JPS5948463A - Phthalazone derivative, its preparation and use - Google Patents

Abstract

NEW MATERIAL:The phthalazone derivative of formula I (R is H or lower alkyl; A is group of formula II or formula III; n is 0-14). EXAMPLE:7-Ethoxycarbonyl-6,8-dimethyl-1( 2H )-phthalazinon-4-ylmethyl hydrogen succinate. USE:Useful as a biotransformation precursor of phthalazinol which is useful as a preventive and remedy for hypertensive, arteriosclerotic and thrombotic diseases. The compound is converted to phthalazinol in the body to exhibit the pharmacological activity, and is useful as a remedy for angiopathy. PROCESS:Phthalazinol of formula IV is esterified with a carboxylic acid or its functional derivative, and the 4-hydroxymethyl group is converted to CH2-A-OR group to obtain the compound of formula I . The carboxylic acid or its functional derivative is, e.g. oxalic acid, adipic acid monoethyl ester, etc.

Description

[Detailed description of the invention]

The present invention relates to a phthalazine derivative, a method for producing the same, and a method for use in fl, which have not been disclosed in any known literature.In particular, the bath η/r properties of the known medicinal compound phthalazinol are unsatisfactory.
The absorption rate into the body is relatively slow, and it is more susceptible to in vivo metabolism.
g) Useful as phthalazine, λ? Regarding one thing. More specifically, the present invention, 1, the following formula (+)(,'H8
0 However, in the formula, l? represents a hydrogen atom or a lower alkyl group, and A represents -C゛- or -C-fcH, 翰-c- (here, j represents 0 or an integer from 1 to 14), a phthalazine derivative represented by Regarding the formula (+
) Also relates to the manufacturing method and use of chemical additives. Conventionally, the medicinal compound phthalasonol (6,8-tumethyl-7-nitoxycarbonyl-4-hydroxymethyl-1-7 talazone) represented by the following formula (It) t'E, IO, its production method and pharmacological activity have been reported. known (e.g. US Patent No. 3963.716; Canadian Patent No. 1029377; British Patent No. 145960)
No. 6; West German State License No. 2451417; Japanese Patent Application Publication No. 1983
-68609; etc.). For example, the above U.S. patent describes phthalazinol, its manufacturing process,
Pharmacological activity tests, etc. are disclosed in detail, and hypertensive diseases
), arteriosclerotic and thrombotic diseases (a, theros
-clerotic and thrombo
It has been described that it is useful as a treatment agent for the prevention and treatment of tic diseases.
), coronary artery thrombosis (coron'J/lhro
mbosis), periph
Cerebral arteriosclerosis (cerebral arteriosclerosis)
roSclero-sis), coronary artery (+ keratosis (c
oronary ath, e-rosclerosi
s), arterial atresia (arte-rioscL)
ttrosis obliterans), thromboangiitis vera (thromboang),
literans diabetic vasculopathy
, y of diabetesme LLitus)
X diabetic retinopathy (re t 1nopa, -thy
of diabetes mellitv, s)
Treatment of various vascular disorders such as arteriosclerotic diseases such as
It is disclosed that it is useful as culm 1. father,[
History of Medicine J Volume 102 describes the therapeutic effect of phthalazinol on cerebellar atrophy, ``Modern Medicine'' Volume 13 describes its therapeutic effect on diabetic retinopathy, and ``Late Autumn and Research'' 59
The volume introduces the clinical effects of phthalazinol on subjective symptoms, psychiatric symptoms, and central pain of cerebrovascular accident sequelae. For example, the above-mentioned Japanese Patent Application Laid-Open No. 56-686o9-'
As introduced in 41C%, when 77N-nol is used as a treatment agent for vascular disorders, the phthalazinol is
Its hydrophilicity and lipophilicity are relatively low (about 2), its hydrolyzability is unsatisfactory, its absorption into the body is relatively slow, and on the other hand, it has the disadvantage of being susceptible to metabolism in the body. hand,
A disadvantage is that it is difficult to maintain desired blood levels at appropriate doses. For the purpose of pharmaceutically improving such adverse effects, the above-mentioned Japanese Patent Application Laid-Open No. 56-68609
In this proposal, a phthalazinol formulation is proposed that contains a water-soluble cellulose ether, preferably a water-soluble cellulose ester, and a polyhydric monoalcohol. The present invention differs from the above proposal by using chemically modified phthalazinol compounds, so-called glodrugs (in vivo As a result, we have conducted research to develop a precursor substance represented by the formula (n):
C′ 11 , O-A-OR (where A and R are the same as defined for +1), and the compound of formula (1) can be easily formed into W,...!
