CN108299465B - medicine for treating pancreatitis and its preparing process - Google Patents
medicine for treating pancreatitis and its preparing process Download PDFInfo
- Publication number
- CN108299465B CN108299465B CN201810180428.7A CN201810180428A CN108299465B CN 108299465 B CN108299465 B CN 108299465B CN 201810180428 A CN201810180428 A CN 201810180428A CN 108299465 B CN108299465 B CN 108299465B
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- base
- alkyl
- pharmaceutically acceptable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to novel pyrimidinones
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to medicaments for treating pancreatitis and a preparation method thereof, and also relates to application of the medicaments.
Background
Pancreatitis is an inflammation of the pancreas and is classified into acute pancreatitis and chronic pancreatitis. Pancreatic juice contains digestive enzymes such as amylase (for decomposing carbohydrates), trypsin (for decomposing proteins), and lipase (for decomposing fats). Pancreatitis refers to a state in which pancreatic juice cannot flow smoothly due to excessive intake of alcohol, gallstones, or the like, and the pancreas is self-digested by the above-mentioned enzymes. The present invention is roughly classified into a mild type in which interstitial edema and peripancreatic fat necrosis are observed, and a severe type in which peripancreatic and intrapancreatic fat extensive necrosis, pancreatic parenchymal necrosis, or hemorrhage is observed.
In the clinical treatment of japan, since it is thought that causes complications such as poor respiration or renal insufficiency after flowing into the blood, pancreatic enzyme inhibitors such as aprotinin, gabexate mesylate (FOY), camostat mesylate, etc. are used, light and moderate symptoms are relieved by the treatment for about 1 week, and in the case of severe cases, various organs are damaged, and therefore, when the patients are in a state of falling into shock, a large amount of an anti-inflammatory agent, such as aprotinin , is required.
However, the current products on the market do not meet the actual demand, and therefore it is very necessary to develop new drug products that can be used for treating pancreatitis.
Disclosure of Invention
Summary of The Invention
The present invention provides a compound of formula I, or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof, capable of treating pancreatitis:
wherein:
m represents S or O;
R1、R2、R3independently represent hydrogen, cyano, C1-6 alkyl, haloC 1-6 alkyl, C1-6 alkoxy, di (C1-6 alkyl) amino or C6-10 aryl;
R4represents hydrogen or C1-6 alkyl;
l represents- (CHR)10)n-；
R5、R6Independently represent hydrogen, C1-6 alkyl, or R5And R6 form oxo;
R7、R8independently represent hydrogen, C1-6 alkyl, C3-6 cycloalkyl, haloC 1-6 alkyl or cyano C1-6 alkyl;
R9independently for each occurrence, hydrogen, halogen, cyano, carboxy, C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 cycloalkyl or 5-10 membered heterocyclyl;
R10represents hydrogen or C1-6 alkyl;
k is selected from 0, 1,2 or 3.
In aspects of the invention, the invention relates to pharmaceutical compositions containing the compound of formula I or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof and processes for preparing the same.
In another aspects of the invention, there is provided the use of the compound of formula I, or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof, for the prevention and treatment of diseases, including pancreatitis, particularly acute pancreatitis.
In another aspects of the invention, there is provided the use of a compound of formula I, or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof, for the manufacture of a medicament for the prevention and treatment of diseases, including pancreatitis, particularly acute pancreatitis.
In another aspects of the invention, there are provided processes for the preparation of the compounds of formula I.
Detailed Description
embodiments of the present invention relate to compounds of formula I or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof:
wherein:
m represents S or O;
R1、R2、R3independently represent hydrogen, cyano, C1-6 alkyl, haloC 1-6 alkyl, C1-6 alkoxy, di (C1-6 alkyl) amino or C6-10 aryl;
R4represents hydrogen or C1-6 alkyl;
l represents- (CHR)10)n-；
R5、R6Independently represent hydrogen, C1-6 alkyl, or R5And R6 form oxo;
R7、R8independently represent hydrogen, C1-6 alkyl, C3-6 cycloalkyl, haloC 1-6 alkyl or cyano C1-6 alkyl;
R9independently for each occurrence, hydrogen, halogen, cyano, carboxy, C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 cycloalkyl or 5-10 membered heterocyclyl;
R10represents hydrogen or C1-6 alkyl;
k is selected from 0, 1,2 or 3.
