JP2001512110A - 1,4-disubstituted piperazine - Google Patents

Abstract

(57) [Summary] General formula (I) Wherein n, Het, R, R ₃ , Z and B are as defined herein. The compound binds to the 5HT1A receptor and is therefore useful for the treatment of neuromuscular dysfunction of the lower urinary tract. Useful. Z = bond, B = substituted phenyl compound of formula (a) (Where R ₁ , R ₂ are as defined herein) and compounds (where Z is as defined herein) are claimed; It is claimed for use in the preparation of a medicament for treating urinary tract neuromuscular dysfunction.

Description

DETAILED DESCRIPTION OF THE INVENTION

FIELD OF THE INVENTION The present invention relates to novel 1,4-disubstituted piperazines that bind to serotonergic receptors, pharmaceutical compositions containing them, and the use of such derivatives and compositions.

BACKGROUND OF THE INVENTION In mammals, urination (urination) is a three-stage neurological control of the bladder, its internal and external sphincter muscles, the pelvic floor musculature, and these muscles (bladder wall or bladder). Or the sphincter itself, in the autonomic center of the spinal cord, and under the control of the cerebral cortex in the central nervous system (at the level of the pontine voiding center (PMC) in the brainstem (pontine)). Process (De Groat, Neurolobiogy of
Incontinence, (Ciba Foundation Symposium 151 : 27, 1990). Urination results from contraction of the detrusor muscle, which consists of interlaced smooth muscle fibers under parasympathetic autonomous control from the sacral spinal cord. A simple voiding reflex is formed by sensory nerves for pain, temperature, and distension that run from the bladder to the sacral spinal cord. However, sensory nerves from the bladder also reach PMC, resulting in the generation of nerve impulses that normally suppress the sacral spinal reflex, which controls bladder urination. Thus, normal urination is initiated by the voluntary suppression of cortical inhibition of the reflex arch and by relaxation of the pelvic floor and external sphincter muscles. Eventually, the detrusor contracts and urination occurs.

[0002] Abnormalities in lower urinary tract function, such as dysuria, incontinence, and enuresis, are common in the general population. Dysuria, including frequent urination, nocturia, and urge incontinence, is caused by cystitis, prostatitis or benign prostatic hyperplasia (BPH), which affects about 70% of older men, or by neurological disorders Can be Incontinence syndrome includes stress incontinence, urge incontinence, and excess flow incontinence. Enuresis refers to involuntary passage of urine at night or during sleep.

Prior to the work of the present invention, the treatment of neuromuscular dysfunction of the lower urinary tract was based on bladder muscles such as flavoxate, antispasmodics (Ruffman, J. Int. Med. Res. 16 : 317, 1988). direct action further PMC (Guarneri et al., Drugs of Today 30: 91, 1994) compounds of activity in, or oxybutynin (Andersson, Drugs 35: 477, 1988) the administration of anticholinergic of compounds such as Included. The use of a1-adrenergic receptor antagonists for the treatment of BPH is also common, but is based on a different mechanism of action (Lepor, Urology, 42 : 483, 1993).

[0004] However, treatments involving direct inhibition of the pelvic musculature (including the detrusor muscle) can have incomplete voiding or undesirable side effects such as paralysis, tachycardia and dry mouth (Andersson, Drugs 35 : 477, 1988).

Thus, using compounds that act through the peripheral or central nervous system, for example,
Preferably, the sacral reflex arch and / or the PMC inhibition pathway will act to restore the normal functioning of the voiding mechanism.

1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4- (2-methoxyphenyl) -piperazine (compound A below) is described in GB 2255 337A, It is reported to have -HT _1A antagonist properties. It is also disclosed that it may be used in the treatment of central nervous system disorders, for example as an anxiolytic in the treatment of anxiety.

[0007]

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[0008] The compounds of the present invention shown below represent compounds A with a novel substituent on the aromatic ring attached to the piperazine moiety and the insertion of a series of spacers (Z) between the piperazine ring and the phenyl ring. Structurally different. These structural changes are not disclosed in GB 2255337 A, especially with respect to compounds that can be used to improve urinary tract function. These new compounds also have longer action times than A in pharmacological tests that can predict effects on the lower urinary tract. This is particularly true with regard to the effect of the compounds of the invention on urinary incontinence, which is a novel therapeutic indicator for this class of compounds acting at the 5-HT _1A receptor.

SUMMARY OF THE INVENTION In one aspect, the present invention provides a compound of general formula I:

[0010]

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Wherein n is 1 or 2, Het represents a monocyclic heteroaryl group, R represents a cycloalkyl or monocyclic heteroaryl group, R ₃ represents a hydrogen atom or a lower alkyl group, Z is a bond or the formula _{-CH 2 -, - CH 2 CH} 2 -, - CH 2 C (O) -, - CH 2 CH (OH) -, - O -, - OCH 2 - Or --C (O)-, each of which represents that the left end is the end bonded to the piperazine ring and the right end is the end bonded to the group B, wherein B is substituted or Which represents an unsubstituted aryl or heteroaryl group] in the preparation of a medicament for treating neuromuscular dysfunction of the lower urinary tract in a mammal.

Z represents a bond, and B represents a formula

[0013]

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Wherein R ₁ represents hydrogen or a halogen atom or an alkoxy, nitro, amino, acylamino or alkylsulfonylamino group, and R ₂ represents a halogen atom or an alkoxy, polyfluoroalkoxy, cyano or carbamoyl group However, when R ₁ does not represent an acylamino or alkylsulfonylamino group, R ₂ represents a polyfluoroalkoxy group.] Compounds I representing a substituted phenyl group of formula I;
Compound I showing a group of H _2- , -CH ₂ CH _2- , -CH ₂ C (O)-, -CH ₂ CH (OH)-, -O-, -OCH ₂ -or -C (O)- Is novel and provided in another aspect of the invention.

The present invention relates to the enantiomers, diastereomers, N-oxides, crystalline forms, hydrates and pharmaceutically acceptable salts of these compounds, as well as metabolites (hereinafter hereinafter) of these compounds having the same type of activity. And sometimes referred to as “active metabolites”).

The present invention further relates to a compound of the general formula I, or an enantiomer, diastereomer, N-oxide, crystalline form, hydrate or pharmaceutically acceptable salt of said compound. There is provided a pharmaceutical composition comprising a mixture with a diluent or carrier.

The compounds of the present invention administer one or more selected compounds of general formula I in an amount effective for a particular use to a mammal (including humans) in need of such treatment. This is useful for reducing the frequency of bladder contractions due to bladder distension.

The compounds of the present invention may also comprise an effective amount of a general formula for improving at least one of urinary urgency, increased urinary frequency, incontinence, urine leakage, enuresis, dysuria, urinary hesitation, and bladder dysuria. The administration of a compound of I is useful for treating a disease of the urinary tract in a subject in need of such treatment.

The compounds of the present invention have been found to bind to the 5-HT _1A serotonergic receptor and, due to this activity, may be useful in treating CNS disorders due to serotonergic dysfunction. Such dysfunctions include anxiety, depression, hypertension, abnormal sleep / wake cycles, feeding behavior, sexual function and cognitive abnormalities in mammals, especially humans. Treatment may be effected by delivering an effective amount of a compound of the invention to the environment of the 5-HT _1A serotonergic receptor, such as an extracellular medium (or by administration to a mammal having such a receptor). .

DETAILED DESCRIPTION OF THE INVENTION All patents, patent applications, and references cited herein are hereby incorporated by reference in their entirety. In the case of incontinence, the present disclosure, including definitions,
effective.

The activity of the compounds of the present invention as inhibitors of pollakiuria may be useful in treating neuromuscular dysfunction of the lower urinary tract in mammals, including but not limited to dysuria, incontinence and enuresis Let

Surprisingly, the introduction of selected substituents on the phenyl ring directly attached to the piperazine moiety of the general formula I and of the Z group in the compounds of the general formula I It gives a significantly longer duration of action than is possible.

Preferred cycloalkyl groups R are C ₅ -C ₇ cycloalkyl groups; preferred monocyclic heteroaryl groups R and Het have one or more heteroatoms (eg, oxygen, nitrogen or sulfur). Having 5 to 7 ring atoms. Lower alkyl as used herein includes C ₁ -C ₆ alkyl. Alkyl, even when used in, for example, "alkylsulfonylamino", lower alkyl, preferably means C ₁ -C ₆ alkyl.

Preferred heteroaryl groups B include one or more heteroatoms (eg, nitrogen, oxygen,
A monocyclic or bicyclic aromatic group having 5 to 12 ring atoms, including (sulfur).

Preferably, n is 1, R represents a cyclohexyl group, Het represents a 2-pyridyl group, R ₃ represents a hydrogen atom, all of which are independent of each other. A preferred group of compounds is
Z represents a bond, R ₁ represents hydrogen or a halogen atom or a nitro, amino, acylamino or alkylsulfonylamino group, and R ₂ represents an alkoxy, trifluoroalkoxy, cyano or carbamoyl group. More preferably, Z represents a bond and B is 2-trifluoromethoxyphenyl, 2- (2,2,2-trifluoroethoxy) -phenyl, 5-chloro-2- (2,2,2-trifluoro (Ethoxy) -phenyl, 4-acetamido-2-methoxyphenyl, 2-methoxy-4-methylsulfonylamino
-Phenyl, 2-methoxy-4-pivaloylaminophenyl or 4-butanoylamino
A group of compounds showing a 2-methoxyphenyl group.

