WO2005039569A1

WO2005039569A1 - 5-substituted 2-(phenylmethyl) thio-4-phenyl-4h-1,2,4-triazole derivatives and related compounds as gaba-agonists for the treatment of urinary incontinence and related diseases

Info

Publication number: WO2005039569A1
Application number: PCT/EP2004/011101
Authority: WO
Inventors: Marcus Bauser; Joachim Krüger; Heinrich Meier; Verena Vöhringer; Bettina Beyreuther; Muneto Mogi; Makiko Marumo; Naoki Tsuno; Haruka Shimizu; Hiroshi Fujishima; Hiroaki Yuasa; Mayumi Hayashi; Masaomi Umeda; Atsuko Iwata
Original assignee: Bayer Healthcare Ag
Priority date: 2003-10-18
Filing date: 2004-10-05
Publication date: 2005-05-06
Also published as: JP2007509045A; CA2542682A1; EP1677786A1

Abstract

This invention relates to phenyltriazole derivatives of the formula (I) and salts thereof which is useful as an active ingredient of pharmaceutical preparations : (I) wherein R1 represents alkyl optionally substituted or 3-8 membered saturated or unsaturated ring optionally substituted, R2 represents -COR21, -(CH2)n-R21 or tert-butyl, X represents CR10R11, NR12, S, O, SO2, or SO wherein R10, R11 and R12 independently represent hydrogen or methyl. The other substituents are as defined in the claims. The phenyltriazole derivatives of the present invention have an excellent activity as GABAb agonist and are useful for the prophylaxis and treatment of diseases associated with GABAb activity, in particular for the treatment of overactive bladder, urinary incontinence such as urge urinary incontinence, benign prostatic hyperplasia (BPH), chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, neuralgia, neuropathies, algesia, or nerve injury.

Description

5-SUBSTITUTED 2- ( PHENYLMETHYL) THI0-4- PHENYL-4H- 1 , 2 , 4 -TRIAZOLE DERIVATIVES AND RELATED COMPOUNDS AS GABA-AGONISTS FOR THE TREATMENT OF URINARY INCONTINENCE AND RELATED DISEASES

DETAILED DESCRIPTION OF INVENTION

TECHNICAL FIELD

The present invention relates to a phenyltriazole derivative which is useful as an active ingredient 5 of pharmaceutical preparations. The phenyltriazole derivative of the present invention has γ- aminobutyric acid receptor (GABA_B receptor) agonistic activity, and can be used for the prophylaxis and treatment of diseases associated with GABA_B receptor activity, in particular for the treatment of overactive bladder, urinary incontinence such as urge urinary incontinence, benign prostatic hyperplasia,spasticity and motor control, pain, epilepsy, cognitive defects, psychiatric 10 disorders, alcohol dependence and withdrawal, feeding behaviour, cardiovascular, respirator}' disorders and gastrointestinal disorders.

BACKGROUND ART

GABA_B receptors are the first example of G protein-coupled receptors where heteromerization of two receptor subtypes has been demonstrated to be necessary for normal - function (Jones et a/., 15 Nature, (1998) 396, 674- 679); Kaupmann et al., Nature, (199S) 396, 683-687; Kuner et a/. Science, (1999) 283, 74-77). Currently there are two GABA_B receptor subtypes known, GABA_BR1 and R2. In the brain there are two predominant N terminal splice variants expressed from the GABA_B RI gene, GABA_BRla and Rib, which heterodimerize with the R2 subunit. Pharmacologically, the different splice forms of GABA_BR1 could not be distinguished (Kaupmann 20 et al., Nature, (1997) 386,239-246.

GABA_B receptors are located throughout the central and peripheral nervous systems (see Ong and Keιτ, Life Sciences, (1990) 46,1489-1501; Bower}' et al., Drug Res. (1992) 42(1), 2a, 215-223), and are thus involved in the regulation of a wide variety of neurally-controlled physiological responses, from memory and learning to muscle contraction. This makes the GABA_B receptor a 25 target for pharmaceutical agents intended to treat central and peripheral neural disorders, and indeed a variety of GABA_B agonists and antagonists are known and have been proposed for use in therapy including pain, spasticity and motor control, epilepsy, cognitive defects, psychiatric disorders, alcohol dependence and withdrawal, feeding behaviour, cardiovascular, respiratory disorders and gastrointestinal disorders (Bittiger et al., in GABA: Receptors, Transporters and 30 Metabolism, Tanaka, C, and Bowery, N.G. (Eds). Birkhauser Verlag Basel/Switzerland (1996), 297-305; Bittiger et al, Trends Pharmacol. Sci., 14, 391-394,1993; Froestl et al., J. Med. Chem., 38, 3297-3312,1995; Froestl et al., Ibid., 3313-3331). The GABA_B receptor agonist baclofen given intrathecally is used clinically for reducing uYethral resistance and detrusor overactivity associated with spasticity (Steers et al.,- J. Urol., 148, 1849- 1855,1992; Mertens et al., Ada Neurochir., 64, 17-25 1995). The main effect of baclofen within the central nervous system is to reduce transmitter release. In the spinal cord it affects the activity of motoneurons and interneurons that are important for micturition and baclofen has previously been reported to have an inhibitory action on rat micturition after intrathecal administration (Igawa et al. J. Urol, 150, 537-542, 1993; Pehrson et al. J. Urol, 168, 2700-2705 ,2002).

Taken together, it is suggested that GABA_B system is involved in the micturition control, both in animals and human. A potent and selective GABA_B agonist can provide therapeutic benefit in the treatment of urinary bladder dysfunction as well as other indications described above.

GABA_B agonists are also known to have smooth muscle relaxation action, thus a potent and selective GABA_B agonist can provide therapeutic benefit in the treatment of BPH.

Urinary incontinence

UI is the involuntary loss of urine. UUI is one of the most common types of UI together with stress urinary incontinence (SUI) which is usually caused by a defect in the uretliral closure mechanism. UUI is often associated with neurological disorders or diseases causing neuronal damages such as dementia, Parkinson's disease, multiple sclerosis, stroke and diabetes, although it also occurs in individuals with no such disorders. One of the usual causes of UUI is overactive bladder (OAB) which is a medical condition referring to the symptoms of frequency and urgency derived from abnormal contractions and instability of the detrusor muscle.

There are several medications for urinary incontinence on the market today mainly to help treating UUI. Therapy for OAB is focused on drugs that affect peripheral neural control mechanisms or those that act directly on bladder detrusor smooth muscle contraction, with a major emphasis on development of anticholinergic agents. These agents can inhibit the parasympathetic nerves which control bladder voiding or can exert a direct spasmolytic effect on the detrusor muscle of the bladder. This results in a decrease in intravesicular pressure, an increase in capacity and a reduction in the frequency of bladder contraction. Orally active anticholinergic drugs are the most commonly prescribed dings. However, their most serious drawbacks are unacceptable side effects such as dry mouth, abnormal visions, constipation, and central nervous system disturbances. These side effects lead to poor compliance. Dry mouth symptoms alone are responsible for a 70% non- compliance rate with oxybutynin. The inadequacies of present therapies highlight the need for novel, efficacious, safe, orally available drugs that have fewer side effects. Benign prostatic hyperplasia (BPH)

BPH is the benign nodular hyperplasia of the periurethral prostate gland commonly seen in men over the age of 50. The overgrowth occurs in the central area of the prostate called the transition zone, which wraps around the urethra. BPH causes variable degrees of bladder outlet obstruction - resulting in progressive lower urinary tract syndromes (LUTS) characterized by urinary frequency, urgency, and nocturia due to incomplete emptying and rapid refilling of the bladder. The actual cause of BPH is unknown but may involve age-related alterations in balance of steroidal sex hormones.

The selective αl-adrenoceptor antagonists, such as prazosin, indόramin and tamsulosin are used as an adjunct in the symptomatic treatment of urinary obstruction caused by BPH, although they do not affect on the underlying cause of BPH. In BPH, increased sympathetic tone exacerbates the degree of obstruction of the urethra through contraction of prostatic and urethral smooth muscle. These compounds inhibit sympathetic activity, thereby relaxing the smooth muscle of the urinary tract. Uroselective αl -antagonists and αl -antagonists with high tissue selectivity for lower urinary tract smooth muscle that do not provoke hypotensive side-effects should be developed for the treatment.

Drugs blocking dihydrotestosterone have been used to reduce the size of the prostate. 5α-reductase inhibitors such as finasteride are prescribed for BPH. These agents selectively inhibit 5α-reductase which mediates conversion of testosterone to dihydrotestosterone, thereby reducing plasma dihydrotestosterone levels and thus prostate growth. The 5α-reductase inhibitors do not bind to. androgen receptors and do not affect testosterone levels nor do they possess feminizing side- effects.

Androgen receptor antagonists are used for the treatment of prostatic hyperplasia due to excessive action or production of testosterone. Various antiandrogens are under investigation for BPH including chlomiadione derivatives with no estrogenic activity, orally-active aromatase inhibitors, luteinizing hormone-releasing hormone (LHRH) analogues.

WOO 1/87855 discloses phenyltriazole derivatives represented by the general formula:

wherein

A represents optionally substituted aryl, etc;

B and D independently represent optionally substituted aryl, carbocycles, or 5-or 6-membered heterocycles;

Ra represents H, halgen-substituted alkyl, (un)substituted aryl, (un)substituted heterocycles, (un)substituted cycloalkyl, or -[Alkl]m-X^p-[Alk2]n-Y^p-Rl^p; wherein

Rl^p represents H, optionally substituted aryl, etc;

X^p represents direct bond, -0-, -S-, etc; Y represents direct bond, m and n independently represent an integer of 0 orl ;

Alkl and Alk2 independently represent alkyl, etc,

as an inhibitor of glycine transporter.

Yamada, N. et al. discloses phenyltriazole derivatives represented by the general formula:

wherein

Rb_j represents H, methyl, or ethyl;

Rb2 represents H, chloro, fluoro, dichloro, methyl, methoxy, or trifluoromethyl;

Rb3 represents H, chloro, methyl, ethyl, methoxy, ethoxy, fluoro, trifluoromethoxy, or dichloro,

as a bleaching herbicide (Bioscience, Biotechnology, and Biochemistry (2002), 66(8), 1671-1676).

However, none of these references discloses phenyltriazole derivatives having GABA_B receptor agonistic activity. The development of a compound which has effective GABA_B agonistic activity and can be used for the prophylaxis and treatment of diseases associated with GABA_B receptor activity, in particular for the treatment of urinar}' incontinence, urge urinary incontinence, overactive bladder as well as pain, such as chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, neuralgia, neuropathies, algesia or nerve injur}' induced pain, spasticity and motor control, epilepsy, cognitive defects, psychiatric disorders, alcohol dependence and withdrawal, feeding behaviour, cardiovascular, respiratory disorders and gastrointestinal disorders has been desired.

SUMMARY OF THE INVENTION

This invention is to provide phenyltriazole derivatives of the formula (I), their tautomeric and stereoisomeric form, and salts thereof:

wherein

R¹ represents alkyl optionally substituted by one or two substituents selected from the group consisting of alkoxy, amino, alkylamino, di(alkyl)amino, alkanoyloxy, hydroxy, carboxy, alkoxycarbonyl, cycloalkylphenyloxy, halogen, morpholino, carbamoyl, alkylsulfonyl- amino, phenyloxy optionally substituted by cycloalkyl, and 3- 8 membered saturated ring optionally having one or two N atom which ring optionally substituted by hydroxy or alkanoyl, or 3-S membered saturated or unsaturated ring optionally having one or two hetero atoms selected from the group consisting of N and O, and which ring is optionally substituted by one or two substituents selected from the group consisting of alkyl, halogen, alkoxy, nitro, amino, cyano, alkylamino, di(alkyl)amino, 4-7 membered saturated cyclic amine optionally substituted by hydroxy, and mono-, di-, or tri- halogen substituted alkyl;

R² represents -COR²¹ , -(CH_{2 n}-R²¹ or tert-butyl, wherein

R²¹ is alkoxy, hydroxy, mono-, di-, or tri- halogen substituted alkyl, or 3-8 membered saturated or unsaturated ring optionally having one for two heteroatoms selected from the group consisting of N, O, and S and which ring is optionally substituted by one or two substituents independently selected from the group consisting of alkanoyl, halogen, benzyl, alkoxycarbonyl, haloalkyloxy- carbonyl, cyano, hydroxy, amino, alkylamino, di(alkyl)amino, cycloalkylamino, . alkoxycarbonyl, sulfamoyl, alkylaminosulfonyl, di(alkyl)aminosulfonyl, alkanoyl, alkanoylaminό, carbamoyl, alkylcarbamoyl, di-(alkyl)carbamoyl, alkylsulfonyl, alkyl optionally substituted by alkoxycarbonyl or mono-, di-, or tri-halogen, alkoxy optionally substituted by mono-, di-, or tri- halogen, and alkylthio optionally substituted by mono-, di-, or tri- halogen; n is 0 or 1 ;

R³ and R⁴ independently represent hydrogen, halogen, cyano, hydroxy, amino, alkylamino, di(alkyl)amino, cycloalkylamino, carboxy, alkoxycarbonyl, sulfamoyl, alkylaminosulfonyl, di(alkyl)aminosulfonyl, alkanoyl, alkanoylamino, carbamoyl, alkylcarbamoyl, di- (alkyl) carbamoyl, alkylsulfonyl, alkyl optionally substituted by hydroxy, alkoxycarbonyl or mono-, di-, or tri-halogen, alkoxy optionally substituted by mono-, di-, or tri- halogen, or alkylthio optionally substituted by mono-, di-, or tri- halogen;

R^{5 ■} represents hydrogen, hydroxy, nitro, cyano, halogen, sulfamoyl, alkylsulfonyl, alkylaminosulfonyl, di(alkyl)aminosulfonyl, -(CH₂)_m-CO-R⁵⁰, -(CH₂)_m-R⁵¹, -NR⁵²R⁵³, or -OR⁵⁴, wherein m is O, 1, 2, or 3

