JPH09507472A - Aminosulfonyl-phenyl-1H-pyrrole derivatives, process for their preparation and their use - Google Patents

Abstract

(57) [Summary] A compound represented by formula (I) and a salt thereof, wherein R ¹ represents C _1-4 alkyl; and one of R ² , R ³ , R ⁴ and R ⁵ is , A sulfonamide group R ⁶ R ⁷ NSO ₂ —, wherein R ⁶ represents hydrogen, C _1-6 alkyl or C _1-4 alkoxy C _1-4 alkyl; R ⁷ represents a group (R ^a ) _p- (Ar)-(CH ₂ ) _j- , wherein Ar is phenyl, naphthyl, a 5- or 6-membered heterocyclic aryl group, or a 5- or 6-membered fused with a phenyl ring. a heterocyclic aryl radical; j represents an integer of 0 or 1 to 4; R ^a is halogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, hydroxyalkyl C _1-4 alkyl, C _1-4 alkanoyl, C _1-4 alkoxy Represents or di -C _1-4 alkylamino, C _1-4 alkylthio, a C _1-4 alkylsulfinyl, substituents selected from C _1-4 alkylsulfonyl and phenyl C _1-4 alkoxy - carbonyl, amino, mono P represents 0 or an integer of 1 to 4; or R ⁶ R ⁷ N- is fused with a phenyl group or substituted by a phenyl group, or is a 5- or 6-membered heterocyclic aryl group. 5 represents a substituted 5-7 membered heterocyclic ring, wherein the phenyl or heteroaryl group may be optionally substituted by ^a group (R ^a ) _p , where R ^a and p are , Is the same as the above definition; Y represents a group selected from (a) to (e)] is active at the dopamine receptor and is useful in the treatment of psychosis such as schizophrenia.

Description

Detailed Description of the Invention   Aminosulfonyl-phenyl-1H-pyrrole derivatives, their production method and And their use   The present invention relates to novel pyrrole derivatives, a method for producing them, and pharmaceuticals containing them. Compositions and their use in therapy, especially as antipsychotics.   In European Patent Application No. 241053, the formula: [In the formula, A is 2,5-pyrrolyl, or 3,5- or 1,4-pyrazolyl. Any unsaturated 5-membered heterocyclic ring; X is a nitrogen or carbon atom; R₁, R₂ , R_ThreeAre each hydrogen or alkyl; R_FourIs aryl, heteroaryl , Arylcarbonyl or heteroaryl-carbonyl; R is various Selected from substituents; n is 0-4] The compounds represented by are disclosed.   In European Patent Application No. 259930, the formula: [In the formula, A is 2,5-pyrrolyl, 1,4-pyrazolyl or 2,5-furyl, etc. An unsaturated 5-membered heterocyclic ring of; R is hydrogen, alkyl or optionally substituted Optionally phenyl; R¹Is alkyl, alkenyl, or Forms a ring with a phenyl group; R²Is hydrogen, hydroxy or alkoxy R;^ThreeIs selected from a variety of substituents; n is 0-3] The compounds represented by are disclosed. These compounds also have antipsychotic properties. It is said that.   In European Patent Application No. 538281, the formula: [In the formula, Z is 2-aminomethyl-N-alkyl-pyrrolidine, 2-aminoethyl Le-N, N-diethylamine, 2-aminoethyl-morpholine, 2-aminoethyl Ru-N, N-dibutylamine, 4-amino-N-butyl (or N-benzyl) A residue derived from piperidine or 2-aminoethyl-pyrrolidine; Y Is alkyl or alkenyl; X is H, Cl, Br, amino, amino Alkyl, aminosulfamoyl, S-containing groups (eg thiocyanate, alkyl Thio, alkylsulfinyl, alkylsulfonyl) methoxy, nitro, cyano , Or an electron-withdrawing group; R is H or methoxy] The compounds represented by are disclosed. The compound is D_ThreeDo acting at the receptor -It is a pamine antagonist and is said to be particularly useful as an antipsychotic drug.   The present inventors have an affinity for the dopamine receptor, thus We have found a new pyrrole derivative that is effective as a medicine.   In a first aspect, the invention provides a compound of formula (I): [Where,   R¹Is C_1-4Represents alkyl;   R², R^Three, R^FourAnd R^FiveOne of which is a sulfonamide group R⁶R⁷NSO₂− Where:   R⁶Is hydrogen, C_1-6Alkyl or C_1-4Alkoxy C_1-4Represents alkyl;   R⁷Is a group (R^a)_p-(Ar)-(CH₂)_jRepresents-, where Ar is phenyl, na Futyl fused with a 5 or 6 membered heterocyclic aryl group or a phenyl ring Represents a 5- or 6-membered heterocyclic aryl group; j represents 0 or an integer of 1 to 4; Represents; R^aIs halogen, C_1-4Alkyl, C_1-4Alkoxy, C_1-4Alkoxy C_1-4 Alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, Hydroxy, hydroxy C_1-4Alkyl, C_1-4Alkanoyl, C_1-4Alkoxy Carbonyl, amino, mono- or di-C_1-4Alkylamino, C_1-4Alkyl Thio, C_1-4Alkylsulfinyl, C_1-4Alkylsulfonyl and phenyl C_1-4Represents a substituent selected from alkoxy, p is 0 or an integer from 1 to 4 Represents; or   R⁶R⁷N- is fused with or substituted by a phenyl group Or 5-substituted by a 5- or 6-membered heterocyclic aryl group Represents a 7-membered heterocyclic ring, wherein the phenyl or heteroaryl group is optionally More group (R^a)_pMay be substituted by where R^aAnd p are the constants Same as righteousness;   R², R^Three, R^FourAnd R^FiveThe rest of the above are each independently hydrogen, halogen, C_1-4 Alkyl, C_1-4Alkoxy, C_1-4Alkoxy C_1-4Alkyl, C_1-4Archi Lesulfonyl, trifluoromethylsulfonyl; optionally substituted Arylsulfonyl, optionally substituted heteroarylsulfo Nyl, optionally substituted aralkylsulfonyl, optionally substituted Optionally substituted heteroaralkylsulfonyl, nitro, cyano, amino, mono -Or di-alkylamino, trifluoromethyl, trifluoromethoxy, Hydroxyl, hydroxyalkyl, C_1-4Alkylthio, C_1-4Alkanoyl Or C_1-4Represents alkoxycarbonyl; or   R¹And R²Together, C_2-4Forming an alkyl chain, the chain being the desired 1 or 2 C_1-4Optionally substituted by an alkyl group, in which case , R^Three, R^FourAnd R^FiveOne of which is a sulfonamide group as defined above and the other Two are the same as defined above; or R²And R^ThreeTogether Form a phenyl ring, in which case R^FourRepresents a sulfonamide group as defined above, R^FiveRepresents hydrogen;   Y is (a) to (e):     (Where       In the group (a),       R⁸And R⁹Is independently hydrogen, C_1-6Alkyl, optionally substituted Optionally aryl C_1-6Alkyl or optionally substituted Terror aryl C_1-6Represents alkyl;       R^TenIs C_1-6Alkyl, C_3-6Alkenyl or C_3-6Cycloalkyl C_{1 -Four} Represents alkyl;       R¹¹Is C_1-6Alkyl; C_3-6Alkenyl; C_3-6Cycloalkyl C_1-4A Rukyi, optionally substituted aryl C_1-4Alkyl or optionally More optionally substituted heteroaryl C_1-4Represents alkyl; or       NR^TenR¹¹Forms a heterocyclic ring;       In the group (b),       R¹²Is C_1-6Alkyl; C_3-6Alkenyl; C_3-6Cycloalkyl C_1-4A Rukyi, optionally substituted aryl C_1-4Alkyl or optionally More optionally substituted heteroaryl C_1-4Represents alkyl;       q is 1 to 4;       In group (c),       R¹³And R¹⁴Is independently hydrogen, C_1-6Alkyl, optionally substituted Optionally aryl C_1-6Alkyl or optionally substituted Heteroaryl C_1-6Represents alkyl;       R^FifteenIs optionally substituted aryl or optionally substituted Represents an optionally substituted heteroaryl group;       Z is-(CH₂)_u(Where u is 1 to 8) or-(CH₂)_vCH = CH (CH₂)_w(Wherein v and w independently represent 1 to 3);       In the group (d), each of r and s independently represents an integer of 1 to 3;       In the group (e), R¹⁶Is C_1-6Alkyl, C_3-6Alkenyl or C_3-6Cycloalkyl C_1-4Represents alkyl; R¹⁷, R¹⁸, R¹⁹And R²⁰Is each Independently, hydrogen, halogen, C_1-4Alkyl, C_1-4Alkoxy, C_1-4Arco Kishi C_1-4Alkyl, nitro, cyano, trifluoromethyl, trifluorometh Xy, hydroxy, hydroxyalkyl, C_1-4Alkanoyl, C_1-4Alkoxy Represents carbonyl, amino or mono- or dialkylamino;       X is CH₂, S or O;       (t is 0, 1 or 2) Represents a group selected from And a salt thereof.   In the compound of formula (I), the alkyl group or moiety is linear May also be branched. Examples of the alkyl group used include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and isopropyl , T-butyl, sec-pentyl and their branched isomers.   The halogen atom present in the compound represented by formula (I) is fluorine, chlorine, bromine or Is iodine.   Ar fused with a 5- or 6-membered heterocyclic aryl ring or phenyl When representing a ring, the heterocyclic ring or moiety is selected from oxygen, sulfur or nitrogen It contains one or more, for example 1, 2, 3 or 4 heteroatoms. Thus, Suitable examples are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, Imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazyl, pi Examples include rimidyl and pyrazolyl. Preferably, a heterocyclic aryl group Ar Contains 1 to 3 heteroatoms.   Other substituents R in the compound of formula (I)², R^Three, R^Four, R^Five, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴And R^FifteenTypical aryl groups present in any of Or moieties include phenyl, naphthyl and tetrahydronaphthyl. You. Preferable examples of the heteroaryl group include furyl, thienyl, pyrrolyl and oxy. Sazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pi One or more oxygen atoms such as lysyl, pyridazyl, pyrimidyl and pyrazolyl , 5- and 6-membered heterocycles containing sulfur or nitrogen atoms. A Substituents for the reel and heteroaryl groups include halogen, C_1-4 Alkyl, C_1-4Alkoxy, C_1-4Alkoxy C_1-4Alkyl, nitro, cyano , Trifluoromethyl, trifluoromethoxy, hydroxy, hydroxy C_1-4 Alkyl, C_1-4Alkanoyl, C_1-4Alkoxycarbonyl, amino and mono -Or the C_1-4Alkylamino is mentioned.   The nitrogen atom present in the heteroaryl ring defined above is a hydrogen atom or Suitable substituents selected from the defined substituents, eg C_1-4Even if you have an alkyl Good.   R⁶R⁷N-is fused to an optionally substituted phenyl ring Or fused with an optionally substituted 5- or 6-membered heterocyclic ring Or a sulfone if it represents a 5 to 7 membered ring substituted by the heterocyclic ring The amide group has the formula (f) or (g): [Wherein, R^aAnd p are as defined above;   Ar 'represents phenyl or a 5- or 6-membered heterocyclic ring;   R^{twenty one}Is-(CH₂)_m-Or- (CH₂)_kW (CH₂)₂Represents-;   m represents 0 or an integer of 1 to 4;   k represents 0 or 1;   W is O, S, SO or SO₂Represents;   n represents 0 or an integer of 1 to 4;   However, in the group (f), the total of n + m is 2 to 4, and the total of n + k is 0 or 1, and in the group (g), the total of n + m is 3 to 5, and n + k is The total is 1 or 2.] Indicated by.   In the group (g), Ar 'preferably represents phenyl. In the group (f), R^{twenty one} Is-(CH₂)_mWhen representing −, m is such that the sum of n + m represents 2 or 3. Preferably, it represents 0 or 1, and n preferably represents 2 or 3. R^{twenty one}But -(CH₂)_kW (CH₂)₂When representing-, W preferably represents O, k and n Each preferably represents 0. R⁶R⁷When N- represents a 5-7 membered ring, it is generally , A fused sulfonamide containing the group (f) is preferred.   R⁶R⁷NSO₂When-represents a monocyclic sulfonamide group, R⁶Is preferably Hydrogen or C_1-4Represents alkyl, for example methyl or ethyl. R⁷Is a group (R^a )_p-(Ar)-(CH₂)_jWherein Ar is preferably phenyl or 5 member containing 1, 2 or 3 atoms selected from O, N and S or Represents a 6-membered heterocyclic aryl group. R^aIs preferably halogen, C_1-4Arco Xy (eg, methoxy), cyano, C_1-4Alkylthio (for example, methylthio), C_1-4Alkylsulfinyl (eg methylsulfinyl), phenyl C_1-4Al Coxy (eg, benzyloxy), hydroxy and C_1-4Alkyl (eg, Represents one or more substituents selected from methyl). p is preferably 0, 1 or Or 2, and n preferably represents 0, 1 or 2.   Preferably, a sulfonamide group R⁶R⁷NSO₂-Is R^ThreeOr R^FourBy More preferably, R^FourRepresented by Remaining substituents R², R^Three, R^FourOr R^FiveIs good More preferably, hydrogen or C_1-4Represents alkyl, for example methyl. Conveniently, R^Four Is a group R⁶R⁷NSO₂Represents-, R^ThreeRepresents hydrogen or methyl, R²And R^Five Each represent hydrogen.   R¹Preferably represents methyl, ethyl or isopropyl.   When Y is a group (a), R⁸And R⁹At least one of them is preferably Hydrogen. Preferably, R⁸And R⁹One is hydrogen and the other is hydrogen , C_1-6Alkyl and optionally substituted aryl C_1-6Alkyl Is selected from -NR^TenR¹¹When forms a heterocyclic ring, this is preferred Is It has 4 to 10, for example 5 to 8 ring atoms, which may be fully or partially saturated. It is sum. Heterocyclic ring-NR^TenR¹¹Is, for example, C_1-3An alkylene chain, for example It may also be crosslinked by methylene or ethylene groups. Furthermore, complex Cyclic ring is one or more C_1-4Substituted with an alkyl group, or It may be condensed with an aromatic ring such as phenyl. Most preferably Y is a group (a) R⁸And R⁹One is hydrogen and the other is hydrogen or C_1-6 Represents alkyl; R^TenIs C_1-6Represents alkyl; R¹¹Is C_1-6Alkyl or Phenyl C_1-4Represents alkyl or -NR^TenR¹¹Is a 5 or 6 member Form a saturated heterocyclic ring.   When Y is a group (b), q is preferably 1 or 2 and R¹²Is preferred Or C_1-6Alkyl, for example ethyl.   When Y is a group (c), R¹³And R¹⁴At least one of, preferably , Represents hydrogen.   Preferably, R¹³And R¹⁴One is hydrogen and the other is hydrogen, C_1-6 Alkyl and optionally substituted aryl C_1-6Select from alkyl Selected. R^FifteenIs preferably optionally substituted phenyl or Represents an optionally substituted furyl. Z is preferably (CH₂)_u (Where u is 3, 4 or 5). Most preferably R¹³and R¹⁴One is hydrogen and the other is hydrogen or C_1-6Alkyl; R^FifteenRepresents phenyl or optionally substituted furyl, and z is (CH₂)_u(Where u is 3 or 5).   When Y is a group (d), r and s preferably independently represent 1 or 2. Represent.   Conveniently, Y is a group (a), (b) or (c), most preferably (c) is there.   For use in medicine, the salts of formula (I) should be physiologically acceptable. It will be recognized that this is the case. Suitable physiologically acceptable salts are those skilled in the art , Such as hydrochloride, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid. Inorganic acids; and succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, ammonium Benzoic acid, p-toluenesulfonic acid, methanesulfonic acid or naphthalene sulfone Acid addition salts formed with organic acids such as acids are mentioned. Other physiology such as oxalate The pharmaceutically unacceptable salts are used, for example, in the isolation of compounds of formula (I) Included within the scope of the invention. Solvates of compounds of formula (I) and water Japanese products are also included within the scope of the present invention.   When the asymmetric center is present in the compound represented by the formula (I), the compound is an optical isomer. It will exist in the form of (enantiomer). The invention relates to all such enantiomers. And within its scope that mixture, including racemic mixtures. Furthermore, in formula (I) All possible stereoisomeric forms of the indicated compound (individual diastereomers and their (Mixtures of) are also included in the scope of the present invention.   In a further aspect, the invention provides compounds of formula (IA): [Where,   R², R^Three, R^FourAnd R^FiveOne of them is a sulfonamide group:     (Where       The dotted line is the hydrogen atom or the substituent R bonded to the phenyl ring.^{twenty three}Represents;       R^{twenty two}Is hydrogen, C_1-6Alkyl, or C_1-4Alkoxy C_1-4Alkyl Representation;       n represents 0 or an integer of 1 to 4; or       The dotted line represents a single bond;       R^{twenty two}Is-(CH₂)_mRepresents-;       n and m are each 0 or 1 such that the sum of n + m is 2-4. Represents an integer of 4;       In either case,       R^{twenty three}Is halogen, C_1-4Alkyl, C_1-4Alkoxy, C_1-4Alkoxy C_1-4Alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy , Hydroxy, hydroxy C_1-4Alkyl, C_1-4Alkanoyl, C_1-4Alkoki Cycarbonyl, amino and mono- or di-C_1-4Selected from alkylamino Represents a substituent;       p represents 0 or an integer of 1 to 4) Represents   R², R^Three, R^FourAnd R^FiveThe rest of, as well as R¹And Y are in formula (I) The same definition as It also provides a compound represented by:   Specific compounds of the invention include the following compounds:   2- (2-methoxy-5-((N-methyl-N-phenyl) aminosulfonyl) phenyl Phenyl) -5- (1- (2- (R, S) -phenylazacycloheptyl) -methyl) -1 H-pyrrole;   2- [5-((N-benzyl-N-methyl) aminosulfonyl) -2-methoxyphenyl Phenyl] -5- [1- (2- (R, S) -phenylazacycloheptyl) methyl] -1H -Pyrrole;   2- [2-methoxy-5-((N-methyl-N-phenyl) aminosulfonyl) phenyl Phenyl] -5- (1- (R, S)-(2-phenylpyrrolidinyl) methyl) -1H-pyro Tool;   (−)-2- [2-Methoxy-5-((N-methyl-N-phenyl) aminosulfoni L) phenyl] -5- (1- (2-phenylpyrrolidinylmethyl) -1H-pyrrole;   (+)-2- [2-methoxy-5-((N-methyl-N-phenyl) aminosulfoni ) Phenyl] -5- (1- (2-phenylpyrrolidinyl) methyl) -1H-pyrrole;   (−)-2- [2-Methoxy-5-((N-methyl-N-phenyl) aminosulfoni L) phenyl] -5- (1- (2-phenylpiperidinylmethyl) -1H-pyrrole;   (+)-2- [2-methoxy-5-((N-methyl-N-phenyl) aminosulfoni ) Phenyl] -5- (1- (2-phenylpiperidinyl) methyl) -1H-pyrrole;   2- (5-((N- (4-bromophenyl) -N-methyl) aminosulfonyl) -2 -Methoxyphenyl) -5- (1- (2- (R, S) -phenylazacycloheptyl) Methyl) -1H-pyrrole;   2- (2-methoxy-5-((N- (4-methoxyphenyl) -N-methyl) amino -Sulfonyl) phenyl) -5- (1- (2- (R, S) -phenylazacyclohepty Ru) methyl) -1H-pyrrole;   2- (5-((N- (4-cyanophenyl) -N-methyl) aminosulfonyl) -2 -Methoxyphenyl) -5- (1- (2- (R, S) -phenylazacycloheptyl) Methyl) -1H-pyrrole;   2- (5- (4- (3,4-dihydro-1,4-benzoxazinyl) sulfonyl) 2-Methoxy-phenyl) -5- (1- (2- (R, S) -phenylazacyclohep Tyl) methyl) -1H-pyrrole;   2- (5-((N- (3,4-dimethoxybenzyl) -N-ethyl) aminosulfoni ) -2-Methoxyphenyl) -5- (1- (2- (R, S) -phenylazacyclohe Butyl) methyl) -1H-pyrrole;   2- (2-methoxy-5-((N-methyl-N- (4-methylthio) phenyl) ami) Nosulfonyl) phenyl) -5- (1- (2- (R, S) -phenylazacyclohepty Ru) methyl) -1H-pyrrole;   2- (2-methoxy-5-((N-methyl-N-phenyl) aminosulfonyl) phenyl