CN111303161B - Pyrimido-nitrogen heterocyclic compound and application thereof - Google Patents
Pyrimido-nitrogen heterocyclic compound and application thereof Download PDFInfo
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Abstract
The application discloses a pyrimido-nitrogen heterocyclic compound shown as a general formula I in the technical field of organic chemistry and a pharmaceutically acceptable salt thereof, wherein a substituent X, Ar has a meaning given in the specification, and the application of the compound shown as the general formula I and the pharmaceutically acceptable salt thereof in the preparation of medicines for treating diseases caused by abnormal high expression of URAT1, particularly medicines for treating and/or preventing gout, wherein the general formula I is shown as follows.
Description
Technical Field
The invention relates to the field of organic chemistry, in particular to a pyrimido-nitrogen heterocyclic skeleton compound, a pharmaceutically acceptable salt, a hydrate or a prodrug thereof, a preparation method thereof and a pharmaceutical composition containing the compound. The invention also relates to application of the compounds and the compositions in preparing medicines for treating and/or preventing gout and application of medicines for treating diseases caused by abnormal high expression of URAT 1.
Background
Gout is an inflammatory arthritis caused by the continuous rise of uric acid levels in the blood, and when uric acid is at high levels, uric acid crystals are deposited in joints, tendons, and surrounding tissues, resulting in gout attacks characterized by recurrent joint redness and pain. At present, gout medication comprises two schemes of acute attack medication and long-term medication. In the acute stage, nonsteroidal anti-inflammatory drugs (NSAIDs), steroids or colchicine are used to relieve symptoms. Long-term administration of allopurinol or probenecid is often performed by inhibiting uric acid production or promoting uric acid excretion. Investigation shows that gout affects the health and normal life of 1-2% of people, and meanwhile, along with gout, the risk of other diseases is increased, such as metabolic syndrome, which becomes a serious metabolic disease threatening the health of human beings. Therefore, the prevention and treatment of gout is a major challenge in current medical research.
Uric acid is produced by purine metabolism in the liver or small intestine in vivo, and the amount of production thereof depends on the amount of exogenous purine taken up, the amount of endogenous purine produced in the cell, the amount of recycling, and the activities of various enzymes in the purine metabolic pathway. Among them, defects in various enzymes in the purine metabolic pathway are the leading cause of an increase in the production of uric acid. Under normal physiological conditions (body fluid pH 7.4), 98% of uric acid (a weak acid pKa 5.57) combines with sodium ions in the extracellular fluid to form Monosodium urate (MSU). The salt forms crystals at concentrations in the body fluid exceeding 380. mu.M, resulting in precipitation of MSU, which causes gouty arthritis when deposited in the joint space. In addition, the pH, ionic strength, temperature of the in vivo environment, and microparticles in plasma that bind to uric acid all can affect the precipitation of MSU crystals. The specific generation mechanism is that MSU crystals are phagocytized by mononuclear macrophages, and the macrophages are stimulated to release proinflammatory factors such as interleukin-1 beta (IL-1 beta) and Tumor necrosis factor-alpha (TNF-alpha) and the like, so as to trigger a series of typical inflammatory reactions, and further generate gout.
Hyperuricemia is an important pathogenic factor in various diseases such as gout and cardiovascular diseases, and the excretion function of the kidney plays a leading role in maintaining plasma urate levels. The Urate reabsorption transport factor I (Urate reabsorption transport factor 1, URAT1) is an important target for mediating the reabsorption of Urate at the root tip of the proximal tubule of kidney.
URAT1 is a member of the SLC22A family, a transporter responsible for reabsorption of urate in the renal proximal tubule. Furthermore, anion transporter 1 (OAT 1) and anion transporter 3 (OAT 3) are also members of the SLC22A family, responsible for the secretion of uric acid into the urine, while URAT1 is responsible for reabsorption. The cells, while taking up sodium from the lumen membrane, take up anions and then exchange urate with anions via URAT1 in the proximal tubule, which are pumped into the proximal cells from the apical or basolateral side and also produce organic anions inside the cells which promote the reabsorption of urate. Therefore, selective inhibition of URAT1 can enhance uric acid excretion.