R⁵⁰ is hydroxy, hydrogen, alkoxy, morpholino, di(phenyl)methyloxy, di(halogen substituted phenyl)methyloxy, -NR^50IR⁵⁰² (wherein said R⁵⁰¹ and R⁵⁰² independently represent hydrogen, alkoxyalkyl, alkyl, hydroxyalkyl, alkoxycarbonylalkyl, or carboxyalkyl or

R⁵⁰¹ and R⁵⁰² together form with the adjuscent N atom, morpholino, piperazino optionally substituted by oxo, or 4-7 membered saturated cyclic amino optionally substituted by one substituent selected from the group consisting of carboxy, hydroxyalkyl, hydroxy, and carbamoyl) or alkyl optionally substituted by halogen, R⁵¹ is hydrogen, hydroxy,- or -NR⁵¹¹R⁵¹² (wherein said R⁵" and R⁵¹² independently represent hydrogen, alkoxyalkyl, alkyl, hydroxyalkyl, alkoxycarbonylalkyl, or carboxyalkyl, or R^su and R⁵¹² together form with the adjuscent N atoxn, 4-7 membered ' saturated cyclic amino optionally substituted by one substituent selected from the group consisting of carboxy, hydroxyalkyl, hydroxy, and carbamoyl), R⁵² and R⁵³ independently represent hydrogen, alkyl, hydroxy, cycloalkylcarbonyl, hydroxyalkyl, alkylsulfonyl, hydroxyalkylcarbonyl, carboxyalkylcarbonyl, alkanoyloxyalkylcarbonyl, or alkoxycarbonylalkylcarbonyl, or R⁵² and R⁵³ together form with adjuscent N atom, morpholino, cyclic amino optionally substituted by one substituent selected from the group consisting of carboxy, hydroxyalkyl, hydroxy, and carbamoyl,

R⁵⁴ represents alkyl optionally substituted by morpholino, amino, di(alkyl)amino, carboxy, alkoxycarbonyl, or mono-, di-, or tri- halogen, or piperazino substituted by carboxy;

R⁶ and R⁷ independently represents hydrogen, morpholino, hydroxypyrrolidinylcarbonyl, hydroxyalkylaminocarbonyl, cyano, hydroxy, hydroxyalkyl, hydroxyamino, carboxy, fluoro, chloro, bromo, nitro, amino, alkylamino, di(alkyl)amino, cycloalkylamino, alkoxycarbonyl, sulfamoyl, alkylaminosulfonyl, di(alkyl)aminosulfonyl, alkanoyl, alkanoylamino, carbamoyl, diphenylmethyloxycarbonyl, alkylcarbamoyl, di-(alkyl)carb- amoyl, alkylsulfonyl, alkyl optionally substituted by alkoxyalkyl(alkyl)amino, di(alkyl)amino, alkoxycarbonyl, carboxy, or mono-, di-, or tri-halogen, alkoxy optionally substituted by morpholino, di(alkyl)amino, or mono-, di-, or tri- halogen, or C_1-6 alkylthio optionally substituted by mono-, di-, or tri- halogen

or R⁶ and R⁷ together form phenyl fused to adjacent phenyl; and

X represents CR^R^{1 ]} , NR.¹², S, O, S0₂, or SO

wherein R¹⁰, R¹¹, and R¹² independently represent hydrogen or methyl.

The phenyltriazole derivatives of formula (I), their tautomeric and stereoisomeric form, and salts thereof surprisingly show excellent GABA_B agonistic activity. They are, therefore, suitable especially for the prophylaxis and treatment of diseases associated with GABA_B receptor activity, in particular for the treatment of urinary incontinence, urge urinary incontinence and/or overactive bladder.

The compounds of the present invention are also effective for treating or preventing a disease selected from the group consisting of pain, such as chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, neuralgia, neuropathies, algesia, or nerve injur}' induced^' pain, spasticity and motor control, epilepsy, cognitive defects, psychiatric disorders, alcohol dependence and withdrawal, feeding behaviour, cardiovascular, respiratory disorders and gastrointestinal disorders since the diseases also relate to GABA_B receptor activity.

h another embodiment, the phenyltriazole derivatives of formula (I) are those wherein;

wherein

R¹ represents alkyl optionally substituted by one or two substituents selected from the group consisting of alkoxy, amino, alkylamino, di(alkyl)amino, alkanoyloxy, hydroxy, carboxy, alkoxycarbonyl, cycloalkylphenyloxy, halogen, morpholino, carbamoyl, phenyloxy optionally substituted by cycloalkyl, and 3- 8 membered saturated ring optionally having one or two N atom which ring optionally substituted by hydroxy or alkanoyl, or 3-8 membered saturated or unsaturated ring optionally having one or two hetero atoms selected from the group consisting of N and O, and which ring is optionally substituted by one or two substituents selected from the group consisting of alkyl, halogen, alkoxy, nitro, amino, cyano, alkylamino, di(alkyl)amino, 4-7 membered saturated cyclic amine optionally substituted by hydroxy, and mono-, di-, or tri- halogen substituted alkyl;

R² represents -COR²¹ or -(CH₂)_n-R²¹, wherein

R²¹ is alkoxy, hydroxy, mono-, di-, or tri- halogen substituted alkyl, or 3-8 membered saturated or unsaturated ring optionally having one or two heteroatoms selected from the group consisting of N, O, and S and which ring is optionally substituted by one or two substituents independently selected from the group consisting of alkanoyl, halogen, benzyl, alkoxycarbonyl, haloalkyloxy- carbonyl, cyano, hydroxy, amino, alkylamino, di(alkyl)amino, cycloalkylamino, alkoxycarbonyl, sulfamoyl, alkylaminosulfonyl, di(alkyl)aminosulfonyl, alkanoyl, alkanoylamino, carbamoyl, alkylcarbamoyl, di-(alkyl)carbamoyl, alkylsulfonyl, alkyl optionally substituted by alkoxycarbonyl or mono-, di-, or tri-halogen, alkoxy optionally substituted by mono-, di-, or tri- halogen, and alkylthio optionally substituted by mono-, di-, or tri- halogen; n is O or l; R³ and R⁴ independently represent hydrogen, halogen, cyano, hydroxy, amino, alkyramino, dι(alkyl)amino, cycloalkylamino, alkoxycarbonyl, sulfamoyl, alkylaminosulfonyl, dι(alkyl)aminosulfonyl, alkanoyl, alkanoylamino, carbamoyl, alkylcarbamoyl, di- (alk}'l)carbamoyl, alkylsulfonyl, alkyl optionally substituted by alkoxycarbonyl or mono-, di-, or tri-halogen, alkoxy optionally substituted by mono-, di-, or tri- halogen, or alkylthio optionally substituted by mono-, di-, or tri- halogen;

R⁵ represents hydrogen, hydroxy, nitro, cyano, halogen, sulfamoyl, alkylsulfonyl, alkylaminosulfonyl, di(alkyl)aminosulfonyl, -(CH₂)_m-CO-R⁵⁰, -(CH₂)_m-R⁵¹, -NR⁵²R⁵³, or -OR⁵⁴, wherein m is 0, 1, 2, or 3

R⁵⁰ is hydroxy, hydrogen, alkoxy, morpholino, di(phenyl)methyloxy, di(halogen substituted phenyl)methyloxy, -NR⁵⁰¹R⁵⁰² (wherein said R⁵⁰¹ and R⁵⁰² independently represent hydrogen, alkoxyalkyl, alkyl, hydroxyalkyl, alkoxycarbonylalkyl, or carboxyalkyl or R⁵⁰¹ and R⁵⁰² together form with the adjuscent N atom, morpholino, or 4-7 membered saturated cyclic amino optionally substituted by one substituent selected from the group consisting of carboxy, hydroxyalkyl, hydroxy, and carbamoyl) or alkyl optionally substituted by halogen,

R⁵¹ is hydrogen, hydroxy, or -NR⁵¹¹R⁵¹² (wherein said R⁵¹¹ and R⁵¹² independently represent hydrogen, alkoxyalkyl, alkyl, hydroxyalkyl, alkoxycarbonylalkyl, or carboxyalkyl, or R⁵¹¹ and R⁵¹² together foπn with the adjuscent N atom, 4-7 membered saturated cyclic amino optionally substituted by one substituent selected from the group consisting of carboxy, hydroxyalkyl, hydroxy, and carbamoyl), R⁵² and R⁵³ independently represent hydrogen, alkyl, hydroxy, cycloalkylcarbonyl, or hydroxyalkyl, or R⁵² and R⁵³ together form with adjuscent N atom, morpholino, cyclic amino optionally substituted by one substituent selected from the group consisting of carboxy, hydroxyalkyl, hydroxy, and carbamoyl,

R⁵⁴ represents alkyl optionally substituted by morpholino, amino, di(alkyl) amino, or mono-, di-, or tri- halogen; R⁶ and R⁷ independently represents hydrogen, morpholino, hydroxypyrrolidinylcarbonyl, hydroxyalkylaminocarbonyl, cyano, hydroxy, hydroxyalkyl, hydroxyamino, carboxy, fluoro, chloro, bromo, nitro, amino, alkylamino, di(alkyl)amino, cycloalkylamino, alkoxycarbonyl, sulfamoyl, alkylaminosulfonyl, di(alkyl)aminosulfonyl, alkanoyl, alkanoylamino, carbamoyl, diphenylmethyloxycarbonyl, alkylcarbamoyl, di-(alkyl)carb- amoyl, alkylsulfonyl, alkyl optionally substituted by alkoxyalkyl(alkyl)amino, di(alkyl)amino, alkoxycarbonyl, carboxy, or mono-, di-, or tri-halogen, alkoxy optionally substituted by morpholino, di(alkyl)amino, or mono-, di-, or tri- halogen, or „6 alk}'lthio optionally substituted by mono-, di-, or tri- halogen

or R⁶ and R⁷ together form phenyl fused to adjacent phenyl; and

X represents CR¹⁰Rⁿ, NR¹², S, O, S0₂, or SO

wherein Rⁱ⁰, R¹¹, and R¹² independently represent hydrogen or methyl.

Yet another embodiment of formula (I) can be those wherein:

X represents CH₂, NH, S, O, S0₂, or SO;

R¹ represents C₃ to C₈ cycloalkyl,

Cj-C_ό alkyl optionally substituted by one or two substituents selected from the group consisting of Cι-C₆ alkoxy, amino, C C₆ alkylamino, di(C C₆ alkyl)amino, C_rC₆ alkanoyloxy, hydroxy, C₃-C₈ cycloalkyl, carboxy, C C₆ alkoxycarbonyl, C₃-C₈ cycloalkylphenyloxy, halogen, morpholino, and pyrrolidinyl, pyridyl, pyrrolidinyl, piperidinyl optionally substituted by methyl, or phenyl optionally substituted by one selected from the group consisting of halogen, Cι-C₆ alkoxy, nitro, amino, cyano, Ci-Cβalkylamino, di(Cι-C₆alkyl)amino, and mono-, di- or tri- halogen substituted d-C₆alkyl,

R" represents -COR' or ~(CH₂) -R^~ , wherein R represents mono-, di-, tri- halogen sub- stituted C C₆ alkyl, morpholino, Ci-C_δ alkoxy, hydroxy, C₃ to C₈ cycloalkyl, pyridyl, furanyl, thiophenyl, pyrrolidinyl, piperidinyl optionally substituted by one substituent selected from the group consisting of benzyl, Ci-Cg alkoxycarbonyl, and halo C C₆ alkyloxycarbonyl, or phenyl optionally substituted by one substituent selected from the group consisting of C C₆ alkyl, halogen, Cj-Cβ alkoxy, and mono-, di-, or tri- halogen substituted Cι-C₆alkyl; n is 0 or 1 ;

R³ and R⁴ independently represent hydrogen, halogen, cyano, hydroxy, amino, Cι_-6 alkylamino, di(Cj.₆ alkyl)amino, C₃.₈ cycloalltylamino, Cι_-6 alkoxycarbonyl, sulfamoyl, Cι_-6 alkylaminosulfonyl, di(C].₆ alkylaminosulfonyl, C alkanoyl, Cι_₆ alkanoylamino, carbamoyl, C|.₆ alkylcarbamoyl, di-(C_]-6 alkyl)carbamoyl, C].₆ alkylsulfonyl, Cj.₆ alkyl optionally substituted by Cι.₆ alkoxycarbonyl or mono-, di-, or tri-halogen, Cj.₆ alkoxy optionally substituted by mono-, di-, or tri- halogen, or Cι_-6 alkylthio optionally substituted by mono-, di-, or tri- halogen;

R⁵ represents hydrogen, nitro, cyano, hydroxy, halogen, sulfamoyl, Cι-C₆alkylsulfonyl, Cj- C₆alkylaminosulfonyl, di(C,-C₆alkyl)aminosulfonyl, -(CH₂)_m-CO-R⁵⁰, -(CH₂)_m-R⁵¹, -NR⁵²R⁵³, or -OR⁵⁴, wherein m is 0, 1, 2, or 3

R⁵⁰ is hydroxy, hydrogen, Cι-C₆alkoxy, morpholino, diphenylmethyloxy, -NR⁵⁰¹R⁵⁰² (wherein said R⁵⁰¹ and R⁵⁰² independently represent hydrogen, -Cealkoxyalkyl, C C₆alkyl, hydroxy C C_όalkyl, Cι-C₆alkoxycarbonyl C C₆alkyl, or carboxy C C₆alkyl or R⁵⁰¹ and R⁵⁰² together form with the adjacent N atom morpholino, 4-6 membered saturated cyclic amino optionally substituted by one substituent selected from the group consisting of carboxy, hydroxyalkyl, hydroxy, and carbamoyl) or Cι-C₆ alkyl optionally substituted by halogen, R⁵¹ is hydrogen, hydroxy, or -NR⁵ⁿR⁵¹² (wherein said R⁵¹¹ and R⁵¹² independently represent hydrogen, C C₆ alkoxy alkyl, Cj-C₆ alkyl, hydroxyalkyl, C_rC₆ alkoxycarbonylalkyl, or carboxyalkyl or R⁵¹¹ and R⁵¹² together form with the adjacent N atom, 4-7 membered saturated cyclic amino optionally substituted by one substituent selected from the group consisting of carboxy, hydroxyalkyl, hydroxy, and carbamoyl)

R⁵² and R⁵³ independently represent hydrogen, C]-C₆ alkyl, hydroxy, C₃-C₃cycloalkyl- carbonyl, or hydroxy C C₆ alkyl or R⁵² and R⁵³ together form with adjacent N atom, morpholino, 4-7 membered saturated cyclic amino optionally substituted by one substituent selected from the group consisting of carboxy, hydroxyalkyl, hydroxy, and carbamoyl

R⁵⁴ represents alkyl optionally substituted by morpholino, amino, or di(alkyl) amino, or mono-, di-, or tri- halogen; and R⁶ and R⁷ independently represent hydrogen, morpholino, . hydroxypyrrolidinylcarbonyl, hydroxyCι-C₆alkylaminocarbonyl, cyano, hydroxy, hydroxyCι-C₆alkyl, hydroxyamino, carboxy, fluoro, chloro, bromo, nitro, amino, Cι_-6 alkylamino, di(C_1-6 alkyl)amino, C₃._s cycloalkylamino, d_-6 alkoxycarbonyl, sulfamoyl, Cι.₆ alkylaminosulfonyl, di(C_]-6 alkylaminosulfonyl, Cι-6 alkanoyl, Cι-6 alkanoylamino, carbamoyl, diphenylmeth- yloxycarbonyl, d-β alkylcarbamoyl, di-(Cι.₆ alk}'l)carbamoyl, Ci-β alkylsulfonyl, Cι_-6 alkyl optionally substituted by alkoxyalkyl(alkyl)amino, di(alkyl)amino, C .₆ alkoxycarbonyl, carboxy, or mono-, di-, or tri-halogen, -β alkoxy optionally substituted by morpholino, di(alkyl)amino, or mono-, di-, or tri- halogen, or Cι-₆ alkylthio optionally substituted by mono-, di-, or tri- halogen or R⁶ and R⁷ together form phenyl fused to adjacent phenyl.

