GB2056968A

GB2056968A - Piperazine derivative, processes for the preparation thereof and pharmaceutical composition comprising the same

Info

Publication number: GB2056968A
Application number: GB7929092A
Authority: GB
Original assignee: Fujisawa Pharmaceutical Co Ltd
Current assignee: Fujisawa Pharmaceutical Co Ltd
Priority date: 1979-08-21
Filing date: 1979-08-21
Publication date: 1981-03-25
Also published as: JPS5632474A

Abstract

A compound of the formula: <IMAGE> wherein R<1> is carboxy, carboxy derivative, oxalo, or acylamino, R<2> is hydrogen, halogen, lower alkyl, lower alkoxy, aryl or acylamino, R3 is ar(lower) alkyl, X is A is lower alkylene, and <IMAGE> -O-, -S-, or -HNCO-, in which R<4> is hydrogen or acyl, and a pharmaceutically acceptable salt thereof. These derivatives and their pharmaceutically acceptable salts have anti-allergic activity.

Description

SPECIFICATION Piperazine derivative, processes for the preparation thereof and pharmaceutical composition comprising the same The present invention relates to new piperazine derivative and pharmaceutically acceptable salt thereof. More particularly, it relates to new piperazine derivative and pharmaceutically acceptable salt thereof which have antiallergic activity, to processes for the preparation thereof, to pharmaceutical composition comprising the same, and to a method of using the same therapeutically in the treatment of allergic symptoms in human being and animals.

Accordingly, one object of the present invention is to provide piperazine derivative and pharmaceutically acceptable salt thereof, which are useful as an antiallergic agent.

Another object of the present invention is to provide processes for the preparation of piperazine derivative and pharmaceutically acceptable salt thereof.

A further object of the present invention is to provide a pharmaceutical composition comprising said piperazine derivative and pharmaceutically acceptable salt thereof as an active ingredient.

Still further object of the present invention is to provide a method of using said piperazine derivative therapeutically in the treatment of allergic symptoms in human being and animals.

The piperazine derivative of the present invention is novel and can be represented by the following formula (I):

wherein R1 is carboxy, carboxy derivative, oxalo, or acylamino, R2 is hydrogen, halogen, lower alkyl, lower alkoxy, aryl or acylamino, R3 is ar(lower)alkyl, A is lower alkylene, and Xis -N-, -O-, -S- or-NHCO-, R4 in which R4 is hydrogen or acyl.

As to the various definitions as indicated above, suitable illustrations and examples are explained in details as follows.

The term "lower" is intended to mean 1 to 6 carbon atom(s), unless otherwise indicated.

The "carboxy derivative" for R' includes an esterified carboxy, amide and the like.

The esterified carboxy may include: loweralkoxycarbonyl (e.g. methoxycarbonyl, ethoxyca rbonyl, propoxyca rbonyl, isopro poxycarbonyl, butoxycarbonyl, isobutoxyca rbonyl, tertbutoxycarbonyl, pentyloxyca rbonyl, hexyloxycarbonyl, etc.); lower alkenyloxycarbonyl (e.g. vinyloxycarbonyl, allyloxycarbonyl, etc.); lower alkynyloxycarbonyl (e.g. ethynyloxycarbonyl, propynyloxycarbonyl, etc.); aryloxycarbonyl (e.g. phenoxycarbonyl, tolyloxycarbonyl, etc.); ar(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxyca rbonyl, benzhydryloxyca rbonyl, etc.) and the like; and the alkyl and aryl moieties of which may be substituted by suitable substituents such as halogen (e.g. fluoro, chloro, bromo, etc.), nitro, loweralkoxy (e.g. methoxy, ethoxy, etc.) and the like.

The amide may include N-(lower)alkyl- or N,N di(lower)alkyl - amide, i.e. N - (lower)alkyl - or N,N, ii(lower)alkyl - carbamoyl, in which the lower alkyl noiety is the same ones as exemplified hereinafter for the "lower alkyl" group for R2, and N heterocyclic - or N - (lower)alkyl - N - heterocyclic amide, i.e. N - heterocyclic - or N - (lower)alkyl - N heterocyclic - carbamoyl, in which the heterocyclic moiety is a heterocyclic group containing one or more hetero-atom(s) selected from nitrogen, oxygen and sulfur atoms such as 5-or 6-membered heterocylic group containing 1 to 4 nitrogen atom(s) (e.g. pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, etc.); 5-or 6-membered heterocyclic group containing 1 to 2 oxygen atom(s) (e.g. furyl, pyranyl, etc.);; 5-or 6-membered heterocyclic group containing 1 to 2 sulfur atom(s) (e.g. thienyl, etc.); .5for 6-membered heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 2 nitrogen atom(s) (e.g.

oxazolyl, isoxazolyl, oxadiazolyl, etc.); 5-or 6-membered heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 2 nitrogen atom(s) (e.g.

thiazolyl, isothiazolyl,thiadiazolyl, etc.); orthe like.

The "acyl" moiety in the "acylamino" group for F1 and R2 and "acyl" for R4 may include lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, succinyl, pivaloyl, etc.); lower alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl, butanesulfonyl, pentanesulfonyl, hexanesulfonyl, etc.); lower alkoxycarbonyl (e.g. methoxycarbonyl, ethox yca rbonyl, propoxyca rbonyl, isopropoxyca rbonyl, butoxycarbonyl, tert-butoxyca rbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.); carbamoyl; lower alkyl carbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, tert-butylcarbamoyl, pentylcarbamoyl, hexyicarbamoyl, etc.), and the like.

The "halogen" for R2 may include fluoro, chloro, bromo and iodo.

The "lower alkyi" for R2 may include methyl, ethyl, The chemical formula(e) appearing in the printed specification was/were submitted after the date of filing, the formula(e) originally submitted being incapable of being satisfactorily reproduced.

propyl, isopropyl, butyl, isobutyl,tert-butyl, pentyl, hexyl, and the like.

The "lower alkoxy" for F2 may include methoxy, ethoxy, pro poxy, iso pro poxy, butoxy, isobutoxy, pentyloxy, hexyloxy, and the like.

The "aryl" for R2 may include phenyl, tolyl, xylyl, mesityl, cumenyl, naphthyl, and the like.

The "ar(lower)alkyl" for R3 may include mono-, diortriaryl (lower) alkyl such as benzyl, phenethyl, phenyl propyl, benzhydryl, 2,2-diphenylethyl, trityl and the like, in which the preferred embodiment is diphenyl (lower) alkyl, particularly, benzhydryl.