Lesinurad is used as the first single acting on URAT1 inhibitor, and can obviously increase uric acid excretion and reduce the level of uric acid in serum. The medicine has obvious effect on treating gout, weak cross action, less adverse reaction, good tolerance and safety, and is a promising gout treatment medicine. However, the dosage window is narrow (200 mg-400 mg), and the inhibitory activity is only micromolar. Therefore, the method has important practical significance for the modification research of Lesinurad.
Disclosure of Invention
The inventor takes the structure-activity relationship of a URAT1 inhibitor Lesinurad as a starting point, adopts the principle of electronic isostere, reserves an important pharmacodynamic group thioglycolic acid segment in Lesinurad, replaces triazole with pyrimido five-membered azacyclo, replaces a cyclopropyl naphthalene ring with a substituted benzene ring and other means, designs and synthesizes a series of unreported pyrimido nitrogen heterocyclic compounds, and in vitro experiments prove that the compounds have good URAT1 inhibition activity, and the results show that the compounds have the potential effect of treating gout.
The invention provides a pyrimido nitrogen heterocyclic compound of a general formula I and pharmaceutically acceptable salts thereof, wherein the general formula I is as follows:
wherein X is C or N;
ar is (C)6-C10) Aryl or 5-10 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Ar is 1-3 identical or different R1A substituent group;
R1is 1-4 selected from hydrogen, hydroxyl, halogen, nitro, amino, cyano, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkoxy, optionally hydroxy, amino or halo (C)1-C6) Alkyl or (C)1-C6) Alkoxy radical, 1-2 (C)1-C6) Alkyl-substituted amino, C1-C6Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkoxy group, (C)1-C6) Alkyl, (C)1-C6) Alkyl acyl, carbamoyl, substituted by 1-2 (C)1-C6) Alkyl-substituted carbamoyl group, (C)1-C3) Alkylenedioxy or allyl.
The invention preferably relates to a compound shown in a general formula I and pharmaceutically acceptable salts thereof, wherein X is C or N;
ar is phenyl, naphthyl, quinolyl, isoquinolyl, quinazolinyl, indolyl, pyridyl, furyl, thienyl, pyrrolyl or pyrimidinyl, and Ar is 1-3 identical or different R1And (4) a substituent.
The invention preferably relates to a compound shown as a general formula I and pharmaceutically acceptable salts thereof, wherein X is C, N;
ar is phenyl, naphthyl, furyl or thienyl, and Ar is 1-3 same or different R1A substituent group;
R1is hydrogen, halogen, hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, methoxy, methylthio, tert-butyl or methylsulfonyl.
The compounds of the general formula I according to the invention and their pharmaceutically acceptable salts are particularly preferably the following compounds, but these are not intended to limit the invention in any way:
2- [ (9-phenyl-4, 5-dihydro-9H-purin-2-yl) thio ] acetic acid;
2- { [3- (4-methoxyphenyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-5-yl ] thio } acetic acid;
2- { [9- (4-methoxyphenyl) -9H-purin-2-yl ] thio } acetic acid;
2- { [9- (4-fluorophenyl) -9H-purin-2-yl ] thio } acetic acid;
2- { [9- (p-tolyl) -9H-purin-2-yl ] thio } acetic acid;
2- { [3- (naphthalen-1-yl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-5-yl ] thio } acetic acid;
2- { [9- (naphthalen-1-yl) -9H-purin-2-yl ] thio } acetic acid;
2- { [3- (3-fluorophenyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-5-yl ] thio } acetic acid;
2- { [9- (3-fluorophenyl) -9H-purin-2-yl ] thio } acetic acid;
2- { [9- (2-methylphenyl) -9H-purin-2-yl ] thio } acetic acid;
2- { [9- (3, 4-difluorophenyl) -9H-purin-2-yl ] thio } acetic acid;
2- { [9- (2-methyl-4-chlorophenyl) -9H-purin-2-yl ] thio } acetic acid.
