United States Patent (19) 11 Patent Number: 4,971,985 Otsuka et al. 45 Date of Patent: Nov. 20, 1990

54 PYRIDYLKETOXIMEETHER COMPOUND AND PHARMACEUTICAL COMPOST ON OTHER PUBLICATIONS CONTAINING T Chemical Abstracts, vol. 90, No. 13, Mar. 1979, U.S.A., Tankaka et al., Abstract No. 103840m. 75 Inventors: Katsuyuki Otsuka; Nobuo Ishiyama; Chemical Abstracts, vol. 111, No. 9, Abstract 70,646z. Makoto Watanabe; Kenji Seri; Aug. 28, 1989, p. 51. Kazuko Sanai; Kanji Muraoka, all of Primary Examiner-Mary C. Lee Tokyo, Japan Assistant Examiner-Zinna Northington-Davis Attorney, Agent, or Firm-Oblon, Spivak, McClelland, 73 Assignee: Kaken Pharmaceutical Co., Ltd., Maier & Neustadt Tokyo, Japan 57 ABSTRACT 21 Appl. No.: 424,129 A pyridylketoxime compound of the formula: Ar (I) 22 Filed: Oct. 19, 1989 / C (30) Foreign Application Priority Data S. Oct. 24, 1988 (JP) Japan ...... 63-267893 wherein Aris a phenyl, naphthyl, or heterocyclic group 5) Int. Cl...... A61K 31/44; C07D 213/54 unsubstituted or substituted by a C1-C8 group, a 52 U.S. C...... 514/357; 514/323; C1-C8 alkylamino group, a C1-C8 alkoxy group, a 514/332; 514/336; 514/338; 546/236; 546/264; C1-C8 alkoxycarbonyl group, a trifluoromethyl group, 546/270; 546/283; 546/284; 54.6/334 a nitro group or a halogen atom, X is a -(CH2)n- 58 Field of Search ...... 546/264, 270, 284,334, group wherein m is an integer of from 1 to 5, a -(CH2 546/256, 283; 514/332, 336, 338, 357, 333 )n-Y-group wherein Y is an or sulfur atom and m is as defined above, or a -CH2-(CH=CH)n- group wherein n is an integer of 1 or 2, and R is a 56) References Cited phenyl, naphthyl, C3-C8 cycloalkyl or heterocyclic U.S. PATENT DOCUMENTS group unsubstituted or substituted by a C1-C8 alkyl 4,297,359 10/1981 van Zorge ...... 546/283 group, a C1-C8 alkylamino group, a C1-C3 alkoxy 4,352,804 10/1982 van Zorge ...... 54/252 group, a C1-C8 akloxycarbonyl group, a trifluoro , a nitro group or a halogen atom, or a salt FOREIGN PATENT DOCUMENTS thereof. 0221601 5/1987 European Pat. Off...... 546/252 2117772 10/1983 United Kingdom ...... 546/252 6 Claims, No Drawings 4,971,985 1. 2 methyl group, a nitro group or a halogen atom, or a salt PYRIDYLKETOXIME ETHER COMPOUND AND thereof. PHARMACEUTICAL COMPOSITION The present invention also provides a pharmaceutical CONTAINING IT composition comprising an effective amount of the compound of the formula I or its salt, as the active The present invention relates to novel pyridylketox ingredient, and a pharmaceutical carrier or diluent and ime compounds and pharmaceutical compositions con having a calmodulin antagonism. taining them. Now, the present invention will be descirbed in detail In recent years, as the old aged population has in with reference to the preferred embodiments. creased, various ischemic diseases which cause serious O Firstly, the pyridylketoxime ether compounds of the health troubles and various cerebral diseases, heart dis present invention will be described. eases and pheripheral circulatory failures related The pyridylketoxime ether compounds of the for thereto, such as myocardial infarction, angina pectoris, mula I are novel compounds which are distinguished cerbral apoplexy, cerebral thrombosis and cerebral in from the compounds disclosed in the above-mentioned farction, have increased. 