GB2127805A - Phthalazones - Google Patents
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- GB2127805A GB2127805A GB08324389A GB8324389A GB2127805A GB 2127805 A GB2127805 A GB 2127805A GB 08324389 A GB08324389 A GB 08324389A GB 8324389 A GB8324389 A GB 8324389A GB 2127805 A GB2127805 A GB 2127805A
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- phthalazinol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
- C07D237/30—Phthalazines
- C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
Abstract
Compounds of the general formula <IMAGE> (R<1> represents a C1-C12 alkyl group or the group -OR in which R represents a C1-4 alkyl group; A represents <IMAGE> in which n represents 0 or an integer of 1 to 14; R<2> represents a hydrogen atom or the group <IMAGE> in which R<3> represents a C1-C12 alkyl group; provided that when R<2> is the group <IMAGE> R<1> is a C1-C12 alkyl group and A is <IMAGE> and when R<2> is a hydrogen atom, R<1> is the group -OR) are phthalazinol prodrugs.
Description
SPECIFICATION
Phthalazone derivatives, and their preparation and use
This invention relates to phthalazone derivatives not described in the known literature, a process for production thereof, and to use thereof. Particularly, it relates to phthalazone derivatives useful as a prodrug for phthalazinol, a known pharmaceutically effective compound, which are free from the unsatisfactory solubility, the relatively slow speed of absorption into the body and the susceptibility to in vivo metabolism of the phthalazinol.
More specifically, this invention pertains to phthalazone derivatives of the following formula (I)
wherein R1 represents a C1-C12 alkyl group or the group -OR in which R represents a lower alkyl group;
A represents
in which n represent 0 or an integer of 1 to 14; R2 represents a hydrogen atom or the group
in which R3 represents a C1-C12 alkyl group; provided that when R2 is the group
R' is a C1-C12 alkyl group and A is
and when R2 is a hydrogen atom, R1 is the group -OR.
The present invention also relates to an agent for treating vascular troubles comprising the compound of formula (I) as an active ingredient, and to a process for producing the compound of formula (I).
Heretofore, a pharmaceutically effective compound, phthalazinol (7-ethoxycarbonyl-4 hydroxymethyl-6,8-dimethyl- 1 -phthalazone),
a method for its production and its pharmacological activities have been known (see, for example, U.S.
Patent No.3,963,716; Canadian Patent No. 1029377; British Patent No. 1459606; West German
Patent No. 2451417; and Japanese Laid-Open Patent Publication No. 68609/1981).
For exmaple, the above-cited U.S. Patent gives a detailed disclosure of phthalazinol, a process for its production and its pharmacological tests, and states that it is useful as a treating agent for various vascular troubles, for example thrombotic diseases such as cerebral thrombosis, coronary thrombosis and peripheral thrombosis, and arteriosclerotic diseases such as cerebral atherosclerosis, coronary atherosclerosis, arteriosclerosis obliterans, thromboangiitis obliterans, angiopathy of diabetes mellitus and retinopaty of diabetes mellitus. A Japanese-language publication "Advance in Medicine", Vol. 102 reports the therapeutic effect of phthalazinol on cerebellar ataxia. A Japanese-language Publication "Modern Medical Therapy", Viol. 13 reports its therapeutic effect on retinopathy of diabetes mellitus.
Furthermore, a Japanese-language journal "Clinic and Study", Vol. 59 discloses the clinical effect of phthalazinol on the subjective symptoms, mental symptoms and central pain of sequelae of cerebrovascular troubles.
As stated in the above-cited Japanese Laid-Open Patent Publication No. 68609/1981, phthalazinol has the disadvantage that in its utilization as an agent for treating vascular troubles, it has relatively poor hydrophilicity and oleophilicity and unsatisfactory solubility, the speed of its absorption into the body is relatively slow, and it is susceptible to metabolism in vivo, and that at suitable dosages, its desired concentration in blood is difficult to maintain. In order to overcome this disadvantage pharmaceutically, the above-cited Japanese Laid-Open Patent Publication No. 68609/1981 proposes a phthalazinol preparation comprising phthalazinol and a water-soluble cellulose ether, preferably a water-soluble cellulose ester, and a polyhydric alcohol.
The present inventors have made investigations from a different standpoint from the above prior proposal in order to develop a chemically modified compound, i.e. a prodrug, for phthalazinol which by itself does not show biological activity, but in vivo, returns to phthalazinol and exhibits biological activity.
These investigations have led to the discovery that the compounds of formula (I), which are the derivatives of the known pharmaceutically effective compound phthalazinol represented by formula (Il) can be easily produced, that the compounds of formula (I) are novel compounds not described in the prior literature, and that the compounds of formula (I) are converted in vivo to phthalazinol of formula (II) and are useful as a prodrug for phthalazinol which shows improved properties in solubility, absorbability into the body, metabolizability, etc.