In addition, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the invention are derivatives of formula I which may themselves have poor or no activity, but which, upon administration, are converted under physiological conditions (e.g., by metabolism, solvolysis, or otherwise) to the corresponding biologically active form.
The term "halo" as used herein, unless otherwise indicated, refers to fluoro, chloro, bromo or iodo; "alkyl" refers to straight or branched chain alkyl; "cycloalkyl" refers to a substituted or unsubstituted cycloalkyl; "alkenyl" means straight or branched chain alkenyl; "alkynyl" refers to straight or branched chain alkynyl groups; "aryl" refers to an organic group obtained by removing one hydrogen atom from an aromatic hydrocarbon, such as phenyl, naphthyl; 5-to 10-membered heteroaryl includes those containing one or more heteroatoms selected from N, O and S, wherein the ring system of each heteroaryl group may be monocyclic or polycyclic, the ring system is aromatic, and contains a total of 5 to 10 atoms, and examples thereof include imidazolyl, pyridyl, pyrimidinyl, pyrazolyl, (1,2,3) -and (1,2,4) -triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzothiazolyl, indolyl, quinolyl and the like; 5-10 membered heterocyclic groups include those containing one or more heteroatoms selected from N, O and S, wherein the ring system of each heteroaryl group may be monocyclic or polycyclic but is non-aromatic, the ring system containing a total of 5 to 10 atoms and may optionally include 1 or 2 carbon-carbon double or triple bonds, and there may be mentioned, for example, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, thiazolinyl and the like.
The invention can contain the pyrimido-nitrogen heterocyclic compound of the formula I and pharmaceutically acceptable salt thereof as active ingredients, and the active ingredients are mixed with pharmaceutically acceptable carriers or excipients to prepare a composition and prepare a clinically acceptable dosage form, wherein the pharmaceutically acceptable excipients refer to any diluents, auxiliary agents and/or carriers which can be used in the pharmaceutical field. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.
The clinical dosage of the pyrimido-azaheterocyclic compounds of formula I above of the invention for use in patients may be based on: the therapeutic efficacy and bioavailability of the active ingredients in the body, their metabolism and excretion rates and the age, sex, disease stage of the patient are suitably adjusted, although the daily dose for an adult should generally be 10-500mg, preferably 50-300 mg. Thus, when the pharmaceutical composition of the present invention is formulated into a unit dosage form, each unit preparation should contain 10 to 500mg of the pyrimido-azaheterocyclic compound of the above formula I, preferably 50 to 300mg, in view of the above effective dose. These formulations may be administered in several doses (preferably one to six times) at regular intervals, according to the guidance of a doctor or pharmacist.
The pharmaceutical composition of the present invention can be formulated into several dosage forms containing some excipients commonly used in the pharmaceutical field. The above-mentioned several dosage forms can adopt the dosage forms of injection, tablet, capsule, aerosol, suppository, membrane, dripping pill, external liniment and ointment, etc.
Carriers for the pharmaceutical compositions of the present invention are of the usual type available in the pharmaceutical art, including: binder, lubricant, disintegrating agent, cosolvent, diluent, stabilizer, suspending agent, pigment-free, correctant, antiseptic, solubilizer, matrix, etc. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they may be formulated as enteric coated tablets.
The compound of the invention is found to have certain anti-gout activity by an in vitro enzyme activity test method, so that the compound of the invention can be used for preparing medicines for treating and/or preventing various gout. In addition, the compound of the invention can be used for preparing medicines for treating and/or preventing diseases caused by abnormally high expression of URAT 1.
The active compound or the medicinal salt and the solvate thereof can be used independently as a unique antitumor drug or can be used together with gout treatment drugs (such as Lesinurad, Verinurad, Arhalofenate and the like) on the market. Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and their methods of preparation. It should be understood that the scope of the following examples and preparations is not intended to limit the scope of the present invention in any way.