Phenyl) -5- (1- (2- (R) -phenylazacycloheptyl) methyl) -1H- Pyrrole;   2- (2-methoxy-5-((N-methyl-N-phenyl) aminosulfonyl) phenyl Eh Nyl) -5- (1- (2- (S) -phenylazacycloheptyl) methyl) -1H-pi roll;   2- [5-((N-benzyl-N-ethyl) aminosulfonyl) -2-methoxyphenyl And]]-5- (1- (2- (R, S) -Phenylazacycloheptyl) methyl) -1H -Pyrrole;   2- [5-((N- (2,4-difluorophenyl) -N-methyl) aminosulfoni 2-Methoxyphenyl] -5- (1- (2- (R, S) phenyl azacyclohepty Ru) methyl) -1H-pyrrole;   2- [2-methoxy-5-((1- (2-phenylpyrrolidinyl) sulfonyl) phene Nyl] -5- (1- (2- (R, S) -phenylazacycloheptyl) methyl) -1H- Pyrrole;   2- [2-methoxy-5-((N-ethyl-N- (2-phenyl) ethyl) aminos Rufonyl) -phenyl] -5- (1- (2- (R, S) -phenylazacycloheptyl) Methyl) -1H-pyrrole;   2- [2-methoxy-5-((N-methyl-N- (5-methyl-3-isoxazo Ryl)) amino-sulfonyl) phenyl] -5- (1- (2- (R, S) -phenylaza Cycloheptyl) methyl) -1H-pyrrole;   2- [2-methoxy-5-((N-methyl-N-phenyl) aminosulfonyl) phenyl ]]-5- (1- (R, S)-(1-Piperidinyl) ethyl) -1H-pyrrole;   2- [5-((N-ethyl-N- (2-pyridyl) methyl) aminosulfonyl) -2 -Methoxy-phenyl] -5- (1- (2- (R, S) -phenylazacycloheptyl ) Methyl) -1H-pyrrole;   2- [5-((N-ethyl-N- (2-furyl) methyl) aminosulfonyl) -2- Methoxy-phenyl] -5- (1- (2- (R, S) -phenylazacycloheptyl) Methyl-1H-pyrrole;   2- [5-((N- (4-fluorophenyl) -N-methyl) aminosulfonyl)- 2-Methoxyphenyl] -5- (1- (2- (R, S) -phenylazacycloheptyl ) Methyl) -1H-pyrrole;   2- [2-methoxy-4-((N-methyl-N-phenyl) aminosulfonyl) phenyl Phenyl] -5- [1- (2- (R, S) -phenylazacycloheptyl) methyl] -1H -Pyrrole;   2- [5-((N-benzyl-N-ethyl) aminosulfonyl) -2-methoxyphenyl Phenyl] -5- [1- (2- (R) -phenylazacycloheptyl) methyl] -1H- Pyrrole;   2- [5-((N-benzyl-N-ethyl) aminosulfonyl) -2-methoxyphenyl Phenyl] -5- [1- (2- (S) -phenylazacycloheptyl) methyl] -1H- Pyrrole;   2- [2-methoxy-5-((2- (1,2,3,4-tetrahydroisoquinolinyl) ) Sulfonyl) phenyl] -5- [1- (2- (R, S) -phenylazacycloheptyl ) Methyl] -1H-pyrrole;   2- [2-methoxy-5-((1- (1,2,3,4-tetrahydroquinolinyl)) s Rufonyl) phenyl] -5- (1- (2- (R, S) -phenylazacycloheptyl) me Chill-1H-pyrrole;   2- [5-((N-ethyl-N-phenyl) aminosulfonyl) -2-methoxyphenyl And]]-5- (1- (2- (R, S) -Phenylazacycloheptyl) methyl) -1H -Pyrrole;   2- [2- (R, S)-(1-ethylpyrrolidinyl)]-5-[(2-methoxy-4- Methyl-5-((N-methyl-N-phenyl) aminosulfonyl) phenyl] -1H -Pyrrole;   2- [2- (R, S)-(1-ethylpyrrolidinyl))-5- (2-methoxy-5-(( N-methyl-N-phenyl] aminosulfonyl) phenyl) -1H-pyrrole;   2- (2- (R, S)-(1-ethylpyrrolidinyl))-5- [2-methoxy-5-(( 1- (1,2,3,4-tetrahydroquinolinyl)) aminosulfonyl) phenyl] -1 H-pyrrole;   2- (2- (R, S)-(1-ethylpyrrolidinyl))-5- (1-methoxy-4-(( N-methyl-N-phenyl) aminosulfonyl) -2-naphthyl) -1H-pyro Tool;   2- (2- (R, S)-(1-n-butylpyrrolidinyl))-5- [2-methoxy-5 -((N-methyl-N-phenyl) aminosulfonyl) phenyl] -1H-pyrrole;   2- [2- (R, S)-(1-ethylpyrrolidinyl)]-5- [2-methoxy-4-(( N-methyl-N-phenyl) aminosulfonyl) phenyl] -1H-pyrrole;   2- [2-methoxy-4-methyl-5-((N-methyl-N-phenyl) aminos Rufonyl) phenyl) -5- (1- (2- (R) -phenylazacycloheptyl) methyl Le) -1H-pyrrole;   2- [5-((N- (4-hydroxyphenyl) -N-methyl) aminosulfonyl) -2-Methoxyphenyl] -5- [1- (2- (R, S) -phenylazacyclohepti Le) methyl] -1H-pyrrole;   2- (5-((N- (4-iodophenyl) -N-methyl) aminosulfonyl) -2 -Methoxyphenyl) -5- (1- (2- (R, S) -phenylazacycloheptyl) Methyl) -1H-pyrrole;   2- (N-benzyl-N-ethyl) aminomethyl-5- (2-methoxy-5-(( N-methyl-N-phenyl) aminosulfonyl) phenyl) -1H-pyrrole;   2- (N-benzyl-N-ethyl) aminomethyl-5- [2-methoxy-4-(( N-methyl-N-phenyl) aminosulfonyl) phenyl] -1H-pyrrole;   2- [2-methoxy-4-((N-methyl-N-phenyl) aminosulfonyl) phenyl [Ethyl] -5- [1- (R, S)-(1-piperidinyl) ethyl] -1H-pyrrole;   2- (2-methoxy-5-((N-methyl-N- (4-methylsulfinyl) phene) Nyl) aminosulfonyl) phenyl) -5- (1- (2- (R, S) -phenylazasic Loheptyl) methyl) -1H-pyrrole;   And their salts.   The present invention   (A) Formula (II) in the presence of formaldehyde: And a compound of formula (III), (IV) or (V): The Mannich reaction with an amine represented by is carried out, and Y is a group (a) or (c) (here And R⁸, R⁹, R¹³And R¹⁴Is hydrogen) or formula (I) wherein Y is a group (e). Or a compound represented by   (B) a compound represented by the formula (II) and a formula (VI), (VII) or (VIII): With an appropriate oxo derivative of the amide or group (b) or (c) A Meyer reaction is carried out, and then the intermediate product is treated with, for example, sodium borohydride. Alternatively, it is reduced with sodium cyanoborohydride so that Y is a group (a) (where R⁸And And R⁹At least one of which is hydrogen), a group (c) (wherein R is¹³Or R¹⁴ At least one of them is hydrogen), a group (e) or a group represented by the formula (b) or (d). A compound that is a group that is   Expression (IX): Of the compound represented by formula (III), (IV) or (V) with an amine Whether Y is a group (a) or (c), depending on the⁸, R⁹, R¹³and R¹⁴Is hydrogen), or Y is a group (e);   (D) Oxidation of thiol functional groups to sulfinyl or sulfonyl functional groups, or Or a compound of formula (I) such as hydrogenation of a benzyloxy group to hydroxy. Conversion of the compound to another compound of formula (I) A process for producing a compound of formula (I), characterized in that There is also.   The Mannich reaction according to step (a) may be carried out according to conventional methods. Or For example, an amine of formula (III), (IV) or (V) A Reacting with aldehyde and then reacting the product with a compound of formula (II) . The reaction is preferably a protic solvent, for example an alcohol such as ethanol. It is done in Le. Organic or inorganic acids such as acetic acid may be used as catalyst .   The Vilsmeier reaction according to step (b) is also carried out according to conventional methods. Good. Thus, for example, an amide of formula (VI), (VII) or (VIII) Or the oxo derivative of the group (b) or (d) is first treated with phosphorus oxychloride (POCl)._Three) And react The resulting product is then conveniently converted to dichloromethane or dichloro React with a compound of formula (II) in a solvent such as ethane. Then this reaction The product of, for example, sodium borohydride or sodium cyanoborohydride Reduce with. The reduction can be carried out in a suitable solvent, for example dichloroethane, dichloromethane. Done in tan, methanol, ethanol, water or mixtures thereof.   Reductive amination according to step (c) generally involves sodium borohydride or cyanide. Using a reducing agent such as sodium noborohydride, a Lewis acid such as titanium (IV) chloride Will be done in the presence of. The reaction of compound (IX) with an amine is conveniently carried out by It is carried out in a solvent such as chloromethane or dichloroethane.   The interconversion of step (d) is carried out using standard methods; eg thiol The oxidation of the alcohol is carried out with hydrogen peroxide. Hydroxy group of benzyloxy group The conversion to is carried out by hydrogenation, for example using palladium on charcoal. .   The compound represented by the formula (II) has the formula (X): It is produced by cyclization of a dicarbonyl compound represented by.   The reaction is carried out in a solvent such as ethanol in an ammonium salt such as ammonium acetate. [Eg, CG Kruse, et al., Hetero] See Heterocycles, Vol. 26, p. 3141, 1987].   The compound of formula (X) is itself a compound of formula (XI): [Wherein, R^{twenty four}Is a halogen atom, for example chlorine, or the group --N (CH_Three) OCH_Three Represents R¹-R^FiveIs the same as the above definition] An appropriately substituted aroyl halide or methoxyamide represented by 2- ( 2-haloethyl) -1,3-dioxolane or 2- (2-haloethyl) -1,3- By reacting with a metallo derivative of dioxane, followed by acid hydrolysis Manufactured.   R^{twenty four}A compound of formula (XI) in which is a hydrogen atom can be paired using standard methods. Manufactured from the corresponding benzoic acid. R^{twenty four}Is -N (CH_Three) OCH_ThreeTakes if The compound is present in the presence of a base such as triethylamine and a solvent such as dichloromethane. Below, the corresponding aroyl halide or anhydride was replaced with N- (methoxy) methylamine It is produced by reacting. The anhydride is a suitable benzoic acid or naphthoic acid. Reacting an acid derivative with an alkyl haloformate, eg isobutyl chloroformate And is conveniently used in situ.   The compound represented by the formula (II) also has the formula (XII): [In the formula, Hal is a halogen atom, for example, bromine] A halo-substituted aryl derivative represented by the formula (XIII): [Wherein, R^{twenty five}Represents an N-protecting group, for example t-butoxycarbonyl] A N-protected pyrrole derivative represented by^{twenty five}Can be removed Manufactured by   The reaction is carried out using benzene, toluene, aqueous dimethoxyethane, aqueous tetrahydrofuran. Salts such as sodium carbonate in a suitable solvent such as orchid or dimethylformamide Group and Pd (PPh_Three)_FourOr palladium dibenzylideneacetone and triphe It is carried out in the presence of a palladium catalyst such as nilphosphine.   The N protecting group is removed by methods well known in the art. For example, The t-butoxycarbonyl group is the same as sodium methoxide in tetrahydrofuran. Alternatively, it is cleaved with trifluoroacetic acid in dichloromethane.   Compounds of formula (III) and (IV) are commercially available, or , Manufactured by standard methods.   The amine (V) was added in the presence of titanium (IV) chloride as described above for step (c). Formula (XIV): The amine R of the ketone represented by¹⁶NH₂Reductive amination with, then cyanoboro Obtained by reduction such as with sodium hydride.   Each R⁸And R¹³The compounds of formulas (VI) and (VII) in which is other than hydrogen are , Of the formula (III) or (IV) using, for example, the corresponding acyl halide Prepared by acylation of the appropriate amine.   Each R⁸And R¹³And compounds of formulas (VI) and (VII) in which is hydrogen The compound represented by the formula (VIII) is a suitable compound represented by the formula (III), (IV) or (V). Made by reacting min with a formylating agent, for example acetic anhydride in formic acid. Is built.   The compound represented by the formula (IX) is obtained by reacting diethylformamide with phosphorus oxychloride, Reacting the product with a compound of formula (II) in a solvent such as dichloromethane, It is then produced by performing a Vilsmeier reaction of hydrolysis.   Substituent R¹~ R^FiveAt any suitable stage of the synthesis, preferably The formation of or the interaction with the pyrrole part using methods known in the field. Introduced at an early stage before pulling. Thus, for example, the substituent R⁶R⁷ NSO₂− Represents formula (XV): [Wherein, R²⁷Represents a carboxyl group or a halogen atom such as bromine, R²⁸ Is OR¹, R², R^Three, R^FourAnd R^FiveRepresents any ring substituent selected from] The compound represented by⁶R⁷It is formed by reacting with NH.   The reaction is conveniently carried out in the presence of a solvent such as tetrahydrofuran or water. And optionally in the presence of a base. Excess amine R⁶R⁷NH is the base It is convenient to act as. Is the compound represented by the formula (XV) known ( For example, German OLS 2,721,643) or manufactured by standard methods Is done.   R⁶A compound of formula (XV) Using the same conditions as above, the amine R⁷NH₂And the product is reacted with tetra R in the presence of a base such as sodium hydride in a suitable solvent such as hydrofuran⁶ Is reacted with an alkylating agent corresponding to, for example, a halide or a tosyl derivative. May be.   R⁷Is based on (R^a)_p-(Ar)-(CH₂)_jRepresents-(where j represents 0), R⁶But C_1-6Alkyl or C_1-4Alkoxy C_1-4When representing alkyl, amine R⁶R⁷ NH is the corresponding primary amine (R) in the presence of an acid catalyst such as trifluoroacetic acid.^a)_p− (Ar) -NH₂R⁶Orthoester R⁶'C (OEt)_ThreeAnd then obtained Imidized ester derivative (R^a)_p-(Ar) N = C (R) OEt was dissolved in ethanol. C. It is produced by reducing with sodium hydride. Alternatively, n is When representing 0 or 1-4, amine R⁶R⁷NH is a base such as triethylamine And a suitable primary amine (R^a)_p-(Ar)-( CH₂)_j-NH₂R⁶Acyl halide R corresponding to⁶'React with COCl and For reduction with lithium aluminum hydride in lahydrofuran Therefore, it is manufactured.   If desired, a substituent R which is sensitive to any of the reactions used in the preparation of compound (I)¹ ~ R^FiveGroups or moieties present on any of the groups or groups Y are well known in the art. It may be protected during the reaction by any of the methods described and the protecting group is By a quasi-method, at any convenient stage of the synthesis, for example in the final stage, To be removed. Thus, for example, a hydroxy group is protected as a benzyloxy group. And deprotection is carried out by hydrogenation, for example using palladium on charcoal.   When the compounds of formula (I) are obtained as a mixture of enantiomers, these are , Crystallization in the presence of a resolving agent, or using, for example, a chiral HPLC column. It is separated by a conventional method such as chromatography.   Alternatively, the compound of formula (I) may be synthesized in step (a) or Kira can be used directly in (c) or in the preparation of an amide for use in step (b). It is prepared as a single enantiomer by using ruamine. Formula (III) , (IV) or (V) is a suitable enantiomer mixture of amines. Is divided into, for example, (S)-(+)-α-methoxyphenylacetic acid, etc. The resulting diastereoisomers were chromatographed by coupling to the chiral auxiliary of Manufactured by separating by Raffy. Auxiliary part is standard Removed by the method to give the desired chiral amine. Thus, for example, (( The S)-(+)-α-methoxyphenylacetyl moiety is preferably present under basic conditions, Cleaved using methyllithium in hexane or tetrahydrofuran .   The compounds of formula (I) are dopamine receptors, especially D_ThreeTo the receptor Has been shown to have an affinity for, and is associated with such receptors, such as psychotic symptoms. It is also expected to be useful in the treatment of medical conditions that require regulation of the metabolism. Enter now Generally, the therapeutic effect of available antipsychotic drugs (neuroleptics) is D₂Interception of receptors It is exerted through discontinuity; however, this mechanism is the basis for many neuroleptic drugs. Is also thought to be responsible for unwanted extrapyramidal side effects (eps) associated with You. The recently characterized dopamine, unless you want to be bound by a hypothesis D_ThreeReceptor blockade appears to produce beneficial antipsychotic activity without significant eps [Eg Sokoloff et al., Nature, 1990; 3 47: 146-151; and Schwartz et al., Clinical Ni. Clinical Neuropharmacology, Volume 16, Issue 4, 295-314, 1993]. Therefore, the preferred compounds of the present invention are: Dopamine D₂Dopamine D rather than to the receptor_ThreeBetter for receptors It has a high affinity (such affinity can be For example, it can be measured using a cloned dopamine receptor.) . The compound is conveniently D_ThreeUsed as a selective modulator of receptors . In particular, the compound of formula (I) is dopamine D_ThreeIs a receptor antagonist, As is, for example, schizophrenia, schizophrenia-affective psychosis, psychotic depression and mania. It is useful as an antipsychotic drug in the treatment of. Dopamine D_ThreeRegulation of receptors Other symptoms treated by Parkinson's disease, psycholeptic-induced par Movement disorders such as Kinson's syndrome and tardive dyskinesia; depression; and drugs (Eg, cocaine) addiction.   Therefore, in a further aspect, the present invention provides a patient in need of treatment with Formula (I) Administering an effective amount of a compound represented by: or a physiologically acceptable salt thereof. Dopamine D_ThreeConditions that require receptor regulation, such as schizophrenia It is intended to provide a cure for mental illness such as illness.   The present invention relates to dopamine D_ThreeSymptoms requiring receptor regulation, eg, mental A compound of formula (I) or a compound thereof in the manufacture of a therapeutic agent for psychosis such as schizophrenia It also provides the use of physiologically acceptable salts.   For use in medicine, the compounds of the present invention will usually be formulated into standard pharmaceutical compositions. Administered. Therefore, the present invention, in a further aspect, is a novel compound of formula (I) Is the reference compound or a physiologically acceptable salt thereof and a physiologically acceptable carrier? A pharmaceutical composition comprising the same is provided.   The compounds of formula (I) may be prepared by any convenient method, eg by oral administration, non-administration. By oral, buccal, sublingual, nasal, rectal or transdermal administration Administered, the pharmaceutical composition is adapted accordingly.   Compounds of formula (I) which are active when administered orally and their physiological Acceptable salts may be liquids or solids, for example syrups, suspensions or Can be formulated as emulsions, tablets, capsules and lozenges.   Liquid formulations generally comprise a suitable compound of the compound or a physiologically acceptable salt thereof. A liquid carrier, for example, an aqueous solvent such as water, ethanol or glycerin, or Suspension or solution in a non-aqueous solvent such as, polyethylene glycol or oil Will consist of The formulation may be a suspending agent, preservative, flavoring agent or coloring agent. An agent may be contained.   