PT94599A - PREPARATION PROCESS OF PIPERIDINE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Description

-3- 71 169 ΟΡ 90043-5

DESCRIPTIVE MEMORY

Background of the Invention

Gamp-Q-Aa-Iny-gnt.o. The present invention relates to novel piperidine derivatives and their pharmacologically acceptable salts which have antihistaminic and antiallergic activity and are useful for the treatment of, for example, bronchial asthma, allergic rhinitis, dermatosis, and urticaria, and to their preparation process. The present invention also relates to the process for the preparation of a pharmaceutical composition comprising an effective amount thereof.

Description of Prior Art

Among the piperidine compounds containing a tricyclic ring substituent, for example, the dibenzocycloheptene ring or a dibenzoxepine ring at the 4-position of the piperidine ring, a compound such as cyproheptadine (The Merck Index, 11th edition, 2779: 4- (5H-dibenzo [a, d] cyclohepten-5-ylidene) -1-methylpiperidine) represented by the following formula:

has been developed as an antihistaminic agent and is widely used clinically for the treatment of disorders such as allergic rhinitis and dermatosis.

However, this class of compounds containing a carboxyl or lower alkoxycarbonyl group on the 1-position of the piperidine ring has never been known. IM large number of antihistaminic agents have been developed, so far,

71 169 ΟΡ 90043-5 -4- and are used for the treatment of, for example, allergic dermatosis or allergic rhinitis. However, adverse reactions of a central inhibitory action caused by the administration of the known antihistaminic agents such as drowsiness or sedation are considered as a major problem with these known agents. In addition, an anticholinergic action which is considered to be one of the possible approaches for anadipsia or mydriasis, is another undesirable adverse reaction of the antihistaminic agents. Various types of research have been conducted to solve the above problems, however, presently available antihistaminic agents are clinically insufficient.

Summary of the Invention

It is an aim of the present invention to provide novel compounds having excellent antihistamine activity as well as excellent antiallergic activity.

Another object of the present invention is to provide novel compounds that extensively eliminate undesirable adverse reactions such as a central inhibitory action when administered for the treatment of disorders such as bronchial asthma, allergic rhinitis, dermatosis and urticaria.

A further object of the present invention is to provide a process for the preparation of the foregoing new compounds. Yet another object is to provide a pharmaceutical composition comprising the novel compounds which is useful in the treatment of disorders such as bronchial asthma, allergic rhinitis, dermatosis and urticaria.

The inventors of the present invention employ various studies to achieve the above objects and have found that the objects can actually be achieved by providing novel piperidine derivatives of the present invention.

These derivatives have potent antihistamine and anti-allergic activities and induce rare adverse reactions, such as central inhibition. 71 169 ΟΡ 90043

5-

In accordance with the above objects, the present invention provides a piperidine derivative represented by the following general formula (I):

N-Y-C00R (I) in which R represents a hydrogen atom or a lower alkyl group; X represents -CH = CH-, -CH 2 CH 2 -, or -CH 2 O; Y represents an alkylene group containing 1 to 5 carbon atoms which may be optionally substituted with a lower alkyl group, or Y is -OB- in which A and B are the same or different and each independently of the other, represents an alkylene group containing 1 to 3 carbon atoms which may be optionally substituted with a lower alkyl group, and pharmacologically acceptable salts of the above compounds.

According to another embodiment of the present invention, the present invention provides a process for the preparation of a piperidine derivative represented by the general formula (I). The process comprises the steps of reacting a piperidine derivative represented by the following general formula (II):

(II) in which X is the same as defined above, with a compound represented by Z-Y-COOR (IIIa) or CH2 = CH-C00R (IIIb), in which R and Y are the same as defined above, and Z represents

A halogen atom, in a solvent or without solvent, and in the presence or absence of a base as an acid scavenger, followed by the step of hydrolysis in a solvent using an acid or a base if necessary .

According to yet another embodiment, the present invention provides an antihistamine and antiallergic agent comprising an effective amount of a piperidine derivative represented by the general formula (I).

According to a further embodiment, the present invention provides a pharmaceutical composition for the treatment of an allergic disease comprising an effective amount of a compound represented by the general formula (I). The invention also provides a process for the treatment of an allergic disease comprising the step of administering to a mammal an effective amount of a piperidine derivative represented by the general formula (I), a pharmacologically acceptable salt of the above compound, an antihistaminic and antiallergic agent comprising the same, or a pharmaceutical composition comprising the same.

Additional objects, features and advantages of the present invention will be apparent from the following Description of Preferred Embodiments, when read with reference to the accompanying examples.

Detailed Description of the Preferred Embodiments The present invention provides a piperidine derivative represented by the following general formula (I):

a) -7- 71 169 ΟΡ 90043-5 in which R represents a hydrogen atom or a lower alkyl group; X represents -CH = CH-, -Cl-Cl-Cl-, or -CH 2 O-; Y represents an alkylene group containing 1 to 5 carbon atoms which may optionally be substituted with a lower alkyl group, or Y is -A-O-B- in which A and B are the same or different and each independently of the another represents an alkylene group containing 1 to 3 carbon atoms which may be optionally substituted with a lower alkyl group. The present invention also provides pharmacologically acceptable salts of the foregoing compounds. Additionally, the present invention provides a process for the preparation of the compounds of formula (I), and a pharmaceutical composition comprising an effective amount thereof, together with a pharmaceutically acceptable carrier or coating.

In the general formula (I) above, the lower alkyl group represented by R or the lower alkyl group which may be a substituent of the alkylene group represented by Y, A or B may be, for example, a methyl, ethyl, n-propyl group , isopropyl, n-butyl, isobutyl, or tert-butyl.

