KR810000805B1 - Process for preparing phthalazines - Google Patents

Abstract

Title compds. (I; R1 = H or lower alkyl; R2 = hydroxy or lower alkoxy; n= 1-3; Y = -Z1-COR3, -NZ2-SO2R5, -z2-CO, -N-R6R7, hydroxy, lower alkanoloxy, or NR6Ralkoxy; n 7 substituted lower alkyl or lower alkoxy; R3 = amino, hydroxy, lower alkoxyary1 heteroaryl substituted lower alkyl; R5 = R3 or -NR6R7; R6 = R4; R7 = H or lower alkyl; Zl = -CH2 or -NR4; Z2 = NR4 or -o-; R4 = H, amino, lower alkoxy, hydroxy, aryl or heteroaryl substituted lower alkyl), useful as cardiac stimulants and phosphodiesterase inhibitors, were manufd. by reacting II with III, followed by eliminating HQ1(Q1 = eliminating group).

Description

Method of manufacturing phthalazines

The present invention relates to a method for preparing a phthalazine compound of formula (I), which is effective as a therapeutic agent for heart disease.

In the above structural formula

R ¹ is a hydrogen atom or a lower alkyl group;

(R ² ) n is one to three substituents, each R ² is a hydroxy or lower alkoxy group, n is an integer of 1 to 3, or methylenedioxy wherein any two groups in R ² are connected to the adjacent position of the benzene ring Or an ethylenedioxy group;

Y is group connected to the 3- or 4-position of a papridino ring, and represents the following group.

i) -Z ¹ -COR ³ group

In the above structural formula

이며Z ¹ is -CH ₂ -or

And

R ³ is a lower alkyl group optionally substituted with amino, hydroxy, lower alkoxy, aryl or heteroaryl group; Lower alkenyl- or lower alkynyl-methyl group; Lower alkoxy groups optionally substituted with amino, aryl, heteroaryl, lower alkoxy or hydroxy groups; Aryl group; Aryloxy group; Heteroaryl group

R ⁴ is a hydrogen atom; Lower alkyl groups optionally substituted with amino, lower alkoxy, hydroxy aryl or heteroaryl groups; Lower alkenyl- or lower alkynyl-methyl groups; Aryl group or hetero aryl group.

그룹ii)

group

In the above structural formula

R ⁴ is as defined above,

그룹이고(여기에서 R⁷은 수소원자 또는 저급알킬그룹이고, R⁶는 R⁴에서 정의된 바와 같거나, 또는 R⁶및 R⁷은 수소와 함께 포화 모노사이클릭 이소환을 형성한다.)R ⁵ is as defined in R ⁴ or

Group (wherein R ⁷ is a hydrogen atom or a lower alkyl group, R ⁶ is as defined for R ⁴ , or R ⁶ and R ⁷ together with hydrogen form a saturated monocyclic isocycle.)

그룹iii)

group

In the above structural formula

또는 -0-이고, R⁴, R⁶및 R⁷은 상기에서 정의된 바와 같거나, 또는 Z²는

이고 R⁴및 R⁷은 함께 -(CH₂)₂- -(CH₂)₃-, 0-페닐렌그룹을 나타낸다.Z ² is

Or -0-, R ⁴ , R ⁶ and R ⁷ are as defined above, or Z ² is

And R ⁴ and R ⁷ together represent — (CH ₂ ) ₂ — — (CH ₂ ) ₃ —, 0-phenylene group.

iv) hydroxy, lower alkanoyloxy or lower alkoxy groups; Lower alkyl or lower alkoxy group substituted with hydroxy, lower alkoxy or —CONR ⁶ R ⁷ (R ⁶ and R ⁷ are as defined above).

The present invention also includes pharmaceutically harmless in vivo precursors of compounds of formula (I).

The term "lower" used in alkyl, alkenyl, alkynyl, alkoxy and alkanoyl groups is a straight-chain, suitably branched group containing up to 6 carbon atoms (preferably up to 4 carbon atoms), but lower alkyl Or when the lower alkoxy group is substituted with an amino, lower alkoxy or hydroxy group, any of the oxygen or nitrogen atoms in the above substituents has at least two carbon atoms in between the other oxygen or nitrogen atoms.

The terms “aryl” and “heteroaryl” refer to aryl and heteroaryl groups substituted with unsubstituted aryl, heteroaryl groups and one or two substituents selected from lower alkyl, lower alkoxy, hydroxy, halogen. Phenyl or di (C ₁ -C ₄ alkoxy) phenyl is preferable, and a heteroaryl group is preferably 2-, 3- or 4-pyridyl. The aryloxy group is preferably a phenoxy group. Alkenyl and alkynyl groups are preferably -CH-CH ₂ and -C≡CH, and an alkanoyl group is preferably an acetyl group.