According to embodiments, the R1、R2、R3Independently represent hydrogen, C1-6 alkyl or C6-10 aryl, preferably hydrogen, ethyl or phenyl.
According to embodiments, the R4Represents hydrogen or methyl.
According to embodiments, the R5、R6Represents hydrogen, or said R5、R6Indicating as forming an oxo group.
According to embodiments, the R7、R8Represents hydrogen.
According to embodiments, L represents-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-、-CH2CH(CH3)CH2-or-CH2C(CH3)2CH2-, preferably represents-CH2-、-CH2CH2-or-CH2CH2CH2-。
According to embodiments, the R9Represents hydrogen, cyano, carboxyl, C1-6 alkoxy or 5-10 membered heterocyclyl, preferably hydrogen, cyano, carboxyl, methoxy or pyrrolidinyl.
According to embodiments, the compound of formula I is selected from:
compound I-1: 5- ((2-methoxypyridin-4-yl) methyl) -2- (thiophen-3-yl) -6, 7-dihydro-5H-pyrimidine [4, 5-b)][1,4]
An oxazine;
compound I-2: 4- (3- (4-methyl-2- (thiophen-3-yl) -6, 7-dihydro-5H-pyrimidine [4, 5-b)][1,4]
Oxazin-5-yl) propyl) -2-cyanopyridine;
compound I-3: 2- (5-Phenylfuranyl-3-Yl) -5- (3- (pyridin-4-Yl) propyl) -6, 7-dihydro-5H-Pyrimidin [4,5-b][1,4]
An oxazine;
compound I-4: 5- (2- (2- (pyrrolidin-1-yl) pyridin-4-yl) ethyl) -2- (5- (trifluoromethyl) thiophen-3-yl) -6, 7-dihydro-5H-pyrimidine [4, 5-b)][1,4]
An oxazine;
compound I-5: 4- ((2- (5-ethylthiophen-3-yl) -6-oxo-6, 7-dihydro-5H-pyrimidine [4, 5-b)][1,4]
Oxazin-5-yl) methyl) pyridine-2-carboxylic acid.
It is to be understood that the compounds of formula I structurally include all stereoisomers, enantiomers and diastereomers, as well as pharmaceutically acceptable salts that may be considered from the chemical structures of general formula I described herein.
The absolute configuration at an asymmetric atom is represented by R or S. Analytical compounds whose absolute configuration is unknown can be represented by (+) or (-) depending on the direction in which they rotate along the plane of polarized light. When a particular stereoisomer is identified, this means that the stereoisomer is substantially free of other isomers, i.e. less than 50%, preferably less than 20%, more preferably less than 5%, in particular less than 2% or 1% of the other isomers. Thus, when a compound of formula (1) is defined, for example, as (R), this means that the compound is substantially free of the (S) isomer; when a compound of formula (1) is defined as E, for example, this means that the compound is substantially free of the Z isomer; when the compound of formula (1) is defined, for example, as a cis isomer, this means that the compound does not contain a trans isomer.
In another embodiments of the invention, pharmaceutical compositions are provided that contain a compound of the invention and at least pharmaceutically acceptable excipients preferably, the pharmaceutical compositions contain a therapeutically effective amount of at least compounds of the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this subject belongs .
The term "alkyl" denotes a saturated hydrocarbon chain which may be straight or branched and contain the indicated number of carbon atoms, e.g., C1-6 alkyl may have 1-6 (inclusive) carbon atoms. Examples of C1-6 alkyl include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.
The term "aryl" denotes an optionally substituted monocyclic, bicyclic or polycyclic aromatic hydrocarbon ring system having about 6 to 14, preferably 6 to 10 carbon atoms. Examples of C6-10 aryl include, but are not limited to, phenyl and naphthyl.
The term "cycloalkyl" denotes a non-aromatic, saturated, monocyclic, bicyclic or polycyclic C3-10 hydrocarbon ring system. Representative examples of C3-10 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like.
The term "halo" or "halogen" denotes-F, -Cl, -Br and-I.
The term "heterocyclyl" includes the definitions of "heterocycloalkyl" and "heteroaryl".
