.59 (2H, t), 2.14 (2K, t), 1.85-1.05 (2H, m), 1.28 (βΚ, d), 0 , 93 (3H, t) MS (m / e): 401 (M ⁺ ), 343, 194, 180, 167 (100%), 152, 125.

Example 23

4-Chloro-5- [3- [2-ethyl-4- (2-carboxyethenyl) -phenoxy] -propylamino 1-2-ethyl-5 (2H) -pyridazinone (Compound No. 93)

A mixture of 1.34 g of 4-chloro-5- [3- (2-ethyl-4-formylphenoxy) -propylamino] -2-ethyl-3 (2H) -pyridazinone (Compound No. 92), 0.73 g Malonic acid, 1 drop of piperidine and 12 ml of pyridine is heated at 100 ° C for 3 hours with stirring. After cooling, the reaction solution is acidified with hydrochloric acid and extracted with ethyl acetate. The extract is washed twice with water and dried over sodium sulfate. Then, the solvent is distilled off and the obtained residue is crystallized from ethyl acetate / ethyl ether. 1.2 g of the compound indicated above are obtained as pale yellow crystals, mp. 145 to 147 ° C.

M-IR (CDCl _3): 7.73 (1H, s), 7.59 (1H, d), 7.55-7.15 (2H, m), 6.86 (1H, d), 6 26 (1H, d), 5.92 (1H, brs), 4.37-3.87 (4H, m), 3.60 (2H, q), 2.69 (2H, q), 2.45 -1.95 (2H, m), 1.31 (3H, t), 1.22 (3H, t)

MS (m / e): 405 (M ⁺ ), 370, 187 (100%).

Example 24

4-chloro-5- [3- (2-n-butyl-4-carbamoyl-phenoxy) -propylamino ] -2-i-propyl-B (2H) -pyridazinone (Compound No. 114)

N CH ₉ CH ₀ OH ^{ά Δ ι}

n-Bu

A mixture comprising 168 mg of 4-chloro-5- [3- (2-n-butyl-4-carboxyphenoxy) -propylamino] -2-i-propyl-3 (2H) -pyridazinone (Compound No. 112), 119 mg of thionyl chloride and 10 ml of dry tetrahydrofuran is refluxed for 1 h with stirring. The reaction mixture is distilled under reduced pressure and the residue is treated with 20 ml of dry benzene. The mixture is distilled again under reduced pressure to remove excess thionyl chloride by azeotropic distillation. The obtained residual oily substance is dissolved in 10 ml of dried tetrahydrofuran, and ammonia gas is introduced for 5 minutes under ice-cooling. Then the reaction solution is stirred for a further 15 min. The reaction mixture is distilled under reduced pressure and water is poured into the residue obtained. The mixture is extracted with chloroform and the extract is washed successively with 5% sodium hydroxide aqueous solution and saturated sodium chloride aqueous solution and dried over sodium sulfate. The solvent is distilled off and the resulting pale yellow oily substance is crystallized from methanol / ethyl ether. This gives 143 mg of the title compound as colorless crystals, mp. 172 to 174 ⁰ C.

NMR (CDCl ₃ + DMSO-d _6): 7.8-7.5 (3H, 'm), 6.79 (1H, d), 7.0 to 6.1 (2H, brs), 5.5 -4.9 (2H, m), 4.11 (2H, t),

3.8-3.3 (2H, m), 2.64 (2H, t), 2.5-1.0 (6H, m), 0.92 (3H, co-ordinated t). MS (m / e): 420 (M ⁺ ), 385, 368, 228, 214, 201 (100%).

Example 25

4-bromo-5- [3- (2-n-butyl-4-cyanophenoxy) -propyl! Amino] -2-

ethyl-3 (2H) -pyridazinone (Compound No. 181) ^^

CH ₉ CH CH Ο-H ^{Δ 1 Δ}

n-Bu

A mixture of 316 mg of 4-bromo-5- [3- (2-n-butyl-4 carb

amoylphenoxy-O-propylamino -] - 2 - ethyl-3 "" C 2 H) -pyridazinone

(Compound No. 180), 174 mg of p-toluenesulfonyl chloride, 110 mg of pyridine and 5 ml of Ν, Ν-dimethylformamide is stirred at 95 ⁰ C for 1.5 h. The reaction mixture is subjected to distillation under reduced pressure, water is poured into the remaining oily substance, and the mixture is extracted with ethyl acetate. The extract is washed successively with 5% dilute hydrochloric acid, water and saturated sodium bicarbonate aqueous solution and dried over sodium sulfate. Then, the solvent is distilled off to form a pale yellow, oily substance. The oily substance is crystallized from ethyl ether, to give 248 mg of the above-identified compound as colorless crystals, mp. 107.5 to 108.5 ⁰ C.

NMxR _(CDCl3): 7.7-7.3 (3H, m), 6.82 (1H, d), 5.2 to 4.7 (1H, m), 4.4 to 3.9 (4H , m), 3.8-3.4 (2H, m), 2.65 (2H, brt), 2.5-1.1 (6H, m), 1.32 (3H, t), 0, 93 (3H, collaborated t)

MS (m / e): 432 (M ⁺ ), 353 (10056), 327, 258, 244, 231, 137.

BeisDiel

26

Sodium salt of Compound No. 41 (Compound No. 67)

i-Pr-N

CH ₂ CH ₂ CH ₂ O

CO ₂ Na

n-Pr

125 mg of 4-chloro-5- [3- (2-n-propyl-4-carboxyphenoxy) propylamino] -2-i-propyl-3 (2H) -pyridazinone (Compound No. 41) are dissolved in a mixture of 0 , 5 ml of 2N sodium hydroxide aqueous solution and 2 ml of water, and subjected to adsorption column chromatography using 30 ecm of Amberlite XAD-8. The sample is adsorbed and. to ... to neutrality. the washing solution washed with purified water and then eluted with methanol. The solvent is distilled off under reduced pressure from the eluate, the residue is treated with 30 ml of purified water and then filtered. The resulting aqueous solution is freeze-dried to obtain 72 mg of the above-identified compound as a colorless powder.

MS (FD; m / e): 430 (M + 1)

cm

" ¹

: 3320, 1615.

example

27

4-Chloro-5- [3- (2-n-propyl-4-hydro: cypheno: cy) -propylamino 2-ethyl-5 (2H) -pyridazinone (Compound No. 108)

NH-CH _n CH ₀ CH ₀ -O ^ f V-OH n-Pr

  i 07

One by dissolving 0.35 g of 4-chloro-5- [3- (2-n-propyl-4-methoxyphenoxy) propylamino] -2-ethyl-3 (2H) -pyridazinone (Compound No. 82) in FIG. 10 ml of methylene chloride is added dropwise with stirring and ice cooling to a mixture of 0.36 g of aluminum chloride, 0.44 g of di-npropylsulfid and 15 ml of methylene chloride. After completion of the dropwise addition, the mixture is stirred for 2 h at ⁰ ° C and then allowed to stand overnight in a refrigerator. To decompose excess aluminum chloride, ice pieces are gradually added to the mixture and extracted with chloroform. The extract is washed with water and dried over sodium sulfate. After distilling off the solvent, the resulting residue is crystallized from ethyl ether / η-hexane. The above-indicated compound (0.26 g) is obtained as colorless crystals, mp 11.2 to 112.5 ° C.

NMR _(CDCl3): 7.62 (1H, s) (, 6.82 to 6.42 (3H, m), 5.07 (1H, brs), 4.26 (2H, q), 3.95 2H, q), 3,54 (2H, q), 2,52 (2H, t), 2,35-1,13 (4H, m), 'i, 32 (3H, t), 0,91 ( 3H, t)

MS (m / e): 365 (M ⁺ ), 330., 214 (100%), 186.

