WO1991012251A1 - Novel fused heterocyclic compound and antiasthmatic agent prepared therefrom - Google Patents

Abstract

A compound of general formula (I) and a pharmaceutically acceptable acid addition salt thereof, which have both bronchodilating and thromboxane A2 synthetase inhibiting actions, and are useful as antiasthmatic agent and bronchodilator, wherein (a) represents an unsaturated five- or six-membered ring with 0 or 1 nitrogen atom and 0 or 1 sulfur atom; R1 represents hydrogen, halogen, carboxyl, lower alkoxycarbonyl, nitro or lower alkoxy; R2 represents lower alkyl, cyclohexyl, (un)substituted benzyl, thienylmethyl, (un)substituted unsaturated five- or six-membered ring with 1 to 3 nitrogen atoms and 0 to 1 sulfur atom, or (un)substituted phenyl; and R3 represents lower alkyl, lower alkenyl, lower alkynyl, aralkyl, cycloalkyl, cycloalkylmethyl, acyl, acylmethyl, benzenesulfonyl, (un)substituted lower alkyl, or (b) (wherein B represents an open-chain hydrocarbon group).

Description

 Specification

 Novel condensed heterocyclic compound and anti-asthmatic agent using the same

 Technical field

The present invention has combined both bronchodilation and preparative π Nbokisa emissions A ₂ synthetase bile adverse effects, anti-asthmatic agents, relates to a bronchodilator useful novel condensed heterocyclic compound. The present invention also relates to an anti-asthmatic agent using such a condensed heterocyclic compound.

 Onganeji Eju

 Bronchial asthma can be regarded as a disease associated with an immediate asthmatic response (hereinafter abbreviated as IAR) and a delayed asthmatic response (hereinafter abbreviated as LAR) and airway hypersensitivity (J. Allergy Clin. Immunol. 54, 244-254, 1974 and Am. Rev. Respir. Dis. 112, 829-859, 1975.) Of these, IAR can be controlled by stimulants and other bronchodilators. In contrast, LAR is thought to be a response caused by airway inflammation, and it is difficult to control this response with conventional bronchodilators (Am.Kev.Respir. Dis. 136, 740-751, 1987).

On the other hand, (hereinafter referred to as TX) collected by filtration Nbokisa emissions A _z is believed to be deeply involved in B A co Application Benefits Enya platelet activating factor (PAF), etc. with LAR and airway hypersensitivity of expression I have. (See Pharmacol. Rev. 40, 49-84, 1988 and Am. Rev. Respir. Dis. 127, 686-690, 1983) In addition, the enhancement of LAR and airway hyperresponsiveness is suppressed by D-X synthase inhibitors This has been reported. '(Am. Rev. Respir. Dis. 134, 258-261, 1986; Allergy, 35 (7) _s 437-446, 1986, Thorax, 41, 955-959, 1986, J. sthma, 25 .. 117-124, 1988).

Clarification-The present inventors have conducted intensive studies to search for an excellent anti-asthmatic drug capable of suppressing IAR and LAR and enhanced airway hyperreactivity with the same drug, and as a result, suppressed the IAR and acting as a bronchodilator, a compound represented Te general formula (I) simultaneously having both action as LAR and suppress the enhanced airway hyperresponsiveness TXA ₂ synthetase inhibitors were synthesized and completed the present invention . That is, the present inventors, the general formula [1 compound represented by〗 may have subjected both bronchodilation and T XA ₂ synthase inhibitory action, anti-asthmatic agents, useful as a gas Kan支extender That was found.

 The compound of the present invention has the general formula (I)

 0

 What.

 ゝ N— R:

 ! (I)

In the formula, -Aί is an unsaturated 5- or 6-membered ring having 0 or 1 nitrogen atom and 0 or] sulfur atoms,

 R, is a hydrogen atom, a halogen, a carboxyl group, a lower alkoxyl propyl group, a nitro group or a lower alkoxy group;

R ₂ , a lower alkyl group, a cyclohexyl group, a benzyl group which may be substituted with a halogen, a phenyl group, a phenyl group, a lower alkyl group Individual Unsaturated 5- or 6-membered heterocyclic ring having an elemental atom and 0 or 1 sulfur atom, lower alkyl group as a substituent · Hagage: · lower alkoxy group · lower thioalkyl group · lower α geometry KOKI :: force; a phenyl group which may have a resin group, a carboxyl group, a trifluoromethyl group,

 Is a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an alkaryl group, a cycloalkynole group, a cycloalkyl group: 1,000), an acyl group, an acylmethyl group.酸 水 水 '....................... ..

1ϋRϋFonamide group · Lower alcone 'Nolefonyl group'

ハ, ハ, 基, フ, 力, S, チ ア, チ ア, チ ア, チ ア, チ ア, 力, S, ¾ have a O group / even lower alkyl group, or, B Me C ^mu - (CH

Integer to.

, 、， '一' ™ Γ. W ^、ゾ ' ' -、■ , へ " , ί . ' -C nitrogen atom or

,,, 'Ichi' ™ Γ. W ^, zo ''-, ■, to ", ί. '-

\,, ..

ζ, ^, _-r ,. ,, -yo,-, etc.

K, is a hydrogen atom, C α Gen force Rupokishiru group, a lower § Λ co emissions' Ca carbonyl group, is then _c androgenic as a two collected by filtration group also lower alcohol key sheet group, full source containing chlorine, bromine, and the _e-lower an alkoxy group tio © containing a capable to twenty-one is exemplified, i rk 'Rubonino, preparative key deer Lupo sulfonyl, blanking opening Boki scolding - O: nil ^ top' - carbon The carbonyl group substituted with the number 1 to G

- - 2 ί

--2 ί

 G

 N N, N

 N-one

s

Η

 Roh Ν

 \ '; —: —— \-a κ'

 --. And the like; and as the substituted phenyl group: —: methiso i_, ethyl ^, I! -F σ pinole, i-p G-pill, r! -Buki .:-7 "thousand liters, ventil, etc. C:> a carbon group having a carbon number of i ~; a fuynyl group substituted with an alkyl group; fluorine, chlorine. Methoxy group, bromine, iodine, etc .: substituted methoxy group: methoxy, poly I-oxy, -co-poxy-which is substituted by an alkoxy group having 1 to 6 carbon atoms / uni group: 丄手 手 の 、 、 、 、 、 、 、 、 、.

 A phenyl group substituted with a thioalkyl group; quinine, ethoxy-nocarbonyl, which has a carbon number of ~ a; Examples of such a compound include: ¾; -a phenyl group having a noroxy group; and trifluor, '+ :; a phenyl group.

R ₃ , lower alkyl group, lower alkenyl group, lower alkenyl group: group .. alkaryl group, cycloalkyl group,;> quartyl group masyl group.ン, ゼ ¾ 水 ¾ 水 水 水 置 置 水 水 水 水 水 水 水 水 水 水 水 水 水 水 置 水 水. X-forceRubonyl group A lower alkyl group or BN which may have a pyrimidinylthio group; a carbamoyl group, a phthalimid group, a tetrazolyl group, a thiophenoxy-thiazolinylthio group, and a pyrimidinylthio group. As the lower alkyl group, and the like as exemplified in the paragraph of R _2. Examples of the lower alkenyl group include alkenyl groups having 2 to 6 carbon atoms, such as butyl, aryl, 1-methylaryl, butyr, and pentyl. Examples of the lower alkynyl group include alkynyl groups having 2 to 6 carbon atoms such as ethur and provalgyl. Examples of the aralkyl group include substituted or unsubstituted benzyl. Examples of the cycloalkyl group include a cycloalkyl group having 3 to "/ carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples of such a group include a methyl group substituted with a cycloalkyl group having 4 to 8 carbon atoms, such as cyclopentylmethyl, cyclohexylmethyl, and cyclohexylmethyl. And alkenyl groups such as acetyl, etc. Examples of the acetyl group include methyl groups substituted with these acetyl groups, and B represents one (CH ₂ ) _n —,-(CHz) p-CH = CH- (CH ₂ ) <,-

— (CH ₂ ) _P — C C — (CH ₂ ) q—,--or

CH ₃

 I

-CHz—CH ₂ —CH ₂ —CH— where n represents an integer from 2 to 8, and P and q represent an integer from 0 to 2. In addition, Japanese Patent Publication No. 54-203 / 19 and Japanese Patent Publication No. 54-26i

66 No. 6 describes that 4—pi '' J dinofucrazinone compounds belonging to the general formula Π) are useful as photosensitive materials. There is no description of the usefulness of the compound as an anti-asthmatic agent.

The compound represented by formula (I), Ru can and two-obtained Ri by the method shown below, for example _s

 (Method A)

 ϋ

 No

Then ^ Η —

 One R

R,

 (n) (I :)

(Wherein, A., R, and K are the same as above. R:;.

 Lower alkyl group, lower alkenyl group, lower alkynyl

 Group, sigma group. ÷:: — ―. '.

マ メ ン ン ン ン ン 置換 置換 ゼ 置換 置換 置換 ゼ ゼ 置換 置換 置換 置換 置換 置換 置換 置換 置換 置換 ゼ ス 置換 置換 置換. <· A lower alkyl group substituted with a fluoromethyl group. That is, by reacting a compound represented by the formula (Π) as a starting material with a compound represented by the following formula in an inert solvent in the presence of a base: The compound of the present invention can be obtained using a base such as a hydrogenated alcohol, a carbonated alkaline carbonate, or a hydroxylated alcohol. Is it preferable? Sodium hydride, hydrogenation power

5 o ゥ, carbonic acid:.! Examples of the inactive solvent include, but are not limited to, I-, which is not particularly limited as long as it is inert in the reaction, dimethylformamide, titra, and the like. Hidden mouth:, „.

 R

 Oxane 5% is preferably used. Reaction temperature

The compound represented by the formula (II) used as a starting material, which proceeds at the reflux temperature after 10 minutes and increases the reaction time by 0.5 to 24 hours. 0-Masylbenzoic acid or its esuccinate by a conventional method Le body and heat Denis: - emission arsenide ^1: "- - DOO and the lower a Le copolymers, such as, for example, two to be changed heated ethanolate Lumpur with: Ru can child stranded possible to get Ri is:

0 (B method J

 0 '0

 'Pa, NH Ma Pawa,:-, one B-?ノ-. Ν '...'

(Π

, N―Γβ

(Wherein,, F-, Κ, and R ₂ represents the same as the - Z and optionally I also differ a Z one force, "r, down the shown _ R _5, Ma Mi NoSen, Imita's group;; -id group. Chitrazol group, group: Ninoki ¾ :, group ... '·:.! Nirchi A pyrimidinylthio group. ) That is, a compound represented by the general formula (Π ′) is used as a starting material, and is reacted with a compound represented by the formula Ζ—Β-Z ′ in a base and an inert solvent. - obtaining one Ru compound represented then, a this is reacted with the formula R _S represented by H compounds of formula (IV) represented Te is of ^ in an inert solvent:.. two from the formula (\ ' The compound of the present invention can be obtained as follows: Examples of the base used herein include a carbonic acid power 'J, and a hydroxide hydroxide power ^: and preferably, a carbonic acid power C, carbonic acid +; · 'and so on: as an _e -inert solvent, it can be used at the time of anti-it: ^ ^ umma-.preferred: σ te, 2 ru-anti-jl 24 hours

 (VI ί (1)

(Wherein, A, K ′, and R ₂ represent the same øb as described above, and R ₆ represents a low-alkyl group substituted with an unsubstituted thioloxy group or an alkoxynil group. _e R ₇ represents a hydroxyl group or a substituted lower alkyl group substituted with a carboxynor II.) In other words, the formula: The compound of the present invention represented by the formula (VI) can be obtained by hydrolysis of the compound to be obtained with a base. Examples of the base used herein include alkali hydroxide and alkali carbonate, and preferably, sodium hydroxide, potassium hydroxide and the like.

 / 2

The reaction time proceeds from 0 to the reflux temperature, preferably from 20 to 60. The anti-time is from 0.5 to 12 hours, preferably from 0.5 to 3 hours.

 (D method)

1) Halogenating agent

2) R _B NH ₂

(VI)

 0.

(Wherein A, i ?, and R ₂ are the same as defined above. 2. R ₇ is

-Represents a substituted lower alkyl group substituted with N, -boxyl; R ₈ represents a lower alkyl group; and R ₉ represents a lower mal group substituted with a carbamoyl group. '; That is, a compound represented by the formula (V;) obtained by the method C is led to an acid halide with a halogenating agent, and then reacted with a compound represented by the formula ReN! K to obtain a compound represented by the formula: The compound of the present invention represented by (1) can be obtained as the oxidizing agent used herein is phosphorus pentachloride, phosphorous trichloride, thionyl chloride or phosphorous oxychloride. The reaction temperature is from 10'C to the reflux temperature, preferably from 15 to room temperature, and the reaction time is from 0 to 24 hours-The preferred is from 3 to 8 hours And

This amidation reaction is regarded as the above-mentioned acid halide method. The mixed acid anhydride method, active ester method or active amide method is also possible. '

 (Method E)

 C K) (X)

 Two

 o

(In the formula, A, β, and _Rz are the same as those in the preceding H. <·, r. Is a substituted lower alkyl group substituted with a substituted amino group, and R, is a lower alkyl group.) R or ₂ represents a substituted lower alkyl group substituted by a sulfonate group, that is, a compound represented by the formula (K) as a starting material, and the presence of a base. standing under an inert solvent, wherein, by the this reacting a compound represented by S0 ₂ C1, used. here which can on this to obtain the compound of the present invention represented by the formula (X! bases And the same solvent used for the inert solvent A. The reaction proceeds from the reaction temperature to the reflux temperature, preferably to 050 ° C.-The reaction time: 0.5 to 24 hours, preferably The duration is 15 hours

 (F method)

 C1 0

A 1) R _{I 3} HA

 No,

 R 'C] R' 1 3

(XI) (X Π) (Wherein, A and B ₁₃ represent the same as described above)

,, ^ Ν

-Indicates Ν or Ν, ----. ) That is, 1,4-dichloroethylene b furnace lid Rajin (XI) in the presence of a base thereto as a starting material, the reaction is zero with a compound of an inert solvent represented by the formula R ₁₃ il, and have the following, Al By hydrolyzing under force, the compound of the present invention represented by the formula (X に よ) can be obtained. The base and the inert solvent are the same as those mentioned in Method A. It is possible to use the hydrolysis bases listed in Method c. The reaction temperature should be between 10'C and the reflux temperature. The reaction time is 0.5 to 24 hours. Preferred: 1 to 5 hours.

 ί G method)

A Ϊ) Π]

2) KH _E ii:-Η _Σ ( ^;

 0

 (XI) LXIV-;

(Wherein A and ^ represent the same as described above.

 , S, — N

 o. 'Show one

 ,,;-— K '— N

X 'is emission represented by ter I- Buchirujime chill Shi Li Le ^group; and Le residue. *; Υ represents a halogen atom or a hydrogen atom-'

That is, the acid anhydride (（Χ) is used as a starting material and the base is preserved. -1

 1ϋ

. Under the formula in an inert solvent Upsilon - compound Butsujo represented by R ₁₄ ¾It r: ¾ arsenide de run-down human Dollar preparative reaction is zero, 'The R "i

 r "e,, · *»

 In the case of (2), the compound is further hydrolyzed with acid. In order to obtain the compound of the present invention represented by general formula (IV), the base is butyllithium. Organometallic represented by ^.

: 'Gunia a', etc., represented by methylmagnifuff's mouth, is used as an inert solvent.-. Uno-

• Ί;, Oxa: ', II XII.

 Preferable: Anhydrous te te 7} · ヒ 反 応 反 応 反 応 反 応 反 応 Reaction temperature — 110! 0.

[Tooth 'reaction time from 0.5 to 12 pm ^ Te to 3 hours and ^ good may' .. and cutting edge Roh atom on ϋ ^ atom shown, an iodine atom and the like _£ NOTE: '

 Ring closure α == 'rfr · .. · ps = · ■ ·;-' r 'Ma: · ·-' Line in solvent ::. Inn

;: 6 hours to anti-time preferred; W .. ^: --". Ίί."-"Τ ί £: Γ, .. Performed by mineral acid typified by hydrochloric acid". J _.:

~ 30'L, reaction time I ~ 5 hours is preferred

20 ^ H method; '. ^: R,-,

 1) "::

C00H 2 ΗζΝΗ: H ₂ 0

(X \ 1 ο

 14

(In the formula, Z represents a halogen atom, and R '! ₅ is an alcohol earth group

 Indicates the atom. ) That is, a compound represented by the formula (X Y) is used as a starting material, and the compound is added in an inert solvent in the presence of a base.

