CN106916104A - medicine for treating colitis - Google Patents
medicine for treating colitis Download PDFInfo
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- CN106916104A CN106916104A CN201710116082.XA CN201710116082A CN106916104A CN 106916104 A CN106916104 A CN 106916104A CN 201710116082 A CN201710116082 A CN 201710116082A CN 106916104 A CN106916104 A CN 106916104A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Abstract
The invention discloses a kind of medicine for treating colitis, it is the qualone derivative that formula (1) is represented.The qualone derivative that formula (1) of the present invention represents can reduce the situation that the weight loss and colon lengths of the animal with colitis shorten, its disease activity value can be reduced, show that the compounds of this invention has preventive and therapeutic action for colitis, therefore can be used in the treatment of inflammatory bowel disease particularly colitis.
Description
Technical field
The present invention relates to pharmaceutical technology field, the invention discloses for treating colitis and other inflammatory bowel diseases especially
Clone disease, intestinal tuberculosis, ischemic colitis, the enterelcosis that produces with behcet's disease.
Background technology
Colitis is the term for describing colitis, and it refers to that the colitis venereal disease that a variety of causes causes becomes.It is main
Want clinical manifestation to suffer from diarrhoea, stomachache, abdominal distension and pus and blood stool, it is tenesmus, very then constipation, stool can not be led in a few days；Often
It is weak etc. with becoming thin, many recurrent exerbations.Most of patients with abdominal distension, become thin, weak, borborygmus, insomnia, dreaminess, the disease such as cold.
There is the inducement of various colitis, including infect, blood supply is weak and autoimmune response.Colon wall has many layers.Have
It is wrapped in outside and is responsible for that smooth muscle layer of the food along the longitudinal direction extruding of colon will not be digested.Internal layer or mucous membrane are contacted simultaneously with fluid
Make water and electrolyte absorption to help solidify excrement.Mucous layer is that colitis occur position, and bears colitis symptoms.
Nowadays inflammatory bowel disease such as colitis be controlled by the drug regimen used with stepped approach.Initially use anti-inflammatory agent
Thing, can add the medicine for suppressing immune system if its is unsuccessful.In most of several cases, it may be necessary to perform the operation to remove
Remove all or part of colon and small intestine.Treatment to ischemic colitis is initially supportive, is come using intravenous fluid
Stablize intestines and prevent dehydration.If not recovering the blood supply enough to intestines, may need operation that the portion of blood supply is lost to remove
Divide intestines.
The invention provides a kind of medicine and method that can be used to treat inflammatory bowel disease particularly colitis, the present invention is also carried
Its preparation method, and the pharmaceutical composition comprising it are supplied.
The content of the invention
The present invention relates to comprising the qualone derivative or its pharmaceutically acceptable salt represented using following formulas (1) as
The therapeutic agent for inflammatory bowel disease of active ingredient.
One aspect of the present invention provides the qualone derivative or its pharmaceutically acceptable salt that a kind of formula (1) is represented：
In formula (1),
A is each independently selected from：N or CR1；
R1、R2It is each independently selected from：Hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, alkylthio group, alkoxy
Alkyl, alkyl sulphonyl, hydroxyl, amino, alkyl monosubstituted amino, dialkyl amido, carboxyl, cyano group, nitro, alkyl monosubstituted amino formyl
Base and dialkyl carbamoyl；
R3、R4Can be each independently selected from identical or different：Hydrogen, halogen, alkyl or cycloalkyl, or R3、R4Can be with
Cycloalkyl is formed together with the carbon atom being connected with it；
Het represents heterocyclic radical, and it is optionally selected from halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, alkylthio group, alkane
Epoxide alkyl, alkyl sulphonyl, hydroxyl, amino, alkyl monosubstituted amino, dialkyl amido, carboxyl, cyano group, nitro, alkyl monosubstituted amino
The group of formoxyl and dialkyl carbamoyl is replaced；
N represents 0,1 or 2；
M represents 0,1,2,3 or 4.
