RU2128175C1 - Condensed pyridazine or its pharmaceutically acceptable salt, an agent showing inhibitory activity with respect to cyclic gmp-phosphodiesterase - Google Patents

Abstract

FIELD: organic chemistry, biochemistry, pharmacy. SUBSTANCE: invention relates to condensed pyridazine of the general formula (I)

where n = 1 or 2; R₁- - hydrogen, halogen atom, nitro-, cyano-, amino-group or 4-hydroxypiperidine-1-yl; R₂ and R₃- - halogen atom or lower alkoxy-group, or R₂ and R₃ form together methylenedihydroxy- -group; symbol _ _ _ means double or simple bond; when _ _ _ is a double bond then X - nitrogen atom and Y means =C-Z where Z - halogen atom, group of the formulas (a), (b), (c), (d), (e), (f); p = 0 or 1; m = 0, 1, 2; R₄ means carbamoyl-, carboxy-, carboxylate-group with cation, alkoxycarbonyl- or dialkylamino-group; R₅ or R₆ means H and other - hydroxyl; R₇ means pyridyl, pyrimidyl or lower hydroxyalkyl; R₈- means H, lower alkyl; R₉- means pyridyl, lower hydroxyalkyl, carboxyalkyl, lower alkoxy-, lower hydroxyalkoxy-group, hydroxymethylpyrrolidinyl, imidazolyl, morpholinyl, pyridylmethyl; when _ _ _ means a simple bond then X means NR₁₀ where R₁₀ means H, carboxymethyl, lower alkoxycarbonylmethyl, tetrahydropyranylalkyl or hydroxyalkyl; Y means carbonyl. Synthesized compounds show inhibitory activity with respect to cyclic GMP-phosphodiesterase. EFFECT: improved method of synthesis. 13 cl, 1 tbl, 73 ex

Description

 The present invention relates to a novel fused pyridazine. In particular, the present invention relates to a novel fused pyridazine useful as a medicine.

 Recently, studies have been conducted of compounds exhibiting inhibitory activity against cyclic GMF (guanosine monophosphate) phosphodiesterase (hereinafter referred to as “cGMP-PDE”), and attempts have been made to use such compounds to prevent and treat circulatory disorders such as hypertension, angina pectoris and heart attack myocardium.

 Known examples of compounds useful in the prevention and treatment of circulatory disorders include the quinazolines described in JP-A-29582/1975, 5H-3,1-benzoxazin-4-ones described in WO 88/09790, 1H-2,3, 4,5-tetrahydroimidazo [2,1-b] quinazolin-2-one and 1,2,3,4,5,6-hexahydro-pyrimido [2,1-b] quinazolin-2-one described in JP-A- 86894/1973, nitrogen-containing heterocyclic compounds described in WO 93/07124, and 4-aminoquinazoline derivatives described in EP 579496.

 However, most of the above compounds are not on the market and for many of them there are problems associated with solubility, in vivo dynamics and toxicity, which must be solved before using such compounds as medicines.

 Under the above circumstances, the creators of the present invention began research aimed at finding a compound exhibiting high activity in inhibiting cGMP-PDE, high solubility in water, providing good absorption in a living organism, and lower toxicity.

 As a result of these studies, it was found that the above goal can be achieved using fused pyridazine represented by the following general formula (I), or a pharmacologically acceptable salt thereof. Based on this finding, the present invention was created.

(где кольцо C представляет пяти- или шестичленное кольцо, которое может содержать гетероатом:
n=0-4, целое число;
R¹ представляет атом галогена, необязательно замещенную низшую алкильную группу, необязательно замещенную низшую алкоксигруппу, необязательно замещенную циклоалкильную группу, нитрогруппу, цианогруппу, -NR²R² (где каждый из радикалов R² и R³ независимо представляет атом водорода, необязательно замещенную низшую алкильную группу, ацильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу или в соответствии с другим вариантом R² и R³ вместе с атомом азота, к которому они присоединены, могут образовывать кольцо, которое может быть замещенным), -O-R⁹ (где R⁹ представляет атом водорода, необязательно замещенную низшую алкильную группу, ацильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу), -S-R¹⁰ (где R¹⁰ представляет атом водорода, необязательно замещенную низшую алкильную группу, ацильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу),

(где R¹¹ представляет атом водорода, низшую алкильную группу или аминогруппу и m = 0, 1, 2),
или необязательно замещенную карбоксильную группу при условии, что когда n= 2-4, то каждый из R¹ независимо представляет заместитель, выбранный из тех, что указаны выше;
A представляет атом водорода, атом галогена, -NR⁴R⁵ (где каждый из радикалов R⁴ и R⁵ независимо представляет атом водорода, необязательно замещенную низшую алкильную группу, ацильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу или в соответствии с другим вариантом R⁴ и R⁵ вместе с атомом азота, к которому они присоединены, могут образовывать кольцо, которое может быть замещенным), необязательно замещенную арильную группу, необязательно замещенную гетероарильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу;
X представляет -NR⁶- (где R⁶ представляет атом водорода, необязательно замещенную низшую алкильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу) или -N=;
Y представляет -CO- или -CD= [где B представляет атом водорода, атом галогена], -NR⁷R⁸ (где каждый из радикалов R⁷ и R⁸ независимо представляет атом водорода, необязательно замещенную низшую алкильную группу, ацильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу или в соответствии с другим вариантом R⁷ и R⁸ вместе с атомом азота, к которому они присоединены, могут образовывать кольцо, которое может быть замещенным), -O-R¹² (где R¹² представляет атом водорода, необязательно замещенную низшую алкильную группу, ацильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу), -S-R¹³ (где R¹³ представляет атом водорода, необязательно замещенную низшую алкильную группу, ацильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу), необязательно замещенную арильную группу, необязательно замещенную гетероарильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу];
символ

представляет двойную связь или одинарную связь, при условии, что исключены случаи, когда C представляет бензольное кольцо и n=0.

(where ring C represents a five- or six-membered ring, which may contain a heteroatom:
n is 0-4, an integer;
R ¹ represents a halogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted cycloalkyl group, a nitro group, a cyano group, —NR ² R ² (where each of the radicals R ² and R ³ independently represents a hydrogen atom, an optionally substituted lower alkyl a group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group or, in accordance with another embodiment, R ² and R ³ together with the nitrogen atom to which they are attached inenes may form a ring that may be substituted), —OR ⁹ (where R ⁹ represents a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group), —SR ¹⁰ (where R ¹⁰ represents a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group),

(where R ¹¹ represents a hydrogen atom, a lower alkyl group or an amino group and m = 0, 1, 2),
or an optionally substituted carboxyl group, provided that when n = 2-4, each of R ¹ independently represents a substituent selected from those indicated above;
A represents a hydrogen atom, a halogen atom, —NR ⁴ R ⁵ (where each of the radicals R ⁴ and R ⁵ independently represents a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group, or in accordance with another embodiment of R ⁴ and R ⁵ together with the nitrogen atom to which they are attached, may form a ring which may be substituted), an optionally substituted aryl group, an optionally substituted heteroaryl group, neo yazatelno substituted arylalkyl group or an optionally substituted heteroarylalkyl group;
X represents —NR ⁶ - (where R ⁶ represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted arylalkyl group, or an optionally substituted heteroarylalkyl group) or —N =;
Y represents —CO— or —CD = [where B represents a hydrogen atom, a halogen atom], —NR ⁷ R ⁸ (where each of the radicals R ⁷ and R ⁸ independently represents a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, optionally a substituted arylalkyl group or an optionally substituted heteroarylalkyl group or, in accordance with another embodiment, R ⁷ and R ⁸ together with the nitrogen atom to which they are attached may form a ring which may be substituted), -OR ¹² (where R ¹² represents a hydrogen atom, optionally substituted by neither a higher alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group), SR ¹³ (where R ¹³ represents a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group), optional a substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group, or an optionally substituted heteroaryl kilnuyu group];
symbol

represents a double bond or a single bond, provided that the cases where C represents a benzene ring and n = 0 are excluded.

The lower alkyl group forming the optionally substituted lower alkyl specified for R ¹ -R ¹³ in the definition of general formula (I) may be a straight or branched lower alkyl group having from 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamine and n-hexyl. A substituent comprising it includes a hydroxyl group; nitro group; an amino group; cyano, acyl groups such as acetyl and benzoyl; lower alkoxy groups such as methoxy and ethoxy; halogen atoms such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; and optionally a protected carboxyl group. One or more of these substituents may be bonded to one or more carbons by atoms of a lower alkyl group.

The lower alkoxy group constituting the optionally substituted lower alkoxy group indicated for R ¹ may be derived from the aforementioned lower alkyl group, and examples thereof include a methoxy group, an ethoxy group and a propoxy group.

 A substituent comprising it includes a hydroxyl group; nitro group; an amino group; cyano group; acyl groups such as acetyl and benzoyl; lower alkoxy groups such as methoxy and ethoxy; halogen atoms such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; and optionally substituted carboxyl group. One or more of these substituents may be bonded to one or more carbon atoms of a lower alkoxy group.

The cycloalkyl group constituting the optionally substituted cycloalkyl group indicated for R ¹ may be a group having from 3 to 8 carbon atoms, and the substituent constituting it includes a hydroxyl group; nitro group; an amino group; cyano group; acyl groups such as acetyl and benzoyl; lower alkoxy groups such as methoxy and ethoxy; halogen atoms such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; and optionally a protected carboxyl group. One or more of these substituents may be bonded to one or more carbon atoms of a cycloalkyl group.

The acyl group indicated for R ² - R ⁸ , R ¹⁰ , R ¹² and R ¹³ may be a group derived from an aliphatic, aromatic or acyl group derived from a heterocyclic ring, and examples thereof include lower alkanoyl groups such as formyl, acetyl, propionyl, butyryl, valeryl, isovaleryl and pivaloyl groups; aroyl groups such as benzoyl, toluoyl and naphthoyl groups; and heteroaroyl groups such as furoyl, nicotinoyl and isonicotinoyl groups. In short, the group may be a group derived from any carboxylic acid. Of these groups, formyl, acetyl and benzoyl groups are preferred.

 The aryl group constituting the optionally substituted aryl indicated for A and B may be a group derived from an aromatic ring, and examples thereof include phenyl, 1-naphthyl, 2-naphthyl and anthracenyl. A substituent comprising it includes a hydroxyl group; an amino group; cyano group; acyl groups such as acetyl and benzoyl; lower alkoxy groups such as methoxy and ethoxy; halogen atoms such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; and optionally a protected carboxyl group.

 The heteroaryl group constituting the optionally substituted heteroarylalkyl group indicated for A and B may be a mono- or polycyclic group having one or more heteroatoms selected from nitrogen, sulfur and oxygen atoms. Examples thereof include pyridyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazyl, pyrimidinyl, pyridazyl, thienyl, pyranyl, isothiazolyl, isoxazolyl, furazanyl, benzothienyl, furyl, indolyl, indolisinyl, isoindolyl, benzothiazizolyl. A substituent comprising it includes a hydroxyl group; nitro group; an amino group; cyano, acyl groups such as acetyl and benzoyl; lower alkoxy groups such as methoxy and ethoxy; halogen atoms such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; and optionally a protected carboxyl group.

As indicated above, R ⁷ and R ^8, together with the nitrogen atom to which they are attached, may form a ring which may be substituted, and examples of the ring include piperidinyl, pyrrolidinyl and piperazinyl. The ring substituent includes a hydroxyl group, an optionally substituted amino group, an aminoalkyl group, a nitro group, a nitroalkyl group, a lower alkoxy group, a lower alkoxyalkyl group, a hydroxyalkyl group, an optionally protected carboxy group and an optionally protected carboxyalkyl group, of which hydroxy, hydroxymethyl, and carboxyethyl groups.

The aryl group constituting the optionally substituted arylalkyl group indicated for R ² - R ¹⁰ , R ¹² , R ¹³ and Y may be a group derived from an aromatic ring, and examples thereof include phenyl, 1-naphthyl, 2-naphthyl and anthracenyl. The group corresponding to its constituent "alkyl" moiety may be a derivative of the above alkyl group. A substituent comprising it includes a hydroxyl group; nitro group; an amino group; cyano group; acyl groups such as acetyl and benzoyl; lower alkoxy groups such as methoxy and ethoxy; halogen atoms such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; and optionally a protected carboxyl group.

A heteroaryl group constituting an optionally substituted heteroarylalkyl indicated for R ² - R ¹⁰ , R ¹² and R ¹³ and Y may be a mono- or polycyclic group having one or more heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, and examples thereof include pyridinyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazyl, pyrimidyl, pyridazyl, thienyl, pyranyl, isothiazolyl, isoxazolyl, furazanyl, benzothienyl, furyl, indolyl, indolisinyl, isoindolyl, benzothiazolazole and The group corresponding to its constituent "alkyl" moiety may be derived from the aforementioned lower alkyl group. A substituent comprising it includes a hydroxyl group: a nitro group; an amino group; cyano group; acyl groups such as acetyl and benzoyl; lower alkoxy groups such as methoxy and ethoxy; halogen atoms such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; and optionally a protected carboxyl group.

The halogen atom indicated for R ¹ , R ¹² , R ¹³ and R ¹⁴ includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

 The pharmacologically acceptable salt of the present invention includes salts of inorganic acids such as hydrochloride, sulfate, hydrobromide and phosphate; organic acid salts such as formate, acetate, trifluoroacetate, maleate, fumarate, tartrate, methanesulfate, benzenesulfonate and toluenesulfonate.

 There is no need to say that hydrates, although some of the compounds of the present invention form them, are included in the scope of the present invention.

где R¹ представляет атом водорода, атом галогена, необязательно замещенную низшую алкильную группу, необязательно замещенную низшую алкоксигруппу, необязательно замещенную циклоалкильную группу, нитрогруппу, цианогруппу, -NR²R³ (где каждый из радикалов R² и R³ независимо представляет атом водорода, необязательно замещенную низшую алкильную группу, ацильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу или в соответствии с другим вариантом R² и R³ вместе с атомом азота, к которому они присоединены, могут образовывать кольцо, которое может быть замещенным), -O-R⁹ (где R⁹ представляет атом водорода, необязательно замещенную низшую алкильную группу, ацильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу), -S-R¹⁰ (где R¹⁰ представляет атом водорода, необязательно замещенную низшую алкильную группу, ацильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу),

(где R¹¹ представляет атом водорода, низшую алкильную группу или аминогруппу и m = 0, 1, 2) или необязательно замещенную карбоксильную группу, при условии, что когда n = 2-4, то каждый из R¹ независимо представляет заместитель, выбранный из тех, что указаны выше;
A представляет атом водорода, атом галогена, - NR⁴R⁵ (где каждый из радикалов R⁴ и R⁵ независимо представляет атом водорода, необязательно замещенную низшую алкильную группу, ацильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу или в соответствии с другим вариантом R⁴ и R⁵ вместе с атомом азота, к которому они присоединены, могут образовывать кольцо, которое может быть замещенным), необязательно замещенную арильную группу, необязательно замещенную гетероарильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу;
X представляет -NR⁶- (где R⁶ представляет атом водорода, необязательно замещенную низшую алкильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарильную группу) или -N=;
Y представляет -CO- или -CB= [где B представляет атом водорода, атом галогена], -NR⁷R⁸ (где каждый из радикалов R⁷ и R⁸ независимо представляет атом водорода, необязательно замещенную низшую алкильную группу, ацильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу или в соответствии с другим вариантом R⁷ и R⁸ вместе с атомом азота, к которому они присоединены, могут образовывать кольцо, которое может быть замещенным), -O-R¹² (где R¹² представляет атом водорода, необязательно замещенную низшую алкильную группу, ацильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу), -S-R¹³ (где R¹³ представляет атом водорода, необязательно замещенную низшую алкильную группу, ацильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу), необязательно замещенную арильную группу, необязательно замещенную гетероарильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу];
cимвол

представляет двойную связь или одинарную связь, при условии, что исключены случаи, когда C представляет бензольное кольцо и n = 0.Of the compounds of the present invention, condensed pyridazines represented by the following general formula (II) and their pharmacologically acceptable salts are preferred:

where R ¹ represents a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted cycloalkyl group, a nitro group, a cyano group, —NR ² R ³ (where each of the radicals R ² and R ³ independently represents a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group, or an optionally substituted heteroarylalkyl group or, in accordance with another embodiment, R ² and R ³ together with a nitrogen atom, to to which they are attached, may form a ring that may be substituted), —OR ⁹ (where R ⁹ represents a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group), —SR ¹⁰ (where R ¹⁰ represents a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group),

(where R ¹¹ represents a hydrogen atom, a lower alkyl group or an amino group and m = 0, 1, 2) or an optionally substituted carboxyl group, provided that when n = 2-4, each of R ¹ independently represents a substituent selected from those indicated above;
A represents a hydrogen atom, a halogen atom, - NR ⁴ R ⁵ (where each of the radicals R ⁴ and R ⁵ independently represents a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group or in accordance with in another embodiment, R ⁴ and R ^5, together with the nitrogen atom to which they are attached, may form a ring that may be substituted), an optionally substituted aryl group, an optionally substituted heteroaryl group, neo optionally substituted arylalkyl group or optionally substituted heteroarylalkyl group;
X represents —NR ⁶ - (where R ⁶ represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted arylalkyl group, or an optionally substituted heteroaryl group) or —N =;
Y represents —CO— or —CB = [where B represents a hydrogen atom, a halogen atom], —NR ⁷ R ⁸ (where each of the radicals R ⁷ and R ⁸ independently represents a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, optionally a substituted arylalkyl group or an optionally substituted heteroarylalkyl group or, in accordance with another embodiment, R ⁷ and R ⁸ together with the nitrogen atom to which they are attached may form a ring which may be substituted), -OR ¹² (where R ¹² represents a hydrogen atom, optionally substituted by neither a higher alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group), SR ¹³ (where R ¹³ represents a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group), optional a substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group, or an optionally substituted heteroaryl kilnuyu group];
symbol

represents a double bond or a single bond, provided that the cases where C represents a benzene ring and n = 0 are excluded.

