JPH06329626A - Pyrrolidine derivative - Google Patents

Abstract

PURPOSE:To provide a new pyrrolidine derivative having high affinity to the receptor of dopamine I and useful as an agent for treating and preventing hypertension and cardiac failures. CONSTITUTION:A compound of formula I [Y is -NH-, -(CH2)n- (n is 0-2), -S(O)p- (p is 0-2); R<1>, R<2> are H, OH, -SO2NR<3>R<4> (R<3>, R<4> are H, lower alkyl and acyl, and R<3>, R<4> may be combined to each other together with the bonded N atom to form a ring), -NR<5>R<6> (R<5>, R<6> are H, alkylsulfonyl, acyl, but a case where both R<5>, R<6> are H is excluded, and R<5>, R<6> may form a ring together with the bonded N atom); but a case where both R<1>, R<2> are H or OH, and a case where either of R<1>, R<2> is H and the other is OH are excluded] or its pharmacologically acceptable salt, e.g. (-)-trans-3-(3-aminosulfonyl-2,6-dihydroxyphenyl)methyl-4-(3,4- dihydroxyphenyl)pyrrolidine hydrochloride.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a pyrrolidine derivative useful as a medicine or a pharmaceutically acceptable salt thereof. More specifically, it relates to a pyrrolidine derivative having a hypotensive action and a pharmaceutically acceptable salt thereof.

[0002]

BACKGROUND OF THE INVENTION AND PRIOR ART Hypertension is about 2 in Japanese.
Although it is said that 0% of the patients are affected, the disease has a large number of patients, but the disease states and causes thereof are very diverse.
In particular, the cause is often unclear, and it is said that 70% of patients diagnosed with hypertension have so-called essential hypertension whose cause cannot be clearly defined. In many cases, there are cases of transition from hypertension to various brain diseases such as intracerebral hemorrhage, heart diseases such as heart failure, and cases with serious complications, and appropriate treatment at an early stage is now an important issue. Has become.

Currently, as drug treatments for hypertension, drugs having various mechanism of action such as antihypertensive diuretics, β-blockers, calcium antagonists, ACE inhibitors are actually used clinically. Since the pathophysiology and causes of hypertension are extremely diverse, it is difficult at this stage to predominantly control all types of hypertension. From the viewpoint of safety, for example, β-blockers include cardiac depression, bronchospasm, diuretics include hyperuricemia, electrolyte abnormalities, abnormal glucose metabolism, and calcium antagonists. Atrioventricular block, transient cardiac arrest, etc. may be seen, and further, ACE inhibitors show dry cough and the like. Thus, drug selection, especially for patients with complications, is rather difficult and requires careful attention.

Under these circumstances, there is still a long-felt need for drugs having different types and different mechanisms of action.

Therefore, the present inventors have conducted extensive studies over a long period of time, particularly dopamine acting substances, in order to develop a new type of antihypertensive agent, especially an antihypertensive agent having an effect of increasing renal blood flow. It was found that the pyrrolidine derivative has an excellent action.

US Pat. No. 2,852,526 discloses a pyrrolidine derivative, which has a structure different from that of the compound of the present invention, and also has a bronchodilator action, an antihistamine action,
Only the description that it has an anticholinergic effect is significantly different from the efficacy of the compound of the present invention.

[0007] Phenodopam has been proposed as a compound having a renal vasodilatory action, but this compound is a benzazepine compound and has a structure different from that of the compound of the present invention.

Furthermore, Japanese Patent Laid-Open Nos. 2-288855 and 3-118361 disclose pyrrolidine derivatives as antihypertensive agents having an effect of increasing renal blood flow. Be different.

[0009]

The present invention is a pyrrolidine derivative represented by the following general formula (I) and a pharmaceutically acceptable salt thereof.

[0010]

[Chemical 3]

[Wherein Y is a group represented by the formula -NH-,
_{(CH 2) n - (.} N in the formula for an integer of 0, 1, 2) a group of the formula:

[0012]

[Chemical 4]

(In the formula, p means an integer of 0, 1, or 2) and means a group represented by the following formula. R ¹ and R ² are the same or different hydrogen atom, hydroxyl group, formula —SO ₂ NR ³ R ⁴
(In the formula, R ³ and R ⁴ represent a hydrogen atom, a lower alkyl group or an acyl group. Further, R ³ and R ⁴ may form a ring together with the nitrogen atom to which they are bonded. Or a group represented by the formula: —NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ are the same or different hydrogen atoms, alkylsulfonyl groups or acyl groups, provided that R ⁵ and R ⁶ are both hydrogen atoms). And R ⁵ and R ⁶ may form a ring together with the bonded nitrogen atom. However, R ¹ , R
^When both ² are a hydrogen atom or a hydroxyl group, and R ¹
When either one of R ² and R ² is a hydrogen atom and the other is a hydroxyl group, it is excluded. ]

The lower alkyl group in the definition of R ³ and R ⁴ is a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, n-butyl, Isopropyl, isobutyl, 1-methylpropyl,
It means tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl, n-hexyl and the like, and the most preferable examples include a methyl group and an ethyl group.

Further, the lower alkyl group may be substituted with a halogen atom such as trifluoromethyl.

[0016] R ^3, seen in the definition of R ⁴ "R ³ and R ⁴
May form a ring together with the nitrogen atom to which is bonded. Examples of the “” include a pyrrolidinyl group and a piperidinyl group.

In the alkylsulfonyl group found in the definitions of R ⁵ and R ⁶ , alkyl has the same meaning as the above lower alkyl group. Also, "R ⁵ and R ⁶ may form a ring together with the nitrogen atom to which they are bound"
The pyrrolidinyl group and the piperidinyl group can be cited as examples.

In the present invention, the pharmacologically acceptable salts include, for example, inorganic acid salts such as hydrochlorides, sulfates, hydrobromides and phosphates, formates, acetates and trifluoroacetates. And organic acid salts such as maleic acid salts, fumaric acid salts, tartaric acid salts, methanesulfonic acid salts, benzenesulfonic acid salts, and toluenesulfonic acid salts. It goes without saying that some compounds may form hydrates, which are within the scope of the present invention.

The compound of the present invention may have various isomers, as is clear from its chemical structural formula. That is, in addition to cis / trans stereoisomers, there are optical isomers such as d-form and l-form. It goes without saying that these isomers belong to the scope of the present invention.

Next, the main methods for producing the compound of the present invention will be described.

Production Method 1 The compound of the present invention has a cis form and a trans form as described above. The method of manufacturing the transformer body is as follows. (First step)

[0022]

[Chemical 5]

(In the series of formulas, Y, R ¹ and R ² have the same meanings as described above.) The compound represented by the general formula (II) and the β-nitroaryl represented by the general formula (III). By reacting with an ethene derivative,
This is a step of producing a compound represented by the general formula (IV).
This reaction is carried out according to a conventional method, for example, an ether solvent such as diethyl ether, tetrahydrofuran or diglyme, a hydrocarbon solvent such as benzene or toluene, a solvent such as N, N′-dimethylformamide or dimethyl sulfoxide, and a base. The reaction is carried out in the presence of. Specifically, one preferable example is to prepare lithium diisopropylamide with n-butyllithium and diisopropylamine in tetrahydrofuran at a low temperature, add a tetrahydrofuran solution of the compound represented by the general formula (IV), and then add The reaction is performed by allowing a tetrahydrofuran solution of the compound represented by the formula (V) to act. Formulas (II) and (IV)
In, R ⁷ means a hydroxyl-protecting group. Any group may be used as long as it can protect a hydroxyl group, but typical examples include lower alkyl groups such as methyl, ethyl, propyl and butyl, aralkyl groups such as benzyl and phenethyl, acetyl, propionyl and butyroyl. An acyl group such as pivaloyl, a tetrahydropyranyl group, and two R ^{7 s} may be combined to form an alkylene group such as a methylene group. The most preferred of these is a lower alkyl group such as a methyl group or an ethyl group, or two R ⁷ together form a methylene group,
That is, there may be mentioned a case where two R ⁷ 's together form methylenedioxy. Further, in the general formulas (II) and (IV), R ⁸ means a protecting group for a carboxyl group. Any group may be used as long as it can protect the carboxyl group, but typical examples thereof include lower alkyl groups such as methyl, ethyl, propyl and butyl, and aralkyl groups such as benzyl and phenethyl. . (Second step)