The compounds prepared according to the above examples are given in Table 8. The process number (Vf) refers to the number of each production process, and the example number (B) refers to the respective example according to which the specific compound (Vb) was produced.

In the NMR (CDCl ^) 6 values, only the characteristic absorptions are indicated. Similarly, only the main signal and the largest signal are indicated as MS data.

ca

CS

CQ Φ

.Ω CÖ

m in 'JS • ca " C- CJ Cl 33 Cl ; r ιη Cl up Cl Cl <Η ta ft * "'" * -> C- 5 Cl 33 Cl Cl - - Cl co ca ~ ei * · NH Cl S ta! 1-4 CI in ~ • Η • »» • Η Cl φ ~ / ^ - • ^ 3 ** , a in> ^ CP τ- ca η - φ + ca σ 03 o φ • C3 · CO. ₌ cn _j 73 03 p 03 Λ "T _w o <Ί " Cl 00 CU ο co - "m ¹ Ό Φ • Η * αά " IN • • S ϋ , 3 η • CQ cn ct cn • ύ - ft ft ca 4 · t-ro ti _r N ca in »I · 3 ft = ^ r ft ca ca σ Λ. - - ' • S , CS ca σι - egg ca • Η • Η ο - - • C- ' CJ • Η in •H φ φ 4 · I-- - .. O φ , cm · Φ C- · PQ U CJ ^, 03 - cn ^^ - * · - ' PQ C-V 1-1 PQ C- φ Φ C S ^. co _T .85 311, in - .20 ¹ * ΐ 2 Φ in Φ ι CI Γ * Λ - p φ φ CI , ii CO % • Η ο Cl ' co Φ • Η cn ei ^ • Η • Η CQ C NII cn · 03 _ ' cn _I 03 'Ώ - ^ · * - ^ * ca τ-I I -10 CO ™ ^^ ΐϋ CJ - ^. = '. ^. = ^; 5 "" .- " O in · - * C- 3 3 v ^w C- * 03 * in co ca C- ιη _ Ci Z ! S ™ te - OK ^ * " C-CJ ^ J ™ * = O , Cl. , CJ , C? = C- ^ O C-> ^ c- ^ * C- "" - "   I ι. Ι..Ι ~ * co ι ι • ζ ζ = CJ ιη VO C to 99th C-3 I ft C-Cl ϋ 1 1 m o E ^ - ] *** J I  <? Cl t O ta Cl Cl • r-4 te o £ -5 Cl co - "·" ₌ = _{= = =} CJ CJ C 5 ^ - a CJ O CJ CM CJ 2 3 CJ Q O O O O O O ϋ Nile r λ ϋ O O , CJ O- 1 'S · Nile "* * 1 I 'S · I U ε ι I κ = 3 5 5 3 CJ CJ CxJ ι CM I CJ I CJ I Cl C O ro C O C O Cl CC CJ CJ CI Cl 3 5 3 r ". 3 - 2 < 2 NH 2 Nile Nile Nile 3 5 3 CJ .2 ν I t-llu 1 ht - CVJ O ν  * ~ CO σΥ T-

13 kt Cl NU C ₂ O 2-Cl 4-CO ₀ Me ύ 4-Cl II 4-0Me II II O VCO ₂ Et 123-124 7.70 (HI, s), 5.03 (HI, brs) ) ,, 3.89 (311, s), 1.39 (311, t) 4 14 t-Bu Cl Nile ^CII 2 S 3-OMQ ' II 3,4- (OMe) ₂ 4-OMe II II ³ · Α 0 CO ₂ Il visk.öligi substance ^! 7.48 (111, 3), 4.64 (111, brs), 3.65 (311, s), 3.00 (211, t) 4 15 t-Bu Cl Nile CIl ₂ OSO 4-Me U H Il II dito see example 4 5 16 t-Bu Cl Nile - - 3,4- (OMe) ₂ 4-Me II II 123.5-124.5 7.50 (111, s), 4.87 (111, brs ^, 3.82 (GII., S), 2.86 (211, t), 1.62 (911, b) 1 17 et Cl Nile cn ₂ OCO 2-n-Pr II 125-126 7.88, 7.32 (each ^2M ABq), 7.49 (111, s), 4.91 (111, brs), 4.42 (211, t.), 4.13 (211, q), 3.47, 2.1l (euoh 211, in) 5 18 et Cl Nile 2-n-Pr II 111 7.55 (111, s), 4.90 (111, brS), 4.17 (211, q), 3.85 (611, s), 2.89 (211, t), 1.32 (311, t) 1 19 t-Bu Cl Nile - - 11 77-78 7.51 (111, 8), 4.87 (111, brs), 3.77 ((31I, s), 2.86 (211, t), 1.61 (911, s) 1 20 et Cl Nile - - II 135-135.5 see example 1 1 21 t-Bu Cl O - 0 II 123-125 7.84 (1II, s), 4.55 (211.t), 4.38 (211, t). 1.65 (911, s) 3 22 t-Uu Cl O CII ₂ / 0 II 97 7.79 (111, s), 4.40 (211, t), 4.13 (211, t), 2.27 (211, t), 1.63 (011, s) 3 23 t-Bu Cl O Ci ₂ 0 Visc. oily substance > 8.01 (111, d, .1 = 9th OHz), 7.72 (111, s), 7.05 (111, d, .1 = 9.OHz), 6.90 (111, s), 4.05-4.20 (611, in ), 2.88 (211, t), 2.40 (211, I), · 1.61 (911, t), 1.42 (311, t), 0.94 (311, t) 2 24 t-Bu Cl O CH ₂ O 85-90 8.04 (111, d, .I = 9.0Ilz), 7.82 (111, 3), 7.28 (111, d, J = 9.0llz), 4.70-4.10 (411, in), 2.85 (211, t), 2.41 ( 211, t), 1.65 (911, s), 0.94 (311, t) 9

