巴西专利BR112015007586B1 pyrrole [3,2-d] pyrimidine derivatives, their use and pharmaceutical composition comprising them

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专利摘要:
PIRROLEUM DERIVATIVES [3,2-D] PYRIMIDINE FOR THE TREATMENT OF VIRAL INFECTIONS AND OTHER DISEASES. This invention relates to pyrrolo [3,2-d] pyrimidine derivatives, processes for their preparation, pharmaceutical compositions, and their use in the treatment and / or therapy of diseases.
公开号:BR112015007586B1
申请号:R112015007586-0
申请日:2013-10-09
公开日:2021-02-09
发明作者:Tim Hugo Maria Jonckers；Werner Embrechts；Serge Maria Aloysius Pieters；Pierre Jean-Marie Bernard Raboisson；David Craig Mc Gowan；Stefaan Julien Last
申请人:Janssen Sciences Ireland Uc；
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[001] This invention relates to pyrrole [3,2- d] pyrimidine derivatives, processes for their preparation, pharmaceutical compositions, and their use in the treatment and / or therapy of diseases.
[002] The present invention relates to the use of pyrrole-pyrimidine derivatives, more specifically with the use of pyrrole [3,2-d] pyrimidine derivatives, in the treatment of viral infections, immune or inflammatory disorders, where modulation , or agonism, of toll-like receptors (TLRs) is involved. Toll-like receptors are primary transmembrane proteins characterized by an extracellular domain rich in leucine and a cytoplasmic extension that contains a conserved region. The innate immune system is able to recognize molecular patterns associated with pathogens through these TLRs expressed on the cell surface of certain types of immune cells. The recognition of foreign pathogens activates the production of cytokines and a regulation over co-stimulating molecules in phagocytes. This leads to the modulation of the behavior of T lymphocytes.
[003] A majority of mammalian species have between ten and fifteen types of Toll-like receptors. Thirteen TLRs (simply named TLR1 to TLR13) have been identified in humans and mice together, and equivalent forms of many of these have been found in other mammalian species. However, equivalents of certain TLRs found in humans are not present in all mammals. For example, a gene encoding a protein analogous to TLR10 in humans is present in mice, but appears to have been damaged at some point in the past by a retrovirus. On the other hand, mice express TLRs 11, 12 and 13, none of which are represented in humans. Other mammals can express TLRs that are not found in humans. Other non-mammalian species may have TLRs other than mammals, as demonstrated by TLR14, which is found in the Takifugu puffer fish. This can complicate the process of using experimental animals as models of human innate immunity.
[004] For reviews on toll-type receivers see the following magazine articles. Hoffmann, J.A., Nature, 426, p33-38, 2003; Akira, S., Takeda, K., and Kaisho, T., Annual Rev. Immunology, 21, p335-376, 2003; Ulevitch, R. J., Nature Reviews: Immunology, 4, pp. 512-520, 2004.
[005] Compounds indicating activity at Toll-like receptors have previously been described such as heterocyclic derivatives in W02000006577, adenine derivatives in WO 98/01448 and WO 99/28321, and pyrimidines in WO 2009/067081.
[006] In the treatment of certain viral infections, regular injections of interferon (IFN-alpha) can be administered, such as the hepatitis C virus (HCV) (Fried et al. Peginterferon-alfa plus ribavirin for chronic hepatitis C virus infection, N Engl J Med 2002; 347: 975-82). Orally available small IFN-inducing molecules offer the potential advantages of reduced immunogenicity and convenience of administration. Thus, new IFN inducers are a class of potentially effective drugs for treating virus infections. For an example in the literature of a small IFN-inducing molecule having an antiviral effect see De Clercq, E .; Descamps, J .; De Somer, P. Science 1978, 200, 563-565.
[007] Alpha interferon is also given to patients in combination with other drugs in the treatment of certain types of cancer (Eur. J. Cancer (46) p 2849-57, and Cancer Res. 1992 (52) p.1056). TLR 7/8 agonists are also of interest as vaccine adjuvants due to their ability to induce a pronounced Th1 response (Hum. Vaccines, 2009 (5), 381-394).
[008] However, there is a strong need for new Toll-type receptor modulators having preferential selectivity, and an improved safety profile compared to prior art compounds.
[009] According to the present invention there is provided a compound of formula (I)