The term "heterocycloalkyl" denotes a non-aromatic 5-10 membered saturated monocyclic ring system, whichHas at least selected from O, N, S, S (O), S (O)2NH and C (O). Examples of heterocycloalkyl include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, 1, 3-dioxolanyl, tetrahydro-2H-pyran, and the like.
The term "heteroaryl" denotes a 5-10 membered unsaturated monocyclic, bicyclic or polycyclic aromatic ring system containing at least heteroatoms selected from O, N, S examples of heteroaryl include, but are not limited to, furyl, thienyl, indolyl,
azolyl, thiazolyl, thiadiazolyl, isoxazolyl
Oxazolyl, isothiazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl,
diazole, triazolyl, tetrazolyl, benzophenones
Azolyl, benzothiazolyl, benzofuranyl, benzisoxazoyl
Oxazolyl, benzimidazolyl, indazolyl, quinazolinyl, quinolyl, isoquinolyl and the like.
The term "comprising" or "comprises" is used in its ordinary sense to mean inclusion, that is, to allow or more features or components to be present.
The use of the term "including" as well as other forms, such as "includes" and "included," is not limiting.
The terms "for treating," "treating," and "treatment" include both responding to and preventing measures , such as measures for inhibiting or delaying the onset of a disease or condition, effecting a reduction in symptoms or disease state, in whole or in part, and/or alleviating, reducing, or curing the disease or condition and/or symptoms thereof.
The term "therapeutically effective amount" means a sufficient amount of a compound or composition administered that will provide a degree of relief from or more symptoms of the disease or disorder being treated.
The term "pharmaceutically acceptable" means that which can be used to prepare pharmaceutical compositions that are generally safe, non-toxic, and neither biologically toxic nor otherwise undesirable, and includes those acceptable for veterinary as well as human pharmaceutical use.
The term "pharmaceutically acceptable salt" refers to salts of a compound that are pharmaceutically acceptable and possess the desired pharmaceutical activity of the parent compound. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. These salts include: acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and the like.
In another embodiments of the invention, pharmaceutical compositions are provided that contain a compound of the invention and at least pharmaceutically acceptable excipients preferably, the pharmaceutical compositions contain a therapeutically effective amount of at least compounds of the invention.
The pharmaceutical compositions of the present invention may be formulated as compatible with their intended route of administration and may preferably be administered orally. For example, the pharmaceutical compositions of the present invention may be formulated for administration by inhalation, such as an aerosol or dry powder; for oral administration, e.g., in the form of tablets, capsules, gels, syrups, suspensions, emulsions, medicaments, solutions, powders or granules; for rectal or vaginal administration, e.g. suppositories; or for intravenous injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) such as sterile solutions, suspensions or emulsions.
The compounds of the invention can also be prepared by entrapment in microcapsules, for example by coacervation techniques or by interfacial polymerization, for example hydroxymethylcellulose or gelatin-microcapsules and polymethylmethacrylate microcapsules, in colloidal drug delivery systems (for example liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions, respectively.
-like synthesis method of compound of the invention
The compounds of formula I of the present invention can be prepared from available starting materials using the following general methods and procedures. It should be understood that while typical or preferred experimental conditions (i.e., reaction temperatures, times, molar amounts of reagents, solvents, etc.) are described, other conditions may also be used unless otherwise specified. The optimal reaction conditions may vary depending on the particular reactants or solvents used, but these conditions may be determined by one skilled in the art using routine optimization procedures.
Disclosed herein is a general method for preparing a compound of formula I, comprising the steps of:
step , Synthesis of intermediate 1A Compound of formula IV:
reacting a 2-halo-5-amino-6-hydroxypyrimidine of formula II with a dihalogen compound of formula III in the presence of a base, a phase transfer catalyst to produce intermediate 1: a compound of formula IV;
wherein the base is selected from inorganic bases including hydroxide, carbonate, bicarbonate or acetate, preferably sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate or potassium acetate, more preferably potassium carbonate or potassium acetate;
the phase transfer catalyst is selected from quaternary ammonium salts, preferably: benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium fluoride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride or tetradecyltrimethylammonium chloride;
step two, synthesizing an intermediate 2: a compound of formula VI:
reacting a compound of formula IV with a compound of formula V in the presence of a palladium catalyst to form intermediate 2: a compound of formula VI;
wherein the palladium catalyst is selected from tetrakis (triphenylphosphine) palladium or palladium acetate, preferably tetrakis (triphenylphosphine) palladium;
step three, synthesizing a compound of formula I:
reacting a compound of formula VI and a compound of formula VII in the presence of a base to produce a compound of formula I;
wherein the base represents an inorganic base including a hydroxide or a carbonate, preferably sodium hydroxide, potassium carbonate or cesium carbonate;
M、R1-R9l, k are as defined herein; x1-X4Represents halogen, preferably chlorine or bromine.