The "lower alkylene" for A may include methylene, ethylene, trimethylene, propylene, tetramethylene, ethyl ethylene, pentamethylene, hexamethylene and the like, in which the preferred embodiment is C1-C4alkylene.

The pharmaceutically acceptable salt of the object compound (I) is conventional non-toxic, pharmaceutically acceptable salt and may include an acid addition salt such as an inorganic acid salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.), an organic acid salt (e.g. acetate, oxalate, maleate, fuma rate, ta rtrate, methanesu Ifonate, benzenesulfonate, toluenesulfonate, etc) or a salt with an amino acid (e.g. arginine, aspartic acid, lysine, glutamic acid, etc.) and a salt with a base including an inorganic or organic base such as alkali metal salt (e.g.

sodium salt, potassium salt, etc.), alkaline earth metal salt (e.g. calcium salt, etc.), ammonium salt, an organic amine salt (e.g. ethanolamine salt, triethylamine salt, triethanolamine salt, pyridine salt, dicyclohexylamine salt etc.) or the like.

The object compound (I) and pharmaceutically acceptable salt thereof can be prepared by the processes as illustrated by the following reaction schemes.

In the definitions for each of the above Processes, R', Ra, Ra, A and X are each as defined above, Ra is a protected carboxy group, Rb is an esterified carboxy group, Ra4 is acyl, Ra is hydrogen or lower alkyl, Rb is lower alkyl or a heterocyclic group, Xais-NH-,-O-or-S-,and Z is an acid residue.

The "protected carboxy group" for R3 means carboxy which is protected with a protective group conventionally used for protection of the carboxy function, including the same esterified carboxy and amide as illustrated and exemplified in the above explanation of "ca rboxy derivative" for F1.

The "esterified carboxy group" for Rb is the same ones as illustrated and exemplified in the above explanation of the "carboxy derivative group" for R .

The "acyl" for Ra4 is the same ones as illustrated and exemplified for "acyl" group for Rd.

The "lower alkyl" for R" and Rb and "a heterocyclic group" for Rb are the same ones as illustrated and exemplified for "lower alkyl" moiety and "heterocyclic" moiety in the above explanation of the "carboxy derivative group" for R1.

The "acid residue" for Z means a residue of an inorganic acid and an organic acid, and may include halogen (e.g. chloro, bromo, iodo, etc.), azido, acyloxy (e.g. benzenesulfonyloxy, tosyloxy, etc.) and the like.

The processes as shown above are explained in details in the following.

Process Z: The compound (I) and its salt can be prepared by reacting a compound (II) or its salt with a compound (Ill) or its salt.

Suitable salt ofthe compound (II) may be the same as ones as exemplified in the explanation of "pharmaceutically acceptable salt" for the compound (I), and suitable salt of the compound (III) may be the acid addition salt as exemplified hereinabove.

This reaction can preferably be carried out in the presence of a base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e.g. magnesium hyd roxide, calcium hydroxide, etc.), alkali metal carbo nate (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g. mag nesium carbonate, calcium carbonate, etc.), alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkali metal hydride (e.g.

sodium hydride, etc.), alkaline earth metal hydride (e.g. calcium hydride, etc.), alkali metal alkoxide (e.g.

sodium methoxide, sodium ethoxide, potassium tert-tuboxide, etc.), trialkylamine (e.g. triethylamine, etc.), pyridine compound (e.g. pyridine, lutidine, picoline, etc.), quinoline, diazabicyclo compound (e.g. 1,5 - diazabicyclo L5,4,0t undecene - 5, 1,4 diazabicyclo [2,2,22 octane, etc.) and the like.

The reaction may preferably be carried out in the presence of an iodine compound such as metal iodide (e.g. sodium iodide, potassium iodide, etc.) or the like.

The reaction is usually carried out in a solvent such as methanol, ethanol, propanol, dioxane, tet rahydrofuran, dimethylformamide or any other solvent which does not adversely influence the reaction.

The reaction temperature is not critical and the reaction is preferably carried out under warming or heating.

Process 2: The compound (I-i) and its salt can be prepared by reacting a compound (IV) or its salt with a compound (V) or its salt.

Suitable salt of the compound (IV) may be a salt with a base and suitable salt of the compound (V) may be the acid addition salt, both of which are exemplified in the above.

This reaction can be carried out substantially in the same manner as that of Process 1, and therefore the reaction mode and reaction conditions (e.g. base, solvent, etc.) are to be referred to those as explained in Process 1.

Process 3: The compound (1-2) and its salt can be prepared by subjecting a compound (VI) or its salt to hydrolysis.

Suitable salt of the compound (Vl) may be the acid addition salt as exemplified in the above.

The hydrolyzing agent to be used in this reaction includes the one which can be applied to conventional cleavage reaction of an amide linkage to form carboxy and amino groups, for instance, a base such as exemplified in the explanation of Process 1.

This reaction is usually carried out in water, a hydrophilic solvent such as methanol, ethanol, acetone, dioxane, N,N - dimethylformamide or any other solventwhich does not adversely influence the reaction.

The reaction temperature is not critical and the reaction is preferably carried out under cooling, at ambient temperature or under warming.

Process 4: The compound (1-3) and its salt can be prepared by reacting a compound (1-2) or its salt with an oxidizing agent.

The oxidizing agent includes the one which can be applied to oxidation of an oxalo group to form a carboxy group, for example, a peroxide compound such as hydrogen peroxide, an organic peracid (e.g.

peracetic acid, trifluoroperacetic acid, perbenzoic acid, m-chloroperbenzoic acid, etc.), permanganate (e.g. potassium permanganate, etc.) and the like.

This reaction is usually carried out in a solvent such as water, acetone, tetrahydrofuran, acetic acid or any other solvent which does not adversely influence the reaction.

The reaction temperature is not critical, and the reaction is preferably carried out at ambient temperature or under heating.

Process 5: The compound (1-5) and its salt can be prepared by subjecting a compound (1-4) or its salt to hydrolysis.

Suitable salt of the compound (1-4) may be a salt as exemplified in the above.

This reaction can be carried out substantially in the same manner as that of Process 3, and therefore the hydrolyzing agent, reaction mode, and reaction con ditions (e.g. solvent, reaction temperature, etc.) are to be referred to those of Process 1, and further this reaction can be carried out in the presence of an acid such as an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc.), an organic acid (e.g. formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, etc.) and the like.

