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Definitions

• 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 ⁇ - 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.
• GABA B receptor ⁇ - aminobutyric acid receptor
• 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).
• GABA B R1 and R2 there are two GABA B receptor subtypes known, GABA B R1 and R2.
• GABA B Rla and Rib which heterodimerize with the R2 subunit. Pharmacologically, the different splice forms of GABA B R1 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 Ke ⁇ , 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.
• GABA B receptor a 25 target for pharmaceutical agents intended to treat central and peripheral neural disorders
• 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
• Botiger 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.
• 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.
• 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.
• UUI 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.
• OAB overactive bladder
• BPH Benign prostatic hyperplasia
• 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.
• LUTS progressive lower urinary tract syndromes
• the selective ⁇ l-adrenoceptor antagonists such as prazosin, ind ⁇ ramin 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.
• 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 ⁇ l -antagonists and ⁇ l -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.
• 5 ⁇ -reductase inhibitors such as finasteride are prescribed for BPH. These agents selectively inhibit 5 ⁇ -reductase which mediates conversion of testosterone to dihydrotestosterone, thereby reducing plasma dihydrotestosterone levels and thus prostate growth.
• the 5 ⁇ -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:
• 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,
• Yamada, N. et al. discloses phenyltriazole derivatives represented by the general formula:
• 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,
• This invention is to provide phenyltriazole derivatives of the formula (I), their tautomeric and stereoisomeric form, and salts thereof:
• R 1 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 membere
• R 2 represents -COR 21 , -(CH 2 n -R 21 or tert-butyl, wherein
• R 21 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, alkanoylamin ⁇ , 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 ;
• R 3 and R 4 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, -(CH 2 ) m -CO-R 50 , -(CH 2 ) m -R 51 , -NR 52 R 53 , or -OR 54 , wherein m is O, 1, 2, or 3
• R 50 is hydroxy, hydrogen, alkoxy, morpholino, di(phenyl)methyloxy, di(halogen substituted phenyl)methyloxy, -NR 50I R 502 (wherein said R 501 and R 502 independently represent hydrogen, alkoxyalkyl, alkyl, hydroxyalkyl, alkoxycarbonylalkyl, or carboxyalkyl or
• R 501 and R 502 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
• R 51 is hydrogen, hydroxy,- or -NR 511 R 512 (wherein said R 5 " and R 512 independently represent hydrogen, alkoxyalkyl, alkyl, hydroxyalkyl, alkoxycarbonylalkyl, or carboxyalkyl, or R su and R 512 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), R 52 and R 53 independently represent hydrogen, alkyl, hydroxy, cycloalkylcarbonyl
• R 54 represents alkyl optionally substituted by morpholino, amino, di(alkyl)amino, carboxy, alkoxycarbonyl, or mono-, di-, or tri- halogen, or piperazino substituted by carboxy;
• R 6 and R 7 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
• X represents CR ⁇ R 1 ] , NR. 12 , S, O, S0 2 , or SO
• R 10 , R 11 , and R 12 independently represent hydrogen or methyl.
• 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.
• 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.
• phenyltriazole derivatives of formula (I) are those wherein;
• R 1 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
• R 2 represents -COR 21 or -(CH 2 ) n -R 21 , wherein
• R 21 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 optional
• R 5 represents hydrogen, hydroxy, nitro, cyano, halogen, sulfamoyl, alkylsulfonyl, alkylaminosulfonyl, di(alkyl)aminosulfonyl, -(CH 2 ) m -CO-R 50 , -(CH 2 ) m -R 51 , -NR 52 R 53 , or -OR 54 , wherein m is 0, 1, 2, or 3
• R 50 is hydroxy, hydrogen, alkoxy, morpholino, di(phenyl)methyloxy, di(halogen substituted phenyl)methyloxy, -NR 501 R 502 (wherein said R 501 and R 502 independently represent hydrogen, alkoxyalkyl, alkyl, hydroxyalkyl, alkoxycarbonylalkyl, or carboxyalkyl or R 501 and R 502 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,
• R 51 is hydrogen, hydroxy, or -NR 511 R 512 (wherein said R 511 and R 512 independently represent hydrogen, alkoxyalkyl, alkyl, hydroxyalkyl, alkoxycarbonylalkyl, or carboxyalkyl, or R 511 and R 512 together fo ⁇ n 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), R 52 and R 53 independently represent hydrogen, alkyl, hydroxy, cycloalkylcarbonyl, or hydroxyalkyl, or R 52 and R 53 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 54 represents alkyl optionally substituted by morpholino, amino, di(alkyl) amino, or mono-, di-, or tri- halogen;
• R 6 and R 7 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 substitute
• X represents CR 10 R n , NR 12 , S, O, S0 2 , or SO
• R i0 , R 11 , and R 12 independently represent hydrogen or methyl.