The compound of formula (1) is a compound that has not been previously described in any known literature, and is converted into phthalanonol of formula (n) in vivo, and has a high solubility, absorbability into the body, metabolic property, etc. It was discovered that this compound is useful as an in vivo precursor of phthalazinol, which exhibits ameliorating properties. Therefore, an object of the present invention is to provide a compound of formula (1) useful as an in vivo precursor of Phthaladuno/L7 Q:/21. Another object of the present invention is to prepare the compound of the formula (1) and to use a compound rich in the compound of the formula (1) as an active ingredient, which is useful for the treatment of various JfIl disorders, such as those exemplified in Section M.
to provide the agent. The above objects and further objects and advantages of the present invention will become apparent from the following description. The formula (1) of the present invention is phthalazine induced by the formula (If
) of phthalazinol as a carboxylic acid or 11=,? 47! > esterification with iX formula ([1
) The -C' II 2011 group at the 4-position of phthalazinol can be easily converted into the formula (-C1120-A-01<). J, υ below, several aspects of this will be exemplified. ! Ren-sama (1): As a functional substance of carboxylic acid,
An embodiment in which the anhydride of dicarboxylic acid is brought into contact with the anhydride of the dicarboxylic acid of formula ('IL), -C1i,OH at the 4-position of the formula (II) phthalazinol is esterified to form -CH,0-A'-OR (here, A'
is A in the formula (+).Thus, in formula (1), a compound in which A is A' and R is a hydrogen atom can be easily produced. The reaction is preferably carried out in a suitable solvent, and the reaction temperature and time can be appropriately selected. If this is the case, the reaction will proceed even at room temperature, so there is no need to heat it. Time can be given as an example. The reaction molar ratio can also be selected appropriately, for example, formula (Il, , )
An example may be an amount of about 1 to about 3 moles of the hydrate per mole of the compound. After the completion of the reaction, the solvent is distilled off, the residue is washed with water as desired, and the desired product is obtained in the form of crystals by, for example, crystallizing it as an acid between the groups.
In some cases, it can be purified by recrystallization or other purification means. i for 4/11? Examples of tno, 'i: include, for example, pridine, triethylamine, etc., amide solvents such as nomethylformamide, diethylformamide, and carboxylic acids such as acetic acid, zolopion C (do, etc.); Examples include halogenated hydrocarbons such as chloroform, dichloromethane, etc.; ketones such as acetone, methyl ethyl ketone, etc.; and ethers such as dioxane, tetrahydrofuran, etc. :f, there are no particular restrictions, and the amount of solvent can be fully selected for IJ as appropriate. The dicarvone 1ζ utilized in this manner! Examples of anhydrides: For example, shu [shun, malonic acid, phosphoric acid,
Mention may be made of the anhydrides of aliphatic saturated dicarboxylic acids of 62 to 62C, such as azelaic acid and sepacic acid. In the formula (1) that can be obtained by the above-mentioned aspect (1), A is =(,'-(-(,'E,suC゛-(here, U is 0 or an integer from 1 to 14) For example, a compound in which R is a hydrogen atom is halogenated at the terminal 011 by the action 1-v with a halogen 7111 such as thionyl chloride, and then contacted with a lower alcohol, preferably (
can be easily converted into a compound (11) in which R in the terminal OR is a lower alkyl group by contacting it in the presence of a suitable acid acceptor such as triethylamine. The reaction is, for example, 91 in chloroform or benzene fxt.
In the presence of J solvent or in the absence of &j, J: embodiment (
The compound of formula (1,3) obtained in 1) and the halogenating agent are brought into contact with each other under conditions of cooling or cooling to about 80° C. for about 0.5 to about 8 hours to form a terminal OR. After halogenation, the product is dissolved in lower alcohol, trace &
f) Adding an acid acceptor such as triethylamine, f) can be carried out by leaving the mixture at room temperature for about 0.5 to about 3 hours. The amount of halogen compound to be used can be selected as appropriate.For example, the formula (+
) Prepare a fecal dose of about 1 to about 10 moles per mole of compound in 13'lJ. Father, the field for lower alcohols is also a suitable choice, for example, about 1 to about 20 moles for halogenation generation and 11 moles! One historical dose can be exemplified. Section T of the reaction path: The precipitated ax-9 crystals were collected and the hydrogen atom of H in the compound of formula (1) obtained in the above embodiment (1) was
A compound of formula (1), which is an alkyl group corresponding to the lower atomyl group of the lower alcohol used, can be used. As an example of the above embodiment (1), using gluguric anhydride,
An example of converting the hydrogen atom of R in the obtained product 2 (1) into an ethyl group can be expressed as follows. 0 0 t'H30 Formula (1) Compound 0 0 C゛noi0 Formula (+1 Compound Embodiment (ii): Embodiment in which an aliphatic Nj1-socarboxylic acid monohalide monoalkyl ester is used as the functional d♂ soul of the carboxylic acid. By contacting phthalazinol of formula (Il) with an aliphatic saturated dicargonic acid monohalide mono-lower alkyl ester of C'', ~C16, 4 of phthalazinol of formula (■) can be prepared.