It is an object of this invention therefore to provide compounds of formula (I) which are useful as a prodrug for phthalazinol.
Another object of this invention is to provide a process for producing the compounds of formula (I).
Still another object of this invention is to provide an agent for treating various vascular troubles of the types exemplified hereinabove which comprises the compound of formula (I) as an active ingredient.
The phthalazone derivatives of formula (I) in accordance with this invention can be produced easily, for example, by reacting phthalazinol of formula (II), which is a known active compound for treating vascular troubles, with carboxylic acids capable of forming the compounds of formula (I) or their functional derivatives.
The above reaction can be carried out in accordance with various embodiments by utilizing methods known per se. These embodiments of the reaction are described below in detail.
Embodiment (i): Embodiment in which an aliphatic saturated dicarboxylic acid anhydride is used as the above functional derivative: By contacting phthalazinol of formula (II) with a C2-C16 aliphatic saturated dicarboxylic acid anhydride, -CH2OH at the 4-position of phthalazinol is esterified to -CH2O-A'-OH in which A' represents the group
within the definition of A to give a compound of formula (I) in which A is A' and R1 is the group -OR in which R is a hydrogen atom.
The reaction is preferably carried out in a suitable solvent, and the reaction temperature and time can be selected as desired. The reaction proceeds even at room temperature, and no particular heating or cooling is required. For example, a reaction temperature of about 0 to about 1 500C and a reaction time of about 1 to about 8 hours can be cited.
The mole ratio of the reaction materials can be selected as desired, and for example, about 1 to 3 moles of the anhydride can be used per mole of phthalazinol. After the reaction, the desired product can be isolated as crystals from the reaction mixture, by, for example, distilling off the solvent, optionally washing the residue with water, and crystallizing the residue by, for example, treating it with hydrochloric acid. If desired, the product can be purified by various purifying means such as recrystallization.
Examples of suitable solvents include amines such as pyridine and triethylamine, amide such as dimethylformamide and diethylformamide, carboxylic acids such as acetic acid and propionic acid, halogenated hydrocarbons such as dichloromethane, ketones such as acetone and methyl ethyl ketone and ethers such as dioxane and tetrahydrofuran. There is no particular restriction on the amount of the solvent used, and any suitable amount effective as solvent can be used.
Examples of the C2-C16 aliphatic saturated dicarboxylic acid anhydride used in this embodiment include oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid and sebacic acid.
The compound of formula (I) obtained as above in which A is
wherein n is O or an integer of 1 to 14 and R1 is the group -OR in which R is a hydrogen atom can be
easily converted to a compound of formula (I) wherein the terminal R' is the group OR in which R is a
lower alkyl group by reacting it with a halogenating agent such as thionyl chloride to haiogenated the terminal OH, and contacting the product with a lower alcohol preferably in the presence of a suitable acid acceptor such as triethylamine.
The reaction can be carried out, for example, by contacting the compound of formula (I) obtained in embodiment (i) with the halogenating agent in the presence or absence of a solvent such as chloroform or benzene under cooling or at room temperature to about 800C for a period of, for example about 0.5 to about 8 hours, dissolving the product in a lower alcohol, adding an acid acceptor such as triethylamine, and allowing the mixture to stand, for example, at room temperature for about 0.5 to about 3 hours. The amount of the halogenating agent used can be selected as desired, and for example, it is about 1 to about 10 moles per mole of the compound of formula (I) obtained by the above embodiment (i). The amount of the lower alcohol used can also be selected suitably, and for example, it is about 1 to about 20 moles per mole of the halogenation product.
After the reaction, the precipitated crystals are collected to form a compound corresponding to formula (I) in which the hydrogen atom of the group -OR (R being hydrogen) has been converted to an alkyl group corresponding to the lower alkyl group of the lower alcohol used in the reaction.
One example of the embodiment (i) is schematically shown below with regard to the case wherein glutaric anhydride is used and the hydrogen atom of the group -OR (R being hydrogen) for R1 in the resulting compound of formula (I) is converted to an ethyl group.
Compound of formula (II) glutaric anhydride
Compound of formula (I)
Embodiment (ii): Embodiment in which a monoalkyl ester of an aliphatic saturated dicarboxylic acid monohalide is used as the functional derivative of a carboxylic acids A compound of formula (I) in which A is A' and R' is the group -OR (R being a lower alkyl group) can be easily produced by contacting phthalazinol of formula (II) with a mono(lower alkyl) ester of a C2-C16 aliphatic saturated dicarboxylic acid monohalide to esterify the group -CH2OH at the 4position of phthalazinol (II) to the group -CH2O-A'-OR in which A' is
within the definition of A. The reaction is carried out preferably in the presence of an acid acceptor.