25 lit Cl O CII ₂ O 2-n-Pr \ * \ ^ O CO ₂ Kt II 4-CO ₂ Et II 109-114 8.04 (111, d, J = 9.0IIz), 7.80 (111, s), 7.05 (111, d, J = g.Ollz), 7.02 (111, b), 4. (55-4.05 (811, ni) 2.90 (211, t), 2.42 (211, t), 1.43 (311, t), 1.37 (311, t), O. 0G. (3H, t) 2 26 t-UEU lit O CN ₂ O 2-n-Pr ^ O CO ₂ Et H 4-CO ₀ H -J II 164-167 8.01 (111, d, J = 9.0Hz), 7.70 (111, a), 7.01 (111, d, J = 9, 0Hz), 6.90 (111, s), 4.60-4.20 (611, ni), 1.61 ( 911, s), 1.42 (311, t), 1.06 (611, t) 2 27 t-Bu Cl O CIl ₂ O 3-OMe H 4-CO ₂ Et II 58-59 7.74 (111, s), 4.38 (211, t), 4.12 (211, t), 3.76 (311, b), 2.24 (211, t), 1.58 (911, s) 2 28 lit Cl O CH ₂ Ü 3-OMe H 4-CO ₂ II H 70-75 7.73 (111, s), 4.37 (211, t), 4.11 (211, t), 2.23 (211, t), 3.73 (311, s), 2.41 (211, q), 1.37 (311, t) 2 29 lit Cl O CIl ₂ O 2-n-Pr II II 109-111 8.07 (111, d, j = 9.OIIz), 8.87 (111, a), 7.08 (111, d, .1 = 9.OHz), 4.60-4.15 (611, in), 2.94 (211, t), 1.30 (311, t), 0.94 (311, t) 9 30 kt Cl O CII ₂ O 2-Cl II II 101-103 see example 2 2 31 lit Cl O CII ₂ O 2-Cl H II 182-184 7.80 ( U1 , s), 4.51 (211, t), 4.20 (211, t), 1.37 (311, t) 9 32 t-Bu Cl O CH ₂ O 2-Cl 69-71 7.85 (111, a), 4.41 (211, t), 4.53 (211, η), 4.32 (211, t), 2.40 (211, t), 1.03 (911, a), 1.49 (311, t) 2 33 t-Bu Cl O CIl ₂ O 2-Cl 141-144 9.70 (111, brs), 7.79 (111, s), 4.38 (211, t) 4.28 (211, t), 2.38 (211, t), 1.61 (911, a) 9 34 t-Bu Mr O CH ₂ O 3-0Mo 63.5-64.5 7.64 (111, a), 4.40 (211, t), 4.13 (211, t), 3.76 (311, a), 2.29 (211, t), 1.64 (911, s) 2 35 i-Pr Cl O CH ₂ O 3-0Me 81 7.82 (111, a), 5.30 (111, q), 4.40 (211, t), 4.12 (211, t), 3.77 (311, a), 2.30 (211, t), 1.34 ((HI, d) 2 36 lit Cl O (CIl ₂ ), O 2-Hr visk.öl. substance 7.78 (111, a), 4.50-3.97 (411, in), 3.70 (211, t) 1.93 (411, in). 1.37 (311, t) 2

37 t-Bii Cl O CH ₂ O 2-n-Pr, 3-OH 4-Ac visc. oil, substance see example 3 3 3 38 t-Bti Cl O - - II II H 121 7.69 (111, s), 7.30 (511, s), 4.40 (211, s), 3.12 (211, t), 1.Cl (OII, a) 1 1 39 t-Bu kt O - - 4-C1 II II 130-131 7.69 (111, s), 7.30 (411, s), 4.41 (211, s), 3.11 (211, t), 1.62 (911, s) 1 1 40 t-Bu Cl O CH ₂ - II II II visk.öl. substance 7.70 (111, β), 4.20 (211, t), 2.88 (211, t) 2.18 (211, t), 1.66 (911, s) 1 1 41 i-Pr Cl Nile ClI ₂ O 2-n-Pr 4-CO ₂ II II 1 97-198 7.66 (111, S), 4.23 (211, t), 1.39 (611, d), 0.95 (311, t) 9 9 42 i-Pr Cl Nile CH ₂ O 2-n-Pr 4-C0NII H 134-135 see example 10 10 10 43 me Cl Nir Ci ₂ O 2-n-Pr 4-CO ₂ Me II 99-99.5 7.52 (HI, s), 4.9G (III, brs), 4.11 (211, t), 3.83 (311, 3), 3.09 (311, 3), 2.64 (211, t), 0.95 (311, t) 8th 3 44 i-Pr Cl Nile ClI ₂ O 2-n-Pr 4-CO ₂ Mc H 120.5 7.73 (111, 3), 3.86 (311, s), 1.35 (611, d), 0.95 (311, t) 8th 3 45 i-Pr Cl O - O 3-OMe II II visk.öl. substance 7.58 (111, s), 5.25 (111, q), 3.80 (311, 3), 3.73 (411, s), 1.33 (611, ti) 3 3

Vb. ¹ H ¹¹ 2 Λ X 13 ^Y l ^Y 2 ^Y 3 FPRC) MS (m / o) Vf. B 26 46 t-nu Cl O CH ₂ O 2-Cl 4-CO ₂ Nn II 155-176 9 5 6, 47 48 Et Kt CI CI Nile Nile CH ₂ CH ₂ O O 2-n-Pr 2-n-Pr 4-CN NN // I NN Il II II 113-114 207-208 374 (M ⁺ ), 187 (100%) 417 (M ⁺ ), 298 (100%) 4 6 5 49 et CI NH C ₂ O 2-OMe. 4-CO ₂ Et Il 134 409 (M ⁺ ), 186 (100%) 4 5 50 et Cl NH CII ₂ O 2-OMe II II 84 337 (M ⁺ ), 186 (100%) 4 5 51 et Cl Nile CII ₂ O 2-OEt II II 100 352 ([M-JIl] ⁺ ), 336 (100%) , 4 9 52 et Cl Nile C ₂ O 2-OMe 4-CO ₂ Il II 143 381 (M ⁺ ), 186 (100%) 9 , 5 53 kt Cl Nile CH ₂ O 4-OEt II II 95 351 (M ⁺ ), 214 (100%) 4 , 5 54 et Cl NH CII ₂ O 4-Me Il II 96-97 321 (M ⁺ ), 214 (100%) 4 1 55 i-Pr Cl Nile - - 4-OMe ii II 98-99 321 (M ⁺ ), 122 (100%) 1 5 - * FO 56 et Cl Nile CII ₂ O 4-OMe II Il 86-86.5 337 (M ⁺ ), 214 (100%) 4 5 57 et Cl Nile CII ₂ O. 2-Me II II 84-88 321 (M ⁺ ), 286 (100%) 4 5 58 i-Pr Cl Nile CII ₂ O 4-0Me II II visk.öl. substance 351 (M ⁺ ), 186 (100%) 4 5 59 i-Pr C] Nile CII ₂ O 2-0Me II II 94 351 (M ⁺ ), 274 (100%) 4 5 60 i-Pr Cl Nile CH ₂ O 2-n-Pr 4-CN π 121-123 388 (M ⁺ ), 311 (100%) 4 5 61 i-Pr Cl NH CH ₂ S 2-n-Pr 4-CN II 98-98.5 404 (M ⁺ ), 327 (100%) 4 9 62 i-Pr Cl Nile CIl ₂ S 2-n-Pr 4-CO ₂ II Il 177.5-178 423 (M ⁺ ), 201 (100%) 9 22 63 i-Pr II Nile C ₂ O 2-n-Pr 4-CO ₂ Et II 115-116 see example 15 5 64 i-Pr Cl Nile CII .. Ct O 2-n-Pr 4-CO ₂ Et II 110-112 435 (M ⁺ ), 201 (100%) 4 3 65 kt Cl O CII ₂ O 2-n-Pr 4-CN II 90-91.5 375 (M ⁺ ), 175 (100%) 3 1 66 i-Pr Cl Nile - - 4-OH II π 157-158 307 (M ⁺ ), 200 (100%) 1

i-Pr Cl Nile · i-Pr Cl Nile i-Pr Cl NH i-Pr Cl Nile i-Pr Cl Nile i-Pr Cl NH i-Pr Cl NMe 1-Pr Cl NMo i-Pr Cl NH i-Pr Cl NH i-Pr Cl NMe i-Pr Cl NMe i-Pr , Cl O Rt Cl NH ILt Cl NH et Cl Nile et Cl O et Cl O i-Pr Cl O

