2-Arylbenzothiazoline Derivatives and Their Use in Treating Angina Cordis

This invention relates to the compounds of the formula [I] and salts thereof, ##STR2## wherein

R.sup.1 is formyl or lower alkanoyl;

R.sup.2 is hydrogen, lower alkyl, lower alkoxy or nitro;

R.sup.3 is hydrogen, lower alkyl, lower alkoxy or halogen;

A is lower alkylene;

B is --CO--(CH.sub.2).sub.m --or --CH(OH)--;

m is 0 to 1; and

when m is 0, R.sup.3 is not hydrogen.

The term "lower alkanoyl" is intended to designate C.sub.2 -C.sub.6 alkanoyl exemplified by acetyl, propanoyl and hexanoyl.

The term "halogen" is intended to designate fluorine, chlorine or bromine.

The term "lower alkyl" is intended to designate C.sub.1 -C.sub.6 alkyl exemplified by methyl, ethyl, propyl, butyl and hexyl.

The term "lower alkoxy" is intended to designate C.sub.1 -C.sub.6 alkoxy exemplified by methoxy, ethoxy, propoxy and hexyloxy.

The term "lower alkylene" is intended to designate straight or branched C.sub.1 -C.sub.6 alkylene exemplified by methylene, ethylene, propylene, butylene and hexylene.

The compounds of this invention are novel 2-phenylbenzothiazoline derivatives which are useful for treatment of cardiovascular diseases. The compounds of this invention have a specific structure where the 2-position of the benzothiazoline ring is substituted by a phenyl group having a heterocycle at the side chain.

Recently, we synthesized 2-phenylbenzothiazoline derivatives and disclosed them in GB Pat. No. 2115815 published on Sept. 14, 1983.

We continuously studied the derivatives of 2-phenylbenzothiazoline in order to find more useful compounds.

As the result of our precise examination, we found novel, very useful 2-phenylbenzothiazoline derivatives represented by the formula [I].

The compounds of this invention possess superior platelet anti-aggregation effect and calcium antagonization. Iihibitors of platelet aggregation and calcium antagonists are used as therapeutic agents for cardiovascular diseases such as angina cordis, arrhythmia, thrombosis, etc., so the compounds of this invention are useful for treatment of cardiovascular diseases.

The pharmacological tests prove the superior effect of the compounds of this invention.

The compounds of this invention can be prepared by the reaction of halide of the formula [II] with amine derivative of the formula [III]. ##STR3## wherein X is halogen.

The above reaction needs no specific conditions, and known methods which are generally used for a reaction of amine derivatives with halides can be used. For example, heating of a mixture of amine derivative and halide, a reaction of amine derivative with halide in a presence of base such as triethylamine in an organic solvent.

The compounds of the formula [II] can be prepared according to the disclosure of GB Pat. No. 2115815.

The compounds of the formula [III] can be prepared by known methods which are summarized as follows. ##STR4## The compounds of the formula [III], wherein B is --CH(OH)--, can be prepared by reduction of the corresponding carbonyl compound.

The compounds [I] of this invention can be converted into acid salts. Said salts are obtained by usual methods using inorganic or organic acids. Examples of pharmaceutically acceptable salts of the compounds are hydrochloric acid salt, sulfuric acid salt, phosphoric acid salt, lactic acid salt, maleic acid salt, fumaric acid salt, oxalic acid salt, succinic acid salt, citric acid salt, methanesulfonic acid salt, p-toluenesulfonic acid salt, etc.

The compounds of this invention have stereoisomers because of the existence of one or more asymmetric carbon atoms, and these isomers are included in this invention.

Examples are shown below.

