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Publication numberUS3833579 A
Publication typeGrant
Publication dateSep 3, 1974
Filing dateFeb 16, 1972
Priority dateNov 11, 1935
Publication numberUS 3833579 A, US 3833579A, US-A-3833579, US3833579 A, US3833579A
InventorsM Inoue, M Ishikawa, T Tsuchiya, T Shimamoto
Original AssigneeInoue Michiro, Shimamoto Takio, Tsuchiya Takashi, M Ishikawa
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
4-carbamoyl phthalazones
US 3833579 A
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Description  (OCR text may contain errors)

United States Patent "ice US. Cl. 260-250 P 10 Claims ABSTRACT OF THE DISCLOSURE 4-Carbamoxymethyl-l-phthalazone derivatives represented by the general formula I:

O "l CHzO NRrR:

wherein R stands for a hydrogen atom or an alkyl group, R stands for ahydrogen atom, an alkyl group which can be branched or cyclic, or an alkenyl, aryl, aralkyl, dialkylaminoalkyl, furfuryl, picolyl, or pyridyl group, R stands for a hydrogen atom, an alkyl, aryl carbamoyl, N- alkylcarbamoyl, N,N-dialkylcarbamoyl, alkylsulfonyl, or arylsulfonyl group, R stands for a hydrogen or halogen atom, an alkyl or alkoxy group, R stands for a hydrogen or halogen atom, an alkyl, alkoxy, amino, acylamino, alkoxycarbonyl, or carbamoyl group, and R, can form together with R a divalent alkylene group which can be interrupted by a hetero atom, and R and R can be present in any of the C-5, C6, C-7, or C8 positions of the phthalazone nucleus, and a process for their manufacture. Y

The present invention relates to new l-phthalazone derivatives for pharmaceutical use, and their manufacture.

In one aspect the invention consists in 4-carbamoxymethyl-l-phthalazone derivatives which are represented by the general formula:

SN I 21% R:

wherein, R stands for a hydrogen atom or an alkyl group, preferably C -C alkyl group, especially C -C alkyl group; R stands for a member selected from the group consisting of a hydrogen atom, an alkyl group which can be branched or cyclic alkyl group, preferably C -C alkyl group, an alkenyl group, preferably C cgalkenyl group, especially C -C alkenyl group, an aryl group preferably phenyl or tolyl group, an aralkyl group preferably benzyl or phenethyl, a dialkylaminoalkyl group, preferably r 3,833,579 Patented Sept. 3, 19,74;

C -C alkyl group having a C or C alkylamino groups, a furfuryl group, a picolyl group and a pyridyl group; R stands for a member selected from the group consisting of a hydrogen atom, an alkyl group, preferably C C alkyl group, especially C -C alkyl group, aryl group preferably phenyl or tolyl group, a carbamoyl group, an N-alkylcarbamoyl group, preferably an N-alkylcarbamoyl group ha'Ving C -C alkyl group, an N-N-dialkylcarbamoyl group, preferably an N-N-dialkylcarbamoyl group having C -C alkyl groups, an alkylsulfonyl group, preferably an alkylsulfonyl group having C -C alkyl group, especially having C -C alkyl group and an" arylsulfon-yl group, preferably an arylsulfonyl group having a phenyl or tolyl group; R stands for a member selected from the group consisting of a hydrogen atom, a halogen atom such as Cl, Br, I or F, preferably C1 or Br, an alkyl group, preferably C -C alkyl group, especially C -C alkyl group and an alkoxy group, preferably C -C alkoxy group; R stands for a member" selected from the group consisting of a hydrogen atom, a halogen atom such as Cl, Br, I or F, preferably C1 or Br, an alkyl group, preferably C -C alkyl group, especially C -C alkyl group, an alkoxy group, preferably C -C alkoxy group, an amino group, an'acylamino group, preferably acyl amino group having C -C acyl group, an alkoxycarbonyl group, preferably an alkoxycarbonyl group having C -C alkoxy group and a carbamoyl group; with the proviso that R can form together with R a divalent alkylene group which may be interrupted by a hetero atom, preferably oxygen or nitrogen atom (except N of NR R of formula I). a

The above compounds can be manufactured by any of the following processes:

(a) A compound of the general formula:

CH: CH 4 l i N-R3 R5 0 II wherein R R and R have the same meanings as in formula (I), is reacted with an isocyanate of the formula:

R NCO III wherein R has the same meanings as in formula (1) excluding a hydrogen atom, or

(b) The compound of general formula (II) is converted by known methods to a compound of the general formula:

wherein R R and K, have the same meanings as'in' J formula (I), and X stands for an oxygen or sulfur atom,

Z stands for a lower alkyl group or an aryl group which NHR Rg V 3 wherein R and R have the same meanings as in formula (I), or

(c) The compound of formula (II) is reacted with phorgene, and thereafter the intermediate compound of the formula:

wherein R R and R have the same meanings as in formula (I), is reacted with ammonia or the amine of formula (V), or

(d) The compound of formula (II) is reacted with a derivative of a carbamic acid of the formula:

wherein R and R have the same meanings as in formula (I), and Y stands for a halogen atom, an alkoxy, aryloxy, alkylthio, or arylthio group, or

wherein R R R and R have the same meanings as in formula (I), is reacted with a hydrazine derivative of the formula:

wherein R has the same meanings as in formula (I).

The compounds of the present invention can be manufactured by any process described above. These compounds prepared by the above processes are new, and in the experimental atherosclerosis induced by cholesterol feeding, they showed a profound effect for the prevention of atherosclerosis, inhibiting cholesterol to deposit on arterial walls. They also prevented the enhancement of coagulability and thrombogenicity induced by one shot treatment of animals with cholesterol or adrenaline, that is, they prevented the shortening of clotting times of the blood as well as the enhancement of adenosine diphosphate-induced platelets-aggregation in the animals. The compounds of this invention are useful for treatment of atherosclerotic and thrombotic diseases.