O 2-n-Pr 4-CO.N α Δ II powder see example p.26 9 S 2-n-Pr ^, NN ^N NN II II 189-191 447 (M ⁺ ), 143 (100%) 6 O 2-allyl 4-CN II 106 387 ([Millions] ⁺ ), 309 (100%) 4 " O 2-allyl 4-CO ₂ H η 185-188 405 (M ⁺ , 100%) 9 O 2-OEt H II 75 3GS (M ⁺ ), 350 (100%) 4 O 2-Me II II 105-110 336 ([M + HJ ⁺ ), 258 (100%) 4 O 2-n-Pr 4-CO ₀ Me Δ II visk.öl. substance see example i6 12 O 2-n-Pr 4-CO ₂ Il U 158-159 421 (M ⁺ ), 200 (100%) 9 O 4-C- (CII ₂ ) ₂ CO ₂ II II II 103-106 421 (M ⁺ ), 186 (100%) 9 O O VJ 4-C- (CII ₂ ) ₂ CO, Me O 4-C- (CH ₂ ) ₂ CO.p II II H II visk.öl. Substance ditto. 435 (M ⁺ ), 361 (100%) 449 (M ⁺ ), 20G (100%) 4 12 O 4-C- (CH ₂ ) ₂ CO ₂ II II II 113-115 435 (M ⁺ ), 417 (100%) 9 O O 2-i-Pr 4-CO ₀ Me Δ Il visk.öl. substance 422 (M ⁺ ), 193 (100%) 4 O 2-allyl 4-CN II 128 372 (M ⁺ ), 337 (100%) 4 O O 2-allyl 2-n-Pr 4-CO ₀ Me 4-OMe II visk.öl. Substance 65-66 405 (M ⁺ ), 370 (100%) 379 (M ⁺ ), 214 (100%) 4 4 O 2-n-Pr 4-CO ₂ II II 123-129 394 (M ⁺ ), 359 (100%) 9 O 2-n-Pr 4-CO ₀ Me Δ II visk.öl. substance 408 (M ⁺ ), 341 (100%) 3 O 2-n-Pr 4-CO ₂ Me II 62-63 422 (M ⁺ ), 387 (100%) 3

26 6

5 9 5 5 16

9 9

16 9 5

5 5 5 9 3

86 i-Pr Cl O ^C1I 2 O 2-n-Pr 87 i-Pr Cl O CII ₂ O 2-n-Pr 88 1-Pr Cl Nile CH ₂ O 2-i-Pr 89 1-Pr Cl NII CII ₂ O 2-i-Pr 90 i-Pr Cl NII C ₂ O 2-OEt 91 1-Pr Cl NLI CII ₂ O 2-OEt U2 Rt Cl NU CIl ₂ O 2-Et 93 ht Cl NII CII ₂ O 2-Et 94 1-Pr C! NII C ₂ O 2-Et 95 i-Pr Cl NII CIl ₂ O 2-Et 96 151 Cl NII CII ₂ O 2-Et 97 i-Pr Cl NII C ₂ O 2-Et 98 i-Pi Cl NII CII ₂ O 2-Et 99 nt Cl NII C ₂ O 2-OMe 100 i-Pr Cl NII C ₂ O 2-OMe 101 1-Pr Cl Nile C ₂ O 2-Et 102 i-Pr Cl MLI CII ₂ O 2-Et 103 Gt Cl NII CII ₂ O 2-i-Pr 104 ht Cl Nile ClI ₂ O 2-i-Pr 105 i-Pr Cl. NII CII ₁ . ct O 2-n-Pr 106 kt Cl Nile C ₂ O 2-Et 107 i-Pr Cl NII CH ₂ O 2-Et

4-CO 2 ^H 4-CN 4-CO ₂ Me 4-CO 2 ^H 4-CO ₂ Me 4-CO 2 '

4-CHO

4-Ch = CIICO ₂ H 4 -CHO

4-CH = CHCO ₂ H 4-CO.Me

4-CO ₀ II 4-CN 4-Me 4-Me

>, 4-CO ₂ Mo 4-CONH ₂

4-CÖ Mt 4-CO ₂ II 4-OMe 4-OMe

4-OMe

II

II H II

II H

H II II II

II II II II II II II II

171-172 88.5-89

99-101 219-221

/isk.öl

 substance

1G7-171

/isk.öl

 substance

145-147 122-126 150-151

/Isk.öl

 substance

178-180

14Π-147.5

111-113

125-126

156-157

65-70

157-158

94-97

/•isk.öl

 iubstanz

112-113

408 (M), 373 (100%) 389 (M ⁺ ), 354 (100%)

421 (M ⁺ ), 159 (100%) 407 (M ⁺ ), 159 (100%) 423 (M ⁺ ) ^-

409 (M ⁺ )

363 (M), 187 (100%)

see example p.23

377 (M ⁺ ), 342 (100%) 419 (M ⁺ ), 384 (100%) 393 (M ⁺ ), 187 (100%)

393 (M ⁺ ), 374 (M ⁺ ), 351 (M ⁺ ), 365 (M ⁺ ), 407 (M ⁺ ), 392 (M ⁺ ), 407 (M ⁺ ), 393 (M ⁺ ), 393 ( M ⁺ ), 305 (M ⁺ ),

358 (100%) 297 (100%) 214 (100%) 228 (100%) 372 (100%) 357 (100%) 187 (100%) 187 (100%) 228 (100%) 214 (100%)

370 (M), 344 (100%)

9 4 10 9 3 4 3 4 9 5 9 4 9 4 4 5 9 9 4 5 16 23 4 5 in 23 4 5 9 9 19 25 4 5 4 5 5 10 5 9 5 5

et Cl NII I-Pr Cl NU i-Pr Cl NLI et Cl NII i-Pr Cl NU lit Cl NU i-Pi Cl NII ßt Cl NII et Dr NII et rr NII et Mr NII et br NII i-Pr Mr NII kt ur Nile i-Pr br NH i-Pr br NII i-Pr br Nile i-Pr br Nile i-Pr br Nile i-Pr br NII t-llii n-Pr Nile t-nu n-Pr NII

O 2-n-Pr 4-OH H 112-112.5 see example p.27 O 2-n-Pr 4-OH II 127-128 379 (M ⁺ ). 228 (100%) O 2-n-Bu 4-CO ₀ Me ti II .106-110 435 (M ⁺ ), 400 (100%) O 2-n-Bu 4-COgMe II 70-72 421 (M ⁺ ), 187 (100%) O 2-n-Bu 4-COgII II 198-199 421 (M ⁺ ), 386 (100%) ' O 2-n-Bu 4-CO ₀ H II 190-199 407 (M ⁺ ), 187 (100%) O 2-n-Bu 4-CONH ₂ H 172-174 see example p.24 O 2-n-Bu 4-CONH ₂ H 178-179 4Of) (M ⁺ ), 187 (100%) O 2-n-Pr 4-CN II 113-115 418 (M ⁺ ), 339 (100%) O 2-AUyl 4-CN H 124-120 418 (M ⁺ ), 337 (100%) O 2-n-Pr 4-COJe ύ H 90-92 451 (M ⁺ ), 372 (100%) O 2-n-Pr 4-COgll H 204-205 437 (M ⁺ ), 358 (100%) O 2- η-Pr 4-CN II 106-107 432 (M ⁺ ), 311 (100%) O 2-n-Pr 4-CONH. Δ H 180 436 (M ⁺ ), 340 (100%) O 2-n-Pr 4-CONIIg H 129-130 450 (M ⁺ ), 311 (100%) O 2-allyl 4-CN II 127-128.5 432 (M ⁺ ), 309 (100%) O 2-n-Pr 4-COgMe II 114.5-115 407 (M ⁺ ), 386 (100%) O 2-n-Pr 4-CO ₂ H II 195-196 451 (M ⁺ ), 372 (100%) O 2-n-Bu 4-COgMe II 105-108 479 (M ⁺ ), 400 (100%) O 2-n-Bu 4-COgH II 192-194 465 (M ⁺ ), 386 (100%) O 2-n-Pr 4-CN II visc. oil .. substance 410 (M ⁺ ), 354 (100%) O 2-Cl 4-COGET II dito 449 (M ⁺ ), 358 (100%)