 C

 After reacting the conductor (xvn, the hydrazine hydrate and the anti-it ′ are reacted with each other to obtain the taradidinone derivative (Xπ) which is the compound of the present invention. Reaction temperature, reaction time with base and inert solvent used here, κC, ring closure reaction with hydrazine

 It is preferable to carry out the reaction under the same conditions as in the G method. . R 1 L

 ''

(Χ \ Ι; ·-,

(X K (X X

Γ.

(Formula. H,, ano group or L; nixica) 1-^-diyl group: 2 .. ', π-one atom

S

S— ', a substituted chiofuni (reacted with Χϋi as a starting material, in the presence of a base, with a substituted pyridine:' 〖Xκ), in the presence of a base. To obtain the compound of the present invention, which is represented by XX; hand Examples of the base to be used include organometallics represented by butyrylchim, methane and Grignard reagent represented by ethylmagnesium bromide. Examples of the inert solvent include ether, tetrahydrofuran, dioxane, n ^ xane, benzene, etc., and preferably, anhydrous ether and anhydrous tetrahydrofuran are used. You. The reaction temperature is between 110 and 120, preferably between 80 and -40. The reaction time is 0.5 to: 12 hours, preferably 0.5 to 3 hours. Ring closure reaction by heat Dora Jin-hee Dollar metropolitan desirable to carry out ring closure reaction and伺one condition in (G method) correct _e

 (J method)

(X X I) (X X I)

(Wherein, A and R 1 are the same as defined above. R and _{7 each} represent an unsaturated C ′ 5- or 6-membered heterocyclic ring having i to 3 nitrogen atoms and 0 or 1 sulfur atom. R _{1 B} represents a lower alkyl group. That is, the compound represented by the general formula (XXI) is reacted with a substituted hydrazine (Χ Χ 中 で) in an alcohol solvent to obtain a compound represented by the general formula (XXI): xx m) The reaction temperature at which the compound of the present invention can be obtained is preferably a reflux temperature, and the reaction time is preferably 1 to 6 hours.

When the compound represented by the general formula (I) of the present invention is used as an anti-asthmatic drug, the compound is in the range of 0.1 mg / kg to 100 mg / k body weight / day, preferably 0.1 to 30 mg / kg body weight. Especially effective when administered in the range of days 5 O

 16

 The results were obtained, and the administration method can be oral, intravenous, intramuscular or subcutaneous rectus, and also as an aerosol.

 Hereinafter, specific synthesis examples of the compound represented by the formula (I) will be shown as examples, but the scope of the present invention is not limited to these compounds.

 Example 1

 4 — phenyl 2 — to 2 — ί 1 — 1 H—imidazolyl.

0 4 1-Funyl mono 1- (2H) phthalazinone '2.0 g-, 1, -di-romuetan 5.5 g and potassium carbonate 7.5 g are suspended in dry dimethyl phono L muamide 60. After turbidity, stir at 65 degrees for 2 hours. Then, 4.3 g of imidazole is added to the reaction mixture, and the mixture is further stirred at 70'C for 5 hours. C After cooling, the reaction mixture is acidified with 2N hydrochloric acid, and ethyl acetate 200 is added and stirred. Separate the aqueous layer, make it water-cooled with 5% water hydroxide + water solution under cooling, and extract with H 2 times with a 300 ffif. After drying over sulfate magnetic Siu, distilling solvent under reduced Ryo ^ - The residue was re-force Geruka la Solid Loma preparative graph I _t click co subjected to an Holm and METHANOL Ichiru the mixture (20: 1, v / v) and eluted to give the desired product (0.5 g) as colorless crystals. -mp 1 6 4 ~: I 6 5

Element analysis value (C ₁₉ H ₁₆ 0)

 Total value (%) C72.13 H5.10 N17.71

 Measured value (%) C71.67 H5.29 N 17.61

I (KBr) cm "¹; _c = 1660 NMR (CDC1 ₃₎ (5 values; 4.4~4.7 (4H, m), 6.8~ 7.9 (11 H, m ').

 8.3 to 8.6 (lH, m)

Example 2

 4 1-Phenyl-1 2-2- (1-1H-imidazolyl) Nichil: Production of 1-1 (2H) phthalazinone (Method B)

4—Phenyl-1- (2H) phthaladinone 3.2 g and carbonated lithium 2.4 g are suspended in dry dimethylformamide and heated to 40 ° C., and then 2—bromethylimidazole 3.0 g of dimethylformamide solution 20 was added, and the mixture was stirred at 70 g for 4 hours. After the anti-ID, pour the mixture into cold dilute hydrochloric acid and ethyl acetate mixture and separate the aqueous layer. Then, make the aqueous layer alkaline with 5% aqueous sodium hydroxide solution, and then close the mouth. Extract with Hor. After drying over magnesium sulfate, the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography in the same manner as in Method A of Example 1 to obtain the desired product (1.5 g> as colorless crystals. , those obtained by method a and罔one shows the physical properties _f

Example 3

 4 — (4 ロ η-phenyl) 1 2 — 2-(1 1 1H — imidazolyl) ethyl 1 1 (2Η) Manufacture of phthalazinone

 The same procedure as in Example 1 was carried out using 41- (4-cyclophenyl) -1]-(2Η) phthalazinone as a raw material to obtain the desired product.

 mp 1 9 9 ~ 2 0 0

Element analysis value (C ₁₉ H ₁₅ C1N ₄₀ )

Total value (%) C 65.05 H4.31 N15.97

δ 5

 IB

 Measured value (%) C 64.83 H4.2G N 15.80

I (KBr) or ¹ ; i _c =. 1660

NR (CDC1 ₃ '5 value; 4.4 to 4.7 (4H, m), 6.8 to 9.9 (10H, m)

 8.3 ~ 8.6 (1H, π

 Example 4

 4 1 [4 -methylphenyl) 1 2-丄 2-1-1 H-diazolyl) ethyl] 1 1-(2 H) Manufacture of phthalazinon 4-(4 -methylphenyl) Using 1- (2H) phthalazinone, the same operation as in Example 1 was carried out.

 mp 1 7 7 to 1 7 8

Elemental analysis (C _2, H ₁₈ N ₄₀ )

 Calculated value (%) C 72.70 Ηδ.49 K16.96

 Actual value (%) C 72.43 H5.53 N16.78

IR (KBr) cnr ¹ ; t _{c =} . 1660

M (CDC1 ₃₎ value; 2.41 (3H, s), 4.4~ 4.7 (4H, m), 6.8~7.9

 (lOH'm ::, 8.3 ~ 8.6 (lH, m)

 Example 5

 4 — (4 1-Ethylphenyl) 1 2 — [2-(1 — 1 H — 0 dazolyl) ethyl] 1 1 — (2 H) Manufacture of phthalazinone

 The same procedure as in Example 1 was carried out using 4- (4-ethylphenyl) -111 (2H) phthalazinone as a raw material to obtain the desired product.

 mp 1 3 3 〜 1 3 5

Element analysis value (C ₂₁ H _ZO N ₄₀ ) Calculated value (%) C 73.23 Η δ.δδ Ν 16.27

Actual value (%) C73.18 Η 5.83 16.26

IR (KBr) cin-; _C = _Q 1640

NR (CDC1 ₃ ) <rect; 1.28 (3Η, t, J = 7Hz), 2.72 (2Η, q, J = 7Hz) _:

 4.4 to 4.7 (4H, m), 6.8 to 7.8 (1 OH, m): 8.2 to 8.5 (lH, m)

Example 6

 4-(4-Isopro Birufenyl)-2-L 2-(1-1 H-imidazolyl) Manufacture of 1 1 1 (2H,) phthalazinone The same operation as in Example 1 using 4 1 (4—isopropylphenyl) 1] — (2H) phthalazinone as a raw material The objective was obtained by performing

 mp 1 3 2 ~ 1 3 4

Element analysis value (C ₂₂ H ₂₂ N ₄₀ )

Total value (%) C73.72 H 6.19 N 15.63

Actual value (%) C73.46 H 6.28 N 15.60

IR (KBr) cm "¹; _{c = c} 1640

NMR (CDC1 ₃₎ (M straight 1.30 (6H, d, J = 7Hz), 2.98 (1H, septet, J = 7H z), 4.3~4.7 (4H, m), 6.8~ Ma, 9 (1 OH, m ), 8.3 ~ 8.6 (lH, m)

Example 7

 4--(4-methoxyphenyl)-1 2-J 2-1 1 H-imidazolyl) ethyl] 1 1-(2H) Manufacture of phthalazinone

The same procedure as in Example 1 was carried out using 4- (4-methoxyethoxy) -1-1 (2H) phthalazinone as the starting material, and the desired product was obtained. I got

 mp l 5 0 -1 5 1 'C

Elemental analysis value (C ₂ .H _{1 B} N ₄ 0 ₂ )

Calculated value (%) C 69.35 H5.24 16.18

Measured value (%) C 69.30 H5.40 16.01

IR (KBr) cm- ¹ ; 1660

NMR (CDC1 ₃₎ (M straight; 3.81 (3H: s), 4.4~4.7 (4H, m): 6.8 ·

(10H, m) _: 8.3 ~ 8.6 (lH, m)

Example 8

 Manufacture of 4- (4-hydroxyphenyl) ethyl (1-1H-midazolyl) ethyl: 1] -1 (2H) phthalazinone

 The same procedure as in Example 1 was carried out using 4-((4-ethoxyethoxyunyl) -11- (2H) phthalazinone as a raw material to obtain the desired product.

m _P 1 3 7 to 1 3 9

Element analysis value (C ₂₁ H _{Z 0} N)

Total value (%) C 69.98 H 5.59 K15.55

Measured value (%) C 69.60 H5.62 15.28

IR (KBr) cm- ¹ ; ι- '. 1650

Image (CDC1 _{3) value; 1.44. (3H: t:} J = 7Hz): Οδ (2H, q, J = 7Hz),

 4.3 to 4.7 (4 mm, m), 6.8 to 7.8 (10 mm, m):

 8.2 to 8.5 (lH, m)

Example 9

4 I- (3,4 dimethyoxyphenyl) I 2 — (_2 1-1 H-imidizoryl) _ ethyl: _ I 1 — (_2 HJ Production of flazinone 2!

 o 21

 The same operation as in Example 1 was carried out using 4- (3,4-dimethyoxyfuran) 1 1- (2H:) phthalazinone as the raw material. I got .

 mp 1 3 4 〜 1 3 5

Elemental Ki value (CH, HZ ON40 ₃ )

 Calculated value (%) C 67.01 H 5.36 K 14.89

 Actual value (%) C 68.69 H 5.23 14.65

_{^{1R (KBr * ra-;! C}} = c 1660

 .NM (CDC1: · Value: 2.90 (to 6H.s 4.4 7 (4H ... h.

 (9Η, πί)-S.? ~ 8. [; (lH, ro

 Ki

 Example 10

 No

 4 one (3 one full

-1 H-G. Child production (2 H '!

 1: For raw material, use 4 — (3 几 几 4 4 ー>>>>>>>>>> · · · · 2 2 2 2 2.) I. Same as in Example 1. Get the desired product.

 mp 1 2 8 〜 1 3 0

 Elemental Ki value (C 20 Γί I 7 F Ν 402)

 Calculated value (%) C 65.93 Η 4.70 Ν 15.38

 Measured value (% 'j C65.81 K 4.85 X i5.lL'

 IR (KBr: 'c-' '; i. 1650

N.1R (CDC1 ₂ 3 values;. 3.91 - 4 · 3-4 Ryo UH, n;

 (9Η, m: 8. to 8.6 (1H: m :)

25 Example 1] Preparation of 4- (4-Methylthiophenyl) -1-2- (2- (1-1H-imidazolyl) ethyl) -11- (2H) phthalazinone 24.0 g of phthalic anhydride and 24.6 g of aluminum chloride anhydrous Dissolve in dichlormethan 300 and add dropwise dichloromethan 50 containing 20.1 g of thioanisole under cooling with ice and water. After stirring at room temperature for 5 hours, the solvent is distilled off under reduced pressure. A mixture of ethyl acetate 500 and dilute hydrochloric acid 300 is gradually added to the residue under cooling, and the mixture is stirred to separate an organic layer. After drying over magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is triturated with η-hexane. The insolubles are recrystallized with ether-n-hexane to give 2 — (4-Methylthiobenzoyl) benzoic acid (31.0 g) was obtained.

 m 1 5 2 to 1 5 4

In addition, 35.0 g of the obtained 2-((4-methylthiobenzoyl) benzoic acid and 16.1 g of 80% hydrazine hydrate were dissolved in ethanol 400, and the mixture was stirred under reflux for 4 hours. I do. After standing overnight, the precipitated collected by filtration to 4 one (4-menu Chiruchiofu enyl) crystal one 1 one obtain (2 H) off piperazino down 33.0 g _c

 mp 2 5 0-2 5 1

 The same procedure as in Example 1 was carried out using 4- (4-methylthioethyl) 1) — (2H; phthalazinone) as a raw material to obtain the desired product.

 mp 168 to 169. C

Elemental folding value _{(C 2 .H 1 8 N 40S} )

Calculated value (%) C 66.28 H5.01 N15.46

Actual value (%) C66.19 H5.04 15.33 twenty three

IR (KBr) cm _c = o 1650

MR (CDC1 ₃ ) δ value; 2.51 (3H, s), 4.4 4.4H, m.) 6.b '

 (10Η, m) 8.3 to 8.6 (1H, m)

 Example 1 2

 4 1 (4-Fluorophenyl) 1-2 (1-1H Midazoline) ethyl) 1 1-(2H) Production of phthalazinone

 The desired product was obtained by performing the same operation as in Example 1 using 4- (4-fluorophenyl) -1-1 (2H) phthalazinone as a raw material.

24

twenty four

 Calculated value (%) C 62.50 H 3.93 14.58

 Actual value (%) C 62.35 H 3.87 N 14.38

 IR (KBr) cm-; c = 0 1650

M (CDC1 ₃₎ δ value; 4.3~4.7 (4H, m), 6.8~7.9 (10H, m)

 8.3 to 8,6 (lH, m)

 Example 14

 4-(3-Trifluoromethyl unit)] _ 1-2-2-(1H-imidari "lil ') ethyl:: Production of 1-1 (2H) phthalazine

 10 Ingredients 4 — (3 — trifluorene methyl phenyl) 1) — (2

 H) The desired product was obtained by performing the same operation as in Example 1 using phthalazinone.

 mp 1 2 6 to 1 2 8

Elemental folding value _{(C 2 oH t 5 F 3} N40)

元素分析値 （ C ₁₉H _{1 S}C 1 N ₄0〉

Elemental analysis value (C ₁₉ H _{1 S} C 1 N ₄ 0>

Calculated value (%) C 65.05 Η 4.31 Ν 15.9 実 Actual measured value (% ') C 65.05 Η 4.4.5 5 N 16.0 丁

1 R (KB r) cm- ¹ ; c = ο 1 650

NMR (CDC 1 ₃₎ value;... 4 4~ 4 6 (4 H, m), 6 .8~ 7 S (1 0 H, m), 8.2~ 8.5

 (1 H, m) '

Example 16

 6 — Black /! ■ 1 4 1 (3 — F / Rolo 4 — Methoxyfeni) 1

2 — [2 — (1 —. 1 H—Im'ta 'V-R yl)] 1 1, 2 H Manufacture of phthalazinone

 The same operation as in Example 1 was carried out using 6-chloro-4 (3-fluoro-4-methoxykiphenyl) 1-1-1 (2H) phthalazinone as the raw material. I got something.

 m p 1 4 7 to 150 ° C

^{IR (KB r) cm -:} ; Les c = have 1 6 6 0

NMR (CDC 1 ₃₎ value;. 3 .9 0 (3 H , s) A .3 - 4 .7 (4 H, m), (S .8~ 7 .8 (8 H, m),

 8.2 to 8.5 (l H, m)

Example 1

 4 -— <41-chlorobenzil) 1-2— [2— (1—1H—imidazolyl) ethyl] _1— (2H) Manufacture of phthalazinone

The same procedure as in Example 1 was performed using 41- (4-chlorobenzyl) -11- (2H) phthalazinone as a raw material to obtain the desired product.