The starting material of this invention, which is represented by formula (II), can be manufactured either by the methods known in the art or the new methods described hereinafter.

(1) 4-hydroxymethyl-l-phthalazone can be prepared from 2-carboxy-acetophenone through the reaction sequence described below. This process is described in Ber. 40, 72 (1907) and Annual Report of Department of Pharmacy,.Kanazawa University, Vol. 12, 1-6 (1961).

COCH; Bra COCHQBI' N+ O OH "-00 OH CHnOH coon on NH2NH2 I? -oo OH NH v (2) Method 1) described above can not be applied for the substituted phthalazone derivatives, because the starting materials are generally inaccessible. Now it has been found that a compound of the formula:

wherein R R and R have the same meanings as in formula (I), and Y stands for an alkoxy group or a halogen atom, can be reduced smoothly to the com-pound of formula (II) with sodium borohydride (cf. Japanese Patent Application No. 58,643/71). The compounds of formula (X) can be prepared by the known methods, e.g. the method described in J. of Am. Chem. Soc., 68, 1316 1946) (3) It has also been found that the compound of formula (II) can be prepared by reacting a compound of the formula:

wherein R and R have the same meanings as in formula (I), with hydrazine derivatives of formula (IX). The compounds of formula (XI) can be manufactured either in an analogous Way described in Ber. 40, 72 (1907) or by the following reaction scheme.

onion 000E soon 0 *7 \C/ C O 0 CH1 R5 0 R,

oo 01 oo CHzNz 0mm I nisot COUCH: COUCH: R5 R5 0 R4 )1 Q 0 s Y The process from the compound (XI) to the compound (II) can be shown by following scheme.

This method is particularly useful for the manufacture of phthalazone compounds which are substituted at the N-Z position of the phthalazone nucleus.

Examples of the compounds represented by formula (II) include 4-hydroxyrnethyll-phthalazone, 4-hydroxymethyl-2-methyll-phthalazone, 2-ethyl-4-hydroxymethyll-phthalazone, 4-hydroxymethyl-Z-phenyll-phthalazone, 4-hydroxymethyl-2 tolyl-l-phthalazone, 2-carbamoyl-4-hydroxymethyl-l-phthalazone, 4-hydroxymethyl-2-(N-methyl-carbamoyl)-1- phthalazone, 2-(N,N-dimethyl-carbamoyl)-4-hydroxymethyl-1- phth alazone, 4-hydroxymethyl-Z-methylsulfonyll-phthalazone, 2-benzenesulfonyl-4-hydroxymethyl-l-phthalazone, and 4-hydroxymethyl-2-( p-toluenesulfonyl l-phthalazone.

Furthermore, 4-hydroxymethyl-l-phthalazone derivatives which have one or two substituents such as a chlorine atom, a bromine atom, an alkyl, alkoxy, amine, acetylamino, alkoxycarbonyl and carbamoyl group in any of the C5, C6, C7, and C8 positions in the phthalazone nucleus, can also be used. For example,

can be mentioned.

In process (e), starting compounds (VIII) can be manufactured from the compounds of formula (XI) described hereinbefore by the following scheme.

- o R4X\ II R4 1G I NHS mmnzon carbamoy,

As an example of compound (VIII),

w-carbamoxy-Z-carbamoylacetophenone,

a:- N-methylcarbamoxy) -2-carbamoylacetophenone,

w- (N ,N -dimethylcarbamoxy -Z-carbamoylacetophenone,

w- (N,N-tetramethylenecarb amoxy -2-carbamoylacetophenone, and

w- (N,N-pentamethylenecarbamoxy) -2c arb amoylacetophenone can be mentioned. Furthermore, the acetophenone derivatives described above, which have one or two of the substitutents represented by R or R in formula (I) in any of the C-3, C-4, (3-5, or C6 positions of the phthalazone (II) in an inert solvent or diluent, such as benzene,

toluene, chlorobenzene, acetonitrile, chloroform, dioxane, tetrahydrofuran, or pyridine. The reaction is preferably carried out at a temperature between room temperature and 150 0., especially below C. At a temperature between 50100 C., the reaction usually is complete in one to 5 hours. At around room temperature a longer reaction time, for example, between 5 and 24 hours is preferred. If necessary, a catalyst such as a tertiary amine, for example, trimethylamine, triethylamine, an N-alkylpiperidine or pyridine may be used.

Examples include isocyanate (HI) includemethyl-, ethyl-, propyl-, isopropyl-, butyl-, amyl-, cyclohexyl-, allyl-, phenyl-, tolyl-, xylyl-, ,B-dimethylaminoethyl-, 'y-diethylaminopropyl-, aand 8-furfury1-, 11-, 3-, and 'ypicoly1-, 04-, 13-, and 'y-pyridyl isocyanate can be men- I tioned.

In place of isocyanate (III), compounds which can be converted to the isocyanate of the formula (III) under the reaction conditions can be used, and if necessary a catalyst to generate the isocyanate in situ may be used. For example, an acyl azide represented by the formula:

R CON wherein R has the same meanings as in formula (I) excluding a hydrogen atom, or S-alkyl thiolcarbamates represented by the formula:

wherein R has the same meanings as in formula (I) excluding a hydrogen atom, and alkyl means a lower alkyl group such as methyl or ethyl group, may be used with heating. S-alkyl thiolcarbamates may also be used in the presence of a trialkylamine and a heavy metal salt such as silver nitrate.

Accordingly, the reaction in this invention of the compound of formula (II) with the compound of formula (III) also includes therecation of compound (II) with a compound capable of being converted to the compound of formula (III) under the reaction conditions. The process (a) can only be used to make compounds in which R is a hydrogen atom, and R is not.