and its pharmaceutically acceptable salt, solvate, prodrug, stereoisomers or polymorph wherein R1 is H, fluorine or methyl; R2 is H, halogen or C1-3 alkyl; R3 is C1-6 alkyl optionally substituted by aryl optionally additionally substituted by one or more substituents independently selected from aryloxy, halogen, aryl, alkylamino, dialkylamino, heterocycloalkyl, C1-6 cycloalkyl, C1-6 alkyl, carboxylic acid, carboxylic ester, amide carboxylic, nitrile, or C1-6 alkoxy; or R3 is C1-6 alkyl optionally substituted by C1-6 alkene, C3-7 cycloalkyl or C3-7 heterocycloalkyl; or R3 is C1-6 alkyl optionally substituted by C1-6 alkoxy optionally additionally substituted by aryl; R4 is C1-8 alkyl optionally substituted by one or more substituents independently selected from hydroxyl, C1-6 alkoxy, C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, aryl, heteroaryl optionally additionally substituted by C1-6 alkyl, and C3-7 cycloalkyl optionally additionally substituted by C1-6 alkyl @ as long as 2-amino-4- (N-butylamino) -5- (alpha-methylbenzyl) pyrrolo [3,2-d] pyrimidine is excluded.
Preferred compounds are those of formula (I) in which R3 is a C1-3 alkyl group substituted by an aryl (substituted or unsubstituted), and R1, R2, and R4 are described as above.
[0011] In a second embodiment are the compounds of formula (I) in which R3 and R4 are C1-3 alkyl substituted by an aryl, optionally additionally substituted as described above.
[0012] In an additional embodiment are those of formula (I) in which R1 is hydrogen, R2 is fluorine, and R3 and R4 are as described above.
[0013] Other preferred modalities are those of formula (I) in which R1 is fluorine, R2 is hydrogen, and R3 and R4 are as described above.
[0014] The compounds, as listed in Tables I and II, having the following numbers # 89, 94, 101, 144, 154, 156, 175, 192, 209, 213 and 215 are of special interest due to their properties according to with the invention disclosed here.
[0015] The compounds of formula (I) and their pharmaceutically acceptable salt, solvate or polymorph have activity as pharmacists, in particular as modulators of Toll-like Receptor activity (especially TLR7 and / or TLR8).
[0016] In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof together with one or more pharmaceutically acceptable excipients, diluents or vehicles.
[0017] Furthermore, a compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof according to the present invention, or a pharmaceutical composition comprising said compound of formula (I) or a salt thereof, solvate or pharmaceutically acceptable polymorph can be used as a medicine.
[0018] Another aspect of the invention is that a compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof, or said pharmaceutical composition comprising said compound of formula (I) or a pharmaceutically salt, solvate or polymorph thereof acceptable, can be used accordingly in the treatment of any disorder in which the modulation of TLR7 and / or TLR8 is involved.
[0019] The term "alkyl" refers to a saturated straight chain or branched chain aliphatic hydrocarbon containing the specified number of carbon atoms.
[0020] The term "halogen" refers to fluorine, chlorine, bromine or iodine.
[0021] The term "alkenyl" refers to an alkyl as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond.
[0022] The term "cycloalkyl" refers to a carbocyclic ring containing the specified number of carbon atoms.
[0023] The term "alkoxy" refers to an alkyl group (carbon and hydrogen chain) linked by simple bond to oxygen such as a methoxy or ethoxy group.
[0024] The term "aryl" means an aromatic ring structure optionally comprising one or two heteroatoms selected from N, O and S, in particular N and O. Said aromatic ring structure can have 5, 6 or 7 atoms in ring. In particular, said aromatic ring structure can have 5 or 6 ring atoms. Said aromatic ring structure can also be fused with another aryl ring giving a bicyclic structure (examples include, but are not limited to: quinoline, isoquinoline, quinazoline, benzoxazole).
[0025] The term "aryloxy" refers to an aromatic ring structure. Said aromatic group is linked by simple bonding to oxygen (e.g., phenoxy).
[0026] The term "alkene" refers to a saturated hydrocarbon chain containing the specified number of carbon atoms containing at least one carbon-to-carbon double bond.
[0027] The term "heterocycle" refers to molecules that are saturated or partially saturated and includes tetrahydrofuran, dioxane or other cyclic ethers. Nitrogen-containing heterocycles include, for example, azetidine, morpholine, piperidine, piperazine, pyrrolidine, and the like. Other heterocycles include, for example, thiomorpholine, dioxolinyl, and cyclic sulfones.
[0028] Pharmaceutically acceptable salts of the compounds of formula (I) include their acid and base addition salts. Suitable acid addition salts are formed from acids that form non-toxic salts. Appropriate basic salts are formed from bases that form non-toxic salts.
