WO1998047901A1

WO1998047901A1 - Process for producing tricyclic compounds and their intermediates

Info

Publication number: WO1998047901A1
Application number: PCT/JP1998/001752
Authority: WO
Inventors: Tomomi Ikemoto; Mitsuhiro Wakimasu
Original assignee: Takeda Chemical Industries, Ltd.
Priority date: 1997-04-18
Filing date: 1998-04-16
Publication date: 1998-10-29
Also published as: AU6852798A

Abstract

The present invention provides a process for producing tricyclic compounds which are useful as agents for treating renal diseases and arteriosclerosis, which process requires few steps and uses inexpensive materials, by using a compound of formula (III), wherein Z is a leaving group, X is an optionally substituted divalent hydrocarbon group, ring Y is an optionally substituted nitrogen-containing 5- or 6-membered heterocyclic ring and R is an optionally substituted divalent hydrocarbon group, or a salt thereof.

Description

Description Process for producing tricyclic compounds and their intermediates

Technical field

The present invention relates to a process for producing tricyclic compounds having excellent activity in, for example, inhibiting platelet-derived growth factor (PDGF), ameliorating the activity of renal diseases, lowering cholesterol levels, and their useful intermediates .

Background art

PCT international published application No. WO 96/02542, discloses a process for producing tricyclic compounds which are useful as medicines , having an excellent activity in, for example, inhibiting platelet-derived growth factor (PDGF), antihypertensive activity, ameliorating activity of renal diseases, and lowering cholesterol levels.

However, the process disclosed in the above PCT published application suffers from the faults of requiring many steps and the need for expensive materials.

Disclosure of the Invention

Circumstances being such as above, a process for producing the above-mentioned tricyclic compounds, having few steps and using inexpensive materials, has been desired. The present inventors have made extensive and intensive studies, and as a result, have found that the above-mentioned tricyclic compounds can be obtained with a high yield in addition to having the advantages of requiring few steps and being less expensive, by using a compound of the formula (III):

wherein Z is a leaving group, X is an optionally substituted divalent hydrocarbon group, ring Y is an optionally substituted nitrogen-containing 5- or 6-membered heterocyclic ring and R is an optionally substituted hydrocarbon group, or a salt thereof, and have further developed studies to accomplish the present invention.

Namely, the present invention relates to (1) a process for producing a compound of the formula

(I)

wherein ring A may be substituted, ring B may have one oxo group, R¹ is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an acyl group, X is an optionally substituted divalent hydrocarbon group, ring Y is an optionally substituted nitrogen-containing 5- or 6-membered heterocyclic ring and R is an optionally substituted hydrocarbon group, or a salt thereof, which comprises reacting a compound of the formula (II):

wherein the symbols are as defined above, or a salt thereof, with a compound of the formula (III):

wherein Z is a leaving group and the other symbols are as defined above, or a salt thereof,

(2) a process described in the above item 1, wherein ring A may be substituted with 1 to 3 groups selected from halogen , C₁.₆ alkyl,

alkoxy,

alkoxy, C^ alkylthio, halogeno-C_j.g alkylthio, hydroxy, carboxy, cyano, nitro, amino, mono- or

alkylamino, formyl, mercapto, C₁_₆ alkyl-carbonyl, C_x__β alkoxy-carbonyl, sulfo, C-_L.J alkylsulfonyl , carbamoyl and mono- or

alkyl-carbamoyl , ring B is a ring of the formula:

X is (l)a C_x_₁₅ alkylene group, a C₂.₁₆ alkenylene group or a C₂_₁₆ alkynylene group, which may be substituted with 1 to 5 groups selected from C₁_₆ alkyl and phenyl, (2)a phenylene group which may be substituted with 1 to 4 groups selected from halogen, C₁_₆ alkyl, C_λ_₆ alkoxy, C^ alkylthio, hydroxy, carboxy, cyano, nitro, amino, mono- or

alkylamino, formyl, mercapto, C^ alkyl-carbonyl, C^. alkoxy-carbonyl, sulfo,

alkylsulfonyl, carbamoyl and mono- or

alkyl-carbamoyl, or (3)a divalent group formed by combining these groups , ring Y is a piperidine, a pyrrolidine or a pyridine which may be substituted with 1 to 3 groups selected from halogen,

alkyl, C_x_₆ alkoxy, halogeno- C₁_₆ alkoxy,

alkylthio,

alkylthio , hydroxy, carboxy, cyano, nitro, amino, mono- or alkylamino, formyl, mercapto,

alkyl-carbonyl

alkoxy-carbonyl, sulfo,

alkylsulfonyl, carbamoyl and mono- or di-C^_g alkyl-carbamoyl, R is a C_x.₁₅ alkyl group, a C₃.₈ cycloalkyl group, a C₂_₁₈ alkenyl group, a C₇.₁₆ aralkyl group or a C₆.₁₄ aryl group, which may be substituted with 1 to 5 groups selected from nitro, hydroxy, cyano, carbamoyl, mono- or alkyl-carbamoyl, carboxy, C_1-6 alkoxy-carbonyl, sulfo, halogen, C_x_₆ alkoxy, phenoxy, halogeno-phenoxy, C^ alkylthio, mercapto, phenylthio, pyridylthio, C^ alkylsulfinyl,

alkylsulfonyl, amino, C₁_₆ acylamino , mono- or

lkylamino, 4- to 6-membered cyclic amino, C₁.₁ acyl, benzoyl, 5- or 6-membered monocyclic heteroaromatic ring containing 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, bicyclic heteroaromatic ring which is formed by condensing 5- or 6-membered heteroaromatic ring containing 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom with benzene ring, and a C₇_₁₆ aralkyl group or a C₆.₁₄ aryl group which may be substituted with

alkyl, halogeno-Ci.g alkyl or oxo, R¹ is ( 1 )a hydrogen atom, ( 2 )a halogen atom, (3)anacyl group derived from carboxylic acid or (4)a C^^ alkyl group, ^a C₃.₈ cycloalkyl group, a C₂.₁₈ alkenyl group, a C₇_₁₆ aralkyl group or a C₆_₁₄ aryl group, which may be substituted with 1 to 5 groups selected from nitro, hydroxy, cyano, carbamoyl, mono- or alkyl, carboxy, CAg lkoxy-carbonyl, sulfo, halogen,

lkoxy, phenoxy, halogeno-phenoxy alkylthio, mercapto, phenylthio, pyridylthio,

alkylsulfinyl,

acylamino, mono- or

alkylamino, 4- to 6-membered cyclic amino, C₁.₇ acyl, benzoyl, 5- or 6-membered monocyclic heteroaromatic ring containing 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, bicyclic heteroaromatic ring which is formed by condensing 5- or 6-membered heteroaromatic ring containing 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom with benzene ring, or a C₇.₁₆ aralkyl group or a C₆_₁₄ aryl group which may be substituted with C_λ_₆ alkyl, halogeno-Ci.g alkyl or oxo, and

Z is a halogen atom, a C^,, alkylsulfonyloxy group or a C₆.₁₀ arylsulfonyloxy group. (3) a process described in the above item 1, wherein ring A is unsubstituted, ring B is a ring of the formula:

R is a hydrogen atom or a

alkyl group, X is a

alkylene group, ring Y is a piperidine and R is a halogeno-C^ alkyl group ,

(4) a process described in the above item 1, wherein ring A may be substituted with halogen,

alkylthio, C^ alkoxy, hydroxy, carboxy, nitro or amino, R¹ is (l)a hydrogen atom, (2)a C₁_₁₀ alkyl group or a C₆_₁₄ aryl group which may be substituted with halogen, hydroxy, carboxy, nitro or amino, (3)a

alkoxy-carbonyl group or (4)a C₁.₆ alkanoyl group, Z is a halogen atom, a C^,, alkylsulfonyloxy group or a C_λ_₁₀ arylsulfonyloxy group, X is a

alkylene group which may be substituted with halogen, hydroxy, C^ alkyl or C₆_₁₄ aryl, ring Y is a nitrogen-containing 6- membered heterocyclic ring, and R is a C_λ_₁₅ alkyl group, ^a C₃_₈ cycloalkyl group, a C₂„₁₀ alkenyl group, a C₆.₁₄ aryl group or a C₇.₁₆ aralkyl group which may be substituted with (i)halogen, (ii)cyano, ( iii)hydroxy, ( ±v ) C₁_₆ alkyl which may be substituted with halogen, (v) C₁,₆ alkoxy which may be substituted with halogen, (vi)C₆.₁₄ aryl, (vii) carboxy which may be esterified or (viii)5- or 6-membered heterocyclic group,

(5) a process described in the above item 1, wherein ring A may be substituted with halogen or C₂.₄ alkyl, ring B is a ring of the formula:

R¹ is a hydrogen atom, a alkyl group or a C₆.₁₄ aryl group, X is a

alkylene group which may be substituted with halogen, hydroxy or C_:_₄ alkyl, ring Y is a nitrogen- containing 6-membered heterocyclic ring, and R is a C_λ.10 alkyl group which may be substituted with halogen, hydroxy or carboxy which may be esterified,

(6) a process described in the above item 1, wherein ring A is unsubstituted, ring B is a ring of the formula:

R¹ is a hydrogen atom, ring Y is a nitrogen-containing 6-membered heterocyclic ring and R is a

alkyl group,

(7) a process described in the above item 1, wherein ring A is unsubstituted, ring B is a ring of the formula:

R¹ is a hydrogen atom, Z is a chlorine atom, X is an ethylene group, ring Y is a piperidine and R is a trifluoromethyl group ,

(8) a process described in the above item 1, which is employed under basic conditions,

(9) a compound of the formula (III):

wherein the symbols are defined as above, or a salt thereof. (10) a compound described in the above item 9, wherein X is (l)a C_x_₁₅ alkylene group, a C₂.₁₆ alkenylene group or a C₂.₁₆ alkynylene group, which may be substituted with 1 to 5 groups selected from

alkyl and phenyl, (2)a phenylene group which may be substituted with 1 to 4 groups selected from halogen,

alkyl,

alkoxy,

alkylthio, hydroxy, carboxy, cyano, nitro, amino, mono- or

alkylamino, formyl, mercapto,

alkoxy-carbonyl, sulfo, alkylsulfonyl , carbamoyl and mono- or

alkyl-carbamoyl, or (3)a divalent group formed by combining these groups, ring Y is a piperidine, a pyrrolidine or a pyridine which may be substituted with 1 to 3 groups selected from halogen,

alkyl,

alkoxy,

alkoxy, C₁.₆ alkylthio,

alkylthio, hydroxy, carboxy, cyano, nitro, amino, mono- or di-C₁_₆ alkylamino, formyl, mercapto,

alkoxy-carbonyl, sulfo,

alkylsulfonyl, carbamoyl and mono- or

alkyl-carbamoyl,

R is a C_j^_s alkyl group, a C₃_₈ cycloalkyl group, a C₂.₁₈ alkenyl group, a C₇.₁₆ aralkyl group or a C₆_₁₄ aryl group, which may be substituted with 1 to 5 groups selected from nitro, hydroxy, cyano, carbamoyl, mono- or

alkyl, carboxy,

alkoxy, phenoxy, halogeno-phenoxy,

alkylthio, mercapto, phenylthio, pyridylthio, C₁_₆ alkylsulfinyl, C₁_₆ alkylsulfonyl, amino,

acylamino, mono- or

alkylamino, 4- to 6-membered cyclic amino, C_1-7 acyl, benzoyl, 5- or 6-membered monocyclic heteroaromatic ring containing 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, bicyclic heteroaromatic ring which is formed by condensing 5- or 6-membered heteroaromatic ring containing 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom with benzene ring, and a C₇_₁₆ aralkyl group or a C₆.₁₄ aryl group which may be substituted with

alkyl,

alkyl or oxo, and

Z is a halogen atom, a C_x_₄ alkylsulfonyloxy group or a C₆.₁₀ arylsulfonyloxy group,

(11) a compound described in the above item 9, wherein X is a C^_g alkylene group, ring Y is a piperidine and R is a

alkyl group,

(12) a compound described in the above item 9, wherein X is an ethylene group, ring Y is a piperidine and R is a trifluoromethyl group. (13) a process for producing a compound of the formula (III):

wherein the symbols are as defined above, or a salt thereof, which comprises reacting a sulfonylating reagent which contains an optionally substituted hydrocarbon group, with a compound of the formula (IV):

wherein the symbols are as defined above, or a salt thereof, (14) use of the compound of the formula (III):

wherein the symbols are as defined above, or a salt thereof, for producing the compound of the formula ( I ) :

wherein the symbols are as defined above, or a salt thereof, and

( 15 ) a method for producing the compound of the formula ( I ) :

wherein the symbols are as defined above, or a salt thereof, which comprises utilizing a compound of the formula (III) :

wherein the symbols are as defined above, or a salt thereof.

In the above-mentioned formulae, ring A may be substituted. Example substituents of ring A, include (1) halogen(e.g. fluorine, chlorine, bromine and iodine), (2)C_X_₆ alkyl (e.g. methyl, ethyl, propyl, isopropyl and butyl), ( 3)halogeno-C_x_₆ alkyl such as

alkyl which is substituted with 1 to 5 halogens ( e. g. trifluoromethyl and trichloroethyl) , (4)^.₆ alkoxy(e.g. methoxy, ethoxy, propoxy and isopropoxy) , ( 5

alkoxy such as

alkoxy which is substituted with 1 to 5 halogens (e. g . trifluoromethoxy and trichloroethoxy) , ( 6 ) C₁_₆ alkylthio(e.g. methylthio, ethythio, propylthio and isopropylthio) , ( 7

alkylthio such as C₁.₆ alkylthio which is substituted with 1 to 5 halogens (e. g. trifluoromethylthio and trichloroethylthio) , ( 8)hydroxy, (9)carboxy, (10) cyano, (11)nitro, (12) amino, (13)mono- or alkylamino ( e . g . methylamino, ethylamino, dimethylamino and diethylamino ) , (14)formyl, ( 15 )mercapto, (16)0^₆ alkyl-carbonyl (e.g. acetyl, propionyl and butyryl), (17)0^₆ alkoxy-carbonyl ( e. g. methoxycarbonyl , ethoxycarbonyl and propoxycarbonyl) , (18) sulfo, (19)C₁„₆ alkylsulfonyl (e.g. methylsulfonyl, ethylsulfonyl and propylsulfonyl) , ( 20)carbamoyl, (21)mono- or

alkyl-carbamoyl(e.g. N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl and N,N-diethylcarbamoyl) . The ring A may be substituted with these same or different 1 to 3 substituents at substitutable positions.