• X represents CH 2 , NH, S, O, S0 2 , or SO;
• R 1 represents C 3 to C 8 cycloalkyl
• Cj-C ⁇ alkyl optionally substituted by one or two substituents selected from the group consisting of C ⁇ -C 6 alkoxy, amino, C C 6 alkylamino, di(C C 6 alkyl)amino, C r C 6 alkanoyloxy, hydroxy, C 3 -C 8 cycloalkyl, carboxy, C C 6 alkoxycarbonyl, C 3 -C 8 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, C ⁇ -C 6 alkoxy, nitro, amino, cyano, Ci-C ⁇ alkylamino, di(C ⁇ -C 6 alkyl)amino, and mono-, di- or tri- halogen substituted d-C 6 alkyl,
• R" represents -COR' or ⁇ (CH 2 ) -R ⁇ , wherein R represents mono-, di-, tri- halogen sub- stituted C C 6 alkyl, morpholino, Ci-C ⁇ alkoxy, hydroxy, C 3 to C 8 cycloalkyl, pyridyl, furanyl, thiophenyl, pyrrolidinyl, piperidinyl optionally substituted by one substituent selected from the group consisting of benzyl, Ci-Cg alkoxycarbonyl, and halo C C 6 alkyloxycarbonyl, or phenyl optionally substituted by one substituent selected from the group consisting of C C 6 alkyl, halogen, Cj-C ⁇ alkoxy, and mono-, di-, or tri- halogen substituted C ⁇ -C 6 alkyl; n is 0 or 1 ;
• R 3 and R 4 independently represent hydrogen, halogen, cyano, hydroxy, amino, C ⁇ -6 alkylamino, di(Cj. 6 alkyl)amino, C 3 . 8 cycloalltylamino, C ⁇ -6 alkoxycarbonyl, sulfamoyl, C ⁇ -6 alkylaminosulfonyl, di(C]. 6 alkylaminosulfonyl, C alkanoyl, C ⁇ _ 6 alkanoylamino, carbamoyl, C
• R 5 represents hydrogen, nitro, cyano, hydroxy, halogen, sulfamoyl, C ⁇ -C 6 alkylsulfonyl, Cj- C 6 alkylaminosulfonyl, di(C,-C 6 alkyl)aminosulfonyl, -(CH 2 ) m -CO-R 50 , -(CH 2 ) m -R 51 , -NR 52 R 53 , or -OR 54 , wherein m is 0, 1, 2, or 3
• R 50 is hydroxy, hydrogen, C ⁇ -C 6 alkoxy, morpholino, diphenylmethyloxy, -NR 501 R 502 (wherein said R 501 and R 502 independently represent hydrogen, -Cealkoxyalkyl, C C 6 alkyl, hydroxy C C ⁇ alkyl, C ⁇ -C 6 alkoxycarbonyl C C 6 alkyl, or carboxy C C 6 alkyl or R 501 and R 502 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 C ⁇ -C 6 alkyl optionally substituted by halogen
• R 51 is hydrogen, hydroxy, or -NR 5n R 512 (wherein said R 511 and R 512 independently represent hydrogen, C C 6 alkoxy alkyl, Cj-C 6 alkyl, hydroxyalkyl, C r C 6 al
• R 52 and R 53 independently represent hydrogen, C]-C 6 alkyl, hydroxy, C 3 -C 3 cycloalkyl- carbonyl, or hydroxy C C 6 alkyl or R 52 and R 53 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
• R 54 represents alkyl optionally substituted by morpholino, amino, or di(alkyl) amino, or mono-, di-, or tri- halogen; and R 6 and R 7 independently represent hydrogen, morpholino, . hydroxypyrrolidinylcarbonyl, hydroxyC ⁇ -C 6 alkylaminocarbonyl, cyano, hydroxy, hydroxyC ⁇ -C 6 alkyl, hydroxyamino, carboxy, fluoro, chloro, bromo, nitro, amino, C ⁇ -6 alkylamino, di(C 1-6 alkyl)amino, C 3 . s cycloalkylamino, d -6 alkoxycarbonyl, sulfamoyl, C ⁇ .