When Z does not show a bond, B is preferably an unsubstituted phenyl group or a substituted phenyl group.
Represents a halogen atom and alkoxy, cyano, nitro, amino
, Acylamino, alkylsulfonylamino, polyfluoroalkoxy and
Selected from rubamoyl groups. Another preferred group of compounds are those wherein Z is of the formula -CH_Two-, -CH_TwoCH _Two -, -CH_TwoC (O)-, -CH_TwoIt represents a CH (OH)-or -C (O)-group. Even better
In a preferred group of compounds, Z has no valence bonds and B has phenyl, 2,5-dichlorophenyl.
Phenyl or 2-bromo-5-methoxyphenyl group.

Subjects that would benefit from administration of the compounds and compositions of the present invention include EJMcGuir
e, including humans suffering from neuromuscular dysfunction of the lower urinary tract, as described in Campbell's UROLOGY, 5th edition, 616-638, 1986, by WBSunders Company;
Also includes patients suffering from physiological dysfunction associated with impaired HT _1A receptor function. Such dysfunctions include, without limitation, disorders of the central nervous system such as depression, anxiety, eating disorders, sexual dysfunction, addiction, and related problems.

The present invention relates to pharmaceutical formulations comprising the compounds disclosed above, as well as dysuria, incontinence,
Includes methods of using these formulations to treat neuromuscular dysfunction of the lower urinary tract, such as enuresis. Urinary disorders include frequent urination, nocturia, urgency and bladder dysuria, ie, a suboptimal amount of urine being excreted during urination.

Incontinence syndrome includes stress incontinence, urge incontinence, and excessive incontinence. Enuresis refers to the involuntary passage of urine at night or during sleep.

Without wishing to be bound by theory, it is believed that administration of a 5-HT _1A receptor antagonist prevents the undesirable effects of cortical mechanisms controlling sacral reflexes and / or voiding. . Therefore, it is expected that extensive neuromuscular dysfunction of the lower urinary tract can be treated with the compounds of the present invention.

An “effective amount” of the compound for treating a urine disease is an amount that results in a measurable improvement in at least one symptom or parameter of the disease.

An effective amount for treating the disease can be determined by empirical methods known to those skilled in the art, for example, establishing a matrix of dosages and frequency of administration, and combining an experimental unit or group of subjects with each point in the matrix. It can be easily determined by comparing. Precise amounts to be administered to a patient will vary depending on the condition and the severity of the disease and the physical condition of the patient. A measurable improvement in any condition or parameter can be determined by a physician skilled in the art or reported by a patient to a physician. It is understood that any clinically or statistically significant attenuation or improvement of any symptom or parameter of urinary tract disease is within the scope of the invention. A clinically significant attenuation or improvement means that it is recognizable to the patient and / or physician.

For example, one patient may simultaneously suffer from several symptoms of dysuria, such as, for example, urgency and excessive frequency, one or both of which may be reduced using the methods of the invention. In the case of incontinence, a reduction in the frequency or amount of undesired passage of urine is considered to be a beneficial effect of the treatment of the method of the invention.

The compounds of the invention may be formulated in a liquid dosage form together with a physiologically acceptable carrier such as, for example, phosphate buffered saline or deionized water. Pharmaceutical formulations may also include excipients including preservatives and stabilizers, which are well known to those skilled in the art. The compounds may be formulated in solid oral or parenteral dosage units such as, for example, tablets, capsules, powders, and suppositories, and may additionally contain lubricants, plasticizers, coloring agents, absorption enhancers, and the like. Excipients, including but not limited to agents, bactericides, and the like.

The modes of administration include oral and enteral, intravenous, intramuscular, subcutaneous, transdermal, transmucosal (including rectal and buccal), and by inhalation routes. Preferably, the oral or transdermal route is used (ie, via a solid or liquid oral formulation, or via a skin patch, respectively).

The amount of drug to be administered is between about 0.01 and about 25 mg / kg / day, preferably between about 0.1 and about
It may range from 10 mg / kg / day, most preferably from about 0.2 to about 5 mg / kg / day. Pharmaceutical formulations of the present invention may themselves include the total amount of an agent that is effective in treating the disease, as such an effective amount may be achieved by multiple administrations of such pharmaceutical formulation dosages. It does not need to be included.

In a preferred embodiment of the invention, the compounds are formulated in capsules or tablets, each preferably containing 50-200 mg of a compound of the invention, responsive to treatment with a 5-HT _1A receptor ligand. Most preferably, the patient is administered a daily dose of 50-400 mg, preferably 150-250 mg, most preferably about 200 mg for the reduction of urinary incontinence and dysfunction.

The methods, tables and examples set forth below are intended to fully illustrate preferred embodiments of the invention, and demonstrate its advantages and applicability, in any way limiting the scope of the invention. It does not do.

Synthesis of Compounds of the Invention Compounds of the invention, ie, compounds of general formula (I), may generally be prepared as shown in Scheme 1, where Het, n, Z, B, R ₃ has the same meaning as above:

[0040]

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Starting materials for amino-substituted heteroaromatic rings of general formula II (Y = NH ₂ ) are commercially available and their synthesis is well known to those skilled in the art. Intermediates of general formula II can be prepared by conventional acylation procedures known to those skilled in the art, for example, of the formula X-CH (R ₃ )-(CH ₂ ) _n-1 -C (O) -X ₁ [where Wherein X is a leaving group, for example, Br, Cl, I, p-toluenesulfonyloxy, methylsulfonyloxy, and X ₁ is, for example, Br, Cl, OH, etc. It can be converted to an intermediate having the general formula III. When n is 2, the acylating agent is acryloyl acylating agent obtained which produces a formula Het-NH-C (O) of the -CH = CH-R ₃ 2,3- unsaturated amides.

The intermediate having the general formula III can be condensed with a piperazine derivative IV in a conventional manner in the presence of a base to give an intermediate having the general formula V.

An alternative method of preparing an intermediate having the general formula V consists in acylating a starting material having the general formula II with a compound of the general formula VII wherein X ₁ , Z, B, R_ThreeAnd n are defined as above.

[0044]

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Acylation can be performed by conventional procedures known to those skilled in the art. For example, when X _{1 of the} acylating agent is OH, the amine-substituted heteroaromatic ring may be aprotic or optionally in the presence of an accelerator (e.g., N-hydroxysuccinimide, 4-dimethylaminopyridine). In a chlorinated solvent (e.g., N, N-dimethylformamide, chloroform, methylene chloride) at -20 ° C / 140 ° C, a coupling agent (e.g., diethylcyanophosphonate, dicyclohexylcarbodiimide or N, N'-carbonyldiethyl) Can be acylated by the addition of imidazole (Albertson, Org
React. 1962, 12, 205-218; Doherty et al., J. Med. Chem. 1992, 35, 2; Staab et al., Newer Methods Prep. Org. Chem. 1968, 5, 61; Ishihara, Chem. Pharm. B ull. 1991, 39, 3236).

Another well-known reaction procedure for acylating amines is the reaction of an intermediate having general formula VII with an alkyl chloroformate in the presence of a tertiary amine (eg, triethylamine), followed by An aprotic solvent (e.g., dioxane, methylene chloride), optionally in the presence of a promoter such as 1-hydroxypiperidine
( Org. React. 1962, 12, 157). When X _{1 of the} acylating agent is Cl or Br, the intermediate having the general formula VII is prepared in the presence of a base (for example, triethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate or cesium carbonate or sodium carbonate). Aprotic solvents (e.g., chloroform, 1,2-dichloroethane, dimethylformamide, dioxane,
In toluene) with the starting material of general formula II. Intermediates of general formula VII are aryl piperazines and formula _{X-CH (R 3) -} (CH 2) n-1 -C (O) -X 1 compound [wherein, X is defined as above Symbol , X ₁ is OH or OAlk (Alk preferably denotes lower alkyl, such as methyl or ethyl).

Compounds of general formula VII can also be synthesized from piperazine IV and compounds of formula R ₃ —CH = CH—C (O) —X ₁ . This alternative method of preparing an intermediate of general formula V by acylating a starting material of general formula II is useful if Z is CHOHCH if the OH group is previously protected by procedures well known to those skilled in the art. It is also useful when it is ₂ .

[0048]

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The intermediate having general formula V can be subsequently reduced to an intermediate of general formula VI by using a reducing agent capable of converting an amide functionality to an amino group. Such reducing agents include complex metal hydrides, such as lithium aluminum hydride in diethyl ether or tetrahydrofuran, or borane-tetrahydrofuran or borane-dimethylsulfide used in solvents suitable for the reduction reaction, such as tetrahydrofuran (J. Org. Chem 1982, 47, 1389). When Z is CH ₂ C (O), these reduction procedures can be applied in any case, provided that the keto group is previously protected by procedures well known to those skilled in the art.

Subsequent acylation of an intermediate of general formula VI using RC (O) Cl or another acylating agent according to conventional procedures (see above) provides a compound of the invention of general formula I Is generated. The intermediate of general formula VI can be prepared by converting the intermediate of general formula VI into a hard base (e.g., sodium hydride, butyllithium) in a suitable solvent (e.g., tetrahydrofuran, toluene, dioxane, 1,2-dimethoxyethane, diglyme). , Lithium bis (trimethylsilyl) amide), which are also acylated as their aza anions.