[где R^1a представляет атом галогена, необязательно замещенную низшую алкильную группу, необязательно замещенную низшую алкоксигруппу, необязательно замещенную циклоалкильную группу, нитрогруппу, цианогруппу или -NR²R³ (где каждый из радикалов R² и R³ независимо представляет атом водорода, необязательно замещенную низшую алкильную группу, ацильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу или в соответствии с другим вариантом R² и R³ вместе с атомом азота, к которому они присоединены, могут образовывать кольцо, которое может быть замещенным);
R¹ представляет атом водорода, атом галогена, необязательно замещенную низшую алкильную группу, необязательно замещенную низшую алкоксигруппу, необязательно замещенную циклоалкильную группу, нитрогруппу, цианогруппу, -NR²R³ (где каждый из радикалов R² и R³ независимо представляет атом водорода, необязательно замещенную низшую алкильную группу, ацильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу или в соответствии с другим вариантом R² и R³ вместе с атомом азота, к которому они присоединены, могут образовывать кольцо, которое может быть замещенным), -O-R⁹ (где R⁹ представляет атом водорода, необязательно замещенную низшую алкильную группу, ацильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу), -S-R¹⁰ (где R¹⁰ представляет атом водорода, необязательно замещенную низшую алкильную группу, ацильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу),

(где R¹¹ представляет атом водорода, низшую алкильную группу или аминогруппу и m = 0, 1, 2),
или необязательно защищенную карбоксильную группу, при условии, что когда n = 2-4, то каждый из R¹ независимо представляет заместитель, выбранный из тех, что указаны выше;
A представляет атом водорода, атом галогена, -NR⁴R⁵ (где каждый из радикалов R⁴ и R⁵ независимо представляет атом водорода, необязательно замещенную низшую алкильную группу, ацильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу или в соответствии с другим вариантом R⁴ и R⁵ вместе с атомом азота, к которому они присоединены, могут образовывать кольцо, которое может быть замещенным), необязательно замещенную арильную группу, необязательно замещенную гетероарильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу;
B представляет атом водорода, атом галогена, -NR⁷R⁸ (где каждый из радикалов R⁷ и R⁸ независимо представляет атом водорода, необязательно замещенную низшую алкильную группу, ацильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу или в соответствии с другим вариантом R⁷ и R⁸ вместе с атомом азота, к которому они присоединены, могут образовывать кольцо, которое может быть замещенным), -O-R¹² (где R¹² представляет атом водорода, необязательно замещенную низшую алкильную группу, ацильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу), -S-R¹³ (где R¹³ представляет водород, необязательно замещенную низшую алкильную группу, ацильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу), необязательно замещенную арильную группу, необязательно замещенную гетероарильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу].Of the preferred compounds described above, condensed pyridazines represented by the following general formula (III) and their pharmacologically acceptable salts are desirable:

[where R ^1a represents a halogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted cycloalkyl group, a nitro group, a cyano group or —NR ² R ³ (where each of the radicals R ² and R ³ independently represents a hydrogen atom, optionally substituted a lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group or, in accordance with another embodiment, R ² and R ³ together with the nitrogen atom to which they attached, may form a ring that may be substituted);
R ¹ represents a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted cycloalkyl group, a nitro group, a cyano group, —NR ² R ³ (where each of the radicals R ² and R ³ independently represents a hydrogen atom, optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group, or in accordance with another embodiment of R ² and R ³ together with the nitrogen atom to which mu they are attached, may form a ring which may be substituted), -OR ⁹ (wherein R ⁹ represents a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group), -SR ¹⁰ (wherein R ¹⁰ represents a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group),

(where R ¹¹ represents a hydrogen atom, a lower alkyl group or an amino group and m = 0, 1, 2),
or an optionally protected carboxyl group, provided that when n = 2-4, then each of R ¹ independently represents a substituent selected from those indicated above;
A represents a hydrogen atom, a halogen atom, —NR ⁴ R ⁵ (where each of the radicals R ⁴ and R ⁵ independently represents a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group, or in accordance with another embodiment of R ⁴ and R ⁵ together with the nitrogen atom to which they are attached, may form a ring which may be substituted), an optionally substituted aryl group, an optionally substituted heteroaryl group, neo yazatelno substituted arylalkyl group or an optionally substituted heteroarylalkyl group;
B represents a hydrogen atom, a halogen atom, —NR ⁷ R ⁸ (where each of the radicals R ⁷ and R ⁸ independently represents a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group, or in accordance with another embodiment of R ⁷ and R ⁸ together with the nitrogen atom to which they are attached, may form a ring which may be substituted), -OR ¹² (wherein R ¹² represents a hydrogen atom, an optionally substituted lower alkyl group, acyl th group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group), -SR ¹³ (wherein R ¹³ represents hydrogen, optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group), an optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted arylalkyl group or optionally substituted heteroarylalkyl group].

(где R^1a представляет атом галогена, необязательно замещенную низшую алкильную группу, необязательно замещенную низшую алкоксигруппу, необязательно замещенную циклоалкильную группу, нитрогруппу, цианогруппу или -NR²R³ (где каждый из радикалов R² и R³ независимо представляет атом водорода, необязательно замещенную низшую алкильную группу, ацильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу или в соответствии с другим вариантом R² и R³ вместе с атомом азота, к которому они присоединены, могут образовывать кольцо, которое может быть замещенным);
B представляет атом водорода, атом галогена, -NR⁷R⁸ (где каждый из радикалов R⁷ и R⁸ независимо представляет атом водорода, необязательно замещенную низшую алкильную группу, ацильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу или в соответствии с другим вариантом R⁷ и R⁸ вместе с атомом азота, к которому они присоединены, могут образовывать кольцо, которое может быть замещенным), -O-R¹² (где R¹² представляет атом водорода, необязательно замещенную низшую алкильную группу, ацильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу), -S-R¹³ (где R¹³ представляет атом водорода, необязательно замещенную низшую алкильную группу, ацильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу), необязательно замещенную арильную группу, необязательно замещенную гетероарильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу; и
каждый из R¹², R¹³ и R¹⁴ независимо представляет атом водорода, атом галогена, необязательно замещенную низшую алкильную группу или необязательно замещенную низшую алкоксигруппу или в соответствии с другим вариантом два из радикалов R¹², R¹³ и R¹⁴, присоединенные к углеродным атомам, расположены по соседству друг с другом, могут быть объединены для образования метилендиокси или этилендиокси).Further, fused pyridazines represented by the following general formula (V) and their pharmacologically acceptable salts are more desirable:

(where R ^1a represents a halogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted cycloalkyl group, a nitro group, a cyano group or —NR ² R ³ (where each of the radicals R ² and R ³ independently represents a hydrogen atom, optionally substituted a lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group or, in accordance with another embodiment, R ² and R ³ together with the nitrogen atom to which they attached, may form a ring that may be substituted);
B represents a hydrogen atom, a halogen atom, —NR ⁷ R ⁸ (where each of the radicals R ⁷ and R ⁸ independently represents a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group, or in accordance with another embodiment of R ⁷ and R ⁸ together with the nitrogen atom to which they are attached, may form a ring which may be substituted), -OR ¹² (wherein R ¹² represents a hydrogen atom, an optionally substituted lower alkyl group, acyl th group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group), -SR ¹³ (wherein R ¹³ represents a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group), an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group, or an optionally substituted heteroarylalkyl group; and
each of R ¹² , R ¹³ and R ¹⁴ independently represents a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group or an optionally substituted lower alkoxy group or, in another embodiment, two of the radicals R ¹² , R ¹³ and R ¹⁴ attached to carbon atoms located adjacent to each other, can be combined to form methylenedioxy or ethylenedioxy).

где R^1a представляет атом галогена, нитрогруппу или цианогруппу, предпочтительно цианогруппу;
B желательно представляет -NR⁷R⁸ (где каждый из радикалов R⁷ и R⁸ независимо представляет атом водорода, необязательно замещенную низшую алкильную группу, ацильную группу, необязательно замещенную арилалкильную группу или необязательно замещенную гетероарилалкильную группу или в соответствии с другим вариантом R⁷ и R⁸ вместе с атомом азота, к которому они присоединены, могут образовывать кольцо, которое может быть замещенным), более желательно -NR⁷R⁸ (где R⁷ и R⁸ вместе с атомом азота, к которому они присоединены, образуют кольцо, предпочтительно замещенное гидроксильной, карбоксильной, гидроксиалкильной, карбоксиалкильной или подобной группой, предпочтительно в положении 4. Наиболее желательным заместителем является гидроксильная или гидроксиалкильная группа.In addition, compounds represented by the following general formula (V ′) are most desirable:

where R ^1a represents a halogen atom, a nitro group or a cyano group, preferably a cyano group;
B preferably represents —NR ⁷ R ⁸ (where each of the radicals R ⁷ and R ⁸ independently represents a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group, or an optionally substituted heteroarylalkyl group, or in accordance with another embodiment R ⁷ and R ⁸ together with the nitrogen atom to which they are attached can form a ring that can be substituted), more preferably —NR ⁷ R ⁸ (where R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a ring, preferably optionally substituted with a hydroxyl, carboxyl, hydroxyalkyl, carboxyalkyl or the like group, preferably at position 4. The most desirable substituent is a hydroxyl or hydroxyalkyl group.

 Compounds of the present invention can be easily obtained by known methods or combinations of known methods. Some basic methods for preparing the compounds of the present invention are described below, but, of course, the compounds of the present invention are not limited to those obtained by these methods.

 Method 1 of receipt.

(где каждый из символов A' и B' независимо представляет атом галогена и каждый из R¹ и n такой, как указан выше).The compounds represented by general formula (I), where each of the symbols A and B represents a halogen atom, can be obtained in the following way:

(where each of the symbols A 'and B' independently represents a halogen atom and each of R ¹ and n is as indicated above).

In particular, the above compound can be obtained by halogenation of the corresponding 1,4-phthalisinedione derivative. This halogenation can be carried out in the usual manner. Examples of a chlorinating agent suitable for this case include phosphorus pentachloride, phosphorus oxychloride, and a mixture thereof. Halogenation can be carried out without a solvent, but any solvent inert to halogenation can be used. In some cases, the use of a tertiary amine such as diisopropylethylamine or N, N-dimethylformamide gives better results. The reaction temperature is preferably in the range of from about room temperature to about 150 ^° C.

 Method 2 of receipt.

(где каждый из A' и B' такой, как указан выше).A compound represented by general formula (I) wherein ring C represents a benzene ring; each of A and B independently represents a halogen atom; R ¹ represents a cyano group and n = 1, can also be obtained in the following way:

(where each of A 'and B' is as defined above).

 (First stage).

 At this stage, the amino group of 4-aminophthalimide is converted to a cyano group. This conversion is preferably carried out using the Sandmeyer reaction, although it can be carried out in any conventional manner. According to the Sandmeyer reaction, conversion is carried out by converting 4-aminophthalimide to a diazonium salt in the usual manner and then reacting the diazonium salt with a nucleophilic reagent such as a copper salt to replace the diazonium group with a cyano group. Although commercially available copper cyanide can be used in this reaction, better results can be obtained using copper cyanide obtained from potassium cyanide and copper chloride (1) immediately before use.

 (Second stage).

 At this stage, the phthalimide derivative obtained in the first stage is converted to the corresponding 1,4-phthalazinedione. This transformation can be carried out by the method described in Castle: "Heterocyclic compounds", Vol. 27.

 (Third stage).

 In this step, the 1,4-phthalazinedione obtained in the second step is prepared according to production method 1.

 Method 3 of receipt.

(где каждый из A' и B' такой, как указан выше).A compound represented by general formula (I) wherein ring C is a benzene ring; each of A and B independently represents a halogen atom; R ¹ represents a cyano group and n = 1, can also be obtained in the following way:

(where each of A 'and B' is as defined above).

 (First stage).

At this stage, 4-carbamoylphthalimide is prepared by reacting trimellitoyl chloride with ammonia and dehydrating the resulting product. In particular, this reaction is carried out by reacting trimellitoylcholoride with an aqueous solution of ammonia, either without any solvent or in a solvent at a temperature in the range of about -15 ^° C. to room temperature. The solvent used in this case is preferably acetone, dichloromethane, chloroform or ethyl acetate, but any organic solvent interfacial with the reaction can be used. The resulting reaction mixture was treated with acid to obtain a mixture containing 2,4-dicarbamoylbenzoic acid and 2,5-dicarbamoylbenzoic acid and 2,5-dicarbamoylbenzoic acid. This mixture is further treated in the absence or presence of a solvent for 0.5-24.0 hours, and the target compound is obtained. This treatment is carried out at a temperature of about 200 ^° C. The solvent used in this treatment is preferably N-methyl-2-pyrrolidinone, although any solvent inert to the reaction can be used.

 (Second stage).

 At this stage, the phthalimide derivative obtained in the first stage is converted in the usual manner into phthalisinedione.

This conversion can be carried out in a conventional manner, such as by reaction with hydrazine hydrate or the like. The reaction temperature is preferably in the range of 0 ^° C. to room temperature.

 (Third stage).

 At this stage, the 6-carbamoyl-2,3-dihydro-1,4-phthalisinedione obtained in the second stage is converted to 6-cyano-1,4-dichlorophthalazine through hydration and chlorination. A suitable reagent for this case includes phosphorus oxychloride, thionyl chloride, phosphorus pentachloride and a mixture of two or more of them. The reaction temperature may range from room temperature to the boiling point of the reagent, and the reaction time is about 0.5 to 36.0 hours. In some cases, better results can be obtained by adding N, N-dimethylformamide or a tertiary amine such as diisopropylethylamine.

 Method 4 of obtaining.

(где A' представляет атом галогена; R¹, R² , R³, X и Y такие, как указаны выше).The compound represented by formula (I), where A is —NR ² R ³ (where each of the radicals R ² and R ³ independently represents a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group or in accordance with another embodiment, R ² and R ³ together with the nitrogen atom to which they are attached can form a ring that can be substituted) and B represents a halogen atom, can be obtained in the following way:

(where A 'represents a halogen atom; R ¹ , R ² , R ³ , X and Y are as defined above).

 In particular, the above compound is prepared by a conventional substitution reaction. The solvent used in the reaction may be any organic solvent inert to the reaction, and preferred examples of the solvent include alcohols, such as isopropyl alcohol; ethers such as tetrahydrofuran and 1,4-dioxane; dimethylformamide; dimethylacetamide and N-methyl-2-pyrrolidinone.

 The reaction temperature may preferably range from about room temperature to the boiling point of the solvent by heating under reflux.

 Better results can be obtained by adding salt, such as potassium carbonate, sodium carbonate or barium carbonate, or a thermal amine, such as diisopropylethylamine or DBM (dibutylurea). In particular, the addition of a tertiary amine such as diisopropylethylamine or DBM may give best results.

 After completion of the reaction, the reaction mixture is subjected, in the usual manner, to a subsequent treatment and the undesired isomers are freed of by recrystallization or column treatment, whereby the desired compound is obtained.

 Method 5 of receipt.

(где R¹, A, B, A', B', X и n такие, как указаны выше).The compound represented by General formula (I) can also be obtained in the following way:

(where R ¹ , A, B, A ', B', X and n are as described above).

 In accordance with this method, the target compound is obtained from a halophthalazine derivative obtained by method 4 or the like, by conventional substitution. The solvent used in this case is preferably N-methyl-2-pyrrolidinone, but any solvent inert to the reaction can be used. Reagent B-H is used in excess of the starting halogenphthalazine derivative. In some cases, better results can be obtained by adding an organic base such as diisopropylethylamine, a salt such as potassium carbonate, sodium carbonate or sodium bicarbonate, or an acid such as para-toluenesulfonic acid. And even better results can be obtained using the hydrochloride of compound B-H without the above additives.

The reaction temperature may range from about room temperature to the boiling point of the solvent, preferably 100 ^° C. or higher.

 Method 6 of receipt.

(где R¹, A, B', X и n такие, как указаны выше).The compound represented by general formula (I), where Y is —CO—, can be prepared as follows:

(where R ¹ , A, B ', X and n are as described above).

According to this method, the target compound is obtained by conventionally hydrolyzing the corresponding halophthalazine derivative. In particular, the compound can be obtained by heating the corresponding halophthalazine derivative in an acidic or alkaline solution. In some cases, a better result can be obtained by stirring the halogenphthalazine derivative with heating at 100-200 ^° C in an organic solvent such as N-methyl-2-pyrrolidinone in the presence of acetic acid for about 0.5-12.0 hours.

 To illustrate the effects of the present invention, pharmacological experimental examples are described below.

 Experimental Example 1. Inhibitory activity against cGMP-PDE prepared from pig lung.

 1. The experimental method.

 The enzymatic activity of cGMP-PDE prepared from pig lung was determined by the method of Thompson et al. This determination was carried out in the presence of 1 mM EGTA [(ethylenedioxy) diethylene dinitrile tetraacetic acid] using 1 mM cGMP as a substrate. Each compound of the present invention was dissolved in DMSO (dimethyl sulfoxide) and then added to the reactive system to determine the inhibitory activity of the compound. The final concentration of DMSO in the reaction solution was adjusted to 5% or lower.

 The cGMP-PDE enzyme was prepared as follows.

 The pig’s lung was crushed and then five times (by volume) buffer A (containing Tris / HCl (20 mM), Mg acetate (2 mM), 2-mercaptoethanol (10 mM), EGTA (0.1 mM) and PMSF (phenylmethanesulfonyl fluoride) was added ) (0.2 mmol) and adjusted to pH 7.4). The resulting mixture was homogenized and centrifuged at 1000 g for 5 minutes. Ammonium sulfate was added to the obtained supernatant, and the resulting mixture was centrifuged at 20,000 g for 45 minutes to collect the fraction that precipitated between 30 and 40% saturation with ammonium sulfate. This fraction was dialyzed on buffer A and passed through a DEAE-Toyopearl 650S column (manufactured by F. Tosoh, Tokyo, Japan). The column was washed with buffer A and gradient elution was carried out with a mixture of 0.05-0.2 cm NaCl / buffer A to collect the cGMP-PDE fraction.

 This cGMP-PDE fraction was passed through Blue-Sepharose CL-6B (manufactured by F. "Pharmacia" Uppsala, Sweden). The column was washed with buffer A containing cAMP (cyclic adenosine monophosphate) (10 mM) and NaCl (0.5 M) and eluted with buffer A containing cGMP (10 mm) and NaCl (0.5 M). The resulting fraction was dialyzed, concentrated and stored.

 2. The results of the experiment.

 The values of cGMP-PDE inhibitory activity of the compounds of the present invention, determined by the method described above, are given in table. 1.

 Experimental example 2. Activity in reducing pressure in the pulmonary artery in a dog thoracotomized under anesthesia with intravenous administration.

 1. The experimental method.

Male and female individuals of hybrid dogs having a weight of about 10 kg were operated on under anesthesia with enflurane with N ₂ O / O ₂ as a carrier. Each dog was given a thoracotomy in the left quarter of the intercostal space and a pressure sensor (MPC-500, manufactured by F. Miller) was inserted into the pulmonary artery to determine pulmonary artery pressure (PAP). This experiment was performed with an average PAP (mPAP) increased by about 10 mmHg. by reducing the pressure of the supplied oxygen by about 40% of normal. Each compound of the present invention was dissolved in Polyethylene glycol 400 (product of Wako Pure Chemical Industries, Ltd.) at a concentration of 1 mg / ml and, if necessary, was further diluted with Polyethylene glycol 400. The resulting solution was administered to the dog intravenously through a polyethylene catheter located in the femoral vein.

 2. The results of the experiment.

 The values of the activity of the compounds of the present invention in reducing PAP, determined by the method described above, are given in table 1 as relative values to the activity of 1- [chloro-4- (3,4-methylenedioxybenzyl) aminoquinazolin-2-yl] piperidine-4-carboxylate sodium.

 Experimental example 3. Inhibitory activity against platelet aggregation in vitro.

1. The experimental method
Blood samples (100 ml) were taken from the veins of the forearm of ordinary male volunteers (age: 30–40 years old, weight: 60–75 kg), who had not taken any medicine at least a week before. To prevent blood coagulation, a 3.8% sodium citrate solution (Citral, product of Jamanouchi Pharmaceutical Co., Ltd.) was added to the blood in an amount of one tenth of the blood volume. The resulting blood was centrifuged at room temperature (22-25 ^° C) at 700 rpm for 10 minutes to extract the supernatant in the form of platelet-rich plasma (PRP). A blood coagulation solution (Terumo Corporation product) was added to the PRP at a final concentration of 15% (v / v). The resulting mixture was centrifuged at 3000 rpm for 10 minutes, resulting in a platelet pellet. This pellet was suspended in physiological saline containing 0.1% EDTA (ethylenediaminetetraacetic acid), and the resulting suspension was again centrifuged, resulting in another platelet pellet. This precipitate was suspended in a Ca ²⁺ Tyrode-free solution at a final concentration of about 40 x 10 ⁷ / ml.

Platelet aggregation was determined by the turbidimetric method of Born and others using an aggregometer (PAM-8C, manufacturer F. "Mebanix"). Each compound of the present invention was dissolved in DMSO at a concentration of 50 mM, followed by serial dilution with a Ca ²⁺ free Tyrode solution. Tyrode-free Ca ²⁺ solution was also used as a control.