Process 6: The compound (1-6) and its salt can be prepared by reacting a compound (1-5) or its reactive derivative with an amine compound (VII) or its salt.

Suitable reactive derivative at the carboxy group of the compound (1-5) may include, for example, the corresponding acid halide, acid an hydride and the like, and preferred example of the acid halide may be an acid chloride, acid bromide and the like, and pre ferred ones of the acid anhydride may be a mixed acid anhydride with an organic acid such as alkyl carbonate (e.g. methyl carbonate, ethyl carbonate, etc.) alkanoic acid (e.g. pivalic acid, trifluoroacetic acid, etc.), aroic acid (e.g. benzoic acid, etc.) or the like.

Suitable reactive derivative at the carboxy group of the compound (1-5) can optionally be selected from the above according to the kind of the com pound (1-5) to be used practically.

Suitable salt of the compound (VIZ) may be an acid addition salt as exemplified in the above.

This reaction is preferably carried out in the presence of a base as exemplified in the above Process 1.

When the compound (1-5) is used in a form of a free carboxylic acid, the reaction is preferably carried out in the presence of a condensing agent, which is conventionally used in amidation reaction, such as a carbodiimide compound te.g. N,N' - dicyclohexyl carbodiimide, N - cyclohexyl - N' - morphoiinoethyl- carbodiimide, N - cyclohexyl - N' - (4 - dieth- yEaminocyclohexyl) carbodiimide, X,N' - diethylcar- bodiimide, N,N' - diisopropylcarbodiimide, N - ethyl N' (3-dimethylaminopropyl)carbodiimide, etc., a ketenimine compound (e.g.N,N' - carbonyldiimidazole, N,N' - carbonylbis (2 methylimidazole), etc.), pentamethyleneketene - IN - cyclohexylimine, diphenylketene - N - cyclohexylimine, etc.); a sulfonic acid ester of N - hydroxybenzotriazole derivative j e.g. 1 - 54 - chloroben zenesulfonyloxy) - 6 - chloro -1 H - benzotriazole, etc., a combination oftrialkylphosphite or triphenylphosphine and carbon tetrachloride, disulfide or diazacarboxylate, a phosphorus compound (e.g., ethyl polyphosphate, isopropyl polyphosphate, phosphoryl chloride, phosphorus trichloride, etc.), thionyl chloride, oxalyl chloride, N-ethylbenzisoxazolium salt, N - ethyl - 5 - phenylisoxazolium - 3 - sulfate, a reagent (referred to as so-called "Vilsmeier reagent") formed by the reaction of an amide compound (e.g. dimethylfor mamide, diethylacetamide, N-methylformamide, etc.) with a halogen compound (e.g. thionyl chloride, phosphoryl chloride, phosgene, etc.).

The reaction is usually carried out in a solvent such as water, acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N - dimethylformamide, pyridine or any other solvent which does not adversely influence the reaction.

The reaction temperature is not critical and the reaction is preferably carried out under cooling or at ambient temperature.

Process 7: The compound (1-7) and its salt can be prepared by esterification of a compound (1-5) or its reactive derivative with an esterifying agent.

Suitable reactive derivative of the compound (1-5) may be the same ones as exemplified in Process 6.

The esterifying agent may be the one which can be applied to transformation of a carboxy group or its reactive derivative into an esterified carboxy group.

Suitable esterifying agent include a hydroxy compound, its metal salt and its reactive equivalent, for example, a lower alkanol, lower alkenol, lower alkynol, ar(lower-alkanol or reactive equivalent (e.g.

halide, sulfonate, sulfate, diazo compound, etc.) thereof, arenol or its metal salt, and the like.

Suitable metal salt of the hydroxy compound may be an alkali metal salt (e.g. sodium salt, potassium salt, lithium salt, etc.) or the like.

This reaction can be carried in a conventional manner, more particularly, for example, in case that the reaction is conducted by a) using a free carboxylic acid (1-5) or its salt and the reaction equivalent of the esterifying agent; or b) using the reactive derivative of the compound (1-5) or its salt and the free hydroxy compound or its salt, the reaction is usually carried out in the presence of a base as exemplified in Process 1, and in case that the reaction is conducted by using a free carboxylic acid (1-5) or its salt and the free hydroxy compound, the reaction is usually carried out in the presence of a condensing agent as exemplified in Process 6.

The reaction is usually carried out in a solvent such as dioxane, tetrahydrofuran, diethyl ether, water, or any other solvent which does not adversely influence the reaction. A liquid esterifying agent can also be used as a solvent.

Process 8: The compound (1-9) and its salt can be prepared by acylating a compound (1-8) or its salt with a compound (VIII) or its reactive derivative.

Suitable reactive derivative of the compound (VIII) may be the same ones as exemplified in the explanation of the reactive derivative at the carboxy group of the compound (1-5) in Process 6.

This reaction can be carried out substantially in the same manner as that of Process 6, and therefore the reaction mode and reaction conditions (e.g. base, solvent, etc.) are to be referred to those of Process 6.

The object compound (i) obtained in the above Processes 1 to 8 can be isolated and purified in a conventional manner, for example, extraction, precipitation, fractional chromatography, fractional crystallization, recrystallization, and the like.

The object compound (I) can be transformed into optional pharmaceutically acceptable salt by a conventional method, if desired.

The starting compounds (II), (V) and (VI), which are novel, can be prepared by the following processes.

In the definitions for each of the above Processes Ato D, Rg, Ra, Ra, A, Xa and Z are each as defined above, and Z' is an acid residue.

The "acid residue" for Z' is the same ones as the acid residue for Z.

Details of these Processes Ato D should be referred to the Preparation described below.

The object compound (I) obtained according to the processes of this invention has potent and long lasting antiallergic activity and can be used symptomatically as well as prophylactically as antiallergic agents for relieving or inhibiting allergic symptoms of human being and animals.

Pharmacological test data on the representative compound of the compound (I) are explained in the following.

Pharmacological Test Test Compound: N -t3 - (4- Benzhydryl -1 - piperadinyl) propyU - anthranilic acid.

Test Method: (1) Preparation ofrabbit antiserum against egg albumin Equal volumes of a saline solution of egg albumin (200 mg./ml.) and of Freund's Complete Ajuvant were mixed and emulsified. Each male New Zealand white strain rabbits, each weighing 2 to 2.5 kg., received an intramuscular injection of 0.5 ml. of the emulsion in the left and rig ht thigh regions. One week later, they received an intradermal injection of 0.25 ml. of a saline solution of egg albumin (concentration: 20 mg./ml.) in the different four sites of the dorsal skin surface three times every other week.