Advantageous effects
The compound can obviously inhibit the increase of the amylase and lipase activities of the acute pancreatitis rat serum, and can obviously reduce the water content of acute pancreatitis rat pancreatic tissue, so the compound has good treatment effect on acute pancreatitis. Compared with the existing medicine gabexate, the treatment effect is more remarkable.
Detailed Description
While the invention has been described by through the above examples, it is not intended to be limiting of the invention, and in fact, the invention encompasses the general scope as set forth above.
Example 1: synthesis of Compound I-1
5- ((2-methoxypyridin-4-yl) methyl) -2- (thiophen-3-yl) -6, 7-dihydro-5H-pyrimidine [4, 5-b)][1,4]
Oxazines
Step Synthesis of 2-chloro-6, 7-dihydro-5H-pyrimidine [4,5-b ]][1,4]
Oxazines
To a solution of 15.0mmol of 5-amino-2-chloropyrimidin-4-ol in 200mL of dichloromethane were added 60.0mmol of 1, 2-dibromoethane, 60.0mmol of sodium hydroxide, and 0.75g of benzyltriethylammonium chloride, and the mixture was stirred at room temperature for 20 hours. After completion of the reaction, the reaction mixture was poured into 300mL of water, followed by extraction with ethyl acetate, and the organic layer was washed with brine, water and dried over anhydrous sodium sulfate to give 2-chloro-6, 7-dihydro-5H-pyrimidine [4,5-b ]][1,4]
2.0g of oxazine and 78.2% yield. LC-MS: m/z172.0(M +1)+。
Step two, synthesizing 2- (thiophene-3-yl) -6, 7-dihydro-5H-pyrimidine [4,5-b][1,4]Oxazines
Under the protection of nitrogen, 2-chloro-6, 7-dihydro-5H-pyrimidine [4,5-b ] is reacted][1,4]
Oxazine 10.0mmolTo a solution of 50mL of toluene and 10mL of water were added 20.0mmol of thiophene-3-boronic acid, 15.0mmol of sodium carbonate, and then 0.5mmol of palladium tetrakis (triphenyl) phosphine, and reacted at 110 ℃ for 10 hours. After completion of the reaction, the reaction mixture was diluted with 100mL of ethyl acetate, washed with brine, water, and the organic layer was dried over anhydrous sodium sulfate and concentrated to give a residue, which was separated by column chromatography (ethyl acetate/petroleum ether ═ 1:4) to give 2- (thiophen-3-yl) -6, 7-dihydro-5H-pyrimidine [4, 5-b)][1,4]
Oxazine 1.8g, yield 81.4%. LC-MS: m/z 220.0(M +1)+。
Step three, synthesizing 5- ((2-methoxypyridin-4-yl) methyl) -2- (thiophene-3-yl) -6, 7-dihydro-5H-pyrimidine [4,5-b][1,4]
Oxazines
To 2- (thien-3-yl) -6, 7-dihydro-5H-pyrimidine [4,5-b][1,4]
Oxazine 5.0mmol in 100mL acetonitrile was added cesium carbonate 15.0mmol followed by 4- (bromomethyl) -2-methoxypyridine and the reaction stirred at 60 ℃ for 4 hours. After completion of the reaction, concentrated under reduced pressure, diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue which was separated by column chromatography (methanol/cyclohexane ═ 1:5) to give 5- ((2-methoxypyridin-4-yl) methyl) -2- (thiophen-3-yl) -6, 7-dihydro-5H-pyrimidine [4, 5-b)][1,4]
Oxazine 1.5g, yield 89.3%.
LC-MS：m/z 341.1(M+1)+。
Hydrogen spectra (400MHz, DMSO) δ 8.21(s,1H),7.90(s,1H),7.78(d,1H),7.64(d,1H),7.04(d,1H),6.67(d,1H),6.02(d,1H),4.58(s,2H),4.23(t,2H),3.91(s,3H),3.57(t, 2H).
