Pyrimidine derivatives

Abstract

The present application relates to a compound of the formula (I) or a salt thereof, which has mPGES-1 inhibitory action, is useful as an effective ingredient of a drug for preventing and / or treating diseases such as inflammation, pain, or rheumatic diseases, etc. (R represents a methyl group or a fluorine atom).

Description

Technical Field

[0001] This invention relates to novel pyrimidine derivatives. More specifically, it relates to pyrimidine derivatives that are active ingredients in medicaments for the prevention and / or treatment of diseases such as inflammation, pain, and rheumatism, and that have mPGES-1 inhibitory activity. Background Technology

[0002] Prostaglandin E2 (PGE2) participates in inflammation, pain, and fever through PGE receptors, and inflammation can be suppressed by inhibiting PGE2 production. Nonsteroidal anti-inflammatory drugs (NSAIDs) exert their anti-inflammatory effects by inhibiting cyclooxygenase (COX) upstream of the prostaglandin biosynthesis pathway. However, because they also inhibit all downstream biosynthetic pathways involving COX in the production of prostaglandin compounds, they can cause gastric mucosal damage as a side effect, resulting in inhibition of gastric mucus secretion or gastric mucosal blood flow.

[0003] COX contains two isoenzymes, COX-1 and COX-2. COX-2 is expressed and induced in inflamed tissues by various pro-inflammatory stimuli (e.g., cytokines such as interleukin-1β). While drugs that selectively inhibit COX-2 may suppress the production of PGI2, which has vasodilatory and platelet-aggregating effects, they do not inhibit the production of thromboxane A2 (TXA2), which is catalyzed by COX-1 and causes vasoconstriction and platelet aggregation. Therefore, they are considered to increase the risk of thrombosis and consequently, cardiovascular events.

[0004] Downstream of the PGE2 biosynthetic pathway, PGE2 is biosynthesized from PGH2 via prostaglandin E synthase (PGES). PGES contains three enzymes: mPGES-1 (microsomal prostaglandin E2 synthase-1), mPGES-2 (microsomal prostaglandin E2 synthase-2), and cPGES (cytosolic prostaglandin E synthase). Among these, mPGES-1 is known to be an inducible enzyme whose expression of trimers increases in response to inflammatory stimuli (Proc. Natl. Acad. Sci. USA, 96, pp. 7220-7225, 1999), and it is involved in cancer, inflammation, pain, fever, and tissue repair.

[0005] Inhibitors of mPGES-1 are expected to act as anti-inflammatory agents that do not cause gastric mucosal damage like nonsteroidal anti-inflammatory drugs (NSAIDs) because they can selectively inhibit the final stage of PGE2 biosynthesis at the site of inflammation (Pharmacol. Rev., 59, pp. 207-224, 2007; J. Biol. Chem., 279, pp. 33684-33695, 2004). Furthermore, mPGES-1 inhibitors are expected to be effective in the prevention and / or treatment of pain, rheumatism, osteoarthritis, fever, Alzheimer's disease, multiple sclerosis, arteriosclerosis, ocular hypertension such as glaucoma, ischemic retinal diseases, systemic scleroderma, malignancies such as colorectal cancer, or diseases where inhibiting PGE2 production would be effective (for information on the uses of PGE2, PGES, and mPGES-1, and mPGES-1 inhibitors, see international publication WO2015 / 125842). It should be noted that mPGES-1 inhibitors are also known to increase the production of other prostaglandin compounds while inhibiting PGE2 production (J. Biol. Chem., 280, pp. 16579-16585, 2005).

[0006] As mPGES-1 inhibitors, known examples include heterocyclic derivatives disclosed in Japanese Patent No. 5601422, substituted pyrimidine compounds disclosed in International Publication WO2015 / 59618, and triazine compounds disclosed in International Publication WO2015 / 125842. International Publication WO2015 / 59618 discloses pyrimidine compounds substituted with p-trifluoromethylphenyl and 2-chloro-5-isobutyramide benzyl (Example 2), and International Publication WO2015 / 125842 discloses triazine compounds substituted with p-trifluoromethylphenyl and 2-chloro-5-isobutyramide benzyl (Examples 1-28).

