Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines

Definitions

• ABSTRACT l-Phthalazone derivatives or acid salts thereof which are represented by the formula:
• R is a hydrogen atom or an alkyl group
• R is a hydrogen atom, an alkyl, alkylsulfonyl, or arylsulfonyl group
• aryl group which is represented by the formula:
• R is hydrogen or halogen atom, an alkyl, or alkoxy group;
• R is a hydrogen or halogen atom, an alkyl, alkoxy, or alkoxycarbonyl group;
• R is a hydrogen or halogen atom, an alkyl, or alkoxy group; R is a hydrogen or halogen atom, an alkyl, alkoxy, alkoxycarbonyl, amino, or acylamino group; with the proviso that at least one of R, R R and R is not hydrogen.
• the present invention relates to new phthalazone derivatives or pharmaceutically acceptable acid salts thereof for pharmaceutical use, and to a process for their manufacture.
• One aspect ofthe invention consists of l-phthalazone derivatives which are represented by the formula:
• R is a member selected from the group consisting of a hydrogen atom and an alkyl group, preferably a C -C alkyl group; R, is a member selected from the group consisting of a hydrogen atom, an alkyl group,
• alkyl group preferably a C C; alkyl group, an alkylsulfonyl group,
• alkylsulfonyl group having a C,C,, alkyl group, an arylsulfonyl group, preferably benzenesulfonyl and toluenesulfonyl groups and an aryl group which is represented by the formula:
• R is a member selected from the group consisting of a hydrogen atom, a halogen atom such as Cl, Br, I and F, preferably Cl and Br, an alkyl group, preferably a C,C alkyl group, and an alkoxy group, preferably a C -C alkoxy group;
• R is a member selected from the group consisting of a hydrogen atom, a halogen atom such as Cl, Br, I and F, preferably Cl and Br, an alkyl group, preferably a C -C alkyl group, an alkoxy group, preferably a C -C alkoxy group, and an alkoxycarbonyl group, preferably an alkoxycarbonyl group having a C -C alkoxy group;
• R is a member selected from the group consisting of a hydrogen atom, a halogen atom such as Cl, Br, I and F, preferably Cl and Br, an alkyl group, preferably a C -C alkyl group, and an alkoxy group, preferably a C -C alkoxy group;
• R is a member selected from the group consisting of a hydrogen atom, a halogen atom such as Cl, Br, I and F, preferably Cl and Br, an alkyl group, preferably a C -C alkyl group, an alkoxy group, preferably a C -C alkoxy group, an alkoxycarbonyl group, preferably an alkoxycarbonyl group having a C -C5 alkoxy group, an amino group, and an acylamino group, preferably an acylamino group having a C C acyl group with the proviso that at least one of R, R R and R is not a hydrogen atom.
• R,, R and R have the same meanings as in formula (I) and Y is an alkoxycarbonyl group, preferably an alkoxycarbonyl group having a C -C alkoxy group, or a halogenocarbonyl group having a halogen atom such as Cl or Br, is reacted with an alkali metal borohydride in the presence or absence ofa metal halogenide.
• R,, R and R have the same meanings as in formula (I), and Z is an alkoxycarbonyl group, preferably an alkoxycarbonyl group having a C -C alkoxy group, an aldehyde or acyl group, preferably a C -C acyl group, is reacted with a Grignard compound of the formula,
• R has the same meaning as in formula (1), excluding a hydrogen atom, and X is a halogen atom such as Cl, Br or I.
• the compounds of the present invention can be manufactured by any process described above. These compounds prepared are new. In the ex'perimental atherosclerosis induced by cholesterol feeding, they showed a profound effect for preventing atherosclerosis, inhib iting cholesterol deposition on arterial wall. They also prevented the enhancement of coagulability and thrombogenicity induced a one shot treatment of an animal with cholesterol or adrenaline. That is to say, they prevented the shortening of clotting times of the blood as well as the enhancement of adenosine diphosphate-induced platelets-aggregation in the animal.
