AU673754B2 - Tetrazole derivatives having antihistaminic and antiallergic activity - Google Patents

Description

WO 95/01350 PCT/JP94/01010 -1-

DESCRIPTION

TETRAZOLE DERIVATIVES HAVING ANTIHISTAMINIC AND ANTIALLERGIC ACTIVITY BACKGROUND OF THE INVENTION: This invention relates to novel tetrazole derivatives or salts thereof, as well as antihistamines, antiallergic agents and asthma treating agents that contain the novel tetrazole derivatives or salts thereof and which exhibit satisfactory antihistaminic and antiallergic actions while causing less central nervous system depressing effects.

The compounds of the invention are also effective in the treatment of rhinitis, nephritis, atopic dermatitis and psoriasis.

A number of benzhydryl derivatives have heretofore been synthesized and their various pharmacological actions including antiallergic action are under review. European Patent No. 82-870006 and Japanese Patent Public Disclosure (Kokai) No. Hei 3-246287 teach certain kinds of carboxylic acid derivatives, and WO 93/02062 teaches certain kinds of tetrazole derivatives. Japanese Patent Public Disclosure (Kokai) Nos. Hei 4-234359 and 4-234387 teach piperazine derivatives. However, these compounds have been unsatisfactory in that their efficacy is insufficient or that they cause central nervous system depressing effects such as sleepiness and sedation. It should also be mentioned that the prior art compounds are capable of suppressing the early-phase reaction in asthma but their ability to suppress the late-phase reaction has been insufficient. Under the circumstances, steroids are currently used in the treatment of asthma of the late-phase reaction type but steroids have their own problems, namely, those of side effects. Conventional antihistamines also have had defects, one of which is that they have anticholinergic actions causing side effects such as thirst and mydriasis. With a view to solving these problems, various studies have so far been conducted but the results have not been completely satisfactory.

WO 95/01350 PCT/JP94/01010 -2- SUMMARY OF THE INVENTION: An object, therefore, of the present invention is to provide compounds that exhibit more satisfactory antiallergic and antihistaminic actions, that are effective against both early- and late-phase reaction in asthma and which yet are highly safe in use.

Under the circumstances described above in connection with the prior art, the present inventors synthesized many tetrazole derivatives and reviewed their antihistaminic, antiallergic and central nervous system depressing actions.

Surprisingly enough, they found that tetrazole derivatives of the general formula to be defined below or salts thereof exhibited satisfactory antihistaminic and antiallergic actions and that, in addition, those derivatives or salts thereof were as effective as steroids in suppressing the late-phase reaction in asthma, while causing only weak central nervous system depressing effects.

The present invention has been accomplished on the basis of this finding.

The present invention, in its first aspect, provides tetrazole derivatives of the general formula(l):

X

a N, 7WZ N-(CH2)n A wZNN

Y

(where A represents -CH=CH-, -CH 2

-CH

2

-CH

2 and oxygen atom or a sulfur atom or in the case where A does not interconnect the adjacent aromatic rings, it represents two hydrogen atoms each bonded to the adjacent aromatic ring; V represents -CH=CH- or a sulfur atom; X and Y each independently represents an alkoxy group, a halogen atom or a hydrogen atom: W represents a bond, Z represents a carbon atom or methine, and B either forms a bond together WO 95/01350 PCT/JP94101010 -3with Z or represents a hydroxyl group, or W, Z and B represent a bond, a nitrogen atom and a hydrogen atom, respectively, or W, Z and B represent an oxygen atom, methine and a hydrogen atom, respectively; p represents an integer of 2 or 3; and n represents an integer of 1 6) or pharmacologically acceptable salts thereof.

In its second aspect, the invention provides an antihistamine, an antiallergic agent and an asthma treating agent that contain those tetrazole derivatives or pharmacologically acceptable salts thereof as effective ingredients.

DETAILED DESCRIPTION OF THE INVENTION: Some of the compounds of the present invention have optical isomers and in that case the invention encompasses all applicable isomers.

Salts of the compounds of the invention are any medicinally acceptable salts that are exemplified by, but in no way limited to, addition salts of acids including hydrochloric acid, nitric acid, sulfuric acid, maleic acid, fumaric acid, oxalic acid, citric acid, hydrobromic acid, tartaric acid, succinic acid, sulfamic acid, mandelic acid, malonic acid and phosphoric acid, as well as basic salts including sodium salts, potassium salts, lithium salts, calcium salts and zinc salts.

Compounds of the invention may be produced by the following reaction scheme i): WO 95/01350 PCT/JP94/01010 -4- 1) X X (4) B L-(CH 2 )rr-C=N Z B A -W-Z N-H -A W-Z N-(CH 2 )n-C=N SCH CH -V V Y Y (3) x A W-Z

N-(CH

2 )n X- H

N-N

-v

Y

(where V, W, X, Y, Z, p, n, A and B have the same meanings as defined above, and L represents a halogen atom).

In this step, the compounds represented by the general formula are reacted with compounds of the general formula in the presence of bases to prepare compounds represented by the general formula The reaction is preferably carried out in inert solvents.

Exemplary solvents include:water; esters such as methyl acetate and ethyl acetate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; ketones such as acetone and methyl ethyl ketone; halogenated hydrocarbons such as dichloromethane and chloroform; aromatic hydrocarbons such as benzene, toluene and xylene; others such as acetonitrile, dimethyl sulfoxide and dimethylformamide. These solvents may be used either independently or in combination. The reaction temperature varies with the starting materials to be used but the range from 0 to 200*C may typically be adopted. Base catalysts are generally effective for but by no means indispensable to the progress of the WO 95/01350 PCT/JP94/01010 reaction. Preferred bases include potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, triethylamine, pyridine and tributylammonium hydroxide.

Compounds of the general formula may further be reacted with trialkyltin azide or trialkylsilye azide; alternatively, the compounds may be reacted with metal salts of hydrogen azide such as sodium azide or potassium azide in the presence of ammonium salts. This reaction is preferably carried out in inert solvents such as xylene, toluene, benzene, tetrahydrofuran, dioxane, dimethylformamide and N-methylpyrrolidone, which may be used either independently or in combination. The reaction temperature varies with the starting materials to be used but the range from 0 to 200*C may typically be adopted.

Compounds represented by the structural formula (2) are either known or synthesizable by reaction in accordance with one of the following schemes 3) or 4): 2) X X X 0 V .HO \N HO NH

N-H

y H.v -v Y y Y (2a) Conversion from to can be accomplished by causing a substituted phenyl magnesium halide or substituted phenyl lithium to act on Conversion from to can be accomplished by causing a catalyst platinum oxide, palladium on carbon, or palladium) to act in hydrogen at either atmospheric or superatmospheric pressure. Conversion from to (2a) can readily be accomplished either under acidic conditions acetic acid-sulfuric acid) or under ordinary dehydrative reactive conditions toluenesulfonic acid-benzene).

