AU621087B2 - Pyridazinone derivatives - Google Patents

Description

OPI DATE 06/09/89 A0JP DATE 05/10/89 APPLN. ID 30466-/ 89 PCT NUMBER PCT/JP89/00127 k Im ML -iN TREATY (POT) INTERN, T 7~U U (51) International Patent Classification 4 C07D 237/04, 237/14, 237/36 C07D 491/044, A61K 31/50 1) i nab Putcation Numr: W0 89/ 07594 (43) International Pu ,ication Date: 24 August 1989 (24.08.89) (21) International Application Number: PCTYJP89/00 1271 (22) International Filing Date: 9 February 1989 (09.02.89) (31) Priority Application Numbers: 63/3 1618 63/7159 10 (74) Agent: YOKOYAMA, Yoshimi; Nippon Soda Co,, Ltd., 2-1, Ohtemachi 2-chome, Chiyoda-ku, Tokyo 1 0c0 (81) Designated States: AT (Europeani patent), AU, BE (European patent), BO, BR, OH (European patent), DE (European patent), DK, FI, FR (European patent).

GB (European patent), HU, IT (European patent), KR, LU (European patent), NL (European patent), NO, RO, SE (European patent), SU, US.

Published With International search report.

(32) Priority Dates: 13 February 1988 (13.02.88) 31 March 1988 (31,03,88) (33) Priority Country: .JP (71) Applicant (for all designated States except US); NIP- PON SODA 00., LTD, [JP/JP]; 2-1, Ohtemachi 2chome, Chiyoda-ku, Tokyo 100 (JP).

(72) Inventors; and Inventors/Applicants (for US only) KUSASE, You [JP/ JP]; MURAKATA, Masatoshi [JP/JP]; MOOHIZU- KI, Nobuo TAKEBAYASHI, Michinori [JP/ JP]; Odawara Research Center, Nippon Soda Co., Ltd., 345, Aza Yanagimachi, Takada, Odawara-shi, Kanagawa 250-02 (JP).

(54) Title: PYRIDAZINONE DERIVATIVES R3 R o~Nr 0 'R N-N 1 2H r I r2 (a i I(a -c W C- (57) Abstract The present invention relates to a compound having formula which has an excellent cardiotonik action. in said formula, Y represents C1. alkylene which may be substituted by C1.18 alkyl, C1.5 alkoxy, C1, alkylthlo CI.S alkyl, C1. alkoxcycarbonyl or benzyl, or (where each rl and rz represents hydrogen, C1, 1 8 alkyl.,CI. alkoxy, C1. alkylthio C1.$ alkyl, C1. alkoxycarbonyl or benzyl);, and Rt represents hydrogen, Cl. alkyl which, may be, substituted by 01.5 alkoxy, acetyl or C1. alkenyl,- and R 2 represents hydrogen or methyl;, and each R 3 and R4 represe~nts hydrogen, halogen, hydroxy, C1, atkyl, or Cl$ alkoxy; and RS represents hydrogen or C1. alkyl which. may be substituted by hydroxy; and R 4 and Rs may form ring by joining each other; and =represents single or double bond, WO 89/07594 WO 8907594PCr/JP89/00127 I7

I

WO 89/07594 PC~i'JP89I00127 1

DESCRIPTION

Pyridazinone Derivatives Technical Field: The present invention relates to new pyridazinone derivatives and the processes for the production of such compounds.

Background Art: Several drugs under development are known as cardiotonic drugs. The following compounds are typical examples:

N

CH

3

H

milrinone -0

H

H

CI-914 The purpose of the present invention is to seek a new substance that has an excellent cardiotonic action and that is safe and free from side effects. It is also to offer the method in which this new substance can be manufactured in a commercially advantageous manner.

Disclosure of Invention; The present invention relates to a compound having the 'i 2 formula below, and the processes for the production of such compound: S-Y R3 4R5-- R, 2

H

wherein Y represents C1- 4 alkylene which may be substituted by

C

1 18 alkyl, CI 5 alkoxy, C_5 alkylthio C1_ 5 alkyl, 1 2 r r I I C C_ 5 alkoxycarbonyl or benzyl, or -C C- (where each 1 2 r and r represents hydrogen, C118 alkyl, C1_ alkoxy, CI 5 alkylthio C 1 alkyl, C1-5 alkoxycarbonyl or benzyl); and R represents hydrogen, acetyl, or C2-5 alkenyl, or alkyl which may be substituted by C1-5 alkoxy; and

R

2 represents hydrogen or methyl; and each R 3 and Ri represents hydrogen, halogen, hydroxy, C_5 alkyl, or C_ 5 alkoxy; and R represents hydrogen or C -5 ,al k y l which may be substituted by hydroxy; and

R

4 and R 5 may form ring by joining each other; and represents single' or double bond.

Compared to milrinone and CI- 9 14, the compounds of the present invention exhibit a potent and selective inhibition of the phosphodiesterase III, have an excellent cardiotonic activity, are safe, non-toxic and orally effective, and are useful for the treatment of congestive heart failure. In addition, the compounds of the present invention inhibit a platelet aggregation and have an antithrombotic activity. The j I

I-

WO 89/07594 PCT/JP89/0017 3 compounds of the present invention have a bronchodilatory activity and are useful for the treatment of chronic obstructive pulmonary disease such as asthma and bronchitis.

Moreover, the compounds of the present invention are useful for the treatment of various diseases (hypertension, ulcer, diabetes, cancer, etc.) which are associated with the intracellular level of cyclic AMP.

Best Mode for Carrying Out the Invention: The compounds under the present invention can be manufactured in the methods specified below.

when R 1 is not acetyl; Y R4R I N-N

R'

1

R

2

H

(III)

wherein R' is hydrogen, C 1 5 alkyl which may be substituted by C1-5 alkoxy, or C 25 alkenyl.

The reaction is carried out in an inert organic solvent, preferably in such a solvent as benzene, toluene, xylene, a lower alcohol or DMF, in the presence of an acid catalyst, preferably such a catalyst as hydrochloric acid, sulfuric acid, acetic acid or paratoluene sulfonic acid, at room temperature or by heating to a temperature above room temperature to 2000C.

The reaction may be performed more efficiertly if formed water is removed by such a means as azeotropic dehydration during the reaction.

ILi WO 89/07594 PCT/JP89/00127 when R 1 is acetyl: Y R3

R

4 R-- 0 X H 0 (I N -N R"2 H 1 (IV)

(III)

Wherein R" is acetyl, and X is C1-5 alkoxy.

The reaction is carried out in an inert organic solvent, preferably in such a solvent as a lower alcohol or DMF, at room temperature or by heating to a temperature above room temperature to 2000C. After the reaction is completed, a usual post-treatment gives the intended product.

The structure of the compounds of this invention has been determined from IR, NMR, MASS spectra, etc, The compounds of this invention are expressed as pyridazinone-3(2H)-one compounds. However, the pyridazinone part can be a tautomer of pyridazinol, and if R 2 is hydrogen, the cycloacetylamino part be a tautom of enol form or keto form shown below

Y

y SNH 0 n R

R"HN-

1

R

T

n adilion, if R 5 is a methyl group and is a single bond in the compound of this invention, an optical isomer is present.

This invention includes all these isomers.

Furthermore, each raw material having the formuta (II), (III) or (IV) can be a a4i-e tautomer.

The following Examples illustrate the present invention, WO 89/07594 WO 8907594PCT/jTP89/00127 Example 1: 4 ,5-Dihydro-6- (3-oxo-lcyclopentenyl) amino) phenyl)-3(2H)-pyridazinone (Compound No. 2) H 2 N 0' N1 o 0I tNH 0 {0 00 430 mg of 4,5-dihydro-6-(4-aminophenyl)-3(2H)-pyridazinonie and 220 mg of cyclopentane-1,3-dione were suspended in 4 ml of ethanol, to which 2 ml of acetic acid was added. The resulting mixture was heated to reflux for 2 hours. After cooled, deposited crude crystal was collected by filtrating, and purified by silica gel column chromatography (eluting solvent: chloroform: methanol 520 mg of the title compound was obtained. >360*C. NMR (solvent: DMSO-d 6 6S 1.80 2.80 (in, 8H) 5 .13 1H-) 7. 10 dd, 4IH) 9. 33 (S I 1H) 10.-50 1H).

Example 2: 4,-lyr--4((-ehl3ool cyclopentenyl)-amino)phenyl)-3(2H)-phridLzinone (Com~pound. No. 4I) 00 GH 3 +H2N I& T. 0 2 N-N

H

0 Z N N CH 3

H

3.4 g of 4.5-dihydro-6-(4i-aminophenyl)-3(2H)-pyridazinone and 2,0 g of 2-methylcyclopentane-1,3-dione were suspended in ml of tol~uene, to which a catalytic amount of p-toluene laL it- WO 89/07594 PCT/JP89/00127 6 sulfonate-hydrate was add while the resulting suspension was heated to reflux with stirring for 8 hours, with removal of water as an azeotropic mexture. After cooled, deposited crude crystal was collected by filtrating, and purified by silica gel column chromatography (eluting solvent: chloroform: methanol 10:1). 4.7 g of the title compound was obtained. m.p. 284- 285°C.

Example 3 3,5-Dihydro-6-(4-((2-acetyl-5,5-dimethyl-3-oxo-1cyclohexenyl)amino)phenyl)-3(2H) pyridazinone (Compound No. 6) o 0 0 o 0 CH N- N 0 N-N 3 H COCH COCH 3 230 mg of 2-acetyl-5,5-dimethyl-3-methoxy-2-cyclohexeni-lone and 284 mg of 4,5-dihydro-6-(4-aminophenyl)-3(2H)pyridazinone was suspended in 2 ml of ethanol, and the resulting mixture was heated to reflux,,for an hour. After cooled, crude crystal was collected by filtrating, and purified by silica gel column chromatography (eluting solvent: chloroform: methanol 30:1). 390 mg of the title compound was obtained. m.p. 212.0-213.5 0

C,

Iii WO 89/07594 PCT/jI 7 Example 14 4,5-D ihydro- 6- 1cyclopentenyl) amino)pheryl)-5-methyl-3( 2H)pyridazinone (Compound No. 114) 89/O0127 0 0:1 H2N 0 CH N H 0N 0

H

0.51 g of 4,5-dihydro-6-(4-aminophenyl)-5--methyl-3(2H)pyri,dazinone and 0.25 g of cyclopentane-1,3-dione were suspended in a mixture of 5 ml of ethanol and 5 ml of acetic acid and the resulting suspension was refluxed for 7 hours.

After cooled, deposited crude crystal was collected by filtrating and recrystallized from DMF-heptane-CHC1 to give 1 3 0.241 g of the title compound. m.p. >300 0 C, NMR (solvent d 6 CDC 3 6 1. 20 d, 3H) 2,.32-3.32 (in, 7H) 5. 60 1H) 7. 56 (dd, I4H), 9. 82 1H) 10. 10 (3,I Example 5 1,5-Dihydro-6- ((2-rethyl-3-oxo-1cyclopentenyl)amino)phenyl)-5-methyl-3(2H)pyridazinone (Compound No. C11

±H

2 N N-N

H

H

3 -KO N-N

H

A mixtur'e of 0.51 g of LI,5-.dihydro.6-.(4-minopheny)......

methyl-3(2H) pyridazinone and 0.28 g of 2-.methyl-cyclope'tane- 1,3-dione in 5 ml of ethanol and 5 ml of acetic acid was refluxed over night. Arter cooling, the solution was ^^*-iniC~Li.ilr-H'llI I

L

WO 89/07594 PCT/JP89/00127 8 evaporated in vacuo. The residue was purified by silica gel column chromatcgraphy (eluting solvent: chloroform: methanol 20:1) and recrystallized from methanol to give 0.32 g of the title compound. m.p.285-28 6

°C.

Reference Example 1: 7-Acetamido-3-cyanomethylchroman-4-one CH CONH 9 3 ,N(CH 3 3 2

CN

CH CONH 3 A mixture of 37% aqueous formaldehyde (1 dimethylamine hydrochloride (1.1g) were stirred temperature for one hour.

ml) and at room After an addition of acetic anhydride (6 ml) the mixture was gradually heated until a one-phase system resulted.

To the solution 7-acetamidochroman-4-one (1.5 g, 7,3 m mole) was added, and the solution was heated (90-100C) for one hour, The solvent was removed under reduced pressure, acetone ml) was added, and the solution was heated at reflux for minutes. A residue obtained by evaporation of solvent under reduced pressure was dissolved in IN aqueous NaOH (50 ml).

The solution was extracted with a mixture of chloroform/2- WO 89/07594 PCT/JP89/00127 9 propanol and the combined extracts were dried with anhydrous magnesium sulfate.

After remove of magnesium sulfate the solvent was evaporated to provide 'an oil.

After an addition of methyl iodide (2.8 g, 20 m mole) to the oil in acetone (50 nl), the solution was heated at reflux for one hour. After cooling the resulting solid was collected to provide the quaternary salt (1.78 g, yield 60.4).

To a suspension of quaternary salt (510 mg, 1.26 m mole) in a mixture of methanol/water 10 ml), potassium cyanide (100 ml, 1, 5 4 m mole) in water (2 ml) was added.

The mixtupe was stirred at room temperature for eight hours, Then, the resulting solid was collected to provide 7acetamido -3-cyanomethylchroman-4-one (200 mg. Yied 65.1%), (NMR (CD OD), 6: 243 (3H, 2,70-3.00 (21-1, 4.10-4,83 (3H, Tn), 7.05 (lii dd), 7,43 (11i,d), 7.73 (1H, d)) Reference Example 2 8-Amino-3,4,,5-tetrahydro H- (1) benzopyrano (4 3-c)pyridazina-3-one CH ON -nl' i-N 0. *0 cH cON N-N 3 H A suspension of 7-acetamido-3-cyanomethylchroman-4-one (200 mg, 0,82 i moe) in 6N aqueous H0 (8 ml) was heated at retlux for one hour, After cooling 6N aqueous NaOH was added until a solution was adjusted to pH 5, and 100% hydrazine hydrate (100 mg, 2 m mole) was added, Then the solution was heated at reflux for 11 hours. After /M~r" WO 89/07594 PCT/JP89/00127 cooling the product was collected to provide 8-arnino-3,4,Lla,5tetrahydro-2H-(l)benzopyrano(4,3-c)pyidazi-3-ole (130 mng, yield m.p. 232-2350C (dec.)- Example 6 8-3oo'-ylpnI~nlmn)31,a5 tetrahydro-2H-(1) benzopyrano )-pyriclazinon-3one (Compound No. 241) 0

H

2 0 F HL -0 2

-N

HH

To a suspension of 8-amino-3,'4,4a,5-tetrahydro-2H" benz opyrano (4,3-c )pyridaz in- 3- one (120 mg, 0.6 m mo2.) in a mixture of ethanol/acetic acid 2m1), 1.3- 'I cyclopentanedione (120 mg, 1.2 m, mole) was added, and the A hsuspension was heated at reflux for 4 hours, A residue obtained by evaporat~ion of solvent was chromatographed on silica gel (eluting solvent: chloroform; metanol -50:1l) to provide the r(44.e compound (170 Mg, yield m.p. 32700 (dec.) inclusive the above, compounds within the scope of this inventio,,n which can be prepared in analogous method(s) tabulated in Ta.ble 1.

PCT/JP89/00127 WO 89/07594 11 Table 1 I Structure Formula Compound No.

Physical Properties m.p. *C 1 1. i -4 1 1 1 I CH 3 CH3 -ICH2 /H2- 2 CF2 CH2 -CH CH2 -CH CH 2 2 C i CH 3 -C-CH -CH 2- CH 3 CH 014 Q -H 2 COOCH CH H

OH

3

OH

3 -C -C-CH 2- 2 2 H i O 22 (CH3 -CUH-C 12 _LM 2CH/CHK U -U 4position

I,

single bond 272-274 360 up 2 5 2-254 284-285 283-M85

CH

3 H 3 cOO1HI

U:

S23,2-213.5) S189-191 272-73.5) dec 25$-60 dec, (8$.5-28415) 25at7-26(0 A JI i al a I a S-- I i; r PCT/JP89/00127 'NO 89/07594 k j_ r r 0 3

H

7 -OW7, *C1-CH- 2 -CH OH CH 222 -CH CH 2 2 CH 3CH'3 -CT -C-CH 2 2.

-CH OC' CH H 2 CH2 22 4posi- tion

II

gon bond 270-272 II t II It double bond

II

II

single bond 11 263.5-266 300 up 285-286 302-305 273-276 340 up 300 up 3-

PQ-

sition 4- P sition 4-C 3 241-244 51 -2533 21 11) CH1

H

C Rg 14 9 -OH -CI-CU 2 2 OHi -CU -OH-CU 2 2,,a~ (261 5-26 3 29 29 -CH O CH 2C2 CH2 2CHH O.d3 00 o I- 37l~ -OCH 2 H Il 2 :i It 256-258 327 dec 197-19 280-281.5) 222-223 237-238 C 174-175 i ,Lr WO 89/07594 WO 8907594PCT/JP89/00127 1 7 1 5 -OHi 2-CH-CHk 2- 2 2 -OH 2-CH-CI- 2- 2H 2

SCH

13

O

3 1-O 3 -OH 2-OH-OHi2 -OH O H 2- 22 4po sit ion it It 3p0-

BI-

tion p0sitiori 2- Pasit ion Pa sit ion s in gle bond (253 .5-26o 260-261 -OH O H 2- 22 OH 2 Ct=CH2

H

OH 3

H

OH 3

H

OH

3

H

OH

3 I I 3- CH

H

Ht Ii -OH 2- H H

-CH

(238-24I0 300 up 162-163 (300 up (263-264 276-277 276-277 230-231 217-218 305 dec.

24I2 dec dec.

WO 89/07594 PCT/JP89/00127 44 46 47 48 49 51 52 -CH 2CH 2 CH 2- -OH 2CH 2it It It It 4p0sit ion It It H IH -CH 2sin-I( 292-294) 3-Cl 3-Br 3-H 0 2 -OH0

H

It It gle bond it It it It dec.

115-116 (104.5-106.5) 260-261 220 dec.

216-22Q 280 dec.

200-205 270 d, HOCH 2 It dottble bond singl e bone 224 dec.

1j2 t1 SubstitUted position of in the benzene r'ing Disclosure of Invention: The present invention relates to a compound having the

I

j i ii i v :1 i II-P K i. 1. WO 89/07594 PCT/JP89/00127 Industrial Applicability: The pharmacological effects in the compounds of the present invention is described by the following tests.

Test 1 Cardioton-ic action: Electrically stimulating isolated guinea pig left atria Male Hartley guinea pigs weighing 350-500 g were used.

The hearts were excised from the animals. The left atria were dissected from the hearts and mounted in an organ bath.

The bath was filled with 50 ml oxygenated (95% 02 and C0 2 Krebs-Henseleit solution at 30°C of the following composition: NaCI 118 mM; KC1 4.7 mM; CaCI '2H 2 0 2.5 mM; MgSO4'7H20 1.2 mM; KH 2

PO

4 1.2 mM; NaHCO 3 25.0 mM; glucose 10.0 mM, The atria were stimulated by square wave pulses of 3 msec duration and a voltage ranging from 1.2-fold to 1.5-fold of the threshold at a frequency of 60/min with an electric stimulator.

Resting tension was adjusted to 0.5 g and contraction was recorded on the Polygraph Systems with a force-displacement transducer.

All preparations were allowed to equilibrate with the bath medium for 90 to 120 min.

The test compounds were added cumulatively to the bath and the concentrations causing a 50% increase in contractility

(EC

5 0 were calculated from the concentration-response curves.

The results are shown in Table 2.

i i i n WO 89/07594 PCr/JP9/00127 16 Table 2 contractility of guinea pig left atria Compound No.

EC

50 (Pg/ml) 1 0.23, 2 0.11 3 0.23 4 0.24 14 0.12 0.054 Milrinone 0.43 CI-914 1.8 Test 2 Cardiotonic action: Anesthetized dogs Adult mongrel dogs of either sex weighing 8 to 15 kg were used.

The animals were anesthetized with sodium pentobarbital mg/kg, and maintained by an intravenous infusion of the anesthetic at a rate of 4 mg/kg per hour.

A cuffed endotracheal tube was inserted and an artificial respirator installed. The animals were ventilated with room air in a tidal volume of 20 ml/kg at a rate of 20 brearhs per minute.

Cannulae were inserted into the femoral vein for a falling drop of a physiological saline or for an infusion of the anesthetic, and into the femoral artery for measuring arterial blood pressure with a pressure transducer. Heart rate was recorded with a heart rate counter triggered by the R wave of is removed by such a means as azeotropic dehydration during the reaction.

m I 1 -EI -J r .Ii WO 89/07594 PCT/JP8900127 17 the electrocardiogram (ECG).

ECG in standard lead II was monitored with a bioelectric amplifier.

Left ventricular pressure was measured with a catheter tip pressure transducer inserted via the right carotid artery into the left ventricle. Left ventricular dp/dtm x was obtained by max an electric differentiator, The compounds were injected through the cannula in the femoral vein at a dose of .0.001-0.3 mg/0,1 ml/kg.

The doses producing a 50% increase in LVdp/dt (ED 5 max Pv were calculated from the dose-response curves.

The results are shown in Table 3.

Table 3 LVdp/dt Changes in Compound No. Eax

ED

5 0 (pg/kg,i.v.) Heart rate Blood pressure 1 43 5 -1 2 6 6 -2 3 9 2 -4 4 12 5 -2 14 8 13 -11 12 19 -18 24 22 4 -7 26 30 8 -6 23 3 Milrinone 23 6 -6 CI-914 95 9 Furthermore, each raw material having the formula (II), (III) or (IV) can be aA e+fimfl4 tautomer.

Q 'TE The following Examples illustrate the present invention.

WO 89/07594 PCT/JP89/00127 Test 3 Inhibition of phosphodiesterase The preparation of different forms of cyclic nucleotide phosphodiesterase from guinea big left ventricular muscles was done by following the procedure of Weishaar, et al. (R.

Weishaar, et al., Biochemical Pharmacology, 35, 787-800, 1986) with the minor modified method of Thompson, et al. (W.J.

Thompson, et al. Advances in Cyclic Nucleotide Research, 69-92, 1979). Briefly, the three active forms of S phosphodiesterase (PDE-I, PDE-II, PDE-III) present in the ventricular muscles were discretely eluted from a DEAEcellulose column (Whatman, DE-52, 2.5 x 20 cm) using a continuous 70-800 mM sodium acetate gradient.

The phosphodiesterase activity was assayed by minor modifications of the method described by Furutani et al. (Y.

Furutani, et al., Journal of Antibiotics, 28, 558-560, 1975).

3 Briefly, 1 pM H -cAMP was hydrolyzed by the phosphodiesterase and the unhydrolyzed 3 H -cAMP which was separated from the formed 5'-AMP by a dry alumina (Merck, activity 1, neutral) was counted by a liquid scintillation counter,, The concentrations causing a 50% inhibition of the phosphodiesterase activity (IC50 were calculated from the concentration-inhibition curves.

The results are shown in Table 4.

I

3.4I g of L.5-dihydro-6-(4-~am.inophenyl)-3(2H)-pyridazinfole and 2.0 g of 2-methYlcYclopentane-1,3-dione were suspended in ml of toluene, to which a catalytic amount, of p-toluene m WO 89/07594 PCT/JP89/00127 19 Table 4I Comoud o. phosphodiesterase inhibition IC 5 0 (i.PM) PDE-I PDE-II PDE-III 1 900 250 1.2 2 1000 235 1.2 3 210 180 o.4I7 4I 61o 3-3 0 14 310 260 0.88 >1000 940 0.59 24 100 100 4.1 26 >'1000 100 2.3 100 149 1.6 Milrinone 151 142 2.8 CI-914 100 0 276 5.7 W-1 rl i I _i-:rii *111 i WO 89/07594 PCT/JP89/00127 Test 4 Acute toxicity The acute toxicity of the test compounds was studied in male mice after oral administration of a single dose. The animals were observed for 7 days and the mortality was determined.

The results are shown in table Table Compound No.

acute toxicity in mice, 300 mg/kg,p.o.

mortality (number of dead animals/ number of treated animals) 0/3 0/3 0/3 1/3 i Milrnone CI-914 3/3 2/3

Claims (7)

1. A compound having the formula oZ o R 3 R N, -N 0 I N -N R 2 H wherein Y represents C1- 4 alkylene which may be substituted by C 1 _1 8 alkyl, C1- 5 alkoxy, C 1 alkylthi C 5 alkyl, C 1 5 alkoxycarbonyl or benzyl, ri r 2 I I Al or -C C- (where each 5l and r 2 represents hydrogen, C1-18 akyl, 01-5 alkoxy, C1-5 alkylthio C 1 -5 alkyl, C1- 5 alkoxycarbonyl or benzyl); and Ri represents hydrogen, acetyl, C 2 5 alkenyl, or *6C 1 -5 alkyl which may be substituted by C.S 5 alkoxy; and R 2 represents hydrogen or methyl; and each R 3 and R4 represents hydrogen, halogen, hydroxy, C 1 -5 alkyl, or C 1 alkoxy; and R 5 represents hydrogen or C 1 5 alkyl which may be substituted by hydroxy; and R 4 and as may form ring by joining each other; and represents single or double bond.

2. A process for the production of a Oompound having the formula R R R145 Yi 3 1 R2 U which comprises reacting a compound having the formula <i until a solution was adjusted to pH 5, and 100% hydrazine hydrate (100 mg, 2 m mole) was added, Then th. solution was heated at reflux for 4{ hours. Af ter I 0 0 with a compound having the formula 09 a: got. wherein R, represents hydrogen, CI,S alkcyl which may be substituted by Cl.. 5 alkcoxY, Or C 2 -5 alkenyl; and Y, R 2 R 3 h 4 f R 5 and re as def ined in claim 1. S. A process for the -production of a compound having thie formula II which comprises reacting a compound having the formnula 0X 1 with a compound havin~g the formul~a UN 9 11 21' X I PAT.Oflqx VN 1,166"'It" rev"', -23- wherein R1 represents acetyl; and X represents CI_ 5 alkoxy; and R 2 R

3 R 4 R 5 and are as defined in claim 1.

4. A pharmaceutical composition comprising a compound as claimed in claim 1 and a pharmaceutically acceptable diluent, carrier or adjuvant.

A method of treatment of congestive heart failure, chronic obstructive pulmonary disease and/or diseases associated with the intracellular level of cyclic AMP which comprises administering to a patient in need thereof an effective amount of a compound as claimed in •claim 1 or a composition as claimed in claim 4. .*OO *e0 S..o

6. A compound as claimed in claim 1 substantially as hereinbefore described with reference to any one of the exampiles other than the reference examples.

7. A process as claimeci in claim 2 or claim 3 substantially as hereinbefore described with reference to any one of the examples other than the reference examples. DATED this 18th day of December, 1991, NIPPON SODA CO., LTD. By Its Patent Attorneys DAVIES COLLISON CAVE Q1 III, I F! r)%T.Ola\ Ig p rc 1 29 It I" 4E I"I I I 1741-175 )I I I Q INTERNATIONAL S3EARCH REPORT InlernatinaI Application No Pt F/JP 89/00127 1. CLASSIFICATION Of SUGJECT MATTER (it severae classinecation symbol$ apply, Indicate all) ccording to International Patent Claseificatio (IP t o b t I ainq CIsaf Cl con nd IPC4: C 07 0 237/0', /14,/36, 0491/004 A01/50 01. FIELDS SEARCHED M nimum Documentation Zoarched Classification 3yatem CIe~Atlion aymbois IPC4 C 070D Documentationi $4arched other than Minimum Docum, ntalicn vo Eutent that ouch Dqcuments tire Included In the Fleldi; ewched a Ill. D'(1CUM9NTS CQ~ziiID TO 0 41 RELEVANT' Category'T Cititri_'ofa Doe 'ment,' with I ndication, where appropriate, of the ;e'evant passages r Relevant to Claim No, is X EP, A2, 0084250 (MITSUI TOATSU KAGAKU K,.SUSHILi 1-2 I KAISHA) 27 July 1983, see page claims 1-17 x EP, A2, 0129791 (CASSELLA AKTIENGESELLSCHAFT) 1 2Jantiary 1985, see page 54; claims 1-6 x DE, Al, 3302442 (BASF AG) 26 July 1984, 1 see page 46; claims 1-12 X GBI A, 4177689 (BOEHRINGER BIOCHEMIA ROBIN S.F.A4) 1 28 January 1987, see page 6; claims 1-6 Special caegi? A of elikd documental is later rdocument pubihed after the In: tai filing date document deonning tris general sate to the art which Is not or priority date and not In c flvitn the spvllc;-tion but C~sco ited to undm~aland the print.1olW n. feory undorlyir.,4 the cosierd t,4 be ul p2erficular relevance Inven'tion "s arner document out published on or after the international NX document of isoriigiifst relevancet the claimed invention filing date cannqt be conari1erfid novel of cannot be considered to locument which may i,4row doubleatin priority' claim(s) or Involve an iflvefliva ileo vihich Is cited to *stab 10h the Publication L~ate o1 another document of particular rsievane4st the ;taimed Invention ltiation or other 4pecisl reason toe tpo-tiled) Cannot be Conaidered to InvovG an Inventhe oteo when the I'0 document retgrnIni4 to an, oval diaclootwi use, exhibition or document Is combined with one or more other erich docU- Other means Monte, such Combination being obvious to a portion skilled docimer oublsh 'I prior to the international filing dale but In the arm. later than ts Pilohty dots clilmed document member of the same patent familyt IV# CERTIFICATION__ Date of the Actual. Completion CI the International 3earch Data of Mailing of this lntevfatiotal $earch 27th April 1989 8,5.8 Internatlopital Seatching Authority L EURO~PEAN PATENT OFfPICE Fkrm PPIT/IA/2O (Aecond sheaf) (January 101116 Signature*(A *01ux D~to L. ROSS international Application No. PCT/JP 89/00127 inl. oOCUMENTs coNsIcEnaO TO 5E RELEVANT (CONTIMND FROM THE SECOND SHEET) Cat~oryCitation of Document. w0t Indication, where appropriate, of the relevant passages Relevant to Claim No X EP, A2, 0169443 (BOEHRINGER BIOCHEMIA ROBIN 1 29 January 1986, see page 19 page 24; claims 1-6 X Patent Abstracts of Japan, Vol 6, No 18, C1711, 1-2 abstract of JP 57- 46966, pubi 1982-03-17 (MITSUI TOATSU KAGAKU K.K.) x EP, A2, 0124314 (WARNER~-LAMBERT COMPANY) 1 7 Novefiiber 1984, see page claims 1-8 Form PCTISA/210 (oxtra sheet) (Januniq I110) ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. PCT/JP 89/00 127 SA 26725 This annex lits the poitc~t family memnher, relating to the patent doecmentc cited in the shove-oeinned international senrrh rejior!. The members are its contak'ned in (tic Fusrepean Pateat Office mr11 tie on03/03/ 89 The Euiropean Patent Ofic, is in no way iahie for these pirticularx which n w mee yien fr~ the pu rpnco ifrmation Patent document Pubhlication Patent family Pubhlication citedl in search report date mrmber(;) do~te EP-A2- 0084250 27/07/83 JP-A- 581131S0 05/07 '/83 US-A- 45214i5 04/06/85I US-A- 4523011 11/06/85 OE-A- 3278688 28/07/88 EP-A2- 0129791 02/01/85 DE-A- 3322079 201/12/84 JP-A- 60013766 24/01/85 AU-D- 29518/84 13/06/85 US-A- 4666902 19/05/87 DE-A- 3411850 10/10/85 IJE-Al- 3302442 26/07/84 EP-A- 0116853 29/08/84 JP-A- 59141563 14/08/84 GB-A- 2177689 28/01/87 NONE EP-A2- 0169443 29/01/86 AU-D- 44814/85 30/01/86 JP-A- 61047468 07/03/86 GB-A-B- 21634643 26/03/86 US-A- 4692447 08/09/87 AU-A- 576253 18/08/88 EP-A2- 0124314 07/11/84 JP-A- 59205367 20/11/84 AU-D-, 26496/84 08/11/84 US-A- 4602019 22/07/86 AU-A- 566154 08/10/87 US-A- 4701453 20/10/87 r or more iletails; ahnttt this annex see Ofliciialtinrnol of the Iiiropetin isions 0111, No. 12A