-cB and On at -position are esterified, -CE, 0-A'
−011 (Here, A' is given by formula (1)
In, A is A′ and l? Compounds in which is a lower alkyl group can be easily produced. At this time, it is preferable to carry out the reaction in the presence of an acid acceptor. The reaction is preferably carried out in a suitable bath medium such as pyridine or dimethylformamide, and the reaction humidity and time can be selected as appropriate. For example, since the reaction proceeds even at room temperature, there is no need for particular heating or cooling; however, the reaction temperature may be, for example, about θ to about 150°C, and the reaction time may be, for example, about 1 to about 8 hours. can. The reaction molar ratio can also be selected appropriately. example is,
It can be shown that about 1 to about 3 moles of the dicarboxylic acid monohalide monolower alkyl ester can be added per mole of the compound. (7) If desired, the residue can be washed with water, dried, and purified by recrystallization or other purification methods if desired. Examples include acid acceptors such as trimethylaniline and triethylamine. 1, about 1 to about 20 moles relative to the phthalazinol of formula (n) can be exemplified. Examples of lower alkyl esters include 3 <Sida C'', ~C'' in the above aspect (i).
1. A monohalide of an aliphatic saturated dicarboxylic acid can be exemplified. As an example of Recommendation 41M(ii) above, an example using adipic acid monoethyl ester can be expressed as follows. C1i, 0 Formula (n) Compound 0 1130 Formula (1) Compound Embodiment (iii): Monocarboxylic acid lower alkyl ester halide (or halocarbon 1"i) lower alkyl) as a functional conductor of carboxylic acid 3 Embodiment. Formula (■) Phthalazunol is monocarboxylic acid lower alkyl ester halide X, (, '0UR (where Xi
The formula (I
f) -(,' li zo
Esterified to 11 -r, -c″It20-A″-O
R (here A” irJ formula (j) K o IrJ le A
In E (+), A is A" and R is a lower algirma: y, the compound Il et al. 1 is easily prepared by converting to The reaction can be carried out using a suitable solvent such as vinegar, bi'lysine, or

[It is common to wart in Goroholm etc., and the time and time are also l'l ■ 1
Examples include temperatures such as i:f O to about 100°C, preferably about room temperature to about 80°C, and reaction times such as about 1 to about 8 hours. After the reaction is completed, the solvent is distilled off, and if desired, the solution is washed with water and dried, and further,
qW? by recrystallization or other purification means if desired. can do. An example using ethyl chlorocarbonate as an example of the above-mentioned method 5(111) can be expressed as follows. IJ30 Formula (11) Compound esterification CM, 0-C-0(,'', 11゜Embodiment (iv): As carboxylic acid or its functional carboxylic acid; 1 aliphatic group fII dicarboxylic acid% L <
rP using monoalkyl ester of 1i(-,
. Formula ([1) phthalazinol is converted to c゛2 to c゛1. The -C' 1120 Hf at the 4-position of the phthalazinol of formula (Il) is esterified by contacting with a monoalkyl ester of a monoalkyl ester of phthalazinol of the formula (Il), and =(,' II 20 -A'-U jt'
(Here, by adding 0 0 to A (+), it is possible to produce a compound Q'i with the formula (I) where A is A'. If desired, the above v'
In the solvent exemplified in X'-like (1), amine 4 + J] and calyF acid human tt etho can contain f valley 1 (b+,'. Also, reaction -1 is used) i ■ 4 (existence 1
For example, 4J dihydrochloric acid, mineral acid such as bamboo acid, and sulfonic acids such as para-toluenesulfonic acid can be used. )i-1f. The present invention i < (representing an integer of 1 to 14). Examples of the lower alkyl group for R are C1 to C such as methyl, ethyl, propyl, impropyl, butyl, inobutyl, sec, butyl, tert, and butyl.