Yet another embodiment of formula (I) can be those wherein:

X represents CH₂, NH, S, or SO;

R¹ represents cyclopropyl, pyridyl, phenyl optionally substituted by halogen, C_rC₆alkoxy, nitro, amino, cyano, C C_fialkylamino, di(Cι-C₆alkyl)amino, or halogen substituted C C₆alkyl,

Ci-Ce alkyl optionally substituted by one or two substituents selected from the group consisting of d-C₆alkoxy, amino, Cι-C₆ alkylamino, di(C-ι-C₆ alkyl)amino, C C₆ alkanoyloxy, hydroxy, C₃-C₈ cycloalkyl, carboxy, d- alkoxycarbonyl, C₃-C₃ cycloalkylphenyloxy, halogen, morpholino, and pyrrolidinyl, pyrrolidinyl, or piperidinyl optionally substituted by methyl;

R" represents -COR" or -(CH₂)_n-R , wherein R" represents mono-, di- or tri- halogen substituted alkyl, morpholino, Ci-dalkoxy, hydroxy, C₃ to C₈ cycloalkyl, pyridyl, furanyl, thiophenyl, pyrrolidinyl, piperidinyl optionally substituted by one selected from the group consisting from benzyl, d-Cβalkoxycarbonyl, and haloCi-C_όalkyloxycarbonyl, or phenyl optionally substituted by one selected from the group consisting of C C₆ alkyl, halogen, d-C_ό alkoxy, and mono-, di- or tri- halogen substituted Ci-Cgalkyl; n is 0 or 1 ;

R³ and R⁴ independently represent hydrogen, halogen, methyl, or amino; R⁵ represents hydrogen, moφholino, hydroxypyrrolidinylcarbonyl, hydroxyalkylaminocatbonyl, cyano, hydroxy, hydroxyalkyl, hydroxyamino, carboxy, fluoro, chloro, bromo, nitro, amino, d-β alkylamino, di(Cι.₆ alkyl)amino, C₃.₈ cycloalkylamino, C .₆ alkoxycarbonyl, sulfamoyl, C_1-6 alkylaminosulfonyl, di(C_1-6 alkylaminosulfonyl, C_1-6 alkanoyl, Ci-e alkanoylamino, carbamoyl, diphenylmethyloxycarbonyl, C_]-6 alkylcarbamoyl, di-(Cι.₆ alkyl)carbamoyl, Ci-β alkylsulfonyl, d„₆ alkyl optionally substituted by alkoxy- alkyl(alk}'l)amino, di(alk}'l)amino, Ci-β alkoxycarbonyl, carboxy, or mono-, di-, or tri- halogen, Cj.6 alkoxy optionally substituted by moφholino, di(alkyl)aιrιino, or substituted by mono-, di-, or tri- halogen, or Ci.₆ alkylthio optionally substituted by mono-, di-, or tri- halogen; and

R⁶ andR⁷ represent hydrogen, or R° and R⁷ together form phenyl fused to adjacent phenyl.

Yet another embodiment of formula (I) can be those wherein:

X represents CH₂, NH, or S;

R¹ represents cyclopropyl, pyridyl, phenyl optionally substituted by halogen, alkoxy, nitro, amino, cyano, alkylamino, di(alkyl)amino, or halogen substituted alkyl, d-C₆ alkyl optionally substituted by one or two substituents selected from the group consisting of alkoxy, amino, d-C₆ alkylamino, di(d-C₆ alkyl)amino, C C₆ alkanoyloxy, hydroxy, C₃-C₈ cycloalkyl, carboxy, d-C₆ alkoxycarbonyl, C₃-C₈ cycloalkylphenyloxy, halogen, moipholino, and pyrrolidinyl, pyrrolidiny, or piperidinyl optionally substituted by methyl.

Further, another embodiment of formula (I) can be those wherein:

X represents CH₂, NH, or S;

R² represents -COR²¹, -(CH₂)_nR²¹, wherein R²¹ is phenyl optionally substituted by C,-C₆ alkyl, halogen, halogen substituted alkyl or alkoxy and n is 0 or 1.

Additional embodiment of formula (I) can be those wherein:

X represents CH₂, NH, or S; .

R³ and R⁴ independently represent hydrogen, halogen, methyl, amino; and R⁵ represents hydrogen, moφholino, hydroxypyrrolidinylcarbonyl, hydroxyalkylaminocarbonyl, cyano, hydroxy, hydroxyalkyl, hydroxyamino, carboxy, fluoro, chloro, bromo, nitro, amino, d-β alkylamino, di(C].₆ alk}'l)amino, C_3-8 cycloalkylamino, Ci-s alkoxycarbonyl, sulfamoyl, Cι.₆ alkylaminosulfonyl, di(Cι_-6 alkylaminosulfonyl, C_1-6 alkanoyl, Cι-6 alkanoylamino, carbamoyl, diphenylmethyloxycarbonyl, d-₆ alkylcarbamoyl, di-(Cι_-6 alkyDcarbamoyl, Ci.6 alkylsulfonyl, Cι.₆ alkyl optionally substituted by alkoxy- alkyl(alkyl)amino, di(alkyl)amino, Cι-6 alkoxycarbonyl, carboxy, or mono-, di-, or tri- halogen, Cj.6 alkoxy optionally substituted by moφholino, di(alkyl)amino, or substituted by mono-, di-, or tri- halogen, or C].₆ alkylthio optionally substituted by mono-, di-, or tri- halogen; and

R° and R⁷ represents hydrogen.

More preferably, said phenyltriazole derivative of the formula (I) is selected from the group consisting of:

(4-{3-cyclopropyl-5-[(diphenylmethyl)thio]-4H-l,2,4-triazol-4-yl}phenyl)dimethylamine;

(4-{3-[(diphenylmethyl)thio]-5-ethyl-4H-l,2,4-triazol-4-yl}phenyl)dimethylamine;

(4-{3-[(diphenylmethyl)thio]-5-propyl-4H-l,2,4-triazol-4-yl}phenyl)dimethylamine;

[4-(3-cyclopropyl-5-{[(2-methylphenyl)(phenyl)methyl]thio}-4H-l,2,4-triazol-4-yl)phenyl]dimeth- ylamine;

[4-(3-{[bis(4-chlorophenyl)methyl]thio}-5-cyclopropyl-4H-l,2,4-triazol-4-yl)phenyl]dimethyl- amine;

[4-(3 -cyclopropyl-5 - {[(4-methylphenyl)(phenyl)methyl] thio } -4H- 1 ,2,4-triazol-4-yl)phenyl] dimeth- ylamine;

[4-(3-{[bιs(4-fluorophenyl)methyl]thio}-5-cyclopropyl-4H-l,2,4-triazol-4-yl)phenyl]dimethyl- amine;

[4-(3-{[(4-chlorophenyl)(phenyl)methyl]thio}-5-cyclopropyl-4H-l,2,4-triazol-4-yl)phenyl]dimeth- ylamine;

(4-{3-cyclobutyl-5-[(diphenylmethyl)thio]-4H-l,2,4-triazol-4-yl}phenyl)dimethylamine;

(4-{3-butyl-5-[(diphenylmethyl)thio]-4H-l,2,4-tι-iazol-4-yl}phenyl)dimethylamine; [4-(3 - { [bis(4-methylphenyl)methyl]thio } -5 -cyclopropyl-4H- 1 ,2 ,4-triazol-4-yl)phenyl]dimetK- ylamine;

{4-[3-cyclopropyl-5-({phenyl[4-(trifluoromethyl)phenyl]methyl}thio)-4H-l,2,4-triazol-4-yl]phen- yl} dimethylamine;

[4-(3-{[(4-chlorophenyl)(cyclohexyl)methyl]thio}-5-cyclopropyl-4H-l,2,4-triazol-4-yl)phenyl]di- methylamine;

3-[(diphenylmethyl)thio]-5-ethyl-4-(4-isopropylphenyl)-4H-l,2,4-triazole;

{4-[3-{[bis(4-chlorophenyl)methyl]thio}-5-(3-fluorophenyl)-4H-l,2,4-triazol-4-yl]phenyl}dimeth- ylamine;

[4-(3-{[bis(4-chlorophenyl)methyl]thio}-5-propyl-4H-l,2,4-triazol-4-yl)phenyl]dimethylamine;

3-(3-{[bis(4-chlorophenyl)methyl]thio}-5-propyl-4H-l,2,4-triazol-4-yl)benzoic acid;

3-{5-{[bis(4-chlorophenyl)methyl]thio}-4-[4-(dimethylamino)phenyl]-4H-l,2,4-triazol-3- yl}propan-l-ol;

3 -[3 -{ [bis(4-chlorophenyl)methyl]thio } -5 -(3 -fluorophenyl)- 4H- 1 ,2,4-triazol-4-yl]benzoic acid;

3-[3-{[bis(4-chlorophenyl)methyl]thio}-5-(3-fluorophenyl)- 4H-l,2,4-triazol-4-yl]phenol;

3-(3-{[bis(4-chloiOphenyl)methyl]thio}-5-propyl-4H-l,2,3-triazol-4-yl)benzoic acid;

3-(3-{[bis(4-chlorophenyl)methyl]thio}-5-cyclopropyl-4H-l,2,4-triazol-4-yl)benzoic acid;

5-[3-{[bis(4-chlorophenyl)methyl]thio}-5-(3-fluorophenyl)-4H-l,2,4-triazol-4-yl]-2-(dimethyl- amino)benzoic acid;

l-[4-(3-{[bis(4-chlorophenyl)methyl]thio}-5-propyl-4H-l,2,4-triazol-4-yl)phenyl]-piρeridine-3- carboxylic acid; and

l-{4-[3-{[bis(4-chlorophenyl)methyl]thio}-5-(3-fluorophenyl)-4H-l,2,4-triazol-4-yl]-phenyl}- piperidine-3 -carboxylic acid

or the salt thereof.

Further, the present invention provides a medicament, which includes one of the compounds, described above and optionally pharmaceutically acceptable excipients. Alkyl per se and "alk" and "alkyl" in alkenyl, alkynyl, alkoxy, alkanoyl, alkylamino, alkylamino- ^• carbonyl, alkylaminosulphonyl, alkylsulphonylamino, alkoxycarbonyl and alkoxycarbonylamino represent a linear, branched alkyl radical having generally 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3 carbon atoms, representing illustratively and preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

"Alk" in alkanoylamino represent a linear, branched and cyclo alkyl radical having generally 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3 carbon atoms, representing illustratively and preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl, n-hexyl, and cyclopropyl.

Alkoxy illustratively and preferably represents methoxy, ethoxy, n-propoxy, isopropoxy, tert- butoxy, n-pentoxy and n-hexoxy.

Alkylamino illustratively and preferably represents an alkylamino radical having one or two (independently selected) alkyl substituents, illustratively and preferably representing methylamino, ethylammo, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexyl-amino, N,N- dimethylamino, ^■ N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N- isopropyl-N-n-propylamino, N-t-butyl-N-methylamino, N-ethyl-N-n-pentylamino and N-n-hexyl- N-methylamino.

4-7 membered .saturated Cyclic amine illustratively and preferably represent pyrrolidine, piperidine, azepane, and azetidine.

Heterocycle and/or heterocyclic as used herein, designate a closed ring structure, in which one or more of the atoms in the ring is a heteroatom such as sulfur, nitrogen, oxygen, and the like. Suitable examples include, without limitation, pyrrolidinyl, piperidino, piperazinyl, homo- piperidino, moφholinyl, thiomoφholinyl, tetrahydrofuryl, furyl, thienyl, pyiτolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl and the like.

EMBODIMENT OF THE INVENTION

The compound of the formula (I) of the present invention can be, but not limited to be, prepared by combining various known methods. In some embodiments, one or more of the substituents, such as amino group, carboxyl group, and hydroxyl group of the compounds used as starting materials or intermediates are advantageously protected by a protecting group known to those skilled in the art. Examples of the protecting groups are described in "Protective Groups in Organic Synthesis (3rd Edition)" by Greene and Wuts, John Wiley and Sons, New .York 1999. The compound of the formula (I-a) of the present invention can be, but not limited to be, prepared by the Method [A] below.