WO 95/01350 WO 9501350PCT/IJP941O0iO0 x

A-

0 O {JN 11R (9) x X A 0 A N-LR'

NV

y x A k N-H

NV

(2b)

Y

Conversion from to (10) can be accomplished by using titanium in a lower oxidation state. Any inert solvents may be used and preferred examples are ethereal solvents such as dioxane, tetrahydrofuran, dimethoxyethane and ether.

4) x A _0

NV

CIMg-GJN Me (11) I-Me (12) (13) (2b) WO 95/01350 WO 9501350PCTIJP'94OI 010 -7- Conversion from to (12) can be accomplished by known methods. Conversion from (12) to (13) can readily be accomplished either under acidic conditions acetic acid-sulfuric acid) or under ordinary dehydrative reaction conditions t,-oluenesulfonic acid-benzene). Conversion from (13) to (2b) can be accomplished by first c'ausing an alkyl chloroformate to act on (13) to form a carbamate and then hydrolyzing it with an alkali.

Specific examples of the compounds of t~he present invention are listed below.

Compound 1: 4-Dibenzo~a,dllcyclohepten-5-yJlidene-1-[3-(1H-tetrazole-5yl )propy. piperidine Compound 2: 4-Dibenzo[a,d]cyclohepten-5-ylidene-i-(1H-tetrazol-5ylmethyl )piperidine Compogund 3: 4-Dibenzota,dlcyclohepten-5-ylidene-l-[4-(lH-tetrazol-5-yl)butyl Ipiperidine Compound 4: 4- (10, 1l-Dihydrodibenzo d]cyclohepten-5-ylidene) -1-13- (11- )propyl 1piperidine Compound 4-(61-Dibenzo~b,e)oxepin-11-ylidene)-I-j13-(1H-tetrazol-5yl)-propyllpipericline Compound 6: 4-jBis(4-fluorophenyl)methylene]-l-[3-(1II-tetrazol-5yl )propyl ]piperidine Compound 7: 4-(phenyl-2-thienylmcthylene)-1-13-(111-tetrazol-5yIl)propyl Ipiparidine Compound 8: 4-Benzhiydryiylidcne-i-[3-(JI-totrazol-5-yl)propyilpiparldinc Compound 9: 4-Blanzydrylylidene-i-[5-(.I-ttrazoi-5-yl)pontyl Jpiporidino Compound yI~iuothano 1 WO 95101350 WO 9501350PCT/JP94/0101O -8- Compound 11: 4- [Bis(4-methoxyplhenyljmethylene yl )butyl Ipiperidine Compound 12: 4-Dlbenzo[a,dlcyclohepten-5-yldene--[5-(H-tetrazol-5yl )pentyl Ipiper idine Compound 13: 4-Xanthen-9-ylidene-1- (1H-tetrazol-5-y propyl Ipiperidine Compound 14: 4-Thioxanthen-9-ylidene--[3-(H-tetrazol-5yl )propyl Ipiperidine Compound 1-Benzhydryl-4- Compound 16: l-Benzhydry1.-4-[3-(11--tetrazo-5-y)propy]-[1,4)diazepan Compound 17: 1-Benzhydryl-4- (1H-tetrazol-5-ylmetliyl )piperazine Compound 18: 1-Benzhydryl-4- (1H-tetrazol-5-yl )butyl ]piperazine Compound 19: 1-f (4-chlorophenyl)phenylmethyl]-4-(3-(1fI-tetrazol-5yl )propyl Ipiperazine Compound yl)propyllpiperazine Compound 21: 4 -IBenzhydryloxy-1-[3-(1-tetrazol-5-y)propyi.plperldine Compound 22: '4-chlorophenyl)phenylmethoxy]l--3-(111-tetrazol-5yl)propyllpiperldlne CoMpound 23: 4-IIIis(4-fluorophe!.nyl)methioxyl-1-113-(iII-totrazol-5yI)propyl Iptperidine Compound 24: 3s 4-t(4-chilorophenyi)phecnylmethoxyl-l-[4-(1II-tetrazol-5yl~bultyl Ipiperidine WO 95101350 WO 9501350PCT/JP94/01010 Compound 4- (Phenyl-p--chlorophenylmethylene) H- yl)propyllplperidlne Compound 26: 4-(10,11-Dlhydrodbenzo[a,dcycloheptan5y)1[3(H.

Compound 27: 4-(10,11-Dihydrodibenzo[a,dlcycoheptan-5yl)..[4(H.

)butyl ]piperazine Compound 28: yl)propyllpiperazlne Compound 29: 4 -(Dibenzo~a,dlcyclohepten-5-yl)-l-[3-(lll-tetrazols.yl)propyl]piperldine Compound 4 -(Dlbenzo~a,d)cyclohepten-5-yl)-l-[4-(lH-tetrazol.5yl)butyllpiperidine Compound 31: 4-(6H-Dibenzo~b ,eloxepin-11-yl)-1-[4- yl )butyl Ipiperazine Compound 32: 4-f 4 yl )butyl Ipiperidine Compound 33: 4-f 4 yl )propyl Ipiperldine The compounds of the Invention or pharmacologically acceptable salts thereof may be formulated for peroral or parenteral administration by mixing them with adjuvants that are acceptable In pharmaceutical formulation procedures.

Solid pharmaceutical formulations for peroral administration Include tablets, powders, granules and capsules and these can be produccd by combining the compound of the Invention with suitable additives such as exciplents lactose, mannitol, corn starch and crystalline cellulose), binders cellulose derivatives, gum arabic and geLatin), dIsintegrators WO 95/01350 PCT/JP94/01010 carboxymethyl cellulose calcium), and lubricants talc and magnesium stearate). If desired, these solid preparations may be formulated as enteric drugs by coating with bases such as hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, cellulose acetate phthalate and methacrylate copolymer.

Liquids for peroral administration may be exemplified by emulsions, solutions, suspensions, syrups and elixirs and these can be produced by combining the compound (1) of the invention with commonly employed inert diluents such as purified water and ethanol. In addition to inert diluents, the resulting compositions may contain adjuvants wetting agents or suspending agents), sweeteners, flavoring agents, fragrances and antiseptics. Other applicable dosage forms are aerosols that can be produced by known methods.

Pharmaceutical preparations for parenteral administration include liquids for injection and they can be produced by combining the compound of the invention with water, ethanol, glycerin, common surfactants, etc.

Other parenteral dosage forms include inhalers, liquids for external application, eye drops, nasal solutions and liniments such as ointments.

The dosage of the compound of the invention depends on various factors including age, body weight, the severity of the disease, the efficacy in treatment, the method of administration and the period of administration. Typically, the compounds are administered perorally one to three times a day at doses of 1 500 mg, preferably 5 50 mg. Alternatively, they may be administered parenterally one to several times a day at doses of 0.1 500 mg.

The pharmacological actions of representative examples of the compound and salts thereof are described below.

WO 95/01350 PCT/JP94/01010 -11- Test 1: Histamine Hi-receptor antagonism in vitro Trachea were removed from Male Hartley guinea-pigs (300 600g) and cut into strips. The tissues were suspended in 20-ml jacketed organ baths containing Tyrode physiological solution, aerated with 95% 02: 5% C02 and maintained at 37 0 C. Changes in isometric tension were measured with a force-displacement transducer and recorded on a polygraph. The preparations were placed under 1 g of passive ternsion and allowed to equilibrate for 30 60 min.