In the embodiment of the process (b), a compound of formula (II) is converted to a compound of formula (IV) by known methods with an ester of chlorocarbonic or chlorothiolcarbonic acid represented by theformula:

where in X and Z have the same meanings as in formula (IV). In this process, 4-phenoxycarbonyloxymethyl-1- phthalazone derivaties where X and Z represent an oxygen atom and a phenyl group respectively in formula (IV), are preferred, because of the economic standpoint and accessibility. In place of the phenyl group, the substituted phenyl group, for example, p-chlorophenyl, 'p-

bromophenyl and p-nitrophenyl group, and aand 8- naphthyl group may also be used. Other phthalazone derivatives, such as 4-alkoxycarbonyloxymethyl-l-phthalazone, 4 alkylthiocarbonyloxymethyl 1 phthalazone, and 4 arylthiocarbonyloxymethyl-l-phthalazone derivatives can be used, if necessary. Examples of the compounds of formula (IV) are 4 -methoxycarbonyloxymethyl-1-phthalazone, 4-phenoxycarbonyloxymethyl-1-phthalazone,

4- p-chlorophenoxycarbonyloxymethyl) -1-phthalazone, 4-methylthiocarbonyloxymethyl-l-phthalazone, 4-ethylthiocarbonyloxymethyl-l-phthalazone, and 4-phenylthiocarbonyloxymethyl-1-phthalazone.

Furthermore, the phthalazone derivatives described above, which have one or two of the substituents represented by R, or R in the formula (I) in any of the C-5, C-6, C-7, and G8 positions of the phthalazone nucleus and/or the substituent represented by R in formula (I) in the N-2 of the phthalazone nucleus, can also be used. The compound of formula (IV) is then reacted with ammonia or an amine of formula (V). The process (b) can be represented by the following reaction scheme.

The reaction of compound (IV) with the amine can be effected in the presence or absence of solvents or diluents, e.g. methanol, ethanol, and propanol. Generally the reaction proceeds smoothly at a temperature between 0 and 100 (3., even at around room temperature, and is complete within several hours. Ammonia or the amine can be used in excess quantity, usually a quantity of 1-10 moles of amine per mole of compound (IV) is satisfactory. Examples of the amine of formula (V) are primary amines such as methyl-, ethyl-, propyl-, isopropyl-, butyl-, amyl-, allyl-, cyclohexyl-, benzyl-, fi-dimethylaminoethyl, 'y-diethylaminopropl, picolyl-, and furfurylamine, and secondary amines such as dimethylamine, diethylamine, pyrrolidine, piperidine, N-methylpiperazine and morpholine.

In the embodiment of process (c), a compound of formula (II) is converted to an ester of the chlorocarbonic acid of formula (VI) through reaction with phosgene. Thereafter the intermediate product of formula (VI) is reacted with ammonia or an amine of formula 8 (IV). Process (b) can be represented by the following reaction scheme.

0 CHzOH cnzoii-ci R4 R4 l I f+coc1i I f+rrc1 R5 (II R3 R5 (1) I (II) (VI) (II) ll cmoo-ci CH2OCNR1R2 R4 I R4 NHRIRZ I f+ H01 N N \K \K R2 (5 R3 R5 (g R3 (VI) (V) (1) Process (c) can be effected through two stages independently, namely the reaction with phosgene and the reaction with an amine. As intermediate product (VI) is labile and difficult to purify, it is preferred to carry out the process in one step without isolating product (VI). In the embodiment of process (b), a compound of formula (II) is dissolved or suspended in an inert solvent or diluent such as an aromatic hydrocarbon, ether, and chlorinated hydrocarbon. Examples of the solvent or diluent are benzene, toluene, xylene, ethyl ether, dioxane, chloroform, and ethylene dichloride, or their mixtures. To the solution or suspension, a tertiary amine, such as dimethylaniline, diethylaniline, triethylamine, N- alkylpiperidine, and pyridine is preferably added as a dehydrochlorinating agent or catalyst. As shown in the above reaction scheme, two moles of hydrochloric acid are produced, and it is necessary to use at least two moles of the tertiary amine. In the reaction with amine, replacement of the tertiary amine with the reactant amine is possible. The quantity of phosgene is usually between 1.0- 1.2 mole per mole of the phthalazone, but excessive use of amine (V) does not hinder the reaction. The reaction is effected at a temperature between 1010 C., and is complete in 1-20 hours.

In the embodiment of process ((1) compound (II) is reacted with an equimolecular quantity or an excess, especially between 1.5-5 moles, of compound (VII) in an inert solvent in the absence or presence of a catalyst. As the derivatives of carbamic acid represented by formula (VII), non-substituted, or N-monosubstituted or N,N-disubstituted carbamylchloride, alkyl carbamate, aryl carbamate, alkyl thiolcarbamate, and aryl thiolcarbamate can be used. For example, a carbamylchloride, such as carbamylchloride, methylcarbamylchloride, ethylcarbamylchloride, dimethylcarbamylchloride, N,N pentamethylenecarbamylchloride, and phenylcarbamylchloride; an alkyl carbamate, such as methyl carbamate, methyl N-methylcarbamate, methyl N-isopyropylcarbamate, methyl N,N-dimethylcarbamate, and methyl N,N-(ethylene-oxo-ethylene)carbamate; an aryl carbamate, such as phenyl carbamate, phenyl N-methylcarbamate, and phenyl N-phenyl carbamate; an alkyl thiolcarbamate such as methyl N- methylthiolcarbamate, ethyl N,N dimethylthiolcarbamate, and methyl N-pyridylthiolcarbamate; an aryl thiolcarbamate such as phenyl N-methylthiolcarbamate and phenyl N,N-pentamethylenecarbamate can be mentioned. As an example of the solvent or diluent, an inert organic solvent such as ethyl ether, tetrahydrofuran, dioxane, hexane, chloroform, benzene, toluene, monochloro-, dichloro-, and trichlorobenzene can be mentioned. In this process a catalyst can be used, if necessary. When compound (VII) is a carbamylchloride, a dehydrochlorinating agent such as dimethylaniline, diethylaniline, N-