In the above-mentioned formulae, ring B may have one oxo group. Examples of ring B include a nitrogen-containing 5- or 6-membered heterocyclic ring such as rings of the formula :

Among others, rings of the formula:

are preferable and especially, a ring of the formula:

is commonly used.

In the above-mentioned formulae, X is an optionally divalent hydrocarbon group. Examples of the divalent hydrocarbon group of an optionally divalent hydrocarbon group represented by X include linear divalent hydrocarbon group such as C₁.₁₅ alkylene group (e.g. methylene, ethylene, propylene, butylene, pentamethylene, hexamethylene , heptamethylene and octamethylene) , C₂.₁₆ alkenylene group(e.g. vinylene, propenylene, 1-butenylene, 2- butenylene, 1-pentenylene, 2-pentenylene and 3- pentenylene) , C₂.₁₆ alkynylene group(e.g. ethynylene, propynylene, 1-butynylene, 2-butynylene, 1-pentynylene, 2-pentynylene and 3-pentynylene) , phenylene group and divalent groups formed by combining these groups . Preferable examples are C^^ alkylene groups (e.g. methylene , ethylene, propylene, butylene, pentamethylene, hexamethylene, heptamethylene and octamethylene), more preferably C_x_₆ alkylene groups (e.g. methylene, ethylene and propylene) . The said linear divalent hydrocarbon group may have same or different 1 to 5 substituents selected from C₁_₆ alkyl(e.g. methyl, ethyl, propyl, isopropyl and butyl) and phenyl at substitutable positions.

Examples of the substituents which the said phenylene group may have at substituable positions, include same or different 1 to 4 substituents selected from, ( l)halogen(e.g. fluorine, chlorine, bromine and iodine) , ( 2 ) C₁_₆ alkyl (e.g. methyl, ethyl, propyl, isopropyl and butyl), (3)0^ alkoxy(e.g. methoxy, ethoxy, propoxy, isopropoxy and butoxy) , { ) C₁_₆ alkylthio (e.g. methylthio , ethythio, propylthio, isopropylthio and butylthio) , (5)hydroxy, (6)carboxy, (7)cyano, (8)nitro, (9)amino, (lθ)mono- or alkylamino (e.g. methylamino , ethylamino , dimethylamino and diethylamino ) , (ll)formyl, ( 12 )mercapto, ( 13)0^₆ alkyl-carbonyl(e.g. acetyl, propionyl and butyryl) , (14)^.₅ alkoxy-carbonyl ( e. g. methoxycarbonyl , ethoxycarbonyl and propoxycarbonyl) , (15)sulfo, (16)0^₆ alkylsulfonyl(e.g. methylsulfonyl, ethylsulfonyl and propylsulfonyl) , ( 17 )carbamoyl and (18)mono- or

alky1-carbamoyl ( e. g. -methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl and N,N-diethylcarbamoyl) . In the above-mentioned formulae, ring Y is an optionally substituted nitrogen-containing 5- or 6- membered heterocyclic ring.

The said nitrogen-containing 5- or 6-membered heterocyclic ring may be saturated or unsaturated. Examples of the said nitrogen-containing 5- or 6-membered heterocyclic ring include a piperidine, a pyrrolidine or a pyridine. Practically, examples of the group of the formula :

include

preferably.

and especially

is commonly used.

In the above-mentioned formulae, R is an optionally substituted hydrocarbon group. Examples of the hydrocarbon group of the optionally substituted hydrocarbon group represented by R include an alkyl group , a cycloalkyl grou , an alkenyl group, an aralkyl group and an aryl group.

Examples of the said alkyl group include C₁.₁₅ alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, tridecyl, tetradecyl and pentadecyl . Preferable examples are C₁.₆ alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.

Examples of the said cycloalkyl group include C₃_₈ cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Examples of the said alkenyl group include C₂_₁₈ alkenyl groups such as vinyl, allyl, isopropenyl, 3-butenyl, 3- octenyl and 9-octadecenyl. Preferable examples are C_2.6 alkenyl groups such as vinyl, allyl, 2-butenyl and 3- butenyl.

Examples of the said aralkyl group include C₇.₁₆ aralkyl groups, practically,

alkyl group such as benzyl, phenethyl, 3-phenylpropyl and 4-phenylbutyl, and

alkyl group such as ( 1-naphtyl)methyl and 2- ( 1-naphtyl) ethyl. Preferable examples are

alkyl groups such as benzyl .

Examples of the said aryl group include monocyclic, bicyclic or tricyclic aromatic C₆.₁₄ aryl groups such as phenyl, 1-naphtyl, 2-naphtyl, phenanthryl and anthryl. Preferable examples are C₆_₁₀ aryl group such as phenyl.

Examples of the substituents which the said hydrocarbon group may have , include (l)nitro, (2)hydroxy, (3)cyano, ( 4 ) carbamoyl , (5)mono- or

alkyl (e.g. N-methylcarbamoyl, N-ethylcarbamoyl, N,N- dimethylcarbamoyl and N,N-diethylcarbamoyl) , (6)carboxy, ( 7 ) C_X_₆ alkoxy-carbonyl(e. g.methoxycarbonyl, ethoxycarbonyl , propoxycarbonyl and isopropoxycarbonyl) , (8)sulfo, ( 9 )halogen(e.g. fluorine, chlorine, bromine and iodine),

alkoxy(e . g.methoxy , ethoxy, propoxy and isopropoxy) , (ll)phenoxy, ( 12 )halogeno-phenoxy such as phenoxy which may be substituted with 1 to 3 halogens (e . g. o- , m- or p-chlorophenoxy and o- , m- or p-bromophenoxy) , (13)0^₆ alkylthio(e.g. methylthio, ethylthio, n- propylthio, isopropylthio and n-butylthio) , ( 14)mercapto, (15)phenylthio, ( 16 )pyridylthio , (17)0^₆ alkylsulfinyl (e.g. methylsulfinyl and ethylsulfinyl) , alkylsulfonyl(e.g. methylsulfonyl and ethylsulfonyl) , (19) amino, (20)0^ acylamino ( e . g . acetylamino and propionylamino ) , (21)mono- or

alkylamino (e.g. methylamino , ethylamino , dimethylamino and diethylamino), (22) cyclic amino (e.g. 4- to 6-membered cyclic amino such as 1-azethydinyl, 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino and 1-piperadinyl) , (23)0^₇ acyl(e.g. formyl and C^ alkyl-carbonyl such as acetyl), ( 24)benzoyl and (25)heterocyclic group(e.g. 5- or 6-membered monocyclic heteroaromatic group containing 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, and bicyclic heteroaromatic group which is formed by condensing 5- or 6-membered cyclic heteroaromatic ring containing 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom with benzene ring such as 2- or 3-thienyl, 2- or 3-furyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5- isothiazolyl, 2-, 4- or 5-oxazolyl, 1,2,3- or 1,2,4- triazolyl, 1H- or 2H-tetrazolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidyl, 3- or 4-pyridazinyl, quinolyl, isoquinolyl and indolyl) .