H mp 150 to 15 1 ^C C

 H

 Elemental analysis value (C = H,, C 1, 0)

 Les

Calculated value () C65.84H4.70N15.36 Actual value (%) 1 C65.76H4.S3N15.4.41

 I R (K B r) c rn ''; = o 1 6 6 0

NMR (CDC13) value; 4.13 (2H, s), 4.4 to

 H

 4.6 (4H, m), 6.8 to 7.8 (10H, m), S.2 to 8.5 (1H, m)

Example 18

4 1 (2 — Che 2 IV) — 2 — “2 () 1 1 H — Imige, L / L ') 4 — (2 — Chenyl) 1 1 — (2 H) Non-made

The intended product was obtained by performing the same operation as in Example 1 using the above method.

 m p 1 3 2 1 3 4 ° C

 Elemental analysis value (C, 7H, N40S)

 ! Calculated value (%) C 6 3.3 4 H 4.3 S N 1 .3 8 Actual measurement value (%, C 65.2 1 H 4.5 -4 N 16 .S

 I R (K B r) cm − '; レ-c = o 1 6 6 0

NMR (CDC13) S value: 4.3 to 4.7 (4H, rn),

 6.8 to 7.2 (H, m), S.3 to 8.6 (1H, m) Example 19

4-2--(3-Metizolenyl) 1 1-imidazolyl) ethyl 1H) Phthalane Manufacture 4-11 (3-tilchenyl)]-1-1 (2H) phthalazinone By performing the same operation as in Example 1, The desired product was obtained.

 m p 139-140. C

 Elemental analysis value (C Η τΗ, ^ Ν, Ο S)

Calculated value (%) C64.27H4.77.966.5 Actual measurement value (%) C64.42H4.992N16.73

IR (KB r) cm- ¹ ; c = o 1 660

 M R (CDC 13) value; 2.08 (3H, s), 4.4

 4.Cho (4H, m), ό0.8-7.9 (8H, m),

 8.2 to 8.5 (1H, rn; '

Example 20

 4 — [2-(5 — Met / Le + nil ”)“ one — “2 — (1-1 H

-Imidazolyl) ethyl] 1-(2H) Phthalazinone Manufactured using 4-[2-(5-Methylcenyl)]-1-(2H) phthalazinone as raw material The desired product was obtained by performing the same operation as in Example 1.

 m 1 3 [卜] 3 1 T;

 Elemental analysis value (Η 0 S)

Calculated value () C ό 4.27 Η 4.79 Ν 1 υ. Ό

Actual measured value (%) C ό 4.17 Η 4. S4 Ν 1 G. 56

IR (KB r) cm -; ! C = o 1 6 4 0

NMP, (CDC1: :) value; 2.53 (3H, s) '4.4-4.7 (4H, m), 6.7 to 8.2 (8H, m),

 S.2-8.5 (1H, m)

Example 2 1

4-[2 -_ (? Etilchenil) One 2-(1-1 Η I-I-D-A-S-R-I-R-I-I-I-I-I- (2H) As a raw material for producing 4-radio 4-1-1 [2- (5-ethyl-chirenyl)] --1 I- \ 2H, F-Razino The same operation as in Example 1 was carried out using a gas to obtain a G target.

 m p 1 1 0 to 1 1 2

Elemental analysis value (C ₉ H _{1 S} N ₄₀ S)

Calculated value (? Ό) C 6 5.1 2 H 5.1 S N 15.

Measured value (?. ') C 64 .7? H 5.2 3 15. S (-1 Fi (KBr c rii "": c c = 2 (.' 1 ': ■> 60)

 8

1.3 (3H, t, J- "Z. 2.S) 0 (2H, q, J = 7Hz), 4.4-4.

 (4 H, m}, 6.7-8.2 (S H, m), S .3

 8.6 (1 H, m)

Example 22

 U

 4-[2--(^-Chlor Handicraft Nil)-1 2-[2-■■: 1 H

 IV] Using 4 1 [2— (one crochet)]-'12 H-phthalazinone as the raw material for production. Perform the same operation as in Example 1, Obtained.

 m p 1 3 8-: L 4 0

Elemental analysis _{(C i 7 H) 3 C} 1 N, O s)

Calculated value (%) C 5 7.2 2 H 3.6 7 15.7> Actual value C 5 6.9 7 H 3.6 2 15.5 t

 I R (KBr) cm; c = o 1 64 0

MR (G Γ) CI 3) value; 4.4 to 4. (4 H, m), 6.8 to 8.1 (8H, m), 8.2 to 8.5 (1 layer, m)

 6—Chlor 1 4 1 (2—Chenyl), — 2— [2— (（—1H-dimidazolyl) ethyl 1— (2H) Manufacture of phthalazinone 6—Chlor 1 4 1 (2— The desired product was obtained by performing the same operation as in Example 1 using (Chenyl) -111 (2H) phthalazinone.

 m p 1 8 5-1 8 7 ° C

 Elemental analysis (C-H, 3C1N, 0S)

^{IR (KB r) cm -:} ; Les c = 2

 9 o 1 6 5 0

NMR (CDC13) value; 4.4-4, 6 (4 6, m),

 8 to 8.5 (9H, m)

Example 2 4

 Production of 4- (3-pyridyl) -1 1 _ (2H) phthalazinone

2 Anhydrous tetrahydrofuran solution containing 25.0 s of 1-bromotoluene 300 m 1 in a nitrogen atmosphere under a nitrogen atmosphere at 180 ° C, 15 ° C, butane hexane solution 100 rn! The mixture was stirred for 1 hour at the same temperature, and 100 ml of an anhydrous trihydrofuran solution containing 14.6 g of 3-cyanoviridine was added dropwise. After stirring for 1 hour, the temperature was gradually raised to room temperature. The mixture was further stirred at room temperature for 1 hour. 200 ml of 4N monohydrochloric acid was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes, and then tetrahydrofuran was distilled off under reduced pressure. Make it alkaline with 5% aqueous solution of sodium hydroxide, extract with chloroform, dry with magnesium sulfate, evaporate the solvent under reduced pressure, and subject the residue to silica gel column chromatography. Elute with chloroform and elute 2-Nicotinol Toluene 8.5s. Next, 8.0 g of 2-nicotinyl toluene was suspended in 300 ml of water, and potassium permanganate IS.4s was added. The mixture was stirred under reflux for 1.5 hours. Wash with hot water and wash the manganese dioxide twice with 100 ml of hot water. 4 Adjust the pH of the solution to 3-4 with monohydrochloric acid, and distill off water under reduced pressure until the volume of the solution becomes about 150 ml. Extract with a mixture of black-mouthed form and tetrahydrofuran, dry over magnesium sulfate, and leave the solvent under reduced pressure. The residue is triturated with n-hexane to give 3.5 g of 2-nicotinoylbenzoic acid.

Further, 80% hydrazine hydrate 1.7 _S is added to 7 O ml of an ethanol suspension containing 3.9 g of 2-nicotinoylbenzoic acid, and the mixture is stirred under reflux for 4 hours. After standing overnight, the precipitated crystals are collected to obtain 2.7 g of the desired product.

 Melting point: 2 6 8-9

 I R (K B r) cm 1

D c = o 1 b 8 0 cm " ¹

NMR (DMS 0-d ₆ ) o value; 73 to 9.0 (SH, m

 1 2.9.8 (1H, s)

Example 2 5

4 —— (3-Pyridyl) 1-1-1 _ (2H) phthalazino Manufacture Anhydrous ether 150 ml was cooled to 178 ° C under nitrogen atmosphere, and 15% butyllithium hexane solution 10 Add 0 m1. At the same temperature, 150 ml of anhydrous ether containing 23.0 g of 3-bromopyridine was added dropwise, and the mixture was stirred for 30 minutes. Then, add 150 ml of tetrahydrofuran anhydride containing 21.5 g of phthalic anhydride at a time with -78. Stir at the same temperature for 1 hour, then gradually return to room temperature for another 1 hour. Continue stirring for a while.

 30 O ml of cold water is added to the reaction solution, and the mixture is stirred at room temperature for 5 minutes, and the aqueous layer is separated. After adjusting the pH to 3 to 4 with 6N-hydrochloric acid, add saturated saline, and extract with 500 ml of tetrahydrofuran in three portions. After drying over magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is subjected to silica gel column chromatography. Develop and elute with a mixed solution of chloroform and methanol / le (30: 1, VV) to obtain 20.5 g of 21-nicotinoy / le-benzoic acid. Then, the same operation as in Example 24, that is, 80% hydrazine hydrate was added to 250 ml of an ethanol suspension containing 20.5 s of 2-nicotinylbenzoic acid was carried out.

Add 9.6 _S and stir under reflux for 4 hours. After leaving overnight, the precipitated crystals are collected to obtain 14.8 s of the desired product. The melting point, IR. Value and NMR value were the same as those in Example 24.

Example 26

 4 1 (3 — pyridyl) 1 2 — “2 — (1 — 1 H — imida ,, '/ L:) //]]-1-(2 H) Manufacture of phthalazinone

 The desired product was obtained by performing the same operation as in Example 1 using 4- (3-pyridyl) -111 (2H) phthalazine as a raw material. 9. C

 Elemental analysis 值

Calculated value (% ') C6S.12H4.76N22.07

Measured value (%) C6.7.8H4.79N21.85

IR (KE r) cm -; ! C = 1 6 5 0

NMR (CDC13) tri-value; 4.4 to 4.6 (4H, m),

8 to 9 (8H, m), 8.2 to 8.5 (1H, m) , S.-S. 8 (2 H, m)

Example 2 7

 Manufacture of 4- (bi-silyl) -1 2 [2— (1 1H imidyl: dimethyl) 1-1-1 (2H) phthalazinone

 The same procedure as in Example 1 was carried out using 4-((4-viridyl) -111 (2H) phthalazinone as a raw material to obtain the desired product.

mp 1 7 (:) to 1 end 2 ^e C

 Elemental analysis value

Calculated value (%) C ό S. 12 Η 4.7 t K 2 2. C; 7

Measured value (%) C 67.89 H4.6 1.6 2 1.S 1

 I R (KBr) cm;

 NMR (CDC13), value; 4.3, 4.8 (4H, m).

 〜 7 7-〜 9 9 (8 H. rn), S. 3-S. 6 (1 H, m)

, 8.6 to 8.8 (2H, m)

Example 2 8

 4 — (2 — Viridyl)-2-[2-i-] Η — Imi ^-Riechil:-1-(2))

 The desired product was obtained by performing the same operation as in Example 1 using 4- (: ί—bilge / re) 1-11 (2H) phthalazinone as a raw material-mp 11 3 to 1 15 V

 Elemental analysis value

Calculated value (%) C68.12H4.76N22.0

Actual value (%) C 67 .S 3 H 4.8 2 N 2 2.0 2

IR (KB r) cm ^_ :;

NMR (CDC 1 3 (values;?.. 4 3 to 4 chome (4 h ^T, m}, 6 8 8.0 (8H, m) 8.1 $ .5 (2H, m) 8.5 8.8 (1Hm)

Example 2 9

 4- (2-furyl) -1-2- (2 — () — 1H—imidazolyl) ethyl] —1- (2H) phthalazinone

 The desired product was obtained by performing the same operation as in Example 1 using 4- (2-furyl ')-11 (2H) phthalazinone as a raw material.

 m p 1 4 2 1 4 3

 Elemental analysis value

Calculated value (. ') C66.65H4.611.829 Actual value (%) C66.43H4.57N1S.1.22

IR <KBr) cm "¹; c = o1650

NMR (CDC13) value; 4.4.4.6 (4H, m)

 6.4 7.9 (8H, m) 8.1 8.5 (2H, m) Example 30

 4-methyl-2— [2- (1—1H—imidazolyl) ÷: -i- (2H) phthalazinoni

 The desired product was obtained by performing the same operation as in Example 1 using 4-methyl-11- (2H) -phthalazi'none as a raw material.

 m 8 9 9 1 C

IR (KBr) cm "¹; 1650

 NMR (CDC13) value; 2.50 (3H, s) 4.3

 4.6 (4 H, m), 6.8 7.9 (6 H, m),

 8.2 8.5 (1 H, m)

Example 3 1 4-cyclohexyl 1 2— [2-(_ 1.H—imigzo'lyl) ethyl] — 1- (2H) phthalazinone

 The desired product was obtained by performing the same operation as in Example 1 using 4-cyclohexyl-1- (2H) phthalazino as a raw material.

 m p 1 5 1 1 54 C

 I R (K B r) cm-; 1 64 0

 NMR (CDC13) value; 1.0 2.3 (10H, m)

 2 3 (1 H, m), 4.3 4.6 (4 H

 6, '-丁 .9 (6 H, rn) S S .5 (I K, m)

 6-Chlor-1--4-[2 -_ (5 Chill Chenyl)

 -(1-1 H-imidazolyl) Manufacturing of (1 H) (2 H) phthalazinone

 The desired product was obtained by performing the same operation as in Example 1 using 6-chloro-1-41 [2- (5-methyl-2- / L)]-111 (2H) phthalazinone as the raw material. .

 m V 102-166 ° C

 I R (KBr) cm-;; 1650

MR (CDC 1 ₃₎ value; 2 .5 1 (3 H, s), -4 .2

 4.8 (4 H, m), 6.6 8.5 (8 H, m)

Example 3 3

Ding —Nitro— 4— [2— (5-Ethircenyl)? 1 2 —: 2-(1-1 H—Imidazo'lyl) ethyl] — 1 — (2 H.)

The raw material is Ding —Nitro 1 4— [2— (5-Echi 'Che 2) j 1- The same procedure as in Example 1 was performed using 1- (2H) phthalazinone to obtain the desired product.

 m p 1 2 3 to 1 2 5

IR (KBr) cm- ¹ ; 1660, 1530, 1340

NMR (CDC 1 ₃₎ values; 1 .3 7 (3 H, t, J = 7 H z), 2.9 0 (2 H, q, J = 7 H z), 4 .4~ 4 .0

 (4H, m), to 6.7 to 8.4 (5H, m), 8.0

 8. G (2H, m), 9.12 (1H, d, J = 2Hz) Example 34

 6-Methoxy-4- (2-ethylsilenyl) Ί-2- [2-\ 11H-imidazolyl) ethyl Ί-1-(2H) Manufacture of phthalazinone

 The same procedure as in Example 1 was carried out using 6-methoxy-1-41- (2-chenyl) -11- (2H) phthalazinone as the starting material to obtain the desired product.

 mp186-: L88. C

^{IR (KB r) cm -:} ; 1 64 0

NMR (CDC 1 ₃₎ value; 3 .84 (3 H, s ), 4 .2,

 4.7 (4H, m), 6.8-7, 6 (SH, m),

 8.3 1 (1 H, d, J = 9 H z)

Example 3 5

7—Methoxy 4- (2-Chenyl) — 2 -— [2- (1-1H) —Imidazolyl) ell] 11—1 (2H) phthalazinone 4 1 (2-Chenyl) — 1 — (2H) Using radiazine. By performing the same operation as in Example 1. Got the object-mp 1 3 (: 1 3 2 "C

 I R (KBr) cm-: 1!, 40

NMR (CDC 1 ₃₎ όゝvalue; 3 .9 2 <3 H> s <, 4

 4.8 (4H, rn), 6.8 to 8.1 (H, m)

Example 3 6

 6 —Metro 4 1 Γ_2-5 5 —Echilchenyl L ― “One- (1 1 Η —Imidazolyl) ethyl Ί-1-(2))

 Manufacturing of

 The desired product was obtained by performing the same operation as in Example 1 using phthalazinone as the raw material, 6-toki 4- 1 [2-(5-chininii ΰ.): -1-(2 Η) phthalazinone. Was.

 m p 13 9 to 14 2 ° C

IR (KBr) cm '¹; 1 6 4 0

 NMR (CDC 13) ό, value; 1.36 (3H.t, J = DzHz), 2.88 (2H, q, J = 7Hz), 3.85 (3 4.3 to 4.6 (4H, m), 6.7 to 7.5 (7H, m), 8.29 (1H, d, J = 9Hz)

Example 3 7

1-1 [2-(5-Echi / Rechenir)]-2-[2-1 (1-1H-imidazolyl) ethyl]-1-1 <2H ') Production of Tadinenon

The desired product was obtained by performing the same operation as in Example 1 using cinna — cinnamon 4 — [2 — (— ヱ tyltinini) — 11-2H) phthalazinone as a raw material. rn p 9 9, 1 0 2

IF; KB r! · ■ in "^;; 1 t". 5 0

NMR (CDC 1 _{3) 3} values;... 1 3 5 ( 3 H, t, J = 7 H zi, 2 8 6 (2 H, q, J = 7 H z), 3 1 3 H, s> , 4.3 to 4.7 (4H, m), 6-7 to 8.1 (8H, m)

Real Shawar 3 8

 7—Ethoxycarbonyl—4-1—2— (5-Ethyl'Chenyl) —2— [2— (1—1H—imidazolyl) 1 11— (2H) phthalazinone Manufacture

 7-Carboxy-4-1 [2- (5-ethylethyl)] 1 1 (2H) Phthalazinone 2.0 g was dissolved in ethanol 200 ml, and a catalytic amount of Port Ryuic acid was added. Reflux for hours. The solvent was distilled off under reduced pressure, and a mixed solution of ethyl ethyl acetate 200% and a 5% aqueous solution of carbon dioxide 10 Oml was added to the residue. After stirring, the organic layer was separated. After drying over magnesium sulfate, the ethyl acetate is distilled off under reduced pressure, and the residue is subjected to silica gel column chromatography. The mixture is developed and eluted with a mixture of chloroform and methanol (20: 1, V / V) to obtain 7-ethoxycarbonyl-2- [2- (5-ethylethyl)]-111 (2H) phthalazinone. The same operation as in Example 1 was carried out by using 7-ethoxycarbonyl 4- [2- (5-ethylthienyl)] — 1— (2H) phthalazinone as a raw material. I got something.