The efficacy of test compounds on histamine(10 5 M)-induced constriction was calculated and expressed as Inhibitory concentration of 50% (ICso). The data obtained are shown in Table 1.

Cetirizine (see Japanese Patent Public Disclosure No. Sho 57-149282) used as a control had an ICso of 2.40 pM.

Table 1 Compounds ICso (pM) compound 1 0.08 compound 5 0.04 compound 15 0.07 compound 20 0.08 compound 21 0.01 oxatomide 0.13 diphenhydramin 0.3 ketotifene 0.08 Test 2: Antiallergic effect(s) Passive cutaneous anaphylaxis (PCA) in rats: Male SD rats were sensitized intradermally on their shaved backs with 0.1 ml of appropriately diluted homologous anti-serum containing anti-dinitrophenyl conjugated Ascarls (DNP-As).

Forty eight hours later, the rats were challenged with 1 ml of saline containing 300 pg of DNP-As and 5 pg of Evans blue. Thirty minutes after the challenge, the rats were killed, and the skin of the back was removed. The severity of PCA was assessed by measuring the dye exudate Into the 12 skin according to the method of Harada (Japanese Journal of Allergology, 15,1). Test compounds were suspended in methyl cellulose in saline and administered 10mg/4ml/kg before 60 min. of the challenge. The data of inhibiting PCA was expressed by the amount of dye exudate on the site (Table 2).

Table 2 Compounds Inhibition(%) compound 1 99 compound 7 99 compound 19 compound 20 81 compound 21 compound 22 79 compound 25 71 ketotifene 99 oxatomide 53 Test 3: Acute toxicity Groups of 4 5 wk-old ICR mice were used, each group consisting of 5 animals.

Each compound was suspended in 0.5% methyl cellulose in saline and administered 100 mg/Kg Observation was made for 7 days. No animals administered the test compounds were dead at this dosage, but diphenhydramin was lethal at 100 mg/Kg.

Test 4: Effect on Pentobarbital Induced Sleep Groups of 4 or 5 wk-old ICR mice were used, each group consisting of 10 animals.

Each of the test compounds was suspended in methyl cellulose solution and administered orally at a dose of 25 mg/Kg. One hour later, pentobarbital was injected intraperitoneally at a dose of 40 mg/Kg to Induce coma. The moment the animal lost the righting reflex to lie on the back was regarded the start of coma and the s^" <yt WO 95/01350 PCT/JP94/01010 -13moment it recovered the righting reflex was regarded as the end of coma.

Terfenadine was used as a control compound, which is a known antiallergic agent that is not a strong sleep inducer. The data obtained are shown in Table 3 as the percent increase in sleep time compared to the negative control group (given no compounds).

Table 3 Compounds Increase in Sleep Time Terfenadine 44 Compound 3 9 Compound 6 4 Compound 20 31 Thus, the invention compounds were verified to have a smaller central nervous system depressing action.

Test 5: Inhibitory effects on leukocytes recruited into Guinea-pig broncoalveolar lavage fluid This experiment was conducted according to the methods described in America Review of Respiratory Disease, 1990,142,680-685. Male Hartley Guinea-pig (5 weeks old) was passively sensitized with injection of 0.25 ml of anti-ovalbumin (raised in rabbit). Forty eight hours later the animals were treated with mepyramin (an H 1 receptor antagonist, in order to avoid anaphylactic death, then applied to plastic exposure-chamber connected with ultrasonic nebulizer, where 0.25% ovalbumin in saline was inhalated for 10 min. Twenty four hours later, the treated guinea-pigs were administered overdose of pentobarbital, and lung were lavaged with 25 ml of phosphate buffered saline (pH 7.4) through a polyethylene tube introduced through tracheostomy. Total cells in the lavage fluid were counted by Coulter Counter, and differential cell counts were determined from cytospun preparations and stained by May-Gruenwald Giemza stain.

WO 95101350 PCT/JP94/01010 -14- Cells were identified as macrophage, neutrophils, eosinophils and lymphocytes by standard morphology, and absolute number of each cell type were calculated. Each compound suspended in 0.5% methyl cellulose containing 0.05% Tween 80 was administered (30 mg/Kg, two times (1 hour before and 6 hours after ovalbumin-challenge).

Inhibition of recruitment of leukocytes into lavage fluid were expressed; Inhibition (cells in treated animals) (cells in non-challenged animals) (cells in non-treated animals) (cells in non-challenged animals) J x 100 In these series of experiments, the compounds tested showed the efficacy to inhibiting the recruitment of leukocytes into bronchoalveolar fluid; showing the ability to employ to allergic late phase reactions. In contrast, oxatomide, ketotifene and diphenyldramin showed no inhibitory effects on this experiment. Cetirizine had weak effects as noted below.

Table 4 Inhibition Compounds Eosinophils Neutrophils Monocyte compound 22 69 46 14 compound 19 53 67 63 compound 21 60 20 compound 26 29 73 84 compound 6 28 70 79 compound 20 52 67 0 cetirizine 15 10 8 WO 95/01350 PCT/JP94/01010 Test 6: Anti-Anaphylactic Bronchoconstriction Bronchoconstriction was measured by the overflow technique of Konzett and Roessler. Male guinea-pigs weeks, 300-350 g) were passively sensitized by an injection with anti-ovalbumin rabbit serum (0.1 ml/animal, Two days later, the animals were anesthetized with urethane (1.5 g/Kg; The trachea was canulated for artificial ventilation. The right jagular vein was canulated for administration of test compound and antigen. Spontaneous respiration was abolished by gallamine triethiodide (5 mg/Kg). The animals were artificially ventilated at 60 strokes per minute (stroke volume of 10 ml/Kg). Bronchoconstriction was measured as the volume of inspiration overflow using a Ugo Bassile 7020 bronchospasm transducer. The compounds (1 mg/Kg) were administered intravenously 15 min. before antigen challenge.

In control group, vehicle alone was administered instead of the compounds.

The guinea-pigs were challenged with intravenous administration of ovalbumin (0.1 mg/Kg), then changes in the overflow volume were recorded for 30 min.

Bronchoconstriction was represented as, the peak height and the area under the curve (AUC) of each trace. Percent inhibition of bronchoconstriction is then calculated in terms of the peak height or the AUC as follows; Increase in V (control group) Increase in V (test group) 00 Increase in V (control group) 00 where V means "Bronchoconstriction represented as peak hight or AUC" WO 95/01350 PCT/JP94/01010 -16- Table Inhibition (peak height, Inhibition (AUC, compound 22 35 52 compound 21 53 59 centilizine 20 19 Example 62 18 16 (WO 93/02062) The results of Tests 1 6 show that the compounds of the invention had satisfactory antihistaminic and antiallergic effects and proved to be significantly effective against both late- and early-phase reactions in asthma. It should particularly be noted that compounds 21 and 22 at the most preferred since they are potent suppressors of not only bronchoconstriction which occurs at the early phase of asthma but also the recruitment of leukocytes into bronchoalveolar fluid which occurs at the late stage of asthma. In view of these pharmacological effects they have, the compounds of the invention are also useful for the treatment of rhinitis, nephritis, atopic dermatitis and psoriasis.