Preferred examples of the present invention include: 4- (5H-dibenzo [a, d] cyclohepten-5-ylidene) -1-piperidineacetic acid; 4- (5H-dibenzo [a, d] cyclohepten-5-ylidene) -1-piperidinepropionic acid; 4- (5H-dibenzo [a, d] sky-hepten-5-ylidene) -1-piperidinebutyric acid; 4- (5H-dibenzo [a, d] cyclohepten-5-ylidene) -1-piperidinovaleric acid; 4- (5H-dibenzo [a, d] cyclohepten-5-ylidene) -1-piperidinecarboxylic acid; 2- [4- (5H-dibenzo [a, d] cyclohepten-5-ylidene) piperidine] ethoxyacetic acid; 4- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-ylidene) -1-piperidineacetic acid; 4- (10,11-dihydro-5H-dibenzo [a, d] isohepten-5-ylidene) -1-piperidinepropionic acid;

4- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-ylidene) -1-piperidinebutyric acid; 4- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-ylidene) -1-piperidinovaleric acid; 4- (10,11-dihydro-5H-dibenzo [a, d] sky-hepten-5-ylidene) -1-piperidinecaproic acid; 2- [4- (5H-dibenzo [a, d] cyclohepten-5-ylidene) piperidine] ethoxyacetic acid; 4- (dibenz [b, e] oxepin-11 (6H) -ylidene) -1-piperidineacetic acid; 4- (dibenz [b, e] oxepin-11 (6H) -ylidene) -1-piperidinopropionic acid; 4- (dibenz [b, e] oxepin-11 (6H) -ylidene) -1-piperidenebutyric acid; 4- (dibenz [b, e] oxepin-11 (6H) -ylidene) -1-piperidenovaleric acid; 4- (dibenzo [b, e] oxepin-11 (6H) -ylidene) -1-piperidenecaproic acid; 2- [4- (dibenz [b, e] oxepin-11 (6H) -ylidene) piperidino] ethoxyacetic acid; Ethyl 4- (5H-dibenzo [a, d] cyclohepten-5-ylidene) -1-piperidinopropionate, 2- [4- (5H-dibenzo [a, d] cyclohepten-5-ylidene) piperidine ] ethoxyacetate; Ethyl 4- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-ylidene) -1-piperidinopropianate; Ethyl 4- (dibenz [b, e] oxepin-11 (6H) -ylidene) -1-piperidineacetate; and 2- [4- (dibenz [b, e] oxepinyl) (6H) -ylidene) piperidine] ethoxyacetate.

Compounds of the present invention represented by the foregoing general formula (I) may be converted into pharmacologically acceptable salts, if desired, and may then be reconverted to produce the free compound from the salts obtained.

The pharmacologically acceptable salts of the compounds of the present invention represented by the general formula (I) may be acid addition salts or base addition salts. Examples of acid addition salts include those of mineral acids such as, for example, hydrochloride, hydrobromide, sulfate, nitrate and phosphate, and salts of organic acids such as, for example,

71 169 ΟΡ 90043-5 acetate, maleate, fumarate, malate, citrate, oxalate, lactate and tartrate. Examples of base addition salts include metal salts such as, for example, sodium, potassium and calcium salts, and salts of organic bases such as, for example, ammonium salts, methylamine salts, ethylamine, dimethylamine, triethylamine, ethanolamine, piperidine, and piperazine. The compound of the present invention represented by the foregoing general formula (I) may have one or more asymmetric carbon atoms in the molecule, and accordingly, optically active and diastereomeric isomers may exist. These isomers, as well as the racemate and the mixture of diastereoisomers, are incorporated within the scope of the present invention.

The novel piperidine derivatives of the present invention represented by the above general formula (I) may be prepared by reacting a piperidine derivative represented by the following general formula (II):

(II) in which X is the same as defined above, with a compound represented by ZY-COOR (IIIa) or CH 2 CHCGOR (IIIb) in which R 1 and Y are the same as defined above and Z represents a halogen atom, in the presence or absence of a base as an acid scavenger, followed by the step of hydrolysis in a solvent, using an acid or base, if necessary.

Any solvent inert in the alkylation process of the present invention may be used. Examples of the inert solvent include benzene, toluene, tetrahydrofuran, dioxane, acetone, acetonitrile, methanol, ethanol, isopropanol, n-butanol, dimethyl-

sulfoxide, and Ν, Ν-dimethylformamide.

Examples of the base used in the process of the present invention include potassium carbonate, sodium carbonate, pyridine, and triethylamine. The reaction can be carried out at a temperature of 0 to 200 ° C.

For the hydrolysis process an acid such as, for example, hydrochloric acid or sulfuric acid, or a base such as, for example, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, or bicarbonate of sodium. A solvent used in the hydrolysis may be, for example, water, methanol, ethanol, acetone, or tetrahydrofuran, and the hydrolysis may be carried out at a temperature of 0 to 100 ° C.

In addition, the compounds represented by the above general formula (II), used as starting materials for the above process, are known compounds described in Journal of Medicinal Chemistry, & 829 (1965) and Japanese Patent Application Laid-Open No. . 18478/1975 which have not yet been examined and can be readily prepared by the following procedure:

(II) in which X represents the same as defined above, Z 'represents a halogen atom, and R' represents a lower alkyl group. The novel piperidine compound of the present invention represented by the foregoing general formula (I) and its pharmacologically acceptable salt has excellent antihistaminic and antiallergic activity and is therefore very useful for the

Treatment of an allergic disease, such as, for example, bronchial asthma, allergic rhinitis, dermatosis and urticaria.

The piperidine compounds of the present invention and their pharmacologically acceptable salts may be administered to a patient orally or parenterally in the form of a pharmaceutical composition which comprises an effective amount of the aforesaid compound or the salt thereof, together with a carrier or coating pharmaceutically acceptable salts. The pharmaceutical composition suitable for oral administration may be, for example, tablet, capsule, powder, refined granule, granule, solution or syrup. The pharmaceutical composition suitable for parenteral administration may be injection, suppository, inhalant, eye drops, nasal drops, ointment, or poultice. The pharmaceutically acceptable carrier or coating used for the preparation of the pharmaceutical composition may be excipient, disintegrant, or disintegrating accelerating agent, binding agent, lubricant, coating agent, pigment, diluent, base, solubilizing agent, solubilizer, isotonicity agent , pH adjusting agent, stabilizer, propellant and tackifier.