Another method for synthesizing compounds of general formula I is shown in Scheme 2 (above). Heteroaryl compounds having the general formula II (Y = halogen) are used to alkylate protected aminoalkyl aldehydes or aminoalkyl ketones of formula VIII (X = NH ₂ ), respectively, wherein the heteroaryl aminoalkyl aldehyde or This gives the corresponding acetal or ketal of the heteroarylaminoalkyl ketone IX. The reaction is in the presence of a base such as optionally Et ₃ N, pyridine, DMF, in an aprotic solvent any polar toluene, rows at a temperature of about + 40 ° C. ~ about + 120 ° C. We can.

Alternative reaction procedures for preparing intermediates of general formula IX are by conventional methods or by strong bases (eg n-butyllithium, lithium diisopropylamide, lithium hexamethyldisilylamide, hydrogenation Sodium, sodium amide) in a non-polar or polar aprotic solvent (e.g., toluene, THF) via the aza anion of a compound of general formula II obtained (Y = NH ₂ ) Of the heteroaryl compound of formula I with a protected compound of general formula VIII (X = Br or other leaving group).

An intermediate of general formula IX can be acylated with RCOCl to give an intermediate of general formula X using the same acylation conditions as described above (see Scheme 1). These intermediates are stable under normal laboratory conditions (i.e., light, humidity, temperature, etc.), can be stored, and can be stored in standard procedures (e.g., acid hydrolysis) just before they are used in the next step. ).

The carbonyl derivative of general formula XI resulting from the deprotection of compound X can react with a suitable N-substituted piperazine of general formula IV under reductive amination conditions to give compound I of the present invention. These reactions can be performed in a polar solvent such as methanol or ethanol, or in a chlorinated solvent such as dichloromethane or chloroform. Typically, an alkali borohydride such as NaBH _4, NaBH ₃ CN, and NaBH (OAc) ₃ is used as the reducing agent. In addition, optimal reaction components include an acid promoter such as acetic acid. These reactions proceed at temperatures between + 10 ° C and 100 ° C. When a compound having the general formula IV (Z = CH ₂ CO) is used, reduction of the ketone to the alcohol functionality can be achieved using NaBH ₄ as a reducing agent.

Alternatively, a carbonyl compound of general formula XI can be reacted with an N-protected piperazine of general formula XII using the same reducing conditions as described above to yield an intermediate having structure XIII. Piperazinyl derivatives of general formula XIV obtained by deprotection by standard methods of a compound having the general formula XIII, except when Z is O and OCH _2, BZX reagent
(X = leaving group) or with a BZ-CHO reagent (by standard reductive amination, see above) to give compound I of the present invention.

An alternative method for synthesizing compounds of general formula I is shown in Scheme 3.

[0057]

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A heteroarylamine of general formula II (Y = NH ₂ ) can be alkylated with a suitable 1, w-disubstituted alkane of general formula XV to yield an intermediate having general formula XVI.

The reaction is carried out at 0 ° C. in a polar aprotic solvent such as N, N-dimethylformamide (DMF), tetrahydrofuran (TMF), dioxane, acetone, acetonitrile or a chlorinated solvent such as dichloromethane or chloroform. It can be performed at a temperature of ~ 120 ° C. The reaction is typically performed in the presence of a proton acceptor such as triethylamine (Et ₃ N), diisopropylethylamine, and the like, and optionally potassium iodide.

In intermediates of general formula XV, X and X ₁ can be chloro, bromo, iodo, alkyl- or arylsulfonyloxy.

Another approach to synthesizing intermediates of general formula XVI is that of general formula II (Y = halogen, OTf)
Are utilized as starting materials. Het-Y has the general formula XV (X = NH ₂₎ by direct nucleophilic substitution performed by routine procedures known to those skilled in the art.
X ₁ = OH or protected OH) with a suitable amino alcohol, usually in the presence of a base (eg, diisopropylethylamine, sodium carbonate, lithium diisopropylamide, sodium tert-butoxide, etc.). One equivalent excess of reagent XV with X = NH ₂ as a proton acceptor is described by G. Doleschall et al., Tetrahedron, 32,
Used in the reaction as described in 57-64 (1976). These alkylation reactions can be carried out in aprotic polar solvents such as DMF, toluene and the like, or in protic solvents such as n-BuOH at a temperature between + 40 ° C and + 140 ° C. Nucleophilic substitution uses a hard base (e.g., sodium hydride, butyllithium, lithium bis (trimethylsilyl) amide) in a suitable solvent (e.g., tetrahydrofuran, toluene, dioxane, 1,2-dimethoxyethane, diglyme). It can also be obtained via the arylation of the aza anion of XV obtained (with protected OH). Het-Y (Y = h
al, Otf) can also be made in the presence of a metal catalyst, such as copper metal, copper (I) iodide or bromide, in the presence of a metal catalyst. Copper (I)
Or copper (I) oxide ( Tetrahedron, 1984, 40, 1433), nickel catalyst ( J. Org.Chem . , 1975, 40, 2267) palladium dichloride, palladium diacetate, palladium tetrakis, bis (diphenylphosphine) palladium dichloride, Palladium dibenzylideneacetone, bis (diphenylphosphinoferrocene) palladium dichloride ( Synlett, 1996, 329; J. Org.Chem., 1997, 62, 1568; 1997, 62, 1
268; 1997, 62, 1264). The reaction is carried out between room temperature and the reflux temperature of the solvent (e.g., dimethylacetamide, dimethylformamide, dioxane, acetonitrile, toluene, tetrahydrofuran) between the phosphine ligand (e.g., triphenylphosphine or tri-o-tolylphosphine or bis This can be done with or without (diphenylphosphino) ferrocene or 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl or other commercially available phosphine ligand).

The amino alcohol XVI (X ₁ = OH) is reacted with a halogenating agent such as POCl ₃ , SOCl ₂ , PCl ₅ or PBr ₃ to form an intermediate of the general formula XVI (X ₁ = Cl, Br) Is generated. These reactions are typically performed in an aprotic solvent such as chloroform, DMF, or pyridine, at a temperature between + 50 ° C and the reflux temperature of the solvent. These intermediates are used in the alkylation of suitable piperazine derivatives having the general formula IV to give intermediates of the general formula VI. These alkylations are carried out in chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane, or in polar aprotic solvents such as DMF, THF, acetone, acetonitrile, n-butanol, etc.
Alternatively, in a non-polar solvent such as toluene, benzene, n-heptane, etc.
C. can be performed. The reaction mixture may optionally, Et ₃ N, 4-dimethylaminopyridine, potassium carbonate, may include a proton acceptor, such as cesium carbonate. The reaction can typically be performed in the presence of potassium iodide.

The intermediate having the general formula VI is a derivative of the compound of the general formula II (Y = NH ₂ ) of the general formula XVII, wherein B, R ₃ , Z, X and n are the same as defined above. Significant] can also be obtained. Such reactions can be carried out without solvent at the melting temperature of the reactants or in an aprotic solvent such as dichloromethane, chloroform, DMF, THF, acetone, acetonitrile, or a protic solvent such as n-butanol and the like. It can be carried out in a solvent at a temperature between 0 ° C and + 160 ° C. The reaction is optionally, Et ₃ N, potassium carbonate or cesium, 4-dimethylaminopyridine proton acceptor may be conducted in the presence of a such as pyridine; reactants used depending on other needs are iodine Potassium chloride. Further, the intermediate of general formula VI can be prepared by the method shown above for the preparation of XVI (X ₁ OHOH), with the compound of general formula XVII (X = NH ₂ ) on the compound of general formula II (Y = Hal, OTf) )) Can be prepared by nucleophilic substitution of the compound

The intermediate of general formula VI can be acylated with a suitable acyl chloride to give a compound of general formula I as described above.

A further procedure for producing compounds of general formula I is by conventional procedures
Acylation of XVI gives compound XVIII (X ₁ = leaving group), which can finally be reacted with the appropriate piperazine derivative IV.

An intermediate having the general formula IV and / or VI or XVII, where Z = CH ₂ CH (OH) ₂ , is obtained by reduction from the same intermediate where Z = CH ₂ C (O) . Reduction of the carbonyl group to an alcohol is described in LiAlH ₄ (Rickborn J., J. Org. Chem. 35, 1041 (1970
_{)), NaBH 4, Na (} OAc) 3 BH (Gribble N., Tetrahedron Lett. 24, 4287 (1983)), Zn
It can be carried out using a metal hydride such as (BH ₄ ) ₂ (Chakraborty R., Tetrahedron Lett. 31, 7663 (1990)) as a reducing agent. Diethyl ether, THF, methanol, ethanol, dioxane and its solvent mixtures, which are suitable for use with strong bases and reducing agents, are used as reaction solvents at temperatures between + 10 ° C. and the reflux temperature of the solvents. obtain.

Alternatively, these reductions can be carried out using lithium tri-t-butoxyaluminum hydride (Endy L., J. Org. Chem. 35, 549 (1970)) or other selective reducing agents. It can be carried out to obtain compounds of formula I wherein Z is CH ₂ C (O).