The above reaction is preferably carried out in a suitable solvent such as pyridine and dimethylformamide. The reaction temperature and time can be selected as desired. Since the reaction proceeds even at room temperature, no particular heating or cooling is required. For example, a reaction temperature of about 0 to about 1 500C and a reaction time of about 1 to about 8 hours may be cited.
The mole ratio of the reaction materials can be suitably selected. For example, the lower alkyl ester of a dicarboxylic acid monohalide may be used in an amount of about 1 to about 3 moles per mole of phthalazinol. After the reaction, the reaction mixture may be worked up, for example, by distilling off the solvent, optionally washing the residue with water, drying it and as required purifying it by recrystallization or other purifying means.
Examples of the acid acceptor used are pyridine, dimethylaniline and triethylamine. There is no particular restriction on the amount of the acid acceptor used. For example, it is about 1 to about 20 moles per mole of phthalazinol.
The mono(iower alkyl) ester of the aliphatic saturated dicarboxylic acid monohalides used in this embodiment may include mono(lower alkyl)esters of monohalides, preferably monochlorides, of the C2-C16 aliphatic saturated dicarboxylic acids exemplified in embodiment (i).
One example of embodiment (ii) is schematically shown below for ethyl adipoyl chloride.
Compound of formula (II)
Compound of formula (I)
Embodiment (iii): Embodiment in which a halide of a lower alkyl ester of an aliphatic monocarboxylic acid (or a lower alkyl haloformate) is used as the functional derivative of a carboxylic acid:
A compound of formula (I) in which A is A", R1 is the group -OR and R is a lower alkyl group can be easily produced by contacting phthalazinol of formula (II) with a halide of a lower alkyl ester of an aliphatic monocarboxylic acid, XCOOR, in which X represents a halogen atom, preferably a chlorine atom, and R represents a lower alkyl group to esterify -CH2OH at the 4-position of phthalazinol of formula (II) to -CH2O-A"-OR in which A" represents
This reaction is carried out preferably in a suitable solvent such as ethyl acetate, pyridine or chloroform, and the reaction temperature and time can be selected as desired. For example, a reaction temperature of about 0 to about 100 C, preferably room temperature to about 80"C, and a reaction time of about 1 to about 8 hours may be cited. After the reaction, the reaction mixture may be worked up by distilling off the solvent, optionally washing the residue with water and drying it and as desired, purifying the product by recrystallization or other purifying means.
One example of embodiment (iii) is schematically shown below for ethyl chloroformate
Compound of formula (II) esterification
Compound of formula (I)
Embodiment (iv): Embodiment in which an aliphatic saturated dicarboxylic acid or its monoalkyl ester is used as the carboxylic acid or its functional derivative: A compound of formula (I) wherein A is A', R' is the group -OR, and R is a lower alkyl group can be easily produced by contacting phthalazinol of formula (II) with a C2-C16 aliphatic saturated dicarboxylic acid or its monoalkyl ester to esterify -CH2OH at the 4-position of phthalazinol to -CH2O-A'-OR in which A' is
within the definition of A.If desired, the reaction may be carried out in the presence of the solvents exemplified in embodiment (i) excepting amines and carboxylic acids. Preferably, the reaction is carried out in the presence of an acid catalyst, for example mineral acids such as hydrochloric acid and sulfuric acid and sulfonic acids such as p-toluenesulfonic acid. The reaction can be carried out in accordance with the case of embodiment (i) which uses acid anhydrides.
Embodiment (v): Embodiment in which an aliphatic monocarboxylic acid anhydride or an aliphatic monocarboxylic acid monohalide is used as the functional derivative of a carboxylic acid:- A compound of formula (I) in which A is A", R' is a C1-C12 alkyl group and R2 is
can be easily produced by contacting phthalazinol of formula (II) with a C1-C12 aliphatic monocarboxylic acid anhydride or a C1-C12 aliphatic monocarboxylic acid monohalide to esterify H2OH at the 4-position of phthalazinol of formula (II) to -CH2O-A"-R1 in which A" represents
within the definition of A in formula (I) and simultaneously acylate the nitrogen atom at the 2-position of phthalazinol.
The reaction is preferably carried out in a suitable solvent, and the reaction temperature and time may be selected as desired. Since the reaction proceeds even at room temperature, no particular heating or cooling is required. For example, a reaction temperature of about 0 to about 1 500C and a reaction time of about 1 to about 8 hours may be cited.