15 U.S. Pat. Nos. 4,352,804 and 4,297,359 in respect of the At present, a calcium antagonistic agent, particularly, following structural diferences (a) and (b). a calcium channel blocking agent, is clinically widely (a) The pyridylketoxime ether compounds of the used as one of curing agents of these diseases. In future, formula I of the present invention have a pyridyl group however, it is desired to develop a drug having a cal as an essential substituent. Whereas, the compounds modulin antagonism as a calcium antagonistic agent disclosed in U.S. Patent 4,352,804 have, instead of the having a better functional mechanism. pyridyl group, a heterocyclic group containing two On the other hand, it has been reported that various hetero atoms, at least one of which is a nitrogen atom. ketoxime ether derivaties are useful as drugs. Namely, (b) The pyridylketoxime ether compounds of the e.g. U.S. Pat. No. 4,352,804 discloses pyradinylketox formula I of the present invention are different from the ime ether derivatives, and U.S. Pat. No. 4,297,359 dis 25 compounds disclosed in U.S. Pat. Nos. 4,352,804 and closes ketoxime alkyl ether derivatives. However, these 4,297,359 in the substitutent bonded to the oxygen atom derivaties are all disclosed to be used for the treatment of the ketoxime ether group. of the gastroenteric tract, and no study has been made In the formula I representing the pyridylketoxime for their application to the treatment of ischemic dis ether compounds of the present invention, the aromatic eases or various diseases related thereto. 30 ring for Ar and R is preferably a or a Accordingly, a first object of the present invention is naphthyl group, and the heterocyclic group is prefera to provide a novel compound having a calmodulin an bly a single ring or condensed ring heterocyclic group tagonism and being useful for the treatment of ischemic having from 1 to 3 nitrogen, oxygen or sulfur atoms as diseases and various diseases related thereto. hetero atoms, more preferably a single ring heterocyclic A second object of the present invention is to provide 35 group containing one nitrogen, oxygen or sulfur atom as a pharmaceutical composition containing such a novel a hetero atom or a condensed ring heterocyclic group compound as an active ingredient. containing two oxygen atoms as hetero atoms, As a The present inventors have synthesized novel pyri single heterocyclic group containing one nitrogen, oxy dylketoxime ether compounds and studied their cal gen or sulfur atom as a hetero atom, a furyl group, a modulin antagonism. As a result, it has been found that thienyl group or a pyridyl group is, for example, pre these compounds have not only a calmodulin antago ferred. Likewise, as a condensed ring heterocyclic nism but also a calcium channel antagonism and an group containing two oxygen atoms as hetero atoms, a activity to improve the deformation of erythrocytes, 1,3-dioxaindanyl group is, for example, preferred. and as such they are very useful as curing agents for In the formula I, the cycloalkyl group for R is prefer 45 ably a cycloalkyl group having from 3 to 8 carbon ischemic diseases. The above objects have been accom atoms such as a cyclopropyl group, a cyclobutyl group, plished on the basis of this discovery. a cyclopentyl group, acyclohexyl group, a cycloheptyl The present invention provides a pyridylketoxime group or a cyclooctyl group. ether compound of the formula: In the formula