Compositions in the form of tablets are suitable for conventional use in preparing solid formulations. It can be prepared using a pharmaceutical carrier. Examples of such carriers include stearin Magnesium acid, starch, lactose, sucrose and cellulose are listed. You can   The composition in the form of capsules may be prepared using conventional encapsulation methods. Wear. For example, using standard carriers to prepare pellets containing the active ingredient, Alternatively, it can be filled into hard gelatin capsules; Dispersions or dispersions using pharmaceutical carriers such as aqueous gums, celluloses, silicates or oils. Or a suspension is prepared, and the dispersion or suspension is then placed in a gelatin soft capsule. Can be filled.   A typical parenteral composition comprises the compound or a physiologically acceptable salt thereof, Sterile aqueous carrier or parenterally acceptable oils such as polyethylene glycol Solution in water, polyvinylpyrrolidone, lecithin, peanut oil, or sesame oil. It consists of a suspension. Alternatively, the solution is lyophilized and then suitable immediately before administration. It can be reconstituted with a suitable solvent.   Compositions for intranasal administration are conveniently aerosols, drops, gels and powders. It is formulated as a powder. Aerosol formulations are active, physiologically acceptable A solution or fine suspension in an aqueous or non-aqueous solvent Nothing in a closed container that can take the form of a cartridge or refill for use with Present in single or multiple doses in fungal form. Alternatively, the closed container Single dose intranasal inhalation with a metering valve that is disposed of when the contents are exhausted It may be a unit-type dispensing device such as a container or an aerosol dispenser. If the dosage form consists of an aerosol dispenser, compressed gas such as compressed air or Or will contain propellants that are organic propellants such as fluorochlorohydrocarbons . Aerosol dosage forms can also take the form of pump atomizers.   Compositions suitable for buccal or sublingual administration include tablets, lozenges and And fragrances, wherein the active ingredients are sugar and gum arabic, tragacanth. Or a carrier such as gelatin and glycerin.   Compositions for rectal administration may conveniently contain conventional suppository bases such as cocoa butter. It is in the form of a suppository.   Compositions suitable for transdermal administration include ointments, gels and patches. Can be   Preferably the composition is in a single dose, such as a tablet, capsule or ampoule. It is a given form.   Each dosage unit for oral administration is preferably of formula (I) calculated as the free base. 1 to 250 mg of the compound represented by or a physiologically acceptable salt thereof ( For parenteral administration, it preferably contains 0.1 to 25 mg).   Physiologically acceptable compounds of the invention are typically calculated, eg, as the free base. And a compound of formula (I) or a physiologically acceptable salt thereof 1 mg to 500 Oral dose of 10 mg to 400 mg, preferably 10 to 250 mg, or Or 0.1 mg to 100 mg, preferably 0.1 to 50 mg, for example 1 to 25 mg Administered in a daily dose regimen (for adult patients) of intravenous, subcutaneous or intramuscular dose And the compound is administered 1 to 4 times per day. Suitably, the compound is It will be administered for a period of continuous therapy, for example for a week or more.   The invention is further described by the following non-limiting examples.   Description 1   2- (R, S) -Phenylazacycloheptane   A solution of 1-aza-2-methoxy-1-cycloheptene (50.9 g) under argon was prepared. Phenylmagnesium bromide (3M solution in ether 3 00 ml) was added and the mixture was heated at reflux for 4 hours. The reaction mixture is Cool (ice / water), LiAlH_Four(16.9 g) was added dropwise. Then return the mixture The mixture was heated for 5 hours while flowing, and then cooled to room temperature. The mixture is whipped strongly Then, it was poured on crushed ice. The obtained slurry is 10% aqueous sodium hydroxide solution Basify with liquor, filter through kieselguhr, then a. Washed with tel. The layers were separated and the aqueous fraction was further extracted with ether. . The combined ether layers were dried (Na₂SO_Four), Evaporated to dryness in a vacuum, and orange- A golden liquid was obtained and after distillation (0.5 mmHg) the title compound was obtained as a colorless liquid ( 46.43 g, 66%). Boiling point 82-9 [deg.] C.   ¹1 H NMR (CDCl_Three) Δ: 1.50-2.09 (8H, br m), 2.75-2.9 5 (1H, m), 3.06-3.24 (1H, m), 3.65-3.81 (1H, dd, J = 4,10 Hz), and 7.13-7.45 (5 Hz, m).   Descriptions (2a) and (2b)   1-[(S) -2-methoxy-2-phenyl] acetyl-2- (R) -phenylaza Cycloheptane (D2a) and 1-[(S) -2-methoxy-2-phenyl] acetate Cyl-2- (S) -phenylazacycloheptane (D2b)   (S)-(+)-2-methoxy-2-phenylacetic acid (3.65 g, 22 mmol) A solution in loromethane (35 ml) and dimethylformamide (1 drop) was charged with argon. Under room temperature, oxalyl chloride (2.8 ml, 33 mmol) was added dropwise. After 2 hours, The evolving component was removed in vacuo and the residue was dissolved in dichloromethane (90ml). The solution Of 2- (R, S) -phenylazacycloheptane (3.88 g, 22 mmol) in dichloromethane. Mechanically to a solution in dichloromethane (90 ml) and 5% aqueous NaOH (190 ml). With vigorous stirring, the mixture was added dropwise at room temperature. After 0.25 hours the layers were separated and the organic layer was washed with water. Washed with, dried and evaporated in vacuo to give a colorless oil. On silica gel Chromatography eluting with 20-30% ethyl acetate / pentane, 2 The title compound was obtained as two types of diastereoisomers [total yield 88%]:   Fast eluting isomer (D2a) (3.18g, 45%)   ¹1 H NMR (CDCl_Three) (Present as a mixture of E / Z isomers) δ: 0.8 0-1.06 (wide m) and 1.14-1.47 (br m) (1H together), 1.55-1. 90 (6H, br m), 2.17-2.40 (1H, br m), 2.80-2.97 (1H, br m) ), 3.14 (s) and 3.47 (s) (3H together), 3.90-4.05 (br d, J = 1) 3Hz) and 4.29-4.45 (br d, J = 13Hz) (1H together), 4.98 (s) And 5.08 (s) (1H together), 5.12 (q, J = 5Hz) and 5.42 (q, J = 5H) z) (1H together), as well as 7.02-7.48 (10H, m).   Late eluting isomer (D2b) (3.04 g, 43%)   ¹1 H NMR (CDCl_Three) (Present as a mixture of E / Z isomers) δ: 0.5 4-0.79 (br m) and 1.10-1.45 (br m) (1 H together), 1.50-1. 98 (6H, br m), 2.13-2.49 (br m) and 2.76-3.10 (br m) (2 H together), 3.18 (s) and 3.40 (s) (3 H together), 3.78 and And 4.58 (br d, J = 16 Hz) (1 H together), 4.64 (s) and 5.03 (s) (together 1H), 4.72 (q, J = 5Hz) and 5.64 (q, J = 5Hz) (1H together), Rabini 6.94-7.50 (10H, m).   Description 3   2- (R) -phenylazacycloheptane   Fast eluting amide diastereoisomer (D2a) (3. Methyllithium was added to a solution of 18 g, 9.8 mmol) in dry tetrahydrofuran (32 ml). (25.4 ml of a 1.5M solution in ether, 4 eq) was added. 40 minutes later, the reaction The material was basified with saturated aqueous potassium carbonate and extracted into ether. Ethereal The fraction was extracted into a 5N aqueous hydrochloric acid solution, basified again and extracted into ether. Was. Dried (Na₂SO_Four), Evaporated to dryness in vacuo to give crude crude as a yellow oil. A product is obtained which is evaporated using a Kugelrohr to give a colorless oil. The title compound was obtained as a substance (0.67 g, 39%). Boiling point 100 ℃ (0.3mmHg), [α]²⁰ _D= 35 ° (c, 0.89%, MeOH), ee> 92.6% (as eluent HPLC on a Chiralcel OJ column with xane / ethanol by).   ¹1 H NMR (CDCl_Three) Δ: 1.54-2.04 (8H, br m), 2.78-2.9 6 (1H, m), 3.07-3.23 (1H, m), 3.68-3.84 (1H, m), and 7. 18-7.47 (5H, m).   Description 4   2- (S) -phenylazacycloheptane   In the same manner as in description 3, the slower eluting diastereoisomer (D 2b) (3.04 mg, 9.4 mmol) was used to give the title compound in 33% yield. [α]²⁰ _D-30.1 ° (c, 0.9%, MeOH), ee> 98.8% (as eluent HPLC on a Chiralcel OJ column with xane / ethanol by).   ¹1 H NMR (CDCl_Three) Δ: 1.49-2.10 (8H, br m), 2.76-2. 97 (1H, m), 3.05-3.23 (1H, m), 3.68-3.84 (1H, m), and And 7.12-7.50 (5H, m).   Description 5   1-formyl-2- (R, S) -phenylazacycloheptane   2-to a mixture of 98-100% formic acid (30 ml) and acetic anhydride (100 ml). (R, S) -Phenylazacycloheptane (10 g, 57.1 mmol) was added and the mixture was mixed. The mixture was warmed to 70 ° C. for 2 hours. The reaction mixture is then cooled and steamed under vacuum. It was evaporated to dryness and the residue was partitioned between ether and saturated aqueous potassium carbonate solution. D The ether layer is separated, evaporated to dryness in vacuo and labeled as a mixture of E / Z isomers. The compound was obtained (11.24 g; 97%).   ¹1 H NMR (CDCl_Three) Δ 1.2-2.1 (5H, m), 2.3-2.6 (1.5H, m) ) 2.7-2.95 (0.5 H, m), 2.8 (t, J = 12 Hz) and 2.95 (t, J = 1) 2Hz) (1H together), 3.15 (m) and 3.77 (m) (1H together), 3.65 (br d , J = 12Hz) and 4.24 (br d, J = 12Hz) (1H together), 4.67 (dd, J) = 12,4 Hz) and 5.3 (dd, J = 12,4 Hz) (1 H together), 7.13-7.45 (5H, m), 8.15 (s) and 8.3 (s) (1H together).   Description 6   1-formyl-2- (R) -phenylazacycloheptane   A mixture of 98-100% formic acid (8.3 ml) and acetic anhydride (2.7 ml) was added to the mixture. 2- (R) -Phenylazacycloheptane (0.92 g) was added dropwise under Lugone to dissolve the solution. The liquid was stirred at 70 ° C. for 2 hours. Cool the reaction mixture and remove volatiles in vacuo. did. The residual oil was taken up in water and extracted into dichloromethane. Combined organic extraction The product was washed with a saturated aqueous solution of sodium bicarbonate, water and brine, dried (Na₂SO_Four ), And evaporated in vacuo to give the title compound as a straw colored oil (0.75g, 7 1%).   ¹1 H NMR (CDCl_Three) (Present as a mixture of E / Z isomers) δ: 1.1 9-2.09 (7H, m), 2.39 (m) and 2.57 (m) (1H together), 2.81 (t, J = 13 Hz) and 3.34 (t, J = 13 Hz) (1 H together), 3.68 (br d, J = 13Hz) and 4.24 (br d, J = 13Hz) (1H together), 4.68 (q, J = 7 Hz) and 5.31 (q, J = 7 Hz) (1 H together), 7.13-7.50 (5 H, m), 8.15 (s) and 8.29 (s) (1H together).   Description 7   1-formyl-2- (S) -phenylazacycloheptane   Using a method similar to that of Description 6, 2- (S) -phenylaza was used. The title compound was prepared from cycloheptane in 85% yield.   ¹1 H NMR (CDCl_Three) (Present as a mixture of E / Z isomers) δ: 1.2 6-2.12 (7H, m), 2.36 (m) and 2.57 (m) (1H together), 2.81 (dt, J = 13.1Hz) and 3.34 (dt, J = 13.1Hz) (1H together), 3.70 (br d, J = 13Hz) and 4.25 (br d, J = 13Hz) (1H together), 4.69 (q, J) = 5Hz) and 5.32 (q, J = 5Hz) (1H together), 7.13-7.45 (5H, m) , 8.16 (s) and 8.29 (s) (1H together).   Description 8   2-Methoxy-5-((N-methyl-N-phenyl) aminosulfonyl) benzoic acid   5-Chlorosulfonyl-2-methoxybenzoic acid at 0 ° C [Davryu Ribeno W. Liebenow et al., Ger. Offen 2,721,643 (CA 90 10367). 3j)] (10 g, 43 mmol) in water (70 ml) was suspended in N-methylaniline (1 8.2 g, 172 mmol) and stirred for 10 minutes, the mixture is allowed to reach room temperature over 1 hour. Heated. The reaction mixture was then adjusted to pH1 with 5N hydrochloric acid. The product is Recovered by extraction into chloromethane, dried the extract (Na₂SO_Four),true Concentrate in air to a gum and crystallize the gum from ether to give a needle. This gave the title compound (8.3 g; 60%). Melting point 160-161 [deg.] C.   ¹1 H NMR (CDCl_Three) Δ: 3.2 (3H, s), 4.1 (3H, s), 7.08 (1H, d) , J = 8.5 Hz), 7.1 (2H, m), 7.3 (3H, m), 7.6 (1H, dd, J = 8.5,2 .5 Hz), and 8.35 (1 H, d, J = 2.5 Hz).   The following compounds were prepared in a similar manner to Description 8:   (A) 5-[(N-benzyl-N-methyl) aminosulfonyl] -2-methoxyammonium Benzoic acid   Melting point 142-144 [deg.] C (ether). Measurements: C, 55.28; H, 4.96; N, 4.27. C₁₆H₁₇NO_FiveS 0.75H₂Theoretical value of O: C, 55.08; H, 5.34 N, 4.05%.   (B) 5-[(N- (4-benzyloxyphenyl) -N-methyl) aminosulfo Nyl] -2-methoxybenzoic acid   Melting point 155-157 [deg.] C (ether). Measured: C, 61.88; H, 4.93; N, 3.45. C_{twenty two}H_{twenty one}NO₆Theoretical value of S: C, 61.81; H, 4.95; N, 3.28% .   (C) 5-[(N- (2,4-difluorophenyl) -N-methyl) aminosulfoni ] -2-Methoxybenzoic acid   ¹1 H NMR (CDCl_Three) Δ: 3.22 (3H, s), 4.15 (3H, s), 6.73- 6.95 (2H, m), 7.15 (1H, d), 7.35 (1H, m), 7.85 (1H, m), 8. 48 (1H, d).   (D) 5-[(N- (4-bromophenyl) -N-methyl) aminosulfonyl] -2 -Methoxybenzoic acid   Melting point 178-180 [deg.] C. Found: C, 44.77; H, 3.59; N, 3.52. C_Fifteen H₁₄BrNO_FiveTheoretical value for S: C, 45.01; H, 3.53; N, 3.50%.   (E) 2-methoxy-5-[(N- (4-methoxyphenyl) -N-methyl) ami No sulfonyl] benzoic acid   Mass spectrometry: Measured value M⁺351.0787. C₁₆H₁₇NO₆Theoretical value of S: 351.0 776.   (F) 5-[(N- (4-cyanophenyl) -N-methyl) aminosulfonyl] -2 -Methoxybenzoic acid   Mass spectrometry: Measured value M⁺346.0609. C₁₆H₁₄N₂O_FiveTheoretical value of S: 346. 0623.   (G) 5- [4- (3,4-dihydro-2H-1,4-benzoxazinyl)] sul Honyl-2-methoxybenzoic acid   Found: C, 54.83; H, 4.44; N, 4.16. C₁₆H_FifteenNO₆Theoretical value of S : C, 55.01; H, 4.33; N, 4.01%.   (H) 2-methoxy-5- (1- (2-phenyl) pyrrolidinyl) sulfonylbenzoate Perfume   ¹1 H NMR (CDCl_Three) Δ: 1.70-2.0 (3H, m), 2.10 (1H, m), 3. 52 (1H, m), 3.65 (1H, m), 4.13 (3H, s), 4.80 (1H, m), 7.06 (1H, d, J = 9Hz), 7.25 (5H, m), 7.88 (1H, dd, J = 9,3Hz) and 8.50 (1H, d, J = 3Hz).   (I) 2-methoxy-5- (N-ethyl-N-((2-phenyl) ethyl) amino Sulfonyl) benzoic acid   Mass spectrometry: Measured value M⁺363.1149. C₁₈H_{twenty one}NO_FiveTheoretical value of S: 363.1 158.   (J) 5-((N-ethyl-N- (3-pyridyl) methyl) aminosulfonyl) -2 -Methoxybenzoic acid   ¹1 H NMR (CDCl_Three) Δ: 1.00 (3H, t, J = 7Hz), 3.15 (2H, q, J = 7Hz), 4.00 (3H, s), 4.35 (2H, s), 7.05 (1H, d, J = 8Hz), 7.30 (1H, m), 7.70 (2H, m), 8.25 (1H, d, J = 2Hz), 8.55 (2 H, m).   (K) 2-methoxy-5-((N-methyl-N- (5-methyl-3-isooxa Zolyl)) aminosulfonyl) benzoic acid   ¹1 H NMR (CDCl_Three) Δ: 2.40 (3H, s), 3.29 (3H, s), 4.15 (3 H, s), 6.50 (1H, s), 7.16 (1H, d, J = 9Hz), 7.92 (1H, dd, J = 9,3 Hz), 8.53 (1 H, d, J = 3 Hz).   (L) 5-[(N- (4-fluorophenyl) -N-methyl) aminosulfonyl]- 2-methoxybenzoic acid   ¹1 H NMR (CDCl_Three) Δ: 3.15 (3H, s), 4.00 (3H, s), 7.00 (5 H, m), 7.55 (1H, dd, J = 9Hz), 8.08 (1H, d, J = 2Hz).   (M) 2-methoxy-5-[(N-methyl-N- (3-pyridyl) aminosulfoni Le] benzoic acid   ¹H NMR (d₆-DMSO) δ: 3.15 (3H, s), 3.91 (3H, s), 7.3 3 (1H, d, J = 9Hz), 7.40 (1H, dd, J = 9.6Hz), 7.56 (1H, m), 7 .63 (1H, dd, J = 9,3Hz), 7.71 (1H, d, J = 3Hz), 8.40 (1H, d, J = 3 Hz), 8.48 (1 H, d, J = 6 Hz).   (N) 5-[(N-ethyl-N- (4-pyridyl) methyl) aminosulfonyl] -2 -Methoxybenzoic acid   ¹1 H NMR (CDCl_Three) Δ: 1.00 (3H, t, J = 8Hz), 3.26 (2H, q, J = 8Hz), 4.09 (3H, s), 4.41 (2H, s), 7.15 (1H, d, J = 9Hz), 7.39 (2H, d, J = 6Hz), 7.60-8.50 (1H, br s), 7.99 (1H, dd, J = 9,3 Hz), 8.45 (1 H, d, J = 3 Hz), 8.65 (2 H, d, J = 6 Hz).   (O) 5 (1-Indolinesulfonyl) -2-methoxybenzoic acid   ¹1 H NMR (CDCl_Three) Δ: 2.9 (2H, t, J = 8Hz), 3.95 (2H, t, J = 8Hz), 4.10 (3H, s), 7.0 (1H, t, J = 8Hz), 7.1 (2H, t, J = 8Hz) ), 7.2 (1H, t, J = 8Hz), 7.6 (1H, d, J = 8Hz), 7.95 (1H, d, J = 8 Hz), 8.55 (1 H, d, J = 2 Hz), 8.5-9.5 (1 H, br s).   (P) 5-[(N-ethyl-N- (2-furyl) methyl) aminosulfonyl] -2- Methoxybenzoic acid   ¹H NMR (d₆-DMSO) δ: 0.95 (3H, t, J = 7Hz), 3.10 (2H, q, J = 7Hz), 3.90 (3H, s), 4.40 (2H, s), 6.40 (2H, m), 7.30 (1H, d, 8Hz), 7.50 (2H, m), 7.90 (1H, dd, J = 8,2Hz), 8.00 ( 1H, d, J = 2Hz).   Description 9   3- [3- (2- (1,3-dioxanyl)) propionyl] 4-methoxy- (N-me Cyl-N-phenyl) benzenesulfonamide   2-Methoxy-5 in dichloromethane (50 ml) at room temperature under argon atmosphere. -((N-Methyl-N-phenyl) aminosulfonyl) benzoic acid (7 g, 21.8 mmol) With oxalyl chloride (8.2 g, 65 mmol) and 1 drop of dimethylformamide, The treatment was continued for 2 hours with continuous stirring until the generation of gas stopped. Then the reaction mixture Was evaporated to dryness in vacuo in a vacuum and the gum was co-repeated with toluene repeatedly. Boil to remove the final traces of oxalyl chloride and hydrochloric acid to give the acid chloride. It was used directly in the next step.   Dry tetrahydrofuran of magnesium (10 g, 0.41 mol) under argon 2- (2-Bromoethyl) -1,3-dioxane (5 The reaction was then heated at reflux for an additional 0.5 h. Then the solution is cooled , Separated from unreacted magnesium by syringe, at 0 ° C under argon atmosphere Store and store 1- (2- bromide in tetrahydrofuran (278 ml of 0.893 M solution). (2- (1,3-Dioxanyl)) ethyl) magnesium was obtained. -78 under argon At 1C, 1- (2- (2- (2- (1,3-dioxanyl)) ethyl) magnesium bromide (27m l, 24 mmol) solution at a rate such that the internal temperature does not rise above -70 ° C. 2-methoxy-5-((N-methyl-N-phenyl) aminosulfonyl) benzoyl Chloride (above) was added to a solution in dry tetrahydrofuran (150 ml). The The reaction was held at this temperature for 0.5 hour then allowed to warm to room temperature over 1 hour. . The reaction mixture was then evaporated in vacuo, washed with dichloromethane and 10% Partitioned into aqueous acid solution. The organic phase is separated, dried (Na₂SO_Four), In vacuum, The gum was evaporated to dryness and the gum chromatographed on silica. Elute with 5% -10% ethyl acetate in chloromethane to give the title compound as a gum. Was obtained (4.03 g; 46%).   ¹1 H NMR (CDCl_Three) Δ. 1.33 (1H, m), 2.0 (3H, m), 3.03 (2H, m t, J = 7Hz), 3.2 (3H, s), 3.75 (2H, t, J = 12Hz), 3.98 (3H, s) ), 4.08 (2H, m), 4.62 (1H, t, J = 5Hz), 6.95 (1H, d, J = 9Hz) , 7.1 (2H, m), 7.3 (3H, m), 7.53 (1H, dd, J = 9,2Hz), and 7. 85 (1H, d, J = 2Hz).   Description 10   4-Methoxy-3- (4-oxobutanoyl)-(N-methyl-N-phenyl) be Nzensulfonamide   3- [3- (2- (1,3-dioxanyl)) propio in methanol (200 ml) Nyl] -4-methoxy- (N-methyl-N-phenyl) benzenesulfonamide ( 4.0 g, 10 mmol) was treated with 4-toluenesulfonic acid (0.5 g) and refluxed. The solution was heated for 1 hour and then cooled. Add excess potassium carbonate solution The mixture was evaporated in vacuo, the residue was washed with aqueous potassium carbonate solution and dichloromethane. Partitioned to methane. Separate the organic phase, wash with water and evaporate to a gum in vacuo to dryness. Hardened. The gum was treated with tetrahydrofuran (25 ml) and 5N HCl (25 ml). ml) and then heated under reflux for 1 hour. The reaction mixture is cooled and Evaporated in the air. The product was collected by extraction into dichloromethane and vacuum Evaporate the product to dryness in to give the title compound as a gum (3.43 g; 9 5%), which was used without further purification.   ¹1 H NMR (CDCl_Three) Δ: 2.88 (2H, t, J = 6Hz), 3.18 (3H, s), 3.3 (2H, t, J = 6Hz), 4.0 (3H, s), 7.1 (2H, m), 7.3 (4H, m), 7 .57 (1H, dd, J = 9,2.5Hz), 8.0 (1H, d, J = 2.5Hz), and 9.8 8 (1H, s).   Description 11   2- (2-methoxy-5-((N-methyl-N-phenyl) aminosulfonyl) phenyl 1-H-pyrrole   4-Methoxy-3- (4-oxobutanoic acid) in tetrahydrofuran (20 ml) )-(N-methyl-N-phenyl) benzenesulfonamide with ammonium acetate (7 g) was added to a solution in ethanol (100 ml) and the reaction mixture was refluxed under argon. The reaction was heated for 2 hours. The reaction mixture was cooled to room temperature and ethanol was removed in vacuo. To give a gum which was partitioned between saturated aqueous potassium carbonate and ether. I let you. Ether solution is Na₂SO_FourDried in vacuo and evaporated to a gum in vacuo, Crystallize the gum from ether to give the title compound as a slightly yellow solid. Obtained (2.07 g, 53%). Melting point 136-138 [deg.] C. Measured value: C, 62.44; H, 5.41; N, 7.81. C₁₈H₁₈N₂O_ThreeS ・ 0.25H₂Theoretical value of O: C, 62.3 2; H, 5.38; N, 8.07%.   Description 12   2- (5-((N-benzyl-N-ethyl) aminosulfonyl) -2-methoxy group 1-H-pyrrole   Using the method of Description 8, 5-chlorosulfonyl-2-methoxy Benzoic acid was reacted with N-benzylethylamine to give 5-((N-benzyl-N- Ethyl) aminosulfonyl) -2-methoxybenzoic acid (melting point 94-96 ° C) was obtained, This product was further reacted by the route described in Description 9-11. The title compound was obtained. Mp 115-117 ° C (ether). Measured value: C, 64. 61; H, 6.09; N, 7.59. C₂₀H_{twenty two}N₂O_ThreeTheoretical value of S: C, 64.84; H , 5.99; 7.5%.   Description 13   2- [2-methoxy-5- (2- (1,2,3,4-tetrahydroisoquinolinyl)) Sulfonyl] phenyl-1H-pyrrole   Using the method of Description 8, 5-chlorosulfonyl-2-methoxy Benzoic acid is reacted with 2- (1,2,3,4-tetrahydroisoquinoline to give 2- [ 2-methoxy-5- [2- (1,2,3,4-tetrahydroisoquinolinyl) sulfoni And b) benzoic acid (mp 158-160 ° C., ethyl acetate). Further reaction by the route described in Cryption 9-11 to give the title compound. Was. Melting point 169-172 [deg.] C. (ether). Measurements: C, 65.01; H, 5.47; N , 7.54. C₂₀H₂₀N₂O_ThreeTheoretical value of S: C, 65.20; H, 5.47; 7.60% .   Description 14   2-methoxy-5- (1- (1,2,3,4-tetrahydroquinolinyl) sulfonyl ) -2-Methoxybenzoic acid   According to the method described in Description 8, 5-chlorosulfonyl-2-me Treatment of toxybenzoic acid with 1,2,3,4-tetrahydroquinoline to give the title compound Was obtained with a yield of 77%. Melting point 135-137 [deg.] C. Measured value: C, 59.05; H, 5.0 8; N, 3.97; C₁₇H₁₇NO_FiveTheoretical value of S: C, 58.78; H, 4.93; N, 4 0.03%.   Description 15   2- (2-methoxy-5- (1- (1,2,3,4-tetrahydroquinolinyl) sul Honyl) phenyl) -1H-pyrrole   2-Methoxy-5- (1- (1,2, Reacted with 3,4-tetrahydroquinolinyl) sulfonyl) -2-methoxybenzoic acid The title compound was obtained with a yield of 31%. Melting point 162.5-163.5 ° C (ether) . Measured value: C, 64.9; H, 5.52; N, 7.55; C₂₀H₂₀N₂O_ThreeTheoretical value of S; C, 65.2, H, 5.47; N, 7.60%.   Description 16   5-((N-ethyl-N-phenyl) aminosulfonyl) -2-methoxybenzoic acid   5-chlorosulfonyl-2-meth according to the method described in description 8 Treatment of xybenzoic acid with N-ethylaniline gave the title compound.   ¹1 H NMR (CDCl_Three) Δ: 1.1 (3H, t, J = 7Hz), 3.64 (2H, q, J = 7Hz), 4.13 (3H, s), 7.05 (1H, m), 7.1 (2H, m), 7.33 (3H, m) , 7.71 (1H, dd, J = 9,2Hz) and 8.49 (1H, d, J = 2Hz).   Description 17   2- [5-((N-ethyl-N-phenyl) aminosulfonyl) -2-methoxyphenyl Phenyl] -1H-pyrrole   5-((N-ethyl-N-phenyl) according to the method of Description 9-11. ) Aminosulfonyl) -2-methoxybenzoic acid was reacted to give the title compound.   ¹1 H NMR (CDCl_Three) Δ: 1.08 (3H, t, J = 7Hz), 3.60 (2H, q, J = 7 Hz), 4.04 (3 H, s), 6.27 (1 H, m), 6.54 (1 H, m), 6.89 (1 H, m), 6.97 (1H, d, J = 9Hz), 7.08 (2H, m), 7.34 (4H, m), 7. 81 (1H, d, J = 2Hz), and 9.70 (1H, br s).   According to the method of Description 9-11, Made from benzoic acid.   (A) 2- [5-((N-benzyl-N-methyl) aminosulfonyl) -2-meth Xyphenyl] -1H-pyrrole   Melting point 113-115 [deg.] C (ether). Measured value: C, 63.27; H, 5.66; N, 7.86. C₁₉H₂₀N₂O_ThreeS ・ 0.25H₂Theoretical value of O: C, 63.4; H, 5.85 N, 7.75%.   (B) 2- [5-((N- (4-benzyloxy) -N-methyl) aminosulfonyl ) -2-Methoxyphenyl] -1H-pyrrole   Melting point 123-124 [deg.] C (ether). Measurements: C, 66.77; H, 5.52; N, 6.49. C_{twenty five}H_{twenty four}N₂O_FourTheoretical value of S: C, 66.95; H, 5.39; N, 6.25 %.   (C) 2- [5-((N- (2,4-difluorophenyl) -N-methyl) aminos Rufonyl) -2-methoxyphenyl] -1H-pyrrole   Found: C, 56.21; H, 4.26; N, 7.32%. C₁₈H₁₆F₂N₂O_ThreeS. 0.5H₂Theoretical value for O: C, 55.81; H, 4.42; N, 7.23%.   (D) 2- [5-((N- (4-bromophenyl) -N-methyl) aminosulfonyl ) -2-Methoxyphenyl] -1H-pyrrole   Melting point 158-159 [deg.] C. Found: C, 51.23; H, 4.19; N, 6.53. C₁₈ H₁₇BrN₂O_ThreeTheoretical value for S: C, 51.31; H, 4.07; N, 6.65%.   (E) 2- [2-methoxy-5-((N- (4-methoxyphenyl) -N-methyl)) Aminosulfonyl) phenyl] -1H-pyrrole   Found: C, 61.18; H, 5.37; N, 7.61. C₁₉H₂₀N₂O_FourTheoretical value of S : C, 61.27; H, 5.41; N, 7.52%.   (F) 2- [5-((N- (4-cyanophenyl) -N-methyl) aminosulfonyl ) -2-Methoxyphenyl] -1H-pyrrole   Found: C, 62.00; H, 4.81; N, 11.35. C₁₉H₁₇N_ThreeO_ThreeTheory of S Value: C, 62.11; H, 4.66; N, 11.44%.   (G) 2- [5-((4- (3,4-dihydro-1,4-benzoxazinyl)) sul Honyl) -2-methoxyphenyl] -1H-pyrrole   Melting point 115-117 [deg.] C. Found: C, 61.63; H, 4.98; N, 7.54. C₁₉ H₁₈N₂O_FourS theoretical value: C, 61.61; H, 4.90; 7.56%.   (H) 2- [5-((N- (3,4-dimethoxybenzyl) -N-ethyl) aminos Rufonyl) -2-methoxyphenyl] -1H-pyrrole   Found: C, 61.17; H, 6.02; N, 6.67. C_{twenty two}H₂₆N₂O_FiveTheoretical value of S : C, 61.38; H, 6.09; N, 6.51%.   (I) 2- [2-methoxy-5-((N-methyl-N- (2-methylphenyl) a) Minosulfonyl) phenyl] -1H-pyrrole   ¹1 H NMR (CDCl_Three) Δ: 2.44 (3H, s), 3.14 (3H, s), 4.06 (3 H, s), 6.27 (1H, m), 6.58 (1H, m), 6.66 (1H, d, J = 8Hz), 6.9 1 (1H, m), 7.04 (2H, m), 7.25 (2H, m), 7.47 (1H, dd, J = 8,3) Hz), 7.93 (1H, d, J = 3Hz) and 9.74 (1H, br s).   (J) 2- [2-methoxy-5-((2- (7-methylthio-1,2,3,4-teto Lahydroisoquinolinyl)) sulfonyl) phenyl] -1H-pyrrole   (15-20% contaminated with regioisomers-description 21 reference)   ¹1 H NMR (CDCl_Three) Δ: 2.44 (3H, s), 2.88 (2H, t, J = 6Hz), 3.36 (2H, t, J = 6Hz), 4.04 (3H, s), 4.24 (2H, s), 6.32 (1) H, m), 6.70 (1H, m), 7.00 (5H, m), 7.60 (1H, dd, J = 8,3Hz), 8.06 (1H, d, J = 3Hz), 9.74 (1H, br s).   (K) 2- [1-methoxy-4-((N-methyl-N-phenyl) aminosulfoni )]-2-Naphthyl-1H-pyrrole   Melting point 113-115 [deg.] C.   (L) 2- [2-methoxy-5-((1- (2-phenylpyrrolidinyl)) sulfoni Lu) phenyl] -1H-pyrrole   Mass spectrometry: Measured value M⁺382.1372. C_{twenty one}H_{twenty two}N₂O_ThreeTheoretical value of S: 382. 1393.   (M) 2- [2-methoxy-5-((N-ethyl-N- (2-phenyl) ethyl) a Minosulfonyl) phenyl] -1H-pyrrole   ¹1 H NMR (CDCl_Three) Δ: 1.12 (3H, t, J = 7Hz), 2.85 (2H, m), 3.25 (2H, q, J = 7Hz), 3.38 (2H, m), 4.04 (3H, s), 6.32 (1 H, m), 6.72 (1H, m), 6.90 (1H, m), 7.02 (1H, d, J = 9Hz), 7. 25 (5H, m), 7.59 (1H, dd, J = 9.3Hz), 8.08 (1H, d, J = 3Hz) And 9.72 (1H, br s).   (N) 2- [2-methoxy-5-((N-methyl-N- (5-methyl-3-isoo Xazolyl)) aminosulfonyl) phenyl] -1H-pyrrole   ¹1 H NMR (CDCl_Three) δ: 2.41 (3H, s), 3.29 (3H, s), 4.04 (3H) , s), 6.31 (1H, m), 6.53 (1H, s), 6.63 (1H, m), 6.91 (1H, m) , 7.02 (1H, d, J = 9Hz), 7.49 (1H, dd, J = 9.3Hz), 7.99 (1H , d, J = 3 Hz), 9.69 (1H, br s).   (O) 2- [5-((N- (4-fluorophenyl) -N-methyl) aminosulfoni ) -2-Methoxyphenyl] -1H-pyrrole   ¹1 H NMR (CDCl_Three) δ: 3.15 (3H, s), 4.05 (3H, s), 6.29 (1H) , m), 6.53 (1H, m), 6.90 (1H, m), 6.92-7.18 (5H, m), 7.30 (1H, dd, J = 9,3Hz), 7.78 (1H, d, J = 3Hz), 9.53 (1H, br s).   (P) 2- (5- (1-indolinesulfonyl) -2-methoxyphenyl) -1H -Pyrrole   Found: C, 64.37; H, 5.27; N, 7.85. C₁₉H₁₈N₂O_ThreeTheoretical value of S : C, 64.39; H, 5.12; N, 7.80%.   (Q) 2- (2-methoxy-5-((N-methyl-N- (4-methylthio) phenyl) ) Aminosulfonyl) phenyl) -1H-pyrrole   Melting point 125-127 [deg.] C (ether).   ¹1 H NMR (CDCl_Three) Δ: 2.5 (3H, s), 3.15 (3H, s), 4.0 (3H, s) ), 6.3 (1H, m), 6.5 (1H, m), 6.8-7.4 (7H, m), 7.75 (1H, m), 9.7 (1H, s).   (R) 2- [2-methoxy-4-((N-methyl-N-phenyl) aminosulfoni Lu) phenyl] -1H-pyrrole   ¹1 H NMR (CDCl_Three) Δ: 3.16 (3H, s), 3.74 (3H, s), 6.29 (1 H, m), 6.72 (1H, m), 6.90 (2H, m), 7.2 (6H, m), 7.70 (1H, d, J = 9Hz), 9.90 (1H, brs).   (S) 2- [5-((N-ethyl-N- (2-furyl) methyl) aminosulfonyl) 2-Methoxyphenyl] -1H-pyrrole   ¹1 H NMR (CDCl_Three) Δ: 1.05 (3H, t, J = 7Hz), 3.20 (2H, q, J = 7Hz), 4.00 (3H, s), 4.45 (2H, s), 6.25 (3H, m), 6.70 (1 H, m), 6.90 (1H, m), 7.00 (1H, d, J = 8Hz), 7.25 (1H, m), 7. 55 (1H, dd, J = 8,2Hz), 8.05 (1H, d, J = 2Hz), 9.75 (1H, br s ).   Description 18   2-Methoxy-4-methyl-5-((N-methyl-N-phenyl) aminosulfo Nyl) benzoic acid   2-Methoxy-4-methylbenzoic acid [M Julia and Mada Mme. Chastrette Bull. Soc. Chim. Fr 1962, 2255] (16.6 g, 100 mmol) and sodium chloride (6 g) Chlorosulfonic acid (35 ml) was added dropwise to the mixture in tan (40 ml) over 2 hours. . The mixture was warmed to 40 ° C. for 1 hour and then heated to 65 ° C. for 17 hours. cooling The resulting mixture was poured into ice / water (about 500 ml) and the solid obtained was filtered, washed with water and It was washed with hexane and dried (about 24 g). This solid (11.5 g, 43 mmol) Add N-methylaniline (14 g, 130 mmol) to a stirred mixture in water (100 ml). Added. The mixture was stirred at room temperature for 24 hours. The oily mixture obtained was Partitioned between tan (100 ml) and water (100 ml). Wash the organic layer with water, 2 It was extracted with 0.5M sodium hydroxide and separated. Dilute the aqueous alkaline extract Washed with tan (50 ml), acidified with 5M HCl and dichloromethane (2 × 100). ml) and re-extracted. The combined extracts are Na₂SO_FourDried in vacuo, filtered, in vacuo, evaporation I let it. The oil obtained was triturated with dry ether to give a colorless crystalline solid. This gave the title compound (8.0 g; 57%). Melting point 147-148 [deg.] C.   ¹1 H NMR (CDCl_Three) Δ; 2.23 (3H, s), 3.23 (3H, s), 4.07 (3 H, s), 6.85 (1H, s), 7.15-7.32 (5H, m), 8.57 (1H, s).   Description 19   5- [3- (2- (1,3-dioxanyl)) propionyl] -4-methoxy-2- Methyl- (N-methyl-N-phenyl) benzenesulfonamide   2-Methoxy-4 in dichloromethane (50 ml) at room temperature under argon atmosphere. -Methyl-5-((N-methyl-N-phenyl) aminosulfonyl) benzoic acid (5. 0 g, 14.9 mmol) to oxalyl chloride (2.4 g, 19.5 mmol) and dimethyl Treated with 2 drops of formamide with continuous stirring for 2 hours after gas evolution ceased. . The reaction mixture was repeatedly azeotroped with toluene to give the final traces of chlorinated chloride. Salyl and hydrochloric acid were removed and then triturated with hexane to give the acid chloride (5 .3g) was obtained. Freshly dry the acid chloride (5.3 g, 15 mmol) under argon. Dissolve in distilled tetrahydrofuran (50 ml), then cool to -75 ° C. Was. Cooled Grignard reagent (15 mmol) (1 hour at reflux, magnesia 2- (2-Bromoethyl) -1,3-dioxane (2.9 g, 5 mmo) in um (0.5 g) produced by adding l)), the internal temperature does not rise above -70 ° C. At the same rate. The reaction was held at this temperature for 0.5 hours, then at 1 hour. The temperature was raised to room temperature over a period of time. Concentrate the reaction mixture in vacuo then dichloromethane. Partitioned between methane and 10% aqueous citric acid. The organic phase is separated and Na₂SO_Four Dried in vacuo, filtered and evaporated in vacuo to an oil which was washed on silica. Chromatographically eluting with 20-30% ethyl acetate in pentane, colorless The title compound was obtained as a crystalline solid (2.3 g; 35%). Melting point 90-91 [deg.] C.   ¹1 H NMR (CDCl_Three) Δ: 1.22-1.36 (1H, m), 1.71-2.04 ( 3H, m), 2.20 (3H, s), 2.99-3.06 (2H, t, J = 7.2Hz), 3.21 (3H, s), 3.69-3.81 (2H, m), 3.94 (3H, s), 4.04-4.17 (2 H, m), 4.59-4.65 (1H, t, J = 5Hz), 6.76 (1H, s), 7. 15-7.32 (5H, m), 8.18 (1H, s).   Description 20   2- [2-methoxy-4-methyl-5-((N-methyl-N-phenyl) aminos Rufonyl) phenyl] -1H-pyrrole   Under argon, 5- [3- (2- (1,3-dioxanyl)) propionyl] -4-me Toxy-2-methyl- (N-methyl-N-phenyl) benzenesulfonamide (2 0.0 g, 4.6 mmol) was dissolved in warm acetic acid (30 ml) and treated with acetic acid in water (5.0 ml). Treated with monium (5.0 g). The mixture was heated under reflux for 1.5 hours. The mixture The mixture was cooled, evaporated in vacuo and partitioned between ethyl acetate and water. Organic layer Separated, washed with water, brine, Na₂SO_FourDried in vacuo, filtered and evaporated in vacuo. I let you. The oil obtained was chromatographed on silica 20 in pentane. Elution with -30% ethyl acetate gave the title compound as a colorless crystalline solid (1.5. g, 91%). Melting point 146-147 [deg.] C. Measurements: C, 63.23; H, 5.69; N, 7.63. C₁₉H₂₀N₂O_ThreeS ・ (0.25H₂Theoretical value of O): C, 63.25; H, 5. 68; N, 7.77%.   Description 21   1-formyl-2- (R, S)-(2- (5-methylfuryl))-azacyclohepta N   M. Malmberg and K. Nyberg Acta Chemica Scandinavia 1981, See B35, 411-417.   At room temperature, 1-formyl-2-methoxy-azacycloheptane (2.24 g) and And 2-methylfuran (15 g) were stirred, and 4-toluenesulfonic acid was added under argon. (2.0 g) was added at once. After stirring for 1.5 hours at room temperature, saturated sodium hydrogen carbonate Lithium (40 ml) was added followed by diethyl ether (100 ml). Organic layer The layers were separated and the aqueous layer re-extracted with diethyl ether (2 x 40 ml). Organic combined The layers were washed with water (30 ml), dried (Na₂SO_Four), The solvent was removed in vacuo. This gave an oil (2.5 g) which was used as eluent in ethyl acetate: pentane. Chromatography (silica gel) using (1: 1). With this The above compound was obtained in a yield of 100%.   ¹1 H NMR (CDCl_Three) (Present as a mixture of E / Z isomers) δ: 1.2 -2.0 (6H, m), 2.25 (3H, s), 2.3-2.5, 2.65-2.75 and 3 .2-3.35 (3H, 3xm together), 3.45-3.55 and 3.92-4.05- Starting with (1H, 2xm), 4.5-4.6 and 5.32-5.45 (1H, 2xm together), 5.87 (1H, m), 6.05 (1H, m) and 8.20 (1H, s).   Description 22   2-Methoxy-5-((N-methyl-N- (4-methylthio) phenyl) aminos (Rufonyl) benzoic acid   5-Chlorosulfonyl-2-methoxybenzoic acid (10 g, 40 mmol) was added to water (7 0 ml) and cooled to 0 ° C. While stirring, add N-methyl-4-me Tylthioaniline (6.12 g, 40 mmol), then potassium carbonate in water (50 ml) (16.56 g, 120 mmol) was added over 1 hour. Then, the reaction mixture was mixed with 5 Acidified to pH 0 with NH Cl and extracted into dichloromethane. Dry the organic phase ( Na₂SO_Four), Evaporate to a gum in vacuo and grind the gum with ether. This gave the title compound (11.65 g, 85.9%) which was crystallized as needles. I let you. Melting point 153-157 [deg.] C. Found: C, 52.21; H, 4.65; N, 3.91. . C₁₆H₁₇NO_FiveS₂Theoretical value: C, 52.30; H, 4.66; N, 3.81%.   Prepare the following compounds using a method similar to that of Description 22: Was:   (A) 2-methoxy-5-((N-methyl-N- (2-methylphenyl)) amino Sulfonyl) benzoic acid   Found: C, 57.02; H, 5.07; N, 4.20. C₁₆H₁₇NO_FiveTheoretical value of S : C, 57.30; H, 5.11; N, 4.18%.   (B) 2-methoxy-5-[(2- (7-methylthio) -1,2,3,4-tetrahi Droisoquinolinyl) sulfonyl] benzoic acid   According to US Pat. No. 4,228,170, the required starting 7-methylthio- 1,2,3,4-tetrahydroisoquinoline was prepared, and 15-20% impurities (-S Me regioisomer) with similar regioisomeric impurity levels The compound was obtained. Mass spectrometry: Measured value M⁺393.0715. C₁₈H₁₉NO_FiveS₂Theory of Value: 393.0704.   (C) 1-methoxy-4-((N-methyl-N-phenyl) aminosulfonyl)- 2-naphthoic acid   Mass spectrometry: Measured value M⁺371.0831. C₁₉H₁₇NO_FiveTheoretical value of S: 371.0 827.   (D) 5-[(N- (3,4-dimethoxybenzyl) -N-ethyl) aminosulfoni ] -2-Methoxybenzoic acid   Melting point 126-127 ° C. Found: C, 55.43; H, 5.50; N, 3.46. C₁₉H_{twenty three}NO₇Theoretical value for S: C, 55.75; H, 5.62; N, 3.42%.   Description 23   N- (3-pyridyl) methyl-ethylamine   3-Pyridylmethylamine (100 g, 0.924 mol) and triethylami Salt (135 ml; 0.971 mol) in a stirred solution of tetrahydrofuran (0.5 l). Acetyl iodide (69 ml; 0.971 mol) was added dropwise with ice-methanol cooling. . The resulting mixture was stirred at room temperature for 18 hours, filtered and the filtrate evaporated in vacuo. , An oily product was obtained. The latter was distilled at 1.5 mmHg using argon entrainment to give 15 A fraction boiling at 8-168 ° C was obtained (98g).   