[0024]

[Chemical 6]

(In the formula, Y, R ¹ , R ² , R ⁷ and R ⁸ have the above-mentioned meanings.) Reduction or catalytic reduction of the nitro compound represented by the general formula (VI) with a metal or a metal salt. Is a step of obtaining an amino compound represented by the general formula (V). The metal or metal salt used is zinc, iron, stannous chloride or the like, and the catalyst used for catalytic reduction is palladium / carbon, platinum oxide, Raney nickel or the like. (Third step)

[0026]

[Chemical 7]

(In the series of formulas, Y, R ¹ , R ⁷ and R ⁸ have the above-mentioned meanings.) The compound represented by the general formula (V) may be used in the absence of a solvent or in an ordinary organic solvent with heating or This is a step of ring-closing by heating to obtain a 5-membered ring lactam represented by the general formula (VI). This reaction is usually an alcohol solvent such as methanol, ethanol or butanol, a halogenated alkyl solvent such as dichloromethane, chloroform, dibromoethane or dichloroethane, an ether solvent such as tetrahydrofuran or diglyme, N, N-dimethylformamide,
It is carried out in a solvent such as dimethyl sulfoxide. The ring-closed compound (VI) can be obtained without isolating the compound (V) by performing the reduction reaction of the nitro group in the second step at high temperature or in an autoclave at high temperature. (Fourth step)

[0028]

[Chemical 8]

(In the series of formulas, Y, R ¹ and R ⁷ have the above-mentioned meanings.) A mixture of cis and trans 5-membered lactams represented by the general formula (VI) is allowed to have a base in the presence or absence. Is a step of isomerizing the cis isomer contained in the organic solvent by heating in an organic solvent to obtain only the trans isomer represented by the general formula (VII).
As a specific preferred example, the reaction is carried out by heating in ethanol in the presence of potassium t-butoxide or a mixed solvent of ethanol-xylene, or in xylene in the presence of potassium trimethylsilanoate. (Fifth step)

[0030]

[Chemical 9]

(In the series of formulas, R ¹ , R ⁷ , and Y have the above-mentioned meanings.) The trans 5-membered ring lactam represented by the general formula (VII) is reduced with diborane or a metal-hydrogen complex compound to give a general formula (VIII)
Is a step of producing a pyrrolidine derivative represented by. As the metal hydrogenation compound, lithium aluminum hydride and sodium bis (2-methoxyethoxy) aluminum hydride are preferable, and ether solvents such as ether, tetrahydrofuran and diglyme, or aromatic hydrocarbons such as benzene, toluene and xylene. It is carried out in a system solvent. (Sixth step)

[0032]

[Chemical 10]

(In the series of formulas, R ¹ , R ⁷ , and Y have the above-mentioned meanings.) The compound represented by the general formula (VIII) is converted into boron tribromide, boron trichloride, hydrobromic acid, and iodide. In this step, the compound represented by the general formula (IX) is produced by removing the protecting group by treatment with hydrolic acid or another ether cleaving agent.

Manufacturing method 2

The compounds of the general formula (I) include d-form and l-form optical isomers in addition to cis and trans positional isomers. The optical isomers can be resolved by a conventional method, for example, a method of applying an optical isomer separation column such as a chiral column, (+)
-Tartaric acid, (+)-camphoric acid, (+)-dibenzoyltartaric acid, (+)-10-camphorsulfonic acid,
Examples thereof include a method in which a salt with an optically active acid such as (+)-mandelic acid is fractionally crystallized from a suitable solvent. Further, at the stage of the compound represented by the general formula (VIII) or a derivative thereof, the compound is optically resolved in the same manner as above, and subjected to the sixth step to give an optically active form of the compound represented by the general formula (I). Can be obtained.

Production Method 3 In the general formula (I), when Y is a group represented by the formula —CH ₂ —, that is, n = 1, it can be produced by the following method. (First step)

[0037]

[Chemical 11]

(In the series of formulas, X, R ¹ , R ² and R ⁷ are
It has the same meaning as above and G is a protecting group for the nitrogen atom of the amide. ) A step of protecting the nitrogen atom of the amide of the compound represented by the general formula (X). Examples of the protecting group for the nitrogen atom of the amide include a benzyl group, an acyl group and an alkoxyalkyl group which may have a substituent.
Of these, preferred groups include benzyl group, 3,4
Examples thereof include a dimethoxybenzyl group and a 3-methoxymethyl group. This step is carried out by a conventional method, but preferably, for example, the compound can be obtained by reacting a halide such as the above-mentioned optionally substituted benzyl group or acyl group with the compound (X). it can. This reaction is preferably performed in the presence of a base. As the base, for example, alkylammonium hydroxide such as tetrabutylammonium hydroxide, tertiary amine, metal hydride such as sodium hydride and the like are used. At this time, as the solvent, for example, tetrahydrofuran, ether, benzene, toluene, xylene and the like are preferably used. (Second step)

[0039]

[Chemical 12]

(In the series of formulas, R ¹ , R ⁷ and G have the above-mentioned meanings.) In this step, a substituent is introduced at the α-position of the carbonyl group of the compound represented by the general formula (XI). Specific preferred examples include the compound represented by the general formula (XI) in the presence of lithium diisopropylamide or sodium hydride in tetrahydrofuran, represented by the general formula R-CH ₂ -Z (wherein Z is halogen,
It means a leaving group such as a toluenesulfonyloxy group. ) Is added to carry out the reaction. (Third step)

[0041]

[Chemical 13]

(In the series of formulas, R ¹ , R ⁷ and G have the above-mentioned meanings.) The reaction is carried out according to the method of the fourth step described in the manufacturing method 1. That is, a mixture of cis and trans 5-membered ring lactams represented by the general formula (XII) is heated in an organic solvent in the presence or absence of a base to isomerize the cis isomer, In this step, only the trans form represented by (XIII) is obtained. To give a concrete example,
The reaction is carried out by heating in a mixed solvent of ethanol or ethanol xylene in the presence of potassium t-butoxide, or in xylene in the presence of potassium trimethylsilanolate. (Fourth step)

[0043]

[Chemical 14]

(In the series of formulas, R ¹ , R ⁷ , and G have the above-mentioned meanings.) The reaction is carried out according to the method of the fifth step detailed in Production Method 1. That is, the transformer 5 represented by the general formula (XIV)
This is a step of producing a pyrrolidine derivative represented by the general formula (XV) by reducing a membered ring lactam with diborane and a metal hydrogen complex compound. As the metal complex compound, lithium aluminum hydride and sodium bis (2-methoxyethoxy) aluminum hydride are preferable, and ether solvents such as ether, tetrahydrofuran and diglyme, or aromatic hydrocarbon solvents such as benzene, toluene and xylene. Done in. (Fifth step)

[0045]

[Chemical 15]

(In the series of formulas, R ¹ , R ⁷ and G have the above-mentioned meanings.) In this step, the protecting group introduced in the first step is removed. First
Although the content varies depending on the reaction reagent used in the step, for example, when benzyl halide is used in the first step, hydrogenation is carried out under a metal catalyst such as palladium / carbon or Raney nickel. Moreover, this process can be performed simultaneously with the following 6th process depending on the case. (Sixth step)

[0047]

[Chemical 16]

(In the series of formulas, R ¹ and R ⁷ have the above-mentioned meanings.) The reaction is carried out according to the method of the 6th step described in detail in Production Method 1. That is, the compound represented by the general formula (XVI) is treated with boron tribromide, boron trichloride, hydrobromic acid, hydroiodic acid or other ether cleaving agent to remove the protecting group, This is a step of producing a compound represented by XVII).