Examples of the substituents which the said aralkyl group or aryl group may have include, in addition to these substituents, groups selected from

alkyl(e.g. methyl, ethyl, propyl, isopropyl and butyl),

alkyl such as C_λ_₆ alkyl which is substituted with 1 to 5 halogens (e.g.

alkyl group such as C₁.₆ alkyl group which is substituted with 1 to 5 halogens , exemplified by chloromethyl , trifluoromethyl, trichloromethyl, 2,2, 2-trifluoroethyl, 3 , 3 , 3-trifluoropropyl and pentafluoroethyl) and oxo.

The said hydrocarbon group may have these 1 to 5 substituents at substituable positions.

In the above-mentioned formulae, R¹ is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an acyl group.

Examples of halogen atoms represented by R¹ include fluorine, chlorine, bromine and iodine.

Examples of the hydrocarbon group of the optionally substituted hydrocarbon group represented by R¹ include the same ones as the above-mentioned hydrocarbon group represented by R, and examples of the substituents include the same ones as the above-mentioned substituents which the hydrocarbon group may have. Examples of the acyl group represented by R¹ include acyl groups derived from carboxylic acid such as alkoxycarbonyl group, alkylcarbamoyl group and alkanoyl group . Examples of the said alkoxycarbonyl group include

alkoxy-carbonyl groups such as methoxycarbonyl , ethoxycarbonyl , propoxycarbonyl , isopropoxycarbonyl, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl , isopentyloxycarbonyl , neopentyloxycarbonyl and tert-pentyloxycarbonyl.

Examples of the said alkylcarbamoyl group include mono-C₁_₆-N-alkyl-carbamoyl groups such as N- methylcarbamoyl , N-ethylcarbamoyl, N-propylcarbamoyl and N-butylcarbamoyl,

groups such as N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N- dipropylcarbamoyl , N,N-dibutylcarbamoyl and N-ethyl-N- methylcarbamoyl and 4- to 6-membered cyclic carbamoyl groups combined with dialkyl(e.g. 1-azethydinylcarbonyl, morpholinocarbonyl , 1-pyrrolidinylcarbonyl, 1- piperidinylcarbonyl and 1-piperadinylcarbonyl) .

Examples of the said alkanoyl group include C^^ alkanoyl groups such as formyl, C₁_₉ alkyl-carbonyl group(e.g. acetyl, propionyl, butyryl, isobutyryl, valelyl, isovalelyl, pivaloyl and hexanoyl) . In the above-mentioned formulae, Z is a leaving group. Examples of leaving groups represented by Z include (l)a halogen atom such as fluorine, chlorine, bromine and iodine, (2)a

alkanoyloxy group such as acetoxy and propionyloxy, (3)a C₇_ arylcarbonyloxy group such as benzoyloxy, (4)a C_x_₄ alkylsulfonyloxy group such as methanesulfonyloxy and ethanesulfonyloxy and (5)a C₆.₁₄ arylsulfonyloxy group such as benzenesulfonyloxy and p- toluenesulfonyloxy.

Preferable examples of each group in the above- mentioned formulae are as follows. Ring A is preferably unsubstituted or substituted with halogen,

alkylthio, C_x_₄ alkoxy, hydroxy, carboxy, nitro or amino. Ring A is more preferably unsubstituted or substituted with halogen or

alkyl. The most preferable example of ring A is unsubstituted pyridine ring.

Preferable examples of ring B include the ring of the formula :

Preferable examples of R¹ include (l)a hydrogen atom, (2)a C^_o alkyl group or a C₆_₁₄ aryl group which may be substituted with halogen, hydroxy, carboxy, nitro or amino, (3)a

alkoxy-carbonyl group and (4)a C₁_₆ alkanoyl group, and R¹ is more preferably a hydrogen atom, a

alkyl group or a C₆_₁₄ aryl group. The most preferable example of R¹ is a hydrogen atom.

Preferable examples of Z include a halogen atom, a C^ alkylsulfonyloxy group and a C₆.₁₀ arylsulfonyloxy grou . The most preferable example of Z is a chlorine . Preferable examples of X include a C_x_ alkylene group which may be substituted with halogen, hydroxy, C_λ_. alkyl or C₆.₁₄ aryl, and more preferable examples are

alkylene groups which may be substituted with halogen, hydroxy or C^ alkyl. The most preferable example is an ethylene group. Preferable examples of ring Y include nitrogen- containing 6-membered heterocyclic rings and a piperidine is most preferable.

Preferable examples of R include a C_λ_₁₅ alkyl group, ^{a C} ₃-₈ cycloalkyl group, a C₂.₁₀ alkenyl group, a C₆.₁₄ aryl group and a C₇_₁₆ aralkyl group which may be substituted with (i)halogen, (ii) cyano, (iii)hydroxy, ( ±v ) C_λ.₆ alkyl,

alkyl which may be substituted with halogen,

alkoxy group which may be substituted with halogen, (vii)C₆_₁₄ aryl. (viii) carboxy which may be esterified or (ix)5- or 6- membered heterocyclic ring. More preferable examples of R are C₁.₁₀ alkyl groups which may be substituted with halogen, hydroxy or carboxyl which may be esterified. An especially preferable example of R is a

alkyl group. The most preferable example of R is a trifluoromethyl group.

Also , preferable examples of compounds of the formula ( I ) or a salt thereof include compounds wherein ring A is unsubstituted, ring B is a ring of the formula:

R¹ is a hydrogen atom or a

alkyl group, X is a

alkylene group, ring Y is a piperidine group and R is a

alkyl group .

