JPH01246256A - 2-azetidinone derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [R<l> is benzyl which may be replaced with halogen ; R<2> is -NR<3>R<4> (R<3> and R<4> are alkyl or lower alkenyl), pyrrolidyl, piperidyl, tetrahydroazevinyl, piperidyl which may be replaced with lower alkyl or benzyl, morpholyinyl, etc.; n is 1-3] and a salt thereof. EXAMPLE:(E)-1-Benzyl-3-(2-oxopropylidene)-4-phenyl-azetidinone. USE:An inhibitor of blood platelet aggregation having extremely weak hemorrhagic tendency as a side effect. PREPARATION:A compound shown by formula II is reacted with a compound shown by formula III in an inert solvent such as methanol, THF or benzene in the presence of a catalyst (e. g., inorganic acid, organic acid or amine) at room temperature-reflux temperature of the solvent to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to 2-azetidinone derivatives having platelet aggregation inhibiting activity.

2. Description of the Related Art Compounds having an azetidinone skeleton that have antibacterial effects have been well known, but the present inventors have disclosed for the first time a compound having an azetidinone skeleton that has an inhibitory effect on platelet aggregation (Japanese Patent Laid-Open Publication No. 1983-1993). 87562 and JP-A-62-87563).

Problems to be Solved by the Invention An object of the present invention is to provide a more potent platelet aggregation inhibitor.

Means for Solving the Problems As a result of intensive studies on compounds having an azetidinone skeleton, the present inventors discovered a novel 2-azetidinone derivative useful as a platelet aggregation inhibitor and completed the present invention.

In other words, the present invention is a formula! [In the formula, R' represents a benzyl group or a benzyl group substituted with a halogen atom, and R8 is represented by the formula (wherein R1 and R4 are the same or different and represent an alkyl group or a lower alkenyl group) group, a pyrrolidyl group, a piperidyl group, a tetra-troazepinyl group, a piperidyl group substituted with a lower alkyl group or a benzyl group, a morpholyl group or a morpholyl group substituted with a lower alkyl group,
The present invention relates to a 2-azetidinone derivative and a salt thereof, represented by the following formula, where n is an integer of 1 to 3.

In the present invention, a lower alkyl group has 1 to 1 carbon atoms.
4 alkyl group, such as methyl group, ethyl group,
Propyl group, isopropyl group, butyl group, and alkyl group is an alkyl group having 1 to 8 carbon atoms, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, pentyl group, These include isopentyl group, hexyl group, isohexyl group, etc. The lower alkenyl group is an alkenyl group having 3 to 5 carbon atoms, such as an allyl group, a butenyl group, and a prenyl group. A halogen atom is fluorine, chlorine, bromine or iodine. The term "salt" refers to a pharmacologically acceptable salt, for example, a salt with an inorganic or organic acid such as hydrochloride, sulfate, acetate, or maleate.

The compound represented by the formula ■ is a compound represented by the following formula ■ (wherein R1 has the same meaning as above).
Azetidinone derivative and the following formula ■H2N-0-(CH2)
, -R211 [(wherein, R1 has the same meaning as above)
It can be produced from the following hydroxylamine derivatives: That is, the compound of the present invention represented by the formula I is obtained by reacting the compound represented by the formula (1) and the compound represented by the formula (2) in an inert solvent in the presence of a catalyst. Inert solvents used in this reaction include alcohols such as methanol and ethanol, as well as tetrahydrofuran, chloroform, methylene chloride, benzene, toluene, ethyl acetate, dioxane, and xylene. Catalysts include inorganic acids such as hydrochloric acid gas and sulfuric acid, organic acids and their salts such as P-toluenesulfonic acid, camphorsulfonic acid, and acetic acid, amines and their salts such as triethylamine and pyridine, and magnesium sulfate. . The reaction temperature is 0°
C to the reflux temperature of the solvent, preferably from room temperature to the reflux temperature of the solvent.

The steric configuration of the iminoalkylidene substituent in the compound of the present invention represented by the formula (3) is E-configuration, and the steric configuration based on the asymmetric carbon at the 4-position is dl-one.

On the other hand, the compound represented by formula (1) can be produced, for example, as follows. That is, a compound represented by the formula (1) (wherein R' has the same meaning as above) and acetylmethylenetriphenylphosphorane [C1bCOCH=
P(CsHs)-] (ie, Wittig reaction).

The reaction solvent in this reaction may be any solvent used in normal Wittig reactions. For example, benzene,
Examples include ethyl ether, tetrahydrofuran, toluene, chloroform, methylene chloride, and dimethoxyethane. The reaction temperature is -30°C to the boiling point temperature of the solvent.