 A mixture containing 25 ml of each of the diluted solutions of the compounds of the present invention prepared as described above and 200 ml of washed platelets obtained as described above were incubated, followed by the addition of 25 ml of platelet coagulant. Aggregation was observed in the resulting mixture. As a platelet coagulant used 3 mg / ml collagen (product F. Hormon-Chemie), 0.3 mm U46619 (product F. Cayman Chemical) or 0.04 U / ml thrombocin (product F. Sigma )

 Values of the inhibitory activity of the compounds of the present invention were presented through the inhibition ratios based on the intensity of aggregation of the control solution (region of the nomogram turbidity of the aggregometer).

 2. The results of the experiment.

 The values of the inhibitory activity of the compounds of the present invention against platelet aggregation, as determined by the method described above, are presented in table. 2 in terms of concentration (mM) for 50% inhibition of aggregation.

 From the results of the pharmacological experiments described above, it is understood that the compounds of the present invention exhibit inhibitory activity against cGMP-PDE, inhibitory activity against platelet aggregation and activity in reducing pressure in the pulmonary artery. Therefore, the compounds of the present invention are useful as prophylactic and therapeutic agents against diseases for which inhibition of cGMP-PDE, inhibition of platelet aggregation, or decrease in pulmonary pressure are effective. Specific examples of such diseases include coronary heart disease such as angina pectoris, myocardial infarction, and chronic and acute heart failure; pulmonary hypertension, accompanied and not accompanied by a pulmonary heart; thrombosis caused by trauma of the vascular wall, atherosclerosis, vasculitis, etc .; hypertension caused by atherosclerosis, etc .; cerebrovascular disorders, such as peripheral circulatory failure and cerebral infarction; impaired brain function and allergic diseases such as bronchial asthma, atopic dermatitis and allergic rhinitis.

 The compounds of the present invention have a higher solubility in water than known compounds with similar activities and structure. Therefore, when administered orally, they are excellently absorbed by a living organism, which is an advantage of the compounds of the present invention.

 In addition, the compounds of the present invention are less toxic and highly harmless and therefore very useful as medicaments.

 The compound of the present invention can be administered orally or parenterally as a therapeutic or prophylactic drug for the above diseases. Its dose is not particularly limited, but it varies depending on the symptom, age, gender and sensitivity of the patient to the drug, on the method, time and interval of administration, on the properties and type of drug, on the type of active component, etc., and the daily dose for an adult is preferably about 0.1-1000.0 mg and can be administered at one time or in parts.

 The compounds of the present invention can be converted into drugs by conventional methods using conventional carriers.

 In particular, a solid drug for oral administration in accordance with the present invention is obtained by adding a filler and, if necessary, a binding, disintegrating, lubricating, coloring, corrective and / or antioxidant substances to the active component and giving the resulting mixture a tablet, coated tablet granules, powder or capsules.

 Examples of filler include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose, and silicon dioxide.

 Examples of the binder include polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, calcium citrate, dextrin and pectin, and examples of the lubricant polyethylene silica, tartaric oils.

 Examples of a coloring agent include those coloring agents which are approved for use as pharmaceutical additives. Examples of the corrective substance include cocoa powder, menthol, aromatic powder, menthol oil, borneol and powdered cinnamon bark, and examples of antioxidant substances include those that are approved as pharmaceutical additives, such as ascorbic acid and α-tocopherol. Of course, tablets and granules may, if necessary, be coated with sugar, gelatin or the like.

 Alternatively, the injection solution of the present invention can be prepared in a conventional manner by adding to the active component a pH modifier, a buffer, a suspending agent, a solubilizing agent, a stabilizer, a tonic, an antioxidant and / or preservative and preparing the mixture in the form of an injection for intravenous, subcutaneous or intramuscular injection. If necessary, the injection solution can be lyophilized.

 Examples of the suspending agent include methyl cellulose, Polysorbate 80, hydroxyethyl cellulose, gum arabic, tragacanth powder, sodium carboxymethyl cellulose and polyoxyethylene sorbitan monolurinate.

 Further, examples of the solubilizing agent include polyoxyethylene cured castor oil, Polysorbate 80, nicotinamide and polyoxyethylene sorbitan monolaurate.

 In addition, examples of the stabilizer include sodium sulfite, sodium metasulfite and ether, and examples of a preservative include methyl para-hydroxybenzoate, ethyl para-hydroxybenzoate, sorbic acid, cresol and chlorocresol.

 The following is a description of examples that facilitate understanding of the present invention, but it is not worth saying that they do not limit the present invention. These examples are preceded by examples of the preparation of starting compounds. For convenience, some compounds of the present invention are described as preparation examples, which do not limit the present invention.

4-Аминофталимид (40,0 г) суспендировали в 300 мл воды, после чего добавляли концентрированную хлороводородную кислоту. Полученную суспензию перемешивали при охлаждении льдом. В эту суспензию при средней температуре 5^oC или ниже добавляли по каплям раствор 20,6 г нитрита натрия в 69 мл воды.Production example 1. 4-cyanphthalimide

4-aminophthalimide (40.0 g) was suspended in 300 ml of water, after which concentrated hydrochloric acid was added. The resulting suspension was stirred under ice cooling. A solution of 20.6 g of sodium nitrite in 69 ml of water was added dropwise to this suspension at an average temperature of 5 ^° C. or lower.

The resulting mixture was cooled to -20 ^° C, after which 300 ml of toluene was added. The resulting mixture was adjusted to pH 7 with sodium bicarbonate with vigorous stirring to obtain a diazonium salt.

 Separately, a solution of 105.7 g of potassium cyanide in 206 mol of water was added dropwise to a suspension of 63.4 g of copper (I) chloride in 250 ml of water, while intensively stirring the suspension under ice-cooling. The resulting mixture was stirred under ice-cooling for another hour, after which 500 ml of ethyl acetate was added. The previously obtained diazonium salt was added to the resulting mixture in several portions, and the mixture was stirred under ice cooling for one hour.

 The resulting mixture was filtered through Celite to remove insoluble materials, and Celite was washed with ethyl acetate / tetrahydrofuran. The combined filtrates were sedimented to cause liquid-liquid phase separation. The organic phase was washed with saturated aqueous sodium hydrogen carbonate, diluted with hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and freed of the solvent by vacuum distillation. The title compound (41 g) was obtained as a reddish-brown solid.

Mp: 237 - 238 ^o C.

MS: 173 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.00 (1H, dd, J = 7.5, 1.0 Hz), 8.29 (1H, dd, J = 7.5, 1.5 Hz), 8.36 (1H, dd, J = 1.5, 1.0 Hz), 11.73 (1H, s).

4-Цианфталимид (80 г) суспендировали в 1000 мл этанола, после чего добавляли 25 мл моногидрата гидразина. Полученную смесь перемешивали при комнатной температуре 5 часов.Production Example 2 6-cyano-2,3-dihydro-1,4-phthalazinedione

4-Cyanphthalimide (80 g) was suspended in 1000 ml of ethanol, after which 25 ml of hydrazine monohydrate was added. The resulting mixture was stirred at room temperature for 5 hours.

 The resulting mixture was concentrated in vacuo to about half its original volume, after which 1000 ml of water was added. The resulting mixture was acidified with dilute hydrochloric acid until crystals precipitated, which were recovered by filtration, to obtain 71 g of the target compound as a brown powder.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.19 (1H, br.s.), 8.27 (1H, dd, J = 8.00, 1.0 Hz), 8.48 (1H, br.s.), 11.39 (2H, br.s.).

6-Циано-2,3-дигидро-1,4-фталазиндион (69 г) суспендировали в 400 мл оксихлорида фосфора с последующим добавлением 75 мл диизопропилэтиламина. Полученную смесь нагревали с обратным холодильником в течение 40 минут.Production Example 3 6-cyano-1,4-dichlorophthalazine

6-Cyano-2,3-dihydro-1,4-phthalazinedione (69 g) was suspended in 400 ml of phosphorus oxychloride, followed by the addition of 75 ml of diisopropylethylamine. The resulting mixture was heated under reflux for 40 minutes.

 Excess phosphorus oxychloride was distilled off in vacuo and the residue was dissolved in methylene chloride. The resulting solution was poured into ice water. The resulting mixture was filtered through Celite to remove insoluble materials, and Celite was washed with methylene chloride. The combined filtrates were extracted with methylene chloride and the organic phase was washed with saturated aqueous sodium hydrogen carbonate, diluted with hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered through silica gel. The filtrate was distilled in vacuo to remove the solvent. The title compound (66 g) was obtained as a pale yellowish-orange solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.24 (1H, dd, J = 8.5, 1.5 Hz), 8.47 (1H, dd, J = 8.5, 1.0 Hz), 8.68 (1H, dd, J = 1.5 , 1.0 Hz).

Раствор 21,1 г (0,10 моль) триметиллитоилхлорида в 25 мл ацетона добавляли по каплям к 200 мл 29%-ного водного раствора аммиака, причем водный раствор аммиака перемешивали при охлаждении льдом. Полученную в результате смесь перемешивали в течение часа, деаэрировали в вакууме и подкисляли концентрированной хлороводородной кислотой при охлаждении льдом. Выпавшие при этом кристаллы извлекали путем фильтрования, промывали водой и сушили горячим воздухом, получив в результате 18,5 г смеси 2,4-дикарбамоилбензойной кислоты и 2,5-дикарбамоилбензойной кислоты в виде белого кристалла (выход: 89%).Production Example 4 4-carbamoylphthalimide

A solution of 21.1 g (0.10 mol) of trimellitoyl chloride in 25 ml of acetone was added dropwise to 200 ml of a 29% aqueous ammonia solution, the aqueous ammonia solution being stirred under ice-cooling. The resulting mixture was stirred for one hour, deaerated in vacuo and acidified with concentrated hydrochloric acid under ice-cooling. The crystals thus precipitated were recovered by filtration, washed with water and dried with hot air to obtain 18.5 g of a mixture of 2,4-dicarbamoylbenzoic acid and 2,5-dicarbamoylbenzoic acid as a white crystal (yield: 89%).

This mixture (16.0 g, 0.077 mol) was suspended in 80 ml of N-methyl-2-pyrrolidinone. The resulting suspension was stirred under heating at 150 ^° C. for 3 hours and cooled, allowing to stand, after which 200 ml of water was added. The crystals thus precipitated were recovered by filtration, washed with water and dried with hot air. The title compound (13.3 g) was obtained as a light brown crystal (yield: 91%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 7.70 (1H, br s), 7.90 (1H, dd, J = 7.2, 1.2 Hz), 8.28 - 8.31 (2H, m), 8.32 (1H br.s), 11.48 (1H, br.s).

4-Карбамоилфталимид (2,00 г, 0,011 моль) суспендировали в 12 мл N-метил-2-пирролидинона с последующим добавлением по каплям 0,8 мл гидрата гидразина. Полученную смесь перемешивали при комнатной температуре в течение 30 минут, после чего добавляли 5,5 мл 3 н. хлороводородной кислоты и 50 мл воды. Выпавшие при этом кристаллы извлекали фильтрованием, промывали водой и сушили горячим воздухом. Получили целевое соединение (2,0г) в виде светло-коричневого кристалла (выход: 94%).Production Example 5 6-carbamoyl-2,3-dihydro-1,4-phthalazinedione

4-Carbamoylphthalimide (2.00 g, 0.011 mol) was suspended in 12 ml of N-methyl-2-pyrrolidinone, followed by the dropwise addition of 0.8 ml of hydrazine hydrate. The resulting mixture was stirred at room temperature for 30 minutes, after which 5.5 ml of 3N was added. hydrochloric acid and 50 ml of water. The crystals thus precipitated were recovered by filtration, washed with water and dried with hot air. The title compound (2.0 g) was obtained as a light brown crystal (yield: 94%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 7.68 (1H, br.s), 8.12 (1H, br.s, J = 8.4 Hz), 8.32 (1H, dd, J = 8.4, 1.6 Hz ), 8.39 (1H, br.s), 8.59 (1H, br.s), 11.69 (2H, br.s).

6-Карбамоил-2,3-дигидро-1,4-фталазиндион (1,00 г, 0,0049 моль) суспендировали в смеси, содержавшей 20 мл оксихлорида фосфора и 20 мл тионилхлорида. Полученную суспензию нагревали с обратным холодильником в течение всего дня и ночи и перегоняли в вакууме для удаления растворителя. Полученный остаток растворяли в метиленхлориде и затем промывали водой. Органическую фазу осушали над безводным сульфатом магния и очищали путем колоночной хроматографии на силикагеле, получив в результате 0,76 г целевого соединения в виде светло-коричневого кристалла (выход: 70%).Production Example 6 6-cyano-1,4-dichlorophthalazine

6-Carbamoyl-2,3-dihydro-1,4-phthalazinedione (1.00 g, 0.0049 mol) was suspended in a mixture containing 20 ml of phosphorus oxychloride and 20 ml of thionyl chloride. The resulting suspension was refluxed all day and night and distilled in vacuo to remove the solvent. The resulting residue was dissolved in methylene chloride and then washed with water. The organic phase was dried over anhydrous magnesium sulfate and purified by silica gel column chromatography to obtain 0.76 g of the target compound as a light brown crystal (yield: 70%).

Целевое соединение получали из 6-циано-2,3-дигидро-1,4-фталазиндиона так же, как описано в примере 3 получения.Production Example 7 1,4,6-Trichlorophthalazine

The target compound was obtained from 6-cyano-2,3-dihydro-1,4-phthalazinedione as described in Production Example 3.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.01 (1H, dd, J = 9.0, 2.0 Hz), 8.29 (1H, d, J = 9.0 Hz), 8.31 (1H, d, J = 2.0 Hz) .

Целевое соединение получали из 2,3-дигидро-6-нитро-1,4-фталазиндиона так же, как описано в примере 3 получения.Production Example 8 1,4-Dichloro-6-nitrophthalazine

The target compound was obtained from 2,3-dihydro-6-nitro-1,4-phthalazinedione in the same manner as described in Production Example 3.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.02 (1H, dd, J = 9.0, 0.5 Hz), 8.83 (1H, dd, J = 9.0, 2.0 Hz), 9.20 (1H, dd, J = 2.0 , 0.5 Hz).

Смесь, содержавшую 5,0 г 4-хлорфталевого ангидрида, 5,5 г гидрохлорида 3-пиридилуксусной кислоты и 0,5 г безводного ацетата натрия перемешивали без растворителя при 200^oC в течение 10 минут.Production Example 9 5-Chloro-3- (pyrid-3-yl) methylene flalide

A mixture containing 5.0 g of 4-chlorophthalic anhydride, 5.5 g of 3-pyridylacetic acid hydrochloride and 0.5 g of anhydrous sodium acetate was stirred without solvent at 200 ^° C. for 10 minutes.

 Ethanol (100 ml) was added to the reaction mixture, and the resulting mixture was cooled with ice, whereby crystals precipitated, which were recovered by filtration, to obtain 2.68 g of the target compound as a yellowish-orange crystal.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 7.24 (1H, s), 7.79 (1H, dd, J = 8.0, 2.0 Hz), 7.89 (1H, dd, J = 8.0, 5.5 Hz), 8.03 (1H, dd, J = 0.8, 0.5 Hz), 8.35 (1H, dd, J = 2.0, 1.5 Hz), 8.56 (1H, ddd, J = 8.0, 2.0, 0.54 Hz), 8.74 (1H, dd, J = 5.5, 1.5 Hz), 9.00 (1H, d, J = 2.0 Hz).

5-Хлор-3-(пирид-3-ил)метиленфталид (2,68 г) растворяли в 100 мл этанола, после чего добавляли 2,0 мл моногидрата гидразина. Полученную смесь нагревали с обратным холодильником в течение 4 часов с последующим добавлением 200 мл воды. Полученную смесь нейтрализовали разбавленной хлороводородной кислотой, в результате чего выпали кристаллы, которые извлекали фильтрованием, получив в результате 1,87 г целевого соединения в виде желтого порошка.Production Example 10, 6-Chloro-4- (3-pyridylmethyl) -1 (2H) - phthalazinone

5-Chloro-3- (pyrid-3-yl) methylenephthalide (2.68 g) was dissolved in 100 ml of ethanol, after which 2.0 ml of hydrazine monohydrate was added. The resulting mixture was heated under reflux for 4 hours, followed by the addition of 200 ml of water. The resulting mixture was neutralized with dilute hydrochloric acid, whereupon crystals precipitated, which were recovered by filtration, to obtain 1.87 g of the target compound as a yellow powder.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.37 (2H, s), 7.33 (1H, ddd, J = 8.5, 4.5, 1.0 Hz), 7.67-7.70 (1H, m), 7.89 (1H , dd, J = 8.0, 2.0 Hz), 8.11 (1H, d, J = 2.0 Hz), 8.26 (1H, d, J = 8.5 Hz), 8.44 (1H, dd, J = 4.5, 1.5 Hz), 8.58 -8.59 (1H, m), 12.68 (1H, s).

6-Хлор-4-(3-пиридилметил)-1(2H)-фталазинон (0,86 г) суспендировали в 10 мл оксихлорида фосфора. Полученную суспензию нагревали с обратным холодильником в течение 2 часов и освобождали от оксихлорида фосфора путем вакуумной перегонки. Остаток растворяли в тетрагидрофуране. Полученный раствор нейтрализовали триэтиламином, после чего добавляли воду. Полученную смесь экстрагировали этилацетатом. Органическую фазу промывали водой и насыщенным водным раствором поваренной соли, осушали над безводным сульфатом магния и освобождали от растворителя путем вакуумной перегонки. Остаток очищали путем колоночной хроматографии на силикагеле и получили в результате 0,49 г целевого соединения в виде бледно-желтого кристалла.Production Example 11 1,6-Dichloro-4- (3-pyridylmethyl) phthalazine

6-Chloro-4- (3-pyridylmethyl) -1 (2H) -phthalazinone (0.86 g) was suspended in 10 ml of phosphorus oxychloride. The resulting suspension was heated under reflux for 2 hours and freed from phosphorus oxychloride by vacuum distillation. The residue was dissolved in tetrahydrofuran. The resulting solution was neutralized with triethylamine, after which water was added. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and freed of the solvent by vacuum distillation. The residue was purified by silica gel column chromatography to give 0.49 g of the target compound as a pale yellow crystal.

1 H NMR (400 MHz, CDCl ₃ ) δ: 4.68 (2H, s), 7.23 (1H, dd, J = 8.0, 4.5 Hz), 7.63 (1H, ddd, J = 8.0, 2.0, 1.5 Hz), 7.90 (1H, dd, J = 8.5, 2.0 Hz), 8.03 (1H, d, J = 8.5 Hz), 8.28 (1H, d, J = 8.5 Hz), 8.50 (1H, dd, J = 4.5, 1.5 Hz) 8.66 (1H, d, J = 2.0 Hz).

Смесь, содержащую 5,0 г 4-хлорфталевого ангидрида, 5,5 г гидрохлорида 3-пиридилуксусной кислоты и 0,5 г безводного ацетата натрия, перемешивали без растворителя при 200^oC в течение 10 минут.Production Example 12 4,6-Dichloro-1- (3-pyridylmethyl) phthalazine

A mixture containing 5.0 g of 4-chlorophthalic anhydride, 5.5 g of 3-pyridylacetic acid hydrochloride and 0.5 g of anhydrous sodium acetate was stirred without solvent at 200 ^° C. for 10 minutes.

 Ethanol (100 ml) was added to the reaction mixture, and the resulting mixture was cooled with ice, whereupon crystals precipitated, which were filtered off, and the filtrate was concentrated in vacuo. The resulting residue was subjected to silica gel column chromatography, and the initial fraction was removed. The effluent (effluent) was concentrated in vacuo and the residue was dissolved in 50 ml of ethanol, after which 2.0 g of hydrazine monohydrate was added. The resulting mixture was heated under reflux for 6 hours.