The following synthetic schemes describe the preparation of the derivatives of formula I of the present invention, all starting materials being prepared by the methods described in these synthetic schemes, by methods well known to those of ordinary skill in the art of organic chemistry or commercially available. All of the final compounds of the present invention are prepared by the methods described in these synthetic routes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All variables used in these synthetic routes are as defined below or in the claims.
According to the general formula I derivative, 2, 4-dichloro-5-nitropyrimidine is used as a starting material, and an intermediate A-4 is obtained through substitution and reduction reactions. Then A-4 is respectively combined with triethyl orthoformate or sodium nitrite buckle ring to obtain corresponding purine intermediate A-5-1 and triazole pyrimidine intermediate A-5-2; finally, a thioglycolic acid group is introduced to the intermediate through substitution reaction to obtain two series of target compounds of T-1 and T-2. As shown in the synthetic route:
the synthetic route is as follows:
Detailed Description
The nuclear magnetic resonance hydrogen spectrum of the compound is measured by a BrukeraRX-400 type nuclear magnetic resonance analyzer (DMSO-d6) as a solvent, and TMS as an internal standard; the mass spectrum is measured by Agilent 1100 LC/MS; the melting point is measured by a WRS-1A digital melting point instrument, and the temperature is not corrected; the reagents used in the experiment are all analytically pure or chemically pure.
Example 12 preparation of- [ (9-phenyl-4, 5-dihydro-9H-purin-2-yl) thio ] acetic acid (T-1)
Preparation of intermediate 2-chloro-5-nitro-N-phenylpyrimidin-4-amine (A-3)
3.0g (15.6mmol) of A-1 was dissolved in 15mL of THF, cooled to 0 ℃ in an ice bath, and while stirring, a solution of 1.8g (16.8mmol) of aniline in 10mL of THF and a solution of 1.89g (18.7mmol) of triethylamine in 10mL of THF were added dropwise, while controlling the reaction temperature to not higher than 5 ℃. Stirring for 30min at 5 ℃, and raising the temperature to room temperature for further reaction for 5 h. After the reaction, the reaction solution was filtered, the filter cake was washed with 1 mL of THF, the filtrate was collected, concentrated under reduced pressure, and the residue was added to 20mL of water and stirred for 30min, filtered, washed with water, and dried to give 3.5g of yellow powder with a yield of 90.7%.
Preparation of intermediate 2-chloro-N-phenylpyrimidine-4, 5-diamine (A-4)
A50 mL three-necked flask was charged with 20mL of 90% ethanol, 0.2mL of concentrated hydrochloric acid, and 2.7g (48.0mmol) of iron powder, and heated to 60 ℃ to activate for 10 min. 2.0g (8.0mmol) of A-3 was added and the temperature was raised to reflux. After 1.5h, after the reaction is finished, 0.01g of activated carbon is added, the mixture is refluxed for 0.5h, filtered by diatomite, naturally cooled to room temperature, concentrated to 1/3 of the original product, the filtrate is poured into 10mL of 10% NaOH aqueous solution, crystallized for 1h at room temperature, and the pH value is measured again to be 11. Suction filtration and drying are carried out to obtain 1.6g of gray solid with the yield of 90.5 percent.
Preparation of intermediate 2-chloro-9-phenyl-9H-purine (A-5-1)
1.5g (6.8mmol) of A-4 was dissolved in 15mL triethyl orthoformate. Under stirring at room temperature, 2 drops of trifluoroacetic acid were added dropwise, and the reaction was completed after 3 hours. The reaction solution was poured into 30mL of a saturated aqueous solution of sodium bicarbonate, stirred at room temperature for 3 hours to precipitate a brown solid, which was then filtered and dried to obtain 1.2g of a brown powder with a yield of 75.7%.
