From the above, it was confirmed that the Example compounds listed in Table 4 alone do not show elevation of the intravesical pressure but have an action of enhancing effect on the pelvic nerve electrical stimulation-induced elevation of intravesical pressure in the anesthetized rats. [0078]
As shown in the results of each the tests above, it was confirmed that the compound of the formula (I) has a muscarinic M3 receptor-positive allosteric modulator activity, and further, it enhances the bladder contraction in a nerve stimulation-dependent manner in in vitro, as well as enhances an elevation in the intravesical pressure in a nerve stimulation-dependent manner in in vivo. Accordingly, the compound of the formula (I) can be used to prevent or treat bladder/urinary tract diseases associated with bladder contractions via a muscarinic M3 receptor, in particular, voiding dysfunction or urine storage dysfunction in the bladder/urethral diseases. The compound of the formula (I) can be used for preventing or treating, for example, voiding dysftinction or urine storage dysfunction in underactive bladder, hypotonic bladder, acontractile bladder, detrusor underactivity, neurogenic bladder, urethra relaxation failure, detrusor-external urethral sphincter dyssynergia, overactive bladder, urinary frequency, nocturia, urinary incontinence, benign prostatic hyperplasia, interstitial cystitis, chronic prostatitis, and urinary tract stones. In particular, the compound of the formula (I) can be used for preventing or treating voiding dysfunction or urine storage dysfunction in underactive bladder, hypotonic bladder, acontractile bladder, detrusor underactivity, and neurogenic bladder.
In addition, the compound of formula (I) can become a therapeutic drug that is more excellent in safety from the viewpoint that the compound alone does not show an agonistic effect on a muscarinic M3 receptor, but shows an effect on enhancing the nerve stimulation-dependent bladder contraction, and accordingly, cholinergic side effects that have been reported in the existing drugs can be avoided.
[0079]
A pharmaceutical composition including one or two or more kinds of the compound of the formula (I) as an active ingredient can be prepared using an excipient which is usually used in the art, that is, an excipient for a pharmaceutical preparation, a carrier for a pharmaceutical preparation, and the like, according to a method usually used.
Administration can be accomplished either by oral administration via tablets, pills, capsules, granules, powders, solutions, and the like, or parenteral administration via injections, such as intraarticular, intravenous, and intramuscular injections, suppositories, transdermal liquid preparations, ointments, transdermal patches, transmucosal liquid preparations, transmucosal patches, inhalers, and the like.

(wherein
R! is -N(-Rn)(-Ri2), or cyclic amino which may be substituted,
RuisCi.6alkyi,
R!2 is C}-6 alkyi which may be substituted, or C3_8 cycloalkyl which may be substituted,
R2 is aryl which may be substituted, monocyclic aromatic hetero ring which may be substituted, or bicyclic aromatic hetero ring which may be substituted,
R3's are the same as or different from each other, and are each Ci_6 alkyi,
W is Ci_6 alkylene, and
n is an integer of 0 to 4).
[Claim 2] The compound or a salt thereof according to claim 1, wherein
R! is
i. cyclic amino which may be substituted with 1 to 5 substituents selected from the group consisting of Group G and oxo, or
ii.-N(-Ru)(-R!2),
R11 is d-6 alkyi, and
R12 is Ci-6 alkyi which may be substituted with 1 to 3 substituents selected from the substituents described in (b) to (g), and (n) of Group G,
R2is
i. phenyl which may be substituted with 1 to 5 substituents selected from Group G,
ii. thienyl which may be substituted with 1 to 3 substituents selected from Group Q
iii. pyridyl which may be substituted with 1 to 3 substituents selected from Group G, or
iv. benzothienyl which may be substituted with 1 to 5 substituents selected from Group G, and
Group G is a substituent selected from the group consisting of:

(a) C|„6 alkyl which may be substituted with at least one group selected from the group consisting of-OH, -0-(Ci-6 alkyl), -CN, -S02-(Ci_6 alkyl), and halogen,
(b) "OH,
(c) -0-(Cs-6 alkyl which may be substituted with at least one group selected from the group consisting of-OH, -0-(Ci-6 alkyl), -CN, -S02-(Ci_6 alkyl), and halogen),
(d) C3-s cycloalkyl,
(e) -0-(C3-8 cycloalkyl),
(f) halogen,
(g) -CN,
(h) -S02-(Ci.6 alkyl),
(i) -COS-CCLS alkyl) and -COOH,
(j) -CO-N(Ci-6 alkyl)2, -CO-NH(d,6 alkyl), and -CONH2,
(k) -CO-(d.6 alkyl),
(1) -S02-N(Ci-6 alkyl)2, -S02-NH(Ci.6 alkyl), and -S02NH2,
(m) -N(Ci.6 alkyl)2, -NH(CM alkyl), and -NH2,
(n) saturated hetero ring, and
(o) -O-saturated hetero ring.
[Claim 3] The compound or a salt thereof according to claim 2, wherein
R1 is
i. pyrrolidin-1-yl or piperidin-1-yl, in which pyrrolidin-1-yl and piperidin-1-yl are each substituted with 1 to 2 substituents selected from the group consisting of C1-6 alkyl and halogeno-Ci.6 alkyl, or
ii.-N(-R11)(-RI2)J
R11 is Ci-6 alkyl, and
R12 is C1-6 alkyl which may be substituted with one group selected from the group consisting of C3.8 cycloalkyl and -0-(Cj^ alkyl),
R2is
i. phenyl which may be substituted with 1 to 3 groups selected from the group consisting of C\.e alkyl, halogeno-Cj^ alkyl, -0-(Ci-6 alkyl), -0-(halogeno-Ci_6 alkyl), halogen, C3.8 cycloalkyl, and -CN,
ii. thienyl which may be substituted with 1 to 3 groups selected from the group consisting of Ci-e alkyl, halogeno-Ci-6 alkyl, -0-(Ci-6 alkyl), C3-8 cycloalkyl, and halogen,
iii. pyridyl which may be substituted with 1 to 3 groups selected from the group consisting of C1-6 alkyl, halogeno-Ci.6 alkyl, -0-(Ci-6 alkyl), C3-8 cycloalkyl, and halogen, or
iv. benzothienyl,
W is C1-3 alkylene, and

[Claim 4] The compound or a salt thereof according to claim 3, wherein
R2is
(a) phenyl di-substituted with trifluoromethyl and fluoro,
(b) thienyl mono-substituted with trifluoromethyl or chloro, or
(c) pyridyl di-substituted with trifluoromethyl and methoxy, and W is methylene or ethylene.
[Claim 5] The compound or a salt thereof according to claim 3, wherein
R1 is pyrrolidin-l-yl or piperidin-1-yl, in which pyrrolidin-1-yl and piperidin-1-yl are each substituted with 1 to 2 substituents selected from the group consisting of Cj_6 alkyl and halogeno-Ci-6 alkyl, and
R2is
i. thienyl which may be substituted with 1 or 2 substituents selected from the group consisting of halogeno-Ci_6 alkyl and halogen, or
ii. phenyl which may be substituted with 1 or 2 substituents selected from the group consisting of halogeno-Cj^ alky! and halogen, and
W is methylene or ethylene.
[Claim 6] The compound or a salt thereof according to claim 1, wherein the
compound is a compound selected from the group consisting of:
3-[(2S)-4-(5-{[4-(4-chlorothiophen-2-yl)-5-(t(2R)-2-methylpyrrolidin-l-yl]methyi}-l,3-thiazol-2-yl]carbamoyl}pyrazin-2-yl)-2-methylpiperazin-l-yl]propanoic acid,
3-[(3R)-4-{5-[(4-[3-fluoro-5-(trifluoromethyl)phenyl]-5-{[(2R)-2-methylpyrrolidin-l-yl]methyl}-l,3-thiazol-2-yl)carbamoyl]pyrazin-2-yl}-3-methylpiperazin-1 -y l]propanoic acid,
[(3R)-4-{5-[(4-[3-fluoro-5-(trifluoromethyl)phenyl3-5-{[(2R)-2-methylpyrrolidin-1 -yl]methyl} -1,3-thiazol-2-yl)carbamoyl]pyrazin-2-y 1} -3 -methylpiperazin-1 -yl]acetic acid,
3-(4-{5-[(4-[3-fluoro-5-(trifluoromethyl)phenyl]-5-{[(2R)-2-methylpyrrolidin-l-yl]methyl} -1,3-thiazol-2-yl)carbamoyl]pyrazin-2-y 1} piperazin-1 -yl)propanoic acid,
3-[(2R)-4-(5-{[4-(4-chlorothiophen-2-yl)-5-{[(2R)-2-ethylpyrrolidin-l-yl]methyl}-l,3-thiazol-2-yl]carbamoyl}pyrazin-2-yl)-2-methylpiperazin-l-yl]propanoic acid,
3-[(3R)-3-methyl-4-{5-[(5-{[(2R)-2-methylpyrrolidin-l-yl]methyl}-4-[4-(trifluoromethyl)thiophen-2-yl]-l,3-thiazol-2-yl)carbamoyl]pyrazin-2-yl}piperazin-l-yl]propanoic acid,