 The solvent was distilled off in vacuo, and hydrochloric acid diluted with water was added to the residue to form a solution. This solution was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, extracted with a mixture of magnesium chloroform and freed of the solvent by vacuum distillation. A mixture (2.27 g) containing 7-chloro-4- (3-pyridylmethyl) -1 (2H) -phthalazinone and 6-chloro-4- (3-pyridylmethyl) -1 (2H) was obtained as a light brown substance. ) -phthalazinone. This mixture (2.24 g, 8.25 mmol) was suspended in 20 ml of phosphorus oxychloride. The resulting suspension was heated under reflux for 2 hours and evaporated to dryness in vacuo. The residue was dissolved in dichloromethane. The resulting solution was neutralized with saturated aqueous sodium carbonate and extracted with dichloromethane twice. The organic phases were combined, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and freed of the solvent by vacuum distillation, resulting in 1.22 g of a crude product. This product was purified by silica gel column chromatography [40: 1 dichloromethane-methanol mixture], to give 609 mg (2.10 mmol) of the target compound as a white crystal.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.71 (2H, s), 7.20 (1H, dd, J = 8.0, 5.0 Hz), 7.60 (1H, ddd, J = 8.0, 2.0, 1.5 Hz), 7.86 (1H, dd, J = 8.5, 2.0 Hz), 8.06 (1H, d, J = 8.5 Hz), 8.27 (1H, d, J = 2.0 Hz), 8.47 (1H, dd, J = 5.0, 1.5 Hz ), 8.65 (1H, d, J = 2.0 Hz).

6-Циано-1,4-дихлорфталазин (66,2 г), полученный в примере 3 получения, и 3-хлор-4-метоксибензиламин (92 г) суспендировали в 1200 мл тетрагидрофурана. Полученную смесь нагревали с обратным холодильником в течение 6 часов.Example 1. 1-Chloro-4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine

6-Cyano-1,4-dichlorophthalazine (66.2 g) obtained in Production Example 3 and 3-chloro-4-methoxybenzylamine (92 g) were suspended in 1200 ml of tetrahydrofuran. The resulting mixture was heated under reflux for 6 hours.

 The crystals thus precipitated were filtered off and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography [solvent: 10: 1 mixture of toluene-tetrahydrofuran] to recover a less polar product. The target compound (59 g) was obtained as a pale yellow crystal.

Mp: 213.0 - 214.5 ^o C.

MS: 359 (MH ⁺ ).

1 H NMR (400 MHz, CDCl ₃ ) δ: 3.87 (3H, s), 4.78 (2H, d, J = 5.0 Hz), 5.75 (1H, t, J = 5.0 Hz), 6.87 (1H, d, J = 8.5 Hz), 7.31 (1H, dd, J = 8.5, 2.0 Hz), 7.43 (1H, d, J = 2.0 Hz), 8.05 (1H, dd, J = 8.5, 1.5 Hz), 8.24 (1H , dd, J = 1.5, 1.0 Hz), 8.29 (1H, dd, J = 8.5, 0.5 Hz).

Извлекали более полярный продукт, повторяя такую же, как в примере 1, процедуру, и в результате получили 27 г целевого соединения в виде белого кристалла.Example 2. 1-Chloro-1- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine

A more polar product was recovered by repeating the same procedure as in Example 1, and as a result, 27 g of the target compound was obtained as a white crystal.

Mp: 122.0-123.5 ^o C.

MS: 359 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.91 (3H, s), 4.80 (2H, d, J = 5.5 Hz), 5.43 (1H, t, J = 5.5 Hz), 6.92 (1H, d, J = 8.5 Hz), 7.33 (1H, dd, J = 8.5, 2.0 Hz), 7.45 (1H, d, J = 2.0 Hz), 7.89 (1H, dd, J = 8.5, 0.5 Hz), 8.03 (1H, dd, J = 8.5, 1.5 Hz), 8.55 (1H, dd, J = 1.5, 0.5 Hz).

1-Хлор-4-(3-хлор-4-метоксибензил)амино-6-цианофталазин (10,0 г), полученный в примере 1, растворяли в 50 мл N-метил-2-пирролидинона, после чего добавляли 43,32 г 4-гидроксипиридина и 10 мл диизопропилэтиламина. Полученную смесь нагревали при 170^oC в течение 8 часов.Example 3. 4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1- (4-hydroxypiperidino) phthalazine

1-Chloro-4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine (10.0 g) obtained in Example 1 was dissolved in 50 ml of N-methyl-2-pyrrolidinone, after which 43.32 was added g of 4-hydroxypyridine and 10 ml of diisopropylethylamine. The resulting mixture was heated at 170 ^° C. for 8 hours.

 Ethyl acetate was added to the reaction mixture, and the resulting mixture was washed three times with water and once with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography [solvent: 30: 1 mixture of methylene chloride-methanol], to give 10.1 g of the target compound as a yellow crystal.

Mp 172.0-173.5 ^o C.

MS: 424 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.70 (1H, br.s), 1.80-1.90 (2H, m), 2.07-2.15 (2H, m), 3.05-3.15 (2H, m), 3.50-3.60 (2H, m), 3.87 (3H, s), 3.90-4.00 (1H, m), 4.74 (2H, d, J = 5.0 Hz), 5.41 (1H, t, J = 5.0 Hz), 6.87 (1H, d, J = 8.5 Hz), 7.29 (1H, dd, J = 8.5, 2.0 Hz), 7.42 (1H, d, J = 2.0 Hz), 7.95 (1H, dd, J = 8.5, 1.5 Hz) 8.12 (1H, d, J = 8.5 Hz); 8.21 (1H, s).

1-Хлор-4-(3-хлор-4-метоксибензил)амино-6-цианофталазин (10,0 г), полученный в примере 1, растворяли в 50 мл N-метил-2-пиперидона, после чего добавляли 43,32 г 4-гидроксипиридина и 10 мл диизопропилэтиламина. Полученную смесь нагревали при 170^oC в течение 8 часов.Example 4. 4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1- (4-hydroxypiperidino) phthalazine hydrochloride

1-Chloro-4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine (10.0 g) obtained in Example 1 was dissolved in 50 ml of N-methyl-2-piperidone, after which 43.32 was added g of 4-hydroxypyridine and 10 ml of diisopropylethylamine. The resulting mixture was heated at 170 ^° C. for 8 hours.

 Ethyl acetate was added to the reaction mixture. The resulting mixture was washed three times with water and once with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and freed of the solvent by vacuum distillation. The residue was purified by silica gel column chromatography (solvent: 30: 1 mixture of methylene chloride-methanol), to give 10.1 g of 4- (3-chloro-4-methoxybenzyl) amino-6-cyano-1- (4- hydroxypiperidino) phthalazine as a yellow crystal. This product (10.8 g) was suspended in a mixture containing 60 ml of ethanol and 30 ml of water, followed by the addition of 30 ml of 1N. an aqueous solution of hydrochloric acid. The resulting mixture was dissolved by heating and cooled, allowing to stand at room temperature.

The crystals thus precipitated were filtered off and dried with hot air at 80 ^° C. overnight, resulting in 9.37 g of the target compound as a yellow crystal.

Mp: 217-227 ^o C (decomp.).

MS: 424 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ /: 1.61-1.70 (2H, m), 1.90-1.97 (2H, m), 2.97-3.04 (2H, m), 3.37-3.48 (2H, m ), 3.70-3.79 (1H, m), 3.84 (3H, s), 4.70 (2H, d, J = 5.5 Hz), 7.15 (1H, d, J = 8.5 Hz), 7.44 (1H, dd, J = 8.5, 2.0 Hz), 7.59 (1H, d, J = 2.0 Hz), 8.23 (1H, d, J = 8.5 Hz), 8.45 (1H, d, J = 8.5 Hz), 9.33 (1H, s), 10.10 (1H, br.s), 14.00 (1H, br.s).

Целевое соединение получали так, как в примере 3.Example 5. 4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1- (4-oxo-1,4-dihydropyrid-1-yl) phthalazine

The target compound was obtained as in example 3.

Mp: 218-219 ^o C.

MS: 418 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.83 (3H, s), 4.67 (2H, d, J = 5.6 Hz), 7.11 (1H, d, J = 8.4 Hz), 7.27 (2H, dd, J = 1.6 Hz, 4.4 Hz), 7.36 (1H, dd, J = 8.4, 2.0 Hz), 7.48 (1H, d, J = 2.0 Hz), 8.18-8.24 (2H, m), 8.31 (1H, dd, J = 8.4, 1.2 Hz), 8.56 (2H, dd, J = 1.6 Hz, 4.4 Hz), 9.02 (1H, d, J = 1.2 Hz).

Целевое соединение получали так, как в примере 4.Example 6. 4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1- [4- (hydroxymethyl) piperidino] phthalazine hydrochloride

The target compound was obtained as in example 4.

MS: 438 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.40-1.50 (2H, m), 1.61 (1H, br s), 1.78-1.84 (2H, m), 2.82-2.91 (2H, m) , 3.33 (2H, d, J = 6.1 Hz), 3.52-3.62 (2H, m), 3.83 (3H, s), 4.71 (2H, d, J = 5.0 Hz), 7.14 (1H, d, J = 8.4 Hz), 7.45 (1H, dd, J = 8.4 Hz, 2.4 Hz), 7.61 (1H, d, J = 2.4 Hz), 8.21 (1H, d, J = 8.8 Hz), 8.46 (1H, d, J = 8.8 Hz), 9.42 (1H, s).

Целевое соединение получали так, как в примере 3.Example 7. 4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1- (3-hydroxypropyl) aminophthalazine

The target compound was obtained as in example 3.

Mp: 132-135 ^o C.

MS: 398 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.91-1.98 (2H, m), 3.40 (1H, bs), 3.71-3.76 (1H, m), 3.80 (2H, t, J = 5.6 Hz ), 3.81 (2H, t, J = 5.6 Hz), 3.91 (3H, s), 4.68 (2H, d, J = 6.4 Hz), 5.30-5.34 (1H, t, J = 6.4 Hz), 6.92 (1H , d, J = 8.4 Hz), 7.32 (1H, dd, J = 8.4, 2.4 Hz), 7.46 (1H, d, J = 2.4 Hz), 7.85 (1H, d, J = 8.8 Hz), 7.95 (1H , dd, J = 8.8, 1.6 Hz), 8.10 (1H, d, J = 1.6 Hz).

Целевое соединение получали так, как в примере 4.Example 8. 4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1- [4- (2-hydroxyethyl) piperidino] phthalazine hydrochloride

The target compound was obtained as in example 4.

Mp: 230 ^° C (decomp.).

MS: 452 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ /: 1.39 - 1.53 (4H, m), 1.65 (1H, m), 1.82 (2H, m), 2.87 (2H, m), 3.50 (2H, t, J = 6.8 Hz), 3.56 (2H, m), 3.85 (3H, s), 4.77 (2H, d, J = 5.3 Hz), 7.15 (1H, d, J = 8.6 Hz), 7.49 (1H, dd, J = 8.6, 2.0 Hz), 7.63 (1H, d, J = 2.0 Hz), 8.23 (1H, d, J = 8.6 Hz), 8.47 (1H, dd, J = 8.6, 1.5 Hz), 9.53 ( 1H, br.s).

Целевое соединение получали так, как в примере 4.Example 9. 4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1- (4-hydroxyethyl-4-methylpiperidino) phthalazine hydrochloride

The target compound was obtained as in example 4.

Mp: 230-240 ^° C (decomp.).

MS: 438 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.22 (3H, s), 1.61 - 1.71 (2H, m), 1.73 - 1.84 (2H, m), 3.18 - 3.33 (4H, m), 3.85 (3H, s), 4.76 (2H, d, J = 5.1 Hz), 7.15 (1H, d, J = 8.6 Hz), 7.51 (1H, dd, J = 8.6, 2.0 Hz), 7.66 (1H, d, J = 2.0 Hz), 8.23 (1H, d, J = 8.4 Hz), 8.46 (1H, dd, J = 8.4, 1.0 Hz), 9.63 (1H, s).

Целевое соединение получали так, как в примере 4.Example 10. 4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1- (3-hydroxypiperidino] phthalazine hydrochloride

The target compound was obtained as in example 4.

Mp: 189 - 199 ^o C.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.45 (1H, m), 1.71 (1H, m), 1.84 - 1.97 (2H, m), 2.86 (1H, m), 2.98 (1H, m ), 3.32 (1H, m), 3.42 (1H, m), 3.83 (1H, m), 3.85 (1H, s), 4.76 (2H, d, J = 5.7 Hz), 7.16 (1H, d, J = 8.6 Hz), 7.51 (1H, dd, J = 8.6, 2.0 Hz), 7.66 (1H, d, J = 2.0 Hz), 8.31 (1H, d, J = 8.4 Hz), 8.49 (1H, dd, J = 8.4, 1.3 Hz), 9.61 (1H, s).

Целевое соединение получали так, как в примере 4.Example 11. 4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1- (2-pyridylmethyl) aminophthalazine hydrochloride

The target compound was obtained as in example 4.

Mp: 188 - 190 ^o C.

MS: 431 (MH ⁺ ).

¹ H-NMR (400 MHz, CD ₃ OD) δ: 3.83 (3H, s), 4.62 (2H, s), 5.02 (2H, s), 7.08 (1H, d, J = 8.5 Hz), 7.35 (1H , dd, J = 8.5, 2.0 Hz), 7.47 (1H, d, J = 2.0 Hz), 7.98 (1H, ddd, J = 8.0, 6.0, 1.5 Hz), 8.16 (1H, d, J = 8.0 Hz) , 8.48 (1H, dd, J = 8.5, 1.5 Hz), 8.57 (1H, ddd, J = 8.0, 8.0, 1.5 Hz), 8.62 (1H, d, J = 8.5 Hz), 8.76 - 8.78 (1H, m ), 9.06 (1H, d, J = 1.5 Hz).

Целевое соединение получали так, как в примере 4.Example 12. 4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1- (4-pyridylmethyl) aminophthalazine dihydrochloride

The target compound was obtained as in example 4.

Mp: 212 - 214 ^o C.

MS: 431 (MH ⁺ ).

¹ H-NMR (400 MHz, CD ₃ OD) δ: 3.88 (3H, s), 4.61 (2H, s), 4.97 (2H, s), 7.08 (1H, d, J = 8.5 Hz), 7.34 (1H , dd, J = 8.5, 2.0 Hz), 7.47 (1H, d, J = 2.0 Hz), 8.11 - 8.14 (2H, m), 8.48 (1H, dd, J = 8.5, 1.5 Hz), 8.61 (1H, d, J = 8.5 Hz), 8.77 - 8.79 (2H, m), 9.04 (1H, d, J = 1.5 Hz).

Целевое соединение получали так, как в примере 4.Example 13. 4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1- (3-pyridylmethyl) aminophthalazine dihydrochloride

The target compound was obtained as in example 4.

Mp: 195.0 - 196.5 ^o C.

MS: 431 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ /: 3.84 (3H, s), 4.59 - 4.63 (2H, m), 4.78 - 4.82 (2H, m), 7.12 (1H, d, J = 8.5 Hz), 7.40 (1H, dd, J = 8.5, 2.0 Hz), 7.55 (1H, d, J = 2.0 Hz), 7.92 (1H, dd, J = 8.0, 5.5 Hz), 8.46 - 8.52 (1H, m ), 8.58 (1H, dd, J = 8.5, 1.5 Hz), 8.77 (1H, d, J = 5.5 Hz), 8.82 - 8.92 (1H, m), 8.93 (1H, d, J = 1.5 Hz), 9.36 - 9.42 (1H, m).

Целевое соединение получали так, как в примере 3.Example 14. 4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1- [N- (3-hydroxypropyl) -N-methylamino] phthalazine

The target compound was obtained as in example 3.

 Mp: amorphous.

MS: 412 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.72-1.79 (1H, m), 2.83 (3H, s), 3.14-3.22 (2H, m), 3.41-3.48 (2H, m), 3.83 (3H, s), 4.45 (1H, t, J = 4.8 Hz), 4.64 (2H, d, J = 5.6 Hz), 7.10 (1H, d, J = 8.0 Hz), 7.36 (1H, dd, J = 8.2 Hz), 7.46 (1H, d, J = 2 Hz), 7.85 (1H, t, J = 5.6 Hz), 8.13-8.22 (2H, m), 8.88 (1H, d, J = 1.2 Hz).

Целевое соединение получали так, как в примере 4.Example 15. 4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1- [4- (2-pyridyl) piperazin-1-yl] phthalazine dihydrochloride

The target compound was obtained as in example 4.

Mp: 205-215 ^o C (decomp.).

MS: 486 (MH ⁺ ).

¹ H-NMR (400 MHz, CD ₃ OD) δ: 3.59 (4H, m), 3.90 (3H, s), 4.01 (4H, m), 4.74 (2H, s), 4.07 (1H, m), 7.12 (1H, d, J = 8.6 Hz), 7.41 (1H, dd, J = 8.6, 2.4 Hz), 7.50 (1H, d, J = 9.2 Hz), 7.54 (1H, d, J = 2.4 Hz), 8.02 (1H, m), 8.11 (1H, m), 8.44 (1H, dd, J = 8.4, 1.6 Hz), 8.49 (1H, dd, J = 8.4, 0.8 Hz), 9.09 (1H, dd, J = 1.6 , 0.8 Hz).

Целевое соединение получали так, как в примере 4.Example 16. 4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1- [4- (2-pyrimidinyl) piperazin-1-yl] phthalazine dihydrochloride

The target compound was obtained as in example 4.

Mp: 205 - 209 ^o C (decomp.).

MS: 487 (MH ⁺ ).

¹ H-NMR (400 MHz, CD ₃ OD) δ: 3.52 (4H, m), 3.90 (3H, s), 4.17 (4H, m), 4.73 (2H, s), 6.94 (1H, t, J = 4.8 Hz), 7.12 (1H, d, J = 8.4 Hz), 7.41 (1H, dd, J = 8.4, 2.4 Hz), 7.54 (1H, d, J = 2.4 Hz), 8.43 (1H, dd, J = 8.4, 1.6 Hz), 8.49 (1H, dd, J = 8.4, 0.6 Hz), 8.57 (2H, d, J = 4.8 Hz), 9.08 (1H, dd, J = 1.6, 0.6 Hz).

Целевое соединение получали так, как в примере 3.Example 17. 1- (4-Carbamoylpiperidino) -4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine

The target compound was obtained as in example 3.

Mp: 228-230 ^° C (decomp.).

MS: 451 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ /: 1.80 - 1.95 (4H, m), 2.30 (1H, m), 2.82 (2H, m), 3.44 (2H, m), 3.82 (3H, s), 4.64 (2H, d, J = 5.8 Hz), 6.80 (1H, b.s), 7.10 (1H, d, J = 8.4 Hz), 7.32 (1H, b.s.), 7.35 (1H, dd, J = 8.4, 2.0 Hz), 7.46 (1H, d, J = 2.0 Hz), 7.91 (1H, t, J = 5.8 Hz), 8.08 (1H, d, J = 8.8 Hz), 8.20 (1H, dd, J = 8.8, 1.2 Hz), 8.89 (1H, d, J = 1.2 Hz).