를 뜻하며The term "amino"

Means

In the above structural formula

R ⁸ is hydrogen or lower alkyl,

R ⁹ is lower alkyl substituted with hydrogen, lower alkyl or aryl or R ⁸ and R ⁹ are monocyclic isocyclic rings having 5 to 7 carbon atoms with nitrogen atoms.

The term "halogen" refers to fluorine, chlorine, bromine and iodine.

Since the compounds according to the invention have one or more absent carbons, there are one or more pairs of colon antibodies, and their pairs and individual isomers are fractionally determined with free or suitable salts or chromatographed with free bases. It may be separated by a method such as graphigraphy. The present invention also encompasses isolated partners, as well as mixtures thereof, racemic mixtures, isolated D- and L-type optically active isomers.

Pharmaceutically nontoxic acid addition salts of the compounds according to the present invention are hydrochloride, hydrobromide, hydrochloride iodide, sulfate, bisulfate, phosphate (phosphate), acetate, maleate, fumarate, lactate, tartarate, citrate Salts such as, gluconate, sacrate and P-toluene-sulfonate.

The term pharmacologically toxic in vivo precursor described above requires some explanation. This, of course, is a common technique in the field of pharmaceutical chemistry, which converts drugs into chemical derivatives that do not have undesirable properties, administers them to animals or humans, and enters the original drugs in vivo. How to overcome For example, when a drug is orally administered to an animal or a patient, if the absorption is not good, the drug is easily converted to a derivative which is easily absorbed and returned to the original compound in serum or tissue. If the drug is unstable in solution, it is administered in the form of a derivative that is stable in solution and returns to the original drug in the body. Pharmacists are well aware of this method.

The pharmacologically toxic in vivo precursor of the compound of formula (I) in the present specification has a structure different from that of formula (I), but when used by animals or humans, the compound is a compound of formula (I) in the body. Is switched.

The cardiac excitability of the compounds according to the invention has been demonstrated to be effective by one or more of the following experiments.

a) an increase in the contractile force of the two atria of the beating isolated guinea pig

b) Increase in myocardial contractility (maximum dp / dt of left ventricle) in anesthetized dogs implanted with a left ventricular catheter

c) Increased myocardial contractility in conscious dogs implanted with left ventricular transducers

In experiment (a), the increase in myocardial contractility and heart rate by the test compound was measured at various doses and compared with the response induced by isoprenal. As a result of comparing the obtained dose response curves, contraction force versus pulsation rate selectivity of the test compound was observed.

In experiment (b), an increase in muscle contractility in anesthetized dogs when the drug was injected intravenously was measured. Efficacy of the present muscle contractile agent, selectivity for pulsating rate vs. contractility increase, action time and peripheral effect on the contractile force increase effect, that is, the effect on blood pressure were observed.

In experiment (c), the test compound was administered orally or intravenously in a conscious dog implanted with a left ventricular transducer to observe the increase in muscle contractility. Efficacy and contractility of this myotropin-increasing agent: selectivity for the increase in the rate of pulsation, action time and the peripheral effect of the contractile force increase, ie, the effect on the blood pressure were observed.

Compounds of the formula (I) suitable for constant testing are as follows.

R ¹ is a hydrogen atom,

(R ² ) n is 6,7-di (C ₁ -C ₄ alkoxy), in particular 6,7-dimethoxy,

Y is at position 4 of the piperidino group.

Most suitable compounds according to the invention have the following structure (II).

In the above structural formula

Y is as defined in structural formula (I), and especially the following group is preferable.

i) -CH ₂ COR ³ ,

Wherein R ³ is alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms; or

ii)

Wherein R ³ is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, phenyl, benzyloxy;

R ⁴ is hydrogen or alkyl of 1 to 4 carbon atoms; or

iii)

Wherein R ⁴ is hydrogen or alkyl of 1 to 4 carbon atoms, R ⁵ is alkyl of 1 to 4 carbon atoms, phenyl, di (alkoxy of 1 to 4 carbon atoms) phenyl, benzyl or 2-, 3- or 4-pyridyl ; or

iv)

