Derivatives phthalazine and a therapeutic agent for erectile dysfunction

 

(57) Abstract:

The invention relates to a derivative phthalazine General formula (I) or their pharmaceutically acceptable salts, or hydrates, where R1and R2are the same or different from each other and each represents a halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, a hydroxyl group or a C1-C4alkoxygroup, which may be substituted by a halogen atom, or cyano; X represents a cyano, a halogen atom, hydroxyimino, optional O-substituted C1-C4alkyl group, or a heteroaryl group selected from thiazoline, thienyl, pyrazolidine, triazolinones and tetrazolyl groups that may be substituted WITH1-C4alkyl group; Y represents a cyclic amino group (i) - (v) described in paragraph 1 of the claims; (vi) etinilnoy or ethyl group substituted WITH1-C4alkyl group, which, in turn, replaced by a number of deputies referred to in paragraph 1 of the claims; (vii) optionally substituted phenyl group; (viii) pyridyloxy or thiazolidine group. These compounds inhibit cyclic same applies to preventive and therapeutic agent for erectile dysfunction, which contains as an active ingredient the above-mentioned compounds of the invention. The object of the invention is a therapeutic agent for erectile dysfunction, which comprises as active ingredient a compound of the formula (VII), its pharmacologically acceptable salt or hydrate, where lrepresents an integer from 1 to 3; R6halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, or cyano; X1represents a cyano or halogen atom; Y1represents group (i) - (v) described in paragraph 20 of the claims. In addition, the proposed method of obtaining some representatives of the compounds of General formula (I), pharmaceutical composition for the treatment of erectile dysfunction and treatment of erectile dysfunction. 6 C. and 21 C.p. f-crystals, 2 PL.

Technical field of invention

This invention relates to a derivative phthalazine. More precisely, it relates to prophylactic and therapeutic remedies for male erectile dysfunction, as well as preventive and therapeutic means for female sexual dysfunction or dysmenorrhea.

Prior to ur is t about 3000000 people. It is reported that in the USA the number of patients with erectile dysfunction reaches 20000000, and 15% of men aged fifty to sixty years, and about 1/3 of men aged sixty to seventy years suffers from this disease. In this age group, sexual intercourse is regarded as a pleasant and emotional behavior. When required to improve the quality of life it is expected that in the future the erectile dysfunction will be raised to the power of not only medical but also social problems. This disease is divided into organic impotence caused by disorders of the nerves, blood vessels or muscles in the penis, and functional (mental) impotence caused by mental or psychological problems. For the erection of the necessary three factors, namely: increasing blood flow to the penis, regulation of the outflow of blood from the veins of the penis and relaxation (relaxation) of the cavernous tissue. When at least one of these States ingibirovalo, there is erectile dysfunction.

Urological treatments of erectile dysfunction, ongoing, include drug therapy and surgical prosthetic penis with ispolzovanie to enter papaverine hydrochloride or prostaglandin El. However, this treatment is currently difficult to do, because in Japan it is not acceptable to the patient himself had introduced himself an injection, and to go to the doctor every time you have sex is impossible in practice. In addition, injection of papaverine hydrochloride would cause, although in exceptional cases, a painful symptom, called priapism. Thus, treatment with existing drugs is almost impossible. Therefore, the development of drug therapy, clinically effective in practice, is urgently needed.

In 1984, Bowman and Drummond reported that a selective inhibitor of cyclic GMP phosphodiesterase M&V (zaprinast) increased the content of cyclic GMP in the tissue and relacional retractor muscle of the penis of a bull (Cyclic GMP mediates neurogenic relaxation in bovine retractor penic muscle, Br. J. Phamacol., 81, 665-674, 1984). Then, other authors, one after another described the relaxation of cavernous bodies of the penis by increasing the content of cyclic GMP in the tissue (Int. J Impotence Res., 4, 85-93, 1992; J. Urol., 147, 1659-1655, 1992; N. Engl. J. Med., 326, 90-94, 1992). However, none of the compounds used in these studies could not satisfactorily be used clinically due to low efficiency and so on

Inhibitor of phosphodiesterase type V e iternum action on phosphodiesterase V-type, described in WO 9605176 (JP-A 8-225541), but were not documented nor spiraeoideae containing nitrogen atoms, or their bicyclic and 6-membered heterocyclic derivative or the prophylactic and therapeutic use of such compounds for the treatment of erectile dysfunction.

Description of the invention

The applicants of this invention have conducted comprehensive research, therefore it is established that phthalazinone compounds represented by formula (I), exhibit high selectivity for phosphodiesterase type V type, which is a enzyme that breaks down cyclic GMP, have a powerful inhibitory effect on her, and also have a strong relaxing (relaxing) the effect on the cavernous body of penis increasing biological abilities and have a high safety, and thus was formulated the invention.

This invention relates to phthalazinone compounds not specifically described in the publication JP-A-225541, phthalazinium connections, not assumed in this publication, as well as the method of production of some of these compounds.

The invention relates to phthalazinone the compound represented by formula (I), it fayme or different from each other and represent a halogen atom, C1-C4alkyl group which may be substituted by a halogen atom, a hydroxyl group, a C1-C4alkoxygroup, which may be substituted by a halogen atom, or cyano;

X represents a cyano, a nitro-group, a halogen atom, thiocarbamoyl group, hydroxyimino, which may be substituted C1-C4alkyl group, aryl-C1-C4alkyl group, a carboxy C1-C4alkyl group or heteroaryl group which may be substituted by 1 to 3 substituents selected from the following group of substituents AS;

Y is:

i) a group represented by the formula (II):

where ring a represents a 4-to 8-membered amine ring which may be substituted by a methyl group and may contain a double bond; D represents a single bond or an oxygen atom; R3represents a hydrogen atom, a C1-C4alkyl group or halogen atom; m represents an integer from 0 to 3; W represents an amino group, hydroxyl group, cyano, carboxyl group which may be protected, or C1-C4alkoxygroup;

ii) a group represented by the formula (th link, and n and R are the same or different from each other and represent 0 or an integer from 1 to 3;

iii) a group represented by the formula (IV):

where the ring G represents a 4-8-membered amine ring, which may contain a double bond, E represents a hydroxyl group, a halogen atom, a C1-C4alkyl group or a C1-C4alkoxygroup, J represents the formula -(CHR4)q-Q (where R4represents a hydrogen atom or a C1-C4alkyl group, Q represents a hydroxyl group, halogen atom, carboxyl group which may contain a protective group, karbamoilnuyu group or asailing group containing no heteroatom other than the nitrogen atom, q represents 0 or an integer from 1 to 4), or E and J can form a 3-6-membered ring together with the carbon atom to which they are attached, and the ring optionally containing a heteroatom and optionally containing a Deputy;

iv) a group represented by the formula (V):

where M represents a single bond or C1-C4alkylenes group which may be substituted by a hydroxyl group, a carboxyl group, a C1-C4alkyl g the e ring M, and the ring L represents a 5-8-membered alkyl ring which may contain a substituent and may contain an oxygen atom;

v) a group represented by the formula (VI):

where the ring R is a 5-7 membered amine ring and R5represents a hydrogen atom or a C1-C4alkyl group which may be substituted by halogen atom, hydroxyl group or carboxyl group;

vi) alkylamino group, alkenylphenol group or alkyl group, which may contain a Deputy;

vii) a phenyl group which may be substituted by 1-3 substituents selected from the following group of substituents A, or

viii) pyridyloxy group, pyramidalnou group, thienyl group, thiazolino group or follow group which may be substituted by 1-3 substituents selected from the following group of substituents AS;

the group of substituents (A: C1-C4alcalina group which may be substituted by a halogen atom, a cyano, a nitro-group or a hydroxyl group; C1-C4alkoxygroup, which may be substituted by a halogen atom, a cyano, a nitro-group or a hydroxyl group; cyanoprop the em to have a protective group; carnemolla group which may be substituted by a group of lower alkyl; halogen atom; an amino group which may be substituted C1-C4acyl group, a C1-C4alkylsulfonyl group or arylsulfonyl group which may contain a Deputy;

l represents an integer from 1 to 3;

provided that excluded the following cases:

the case when l is 1 or 2, X represents a cyano, a nitro-group or a chlorine atom, R1represents a chlorine atom, R2represents a methoxy group, the ring a represents a 5 - or 6-membered amine ring, D represents a single bond, m is 0, and W represents a carboxyl group which may contain a protective group or a C1-C4CNS group; the case where l is equal to 1, R1represents a chlorine atom, R2represents a methoxy group, the ring a represents a saturated 5 - or 6-membered amine ring, D represents a single bond, and W represents a hydroxyl group; the case where l is equal to 1, the ring is 5 - or 6-membered amine ring, n and p are 0; the case where l is equal to 1, E and Q represent a hydroxyl group and q is 0, and the case where l is equal to 1, X represents a chlorine atom and Y before which I had installed, what connections the following formula (VII) also show a strong relaxing effect on the cavernous body of penis increasing isposable and have a high safety. Thus, the compounds (VII) are also included in the scope of this invention.

Therapeutic agent for erectile dysfunction, which includes phthalazinone compound represented by the formula (VII), its pharmacologically acceptable salt or hydrate as an active ingredient:

where l’ represents an integer from 1 to 3; R6represents a halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, or cyano;

X1represents a cyano, a nitro-group or halogen atom;

Y1is:

i) a group represented by the formula (VIII):

where the ring A1 represents a 5 - or 6-membered amine ring;

m1 is 0 or represents an integer from 1 to 3; Z represents an amino group, a hydroxyl group which may have a protective group, a carboxyl group which may have a protective group, a C1-C4alkoxygroup or cyano;

ii) the group pree represent 0 or integers from 1 to 3;

iii) thiomorpholine in which morpholinopropan or sulfur atom may be oxidized;

iv) a phenyl group which may be substituted by 1-3 substituents selected from the following group of substituents A1;

v) a heteroaryl group, which is pyridyloxy group, pyramidalnou group, thienyl group or follow group which may be substituted by 1-3 substituents selected from the following group of substituents A1, or

vi) a group of the formula-N(R7)-(CH2)s-Het, where R7represents the group of lower alkyl, Het represents pyridyloxy group or pyramidalnou group which may be substituted by 1-3 substituents selected from the following group of substituents A1, and s is 0 or represents an integer from 1 to 3;

the group of substituents A1: the group of lower alkyl, substituted by a halogen atom, a cyano, a nitro-group or a hydroxyl group, a lower alkoxygroup, which may be substituted by a halogen atom, a cyano, a nitro-group or a hydroxyl group; a cyano; a nitro-group; a carboxyl group which may have a protective group; a hydroxyl group which may have a C is nilina group, which may be substituted by an alkyl group, alkoxygroup, a halogen atom or amino group.

This invention is a method of obtaining a compound represented by the formula (XI):

(where X, R1, R2and l take the values defined above, Y3represents a phenyl group, pyridyloxy group, pyramidalnou group, thienyl group or follow group which may have a Deputy, selected from the above group of substituents A1), which includes the stage of interaction of the compounds represented by formula (X)

(where Hal represents a halogen atom and R1, R2l and X take the values defined above) with the compound of the formula Y3-B(OH)2.

This invention where Y3matter, mentioned above, provides a preventive and therapeutic agent for erectile dysfunction, which includes phthalazinone compound represented by the above formula (I), its pharmacologically acceptable salt or hydrate as an active ingredient. It also provides a preventive or therapeutic agent for female sexual dysfunction, and (VII), its pharmacologically acceptable salt or hydrate as an active ingredient.

This invention is a pharmaceutical composition comprising a pharmacologically or clinically effective amount phthalazinone compounds represented by the above formula (I) or (XI), its pharmacologically acceptable salt or hydrate, and pharmacologically acceptable carriers.

This invention provides a method or use for the prevention or treatment of erectile dysfunction, female sexual dysfunction or dysmenorrhea, which includes a step of introducing pharmacologically or clinically effective amount phthalazinone compounds represented by the above formula (I) or (VII), its pharmacologically acceptable salt or hydrate the patient suffering from erectile dysfunction, female sexual dysfunction or dysmenorrhea.

In the definitions stated in this invention, the halogen atoms defined in X, R1, R2, R3, R4, R5, E, Q, in groups of substituents a and A1 denote a fluorine atom, chlorine atom, bromine atom and iodine atom.

WITH1-C4alkyl group, as defined in R1, R2is by alkyl groups, containing 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl and tert-butyl. WITH1-C4alkoxygroup defined in R1, R2and groups of the substituents a and A1 denote groups derived from the above WITH1-C4alkyl groups, and such groups include, for example, a methoxy group, ethoxypropan, propoxylate etc.

The protective group in the carboxyl group, which may have a protective group, defined in Q, W, in groups of substituents a and A1 indicate, for example, lower alkyl groups such as methyl group, ethyl group and tert-bucilina group; a lower alkyl group, a substituted phenyl group, which may contain a Deputy, such as p-methoxybenzyl, p-nitrobenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl and phenethyl; halogenated lower alkyl groups such as 2,2,2-trichloroethyl and 2-Iodate; lower alkanoyloxy-lower alkyl groups, such as pivaloyloxymethyl, acetoxymethyl, propionylacetate, butylacetyl, allelochemical, 1-acetoxyethyl, 2-acetoxyethyl, 1-pivaloyloxymethyl and 2-pivaloyloxymethyl; the highest alkanoyloxy-lower alkyl groups, such as palmitoleate, heptadec-carbonylmethyl, 1-butoxycarbonyloxyimino and 1-(isopropoxy-bicarbonate)ethyl; carboxy-lower alkyl groups such as carboxymethyl and 2-carboxyethyl; heteroaryl group such as 3-phthalidyl; benzoyloxy-lower alkyl group, optionally containing a Deputy, such as 4-glycidoxypropyl; (substituted dioxolene)-lower alkyl groups such as (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl; cycloalkylcarbonyl lower alkanoyloxy-lower alkyl groups such as 1-cyclohexanediacetic, and cycloalkylcarbonyl-lower alkyl groups such as 1-cyclohexyloxycarbonyloxy. In other words, any group that can be decomposed by any means in vivo for the formation of a carboxylic acid, can serve as a protective group for carboxyl group.

The protective group of hydroxyl group, which may have a protective group, in certain groups of the substituents a and A1 indicate, for example, acyl groups such as formyl group, acetyl group and benzoline group; lower alkoxymethyl groups such as 2-methoxyethoxymethyl group. In other words, any group that can be decomposed by any means in vivo for the formation of hydroxurea heteroatoms, other than the nitrogen atom, and Q means a group derived from pyrrole, pyrazole, imidazole, triazole, tetrazole, indazole, benzimidazole and benzotriazole.

In the formula (IV) compound, obtained from the ring formed by using E and J with the carbon atom to which they are attached, and the ring G represents spirochetemia. The ring formed by using E and J together with the carbon atom to which they are attached, includes CYCLOBUTANE, cyclopentane, cyclohexane, oxirane, tetrahydrofuran, tetrahydropyran, butyrolactone and butyrolactam. In addition, the substituents on these rings include hydroxyl group, carboxyl group, which may have the above-mentioned protective group, a C1-C4alkyl group which may be substituted by a hydroxyl group, such as hydroxymethylene group and hydroxyethylene group, carbonyl group and a halogen atom such as fluorine atom or chlorine.

In the formula (V) bicyclic ring which, when M represents C1-C4alkylenes group, formed from the rings K and L, as implied, is made by the ring. Deputy ring L include hydroxyl group, carboxyl group, which may school group such as hydroxymethylene group and hydroxyethylene group, C1-C4alkylcarboxylic group which may be substituted by a carboxyl group, such as carboxymethyl group and carboxyaniline group, a halogen atom such as fluorine atom and chlorine atom, vinyl group, etc.

The substituents in alkenylphenol group, alkenylphenol group or alkyl group, Y may have a Deputy, include 1-C4alkyl groups such as methyl group, ethyl group, through the group, isopropyl group, bucilina group, isobutylene group, sec-bucilina group and tert-bucilina group; groups derived from cycloalkanes such as cuprophan, CYCLOBUTANE, cyclopentane and cyclohexane; C1-C4alkoxygroup obtained from the above C1-C4alkyl groups such as a methoxy group, ethoxypropan and propoxylate and so on; hydroxyl group; amino group which may be substituted C1-C4alkyl group; cyclic amines, which may be substituted by a hydroxyl group, such as aziridine, azetidine, pyrrolidine and piperidine; hydroxy-C1-C4alkyl groups; hydroxy-C1-C4alkoxygroup; carlucet group, derived from pyrrole, pyrazole, imidazole, triazole, tetrazole, indazole, benzimidazole, benzothiazole, thiazole, isothiazole, thiadiazole, benzothiazole, pyridine, pyrimidine, triazine, quinoline, isoquinoline, naphthylidine, phthalazine etc.

In this invention pharmacologically acceptable salt includes, for example, inorganic salts such as hydrochloride, sulfate, Hydrobromic and phosphate, and organic acid salts such as formate, acetate, maleate, fumarate, tartrate, methanesulfonate, bansilalpet and toluensulfonate.

It goes without saying that the present invention in the case of compounds having an asymmetric atoms, their optically active compounds included in the scope of this invention.

In addition, compounds that are metabolized in vivo to form compounds of the present invention, and compounds, formed through the metabolism of the compounds of the present invention, also included in the scope of this invention.

Thanks to the wonderful ability to be absorbed when administered orally and duration of action (ling-lasting action) these phthalazinone compounds, their pharmaceutically acceptable salts or hydrates may be injected subcutaneously, nutrivene bodies, what makes them preferable as preventive and therapeutic agents for erectile dysfunction and as a prophylactic and therapeutic drugs for female sexual dysfunction or dysmenorrhea.

Although the injected dose of the compounds of this invention are not specifically limited, usually they are adults in a dose of from 5 to 100 mg, preferably from 10 to 1000 µg intravenously or in a dose of from 1 to 1000 mg, preferably from 5 to 100 mg for oral administration.

The method of obtaining 1

Methods for obtaining compounds similar to the compounds of this invention or their pharmacologically acceptable salts, are described in the publication WO 965176 (JP-A-225541), and phthalazinone the compounds of this invention receives the same way, as shown below:

where Y2is:

where ring A, D, R3m and W take the values defined above;

where ring B, n and p take the values defined above;

where the ring G, E and J take the values defined above;

where the ring To the ring L and M take the values defined above, and

DG is UP>, R2l and X take the values defined above.

This is a reaction in which a compound represented by the formula (X), subject to interaction with HY2in the solvent, giving a compound represented by the formula (XII). As the reaction solvent, the preferred N-methyl-2-pyrrolidin, but can be used any solvent inert to this reaction. Preferred results may be obtained when using HY2excess amount relative to compound (X) or by using organic bases, such as diisopropylethylamine, or salt, such as potassium carbonate, sodium carbonate or sodium bicarbonate. The reaction temperature is in the range from room temperature up to the boiling point of the solvent, preferably 100C or more.

Synthesis HY2required to obtain compounds in which W represents cyano, not described in WO 9605176 (JP-A 8-225541), and it is as follows:

And in the case when W defined above, represents the amino group, which is not specifically defined in the above publication, synthesize HY2in which the amino group is protected, and then remove the protective group shall be obtained using a connection described in the publication WO 9806720, or using the method described in this publication. 1) for Example, some of the compounds represented by formula (IV) obtained by the following process.

where G1 is 4-to 8-membered ring; Q1 represents pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, indazoles, benzimidazoles, benzotriazoles or fluorine atom and Pro represents a protective group for the nitrogen atom.

In a solvent such as toluene, xylene or tetrahydrofuran, methyltriphenylphosphonium is treated with base, such as tert-piperonyl potassium or utility, and subjected to interaction with a ketone compound represented by the formula (a), the result can be obtained compound represented by the formula (b). The reaction temperature is preferably from-S to room temperature.

The compound (b) is subjected to interaction with trichloroacetamido in a solvent such as diethyl ether, dimethoxyethane or tetrahydrofuran, to obtain dichlorocyclopentane connection (f). (Alternatively, when it interacts with diacetylenic get monochloropropane. Monochloroacetate). And then the product is treated with reducing agent, such as powdered zinc, the result can be obtained cyclobutanone compound represented by the formula (g). The reaction temperature is preferably from 10 to 50C. When the compound (g) is processed using a peroxide such as 3-chloroperbenzoic acid, in the presence of sodium bicarbonate in a solvent such as dichloromethane, can be obtained lactoovo compound represented by formula (h). The reaction temperature preferably ranges from room temperature to 40C. When the compound (b) is processed by dichloroethene and diazomethane, get Cyclopentanone compound of formula (f), and when the compound (g) is treated with diazomethane, get Cyclopentanone compound of formula (g). When Cyclopentanone connection is further processed by diazomethane, get cyclohexanone connection.

When the compound (b) is processed by percolate, such as magnetoluminescence receive epoxy compound represented by the formula (C). When the epoxy compound (C) is subjected to interaction with the sodium salt of azole containing ka the connection, represented by formula (d) (Q1 is 1-imidazolidinyl group, 1-triazolyl group, and so on). Treatment gidroftoridakh potassium at a temperature of 100-150C in the presence of Bu4N+H2F3as the compounds of formula (d) receive formatline connection, where Q1 represents a fluorine atom.

On the other hand, fluoride compound represented by the formula (e), is obtained by treating compound (s) gidroftoridakh pyridine in a solvent such as methylene chloride at temperatures from -10 to 10 SECONDS.

2) Among the compounds represented by formula (V), compounds in which M represents methylene substituted by hydroxyl group, receive, for example, by the method shown below.

Compounds in which L contains an oxygen atom can also be obtained by this method.

The method of obtaining 2

The compounds of formula (I) where Y represents alkylamino group, alkenylphenol group or alkyl group, which may contain the Deputy can be obtained in the following way.

where Hal represents a halogen atom; R8represents optionally substituted C1-C4alkyl group or the optional Sames what's up.

The reaction of the compound of formula (X) with alkhanovym (acetylene) compound is carried out in the presence of catalytic amounts dichlorobistriphenylphosphine(II), copper iodide and tertiary amine at room temperature or when heated. Used solvent includes dimethylformamide or 1-methylpyrrolidine. Used a tertiary amine include triethylamine, diisopropylethylamine, DBU and dimethylaniline.

The reaction temperature is preferably 0 to 150C.

Turning olkinuora compounds represented by the formula (XIII), in alkenone compound represented by the formula (XIV), or in alonovoa compound represented by the formula (XV), carried out by catalytic reduction, for example, in the presence of Lindlar catalyst or Pd-C catalyst.

The method of obtaining 3

In addition, phthalazinone compounds, where Y represents the Y3that represents optionally substituted aryl or heteroaryl group, was prepared as follows:

Y3represents a phenyl group, pyridyloxy group, pyramidalnou group, thienyl group or follow group, which may contain from 1 to 3 substituents selected from A, defined above.

The reaction is carried out by the interaction of 1-halogencontaining compounds represented by formula (X), with a complex of palladium with a valency of 0 or 2 and boric acid, dialkoxybenzene or triamcinolonum containing the aryl group or heteroaryl group. Boric acid, dialkoxybenzene or triamcinolone, aryl group or heteroaryl group, and a palladium complex is dissolved or suspended in a 2-phase solvent consisting of an organic solvent and an aqueous solution of sodium carbonate. The mixture is subjected to interaction at a temperature in the range from room temperature to the boiling temperature of the solvent for from about 1 to 24 hours in a stream of nitrogen gas. As a palladium complex may be used any palladium complex, which allows the reaction, and preferred tetrakis(triphenylphosphine)palladium, etc. as organic solvent can be any solvent that is inert to the reaction, and preferred are xylene, toluene, tetrahydrofuran or a mixture of these solvents.

The method of obtaining 4

In f the shares using the compound (XVII), where X represents cyano.

where R9represents a hydrogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, aryl-C1-C4is an alkyl group or a carboxy-C1-C4is an alkyl group; R10represents C1-C4alkyl group, and R1, R2l and Y take the values defined above.

The method of obtaining 5

Some of the compounds of formula (I) in which X represents a heteroaryl group can be obtained by the method described in the Method of obtaining 3.

where Hal represents a halogen atom; Het1represents a heteroaryl group and R1, R2, l and Y have the meanings defined above.

The halogen atom is preferably a bromine atom or an iodine atom.

In addition, the compounds of formula (I) with soleley group containing no heteroatom other than the nitrogen atom, to receive according to the above Method of obtaining 1 after first receiving a corresponding compound represented by the formula (X). The corresponding compound of formula (X) are obtained, for example, according to the method described in the publication WO 9605176, PEFC is methyl-4-osalistelt, which is then treated with hydrazine, giving 6-azolyl-2,3-dihydro-1,4-phthalazinedione.

The method of obtaining 6

The compound of formula (I) in which Y is represented by formula (VI) can be obtained by transformation of a compound represented by the following next formula (XXIV), the oxime in a known manner:

where R1, R2, R5l and X take the values defined above.

The following describes the effect of the compounds of this invention with reference to Experimental examples.

1) Inhibitory effect on the enzyme cGMP-PDE derived from platelets pigs

Inhibitory activity of the test compound on the enzyme cGMP-PDE prepared from platelets pigs, appreciate the addition of a solution of test compound in DMSO in the reaction solution, where 1 μm cGMP is used as substrate, in the presence of 1 mm EGTA in accordance with the method Tompson et al. The final concentration of DMSO in the reaction solution is 1% or less. Obtaining cGMP-PDE is as follows. Platelets pigs add in buffer A (20 mm Tris/HCl, 2 mm magnesium acetate, 10 mm 2-mercaptoethanol, 0.1 mm EGTA; pH 7.4) and subjected to sonication. The resulting suspension price apan). After that, the column was washed with buffer A, the enzyme elute with a gradient of 0.075 to 0.25 M NaCl in buffer A, receiving a fraction of cGMP-PDE. The resulting fraction is subjected to dialysis, concentrate, and store.

2) Enhance the action of PDE5 inhibitor in relation to the relaxing effects of sodium nitroprusside on the drug cavernous body of penis, isolated from rabbit

The penis is removed at the white rabbit NZW (weighing approximately 3 kg), umarsultanova through intravenous pentobarbital (50 mg/kg). After removal of the cavernous body open by removing the surrounding tissue, such as protein shell receiving the drug (approximately 101,51,5 mm). This drug is in the tube of the Magnus tube) suspended in 10 ml of nutrient solution of Krebs-Henseleit (Krebs-Henseleit''s nutritive solution) (118,4 mm NaCl, of 4.7 mm KCl, 2.5 mm CaCl2, 1.3 mm MgSO4, 1.2 mm KN2RHO4, 25.0 mm NaHCO3, 11,0 mm glucose, 0,026 mm EDTA and 0.001 mm indomethacin) when S and it bubbled gas mixture of 95% oxygen +5% carbon dioxide). Then under a load of 2 g measure isometric tension (isometric tension). To stabilize the reduction the reduction is called a solution of potassium chloride (final concentration 100 mm), washing is carried is romescu.

Again the tube with 10 ml of Krebs-Henseleit and add the methyl ester of L-NG-nitroarginine (final concentration 100 μm) for inhibition of endogenous nitrogen monoxide. The reduction causes the addition of phenylephrine (final concentration 10 μm) and add a solution of chemical compounds at final concentrations of 3, 30 or 300 nm. As reaction medium using dimethyl sulfoxide. 15 minutes after adding chemicals to the relaxation of the drug add nitroprusside (final concentration 300 μm). In addition, to determine the maximum relaxation add papaverine (final concentration 100 μm).