To mp 1 3 3 1 3 6 ^C C

IR (KB r) cm "¹; 1710, 1660 NMR (CDC 1 ₃₎ value;... 1 3 6 ( 3 H, t, J two weapons H z), 1 4 1 ( 3 H, t, J = 7 H z), 2 8 9 (2 H, q, J = 7 Hz), 4.2-4 (6H, m), ό-7.4 (5H, m), 7.9-8.5 (2, rri) , 9.0. 0 0 (1 Η, d, J = 2 Η ζ)

 Example 3 9

 7—Carboxy—4- [2— (5—ethylsilenyl)] — 2— “2— (1—1Η—imidazolyl) ethyl 1— (2Η) Manufacture of phthalazinone

 10 Example 3 7-Ethoxycarbonitrile obtained in 8-4—2- (5—Ethircenyl)] — 2— [2— (111—Imidazo'ril) ethyl] —1— ( 2)) After dissolving 1.0 g of phthalazinone in 50 ml of methanol, add an aqueous solution containing 0.3 g of sodium hydroxide, and stir at room temperature for 3 hours. After the reaction, the solvent is distilled off under reduced pressure

Fifteen

 And then add 20 ml of cold water to the residue. After removing insolubles, the solution is neutralized with 6 N hydrochloric acid under cooling. After water was distilled off under reduced pressure, the residue was triturated with aqueous ethanol to obtain an L-like substance.

 m p> 280 ° C

 20

IR (KBr) cm "¹; 700-230, 1ό60 NMR (D2O) value:]. 02 (3Ht, J = Dzz)

 2.4 7 (2 H, q J = 7 H z) 4.1 7 (4 H, b rs), 6.2-S. 2 (7 H m), S. 4 1

 (1 H, s)

Z5 8-J 2-(5-Chlorchenil)] 1-6-[2-(1-1 H imidazolyl _) ell _ 1 5-6_H_)

 The same operation as in Example 1 was carried out using 8-ri [2— (5-chlorozenyl)] — 5— (6H pyrido [2,3 le d) pidazinone as the raw material. I got something.

 H

 m p 2 04 to 20 7

 Les

IR (KB r) c m '1; 1 6 6 0

NMR (CDC13) value; 44.3-3, 8 (quadratic, m).

 To 6.8 7.4 (5H, m), 7.5 to Ding. 9 (1 story, rii, 8.2 to 8.5 (1H, m), 39.0 to 9.2 ( 1 H,

 H

 m),

 Pi

Example 4

 1 1 “2 Upper J—1000 thousand ruchenyl) 1_-3-L 11-1 H

 Γ

 Three

Production of pyridazinone

 The same process as in Example 1 was performed using 11- [2— (5—methyl'handi-nil >>) 43H-H-d'lide '[3,4-1d] pyridazinone as the raw material. As a result, the desired product was obtained.

 mp146-147. C

IR (KBr) cm "¹; 1 660

NMR (CDCl ₃ ) ^; 2.54 (3 H, s), 4.3.4.7 (4 H, m), 6.7 to 7.5 (5 H, m),

 8 1 (1 H, d, J = 6 H z), 8.1 (1 II, a

J = 6 H z), 9-6 1 (1 H, s) Example 4 2

 4 — [(2-Chenyl) methyl] — 2— [2 (1—1H—imidazo'ryl) ル-1- (2H) Manufacture of phthalazinone

 The same procedure as in Example 1 was carried out using 41-[(2-phenyl) methyl] -1- (2H) phthalazinone as a raw material to obtain the desired product.

 m p 135-138. C

 I R (K B r) cm- '; 1 660

N M R (C D C 1 c-) ~ value; 4.2 to 4 (4 ,, rn) '

 4.3 3 (2 H, s), 6.6 to 7.8 (9 Η, m)

8.1 to 8.5 (1H, m)

Example 4 3

 4-Phenyl-1- (3-((1-1H-λdazolyl) propyl)]-(2H) phthalazinone

 Using 1,3-dibromopropane instead of 1,2-dibromoethane, the same procedure as in Example 1 was carried out to obtain the desired product +, mp136-138. C

 Elemental analysis value

Calculated value (%) C72.70H 5.49N16.96 Actual value (%) C72.78H5.62N16.7 SIR (KBr) cm- ¹ ; 1 6 6 0

NMR (CDC 1 ₃₎ value; 2. 37 (2 H, quintet .

J = 7 Hz), 4.0 ό (2 H, t, J = 7 Hz), 4.3 2 (2 H, t, J = 7 Hz), D, 00 (2 H, s 4 to 7.9 (9H, m), 8.4 to 8.7 (1 layer,

 _ 1 m)

Example 44

4 — 1- 1 H-imidazo-butyl)

-1-(2 H) Production of phthalazinone

 Using 1,4-dibromobutane instead of 1,2-dibromobutane, the same procedure as in Example 1 was carried out to obtain the desired product.

 Elemental analysis value

Calculated value (%) C 7 3.23 H 5.85 Actual measurement value (%) C 7 2.84 H 5.86 N 15.98 IR (KBr) cm "¹; 1640

 NMR (CDC13) tri-value; 1.7 to 2.1 (4H, m),

 4.02 (2H, t, J = 7Hz), 4.34 (2H

 J = 7 Hz), 6.8 to 7.9 (11H, m), S. 3., 8. (1H, m)

Example 4 5

 4 1 2 1-2-[5 -_ (, 1 1-1 H-imidazo 'Ril) 2'

 1 Manufacture of 1 (2H) phthalazinone

 The desired product was obtained by performing the same operation as in Example 1 using 1,5-dibromopentane instead of 1,2-dibromopentane.

 m p 164-165. C

 Elemental analysis value

Calculated value (%) C 7 2 H 5.10 N 1 Actual value (%) C71.80H5.16N17.67IR (KBr) cm "¹; 1660

 NMR (CDC13) 5 values; 1.2 to 2.2 (6H, m)-.

 3.90 (2H, t, J = 7Hz), 4.28 (2H, tJ = 7Hz), 6.8 to 7.9 (11H, m), 8.3 Up to 8.7 (1H, m)

Example 4 6

 4 —Phenyl— 2— [6— (1 — 1 H—Imidazolyl) hexyl

/ Reproduction of (2H) phthalazinone

 The desired product was obtained by performing the same operation as in Example 1 except that 1,6-dibromohexane was used instead of 1,2-dibromoethane.

 mp101-: L03. C

 Elemental analysis value

Calculated value (%) C 74 17 H 6.50 N 15 .04 Actual value. ') C 7394 H ό. 49 Ν 14.7 .70 IR (KBr) cm- ¹ 1 6 5 0

 NMR (CDC13) tri-value; 1.2 to 2.1 (8H, ni),

3.90 (2 H, t, J = 7 Hz), 4.30 (2 H t

J = 7 Hz), 6.8 to 9.9 (11H, m), 8.3

8.7 (1 H, m)

Example 4 7

 4-Phenyl-1-2- [7- (1-1H-imidazolyl) octyl] 1-1-1 (2H) Phthalazinone

1, 8-dibromocta instead of 1, 2-dibromjetan The desired product was obtained by performing the same operation as in Example 1 using the

 m p 81-82. C

 Elemental analysis value

Calculated value (%) C 7 4. 9 6 H 7 0 5 9 9

 One

Actual value (%) C74.79H704N89IR (KBr) cm "'; 1650

NMR (CDC13) value; 1.2 ', 2Hm)

 8 4 (2 H, t, J-7 H z) 4 2 Η

J = 7 Hz), 6.8-79 (11 Η, m 8.

 8.6 (1 H, m)

Example 4 8

 Manufacture of 4-phenyl _ 2 — 1 4 — ί 1-1 H (midazo'lyl) 1-2 butenyl, 1 1 1 (2H) phthalazinone

 The same procedure as in Example 1 was carried out except that 1,4-dibromo-2-butene was used instead of 1,2-dibromethane to obtain the objective ^.

 m p 1 6 9 to 1 7 2

IR (KBr) cm "¹; 1 660

NMR (C. DC 1 ₃₎ value;. 4 4~ 4 7 (2 H, m),

4.7 to 5.0 (2H, m)> 57 to 6.0 · (2H, m

, 6.7 to 8.0 (11 Η, m) .8.3 to 8.3 ό (1 Ηm)

Example 4 9

4 1 phenyl 1 2 — “4 1 (1 1 1 H — imidazolyl) 1 2 — [Butenil] 1 1 1 (2H) Manufacture of phthalazinone

 The target compound was obtained by performing the same operation as in Example 1 using 1,4-dibromo-2-butyne instead of 1,2-dibromethane.

 m p 1 1 1 to 1 1 4. C

IR (KBr) cm "¹; 1650

NMR (CDC 1 ₃₎ value;.... 4 64 ( 2 H, s), 5 0 3 (2 H, s), 6 7~ 7 · 8 (1 1 H, m), S 3 ~ 8. 6 (1 H, rn)

Example 5 0

 4-phenyl-2- 1- (1-1H-imidazo'ryl) bentyl]-1- (2H) phthalazinone production

 4 1 2 1- (2H) phthalazinone 4.0 g, 1, 4 1-dibromopentane 13.7 g and calcium carbonate 14.9 g are suspended in 50 ml of dry dimethylformamide. After turbidity, stir for 2 hours at 65. After the reaction, pour into cold water and extract with chloroform.-Dry with magnesium sulfate, evaporate the solvent under reduced pressure, and evaporate the residue. The product is developed with dichloromethane, and the product is eluted to give 4-phenyl-2- (4-bromobentyl) -1 (2H) phthalazinone (4.1 g) as colorless crystals.

 m p 1 3 2 to 1 3 3 V

NMR (CDC13) S value; 1.6 to 2.4 (4H, m),

1.69 (3H, d, J = 7Hz), 4.0 to 4.5 (3

H, m), 7.3 to 7.9 (octave, m), S. 3 to 8.3 (1H, m) After suspending 0.37 g of imidazole and 0.16 g of sodium hydride in 30 ml of dry tetrahydrofuran, the suspension was cooled with ice and water, and the above solution was cooled. —Bromopentyl> A dry tetrahydrofuran solution containing 1.01 g of 11 (2H) -tarazinone is dropped, and the mixture is heated under reflux for 10 hours.

 After the reaction, the solvent was distilled off under reduced pressure. To the residue was added a mixture of chloroform 100 m and cold water 10 O ml, followed by stirring. The organic layer is separated, dried over magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is subjected to silica gel chromatography. The mixture is developed with a mixture (20: 1, VV) of a mixture of black mouth and methanol, and eluted to obtain the desired substance (0.40 g).

 m p 107 to 1109

IR (KBr) cm "¹; 1650

NMR (CDC 13) values: 1.47 (3H, cl, J = 7 Hz, 1.6-2.0 (4H, rn), 3.7-45 (3H, rn. 6.8 to 8.0 (11H, ni), 8.0 S.6 (1H, rn)

Example 5 1

4 1-Phenylyl 2 [4- (1H-imidazolyl tyl) cyclohexylmethyl] 1 1— (2H) phthalazinone

 The same procedure as in Example 1 was carried out using 1,4-bis (bromomethyl) cyclohexane instead of 1,2-dibromoethane to obtain the desired product.

 m 208-210. C

NMR (CDC 1 ₃₎ (5 values;.. 0 Ί~ 2 1 ( 1 0 H, rn, '-? ">

 J (2 H, d, J = D Hz .4. 11 (2 K, d J = D Hz), ό. 7 to D. 8 (11 H, m), S. 3-S . 6 (1 H, m)

Example 5 2

 4 (2—handicraft).-2-[3-(1 — 1H) Production of imida, ril propyl and 1-11 (2H) phthalazinone

 Same as in Example 1, except that 1,3-dibutene pan was used instead of 1,2-dibromogetane, and 4- (2-Chenyl) —1— (2H phthalazinone was used as a raw material. The desired object was obtained by performing the above operations.

 m S 2 to 84 V.

 Elemental analysis value

Calculated value () C 64.27 Η 47 9 i.b5 Actual value () C 63 .7 S Η48 9 N1 ό.59

I R (Κ Β r) cm ~ · '; 1 6 5 0

_{Ν Μ P t (CDC 1 3} ) value:. 2. 3 2 (2 Η quinte 1,

J =-7 H 2}, 4.0 Γ) · 2 H, t.

 4.2 2 (2H, t, J = 7Hz), .8, .S.1

(9 H, m), 8.1 ~ S. ό (1 H, m)

Example 5 3

 4— (2-Chenyl) — [5— (1—1H—imidazo'yl pentyl) 1 Manufacture of (2H) phthalazinone

The same operation as in Example 1 using 1,5-dibu-sigmabentan instead of 1,2-dibromethane and 4- (2-phenyl) _1- (2Η) phthalazinone as raw material By doing The 4 "target was obtained as a colorless oil.

IR (KB r) cm -; ! 1 6 5 0

_{NMR (CDC 1 3) a;} . 1 2~ 2. 2 (6 H, m),

 3.93 (2H, t, J = 7Η ζ), 4.29 (2Η, t.J-7Η), G-8 to · 2 (9Η, m), 8.3 To 8.6 (1 Η, m)

 This oil was dissolved in ethanol saturated with hydrogen chloride. The solvent was distilled off under reduced pressure, and the residue was triturated with ether to obtain the desired hydrochloride.

 m p 16 9 to 17 1 ° C

Example 54

 6, 7-Dimethoxy 4-fluoro 2-— “5— (1-1H-imidazolyl) pentyl] 1-11 (2H) phthalazinone

 Same as in Example 1, except that 1,5-dibromomethane was used instead of 1,2-dibromomethane, and 6,7-dimethoxy-14-phenyl-11- (2H) phthalazinone was used as a raw material. By performing the above operation, the desired product was obtained as a colorless oily substance.

IR (KBr) cm- ¹ ; 1650

 NMR (CDC13) value; 1.2 to 2.2 (6H, m),

 3.81 (3H, s), 3.90 (2H, t, J = 7Hz), 4.01 (3H, s), 4.24 (2H, t, J- 7 Hz), 6.7-8.0 (10H, m)

 The desired hydrochloride was obtained by performing the same operation as in Example 53.

mp 1 0 5 Example 5 5

 4 1 (3-pyridyl) 1 2— “5— (1—1H—imidazolyl. :) Pentyl-1-(2H) Production of phthalazinone

 The same as in Example 1 except that 1,5-dibutene methane was used instead of 1,2-dibromomethane, and 4- (3-pyridyl) 111 (2H) phthalazinone was used as a raw material. The objective was obtained by performing the operation.

 m p 1 26-: L 28 V

IR (KB r) c m '1; 1 6 5 0

 NMR (CDC13) value; 1.0 to 2.2 (6H, m).

 3.89 (2H, t, J = 7Hz), 4.25 (2H, t, J = 7Hz), 6-7 to 8.0 (8H, m), 8. 3 to 8.6 (1H, m), 8.6 to 8.9 (2H, m)

Example 5 6

 4— (4_pyridyl) 1 2— “5— (1—1H—imidazolyl) pentyl—1— (2H) phthalazinone production

 Method A of Example 1 using 1,5—dibutene methane in place of 1,2-dibromomethane and 4- (4-pyridyl) —1— (2H) phthalazinone as raw material The target product was obtained by performing the same operation as in.

 m p 1 1 8 to 12 0 ° C

IR (KBr) cm "¹; 1 660

 NMR (CDC13) 5 values; 1, 1 to 2.2 (6H, m),

3.89 (2H, t, J = 7Hz), 4.26 (2H.t.J = 7Hz), ό.7 to 9 (8H, m), 8.3 ~ 8.6 (1H, m), 8.6 to 8.6 (2H, m)

Example 5 7

 4 Manufacture of 1- (2-pyridyl) -1-2— [5- (1—1H—imidazolyl) pentyl] —1— (2H) phthalazinone

 The same operation as in Example 1 is performed using 1,5-dibromopentane instead of 1,2-dibromomethane and 4- (2-pyridyl) 111 (2H) phthalazinone as a raw material. Thus, the target substance was obtained as an oily substance.

