AU427119B2 - Novel phthalazine derivatives - Google Patents

Description

33.31 271 The present invention relates to novel phthalazine derivatives and to processes for the same. More particularly,

this invention relates to novel alkenylidene hydraiinophthala- zine derivatives represented by the following general formulai

N

R1 R2 NEHN= -R 4

wherein R1 R2 R3 and R4 each represents a hydrogen atom or a lower alkyl group/ f-fr 4 /t I r A A.

The object of this invention is to provide excel-l-- -end- antihypertensive agents which are safely usable with less side-effects. Up to now, hydralazine (1-hydrazinophthalazine) have been used in the treatment of hypertension, but it is

not satisfactory for clinical use because of its undesirable side-effects. On the other hand, many hydrazones of hydralazine with saturated carbonyl compounds were synthesized and their biological activities were reported (Emil Schlittler: Anti- hypertensive Agents, pages 227-229 (1967)). These hydrazones,

however, have never been used as antihypertensive drugs, since they have undesirable side-effects or low activities. The compounds of this invention can be prepared by reacting l-hydrazinophthalazine having the formula;

NHNH 2

-2- 427.119

33. 31 2 /71 or salt thereof, with an c, )f-unsaturated aliphatic aldehyde or -unsaturated aliphatic ketone having the formula;

R1 R2 3

0= C -C R (III) wherein R1 R2 R and R4 each represents a hydrogen atom or a lower alkyl group. The reaction may be generally carried out in a suitable solvent such as methanol, ethanol or dioxane at a temperature between room temperature and 100 0 C. The desired compounds may be isolated from the reaction mixture in a foam of free base or acid addition salt, each can be converted into the other form by conventional methods. The compounds of the invention having characteristic double bond conjugated with hydrazone bond, show the reliable antihypertensive effect and the activity has very favourable characteristics which are not realized by hydralazine,mene- o ly,.ArI-.ArAl v nt^- /of-thewell-known antihypertensive drugs -and-the-l-iker- For example, mention is made of the pharmacological properties of 1-(2-methyl-2-butenylidene)hydrazinophthalazine (R1 R H R2 R4 CH3 in formula referred to as buteralazine hereafter), one of the representative compounds of this invention, in comparison with those of hydralazine and 1-isopropylidenehydrazinophthalazine. Administration was made as hydrochloride of buteral- .azine intravenously and as free base per os. I) Antihypertensive effect by single oral admin- istration and acute toxicity: Experimentally renal hypertensive rats were prep-

3 427.1 19

33.312/71 ared essentially according to the method of Goldblatt et. al. (Journal of Experimental Medicine 59 347 (1934)) The animals were administered orally with the test compounds in single doses. ED 30 mmHg value, the dose which is estimated to produce a 30 mmHg fall in blood pressure of the animals, was determined for each test compound. On the other hand, the oral LD5 0 value was determi in mice and rats. The results are shown in Table 1. Table 1 Antihypertensive activities and acute toxicity ED 30 mmHg(mg/Kg,p.o.) LD5 0 (g/Kgp.o.) in ;f in rats mice rats c Sfy'ralazine 2.8 0.25 0.25 Buteralazine 32 3 These data indicate that buteralazine is less toxic than hydralazine, though the former has lower antihyper tensive activities. However, it should be noticed that sudden fall in blood pressure takes place immediately after hydralazine/and- -he like' rc/ administered, while the compounds of this invent- ion produce gradual fall. That is, the maximum fall in blood pressure with hydralazine or 1-isopropylidenehydrazinophthala-

zine appeared within 30 minutes after administration, while within 3 to 4 hours after administration of buteralazine. This property of buteralazine is expected to reduce dizziness or other unpleasant side-effects which has often been observed in the therapy with hydralazine as hydralazine syndrome.