Preparation of 2- [ (9-phenyl-4, 5-dihydro-9H-purin-2-yl) thio ] acetic acid, a target compound (i.e., T-1)
5.7g (62.0mmol) of thioglycolic acid were dissolved in 20mL of ethanol and slowly added to a solution of 20mL of sodium hydroxide (5.5g,138mmol) in ethanol. The temperature is increased to 45 ℃ and the reaction is carried out for 2 h. Cooling to room temperature, suction filtering, washing the filter cake with absolute ethyl alcohol, and drying to obtain 6.2g of white sodium thioglycolate. 1.0g (4.3mmol) of A-5-1, 0.7g (5.2mmol) of the sodium salt of thioglycolic acid was added to 10mL of methanol, and the reaction was completed after refluxing for 3 hours. After cooling to room temperature, the reaction mixture was poured into 20mL of water and stirred for 10 min. Filtering to remove solid impurities, adjusting pH of the filtrate to 4 with 10% hydrochloric acid, precipitating white solid, filtering, and drying to obtain white powder 0.73g with yield of 55.7%. M.p. 102-; MS (ESI) M/z (%) 285.59 [ M-H ]; 1H NMR (400MHz, DMSO-d6)12.76(s,1H),9.11(s,2H),8.94(s,2H),7.93(d, J ═ 7.7Hz,2H),7.61(d, J ═ 8.1Hz,2H),7.49(d, J ═ 7.4Hz,1H),3.99(s, 2H).
EXAMPLE 22 preparation of- { [3- (4-methoxyphenyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-5-yl ] thio } acetic acid (T-2)
Preparation of 5-chloro-3- (4-methoxyphenyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidine (A-5-2)
In a 25mL eggplant-shaped bottle, 10mL of glacial acetic acid and 1.0g (4.0mmol) of 2-chloro-N4- (4-methoxyphenyl) pyrimidine-4, 5-diamine were placed under ice-cooling (0 ℃ C.). Stirring, after complete dissolution, 0.3g (4.4mmol) of sodium nitrite in 0.8g (48.0mmol) of water solution is slowly dropped into the mixture for reaction for 4 hours. The reaction solution was poured into water and stirred, filtered and dried to obtain 0.8g of a gray solid with a yield of 79.2%.
Preparation of 2- { [3- (4-methoxyphenyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-5-yl ] thio } acetic acid (T-2)
0.8g (3.1mmol) of A-5-2, 0.5g (3.7mmol) of the sodium salt of thioglycolic acid was added to 8mL of methanol, and the reaction was completed after refluxing for 3 hours. After cooling to room temperature, the reaction mixture was poured into 20mL of water and stirred for 10 min. Filtering to remove solid impurities, adjusting pH of the filtrate to 4 with 10% hydrochloric acid, precipitating white solid, filtering, and drying to obtain white powder 0.52g with yield of 52.6%. M.p. 120-; MS (ESI) M/z (%) 316.26[ M-H ]; 1H NMR (400MHz, DMSO-d6)9.53(s,1H),8.05(d, J ═ 8.8Hz,2H),7.21(d, J ═ 8.8Hz,2H),3.85(s,3H),3.78(s, 2H).
EXAMPLE preparation of 32- { [9- (4-methoxyphenyl) -9H-purin-2-yl ] thio } acetic acid (T-3)
2, 4-dichloro-5-nitropyrimidine and p-anisidine are used as raw materials, 0.41g of white solid is prepared according to the preparation method I, and the total yield is 36.7%. M.p. 132-; MS (ESI) M/z (%) 315.31[ M-H ]; 1H NMR (400MHz, DMSO-d6)9.00(s,1H),8.75(s,1H),7.81(d, J ═ 8.9Hz,2H),7.16(d, J ═ 8.9Hz,2H),3.84(s, 3H),3.75(s, 2H).