After the experiment the voltage obtained by adding papaverine, is used as the initial value, the relaxation of the drug by the addition of sodium nitroprusside write on the chart using DEGIMATIC CALIPER to determine the degree of relaxation.

Values in the table show the relaxation ratio (%) after addition of sodium nitroprusside to the drug, pre-treated for 3, 30 and 300 nm connection, and the recorded values obtained in the re-experience. In addition, C is ω, relaxes by 50%, and this value is calculated regression analysis of the curve of the relaxation of the double experiment.

The nitric monoxide formed from sodium nitroprusside, activates guanilatziklazu for promotion of the formation of cGMP from GTP, relaxia thus the cavernous body of penis. PDE5 inhibitor enhances this relaxing effect by inhibition of the degradation of cGMP.

As described above, this clearly shows that the compounds of this invention possess inhibitory effect on PDE5 and enhances the relaxing effect of sodium nitroprusside on the sample cavernous body of penis rabbit dependent on dose.

As described above, this clearly shows that the compounds of this invention possess inhibitory effect on PDE5 and enhances the relaxing effect of nitroprusside on a sample of the cavernous tissue of the penis rabbit dependent on dose. That is, this invention is useful as a preventive and therapeutic agent for erectile dysfunction.

Examples of obtaining and Examples are provided to facilitate understanding of the present invention, but, needless to say, this invention is not limited to these compounds.

The example on the ptx2">

A mixture of 1.0 g of 1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalide, 1.92 g of (R)-(+)-3-hydroxypiperidine hydrochloride, 1,80 g diisopropylethylamine and 12 ml of 1-methyl-2-pyrrolidone was stirred at C for 1 hour and 15 minutes. After cooling, the reaction solution is added ethyl acetate, the solution washed with water and brine. The solution is dried over anhydrous sodium sulfate, the solvent is evaporated and the resulting residue is purified column chromatography (filler: silica gel). Obtained free compound suspended in a mixture of acetic acid/ethanol/water, was added 1 N aqueous hydrochloric acid and dissolved by heating. After cooling, the resulting crystals are filtered, getting 860 mg of the target compound as a yellow powder.

MASS (ESI): 424,1 (MN+).

1H-NMR (400 MHz, DMSO-d6) : 1,39 of 1.50 (1H, m), 1,65-of 1.78 (1H, m), a 1.75-to 1.98 (2H, m), 2,82-only 2.91 (1H, m), 2,93-to 3.02 (1H, m), 3.33 and-of 3.48 (2H, m), 3,79-3,88 (1H, m), 3,85 (3H, s), 4.72 in (2N, ush.), 7,16 (1H, d, J=8,4 Hz), 7,47 (1H, DD, J=8,4; and 1.6 Hz), a 7.62 (1H, d, J=1.6 Hz), 8,31 (1H, d, J=8,4 Hz), 8,48 (1H, d, J=8,4 Hz), 9,38-9,46 (1H, m), 10,27 (1H, ush.).

Example of getting 2

4-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-[(3S)-3-hydroxypyrrolidine]phthalazine hydrochloride

The target connection receive .

MASS (ESI): 410,0 (MN+).

1H-NMR (400 MHz, DMSO-d6) : 1,94-2,10 (2H, m), 3,50-3,62 (1H, m), 3,42-3,68 (1H, m), 3,83 (3H, s), 3,93-4,10 (2H, m), 4,43-4,50 (1H, m), 4,50 with 4.64 (2H, m), and 5.30 (1H, ush.), 7,13 (1H, d, J=8,4 Hz), 7,34-7,44 (1H, m), of 7.48-7,56 (1H, m), scored 8.38-8,46 (1H, m), 8,62-a total of 8.74 (1H, m), 9,10-to 9.32 (1H, m).

Example of getting 3

4-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-[(2S)-2-hydroxy-methylpyrrolidine]phthalazine hydrochloride

The target connection receive according to the method of Example obtaining 1, using (S)-2-hydroxyethylpyrrolidine instead of (R)-(+)-3-hydroxypiperidine hydrochloride.

MASS (ESI): 424,1 (MN+).

1H-NMR (400 MHz, DMSO-d6) : 1,60-2,39 (4H, m), 3,44-of 3.53 (1H, m), 3,83 (3H, s), 3,89-to 3.99 (1H, m), 4,34-4,70 (3H, m), 7,12-7,16 (1H, m), 7,38-7,46 (1H, m), 7,52-to 7.59 (1H, m), 8,40-8,43 (1H, m), 8,43 at 8.60 (1H, m), 9,23-of 9.30 (1H, m).

Example 4

4-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-(3-hydroxymethyl-piperidine)phthalazine hydrochloride

The target connection receive according to the method of Example obtaining 1, using 3-hydroxyethylpiperazine instead of (R)-(+)-3-hydroxypiperidine hydrochloride.

MASS (ESI): 438,2 (MN+).

1H-NMR (400 MHz, DMSO-d6) : 1,13 of 1.28 (1H, m), 1.70 to to 1.86 (3H, m), 1,87 of 1.99 (1H, m), 2,67 is 2.75 (1H, m), 2,86-2,95 (1H, m), 3.33 and-a 3.50 (3H, m), 3,51-of 3.60 (1H, m), and 3.16 (3H, s), 3,85 (3H, s), 4,71 (2H, the 00 (1H, ush.).

Example of getting 5

4-(3-Chloro-4-methoxyphenethyl)amino-6-cyano-1-(3-hydroxymethyl-piperidine)phthalazine hydrochloride

The target connection receive according to the method of Example 4, using 1-chloro-4-(3-chloro-4-methoxyphenethyl)amino-6-cyanophthalide instead of 1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalide.

MASS (ESI): 452,3 (MN+).

1H-NMR (400 MHz, DMSO-d6) : 1,70-1,90 (2H, m), 1,90-of 2.05 (2H, m), 2,70 (1H, ush.-t) is 2.88 (1H, ush.), 2,95-is 3.08 (2H, m), 3.25 to 3,63 (2H, m), of 3.78 (2H, m), 3,83 (3H, s), to 7.09 (1H, d, J=8.6 Hz), 7,29 (1H, d, J=8.6 Hz), 7,47 (1H, s), of 8.25 (1H, d, J=8.6 Hz), 8,49 (1H, d, J=8.6 Hz), 9,48 (1H, s).

An example of obtaining 6

4-(3-Chloro-4-methoxyphenethyl)amino-6-cyano-1-(4-hydroxyethylpiperazine)phthalazine

The target connection receive according to the method of Example obtaining 5, using 4-hydroxyethylpiperazine instead of 3 hydroxyethylpiperazine.

MASS (ESI): 452,3 (MH+).

1H-NMR (400 MHz, CDCl3) : 1,51-of 1.65 (2H, m), 1,79-of 1.85 (1H, m) of 1.93 (2H, m), 2,99-to 3.09 (4H, m), 3,56-3,68 (4H, m), 3,90 (3H, s), 3,85-3,99 (2H, m), 4,94 (1H, ush.-t), to 6.88(1H, d, J=8,4 Hz), 7,13 (1H, DD, J=2,2; and 8.4 Hz), 7,28 (1H, d, J=2.2 Hz), 7,94 (1H, d, J=8,4 Hz), 7,98 (1H, s), 8,13 (1H, d, J=8,4 Hz).

Example of getting 7

4-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-[methyl(2-pyridylmethyl is s 1 with the difference, N-methyl-[(2-pyridyl)methyl]amine is used instead of (R)-(+)-3-hydroxypiperidine hydrochloride.

MASS (ESl): 445.3 (MN+).

1H-NMR (400 MHz, DMSO-d6) : 2,95 (3H, s), 3,85 (3H, s), 4,73-4,79 (4H, m), 7,16 (1H, d, J=8,4 Hz), 7,49 (1H, DD, J=8,4; 2.0 Hz), to 7.64 (1H, d, J=2.0 Hz), 7,65-7,72 (1H, m), 7,83-7,87 (1H, m), 8,18 compared to 8.26 (1H, m), charged 8.52 (1H, DD, J=8,4; 1.2 Hz), at 8.60 (1H, d, J=8,4 Hz), a total of 8.74 (1H, d, J=4,8 Hz), at 9.53-of 9.55 (1H, m), at 10.64 (1H, ush.).

Example obtain 8

4-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-{N-methyl-[2-(2-pyridyl)ethyl]amino}phthalazine hydrochloride

The target connection receive according to the method of Example get 7 with the difference that N-methyl-[2-(2-pyridyl)ethyl]amine is used instead of N-methyl-[(2-pyridyl)methyl]amine.

MASS (ESI): 459,2 (MIT).

1H-NMR (400 MHz, DMSO-d6) : of 3.00 (3H, s) to 3.35 (2H, t, J=6.4 Hz), 3,76 (2H, t, J=6.4 Hz), 3,85 (3H, s), 4,73-of 4.77 (2H, m), 7,18 (1H, d, J=8,4 Hz) to 7.50 (1H, d, J=8,4 Hz), 7,53-to 7.64 (1H, m), the 7.65 (1H, s), 7.68 per-to 7.77 (1H, m), 8,10-8,30 (1H, m), 8,16 (1H, d, J=8.6 Hz), 8,44 (1H, d, J=8.6 Hz), 8,55-8,61 (1H, m), 9,45-of 9.51 (1H, m), 10,53 (1H, ush.).

Example of getting 9

4-(3-Chloro-4-methoxyphenethyl)amino-6-cyano-1-(4-methoxybiphenyl-Dino)phthalazine hydrochloride

The target connection receive according to the method of Example obtaining 5 with the difference that 4-methoxypiperidine hydrochloride is used instead of 6 (2H, m) 2,00-of 2.08 (2H, m), 2.91 in-of 2.97 (2H, m), 2,99-of 3.07 (2H, m), 3,29 (3H, s), 3,37-to 3.49 (3H, m), 3,70-of 3.77 (2H, m), 3,81 (3H, s), 7,07 (1H, d, J=8.6 Hz), 7,26 (1H, DD, J=8,6, 2.0 Hz), the 7.43 (1H, d, J=2.0 Hz), 8,24 (1H, d, J=8,3 Hz), to 8.45 (1H, DD, J=8,3; and 1.6 Hz), which 9.22 (1H, d, J=1.6 Hz).

Example 10

4-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-(4-methoxyphenyl)phthalazine hydrochloride

423 mg of tetrakis(triphenylphosphine)palladium(0) is added to a mixture of 1.0 g of 1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalide, 423 mg 4-ethoxyphenylurea acid, 30 ml of toluene, 30 ml of tetrahydrofuran and 30 ml of 2 M aqueous sodium carbonate in a nitrogen atmosphere. The mixture is stirred at 80 ° C for 2 hours and further at 10C in the course of 15.5 hours. The reaction solution allowed to warm to room temperature and extracted with aqueous solution of ammonium chloride and ethyl acetate. The organic layer was washed with an aqueous solution of ammonia, water and brine and dried over anhydrous sodium sulfate. The solvent is evaporated and the resulting residue is purified column chromatography (filler: silica gel). Obtained a bound compound is dissolved in a mixture of ethyl acetate/ethanol, add a solution of 4 N hydrochloric acid/ethyl acetate and the resulting crystals are filtered, getting 460 mg of the target compounds is, is), a 3.87 (3H, s), 4,82-4,85 (2H, m), 7,16-7,21 (3H, m), 7,49 (1H, DD, J=8,6; 2.2 Hz), 7,60-7,63 (3H, m), 8,08 (1H, d, J=8,4 Hz), to 8.45 (1H, DD, J=8,4; and 1.4 Hz), 9,45-9,49 (1H, m), accounted for 10.39 (1H, ush.).

Example of getting 11

4-[(3-Chloro-4-methoxybenzyl)amino]-1-(4-hydroxy-3-methylpiperidino)-6-phthalazinone hydrochloride

The target connection receive according to the method of Example obtaining 1 with the difference that 4-hydroxy-3-methylpiperidin used instead of (R)-(+)-3-hydroxypiperidine hydrochloride.

1H-NMR (400 MHz, DMSO-d6) : of 0.94 (3H, t, J=8.0 Hz), 1,59-2,03 (3H, m), 2,74-of 3.96 (5H, m), 3,83 (3H, s), and 4.68 (2H, d, J=5,2 Hz), to 7.15 (1H, d, J=8,4 Hz), the 7.43 (1H, d, J=8.0 Hz), 7,58 (1H, s) 8,23 (1H, t, J=8.0 Hz), to 8.45 (1H, d, J=8,4 Hz), 9,29 (1H, s).

Example 12

4-[(3-Chloro-4-methoxybenzyl)amino]-1-(4-hydroxy-3,3,5,5-tet-remedilean)-6-phthalazinone hydrochloride

The target connection receive according to the method of Example obtaining 1 with the difference that 4-hydroxy-3,3,5,5-tetramethylpiperidine used instead of (R)-(+)-3-hydroxypiperidine hydrochloride.

1H-NMR (400 MHz, DMSO-d6) : 0,91 (6N,) and 1.15 (6N, (C), to 2.57 (1H, d, J=12,4 Hz), 2,95 (1H, s), 3,21 (2H, d, J=12.0 Hz), 3,83 (3H, s), 4,47 (2H, d, J=5.6 Hz), 7,14 (1H, d, J=8,4 Hz), 7,47 (1H, d, J=8,8 Hz), 7,63 (1H, s), 8,29 (1H, d, J=8,4 Hz), 8,55 (1H, d, J=8,4 Hz) 9,52 (1H, s), as 10.63 (1H, ush.-C).

Getting ptx2">

A mixture of 10 g of 2-triptoreline, 17 g of potassium carbonate, 150 ml of acetone and 7.7 ml of iodomethane refluxed for 2 hours. After cooling, insoluble materials are removed by filtration and the filtrate evaporated. The resulting residue is dissolved in ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated, getting 12,15 g of 2-cryptomaterial.

A mixture of 8.5 g 2-cryptomaterial and 7.0 g of hexamethylenetetramine was stirred at 90 ° C for 1.5 h in 80 ml triperoxonane acid. The reaction solution is evaporated. The resulting residue is dissolved in ethyl acetate and the solution is added dropwise into a cooled on an ice bath, saturated solution of sodium bicarbonate. An ethyl acetate layer is isolated and washed with brine, then dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting residue is purified column chromatography (filler: silica gel) to give 5.8 g of 3-trifluoromethyl-p-anisaldehyde.

A mixture of 5.8 g of 3-trifluoromethyl-p-anisaldehyde, 8.6 ml of formaldehyde and 13.6 ml of formic acid was stirred at 130C for 9 hours. After cooling, add water and ethyl acetate. An ethyl acetate layer is separated and washed Russolo chromatography (filler: silica gel), obtaining 3.8 g of N-[4-methoxy-3-(trifluoromethyl)benzyl]formamide.

3.8 g of N-[4-methoxy-3-(trifluoromethyl)benzyl]formamide was dissolved in 20 ml of ethanol, add 2 ml of concentrated hydrochloric acid, the mixture is boiled at reflux for 3 hours. After cooling, add diethyl ether, the resulting crystals are filtered, obtaining 2.5 g of 4-methoxy-3-(trifluoromethyl)benzylamine hydrochloride.

3.7 g DBU is added to a mixture of 2.2 g of 1,4-dilahtin-6-carbonitrile, 2.5 g of 4-methoxy-3-(trifluoromethyl)benzylamine hydrochloride and 25 ml of 1-methyl-2-pyrrolidinone, the mixture is stirred at room temperature for 1.25 hours. In the reaction solution is added ethyl acetate, the solution washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting residue is purified column chromatography (filler: silica gel) to give 1.66 g of the target compound as the less polar compounds.

1H-NMR (400 MHz, DMSO-d6) : 3,86 (3H, s), 4,74 (2H, d, J=5,2 Hz), 7,22 (1H, d, J=9.6 Hz), to 7.67-7,71 (2H, m), to 8.20 (1H, d, J=8,4 Hz), 8,35 (1H, DD, J=8,4, 1,4 Hz) and 8.50 (1H, t, J=5,2 Hz), 8,99 (1H, d, J=1.4 Hz).

Similarly receive 1-chloro-4-[(3-iodine-4-methoxybenzyl)amino]-6-phthalazinedione from commercial 2-iodine is oxybenzyl)amino]-6-phthalazinedione of 3-fluoro-p-anisaldehyde and 1-chloro-4-[(4-methoxy-3-methylbenzyl)amino]-6-phthalazinedione of 3-methyl-p-anisaldehyde.

The intermediate product of Example 2

1-Chloro-4-[(3-iodine-4-methoxybenzyl)amino]-6-phthalazinedione

1H-NMR (400 MHz, DMSO-d6) : of 3.80 (3H, s), of 4.67 (2H, d, J=5,2 Hz), of 6.96 (1H, d, J=8,4 Hz), 7,42 (1H, DD, J=8,4; 2.0 Hz), 7,83 (1H, d, J=2.0 Hz), 8,18 (1H, d, J=8,4 Hz), a 8.34 (1H, DD, J=8,4; 1.2 Hz), to 8.45 (1H, t, J=5,2 Hz), 8,99 (1H, d, J=1.2 Hz).

The intermediate product of Example 3

4-[(3-Bromo-4-methoxybenzyl)amino]-1-chloro-6-phthalazinedione

1H-NMR (400 MHz, DMSO-d6) : is 3.82 (3H, s), 4,70 (2H, d, J=5,2 Hz), 7,07 (1H, d, J=8,4 Hz), 7,41 (1H, DD, J=8,4; 2.0 Hz), 7,63 (1H, d, J=2.0 Hz), to 8.20 (1H, d, J=8,4 Hz), a 8.34 (1H, DD, J=8,4; 1.2 Hz), of 8.47 (1H, t, J=5,2 Hz), 8,99 (1H, d, J=1.2 Hz).

The intermediate product of Example 4

1-Chloro-4-[(3-fluoro-4-methoxybenzyl)amino]-6-phthalazinedione

1H-NMR (400 MHz, DMSO-d6) : 3,81 (3H, s), 4,70 (2H, d, J=5.4 Hz), 7,11 (1H, t, J=8,8 Hz), 7,19 (1H, d, J=8,8 Hz), 7,26 (1H, DD, J=12,8; 2.0 Hz), to 8.20 (1H, d, J=8,4 Hz), 8,35 (1H, DD, J=8,4; 0,8 Hz), 8,46 (1H, d, J=5.4 Hz), 9,01 (1H, d, J=0.8 Hz).

The intermediate product of Example 5

1-Chloro-4-[(3-cyano-4-methoxybenzyl)amino]-6-phthalazinedione

A mixture of 20 g of 4-methoxybenzylamine, 26 g phthalimide potassium and 100 ml of dimethylformamide was stirred at 50C for 5 hours. After cooling the reaction process is th 31 g of N-(4-methoxybenzyl)phthalimide.

18 g of hexamethylenetetramine gradually added to a mixture of 31 g of N-(4-methoxybenzyl)phthalimide and 100 ml triperoxonane acid, stirred at room temperature for 1 hour, then heated under reflux for 4 hours. The reaction solution is cooled to 0C and add water. Add the potassium carbonate and the resulting crystals are filtered. The crystals are dried, obtaining 20 g of N-(3-formyl-4-methoxybenzyl)phthalimide.

to 5.2 g of hydroxylamine hydrochloride, 12.2 g of sodium acetate and 50 ml of water is added to the mixture of 20 g of N-(3-formyl-4-methoxybenzyl)phthalimide and 200 ml of tetrahydrofuran and stirred at room temperature for 1 hour. The mixture was stirred at 60C for 1 hour and then evaporated. To the obtained residue, add water and insoluble substances are filtered. The precipitate was washed with diethyl ether, obtaining 20 g of N-(3-hydroxyimino-4-methoxybenzyl)phthalimide.

of 6.7 ml of acetic anhydride is added to a mixture of 20 g of N-(3-hydroxyimino-4-methoxybenzyl)phthalimide and 200 ml of xylene and the mixture heated under reflux for 10 hours. The mixture is allowed to cool to room temperature, the formed crystals are filtered and washed with xylene, receiving 15 g of N-(3-ensil)phthalimide and 200 ml of ethanol and the mixture heated under reflux for 3 hours. After cooling, insoluble materials are removed by filtration. The filtrate is evaporated, the obtained residue was added 1 N aqueous sodium hydroxide solution, then extracted with dichloromethane. The extract is dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated, obtaining 8.0 g of 3-cyano-4-methoxybenzylamine.

1,4-Dilahtin-6-carbonitrile and 3-cyano-4-methoxybenzylamine stirred at room temperature in 1-methyl-2-pyrrolidinone in the presence of DBU, therefore producing 1-chloro-4-[(3-cyano-4-methoxybenzyl)amino]-6-phthalazinone as the less polar product.

1H-NMR (400 MHz, DMSO-d6) : a 3.87 (3H, s), 4,70 (2H, d, J=5.6 Hz), 7,20 (1H, d, J=8,4 Hz), of 7.70 (1H, DD, J=2,4; and 8.4 Hz), of 7.75 (1H, d, J=2.4 Hz), 8,19 (1H, d, J=8,4 Hz), a 8.34 (1H, DD, J=1,2; and 8.4 Hz), 8,48 (1H, t, J=5.6 Hz), 8,97 (1H, s).

The intermediate product of Example 6

1-Chloro-4-[(3-ethyl-4-methoxybenzyl)amino]-6-phthalazinedione

3,99 g butoxide potassium added to 80 ml of a solution of 12.7 g of methyltriphenylphosphonium in tetrahydrofuran at 0 ° C, add 7 g of N-(3-formyl-4-methoxybenzyl)phthalimide and the mixture is stirred at room temperature for 1 hour.

The reaction solution is filtered through celite and then evaporated. Polycentrality.

of 2.75 g of N-(4-methoxy-3-vinylbenzyl)phthalimide dissolved in 50 ml of tetrahydrofuran, add 0.1 g of 10% Pd-C and the mixture is stirred for 40 minutes in an atmosphere of hydrogen. The reaction solution is filtered through celite and the filtrate evaporated. The resulting residue is purified column chromatography (filler: silica gel) to give 2.55 g of N-(3-ethyl-4-methoxybenzyl)phthalimide.

0,84 ml of hydrazine monohydrate is added to the mixture of 2.55 g of N-(3-ethyl-4-methoxybenzyl)phthalimide and 60 ml of ethanol and the mixture heated under reflux for 1 hour. After cooling, the mixture was evaporated and to the obtained residue is added 2 N aqueous sodium hydroxide solution, then the mixture is extracted with dichloromethane. The extract is dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated, add ethyl acetate and then the insoluble substance was filtered. Add a solution of 4 N hydrochloric acid/ethyl acetate, the resulting crystals are filtered, receiving of 1.75 g of 3-ethyl-4-methoxybenzylamine hydrochloride.

1,4-Dilahtin-6-carbonitrile and 3-ethyl-4-methoxybenzylamine hydrochloride is stirred at room temperature in 1-methyl-2-pyrrolidinone in the presence of DBU, therefore producing 1-chloro-4-[(3-ethyl-4-methoxybenzyl)amino]-6-Talas Hz), 2,60 (2H, q, J=7.5 Hz), 3,81 (3H, s), 4,84 (2H, s), to 6.80 (1H, d, J=8,2 Hz), 7,25 (1H, d, J=2.0 Hz), 7,30 (1H, DD, J=2,0; 8,2 Hz), of 8.06 (1H, d, J=9.0 Hz), of 8.27 (1H, d, J=9.0 Hz), 8,42 (1H, m).

The intermediate product of Example 7

1-Chloro-4-[(3-chloro-4-methylbenzyl)amino]-6-phthalazinedione 15 ml of a solution of 2.0 g of 3-chloro-4-methylbenzonitrile in tetrahydrofuran are added dropwise 40 ml of a solution of 453 mg of lithium aluminum hydride in tetrahydrofuran in a nitrogen atmosphere. The mixture is heated under reflux for 2 hours and 10 minutes. The mixture is cooled with ice and added dropwise to 0.45 ml of water, 0.45 ml of 15% aqueous sodium hydroxide solution and 1.35 ml of water so that the solution temperature was kept at 10 ° C or below. The solution is filtered through celite and the resulting filtrate is dried by adding anhydrous sodium sulfate. The mixture is filtered through NH-forming silica gel, the filtrate evaporated, receiving of 1.74 g of 3-chloro-4-methylbenzylamine.

1,4-Dilahtin-6-carbonitrile and 3-chloro-4-methylbenzylamine stirred at room temperature in 1-methyl-2-pyrrolidinone in the presence of DBU, resulting in obtaining the target compound as the less polar compounds.

1H-NMR (400 MHz, DMSO-d6) ; to 2.29 (3H, s), to 4.73 (2H, d, J=5,2 Hz), 7,28-to 7.32 (2H, m), 7,45 (1H, d, J=0.8 Hz), 8 the example 8

1-Chloro-4-[(4-chloro-3-methoxybenzyl)amino]-6-phthalazinedione

4-Chloro-3-methoxybenzylideneamino hydrochloride synthesized in accordance with the method described in the publication WO 9518097, and 1,4-dilahtin-6-carbonitrile stirred at room temperature in 1-methyl-2-pyrrolidinone in the presence of DBU, therefore producing 1-chloro-4-[(4-chloro-3-methoxybenzyl)amino]-6-phthalazinone as the less polar product.

1H-NMR (400 MHz, DMSO-d6) : 3,86 (3H, s), was 4.76 (2H, d, J=5.5 Hz), 4,74 (1H, d, J=4, 2 Hz), of 6.99 (1H, DD, J=1,8; 8,1 Hz), 7,22 (1H, d, J=1,8 Hz), 7,35 (1H, d, J=8.1 Hz), 8,21 (1H, d, J=8.6 Hz), at 8.36 (1H, d, J=8.6 Hz), charged 8.52 (1H, t, J=5,2 Hz), 9,03 (1H, s).

The intermediate product of Example 9

1-Chloro-4-[(3,4-dichlorobenzyl)amino]-6-phthalazinedione

1H-NMR (400 MHz, DMSO-d6) : was 4.76 (2H, d, J=5.4 Hz), 7,40 (1H, DD, J=8,4, 1.8 Hz), 7,58 (1H, d, J=8,4 Hz), to 7.68 (1H, d, J=1,8 Hz), 8,21 (1H, DD, J=8,4; 0,4 Hz) at 8.36 (1H, DD, J=8,4, and 1.6 Hz), to 8.57 (1H, t, J=5.4 Hz), 8,99 (1H, d, J=1,6 Hz).

The intermediate product of Example 10

Benzyl-4-fluoro-4-hydroxymethyl-1-piperidinecarboxylate

of 51.1 g of methylolmethacrylamide added to a mixture of 16.1 g of tert-butoxide potassium and 500 ml of tetrahydrofuran and then stirred for 1 hour 2 is more within 2 hours and 40 minutes at room temperature. The reaction solution is evaporated, add diethyl ether and filtered through celite. The filtrate is washed with water and brine, dried over anhydrous magnesium sulfate and then filtered. The filtrate is evaporated and the resulting residue is subjected to column chromatography on silica gel, receiving of 25.5 g of benzyl 4-methylene-1-piperidinecarboxylate.

of 14.7 g of benzyl-4-methylene-1-piperidinecarboxylate dissolved in 300 ml of methanol to the mixture of 20.4 g nanoparticulates magnesium salts of phthalic acid and 13.3 g of sodium bicarbonate and the mixture is stirred at room temperature for 7.5 hours. The reaction solution is evaporated. To the obtained residue is added ethyl acetate, then washed with water and brine, dried over anhydrous magnesium sulfate and then filtered. The filtrate is evaporated and then subjected to column chromatography on silica gel, receiving 11.3 g benzyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate.