Preferable examples of compounds of the formula ( I ) or a salt thereof include

1 , 2-dihydro-l- ( 1-trifluoromethanesulfonylpiperidin-4- ylmethyl ) - 1 , 4 , 7b-triazacyclopent [ cd] inden- 2 -one , 1 , 2-dihydro-l- [ 2- ( 1-trifluoromethanesulfonylpiperidin- 4-yl)ethan-l-yl] -1,4, 7b-triazacyclopent [cd] inden- 2-one, 1 , 2-dihydro-l- [3- ( 1-trifluoromethanesulfonylpiperidin- 4-yl )propan-1-yl ] - 1 , 4 , 7b-triazacyclopent [ c ] inden-2- one,

4 , 5-dihydro-4- ( 1-trifluoromethanesulfonylpiperidin-4- ylmethyl] -3H-1, 4 , 8b-triazaacenaphthylen-3-one, 4,5- ihydro-4- [ 2- ( 1-trifluoromethanesulfonylpiperidin- 4-yl ) ethan- 1-yl ] -3H- 1 , 4 , 8b-triazaacenaphthylen-3 -one , 4 , 5-dihydro-4- [ 2- ( 1-trifluoromethanesulfonylpiperidin- 4-yl)ethan-l-yl] -3H-1, 4 , 8b-triazaacenaphthylen- 5-one, 4 , 5-dihydro-4- [ 2- ( 1-trifluoromethanesulfonylpiperidin- 4-yl)ethan-l-yl] -3H-1 , 4 , 8b-triazaacenaphthylene,

4, 5-dihydro-4- [3- ( 1-trifluoromethanesulfonylpiperidin- 4-yl)propan- 1-yl] -3H-1 , 4 , 8b-triazaacenaphthylen-3-one, l , 2 - dihydro- 3-methyl- l - [ 3- ( l - trifluoromethanesulfonylpiperidin- 1-yl)propan- 1-yl] - 1,4, 7b-triazacyclopent [ cd] inden-2 -one ,

4 , 5-dihydro-4- [ 2- ( 1-trifluoromethanesulfonylpiperidin- 4-yl)ethan-l-yl] -3H-1 , 4 , 8b-triazaacenaphthylen-3 , 5- dione,

4,5-dihydro-2-methyl-4- [ 2- ( 1- trifluoromethanesulfonylpiperidin-4-yl ) ethan- 1-yl ] -3H- 1,4, 8b-triazaacenaphthylen-3 , 5-dione, 4,5-dihydro-2-methyl-4-[2-(l- trifluoromethanesulfonylpiperidin-4-yl ) ethan- 1-yl ] -3H-

1,4, 8b-triazaacenaphthylene ,

4,5-dihydro-2-methyl-4 - [ 2- ( 1- trifluoromethanesulfonylpiperidin- 4 -yl ) ethan- 1-yl ] -3H- 1,4, 8b-triazaacenaphthylen-3-one, 4,5- ihydro-2-methyl-4- [ 2- ( 1 - trifluoromethanesulfonylpiperidin-4-yl)ethan- 1-yl ] -3H- 1 , 4 ,8b-triazaacenaphthylen- 5-one and their salts.

The compound ( I ) obtained by the process of the present invention may form salts, preferably physiologically acceptable acid addition salts . Examples of the salts of the compound in the present invention are inorganic acid salts (e.g. hydrochloric acid salt, phosphoric acid salt, hydrobromic acid salt and sulfuric acid salt ) , organic acid salts (e.g. acetic acid salt, formic acid salt, propionic acid salt, fumaric acid salt, maleic acid salt, succinic acid salt, tartaric acid salt, citric acid salt, malic acid salt, oxalic acid salt, benzoic acid salt, methanesulfonic acid salt and benzenesulfonic acid salt) . When the compound (I) has an acid group such as carboxylic group, examples of salts of the compound (I) include inorganic base salts (e.g. an alkali metal salt or an alkaline earth metal salt such as sodium salt, potassium salt, calcium salt and magnesium salt, aluminum salt and ammonium salt) or organic base salts (e.g. trimethylamine salt and triethylamine salt). The compound (I) may be hydrate or non-hydrate. The compound ( I ) or a salt thereof has , in some instances, asymmetric carbons in the molecule and when two kinds of stereoisomers of R-configuration and S- configurated isomers are present, each of them and mixture of them are all included in the scope of the present invention.

In the reaction between the compound (II) or a salt thereof and the compound (III) or a salt thereof, one equivalent to a large excess amount (1 to 10 equivalents) of the compound (III) are employed relative to the compound ( II ) . Examples of the solvents to be employed include water, lower alcohols (e.g. methanol, ethanol and propanol) , ketones(e.g. acetone and methylethylketone) , ethers (e.g. tetrahydrofuran) and aprotic polar solvents (e. g. N,N- dimethylformamide , acetonitrile and dimethylsulfoxide) . This reaction is employed efficiently under basic conditions. Examples of the base include basic compounds such as sodium hydroxide, potassium hydroxide, sodium hydride, potassium carbonate, triethylamine, diisopropylethylamine and 1 , 8-diazabicyclo[ 5.4.0 ] -7- undecene. The base is preferably used in an amount of 1 to 10 equivalents. Further, in the said reaction, sodium iodide as a reaction-promoting agent may be added in an amount ranging from one equivalent to a large excess (1 to 10 equivalents).

The reaction temperature ranges from about -20 to 200°C . The reaction time ranges usually from about 10 minutes to 24 hours, preferably from about 0.5 to 6 hours.

When the compound (I) in the above-mentioned reaction is obtained in the free form, it can be converted to a salt by per se known means or analogous means thereto (e.g. neutralization), and conversely, when the compound (I) is obtained in the form of a salt, it can be converted to the free form or any other salt by per se known means or analogous means thereto. The compound ( I ) thus obtained can be isolated and purified by a conventional separating means such as washing , concentration, extraction of solvents, filtration, crystallization, recrystallization, distillation, chromatography) .

When the compound ( I ) or a salt thereof is , for example , a diastereoisomer , conformer or etc. , it can be isolated by a conventional separating or purifying means. Further, when compound (I) or a salt thereof is a racemic compound, it can be resolved into d-isomer and 1-isomer by a conventional means for optical resolution.

The starting material compounds (II) and (III) to be used in the process of the present invention can be produced by the following methods . The compound (II) used in the process of the present invention can be produced by the methods disclosed in Journal of Heterocyclic Chemistry, Vol.9, page 81 (1972) and Japanese unexamined published application No. H8( 1996) -81467 (corresponding to PCT international published application No. WO 96/02542).

For producing the compound (III), a sulfonylating reagent containing an optionally substituted hydrocarbon group is reacted with the compound (IV).

Examples of the optionally substituted hydrocarbon group which the sulfonylating reagent contains include the same ones as the above-mentioned optionally substituted hydrocarbon group represented by R.

Examples of the said sulfonylating reagent include trifluoromethanesulfonylating reagent (e.g. trifluoromethanesulfonic acid anhydride, trifluoromethanesulfonylchloride and N- phenyltrifluoromethanesulfonimide) , alkylsulfonylating reagent (e.g. methanesulfonylchloride ) , aromaticsulfonylating reagent (e.g. benzenesulfonylchloride and p-toluenesulfonylchloride ) . The said sulfonylating reagent is used in an amount of one equivalent to large excess, preferably about 1 to 5 equivalents .

Examples of the solvents to be employed in the reaction include halogenated hydrocarbon( e. g. methylene chloride, chloroform and dichloroethane) , ethers (e.g. diethylether and tetrahydrofuran) , esters (e.g. methyl acetate and ethyl acetate), aprotic polar solvents (e.g. acetonitrile, acetone and dimethylsulfoxide) and aromatics(e.g. benzene and toluene) . For the reaction, bases may be employed. Examples of the bases to be employed include inorganic base(e.g. potassium carbonate and sodium carbonate), organic base (e.g. triethylamine and tributylamine) and alcoholate(e. g. sodium methylate and sodium ethylate) . The reaction temperature ranges from about -80 to 100°C , preferably about -30 to 50°C . The reaction time ranges usually from about 1 minutes to 24 hours, preferably from about 1 minutes to 10 hours.