• alkylaminosulfonyl di(C ]-6 alkylaminosulfonyl, C ⁇ -6 alkanoyl, C ⁇ -6 alkanoylamino, carbamoyl, diphenylmeth- yloxycarbonyl, d- ⁇ alkylcarbamoyl, di-(C ⁇ . 6 alk ⁇ 'l)carbamoyl, Ci- ⁇ alkylsulfonyl, C ⁇ -6 alkyl optionally substituted by alkoxyalkyl(alkyl)amino, di(alkyl)amino, C .
• X represents CH 2 , NH, S, or SO
• R 1 represents cyclopropyl, pyridyl, phenyl optionally substituted by halogen, C r C 6 alkoxy, nitro, amino, cyano, C C fi alkylamino, di(C ⁇ -C 6 alkyl)amino, or halogen substituted C C 6 alkyl,
• Ci-Ce alkyl optionally substituted by one or two substituents selected from the group consisting of d-C 6 alkoxy, amino, C ⁇ -C 6 alkylamino, di(C- ⁇ -C 6 alkyl)amino, C C 6 alkanoyloxy, hydroxy, C 3 -C 8 cycloalkyl, carboxy, d- alkoxycarbonyl, C 3 -C 3 cycloalkylphenyloxy, halogen, morpholino, and pyrrolidinyl, pyrrolidinyl, or piperidinyl optionally substituted by methyl;
• R" represents -COR" or -(CH 2 ) n -R , wherein R" represents mono-, di- or tri- halogen substituted alkyl, morpholino, Ci-dalkoxy, hydroxy, C 3 to C 8 cycloalkyl, pyridyl, furanyl, thiophenyl, pyrrolidinyl, piperidinyl optionally substituted by one selected from the group consisting from benzyl, d-C ⁇ alkoxycarbonyl, and haloCi-C ⁇ alkyloxycarbonyl, or phenyl optionally substituted by one selected from the group consisting of C C 6 alkyl, halogen, d-C ⁇ alkoxy, and mono-, di- or tri- halogen substituted Ci-Cgalkyl; n is 0 or 1 ;
• R 3 and R 4 independently represent hydrogen, halogen, methyl, or amino;
• R 5 represents hydrogen, mo ⁇ holino, hydroxypyrrolidinylcarbonyl, hydroxyalkylaminocatbonyl, cyano, hydroxy, hydroxyalkyl, hydroxyamino, carboxy, fluoro, chloro, bromo, nitro, amino, d- ⁇ alkylamino, di(C ⁇ . 6 alkyl)amino, C 3 . 8 cycloalkylamino, C .
• R 6 andR 7 represent hydrogen, or R° and R 7 together form phenyl fused to adjacent phenyl.