Wherein R ⁴ is hydrogen or alkyl of 1 to 4 carbon atoms

R ⁶ is alkyl, benzyl or 2-, 3- or 4-pyridyl having 1 to 4 carbon atoms

R ⁷ is hydrogen or alkyl of 1 to 4 carbon atoms; or

v) -OCONHR ⁶

Wherein R ⁶ is alkyl, phenyl, benzyl or 2-, 3- or 4-pyridyl having 1 to 4 carbon atoms;

vi) hydroxy, alkanoyloxy up to 4 carbon atoms, alkoxy 1 to 4 carbon atoms, or

vii) hydroxy, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 5 carbon atoms substituted by -CONR ⁶ R ⁷ group; Or wherein R ⁶ and R ⁷ are each hydrogen or alkyl of 1 to 4 carbon atoms

viii) alkoxy having 2 to 4 carbons substituted with hydroxy or alkoxy having 1 to 4 carbon atoms and carbon other than α-carbon.

The best individual compound is the compound of formula II, wherein Y is the following group.

The compounds according to the invention may be administered alone, but are usually administered in admixture with a pharmaceutical carrier, selected according to the method of administration or basic pharmaceutical practice. For example, it can be administered orally in the form of tablets containing excipients such as starch or lactose, capsules containing excipients alone or excipients, elixirs or suspending agents containing flavors or coloring agents. In addition, intravenous injection, intramuscular injection, and subcutaneous injection may be administered. In this case, it is preferable to use in the form of a sterile aqueous solution containing a sufficient amount of salt or glucose as an isotonic agent.

When orally administered to humans for the treatment or prophylaxis of congestive deep vein, etc., it is preferable to administer orally divided 20 mg to 1 g two to four times a day to an adult of 70 kg body weight. Intravenous injections are used in acute deep vein therapy in doses of 1 to 300 mg per dose, if necessary. Thus, adults are usually given individual tablets or capsules containing 5 to 500 mg of the active ingredient together with suitable pharmaceutically toxic carriers or excipients.

The present invention also includes a pharmaceutical composition containing a compound of formula (I) as described above, pharmaceutically harmless acid addition salts thereof, pharmaceutically harmless in vivo precursors, pharmaceutically harmless diluents Carriers are also included.

The present invention also includes a method of exciting an animal's heart by administering a compound of formula (I), a salt or in vivo precursor thereof, or a pharmaceutical composition thereof in sufficient amount to excite the heart to the animal.

The compound of formula (I) of the present invention is prepared as follows.

A) prepared by reacting the substituted phthalazine of the following formula (III) with the amine of the following formula (IV) and then removing HQ ¹ ; or

In the above structural formula

Q ¹ is a good leaving group such as chlorine-, bromo-, urethra-, lower alkoxy or (lower alkyl) thio (especially chlorine and bromo).

The reaction is carried out in an inert organic solvent such as isoamyl alcohol at a temperature of 75 ° to 150 ° C. (eg reflux) for up to 24 hours. When it is chlorine, bromo-, urethra-, it is convenient to carry out in the presence of a base such as triethylamine or an excess of reactant of the formula (IV).

Any substituents for which leaving group Q ¹ may be substituted, for example, hydroxy, primary amine and secondary amine should be protected by conventional methods prior to reaction and removed by standard processes after the reaction. The hydroxy group can be protected by benzyl group if necessary, and removed by hydrocracking at the end of the reaction. Primary or secondary amines, if necessary, may also be protected with benzyl or t-butoxycarbonyl groups and, after completion of the reaction, hydrolyzed with hydrolysis or weak acid, respectively.

The product is separated and purified by conventional methods.

B) A compound of formula (I) wherein Y is —NR ⁴ CONHR ⁶ is prepared by reacting phthalazine of formula (V) with an isocyanate R ⁶ NCO (R ⁶ is not hydrogen) or R ⁶ is hydrogen The compound is prepared by reacting with sodium or potassium cyanate in the presence of acid. As acid, an acid addition salt of formula (V) may be used as a starting material.

This process is carried out by heating and refluxing phthalazine and isocyanate together for 12 to 24 hours in a suitable organic solvent such as chloroform and the product is separated and purified by conventional methods.

All groups reacting with isocyanate groups or especially cyanate groups must be protected before the reaction and the protective group must be removed by standard processes after the reaction. Groups in need of protection include hydroxy, primary and secondary amino groups which may be present in R ² , R ⁴ and R ⁶ and the like.