[0029] The compounds of the invention can also exist in solvated and unsolvated forms. The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
[0030] The term "polymorph" refers to the ability of the compound of the invention to exist in more than one crystal shape or structure.
The compounds of the present invention can be administered as crystalline or amorphous products. They can be obtained, for example, as solid buffers, powders, or films, by methods such as precipitation, crystallization, lyophilization, spray drying, or evaporative drying. They can be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs. Generally, they will be administered as a formulation in combination with one or more pharmaceutically acceptable excipients. The term "excipient" is used here to describe any ingredient other than the compound (s) of the invention. The choice of excipient depends largely on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
The compounds of the present invention or any subgroup thereof can be formulated in various dosage forms for administration purposes. As appropriate compositions, all compositions usually used for systemic drug administration can be cited. To prepare the pharmaceutical compositions of the present invention, an effective amount of the particular compound, optionally in the form of an addition salt, as the active ingredient is combined in admixture with a pharmaceutically acceptable carrier, the carrier of which can take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unit dosage form suitable, for example, for oral, rectal, or percutaneous administration. For example, in the preparation of compositions in oral dosage form, any of the usual pharmaceutical means such as, for example, water, glycols, oils, alcohols and the like can be employed in the case of liquid oral preparations such as suspensions, syrups, elixirs , emulsions and solutions; or solid vehicles such as starches, sugars, kaolin, thinners, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Due to their ease of administration, tablets and capsules represent the most advantageous oral unit dose forms, in which case solid pharmaceutical carriers are obviously employed. Also included are preparations in solid form that can be converted, shortly before use, into liquid forms. In compositions suitable for percutaneous administration, the vehicle optionally comprises a penetration enhancing agent and / or a suitable wetting agent, optionally combined with suitable additives of any nature in minimal proportions, the additives of which do not introduce a significant deleterious effect on the skin. Said additives can facilitate administration to the skin and / or can be useful for preparing the desired compositions. These compositions can be administered in a variety of ways, e.g., as a transdermal patch, as an adhesive, as an ointment. The compounds of the present invention can also be administered via inhalation or insufflation using methods and formulations employed in the art for administration via this route. Thus, in general the compounds of the present invention can be administered to the lungs in the form of a solution, a suspension or a dry powder.
[0033] It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. The unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including grooved or coated tablets), capsules, pills, powder packs, cookies, suppositories, injectable solutions or suspensions and the like, and their multiple secretions.
[0034] Those with expertise in the treatment of infectious diseases will be able to determine the effective amount from the test results presented hereinafter. In general, it is contemplated that an effective daily amount would be 0.01 mg / kg to 50 mg / kg of body weight, more preferably 0.1 mg / kg to 10 mg / kg of body weight. It may be appropriate to administer the required dose as two, three, four or more underdoses at appropriate intervals throughout the day. Such underdoses can be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.
[0035] The exact dosage and frequency of administration depend on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient as well as other medication that the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective amount can be decreased or increased depending on the response of the treated subject and / or depending on the physician's judgment in prescribing the compounds of the present invention. The ranges of effective amounts mentioned above are therefore guidelines only and are not intended to limit the scope or use of the invention to any extent. Experimental Section Scheme 1. Global reaction scheme