Example 2: synthesis of Compound I-2
4- (3- (4-methyl-2- (thiophen-3-yl) -6, 7-dihydro-5H-pyrimidine [4, 5-b)][1,4]
Oxazin-5-yl) propyl) -2-cyanopyridine
The procedure was followed as in example 1, except for using 4-methyl-5-amino-2-chloropyrimidin-4-ol in place of 5-amino-2-chloropyrimidin-4-ol and 4- (3-bromopropyl) -2-cyanopyridine in place of 4- (bromomethyl) -2-methoxypyridine to give 4- (3- (4-methyl-2- (thien-3-yl) -6, 7-dihydro-5H-pyrimidine [4, 5-b)][1,4]
Oxazin-5-yl) propyl) -2-cyanopyridine with a total yield of 51.3% in three steps.
LC-MS：m/z 378.1(M+1)+。
Hydrogen spectra (400MHz, DMSO) δ 8.84(d,1H),8.24(s,1H),8.01(d,1H),7.92(s,1H),7.78(d,1H),7.04(d,1H),4.25(t,2H),3.55(t,2H),3.47(t,2H),2.65(t,2H),2.31(s,3H),2.02(m, 2H).
Example 3: synthesis of Compound I-3
2- (5-Phenylfuranyl-3-Yl) -5- (3- (pyridin-4-Yl) propyl) -6, 7-dihydro-5H-Pyrimidin [4,5-b][1,4]
Oxazines
By following the procedure of example 1, except for using 5-phenylfuran-3-boronic acid instead of thiophene-3-boronic acid and 4- (3-bromopropyl) -pyridine instead of 4- (bromomethyl) -2-methoxypyridine, 2- (5-phenylfuranyl-3-yl) -5- (3- (pyridin-4-yl) propyl) -6, 7-dihydro-5H-pyrimidine [4,5-b ] is obtained][1,4]
And (5) oxazine, wherein the total yield of the three steps is 49.1%.
LC-MS：m/z 399.1(M+1)+。
Hydrogen spectra (400MHz, DMSO) δ 8.65(d,2H),8.24(s,1H),8.14(d,2H),7.61(t,2H),7.51(s,1H),7.40(t,1H),7.24(d,2H),6.31(s,1H),4.26(t,2H),3.54(t,2H),3.48(t,2H),2.65(t,2H),2.02(m, 2H).
Example 4: synthesis of Compound I-4
5- (2- (2- (pyrrolidin-1-yl) pyridin-4-yl) ethyl) -2- (5- (trifluoromethyl) thiophen-3-yl) -6, 7-dihydro-5H-pyrimidine [4, 5-b)][1,4]Oxazines
By following the procedure of example 1, with the difference that 5- (trifluoromethyl) thiophene-3-boronic acid is used instead of thiophene-3-boronic acid and 4- (2-bromoethyl) -2- (pyrrolidin-1-yl) -pyridine is used instead of 4- (bromomethyl) -2-methoxypyridine, 5- (2- (2- (pyrrolidin-1-yl) pyridin-4-yl) ethyl) -2- (5- (trifluoromethyl) thiophen-3-yl) -6, 7-dihydro-5H-pyrimidine [4,5-b][1,4]
And (3) oxazine, wherein the total yield of the three steps is 43.8%.
LC-MS：m/z 462.1(M+1)+。
Hydrogen spectra (400MHz, DMSO) δ 8.28(s,1H),7.98(d,1H),7.39(s,1H),6.71(d,1H),6.50(s,1H),6.41(s,1H),4.26(t,2H),3.54(t,2H),3.41(t,4H),3.31(t,2H),2.85(t,2H),1.93(t, 4H).
Example 5: synthesis of Compound I-5
4- ((2- (5-ethylthiophen-3-yl) -6-oxo-6, 7-dihydro-5H-pyrimidine [4, 5-b)][1,4]Oxazin-5-yl) methyl) pyridine-2-carboxylic acid
By following the procedure of example 1, with the difference that 2-bromoacetyl bromide was used instead of 1, 2-dibromoethane, 5-ethyl-thiophene-3-boronic acid was used instead of thiophene-3-boronic acid, and 4- (bromomethyl) pyridine-2-carboxylic acid was used instead of 4- (bromomethyl) -2-methoxypyridine, 4- ((2- (5-ethylthiophen-3-yl) -6-oxo-6, 7-dihydro-5H-pyrimidine [4, 5-b)][1,4]
Oxazin-5-yl) methyl) pyridine-2-carboxylic acid, with a total yield of 45.3% in the three steps.