I, the phenyl group, the naphthyl 50 group and the heterocyclic group for Ar or the phenyl (I) group, the naphthyl group, the cycloalkyl group and the heterocyclic group for R may be substituted prefer ably by one or two substituents. Such substitutents may Of be an alkyl group having from 1 to 8 carbon atoms, an 55 alkylamino group having from 1 to 8 carbon atoms, an wherein Ar is a phenyl, naphthyl or heterocyclic group alkoxy group having from 1 to 8 carbon atoms, an al unsubstituted or substituted by a C1-C8 alkyl group, a koxycarbnyl group having from 1 to 8 carbon atoms, a C1-C8 alkylamino group, a C1-C8 alkoxy group, a trifluoromethyl group, a nitro group or a halogen atom. C1-C3 alkoxycarbonyl group, a trifluoromethyl group, The alkyl group having from 1 to 8 carbon atoms may a nitro group or a halogen atom, X is a -(CH2)n- be a straight chain or branched alkyl group such as a group wherein m is an integer of from 1 to 5, a methyl group, an , a n-, an -(CH2)m-Y-group wherein Y is an oxygen or sulfur isopropyl group, a nbutyl group, a s-, a atom and m is as defined above, or a -CH t-butyl group, a n-, a n-hexyl group, a n 2-(CH=CH)n-group wherein n is an integer of 1 or 2, heptyl group or a n-octyl group. The alkylamino group and RiS a phenyl, naphthyl, C3-C8 cycloalkyl or heter 65 having from 1 to 8 carbon atoms may preferably be, for ocyclic group unsubstituted or substituted by a C1-C8 example, a methylamino group, a dimethylamino group, alkyl group, a C1-C3 alkylamino group, a C1-C3 alkoxy an ethylamino group, a diethylamino group, a n group, a C1-C3 alkoxycarbOnyl group, a trifluoro propylamino group, an isopropylamino group, a n 4,971,985 3 4. butylamino group, a s-butylamino group, at butylamino propanol, or toluene may, for example, be used. group, a n-pentylamino group, a n-hexylamino group, a In this case, particularly good results can be obtained by n-heptylamino group or a n-octylamino group. The conducting the reaction in the presence of a base such as alkoxy group having from 1 to 8 carbon atoms may sodium hydride (NaH), triethylamine, dimethylaniline, preferably be, for example, a , an ethoxy 5 group, a n-propoxy group, an isopropoxy group, a n potassium hydroxide, sodium methoxide, sodium ethox butoxy group, a s-butoxy group, a t-butoxy group, a ide or potassium t-butoxide. n-pentoxy group, a n-hexoxy group, a n-heptoxy group (2) Production process (b) or a n-octoxy group. The alkoxycarbonyl group having from 1 to 8 carbon atoms may preferably be, for exam O ple, a methoxy , an ethoxycarbonyl HNO-X-R (V) group, a n-propoxycarbonyl group, an isopropoxycar a S. G. bonyl group, a n-butoxycarbonyl group, a s-butoxycar N O bonyl group, a t-butoxycarbonyl group, an pentoxycar (IV) bonyl group, a n-hexoxycarbonyl group, a n-heptox 15 ycarbonyl group or a n-Octoxycarbonyl group. A. The halogen atom is preferably, for example, a fluo rine atom, a chlorine atom or a bromine atom. The pyridylketoxime ether compounds of the present ON N-O-X-R invention may be salts. As such salts, acid addition salts (I) may be mentioned. Such acid addition salts can readily be obtained by reacting the pyridylketoxime ether com In the above formula, Ar, X and Rare as defined above. pounds with inorganic acids or organic acids. Such To the compound of the formula IV, an 0-substituted inorganic acids include, for example, hydrochloric