Pyrimidine derivative

Abstract

A compound of the formula (I) or a salt thereof (R represents methyl group or fluorine atom) having an mPGES-1 inhibitory activity and useful as an active ingredient of a medicament for prophylactic and / or therapeutic treatment of such diseases as inflammation, pain, or rheumatism.

Description

Pyrimidine Derivatives

[0001] The present invention relates to novel pyrimidine derivatives, more specifically, pyrimidine derivatives that have mPGES-1 inhibitory activity and are useful as active ingredients in medicines for the prevention and / or treatment of diseases such as inflammation, pain, and rheumatism.

[0002] Prostaglandin E2 (PGE2) is involved in inflammation, pain, fever, etc. via 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 biosynthetic pathway, but they also suppress all biosynthetic pathways downstream of prostanoid production involving COX in the prostaglandin biosynthetic pathway, resulting in side effects such as gastric mucosal damage due to the suppression of gastric mucus secretion and gastric mucosal blood flow.

[0003] COX has two isozymes, COX-1 and COX-2. Of these, COX-2 is induced in inflamed tissues by various pro-inflammatory stimuli (e.g., cytokines such as interleukin-1β). While drugs that selectively inhibit COX-2 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. This is thought to increase the risk of thrombosis and further cardiovascular events.

[0004] Downstream of the PGE2 biosynthetic pathway, PGE2 is synthesized from PGH2 by prostaglandin E synthase (PGE synthase, PGES). There are three types of PGES: mPGES-1 (microsomal prostaglandin E2 synthase-1), mPGES-2 (microsomal prostaglandin E2 synthase-2), and cPGES (cytosolic PGE synthase). Of these, mPGES-1 is an inducible trimer whose expression is upregulated by inflammatory stimuli (Proc. Natl. Acad. Sci. USA, 96, pp. 7220-7225, 1999). It is known to be involved in cancer, inflammation, pain, fever, tissue repair, and other conditions.

[0005] Because mPGES-1 inhibitors can selectively suppress the final step of the PGE2 biosynthetic pathway at inflammatory sites (Pharmacol. Rev., 59, pp. 207-224, 2007; J. Biol. Chem., 279, pp. 33684-33695, 2004), they are expected to be effective anti-inflammatory agents that do not cause gastric mucosal damage like nonsteroidal anti-inflammatory drugs. 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 disease, systemic sclerosis, malignant tumors such as colorectal cancer, and diseases in which inhibition of PGE2 production is effective (see International Publication WO2015 / 125842 for information on PGE2, PGES, and mPGES-1, as well as uses of mPGES-1 inhibitors). It is also known that mPGES-1 inhibitors increase the production of other prostanoids in conjunction with the suppression of PGE2 production (J. Biol. Chem., 280, pp. 16579-16585, 2005).

[0006] Known mPGES-1 inhibitors include the heterocyclic derivatives disclosed in Japanese Patent No. 5601422, the substituted pyrimidine compounds disclosed in International Publication WO2015 / 59618, and the triazine compounds disclosed in International Publication WO2015 / 125842. International Publication WO2015 / 59618 discloses a pyrimidine compound substituted with a p-trifluoromethylphenyl group and a 2-chloro-5-isobutylamidobenzyl group (Example 2), and International Publication WO2015 / 125842 discloses triazine compounds substituted with a p-trifluoromethylphenyl group and a 2-chloro-5-isobutylamidobenzyl group (Examples 1-28).

[0007] Furthermore, International Publication WO2017 / 73709 discloses pyrimidine derivatives substituted with an m-phenylene group and having mPGES-1 inhibitory activity, and International Publication WO2019 / 44868 discloses pyrimidine derivatives substituted with a heterocycle and having mPGES-1 inhibitory activity.

[0008] Patent No. 5601422 International Publication WO2015 / 59618 International Publication WO2015 / 125842 International Publication WO2017 / 73709 International Publication WO2019 / 44868

[0009] Proc. Natl. Acad. Sci. USA, 96, pp.7220-7225, 1999Pharmacol. Rev., 59, pp.207-224, 2007J. Biol. Chem., 279, pp.33684-33695, 2004J. Biol. Chem., 280, pp.16579-16585, 2005

[0010] An object of the present invention is to provide a novel compound that has an mPGES-1 inhibitory effect and is useful as an active ingredient of a medicine for the prevention and / or treatment of diseases such as inflammation, pain, or rheumatism.