17 27 17 27 4 5 4 5 9 9 9 9 10 24 10 24 4 5 4 5 4 5 9 9 1 10 24 10 24 4 5 4 5 9 9 4 5 9 9 4 5

130 131 132 133

134 135 136 137

138 139

140 141 142 143

144 145 146 147 148 149 150

Il II II

fit

II is leasing

i-pint

II II

i-Pr i-Pr i-Pr i-Pr

1-Pri-Pri-Pri-Pri-Pr i-Pr

IJT

n-Prn-Prn-Prn-Pr

n-Pr Hr Dr Dr

n-Bu

n-Bn

Cl Cl Cl Cl

Cl Cl Cl Cl Cl Cl

ci

Nile CII ₂ O 2-Cl 4-CO ₂ Et H 179-181 393 (M ⁺ ), 180 (100%) Nile CH ₂ O 2-n-Pr 4-CO ₀ Me Ct II 185-187 387 (M ⁺ ), 180 (100%) Nile CH ₂ O 2-n-Pr 4-CO ₂ H H 106-188, 373 (M ⁺ ), 180 (100%) Nile CII ₂ O 2-n-Pr 4-CO ₀ Me it II visk.öl. substance 415 (M ⁺ ), 150 (100%) Nile C ₂ O 2-Cl 4-CO ₂ H II 150-153 365 (M ⁺ ) Nile CH ₂ O 2-n-Pr 4-OMe II 75-79 423 (M ⁺ ), 344 (100%) Nile CII ₂ O 2-n-Pr 4-OMe II 96-98 439 (M ⁺ ), 358 (100%) Nile Ci ₂ O 2-Et 4-OMe · II semi-solid substance 3 409 (M ⁺ ), 330 (100%) Nile CH ₂ O 2-n-Pr 4-CO ₂ Me II 140-142 401 (M ⁺ ), 152 (100%) Nile CII ₂ O 2-n-Pr 4-CO ₂ H II i semi-solid substance 387 (M ⁺ ), 152 (100%) O CII (OII) O 3-OMe H II visk.öl. substance 368 (M ⁺ ), 124 (100%) O CII (OH) O 2-OEt H II dito 382 (M ⁺ ), 138 (100%) O CII (OH) O 2-i-Pr II II dito 380 (M ⁺ ), 136 (100%) Nile CII (Oil) OSO ₂ 4-Me H H dito see example. ' Nile CII (OH) O 2-n-Pr II II 128-129 379 (M ⁺ ), 344 (100%) Nile CH (OII) O 2-n-Pr 4-CN II 150.5-151 404 (M ⁺ ), 327 (100%) Nile CII (OH) O 2-n-Pr 4-CO ₂ H II 204.5-205.5 423 (M ⁺ ), 388 (100%) Nile Cll (OII) O 2-n-Pr 4-CO ₂ Me H 129.5-130 437 (M ⁺ ; l ^r D mnss) Nile CII (OH) O 2-n-Pr 4-CONH ₂ II powder 423 (M ⁺ ), 200 (100%) Nile CO O 2-n-Pr 4-CN H 124-124.5 402 (M ⁺ ), 132 (100%) Nile -CH (OII) OSO ₂ 4-Me H II powder 401 (M ⁺ ), 186 (100%)

7 7 7 7 9 9 8th 8th 9 9 4 5 4 5 4 5 7 7 9 9

11

11

11 11 5 12 4 13 4 13 9 9 4 13 10 10 14 21 5 12

i-Pr Cl 13 t Cl i-Pr Cl i-Pr Cl i-Pr Cl i-Pr Cl i-Pr Cl i-Pr Cl et Cl i-Pr Cl i-Pr Cl i-Pr Cl i-Pr Cl i-Pr Cl i-Pr Cl i-Pr Cl i-Pr Cl i-Pr Cl i-Pr H

Nile

Nile

Cll (OII)

Cll (Oil)

NH -CH (OII) NH CII (OII) NU Cll (OH) Nile CO NMo CII (OMe) Nile CH (OMe) Nile -CH (OII) NH Cll (OII) Nile CO Nile Cll (OMo) Nile CII (OMe) NMC CII (OMe) NMe CII (OMe) Nile CII (OH) NMe CII (OMo) NMe CH (OMe) O Cll (OLI)

O O

S S S S O

O O O O

O O

O O

O O O

2-Cl

J.

2-n-Pr

2-n-Pr 2-n-Pr 2 -n-Pr 2 -n-Pr 2-n-Pr

2-n-Pr

2-Cl II 2-n-Pr 4-OMe 2-n-Pr 4-CO ₂ Me 2-n-Pr 4-CO ₃ Me 2-n-Pr 4-CO ₂ H 2-n-Pr 4-CO ₂ Me 2-n-Pr 4-CO ₂ H 4-C- (CH ₂ ) ₂ CO ₂ Me H 4-C-CH-CILCOMe II I 2 I O Me Ή 4-C-CII-CILCO ₀ H JI I 2 2 O Me H

2-i-Pr

4-OMe

4-CN

4-CO ₂ Me 4-CO.Me

4-CN

4-CN

II

II H H II II

II II II II

II II

H II

II

visk.öl

 substance

dito

151.5-152.5 174-174.5 155-156 102-105

visk.öl

 substance

dito

13C-142 112-114 133

visk.öl

 substance

173-174.5

visk.öl

 substance

lf) 5-LC8

visk.öl

 substance

ditto ditto ditto

371 (M), 158 (100%) 395 (M ⁺ ), 166 (100%)

see Ex.13 see Ex.14 see Ex.15

451 (M ⁺ ), 210 (100%)

see Ex. 18 see Ex. 19

357 (M ⁺ ), 186 (100%) 409 (M ⁺ ), 166 (100%)

see example 21

451 (M ⁺ ), 200 (100%)

437 (M ⁺ ), 200 (100%) 405 (M ⁺ ), 214 (100%)

451 (M ⁺ ), 214 (100%) 451 (M ⁺ ), 121 (100%)

see example p.20

480 (M ⁺ , 100%) 340 (M ⁺ ), 155 (100%)

4 13 9 14 18 15 14 21 12 18

13

15

4 13 4 13 14 21 13 19 9 9 12 18 9 9 4 13 12 20 9 '9

177 178 179 180 181 182 183 184 185

i-Pr Cl O i-Pr Cl O 1-Pr Cl O i-Pr Cl O i-Pr Cl O 1-Pr Cl O II n-Pen Nile 1-Pr br Nile et br Nile. Rt br NU kt fir Nile 12 t br Nile t-Πιι br Nile II fir Nile II fir Nile t-fiu br Nile et bi- Nile ht Cl Nile i-Pr br Nile

CII (OH)

CIl (OlI) CII (OMo)

CO CII (OH)

CII (OMe)

^CII 2

CII ₂ CH ₂ CH ₂

^CII 2 CH ₂ ·

CH ₂ CH ₂ CII ₂ CII ₂

CH ₂ CH ₂ CU _n

Nile - O O O O O O 2 O 2 O 2 O 2 O O O O O OSO OSO OSO OSO

3-OMe

4-OMe

2-n-Pr 4-CN 2-n-Pr 4-CN 2-n-Pr 4-CN 2-n-Pr 4-CO.Me 2-n-Pr 4-CO ₂ Me 2-n-Pr 4-COMe Sec-Bu 4-CO.Me Λ 2-n-Bu 4-CO ₂ Me 2-n-Bu 4-CO ₂ H 2-n-Bu 4-CONH, 2-n-Bu 4-CN 2-n-Bu 4-CO ₂ Me 2-n-Bu 4-CO ₂ Me 2-n-Bu 4-CO ₂ H 4-Me II 4-Me II 4-Me H 4-Me II