acid, hydroxylamine derivative of the formula V is reacted hydrobromic acid, hydroiodic acid and sulfuric acid. 25 for condensation to obtain the desired compound of the The organic acids include, for example, maleic acid, formula I". In this process (b), the reaction temperature fumaric acid, succinic acid, acetic acid, malonic acid, a is usually from about 0 to 200 C, and as the solvent, citric acid, benzoic acid, oxalic acid and methane sul methanol, ethanol, propanol, benzene, toluene or water fonic For the production of the pyridylketoxime com may, for example, be used. pounds of the formula I of the present invention, the 30 Now, the representative examples of the pyridiylk following processes are preferably employed. etoxime ether compound of the formula I of the present (1) Production process (a) invention will be given. However, these examples are presented to facilitate the understanding of the present 21 Air invention, and it should be understood that the present cy (Step A) G 35 invention is by no means restricted by such specific S. NH2OH examples. N O O-benzyl-phenyl-2-pyridylketoxime, O-benzyl-phenyl-3-pyridylketoxime, (IV) O-benzyl-phenyl-4-pyridylketoxime, Air O-(4-methylbenzyl)-phenyl-2-pyridylketoxime, 21 c? (Step B) G O-(4-methylbenzyl)-phenyl-3-pyridylketoxime, s Ha-X-rR O-(4-methylbenzyl)phenyl-4-pyridylketoxime, N N-OH (III) O-(4 chlorobenzyl)-phenyl-2-pyridylketoxime, (II) O-(4-chlorobenzyl)-phenyl-3-pyridylketoxime, 45 O-(4-chlorobenzyl)-phenyl-4-pyridylketoxime, O-(3,4-dimethoxybenzyl)-phenyl-2-pyridylketoxime, O-(3,4-dimethoxybenzyl)-phenyl-3-pyridiylketoxime, O-(3,4-dimethoxybenzyl)-phenyl-4-pyridylketoxime, O-(2-pyridylmethyl)-phenyl-2-pyridylketoxime, (I) (I) 50 O-(2-pyridylmethyl)-phenyl-3-pyridylketoxime, O-(2-pyridylmethyl)-phenyl-4-pyridylketoxime, In the above formulas, Ar, X and R are as defined O-(1-naphthylmethyl)-phenyl-2-pyridylketoxime, above, and Hal is a halogen atom. O-(1-naphthylmethyl)-phenyl-3-pyridylketoxime, Namely, a pyridylketone of the formula IV is reacted O-(1-naphthylmethyl)-phenyl-4-pyridylketoxime, with hydroxylamine to obtain a pyridylketoxime of the 55 formula II (Step A). O-(2-thienylmethyl)-phenyl-2-pyridylketoxime, Then, a halide of the formula III is reacted thereto for O-(2-thienylmethyl)-phenyl-3-pyridylketoxime, a condensation reaction to obtain a compound of the O-(2-thienylmethyl)-phenyl-4-pyridylketoxime, formula I as the desired substance (Step B). Further, if O-cinnamyl-phenyl-2-pyridylketoxine, necessary, this product is converted to its salt. 60 O-cinnamyl-phenyl-3-pyridylketoxine, In Step A, the reaction temperature is usually from O-cinnamyl-phenyl-4-pyridylketoxime, about 0 to 200 C., preferably from room temperature O-2-(2-methylphenyl)ethyl-phenyl-3-pyridylketox to 100 C. As the solvent, methanol, ethanol, propanol, lme, benzene, toluene or water may, for example, be em O-2-(3-methylphenyl)ethyl-phenyl-3-pyridylketox ployed. 