The mole ratio of the reaction materials may be selected as desired. For example, the anhydride or monohalide may be used in an amount of about 2 to about 6 moles per mole of phthalazinol. After the reaction, the reaction mixture may be worked up, for example, by distilling off the solvent, optionally washing the residue with water, and crystallizing it by treatment with hydrochloric acid to give the final product in the form of crystals. If desired, the product may be purified by recrystallization and other means.
Examples of the solvent used may be the same as those exemplified in embodiment (i). There is no particular restriction on the amount of the solvent, and any amount effective as solvent can be used.
The reaction with the acid halide is preferably carried out in the presence of an acid acceptor such as pyridine, dimethylaniline or triethylamine. The amount of the acid acceptor is not particularly limited.
and for example, about 2 to about 20 moles of the acid acceptor may be used per mole of phthalazinol of formula (II).
The phthalazone derivative of formula (I) in accordance with this invention which can be produced as described above is represented by the following formula (I).
wherein
R1 represents a C1-C12 alkyl group or the group -OR in which R represents a lower alkyl group;
A represents
in which n represents 0 or an integer of 1 to 14; R2 represents a hydrogen atom or the group
in which
R3 represents a C1-C12 alkyl group; provided that when R2 is the group
R' is a C1-C12 alkyl group and A is
and when R2 is a hydrogen atom, R1 is the group -OR.
Examples of the C1-C12 alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 2-methylbutyl, 1 -ethylpropyl, hexyl, isohexyl, 2-methylpentyl, 3-methylpentyl, 2-ethylbutyl, heptyl, 1 -ethylpentyl, octyl, nonyl, decyl, undecyl and dodecyl. Preferred alkyl groups have 1 to 8 carbon atoms, especially 1 to 6 carbon atoms. When R1 is the group -OR, examples of the lower alkyl group for R are C1-C4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. C1-C2 alkyl groups are preferred.
When A is the group
n is O or an integer of 1 to 14, preferably 0 or 1 to 10, more preferably 0 or 1 to 8. When R2 is
R3 is a C1-C12 alkyl group, examples of which are the same as those exemplified hereinabove for R1.
Such alkyl groups preferably have 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms.
The phthalazone derivatives of formula (I) in accordance with this invention are useful as prodrugs for phthalazinol, a known pharmaceutically effective substance. They are converted in vivo to phthalazinol and exhibit the known pharmacological effects of phthalazinol.
Thus, according to this invention, there can be provided an agent for treating vascular troubles, comprising a phthalazone derivative of formula (I) as an active ingredient. There can also be provided a pharmaceutical composition composed of an amount, effective for treating vascular troubles, of a phthalazone derivative of formula (I) and a pharmaceutically acceptable diluent or carrier.
The treating agent or composition in accordance with this invention may be in various dosage forms, such as powders, granules, tablets, capsules, trouches, and other orally administrable forms. In formulation, various pharmaceutically acceptable diluents or carriers may be utilized. For example, there may be used pharmaceutically acceptable solid or liquid carriers or diluents such as polyethylene glycol, propylene glycol, glycerol, vegetable oils, glucose, lactose, starch, sucrose, cetyl alcohols and cacao butter. Means for formulation are well known, and various known means can be used in formulating the above dosage forms.
The treating agent or composition of this invention may contain a suitable amount of the active ingredient of formula (I). The amount is, for example, about 0.1 to about 80% by weight based on the total weight of the formulated treating agent or composition.
The treating agent of this invention may be administered through various routes, but oral administration is preferred.
The dose of the compound of formula (I) is, for example, about 1 to about 80 mg/kg-body/day.
The compounds of formula (i) are converted in vivo to known phthalazinol, but by themselves, do not exhibit pharmacological properties.
A test was conducted to determine the conversion of the compound of formula (I) as a prodrug for phthalazinol to phthalazinol in vivo.
Testing procedure
Three male adult Beagle dogs were used as experimental animals, and each of the compounds of formula (I) of this invention and phthalazinol (control) filled in capsules were orally administered to the dogs each in a dose of 30 mg (calculated as phthalazinol) per kg of each experimental animal. The test for administering the compounds of formula (I) was conducted about 2 weeks after the test for administering phthalazinol.
At 0.5, 1, 2, 4 and 8 hours after the administration, blood was taken from the vein of the forepaw of each animal, and centrifuged at 3,000 rpm for 20 minutes to prepare serum samples. One milliliter of each serum sample was extracted with three 2 ml portions of ethyl acetate. The extracts were combined and dehydrated over an hydros sodium sulfate, followed by distilling off ethyl acetate under reduced pressure. To the residue was added 0.5 ml of a 50% aqueous solution of methanol, and the concentration of phthalazinol in the serum was measured by high-performance liquid chromatography under the following measuring conditions.