EXAMPLE 42 preparation of- { [3- (4-fluorophenyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-5-yl ] thio } acetic acid (T-4)
2, 4-dichloro-5-nitropyrimidine and para-fluoroaniline are used as raw materials, and 0.36g of white solid is prepared according to the preparation method II, wherein the total yield is 40.6%. M.p. 125-126 ℃; MS (ESI) M/z (%): 304.22[ M-H ] - (see Figure 7); 1H NMR (400MHz, DMSO-d6)9.67(s,1H), 8.32-8.08 (m,2H),7.52(t, J ═ 8.8Hz,2H),4.07(s,2H).
Example preparation of 52- { [9- (4-fluorophenyl) -9H-purin-2-yl ] thio } acetic acid (T-5)
2, 4-dichloro-5-nitropyrimidine and para-fluoroaniline are used as raw materials, 0.37g of white solid is prepared according to the preparation method I, and the total yield is 35.6%. M.p. 119-121 ℃; MS (ESI) M/z (%) 303.21[ M-H ]; 1H NMR (400MHz, DMSO-d6) 9.02(s,1H),8.82(s,1H), 8.08-7.87 (m,2H),7.48(t, J ═ 8.8Hz,2H),3.70(s,2H).
Example preparation of 62- { [9- (p-tolyl) -9H-purin-2-yl ] thio } acetic acid (T-6)
2, 4-dichloro-5-nitropyrimidine and p-methylaniline are used as raw materials, 0.40g of white solid is prepared according to the preparation method I, and the total yield is 36.9%. M.p. 122-123 ℃; MS (ESI) M/z (%) 299.30[ M-H ]; 1H NMR (400MHz, DMSO-d6)9.10(s,1H),8.89(s,1H),7.80(d, J ═ 8.4Hz,2H),7.41(d, J ═ 8.2Hz,2H),3.99(s, 2H),2.40(s,3H).
EXAMPLE 72 preparation of- { [3- (Naphthalen-1-yl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-5-yl ] thio } acetic acid (T-7)
2, 4-dichloro-5-nitropyrimidine and 1-naphthylamine are used as raw materials, 0.51g of white solid is prepared according to the preparation method II, and the total yield is 38.9%. M.p. 131-; MS (ESI) M/z (%) 336.29[ M-H ]; 1H NMR (400MHz, DMSO-d6) 9.65(s,1H),8.29(d, J ═ 8.2Hz,1H),8.18(d, J ═ 8.2Hz,1H),7.88(d, J ═ 6.4Hz,1H),7.80(t, J ═ 7.8Hz,1H),7.69(t, J ═ 7.1Hz,1H), 7.62-7.54 (m,1H),7.47(d, J ═ 8.4Hz,1H),3.57(s,2H).
Example preparation of 82- { [9- (Naphthalen-1-yl) -9H-purin-2-yl ] thio } acetic acid (T-8)
2, 4-dichloro-5-nitropyrimidine and 1-naphthylamine are used as raw materials, 0.40g of white solid is prepared according to the preparation method I, and the total yield is 35.3%. M.p. 134-; MS (ESI) M/z (%) 335.35[ M-H ]; 1H NMR (400MHz, DMSO-d6)9.11(s,1H), 8.70(s,1H),8.21(d, J ═ 7.7Hz,1H),8.15(d, J ═ 8.2Hz,1H), 7.80-7.70 (m,2H), 7.66(t, J ═ 7.5Hz,1H),7.56(t, J ═ 7.6Hz,1H),7.33(d, J ═ 8.4Hz,1H),3.55(s,2H)
EXAMPLE preparation of 92- { [3- (3-fluorophenyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-5-yl ] thio } acetic acid (T-9)
2, 4-dichloro-5-nitropyrimidine and m-fluoroaniline are used as raw materials, and 0.51g of white solid is prepared according to the preparation method II, wherein the total yield is 38.3%. M.p. 111-; MS (ESI) M/z (%) 304.22[ M-H ]; 1H NMR (400MHz, DMSO-d6) 9.57(s,1H), 8.17-8.06 (m,2H), 7.82-7.69 (m,1H),7.41(td, J ═ 8.5,2.2Hz,1H),3.80(s,2H, g
Example preparation of 102- { [9- (3-fluorophenyl) -9H-purin-2-yl ] thio } acetic acid (T-10)
2, 4-dichloro-5-nitropyrimidine and p-anisidine are used as raw materials, 0.45g of white solid is prepared according to the preparation method I, and the total yield is 37.1%. M.p. 124-127 ℃; MS (ESI) M/z (%) 303.23[ M-H ]; 1H NMR (400MHz, DMSO-d6)9.12(s,1H),8.99(s,1H),7.90(dd, J ═ 14.7,9.2Hz,4H),7.66(q, J ═ 7.7Hz,2H), 7.35(t, J ═ 7.4Hz,2H),4.01(s,2H).