Compounds of general formula I wherein Z is O or OCH ₂ and B is aryl can be converted to a compound of general formula I wherein Z is a bond by thermal rearrangement (Meisenheimer isomerization) Or CH ₂ ] can be prepared from the corresponding N-oxide derivative of the compound of formula I

[0069]

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This reaction is carried out in a polar aprotic solvent such as dioxane (Khuthier AH
Et al., J. Org. Chem. 52, 1710-1713 (1987) and references cited herein), which can be carried out at a temperature between 60 ° C. and the reflux temperature of the solvent.

Another method for synthesizing compounds of general formula I is shown in Scheme 4 below.

[0072]

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The intermediate of general formula XVI obtained as described in Scheme 3 is a monovalent compound of general formula XII, wherein P is t-butoxycarbonyl or benzyloxycarbonyl or another suitable protecting group. Used to alkylate protected piperazines, which can result in intermediates having the general formula XIX. Some examples of protection and deprotection for various reactive groups can be found in TWGreene, "Protective Groups in Organic Synthesis" Wiley
Can be found in Interscience (1991).

The reaction conditions for preparing the intermediate of general formula XIX are the same as those shown above in Scheme 3.

The acylation of the intermediate of the general formula XIX during the synthesis of the intermediate having the general formula XIII (Scheme 2) is carried out under the same conditions used for the synthesis of the final compound I in the scheme 1. Can be.

Another method for synthesizing intermediates having the general formula VI involves alkylating a suitable aryl piperazine with an intermediate of general formula XX, the synthesis of which is shown in Scheme 5. :

[0077]

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[Where Het, n and R ₃ have the same meaning as above, and X ₁ is OH].

In particular, when Het is 2-pyridyl, in other cases also the amino alcohol XVI ′ obtained as described in Scheme 3 has the reactive oxathiazolidine-2,2-dioxide XX (PCT / WO95 / 33743). The intermediate of general formula XVI 'or XX is
Reaction with a suitable piperazine derivative to give an intermediate of general formula VI. These reactions are performed by conventional methods well known to those skilled in the art. Usually, the condensation is carried out in an aprotic solvent (e.g., acetonitrile, dimethylformamide, toluene, dioxane, tetrahydrofuran) or a protic solvent (e.g., ethanol, n-butanol) or without using any solvent. (For example, in the presence or absence of triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate) at a temperature from room temperature to 180 ° C.

[0080]

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Another method of synthesizing the compounds of the present invention involves alkylating the aza anion of the amide of general formula XXI above, wherein R and Het have the same meaning as described above.

The aza anion can be formed using a base (eg, sodium amide, butyllithium, lithium diisopropylamide, sodium hydride, and the like), and the alkylating agent can be, for example, of the general formula X- (CH ₂ ) _n -CH (R ₃ ) -X ₁ where X ₁ can be Br, Cl, OH or protected OH (eg, 0-tetrahydropyranyl), as described above. To give a compound of general formula XVIII (X = leaving group) or XVIII ′ (X ₁ OHOH).
As shown in Scheme 6, compound XVIII 'was prepared using the previously described halogenation procedure (
(With or without prior deprotection step) to compound XVIII.

[0083]

Embedded image

Compounds of general formula XVIII ′ (X ₁ OHOH) can also be prepared by alkylation of a compound having general formula XVI by conventional procedures, followed by alkaline hydrolysis of the resulting ester. Can be done.

A further method for obtaining the compounds of the invention is to convert the aza anion of the amide XXI to a 1- (wX-alkyl) -4-ZB derivative of the general formula XVII (X = leaving group, for example Br, Cl, I, p-toluenesulfonyloxy, methylsulfonyloxy).

The aza anion of the embedded amide XXI can be prepared in a suitable aprotic solvent such as toluene, tetrahydrofuran, dimethoxyethane, dioxane, diglyme or others in a base (eg, butyllithium, sodium amide, sodium hydride). , Lithium diisopropylamide, lithium bis (trimethylsilyl) amide or others known to those skilled in the art) can be formed and alkylated at a temperature between -20 ° C and the reflux temperature of the solvent.

The compounds of the invention of the general formula Ia [R ₁ is nitro] can be prepared by customary reaction procedures, such as by catalytic hydrogenation, transfer hydrogenation or reduction of the nitro group via well-known chemical methods. , To give an amino compound of general formula I, which is subsequently suitably acylated or methylsulphonylated by known methods to give a compound of general formula I wherein R ₁ is amino, acylamino or alkylsulphonylamino It can be easily converted to

The following examples are offered only to illustrate the invention and its advantages and are not meant to constitute a limitation on the scope of the invention in any way. The present invention
It is meant to include obvious modifications of the compounds and methods described herein. Example 1 1-[N-cyclohexylcarbonyl-N-(2-pyridyl) -2-aminoethyl] -4- (2-triflate Le Oro methoxyphenyl)] - a 2.5N solution 13.1 ml of butyl lithium in piperazine hexane In 40 ml tetrahydrofuran
5.97 g of a solution of 2- (2,2-dimethoxyethylamino) -pyridine [prepared as described in I. Kaye, J. Am. Chem. Soc ., 73, 5467 (1951)] The mixture was added dropwise and stirred at 0 ° C. under a nitrogen atmosphere. Then the cooling bath was removed and the mixture was stirred at room temperature for 1 hour, after which 4.46 ml of cyclohexylcarbonyl chloride were added dropwise. Stirring was continued at room temperature for 5.5 hours, after which 2 ml of methanol was added. Subsequently, the solution was evaporated to dryness in vacuo to give a maroon oil, which was purified by flash chromatography (chloroform: ethyl acetate 7: 3). The fractions containing the product are evaporated to dryness, yielding 8.3 g of N- (2,2-dimethoxyethyl) -N- (2-pyridyl) -cyclohexylcarboxamide (78% yield); This material is suitable for use in the next reaction without further purification.

¹ H-NMR 200 MHz (CDCl ₃ , δ): 8.50 (dd, 1H, H6); 7.75 (dt, 1H, H4); 7.30 (d, 1H, H3)
; 7.20 (dt, 1H, H5 ); 4.65 (t, 1H, C H (OCH 3) 2); 3.90 (d, 2H, C H 2 CH); 3.31 (s, 6H, 2 OC
_{H 3); 2.20-2.43 (m,} 1H, CHC (O));. 0.80-1.80 (m, 10H, cyclohexyl protons) in 10 ml 2N hydrochloric acid, the 0.6 g N- (2,2- dimethoxyethyl) -N- (2-pyridyl) -cyclohexylcarboxamide and 0.02 g of hydroquinone solution were added under nitrogen atmosphere for 30
Stirred at a temperature of 80 ° C. for minutes. Subsequently, the mixture is cooled using a water bath and ice,
The pH was adjusted to 9 by adding a 5% aqueous sodium carbonate solution. Mix the mixture with dichloromethane
(2 × 10 ml); the extracts were combined, dried over anhydrous sodium sulfate and evaporated to dryness to give a 68% yield of N-formylmethyl-N- (2-pyridyl) -cyclohexyl Carboxamide was obtained and was suitable for use in the next reaction without further purification.

¹ H-NMR 200 MHz (CDCl ₃ , δ): 9.66 (s, 1H, CHO); 8.50 (dd, 1H, H6); 7.79 (dt, 1H, H4
); 7.20-7.38 (m, 2H, H3, H5); 4.52 (s, 2H, C H 2 CHO); 2.37-2.55 (m, 1H, CHC (O)); 0.8
0-1.80 (m, 10H, cyclohexyl proton) .0.459 g of N-formylmethyl-N- (2-pyridyl) -cyclohexylcarboxamide, 0.445 g of 1- (2-trifluoromethoxyphenyl) -piperazine (EP 711757) , 0.6
34 g sodium triacetoxyborohydride, 0.23 ml glacial acetic acid and 15 ml
The mixture of 1,2-dichloroethane was stirred under a nitrogen atmosphere for 4 hours. The resulting solution was kept at room temperature overnight. The next day, 10 ml of water was added, and a 20% aqueous sodium carbonate solution was added to make the mixture alkaline. The phases separated. The aqueous phase was extracted with 2 × 20 ml of dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was purified by flash chromatography (ethyl acetate: petroleum ether, gradient 90: 10-10: 0). The solvent was distilled off to obtain 0.44 g of the title compound (yield: 51%).

¹ H-NMR 200 MHz (CDCl ₃ , δ): 8.52 (dd, 1H, pyridine H6); 7.74 (ddd, 1H, pyridine H
4); 7.16-7.34 (m, 4H, pyridine H3 and H5, two aromatic rings of trifluoromethoxyphenyl); 6.33-7.02 (m, 2H, two aromatic rings of trifluoromethoxyphenyl); 3.97 (t, 2H ,
_{C (O) NC H 2 CH} 2); 2.85-3.05 (m, 4H, piperazine protons); 2.45-2.70 (m, 6H, Pipera Jin _{protons, C (O) NCH 2 C} H 2); 2.10-2.32 ( m, 1H, CHC (O)); 0.80-1.80 (2m, 10H, cyclohexyl proton). Example 2 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4- [ 2- (2,2,2 -trifluoroethoxy) phenyl] -piperazine Instead of 1- (2-trifluoromethoxyphenyl) -piperazine, 1- [2- (2,2,2-trifluoroethoxy)- The title compound was prepared as described in the final step of Example 1, except using [phenyl] -piperazine (EP 748800). The residue obtained is purified by flash chromatography (ethyl acetate: petroleum ether, gradient 90:10 to 10).
: 0). The solvent was distilled off to give the title compound, yield 51%.