4-(3-Хлор-4-метоксибензил)амино-6-циано-1-[4-(2-гидроксиэтил)пиперазин-1-ил] фталазин (12,0 г, 26,5 ммоль), полученный так, как в примере 4, суспендировали в 600 мм ацетона, после чего добавляли 60 мл 1 н. хлороводородной кислоты. Полученную смесь перемешивали при комнатной температуре 30 минут, в результате чего выпали кристаллы, которые извлекали путем фильтрования и сушили при 90^oC в течение 6 часов, получив в результате 13,06 г целевого соединения в виде бледно-желтого порошка.Example 18. 4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1- [4- (2-hydroxyethyl) piperazin-1-yl] phthalazine dihydrochloride

4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1- [4- (2-hydroxyethyl) piperazin-1-yl] phthalazine (12.0 g, 26.5 mmol), obtained as in example 4, suspended in 600 mm of acetone, after which was added 60 ml of 1 N. hydrochloric acid. The resulting mixture was stirred at room temperature for 30 minutes, whereby crystals precipitated, which were recovered by filtration and dried at 90 ^° C. for 6 hours, to obtain 13.06 g of the target compound as a pale yellow powder.

Mp: 185-189 ^o C.

MS: 453 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.25-3.31 (2H, m), 3.37-3.52 (5H, m), 3.60-3.70 (4H, m), 3.85 (3H, s), 3.86 (2H, bt, J = 5.7 Hz), 4.82 (2H, d, J = 5.7 Hz), 7.16 (1H, d, J = 8.8 Hz), 7.53 (1H, dd, J = 8.8, 2.0 Hz) , 7.67 (1H, d, J = 2.0 Hz), 8.33 (1H, d, J = 8.4 Hz), 8.65 (1H, dd, J = 8.4, 1.1 Hz), 9.67 (1H, s), 11.14 (w, 1H).

4-(3-Хлор-4-метоксибензил)амино-6-циано-1-(4,4- этилендиоксипиперидино)фталазин (565 мг, 1,21 ммоль), полученный так, как в примере 3, растворяли в 5 мл трифторуксусной кислоты. Полученный раствор перемешивали при комнатной температуре 18 часов и выпаривали в вакууме досуха. Остаток растворяли в дихлорметане. Полученный раствор нейтрализовали насыщенным водным раствором гидрокарбоната натрия и экстрагировали дихлорметаном два раза. Органические фазы объединяли, промывали водой и насыщенным водным раствором поваренной соли, осушали над сульфатом магния и освобождали от растворителя путем вакуумной перегонки. Полученный при этом сырой продукт очищали путем колоночной хроматографии на силикагеле [смесь (3:1) этилацетат-гексан], что дало 565 мг бледно-желтого твердого вещества. Это твердое вещество перекристаллизовывали из 50%-ного водного этанола, получив в результате 423 мг (1,00 ммоль) 4-(3-хлор-4-метоксибензил)амино-6-циано-1-(4-оксопиперидино)фталазина. Это соединение превращали в гидрохлорид таким же способом, какой использовали в примере 4 для получения гидрохлорида.Example 19. 4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1- (4-oxopiperidino) -phthalazine hydrochloride

4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1- (4,4-ethylenedioxypiperidino) phthalazine (565 mg, 1.21 mmol), obtained as in example 3, was dissolved in 5 ml of trifluoroacetic acids. The resulting solution was stirred at room temperature for 18 hours and evaporated to dryness in vacuo. The residue was dissolved in dichloromethane. The resulting solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane twice. The organic phases were combined, washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and freed of the solvent by vacuum distillation. The crude product thus obtained was purified by silica gel column chromatography [3: 1 ethyl acetate-hexane mixture], which afforded 565 mg of a pale yellow solid. This solid was recrystallized from 50% aqueous ethanol to give 423 mg (1.00 mmol) of 4- (3-chloro-4-methoxybenzyl) amino-6-cyano-1- (4-oxopiperidino) phthalazine. This compound was converted to the hydrochloride in the same manner as used in Example 4 to prepare the hydrochloride.

Mp: 206 ^° C (decomp.).

MS: 422 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.62-2.68 (4H, m), 3.55-3.61 (4H, m), 3.85 (3H, s), 4.77 (2H, d, J = 5.5 Hz ), 7.15 (1H, d, J = 8.5 Hz), 7.49 (1H, dd, J = 8.5, 2.0 Hz), 7.64 (1H, d, J = 2.0 Hz), 8.40 (1H, d, J = 8.5 Hz ), 8.50 (1H, dd, J = 8.5, 1.5 Hz), 9.55 (1H, d, J = 1.5 Hz).

1-Хлор-4-(3-хлор-4-метоксибензил)амино-6-цианофталазин (2 г), полученный в примере 1, и трет-бутилизонипекотат (2 г) растворяли в 20 мл N-метил-2-пирролидона. Полученный раствор нагревали при 170^oC в течение 5 часов и охлаждали с последующим добавлением воды. Полученную смесь экстрагировали этилацетатом. Органическую фазу промывали водой, осушали над безводным сульфатом магния и концентрировали в вакууме. Полученный остаток подвергали колоночной хроматографии на силикагеле с элюированием смесью толуол-тетрагидрофуран (10: 1) и в результате получили 1,6 г 1-(4-трет-бутоксикарбонилпиперидино)-4-(3-хлор-4-метоксибензил) амино-6-цианофталазин.Example 20. 1- (4-Carboxypiperidino) -4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine hydrochloride

1-Chloro-4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine (2 g) obtained in Example 1 and tert-butylisone pecotate (2 g) were dissolved in 20 ml of N-methyl-2-pyrrolidone. The resulting solution was heated at 170 ^° C. for 5 hours and cooled, followed by the addition of water. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was subjected to silica gel column chromatography, eluting with toluene-tetrahydrofuran (10: 1), to give 1.6 g of 1- (4-tert-butoxycarbonylpiperidino) -4- (3-chloro-4-methoxybenzyl) amino-6 cyanophthalazine.

 1- (4-tert-Butoxycarbonylpiperidino) -4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine (1.2 g) was stirred in 20 ml of formic acid at room temperature for 20 hours.

 The resulting mixture was concentrated in vacuo and the obtained residue was subjected to silica gel column chromatography, eluting with dichloromethane-methanol (10: 1), to give 1.05 g of the target compound.

Mp:> 270 ^o C.

MS: 454 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.8 - 1.93 (2H, m), 1.96 - 2.03 (2H, m), 2.50 - 2.59 (1H, m), 2.92 - 3.01 (2H, m) . 3.50 - 3.58 (2H, m), 3.85 (3H, s), 4.74 (2H, d, J = 5.2 Hz), 7.16 (1H, d, J = 8.4 Hz), 7.48 (1H, dd, J = 8.4, 2.4 Hz), 7.63 (1H, d, J = 2.4 Hz), 8.26 (1H, d, J = 8.4 Hz), 8.46 (1H, dd, J = 8.4, 1.2 Hz), 9.49 (1H, d, J = 1.2 Hz).

1-Хлор-4-(3-хлор-4-метоксибензил)амино-6-цианофталазин (1 г), полученный в примере 3, растворяли в 10 мл N-метил-2-пиперидона, после чего добавляли 0,26 мл уксусной кислоты и 2,1 мл диизопропилэтиламина. Полученную смесь перемешивали при 170^oC в течение 7 часов и затем добавляли 100 мл воды. Выпавшие при этом кристаллы извлекали путем фильтрования.Example 21. 4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1 (2H) -phthalazinone

1-Chloro-4- (3-chloro-4-methoxybenzyl) amino-6-cyanophthalazine (1 g) obtained in Example 3 was dissolved in 10 ml of N-methyl-2-piperidone, after which 0.26 ml of acetic acid was added. acid and 2.1 ml of diisopropylethylamine. The resulting mixture was stirred at 170 ^° C. for 7 hours, and then 100 ml of water was added. The crystals thus precipitated were recovered by filtration.

 The crystals were recrystallized from ethanol-water, thereby obtaining the target compound as a yellow crystal.

Mp: 292.5 - 294 ^o C.

MS: 341 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ /: 3.81 (3H, s), 4.36 (2H, d, J = 5.5 Hz), 7.07 (1H, d, J = 8.5 Hz), 7.29 (1H , dd, J = 8.5, 2.0 Hz), 7.30 (1H, t, J = 5.5 Hz), 7.41 (1H, d, J = 2.0 Hz), 8.19 (1H, dd, J = 8.0, 1.0 Hz), 8.32 (1H, d, J = 8.0 Hz), 8.73 (1H, d, J = 1.0 Hz), 11.86 (1H, s).

2-(3-Хлор-4-метоксибензил)амино-6-циано-1(2H)фталазинон (0,20 г), полученный в примере 21, растворяли в 5 мл N-метил-2-пирролидинона, после чего добавляли 0,14 г трет-бутилбромацетата и 0,24 г карбоната калия. Полученную смесь перемешивали при 80^oC в течение 4 часов и вливали в воду, после чего экстрагировали этилацетатом. Органическую фазу промывали водой два раза и насыщенным водным раствором поваренной соли, осушали над безводным сульфатом магния и освобождали от растворителя путем вакуумной перегонки. В результате получили целевое соединение (0,41 г) в виде желтого кристалла.Example 22. 2-tert-Butoxycarbonyl-methyl-4- (3-chloro-4-methoxybenzyl) amino-6-cyano-1 (2H) -phthalazinone

2- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1 (2H) phthalazinone (0.20 g) obtained in Example 21 was dissolved in 5 ml of N-methyl-2-pyrrolidinone, after which 0 was added , 14 g of tert-butyl bromoacetate and 0.24 g of potassium carbonate. The resulting mixture was stirred at 80 ^° C. for 4 hours and poured into water, after which it was extracted with ethyl acetate. The organic phase was washed twice with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and freed of the solvent by vacuum distillation. The result was the target compound (0.41 g) as a yellow crystal.

M.p .: 173.5 - 175 ^o C.

MS: 454 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.49 (9H, s), 3.90 (3H, s), 4.37 (2H, d, J = 5.0 Hz), 4.91 (2H, d, J = 5.0 Hz), 6.90 (1H, d, J = 8.5 Hz), 7.25 (1H, dd, J = 8.5, 2.0 Hz), 7.42 (1H, d, J = 2.0 Hz), 7.93 (1H, dd, J = 8.0 , 1.5 Hz), 8.00 (1H, d, J = 1.5 Hz), 8.53 (1H, d, J = 8.0 Hz).

Трифторуксусную кислоту (5 мл) добавляли к 0,41 г трет-бутилового эфира, полученного в примере 22. Полученную смесь перемешивали при комнатной температуре в течение часа и освобождали от трифторуксусной кислоты путем вакуумной перегонки. Полученный остаток перекристаллизовывали из смеси этанол-вода и в результате получили 0,06 г целевого соединения в виде желтого кристалла.Example 23. 2-Carboxymethyl-4- (3-chloro-4-methoxybenzyl) amino-6-cyano-1 (2H) -phthalazinone

Trifluoroacetic acid (5 ml) was added to 0.41 g of the tert-butyl ether obtained in Example 22. The resulting mixture was stirred at room temperature for one hour and freed from trifluoroacetic acid by vacuum distillation. The resulting residue was recrystallized from ethanol-water, and 0.06 g of the target compound was obtained as a yellow crystal.

Mp: 173 - 175 ^o C.

MS: 399 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.81 (3H, s), 4.34 (2H, d, J = 5.5 Hz), 4.62 (2H, s), 7.06 (1H, d, J = 8.5 Hz), 7.32 (1H, dd, J = 8.5, 2.0 Hz), 7.43 (1H, t, J = 5.5 Hz), 7.45 (1H, d, J = 2.0 Hz), 8.22 (1H, dd, J = 8.0 , 1.0 Hz), 8.34 (1H, d, J = 8.0 Hz), 8.74 (1H, d, J = 1.0 Hz), 12.95 (1H, br.s.).

4-(3-Хлор-4-метоксибензил)амино-6-циано-1(2H)-фталазинон (0,20 г), полученный в примере 21, растворяли в 5 мл N-метил-2-пирролидинона, после чего добавляли 0,24 г 3-бромпропил-2-тетрагидропиранилового эфира и 0,24 г карбоната калия. Полученную смесь перемешивали при 50^oC в течение 4 часов и вливали в воду, после чего экстрагировали этилацетатом. Органическую фазу промывали водой два раза и насыщенным водным раствором поваренной соли, осушали над безводным сульфатом магния и освобождали от растворителя путем вакуумной перегонки. Остаток очищали путем колоночной хроматографии на силикагеле [растворитель: смесь н-гексан-этилацетат (1: 1)] и получили в результате 0,20 г целевого соединения в виде желтого кристалла.Example 24. 4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-2- [3- (tetrahydropyran-2-yloxy) propyl] -1 (2H) -phthalazinone

4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-1 (2H) -phthalazinone (0.20 g) obtained in Example 21 was dissolved in 5 ml of N-methyl-2-pyrrolidinone, after which was added 0.24 g of 3-bromopropyl-2-tetrahydropyranyl ether and 0.24 g of potassium carbonate. The resulting mixture was stirred at 50 ^° C. for 4 hours and poured into water, after which it was extracted with ethyl acetate. The organic phase was washed twice with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and freed of the solvent by vacuum distillation. The residue was purified by silica gel column chromatography [solvent: n-hexane-ethyl acetate (1: 1)], and 0.20 g of the target compound was obtained as a yellow crystal.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.44 - 1.83 (6H, m), 2.08 - 2.17 (2H, m), 3.45 - 3.51 (2H, m), 3.81 - 3.87 (2H, m), 3.89 (3H, s), 4.17 - 4.30 (2H, m), 4.46 (2H, d, J = 5.5 Hz), 4.57 - 4.59 (1H, m), 5.02 (1H, t, J = 5.5 Hz), 6.90 ( 1H, d, J = 8.5 Hz), 7.28 (1H, dd, J = 8.5, 2.0 Hz), 7.44 (1H, d, J = 2.0 Hz), 7.93 (1H, dd, J = 8.0, 1.5 Hz), 8.06 (1H, dd, J = 1.5, 1.0 Hz), 8.55 (1H, dd, J = 8.0, 0.5 Hz).

К 4-(3-хлор-4-метоксибензил)амино-6-циано-2-[3-(тетрагидропропан-2-илокси)пропил]-1(2H)-фталазинону (0,20 г), полученному в примере 24, добавляли метанол (20 мл) и 1 н. хлороводородную кислоту ( 2 мл). Полученную смесь перемешивали при комнатной температуре в течение 3 часов.Example 25. 4- (3-Chloro-4-methoxybenzyl) amino-6-cyano-2- (3-hydroxypropyl) -1 (2H) -phthalazinone

To 4- (3-chloro-4-methoxybenzyl) amino-6-cyano-2- [3- (tetrahydropropan-2-yloxy) propyl] -1 (2H) -phthalazinone (0.20 g) obtained in Example 24 was added methanol (20 ml) and 1 N. hydrochloric acid (2 ml). The resulting mixture was stirred at room temperature for 3 hours.

 The solvent was distilled off in vacuo and the residue was recrystallized from ethanol-water, resulting in 0.14 g of the target compound as a yellow crystal.

Mp: 191.5 - 193.0 ^o C.

MS: 399 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.79 (2H, quintet, J = 6.0 Hz), 3.40 (2H, d, J = 6.0 Hz), 3.81 (3H, s), 3.99 (2H, t, J = 6.0 Hz), 4.36 (2H, d, J = 5.5 Hz), 7.07 (1H, d, J = 8.5 Hz), 7.33 (1H, dd, J = 8.5, 2.0 Hz), 7.45 (1H, t, J = 5.0 Hz), 7.46 (1H, d, J = 2.0 Hz), 8.19 (1H, dd, J = 8.0, 1.5 Hz), 8.34 (1H, d, J = 8.0 Hz), 8.71 (1H, d, J = 1.5 Hz).

Целевое соединение получали из 1-хлор-6-циано-4-(3,4- метилендиоксибензил)аминофталазина, полученного так, как описано в примере 1, аналогичным примеру 4 образом.Example 26. 6-Cyano-1- (4-hydroxypiperidino) -4- (3,4-methylenedioxybenzyl) aminophthalazine hydrochloride

The target compound was obtained from 1-chloro-6-cyano-4- (3,4-methylenedioxybenzyl) aminophthalazine obtained as described in example 1 in a manner analogous to example 4.

MS: 404 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ /: 1.52-1.70 (2H, m), 1.86-1.95 (2H, m), 2.94-3.02 (2H, m), 3.38-3.46 (2H, m ), 3.69-3.75 (1H, m), 4.73 (2H, d, J = 5.0 Hz), 6.87 (1H, d, J = 8.0 Hz), 7.04 (1H, dd, J = 8, 1.6 Hz), 7.16 (1H, d, J = 1.6 Hz), 8.19 (1H, d, J = 8.4 Hz), 8.44 (1H, d, J = 8.4 Hz), 9.69 (1H, s).

Целевое соединение получали из 1,4,6-трихлорфталазина, полученного в примере 7 получения, аналогичным примеру 1 образом.Example 27. 4- (3-Chloro-4-methoxybenzyl) amino-1,6-dichlorophthalazine

The target compound was obtained from 1,4,6-trichlorophthalazine obtained in Production Example 7, in a manner analogous to Example 1.

Mp: 197-198.5 ^o C.

MS: 368 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.89 (3H, s), 4.78 (2H, d, J = 5.5 Hz), 5.32 (1H, t, J = 5.5 Hz), 6.89 (1H, d, J = 8.5 Hz), 7.32 (1H, dd, J = 7.5, 2.0 Hz), 7.45 (1H, d, J = 2.0 Hz), 7.77 (1H, d, J = 2.0 Hz), 7.82 (1H, dd, J = 9.0, 2.0 Hz), 8.15 (1H, d, J = 9.0 Hz).

Целевое соединение получали из 1,4,6-трихлорфталазина, полученного в примере 7 получения, аналогичным примеру 2 образом.Example 28. 1- (3-Chloro-4-methoxybenzyl) amino-4,6-dichlorophthalazine

The target compound was obtained from 1,4,6-trichlorophthalazine obtained in Production Example 7, in a manner analogous to Example 2.

Mp: 168-169.5 ^o C.

MS: 368 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.90 (3H, s), 4.78 (2H, d, J = 5.5 Hz), 5.30 (1H, t, J = 5.5 Hz), 6.91 (1H, d, J = 8.5 Hz), 7.33 (1H, dd, J = 8.5, 2.0 Hz), 7.45 (1H, d, J = 2.0 Hz), 7.72 (1H, d, J = 9.0 Hz), 7.78 (1H, dd, J = 9.0, 2.0 Hz), 8.18 (1H, d, J = 2.0 Hz).

Аналогично тому, как описано в примере 3, получали целевое соединение из 4-(3-хлор-4-метоксибензил)амино-1,6-дихлорфталазина, полученного в примере 27.Example 29. 6-Chloro-4- (3-chloro-4-methoxybenzyl) amino-1- (3-hydroxypyrrolidino) phthalazine

In the same manner as described in example 3, the desired compound was obtained from 4- (3-chloro-4-methoxybenzyl) amino-1,6-dichlorophthalazine obtained in example 27.

Mp: 191-193 ^o C.

MS: 419 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.01-2.08 (1H, m), 2.14-2.24 (1H, m), 3.56-3.64 (1H, m), 3.73 (1H, dt, J = 14 Hz , 4 Hz), 3.82 (1H, dd, J = 6 Hz, 16 Hz), 3.88 (3H, s), 3.94 (1H, dt, J = 14 Hz, 16 Hz), 4.58-4.62 (1H, m) , 4.69 (2H, d, J = 6 Hz), 4.83-4.90 (1H, bt), 6.89 (1H, d, J = 8.4 Hz), 7.31 (1H, dd, J = 2.2 Hz, 8.4 Hz) , 7.45 (1H, d, J = 2.2 Hz), 7.68 (1H, dd, J = 2.0 Hz, 8.8 Hz), 7.72 (1H, d, J = 2.0 Hz), 8.10 (1H, d, J = 8.8 Hz )

Аналогично тому, как описано в примере 4, получали целевое соединение из 4-(3-хлор-4-метоксибензил)аминно-1,6-дихлорфталазина, полученного в примере 27.Example 30. (R) -6-Chloro-4- (3-chloro-4-methoxybenzyl) amino-1- [2- (hydroxymethyl) pyrrolidino] phthalazine hydrochloride

In the same manner as described in Example 4, the title compound was obtained from 4- (3-chloro-4-methoxybenzyl) amino-1,6-dichlorophthalazine obtained in Example 27.