IR (KBr) cm "¹; 1 660

 NMR (CDC13) value; 1.1 to 2.2 (6H, m),

 3.88 (2H, t, J = 7Hz), 4.27 (2H, t, J = 7Hz), 6.7 to 8.8 (11H, in)

 After dissolving 0.60 g of this oily substance in 5 ml of ethanol, 3 ml of an ethanol solution containing 0.21 g of oxalic acid was added, and the mixture was stirred at room temperature for 5 minutes.

 Then, the solvent was distilled off under reduced pressure, and the residue was triturated with a mixture of ether and ethanol (1: 1, V / ~ '), whereby the oxalate of the desired product was obtained. 0.50 g).

 m p 11 14 to 1 18. C

Example 5 8

 4- [2 — (1-methyl-1 H-imidazolyl)] 2— [5-(11-1 H-imidazolyl) pentyl] 1-1 (2 H) phthalazinone

1,5-dibromopentane instead of 1,2-dibromoethane, and 4- [2- (1-methyl-1H-imidazo) as raw material Ryl)] The desired product was obtained as an oily substance by performing the same operation as in Example 1 using 1 (2H) phthalazinone.

I R (K B r) cm- '; 1650

 NMR (CDC1a) value; 1.1 to 2.1 (6H, m),

 3.82 (2H, t, J = 7Hz), 3.83 (3H, s), 4.12 (2H, t, J = 7Hz), 6.7-8. 0 (8H, m), 8.3 to 8.6 (1H, m)

Example 5 9

 4-1- _ [2— (—1—Iso-Aropyryl 1 H—Imidazolyl〉] One-two-one 5— (1H_Z '| _R) _pentyl

 Use 1,5-dibromopentane in place of 1,2-dibromomethane and 4- [2- (1-isopropyl-1-H-imidazolyl)]-111 (2H) phthalazinone as raw material By performing the same operation as in Example 1, the desired product was obtained as an oily substance.

IR (KBr) cm- ¹ ; 1660

NMR (CDC 1 ₃₎ <ϊ value;. 1 0~ 2 L (6 H, m),

 1.40 (6 H, d, J = 7 H z) 3.78 (2 H t,

J = 7 Hz), 4.18 (2 H, t J = 7 Hz),

 5.48 (1 H, q u i n t e t, J = 7 H z), 6. 7

~ 8.0 (7H, m), 8.2 to 8.6 (2H, m)

4- [3-ethoxycarbonylcarbonyl> — 2— [2— (1—_1H imi dazo J, le ') ethyl “1-11 (2H) phthalazinone Manufacture

 The same procedure as in Example 1 was carried out using 4- (3-ethoxycarbonylphenyl) 111 (2H) phthalazinone as a raw material to obtain the desired product.

 mp 11 16-18. C

1 R (KB r) cm- ¹ ; c c = o 1 7 3 0, 1 6 5 0

N MR (CDC 1 ₃₎ value;. 1 38 (3 H, t, J - 7 H z)

, 4.35 (2 q, q, J = 7 Η), 4.3 to 4> 7 (4 m, m), 6.8 to 8.6 (11 Η, m)

Example 6 1

 2-Ethyl-1-4- (3-pyridyl) 1-1- (2H) Production of phthalazinone

 Under a nitrogen atmosphere, in a suspension of sodium hydride (40 mg) in dimethylformamide (5 ml), 4- (3-pyridyl) -11- (2H) phthalazinone (0.20 g) was added. The reaction mixture was ice-cooled, ethylpromide (0.08κ «1) was added, and the mixture was stirred at the same temperature for 1 hour.The reaction mixture was poured into cold water, and extracted with chloroform. The port-form layer was washed with water and dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was applied to a silica gel column chromatography. (99: 1, VV), eluted with and eluted to give the desired product (0.17 g) as colorless crystals.

 mp156-157. C

NMR (CDC 1 ₃₎ value; 1.45 (3H, t, J = 7Hz), 4.34 (2H, q, J-- 7Ηζ), 7.2-8.1 (5Η, η.); 8.3-8.9 (3Η, m) Example 6 2

 Production of 2-Methyl-41- (3-pyridyl) 1-1- (2H) phthalazinone

 The target compound was obtained by performing the same operation as in Example 61 using methyl iodide instead of ethyl amide.

 mp 153-15-154. C

NMR (CDC 1 ₃₎ S value; 3.90 (3H, s), 7.2,8.0 (5H, m), 8.3,

Example 6 3

 2- (2-Methoxyxetil) 1-4 1 (3-pyridyl) — 1 (2H) Production of phthalazinone

 The same procedure as in Example 61 was carried out using 2-methoxyl chloride instead of ethyl bromide to obtain the desired product.

 m p 1 0 7 to 1 08 ° C

NMR (CDC1a) 5 values; 3.35 (3H, s), 3.83 (2H, t, J = 5Hz),

 4.46 (2H, t, J = 5Hz), 7.2-8.1 (5H, rn), 8.4-9.0 (3H, rn)

Example 64

 Production of 2-ethoxycarbonylmethyl-4- (3-pyridyl) — 1 — (2H) phthalazinone

 The desired product was obtained by performing the same operation as in Example 61 using ethyl bromoacetate instead of ethyl bromide.

 mp 180-: L81. C

NMR (CDC13) 5 values; 1.30 (3H, t, J = 7Hz), 4.23 (2H, q, J:

7Hz), 5.04 (2H, s), 7.2-8.1 (5H, m), 8.4-9.0 (3H, rn) Example 6 5

 2-Ethoxycarbonyl'propyl—Preparation of 4- (3-pyridyl) -1-1 (2H) phthalazinone

 The desired product was obtained by performing the same operation as in Example 61, using ethyl bromobromide instead of ethylpromide.

 mp104-: L05. C

NMR (CDC 13) value; 1.20 (3H, t, J-7i), 2.0-2.5 (4H, lη), 4.05 (2H, q, J = 7 Hz), 4.35 (2Η, t, J = 7 Hz) 7. Ζ-8.1 (5Η, in), 8.3-

Example 6 6

 2—Isopropyl 1 4 1 (3—Pyridyl) 1 1— (2H) phthala

 The desired product was obtained by performing the same operation as in Example 61, using an isolopi / reb mouth guide instead of ethyl bromide. C

NMR (CDC 1 ₃₎ value; 1.45 (6H, d, J -7Hz), 5.50 (lH, "n), 7.2

-S.2 (5H, m), S.4-9.1 (3H, m

Example 6 7

 Production of 2-aryl-1 4- (3-pyridyl) -1-1-1 (2H) phthalazinone

 The desired product was obtained by performing the same operation as in Example 61 using arylpromide instead of ethylpromide.

 m p 1 4 5 to: L 46

NMR (CDC 13) ^ value; .8-5.5 (4H, rn), 5.7-6.4 (1H, m), 7.2-8.1 (5H, rn) 8.4-8.9 (3H, rn) Example 68

 Production of 2-acetyl-1 4- (3-pyridyl) 1-1- (2H) phthalazinone

 The desired product was obtained by performing the same operation as in Example 61 using an acetilk mouth ride instead of ethylpromide.

 mp 167-16-168. C

NMR (CDC13) value; 2.77 (3H, s), 7.3-8.1 (5H, m), 8.4,

9.0 (3H, m)

Example 6 9

2— ri—propyl 1 4- (3-pyridyl) 1 1— (2Η) Production of phthalazinone

 The desired product was obtained by performing the same operation as in Example 61, using η-propyl bromide instead of ethyl bromide, to obtain mp 142.5 to 143.5. C

NMR (CDC 13) value: 1 · 02 (3H, t,, 7 Hz), 1.91 (2H, rn), 4.23 (2H, t, J-7 Hz), 7.2-Sl (5H, in), 8.3-9.0 (3H, _f fl)

Example 7 0

 Production of 2-n-butyl-41- (3-pyridyl) 1-1- (2H) phthalazinone

 The desired product was obtained by performing the same operation as in Example 61 using n-butyl bromide instead of ethyl bromide.

mp 1 15 to 1 16 ^C C

NMR (CDC 1 ₃₎ value; 0.98 (3H't, J = 7Hz ) '1 ·: ΐ · υ (4Η' «ι), 4.33 (2H, t, J = 7Hz), 7.E-8.2 (5H , m), 8.4-9.1 (3H, rn)

Example 7 1 2—Propargyl 1 4- (3—pyridyl) .— 1— (2H) phthaladinone

 Propargyl promide was used in place of ethylpromide, and the same procedure as in Example 61 was carried out to obtain the desired product, mp187-188. C

 NMR (CDC13) value; 2.22 (lH, t, J-2Hz), 5, 02 (2H, d, J--

7Hz), 7.2-8.1 (5H, m), 8.3-8.9 (3H, tn)

Example 7 2

 2 — (3 — butyryl 2 — butenyl) — 4 1 (3 — pyridi) 1)-1 1 (2 H) Manufacture of phthalazinone

 The desired product was obtained by performing the same operation as in Example 61 using 4-bromo-2-methyl-2-butene instead of ethyl bromide.

 m P 1 5 2 .5 to 1 5 3 .5 ° C

NMR (CDC 1 _{3) 3} values; 1 · 75 (3H, s ), 1.86 (3H, s>, 4.90 (2H, d J = 7Hz), 5.54 (lH, m), 7.3-8.2 (5H, ι « ), 8.4-9.1 (3H, m)

Example 7 3

 2 — Cyclopentyl 4- 1 (3 — pyridyl) — 1 — (2 H) Production of matalazinone

 The desired product was obtained in the same manner as in Example 61, except that cyclopentyl bromide was used instead of ethyl bromide. C

NMR (CDC 1 ₃₎ value; 1.5-2.5 (8H, m), 5 · 3,5.9 (1H, m), 7 · 2 -8.2 (5H, m), 8.4-9.1 (3H, tn)

Example 7 4 Preparation of 2-cyclohexylmethyl-1- (3-pyridyl) — 1 — (2H) phthalazinone

 The desired product was obtained by performing the same operation as in Example 61 using cyclohexylmethyl bromide instead of ethyl bromide.

 mp170-: L72. C

NMR (CDC 1 ₃₎ value; 0.8-2.5 (llH, rn), 4.18 (2H, d, J = 7flz)

7.2-S.2 (5H, m), 8.4, 9 · 1 (3H, HI)

Example 7 5

2-n-octyl 4- (3-pyridyl) — 1 — (2H) phthalazinone

Instead of Echiruburomai de, n- Okuchirupuromai de have use of, N MR to obtain a particularly good Ri desired product carrying out the same operation as in Example _{6 1 (CDC 1 3) <} J value; 1.6～2,2 ( 15H, m>, 4.28 (2H, t, J-7Hz) 7.2-8.1 (5H, m), 8.3-8.9 (3H, m)

Example 7 6

 2—Benzyl 1 4- (3-Pyridyl) 1 1— (2H, 'Manufacture of phthalazinone

 Using benzyl bromide instead of ethyl bromide, the same procedure as in Example 61 was carried out to obtain the desired product.

 m p 1 80 to 18 2 ° C

NM R (CDC 1 ₃₎ value; 5.47 (2H, s), 7.2,8.1 (10H, ""), 8.4-

9.1 (3H, M)

Example 7 7

2—-(2—Oki, Noguchi pill) 1—4— (3—pyridyl,) — 1— ( H) Production of phthalazinone

 The desired product was obtained by performing the same operation as in Example 61 using black mouth acetone instead of ethylpromide.

mp 1 5 0~ 1 5 1 Te _{- NMR (CDC 1 3) δ} ·, 2.28 (3H, s), 5.08 (2H, s), 7.2-8.1 (5H, M), 8 · 4, · 9.0 (3Η , << ι)

Example 7 8

 Production of 2- [2- (1-pyrrolidino) ethyl] 1-41- (3-pyridyl) — 1 — (2Η) phthalazinone

 Under a nitrogen atmosphere, a suspension of sodium hydride (0.40 g) in dimethylformamide (50 «11>) was added with 4- (3-pyridyl) — 11- (2H) phthalazinone (2.0 s). The mixture was stirred for 30 minutes at room temperature, then cooled forever, added with 1,2-dibromoethane (2.3 ml), and stirred at the same temperature for 1.5 hours. 2- (2-Bromoethyl) -4-1 (3-pyridi / le) 111 (2H) phthalazinone (2.5s) was obtained as colorless crystals.

 m P 1 4, 1 4 2

NMR (CDC 1 ₃₎ value; 3.76 (H, t, J : 7Hz), 4.64 (2H, t, J = 7H z), 7.2-8.0 (5H, rn), 8.2-8.9 (3H, m)

Then, the obtained 2-((2-promoethyl) —4— (3-biridyl) 1-1— (2H) phthalazinone (0.30 s) solution in dimethylformamide (10 ml) was added to a pyrrolidine ( (0.30 ml) was added and the mixture was heated at 70 to 2 hours. After the reaction, the same post-treatment as in Example 61 was carried out to obtain the desired product (0.14 s) as colorless crystals. mp 1 4 3-: L44. C

NMR (CDC13) 3 values; 1 · 75 (4Η, ηι), 2.62 (4H, m>, 2.96 (2H, t

J = 7Hz), 4.46 (EH, t, J = 7Hz), 7.2-8.1 (5H, rn), 8.4-9.0 (3H, m) Example 7 9

 Production of 2- (2-thiophenoxetil) 4- (3-pyridyl) 1-111 (2H) phthalazinone

 The same procedures as in Example 78 were carried out using thiophenol and sodium hydride instead of pyrrolidine to obtain the desired product.

 m p 133-134. C

NMR (CDC i ₃ >value; 3.44 (2H, t, J = 7 Hz), 4.57 (2H, t, J-7ί ^ z), 7.0-8.0 (10H, rn), 8.4-9.0 (3H, ro)

Example 8 0

 2— [2— “1— (1H) tetrazolyl] ethyl]-4- (3-pyridyl) 1 1 1 (2H) phthalazinone

Using 1 H- tetrazole in place of pyrrolidine gave the O Ri target compound and this for the same procedure as in Example 7 8 _t

 m p 1 4 1 ~: L 42 ° C

NMR (CDC 1 ₃₎ value; 4.6-5.0 (2H, rn), 5. l-δ .4 (. 2H rn), 7.2

-8.0 (5H, m), 8.4-8.9 (4H, m)

Example 8 1

 2— [2 — (2 — pyrimidinyl) thioethyl]--(3 — biridyl) 1 1 — (2 H) Production of phthalazinone

Using 2-mercaptopyrimidine and sodium hydride in place of pyrrolidine, the same procedure as in Example 78 was carried out. The desired product was obtained.

 m p 1 4 5 to 1 4 6 ° C

NM R. (CDC 1 ₃₎ value; 3.70 (2H, t, J -6Hz), 4.71 (2H, t, J = 6H z), 6.90 (lH, t, J = 5Hz), .2-8.1 (5fl , m), 8.44 (2H, d, J = 5Hz).