A solution of this material in dry tetrahydrofuran (100 ml) was added to aluminum hydride. Lithium (27.25g, 0.718mol) in dry tetrahydrofuran (400ml) To the medium ice-cold suspension was added dropwise to maintain an internal temperature of <20 ° C. The resulting solution Heat at reflux for 3 hours, then cool to room temperature. Then, while cooling with ice, A 1% solution of water in tetrahydrofuran (200 ml) was added dropwise, then potassium tartrate. A saturated solution of sodium sodium in water (120 ml) was added dropwise. Allow the resulting mixture at room temperature Stirred at 18 h, then filtered through kieselguhr. The filtrate is evaporated in vacuo and the residue is evaporated at 1.0 mm Hg using entrainment of argon. Purified by distillation. The title compound was obtained as an oil (23.6 g, 26 %). Boiling point 186-190 [deg.] C. (1.0 mmHg).   ¹1 H NMR (CDCl_Three) Δ: 1.15 (3H, t, J = 7Hz), 2.70 (2H, q, J = 7Hz), 3.80 (2H, s), 7.28 (1H, m), 7.70 (1H, d, J = 6Hz), 8.45-8.60 (2H, m).   The following compounds were prepared in a similar manner to Description 23:   (A) N-ethyl- (2-phenyl) ethylamine   ¹1 H NMR (CDCl_Three) Δ: 1.10 (3H, t, J = 7Hz), 2.66 (2H, q, J = 7 Hz), 2.88 (4H, m) and 7.25 (5H, m).   (B) N- (4-pyridyl) methyl-ethylamine   ¹1 H NMR (CDCl_Three) Δ: 1.16 (3H, t, J = 8Hz), 2.68 (2H, q, J = 8Hz), 3.83 (2H, s), 7.28 (2H, d, J = 6Hz), 8.55 (2H, d, J) = 6 Hz).   Description 24   3-Bromo-4-methoxybenzenesulfonyl chloride   While stirring and cooling with ice to an internal temperature of 10 ° C. or lower, 2-bromoanisole (93 0.5 g, 0.5 mol) was added dropwise to chlorosulfonic acid (165 ml). Room temperature of the mixture The mixture was warmed up to and stirred for 23 hours. The resulting solution was crushed with vigorous stirring (1 kg) Pour carefully over and filter the precipitated solid to give the title compound (126 g, 99 %).   ¹1 H NMR (CDCl_Three) Δ: 4.04 (3H, s), 7.05 (1H, d, J = 9Hz), 7.99 (1H, dd, J = 9,3Hz), 8.23 (1H, d, J = 3Hz).   Description 25   3-Bromo-4-methoxy-N- (2-pyridyl) methylbenzenesulfonami Do   3-Bromo-4-methoxybenzenesulfonyl chloride at room temperature (23 g, 0. Tetrahydrofuran was added to a stirred solution of (09 mol) in tetrahydrofuran (100 ml). 2-Pyridylmethylamine (20 g, 0.186 mol) in (20 ml) was added. . The reaction mixture was stirred at room temperature for 1.5 hours, water (300 ml) and ethyl acetate- Partitioned between ether (1: 1) (200 ml). The organic phase is dried (Na₂SO_Four) , Evaporate in vacuo and chromatograph on silica using an ethyl acetate eluent. To give the title compound (18.5 g, 57%).   ¹1 H NMR (CDCl_Three) Δ: 3.93 (3H, s), 4.26 (2H, d, J = 6Hz), 6.09 (1H, brt, J = 6Hz), 6.89 (1H, d, J = 9Hz), 7.17 (2H, m) , 7.62 (1H, dt, J = 8, 2Hz), 7.78 (1H, dd, J = 9.3Hz), 7.99 ( 1H, d, J = 3Hz), 8.45 (1H, m).   It was manufactured by the same method as the description 25.   (A) (3-Bromo-4-methoxy-N-phenyl) benzenesulfonamide   ¹1 H NMR (CDCl_Three) Δ: 3.93 (3H, s), 6.35-7.00 (1H, br s) , 6.86 (1H, d, J = 9Hz), 7.09 (2H, m), 7.16 (1H, m), 7.27 ( 2H, m), 7.65 (1H, dd, J = 9,3Hz), 7.97 (1H, d, J = 3Hz).   Description 26   3-Bromo- (N-ethyl-N- (2-pyridyl) methyl) -4-methoxyben Zen-sulfonamide   Drying sodium hydride (80%; 0.66 g, 22 mmol) at room temperature under argon. 3-Bromo-4-methoxy-to a stirred suspension in dry tetrahydrofuran (100 ml). N- (2-pyridyl) methylbenzene-sulfonamide (7.14 g, 20 mmol) It was added dropwise over 0.1 hour. The mixture was stirred for 0.75 hours and then diluted with diethyl sulfate. (2.9 ml; 22 mmol) was added in one portion and stirring was continued for 2 hours, then 2 hours. Reflux. The resulting mixture was then water (400 ml) and ethyl acetate (3x). 200 ml). Combine the organic extracts with 1% aqueous sodium hydroxide Washed and dried (Na₂SO_Four), Evaporated in vacuo to give an oil. On silica Chromatography on eluent ethyl acetate-hexane (1: 1) to give an oil. The title compound was obtained as a substance (6.24 g, 81%).   ¹1 H NMR (CDCl_Three) Δ: 1.01 (3H, t, J = 8Hz), 3.30 (2H, q, J = 8Hz), 3.97 (3H, s), 4.48 (2H, s), 6.97 (1H, d, J = 9Hz), 7.21 (1H, m), 7.55 (1H, d, J = 8Hz), 7.70 (1H, dt, J = 8,2Hz) ), 7.78 (1H, dd, J = 9,3Hz), 8.03 (1H, d, J = 3Hz), 8.50 (1 H, m).   Description 27   1- (tert-butoxycarbonyl) pyrrole-2-boronic acid   Manufactured by a method similar to that disclosed in WO 93/10127 ( 80%).   ¹1 H NMR (CDCl_Three) Δ: 1.62 (9H, s), 6.29 (1H, t, J = 3Hz), 7.12 (1H, m), 7.22 (2H, s) and 7.46 (1H, m).   Description 28   1- (tert-butoxycarbonyl) -2- (2-methoxy-5- (N-phenyla Minosulfonyl) phenyl) -1H-pyrrole   1- (tert-Butoxycarbonyl) pyrrole-2-boronic acid under argon at room temperature (1.74 g, 8.2 mmol) and (3-bromo-4-methoxy-N-phenyl) beta. Benzene sulfonamide (2.12 g, 6.2 mmol) in 1,2-dimethoxyethane (1 30 ml) in 2M aqueous sodium carbonate solution (9.4 ml, 18.8 mmol), then , Tetrakistriphenylphosphine palladium (0) (0.36 g, 0.3 mmol, 5 mol%) was added. The resulting mixture was heated under reflux for 3 hours. Water after cooling (100 ml) was added and the mixture was extracted with dichloromethane (2 x 100 ml). . The combined organic extracts were dried (Na₂SO_Four), Evaporated to dryness in vacuo, silica Chromatography on gel, hexane / ethyl acetate (9: 1), then , Hexane / ethyl acetate (7: 3). The title compound was obtained as a white solid (1.66 g, 63%).   ¹1 H NMR (CDCl_Three) Δ: 1.25 (9H, s), 3.80 (3H, s), 6.04 (1 H, m), 6.22 (1H, t, J = 3Hz), 6.60 (1H, s), 6.85 (1H, d, J = 9) Hz), 7.08-7.40 (5H, m), 7.66 (1H, d, J = 2Hz) and 7.76 (1H, dd, J = 9,2Hz).   Made by a method similar to that of Description 28:   (A) 1- (tert-butoxycarbonyl) -2- (2-methoxy-5-((N- (5 -(1-ethyl) pyrazolyl) -N-methyl) aminosulfonyl) phenyl) -1H- Pyrrole   ¹1 H NMR (CDCl_Three) Δ: 1.40 (9H, s), 1.52 (3H, t, J = 7Hz), 3.10 (3H, s), 3.88 (3H, s), 4.28 (2H, q, J = 7Hz), 5.65 (1 H, d, J = 2Hz), 6.18 (1H, m), 6.28 (1H, t, J = 3Hz), 6.96 (1 H, d, J = 9Hz), 7.38 (1H, m), 7.42 (1H, d, J = 2Hz), 7.62 (1 H, d, J = 2Hz) and 7.69 (1H, dd, J = 9,2Hz).   (B) 1- (tert-butoxycarbonyl) -2- (5- (N-methyl-N- (5- Methyl-2- (1,3,4-thiadiazolyl)) aminosulfonyl) -2-methoxy group 1-H-pyrrole   ¹1 H NMR (CDCl_Three) Δ: 1.30 (9H, s), 2.70 (3H, s), 3.47 (3 H, s), 3.80 (3H, s), 6.15 (1H, m), 6.25 (1H, m), 6.90 (1H, d) , J = 9Hz), 7.38 (1H, m), 7.68 (1H, d, J = Hz), 7.75 (1H, dd, J = 9.2.Hz).   Description 29   2- (2-methoxy-5- (N-phenylaminosulfonyl) phenyl) -1H- Pyrrole   1- (tert-butoxycarbonyl) -2- (2-methoxy-5- (N -Phenylaminosulfonyl) phenyl) -1H-pyrrole (0.60g, 1.40m) mol) in anhydrous tetrahydrofuran (1.4 ml) to give a solution of sodium methoxide. IM solution in tanol (8.4 ml, 8.4 mmol) was added at room temperature. Room temperature of the mixture The reaction was completed by stirring at 50 ° C. for 1 hour and then at 50 ° C. for 2 hours. Cool to room temperature After discarding, water (20 ml) was added, the mixture was brought to pH 7 and ether (2 x 20 m). Extracted in l). The combined organic extracts were washed with brine (20 ml), dried (N a₂SO_Four), Evaporated in vacuo. Chromatography of the crude product on silica Hexane / ethyl acetate (9: 1), then hexane / ethyl acetate ( Elution 7: 3) gave the title compound as a white solid (0.37g, 80%).   Mass spectrometry: Measured value M⁺328.0870. C₁₇H₁₆N₂O_ThreeTheoretical value of S 328.0 859.   Made by a method similar to that of Description 29:   (A) 2- [5-((N- (5- (1-ethyl) pyrazolyl) -N-methyl) aminos Rufonyl) phenyl] -1H-pyrrole   Mass spectrometry; measured value M⁺360.12.60. C₁₇H₂₀N_FourO_ThreeTheoretical value of S 360.1 265.   Description 30   2- [2-methoxy-5- (N-methyl-N- (5-methyl-2- (1,3,4-thiophene Asiazolyl)) aminosulfonyl) -2-methoxyphenyl] -1H-pyrrole   1- (tert-butoxycarbonyl) -2- [2-methoxy- under argon at 0 ° C. 5-((N-methyl-N- (5-methyl-2- (1,3,4-thiadiazolyl))) ami Nosulfonyl) phenyl] -1H-pyrrole (0.6 g, 1.29 mmol) in dichloro Trifluoroacetic acid (6 ml) was added to a stirred solution in methane (12 ml). The mixture Was stirred at room temperature for 1 hour and then poured onto ice / dilute aqueous potassium carbonate solution. Dichlorome Extract with tan (2 x 35 ml) and dry the organic extract (Na₂SO_Four), Then true Evaporation in air gave the crude title compound. 10-50% ethyl acetate in hexane Chromatography on silica using to give the title compound in 80% yield. .   ¹1 H NMR (CDCl_Three) Δ: 2.68 (3H, s), 3.48 (3H, s), 4.00 (3 H, s), 6.30 (1H, m), 6.65 (1H, m), 6.90 (1H, m), 7.00 (1H, d) , J = 9 Hz), 7.50 (1 H, dd, J = 9,2 Hz), 8.05 (1 H, d, H = 2 Hz), 9.70 (1H, br s).   Description 31   5-methyl-3-methylaminoisoxazole   3-Amino-5-methylisoxazole (26 g, 0.27 mmol) and A mixture of triethyl formate (130 ml) was warmed to a solution. Trifluoro Acetic acid (1 ml) was added and the result was stirred under vigorous reflux under argon. The ethanol was heated while being distilled for 2 hours. Excess triethyl orthoformate in vacuum The chill was evaporated and the resulting oil was dissolved in ethanol (1l). Borohydride Sodium iodide (11.8 g, 0.31 mol) was added dropwise while cooling with ice. The resulting mixture The mixture was stirred at room temperature for 18 hours, then evaporated in vacuo to give a residue which Was partitioned between water (500 ml) and dichloromethane (3 x 200 ml). Matching Dried extract (Na₂SO_Four), And evaporated in vacuo to give the title compound (27 g, 91%).   ¹1 H NMR (CDCl_Three) Δ: 2.29 (3H, s), 2.88 (3H, d, J = 7Hz), 3.89 (1H, brs), 5.48 (1H, s).   The title compound was prepared by a method similar to that of Description 31:   (A) N-methyl-4-fluoroaniline   ¹1 H NMR (CDCl_Three) Δ: 2.80 (3H, s), 3.60 (1H, br s), 6.50 (2H, m), 6.90 (2H, m).   (B) (3-methylamino) pyridine   ¹1 H NMR (CDCl_Three) Δ: 2.86 (3H, d, J = 7Hz), 3.84 (1H, br s ), 6.86 (1H, m), 7.10 (1H, m), 7.95 (1H, m), 8.02 (1H, d, J) = 3 Hz).   Description 32   3-Bromo- (N- (1-ethyl- (5-pyrazolyl))-N-methyl) -4-meth Xybenzenesulfonamide   5-amino-1-ethyl-by the methods of Descriptions 25 and 31 Prepared from 1H-pyrazole in 39% yield.   ¹1 H NMR (CDCl_Three) Δ: 1.50 (3H, t, J = 9Hz), 3.09 (3H, s), 4.00 (3H, s), 4.28 (2H, q, J = 8Hz), 5.59 (1H, d, J = 2Hz), 6.98 (1H, d, J = 9Hz), 7.44 (1H, d, J = 2Hz), 7.63 (1H, dd, J) = 9,3 Hz), 7.93 (1 H, d, J = 3 Hz).   Description 33   2- [5-((N-ethyl-N- (3-pyridyl) methyl) aminosulfonyl) -2 -Methoxy) -phenyl] -1H-pyrrole   5-((N-ethyl-N- (3-pyridyl) methyl) aminos under argon at 0 ° C Rufonyl) -2-methoxybenzoic acid (10.8 g, 30.9 mmol) in dichloromethane To a stirred solution in (250 ml) was added triethylamine (4.8 ml, 33.9 mmol). Then, isobutyl chloroformate (4.2 g, 33.9 mmol) was added dropwise. Reaction mixture The mixture was stirred at 0 ° C. for 2 hours, then N, O-dimethylhydroxyammonium Chloride was added, followed by triethylamine (9.54 ml; 67.8 mmol). Added. The resulting mixture was stirred at room temperature for 18 hours, then saturated with sodium bicarbonate. It was washed with an aqueous solution of water (0.5 l). Extract the aqueous phase with dichloromethane (2 x 200 ml). Then, the combined organic phase is dried (Na₂SO_Four), Evaporate in vacuo to an oil This was chromatographed on silica, 50-100% ethyl acetate- Elute with hexane. The methoxyamide thus obtained (4.42 g, 11.2 mmo l) was dissolved in dry tetrahydrofuran (100 ml) and 1- (2- (2- (1 , 3-Dioxanyl)) ethyl) magnesium in tetrahydrofuran (0.99 M; 2 5.6 ml, 25.3 mmol). The resulting mixture was stirred at room temperature for 18 hours. Stir and then quench with 10% aqueous citric acid (100 ml). The mixture Partitioned between water (200 ml) and dichloromethane (3 x 100 ml). Combined The organic extract was dried (Na₂SO_Four), And evaporated in vacuo to give an oil (5.3 4g). The latter was dissolved in glacial acetic acid (100 ml) and ammonium acetate (7.34 g, 9 5.4 mmol) solution. This solution was refluxed under argon for 2 hours. Heated for a period of time, then evaporated in vacuo. The residue is saturated aqueous sodium hydrogen carbonate It was partitioned between liquid (0.5 L) and dichloromethane (3 x 100 ml). Combined The extract was dried (Na₂SO_Four), Evaporated in vacuo to give an oil, which was By chromatography on neutral alumina using an ethyl acid eluent. And purified to give the title compound as an oil (0.35g, 8%).   Mass spectrometry: Measured value M⁺371.1312. C₁₉H_{twenty one}N_ThreeO_ThreeTheoretical value of S 371.1 302.   Prepared by a method similar to that described in Description 33:   (A) 2- [2-methoxy-5-((N-methyl-N- (3-pyridyl)) aminos Rufonyl) phenyl] -1H-pyrrole   ¹1 H NMR (CDCl_Three) Δ: 3.22 (3H, s), 4.03 (3H, s), 6.28 (1 H, m), 6.54 (1H, m), 6.89 (1H, m), 6.98 (1H, d, J = 9Hz), 7.2 5 (2H, m), 7.56 (1H, m), 7.82 (1H, d, J = 3Hz), 8.35 (1H, d) , 8.53 (1H, m), 9.71 (1H, br s).   (B) 2- [5-((N-ethyl-N- (4-pyridyl) methyl) aminosulfonyl ) -2-Methoxy-phenyl] -1H-pyrrole   ¹1 H NMR (CDCl_Three) Δ: 0.98 (3H, t, J = 8Hz), 3.25 (2H, q, J = 8 Hz), 4.05 (3 H, s), 4.35 (2 H, s), 6.32 (1 H, m), 6.72 ( 1H, m), 6.93 (1H, m), 7.05 (1H, d, J = 9Hz), 7.27 (2H, d, J = 6Hz), 7.62 (1H, dd, J = 9,3Hz), 8.10 (1H, d, J = 3Hz), 8.5 8 (2H, d, J = 6Hz), 9.78 (1H, br s).   Description 34   2- [5-((N-ethyl-N- (2-pyridyl) methyl) aminosulfonyl) -2 -Methoxyphenyl] -1H-pyrrole   Prepared by a method similar to that of Descriptions 28 and 30.   ¹1 H NMR (CDCl_Three) Δ: 1.00 (3H, t, J = 8Hz), 3.29 (2H, q, J = 8 Hz), 4.04 (3 H, s), 4.49 (2 H, s), 6.32 (1 H, m), 6.71 ( 1H, m), 6.93 (1H, m), 7.05 (1H, d, J = 9Hz), 7.20 (1H, m), 7 .55-7.77 (3H, m), 8.12 (1H, d, J = 3Hz), 8.50 (1H, m), 9. 75 (1H, br s).   Description 35   3-Bromo-4-methoxy-N-methyl-N- (5-methyl-2- (1,3,4- Thiadiazolyl)) benzenesulfonamide   2-amino-5-methyl- by the method of Descriptions 25 and 31 Prepared from 1,3,4-thiadiazole in 21% yield.   ¹1 H NMR (CDCl_Three) Δ: 2.70 (3H, s), 3.48 (3H, s), 3.97 (3 H, s), 6.97 (1H, d, J = 9Hz), 7.71 (1H, dd, J = 9,3Hz), 7.97 (1H, d, J = 3Hz).   Description 36   N-formyl-4-methylthioaniline   4-Methylthioaniline was added to a mixture of acetic anhydride (300 ml) and formic acid (1 l). (25 g, 0.18 mol) was added and the reaction was warmed to 70 ° C. for 2 hours. Next The reaction was evaporated in vacuo at 50 ° C., then taken up in 5N HCl and dichloromethane. Allowed to dispense. The organic phase is separated, K₂CO_ThreeWash with saturated aqueous solution, evaporate in vacuo To give a gum, which is crystallized from ether to give the title compound as needles. Was obtained (28.5 g, 93%). Melting point 83-84 [deg.] C. Found: C, 57.32; H, 5. 43; N, 8.22; C₈H₉Theoretical value of NOS: C, 57.46; H, 5.42; N, 8. 38%.   Description 37   N-methyl-4-methylthioaniline   LiAlH_FourTo a solution of (5.5 g, 150 mmol) in ether (500 ml) was added THF ( N-formyl-4-methylthioaniline (25 g, 0.148 mol) in 100 ml) ) Was added. The reaction was heated at reflux for 2 hours to remove excess 10% NaOH solution. Quenched by addition. The organic phase is then separated, dried (Na₂SO_Four), Evaporation in vacuo gave the title compound (22.16g, 97%).   ¹1 H NMR (CDCl_Three) Δ: 2.4 (3H, s), 2.85 (3H, s), 3.75 (1H) , s), 6.5 (2H, d, J = 8Hz), 7.25 (2H, d, J = 8Hz).   Description 38   2-Methoxy-4-chlorosulfonylbenzoic acid ethyl ester   Ethyl ester of 4-amino-2-methoxybenzoic acid (30.0 g, 0.154 m ol) together with a mixture of concentrated hydrochloric acid (150 ml) and acetic acid (36 ml) until dissolved Stirred. The mixture was cooled to -10 ° C. Sodium nitrite (10.80g, 0 A solution of 0.154 mol) in water (15 ml) was added while maintaining the reaction temperature at -10 ° C. Added over 45 minutes. The reaction was stirred at this temperature for a further 3 hours.   Suspension of cuprous chloride (3.84 g, 0.04 mol) in acetic acid (154.5 ml) at room temperature. The liquid was saturated with sulfur dioxide. The mixture was cooled to 10 ° C. and the dia The solution of zonium salt was added over 45 minutes. Keep the reaction temperature below 30 ° C Was.   The reaction mixture was stirred at 10 ° C. for 30 minutes, then poured into water (1 l) and stirred. It was extracted with loromethane. The organic phase is washed with water, dried (Na₂SO_Four), Evaporate An oil was obtained (38.08 g).   Chromatography (Si gel) using dichloromethane as the eluent. An oil was obtained (26.51 g, 73%).   ¹1 H NMR (CDCl_Three) Δ: 1.40 (3H, t, J = 7Hz), 4.01 (3H, s), 4.39 (2H, q, J = 7Hz), 7.56 (1H, d, J = 3Hz), 7.64 (1H, dd, J) = 9,3 Hz), 7.90 (1 H, d, J = 9 Hz).   Description 39   2-Methoxy-4-((N-methyl-N-phenyl) aminosulfonyl) benzoic acid Ethyl ester of   Ethyl ester of 2-methoxy-4-chlorosulfonylbenzoic acid under argon (15.00 g, 0.064 mol) was dissolved in dichloromethane (130 ml). N -Methylaniline (20.80 ml, 0.19 mol) was added and the mixture was stirred at room temperature for 4 hours. Stirred for hours. The reaction mixture was extracted with 5N hydrochloric acid then water. Dry the organic phase Let (Na₂SO_Four), Evaporated to give an oil (19.45 g, 77% yield).   ¹1 H NMR (CDCl_Three) Δ: 1.38 (3H, t, J = 7Hz), 3.19 (3H, s), 3.72 (3H, s), 4.36 (2H, q, J = 7Hz), 6.93 (1H, d, J = 3Hz), 7.21 (6H, m), 7.80 (1H, d, J = 9Hz).   Description 40   2-Methoxy-4-((N-methyl-N-phenyl) aminosulfonyl) benzoic acid   2-Methoxy-4-((N-methyl-N-phenyl) aminosulfonyl) benzoic acid Ethyl ester of (19.45 g, 0.049 mol) in methanol (400 ml) Dissolution Let it go. A 40% w / v solution of sodium hydroxide in water (51 ml) was added and the mixture was mixed. The mixture was stirred at room temperature for 1 hour. Evaporate the methanol in a vacuum and dissolve the residue in water. Let it go. The mixture was acidified with concentrated hydrochloric acid, the solid obtained was filtered, washed with water, Dry with phosphorus pentoxide in vacuo to give the title compound as a white solid (16.11). g, 83%).   ¹1 H NMR (CDCl_Three) Δ: 3.22 (3H, s), 3.89 (3H, s), 7.02 (1 H, d, J = 3Hz), 7.09 (2H, m), 7.27 (4H, m), 8.21 (1H, d, J = 9) Hz).   Description 41   4-chlorosulfonyl-1-methoxy-2-naphthoic acid   Chlorosulfonic acid (125 ml) in 1-methoxy-2-naphthoic acid (25 g, 0. (124 mol) was added dropwise with stirring, and the mixture was cooled in an ice-methanol bath. Then, the anti The reaction mixture was stirred at room temperature for 4 hours and added dropwise to crushed ice (50 g). Off by filtration The title compound was obtained as a white solid (8.3 g).   NMR (CDCl_Three) Δ 4.27 (3H, s), 7.81 (1H, t, J = 7Hz), 7.9 5 (1H, dt, J = 7,1Hz), 8.50 (1H, d, J = 7Hz), 8.81 (1H, d, J = 7Hz), 8.95 (1H, s).   Example 1   2- (2-methoxy-5-((N-methyl-N-phenyl) aminosulfonyl) phenyl Phenyl) -5- (1- (2- (R, S) -phenylazacycloheptyl) -methyl) -1 H-pyrrole oxalate   1-formyl-2- (R, S) -phenylene under continuous stirring at 0 ° C. under argon. Luazacycloheptane (1.185 g, 5.84 mmol) was converted to phosphorus oxychloride (0.887 g). , 5.84 mmol). The reaction was allowed to warm to room temperature over 1 hour and Dilute with chloroethane (10 ml). The solution was cooled to 0 ° C., then 2- (2 -Methoxy-5-((N-methyl-N-phenyl) aminosulfonyl) phenyl)- Treated with 1H-pyrrole (1 g, 2.92 mmol) and stirred the reaction at 0 ° C. for 3 hours. , Then warmed to room temperature overnight. The reaction mixture was cooled to 0 ° C. and then buffed. water Treated with sodium iodide (1 g) and stirred at this temperature for 1 hour. The reaction mixture is Treat with methanol (5 ml) at such a rate that the temperature does not rise above 10 ° C, and Avoided excess foaming. It was then quenched by the addition of water (10 ml). The reaction mixture was partitioned between water and saturated aqueous potassium carbonate solution. The organic phase is separated and Na₂ SO_FourDried in vacuo and concentrated in vacuo to a gum. Chromatograph on silica Eluate with 10% ethyl acetate in dichloromethane and elute as a gum. The free base of the title compound was obtained. The gum is dissolved in ether and the excess in ether is added. Treatment with excess oxalic acid gave the title compound as a powder (1.16g, 65%). . Melting point 86-89 ° C (half melt). Found: C, 62.36; H, 5.91; N, 6.5; C₃₁ H₃₅N_ThreeO_ThreeS ・ C₂H₂O_Four・ H₂Theoretical value of O: C, 62.15; H, 6.02; N, 6.78%.   The following compounds were prepared from the corresponding pyrroles according to the method of Example 1:   (A) 2- [5-((N-benzyl-N-methyl) aminosulfonyl) -2-meth Xyphenyl] -5- [1- (2- (R, S) -phenylazacycloheptyl) methyl] -1H-pyrrole oxalate   Mp 92-96 ° C (ether). Found: C, 62.96; H, 6.04; N, 6.5. One. C₃₂H₃₇N_ThreeO_ThreeS ・ C₂H₂O_Four・ H₂Theoretical value of O: C, 62.66; H, 6.34 N, 6.45%.   (B) 2- [2-methoxy-5-((N-methyl-N-phenyl) aminosulfoni ) Phenyl] -5- (1- (R, S)-(2-phenylpyrrolidinyl) methyl) -1H -Pyrrole oxalate   Melting point 133-135 [deg.] C.¹1 H NMR (d₆-DMSO) δ: 1.89-2.10 ( 3H, br m), 2.23-2.41 (1H, br m), 2.93-3.09 (1H, br m), 3.11 (3H, s), 3.31-3.46 (1H, brs), 3.92 (3H, s), 3.95- 4.27 (3H, br m), 6.18 (1H, br s), 6.43 (1H, m), 7.08-7.4 2 (10H, m), 7.49 (2H, d, J = 7Hz), 7.62 (1H, s), 11.20 (1H , Br s).   (C) (-)-2- [2-methoxy-5-((N-methyl-N-phenyl) aminos Rufonyl) phenyl] -5- (1- (2-phenylpyrrolidinylmethyl) -1H-pi Roll oxalate   Melting point 86-88 [deg.] C.¹H NMR (d₆-DMSO) δ: 1.90-2.11 (3H, br m), 2.28-2.43 (1H, br m), 2.97-3.10 (1H, br m), 3.15 (3H, s), 3.35-3.49 (1H, brs), 3.92 (3H, s), 3.95-4.28 (3H, br m), 6.19 (1H, m), 6.45 (1H, m), 7.08-7.52 (12H, m) ), 7.61 (1 H, d, J = 2 Hz), 11.20 (1 H, br s).   (D) (+)-2- [2-methoxy-5-((N-methyl-N-phenyl) aminos Rufonyl) phenyl] -5- (1- (2-phenylpyrrolidinyl) methyl) -1H-pi Roll oxalate   Melting point 88-90 [deg.] C.¹H NMR (d₆-DMSO) δ: 1.90-2.10 (3H, br m), 2.24-2.41 (1H, br m), 2.93-3.09 (1H, br m), 3.14 (3H, s), 3.33-3.48 (1H, brm), 3.92 (3H, s), 3.96-4.29 ( 3H, br m), 6.18 (1H, br s), 6.45 (1H, br s), 7.08-7.54 (1 2H, m), 7.63 (1H, s), 11.20 (1H, br s).   (E) (-)-2- [2-methoxy-5-((N-methyl-N-phenyl) aminos Rufonyl) phenyl] -5- (1- (2-phenylpiperidinylmethyl) -1H-pi Roll oxalate   Melting point 111-113 [deg.] C.¹H NMR (d₆-DMSO) δ: 1.39-1.61 ( 1H, br m), 1.73-2.01 (6H, br m), 2.55-2.72 (1H, br m), 3.14 (3H, s), 3.24 (1H, br d, J = 11Hz), 3.75 (1H, br d, J = 15Hz), 3.91 (1H, brd, J = 15Hz), 3.95 (3H, s), 6.11 (1H, m), 6.47 (1H, m), 7.10-7.68 (13H, m), 11.28 (1H, br s).   (F) (+)-2- [2-methoxy-5-((N-methyl-N-phenyl) aminos Rufonyl) phenyl] -5- (1- (2-phenylpiperidinyl) methyl) -1H-pi Roll oxalate   Melting point 112-114 [deg.] C.¹H NMR (d₆-DMSO) δ: 1.39-1.61 (1H, br m), 1.71-2.02 (6H, br m), 2.53-2.71 (1H, br m), 3.14 (3H, s), 3.25 (1H, br d, J = 11Hz), 3.74 (1H, br d, J = 14 Hz), 3.90 (1 H, br d, J = 14 Hz), 3.95 (3 H, s), 6.11 (1 H, m), 6.48 (1H, m), 7.09-7.69 (13H, m), 11.26 (1H, br s).   (G) 2- (5-((N- (4-bromophenyl) -N-methyl) aminosulfonyl ) -2-Methoxyphenyl) -5- (1- (2- (R, S) -phenylazacyclohep (Cyl) methyl) -1H-pyrrole oxalate   Melting point 100-102 [deg.] C. Found: C, 55.51; H, 5.04; N, 5.78. C₃₁ H₃₄BrN_ThreeO_ThreeS ・ C₂H₂O_Four・ H₂Theoretical value of O: C, 55.31; H, 5.34; N, 5.86%.   (H) 2- (2-methoxy-5-((N- (4-methoxyphenyl) -N-methyl)) Amino-sulfonyl) phenyl) -5- (1- (2- (R, S) -phenylazacyclo Heptyl) methyl) -1H-pyrrole oxalate   Melting point 91-92 [deg.] C. Found: C, 61.85; H, 5.89; N, 6.38. C₃₂H₃₇ N_ThreeO_FourS ・ C₂H₂O_Four・ 0.5H₂Theoretical value of O: C, 61.99; H, 6.12; N, 6.38%.   (I) 2- (5-((N- (4-cyanophenyl) -N-methyl) aminosulfonyl ) -2-Methoxyphenyl) -5- (1- (2- (R, S) -phenylazacyclohep (Cyl) methyl) -1H-pyrrole oxalate   Melting point 101-102 [deg.] C. Mass spectrometry: Measured value MH⁺555. C₃₂H₃₄N_FourO_ThreeOf S Theoretical value MH⁺555.   (J) 2- (5- (4- (3,4-dihydro-1,4-benzoxazinyl) sulfo Nyl) -2-methoxy-phenyl) -5- (1- (2- (R, S) -phenylazacic Roheptyl) methyl) -1H-pyrrole   Melting point 123-124 [deg.] C. Found: C, 68.81; H, 6.34; N, 7.68. C₃₂ H₃₅N_ThreeO_FourTheoretical value for S: C, 68.92; H, 6.33; N, 7.53%.   A small sample of the title compound was converted to the oxalate salt. Melting point 103-105 [deg.] C.   (K) 2- (5-((N- (3,4-dimethoxybenzyl) -N-ethyl) aminos Rufonyl) -2-methoxyphenyl) -5- (1- (2- (R, S) -phenyl seal Chloheptyl) methyl) -1H-pyrrole oxalate   Melting point 90-94 [deg.] C. Mass spectrometry: Measured value M⁺617.2934. C₃₅H₄₃N_ThreeO_FiveS Theoretical value of M⁺617.2923.   (L) 2- (2-methoxy-5- (2- (7-methylthio-1,2,3,4-tetra Hydroisoquinolin-2-yl) sulfonyl) phenyl) -5- (1- (2- (R, S)) -Phenylazacycloheptyl) methyl-1H-pyrrole (15-20% position difference) It was contaminated with the body)   Melting point 70-71 [deg.] C. Found: C, 67.20; H, 6.44; N, 6.85. C₃₄H₃₉ N_ThreeS₂O_Three・ 0.5H₂Theoretical value of O; C, 66.85; H, 6.60; N, 6.88% .   (M) 2- (5- (1-indolinesulfonyl) -2-methoxyphenyl) -5- (1- (2- (R, S) -Phenylazacycloheptyl) methyl) -1H-pyrrole Oxalate   Melting point 106-109 <0> C (ether). Measurements: C, 63.54; H, 5.91; N, 6.53. C₃₂H₃₅N_ThreeO_ThreeS ・ C₂H₂O_Four・ 0.5H₂Theoretical value of O: C, 63.73; H, 5.98; N, 6.56%.   (N) 2- (2-methoxy-5-((N-methyl-N- (4-methylthio) phenyl) ) Aminosulfonyl) phenyl) -5- (1- (2- (R, S) -phenylazacyclo Heptyl) methyl) -1H-pyrrole oxalate   Melting point 104-107 [deg.] C. Found: C, 60.63; H, 5.73; N, 6.47. C₃₂ H₃₇N_ThreeO_ThreeS₂・ C₂H₂O_Four・ 0.5H₂Theoretical value of O: C, 60.52; H, 5.97 N, 6.23%.   Example 2   2- (2-methoxy-5-((N-methyl-N-phenyl) aminosulfonyl) phenyl Phenyl) -5- (1- (2- (R) -phenylazacycloheptyl) methyl) -1H- Pyrrole oxalate   Using a method similar to that of Example 1, 1-formyl-2- (R) -phenylene Zacycloheptane (0.21 g) and 2- (2-methoxy-5-((N-methyl- N-phenyl) aminosulfonyl) phenyl) -1H-pyrrole (0.31 g) The title compound was obtained (0.26 g, 42%). Melting point 95-97 [deg.] C.   ¹H NMR (d₆-DMSO) δ: 1.45-2.14 (8H, br m), 2.93-3 .31 (2H, br m), 3.12 (3H, s), 3.79 (2H, br s), 3.95 (3H, s) 4.12 (1H, br s), 6.10 (1H, br s), 6.45 (1H, br s), 7.08- 7.46 (10H, m), 7.52 (2H, d, J = 7Hz), 7.62 (1H, br s), and 10.86-11.02 (1H, brs). [α]²⁰ _D+ 19.3 ° (c, 0.86%, MeOH) .   Example 3   2- (2-methoxy-5-((N-methyl-N-phenyl) aminosulfonyl) phenyl Phenyl) -5- (1- (2- (S) -phenylazacycloheptyl) methyl) -1H- Pyrrole oxalate   Using a method similar to that of Example 1, 1-formyl-2- (S) -phenylene Zacycloheptane (0.21 g) and 2- (2-methoxy-5-((N-methyl- N-phenyl) aminosulfonyl) phenyl) -1H-pyrrole (0.31 g) The title compound was obtained (0.244 g, 39%). Melting point 96-98 [deg.] C.   ¹H NMR (d₆-DMSO) δ: 1.46-2.18 (8H, br m), 2.96-3 .34 (2H, br m), 3.12 (3H, s), 3.81 (2H, br s), 3.95 (3H, s) 4.16 (1H, br s), 6.12 (1H, br s), 6.45 (1H, br m), 7.10- 7.48 (10H, m), 7.53 (2H, d, J = 7Hz), 7.63 (1H, s), and 1 0.90-11.10 (1H, brs). [α]²⁰ _D-20. 1 ° (c, 0.72% MeOH).   Example 4   2- [5-((N-benzyl-N-ethyl) aminosulfonyl) -2-methoxyphenyl And]]-5- (1- (2- (R, S) -Phenylazacycloheptyl) methyl) -1H -Pyrrole / hydrochloride   Under argon at 0 ° C., 1-formyl-2- (R, S) -phenylazacyclohep Phosphoryl chloride (0.33 ml, 0.54 g, 3.5 m) in tan (0.65 g, 3.2 mmol) mol) and then stirred at room temperature for 0.5 hours. 1,2-dichloroethane ( 20 ml) was added and the solution was cooled (ice / salt) then 2- (5-((N-benzyl -N-ethyl) aminosulfonyl) -2-methoxyphenyl) -1H-pyrrole ( A solution of 0.6 g, 1.6 mmol) in 1,2-dichloroethane (20 ml) was added dropwise. The mixture was stirred at room temperature for 18 hours. The reaction mixture was cooled to 0 ° C. (ice) and washed with Sodium hydride (0.66g) was added dropwise. The mixture was stirred at room temperature for 2 hours. Excess hydride was decomposed by dropwise addition of methanol (5 ml) and water (10 ml). did. The mixture was partitioned between water and dichloromethane and the aqueous fraction was diluted with dichloromethane. Further extraction with tongue. Dry the combined organic fractions (Na₂SO_Four),true Evaporate in air and chromatograph on silica gel using hexane, then Of the title compound as an oil, eluting with hexane / ether (1: 1). The free base was obtained (0.5 g, 55%). The product was taken all at once (0.35 g) in chloroform. It was allowed to dissolve and then shaken with 0.5N hydrochloric acid. The organic phase is dried (Na₂SO_Four ), Evaporated to dryness in vacuo to give a semi-solid which was triturated with ether, The title compound was obtained (0.32 g). Melting point 82-85 [deg.] C. Measured value: C, 66.55; N, 6.53; N, 7.01. C₃₃H₃₉N_ThreeO_ThreeTheoretical value of S · HCl: C, 66.70; H, 6.79; 7.07%.   The following compounds were prepared from the corresponding pyrrole according to the method of Example 4.   (A) 2- [5-((N- (4-benzyloxyphenyl) -N-methyl) aminos Rufonyl) -2-methoxyphenyl] -5- [1- (2- (R, S) -phenyl seal Chloheptyl) methyl] -1H-pyrrole   Melting point 137-139 ° C (CHCl_Three-Et₂O). Measured value: C, 71, 38; H, 6.4 8; N, 6.61. C₃₈H₄₁N_ThreeO_FourTheoretical value of S: C, 71.78; H, 6.50; N, 6.61%.   (B) 2- [5-((N- (2,4-difluorophenyl) -N-methyl) aminos Rufonyl-2-methoxyphenyl] -5- (1- (2- (R, S) -phenylazacic Roheptyl) methyl) -1H-pyrrole hydrochloride   Found: C, 61.22; H, 5.91; N, 6.65%. C₃₁H₃₃F₂N_ThreeO_ThreeS. HCl ・ 0.5H₂Theoretical value for O: C, 60.92; H, 5.77; N, 6.88%.   (C) 2- [2-methoxy-5- (N-methyl-N-phenyl) aminosulfoni ) Phenyl] -5- (1- (2- (R) -phenylazacycloheptyl) methyl) -1 H-pyrrole / hydrochloride   Melting point 106-108 [deg.] C.   ¹H NMR (d₆-DMSO) (as protomer) δ: 1.60-2.12 (7 H, br m), 2.23-2.46 (1H, br m), 3.15 (3H, s), 3.21-3.32. (1H, br m), 3.45-3.59 (1H, br m), 3.96 and 4.00 together (3H , s), 4.01-4.17 (2H, m), 4.41 (1H, t, J = 8Hz), 6.21 and 6.26 together (1H, t, J = 2Hz), 6.37 and 6.44 together (1H, t, J = 2Hz), 7.16 (2H, d, J = 8Hz), 7.20-7.52 (9H, m), 7.63 (1 H, s), 7.74 (1H, d, J = 7Hz), 11.02 (1H, br s), 11.47 and 11.86 together (1H, br s).   (D) 2- [2-methoxy-5-((1- (2-phenylpyrrolidinyl)) sulfoni ) Phenyl] -5- (1- (2- (R, S) -phenylazacycloheptyl) methyl) -1H-pyrrole hydrochloride   Found: C, 66.87; H, 6.66; N, 6.85. C₃₄H₃₉N_ThreeO_ThreeS ・ HCl ・ 0.5H₂Theoretical value for O: C, 66.87; H, 6.68; N, 6.88%.   (E) 2- [2-methoxy-5-((N-ethyl-N- (2-phenyl) ethyl) a Minosulfonyl) -phenyl] -5- (1- (2- (R, S) -phenylazacyclohe (Putyl) methyl) -1H-pyrrole hydrochloride   Found: C, 66.14; H, 6.82; N, 6.62. C₃₄H₄₁N_ThreeO_ThreeS ・ Cl ・ 0.5H₂Theoretical value for O: C, 66.16; H, 7.02; N, 6.81%.   (F) 2- [2-methoxy-5- (N-phenylaminosulfonyl) phenyl]- 5- (1- (2- (R, S) -phenylazacycloheptyl) methyl) -1H-pillow Le hydrochloride   Found: C, 64.44; H, 6.32; N, 7.26. C₃₀H₃₃N_ThreeO_ThreeTheoretical value of S : C, 64.21; H, 6.29; N, 7.49%.   (G) 2- [5-((N- (5- (1-ethyl) pyrazolyl) -N-methyl) aminos Rufonyl) -2-methoxyphenyl] -5- (1- (2- (R, S) -phenyl seal Chloheptyl) methyl) -1H-pyrrole hydrochloride   Found: C, 60.60; H, 6.55; N, 11.63. C₃₀H₃₇N_FiveO_ThreeS ・ HC l · 0.5H₂Theoretical value for O: C, 60.74; H, 6.63; N, 11.81%.   (H) 2- [2-methoxy-5-((N-methyl-N- (5-methyl-3-isoo Xazolyl)) amino-sulfonyl) phenyl] -5- (1- (2- (R, S) -phenyl Luazacycloheptyl) methyl) -1H-pyrrole hydrochloride   FAB mass spectrometry: MH⁺535.2310. C₂₉H₃₅N_FourO_FourTheoretical value of S: 535 , 2379.   (I) 2- [5-((N-ethyl-N- (3-pyridyl) methyl) aminosulfonyl ) -2-Methoxyphenyl] -5- (1- (2- (R, S) -phenylazacyclohep (Cyl) methyl) -1H-pyrrole hydrochloride   FAB mass spectrometry: M⁺558.2690. C₃₂H₃₈N_FourO_ThreeTheoretical value of S: 558. 2664.   (J) 2- [2-methoxy-5-((N-methyl-N- (3-pyridyl)) aminos Rufonyl) phenyl] -5- (1- (2- (R, S) -phenylazacycloheptyl) me Chill) -1H-pyrrole hydrochloride   Found: C, 61.35; H, 6.17; N, 9.42. C₃₀H₃₄N_FourO_ThreeS ・ HCl ・ H₂Theoretical value for O: C, 61.58; H, 6.37; N, 9.57%.   (K) 2- [2-methoxy-5-((N-methyl-N-phenyl) aminosulfoni L) phenyl] -5- (1- (R, S)-(1-piperidinyl) ethyl) -1H-pillow Le hydrochloride   Melting point 120-30 [deg.] C. Found: C, 59.47; H, 6.42; N, 8.45. C_{twenty five} H₃₁N_ThreeO_ThreeS ・ HCl ・ H₂Theoretical value for O: C, 59.10; H, 6.75; N, 8.27 %.   (L) 2- [5-((N-ethyl-N- (4-pyridyl) methyl) aminosulfonyl ) -2-Methoxy) phenyl] -5- (1- (2- (R, S) -phenylazacyclohep (Cyl) methyl) -1H-pyrrole hydrochloride   Melting point 130-160 ° C decomposition. Mass spectrometry: Measured value M⁺558.2708. C₃₂H₃₈ N_FourO_ThreeTheoretical value of S is 558.2664.   (M) 2- [5-((N-ethyl-N- (2-pyridyl) methyl) aminosulfonyl ) -2-Methoxy-phenyl] -5- (1- (2- (R, S) -phenylazacyclohe (Putyl) methyl) -1H-pyrrole hydrochloride   Melting point 135-150 ° C decomposition. FAB mass spectrometry: measured value M⁺558.2669. C₃₂ H₃₈N_FourO_ThreeTheoretical value of S is 558.2664.   (N) 2- [5-((N-ethyl-N- (2-furyl) methyl) aminosulfonyl) 2-Methoxy-phenyl] -5- (1- (2- (R, S) -phenylazacyclohep (Cyl) methyl) -1H-pyrrole hydrochloride   Found: C, 63.20; H, 6.33; N, 7.07. C₃₁H₃₇N_ThreeO_FourS ・ HCl ・ 0.25H₂Theoretical value for O: C, 63.25; H, 6.59; N, 7.14%.   (O) 2- [5-((N- (4-fluorophenyl) -N-methyl) aminosulfoni ) -2-Methoxyphenyl] -5- (1- (2- (R, S) -phenylazacyclohe (Putyl) methyl) -1H-pyrrole hydrochloride   Melting point 116-120 [deg.] C. Found: C, 61.79; H, 5.79; N, 6.97. C₃₁ H₃₄FN_ThreeO_ThreeS ・ HCl ・ H₂Theoretical value of O: C, 61.83; H, 6.19; N, 6. 98%.   (P) 2- [2-methoxy-5-((N-methyl-N- (5-methyl-2- (1,3 , 4-Thiadiazolyl)) aminosulfonyl) phenyl] -5- (1- (2- (R, S)- Phenylazacycloheptyl) methyl) -1H-pyrrole hydrochloride   Melting point 123.5-126 [deg.] C. Mass spectrometry: Measured value MH⁺552.2070. C₂₈H_{Three Three} N_FiveO_ThreeS₂Theoretical value MH⁺552.2103.   (Q) 2- [2-methoxy-4-((N-methyl-N-phenyl) aminosulfoni ) Phenyl] -5- [1- (2- (R, S) -phenylazacycloheptyl) methyl] -1H-pyrrole hydrochloride   Melting point 122-132 ° C (ether). Measurements: C, 64.73; H, 6.16; N, 7.29. C₃₁H₃₅N_ThreeO_ThreeS ・ HCl ・ 0.5H₂Theoretical value of O: C, 64.73; H, 6.48; N, 7.36%.   (R) 2- [2-methoxy-4-((N-methyl-N-phenyl) aminosulfoni ) Phenyl] -5- (1- (2- (R, S) -phenyl-1-pyrrolidinyl) methyl) -1H-pyrrole hydrochloride   Melting point 99-110 [deg.] C. (ether). Found: C, 62.28; H, 5.75; N, 7. 52. C₂₉H₃₁N_ThreeO_ThreeS ・ HCl ・ H₂Theoretical value for O: C, 62.63; H, 5.98; N, 7.56%.   (S) 2- (2-methoxy-5-((N-methyl-N- (2-methylphenyl)) a Minosulfonyl) phenyl) -5- (1- (2- (R, S) -phenylazacyclohep (Cyl) methyl) -1H-pyrrole hydrochloride   Melting point 125-130 [deg.] C. Found: C, 64.96; H, 6.46; N, 7.22. C₃₂ H₃₇N_ThreeO_ThreeS ・ HCl ・ 0.5H₂Theoretical value of O: C, 65.24; H, 6.66; N, 7.13%.   Example 5   2- [5-((N-benzyl-N-ethyl) aminosulfonyl) -2-methoxyphenyl Phenyl] -5- [1- (2- (R) -phenylazacycloheptyl) methyl] -1H- Pyrrole oxalate   Using a method similar to that of Example 1, 1-formyl-2- (R) -phenylene Zacycloheptane and 2- [5-((N-benzyl-N-ethyl) aminosulfoni (2) -methoxyphenyl] -1H-pyrrole to give the title compound. Obtained at 27%. Melting point 78-79 [deg.] C.   ¹H NMR (d₆-DMSO) δ: 0.83 (3H, t, J = 7Hz), 1.50-1. 83 (6H, br m), 1.89-2.12 (2H, br m), 3.01-3.17 (1H, br m) ), 3.11 (2H, t, J = 7Hz), 3.22-3.34 (1H, br m), 3.82 (2H, br s), 3.98 (3H, s), 4.10-4.22 (1H, br m), 4.32 (2H, s), 6.14 (1H, br s), 6.67 (1H, t, J = 3Hz), 7.21 -7.43 (9H, m), 7.52 (2H, d, J = 7Hz), 7.66 (1H, dd, J = 8,2) Hz), 7.97 (1H, d, J = 2Hz), and 10.93-11.10 (1H, brs). [α]²⁰ _D+ 22.7 ° (c, 0.48% MeOH).   