Used as " alkyl " in the present invention, it is the alkyl of 1-6, such as first that can enumerate the carbon number of straight-chain or branch's chain state
Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, isopentyl, n-hexyl, dissident
Base.Wherein, preferably carbon number is the alkyl of 1-4.
As " haloalkyl ", " alkoxy ", " alkylthio group ", " alkoxyalkyl ", " alkyl sulphonyl " in the present invention,
The moieties of " alkyl monosubstituted amino ", " dialkyl amido ", " alkyl monosubstituted amino formoxyl " and " dialkyl carbamoyl ", can
To enumerate and described alkyl identical group.
As " cycloalkyl " in the present invention, the cycloalkyl that carbon number is 3-8, such as cyclopropyl, cyclobutyl, ring can be enumerated
Amyl group, cyclohexyl, suberyl, cyclooctyl.Wherein, preferably carbon number is the cycloalkyl of 5-7.
As " halogen " in the present invention, such as fluorine, chlorine, bromine, iodine can be enumerated.
As " heterocyclic radical " in the present invention, following (1) or (2) can be enumerated：
(1) heteroatomic five or hexa-atomic aromatic ring yl with the 1-4 selected from nitrogen-atoms, oxygen atom and sulphur atom or
Their benzene fused rings, when described ring member nitrogen atoms are nitrogen-atoms or sulphur atom, described nitrogen-atoms, sulphur atom can form oxygen
Compound.For example, 1- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 3- indyls, 2- furyls, 3- furyls, 3- benzene can be enumerated
And furyl, 2- thienyls, 3- thienyls, 3- benzothienyls, 2- thiazolyls, 5- thiazolyls, 2-[4-morpholinodithio base, 1- imidazoles
Base, 2- imidazole radicals, 4- imidazole radicals, 2- benzimidazolyls, 2H-1,2,3- triazole -2- bases, 1H-1,2,4- triazol-1-yls, 1H- tetra-
Azoles -5- bases, 2H- tetrazolium -5- bases, 2- pyridine radicals, 3- pyridine radicals, 4- pyridine radicals, 3- pyrazolyls, 2- pyrimidine radicals, 4- pyrimidine radicals, 2-
Pyrazinyl, 1,3,5-triazines -2- bases.
(2) can be containing 1-4 identical or different nitrogen-atoms, oxygen atom or sulphur atom as four to eight yuan of ring member nitrogen atoms
Ring filling ring group or their benzene condense ring group, when described ring member nitrogen atoms are nitrogen-atoms or sulphur atom, described nitrogen-atoms,
Sulphur atom can form oxide.For example, can enumerate 1- piperidyls, 1- piperazinyls, 4- methylpiperazine-1-yls, equal piperazinyl,
Morpholine -4- bases, thiomorpholine -4- bases, 1- pyrrolidinyls, 2- pyrrolidinyls, 2- tetrahydrofuran bases.
In a preferred embodiment of the invention, R1、R2It is each independently selected from：Hydrogen, halogen, C1-C6 alkyl, C3-
C8 cycloalkyl, halo C1-C6 alkyl, C1-C6 alkoxies, C1-C6 alkylthio groups, C1-C6 alkoxy C 1-C6 alkyl, C1-C6 alkyl
Sulfonyl, hydroxyl, amino, list C1-C6 alkyl aminos, two C1-C6 alkyl aminos, carboxyl, cyano group, nitro, list C1-C6 alkyl ammonia
Base formoxyl and two C1-C6 alkyl-carbamoyls.
In a preferred embodiment of the invention, R3、R4Can be each independently selected from identical or different：Hydrogen, halogen
Element, C1-C6 alkyl or C3-C8 cycloalkyl, or R3、R4C3-C8 cycloalkyl is formed together with the carbon atom that can be connected with it.