[0007] In addition, international publication WO2017 / 73709 discloses a pyrimidine derivative with mPGES-1 inhibitory activity substituted with m-phenylene, and international publication WO2019 / 44868 discloses a pyrimidine derivative with mPGES-1 inhibitory activity substituted with heterocyclic ring.

[0008] Existing technical documents

[0009] Patent documents

[0010] Patent Document 1: Japanese Patent No. 5601422;

[0011] Patent Document 2: International Publication WO2015 / 59618;

[0012] Patent document 3: International publication WO2015 / 125842;

[0013] Patent document 4: International publication WO2017 / 73709;

[0014] Patent document 5: International publication WO2019 / 44868;

[0015] Non-patent literature

[0016] Non-patent literature 1: Proc. Natl. Acad. Sci. USA, 96, pp. 7220-7225, 1999;

[0017] Non-patent literature 2: Pharmacol. Rev., 59, pp. 207-224, 2007;

[0018] Non-patent literature 3: J. Biol. Chem., 279, pp. 33684-33695, 2004;

[0019] Non-patent literature 4: J. Biol. Chem., 280, pp. 16579-16585, 2005. Summary of the Invention

[0020] The problem that the invention aims to solve

[0021] The objective of this invention is to provide novel compounds that have mPGES-1 inhibitory activity and are useful as active ingredients in medicaments for the prevention and / or treatment of diseases such as inflammation, pain, or rheumatism.

[0022] Methods for solving problems

[0023] To address the aforementioned issues, the inventors conducted in-depth research and evaluated various m-phenylene-substituted pyrimidine derivatives. They discovered that the pyrimidine derivative represented by the following general formula (I) exhibits strong inhibitory activity against mPGES-1, making it useful as an active ingredient in drugs for the prevention and / or treatment of diseases such as inflammation, pain, or rheumatism. Furthermore, this pyrimidine derivative possesses high solubility, allowing for rapid delivery of high blood concentrations upon oral administration, demonstrating reliable efficacy. This led to the completion of this invention. It should be noted that the pyrimidine derivative represented by the following formula is not specifically disclosed in international publication WO2017 / 73709.

[0024] That is, according to the present invention, a compound represented by the following general formula (I) or a salt thereof can be provided:

[0025] [Chemical Formula 1]

[0026]

[0027] (In the formula, R represents a methyl or fluorine atom).

[0028] According to the preferred embodiment of the invention described above, a compound or salt thereof represented by the above general formula (I) with R being methyl can be provided.

[0029] From another perspective, the present invention can provide mPGES-1 inhibitors containing compounds represented by the above general formula (I) or salts thereof; and PGE2 biosynthesis inhibitors containing compounds represented by the above general formula (I) or salts thereof.

[0030] Furthermore, from another perspective, this invention provides a drug containing a compound represented by the above general formula (I) or a physiologically acceptable salt thereof as an active ingredient. This drug can be used for the prevention and / or treatment of diseases such as inflammation, pain, rheumatism, osteoarthritis, fever, Alzheimer's disease, multiple sclerosis, arteriosclerosis, ocular hypertension such as glaucoma, ischemic retinal diseases, systemic scleroderma, malignant tumors such as colorectal cancer, or diseases where inhibiting PGE2 production shows effectiveness.

[0031] Furthermore, the present invention provides the use of the compound represented by the above general formula (I) or a salt thereof in the manufacture of the above mPGES-1 inhibitor, the above PGE2 biosynthesis inhibitor, or the above-mentioned drug; a method for inhibiting mPGES-1 in mammalian organisms, including humans, the method comprising administering an effective amount of the compound represented by the above general formula (I) or a physiologically acceptable salt thereof to mammalian organisms, including humans; a method for inhibiting PGE2 biosynthesis in mammalian organisms, including humans, the method comprising administering an effective amount of the compound represented by the above general formula (I) or a physiologically acceptable salt thereof to mammalian organisms, including humans; and a method for promoting the production of other prostaglandin compounds by inhibiting PGE2 biosynthesis in mammalian organisms, including humans, the method comprising administering an effective amount of the compound represented by the above general formula (I) or a physiologically acceptable salt thereof to mammalian organisms, including humans.