Example 6   2- [5-((N-benzyl-N-ethyl) aminosulfonyl) -2-methoxyphenyl Phenyl] -5- [1- (2- (S) -phenylazacycloheptyl) methyl] -1H- Pyrrole oxalate   Using a method similar to that of Example 1, 1-formyl-2- (S) -phenylene Zacycloheptane and 2- [5-((N-benzyl-N-ethyl) aminosulfoni (2) -methoxyphenyl] -1H-pyrrole to give the title compound. Obtained in 29%. Melting point 78-79 [deg.] C.   ¹H NMR (d₆-DMSO) ?: 0.83 (3H, t, J = 8Hz), 1.49-1. 84 (6H, br m), 1.88-2.00 (1H, br m), 2.01 -2.15 (1H, br m ), 3.00-3.16 (1H, br m), 3.11 (2H, q, J = 8Hz), 3.20-3. 33 (1H, br m), 3.82 (2H, brs), 3.98 (3H, s), 4.10-4.21 ( 1H, br m), 4.32 (2H, s), 6.14 (1H, br s), 6.68 (1H, t, J = 3H z), 7.21 to 7.44 (9H, m), 7.53 (2H, d, J = 7Hz), 7.66 (1H, dd) , J = 7,2 Hz), 7.96 (1 H, d, J = 2 Hz), and 10.96-11.11 (1 H, br s). [α]²⁰ _D-19.1 ° (c, 1% MeOH).   Example 7   2- [2-methoxy-5-((2- (1,2,3,4-tetrahydroisoquinolinyl) ) Sulfonyl) phenyl] -5- [1- (2- (R, S) -phenylazacycloheptyl ) Methyl] -1H-pyrrole oxalate   Using a method similar to that of Example 1, 1-formyl-2- (R, S) -phenyl Ruazacycloheptane and 2- [2-methoxy-5-((2- (1,2,3,4- Reacting with trahydroisoquinolinyl)) sulfonyl) phenyl) -1H-pyrrole Thus, the title compound was obtained with a yield of 50%. Mp 116-118 ° C (ether). measured value : C, 64.12; H, 5.95; N, 6.46. C₃₃H₃₇N_ThreeO_ThreeS ・ C₂H₂O_Four・ 0. 5H₂Theoretical value for O: C, 64.20; H, 6.15; 6.42%.   Example 8   2- [2-methoxy-5-((1- (1,2,3,4-tetrahydroquinolinyl)) s Rufonyl) phenyl] -5- (1- (2- (R, S) -phenylazacycloheptyl) me Chill) -1H-pyrrole oxalate   By the method of Example 1, 1-formyl-2- (R, S) -phenylazacyclo Heptane (0.77 g, 3.8 mmol) and 2- [2-methoxy-5-((1- (1,2 , 3,4-Tetrahydroquinolinyl)) sulfonyl) phenyl] -1H-pyrrole (1 g, 2.71 mmol) to give the title compound as needles (1.45 g, 8 3%). Melting point 102-105 [deg.] C. Found: C, 63.68; H, 5.89; N, 6.3. 8. C₃₃H₃₇N_ThreeO_ThreeS ・ C₂H₂O_Four・ H₂Theoretical value of O: C, 63.33; H, 6.23 N, 6.33%.   Example 9   2- [5-((N-ethyl-N-phenyl) aminosulfonyl) -2-methoxyphenyl And]]-5- (1- (2- (R, S) -Phenylazacycloheptyl) methyl) -1H -Pyrrole / hydrochloride   By the method of Example 4, 2- (5-((N-ethyl-N-phenyl) aminosulfur (Honyl) -2-methoxyphenyl) -1H-pyrrole and 1-formyl-2- ( R, S) -Phenylazacycloheptane was reacted to give the title compound.   ¹1 H NMR (CDCl_Three) (Mixture of protomers) δ: 1.07 (3H, t, J = 7) Hz), 1.45 (m) and 1.70 (m) (1H together), 1.8-2.18 (5H, m), 2 .33 (m) and 2.47 (m) (together 1H), 2.55 (m) and 2.82 (m) (together 1H), 3.03 (m) and 3.25 (m) (1H together), 3.15 (m) and 3.60 (m) ) (1H together), 3.45 (m) and 4.27 (m) (1H together), 3.60 (2H, m), 3.96 (m) and 5.03 (m) (together 1H), 4.13 (s) and 4.20 (s) (together) 3 H), 6.00 (m) and 6.33 (m) (1 H together), 6. 14 (m) and 6.33 (m) (1 H together), 6.93 (d, J = 9 Hz) and 6.96 (d , J = 9Hz) (1H together), 7.08 (m) and 7.70 (m) (1H together), 7.08 (1H, m), 7.27-7.54 (9H, m), 7.77 (1H, d, J = 9Hz), 11.39 (br s) and 11.95 (br s) (1H together), 11.45 (br s) and 12.27 ( br s) (1H together).   Example 10   2- [2- (R, S)-(1-ethylpyrrolidinyl)]-5-[(2-methoxy-4- Methyl-5-((N-methyl-N-phenyl) aminosulfonyl) phenyl] -1H -Pyrrole   1-Ethyl-2-pyrrolidinone (0.31 g, 2.7 mmol) at 0 ° C. under argon ) Was treated with phosphorus acid chloride (0.55 g, 2.7 mmol) with continuous stirring. The anti The reaction was warmed to room temperature over 1 hour and diluted with dichloroethane (10 ml). The solution The liquid was cooled to 0 ° C., and 2- (2-methoxy-4-methyl-5-((N-methyl-N- Phenyl) aminosulfonyl) phenyl) -1H-pyrrole (0.75 g, 2.1 mmol) ), The reaction was stirred at 0 ° C. for 3 hours and allowed to warm to room temperature overnight. The reactant Was cooled to 0 ° C and then treated with sodium borohydride (0.75g) at this temperature. And stirred for 1 hour. The reaction mixture was cooled to 0 ° C. and stirred with methanol ( 3 ml). Quenched by addition of water (10 ml), saturated potassium carbonate Partitioned between aqueous solution (20 ml) and dichloromethane (3 x 50 ml). Organic phase Separated, washed with brine and dried (Na₂SO_Four) And evaporated in vacuo. Get The oil obtained is chromatographed on silica 3-5 in dichloromethane. Elution with% methanol gave the title compound as a foam (0.322g, 34%). .   ¹1 H NMR (CDCl_Three) Δ: 1.06-1.21 (3H, m), 1.80-2.60 ( 9H, m), 2.72-2.95 (1H, m), 3.20 (3H, s), 3.47-3.72 (2 H, m), 4.03 (3H, s), 6.11 (1H, m), 6.46 (1H, m), 6.73 (1H, s) ), 7.21-7.31 (5H, m), 8.00 (1H, s), 9.90-10.30 (1H, br)  s).   The following compounds were prepared by a method similar to that of Example 10:   (A) 2- [5-((N- (4-cyanophenyl) -N-methyl) aminosulfonyl ) -2-Methoxyphenyl] -5- (2- (R, S)-(1-ethylpyrrolidinyl))- 1H-pyrrole hydrochloride   Melting point 108-110 [deg.] C. Mass spectrometry measurement value M⁺464.1894. C_{twenty five}H₂₈O_Three N_FourTheoretical value of S: 464_.1883.   (B) 2- [2- (R, S)-(1-ethylpyrrolidinyl))-5- (2-methoxy- 5-((N-methyl-N-phenyl] aminosulfonyl) phenyl) -1H-pillow Le   Melting point 55-57 [deg.] C. Mass spectrometry: Measured value M⁺439.1947. C_{twenty four}H₂₉N_ThreeO_ThreeS Theoretical value of 439.1910.   (C) 2- (2- (R, S)-(1-ethylpyrrolidinyl))-5- [2-methoxy- 5-((N-methyl-N- (4-methylthio) phenyl) aminosulfonyl) phenyl ] -1H-pyrrole / hydrochloride   Melting point 106-108 [deg.] C. Found: C, 55.38; H, 6.05; N, 7.68. C_{twenty five} H₃₁N_ThreeO_ThreeS₂・ HCl ・ H₂Theoretical value for O: C, 55.59; H, 6.34; N, 7. 78%.   (D) 2- (2- (R, S)-(1-ethylpyrrolidinyl))-5- [2-methoxy- 5-((1- (1,2,3,4-tetrahydroquinolinyl)) aminosulfonyl) phenyl Le] -1H-pyrrole   Melting point 51-53 [deg.] C. Mass spectrometry: Measured value M⁺465.2087. C₂₆H₃₁N_ThreeO_ThreeS Theoretical value of 465.2086.   (E) 2- (2- (R, S)-(1-ethylpyrrolidinyl))-5- (1-methoxy- 4-((N-methyl-N-phenyl) aminosulfonyl) -2-naphthyl) -1H- Pyrrole / hydrochloride   Melting point 161-163 [deg.] C. Mass spectrometry: Measured value M⁺489.2100. C₂₈H₃₁N_Three O_ThreeTheoretical value of S is 489.287.   (R) 2- (2- (R, S)-(1-n-butylpyrrolidinyl))-5- [2-methoxy Ci-5-((N-methyl-N-phenyl) aminosulfonyl) phenyl] -1H-pi Roll / hydrochloride   97-99 ° C. Mass spectrometry: Measured value M⁺467.2240. C₂₆H₃₃N_ThreeO_ThreeS Theoretical value of 467.2243.   (G) 2- [2- (R, S)-(1-ethylpyrrolidinyl)]-5- [2-methoxy- 4-((N-methyl-N-phenyl) aminosulfonyl) phenyl] -1H-pillow Le hydrochloride   Mp 195-196 [deg.] C (ethyl acetate). Measurements: C, 60.30; H, 6.21; N , 8.75. C_{twenty four}H₂₉N_ThreeO_ThreeTheoretical value of S · HCl: C, 60.56; H, 6.35; N, 8.83%.   Example 11   2- [2-methoxy-4-methyl-5-((N-methyl-N-phenyl) aminos Rufonyl) phenyl) -5- (1- (2- (R) -phenylazacycloheptyl) methyl Le) -1H-pyrrole   Using a method similar to that of Example 4, 1-formyl-2- (R) -phenylene was used. Zacycloheptane (0.365 g, 1.76 mmol) and 5- [2-methoxy-4- Methyl-5-[(N-methyl-N-phenyl) aminosulfonyl) phenyl] -1H -Pyrrole (0.492 g, 1.38 mmol) was reacted to give the title compound as a foam. The product was obtained (0.40 g, 53%).   ¹1 H NMR (CDCl_Three) Δ: 1.45-2.05 (8H, m), 2.18 (3H, s), 2.72-3.12 (2H, m), 3.20 (3H, s), 3.47-3.72 (3H, m), 4. 03 (3H, s), 5.99 (1H, m), 6.42 (1H, m), 6.74 (1H, s), 7.15 -7.51 (10H, m), 8.00 (1H, s), 9.65-9.70 (1H, brs).   Example 12   2- [5-((N- (4-hydroxyphenyl) -N-methyl) aminosulfonyl) -2-Methoxyphenyl] -5- [1- (2- (R, S) -phenylazacyclohepti ) Methyl] -1H-pyrrole   2- [5-((N- (4-benzyloxyphenyl) -N-methyl) aminosulfoni ) -2-Methoxyphenyl] -5- [1- (2- (R, S) -phenylazacyclohe (Putyl) methyl] -1H-pyrrole (0.45 g) containing 5N HCl (0.5 ml) Solution in ethanol (200 ml) under atmospheric pressure for 18 hours, 5% palladium- Hydrogenated with charcoal. The mixture was filtered and the filtrate was evaporated to dryness in vacuo. Dicro The residue in dichloromethane was washed with aqueous sodium bicarbonate solution, water, Na₂SO_FourDry I let it. The product was chromatographed on silica with 10-30% acetic acid. Elution with chill-dichloromethane gave the title compound (0.35g). Melting point 50-7 0 ° C (ether-pentane). Mass spectrometry: Measured value M⁺545.2365. C₃₁H₃₅N_Three O_FourTheoretical value of S is 545.2398.   Example 13   2- (2-methoxy-5-((N-methyl-N-phenyl) aminosulfonyl) phenyl Phenyl) -5- (1- (2- (R, S)-(2- (5-methylfuryl)) azacyclohepty ) Methyl) -1H-pyrrole hydrochloride   According to the method described in Example 4, 2- (2-methoxy-5-((N-methyl-N -Phenyl) aminosulfonyl) phenyl) -1H-pyrrole and 1-formyl 2- (R, S)-(2- (5-methylfuryl)) azacycloheptane was produced in a yield of 9%. I made it.   FAB mass spectrometry: measured value MH⁺534. C₃₀H₃₅N_ThreeO_FourTheoretical value of S: M⁺533 .   Example 14   2- (5-((N- (4-iodophenyl) -N-methyl) aminosulfonyl) -2 -Methoxyphenyl) -5- (1- (2- (R, S) -phenylazacycloheptyl) Methyl) -1H-pyrrole oxalate   2- (5-((N- (4-bromophenyl) -N-methyl) aminosulfonyl) -2 -Methoxyphenyl) -5- (1- (2- (R, S) -phenylazacycloheptyl) Methyl) -1H-pyrrole (0.730 g, 1.2 mmol) and tetrakis (trif Phenylphosphine) palladium (0) (0.140 g, 0.12 mmol) in dry triethyl ether Bis (tributyltin) (0.73 ml, 1.4 mmol) in a mixture in luamine (15 ml) Was added. The reaction was heated at reflux under argon for 6 hours. The resulting mixture To Cool to room temperature and remove the triethylamine in vacuo to give an oil which is Chromatography on silica gel eluting with 0-20% ethyl acetate in pentane. Was. The obtained tin (0.356, 0.4 mmol, yield 29%) was converted into chloroform (20 ml) and added iodine (0.107 g, 0.4 mmol) with stirring at -5 ° C. The solution was treated dropwise with a solution in chloroform (10 ml). Then immediately Natrithiosulfate Aqueous saturated aqueous solution (10 ml) was added. The organic phase is separated and then sodium thiosulfate is added. It was washed successively with a saturated aqueous solution of sodium and brine. Organic phase Na₂SO_FourDry The solvent was removed in vacuo to give a yellow oil. Chroma on silica Subjected to chromatography and eluted with 0-30% ethyl acetate in pentane. The resulting oil The product was dissolved in acetonitrile (20 ml) and washed with hexane (3 x 10 ml). To remove any residual alkyltin impurities. Remove the solvent in vacuo, A colorless oil was obtained which was treated with oxalic acid to give the title compound (0.110 g). , 42%). Melting point 107-109 [deg.] C. Measured value: C, 52.35; H, 4.85; N, 5 .57. C₃₁H₃₄IN_ThreeO_ThreeS ・ C₂H₂O_Four・ 0.5H₂Theoretical value of O: C, 52.52; H, 4.94; N, 5.57%.   Example 15   2- [2-methoxy-5-((2- (7-methylsulfinyl) -1,2,3,4-tetra- Trahydroisoquinolinyl) aminosulfonyl) phenyl] -5- (1- (2- (R, S) -Phenylazacycloheptyl) methyl) -1H-pyrrole   According to Example 17, 2- (2-methoxy-5-((2- (7-methylthio) -1, 2,3,4-Tetrahydroisoquinolinyl) aminosulfonyl) phenyl) -5- (1 -(2- (R, S) -Phenylazacycloheptyl) methyl) -1H-pyrrole Treatment with hydrogen hydride produced the title compound. Melting point 87-89 [deg.] C. Mass spectrometry: M⁺617.2376. C₃₄H₃₉N_ThreeO_FourS₂Theoretical value: 617_.2376.   Example 16   2- [5-((N-ethyl-N- (2-furanyl) methyl) aminosulfonyl) -2 -Methoxyphenyl] -5- (1-piperidinylmethyl) -1H-pyrrole / hydrochloric acid salt   To a stirred solution of piperidine (0.14 ml, 1.39 mmol) in ethanol (10 ml). 37-40% aqueous formaldehyde solution (0.12 ml, 1.39 mmol) was added and the The mixture was stirred at room temperature for 0.5 hours. Glacial acetic acid (0.12 ml, 1.94 mmol) was added 16 hours later, 2- (5-((N-ethyl-N- (2-furanyl) methyl) aminos Rufonyl) -2-methoxyphenyl) -1H-pyrrole (0.5 g, 1.39 mmol) Was added. After a further 20 hours, the reaction mixture was evaporated in vacuo and the residue was diluted. Partitioned between ethyl ether and 0.5N HCl. Acidic layer with 2.5N NaOH Basified and extracted into dichloromethane (3 x 50 ml). Combined organic extracts Dried (Na₂SO_Four), Evaporated in vacuo. 0-2% meta in dichloromethane Chromatography on silica with sol. Marked as free base The compound was obtained. Dissolve this in diethyl ether and add 0.5N HCl (2 x 50m l). Combine the acidic extracts and extract with dichloromethane (4 x 40 ml) did. The combined organic extracts were dried and evaporated in vacuum. Diethyl ether Trituration with to give the title compound in 56% yield.   Found: C, 58.04; H, 6.39; N, 8.47. C_{twenty four}H₃₁N_ThreeO_FourS ・ HCl Theoretical value: C, 58.35; H, 6.53: N, 8.51%.   Prepared by a method similar to that of Example 16:   (A) 2- (N-benzyl-N-ethyl) aminomethyl-5- (2-methoxy- 5-((N-methyl-N-phenyl) aminosulfonyl) phenyl) -1H-pillow Le hydrochloride   Melting point 85-95 [deg.] C. Found: C, 62.96; H, 6.25; N, 7.79. C₂₈H₃₁ N_ThreeO_ThreeS / HCl / 0.4H₂Theoretical value of O C, 63.04; H, 6.20; N, 7.8 8%.   (B) 2- (N-benzyl-N-ethyl) aminomethyl-5- [2-methoxy- 4-((N-methyl-N-phenyl) aminosulfonyl) phenyl] -1H-pillow Le hydrochloride   Melting point 110-114 [deg.] C. Found: C, 63.08; H, 6.08; N, 7.93. C₂₈ H₃₁N_ThreeO_ThreeS ・ HCl ・ 0.5H₂Theoretical value for O: C, 62.85; H, 6.03; N, 7.85%.   (C) 2- [2-methoxy-4-((N-methyl-N-phenyl) aminosulfoni ) Phenyl] -5- (1-piperidinylmethyl) -1H-pyrrole hydrochloride   Melting point 165-167 [deg.] C (ether). Measurements: C, 60.34; H, 6.11; N, 8.89. C_{twenty four}H₂₉N_ThreeO_ThreeTheoretical value of S · HCl C, 60.56; H, 6.35; N, 8. 83%.   (D) 2- (N, N-diethylaminomethyl) -5- [2-methoxy-4-((N- Methyl-N-phenyl) aminosulfonyl) phenyl] -1H-pyrrole hydrochloride   Measurements: C, 59.62; H, 5.93; N, 9.05, C_{twenty three}H₂₉N_ThreeO_ThreeS ・ HCl Theor. C, 59.53; H, 6.52; N, 9.06%.   (E) 2- [2-methoxy-4-((N-methyl-N-phenyl) aminosulfoni ) Phenyl] -5- [1- (R, S)-(1-piperidinyl) ethyl] -1H-pillow Le hydrochloride   Melting point 147-148 [deg.] C (ethyl acetate). Measured value: C, 61.06; H, 6.40; N , 8.53. C_{twenty five}H₃₁N_ThreeO_ThreeTheoretical value of S · HCl: C, 61.27; H, 6.58; N, 8.57%.   Example 17   2- (2-methoxy-5-((N-methyl-N- (4-methylsulfinyl) phenyl) phenyl ) Aminosulfonyl) phenyl) -5- (1- (2- (R, S) -phenylazacyclo Heptyl) methyl) -1H-pyrrole   2- (2-Methoxy-5-((N-methyl- in acetic acid (20 ml) at room temperature for 2 hours. N (4-methylthio) phenyl) aminosulfonyl) phenyl) -5- (1- (2- (R , S) -Phenylazacycloheptyl) methyl) -1H-pyrrole (500 mg, 0. 75 mmol) was treated with hydrogen peroxide (280 mg, 27% solution, 2.2 mmol). Next The reaction was poured into excess aqueous potassium carbonate solution and extracted with ether. Existence Separating the machine phase, Na₂SO_FourDry in vacuo, evaporate in vacuo and label as a foam. The compound was obtained.   Melting point 73-78 [deg.] C. (half melt). Found: C, 64.57; H, 6.28; N, 6.96. C₃₂H₃₇N_ThreeO_FourS₂Theoretical value: C, 64.95; H, 6.30; N, 7.10%.   Biological test method   Compound of human D_ThreeThe ability to selectively bind to dopamine receptors Can be demonstrated by measuring its binding to the cloned receptor. C D expressed in HO cells_ThreeTo the dopamine receptor [¹²⁵I] Iodosulpride ( Inhibition constant (IC) of the test compound for displacement of iodosulpride) binding₅₀) Was measured . The cell line has been shown to be immune to bacterial, fungal and mycoplasma contaminations, The mother liquor was stored frozen in liquid nitrogen. Cultures in standard cell culture medium It was grown as a monolayer or in suspension. Scrape cells (from monolayer) Or phosphate recovery (from suspension culture) by centrifugation. 2 or by suspending in an impregnated saline solution and then collecting by centrifugation. Washed three times. The cell pellet was stored frozen at -40 ° C. Homogenization , Then, prepare the crude cell membrane by high speed centrifugation for radioligand binding. Therefore, the cloned receptor was characterized.   Preparation of CHO cell membrane   The cell pellet was slowly thawed at room temperature and approximately 20 volumes of ice-cold 50 mM Tris salt ( pH 7.4 @ 37 ° C), 20 mM EDTA, 0.2 M sucrose Was. The suspension was homogenized using an Ultra-Turrax at full speed for 15 seconds. In a Sorvall RC5C centrifuge at 4 ° C. for 20 minutes at 18,000 r.p.m. The modinate was centrifuged. Membrane pellets are iced using an Ultra-Turrax Resuspend in cold 50 mM Tris salt (pH 7.4 @ 37 ° C) and in Sorvall RC5C, Centrifuge again at 18,000 rpm for 15 minutes at 4 ° C. Membrane ice-cooled 50m It was washed twice more with M Tris salt (pH 7.4 @ 37 ° C). 50m final pellet Resuspend in M Tris salt (pH 7.4 @ 37 ° C) and use bovine serum al as a standard sample. Protein content was measured using bumin [Bradford, M.M. ord, M.M.) (1976) Anal. Biochem. 72, 248-254].   Binding experiments on cloned dopamine receptors   The crude cell membrane was adjusted to 0.1 nM [¹²⁵I] Iodosulpride (-2000 Ci / mmol; flax) -Amersham, UK) and 50 mM Tris salt (pH 7.4@37°C) , 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂1 mM MgCl₂, 0.1% ( w / v) total volume with test compound in buffer containing bovine serum albumin Incubated with 1 ml for 30 minutes at 37 ° C. After incubation, Brandel  Samples were filtered using a Cell Harvester and ice-cold 50 mM Tris salt (pH 7.4@3). 7 ° C), 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂1 mM MgCl₂3 times Washed. Cobra Gamma Counter [Canberra Pack ard)] was used to measure the radioactivity on the filter. Nonspecific binding is 100μ Radioactive ligand remaining after incubation in the presence of M-iodosulpride It was defined as a do-join. About the competition curve, 14 different concentrations (semi-log dilution) competition I used a cold medicine.   Non-linear least-squares fit with the ability to fit one, two or three different site models Competition curves were analyzed simultaneously whenever legal methods could be used.   