• X represents CH 2 , NH, or S
• R 1 represents cyclopropyl, pyridyl, phenyl optionally substituted by halogen, alkoxy, nitro, amino, cyano, alkylamino, di(alkyl)amino, or halogen substituted alkyl, d-C 6 alkyl optionally substituted by one or two substituents selected from the group consisting of alkoxy, amino, d-C 6 alkylamino, di(d-C 6 alkyl)amino, C C 6 alkanoyloxy, hydroxy, C 3 -C 8 cycloalkyl, carboxy, d-C 6 alkoxycarbonyl, C 3 -C 8 cycloalkylphenyloxy, halogen, moipholino, and pyrrolidinyl, pyrrolidiny, or piperidinyl optionally substituted by methyl.
• X represents CH 2 , NH, or S
• R 2 represents -COR 21 , -(CH 2 ) n R 21 , wherein R 21 is phenyl optionally substituted by C,-C 6 alkyl, halogen, halogen substituted alkyl or alkoxy and n is 0 or 1.
• X represents CH 2 , NH, or S; .
• R 3 and R 4 independently represent hydrogen, halogen, methyl, amino; and R 5 represents hydrogen, mo ⁇ holino, hydroxypyrrolidinylcarbonyl, hydroxyalkylaminocarbonyl, cyano, hydroxy, hydroxyalkyl, hydroxyamino, carboxy, fluoro, chloro, bromo, nitro, amino, d- ⁇ alkylamino, di(C]. 6 alk ⁇ 'l)amino, C 3-8 cycloalkylamino, Ci-s alkoxycarbonyl, sulfamoyl, C ⁇ .
• alkylaminosulfonyl di(C ⁇ -6 alkylaminosulfonyl, C 1-6 alkanoyl, C ⁇ -6 alkanoylamino, carbamoyl, diphenylmethyloxycarbonyl, d- 6 alkylcarbamoyl, di-(C ⁇ -6 alkyDcarbamoyl, Ci.6 alkylsulfonyl, C ⁇ .
• 6 alkyl optionally substituted by alkoxy- alkyl(alkyl)amino, di(alkyl)amino, C ⁇ -6 alkoxycarbonyl, carboxy, or mono-, di-, or tri- halogen, Cj.6 alkoxy optionally substituted by mo ⁇ holino, 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 R 7 represents hydrogen.
• said phenyltriazole derivative of the formula (I) is selected from the group consisting of:
• 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.
• 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, mo ⁇ holinyl, thiomo ⁇ holinyl, tetrahydrofuryl, furyl, thienyl, pyi ⁇ olyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl and the like.
• the compound of the formula (I) of the present invention can be, but not limited to be, prepared by combining various known methods.
• 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.
• the compound of the formula (I-a) (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are the same as defined above and X' represents O, S or NR 12 ) can be prepared by reacting the compound of the formula (If) (wherein R 1 , R 5 , R 6 and R 7 are the same as defined above) with the compound of the formula (HT) (wherein R 2 , R 3 and R 4 are the same as defined above and Li represents a leaving group including, for instance, halogen atom such as chlorine, bromine, or iodine atom; C 6 . ⁇ o 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.
• a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-d
• 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.
• a base including, for instance, organic amines such as pyridine, triethylamine and N,N-diisopropylethylamine, dimethylaniline, diethylaniline, or 4-dimethylaminopyridine
• inorganic base such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, or potassium bicarbonate, and others.
• X' is further modified to be converted to SO or S0 2 .
• the compound of the formula (Il-a) (wherein R 1 , R 5 , R ⁇ and R 7 are the same as defined above) can be prepared by the following procedures in two steps.
• Step i-1 the compound of the formula (VI) (wherein R 1 , R 5 , R 6 and R 7 are the same as defined above) can be prepared by reacting the compound of the formula (IV) (wherein R 1 is the same as defined above) with the compound of the formula (V) (wherein R 5 , R 6 and R 7 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.
• a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1 ,2-
• 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.
• the compound of the formula (11-a) (wherein R 1 , R , R 6 and R 7 are the same as defined above) can be prepared by cyclization reaction of the compound of the formula (VI) (wherein R 1 , R 5 , R°and R 7 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.
• a base including, for instance, organic amines such as pyridine, triethylamine and N,N-diisopropylethylamine, dimethylaniline, diethylaniline, or 4-dimethylaminopyridine
• 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.