A mixture of 5 ml of pyridine hydrohloride and 20 ml of methylene chloride is cooled and added dropwise within 25 minutes, add 10 ml of a solution of 4.95 g of benzyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate in methylene chloride so that the temperature of the mixture was maintained at 0C. The mixture is stirred for 35 minutes under cooling in an ledjanoi separated, dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated and then subjected to column chromatography on silica gel, receiving 2,84 g of target compound.

The intermediate product of Example 11

tert-Butyl-4-hydroxy-4-(1H-1-imidazolidinyl)-1-piperidinecarboxylate

13.5 g of tert-butyl-4-methylene-1-piperidinecarboxylate dissolved in 300 ml of methanol and 28.3 g nanoparticulates magnesium salts of phthalic acid and add to 8.62 g of sodium bicarbonate and the mixture is stirred at room temperature for 1 day. The reaction solution is filtered through celite and the resulting filtrate evaporated. To the obtained residue is added ethyl acetate, the mixture was then washed with water and brine, dried over anhydrous magnesium sulfate and then filtered. The filtrate is evaporated and subjected to column chromatography (silica gel) to give 12.2 g of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate.

of 4.25 g of tert-butyl-oxa-6-azaspiro[2.5]octane-6-carboxylate was dissolved in 30 ml of dimethylformamide, add 5,38 g nitroimidazole and the mixture was stirred at 60C for 3 hours and 40 minutes. After cooling, the reaction solution is added ethyl acetate and the solution washed three times with water, then Rasso is Sofia (silica gel), receiving is 4.93 g of tert-butyl-4-hydroxy-4-(1H-1-imidazolidinyl)-1-piperidinecarboxylate.

The intermediate product of Example 12

tert-Butyl-4-hydroxy-4-(1H-1,2,4-triazole-1-ylmethyl)-1-piperidinecarboxylate

The target connection receive according to the method of Obtaining the intermediate product of Example 11, using 1,2,4-triazoline instead imidazolate.

The intermediate product of Example 13

Benzyl-4-vermeil-4-hydroxy-1-piperidinecarboxylate

3.2 g of hydrohloride sodium and 610 mg of Tetra-n-butylmethacrylate added to 5 g of benzyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate and the mixture was stirred at 120C for 7 hours. After cooling, add methylene chloride and the mixture filtered through celite. The filtrate is evaporated and the resulting residue is subjected to column chromatography (silica gel) to give 4.7 g of the target compound.

The intermediate product of Example 14

4-Hydroxy-4-piperazinecarboxamide hydrochloride

Mixing a solution of 18 ml conc. sulfuric acid and 1.8 ml of water is cooled to 0C and the solution gradually add 5 g of 1-benzyl-4-hydroxy-4-piperidinecarbonitrile hydrochloride. To the resulting solution was added Sov. The mixture is left overnight in the refrigerator. The reaction solution was poured into ice and there small portions add 47 g of sodium hydroxide. The mixture is extracted 3 times mixed solvent consisting of tetrahydrofuran and ethyl acetate (1:1). The extract was washed with brine, dried over anhydrous magnesium sulfate and then filtered. The filtrate is evaporated and purified column chromatography (filler: silica gel), receiving 3,19 g of 1-benzyl-4-hydroxy-4-piperazinecarboxamide.

3,19 g of 1-benzyl-4-hydroxy-4-piperazinecarboxamide dissolved in 150 ml of methanol and the resulting solution was added 1.5 g of 20% aqueous solution of palladium hydroxide. The mixture is subjected to vibration for 4 hours in an atmosphere of hydrogen under a pressure of 4 atmospheres. The reaction solution is filtered through celite and to the filtrate add 5 ml of 4 N Hcl in dioxane, the filtrate is evaporated. The resulting crystalline residue was washed with diisopropyl ether and was isolated by filtration, receiving a 1.96 g of the target compound.

The intermediate product of Example 15

N-(3-Chloro-4-methoxybenzyl)-N-[4-chloro-7-(1H-1-pyrazolyl)-1-Paladini]Amin

110 ml of thionyl chloride are added dropwise within 30 minutes added to a mixture of 100 g of 4-ftoh obtained residue, add ice water, the mixture was then extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated, receiving 125 g of dimethyl-4-Portulaca.

26 g of sodium hydride in oil for 40 minutes added to 200 ml of a solution of 44 g of pyrazole, 1-methyl-2-pyrrolidinone. In the resulting mixture for 30 minutes, add 125 g of dimethyl-4-Portulaca and stirred at room temperature for 2 hours. The reaction solution is cooled to 0C and poured into ice water. The mixture is extracted with ethyl acetate and washed with saturated sodium bicarbonate solution and brine. The mixture is dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated, the obtained crystalline residue is added diethyl ether, the precipitate are filtered, receiving 77 g of dimethyl-4-(1H-1-pyrazolyl)phthalate.

22 ml of hydrazinoacetate added to a mixture of 77 g of dimethyl-4-(1H-1-pyrazolyl)phthalate and 500 ml of ethanol and heated under reflux for 6 hours. After cooling, the precipitate are filtered, receiving 36 g of 6-(1H-1-pyrazolyl)-1,4-phthalazinedione.

15 ml diisopropylethylamine added to a mixture of 5.0 g of 6-(1H-1-pyrazolyl)-1,4-phthalazinedione and 20 ml of phosphorus oxychloride, the mixture parameterType add ice and water. The reaction solution was stirred at C for 0.5 hour and the insoluble matter is removed by filtration. An ethyl acetate layer was separated, washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated, the obtained crystalline residue is added ethyl acetate, the precipitate then allocate by filtration, obtaining 3.8 g of 1,4-dichloro-6-(1H-1-pyrazolyl)phthalazine.

14 ml of DBU is added to the mixture of 8 g of 1,4-dichloro-6-(1H-1-pyrazolyl)phthalazine, 9.5 g of 3-chloro-4-methoxybenzylamine hydrochloride and 30 ml of 1-methyl-2-pyrrolidinone and the mixture is stirred at room temperature for 1 hour. The mixture is additionally stirred at 60C for 3 hours. The reaction solution is cooled to 0C, add ethyl acetate, then washed with water and brine. The mixture is dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated. The resulting residue is purified column chromatography (filler: silica gel), resulting in obtaining 2.6 g of the target compound as the less polar compounds.

1H-NMR (400 MHz, DMSO-d6) : of 3.80 (3H, s), and 4.68 (2H, d, J=6.0 Hz), 6,70 (1H, t, J=2.0 Hz), to 7.09 (1H, d, J=8,8 Hz), 7,35 (1H, DD, J=2,0; and 8.4 Hz), 7,47 (1H, d, J=2.0 Hz), to $ 7.91 (1H, d, J=2.0 Hz), 8,18 (1H, d, J=9,2 Hz), 8,32 (1H, t, J=5.6 Hz), and 8.50 (1H, DD, J=2,0; 8,8 Hz), 8,68 (1H, d, J=2.4 Hz), 8,78 (1H, d, J=2,,2,3-triazole-1-yl)-1-phthalazine]Amin

The target connection receive according to the method of Example 15 with the difference that the 1,2,3-triazole used in place of pyrazole.

1H-NMR (400 MHz, CD3OD) : is 3.82 (3H, s), 4.72 in (2N, C), 6,97 (1H, d, J=8,4 Hz), 7,34 (1H, DD, J=1,6; and 8.4 Hz), 7,44 (1H, d, J=1.6 Hz), to 7.99 (1H, d, J=1.2 Hz), a 8.34 (1H, d, J=8,8 Hz), charged 8.52 (1H, DD, J=1,6; 8,8 Hz), 8,72 (1H, d, J=1.2 Hz), 8,81 (1H, d, J=2 Hz).

The intermediate product of Example 17

6-Bromo-1-chloro-4-[(3-chloro-4-methoxybenzyl)amino]phthalazine

to 96.9 ml hydrazinoacetate add in a mixture of 20 g of 4-Brattleboro anhydride and 100 ml of ethanol and the mixture heated under reflux for 8 hours. After cooling, the resulting precipitates are filtered, obtaining 28 g of 6-bromo-1,4-phthalazinedione.

15 ml diisopropylethylamine added to a mixture of 6.8 g of 6-bromo-1,4-phthalazinedione and 15 ml of phosphorus oxychloride and the mixture is heated under reflux for 1.5 hours. After cooling, the reaction solution was poured into ice-cold water, thoroughly stirred, and extracted with methylene chloride. The aqueous layer was extracted with ethyl acetate. The combined extract is dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated and the resulting residue is purified column chromatography (filler: silica gel) to give 4.3 g of 6-bromo-Lamine hydrochloride and 30 ml of 1-methyl-2-pyrrolidinone and the mixture was stirred at 100C for 3 hours. After cooling the reaction solution, water is added, then the mixture is extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated. The resulting residue is purified column chromatography (filler: silica gel) to give 1.8 g of the target compound as the less polar compounds.

The intermediate product of Example 18

1-(1,1-Dimethyl-2-PROPYNYL)-4-piperidinol

24 mg of copper chloride and 15 mg of powdered copper added to a mixed solution of 5 ml of a solution of 7.3 g of 4-hydroxypiperidine in diethyl ether (5 ml) and water (2.5 ml) under nitrogen atmosphere. The mixture is cooled with ice and added dropwise 2.5 ml of a solution of 2.7 ml of 3-chloro-3-methyl-1-butyne in diethyl ether, maintaining the temperature within the reaction medium in the range from 17 to 22℃. The mixture is then stirred at room temperature overnight. Water is added and the resulting mixture extracted with diethyl ether 5 times. The organic layers are combined and dried over potassium carbonate, and then over sodium hydroxide and filtered. The filtrate is concentrated under normal pressure. The resulting crystals are filtered, adding a mixture of ethyl acetate/hexane, receiving opinel)pyrrolidin

The target connection receive according to the method of Obtaining the intermediate product of Example 18 from pyrrolidine and 3-chloro-3-methyl-1-butyne.

The intermediate product of Example 20

(2R)-1-oxa-8-azaspiro[4.5]DECA-2-ylmethanol

of 105.5 g of (5S)-5-(hydroxymethyl)tetrahydro-2-furanone dissolved in 1.2 l of pyridine, add 380 g Fritillaria at room temperature and the mixture is stirred at 80 ° C during the night. After completion of the reaction the mixture is cooled, water is added, extracted with ethyl acetate and then washed with brine. The solvent is removed and the resulting residue is dissolved in 300 ml of chloroform, after which it add 600 ml of silica gel, the solvent is removed. The resulting residue is purified column chromatography (filler: silica gel), get 149,3 g (5S)-5-[(trityloxy)methyl]tetrahydro-2-furanone.

26,9 g (5S)-5-[(trityloxy)methyl]tetrahydro-2-furanone dissolved in 200 ml of THF, add 300 ml of a 1 M vinylmania in THF at room temperature and the mixture is stirred for 1.5 hours while heating under reflux. After completion of the reaction to the mixture is added saturated aqueous solution of ammonium chloride under ice cooling, extracted with ethyl acetate and then twice procylical), getting 13,0 g of (2S)-1-(trityloxy)-5-vinyl-6-hepten-2,5-diol.

13,0 g of (2S)-1-(trityloxy)-5-vinyl-6-hepten-2,5-diol and 57.2 g of toluensulfonate dissolved in 200 ml of pyridine and stirred at 80 ° C during the night. After completion of the reaction the mixture was added water and stirred at room temperature for 10 minutes. After extraction 2 times with ethyl acetate, the mixture was washed with brine and dried over magnesium sulfate. The solvent is removed and the resulting residue is dissolved in toluene. After repeated removal of the solvent, the obtained residue is purified column chromatography (filler: silica gel), receiving 5,88 g (5R)-5-[(trityloxy)methyl]-2,2-divanillytetrahydrofuran.

4.68 g (5R)-5-[(trityloxy)methyl]-2,2-divanillytetrahydrofuran, 100 ml of 0.5 M 9-BBN and 6.1 g of 9-BBN dimer suspended in 100 ml of THF and stirred for 30 hours under reflux. After cooling, add 50 ml of 30% hydrogen peroxide and 50 ml of 3 N sodium hydroxide under ice cooling and stirred at 50C for 20 hours. After completion of the reaction, the reaction solution is allowed to cool to room temperature, then it is extracted with ethyl acetate, washed with brine and dried over magnesium sulfate. The solvent is removed is ITIL)-5-[(trityloxy)methyl]tetrahydro-2-furanyl-1-ethanol.

of 2.68 g of 2-(5R)-2-(2-hydroxyethyl)-5-[(trityloxy)methyl]tetrahydro-2-furanyl-1-ethanol and 12 ml of pyridine are dissolved in 30 ml of dichloromethane, add 11,82 g toluensulfonate under ice cooling and stirred for 2.5 hours. After completion of the reaction, add 30 ml of pyridine and the mixture is then concentrated. After adding pyridine and water, the mixture was again cooled with ice and stirred for 15 minutes. The mixture is extracted with ethyl acetate, washed with brine and then dried over magnesium sulfate. The solvent is distilled off, add toluene, the solvent is again distilled off and the resulting residue is purified column chromatography (filler: silica gel), receiving of 4.17 g of 2-(5R)-2-[2-[(4-IU-terphenyl)sulfonyl]oxyethyl]-5-[(trityloxy)methyl]tetrahydro-2-fornicates-4-methyl-1-benzosulfimide

of 4.17 g of 2-(5R)-2-[2-[(4-were)sulfonyl]oxyethyl]-5-[(trityloxy)methyl]tetrahydro-2-fornicates-4-methyl-1-benzosulfimide and are 5.36 g benzylamine dissolved in 80 ml of DMF and stirred at 110S for 11.5 hours. After completion of the reaction, water is added, extracted with ethyl acetate and washed twice with brine and saturated aqueous sodium bicarbonate. The mixture is then dried over magnesium sulfate, the solvent is removed and received the yl]-1-oxa-8-azaspiro[4.5]decane.

2.10 g (2R)-8-benzyl-2-[(trityloxy)methyl]-1-oxa-6-azaspiro[4.5]decane was dissolved in 20 ml of THF, add 8 ml of 4 N hydrochloric acid in 1,4-dioxane under ice cooling and then the mixture is stirred for 1 hour. After completion of the reaction, water is added and saturated aqueous sodium bicarbonate solution, extracted twice with ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine and then dried over magnesium sulfate. The solvent is removed and the resulting residue is purified column chromatography (filler: silica gel), receiving of 1.03 g of [(2R)-8-benzyl-1-oxa-8-azaspiro[4,5]DECA-2-yl]methanol.

1,03 g [(2R)-8-benzyl-1-oxa-8-azaspiro[4.5]DECA-2-yl]methanol and 0.45 g of 10% palladium on carbon are suspended in 30 ml of ethanol and stirred at room temperature for 18 hours in a hydrogen atmosphere with a pressure of 1 atmosphere. Insoluble substances are removed by filtration, the solvent is removed and dried, obtaining 0,76 g of target compound.

The intermediate product of Example 21

800 ml of a solution of 25.0 g of tert-butyl 4-oxo-1-piperidinecarboxylate in diethyl ether cooled in a mixture of ice/methanol and added dropwise 138 ml of allylanisole (1 M in diethyl ether). Reactivator of ammonium chloride and ice. A layer of diethyl ether is isolated and washed with brine. The layer is dried over anhydrous magnesium sulfate and then filtered. The filtrate is evaporated and the resulting residue is purified column chromatography (filler: silica gel) to give 15.9 g of tert-butyl 4-allyl-4-hydroxy-1-piperidinecarboxylate.

9,83 g of tert-butyl 4-allyl-4-hydroxy-1-piperidinecarboxylate dissolved in 60 ml of a mixture of tetrahydrofuran/water (9:1), add a solution (2.5 wt.%, 2 ml) of osmium tetroxide in tert-butyl alcohol and 6.68 g of N-methylmorpholin-N-oxide and the mixture is stirred at room temperature overnight. The reaction solution is evaporated and the resulting residue is distributed between ethyl acetate and water, washed with brine and dried over magnesium sulfate. After filtration the solvent is evaporated and the resulting residue is purified column chromatography (filler: silica gel) (ethyl acetate/methanol) to give 9,11 g of tert-butyl 4-(2,3-dihydroxypropyl)-4-hydroxy-1-piperidinecarboxylate.

9,11 g of tert-butyl 4-(2,3-dihydroxypropyl)-4-hydroxy-1-piperidinecarboxylate dissolved in 40 ml of pyridine, add 10.0 g chlorotriphenylmethane and the mixture is stirred at room temperature overnight. The reaction solution is partitioned between utilized and dried over magnesium sulfate. After filtration the solvent is evaporated and the resulting residue is purified column chromatography (filler: silica gel; hexane/ethyl acetate) to give 10.3 g of tert-butyl 4-[3-(tert-butoxy)-2-hydroxypropyl]-4-hydroxy-1-piperidinecarboxylate.

2,59 g of tert-butyl 4-[3-(tert-butoxy)-2-hydroxypropyl]-4-hydroxy-1-piperidinecarboxylate dissolved in 10 ml of dimethylformamide, add 400 mg of sodium hydride and 823 mg benzylchloride and the mixture is stirred at room temperature for 20 minutes. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with water and brine and dried over magnesium sulfate. After filtration the solvent is evaporated and the resulting residue is purified column chromatography (filler: silica gel; hexane/ethyl acetate) to give 2.66 g of tert-butyl 4-[2-(benzyloxy)-3-(tert-butoxy)propyl]-4-hydroxy-1-piperidinecarboxylate.

of 2.36 g of tert-butyl 4-[2-(benzyloxy)-3-(tert-butoxy)propyl]-4-hydroxy-1-piperidinecarboxylate dissolved in 40 ml of acetonitrile, add 426 mg ammoniumnitrate cerium (cerium ammonium nitrate) and the mixture is stirred at room temperature overnight. In the reaction solution was added silica gel and then the solution is evaporated. The residue is purified group is tracecut, getting 547 mg of tert-butyl 4-[2-(benzyloxy)-3-hydroxypropyl]-4-hydroxy-1-piperidinecarboxylate.

to 4.81 g of tert-butyl 4-[2-(benzyloxy)-3-hydroxypropyl]-4-hydroxy-1-piperidinecarboxylate dissolved in 20 ml of pyridine, added 2.76 g Teilhard and the mixture is stirred at room temperature for 2 hours. Add a 1.00 g taillored advanced, and the mixture is stirred at room temperature for 30 minutes, then at 50 ° C for 35 minutes. The reaction solution was distributed between ethyl acetate and water, washed with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. After filtration the solvent is evaporated and the resulting residue is purified column chromatography (silica gel; hexane/ethyl acetate), obtaining and 3.72 g of tert-butyl 3-(benzyloxy)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate.

6,47 g of tert-butyl 3-(benzyloxy)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate are dissolved in 100 ml of tetrahydrofuran, add 1.3 g of palladium on carbon and the mixture is stirred overnight in a hydrogen atmosphere. The catalyst removed from the reaction solution by filtration, add 1.3 g of palladium on carbon and the solution is stirred overnight in an atmosphere of water is the PR stirred overnight in a hydrogen atmosphere under a pressure of 4.2 atmosphere. The catalyst removed from the reaction solution by filtration, the solvent is evaporated and the resulting residue is purified column chromatography (silica gel; ethyl acetate/methanol) to give 4,27 g of tert-butyl 3-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carboxylate.

The intermediate product of Example 22

(anti)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol hydrochloride

2.0 g of lithium aluminum hydride are suspended in 200 ml of tetrahydrofuran and added dropwise the solution of a 14.17 g of 9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-she's in 20 ml of tetrahydrofuran while cooling with ice. After stirring the mixture for 35 minutes in the reaction solution was successively added 2.0 ml of water, 2.0 ml of 15% aqueous sodium hydroxide solution and 6.0 ml of water and the mixture is stirred at room temperature. The reaction solution is filtered, the solvent is evaporated. The resulting residue is dissolved in ethyl acetate and filtered through alumina. The solvent is evaporated, getting 10,00 g (anti)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol as a yellow wax.

10.0 g (anti)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol are dissolved in 100 ml of tetrahydrofuran, add to 10.7 ml of triethylamine, to 7.2 ml of acetic anhydride and 0.77 g of 4-dimethylaminopyridine and CME is between ethyl acetate and filtered through alumina. The filtrate is concentrated and purified column chromatography (aluminium oxide; solvent: n-hexane/ethyl acetate), obtaining 8,68 g (anti)-3-oxa-9-azabicyclo[3.3.1]nonan-7-racette in the form of a pale yellow oil.

8,68 g (anti)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ilaclama dissolved in 40 ml of 1,2-dichloroethane and added to 7.0 ml of vinylnorbornene. The mixture is stirred at room temperature for 30 minutes and then heated under reflux for 2 hours 35 minutes. The reaction solution is evaporated and purified column chromatography (filler: silica gel; solvent: n-hexane/ethyl acetate), obtaining 8,96 g (anti)-3-oxa-9-vinyloxycarbonyl-9-azabicyclo[3.3.1]nonan-7-racette in the form of a pale yellow oil.

8,96 g (anti)-3-oxa-9-vinyloxycarbonyl-9-azabicyclo[3.3.1]nonan-7-ilaclama dissolved in 45 ml of methanol and add 30 ml of water and 7.3 g of potassium carbonate. The mixture is stirred at room temperature for 1 hour and 30 minutes and at 50 ° C for 30 minutes. The reaction solution is evaporated, then add the brine and the mixture is extracted with ethyl acetate. After drying over anhydrous magnesium sulfate the solvent is evaporated, resulting in obtaining 7,37 g (anti)-3-oxa-9-vinyloxycarbonyl-9-azabicyclo[3.3.1]nonan-7-ol in the form of bled is bonil-9-azabicyclo[3.3.1]nonan-7-ol and the mixture is stirred at room temperature for 30 minutes. In the reaction solution is added 40 ml of ethanol and the mixture heated under reflux for 1 hour. The solvent is evaporated, to the residue is added ethyl acetate, and the resulting precipitates are filtered, resulting in obtaining of 5.55 g of target compound as white needles.

The intermediate product of Example 23

(SYN)-3-Azabicyclo[3.2.1]Octan-8-ol hydrochloride

The target connection receive according to the method of Obtaining the intermediate product of Example 22 from 3-methyl-3-azabicyclo[3.2.1]octane-8-it.

The intermediate product of Example 24

(anti)-3-oxa-7-azabicyclo[3.3.1]nonan-9-ol hydrochloride

The target connection receive according to the method of Obtaining the intermediate product of Example 22 from 7-methyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-it.

The intermediate product of Example 25

(anti)-9-Azabicyclo[3.3.1]nonan-3-ol hydrochloride

The target connection receive according to the method of Obtaining the intermediate product of Example 22 from 9-methyl-9-azabicyclo[3.3.1]nonan-3-one.

The intermediate product of Example 26

(Exo)-8-Azabicyclo[3.2.1]Octan-3-ol hydrochloride

The target compound is obtained after ACE the La.

The intermediate product of Example 27

(endo)-8-Azabicyclo[3.2.1]Octan-3-ol hydrochloride

The target compound is obtained after acetylation according to the method of Obtaining the intermediate product of Example 22 from (endo)-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol.

The intermediate product of Example 28

(anti)-3-Azabicyclo[3.3.1]nonan-9-ol hydrochloride

1.0 g of lithium aluminum hydride are suspended in 100 ml of tetrahydrofuran and added dropwise a solution of 7.00 g of 3-methyl-3-azabicyclo[3.3.1]nonan-9-she's in 20 ml of tetrahydrofuran while cooling with ice. After stirring for 50 minutes in the reaction solution was successively added with 1.0 ml of water, 1.0 ml of 15% aqueous sodium hydroxide solution and 3.0 ml of water and stirred at room temperature. After filtering the reaction solution, the solvent is evaporated, the result was 7.08 g of pale yellow oil. The oil is dissolved in 90 ml of tetrahydrofuran, add of 9.55 ml of triethylamine and the mixture is then stirred while cooling with ice. The mixture was added 6,46 ml of acetic anhydride and 0.56 g of 4-dimethylaminopyridine and the mixture is stirred at room temperature for 14 hours. Add approximately 20 ml of methanol, after which the reaction by the ITAT. The organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. The solvent is evaporated and the resulting residue is purified column chromatography (filler: silica gel; solvent: n-hexane/ethyl acetate) to give 3.33 g (anti)-3-methyl-3-azabicyclo[3.3.1]nonan-9-ilaclama (colorless oil) as a less polar compounds. In addition, gain of 2.06 g (SYN)-3-methyl-3-azabicyclo[3.3.1]nonan-9-ilaclama (pale orange oil) as a more polar compounds.

of 2.06 g (anti)-3-methyl-3-azabicyclo[3.3.1]nonan-9-ilaclama dissolved in 10 ml of 1,2-dichloroethane, add 2,07 ml vinylnorbornene and the mixture is stirred at room temperature for 50 minutes. The mixture is then heated under reflux for 5 hours 25 minutes. The reaction solution was evaporated, to the residue water is added and the mixture extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid, saturated sodium bicarbonate solution and brine and dried over anhydrous magnesium sulfate. The solvent is evaporated, receiving of 2.51 g (anti)-3-vinyloxycarbonyl-3-azabicyclo[3.3.1]nonan-9-racette in the form of a pale orange oil.

as 4.02 g (anti)-3-vinyloxycarbonyl-3-azabicyclo[3.3.1]nonan-9-ilace the t at room temperature for 1 hour 50 minutes. The reaction solution was evaporated, to the residue water is added, the mixture was then extracted with ethyl acetate. The organic layer is washed with water, saturated aqueous sodium bicarbonate and brine and dried over anhydrous magnesium sulfate. The solvent is evaporated and then the resulting residue is purified column chromatography (filler: silica gel; solvent: n-hexane/ethyl acetate) to give to 3.09 g (anti)-3-vinyloxycarbonyl-3-azabicyclo[3.3.1]nonan-9-ol as a yellowish oil.

7 ml of a solution of 4 N hydrogen chloride/dioxane add to 3.09 g (anti)-3-vinyloxycarbonyl-3-azabicyclo[3.3.1]nonan-9-ol and the mixture is stirred at room temperature for 50 minutes. The reaction solution is evaporated and to the obtained residue, add 30 ml of ethanol, the resulting mixture was then heated under reflux for 50 minutes. The solvent is evaporated and then the resulting residue is added ethyl acetate. The resulting precipitates are filtered, getting to 2.41 g of target compound in the form of petty-white powder.