The type A compounds in scheme 1 can be alkylated with benzyl bromides using a polar aprotic solvent, for example DMF. The reaction of alkyl halides with intermediate A requires a stronger base (eg, cesium carbonate) and possibly a longer reaction time and / or increased temperature. The substitution of chlorine in intermediate B for an amine to form type C compounds may require additional heating or extended reaction time as observed with amino alcohols (for the preparation of amino alcohols see W02009067081 and W02008147697). The replacement of chlorine in intermediate B by an amine can also proceed at room temperature in a polar solvent (eg, DMF or acetonitrile). A variety of bases can be used to assist in the reaction from B to C including, but not limited to, the following: triethylamine, diisopropylamine, cesium carbonate, potassium carbonate, or sodium hydride. The reduction of the azido group in compounds represented by intermediate D above can also proceed on Pd / C in a hydrogen atmosphere. The fluorine-containing intermediates B, C, and D can be substituted under the same protocols as the unsubstituted analogs, so the described reaction schemes apply to both types of compounds.
[0037] Preparation of intermediate B

[0038] 2,4-dichloro-5H-pyrrolo [3,2-d] pyrimidine [CAS 63200-54-4] (1 g, 5.319 mmol), DMF (10 mL) were placed in a 50 mL flask, DIPEA (2.75 ml, 16 mmol) and benzyl bromide (0.7 ml, 5.85 mmol). The flask was sealed and shaken for 16 hours at room temperature. The solvents were removed under reduced pressure. The crude was purified by silica gel column chromatography using a gradient of heptane to ethyl acetate. The best fractions were grouped and the solvents were removed under reduced pressure to give B. LC-MS (M + H) m / z = 278 Preparation of intermediate B2

[0039] In a 50 mL flask equipped with a magnetic stir bar, anhydrous A (1 mL), cesium carbonate (0.259 g, 0.8 mmol) and then 2-bromoethyl and methyl ether (0.03) were placed mL, 0.29 mmol). The flask was sealed, and the reaction was allowed to stir at 70 ° C for 2 hours. The solvents were removed under reduced pressure. The crude was purified by silica gel column chromatography using a gradient of heptane to ethyl acetate. The best fractions were grouped and the solvents were removed under reduced pressure to give B2. LC-MS (M + H) m / z = 246 Preparation of intermediate C

[0040] In a 50 mL flask equipped with a magnetic stir bar, B (1.4 g, 5.03 mmol), n-butylamine (0.59 mL, 6.04 mmol), and 1.4 -dioxane (5 ml). The flask was equipped with a reflux condenser and allowed to heat with stirring at 100 ° C for 16 hours. After cooling to room temperature, the solvents were removed under reduced pressure. The crude was purified by silica gel column chromatography using a gradient of heptane to ethyl acetate. The best fractions were grouped and the solvents were removed under reduced pressure to give C. LC-MS (M + H) m / z = 315 Preparation of intermediate D

[0041] C (1 g, 3.18 mmol), sodium azide (0.62 g, 9.53 mmol), and NMP: water (9: 1.4 ml). The glass flask was sealed and the mixture was heated with stirring to 170 ° C for 5 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (20 ml) and washed with water (5 x 15 ml). The organic layer was dried over magnesium sulfate, the solids were removed by filtration and the solvents in the filtrate were removed under reduced pressure. The crude was purified by silica gel column chromatography using a gradient of heptane to ethyl acetate. The best fractions were combined and the solvents were removed under reduced pressure to give D. LC-MS (M + H) m / z = 322 Preparation of 1