The compound of formula
984〉] It can be easily manufactured according to the method used in the war.

Further, the compound represented by formula (1) can be produced, for example, as follows. That is, first, by reacting a compound represented by the formula (1) G-(CH2)n-R2V (wherein R1 has the same meaning as above) with N-hydroxylphthalimide in an inert solvent in the presence of a base. , (wherein R1 has the same meaning as above) is obtained. Inert solvents in this reaction include acetone,
N,N-dimethylformamide, dimethyl sulfoxide, etc., and bases include sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, triethylamine, diazabicyclo[5,4,
0] unde-7-sen, etc. The reaction temperature is from 0° C. to the reflux temperature of the solvent, preferably from room temperature to the reflux temperature of the solvent. Next, the compound represented by the formula (2) can be obtained by treating the compound represented by the formula (2) with, for example, hydrazine in an inert solvent according to a conventional method.

The compound of the present invention thus obtained exhibits an excellent platelet aggregation inhibitory effect and has an extremely weak tendency to cause bleeding as a side effect, making it useful as a platelet aggregation inhibitor.

EXAMPLESNext, the IfIL platelet aggregation inhibiting effect of the compounds of the present invention will be specifically explained using Examples and test examples.

Example 1 A solution of 2.98 g of acetylmethylenetriphenylphosphorane (1-1-
Benzyl-4-phenyl-2,3-azetidinedione 2
．． 35 g of benzene solution 15rrT! L was added and stirred overnight. After the reaction, benzene was distilled off, the residue was subjected to silica gel column chromatography (developing solvent: methylene chloride), the desired fractions were collected, the solvent was distilled off, and the residue was recrystallized with ethanol to give pale yellow needles. Crystalline (E)-1-benzyl-3-(2-oxopropylidene)-4-phenyl-
2.18 g of 2-azetidinone was obtained.

m, p, 76.5-78.5°C Performed in the same manner as in Example 1 to obtain (E)-1-(2-chlorobenzyl)-3-(2-oxopropylidene)-4-phenyl-2-azetidinone I got it.

m, p, 78-79°C Example 2 11.9 g of N-hydroxyphthalimide and 60 ml of N,N-dimethylformamide were added to 1.75 g of sodium hydride suspended in 20 ml of N,N-dimethylformamide.
A mixture of 15 g of 3-chloropropyldibutylamine and 10 ml of N,N-dimethylformamide was added to the reaction mixture, which was stirred for 30 minutes, and heated under reflux for 5 hours.

After distilling off the solvent, ethyl acetate was added to the residue, and after washing with water, the solvent was distilled off to obtain 23.4 g of N-(3-dibutylaminopropyloxy)phthalimide.

Then, dissolve this in methylene chloride 200TIIQ,
20 mQ of hydrazine hydrate was added, and the mixture was stirred at room temperature for 3 hours. After filtering off insoluble matter, the filtrate was concentrated under reduced pressure and further distilled under reduced pressure to obtain 10.3 g of 0-(3-dibutylaminopropyl)-hydroxylamine.

b, p, 84-85°C (0.5 mmHg) The following compound was obtained in the same manner as in Example 2 above.

0-(3-pyrrolidylpropyl)-hydroxylamine b, p, 61°C (0,6 mmHg) 0-<3-piperidylpropyl)-hydroxylamine b, p, 70°C (0,6 mmHg) 0-(3 -morpholylpropyl)-hydroxylamine b, p, 80-829C (0,4mm1g>0-[
3-(2,6-dimethylmorpholyl)propyl]-hydroxylamine b, p, 103-110°C (0,6 mmHg) 0-[
3-(4-benzylpiperidyl>propyl]-hydroxylamine b, p, 156-161°C (0.4 mmHg) 0-
[3-(diethylamino>propyl]-hydroxylamine b, p, 70-75°C (0,2 mmHg) 0- [
3-(Butylethylamino)propyl]-hydroxylamine b, p, 68-70°C (0.1 mmHg) 0-[3-
(diethylamino)propyl]-hydroxylamine b, p, 120-124°C (0,3 mm 1g > xylamine b, p, 107-112°C (0,2 mmHg) 0
-[3-(3,5-dimethylpiperidyl)propyl]-
Hydroxylamine b, p, 83-85℃ (0.3mmHg) 0-[3
-(tetrahydroazepinyl)propyl]-hydroxylamine b,p,'ys ~81℃ (0,4mmHg>0-
[3-(diisobutylamino)propyl]-hydroxylamine b, p, 78-82°C (0,2 mmHg) Example 3 (E)-1-benzyl-3-(2-oxopropylidene>-4-phenyl- 2-Azetidinone 1.5g, 0-(
3-dibutylaminopropyl) hydroxylamine 1.
A mixture of 04 g of 10-camphorsulfonic acid, 50 ml of benzene and 50 ml of benzene was heated under reflux for 3 hours, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (developing solvent: methylene chloride: methanol - 20:1), the desired fractions were collected, and the solvent was distilled off. Hydrochloric acid gas and ethyl acetate solution were added to the residue, and the solvent was distilled off to give (E)-1-benzyl-3-[2-(3-dibutylaminopropyloxyimino>propylidene]-4-phenyl-2-azetidinone hydrochloride) I got 1.0g.