C) A compound of formula (I) wherein Y is -NR ⁴ COR ³ , -NR ⁴ SO ₂ R ⁵ or -NR ⁴ CONR ⁶ R ⁷ is a compound of formula (V)

a) acyl halide or haloformate of Q ² COR ³ (Q ² = Cl-, Br-),

b) halosulfonate, sulfamoyl halide or sulforyl halide of Q ² SO ₂ R ⁵ (Q ² = Cl-.Br-)

c) carbamyl halides of R ⁶ R ⁷ NCOQ ² (R ⁶ and R ⁷ not hydrogen),

d) prepared by reacting with anhydride or pyrocarbonate of (R ³ CO) ₂ O, respectively.

The reaction is left at room temperature for up to 72 hours in the presence of a base such as triethylamine in an inert organic solvent such as chloroform.

Groups reacted or substituted with anhydrides, pyrocarbonates or groups Q ^{2 in} R ² to R ⁷ , for example hydroxy, primary amino, secondary amino groups, are protected with conventional protecting groups prior to the reaction and at the end of the reaction The protective group must be removed by the process.

The product is separated and purified by conventional methods.

D) A compound of formula (I) wherein Y is -O-CONHR ⁶ is prepared by reacting phthalazine of the following formula (VI) with isocyanate R ⁶ NCO (R ⁶ ≠ H), where R ⁶ is hydrogen. Prepared by reaction with sodium or potassium cyanate in the presence. The phthalazine and the isocyanate are reacted together for a maximum of 12 hours in a suitable organic solvent such as chloroform (eg reflux) in the presence of a base such as triethylamine.

Except for the -OH group of the piperidino ring, all groups capable of reacting with cyanates and isocyanates should be protected before the reaction as mentioned in B). The final product is separated by conventional methods.

E) The compound of formula (I) wherein Y is NHCONR ⁶ R ⁷ is reacted with phosgene in an inert inorganic solvent such as chloroform or toluene in the presence of a base such as triethylamine in the phthalazine of the following formula (VII), The -NH ₂ group is then converted to the -NCO group. R ⁶ R ⁷ NH compound is then added to the reaction mixture to react with the -NCO group. The phthalazine containing —NCO may be separated and purified, if necessary, before reacting with R ⁶ R ⁷ NH.

The hydroxy group, the primary amino group (except -NH ₂ of the piperidine ring), the secondary amino group should be protected prior to reaction and the protecting group removed after the reaction. The product is separated and purified by conventional methods.

F) A compound of formula (I) wherein Y is -NR ⁴ COR ³ and R ³ is not lower alkoxy, substituted lower alkoxy and aryloxy, is a compound of formula (V) Prepared by reaction with oxy succinimide ester.

The hydroxy group, primary or secondary amino group in R ² to R ⁶ should be protected prior to the reaction and the protecting group removed by standard process after the reaction. The product is separated by conventional methods.

G) A compound of formula (I) wherein Y is a lower alkyl group substituted with -CONR ⁶ R ⁷ is prepared by reacting a compound of formula ( ^VII ) with R ⁶ R ⁷ NH. Wherein Q ¹ is a good leaving group (e.g. Cl-, Br-, lower alkoxy,

Wherein R ¹⁰ is lower alkyl or lower alkoxy group), m is an integer from 1 to 6.

The material of formula (VII) as starting material is prepared by a known method. For example, acid chlorides and bromide are prepared by reacting the corresponding free acid with thionyl chloride or bromide. Similarly, succinimido and phthalimido esters are prepared by reacting the free acid with N-hydroxy-succinimide or -phthalimide. Mixed anhydrides of formula IV are also prepared by reacting the corresponding free acid with lower alkanoyl chlorides or bromide or lower alkyl chloroformates or bromoformates.

Substituents (e.g., primary or secondary amino groups) that can react with the-(CH ² ) mCOQ ¹ groups present in R ² , R ⁶ and R ⁷ must be protected before the reaction and the protective group removed after the reaction. do. The product is separated and purified by conventional methods.

H) A compound of formula (I) wherein F is -NR ⁴ COR ³ and R ³ is a lower alkyl group substituted with an amino group is reacted with a R ⁸ R ⁹ NH compound of phthalazine of the following formula (VII). Wherein Q ³ is lower alkyl substituted with Cl- or Br-. The reaction is carried out in the presence of a base such as triethylamine or R ⁸ R ⁹ NH.

Substituents, such as hydroxy, primary and secondary amino groups, which are substituted with the Q ³ groups present in R ² and R ⁴ , should be protected before the reaction and the protecting group should be removed after the reaction.