[Method A]

The compound of the formula (I-a) (wherein R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are the same as defined above and X' represents O, S or NR¹²) can be prepared by reacting the compound of the formula (If) (wherein R¹, R⁵, R⁶ and R⁷ are the same as defined above) with the compound of the formula (HT) (wherein R², R³ and R⁴ are the same as defined above and Li represents a leaving group including, for instance, halogen atom such as chlorine, bromine, or iodine atom; C₆.ιo arylsulfonyloxy group such as benzenesulfonyloxy, or p-toluenesulfonyloxy; and C_r4 alkylsulfonyloxy group such as methanesulfonyloxy, and the like.)

The reaction may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1 ,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N, N-dimethyl- formamide (DMF), N, N-dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP); urea such as l,3-dimethyl-2-imidazolidinone (DMI); sulfoxides such as dimethylsulfoxide (DMSO); and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature can be optionally set depending on the compounds to be reacted. The reaction temperature is usually, but not limited to, about 20°C to 50 °C. The reaction may be conducted for, usually, 30 minutes to 10 hours and preferably 1 to 24 hours.

The reaction can be advantageously carried out in the presence of a base including, for instance, organic amines such as pyridine, triethylamine and N,N-diisopropylethylamine, dimethylaniline, diethylaniline, or 4-dimethylaminopyridine, and inorganic base such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, or potassium bicarbonate, and others. R⁵, R⁶, and/or R⁷ of compound of the formula (I) can be further modified using conventional methods.

X' is further modified to be converted to SO or S0₂.

Preparation of intermediate (H-a)

[Method (i)]

The compound of the formula (Il-a) (wherein R¹, R⁵, R^δ and R⁷ are the same as defined above) can be prepared by the following procedures in two steps.

In Step i-1, the compound of the formula (VI) (wherein R¹, R⁵, R⁶ and R⁷ are the same as defined above) can be prepared by reacting the compound of the formula (IV) (wherein R¹ is the same as defined above) with the compound of the formula (V) (wherein R⁵, R⁶ and R⁷ are the same as defined above).

The reaction may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1 ,2-dichloroethane; ethers such as diethyl ether, iso- propyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N, N- dimethylformamide (DMF), N, N-dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP); urea such as l,3-dimethyl-2-imidazolidinone (DMI); sulfoxides such as dimethylsulfoxide (DMSO); and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature can be optionally set depending on the compounds to be reacted. The reaction temperature is usually, but not limited to, about room temperature to 100°C. The reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 1 to 24 hours. In Step i-2, the compound of the formula (11-a) (wherein R¹, R , R⁶ and R⁷ are the same as defined above) can be prepared by cyclization reaction of the compound of the formula (VI) (wherein R¹, R⁵, R°and R⁷ are the same as defined above).

The reaction can be advantageously carried out in the presence of a base including, for instance, organic amines such as pyridine, triethylamine and N,N-diisopropylethylamine, dimethylaniline, diethylaniline, or 4-dimethylaminopyridine, and inorganic base such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, or potassium bicarbonate, and others.

The reaction can be carried out in a solvent including, for instance, alcohols such as methanol, ethanol, 1-propanol, isopropanol and tert-butanol, water and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature is usually, but not limited to, about 0°C to 200°C and preferably about 20°C to 100°C. The reaction may be conducted for, usually, 30 minutes to 4S hours and preferably 2 hours to 24 hours.

The compound of the formula (V) is commercially available or can be prepared by the use of known techniques.

Preparation of intermediate (TV)

[Method (ii)]

( ^lll> (IX)

In step ii-la, the compound of the formula (IN) (wherein R¹ is the same as defined above) can be prepared by reacting the compound of the formula (VET) (wherein R¹ is the same as defined above and L₂ represents a leaving group including, for instance, halogen atom such as chlorine, bromine, or^' iodine atom, hydroxy and Cι„₆ alkoxy) with hydrazine (free base, its salt or its hydrate). The reaction can be carried out in a solvent including, for instance, alcohols such as me'tnanol, ethanol, 1-propanol, isopropanol and tert-butanol, water and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature is usually, but not limited to, about 0°C to 200°C and preferably about 0°C to 100°C. The reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 2 hours to 24 hours.

Alternatively, the compound of the formula (IN) can be prepared by the following procedures.

In Step ii-lb, the compound of the formula (LX) (wherein wherein R¹ is the same as defined above and L₃ represents a protecting group including, for instance, tert-butoxycarbonyl) can be prepared by reacting the compound of the formula (VII) (wherein R¹ and L₂ are the same as defined above) with the compound of the formula (VuT) (wherein L₃ is the same as defined above).

When L₂ is hydroxy, the reaction can be done using a coupling agent including, for instance, carbodiimides such as Ν, Ν-dicyclohexylcarbodiimide and l-(3-dimethylaminopropyl)-3-ethyl- carbodiimide, benzophenyltriazole- 1 -yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl azide. Ν-hydroxysuccinimide, 1-hydroxybenzotiazole monohydrate (HOBt), and the like can be used as an accelerator of the reaction.

The reaction may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1 ,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as Ν, Ν- dimethylformamide (DMF), Ν, Ν-dimethylacetamide (DMAC) and Ν-methylpyrrolidone (ΝMP); urea such as l,3-dimethyl-2-imidazolidinone (DMI); sulfoxides such as dimethylsulfoxide (DMSO); and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature is usually, but not limited to, about 0°C to 180°C and preferably about 20°C to 100°C. The reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 2 hours to 12 hours.

In Step ii-2b, the compound of the formula (IV) (wherein R¹ is the same as defined above) can be prepared by removing the protecting group L₃ of the compound of the formula (LX) (wherein R¹ and L₃ are the same as defined above). The removal of protective group L₃ can be done by using a reagent including, for instance, 'an acid such as trifluoroacetic acid and hydrochloric acid.

The reaction may be carried out without solvent or in a solvent including, for instance, ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitiiles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAC) and N- methylpyrrolidone (NMP); urea such as l,3-dimethyl-2-imidazolidinone (DMI); and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature can be optionally set depending on compoundss to be reacted. The reaction temperature is usually, but not limited to, about 20°C to 120°C. The reaction may be conducted for, usually, 30 minutes to 60 hours and preferably 1 to 48 hours.

Hydrazine (free base, its salt or its hydrate), the compound of the formula (VH) and (VHJ) are commercially available or can be prepared by the use of known techniques.

Alternative procedures for the preparation of intermediate (VI)

[Method (iii)]

The compound of the formula (VI) (wherein R¹, R , R⁶ and R⁷ are the same as defined above) can be alternatively prepared by the following procedures in three steps.

In Step iii-1, the compound of the formula (X) (wherein wherein L₃, R⁵, R⁶ and R⁷ are the same as defined above) can be prepared by reacting the compound of the formula (VITI) (wherein L is the same as defined above) with the compound of the formula (V) (wherein R⁵, R⁶ and R⁷ are th'e same as defined above) in a similar manner described in Step i-1 for the preparation of compounds of the formula (VI).

In Step iii-2, the compound of the formula (XI) (wherein R⁵, R⁶ and R⁷ are the same as defined above) can be prepared by removing the protecting group L₃ of the compound of the formula (X) (wherein L₃, R⁵, R⁶ and R are are the same as defined above) in a similar manner described in Step ii-2b for the preparation of compounds of the formula (IV).

In Step iii-3, the compound of the formula (VI) (wherein R¹, R⁵, R° and R⁷ are the same as defined above) can be prepared by reacting the compound of the formula (XT) (wherein R⁵, R⁶ and R⁷ are the same as defined above) with the compound of the formula (VIT) (wherein R¹ and L₂ are the same as defined above) in a similar manner described in Step ii-la for the preparation of compounds of the formula (IV).

Preparation of intermediate (Il-b)

[Method (iv)]

^(XV) (ll-b)

The compound of the formula (Il-b) (wherein R¹, R⁵, R^δ and R⁷ are the same as defined above) can be prepared by the following procedures.

In Step iv-1, the compound of the formula (XlTf) (wherein R¹, R⁵, R° and R⁷ are the same as defined above) can be prepared by reacting the compound of the formula (XII) (wherein R⁵, R^δ and R⁷ are the same as defined above) with the compound of the formula (VIT) (wherein R¹ and L₂ are the same as defined above). When L₂ is hydroxy, the reaction can be done using a coupling agent including, for rrfstance, carbodiimides such as N, N-dicyclohexylcarbodiimide and l-(3-dimethylaminopropyl)-3-ethyl- carbodiimide, benzophenyltriazole- 1 -yl-oxy-tris-pyrrolidino~phosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl azide. N-hydroxysuccinimide, 1-hydroxybenzotiazole monohydrate (HOBt), and the like can be used as an accelerator of the reaction.

The reaction may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloro form and 1 ,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N, N-dimethyl- formamide (DMF), N, N-dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP); urea such as l,3-dimethyl-2-imidazolidinone (DMT); sulfoxides such as dimethylsulfoxide (DMSO); and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

In Step iv-2, the compound of the formula (XIV) (wherein R¹, R⁵, R⁶ and R⁷ are the same as defined above) can be prepared by reacting the compound of the formula (XIH) (wherein R¹, R⁵, R⁶ and R⁷ are the same as defined above) with an appropriate halogenating reagent including, for instance, SOCl₂, POCl₃, and the like.

The reaction may be carried out without solvent or in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene, and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature is usually, but not limited to, about 0°C to 200°C and preferably about 20°C to 100°C. The reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 2 hours to 24 hours.

In Step iv-3, the compound of the formula (XV) (wherein R¹, R⁵, R^δ and R⁷ are the same as defined above) can be prepared by reacting the compound of the formula (XIV) (wherein R¹, R⁵, R^δ and R⁷ are the same as defined above) with hydrazine (free base, its salt or its hydrate). The reaction may be carried out in a solvent including, for instance, halogenated hydro arbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as^'N, N-di- methylformamide (DMF), N, N-dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP); urea such as l,3-dimethyl-2-imidazolidinone (DMI); sulfoxides such as dimethylsulfoxide (DMSO); and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

In Step iv-4, the compound of the formula (11-b) (wherein R¹, R⁵, R^δ and R⁷ are the same as defined above) can be prepared by reacting the compound of the formula (XV) (wherein R¹, R⁵, R^δ and R⁷ are the same as defined above) with cyanogen halides such as cyanogen bromide.

The reaction may be carried out in a solvent including, for instance, ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide and N-methylpyrrolidone; alcohols such as methanol, ethanol, 1-propanol, isopropanol and tert-butanol; and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature is usually, but not limited to, about -10°C to 200°C. The reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 1 hour to 24 hours.

The compound of the formula (XTf) is commercially available or can be prepared by the use of known techniques.

Preparation of intermediate (HI)

[Method (v)] ^■

The compound of the formula (EH) (wherein R , R³ and R⁴ are the same as defined above) can be prepared by the following procedures.

In Step v-1, the compound of the formula (XVIH) (wherein wherein R², R³ and R⁴ are the same as defined above) can be prepared by reacting the compound of the formula (XVI) (wherein R³ and R⁴ are the same as defined above) with the compound of the formula (XVH) (wherein R² is the same as defined above and L₄ represents metal or metal complex including, for instance, lithium, magnesium chloride and magnesium bromide).

The reaction may be carried out in a solvent including, for instance, ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aliphatic hydrocarbons such as n-hexane, cyclohexane; aromatic hydrocarbons such as benzene, toluene and xylene; and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature can be optionally set depending on the compounds to be reacted. The reaction temperature is usually, but not limited to, about -20°C to 50°C.

The reaction may be conducted for, usually, 30 minutes to 10 hours and preferably 1 to 24 hours.

The compound of the formula (XVHI) (wherein wherein R², R³ and R⁴ are the same as defined above) can be alternatively prepared by reacting the compound of the formula (XLX) (wherein R², R³ and R⁴ are the same as defined above) with a reducing agent including, for instance, sodium borohydride or lithium aluminum hydride as shown in Step v'-l .

The reaction may be carried out in a solvent including, for instance, ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aliphatic hydro- carbons such as n-hexane, cyclohexane; aromatic hydrocarbons such as benzene, toluene and xylene; and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature can be optionally set depending on the compounds to be reacted. The reaction temperature is usually, but not limited to, about 20°C to 50°C.

The reaction may be conducted for, usually, 30 minutes to 24 hours and preferably 1 to 10 hours.

In Step v-2, the compound of the formula (IE) (wherein Li, R², R³ and R⁴ are the same as defined above) can be prepared by reacting the compound of the formula (XVECT) (wherein wherein R², R³ and R⁴ are the same as defined above) with an appropriate halogenating reagent including, for instance, POCl₃, PC1₃, SOCl₂, and the like; or with the corresponding sulfonyl chloride for instance methanesulfonyl chloride.

The reaction may be carried out without solvent or in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as dioxane and tetrahydrofuran (THF)and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene, and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction can be advantageously conducted in the presence of a base, including, for instance, pyridine, triethylamine and N,N-diisopropylethylamine, dimethylaniline, diethylaniline, and others.

The compound of the formula (XVI), (XVET) and (XTX) are commercially available or can be prepared by the use of known techniques.

Preparation of compound of (I-b)

The compound of the formula (I-b) of the present invention can be, but not limited to be, prepared by the Method [B] below.

[Method B]

The compound of the formula (I-b) (wherein R¹, R², R³, R⁴, R⁵, R^δ, R⁷, R¹⁰ and R¹¹ are the same as defined above) can be prepared by reacting the compound of the formula (Xλ (wherein R¹, R⁵, R^b and R⁷ are the same as defined above) with the compound of the formula (XX) (wherein R², R³, R⁴, R¹⁰ and R¹¹ are the same as defined above and L₄ represents a leaving group including, for instance, halogen atom such as chlorine, bromine, or iodine atom).

he reaction temperature can be optionally set depending on the compounds to be reacted. The reaction temperature is usually, but not limited to, about 20°C to 50 °C. The reaction may be conducted for, usually, 30 minutes to 24 hours and preferably 1 to 10 hours.

The compound of the formula (XX) is commercially available or can be prepared by the use of known techniques.