methylpiperidine, and pyridine is preferably added. When compound (VII) is a carbamate or thiolcarbamate, sulfuric acid, an organic acid, e.g. benzenesulfonic acid or toluenesulfonic acid, an ester-exchange agent such as an organotin compound such as dimethyltin oxide, dibutyltin oxide, or dibutyltin diacetate, an alkali metal acetate such as sodium acetate, an alkali metal alkoxide such as sodium methoxide, sodium ethoxide, or potasium t-butoxide, an alkali metal phenoxide such as sodium phenoxide can be used. In some cases, while the reaction proceeds, azeotropic distillation of the alcohol formed during the reaction improves the yield of product (I) considerably. The process ((1) can be performed at a temperature between 50-200 C., especially 60-150 C.

In the embodiment of process (e), the compound of formula (VIII) is reacted with hydrazine derivative (IX) in a solvent or diluent. As compound (IX), hydrazine and monosubstituted hydrazine, for example, methylhydrazine, ethylhydrazine, phenylhydrazine, semicarbazide, 4- methylsemicarbazide, 4,4-dimethylsemicarbazide, methylsulfonylhydrazine, benzenesulfonylhydrazine, and p-toluenesulfonyhydrazine can be used. As the solvent or diluent, water, methanol, ethanol, and propanol can be preferably used. The quantity of the hydrazine can be in excess, for example, 1-20 moles, especially 25 moles of the hydrazine compound per one mole of the phthalazone may be used. The reaction can be effected at a temperature between 50200 C., particularly at around 100 C. The reaction of process (e) can be represented by the following scheme.

Whatever process of manufacture is used, the product can be separated and purified by conventional methods as described hereinafter.

The invention is illustrated but not limited by the following Examples.

EXAMPLE 1 To a solution of 5 g. of 4-hydroxymethyl-1-phthalazone in 100 ml. of dried pyridine, 2 g. of methyl isocyanate were added. The solution was allowed to stand at room temperature for one night, and then heated at 80 C. for one hour in a water bath. The pyridine was distilled off under reduced pressure, and the residue was recrystallized from methanol to yield 5 g. of 4-(N-methylcarbamoxymethyl)-1-phthalazone melting at 230-232 C. The product has the following formula:

II CHrOCNHCHz Analysis.-Calcd. for C H O N (percent): C, 56.65; H, 4.75; N, 18.02. Found (percent): C, 56.26; H, 4.70; N, 18.06.

l 0 EXAMPLE 2 O H CH2 0 N HCH:

Analysis.Calcd. for C H O N Br (percent): C, 44.17; H, 3.68; N, 12.88. Found (percent): C, 44.46; H, 3.49; N, 13.01.

EXAMPLE 3 Three grams of 4-hydroxymethyl-l-phthalazone and 5 g. of 3-pyridinecarboxylic azide were dissolved in 40 ml. of anhydrous pyridine. The temperature of the reaction mixture was raised slowly to around C., and was maintained at this temperature for 40 minutes. Then the solution was refluxed at C. for 8 hours. The pyridine was distilled off from the reaction mixture, and the resulting residue was recrystallized from acetone to yield 2.8 g. of 4-(N-B-pyridylcarbamoxymethyl)-1-phthalazone melting at 194196 C. The product has the follawirz,

structure.

0 (3H1 0 iinnm I? \N/ N H Y 0 Analysis of elemenrs.Calcd. for C H O N (percent): C, 60.80; H, 4.08; N, 18.91. Found (percent): C, 60.42; H, 4.27; N, 19.00.

EXAMPLE 4 Four grams of 4-hydroxymethyl-l-phthalazone, 6 g. of S-methyl-N-a-furfurylthiolcarbamate, and 3 g. of triethylamine were added to a mixed solution of 40 ml. of pyridine and 10 mg. of acetonirile. To the solution a solution of 5.2 g. of silver nitrate in 10 ml. of acetonitrile was added with cooling and stirring. After completion of the addition, the reaction mixture was left to stand for 24 hours and then heated at 100 C. for 2 hours. After. cooling, the reaction mixture was diluted with chloroform, and the precipitate was filtered. The chloroform was washed with water, and then distilled off. The residue so obtained was recrystallized from ethanol and water to yield 3 g. of 4-(N-ot-furfurylcarbamoxymethyl)-1-phthalazone melting at 182184 C.

Analysis of elements.-Calcd. for C H O N (per cent: C, 60.19; H, 4.38; N, 14.04. Found (percent): C, 60.03; H, 4.25; N, 14.34.

I EXAMPLES s-27 In a similar manner to Examples 1-4, the products of formula (I) were obtained from the compounds of formula (II) and the isocyanate of formula (III) in a 70- in the following Table II.

TABLE I l CHzOH HO0NHR2 a B4 A m f RzNCO f X/ N-Ra R: Y s 1 0 0 (II) (III) (I) Number R3 R4 R5 R2 Product M.P. (recrys. solvent) H H CH 115116 0., ethyl acetate/petroleurn ether. H H CH3 136138 0., ethanol/n-hexane. H 7-CH O CH; 219-220 0., methanol. H 7-0H30 0H 1711-172? 0., methanol/ethyl acea e. H 7-01 0H 230-232 0., methanol. H 7'CQH5000 0H; 23023? 0., methanol. H 7-H2N0O 0H 248-250" 0., methanol. H 5-0H300N H CH 215-217 0., acetone. 7-01 8-NH2 0H 228-230 0.,methan0l/acetone. 7-0H3O 8-0H 0ONH 0H3 210211 0., ethyl acetate. G-CHa 7-0H3 CHa 219-220 0., methanol. 6-0H 7-0H 0H3 205-206 0., ethyl acetate. H H 02115 186-188 0., ethanol/water: H H 1-0 H 203-205 0., ethanol/water. H 7-01 Allyl BOB-204 0., methanol. H H 011200115 193-195" 0., ethanol/water. H 7-Br Cyclohexyl 207-208 0., methanol/water. H H B-Picolyl 180-182 0., ethnol/water H H CoHs 223-224 0., methanol. 24 CHQCONH H H CH 2l4 2l5 0., acetone.