Production Method 4 As a method for obtaining an optically active compound of the general formula (I),
Although a method of optically resolving the racemate of the target compound in the final step as shown in Production Method 2 is also used, it is possible to obtain the desired optically active compound by optically resolving it as an intermediate as shown below. A method of obtaining the target compound using the body is also effective. (First step)

[0050]

[Chemical 17]

(In the formula, R ⁹ means a carboxylic acid protecting group.) That is, a compound represented by the general formula (XVIII) is reacted with a malonic acid ester derivative represented by the general formula (XX). Is a step of producing a compound represented by the general formula (XIX). This reaction is carried out according to a conventional method, for example, an ether solvent such as diethyl ether, tetrahydrofuran or diglyme, a hydrocarbon solvent such as benzene or toluene, N,
The reaction is carried out in the presence of a base using a solvent such as N'-dimethylformamide or dimethyl sulfoxide. As a specific preferred example, a tetrahydrofuran solution of the compound represented by the general formula (XXII) is allowed to act on sodium hydride in tetrahydrofuran at low temperature, and then a tetrahydrofuran solution of the compound represented by the general formula (XXII) is added. React to carry out the reaction.

In the compound represented by the general formula (XXII), R ⁹ represents a carboxylic acid protecting group. Any group may be used as long as it can protect a hydroxyl group, but typical examples include lower alkyl groups such as methyl, ethyl, propyl and butyl, aralkyl groups such as benzyl and phenethyl, acetyl, propionyl and butyroyl. An acyl group such as pivaloyl, a tetrahydropyranyl group, and two R ^{9 s} may be combined to form an alkylene group such as a methylene group. The most preferred of these is a lower alkyl group such as a methyl group or an ethyl group, or two R ⁹ together form a methylene group,
That is, the case where two R ^9's are taken together to form methylenedioxy can be mentioned.

(Second step)

[0054]

[Chemical 18]

(In the series of formulas, R ⁹ has the above-mentioned meaning.) This is a reaction for synthesizing 3-substituted pyrrolidone by reductive cyclization of a nitroester represented by the general formula (XIX). The reaction is carried out by a conventional method. For example, the general formula
(XIX) nitroester under high temperature, or
This is a method for obtaining 3-substituted-pyrrolidone by performing reduction or catalytic reduction using a metal or a metal salt in an autoclave at high temperature. The metal or metal salt used is preferably zinc, iron, stannous chloride or the like, and the catalyst used for catalytic reduction is palladium / carbon, platinum oxide, Raney nickel or the like.

The reaction proceeds without solvent, but when a reaction solvent is used, an alcohol solvent such as methanol, ethanol, butanol, a halogenated alkyl solvent such as dichloromethane, chloroform, dibromoethane, dichloroethane, tetrahydrofuran, diglyme, etc. The ether solvent, N, N-dimethylformamide, dimethylsulfoxide, etc. can be used. (Third step)

[0057]

[Chemical 19]

(In the series of formulas, R ⁹ has the above-mentioned meaning.) That is, it is a reaction for deprotecting the carboxylic acid of the compound (XXI) obtained in the second step. Although the reaction varies depending on the protecting group R ⁹ of the carboxylic acid, the purpose can be achieved by a commonly used method such as hydrolysis or hydrogenation. For the hydrolysis, a basic aqueous solution such as sodium hydroxide or an acid such as hydrochloric acid can be used. In the case of a substituted benzyl type protecting group, hydrogenation in various solvents in the presence of a catalyst such as palladium / carbon or platinum oxide is particularly useful. Further, a method of removing the protective group after conversion is also effective. (Fourth step)

[0059]

[Chemical 20]

That is, the compound (XXI obtained in the third step
It is a step of optically resolving I) using an optically active base.
The resolving agent is not particularly limited, such as optically active α-phenethylamine, brucine, cinchonine, cinchonidine, and ephedrine, but preferably (-) or (+) aminodiphenylethanol is allowed to act in hydrous ethanol. Can be mentioned. (Fifth step)

[0061]

[Chemical 21]

The optically active compound (XXI
This is a step of synthesizing 3-alkoxycarbonylpyrrolidone by esterifying II). R ¹⁰ represents a protecting group for carboxylic acid, and is preferably a lower hydrocarbon such as methyl, ethyl or propyl, or a group such as a substituted benzyl. An alcohol corresponding to these groups and a compound (XXI
II) is dehydrated and condensed by a general method such as a DCC method or a DPC method to synthesize an ester. (Sixth step)

[0063]

[Chemical formula 22]

The compound (XXIII) obtained in the fifth step has the formula

[0065]

[Chemical formula 23]

(In the formula, Q means a leaving group. R ¹ and R
² has the meaning given above. R ¹¹ means a protective group for a hydroxyl group. ) Is a step of introducing an aralkyl group. The reaction can be carried out in the presence of a base, but as a preferred base, any organic base not involved in the reaction,
For example, an alkali metal hydride such as sodium hydride,
In addition to sodium methylate, metal alcoholate such as potassium t-butoxide, tertiary amine, lithium diisopropylamide, and the like, any inorganic base that does not participate in the reaction, such as potassium carbonate, can be used.
As the reaction solvent, any organic solvent that does not participate in the reaction can be used, and examples thereof include dimethylformamide, DMSO, tetrahydrofuran, dioxane, ethyl ether and the like. The hydroxyl-protecting group represented by R ¹¹ is preferably a lower alkyl group such as methyl, ethyl, propyl or butyl, an aralkyl group such as benzyl or phenethyl, or an acyl group such as acetyl, propionyl, butyroyl or pivaloyl. be able to. (Seventh step)

[0067]

[Chemical formula 24]

(In the series of formulas, R ¹ , R ² , R ¹⁰ , R
¹¹ has the meaning given above. ) A step of removing the alkoxycarbonyl group of the pyrrolidone derivative obtained in the sixth step by a usual method. A method of hydrolyzing with an aqueous solution of sodium hydroxide, followed by acid treatment, followed by decarboxylation, a method of heating in acetic acid-sulfuric acid, or a method of hydrogenating and acid treatment if R ¹⁰ is a substituted benzyl group. And so on. (Eighth process)

[0069]

[Chemical 25]

(In the series of formulas, R ¹¹ has the above-mentioned meaning.) The reaction is carried out according to the method of the fourth step described in the manufacturing method 1. That is, the mixture of five-membered ring lactam represented by the general formula (XVII) is heated in an organic solvent in the presence or absence of a base to isomerize the cis isomer, and represented by the general formula (XXIX). This is a process of obtaining only the trans form.
Specifically, preferred examples include heating in ethanol or a mixed solvent of ethanol-xylene in the presence of potassium t-butoxide to carry out the reaction, or heating in xylene in the presence of potassium trimethylsilanoate to carry out the reaction. Alternatively, heating is performed in methanol in the presence of sodium hydroxide. (9th step)

[0071]

[Chemical formula 26]

(In the series of formulas, R ¹ , R ² and R ¹¹ have the above-mentioned meanings.) The reaction can be carried out according to the method of the fifth step described in detail in Production Method 1. That is, it is a step of producing a pyrrolidine derivative represented by the general formula (XXX) by reducing the trans five-membered ring lactate represented by the general formula (XXIX) with diborane and a metal hydrogen complex compound. The metal hydrogen complex compound is preferably lithium aluminum hydride or sodium bis (2-methoxyethoxy) aluminum hydride, an ether solvent such as ether, tetrahydrofuran or diglyme, or an aromatic hydrocarbon such as benzene, toluene or xylene. It is carried out in a system solvent. (10th process)

[0073]

[Chemical 27]

(In the series of formulas, R ¹ , R ² and R ¹¹ have the above-mentioned meanings.) The reaction can be carried out according to the method of the sixth step described in Preparation Method 1. That is, the compound represented by the general formula (XXX) is treated with boron tribromide, boron trichloride, hydrobromic acid, hydroiodic acid or another ether cleaving agent to remove the protecting group, and then the general formula ( This is a step of producing the target compound represented by XXXI).

Next, in order to show the effect of the present invention, examples of pharmacological experiments are listed. Pharmacological experiment example Experimental example 1 D1 and D2 receptor binding in rat brain striatum
Examination

1. Experimental method Rat brain striatum was extracted and homogenized with 0.05M Tris buffer,
The synaptosome fraction was collected by centrifugation at 20000 × g. This precipitate was added to 0.25M Tris buffer (1
20 mM NaCl, 5 mM KCl, 2 mM CaC
1 ₂ , containing 1 mM MgCl ₂ ), dispensed and stored frozen at −80 ° C. ³ H-Sch233 in D1
90 (final concentration 0.2 nM) was added along with the sample 37
Incubation at 15 ° C for 15 minutes, filtration through Whatman GF / B filter, and measurement with liquid scintillation counter. For the measurement of non-specific binding, SKF-82526
And Spiperone were used respectively. IC ₅₀ is a specific amount, that is, S labeled with a radioisotope
50% each with ch23390 and Spiperone
It was determined as the concentration of the test substance that was displaced.