I) A compound of formula (I) wherein Y is a lower alkanoyloxy group is prepared by acylating the corresponding compound where Y is a hydroxy group with lower alkanophosphoric acid or lower alkanoyl chloride or anhydride of bromide. The reaction is carried out in a conventional manner, ie, starting materials containing hydroxyl groups with a suitable anhydride (acetic anhydride) at a temperature of 50 to 100 ° C. in the presence of the corresponding free acid for up to 24 hours.

The hydroxy group present in R ² is protected prior to the reaction and the protecting group is removed at the end of the reaction.

(저급알킬)인 상응하는 화합물을 CrO₃로 산화시켜 제조한다. 후자 화합물은 Y가

인 상응하는 화합물을 NaOH로 가수분해시켜 제조한다. 구조식(Ⅰ) 화합물의 산부가염은 불활성 유기용매중에서 유리염기와 산을 반응시켜 통상의 방법으로 제조한다. 생성물은 재결정시켜 정제시킨다.J) A compound wherein Y is -CH ₂ CO (lower alkyl) is

Prepared by oxidation of the corresponding compound which is (lower alkyl) with CrO ₃ . The latter compound is Y

Phosphorus The corresponding compound is prepared by hydrolysis with NaOH. Acid addition salts of the compound of formula (I) are prepared by conventional methods by reacting the free base with an acid in an inert organic solvent. The product is purified by recrystallization.

The following examples illustrate the invention (all temperatures are in degrees Celsius).

Example 1

Preparation of 6,7-dimethoxy-1- [4-N-ethylcarbamoyloxy) piperidino] phthalazine

1-Chloro-6,7-dimethoxyphthalazine (2.69 g) and 4- (ethylcarbamoyloxy) piperidine (4.4 g) together are heated to 90 ° in isoamyl alcohol (60 ml) for 18 hours. The mixture was filtered while hot and the filtrate was evaporated to dryness to give a brown oil, which was treated with ethyl acetate (30 ml) to filter the resulting solid. Dissolving and cooling this solid in a small amount of boiling acetonitrile immediately precipitates 4- (ethylcarbamoyloxy) piperidine (1.8 g) crystals.

After filtration, the filtrate was treated with ethyl acetate, which was collected and evaporated to dryness in vacuo. The crude product is dispersed in water (50 ml), adjusted to pH 10 with 5N sodium hydroxide solution, and extracted with chloroform (2 x 50 ml). The extract is dried over anhydrous sodium carbonate and then fractionated and purified on a silica powder column (30 × 25 cm) (eluent; chloroform + 21/2% methanol chloroform solution).

Fractions (40 ml) identified by TLC were collected and dried to give a glassy solid. This solid is dissolved in warm ethyl acetate (25 ml), cooled, diluted with excess ether and the precipitate collected. Recrystallization from acetonitrile gives 6,7-dimethoxy-1- [4- (N-ethylcarbamoyloxy) piperidino] phthalazine (1.6 g) as pale yellow crystals (melting points 182 to 186 °). .

% Analyzed; For C ₁₈ H ₂₄ N ₄ O ₄

Found: C 59.6; H 6.8; N 15.8

Calculated: C 60.0; H 6.7; N 15.6

(Repeat the same process using triethylamine instead of piperidine to get the same result.)

[Examples 2 to 37]

The following phthalazines are obtained as in Example 1 from 1-chloro-6,7-dimethoxyphthalazine and suitable 3- or 4-substituted piperidine.

Example 38

6,7-dimethoxy-1- [4- (3'-benzyl-1'-methylureido) piperidino] phthalazine hydrochloride

Anhydrous chloroform solution (30 ml) containing 6,7-dimethoxy-1- [4- (N-methylamino) piperidino] phthalazine (1.5 g as oxalate salt) was converted to benzyl isocyanate (1.5 g). The resulting mixture is heated with reflux for 16 h.

The chloroform is then evaporated in vacuo, the residue is redissolved in ethyl acetate (5 ml) and added to a glass column filled with 100 g of Florisil. Elution with chloroform (1000 ml) yields 100 ml of fractions. Identify the fractions by TLC, collect and evaporate.

The crude product obtained is dissolved in ethanol (5 ml) and precipitated with hydrochloride through hydrogen chloride gas. Recrystallization from methanol: ether (1: 5) mixture gives 6,7-dimethoxy-1- [4- (3'-benzyl-1'-methylureido) piperidino] phthalazine hydrochloride (melting point: 221 °). 0.35 g) is obtained.