The intermediate product of Example 29

(SYN)-3-Azabicyclo[3.3.1]nonan-9-ol acid salt

The target connection get method Get ex is th product Example 30

(anti)-2-(3-Azabicyclo[3.3.1]non-9-yl)-1-ethanol hydrochloride

1.0 g of lithium aluminum hydride are suspended in 30 ml of tetrahydrofuran and added dropwise 25 ml of suspension 3,24 g (anti)-methyl(3-azabicyclo[3.3.1]non-9-yl)acetate in tetrahydrofuran under ice cooling. After stirring for 35 minutes in the reaction solution was successively added with 1.0 ml of water, 1.0 ml of 15% aqueous sodium hydroxide solution and 3.0 ml of water and stirred at room temperature. The reaction solution was filtered and added celite and anhydrous sodium sulfate, and the solvent is evaporated. The residue is dissolved in ethyl acetate, add 5 ml of a mixture of 4 N hydrogen chloride/ethyl acetate and the resulting precipitates are filtered, getting to 2.29 g of the target compound as a white powder.

The intermediate product of Example 31

1-Chloro-4-[(4-methoxy-3-methylbenzyl)amino]-6-phthalazinedione

1H-NMR (400 MHz, DMSO-d6) : 2,10 (3H, s), of 3.73 (3H, s), with 4.64 (2H, d, J=5.4 Hz), 6,85 (1H, d, J=8.0 Hz), 7,17-7,21 (2H, m), 8,15 (1H, d, J=8.6 Hz), 8,31 (1H, DD, J=8,6; 1.2 Hz), 8,35 (1H, t, J=5.4 Hz), of 9.00 (1H, d, J=1.2 Hz).

Example 1

4-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-(3-pyridyl)phthalazine the dihydrochloride

10 ml (1.6 M) no-70C or lower and stirred for 30 minutes. 10 ml of the solution to 5.21 g of chloride tri-n-butyanova in anhydrous diethyl ether is added to the mixture. The reaction solution allowed to warm to room temperature over 1 hour. The reaction solution was poured into brine and the organic layer washed with brine. The solution is dried over anhydrous magnesium sulfate and then evaporated, obtaining 3-(1,1,1-tri-n-butylstannyl)pyridine as a yellow oil.

A mixture of 1.80 g of 1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalide, 579 mg of tetrakis(triphenylphosphine)palladium, 25 ml of xylene and 3 ml of 1-methyl-2-pyrrolidinone vigorously stirred, heated under reflux, and over 1 hour and added dropwise 25 ml of a solution of 3-(1,1,1-tri-n-butylstannyl)pyridine obtained above, in xylene. The reaction solution further heated under reflux for 15 minutes. The reaction solution is cooled to room temperature, washed 3 times with water and once with brine. The mixture was purified column chromatography (filler: silica gel), get a related product. It is suspended in smeshannom solvent consisting of tetrahydrofuran and methanol, then add a solution of 4 N hydrochloric acid/utilized and the mixture evaporated. The resulting product of precrystallization): 402,0 (MN+).

1H-NMR (400 MHz, DMSO-d6) : of 3.85 (3H, s) 4,06 (2H, ush.), 4,89 (2H, ush.), to 7.18 (1H, d, J=8.0 Hz), 7,53 (1H, DD, J=8.0 a; 1.2 Hz), to 7.67 (1H, d, J=1.2 Hz), 7,81-of 7.90 (1H, m), 8,07 (1H, DD, J=8,8; 0,4 Hz), scored 8.38-to 8.45 (1H, m), 8,46 (1H, DD, J=8,8; and 1.4 Hz), 8,90-9,00 (2H, m), to 9.57 (1H, DD, J=1,4; 0,4 Hz) of 10.76 (1H, ush.).

Example 2

4-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-(2-pyridyl)phthalazine the dihydrochloride

The target connection receive according to the method of Example 1 with the difference that 2-bromopyridin used instead of 3-bromopyridine.

MASS (ESI): 402,0 (MN+).

1H-NMR (400 MHz, DMSO-d6) : a 3.83 (3H, s), a 4.86-of 4.90 (2H, m), 7,16 (1H, d, J=8.6 Hz), 7,52 (1H, DD, J=8,6; and 2.1 Hz), 7,63-of 7.69 (2H, m), of 7.97 (1H, d, J=8.5 Hz), 8,08-8,13 (1H, m), of 8.47 (1H, DD, J=8,5; and 1.4 Hz), 8,72-8,83 (2H, m), of 9.56 (1H, d, J=1.4 Hz), 10,82-10,92 (1H, m).

Example 3

4-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-(4-cyanopiperidine)phthalazine hydrochloride

A mixture of 15 g of 4-piperazinecarboxamide, 16.3 g of benzylchloride, and 32.3 g of potassium carbonate and 200 ml of N,N-dimethylformamide is stirred at 80 ° C for 4 hours. The reaction solution is cooled to room temperature, add aqueous sodium hydroxide solution and then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and then the UPA is ucaut 12.7 g of 1-benzyl-4-piperazinecarboxamide white casuistic crystals.

5 ml of N,N-dimethylformamide is added to the mixture of 12.7 g of 1-benzyl-4-piperazinecarboxamide and 60 ml of phosphorus oxychloride under ice cooling and stirred at room temperature for 1.5 hours. The mixture is evaporated and the resulting residue is dissolved in ethyl acetate and washed with aqueous sodium hydroxide solution and brine. After drying over anhydrous sodium sulfate, the mixture is evaporated and the resulting residue is purified column chromatography (filler: silica gel), receiving of 11.0 g of 1-benzyl-4-piperidinecarbonitrile.

of 11.0 g of 1-benzyl-4-piperidinecarbonitrile dissolved in 100 ml of 1,2-dichloroethane, type of 7.1 ml of 1-chloroethylphosphonic while cooling with ice. The mixture is stirred at room temperature for 15 minutes and then heated under reflux for 1 hour and 20 minutes. After evaporation add 50 ml of methanol and the mixture is heated under reflux for 1 hour. The reaction solution is evaporated, and the crystalline residue is washed with ethyl acetate and was isolated by filtration, obtaining 8.0 g of 4-piperidinecarbonitrile hydrochloride as white crystals.

A mixture of 1.2 g of the obtained 4-piperidinecarbonitrile hydrochloride, 1.0 g of 1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalide, 1.8 g of disor clanny solution is added ethyl acetate, then washed with water and brine.

After drying over anhydrous sodium sulfate the solvent is evaporated and the resulting residue is purified column chromatography (filler: silica gel). Obtained free compound was dissolved in ethyl acetate, then add a solution of 4 N hydrochloric acid/utilized, the obtained crystals are filtered, getting 880 mg of the target compound as a yellow powder.

MASS (ESI): 433,2 (MN+).

1H-NMR (400 MHz, DMSO-d6) : 1,98-2,17 (4H, m), 3,10-3,33 (5H, m), 3,86 (3H, s), 4,70-4,74 (2H, m), 7,17 (1H, d, J=8,4 Hz), was 7.45 (1H, DD, J=8,4; 2.0 Hz), to 7.61 (1H, d, J=2.0 Hz), of 8.27 (1H, d, J=8,4 Hz), of 8.47 (1H, DD, J=8,4; and 0.8 Hz), 9,34-9,38 (1H, m), 10,28 (1H, ush.).

Example 4

4-(3-Chloro-4-methoxyphenethyl)amino-6-cyano-1-(4-cyanopiperidine)phthalazine hydrochloride

The target connection receive according to the method of Example 3 using 1-chloro-4-(3-chloro-4-methoxyphenethyl)amino-6-cyanophthalide instead of 1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalide.

MASS (ESI): 447,1 (MN+).

1H-NMR (400 MHz, DMSO-d6) : 1,97-to 2.18 (4H, m), 2,94-of 3.00 (2H, m), 3,11-of 3.23 (3H, m), 3.33 and is 3.40 (2H, m), 3.72 points-of 3.80 (2H, m), 3,82 (3H, s), to 7.09 (1H, d, J=8,4 Hz), 7,27 (1H, DD, J=8,4; 2.0 Hz), 7,44 (1H, d, J=2.0 Hz), of 8.28 (1H, d, J=8,4 Hz), of 8.47 (1H, DD, J=8,4; 0,8 Hz), 9,23-9.28 are (1H, m), 9,85 (1H, ush.).

10.0 g of 1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalide dissolved in 50 ml of 1-methyl-2-pyrrolidinone, then add 43,32 g of 4-hydroxypiperidine and 10 ml of diisopropylethylamine and the mixture is heated to C and kept at this temperature for 8 hours. After cooling, add ethyl acetate and the mixture is washed 3 times with water and once with brine. After drying over anhydrous magnesium sulfate the solvent is evaporated. The resulting residue is purified column chromatography (filler: silica gel) to give 10.1 g of 1-(4-hydroxypiperidine)-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalide in the form of yellow crystals.

Then 30 ml of a solution of 3.48 g of diethylazodicarboxylate in tetrahydrofuran added dropwise within 30 minutes to 100 ml of a solution of 4.2 g of 1-(4-hydroxypiperidine)-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalide, 2,94 g phthalimide and of 5.24 g of triphenylphosphine in tetrahydrofuran under ice cooling and then the mixture was stirred at 4C for 24 hours. The reaction solution is evaporated, add water and ethyl acetate, and then the insoluble matter is removed by filtration. The organic layer is concentrated and the resulting residue is purified column chromatography (filler: silica gel), receiving 4,85 g of 4-(3-chloro-4-medoxomil)amino-6-cyano-1-(4-phthalimidopropyl)phthalazine, 4 ml of hydrazinoacetate and 40 ml of ethanol is heated under reflux for 1 hour. The reaction solution is evaporated, the residue is dissolved in ethyl acetate, was added 1 N hydrochloric acid to bring the pH to 3, and insoluble materials are removed by filtration. the pH of the aqueous layer in the filtrate was adjusted to 11 with 1 N sodium hydroxide and then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, evaporated and then purified column chromatography (filler: silica gel). The resulting product is suspended in a mixture of ethanol/water, then add IN aqueous hydrochloric acid and dissolved by heating. After cooling, the resulting crystals are filtered, getting 440 mg of the target compound as a yellow powder.

MASS (FAB): 423 (MH+).

1H-NMR (400 MHz, DMSO-d6) : 1,78-of 1.92 (2H, m), 2,03-2,11 (2H, m), 2,90 to 3.0 (2H, m), 3,20-to 3.34 (1H, m), 3,54-3,63 (2H, m), 3,82 (3H, s), 4,70 (2H, d, J=5.6 Hz), 7,13 (1H, d, J=8,4 Hz), 7,47 (1H, DD, J=8,4; 2.0 Hz), a 7.62 (1H, d, J=2.0 Hz), 8,17 (1H, d, J=8,4 Hz), 8,35-to 8.45 (2H, m), of 8.47 (1H, DD, J=8,4; 1.0 Hz), 9,54 (1H, d, J=1.0 Hz), as 10.63 (1H, ush.).

Example 6

4-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-[4-hydroxy-4-(hydroxymethyl)piperidino]phthalazine hydrochloride

To 100 ml of a solution of 6.8 G. of 6-benzyl-1-oxo-6-azaspiro[2.5]octane in tetrahydrofuran was added 100 ml of water and 10 ml perchloro acid and the mixture is stirred at room temperature for 7 hours. The mixture is cooled with ice, add an aqueous solution of sodium carbonate to bring the pH to 7 and then evaporated. To the obtained residue is added ethyl acetate, and insoluble materials are removed by filtration. The filtrate is evaporated and then purified column chromatography (filler: silica gel) to give 4 g of 1-benzyl-4-(hydroxymethyl)-4-piperidinol.

the slots and 10% Pd-C and then hydronaut under pressure of 4 atmospheres. The reaction solution is filtered through celite, the filtrate evaporated and the residue is dissolved in methanol. Add a solution of 4 N hydrochloric acid/utilized and the mixture is then concentrated. The obtained crystals are recrystallized from methanol/ethyl acetate, isolated by filtration, getting 880 mg of 4-(hydroxymethyl)-4-piperidinol hydrochloride.

The obtained 4-(hydroxymethyl)-4-piperidinol hydrochloride is subjected to interaction with 1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalide by the method of Example 4, obtaining the target compound.

MASS (FAB): 454,2 (MN+).

1H-NMR (400 MHz, DMSO-d6) : 1,46-and 1.54 (2H, m), 1,82-of 1.94 (2H, m), 3,16-3,30 (6N, m) of 3.84 (3H, s), and 4.68-4.72 in (2H, m), to 7.15 (1H, d, J=8.6 Hz), 7,44 (1H, DD, J=8,6; 2.0 Hz), to 7.59 (1H, d, J=2.0 Hz), by 8.22 (1H, d, J=8.6 Hz), to 8.45 (1H, DD, J=8,6; 1.0 Hz), 9,36 (1H, d, J=1.0 Hz).

Example 7

4-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-[(2S)-2-(methoxymethyl)pyrrolidino]phthalazine hydrochloride

The target connection receive according to the method of Example obtaining 1, using (S)-2-methoxypiperidine instead of (R)-(-)-3-hydroxypiperidine hydrochloride.

MASS (ESI): 438,1 (MN+).

1H-NMR (400 MHz, DMSO-d6) : 1,81-1,89 (2H, m), 1,95-2,03 (1H, m), 2,15-of 2.24 (1H, m), and 3.16 (3H, s), 3,28-3,37(1H, m), 3.46 in-to 3.58 (2H, m), of 3.84 (3H, s), a 3.87-3,9), 13,79 (1H, ush.).

Example 8

4-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-phenolphtalein hydrochloride

The target connection receive according to the method of Example 10 with the difference that phenylboric acid is used instead of methoxyflavones acid.

MASS (ESI): 401,1 (MN+).

1H-NMR (400 MHz, DMSO-d6) : of 3.84 (3H, s), 4,81-4,85 (2H, m), to 7.15 (1H, d, J=8.6 Hz), of 7.48 (1H, DD, J=8,6; and 2.1 Hz), 7,60-7,66 (6N, m), of 8.00 (1H, d, J=8.6 Hz), to 8.41 (1H, DD, J=8,6; and 0.9 Hz), 9,42 (1H, d, J=0.9 Hz).

Example 9

4-[(3-Chloro-4-methoxybenzyl)amino]-1-(2-hydroxy-7-azaspiro[3.5]non-7-yl)-6-phthalazinone hydrochloride

to 47.2 g methylolmethacrylamide and 21.9 g of tert-butyl 4-oxo-1-piperidinecarboxylate added to a mixture of 14.8 g of potassium tert-butylate and 300 ml of tetrahydrofuran and stirred for 40 minutes at room temperature. The reaction solution is evaporated, add diethyl ether and then filtered through celite. The filtrate is washed with water and brine, dried over anhydrous magnesium sulfate and then filtered. The filtrate is evaporated and the resulting residue is subjected to column chromatography (silica gel), getting to 20.8 g of tert-butyl-4-methylene-1-piperidinecarboxylate.

to 49.3 g of tert-butyl-4-methylene-1-Pieper the hours add 900 ml 181,8 g trichloroacetamide in dimethoxyethane. After stirring for 30 minutes the reaction solution is cooled and added saturated aqueous sodium bicarbonate solution at 0C or below. The mixture is filtered through celite and evaporated. The resulting residue is extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated and the resulting residue is subjected to column chromatography (silica gel) to give 62.5 g of tert-butyl 1,1-dichloro-2-oxo-7-azaspiro[3.5]nonan-7-carboxylate.

106,1 g of zinc powder is added to the mixture of 62.5 g of tert-butyl 1,1-dichloro-2-oxo-7-azaspiro[3.5]nonan-7-carboxylate and 500 ml of saturated solution of ammonium chloride in methanol. The mixture is stirred for 1 hour and 20 minutes at room temperature and filtered through celite. The filtrate is evaporated, add a mixture of 1 N hydrochloric acid/ethyl acetate and the organic layer separated. The extract is washed with water, saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated and the resulting residue is subjected to column chromatography on silica gel, receiving of 38.9 g of tert-butyl-2-oxo-7-azaspiro-[3.5]nonan-7-carboxylate.

300 ml of ethanol is cooled on ice and dissolve in it 6,13 g borage the-7-azaspiro[3.5]nonan-7-carboxylate in ethanol. The reaction solution is treated with saturated aqueous ammonium chloride and evaporated. The resulting residue is distributed between ethyl acetate and water, an ethyl acetate layer was washed with brine and dried over magnesium sulfate. After filtration the solvent is evaporated and the resulting residue is purified column chromatography (filler: silica gel, hexane/ethyl acetate), obtaining of 36.6 g of tert-butyl-2-hydroxy-7-azaspiro[3.5]nonan-7-carboxylate.

1H-NMR (400 MHz, Dl3) : 1,45 (N, C), 1,43-of 1.57 (4H, m), 1,65-1,72 (2H, m), 3.27 to the 3.35 (4H, m), 4,32 (1H, Quint, J=7.2 Hz).

to 6.22 g of tert-butyl-2-hydroxy-7-azaspiro[3.5]nonan-7-carboxylate was dissolved in 20 ml of tetrahydrofuran, the resulting solution was added 80 ml of a solution of 4 N hydrogen chloride/dioxane and then stirred at room temperature for 1 hour. The reaction solution is evaporated and the resulting residue is dissolved in 20 ml of 1-methyl-2-pyrrolidinone add 4,67 g of 1-chloro-4-[(3-chloro-4-methoxybenzyl)amino]-6-phthalazinedione and 6,72 g diisopropylethylamine and then stirred at 160S for 9 hours. The reaction solution is cooled to room temperature, distributed between ethyl acetate and water and the aqueous layer was extracted with ethyl acetate. An ethyl acetate layers obedinitel is evaporated, the resulting residue is purified column chromatography (filler: silica gel; ethyl acetate/methanol) and the resulting crude crystals are crushed and washed with diethyl ether, receiving a 4.86 g of yellow crystals. The obtained product is dissolved in 150 ml of ethanol, add 15 ml of 4 N hydrogen chloride/dioxane and the solvent is evaporated. The resulting residue is dissolved in 150 ml of ethanol, heated to 80C and contribute as seed crystals synthesized separately in aqueous ethanol, and when the crystallization is initiated, the heating is stopped. The solution is left to cool to room temperature and after separation by filtration and washing with ethanol 35 g of target compound.

1H-NMR (400 MHz, DMSO-d6) : 1,58-of 1.66 (2H, m), by 1.68 to 1.76 (4H, m), 2,14-2,22 (2H, m), 3,05-and 3.16 (4H, t), 3,83 (3H, s), of 4.12 (1H, t, J=7.2 Hz), 4.72 in (2H, d, J=5.6 Hz), 7,14 (1H, d, J=8,8 Hz), was 7.45 (1H, DD, J=8,8; 2.0 Hz), 7,60 (1H, d, J=2.0 Hz), to 8.20 (1H, d, J=8,4 Hz), 8,44 (1H, DD, J=8,4; 1.2 Hz), 9,46 (1H, s).

Example 10

4-[(3-Chloro-4-methoxybenzyl)amino]-1-(4-pyridyl)-6-phthalazinedione

The target connection receive according to the method of Example 1.

1H-NMR (400 MHz, DMSO-d6) : of 3.80 (3H, s), was 4.76 (2H, d, J=5.5 Hz), 7,10 (1H, d, J=8,8 Hz), 7,38 (1H, dd, J=8,8; and 2.4 Hz), to 7.50 (1H, d, J=2.4 Hz), to 7.64 (2">

4-[(3-Chloro-4-methoxybenzyl)amino]-1-(3-oxo-2-oxa-8-azaspiro[4.5]Dec-8-yl)-6-phthalazinedione

567 ml of a solution of 37.8 g of tert-butyl-2-oxo-7-azaspiro[3.5]nonan-7-carboxylate in methanol cooled in the ice water and added dropwise 43 g of 30% aqueous solution peroxide hydrogen. In the resulting solution was added dropwise 63 ml of 1 N aqueous sodium hydroxide solution and the mixture is stirred at room temperature for 2 hours. Add 1000 ml of ethyl acetate and 600 ml of water and 100 ml saturated aqueous solution of sodium thiosulfate pentahydrate and the organic layer separated. Extracted solution was washed with brine, dried over anhydrous magnesium sulfate and then filtered. The filtrate is evaporated, getting 28.4 g of tert-butyl 3-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate.

of 1.16 g of tert-butyl 3-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate was dissolved in 2.3 ml of methanol, add 4.6 ml of a solution of 4 N hydrochloric acid/ethyl acetate and the mixture is stirred at room temperature for 1 hour. Add 5 ml of ethyl acetate and the resulting crystals are filtered, receiving 700 mg of 3-oxo-2-oxa-8-azaspiro[4.5]decane hydrochloride.

The mixture 657 mg 1-chloro-4-[(3-chloro-4-methoxybenzyl)amino]-6-phthalazinedione is religion stirred at 130C for 15 hours and 40 minutes. After cooling, the reaction solution was diluted with 40 ml of tetrahydrofuran, 100 ml of ethyl acetate and 15 ml of 1-methyl-2-pyrrolidinone and then washed with saturated aqueous sodium bicarbonate and brine. The mixture is dried over anhydrous magnesium sulfate and then filtered. The filtrate is evaporated and the resulting residue is purified column chromatography (silica gel) to give 713 mg 4-[(3-chloro-4-methoxybenzyl)amino]-1-(3-oxo-2-oxa-8-azaspiro[4,5]Dec-8-yl)-6-phthalazinedione.

1H-NMR (400 MHz, CDCl3) : 1,88 is 2.01 (4H, t), 2,53 (2H, s), 3,22 is 3.40 (4H, m), 3,90 (3H, s), 4,20 (2H, s), of 4.77 (2H, d, J=5,2 Hz), 5,20 (1H, t, J=5,2 Hz), 6,92 (1H, d, J=8,4 Hz), 7,32 (1H, DD, J=8,4; 2.0 Hz), 7,46 (1H, d, J=2.0 Hz), of 7.96 (1H, DD, J=8,4; 2.0 Hz), 8,11 (1H, d, J=8,4 Hz) to 8.14 (1H, d, J=0.8 Hz).

Example 12

4-[(3-Chloro-4-methoxybenzyl)amino]-1-(2-oxo-7-azaspiro[3.5]non-7-yl)-6-phthalazinedione

500 mg of 4-[(3-chloro-4-methoxybenzyl)amino]-1-(2-hydroxy-7-azaspiro[3.5]non-7-yl)-6-phthalazinedione suspended in 20 ml dichloromethane and 10 ml of tetrahydrofuran, then added 690 mg 1,1,1-triacetoxy-1,1-dihydro-1,2-dimensionality-3-(1H)-she and the mixture is stirred at room temperature for 15 minutes. Add ethyl acetate, 30 ml of a saturated aqueous solution of sodium bicarbonate and 2 ml saturated Vodacom. The extracts are combined, washed with brine, dried over anhydrous magnesium sulfate and then filtered. The filtrate is evaporated, the obtained residue is purified column chromatography (filler: silica gel), crystallized from ethanol and the resulting crystals are filtered when adding hexane, getting 420 mg of 4-[(3-chloro-4-methoxybenzyl)amino]-1-(2-oxo-7-azaspiro[3.5]non-7-yl)-6-phthalazinedione.

1H-NMR (400 MHz, DMSO-d6) : 1,90 (4H, m), of 2.86 (4H, m) to 3.09 (4H, s), of 3.80 (3H, s), to 4.62 (2H, d, J=5.6 Hz), 7,07 (1H, d, J=8.5 Hz), 7,33 (1H, d, J=8,8 Hz), 7,44 (1H, s), 7,89 (1H, t, J=5.6 Hz), of 8.09 (1H, d, J=8.0 Hz), 8,19 (1H, d, J=8.0 Hz), 8,88 (1H, s).

Example 13

4-[(3-Chloro-4-methoxybenzyl)amino]-1-[4-hydroxy-4-(1H-1-imidazolidinyl)piperidino]-6-phthalazinedione the dihydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,49 (2H, d, J=12,4 Hz), 1,82-of 1.93 (2H, m), of 3.13 (2H, t, J=10,8 Hz), 3,37 (2H, d, J=12,4 Hz), 3,82 (3H, s), 4,30 (2H, s), 4,74 (2H, d, J=5, 6 Hz), 7,13 (1H, d, J=8,8 Hz), of 7.48 (1H, dd, J=2,0; 8,4 Hz), 7,63 (1H, d, J=2.0 Hz), 7,66-7,71 (2H, m), 8,18 (1H, d, J=8,4 Hz), 8,48 (1H, d, J=8,4 Hz), 9,10 (1H, s), a 9.60 (1H, s).

Example 14

4-[(3-Chloro-4-methoxybenzyl)amino]-1-[4-hydroxy-4-(1H-1,2,4-triazole-1-ylmethyl)piperidino]-6-phthalazinedione the dihydrochloride

1H-NMR (400 MHz, DMSO-d6) : and 1.54 (2H, d, J=12,8 Hz), ,62 (1H, d, J=2.0 Hz), to 8.20 (1H, d, J=8,4 Hz), 8,21 (1H, s), to 8.45 (1H, DD, J=1,2; and 8.4 Hz), 8,79 (1H, s), of 9.56 (1H, s), is 10.75 (1H, ush.-C).

Example 15

1-[4-[(3-Chloro-4-methoxybenzyl)amino]-6-(1H-1,2,3,4-tetrazol-5-yl)-1-phthalazine]-4-piperidinol

0.55 g of sodium azide are added to a mixture of 1.0 g of 4-[(3-chloro-4-methoxybenzyl)amino]-1-(4-hydroxypiperidine)-6-phthalazinedione, 1.2 g of triethylamine hydrochloride and 20 ml of 1-methyl-2-pyrrolidinone, stirred at 100C for 8 hours. The reaction solution is allowed to cool to room temperature, water is added and the resulting crystals are filtered, obtaining 1.0 g of the target compound.

1H-NMR (400 MHz, DMSO-d6) : 1,58-1,7 (2H, m), 1,8-of 1.97 (2H, m), 2,8-2,98 (2H, m), 3,3-of 3.43 (2H, m), up 3.6-3.7 (1H, m), with 3.79 (3H, s), and 4.6 (2H, s), 7,06 (1H, d, J=8 Hz), 7,34 (1H, d, J=8 Hz), 7,45 (1H, s), 7,95 (1H, d, J=8 Hz), to 8.45 (1H, d, J=8 Hz), 8,89 (1H, s).

Example 16

1-[4-[(3-Chloro-4-methoxybenzyl)amino]-6-(1-methyl-1H-1,2,3,4-tetrazol-5-yl)-1-phthalazine]-4-piperidinol

0.037 ml methyliodide added to a mixture of 0.25 g of 1-[4-[(3-chloro-4-methoxybenzyl)amino]-6-(1H-1,2,3,4-tetrazol-5-yl)-1-phthalazine]-4-piperidinol, 1.2 g of potassium carbonate and 5 ml of dimethylformamide and stirred at room temperature for 3 hours. To the reaction solution was added water and the wasp is ü: silica gel), receiving 50 mg of the target compound.

1H-NMR (400 MHz, DMSO-d6) : 1,6-1,7 (2H, m), 1.85 to 1,95 (2H, m), 2,85-2,95 (2H, m), of 3.25 to 3.45 (2H, m), up 3.6-3.7 (1H, m), of 3.80 (3H, s), 4,48 (3H, s), br4.61 (2H, d, J=8.6 Hz), to 4.73 (1H, d, J=4.0 Hz), 7,07 (1H, d, J=8,4 Hz), 7,34 (1H, dd, J=2,0; and 8.4 Hz), 7,44 (1H, d, J=2.0 Hz), 8,07 (1H, t, J=5.6 Hz), 8,10 (1H, d, J=8,4 Hz), of 8.47 (1H, d, J=8,8 Hz), of 9.00 (1H, s).