The following examples are provided for the purpose of further illustrating the present invention but are in no way to be taken as limiting.

Example 1 4-Dibenzo[a,d]cyclohepten-5-ylidene-l-[3-(iH-tetrazol-5yl)propyl]piperidine: WO 95/01350 PCT/JP94/O101.0 -17- 4 -Dibenzo[a,d]cyclohepten-5-ylidenepiperidine (5 g, 18.3 mmol), bromobutyronitrile (2.7 g, 18.3 mmol) and potassium carbonate (10 g) were suspended in DMF and stirred at 100*C for 3 h. The reaction solution was poured into water, subjected to extraction with ether, dried and concentrated under vacuum to yield an oil of 4-(4-di-benzo[a,d]cyclohepten-5-ylidenepiperidin-lyl)butyronitrile.

IR(nujol): cm- 1 2250, 1490, 1435, 1135 Without further purification, sodium azide (5.9 g, 0.92 mmol) and ammonium chloride (4.9 g, 0.92 mmol) were added to the compound and the mixture was stirred overnight at 110°C. The stirred reaction mixture was poured into water, adjusted to a pH of 6, subjected to extraction with chloroform, dried and concentrated under vacuum to an approximate volume of 30 ml. The concentrate was left to stand and the precipitating crystals were collected to yield the titled compound as a powder.

m.p. (with decomposition): 134 139*C Elemental analysis for C 24

H

2 sNs-2H20 C H N Cal'd 68.71 6.97 16.69 Found 69.08 7.21 16.85 MS(m/z): 384 (SIMS) IR(nujol): cm- 1 1300, 1160, 1080, 990, 960, 950, 880 NMR(DMSO-ds) 6ppm: 7.37: 7.28 6.96 2,85 2.66 2.46 (2H,m), 2,27 2.01 1.86 (2H,m) Example 2 4-Dibenzo[a,d]cyclohepten-S-ylidene-1(lH-tetrazol-5ylmethyl)piperldine: WO 95/01350 PCT/JP94/01010 -18- (3.8 g, 14 mmol), bromoacetonitrile (1.68 g, 14 mmol) and potassium carbonate (5.5 g) were suspended in DMF and stirred at 100"C for 3 h. The reaction solution was poured into water, subjected to extraction with ether, dried and concentrated under vacuum to yield an oil of 4-(4-dibenzo[a,d]cyclohepten-5-ylidenepiperidin-1-yl)acetonitrile. Without further refining, sodium azide (2.99 g, 40.2 mmol) and triethylammonium chloride (2,77 g, 20.1 mmol) were added to the compound and the mixture was stirred in methylpyrrolidone (50 ml) for 3 h at 150°C.

The stirred reaction mixture was poured into water and adjusted to a pH of 6, subjected to extraction with chloroform, dried and concentrated under vacuum. The residue was subjected to silica gel chromatography and crystallized from ethyl acetate, yielding the titled compound in an amount of 3.19 g 231 233*C MS(m/z): 356(M+H), 277, 185 IR(nujol): cm-1: 1630, 1305, 1270, 1160, 1025, 950 Similar procedures were taken in Examples 3 to 14 to synthesize the titled compounds.

Example 3 4-Dibenzo[a,d]cyclohepten-5-ylidene-l-[4-(1H-tetrazol-5yl)butyl]piperidine: y \H

N-N

WVO 95/0 1350 PTJ9/11 PCT/JP94/01010 Foam NIS(m/z): 398(M+H), 286, 185(SIMS) IR(nujol): cm-1: 1650, 1550, 1300, 1250, 950, 800, 760 NMR(DMSO-d 6 6ppm: 7.49 7.40 7.31 7.08 (211,s), 2.95 2.71 2.49 2.37 2.12 (2H,m), 1.77 (2H~rn), 1.58 (21I,m) Example 4 4- (10, 11-Dihydrodibenzo[ a,d] cyclohiepten-5-ylldene)

H

/N X> N.N

N-N

Foam MS(m/z): 386 (SIMS) IR(nujol): cm-1: 1640, 1295, 950, 750 NMR(DMSO-ds) bppm: 7.0 7.4 (811,m), 4.03 3,89 2,85 (2Ht,J=7), 2.72 2.44 1,84 Example 4-(6H-Dibenzo~b,eloxepin--11-ylidene)-1-t3-(1H-tetrazol-5yl )propy. Ipiperidine:

H

c

N

N-N

WO 95/01350 PCT/J'P94/01010 m.p. (with decomposition): 192 196*C MS(m/z): 388 290 (SIMS) IR(nujol): cuV 1 2700, 1550, 1290, 1220, 760 NMR(DMS0-dG) 6ppm: 7.50 7.35 7.0-7.3 6,84 6.73 3.1-3.8 Mon) 2.99 2.88 2.79 2.13 quintet, J=7) Example-6 4- [Bis (4-fluorophenyl )methylene] yl )propyl )piperidine:

F

H

N-N

F

Colorless powder m.p. 185 1870C (from ethyl acetate) MS(m/z): 396(M+H). 298, 106 (SIMS) IR(nujol): cm-1: 1600, 1500. 1450, 1410, 1220, 1160, 840 NMR(DMSO-d 6 6ppm: 7.21 2.96 (2H,tJ=7.3), 2.68 2.59 (4H~tJ=2.0), 2.35 1.98 (2H,m) Example 7 4-(Phenyl-2-thienylmethylene)-1-[3-(lH-tetrc, yl)propyllpiperidine:

H

NN

WO 95/01350 JC/P400 PCT/JP94/01010 -21- 2259 219"C MS(m/z): 366(M+H), 268(SI4S) IR(nujol): cm- 1 1405, 1340, 1080, 970, 830, 705 NMR(DMSO-d 6 6ppm: 7.57 (lH,dd,J=1.0,5.3), 7.43 (3H,m), 7.26 7.12 (1l,dd,J=4.9,3.3), 6.97 3.00 2.62 2.35 2.00 (2H,m) Example 8 4-Benzhydrylylidene-1- y1)propyllpiperidine:

H

N

N-N

Colorless powder 223 226*C (from ithyl acetate) MS(m/z): 360(M+H), 282, (SIMS) IR(nujol): cm-1: 1600, 1500, 1450, 1410, 1220, 1160, 840 NMR(DMSO-ds) 6ppm: 7.21 (lOH,m), 2.96 (211,t,J=7.3), 2.68(4H,t,J=5.3), 2.59 2.35 (211,t,J=5.3). 1.98 (211,m) Example9 4-lBenzhydrylylidene-1-(5-(1H-tetrazol-5yl)penty) ]piperidJne: WO 95101350PC/9/100 PCT/JP94/01010 -22- Foam MS(m/z): 388(M+H), (SIMS) IR(nujol): cm-1: 1600, 1500, 1450, 1410, 1220, 1160, 840 NMR(DMSO-ds) bppm: 7.2-7.6 (1OH,m), 3.01 2,81 2.64(4H-,m), 1.48 1.86 (2H,quintet,J=7), 1.66 (2H,quintet,J=7), 1.48 (2H,quintet,J=7) Example w,u-Diphenyl-N-[3-(lH-tetrazol-5-yl)propyl]piperidin-4-ylmethanol:

H

HO N-N rr.p.(with decomposition Z: 250 0

C

MS(mi/z): 378(M+H), 133, 105 IR(nujol): cm- 1 1660, 1170, 1100. 1060 NMR(DMSO-ds) 6ppm: 7.51 (411,d,J=7.6), 7.27 7.14 (2H~dd,J-7.6,6.9), 3.20 (2H,d 7=1l.2), 2.50 1.92 1.63 1.35 2.79 (411,m), (2H,d,J=12.6) Example 11 4-[Bis(4-methoxyphenyl)methylene] -1-[4-(1H1-tetrazol-5yl )butyl I-piperidine: H3CO WO 95/01350 CIPIO00 PCT/JM4/01010 -23- 120 123*C MS(m/z): 434(M+H), 322, 121 NMR(DMSO-d 6 6ppm: 6.95 (4H,dJ=8.6), 6.85 (411,d,J=8.6), 3.72 2.84 2.55 (4H,brs), 2.50 (4H,brs), 2.30 1.69 (211,m), 1.50 (2H,m) Example-12 4-Dibenzola, dlcyclohepten-5-y11.dene-1- y1 )pentyl ]piperidine:

H

Colorless powder MS(m/z): 412(M+H), (SIMS) IR(nujol): cm- 1 1650, 1550, 1300, 1250, 950, 800, 760 NMR(DMSO-ds) 6ppm: 7.51 (411,m), 7.43 7.33 (2HdJ8.~),7.1.0 (211,s), 2.94 (2H1,t,J-7.2),2.75 (211,t,J-7.2), 2.40 (4fl,t,J-6.9). 2.16 (4fl,m). 1.80 (2H-Im), 1.59 (211,r), 1.44 (2fl,m) Example-13 4-Xantlhen-9-yfldexie-1-f3-(1H-tetrazol-5y1)propyl)piP#!r'idLne:

H

N N WO 95101350PC/P40 PCI'/Jlx)4/01'110 -24m.p. Z; 25000 (from ethyl acetate) MS(m/z): 374(M+H), (SIMS) IR(nuJol): cm- 1 2450, 1590, 1550, 1250, 1200, 1150, 1100, 1060, 1050, NMR(DMS0-d6) 6ppm: 7.2-7.7 2.8-3.6 (12H,m), 2.25 (2H,quintet,J=7) Example 14 4-Thioxanthen-9-ylidene-1- yl )propyl Ipiperidine:

H

II

s -N N N m.p Z: 2500C MS(m/z): 390 (SIMS) NMR(DMSO-ds) 6ppm: 7.2-7.7 2.8-3.6 (12H,m), 2.26 (2H,quintet.J=7) Example 1-Benzhydryl-4-[3-(lH-tetrazol-5-yl)propyl]-piperazine:

H

N

Berizhydrylpiperazine (10.62 g,42 mmol), 4bromobutyronitrile (6.23 g, 42 mrnol) and potassium carbonate(1I.6 g, 84 mmol) were suspended in acetonitrile (200ml) and stirred overnight at 606C. The reaction solution was cooled and, thereafter, the Inorganic matter WO 95/01350 PCT/JP94/01010 was filtered off and the acetonitrile was concentrated under vacuum to yield an oil of 4-(4-benzhydrylpiperazinl-yl)butyronitrile (13.4 g, 99%).

MS SI-MS,Pos: 319(M+H) IR (Neat), cm- 1 2250 (nitrile), 1490, 1445 Without further purification, 4-(4benzhydrylpiperazin-1-yl)-butyronitrile was dissolved in DMF (150 ml) and ammonium chloride (6.74 g) and sodium azide (8.19 g) were added to the solution, followed by stirring at 90°C for 48 h. The reaction mixture was poured into water (300 ml), extracted with ethyl acetate (200 ml) and the extract was removed.

Then, the aqueous layer was extracted twice with chloroform (200 ml). The chloroform layer was combined, dried with magnesium sulfate and concentrated under vacuum to reduce the volume of the solution to approximately 30 ml. Upon leaving the solution to stand, crystals precipitated and recovered by filtration to yield the titled compound g).

Decomposition point: 218°C M; SI-MS,Pos: 363 (M+H) Elemental analysis for C 21

H

2 sN C H N Cal'd 69.58 7.23 23.19 found 69.70 7.32 23.10 IR(nuJol) cm- 1 1405, 1310, 1192, 1087 'H-NMR(DMSO-ds) 6ppm: 50*C, 1.84 2.2-3.7 2.85 4.27 5.60 (211,brs,H1 2 7.0-7.4 (10 H,m) 'tC-NMR(DMSO-ds) 6ppm: 500C, 156.07, 142.48, 128.16, 127.35, 126.54, 95.29, 74.83, 56.41, 52.42, 50.95, 23.80, 20.87 WO 95/01350 CTJ4/10 PCT/JP94/01010 -26- Example 16 l-Benzhydryl-4- (1H-tetrazol-5-yl )propyl] diazepan:

H

N

N N N,

N-N

The titled compound was synthesized via an intermediate nitrile form as in Example 1.

ri.p. 172 175 0 C (from ethyl acetate) MS SI-MS :377(M+H) Elemental analysis for C 22

H

2 8NG-l/2H 2

O

C H N Cal'd 68.54 7.58 21.80 found 68.60 7.45 21.85 TR(nujol) cm- 1 1600. 1495, 1405. 1330, 1320 IH-NMR(DMSO-d 6 6ppm: 21.8*C, 1.81 1.94 (2H,m), 2.4-2.7 (10H,m), 3.13 4.71 7.0-7.4 (lOH,m) Example 17 l-Benzhydryl-4- (lH-tetrazol-5-ylmethyl )piperazine:

H

N m.p. 179 182*C (from ethyl acetate) MS(m/z) SI-MS,Pos 335(M+fl) WO 95101350 PTJ9/11 PCT/3"4/01010 -27- Elemental analysis for C 19

H

2 2

N

6 C H N Cal'd 68.24 6.63 25.13 found 68.10 6.54 25.10 IR(nujol) cm- 1 2450, 1600, 1490. 1410, 1340, 1190, 1080, 1040, 970, 750, 710 Example 18 1-Benzhydry-4- [4-C lH-tetrazol-5-yl )butyl] -piperazine

H

N-N

m.p. 67 680C Elemental analysis for C 22

H

28

N

6 c H N Cal'd 70.18 7.50 22.30 found 70.10 7.40 22.35 MS SI-MS,Pos: 377(M+H) IR(nujol) cm'1: 1655, 1600, 1310, 1280, 1080, 970, 750, 710 IH-NMR(DMSO-d 6 6PPM: 1.56 1.78 (2f1,m), 2.49 2.60 2.95 (2H,tJ=7.2), 4.38 7.28 7.39 7.52 (2H~d.J=7.6) WO 95/01350 PCT/JP94/01010 -28- Example 19 1-[(4-Chlorophenyl)phenylmethyl]-4-[3-(lH-tetrazol-5yl)propyl]Piperazine dihydrochioride: t HC