65 1me, In Step B, the reaction temperature is usually from O-[2-(4-methylphenyl)ethyl]-phenyl 3-pyridylketoxime, about 0 to 100 C. As the solvent, dimethylformamide O-[2-(2 methoxyphenyl)ethyl-phenyl 3-pyridylketox (DMF), dimethylsulfoxide (DMSO), methanol, ethanol, 1ne, 4,971,985 5 6 O-[2-(3-methoxyphenyl)ethyl-phenyl-3-pyridylketox O-2-(3,4-dimethoxyphenyl)ethyl-3,4-dimethoxylphe nyl-4-pyridylketoxime, O-2-(4-methoxyphenyl)ethyl-phenyl-3-pyridylketox1me, O-(2-thienylethyl3,4 dimethoxyphenyl-4-pyridylketox ne, O-[2-(2,5-dimethoxyphenyl)ethyl-phenyl-3-pyridylk1me, O-[2-(3,4-dimethoxyphenyl)ethyl)-3-nitrophenyl-4- etoxime, pyridylketoxime, O-2-(3,4-dimethoxyphenyl)ethyl-phenyl-3-pyridylk O-[2-(4-chlorophenyl)ethyl-3,4-dimethoxyphenyl-4- etoxime, pyridylketoxime, and O-2-(2,6-dimethoxyphenyl)ethyl-phenyl-3-pyridylk O-2-(3,4-dimethoxyphenyl)ethyl)-bis-(3-pyridyl)ketox etoxime, 10 E. O-0-2-(2-thienyl)ethyl-phenyl-3-pyridylketoxime, Now, the pharmaceutical composition of the present O-0-2-(3-thienyl)ethyl-phenyl-3-pyridylketoxime, invention will be described. O-0-2-(1-naphthyl)ethyl-phenyl-3-pyridylketoxime, The pyridylketoxime ether compounds of the present O-2-furyl)ethyl-phenyl-3-pyridylketoxime, invention are found to have not only an excellent cal O-[2-(3-pyridyl)ethyl-phenyl-3-pyridylketoxime, 15 modulin antagonism but also a Catchannel antago O-(2-cyclohexylethyl)-phenyl-3-pyridylketoxime, nism and an acitivity to improve the deformation of O-(3-phenylpropyl)-phenyl-3-pyridylketoxime, erythrocytes. Accordingly, the pharmaceutical compo O-(4-phenylbutyl)-phenyl-3-pyridylketoxime, sitions of the present invention containing such pyri O-(5-phenylpentyl)-phenyl-3-pyridylketoxime, dylketoxime ether compounds as active ingredients, are O-(2-phenylethyl)-o-tolyl-3-pyridylketoxime, 20 useful as curing agents based on these activities, for O-(2-phenylethyl)-m-tolyl-3-pyridylketoxime, example, as curing agents for isochemic diseases or O-(2-phenylethyl)-p-tolyl-3-pyridylketoxime, vasodilators. Specifically, they are useful for curing or O-(2-phenylethyl) 2,4-dimethoxyphenyl-3-pyridylk preventing cerebral vessel troubles such as ephemeral etoxime, cerebral ischemic attack, cerebral infarction and en O-(2-phenylethyl)-2,5-dimethoxyphenyl-3-pyridylk 25 cephalo-arteriosclerosis, or ischemic heart troubles such etoxime, as angina pectoris and myocardial infarction. Further, O-(2-phenylethyl)-3,4-dimethoxyphenyl-3-pyridylk they are useful for the prevention of the recurrence of etoxime, these diseases or for improvement after the treatment. O-(2-phenylethyl)-2-chlorophenyl-3-pyridylketoxime, The pharmaceutical composition of the present inven O-(2 phenylethyl)-3-chlorophenyl-3-pyridylketoxime, 30 tion may be constituted solely by the pyridylketoxime O-(2 phenylethyl)-3-fluorophenyl-3-pyridylketoxime, ether compound of the formula I and/or its salt. How O-(2-phenylethyl)-3-trifluoromethylphenyl-3-pyridylk ever, it is usually preferred to formulate it with a suit etoxime, able carrier into a drug formulation for oral or non-oral O-(2-phenylethyl)-3-nitrophenyl-3-pyridylketoxime, administration. As formulations for oral administration, O-(2-phenylethyl-2,5-xylyl-3-pyridylketoxime, 35 tablets, capsules and granules may be mentioned. As O-(2-phenylethyl)-2-thienyl-3-pyridylketoxime, formulations for non-oral administration, intravenous, O-(2-phenylethyl)-2-furyl-3-pyridylketoxime, intramuscular or subcutaneous injection drugs, or sup O-(2-phenylethyl)-4-N,N-dimethylaminophenyl-3- positories may be mentioned. These formulations can be pyridylketoxime, prepared readily in accordance with conventional O-(2-phenylethyl) 1-naphthyl-3-pyridylketoxime, methods. O-(2-phenylethyl)-3,4-methylenedioxyphenyl-3- The dose of the pyridylketoxime ether compound of pyridylketoxime, the present