The assignments of the NMR spectra are made according to the numbers of the formula [IV] and aromatic protons, not assigned, are shown as aromatic H. When R.sup.2 or R.sup.3 of the formula [I] is methoxy group, the former is shown as --OCH.sub.3 (P) and the latter is --OCH.sub.3 (A). ##STR5##

3-Acetyl-2-[5-methoxy-2-[4-[4-(4-methoxybenzoyl)-1-piperidyl]butoxy]phenyl] benzothiazoline oxalate (compound 1)

A mixture of 3-acetyl-2-[2-(4-chlorobutoxy)-5-methoxyphenyl]benzothiazoline (1.60 g) and 4-(4-methoxybenzoyl)piperidine (1.78 g) is stirred for 2 hours at 110.degree.-120.degree. C. After cooling to room temperature, the mixture is dissolved in chloroform (30 ml). The solution is washed with N hydrochloric acid, N sodium hydroxide solution and then saturated sodium chloride solution. The solution is dried over anhydrous magnesium sulfate and concentrated in vacuo. To the oily residue, a solution of oxalic acid (0.36 g) in methanol (5 ml) is added to give 1.21 g (45%) of the titled compound.

mp 97.degree.-103.degree. C. (methanol-acetonitrile)

IR (KBr, cm.sup.-1): 1664, 1597, 1465, 1377, 1276

NMR (DMSO-d.sub.6, .delta.): 1.50-2.36 ##STR6## 2.22 (3H, s, --COCH.sub.3), 2.73-3.85 ##STR7## 3.62 (3H, s, --OCH.sub.3 (P) ), 3.88 (3H, s, --OCH.sub.3 (A) ), 3.92-4.32 (2H, m, -OCH.sub.2 -), 6.36-6.73 (3H, m, C.sub.6'-H and --CO.sub.2 H.times.2), 6.73-7.39 (8H, C.sub.2 -H and aromatic H), 7.73-8.22

The following compound was prepared by the similar method as in Example 1.

2-[2-[4-[4-(4-fluorobenzoyl)-1- piperidyl]butoxy]-5-methoxyphenyl]-3-formylbenzothiazoline fumarate (compound 2)

Yield 45%

mp 160.degree.-161.degree. C. (dec.), (methanol-acetonitrile) IR (KBr, cm.sup.-1): 1712, 1671, 1592, 1577, 1497, 1470, 1353, 1274, 1212, 1155, 1033, 744 NMR (DMSO-d.sub.6, .delta.): 1.27-2.13 ##STR8## 2.30-3.50 3.58 (3H, s, --OCH.sub.3 (P) ), 3.80-4.27 (2H, m, --OCH.sub.2 -), 6.33-8.20 (12H, m, C.sub.2 -H and aromatic H), 6.53 ##STR9## 8.23-8.67 (2H, br, --CO.sub.2 H.times.2), 8.47 and 8.93 (1H, each s, --CHO)

3-Acetyl-2-(5-methoxy-2-[4-[4-(4-methylbenzoyl)-1-piperidyl]butoxy]phenyl]b enzothiazoline maleate (compound 3)

A mixture of 3-acetyl 2-]2-(4-bromobutoxy)-5-methoxyphenyl]-benzothiazoline (1.31 g) and 4-(4-methylbenzoyl)piperidine (1.22 g) is stirred for one hour at 80.degree.-90.degree. C. After cooling to room temperature, the reaction procedure is followed by the similar procedure as in Example 1 to give 1.01 g (50%) of the titled compound.

mp (175.degree.-178.degree. C.

IR (KBr, cm.sup.-1): 1671, 1604, 1577, 1493, 1465, 1379, 1275, 1208

NMR (DMSO-d.sub.6), .delta.): 1.65-2.36 ##STR10## 2.27 (3H, s, --COCH.sub.3), 2.42 ##STR11## 2.87-4.03 ##STR12## 3.67 (3H, s, -OCH.sub.3 (P), 3.97-4.35 (2H, m, --OCH.sub.2), 6.12 ##STR13## 6.46 (2H, d, J=2.4Hz, C.sub.6 '-H), 6.65-7.40 (5H, m, aromatic H), 6.97 (1H, s, C.sub.2 -H), 7.31 ##STR14## .sec 7.76-8.07 (1H, m, C.sub.4 -H), 7.88 ##STR15##

The following compounds were prepared by the similar method as in Example 2.