NMR; (Trifluoroacetic acid and tetramethylsilane as reference standards): chemical shift (δ.ppm): single bond (3H), 3.15 (NCH ₃ ); Single bond (3H), 4.25 and 4.29 (2 × OCH ₃ ); Single bond (2H), 4.66 (benzylic methylene); Single bond (5H) 7.35 (protons of benzylic phenyl); Single bond (2H) 7.74 (protoned phthalazine) and single bond (1H) 9.26 (proportioned phthalazine).

Example 39

6,7-dimethoxy-1- according to Example 38 with 6,7-dimethoxy-1- [4-N-methylaminopiperidino] phthalazine and 3-isocyanidopyridine as starting materials [4- (3 '-{pyridyl) -1'-methyl uedo} piperidino] phthalazine (melting point: 75 to 77 °) was prepared.

CHCl₃ Analytical Value (%): C ₂₂ H ₂₆ N ₆ O ₃ ㆍ

CHCl ₃

Found: C 53.2; H 5.2; N 16.7

Calculated: C 53.4; H 5.3; N 16.4

Example 40

Preparation of 6,7-dimethoxy-1- [4- (N-methylacetamino) piperidino] phthalazine

H₂O(1.0g)이 얻어진다.Anhydrous chloroform (20 ml) solution in which 6,7-dimethoxy-1- [4- (N-methylamino) piperidino] phthalazine (1.8 g) and triethylamine (0.8 g) were dissolved after stirring and cooling. Acetic anhydride (0.4 ml) is added. The solution is stirred for 18 hours at room temperature, concentrated in vacuo, shaken with water and extracted with chloroform (2 x 50 ml). The combined organic extracts were shaken with recovered sodium oxide (50 ml), dried over sodium sulfate and dried in vacuo to give a brown oil which was treated with 30-40 ° C., petroleum ether (70 ml) and decanted. To prepare the oxalate salt, the residue is dissolved in warm ethyl acetate, filtered and evaporated to dryness in vacuo and then redissolved in ethyl acetate. The solution was made acidic (pH 4) with acetic acid in ethyl acetate, and the obtained solid was collected and recrystallized from isopropyl-alcohol to give 6,7-dimethoxy-1- [4- (N-methylacetamido) piperidino. Phthalazine monooxalate

H ₂ O (1.0 g) is obtained.

Melting Point: 211 to 214 °

H₂OAnalytical Values (%): C ₁₈ H ₂₄ N ₄ O ₃ : C ₂ H ₂ O ₄

H ₂ O

Found: C 54.8; H 6.1; N 12.9

Calculated: C 54.7; H 6.1; N 12.8

Example 41

N, butyric anhydride is used instead of acetic anhydride to prepare 6,7-dimethoxy-1- [4- (N-methyl-n-butyramido) piperidino] phthalazine hydrochloride-hemihydrate.

Melting Point: 110 to 111 °

Analytical Value (%): C ₂₀ H ₂₈ N ₄ O ₃ ㆍ HCl ° 1/2 H ₂ O

Found: C 57.3; H 7.0; N 13.7

Theoretic value: C 57.5; H 7.3; N 13.4

Example 42

Preparation of 6,7-dimethoxy-1- [4- (N-ethoxycarbonyl-N-methylamino) piperidino] phthalazine oxalate

Ethylchloroform in anhydrous chloroform (20ml) solution containing 6,7-dimethoxy-1- [4- (N-methylamino) piperidino] phthalazine (1.0 g) and triethylamine (0.9 ml) Mate (0.36 g) is slowly added at 5 ° and the reaction mixture is stirred for 18 hours at room temperature. If the reaction was not completed by thin layer chromatography, 0.45 ml of triethylamine and 200 mg of ethyl chloroformate were added and stirred for 72 hours. The reaction mixture is shaken with 2N hydrochloric acid (15 ml), the chloroform layer is washed with 2N sodium hydroxide (20 ml), dried over MgSO ₄ vacuum and concentrated. The residue, yellow oil, is dissolved in a minimum amount of ether, filtered and concentrated in vacuo, then dissolved in a minimum amount of ethyl acetate and acidified with pH in ethyl acetate (pH 4). The pale yellow oxalate salt was collected and crystallized from ethanol and acetonitrile to give 6,7-dimethoxy-1- [4- (N-ethoxycarbonyl-N-methylamino) piperidino] phthalazine mono-oxalate ( 540 mg) is obtained.

Melting Point: 206 to 209 °

Analytical Values (%): C ₁₉ H ₂₆ N ₄ O • C ₂ H ₂ O ₄

Found: C 54.5; H 6.5; N 12.5

Theoretic value: C 54.3; H 6.1; N 12.1

Example 43

6,7-dimethoxy-1- [4-benzyloxycarbonyl- using benzylchloroformate, 6,7-dimethoxy-1- [4- (N-methylamino) piperidino] phthalazine N-methylamino) piperidino] phthalazine hydrochloride-hemihydrate (melting point: 235 °) is obtained.

