# Patent

## Title
Substituted pyridinylamino benzo[b]thiophene compounds

## Abstract

The derivatives are useful as antiarrhythmic agents.

## Background
The present invention relates to novel antiarrhythmic agents, more particularly to novel piperidine derivatives and their use in the treatment of arrhythmia.

Arrhythmia is the disfunction of cardiac normal conduction, which is a life-threatening disease, because it disturbs the rhythmic beating of the heart, worsening hemodynamics. Therefore, therapy for cardiac arrhythmia is clinically essential.

Antiarrhythmic drugs have been grouped together according to the pattern of mechanism: Na channel blocker, Beta blocker, Ca channel blocker and drugs which prolong Repolarization. Drug therapy of cardiac arrhythmias is not established, because many drugs have severe adverse effects, such as undesirable hemodynamic effects, hypotension, gastrointestinal symptoms, effects on the central nervous system and arrhythmogenic effects. Also, at higher plasma concentrations of drug, cardiac toxicity may become severe, so the monitoring of plasma concentration is essential for drug therapy.

It is therefore required to develop new antiarrhythmic drugs having excellent pharmaceutical effects and safety which can be industrially prepared at low cost in a simple manner.

It has now been found that certain piperidine derivatives have antiarrhythmic activity, which derivatives are represented by the following general fomula (I): ##STR3## wherein ##STR4## is any of the following groups: ##STR5## wherein B is a fused aromatic or heterocyclic ring selected from the group consisting of benzene, pyridine and thiophene;

--Z--is selected from: ##STR6##

X is selected from: ##STR7## wherein R.sup.1 and R.sup.2 are the same or different and are independently selected from hydrogen, methyl, ethyl, or propyl; R.sup.3 is hydrogen, alkyl of from 1 to 12 carbon atoms, or aryl of from 6 to 12 carbon atoms;

Q is phenyl, cyclohexyl, piperidinyl, tetrahydropyranyl, pyridyl, pyrrolyl, N-methylpyrrolyl, thienyl furyl, 1-hexyl, or cyano; from 1 to 3 hydrogen atoms in Q may be independently substituted by alkyl of from 1 to 3 carbon atoms, perfluoroalkyl of from 1 to 3 carbon atoms, acylamino of from 1 to 6 carbon atoms. perfluoroacylamino of from 1 to 3 carbon atoms, alkoxy of from 1 to 3 carbon atoms, alkanesulfonylamino of from 1 to 3 carbon atoms, perfluoroalkanesulfonylamino of from 1 to 3 carbon atoms, acetoxy of from 1 to 3 carbon atoms, aminocarbonyl, aminosulfonyl, fluoro, chloro, cyano, hydroxy, nitro, amino, imidazolylmethyl, cinnamoylamino, p-fluorobenzoyl, cyanomethyl, cyanoethyl, methoxyacetoxy, alkoxycarbonyl of from 1 to 3 carbon atoms; 1 is an integer of from 0 to 1; m is an integer of from 0 to 1; n is an integer of from 0 to 6.

These compounds may be in their free base form or in the form of a pharmaceutically acceptable salt thereof.

A compound of the above formula can be prepared by the following procedure: ##STR8##

The pharmaceutically acceptable salts of the piperidine derivatives of this invention are acid addition salts formed from the compound and an organic or inorganic acid well known in the art as providing a pharmaceutical addition salt, such as a hydrochloride, sulfate, citrate, tartarate, mesylate, maleate, fumarate, or the like.

These salts are readily prepared by mixing a solution of equimolar amounts of the free base form of the compound and desired acid in a suitable solvent such as water, alcohol, or ether, followed by recovery of the product by collecting the precipitated salt or by evaporation of the solvent.

When used as antiarrhythmic drugs, the piperidine derivatives of the present invention may be administered by an oral or parenteral route, which may be determined depending upon age, body weight, condition of the patient. A daily dose may generally be from about 0.001 about 2000 mg/patient or animal for oral administration; in the case of patenteral administration, a daily dose may generally be from about 0.001 to about 1000 mg/patient or animal.

The piperidine derivatives of the present invention may be formulated into conventional preparation forms, for example, tablets, powders, capsules, solutions, sugar-coated tablets or depots, which may be prepared in a conventional manner using conventional techniques. For example, tablets can be obtained by mixing a piperidine derivative of the present invention with known auxiliary substances, for example, inactive diluents (e.g. lactose, calcium carbonate or calcium phosphate), binders (e.g. gum arabic, corn starch or gelatin), sweeteners (e.g. sucrose or saccharine), flavours (e.g. peppermint, Gaultheria adenothrix oil or cherry), lubricating and wetting agents (e.g. magnesium stearate, talc or carboxymethyl cellulose).

The present invention further provides a novel antiarrhythmic agent which is a composition comprising a pharmaceutically effective amount of a piperidine derivative as defined above.

The pharmaceutical composition of the present invention is advantageous as an antiarrhythmic drug for treating mammals including humans. This can be administered perorally in the form of tablet, capsule or elixir, or parenterally in the form of a sterile solution or suspension, for the purpose of reducing or eliminating arrhythmia. The pharmaceutical composition of the present invention can be administered to patients or animals which are to be treated generally several times each in a unit dosage of from about 0.001 to about 500 mg/patient or animal, and accordingly the total dosage of the derivative may be from about 0.001 to about 2000 mg/patient or animal/day. Of course, the amount of the dosage may be varied in accordance with the condition of the disease, the weight of the patient or animal and other factors which are considered appropriate by one skilled in the art.

The above-mentioned typical combinations may be formulated as a pharmaceutical composition in a conventional manner. For example, from about 0.2 to about 500 mg of the derivative of the present invention or a pharmaceutically acceptable salt thereof or a mixture thereof is blended together with a pharmaceutically acceptable vehicle, carrier, extender, binder, antiseptic, stabilizer, flavour and the like, in an amount as required for conventional pharmaceutical preparations.

Examples of pharmaceutical additives to be used for the preparation of tablets, capsules and the like are: binders such as tragacanth, gum arabic, corn starch or gelatin; vehicles such as fine crystalline cellulose; extenders such as corn starch, pre-gelatinised starch or alginic acid; sweeteners such as sucrose, lactose or saccharin; flavours such as peppermint, an oil from Gaulthenia adenothrix Maxim or cherry. When the preparation is in the form of a capsule, this may further contain a liquid carrier such as a fat and oil, in additional to the above mentioned materails. Other various materails can further be employed so as to form coated pills or to vary the physical form of the preparation by a different method. For example, tablets can be coated with shellac, sugar or both. A syrup or elixir can contain the active compound together with sucrose as a sweetener, methyl- or propyl-paraben as an antiseptic, a dye, and cherry or orange essence as a flavour.

A sterile composition for injection can be prepared in a conventional manner, for example, by dissolving or suspending the active substance in a vehicle such as distilled water for injection, together with a natural vegetable oil such as sesame oil, coconut oil, peanut oil, cotton seed oil, or a synthetic fat vehicle such as ethyl oleate. If desired, a buffer, an antiseptic, an antioxidant or the like can be incorporated into the composition.

The present invention will be further illustrated by reference to the following examples.

Retention factor (Rf) was determined by silica gel thin layer chromatography (TLC:Merck Art 5715). Unless otherwise noted, mass spectroscopy was determined on JEOL-DX 300 by FD mode; .sup.1 H NMR spectra were obtain in CDCl.sub.3 with tetramethylsilane as internal standard on a Varian VXR-300 spectrometer. "Intermediate (1)" represents 4-(5H-dibenzo[a, d]cyclohepten-5-ylidene)piperidine. piperidine

To a solution of 4-(N-imidazolylmethyl)cinnamic alcohol (4.5 mmol) in CHCl3, thionyl chloride (5.4 mmol) was added, and stirred for 2 h at room temperature. After a usual procedure, the product was used without further purification.