[0032] Invention Effects

[0033] The compounds represented by the above general formula (I) or their salts provided by this invention exert a strong inhibitory effect on mPGES-1 and can inhibit the biosynthesis of PGE2. Furthermore, the compounds represented by the above general formula (I) or their salts have high solubility, are rapidly absorbed upon oral administration, provide high blood concentrations in a short time, and exhibit excellent bioavailability. In addition, they possess excellent metabolic stability (stability to cytochrome P450 (CYP) or UDP-glucuronyl transferase (UGT)).

[0034] Therefore, the compounds represented by the above general formula (I) or their salts are useful as active ingredients in drugs for the prevention and / or treatment of diseases such as inflammation, pain, rheumatism, osteoarthritis, fever, Alzheimer's disease, multiple sclerosis, arteriosclerosis, ocular hypertension such as glaucoma, ischemic retinal disease, systemic scleroderma, malignant tumors such as colorectal cancer, or diseases in which inhibiting the production of PGE2 would be effective. Attached Figure Description

[0035] Figure 1 This is a graph showing the shift in unchanged body concentration in the plasma of male guinea pigs after oral administration of compound (□) of Example 1 of the present invention and compound (◇) of Example 182 disclosed in International Publication WO2017 / 73709. Detailed Implementation

[0036] In the above general formula (I), R represents a methyl or fluorine atom, and R is preferably a methyl atom.

[0037] The compounds of the present invention can be readily prepared according to synthetic methods for pyrimidine derivatives disclosed, for example, in International Publication WO2017 / 73709. Examples in this specification specifically illustrate methods for synthesizing the compounds of the present invention.

[0038] The compound represented by general formula (I) can be in the form of a salt. There are no particular restrictions on what constitutes a salt, and it can be appropriately selected according to the purpose. Examples include: alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium and magnesium; organic amine salts such as methylamine, ethylamine, and diethanolamine; inorganic acid salts such as hydrochloride, sulfate, and nitrate; and organic acid salts such as p-toluenesulfonate, maleate, and tartrate.

[0039] The compound represented by general formula (I) or its salt may exist as a hydrate or a solvate. There is no particular limitation on the type of solvent that forms the solvate; examples include ethanol, ethyl acetate, and acetone.

[0040] The compounds of the present invention represented by general formula (I) have mPGES-1 inhibitory activity, which inhibits PGE2 biosynthesis. Therefore, medicaments of the present invention containing compounds of the present invention represented by general formula (I) or physiologically acceptable salts thereof as active ingredients, based on mPGES-1 inhibitory activity, can be used to prevent and / or treat diseases such as inflammation, pain, rheumatism, osteoarthritis, fever, Alzheimer's disease, multiple sclerosis, arteriosclerosis, ocular hypertension such as glaucoma, ischemic retinal disease, systemic scleroderma, malignant tumors such as colorectal cancer, or diseases where inhibiting PGE2 production would be effective.

[0041] More specifically, the medicaments of the present invention can be used, for example, for the prevention and / or treatment of inflammatory colitis, irritable bowel syndrome, migraine, headache, low back pain, lumbar spinal stenosis, herniated disc, temporomandibular joint disorder, cervicobrachial syndrome, cervical spondylosis, endometriosis, adenomyosis, premature birth, threatened premature birth, dysmenorrhea, overactive bladder, urinary disorders associated with benign prostatic hyperplasia, nocturia, urinary incontinence, neurogenic bladder, interstitial cystitis, bladder pain syndrome, urinary calculi, benign prostatic hyperplasia, chronic prostatitis, pelvic pain syndrome, erectile dysfunction, cognitive impairment, neurodegenerative diseases, Alzheimer's disease, pulmonary hypertension, psoriasis, rheumatoid arthritis, rheumatic fever, fibromyalgia, neuralgia, and complex regional pain syndrome. This medication is indicated for pain associated with various conditions including: myofascial disorders, ischemic heart disease, hypertension, angina pectoris, viral infections, bacterial infections, fungal infections, burns, post-operative, post-traumatic, and post-extraction inflammation / pain, malignant tumors, myocardial infarction, atherosclerosis, thrombosis, embolism, type I diabetes, type II diabetes, stroke, gout, arthritis, osteoarthritis, juvenile arthritis, ankylosing spondylitis, tenosynovitis, ossification of ligaments, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, conjunctivitis, iritis, scleritis, uveitis, trauma treatment, dermatitis, eczema, osteoporosis, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, allergic diseases, familial adenomatous polyposis, scleroderma, bursitis, and pain associated with uterine fibroids or cancer. For information on the relationship between mPGES-1 inhibition and drug use, please refer to, for example, international publication WO2015 / 125842. The aforementioned internationally disclosed information and the full contents of the references cited therein are incorporated herein by reference.