8.4, 9.0 (3Η, >>)

Example 8 2

 2 — (2 — phthalimid I: chill) 1 4 — (3 — pyridyl) 1 1 1 (2 Η) Manufacture of phthalazinone

 The desired product was obtained by performing the same operation as in Example 78 using phthalimidocadium instead of pyrrolidine.

 m p 2 1 9 to 2 2 1

NMP, (CDC13) ^ value; 4,0.4 (2H, m), 4.4,4.8 (2H, m), 7.1

, 7.9 (9H, ni), 8.3 to 8.7 (3H, w)

Example 8 3

 2 — [2 — (2 — thiazolinyl) thioethyl] 1-4 1 (3 — bilidyl) 1 1 — (2 H) Production of phthalazinone

 The same procedures as in Example 78 were carried out using 2-mercaptothiazolinyl and sodium hydride instead of vial resin to obtain the desired product.

 m p 1 2 3 to 1 24 ° C

NMR (CDC 1 ₃₎ value; 3.27 (2H, t, J -7Hz), 3.68 (2H, t, J = 6H z), 4.03 (2H, t, J - 7Hz), 4.59 (2H, t, J = 6Hz), 7.1, S.0 (5H, m), 8.3-8.9 (3H, m)

Example 84

2-—4- (2-pyrimidyl) obutyl] Jil) 1 1 — (2H) Production of phthalazinone

By using 1,4-dibromobutane in place of 1,2-dibromoethane and performing the same operation as in Example 78, 2— (4-bromobutyl) 1-141 (3-pyridyl) 1-1 one (2 H) lid Rajinon [mp 1 3 4~ 1 3 5 C, NMR (CDC 1 3) d; 1.6-2.4 (4H, M), 3.45 (2H, t, J = 7Hz), 4.33 (2H, t, J = 7 Hz), 7.2, 8.0 (5H, tn), 8.3, 9.0 (3H, m)], and then using 2-mercaptopyrimidine and sodium hydride instead of pyrrolidine. The target was obtained.

 m p 1 17-: L 18. C

NMR (CDC 1 ₃₎ value; 1.6,2.5 (4H, m), 3.20 (2H, t, J = 7Hz),

4.34 (2H, t, J = 7Hz), 6.85 (lH, t, J = 5Hz), 7.3-8.2 (5H, m), 8.42

(2H, d, J = 5Hz), 8.4,9.1 (3H, w)

Example 8 5

 2- (2-Hydroxyshetyl) -1-4- (3-pyridyl) -1-1 (2H) Production of phthalazinone

According to a method similar to that of Example 61, 4- (3-pyridin-1 (2H) phthalazinone (0.30 s) and 2-bromoethylacetate (from 0 · 17m, 2— ( 2—acetoxityl) —4— (3—pyridyl) 111 (2H) phthalazinone (0.35 g) was synthesized, and this (0.35s) was dissolved in 5 ml of tetrahydrofuran. Then, 10% sodium hydroxide was added. 5 ml of an aqueous solution was added, and the mixture was stirred for 2.5 hours at 40. After hydrolysis, the reaction solution was neutralized with 3 3-hydrochloric acid under ice-cooling, and the desired product was mixed with tetrahydrofuran and chloroform-form. The organic layer was washed with saturated saline solution, separated, and treated with magnesium sulfate. And dried. Next, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. Chloroform and methano

The mixture was developed and eluted with a mixed solvent (99: 1, ν / 'V) to obtain the desired product as (0.27 s) colorless crystals.

 mp 172-174. C

N M R (C DC 1 a) ^ value-; 3.0 (lH, br s), 4.07 (2H, t, J = 5Hz),

4.51 (2fi, t, J-5Hz), 7.2-8.0 (5Η, κι), 8.4-9.0 (3Η, ιη)

Example 86

 Manufacture of 2-carboxymethyl-1- (3-pyridyl) -1-1 (2 2) phthalazinone

 By carrying out the same hydrolysis as in Example 85, the desired product was obtained from 2-ethoxycarbonylmethyl-4-1 (3-pyridyl) -111 (2Η) phthalazinone obtained in Example 64. Obtained.

mp 241-242. C ¹

NMR (DMSO-d6) value; 4.93 (2H, s), 7.5, 9.0 (SH, [n) Example 87

 2- (3-carboxypropyl) 1-4 1 (3-pyridyl) — 1- (2Η) phthalazinone

 By performing hydrolysis in the same manner as in Example 85, the 2- (3-ethoxycarbonyldiaropyryl) -4-1 (-pyridyl) -11- (2Η) phthalazinone obtained in Example 65 was obtained. M ρ 189 ~: L 90.C

NMR (DMSO-d6) value; 1.7, 2.7 (4H, m), 4.23 (2H, t, J-

Example 88 Production of 2-vinyl-1- (3-pyridyl) -1-1 (2H) phthalazinone

Under a nitrogen atmosphere, a methanol solution of sodium hydride (0.15 _S), 2 - (2-Puromoechiru) Single 4 (3 - pyridyl) - 1 - (2 H) phthalazinone a (0.30 s) added for 1 hour at 50 Stirred. Then, the same post-treatment as in Example 61 was performed to obtain the desired product (0.21 s).

mp 19 0-: L 9 2 ^e C

NMR (CDC 1 ₃₎ value; 4.97 (lH, d, J : 9Hz), 5.79 (1H, d, J = 16

Hz), 7.2-8.2 (6H, m), 8.5-9.1 (3H, »n)

Example 8 9

 2 — (2-aminoethyl) — 4- (3-pyridyl) — 1 — (2H) Production of phthalazinone

 In a nitrogen atmosphere, 2— (2—phthalimidethyl) 1-141 (3—pyridyl) 1-1— (2H) phthaladinone (1.0 s) and 80% hydrazine hydrate (0.46) obtained in Example 8 2 were obtained. After suspending s) in ethanol I (30 ml), the suspension was refluxed for 3 hours. After cooling, the precipitated insolubles were removed, and the filtrate was concentrated under reduced pressure. Then, the residue was subjected to silica gel column chromatography, developed and eluted with a mixture of black form and methanol (96: 4: vZV) to elute the desired product (0.58s) as colorless crystals. I got it.

 m p 16 2 to 16 3. C

NMR (DMSO - d ₆₎ values; 1.86 H, s), 3.00 (2H, t, J-7Hz) 4.20 (2H, t, J = 7Hz), 7.4-8.2 (5Η, ιη), 8.2-8.6 (1H , m), 8.6-8.9 (2H, BI) Example 9 0

 Production of 2- (2-benzenesulfonamidoethyl) 1-14-1 (3-pyridyl) 1-111 (2H) phthalazinone

Under a nitrogen atmosphere, a suspension of sodium hydride (53 »g) in dimethylformamide (1 Oral) was added to a suspension of 2- (2-aminoethyl) -14- (3-pyridyl) 1-1 obtained in Example 8. One (2H) phthalazinone (0.30 _S ) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was ice-cooled, benzenesulfonyl chloride (0.21 ml) was added, and the mixture was further stirred under water cooling for 1 hour. The reaction mixture was poured into cold water and extracted with chloroform. The foam layer was washed with water and then dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. The mixture was developed and eluted with a mixture of chloroform and methanol (99: 1, v / V) to give the desired product (0.20 s) as colorless crystals.

 m p 15 7-: L 59. C

NMR (CDC 1 ₃₎ ί value; 3.51 (EH, t, J = 6Hz), 3.60 {2H, t, J = 6H z), 5.8S (lH, t, J = 6Hz), 7.1-S .1 ( 10H, m), S .3-8.7 (111, m), 8.

-9.0 (EH, m)

Example 9 1

 2— (3-Isopropyl power rubamoylp mouth pill) 1-4 1 (3-pyridyl) 1 1 1 (2H) Production of phthalazinone

Example 8 2- (3-Carboxyporyl) 1-141 (3-pyridyl) 1-111 (2H) phthalazine (0.29 _S ) obtained in 7 and triethylamine (0.14η> 1) in dichloromethane (0.14η> 1) To the solution (10 ml) was added phosphorus pentachloride (0.21 g) under cooling, and the mixture was stirred for 15 minutes. The reaction solution was concentrated under reduced pressure. After methylene chloride (10 ml) and tetrahydrofuran (10 ml) were added to the residue, the mixture was similarly compressed. Further, tetrahydrofuran (20 ml) was added and the mixture was compressed, dimethylformamide (IOBI1) was added, and isopropylamine (O.lSml) was added dropwise thereto under ice cooling. Next, the mixture was stirred for 1 hour under ice-cooling and for 3 hours at room temperature, then poured into cold water and extracted with a black hole form. The pore-form layer was washed with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. The desired product (0.04 g) eluted and eluted with a mixed solution of foam and formanol (99: 1, V.V) was obtained as colorless crystals.

 in 1 58-: L 59. C

NMR (CDC 1 _3> <5 value; 1.13 (6H, d, J = 7Hz), 2.24 (2H, rn),

4.00 (lH, m), 4.37 (EH, t, J = 7Hz), 6.1 (lH, br s), 7.2-8.Z (5H, m), 8.4-9.1 (3H, rn)

Example 9 2

 2-Ethyl — 7 —Fluoro-4 1 (3 —pyridyl) 1 1 — (2 H) Production of phthalazinone

 4— (3—Pyridyl) 1—11— (2H) Phthalazinone is replaced by 7—fluoro—4— (3-pyridyl;) 1-1— (2H) phthalazinone, and the same operation as in Example 61 is performed. The purpose was obtained by doing.

 m F> 1 6 3 ·. C

NMR (CDC 1 ₃₎ value; 1.44 (3H, t, J = 7Hz), 4.33 (2H, q, J--

7Hz), 7.2-8.3 (5H, m), 8.6,8.9 (2H, rn)

Example 9 3 Production of 2- (4-methoxybenzyl) .4- (3-pyridyl) -1-1 (2H) phthalazinone

 The same procedure as in Example 61 was carried out, except that methyl-41- (bromomethyl) benzoate was used instead of ethylpromide, to obtain the desired product.

 mp 174-176. C

NMR (CDC13) value; 3.87 (3H, s), 5.50 (2H, s), 7.2 to 8.1

OH.rn), 8,3,9.0 (3Η, ίη)

Example 94

 2—Isobutyl 1— (3—Pyridyl) 1—1 (2Η) Production of phthalazinone

 The desired product was obtained by performing the same operation as in Example 61 using isobutyl bromide instead of ethylpromide.

 m p 150-: L 51. C

NMR (CDC 1 _{3) 3} values; 1.03 (6H, d, J = 7Hz), 2.41 (1Η, ιη),

 4.17 (2H, d, J = 7Hz), 7.2-8.1 (5H, rn), 8.4-9.1 (3Η, ι «)

Example 9 5

 2 —Phenylsulfonyl-4 — (3 —Pyridyl) 1 1 1 (2 2) Preparation of phthalazinone

 The same procedures as in Example 61 were carried out using benzenesulfonyl chloride instead of ethyl bromide to obtain the desired product.

m ρ 17 2-: NMR (CDC 13) value at L 73; 7.2 to 8.6 (11Η, << ι), 8.7 to 9,0 (2H, m) Example 96 2- (2-Tenoinole) 1 4 — (3-Pyridyl) 1 1 — (2 H) Production of phthalazinone

 The intended product was obtained by performing the same operation as in Example 61, using 2-thiophene carboxylate instead of ethylpromide.

 m p 1 65-: L 67

NMR (CDC 1 ₃₎ value; 7.0-8.6 (8H, m), S.4-9.1 (3H, m) Example 9 7

 Production of 2- (3-cyclopentyl) 1-4- (3-pyridyl) 1 1 (2H) phthalazinone

 The desired product was obtained by performing the same operation as in Example 61 using benzyl chloride of 3-chloro mouth instead of ethyl bromide.

 m P 17 0 ~ 1 7 1

NMR (CDC 1 ₃₎ value; 5.39 (2H, s), 7.1, S · 0 (9H, [n), the S .3

 8.9 (3H, rn)

Example 98

 2— (2,2,2—Trifluoroethyl) 1-4— (3-pyridyl) 1-1— (2H) Production of phthalazinone

 The desired product was obtained by performing the same operation as in Example 61 using 2,2,2-trifluoroethyl chloride instead of ethyl bromide.

 m p 1 4 3 ~: L 45 ° C

NMR (CDC 1 ₃₎ value; 4.93 (2H, q, J = 8Hz), 7.2-8.1 (5H .m), 8.4-9.0 (3H, m) Example 9 9

 Preparation of 2 — (4-lipoxybenzyl)-4 '-(3-pyridyl) 1-(2 H) phthalazinone

 By performing hydrolysis in the same manner as in Example 85, 2— (4-methoxycarbonylcarbonyl) -4- (3-pyridyl) 1-1 obtained in Example 93—1— (2H) The desired product was obtained from phthalazinone.

 m p> 300 ° C

NMR (DMSO-d6) S value; 5,48 (2H, s), 7.3-9.0 (12H, in) Example 100

 4 Production of I- (1-imidazolyl) I-I- (2H) phthalazinone In a nitrogen atmosphere, imidazole (0.78g) was added to a suspension of sodium hydride (0.55g) in dimethylformamide (lOOwl). After stirring at room temperature for 30 minutes, the reaction solution was ice-cooled, and 1,4-dichlorophthalazine (2.2 g) was added. After stirring at room temperature for 2 hours, a 1N aqueous solution of sodium hydroxide (2 O ml) was added at room temperature, and the mixture was further stirred for 1 hour, and dimethylformamide was distilled off under reduced pressure. A mixed solution of diluted hydrochloric acid and ethyl acetate was added to the mixture, and the mixture was stirred for 5 minutes.After confirming that the aqueous layer was acidic, the aqueous layer was separated, and the aqueous layer was adjusted to pH 8 with a 5% aqueous sodium hydrogen carbonate solution. After standing in a refrigerator overnight, the precipitated insolubles were collected and recrystallized from ethanol to obtain the desired product (0.8 g) as pale yellow crystals.

 m p 2 8 7 to 2 8 9

NMR (DMS 0-d 6) value; 7.25 to 8.60 (7H, m) Example 10 1

 4-[1-(1 H-1, 2, 4-triazolyl)]-1-(2 Η) Production of phthalazinone

 The desired product was obtained by performing the same operation as in Example 100, except that 1Η-1,2,4-triazole was used instead of imidazole.

 m ρ 27 1-2 7 2. C

NMR (DMS 0-d ₆ ) value; 7.80 to S.20 (3H, “η”, 8.25, 8 · 60)

(2H, rn), 9.18 (lH, s)

Example 10

 Production of 4- (2-thiazolyl) -111 (2H) phthalazinone under nitrogen atmosphere. A solution of 2-bromothiazole (10.0 g) in tetrahydrofuran (5 Oml) was added dropwise to a 15% butyllithium hexane solution (45 ml) cooled to C, and the mixture was stirred at the same temperature for 1.5 hours. Then, the reaction solution was added to a solution of phthalic anhydride (10.8 g) in dry trihydrofuran (400 ml) with a pressure of -78, and the mixture was stirred under a nitrogen atmosphere for 1 hour. After the temperature was returned to room temperature, a mixed solvent of a 5% aqueous solution of carbon dioxide and ethyl acetate was added thereto, followed by stirring for 5 minutes. After confirming that the aqueous layer was alkaline, the aqueous layer was separated and then made acidic by adding 4N-hydrochloric acid, and extracted with ethyl acetate. After drying over magnesium sulfate, the solvent is distilled off under reduced pressure, and the residual crude crystals are recrystallized from ethyl acetate / ethyl acetate to give 2- (2-carboxybenzoyl) thiazole (6.0 g). Obtained.

mp 17 2 to 17 3 ° C NMR (DMSO-d6) value; 7 · 50 to S.40 (6H, tn)

 The obtained 2- (2-carboxybenzoyl) thiazole (6.0 g) was dissolved in ethanol (200 <1>), and 80% hydrazine hydrate (2 <1) was added. After stirring under reflux with heating for 1 hour, the mixture was cooled, the precipitated insoluble material was collected, washed with water, and recrystallized from ethanol to obtain the desired product (4.2 g).

 m p 254-255. C

NMR (DMSO-d6) value; 7.80 to 8.30 (4H, m), 8.30-8.55

(lH, m), 9.35-9.60 (lH, m)

Example 1 0 3

 Preparation of 4- (5-thiazolyl) -11- (2H) phthalazinone Under a nitrogen atmosphere, 15% butyllithium hexane solution (110 ml) cooled to 178 was added to thiazole (12.8 g) in tetrahydrofuran (5 Oml) was added dropwise, and the mixture was stirred at the same temperature for 40 minutes, and then t-butyldimethylsilyl D-ride (24.8 g) in tetrahydrofuran (5 Oml) was added thereto. 0, nl) was added dropwise, and the mixture was stirred at the same temperature for an additional hour, and then returned to room temperature.

 A saturated aqueous sodium hydrogen carbonate solution (200 ml) was added to the reaction solution, and the mixture was extracted with ether. The organic layer was dried over sodium sulfate. Next, 2-t-butyldimethylsilylthiazole (21. Og) was obtained by distillation under reduced pressure.

 b p 102-: L 05. C,, 22 m m H g

NMR (CDC13) value; 0.40 (6H, s), 1.00 (9H, s) 7.50 (lH, d, J = 3Hz), 8.15 (lH, d, J = 3Hz)

The obtained 2-t-butyldimethylsilylthiazone (5. 0 g) of as tetrahydrofuran solution. The (5 O n »l), nitrogen atmosphere under was added dropwise to hexanes (1 8 in!) To 1 5% butyl lithium in one 7 8 ^e C, the Stirred at temperature for 30 minutes. Next, this reaction solution was added to a solution of phthalic anhydride (4.4 g) in tetrahydrofuran (10 Ontl) at 178 C, and the mixture was stirred at the same temperature for 1 hour and further at room temperature for 30 minutes. .