[0092]¹H-NMR 200 MHz (CDCl_Three, δ): 8.46 (dd, 1H, pyridine H6); 7.68 (ddd, 1H, pyridine H
4); 7.06-7.28 (m, 2H, pyridine H3 and H5); 6.72-7.02 (m, 4H, aromatic ring of trifluoroethoxyphenyl); 4.30 (q, 2H, OCH_TwoCF_Three); 3.91 (t, 2H, C (O) NCH ₂ CH_Two); 2.80-
3.05 (m, 4H, piperazine proton); 2.40-2.55 (m, 6H, piperazine proton, C (O) NCH _Two CH ₂ ); 2.05-2.25 (m, 1H, CHC (O)); 0.70-1.80 (m, 10H, cyclohexyl proton). Example 3 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4- [5-chloro -2- (2,2,2-trifluoroethoxy) -phenyl] -piperazine: Instead of 1- (2-trifluoromethoxyphenyl) -piperazine, 1- [5-chloro-2
The title compound was prepared as described in the final step of Example 1, except using-(2,2,2-trifluoroethoxy) -phenyl] -piperazine (EP 748800). Obtained
The residue obtained is purified by flash chromatography (ethyl acetate: petroleum ether, gradient 9
0:10 to 10: 0). The solvent was distilled off to obtain the title compound, yield: 19.5%.

[0093]¹H-NMR 200 MHz (CDCl_Three, δ): 8.54 (dd, 1H, pyridine H6); 7.70 (ddd, 1H, pyridine H
4); 7.15-7.33 (m, 2H, pyridine H3 and H5); 6.70-6.95 (m, 3H, aromatic ring of trifluoroethoxyphenyl); 4.32 (q, 2H, OCH_TwoCF_Three); 3.97 (t, 2H, C (O) NCH ₂ CH_Two); 2.85-
3.10 (m, 4H, piperazine proton); 2.45-2.65 (m, 6H, piperazine proton, C (O) NCH _Two CH ₂ ); 2.10-2.32 (m, 1H, CHC (O)); 0.75-1.85 (2m, 10H, cyclohexyl proton). Example 4 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4- (2-cyano Phenyl) -piperazine: Instead of 1- (2-trifluoromethoxyphenyl) -piperazine, 1- (2-cyanofu
Enyl) -piperazine [Martin et al.J. Med. Chem., 32, 1052 (1996)] was used, but the title compound was prepared as described in the final step of Example 1. The resulting residue was purified by flash chromatography (ethyl acetate: petroleum ether, gradient 90:10 to 10: 0). Evaporate the solvent and
The compound was obtained with a yield of 19.5%.

¹ H-NMR 200 MHz (CDCl ₃ , δ): 8.55 (dd, 1H, pyridine H6); 7.75 (ddd, 1H, pyridine H
4); 7.53-7.75 (dd, 1H, cyanophenyl H3); 7.45 (dt, 1H, cyanophenyl H5);
7.20-7.30 (m, 2H, pyridine H3 and H5); 6.97 (t, 1H, H4 of cyanophenyl); 6.94
(d, 1H, H6 of cyanophenyl); 3.99 (t, 2H, C (O) NC H 2 CH 2); 3.06-3.19 (m, 4H, piperazinyl Rajinpuroton); 2.55-2.70 (m, 6H, piperazine Proton, C (O) NCH ₂ C H ₂ ); 2.35-2.
15 (m, 1H, CHC (O)); 0.80-1.80 (2m, 10H, cyclohexyl proton). Example 5 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4 - (4-nitro-2-methoxyphenyl) - piperazine 1- (2-trifluoromethoxy-phenyl) - instead of piperazine, 1- (2-methoxy
The title compound was prepared as described in the final step of Example 1, except using (-4-nitrophenyl) -piperazine (WO 95/17831). The crude product was purified by flash chromatography (ethyl acetate: methanol, gradient 98: 2 to 95: 5). The solvent was distilled off to obtain the title compound. Yield 60%.

¹ H-NMR 200 MHz (CDCl ₃ , δ): 8.54 (dd, 1H, pyridine H6); 7.85 (dd, 1H, nitrophenyl H5); 7.75 (ddd, 1H, pyridine H4); 7.68 (d , 1H, Nitrophenyl H3); 7.18-7.33
(m, 2H, pyridine H3 and H5); 6.85 (d, 1H, nitrophenyl H6); 3.97 (t, 2H, C (O) NC
_{H 2 C H 2 CH 2)} ; 3.91 (s, 3H, OCH 3); 3.05-3.20 (m, 4H, piperazine protons); 2.55-2.7
0 (m, 6H, piperazine _{protons, C (O) NCH 2 C} H 2); 2.15-2.35 (m, 1H, CHC (O)); 0.80-1.8
0 (m, 10H, cyclohexyl proton). Example 6 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4- (4-amino- 2-methoxyphenyl) -piperazine 1.70 g of 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4
-(4-Nitro-2-methoxyphenyl) -piperazine (prepared as described in Example 5), 18 ml of tetrahydrofuran, 18 ml of methanol, 50 mg of Raney nickel and 1 ml of hydrazine The mixture of hydrates was stirred at room temperature for 2 hours. An additional 1 ml of hydrazine hydrate was added and the solution was stirred for a further hour at a temperature of 50 ° C. Next, the catalyst was filtered off and the recovered solution was distilled off until dry,
A crude product was obtained. Purification by flash chromatography (ethyl acetate: 3N methanolic ammonia, 95: 5) and removal of the solvent by evaporation gave 1.33 g of the title compound (84% yield).

[0096]¹H-NMR 200 MHz (CDCl_Three, δ): 8.52 (dd, 1H, pyridine H6); 7.75 (ddd, 1H, pyridine H
4); 7.25-7.35 (m, 2H, pyridine H3 and H5); 6.75 (d, 1H, aminophenyl H6); 6.2
4 (d, 1H, aminophenyl H5); 6.21 (d, 1H, aminophenyl H3); 3.97 (t, 2H, C (O) NCH _Two CH ₂ ); 3.78 (s, 3H, OCH_Three); 3.00-4.00 (bs, 2H, NH_Two); 2.78-3.00 (m, 4H, piperazine proton); 2.52-2.70 (m, 6H, piperazine proton, C (O) NCH_TwoCH ₂ ); 2.22 (tt, 1H, CH
C (O)); 0.80-1.80 (m, 10H, cyclohexyl proton).Example 7 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4- (4-acetyl (Lumino-2-methoxyphenyl) -piperazine 0.35 g of 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4
-(4-amino-2-methoxyphenyl) -piperazine (prepared as described in Example 6)
Mixture), 5 ml of chloroform, and 0.063 ml of acetyl chloride
Stirred at room temperature for hours. Then the mixture is diluted with 50 ml of dichloromethane, washed with saturated sodium carbonate solution and twice with water and dried over anhydrous sodium sulfate.
And evaporated to dryness. The crude product was purified by flash chromatography (ethyl acetate: 3N methanolic ammonia, 95: 5) and the collected fractions were evaporated to dryness to give 0.300 g of the title compound (yield Rate 78%).

¹ H-NMR 200 MHz (CDCl ₃ , δ): 8.50 (dd, 1H, pyridine H6); 7.75 (ddd, 1H, pyridine H
4); 7.12-7.34 (m, 4H, pyridine H3 and H5, methoxyphenyl H6 and NH); 6.75-
6.85 (m, 2H, methoxyphenyl H3 and H5); 4.00 (t, 2H , C (O) NC H 2 CH 2); 3.82 (s, 3H
_{, OCH 3); 2.80-3.05 (m} , 4H, piperazine protons); 2.50-2.71 (m, 6H, Piperajinpu proton and _{C (O) NCH 2 C H} 2); 2.05-2.10 (m, 1H, CHC (O )); 2.14 (s, 3H, CH ₃ CO); 0.8
Example 8 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4- (4- methylsulfonylamino-2-methoxyphenyl ) 0-1.80 (m, 10H, cyclohexyl proton). ) -Piperazine This compound was prepared and purified by the method described in Example 7, except that methylsulfonyl chloride was used instead of acetyl chloride. Yield 75%.

¹ H-NMR 200 MHz (CDCl ₃ , δ): 8.50 (d, 1H, pyridine H6); 7.55 (ddd, 1H, pyridine H4
); 7.18-7.32 (m, 2H, pyridine H3 and H5); 6.70-6.90 (m, 3H , methyl phenyl aromatic ring); 3.95 (t, 2H, C (O) NC H 2 CH 2); 3.82 (s _{, 3H, OCH 3); 2.80-3.05} (m, 7H, piperazine protons and _{CH 3 S); 2.50-2.72 (m} , 6H, piperazine protons and _{C (O) NCH 2 C H} 2)
2.05-2.20 (m, 1H, CHC (O)); 0.80-1.80 (m, 10H, cyclohexyl proton) .Example 9 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl ] -4- (2-carbamoyl-phenyl) - piperazine 1- (2-trifluoromethoxy-phenyl) - instead of piperazine, 1- (2-carbamoyl-phenyl) - but using piperazine (WO 96/14846), The title compound was prepared as described in the final step of Example 1. The crude product was purified by flash chromatography (dichloromethane: methanol 95: 5). The solvent was distilled off to obtain the title compound. 9% yield.