The product obtained according to above-mentioned procedure was dissolved in methyl isobutyl ketone, and then intermediate (1) (4.0 mmol), potassium carbonate (8.75 mmol) and NaI (8.75 mmol) were added to the solution, stirred at 90.degree. C. for overnight. The mixture was washed with water, extracted with CH2Cl2, washed with 1M HCl, saturated aqueous solution of NaHCO3, and then brine, dried over MgSO4. The solvent was evaporated at reduced pressure, the resulting mixture was purified by column chromatography (SiO2). MS                   469(M+) NMR 2.2-2.4(4H, m)       2.5-2.6(2H, m) 2.8-2.9(2H, m)       3.28(2H, d) 5.07(2H, s)          6.38(1H, dt) 6.52(1H, d)          6.95(2H, s) 7.0-7.6(15H, m) ______________________________________ droxypiperidine TLC(CHCl3:MeOH=9:1)    Rf=0.58 MS                     442(M+) NMR 1.4-1.6(2H, m)         1.8-2.0(4H, m) 2.1-2.2(4H, m)         2.3-2.4(4H, m) 2.5-2.6(2H, m)         2.89(1H, m) 3.19(1H, m)            3.7-3.8(2H, m) 3.9-4.0(2H, m)         4.0-4.2(2H, m) 6.91(2H, s)            7.1-7.4(8H, m) ______________________________________

According to the practically same procedure described in preparation of compound 1,4-bromo-1-cyclohexylbutane and 4-dibenzo[b,e]thiepine-11-(6H)-ylidenepiperidine were used. TLC(CHCl3:MeOH=9:1)   Rf=0.74 MS                    431(M+) NMR 0.8-1.0(2H, m)        1.1-1.4(10H, m) 1.4-1.6(1H, m)        1.6-1.8(6H, m) 2.1-2.4(4H, m)        2.51(2H, t) 2.6-2.8(4H, m)        3.39(1H, d) 4.99(1H, s)           6.9-7.1(4H, m) 7.2-7.4(4H, m) ______________________________________

After the stepwise addition of 4-Nitrocinnamyl alcohol (5.58 mmol) to a ice-cooled solution of SOCl2 (10 g), the mixture was stirred for a few minites. The residue obtained by general procedure was condensed with intermediate (1) (6.59 mmol) in the presence of potassium carbonate. Yield 2.02 mmol (36.2%) MS                  434(M+) NMR 2.16-2.24(4H, m)    2.31-2.42(2H, m) 2.60-2.68(2H, m)    3.18(2H, d) 6.46(1H, dt)        6.55(1H, d) 6.92(2H, s)         7.18-7.36(8H, m) 7.42-7.48(2H, m)    8.17-8.20(2H, m) ______________________________________ 4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-(4-nitrocinnamyl)piperidine (compound 4) was reduced by zinc in acetic acid at room temperature for 4 h. Yield 84.5% MS                 404(M+) NMR 2.20-2.42(6H, m)   2.60-3.32(4H, m) 3.40(2H, d)        6.11(1H, dt) 6.43(1H, d)        6.59-6.64(2H, s) 6.91(2H, s)        7.14-7.36(10H, m) ______________________________________

1-(4-Aminocinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (compound 5) was N-acetylated by acetic anhydride using triethyl amine as base. Yield 92.3% MS                  446(M+) NMR 2.18(3H, s)         2.20-2.55(6H, m) 4.70(1H, bs)        6.20(1H, dt) 6.42(1H, d)         6.91(2H, s) 7.15-7.36(10H, m)   7.42-7.56(2H, m) ______________________________________ l)propane

a) 1-Bromo-3-(4-nitrophenyl)propane

1-Bromo-3-phenylpropane (19.7 mmol) was added slowly to a solution of sulfuric acid (7.4 g) and nitric acid (5.4 g) at ambient temperature and stirred at 60.degree. C. The residue (mixture of ortho and para) was purified by column chromatography on silica gel. Yield 63.7% NMR 2.20(2H, quint.)     2.92(2H, t) 3.40(2H, t)          7.35(2H, d) 8.16(2H, d) ______________________________________

b) compound 7

This was prepared from 1-Bromo-3-(4-nitrophenyl)propane and intermediate (1). Yield 94.6% MS                   436(M+) NMR 1.84(2H, m)          2.15(4H, m) 2.30(4H, m)          2.59(2H, m) 2.70(2H, t)          6.90(2H, s) 7.2-7.4(10H, m)      8.10(2H, d) ______________________________________ ]propane

3-[4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl]-1-(4-nitrophenyl )propane (compound 7) was reduced by zinc. Yield 97.3%. MS                 406(M+) NMR 1.70(2H, m)        2.0-2.6(12H, m) 3.48(2H, br)       6.55(2H, d) 6.85(2H, s)        6.92(2H, d) 7.20(4H, m)        7.25(4H, m) ______________________________________ idinyl]propane

This was prepared from 1-(4-Aminophenyl)-3-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidiny l]propane (compound 8) and acetic anhydride. Yield 92.9% MS                  48(M+) NMR 1.6-1.8(4H, m)      2.15(3H, s) 2.0-2.2(2H, m)      2.2-2.4(4H, m) 2.55(4H, m)         7.1-7.4(12H, m) ______________________________________ ethoxyanilide MS(FAB, m/z)        481(M+) NMR 2.25-2.36(4H, m)    2.40-2.46(2H, m) 2.52(2H, t)         2.70(2H, t) 2.68-2.80(2H, m)    3.85(3H, s) 3.88(3H, s)         6.79(2H, s) 6.93(2H, s)         7.18-7.35(8H, m) 7.52(1H, s) ______________________________________ hydropyran MS                  413(M+) NMR 1.1-1.6(10H, m)     1.7-1.8(1H, m) 2.1-2.4(8H, m)      2.5-2.6(2H, m) 3.35(2H, t)         3.93(2H, d) 6.90(2H, s)         7.2-7.4(8H, m) ______________________________________ peridinyl]propane

a) 3-(4-Piperidinyl)-1-propanol

1-(4-Pyridyl)-1-propine-3-ol was hydrogenated with rhodium on alumina as catalyst.

b) 1-Acetoxy-3-(N-acetyl-4-piperidinyl)propane

This was prepared from 3-(4-Piperidinyl)-1-propanol and acetic anhydride. NMR 1.0-1.8(9H, m)       2.04(3H, s) 2.07(3H, s)          2.51(1H, t) 3.00(1H, t)          3.78(1H, br d) 4.04(2H, t)          4.58(1H, br d) ______________________________________

c) 3-(N-Acetyl-4-piperidinyl)propanol

1-Acetoxy-3-(N-acetyl-4-piperidinyl)propane was saponificated by potassium carbonate. NMR 1.0-1.2(2H, m)      1.2-1.4(2H, m) 1.4-1.8(6H, m)      2.08(3H, s) 2.53(1H, dt)        3.02(1H, dt) 3.64(2H, t)         3.79(1H, br d) 4.58(1H, br d) ______________________________________

d) 1-(N-Acetyl-4-piperidinyl)-3-bromopropane 3-(N-Aceytl-4-piperdinyl)propanol was brominated with phosphorus tribromide. NMR 1.0-1.2(2H, m)       1.40(2H, t) 1.50(1H, m)          1.74(2H, br t) 1.78(2H, quint)      2.08(3H, s) 2.53(1H, dt)         3.02(1H, dt) 3.40(2H, t)          3.80(1H, br d) 4.59(1H, br d) ______________________________________

e) compound 12 Yield 77.8% MS                  440(M+) NMR 1.0-1.2(2H, m)      1.22(2H, m) 1.4-1.6(3H, m)      1.68(2H, m) 2.05(3H, s)         2.1-2.6(11H, m) 2.96(1H, dt)        3.74(1H, br d) 4.55(1H, br d)      6.90(2H, s) 7.2-7.4(8H, m) ______________________________________ hylindan MS                  460(M+) NMR 2.0-2.3(7H, m)      2.3-2.5(1H, m) 2.5-2.8(6H, m)      2.9-3.1(2H, m) 6.92(2H, s)         7.0-7.5(11H, m) ______________________________________

4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-(2,4-dimethoxycinnamyl)piperidin

a) 4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-(2,4-dimethoxycinnamoyl)piperid ine

2,4-Dimethoxycinnamic acid (10.0 mmol) and intermediate (1) was condensed by N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride.