3-(4-{5-[(5-{[(2R,5R)-2,5-dimethylpyrrolidin-l-yl]methyl}-4-[3-fluoro-5-(trifiuoromethyl)phenyl]-l,3-thiazol-2-yl)carbamoyl]pyrazin-2-yl}piperazin-l-yl)propanoic acid, and
3-{(2R)-4-[5-({5-[(diethylamino)methyl]-4-[3-fluoro-5-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}carbamoyl)pyrazin-2-yl]-2-methylpiperazin-l-yl}propanoic acid.
[Claim 7] The compound or a salt thereof according to claim 1, wherein the
compound is
3-[(2S)-4-(5-{[4-(4-chlorothiophen-2-yl)-5-{[(2R)-2-methylpyrrolidin-I-yl]methyl}-l,3-thiazol-2-yl3carbamoyl}pyrazin-2-yl)-2-methylpiperazin-l-yI]propanoic acid.
[Claim 8] The compound or a salt thereof according to claim 1, wherein the
compound is
3-[(3R)-4-{5-[(4-[3-fluoro-5-(trifluoromethyl)phenyl]-5-{[(2R)-2-methylpyrrolidin-l-yl]methyl}-l,3-thiazol-2-yl)carbamoyl]pyrazin-2-yl}-3-methyl piperazin-1 -yl]propanoic acid.
[Claim 9] The compound or a salt thereof according to claim 1, wherein the
compound is
[(3R)-4-{5-[(4-[3-fluoro-5-(trifluoromethyl)phenyl]-5-{[(2R)-2-methylpyrrolidin-1 -yljmethyl}-1,3-miazol-2-yl)carbamoyl]pyrazin-2-yl}-3-methylpiperazin-1 -yljacetic acid.
[Claim 10] The compound or a salt thereof according to claim 1, wherein the
compound is
3-(4-{5-[(4-[3-fluoro-5-(trifluoromethyl)phenyl]-5-{[(2R)-2-methylpyrrolidin~l-yl]methyl}-l,3-thiazol-2-yl)carbamoyl]pyrazin-2-yl}piperazin-l-yl)propanoic acid.
[Claim 11 ] The compound or a salt thereof according to claim 1, wherein the
compound is
3-[(2R)-4-(5-{[4-(4-chlorothiophen-2-yl)-5-{[(2R)-2-ethylpyrrolidin-l-yl]methyl}-l,3-thiazol-2-yl]carbamoyl}pyrazin-2-yl)-2-methylpiperazin-l-yl]propanoic acid.
[Claim 12] The compound or a salt thereof according to claim 1, wherein the
compound is

3-[(3R)-3-methyl-4-{5-[(5-{[(2R)-2-methylpyrrolidin-l-yI]methyI}-4-[4-(trifluoromethyl)thiophen-2-yl]-l,3-thiazoI-2-yl)carbamoyl3pyrazin-2-yl}piperazin-l-yijpropanoic acid.
[Claim 13] The compound or a salt thereof according to claim 1, wherein the
compound is
3-(4-{5-[(5-{[(2R,5R)-2,5-dimethylpyrrolidin-l-yl]methyl}-4-[3-fluoro-5-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl)carbamoyl]pyrazin-2-yl}piperazin-l-yl)propanoic acid.
[Claim 14] The compound or a salt thereof according to claim 1, wherein the
compound is
3-{(2R)-4-[5-({54(diethylamino)methyl]-443-fluoro-5-(trifluoromethyl)phenyl]-K3-thiazol-2-yl}carbamoyl)pyrazin-2-yl]-2-methylpiperazin-l-yl}propanoicacid.
[Claim 15] A pharmaceutical composition comprising the compound or a salt thereof
according to claim 1, and a pharmaceutically acceptable excipient.