4 427.119

33.312 /71 II) Antihypertensive effects by repeated oral administration: When hydralazine was administered to the experimen- tally renal hypertensive rats in a dose of 5 mg/Kg, two times daily for 5 days, the reduced blood pressure fluctuated at a range of about 50 mmHg during the medication period. In contrast with the case of hydralazine, the fluctuation range of buteralazine was not so wide (about 25 mmHg) in an equipo- tent dose (40 mg/Kg x 2 times daily for 5 days). These experimental results indicate that the activity of buteralazine is more lasting than that of hydral- azine. In addition, buteralazine proved to show the anti- hypertensive effect not only in experimentally hypertensive rats but also in spontaneously hypertensive rats. The fact suggests that the compound would be effective on essential hypertension in human. III) Influence on the heart rate: Hydralazine has been known to cause tachy- cardia, an undesirable side-effect, when used in patients. In this connection, comparison was made of the influence of hydralazine and buteralazine on the heart rate in unanesthetized rats. The oral administration with 2.8 mg/Kg of hydralazine produced 30% increase in heart rate, while only 14% increase was observed by 32 mg/Kg of buteralazine. Likewise, in the case of intravenous injection, the extent of the heart rate increasing effect of buteralazine was also far less than that of hydralazine, 19% even with 16 mg/Kg dose of buteralazine in contrast to 46% with 0.33 mg/Kg dose of hydralazine. 427.1 19

33 331 2 /71 As described above, the compounds of this inventi are useful for antibypertensive agents having sure activity and less side-effects. Example 1

A mixture of 1.6 g of 1-hydrazinophthalazine, g of ereteneialdehyde and 50 ml of methanol was refluxed for 2 hours. The reaction mixture was concentrated and the residue was dissolved in benzene. The benzene solution was passed through a comparatively short column of alumina and the solvent was removed. The resulting residue was crystall- ized from ether to give 1.3 g of 1-(2-butenylidene)- hydrazinophthalazine. m.p. 117 118 0 C. Analysis calcd. for C 12 12 4 C 67.90, H 5.70, N 26.40 found C 68.14, H 5.79, N 26.12 Example 2 A mixture of 8.0 g of 1-hydrazinophthalazine, 6.3 g of 2 -methyl-2-butene-l-al and 250 ml of methanol was refluxed for 3 hours. The reaction mixture was concentrated- and the residue was crystallized from isopropylether to give 7.9 g 2 of 1-( -methyl-2-butenylidene) hydrazinophthalazin m.p. 146 148 0 C.

Analysis calcd. for C13H14 N C 69.00, H 6.24, N 24.76 found C 68.71, H 6.23, N 25.07 Example 3 A mixture of 29.4 g of l-hydrazinophthalazine hydrochloride, 15.1 g of 2 -methyl-2-butene-l-al and 800 ml of methanol was refluxed for 2 hours, The reaction mixture wzas concentrated in vacuo to precipitate crystals. The crystals were collected by filtration, rccrystallied from methanol and dried at 900C in vacuo to give 31.5 g of 427,119

1-( 2 3 3.31 2 i7n -methyl-2-butenylidene)-hydrazinophthalazine hydrochloride. 0 m.p. 210 C (decomposed). Analysis calcd. for C H N4*C1 13 14

C 59.42, H 5.75, N 21.33, Cl 13.50 founds C 59.23, H 5.60, N 21.63, Cl 13.74 Example 4 A mixture of 2.0 g of l-hydrazinophthalazine hydro- chloride, 1.1 g of mesityl oxide (isopropylideneacetone) and 100 ml of ethanol was refluxed for 3 hours. The reaction mixture was concentrated in vacuo and the residue was dissol- ved in water. The water solution was neutralized with sodium bicarbonate, salted out and the product was extracted with benzene. The benzene layer was passed through a compara- tively short column of alumina and the solvent was removed. The residue was crystallized from ether to give 0.7 g of 1-(1,3-dimethyl-2-butenylidene)ydrazinophthalazine. m.p. 131 132 0 C.