Blood samples were collected from the carotid artery one week after the last injection.

(2) Determination of PCA titer The level of anaphylactic anti-egg alubumin antibodies in pools of sera were determined by passive cutaneous anaphylaxis (PCA) reactions using shaven Hartley strain test guinea-pigs.

Antiserurm.was serially diluted (two fold) in saline and 0.1 ml. of each antiserum dilution were injected intradermally into the dorsal skin surface of the test guinea-pigs 24 Hours after intradermal sensitization, Egg albumin-specific PCA reactions were elicited by intravenous injection of 10 mg. of eqg albumin in I ml. of 1% Evans blue dye dissolved in saline. Reactions were read and recorded asthe highest dilution of serum evoking threshold PCA reactivity (5 mm diameter).

(3) Antagonism to anaphylactic asthma in guineapigs Male Hartley strain guinea-pigs, weighing 305 to 400 g, were used. Animals were sensitized by an intravenous injection of rabbit antisewm against egg albumin (4000 PCAtiter) wRh 0.5 ml/animal.

After 24 hrs., animals were plased individually in a plastic chamber of 5.3 liter volume. An aerosol of 5% egg albumin solution was sprayed in the chamber at a rate of 0.16 ml./min. with a commercial nebulizer.

The test compound was given to the animals orally 30 minutes before the challenge with the egg albu min solution. Each dose group consisted often animals. The inhibitory effect of the test compound was determined from the number of surviving animals more than 2 hours after spray of the antigen.

Test Results: Inhibitory effect of anaphylactic asthma in guinea-pig is shown in the following table.

Dose (mglkgJ P.O. Inhibitory Effect /O/oJ 1 40 10 100 As being apparent from the above test results, the object compound (I) of the present invention is useful for the antiallergic medicines.

For therapeutic administration, the object compound (I) of the present invention and pharmaceutically acceptable salt thereof are used in a form of the conventional pharmaceutical preparation in admixture with pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration. The pharmaceutical preparation may be in a solid form such as capsule, tablet, dragee, ointment or suppository, or in a liquid form such as solution, suspension, or emulsion. If needed, there may be included in the above preparation auxiliary substance, stabilizing agent, wetting or emulsifying agent, buffer or any other commonly used additive.

The effective ingredient may usually be aministered with a dose of 1 mg./kg. to 500 mg./kg., 1 to 4 times a day. However, the above dosage may be increased or decreased according to the age, weight or conditions of the patient or the administering method.

The following examples are given onlyforthe purpose of illustrating the present invention in more detail.

Preparation ofthe starting compound Preparation 1 A mixture of l-benzhydn/l 1 -benzhydrylpiperazin (4.13 g), 1 - bromo - 3 - chloropropane (5.18 g) and anhydrous potassium carbonate (2.26 g) in anhydrous acetone (82 ml) was refluxed for 10 hours under stirring. The insoluble materials were filtered off and the filtrate was evaporated to dryness. The residue was subjected to column chromatography on alumina (50 g) using benzene as an eluent. The fractions containing the object compound were collected and evaporated to give oil of 1 - benzhydryl - 4 - (3 - chloropropyl) piperazine (3.04 g).

I.R. (Film): 1600, 1450, 1280, 1130, 1000 cm~ Preparation 2 (1) A mixture of 1 - (3 - chloropropyl)isatin (13.44 g), 1 - benzhydrylpiperazine (19.92 g), triethylamine (7.2 g) and potassium iodide (9.96 g) in N,N - dimethylformamide (144 ml) was stirred for 1.5 hours at 80 to 85"C. The reaction mixture was cooled, poured into a cold aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated. The residue was dissolved in chloroform and subjected to column chromatography on silica gel (60 g) using chloroform as an eluent. The eluate was evaporated, and the remaining oil was dissolved in ethanol (160 ml).To a solution was added 29% ethanolic hydrogen chloride (30 ml) under cooling in an ice bath, and the resulting mixture was stirred for 10 minutes. The precipitated crystals were collected by filtration and then dried to give 1 -j3 - (4 - benzhydryl - 1 - piperazinyl) propyl isatin dihydrochloride (20.17 g), mp 245-248"C (dec.).

The following compounds were obtained in substantially the same manner as that of Preparation 2-(1).

(2) 1 - { 3 - (4 - Benzhydryl - 1 - piperazinyl) propylu - 4-chloroisatin, mp 142 to 143"C.

(3) 1 -(3-(4-Benzhydryl-1 -piperazinyl)propylj 5 - fluoroisatin dihydrochloride, mp 238 to 242"C.

(dec.) (4) 1 - L3 - (4 - Benzhydryl - 1 - piperazinyl) propyl - 6 -fluoroisatin, mp 210 to 212"C.

(5) 1 -[3 - (4 - Benzhydryl - 1 - piperazinyl) propyl - 5 - methylisatin dihydrochloride, mp 231 to 234"C.

(dec.) (6) 1 -L3 - (4- Benzhydryl - 1 - piperazinyl) propyl] 5 - methoxyisatin dihydrochloride, mp 237 to 240 C.

(dec.) Preparation 3 A mixture of N - aminophenyl - N' - methylureide (3 g), 1 - bromo - 3 - chloropropane (5.72 g) and anhydrous potassium carbonate (2.52 g) in dry N,N dimethylformamide (30 ml) was stirred at ambient temperature for 70 minutes and at 80"C for addi tional 40 minutes. After cooling, the mixture was poured into a mixture of ice-water (200 ml) and methylene chloride (50 ml). The organic layer was separated out, washed with water and then dried over anhydrous magnesium sulfate.After the removal of the solvent, the residue (6.14g) was crystallized from a mixed solvent of diisopropyl ether and n-hexane to give crystals (2.72 g), which was recrystallized from diethyl etherto obtain N -t2 - (3 chloropropylaminophenylj - N' - methylureide (1.99 g), mp 101-108"C.

l.R. (Nujol): 3300,3250 (shoulder), 1630, cm~' Preparation of the object compounds Example 1 A mixture of 1 - t3 - (4 - benzhydryl - 1 - piperazinyl) - propylu isatin (4.39 g) and 1 N aqueous solution of sodium hydroxide (12 ml) in tetrahydrofuran (40 ml) was stirred at ambient temperature for 15 minutes.