For the preparation of the pharmaceutical composition suitable for oral administration, dermal administration, or mucosal application, the coating or vehicle may comprise the following: an excipient such as, for example, glucose, lactose, D-mannitol, starch, or crystalline cellulose; a disintegrant or an accelerating agent for disintegration such as, for example, carboxymethylcellulose, starch, or carboxymethylcellulose calcium; a binder such as, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, or gelatin; a lubricant such as, for example, magnesium stearate or talc; a coating agent such as, for example, hydroxypropylmethylcellulose, sucrose, polyethylene glycol, or titanium oxide; a base such as, for example, petroleum jelly, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, or heavy fat; a propellant such as, for example, freon diethyl ether, or compressed gas; an adherent such

Such as, for example, sodium polyacrylate, polyalcoolvinicol, methylcellulose, polyisobutylene, or polybutene; or a laminated base such as a plastic sheet or sheet. The pharmaceutical composition suitable for injection may comprise the following: a solubilizing agent or a solubilizer, e.g., distilled water for injection, saline, or propylene glycol which is useful for an aqueous composition or a composition for preparing aqueous solutions prior to use; an isotonicity agent such as, for example, glucose, sodium chloride, D-mannitol, or glycerin; and a pH adjusting agent such as, for example, an inorganic or organic acid or an inorganic or organic base. The dose of the pharmaceutical composition of the present invention for an adult patient may generally be 1 to 300 mg per day for oral administration, which may be increased or decreased depending on the conditions of the patient being treated. The present invention will be further illustrated by the following examples and reference examples. The examples are given purely as an illustration and should not be construed as limiting.

Examples

The following examples show the excellent effectiveness of the compounds of the present invention. Results of 48 h of passive cutaneous anaphylaxis, homologous (PCA) in rats with anti-allergic activity control; and the results of potentiation of hexobarbital induced anesthesia in mice with central nervous depressant activity control are summarized in table 1. The reference compound used was eiproheptadine hydrochloride. Cutaneous anaphylaxis due to homologous cutaneous anaphylaxis. (PCA) in. rats, a) Preparation of DNP-As and anti-DNP-As serum from rats.

Ascaride extract coupled with a 2,4-dinitrophenyl group (DNP-As) was prepared by the method of Koda et al. (Folia pharmacol., Japanese, 78, 319-334, 1981); and anti-DNP-As was prepared

71 169 ΟΡ 90043-5-13 containing serum IgE antibodies by the method of Tada and Okumura (J. Immunol., 106, 1019, -1025, 1971). The PCA titre of the antiserum was estimated at 1:12 for 48 h of PCA in rats. b) 48 h of passive cutaneous anaphylaxis homologous (PCA) in rats.

Male Wistar rats weighing 160-200 g were passively sensitized by intradermal injection on the back of 0.05 ml of anti-DNP-As serum diluted 21-fold with saline. After 48 h, the animals (18-20 H in fasted) were given 0.5 ml of 1% Evans blue solution containing 1 mg of DNP-As. After 30 min. The animals were killed by stunning and the hides were removed. The intensity of the response was assessed by analyzing the amount of staining lost according to the method of Katayama et al. (Microbiol, Immunol 22, 89-101, 1978). The percent inhibition of PCA was calculated using the following formula:

Amount of colouration - Amount of colon lost with control diet lost with test compound

Percent inhibition = _ X 100

Amount of staining lost with control

Test compounds were given orally at a dose of 1 mg / kg, 1 h prior to antigen challenge. As a control, 5 ml / kg vehicle (0.5% CMC) was given alone, similarly.

The results are shown in Table 1. 2. Potentiation. induced hexobarbital sorption in mice.

The loss of equilibration reflexes induced by hexobarbital was used as the anesthesia index. Groups of 8 male ddY mice (20-24 h in a fasted state) were weighed orally with the test compounds (30 mg / kg) or veiole weighing 19 to 27 g. Thirty min.

71 189 ΟΡ 90043-5 then i.p. in animals, 80 mg / kg of sodium hexobarbital, and the duration of loss of the equilibrium reflex was observed. The percentage increase in sleep time was calculated using the following formula:

Sleep time with _ Sleep time the test compound with the control

Percent increase = _ X 100

Sleep time with control

The results are listed in Table 1.

Table 1

Test Compound

Percent inhibition of PCA in rats (%, 1 mg / kg, p.o)

Percent increase of hexobarbital-induced anesthesia in mice (%, 30 mg / kg, p.o.)

Example 1 71 106 Example 21 91 29 Example 22 81 37 Example 23 81 51 Example 24 87 75 Example 25 78 80 Example 26 59 22 Example 28 89 83 Example 29 94 45 Example 30 91 53 Example 31 59 36 Example 32 77 15 Example 33 91 39 Example 34 69 31 15-71 169 ΟΡ 90043-5

Example 35 85 76 Example 36 54 34 Example 37 85 49 Example 38 83 41 Example 39 78 80 Reference compound 47 203

The present compounds exhibited a more potent antiallergic activity and less potent central nervous depressant activity than the reference compound.

Reference 1 Ethyl 4- (5H-dibenzomethyl) hepten-5-ylidene, < RTI ID = 0.0 >

A mixture of 33 g of 4- (5H-dibenzo [a, d] cyclohepten-5-ylidene) -1-methylpiperidine, 74.9 g of ethyl chlorocarbonate and 170 ml of toluene. After cooling, the reaction mixture was washed with hydrochloric acid and water, and then dried and concentrated. The residue was solidified by treatment with n-hexane to give 37.4 g of pale yellow crystals, which were recrystallized from ethanol to give slightly yellow needles, m.p. 123-124 ° C.

Analysis for C 23 H 23 NO 2

Calc'd C, 79.97; H, 6.71; N, 4.05

Found: C, 80.24; H, 6.73; N, 3.95.

Reference compounds 2 to 3 were prepared in the same manner as described in reference 1.

Reference 2 Ethyl 4- (10,11-dihydro-5H-dibenzomer.d1cyclohepten-5-ylidene) -1-piperidinecarboxylate.

71 169 ΟΡ 90043-5

Yellow Liquid

Mass spectrum m / z: 347 (M +).

IR spectrum (?) Cm-1: 1700 (COO).

NMR Spectrum δ (CDCl 3) ppm: 1.25 (3H, t, J = 7Hz), 2.36 (4H, t, J = 6Hz), 2.60-3.96 (8H, m) 14 (2H, q, J = 7Hz), 6.97-7.31 (8H, m).