Mp: 163-165 ^o C.

MS: 433 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ /: 1.80-1.95 (1H, m), 1.95-2.04 (1H, m), 2.15-2.24 (1H, m), 3.42-3.48 (1H, m), 3.75 (1H, dd, J = 16 Hz, 8 Hz), 3.86 (1H, dd, J = 6 Hz, 16 Hz), 3.90 (3H, s), 3.90-3.97 (1H, m), 4.70 (2H, d, J = 6 Hz), 4.70-4.77 (1H, m), 4.83 (1H, bt, J = 6 Hz), 6.91 (1H, d, J = 8.4 Hz), 7.31 (1H, dd, J = 8.4, 2.2 Hz), 7.45 (1H, d, J = 2.2 Hz), 7.69 (1H, dd, J = 8.4 Hz, 2.0 Hz), 7.72 (1H, d, J = 2.0 Hz), 8.08 (1H, d, J = 2.0 Hz).

Аналогично тому, как описано в примере 3, получали целевое соединение из 4-(3-хлор-4-метоксибензил)амино-1,6-дихлорфталазина, полученного в примере 27.Example 31. 6-Chloro-4- (3-chloro-4-methoxybenzyl) amino-1- (imidazol-1-yl) phthalazine

In the same manner as described in example 3, the desired compound was obtained from 4- (3-chloro-4-methoxybenzyl) amino-1,6-dichlorophthalazine obtained in example 27.

Mp: 221-222.5 ^o C.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.91 (3H, s), 4.86 (2H, d, J = 5.5 Hz), 5.56 (1H, t, J = 5.5 Hz), 6.93 (1H, d, J = 8.5 Hz), 7.31 (1H, br.s), 7.36 (1H, dd, J = 8.5, 2.0 Hz), 7.41-7.42 (1H, m), 7.48 (1H, d, J = 2.0 Hz), 7.67 (1H, d, J = 9.0 Hz), 7.81 (1H, dd, J = 9.0, 2.0 Hz), 7.99 (1H, br.s).

Аналогично тому, как описано в примере 4, получали целевое соединение из 4-(3-хлор-4-метоксибензил)амино-1,6-дихлорфталазина, полученного в примере 27.Example 32. 6-Chloro-4- (3-chloro-4-methoxybenzyl) amino-1- (4-hydroxypiperidino) phthalazine hydrochloride

In the same manner as described in Example 4, the title compound was obtained from 4- (3-chloro-4-methoxybenzyl) amino-1,6-dichlorophthalazine obtained in Example 27.

Mp: 229-232 ^o C (decomp.).

MS: 433 (MH ⁺ ).

¹ H-NMR (400 MHz, DMCO-d ₆ ) δ: 1.60-1.70 (2H, m), 1.86-1.96 (2H, m), 2.95-3.06 (2H, m), 3.38-3.48 (2H, m) , 3.69-3.78 (1H, m), 3.92 (3H, s), 4.68 (2H, d, J = 4.6 Hz), 7.13 (1H, d, J = 8.8 Hz), 7.43 (1H, d , J = 8.8 Hz), 7.58 (1H, s), 8.06-8.15 (2H, m), 9.01 (1H, s).

Целевое соединение получали, как в примере 32, в виде более полярного продукта.Example 33. 1,6-bis- (4-Hydroxypiperidino) -4- (3-chloro-4-methoxybenzyl) aminophthalazine

The target compound was obtained, as in example 32, as a more polar product.

MS: 498 (MH ⁺ ).

¹ H-NMR (400 MHz, DMCO-d ₆ ) δ: 1.40-1.51 (2H, m), 1.55-1.65 (2H, m), 1.80-1.91 (4H, m), 2.78-2.85 (2H, m) , 3.03-3.11 (2H, m), 3.27-3.34 (2H, m), 3.56-3.66 (1H, m), 3.66-3.25 (1H, m), 3.76-3.82 (2H, m), 3.80 (3H, s), 4.60 (2H, d, J = 5.3 Hz), 4.68 (1H, d, J = 4.1 Hz), 4.22 (1H, d, J = 4.1 Hz), 7.34 (1H, d, J = 8.6 Hz) , 7.28 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.38-7.41 (2H, m), 7.43 (1H, t, J = 5.5 Hz), 7.51 (1H, dd, J = 9 Hz, 2.0 Hz ), 7.72 (1H, d, J = 9 Hz).

Аналогично тому, как описано в примере 4, получали целевое соединение из 4-(3-хлор-метоксибензил)амино-1,6-дихлорфталазина, полученного в примере 27.Example 34. 6-Chloro-4- (3-chloro-4-methoxybenzyl) amino-1-morpholinophthalazine hydrochloride

In the same manner as described in example 4, the desired compound was obtained from 4- (3-chloro-methoxybenzyl) amino-1,6-dichlorophthalazine obtained in example 27.

Mp: 255-261 ^o C (decomp.).

MS: 419 (MH ⁺ ).

¹ H-NMR (400 MHz, DMCO-d ₆ ) δ /: 3.20-3.23 (4H, m), 3.82-3.96 (1H, m), 3.85 (3H, s), 4.74 (2H, d, J = 6.0 Hz), 7.15 (1H, d, J = 8.8 Hz), 7.48 (1H, dd, J = 8.8, 2.0 Hz), 7.63 (1H, d, J = 2.0 Hz), 8.13 (1H, dd, J = 8.8, 2.0 Hz), 8.21 (1H, d, J = 8.8 Hz), 9.16 (1H, d, J = 2.0 Hz), 10.50 (1H, bp), 13.97 (1H, bs .).

Аналогично тому, как описано в примере 3, получали целевое соединение из 4-(3-хлор-4-метоксибензил)амино-1,6-дихлорфталазина, полученного в примере 27.Example 35. 6-Chloro-4- (3-chloro-4-methoxybenzyl) amino-1- (3-hydroxypropyl) aminophthalazine

In the same manner as described in example 3, the desired compound was obtained from 4- (3-chloro-4-methoxybenzyl) amino-1,6-dichlorophthalazine obtained in example 27.

Mp: 131-138 ^o C.

MS: 407 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.83-1.94 (2H, m), 3.75 (2H, t, J = 5.4 Hz), 3.80 (2H, t, J = 5.4 Hz), 3.90 (3H, s), 4.59 (1H, bt, J = 4.8 Hz), 4.66 (2H, d, J = 4.8 Hz), 5.14 (1H, bt), 6.91 (1H, d, J = 8.4 Hz ), 7.32 (1H, dd, J = 8.4, 2.4 Hz), 7.45 (1H, d, J = 2.4 Hz), 7.69 (2H, s), 7.72 (1H, d, J = 1.6 Hz).

Аналогично тому, как описано в примере 3, получали целевое соединение из 4-(3-хлор-4-метоксибензил)амино-1,6-дихлорфталазина, полученного в примере 27.Example 36. 6-Chloro-4- (3-chloro-4-methoxybenzyl) amino-1- [4- (hydroxymethyl) piperidino] phthalazine

In the same manner as described in example 3, the desired compound was obtained from 4- (3-chloro-4-methoxybenzyl) amino-1,6-dichlorophthalazine obtained in example 27.

Mp: 128-131 ^o C.

MS: 447 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48-1.63 (3H, m), 1.76 (1H, m), 1.92 (2H, m), 3.01 (2H, dt, J = 12.3, 2.0 Hz), 3.59-3.67 (4H, m), 3.89 (3H, s), 4.74 (2H, d, J = 5.1 Hz), 4.99 (1H, bp, J = 5.1 Hz), 6.89 (1H, d, J = 8.4 Hz), 7.32 (1H, dd, J = 8.4, 2.2 Hz), 7.45 (1H, d, J = 2.2 Hz), 7.70 (1H, dd, J = 8.6, 1.8 Hz), 7.73 (1H d, J = 1.8 Hz), 7.99 (1H, d, J = 8.6 Hz).

Аналогично тому, как описано в примере 3, получали целевое соединение из 4-(3-хлор-4-метоксибензил)амино-1,6-дихлорфталазина, полученного в примере 27.Example 37. 6-Chloro-4- (3-chloro-4-methoxybenzyl) amino-1- [4- (2-hydroxyethyl) piperidino] phthalazine

In the same manner as described in example 3, the desired compound was obtained from 4- (3-chloro-4-methoxybenzyl) amino-1,6-dichlorophthalazine obtained in example 27.

Mp: 153-155 ^o C.

MS: 161 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.41 (br.s), 1.54 (2H, m), 1.60-1.76 (3H, m), 1.88 (2H, m), 2.98 (2H, dt, J = 12.5, 1.8 Hz), 3.59 (2H, m), 3.78 (2H, bw, J = 6.2 Hz), 3.89 (3H, s), 4.74 (2H, d, J = 5.3 Hz) , 5.00 (1H, b.t., J = 5.3 Hz), 6.89 (1H, d, J = 8.4 Hz), 7.31 (1H, dd, J = 8.4, 2.2 Hz), 7.45 (1H, d, J = 2.2 Hz), 7.69 (1H, dd, J = 8.8, 2.0 Hz), 7.73 (1H, d, J = 2.2 Hz), 7.98 (1H, d, J = 8.8 Hz).

Раствор 120 мг 60%-ного маслянистого гидроксида натрия в 20 мл этанола добавляли к 1,0 г 4-(3-хлор-4-метоксибензил)амино-1,6- дихлорфталазина, полученного в примере 27. Полученную смесь нагревали при 150^oC в герметически закрытой пробирке всю ночь, охлаждали и концентрировали в вакууме. Остаток растворяли в этилацетате. Полученный раствор промывали водой и насыщенным водным раствором поваренной соли, осушали над безводным сульфатом магния и концентрировали в вакууме. Полученный остаток подвергали колоночной хроматографии на силикагеле с элюированием смесью дихлорметан-метанол (50 : 1), получив в результате 0,9 г целевого соединения.Example 38. 6-Chloro-4- (3-chloro-4-methoxybenzyl) amino-1-ethoxyphthalazine

A solution of 120 mg of 60% oily sodium hydroxide in 20 ml of ethanol was added to 1.0 g of 4- (3-chloro-4-methoxybenzyl) amino-1,6-dichlorophthalazine obtained in Example 27. The resulting mixture was heated at 150 ^o C in a sealed tube all night, cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate. The resulting solution was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was subjected to silica gel column chromatography, eluting with dichloromethane-methanol (50: 1), to give 0.9 g of the target compound.

Mp: 111 - 115 ^o C.

MS: 387 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.46 (3H, t, J = 7.2 Hz), 3.82 (3H, s), 4.43 (2H, q, J = 7.2 Hz), 4.59 (2H, d, J = 5.6 Hz), 7.08 (1H, d, J = 8.4 Hz), 7.33 (1H, dd, J = 8.4, 2.0 Hz), 7.44 (1H, d, J = 2.0 Hz), 7.65 (1H, t, J = 5.6 Hz), 7.90 (1H, dd, J = 8.8, 2.0 Hz), 8.03 (1H, d, J = 8.8 Hz), 8.45 (1H, d, J = 2.0 Hz).

К 8 мл 1,3-пропандиола добавляли 60%-ный гидрид натрия (0,12 г, 3,0 ммоль). Полученную смесь перемешивали при комнатной температуре в течение часа, после чего добавляли 1,0 г (2,7 ммоль) соединения, полученного в примере 27. Полученную смесь перемешивали при 150^oC в течение часа и затем добавляли к ней воду. Полученную смесь экстрагировали этилацетатом. Органическую фазу промывали водой и насыщенным водным раствором поваренной соли, осушали над безводным сульфатом магния и освобождали от растворителя путем перегонки. Остаток очищали путем колоночной хроматографии на силикагеле [растворитель: смесь дихлорметан-метанол (30 : 1)] и перекристаллизовывали из водного этанола, получив в результате 0,58 г целевого соединения в виде белых игольчатых кристаллов.Example 39. 6-Chloro-4- (3-chloro-4-methoxybenzyl) amino-1- (3-hydroxypropyloxy) phthalazine

To 8 ml of 1,3-propanediol was added 60% sodium hydride (0.12 g, 3.0 mmol). The resulting mixture was stirred at room temperature for one hour, after which 1.0 g (2.7 mmol) of the compound obtained in Example 27 was added. The resulting mixture was stirred at 150 ^° C. for one hour, and then water was added thereto. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and freed of the solvent by distillation. The residue was purified by silica gel column chromatography [solvent: dichloromethane-methanol mixture (30: 1)] and recrystallized from aqueous ethanol to obtain 0.58 g of the target compound as white needle crystals.

Mp: 124 - 126 ^o C.

MS: 408 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.11 (2H, quintet, J = 6.0 Hz), 3.22 (1H, br s), 3.82 (2H, br), 3.87 (3H, s), 4.67 (2H, d, J = 5.3 Hz), 4.70 (2H, t, J = 6.0 Hz), 5.08 (1H, t, J = 5.3 Hz), 6.85 (1H, d, J = 8.4 Hz), 7.28 (1H , dd, J = 8.4, 2.2 Hz), 7.42 (1H, d, J = 2.2 Hz), 7.69 (1H, dd, J = 8.8, 1.8 Hz), 7.75 (1H, d, J = 1.8 Hz), 8.05 (1H, d, J = 8.8 Hz).

Соединение (1,0 г, 2,7 ммоль), полученное в примере 27, растворяли в 9 мл N-метил-2-пирролидона, после чего добавляли 0,7 г (4,1 ммоль) N-метилпропаноламингидробромида и 1,14 г (8,2 ммоль) безводного карбоната калия. Полученную смесь перемешивали при 170^oC в течение 7,5 часов, после чего добавляли воду. Полученную смесь экстрагировали этилацетатом. Органическую фазу промывали водой и насыщенным водным раствором поваренной соли, осушали над безводным сульфатом магния и освобождали от растворителя путем перегонки. Остаток очищали путем колоночной хроматографии на силикагеле [растворитель: смесь дихлорметан-метанол (20 : 1)] и перекристаллизовывали из смеси дихлорметан-эфир, получив в результате 37 мг целевого соединения в виде белых игольчатых кристаллов.Example 40. 6-Chloro-4- (3-chloro-4-methoxybenzyl) amino-1- [N- (3-hydroxypropyl) -N-methylamino] phthalazine

The compound (1.0 g, 2.7 mmol) obtained in Example 27 was dissolved in 9 ml of N-methyl-2-pyrrolidone, after which 0.7 g (4.1 mmol) of N-methylpropanolamine hydrobromide and 1.14 were added. g (8.2 mmol) of anhydrous potassium carbonate. The resulting mixture was stirred at 170 ^° C. for 7.5 hours, after which water was added. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and freed of the solvent by distillation. The residue was purified by silica gel column chromatography [solvent: dichloromethane-methanol mixture (20: 1)] and recrystallized from dichloromethane-ether mixture to obtain 37 mg of the target compound as white needle crystals.

Mp: 115 - 117 ^o C.

MS: 421 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.95 (2H, quintet, J = 6.0 Hz), 2.85 (1H, br s), 2.99 (3H, s), 3.51 (2H, t, J = 6.0 Hz), 3.75 (2H, t, J = 6.0 Hz), 3.90 (3H, s), 4.72 (2H, d, J = 5.3 Hz), 4.95 (1H, broad), 6.91 (2H, d, J = 8.7 Hz), 7.33 (1H, dd, J = 8.4, 2.0 Hz), 7.46 (1H, d, J = 2.2 Hz), 7.72 (1H, dd, J = 9.3, 2.0 Hz), 7.72 (1H, d, J = 2.0 Hz), 8.05 (1H, d, J = 9.3 Hz).

Аналогично тому, как описано в примере 19, получали целевое соединение из соединения, полученного в примере 27.Example 41. 6-Chloro-4- (3-chloro-4-methoxybenzyl) amino-1- (4-oxopiperidino) phthalazine hydrochloride

In the same manner as described in example 19, the desired compound was obtained from the compound obtained in example 27.

Mp: 197 ^° C (decomp.).

MS: 431 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.62 - 2.66 (4H, m), 3.57 - 3.61 (4H, m), 3.85 (3H, s), 4.73 (2H, d, J = 6.0 Hz ), 7.16 (1H, d, J = 8.5 Hz), 7.45 (1H, dd, J = 8.5 Hz, 2.0 Hz), 7.60 (1H, d, J = 2.0 Hz), 8.17 (1H, dd, J = 9.0 , 2.0 Hz), 8.28 (1H, d, J = 9.0 Hz), 9.02 (1H, br.s).

Аналогично тому, как описано в примере 3, получали целевое соединение из соединения, полученного в примере 27.Example 42. 6-Chloro-4- (3-chloro-4-methoxybenzyl) amino-1- (4-ethoxycarbonylpiperidino) phthalazine

In the same manner as described in example 3, the desired compound was obtained from the compound obtained in example 27.

Mp: 162 - 164.5 ^o C.

MS: 489 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.29 (3H, t, J = 7.0 Hz), 1.96-2.14 (4H, m), 2.50-2.58 (1H, m), 2.99-3.07 (2H, m ), 3.57- 3.63 (2H, m), 3.91 (3H, s), 4.19 (2H, q, J = 7.0 Hz), 4.75 (2H, d, J = 5.0 Hz), 4.92 (1H, d, J = 5.0 Hz), 6.91 (1H, d, J = 8.5 Hz), 7.32 (1H, dd, J = 8.5 Hz, 2.0 Hz), 7.46 (1H, d, J = 2.0 Hz), 7.70 (1H, d, J = 2.0 Hz), 7.71 (1H, dd, J = 8.0, 2.0 Hz), 7.99 (1H, d, J = 8.0 Hz).

К 3,00 г соединения, полученного в примере 42, добавляли метанол (50 мл), тетрагидрофуран (50 мл) и 1 н. водный раствор (10 мл) гидроксида натрия. Полученную смесь перемешивали при комнатной температуре всю ночь и освобождали от растворителя путем вакуумной перегонки. Остаток растворяли в 100 мл воды с последующим добавлением 10 мл 1 н. хлороводородной кислоты. Выпавшие при этом кристаллы отфильтровывали, получив в результате 2,76 г целевого соединения в виде бледно-желтого кристалла.Example 43. 1- (4-Carboxypiperidino) -6-chloro-4- (3-chloro-4-methoxybenzyl) aminophthalazine

To 3.00 g of the compound obtained in Example 42, methanol (50 ml), tetrahydrofuran (50 ml) and 1N were added. aqueous solution (10 ml) of sodium hydroxide. The resulting mixture was stirred at room temperature overnight and freed of the solvent by vacuum distillation. The residue was dissolved in 100 ml of water, followed by the addition of 10 ml of 1 N. hydrochloric acid. The crystals thus precipitated were filtered off, yielding 2.76 g of the target compound as a pale yellow crystal.

Mp: 239.5-242 ^° C (decomp.).