[0042] D (100 mg, 0.311 mmol), 1,4-dioxane (4 mL), water (1 mL), and triphenylphosphine (245 mg, 0, 93 mmol). The glass flask was sealed and the mixture heated with stirring to 120 ° C for 48 hours. After cooling to room temperature, the solvents were removed under reduced pressure. The crude product was purified by silica gel column chromatography using a gradient of dichloromethane to 10% methanol in dichloromethane. The best fractions were pooled and the solvents were removed under reduced pressure to give 1. LC-MS (M + H) m / z = 296 Preparation of 86

[0043] In a glass flask equipped with a magnetic stir bar, 1 (110 mg, 0.372 mmol), nitromethane (1.5 mL), and selectfluor (198 mg, 0.56 mmol) were placed. The glass flask was sealed and the mixture stirred at room temperature for 16 hours. The solvents were removed under reduced pressure. The crude was purified by reverse phase chromatography. The best fractions were grouped and the solvents were removed under pressure □ □□ - □ ida to give 86. Preparation of intermediate E

[0044] In a glass flask equipped with a magnetic stir bar, A (600 mg, 3.19 mmol), nitromethane (10 mL), and selectfluor (5.67 g, 16 mmol) were placed. The glass flask was sealed and the mixture stirred at room temperature for 48 hours. NaHCO3 (sat. Aq., 10 ml) was added and extracted with ethyl acetate (3 x 15 ml). The organic layers were combined, dried over magnesium sulfate, the solids were removed by filtration, and the filtrate solvents were removed under reduced pressure to give crude E, used as such in the next step. LC-MS (M + H) m / z = 206 Preparation of intermediate G
Step 1.
[0045] Intermediate F was prepared according to the method used to prepare compound 9 in scheme 3 on page 44 of W02010006025. With the exception that the acetyl group was used instead of the trimethylacetyl group. Step 2. Preparation of intermediate G
[0046] In a 50 ml glass vial equipped with a magnetic stir bar, F (200 mg, 0.97 mmol), anhydrous DMF (5 ml), DBU (0.435 ml, 2.91 mmol) were placed, and BOP (536 mg, 1.2 mmol). The reaction mixture becomes a solution after stirring for several minutes, then n-butylamine (0.48 ml, 4.85 mmol) was added and stirring is continued at room temperature for 16 hours. The solvent was removed under reduced pressure and the crude was purified by reverse phase chromatography. LC-MS (M + H) m / z = 262 Scheme 2. Overall reaction scheme

[0047] General procedure. Type X compounds in scheme 2 can be functionalized with alcohols using Mitsunobu conditions in a polar aprotic solvent, for example THF. Cleavage of methyl carbamate was carried out under basic conditions in 1,4-dioxane to form intermediate Z. The replacement of chlorine in intermediate Z was carried out with an amine and a base (eg, NaH) in a polar solvent (e.g., NMP) to form compounds of the formula (I). Preparation of intermediate X
3-Amino-2-ethoxycarbonylpyrrole hydrochloride (25.8 g, 135.3 mmol) was partitioned between dichloromethane and sat. NaHC03, dried over MgSO4, filtered and evaporated to dryness. The residue was dissolved in methanol (500 ml) together with 1,3-bis (methoxycarbonyl) -2-methyl-2-thiopseudourea (32.1 g, 156 mmol) and acetic acid (39 ml, 677 mmol) and stirred 1 hour at room temperature. A precipitate appeared and stirring was continued overnight. Sodium methoxide (73.1 g, 1353 mmol) was added. An exotherm was observed and the reaction mixture was stirred overnight. The reaction mixture was brought to pH 5 by adding acetic acid and the precipitate was filtered, triturated with water (2 x 350 ml), acetonitrile (1 x 350 ml) and diisopropylether (1 x 350 ml). The methyl N- (4-hydroxy-5H-pyrrolo [3,2-d] pyrimidin-2-yl) carbamate obtained was dried in the oven.
[0048] Methyl N- (4-hydroxy-5H-pyrrolo [3,2-d] pyrimidin-2-yl) carbamate (25 g, 120 mmol) was dispensed in acetonitrile (350 mL) in a 500-well multi-vial mL at room temperature. POCh (22.1 mL, 238.2 mmol) was added and the reaction mixture was heated to 70 ° C while stirring by a mechanical, suspended stirring (300 rpm). Hunig's base (41.4 ml, 240.2 mmol) was added dropwise via a syringe pump at a flow rate of 0.2 ml / min. The reaction mixture was cooled to room temperature and poured into a stirred solution of sodium acetate (78.8 g, 961 mmol) in water (500 ml) at 45 ° C. The organics were evaporated and the remaining liquid was stirred and cooled in an ice bath. The solid formed was isolated by filtration, washed with acetonitrile and triturated with diisopropylether to become intermediate X as a solid which was dried in vacuo. Preparation of intermediate Y