The following substances were used as test substances. Compound A: (-)-trans-3- (3-aminosulfonyl-2,6-dihydroxyphenyl) methyl-4-
(3,4-Dihydroxyphenyl) pyrrolidine hydrochloride Compound B: (−)-trans-3- (5-aminosulfonyl-2-hydroxyphenyl) methyl-4- (3,4
-Dihydroxyphenyl) -pyrrolidine hydrochloride Compound C: trans-3- (5-aminosulfonyl-2)
-Hydroxyphenyl) methyl-4- (3,4-dihydroxyphenyl) -pyrrolidine hydrobromide Compound D: trans-3- (3-aminosulfonyl-
2,6-dihydroxyphenyl) methyl-4- (3,4
-Dihydroxyphenyl) -pyrrolidine hydrobromide Compound E: trans-3- (3,4-dihydroxyphenyl) -4- (2-hydroxyphenyl-5-methanesulfonylamino-2-hydroxyphenyl) methyl-pyrrolidine Odor Hydrohydride Compound F: trans-3- (3,4-dihydroxyphenyl) -4- (2-hydroxyphenyl-5-methylaminosulfonyl) methyl-pyrrolidine hydrobromide 1. Experimental Results The above results are shown in Table 1.

[0078]

[Table 1]

Experimental Example 2 On Circulatory Dynamics in Anesthetized Dogs
Action 1. Test method Hybrids weighing about 10 kg were treated with thiopental sodium 20
After anesthesia induction with mg / kg (iv), a tube was inserted during the period, and artificial respiration and anesthesia were maintained with oxygen-smile-enflurane. (Acoma ventilator ARF-
850E, Acoma anesthesia app
arterus EM-A). The aortic pressure and the left ventricular pressure were measured with a catheter-type pressure transducer (MPC-500, Miller) inserted from the aorta.
The renal blood flow was measured by exposing the renal artery by a flank incision and mounting a probe of an electromagnetic blood flow meter (MFV-2100, Nihon Kohden). All the above measured values were recorded using a polygraph system (RM-600000, Nihon Kohden). The sample was dissolved in 0.9% physiological saline and administered through a catheter inserted into the elbow artery. In addition, in the experiment of intraduodenal administration, the duodenum was exposed by a midline abdominal incision, a minute incision was made, and the sample was administered through the inserted catheter.

2. Experimental Results In Table 2 below, the increase in renal blood flow or the decrease in mean blood pressure with respect to the pre-administration control of the test compound of the present invention is shown by the change rate. Further, the compounds in the table are the same as those in Experimental Example 1 above.
Has the same meaning as used in.

[0081]

[Table 2]

From the results of the above-mentioned pharmacological experiment examples, the compound of the present invention has a high affinity for dopamine I receptor, stimulates dopamine I receptor, and has a clear hypotensive action, renal blood flow increasing action, and heart failure improvement. It has been clarified that it has an action. The compound of the present invention is desirable as an antihypertensive agent, and has a hypotensive action based on a vasodilatory action, a renal blood flow increasing action, and a diuretic action,
Furthermore, since it has low toxicity and high safety, it can be said to be a preferable compound as an antihypertensive agent or a heart failure therapeutic agent. Therefore, the compound of the present invention is useful as a prophylactic / therapeutic agent for various hypertensions such as essential hypertension and renal hypertension, and also as a prophylactic / therapeutic agent for heart failure.

When the present invention is used as these medicines, it can be administered orally or parenterally. Dosage depends on the symptoms and the degree of the patient, age, sex, weight of the patient, difference in sensitivity to drugs, administration method,
Timing of administration, interval between administrations, type and nature of pharmaceutical preparation,
It is not particularly limited depending on the types of other agents to be administered at the same time. As an example, in the case of oral administration, it is usually 1
Approximately 1 to 1000 mg per day is administered once or several times in divided doses. In the case of injection, usually about 0.3 μg / kg-100
μg / kg.

In formulating, an ordinary preparation alone is used and the preparation is carried out by a conventional method. That is, when preparing a solid preparation for oral use, after adding the excipient of the main drug, if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent, etc., a tablet by a conventional method, Coated tablets, granules, powders, capsules, etc.

Examples of the excipient include lactose, corn starch, sucrose, glucose, sorbit, crystalline cellulose,
Silicon dioxide or the like, as the binder, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose,
Methylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate, dextrin, pectin and the like, and examples of lubricants include magnesium stearate, talc, polyethylene glycol, silica, hardened vegetable oil and the like. However, as the coloring agent, those that are allowed to be added to pharmaceuticals, as the flavoring agent, cocoa powder, peppermint brain, aromatic acid, peppermint oil, Borneolum, Keihi powder, etc. are used. tablet,
The granules may of course be sugar-coated, gelatin-coated or any other suitable coating, if desired. When preparing an injection, a pH adjuster, a buffer, a stabilizer, a solubilizer, etc. are added to the main drug as necessary, and subcutaneous, intramuscular, or intravenous injection is prepared by a conventional method.

[0086]

EXAMPLES Examples are given below to facilitate understanding of the present invention, but it goes without saying that the present invention is not limited thereto. In addition, prior to Examples, Production Examples of starting compounds of the compounds of the present invention will be shown.

Production Example 1 Ethyl 2-methoxyphenylpropenoate

[0088]

[Chemical 28]

18.53 g of 60% sodium hydride was suspended in 200 ml of tetrahydrofuran, and carboxymethylphosphonic acid triethyl ester was slowly added at 400 ° C. with 400 ml of tetrahydrofuran. 3 at room temperature
After stirring for 0 minutes, 100 g of 2-methoxybenzaldehyde was dissolved in 400 ml of tetrahydrofuran and added. The mixture was stirred as it was at room temperature for 1 hour, and the reaction solution was concentrated. Water and dichloromethane were added, the target compound was extracted into the dichloromethane layer, washed with brine, dried over sodium sulfate, and concentrated. The residue was subjected to vacuum distillation to give the title compound 14
4.1 g was obtained.

-Yield 95% -b. p. 172-174 ° C

NMR (400 MHz, CDCl ₃ )
δ; 1.33 (3H, t, J = 1.8Hz) 3.86 (3H, s) 4.25 (2H, q, J = 7.1,
14.3Hz) 6.52 (1H, d, J = 16.1Hz) 6.89 (1H, dd, J = 0.7,8.4Hz) 6.94 (1H, ddd, J = 1.1,7.6,7.6Hz) 7.32 (1H, ddd, J = 1.8, 8.
4,8.4Hz) 7.49 (1H, dd, J = 1.8,7.6Hz)

Production Example 2 Ethyl 2-methoxyphenylpropenoate

[0093]

[Chemical 29]

144.1 g of ethyl 2-methoxyphenylpropenoate obtained in Preparation Example 1 was dissolved in 1 liter of methanol, and 10 g of palladium-carbon (containing water) was added,
Hydrogenated at room temperature and atmospheric pressure. After 4 hours, the catalyst was removed, the reaction solution was concentrated, and then distilled under reduced pressure to obtain 143.6 g of ethyl 2-methoxyphenylpropionate.

-Yield 99% -b. p. 149-151 ° C

NMR (CDCl ₃ ) δ; 1.23 (3H, t, J = 7.1Hz) 2.60 (2H, t, J = 7.8Hz) 2.94 (2H,
t, J = 7.8Hz) 3.82 (3H, s) 4.12 (2H, dd, J = 7.1,14.3Hz) 6.84 (1Hz, dd,
J = 1.1,8.1Hz) 6.87 (1H, ddd, J = 1.1,7.3,7.3Hz) 7.14 (1Hz, dd, J = 1.7,
7.3Hz) 7.19 (1H, ddd, J = 1.7,8.1,8.1Hz)

Production Example 3 5-chlorosulfonyl-2-methoxyphenylpropio
Ethyl acid

[0098]

[Chemical 30]

102.2 g of ethyl 2-methoxyphenylpropionate obtained in Preparation Example 2 was dissolved in 500 parts of chloroform.
Dissolve in ml and chlorosulfonic acid 127.75 at 0-5 ° C.
ml was added. After stirring at room temperature for 3 hours, the mixture was poured into ice water and the chloroform layer was separated. The aqueous layer was extracted with ethyl ether, the chloroform layer was concentrated, water and ethyl ether were added, and the ethyl ether layer was separated. Ether layer with water,
The extract was washed successively with sodium hydrogen carbonate and saturated brine, dried over sodium sulfate and concentrated to give the title compound (139.0 g).