[0042] As a medicine of the present invention, the compound represented by the above general formula (I) or a physiologically acceptable salt thereof, which is the active ingredient, can be administered. It is preferable to administer the medicine by preparing an oral or non-oral pharmaceutical composition using methods known to those skilled in the art. Examples of pharmaceutical compositions suitable for oral administration include tablets, powders, capsules, granules, liquids, pellets, and syrups. Examples of pharmaceutical compositions suitable for non-oral administration include intravenous injections, intramuscular injections, drops, inhalers, eye drops, nasal drops, suppositories, transdermal absorption agents, and mucosal absorption agents, but are not limited to these.

[0043] The above-described pharmaceutical compositions can be manufactured using formulation additives commonly used in the art to prepare pharmaceutical compositions, through methods known to those skilled in the art. Formulation additives are not particularly limited and can be appropriately selected according to the intended purpose, such as the form of the pharmaceutical composition and the imparting of sustained-release properties. Examples include, but are not limited to, excipients, binders, expanders, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, flavoring agents, fragrances, coating agents, and diluents.

[0044] The dosage of the drug of the present invention is not particularly limited and can be appropriately selected according to the type of disease to be prevented or treated, the purpose of prevention or treatment, the type of active ingredient, the patient's weight or age, symptoms, route of administration, etc. For example, in the case of oral administration, the dosage for adults can be in the range of about 0.01 to 500 mg per day based on the weight of the active ingredient. However, the dosage can be appropriately selected by those skilled in the art and is not limited to the above range.

[0045] Example

[0046] The present invention will now be described in more detail based on embodiments, but the present invention is not limited to these embodiments.

[0047] Reference example: 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-[5-(trifluoromethyl)pyridin-2-yl]pyrimidin-4(3H)-one

[0048] [Chemical Formula 2]

[0049]

[0050] A solution of 8 g of N-(2-fluoro-3-{6-oxo-4-[5-(trifluoromethyl)pyridin-2-yl]-1,6-dihydropyrimidin-2-yl}-4-(trifluoromethyl)benzyl)isobutyramide in 40 mL of concentrated hydrochloric acid was stirred at 130 °C for 9 hours in a sealed tube. The reaction was temporarily stopped, and the mixture was stirred again for 8 hours under the same conditions the next day. 50 mL of water was added to the reaction solution, and then, under ice cooling, 120 mL of an aqueous solution of 17.9 g of sodium hydroxide was added dropwise with stirring for a short time. The precipitated solid was filtered off and washed with water. The solid was resuspended in 130 mL of tert-butyl methyl ether, heated under reflux for 1 hour, stirred at room temperature for 30 minutes, and then filtered off to obtain the title compound.

[0051] 1H-NMR(DMSO-d6,δ):4.25(2H,s),7.42(1H,brs),7.94(1H,d,J=8.4Hz),8.03(1H,t,J= 7.6Hz),8.32(1H,d,J=8.4Hz),8.39(1H,dd,J=8.4,2.0Hz),8.62(2H,brs),9.15(1H,s)

[0052] MS(m / z): 432 (M + )

[0053] Example 1: 2-Fluoro-N-(2-Fluoro-3-{6-oxo-4-[5-(trifluoromethyl)pyridin-2-yl]-1,6-dihydropyrimidin-2-yl}-4-(trifluoromethyl)benzyl)-2-methylpropionamide

[0054] [Chemical Formula 3]

[0055]

[0056] To a mixture of 170 mg of 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-[5-(trifluoromethyl)pyridin-2-yl]pyrimidin-4(3H)-one in 3 mL of N,N-dimethylformamide and 3 mL of tetrahydrofuran, 45 μL of 2-fluoroisobutyric acid, 109 μL of triethylamine, and 164 mg of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate were added, and the mixture was stirred overnight at room temperature. After extraction with ethyl acetate, the mixture was washed once each with saturated ammonium chloride solution, water, and saturated brine, dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography, and the solvent was removed by distillation under reduced pressure. The residue was suspended in tert-butyl methyl ether and filtered to give 119 mg of the title compound.