Column: Shodex ODS, F-41 1 (reversed phase silica gel)
Eluent: acetonitrile/methanol/0.01 M phosphate buffer
(pH 7.4) [10:22.5:67.5]
Wavelength: 220 nm
Test results
From the data obtained by the above test, a time-concentration curve was plotted, and the ratio of the area under the curve (AUC) of phthalazinol in the serum in the case of administering the compound of formula (I) of this invention to the area under the curve of phthalazinol in the serum in the case of administering phthalazinol (control) was calculated. For each compound tested, the average value of the ratio of the area under the curve (AUC ratio) obtained from the results on the three test dogs was calculated. The results are shown in Table 1. In the table, the compound numbers correspond to the number of Examples given hereinafter.
The results were evaluated on the following scale.
AUC ratio (average) Evaluation > 300 A
Over 200 but less than 300 B
Over 100 and up to 200 C
TABLE I
Compound No. Evaluation
1 C
2 A
3 B
4 A
5 C
6 B
7 B
8 A
9 C
10 B
11 A
12 A
13 A
14 B
15 B
The results given in Table 1 demonstrate that the compounds of formula (I) in accordance with this invention are useful as prodrugs for phthalazinol, a known pharmaceutically effective substance, and show an increased concentration in blood over phthalazinol.
The compounds of formula (I) in accordance with this invention exhibit pharmacological effects when converted in vivo to known phthalazinol. Accordingly, the compounds of formula (I) are useful as a treating agent for vascular troubles which is known with regard to phthalazinol, and the same troubles as exemplified with regard to phthalazinol may be cited as troubles to be treated.
The following examples illustrate the compounds of this invention and their production.
EXAMPLE 1 7-Ethoxyearbonyl-6,8-dimethyl-1 (2H)-phthalazinon-4-yl methyl hydrogen glutarate (1.95 g; 0.005 mole) was added to 5 ml of benzene, and about 1 ml of thionyl chloride was added to the mixture with cooling. The mixture was left to stand overnight at room temperature, and then thionyl chloride was distilled off. The residue was dissolved in anhydrous ethanol, and 0.5 g (0.005 mole) of triethylamine was added to the solution. The mixture was left to stand at room temperature for 2 hours.
The precipitated crystals were collected by filtration, and recrystallized from ethanol to give 0.54 g (yield 26%) of 7-ethoxycarbonyl-6,8-dimethyl-1 (2H)-phthalazin-4-yl methyl ethyl glutarate. The properties of this compound are shown in Table 2 below.
EXAMPLE 2
Phthalazinol (2.76 g; 0.01 mole) was dissolved in 30 ml of pyridine, and 2.3 g (0.012 mole) of ethyl adipoyl chloride was added little by little to the solution with stirring. After the addition, the mixture was left to stand overnight at room temperature. After the reaction, pyridine was distilled off under reduced pressure. The residue was dissolved in chloroform and washed twice with water. The chloroform layer was collected and dried over anhydrous sodium sulfate. Chloroform was then distilled off under reduced pressure. The residue was recrystallized from ethanol to give 3.7 g (yield 86%) of 7 ethoxycarbonyl-6,8-dimethyl- 1(2 H)-phthalazinon-4-yl methyl ethyl adipate. The properties of this compound are shown in Table 2.
EXAMPLE 3
Phthalazinol (2.76 g; 0.01 mole) was dissolved in 25 ml of ethyl acetate, and 1 5 cc of pyridine was further added. To the solution was added 1.4 g (0.013 mole) of ethyl chloroformate with stirring, and the reaction was carried out at about 50 to 600C for about 4 to 5 hours. After the reaction, pyridine and ethyl acetate were distilled off under reduced pressure. The residue was dissolved in chloroform, and 1 O/o HCI was added. The mixture was shaken, and the chloroform layer was collected and dried over anhydrous sodium sulfate. Chloroform was then distilled off. The residue was recrystallized from ethanol to give 1.4 g (yield 40%) of 7-ethoxycarbonyl-6,8-dimethyl-1 (2H)-phthalazinon-4-yl methyl ethyl carbonate. The properties of this compound are shown in Table 2 below.
EXAMPLES 4 TO 10
Example 2 was repeated except that ethyl oxalyl chloride (Example 4), ethyl malonyl chloride (Example 5), methyl glutaryl chloride (Example 6), methyl succinyl chloride (Example 7), ethyl pimeroyi chloride (Example 8), methyl sebacoyl chloride (Example 9) and ethyl suberoyl chloride (Example 10) were each used in corresponding molar proportions instead of ethyl adipoyl chloride. The compounds of formula (I) shown in Table 2 below were obtained.