+4 alkyl ha (〆11 can be shown, preferably C',
, -t''2 alkyl group. The formula (1) of the present invention is useful as a prodrug of the known medicinal substance phthalazinol, and is converted into phthalazinol in vivo. Known drugs such as phthalazinol 1) are effective. Therefore, according to the present invention, there is provided a blood flush disorder treatment II'' which is characterized in that it contains as an active ingredient phthalazinol represented by the above formula (1) /iE, 11J in the body, and phthalazinol as an active ingredient. The treatment agent may be in a variety of dosage forms, such as powder, granules, granules, tablets, capsules, lozenges, y'
Examples include dosage forms such as 4 tablets and other arbitrary oral dosage forms. For vtM A11, all kinds of carriers and diluents can be used, such as polyethylene glycol, propylene glycol, glycerol, vegetable oil, dulcose, lactose, starch, sucrose,
Preparative agents such as cetyl alcohol and cacao bak
Examples include solid to laminated carriers and diluents that can be mixed. 11Ai agent means per se are well known, and known means can be used in the sub-tanks of each of the above-mentioned examples. The agent of the present invention may contain an appropriate amount of the active ingredient of formula (1), for example, from about 0.1 to about 80%, based on the weight of the formula (1), based on the weight of the active ingredient. The treatment according to the present invention can be administered in various forms, including oral administration.
ji is preferred. Administration: As a side dish, C (good, A: (as a compound, l + 11, Ql: layer 11~) J B Orr
+7 /yu°b oci? / / An example of this can be Fj's 卆YO-Europe. The compound of the present invention (1f) converts into a known phthalazinol in vivo, but the compound itself does not show antiquity. A test and conclusion J, which tested the conversion to fugradinol in the living body as an in vivo ni, +, rib product.
- Give an example. Test force method 3 large knee peagles (male adult dogs) 1・jl rE'+・4:
The compound of the uninvented formula (1) and phthalanonol (
Fill a control tube and administer orally. The administration test of 4-6 stitches was conducted approximately 2 weeks apart from the administration test of Futhalazunol. After administration, blood was collected from the forelimb vein every 0.5, 1, 2, 4 and 8 hours. The serum was obtained by centrifugation at 3000γ, 71, 77+, 20 minutes.
ml was extracted three times with ethyl acetate and the extracts were combined.
This extract was dehydrated with anhydrous sodium sulfate, and then ethyl acetate was distilled off under pressure. 50% methanol aqueous solution 0
．． 5 ml was added, and the concentration of phthaladunol in the serum was measured by high performance longitudinal chromatography. The measurement conditions for high performance liquid chromatography are as follows. Column: 5hodex 01) SF-411 (reversed phase silica ruf elution ρ niacetonitrile/methanol 70.01M phosphate buffer <pHr, 4) [1o:22, 5:6
7.5) Measurement wavelength: 220?1. frL Yui! From the data obtained by the above test method, time 11+1
- n degree curve was created, and the formula (1) of the present invention for the lower surface A U C of phthalazonol concentration in the serum of the phthalazinol administered example (control) was calculated. The ratio of the lower surface area (AUC) was calculated as p.The average value of the l-4 degree lower surface area ratio (AUC ratio) obtained from the results of the three animals for each live test was calculated. The axis (1k) is shown in Table 1 below. In the table, the compound l ship is the same as the example floor of the steamed bun. ) 3 If you exceed 100 and get 200, then C' Table 1 The compound is public.
It can be seen that the in-vivo precursor of the medicinal substance phthalazinol is useful as a whole and exhibits a better blood circulation than phthalazonol. As shown in FIG. Similar symptoms can be exemplified by already exemplifying phthalazinol.Hereinafter, the present invention formula (II compound and its production example are shown in Examples.Example l Phthalazinol 2.76, ¥(0, 01 mole) was dissolved in 15me of succinic anhydride, and 1.2 g of succinic anhydride was added to this solution.
(0,012 mol) was added little by little under stirring.
The mixture was kneaded for about 4 hours at 0° to 90°C. After the reaction, acetic acid was distilled off under reduced pressure, and the resulting residue was dissolved in ethyl acetate to give a 10%
After adding 1 bottle of sodium carbonate aqueous solution and shaking, collect the aqueous phase, add aged HCI to Il under cooling and stirring conditions, remove the precipitated crystals, and recrystallize with ethanol to yield 1.4
．． 9 (yield 37%) of 7-nitoxycarponyl-131
Symethyl-1(2B)-phtacysonon-4-ylmethylbatrokene succinate was obtained. Example 2: 2.76 & (0,01-F, L) was added to 30 rrt Ic MNL of pyridine, and 1.0 ml of daltaric anhydride was added to this solution. 5.9 (0,013 mol) was added in portions at a time under stirring conditions, and after the addition was completed, it was left to react at room temperature overnight. After the reaction, all of the pyrinone was distilled off under reduced pressure, leaving a residue. Add ice water to the solution, adjust the pH to 3 with concentrated 11Cl, and precipitate 1.