(3,4-dichlorophenyl) piperazin-1 (6H) -ylidene) -1-piperidinecarboxylate

Pale yellowish brown liquid Mass spectrum m / z: 349 (M +).

IR spectrum (ν): 1700 (COO).

NMR Spectrum δ (CDCl 3) ppm: 1.25 (3H, t, J = 7Hz), 2.20-4.03 (8H, m), 4.14 (2H, q, J- (1H, d, J = 12Hz), 5.69 (1H, d, J = 12Hz), 6.70-7.50 (8H, m).

Re. Ser. No. 4, 4, 5H-d ib en z ο Γ a. d 1 e i o - h &p; en-5-ylidene-piperidine

A mixture of 65.6 g of ethyl 4- (5H-dibenzo [a, d] cyclohepten-5-ylidene) -1-piperidinecarboxylate, 32.0 g of potassium hydroxide and 250 ml of n-butanol and concentrated. Water was added to the residue and extracted with toluene. The toluene phase was washed with water, dried and concentrated to give 53.2 g of pale yellow solid, which was recrystallized from methanol to give 47.9 g of colorless needles, mp 145-147øC .

Calc'd for C 20 H 20 N:

Calc'd C, 87.87; H, 7.01; N, 5.12

Found: C, 87.81; H, 7.00; N, 5.07

Reference compounds 5 and 8 were prepared in the same manner as described in reference 4. 90043-5

Reference 5.

4- (10-Dihydro-5H-dibenzomethyl) hepten-5-ylidenepyridine hydrochloride Colorless slides, mp> 300 ° C (MeOH).

Analysis for C 21 H 21 N. HCl:

Calc'd C, 77.03; H, 7.11; N, 4.49

Found: C, 77.00; H, 7.12; N, 4.47.

Reference 6

4-fibenzo [e] oxy) -Phenyl-11 (8H) -ylidenyl]

Colorless prisms, mp> 308 ° C (EtOH).

Analysis for C19 H11 NO4. HCl:

Calc'd C, 72.72; H, 6.42; N, 4.46.

Found: C, 72.72; H, 6.51; N, 4.27.

Example 1

4- (5H-Dibenzo [b] thio-hepten-5-ylidene) -1-piperidinecarbonitrile hydrochloride.

A mixture of 3.01 g of 4- (5H-dibenzo [a, d] cyclohepten-5-ylidene) piperidine was stirred at 80 ° C for 4 h, 2.20 g of 3-bromopropionate ethyl acetate, 1.52 g of potassium carbonate and 20 ml of N, N-dimethylformamide.

After cooling, water was added to the reaction mixture and then extracted with ether. The extract was washed with water, dried and concentrated to give 4.40 g of brown liquid, which was converted to the hydrochloride in the usual manner to give 4.20 g of colorless crystals. The crude hydrochloride was recrystallized from a mixture of acetone and ether to give colorless needles, mp 151-152 ° C.

Analysis for C25 H27 NO2. HCl. H20: Calculated C, 70.16; H, 7.07; N, 3.27

Found: C, 70.26; H, 6.99; N, 3.01

71 169 ΟΡ 90043-5 -18-

Example 2 Methyl 2- [4- (5H-dibenzo [a, d] cyclohepten-5-ylidene) piperidino] ethoxyacetate fumarate

A mixture of 3.01 g of 4- (5H-dibenzo [a, d] cyclohepten-5-ylidene) piperidine, 2.90 g of 2- oloroethoxyacetate, 2.43 g of potassium carbonate and 20 ml of Ν, Ν-dimethylformamide. After cooling, water was added to the reaction mixture and then extracted with ether. The ether phase was extracted with " The aqueous phase was made basic with potassium carbonate and extracted with ether. The ether phase was washed with water, dried and concentrated to give 3.16 g of yellowish brown liquid which was converted to the fumarate in the usual manner and then recrystallized from ethanol to give pale yellow needles , mp 175-176 ° C.

Analysis for C 25 H 27 N 3 O 4:

Calc'd C, 68.90; H, 6.18; N, 2.77.

Found: C, 68.76; H, 6.22; H, 2.68

Example 3

Ethyl 4- (10,11-dihydro-5H-dibenzo [a] cyclohepten-5-ylidene) -1-piperidinebutyrate hydrochloride

A mixture of 3.00 g of 4- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-ylidene) piperidine was stirred at 70 ° C for 3 h. 2.34 g of ethyl 4-bromobutyrate, 1.51 g of potassium carbonate and 18 ml of Ν, Η-dimethylformamide. After cooling, water was added to the reaction mixture and then extracted with ether. The ether layer was washed with water, dried and concentrated to give a pale brown solid, which was converted to the hydrochloride in the usual manner to give 3.88 g of colorless solid. The crude hydrochloride was recrystallized from a mixture of acetone and ether to give colorless crystals, mp 182-184 ° C. 71 169 ΟΡ 90043-5

-19-

Calc'd for C 26 H 31 N 2 O 2. HCl:

Calc'd C, 73.31; H, 7.57; N, 3.29.

Found: C, 73.27; H, 7.70; N, 3.33.

Example. 4. Ethyl 4-dibenz [e] oxyepin-HCl-1-ylidene-1-pyrazinopropionate

A mixture of 3.61 g of 4- (dibenz [b, e] oxepin-11 (6H) -ylidene) piperidine, 2.60 g of ethyl 3-bromopropionate , 1.80 g of potassium carbonate and 25 ml of Ν, Ν-dimethylformamide. After cooling, water was added to the reaction mixture and extracted with ether. The ether layer was washed with water and extracted with hydrochloric acid. The aqueous phase was made alkaline with potassium carbonate and extracted with ether. The ether phase was washed with water, dried and concentrated to give 4.20 g of yellowish brown liquid, which was purified by silica gel column chromatography (eluent: chloroform) to give 3.90 g of pale yellow liquid.

Mass spectrum m / z: 377 (M +).  € ƒâ € ƒâ € ƒIR spectrum (v1) cm-1: 1734 (COO). 1 H-NMR (CDCl 3) ppm: 1.25 (3H, t, J = 7 Hz),

12Hz), 6.66-7.48 (8H, m)

Example 5

Ethyl 4- (dibenzabicyclohexyl) -11β-ylidene) -1-piperidinovalerate hydrochloride.