b) compound 14

4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-(2,4-dimethoxycinnamoyl)piperidi ne was reduced with lithium alminium hydride. Yield 12.3% MS                449(M+) NMR 2.13-2.23(4H, m)  2.30-2.50(2H, m) 2.62(2H, m)       3.13(2H, d) 3.78(6H, s)       6.15(1H, tt) 6.42(2H, m)       6.68(1H, d, J=15.9Hz) 6.91(2H, s)       7.18-7.35(9H, m) ______________________________________

a) 4-Cyanocinnamylalcohol

A Heck reaction of 4-bromobenzonitrile and acrylic acid gave 4-cyanocinnamic acid. The acid was reduced to the corresponding alcohol with ethyl chloroformate and then sodium borohydride. Yield 78.6% NMR 4.38(2H, dd)         6.49(1H, m) 6.65(1H, d)          7.44(2H, d) 7.40(2H, d) ______________________________________

b) compound 15 MS                  414(M+) NMR 2.12-2.22(4H, m)    2.30-2.42(2H, m) 2.52(2H, m)         3.15(2H, d) 6.42(2H, m)         6.92(2H, s) 7.18-7.35(8H, m)    7.40(2H, d) 7.58(2H, d) ______________________________________ piperidinyl]butane

A osmium tetraoxide (0.4 mmol) in acetone was added to the 50% aqueous solution of acetone dissolved in 1-Cyclohexyl-4-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)but ane (4.8 mmol) and N-methylmorpholine-N-oxide (7.2 mmol). The mixture was stirred for over night at ambient temperature. MS                  445(M+) 0.7-1.4(11H, m)     1.4-1.8(8H, m) 2.6-3.0(8H, m)      3.05(1H, bs) 3.26(1H, bs)        5.21(2H, s) 7.0-7.6(4H, m) ______________________________________ dine

1-(4-Aminocinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (compound 5) was N-acylated. Yield 43.9% MS                  460(M+) NMR 1.22(3H, t)         2.2-2.6(8H, m) 2.7-2.9(2H, m)      3.23(2H, d) 4.79(1H, bs)        6.1-6.3(1H, m) 6.43(1H, dd)        6.93(2H, s) 7.1-7.55(12H, m) ______________________________________ iperidine

This compound was prepared from 1-(4-Aminocinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (compound 5) and ethyl chloroformate. Yield 56.7% MS                  476(M+) NMR 1.30(3H, t)         2.2-2.9(8H, m) 3.26(2H, dd)        4.22(2H, q) 6.1-6.3(1H, m)      6.46(1H, d) 6.67(1H, bs)        6.93(2H, s) 7.1-7.4(12H, m) ______________________________________ piperidine

This compound was prepared from 1-(4-Aminocinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (compound 5) and methanesulfonyl chloride. Yield 67.0% MS                  482(M+) NMR 2.1-2.5(6H, m)      2.5-2.7(2H, m) 3.17(2H, d)         3.39(3H, s) 6.2-6.4(1H, m)      6.49(1H, d) 6.93(2H, s)         7.1-7.5(12H, m) ______________________________________ idine

According to the practical same procedure of compound 16, this compound was obtained. MS                  447(M+) NMR 2.16-2.26(4H, m)    2.30-2.44(2H, m) 2.52(2H, m)         3.14(2H, d) 3.91(3H, s)         6.38(1H, m) 6.52(1H, d)         6.92(2H, s) 7.18-7.35(9H, m)    7.52(1H, d) 7.88(1H, d)         8.01(1H, s) ______________________________________ piperidine

This compound was prepared from 1-(4-Aminocinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (compound 5) and methyl chloroformate. Yield 97.5% MS                  462(M+) NMR 2.2-2.9(8H, m)      3.10(2H, m) 3.78(3H, s)         6.2-6.4(1H, m) 6.56(1H, d)         6.72(1H, bs) 6.92(2H, s)         7.1-7.4(12H, m) ______________________________________ ine

This compound was prepared from 1-(4-Aminocinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (compound 5) and pivaloyl chloride. Yield 92.0% MS                 488(M+) NMR 1.34(9H, s)        2.2-3.2(10H, m) 6.2-6.42(1H, m)    6.55(1H, d) 6.93(2H, s)        7.1-7.44(10H, m) 7.45-7.6(2H, m) ______________________________________ piperidine

This compound was prepared from 1-(4-Aminocinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (compound 5) and trifluoroacetic anhydride. Yield 46.0% MS                  500(M+) NMR 2.4-3.7(10H, m)     6.2-6.4(1H, m) 6.58(1H, dd)        6.93(2H, s) 7.17(2H, d)         7.2-7.45(8H, m) 7.69(2H, dd)        8.36(1H, bs) ______________________________________ ine

This compound was prepared from 1-(4-Aminocinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (compound 5) and butanoic acid. Yield 68.5% MS                  474(M+) NMR 0.99(3H, q)         1.6-1.8(2H, m) 2.2-2.43(6H, m)     2.44-2.7(2H, m) 2.8-3.1(2H, m)      3.35(2H, d) 5.50(1H, bs)        6.1-6.3(1H, m) 6.45(1H, dd)        6.92(2H, s) 7.1-7.4(10H, m)     7.49(2H, dd) ______________________________________

The following compound were prepared according to the above-mentioned procedures. MS                  410(M+) NMR 1.33(3H, t)         1.8-2.4(6H, m) 3.18(2H, m)         3.43(3H, m) 4.21(2H, m)         6.32(1H, dt) 6.58(1H, d)         6.6(1H, s) 7.1-7.4(6H, m)      7.92(2H, m) ______________________________________ MS                   396(M+) NMR 1.9-2.3(4H, m)       2.70(3H, m) 3.28(2H, m)          3.42(3H, m) 3.99(3H, m)          6.33(1H, dt) 6.58(1H, d)          6.80(1H, s) 7.1-7.5(6H, m)       7.97(2H, m) ______________________________________ MS                  394(M+) NMR 1.23(3H, t)         1.7-2.2(6H, m) 2.41(2H, q)         3.1-3.5(5H, m) 6.33(1H, dt)        6.58(1H, d) 7.0-7.5(7H, m)      7.98(2H, m) ______________________________________ MS                  435(M+) NMR 2.1-2.2(4H, m)      2.95-3.3(5H, m) 3.80(2H, m)         6.25(1H, dt) 6.68(1H, d)         7.1-7.5(7H, m) 7.98(2H, m) ______________________________________