 After the reaction, a mixed solution of a saturated aqueous solution of sodium hydrogencarbonate and etino acid L was added, and the mixture was stirred for 5 minutes. After confirming that the aqueous layer was strong, the aqueous layer was separated. The pH of the aqueous layer was adjusted to 4 with 4 N hydrochloric acid, extracted with ethyl acetate, and the organic layer was dried over sodium sulfate. Then, the solvent is distilled off under reduced pressure, and the obtained crude product is recrystallized from ethyl acetate-η-hexane to give 2-t-butyldimethylsilyl-5- (2-carboxylic benzoxybenzoate). 3.9 g of ethyl thiazole was obtained.

 mP128-: L30. C

NMR (DMS 0-d ₆ ) value; 0 · 38 (6H, s), 0.92 (9H, s), 7.40-S.20 (4H, ifl), S. 10 (lH, s)

 The above-obtained 2-t-butyldimethylsilyl-5- (2-carboxoxybenzoyl) thiazole (3.5 g) was dissolved in ethanol (200 ml), and then 80% was added thereto. Hydrazine hydroxide (2 ml) was added, and the mixture was stirred under reflux with heating for 6 hours. Then, concentrated hydrochloric acid (2 O rnl) was added, and the mixture was stirred at room temperature for 1 hour. The insoluble material was collected and recrystallized from ethanol to obtain the desired product (2.7 g). Obtained.

mp 229-230. C NMR (DMSO-d6) value: 7.80-8.30 (3H, rn), 8.30-8.55

(2H, «, 9.30 (lH, s)

Example 1 04

 Manufacture of 2-ethyl-4- (5-pyrimidyl) 1-1 (2H) phthalazinone

 Under a nitrogen atmosphere, 5-bromopyrimidine (10.0 g) was mixed with a mixture of ethyl ether and tetrahydrofuran (1: 1, V-Y,

300 ml), and a 15% 15% butyllithium hexane solution (36 inl) was added dropwise thereto. After stirring at the same temperature for 20 minutes, a tetrahydrofuran solution (400 «11) of phthalic anhydride (9.0 s) previously cooled at 178 was added, and the mixture was further stirred at -7 CTC for 1 hour. . After returning to room temperature, a 5% aqueous sodium hydrogen carbonate solution (300 »1) was added, and the aqueous layer was separated. Next, the aqueous layer was acidified with 3N-hydrochloric acid, and the precipitated insoluble material was collected. The obtained insoluble material was dissolved in ethanol (300 in 1), 80% hydrazine hydrate (20 ml) was added thereto, and the mixture was stirred under heating and reflux for 6 hours. After returning to room temperature, the precipitated insoluble material was collected, and then dried with water and H. The obtained insoluble matter was added to a suspension of about 0% sodium hydride (1.4 g) in dimethylformamide (200, ηI) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. Echilpromide

(5.0 ml), and the mixture was further stirred at room temperature for 1 hour. After a small amount of water was added, the solvent was distilled off under reduced pressure, and then a mixed solution of water and ethyl ester (400 in 1) was added to the obtained residue, followed by stirring for 5 minutes. And dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. I attached it. The product was developed and eluted with a black hole form to obtain the desired product (0.3 g).

 m p 202-204. C

NMR (CDC13) value; 1.48 (3H, t, J = 7 Hz), 4.38 (, q, J:

 7Hz), 7.50-8.05 (3H, rn), 8.40-8.70 (lH, rn), 9.00 (2H, s),

9.32 (lH, s)

Example 1 0 5

 Production of 4- (2-birazinyl) 1 1 1 (2H) phthalazinone

 Under a nitrogen atmosphere, a 15% butyllithium hexane solution (70 ml) was added dropwise to a solution of 2-bromobenzoic acid (10.2 g) in motra hydrofuran (300 in 1) at -78 ° C. did. After stirring at the same temperature for 30 minutes, a tetrahydrofurani solution (150 m 1) of 2-pyrazine carboxylic acid methyl ester (7.4 g), previously cooled to 178, was added thereto. The mixture was further stirred for 30 minutes. The temperature was returned to room temperature, a mixed solvent of a 5% aqueous solution of hydrogencarbonate and ethyl acetate was added, and the mixture was stirred for 5 minutes. The aqueous layer was acidified with 31 ^ -salt, and extracted with ethyl acetate (400 ml): dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was ethanol (200) ml) and 80% hydrazine hydrate (1 Oml) were added, and the mixture was stirred under heating and reflux for 3 hours. After cooling, the precipitated insolubles were collected, washed with water, and recrystallized from ethanol to obtain the desired product (1.9 g).

 m p> 300. C

NMR (DMSO-cl 6) value; 7. To S5 S .10 (2H, S · 30-S · 55 (EH.m), 3.85 (2H, s), 9.15 (lH, s) Example 1 0 6

 Production of 2-methyl-4- (5-thiazolyl) 1-1 (2H) phthalazinone

 Using methyl hydrazine instead of 80% hydrazine hydrate, the same operation as in Example 103 was carried out, and purification was carried out by silica gel chromatography. The desired product was obtained.

 m p 198 to 200. C

N MR (CDC 1 ₃₎ value; 3.90 (3H, s), 7.75,8.20 (3H, m>, S.2S

(lH, s), 8.48-8.75 (1Η, κι), 8.98 (lH, s)

Example 1 0 7

 2-—Ethyl—4— (1 I-midazolyl) 1 1 1 (2 H) Phthalazinone

 Under a nitrogen atmosphere, a suspension of 60% sodium hydride (0.45 g) in dimethylformamide (1 O Oml) was prepared using 4- (1-imidazolyl) 1 obtained in Example 100. 1 One (2H)-Phthalazi Noni

(2. 0 g> was added, at room temperature for 30 minutes and stirred. Then. E Ruburomai de (1. 1 _m i) was added was added to the Shohoshi water After stirring for an additional hour at room temperature. Vacuum After distilling off the solvent under reduced pressure, a mixed solvent of water and ethyl acetate was added to the residue, the organic layer was separated, dried over 10% sulfuric acid, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and developed and eluted with a black hole form to obtain the desired product (1.5 g).

 m p 17 2 to 17 3. C

N MR (CDC 13) value; 1.45 (3H, t, J = 7 Hz), 4.30 (2H, q, J = 7Hz), 7.25-8.05 (6H, fn), 8.40-8.70 (lH, m)

Example 108

 2—Ethyl 1—4—1 1—1 H—1, —2—4 J

— 11 (2 H) — Manufacture of phthalazinone

 4— (1-Imidazorimere) 1 1— (2H) —Instead of phthalazinone 4 -— [1— (1H—1,2,4-triazolyl)] —

The desired product was obtained by performing the same operation as in Example 107 using 1 (2H) -phthalazinone.

 mp161-: L62. C

NMR (CDC 1 ₃₎ value; 1.46 (3H, tJ = 7Ik ), 4,32 (2H, Q, J - 7H z), 7.75-8.05 (2H, rn), 8.05-8.40 (2H, in), 8.40-8.65 (1H, m),

8.75 (lH, s)

Example 1 09

 2-Ethyl—4- (5-thiazolyl) —1— (2H) —Phtaradinone

 4— (1—Imidazolinole) 1 1— (2H) —Phthalazinone 4— (5—Thiazolyl) 1 1— (2H) —Phthalazi- ′ The desired object was obtained by performing the operation.

 m p 1 2 1 to 1 22. C

NMR (CDC 1 _3> S value; 1.45 (3H, t, J = 7Hz), 4.35 (2H, q, 7Ηζ), 7.70-8.20 (3Η, ίη), 8.28 (1H, s), 8.35-8.70 (1H , rn), 9.00 (lH, s)

Example 1 1 0

2-Ethyru 4— (2-Biradinil) 1 1 — _ (2 H) —Phtara 目 二 Ί 二)! : ϋ 360 0 ΐ mM ^^^ oz ^ '

<> 厶 a 1/ ェ ― ( H e ) - I - ( Πゾ、 — S 〉 - - V Ά π A - z

<> M a 1 / e-(He)-I-(Π, — S〉--V Ά π A-z

 z I T m 02

( ^UJ 'HI) 0S'6, 02'6' ( ^ul 'Hi) 09'8, 0S'8' ( ^w 'H OO'S, OS'i' (HL

: ^B 'H2〉 2IS' (HL = 'U) ^' \ 'MS ( ^ε Ϊ 0 a 3) Ή WN

 One. (5 s, · s e: ΐ <ί ω ^ eyes, Q:? Z ¾¾.¾} fi? Mfel i 0 I fi ^ Sili ST

,, ί (H Z)-τ-(ri —)-ΐ ^ ί 0

 ? / '^ L ~ (u z) — τ — (/ ("" /

"Shi — (H Z)-τ-(Λ (n .A-^-ζ) — 1 · 1 T— ε

 χ τ χ m 01

( ^S 'HT)

^{52 "6 '(s' H2} ) · 8 '(V1 Ή2) Si · 8-0 ^' 8 '(w' H2) 00 - 'A' (z Hi

-Γ '^&' Η2) Ι ^ · ^ '( ^z Hi = f ^< f'H8) 05-I: Firewood ( ^ε 〖0 (Ι) HWN

 0. M I-9 "[dm

M eyes i :)) r ^^ fei :? o I mmrn,!.

 (Shiichi (H Z)-I-(^ Ά-Ζ) f ^

 G? 'Ku ^ Otsuichi (U Z) Ichi — — ((f-I)-V

 w.mo ^

Si

0ir00 / l6df / IDd mp 74-75. C

NMP, (CDC13) value; 1.47 (6H, d, J = 7Hz), 5.45 (1Η ,, ί,),

7.70-8.25 (3Η, ΓΠ), S.35 (lH, s), 8.40-8.75 (1H, rn), 8.98 (1H, s) Example 1 1 3

 Preparation of 2-aryl-1 4- (5-thiazolyl) -1 1- (2H) -phthalazinone

 The desired product was obtained by performing the same operation as in Example 109, using arylpromide instead of ethylpromide.

 m p 1 05 to 1 106. C

NM R (CDC 1 ₃₎ value; 4.80 5.50 (4H, m) , 5.75 6.45 (111, _{"η;', 7.70,8.15 (3H,} m), 8.25 (1H, s), 8.40-8.70 (1H, in ), 8.98 (1H, s) Example 1 1 4

 2-Isobutyl-4- (5-thiazolyl)-1-1 (2H)-Preparation of phthalazinone

 The desired product was obtained by performing the same operation as in Example 109, except that isobutyl bromide was used instead of ethyl bromide.

 mp 85-86. C

NM R (CDC 1 ₃₎ value; 1.02 (6H, d, J = 7Hz), 2,3S (lH, n, 4.12 (2H, d, J = 7Hz), 7.75-3.20 (3Η, m), S. 30 (1Η, s), 8.45-8.70 (lH, m), 8.9S (lH, s)

Example 1 1 5

 Production of 2-cyclopentyl—4- (5-thiazolyl) —1- (2H) -phthalazinone

Example 10 9 was used instead of ethyl bromide, and the reaction temperature was 70 and the reaction time was 3 hours. By performing the same operation as in the above, the desired product was obtained.

 m p 12 0 to 12 1. C

NMR (CDC 1 ₃₎ value; 1.50-2.90 (8H, m), 5.35-5.90 (lH, iit), 7.70-8.25 (3H, in), 8.32 (lH, s), 8.45-8.75 (1H, .n ), 8.98 (lH, s) Example 1 1 6

 2— (2,2,2-Trifluoroethyl) — 4— (5-Thiazolyl) — 1— (2H) —Preparation of phthalazinone

 The desired product was obtained by performing the same operation as in Example 109, using 2,2,2-trifluoroethyl chloride instead of ethyl bromide, and setting the reaction time to 20 hours.

 m p 12 9 to 13 1. C

NMR (CDC13) value; 4.87 (2H, q, J = 8 Hz), 7.60-8.10 (3Η, ίπ)

, 8.15 (lH, s), 8.30-8.55 (1Η, Μ), 8.85 (1H, S)

Example 1 1 7

 2— (2—Methoxyxetil) 1 4— (1—Imida, no'ryl) 1 1 1 (2Η ') — Production of phthalazinone

 The desired product was obtained by performing the same operation as in Example 107, using 2-methoxethyl π-ite as the frit of the mouth nozzle.

 m p 1 2 8 to 1 2 9

NMR (CDCΊ3) value; 3.35 (3H, s), 3.85 (2H, t, J = DHZ),

4.45 (2H, t, J = 5Hz), 7.25-8.10 (6Η, m), 8.35-8.70 (1Η, «,)

2— (2-acetoxityl) 1—4— (1 imidazolyl) 1 1 1 (2Η) -phthalazinone The desired product was obtained by performing the same operation as in Example 107 using 2-bromo-ethyl acetate instead of ethyl bromide.

 mp 154-155. C

NMR (CDC13) (J value; 2.00 (3H's), 4.52 (4H, s), 7.25-8.15

(6H, «i), 8.40-8.70 (lH, m)

Example 1 1 9

 2— (2—Hydroxitytil) 1-41 (1—Imidazoli / re) 1-1— (2H) Production of phthalazinone

 Example 1 2 — (2 — acetoxityl) 1 4-(1 — imidazolyl) 1 1 (2H) — phthalazino obtained in 18

 (1.6 g) was dissolved in ethanol (100 ml), a 1N aqueous sodium hydroxide solution (10 ml) was added thereto, and the mixture was stirred at room temperature for 30 minutes. After the reaction, the pH was adjusted to 7 with 2N hydrochloric acid, and then the solvent was distilled off under reduced pressure. A mixture of water and ethyl acetate was added to the residue, and the mixture was stirred for 5 minutes, and then the organic layer was separated. After drying over sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude crystals were recrystallized with a mixed solvent of ethyl acetate and n-hexane to obtain the desired product (1.1 g). I got

 m p 140-141. C

NMP, (CDC13) value; 395 to 4.30 (2Η, ίη), 4.35, 4.60 (2H, m)

7.20 to 8.05 (6Η, << ι), 8.40 to S.70 (1H, M)

Example 1 2 0

 1 1 oxo 1, 2-jihi draw 4 ichi (3-pyridi) thieno

 [2,3-d] Pyridazine production

Under a nitrogen atmosphere, 15% butyllithium hexane solution (5 O ml To this was added dropwise a solution of 3-promothiophene (12.2 g) in tetrahydrofuran (5 Oml) at 178. After stirring at the same temperature for 20 minutes, a solution of 3-cyanopyridine (8.0 g) in tetrahydrofuran (5 Oinl) was quickly added dropwise, and the mixture was stirred at the same temperature for 1 hour. After returning to room temperature, stirring was further continued for 1 hour. Then, the reaction solution was cooled to 5 and added with 15% butyllithium hexane solution.

(55 ml) was added all at once. After stirring at 40 ° C for 2 hours, the reaction solution was cooled to 178 C and the reaction solution was crushed into dry ice.

(500 g). After standing overnight, the pH was adjusted to 1 with 4 N hydrochloric acid, and the mixture was stirred at 40 for 30 minutes. Then, ethyl acetate (10 Oml) was added thereto, and the mixture was stirred, and then the aqueous layer was separated. Further, after removing impurities, the pH of the aqueous layer was adjusted to 8 with a 5% aqueous carbonated solution, and ethyl acetate (10 Oml) was added and stirred. The aqueous layer was separated, and 3N-hydrochloric acid was added again. The pH of the aqueous layer was adjusted to 3 to 4, and the mixture was extracted with ethyl acetate (40 Offl), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. (200 «I) and 80% hydrazine hydrate (10) were added, and the mixture was stirred under reflux for 6 hours.After cooling, the solvent was distilled off under quenching.