• the compounds prepared are new. In the ex'perimental atherosclerosis induced by cholesterol feeding, they showed a profound effect for preventing atherosclerosis, inhib iting cholesterol deposition on arterial wall. They also prevented the enhancement of coagulability and thrombogenicity induced a one shot treatment of an animal with cholesterol or adrenaline. That is to say, they prevented the shortening of clotting times of the blood as well as the enhancement of adenosine
• compounds of this invention are useful for treatment of atherosclerotic and thrombotic diseases such as cerebral thrombosis, coronary thrombosis, peripheral thrombosis, cerebral atherosclerosis, coronary atherosclerosis, arteriosclerosis obliterans. thromboangitis obliterans, thrombophlebitis, angiopathy of diabetes mellitus, and nephropathy of diabetes mellitus. l tured by the following reaction schemes.
• the compounds of formula (ll) can bemanufactured by known methods [e.g., .l. of Am. Chem. Soc., 68, 1316 (1946)] from naphthalene derivatives.
• Examples of the compounds include 4-ethoxycarbonyl-2- phenyll -phthalazone, 4-methoxycarbonyl-2-methyll phthalazone, 4-ethoxycarbonyl-2-methanesulfonyl-lphthalazone, 4-methoxycarbonyl-2-benzenesulfonyl-lphthala-zone, 4-ethoxycarbonyl-2-toluenesulfonyl-lphthalazone, 4-ethoxycarbonyl-2-tolyl-l-phthalazone, 4-methoxyc'arbonyl-2-(p-methoxyphenyl l phthalazone, 4-ethoxycarbonyl-2-(p-chlorophenyl)-lphthalazone, 4-ethoxycarbonyl-2-
• 4-alkoxycarbonylor 4-chlorocarbonyl-l-phthalazone derivatives which have one or two substituents such as a chlorine atom, bromine atom, alkyl, alkoxy, amino acetylamino, alkoxycarbonyl group in any of the C-5, C-6, C-7, and C-8 positions in the phthalazone nucleus, can also be used.
• Examples of the compounds of formula (III) include 4-oxo-3,4- dihydroisocoumarin, 3-methyl-4-oxo-3,4- dihydroisocoumarin, 3,3-dimethyl-4-oxo-3,4- dihydroisocoumarin, and their derivatives which have one or two substituents such as a chlorine atom or a bromine atom, an alkyl, alkoxy, amino, acetylamino and alkoxycarbonyl group in any of the C-5, C-o, C7, and C-8 positions in the dihydroisocoumarin nucleus.
• substituents such as a chlorine atom or a bromine atom, an alkyl, alkoxy, amino, acetylamino and alkoxycarbonyl group in any of the C-5, C-o, C7, and C-8 positions in the dihydroisocoumarin nucleus.
• the compound of (ll) is reacted with an equimolar quantity or an excess, preferably between L5 and 10 moles per mole of compound (I), of an alkali metal borohydride such as sodium borohydride, potassium borohydride, or lithium borohydride.
• an alkali metal borohydride such as sodium borohydride, potassium borohydride, or lithium borohydride.
• the reaction is preferably carried out in the presence of metal halogenide, such as calcium chloride, magnesium bromide, lithium chloride, lithium bromide, or lithium iodide.
• metal halogenide such as calcium chloride, magnesium bromide, lithium chloride, lithium bromide, or lithium iodide.
• Sodium trimethoxyborohydride can also be used.
• the compound of (11) is 4-alkoxycarbonyl-l-phthalazone derivative, that is, Y in the formula (11) is an alkoxycarbonyl group
• lower aliphatic alcohols such as methanol, ethanol or propanol can preferably be used as a solvent, and the reaction is preferably carried out at a temperature between 0 and 150C., especially between 0C. and 100C.
• the compound of (11) is the 4-chlorocarbonyl-lphthalazone derivative, that is, Y in the formula (11) is a chlorocarbonyl group
• a solvent such as dioxane, tetrahydrofuran or benzene can preferably be used, and the reaction is preferably carried out at a temperature between 0 and 100C., especially between 0 and 50C.