1-(4-Acetylaminocinnamyl)-4-(4-fluorobenzoyl)piperidine MS                  380(M+) NMR 1.75-1.95(5H, m)    2.1-2.3(4H, m) 3.0-3.3(5H, m)      6.22(1H, dt) 6.50(1H, d)         7.05-7.55(7H, m) 7.98(2H, m) ______________________________________ MS                  338(M+) NMR 1.8-2.2(4H, m)      2.95-3.3(5H, m) 3.68(2H, m)         6.10(1H, dt) 6.41(1H, d)         6.62(2H, m) 7.05-7.40(6H, m)    7.97(2H, m) ______________________________________ MS                  368(M+) NMR 1.8-2.2(4H, m)      3.0-3.35(5H, m) 3.8(2H, m)          6.36(1H, dt) 6.57(1H, d)         7.05-7.5(6H, m) 7.98(2H, m) ______________________________________ ine TLC(CHCl3:MeOH=9:1)     Rf=0.23 MS                      432(M+) ______________________________________ dine TLC(CHCl3:MeOH=9:1)     Rf=0.85 MS                      457(M+) ______________________________________ TLC(CHCl3:MeOH=9:1)     Rf=0.89 MS                      428(M+) ______________________________________ TLC(CHCl3:MeOH=9:1)     Rf=0.72 MS                      457(M+) ______________________________________ iperidine TLC(HEXANE:Ethyl acetate=1:1) Rf=0.13 MS                       457(M+) ______________________________________ TLC(CHC13:MeOH=9:1)    Rf=0.89 MS                     454(M+) NMR 2.1-2.3(4H, m)         2.4-2.6(2H, m) 2.6-2.8(2H, m)         3.21(2H, d) 3.41(1H, d)            4.98(1H, d) 6.48(1H, dt)           6.61(1H, d) 7.0-7.1(4H, m)         7.2-7.4(4H, m) 7.4-7.5(2H, m)         8.1-8.2(2H, m) ______________________________________ TLC(CHC13:MeOH=9:1)    Rf=0.65 MS                     424(M+) NMR 2.1-2.8(8H, m)         3.13(2H, d) 3.39(1H, d)            3.68(2H, bs) 4.95(1H, d)            6.08(1H, dt) 6.39(1H, d)            6.5-6.6(2H, m) 7.0-7.1(5H, m)         7.1-7.3(5H, m) ______________________________________ TLC(CHC13:MeOH=9:1)   Rf=0.58 MS                    466(M+) NMR 2.15(3H, s)           2.2-2.9(8H, m) 3.22(2H, d)           3.40(1H, d) 4.91(1H, d)           6.21(1H, dt) 6.48(1H, d)           7.0-7.5(13H, m) ______________________________________ ne TLC(CHC13:MeOH=9:1)   Rf=0.73 MS                    449(M+) NMR 2.05-2.23(4H, m)      2.30-2.45(2H, m) 2.50-2.66(2H, m)      3.15(2H, d) 3.75(6H, s)           6.15(1H, m) 6.45-7.00(4H, m)      6.91(2H, s) 7.18-7.35(8H, m) ______________________________________ TLC(CHC13:MeOH=9:1)    Rf=0.90 MS                     449(M+) NMR 2.1-2.2(4H, m)         2.3-2.4(2H, m) 2.5-2.7(2H, m)         3.13(2H, d) 3.77(3H, s)            3.80(3H, s) 6.28(1H, dt)           6.79(1H, d) 6.90(2H, s)            7.0-7.1(2H, m) 7.2-7.4(9H, m) ______________________________________ TLC(CHC13:MeOH=9:1)   Rf=0.73 MS                    449(M+) NMR 2.05-2.23(4H, m)      2.28-2.42(2H, m) 2.50-2.66(2H, m)      3.10(2H, d) 3.78(6H, s)           6.10-6.42(3H, m) 6.52(2H, m)           6.91(2H, s) 7.18-7.35(8H, m) ______________________________________ TLC(CHC13:MeOH=9:1)   Rf=0.87 MS                    419(M+) NMR 2.2-2.3(4H, m)        2.3-2.4(2H, m) 2.6-2.7(2H, m)        3.15(2H, d) 3.79(3H, s)           6.28(1H, dt) 6.80(1H, d)           6.8-6.9(1H, m) 6.92(2H, s)           7.1-7.4(11H, m) ______________________________________ TLC(CHC13:MeOH=9:1)    Rf=0.89 MS                     419(M+) NMR 2.1-2.2(4H, m)         2.2-2.4(2H, m) 2.5-2.7(2H, m)         3.12(2H, d) 3.78(3H, s)            6.23(1H, dt) 6.42(1H, d)            6.7-6.9(4H, m) 6.92(2H, s)            7.2-7.4(8H, m) ______________________________________ TLC(CHC13:MeOH=9:1)   Rf=0.85 MS                    419(M+) NMR 2.1-2.2(4H, m)        2.3-2.4(2H, m) 2.6-2.7(2H, m)        3.12(2H, d) 3.79(3H, s)           6.12(1H, dt) 6.41(1H, d)           6.83(2H, d) 6.91(2H, s)           7.1-7.3(10H, m) ______________________________________ peridine TLC(CHC13:MeOH=9:1)    Rf=0.93 MS                     436(M+) NMR 2.7-3.0(8H, m)         3.3-3.4(4H, m) 3.75(2H, d)            6.7-6.8(2H, m) 7.0-7.2(8H, m)         7.5-7.6(2H, m) 8.1-8.2(2H, m) ______________________________________ iperidine TLC(CHC13:MeOH=9:1)    Rf=0.64 MS                     405(M+) NMR 2.4-2.5(4H, m)         2.6-2.7(2H, m) 2.81(2H, dt)           3.12(2H, d) 3.3-3.4(2H, dt)        3.67(2H, bs) 6.08(1H, dt)           6.39(1H, d) 6.60(2H, d)            7.0-7.2(10, m) ______________________________________ idene)piperidine TLC(CHC13:MeOH=9:1)    Rf=0.54 MS                     448(M+) NMR 2.4-2.6(4H, m)         2.7-2.8(8H, m) 3.21(2H, d)            6.21(1H, dt) 6.44(1H, d)            7.0-7.2(8H, m) 7.34(2H, d)            7.44(2H, d) ______________________________________ TLC(CHC13:MeOH=9:1)    Rf=0.88 MS                     445(M+) NMR 2.1-2.2(4H, m)         2.3-2.4(2H, m) 2.6-2.8(2H, m)         3.09(2H, d) 6.17(1H, dt)           6.42(1H, d) 6.87(2H, s)            6.9-7.0(2H, m) 7.2-7.3(10H, m) ______________________________________ propene TLC(CHC13:MeOH=9:1)    Rf=0.44 MS                     390(M+) NMR 2.1-2.2(4H, m)         2.3-2.5(2H, m) 2.55-2.65(2H, m)       3.09(2H, d) 6.31(1H, dt)           6.43(1H, d) 6.90(2H, s)            7.1-7.3(9H, m) 7.62(1H, d)            8.41(1H, dd) 8.54(1H, d) ______________________________________ TLC(CHC13:MeOH=9:1)    Rf=0.55 MS(FAB.m/z)            406(MH+) NMR 2.1-2.3(4H, m)         2.3-2.5(2H, m) 2.6-2.8(2H, m)         3.07(2H, d) 5.97(1H, dt)           6.37(1H, d) 6.63(2H, d)            6.87(2H, s) 7.0-7.3(11H, m) ______________________________________ TLC(CHC13:MeOH=9:1)   Rf=0.87 MS                    447(M+) NMR 2.1-2.2(4H, m)2.29(3H, s) 2.3-2.4(2H, m)        2.6-2.7(2H, m) 3.12(2H, d)           6.21(1H, dt) 6.43(1H, d)           6.92(2H, s) 6.9-7.0(2H, m)        7.2-7.4(10H, m) ______________________________________ eridine TLC(CHC13:MeOH=9:1)    Rf=0.87 MS                     435(M+) NMR 2.1-2.2(4H, m)         2.3-2.4(2H, m) 2.6-2.7(2H, m)         3.08(2H, d) 3.81(3H, s)            6.09(1H, dt) 6.39(1H, d)            6.78(1H, s) 6.8-6.9(2H, m)         6.87(2H, s) 7.1-7.3(9H, m) ______________________________________ eridine TLC(CHC13:MeOH=9:1)   Rf=0.83 MS                    447(M+) NMR 2.1-2.2(4H, m)        2.29(3H, s) 2.3-2.4(2H, m)        2.6-2.7(2H, m) 3.09(2H, d)           3.81(3H, s) 6.08(1H, dt)          6.38(1H, d) 6.80(2H, s)           6.9-7.4(11H, m) 7.2-7.4(9H, m) ______________________________________ TLC(CHC13:MeOH=9:1)   Rf=0.45 MS                    405(M+) NMR(CD3OD) 2.10-2.30(4H, m)      2.31-2.50(2H, m) 2.70(2H, m)           3.16(2H, d) 6.42(1H, m)           6.70(1H, m) 6.84-6.95(2H, m)      6.95(2H, s) 7.10-7.38(10H, m) ______________________________________ TLC(CHC13:MeOH=9:1)   Rf=0.80 MS                    447(M+) NMR 2.13-2.24(4H, m)      2.30-2.45(2H, m) 2.62(2H, m)           3.14(2H, d) 6.28(1H, m)           6.43(1H, d) 6.92(2H, s)           6.92-6.97(1H, m) 7.04(1H, s)           7.18-7.35(10H, m) ______________________________________ peridine TLC(CHC13:MeOH=9:1)   Rf=0.65 MS                    477(M+) NMR(hydrochloride) 