(100 ml), the pH was adjusted to 8 with 3N-hydrochloric acid, the insoluble material was collected, air-dried, and recrystallized from ethanol to obtain the desired product (1.2 g). ).

 m p 2 5 5 to 2 5 6 ° C

N M R (D M S 0-d 6) value 7.45-7.80 (ZH, rn) .8.05-S.45

(2H, tn), 8.70-9.05 (Efi, rn)

Example 1 2 1 1 Production of 1-oxo-1,2-dihydro-4- (3-pyridyl) thieno “3,2-d ピ リ pyridazine

 Under a nitrogen atmosphere, a tetrahydrofuran solution (50 mi) of 2,3-dibumochiophene (18.lg) was added dropwise to a 15% butyllithium hexane solution (5 Oml) at -78 at the same temperature. For 30 minutes. Then, a solution of 3-cyanopyridine (8.0 g) in tetrahydrofuran (5 Ofni) was quickly added dropwise to the mixture, and the mixture was stirred at the same temperature for 30 minutes, then returned to room temperature, stirred for 15 minutes, and then again stirred at 78 ° C. C, and a 15% butyl lithium hexane solution (50 ml) was added dropwise. After stirring at the same temperature for 30 minutes, the reaction solution was poured into finely ground dry ice (500 g). After standing overnight, the pH was adjusted to 1 with 3N-hydrochloric acid, and the mixture was stirred at 4TC for 30 minutes. Next, ethyl acetate (10 Oral) was added thereto, and the mixture was stirred, and then the aqueous layer was separated. In order to further remove impurities, the pH of the aqueous layer was adjusted to 8 with a 5% aqueous carbonated lime solution, and then ethyl ethyl perchlorate (100 ml) was added and stirred, and the aqueous layer was separated. The pH of the aqueous layer was adjusted to 3 to 4 again by adding 3N-hydrochloric acid, dried over sodium sulfate extracted with ethyl acetate (40 O ml), and the solvent was distilled off under reduced pressure. Ethanol (200 ml) and 80% hydrazine hydrate (10 ml) were added to the residue, and the mixture was stirred under heating and reflux for 6 hours. After cooling, the solvent was distilled off under reduced pressure. After adding water (1000), the pH is adjusted to 8 with 3N-hydrochloric acid, the insoluble material is collected, air-dried, and recrystallized from ethanol to obtain the desired product (1). 9 g) was obtained.

m p 286〜2 88 ° C

N MR (DMS 0-d 6) value; 7.50, 7 · 90 (2H, m), 8 · 15, 8.45 (2Η, .η), 8.72-9.20 (2Η, »η)

Example 1 2 2

 1 oxo 1 2 dihi draw 2-ethyl 4- thi (3 pyridyl) thieno "2, 3 d 1 Manufacture of pyridazine

 4- (1-Imidazolyl) 12H) Instead of phthalazinone, 1-oxo-1,2-dihydro 4- (3-pyridyl) thieno [2,3-d] pyridazine obtained in Example 120 was used. The same procedure as in Example 107 was carried out to obtain the desired product.

 m p 1 2 7 1 2 9

NMR (CDC 1 ₃₎ value; 1.50 (3H, t, J = 7Hz) 4.42 (2H, q J =

7Hz), 7.35-7.70 (2H, _m ), 7.85-8.20 (2H, _m ), S.70-9.20 (2H, rn)

 1 oxo 1,2 di-t-dro-2-ethyl 4- (3-pyridyl; I) thieno "3,2-d-pyridazine production

 4 1 (1 1 imidazolyl) 1 1 — (2 H> 1 f tarazinong ') Instead, 1 —oxo-1, 2-dihydro-1 4 obtained in Example 12 1 — 4 — (3 pyridyl) The target product was obtained by performing the same operation as in Example 107 using thieno [3,2-d] pyridazine.

 m p 9 3 94 C

NMP, (CDC13) value; 1.48 (3H, t, J = 7Hz), 4.38 (2H, q J = 7Hz), 7.30-7.65 (lH, m), 7.75 (2H, s), 8.10-8.40 ( 1H, m), 8.68 -9.35 (2H, rn)

Example 1 24 2- (2,2-Dimethylaropyr) — 4 —. (3-Pyridyl) one

1 Production of 1 (2Η) phthalazinone

 The desired product was obtained by performing the same operation as in Example 61 using 2,2-dimethylpropylbutamide instead of ethyl bromide.

mp 19 0 ~ 19 1 ^e C

NMR (CDC 1 ₃₎ value; 1.08 (9H, s>, 4.19 (2H, s), 7.Π 1

(5H, s), 8.4-9.1 (3H, tn)

Example 1 2 5

 2- (2-Hydroxypropyl) -1-41- (3-pyridyl) -1-]-1- (2H) phthalazinone

 The desired product was obtained by performing the same operation as in Example 61 using 2-hydroxypropyl pyramide instead of ethylpromide.

 mp 175-17-177. C

NMR (CDC13) value::! .S3 (3H, m), 3.60 (lH, m), 4

, 7.2-S.l (5H, m), S.4-9.0 (3H, m)

Example 1 2 6

 2- (2-Hydroxy-l- 2-methylpropyl) -l-l- (3-f-Ridyl) -l- (2H) Production of phthalazinone

 The desired product was obtained by performing the same operation as in Example 61 using 2-hydroxy-2-methylpropyl bromide instead of ethylpromide.

 m p 1 3 8 to 1 4 0

NMR (CDC 13) value; 1.33 (6H, s), 4.29 (br s), 4.40 (2H, s), 7.3-8.l (5H, m), S .3-9.0 (3H, in)

Example 1 2 7

 Preparation of 2-ethyl-1-6-fluoro- (3-pyridyl) — 1 — (2H) phthalazinone

 4-1 (3-pyridyl) 1 1 1 (2H) The same operation as in Example 61 was performed using 6-fluoro-1- (3-pyridyl) 1 1 1 (2H) phthalazinone instead of phthalazinone. The purpose was obtained by doing.

 mp 157-159. C

NMR (CDC 1 ₃₎ value; 1.45 (3H, t, J = 7Hz), 4.36 (2H, Q, J = 7H z), 7.2-7.8 (3H, m), 7.8-8.2 (lH, m), 8.4 -9.1 (3H, .n)

Shown to have a an example, the present compounds have excellent TXA ₂ synthase inhibitory activity and bronchodilator activity represented by the general formula (I) Test Examples below.

 (Test Example 1)

Examination of TXA ₂ synthase inhibitory action

Usagi platelets (approximately 1 0 ⁸ ZMI>, porcine aortic Mi black, over beam (about 1 0 g ZML) and the compound represented by the general formula (I) (1 0 - ^£ M) and buffer containing (1 5 ιτι Μ Tris-hydrochloride, 140 mM sodium chloride, 10 mM glucose, pH 7.6) was stirred, and array incubated for 3 minutes at 25. This was followed by arachidonic acid (1 to 3 M). Was added, and the mixture was incubated at 25 ° C for 3 minutes to react.Then, the reaction was stopped by adding 1N hydrochloric acid to make it acidic, and then centrifuged at 1500> g. the TXB ₂ the amount of the supernatant R. IA method to measure Ri by the (Amersham kit) Was.

Similarly, to measure the general formula (I) where the compound was not used represented by the Controls and TXB ₂ amount in the case of using the Aminofu I phosphorus in place of the compound represented by the general formula (I).

Table 1 shows the TXA ₂ synthase inhibition rate based on the TXB ₂ content of the control.

* j

Example No. T X A 2 synthase inhibition rate (% ') None 0

 ( Control>

 1,2 40

 3 74

 4 85

 5 89

 6 70

 7 81

 8 75

 10 85

 11 93

 12 42

 13 51

 14 57

 16 54

 17 39

 20 57

 21 85

 22 73

 24,25 34

 26 38

 32 61

 33 37

 36 43

 37 50

 39 98

 41 50

 43 57

 44 65

 45 69

 79

 47 63

 48/0

 49 51

 50 80

 51 79

 52 36

 55 84

 56 44

57 59

(試験例 2 )

(Test Example 2)

 Examination of relaxing action of isolated tracheal muscle

 Krbs — Hense 1 eit solution in which a Hartley guinea pig weighing 500-800 g was occipitally traumad, exsanguinated, and the trachea was removed and a mixture of 95% oxygen and 5% carbon dioxide gas was ventilated.

 (119.0 mM sodium chloride, 4.8 mM potassium chloride, 2.5 mM calcium chloride, 1.2 mM potassium dihydrogen phosphate, 1.2 mM magnesium sulfate, 24.8 mM sodium bicarbonate, 100 mM About 2 to 3 widths along the cross section in glucose)

10 mm annular sections were made. After connecting each with three threads, the smooth muscle and the contralateral cartilage were dissected and used as a linkage specimen. The specimen was suspended with a pre-load of 1 g in a Magnus bath filled with the above-mentioned nutrient solution, and one end was connected to an isotonic transducer. After passing through the parallel time of about 6 0 minutes, relaxed by iso § b tele Nord (1 0 _ ⁶ M) and washed

Fifteen

When the purification was repeated several times at intervals of 40 to 50 minutes, the specimen spontaneously became tensioned. Thereafter, the compound was added cumulatively into the tank, and the tension was measured at each port to obtain a relaxation degree reaction bending. The EC _so value was calculated from this curve and shown in Table 2 as a negative logarithmic value.

 E0

 In the same manner, the case where aminophylline or 3- [4- (11-imidazolylmethyl) phenyl] -12-aropenic acid was used instead of the compound represented by the general formula (I) was also examined.

twenty five Table 2

摘出気管筋弛緩 摘出気管筋弛緩 実施例 No. 作用 -log[EC₅₀] 実旃例 No.

Relaxation of isolated tracheal muscle Relaxation of isolated tracheal muscle Example No. Action -log [EC ₅₀ ]

61 5.88 88 5.30

62 4.94 90 4.58

63 5.03 91 4.19

64 4.63 92 5.67

65 5.00 94 6.00

66 5.51 96 4.91

67 5.67 98 6.06

68 4.92 99 4.77

69 5.50 103 5.92

70 5.64 106 5.80

71 4.87 107 5.27

72 5.86 109 6.25

73 5.56 112 5.74

74 6.68 114 6.05

75 4.66 116 5.71

7b 5.61 124 5.84

77 4.39 127 5.07

 0 v ¾ ¾ DC 7 7 · * V 4.33

81 4.96 3- [4- (l-

82 4.66 sytem >>)

83 4.98 2 D B Ben

 84 5.21 Acid

85 5.34 (Test Example 3)

Specimen began to have spontaneous tensioned by treatment with I Zopuroterenoru according to the procedure of Test Example 2 applies a fin Dometashin (2.S X10- ⁶ M), while removing the spontaneous tension Hisuta increased tension in the ^{- (6 M 3~ 8 X 1} 0) or acetylcholine (2~ 8 X 1 0 one ^G M) spontaneous tension and comparable prior removal Ri by the Mi emissions. Thereafter, the compound of Example 24 (or 25) was added cumulatively to the tank, and evaluated by the same technique as in Test Example 2 to obtain the results shown in Table 3. Table 3

(Test Example 4)

Examination of the effect on asthma-like attack by airway constriction substance spray

A Hartley male guinea pig (body weight 450-600 g) is placed in a chamber and a 0.03% histamine aqueous solution is sprayed using an ultrasonic nebulizer, and the guinea pig rolls over. The time up to was measured as the collapse time. Guinea pigs fasted for about 20 hours (co 11 apsetime before drug administration) The solvent or the test drug was orally administered to the test sample for 90 to 220 seconds, and after 1 hour, the histamine aqueous solution was sprayed for 9 minutes, and the collapse tite was measured. Immediately after spraying, guinea pigs were taken out of the chamber and checked for life and death. Table 4 shows the results.

 Table 4

(Test Example 5)

Study of the effect on rat serum TXB ₂欉度

After a male SD rat (body weight 240-260 g) was fasted for about 20 hours, a vehicle or a test drug was orally administered at 30 mg / kg each. One hour later, 0.5 mi of blood was collected from the heart, and incubated at 37 C for 90 minutes. Coagulated blood 2 5 0 0 X g at 4 hand, l and 5 minutes簡遠mind, the TXB ₂ of the supernatant was measured by TXB ₂ assay kit, and serum TXB ₂溏度. The reduction of serum TXB ₂ % in each of the solvent-administered groups is represented by the inhibition rate (ό '). The results are shown in Table 5. ^-Mill 1 1> ϊ

 t ν'CO

 1 1

 m

 z, 1

 rn

 ¾i, t

 1 1 t

 1— * h— ^ n

H 1

 OS

 1

 1

* K

1 ess-r Ol t 00

 CO

 O r h- *

Compound A 5

Claims

■■ 51 PCT / JP91 / 00210 93 Scope of request  1 set  Force I,, ノ A — R _:  (I) (Where A is 0 or 1 nitrogen atom and 0 or An unsaturated 5- or 6-membered ring having one sulfur atom, R, is a hydrogen atom, a halogen, a carboxyl group, a lower alkoxycarbonyl group, a dinitro group or a lower alkoxy group, and R ₂ may be replaced by a lower alkyl group, a cyclohexyl group, or a halogen Benzyl group, chenylmethyl group, lower alkyl group as a substituent, optionally having 5 to 6 members having 1 to 3 nitrogen atoms and 0 or 1 sulfur atom which may have halogen It is a phenyl group optionally having a heteroalkyl group, a lower alkyl group, a halogen, a lower alkoxy group, a lower thioalkyl group, a lower alkoxycarbonyl group, a carboxyl group and a trifluoromethyl group as a substituent. However, one ./ J | or! When, R ₂ is low alkyl Group, cyclohexyl group, benzyl group optionally substituted with halogen, phenylmethyl group, lower alkyl group as a substituent, 1 to 3 nitrogen atoms optionally having halogen, 0 or It is an unsaturated 5- or 6-membered heterocyclic ring having one sulfur atom. R ₃ represents a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aralkyl group, a cycloalkyl group, a cycloalkylmethyl group, an acyl group, an acylmethyl group, a benzenesulfonyl group, a hydroxyl group or a lower alkoxy group as a substituent. Group, halogen'amino-sulfonamide group, lower alkoxy group, carbonyl group, rubamoyl group, phthalimid group, tetrazolyl-thiophenoxy group, thiazolinylthio group, pyrimidinylthio group A lower alkyl group [excluding 2-piperidinoethyl group] or B-,. [Where B is-(C H:) ri - '■ CH:) p - CH = CH - (CH:.) Q - one _{(CH: y} - C three C one (CH ₂ q one, '■ C H:) one',. (C H:) or one C H: n H: -C H: — C H—, n is an integer from 2 to 8, P is It is an integer from 0 to 2. ]) However, _t ' _A : "';  —:,. U. Li,  When Γ is hydrogen, Γ is a lower alkyl group which may have a substituent, 3 nitrogen atoms and ϋ or 1 sulfur atom, which may have a nitrogen atom. Having unsaturated. 5 or member complex: every day, excluding lysyl group]. ) And a pharmaceutically acceptable acid addition salt thereof. ― / Irino  I A

 , & Or the compound of claim 1 which is or ..

Its pharmaceutically acceptable acid addition salts, R ₂ is -. I — N ,

And pharmaceutically acceptable acid addition salts thereof. The compound of claim 3 wherein R ₂ is no / \\ and the compound thereof.  ノ NO Pharmaceutically acceptable acid addition salts. , 4- (3-pyridyl) — 1- (2H) phthalazinone Formula:

(Where A is 0 or 1 nitrogen atom and 0 or An unsaturated 5- or 6-membered ring having one sulfur atom, R, is a hydrogen atom, a halogen, a carboxyl group, lower alkoxycarbonyl group, a secondary WINCH port group or a lower alkoxy group der Ri, R ₂ is a lower alkyl group, a cyclohexyl group, have been substitution with halogen A benzyl group, a chenylmethyl group, a lower alkyl group as a substituent, an unsaturated group having 1 to 3 nitrogen atoms and 0 or 1 sulfur atom, which may have a halogen atom, 6-membered heterocyclic ring, lower alkyl group as substituent, halogen. Lower alkoxy group 'lower thioalkyl' group, lower alkoxycarbonyl group, carboxyl group ■ phenyl group even if it has a trifluoromethyl group , R.3 is a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aralkyl group, a cycloalkyl group, a cycloalkylmethyl group, an acyl group, an acylmethyl group, a benzenesulfonyl group, or a hydroxyl group or a lower group as a substituent. Alkoxy, Halogen, Amino-Sulfonamide, 'Lower Alkoxyl-Luponyl, L-Carboxyl', Levamoyl, Phthalimid, Tetrazolyl, Thio 9S Off-enokiji group, thiazo'-dithio group, lower alkyl group optionally having pyrimidini A-1,000 group or B-. [Where Β is — (CH:) η—, _{": 'H:) p -} CH = CH - (CH;) rt - -(CH ₂ ) p— C≡ C— (CH ₂ ) q one, H:) p one '-(CH r) or one CH: C H 3  C H: — CH: — CH—, n is an integer from 2 to 8. P is It is an integer from 0 to 2. ]) An anti-asthmatic agent comprising a compound represented by the formula: or a pharmaceutically acceptable-:: carboxylic acid and a pharmaceutically acceptable carrier.