H II

H H

II II II Π

II II H II

H II

visk.öl. substance 397 (M ^T ), 165 (100%) 118.5-121 see example 11 visk.öl. substance see Ex.17 89-90 403 (M ⁺ ), 18G (100%) visk.öl. substance 438 (M ⁺ ), 189 (100%) dito 452 (M ⁺ ), 189 (100%) dito 411 (M ⁺ ) 91-93 479 (M ⁺ ), 400 (100%) 97-100 4 (55 (M ⁺ ), 380 (100%) 200-201 451 (M ⁺ ), 372 (100%) 174-177 450 (M ⁺ ), 354 (100%) 107.5-108.5 see Ex.25 90 493 (M ⁺ ), 358 (100%) 158-100 437 (M ⁺ ), 358 (100%) 109-110 423 (M ⁺ ), 326 (100%) visc. oil. · Substance 457 (M ⁺ ), 401 (100%) 115-117 429 (100%, M ⁺ ) 113-118 385 (100%, M ⁺ ) 99-100 443 (M ⁺ ), 401 (100%)

11 11 13 17 14 21 11 11

4 5 4 5 9 i 10 24 19 25 4 5 7 7 9 9 5 4 5 4 5 4 5 4

197 198 199 200 201 202 203 204 205 20G 207

I-Pr t-Bu

t-Bu t-Bu t-Bu

i-Pr t-Bu

II

lit i-Pr

nit

i-Pr

Rt

ht

et

kt

lit

kt

Cl n-Bu

n-Pr n-Bu n-Pon

Br Br

br

Br Br Br Bi-Cl Cl Cl Br Br Bi-Cl

Nile Nile

NU Nile Nile

NIi Nile

Nile

Nile Nile NH Nile Nile Nile Nile Nile Nile Nile Nile

OSO

OSO ₂

oso _r

oso _f

O O

O O O O O O O O O O

4-Me 2-n-Pr

4-Me 4-Me 4-Me

4-Me 2-C-n-Pr

T "

2-C-n-Pr

O 2 -n-Pr

2-n-Pr

2-fit

2-Et

2-n-Pen

2-n-Pen

2-n-Pen

2-n-Pen

2-n-Pen

2-n-Pen

2-n-Pen

4-CN

II H II

II 4-Br

4-Br

4-0Π 4-OII 4-CHO 4-CIIO

4-CO ₀ Me

it

4-CO ₀ II 4-CONH _n

4-CO ₂ Me

4-CO ₂ H

4-CONH "

4-CO ₂ Me

II II

II II

II II H II II II II H II II

107-111

visk.öl

 substance

dito

ditto ditto

123-125

visk.öl

 substance

122-122.5

1.11-111.5

106-107.5

115-116

100-104

224.5-225.5

157.5-158.5

93-95

211-211.5

109-170 91-92

399 (M), 357 (100%) 423 (M ⁺ ), 367 (100%)

421 (M), 365 (100%)

435 (M), 379 (100%)

449 (M), 393 (100%)

431 (M), 202 (100%) 528 (M ⁺ ), 150 (100%)

471 (M), 150 (100%)

409 (M ⁺ ), 423 (M ⁺ ), 407 (M ⁺ ),

421 (M), 435 (M ⁺ ),

421 (M ⁺ ), 420 (M ⁺ ), 479 (M ⁺ ), 465 (M ⁺ ), 464 (M ⁺ ), 463 (M ⁺ ),

330 (100%) 272 (100%) 328 (100%)

300 (100%) 400 (100%)

386 (100%) 187 (100%) 400 (100%) 386 (100%) 368 (100%) 372 (100%)

5 4

17 27 17 27 4 5 4 CJL 4 5 9 9 10 24 4 CJL 9 9 10 24 4 5

208 Il CI NII 209 H Cl NII 210 t-Bii br NH 211 U br NII 212 II br NII 213 II br NII 214 Vb u n-Pen NII 215 i-Pr br NII 2 i i-Pr br NI 217 bt br NII 218 et br NII

CII

CII

cn

CII

CII

CII

CH

CII

CII

CII

2 O 2-n-Pen 4-CO Me ύ II 157.5-158 407 (M ⁺ ), 372 (100%) 7 7 2 O 2-n-Pen 4-CO ₂ H II 161-1Π3 393 (M ⁺ ), 158 (100%) 9 9 2 O 2-n-Pen 4-COgMe II 80-80.5 507 (M ⁺ ), 372 (100%) 4 5 2 O 2-n-Pen 4-CO Me it II 153-154 451 (M ⁺ ), 372 (100%) 7 7 2 O 2-n-Pen 4-COgH II 188-190 437 (M ⁺ ), 340 (100%) 9 9 2 O 2-n-Pen 4-CONH-. H 236-237.5 418 (M ⁺ -II ₂ O), 339 (100%) 10 10 2 O 2-n-Pr 4-CN H visk.öl. substance 437 (M ⁺ ), 381 (100%) 4 5 O 2-n-Pr 4-CN II .127-129 420 (M ⁺ ), 297 (100%) 4 5 2 O 2-AEC-Du 4-CO ₀ II II 204.5-205.5 405 (M ⁺ ), 386 (100%) 9 9 2 O 2-AEC-Bu 4-COgMe II 61-63 405 (M ⁺ ), 386 (100%) 4 5 2 O 2-sec-Bu 4-CO ₂ H II 83-84 451 (M ⁺ ), 372 (100%) 9 9

10 G 20 G 4 G 1 G 100 mg 7 42 , 1 g

In the following, examples of the formula I compounds are given.

Formulation Examples 1 and 2 (tablets)

Compound No. β (Formulation Example 1).

 or compound No.127 (formulation example 2)

Lactose starch starch for the paste magnesium stearate carboxymethylcellulose-calcium

a total of

The above components are mixed in the usual manner and formulated into sugar coated tablets, each containing 50 mg of active ingredient.

Formulation Examples 5 and 4 (capsules)

Compound No. 41 (Formulation Example 3)

or compound no. 122 (formulation example 4) 10 g

Lactose 20 g

Crystalline cellulose powder 10 g

Magnesium stearate. 1 g

a total of 41g

The above components are mixed in the usual manner and filled into gelatin capsules, each containing 50 mg of active ingredient.

Formulation Examples 5 and 6 (soft capsules)

Compound No. 7 (Formulation Example 5) or Compound No. 12 (Formulation Example 6) 10g

Corn oil 35 g

a total of 45 g

The above components are mixed in a conventional manner to obtain soft capsules.

1, 0 g 20 S 79

Formulation Examples 7 and 8 (ointment)

Compound No. 93 (Formulation Example 7) or Compound No. 117 (Formulation Ex.

Olive oil white vaseline

a total of 100 g

The above components are mixed in the usual way to give 1 ounces of ointment.

Formulation Examples 9 and 10 (aerosol suspension)

(A) Connection no. 6 (Formierungsbeisp.9) or

Link No.126 (formulation item 10) 0.25 (%)

Isoprocycl myristate '0,10

Ethanol, 26.40

(B) a 60/40 $ mixture of 1,2-dichlorotetrafluoroethane and 1-chloropentafluoroethane 73.25

The above composition (A) is mixed. The resulting solution mixture is placed in a container equipped with a valve. The propellant (B) is injected via a valve nozzle to an overpressure of about 2.46 to 2.81 kg / cm. In this way one obtains an aerosol suspension.