-Yield 99%

NMR (CDCl ₃ ) δ; 1.25 (3H, t, J = 7.1Hz) 2.64 (2H, t, J = 7.7Hz) 3.01 (2H,
t, J = 7.7Hz) 3.96 (3H, s) 4.13 (2H, q, J = 7.1,14.3Hz) 6.98 (1H, d, J
= 8.8Hz) 7.83 (1H, d, J = 2.6Hz) 7.91 (1H, dd, J = 2.6,8.8Hz)

Production Example 4 5-Aminosulfonyl-2-methoxyphenylpropio
Ethyl acid

[0103]

[Chemical 31]

139 g of ethyl 5-chlorosulfonyl-2-methoxyphenylpropionate obtained in Preparation Example 3 was dissolved in 100 ml of dioxane and added to 500 ml of aqueous ammonia. After stirring at an external temperature of 60 ° C. for 30 minutes, the reaction solution was concentrated. Water and dichloromethane were added, and the target compound was extracted into dichloromethane. The dichloromethane layer was separated, washed successively with water and sodium chloride, and dried over sodium sulfate. The dichloromethane layer was concentrated and then purified by silica gel chromatography to obtain 113.7 g of the title compound.

-Yield 82%

NMR (CDCl ₃ ) δ; 1.23 (3H, t, J = 7.1Hz) 2.59 (2H, t, J = 7.5Hz) 2.94 (2H,
t, J = 7.5Hz) 3.89 (3H, s) 4.11 (2H, q, J = 7.1,14.3Hz) 5.25 (2H, s) 6.90 (1H, d, J = 8.8Hz) 7.72 (1Hz, d, J = 2.4Hz) 7.78 (1H, d
(d, J = 2.4,8.8Hz)

Production Example 5 3- (5-Aminosulfonyl-2-methoxyphenylene)
Chill) -2- (3,4-dimethoxyphenyl) -4-ni
Trobuchirate

[0108]

[Chemical 32]

85.4 ml of diisopropylamine was added to 300 ml of tetrahydrofuran, and 224.4 ml of a 2.5 mol n-butyllithium / hexane solution was aerated with nitrogen gas.
Added at -70 ° C. After stirring for 30 minutes at the same temperature, HMPA18
1 ml was added, and the mixture was stirred at the same temperature for 20 minutes. At -70 ° C, 46 g of ethyl 5-aminosulfonyl-2-methoxyphenylpropionate obtained in Preparation Example 4 was added to tetrahydrofuran 3
After dissolving in 00 ml and adding, and stirring at the same temperature for 1 hour, 2-
(3,4-dimethoxyphenyl) nitroethene 33.5
g using tetrahydrofuran (500 ml) -70 to -5
The mixture was added at 0 ° C and then stirred at room temperature for 1 hour. The reaction was stopped by making it acidic with concentrated hydrochloric acid, and then concentrated. Ethyl acetate and water were added, and the target compound was extracted into the ethyl acetate layer, washed three times with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Purification by silica gel chromatography gave 51.6 g of the title compound.

-Yield 65%

Production Example 6 3- (5-aminosulfonyl-2-methoxyphenyl)
Methyl-4- (3,4-dimethoxyphenyl) -2-pi
Loridon

[0112]

[Chemical 33]

3- (5-aminosulfonyl-2-methoxyphenylmethyl) -2- (3,4 obtained in Preparation Example 5
75 g of trobutylate to -dimethoxyphenyl) -4-
Was dissolved in 600 ml of ethanol, 250 ml of concentrated hydrochloric acid was added, and then 85.2 g of zinc was added while paying attention to generation of hydrogen and heat generation. The mixture was heated under reflux for 2.5 hours, allowed to cool to room temperature, and then zinc was filtered. When the reaction solution was concentrated and made alkaline with dilute sodium hydroxide, a large amount of zinc hydroxide was precipitated, so this was filtered through Celite and the filtrate was adjusted to pH 9-10. When the reaction solution became cloudy, extracted with ethyl acetate,
It was washed with water and saturated saline. After drying with sodium sulfate,
Concentrated. To this, 1 liter of xylene was added, further heated at an external temperature of 140 to 160 ° C. for 6 hours, allowed to cool to room temperature, and acidified with concentrated hydrochloric acid. The reaction mixture was concentrated, ethyl acetate and water were added, the ethyl acetate layer was separated, washed with water and saturated brine, dried over sodium sulfate, concentrated, and purified by silica gel chromatography. 30.0 g of the title compound was obtained.

-Yield 49%

NMR (CDCl ₃ ) δ; 2.68 (1H, dd, J = 8.6Hz, 16.1Hz) 3.07 to 3.33 (4H, m)
3.50 ~ 3.57 (1H, m) 3.70 (3H, s) 3,80 (3H, s) 3.81 (3H, s) 5.19 (2H, s)
6.19 (1H, s) 6.52 (1H, dd, J = 2.5Hz) 6.59 (1H, dd, J = 2.5,8.6Hz) 6.64
(1H, d, J = 9.2Hz) 6.67 (1H, d, J = 8.6Hz) 7.62 (1H, dd, J = 2.7,9.2Hz) 7.65
(1H, d, J = 2.7Hz)

Production Example 7 3- (5-aminosulfonyl-2-methoxyphenyl)
Methyl-4- (3,4-dimethoxyphenyl) pyrrolidi
The

[0117]

[Chemical 34]

3- (5-Aminosulfonyl-2-methoxyphenyl) methyl-4- (3,4) obtained in Preparation Example 6
1.1 g of -dimethoxyphenyl) -2-pyrrolidone was dissolved in 58.7 ml of tetrahydrofuran, 58.7 ml of a 1N borohydride / tetrahydrofuran solution was added, and the mixture was heated under reflux with nitrogen gas for 4 hours. 120 ml of 6N hydrochloric acid was added while paying attention to the generation of hydrogen, and the mixture was heated under reflux for 1 hour. The reaction solution was concentrated, and diluted aqueous sodium hydroxide was added thereto, and the solution became cloudy at pH 1, so it was extracted with dichloromethane. If more sodium hydroxide water is added, the pH will be 9
Since it became cloudy at -10, it was extracted with dichloromethane, and this extract alone was washed with saturated brine, dried over magnesium sulfate, and concentrated to obtain 2.6 g of the title compound.

-Yield 67%

NMR (CDCl ₃ ) δ; 2.60 to 2.90 (4H, m) 3.25 (1H, m) 3.14 (1H, m) 3.56
~ 3.70 (2H, m) 3.77 (3H, s) 3.83 (3H, s) 3.84 (3H, s) 6.68 (1H, d, J
= 1.7Hz) 6.72 to 6.77 (3H, m) 7.62 (1H, d, J = 2.6Hz) 7.67 (1H, d
(d, J = 2.6,8.6Hz)

Example 1 (±) -trans-3- (5-aminosulfonyl-2-
Hydroxyphenyl) methyl-4- (3,4-dihydro)
(Xyphenyl) pyrrolidine hydrobromide

[0122]

[Chemical 35]

3- (5-Aminosulfonyl-2-methoxyphenyl) methyl-4- (3,4) obtained in Preparation Example 7
2.55 g of -dimethoxyphenyl) pyrrolidine were dissolved in a little dichloromethane and 200 ml of 1N boron tribromide / dichloromethane was added. After stirring overnight at room temperature under aeration of nitrogen gas, the mixture was slowly poured into methanol to stop the reaction. The reaction solution was concentrated and then purified by ODS column chromatography. 1.2 g of the title compound was obtained.