In a preferred embodiment of the invention, Het is represented：
(1) heteroatomic five or hexa-atomic aromatic ring yl with the 1-4 selected from nitrogen-atoms, oxygen atom and sulphur atom or
Their benzene fused rings, when described ring member nitrogen atoms are nitrogen-atoms or sulphur atom, described nitrogen-atoms, sulphur atom can form oxygen
Compound；
(2) can be containing 1-4 identical or different nitrogen-atoms, oxygen atom or sulphur atom as four to eight yuan of ring member nitrogen atoms
Ring filling ring group or their benzene condense ring group, when described ring member nitrogen atoms are nitrogen-atoms or sulphur atom, described nitrogen-atoms,
Sulphur atom can form oxide.
In a preferred embodiment of the invention, Het is unsubstituted.
In a preferred embodiment of the invention, Het is selected from halogen, C1-C6 alkyl, C3-C8 cycloalkyl, halo
C1-C6 alkyl, C1-C6 alkoxies, C1-C6 alkylthio groups, C1-C6 alkoxy C 1-C6 alkyl, C1-C6 alkyl sulphonyls, hydroxyl,
Amino, list C1-C6 alkyl aminos, two C1-C6 alkyl aminos, carboxyl, cyano group, nitro, list C1-C6 alkyl-carbamoyls and two
The group of C1-C6 alkyl-carbamoyls is replaced.
Currently preferred compound is：
Another aspect of the present invention be related to one kind prepare above-mentioned formula (1) expression qualone derivative or its can pharmaceutically connect
The method of the salt received, the described method comprises the following steps：
Step one：
Wherein A, R1、R2, n, m be as described above, X represents halogen, preferably chlorine or bromine；
Condition：Cs2CO3, THF, room temperature；
Step 2：
Wherein A, R1、R2、R3、R4, Het, n, m be as described above, X represents halogen, preferably chlorine or bromine；
Condition：Lewis acid, toluene, backflow；The lewis acid is preferably alchlor, ferric trichloride, boron trifluoride,
More preferably alchlor；
And
Optional step three：
In case there is a need, the qualone derivative for representing the formula (1) experiences salt-forming steps to prepare it
Pharmaceutically acceptable salt.
In a preferred embodiment of the invention, the present invention provides the medicine of the qualone derivative that formula (1) is represented
Acceptable salt is selected from base addition salts and acid-addition salts on.Preferably, the base addition salts are selected from sodium salt, sylvite, calcium salt, lithium
Salt, magnesium salts, zinc salt, ammonium salt, tetramethyl ammonium, tetraethyl ammonium salt, dimethylamino salt, triethylamine salt, leptodactyline, ethamine
Salt, diethanolamine salt, arginine salt or lysine salt；Or acid-addition salts be selected from hydrochloride, hydrobromate, phosphate, sulfate,
Mesylate or tosilate.
There is geometric isomer (Z bodies and E bodies) in the qualone derivative that formula (1) of the present invention represents, each geometry is different
Structure body and their mixture are also included within the qualone derivative of formula (1) expression.Additionally, the quinoline that formula (1) is represented
Ketone derivatives also exist and have asymmetric carbon compound, and each optical isomer and their racemic modification are also included within formula
(1) in the qualone derivative for representing.Optical isomer, using its alkalescence, can be made by the racemic modification that obtains as described above
With the acid (such as tartaric acid, dibenzoyl tartaric acid, mandelic acid, 10- camphorsulfonic acids) of optical activity, carried out by known method
Optical resolution, or with the compound of previously prepared optical activity to be raw material manufacture.
According to another aspect of the present invention, the invention provides a kind of pharmaceutical composition, it includes at least one present invention
Qualone derivative or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier that the formula (1) represents.
It is used as to include people in the qualone derivative or its pharmaceutically acceptable salt for representing formula of the present invention (1)
In the therapeutic agent of interior mammal, the administration form of various pharmacy can be made according to therapeutic purposes, can be specifically made
The oral agents such as tablet, cladding tablet, pill, powder, granule, capsule, liquor, suspension, emulsion, injection, suppository etc.