LC-MS：m/z 397.1(M+1)+。
Hydrogen spectra (400MHz, DMSO) δ 12.28(s,1H),9.24(s,1H),8.91(d,1H),8.31(s,1H),8.10(d,1H),7.37(s,1H),6.41(s,1H),5.27(s,2H),4.76(s,2H),2.91(t,2H),1.22(s, 3H).
Example 6: pharmacological Activity of the Compounds of the invention
1. Determination of amylase and lipase activities in acute pancreatitis rat serum
80 SD rats weighing 190-220 g are divided into 8 groups by female and male halves at random, wherein the groups are respectively a negative control group, a model group, a positive control bexate group and compound I-1 to I-5 group, each group comprises 10 rats, the other groups except the negative control group are subjected to reverse injection of sodium taurocholate (30 microgram/Kg) in a pancreatic bile duct to cause acute pancreatitis of the rats, the negative control group only opens the abdomen to pull pancreatic tissues and does not give the sodium taurocholate, the rats of each administration group are subjected to gastric lavage for times respectively in 1h before the operation and 3h after the operation, the dose is 20mg/Kg, the rats of the negative control group and the rats of the model group are subjected to pure water with the same volume, at the time points of 6h, 12h and 24h after the model building, all the rats are anesthetized by 25% of urethane, blood is taken from the abdominal aorta, the rats are placed at room temperature for 1h, the medium temperature is placed for 4000r/min, supernatant is taken, and the lipase, the lipase activity in 24h after the model building is measured, and the results of the serum are as shown in the following table 1h and 2:
table 1: amylase Activity in acute pancreatitis rat serum
Note: compared with the negative control group, the test results show that,#P<0.01; compared with model group<0.01; compared with the positive control group, the test results show that,&P<0.05
table 2: lipase activity in acute pancreatitis rat serum
Note: compared with the negative control group, the test results show that,#P<0.01; compared with model group<0.01; compared with the positive control group, the test results show that,&P<0.05
the experimental results in tables 1 and 2 show that the serum amylase and lipase activities of the model group rats at each test time point after modeling are significantly enhanced compared with the negative control group, indicating that the modeling of acute pancreatitis is successful (P < 0.01). Compared with the model group, the activity of the amylase and the lipase in the serum of rats in each group of the compound I-1 to the compound I-5 is obviously weakened (P <0.01) at each time point, which shows that the compound of the formula I has an inhibiting effect on the increase of the activity of the amylase and the lipase in the serum caused by acute pancreatitis, namely has a therapeutic effect on the acute pancreatitis. Compared with the existing medicine gabexate, the activity of amylase and lipase in serum of rats in each group from compound I-1 to compound I-5 is obviously weaker (P is less than 0.05) at each time point, which shows that the compound of the formula I has more obvious treatment effect on acute pancreatitis.