(0H3)-1N0O H H CH3 252253 3., ethanol/n-hexane;

CHzSO2- H H CH3 170 17l 0., ethanol. 27 0H 05H4S0- H H CH3 -155157 0., ethyl acetate/11- hexane.

EXAMPLE 2 reaction mixture was allowed to stand for one night, and

(1) Preparation of 4-phenoxycarboxyloxymethyl-1- phthalazone To a solution of *5 g. of 4-hydroxymethyl-phthalazone in ml. of pyridine, 6 g. of phenyl chloroformate were added with cooling and stirring. The reaction mixture was allowed to stand at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then diluted with water. The resulting precipitate was filtered and recrystallized from ether to yield 6 g. of 4-phenoxycarbonyloxymethyl-l-phthalazone melting at 113-114 C.

(2) Preparation of carbamate EXAMPLE 29 To a stirred solution of methylamine in methanol which was prepared from 4 ml. of 30% aqueous monomethylamine and m1. of methanol, 2 g. of 4-phenoxycarbonyloxymethyl-7-methoxy-Z-methyl-1-phthalazone prepared in a similar manner to Example 28(1) were added. The

then the methanol was distilled off. The residue was taken up in chloroform, and the chloroform extract was washed successively with 5% NaOH solution and water.

The chloroform was distilled oif, and the residue so obtained was recrystallized from methanolethyl acetate to yield 0.7 g. of 4-(N-methyl-carbamoxymethyl)-7-methoxy-2-methyl-l-phthalazone melting at 171-173 C.

Analysis of elements.Calcd. for C I-I O N (percent): C, 59.76; H, 5.79; N, 16.08. Found (percent): C, 59.65; H, 5.47; N, 15.82.

EXAMPLE 30 EXAMPLES 31-50 In a similar manner to Examples 28-30, the products of formula (I) were obtained from the starting compounds represented by formula (IV) and ammonia or the amines represented by formula (V) in a 70-90% yield, as shown in the fololwing Table II.

TABLE II It CHzO X-Z CHzOLNRiRr R4 I R4 I N NHRlRZ N I I I\/N Rs NRa R I Number R3 R4 R5 X Z R R2 Product (I) M.P. (recrys.solvent '11 7-01 0 CGHs H H 243245 0., methanol. H 7-Br O C H H H 255256 C., methanol. H 7-CH3O O C6H5 H CHa 166-168 0,, methanol. 7-CH: 8-CH3CONH O CsH; H CH3 216-211" C., ethyl acetate. H 7-CH3O O C H CH3 CH3 216218 0., methanol. H 7-Br S CH3 CH3 CH3 214215 C., methanol-water. 6-CH3 7-0H= 0 05H; CHa 0H3 19f197 01., ethyl acetate/petroeum et er. H H H O C5H H Allyl 186-188" C., ethanol/n-hexane. H H H S CHa H Cyclohexyl 165168 C., ethanol-water. H H 7-Cl O CGH5 H fl-picolyl 177-179 C., methanol. H H 7-CH3O O CGHS H wFurluryl 203-205" 0., methanol. H H 7-Cl S 0H3 (CH2) 192193 0., methanol-water. H G-CHz 7-CHa 0 Q3115 H2)5 ZOO-202 0-, ethyl acetate. H H 7-Br S Cell (CH2)2O-(CHzl2- 153155 C., methanol-water. H H 'l-CHsO 0 0511 H is0-CsH1 212E220" C., methanol/ethyl acea e. H H 7-0Ha0 O CoHs CeHsCHz 226227 0., methanol. H H 7-CH3O O OGHI; -(CH2) 21t4t216 C., methanol/ethyl acea e. H H H O C6H5 -(C1'Iz)s 156-15 00., ethyl acetate/petro- GIJJH e GT. 49 H H H O CaH -(CH'.')2O(CH2)2 207-209 C., ethanol'water. 50 CH3CBH4SO2 H H O CeH H H 168-169C, ethyl acetate/n-hex anone.

EXAMPLE 51 pleted, the mixture was stirred at 0-5" C. for 5 hours,

To a stirred solution of 3.4 g. of 4-hydr0xymethyl-1- phthalazone and 3.2 g. of dimethylaniline in 100 ml. of dried toluene, a solution of 2.2 g. of phosgene in ml. of toluene was added dropwise at a temperature of 0-5 C. After completion of the addition, the reaction mixture was stirred for 3 hours at 05 C. and 3 hours at around 10 C. While keeping the temperature of the mixture below 10 C., an excessive quantity of ammonia was introduced. The mixture was kept at below 10 C., and then left to stand at room temperature for 3 hours. The mixture was washed with water, the toluene layer was separated, and the' water phase was extracted with ethyl acetate. The combined toluene and ethyl acetate solution was dried and distilled under reduced pressure. The residue thus obtained was recrytallized from methanol to yield 4-carbarnoxymethyl-l-phthalazone melting at 230- and then 5 ml. of 30% aqueous methylamine were added at 0-5" C. with stirring. The reaction mixture was stirred for one hour, and then allowed to stand at room temperature for 3 hours. The mixture was washed with water, and the toluene solution was dried and distilled off. The residue was recrystallized from ethyl acetate to yield 6.5 g. of 7-chloro-4-(N-methyl-carbamoxymethyl)-2-methyll-phthalazone melting at 148-l49 C.