After removal of the solvent, to the remaining aqueous solution was added water. The resultant precipitates were collected and washed with water to give pale yellow crystals (4.70 g), which was recrystallized from water (70 ml) to give yellow crystals (3.8 g) of sodium salt of 2 -IN -13 - (4 - benzhydryl - 1 - piperazinyl) - propyl aminoj phenylglyoxylic acid, mp 65"C.

I.R. (Nujol): 3350, 1650, 1600 cmzt Example 2 (1) To a solution of -L3 -(4- benzhydryl -1 piperazinyl) - propyls isatin (1.76 g) in 1 N aqueous solution of sodium hydroxide (9.2 ml) and tetrahydrofuran (5 ml) was added dropwire 15% aqueous hydrogen peroxide (2 ml) at ambient temperature and the reaction mixture was stirred at 70"C for 5 hours. The reaction mixture was cooled to ambient temperature, treated with sodium sulfite (0.2 g) and adjusted to pH 1 with 10% hydrochloric acid under stirring. To the resultant suspension was added ethyl acetate (50 ml) and the mixture was adjusted to pH 9 with an aqueous solution of sodium bicarbonate and then stirred vigorousiy for halfan hour.The resultant precipitates were collected by filtration, washed with water and ethyl acetate and recrystallized from dimethylformamide (20 ml) to give N -t3 - (4 - benzhydryl - 1 - piperazinyl) propylj anthranilic acid (0.74 9), mp 227-230"C (dec.).

I.R. (Nujol): 3250, 1615, 1585 cm-1 The following compounds 2-(6) were obtained in substantially the same manner as that of Example 2-(1).

(2) N -t3 - (4- Benzhydryl - 1 - piperazinyl) propyU - 6 - chloroanthranilic acid, mp 236.5-237.5 C (dec.).

I.R. (Nujol): 3350,2150, 1665, 1590, 1560 cm~' (3) N -L3 - (4- Benzhydryl - 1 - piperazinyl) propylt 5 - fluoroanthranilic acid, mp 216"C.

I.R. (Nujol): 3220, 1625, 1590 cm-1 (4) N -L3 - (4- Benzhydryl - 1 - piperazinyl) propyU - 4 - fluoroanthranilic acid, mp 219-221"C.

l.R. (Nujol): 3200,2000-1900, 1630, 1590cm-1 (5) N - L3 - (4 - Benzhydryl - 1 - piperazinyl) propylu - 5 - methylanthranilic acid, mp 215-218"C.

I.R. (Nujol): 3240,2250, 1625, 1600 cm~1 (6) N -L3 - (4- Benzhydryl - 1 - piperazinyl) propyU - 5 - methoxyanthranilic acid, mp 190-193"C (dec.).

I.R. (Nujol): 3210, 1610, 1595 cm- Example 3 (1) To a suspension of N-[3-(4-benzhydryl-1 piperazinyl) propyl anthranilic acid (2.15 g) in dry methylene chloride (40 ml) was added phosphorus pentachloride (1.04 g) under ice-water cooling with stirring, and the stirring was continued at the same temperature for half an hour. To this mixture was added dropwise a solution of propylamine (1.48 g) in dry methylene chloride (3 ml) over a period of 10 minutes under ice-water cooling with stirring, and the stirring was continued at the same temperature for 50 minutes. After the reaction mixture was poured into ice-water (200 ml), the organic layer was separated.The remaining aqueous layer was extracted three times with methylene chloride, and the combined methylene chloride solution was washed three times with water and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue (2.82 g) was chromatographed in silica gel (19 g) using chloroform as an eluent. The fractions which contained the desired component were collected and evaporated. The resultant product (1.55 g) was transformed into its hydrochloride using ethanol containing hydrogen chloride in a conventional manner to give crude crystals oftrihydrochloride of N-propyl N' -t3 - (4 - benzhydryl - 1 piperazinyl) propyls anthranilamide (1.71 g).These crystals were dissolved in ethanol and treated with charcoal (0.3 g), and the filtrate was allowed to stand to gives purified crystals of the above compound (0.72 g), mp 196-198"C.

I.R. (Nujol): 3225, 2275, 1630, 1610cm-1 (2) Trihydrochloride of N,N-diethyl N' -L3 - (4 - benzhydryl - 1 - piperazinyl) propyl anthranilamide (1.25 g) was obtained by reacting N - 13 - (4 - benzhydryl - 1 - piperazinyl) propyls anthranilic acid (2.15 g) with phosphorus pentachtoride (1.04 g) and diethylamine (1.84g) in substantiallythe same manner as that of Example 3-(1), mp 187-88'C (dec.).

I.R. (Nujol): 3400,3300, 1625, 1580cm-1 (3) To a suspension of N'-[3 - (4- benzhydryl - 1 piperazinyl) propyl anthranilic acid (2.0 g) in dry N,N - dimethylformamide (14 ml) was added at a time N,N' - carbonyldiimidazole (0.84 g) at ambient temperature with stirring, and the stirring was continued at 90"C for 15 minutes. To this mixture was added at a time 5 - amino - 1 H - tetrazole (0.46 g) at 90"C with stirring, and the stirring was continued at the same temperature for 5 hours.After cooling, the resultant precipitates were collected, washed with a small amount of N,N - dimethylformamide and ethyl acetate to give crude crystals of N - (1 H -tetrazol - 5 - yl) N' -L3 - (4- benzhydryl - 1 - piperazinyl) propyl anthranilamide (1.40 g). Thus obtained crude crystals (2.0 g) were recrystallized from a mixed solvent of ethanol (950 ml) and N,N - dimethylformamide (50 ml)to give purified crystals of the above object compound (1.25 9), mp 202-203"C.

I.R. (Nujol): 3300,3150, 1635 cm- Example 4 (1) A mixture of N - (3 - chloropropionyl) anthranilic acid (3.40 g), 1 - benzhydrylpiperazine (4.03 g), anhydrous potassium carbonate (2.07 g) and potassium iodide (0.83 g) in ethanol (50 ml) was refluxed with stirring for2 hours. The mixture was evaporated to dryness and the residue was dissolved in a mixture of ethyl acetate (100 ml) and water (100 ml).