3-Acetyl-2-[2-[4-[4-(4-chlorobenzoyl)-1-piperidyl]butoxy]-5-methoxyphenyl]b enzothiazoline maleate (compound 4)

Yield 90%

mp 177.5.degree.-179.5.degree. C.

IR (KBr, cm.sup.-1): 1671, 1578, 1498, 1465, 1377, 1278, 1208 NMR (DMSO-d.sub.6, .delta.): 1.66-2.32 ##STR16## 2.23 (3, s, --COCH.sub.3), 2.75-4.05 ##STR17## 3.53 (3H, s, --OCH.sub.3 (P) ), 4.06 (2H, m, --OCH.sub.2 -), 6.04 6.45 (1H, d, J=3.0Hz, C.sub.6 '-H), 6.67-7.38 (5H, m, aromatic H), 6.93 (1H, s, C.sub.2 -H), 7.45 ##STR18## 7.70-8.19 (1H, m, C.sub.4 -H), 7.97 ##STR19##

3-Acetyl-2-[2-[4-[4-(.alpha.-hydroxybenzyl)-1-piperidyl]butoxy]5-methoxyphe nyl]benzothiazoline maleate (compound 5)

Yield 45%

mp 184.degree.-188.degree. C. (methanol-acetonitrile )

IR (KBr, cm.sup.-1): 3370, 1638, 1571, 1487, 1476, 1457 NMR (DMSO-d.sub.6, .delta.): 0.83-2.06 ##STR20## 2.20 (3H, s, --COCH.sub.3), 2.55-3.47 ##STR21## 3.54 (3H, s, --OCH.sub.3 (P) ), 3.80-4.20 (2H, m, --OCH.sub.2 --), 4.20-4.50 (1H, m, --CH(OH)--), 4.83-5.73 (1H, br, --OH), 5.97 ##STR22## 6,35-7.47 (12H, m, C.sub.2 --H and aromatic H), 7.60-8.10 (1H m, C.sub.4 -H)

3Acetyl-2-[2-[4-[4-(4-fluorobenzoyl)-1-piperidyl]butoxy]-5-methoxyphenyl]be nzothiazoline maleate (compound 6)

To a solution of 3-acetyl-2[-2-(4-bromobutoxy)-5-methoxyphenyl]benzothiazoline (1.53 g) and 4-(4-fluorobenzoyl)piperidine (0.73 g) in ethanol (4 ml), triethylamine (0.35 g ) is added and the mixture is refluxed for 1.5 hours. After cooling to room temperature, the mixture is dissolved in chloroform (20 ml). The solution is washed with N hydrochloric acid, water, saturated sodium hydrogen carbonate solution and then saturated sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue is purified by silica gel column chromatography. The oily product (1.28 g) is dissolved in ethyl acetate (5 ml). A solution of maleic acid (0.26 g) in ethyl acetate (5 ml) is added to the solution to give 1.31 g (55%) of the titled compound.

mp 146.degree.-149.degree. C. (ethyl acetate-ethanol)

IR (KBr, cm.sup.-1): 1671, 1594, 1494, 1462, 1375, 1348, 1274, 1232, 1208 NMR (DMSO-d.sub.6, .delta.): 1.43-2.40 ##STR23## 2.23 (3H, s, --COCH.sub.3), 2.77-3.87 ##STR24## 3.57 (3H, s, --OCH.sub.3 (P) ), 3.87-4.36 (2H, m, --OCH.sub.2 -), 6.03 ##STR25## 6.43 (1H, d, J=2.5 Hz, C.sub.6 '-H), 6.60-7.22 (7H, m, aromatic H), 7.19 (1H, s, C.sub.2 -H), ##STR26## 7.60-8.12

The following compound was prepared by the similar method as in Example 3.