EXAMPLE 112 preparation of- { [9- (2-methylphenyl) -9H-purin-2-yl ] thio } acetic acid (T-11)
By using 2, 4-dichloro-5-nitropyrimidine and o-toluidine as raw materials, 0.57g of white solid was prepared according to preparation method I, and the total yield was 41.7%. M.p. 135-137 ℃; MS (ESI) M/z (%) 299.25[ M-H ]; 1H NMR (400MHz, DMSO-d6)9.12(s,1H),8.65(s,1H), 7.51-7.49 (m,2H), 7.46-7.40 (m,2H),3.92(s,2H), 2.10(s,3H).
Example preparation of 122- { [9- (3, 4-difluorophenyl) -9H-purin-2-yl ] thio } acetic acid (T-12)
Starting from 2, 4-dichloro-5-nitropyrimidine and 3, 4-difluoroaniline, 0.45g of a white solid was obtained according to preparation I, with a total yield of 36.9%.
M.p. 131-; MS (ESI) M/z (%): 321.23[ M-H ] - (see Figure 23); 1H NMR (400MHz, DMSO-d6)9.11(s,1H),8.92(s,1H),8.15(ddd, J ═ 11.6,7.1,2.6Hz,1H), 7.88-7.82 (m,1H), 7.70(q, J ═ 9.0Hz,1H),4.00(s,2H).
Example preparation of 132- { [9- (2-methyl-4-chlorophenyl) -9H-purin-2-yl ] thio } acetic acid (T-13)
0.38 g of white solid was prepared according to preparation method I from 2, 4-dichloro-5-nitropyrimidine and 2-methyl-4-chloroaniline with a total yield of 34.6%. M.p. 136-; MS (ESI) M/z (%) 333.27[ M-H ]; 1H NMR (400MHz, DMSO-d6)9.11(s,1H),8.63(s,1H),7.62(s,1H),7.50(s,2H),3.91(s,2H),2.11(s,3H).
The data relating to the target compounds are shown in Table 1
TABLE 1
The product of the invention is directed to anti-URAT 1 inhibitors in vitro against xanthine oxidase activity.
Hyperuricemia is an important pathogenic factor in various diseases such as gout and cardiovascular diseases, and the excretion function of the kidney plays a leading role in maintaining plasma urate levels. The Urate reabsorption transport factor I (Urate reabsorption transport factor 1, URAT1) is an important target for mediating the reabsorption of Urate at the root tip of the proximal tubule of kidney.
URAT1 is a member of the SLC22A family, a transporter responsible for reabsorption of urate in the renal proximal tubule. Furthermore, anion transporter 1 (OAT 1) and anion transporter 3 (OAT 3) are also members of the SLC22A family, responsible for the secretion of uric acid into the urine, while URAT1 is responsible for reabsorption. The molecular mechanism model is shown in FIG. 1.3: the cells, while undergoing luminal membrane sodium uptake, take up anions and then exchange urate for anions via URAT1 in the proximal tubule, organic anions are pumped into the proximal cells from the apical or basolateral side and also organic anions are generated inside the cells which promote the reabsorption of urate [17 ]. Therefore, selective inhibition of URAT1 can enhance uric acid excretion.