Example 17

4-[(3-Chloro-4-methoxybenzyl)amino]-1-(4-hydroxypiperidine)-6-phthalazinedione

3,7 ml diethyldithiophosphate added to a mixture of 2.0 g of 4-[(3-chloro-4-methoxybenzyl)amino]-1-(hydroxypiperidine)-6-phthalazinedione, 1 ml water and 2 ml of isopropanol and the mixture is heated under reflux for 1 hour. After cooling, the reaction solution was added water and the resulting crystals are filtered. The filtrate is extracted with ethyl acetate and washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate is evaporated and the resulting crystalline residue is combined with the crystals obtained previously during the filtration process, resulting in obtaining 1.5 g of the target compound.

1H-NMR (400 MHz, DMSO-d6) : 1,6-1,7 (2H, m), 1.85 to a 2.00 (2H, m), 2,90-3,1 (2H, m), 3,3-3,5 (2H, m), 3,6-3,8 (1H, m), 3,81 (3H, s), and 4.68 (2H, d, J=4 Hz), 7,13 (1H, d, J=8 Hz), 7,40 (1H, d, J=8 Hz), 7,54 (1H, s), 8,08 (1H, d, J=8 Hz), 8,3 an 8.4 (1H, m), 8,9 and 9.1 (1H, m), 9,88 (1H, s), hiperdino

1.5 g of 4-[(3-chloro-4-methoxybenzyl)amino]-1-(4-hydroxypiperidine)-6-phthalazinedione dissolved in 50 ml of dimethylformamide, add 1.1 ml of chloroacetone and the mixture was stirred at 100C for 4 hours. After cooling the reaction solution, water is added and the aqueous layer was removed by decantation. The residue is dried under reduced pressure and then purified by chromatography on silica gel, receiving 200 mg of the target compound.

1H-NMR (400 MHz, DMSO-d6) : 1,6-1,7 (2H, m), 1.85 to 1,95 (2H, m), 2,47 (3H, s), 2,83-to 2.94 (2H, m), 3,3-3,4 (2H, m), up 3.6-3.7 (1H, m), of 3.80 (3H, s), 4,63 (2H, d, J=5.6 Hz), 4.72 in (1H, d, J=4.0 Hz), 7,07 (1H, d, J=8,4 Hz), 7,34 (1H, DD, J=2,0; and 8.4 Hz), 7,44 (1H, d, J=2.0 Hz), of 7.48 (1H, s), of 7.96-of 8.04 (1H, m), 8,01 (1H, d, J=8,4 Hz), at 8.36 (1H, DD, J=1,6; and 8.4 Hz), 8,76 (1H, d, J=1.6 Hz).

Example 19

1-[4-[(3-Chloro-4-methoxybenzyl)amino]-6-(2-thienyl)-1-phthalazine]-4-piperidinol hydrochloride

24 mg of tetrakis(triphenylphosphine)palladium(0) and 1.4 ml of 2-(tributylstannyl)thiophene is added to a mixture of 200 mg of 1-[6-bromo-4-[(3-bromo-4-methoxybenzyl)amino]-1-phthalazine]-4-piperidinol and 2 ml of toluene. The mixture is heated under reflux for 2 hours. After cooling, the reaction solution was poured into ice water and extracted with ethyl acetate. Extracted solution was dried over anhydrous sulfate m the CT make a solution of 4 N hydrochloric acid/ethyl acetate hydrochloride getting 73 mg of the target compound.

1H-NMR (400 MHz, DMSO-d6) : to 1.67 (2H, m), with 1.92 (2H, m) of 3.00 (2H, m), of 3.45 (2H, m), 3,74 (1H, m), 3,82 (3H, s), to 4.73 (2H, m), 7,13 (1H, d, J=7,2 Hz), 7,27 (1H, s), 7,46 (1H, d, J=7,2 Hz), to 7.61 (1H, s), 7,79 (1H, d, J=5.6 Hz), 8,03 (1H, d, J=5.6 Hz), of 8.09 (1H, d, J=8,8 Hz), a 8.34 (1H, d, J=8,8 Hz), 9,20 (1H, ush.-C).

Example 20

4-[(3-Chloro-4-methoxybenzyl)amino]-1-(4-hydroxypiperidine)-6-phthalazinedione hydrochloride

10.0 g of 4-[(3-chloro-4-methoxybenzyl)amino]-1-(4-hydroxypiperidine)-6-phthalazinedione and 5.3 g of tert-butyldimethylchlorosilane dissolved in 80 ml of dimethylformamide and added 4.8 g of imidazole, the mixture is stirred at room temperature overnight. In the reaction solution is added ethyl acetate, and then the obtained mixture is washed once with water and twice with brine. The mixture is dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated, getting 11,7 g 1-[4-[[1-(tert-butyl)-1,1-dimethylallyl]oxy]piperidino]-4-[(3-chloro-4-methoxybenzyl)amino]-6-phthalazinedione.

11,7 g 1-[4-[[1-(tert-butyl)-1,1-dimethylallyl]oxy]piperidino]-4-[(3-chloro-4-methoxybenzyl)amino]-6-phthalazinedione dissolved in 150 ml of methylene chloride and cooled. 44 ml of a 1 M hydrogenated diisobutylaluminum in toluene was added when-S. the about solution of ammonium chloride and the mixture is stirred at room temperature for 0.5 hours. After adding 40 ml of 10% sulfuric acid, the mixture is extracted with ethyl-acetate. Extracted solution was washed with brine, dried over anhydrous magnesium sulfate and then filtered. The filtrate is evaporated and the residue purified column chromatography (filler: silica gel), receiving 5.3g 1-[4-[[(1-(tert-butyl)-1,1-dimethylallyl]oxy]piperidino]-4-[(3-chloro-4-methoxy-benzyl)amino]-6-phthalazinedione.

1.5 g 1-[4-[[(1-(tert-butyl)-1,1-dimethylallyl]oxy]piperidino] -4-[(3-chloro-4-methoxybenzyl)amino]-6-phthalazinedione and 0.35 g of hydroxylamine hydrochloride dissolved in 50 ml of methanol and the mixture is heated under reflux for 2 hours. After cooling, water is added, then the mixture is extracted with ethyl acetate. Extracted solution was washed with brine, dried over anhydrous magnesium sulfate and then filtered. The filtrate is evaporated and the residue purified column chromatography (filler: silica gel) to give 1.18 g 1-[4-[[(1-(tert-butyl)-1,1-dimethylallyl]oxy]piperidino]-4-[(3-chloro-4-methoxybenzyl)amino]-6-phthalazinedione.

1 M solution of tetrabutylammonium fluoride in tetrahydrofuran are added to 30 ml of a solution of 1.18 g 1-[4-[[(1-(tert-butyl)-1,1-dimethylallyl]oxy]piperidino]-4-[(3-chloro-4-methoxybenzyl)amino]Chi. In the reaction solution is added water and the mixture is then extracted with ethyl acetate. Extracted solution was washed with brine, dried over anhydrous magnesium sulfate and then filtered. The filtrate is evaporated and the resulting crystalline residue is washed with ethyl acetate and was isolated by filtration, getting 0.34 g of the target compound. This product makes the usual way in hydrochloride.

1H-NMR (400 MHz, DMSO-d6) : 1,58 is 1.70 (2H, m), 1,86-of 1.95 (2H, m), 2,92-to 3.02 (2H, m), is 3.08-up 3.22 (2H, m), 3,64-to 3.73 (1H, m), 3,82 (3H, s), br4.61-and 4.68 (2H, m), 4,77-rate 4.79 (1H, m), 7,10 (1H, d, J=8 Hz), 7,38 (1H, d, J=8 Hz), 7,51 (1H, c), of 8.06 (1H, d, J=8 Hz), 8,23 (1H, d, J=8 Hz), of 8.28 (1H, s), 8,69-8,76 (1H, m).

Example 21

4-[(3-Chloro-4-methoxybenzyl)amino]-1-[(2R)-2-(hydroxymethyl)-1-oxa-8-azaspiro[4.5]DECA-8-yl]-6-phthalazinone hydrochloride

1.08 g of 1-chloro-4-[(3-chloro-4-methoxybenzyl)amino]-6-phthalazinedione and 0,76 g (2R)-1-oxa-8-azaspiro[4.5]DECA-2-ylmethanol dissolved in 20 ml of N-methyl-2-pyrrolidone and stirred at 160S for 5 hours. After completion of the reaction, the reaction solution is cooled to room temperature, add water and saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate and washed with brine three times. Then the solution is dried over sulfate magnitostaticheskogo connection.

The compound obtained was dissolved in 20 ml of ethanol, add 1,40 ml solution of 1 N hydrochloric acid/ethanol at room temperature and the mixture is stirred for 10 minutes. After removal of solvent the residue is treated with diisopropyl ether and then dried, obtaining 555 mg of the target compound.

1H-NMR (400 MHz, DMSO-d6) : 1,67-to 1.98 (8H, m), 3.15 and is 3.40 (6N, m), 3,82 (3H, s), 3,90-3,98 (1H, m), 4,68-of 4.77 (2H, t), 7,14 (1H, d, J=9 Hz), 7,46 (1H, DD, J=2,9 Hz), a 7.62 (1H, d, J=2 Hz), 8,23 (1H, d, J=9 Hz), to 8.45 (1H, d, J=9 Hz), 9,50 (1H, s).

Example 22

(anti)-4-[(3-Chloro-4-methoxybenzyl)amino]-1-(7-hydroxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)-6-phthalazinone hydrochloride

1.5 g of 1-chloro-4-[(3-chloro-4-methoxybenzyl)amino]-6-phthalazinedione, 1.13 g (anti)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol hydrochloride and 2.16 ml diisopropylethylamine added to 8 ml of 1 M methyl-2-pyrrolidone and the mixture was stirred at C for 9 hours and 15 minutes. In the reaction solution, water is added, the mixture extracted with ethyl acetate and the organic layer washed with water and brine. After drying the mixture over anhydrous magnesium sulfate the solvent is evaporated. The residue is purified column chromatography (filler: silica gel; solvent: dichloromethane/methanol), receiving of 0.085 g of yellow oil.

1H-NMR (400 MHz, DMSO-d6) : 1,69-of 1.78 (2H, m), 2,46-of 2.56 (2H, m), of 3.77-a-3.84 (2H, m), 3,86 (3H, s), 3,86-of 3.95 (3H, m), 4.04 the-4,12 (2H, m), 4,74 (2H, s), 7,17 (1H, d, J=8,4 Hz), 7,46 (1H, DD, J=2,2; and 8.4 Hz), to 7.61 (1H, d, J=2.2 Hz), 8,13 (1H, d, J=8,4 Hz), to 8.45 (1H, d, J=8,4 Hz), 9,39 (1H, m).

Example 23

(anti)-4-[(3-Chloro-4-methoxybenzyl)amino]-1-(9-hydroxy-3-azabicyclo[3.3.1]non-3-yl)-6-phthalazinone hydrochloride

1.5 g of 1-chloro-4-[(3-chloro-4-methoxybenzyl)amino]-6-phthalazinedione, 1.12 g (anti)-3-azabicyclo[3,3.1]nonan-9-ol hydrochloride and 2.18 ml diisopropylethylamine added to 8 ml of N-methyl-2-pyrrolidone and the mixture was stirred at C for 9 hours. In the reaction solution, water is added, the solution is then extracted with ethyl acetate, the organic layer washed with water and brine, dried over anhydrous magnesium sulfate and then the solvent is evaporated. Add dichloromethane and insoluble substances are filtered, receiving of 1.23 g of pale yellow powder. The resulting powder was suspended in ethyl acetate, add 0.7 ml of a solution of 4 N hydrogen chloride/ethyl acetate and the mixture is stirred at room temperature. The resulting precipitates are filtered, receiving 1.28 g CE (2H, t), 1,86-of 1.93 (2H, m), 2,11-of 2.23 (2H, t), of 2.38 (1H, m), 3,15-3,24 (2H, m), 3,62-3,70 (2H, m in), 3.75 (1H, m), 3,85 (3H, s), 4,74 (2H, s), 7,16 (1H, d, J=8,4 Hz), 7,47 (1H, DD, J=1,8; and 8.4 Hz), a 7.62 (1H, d, J=1,8 Hz), 8,23 (1H, d, J=8,4 Hz), 8,56 (1H, DD, J=1,3; and 8.4 Hz), 9,49 (1H, m).

Example 24

(anti)-4-[(3-Chloro-4-methoxybenzyl)amino]-1-[9-(2-hydroxyethyl)-3-azabicyclo[3.3.1]non-3-yl]-6-phthalazinone hydrochloride

1.5 g of 1-chloro-4-[(3-chloro-4-methoxybenzyl)amino]-6-phthalazinedione, 1.29 g (anti)-2-(3-azabicyclo[3.3.1]non-9-yl)-1-ethanol hydrochloride and 2.18 ml diisopropylethylamine added to 8 ml of 1 M methyl-2-pyrrolidone and the mixture was stirred at S within 8 hours 40 minutes. In the reaction solution, water is added, the solution extracted with ethyl acetate and the organic layer washed with water and brine. The reaction solution is dried over anhydrous magnesium sulfate and then the solvent is evaporated. The residue is purified column chromatography (filler: silica gel; solvent: dichloromethane/methanol) and crystallized from a mixture of dichloromethane/ethyl acetate/ether, receiving 1.12 g of pale yellow powder. The resulting powder was suspended in acetone, add 2 ml solution of 4 N hydrogen chloride/ethyl acetate and ethyl acetate, and the mixture is stirred at room temperature. The precipitate are filtered, p. (1H, m), 1,66-of 1.73 (2H, m), 1,73-to 1.87 (5H, m), 1,88 is 2.00 (2H, m), 2,42 (1H, m), 3,14 is 3.23 (2H, m), 3,49 (2H, t, J=6.4 Hz), 3,67 is 3.76 (2H, m), 3,85 (3H, s), to 4.73 (2H, s), 7,16 (1H, d, J=8.6 Hz), 7,47 (1H, DD, J=1,6; 8.6 Hz), a 7.62 (1H, d, J=1.6 Hz), 8,24(1H, d, J=8,4 Hz), 8,55 (1H, DD, J=1,3; and 8.4 Hz), 9,46 (1H, m).

Example 25

1-(3-Amino-3-methyl-1-butenyl)-4-[(3-chloro-4-methoxybenzyl)amino]-6-phthalazinone hydrochloride

of 0.39 ml of triethylamine is added to a mixture of 500 mg of 1-chloro-4-[(3-chloro-4-methoxybenzyl)amino]-6-phthalazinedione, 53 mg of copper iodide, 98 mg dichlorobis(triphenylphosphine)palladium (II), 347 mg of 3-amino-3-methyl-1-butyne and 10 ml of dimethylformamide and the mixture is stirred at 80 ° C for 3 hours in nitrogen atmosphere. After cooling, the reaction solution is added ethyl acetate, and then the water and conc. aqueous ammonia and the organic layer separated. The organic layer is washed with diluted aqueous ammonia solution and brine and dried over anhydrous sodium sulfate. The mixture is filtered and the filtrate evaporated. The resulting residue is purified column chromatography with NH-forming silica gel, getting 446 mg of the target compound. The product is converted into the hydrochloride in the usual way.

1H-NMR (400 MHz, DMSO-d6) : 1,75 (6N, (C), 3,82 (3H, s), was 4.76 (2H, d, J=5.6 Hz), 7,10 (1H, d, J=8,4 Hz), 7,37 (1H, DD, J=8,4; 2.2 Hz), to 7.50 (1H, d, J=2.2 Hz),-4-methoxybenzyl)amino]-1-[4-(methoxyimino)piperidin]-6-phthalazinone hydrochloride

A mixture of 1.19 g of 4-[(3-chloro-4-methoxybenzyl)amino]-1-[4-oxopiperidine]-6-phthalazinedione, 354 mg methoxyamine hydrochloride, 1.2 g of sodium carbonate and 10 ml of ethanol is heated under reflux for 2 hours. After cooling, the reaction solution is added a salt solution, then extracted with ethyl acetate, dried over anhydrous sodium sulfate and filtered. The filtrate is evaporated and the resulting residue is purified column chromatography (silica gel), obtain 620 mg of 4-[(3-chloro-4-methoxybenzyl)amino]-1-[4-(methoxyimino)piperidin]-6-phthalazinedione. This product is dissolved in a mixed solvent consisting of methanol and ethanol, and recrystallized by addition of 0.35 ml of a solution of 4N hydrochloric acid/ethyl acetate, getting 388 mg of 4-[(3-chloro-4-methoxybenzyl)amino]-1-[4-(methoxyimino)piperidin]-6-phthalazinedione hydrochloride.

1H-NMR (400 MHz, DMSO-d6) : 2,50-to 2.55 (2H, m), 2,74 is 2.80 (2H, m), 3,29-to 3.35 (4H, m), of 3.77 (3H, s), 3,85 (3H, s), 4.72 in (2N, ush.), 7,16 (1H, d, J=8,4 Hz), was 7.45 (1H, DD, J=8,4; 2.0 Hz), 7,60 (1H, d, J=2.0 Hz), with 8.33 (1H, d, J=8,8 Hz), 8,48 (1H, DD, J=8,8; 0,8 Hz), 9,35 (1H, d, J=0.8 Hz), 10,19 (1H, ush.).

The following compounds are obtained from the appropriate source products in the manner described in the Examples get elontril hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,62-of 1.73 (2H, m), 1,90 of 1.99 (2H, m), 2,32 (3H, s), 2,98-is 3.08 (2H, m), 3,42-3,50 (2H, m), 3.72 points-of 3.80 (1H, m), was 4.76 (2H, d, J=5, 6 Hz), was 7.36 (2H, s), EUR 7.57 (1H, s) 8,23 (1H, d, J=8,4 Hz), of 8.47 (1H, DD, J=8,4; 1.2 Hz), 9,37 (1H, d, J=1.2 Hz), of 10.21 (1H, ush.).

Example 28

4-[(3-Chloro-4-methoxybenzyl)amino]-1-(5-hydroxymethyluracil-lapenta[C]pyrrol-2-yl)-6-phthalazinedione

1H-NMR (400 MHz, DMSO-d6) : 1,40-1,49 (2H, m), 2,02-2,12 (2H, m), 2,55-of 2.64 (2H, m), 3,24 (4H, d, J=4.0 Hz), 3,80 (3H, s), 3,94-Android 4.04 (1H, m), br4.61 (2H, d, J=5,2 Hz), 4.72 in (1H, d, J=5.6 Hz), 7,07 (1H, d, J=8,4 Hz), 7,32 (1H, dd, J=2,0; and 8.4 Hz), to 7.77-7,83 (1H, m), 8,14-8,23 (2H, m), 8,66 (1H, d, J=0.8 Hz).

Example 29

4-[(3-Chloro-4-methoxybenzyl)amino]-1-[4-(2-hydroxyethyl)-1,2,3,6-tetrahydro-1-pyridinyl]-6-phthalazinedione

1H-NMR (400 MHz, DMSO-d6) : 2,15-2,22 (2H, m), 2,27-2,39 (2H, m), 3,20 (2H, t, J=5.6 Hz), 3,48-of 3.60 (2H, m), of 3.69 (2H, s), of 3.80 (3H, s), 4,47 (1H, t, J=5.6 Hz), br4.61 (2H, d, J=5.6 Hz), of 5.55 (1H, d, J=0.4 Hz), was 7.08 (1H, d, J=8,4 Hz), 7,33 (1H, DD, J=2,0; and 8.4 Hz), 7,44 (1H, d, J=2.0 Hz), 7,83-7,89 (1H, m), of 8.04 (1H, d, J=8,4 Hz), 8,08 (1H, DD, J=1,2; and 8.4 Hz), 8,87 (1H, t, J=0.4 Hz).

Example 30

4-[(3-Chloro-4-methoxybenzyl)amino]-1-[3-hydroxymethyl)tetrahydro-1H-1-pyrrolyl]-6-phthalazinedione

1H-NMR (400 MHz, DMSO-d6) : 1,59 is 1.70 (1H, m), 1,83-2,02 (2H, m), 2,31-to 2.41 (1H, m), 3,34-of 3.60 (5H, m), 4,58 (2H, J8 Hz), 8,820 (1H, d, J=1.2 Hz).

Example 31

4-[(3-Chloro-4-methoxybenzyl)amino]-1-[4-(hydroxymethyl)-1,2,3,6-tetrahydro-1-pyridinyl]-6-phthalazinedione

1H-NMR (400 MHz, DMSO-d6) : 2,28 (2H, ush.-C) 3,19-3,26 (2H, m), of 3.73 (2H, ush.-C) of 3.80 (3H, s) to 3.89 (2H, d, J=4.4 Hz), to 4.62 (2H, d, J=5.6 Hz), 4,78 (1H, t, J=5, 6 Hz), 5,72 (1H, ush.-C) was 7.08 (1H, d, J=8,4 Hz), 7,33 (1H, DD, J=2,0; and 8.4 Hz), 7,44 (1H, d, J=2.0 Hz), 7,87 (1H, t, J=5.6 Hz), with 8.05 (1H, d, J=8,4 Hz), 8,18 (1H, DD, J=1,2; and 8.4 Hz), 8,87 (1H, d, J=1.2 Hz).

Example 32

2-[1-[4-[(3-Chloro-4-methoxybenzyl)amino]-6-cyano-1-phthalazine]-4-piperidinyl]propionic acid hydrochloride

1H-NMR (400 MHz, DMSO-d6) : a 1.08 (3H, d, J=6.8 Hz), 1,46-of 1.64 (2H, m), 1,66 of-1.83 (3H, m), 2,22 of-2.32 (1H, m), 2,78-2,90 (2H, m), 3,54-of 3.64 (2H, m), 3,83 (3H, s), 4.72 in (2H, d, J=6.0 Hz), 7,14 (1H, d, J=8,4 Hz), 7,46 (1H, DD, J=2,0; and 8.4 Hz), to 7.61 (1H, d, J=2.0 Hz), by 8.22 (1H, d, J=8,4 Hz), to 8.45 (1H, DD, J=1,6; and 8.4 Hz), 9,49 (1H, s).

Example 33

2-[1-[4-[(3-Chloro-4-methoxybenzyl)amino]-6-cyano-1-phthalazine]-1,2,3,6-tetrahydro-4-pyridinyl]acetic acid hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 2,38 is 2.44 (2H, m), 3.04 from (2H, s), 3,79-a 3.83 (2H, m), 3,83 (3H, s), 4.72 in (2H, t, J=2,8 Hz), 5,63-of 5.68 (1H, m), to 7.15 (1H, d, J=8,8 Hz), 7,46 (1H, DD, J=2,4; and 8.4 Hz), to 7.61 (1H, d, J=2.4 Hz), 8,21 (1H, d, J=8,8 Hz), 8,46 (1H, DD, J=1,2; and 8.4 Hz), to 9.45 (1H, s).

Example 34

2-[1-[4-[(3-Chloro-4-methoxy>H-NMR (400 MHz, DMSO-d6) : 1,60-1,90 (4H, m), 2,03-of 2.20 (1H, m), 2,83 are 2.98 (2H, m), to 3.58-the 3.65 (2H, m), 3,83 (3H, s), to 4.73 (2H, t, J=2,8 Hz), to 4.98 (1H, DD, J=4,0; 48,4 Hz), 7,14 (1H, d, J=8,4 Hz), 7,46 (1H, DD, J=2,0; and 8.4 Hz), to 7.61 (1H, d, J=2.4 Hz), 8,23 (1H, d, J=8,4 Hz), 8,44 (1H, DD, J=1,2; and 8.4 Hz), 8,46 (1H, s).

Example 35

2-[1-[4-[(3-Chloro-4-methoxybenzyl)amino]-6-cyano-1-phthalazine]-4-piperidyl]acetic acid hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,44-of 1.57 (2H, m), 1,79-of 1.84 (2H, m), 1.85 to a 1.96 (1H, m), of 2.25 (2H, d, J=6.8 Hz), 2,89 (2H, t, J=12.0 Hz), 3,55 (2H, d, J=12.0 Hz), of 3.84 (3H, s), 4,70 (2H, d, J=6.0 Hz), to 7.15 (1H, d, J=8,8 Hz), 7,44 (1H, DD, J=2,0; and 8.4 Hz), 7,94 (1H, d, J=2.0 Hz), 8,21 (1H, d, J=8,4 Hz), 8,46 (1H, DD, J=1,6; 8,8 Hz), 9,37 (1H, s).

Example 36

4-[(3-Chloro-4-methoxybenzyl)amino]-1-[4-(1-fluoro-2-hydroxyethyl)piperidino]-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,56-of 1.78 (3H, m), 1,83 of 1.99 (2H, m), 2,80-only 2.91 (2H, m), 3,51 at 3.69 (4H, m), 3,83 (3H, s), 4,25-or 4.31 (1/2H, m), 4,37-4,43 (1/2H, m), to 4.73 (2H, d, J=5, 6 Hz), 7,14 (1H, d, J=8,4 Hz), 7,47 (1H, DD, J=2,0; and 8.4 Hz), a 7.62 (1H, d, J=2.0 Hz), by 8.22 (1H, d, J=8,4 Hz), to 8.45 (1H, DD, J=1,2; and 8.4 Hz), 9,52 (1H, s), of 10.58 (1H, s).

Example 37

4-[(3-Chloro-4-methoxybenzyl)amino]-1-[4-(2-hydroxyethoxy)piperidine]-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,68-to 1.77 (4H, m), 1,98-2,07 (2H, m), 2,98-of 3.07 (2H, m), 3,44-to 3.52 (2H, the, J=1, 6; and 8.4 Hz), to 9.57 (1H, s), is 10.68 (1H, ush.-C).

Example 38

2-[[1-[4-[(3-Chloro-4-methoxybenzyl)amino]-6-cyano-1-phthalazine]-4-piperidyl]oxy]acetic acid hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,69-to 1.82 (2H, m), 1,99 is 2.10 (2H, m), 2,98-to 3.09 (2H, m), 3,60-3,68 (1H, m), 3,83 (3H, s) 4,08 (2H, s), 4.72 in (2H, d, J=5, 6 Hz), 7,14 (1H, d, J=8,4 Hz), 7,46 (1H, DD, J=2,4; and 8.4 Hz), to 7.61 (1H, d, J=2.0 Hz), 8,24 (1H, d, J=8,4 Hz), 8,46 (1H, DD, J=1,2; and 8.4 Hz), 9,46 (1H, s), 10,46 (1H, ush.-C).

Example 39

4-[(3-Chloro-4-methoxybenzyl)amino]-1-[4-(2-hydroxy-1-methylethyl)piperidin]-6-phthalazinedione

1H-NMR (400 MHz, DMSO-d6) : of 0.85 (3H, d, J=6.4 Hz), 1,40-to 1.59 (4H, m), 1,64-of 1.73 (2H, m), 2,68-and 2.79 (2H, m), 3.33 and-3,47 (4H, m), of 3.78 (3H, m), and 4.40 (1H, t, J=5,2 Hz), 4,60 (2H, d, J=5.6 Hz), 7,06 (1H, d, J=8,4 Hz), 7,31 (1H, DD, J=2,0; and 8.4 Hz), 7,42 (1H, d, J=2.0 Hz), the 7.85 (1H, t, J=6.0 Hz), 8,03 (1H, d, J=8,4 Hz), 8,16 (1H, DD, J=1,6; and 8.4 Hz), cent to 8.85 (1H, d, J=0.8 Hz).