TABLE 2
In formula (I) Melting Mass point spectrum NMR spectrum Example Compound produced Group A Group R ( C) (m/e) 1 7-Ethoxycarbonyl-6,8-di- 418 (M+), 1.14 (t, 3H), methyl-1(2H)phthalazinon- 389, 373, 1.33 (t, 3H), 4-yl methyl ethyl glutarate # -C2H5 82-83 276, 269, 2.0 (m, 6H), 268 2.40 (s, 3H), 2.77 (s, 3H), 4.03 (q, 2H), 4.40 (q, 2H), 5.30 (s, 2H), 7.68 (s, 1H), (C) 2 7-Ethoxycarbonyl-6,8-di- 432 (M+), 1.26 (t, 3H), methyl-1(2H)phthalazinon- 403, 387, 1.46 (t, 3H), 4-yl methyl ethyl adipate # -C2H5 43-44 276, 258 1.7 (m, 4H), 2.3 (m, 4H), 2.52 (s, 3H), 2.93 (s, 3H), 4.20 (q, 2H), 4.58 (q, 2H), 5.43 (s, 2H), 7.67 (s, 1H), (C) TABLE 2 (continued)
In formula (I) Melting Mass point spectrum NMR spectrum Example Compound produced Group A Group R ( C) (m/e) 3 7-Ethoxycarbonyl-6,8-di- 348 (M+), 1.21 (t, 3H), methyl-1(2H)phthalazinon- 319, 303, 1.33 (t, 3H), 4-yl methyl ethyl carbonate -#- -C2H5 142-143 275, 259, 2.40 (s, 3H), 247 2.76 (s, 3H), 4.16 (q, 2H), 4.42 (q, 2H), 5.35 (s, 2H), 7.70 (s, 1H), (C) 4 7-Ethoxycarbonyl-6,8-di- 376 (M+), 1.23 (t, 3H), methyl-1(2H)phthalazinon- 347, 331, 1.36 (t, 3H), 4-yl methyl ethyl oxalate -#-#- -C2H5 162-163 275, 259 2.39 (s, 3H), 2.75 (s, 3H), 4.25 (q, 2H), 4.40 (q, 2H), 5.45 (s, 2H), 7.76 (s, 1H), 12.58 (s, 1H), (C) TABLE 2 (continued)
In formula (I) Melting Mass point spectrum NMR spectrum Example Compound produced Group A Group R ( C) (m/e) 5 7-Ethoxycarbonyl-6,8-di- 390 (M+), 1.19 (t, 3H), methyl-1(2H)phthalazinon- 381, 345, 1.40 (t, 3H), 4-yl methyl ethyl malonate -# CH2 #- -C2H5 127.5-128 276, 259, 2.46 (s, 3H), 247 2.88 (s, 3H), 3.41 (s, 2H), 4.13 (q, 2H), 4.45 (q, 2H), 5.35 (s, 2H), 7.46 (s, 1H), (B) 6 7-Ethoxycarbonyl-6,8-di- 404 (M+), 1.40 (t, 3H), methyl-1(2H)phthalazinon- 375, 359, 2.2 (m, 6H), 4-yl methyl ethyl glutarate -#(CH2)3#- -CH3 81.5-82 276, 259 2.45 (s, 3H), 2.88 (s, 3H), 3.64 (s, 3H), 4.45 (q, 2H), 5.31 (s, 2H), 7.42 (s, 1H), (B) TABLE 2 (continued)
In formula (I) Melting Mass point spectrum NMR spectrum Example Compound produced Group A Group R ( C) (m/e) 7 7-Ethoxycarbonyl-6,8-di- 120-121 390 (M+), 1.42 (t, 3H), methyl-1(2H)phthalazinon- 361, 345, 2.50 (s, 3H), 4-yl methyl methyl 276, 259, 2.68 (s, 4H), succinate -#(CH2)2#- -CH# 247 2.90 (s, 3H), 3.17 (s, 3H), 4.48 (q, 2H), 5.35 (s, 2H), 7.47 (s, 1H), (B) 8 7-Ethoxycarbonyl-6,8-di- 72-74 446 (M+), 1.23 (t, 3H), methyl-1(2H)phthalazinon- 417, 401, 1.42 (t, 3H), 1-yl methyl ethyl pimerate -#(CH2)6#- -C2H5 276, 258 1.5 (m, 6H), 2.3 (m, 4H), 2.46 (s, 3H), 2.90 (s, 3H), 4.12 (q, 2H), 4.48 (q, 2H), 5.33 (s, 2H), 7.42 (s, 1H), 11.10 (s, 1H), (B) TABLE 2 (continued)