2.21-2.40(2H, m)      2.48-2.60(4H, m) 2.92-3.15(2H, m)      3.20-3.65(2H, m) 3.54(3H, s)           4.26(2H, s) 6.40-6.60(2H, m)      6.92(2H, s) 7.00-7.39(12H, m) ______________________________________ idine TLC(CHC13:MeOH=9:1)   Rf=0.55 MS                    447(M+) NMR 2.52-2.68(4H, m)      2.92-3.10(2H, m) 3.30-3.50(2H, m)      3.62(2H, d) 6.42(1H, dt)          6.91(2H, s) 7.18(1H, d)           7.24-7.40(8H, m) 7.42-7.60(3H, m)      7.90-7.95(1H, m) ______________________________________ idine TLC(CHC13:MeOH=9:1)   Rf=0.50 MS                    447(M+) NMR 2.15-2.24(4H, m)      2.32-2.45(2H, m) 2.60-2.68(2H, m)      3.16(2H, d) 3.90(3H, s)           6.39(1H, dt) 6.50(1H, d)           6.92(2H, s) 7.20-7.36(8H, m)      7.37-7.41(2H, m) 7.96-8.00(1H, m) ______________________________________ idine TLC(HEXANOE:EtOAc=1:1) Rf=0.30 MS                    464(M+) NMR 2.1-2.23(3H, m)       2.24-2.42(2H, m) 2.43-2.7(3H, m)       3.07(2H, d) 3.81(3H, s)           6.37(2H, s) 6.8-7.0(3H, m)        7.05-7.4(10H, m) ______________________________________ ine TLC(CHC13:MeOH=9:1)    Rf=0.83 MS                     477(M+) NMR 1.23(3H, t)            2.1-2.2(4H, m) 2.3-2.4(2H, m)         2.5-2.7(2H, m) 3.13(2H, d)            4.18(2H, q) 6.24(1H, d)            6.43(1H, d) 6.90(2H, s)            7.0-7.1(2H, m) 7.1-7.4(10H, m) ______________________________________ idine TLC(CHC13:MeOH=9:1)    Rf=0.75 MS                     477(M+) NMR 2.0-2.2(4H, m)         2.4-2.6(2H, m) 2.5-2.7(2H, m)         3.17(2H, d) 3.52(3H, s)            4.24(2H, s) 6.22(1H, dt)           6.44(1H, d) 6.95(2H, s)            7.0-7.4(12H, m) ______________________________________ TLC(CHC13:MeOH=9:1)   Rf=0.35 MS(FAB.m/z)           422(M+) NMR 2.0-2.3(4H, m)        2.4-2.6(2H, m) 2.6-2.8(2H, m)        3.17(2H, dt) 6.27(1H, dt)          6.41(1H, d) 6.87(2H, s)           6.9-7.5(13H, m) ______________________________________ TLC(CHC13:MeOH=9:1)    Rf=0.75 MS                     469(M+) ______________________________________ amyl)piperidine TLC(CHC13:MeOH=9:1)    Rf=0.71 MS                     451(M+) ______________________________________ TLC(CHC13:MeOH=9:1)    Rf=0.32 MS                     475(M+) ______________________________________ TLC(CHC13:MeOH=9:1)    Rf=0.35 MS                     475(M+) ______________________________________ TLC(CHC13:MeOH=9:1)    Rf=0.31 MS                     458(M+) ______________________________________ TLC(CHC13:MeOH=9:1)    Rf=0.31 MS                     444(M+) ______________________________________ lidene)piperidine TLC(CHC13:MeOH=9:1)    Rf=0.34 MS                     471(M+) ______________________________________ ylidene)piperidine TLC(CHC13:MeOH=9:1)    Rf=0.29 MS                     483(MH+) ______________________________________ lidene)piperidine TLC(CHC13:MeOH=9:1)    Rf=0.45 MS                     483(MH+) ______________________________________ MS                  397(M+) H-NMR 2.1-2.8(8H, m)      3.63(2H, bs) 6.90(2H, s)         7.1-7.3(12H, m) ______________________________________ ne Yield 94% MS                   397(M+) H-NMR 0.8-2.1(15H, m)      2.47(2H, dd) 2.68(2H, d)          2.7-2.9(2H, m) 3.0(2H, dd)          3.49(2H, d) 6.94(2H, s)          7.1-7.4(8H, m) ______________________________________ ne Yield 72% MS                   411(M+) H-NMR 0.8-2.1(15H, m)      2.47(2H, dd) 2.68(2H, d)          2.7-2.9(2H, m) 3.0(2H, dd)          3.49(2H, d) 6.92(2H, s)          7.1-7.4(8H, m) ______________________________________ TLC(CHC13:MeOH=9:1) Rf=0.68 MS                357(M+) H-NMR(CDCL3) 0.85(3H, d, J=8Hz) 1.2-1.4(6H, m) 1.7-1.9(2H, m)    2.31(2H, dd, J=12, 8Hz) 2.53(2H, d, J=12Hz) 2.7-2.8(2H, m) 3.14(2H, td, J=8, 3Hz) 3.40(2H, d, J=12Hz) 6.92(2H, s)       7.2-7.4(8H, m) ______________________________________ TLC(CHC13:MeOH=9:1) Rf=0.75 MS                413(M+) NMR(hydrochloride) 0.85(3H, t, J=8Hz) 1.2-1.4(14H, m) 1.7-1.9(2H, m)    2.33(2H, dd, J=12, 8Hz) 2.54(2H, d, J=12Hz) 2.7-2.8(2H, m) 3.15(2H, td, J=8, 3Hz) 3.39(2H, d, J=12Hz) 6.92(2H, s)       7.1-7.4(8H, m) ______________________________________ nyl-2-isopropylvaleronitrile Yield 69.1% TLC(CHC13:MeOH=9:1) Rf=0.60 MS                  542(M+) H-NMR(CDCL3) 0.77(3H, d, J=8Hz)  1.18(3H, d, J=8Hz) 2.0-3.4(15H, m)     6.90(2H, s) 7.18(H, dd, J=9, 2Hz) 7.2-7.4(8H, m) 7.48(1H, d, J=9Hz)  7.53(1H, s) ______________________________________ o]-1-propyl)piperidine TLC(CHC13:MeOH=9:1) Rf=0.66 MS                  568(M+) H-NMR(CDCL3) 1.73(2H, tt, J=7, 7Hz) 2.0-2.2(4H, m) 2.3-2.4(2H, m)      2.38(2H, t, J=7Hz) 2.5-2.6(2H, m)      2.78(2H, t, J=7Hz) 6.59(1H, d, J=16Hz) 6.88(2H, s) 7.08(1H, tt, J=8, 1Hz) 7.1-7.4(12H, m) 7.5-7.6(3H, m)      7.76(1H, d, J=16Hz) 8.55(1H, d, J=8Hz)  8.78(1H, bs, NH) ______________________________________ TLC(CHC13:MeOH=9:1) Rf=0.69 MS                  389(M+) H-NMR(CDCL3) 2.1-2.3(4H, m)      2.4-2.5(2H, m) 2.6-2.7(2H, m)      3.14(2H, d, J=7Hz) 6.26(2H, dt, J=16, 7Hz) 6.48(2H, d, J=16Hz) 6.92(2H, s)         7.1-7.4(8H, m) ______________________________________ onitrile Yield 57.7% TLC(CHC13:MeOH=9:1)   Rf=0.74 MS                    506(M+) H-NMR(CDCL3) 1.5-1.7(2H, m)        2.0-2.2(4H, m) 2.3-2.6(8H, m)        6.87(2H, s) 7.1-7.4(18H, m) ______________________________________ hylphenyl)-2-isopropylvaleronitrile Yield 47.5% TLC(CHC13:MeOH=9:1) Rf=0.75 MS                  540(M+) H-NMR(CDCL3) 0.76(3H, d, J=7Hz)  1.0-1.2(1H, m) 1.5-1.6(1H, m)      1.9-2.5(13H, m) 6.88(2H, s)         7.1-7.3(8H, m) 7.48(1H, d, J=8Hz)  7.56(1H, d, J=8Hz) 7.59(1H, s) ______________________________________ TLC(CHC13:MeOH=9:1) Rf=0.75 MS                 381(M+) H-NMR(CDCL3) 2.1-2.2(4H, m)     2.3-2.4(2H, m) 2.5-2.6(2H, m)     3.53(2H, s) 6.88(2H, s)        6.96(1H, dd, J=8, 8Hz) 7.04(1H, dd, J=7, 7Hz) 7.1-7.4(10H, m) ______________________________________ TLC(CHC13:MeOH=9:1)   Rf=0.55 MS                    395(M+) H-NMR(CDCL3) 2.1-2.8(12H, m)       6.9-7.4(2H, m) ______________________________________ thylphenyl)valeronitrile TLC(CHC13:MeOH=9:1) Rf=0.56 Ms                  498(M+) H-NMR(CDCL3) 1.5-2.7(14H, m)     3.97(1H, t, J=7Hz) 6.90(2H, s)         7.1-7.6(12H, m) ______________________________________ TLC(CHCl3:MeOH=9:1)   Rf=0.62 MS                    378(M+) H-NMR(CDCL3) 2.1-2.8(8H, m)        3.50(2H, s) 3.4-3.8(2H, bs)       6.5-6.8(2H, m) 6.93(2H, s)           7.0-7.4(10H, m) ______________________________________ utyrophenone TLC(CHCl3:MeOH=9:1) Rf=0.52 MS                  479(M+) H-NMR(CDCL3) 1.8-2.6(12H, m)     2.95(2H, t, J=8Hz) 3.93(3H, s)         3.96(3H, s) 6.85(1H, d, J=10Hz) 6.88(2H, s) 7.2-7.4(8H, m)      7.5-7.7(2H, m) ______________________________________ TLC(CHCl3:MeOH=9:1)   Rf=0.70 MS(FD.m/z)            388(M+) H-NMR 2.2-2.5(2H, m)        2.5-2.8(2H, m) 3.0-3.4(4H, m)        4.03(2H, d) 6.92(2H, s)           7.1-8.0(12H, m) ______________________________________ peridinyl]butane TLC(HEXANE.:EtOAc=1:1) Rf=0.67 