Analysis calcd. for C 14 1 6 74 C 69.97, H 6.71, N 23.32 found s C 70.20, H 6.64, N 23.29 Example A mixture of 1.6 g of l-hydrazinophthalazine, g of 2-methyl-2-n-pentene-1-al and 100 ml of methanol was refluxed for 2 hours. The reaction mixture was concentrated and the residue was crystallized from ether to give 1.4 g of 1-(2-methyl-2-n-pentenylidene)hydrazi ophthalazine. m.p. 84 850C.

Analysis calcd. for C14 16 4 C 69.97, .H 6.71, N 23.32 found C 70.11, H 6.65, N 23.50 Example 6

A mixture of 1.6 g of l-hydrazinophthalazine,

427.119 g of 2 3 3.312 /71 -ethyl-2-butene-l-al and 100 ml of methanol was refluxed for 2 hours. The reaction mixture was concentratec and the residue was crystallized from ether to give 1.5 g 2 of 1-( -ethyl-2-butenylidene)-hydrazinophthalazine.

m.p. 123 1240 C.

Analysis calcd. for C 1 4 H1 6 N 4 C 69.97, H 6.71, N 23.32 found C 70.28, H 6.51, N 23.28 Example 7

A mixture of 1.6 g of l-hydrazinophthalazine, 1.- rne.ZtA vro e, (meZ AXcr I,a/j! Aydlz g of- netaoroel Cnd 100 ml of methanol was refluxed for 2 hours. The reaction mixture was concentrated to dryness and the residue was crystallized from ether-petroleum ether to give 0.8 g of 1-(2-methylpropenylidene)-hydrazinophthalazine.

m.p. 124 125 0 C.

Analysis calcd. for C 1 2 H 1 N C 67.90, H 5.70, N 26.40 2 4

found C 67.92, H 5.70, N 26.26 Example 8

A mixture of 1.6 g of l-hydrazinophthalazine,

1.7 g of ethaeroc4n'and 100 ml of ethanol was refluxed for 2 hours. The reaction mixture was concentrated to dryness and the residue was crystallized from ether-petroleum ether to give 0.9 g of 1-( 2 -ethylpropenylidene)-hydrazinophthalazinI

m.p. 121 0 C.

Analysis calcd. for C 1 3 H 4 N4 C 69.00, H 6.24, N-24.76 found C 68.85, H 6.20, N 25.12

8- 427,119

Claims (1)

1. 3 9. %-N12/71 The claims defining the Invention are as follows: 1. A co=mpoirnd of the f ormla

   .2

   w-herein R2 R3 and each represents a hydrogen atom or a loweTr a) group containing -up to 6 carbon atoms, or acid addition salt thereof. 2. 2-methyl-2-but enylidene) -hydrazinoohthalazine or its acid addition salt.

   3. l-(2-butenylidene)hydrazinopDhthalazino or its acid addition salt.

   4. 1, 3-dimet-hyj.-2-but'envylidene )hydr-azinophtna- lazine or its acid addition salt,

   2--nathl-2-n-po-nt enyli dene )hyd razinophthal- azine or Its acid addition salt. 6. 1- ethyl-2-btiten-yli dene )h-ydrazino-)hetha-lazine or its acid addition salt.

   7. 1-(2--ty-rpnldn~yrzn~taan or its acid addition salt. 8. 1-(2-ethylproponylidene)h,drazinophthalazine or its acid addition 3ait.. 9.A process for preparing novel alkonylidene- hydrazinophthalazine represented by the .following general

   formula:

   R R2

   MN= C C =C R4

   4 27 1 19

   3 3.31 2 /71 wherein R 1 R2 R 3 and R 4 each represents a hydrogen atom or

   a lower alkyl group containing up to 6 carbon atoms, or salt

   thereof, which comprises reacting 1-hydrazinophthalazine or

   its acid addition salt with a compound of the formula:

   R 0 =C C R4

   DATED this NINTH day of AUGUST, 1972. DAIICHI SEIYAKhU CO., LTD.

   Patent Attorneys for the Applicant SPIUSOI FERGUSON

   -lo- 427.1 19

   33.1271

   427.1 19