A mixture of 3.61 g of 4- (dibenz [b, e] oxepin-11 (6H) -ylidene) piperidine, 3.00 g of 5-bromo- ethyl valerate, 1.80 g of potassium carbonate and 25 ml of Ν, Ν-dimethylformamide. After cooling, water was added to the reaction mixture and extracted with ether. The ether phase was washed with water, dried and concentrated to give 5.40 g of liquid 71 189 ΟΡ 90043-5

Which was converted to the hydrochloride in the usual manner to give 4.76 g of colorless crystals. The crude hydrochloride was recrystallized from ethanol to give colorless needles, mp 228-230 ° C.

Calc'd for C 21 H 31 NO 3. HCl:

Calc'd C, 70.65; H, 7.30; N, 3.17.

Found: C, 70.76; H, 7.05; N, 3.22.

The compounds of Examples 6 to 19 were prepared in the same manner as described in Examples 1 to 5.

Example 6. 4- (5H-Dibenzo [b] cyclohepten-5-ylidene) -1-pyridinoacetate. attila Pale brown liquid. Mass spectrum m / z: 359 (M +). IR spectrum (ν): 1746 (COO). 1 H-NMR (CDCl 3) ppm: 1.24 (3H, t, J = 7 Hz)

Example 7

4- (5H-dibenzyl, cyclohepten-5-ylidene) -ethyl] -1-ethyl-1-piperidineacetic acid hydrochloride

Pale brown columns, mp 190-191 ° C (EtOH-Et2O). Analysis for C25 H27 NO2. HCl:

Calc'd C, 73.25; H, 6.88; N, 3.42.

Found: C, 73.10; H, 6.81; N, 3.31.

Example 8 Ethyl 4- (3,5-dibenzomidylcyclohepten-5-ylidene) -1-piperidinobutyrate

71 189 ΟΡ 90043-5 -21-

Yellowish brown liquid Mass spectrum m / z: 387 (M +) *

IR spectrum V (liq) cm -1 1734 (COO).

NMR (CDCl 3) δ ppm: 1.23 (3H, t, J = 7Hz), 1.56-2.80 (14H, m), 4.10 (2H, q, (2H, s), 7.10-7.45 (8H, m).

Example 9 Ethyl 4- (5H-dibenzo [d] cyclohepten-S-ylidene-1-p-piperidinecarboxylate

Pale yellow prisms, mp 185.5-186.5 ° C (EtOH-Et2 O). Calc'd for C 19 H 28 NO 6 úHCl Calc'd C, 74.04; H, 7.36; N, 3.20

Found: C, 74.04; H, 7.22; N, 3.14.

Example 10 Methyl (5H-dibenzo [a] dithiohepten-5-ylidene-1-yl) piperidinecarboxylate

Colorless columns, m.p. 200-201Â ° C (EtOH) analysis for C 27 H 31 NO 2. HCl:

Calc'd C, 74.04; H, 7.36; N, 3.20

Found: C, 73.82; H, 7.42; N, 3.10

Example 11

Ethyl 4- (10,11-dihydro-5H-dibenzo [a] thiohepten-5-ylidene) -1-piperidineacetate hydrochloride

Colorless crystals, m.p. 173-175Â ° C (Me2CO).

For C 24 H 27 NO 2. HCl:

Calc'd C, 72.44; H, 7.09; N, 3.52.

Found: C, 72.23; H, 7.17; N, 3.45.

Example 12 Ethyl 4 - [[(1,1,1-dihydro-5H-dibenzo [a] thiohepten-sylidene) -1-Piearidin-OP-pyrrooponate.

71 169 ΟΡ 90043-5 -22-

Colorless needles, m.p. 198-202 ° C (EtOH-Et2O).

Calc'd for C 25 H 29 N 2 O:

Calc'd C, 72.10; H, 7.38; N, 3.36.

Found: C, 72.04; H, 7.25; N, 3.33.

Example 13

Ethyl 4- (10,11-dihydro-5H-dibenzomethyl) cyclohepten-5-ylidene-1-1-pyroidinovalerate hydrochloride.

Colorless crystals, m.p. 183.5-185 ° C (Me2CO-Et2O). Analysis for C 27 H 33 N 3 O · HCl:

Calc'd C, 73.70; H, 7.79; N, 3.18.

Found: C, 73.40; H, 7.75; N, 3.22.

EXAMPLE 14 Methyl 2- (11,11-dihydro-5H-dibenzomethyl) -thiazole-5-ylidene-1-pyrimidinylethoxyacetate

Yellow Liquid

Mass Spectrum m / z: 391 (M +).

IR spectrum and (liq) cm -1 1758 (COO).

NMR Spectrum 3 (CDCl 3) ppm: 2.04-3.54 (12H, m), 2.63 (2H, t, J = 5.5Hz), 3.68 (2H, t, J = 5.5Hz ), 3.73 (3H, s), 4.12 (2H, s), 6.98-7.22 (8H, m).

Example 15

Ethyl 4- (dibenzyl, oxyepin-HCl-ylidenedol-1-Pyridine-4-carboxylate hydrochloride

Colorless needles, m.p. 153-154 ° C (EtOH-Et2O).

Analysis for C 23 H 25 NO 3. HCl. 1/2 H2O:

Calc'd C, 67.56; H, 6.66; N, 3.43.

Found: C, 67.61; H, 6.49; N, 3.45.

Example 16

4- (Dihydro-4-oxepin-1-yl) -ylidene) -1H-

71 169 ΟΡ 90043-5 ethyl hutirate

Colorless needles, m.p. 242-244 ° C (EtOH) Analysis for ¢ 25 ° C 29 H-3 HCl:

Calculated C, 70.16; H, 7.07; N, 3.27.

Found: C, 70.08; Η, 7.04; N, 3.16.

Exemplary Π 2-4-4- (dibenzyl) -oxoxyepin-11 (6H-1-ylidene) piperidine-1-ethoxyacetate of pale yellow liquid.

Mass spectrum m / z: 393 (M +).

IR spectrum and (liq) cm -1 1756 (COO).