Analytical Value (%): C ₂₄ H ₂₈ N ₄ O ₄ ㆍ HCl 1/2 H ₂ O

Found: C 59.5; H 6.2; N 11.2

Theoretic value: C 59.8; H 6.3; N 11.6

Example 44

Preparation of 6,7-dimethoxy-1- [4- (N-n-propylcarbamoyloxy) piperidino] phthalazine hydrochloride

Reflux 6,7-dimethoxy-1- [4-hydroxyferino] phthalazine (0.81 g), n-propyl isocyanate (0.83 g), triethylamine (0.4 ml) and anhydrous chloroform (20 ml) together Heating for 10 hours. The mixture is cooled, treated with water (15 ml) and then separated. The chloroform layer was shaken with 1N sodium hydroxide (10ml) and dried and evaporated to dryness in MgSO ₄ , vacuum to give yellow oil. This oil is dissolved in a minimum amount of chloroform and chromatographed on silica (3 x 27un). Elute with chloroform while increasing the amount of methanol up to 10%. Discard the first 800 ml of eluate and collect 14 × 70 ml fractions. Selecting a suitable fraction by TLC and evaporating in vacuo yields a yellow oil. This oil is dissolved in a minimum amount of ethyl acetate, diluted with ether (30 ml) and adjusted to pH 3. The precipitates were collected and recrystallized from acetonitrile to give 6,7-dimethoxy-1- [4- (Nn-propylcarbamoyloxy) piperidino] phthalazine hydrochloride (0.32 g).

Melting Point: 175 to 180 °

Analytical Values (%): C ₁₉ H ₂₆ N ₄ OHCl

Found: C 55.3; H 6.5; N 13.8

Theoretic value: C 55.5; H 6.6; N 13.6

[Examples 45 to 49]

The following phthalazines are prepared using 1- (3- or 4-hydroxypiperidino) -6,7-dimethoxy-phthalazine and suitable isocyanates as starting materials.

Example 50

Preparation of 1- (4-acetoxypiperidino) -6,7-dimethoxyphthalazine oxalate

1- (4-hydroxypiperidino) -6,7-dimethoxyphthalazine (1.45 g) and acetic anhydride (1.5 g) acetic acid (12 ml) are heated together at 90 ° for 17 hours. The cooled solution is diluted with water (20 ml), adjusted to pH 10 with sodium carbonate and extracted with chloroform (2 × 50 ml). The chloroform extract was washed with water and evaporated to dryness in vacuo to give a dark oil. The oil is added to a silica powder column (30 x 2.0 cm) and eluted with chloroform with increasing amount of methanol up to 30%.

Collect 15 fractions (100 ml each case), collect 11-13 fractions and evaporate to dryness in vacuo to give an oily residue that is treated with ether. Filtration removes insoluble matters and the ethereal solution is treated with etheric hydroxyl to precipitate gelatinous oxalate. Recrystallization from ethanol yields pink crystals of 1- (4-acetoxypiperidino) -6,7-dimethoxy phthalazine mono-oxalate (120 mg).

Melting Point: 212 to 213 °

Analytical Values (%): C ₁₇ H ₂₁ N ₃ O ₄ ㆍ C ₂ H ₂ O ₄

Found: C 54.1; H 5.5; N 9.9

Theoretic value: C 54.2; H 5.5; N 10.0

Example 51

Preparation of 6,7-dimethoxy-1- [4- (2-hydroxypropyl) piperidino] phthalazine

6,7-dimethoxy-1- [4- (2-acetoxypropyl) piperidino] phthalazine (1 g) is heated to 90 ° in a mixture of 5N sodium hydroxide (5 ml) and ethanol (5 ml) for 30 minutes. . The mixture is evaporated in vacuo and the residue is dispersed in water (25 ml) and extracted with chloroform. The chloroform extract is washed with water (20 ml) and evaporated in vacuo to give an oily crude product which solidifies when treated with ether (20 ml). Recrystallization from acetonitrile gives 6,7-dimethoxy-1- [4- (2-hydroxypropyl) piperidino] phthalazine (400 mg).