[0049] To a suspension of intermediate X (5 g, 22 mmol), 2-pyridinamethanol (2.6 mL, 26.5 mmol) and polystyrene-bound triphenylphosphine (18.4 g, 55.2 mmol) in anhydrous THF (153 ml) DIAD (6.9 ml, 33 mmol) was added at room temperature and the reaction mixture stirred for 30 minutes, then it was concentrated under reduced pressure. The product was purified by silica gel column chromatography using a 100: 0 to 90:10 dichloromethane: methanol gradient. The product fractions were collected and concentrated under reduced pressure. The product was recrystallized from acetonitrile, isolated by filtration and dried in vacuo to give Y as a white solid. Preparation of intermediate Z

[0050] Y (4.5 g, 14.2 mmol) was dissolved in 1,4-dioxane (68 ml) in a 100 ml round bottom flask and 1 N NaOH (34 ml) was added. The mixture was heated to 60 ° C for 5 h. The mixture was cooled and concentrated under reduced pressure. The residue was treated with water and the precipitate was isolated by filtration and dried to give Z. The product was used as such in the next step.

[0051] Z (175 mg, 0.67 mmol), isoxazol-3-ylmethylamine hydrochloride (136 mg, 1.0 mmol), and diisopropylethylamine (173 mg, 1.3 mmol) were dissolved in NMP (2.4 mL) in a 7 mL glass vial. The mixture was stirred at 100 ° C for 2 h, then cooled and concentrated in vacuo. It was purified by HPLC Prep (Stationary phase: RP Vydac Denali C18 - 10 μm, 200 g, 5 cm), Mobile phase: 0.25% NH4OAc solution in water, methanol), the desired fractions were collected and concentrated in vacuo . The product was triturated in acetonitrile, isolated by filtration and dried in vacuo to become 155 as a white solid. Table 1. Compounds of formula (I) and corresponding analytical data.
[0052] The compounds were prepared according to the methods described in the experimental section. * R indicates a pure enantiomer of unknown configuration, drawn in the R configuration. * S indicates a pure enantiomer of unknown configuration, drawn in the S configuration.

Analytical Methods.
[0053] All compounds were characterized by LC-MS according to the following LC-MS methods.
[0054] Method A. Using a Phenomenex Kinetex column (XB-C18, 50 x 4.6 mm ID 2.6 μm) maintained at 35 ° C. Detection of MS: API-ES positive ionization mode, mass range 100 - 1200. Detection of PDA (À = 190 - 400 nm). The following gradient was used with a 2 μL injection:

[0055] Method B. UPLC (Ultra Performance Liquid Chromatography) reverse phase was carried out on a C18 column of ethyl siloxane / bridged silica (BEH) (1.7 μm, 2.1 x 50 mm; Waters Acquity) with a flow rate of 0.8 ml / min. Two mobile phases (10 mM ammonium acetate in <20 / acetonitrile 95/5; mobile phase B: acetonitrile) were used to operate a gradient condition from A to 95% and B to 5% to A to 5% and B 95% in 1.3 minutes and maintenance for 0.7 minutes. An injection volume of 0.75 μL was used. The cone voltage was 30 V for the positive ionization mode and 30 V for the negative ionization mode.
[0056] Method C. The analyzes were carried out on a Waters XTerra C18 column (100 x 4.6 mm D.l. 3.5 μm of the particles) at 40 ° C, with a flow rate of 1.6 mL / min. Gradient elution was performed as follows: from 100% ammonium acetate solution (25 mM) in Water / Acetonitrile 90:10 to a 50:50 Acetonitrile / Methanol mixture in 7.5 min; from the resulting composition to 100% Acetonitrile in 1.0 min; 100% acetonitrile for 1.5 min; 100% Acetonitrile to a 100% solution of ammonium acetate (25 mM) in Water / Acetonitrile 90:10 (25 mM) in 3.0 minutes. The standard injection volume was 3 μL. The acquisition intervals were set at 200-400 nm for UV.
[0057] Method D. The LC measurement was performed using an Acquity UPLC system (Waters) comprising a binary pump, a sample organizer, a column heater (set at 55 ° C), a diode array detector (DAD ) and a column as specified in the respective methods below. The column flow was separated for an MS spectrometer. The MS detector was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 0.18 seconds using a dwell time of 0.02 seconds. The capillary needle voltage was 3.5 kV and the source temperature was maintained at 140 ° C. Nitrogen was used as the nebulizer gas. Reverse phase UPLC (Ultra Performance Liquid Chromatography) was carried out on a C18 column of ethyl siloxane / bridged silica (BEH) (1.7 μm, 2.1 x 50 mm; Waters Acquity) with a flow rate of 0.8 ml / min. Two mobile phases (10 mM ammonium acetate in <20 / acetonitrile 95/5; mobile phase B: acetonitrile) were used to operate a gradient condition from A to 95% and B to 5% to A to 5% and B 95% in 1.3 minutes and maintenance for 0.3 minutes. An injection volume of 0.5 μL was used. The cone voltage was 10 V for the positive ionization mode and 20 V for the negative ionization mode. Method E
Method F

Biological Activity of compounds of formula (I) Description of Biological Assays Evaluation of the activity of TLR7 and TLR8
[0058] The ability of compounds to activate human TLR7 and / or TLR8 was evaluated in a cell reporter assay using HEK293 cells transiently transfected with a TLR7 or TLR8 expression vector and NFKB-IUC reporter construct.
[0059] Soon, HEK293 cells were cultured in culture medium (DMEM supplemented with 10% FCS and 2 mM Glutamine), For transfection of cells in 10 cm plates, the cells were detached with Trypsin-EDTA, transfected with a mixture of plasmid CMV-TLR7 or TLR8 (750 ng), plasmid NFKB-IUC (375 ng) and a transfection reagent and incubated overnight at 37 ° C in a humidified 5% CO2 atmosphere. The transfected cells were then detached with Trypsin-EDTA, washed in PBS and resuspended in medium to a density of 1.67 x 105 cells / mL, Thirty microliters of cells were then dispensed in each well in 384-well plates, where 10 μL of compound in DMSO a 4% were already present. After 6 hours incubation at 37 ° C, 5% CO2, luciferase activity was determined by adding 15 μL of Steady Lite Plus substrate (Perkin Elmer) to each well and reading in a ViewLux ultraHTS microplate imager (Perkin Elmer), Response curves to dose were generated from quadruplicate measurements. The values of the minimum effective concentrations (LEC), defined as the concentration that induces an effect that is at least twice above the standard deviation of the assay, were determined for each compound.
[0060] The toxicity of the compounds was determined in parallel using a series of similar dilutions of compound with 30 μL per well of cells transfected with the CMV-TLR7 construct alone (1.67 x 105 cells / mL), in 384 plates wells. Cell viability was measured after incubation for 6 hours at 37 ° C, 5% CO2, by adding 15 μL of ATP lite (Perkin Elmer) per well and reading in a ViewLux ultraHTS microplate imager (Perkin Elmer). The data were reported as CC50.
[0061] In parallel, a series of similar dilutions of compound was used (10 μL of compound in 4% DMSO) with 30 μL per well of cells transfected with the NFKB-IUC reporter construct (1.67 x 105 cells / mL ). Six hours after incubation at 37 ° C, 5% CO2, luciferase activity was determined by adding 15 μL of Steady Lite Plus substrate (Perkin Elmer) to each well and reading on a ViewLux ultraHTS microplate imager (Perkin Elmer). Counter-tracking data is reported as LEC. Activation of ISRE promoting elements
[0062] The potential of compounds to induce IFN-I was also assessed by measuring the activation of responsive elements stimulated by interferon (ISRE) using conditioned PBMC. The ISRE element of the GAAACTGAAACT sequence is highly responsive to the transcription factor STAT1-STAT2-IRF9, activated after binding of UN-1 to its IFNAR receptor (Clontech, PT3372-5W). Clontech's pISRE-Luc plasmid (ref. 631913) contains 5 copies of this ISRE element, followed by the ORF of the firefly luciferase. A HEK293 cell line stably transfected with pISRE-Luc (HEK-ISREluc) was established to characterize the conditioned PBMC cell culture medium.
[0063] Briefly, PBMCs were prepared from buffy coat layers from at least two donors using a standard Ficoll centrifugation protocol. Isolated PBMCs were resuspended in RPMI medium supplemented with 10% human AB serum and 2 x 105 cells / well were dispensed in 384-well plates containing compounds (total volume 70 μL). After overnight incubation, 10 μL of supernatant was transferred to 384-well plates containing 5 x 103 HEK-ISREluc cells / well in 30 μL (plated the previous day). After 24 hours of incubation, the activation of the ISRE elements was measured by assessing luciferase activity using 40 cL / well of Steady Lite Plus substrate (Perkin Elmer) and measured with ViewLux ultraHTS microplate imager (Perkin Elmer). The stimulatory activity of each compound in HEK-ISREluc cells was reported as an LEC value, defined as the concentration of compound applied to PBMCs resulting in a luciferase activity at least twice above the standard deviation of the assay. The LEC in turn indicates the degree of activation of ISRE after transferring a defined amount of culture medium from PBMCs. Recombinant α-2a interferon (Roferon-A) was used as a standard control compound.
[0064] Table 2. Activity of compounds of formula (I). All compounds showed no activity (LEC> 25 μM) in the HEK 293 NF-kB counter-screening assay described above.