The aqueous layer was separated out, washed with ethyl acetate and adjusted to pH 1 with 10% hydrochloric acid. The aqueous mixture was adjusted to pH 8 with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was recrystallized from a mixed solvent of N,N dimethylformamide and methanol (1 :1) to give N L3 - (4- benzhydryl - 1 - piperazinyl) - propionylu ant hranilicacid (1.01 9), mp 163-165"C.

I.R. (Nujol): 3340, 1680, 1590 cm-' (2) N -t2 - (4- Benzyhydryl - 1 - piperazinyl) acetyli- anthranilic acid (7.0 g) was obtained by reacting N (2 - chloroacetyl) anthranilic acid (3.7 g) with 1 - benzhydrylpiperazine (4.89) in substantially the same manner as that of Example 4-(I), mp 21 9.5-222.5'C (dec.).

I.R. (Nujol): 3200 (shoulder), 3150,2600,1675, 1580 cml (3) A mixture of N - l2 - (3 - chloropropylamino) phenylu - N' - methylurntde (1.90 g), 1 - benzhydrylpiperazine (2.28 g), anhydrous potassium carbonate (1.1 g) and potassium iodide (1.3 g) in dry N,N dimethylformamide (19 ml) was stirred at ambient temperature for 35 minutes and at 80 C for 2 hours.

After cooling, the reaction mixture was poured into a mixture of ice-water (150 ml) and methylene chloride (30 ml), followed by the organic layer was separated.

The remaining aqueous layer was extracted three times with methylene chloride (each 3Q ml), and the combined methylene chloride solution was washed three times with water (each 80 ml), dried over anhydrous magnesium sulfate and then evaporated to dryness to give the residue (4.75 g), which was chromatographed on silica gel (50 g) using a mixed solventofchloroform and methanol (100:3 by volume) as an eluent.The fractions which contained the desired component were collected and evaporated to dryness and the residue obtained was crystallized from diisopropyl etherto give crude crystals (2.11 g) of N - 12 - 13 - (4 - benzhydryl - 1 - piperazinyl) prop ylamino phenyli - N' - methylureide. 1 g ofthis product was recrystallized from ethanol (80 ml) to obtain the purified crystals (0.65 g) of the above object compound, mp 172-173"C.

I.R. (Nujol): 3400,3300, 1675, 1620, 1600, 1575 cm-' (4) Methyl N -12 -43 - (4- benzhydryl - 1 - piperazinyl) - propylamino phenylu carbamate (2.05 g) was obtained by reacting methyl N - L2 - (3 chloropropylamino) phenylj - carbamate (2.60 g) with benzhydrylpiperazine (3.24 g) in substantially the same manner as that of Example 4-(3), mp 115-116"C.

I.R. (Nujol): 3150, 1710 cm' (5) A mixture of N -L2 - (3 - chloropropoxy) phenyli - N' - methylureide (3.65 g), 1 - benzhydrylpiperazine (4.16 g), anhydrous potassium carbonate (2.07 g) and potassium iodide (0.83 g) in dry N,N - dimethylformamide (40 ml) was stirred at 75"C for 1.5 hours.

After cooling, the reaction mixture was poured into ice-water (200 ml) and extracted twice with ethyl acetate (each 100 ml), followed by the ethyl acetate solution was washed with water and then extracted with hydrochloric acid. The aqueous extract was adjusted to pH 8 with a saturated aqueous solution of sodium bicarbonate and then extracted twice with ethyl acetate. The combined ethyl acetate solution was washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The residue obtained was crystallized from a mixed solvent of diethyl ether and ethanol and collected by filtration to give N - i2 -43 - (4- benzhydryl - 1 - piperazinyl) propoxy) phenylj - N' - methylureide (0.17 g).

Further, the mother liquor was evaporated to dryness under reduced pressure to give the residue (7.36 g), which was chromatographed on silica gel (250 g) using chloroform and then a mixed solvent of chloroform and methanol (99:1 by volume) as an eluent. The fractions which contained the desired component were collected and evaporated to dryness to give the residue (4.63 g), which was crystallized from ethanol and then recrystallized from the same solvent to recover the ethanol solvate of the above object compound (2.95 g).

I.R. (Nujol): 3300,1680,1670,1600 cm-' Example 5 (1) To a cold solution of methyl saiicylate (2.28 g) in N,N - dimethylformamide (50 ml) was added potassium tert-butoxide (2.02 g) and the mixture was stirred for 5 minutes in an ice-bath. To the mixture were added potassium iodide (0.80 g) and 4 - benzhydryl 1 - (3 - chloropropyl) piperazine (4.93 g), and the mixture was stirred for 50 minutes at ambienttempera- ture and for additional 4 hours at 70ZC. The reaction mixture was poured into ice-water and extracted twice with ethyl acetate (each 100 ml). The combined extracts were washed three times with water and then dried over anhydrous magnesium sulfate.After removal ofthe solvent, the residue was chromatographed on silica gel (60 g) using chloroform and then a mixed solvent of chloroform and methanol (99:1 by volume) as an eluent. The fractions which contained the desired component were collected and evaporated to give an oil (2.71 g) of methyl 0 -13 - (4 - benzhydryl - 1 - piperazinyl) propyls salicylate.

I.R. (Film): 1725, 1600 cm-' (2) To a mixture of methyl 4 - methylsalicylate (3.32 g), potassium iodide (3.32 g) and anhydrous potassium carbonate (2.77 g) in N,N - dimethylformamide (20 ml) was added at a time a solution of 4 - benzhydryl - 1 - (3 - chloropropyl) piperazine (7.89 g) in N,N dimethylformamide (20 ml) with stirring, and the stirring was continued at ambient temperature for 1.5 hours and at 70"C for additional 4 hours. After cooling, the reaction mixture was poured into a mixture of ice-water (300 ml) and methylene chloride (60 ml), followed by the organic layer was separated.

The remaining aqueous layer was extracted three times with methylene chloride (each 40 ml), and the combined methylene chloride solution was washed three times with water (each 100 ml), dried over anhydrous magnesium sulfate and then evaporated to dryness to give the residue (10.3 g), which was chromatographed on silica gel (100 g) using chloroform as an eluent. The fractions which contained the desired component were collected and evaporated to dryness to give methyl 0 - 13 - (4 benzhydryl - 1 - piperazinyl) propylj - 4 - methyl- salicylate (6.52 g), mp 102-108"C.

The following compounds (2) to (7) were obtained by reacting 4 - benzhydryl - 1 - (3 - chloropropyl) piperazine with the corresponding compound (IV) in substantially the same manner as that of Example 5-(2).