¹ H-NMR (CDCl ₃ , δ): 9.35-9.55 (br, 1H, CONH ( H )); 8.53 (dd, 1H, pyridine H6); 8.1
3 (dd, 1H, phenyl H6); 7.78 (dd, 1H, pyridine H4); 7.45 (dd, 1H, phenyl H4); 7.1
0-7.32 (m, 4H, remaining aromatic ring); 5.60-5.83 (br, 1H, CON H (H)); 3.97 (t, 2H, C (O) NC H ₂ C
_{H 2); 2.83-3.00 (m,} 4H, piperazine protons); 2.50-2.75 (m, 6H, piperazine protons and _{CONCH 2 C H 2); 2.21} (tt, 1H, CHC (O)); 0.90-1.80 ( . m, 10H, cyclohexyl protons). example 10 1- [N-cyclohexylcarbonyl-N-(2-pyridyl) -2-aminoethyl] -4- (2,5-dichlorobenzoyl Rorofeniru) - piperazine 1- (2- Instead of (trifluoromethoxyphenyl) -piperazine, prepared as described in 1- (2,5-dichlorophenyl) -piperazine (R. Ratouis et al., J. Med.Chem ., 1965, 8, 104-107) . The title compound was prepared as described in the final step of Example 1 except using The crude product was purified by flash chromatography (ethyl acetate: methanol 9: 1). Evaporation of the solvent gave the title compound as an amorphous ivory solid. Yield 45.6%.

[0100]¹H-NMR 200 MHz (CDCl_Three, δ): 8.85 (dd, 1H, pyridine H6); 8.08 (ddd, 1H, pyridine H
4); 7.50-7.67 (m, 3H, pyridine H3 and H5, dichlorophenyl H3); 7.27 (s, 1H, dichlorophenyl H6); 7.22 (dd, 1H, dichlorophenyl H4); 4.22-4.50 (t, 2H, C (O) NC H ₂  ); 3.15-3.38 (m, 4H, piperazine proton); 2.80-3.01 (m, 6H, piperazine proto
, C (O) NCH_TwoCH ₂ ); 2.45-2.65 (m, 1H, CHC (O)); 1.15-2.15 (m, 10H, cyclohexyl proton).Example 11 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4- (2-methoxy Ci-4-pivaloylaminophenyl) -piperazine This compound was used except that pivaloyl chloride was used instead of acetyl chloride.
Prepared by the method described in Example 7. The resulting residue is flash chromatographed.
Purification by chromatography (ethyl acetate: 2.2N methanolic ammonia 95: 5)
Compound (49%) was obtained.

¹ H-NMR 200 MHz (CDCl ₃ , δ): 8.50 (d, 1H, pyridine H6); 7.87 (ddd, 1H, pyridine H4)
7.48 (d, 1H, phenyl H3); 7.18-7.25 (m, 3H, pyridine H3 and H5 and NH); 6.7
0-6.90 (m, 2H, phenyl H5,6); 3.95-4.15 (m, 2H , C (O) NC H 2 CH 2); 3.85 (s, 3H, OCH 3);
2.45-3.30 (m, 10H, piperazine protons and _{C (O) NCH 2 C H} 2); 2.25 (s, 1H, CHC (O))
0.85-1.80 (m, 19H, cyclohexyl proton and (CH ₃ ) ₃ C) .Example 12 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4- (4 butano Ilamino-2-methoxyphenyl) -piperazine This compound was prepared and purified by the method described in Example 11 except that butanoyl chloride was used instead of vivanoyl chloride. Yield 53%.

¹ H-NMR 200 MHz (CDCl ₃ , δ): 8.50 (d, 1H, pyridine H6); 7.87 (ddd, 1H, pyridine H4
); 7.40 (d, 1H, phenyl H3); 7.18-7.35 (m, 2H, pyridine H3 and H5); 7.10 (s, 1H,
NH); 6.75-6.85 (bs, 2H, phenylH5,6); 4.00 (s, 2H, C (O) NC H ₂ CH ₂ ); 3.85 (s, 3H, OC
_{H 3); 2.85-3.10 (m,} 4H, piperazine protons); 2.55-2.80 (m, 6H, piperazine protons and _{C (O) NCH 2 C H} 2); 2.15-2.30 (m, 3H, CHC (O) And NHCOCH ₂ ); 0.85-1.80 (m, 1
5H, cyclohexyl proton and CH ₃ CH ₂ ) .Example 13 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4- (2-bromo -5-methoxybenzyl) -piperazine Instead of 1- (2-trifluoromethoxyphenyl) -piperazine, 1- (2-bromo-5
The title compound was prepared as described in the last step of Example 1, except using -methoxybenzyl) -piperazine (AU 71773/96). The crude product was purified by flash chromatography (ethyl acetate: methanol, gradient 100: 0 to 100: 3). The solvent was distilled off to obtain the title compound. 52% yield as a viscous yellow oil.

¹ H-NMR 200 MHz (CDCl ₃ , δ): 8.50 (dd, 1H, pyridine H6); 7.60 (ddd, 1H, pyridine H
4); 7.39 (d, 1H, bromophenyl ring H3); 7.32-7.15 (m, 2H, pyridine H3 and H5); 7
.15-6.95 (m, 1H, bromophenyl ring H6); 6.65 (dd, 1H, bromophenyl ring H4); 4.05-
3.88 (m, 2H, CONC H 2 CH 2); 3.80 (s, 3H, OCH 3); 3.56 (s, 2H, benzyl CH _2); 2.80-2.32
(m, 10H, C (O ) NCH 2 C H 2 and piperazine protons); 2.32-2.10 (m, 1H, CHC (O)); 1.
82-0.82 (m, 10H, cyclohexyl protons). Example 14 1-[N-cyclohexylcarbonyl-N-(2-pyridyl) -2-aminoethyl] -4- (2,5-dichlorobenzoyl Rorobenjiru) -. Piperazin-methyl Sulfonate hemihydrate 2.01 g of 2,5-dichlorobenzyl chloride is added to a mixture of 1.94 g of 1-ethoxycarbonylpiperazine, 3.45 g of anhydrous potassium carbonate and 20 ml of dimethylformamide, at room temperature under a nitrogen atmosphere. Stirred. After stirring at room temperature for another 24 hours,
The reaction mixture was poured into 200 ml of water and extracted with ethyl acetate (3x100 ml). The combined organic phases were dried over anhydrous sodium sulphate and then distilled off in vacuo until dry. The residue was purified by flash chromatography (petroleum ether: ethyl acetate 85: 1
Purified in 5). Next, the solvent was distilled off to obtain 2 g of 1- (2,5-dichlorobenzyl) -4-ethoxycarbonylpiperazine (yield 63%).

¹ H-NMR 200 MHz (CDCl ₃ , δ): 7.50 (d, 1H, H6); 7.27 (d, 1H, H3); 7.15 (dd, 1H, H4);
_{4.13 (q, 2H, CH 3} C H 2 O); 3.58 (s, 2H, benzyl _{CH 2); 3.50 (m,} 4H, piperazine protons); 2.47 (m, 4H, piperazine protons); 1.26 (t, 3H, CH ₃ CH ₂ O). A solution of 13 g of 1- (2,5-dichlorobenzyl) -4-ethoxycarbonylpiperazine in 35 ml of 37% hydrochloric acid was stirred at reflux for 40 hours. Then 30 ml of water and 30 ml
Was added, and the pH was adjusted to 11 by adding 35% sodium hydroxide. Subsequently, the organic phase was separated, dried over anhydrous sodium sulphate and evaporated to dryness in vacuo. The residue was purified by flash chromatography (chloroform: ethanol 7: 7).
Purified in 3). 4.46 g of 1- (2,5-dichlorobenzyl) -piperazine (50% yield) was obtained.

¹ H-NMR 200 MHz (CDCl ₃ , δ): 7.50 (d, 1H, H6); 7.26 (d, 1H, H3); 7.14 (dd, 1H, H4);
3.55 (s, 2H, benzyl _{CH 2); 3.00-2.85 (m,} 4H, piperazine protons); 2.55-2.48 (m
, 4H, piperazine proton); 1.76 (s, 1H, NH) .0.049 g of sodium cyanotrihydroborate was added to 0.164 g of N-formylmethyl.
A mixture of -N- (2-pyridyl) -cyclohexylcarboxamide, 0.210 g of 1- (2,5-dichlorobenzyl) -piperazine and 4 ml of methanol was added and stirred continuously at room temperature under nitrogen. Subsequently, the resulting mixture was stirred at room temperature for 13 hours. Then it was diluted with 10 ml of water and extracted with ethyl acetate (3x10 ml). Subsequently, the combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was purified by flash chromatography (chloroform: methanol 95: 5). The collected fractions were evaporated to dryness and the residue was taken up in 2 ml of ethyl acetate. 0.08 ml of 2M ethanolic methyl sulfonic acid was added, followed by diethyl ether until complete precipitation of the product. 0.071 g (19% yield) of precipitate was collected by vacuum filtration.