-Yield 41% -MASS MH ⁺ (365)

NMR (D ₂ O) δ (ppm): 2.46 to 2.55 (1H, m) 2.74 to 3.06 (5H, m) 3.48 to 3.62
(2H, m) 6.40 (1H, dd, J = 2.5,8.1Hz) 6.44 (1H, d, J = 2.5Hz) 6.50
(1H, d, J = 8.1Hz) 6.55 (1H, d, J = 8.6Hz) 7.28 (1H, dd, J = 2.5,8.6Hz) 7.32
(1H, d, J = 2.5Hz)

Example 2 (±) -trans-3- (5-aminosulfonyl-2-
Hydroxyphenyl) methyl-4- (3,4-dihydro)
Xyphenyl) pyrrolidine hydrochloride

[0127]

[Chemical 36]

Chloride ion exchanger (TSK gel; TOYO
750 ml of PEAL) was filled in a column tube in a water suspension state, and purified (±) -trans-3-obtained in Example 1 was used.
30 ml of an aqueous solution of 13.4 g of (5-aminosulfonyl-2-hydroxyphenyl) methyl-4- (3,4-dihydroxyphenyl) pyrrolidine hydrobromide was charged. It was washed 3 times with 10 ml of water and further eluted with water. Confirm the eluate with high performance liquid chromatography for each fraction,
The aqueous solution of the eluate is collected except the impurities that appear first, the water is concentrated under reduced pressure at 40 ° C. or lower, water is further added, and the water is concentrated under reduced pressure. Yield 8.373g.

・ Yield 69% ・ MASS (FAB) 365 (M + 1) ・ Elemental analysis C ₁₇ H ₂₀ N ₂ O ₅ S.HCl ・ 0.7 H ₂ O

[0130]

[Table 3]

NMR (D ₂ O) δ (ppm) 2.83 (1H, dd, J = 0.3,5.1Hz) 3.11 (1H) 3.13 (1H)
3.20 ~ 3.35 (3H) 3.84 (1H, dd, J = 7.3,11.2Hz) 3.88 (1H, dd, J = 7.3,11.7Hz) 6.73 (1H, dd, J = 2.0,8.3Hz) 6.76 (1H, d , J = 2Hz) 6.82 (1
H, d, J = 8Hz) 6.87 (1H, d, J = 8.3Hz) 7.60 (1H, dd, J = 2.4,8.3Hz) 7.63
(1H, d, J = 2.4Hz)

Example 3 (-)-trans-3- (3-aminosulfonyl-2,
6-dihydroxyphenylmethyl) -4- (3,4-di
Hydroxyphenylmethyl) -4- (3,4-dihydro
(Xyphenyl) pyrrolidine hydrobromide

[0133]

[Chemical 37]

(1) 3-chlorosulfonyl-2,6-
Production of dimethoxytoluene

[0135]

[Chemical 38]

To a solution of 100 g of 2,6-methoxytoluene in chloroform (1.71 l) was added 262 ml of chlorosulfonic acid at 6 to 11 ° C. over 30 minutes. After the dropping is completed, the cold bath is removed and the temperature is slowly raised. After about 40 minutes, the reaction solution was added to 2 l of ice and extracted with dichloromethane. After adding magnesium sulfate and drying, filtration with Celite and concentration were performed to obtain crude crystals. Recrystallization from dichloromethane-hexane gave 171 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ; 2.21 (3H, s) 3.94 (3H, s) 3.97 (3H, s) 6.73 (1H, d, J
= 9Hz) 7.81 (1H, d, J = 9Hz)

(2) 1-Bromomethyl-3-chloros
Production of Ruphonyl-2,6-dimethoxybenzene

[0139]

[Chemical Formula 39]

To 171 g of the compound obtained in (1) were added 121.4 g of N-brocosuccinimide and 4.4 g of benzoyl peroxide, 1.58 l of carbon tetrachloride and 0.1 g of chloroform.
Mix in 47 liters and heat to reflux for 3 hours. After cooling, unnecessary substances were removed with a glass filter G4 and concentrated. 500 ml of carbon tetrachloride was added to the residue, unnecessary substances were removed again, and the mixture was concentrated to obtain 242.7 g of crude crystals of the title compound.

¹ H-NMR (CDCl ₃ ) δ; 4.05 (3H, s) 4.20 (3H, s) 4.59 (2H) 6.81 (1H, d, J = 9
Hz) 7.96 (1H, d, J = 9Hz)

(3) 3-Aminosulfonyl-2,6-
Preparation of dimethoxy-benzyl bromide

[0143]

[Chemical 40]

A solution of concentrated aqueous ammonia (141 ml) and water (141 ml) was added dropwise to a solution of the bromide obtained in (2) in tetrahydrofuran (670 ml) at 5 to 10 ° C over 1.5 hours. Concentrated ammonia water (40 ml), water (40 ml)
Was further added and the mixture was stirred for 10 minutes. After the reaction was completed, 2N hydrochloric acid (400 ml) was added to adjust the pH to 1 and the mixture was extracted with dichloromethane, washed with 1 l of brine and concentrated. 500 ml of isopropyl alcohol was added to the residue, and the precipitated crystals were collected by filtration,
138 g of the title compound are obtained.

¹ H-NMR (CDCl ₃ ) δ; 3.98 (3H, s) 4.15 (3H, s) 4.58 (2H, s) 5.04 (2H, br-
s) 6.76 (1H, d, J = 9Hz) 7.87 (1H, d, J = 9Hz)

(4) 2- (3,4-methylenedioxy
Production of phenyl) -1-nitroethene

[0147]

[Chemical 41]

1310 ml of an ethanol solution of 21% sodium methoxide was dissolved in 2500 ml of ethanol, and
Diethylmalonic acid (561.7 g) was added at -5 ° C, and the mixture was stirred at the same temperature for 30 minutes. 62.52 g of 2- (3,4-methylenedioxyphenyl) -1-nitroethene was rapidly added as a crystal so that the reaction solution kept at 0 to 5 ° C, and stirred at room temperature for 1 hour. After filtering a small amount of unnecessary substances,
800 ml of normal hydrochloric acid water was slowly added, and the precipitated crystals were collected by filtration to obtain 973 g of white crystals as an adduct.

(5) 3-Ethoxycarbonyl-4-
(3,4-methylenedioxyphenyl) -2-pyrrolide
Manufacturing

[0150]

[Chemical 42]

390.7 g of the adduct obtained in (4), 675 ml of concentrated hydrochloric acid and 3910 ml of ethanol were mixed and suspended, and 362 g of zinc was added little by little while cooling with stirring.
After keeping the reaction temperature at 40 to 60 ° C. for 1 hour, the temperature is kept at room temperature for 15 hours.
Stir for hours. After filtering unnecessary substances such as zinc, the filtrate was concentrated. The concentrated product was extracted with ethyl acetate. It was extracted with ethyl acetate. The ethyl acetate solution was mixed with 750 ml of saturated potassium carbonate solution, 950 ml of 0.3N aqueous sodium hydroxide,
The extract was washed successively with 950 ml of water and 950 ml of saturated saline, dried over sodium sulfate and concentrated. Concentrate is 1 liter of isopropyl ether
The crystals were washed with water to obtain 235 g of the title compound as white crystals.

(6) 3-benzyloxycarbonyl-
4- (3,4-methylenedioxyphenyl) -2-pyro
Redon production

[0153]

[Chemical 43]

43.77 g (1.58 mol) of the ethyl ester obtained in (5) in 2.18 l of benzyl alcohol.
And 54.6 ml (0.266 mol) of tetraethoxy titanium were added and heated at 100 to 110 ° C. for 3 hours. During the reaction, the pressure was reduced to 80 to 150 mmHg, and the produced ethanol was distilled off. The reaction solution was cooled, about 5.0 l of 5% hydrous diethyl ether was added, the mixture was stirred well, and the precipitated white crystals were collected by filtration. It was dissolved in about 10 l of dichloromethane, unnecessary inorganic salts were filtered off with Celite, and the filtrate was concentrated. The precipitated crystals were washed with isopropyl ether and collected by filtration to give the title compound (404.9 g).