NMR (CDCl3) ppm: 2.00-3.00 (10H, m), 3.68 (2H, t, J = 5.5Hz), 3.73 (3H, s), 4.11 2H, s), 4.76 (1H, d, J = 12Hz), 5.72 (1H, d, J = 12Hz), 6.64-7.46 (8H, m).

Example 18

Ethyl 4- (10,11-dihydro-5-H-dibenzo [b] diene-hepten-5-ylidene] -1-piperidinecarboxylate hydrochloride.

Colorless needles, m.p. 188-190 ° C (Me2CO).

Analysis for C27 H33 NO2 Â · HCl

Calc'd C, 73.70; H, 7.79; N, 3.18.

Found: C, 73.47; H, 7.74; N, 3.14

Example 19

4- (dibenzabicyclo [2.2.1] octane-6-ylidene) -piperidine-1-carboxylate

Colorless needles, m.p. 214-217Â ° C (Me2CO).

Analysis for C26 H31 NO3. HCl:

Calc'd C, 70.65; H, 7.30; N, 3.17.

Found: C, 70.61; H, 7.41; N, 3.31.

71 169 ΟΡ 90043-5

Example 20 4- (5H-dibenzo [b], d] cyclohepten-5-ylidene] -piperidin-

A mixture of 4.00 g of 4- (5H-dibenzo [a, d] cyclohepten-5-ylidene) piperidine, 2.1 ml of ethyl acrylate and 20 ml of ethyl acrylate was refluxed for 1 h. ethanol, and concentrated to give 5.35 g of colorless liquid. The liquid was purified by silica gel column chromatography (eluent: chloroform) to give 5.30 g of colorless solid, which was recrystallized from n-hexane to give colorless crystals, mp 66-67 ° C.

Analysis for C25 H27 NO2:

Calc'd C, 80.40; H, 7.29; N, 3.75.

Found: C, 80.35; H, 7.39; N, 3.77.

Example 21

4- (5H-Dibenzomethyl) cyclohepten-5-ylidene) -1-piperidinopropionic acid.

A mixture of 5.30 g of ethyl 4- (5H-dibenzo [a, d] cyclohepten-5-ylidene) -1-piperidinopropionate hydrochloride was refluxed for 1 hr, 19.3 ml of 2N aqueous sodium hydroxide solution, and 30 ml of methanol, and concentrated. Water was added to the residue, washed with ethyl acetate and adjusted to pH 4-5 with 10% hydrochloric acid. The precipitate was collected by filtration to give 4.47 g of pale yellow crystals, which were recrystallized from a mixture of water and N, N-dimethylformamide to give 4.23 g of pale yellow needles, mp 201-203 ° C.

Analysis for C 23 H 23 NO 2. 21 ^ 0:

Calc'd C, 72.42; H, 7.13; N, 3.67,

Found: C, 72.23; H, 6.94; N, 3.67. 71 169 ΟΡ 90043-5

-25-

Example 22

4- (5H-dibenzo [b] thio-hepten-5-

A mixture of 2.56 g of methyl 2- [4- (5H-dibenzo [a, d] cyclohepten-5-ylidene) piperidine] ethoxyacetate, 6.6 ml of aqueous 2N sodium hydroxide solution and 25 ml methanol, and concentrated. Water was added to the residue, adjusted to pH 2 with 10% hydrochloric acid and extracted with chloroform. The chloroform layer was washed with water, dried and concentrated to give a tan-yellow liquid, which solidified with a mixture of chloroform and ether to give 2.70 g of a pale yellow amorphous solid, mp 75 DEG- 80 ° C.

Analysis for C 24 H 25 NO 3 • HCl • H 2 O:

Calc'd C, 67.05; H, 6.56; N, 3.26.

Found: C, 66.99; H, 6.37; N, 3.04.

Example 23.

Hydrochloride of 4- (10,11-dihydro-5H-dibenz [b] cycloheptyran-5-yl] oxy] piperidine]

A mixture of 3.31 g of 4- (10,11-dihydro-5H-dibenzo [a, d] sky-hepten-5-ylidene) -1- piperidinobutyrate, 11.7 ml of 2N aqueous sodium hydroxide solution and 35 ml of methanol and concentrated. Water was added to the residue, adjusted to pH 1 with 10% hydrochloric acid. The precipitate was collected by filtration to give 2.97 g of brown solid, which was recrystallized from a mixture of ethanol and ether to give 2.48 g of colorless needles, mp 211.5-214.5 ° C.

Analysis for C 24 H 27 NO 2 • HCl •

Calc'd C, 72.44; H, 7.09; N, 3.52.

Found: C, 72.26; H, 7.04; N, 3.50.

71 169 ΟΡ 9οο43-5

Example 24 â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ4-CDIBenz Tb, and T oxo in-11C 610 - 1-yl) -1-piperid inOPrOP Ιόηΐ-βώ.

A mixture of 3.70 g of ethyl 4- (dibenz [b, e] oxopin-11 (6H) -ylidene) -1-piperidinopropionate, 9.9 ml of aqueous hydroxide solution of 2N sodium and 40 ml of methanol, and concentrated. Water was added to the residue, adjusted to pH 3 with 10% hydrochloric acid. The precipitate was collected by filtration and washed with water and ether to give 3.30 g of pale yellow crystals, which were recrystallized from a mixture of water and N, N-dimethylformamide to give 2.75 g of crystals pale yellow, mp 142-143 ° C.

Analysis for C22H23N2O2:

Calc'd C, 68.55; H, 7.06; N, 3.63.

Found: C, 68.82; H, 6.97; N, 3.62.

Example ...... 2

4- (dibenzyloxy) -pyridin-4-yl) -6- (6-O-ylidene) -1-piperidinovaleric acid.

A mixture of 4.20 g of ethyl 4- (dibenz [b, e] oxepin-11 (6H) -ylidene) -1-piperidinovalerate hydrochloride was refluxed for 1 hr, 14.5 ml of 2N aqueous sodium hydroxide solution and 40 ml of methanol, and concentrated. Water was added to the residue, adjusted to pH 2 with 10% hydrochloric acid. The precipitate was collected by filtration and washed with water and ether to give 3.92 g of colorless crystals, which were recrystallized from water to give 3.08 g of colorless prisms, mp 304-306øC (dec.). .).