' H-N M R (CDCR3) δ (ppm); 0
, 94 (61,t, J=7Hz) , 1.38 (4H
, m).

1,56 (3H, s), 1.76 (4H, m),
2.12 (2H, m).

2,96 (6H, m), 3.76 (IH, d, J=
16Hz).

4, 10<2H, n+), 4.86(LH, d, J
=16Hz).

5,04 (In, d, J=2Hz), 6.60 (1
)1. d, J=2Hz).

7, 1-7.5 (IOH, m) The following compounds were obtained in the same manner as in Example 3.

(E)-1-Benzyl-3-[2-(3-pyrrolidylpropyloxyimino)propylideneko4-phenyl-
2-azetidinone hydrochloride 'H-NMR (CDCR3) δ (ppm); 1.58
(3H, s), 2.08 (2H, m), 2.2
0 (4H, m).

2.72 (2H, m), 3.08 (2) 1. m)
.

3゜75 (IH, d, J = 16Hz), 3.77 (
2H, m>.

4.10 (2H, m), 4.88 (111, d, J
=16Hz).

5, 02 (lit, d, J=2Hz), 6.6
0 (LH, d, J: 2Hz).

7, 1-7.4 (10B, m) (E)-1-Benzyl-3-[2-(3-piperidylprobyloxyimino)propylidene]-4-phenyl-
2-Azetidinone' H-N M R (CDCR3) S (ppm)
; 1.44 (2H, m), 1.54 (4H, m)
, 1.56 (3H, s).

1.80 (2H, m), 2.34 (61, m).

3,74(IH,d,J=16Hz>, 4.08(
2H, m).

4,88 (IH, d, J=16Hz), 5.04 (
IH, d, J: 2 ■ z) + 6, 65 (IH, d,, C2
Hz), 7.1-7.4 (10H, m) (E)-1
-Benzyl-3-[2-(3-morpholylpropyloxyimino)propylidene]-4-phenyl-2-azetidinone hydrochloride' H-NMR (CDCff3) l; (ppm
); 1.57 (3H, s), 2.22 (2H
, m), 3.00 (6H, m).

3,76(18,d,J:16Hz), 4.12(
6H, m>.

4,88(IH,d,,Cl6Hz), 5.04(
LH, d, J: 2Hz).

6, 60 (111, d, J=2Hz), 7.1~7
．． 4(10H,m)(E)-1-benzyl-3-(2-
[3-(2,6-dimethylmorpholyl)propyloxyimino]propylidene)-4-phenyl-2-azetidinone' H-NMR(CDCff3) l; (
ppm); 1, 14 (6H, d, J=7Hz),
1.57(3)1. s).

1, 74 (4H, m), 2.32 (2H, m).

2,71 (2H, d, J near Hz), 3.65 (2
H, m).

3,76(IH,d,J=16Hz>, 4.08(
2H, m).

4,88(LH,d,J=16Hz>, 5.02(
IH, d, J=2Hz).

6.64 (IH, d, J=2Hz), 7.1-7.
4(10H,m)'(E)-1-benzyl-3-(2
-[3-(Benzylethylamino)propyloxyimino]propylidene)-4-phenyl-2-azetidinone' H-N M R (CD(J'3) l; (ppm
); 1.30 (LH, m), 1.53 (3H, s
>.

1.60 (4H, m), 1.80 (4H, m),
2.34 (2H, m).

2,85(2H,m), 3.71(LH,d,J=
16Hz).

3, 73 (IH, d, J: 16Hz), 4.05 (
2H, m).

4,79(LH,d,J=16Hz>, 4.92(
LH, d, J = 16Hz).

5,01(IH,d,J=2Hz), 6.60(1
11,d,,C2Hz).

7, 1-7.4 (15H, m) 1-benzyl-3-[2-(3-diethylaminopropyloxyimino)propylidene]-4-phenyl-2-
Azetidinone' H-N MR (CD(J)3) S (ppm)
:1, 05 (6H, t, J=7.5Hz), 1.
55 (3H, s).