Analysis 0) elements.Calcd. for C H O' N Cl (percent): C, 51.15; H, 4.26; N, 14.92. Found (percent): C, 50.89; 11,435; N, 14.79.

EXAMPLES 53-59 In a similar manner to Examples 51-52, the products of formula (I) were obtained from the starting compounds represented by formula (II) and the amines represented by formula (V) in a 40-60% yield, as shown in 232 c. Table III.

TABLE III 0 CHzOH CH10iiNR R R4 4 I III i) 000]: I III N-Ra ii)NHR1Rz(V) N-R3 s II s I Number R3 R4 R5 R1 R1 Product (I) M.P., recrys. solvent H H H CH3 136-138 C., ethanol/nhexane. H 7-CH O H CH3 171-173 0., methanol/ethyl acetate. H 7-Br H CH 209-211" 0., methanol. H 7-01 CH3 CH3 208209 C., methanol. H 7-Br H 8115 236-238 C., methanol-water. H 7-CH3O H B-Pyridyl 222-224 C., methanol. H (CH2)5 158159 C., ethanol/n-hexane.

EXAMPLE 52 70 EXAMPLE A solution of 9.2 g. of 7-chloro-4-hydroxymethyl-2- methyl-l-phthalazone and 7 g. of dimethylaniline in 300 ml. of dried toluene was cooled to -5-0 C. To the solution 5.5 g. of phosgene were introduced with stirring at -5-0 C. After the addition of phosgene was com- A mixture of 4 g. of 7chloro-4-hydroxymethyl-Z- methyl-l-phthalazone, 3 g. of dimethylaniline, 2 g. of methylcarbamyl chloride, and 40 ml. of absolute ethyl ether were refluxed for 5 hours. The reaction mixture was washed successively with water, 3% H01 solution,

15 and water. The ethyl ether was dried and distilled olf. The residue was recrystallized from ethyl acetate to give 2.2 g. methyl-l-phthalazone melting at l48-149 C.

EXAMPLE 61 To a solution of 3 g. of 4-hydroxymethyl-2-methyl-lphthalazone and 1.3 g. of methyl N-methylcarbamate in 100 m1. of n-heptane, 0.3 g. of sodium methoxide was added. While the reaction mixture gently boiled, the heptane was gradually distilled off. The distillate was introduced into a Dean-Stark separator, through which the methanol separated was drawn otf, and the heptane was returned to the reaction flask. After the formation of methanol had ceased, the volume of the reaction mixture was concentrated to about one-half of the original volume by distillation. The residue was diluted with ice water, and the heptane was separated and the water layer was extracted with ether. The heptane solution and ether extract were combined, and the solvent was distilled off. The residue thus obtained was recrystallized from ethyl acetate-petroleum ether to give 1.7 g. of 4-(N- methyl-carbamoxymethyl)-2-methyl-l-phthalazone melting at ll-l16 C.

EXAMPLE 62 A mixture of 3 g. of 4-hydromethyl-7-methoxy-1- phthalazone, g. of phenyl N-methylcarbamate, 0.5 g. of sodium acetate, and 20 ml. of trichlorobenzene was heated for 5 hours at the temperature of 80-90 C. in a water bath. Low-boiling substances were distilled olf under reduced pressure and the resulting residue was extracted with chloroform. The chloroform solution was Washed with water, and the solvent was distilled off. The residue was recrystallized from methanol to give 2.3 g. of 4-(.N-methyl-carbamoxymethyl)-7-methoxy-1- phthalazone melting at 219-220 C.

Analysis of elements.- Calcd. for C H O- N (percent): C, 44.17; H, 3.68; N, 12.88. Found (percent): C, 43.85; H, 3.50; N, 12.62.

EXAMPLE '63 A mixture of 1 g. of 7-chloro-4-hydroxymethyl-1- phthalazone, 3 g. of phenyl thiolcarbamate, 0.2 g. of sodium acetate, and ml. of dioxane was heated for 3 hours at the temperature of 80-90 C. By distillation in vacuum, low-boiling substances were eliminated. The resulting residue was extracted with chloroform, and the chloroform extract was washed successively with 5% NaOH solution and water. The chloroform was distilled off, and the residue was recrystallized from methanol to give 0.5 g. of 7-chloro-4-carbamoxymethyl-l-phthalazone melting at 243-245 C.

Analysis of elements. Calcd. for C H O N Cl (percent): C, 47.33; H, 3.l5; N, 16.56. Found (percent): C, 46.88; H, 3.25; N, 16.27.

EXAMPLE 64 (l) A solution of 3 g. of w-(N-methyl-carbamoxy)-2- carbamoylacetophenone and 4 ml. of 85% hydrazine hydrate in 100 ml. of methanol was refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure and cooled to room temperature. The precipitated crystals were filtered and recrystallized from methanol to yield 2.5 g. of 4-(N-methyl-carbamoxymethyl)-lphthalazone melting at 230-232 C.

(2) w-(N-methyl-carbamoxy) 2 carbamoylacetophenone, the starting compound in (l), was prepared by the following procedure.

Two grams of 4-oxo-3,4-dihydroisocoumarine (melting point: l47-148 C.) were added portion-wise in 60 ml. of concd. ammonia with stirring. The mixture was stirred for 5 hours further at room temperature, and then dried under reduced pressure at below 50 C. The residue Was recrystallized from acetone to give 1.6 g. of w-oxy-2-carbamoylacetophenone melting at 151-153 C. One gram of w-oxy-2-carbamoylacetophenone prepared above and 0.4 g. of methyl isocyanate were dissolved of 7-chloro-4-(N-methyl-carbamoxymethyl) -2- I in 20 ml. of pyridine. The reaction mixture was allowed to stand for one night and then heated at 40 C. for one hour. After the pyridine was distilled oil", the residue was recrystallized from methanolethyl acetate to give 0.7 g. of w-(N-methyl-carbamoxy)-2-carbamoylacetophenone melting at 180-182 C.