[0011] The present inventors have conducted intensive research to solve the above problems and have evaluated various pyrimidine derivatives substituted with an m-phenylene group, and have found that a pyrimidine derivative represented by the following general formula (I) has a strong inhibitory effect on mPGES-1 and is useful as an active ingredient in pharmaceuticals for the prevention and / or treatment of diseases such as inflammation, pain, or rheumatism, and that the pyrimidine derivative has high solubility, rapidly achieves high blood concentrations when administered orally, and can achieve reliable pharmacological efficacy, thereby completing the present invention. However, International Publication WO2017 / 73709 does not specifically disclose the pyrimidine derivative represented by the following formula.

[0012] That is, according to the present invention, there is provided a compound represented by the following general formula (I): (wherein R represents a methyl group or a fluorine atom) or a salt thereof.

[0013] According to a preferred embodiment of the above invention, there is provided a compound represented by the above general formula (I) or a salt thereof, in which R is a methyl group.

[0014] From another perspective, the present invention provides an mPGES-1 inhibitor comprising a compound represented by the above general formula (I) or a salt thereof; and a PGE2 biosynthesis inhibitor comprising a compound represented by the above general formula (I) or a salt thereof.

[0015] From another aspect, the present invention provides a medicament comprising, as an active ingredient, a compound represented by the above general formula (I) or a physiologically acceptable salt thereof. The medicament can be used for the prevention and / or treatment of, for example, inflammation, pain, rheumatism, osteoarthritis, fever, Alzheimer's disease, multiple sclerosis, arteriosclerosis, ocular hypertension such as glaucoma, ischemic retinal disease, systemic sclerosis, malignant tumors such as colon cancer, or diseases in which inhibition of PGE2 production is effective.

[0016] The present invention also provides the use of the compound represented by the general formula (I) or a salt thereof for the manufacture of the mPGES-1 inhibitor, the PGE2 biosynthesis inhibitor, or the pharmaceutical; a method for inhibiting mPGES-1 in the living body of a mammal, including a human, which comprises administering to the mammal, including a human, an effective amount of the compound represented by the general formula (I) or a physiologically acceptable salt thereof; a method for inhibiting PGE2 biosynthesis in the living body of a mammal, including a human, which comprises administering to the mammal, including a human, an effective amount of the compound represented by the general formula (I) or a physiologically acceptable salt thereof; and a method for promoting the production of other prostanoids by inhibiting PGE2 biosynthesis in the living body of a mammal, including a human, which comprises administering to the mammal, including a human, an effective amount of the compound represented by the general formula (I) or a physiologically acceptable salt thereof.

[0017] The compound represented by the general formula (I) or a salt thereof provided by the present invention exhibits a strong inhibitory effect on mPGES-1 and can inhibit the biosynthesis of PGE2. Furthermore, the compound represented by the general formula (I) or a salt thereof is highly soluble, rapidly absorbed by oral administration, achieving high blood concentrations in a short period of time and exhibiting excellent bioavailability. Furthermore, the compound is characterized by excellent metabolic stability (stability against cytochrome P450 (CYP) or UDP-glucuronosyltransferase (UGT)). Therefore, the compound represented by the general formula (I) or a salt thereof is useful as an active ingredient in pharmaceuticals for the prevention and / or treatment of, for example, inflammation, pain, rheumatism, osteoarthritis, fever, Alzheimer's disease, multiple sclerosis, arteriosclerosis, ocular hypertension such as glaucoma, ischemic retinal disease, systemic sclerosis, malignant tumors such as colon cancer, or diseases in which inhibition of PGE2 production is effective.

[0018] This figure shows the change in plasma unchanged compound concentration after oral administration of the compound of Example 1 of the present invention (□) and the compound of Example 182 disclosed in International Publication WO2017 / 73709 (◇) to male guinea pigs.

[0019] In the above general formula (I), R represents a methyl group or a fluorine atom, and R is preferably a methyl group.