11 The resulting crystals were collected and recrystallized from coarse ethanol to give 7-nidoxycaryl-6,8-dimethyl-1(2M)-phthacysonone-4 in 3.14.9 (yield 54%).
-ylmethylbaitroke 8 glutarate was obtained. The physical property values are shown in the second column. Example 3 The compound obtained in Example 2 above had a weight of 1.9551
[The residue obtained by distillation was dissolved in boat water ethanol, and triethylamine o, 5 M (0,0
In addition, the precipitated crystals were separated from the Wt product for 2 hours and then recrystallized with ethanol to give 0=54
．． ! 7-nitoxycarponyl of $ (26% yield) 6.
From 8-dimethyl-1(2#)-phthalazinon-4-ylmethylethylglutarate. Its physical property values are shown in 1t1. Example 4 Phthalasonol 2.76 & (0,01 mol) dissolved in Je pyridine 30-, 2.3 g (0,012 mol) of acid chloride of monoethyl adipate was added in small portions under stirring conditions, and after the addition was complete. The reaction mixture was allowed to stand overnight at room temperature. After the reaction, pyridine was distilled off under reduced pressure, and the obtained residue was dissolved in chloroform and washed twice with water. The chloroform layer was collected and dried with Glauber's salt. Chloroform was distilled off under reduced pressure.The residue was crystallized from ethanol to give 3.7g (
7-nitoxycarponyl-6,8-dimethyl-1(2H)-phthalazinone-4-ylmethylethylazide was obtained with a yield of 86%. Its physical property values are shown in Table 2 below. Example 5 Phthalasonol 2.76,? (0.01 mol) was dissolved in 25 meKM of ethyl acetate, further 15 cc of pyridine was added, and to this system was added 1 mol of ethyl chlorocarbonate at room temperature under stirring conditions.
．． After adding 4 JV (0,013 mol), about 50 to 6
The reaction was carried out at 0°C for about 4-5 hours. After the reaction, pyridine and ethyl acetate were distilled off under reduced pressure, and the residue was dissolved in chloroform at f8
After the solution was dissolved and 1% BCI water was added and shaken, the chloroform layer was collected, dried with Glauber's salt, and then the chloroform was distilled off. (Recrystallize the resulting residue with ethanol to give 1.4J
/(yield 40%) of 7-nidoxycarbonyl6.8-
Dimethyl-1(2M)-phthalonon-4-ylmethylethyl carbonate was obtained. Its physical properties 410 are shown in the second article below. Examples 6 to 12 In Example 4, instead of the acid chloride of monoethyl adipate, an equivalent mole of the acid chloride of monoethyl oxalate+. (Actual IK+1 Example 7), Acid chloride of monoethyl glutarate (Example 8), Acid chloride of monomethyl succinate (Example 9), Acid chloride of monoethyl adipate (Example 10), Acid chloride of monomethyl sebacate The compounds of the present invention shown in Table 2 below were obtained in the same manner as in Example 4, except that (Example 11) and the acid chloride of monoethylsperate (Example 12) were used. .

Claims (1)

[Claims] 1. Represented by the following formula (11% formula %, where R represents a hydrogen atom or a lower alkyl group, and Y represents 0 or an integer from 1 to 14) Phthalazine derivatives. 2-t Furumi formula (1) However, in the formula, R represents a hydrogen atom or a lower alkyl group, and each represents O or rj: represents an integer from 1 to 1+)
The in-vivo i'\iJ kite Y of phthalazinol represented by
7 (contains the active ingredient [7]! To the samurai's blood disorder treatment 11, agent. By esterifying with a functional dicentrode, the 4-position hydroquine Mevre J, 4 is depleted -C1120-A-OR (here, A and R have the same meaning as defined for the following ♂, : (+))
The following formula (I) is characterized in that it is converted into
(7“Mokuku-t-(,'-(-C“H2←C゛-
(Ko? L Here, j is O or 1.4 touch of 1 to 14), represented by phthalazine village 2.J,) body's 〃(゛) method.