Claims (6)

Patent claims where R is hydrogen or C 1 -C 4 -alkyl, R _{2 is} hydrogen, C _1-8 -alkl, chlorine or bromine; A is -NR, - (wherein R ^ is hydrogen or C ₁ l -alkyl) or -O-; X represents' - (CH ₂ ) - (wherein η is an integer from 1 to 4), -CH (OR ^) - (wherein R ^ represents hydrogen or C ₁ -Zf -alkyl), -CO- or a single bond stands; if X is - (CH ₂ ) - (where η is as defined above) or a single bond, B is -O-, -S-, -NH-, -OSO ₂ - or -OCO or a single bond if X is is -CH (OR * ^) - (wherein R 1 is as defined above), B is -O-, -S-, -NH- or -OSO ₂ = -, and if X is -CO-, B stands for -0-. or S-; and each of Y _1, Y p and Y ^, which may be identical or different, are hydrogen, C _1-8 alkyl, C ₂ _ ₈ -A1--alkenyl, halogen, -OR, - (where R, - Hydrogen or C _{1-Z) is} -alkyl), -CO ₂ Rg (wherein Rg is hydrogen or), -CH = CHCO ₂ R ₇ (where Ry is hydrogen / N-W or C _{1 is} -alkyl), -CN, - ≦ H, -CON (Ro) (R _Q ) "NN ^y ' H (wherein Rq and Rg, which may be the same or different, denote hydrogen or C _{1-Z 1-} alkyl), -COR ₁₀ [wherein R _{10 is} hydrogen, C _1-5 -AHqTl or -CH (CH ₂ ) _m - C0 ₂ R ₁₂ • R ₁₁ -IZH - is (where m is an integer from 0 to 3, R _{1 is} hydrogen or C ₁ - alkyl and R is hydrogen or C., / - Alkyl)], or two of the Radicals Y 1, Y ₀ and Y together form the formula with the proviso that when A is -NH- and both symbols X and B are single bonds, Y ₁ , Yp and Y- are not simultaneously hydrogen and a pharmaceutically acceptable salt thereof, which is characterized in that a compound of the formula V7orin R ₁ and R ₂ are as defined above and Z is chlorine or bromine, with a compound of the formula • HA-CH ₂ XCH ₂ OH (III) wherein A is as defined above and X is - ίH ₂ ) r "(wherein η is an integer of 1 to 4), -CH (OR *) - (where rin R is hydrogen or C 1 -C 4 alkyl means) or "is a single bond, in the presence of a dehydrohalogen nierungsmittels to form a compound of formula E ₂ OE, wherein R ₁ , R ₂ , A and X are as defined above then reacting the compound of formula IV with p-toluenesulfonyl chloride, methanesulfonyl chloride or a halogenating agent in the presence of a dehydrohalogenating agent to give a compound of formula ¹¹ I- ¹ I if ² (V) N- = 5 ^^ / ^ A-CH ₂ XCH ₂ -T in which R 1, R ₂ , A and X are as defined above and T is -OSO ₂ - / 'V) -CH ₂ -, -OSO ₂ CH ,, chlorine, Bromine or iodine, and the compound of formula V with a compound of formula VI wherein Y-, Y ₂ and Y _{3 have} the above meaning and B is -O-, -S- or -NH-, reacting; or optionally a compound of the above formula II with a compound of the formula HA-CH ₂ (CH ₂ ) _n CH-B- ^ _: Y (V 11) wherein A, Y ₁ , Y ₂ and Y _{3 are} as defined above and B is -O-, -S- or a single bond, in the presence of a dehydrohalogenating agent; or, if appropriate, Is a compound of the formula ^R lN 'Ii - (IX) wherein R-, R- and A are as defined above, with a compound of the formula where X-, is chlorine, bromine or iodine, Y-, Y _? , Yg ^unc < ^{n are} as defined above and B is -O-, -S- or -a single bond, in the presence of an organic or inorganic base; or optionally a compound of the above formula IX with a compound of the formula wherein X, and X ", which may be the same or different, stand for chlorine, bromine or iodine and η is as defined above, in the presence of a base to give a compound of the formula where R-, R ₂ , ^A > ^x ? ^{unci n W1e are} defined ^above , and then the compound of formula XII is reacted with a compound of the above formula VI in the presence of a dehydrohalogenating agent; or possibly 1s a compound of the above formula VI with a compound of the formula XV wherein Y, Yp and Y _{3 are} as defined above and Q is -CO- or -SO ₂ ", in the presence of a dehydrohalo genierungsmittels reacts, or optionally a compound of the formula wherein R ^, R ₂ , A, Y ^, Y ₂ and Y _{3 are} as defined above and B is -O- or -S- converted by reaction with an oxidizing agent in a compound of the following formula _imnn (XXXIII) 1 3 wherein R. _f Red A, Y., Ύ and Y are as defined above and B is -O- or -S-; and optionally converting the respective product into a pharmaceutically acceptable salt. 2. The method according to claim I _1, characterized in that R _{2 is} C _1-8 -AIkYl, chlorine or bromine; if X is - (CH ₂ ) - (where η is an integer from 1 to 4) or a single bond, B is -O-, -S-, -OCO- or a single bond, and X is -CH (OR 1) (wherein R, is hydrogen or C 1-4 alkyl) or -CO-, B is -O- or -S-; Y _{1 is} hydrogen; and each of the symbols Y ₂ and Y_ that ^j may be identical or different, are hydrogen, C g-alkyl, C_ g-alkenyl, halogen, -OR- (wherein R ₅ is hydrogen or C ₁ alkyl), -COpRp , (wherein R _{fi is} hydrogen or C ₁ ^ -alkyl), -CH = CHCO ₂ R ₇ (wherein R _{7 is} hydrogen or C, -alkyl), -CN, N-N Il, UH H -CON (RgR) (wherein each of the symbols R_ and R ₁ which may be the same or different, is hydrogen or C ₁ -C 4 alkyl), -COR ₀ £ wherein R _{10 is} hydrogen, C ₁ alkyl or -CH- (CHp) -CO ₂ R ₁₂ (where m is an integer of 1 up to 3, R _Λ Vy'asserstoff or C ₁ --Alkyl and 11 J · - ο R _{2 is} hydrogen or C alkyl)}. 3. The method according to claim 1, characterized in that R _{1 is} hydrogen or C alkyl; R _{2 is} C 9 alkyl, y ι ä Chlorine or bromine; A is -NRp- (wherein R, is hydrogen or methyl) or -O-; X is - ( ^CH ₂ ) _n "(where η is an integer from 1 to 3), -CH (OR ₄ ) - (wherein R, is hydrogen or C 1-4 alkyl) or -CO-; - (CH ₂ ) - (wherein η is as defined above), CH (OR) - (wherein R is as defined above) or -CO-, B is -O- or -S-, Y is hydrogen _?, and each of the symbols Y and Y, which may be the same or different, are hydrogen, C _Q alkyl, C alkenyl, halo, -OR (where R ₁ - is hydrogen or C ₄ alkyl), -CO ₂ R- (wherein R ₅ is hydrogen or C ₁ _ ₄ alkyl), <NN.