MS                    413(M+) H-NMR 0.80-0.88(2H, m)      1.10-1.73(15H, m) 2.12-2.19(2H, m)      2.28-2.30(2H, m) 2.32-2.47(4H, m)      2.64-2.69(2H, m) 2.77-2.86(2H, m)      3.36-3.45(2H, m) 7.05-7.15(8H, m) ______________________________________ TLC(CHCl3:MeOH=9:1)    Rf=0.58 MS(FD.m/z)             369(M+) H-NMR 0.7-2.9(20H, m)        6.91(2H, s) 7.05-7.4(8H, m) ______________________________________ TLC(CHCl3:MeOH=9:1)   Rf=0.63 MS(FD.m/z)            423(M+) H-NMR 2.0-2.8(10H, m)       3.80(3H, s) 3.84(3H, s)           6.7-7.4(11H, m) 6.89(2H, s) ______________________________________ 1.62-2.72(14H, m)     6.92(2H, s) 7.10-7.30(8H, m) ______________________________________ MS                  451(M+) NMR 2.15-2.30(4H, m)    2.37-2.45(2H, m) 2.65-2.75(2H, m)    3.70(2H, s) 3.90(3H, s)         3.92(3H, s) 6.85(1H, d)         6.90(2H, s) 7.18-7.34(8H, m)    7.59(1H, d) 7.66(1H, dd) ______________________________________ ne TLC(CHCl3:MeOH=9:1)   Rf=0.65 MS(FD.m/z)            439(M+) H-NMR 0.8-1.0(2H, m)        1.1-1.4(10H, m) 1.5-1.7(8H, m)        2.2-2.4(1H, m) 2.5-2.9(5H, m)        3.0-3.2(2H, m) 3.4-3.6(3H, m)        6.92(2H, s) 7.1-7.4(8H, m) ______________________________________ TLC(CHCl3:MeOH=9.1)   Rf=0.69 MS(FD.m/z)            417(M+) H-NMR 0.8-1.0(2H, m)        1.1-1.4(9H, m) 1.5-1.7(6H, m)        2.2-2.4(2H, m) 2.5-2.6(2H, m)        2.8-2.9(2H, m) 2.9-3.1(6H, m)        7.1-7.5(8H, m) ______________________________________ TLC(CHCl3:MeOH=9:1)   Rf=0.74 H-NMR 0.8-1.0(2H, m)        1.1-1.4(9H, m) 1.5-1.7(6H, m)        2.3-2.4(2H, m) 2.52(4H, t)           2.91(4H, t) 7.0-7.4(8H, m) ______________________________________ )valeronitrile TLC(CHCl3:MeOH=9:1)   Rf=0.56 MS                    497(M+) H-NMR(CDCL3) 0.76(3H, bs)          1.0-1.2(1H, m) 1.16(3H, bs)          1.4-2.5(12H, m) 2.9-3.4(3H, m)        3.82(3H, s) 3.87(3H, s)           6.6-6.8(2H, m) 6.6-6.8(2H, m)        7.0-7.2(2H, m) 7.8-8.1(2H, m) ______________________________________ ronitrile TLC(CHCl3:MeOH=9:1) Rf=0.70 MS                 592(M+) H-NMR(DMSO-d6) 0.84(3H, t, J=8Hz) 1.2-1.5(22H, m) 1.8-2.1(8H, m)     2.9-3.1(4H, m) 3.4-3.5(2H, m)     3.6-3.8(1H, m) 3.76(3H, s)        3.79(3H, s) 6.9-7.0(3H, m)     7.40(2H, dd, j=8, 8Hz) 8.07(2H, dd, J=10, 8Hz) ______________________________________ pylvaleronitrile TLC(CHCl3:MeOH=9:1) Rf=0.83 MS                  508(M+) H-NMR(CDCL3) 0.80(3H, t, J=6Hz)  1.21(3H, t, J=6Hz) 2.0-3.8(16H, m)     3.89(3H, s) 3.93(3H, s)         3.96(6H, s) 6.86(1H, d, J=8Hz)  6.91(1H, d, J=8Hz) 6.94(1H, d, J=2Hz)  7.00(1H, dd, J=8, 2Hz) 7.44(1H, d, J=2Hz)  7.49(1H, dd, J=8, 2Hz) ______________________________________ 2-isopropylvaleronitrile TLC(CHCl3:MeOH=9:1) Rf=0.54 MS                  544(M+) H-NMR(CDCL3) 0.78(3H, d, J=8Hz)  1.20(3H, d, J=8Hz) 1.6-3.6(15H, m)     3.87(3H, s) 3.94(3H, s)         6.8-7.1(11H, m) ______________________________________ inyl]valeronitrile TLC(CHCl3:MeOH=9:1)   Rf=0.64 MS                    490(M+) H-NMR(CDCL3) 0.8-1.3(6H, m)        1.9-3.6(25H, m) 3.9-4.0(6H, m)        6.8-7.0(5H, m) ______________________________________ leronitrile TLC(CHCl3:MeOH=9:1) Rf=0.70 MS                 421(M+) H-NMR(CDCL3) 0.81(3H, d, J=7Hz) 1.22(3H, d, J=7Hz) 1.5-1.7(2H, m)     2.15(1H, qq, J=7, 7Hz) 2.2-2.5(2H, m)     3.0-3.6(10H, m) 3.89(3H, s)        3.95(3H, s) 6.88(2H, d, J=8Hz) 6.95(2H, d, J=2Hz) 7.04(2H, dd, J=8, 2Hz) 7.1-7.2(3H, m) 7.37(2H, dd, J=8, 8Hz) ______________________________________ TLC(CHCl3:MeOH=9:1) Rf=0.54 MS                  364(M+) H-NMR(CDCL3) 1.6-1.8(2H, m, )    1.8-1.9(4H, m) 1.9-2.0(2H, m)      2.0-2.2(2H, m) 2.41(2H, t, J=7Hz)  2.9-3.0(2H, m) 3.20(1H, m)         3.88(1H, t, J=7Hz,) 7.1-7.2(2H, m)      7.3-7.4(5H, m, ) 7.9-8.0(2H, m) ______________________________________ propylvaleronitrile TLC(CHCl3:MeOH=9:1) Rf=0.73 MS                  450(M+) H-NMR(CDCL3) 0.80(3H, d, J=8Hz)  1.20(3H, d, J=8Hz) 1.5-3.6(15H, m)     3.9-4.0(6H, m) 6.4-6.5(1H, m)      6.8-7.2(7H, m) ______________________________________ nitrile TLC(CHCl3:MeOH=9:1) Rf=0.67 MS                 480(M+) H-NMR(CDCL3) 0.86(3H, t, J=8Hz) 1.0-3.8(21H, m) 3.88(3H, s)        3.96(3H, s) 6.87(1H, d, J=8Hz) 6.92(1H, s) 6.99(1H, d, J=8Hz) 7.18(2H, dd, J=8, 8Hz) 7.92(2H, dd, J=8.6Hz) ______________________________________ leronitrile TLC(CHCl3:MeOH=9:1) Rf=0.54 MS                409(M+) H-NMR(CDCL3) 1.00(3H, d, J=7Hz) 1.08(3H, d, J=7Hz) 1.4-1.5(1H, m, CH2CCN) 1.5-1.7(1H, m, CH2CCN) 1.7-1.9(4H, m)    1.9-2.1(4H, m) 2.24(1H, hept, J=7Hz) 2.3-2.4(2H, m) 2.8-2.9(2H, m)    3.18(1H, pseud hept.) 3.74(3H, s)       6.00-6.03(1H, m) 6.10-6.14(1H, m)  6.52-6.54(1H, m) 7.09-7.16(1H, m)  7.93-7.98(2H, m) ______________________________________ MS(FAB, m/z)      436(MH+) NMR 1.80-2.05(5H, m)  3.04-3.35(6H, m) 3.56-3.65(2H, m)  3.65-3.75(1H, m) 7.90-7.95(2H, m)  7.40(2H, dd, J=8, 8Hz) 8.45(1H, bs)      8.02-8.13(4H, m) ______________________________________ MS(m/z)             424(M+) NMR 1.8-2.4(8H, m)      2.9-3.7(6H, m) 3.85(3H, s)         3.88(3H, s) 3.8-4.4(2H, m)      6.8-6.9(3H, m) 7.1-7.2(2H, m)      7.9-8.0(2H, m) ______________________________________ iperidine MS(FAB, m/z)       478(MH+) NMR 1.12(3H, t, J=8Hz) 1.82-2.10(5H, m) 3.12-3.27(2H, m)   3.65-3.77(4H, m) 4.10(2H, q, J=8Hz) 4.23-4.30(2H, m) 6.16(1H, br)       6.68(1H, dd, J=8, 8Hz) 6.89(1H, d, J=8Hz) 7.36(1H, dd, J=8, 8Hz) 7.40(2H, dd, J=8, 6Hz) 7.59(1H, d, J=8Hz) 8.10(2H, dd, J=8, 6Hz) ______________________________________ 2-[N-methyl-N-2-[2,4-(1H,3H)-quinazolinedione-3-yl]-ethylamino]ethyl-2,6-d imethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate MS                 578(MH+) NMR 2.30(3H, s)        2.34(3H, s) 2.38(3H, s)        2.60-2.95(6H, m) 3.83(3H, s)        4.08(2H, t, J=7Hz) 4.04(1H, s)        5.86(1H, s) 6.91(1H, dd, J=8, 8Hz) 7.08(1H, dd, J=8, 8Hz) 7.23(1H, dd, J=8, 8Hz) 7.48(1H, dd, J=8, 8Hz) 7.70(1H, d, J=8Hz) 7.85(1H, d, J=8Hz) 8.02(1H, s) ______________________________________ NMR 1.65-2.22(12H, m)  2.25-3.33(12H, m) 7.02(4H, dd, J=8, 8Hz) 7.88(4H, dd, J =8, 6Hz) ______________________________________ opropylvaleronitrile MS                469 NMR 0.78(3H, dd, J=7Hz) 1.1-1.2(4H, m) 1.16(3H, d, J=7Hz) 1.2-1.4(1H, m) 1.4-1.6(2H, m)    1.6-1.9(4H, m) 2.0-2.1(2H, m)    2.19(2H, pseud t, J=8Hz) 2.6-2.9(2H, m)    3.86(3H, s) 3.87(3H, s)       4.26(1H, d, J=7Hz) 6.8-7.1(5H, m)    7.1-7.3(2H, m) ______________________________________ NMR 1.9-2.1(4H, m)       3.0-3.1(4H, m) 3.2-3.3(2H, m)       3.7-3.8(1H, m) 7.18(2H, dd, J=8, 8Hz) 7.2-7.5(10H, m) 7.92(2H, dd, J=10, 8Hz) ______________________________________ nitrile MS                 536(M+) NMR 0.86(3H, d, J=8Hz) 1.0-3.8(14H, m) 3.88(3H, s)        3.96(3H, s) 6.87(1H, d, J=8, 2Hz) 6.92(1H, d, J=2Hz) 6.99(1H, dd, J=8, 2Hz) 7.18(2H, dd, J=8, 8Hz) 7.90(2H, dd, J=10, 8Hz) ______________________________________ MS          369(M+) ______________________________________