1.81 (2H, m), 2.60 (6H, m).

3,74 (LH, d, J=15Hz), 4.06
(2H, t, J=7.5Hz).

4,86(IH,d,,C15Hz>, 5.02(
IH, d, J=2Hz).

6, 63 (IH, d, J=2Hz), 7.10~7
．． 48(10)1. m) 1-benzyl-3-[2-(3
-butylethylaminopropyloxyimino)propylidene]-4-phenyl-2-azetidinone'H-NMR (CDC4) 3>&(ppm); 0.9
4 (6H, m), 1.31 (4H, m), 1.
55 (3H, s).

1.73 (2H, m), 2.43 (6H, m).

3, 73 (IH, d, J: 15Hz), 4.05 (
2H, t, J near, 5Hz).

4.86 (LH, d, J: 15Hz), 5.01 (
LH, d, J = 2Hz).

6.64 (LH, d,, C2Hz), 7.10
~7.40 (IOH, m)3-[2-(3-butylethylaminopropyloxyimino>propylidene]-1-
(2-chlorobenzyl)-4-phenyl-2-azetidinone' H-N M R (CD(J13) 8 (pp
m); 0, 88 (3H, t, J near, 5Hz)
, 0.98 (3H, t, J=7.5Hz>.

1.33 (4H, m), 1.56 (3H, s),
1.73 (2H, m).

2.45 (6H, m>, 4.07 (3H, m).

4,83(01,d,J=151(z), 5.06
(111, t, J: 2Hz>.

6.63 (IH, d, J: 2Hz), 7.08-7.4
8(9H,m)1-benzyl-3-[2-(3-dihexylaminoprobyloxyimino)propylidene]-4
-Phenyl-2-azetidinone' H-N M R (CDCR3) S (
ppm): 0, 88 (6H, m), 1.28 (12
H, brs).

1,45(4H,m), 1.55(3H,s),
1.83 (2H, m).

2,53 (64m), 3.73 (LH, d, J=1
5Hz>.

4, 06 (2) 1. m), 4.86 (18, d, J
=15Hz).

5,01(LH,t,J=2Hz), 6.61(L
H, d, J=2Hz).

7, 08-7.40 (108, m) 3-[2-(3-diallylaminopropyloxyimino)propylidene]-1-benzyl-4-phenyl-2-
Azetidinone'H-NMR (CD(J)3) &(ppm); 1.5
5 (3H, s), 1.75 (2H, m), 2.
46 (2H, m).

3,03<4H,m), 3.74(IH,d,J-
15Hz).

4,04(2H,m), 4.96(LH,d,J=
15Hz).

5, 10 (5H, m>, 5.81 (2H, m).

6.63 (IH, d, J=2Hz>, 7.09~7
．． 41 (10H, m) 3-[2-(3-diallylaminopropyloxyimino>propylidene]-1-(2-chlorobenzyl)-4-phenyl-2-azetidinone' H-N MR (CDC#3) S (Isla
m); 1.56 (3H, s), 1.74 (2H,
m>, 2.44 (2H, m).

3, '04 (4H, m), 4.04 (3H, m)
.

4, 81 (IH, d, J: 1511z), 5.11
(5H, m).

5,78 (2H, m), 6.61 (IH, d, J=
2Hz).

7, lO ~ 7.40 (IOH, m) 1-benzyl-3-(2-[3-(3,5-dimethylpiperidyl)propyloxyimino]propylidene)-4
-Phenyl-2-azetidinone' H-NMR (CDCff3) S (ppm)
;0, 89 (6H, m), 1.35 (2H, m)
, 1.56 (3H, s).

1.78 (51 (, m), 2.04 (LH, m>
, 2.32 (3H, m>.

2,78(LH,m), 3.74(IH,d,J=
15Hz), 4,06(2H,m), 4.8
6 (LH, d, J=15Hz>.

5,03(In,d,J=2Hz>, 6.63(I
H, d, J=2Hz).

7.10-7.40 (IOH, m) 1-(2-chlorobenzyl)-3-(2-[3-(3,
5-dimethylpiperidyl)propyloxyimino]brohyritene)-4-phenyl-2-azetidinone' H-
NMR(CDCR3) 8 (ppm); 0, 8
6 (6H, m>, 1.34<2H, m), 1.
58 (3H, s).

1.73 (5H, m), 2.0.1 (IH, rn)
, 2.28 (3H, m).

2, 78 (11, m), 4.05 (3H, m>.