[0020] The compounds of the present invention can be easily produced, for example, according to the synthesis method of pyrimidine derivatives disclosed in International Publication WO2017 / 73709. The examples of the present specification specifically show the synthesis method of the compounds of the present invention.

[0021] The compound represented by general formula (I) may be in the form of a salt. The salt is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof 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; mineral acid salts such as hydrochloride, sulfate, and nitrate; and organic acid salts such as p-toluenesulfonate, maleate, and tartrate.

[0022] The compound represented by formula (I) or a salt thereof may exist in the form of a hydrate or solvate. The type of solvent that forms the solvate is not particularly limited, but examples thereof include ethanol, ethyl acetate, and acetone.

[0023] The compound of the present invention represented by general formula (I) has an mPGES-1 inhibitory activity and can inhibit PGE2 biosynthesis based on this inhibitory activity. Therefore, the pharmaceutical of the present invention comprising the compound of the present invention represented by general formula (I) or a physiologically acceptable salt thereof as an active ingredient can be used, based on its mPGES-1 inhibitory activity, to prevent and / or treat, for example, inflammation, pain, rheumatism, osteoarthritis, fever, Alzheimer's disease, multiple sclerosis, arteriosclerosis, ocular hypertension such as glaucoma, ischemic retinal disease, systemic sclerosis, malignant tumors such as colon cancer, or diseases in which inhibition of PGE2 production is effective.

[0024] More specifically, the medicament of the present invention is useful for treating, for example, inflammatory bowel disease, irritable bowel syndrome, migraine, headache, lower back pain, lumbar spinal stenosis, herniated disc, temporomandibular joint disorder, cervicobrachial syndrome, cervical spondylosis, endometriosis, adenomyosis, premature birth, threatened premature birth, dysmenorrhea, overactive bladder, dysuria associated with benign prostatic hyperplasia, nocturia, urinary incontinence, neurogenic bladder, interstitial cystitis, bladder pain syndrome, urinary tract stones, benign prostatic hyperplasia, chronic prostatitis, pelvic pain syndrome, erectile dysfunction, cognitive impairment, neurodegenerative disease, Alzheimer's disease, pulmonary hypertension, psoriasis, rheumatoid arthritis, rheumatic fever, fibromyalgia, neuralgia, complex regional pain syndrome, fascial disorder, ischemic heart disease, hypertension, angina pectoris, urinary tract disease, urinary incontinence ... urinary tract stones, benign prostatic hyperplasia, chronic prostatitis, pelvic pain syndrome, erectile dysfunction, cognitive impairment, neurodegenerative disease, Alzheimer's disease, pulmonary hypertension, psoriasis, rheumatoid It can be used as a pharmaceutical for the prevention and / or treatment of pain in viral infections, bacterial infections, fungal infections, burns, inflammation and pain after surgery, trauma, and tooth extraction, malignant tumors, myocardial infarction, atherosclerosis, thrombosis, embolism, type I diabetes, type II diabetes, stroke, gout, arthritis, osteoarthritis, juvenile arthritis, ankylosing spondylitis, tenosynovitis, ossification of the ligaments, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, conjunctivitis, iritis, scleritis, uveitis, wound treatment, dermatitis, eczema, osteoporosis, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, allergic diseases, familial adenomatous polyposis, scleroderma, bursitis, uterine fibroids, or cancer. For the relationship between mPGES-1 inhibitory activity and pharmaceutical uses, see, for example, International Publication WO2015 / 125842. The disclosures of the above international publications and all references cited therein are incorporated herein by reference.

[0025] The medicament of the present invention may be a compound represented by the above general formula (I) or a physiologically acceptable salt thereof, which is an active ingredient, but preferably, an oral or parenteral pharmaceutical composition prepared and administered by a method well known to those skilled in the art. Pharmaceutical compositions suitable for oral administration include, for example, tablets, powders, capsules, fine granules, liquids, granules, and syrups, while pharmaceutical compositions suitable for parenteral administration include, for example, injections such as intravenous injections and intramuscular injections, drip infusions, inhalants, eye drops, nasal drops, suppositories, transdermal agents, and transmucosal agents, but are not limited to these.