invention varies depending upon the admin O-(2-phenylethyl)-bis-(3-pyridyl)ketoxime, istration route, the type of formulation, the diseased O-(2-phenylthio)ethyl-phenyl-3-pyridylketoxime, condition of the patient, etc., but is usually within a O-(2-phenoxy)ethyl-phenyl-2-pyridylketoxime, 45 range of from 0.01 to 100 mg/kg of the body weight, O-(2-phenoxy)ethyl-phenyl-3-pyridylketoxime, preferably from 0.1 to 10 mg/kg of the body weight. O-(2-phenoxy)ethyl)-phenyl-4-pyridylketoxime, Now, the present invention will be described in fur O-[2-(4-methoxyphenoxy)ethyl-phenyl-3-pyridylk ther detail with reference to Examples and Test Exam etoxime, 50 ples. However, it should be understood that the present O-2-(4-methoxyphenoxy)ethyl-phenyl-2-pyridylk invention is by no means restricted by such specific etoxime, Examples. O-[2-(4-methoxyphenoxy)ethyl-phenyl-4-pyridylk EXAMPLE 1. etoxime, Preparation of O-[2-(4-chlorophenoxy)ethyl-phenyl-2-pyridylketox 55 O-(2-phenylethyl)-phenyl-3-pyridylketoxime O-[2-(4-chlorophenoxy)ethyl-phenyl-3-pyridylketox1me, (Compound No. 1) 1me, 1.06 g (0.016 mol) of potassium hydroxide was dis O-2-(4-chlorophenoxy)ethyl-phenyl-4-pyridylketox solved in 80 ml of ethanol, and 3.17 g (0.016 mol) of 1me, phenyl-3-pyridylketoxime was added thereto and dis O-[2-(3-trifluoromethylphenoxy)ethyl-phenyl-2- solved under stirring. To this solution, 2.96 g (0.016 pyridylketoxime, mol) of £3-phenylethylbromide was added, and the mix O-2-(3-trifluoromethylphenoxy)ethyl-phenyl-3- ture was stirred at room temperature for two hours. pyridylketoxime, Then, it was stirred and reacted at 80 C. Four hours O-[2-(3-trifluoromethylphenoxy)ethyl-phenyl-4- 65 later, the reaction solution was distilled under reduced pyridylketoxime, pressure to remove ethanol. Then, 100 ml of a 3N so O-2-(4-methoxyphenyl)ethyl-3,4-dimethoxyphenyl-4- dium hydroxide aqueous solution was added to the pyridylketoxime, residue, and the mixture was extracted with benzene. 4,971,985 7 8 The extract solution was washed with a 3N sodium chloride was added thereto. The mixture was stirred hydroxide aqueous solution and water and dried over and reacted at room temperature. Ten hours later, the anhydrous sodium sulfate. Then, benzene was distilled reaction solution was distilled under reduced pressure off under reduced pressure. The residual oily substance to remove ethanol. A 2N sodium hydroxide aqueous was purified by silica gel chromatography to obtain 2.6 solution was added to the reaction solution, and the g of the above-identified compound as an oily sub mixture was extracted with benzene. The extract solu Stace. tion was washed with water and dried over anhydrous NMR(CDCl3)6:2.96(t,2H), 4.40(t,2H), 6.80–7.76(m, sodium sulfate. Benzene was distilled off, and the resid 12H), 8.32-8.72(m,2) ual oily substance was purified by silica gel chromatog O raphy to obtain 2.3 g of the above-identified compound. EXAMPLE 2. NMR(CDCl3)6:2.83(t), 3.00(t)(2H), 3.67(s.3H), Preparation of 3.77(s.3H), 4.36(t), 4.43(t)(2H), 6.67-7.86(m,10H), O-(2-phenylethyl)-3,4-dimethoxyphenyl-3-pyridylk 8.50-8.80(m,2H) etoxime (Compound No. 56) The compounds identified in the following Table 3.48 g (0.015 mol) of 3,4-dimethoxyphenyl- 15 were obtained in a manner similar to Examples 1 and 2. 3pyridylketone was dissolved in 80 ml of ethanol, and 2.7 g (0.015 mol) of o-phenethylhydroxylamine hydro