Melting Point: 154 to 156 °

Analytical Values (%): C ₁₈ H ₂₅ N ₃ O ₃

Found: C 65.2; H 7.6; N 12.6

Theoretic value: C 65.2; H 7.6; N 12.6

Example 52

Preparation of 6,7-dimethoxy-1- [4-acetonylpiperidino] phthalazine hydrochloride

6,7-dimethoxy-1- [4- (2-hydroxypropyl) piperidino in a mixture of stirred chromium trioxide (50 mesh, 3.5 g) anhydrous methylene chloride (90 ml) and anhydrous pyridine (5.5 g) ] Add phthalazine (1.7 g). The mixture is stirred under nitrogen atmosphere for 3 hours, then excess (0.880) ammonia is added and the reaction mixture is stirred for another 2 hours. The organic layer is passed through a short silica column to remove the chromium salt and filtered through Hyflo covered with a carbon layer (0.5 cm).

Evaporation in vacuo yields an oxidation product in the form of a straw straw oil, which is redissolved in a minimum amount of ethyl acetate and treated with excess etheric hydrogen chloride to precipitate hydrochloride. Recrystallization from ethanol yields 6,7-dimethoxy-1- [4-acetonylferridino] phthalazine hydrochloride (0.5 g).

Melting Point: 213 to 214 °

Analytical Values (%): C ₁₈ H ₂₃ N ₃ O ₃ ㆍ HCl

Found: C 58.4; H 6.7; N 11.2

Theoretic value: C 59.1; H 6.6; N 11.5

Claims (1)

The phthalazine of the following structural formula (III) is reacted with the amine of the following structural formula (IV) and the HQ ¹ is subsequently removed, or the phthalazine of the following structural formula (V) is subjected to the following (1), (2) , React with (3), (4), (5), (6), (7), and (8), if necessary, protect the hydroxy group, the primary or secondary amino group before the reaction, and when the reaction is complete Removing the group to prepare the corresponding phthalazines of the following structural formula (I) or acid addition salts thereof.

(A is -NHR ⁴ , -OH, -NH ₂ ,-(CH ₂ ) mCOQ ¹ , -NR ⁴ COQ ^3. )

R ¹ in the above formula is a hydrogen atom or a lower alkyl group; (R ² ) n is 1 to 3 substituents, each R ² is a hydroxy or lower alkoxy group, n is an integer of 1 to 3, or two groups in R ² are bonded to a position adjacent to the benzene ring Forms a methylenedioxy or ethyleneoxy group, Y being a group linked to the 3- or 4-position of a piperidino ring; -Z ¹ -COR ³ ,

,

, Hydroxy, lower alkanoyloxy or lower alkoxy groups; Or a lower alkyl or lower alkoxy group substituted by hydroxy, lower alkoxy or -CONR ⁶ R ⁷ group. Wherein Z ¹ is -CH ₂ -or

ego; R ³ is a lower alkyl group optionally substituted with amino, hydroxy, lower alkoxy, aryl or heteroaryl group; Lower alkenyl- or lower alkynyl-methyl groups; Lower alkoxy groups optionally substituted with amino, aryl, hetero aryl, lower alkoxy or hydroxy groups; Aryl group; Aryloxy group; Or hetero aryl group; R ⁴ is a hydrogen atom; Lower alkyl group optionally substituted with amino, lower alkoxy, hydroxy, aryl or heteroaryl group; R ⁵ is as defined in R ³ or

Group; R ⁶ is as defined for R ⁴ or R ⁶ and R ⁷ together with the nitrogen atom form a saturated monocyclic isocyclic ring, R ⁷ is a hydrogen atom or a lower alkyl group; Z ² is

Or -O-, provided that Z ²

R ⁴ and R ⁷ together represent-(CH ₂ ) ₂ --(CH ₂ ) _3- , 0-phenylene group). (1) Isocyanate R ⁶ NCO, wherein R ⁶ is not hydrogen and is reacted with sodium or potassium cyanate in the presence of acid to produce a compound in which R ⁶ is hydrogen. (2) haloformates or acyl halides of formula Q ² COR ³ . (3) halosulfonates, sulfonyl halides or sulfamoyl halides of formula Q ² SO ₂ R ⁵ . (4) Carbamyl halide of formula R ⁶ R ⁷ NCOQ ² (R ⁶ , R ⁷ ≠ H). (5) anhydride or pyrocarbonate of formula (R ³ CO) ₂ O. (6) phosgene (7) structural formula

Ester of N-hydroxysuccinimide. (8) R ⁶ R ⁷ NH, provided that Q ¹ is a good leaving group, Q ² is chloro or bromo, Q ³ is lower alkyl substituted with chloro or bromo, m is an integer from 1 to 6 .