λVhen the compound shown by the foπnula (I) or a salt thereof has an asymmetric carbon in the structure, their optically active compounds and racemic mixtures are also included in the scope of the present invention.

Typical salts of the compound shown by the formula (I) include salts prepared by reaction of the compounds of the present invention with a mineral or organic acid, or an organic or inorganic base. Such salts are known as acid addition and base addition salts, respectively.

Acids to form acid addition salts include inorganic acids such as, without limitation, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid and the like, and organic acids, such as, without limitation, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p- bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Base addition salts include those derived from inorganic bases, such as, without limitation, ammonium hydroxide, alkaline metal hydroxide, alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, and organic bases, such as, without limitation, ethanolamine, triethylamine, fris(hydroxymethyl)aminomethane, and the like. Examples of inorganic bases include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.

The compound of the present invention or a salt thereof, depending on its substituents, may be modified to form lower alkylesters or known other esters; and/or hydrates or other solvates. Those esters, hydrates, and solvates are included in the scope of the present invention.

The compound of the present invention may be administered in oral forms, such as, without limitation normal and enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solution, suspensions, syrups, solid and liquid aerosols and emulsions. They may also be administered in parenteral forms, such as, without limitation, intravenous, intraperitoneal, subcutaneous, intramuscular, and the like forms, well-known to those of ordinary skill in the pharmaceutical arts. The compounds of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal delivery systems well-known to those of ordinary skilled in the art.

The dosage regimen with the use of the compounds of the present invention is selected by one of ordinary skill in the arts, in view of a variety of factors, including, without limitation, age, weight, sex, and medical condition of the recipient, the severity of the condition to be treated, the route of administration, the level of metabolic and excretory function of the recipient, the dosage form employed, the particular compound and salt thereof employed.

The compounds of the present invention are preferably formulated prior to administration together with one or more pharmaceutically-acceptable excipients. Excipients are inert substances such as, without limitation carriers, diluents, flavoring agents, sweeteners, lubricants, solubilizers, suspending agents, binders, tablet disintegrating agents and encapsulating material. -

Yet another embodiment of the present invention is pharmaceutical formulation comprising a compound of the invention and one or more pharmaceutically-acceptable excipients that are compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Pharmaceutical formulations of the invention are prepared by combining a therapeutically effective amount of the compounds of the invention together with one or more pharmaceutically- acceptable excipients therefore. In making the compositions of the present invention, the active ingredient may be mixed with a diluent, or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container. The carrier may serve as a diluent, which may be solid, semi-solid, or liquid material which acts as a vehicle, or can be in the form of tablets, pills powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

For oral administration, the -active ingredient may be combined with an oral, and non-toxic, pharmaceutically-acceptable carrier, such as, without limitation, lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate, methyl cellulose, and the like; together with, optionally, disintegrating agents, such as, without limitation, maize, starch, methyl cellulose, agar bentonite, xanthan gum, alginic acid, and the like; and optionally, binding agents, for example, without limitation, gelatin, natural sugars, beta- lactose, com sweeteners, natural and synthetic gums, acacia, tragacanth, sodium alginate, carboxymefhylcellulose, polyethylene glycol, waxes, and the like; and, optionally, lubricating agents, for example, without limitation, magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium benzoate, sodium acetate, sodium chloride, talc, and the like.

In powder forms, the carrier may be a finely divided solid which is in admixture with the finely divided active ingredient. The active ingredient may be mixed with a carrier having binding properties in suitable proportions and compacted in the shape and size desired to produce tablets. The powders and tablets preferably contain from about 1 to about 99 weight percent of the active ingredient which is the novel composition of the present invention. Suitable solid carriers are magnesium carboxymethyl cellulose, low melting waxes, and cocoa butter.

Sterile liquid formulations include suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carriers, such as sterile water, sterile organic solvent, or a mixture of both sterile water and sterile organic solvent.

The active ingredient can also be dissolved in a suitable organic solvent, for example, aqueous propylene glycol. Other compositions can be made by dispersing the finely divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil.

The formulation may be in unit dosage form, which is a physically discrete unit containing a unit dose, suitable for administration in human or other mammals. A unit dosage form can be a capsule or tablets, or a number of capsules or tablets. A "unit dose" is a predetermined quantity of the active compound of the present invention, calculated to produce the desired therapeutic effect, in association with one or more excipients. The quantity of active ingredient in a unit dose may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved.

Typical oral dosages of the present invention, when used for the indicated effects, will range from about 0.01 mg/kg/day to about 100 mg kg/day, preferably from 0.1 mg kg/day to 30 mg/kg/day, and most preferably from about 0.5 mg/kg/day to about 10 mg/kg/day. In the case of parenteral administration, it has generally proven advantageous to administer quantities of about 0.001 to lOOmg /kg/day, preferably from 0.01 mg/kg/day to 1 mg/kg/day. The compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses, two, three, or more times per day. Where deliver}' is via transdermal forms, of course, administration is continuous.

EXAMPLES

The present invention will be described as a form of examples, but they should by no means be construed as defining the metes and bounds of the present invention.

In the examples below, all quantitative data, if not stated otherwise, relate to percentages by weight.

Mass spectra were obtained using electrospray (ES) ionization techniques (micromass Platform LC). Melting points are uncorrected. TLC was performed on a precoated silica gel plate (Merck silica gel 60 F-254). Silica gel (WAKO-gel C-200 (75-150 μm)) was used for all column chromatography separations. All chemicals were reagent grade and were purchased from Sigma- Aldrich, Wako pure chemical industries, Ltd., Great Britain, Tokyo kasei kogyo Co., Ltd., Nacalai tesque, Inc., Watanabe Chemical Ind. Ltd., Maybridge pic, Lancaster Synthesis Ltd., Merck KgaA, Germany, Kanto Chemical Co., Ltd.

Analytical HPLC Retention times of intermediates and examples are measured as follows:

Method A

Equipment: Waters 2690 separation module

Column temperature: 40 °C.

Mobile phase: water / acetonitrile (each of them containing lOmM ammonium acetate)

Column: Chromolith Rash RP-18e, 25 * 4.6mm

Flow rate: 1.3 mL/min.

Injection volume: 5 μL

Gradient (Time ) : (water / acetonitrile)

0 Minutes : 9 / 1

0.2 Minutes: 9 / 1

2.0 Minutes: 1 / 9

3.5 Minutes: 1 / 9

4.0 Minutes: 9 / 1 Method B

Equipment: Hewlett Packard series 1100

Column temperature: 40 °C.

Column: YMC PackPro C-l 8, 35 * 4.6mm

Flow rate: 1.0 mL/min.

Injection volume: 5 microL

Gradient (Time ) : (water / acetonitrile)

1 Minutes : 9 / 1

0.1 Minutes: 9 / 1

1.5 Minutes: 1 / 9

3.5 Minutes: 1 / 9

4.5 Minutes: 9 / 1

Method C

Equipment: Hewlett Packard series 1100

Column temperature: 40 °C.

Column: Phenomenex Luna 3u C18(2) 30 * 4.6mm

Flow rate: 1.0 mL/min.

Injection volume: 10 mi croL

Gradient (Time ) : (water / acetonitrile)

2 Minutes : 9 / 1

0.5 Minutes: 9 / 1 4.5 Minutes: 1 / 9

6.5 Minutes: 1 / 9

8.5 Minutes: 9 / 1

HPLC-Methods:

Analytical HPLC as follows were determined on a HP 1100 with DAD-detection (Hewlett Packard) under the following conditions:

Method 2A

Column: Kromasil CIS 60*2 at 30 °C; injection volume: 1.00 μl; flowrate: 0.75 rnl/min; eluent: A= 0.01 M H₃P0₄ in H₂0, B= CH₃CN; gradient [t(rnin): A/B]: 0.0: 90/10; 0.5: 90/10; 4.5: 10/90; 8.0: 10/90; 8.5: 90/10 10.0: 90/10.

Method 2B

Column: Kromasil C18 60*2 at 30 °C; injection volume: 0.20 - 0.30 μl; flowrate: 0.75 πϋ/min; eluent: A= 0.01 M H₃P0₄ in H₂O_f B= CH₃CN; gradient [t(min): A/B]: 0.0: 90/10; 0.5: 90/10; 4.5: 10/90; 6.5: 10/90; 7.5: 90/10.

Method 2C

Column: Kromasil CIS 60*2 at 30 °C; injection volume: 1.0 μl; flowrate: 0.75 ml/min; eluent: A= 5ml 70% HCIO₄/IL H₂0, B= CH₃CN; gradient [t(min): A/B]: 0.0: 98/2; 0.5: 98/2; 4.5: 10/90; 6.5: 10/90; 6.7: 98/2; 7.5: 98/2.

LC/MS-Methods:

Retention times for peaks with the correct product mass were recorded as follows:

Method 2D

Instrument MS: Micromass TOF (LCT); instrument HPLC: Watβrs2690; column: YMC-ODS-AQ, 50 mm x 2.0 mm, 3.0 μm; eluent A: water + 0.1% formic acid, eluent B: CH₃CN + 0.1% formic acid; gradient: 0.0 min 100%A -» 0.2 min 100%A -» 2.9 min 30%A -> 3.1 min 10%A -> 4.5 min 10%A ^■> 4.51 min 100%A-> 6.5 min 100%A; oven: 40°C; flow rate: 0.8 ml/min; UN-detection: 210 nm. Method 2E

Instrument MS: Micromass ZQ; instrument HPLC: Waters Alliance 2790; column: Uptisphere C 18, 50 mm x 2.0 mm, 3.0 μm; eluent A: water + 0.05% formic acid, eluent B: CH₃CN + 0.05% formic acid; gradient: 0.0 min 5%B - 2.0 min 40%B -» 4.5 min 90%B-> 5.5 min 90%B; oven: 45°C; flow rate: 0.0 min 0.75 ml/min -> 4.5 min 0.75 ml/min-^ 5.5 min 1.25 ml/min; UV- detection: 210 nm.

*H NMR spectra were recorded using either Bruker DRX-300 (300 MHz for Η) spectrometer or Brucker 500 UltraShieled™ (500 MHz for IH) . Chemical shifts are reported in parts per million (ppm) with tetramefhylsilane (TMS) as an internal standard at zero ppm. Coupling constant (J) are given in hertz and the abbreviations s, d, t, q, m, and br refer to singlet, doublet, triplet, quartet, multiplef, and broad, respectively. The mass determinations were carried out by MAT95 (Finnigan MAT).

All starting materials are commercially available or can be prepared using methods cited in the literature.

The effect of the present compounds was examined by the following assays and pharmacological tests.

[Measurement of change of intracellular cAMP accumulation by luciferase detection in the human GABA_B receptor-transfected HEK293 cell line] (Assay 1)

(1) Cloning of GABA_B receptors and generation of stable cell lines The human GABA_B(ia), GABA_B(ib) and GABA_B(₂) receptor subunits were cloned into pcDNA3 (Invitrogen) as previously described (White J. H. et al., Nature 1998, 396(6712):679-82). The cell culture and transfection of Human Embryonic Kidney (HEK293) cells was done as follows. HEK293-Luc cells were grown in Dulbecco's modified Eagle's medium (DMEM, Gibco BRL) supplemented with 5% modified bovine serum (MBS, Gibco BRL) in fibronectin coated 96-well microtiter plates. For transfection (mammalian transfection kit; Stratagene) cells were grown at 20000 cells per well at 35 °C with 3% C0₂ for 24 h with 0.1 ml per well. DNA suspension: 10 μg expression plasmid DNA of each human GABA_B(i_a) and human GABA_B(₂) in pcDNA3 was dissolved in 450 μl of water with 50 ml CaCl₂ (2.5 M) + 500 μl 2x phosphate buffered saline (PBS, pH 6.95) and incubated for 10 to 20 min at room temperature. In the meantime cell medium was aspirated and cells were washed twice with 200 μl PBS per well and then 200 μl medium plus 5% MBS was added. For transfection 20 μl of suspended DNA was added and incubated for 3 h at 35 °C with 3% C0₂, cell's were washed with PBS and 200 μl of growth medium was added and cells were grown for 2 days. Cells were then trypsinized and diluted 1: 10 in fϊbronectin coated wells and incubated with growth medium supplemented with 1 mg/ml G418 (Gibco BRL) and grown under selection pressure for 10 days with 2-3 medium changes. After G418 selection cells were grown until colonies had formed.

(2) Folskolin-stimulated luciferase-reporter gene assay

GABA_B(lb/2)-HEK293/CRE-luc cells were seeded into poly-D-lysine-coated 3S4-well white/opaque plates (BD BIOCOAT) at 4000 cells/well in 40 μl DMEM/F12 medium supplemented with 2.5% FBS, and grown for 48 hours at 37D in a humidified atmosphere with 5% C0₂. Test compounds dissolved in DMSO were diluted into DMEM/F12 medium containing 0.1% BSA and transferred to the test cultures at 5 μl/well. 10 minutes after the test compound addition, forskolin prepared in a manner similar to the test compounds was added at 5 μl/well (1.6 μM of final concentration), and cells were then incubated for 3 hours at 37 D in 5% C0₂. After the incubation, the medium was discarded, followed by addition of 20 μl/well of 1 : 1 mixture of Steady-Glo™ reagent (Promega) and Phenol-red free DMEM/F12 medium. The plates were incubated at least 5 minutes to ensure complete cell lysis and then luciferase activity was measured with ViewLux microplate imager (Perkin Elmer).

[Measurement of rhytlimic bladder contraction in anesthetized rats] (Assay 2)

(1) Animals

Female Sprague-Dawley rats (200-250 g / Charles River Japan) were used.