The compound (II), compound (III) and compound (IV) may form salts and examples of salts include the same ones of the above-mentioned salt of the compound (I).

The compound ( I ) or a salt thereof obtained by the process of the present invention has an excellent inhibiting activity of PDGF action, ameliorating activity of renal diseases and activity of lowering lipid level, and are low in toxicity. Therefore, these compounds or their salts can be safely used in mammals (e.g. mouse , rat , hamster , rabbit, cat, dog, cow, horse, sheep, monkey and human ) , as agents for preventing or treating renal diseases [e.g. acute renal failure, diabetic nephropathy, nephritis (e.g. chronic or acute glomerulonephritis such as mesangial proliferative glomerulonephritis, endocapillary proliferative glomerulonephritis , membranoproliferative glomerulonephritis type I, II, III, crescentic glomerulonephritis and diffuse sclerosing glomerulonephritis], arteriocslerotic diseases, restenosis after PTCA(percutaneous transluminal coronary angioplasty) , chronic rheumatoid arthritis, cancers and hyperlipidemia . While the compound ( I ) or a salt thereof can be administrated as it is, it is usually administered in the form of a composition formulated by a conventional method using carriers for pharmaceutical compositions adequately selected from excipients (e.g. calcium carbonate, kaolin, sodium hydrogencarbonate, lactose, corn starch, crystalline cellulose, talc, fine granulated sugar and porous substance), binders (e.g. dextrin, gum, -starch, gelatin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and furran) , thickener(e. g. natural rubbers and cellulose derivatives ) , disintegrants (e. g. carboxymethyl cellulose calcium, closcarmellose sodium, clospovidone, low-substituted hydroxypropyl cellulose and partial α - starch), solvents(e. g. water for injection, physiological saline, ringels solution, alcohol, propylene glycol, sesame oil and corn oil), dispersing agent (e.g. Tween 80, HCO 60, carboxymethyl cellulose and sodium alginate) , suspending agents (e.g. sodium lauryl sulfate and benzalkonium chloride), dissolution acids (e.g. polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, torisaminomethane, triethanolamine, sodium carbonate and sodium citrate), anesthetizing agent (e.g. benzylalcohol) , buffers (e.g. phosphate, acetate, carbonate and citrate) , lubricants (e.g. magnesium stearate, calcium stearate, talc, starch and sodium benzoate), colorants (e.g. tar pigment, caramel, iron sesquioxide, titanium oxide and riboflavins) , flavoring agents (e.g. sweeteners and perfume), stabilizers ( e. g. sodium sulfite and ascorbic acid) and preservatives (e.g. parabens and sorbic acid) in adequate amounts respectively. The pharmaceutical composition in the present invention which may contain the above-mentioned carriers for pharmaceutical compositions contains the compound (I) or a salt thereof in pharmaceutically effective amounts. The content of the a salt thereof in the pharmaceutical composition ranges usually from 0.1 to 100 weight % relative to the whole weight of the pharmaceutical composition. And, the pharmaceutical composition may contain, as active components, medicinal components other than the compound (I) or a salt thereof. These medicinal components are not specifically restricted so long as the object of the medicines is attained, and can be used in adequate ratios. Examples of the said medicinal components include diuretic, angiotensin II receptor antagonist, calcium blocker, angiotensin converting enzyme (ACE) inhibitor, Chymase inhibitor, antiphlogistic, hydroxymethylglutaryl-

CoA(HMG-CoA) reductase inhibitor and squalene synthetase inhitor .

Specific examples of the formulation include tablets (including sugar-coated tablets and film-coated tablets) , pills, capsules, granules, powdery preparations , syrups, emulsions, suspensions, injections, inhalants and ointments . These formulations are prepared by a conventional method (e.g. the method described in the Japanese Pharmacopenia) . More specifically, examples of the processes for preparing the pharmaceutical composition are as follows, but it is not intended to restrict the invention: (1) Tablets

The compound ( I ) or a salt thereof as it is , or a homogeneous mixture of them with an excipient, a binder, a disintegrant or any other suitable additive, is granulated by an adequate means, to which is added, for example, a lubricant, and the whole mixture is subjected to compression molding. Furthermore, this pharmaceutical composition may be coated with a coating agent for purpose of, for example, masking the taste, insuring dissolution in the intestinal fluid or sustaining release. (2) Injection

Injections can be prepared by dissolving, suspending or emulsifying a given amount of the compound (I) or a salt thereof in, for example, water for injection, to which is added, if necessary, for example, stabilizers, dissolution aids, suspending agents, buffers and preservations or by filling a given amount of the compound (I) or a salt thereof into a vessel for injections. (3) Capsules

Capsules can be prepared by, for example, filling granules, granules coated with a coating agent or a homogenous mixture of the compound (I) or a salt thereof with pharmaceutical carriers such as excipients, into a capsule.

The pharmaceutical compositions thus obtained have PDGF-inhibiting activity, ameliorating activity of renal diseases and lipid lowering activity and are low in toxicity . Therefore, the pharmaceutical compositions are useful as medicines for preventing or treating diseases due to these pharmacological activities . The pharmaceutical composition according to the invention can be used to prevent or treat hypertension, acute renal failure, diabetic nephropathy, nephritis (e.g. proliferative glomerulonephritis such as mesangial proliferative glomerulonephritis, diffuse sclerosing glomerulonephritis), arteriosclerosis, restenosis after PTCA, chronic rheumatoid arthritis, cancers and hyperlipemia . The dose of the pharmaceutical composition varies with administration routes , symptoms , the age and body weight of patients. For example, it is desirable that the dose of the compound (I) or a salt thereof as effective components, for oral administration to adult patient of diabetic nephropathy, is about 0.05 to 50mg/kg, preferably about 0.1 to 30 mg/kg per day which is given once or divided into several times per day (for example 1 to 3 times). The administration route is not intended to be restricted by various situations and may be either oral or non-oral. Examples of the non-oral administration route include intravenously, intramuscularly, subcutaneously, intranasally, intrarectally, intravaginally and intraperitoneally.

Best mode for carrying out the invention The present invention will be explained in more detail by the following examples and reference examples . The scope of the present invention is not intended to be restricted to them.

In the examples and reference examples , abbreviations mean as follows. s : singlet, d : doublet, t : triplet. Q : quartet, dd : double doublet, m : multiplet, br : broad, J : coupling constant

Reference Example 1

Production of 4- ( 2-chloroethan- 1-yl)piperidine hydrochloride :

A solution of 4-piperidineethanol( 310g) in tetrahydrofuran(3.1L) was ice-cooled and thionylchloride(511g) was added dropwise. Then, the mixture was warmed and stirred for 3 hours under reflux. The reaction mixture was ice-cooled and the formed crystals were collected by filtration. The crystals were washed with tetrahydrofuran( 1L) and dried to provide 321 g(yield 90%) of 4- (2-chloroethan- 1-yl)piperidine hydrochloride. ¹H-NMR(CDC1₃, δ , 300MHz ) : 1.63-1.93(m, 7H) , 2.85- 2.93(m,2H), 3.49-3.53(m, 2H) , 3.85 ( t , J=6.3Hz , 2H) , 9.39- 9.58(m,2H) .