2. Determination of water content of pancreatic tissue of rat with acute pancreatitis
160 SD rats weighing 190-220 g are divided into 8 groups randomly, namely a negative control group, a model group, a positive control bexate group and compounds I-1 to I-5 groups, wherein each group comprises 20 rats, the rats in the other groups except the negative control group are subjected to retrograde injection of sodium taurocholate (30 microgrammer/Kg) in the pancreatic bile duct to cause acute pancreatitis, the negative control group only opens the abdomen to pull pancreatic tissues and does not give the sodium taurocholate, the rats in the administration group are subjected to gastric lavage for times respectively in 1h before the operation and 3h after the operation, the dosage is 20mg/Kg, the rats in the negative control group and the rats in the model group are subjected to pure water with the same volume, 10 rats are respectively taken at the time points of 6h and 12h after the model is manufactured, pancreatic tissues are cut into proper amount, the rats are weighed and then placed in an oven for drying at the temperature of 80 ℃ for 12 hours, the water content after the weighing is times, the water content after the operation is calculated, and the pancreatic tissues are equal to the weight of (wet weight of the pancreas-dry weight)/the weight of the pancreas multiplied by 100, the:
table 3: water content of pancreatic tissue of rat with acute pancreatitis
Note: compared with the negative control group, the test results show that,#P<0.01; compared with model group<0.01; compared with the positive control group, the test results show that,&P<0.05
the experimental results in table 3 show that compared with the negative control group, the pancreatic tissue water content of the model group rats at each test time point after modeling is significantly increased, which indicates that the modeling of the acute pancreatitis is successful (P < 0.01). Compared with the model group, the rats of each group of the compound I-1 to the compound I-5 have obviously reduced water content of pancreatic tissues at each time point (P <0.01), which shows that the compound of the formula I has an inhibiting effect on the increase of the water content of the pancreatic tissues caused by acute pancreatitis, namely has a therapeutic effect on the acute pancreatitis. Compared with the existing medicine gabexate, the pancreatic tissue water content of rats in each group of the compound I-1 to the compound I-5 is obviously lower (P <0.05) at each time point after the administration, which shows that the compound of the formula I has more remarkable treatment effect on acute pancreatitis.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (19)
1, A compound of formula I or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof:
wherein:
m represents S or O;
R1、R2、R3independently represent hydrogen, C1-6 alkyl or haloC 1-6 alkyl;
R4represents hydrogen or C1-6 alkyl;
l represents-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-、-CH2CH(CH3)CH2-or-CH2C(CH3)2CH2-；
R5、R6Independently represent hydrogen;
R7、R8independently represent hydrogen;
R9independently at each occurrence, represents hydrogen, halogen, C1-6 alkyl, haloC 1-6 alkyl or C1-6 alkoxy;
k is selected from 0, 1,2 or 3.
2. The compound of claim 1, wherein R is1、R2、R3Independently represents hydrogen or C1-6 alkyl.
3. The compound of claim 1, wherein R is1、R2、R3Independently represents hydrogen or ethyl.
4. The compound of claim 1 or 2, wherein R is4Represents hydrogen or methyl.
5. The compound of claim 1, wherein L represents-CH2-、-CH2CH2-or-CH2CH2CH2-。
6. The compound of claim 1, wherein R is9Represents hydrogen or C1-6 alkoxy.
7. The compound of claim 1, wherein R is9Represents hydrogen or methoxy.
8. The compound of claim 1, wherein the compound is selected from:
compound I-1: 5- ((2-methoxypyridin-4-yl) methyl) -2- (thiophen-3-yl) -6, 7-dihydro-5H-pyrimidine [4, 5-b)][1,4]
And (3) an oxazine.
A process for the preparation of compounds of formula I according to claim 1, which comprises the steps of:
step , Synthesis of intermediate 1A Compound of formula IV:
reacting a 2-halo-5-amino-6-hydroxypyrimidine of formula II with a dihalogen compound of formula III in the presence of a base, a phase transfer catalyst to produce intermediate 1: a compound of formula IV;
wherein the base is selected from inorganic bases;
the phase transfer catalyst is selected from quaternary ammonium salts;
step two, synthesizing an intermediate 2: a compound of formula VI:
reacting a compound of formula IV with a compound of formula V in the presence of a palladium catalyst to form intermediate 2: a compound of formula VI;
wherein the palladium catalyst is selected from tetrakis (triphenylphosphine) palladium or palladium acetate;
step three, synthesizing a compound of formula I:
reacting a compound of formula VI and a compound of formula VII in the presence of a base to produce a compound of formula I;
wherein the base represents an inorganic base;
M、R1-R9l, k is as defined in claim 1; x1-X4Represents halogen.
10. The method of claim 9, wherein the base of step is selected from hydroxide, carbonate, bicarbonate, or acetate, and the phase transfer catalyst of step is selected from benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium fluoride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, or tetradecyltrimethylammonium chloride.
11. The method of claim 9, wherein the base of step is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate, or potassium acetate.
12. The method of claim 9, wherein the base of step is selected from potassium carbonate or potassium acetate.
13. The method according to claim 9, wherein the palladium catalyst of the second step is selected from tetrakis (triphenylphosphine) palladium.
14. The method according to claim 9, wherein the base of the third step is selected from hydroxide or carbonate.
15. The method of claim 9, wherein the base of step three is selected from sodium hydroxide, potassium carbonate or cesium carbonate.