[0026] The pharmaceutical compositions described above can be prepared by methods well known to those skilled in the art using formulation additives commonly used in the art for preparing pharmaceutical compositions. The formulation additives are not particularly limited and can be appropriately selected depending on the purpose, such as the form of the pharmaceutical composition or the ability to provide sustained release. Examples of the formulation additives include, but are not limited to, excipients, binders, fillers, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, flavoring agents, fragrances, coating agents, diluents, etc.

[0027] The dosage of the medicament of the present invention is not particularly limited and can be appropriately selected depending on the type of disease to be prevented or treated, the purpose of the prevention or treatment, the type of active ingredient, the patient's body weight and age, symptoms, route of administration, etc. For example, in the case of oral administration, the dosage can be in the range of about 0.01 to 500 mg in terms of the weight of the active ingredient per day for an adult. However, the dosage can be appropriately selected by those skilled in the art and is not limited to the above range.

[0028] The present invention will be described in more detail below based on examples, but the present invention is not limited to these examples.

[0029] Reference Example: 2-[3-(aminomethyl)-2-fluoro-6-(trifluoromethyl)phenyl]-6-[5-(trifluoromethyl)pyridin-2-yl]pyrimidin-4(3H)-one

[0030] 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 in a sealed tube at 130°C for 9 hours. The reaction was stopped once, and the next day, stirring was continued under the same conditions for 8 hours. 50 mL of water was added to the reaction solution, and then a solution of 17.9 g of sodium hydroxide in 120 mL of water was added dropwise under ice cooling and stirred for a while. The precipitated solid was collected by filtration and washed with water. The mixture was again suspended in 130 mL of t-butyl methyl ether and heated to reflux for 1 hour. After stirring at room temperature for 30 minutes, the suspended solid was collected by filtration to obtain the title compound. 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) MS(m / z):432(M + )

[0031] 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-methylpropanamide

[0032] To a solution 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'-tetramethyluronium hexafluorophosphate were added and stirred overnight at room temperature. After extraction with ethyl acetate, the mixture was washed once each with saturated aqueous ammonium chloride, water, and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography, and the solvent was evaporated under reduced pressure. The residue was suspended in t-butyl methyl ether and collected by filtration to give 119 mg of the title compound. 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) MS(m / z):520(M + )

[0033] 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)propanamide

[0034] To a solution 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'-tetramethyluronium hexafluorophosphate were added and stirred overnight at room temperature. After extraction with ethyl acetate, the mixture was washed once each with saturated aqueous ammonium chloride, water, and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography, and the solvent was evaporated under reduced pressure. The residue was suspended in a mixed solvent of t-butyl methyl ether and hexane and collected by filtration to give 173 mg of the title compound. 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) MS(m / z):524(M + )

[0035] Test Example 1: mPGES-1 Inhibitory Activity Test 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 in sodium phosphate buffer (pH 7.2) containing reduced glutathione (2.5 mM) and EDTA (1 mM), and DMSO or a DMSO solution of the test compound (final DMSO concentration: 1%) was added and pre-incubated at 4°C for 15 minutes. Next, the substrate PGH2 was added to a final concentration of 1 μM to initiate the enzyme reaction. After incubation at 4°C for 4 minutes, the enzyme reaction was stopped by adding a solution of ferric chloride (25 mM) and citric acid (50 mM). The produced PGE2 was measured using a Prostaglandin E2 Express EIA kit (Cayman Chemical). The IC was determined using standard methods. 50 The values ​​were measured.

[0036] As a result, the IC of the compound of Example 1 50 The IC value was 1.8 nM. For comparison, the IC value of the pyrimidine derivative disclosed in International Publication WO2017 / 73709 (the compound of Example 182 listed in Table 1-11) was 50 The value was measured in the same manner and was found to be 1.2 nM.