Female Guinea Pigs, weighing 250-350 g, were anesthetized with urethane. The lead II ECG was continuously recorded.

Drugs, compound 1 and compound 2, were dissolved in the 2.5% nicol 2.5% ethanol solution, and injected into the femoral vein.

After 30 min of drug injection ouabain was infused intravenously through the left femoral vein at a rate of 10 ug/kg/min.

The time, ventricular premature contractions (VPC) ventricular fibrillation (VF) and cardiac arrest (CA) appeared on ECG, were measured, and the cumulative ouabain dosage to induce ventricular premature contractions, ventricular fibrillation and cardiac arrest, respectively, was calculated.

The results are summarized in Table 1.

Mongrel dogs of either sex, weighing 8-20 kg, were anesthetized with pentobarbitone sodium, 30 mg/kg. The lead II ECG, atrial electrogram from catheter tip electrodes in the right atrium, and blood pressure were continuously recorded. Ouabain 40 ug/kg was injected intravenously and with an additional 10 ug/kg every 20 min until stable ventricular arrhythmias were produced. The severity of arrhythmia was expressed by the arrhythmic ratio i.e. number of ventricular ectopic beats divided by the total heart rate. The arrhythmic ratio was calculated for 60 min after bolus intravenous administration.

The results are summarized in Table 2.

Mongrel dogs of either sex, weighing 8-20 kg, were anaesthetized initially with thiopentone sodium. After incubation, 1.0% halothane, vaporized with 100% 02, was administered with volume limited ventilator. Adrenaline was infused through the left femoral vein at the rate of 2.5-5 ug/kg/min. After 3 min of adrenaline infusion, drugs were injected into the right femoral vein. The lead II ECG, atrial electrogram from catheter tip electrodes in the right atrium and blood pressure were continuously recorded. The severity of ectopic beats divided by the total heart rate. The arrhythmic ratio was calculated for 15 min after drug administration.

The results are summarized in Table 3.

Three mice were subjected to one group experiment.

Drugs were administered with intraperitoneal injection in three mice 30 min before deep chloroform anaesthesia. If less than two mice displayed cardiac arrhythmia or tachycardia, above 200 beats/min, when exposed to deep chloroform anaesthesia, the drug was judged as having an antiarrhythmic effect.

The results are summarized in Table 4. ______________________________________ Dose       VPC      VF       CA Compound # (mg/kg)    (.mu.g/kg) (.mu.g/kg) (.mu.g/kg) ______________________________________ control             153      221      324 9       1          169      236      294 10       1          166      245      304 11       1          163      256      304 13       1          169      253      299 14       1          144      333      416 16       1          172      217      273 17       1          184      275      380 18       1          203      330      395 20       1          181      366      420 21       1          163      334      393 22       1          178      346      409 23       0.3        142      442      499 24       1          168      250      306 25       1          155      269      326 27       1          163      255      309 28       1          150      291      348 29       1          159      288      344 30       1          145      279      358 31       1          113      271      349 32       1          212      308      374 33       1          152      606      646 34       1          125      556      579 35       1          159      342      413 36       1          149      344      399 37       1          160      298      368 38       1          175      357      427 39       1          254      334      422 40       1          170      321      372 41       1          152      295      357 42       1          225      386      454 43       1          203      372      469 44       3          205      617      656 45       1          147      335      389 46       1          180      347      431 47       1          240      265      351 48       1          212      247      334 49       1          140      311      380 51       1          146      259      344 52       3          205      441      476 53       3          202      398      458 54       1          193      264      350 55       1          175      320      374 56       3          187      254      309 57       1          136      280      346 58       3          174      384      448 59       1          203      367      419 60       1          186      534      586 61       1          232      294      356 62       1          186      389      454 63       1          211      322      398 64       1          121      309      365 65       1          146      325      381 66       3          164      264      312 67       3          155      193      245 69       3          185      202      274 70       1          153      373      432 72       1          171      282      363 74       1          182      239      289 75       1          178      257      305 76       1          196      205      274 77       1          179      310      369 78       1          154      279      337 79       1          172      302      358 80       1          200      329      383 81       1          183      267      329 82       1          160      285      339 83       1          176      261      305 84       1          168      277      335 85       1          184      270      318 86       1          162      240      292 87       1          199      260      305 88       1          185      254      318 89       1          204      257      312 90       1          178      228      273 91       1          169      286      338 94       1          178      301      357 95       1          174      264      305 96       1          178      264      312 97       1          134      332      397 98       1          160      318      370 100      1          185      275      355 101      1          161      221      293 102      1          163      246      297 103      1          184      308      351 104      1          168      244      311 106      1          199      312      362 ______________________________________ ______________________________________ time after   Arrhythmic Ratio administration Compound #23 Compound #75 (min)        30 ug/kg     300 ug/kg ______________________________________ 0            1.00         1.00 2            1.00         0.80 4            1.00         0.71 6            0.60         0.41 8            0.77         0.19 10           0.50         0.19 12           0.50         0.43 15           0.50         0.43 20           0.00         0.38 30           0.00         0.45 60           0.00         0.45 ______________________________________ ______________________________________ time after   Arrhythmic Ratio administration Compound #23 Compound #75 (min)        10 ug/kg     300 ug/kg ______________________________________ 0            1.00         1.00 2            0.80         0.66 4            0.50         0.41 6            0.00         0.18 8            0.00         0.08 10           0.00         0.07 12           0.00         0.07 15           0.00         0.00 ______________________________________ ______________________________________ mimimum effective Compound #    dose (mg/kg) ______________________________________ 107           100 108            50 109           100 110           100 111           100 112           100 113            10 114            25 115            50 ______________________________________