3-Acetyl-2-[2-[4-(4-benzylcarbonyl-1piperidyl)butoxy]-5-methoxyphenyl]benzo thiazoline maleate (compound 7)

Yield 55%

mp 152.degree.-154.degree. C. (methanol)

IR (KBr, cm.sup.-1): 3400, 1706, 1669, 1571, 1490, 1458

NMR (DMSO-d.sub.6, .delta.): 0.82-2.36 ##STR27## 2.23 (3-H, s,--COCH.sub.3), 2.58-3.76 ##STR28## 3.57 (3H, s, --OCH.sub.3 (P) ), 3.79-4.26 (2H, m, --OCH.sub.2 -), 3.89 (2H s, --COCH.sub.2 -), 6.03 ##STR29## 6.12 (1H, d, J=2.0Hz, C.sub.6 '--H), 6.26-7.36 (11H, m, C.sub.2 -H and aromatic H), 7.58-8.08 (1H, m, C.sub.4 -H)

3-Acetyl-2-[2-[3-[4-(4-fluorobenzoyl)-1-piperidyl]propoxy]-5-nitrophenyl]be nzothiazoline (compound 8)

To a solution of 3-acetyl-2-[2-(3-chloropropoxy)-5-nitrophenyl]benzothiazoline (3.93 g) in acetone (20 ml), sodium iodide (1.50 g) is added and the mixture is refluxed for 2 hours. After cooling to room temperature, the reaction mixture is concentrated in vacuo to remove acetone. To the residue, benzene (20 ml) and 4-(4-fluorobenzoyl)piperidine (4.20 g) are added and the mixture is refluxed for 9 hours.

After cooling to room temperature, chloroform (100 ml) is added to the reaction mixture. The mixture is washed with N hydrochloric acid, N sodium hydroxide solution and then saturated sodium chloride solution. The solution is dried over anhydrous magnesium sulfate and concentrated in vacuo.

The oily residue is purified by silica gel column chromatography to give 3.10 g (55%) of the titled compound.

mp 169.degree.-172.degree. C.

IR (KBr, cm.sup.-1): 1665, 1588, 1508, 1489, 1460, 1449, 1376, 1330, 1262 NMR (DMSO-d.sub.6, .delta.): 1.57-3.53 ##STR30## 2.33 (3H, m, --COCH.sub.3), 4.25 (2H, t, J=6.0 Hz, --OCH.sub.2 --), 6.83-8.30 (12H, m, C.sub.2 -H and aromatic H)

Following compounds can be prepared by the similar method as in the above examples.

3-Acetyl-2-[2-[4-[4-(4-fluorobenzoyl)-1-piperidyl]methoxy]-5-methoxyphenyl] benzothiazoline

3Acetyl-2-[2-[4-[4-(4-fluorobenzoyl)-1-piperidyl]propoxy]-5-methoxyphenyl]b enzothiazoline

3Acetyl-2-[2-[4-[4-(4-fluorobenzoyl)-1-piperidyl]hexyloxy]-5-methoxyphenyl] benzothiazoline

3Acetyl-2-[2-[4-[4-(4-fluorobenzylcarbonyl)-1-piperidyl]butoxy]-5-methoxyph enyl]benzothiazoline

3-Acetyl-2-[2-[4-[4-(4-fluoro-.alpha.-hydroxybenzyl)-1-piperidyl]-butoxy]-5 -methoxyphenyl]benzothiazoline

3-Acetyl-2-[2-[4-[4-(4-fluorobenzoyl)-1-piperidyl]-butoxy]-phenyl]benzothia zoline

3-Acetyl-2-[2-[4-[4-(4-fluorobenzoyl)-1-piperidyl]-butoxy]-5-methylphenyl]b enzothiazoline

3-Acetyl-2-[5-ethyl-2-[4-[4-(4-fluorobenzoyl)-1-piperidyl]-butoxy]phenyl]be nzothiazoline