Example 1 Production of 4- (2-chloroethan-l-yl) -1- trifluoromethanesulfonylpiperidine

A mixture of 4- ( 2-chloroethan- 1-yl)piperidine hydrocloride(311g) in toluene( 3. IL) was cooled at -30°C and trifluoromethanesulfonic anhydride ( 7lOg) was added dropwise while keeping this temperature. Then, triethylamine( 514g) was added dropwise. The reaction mixture was stirred for 4 hours at 0 to 5°C . Water(760ml) was added to the reaction mixture and separated, and further, washed with water( 760ml) . The organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained oily product was purified by silica gel column chromatography to provide 336g of oily product. The oily product was distilled under reduced pressure to provide 293g of 4- ( 2-chloroethan- 1-yl) -1- trifluoromethanesulfonylpiperidine (yield 50%) . ¹H-NMR(CDC1₃, δ , 300MHz ) : 1.25- 1.36 (m, 2H) , 1.74- 1.85(m,5H), 3.00-3.07 (m, 2H) , 3.59 ( t , J=6.3Hz , 2H) , 3.93- 4.00(m,2H) .

Example 2

Production of 1 , 2-dihydro- 1- [ 2- ( trifluoromethanesulfonylpiperidin-4 -yl)ethan-1 -yl] - 1,4, 7b-triazacyclopent [cd] inden-2-one To a mixture of 1 , 2-dihydro-1 , 4 , 7b- triazacyclopent [cd]inden-2-one( 5.3g) and 4-(2- chloroethan-1-yl ) - 1- trifluoromethanesulfonylpiperidine ( 5.3g) in N,N- dimethylformamide ( 53ml) was added 1.8- diazabicyclo[ 5.4.0] -7-undecene( 9.7g) and the reaction mixture stirred for 3 hours at 80°C. The reaction mixture was ice-cooled and the formed crystals were collected by filtration. The crystals were washed with 20% water containing methanol( 50ml) and dried to provide 10.8g of 1 , 2-dihydro-l- [2- (trifluoromethanesulfonylpiperidin- 4- yl ) ethan- 1 -yl ] - 1 , 4 , 7b-triazacyclopent [ cd] inden-2- one(yield 81%) .

¹H-NMR(CDC1₃, δ , 300MHz ) : 1.35-1.45 (m, 2H) , 1.54- 1.59(m,lH), 1.83-1.99(m,4H) , 2.96-3.05 (m, 2H) , 3.95- 3.99(m,2H), 4.15 ( t , J=7.0Hz , 2H) , 6.85(d, J=7.0Hz , IH) ,

7.67(d, J=8.6Hz,lH) , 7.78(dd, J=7.0 , 8.6Hz , IH) , 8.36(s,lH).

Industrial applicability

By the process of the present invention, tricyclic compounds having excellent pharmacological activities can be obtained having few steps , high yield and without the use of expensive materials.

Claims

Claims 1. A process for producing a compound of the formula ( I ) :

wherein Z is a leaving group and the other symbols are as defined above, or a salt thereof.

2. A process of claim 1 , wherein ring A may be substituted with 1 to 3 groups selected from halogen, C_1-6 alkyl,

alkyl,

alkoxy,

alkylthio,

alkylthio, hydroxy, carboxy, cyano, nitro, amino, mono- or

alkylamino, formyl, mercapto, C₁_₆ alkyl-carbonyl,

alkoxy-carbonyl, sulfo,

alkylsulfonyl , carbamoyl and mono- or

alkyl- carbamoyl. ring B is a ring of the formula:

X is (l)a C^^ alkylene group, a C₂.₁₆ alkenylene group or a C₂_₁₆ alkynylene group, which may be substituted with 1 to 5 groups selected from

alkyl alkoxy,

alkylthio, hydroxy, carboxy, cyano, nitro ino, mono- or alkylamino, formyl, mercapto,

alkyl-carbonyl

alkoxy-carbonyl, sulfo,

alkylsulfonyl , carbamoyl and mono- or

alkyl-carbamoyl, or (3)a divalent group formed by combining these groups , ring Y is a piperidine, a pyrrolidine or a pyridine which may be substituted with 1 to 3 groups selected from halogen, C_x_₆ alkyl,

alkyl, C₁.₆ alkoxy,

alkoxy, C₁.₆ alkylthio,

alkylthio, hydroxy, carboxy, cyano, nitro, amino, mono- or

alkylamino, formyl, mercapto,

alkyl-carbonyl, C₁.₆ alkoxy-carbonyl, sulfo,

alkylsulfonyl, carbamoyl and mono- or

alky1-carbamoyl, ,

R is a C₁_₁₅ alkyl group, a C₃.₈ cycloalkyl group, a C₂.₁₈ alkenyl group, a C₇.₁₆ aralkyl group or a C₆_₁₄ aryl group, which may be substituted with 1 to 5 groups selected from nitro, hydroxy, cyano, carbamoyl, mono- or

alkyl-carbamoyl, carboxy, C^g alkoxy-carbonyl, sulfo, halogen,

alkoxy, phenoxy, halogeno-phenoxy alkylthio, mercapto, phenylthio, pyridylthio,

alkylsulfinyl,

alkylsulfonyl, amino,

acylamino, mono- or

alkylamino, 4- to 6-membered cyclic amino, C₁.₇ acyl, benzoyl, 5- or 6-membered monocyclic heteroaromatic ring containing 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, bicyclic heteroaromatic ring which is formed by condensing 5- or 6-membered heteroaromatic ring containing 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom with benzene ring, and a C₇_₁₆ aralkyl group or a C₆_₁₄ aryl group which may be substituted with C_x.₆ alkyl, halogeno-C_j.g alkyl or oxo,

R¹ is ( l)a hydrogen atom, ( 2 )a halogen atom, (3)anacyl group derived from carboxylic acid or (4)a C^^ alkyl group, ^{a C} ₃-₈ cycloalkyl group, a C₂.₁₈ alkenyl group, a C₇.₁₆ aralkyl group or a C₆.₁₄ aryl group, which may be substituted with 1 to 5 groups selected from nitro, hydroxy, cyano, carbamoyl, mono- or di-C_x.g alkyl, carboxy, C₁.₆ alkoxy-carbonyl, sulfo, halogen, C_╬╗_₆ alkoxy, phenoxy, halogeno-phenoxy,

alkylthio, mercapto, phenylthio, pyridylthio, C₁.₆ alkylsulfinyl,

alkylsulfonyl, amino, C₁.₆ acylamino, mono- or

alkylamino, 4- to 6-membered cyclic amino, C_!., acyl, benzoyl, 5- or 6-membered monocyclic heteroaromatic ring containing 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, bicyclic heteroaromatic ring which is formed by condensing 5- or 6-membered heteroaromatic ring containing 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom with benzene ring, or a C₇.₁₆ aralkyl group or a C₆.₁₄ aryl group which may be substituted with

alkyl, halogeno-Ci.g alkyl or oxo, and Z is a halogen atom, a C_x_₄ alkylsulfonyloxy group or a C₆.₁₀ arylsulfonyloxy group.