II, -CONI-U or COR _ is NN * ^1U H
[wherein R _{0 is} hydrogen, C ₁ alkyl or - ^C in which R. Is hydrogen or methyl, m is O or 1 and R "is hydrogen or methyl) 7. 4. The method according to claim 1, characterized in that R. is hydrogen or C. Alkyl; R _{0 is} C _1-6 alkyl, chloro or bromo; A is -NH- or -O-; X is -CH ₂ -, -CH (OR ₄ ) - (wherein R _{4 is} hydrogen or methyl) or -CO-; B is -O-; Y is hydrogen; and each of the symbols Y.sup.1 and Y.sup., which may be the same or different, is C.sub.1-alkyl, C is alkenyl, halo, -OR (where R is hydrogen, methyl) _ 253 8 I 7 or ethyl), -CO ₂ R g (wherein R _ß hydrogen, methyl or ethyl, -CN, Il, -CONH ₂ , -CHO, -CH = CHCO ₂ H or -COR ₇ H
(wherein R _{7 is} hydrogen or C ₁ - alkyl). 5. The method according to claim 1, characterized in that R. is hydrogen, ethyl or i-propyl; R ₉ for Chlorine or bromine; A is -NH- or -O-; X is -CH ₂ -, -CH (OR) - (wherein R _{4 is} hydrogen or methyl); B stands for -O-; Y _{1 is} hydrogen; and each "of the symbols Y ₂ and Y ₃ , which may be the same or different, is C ₁ - alkyl, allyl, -OR ₁ (wherein R _{1 is} hydrogen, methyl or ethyl), -COpR ₄ (wherein R ₄ Is hydrogen, methyl or ethyl), -CN, -CONH ₂ or -CHO. 6. The method according to claim 1, characterized in that one receives the following compounds: - 434 " -S- [3- (2-n-propyl-4-methoxycarbonylphenoxy) -propyl-2-chloro-2-ethyl-3 (2H) -pyridazinone; 4-Chloro-5- [3- (2-n-propyl-4-methoxycarbonyl phenoxy) -propyl amino!] -2-i-propyl-3 (2H) -pyridazinone; 4-chloro-5- [3- (2-n-propyl-4-carboxyphenoxy) propylamino] -2-i-propyl-3 (2H) -pyridazinone; 4-Chloro-5- [3- (2-n-propyl-4-carbamoyl-phenoxy) -propylamino] -2-i-propyl-3 (2H) -pyridazinone; 4-Chloro-5- [3- (2-n-propyl-4-phenoxy ethoxycarbony!) -Propylamino] -2-i-propyl-3 (2H) -pyridazinone; 4-n-propyl-5- [3- (2-n-propyl-4-methoxycarbonylphenoxy) propylamino] -2-ethyl-3 (2H) -pyridazinone; 4-Chloro-5- [3- (2-allyl-4-cyanophenoxy) -propylamino] -2-i-propyl-3 (2H) -pyridazinone; 4-Chloro-5- [3- (2-allyl-4-cyanophenoxy) -propylamino] -2-ethyl-3 (2H) -pyridazinone; 4-chloro-5- [3- (2-ethyl-4-formylphenoxy) -propylamino] -2-i-propyl-3 (2H) -pyridazinone; 4-chloro-5- [3- (2-ethyl-4-cyanophenoxy) -propylamino] -2-i-propyl-3 (2H) -pyridazinone; 4-chloro-5- [3- (2-ethyl-4-methoxycarbonylphenoxy) propylamino] -2-i-propy1-3 (2H) -pyridazinone; 4-chloro-5- [3- (2-n-propyl-4-methoxyphenoxy) -propylamino] -2-i-propyl-3 (2H) -pyridazinone; 4-Chloro-5- [3- (2-ethyl-4-methoxyphenoxy) -propylamino] -2-ethyl-3 (2H) -pyridazinone, 4-chloro-5- [3- (2-ethyl-4-methoxyphenoxy ) -propylamino] -2-i-propyl-3 (2H) -pyridazinone; 4-chloro-5- [3- (2-n-propyl-4-hydroxyphenoxy) -propylamino] -2-ethyl-3 (2H) -pyridazinone; 4-Chloro-5- [3- (2-n-propyl-4-hydroxyphenoxy) -propylamino] -2-i-propyl-3 (2H) -pyridazinone; 4-chloro-5- [3- (2-n-butyl-4-methoxycarbonyl phenoxy!) -Propylamino] -2-ethyl-3 (2H) -pyridazinone; 4-chloro-5- [3- (2-n-butyl-4-carboxyphenoxy) propylamino] -2-i-propyl-3 (2H) -pyridazinone; 4-chloro-5- [3- (2-n-butyl-4-carboxyphenoxy) propylamino] -2-ethyl-3 (2H) -pyridazinone; 4-chloro-5- [3- (2-n-butyl-4-carbamoylphenoxy) propylamino] -2-i-propyl-3 (2H) -pyridazinone; 4-chloro-5- [3- (2-n-butyl-4-carbamoylphenoxy) propylamino] -2-ethyl-3 (2H) -pyridazinone; 4-bromo-5- [3- (2-n-propyl-4- Ö ι cyanophenoxy) -pr opylam in o.-2-e thym 1-3 (2H) -pyridazinone; 4-bromo-5-C3- (2-allyl-4-gyanophenoxy) -propylaminq7-2-ethyl-3 (2H) -pyridazinone; 4-bromo-5-C3- (2-n-propyl-4-methoxycarbonyl phenoxy) -propylaminoj-2-ethy1-3 (2H) -pyridazinone; 4-bromo-5- ^ 3- (2-η-propy1-4-carbamoylphenoxy) -propylaminoJ-2-i-propyl-3 (2H) -pyridazinone; 4-bromo-5-C3- (2-allyl-4-cyanophenoxy) -propylaminoJ-2-i-propyl-3 (2H) -pyridazinone; 4-bromo-5- | [3- (2-η-p-ropy 1-4-methoxy-carbonyl-phenoxy) -piperopylamino-2-i-propyl-3 (2H) -pyridazinone; 4-bromo-5-R3- (2-n-propyl-4-carboxyphenoxy) -propylaminoJ-2-i-propyl-3 (2H) -pyridazinone; 4-bromo-5- * 3- (2-n-butyl-4-methoxy-carbonyl-phenoxy) -propyl-amine * -2-i-propyl-3 (2H) -pididazinone; 4-bromo-5-j ["3- (2-n-butyl-4-carboxyphenoxy) -propylamino] J-2-i-propyl-3 (2H) -pyridazinone; 4-bromo-5- / 73- (2 n-propiryl-4-methoxyphenoxy) -popropylamino-2-ethyl-3 (2H) -pyridazinone; 4-bromo-5-f 3 - (2-ethyl-4-methoxyphenoxy) -propylamino-2-ethyl-3-yl (2H) -pyridazinone; 4-chloro-5- ^ 3- (2-η-pr, oxy-1-methyl-phenoxy ) -poxy- oxy "} ~ 2- ethyl-Si 2H) -pyridazinone; 4-Chloro-5-10- "3- (2-n-propyl-4-cyanophenoxy) -propoxyJ-2-ethyl-3 (2H) -pyridazinone; 4-n-butyl-5-30- (2-n -propyl-4-methoxyearbonylphenoxy) -propylaminoj-3 (2H) -pyridazinone; 4-chloro-5-10- (2H) -ethoxy-3- (2-η-ropy 1-4-cyanophenoxy ) -propylamino3-2-i-propyl-3 (2H) -pyridazinone; or 4-chloro-5- / 2-hydroxy-3- (2-η-propyl-4-cyanophenoxy) -propylamino J-2-ipropyl-3 (2H) -pyridazinone.