¹ H-NMR (DMSO-d ₆ ) δ; 3.19 (1 H, t, J = 9 Hz) 3.46 (1 H, d, J = 9 Hz) 3.54 (1 H, t, J =
9Hz) 3.79 (1H, q, J = 9Hz) 5.98 (2H, s) 6.77 (1H, dd, J = 2,8H
z) 6.85 (1H, d, J = 8Hz) 7.00 (1H, d, J = 2Hz) 8.04 (1H, s)

(7) 3-carboxyl-4- (3,4
-Methylenedioxy) -2-pyrrolidone optical resolution

[0157]

[Chemical 44]

70 g of dl body obtained in (6) (280 mmo
1), 60.5 g (284 mmol) of (1R, 2S) -2-amino-1,2-diphenylethanol was dissolved in hot ethanol (2240 ml) -water (1400 ml), seeded and left at room temperature for 4 hours. . The precipitated crystals were collected by filtration, washed with a small amount of 50% ethanol, and dried at 50 ° C. overnight to obtain 54.04 g of a salt of the title compound. This salt 39
9.63 g of water, about 3.5 l of water, and about 0.3 l of 6N hydrochloric acid were vigorously stirred at room temperature for 2 hours. The crystals were collected by filtration, washed thoroughly with water, and dried at 50 ° C. for 2 days to give the desired optically active compound 22.
4.75 g were obtained.・ Optical purity 97.5% ee

(8) 3-benzyloxy-4- (3,3
Preparation of 4-methylenedioxyphenyl) -2-pyrrolidone
Construction

[0160]

[Chemical formula 45]

150.0 g (6) of the compound obtained in (7)
72.4 ml (722.9 mmol) of benzyl alcohol, 44.64 g (301.2 mmol) of 4-pyrrolidinopyridine and 136.5 g (66) of dicyclohexylcarbodiimide are added to a suspension of 02.4 mmol) in 3.0 l of dichloromethane.
2.6 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate was mixed with 2N hydrochloric acid (500 ml x 2) and water (500 ml).
ml), saturated sodium hydrogen carbonate solution (500 ml), brin
It was washed with e (500 ml), dried over magnesium sulfate and concentrated. After concentrating to a total volume of about 500 ml, 1.0 l of ethyl acetate was added to precipitate white crystals (urea). It was filtered off again and the filtrate was concentrated to a total volume of about 500 ml. Ethyl ether (100 ml) and isopropyl ether (1.0 liter) were added to this, and the mixture was stirred well and the precipitated crystals were collected by filtration to give the title compound (301.0 g).

¹ H-NMR (CDCl ₃ ) δ; 3.38 (1H, t, J = 8Hz) 3.54 (1H, d, J = 8Hz) 3.75 (1H, t, J = 8Hz) 4.01 (1H, q, J =
8Hz) 5.21 (2H, s) 5.95 (2H, s) 6.50 (1H, br-s) 6.66 (1H,
dd, 2,8Hz) 6.70 (1H, d, J = 2Hz) 6.73 (1H, d, J = 8Hz) 7.38 ~ 7.27 (5
H, m)

(9)

[0164]

[Chemical formula 46]

60% sodium hydride 11.70 g (2
92.03 mmol) in 650 ml suspension of dimethylformamide 90.0 g (2) of the benzyl ester obtained in (8)
A solution of 65.49 mmol) in 400 ml of dimethylformamide was added dropwise at 0 to 10 ° C. After stirring the mixture at 15 ° C. for 30 minutes, 82.3 g of the bromo compound obtained in (3) (265.
49 mmol) of dimethylformamide solution was added dropwise at -5 to 0 ° C. The mixture was stirred overnight at room temperature and then concentrated. 500 ml of ethyl acetate was added to the residue, and the precipitated white crystals were collected by filtration.

¹ H-NMR (CDCl ₃ ) δ; 3.28 (1H, t, J = 8Hz) 3.37 (1H, t, J = 8Hz) 3.51 (1H, d, J = 12Hz) 3.56 (1H, t, J =
8Hz) 3.88 (1H, d, J = 12Hz) 3.89 (3H, s) 4.94 (2H, AB, J = 12H
z) 5.30 (2H, s) 5.87 (2Hz, dd, J = 1,10Hz) 6.24 (1H, d, J = 2Hz) 6.39 (1
H, dd, J = 2,8Hz) 6.41 (1H, s) 6.55 (1H, d, J = 8Hz) 6.73 (1H, d, J = 8Hz) 7.13 ~ 7.20 (2H, m) 7.27 ~ 7.34 (3H, m) 7.84 (1H, d, J
= 8Hz)

(10) 3- (3-aminosulfonyl-
2,6-dimethoxyphenylmethyl) -3-carboxy
-4- (3,4-methylenedioxyphenyl) -2-pi
Manufacture of loridone

[0168]

[Chemical 47]

Benzyl ester 19 obtained in (9)
19.50 g of palladium-carbon was added to a solution of 5.8 g (344.4 mmol) of dimethylformamide (600 ml), and the mixture was vigorously infiltrated in a ¹ H-atmosphere (4.5 to 3.8 atm). After 50 minutes, the catalyst was filtered off and the filtrate was concentrated. 400 ml of 1N aqueous hydrochloric acid solution and 90% dioxane were added to this concentrated solution.
0 ml was added and stirred for 10 hours. Dichloromethane 3.0
1, and 600 ml of water were added, and the mixture was extracted with dichloromethane. After washing with 500 ml of water and 500 ml of brine, concentrate the filtrate,
Crude crystals of the title compound were obtained. This crystal was used for the next reaction without purification.

(11) 3- (3-aminosulfonyl-
2,6-dimethoxyphenylmethyl) -4- (3,4-
Production of methylenedioxyphenyl) -2-pyrrolidone

[0171]

[Chemical 48]

3- (3-Aminosulfonyl-2,6-dimethoxyphenylmethyl) -4-obtained in (10)
To the crude crystals of (3,4-methylenedioxyphenyl) -2-pyrrolidone (mixture of cis / trans) was added 1N sodium hydroxide-methanol solution, and the mixture was heated under reflux for 10 hours. 4N aqueous hydrochloric acid solution was added dropwise to the mixture to adjust the pH to 5,
Upon concentration, white crystals precipitated. The mixture was concentrated to about one-third volume, water was added to almost precipitate crystals, and the crystals were allowed to stand at room temperature and then collected by filtration. After drying with warm air, it was recrystallized from 1 liter of dichloromethane-methanol (1: 1 solution) to give the title compound 1
20.0 g was obtained.

¹ H-NMR (DMSO-d ₆ ) δ; 2.64 (1H, m) 2.92 to 3.08 (4H, m) 3.38 (1H, m) 3.62 (3H, s) 3.78 (3H, s) 5.87 ( 2H, d
t, J = 1,8Hz) 6.25 (1H, dd, J = 2,8Hz) 6.47 (1H, d, J = 8Hz) 6.57 (1H,
d, J = 8Hz) 6.65 (1H, d, J = 2Hz) 7.01 (2H, s) 7.40 (1H, d, J = 8Hz)
7.74 (1H, s)

(12) 3- (3-aminosulfonyl-
2,6-dimethoxyphenylmethyl) -4- (3,4-
Production of methylenedioxyphenyl) -2-pyrrolidine

[0175]

[Chemical 49]

Translactam 4 obtained in (11)
1.0 g of a 1 mol diborane-tetrahydrofuran solution was added to a suspension of 3.4 g (100.0 mmol) of dioxane in 1.0 l.
Was added dropwise, and the mixture was heated under reflux for 10 hours. The reaction solution was cooled, 500 ml of methanol was added dropwise at 0 ° C., the mixture was stirred at room temperature for 20 minutes, and after confirming that foaming was contained, it was concentrated. To the residual solid, 400 ml of methanol was added, followed by 200 ml of concentrated hydrochloric acid while cold, and the mixture was heated under reflux for 2 hours and 30 minutes. The mixture was concentrated, 2.0 l of dichloromethane was added to the residual solid, and 500 ml of saturated aqueous sodium hydrogen carbonate solution was added with vigorous stirring. The dichloromethane layer was separated and sodium hydrogen carbonate was washed with about 500 ml of dichloromethane. The dichloromethane solutions were combined and concentrated, and the residue was subjected to silica gel column chromatography to obtain 59.2 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ; 2.60 to 2.88 (3H, m) 2.93 to 3.03 (3H, m) 3.27 (1H, m) 3.45 (1H, m) 3.79 (6
H, m) 5.90 (2H, d, J = 8Hz) 6.66 ~ 6.78 (4H, m) 7.62 (1H, d, J = 8H
z)