In formula (I) Melting Mass point spectrum NMR spectrum Example Compound produced Group A Group R ( C) (m/e) 9 7-Ethoxycarbonyl-6,8-di- 474 (M+), 1.4 (m, 12H), methyl-1(2H)phthalazinon- 445, 429, 1.43 (t, 3H), 1-yl methyl methyl -#(CH2)3#- -CH3 70-71 413,401, 2.3 (m, 4H), sebacate 276,258 2.47 (s, 3H), 2.90 (s, 3H), 3.66 (s, 3H), 4.48 (q, 2H), 5.33 (s, 2H), 7.43 (s, 1H), 11.09 (s, 1H), (B) 10 7-Ethoxycarbonyl-6,8-di- 460 (M+), 1.23 (t, 3H), methyl-1(2H)phthalazinon- 431, 415, 1.41 (t, 3H), 1-yl methyl ethyl suberate -#(CH2)5#- -C2H5 69-70 276, 258 1.5 (m, 8H), 2.3 (m, 4H), 2.45 (s, 3H), 2.89 (s, 3H), 4.12 (q, 2H), 4.47 (q, 2H), 5.32 (s, 2H), 7.42 (s, 1H), 10.86 (s, 1H), (B) EXAMPLE 11
Acetyl chloride (1.9 g) was added under ice cooling to a solution of 2.8 g of 7-ethoxycarbonyl-4hydroxymethyl-6,8-dimethyl-1 (2H)phthalazone in 30 ml of pyridine, and then the mixture was heated at 600C for 4 hours. Pyridine was distilled off under reduced pressure from the reaction mixture, and the residue was dissolved in chloroform and washed twice with water. The chloroform layer was dried over anhydrous sodium sulfate, and chloroform was distilled off. The residue was recrystallized from ethanol to give 2.0 g (yield 56%) of 4-acetoxymethyi-2-acetyl-7-ethoxy-carbony-6,8-dimethyl- 1 (2H)phthalazone.
Melting point: 134-1 350C Mass spectrum: m/e 360 (M+), 331, 318, 31 5, 289, 276.
NMR spectrum, a (ppm, measured in CDCI2): 1.42 (3H, t), 2.13 (3H, s), 2.47 (3H, s) 2.69 (3H, s), 2.82 (3H, s),4.47 (2H, q), 5.34 (2H, s), and 7.40 (1 H, s).
EXAMPLE 12
Acetic anhydride (3.0 g) was added to a solution of 2.2 g of 7-ethoxycarbonyl-4-hydroxymethyl6,8-dimethyl-1 (2H)phthalazone in 30 ml of pyridine, and the mixture was heated at 700C for 3 hours.
The reaction mixture was worked up in the same way as in Example 11 to give 2.2 g (yield 76%) of 4acetoxymethyl-2-acetyl-7-ethoxycarbonyl-6,8-di methyl- 1(2 H)phthalazone.
EXAMPLE 13
A pyridine solution of 2.8 g of 7-ethoxycarbonyl-4-hydroxymethyl-6,8-dimethyl-1 (2H)phthalazone was treated in the same way as in Example 11 except that 2.5 g of propionyl chloride was used instead of acetyl chloride in Example 11. There was obtained 2.0 g (yield 52%) of 7-ethoxycarbonyl-6,8dimethyl-2-propionyl-4-propionyloxymethyl-1 (2 H)phthalazone.
Melting point: 92-940C Mass spectrum: m/e 338 (M+), 359, 343, 332, 303, 276.
NMR spectrum, # (ppm, measured in CDCI2): 1.14 (3H, t), 1.25 (3H, t), 1.40 (3H, t), 2.38 (2H, q), 2.44 (3H, s), 2.81 (3H, s), 3.05 (2H, q), 4.45 (2H, q), 5.32 (2H, s),7.39 (1 H, s).
EXAMPLE 14
A pyridine solution of 2.2 g of 7-thoxycarbonyl-4-hydroxymethyl-6,8-dimethyl-1 (2H)phthalazone was treated in the same way as in Example 13 except that 3.0 g of enanthoyl chloride was used instead of acetyl chloride in Example 11. There was obtained 1.8 g (yield 45%) of 2-enanthoyl-4enanthoyloxymethyl-7-ethoxycarbonyl-6,8-dimethyl-1(2H)phthalazone.
Melting point: 56 to 580C
Mass spectrum: m/e 500 (M+), 455, 430, 388, 359, 343, 276.
NMR spectrum, # (ppm, measured in CDCI3): 0.8-2.0 (22H, m), 1.41 (3H, t), 2.32 (2H, q), 2.45 (3H, s), 2.82 (3H, s), 2.98 (2H, q), 4.46 (2H, q), 5.34 (2H, 5), 7.40 (1 H, s).