¹ H-NMR 200 MHz (CDCl ₃ , δ): 8.51 (dd, 1H, pyridine H6); 7.83 (ddd, 1H, pyridine H
4); 7.12-7.50 (m, 6H, pyridine H3 and H5, phenyl proton and NH ⁺ ); 4.10-4
.25 (m, 2H, C ( O) C H 2 CH 2); 3.50-3.85 (m, 4H, piperazine protons); 3.15-3.40 (m, 2H
_{, C (O) CH 2 C} H 2); 2.75-3.15 (m, 6H, piperazine protons, benzyl _{CH 2); 2.74 (s,} 3H,
_{CH 3 S); 2.33-2.18 (m} , 1H, cyclohexyl H1);. 0.80-1.80 (2m, 11H, cyclohexyl protons, 0.5H ₂ O) Example 15 1-[N-cyclohexylcarbonyl-N-(2- pyridyl) -2-aminoethyl] -4-benzylpiperazine 0.3 g of N- formylmethyl-N-(2-pyridyl) - cyclohexyl carboxamide, 0
A mixture of .2 ml of 1-benzylpiperazine, 0.14 ml of acetic acid, 0.38 g of sodium triacetoxyborohydride and 7 ml of dichloromethane was stirred at room temperature for 24 hours. Subsequently, the mixture was diluted with water and made alkaline with a 5% aqueous sodium hydrogen carbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate and evaporated in vacuo to dryness. The crude product was purified by flash chromatography (dichloromethane: methanol 95: 5) to give 0.03 g of the title compound.

¹ H-NMR 200 MHz (CDCl ₃ , δ): 8.50 (dd, 1H, pyridine H6); 7.75 (ddd, 1H, pyridine H
4); 7.10-7.40 (m, 7H, pyridine H3 and H5, phenyl proton); 4.00 (t, 2H, C (O) N
_{C H 2); 3.60 (s} , 2H, PhCH 2); 2.30-2.90 (m, 10H, piperazine _{protons, C (O) NCH 2 C} H 2);
2.10-2.25 (m, 1H, CHC (O)); 0.80-1.80 (m, 10H, cyclohexyl proton). Example 16 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] 4-phenylpiperazine this compound, in place of 1-benzyl piperazine, except using 1-phenethyl-ethylpiperazine (Beil. was prepared as described in EIII / IV.62), example 15
Prepared as described in The crude product was purified by flash chromatography (chloroform: methanol 97: 3) to give the title compound in 61% yield.

¹ H-NMR 200 MHz (CDCl ₃ , δ): 8.51 (dd, 1H, pyridine H6); 7.75 (ddd, 1H, pyridine H
4); 7.10-7.20 (m, 7H, pyridine H3 and H5, phenyl proton); 3.96 (t, 2H, C (O) N
_{C H 2); 2.45-2.90 (m} , 14H, PhC H 2 C H 2, CH 2 C H 2 N and piperazine _{CH 2 s); 2.20 (tt} , 1H,
CHC (O));. 0.85-1.80 (m, 10H, cyclohexyl protons). Example 17 1-[N-cyclohexylcarbonyl-N-(2-pyridyl) -2-aminoethyl] -4-benzoyl Rupiperajin The compound , Instead of 1-benzylpiperazine, 1-benzoylpiperazine (K
.-R. Jacobi Chem. Ber. 1933, prepared as described in 113-116), except that was used. The crude product was purified by flash chromatography (chloroform: methanol 97.5: 2.5) to give the title compound in 54% yield.

[0109]¹H-NMR 200 MHz (CDCl_Three, δ): 8.51 (dd, 1H, pyridine H6); 7.75 (ddd, 1H, pyridine H
4); 7.15-7.45 (m, 7H, pyridine H3 and H5, phenyl proton); 3.95 (t, 2H, C (O) N
CH ₂ CH_TwoN); 3.45-3.80 (m, 2H, eq.H3 and H5 piperazine protons); 3.15-3.45 (m, 2
H, ax.H3 and H5 piperazine protons); 2.30-2.65 (m, 6H, CH_TwoCH ₂ N and remaining CH _Two s); 2.18 (tt, 1H, CHCO); 0.85-1.80 (m, 10H, cyclohexyl proton).Example 18 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4-benzoy Rumethylpiperazine hydrochloride This compound was prepared using 1- (2-trifluoromethoxyphenyl) -piperazine instead of 1-benzoylmethylpiperazine (prepared according to the procedure described in Beil. 23, V / 2, 200). Prepared as described in the final step of Example 1. The crude product was purified by flash chromatography (ethyl acetate-2N methanolic anhydride).
Monia, gradient 97: 3 to 95: 5). Residue obtained by evaporating the collected fraction
Was dissolved in ethyl acetate. Add excess 5N isopropanolic hydrogen chloride and precipitate.
The residue was collected by filtration to give the title compound, 18% yield. m.p.
.¹H-NMR 200 MHz (DMSO-d6, δ): 8.55 (dd, 1H, pyridine H6); 7.90-8.00 (m, 3H, pyri
7.70 (dd, 1H, pyridine H3); 7.50-7.65 (m, 3H, phenylH3, H4 and H5); 7.35-7.50 (ddd, 1H, pyridine H5); 5.30- 6.80 (bs, 1H, NH⁺);
5.05 (s, 2H, CH_TwoCO); 4.05 (t, 2H, CH_TwoNCO); 3.45-3.65 (m, 8H, piperazine proton);
 3.30 (t, 2H, CH_TwoCH_TwoNCO); 2.20 (q, 1H, CHC (O)); 0.80-1.70 (m, 10H, cyclohexyl
proton).Example 19 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4- (β-hydr Roxyphenethyl) piperazine 0.158 g of sodium borohydride is dissolved in 4.2 ml of methanol in 0.18 g of 1- [N-
Cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4-benzoylmethy
A solution of lupiperazine (prepared as described in Example 18) was added at 10 ° C.
After stirring at room temperature for 3 hours and standing overnight, the solvent was removed and the residue was dissolved in water.
Extracted with ethyl. The crude product obtained after evaporation of the solvent is purified by flash chromatography.
Raffy (ethyl acetate -2N methanolic ammonia 97.5: 2.5), 0.112 g (
61%) of the title compound, m.p. 140-142 ° C.

¹ H-NMR 200 MHz (CDCl ₃ , δ): 8.55 (dd, 1H, pyridine H6); 7.75 (ddd, 1H, pyridine H
4); 7.20-7.40 (m, 7H, pyridine H3 and H5, phenyl CHs); 4.65-4.80 (dd, 1H, CHOH
); 3.90-4.05 (m, 3H, OH, CH ₂ NCO); 2.30-2.80 (m, 12H, piperazine proton, CH ₂ CHOH
, CH ₂ CH ₂ NCO); 2.15-2.30 (q, 1H, CHC (O)); 0.90-1.80 (m, 10H, cyclohexylprotone) Example 20 Volume-Induced Rhythmic Bladder in Anesthetized Rats Effect on contraction A. Method: Female Sprague Dawley rats weighing 225-275 g (Crl: CDo BR, Charles River Ita)
lia). Animals were housed with free access to food and water and maintained at 22-24 ° C with a forced light-dark cycle every 12 hours for at least one week except for the duration of the experiment. Activity on rhythmic bladder voiding contractions was determined by Dray (J. Pharmacol. Methods, 13
: 157, 1985) with some modifications, such as Guaneri (Pharmacol. Res., 27: 173, 1993). Briefly, rats were weighed at 1.25 g / kg (5 ml / k
g) Anesthetized by subcutaneous injection of urethane, then catheterized into the bladder via the urethra using a PE 50 polyethylene tube filled with saline. The catheter was tied in place with a ligature around the external urethral opening and connected to a conventional pressure transducer (Statham P23 ID / P23 XL). Pressure in the bladder was continuously displayed on a chart recorder (Battaglia Rangoni KV 135 with DC1 / TI amplifier). The bladder was filled (usually 0.8-1.5 ml) with incremental volumes of warm (37 ° C.) saline via a recording catheter until reflex bladder voiding contraction occurred. For intravenous (iv) administration of the bioactive compound, a PE 50 polyethylene tube filled with saline was inserted into the jugular vein.

From the cystometry, the number of contractions recorded 15 minutes before (basal value) and after treatment and the average amplitude of these contractions (mean height of the peak in mmHg) were evaluated.

Since most compounds produced an effect that was relatively fast to initiate and led to complete cessation of bladder contractions, the biological activity was measured as the duration of bladder resting (ie, the duration during which no contractions occurred).
Was conveniently evaluated by measuring After the effect of the drug injection ceased, the peak height was compared to that previously recorded after intravenous injection of vehicle alone.
The potency of the test compounds (ED ₅₀ value: extrapolated dose that induces a 30% reduction in the amplitude of contraction in 50% of treated rats) was determined by the method of Bliss (Bliss CI, Quart. J. Pharm. Pharmaco.
l. 11, 192-216, 1938). B. Results The rapid distension of the bladder in urethane anesthetized rats has been characterized (Maggi et al., Brain Res., 380: 83, 1986; Maggi et al., J. Pharmacol. Exp. Th.
er., 230: 500, 1984) produced a series of rhythmic bladder voiding contractions. The frequency of these contractions is related to the integration of the sensory afferent arm of reflex urination and the micturition center, while their amplitude is a property of the efferent arm of reflex. In this model system, compounds that act predominantly on the CNS (such as morphine) result in blocking detrusor contractions, whereas drugs that act at the level of the detrusor muscle, such as oxybutynin, decrease the amplitude of bladder contractions.

Table 1 shows the results obtained with the test compounds. All compounds of the present invention produced superior results in terms of bladder contraction elimination time than could be achieved with Compound A. They produced longer-term contraction inhibition than flavoxate.