(13) 3- (3-aminosulfonyl-
2,6-dihydroxyphenyl) methyl-4- (3,4
-Methylenedioxyphenyl) pyrrolidine hydrobromic acid
Salt production

[0179]

[Chemical 50]

3. The pyrrolidine derivative obtained in (12).
60 g of 1M boron tribromide dichloromethane solution 109 ml
At room temperature. After stirring for 2 days, the reaction solution is cooled, and 50 ml of a methylene chloride solution (1: 1) of methanol is added dropwise to stop the reaction. The reaction solution was evaporated to dryness, water was added, the insoluble matter was filtered off, and the filtrate was concentrated and freeze-dried to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ; 2.66 to 2.86 (3H, m) 3.03 to 3.18 (2H, m) 3.22 (1H, m)
t, J = 11Hz) 3.41 (1H, dd, J = 7,11Hz) 3.64 (1H, dd, J = 7,10Hz) 6.41 (1H, d, J = 8Hz) 6.67 (1H, dd, J = 2, 8Hz) 6.73 (1H, d,
J = 8Hz) 6.78 (1H, d, J = 2Hz) 7.40 (1H, d, J = 8Hz) 8.69 (1H, br)

Example 4 (-)-trans-3- (5-aminosulfonyl-2,
6-dihydroxyphenyl) methyl-4- (3,4-di
Hydroxyphenyl) pyrrolidine hydrochloride

[0183]

[Chemical 51]

(1) (−)-trans-3- (5-ami
Nosulfonyl-2,6-dihydroxyphenyl) -4-
(3,4-dihydroxyphenyl) -N-triphenyl
Methyl-pyrrolidine

[0185]

[Chemical 52]

(-)-Trans-3 obtained in Example 3
-(5-Aminosulfonyl-2,6-dihydroxyphenyl) methyl-4- (3,4-dihydroxyphenyl)
Pyrrolidine hydrobromide 32.9 g of dioxane (2
(00 ml) -water (200 ml) solution with triethylamine 3
0.60 ml of dioxane solution was added dropwise at 10.degree. About 1
After adding / 2 volume (about 1.5 molar equivalents), a solution of 17.10 g of anhydrous t-butoxycarboxylic acid in dioxane (100 ml) was started to be added at about the same rate.

After the dropping, the mixture was started to be stirred at 10 ° C. and allowed to reach room temperature for 1.5 hours. Add 500 ml of ethyl acetate and 500 ml of water to extract the target compound into the ethyl acetate layer.
The ethyl acetate layer was washed twice with 500 ml of 0.5N aqueous hydrochloric acid solution and 500 ml, dried over magnesium sulfate and then concentrated. About 50 ml of ethyl acetate and 400 ml of dichloromethane were added to the residue, and the mixture was warmed with shaking to precipitate white crystals of the title compound. After filtration, ethyl acetate-dichloromethane (1: 1
0) Wash with solution. Yield 27.32g.

(2) (-)-trans-3- (5-a)
Minosulfonyl-2,6-dihydroxyphenyl) meth
Lu-4- (3,4-dihydroxyphenyl) pyrrolidine
・ Hydrochloride

[0189]

[Chemical 53]

(-)-Trans-3-obtained in (1)
22.57 g of (5-aminosulfonyl-2,6-dihydroxyphenyl) -4- (3,4-dihydroxyphenyl) -N-triphenylmethyl-pyrrolidine was added to 4N hydrochloric acid-ethanol solution, and stirred at room temperature for 3 hours. did. The mixture was completely concentrated, and 200 ml of water was added to the residue for azeotropic distillation. After repeating the azeotropic process with water two more times, 250 ml of water
And lyophilized. Yield 20.30g.

NMR (D ₂ O) δ (ppm) 2.83 (1H, dd, J = 0.3,5.1Hz) 3.11 (1H) 3.13 (1H) 3.
20〜3.35 (3H) 3.84 (1H, dd, J = 7.3,11.2Hz) 3.88 (1H, dd, J = 7.3,11.7H
z) 6.73 (1H, dd, J = 2.0,8.3Hz) 6.76 (1H, d, J = 2Hz) 6.82 (1
H, d, J = 8.3Hz) 6.87 (1H, d, J = 8.3Hz) 7.60 (1H, d, J = 8.3Hz) Examples 5-6 According to the method of Examples 1 and 3, the following compounds Got Example 5

[0192]

[Chemical 54]

MASS MH ⁺ (379) ¹ H-NMR (D ₂ O) δ; 2.31 (3H, d, J = 2.4Hz) 2.50 to 2.60 (1H, m) 2.76 to 2.
86 (2H, m) 2.92 ~ 3.08 (3H, m) 3.48 ~ 3.58 (1H, m) 3.58 ~ 3.62
(1H, m) 6.42 (1H, dt, J = 2.4,8.2Hz) 6.48 (1H, m) 6.51 (1H, dd,
J = 1.8,8.2Hz) 6.63 (1H, dd, J = 3.0,8.2Hz) 7.24 (1H, dt, J = 2.4,8.2Hz)
7.28 (1H, m)

Example 6

[0195]

[Chemical 55]

MASS MH ⁺ (379) ¹ H-NMR (D ₂ O) δ; 2.28 (1H, m) 2.48 (1H, m) 2.62 (1H, m) 2.78 (3H, s) 2.90 to 3.02 ( 2H, m) 3.45 ~ 3.55 (3H, m) 6.42 ~ 6.57
(4H, m) 6.67 ~ 6.73 (2H, m)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location C07D 207/14 8217-4C (72) Inventor Kazutoshi Miyake 1 56-51 Sakaemachi, Ushiku City, Ibaraki Prefecture (72) Inventor Norio Minami 709-54 Shimohirooka, Tsukuba City, Ibaraki Prefecture (72) Inventor Toshiyuki Matsuoka 4-19-13 Kasuga, Tsukuba City, Ibaraki Prefecture (72) Hiroki Ishihara 42-10 Midorigaoka, Tsukuba City, Ibaraki Prefecture (72) Inventor Nobuyuki Mori 410-9 Shimohirooka, Tsukuba City, Ibaraki Prefecture (72) Inventor Mitsumasa Shino 1037-3 Togashira, Toride City, Ibaraki Prefecture (72) Inventor Shigeru Soda 1687-21 Ushiku Town, Ushiku City, Ibaraki Prefecture

Claims (5)

[Claims] 1. A compound represented by the general formula (I): Wherein Y is a group of formula -NH-, - (CH _{2) n}
A group represented by-(wherein n represents an integer of 0, 1, 2); (In the formula, p means an integer of 0, 1, or 2.). R ¹ and R ² are the same or different hydrogen atom, hydroxyl group, formula —SO ₂ NR ³ R ⁴ (in the formula, R ³ , R ⁴
Means a hydrogen atom, a lower alkyl group or an acyl group. Further, R ³ and R ⁴ may form a ring together with the nitrogen atom to which R ³ and R ⁴ are attached. Or a group represented by the formula: —NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ are the same or different hydrogen atoms, alkylsulfonyl groups or acyl groups, provided that R ⁵ and R ⁶ are both hydrogen atoms). And R ⁵ and R ⁶ may form a ring together with the bonded nitrogen atom. However, it is excluded when both R ¹ and R ² are a hydrogen atom or a hydroxyl group, and when ^one of R ¹ and R ² is a hydrogen atom and the other is a hydroxyl group. ] The pyrrolidine derivative represented by these, or its pharmacologically acceptable salt. 2. A therapeutic / prophylactic agent for a disease for which the action of dopamine 1 is effective, which comprises the pyrrolidine derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient. 3. A dopamine 1 agonist comprising the pyrrolidine derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient. 4. A therapeutic / preventive agent for hypertension, which comprises the pyrrolidine derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient. 5. A therapeutic / preventive agent for heart failure comprising the pyrrolidine derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.