EXAMPLE 15
A solution of 1.0 g of 7-ethoxycarbonyl-6,8-dimethyl-4-propionyloxymethyl-1 (2H)phthalazone in
10 ml of pyridine was reacted with 0.4 g of acetyl chloride in the same way as in Example 11 to give 0.7 g (yield 63%) of 2-acetyl-7-ethoxycarbonyl-6,8-dimethyl-4-propionyloxymethyl-l (2H)phthalazone.
Melting point: 113-11 50C Mass spectrum: m/e 374 (M+), 345, 332, 329, 303, 287, 276.
NMR spectrum, # (ppm, measured in CDCl3) : 1.15 (3H t), 1.41 (3H, t), 2.39 (2H, q), 2.45 (3H, s), 2.68 (3H, s),2.82 (3H, s),4.46 (2H, q), 5.33 (2H, s), 7.40 (1 H, s).
Claims (6)
1. A phthalazone derivative of the formula (I)
wherein R1 represents a C1-C12 alkyl group or the group -OR in which R represents a C1-C4alkyl; A0 represents
in which n represents 0 or an integer of 1 to 14; R2 represents a hydrogen atom or the group
in which R3 represents a C1C,2 alkyl group; provided that when R2 is the group
R' is a C1-C12 alkyl group and A is
and when R2 is a hydrogen atom, R' is the group -OR.
2. A phthalazone derivative according to claim 1 substantially as described in any one of the
Examples.
3. A pharmaceutical composition composed of an amount, effective for treating a vascular trouble, of a phthalazone derivative as claimed in claim 1 or 2 and a pharmaceutically acceptable diluent or carrier.
4. A process for producing a phthtalazone derivative as claimed in claim 1 which comprises reacting phthalazinol of the formula (II)
with a carboxylic acid capable of forming the compound of formula (I) or a functional derivative of said carboxylic acid,
5. A process according to claim 4 wherein said carboxylic acid or its functional derivative is a
C2-C16 aliphatic saturated dicarboxylic acid anhydride, a mono-(C1-C4alkyl) ester of a C2-C16 aliphatic saturated dicarboxylic acid monohalide, a halide of a C1-C4 alkyl ester of an aliphatic monocarboxylic acid of the formula XCOOR in which X represents a halogen atom and R represents a
C1-C4 alkyl group, a C2-C16 aliphatic saturated dicarboxylic acid, a monoalkyl ester of a C2-C12 aliphatic saturated dicarboxylic acid, a C1-C12 aliphatic monocarboxylic acid anhydride or a C1-C12 aliphatic monocarboxylic acid monohalide.
6. A process according to claim 4 substantially as described with reference to any one of the
Examples.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP15818182A JPS5948463A (en) | 1982-09-13 | 1982-09-13 | Phthalazone derivative, its preparation and use |
JP18600082A JPS5976069A (en) | 1982-10-25 | 1982-10-25 | Phthalazone derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
GB8324389D0 GB8324389D0 (en) | 1983-10-12 |
GB2127805A true GB2127805A (en) | 1984-04-18 |
Family
ID=26485386
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB08324389A Withdrawn GB2127805A (en) | 1982-09-13 | 1983-09-12 | Phthalazones |
Country Status (3)
Country | Link |
---|---|
DE (1) | DE3332996A1 (en) |
FR (1) | FR2532934A1 (en) |
GB (1) | GB2127805A (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4345266C2 (en) * | 1993-10-04 | 1996-12-19 | Luitpold Pharma Gmbh | Heterocyclic carbamates, process for their preparation and pharmaceuticals |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AR205004A1 (en) * | 1973-10-30 | 1976-03-31 | Ishikawa M | PROCEDURE TO PREPARE 6,8-DIALKYL-7-ALCOXY-CARBONYL-4-HYDROXIMETHYL-1-PHTHALAZONE AND 7,8-LACTONE DERIVATIVES |
JPS58116471A (en) * | 1981-12-29 | 1983-07-11 | Nippon Kayaku Co Ltd | 4-hydroxymethyl-1-phthalazone ester derivative and its ester |
-
1983
- 1983-09-12 GB GB08324389A patent/GB2127805A/en not_active Withdrawn
- 1983-09-13 DE DE19833332996 patent/DE3332996A1/en not_active Withdrawn
- 1983-09-13 FR FR8314524A patent/FR2532934A1/en not_active Withdrawn
Also Published As
Publication number | Publication date |
---|---|
FR2532934A1 (en) | 1984-03-16 |
DE3332996A1 (en) | 1984-03-15 |
GB8324389D0 (en) | 1983-10-12 |
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