Analysis for C 24 H 27 N (V + Cl:

Calc'd C, 69.64; H, 6.82; N, 3.38.

Found: C, 89.86; H, 6.62; N, 3.53. The compounds of examples 26 to 39 were prepared from the same

71 169 ΟΡ 90043-5 as described in examples 21 to 25.

Example 26

Hydrazone, 4- (5H-Dibenzo [b, d] cyclohepten-5-ylidene) -1-piperidinecarboxylic acid

Pale brown needles, p. 162-165 ° C <EtOH-Et2 O).

Calc'd for C 22 H 21 NO 2 - HCl .1 / 20-20:

Calc'd C, 70.11; H, 6.15; N, 3.72.

Found: C, 70.29; H, 6.23; N, 3.51.

Example 27

4- (5 H) -Dibenzo [b] [dia] hepten-5-ylidene) -α-methyl-1-Piperidinoacetic acid.

Pale brown columns, p. 184-186 ° C (MeOH-Et2O).

Analysis for C 23 H 23 NO 2 --H 2 O:

Calc'd C, 76.01; H, 6.93; N, 3.85.

Found: C, 76.11; H, 7.03; N, 3.87.

Example 28

Hydrochloride of 4-X5H-Pbenzo [d] cyclohepten-5-ylidene] -1-piperidinobutyric acid

Pale yellow prisms, mp 237-239 ° C (H2 O).

Calc'd for C 24 H 25 N 2 O 2 · HCl:

Calc'd C, 71.19; H, 6.72; N, 3.46.

Found: C, 71.46; H, 6.82; N, 3.37.

Example 29

4- (5H-Dibenzomethyl) cyclohepten-5-ylidene] -1-piperidineacetic acid hydrochloride

Pale brown needles, m.p. 229-230 ° C (EtOH-Et2 O). Analysis for C 25 H 27 N 2 O 2. HCl:

Calc'd C, 73.25; 6.88; N, 3.42.

Found: C, 73.25; H, 6.84; N, 3.30.

71 169 ΟΡ 90043-5 -28

Example 30

4- (5H-Dibenzomethyl) hepten-5-ylidenol-1-piperidinecaproic acid hydrochloride

Pale brown prisms, mp 213-214 ° C &lt; Et0 H-Et2 O). Calc'd for C 26 H 29 NO 2. HCl:

Calc'd C, 73.66; H, 7.13; N, 3.30.

Found: C, 73.37; H, 7.25; N, 3.26.

Example 31

Hydrochloride of 4- (1-fluorophenyl) -5H-indazol-4-yl) piperidinecarboxylic acid

Colorless crystals, m.p. 237.5-239 ° C (dec.) (EtOH-Et2O). For C 22 H 23 SO 2 · HCl:

Calc'd C, 71.44; H, 6.54; N, 3.79.

Found: C, 71.17; H, 6.81; N, 3.80.

Example 32

4- (10,11-Dihydro-5H-dibenzomethyl) cyclohepten-5-ylidene-1-piperidinopropionic acid

Colorless needles, m.p. 189-191Â ° C (DMF-H2 O).

For C 23 H 25 NO 2 5/2 H 2 O:

Calc'd C, 70.38; Η? 70; N, 3.57.

Found: C, 70.70; H, 7.40; N, 3.63.

Example 33

Hydrochloride_of_LCLQ_4-Γ10. dihydro-5H-dibenzo [a] dloxyhepten-5-ylidene] -1-piperidineacetic acid

Colorless needles, m.p. 204-206 ° C (H2 O).

 € ƒâ € ƒâ € ƒ1 H-NMR:

Calc'd C, 72.10; H, 7.38; N, 3.36.

Found: C, 72.20; H, 7.19; N, 3.33.

Exeimlo 34

2-T4- (10,11-Dihydro-5H-dibenzomethyl) cyclohepten-5-ylidene] hexydino] ethoxyacetic acid

71 169 ΟΡ 90043-5 -29-

Colorless needles, m.p. 167.5-169Â ° C (H2 O).

Mass spectrum m / z: 377 (M +).

IR spectrum and (KBr) cm-1: 1590 <C00>)

NMR Spectrum δ (DMSO-d6) ppm: 2.24-3.04 (12H, m), 3.14-3.55 (2H, m), 3.65 (2H, t, J = 5.5Hz) , 3.89 (2H, s), 6.96-7.28 (8H, m).

Exemp 10-3.5.

Hydrochloride of 4- (Dibenzabicyclohexepin-11 (6H) -ylidene) -1-piperidinobutyric acid

Colorless needles, m.p. 244-245 ° C (H2 O).

Analysis for. HCl:

Calc'd C, 69.08; H, 6.55; N, 3.50.

Found: C, 69.09; H, 6.50; N, 3.42.

Example 36

2- [4- (Dibenzabicyclohexyl) -6- (6H-ylidene) propyl] ethoxy] acetic acid hydrochloride.

Pale yellow crystals, mp. 232-224 ° C (MeOH-Me2 CO). For C 23 H 25 NO 4 • HCl:

Calc'd C, 66.42; H, 6.30; N, 3.37.

Found: C, 66.25; H, 6.30; N, 3.41

Example 37

Hydrochloride Acid 4- (10,11-Dihydro-5H-dibenzomethane-hepten-S-ylidene-1-piperidine epoxide

Colorless needles, m.p. 215-219 ° C (EtOH).

Analysis for C23 H31 N0 O2. HCl: Calculated C, 73.31; H, 7.57; N, 3.29. Found: C, 73.32; H, 7.70; N, 3.38.

Example 33

Acid 4- (Dibenz [b, e] oxazepin-11 (6H-1-ylidene) -1-piperazinecarbonyl 71 169 ΟΡ 90043-5

-30

Colorless crystals, m.p. 132-135 ° C (H2 O). Analysis for (21α, 21β,

Calc'd C, 67.91; H, 6.78; N, 3.77.

Found: C, 67.76; H, 6.58; N, 3.68.

Example 39

(Dibenzyl) -eloxopin-11β-ylidenol-1-piperidinecaproic acid

Colorless crystals, mp. 228-231 ° C <EtOH-Et2 O).