EXAMPLE 65 A solution of 2 g. of w-(N-methyl-carbamoxy)-2- carbamoylacetophenone described in Example 64(2) and 5 ml. of phenylhydrazine in 20 ml. of ethanol were refluxed for 3 hours in a water bath. The solvent was distilled off, and the residue was recrystallized from ethanol-n-hexane to give 3 g. of 4-(N-methyl-carbamoxymethyl)-2-phenyl-l-phthalazone melting at 136-138 C.

EXAMPLES 66-70 In a similar manner to Example 1, from the reaction of 4-hydroxymethyl-l-phthalazone and B-dimethylaminoethyl isocyanate, 4-[N-(fi-dimethylaminoethyl)-carbamoxymethyl]-1-phthalazone melting at 148l50 C. '(recrystallized from ethyl acetate) was obtained in 75% yield, the structure of which is shown below.

Similarly, 4-[N- (;8 diethylaminoethyl) carbamoxymethyl]-1-phthalazone melting at 116l20 C. (recrystallized from ethyl ether), 4-[N-(y-dimethylaminopropyl)- carbamoxymethyl]-2-phenyl 1 phthalazone melting at l59-160 C. (recrystallized from ethyl acetate), 7-bromo- 4-[N ([3 dimethylaminoethyl) carbamoxymethyl]-lphthalazone melting at 184-186 C. (recrystallized from ethyl acetate), and 4 [N ('y dimethylaminopropyl)- carbamoxymethyl]-2-rnethyl-l-phthalazone oxalate melting at 168-l69 C. (recrystallized from ethanol) were obtained.

EXAMPLES 71-78 In a similar manner to Example 28, from the reaction of 4-phenoxycarbonyloxymethyl 1 phthalazone and N- methylpiper-azine, 4-[N,N-(ethylene-methylimino ethylene)-carbamoxymethyl] l phthalazone melting'at'1'52- 154 C. (recrystallized from methanol) was obtained in yield,-the st'ructureof which is shown below.

CHzO

Similarly, 4-[N('y diethylaminopropyl) c-ar'bamoxymethyl]-1-plrth-alazone melting at 133-l-35 C. (recrystallized from ethyl acetate/petroleum ether), 4 [N ('ydiethylaminopropyl)-carbamoxymethyl] 7 methoxy-lphthalazone melting at 162-163 C. (recrystallized from ethylacetate), 4-[N- (fl dimethylaminoethyl) carbamoxymethyl]-7-methoxy 1 phthalazone melting at 159- 160 C. (recrystallized from ethyl acetate), 6,7-dimethyl- 4-[N-(B dime'thylaminoethyl) carbamoxymethyl] lph'thalazone melting at 172-173 C. (recrystallized from ethyl acetate), 6,7-dimethyl-4-[N,N (ethylene methylimino-ethylene)-oarbamoxymethyl]-1 phthalazone melting at 208-2l0 -C. (recrystallized from ethanol/n-hexane), 7-chloro-4-[N,N-(ethylene-methyliminoethylene)- carbamoxyme'thyl]-l-ph-thal-azone melting at 171-172 C: (recrystallized from ethanol/n-hexane), and 5-acetylamino-4-[N,N-(ethylenemethyliminoethylene) carbamoxymethyl1-1-ph'thalazone melting at 243-245 C. (re: crystallized from ethanol/n-hexane) were obtained.

I 7 EXAMPLES 79-80 In a similar manner to Example 52, from the reaction of 4-hydroxymethyl-2-methyl-l-phthalazone and fl-dimethylaminoethylamine, 4-[N (B dimethylaminoethyl)-carbamoxymethyl]-2-methyl-1-phthalazone oxalate melting at 193-195 C. (recrystallized from ethanol) was obtained in 54% yield. Similarly, 4-[N 3 dimethylaminoethyl)-carbamoxymethyl]-2-phenyl-1 phthalazone melting at 155-157 C. (recrystallized from ethyl acetate) was obtained.

'EXAM-P'LE 81 (Biological Effect) After oral administration of 10 mg./kg. the compound of present invent-ion to a rabbit, intensity of platelet aggregation induced by adenisine diphosphate was measured by the Borns method ('Born, J. Physiol. 162, 67 (1962), see also OBrien, J. Clin. Path. 15, 452 (1962), Lancet, 1, 779 (1968).

A rabbit was injected with adrenaline -(1 ,ug./kg.) 3 hours after oral administration of the sample. Five minutes after the injection, 4.5 ml. of blood were taken from the carotid artery and then diluted with 0.5 ml. of 3.8% solution of sodium citrate. After centrifugation of the blood at 1000 g. for 30 minutes, aliquots of 0.9 ml. each 'were taken from the supernatant. To the aliquots 0.1 ml. of 3 10- molar and 10 molar solutions of adenosine diphosphate were added. Therefore the molar concen trations of ADP in the serum were 3 10 and 10- respectively. The intensity of platelet aggregation was measured using a platelet aggregation meter (Model 169, Evans Elect. Ltd., England). Intensities of the ADP-induced platelet aggregation were shown as percentage of the pre-injection value. As shown in the Table IV, the compounds of this invention showed lower values of the ADP-induced platelet aggregation, thus preventing enhancement of coagulabil-ity and thrombogenici-ty.