[0057] 1 H-NMR (DMSO-d6, δ): 1.51 (6H, d, J = 22.0Hz), 4.46 (2H, d, J = 6.4Hz), 7.35 (1H, brs), 7.67 (1H ,t,J=7.2Hz),7.81(1H,d,J=8.4Hz),8.36(2H,s),8.87(1H,m),9.14(1H,s),13.51(1H,brs)

[0058] MS(m / z): 520(M + )

[0059] Example 2: 2,2-Difluoro-N-(2-fluoro-3-{6-oxo-4-[5-(trifluoromethyl)pyridin-2-yl]-1,6-dihydropyrimidin-2-yl}-4-(trifluoromethyl)benzyl)propionamide

[0060] [Chemical Formula 4]

[0061]

[0062] To a mixture of 170 mg of 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-[5-(trifluoromethyl)pyridin-2-yl]pyrimidin-4(3H)-one in 3 mL of N,N-dimethylformamide and 3 mL of tetrahydrofuran, 40 μL of 2,2-difluoropropionic acid, 109 μL of triethylamine, and 164 mg of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate were added, and the mixture was stirred overnight at room temperature. After extraction with ethyl acetate, the mixture was washed once each with saturated ammonium chloride aqueous solution, water, and saturated brine, dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography, and the solvent was removed by distillation under reduced pressure. The residue was suspended in a mixed solvent of tert-butyl methyl ether and hexane and filtered to give 173 mg of the title compound.

[0063] 1 H-NMR(DMSO-d6,δ):1.80(3H,t,J=19.6Hz),4.51(2H,d,J=6.0Hz),7.36(1H,brs),7.71(1H,t,J =7.2Hz),7.82(1H,d,J=8.4Hz),8.36(2H,m),9.14(1H,s),9.46(1H,t,J=6.0Hz),13.52(1H,brs)

[0064] MS(m / z): 524 (M + )

[0065] Experimental Example 1: mPGES-1 Inhibitory Activity Assay

[0066] Microsomes were prepared from COS-1 cells transiently transfected with a plasmid encoding human mPGES-1 cDNA and used as the mPGES-1 enzyme. The mPGES-1 enzyme was diluted with sodium phosphate buffer (pH 7.2) containing 2.5 mM reduced glutathione and 1 mM EDTA, and DMSO or a DMSO solution of the test compound (DMSO final concentration 1%) was added. Pre-incubation was performed at 4°C for 15 min. Then, PGH2 as substrate was added to a final concentration of 1 μM to initiate the enzyme reaction. After incubation at 4°C for 4 min, 25 mM ferric chloride and 50 mM citrate solution were added to stop the enzyme reaction. The generated PGE2 was measured using the Prostaglandin E2 Express EIA kit (Cayman Chemical). IC50 was measured using standard methods. 50 value.

[0067] As a result, the IC50 of compound 1 in Example 1 50 The value was 1.8 nM. For comparison, the IC50 values ​​of the pyrimidine derivatives disclosed in International Publication WO2017 / 73709 (the compounds of Example 182 described in Table 1-11) were also determined. 50 The value is 1.2nM.

[0068] Experimental Example 2: Blood Concentration

[0069] 10 mg of each of the compounds from Example 1 and Example 182 disclosed in International Publication WO2017 / 73709 were weighed at a dose of 10 mg / kg and micronized in an agate mortar for approximately 30 seconds. A small amount of 0.5% methylcellulose 400 solution (manufactured by Fujifilm and Koichi Chemical Co., Ltd.) was added to suspend the compound each time, and the mortar was finally rinsed with a small amount of 0.5% MC400 solution to bring the combined volume to 10 mL. The mixture was sonicated for approximately 1 minute to prepare a 1 mg / mL dosing solution. Two female guinea pigs were administered the solution at a dose of 10 mL / kg using a flexible oral probe (CLEA Japan, RZ-1). Blood samples were collected at 0.5, 1, 2, 4, 6, 10, and 24 hours after oral administration, and plasma was obtained by centrifugation. The plasma concentration was measured by LC-MS / MS (liquid chromatography-tandem mass spectrometry). Pharmacokinetic parameters are shown in Table 1 below.