• a solvent including, for instance, alcohols such as methanol, ethanol, 1-propanol, isopropanol and tert-butanol, water and others.
• alcohols such as methanol, ethanol, 1-propanol, isopropanol and tert-butanol
• water and others e.g., water and others.
• 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.
• the compound of the formula (IN) (wherein R 1 is the same as defined above) can be prepared by reacting the compound of the formula (VET) (wherein R 1 is the same as defined above and L 2 represents a leaving group including, for instance, halogen atom such as chlorine, bromine, or ' iodine atom, hydroxy and C ⁇ profession 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.
• 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.
• the compound of the formula (IN) can be prepared by the following procedures.
• the compound of the formula (LX) (wherein wherein R 1 is the same as defined above and L 3 represents a protecting group including, for instance, tert-butoxycarbonyl) can be prepared by reacting the compound of the formula (VII) (wherein R 1 and L 2 are the same as defined above) with the compound of the formula (VuT) (wherein L 3 is the same as defined above).
• the reaction can be done using a coupling agent including, for instance, carbodiimides such as ⁇ , ⁇ -dicyclohexylcarbodiimide and l-(3-dimethylaminopropyl)-3-ethyl- carbodiimide, benzophenyltriazole- 1 -yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl azide.
• ⁇ -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 ⁇ , ⁇ - dimethylformamide (DMF), ⁇ , ⁇ -dimethylacetamide (DMAC) and ⁇ -methylpyrrolidone ( ⁇ MP); urea such as l,3-dimethyl-2-imidazolidinone (DMI); sulfoxides such as dimethylsulfoxide (DMSO); and others.
• a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and
• 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.
• the compound of the formula (IV) (wherein R 1 is the same as defined above) can be prepared by removing the protecting group L 3 of the compound of the formula (LX) (wherein R 1 and L 3 are the same as defined above).
• the removal of protective group L 3 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; niters 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.
• ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane
• aromatic hydrocarbons such as benzene, toluene and xylene
• 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.
• Step iii-1 the compound of the formula (X) (wherein wherein L 3 , R 5 , R 6 and R 7 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 R 5 , R 6 and R 7 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).
• Step iii-2 the compound of the formula (XI) (wherein R 5 , R 6 and R 7 are the same as defined above) can be prepared by removing the protecting group L 3 of the compound of the formula (X) (wherein L 3 , R 5 , R 6 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).
• Step iii-3 the compound of the formula (VI) (wherein R 1 , R 5 , R° and R 7 are the same as defined above) can be prepared by reacting the compound of the formula (XT) (wherein R 5 , R 6 and R 7 are the same as defined above) with the compound of the formula (VIT) (wherein R 1 and L 2 are the same as defined above) in a similar manner described in Step ii-la for the preparation of compounds of the formula (IV).
• Step iv-1 the compound of the formula (XlTf) (wherein R 1 , R 5 , R° and R 7 are the same as defined above) can be prepared by reacting the compound of the formula (XII) (wherein R 5 , R ⁇ and R 7 are the same as defined above) with the compound of the formula (VIT) (wherein R 1 and L 2 are the same as defined above).
• 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.
• a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloro form and 1 ,
• 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.
• the compound of the formula (XIV) (wherein R 1 , R 5 , R 6 and R 7 are the same as defined above) can be prepared by reacting the compound of the formula (XIH) (wherein R 1 , R 5 , R 6 and R 7 are the same as defined above) with an appropriate halogenating reagent including, for instance, SOCl 2 , POCl 3 , 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.
• 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.
• 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.
• Step iv-3 the compound of the formula (XV) (wherein R 1 , R 5 , R ⁇ and R 7 are the same as defined above) can be prepared by reacting the compound of the formula (XIV) (wherein R 1 , R 5 , R ⁇ and R 7 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.
• a solvent including, for instance, halogenated hydro arbons such as dichloromethane, chloroform and
• 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.