TABLE IV The enahancement of intensity of ADP- induced platelet aggregation Compound, percent 3 10- M 10- M Saline (control) 121. 8=!=7.8 115. 1=|=4. 9 Dibenzyline (control) 101.7i8.7 106. 7=|=7.3 Pyridinolcarbamate (control 109. :l=5.9 100. 8=|=6.5 Aspirin (control) 106.0:b3.0 111. ;l:2.6 4-(N-methylcarbamoxyrnethy1) 90. 41:5. 1 85. 7:!=5.2 4-(N-ethylcarbamoxymethyl)-1-phthalazone 91. 3:1;5. 1 86. 0:|=5.2 4-(N-methylcarbamoxymethyl)-2-phenyl-1- phthalazone 101. 1:1;6. 7 96. 214.8 4-(N-methylcarbamoxymethyl)-7-methoxyl-1- h D1 h h 1 94.6=|=5.5 95.2:!=5.7 4- N N-dimeth lcarbamox et t aswdnn y h ym y D 10o.2=|=e.s oasis. 7 4- N,N- entamet lenecarbamoxymet y -1- phthaPazoneuui 97. 0:l:6.8 96.1:l:5.8 -(N-methylcarbamoxymethyl) -2-(N -metl1y1- carbamoyD-l-phthalazone 96. 2=l=5.6 93. 2;};6. 0 4-(N-methylcarbamoxymethyl)-2-methylsu.l-

fonyl-l-phthalazone 98. 5i6.1 96. 85:5. 1 7-bromo-4-(N-methylcarbamoxymethyl)-1- phthalazone -.1 1. 1$.5 .1 95. 1:]:5. 2 93. 93:5. 8 4- N- th l bamox et -ace aminoiiiimizq iz m y y 99.6i5.9 96. 25:5.6

What we claim is: 1. A compound of the following formula:

0 CHQO gN B1B: R4

i NR:

wherein R is a member selected from the group consisting of hydrogen and alkyl of 1-6 carbon atoms; R is a member selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-5 carbon atoms, cyclohexyl, phenyl, tolyl, benzyl, phenethyl, u-furfuryl, fl-picolyl, B-pyridyl, and dialkylaminoalkyl wherein the alkyl has 1-5 carbon atoms and the alkylamino group has 1-2 carbon atoms; R, is a member selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, phenyl, tolyl, carbamoyl, N-alkylcarbamoyl wherein the alkyl group has 1-3 carbon atoms, N,N-dialkylcarbamoyl wherein each alkyl has 1-3 carbon atoms, alkylsulfonyl wherein the alkyl group contains 1-5 carbon atoms, phenylsulfonyl and tolylsulfonyl; R is a member selected from the group consisting of hydrogen, chlorine, bromine, alkyl of 1-6 carbon atoms and alkoxy of l-4 carbon atoms; R is a member selected from the group consisting of hydrogen, chlorine, bromine, alkyl of 1-6 carbon atoms; with the proviso that R can, together with R form {-OH wherein m is 4 or 5 and R and R are present in any of C-6 or C-7 positions of the phthalazone nucleus.

2. The compound of claim 1, wherein said compound is 4-(N-methylcarbamoxymethyl)-1-phthalazone.

3. The compound of claim 1, wherein said compound is 4-(N-isopropylcarbamoxymethyl)-1-phthalazone.

4. The compound of claim 1, wherein said compound is 4-(N-methylcarbamoxymethyl)-7-methoxy 1 phthalazone.

5. The compound of claim 1, wherein said compound is 7-chloro 4 (N-methylcarbamoxymethyl) 1 phthalazone.

6. The compound of claim 1, wherein said compound is 4-( N,N-dimethylcarbamoxymethyl)-1-phthalazone.

7. The compound of claim 1, wherein said compound is 4-(N,N-pentamethylenecarbamoxymethyl) 1 phthalazone.

8. The compound of claim 1, wherein said compound is 6,7 dimethy1-4-(N-methylcarbamoxymethyl)-1-phthalazone.

9. The compound of claim 1, wherein said compound is 4-[N 8 dimethylaminoethyl)carbamoxymethyl]-1- phthalazone.

10. The compound of claim 1, wherein said compound is 4-[N ('y diethylaminopropyl)carbamoxymethyl]-1- phthalazone.

References Cited UNITED STATES PATENTS 3,644,361 2/1972 Bellasio et al. 260250 A 3,244,714 4/ 1972 Geary 260250 A OTHER REFERENCES Foldeak, S., et al.: Phthalazine and Related Heterocycles X. Derivatives of 3-Substituted 4-Phthalazone-1- Ylacetic Acids, C.A., 73:77173y (1970).

ALEX MAZEL, Primary Examiner R. D. MCCLOUD, Assistant Examiner US. Cl. X.R.

- UNl IED USIIATES PATENT OFFICE QETIFICATE 0F CORRECTION Patent No. 3,833,579 I Dated September 3, 1974 Inventofls) u p Miclgizg L g ue g 3; 11,

It is certified that error appears in the ahove-identified patent and that said Letters Patent are hereby corrected as shown below:

In the Heading under patentees' foreign application priority data, cancel "ho/59,906" andeubstitute 46/59,904 in lieu thereof. Also insert the following: 1'

-- August 16, 1971, 46/61,.636; August 21, 1971, 46/633,340;

September 8, 1971, 46/68, 940; and September 9', 1971, 46/69,250.

signed and sealed this 5th day of November 1974.

(SEAL) Attest:

McCOY M, GIBSON JR. c. MARSHALL DANN Attesting Officer Commissioner of Patents RM PO-1050 (0-69) USCOMM-DC 60376-P69 9 US. GOVEINMINT PRINYING OFFICQ 1969 0-366-334

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4120960 *Aug 1, 1977Oct 17, 1978The Boots Company LimitedTherapeutic agents
US4393062 *Oct 6, 1980Jul 12, 1983Imperial Chemical Industries PlcAldose reductase inhibitor
Classifications
U.S. Classification544/237, 544/165, 544/119, 544/158, 514/824, 544/116, 544/169, 514/822, 544/172
International ClassificationA01N57/16
Cooperative ClassificationA01N57/16, Y10S514/822, Y10S514/824
European ClassificationA01N57/16