[0070] [Table 1]

[0071]

[0072] Average (n=2)

[0073] The shift in unchanging concentrations of plasma is shown in Figure 1 The results above show that, compared with the comparative compounds, the compounds of the present invention exhibit superior bioavailability when administered orally.

[0074] Experimental Example 3: Metabolic Stability Test (UGT)

[0075] After dissolving the compound from Example 1 in DMSO, acetonitrile and water were added to prepare a 10 μM test compound solution. A potassium phosphate buffer (pH 7.4) containing the test compound solution (final concentration 1 μM), 9 mM MgCl2, and 25 μg / mL alammethicin, along with rat and guinea pig liver or small intestinal microsomal suspensions (final concentration 0.5 mg protein / mL), was mixed under ice-cooling. After pre-incubation at 37°C for 5 minutes with stirring, UDPGA solution (final concentration 2 mM) was added to initiate the reaction. After incubation at 37°C for 5 minutes with stirring, three volumes of acetonitrile were added, and stirring was continued to stop the enzyme reaction. The reaction mixture was centrifuged (1500 × g, 10 min, 4°C), and the supernatant was mixed with an internal standard solution to prepare the assay sample. The concentration of the compound in the sample was determined by LC-MS / MS. Additionally, an unreacted sample was prepared as an initial value. For comparison, the same tests were performed on the compound of Example 182 disclosed in International Publication WO2017 / 73709. The results of metabolic stability are shown in Table 2 below. Clearly, the compound of the present invention exhibits superior metabolic stability compared to the comparative compound.

[0076] [Table 2]

[0077]

[0078] Test Example 4: Solubility Test

[0079] A 10 mM DMSO solution of the compound from Example 1 was prepared and diluted 50-fold with JP2 solution (pH 6.8). After incubation for 16–24 hours, the test solution was filtered, and the concentration in the filtrate was measured using HPLC-UV or a plate reader. For comparison, the same test was performed on the compound of Example 182 disclosed in International Publication WO2017 / 73709. The results of the solubility test are shown in Table 3 below. Clearly, the compound of the present invention exhibits superior solubility compared to the comparative compound.

[0080] [Table 3]

[0081]

[0082] Industrial practicality

[0083] The compounds represented by general formula (I) of the present invention have mPGES-1 inhibitory activity and are useful as active ingredients in drugs for the prevention and / or treatment of diseases such as inflammation, pain or rheumatism.

Claims

1. The compound or its salt represented by the following general formula (I): In the formula, R represents methyl.

2. An mPGES-1 inhibitor comprising a compound of formula (I) as claimed in claim 1 or a salt thereof.

3. A PGE2 biosynthesis inhibitor comprising a compound of formula (I) as claimed in claim 1 or a salt thereof.

4. A drug comprising a compound of formula (I) as claimed in claim 1 or a physiologically acceptable salt thereof.

5. Use of the compound represented by general formula (I) of claim 1 or a physiologically acceptable salt thereof in the manufacture of a preventive and / or therapeutic agent for a disease in which the inhibition of PGE2 production is effective.

6. Use of the compound represented by general formula (I) according to claim 5, wherein, The disease in question is inflammation, pain, or multiple sclerosis.

7. Use of the compound represented by general formula (I) according to claim 5 or 6, or a physiologically acceptable salt thereof, wherein, The diseases mentioned include rheumatism, osteoarthritis, fever, Alzheimer's disease, arteriosclerosis, ocular hypertension, ischemic retinal disease, systemic scleroderma, malignant tumors, overactive bladder, urinary disorders associated with benign prostatic hyperplasia, nocturia, urinary incontinence, neurogenic bladder, interstitial cystitis, bladder pain syndrome, urinary tract stones, or benign prostatic hyperplasia.

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