Analysis for C 25 H 29 N 3 O:

Calc'd C, 70.16; H, 7.07; N, 3.27.

Found: C, 70.12; H, 7.15; N, 3.26.

Example 40

Acid 4- (5H-dibenzo [d] isohepten-5-ylidenol-1-piperidinopropionic acid

A mixture of 146 g of 4- (5H-dibenzo [a, d] sky-hepten-5-ylidene) piperidine, 733.0 g of ethyl acrylate and 500 ml of methanol was refluxed for 1 h. and then 675 ml of aqueous sodium hydroxide solution ZN was added to the reaction mixture. The reaction mixture was refluxed for 1 h and concentrated. Water was added to the residue and adjusted to pH 4 with hydrochloric acid. The precipitate was collected by filtration to give 200 g of colorless crystals, which were recrystallized from a mixture of water and N, N-dimethylformamide to give 198 g of colorless crystals. This compound was identified by comparing its mp, IR spectrum and NMR spectrum with those of the compound of example 21.

EXAMPLE 41.

Tablets of a pharmaceutical preparation according to the present invention were prepared in the usual manner using the following constituents:

Compound of the present invention 10 mg Lactose q.s. Corn starch 34 mg Magnesium stearate 2 mg Hydroxypropylmethylcellulose 8 mg Polyethylene glycol 6000 0.5 mg titanium dioxide 0.5 mg 120 mg

Example 42

Capsules of a pharmaceutical preparation according to the present invention were prepared in the usual manner using the following constituents:

Compound of the present invention 10 mg

Lactose q.s

Carboxymethylcellulose calcium 15 mg

Hydroxypropyleelulose 2 mg

Magnesium stearate 2 mg 100 mg

Exemolo 43

Powders of a pharmaceutical preparation according to the present invention were prepared in the usual manner using the following constituents:

Compound of the present invention 20 mg Lactose q. .s. D-Mannitol 500 mg Hydroxypropyleelulose 5 mg Talc 2 mg 1000 mg 71 169 ΟΡ 90043-5

-32-

Example 44

Injections of a pharmaceutical preparation according to the present invention were prepared in the usual manner using the following constituents:

Compound of the present invention 1 mg Glucose 50 mg hydrochloric acid q.s. distilled water for injection q.S. 2 ml

Example 45

Suppositories of a pharmaceutical preparation according to the present invention were prepared in the usual manner using the following constituents:

Compound of the present invention 5 mg

Heavy fat 1295 mg 1300 mg

Example 46

Patches of a pharmaceutical preparation according to the present invention were prepared in the usual manner using the following constituents:

Compound of the present invention 10 mg Gelatin 1100 mg Polyvinyl alcohol 250 mg Methylcellulose 100 mg Glycerin 1500 mg 71 169 ΟΡ 90043-5

-33-

Kaolin 850 mg Sodium polyacrylate 50 mg Polybutene 150 mg Purified water 990 mg 5000 mg

Claims (1)

71 169 ΟΡ 90043-5 . A process for the preparation of a piperidine derivative represented by the following general formula (I): (I) in which R represents a hydrogen atom or a lower alkyl group; X is -CH = CH-, or -O-20-; Y represents an alkylene group containing 1 to 5 carbon atoms, which may be optionally substituted with a lower alkyl group, or Y is -OB-, in which A and B are the same or different and each represents, independently of the alkylene group containing 1 to 3 carbon atoms, which may optionally be substituted with a lower alkyl group, and pharmacologically acceptable salts of the compounds of formula (1), characterized in that said process comprises the steps of reacting a piperidine derivative represented by the following general formula (II): in which X is defined as above, with a compound represented by ZY-C00R (IIIa) or CH2 = CHCOOR (IIIb), in which R and Y are as defined above, and Z represents a halogen atom, followed by the hydrolysis step solvent. 71169 ΟΡ 90043-5 using an acid or a base, if necessary. 2. A process according to claim 1, characterized in that said reaction step is carried out in the presence of a solvent, 2. A process according to claim 1, characterized in that said reaction step is carried out in the absence of solvent. 4. A process as claimed in claim 1, wherein said reaction step is carried out in the presence of a base as a dehydrohalogenating agent. 5a. 6. A process according to claim 1, wherein said reaction step is carried out in the absence of a base as a dehydrohalogenating agent. 6 &amp; A process according to the preceding claims, characterized in that 4- (5H-dibenzo [a, d] cyclohepten-5-ylidene) -1-piperidinepropionic acid and its pharmacologically acceptable salts are prepared. 7. A process according to claims 1-5, characterized in that 2- [4- (5H-dibenzo [a, d] cyclohepten-5-ylidene) piperidine] ethoxyacetic acid and salts thereof pharmacologically acceptable. 8. A process according to claims 1-5, wherein 4- (10,11-dihydro-5H-dibenzo [a, d] -cyclohepten-5-ylidene) -1- and the pharmacologically acceptable salts thereof. 9. A process according to any one of claims 1-5, characterized in that 4- (dibenzo [b, e] oxepin-11 (6H) -ylidene) -1-piperidineacetic acid and its pharmacologically acceptable salts are prepared. 10. A process according to claims 1-5, characterized in that 2- [4- (dibenzo [b, e] oxepin-11 (BH) -ylidene) piperidino] ethoxyacetic acid and the pharmacologically acceptable salts thereof are prepared. -36 71 169 ΟΡ 90043-5 llg ,. A process for the preparation of a pharmaceutical composition for the treatment of an allergic disease comprising combining an effective amount of a piperidine derivative represented by the following general formula (I). 1 (I) in which R represents a hydrogen atom or a lower alkyl group; X represents -CH = CH-; -Câ C ¡Câ,,, or -CHâ,,O-; Y represents an alkylene group containing 1 to 5 carbon atoms, which may optionally be substituted with a lower alkyl group, or Y is -A-O-B-, in which A and B are the same or different and each represents, independently of the other, an alkylene group containing 1 to 3 carbon atoms, which may be optionally substituted with a lower alkyl group; and pharmacologically acceptable salts of the compounds of formula (I), with a pharmaceutically acceptable carrier or coating. Lisboa By HGKURIKU PHARMACEUTICAL GO., LTD - 0 OFFICIAL AGENT -