(3) Methyl O -L3 - (4- benzhydryl - 1 - piperazinyl) propylJ - 5 - methylsalicylate.

I.R. (Film): 1720, 1665cm1 (4) Methyl O -L3 - (4- benzhydryl - 1 - piperazinyl) propylj - 3 - phenylsalicylate.

I.R. (Film): 1720, 1670, 1590cm-1 (5) Methyl O - L3 - (4 - benzhydryl - 1 - piperazinyl) prnpylj - 4 - acetamidosalicylate.

I.R. (Nujol): 3400,3200,1685,1585 cm~' (6) Methyl O -t3- (4- benzhydryl - 1 - piperazinyl) propylj 4- mesylaminosalicylate.

l.R. (Film): 1655, 1605, 1565 cam~' (7) Methyl 2 -[3 - (4 - benzhydryl - 1 - piperazinyl) propylthioj - benzoate.

i.R. (Film): 1705, 1670 cm-' Example 6 (1) A mixture of methyl 0 -[3 - (4 - benzhydryl - 1 piperazinyl) propylj salicylate (2.66 g) and 1 N aque oussolutionofsodium hydroxide (9.5 ml) in methanol (30 ml) was refluxed for 7 hours. After removal ofthe methanol, 1 N hydrochloric acid (9.5 ml) was added thereto and extracted twice with ethyl acetate (each 50 ml). The combined extracts were washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and evaporated to dryness to give crystals, which were treated with diethyl ether to obtain crude crystals of monohydrochloride of O -[3 - (4 - benzhydryl 1 - piperazinyl) propyls - salicylic acid (1.86 g).The crystals were dissolved in acetonitrile (20 ml) and the insoluble substance was removed by filtration. The filtrate was gradually concentrated to one third of the original volume and the resultant precipitates were collected by filtration to give the purified crystals (1.01 g) of the above object compound, mp 197-201 tC.

I.R. (Nujol): 2570, 1680, 1590 cm' The following compounds (2) to (3) were obtained in substantially the same manner as that of Example 6-(1).

(2) Dihydrochloride of 0 -[3 - (4 - benzhydryl - 1 piperazinyl) - propyls -4- methylsalicylic acid, mp 165-168"C.

I.R. (Nujol): 3375,2450, 1675, cm~' (3) Dihydrochloride of 0 -[3 - (4- benzhydryl - 1 - piperazinyl) - propyl - 4 - acetamidosalicylic acid, mp 175-179"C (dec.).

I.R. (Nujol): 3350, 1670, 1590 cm~' (4) A mixture of methyl 0 - [3- (4 - benzhydryl - 1 piperazinyl) propyl - 5 - methylsalicylate (4.96 g) and 10% aqueous solution of sodium hydroxide (10.4 ml) in methanol (55 ml) was refluxed for 21 hours. After removal of the methanol, to the resultant aqueous solution were added diethyl ether and water. The aqueous solution was separated, washed with diethyl ether and adjusted to about pH 6 with 10% hydrochloric acid under ice-water cooling while stirring. The resultant oily substance was separated by decantation, triturated with water.These crystals were collected by filtration, washed several times with water and dried to give crude crystals (3.43 g) of O -t3 - (4- benzhydryl - 1 - piperazinyl) propylu - 5 - methylsalicylic acid. These crystals were recrystallized from a mixed solvent of ethyl acetate (90 ml) and ethanol (12 ml) to obtain the purified crystals (0.9 g) of the above object compound, mp 168-169 C.

I.R. (Nujol): 3650,3400,2550,1680 cm~' (5) O - L3 - (4 - Benzhydryl - 1 - piperazinyl) propyls 4- mesylaminosalicylic acid (2.80 g) was obtained by hydrolysing methyl O -L3 - (4- benzhydryl - 1 piperazinyl) - propyld - 4 - mesylaminosalicylate (4.82 g) with 10% aqueous solution of sodium hydroxide (6.5 ml) in substantiallythe same manner as that of Example 6-(4), mp 253-255"C (dec.).

I.R. (Nujol): 3575,3350, 1625, 1585 cm-' (6) A mixture of methyl 0 -t3 - (4 - benzhydryl - 1 piperazinyl) - propyls -3 - phenylsalicylate (9.02 g) and 10% aqueous solution of sodium hydroxide (16.8 ml) in methanol (89 ml) was refluxed for 20 hours and 40 minutes. After removal of the methanol, 1 N aqueous solution of sodium hydroxide (6 ml) and water (250 ml) were added thereto and then warmed. After filtration, to the filtrate was added diethyl ether (30 ml) and allowed to stand.

The resultant precipitates were collected, washed twice with diethyl ether and three times with water and then dried to give sodium salt of O - [3 - (4 benzhydryl - 1 - piperazinyl) propylu - 3 - phenyl- salicylic acid (6.37 g), mp 253-255"C (dec.).

I.R. (Nujol): 3350,1590, 1560cm1 (7) A mixture of methyl 2 -[3 - (4 - benzhydryl - 1 piperazinyl) propylthioj benzoate (3.52 g) and 1 N aqueous solution of sodium hydroxide (12.1 ml) in methanol (38 ml) was refluxed for 6 hours. After cooling, the methanol was removed by distillation from the reaction mixture to give the residue, to which a small amount of water and diethyl ether (30 ml) were added. The aqueous layer was separated and thereto was added ethyl acetate (50 ml). The mixture was adjusted to pH 4 with 1 N hydrochloric acid, and the resultant precipitates (1.2 g) were collected by filtration. 1 g of these precipitates were recrystallized from ethanol to give 2 -i3 - (4 - benzhydryl - 1 - piperazinyl) - propylthioj benzoic acid (0.37 g), mp 210-212 C.

I.R. (Nujol): 1655 cml Further, the ethyl acetate layer was separated from the filtrate obtained above, and the remaining aqueous solution was extracted with ethyl acetate (50 ml).

The combined ethyl acetate solution was washed with an aqueous solution of sodium chloride (50 ml) and dried over an hydros magnesium sulfate. After removal of the solvent, the residue was triturated with diethyl etherto give hydrochloride of the above object compound (0.78 g), mp 108-111"C (dec.).