16. The method according to claim 9, wherein X1-X4Represents chlorine or bromine.
Pharmaceutical compositions of comprising a therapeutically effective amount of at least compounds of formula I according to claim 1 or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof and at least pharmaceutically acceptable excipients.
18. The use of a compound of formula I according to claim 1 or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof for the preparation of a medicament for the prevention and treatment of pancreatitis.
19. The use according to claim 18, wherein the medicament is for the prevention and treatment of acute pancreatitis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810180428.7A CN108299465B (en) | 2018-03-05 | 2018-03-05 | medicine for treating pancreatitis and its preparing process |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810180428.7A CN108299465B (en) | 2018-03-05 | 2018-03-05 | medicine for treating pancreatitis and its preparing process |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108299465A CN108299465A (en) | 2018-07-20 |
| CN108299465B true CN108299465B (en) | 2020-01-31 |
Family
ID=62849243
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810180428.7A Expired - Fee Related CN108299465B (en) | 2018-03-05 | 2018-03-05 | medicine for treating pancreatitis and its preparing process |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108299465B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4052759A4 (en) | 2019-11-01 | 2023-12-20 | Unimatec Co., Ltd. | Fluorine-containing pyrimidine compound and manufacturing method for same |
-
2018
- 2018-03-05 CN CN201810180428.7A patent/CN108299465B/en not_active Expired - Fee Related
Non-Patent Citations (1)
| Title |
|---|
| REGISTRY[Online];Columbus，Ohio，US;《REGISTRY》;20180906;2242644-64-8,2242644-65-9,2242644-66-0,2242644-67-1,2242644-68-2 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108299465A (en) | 2018-07-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TW201738213A (en) | Method of treating cancer | |
| JP2016525075A (en) | Heteroaryl substituted pyrazoles | |
| CN111315747A (en) | Dihydropyrazolone pyrimidine compound and preparation method and application thereof | |
| JP2002513025A (en) | Imidazopyridine derivatives that inhibit gastric acid secretion | |
| JP7025555B2 (en) | Inhibition of transient receptor potential A1 ion channels | |
| JP2021501184A (en) | P2X3 and / or P2X2 / 3 receptor antagonists, pharmaceutical compositions containing them and their use | |
| CA2991572A1 (en) | 6-amino-quinoline-3-carbonitrils as cot modulators | |
| JP2023550444A (en) | Triazinedione derivatives, their preparation methods and their pharmaceutical applications | |
| WO2016145622A1 (en) | Benzimidazole derivatives, preparation method therefor and medicinal use thereof | |
| CN108299465B (en) | medicine for treating pancreatitis and its preparing process | |
| WO2011095057A1 (en) | Benzimidazole derivatives and pharmaceutical compositions and uses thereof | |
| WO2018133875A1 (en) | Jak kinase inhibitor and preparation method and use thereof | |
| JP2013525267A (en) | Selenazole derivative of peroxisome proliferator activated receptor ligand, method for producing the same and use of the compound | |
| JP6199406B2 (en) | Novel compounds as diacylglycerol acyltransferase inhibitors | |
| JP2023511222A (en) | Substituted pyridazinone compounds and uses thereof | |
| US9725436B2 (en) | Cytochrome P450 inhibitors and their method of use | |
| JP7266676B2 (en) | Potassium salt monohydrate of thienopyridone derivative and its preparation | |
| KR102640385B1 (en) | Composition for treating hypertension and/or pulmonary fibrosis | |
| KR880000132B1 (en) | Processing method for substituted quinoline | |
| JPS61158980A (en) | 8 alpha-acylaminoergolines, manufacture and medicinal composition | |
| JP2016536273A (en) | Novel functionalized 5- (phenoxymethyl) -1,3-dioxane analogs exhibiting cytochrome P450 inhibition | |
| CN111057120B (en) | Etogestrene derivative A and preparation method and application thereof | |
| KR101141556B1 (en) | Selenazole derivatives as ppar ligands, their manufacturing process and their use | |
| JPH01104053A (en) | Substituted pyridines as dopamine-beta- hydroxylase inhibitor | |
| WO2015112369A1 (en) | Novel cytochrome p450 inhibitors and their method of use |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20200131 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |