JPS5989681A - Novel pyridopyrimidinone compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention This invention relates to novel pyrimidinone compounds useful as antiarrhythmic agents.

Arrhythmia is a disease related to the generation of heartbeats in the heart. The disease includes abnormal or ectopic focal premature contractions in the arteries or ventricles (extrasystoles), paroxysmal supraventricular tachycardia, atrial flutter, atrial fibrillation and ventricular tachycardia, and movement is included. To discuss these diseases, for example, Pharmacological Ba5is
of Therapeutics.

Goodman and Gilman, the Mac
Millan Co.

709-711 (1970).

Many compounds have been developed to alter cardiovascular factors related to heart rate and rhythm.

Cardiac glycosides, including digitalis, have as their primary pharmacodynamic property the ability to increase myocardial contractility. The favorable effects of this drug in congestive heart disease, namely increasing cardiac output, decreasing cardiac dimensions, arterial blood pressure and blood volume, diuretic and reducing edema, are all due to
The explanation is based on the increased contractile force, a positive inotropic effect.

Quinidine is useful in the treatment of atrial fibrillation, but exhibits some toxic effects similar to quinine toxicity. The cardiac effects of zolocainamide are virtually identical to quinidine, and zolocainamide exhibits toxic side effects similar to quinidine.

Lidocaine (L:1ocaine), widely used as a local anesthetic by intramuscular administration, can be used to treat paroxysmal ventricular rhythms, but is not recommended for treating supraventricular arrhythmias. Prosilanolol has found use in the treatment of supraventricular tachycardia and ventricular arrhythmias, but serious arrhythmias are usually ,
The use of this drug for its antiarrhythmic effects requires great caution, as it is encountered in the presence of overt or early heart failure. Perilla disopyramide shortens the sinus node recovery period and prolongs the atrial effective refractory period, and has the lowest effect on the AV type effective refractory period.

However, since type 1 antiarrhythmic agents (like analytes) have anticholinergic effects, they should not be used in patients with glaucoma, myasthenia gravis, or urinary retention problems.

PRIOR ART As noted above, many compounds are useful in treating arrhythmias. The giridogirimidinone compounds of the present invention are novel and belong to a new group of compounds useful in the treatment of arrhythmia with reduced anticholinergic activity.

SUMMARY OF THE INVENTION It is an object of the present invention to develop new chemical compounds that are useful in the treatment of arrhythmia conditions and have reduced anticholinergic activity.

In accordance with this purpose, in particular the formula [wherein R1 is a] hydrogen; b) alkyl having 1 to 6 carbon atoms; or C) phenyl; a) hydrogen; b) /% CI'f; C) 1 to
a) alkyl having 6 carbon atoms; d) alkoxy having 1 to 6 carbon atoms; or e) phenyl; 2 is a) hydrogen; or b) -(OH2)n-NR2
R3, where n is 1 to 6, R2 and R3
a) are the same or different alkyl, each having 1 to 6 carbon atoms, or b) R2 and R3 together are saturated or unsaturated alkyl having 4 to 6 carbon atoms; Forms a ring structure; R4 is a) hydrogen:
or b) alkyl having 1 to 6 carbon atoms] and their pharmacologically acceptable salts are useful for their antiarrhythmic activity and exhibit reduced anticholinergic activity. It was found that

Examples of alkyl having 1 to 6 (inclusive) carbon atoms include methyl, ethyl, propyl, butyl, pentyl, hexyl and its isomeric forms.

Examples of halogens are chlor and bromo.

Examples of alkoxy having 1 to 6 (inclusive) carbon atoms include methoxy, ethoxy, zoloboxy, butoxy, pentoxy, hexoxy and its isomeric forms.

Examples of saturated nitrogen-containing ring structures having 5 to 7 atoms (inclusive) are 1-azacyclopentyl, 1-azocyclohexyl and 1-azucyclohezotyl.

Examples of unsaturated nitrogen-containing ring structures having 5 to 7 atoms (including 5 and 7) include 1-gyrolinyl, 1-pyrrolyl, 1
- Dihyr mouth lysinyl, 1-tetrahyP mouth seal,
There are 1-azocyclohezotenyl, 1-azucycloheptagenyl, and 1-azepinyl.

Antiarrhythmic activity was confirmed using ventricular arrhythmias induced in unanesthetized dogs. Ventricular arrhythmia is induced in two or more dogs by ligating the anterior branch vessels of the left coronary artery at two locations. A test compound is evaluated as active if it produces at least a 25% reduction in ectopic beats for at least 10 minutes in half or more of the test dogs. Active compounds can act by inhibiting the ectopic pacemaker, thus allowing a return to normal rhythm. This arrhythmia is believed to be essentially similar to the arrhythmia resulting from myocardial infarction in humans. Quinidine and zolocainamide were active in this test and are effective in humans.

In view of their antiarrhythmic activity, compounds of Formula V are useful in the treatment of arrhythmias in mammals. A physician or veterinarian of ordinary skill can easily identify subjects exhibiting arrhythmia.

Regardless of the route of administration chosen, the compounds of the invention can be formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the pharmaceutical arts.

These compounds can be administered in oral units such as tablets, capsules, pills, powders or granules. They may also be administered in forms known for intraperitoneal, subcutaneous or intramuscular use to those skilled in the pharmaceutical arts. Generally, the preferred form of administration is oral.

The compounds are used in treatment in effective but non-toxic amounts. Dosage ranges for the prevention or treatment of arrhythmias with compounds of the invention will depend on a variety of factors, including patient type, age, weight, sex, and medical conditions, severity of arrhythmia, route of administration, and the particular compound used. To be elected. A physician or veterinarian of ordinary skill can readily determine and establish the amount of antiarrhythmic agent effective to arrest or prevent the progression of the condition.

In such treatments, the physician or veterinarian may initially use relatively low doses and then increase the dose until maximal response is obtained.

The initial dosage of the compounds of the invention ranges from 1.0 to at least 100 kg/kg orally.

The compounds of the invention also include hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates, acetates, zolopionates,
They can also be administered as pharmacologically acceptable acid addition salts such as lactate, maleate, phosphate, succinate, tartrate, and the like. Additionally, the compounds of the invention can be administered in suitably hydrated form.

The compounds of the present invention are prepared from the available racemic butanamide I according to the general reaction scheme shown in the following reaction scheme A: H...1 When the pyridine ring of (17) (2) is reduced, a new chiral center is generated. , a mixture of four diastereomers (2) is obtained. This can be accomplished by catalytic hydrogenation using catalysts such as Raney nickel, platinum, palladium, etc., or by reaction with an alkali metal such as sodium or lithium in ammonia. The mixture of four compounds can be separated into two pairs of racemates, for example by crystallization, and then further reactions can be carried out. In general, where racemates are expected, each racemic pair exhibits different and reproducible physical properties, such as melting points and NMR spectra;
The racemates are distinguishable from each other by these and other properties.

Intermediate compound ■ is, for example, an amide with a dialkyl ketal or acetal, or with an orthoester,
Or, by reaction with other reactive formyl equivalents, it is cyclized to the corresponding cyazyl bicyclo compound (2). Examples of amides that can be used as such ketals or acetals include dimethylformamide, dimethylacetamide and dimethylbenzamide. Examples of orthoesters include triethyl orthoformate, triethyl orthoacetate and triethyl orthobenzoate. Examples of other reactive formyl equivalents include bis(dimethylamino)methoxymethane and tri(dimethylamino)methane. These bicyclic compounds are in turn treated by catalytic hydrogenation using, for example, Raney nickel, platinum or palladium, or active metal hydrides such as lithium aluminum hydride, sodium boron hydride or these reactants.
It can be produced according to the method described in 4.

The method examples further illustrate in detail the preparation and testing of the compounds and salts of the invention. The invention, which has been fully described above, is not to be considered limited in either spirit or scope by these examples. Those skilled in the art will readily appreciate that known variations of the following process conditions and treatments can also be used to prepare the compounds of the present invention.

Example 1 2-phenyl-2-(2-gyperidinyl)-4-[N,
N-bis(1-methylethyl)aminobutanamih4
1 Production of racemic A (II) Ethanol 2.5 J
Racemic 2-phenyl-2-(2-pyridyl)-
A mixture of 105.3 g (0.61 mol) of 4-(N,N-bis(1-methylethyl)amino]detanamide and 27 g (about 0.62 mol) of aqueous hydrochloric acid was hydrogenated over a platinum oxide catalyst. (50pθ1). After filtration to remove the catalyst, the reaction mixture was reduced to a slurry residue and placed on ice/
Dissolve in a water mixture and then neutralize with a slight excess of 25% sodium hydroxide. The resulting mixture is extracted with diethyl ether, dried over magnesium sulphate, filtered and concentrated to dryness. The crude product was dissolved in kellysolve containing a small amount of diethyl ether.
Crystallized twice from B, the title compound 26.0,!
i+ is obtained as a white solid; mp 107-108°.

Structural assignment was confirmed by proton and carbon-i3 NMR spectra and by elemental analysis.

H-NMR (0IXIJ,s)δ-: 0.83.0
．． 92.7.33 Example 2 2-phenyl-2-(2-piperidinyl)-4-[N,
N-bis(1-methylethyl)amine]detanamide,
From Preparation Example 1 of Racemic B (I[), the final filtrate is concentrated under a stream of nitrogen to give an oil that slowly solidifies. The crude product is chromatographed several times on silica del to give all 17F of the title compound as a white solid; mp 81-82°. Structural designations are proton and carbine-1
Confirmed by 3NMR spectrum and elemental analysis.

H-NMR (ODCJ3) δppm: 0.96.1
．． 05.7.30゜Example 6 2-phenyl-2-(2-piperidinyl)-4-[N,
Alternative Preparation of N-bis(1-methylethyl)amino]detanamide The compounds of Examples 1 and 2 were hydrogenated in the same manner as in Example 1, except that about 1.31 g of acetic acid was used as the solvent and no hydrochloric acid was added. Manufactured by Yoshishi.

Example 4 5-phenyl-5-[2-[N,N-bis(1-methylethyl)amine]ethyl)-1,3-sheer IJ'bicyclo[4.4.0]oct-2-ene-4 -one, production of racemic A (III) dimethylformamide) F10
Racemic A (II) of Example 1 in 0 m7 16.35
A solution of g (47 mmol) and dimethylformamide diethyl acetal 8.9y (60 mol) is stirred at room temperature under nitrogen atmosphere overnight. Water is added and the resulting precipitate is collected, washed thoroughly with water and dried to yield 12.99 g of the title compound as a white solid. Structure specification is N
Supported by MR and elemental analysis.

Elemental analysis: Calculated value: 074.33 H9,36N11.82 Actual value: 74.27 9.51 11.91 Characteristic peak: NMR (CD(J3) δriyx: 0.77.
0.82.0.85.0.90.7.18.7.25
; Engineering R (OH (J3): 2980, 1685, 1
580c+++-”; Uv (Meon): λma
X274-275nm0 Example 5 5-phenyl-5-[2-[N,N-bis(1-methylethyl)amino]ethyl]-1,3-cyazubicyclo[
4.4.0] Preparation of octan-4-one, racemic A(V) Racemic A (I[) (prepared according to the method of Example 4) in 260 ml of ethanol 14.0.9 (39,4
A solution of 1 mmol) is hydrogenated over 5% palladium on carbon (5 psi). The catalyst is filtered off and the solvent is removed from the filtrate to give a white solid. The product is recrystallized from ethyl acetate to give 10.0 g of the title compound; mp 204-206°. Structural assignments are confirmed by proton and carbon-13 NMR and infrared spectra, as well as by elemental analysis.

Elemental analysis: Calculated value: 073.91 H9,87N11.75 Actual value: 073.90 H9,71N11.83 NMR (
ODCJ,) δ(9): 1.03, 1.06, 1.
12, Example 6 5-phenyl-s-[z-cNIN-bis(1-methylethyl)amine]ethyl)-1,3-diazo-cyclo[
4.4.0] Oct-2-en-4-one, racemic body B
Preparation of (III) according to the method of Example 4, racemic form B of Example 2 in dimethylformamide 12d (II) 1.7
1 (4.9 mmol) and dimethylformamide diethyl acetal 1.0! i to prepare the title compound. After one day, the solution is concentrated to dryness under reduced pressure.

The residue is recrystallized from diethyl ether to give the title compound as a white solid. Structure designation is by proton NMR
, confirmed by ultraviolet and infrared spectra and by elemental analysis; melting point 155-158°C.

Elemental analysis: Calculated value: 074.33 H9,36N11.82 Actual value: ・74.22 9.53 11.84 NMR
(anci,) Bq: 0.80X O, 82, o,
89.0.91, 7.29: UV (MeOH): λmax273-274 nm
'; Engineering R (OHCz3): 2980.16'80.
1585cm-'Example 7 5-phenyl-5-[2-[N,N-bis(1'-methylethyl)amino]ethyl]-1,3-cyazubicyclo[4.4.0]octane-4- On, racemic B ff
) by the method of Preparation Example 5 J), racemic form B(III) of Example 6 20
0.56 mmol) is used to prepare the title compound. The reaction mixture is concentrated to dryness and the residue is triturated with diethyl ether. White solid (0.18N
The structure of the product obtained as ) is confirmed by proton NMR, infrared and ultraviolet spectra and by elemental analysis; melting point 164-166°C.

Elemental analysis: Calculated value: 073.91 N9.87 N11.75
Actual value: 74.00 9.85 11. /)5
NMR (0DCJ3) aP: 1.00.1.
10.7. o5.7.55° Example 8 2-Methyl-5-phenyl-5-[2-[a.

N-1? (1-methylethyl)amine]ethyl]-1
, 6-diadegicyclo[4.4.0)oct-2-en-4-one, racemic A (II) in Production Example 1 of racemic A (III; R1=methyl) 20.0 ,! 9 (5
7,0 mmol) and N,N-dimethylacetamyl
A mixture of dimethyl acetal 22.0.9' (165 mmol) is heated at 80° for about 14 hours. After cooling, the reaction mixture was diluted with diethyl ether, filtered, washed with diethyl ether, and then air dried to yield the title compound 6. Obtain OI; melting point 191-192°.

The product has the expected elemental composition.

Elemental analysis: Calculated value: 074.75 N9.55 N'11.3
7 Actual measurement value: 74.49 9.57 11.39
NMR (aHct3) δppI: 0.77.0.80
, 0.87.0.90, 1.95, m 7.23
;xR(aHct, ): 2970.1675.1
540゜1 480cm-1: Uv (M150H): λmax 273-274nm
Example 9 2-Methyl-5-phenyl-5-[2-[N.

N-bis(1-methylethyl)amino]ethyl]-1,
3-diazobicyclo[4.4.0)oct-2-en-
Preparation of 4-one, racemate B (m: R1ffi methyl) The title racemate is prepared by the method of example 8 using racemate B (IF) of example 2.

Example 10 2-Methyl-5-phenyl-5-[2-[N.

N-bis-(1-methylethyl)amine]ethyl)-1
Preparation of ,3-zoadebicyclo[4.4.0]octan-4-one, racemic A (V; R1 = methyl) of Example 8 in 40 ml of freshly distilled tetrahydrofuran (■; R1 = methyl) 2.8 g (7,6
1 lithium aluminum hydride in a solution of 0 mmol)
．． Add 57# (15.0 mmol) little by little.

The mixture is stirred at room temperature for 2 hours and then cooled in a water bath.

The reaction mixture is cooled by adding 1.2 m/ml of water, an aqueous solution of 15% sodium hydroxide and a further 3.0 m/ml of water. The precipitate that forms is filtered off. The filtrate is concentrated to dryness and the residue is dried under reduced pressure at about 50° for 12-15 hours to obtain 2.4 g of the title compound as a white solid. Structural designation is confirmed by proton NMR and infrared spectroscopy, as well as by elemental analysis: Melting point: 70-75°C Elemental analysis: Calculated value: c74.35 Hlo, 04 N11.3
1 Actual value: 74.36 9.95 11.3
4NMR(0DCJ3)δ-: 0.99.1.01.
1.08.1.10.1.28.1.35.7.50
; Engineering R (OHCjr: 3400.2985.16
65 cm''''1 Example 11 2-Methyl-5-phenyl-5-[2-(N.

N-bis(1-methylethyl)amine]ethyl]-1,
Preparation of 3-diazobicyclo[4.4.0]octan-4-one, racemic form B (V; R1=methyl) According to the method of Example 10, using racemic form B (III) of Example 9. , to prepare the title racemate.

Example 12 Racemic 2-(4-phenylphenyl)-2-(2-gyridyl)-4-[:N,N-bis(1-methylethyl)
Production of amine cobutane nitrile Toluene 100011L
2-(4-phenylphenyl)-4-(N,N-
Bis(1-methylethyl)amine]dethanenitrile 50
．． 0.9 (0.16 mol) and potassium hydride 2
A mixture of 9.71i (approximately 0.26 mol as a 65ti dispersion in oil) is heated at 65°. A solution of 2-bromoviridine 32 Ii (0.20 mol) in 450 m of toluene is slowly added. After the addition is complete, mix the mixture with 3 more
Stir for 50 minutes, cool in a water bath, then add 750 WLl of water.
! Process with. The toluene layer is separated and extracted with a 10% aqueous solution of hydrochloric acid. The acidic aqueous layer is neutralized with a slight excess of aqueous sodium hydroxide and extracted with dichloromethane. The organic phase is washed with brine, dried over magnesium sulfate, filtered and concentrated to dryness to give the title compound 56.511 as an oil with the expected NMR spectrum. This intermediate nitrile is used without further purification.

Example 13 Preparation of racemic 2-(4-phenylphenyl)-2-(2-pyridyl)-4-[N,N-bis(1-methylethyl)amine]detanamide t-Detyl alcohol 10
Nitrile from Example 12 in TrLl 1.09 (2,5
A mixture of powdered potassium hydroxide (IJ mol) and powdered potassium hydroxide 2I is heated to reflux for about 12 hours. After cooling, the reaction mixture is treated with water and extracted with diethyl ether. The organic phase is dried over magnesium sulphate, filtered and concentrated to an oil. Crystallization from Schellisolde B gives the title compound (0.46 g) as a white solid. The structural assignment was supported by proton NMR and infrared spectra and by elemental analysis.

Elemental analysis: Calculated value: 078.04 H8, OON10.11 Actual value: 77.92 8.06 9.88 NMR
(ODCJ3) δpIm: 0.88.0.95.7.0
~7.75.8.50.8.55; Engineering R (OHct3): 3350.2970.16
70cm-'.

Example 14 5-(4-phenylphenyl)-5-(2-[N,N-
Bis(1-methylethyl)amine]ethyl)-1,3-
Sheazu Bicyclo [4.4.0] Octo-2-en-4-
Preparation of racemate 0 (III:
58°, the structural designation was supported by NMR and infrared spectra as well as by elemental analysis.

Elemental analysis: Calculated value: 077.92 H8,64N9.73 Actual value: 77.93 B, 79 9.74 NMR (
0DCj3) δp*:o, 79.0.85.0.88
．． 0.94.7.05~7.65; Engineering R (aacz3): 2985.1680.157
5σ-10 Example 15 5-(4-phenylphenyl)-5-[2-[N,N-
Bis(1-methylethyl)aminocoethyl)-1,3-
Diazobicyclo[4.4.0]oct-2-en-4-
Preparation of racemate D (m;

Example 16 5-(4-phenylphenyl)-5-[2-[N,N-
Bis(1-methylethyl)amino]ethyl]-1,3-
Preparation of zoadebicyclo[4.4.0]octan-4-one, racemic form a (V; Produce a racemate of. Structural assignment was supported by dNMR, infrared and ultraviolet spectra and by elemental analysis.

Elemental analysis: Calculated value: 077.56 H9,06N9.65 Actual value: 77.11 9.03 9.74 NMR (a
Dct3) δ fermentation: 1.02.1, 05.1.10.1.
13.7.05-7.65: IR (cucz3): 5400.2960.166
0cm-'; UV (MeOH): λmax 254
nm.

Example 17 5-(4-phenylphenyl)-5-[2-[N,
N-bis(1-methylethyl)amine]ethyl)-1,
Production of 3-diazabicyclo[4.4.0]octan-4-one, racemic form D (V: x = phenyl) by the method of Example 5 using racemic form D (lli; x = phenyl) of Example 15 Manufacture.

Example 18 5-(2-chlorophenyl)-5-[2-[N].

N-bis-(1-methylethyl)amine]ethyl J-1
, 3-diazabicyclo[4.4.0]oct-2-en-4-one, racemic E (l [; )-2-(2-pyridyl)-4-[N,N-
Bis(1-methylethyl)amino]detanami r28.
5.9 (fromimole) to prepare the title 2 semimate; mp 154-156°.

Elemental analysis: Calculated value: C! 67.76 H8, 27N10.78
ct9.09 actual value: 67.90 8.28
10.54 9.1ONMR (CD(J3)δ fermentation: 0.90.0.95.0.98.1.06.7.0
5-7.45; Engineering R (aacz, ): 2960.1680.15
80cm-”; UV (MeOH): λmax 273~
274 nm0 Example 19 5-(2-chlorophenyl)-5-[N,N-bis(1
-Methylethyl)amine]ethyl]-1,3-diazobicyclo[4.4.0]oct-2-en-4-one, racemic F (In:X=by the method of Preparation Examples 2 and 4 of dichlor , racemic 2-(2-chlorophenyl)-2-(2-gylysyl)-4-[IJ,N-
Bis(1-methylethyl)amino]detanamide P is used to prepare the title racemate.

Example 20 5-(2-chlorophenyl)-5-[2-[N.

N-bis(1-methylethyl)amine]ethyl]-1,
3-7 Azubicyclo[4.4.0]octan-4-one, racemic form B (V;
= Prepare the title racemate using dichlor; melting point 2
32-265°. Structural assignment was supported by NMR, infrared and ultraviolet spectra, and by elemental analysis.

Elemental analysis: Calculated value: 067.41 H8,74N10.72
C10, o4 actual value: 67.46 8.93
10.40 B, 76N MR (CD (J3)
δpIm: 1.01, 1.09, 7.05-7.6
5; Engineering R (cucz,): 3410.2970.1670c
In-”.

Example 21 5-(2-chlorophenyl)-5-[2-[N.

N-bis(1-methylethyl)amino]ethyl]-1,
3-diazabicyclo[4.4.0]octan-4-one, racemic F (V; The title racemate is prepared by:

Example 22 36 -96) 11-1 Dimension ℃ Dimension 1100 with Q included. 21 To he ``l-fQ, K 0- to h he he singing
Hinoki To Se Nose 1 he he he he he he field QPQ PoU size to CNC%l blue ÷ (67) Example 23 Table 2: Substitution from the compounds in Table 1 1,6-zoazubicyclo [4.4・0] Production of octan-4-one compound 1
year to +1 11 11 11 east to 6)
1) IHDon RO RO Example 24 IJum hydride mineral oil dispersion 0.50% IJum hydride mineral oil dispersion which was pre-washed with IHDon B to remove mineral oil.
26 g (5.5 mmol) of racemic A1.63. of Example 5 in DMF2511L1. ! i+ (4.6 mmol) is added and the reaction mixture is stirred for 15 minutes at room temperature.

After this time methyl iodide 0.97.9 (6,8
mmol) to the reaction mixture and stirred for an additional 40 minutes. After the excess sodium hydride is then sieved with H2O, the reaction mixture is partitioned between H2O and ether/ethyl acetate (1:1). The organic phase is extracted three times with IN HCj solution and the acidic solution is backwashed once with ether. The aqueous acidic solution is made basic with 5% sodium hydroxide solution and then extracted with ether. Dry the ether extract over sodium sulfate. The solvent was removed and the resulting oil was eluted on silica del.
Chromatography using EtoVNH40H affords the pure title compound of the above structure as an oil.

Elemental analysis: Calculated value: 074.35 Hlo, 04 N11.3
1 Actual value: 74.35 10.22 10.8
ONMR (0DCj3) δ fermentation: 1.00.1.10.
5.03.7.17-7.33; Engineering R (0H (J3): 1650 crn-”.

Example 25 Cupric iodide in 201 Il/OH3 of dry tetrahydrofuran (THF) cooled to about -20° C. under a nitrogen atmosphere.
29 II (12 mmol), 2.9 M methylmagnesium chloride P/THp 8.3 m/(24 mmol)
Add dropwise. After stirring for 10 minutes, THF60
2.84 g (8 mmol) of racemate A of Example 4 in 11 tl are added dropwise at the above temperature. After the addition, the reaction mixture is stirred for an additional hour and then allowed to warm to room temperature, where it is stirred for another hour.

After cooling to 0° C., HCj solvent is added until the solution reaches a pHK of 6. After stirring for 30 minutes, the solution is made basic to pH 12 with potassium hydroxide solution and the two layers are separated. The aqueous phase is extracted with additional ether and the combined extracts are saturated 6 times with 3% NH,OH solution and then saturated)
Wash with IJum solution. The solution was then diluted with sulfuric acid) IJ
Dry over aluminum and remove the solvent to obtain a pale yellow solid. This residue was eluted on silica del (3H2
C20/KtOH/NH4OH (85:14:1)
A pure compound with the above structure is obtained by repeated chromatography using 142-145° C. melting point.

Elemental analysis: Calculated value: 074.35 Hlo, 04 N11.3
1 Actual value: 73.97 10.05 11.2
2NMR (0DCj3) δ-: 0.85, o, 87,
o, 94.0.96.1.08.1.14; Engineering R (0HCj 3) 2 3400, 1
6 6 5 cm-1.

Agent Asa Mura Hao

Claims (1)