## Claims

1. A method of reducing or eliminating cardiac arrhythmia, comprising administering orally or parenterally an effective amount of a piperidine derivative of formula (I) or a pharmaceutically acceptable salt thereof: ##STR9## wherein ##STR10## wherein B is benzene; ##STR11## X is ##STR12## wherein R.sup.1 and R.sup.2 are the same or different and are independently selected from hydrogen, methyl, ethyl or propyl; Q is phenyl, cyclohexyl or 1-hexyl; from 1 to 3 hydrogen atoms in Q may be independently substituted by alkyl of from 1 to 3 carbon atoms, perfluoroalkyl of from 1 to 3 carbon atoms, acylamino of from 1 to 6 carbon atoms, perfluoroacylamino of from 1 to 3 carbon atoms, alkoxy of from 1 to 3 carbon atoms, alkanesulfonylamino of from 1 to 3 carbon atoms, perfluoroalkanesulfonylamino of from 1 to 3 carbon atoms, acetoxy of from 1 to 3 carbon atoms, aminocarbonyl, aminosulfonyl, fluoro, chloro, cyano, hydroxy, nitro, amino, imidazolylmethyl, cinnamoylamino, p-fluorobenzoyl, cyanomethyl, cyanoethyl, methoxyacetoxy or alkoxycarbonyl of from 1 to 3 carbon atoms;

2. A method of reducing or eliminating cardiac arrhythmia, comprising administering orally or parenterally an effective amount of a piperidine derivative, or pharmaceutically acceptable salt thereof, selected from the group consisting of: iperidine, 4-(5H-dibenzo[a,b]cyclohepten-5-ylidene)-1-(4-nitrocinnamyl)piperidine, 1-(4-aminocinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, 1-(4-acetylaminocinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidi ne, 3-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene]-1-piperidinyl]-1-(4-nitropheny l)propane, 1-(4-aminophenyl)-3-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidiny l]propane, 1,-(4-acetylaminophenyl)-3-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-pip eridinyl]propane, N-[3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl]propanoyl-3,4-di methoxyanilide 1-(N-acetyl-4-piperidinyl)-3-[4-(5H-dibenzo[a,]cyclohepten-5-ylidene)-1-pi peridinyl]propane, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(2,4-dimethoxycinnamyl)piperidi ne, 1-(4-cyanocinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, 1-cyclohexyl-4-[4-(10,11-dihydroxy-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1 -piperidinyl)butane, 4-(5H-benzo[a,d]cyclohepten-5-ylidene)-1-(4-propanoylaminocinnamyl)piperid ine, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(4-ethoxycarbonylaminocinnamyl) piperidine, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(4-methanesulfonylaminocinnamyl )piperidine, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(3-methoxycarbonylcinnamyl)pipe ridine, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(4-methoxycarbonylaminocinnamyl )piperidine, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(4-pivaloylaminocinnamyl)piperi dine, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(4-trifluoroacetylaminocinnamyl )piperidine, 1-(4-butanoylaminocinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperi dine, 1-(4-ethoxycarbonylaminocinnamyl)-4-(4-fluorobenzoyl)piperidine, 4-(4-fluorobenzoyl)-1-(4-methoxycarbonylaminocinnamyl)piperidine, 4-(4-fluorobenzoyl)-1-(4-propanoylaminocinnamyl)piperidine, 4-(4-fluorobenzoyl)-1-(4-trifluoroacetylaminocinnamyl)piperidine, 1-(4-acetylaminocinnamyl)-4-(4-fluorobenzoyl)piperidine, 1-(4-aminocinnamyl)-4-(4-fluorobenzoyl)piperidine, 4-(4-fluorobenzoyl)-1-(4-nitrocinnamyl)piperidine, 1-(4-aminocarbonylcinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperi dine, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(4-trifluoromethylcinnamyl)pipe ridine, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(4-cyanomethylcinnamyl)piperidi ne, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(3,4-dichlorocinnamyl)piperidin e, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(3,4-dimethoxy-2-nitrocinnamyl) piperidine, 4-(5H-dibenzo[a,d]-cyclohepten-5-ylidene)-1-(2,5-dimethoxycinnamyl)piperid ine, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(2,3-dimethoxycinnamyl)piperidi ne, 4-(5H-dibenzo[a,d]cycohepten-5-ylidene)-1-(3,5-dimethoxycinnamyl)piperidin e, 4(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(2-methoxycinnamyl)piperidine, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(3-methoxycinnamyl)-piperidine, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(4-methoxycinnamyl)piperidine, 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1(4-nitrocinnamyl)p iperidine, 1-(4-aminocinnamyl)-4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene) piperidine, 1-(4-acetylaminocinnamyl)-4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl idene)piperidine, 4-(5H-dibenzo[a,d]cyclohepten-4-ylidene)-1-(4-fluorocinnamyl)piperidine, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(4-hydroxycinnamyl)piperidine, 1-(4-acetoxycinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, 4(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1(4-hydroxy-3-methoxycinnamyl)pipe ridine, 1-(4-acetoxy-3-methoxycinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)pi peridine, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(3-hydroxycinnamyl)piperidine, 1-(3-acetoxycinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-[3-(2-methoxyacetoxy)cinnamyl]p iperidine, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(2-methoxycarbonylcinnamyl)pipe ridine, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(4-methoxycarbonylcinnamyl)pipe ridine, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(3-methoxy-2-nitrocinnamyl)pipe ridine, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(4-ethoxycarboxycinnamyl)piperi dine, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(4-methoxyacetoxycinnamyl)piper idine, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(3,4-dihydroxycinnamyl)piperidi ne, 4-(10,11-dihydro-5-H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(2,4-aminosulfon ylcinnayml)-4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidin e, 1-(4-aminosulfonyl-.alpha.-methylcinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5 -ylidene)piperidine, 1-(4-aminosulfonyl-.beta.-methylcinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5- ylidene)piperidine, 1-(2-chlorobenzyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, 1-cyclohexyl-3-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl]pro pane, 1-cyclohexyl-4-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl]but ane, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-hexylpiperidine, 1-decyl-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, 5-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl]-2-(3,4-dichloro phenyl-2-isopropylvaleronitrile, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-[3-[2-(cinnamoylamino)phenylthi o]-1-propyl)piperidine, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-cinnamylpiperidine, 5-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl]-2,2-diphenylval eronitrile, 5-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl]-2-(3-trifluorom ethylphenyl)-2-isopropylvaleronitrile, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(2-fluorobenzyl)piperidine, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(4-fluorophenylethyl)piperidine , 5-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl]-2-(3-trifluoro methylphenyl)valeronitrile, 1-(3-aminobenzyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, 4-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl]-3',4'-dimethoxy butyrophenone, 1-(4-cyanobenzyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidine, 1-cyclohexyl-4-[4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-p iperidinyl]butane, cyclohexyl-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl]methane , 4(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(2,3-dimethoxybenzyl)piperidine , 3-cyanopropyl-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(3,4-dimethoxyphenacyl)piperidi ne, 1-cyclohexyl-6-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl]hex ane.

3. A method according to claim 1, in which the administration is an oral administration of a daily dose of from 0.001 to 2000 mg of the piperidine derivative or pharmaceutically acceptable salt thereof.

4. A method according to claim 1, in which the administration is a parenteral administration of a daily dose of from 0.001 to 1000 mg of the piperidine derivative or pharmaceutically acceptable salt thereof.

5. A method according to claim 1, in which the administration is of a unit dose of from 0.001 to 500 mg of the piperidine derivative or pharmaceutically acceptable salt thereof.