Example 40

2-[7-[4-[(3-Chloro-4-methoxybenzyl)amino]-6-cyano-1-phthalazine]-7-azaspiro[3.5]non-2-yl]acetic acid hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,45-of 1.53 (2H, m), 1,66-of 1.73 (2H, m), 1.77 in-of 1.84 (2H, m), 1,96-2,04 (2H, m), 2,34 (2H, d, J=7,6 Hz), to 3.02 (2H, ush.-C) 3,11 (2H, ush.-C), 3,82 (3H, c), of 4.67 (2H, s), 7,11 (1H, d, J=8,4 Hz), 7,40 (1H, DD, J=2,0; and 8.4 Hz), 7,54 (1H, d, J=2.0 Hz), 8,15 (1H, d, J=8,8 Hz), a 8.34 (1H, d, J=8,8 Hz), 9,24 (1H, s).

Example 41

1H-NMR (400 MHz, DMSO-d6) : 3,54-to 3.67 (2H, m), 3,80-to 3.92 (2H, m), 4,16 (2/3H, ush.-C) 4,29 (4/3H, ush.-C) of 4.54 (1H, t, J=5,2 Hz), 4,54-to 4.62 (1H, m), 5,16-5,32 (2H, m), 7,11 (1H, d, J=8,4 Hz), 7,34-7,40 (1H, m) to 7.50 (1H, s) of 8.37 (1H, d, J=8,4 Hz), 8,48-8,58 (1H, m), 9,12-of 9.21 (1H, m).

Example 42

4-[(3-Chloro-4-methoxybenzyl)amino]-1-[4-(1-hydroxyethyl)piperidino-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) with 1.07 (3H, d, J=6.0 Hz), 1,34 is 1.60 (3H, m) of 1.65 to 1.76 (2H, m), 1,86-of 1.94 (2H, m), 2,75-of 2.86 (2H, m), 3,55-3,63 (2H, m), 3,82 (3H, s), to 4.73 (2H, d, J=5.6 Hz), 7,13 (1H, d, J=8,8 Hz), of 7.48 (1H, DD, J=2,0; 8,8 Hz), 7,63 (1H, d, J=2.0 Hz), to 8.20 (1H, d, J=8,4 Hz), to 8.45 (1H, DD, J=1,2; and 8.4 Hz), of 9.56 (1H, s), 10,69 (1H, ush.-C)

Example 43

4-[(3-Chloro-4-methoxybenzyl)amino]-1-[4-fluoro-4-(hydroxymethyl)piperidino]-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,69-to 1.77 (2H, m), 1,83-of 2.08 (2H, m), 3,05-and 3.16 (2H, m), 3,48 (2H, d, J=20.0 Hz), 3,82 (3H, s), 4,74 (2H, d, J=5.6 Hz), 7,14 (1H, d, J=8,8 Hz), of 7.48 (1H, DD, J=2,0; 8,8 Hz), 7,63 (1H, d, J=2.0 Hz), compared to 8.26 (1H, d, J=8,4 Hz), 8,46 (1H, DD, J=1,2; and 8.4 Hz), to 9.57 (1H, s), of 10.73 (1H, ush.-C).

Example 44

4-[(3-Chloro-4-methoxybenzyl)amino]-1-[4-(hydroxymethyl)-4-methoxypiperidine]-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,71-to 1.86 (4H, m), 3.04 from-and 3.16 (2H, m), and 3.16 (3H, s) to 3.41 (2H, s), 3,83 (3H, s), 4.72 in (2) - Rev. W.-C).

Example 45

4-[(3-Chloro-4-methoxybenzyl)amino]-1-(2-hydroxy-6-azaspiro[3,4]Oct-6-yl)-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,00-1,08 (2H, m), 1,82-2,04 (4H, m), 2,19 to 2.35 (2H, m), 3,32 is-3.45 (2H, m), 3,55-of 3.60 (2H, m), of 3.80 (3H, s), 4.04 the-4,19 (1H, m), 4,56 (2H, ush.-C), 7,10 (1H, d, J=8,4 Hz), 7,37 (1H, ush.-C) to 7.50 (1H, ush.-C), scored 8.38 (1H, d, J=8,4 Hz), 8,45-8,73 (1H, m).

Example 46

4-[(3-Chloro-4-methoxybenzyl)amino]-1-[3-(hydroxymethyl) 2,5-dihydro-1H-1-pyrrolyl]-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : is 3.82 (3H, s), of 4.12 (2H, s), 4,45 of 4.83 (6N, m) of 5.84 (1H, ush.-C), 7,11 (1H, d, J=9 Hz), 7,33-7,56 (2H, m), to 8.45 (1H, d, J=9 Hz), 8,66-9,14 (2H, m).

Example 47

4-[(3-Chloro-4-methoxybenzyl)amino]-1-[(3R,4S)-3,4-di(hydroxymethyl) tetrahydro-1H-1-pyrrolyl]-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 2,50-to 2.57 (2H, m), 3,38-to 3.49 (2H, m), 3,56-of 3.60 (2H, m), 3,76-a 3.87 (4H, m), 3,81 (3H, s) 4,55 (2H, ush.-C), 7,10 (1H, d, J=8,4 Hz), was 7.36 (1H, d, J=7,6 Hz), 7,49 (1H, s), to 8.41 (1H, d, J=8,4 Hz), 8,68 (1H, d, J=8,4 Hz), 9,13 (1H, s).

Example 48

1-[4-[(3-Chloro-4-methoxybenzyl)amino]-6-cyano-1-phthalazine]-4-hydroxy-4-piperazinecarboxamide hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,56-of 1.64 (2H, m), 2,16-of 2.28 (2H, m), 3,12-3,24 (2H, m), 3,32-of 3.48 (2H, m), 3, =8,4 Hz), 8,44 (1H, d, J=8,4 Hz), 9,52-a 9.60 (1H, m).

Example 49

[4-(3-Chloro-4-methoxybenzyl)amino]-1-[4-(permitil)-4-hydroxypiperidine]-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,54-of 1.64 (2H, m), 1,80-of 1.52 (2H, m), 3,18-3,26 (2H, m), 3,32-3,44 (4H, m), 3,83 (3H, s), 4,22 (2H, d, J=7,6 Hz), 4.72 in (1H, d, J=6.0 Hz), 7,14 (1H, d, J=8,4 Hz), of 7.48 (1H, DD, J=8,4; and 1.6 Hz), a 7.62 (1H, d, J=1.6 Hz), 8,23 (1H, d, J=8,4 Hz), to 8.45 (1H, d, J=8,4 Hz), to 9.45 (1H, ush.-C).

Example 50

4-[(3-Chloro-4-methoxybenzyl)amino]-1-(4-hydroxylaminopurine)-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 2,50-2,52 (2H, m), 2,74 is 2.80 (2H, m), 3,26-to 3.35 (4H, m), 3,85 (3H, s), 4,71 (2H, ush.), 7,17 (1H, d, J=8,8 Hz), was 7.45 (1H, DD, J=8,8; 2.0 Hz), 7,60 (1H, d, J=2.0 Hz), a 8.34 (1H, d, J=8,4 Hz), 8,49 (1H, DD, J=8,4; 0,4 Hz), 9,34 (1H, d, J=0.4 Hz), 10,53 (1H, ush.).

Example 51

(anti)-2-[3-[4-[(3-Chloro-4-methoxybenzyl)amino]-6-cyano-1-phthalazine]-3-azabicyclo[3.3.1]non-9-yl]acetic acid hydrochloride

1H-NMR (400 MHz, DMSO-d6) : of 1.62 (1H, m), 1,75-2,00 (4H, m), 2,12 (1H, m), 2,52 (2H, d, J=8.1 Hz), 3,16-3,24 (2H, m), 3,68 is 3.76 (2H, m), 3,85 (3H, s), 4,74 (2H, s), 7,16 (1H, d, J=8.6 Hz), of 7.48 (1H, DD, J=1,8; 8.6 Hz), a 7.62 (1H, d, J=1,8 Hz), 8,23 (1H, d, J=8,4 Hz), 8,55 (1H, DD, J=1,3; and 8.4 Hz), 9,48 (1H, m).

Example 52

(endo)-4-[(3-Chloro-4-methoxybenzyl)amino]-1-(3-hydroxy-8-AZ is) : 1,81-of 1.88 (2H, m), 1,90-to 1.98 (2H, m), 2,19-of 2.30 (4H, m), 3,85 (3H, s), Android 4.04 (1H, m), 4,16-4.26 deaths (2H, m), 4,71 (2H, s), 7,16 (1H, d, J=8.6 Hz), 7,46 (1H, d, J=8.6 Hz), to 7.61 (1H, s), 8,29 (1H, d, J=8,4 Hz), of 8.47 (1H, DD, J=1,3; and 8.4 Hz), 9,44 (1H, m).

Example 53

(SYN)-4-[(3-Chloro-4-methoxybenzyl)amino]-1-(9-hydroxy-3-azabicyclo[3.3.1]non-3-yl)-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : of 1.53 (1H, m), 1,74 is 1.86 (2H, m), 1,87-of 1.93 (2H, m), 2.05 is with 2.14 (2H, m), is 2.37 (1H, m), 3,28-3,44 (2H, m), 3,41-3,61 (2H, m), 3,68 (1H, m), 3,85 (3H, s), to 4.73 (2H, s), to 7.15 (1H, d, J=8, 6 Hz), 7,47 (1H, d, J=8.6 Hz), a 7.62 (1H, s), by 8.22 (1H, d, J=8, 6 Hz), 8,54 (1H, d, J=8.6 Hz), 9,48 (1H, m).

Example 54

(SYN)-4-[(3-Chloro-4)amino]-1-(8-hydroxy-3-azabicyclo[3.2.1]Oct-3-yl)-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,75 is 1.96 (4H, m), 2,02-of 2.09 (2H, m), 3,06-3,18 (2H, m), 3,50-3,60 (2H, m), 3,86 (3H, s), 3,91 (1H, t, J=4,8 Hz), to 4.73 (2H, s), 7,16 (1H, d, J=8.6 Hz), 7,47 (1H, d, J=8.6 Hz), to 7.61 (1H, s), at 8.36 (1H, d, J=8.6 Hz), 8,48 (1H, DD, J=1.5 and 8.6 Hz), 9,43 (1H, m).

Example 55

(Exo)-4-[(3-Chloro-4-methoxybenzyl)amino]-1-(3-hydroxy-8-azabicyclo[3.2.1]Oct-8-yl)-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,68 of-1.83 (2H, m), 1,90-2,02 (4H, m), 3,85 (3H, s), of 3.97 (1H, m), 4,18-to 4.28 (2H, m), 4,70 (2H, s), to 7.15 (1H, d, J=8.6 Hz), 7,44 (1H, d, J=8.6 Hz), to 7.59 (1H, s), 8,29 (1H, d, J=8.6 Hz), to 8.45 (1H, d, J=8.6 Hz), 9,36 (1H, m).

Note the nitrile hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,69 to 1.76 (2H, m), 3,24-to 3.38 (2H, m), of 3.73-a 3.83 (2H, m), 3,85 (3H, s), 3,85-3,93 (2H, m), 4,11-4,20 (2H, m), to 4.73 (2H, s), 7,16 (1H, d, J=8.6 Hz), 7,47 (1H, d, J=8.6 Hz), a 7.62 (1H, s), at 8.36 (1H, d, J=8,4 Hz), charged 8.52 (1H, d, J=8,4 Hz), 9,43 (1H, m).

Example 57

(anti)-4-[(3-Chloro-4-methoxybenzyl)amino]-1-(3-hydroxy-9-azabicyclo[3.3.1]non-9-yl)-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,38-and 1.54 (4H, m) to 1.59 (1H, m), 1,90-2,02 (2H, m), 2,22 at 2.45 (3H, m), 3,86 (3H, s), a 3.87 (1H, m), 4,08-4,17 (2H, m), 4,69 (2H, s), 7,16 (1H, d, J=8.6 Hz), 7,44 (1H, d, J=8.6 Hz), 7,58 (1H, s), 8,07 (1H, d, J=8.6 Hz), 8,44 (1H, d, J=8.6 Hz), 9,29 (1H, m).

Example 58

N1-[3-[4-[(3-Chloro-4-methoxybenzyl)amino]-6-cyano-1-phthalazine]phenyl]ndimethylacetamide

1H-NMR (400 MHz, DMSO-d6) : 2,05 (3H, s), 3,81 (3H, s), was 4.76 (2H, d, J=6.0 Hz), to 7.09 (1H, d, J=8,4 Hz), 7,24 (1H, d, J=8.0 Hz), 7,38 (1H, DD, J=8.0 a; 1,6 Hz), was 7.45 (1H, DD, J=8,4; 8.0 Hz), to 7.50 (1H, d, J=1.6 Hz), to 7.67 (1H, d, J=8.0 Hz), 7,86 (1H, m), 7,92 (1H, d, J=8,4 Hz), 8,17 (1H, DD, J=8,4; and 1.6 Hz), 8,35 (1H, DD, J=6,0; 6,0 Hz), of 9.00 (1H, s), of 10.09 (1H, s).

Example 59

1-(3-AMINOPHENYL)-4-[(3-chloro-4-methoxybenzyl)amino]-6-ftal-synchronical hydrochloride

1H-NMR (400 MHz, DMSO-d6) : a 3.83 (3H, s), 4,89 (2H, ush.-C) 7,16 (1H, d, J=8.6 Hz), 7,38-7,44 (3H, m), 7,53 (1H, DD, J=8,6; 2.0 Hz), 7,58 to 7.62 (2H, m), 7,68 (1H, d, J=2.0 Hz), 8,02 (1H, d, J=8,4 Hz) is enyl]methanesulfonamide hydrochloride

1H-NMR (400 MHz, DMSO-d6) : a 3.06 (3H, s), of 3.84 (3H, s), a 4.86 (2H, d, J=5.6 Hz), to 7.15 (1H, d, J=8,4 Hz), 7,35 (1H, d, J=7,6 Hz), the 7.43 (1H, d, J=7,6 Hz) to 7.50 (1H, ush.-C), 7,53 (1H, DD, J=8,4; 2.0 Hz), 7,55 (1H, DD, J=7,6; and 7.6 Hz), 7,66 (1H, d, J=2.0 Hz), 8,03 (1H, d, J=8,8 Hz), 8,44 (1H, d, J=8,8 Hz), 9,60 (1H, ush.-C), 10,14 (1H, ush.-C).

Example 61

4-[(3-Chloro-4-methoxybenzyl)amino]-1-[4-(methylsulfinyl)phenyl]-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 2,84 (3H, s), 3,83 (3H, s), to 4.87 (2H, ush.-C) 7,16 (1H, d, J=8,4 Hz), 7,51 (1H, d, J=8,4 Hz), 7,66 (1H, ush.-C), 7,83 (2H, d, J=8,4 Hz), 7,92 (2H, d, J=8,4 Hz), 8,00 (1H, d, J=8,4 Hz), 8,43 (1H, d, J=8,4 Hz), 9,52-9, 60 (1H, m).

Example 62

4-[(3-Chloro-4-methoxybenzyl)amino]-1-[4-(methylsulphonyl)phenyl]-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : of 3.31 (3H, s), 3,82 (3H, s), 4,80 (2H, ush.-C), 7,12 (1H, d, J=8,8 Hz), the 7.43 (1H, DD, J=8,8; 2.0 Hz), 7,56 (1H, d, J=2.0 Hz), of 7.90 (2H, d, J=8.0 Hz), to 7.93 (1H, d, J=8,4 Hz), 8,11 (2H, d, J=8.0 Hz), of 8.28 (1H, d, J=8,4 Hz), 9,19-which 9.22 (1H, m).

Example 63

4-[(3-Chloro-4-methoxybenzyl)amino]-1-(4-formylphenyl)-6-ftal-synchronical of hydrochlorid

1H-NMR (400 MHz, DMSO-d6) : of 3.84 (3H, s), a 4.86 (2H, ush.-C) 7,16 (1H, d, J=8,4 Hz), 7,51 (1H, d, J=8,4 Hz), 7,66 (1H, ush.-C) 7,86 (2H, d, J=8.0 Hz), to 7.99 (1H, d, J=8,8 Hz), 8,13 (2H, d, J=8.0 Hz), 8,42 (1H, d, J=8,8 Hz), 9,48-at 9.53 (1H, m), 10,15 (1H, SL hydrochloride

1H-NMR (400 MHz, DMSO-d6) : of 3.84 (3H, s), to 4.62 (2H, s), 4,84 (2H, ush.-C) 7,16 (1H, d, J=8,4 Hz), 7,49 (1H, DD, J=8,4; 2.0 Hz), 7,55 (2H, d, J=8.0 Hz), 7,60 (2H, d, J=8.0 Hz), the 7.65 (1H, d, J=2.0 Hz), 8,02 (1H, d, J=8,4 Hz), 8,43 (1H, d, J=8,4 Hz), 9,50-9,58 (1H, m).

Example 65

4-[4-[(3-Chloro-4-methoxybenzyl)amino]-6-cyano-1-phthalazine]benzoic acid

1H-NMR (400 MHz, DMSO-d6) : of 3.84 (3H, s), was 4.76 (2H, d, J=6.0 Hz), 7,10 (1H, d, J=8,8 Hz), 7,38 (1H, DD, J=8,8; 2.0 Hz), to 7.50 (1H, d, J=2.0 Hz), 7,72 (2H, d, J=8,4 Hz), to $ 7.91 (1H, d, J=8,8 Hz), 8,08 (2H, d, J=8,4 Hz), 8,19 (1H, DD, J=8,4; and 1.6 Hz), 8,44 (1H, DD, J=6,0, 6,0 Hz), 9,01 (1H, d, J=1.6 Hz).

Example 66

4-[(3-Chloro-4-methoxybenzyl)amino]-1-(1,3-thiazol-2-yl)-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : of 3.80 (3H, s), 4,82 (2H, s), 7,13 (1H, d, J=8,4 Hz), 7,42 (1H, d, J=8,4 Hz), EUR 7.57 (1H, s), 7,94 (1H, d, J=3.6 Hz), 8,11 (1H, d, J=3.6 Hz), 8,46 (1H, d, J=8,4 Hz), 9,20-9,26 (1H, m) to 9.70 (1H, d, J=8,4 Hz).

Example 67

4-[(3-Chloro-4-methoxybenzyl)amino]-1-(3-hydroxy-3-methyl-1-butenyl)-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1.57 in (6N, (C), of 3.84 (3H, s), 4,84 (2H, s), to 7.15 (1H, d, J=8,8 Hz), 7,46 (1H, DD, J=8,8; 2.0 Hz), to 7.61 (1H, d, J=2.0 Hz), a 8.34 (1H, d, J=8,4 Hz), charged 8.52 (1H, DD, J=8,4; 0,4 Hz) 9,04 (1H, d, J=0.4 Hz), 10,36 (1H, ush.).

Example 68

4-[(3-Chloro-4-methoxybenzyl)amino]-1-(3 ) : of 3.84 (3H, C) of 4.49 (2H, s), to 4.81 (2H, d, J=4.0 Hz), 7,14 (1H, d, J=8,4 Hz), the 7.43 (1H, DD, J=8,4; and 2.4 Hz), 7,58 (1H, d, J=2.4 Hz), 8,35 (1H, d, J=8,8 Hz), 8,48 (1H, DD, J=8,8; 0,8 Hz), 9.28 are (1H, d, J=0.8 Hz), 9,92 (1H, ush.).

Example 69

4-[(3-Chloro-4-methoxybenzyl)amino]-1-[3,4-dihydroxy-3-(hydroxymethyl)-1-butenyl-6-phthalazinedione

1H-NMR (400 MHz, DMSO-d6) : 3,54-3,66 (4H, m), 3,82 (3H, s), was 4.76 (2H, d, J=5,2 Hz), to 4.98 (2H, t, J=5,2 Hz), 5,62 (1H, s), 7,10 (1H, d, J=8,8 Hz), was 7.36 (1H, DD, J=8,8; 2.0 Hz), 7,49 (1H, d, J=2.0 Hz), 8,29-to 8.34 (1H, m), 8,51 (1H, t, J=5,2 Hz), 8,96 (1H, s).

Example 70

4-[(3-Chloro-4-methoxybenzyl)amino]-1-[3-(dimethylamino)-1-PROPYNYL]-6-phthalazinedione the dihydrochloride

1H-NMR (400 MHz, DMSO-d6) : 2.91 in (6N, (C) a 3.83 (3H, s) to 4.52 (2H, s), a 4.83 (2H, d, J=4,8 Hz), 7,13 (1H, d, J=8,8 Hz), 7,42 (1H, DD, J=8,8; 2.0 Hz), 7,56 (1H, d, J=2.0 Hz), 8,40 (1H, DD, J=8,4; and 1.4 Hz), 8,46 (1H, d, J=8,4 Hz), 9,27 (1H, d, J=1.4 Hz), 9,76 (1H, ush.), is 11.39 (1H, ush.).

Example 71

2-[[3-[4-[(3-Chloro-4-methoxybenzyl)amino]-6-cyano-1-phthalazine]-1,1-dimethyl-2-PROPYNYL]oxy]acetic acid hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,62 (6N, (C), of 3.84 (3H, c), 4,21-4,24 (2H, m), 4,77-4,82 (2H, ush.), 7,11-to 7.15 (1H, m), 7,38-7,42 (1H, m), 7,51-of 7.55 (1H, m), 8,19-8,24 (1H, m), scored 8.38-8,42 (1H, m), 9,12-9,16 (1H, m).

Example 72

4-[(3-Chloro-4-methoxybenzyl)amino]-1-[3-(2-hydroxyethoxy)-3-methyl-1-Buti is t, J=5.6 Hz), the 3.65 (2H, t, J=5.6 Hz), of 3.84 (3H, s), is 4.85 (2H, d, J=4,8 Hz), 7,14 (1H, d, J=8.6 Hz), 7,46 (1H, DD, J=8,6; 2.2 Hz), to 7.61 (1H, d, J=2.2 Hz), 8,30 (1H, d, J=8,4 Hz), 8,48 (1H, DD, J=8,4; 1,6 Hz), 9,42 (1H, d, J=1.6 Hz), 10,41 (1H, ush.).

Example 73

4-[(3-Chloro-4-methoxybenzyl)amino]-1-[3-(4-hydroxypiperidine)-3-methyl-1-butenyl)-6-phthalazinedione the dihydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,79-2,04 (10H, m), 2,12-of 2.23 (1H, m), 3.04 from-3,19 (1H, m), 3,26-3,37 (2H, m), 3,54-of 3.77 (1H, m), 3,82 (3H, s), a 4.83 (2H, d, J=5, 6 Hz), 7,12 (1H, d, J=8,4 Hz), the 7.43 (1H, DD, J=8,4; 1.2 Hz), 7,56 (1H, d, J=1.2 Hz), scored 8.38 (1H, DD, J=8,4; 0,8 Hz), 8,43 (1H, d, J=8,4 Hz), of 9.30 (1H, d, J=0.8 Hz), to 9.91 (1H, ush.), 11,40-11,66 (1H, m).

Example 74

4-[(3-Chloro-4-methoxybenzyl)amino]-1-(3-methyl-3-tetrahydro-1H-1-pyrrolyl-1-butenyl)-6-phthalazinedione the dihydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,85 (6N, (C), 1,90-of 2.08 (4H, m), 3,30-of 3.42 (2H, m), 3,60-and 3.72 (2H, m), 3,83 (3H, s), 4,80 (2H, d, J=5,2 Hz), 7,11 (1H, d, J=8,4 Hz), 7,39 (1H, DD, J=8,4; 2.0 Hz), 7,52 (1H, d, J=2.0 Hz), of 8.28 (1H, d, J=8,4 Hz), at 8.36 (1H, DD, J=8,4; 0,8 Hz), 9,14 (1H, d, J=0.8 Hz), was 9.33 (1H, ush.), 11,89 (1H, m).

Example 75

1-(4-Hydroxypiperidine)-4-[[4-methoxy-3-(trifluoromethyl)benzyl]amino]-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,62-of 1.73 (2H, m), 1,90 of 1.99 (2H, m), 2,97-of 3.07 (2H, m), 3,40-to 3.52 (2H, m), 3.72 points-of 3.80 (1H, m) to 3.89 (3H, s), 4,80 (2H, d, J=5.6 Hz), 7,28 the p 76

1-(4-Hydroxypiperidine)-4-[(3-iodine-4-methoxybenzyl)amino]-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,62-of 1.73 (2H, m), 1,90-2,00 (2H, m), 2,98-is 3.08 (2H, m), 3,40-3,50 (2H, m), 3.72 points-of 3.80 (1H, m), 3,82 (3H, s), and 4.68 (2H, d, J=4,8 Hz), 7,02 (1H, d, J=8,8 Hz) to 7.50 (1H, DD, J=8,8; 2.2 Hz), to 7.93 (1H, d, J=2.2 Hz), 8,24 (1H, d, J=8.6 Hz), 8,46 (1H, DD, J=8,6; 0,8 Hz), to 9.32 (1H, d, J=0.8 Hz), of 10.05 (1H, ush.).

Example 77

4-[(3-Bromo-4-methoxybenzyl)amino]-1-(4-hydroxypiperidine)-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,62-of 1.73 (2H, m), 1,90 of 1.99 (2H, m), 2,98-of 3.07 (2H, m), 3,39-3,50 (2H, m), 3.72 points-of 3.80 (1H, m), of 3.84 (3H, s), 4,71 (2H, d, J=4,8 Hz), 7,13 (1H, d, J=8.6 Hz), 7,49 (1H, DD, J=8,6; 2.2 Hz), of 7.75 (1H, d, J=2.2 Hz), 8,24 (1H, d, J=0.4 Hz), 8,46 (1H, DD, J=8,4; 0,8 Hz), 9,34 (1H, d, J=0.8 Hz), 10,11 (1H, ush.).

Example 78

4-[(3-Bromo-4-methoxybenzyl)amino]-1-[3-(hydroxymethyl)tetrahydro-1H-1-pyrrolyl]-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,72 is 1.86 (1H, m), 1,99-2,12 (1H, m), 2,39 is 2.51 (1H, m), 3,42 (1H, DD, J=7,2; and 10.8 Hz), 3,48 (1H, DD, J=6,0; and 10.8 Hz), 3,60-are 3.90 (4H, m), of 3.80 (3H, s), 7,06 (1H, d, J=8,4 Hz), 7,38-7,46 (1H, m), of 7.64 (1H, s), to 8.40 (1H, DD, J=1,6; 8,8 Hz), 8,65 (1H, d, J=8.0 Hz), 9,18 (1H, s).

Example 79

4-[(3-Bromo-4-methoxybenzyl)amino]-1-[(3S)-3-(hydroxymethyl)tetrahydro-1H-1-pyrrolyl]-6-phthalazinedione ghidrah the 8 (3H, C), 4,58 (2H, J=6.0 Hz), 4,69 (1H, t, J=5, 6 Hz), 7,03 (1H, d, J=8,4 Hz), was 7.36 (1H, DD, J=2,0; and 8.4 Hz), EUR 7.57 (1H, d, J=2.0 Hz), to 7.59 (1H, d, J=6.0 Hz), 8,13 (1H, DD, J=1,2; and 8.8 Hz), by 8.22 (1H, d, J=8,8 Hz), 8,81 (1H, d, J=0.8 Hz).