(2) Rhythmic bladder contraction in anesthetized rats

Rats were anesthetized by intraperitoneal administration of urethane (Sigma) at 1.25 g/kg. The trachea was cannulated with a polyethylene tube (HIBIKI, No.8) to facilitate respiration; and a cannula (BECTON DICKINSON, PE-50) was placed in the left femoral vein for intravenous administration of testing compounds. The abdomen was opened through a midline incision, and after both ureters were cut, a water-filled baloon (about 1 ml capacity) was inserted through the apex of the bladder dome. The baloon was connected to a pressure transducer onto a polygraph. Rhythmic bladder contraction was elicited by raising up intravesical pressure to approximately 15 cm H₂0. After the rhythmic bladder contraction was stable, a testing compound was administered uitravenously. Activity was estimated by measuring disappearance time and amplitude of the rhythmic bladder contraction. The effect on amplitute of bladder contractions was expressed as a percent suppression of the amplitude of those after the disappearance was recovered. Experimental values were expressed as the mean±S.E.M. The testing compounds-mediated inhibition of the rhythmic bladder contraction was evaluated using Student's t-test. A probability level less than 5% was accepted as significant difference.

Results in folskolin-stimulated luciferase-reporter gene assay (Assay 1) are shown in Examples and tables of the Examples below. For practical reasons, the compounds are grouped in four classes based on activity as follows:

1 μM < D

[Cystometry in anesthetized rats] (Assay 3)

Effect of a compound on cystometric parameters in rats were studied as described previously [Takeda H et al: J. Pharmacol. Exp. Ther. 126: 939- 945, 2000].

Female rats, weighing from 200 to 230 g, were anesthetized with urethane (1.2 g/kg i.p.). Through a midline abdominal incision, the ureter on each side was ligated and cut proximal to the ligature.

A polyethylene catheter (PE-50) was inserted into the urinary bladder and connected through a three-way connector to: 1) a pressure transducer (Viggo-Spectramed Pte Ltd, DT-XXAD) for measurement of bladder pressure, and 2) a syringe infusion pump (TERUMO) for continuous infusion of saline into the bladder. During cystometry, saline was infused at a rate of 2.4 ml/h. Bladder pressure was recorded continuously on a PowerLab systems (BioResearch Center). The following cystometric parameters were obtained: micturition interval and micturition pressure

(maximum bladder pressure during micturition). Two reproducible micturition cycles were recorded before drug administration and used to provide a baseline value to be compared with the first two micturition cycles just after drug administration. Relative values for the various cystometric parameters were calculated as follows: (mean value from two micturition cycles just after drug administration)/(mean value from two micturition cycles just before drug administration). A venous catheter was inserted into the left femoral vein for drug injection.

Z used in Melting point in the following section indicates decomposition. [Example 1-1] Method A 3-(3-benzhydrylsulfanyl-5-cyclopropyl-[l,2,4]triazol-4-yl)-benzoic acid

5 A solution of 3-(3-cyclopropyl-5-thioxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)benzoic acid (152 mg, 0.58 mmol) in N,N-dimethylformamide (1 mL) was added potassium carbonate (403 mg, 2.91 mmol) and bromodiphenylmethane (187 mg, 0.76 mmol), and the mixture was stirred at 60 °C for 16 hours. The inorganic salts were filtered, and the filtrate was diluted with aqueous sodium bicarbonate solution. The mixture was washed with ethylacetate, and the aqueous layer was 10 acidified to pH 2 with IN aqueous HCl solution. The mixture was extracted with ethylacetate, and the organic layer was concentrated under reduced pressure. The obtained residue was recrystallized from the mixture of dichloromethane, diethylether, and hexane to provide 3-{3- cyclopropyl-5-[(diphenylmethyl)thio]-4H-l,2,4-triazol-4-yl}benzoic acid (65.9 mg).

^■H NMR (DMSO- ): δ 0.82-0.89 (m, 4H), 1.48-1.53 (m, IH), 5.88 (s, IH), 7.21-7.30 (m, 10H), ^• 15 7.55 (d, J= 7.9 Hz, IH), 7.70-7.74 (m, 2H), 8.12 (d, J= 7.9 Hz, IH), 13.40 (s(br), IH). mp 193 °C;

Molecular weight : 427.53

MS (M+H): 428

Activity Class : B Preparation of intermediates

Method (i)

A mixture of cyclopropanecarbohydrazide (255 mg, 2.55 mmol) and methyl 3-isothiocyanato- benzoate (492 mg, 2.55 mmol) in ethanol (3 mL) was stirred at refluxing temperature for 16 hours. The mixture was concentrated under reduced pressure, and to the obtained residue was added a solution mixture of diethylether and hexane. The precipitates were collected and dried to afford methyl 3-({[2-(cyclopropylcarbonyl)hydrazino]carbonothioyl} amino) benzoate (399 mg). *H NMR (DMSO- δ 0.77-0.79 (m, 4H), 1.60-1064 (m, IH), 3.32 (s, 3H), 7.47 (t, J= 7.9 Hz, IH), 7.73 (d, J= 7.3 Hz, IH), 7.80 (d, J = 7.3 Hz, IH), 8.08 (s(br), IH), 9.86 (s(br), IH), 10.10 (s(br), IH); ; MS m/z 294 (M⁺+l).

Next, a solution of methyl 3-({[2-(cyclopropylcarbonyl)hydrazino]carbonothioyl} amino) benzoate (399 mg, 1.36 mmol) in 4N aqueous solution of sodium hydroxide (7 mL) was stirred at refluxing temperature for 16 hours. After having cooled to ambient temperature, the mixture was acidified to pH 2 with IN aqueous solution of HCl. The mixture was extracted with ethylacetate, dried over Na₂S0₄, filtered, and concentrated under reduced pressure to obtain 3-(3-cyclopropyl-5- thioxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)benzoic acid (355 mg). Η NMR (DMSO-J₆) δ 0.77-0.92 (m, 4H), 1.47-1.52 (m, IH), 7.70-7.77 (m, 2H), 8.01 (s, IH), 8.09 (d, J= 6.3 Hz, IH), 13.00 (s(br), IH), 13.64 (s, IH) ; MS m/z 262 (M⁺+l). Preparation of intermediates

Method (ii)

cyclopropanecarbohydrazide

To a solution of tert-butyl hydrazinecarboxylate (6.38 g, 48.3 mmol) and triethylamine (7.26 g, 71.8 mmol) in dichloromethane (10 mL) was added cyclopropanecarbonyl chloride (5.00 g, 47.8 mmol) at 0 °C. The mixture was stirred for 16 hours at ambient temperature, and the resulting suspension was filtered and washed with dichloromethane. The filtrate was concentrated under reduced pressure to provide tert-butyl 2-(cyclopropylcarbonyl)hydrazinecarboxylate (13.0 g). ^!H NMR (OMSO-dβ) δ 0.67-0.72 (m, 4H), 1.39 (s, IH), 1.52 -1.54 (m, IH), 8.64 (s, IH), 9.70 (s, IH).

Next, to a stirred solution of tert-butyl 2-(cyclopropylcarbonyl)hydrazinecarboxylate (3.00 g, 15.0 mmol) in 1,4-dioxane (50 mL) was added 4N HCl in 1,4-dioxane (20 mL). The mixture was stirred at 80 °C for 1 hour, and after cooled to ambient temperature, it was concentrated under reduced pressure. To the obtained residue was added ethylacetate and triethylamine (8.04 g, 79.4 mmol), and the organic layer was washed with saturated sodium bicarbonate aqueous solution and brine, dried over Na₂S0₄, filtered, and concentrated under reduced pressure to obtain cyclopropanecarbohydrazide (0.89 g).

Preparation of intermediates

Method (iv)

5-(3-fluorophenyI)-4-phenyl-4H-l,2,4-triazol-3-amine

To a solution of aniline (1.00 g, 10.7 mmol) and pyridine (0.849 g, 10.7 mmol) in dichloromethane (20 mL) was added 3-fluorobenzoyl chloride (1.70 g, 10.7 mmol) at 0 °C and stirred for 1 hour. After water was added, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over Na₂S0₄, filtered, and concentrated under reduced pressure to obtain 3-fluoro-N-phenylbenzamide (2.45 g). Η NMR (DMSO- ₆) δ: 7.09-7.15(m, IH), 7.33-7.40 (m, 2H), 7.41-7.49 (m, IH), 7.55-7.64(m, IH), 7.73-7.84 (m, 4H); m/z 216.15 (M +1).

Next, a mixture of 3-fluoro-N-phenylbenzamide (1.00 g, 4.65 mmol) and thionyl chloride (3.4 mL) was heated at 80 °C for 16 hours. After cooled to ambient temperature, excess of thionyl chloride was removed under reduced pressure to obtain 3-fluoro-N-phenylbenzenecarboximidoyl chloride (1.00 g).

Next, to a solution of anhydrous hydrazine (2.72 g, 84.9 mmol) in benzene (15 mL) was added 3- fluoro-N-phenylbenzenecarboximidoyl chloride (0.800 g, 3.39 mmol) at 0 °C. After having stirred at room temperature for 16 hours, water was added and the mixture was extracted with diethylether. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried over MgS0₄, filtered, and concentrated under reduced pressure to provide 3- fluoro-N-phenylbenzenecarbohydrazonamide (0.822 g). Next, a mixture of 3-fluoro-N-phenylbenzenecarbohydrazonamide (200 mg, 0.65 mmόl) and cyanogen bromide (69.3 mh, 0.65 mmol) in methanol (3 mL) was heated at 90 °C for 48 hours. After having cooled to ambient remperature, the mixture was concentrated under reduced pressure, and the obtained residue was purified by preparative TLC (eluent: dichloromethane 7 methanol = 95 / 5) to provide 5-(3-fluoroρhenyl)-4-phenyl-4H-l,2,4-triazol-3 -amine (108 mg). Η NMR (DMSO-c/s) δ: 5.82 (s, 2H), 6.90 (t, J=7.3Hz, IH), 6.98-7.27 (m, 3H), 7.28-7.42 ( , 3H), 7.52-7.54 (m, 2H); m/z 255.25 (M÷+l).

Preparation of intermediates

Method (v)-l

Phenyl(pyridin-3-yl)methanol

To a solution of 3-pyridinecarboxaldehyde (1.00 g, 9.34 mmol) in tetrahydrofuran (50 mL) was added 1.09 M phenyl magnesium bromide in tetrahydrofuran solution (10.3 mL, 11.20 mmol). After the mixture was stirred at room temperature for 2 hours, water was added and extracted with ethylacetate. The organic layer was washed with brine, dried over MgS0₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / diethyl ether = 4 / 1) to provide phenyl(pyridin-3- yl)methanol (1.07 g). Η NMR (CDC13-Λ): δ 3.S5 (IH, s), 5.83 (IH, sz), 7.20-7.37 (6H, m), 7.69 (IH, ddd, J = 2.5, 2.5, 7.9 Hz), 8.38 (IH, dd, J = 2.5, 4.8 Hz), 8.51 (IH, ά, J = 2.5 Hz); MS m/z 186 (M+l).

Method (v')-l

cyclobutyl(phenyl)methanol

To a solution of cyclobutyl(phenyl)methanone (1.00 g, 6.24 mmol) in methanol was added sodium borohydride (0.315 g, 7.49 mmol) at 0 °C. After the mixture was stirred for 1 hour at 0 °C, water was added and extracted with ethylacetate. The organic layer was dried over MgS0₄, filtered, and concentrated under reduced pressure to obtain cyclobutyl(phenyl)methanol (1.03 g). Η NMR (CDC13-ύ : δ 1.74-1.88 (4H, t, m), 1.91-2.15 (2H, m), 2.63 (IH, m), 4.57 (IH, ά, J= 7.9 Hz), 7.23- 7.35 (5H, m).

Method (v)-2

l,l'-(chloromethylene)bis(4-chIorobenzene)

To a solution of 4,4' -dichlorobenzhydrol (4.7S g, 18.9 mmol) in dichloromethane (400 mL) was added thionyl chloride (2.81 g, 23.6 mmol) and lH-benzotriazole (2.81 g, 23.6 mmol) at room temperature. After the mixture was stirred for 10 minutes, it was filtered, and to the filtrate was added water and extracted with dichloromethane. The organic layer was washed with 3% aqueous sodium hydroxide solution, dried over Na₂S0₄, filtered, and concentrated under reduced pressure to provide l,l'-(chloromethylene)bis(4-chlorobenzene) (5.14 g). Η NMR (CDC13-c : δ 6.05 (IH, s), 7.26-7.32 (8H, m).

In the similar manner as described in Example 1-1 and with the use of intermediates described above, compounds in Example 1-2 to 1-167 as shown in Table 1 were synthesized.

Table 1

Table 1

Table 1

Table 1

Tablel

Table 1

Table 1

Tablel

Table 1

Table 1 Melting Point or HPLC Activity

Example No. Structure MW MS (M+l retention time class

Example 1-42 442,63 443,3 194-198.8 B

Example 1-43 456,66 457,3 108.2-109.1 D

Example 1-44 486,64 487,3 149.8-155.2 A

Example 1-45 456,66 457,3 126.4-127.2 B

Example 1-46 432,633 433 47,1 A

Table 1

Table 1

Table 1

Table 1

Table 1

Table 1

Table 1

Table 1

Table 1

Table 1 Melting Point or HPLC Activity' Example No. Structure MW MS (M+1 retention time class

Example 1-86 497,491 498 53,7 A

Example 1-87 498,432 499 201,6 A

Example 1-8S 496,416 497 139,4 A

Example 1-89 520,63 521,2 95-96 A

Example 1-90 516,44 518,05 61-62 A

Table 1

Table 1

Table 1

Table 1

Table 1

όS-

Tablel

Table 1

Tablel

Table 1

Tablel

Table 1

Table 1

Tablel

Table 1

Tablel

Table 1

Table 1

Tabe 1

Table 1

[Example 2-1]

Method B

3-[3-(2,2-diphenylethyl)-5-(3-fluorophenyl)-4H-l,2,4-triazol-4-yl]benzoic acid

To solution of ethyl m-aminobenzoate (5.36 g, 32.4 mmol) in tetrahydrofuran (100 mL) was added 1-hydroxybenzotriazole (7.67 g, 56.8 mmol), triethylamine (3.61 g, 35.7 mmol), l-ethyl-3-(3- dimethylaminopropyl) carbodiimide (10.9 g, 56.8 mmol), and m-fluorobenzoic acid (5.00 g, 35.7 mmol) at room temperature and stirred for 4 hours. After water was added, the mixture was extracted with ethylacetate. The organic layer was washed with brine, dried over Na₂S0 , filtered, and concentrated under reduced pressure to obtain ethyl 3-[(3-fluorobenzoyl)amino]benzoate.