• Step iv-4 the compound of the formula (11-b) (wherein R 1 , R 5 , R ⁇ and R 7 are the same as defined above) can be prepared by reacting the compound of the formula (XV) (wherein R 1 , R 5 , R ⁇ and R 7 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.
• 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
• 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.
• the compound of the formula (XVIH) (wherein wherein R 2 , R 3 and R 4 are the same as defined above) can be prepared by reacting the compound of the formula (XVI) (wherein R 3 and R 4 are the same as defined above) with the compound of the formula (XVH) (wherein R 2 is the same as defined above and L 4 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.
• 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
• 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 R 2 , R 3 and R 4 are the same as defined above) can be alternatively prepared by reacting the compound of the formula (XLX) (wherein R 2 , R 3 and R 4 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 .
• 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.
• 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
• 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.
• the compound of the formula (IE) (wherein Li, R 2 , R 3 and R 4 are the same as defined above) can be prepared by reacting the compound of the formula (XVECT) (wherein wherein R 2 , R 3 and R 4 are the same as defined above) with an appropriate halogenating reagent including, for instance, POCl 3 , PC1 3 , SOCl 2 , and the like; or with the corresponding sulfonyl chloride for instance methanesulfonyl chloride.
• an appropriate halogenating reagent including, for instance, POCl 3 , PC1 3 , SOCl 2 , and the like
• 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.
• 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.
• 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.
• a base including, for instance, pyridine, triethylamine and N,N-diisopropylethylamine, dimethylaniline, diethylaniline, and others.
• 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.
• the compound of the formula (I-b) of the present invention can be, but not limited to be, prepared by the Method [B] below.
• the compound of the formula (I-b) (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R ⁇ , R 7 , R 10 and R 11 are the same as defined above) can be prepared by reacting the compound of the formula (X ⁇ (wherein R 1 , R 5 , R b and R 7 are the same as defined above) with the compound of the formula (XX) (wherein R 2 , R 3 , R 4 , R 10 and R 11 are the same as defined above and L 4 represents a leaving group including, for instance, halogen atom such as chlorine, bromine, or iodine atom).
• 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.
• a solvent including, for instance, alcohols such as methanol, ethanol, 1-propanol, isopropanol and tert-butanol, water and others.
• alcohols such as methanol, ethanol, 1-propanol, isopropanol and tert-butanol
• water and others e.g., water and others.
• two or more of the solvents selected from the listed above can be mixed and used.
• 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.
• 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.
• inorganic acids such as, without limitation, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid and the like
• 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.
• 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. -
• compositions of the present invention are 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.
• 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.
• 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.
• 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 ole
• 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.
• 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.
• 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.
• 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 ⁇ m)) 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.
• Instrument MS Micromass ZQ
• instrument HPLC Waters Alliance 2790
• column Uptisphere C 18, 50 mm x 2.0 mm, 3.0 ⁇ m
• eluent A water + 0.05% formic acid
• eluent B CH 3 CN + 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.
• DNA suspension 10 ⁇ g expression plasmid DNA of each human GABA B( i a ) and human GABA B ( 2 ) in pcDNA3 was dissolved in 450 ⁇ l of water with 50 ml CaCl 2 (2.5 M) + 500 ⁇ l 2x phosphate buffered saline (PBS, pH 6.95) and incubated for 10 to 20 min at room temperature.
• 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 ⁇ l DMEM/F12 medium supplemented with 2.5% FBS, and grown for 48 hours at 37D in a humidified atmosphere with 5% C0 2 .
• Test compounds dissolved in DMSO were diluted into DMEM/F12 medium containing 0.1% BSA and transferred to the test cultures at 5 ⁇ l/well.
• 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 H 2 0. 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 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 ⁇ M ⁇ D
• urethane 1.2 g/kg i.p.
• 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.
• a pressure transducer Viggo-Spectramed Pte Ltd, DT-XXAD
• TERUMO syringe infusion pump
• Example 1-2 to 1-167 as shown in Table 1 were synthesized.
• Example 2-2 to 2-3 as shown in Table 2 were synthesized.

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