The compound activity test adopts an in vitro enzyme activity test method, and the used kinase is xanthine oxidase kinase provided by Abcam. The specific method comprises the following steps: xanthine oxidase was prepared at 20nM, the compound was concentrated in 100. mu.l buffer, the xanthine oxidase and buffer were preheated to 37 ℃ and incubated at 37 ℃ for 30 min. After that, the cells were quenched with 50. mu.l of 30% trichloroacetic acid and incubated at 52 ℃ for 30 min. Centrifugation was carried out at room temperature, 100. mu.l of the supernatant was taken, and the value was read at a wavelength of 480nm, and the inhibition ratio was calculated from the value, and the activity data are shown in Table 2.
TABLE 2
From the above experimental results, it is clear that the compound of formula I to be protected in the present invention has a certain in vitro anti-gout activity.
Claims (7)
1. The pyrimido nitrogen heterocyclic compound and the pharmaceutically acceptable salt thereof have the following general formula I:
I
wherein X is C or N;
ar is (C)6-C10) Aryl or 5-10 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Ar is substituted with 1-3R, which may be the same or different1Substitution;
R1selected from hydrogen, hydroxy, halogen, nitro, amino, cyano, (C)1-C6) Alkyl radical (C)2-C6) Alkenyl, (C)2-C6) alkynyl, (C)1-C6) Alkoxy, optionally substituted by hydroxy, amino or halogenGeneration (C)1-C6) Alkyl or (C)1-C6) Alkoxy radical, by 1-2 (C)1-C6) Alkyl-substituted amino, C1-C6Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group (C)1-C6) Alkanoyl, carbamoyl, substituted by 1-2 (C)1-C6) Alkyl-substituted carbamoyl group, (C)1-C3) Alkylenedioxy or allyl.
2. The compound of formula I as claimed in claim 1, wherein Ar is phenyl, naphthyl, quinolyl, isoquinolyl, quinazolinyl, indolyl, pyridyl, furyl, thienyl, pyrrolyl or pyrimidinyl, and Ar is substituted by 1-3 identical or different R1And (4) substitution.
3. The compound of formula I and pharmaceutically acceptable salts thereof as claimed in claim 2 characterized in that Ar is phenyl, naphthyl, furyl or thienyl and Ar is substituted by 1-3 identical or different R1Substitution;
R1is hydrogen, halogen, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, methoxy, tert-butyl or methylsulfonyl.
4. A compound according to any one of claims 1 to 3, selected from the following compounds:
2- [ (9-phenyl-4, 5-dihydro-9H-purin-2-yl) thio ] acetic acid;
2- { [3- (4-methoxyphenyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-5-yl ] thio } acetic acid;
2- { [9- (4-methoxyphenyl) -9H-purin-2-yl ] thio } acetic acid;
2- { [9- (4-fluorophenyl) -9H-purin-2-yl ] thio } acetic acid;
2- { [9- (p-tolyl) -9H-purin-2-yl ] thio } acetic acid;
2- { [3- (naphthalen-1-yl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-5-yl ] thio } acetic acid;
2- { [9- (naphthalen-1-yl) -9H-purin-2-yl ] thio } acetic acid;
2- { [3- (3-fluorophenyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-5-yl ] thio } acetic acid;
2- { [9- (3-fluorophenyl) -9H-purin-2-yl ] thio } acetic acid;
2- { [9- (2-methylphenyl) -9H-purin-2-yl ] thio } acetic acid;
2- { [9- (3, 4-difluorophenyl) -9H-purin-2-yl ] thio } acetic acid;
2- { [9- (2-methyl-4-chlorophenyl) -9H-purin-2-yl ] thio } acetic acid.
5. A pharmaceutical composition comprising a compound of any one of claims 1 to 3 and a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable excipient.
6. The use of a compound according to any one of claims 1 to 3, and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment and/or prevention of gout.
7. The use of a compound according to any one of claims 1 to 3, and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment and/or prevention of diseases caused by abnormal expression of URAT 1.
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