Next, a mixture of ethyl 3-[(3-fluorobenzoyl)amino]benzoate (1.11 g, 3.86 mmol) and thionyl chloride was heated at 80 °C for 16 hours. After cooled to room temperature, the excess of thionyl chloride was removed underreduced pressure and obtained ethyl 3-{[(lE,Z)-chloro(3- fluoropheny l)methylene] amino } benzoate

(1.11 g).

Next, to a solution of ethyl 3-{[(lE,Z)-chloro(3-fluorophenyl)methylene]amino}benzoate (320 mg, 1.04 mmol) in acetonitrile (5 mL) was added 3,3-diphenylpropanohydrazide (300 mg, 1.25 mmol) and the mixture was heated to 90 °C for 16 hours. After having cooled to ambient temperature, the mixture was concentrated under reduced pressure. The obtained residue was purified twice ^"by preparative TLC (eluent: dichloromethane / methanol = 95 1.5 and then with ethylacetate / hexane = 1 / 1) to provide ethyl 3-[3-(2,2-diphenylethyl)-5-(3-fluorophenyl)-4H-l,2,4-triazol-4-_:ylJbenzoate (78.0 mg). 'HNMR (DMSO- ) δ: 1.31 (t, J=7.3Hz, 3H), 3.36 (d, J=7.6Hz, 2H), 4.32 (q, J=7.3Hz, 2H), 4.45 (t, J=8.2Hz, IH), 7.04 (d, J=7.9Hz, IH), 7.08-7.24 (m, 12H), 7.337.3S (m, IH), 7.57- 7.59 (m, IH), 7.68 (t, J=1.9Hz, IH), 7.72 (t, J=7.9Hz, IH), 8.15 (d, J=7.9Hz, IH); m/z 492.2 (M*+l).

To a solution of ethyl 3-[3-(2,2-diphenylethyl)-5-(3-fluorophenyl)-4H-l,2,4-triazol-4-yl]benzoate (72.0 mg, 0.15 mmol) in ethanol (2 mL) was added IN aqueous sodium hydroxide solution at room temperature and stirred for 16 hours. The mixture was concentrated under reduced pressure, neutralized with IN HCl aqueous solution, and extracted with ethylacetate. The organic layer was dried over Na₂S0₄, filtered, and concentrated under reduced pressure. The obtained residue was purified by preparative TLC (eluent: dichloromethane / methanol = 95 / 5) to provide 3-[3-(2,2-di- phenylethyl)-5-(3-fluorophenyl)-4H-l,2,4-triazol-4-yl]benzoic acid (37.0 mg).

'H NMR (DMSO- ;) δ: 3.36 (d, J=7.SHz, 2H), 4.44 (t, J=7.9Hz, IH), 7.03-7.22 (m, 13H), 7.35 (q, J=7.9Hz, IH), 7.52 (d, J=7.9Hz, IH), 7.67-7.72 (m, 2H), S.l l (d, J=7.9Hz, IH). mp 233-234 °C;

Molecular weight : 463.51

MS (M+H): 464 Activity Class : D

In the similar manner as described in Example 2-1, compounds in Example 2-2 to 2-3 as shown in Table 2 were synthesized.

Table 2

Example No Structure MW MS (M+l) Melting Point Activity' or HPLC class retention time (Ri) Example 2-2, 419,5 420,3 128-129 D

Example 2-3. 491,56 492,2 Rt =2.92 D (method B)

Example 3-1

(4-{3-cyclopropyl-5-[(diphenylmethyl)sulfinyl]-4H-l,2,4-triazol-4-yl}phenyl)dimethylamine

To a stirred suspension of (4-{3-cyclopropyl-5-[(diphenylmethyl)thio]-4H-l,2,4-triazol-4-yl}phen- yl)dimethylamine (370 mg, 0.87 mmol) in dichloromethane was added m-chloroperoxybenzoic acid (374 mg, 2.17 mmol) at room temperature. After the mixture was stirred for 16 hours, it was filtered, and the filtrate was washed with sodium bicarbonate solution, water, and then with brine. The organic layer was dried over Na₂S0₄, filtered, and concentrated under reduced pressure to obtain (4-{3-cycloproρyl-5-[(diphenylme yl)sulfmyl]-4H-l,2,4-triazol-4tyl}phenyl)dimethyl- amine (326 mg).

Η NMR (DMSO-rf₆) δ 0.83-0.90 (m, 4H), 1.49-1.54 (m, IH), 3.54(s, 6H), 5.87 (s, IH), 7.22- 7.3 l(m, 10H), 7.44 (d, J= S.6 Hz, 2H), 8.30 (d, J= 8.6 Hz, 2H).

Molecular weight : 442.58

MS (M+H): 443

Activity Class : A

In the similar manner as described above and with the use of intermediates described above, compounds in Example 4-1 to 4-73 as shown in Table 3 were synthesized.

Table 3

Table 3

Table 3

Table 3

Table 3

Table 3

Table 3

Table 3

Table 3

Table 3

Table 3

Table 3

Table 3

Claims

1. A phenyltriazole derivative of the formula (T), its tautomeric or stereoisomeric form, or a salt thereof:

wherein

R¹ represents alkyl optionally substituted by one or two substituents selected from the group consisting of alkoxy, amino, alkylamino, di(alkyl)amino, alkanoyloxy, hydroxy, carboxy, alkoxycarbonyl, cycloalkylphenyloxy, halogen, morpholino, carbamoyl, alkylsulfonylamino, phenyloxy optionally substituted by cycloalkyl, and 3- 8 membered saturated ring optionally having one or two N atom which ring optionally substituted by hydroxy or alkanoyl, or 3-8 membered saturated or unsaturated ring optionally having one or two hetero atoms selected from the group consisting of N and O, and which ring is optionally substituted by one or two substituents selected from the group consisting of alkyl, halogen, alkoxy, nitro, amino, cyano, alkylamino, di(alkyl)amino, 4-7 membered saturated cyclic amine optionally substituted by hydroxy, and mono-, di-, or tri- halogen substituted alkyl;

R² represents -COR²¹ , -(CH₂)„-R²¹ or tert-butyl,

Wherein R is alkoxy, hydroxy, mono-, di-, or tri- halogen substituted alkyl, or 3-8 membered saturated or unsaturated ring optionally having one or two heteroatoms selected from the group consisting of N, O, and S and which ring is optionally substituted by one or two substituents independently selected from the group consisting of alkanoyl, halogen, benzyl, alkoxycarbonyl, haloalkyloxy- carbonyl, cyano, hydroxy, amino, alkylamino, di(alkyl)amino, cycloalkylamino, alkoxycarbonyl, sulfamoyl, alkylaminosulfonyl, di(alkyl)aminosulfonyl, alkanoyl, alkanoylamino, carbamoyl, alkylcarbamoyl, di-(alkyl)carbamoyl, alkylsulfonyl, alkyl optionally substituted by alkoxycarbonyl or mono-, di-, ortri-^'halogen, alkoxy optionally substituted by mono-, di-, or tri- halogen, and alkylthio optionally substituted by mono-, di-, or tri- halogen; is O or 1;

R³ and R⁴ independently represent hydrogen, halogen, cyano, hydroxy, amino, al latnino, di(alkyl)amino, cycloalkylamino, carboxy, alkoxycarbonyl, sulfamoyl, alkylaminosulfonyl, di(alkyl)aminosulfonyl, alkanoyl, alkanoylamino, carbamoyl, alkylcarbamoyl, di-(alkyl)carbamoyl, alkylsulfonyl, alkyl optionally substituted by hydroxy, alkoxycarbonyl or mono-, di-, or tri-halogen, alkoxy optionally substituted by mono-, di-, or tri- halogen, or alkylthio optionally substituted by mono-, di-, or tri- halogen;

R⁵ represents hydrogen, hydroxy, nitro, cyano, halogen, sulfamoyl, alkylsulfonyl, alkylaminosulfonyl, di(alkyl)aminosulfonyl, -(CH₂)_m-CO-R⁵⁰, -(CH₂)_m-R⁵¹, - NR⁵²R⁵³, or -OR⁵⁴, wherein m is 0, 1, 2, or 3

R^so is hydroxy, hydrogen, alkoxy, morpholino, di(phenyl)methyloxy, di(halogen substituted phenyl)methyloxy, -NR⁵⁰¹R⁵⁰² (wherein said R⁵⁰¹ and R⁵⁰² independently represent hydrogen, alkoxyalkyl, alkyl, hydroxy- alkyl, alkoxycarbonylalkyl, or carboxyalkyl or R⁵⁰¹ and R⁵⁰² together form with the adjuscent N atom, moφholino, piperazino optionally substituted by oxo, or 4-7 membered saturated cyclic amino optionally substituted by one substituent selected from the group consisting of carboxy, hydroxyalkyl, hydroxy, and carbamoyl) or alkyl optionally substituted by halogen, R⁵¹ is hydrogen, hydroxy, or -NR⁵¹¹R⁵¹² (wherein said R⁵ⁿ and R⁵¹² independently represent hydrogen, alkoxyalkyl, alkyl, hydroxyalkyl, alkoxycarbonylalkyl, or carboxyalkyl, or R⁵¹¹ andR⁵¹² together form with the adjuscent N atom, 4-7 membered saturated cyclic amino optionally substituted by one substituent selected from the group consisting of carboxy, hydroxyalkyl, hydroxy, and carbamoyl), R⁵² an R⁵³ independently represent hydrogen, alkyl, hydroxy, cycloalkylcarbonyl, ^"hydroxyalkyl, alkylsulfonyl, hydroxyalkylcarbonyl, carboxyalkylcarbonyl, alkanoyloxyalkylcafbonyl, or al oxycarbonylalkylcarbonyl, or R⁵² and R⁵³ together form with adjuscent N atom, morpholino, cyclic amino optionally substituted by one substituent selected from the group consisting of carboxy, hydroxyalkyl, hydroxy, and carbamoyl,

R^δ and R⁷ independently represents hydrogen, morpholino, hydroxypyrrolidinylcarbonyl, hydroxyalkylaminocarbonyl, cyano, hydroxy, hydroxyalkyl, hydroxyamino, carboxy, fluoro, chloro, bromo, nitro, amino, alkylamino, di(alkyl)amino, cycloallς lamino, alkoxycarbonyl, sulfamoyl, alkylaminosulfonyl, di(alkyl)aminosulfonyl, alkanoyl, alkanoylamino, carbamoyl, diphenylmethyloxycarbonyl, alkylcarbamoyl, di-(alkyl)caxbamoyl, alkylsulfonyl, alkyl optionally substituted by alkoxyalkyl(alkyl)amino, di(alkyl)amino, alkoxycarbonyl, carboxy, or mono-, di-, or tri-halogen, alkoxy optionally substituted by morpholino, di(alkyl)amino, or mono-, di-, or tri- halogen, or Cι.β alkylthio optionally substituted by mono-, di-, or tri- halogen

or R⁶ and R⁷ together form phenyl fused to adjacent phenyl; and

X represents CR¹⁰Rⁿ, NR¹², S, O, S0₂, or SO

wherein R¹⁰, R^u, and R¹² independently represent hydrogen or methyl.

The phenyltriazole derivative of the formula (I), its tautomeric or stereoisomeric foπn, or a salt thereof as claimed in claim 1 :

wherein

X represents CH₂, NH, S, O, S0₂, or SO;

R¹ represents C₃ to C_s cycloalkyl,

C C₆ alkyl optionally substituted by one or two substituents selected from the group consisting of Cι-C₆ alkoxy, amino, C C₆ alkylamino, di(Cι-C₆ alkyl)amino, C alkanoyloxy, hydroxy, C₃-C₈ cycloalkyl, carboxy, -Cβ alkoxycarbonyl, C₃-C₃ cycloalkylphenyloxy, halogen, morpholino, and pyrrolidinyl, pyridyl, pyrrolidinyl, piperidinyl optionally substituted by methyl, or phenyl optionally substituted by one selected from the group consisting of halogen, C₁-C₆ alkoxy, nitro, amino, cyano, C C₆alkyla ino, di(C C₅alkyl)amino, and mono-, di- or tri- halogen substituted C C₆alkyl,

R² represents -COR²¹ or -(CH₂)_n-R²¹, wherein R²¹ represents mono-, di-, tri- halogen substituted C C₆ alkyl, morpholino, CpC₆ alkoxy, hydroxy, C₃ to C_s cycloalkyl, pyridyl, furanyl, thiophenyl, pyrrolidinyl, piperidinyl optionally substituted by one substituent selected from the group consisting of benzyl, C C₆ alkoxycarbonyl, and halo Cι-C₆ alkyloxycarbonyl, or phenyl optionally substituted by one substituent selected from the group consisting of C C₆ alkyl, halogen, C C₆ alkoxy, and mono-, di-, or tri- halogen substituted Cr alkyl; n is 0 or 1 ;

R³ and R⁴ independently represent hydrogen, halogen, cyano, hydroxy, amino, Cι_-6 alkylamino, di(Cι.₆ alkyl)amino, C_3-s cycloalkylamino, C e alkoxycarbonyl, sulfamoyl, C_1-6 alkylaminosulfonyl, di(C_1-6 alkylaminosulfonyl, Cι_-6 alkanoyl, Cι„₆ alkanoylamino, carbamoyl, Cι.₆ alkylcarbamoyl, di-(Cι_-(5 alkyl)carbamoyl, Cι_-6 alkylsulfonyl, Cι„₆ alkyl optionally substituted by Cι.₆ alkoxycarbonyl or mono-, di- , or tri-halogen, Cι.₆ alkoxy optionally substituted by mono-, di-, or hi- halogen, or Cι_6 alkylthio optionally substituted by mono-, di-, or tri- halogen;

R⁵ represents hydrogen, nitro, cyano, hydroxy, halogen, sulfamoyl, - C₆alkylsulfonyl, Ci-Cβalkylaminosulfonyl, di(C_rCόalkyl)aminosulfonyl, -(CH₂)_m- CO-R⁵⁰, -(CH₂)_m-R⁵¹, -NR⁵²R⁵³, or -OR⁵⁴, wherein m is 0, 1, 2, or 3