4,83(LH,d,J=15Hz), 5.06(
IH, d, J=2Hz).

6, 63 (IH, d, J=2Hz), 7. L.O.
~7.48 (9H, m) 1-benzyl-3-(2-[3
-(4-benzylpiperidyl)propyloxyimino]
propylidene)-4-phenyl-2-azetidinone'H-NMR (CD(J)3)δ (ppm): 1.3
0 (IH, m), 1.53 (3H, s), 1.
60 (4H, m).

1.80 (4H, m), 2.35 (2H, m>,
2.85 (2H, m).

3.72 (LH, d, J = 16Hz), 3.73 (LH
, d, J=16Hz).

4.03 (2H, m>, 4.80 (IH, d, J=16
Hz).

4, 92 (IH, d, J = 16Hz), 5.01 (
LH, d, J=2Hz).

6, 60 (LH, d, J-2Hz), 7.10~7
．． 40(15H,m)1-benzyl-3-(2-[3-
(1-Tetrahydroazepinyl)propyloxyimino]propylidene)-4-phenyl-2-azetidinone' H-N M R (CDCR3) S (ppm)
; 1.55 (3H, s>, 1.60 (8H, m)
, 1.75 (2H, m).

2,59 (6H, m), 3.71 (IH, d, J=
15Hz).

4.05 (2H, t, J=5.5Hz), 4.85
(IH, d, J=15Hz).

5,01(IH,d,J=2Hz>, 6.61(L
H, d, J=2Hz).

7, 10-7.40 (10H, m) 3-[2-(3-dibutylaminopropyloxyimino)propylidene]-1-(2-chlorobenzyl)-4-
Phenyl-2-azetidinone' H-NMR (CDCff3) S (ppm)
;0,90(6H,m>, 1.33(8H,m)
, 1.58 (3H, s).

1,74 (2H, m), 2.39 (6H, m),
4.07 (3H, m).

4, 84 (111, d, J=15Hz), 5.09
(IH, d, J: 2Hz).

6, 64 (IH, d, J=2Hz), 7.10~7
．． 50(9H,m)1-benzyl-3[2-(3-cyisobutylaminopropyloxyimino)propylidene]
-4-phenyl-2-azetidinone'H-NMR (CDCR3) &(ppm); 0, 8
3(12H,t,J=7.5)1z), 1.55(
3H,s).

1, 75 (5H, m), 2.00 (3H, m),
2.34 (2H, m).

3,73(LH,d,J=15Hz), 4.05(
2)1. m).

4, 86 (IH, d, J = 15Hz), 5.01 (
LH, d, J = 2Hz).

6, 64 (IH, d, J=2Hz), 7.08~7
．． 48 (IOH, m) Test Example [Rat ax vivo
Test group - Wistar male rats The test drug suspended in 2% carboxymethyl cellulose was orally administered, and 3 hours later, bendoparbital (40 mg/kg,
ip) Laparotomy was performed under anesthesia, and 9 volumes of blood were collected from the abdominal aorta for 11 volumes of 3.2% sodium citrate solution. This blood was centrifuged at 150g for 15 minutes at room temperature, the supernatant obtained was used as platelet-rich plasma (PRP), and the remaining blood was further
The supernatant obtained by centrifugation at 500 g for 10 minutes was mixed with platelet-poor plasma (
PPP) and use PPP to increase the platelet count of PRP to approximately 5.
00,000 pieces/m! It was prepared to l.

Platelet aggregation was performed by incubating the prepared PRP275- at 37°C.
Aggregation inducing agent 25-[adenosine diphosphoric acid: final concentration 5 μM] was added under stirring at C11O00rp, and measurement was performed for 5 minutes using a platelet aggregation measuring device (Agelicorder-TM PA-3210, Kyoto Daiichi Kagaku) to determine the maximum aggregation. The rate of inhibition was calculated with respect to the maximum aggregation rate of rats to which 0.2% carboxymethylhirulose was administered as a control. The results are shown in comparison with the inhibition rate of the test drug and ticlopidine (positive control) at the same dose as 100.

The results are shown in Table 1 below.

Claims (1)

[Claims] (1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 represents a benzyl group or a benzyl group substituted with a halogen atom, and R^2 is the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ A group represented by (wherein R^3 and R^4 are the same or different and represent an alkyl group or a lower alkenyl group), a pyrrolidyl group, a piperidyl group, a tetrahydroazevinyl group, a lower alkyl group or a benzyl group It represents a substituted piperidyl group, a morpholyl group, or a morpholyl group substituted with a lower alkyl group, and n represents an integer of 1 to 3. ] A 2-azetidinone derivative and a salt thereof.