2-[2-[4-[4-(4-Fluorobenzoyl)-1-piperidyl]-butoxy]-5-methoxyphenyl]-3-propan oylbenzothiazoline

3-Acetyl-2-[2-[4-[4-(4-methoxybenzylcarbonyl)-1-pipreidyl]-butoxy]-5-methyl phenyl]-benzothiazoline

3-Acetyl-2-[2-[4-[4-(4-methylbenzylcarbonyl)-1-piperidyl]-butoxy]-5-nitroph enyl]-benzothiazoline

3-Acetyl-2-[2-[4-[4-(.alpha.-hydroxy-4-methoxybenzyl)-1-piperidyl]-butoxy]- 5-methylphenyl]-benzothiazoline

3-Acetyl-2-[2-[4-[4-(.alpha.-hydroxy-4-methylbenzoyl)-1-piperidyl]-butoxy]- 5-nitrophenyl]-benzothiazoline

Calcium antagonists have not only beneficial effects in the treatment of many diseases but also serve as valuable research tools to elucidate excitation-contraction coupling in various muscule types (A. Fleckenstein, Ann. Rev. Pharmacol. 17, 149-166, 1977). Therefore, we examined the calciumantagonistic activity of the compounds of this invention.

The action potentials on the smooth muscles of uterus, teania coli and portal vein depend on calcium ion, and therefore these smooth muscle preparations are useful for screening of calciumantagonists. We measured the calciumantagonistic activity of the compounds by the method using guineapig teania coli preparation.

Isolated guineapig teania coli was suspended in a 20 ml organ bath with Krebs solution at 32.degree. C. and bubbled with 5% carbon dioxide in oxygen. After equilibration, the muscle was washed with Ca.sup.++ -free Krebs solution, and when the muscle had relaxed to basal level, it was suspended in Ca.sup.++ -free-high-K Krebs solution.

The muscule was exposed to the test compounds for 5 minutes before addition of CaCl.sub.2, and the contraction evoked by CaCl.sub.2 (3.times.10.sup.-4 M) was recorded isotonically. The calciumantagonistic activity was represented by the concentration of the test compound which elicited 50% inhibition of Ca.sup.++ -evoked contraction (IC.sub.50).

As shown in Table 1, the compounds of this invention had calciumantagonistic activity.

Blood platelet plays an important role only in hemostasis but also in thrombosis. Platelet hyperaggregability leads to an increase in the number of circulating platelet aggregates, which may contribute toward the development of cardiac arrhythmia, cardiac arrest or myocardial infarction. These cardiovascular diseases can be prevented by inhibition of platelet aggregation.

Therefore, we screened the influence of the test compounds on platelet aggregation in vitro, and found that they have antiaggregatory activity.

Blood was obtained from an anesthetized rabbit using 0.1 volume of 3.8% sodium citrate as anticoagulant. Platelet rich plasma (PRP) was isolated by centrifugation at 650 rpm for 10 minutes at room temperature. After preincubation of PRP (0.25 ml) with various concentrations of the test compounds (14.mu.l) for 1 minute at 37.degree. C., collagen (3.mu.g/ml: final concentration) or ADP (3.mu.M: final concentration) was added to induce aggregation and the aggregation profiles were monitored by RIKADENKI six-channel aggregometer. The control experiment contained saline instead of the test compound.

The antiaggregatory activity was represented by the concentration of the test compounds which elicited 50% inhibition of the control response.

As shown in the Table 2, the compounds of this invention had antiaggregatory activity.

The compounds can be administered either orally or parenterally. The dosage forms are tablet, capsule, granule, powder, suppository, injection, etc. The dose is adjusted depending on symptom, dosage form, etc., but usual daily dosage is 1 to 5000 mg, preferably 10 to 1000 mg, in one or a few divided doses.

Examples of formulation are shown below.

Example of formulation

The tablets may be treated with the common film-coating and further with sugar-coating.