Air (I)

C s pound Sa Physical Af -X-R properties e Oily 2.96(t, 2H), 4.40(t, 2H) 6.80-7.76(m, 12H), 8.32-8,72(m, 2H)

t 2.60-3.20(m, 2H), 4.00-4.60(m, 2H), 7.0–7.9(m, 13H), 8.56(m, 1H)

fy 3.00(t, 2H), 4.42(t, 2H) 7.23, 7.400m, 2H), 8.63(m, 2H)

5.12(s), 5.25(s)(2H), 6.95 7.70(m, 13H), 8.50(d), 8.55 -CH2 (d)(1H).

Af 5.23(s, 2H), 7.0-8.0(m, 12H), 8.5-8.8(m, 2H).

p 5.21(s), 5.25(s)(2H), 7.34, 7.42 (m, 12H), 8.63(d), 8.77(d)(2H).

Oily 2.27(s, 3H), 5.15(s)5.21(s)(2H), 6.97-7.85(m, 12H), 8.56(d)8.66(d -CH CH3 1H).

r f 2.33(s, 3H), 5.20(s, 2H), 7.0-8.0 (m, 11H), 8.5-8.8(m, 2H).

4,971,985 19 20 -continued 21 Af (I) C Sa N N-O-X-R 21 Com pound as Physical No. N Air -X-R properties NMR (CDCl3)6: 60 H3CO OCH3 '' w 3.00, 3.03(t, 2H), 3.48, 3.66, 3.73, 3.79(s, 6H), 4.40, 4.43(t, 2H), 7.0- O 8.00m, 10H), 8.5-8.8(m, 2H). N

61 O Oily 2.97, 3.00(t, 2H), 4.38, 4.41(t, 2H), y 5.90, 5.94(s, 2H), 6.7-7.9(m, 10H), O -CH2CH2 8.4–8.7(m, 2H). O N

62 H3C FF f 2.03(s, 3H), 2.10(s, 1H), 2.30(s, 3H), 2.97, 3.00(t, 2H), 4.37, 4.40(t, 2H), O 6.8-7.9(m, 10H), 8.4–8.7(m, 2H). N

CH3 63 F f 3.00(t, 2H), 4.43(t, 2H), O 7.0-8.0(m, 11H), 8.5-8.8(m, 2H),

N

64 CF3 FF 3.00(t, 2H), 4.43(t, 2H), (Or 7.0-8.0(m, 11H), 8.43-8.67(m, 2H). N (O) 65 NO2 f 3.00(t, 2H), 4.40(t, 2H), 7.0-8.00m, 9H), 8.0-8.5(m, 2H), O 8.5-8.8(m, 2H). N

66 p 3.00, 3.18(t, 2H), 4.56, 4.63(t, 2H) O 6.3-8.00m, 10H), 8.6–8.8(m, 2H). S N 67 3.00(t, 2H), 4.43(t, 2H), (Or O) 7.0-8.00m, OH), 8.6-8.80m, 2H). N N

Now, the activities of the compounds of the present invention will be described with reference to Test Ex amples. 60 present invention to a reaction system comprising 50 m TEST EXAMPLE 1. units of bovine cerebral calmodulin, 0.1 mM of Ca2+, 1 uM of c-AMP (3H-c-AMP 50n Ci) and 0.875 munits of Calmodulin antagonism bovine myocardial c-AMP-PDE. The formed amount Calmodulin is effective to increase the activities of of 5'-AMP was measured in accordance with the Tomp c-AMP phosphodiesterase (PDE) from 2 to 3 times in 65 son et al's method (Biochemistry 10(2), 311, (1971)). As the presence of Ca2+. The calmodulin antagonism was a control drug, W-7 N-(6-aminohexyl)-5-chloro-1- determined in terms of the inhibitory activity against naphthalenesulfonamide was used. The results are the 5'-AMP forming rate by adding a compound of the shown in Table 1. 4,971,985 21 22 TABLE 1. TABLE 3 Compound Calmodulin antagonism Activity to improve the No. IC5oCM) Compound deformation of erythrocytes No. pass through time (sec.) 3.8 5 14 8.0 12 26 10 13 16 43 4.1 14 5 46 8.8 20 20 47 6.3 26 18 43 14 57 9.5 10 46 18 58 3.5 47 15 62 8.0 57 20 63 5.0 58 2 64 6.5 62 18 W-7 28 63 18 15 64 16 6S 18 66 17 TEXT EXAMPLE 2 W-7 25 Calcium 39 Calcium channel antagonism salt of The cecum string of a male Hartley guinea pig having 20 A 23.87 a body weight of 350 g was taken out, and while air was supplied, it was hanged with a load of 0.5 g in a high potassium Krebs solution bath (32° C) having calcium TEST EXAMPLE 4 removed. Calcium chloride was accumulatively added, Toxicity test 25 and the reaction was recorded by means of an isotonic For the determination of the acute toxicity, 10 male tranduser (manufactured by Nippon Koden K. K.) to mice having body weights of from 22 to 25 g were used obtain a constant standard concentration reaction as a group, and a compound in an amount correspond CVe. ing to the body weight was orally administered. LD50 On the other hand, pretreatment with a compound of 3 O was calculated by an area method from the mortality the present invention was conducted for 30 minutes, after 72 hours. and then calcium chloride was added to the reaction LD50 of compounds of the present invention obtained bath, and from concetration reaction curve thereby in the Examples was more than 500 mg/kg. obtained, pa2 was obtained. The results are shown in FORMULATION EXAMPLE 1. Table 2. 35 TABLE 2. Preparation of tablets Compound Ca' Channel antagonism By using the following components, tablets can be No. (pA2) prepared in accordance with a conventional method.