[0037] Test Example 2: Blood Concentration 10 mg of the compound from Example 1 and the compound from Example 182 disclosed in International Publication WO 2017 / 73709 were weighed out at a dose of 10 mg / kg and pulverized in an agate mortar for approximately 30 seconds. A 0.5% methyl cellulose 400 solution (Fujifilm Wako Pure Chemical Industries, Ltd.) was added in small amounts to form a suspension. Finally, the mortar was rinsed with a small amount of 0.5% MC400 solution to bring the total volume to 10 mL. The suspension was sonicated for approximately 1 minute to obtain a 1 mg / mL administration solution. Two female guinea pigs were administered a 10 mL / kg dose using a flexible oral probe (CLEA Japan, RZ-1). Blood samples were collected 0.5, 1, 2, 4, 6, 10, and 24 hours after oral administration, and plasma was obtained by centrifugation. Plasma concentrations were measured using LC-MS / MS (liquid chromatography-tandem mass spectrometry). The pharmacokinetic parameters are shown in Table 1 below.

[0038]

[0039] The time course of the unchanged drug concentration in plasma is shown in Figure 1. From the above results, it is clear that the compounds of the present invention have superior bioavailability when administered orally compared to the comparative compounds.

[0040] Test Example 3: Metabolic Stability Test (UGT) After dissolving the compound of Example 1 in DMSO, a test compound solution (10 μM) was prepared by adding acetonitrile and water. Under ice cooling, the test compound solution (final concentration 1 μM) was mixed with potassium phosphate buffer (pH 7.4) containing MgCl2 (9 mM) and alamethicin (25 μg / mL), and a rat and guinea pig liver or small intestine microsome suspension (final concentration 0.5 mg protein / mL). The mixture was stirred for 37 minutes. o After pre-incubation at 37°C for 5 minutes, UDPGA solution (final concentration 2 mM) was added to initiate the reaction. o After incubation at 3°C ​​for 5 minutes, three volumes of acetonitrile were added and stirred to stop the enzyme reaction. The reaction solution was centrifuged (1500 × g, 10 minutes, 4 o C), the supernatant was mixed with an internal standard solution to prepare a measurement sample. The compound concentration in the sample was measured by LC-MS / MS. A separate enzyme-unreacted sample was prepared and used as the initial value. For comparison, the compound of Example 182 disclosed in International Publication WO2017 / 73709 was also tested in the same manner. The results of metabolic stability are shown in Table 2 below. It is clear that the compounds of the present invention have superior metabolic stability compared to the comparative compounds.

[0041]

[0042] Test Example 4: Solubility Test A 10 mM DMSO solution of the compound of Example 1 was prepared and diluted 50-fold with JP2 solution (pH 6.8). After 16 to 24 hours of incubation, the test solution was filtered, and the concentration in the filtrate was measured using HPLC-UV or a plate reader. For comparison, the compound of Example 182 disclosed in International Publication WO2017 / 73709 was similarly tested. The results of the solubility test are shown in Table 3 below. It is clear that the compounds of the present invention have superior solubility compared to the comparative compounds.

[0043]

[0044] The compounds of the present invention represented by general formula (I) have an mPGES-1 inhibitory activity and are useful as active ingredients of medicines for the prevention and / or treatment of diseases such as inflammation, pain, or rheumatism.

Claims

1. The following general formula (I): (wherein R represents a methyl group or a fluorine atom), or a salt thereof.

2. The compound according to claim 1, wherein R is a methyl group, or a salt thereof.

3. An mPGES-1 inhibitor comprising the compound represented by the general formula (I) according to claim 1 or 2, or a salt thereof.

4. A PGE2 biosynthesis inhibitor comprising the compound represented by the general formula (I) according to claim 1 or 2, or a salt thereof.

5. A medicament comprising the compound represented by the above general formula (I) according to claim 1 or 2, or a physiologically acceptable salt thereof.

6. For use in the prevention and / or treatment of inflammation, pain, rheumatism, osteoarthritis, fever, Alzheimer's disease, multiple sclerosis, arteriosclerosis, ocular hypertension, ischemic retinopathy, systemic scleroderma, malignant tumor, overactive bladder, micturition disorder associated with prostatic hyperplasia, nocturia, urinary incontinence, neurogenic bladder, interstitial cystitis, painful bladder syndrome, urinary calculus, prostatic hyperplasia, or a disease in which inhibition of PGE2 production shows efficacy, the medicament according to claim 5.