Example 80

4-[(3-Bromo-4-methoxybenzyl)amino]-1-[(3R)-3-(hydroxymethyl)tetrahydro-1H-1-pyrrolyl]-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,72 is 1.86 (1H, m), 1,99-2,12 (1H, m), 2,39 is 2.51 (1H, m), 3,42 (1H, DD, J=7,2; and 10.8 Hz), 3,48 (1H, DD, J=6,0; and 10.8 Hz), 3,60-are 3.90 (4H, m), of 3.80 (3H, s), 7,06 (1H, d, J=8,8 Hz), 7,38-7,46 (1H, m), the 7.65 (1H, s), to 8.40 (1H, d, J=8,8 Hz), 8,59-8,68 (1H, m), 9,26 (1H, s).

Example 81

4-[(3-Bromo-4-methoxybenzyl)amino]-1-[4-(2-hydroxyethyl)piperidino]-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,68-to 1.77 (2H, m), 1,96-2,07 (2H, m), to 3.02 (2H, t, J=12.0 Hz), 3,38-3,59 (6N, m), of 3.80 (3H, s), 3,81-3,99 (3H, m), 4.72 in (2H, d, J=6.0 Hz), 7,10 (1H, d, J=8.6 Hz), 7,49 (1H, d, J=8.6 Hz), 7,76 (1H, s), by 8.22 (1H, d, J=8.6 Hz), to 8.45 (1H, d, J=8.6 Hz), 9,50 (1H, s).

Example 82

4-[(3-Bromo-4-methoxybenzyl)amino]-1-(2-hydroxy-7-azaspiro[3.5]non-7-yl)-6-phthalazinedione of hydrochlorid

1H-NMR (400 MHz, DMSO-d6) : 1,58-of 1.66 (2H, m), by 1.68 to 1.76 (4H, m), 2,14-of 2.23 (2H, m), is 3.08 (2H, ush.-C) of 3.13 (2H, ush.-C) 4,08-4,17 (1H, m), to 4.73 (1H, d, J=5.6 Hz), 7,10 (1H, d, J=8,4 Hz), 7,52 (1H, DD, J=2,0; and 8.4 Hz), of 7.70 (1H, d, J=2.0 Hz), to 8.20 (1H, d, J=8,4 Hz), 8,44 (1H, DD, J=1,6; and 8.4 Hz),talkingabout hydrochloride

Example 84

4-[(3-Bromo-4-methoxybenzyl)amino]-1-[4-(hydroxymethyl)piperidino]-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,41-of 1.52 (2H, m), 1,58 was 1.69 (1H, m), 1,79 is 1.86 (2H, m), 2,85-to 2.94 (2H, m), 3,35 is 3.40 (2H, m) and 3.59 (2H, d, J=12,8 Hz), of 3.84 (3H, s), 4,71 (2H, d, J=5,2 Hz), 7,13 (1H, d, J=8,4 Hz) to 7.50 (1H, DD, J=8,4; 2.0 Hz), 7,76 (1H, d, J=2.0 Hz), by 8.22 (1H, d, J=8, 4 Hz), of 8.47 (1H, DD, J=8,4; 0,8 Hz), 9,38 (1H, ush.), of 10.21 (1H, ush.).

Example 85

(endo)-4-[(3-Bromo-4-methoxybenzyl)amino]-1-(3-hydroxy-8-azabicyclo[3.2.1]Octo-8-yl)-6-phthalazinedione

1H-NMR (400 MHz, DMSO-d6) : 1,70-of 1.95 (4H, m), 2,14-of 2.28 (4H, m), 3,82 (3H, s) to 4.15 (1H, m), 4.09 to (2H, m), 4,49 (1H, d, J=2.2 Hz), to 4.62 (2H, d, J=5.5 Hz), 7,05 (1H, d, J=8.6 Hz), 7,38 (1H, DD, J=2,2; 8.6 Hz), 7,60 (1H, d, J=2.2 Hz), 7,72 (1H, t, J=5.5 Hz), 8,11 (1H, d, J=8.6 Hz), 8,18 (1H, DD, J=1.5 and 8.6 Hz), 8,87 (1H, d, J=1.5 Hz).

Example 86

1-(4-Hydroxypiperidine)-4-[(4-methoxy-3-methylbenzyl)amino]-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,62-of 1.73 (2H, m), 1,90 of 1.99 (2H, m), of 2.15 (3H, s), 2,98-of 3.07 (2H, m), 3,42-3,50 (2H, m), 3.72 points-of 3.80 (1H, m), of 3.78 (3H, s), 4,67-4,70 (2H, m) 6,94 (1H, d, J=8,2 Hz), 7,28 (1H, d, J=2.0 Hz), 7,31 (1H, DD, J=8,2; 2.0 Hz), 8,23 (1H, d, J=8,4 Hz), of 8.47 (1H, DD, J=8,4; 1.2 Hz), to 9.45 (1H, d, J=1.2 Hz), accounted for 10.39 (1H, ush.).

Example 87

1-(2-Hydroxy-7-azaspiro[3.5]non-7-yl)-4-MSO-d6) : 1,57-of 1.66 (2H, m), 1,67-1,8 (4H, m), 2,11 (3H, s), 2,14-of 2.23 (2H, m), of 3.07 (2H, ush.-C) of 3.12 (2H, ush.-C), 3,55-3,61 (1H, m), 4,07-4,17 (1H, m), 4,69 (1H, d, J=5,2 Hz) 6,91 (1H, d, J=8,4 Hz), 7,29 (1H, s), 7,31 (1H, DD, J=2,0; and 8.4 Hz), 8,19 (1H, d, J=8,4 Hz), 8,44 (1H, DD, J=1,2; and 8.4 Hz), of 9.56 (1H, s), 10,59 (1H, ush.-C).

Example 88

1-[4-Fluoro-4-(hydroxymethyl)piperidino]-4-[(4-methoxy-3-methylbenzyl)amino]-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,88-2,10 (4H, m), of 2.15 (3H, s), is 3.08-3,17 (2H, m), 3,40-3,50 (2H, m), 3,51 (2H, d, J=19.6 Hz), of 3.78 (3H, s), and 4.68 (2H, d, J=5,2 Hz) 6,94 (1H, d, J=8.0 Hz), 7,28-7,33 (2H, m), of 8.28 (1H, d, J=8,4 Hz), of 8.47 (1H, DD, J=8,4; and 1.4 Hz), 9,42 (1H, DD, J=1.4 Hz), 10,26 (1H, ush.), 13,96 (1H, ush.).

Example 89

1-[4-(Hydroxymethyl)piperidino]-4-[(3-methoxy-4-methylbenzyl)amino]-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,41-of 1.52 (2H, m), 1,58 by 1.68 (1H, m), 1,79-to 1.87 (2H, m), of 2.15 (3H, s), 2,82-of 2.93 (2H, m), 3,30 is 3.40 (2H, m) to 3.58 (2H, d, J=12,8 Hz), of 3.78 (3H, s), of 4.67 (2H, d, J=5,2 Hz) 6,94 (1H, d, J=8,8 Hz), 7,26-to 7.32 (2H, m), by 8.22 (1H, d, J=8,4 Hz), of 8.47 (1H, DD, J=8,4; 0,8 Hz), 9,36 (1H, ush.), to 10.09 (1H, ush.).

Example 90

(endo)-1-(3-Hydroxy-8-azabicyclo[3.2.1]Octo-8-yl)-4-[(4-methoxy-3-methylbenzyl)amino]-6-phthalazinedione

1H-NMR (400 MHz, DMSO-d6) : 1,79-of 1.93 (4H, m) to 2.13 (3H, s), 2,13-of 2.27 (4H, m in), 3.75 (3H, s), a 4.03 (1H, m), 4,08 (2H, m), 4,49 (1H, d, J=2,2 CLASS="ptx2">

Example 91

1-[3-(Hydroxymethyl)tetrahydro-1H-1-pyrrolyl]-4-[(4-methoxy-3-methylbenzyl)amino]-6-phthalazinedione

1H-NMR (400 MHz, DMSO-d6) : 1,67 (1H, m), from 2.00 (1H, m) of 2.16 (3H, s), of 2.38 (1H, m), 3,36-3,61 (6N, m in), 3.75 (3H, s), 4,58 (2H, d, J=5.5 Hz), and 4.68 (1H, t, J=5.5 Hz), 6,86 (1H, d, J=8.1 Hz), 7,16-7,22 (2H, m) to 7.50 (1H, t, J=5.3 Hz), 8,15 (1H, DD, J=1.5 and 8.6 Hz), 8,24 (1H, DD, J=8.6 Hz), 8,88 (1H, d, J=1.5 Hz).

Example 92

4-[(3-Fluoro-4-methoxybenzyl)amino]-1-(4-hydroxypiperidine)-6-phthalazinedione

1H-NMR (400 MHz, DMSO-d6) : 1,60-of 1.73 (2H, m), 1,88-of 1.97 (2H, m), 2,86-to 2.94 (2H, m), 3,42-3,50 (2H, m), 3,64-3,71 (1H, m), of 3.80 (3H, s), to 4.62 (2H, d, J=5.4 Hz), of 4.77 (1H, d, J=2.0 Hz), to 7.09 (1H, t, J=8,2 Hz), 7,18 (1H, d, J=8,2 Hz), 7.23 percent (1H, DD, J=12, 0mm; 2.0 Hz), to 7.84 (1H, t, J=5.4 Hz), of 8.04 (1H, d, J=8,4 Hz), to 8.20 (1H, DD, J=8,4; 1.2 Hz), 8,89 (1H, d, J=1.2 Hz).

Example 93

4-[(4-Chloro-3-methoxybenzyl)amino]-1-(4-hydroxypiperidine)-6-phthalazinedione

1H-NMR (400 MHz, DMSO-d6) : 1,60-1,72 (2H, m), 1,87 is 1.96 (2H, m), 2,86-2,95 (2H, m), 3,31-3,39 (2H, m), 3,68 (1H, m), of 3.84 (3H, s), 4.72 in (2H, d, J=5.5 Hz), 4,74 (1H, d, J=4, 2 Hz), 6,98 (1H, DD, J=1,8; 8,1 Hz), 7,20 (1H, d, J=1,8 Hz), 7,34 (1H, d, J=8.1 Hz), 7,92 (1H, t, J=5.5 Hz), 8,07 (1H, d, J=8.6 Hz), 8,21 (1H, DD, J=1.5 and 8.6 Hz), of 8.92 (1H, d, J=1.5 Hz).

Example 94

4-[(3-Cyano-4-methoxybenzyl)amino]-1-(4-hydroxypiperidine)-6-phthalazinedione, m), of 3.7-3.8 (1H, m), 3,90 (3H, s), 4,74 (2H, d, J=5.6 Hz), 7,27 (1H, d, J=9,2 Hz), 7,79 (1H, DD, J=2,0; 8,8 Hz), 7,87 (1H, d, J=2.0 Hz), 8,24 (1H, d, J=8,4 Hz), of 8.47 (1H, DD, J=1,2; and 8.4 Hz), 9,38 (1H, C).

Example 95

(endo)-4-[(3-Cyano-4-methoxybenzyl)amino]-1-(3-hydroxy-8-azabicyclo[3.2.1]Oct-8-yl)-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,9 is 1.96 (4H, m), 2,17-to 2.29 (4H, m), 3,91 (3H, s), Android 4.04 (1H, m), is 4.15 (2H, m), and 4.68 (2H, s), 7,25 (1H, d, J=8.6 Hz), 7,74 (1H, d, J=8.6 Hz), 7,80 (1H, s), 8,21 (1H, d, J=8.6 Hz), a 8.34 (1H, m), 9,07 (1H, m).

Example 96

4-[(3-Cyano-4-methoxybenzyl)amino]-1-[3-(hydroxymethyl)tetrahydro-1H-1-pyrrolyl]-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : of 1.84 (1H, m), is 2.09 (1H, m), 2,48 (1H, m), 3,40-3,55 (2H, m), 3,64-are 3.90 (4H, m), 3,91 (3H, s), 4,59 (2H, m), 7,24 (1H, d, J=8,8 Hz), 7,74 (1H, d, J=8,8 Hz), 7,79 (1H, s), 8,42 (1H, d, J=9.3 Hz), to 8.70 (1H, m) to 9.15 (1H, m).

Example 97

4-[(3-Ethyl-4-methoxybenzyl)amino]-1-(4-hydroxypiperidine)-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : to 1.14 (3H, t, J=7.5 Hz), 1,63-of 1.74 (2H, m), 1,90 for 2.01 (2H, m), to 2.57 (2H, q, J=7, 5 Hz), 2,97-is 3.08 (2H, m), 3,40-of 3.54 (2H, m in), 3.75 (1H, m), with 3.79 (3H, s), 4,69 (2H, s), to 6.95 (1H, d, J=8,2 Hz), 7,26-to 7.35 (2H, m), of 8.25 (1H, d, J=8.6 Hz), 8,18 (1H, DD, J=1,3; 8.6 Hz), 9,44 (1H, m).

Example 98

4-[(3-Chloro-4-methoxyphenethyl)amino]-1-(2-hydroc/SUB>) : 1,58-of 1.66 (2H, m), 1,67-of 1.78 (4H, m), 2,14-of 2.23 (2H, m), 2,92-a 3.01 (2H, m), of 3.07 (2H, s), 3,11 (2H, s), 3,70-3,82 (3H, m), of 3.80 (3H, s), 4,08-4,18 (1H, m), 7,06 (1H, d, J=8,4 Hz), 7,26 (1H, DD, J=2,0; and 8.4 Hz), the 7.43 (1H, d, J=2.0 Hz), 8,19 (1H, d, J=8,4 Hz), 8,44 (1H, DD, J=1,2; and 8.4 Hz), of 9.55 (1H, s), of 10.47 (1H, ush.-C) to 13.9 (1H, ush.-C).

Example 99

4-[(3-Chloro-4-methoxyphenethyl)amino]-1-[4-(2-hydroxyethoxy)piperidine]-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,68-to 1.77 (2H, m), 2.00 in to 2.06 (2H, m), was 2.76 (2H, t, J=8.0 Hz), 3,03 (2H, t, J=12.0 Hz), 3,32 (10H, m in), 3.75 (2H, d, J=8.0 Hz), 3,81 (3H, s), 7,07 (1H, d, J=8.6 Hz), 7,25 (1H, d, J=8.6 Hz), the 7.43 (1H, s), 8,24 (1H, d, J=8.6 Hz), to 8.45 (1H, d, J=8.6 Hz), to 9.32 (1H, s).

Example 100

4-[(3-Chloro-4-methoxyphenethyl)amino]-1-[4-fluoro-4-(hydroxide-Tyl)piperidino]-6-phthalazinedione

1H-NMR (400 MHz, DMSO-d6) : 1,82-to 2.06 (4H, m), 2,83-to 2.94 (2H, m), 3.04 from-3,14 (2H, m), 3,24-3,30 (1H, m), 3,49 (2H, DD, J=10,2; 6,0 Hz), 3,54-of 3.60 (1H, m), 3,64-3,70 (2H, m), of 3.80 (3H, s), of 5.03 (1H, DD, J=6,0; 6,0 Hz), 7,05 (1H, d, J=12,6 Hz), 7,19 (1H, DD, J=12,6; 2.0 Hz), 7,32 (1H, d, J=2.0 Hz), 7,40 was 7.45 (1H, m), 8,08 (1H, d, J=8,4 Hz), 8,18 (1H, d, J=8,4 Hz), 8,82 (1H, ush.C).

Example 101

(endo)-4-[(3-Chloro-4-methoxyphenethyl)amino]-1-(3-hydroxy-8-azabicyclo[3.2.1]Oct-8-yl)-6-phthalazinedione

1H-NMR (400 MHz, DMSO-d6) : 1,78-of 1.94 (4H, m), 2,14-of 2.28 (4H, m), of 2.92 (2H, t, J=7,0 Hz) to 3.67 (2H, q, J=7, 0 Hz),8,6 Hz), 8,17 (1H, DD, J=1.5 and 8.6 Hz), 8,80 (1H, d, J=1.5 Hz).

Example 102

4-[(3-Chloro-4-methoxyphenethyl)amino]-1-[3-(hydroxymethyl)tetrahydro-1H-1-pyrrolyl]-6-phthalazinedione

1H-NMR (400 MHz, DMSO-d6) : 1,68 (1H, m), from 2.00 (1H, m), is 2.40 (1H, m), of 2.92 (2H, t, J=7.5 Hz), 3,37-3,70 (8H, m), 3,82 (3H, s), 4,69 (1H, d, J=5.3 Hz), 7,06 (1H, d, J=8.6 Hz), 7,16 (1H, m), 7,20 (1H, DD, J=2,0; 8.6 Hz), 7,33 (1H, d, J=2.0 Hz), 8,15 (1H, DD, J=1,3; 8.6 Hz), of 8.25 (1H, d, J=8.6 Hz), 8,78 (1H, m).

Example 103

4-[(3,4-Dichlorobenzyl)amino]-1-(4-hydroxypiperidine)-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,61-1,72 (2H, m), 1,90-2,00 (2H, m), 3,01-3,18 (2H, m), 3,40-to 3.52 (2H, m), 3.72 points-of 3.80 (1H, m), and 4.75 (2H, d, J=5,2 Hz), 7,49 (1H, DD, J=8,6; 2.0 Hz), 7,66 (1H, d, J=8.6 Hz), 7,79 (1H, d, J=2.0 Hz), of 8.25 (1H, d, J=8.6 Hz), of 8.47 (1H, DD, J=8,6; 1.0 Hz), 9,36 (1H, d, J=1.0 Hz), 10,24 (1H, ush.).

Example 104

1-[6-Bromo-4-[(3-chloro-4-methoxybenzyl)amino]-1-phthalazine]-4-piperidinol hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,59 by 1.68 (2H, m), 1.85 to was 1.94 (2H, m), 2,94-is 3.08 (2H, m), 3,45-3,55 (2H, m), 3,70 is 3.76 (1H, m), 3,83 (3H, s), 4,69 (2H, d, J=4,8 Hz), 7,14 (1H, d, J=8,4 Hz), 7,44 (1H, d, J=8,4 Hz), to 7.59 (1H, s), 8,01 (1H, d, J=8,8 Hz), compared to 8.26 (1H, d, J=8,8 Hz), 9,18 (1H, s).

Example 105

1-[4-[(3-Chloro-4-methoxybenzyl)amino]-6-(1H-1-pyrazolyl)-1-phthalazine]-4-piperidinol hydrochloride

Example 106

7-[4-[(3-Chloro-4-methoxybenzyl)amino]-6-(1H-1-pyrazolyl)-1-phthalazine]-7-azaspiro[3.5]nonan-2-ol hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,55 by 1.68 (2H, m), 1,68 and 1.80 (4H, m), 2,14 was 2.25 (2H, m), to 3.0-3.2 (4H, m), 3,82 (3H, s), 4,14 (1H, Hep., J=7,2 Hz), 4.72 in (2H, m), 6,72 (1H, t, J=2 Hz), 7,14 (1H, d, J=8,4 Hz), 7,47 (1H, d, J=8,4 Hz), a 7.62 (1H, s), to 7.93 (1H, d, J=1.6 Hz), to 8.20 (1H, d, J=9,2 Hz), at 8.60 (1H, DD, J=2,0; 9,2 Hz), to 8.94 (1H, d, J=2.4 Hz), 9,43 (1H, s).

Example 107

[1-[4-[(3-Chloro-4-methoxybenzyl)amino]-6-(1H-1-pyrazolyl)-1-phthalazine]-4-fluoro-4-piperidinyl]methanol hydrochloride

1H-NMR (400 MHz, DMSO-d6) : of 1.85 to 2.0 (2H, m), are 1.95 and 2.1 (2H, m), 3,05 is 3.2 (2H, m), 3,4-3,6 (2H, m), 3,51 (2H, d, J=20 Hz), 3,83 (3H, s), 4,74 (2H, d, J=5,2 Hz), 6,72 (1H, t, J=1.6 Hz), 7,14 (1H, d, J=8,8 Hz), of 7.48 (1H, d, J=8,4 Hz), to 7.64 (1H, s), to 7.93 (1H, d, J=1.6 Hz), of 8.25 (1H, d, J=9,2 Hz), 8,61 (1H, DD, J=2,0;9,2 Hz), of 8.95 (1H, s), 9,44 (1H, c).

Example 108

1-[4-[(3-Bromo-4-methoxybenzyl)amino]-6-(1H-1-pyrazolyl)-1-phthalazine]-4-piperidinol hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,6-of 1.74 (2H, m), 1,87-2,0 (2H, m), 2,9-3,1 (2H, m), 3,4-3,55 (2H, m), of 3.7-3.8 (1H, m), 3,81 (3H, s), 4,65 of 4.8 (2H, m), 6,72 (1H, m), 7,10 (1H, d, J=8,8 Hz), 7,53 (1H, d, J=8.0 Hz), 7,79 (1H, s), to 7.93 (1H, d, J=1.2 Hz), 8,21 (Ino]-6-(1H-1,2,3-triazole-1-yl)-1-phthalazine]-4-piperidinol hydrochloride

1H-NMR (400 MHz, DMSO-d6) : of 1.62 and 1.75 (2H, m), 1,9-2,0 (2H, m), 3,0-3,1 (2H, m), 3,3-to 3.58 (2H, m), of 3.7-3.8 (1H, m), 3,83 (3H, s), to 4.73 (2H, d, J=5.6 Hz), to 7.15 (1H, d, J=8,8 Hz), 7,46 (1H, d, J=8,4 Hz), a 7.62 (1H, s), 8,13 (1H, m), 8,32 (1H, d, J=8,8 Hz), 8,68 (1H, d, J=9,2 Hz), 9,17 (1H, s), of 9.56 (1H, s).

Example 110

4-[(3-Chloro-4-methoxybenzyl)amino]-1-(4-hydroxypiperidine)-6-phthalazinone O6-methyloxime hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,60-1,70 (2H, m), 1,87 is 1.70 (2H, m), 2,96 was 3.05 (2H, m), 3,30-3,50 (2H, m), 3,68-of 3.78 (1H, m), 3,83 (3H, s) to 3.99 (3H, s), 4,66-to 4.73 (2H, m), 7,14 (1H, d, J=8 Hz), 7,42 (1H, DD, J=2; 8 Hz), EUR 7.57 (1H, d, J=2 Hz), 8,13 (1H, d, J=8 Hz), of 8.28 (1H, d, J=8 Hz), 8,39 (1H, s), to 8.94 (1H, ush.-C).

Example 111

4-[(3-Chloro-4-methoxybenzyl)amino]-1-(4-hydroxypiperidine)-6-phthalazinone O6-acyloxy hydrochloride

1H-NMR (400 MHz, DMSO-d6) : of 1.28 (3H, t, J=6 Hz), 1.60-to of 1.73 (2H, m), 1,87-to 1.98 (2H, m), 2,94-of 3.06 (2H, m), 3,39-to 3.52 (2H, m), 3,68-of 3.78 (1H, m), 3,83 (3H, s), 4,25 (2H, q, J=6 Hz), 4,67-4,74 (2H, m), 7,13 (1H, d, J=9 Hz), 7,42 (1H, d, J=9 Hz), 7,58 (1H, s), 8,13 (1H, d, J=8 Hz), 8,30 (1H, d, J=8 Hz), 8,39 (1H, s), 8,97 (1H, s).

Example 112

4-[(3-Chloro-4-methoxybenzyl)amino]-1-(4-hydroxypiperidine)-6-phthalazinone O6-benzyloxy hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,59-1,71 (2H, m), 1,87 is 1.96 (2H, m), 2,94 was 3.05 (2H, m), 3,37-3,51 (2N, is), 9,04 (1H, ush.-C).

Example 113

4-[(3-Chloro-4-methoxybenzyl)amino]-1-[3-fluoro-3-(hydroxymethyl)tetrahydro-1H-1-pyrrolyl]-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 2,09-of 2.28 (2H, m), 3,50-4,05 (6N, m), 3,81 (3H, s), of 4.66 (2H, s), 7,11 (1H, d, J=8.0 Hz), the 7.43 (1H, d, J=8.0 Hz), 7,58 (1H, s), 8,43 (1H, d, J=8,4 Hz), 8,53 (1H, s), to 9.45 (1H, s).

Example 114

4-[(3-Chloro-4-methoxybenzyl)amino]-1-(3-hydroxy-1-oxa-8-azaspiro[4.5]DECA-8-yl)-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,65-of 1.85 (3H, m), 1,87 is 2.01 (2H, m), 3,16-3,63 (8H, m), 3,82 (3H, s), 4,32 (1H, s), to 4.73 (2H, d, J=4,8 Hz), 7,13 (1H, d, J=8,4 Hz), of 7.48 (1H, d, J=8.0 Hz), a 7.62 (1H, s) 8,23 (1H, d, J=8.0 Hz), 8,44 (1H, d, J=8.0 Hz), to 9.57 (1H, s), 10,78 (1H, s).

Example 115

4-[(3-Chloro-4-methoxybenzyl)amino]-1-[2-(1-hydroxycyclopent)-1-ethinyl]-6-fadeinterval

1H-NMR (400 MHz, DMSO-d6) : 1,69-to 1.86 (4H, m), 1,97-2,04 (4H, m), 3,82 (3H, s), and 4.75 (2H, d, J=5.4 Hz), the ceiling of 5.60 (1H, s), 7,10 (1H, d, J=8,8 Hz), was 7.36 (1H, DD, J=8,8; 1.2 Hz), 7,49 (1H, d, J=1.2 Hz), 8,19 (1H, d, J=8,8 Hz), 8,31 (1H, DD, J=8,8; 0.6 Hz), charged 8.52 (1H, t, J=5.4 Hz), 8,97 (1H, d, J=0.6 Hz).

Example 116

4-[(3-Chloro-4-methoxybenzyl)amino]-1-[2-(1-hydroxycyclopent)ethyl]-6-phthalazinone hydrochloride

690 mg of 4-[(3-chloro-4-methoxybenzyl)amino]-1-0% Pd-C and the mixture is stirred for 0.5 hour in an atmosphere of hydrogen. The reaction solution is filtered through celite and the filtrate evaporated. The resulting residue is purified column chromatography (filler: silica gel) to give 400 mg of 4-[(3-chloro-4-methoxybenzyl)amino]-1-[2-(1-hydroxycyclopent)ethyl]-6-phthalazinedione. This product in the usual way converted into hydrochloride.

1H-NMR (400 MHz, DMSO-d6) : 1,47-of 1.78 (8H, m), 1,89-of 1.94 (2H, m), 3,24-to 3.33 (2H, m), of 3.84 (3H, s), 4,74 (2H, d, J=4.4 Hz), to 7.15 (1H, d, J=8,4 Hz), was 7.45 (1H, DD, J=8,4; 2.0 Hz), 7,60 (1H, d, J=2.0 Hz), 8,46 (1H, d, J=8,8 Hz), 8,55 (1H, DD, J=8,8; 1.2 Hz), 9,40 (1H, ush.).