权利要求:
Claims (8)
[0001]
1. Compound, characterized by the fact that it presents the formula (I)
[0002]
A compound of formula (I) according to claim 1, characterized by the fact that R3 is a methyl group substituted by an aryl (substituted or unsubstituted), and R1, R2, and R4 are as defined in claim 1.
[0003]
A compound of the formula (I) according to claim 1, characterized in that R3 and R4 are C1-3 alkyl substituted by an aryl, optionally additionally substituted as defined in claim 1.
[0004]
A compound of formula (I) according to claim 1, characterized by the fact that R1 is fluorine, R2 is hydrogen, and R3 and R4 are as defined in claim 1.
[0005]
5. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1, together with one or more pharmaceutically acceptable excipients, diluents or vehicles.
[0006]
6. Compound of formula (I) according to claim 1, characterized by the fact that it is selected from the group consisting of:
[0007]
7. Compound of formula (I) according to claim 1, characterized by the fact that it is selected from the group consisting of:
[0008]
Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1, or of a pharmaceutical composition comprising said compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 5 , characterized by the fact that it is in the preparation of a drug for the treatment of any disorder in which the modulation of TLR7 and / or TLR8 is involved.

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KR102217111B1|2021-02-18|

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PL2906563T3|2018-10-31|

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US11220504B2|2022-01-11|

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HK1209412A1|2016-04-01|

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KR20210019593A|2021-02-22|

AU2013328732B2|2017-08-31|

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法律状态:
2018-03-06| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

2019-12-17| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

2019-12-31| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

2020-05-19| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

2020-11-24| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

2021-02-09| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 09/10/2013, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

申请号 | 申请日 | 专利标题

EP12187994.4|2012-10-10|

EP12187994|2012-10-10|

PCT/EP2013/070990|WO2014056953A1|2012-10-10|2013-10-09|Pyrrolo[3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases|

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