Oxybutynin only reduced contractile amplitude in a dose-dependent manner, with 240 mg / k
It had an ED ₅₀ value of g, an extrapolated dose that induced a 30% decrease in the amplitude of contraction in 50% of treated rats. That is, oxybutynin does not cause cessation of bladder contraction. The amplitude-reducing effect characteristic of oxybutynin can potentially cause lower bladder contractility and unwanted retention of residual urine in the bladder after voiding and is not a characteristic of the compounds of the invention.

TABLE 1 Effect on rhythmic bladder voiding contractions after intravenous administration The data show the mean duration of bladder resting ± SE (time in minutes of contraction disappearance after iv administration of compound).

[0116]

[Table 1]

Example 21 Radioactive Receptor Binding to Recombinant 5-HT _1A Receptor A. Method: A genomic clone G21 encoding a human 5-HT _1A -serotonergic receptor was
Stably transfect human cell line (HeLa). HeLa cells were grown as monolayers in Dulbecco's modified Eagle's medium (DMEM) with 10% fetal calf serum and gentamicin (100 mg / ml) captured at 5% CO ₂ at 37 ° C. Cells were separated from the growth flash at 95% confluence with a cell scraper, ice-cold 5 mM Tris and 5 μm.
It was dissolved in M EDTA buffer (pH 7.4). The homogenate is centrifuged at 40,000 xgx 20 min and the pellet is resuspended in a small volume of ice-cold 5 mM Tris and 5 mM EDTA buffer (pH 7.4), immediately frozen and stored at -70 ° C until use did. On the day of the experiment, the cell membrane was washed with binding buffer: 50 mM Tris HCl (pH 7.4), 2.5 mM MgCl ₂ , 10 mM pargyline.
(pargiline) (Fargin et al., Nature 335 , 358-360, 1988). Membranes are treated with 0.2-1 nM [ ³ H] in a final volume of 1 ml for 30 min at 30 ° C.
Incubated with 8-OH-DPAT; non-specific binding was measured in the presence of 10 mM 5-HT. Incubation was terminated by the addition of ice-cold Tris HCl buffer and rapid filtration through Whatman GF / B or Schleicher & Schuell GF52 filters pretreated with 0.2% polyethyleneimine. B. Results As shown in Table 2, the compounds of the present invention have high affinity for serotonergic 5-HT _1A receptors. These results indicate that this receptor plays a role in the action of the compounds of the present invention on the bladder.

Table 2 Binding Affinity Data for 5-HT _1A Receptors Data are given in Ki (nM).

[0119]

[Table 2]

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, GM, HR, HU, ID, IL, IS, JP, KE, KG, KP , KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZW Country A-20024 Garbagnate Milanese Via Canova 18 (72) Inventor Poggesi Elena Italy Country A-20148 Milan Via Richalegli 37 F Term (Reference) 4C055 AA01 BA02 BA52 BA53 BB01 BB02 BB03 BB10 CA01 DA01 4C086 AA03 AA01 MA04A NA14 ZA02 ZA05 ZA81 ZC42

Claims (17)

[Claims] 1. A compound of the general formula [Wherein, n is 1 or 2, Het represents a monocyclic heteroaryl group, R represents a cycloalkyl or monocyclic heteroaryl group, R ₃ represents a hydrogen atom or a lower alkyl group. are shown, Z is a bond or the formula _{-CH 2 -, - CH 2 CH} 2 -, - CH 2 C (O) -, - CH 2 CH (OH) -, - O -, - OCH 2 - also is properly -C (O)-, each of which represents that the left end is the end bonded to the piperazine ring and the right end is the end bonded to the group B, B is a substituted or unsubstituted aryl Or a heteroaryl group, provided that when Z represents a bond, B represents a substituted phenyl of the following formula: (Where R ₁ represents hydrogen or a halogen atom or an alkoxy, nitro, amino, acylamino or alkylsulfonylamino group, and R ₂ represents a halogen atom or an alkoxy, polyfluoroalkoxy, cyano or carbamoyl group. R ₁ does not represent an acylamino or alkylsulfonylamino group, R ₂ represents a polyfluoroalkoxy group)], or an enantiomer, diastereomer, N-oxide, crystal form, Rate, active metabolite or pharmaceutically acceptable salt. 2. The compound according to claim 1, wherein n is 1. 3. The compound according to claim 1, wherein R represents a cyclohexyl group. 4. The compound according to claim 1, wherein Het represents a 2-pyridyl group. 5. The compound according to claim 1, wherein R ₃ represents a hydrogen atom. 6. The method according to claim 1, wherein Z represents a bond, R ₁ represents hydrogen or a halogen atom or a nitro, amino, acylamino or alkylsulfonylamino group, and R ₂ represents an alkoxy, trifluoroalkoxy, cyano or carbamoyl group. The compound according to any one of the above items. 7. Z represents a bond, B represents 2-trifluoromethoxyphenyl, 2- (2
, 2,2-trifluoroethoxy) -phenyl, 5-chloro-2- (2,2,2-trifluoroethoxy) -phenyl, 4-acetamido-2-methoxyphenyl, 2-methoxy-4-methylsulfonyl A compound according to any of the preceding claims, which represents an aminophenyl, 2-methoxy-4-pivaloylaminophenyl or 4-butanoylamino-2-methoxyphenyl group. 8. Z has the formula _{-CH 2 -, - CH 2 CH} 2 -, - CH 2 C (O) -, - CH 2 CH (OH) - or -C (O
The group according to any one of claims 1 to 5, wherein a left end is an end bonded to the piperazine ring, and a right end is an end bonded to the group B. Compound. 9. The method according to claim 1, wherein Z does not represent a valence bond and B represents a phenyl, 2,5-dichlorophenyl or 2-bromo-5-methoxyphenyl group. Compound. 10. The following compounds: 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4- (2-trifluoromethoxyphenyl) -piperazine, 1- [N-cyclohexylcarbonyl -N- (2-pyridyl) -2-aminoethyl] -4- [2- (2,2,2
-Trifluoroethoxy) -phenyl] -piperazine, 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4- [5-chloro
-2- (2,2,2-trifluoroethoxy) -phenyl] -piperazine, 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4- (4-acetamido-2 -Methoxyphenyl) -piperazine, 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4- (4-methylsulfonylamino-2-methoxyphenyl) -piperazine, 1- [N -Cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4- (2-methoxy-4-pivaloylaminophenyl) -piperazine, 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) ) -2-Aminoethyl] -4- (4-butanoylamino-2-methoxyphenyl) -piperazine, 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4- ( 2-bromo
-5-methoxybenzyl) -piperazine, 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4- (2,5-dichlorobenzyl) -piperazine, 1- [N-cyclohexyl Carbonyl-N- (2-pyridyl) -2-aminoethyl] -4-benzylpiperazine, 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4-phenethylpiperazine, 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4-benzoylpiperazine, 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4-benzoi Any one of such compounds or 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4- (β-hydroxy-phenethyl) -piperazine; Enantiomers, diastereomers, N-
Oxide, crystalline form, hydrate, active metabolite or pharmaceutically acceptable salt. 11. A pharmaceutical composition comprising a compound according to any of the preceding claims in admixture with a pharmaceutically acceptable diluent or carrier. 12. A compound of the general formula I [Wherein, n is 1 or 2, Het represents a monocyclic heteroaryl group, R represents a cycloalkyl or monocyclic heteroaryl group, R ₃ represents a hydrogen atom or a lower alkyl group. are shown, Z is a bond or the formula _{-CH 2 -, - CH 2 CH} 2 -, - CH 2 C (O) -, - CH 2 CH (OH) -, - O -, - OCH 2 - also is properly -C (O)-, each of which represents that the left end is the end bonded to the piperazine ring and the right end is the end bonded to the group B, B is a substituted or unsubstituted aryl Or a heteroaryl group], or an enantiomer, diastereomer, N-oxide, crystalline form, hydrate, active metabolite or pharmaceutically acceptable salt of such a compound in a mammal. Use in the preparation of a medicament for treating neuromuscular dysfunction of the urinary tract. 13. The compound according to claim 1, wherein the compound is selected from the group consisting of:
Use as described in. 14. The following compounds: 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4- (2-cyanophenyl) -piperazine, 1- [N-cyclohexylcarbonyl-N -(2-pyridyl) -2-aminoethyl] -4- [4-nitro
2-methoxyphenyl) -piperazine, 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4- (4-amino
2-methoxyphenyl) -piperazine, 1- [N-cyclohexylcarbonyl-N- (2-pyridyl) -2-aminoethyl] -4- (2-carbamoylphenyl) -piperazine, and 1- [N-cyclohexylcarbonyl -N- (2-pyridyl) -2-aminoethyl] -4- (2,5-dichlorophenyl) -piperazine, or an enantiomer, diastereomer, N-
13. Use according to claim 12, of an oxide, crystalline form, hydrate, active metabolite or pharmaceutically acceptable salt. 15. Use according to any of claims 12 to 14 for the preparation of a medicament comprising a pharmaceutically acceptable diluent or carrier. 16. The method of claim 12, for preparing a medicament in a form suitable for oral administration.
Use according to any one of claims 15 to 15. 17. Use according to claim 16, for the preparation of a medicament comprising 50-400 mg of the compound in a unit dosage form.