N-

m.p. 198 203 0

C

NIS(m/z) SI-MS, Pos: 397(M+H), 201, 166 Elemental analysis for C 21

H

27

N

6 C1 3 c H N Cal'd 53.68 5.79 17.89 found 53.65 5.90 17.91 IR(nujol) 1550, 1095, 1020, 760, 730 IH-NMR(DMSO-ds) dppm: 2.13 2.98 3.35 3.63 (411,m), 5.53 (lH,brs), 7.2-8.1 (9H,m) Example l-[Bis(4-fluorophenyl)methyl.]-4-[3-(1H-tetiazol-5yl )propyl Ipipe razine:

F

H

N-N

F

m.p. 170 172*C MS SI-MS: 399(M+H),203 WO 95/01350 PTJ9/11 PCT/JP94/01010 -29- Elemental analysis for C 2 jH 24

F

2

N

6 C H N Cal'd 63.30 6.07 21.09 Found 63.25 6.10 21.21 IR(nujol) cm- 1 2100, 1600, 1500, 1400, 1300, 1225, 1090, 970, 870, 830, 725 'H-iNMR(DMSO-ds) 6ppm: 1.85 2.50 (1OH,m), 2.86 (2H,t,J=7.3),4.36 7.12 7.43 (4H,dd,J=8.2, 5.9) Example 21 4-Benzhydryloxy-1-[3-(lH-tetrazol-5-yl)propyljpiperidinie:

H

N

The procedure of Example 20 was repeated to synthesize 4-(4-benzhydryloxypiperidin-1-yl)butyronitrile (2g. 5.3 mmol). This compound, as well as tributyltin azide (3.35 g, 10.6 mmol) were stirred in dimethoxyethane (DME) at 900C for 48 h. Water was added to the reaction solution, followed by the addition of ethyl acetate (20 ml) and hexane (100 ml). The precipitating crystals were recovered by filtration and recrystallized from chloroform-ether to produce the titled compound (1.8 g) in a yield of m.p. 216 217 0

C

MS SI-MS, Pos: 378(M-'H),167,133 Elemental analysis for C 2 0H 27 Ns0 C H N Cal'd 70.00 7.21 18.55 Found 70.31 7.30 18.70 IR(nujol) cm-1 1500, 1400, 1300, 1260, 1220. 1110. 1060, 960, 745, 705 WO 95101350 PTJ9/11 PCT/JP94/01010 IH-NMR (DMS0-cl 6 63ppm: 1.47 1.96 (41H,m), 2.49 2.68 2.93 5.73 (111,s), 7.31 (2H,t,J=B.lHz), 7.43 (8H,m) Example 22 4-[(4-Chlorophenyl)phenylmethoxy]---3-(lH-tetrazol-5yl )propyllpiperidine: C1 The procedure of Example 1 was repeated to synthesize 4-{4--[(4-chlorophenyl)phenylmethoxylpiperidin- 1-yl~butyronitrile (1.7 g, 4.6 mmol). This compound, as well as tributyltin azide (2.87 g, 9.2 mmol) were stirred in dimethoxyethane (DME) at 90*C for 48 h. Acetonitrile ml) was added to the reaction solution, which was further stirred for 6 h at 90 0 C. Water was added to the reaction solution and the precipitating crystals were recovered by filtration. Upon recrystallization from chloroform-ether, the titled compound was obtained (1.3 g) in a yield of 69%.

m.p. 210 213*C MS SI-MS: 412(M+H), 201, 165 Elemental analysis for C 22

H

26 C H N Cal'd 64.15 6.36 17.00 Found 64.13 6.50 17.20 IR(nuJol) cm- 1 1495. 1400, 1300, 1090, 1055, 750, 710 IH-NMR(DMSO-d 6 6ppm: 1.75 1.99 2.61 (211,m), 2.76 (211.t.J-6.9), 2.03 3.01 (211,m), 5.73 (11H,s), 7.44 (9H,m) WO 95/01350 PCT/JF94/O1O10 -31- Example 23 4(Bis(4-fluorophenyl)methoxy]-l-t3-(lH-tetrazol-5yl )propyl] -piperidine:

H

Colorless powder MS SI-MS,Pos: 414(M+H), 203 Elemental analysis for C 22

H

2 sNs0 2

F

2 C H

N

Cal'd 63.91 6.09 16.94 Found 63.81 6.20 16.90 Hydroo..'loride IR(nuJol) cm-1: 1500, 1400, 1260, 1120, 970, 830, 725 'H-NMR(DMS0-d6) 6PPM: 1.95 2.16 2.92 3.52 5.70 (111,s), 7.15 (4FI,m), 7.40 (4H,m) Example 24 54-[ (4-chlorophenyl)phernylmethoxy]-.l-(4-(lH-tetrazol-5yl )buityl ]piperidine: WO 95101350 PT39/11 PCT/JP94/01010 -32- Colorless powder FAB-MS (rn/z) 425(M+H), 278, 202, 187 IR(nujol) cm- 1 1500, 1400, 1260, 1120, 970, 830, 725 1 H-NMR(DMSO-d 6 6ppm: 7.2-7.4 5.62 3.38 2.84 2.73 2.37 2.16 1.4-2.0 (8H,m) Exampe 4-[(4-Chlorophenyl)phenylmethylene]-1-(3-(lH-tetrazol-5yl)propyllpiperidine:

H

N

Colorless powder MS SI-MS,Pos: 393(M+H), 360, 296, 140 Elemental analysis for C 22

H

23 Ns'1.5H 2 0 C H N Cal'd 62.93 6.23 16.68 Found 63.15 5.90 17.09 IR (KBr) cm- 1 3435, 2565, 1487, 1089, 1031, 964, 825, 763, 703, 509 1 H-NMR (CDCl 3 6ppm: 7.32 7.18 3.20 (4H,m), 3.09 2.87 2.23 (2H~t,J=6) WO 95101350 PTJ9/11 PCT/JP94/01010 -33- Example 26 4- (Dibenzo d]cYcloheptan-5-y) yl)propyllpiperazine dihydrochioride: White amorphous MS SI-MS, Pos: 389(M+H), 194, 178, 114 Elemental analysis for C 24

H

3 0N 6 2HC1*H 2 0 C H N Cal'd 57.62 6.30 17.53 Found 57.73 6.78 17.43 IR (KBr) cm- 1 2997, 2725, 2584, 1635, 1560, 1442, 1419, 1076, 906, 630 'H-NMR (CDC1 3 6ppm: 7.35 (811,m), 5.21 (1H,brs), 3.90 3.37 (2H,brt), 3.27 (2fH,t,J=6). 3.08 2.31 (211,m) Example 27 4-(Dibenzo~a,dlcycloheptan-5-yl)-1-[4-(1H-tetrazol-5yl)butyllpiperazine dihydrochioride: N RW 2F(CI White amorphous MS SI-MS. Pos: 403(M+11), 193 WO 95/01350 WO 9501350PCT/JP94/0101O -34- Elemental analysis for C 24