3. A process of claim 1 , wherein ring A is unsubstituted, ring B is a ring of the formula:

R¹ is a hydrogen atom or a C₁_₆ alkyl group, X is a

alkylene group, ring Y is a piperidine group and R is a

alkyl group.

4. A process of claim 1 , wherein ring A may be substituted with halogen, C_╬╗_₆ alkyl, C^ alkylthio, C^₄ alkoxy, hydroxy, carboxy, nitro or amino, R¹ is (l)a hydrogen atom, (2)a C^^ alkyl group or a C₆-₁₄ aryl group which may be substituted with halogen, hydroxy, carboxy, nitro or amino, (3)a C_1-6 alkoxy-carbonyl group or (4)a C_x_₆ alkanoyl group, Z is a halogen atom, a C^ alkylsulfonyloxy group or a C^^ arylsulfonyloxy group, X is a C_1-6 alkylene group which may be substituted with halogen, hydroxy, C_1-4 alkyl or C₆_₁₄ aryl, ring Y is a nitrogen-containing 6-membered heterocyclic ring, R is a C^^ alkyl group, a C₃.₈ cycloalkyl group, a C₂.₁₀ alkenyl group, a C₆.₁₄ aryl group or a C₇_₁₆ aralkyl group which may be substituted with (i)halogen, (ii) cyano, (iii)hydroxy, ( i.v) C₁_₆ alkyl which may be substituted with halogen,

which may be substituted with halogen, (vi) C₆.₁₄ aryl, (vii) carboxy which may be esterified or (viii) 5- or 6-membered heterocyclic group.

5. A process of claim 1 , wherein ring A may be substituted with halogen or C_1-4 alkyl, ring B is a ring of the formula:

R¹ is a hydrogen atom, a C_1-6 alkyl group or a C₆.₁₄ aryl group, X is a

alkylene group which may be substituted with halogen, hydroxy or C_1-4 alkyl, ring Y is a nitrogen- containing 6-membered heterocyclic ring, R is a C_╬╗_₁₀ alkyl group which may be substituted with halogen, hydroxy or carboxy which may be esterified.

6. A process of claim 1 , wherein ring A is unsubstituted, ring B is a ring of the formula:

R¹ is a hydrogen atom, ring Y is a nitrogen-containing 6-membered heterocyclic group and R is a

alkyl group .

7. A process of claim 1 , wherein ring A is unsubstituted, ring B is a ring of the formula:

R¹ is a hydrogen atom, Z is a chlorine atom, X is an ethylene group, ring Y is a piperidine and R² is a trifluoromethyl group .

8. A process of claim 1, which is employed under basic conditions .

9. A compound of the formula (III):

wherein Z is a leaving group, X is an optionally substituted divalent hydrocarbon group, ring Y is an optionally substituted nitrogen-containing 5- or 6- membered heterocyclic ring, and R is an optionally substituted hydrocarbon group, or a salt thereof.

10. A compound of claim 9, wherein X is (l)a C^^ alkylene group, a C₂.₁₆ alkenylene group or a C₂.₁₆ alkynylene group, which may be substituted with 1 to 5 groups selected from alkyl and phenyl, (2)a phenylene group which may be substituted with 1 to 4 groups selected from halogen,

alkyl, C_1-6 alkoxy,

alkylthio, hydroxy, carboxy, cyano, nitro, amino, mono- or

alkylamino, formyl, mercapto, C₁_₆ alkyl-carbonyl,

alkoxy-carbonyl, sulfo, C₁_₆ alkylsulfonyl , carbamoyl and mono- or di-C₁_₆ alkylcarbamoyl, or (3)a divalent group formed by combining these groups , ring Y is a piperidine, a pyrrolidine or a pyridine which may be substituted with 1 to 3 groups selected from halogen,

alkyl,

alkoxy,

alkoxy, alkylthio,

alkylthio, hydroxy, carboxy, cyano, nitro, amino, mono- or di-C^_g alkylamino, formyl, mercapto, alkyl-carbonyl,

alkoxy-carbonyl, sulfo,

alkylsulfonyl, carbamoyl and mono- or

alkyl-carbamoyl, ,

R is a C^_s alkyl group, a C₃.₈ cycloalkyl group, a C₂.₁₈ alkenyl group, a C₇_₁₆ aralkyl group or a C₆_₁₄ aryl group, which may be substituted with 1 to 5 groups selected from nitro, hydroxy, cyano, carbamoyl, mono- or

alkyl, carboxy, C_╬╗_₆ alkoxy-carbonyl, sulfo, halogen, C^ alkoxy, phenoxy, halogeno-phenoxy, C_1-6 alkylthio, mercapto, phenylthio, pyridylthio,

alkylsulfinyl, alkylsulfonyl, amino, C_╬╗_₆ acylamino, mono- o

alkylamino, 4- to 6-membered cyclic amino, C^acyl, benzoyl, 5- or 6-membered monocyclic heteroaromatic ring containing 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, bicyclic heteroaromatic ring which is formed by condensing 5- or 6-membered heteroaromatic ring containing 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom with benzene ring, and a C₇.₁₆ aralkyl group or a C₆.₁₄ aryl group which may be substituted with

alkyl,

alkyl or oxo, and

Z is a halogen atom, a C_1-4 alkylsulfonyloxy group or a C₆.₁₀ arylsulfonyloxy group.

11. A compound of claim 9, wherein X is a

alkylene group, ring Y is a piperidine and R is a halogeno-C₁.₆ alkyl group.

12. A compound of claim 9 , wherein X is an ethylene group, ring Y is a piperidine and R is a trifluoromethyl group.

13. A process for producing a compound of the formula (III):

wherein Z is a leaving group, X is an optionally substituted divalent hydrocarbon group, ring Y is an optionally substituted nitrogen-containing 5- or 6-membered heterocyclic ring, R is an optionally substituted hydrocarbon group, or a salt thereof, which comprises reacting a sulfonylating reagent which contains an optionally substituted hydrocarbon group, with a compound of the formula (IV):

wherein the symbols are as defined above, or a salt thereof,

14. Use of the compound of the formula (III):

wherein Z is a leaving group, X is an optionally substituted divalent hydrocarbon group, ring Y is an optionally substituted nitrogen-containing 5- or 6-membered heterocyclic ring, R is an optionally substituted hydrocarbon group, or a salt thereof, for producing the compound of the formula ( I ) :

wherein ring A may be substituted, ring B may have one oxo group, R¹ is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an acyl group, the other symbols are as defined above, or a salt thereof.

15. A method for producing the compound of the formula (I):

wherein ring A may be substituted, ring B may have one oxo group, R¹ is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an acyl group, X is an optionally substituted divalent hydrocarbon group, ring Y is an optionally substituted nitrogen-containing 5- or 6-membered heterocyclic ring and R is an optionally substituted hydrocarbon group, or a salt thereof, which comprises utilizing a compound of the formula (III):