I.R. (Nujol): 3350, 2550, 1695 cm~' Example 7 To a sospension of N - - (4 - benzhydryl - 1 - piperazinyl) - propylj anthranilic acid (2.15 g) in methylene chloride (40 ml) was added phosphorus pentachloride (1.04 g) and the mixture was stirred for half an hour in an ice-bath. To the solution was added absolute ethanol (10 ml) and the mixture was stirred for one hour in an ice-bath. The reaction mixture was poured into ice-water (100 ml) and extracted with methylene chloride. The extract was washed with water, dried over an hydros magnesium sulfate and evaporated. The residue (2.05 g) was subjected to a column chromatography on silica gel (20 g) using chloroform as an eluent. The fractions which contained the desired component were collected and evaporated.To the residue (1.60 g) dissolved in ethanol (20 ml) was added a solution of maleic acid (0.46 g) in ethanol (10 ml). The resultant precipitates were collected and recrystallized from ethanol to give dimaleate of ethyl N - L3 - (4 - benzhydryl - 1 - piperazinyl) - propyl anthranilate (1.09 g), mp 147-151"C.

I.R. (Nujol): 3350,2350, 1670, 1610cm-1 Example 8 To a suspension of N -t3 - (4 - benzhydryl - 1 piperazinyl) - propylj anthranilic acid (2g) in pyridine (10ml) was added acetic anhydride (1 ml) at ambient temperature with stirring, and the stirring was contin sued for an hour. After removal of the solvent, the residue was triturated and washed with diisopropyl ether. The resultant solid (2.359) was broken up in water and stirred for a while. After washing with water, the solid (1.96g) was recrystallized from ethanol to give N - acetyl - N -t3 - (4 - benzhydryl - 1 piperazinyl) propyls - anthranilic acid (1.5g), mp 158-160"c.

I.R. (Nujol): 3425, 1665, 1600 cam '

Claims

1. Acompound oftheformula:

wherein R1 is carboxy, carboxy derivative, oxalo, or acylamino, Ra is hydrogen, halogen, lower alkyl, lower alkoxy, aryl or acylamino, R3 is ar(lower)alkyl, A is lower alkylene, and Xis-N-, -O-, -S- or-NHCO-, R4 in which Ra is hydrogen or acyl, and a pharmaceutically acceptable salt thereof.

2. The compound accoring to claim 1, wherein R' is carboxy, lower alkoxycarbonyl, N-lower alkylcarbamoyl, N,N - di(lower) - alkylcarbamoyl, N-tetrazolylcarbamoyl, oxalo, N' - (lower) alkylureido or lower alkoxycarbonylamino, Ra is hydrogen, halogen, lower alkyl, lower alkoxy, phenyl, lovver alkanoylamino or lovver alkanesulfonylamino, R3 is diphenyl (lower) alkyl, and Xis -N-, -O-, -S-or-NHCO-, R4 in which Ra is hydrogen or lower alkanoyl.

3. The compound according to claim 2, wherein R3 is benzhydryl, and A is C -C, alkylene.

4. The compound according to claim 3, which is N -t3 - (4- benzhydryl - 1 - piperazinyl) propyl anthranilic acid.

5. The compound according to claim 3, which is N - t3 - (4 - benzhydryí - 1 - piperazinyl) propyl]-4- fluoroanthranilic acid.

6. The compound according to claim 3, which is N -t2 -t3 - (4- benzhydryl - 1 - piperazinyl) prop ylaminot - phenyli - N' - methylureide.

7. The compound according to claim 3, which is monohydrochloride of 0-13 - (4 - benzhydryl - 1 piperazinyl) propyls salicylic acid.

8. The compound according to claim 3, which is N -t3- (4- benzhydryí - 1 - piperazinyl) propionylj - anthranilic acid.

9. A process for preparing a compound of the formula:

wherein R' is carboxy, carboxy derivative, oxalo, or acylamino, R2 is hydrogen, halogen, lower alkyl, lower alkoxy, aryl or acylamino, R3 is ar(lower)alkyl, A is lower alkylene, and Xis -N-, -O-, -S- or-NHCO-, R4 in which R4 is hydrogen or acyl, and pharmaceutically acceptable salt thereof, which comprises (1) reacting a compound of the formula:

wherein Z is an acid residue, and R', R2, A and X are each as defined above, or its salt with a compound ofthe formula:

wherein R3 is as defined above, or its salt to give a compound of the formula:

wherein R', R2, R3, A and X are each as defined above, or its pharmaceutically acceptable salt; or (2) reacting a compound of the formula:

wherein Xa is -NH-, -O-, or-S-, and Ra and R2 are each as defined above, or its salt with a compound of the formula:

wherein R3, A and Z are each as defined above, or its salt to give a compound of the formula:

wherein R1, R2, R3, A and Xa are each as defined above, or its pharmaceutically acceptable salt; or (3) subjecting a compound of the formula

wherein R2, R3 and A are each as defined above, or its salt to hydrolysis to give a compound of the formula.

wherein R2, R3 and A are each as defined above, or its pharmaceutically acceptable salt; or (4) reacting a compound of the formula:

wherein R2, R3, and A are each as defined above, or its salt with an oxidizing agent to give a compound of the formula:

wherein R2, R3 and A are each as defined above, or its pharmaceutically acceptable salt; or (5) subjecting a compound of the formula:

wherein R21 is a protected carboxy group, and Ra, Era, A and X are each as defined above, or its saint to hydrolysis to give a compound of the formula:

wherein R2, R3, A and X are each as defined above, or its pharmaceutically acceptable salt; or (6) reacting a compound of the formula:

wherein R2, R3, A and X are each as defined above, or its salt with an amine compound of the formula:

wherein Ra is hydrogen or lower alkyl, and Rb is lower alkyl or a heterocyclic group, or its salt to give a compound of the formula:

wherein Ra, R3, Ra, Rb, A and X are each as defined above, or its pharmaceutically acceptable salt; or (7) reacting a compound of the formula:

wherein RI, A,A and X are each as defined above, or its salt with an esterifying agent to give a compound ofthe formula:

wherein Rb is an esterified carboxy group, and R2, R3, A and X are each as defined above, or its pharmaceutically acceptable salt; or (8) acylating a compound of the formula:

wherein R', R2, R3 and A are each as defined above, or its salt with a compound ofthe formula: R4aOH wherein R4 is acyl, or its reactive derivative to give a compound of the formula:

wherein R1, Ra, Ra, R4a and A are each as defined above, or its pharmaceutically acceptable salt.

10. A pharmaceutical composition comprising, as an active ingredient, the compound claimed in claim 1 in admixture with pharmaceutically acceptable carrier.