H

3 0N 6 *2HCl'0.SH20 C H N Cal'd 59.50 6.44 17.35 Found 59.41 7.03 16.91 IR (KBr) cm- 1 2960, 1564, 1446, 1396, 1058, 773, 744 'H--NMR(CDC1 3 6ppm: 7.38 7.27 5.21 (1H,brs), 3.91 3.39 3.22 3.01 l.87(4H,m) Example 28 4 -(6H-Dibenzob,e-oxepin...yll43(lf..tetrazol5yl)propyllpiperazine:

H

No-

N-N

White amorphous MS FAB-MS, Pos: 391(M+H), 195 IR(KBr) cm- 1 3389, 2869, 1606, 1574, 1478, 1456, 1255, 1228, 1109, 1004, 761, 725, 638 'Hl-NMR(CDCl 3 6ppm: 7.30 7.15 6.82 6.72 (11H,d,J=11.5), 4.73 (1H,d,J=11.9), 4.03 3.09 (211,m), 2.73 (8H,m), 1.9-2.1 (2fl,m) WO 95/01350PCI9IO01 PCT/JP94/01.010 Example 29 4-(Dibenzo(a,d]cyclohepten-5-yl)-l-[3-(1H-tetrazol-5yl)propylllpiperidine:

H

N

White amorphous MS FAB-MS, Post 387(M+H), 191 IR(KBr) 3392, 1854, 1436, 1402, 1276, 1103, 973, 796, 763, 730, 628, 493 'H-NMR(CDC1 3 6PPm: 7.37 6.94 4.48 (1H,s), 3.18 (2H,t-like) 2.73 (2H,t-2.ike), 2.69 2.29 (4H,m), 1.95 (2H,m) Example 4-(Dibenzo(a,d]cYclohepten-5-yl)--4-(Ii-tetrazol-5- Y butyl Ipiperidine:

H

NIN

N

White amorphous MS FAB-MS, Post 401(M+11) 191 IR(KBr) cm-1: 3045, 2871, 1635, 1436, 1402, 1247, 1103, 997. 798, 763, 730, 464 2.92 (211,tJ-6.0). 2.64 2.28 (411,t,J-4.6), 1.78 (211,m), 1.63 (211,m) WO 95101350 PCT/JP94/01010 -36- Exam~le 31 4-(6H-Dibenzotb,eloxepin-11-yl)-1-[4-(1H-tetrazol-5yl )butyl I-pl.pcrazine:

H

0

W

White amorphous MS FAB-MSPos: 405(M+H-), 195 IR(KBr) 3485, 1487, 1446, 1255, 1228, 1109, 1004, 765 'H-NMR(CDC1 3 a3ppm: 7.29 (61i,m), 6.82 6.69 (1H,d,J=11.5), 4.72 (IFH,d.J=11.5), 4.00 3.00 (2H~tJ=5.6), 2.5-2.9 (1OH,m), 1,87 1.71 (211,m) Example 32 4-((4-Chlorophenyl)phenylmethylene]--4-(H-tetrazol-5yl)butyllpiperidine: Cl

H

White amorphous MS FAB-MS,Pos: 408(M+11), 296 IR(KBr) cm-1: 3438, 3099, 2763, 2650, 1487, 1442. 1398, 1087, 1014, 829, 783, 703 IH-NMR(CDC13) appm: 7.26 (511,m), 7.04 3.00 (411,tlike), 2.87 (211,t-like), 2.70 (411,t-like), 1.83 (41I.M) WO 95/01350 PTJ9/11 PCT/JP)4/01010 -37- Example 33 4-[(4-Chlorophenyl)phenylmethylene]-l-[3-(lH-tetrazol-5yJ.) propyl) piperidine: cl

H

White amorphous MS FAB-MS, Pos: 393([v+H), 296 IR(KBr) cm-1: 3436, 2565, 1487, 1089, 1031, 825, 763, 703 1 H-NMR(CDC1 3 6ppm: 7.32 7.08 (411,m), 3.15 (6H,m), 2.87 (2H,t-like), 2.30 (2H,m) WO 95/01350 PCT/JP94/01010 -38- Example 34 4-[Bis(4-methoxyphenyl)methylene]-l-(ethoxycarbonyl)piperidine:

H

3

CO

o N-L-OEt

H

3

CO

A zinc powder (40.5 g, 0.62 mmol) was suspended in dry THF (500 ml) and titanium tetrachloride (34 ml, 0.30 mol) was added dropwise to the suspension at or below. The mixture was dried for 0.5 h and thereafter heated at 80 0 C for 1 h. The reaction solution was cooled again to 0OC and both 4,4'-dimethoxy-benzophenone (25 g, 0.103 mol) and 1-ethoxycarbonylpiperidone (18 g, 0.103 mol) as dissolved in THF (100 ml) were added. The reaction mixture was transferred to an oil bath, where it was heated under reflux at 80"C for 2 h. The reaction solution was cooled and poured into an aqueous solution of potassium carbonate. The THF layer was recovered and subjected to extraction with ethylacetate. The extracts were combined, dried and concentrated. The concentrate was subjected to silica gel chromatography and eluted with ethyl acetatehexane to yield the end product (34 g, 94%).

Oil IR(nujol) cm-1: 1735, 1605, 1578, 1490, 1390, 1130 iH-NMR(DMSO-ds) 6ppm: 7.01 6.82 (4H,d,J=9), 4.15 3.78 3.49 2.35 1.25 (3H,t,J=7) WO 95/Oi35O WO 950i350PCT/JP94/01010 -39- Example 4- [Bis (4-methoxy'phenyl )methylene ]piperidlne:

H

3 0

-N-H

H

3 00 4- [Bis (4-methoxyphenyl)methylene] -1- (ethoxycarbonyl)piperidine (35 g) was dissolved in ethanol (300 ml) and potassium hydroxide (120 g) was added to the solution, which was then stirred over-night. Ethanol was concentrated, mixed with water (500 ml) subjected to extraction with chloroform (200 ml), dried and concentrated under vacuum. The residue was recrystallized from ethyl acetate-hexane to yield the end compound (20 g).

'H-NMR (CDCl 3 c6ppm: 7.01 (4Hd,J=9), 6.82 (4H,cl,J=9), 3.78 2.90 2.32 (4H,m)

Claims (4)

1. A tetrazole derivative of the general formula X H B N A W-Z N-(CH 2 )n i' N-N V H Y (where A represents -CH=CH-, -CH 2 -CH22-, -CH20-, an oxygen atom or a sulfur atom or, in the case where A does not interconnect the adjacent aromatic rings, it represents two hydrogen atoms each bonded to the adjacent aromatic ring; V represents -CH=CH- or a sulfur atom; X and Y each independently represents an alkoxy group, a halogen atom or a hydrogen atom; W represents a bond, Z represents a carbon atom or methine, and B either forms a bond together with Z or represents a hydroxyl group, or W, Z and B represent a bond, a nitrogen atom and a hydrogen atom, respectively, or W, Z and B represent an oxygen atom, methine and a hydrogen atom, respectively; p represents an integer of 2 or 3; and n represents an integer of 1 6) or a pharmacologically acceptable salt thereof.

2. An antihistamine, an antiallergic agent or an asthma treating agent that contain as an active ingredient a tetrazole derivative of the general formula X S /-H w e Vp Np--Ca Y (where A represents -CH=CH-, -CH2-CH2-, -CH20-, an oxygen atom or a sulfur atom or, in the case where A does not interconnect the adjacent aromatic rings, it represents WO 95/01350 PCT/JP94/01010 -41- two hydrogen atoms each bonded to the adjacent aromatic ring, V represents -CH=CH- or a sulfur atom; X and Y each independently represents an alkoxy group, a halogen atom or a hydrogen atom; W represents a bond, Z represents a carbon atom or methine, and B either forms a bond together with Z or represents a hydroxyl group, or W, Z and B represent a bond, a nitrogen atom and a hydrogen atom, respectively, or W, Z and B represent an oxygen atom, methine and a hydrogen atom, respectively; p represents an integer of 2 or 3; and n represents and integer of 1 6) or a pharmacologically acceptable salt thereof. I L~ INTERNATIONAL SEARCH REPORT Ir. nal Ap Inter, nal Application No PCT/JP 94/01010 A. CIASSIIICATION OF SUIUJCI'I' MATrl'li IPC 6 C07D401/06 C07D405/14 C07D409/14 C07C257/04 C07D403/06 C07D405/12 A61K31/41 A61K31/445 According to International Patent Classification (IPC) or to hoth national classification and IPC

11. FIllI.DS SIACII)Dl Minimum documentation searched (classification system followed by classification symbols) IPC 6 C07D D)ocumentation searched other than minimum documentaton to the extent that such documents arc included in the fields searched .lectronic data base consulted during the international search (name of data base and, where practical, search terms used) C. DOCUMINTS CONSIDIRIlD) TO Illi RKI.lEVANTI' Category' Citation of document, with indication, where appropnate, of the relevant passages Rclevant to claim No. A EP,A,O 058 146 (UCB,S.A.) 18 August 1982 1,2 cited in the application *Document* A EP,A,0 468 884 (LABORATORIOS DEL DR. 1,2 ESTEVE, 29 January 1992 cited in the application JP,A,4 234 387 (LABORATORIOS DEL DR. ESTEVE,S.A.) A EP,A,0 468 885 (LABORATORIOS DEL DR. 1,2 ESTEVE,S.A.) 29 January 1992 cited in the application JP,A,4 234 359 (LABORATORIOS DEL DR. ESTEVE,S.A.) SV Further documents arc listed in the continuation of box C. IPatent family members are listed in annex. Special categories of cited documents: Special categories of cited documents later document published after the international filing date Sdocument deining e general state of the art which is not or prionty date and not in conflict with the application hut Sd entdefn the genras of the art which s not cited to understand the pnncple or theory underlying the considered to be of particular relevance invention earlier document hut published on or after the international document of particular relevance; the claimed invention filing date cannot he considered novel or cannot he considered to document which may throw doubts on pnority claim(s) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another document of particular relevance; the claimed Invention citation or other special reason (as specified) cannot he considered to involve an inventive step when the document refcrnng to an oral disclosure, use, exhibition or document is combined with one or more other such docu. other means ments, such combination being obvious to a person skilled document published pnrior to the international filing date hut in the art. later than the pnonty date claimed document member of the same patent family 1 Date of the actual completion of the international search Date of mailing of the international search report 12 September 1994 20. 09. 94 Name and mailing address of the ISA Authonrzed officer IHuropean Patent Office, PI.1. 581 I atentlaan 2 NI. 21801 IV RI)lwilk Tel 31.70) 340.2040, Tx. 31 651 epo nl, L n, Fax: 1 3170) 340-3016 Luyten, H Form PCT/IS.A'21 (second Iheet) (July 1992) page 1 of 2 INURINAT*ONAL SEARCH% REPRT1 Intei awai Appicaion No P-CT/ 1 JP 94/01010 (C(ontinuauon) I)OCUM II'S CONSIDB-RIDTO FUi UAVA NT Cacgory Citation of documint, wiiti jndvtion, where appropnatc, of the relevant pasagcs Relevant to cia: m No. A DATABASE WPI 1,2 Week 9150, Derwent Publications Ltd., London, GB; AN 91-365831 JP,A,3 246 287 (HOKURIKU PHARM KK) 22 February 1990 cited in the application see abstract Porn PCTIISA/210 (continuAtion or tecand sIhett) (JOlY 1992) page 2 of 2 INTER~NAIONAL SEARCHI REPORT Inicl nal Application No Infornialton on patcrit family nmcmbcrs C P 9 01 0 Patent document Pu Ltion P Iatent fain, Y Publication cited in scarch report dat 1 mcmrbcr(s) 7 1date EP-A-0058146 18-08-82 AT-T- 8140 15-07-84 AU-B- 544066 16-05-85 AU-A- 8023182 12-08-82 CA-A- 1199918 28-01-86 1463099 28-10-88 JP-A- 57149282 14-09-82 JP-B- 63011353 14-03-88 SU-A- 1227113 23-04-86 SU-A- 1310397 15-05-87 SU-A- 1287749 30-01-87 US-A- 4525358 25-06-85 EP-A-0468884 29-01-92 FR-A- 2665161 31-01-92 AU-B- 638857 08-07-93 AU-A- 8128091 30-01-92 CN-A- 1058404 05-02-92 JP-A- 4234387 24-08-92 NZ-A- 239104 23-12-93 US-A- 5182280 26-01-93 JP-A-4234387 24-08-92 FR-A- 2665161 31-01-92 AU-B- 638857 08-07-93 AU-A- 8128091 30-01-92 CN-A- 1058404 05-02-92 EP-A- 0468884 29-01-92 NZ-A- 239104 23-12-93 US-A- 5182280 26-01-93 EP-A-0468885 29-01-92 FR-A- 2665160 31-01-92 AU-B- 638856 08-07-93 AU-A- 8127991 06-02-92 CN-A- 1058397 05-02-92 ES-A- 2043515 16-12-93 JP-A- 4234359 24-08-92 US-A- 5166205 24-11-92 JP-A-4234359 24-08-92 FR-A- 2665160 31-01-92 AU-B- 638856 08-07-93 AU-A- 8127991 06-02-92 CN-A- 1058397 05-02-92 Porm PCTIISA/210 (patent family annex) (July 1992) page I of 2 INTRNKIONL EARH iepour Intcr nal Application No Information on patont family mecmbers PCT/JP 94/01010 Patent document Publication Patent Family Publication cited in search report I date Imember(s) Idatc JP-A-4234359 EP-A- ES-A- US-A- 0468885 20435 15 5166205

29-01-92 16- 12-93 24-11-92 I Fo.rm PtCTJISAI1210 (pstent family innex) (July 1992) page 2 of 2