MS: 489 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ /: 1.78-1.90 (2H, m), 1.93 - 2.00 (2H, m), 2.40-2.50 (1H, m), 2.83-2.90 (2H, m ), 3.35-3.45 (2H, m), 3.82 (3H, s), 4.61 (1H, d, J = 5.5 Hz), 7.09 (1H, d, J = 8.5 Hz), 7.33 (1H, dd, J = 8.5, 2.0 Hz), 7.43 (1H, d, J = 2.0 Hz), 7.75 (1H, d, J = 5.5, Hz), 7.88 (1H, dd, J = 9.0, 2.0 Hz), 7.98 (1H, d , J = 9.0 Hz), 8.44 (1H, d, J = 2.0 Hz).

Из соединения, полученного в примере 27, получали так, как описано в примере 3, 6-хлор-1-[N-(3-этоксикарбонилпропил)-N-метиламино]-4-(3-хлор-4-метоксибензил) аминофталазин, который затем превращали в целевое соединение аналогично тому, как описано в примере 43.Example 44. 1- [N- (3-Carboxypropyl) -N-methylamino] -6-chloro-4- (3-chloro-4-methoxybenzyl) aminophthalazine

From the compound obtained in example 27, was obtained as described in example 3, 6-chloro-1- [N- (3-ethoxycarbonylpropyl) -N-methylamino] -4- (3-chloro-4-methoxybenzyl) aminophthalazine, which was then converted to the target compound in the same manner as described in example 43.

Mp: 248-250 ^° C (decomp.).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.76-1.86 (1H, m), 2.06 -2.14 (1H, m), 2.80 (3H, s), 3.06-3.14 (2H, m), 3.81 (3H, s), 4.59 (2H, d, J = 6 Hz), 7.08 (1H, d, J = 8.4 Hz), 7.34 (1H, dd, J = 8.4, 2.2 Hz), 7.44 (1H, d, J = 2.2 Hz), 7.86-7.95 (2H, m), 8.02 (1H, d, J = 8.8 Hz), 8.54 (1H, d, J = 2.0 Hz).

Из 1.4.6-трихлорфталазина (3,38 г), полученного в примере 7 получения, и пиперониламина (2,21 г) получали так, как описано в примере 1, смесь (4,83 г), содержавшую 1,6-дихлор-4-(3,4-метилендиоксибензил)аминофталазин и 4,6-дихлор-1-(3,4-метилендиоксибензил)аминофталазин. Из 0,8 г смеси таким же способом, как в примере 3, получили целевое соединение (0,22 г) в виде менее полярного продукта.Example 45. 6-Chloro-1- (4-ethoxycarbonylpiperidino) -4- (3,4-methylenedioxybenzyl) aminophthalazine

From 1.4.6-trichlorophthalazine (3.38 g) obtained in Production Example 7 and piperonylamine (2.21 g), a mixture (4.83 g) containing 1,6-dichloro was obtained as described in Example 1 -4- (3,4-methylenedioxybenzyl) aminophthalazine and 4,6-dichloro-1- (3,4-methylenedioxybenzyl) aminophthalazine. From 0.8 g of the mixture in the same manner as in Example 3, the desired compound (0.22 g) was obtained as a less polar product.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.28 (3H, t, J = 7.0 Hz), 1.90-2.10 (4H, m), 2.46-2.55 (1H, m), 2.96-3.05 (2H, m ), 3.53-3.60 (2H, m), 4.16 (2H, q, J = 7.0 Hz), 4.70 (2H, d, J = 5.0 Hz), 5.21 (1H, t, J = 5.0 Hz), 5.91 (2H , s), 6.73 (1H, t, J = 8.0 Hz), 6.87 (1H, dd, J = 8.0, 1.5 Hz), 6.91 (1H, d, J = 1.5 Hz), 7.68 (1H, dd, J = 8.5, 2.0 Hz), 7.78 (1H, d, J = 2.0 Hz), 7.96 (1H, d, J = 8.5 Hz).

Целевое соединение (0,21 г) получали, повторяя такую же процедуру, как в примере 45, и выделяя более полярный продукт.Example 46. 6-Chloro-4- (4-ethoxycarbonylpiperidino) -1- (3,4-methylenedioxybenzyl) aminophthalazine

The target compound (0.21 g) was obtained by repeating the same procedure as in example 45, and highlighting a more polar product.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.25 (3H, t, J = 7.0 Hz), 1.96 - 2.14 (4H, m), 2.48 - 2.57 (1H, m), 3.09 - 3.13 (2H, m ), 3.54 - 3.61 (2H, m), 4.18 (2H, q, J = 7.0 Hz), 4.71 (2H, d, J = 5.0 Hz), 5.13 (1H, t, J = 5.0 Hz), 5.93 (2H , s), 6.75 (1H, t, J = 8.0 Hz), 6.88 (1H, dd, J = 8.0, 1.5 Hz), 6.92 (1H, d, J = 1.5 Hz), 7.65 (1H, dd, J = 9.0, 2.0 Hz), 7.71 (1H, d, J = 9.0 Hz), 7.97 (1H, d, J = 2.0 Hz).

Аналогично тому, как описано в примере 43, получали целевое соединение из соединения, полученного в примере 45.Example 47. 1- (4-Carboxypiperidino) -6-chloro-4- (3,4-methylenedioxybenzyl) aminophthalazine

In the same manner as described in example 43, the desired compound was obtained from the compound obtained in example 45.

Mp: 165 - 167 ^o C.

MS: 441 (MH ⁺ ).

Аналогично тому, как описано в примере 43, получали целевое соединение из соединения, полученного в примере 46. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ /: 1.80-1.91 (2H, m), 1.94 - 2.01 (2H, m), 2.43-2.52 (1H, m), 2.86-2.94 (2H, m ), 3.40-3.50 (2H, m), 4.61 (2H, d, J = 5.0 Hz), 5.98 (1H, s), 6.87 (1H, d, J = 8.0 Hz), 6.90 (1H, dd, J = 8.0, 1.0 Hz), 7.00 (1H, d, J = 1.0 Hz), 7.95 (1H, broad d, J = 9.0 Hz), 8.03 (1H, d, J = 9.0 Hz), 9.58 (1H, br with.)
Example 48. 4- (4-Carboxypiperidino) -6-chloro-1- (3,4-methylenedioxybenzyl) aminophthalazine

In the same manner as described in example 43, the desired compound was obtained from the compound obtained in example 46.

Mp: 152 - 154 ^o C.

MS: 441 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.80-1.90 (2H, m), 1.94 - 2.01 (2H, m), 2.41-2.50 (1H, m), 2.85-2.92 (2H, m) , 3.35-3.43 (2H, m), 4.62 (2H, d, J = 5.0 Hz), 5.96 (2H, s), 6.84 (1H, d, J = 8.0 Hz), 6.88 (1H, dd, J = 8.0 , 1.5 Hz), 6.97 (1H, d, J = 1.5 Hz), 7.89 (1H, d, J = 2.0 Hz), 7.96 (1H, dd, J = 9.0, 2.0 Hz), 8.39 (1H, d, J = 9.0 Hz).

Аналогично тому, как описано в примере 1, получали целевое соединение из 1,4-дихлор-6-нитрофталазина, полученного в примере 8 получения.Example 49. 1-Chloro-4- (3-chloro-4-methoxybenzyl) amino-6-nitrophthalazine

In the same manner as described in Example 1, the desired compound was obtained from 1,4-dichloro-6-nitrophthalazine obtained in Production Example 8.

Mp: 217 - 217.5 ^o C.

MS: 379 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.90 (3H, s), 4.83 (2H, d, J = 5.5 Hz), 5.73 (1H, t, J = 5.5 Hz), 6.91 (1H, t, J = 8.0 Hz), 7.35 (1H, dd, J = 8.0, 2.0 Hz), 7.47 (1H, d, J = 2.0 Hz), 8.38 (1H, d, J = 9.0 Hz), 8.65 (1H, dd, J = 9.0, 2.0 Hz), 8.73 (1H, d, J = 2.0 Hz).

Аналогично тому, как описано в примере 2, получали целевое соединение из 1,4-дихлор-6-нитрофталазина, полученного в примере 8 получения.Example 50. 4-Chloro-1- (3-chloro-4-methoxybenzyl) amino-6-nitrophthalazine

In the same manner as described in Example 2, the desired compound was obtained from 1,4-dichloro-6-nitrophthalazine obtained in Production Example 8.

M.p .: 179 - 180.5 ^o C.

MS: 379 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO - d ₆ ) δ: 3.82 (3H, s), 4.70 (2H, d, J = 5.6 Hz), 7.10 (1H, d, J = 8.4 Hz), 7.35 (1H, d, J = 8.8 Hz), 7.47 (1H, d, J = 2.0 Hz), 8.63 (1H, t, J = 5.6 Hz), 8.65 (1H, d, J = 8.8 Hz), 8.71 (1H, d, J = 2.4 Hz), 8.75 (1H, dd, J = 8.8, 2.4 Hz).

Аналогично тому, как описано в примере 4, получали целевое соединение из соединения, полученного в примере 49 получения.Example 51. 4- (3-Chloro-4-methoxybenzyl) amino-1- (4-hydroxypiperidino) -6-nitrophthalazine hydrochloride

In the same manner as described in Example 4, the desired compound was prepared from the compound obtained in Production Example 49.

Mp: 245-246 ^o C (decomp.).

MS: 444 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ /: 1.70 (2H, m), 1.96 (2H, m), 3.05 (2H, m), 3.48 (2H, m), 3.77 (1H, m) , 3.86 (3H, s), 4.78 (2H, d, J = 5.2 Hz), 7.17 (1H, d, J = 8.4 Hz), 7.48 (1H, dd, J = 8.4, 2.0 Hz), 7.63 (1H, d, J = 2.0 Hz), 8.34 (1H, d, J = 9.2 Hz), 8.78 (1H, dd, J = 9.2, 2.0 Hz), 9.78 (1H, d, J = 2.0 Hz), 10.59 (1H, b.s.), 14.04 (1H, b.s.).

Аналогично тому, как описано в примере 4, получали целевое соединение из соединения, полученного в примере 49 получения.Example 52. 4- (3-Chloro-4-methoxybenzyl) amino-1- [4- (hydroxymethyl) piperidino] -6-nitrophthalazine hydrochloride

In the same manner as described in Example 4, the desired compound was prepared from the compound obtained in Production Example 49.

Mp: 232-233 ^° C (decomp.).

MS: 458 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.48 (2H, m), 1.64 (1H, m), 1.83 (2H, m), 2.90 (2H, m), 3.37 (2H, d, J = 6.4 Hz), 3.61 (2H, m), 3.85 (3H, s), 4.77 (2H, d, J = 6.0 Hz), 7.17 (1H, d, J = 8.4 Hz), 7.48 (1H, dd, J = 8.4, 2.4 Hz), 7.63 (1H, d, J = 2.4 Hz), 8.32 (1H, d, J = 9.2 Hz), 8.78 (1H, dd, J = 9.2, 2.0 Hz), 9.77 (1H, d , J = 2.0 Hz), 10.56 (1H, br.s.).

Аналогично тому, как описано в примере 4, получали целевое соединение из соединения, полученного в примере 49 получения.Example 53. 4- (3-Chloro-4-methoxybenzyl) amino-1- [4- (2-hydroxyethyl) piperidino] -6-nitrophthalazine hydrochloride

In the same manner as described in Example 4, the desired compound was prepared from the compound obtained in Production Example 49.

Mp: 233-236 ^o C (decomp.).

MS: 472 (MH ⁺ ).

Аналогично тому, как описано в примере 3, получали целевое соединение из соединения, полученного в примере 49 получения. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.42 - 1.53 (4H, m), 1.66 (1H, m), 1.84 (2H, m), 2.89 (2H, m), 3.51 (2H , t, J = 6.6 Hz), 3.58 (2H, m), 3.85 (3H, s), 4.76 (2H, d, J = 5.6 Hz), 7.17 (1H, d, J = 8.8 Hz), 7.47 (1H , dd, J = 8.8 Hz, 2.0 Hz), 7.62 (1H, d, J = 2.0 Hz), 8.33 (1H, d, J = 8.8 Hz), 8.77 (1H, d, J = 8.8, 2.0 Hz), 9.74 (1H, d, J = 2.0 Hz), 10.45 (1H, br.s.),
Example 54. 4- (3-Chloro-4-methoxybenzyl) amino-1- [4- (2-hydroxyethyl) piperazin-1-yl] -6-nitrophthalazine

In the same manner as described in Example 3, the desired compound was prepared from the compound obtained in Production Example 49.

Mp: 199-200 ^° C (decomp.).

MS: 473 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.69 (2H, t, J = 5.4 Hz), 2.80 (4H, br.s.), 3.37 (4H, br.s.), 3.70 (2H, t , J = 5.4 Hz), 3.90 (3H, s), 4.79 (2H, d, J = 5.2 Hz), 6.87 (1H, t, J = 5.2 Hz), 6.91 (1H, d, J = 8.4 Hz), 7.37 (1H, dd, J = 8.4, 2.4 Hz), 7.50 (1H, d, J = 2.4 Hz), 8.16 (1H, d, J = 9.2 Hz), 8.51 (1H, dd, J = 9.2, 2.0 Hz ), 9.13 (1H, d, J = 2.0 Hz).

Аналогично тому, как описано в примере 3, получали целевое соединение из соединения, полученного в примере 49 получения.Example 55. 1- (4-Ethoxycarbonylpiperidino) -4- (3-chloro-4-methoxybenzyl) amino-6-nitrophthalazine

In the same manner as described in Example 3, the desired compound was prepared from the compound obtained in Production Example 49.

M.p .: 208.5 - 209.5 ^o C (decomp.).

MS: 500 (MH ⁺ ).

¹ H-NMR (400 Hz, CDCl ₃ ) δ /: 1.30 (3H, t, J = 7.0 Hz), 2.01 - 2.15 (4H, m), 2.53 - 2.59 (1H, m), 3.04 -3.11 (2H, m), 3.56 - 3.64 (2H, m), 3.92 (3H, s), 4.20 (2H, q, J = 7.0 Hz), 4.79 (2H, d, J = 5.5 Hz), 5.23 (1H, t, J = 5.5 Hz), 6.94 (1H, d, J = 8.5 Hz), 7.35 (1H, dd, J = 8.5, 2.0 Hz), 7.48 (1H, d, J = 2.0 Hz), 8.20 (1H, d, J = 9.0 Hz), 8.55 (1H, dd, J = 9.0, 2.0 Hz), 8.65 (1H, d, J = 2.0 Hz).

Из соединения, полученного в примере 55, получали так, как описано в примере 43, 1-(4-карбоксипиперидино)-4-(3-хлор-4-метоксибензил)амино-6-нитрофталазин, который затем превращали в целевое соединение таким же образом, какой использован в примере 4 для получения гидрохлорида.Example 56. 1- (4-Carboxypiperidino) -4- (3-chloro-4-methoxybenzyl) amino-6-nitrophthalazine hydrochloride

From the compound obtained in example 55, was obtained as described in example 43, 1- (4-carboxypiperidino) -4- (3-chloro-4-methoxybenzyl) amino-6-nitrophthalazine, which was then converted into the target compound with the same the manner used in example 4 to obtain hydrochloride.

Mp: 137-143 ^° C (decomp.).

MS: 472 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.85-1.92 (2H, m), 1.97 - 2.05 (2H, m), 2.50-2.60 (1H, m), 2.96-3.03 (2H, m) , 3.52-3.56 (2H, m), 3.86 (3H, s), 4.75 (2H, d, J = 4.5 Hz), 7.18 (1H, d, J = 8.5 Hz), 7.46 (1H, m), 7.61 ( 1H, d, J = 2.0 Hz), 8.36 (1H, d, J = 9.0 Hz), 8.76 (1H, dd, J = 9.0, 2.0 Hz), 9.70 (1H, m).

Аналогично тому, как описано в примере 1, получали целевое соединение из 1,4-дихлор-6-нитрофталазина, полученного в примере 8 получения.Example 57. 1-Chloro-4- (3,4-methylenedioxybenzyl) amino-6-nitrophthalazine

In the same manner as described in Example 1, the desired compound was obtained from 1,4-dichloro-6-nitrophthalazine obtained in Production Example 8.

Mp: 186.5-188.0 ^° C.

MS: 359 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.80 (2H, d, J = 5.0 Hz), 5.73 (1H, t, J = 5.0 Hz), 5.95 (2H, s), 6.78 (1H, d, J = 8.0 Hz), 6.92 (1H, dd, J = 8.0, 2.0 Hz), 6.94 (1H, d, J = 2.0 Hz), 8.37 (1H, d, J = 9.0 Hz), 8.64 (1H, dd, J = 9.0, 2.0 Hz), 8.73 (1H, d, J = 2.0 Hz).

Аналогично тому, как описано в примере 2, получали целевое соединение из 1,4-дихлор-6-нитрофталазина, полученного в примере 8 получения.Example 58. 4-Chloro-1- (3,4-methylenedioxybenzyl) amino-6-nitrophthalazine

In the same manner as described in Example 2, the desired compound was obtained from 1,4-dichloro-6-nitrophthalazine obtained in Production Example 8.

Mp: 240-242 ^o C (decomp.).

MS: 359 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.78 (2H, d, J = 5.0 Hz), 5.52 (1H, t, J = 5.0 Hz), 5.96 (2H, s), 6.78 (1H, d, J = 8.0 Hz), 6.91 (1H, dd, J = 8.0, 1.5 Hz), 6.93 (1H, d, J = 1.5 Hz), 7.98 (1H, d, J = 9.0 Hz), 8.59 (1H, dd, J = 9.0, 2.0 Hz), 9.05 (1H, d, J = 2.0 Hz).

Аналогично тому, как описано в примере 3, получали целевое соединение из 1-хлор-4-(3,4-метилендиоксибензил)амино-6-нитрофталазина, полученного в примере 57.Example 59. 1- (4-Dimethylaminopiperidino) -4- (3,4-methylenedioxybenzyl) amino-6-nitrophthalazine

In the same manner as described in Example 3, the title compound was prepared from 1-chloro-4- (3,4-methylenedioxybenzyl) amino-6-nitrophthalazine obtained in Example 57.

Mp: 105.0-107.0 ^o C.

MS: 451 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.79 (2H, ddd, J = 13.0, 13.0, 4.0 Hz), 2.04 (2H, d, J = 13.0 Hz), 2.31-2.40 (1H, m), 2.38 (6H, s), 3.03 (2H, dt, J = 13.5, 1.5 Hz), 3.66 (2H, d, J = 13.5 Hz), 4.77 (2H, d, J = 5.0 Hz), 5.15 (1H, t , J = 5.0 Hz), 5.98 (2H, s). 6.82 (1H, d, J = 8.0 Hz), 6.94 (1H, dd, J = 8.0, 1.5 Hz), 6.97 (1H, d, J = 1.5 Hz), 8.19 (1H, d, J = 9.0 Hz), 8.54 (1H, dd, J = 9.0, 2.0 Hz), 8.63 (1H, d, J = 2.0 Hz).

Аналогично тому, как описано в примере 3, получали целевое соединение из 1-хлор-4-(3,4-метилендиоксибензил)амино-6-нитрофталазина, полученного в примере 57.Example 60. 1- (Imidazol-1-yl) -4- (3,4-methylenedioxybenzyl) amino-6-nitrophthalazine

In the same manner as described in Example 3, the title compound was prepared from 1-chloro-4- (3,4-methylenedioxybenzyl) amino-6-nitrophthalazine obtained in Example 57.

Mp: 154.0-155.5 ^o C.

MS: 391 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ /: 4.89 (2H, d, J = 5.5 Hz), 5.97 (2H, s), 6.05 (1H, t, J = 5.5 Hz), 6.82 (1H, d , J = 8.0 Hz), 6.96 (1H, dd, J = 8.0, 2.0 Hz), 6.98 (1H, d, J = 2.0 Hz), 7.35 (1H, s), 7.44 (1H, s), 7.99 (1H d, J = 9.0 Hz), 8.02 (1H, s), 8.61 (1H, dd, J = 9.0, 2.0 Hz), 8.85 (1H, d, J = 2.0 Hz).