The following connections get the same way.

Example 117

4-[(3-Chloro-4-methoxybenzyl)amino]-1-(3-hydroxy-3-methylbutyl)-6-phthalazinone hydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,17 (6N, (C), 1,73 and 1.80 (2H, m), 3,17-3,24 (2H, m), of 3.80 (3H, s), 4,78 (2H, d, J=4.4 Hz), 7,10 (1H, d, J=8,4 Hz), of 7.48 (1H, DD, J=8,4; 1,8 Hz), a 7.62 (1H, d, J=1,8 Hz), 8,43 (1H, d, J=8.6 Hz), 8,51 (1H, DD, J=8,6; 1.2 Hz), 9,63 (1H, ush.), 10,30 (1H, ush.).

Example 118

1-(3-Amino-3-methylbutyl)-4-[(3-chloro-4-methoxybenzyl)amino]-6-phthalazinedione the dihydrochloride

1H-NMR (400 MHz, DMSO-d6) : 1,37 (6N, s), 2.00 in 2,19 (2H, m), 3,21 of 3.56 (2H, m), of 3.84 (3H, s), 4,78 (2H, d, J=4.4 Hz), to 7.15 (1H, d, J=8,4 Hz), 7,46 (1H, d, J=8,4 Hz), to 7.61 (1H, s), 8,15-8,29 (4H, m), 8,48 (1H, d, J=8,8 Hz),Il]-6-phthalazinedione the dihydrochloride

1H-NMR (400 MHz, DMSO-d6) : 2,11-2,19 (2H, m), is 2.74 (3H, s) of 2.75 (3H, s), 3,16 to be 3.29 (4H, m), 3,85 (3H, s), 4,80 (2H, d, J=5,2 Hz), 7,16 (1H, d, J=8,4 Hz), of 7.48 (1H, DD, J=8,4; 2.0 Hz), 7,63 (1H, d, J=2.0 Hz), 8,49 (1H, d, J=8,4 Hz), 8,56 (1H, DD, J=8,4; and 1.4 Hz), for 9.47 (1H, d, J=1.4 Hz), 10,56 (2H, ush.).

Example 121

tert-Butyl ether ({1-[4-(3-chloro-4-methoxybenzylamine)-6-cyanophthalide-1-yl]-1,2,3,6-tetrahydropyridine-4-yl}acetic acid

1H-NMR (400 MHz, Dl3) (M. D.): 1,47 (N, C), 2,38 at 2.45 (2H, m) of 3.00 (2H, s) to 3.36 (2H, t, J=6.0 Hz), 3,74 (3H, s), 3,81 (2H, s), of 5.05 (2H, s), 5,62 (1H, s) 6,76 (1H, d, J=8,4 Hz), 7,14-7,20 (1H, m), of 7.48-7,56 (2H, m), 7,97-8,08 (2H, m).

Example 122

tert-Butyl ester 4-tert-butoxycarbonyloxyimino-1-carboxylic acid

To a biphasic mixture of tert-butyl methyl ether 4-hydroxypiperidine-1-carboxylic acid (10.1 g) and tetrabutylammonium hydrosulfate (3,40 g) in toluene (100 ml) and 4 N NaOH (50 ml) is added tert-butylbromide (14.6 g) and stirred for 4 hours at room temperature. Add NaOH (15 g) and tert-butylbromide (9,8 g) and stirred for 13 hours and 50 minutes. Add tert-butylbromide (4.9 g) and stirred for 2 hours at 35C, and then 24 hours for 30 minutes at 50C. The reaction mixture was diluted with ethyl acetate and washed with water and saturated salt solution, OA on silica gel (hexane/ethyl acetate) to obtain tert-butyl ester 4-tert-butoxycarbonyloxyimino-1-carboxylic acid (18,9 g), containing tert-butylbromide.

1H-NMR (400 MHz, CDCl3) (M. D.): 1,49 (N, C), 1,50-to 1.61 (2H, m), 1,80-1,89 (2H, m), 3.04 from-of 3.12 (2H, m), 3,50-3,59 (1H, m), of 3.73-3,81 (2H, m) to 3.99 (2H, s).

Example 123

tert-Butyl ether piperidine-4-biloxicasino acid hydrochloride

To a solution of tert-butyl ester 4-tert-butoxycarbonyloxyimino-1-carboxylic acid (11,0 g) in ethyl acetate (20 ml) is added 4 N hydrogen chloride in ethyl acetate (40 ml) and stirred for 40 minutes at room temperature. The organic solvent is evaporated under reduced pressure and the residue suspended in ether. tert-Butyl ether piperidine-4-biloxicasino acid hydrochloride are filtered.

1H-NMR (400 MHz, DMSO-d6) (M. D.): of 1.40 (9H, s), 1,62-of 1.73 (2H, m), 1,88-of 1.97 (2H, m), 2.91 in-2,96 (2H, m), 3,05-3,17 (2H, m), 3,56-the 3.65 (1H, m) 4,00 (2N, C).

Example 124

tert-Butyl ether ({1-[4-(3-chloro-4-methoxybenzylamine)-6-cyanophthalide-yl]piperidine-4-yloxy}acetic acid

To a solution of 1-chloro-4-(3-chloro-4-methoxybenzylamine)-6-phthalazine-6-carbonitrile (1.44 g) in NNP (10 ml) is added hydrochloride tert-butyl ether piperidinyl-4-biloxicasino acid (3,02 g) and N,N-diisopropylethylamine (3,10 g) and stirred for 2 hours, the organic layer is dried over magnesium sulfate. After concentration the residue is purified column chromatography on silica gel (hexane/ethyl acetate) to obtain tert-butyl ester {1-[4-(3-chloro-4-methoxybenzylamine)-6-cyanophthalide-1-yl]piperidine-4-yloxy}acetic acid (625 mg).

1H-NMR (400 MHz, Dl3) (M. D.): 1,49 (N, C), 1,50-1,60 (2H, m), a 1.75-to 1.86 (2H, m), 2.00 in of 2.08 (2H, m), 3.04 from-of 3.12 (2H, m), 3,40-of 3.48 (1H, m), and 3.72 (3H, s), 4,00-Android 4.04 (2H, m), 5,15 (2N, c), 6,74 (1H, d, J=8,4 Hz), 7,58 (1H, s), 7,63 (1H, d, J=8.0 Hz), 7,99-8,07 (3H, m).

Example 125

tert-Butyl ester of {7-[4-(3-chloro-4-methoxybenzylamine)-6-cyanophthalide-1-yl]-7-azaspiro[3.5]non-2-yl}acetic acid

1H-NMR (400 MHz, Dl3) (M. D.): the 1.44 (9H, s), 1,46-and 1.54 (2H, m), of 1.70 to 1.76 (2H, m), 1,79-of 1.84 (2H, m), 2,04-2,12 (2H, m), a 2.36-of 2.38 (2H, m), 2,58-of 2.64 (1H, m), 3.04 from-3,10 (2H, m), 3,12-3,18 (2H, m), of 3.78 (3H, s), 4,00-Android 4.04 (2H, m), 4,94 (2H, s), 6,76-to 6.80 (1H, m), 7,40-7,46 (2H, m), 7,94-8,08 (3H, m).

1. Derivatives phthalazine General formula (I), their pharmacologically acceptable salts or hydrates

where R1and R2are the same or different from each other and represent a halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, a hydroxyl group, a C1-C4alkoxygroup, which may be substituted by a halo atom is iminomethylene group, optional O-substituted C1-C4alkyl group, or heteroaryl group, which is selected from thiazolidine group, thienyl group, pyrazolidine group, triazolines group and tetrazolyl group and may be substituted WITH1-C4alkyl group;

Y is:

i) a group represented by the formula (II)

where ring a represents a 4-8 membered amine ring which may be substituted by a methyl group and may contain a double bond; D represents a single bond or an oxygen atom; R3represents a hydrogen atom, a C1-C4alkyl group or halogen atom; m represents 0 or an integer from 1 to 3; W represents an amino group, hydroxyl group, cyano, carboxyl group which may have a protective group selected from methyl group, ethyl group and tert-butilkoi group, or C1-C4alkoxygroup;

ii) a group represented by the formula (III)

where ring b is a 4-8 membered amine ring, which may contain a double bond; n and p are the same or different from each other and represent 0 or an integer from 1 to 3;

iii) a group represented by the formula (IV)

where the ring G represents a 4-8-membered amine ring, which may contain a double bond; E represents a hydroxyl group, a halogen atom, a C1-C4alkyl group or a C1-C4alkoxygroup; J represents the formula -(CHR4)q-Q (where R4represents a hydrogen atom or a C1-C4alkyl group, Q represents a hydroxyl group, halogen atom, carboxyl group, karbamoilnuyu group or asailing group containing no heteroatom other than the nitrogen atom, represented imidazolidine group or triazolines group, q represents 0 or an integer from 1 to 4) , or E and J can form a 3-6-membered ring together with the carbon atom to which they are attached, optionally containing an oxygen atom and containing a Deputy selected from hydroxyl group, carbonyl group,1-C4alkyl groups, substituted hydroxyl or carboxyl group;

iv) a group represented by the formula (V)

where M represents a single bond or a methylene group which may be substituted by a hydroxyl group or a C1-C4alkyl glico, formed together with M, and the ring L represents a 5-6-membered alkyl ring which may contain an oxygen atom and may be substituted by hydroxyl or1-C4alkyl group which is substituted by a hydroxyl group; or Y may represent 3-hydroxy-8-azabicyclo[3.2.1]Oct-8-yl when X represents a cyano, R1represents a chlorine atom, R2represents a methoxy group;

v) a group represented by the formula (VI)

where the ring R is a 5-7 membered amine ring and R5represents a hydrogen atom or a C1-C4alkyl group;

vi) etinilnoy or ethyl group substituted WITH1-C4alkyl group which is substituted by hydroxyl(reference) group(s), amino group, di(C1-C4)alkyl substituted amino group, WITH1-C4CNS group, which is substituted by carboxyl or hydroxyl group, a cyclic amino group selected from aziridine, azetidine, pyrrolidine and piperidine which may be substituted by a hydroxyl group; or substituted3-C6cycloalkyl group, which is substituted by hydroxyl group;

vii) phenyl group, kataraina hydroxyl group, WITH1-C4alkoxygroup, carboxyl group, amino group which may be substituted WITH1-C4acyl group, WITH1-C4alkylsulfonyl group; or

viii) pyridyloxy group or thiazolidine group;

l represents an integer from 1 to 3;

provided that excluded the following cases:

the case when l is 1 or 2,X represents cyano or chlorine atom,R1represents a chlorine atom, R2represents a methoxy group, the ring a represents a saturated 5 - or 6-membered amine ring, D represents a single bond, m is 0, and W represents a carboxyl group which may contain a protective group, or a C1-C4alkoxygroup;

the case when l is 1, R1represents a chlorine atom, R2represents a methoxy group, the ring a represents a saturated 5 - or 6-membered amine ring, D represents a single bond, and W represents a hydroxyl group;

the case when l is 1, the ring is 5 - or 6-membered amine ring, n and p are 0;

the case when l is 1, E and Q represent a hydroxyl group and q is 0;

the case when l is 1, q is 0, E is avno 1, X represents a chlorine atom and Y represents a phenyl group substituted by a methoxy group.

2. Derivatives phthalazine under item 1, where R1represents a halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, or cyano, and R2represents a halogen atom, a hydroxyl group or a C1-C4alkoxygroup, their pharmacologically acceptable salts or hydrates.

3. Derivatives phthalazine under item 1 or 2, where Y is represented by formula (II)

(where the ring A, D, R3, W and m have the meanings given above), their pharmacologically acceptable salts or hydrates.

4. Derivatives phthalazine under item 1 or 2,where Y is represented by formula (III)

(where ring B, n and R have the meanings given above), and -(CH2)n-OH and -(CH2)p-OH not attached to the same carbon atom of the ring; their pharmacologically acceptable salts or hydrates.

5. Derivatives phthalazine under item 1 or 2,where Y is represented by formula (IV)

(where the ring G, E and J have the values defined above); and their pharmacologically acceptable salts or hydrates.

6. Derivatives phthalazine under item 1 or 2, where Y present the pharmacologically acceptable salt or hydrates.

7. Derivatives phthalazine under item 1 or2,where Y is represented by formula (VI)

(where the cycle R and R5have the meanings defined above),their pharmacologically acceptable salts or hydrates.

8. Derivatives phthalazine under item 1 or 2, where Y represents etinilnoy or ethyl group substituted WITH1-C4alkyl group which is substituted by hydroxyl(reference) group(s), amino group, di(C1-C4) alkyl substituted amino group, WITH1-C4CNS group, which is substituted by a carboxyl group or a hydroxyl group, a cyclic amino group selected from aziridine, azetidine, pyrrolidine and piperidine which may be substituted by a hydroxyl group; or substituted C3-C6cycloalkyl group, which is substituted by a hydroxyl group; or substituted C3-C6cycloalkyl group, which is substituted by hydroxyl group; a pharmacologically acceptable salt or hydrates.

9. Derivatives phthalazine under item 1 or 2, a pharmacologically acceptable salt or hydrates, where Y represents a phenyl group which may be substituted specified in paragraph 1 Deputy.

10. Derivatives phthalazine on p. a second group.

11. Derivatives phthalazine according to any one of paragraphs.1-3, where Y represents a group represented by the formula (II); the ring a represents a 4-to 8-membered amine ring, which may contain a double bond; W represents a hydroxyl group; m represents 0 or an integer from 1 to 3; and D represents a single bond, and R3represents a halogen atom, or (ii) D is an oxygen atom and R3represents a hydrogen atom, pharmacologically acceptable salts or hydrates.

12. Derivatives phthalazine according to any one of paragraphs.1, 2 and 4, where Y represents a group represented by the formula (III), ring b is 6-membered amine ring, n is 0 or 1 and p is 1, their pharmacologically acceptable salts or hydrates.

13. Derivatives phthalazine according to any one of paragraphs.1, 2 and 5, their pharmacologically acceptable salts or hydrates, where Y represents a group represented by the formula (IV) in which E and J together with the carbon atom to which the are attached, form a 3-6-membered ring which may contain an oxygen atom and has the above-mentioned Deputy, and the ring G represents a 4-8-membered amine ring, which may contain a double bond.

14. Derivatives phthalazine according to any one of paragraphs.1, 2 and 5, where Y is grilo group or a C1-C4alkoxygroup, J is represented by the formula -(CHR4)q-Q (where R4represents a hydrogen atom or a C1-C4 alkyl group, Q represents a hydroxyl group, halogen atom, carboxyl group, karbamoilnuyu group or asailing group containing no heteroatom other than the nitrogen atom, represented imidazolidines or triazolines group, q represents 0 or an integer from 1 to 4) and the ring G represents a 4-8-membered amine ring, which may contain a double bond, their pharmacologically acceptable salts or hydrates.

15. Derivatives phthalazine according to any one of paragraphs.1, 2 and 6, where Y represents a group represented by the formula (V), rings K and L have the meanings defined above, and M represents a methylene group substituted with hydroxyl group, hydroxy-C1-C4alkalinous group or carboxy-C1-C4alkalinous group, their pharmacologically acceptable salts or hydrates.

16. Derivatives phthalazine according to any one of paragraphs.1, 2 and 8, where Y is etinilnoy group, which is substituted by the Deputy, as defined in paragraph 1, their pharmacologically acceptable salts or hydrates.

17. Derived phthalazine under item 1, selected from epipeline)-4-[(3-chloro-4-methoxybenzyl)amino]-6-cyanophthalide;

2) 4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-[4-hydroxy-4-(hydroxymethyl)piperidino]phthalazine;

3) 4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(4-cyanopiperidine)phthalazine;

4) N1-[3-[4-[(3-chloro-4-methoxybenzyl)amino]-6-cyano-1-phthalazine]phenyl]ndimethylacetamide;

5) 4-(3-chloro-4-methoxyphenethyl)amino-6-cyano-1-(4-cyanopiperidine)phthalazine;

6) 4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(2-pyridyl) phthalazine;

7) 4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(3-pyridyl) phthalazine;

8) 4-[(3-chloro-4-methoxybenzyl)amino]-1-(4-pyridyl)-6-phthalazinedione;

9) 4-[(3-chloro-4-methoxybenzyl)amino]-1-(2-hydroxy-7-azaspiro[3.5]non-7-yl)-6-phthalazinedione;

10) 4-[(3-chloro-4-methoxyphenethyl)amino]-1-(2-hydroxy-7-azaspiro[3.5]non-7-yl)-6-phthalazinedione;

11) 4-[(3-bromo-4-methoxybenzyl)amino]-1-(2-hydroxy-7-azaspiro[3.5]non-7-yl)-6-phthalazinedione;

12) 4-[(3-chloro-4-methoxybenzyl)amino]-1-(2-hydroxy-6-azaspiro[3.4]Oct-6-yl)-6-phthalazinedione;

13) 4-[(3-chloro-4-methoxybenzyl)amino]-1-[4-(1-fluoro-2-hydroxyethyl)piperidino]-6-phthalazinedione;

14) 4-[(3-chloro-4-methoxybenzyl)amino]-1-[4-fluoro-4-(hydroxymethyl)piperidino]-6-phthalazinedione;

15) 4-[(3-chloro-4-methoxime is)amino]-1-[4-(2-hydroxy-ethoxy)piperidine]-6-phthalazinedione;

17) 4-[(3-chloro-4-methoxybenzyl)amino]-1-(3-hydroxy-3-methyl-1-butenyl)-6-phthalazinedione;

18) 1-(3-amino-3-methyl-1-butenyl)-4-[(3-chloro-4-methoxybenzyl)amino]-6-phthalazinedione;

19) 4-[(3-chloro-4-methoxybenzyl)amino]-1-(4-hydroxylaminopurine)-6-phthalazinedione;

20) 4-[(3-bromo-4-methoxybenzyl)amino]-1-(4-hydroxypiperidine)-6-phthalazinedione;

21) 1-(4-hydroxypiperidine)-4-[(4-methoxy-Z-methylbenzyl)amino]-6-phthalazinedione;

22) 1-(4-hydroxypiperidine)-4-[[4-methoxy-3-(trifluoromethyl)benzyl]amino]-6-phthalazinedione;

23) 1-(4-hydroxypiperidine)-4-[(3-iodine-4-methoxybenzyl)amino]-6-phthalazinedione;

24) 1-[4-fluoro-4-(hydroxymethyl)piperidino]-4-[(4-methoxy-3-methylbenzyl)amino]-6-phthalazinedione;

25) 4-[(3-bromo-4-methoxybenzyl)amino]-1-[4-(hydroxymethyl)piperidino]-6-phthalazinedione;

26) 4-[(3-chloro-4-methoxybenzyl)amino]-1-[4-(permitil)-4-hydroxypiperidine]-6-phthalazinedione;

27) 4-[(3-chloro-4-methoxybenzyl)amino]-1-(4-hydroxypiperidine)-6-phthalazinone-6-methyloxime;

28) 1-[4-[(3-chloro-4-methoxybenzyl)amino]-6-(1H-1-pyrazolyl)-1-phthalazine]-4-piperidinol;

29) 4-[(3-cyano-4-methoxybenzyl)amino]-1-(4-hidrico[3.2.1]Oct-8-yl)-6-phthalazinedione;

31) (SYN)-4-[(3-chloro-4-methoxybenzyl)amino]-1-(9-hydroxy-3-azabicyclo[3.3.1 ]non-3-yl)-6-phthalazinedione.

18. Derived phthalazine on p. 17, selected from the group of compounds represented below, its pharmacologically acceptable salt or hydrate:

1) 4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(2-pyridyl)-6-phthalazine;

2) 4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(3-pyridyl)-6-phthalazine;

3) 4-[(3-chloro-4-methoxybenzyl)amino]-1-(2-hydroxy-7-azaspiro[3.5]non-7-yl)-6-phthalazinedione;

4) 4-[(3-chloro-4-methoxyphenethyl)amino]-1-(2-hydroxy-7-azaspiro[3.5]non-7-yl)-6-phthalazinedione;

5) 4-[(3-bromo-4-methoxybenzyl)amino]-1-(2-hydroxy-7-azaspiro[3.5]non-7-yl)-6-phthalazinedione;

6) 4-[(3-chloro-4-methoxybenzyl)amino]-1-(2-hydroxy-6-azaspiro[3.4]Oct-6-yl)-6-phthalazinedione;

7) 4-[(3-chloro-4-methoxybenzyl)amino]-1-[4-(1-fluoro-2-hydroxyethyl)piperidino]-6-phthalazinedione;

8) 4-[(3-chloro-4-methoxybenzyl)amino]-1-[4-fluoro-4-(hydroxymethyl)piperidino]-6-phthalazinedione;

9) 4-[(3-chloro-4-methoxybenzyl)amino]-1-[4-(hydroxymethyl)-4-methoxypiperidine]-6-phthalazinedione;

10) 4-[(3-chloro-4-methoxybenzyl)amino]-1-[4-(2-hydroxyethoxy)piperidine]-6-phthalazinedione;

13) 4-[(3-chloro-4-methoxybenzyl)amino]-1-(4-(hydroxylaminopurine)-6-phthalazinedione;

14) 4-[(3-bromo-4-methoxybenzyl)amino]-1-(4-hydroxypiperidine)-6-phthalazinedione;

15) 1-(4-hydroxypiperidine)-4-[(4-methoxy-3-methylbenzyl)amino]-6-phthalazinedione;

16) 1-[4-fluoro-4-(hydroxymethyl)piperidino]-4-[(4-methoxy-3-methylbenzyl)amino]-6-phthalazinedione;

17) 4-[(3-chloro-4-methoxybenzyl)amino]-1-4-(permitil)-4-hydroxypiperidine]-6-phthalazinedione;

18) 4-[(3-chloro-4-methoxybenzyl)amino]-1-(4-hydroxypiperidine)-6-phthalazinone-6-methyloxime;

19) 1-[4-[(3-chloro-4-methoxybenzyl)amino]-6-(1H-1-pyrazolyl)-1-phthalazine]-4-piperidinol;

20) (endo)-4-[(3-chloro-4-methoxybenzyl)amino]-1-(3-hydroxy-8-azabicyclo[3.2.1]Oct-8-yl)-6-phthalazinedione;

21) (SYN)-4-[(3-chloro-4-methoxybenzyl)amino]-1-(9-hydroxy-3-azabicyclo[3.2.1 ]non-3-yl)-6-phthalazinedione.

19. Preventive and therapeutic agent for erectile dysfunction, which comprises as an active ingredient phthalazinone compound according to any one of paragraphs.1-18, its pharmacologically acceptable salt or hydrate.

20. Therapeutic agent for erectile dysfunction, which uchideshi acceptable salt or hydrate

where l’ represents an integer from 1 to 3;

R6represents a halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, or cyano;

X1represents a cyano or halogen atom;

Y1is:

i) a group of the formula (VIII):

where the ring A1 represents a 5 - or 6-membered amine ring; ml is 0 or represents an integer from 1 to 3; Z represents an amino group, hydroxyl group, carboxyl group, which may have a protective group selected from methyl, ethyl or tert-butilkoi group1-C4alkoxygroup or cyano;

ii) a group of the formula (IX)

where the ring B1 represents a 5 - or 6-membered amine ring, n1 and P1 represent 0 or integers from 1 to 3;

and -(CH2)n1-OH and -(CH2)P1-OH not attached to the same carbon atom of ring B1;

iii) a phenyl group which may be substituted by the Deputy selected from alkyl groups, which may be substituted by a hydroxyl group, WITH1-C4alkoxygroup, carboxyl group;

iv) pyridyloxy group ; or

dstanley pyridyloxy group and s is 0 or represents an integer from 1 to 3.

21. Preventive or therapeutic agent for erectile dysfunction on p. 20, comprising as an active ingredient phthalazinone connection, its pharmacologically acceptable salt or hydrate, where Y1represents the

i) a group of the formula (VIII)

where the ring A1, Z and m1 have the meanings defined above;

ii) a group represented by the formula (IX)

where the ring B1, n1 and R1 have the meanings defined above;

and -(CH2)n1-OH and -(CH2)P1-OH not attached to the same carbon atom of ring B1.

22. Preventive or therapeutic agent for erectile dysfunction on p. 20, comprising as an active ingredient phthalazinone connection, its pharmacologically acceptable salt or hydrate, where Y1represents a phenyl group substituted by the Deputy, as defined in paragraph 20, or pyridyloxy group.

23. Preventive or therapeutic agent for erectile dysfunction on p. 20, comprising as an active ingredient phthalazinone connection, its pharmacologically acceptable salt or hydrate, where Y1represents the formula-N(R7)-(CH2)s-Het where Het is the first remedy for erectile dysfunction on p. 20, comprising as an active ingredient phthalazinone connection, its pharmacologically acceptable salt or hydrate selected from the following group:

1) 4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-[(3R)-3-hydroxyethylpiperazine]phthalazine;

2) 4-(4-aminopiperidine)-1-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalide;

3) 4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-[4-(hydroxymethyl)4-methoxypiperidine]phthalazine;

4) 4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(4-hydroxy-4-hydroxyethylpiperazine)phthalazine;

5) 4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(4-cyanopiperidine) phthalazine;

6) 4-(3-bromo-4-methoxybenzyl)amino-6-cyano-1-[(3R)-hydroxypyrrolidine]phthalazine;

7) 4-[(3-chloro-4-methoxybenzyl)amino]-1-[(3-hydroxymethyl)tetrahydro-1H-1-pyrrolyl]-6-phthalazinedione;

8) 4-(3-chloro-4-methoxybenzyl)amino]-1-[(3R,4S)-3,4-di(hydroxymethyl)tetrahydro-1H-1-pyrrolyl]-6-phthalazinedione;

9) 4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-[(2S)-2-(methoxymethyl)pyrrolidino]phthalazine;

10) 4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(4-methoxyphenyl)phthalazine;

11) 4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-[N-methyl-N-(2-pyridylmethyl)amino]phthalazine;

12) 4-(3-chloro-4-methoxyphenethyl-piperidino)phthalazine;

14) 4-(3-chloro-4-methoxyphenethyl)amino-6-cyano-1-(4-hydroxyethylpiperazine)phthalazine;

15) 4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-phenolphthalein;

16) 4-(3-chloro-4-methoxybenzyl)-6-cyano-1-(2-pyridyl)phthalazine;

17) 4-(3-chloro-4-methoxybenzyl)-6-cyano-1-(3-pyridyl)phthalazine;

18) 4-[(3-chloro-4-methoxybenzyl)amino]-1-(4-pyridyl)phthalazinone.

25. The method of obtaining the compounds of formula (XI)

(where X, R1, R2and l have the meanings defined above, Y3represents a phenyl group which may have a Deputy, selected from above in paragraph (1 group of deputies),

which includes a step of interaction between the compounds of formula (X)

(where Hal represents a halogen atom; R1, R2, l and X have the meanings given above) with the compound of the formula Y3-IN(OH)2where Y3has the values listed above.

26. Pharmaceutical composition for the treatment of erectile dysfunction, including pharmacologically or clinically effective dose derived phthalazine under item 1, its pharmacologically acceptable salt or hydrate and pharmacologically acceptable carriers.

27. Method for the prevention and treatment of erectile dysfunction to the Lee 20, its pharmacologically acceptable salt or hydrate the patient suffering from the specified disease.

 

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