• a compound of formula (11]) is reacted with an equimolar quantity or excess [preferably 1-10 moles per mole of the compound (11111 of a hydrazine derivative represented by formula (IV).
• the hydrazine derivative include hydrazine, methylhydrazine, methanesulfonylhydrazine, benzenesulfonylhydrazine, and p-toluenesulfonylhydrazine.
• the reaction can be carried out in the absence of solvent, it is carried out preferably in the presence of a solvent such as water, lower aliphatic alcohols, e.g. methanol, ethanol or propanol, and at a temperature between 0 and 150C, especially between 50 and 100C.
• the reaction can be carried out under the conditions conventional to Grigard reactions. Namely, the reaction is carried out in an anhydrous solvent such as ethyl ether. benzene or tetrahydrofuran.
• the reaction temperature between 0 and 100C, especially 0 and 50C. is preferably used.
• the Grignard compound of formula (V) is used in a quantity of l-3 moles per mole of the compound of formula (V1).
• the product can be separated and purified by conventional methods to be described hereinafter.
• the products of the present invention can form stable salts with a pharmaceutically acceptable inorganic acid such as sulfuric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid, and an organic acid such as oxalic acid, maleic acid, citric acid, tartaric acid, nicotinic acid, salicylic acid and acetylsalicylic acid.
• a pharmaceutically acceptable inorganic acid such as sulfuric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid
• an organic acid such as oxalic acid, maleic acid, citric acid, tartaric acid, nicotinic acid, salicylic acid and acetylsalicylic acid.
• the invention is illustrated but not limited by the following Examples. All the UV spectra described in the Examples were measured in 95 percent ethanol.
• the product has the following structure.
• the precipitated (4,400 )y 312 nm (2,800) crystals were filtered and recrystallized from ethanol to yield 2.0 g of 4-(a-hydroxyisopropyl)-l-phthalazone EXAMPLE 27 melting at 2l22l3C.
• the compound has the follow- A solution of 3 g of 6,7-dimethyl-4-oxo-3,4- g Structuredihydroisocoumarin and 3 g of hydrazine hydrate in 30 CH ml of ethanol was refluxed for 2 hours on a water bath. After cooling, the precipitated crystals were filtered 40 and recrystallized from methanol to yield 2.6 g of 6,7- dimethyl-4-hydroxymethyl-l-phthalazone melting at I 253-255c.
• EXAMPLE 32 38 (recrystallized from ethyl acetate/petroleum ether). 55 In a manner Similar to Example 31, the following products of the formula (I) were obtained from the EXAMPLE 29 compounds of formula (ll) in a -95 percent yield, A solution of 3 g of 4-oxo-3,4-dihydroisocoumarin as shown in the following Table II].
• the remaining 90 rabbits were Phate was measured y the Born's method (Born, divided into six groups. While all ofthe groups were fed Physloh 67 See also OBflen, Clln- Pathwith standardized food, the five groups were adminis- 15,452 (1962), Lancet. 1. 7 tered each with l0 mg per kg of the compound of the A rabbit was injected th adrenaline #g/ g) 3 present invention, the remaining one group with plahours after oral administration ofthe sample.
• l-p thalazone Com- The enhancement of intensity of LD-, 10 i 20 5.3 I 3.2 pound ADP-induced Platelet ggregation (mg/kg) gif gg gggg 6 i 10 12.4 t 2.1 3x 10 M 10 M d I 20 73:26 saline (control) l2l.8:7.87 115.131.9 70 fj$$ 6 289:4" dibenzyline (control) lOl.7i8.7'7c lO6i7i7.3% l0 l4 6 3 5 pyridinolcarbamate l09.0fl.971 100816.59: 20 I (control) 4.

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• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

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• 1971
  • 1971-08-05 JP JP46058643A patent/JPS5116430B2/ja not_active Expired
• 1972
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• 1973
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