[Scope of Claims] (1) Formula [wherein R1 is a) hydrogen; b) alkyl having 1 to 6 carbon atoms; or c) phenyl; a substituent, eL) hydrogen;
1)) /.rodene; C) alkyl having 1 to 6 carbon atoms; d) alkoxy having 1 to 6 carbon atoms; or e) phenyl; ZFia) hydrogen; or b ) -(CH2)n-NR
2R3, where n is 1 to 6 and J', R2 and R3 are each the same or different, alkyl having 1 to 6 carbon atoms, or R2 and R3 together a saturated or unsaturated ring structure having 4 to 6 carbon atoms; R4 is a) hydrogen; or b) alkyl having 1 to 6 carbon atoms; and A pharmacologically acceptable salt thereof. (2) The compound of claim 1, wherein R1 is hydrogen, and a pharmacologically acceptable salt thereof. (3) 5-phenyl-5-[2-[N,N-bis(1-
methylethyl)aminocoethyl)-1,3-diazobicyclo[4.4.0]oct-2-en-4-one and its corresponding isomers and racemates; Pharmacologically acceptable salts. (4) 5-phenyl-5-[2-[:N,N-bis(
1-Methylethyl)amine]ethyl)-1,3-cyazbicyclo[4.4.0]octan-4-one and its corresponding isomers and racemates, and A pharmacologically acceptable salt thereof. (5) 5-(4-phenylphenyl)-5-[2-[N
, N-bis(1-methylethyl)amine]ethyl]-1
, 3-diazobicyclo[4.4.0]oct-2-en-4-one and its corresponding isomers and racemates and their pharmacologically acceptable compounds. salt. (6) 5-(4-phenylphenyl)-5-[2-[N
, N-bis(1-methylethyl)amine]ethyl)-1
, 3-cyazbicyclo[4.4.0]octan-4-one and its corresponding isomers and racemates, and their pharmacologically acceptable salts. (7) 5-(2-chlorophenyl)-5-[2-[N,
N-bis(1-methylethyl)amine]ethyl)-1,
3-Siazu Bicyclo [4.4.0] Octo-2-En-
4-one and its corresponding isomers and racemates, and the compounds of claim 2 and their pharmacologically acceptable salts. (s) 5-(2-chlorophenyl)-5-[2-[N,
N-bis(1-methylethyl)amine]ethyl)-1,
The compound according to claim 2, which is 3-diazobicyclo[4.4.0]octan-4-one and its corresponding isomer and racemate, and a pharmacologically acceptable salt thereof. (9) A compound according to claim 1, wherein R1 is alkyl having 1 to 6 carbon atoms, and a pharmacologically acceptable salt thereof. (102-Methyl-5-phenyl-5-[:2-[N. N-bis(1-methylethyl)amino]ethyl]-1,
6-Diadevicyclo[4.4.0]oct-2-ene-
9. Compounds of claim 9 which are 4-one and its corresponding isomers and racemates, and pharmacologically acceptable salts thereof. (1〃2-Methyl-5-phenyl-5-C2-[:N. N-bis(1-methylethyl)amino]ethyl]-1,
9. The compound according to claim 9, which is 6-zoadebicyclo[4.4.O]octan-4-one and its corresponding isomers and racemates, and pharmacologically acceptable salts thereof. ◇2 2-Mef-5-(4-phenylphenyl)-5
-[2-[u,N-bis(1-methylethyl)amine]
Compounds of claim 9 which are ethyl]-1,3-diazobicyclo[4.4.0]oct-2-en-4-one and its corresponding isomers and racemates and their pharmacological effects Tolerable salt. Ql 2-methyl-5-(4-phenylphenyl)-
5-(2-[N,N-bis('1-methylethyl)amine]ethyl), -1,3-diazobicyclo[4.4.0
] The compound according to claim 9, which is octan-4-one and its corresponding isomer and racemate, and a pharmacologically acceptable salt thereof. 04 2-methyl-5-(2-chlorophenyl)-5-
(2-[N,N-bis-(1-methylethyl)aminocoethyl)-1,3-diazobicyclo[4.4.0]oct-2-en-4-one and its corresponding isomers and racemates A compound according to claim 9 which is and a pharmacologically acceptable salt thereof. αυ 2-methyl-5-(2-chlorophenyl)-5-
[2-[N,n-bis(1-methylethyl)aminocoethyl]-1,3-diazobicyclo[4.4.O]octan-4-one and its corresponding isomers and racemates Compounds of Range No. 9. A compound according to claim 1, wherein αfJ R1 is phenyl, and a pharmacologically acceptable salt thereof. αη 2-phenyl-5-phenyl-5-(2-[N,
N-bis(1-methylethyl)amine]ethyl]-1,
3-diazobicyclo[4.4.0]oct-2-ene-
17. Compounds of claim 16 which are 4-one and its corresponding isomers and racemates, and pharmacologically acceptable salts thereof. (II 2-722-5-phenyl-5-[2-[N
, N-bis(1-methylethyl)amine]-1
, 3-cyazbicyclo[4.4.0]octan-4-one and its corresponding isomers and racemates, and their pharmacologically acceptable salts. α 2-phenyl-5-(4-7enylphenyl)-
5-[:2-[N,N-bis(1-methylethyl)amine]ethyl)-1,3-cyazubicyclo[4.4.0]
17. The compound of claim 16, which is oct-2-en-4-one and its corresponding isomers and racemates, and pharmacologically acceptable salts thereof. Shin 2-phenyl-5-(4-phenylphenyl)-5
-[2-[N,N-bis(1-methylethyl)amine]
ethyl]-1,3-diazabicyclo[4.4.0]octan-4-one and its corresponding isomers and racemic compounds according to claim 16, and pharmacologically acceptable salts thereof . el 2-phenyl-5-(2-chlorophenyl)-5
-[2-(n,N-bis(1-methylethyl)amine]
Compounds of claim 16, which are ethyl)-1,3-cyazbicyclo[4.4.0]oct-2-en-4-one and its corresponding isomers and racemates, and their pharmacology. acceptable salt. (a) 2-phenyl-5-(210ruphenyl)-5
-[2-[N,N-bis(1-methylethyl)amine]ethyl]-1,3-diazobicyclo[4.4.0]octan-4-one and its corresponding isomers and racemates. A compound according to claim 16 and a pharmacologically acceptable salt thereof.