R⁵⁰ is hydroxy, hydrogen, Cι-C_δalkoxy, morpholino, diphenylmethyloxy, -NR⁵⁰¹R⁵⁰² (wherein said R⁵⁰¹ and R⁵⁰² independently represent hydrogen, Cι-C₆alkoxyalkyl, Ci-Cgalkyl, hydroxy C_rC₆alkyl, C_rC₆alkoxycarbonyl ^■ C_rC₆alkyl, or carboxy C_rC₆alkyl or R⁵⁰¹ and R⁵⁰² together form with the adjacent N atom morpholino, 4-6 membered saturated cyclic amino optionally substituted by one substituent selected from the group consisting of carboxy, hydroxyalkyl, hydroxy, and carbamoyl) or -Cβ alkyl optionally substituted by halogen,

R⁵¹ is hydrogen, hydroxy, or -NR⁵¹¹R⁵¹² (wherein said R⁵¹¹ and R⁵¹² independently represent hydrogen, Cι-C₆ alkoxyalkyl, -C₆ alkyl, hydroxyalkyl, -Ce alkoxycarbonylalkyl, or carboxyalkyl or R^5U and R⁵¹² together form with the adjacent N atom, 4-7 membered saturated cyclic amino optionally substituted by one substituent selected from the group consisting of carboxy, hydroxyalkyl, hydroxy, and carbamoyl) R⁵² and R⁵³ independently represent hydrogen, C C₆ alkyl, hydroxy, C₃- Cgcycloalkylcarbonyl, or hydroxy Cι-C₆ alkyl or R⁵² and R⁵³ together form with adjacent N atom, morpholino, 4-7 membered saturated cyclic amino optionally substituted by one substituent selected from the group consisting of carboxy, hydroxyalkyl, hydroxy, and carbamoyl R⁵⁴ represents alkyl optionally substituted by moφholino, amino, or di(alkyl) amino, or mono-, di-, or tri- halogen; and

R^D and R⁷ independently represent hydrogen, moφholino, hydroxypyrrolidinylcarbonyl, hydroxyCi-Cealkylaminocarbonyl, cyano, hydroxy, hyd oxyCr C₆alkyl, hydroxyamino, carboxy, fluoro, chloro, bromo, nitro, amino, C^s alkylamino, di(Cι_-6 alkyl)amino, C₃.₈ cycloalkylamino, Cι_₆ alkoxycarbonyl, sulfamoyl, .₆ alkylaminosulfonyl, di(Cι_-6 alkylaminosulfonyl, C,^ alkanoyl, C^ alkanoylamino, carbamoyl, diphenylmethyloxycarbonyl, Ci. ₆ alkylcarbamoyl, di-(Cι_-6 alkylcarbamoyl, Cι_-6 alkylsulfonyl, C_1-6 alkyl optionally substituted by alkoxyalkyl(alky])amino, di(alkyl)amino, .s alkoxycarbonyl, carboxy, or mono-, di-, or tri-halogen, Cι_-6 alkoxy optionally substituted by moφholino, di(alkyl)amino, or mono-, di-, or tri- halogen, or Cj.6 alkylthio optionally substituted by mono-, di-, or tri-

or R° and R⁷ together form phenyl fused to adjacent phenyl.

The phenyltriazole derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1,

wherein X represents CB2, NH, S, or SO;

^"R¹ Tepresents cyclopropyl, pyridyl, phenyl optionally substituted by halogen, C]-C₆alkoxy, nitro, a ino, cyano, Cj- C₆alkylamino, di(C₁-C₆alkyl)amino, or halogen substituted Cr alkyl, Ci-Cg alkyl optionally substituted by one or two substituents selected from the group consisting of C -C₆alkoxy, amino, C_rC_δ alkylamino, di(C C₆ alkyl)amino, C C_δ alkanoyloxy, hydroxy, C₃-Cs cycloalkyl, carboxy, C C₆ alkoxycarbonyl, C₃-C₈ cycloalkylphenyloxy, halogen, moφholino, and pyrrolidinyl, pyrrolidinyl, or piperidinyl optionally substituted by methyl;

R² represents -COR¹¹ or -(CH₂)_n-R²¹ _; wherein R²¹ represents mono-, di- or tri- halogen substituted alkyl, moφholino, Cι-C_δalkoxy, hydroxy, C₃ to C₈ cycloalkyl, pyridyl, furanyl, thiophenyl, pyrrolidinyl, piperidinyl optionally substituted by one selected from the group consisting from benzyl, d- alkoxycarbonyl, and haloC C_δalkyloxycarbonyl, or phenyl optionally substituted by one selected from the group consisting of - alkyl, halogen, Cj-C alkoxy, and mono-, di- or tri- halogen substituted C C_δalkyl; n is 0 or 1;

R³ and R⁴ independently represent hydrogen, halogen, methyl, or amino;

R⁵ represents hydrogen, moφholino, hydroxypyπOlidinylcarbonyl, hydroxyalkylarnino- carbonyl, cyano, hydroxy, hydroxyalkyl, hydroxyamino, carboxy, fluoro, chloro, bromo, nitro, amino, C_1-6 alkylamino, di(Cι.₆alkyl)amino, C₃_s cycloalkylamino, Cι„ δ alkoxycarbonyl, sulfamoyl, .6 alkylaminosulfonyl, di(Cι_6 alkylaminosulfonyl, Cι-6 alkanoyl, Cι.₆ alkanoylamino, carbamoyl, diphenylmethyloxycarbonyl, C_1-6 alkylcarbamoyl, di-(Cι.₆ alkyl)carbamoyl, Ci-β alkylsulfonyl, Cι_-δ alkyl optionally substituted by alkoxyalkyl(alkyl)amino, di(alkyl)amino, Cι_-δ alkoxycarbonyl, carboxy, or mono-, di-, or tri-halogen, Cι_₆ alkoxy optionally substituted by moφholino, di(alkyl) amino, or substituted by mono-, di-, or tri- halogen, or Cι_-6 alkylthio optionally substituted by mono-, di-, or tri- halogen; and

R° and R⁷ represent hydrogen,

or R^δ and R⁷ together form phenyl fused to adjacent phenyl.

4. The phenyltriazole derivative of the formula (T), its tautomeric or stereoisomeric Jbrm, or a salt thereof as claimed in claim 1, wherein

X represents CH₂, NH, or S; R¹ represents cyclopropyl, pyridyl, phenyl optionally substituted by halogen, alkoxy, nitro, amino, cyano, alkylamino, di(alkyl)amino, or halogen substituted alkyl,

Cι-C_δ alkyl optionally substituted by one or two substituents selected from the group consisting of alkoxy, amino, C_rC_δ alkylamino, di(d-C₆ alkyl)amino, -C_δ alkanoyloxy, hydroxy, C₃-C₈ cycloalkyl, carboxy, Cι-C₆ alkoxycarbonyl, C₃-C₃ cycloalkylphenyloxy, halogen, moφholino, and pyπOlidinyl, pyixolidiny, or piperidinyl optionally substituted by methyl.

5. The phenyltriazole derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1 , wherein X represents CH₂, NH, or S;

R² represents -COR²¹, -(CH₂)„R²¹, wherein R²¹ is phenyl optionally substituted by C C₅ alkyl, halogen, halogen substituted alkyl or alkoxy and n is 0 or 1.

6. The phenyltriazole derivative of the foπnula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1, wherein

X represents CH , NH, or S;

R³ and R⁴ independently represent hydrogen, halogen, methyl, amino; and

R⁵ represents hydrogen, moφholino, hydroxypyrrolidinylcarbonyl, hydroxyalkylaminocarbonyl, cyano, hydroxy, hydroxyalkyl, hydroxyamino, carboxy, fluoro, chloro, bromo, nitro, amino, Cue alkylamino, di(Cι._s alkyl)amino, C₃.₈ cycloalkylamino, C e alkoxycarbonyl, sulfamoyl, Cue alkylaminosulfonyl, di(C_)-6 alkylaminosulfonyl, Cι._δ alkanoyl, ue alkanoylamino, carbamoyl, diphenylmeth- yloxycarbonyl, C_1-6 alkylcarbamoyl, di-(C_1-δ alkyl)carbamoyl, e alkylsulfonyl, Cι_-6 alkyl optionally substituted by alkoxyalkyl(alkyl)amino, di(alkyl)amino, Ci.6 alkoxycarbonyl, carboxy, or mono-, di-, or tri-halogen, C .β alkoxy optionally substituted hy moφholino, di(alkyl)arnino, or substituted by mono-, di-, or tri- halogen, or C_1-β alkylthio optionally substituted by mono-, di~, or tri- halogen; and R⁶ and R⁷ represents hydrogen.

7. The phenyltriazole derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1, wherein said phenyltriazole derivative of the formula (I) is selected from the group consisting of:

(4-{3-cyclopropyl-5-[(diphenylmethyl)thio]-4H-l,2,4-triazol-4-yl}phenyl)dimethylarnine; (4- {3-[(diphenylmethyl)thio]-5-ethyl-4H-l ,2,4-triazol-4-yl}phenyl)dimethylamine;

(4- {3-[(diphenylmethyl)thio]-5-propyl-4H- 1 ,2,4-triazol-4-yl} phenyl)dimethylamine;

[4-(3-cyclopropyl-5-{[(2-methylphenyl)(phenyl)methyl]thio}-4H-l,2,4-triazol-4- yl)phenyl] dimethylamine;

[4-(3-{[bis(4-chlorophenyl)methyl]thio}-5-cyclopropyl-4H-l,2,4-triazol-4-yl)phen- yl]dimethylamine;

[4-(3 -cyclopropyl-5 - { [(4-methylphenyl)(phenyl)methyl]thio } -4H- 1 ,2,4-triazol-4- yl)phenyl]dimethylamine;

[4-(3-{[bis(4-fluorophenyl)methyl]thio}-5-cyclopropyl-4H-l,2,4-triazol-4-yl)phen- yljdimethylamine; [4-(3-{[(4-chlorophenyl)(phenyl)methyl]thio}-5-cyclopropyl-4H-l,2,4-triazol-4- yl)phenyl] dimethylamine;

(4-{3-butyl-5-[(diphenylmethyl)thio]-4H-l,2,4-triazol-4-yl}phenyl)dimethylamine;

[4-(3-{[bis(4-methylphenyl)methyl]thio}-5-cyclopropyl-4H-l,2,4-triazol-4-yl)phen- yljdimethylamine;

{4-[3-cyclopropyl-5-({phenyl[4-(trifluoromethyl)phenyl]methyl}thio)-4H-l,2,4-triazol-4- yl]phenyl} dimethylarnine; [4-(3-{[(4-cUorophen) )(cyclohexyl)methyl]thio}-5-cyclopropyl-4H-l,2,4-triazol-4- yl)phenyl]dimethylamine;

3-[(diphenylmethyl)thio]-5-ethyl-4-(4-isopropylphenyl)-4H-l,2,4-triazole;

{4-[3-{| is(4-chlorophenyl)methyl]thio}-5-(3-fluorophenyl)-4H-l,2,4-triazol-4-yl]phen- yl} dimethylamine;

[4-(3-{[bis(4-chlorophenyl)methyl]thio}-5-propyl-4H-l,2,4-triazol-4-yl)phenyl]dimethyl- amine;

3-{5-{(his(4-chlorophenyl)methyl]thio}-4-[4-(dimethylamino)phenyl]-4H-l,2,4-triazol-3- yl}propan-l-ol;

3-[3-{[bis(4-chlorophenyl)methyl]thio}-5-(3-fluorophenyl)-4H-l,2,4-triazol-4-yl]benzoic acid;

3-[3-{[bis(4-chlorophenyl)methyl]thio}-5-(3-fluorophenyl)-4H-l,2,4-triazol-4-yl]phenol;

3-(3-{[bis(4-chlorophenyl)methyl]thio}-5-proρyl-4H-l,2,3-triazol-4-yl)benzoic acid; 3-(3-{ bis(4-chlorophenyl)methyl]thio}-5-cyclopropyl-4H-l,2,4-triazol-4-yl)benzoic acid;

5-[3-{[bis(4-chlorophenyl)methyl]thio}-5-(3-fluorophenyl)-4H-l,2,4-triazol-4-yl]-2- (dimethyl-amino)benzoic acid;

1 -[4-(3 - { [bis(4-chlorophenyl)methyl]thio } -5-propyl-4H- 1 ,2,4-triazol-4-yl)phenyl] - piperidine-3 -carboxylic acid; and l-{4-[3-{[bis(4-chlorophenyl)methyl]thio}-5-(3-fluorophenyl)-4H-l,2,4-triazol-4-yl]- phenyl } -piperidine-3 -carboxylic acid.

8. A medicament comprising a phenyltriazole derivative of the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof as claimed in claim 1 in as an active in ⁱeg>r¹-edient.

9. The medicament as claimed in claim 8, further comprising one or more pharmaceutically acceptable excipients.

10. The medicament as claimed in claim 8, wherein said phenyltriazole derivative of the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof is a GABAb agonist.

11. The medicament as claimed in claim 8 for the treatment and/or prevention of an urological disorder or disease.

12. The medicament as claimed in claim 11, wherein said urological disorder or disease is urge urinary incontinence, overactive bladder, benign prostatic hypeφlasia.

13. The medicament as claimed in claim 11 for the treatment and/or prevention of pain.

14. The medicament as claimed in claim 11 for the treatment and/or prevention of spasticity and motor control disorders, epilepsy, cognitive defects, psychiatric disorders, alcohol dependence and withdrawal, feeding behaviour, cardiovascular, respiratory disorders, or gastrointestinal disorders.

15. Use of a compound according to claim 1 for manufacturing a medicament for the treatment and/or prevention of an urological disorder or disease.

16. Use of a compound according to claim 1 for manufacturing a medicament for the freatment and/or prevention of pain.

17. Process for controlling an urological disorder or disease in humans and animals by administration of an GABAb-agonistically effective amount of a compound according to claim 1.

18. Process for controlling pain in humans and animals by administration of a GABAb- agonistically effective amount of a compound according to claim 1.