Аналогично тому, как описано в примере 3, получали целевое соединение из соединения, полученного в примере 57.Example 61. 1- (4-Ethoxycarbonylpiperidino) -4- (3,4-methylenedioxybenzyl) amino-6-nitrophthalazine

In the same manner as described in example 3, the desired compound was obtained from the compound obtained in example 57.

Mp: 220-222 ^o C.

MS: 480 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.30 (3H, t, J = 7.0 Hz), 1.99-2.16 (4H, m), 2.52-2.60 (1H, m), 3.03-3.11 (2H, m ), 3.57-3.63 (2H, m), 4.20 (2H, q, J = 7.0 Hz), 4.77 (2H, d, J = 5.0 Hz), 5.17 (1H, t, J = 5.0 Hz), 5.98 (2H , s), 6.82 (1H, d, J = 8.0 Hz), 6.94 (1H, dd, J = 8.0, 1.5 Hz), 6.97 (1H, d, J = 1.5 Hz), 8.20 (1H, d, J = 9.0 Hz), 8.54 (1H, dd, J = 9.0, 2.0 Hz), 8.64 (1H, d, J = 2.0 Hz).

Гидроксид калия (0,5 г) растворяли в 30 мл 50%-ного водного метанола, после чего добавляли 0,26 г соединения, полученного в примере 61. Полученную смесь перемешивали при комнатной температуре 4 часа.Example 62. Potassium salt of 1- (4-carboxypiperidino) -4- (3,4-methylenedioxybenzyl) amino-6-nitrophthalazine

Potassium hydroxide (0.5 g) was dissolved in 30 ml of 50% aqueous methanol, after which 0.26 g of the compound obtained in Example 61 was added. The resulting mixture was stirred at room temperature for 4 hours.

 The solvent was distilled off in vacuo and water was added to the residue to obtain a solution. This solution was neutralized with dilute hydrochloric acid, whereupon a solid precipitated. This solid was recovered by filtration and dissolved in an aqueous solution of potassium carbonate. The resulting solution was adsorbed on an octadecyl silanol column and eluted with a water-methanol mixture to carry out purification. The resulting solid was crystallized from ethanol-ethyl acetate to give 0.15 g of the target compound as a pale yellow solid.

Mp: 206-209 ^o C (decomp.)
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.64-1.76 (2H, m), 1.76-1.84 (2H, m), 1.84-1.92 (1H, m), 2.65-2.73 (2H, m) , 3.26-3.32 (2H, m), 4.53 (2H, d, J = 5.5 Hz), 5.90 (1H, t, J = 5.5 Hz), 5.92 (2H, s), 6.82 (1H, d, J = 8.0 Hz), 6.85 (1H, dd, J = 8.0, 1.0 Hz), 6.95 (1H, d, J = 1.0 Hz), 7.04 (1H, d, J = 2.0 Hz), 7.09 (1H, dd, J = 9.0 , 2.0 Hz), 7.64 (1H, d, J = 9.0 Hz).

Соединение (0,70 г), полученное в примере 61, суспендировали в 50 мл этанола, после чего добавляли 50 мл 10%-ного палладия на угле. Полученную смесь перемешивали в атмосфере водорода при давлении 1 атм всю ночь и фильтровали для удаления катализатора. Фильтрат концентрировали в вакууме и остаток растворяли в этилацетате. К полученному раствору добавляли избыток 4 н. раствора хлороводородной кислоты в этилацетате для получения гидрохлорида. Отгоняли в вакууме растворитель. Полученный остаток перекристаллизовывали из смеси этанол-диизопропиловый эфир и в результате получили 0,54 г целевого соединения в виде белого порошка.Example 63. 6-amino-1- (4-ethoxycarbonylpiperidino) -4- (3,4-methylenedioxybenzyl) aminophthalazine hydrochloride

The compound (0.70 g) obtained in Example 61 was suspended in 50 ml of ethanol, after which 50 ml of 10% palladium-carbon was added. The resulting mixture was stirred in a hydrogen atmosphere at 1 atm pressure overnight and filtered to remove the catalyst. The filtrate was concentrated in vacuo and the residue was dissolved in ethyl acetate. An excess of 4 N was added to the resulting solution. a solution of hydrochloric acid in ethyl acetate to obtain hydrochloride. The solvent was distilled off in vacuo. The obtained residue was recrystallized from ethanol-diisopropyl ether and 0.54 g of the target compound was obtained in the form of a white powder.

Mp: 156.5-158.5 ^o C.

MS: 450 (MH ⁺ ).

¹ H-NMR (400 MHz, CD ₃ OD) δ: 1.28 (3H, t, J = 7.0 Hz), 1.95 - 2.03 (2H, m), 2.04 - 2.12 (2H, m), 2.57 - 2.65 (1H, m), 2.99 - 3.11 (2H, m), 3.60 - 3.68 (2H, m), 4.17 (2H, q, J = 7.0 Hz), 4.62 (2H, s), 5.94 (2H, s), 6.80 (1H d, J = 8.0 Hz), 6.89 (1H, dd, J = 8.0, 2.0 Hz), 6.92 (1H, d, J = 2.0 Hz), 7.29 (1H, br.s), 7.31 (1H, d, J = 9.0 Hz), 7.90 (1H, d, J = 9.0 Hz).

Аналогично тому, как описано в примере 1, получали целевое соединение из 1,4,6,7-тетрахлорфталазина.Example 64. 1- (3-Chloro-4-methoxybenzyl) amino-4,6,7-trichlorophthalazine

In the same manner as described in Example 1, the target compound was obtained from 1,4,6,7-tetrachlorophthalazine.

T. pl.: 208 - 209 ^o C.

MS: 404 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ /: 3.90 (3H, s), 4.77 (2H, d, J = 5.0 Hz), 5.29 (1H, t, J = 5.0 Hz), 6.91 (1H, d , J = 8.0 Hz), 7.32 (1H, dd, J = 8.0, 2.0 Hz), 7.45 (1H, d, J = 2.0 Hz), 7.89 (1H, s), 8.28 (1H, s).

Аналогично тому, как описано в примере 4, получали целевое соединение из соединения, полученного в примере 64.Example 65. 1- (3-Chloro-4-methoxybenzyl) amino-6,7-dichloro-4- (4-hydroxypiperidino) phthalazine hydrochloride

In the same manner as described in example 4, the desired compound was obtained from the compound obtained in example 64.

Mp: 174.0-175.5 ^o C.

MS: 467 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.63-1.73 (2H, m), 1.91-1.99 (2H, m), 3.00-3.08 (2H, m), 3.39-3.49 (2H, m) , 3.73-3.81 (1H, m), 3.86 (3H, s), 4.71 (2H, d, J = 6.0 Hz), 7.14 (1H, d, J = 8.5 Hz), 7.45 (1H, dd, J = 8.5 , 2.0 Hz), 7.59 (1H, d, J = 2.0 Hz), 8.16 (1H, s), 9.26 (1H, s).

Аналогично тому, как описано в примере 3, получали целевое соединение из соединения, полученного в примере 64.Example 66. 1- (3-Chloro-4-methoxybenzyl) amino-6,7-dichloro-4- (4-ethoxycarbonylpiperidino) phthalazine

In the same manner as described in example 3, the desired compound was obtained from the compound obtained in example 64.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.29 (3H, t, J = 7.0 Hz), 1.96-2.13 (4H, m), 2.48 - 2.55 (1H, m), 3.98 - 3.05 (2H , m), 3.53-3.58 (2H, m), 3.86 (3H, s), 4.19 (2H, q, J = 7.0 Hz), 4.71 (2H, d, J = 5.0 Hz), 5.31 (1H, t, J = 5.0 Hz), 6.84 (1H, d, J = 8.5 Hz), 7.27 (1H, dd, J = 8.5, 2.0 Hz), 7.40 (1H, d, J = 2.0 Hz), 7.94 ( 1H, s), 8.08 (1H, s).

Аналогично тому, как описано в примере 43, получали целевое соединение из соединения, полученного в примере 66.Example 67. 1- (4-Carboxypiperidino) -4- (3-chloro-4-methoxybenzyl) amino-6,7-dichlorophthalazine

In the same manner as described in example 43, the desired compound was obtained from the compound obtained in example 66.

M.p .: 268 - 273 ^o C (decomp.).

MS: 495 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.80 - 1.90 (2H, m), 1.93 - 2.00 (2H, m), 2.40 - 2.50 (1H <m), 3.84 - 3.91 (2H, m) , 3.30 - 3.45 (2H, m), 3.82 (3H, s), 4.62 (2H, d, J = 5.5 Hz), 7.10 (1H, d, J = 8.5 Hz), 7.34 (1H, dd, J = 8.5 , 2.0 Hz), 7.44 (1H, d, J = 2.0 Hz), 7.85 (1H, t, J = 5.5 Hz), 8.05 (1H, s), 8.68 (1H, s).

Аналогично тому, как описано в примере 4, получали целевое соединение из соединения, полученного в примере 11 получения.Example 68. 6-Chloro-1- (3-chloro-4-methoxybenzyl) amino-4- (3-pyridylmethyl) phthalazine dihydrochloride

In the same manner as described in Example 4, the desired compound was prepared from the compound obtained in Production Example 11.

M.p ^. : 168.5 - 169.5 ^o C.

MS: 425 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ /: 3.83 (3H, s), 4.77 (2H, s), 4.79 (2H, s), 7.13 (1H, d, J = 8.5 Hz), 7.47 (1H, dd, J = 8.5, 2.0 Hz), 7.62 (1H, d, J = 2.0 Hz), 7.89 (1H, dd, J = 7.5, 5.5 Hz), 8.26 (1H, dd, J = 9.0, 2.0 Hz), 8.34 (1H, d, J = 7.5 Hz), 8.51 (1H, d, J = 2.0 Hz), 8.76 (1H, d, J = 5.5 Hz), 8.87 (1H, s), 9.12 (1H, d, J = 9.0 Hz), 11.01 (1H, br.s).

Аналогично тому, как описано в примере 4, получали целевое соединение из соединения, полученного в примере 12 получения.Example 69. 6-Chloro-4- (3-chloro-4-methoxybenzyl) amino-1- (3-pyridylmethyl) phthalazine dihydrochloride

In the same manner as described in Example 4, the desired compound was prepared from the compound obtained in Production Example 12.

T. pl.: 170.0 - 171.0 ^o C.

MS: 425 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 3.85 (3H, s), 4.78 (2H, d, J = 6.0 Hz), 4.81 (2H, s), 7.13 (1H, d, J = 8.5 Hz), 7.48 (1H, dd, J = 8.5, 2.0 Hz), 7.62 (1H, d, J = 2.0 Hz), 7.95 (1H, dd, J = 8.0, 6.0 Hz), 8.25 (1H, dd, J = 8.5, 2.0 Hz), 8.40 - 8.46 (2H, m), 8.81 (1H, d, J = 6.0 Hz), 8.93 (1H, d, J = 1.0 Hz), 9.26 - 9.31 (1H, m), 10.91 (1H, br s).

Целевое соединение получали так, как описано в примере 45.Example 70. 4- (4-Ethoxycarbonylpiperidino) -1- (3,4-methylenedioxybenzyl) aminopyrido [3,4-d] pyridazine

The target compound was obtained as described in example 45.

T, pl .: 135 - 136 ^o C.

MS: 436 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.30 (3H, t, J = 7.0 Hz), 2.00 - 2.16 (4H, m), 2.52 - 2.59 (1H, m), 3.07 - 3.14 (2H, m ), 3.69 - 3.71 (2H, m), 4.19 (2H, q, J = 7.0 Hz), 4.74 (2H, d, J = 5.0 Hz), 5.00 (1H, t, J = 5.0 Hz), 5.96 (2H , s), 6.80 (1H, d, J = 8.0 Hz), 6.91 (1H, dd, J = 8.0, 1.5 Hz), 6.94 (1H, d, J = 1.5 Hz), 7.48 (1H, dd, J = 5.5, 1.0 Hz), 8.93 (1H, d, J = 5.5 Hz), 9.42 (1H, d, J = 1.0 Hz).

Целевое соединение получали так, как описано в примере 46.Example 71. 1- (4-Ethoxycarbonylpiperidino) -4- (3,4-methylenedioxybenzyl) aminopyrido [3,4-d] pyridazine

The target compound was obtained as described in example 46.

T, pl .: 119 - 120.5 ^o C.

MS: 436 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.30 (3H, t, J = 7.0 Hz), 1.97 - 2.15 (4H, m), 2.51 - 2.59 (1H, m), 3.01 - 3.08 (2H , m), 3.61 - 3.67 (2H, m), 4.19 (2H, q, J = 7.0 Hz), 4.78 (2H, d, J = 5.0 Hz), 5.24 (1H, t, J = 5.0 Hz), 5.97 (2H, s), 6.81 (1H, d, J = 8.0 Hz), 6.93 (1H, dd, J = 8.0, 1.5 Hz), 6.97 (1H, d, J = 1.5 Hz), 7.75 (1H, dd, J = 5.5, 1.0 Hz), 8.93 (1H, d, J = 5.5 Hz), 9.21 (1H, d, J = 1.0 Hz).

Целевое соединение получали так, как описано в примере 43, из соединения, полученного в примере 70.Example 72. 4- (4-Carboxypiperidino) -1- (3,4-methylenedioxybenzyl) -aminopyrido [3,4-d] pyridazine

The target compound was obtained as described in example 43, from the compound obtained in example 70.

M.p .: 138 - 140 ^o C.

MS: 408 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ /: 1.82 - 1.93 (2H, m), 1.94 - 2.20 (2H, m), 2.45 - 2.52 (1H, m), 2.89 - 2.98 (2H, m ), 3.46 - 3.55 (2H, m), 4.62 (2H, d, J = 5.5 Hz), 5.96 (2H, s), 6.85 (1H, d, J = 8.0 Hz), 6.87 (1H, dd, J = 8.0, 1.0 Hz), 6.97 (1H, d, J = 1.0 Hz), 7.88 (1H, t, J = 5.5 Hz), 8.17 (1H, d, J = 5.5 Hz), 8.98 (1H, d, J = 5.5 Hz), 9.29 (1H, s), 12.25 (1H, br s).

Целевое соединение получали так, как описано в примере 43, из соединения, полученного в примере 71.Example 73. 1- (4-Carboxypiperidino) -4- (3,4-methylenedioxybenzyl) aminopyrido [3,4-d] pyridazine

The target compound was obtained as described in example 43, from the compound obtained in example 71.

T. pl.: 205 - 206 ^o C.

MS: 408 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.80 - 1.91 (2H, m), 1.94 - 2.01 (2H, m), 2.42 - 2.50 (1H, m), 2.84 - 2.92 (2H, m) , 3.42 - 3.48 (2H, m), 4.64 (2H, d, J = 5.5 Hz), 5.97 (2H, s), 6.85 (1H, d, J = 8.0 Hz), 6.89 (1H, dd, J = 8.0 , 1.5 Hz), 6.99 (1H, d, J = 1.5 Hz), 7.76 (1H, d, J = 5.5 Hz), 8.05 (1H, t, J = 5.5 Hz), 8.93 (1H, d, J = 5.5 Hz), 9.67 (1H, s).

Claims (13)

1. Condensed pyridazine of the general formula I

or its pharmacologically acceptable salt,
where n = 1 or 2;
R ¹ represents a hydrogen atom, a halogen atom, nitro, cyano, an amino group or 4-hydroxypiperidin-1-yl;
each of the radicals R ² and R ³ independently represents a halogen atom or a lower alkoxy group or, in accordance with another embodiment, R ² and R ³ may together form a methylenedioxy ring;
symbol

means double or single bond and 1) when

means a double bond, then X is a nitrogen atom and Y represents = C - Z, where Z is a halogen atom, a group of the formula

where p = 0 or 1, m = 0.1 or 2, a group of the formula

where R ⁴ represents a carbamoyl, carboxy, cationic carboxylate group, lower alkoxycarbonyl or dialkylamino group, a group of the formula

where R ⁵ or R ⁶ is a hydrogen atom and the other is a hydroxyl group, a group of the formula

where R ⁷ is pyridyl, pyrimidyl or a lower hydroxyalkyl group, a group of the formula

where is the symbol

represents a double bond or a single bond, hydroxypyrrolidinyl, hydroxymethylporrolidinyl, imidazolyl, morpholinyl, pyridylmethyl, a group of the formula

where R ⁸ is a hydrogen atom, lower alkyl, R ⁹ is pyridyl, a lower hydroxyalkyl group or a carboxyalkyl group, a lower alkoxy group, a lower hydroxyalkoxy group,
2) when

denotes a single bond, then X represents an = NR ¹⁰ group, where R ¹⁰ represents a hydrogen atom, carboxymethyl, lower alkoxycarbonylmethyl group, tetrahydropyranylalkyl group or hydroxyalkyl group and Y is a carboxyl group. 2. Pyridazine according to claim 1 by the general formula II

or its pharmacologically acceptable salt,
where R ¹ - R ³ , n, X and Y have the indicated meaning;
symbol

represents a double or single bond. 3. Pyridazine according to claim 1 of the General formula III

or its pharmacologically acceptable salt,
where R ^1a represents halogen, nitro, cyano, amino group or 4-hydroxypiperidin-1-yl;
R ¹ , R ² , R ³ each is as defined above;
Y - = CZ, where Z is indicated above;
n ¹ = 1 or 2. 4. Condensed pyridazine according to claim 1 of General formula IV

or its pharmacologically acceptable salt,
where R ¹ - R ³ , R ^1a , n 'and Y are indicated above. 5. Pyridazine according to claim 1 of the General formula V

or its pharmacologically acceptable salt,
where R ^1a and Y are indicated above;
R ¹² - R ¹⁴ each independently is halogen, methoxy, ethoxy. 6. Pyridazine according to claim 1 of the General formula VI

or its pharmacologically acceptable salt,
where R ^1a and Y are indicated above;
R ¹² - R ¹⁴ each independently is hydrogen, methoxy, ethoxy.  7. An agent exhibiting an inhibitory activity against cyclic GMF phosphodiesterase, comprising an active ingredient and a carrier, characterized in that it contains the condensed pyridazine or its pharmacologically acceptable salt according to claim 1 in an effective amount as an active ingredient.  8. The tool according to claim 7, characterized in that for the prevention and treatment of diseases for which the inhibitory effect against cyclic GMP-phosphodiesterase is effective, it contains, as an active ingredient, condensed pyridazine or its pharmacologically acceptable salt according to claim 1 in an effective amount .  9. The tool according to claim 7, characterized in that against platelet aggregation it contains, as an active component, a condensed pyridazine or its pharmacologically acceptable salt according to claim 1 in an effective amount.  10. The tool according to claim 7, characterized in that for the prevention and treatment of diseases for which the inhibitory effect against platelet aggregation is effective, it contains, as an active ingredient, condensed pyridazine or its pharmacologically acceptable salt according to claim 1 in an effective amount.  11. The tool according to claim 7, characterized in that for the prevention and treatment of hypertension it contains, as an active ingredient, condensed pyridazine or its pharmacologically acceptable salt according to claim 1 in an effective amount.  12. The tool according to claim 7, characterized in that for the prevention and treatment of pulmonary hypertension, it contains, as an active ingredient, condensed pyridazine or its pharmacologically acceptable salt according to claim 1 in an effective amount.  13. The tool according to claim 7, characterized in that for the prevention and treatment of angina pectoris it contains as an active component a condensed pyridazine or its pharmacologically acceptable salt according to claim 1 in an effective amount.

Images