w 6.56 3 6,83 40 Active component: O-(2-phenylethyl)-phenyl-3- 50 mg 14 6.36 pyridylethoxime 20 6.28 Lactose 150 mg 26 6.63 Crystalline cellulose 100 mg 43 6.32 Magnesium stearate 3 mg 57 6.26 58 6.48 45 62 6.03 As described in the foregoing, the present invention 63 6.22 64 6.06 presents novel pyridylketoxime ether compounds hav 65 6.6 ing a calmodulin antagonism, and a pharmaceutical 66 6.28 50 composition containing such a compound. We claim: 1. A pyridylketoxime ether compound of the formula TEST EXAMPLE 3 (I): Activity to improve the deformation of erythrocytes (I) A suspension of washed erythrocytes was prepared 55 from a blood collected by heart puncture from a male New Zealand rabbit having a body weight of about 3 kg N N-O-o-X-R and having Heparin added thereto, by using a Krebs wherein Aris a phenyl, naphthyl, furyl, thienyl, pyridyl Henseleit solution containing 20 mM of HEPES. The or 1,3-dioxaindanyl group unsubstituted or substituted activity of a compound of the present invention to im by a C1-C8 alkyl group, a C1-C8 alkylamino group, a prove the deformation of erythrocytes was examined by C1-C8 alkoxy group, a C1-C8 alkoxycarbonyl group, a measuring the time for erythrocytes to pass through a trifluoromethyl group, a nitro group or a halogen atom; millipore filter (5 um) by treating the suspension with X is a -(CH2)- group wherein m is an integer of Ca2+ and with Ca2+ ionofore A-23187 (Calimycin) in 65 from 1 to 5, a -(CH2)n-Y-group wherein Y is an accordance with a Reid et al’s method (J. Clin. Pathol. oxygen or sulfur atom and m is as defined above, or a 29, 855, (1976)). As a control drug, W-7 was used. Re -CH2-(CH=CH)n-group wherein n is an integer of sults are shown in Table 3. or 2; and R is a phenyl, naphthyl, C3-C8 cycloalkyl, 4,971,985 23 24 furyl, thienyl, pyridyl or 1,3-dioxaindanyl group unsub trifluoromethyl group, nitro group, or halogen atom, or stituted or substituted by a C1-C8 alkyl group, a C1-C8 a salt thereof. alkylamino group, a C1-C3 alkoxy group, a C1-C8 alk 3. The compound according to claim 1, which is oxycarbonyl group, a trifluoromethyl group, nitro O-(2-phenylethyl)-phenyl-3-pyridylketoxime. group or a halogen atom, or a salt thereof. 4. The compound according to claim 1, which is 2. The compound according to claim 1, wherein Aris a phenyl, naphthyl, furyl, thienyl, pyridyl or 1,3-diox O-(2-phenylethyl)-2-chlorophenyl-3-pyridylketoxime. aindanyl group unsubstituted or substituted by a C1-C8 5. The compound according to claim 1, wherein said alkyl group, a C1-C3 alkoxy group, a trifluoromethyl C3-C8 cycloalkyl group for moiety R is selected from group, a nitro group or a halogen atom; X is a -(CH2 10 the group consisting of cyclopropyl, cyclobutyl, cyclo )n-group wherein m is an integer of from 1 to 3, a pentyl, cyclohexyl, cycloheptyl and cyclooctyl. -(CH2)n-Y-group wherein Y is an oxygen or sulfur 6. A pharmaceutical composition for the treatment of atom and m is as defined above, a -CH2-(CH=CH ischemic diseases and diseases related thereto, compris )- group wherein n is an integer of 1 or 2; and R is a ing an effective amount of the pyridylketoxime ether phenyl, naphthyl C3-C8 cycloalkyl, furyl, thienyl, pyri 15 compound or salt thereof as defined in claim 1, and a dyl or 1,3-dioxaindanyl group unsubstituted or substi pharmaceutical carrier or diluent. tuted by a C1-C3 alkyl group, a C1-C8 alkoxy group, a 2k g g

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