Example compounds (Example 11, m; 4a, f, g, i, j, l, p, r, s; 10a, c; 13, 15, 16, 16c and d) are human D_ThreeReceptor 5 to 50 nm IC₅₀Had a value.   Pharmaceutical formulation   A typical pharmaceutical composition according to the invention prepared using standard methods is shown below .   IV infusion     Compound of formula (I) 1-40 mg     Buffer solution Adjust to about pH7     Solvent / complexing agent adjusted to 100 ml   Bolus injection     Compound of formula (I) 1-40 mg     Buffer solution Adjust to about pH7     Co-solvent adjusted to 5 ml   Buffer: Suitable buffers include citrate, phosphate, sodium hydroxide             / Examples include hydrochloric acid.   Solvent: Typically, other than water, cyclodextrin (1-100 mg)             Rabbi propylene glycol, polyethylene glycol and al             Examples include cosolvents such as Cole.   tablet     Compound 1-40mg     Diluent / Filler 50-250mg     Binder 5-25mg     Disintegrant 5-50mg     Lubricant 1-5mg     Cyclodextrin 1-100mg   Also includes cyclodextrin.   Diluent: For example, microcrystalline cellulose, lactose, starch.   Binders: eg polyvinylpyrrolidone, hydroxypropylmethylcellulos             Source.   Disintegrants: eg sodium starch glycolate, crospovidone             (Crospovidone).   Lubricants: eg magnesium stearate, sodium stearyl fumarate           .   Oral suspension     Compound 1-40mg     Suspending agent 0.1-10 mg     Diluent 20-60mg     Preservative 0.01-1.0 mg     Buffer pH adjusted to about 5-8     Cosolvent 0-40mg     Flavor 0.01-1.0mg     Coloring agent 0.001-0.1 mg   Suspending agents: eg xanthan gum, microcrystalline cellulose.   Diluent: For example, a sorbitol solution, typically water.   Preservative: For example, sodium benzoate.   Buffer: eg citrate.   Cosolvent: For example, alcohol, pyropyrene glycol, polyethylene glycol             And cyclodextrin.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification code Internal reference number FI C07D 207/335 9159-4C C07D 207/335 401/12 207 9159-4C 401/12 207 405/12 207 9159- 4C 405/12 207 409/12 207 9159-4C 409/12 207 (81) Designated country EP (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (KE, MW, SD, SZ), AM , AT, AU, BB, BG, BR, BY, CA, CH, CN, CZ, DE, DK, EE, ES, FI, GB, GE, HU, JP, KE, KG, KP, KR KZ, LK, LR, LT, LU, LV, MD, MG, MN, MW, NL, NO, NZ, PL, PT, RO, RU, SD, SE, SI, SK, TJ, TT, UA, US , UZ, VN (72) Inventor Stemp, Jeffrey United Kingdom Essex Seam 19.5 Eddie, Harlow, The Pinnacles, Cold Harbor Road (no address) SmithKline Beecham Pharmaceuticals (72) Inventor Wadsworth, Harry John United Kingdom Essex Seam 19.5 Eddy, Harlow, The Pinnacles, Cold Harbor Road (No street number) SmithKline Beecham Pharmaceuticals (72 ) Inventor Watts, Eric Alfred, Essex CM 19.5 Eddy, Har, England Row, The Pinnacles, Cold Harbor Road (no street number) SmithKline Beecham Pharmaceuticals [Continued Summary]

Claims (1)

[Claims]   1. Formula (I): [Where,   R¹Is C_1-4Represents alkyl;   R², R^Three, R^FourAnd R^FiveOne of which is a sulfonamide group R⁶R⁷NSO₂− Where:   R⁶Is hydrogen, C_1-6Alkyl or C_1-4Alkoxy C_1-4Represents alkyl;   R⁷Is a group (R^a)_p-(Ar)-(CH₂)_jRepresents-, where Ar is phenyl, na Futyl fused with a 5 or 6 membered heterocyclic aryl group or a phenyl ring Represents a 5- or 6-membered heterocyclic aryl group; j represents 0 or an integer of 1 to 4; Represents; R^aIs halogen, C_1-4Alkyl, C_1-4Alkoxy, C_1-4Alkoxy C_1-4 Alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, Hydroxy, hydroxy C_1-4Alkyl, C_1-4Alkanoyl, C_1-4Alkoxy Carbonyl, amino, mono- or di-C_1-4Alkylamino, C_1-4Alkyl Thio, C_1-4Alkylsulfinyl, C_1-4Alkylsulfonyl and phenyl C_1-4Represents a substituent selected from alkoxy, p is 0 or an integer from 1 to 4 Represents; or   R⁶R⁷N- is fused with or substituted by a phenyl group Or 5-substituted by a 5- or 6-membered heterocyclic aryl group Represents a 7-membered heterocyclic ring, wherein the phenyl or heteroaryl group is optionally More group (R^a)_pMay be substituted by where R^aAnd p are the constants Same as righteousness;   R², R^Three, R^FourAnd R^FiveThe rest of the above are each independently hydrogen, halogen, C_1-4 Alkyl, C_1-4Alkoxy, C_1-4Alkoxy C_1-4Alkyl, C_1-4Archi Lesulfonyl, trifluoromethylsulfonyl; optionally substituted Arylsulfonyl, optionally substituted heteroarylsulfo Nyl, optionally substituted aralkylsulfonyl, optionally substituted Optionally substituted heteroaralkylsulfonyl, nitro, cyano, amino, mono -Or di-alkylamino, trifluoromethyl, trifluoromethoxy, Hydroxyl, hydroxyalkyl, C_1-4Alkylthio, C_1-4Alkanoyl Or C_1-4Represents alkoxycarbonyl; or   R¹And R²Together, C_2-4Forming an alkyl chain, the chain being the desired 1 or 2 C_1-4Optionally substituted by an alkyl group, in which case , R^Three, R^FourAnd R^FiveOne of which is a sulfonamide group as defined above and the other Two are the same as defined above; or R²And R^ThreeTogether Form a phenyl ring, in which case R^FourRepresents a sulfonamide group as defined above, R^FiveRepresents hydrogen;   Y is (a) to (e):     (Where       In the group (a),       R⁸And R⁹Is independently hydrogen, C_1-6Alkyl, optionally substituted Optionally aryl C_1-6Alkyl or optionally substituted Terror aryl C_1-6Represents alkyl;       R^TenIs C_1-6Alkyl, C_3-6Alkenyl or C_3-6Cycloalkyl C_{1 -Four} Represents alkyl;       R¹¹Is C_1-6Alkyl; C_3-6Alkenyl; C_3-6Cycloalkyl C_1-4A Rukyi, optionally substituted aryl C_1-4Alkyl or optionally More optionally substituted heteroaryl C_1-4Represents alkyl; or       NR^TenR¹¹Forms a heterocyclic ring;       In the group (b),       R¹²Is C_1-6Alkyl; C_3-6Alkenyl; C_3-6Cycloalkyl C_1-4A Rukyi, optionally substituted aryl C_1-4Alkyl or optionally More optionally substituted heteroaryl C_1-4Represents alkyl;       q is 1 to 4;       In group (c),       R¹³And R¹⁴Is independently hydrogen, C_1-6Alkyl, optionally substituted Optionally aryl C_1-6Alkyl or optionally substituted Heteroaryl C_1-6Represents alkyl;       R^FifteenIs optionally substituted aryl or optionally substituted Represents an optionally substituted heteroaryl group;       Z is-(CH₂)_u(Where u is 1 to 8) or-(CH₂)_vCH = CH (CH₂)_w(Wherein v and w independently represent 1 to 3);       In the group (d), each of r and s independently represents an integer of 1 to 3;       In the group (e), R¹⁶Is C_1-6Alkyl, C_3-6Alkenyl or C_{3- 6} Cycloalkyl C_1-4Represents alkyl; R¹⁷, R¹⁸, R¹⁹And R²⁰Is German Upright, hydrogen, halogen, C_1-4Alkyl, C_1-4Alkoxy, C_1-4Alkoxy C_1-4Alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy , Hydroxy, hydroxyalkyl, C_1-4Alkanoyl, C_1-4Alkoxycal Represents bonyl, amino or mono- or dialkylamino;       X is CH₂, S or O;       (t is 0, 1 or 2) Represents a group selected from And a salt thereof.   2. R¹The compound according to claim 1, wherein is methyl, ethyl, or isopropyl. .   3. R^ThreeOr R^FourR is a radical R as defined in claim 1.⁶R⁷NSO₂Contract representing The compound according to claim 1 or 2.   4. R², R^Three, R^FourAnd R^FourThe remaining ring substituents selected from are hydrogen or C_{1- Four} A compound according to claim 3 which represents alkyl.   5. R⁷Is based on (R^a)_p-(Ar)-(CH₂), Where Ar is phenyl, Is a 5-membered containing 1, 2 or 3 atoms selected from O, N or S or Represents a 6-membered heterocyclic aryl group, R^a, P and j are defined in claim 1. The compound according to any one of claims 1 to 4, which is the same as   6. R⁶R⁷NSO₂Is the formula (f) or (g): [Wherein, R^aAnd p are as defined above;   Ar 'represents phenyl or a 5- or 6-membered heterocyclic ring;   R^{twenty one}Is-(CH₂)_m-Or- (CH₂)_kW (CH₂)₂Represents-;   m represents 0 or an integer of 1 to 4;   k represents 0 or 1;   W is O, S, SO or SO₂Represents;   n represents 0 or an integer of 1 to 4;   However, in the group (f), the total of n + m is 2 to 4, and the total of n + k is 0 or 1, and in the group (g), the total of n + m is 3 to 5, and n + k is The total is 1 or 2.] The compound according to any one of claims 1 to 4, which represents a group represented by:   7. Formula (IA): [Where,   R², R^Three, R^FourAnd R^FiveOne of them is a sulfonamide group:     (Where       The dotted line is the hydrogen atom or the substituent R bonded to the phenyl ring.^{twenty three}Represents;       R^{twenty two}Is hydrogen, C_1-6Alkyl, or C_1-4Alkoxy C_1-4Alkyl Representation;       n represents 0 or an integer of 1 to 4; or       The dotted line represents a single bond;       R^{twenty two}Is-(CH₂)_mRepresents-;       n and m are each 0 or 1 such that the sum of n + m is 2-4. Represents an integer of 4;       In either case,       R^{twenty three}Is halogen, C_1-4Alkyl, C_1-4Alkoxy, C_1-4Alkoxy C_1-4Alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy , Hydroxy, hydroxy C_1-4Alkyl, C_1-4Alkanoyl, C_1-4Alkoki Cycarbonyl, amino and mono- or di-C_1-4Selected from alkylamino Represents a substituent;       p represents 0 or an integer of 1 to 4) Represents   R², R^Three, R^FourAnd R^FiveThe rest of, as well as R¹And Y are in formula (I) The same definition as A compound represented by the formula:   8. Y is a group (c) (where R¹³And R¹⁴At least one of which is hydrogen The compound according to any one of claims 1 to 7, which represents   9. R¹³And R¹⁴One of them is hydrogen, the other is hydrogen, C_1-6Alkyl And optionally substituted aryl C_1-6Contract selected from alkyl The compound according to claim 8.   10. R^FifteenIs phenyl which is optionally substituted. The compound according to any one of claims.   11. Z is (CH₂)_uClaim 1 (where u is 3, 4 or 5) 10. The compound according to any one of items 10 to 10.   12. A compound according to claim 1 selected from the following compounds:   2- (2-methoxy-5-((N-methyl-N-phenyl) aminosulfonyl) phenyl Phenyl) -5- (1- (2- (R, S) -phenylazacycloheptyl) -methyl) -1 H-pyrrole;   2- [5-((N-benzyl-N-methyl) aminosulfonyl) -2-methoxyphenyl Phenyl] -5- [1- (2- (R, S) -phenylazacycloheptyl) methyl] -1H -Pyrrole;   2- [2-methoxy-5-((N-methyl-N-phenyl) aminosulfonyl) phenyl Phenyl] -5- (1- (R, S)-(2-phenylpyrrolidinyl) methyl) -1H-pyro Tool;   (−)-2- [2-Methoxy-5-((N-methyl-N-phenyl) aminosulfoni L) phenyl] -5- (1- (2-phenylpyrrolidinylmethyl) -1H-pyrrole;   (+)-2- [2-methoxy-5-((N-methyl-N-phenyl) aminosulfoni ) Phenyl] -5- (1- (2-phenylpyrrolidinyl) methyl) -1H-pyrrole;   (−)-2- [2-Methoxy-5-((N-methyl-N-phenyl) aminosulfoni L) phenyl] -5- (1- (2-phenylpiperidinylmethyl) -1H-pyrrole;   (+)-2- [2-methoxy-5-((N-methyl-N-phenyl) aminosulfoni ) Phenyl] -5- (1- (2-phenylpiperidinyl) methyl) -1H-pyrrole;   2- (5-((N- (4-bromophenyl) -N-methyl) aminosulfonyl) -2 -Methoxyphenyl) -5- (1- (2- (R, S) -phenylazacycloheptyl) Methyl) -1H-pyrrole;   2- (2-methoxy-5-((N- (4-methoxyphenyl) -N-methyl) amino -Sulfonyl) phenyl) -5- (1- (2- (R, S) -phenylazacyclohepty Ru) methyl) -1H-pyrrole;   2- (5-((N- (4-cyanophenyl) -N-methyl) aminosulfonyl) -2 -Methoxyphenyl) -5- (1- (2- (R, S) -phenylazacycloheptyl) Methyl) -1H-pyrrole;   2- (5- (4- (3,4-dihydro-1,4-benzoxazinyl) sulfonyl) 2-Methoxy-phenyl) -5- (1- (2- (R, S) -phenylazacyclohep Tyl) methyl) -1H-pyrrole;   2- (5-((N- (3,4-dimethoxybenzyl) -N-ethyl) aminosulfoni ) -2-Methoxyphenyl) -5- (1- (2- (R, S) -phenylazacyclohe Butyl) methyl) -1H-pyrrole;   2- (2-methoxy-5-((N-methyl-N- (4-methylthio) phenyl) ami) Nosulfonyl) phenyl) -5- (1- (2- (R, S) -phenylazacyclohepty Ru) methyl) -1H-pyrrole;   2- (2-methoxy-5-((N-methyl-N-phenyl) aminosulfonyl) phenyl Phenyl) -5- (1- (2- (R) -phenylazacycloheptyl) methyl) -1H- Pyrrole;   2- (2-methoxy-5-((N-methyl-N-phenyl) aminosulfonyl) phenyl Phenyl) -5- (1- (2- (S) -phenylazacycloheptyl) methyl) -1H- Pyrrole;   2- [5-((N-benzyl-N-ethyl) aminosulfonyl) -2-methoxyphenyl And]]-5- (1- (2- (R, S) -Phenylazacycloheptyl) methyl) -1H -Pyrrole;   2- [5-((N- (2,4-difluorophenyl) -N-methyl) aminosulfoni 2-Methoxyphenyl] -5- (1- (2- (R, S) phenyl azacyclohepty Ru) methyl) -1H-pyrrole;   2- [2-methoxy-5-((1- (2-phenylpyrrolidinyl) sulfonyl) phene Nyl] -5- (1- (2- (R, S) -phenylazacycloheptyl) methyl) -1H- Pyrrole;   2- [2-methoxy-5-((N-ethyl-N- (2-phenyl) ethyl) aminos Rufonyl) -phenyl] -5- (1- (2- (R, S) -phenylazacycloheptyl) Methyl) -1H-pyrrole;   2- [2-methoxy-5-((N-methyl-N- (5-methyl-3-isoxazo Ryl)) amino-sulfonyl) phenyl] -5- (1- (2- (R, S) -phenylaza Cycloheptyl) methyl) -1H-pyrrole;   2- [2-methoxy-5-((N-methyl-N-phenyl) aminosulfonyl) phenyl ]]-5- (1- (R, S)-(1-Piperidinyl) ethyl) -1H-pyrrole;   2- [5-((N-ethyl-N- (2-pyridyl) methyl) aminosulfonyl) -2 -Methoxy-phenyl] -5- (1- (2- (R, S) -phenylazacycloheptyl ) Methyl) -1H-pyrrole;   2- [5-((N-ethyl-N- (2-furyl) methyl) aminosulfonyl) -2- Methoxy-phenyl] -5- (1- (2- (R, S) -phenylazacycloheptyl) Methyl-1H-pyrrole;   2- [5-((N- (4-fluorophenyl) -N-methyl) aminosulfonyl)- 2-Methoxyphenyl] -5- (1- (2- (R, S) -phenylazacycloheptyl ) Methyl) -1H-pyrrole;   2- [2-methoxy-4-((N-methyl-N-phenyl) aminosulfonyl) phenyl Phenyl] -5- [1- (2- (R, S) -phenylazacycloheptyl) methyl] -1H -Pyrrole;   2- [5-((N-benzyl-N-ethyl) aminosulfonyl) -2-methoxy group Phenyl] -5- [1- (2- (R) -phenylazacycloheptyl) methyl] -1H- Pyrrole;   2- [5-((N-benzyl-N-ethyl) aminosulfonyl) -2-methoxyphenyl Phenyl] -5- [1- (2- (S) -phenylazacycloheptyl) methyl] -1H- Pyrrole;   2- [2-methoxy-5-((2- (1,2,3,4-tetrahydroisoquinolinyl) ) Sulfonyl) phenyl] -5- [1- (2- (R, S) -phenylazacycloheptyl ) Methyl] -1H-pyrrole;   2- [2-methoxy-5-((1- (1,2,3,4-tetrahydroquinolinyl)) s Rufonyl) phenyl] -5- (1- (2- (R, S) -phenylazacycloheptyl) me Chill-1H-pyrrole;   2- [5-((N-ethyl-N-phenyl) aminosulfonyl) -2-methoxyphenyl And]]-5- (1- (2- (R, S) -Phenylazacycloheptyl) methyl) -1H -Pyrrole;   2- [2- (R, S)-(1-ethylpyrrolidinyl)]-5-[(2-methoxy-4- Methyl-5-((N-methyl-N-phenyl) aminosulfonyl) phenyl] -1H -Pyrrole;   2- [2- (R, S)-(1-ethylpyrrolidinyl))-5- (2-methoxy-5-(( N-methyl-N-phenyl] aminosulfonyl) phenyl) -1H-pyrrole;   2- (2- (R, S)-(1-ethylpyrrolidinyl))-5- [2-methoxy-5-(( 1- (1,2,3,4-tetrahydroquinolinyl)) aminosulfonyl) phenyl] -1 H-pyrrole;   2- (2- (R, S)-(1-ethylpyrrolidinyl))-5- (1-methoxy-4-(( N-methyl-N-phenyl) aminosulfonyl) -2-naphthyl) -1H-pillow Le;   2- (2- (R, S)-(1-n-butylpyrrolidinyl))-5- [2-methoxy-5 -((N-methyl-N-phenyl) aminosulfonyl) phenyl] -1H-pyrrole;   2- [2- (R, S)-(1-ethylpyrrolidinyl)]-5- [2-methoxy-4-(( N-methyl-N-phenyl) aminosulfonyl) phenyl] -1H-pyrrole;   2- [2-methoxy-4-methyl-5-((N-methyl-N-phenyl) aminos Rufonyl) phenyl) -5- (1- (2- (R) -phenylazacycloheptyl) methyl Le) -1H-pyrrole;   2- [5-((N- (4-hydroxyphenyl) -N-methyl) aminosulfonyl) -2-Methoxyphenyl] -5- [1- (2- (R, S) -phenylazacyclohepti Le) methyl] -1H-pyrrole;   2- (5-((N- (4-iodophenyl) -N-methyl) aminosulfonyl) -2 -Methoxyphenyl) -5- (1- (2- (R, S) -phenylazacycloheptyl) Methyl) -1H-pyrrole;   2- (N-benzyl-N-ethyl) aminomethyl-5- (2-methoxy-5-(( N-methyl-N-phenyl) aminosulfonyl) phenyl) -1H-pyrrole;   2- (N-benzyl-N-ethyl) aminomethyl-5- [2-methoxy-4-(( N-methyl-N-phenyl) aminosulfonyl) phenyl] -1H-pyrrole;   2- [2-methoxy-4-((N-methyl-N-phenyl) aminosulfonyl) phenyl [Ethyl] -5- [1- (R, S)-(1-piperidinyl) ethyl] -1H-pyrrole;   2- (2-methoxy-5-((N-methyl-N- (4-methylsulfinyl) phene) Nyl) aminosulfonyl) phenyl) -5- (1- (2- (R, S) -phenylazasic Loheptyl) methyl) -1H-pyrrole;   And their salts.   13. (A) Formula (II) in the presence of formaldehyde: And a compound of formula (III), (IV) or (V): The Mannich reaction with an amine represented by is carried out, and Y is a group (a) or (c) (here And R⁸, R⁹, R¹³And R¹⁴Is hydrogen) or formula (I) wherein Y is a group (e). Or a compound represented by   (B) a compound represented by the formula (II) and a formula (VI), (VII) or (VIII): With an appropriate oxo derivative of the amide or group (b) or (c) A Meyer reaction is carried out, and then the intermediate product is treated with, for example, sodium borohydride. Alternatively, it is reduced with sodium cyanoborohydride so that Y is a group (a) (where R⁸And And R⁹At least one of which is hydrogen), a group (c) (wherein R is¹³Or R¹⁴ At least one of them is hydrogen), a group (e) or a group represented by the formula (b) or (d). A compound that is a group that is   Expression (IX): Of the compound represented by formula (III), (IV) or (V) with an amine Whether Y is a group (a) or (c), depending on the⁸, R⁹, R¹³and R¹⁴Is hydrogen), or Y is a group (e);   (D) Oxidation of thiol functional groups to sulfinyl or sulfonyl functional groups, or Or a compound of formula (I) such as hydrogenation of a benzyloxy group to hydroxy. Conversion of the compound to another compound of formula (I) A process for producing a compound of formula (I), characterized in that   14． In the manufacture of a therapeutic agent for a condition requiring modulation of dopamine receptors Use of a compound of formula (I) or a physiologically acceptable salt thereof.   15. Dopamine receptor is dopamine D_Three15. A receptor according to claim 14. Use of the listing.   16. Use according to claim 14 or 15, wherein a dopamine antagonist is required.   17． Use according to any one of claims 14 to 16, wherein the symptom is a psychotic symptom. .   18. A compound of formula (I) or a physiologically active compound thereof in a patient in need of treatment It is necessary to modulate the dopamine receptor by administering an effective amount of an acceptable salt. How to treat the required symptoms.   19. Compounds of formula (I) or physiologically acceptable salts and physiology thereof A pharmaceutical composition comprising a pharmaceutically acceptable carrier.   20. Novel intermediates selected from formulas (II), (IX), (X), (XI) and (XII).