Parenteral dose.These drug-delivery preparations can be using pharmaceutically acceptable carrier etc., using commonly known usual in the field
Formulation method is formulation.For example, when tablet form is formed as, as carrier, for example can using lactose, white sugar, glucose,
The excipient such as urea, starch, calcium carbonate, silicic acid, water, ethanol, propyl alcohol, simple syrup, Glucose Liquid, gelatin solution, carboxymethyl are fine
Dimension element, methylcellulose, hydroxypropyl cellulose, the adhesive such as polyvinylpyrrolidone, dry starch, mosanom, calcium carbonate, gather
The disintegration inhibitors, quaternary ammonium salt such as the disintegrants such as oxygen ethene sorbitan fatty acid ester class, lactose, white sugar, stearic acid, fixed oil
Deng sorbefacient, the NMF such as glycerine, starch, the adsorbent, Talc, polyethylene glycol such as lactose, kaolin, colloidal magnesium
Deng lubricant etc..During manufacture oral liquid preparations, it is possible to use flavouring, buffer, stabilizer, flavoring agent etc., using logical
Chang Fangfa manufactures mixture for internal use, syrup, elixir etc..Now, as flavouring, white sugar, citric acid, tartaric acid can be enumerated
Deng；As buffer, sodium citrate etc. can be enumerated；As stabilizer, Arabic gum, gelatin etc. can be enumerated.Noted in manufacture
When penetrating agent, preferably liquor, emulsion and suspension are sterilized, and isotonic with blood, when these forms are configured to, as dilution
Agent, for example, can use water, lactic acid aqueous solution, ethanol, propane diols etc..Can also coordinate in above-mentioned each preparation as needed
Colouring agent, preservative agent, spices, flavouring agent, sweetener etc. or other pharmaceuticals.Contained formula (1) table in preparation of the invention
The amount of the qualone derivative for showing or its pharmaceutically acceptable salt is not particularly limited, and can suitably select, common preparation
In be both preferably 0.01~70 weight % or so.
Another aspect of the present invention provides the qualone derivative that formula (1) of the present invention represents or its is pharmaceutically acceptable
Salt treat inflammatory bowel disease in application, it includes giving at least one of the present invention of effective dose to individuality in need
Qualone derivative or its pharmaceutically acceptable salt that formula (1) is represented.
Another aspect of the present invention provides the qualone derivative that formula (1) of the present invention represents or its is pharmaceutically acceptable
Application of the salt in medicine is prepared, the medicine is used to treat inflammatory bowel disease.
As inflammatory bowel disease of the invention, such as colitis, clone disease, intestinal tuberculosis, ischemic colitis, companion can be enumerated
With the enterelcosis that behcet's disease is produced, preferably medicable inflammatory bowel disease is colitis.
The qualone derivative that formula (1) of the present invention represents can reduce the weight loss of the animal with colitis
Situation about being shortened with colon lengths, can reduce its disease activity value, show that the compounds of this invention has prevention for colitis
And therapeutic action, therefore can be used in the treatment of inflammatory bowel disease particularly colitis.
Specific embodiment
The present invention is described below in more detail to contribute to the understanding of the present invention.
Those skilled in the art will realize that：Chemical reaction described in the invention can be used to suitably prepare perhaps
Other compounds more of the invention, and be considered as in model of the invention for preparing other methods of compound of the invention
Within enclosing.For example, the synthesis of the compound according to those non-illustrations of the invention can successfully by those skilled in the art
Completed by method of modifying, such as appropriate protection interference group, by using other known reagents except described in the invention
, or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged
Ground is applied to the preparation of other compounds of the invention.
Embodiment 1：1- { 4- [(4- { [4- methylpiperazine-1-yls] methyl } -2- Oxoquinolines -1 (2H)-yl) methyl] benzene
Base } guanidine (compound I)
Step one：At 0 DEG C, 1- [4- (chloromethyl) phenyl] guanidine (3.20g, 16.5mmol) is existed under an inert atmosphere
Solution in THF (50mL) is added dropwise over quinoline -1 (2H) -one (6.75g, 15.0mmol) and Cs2CO3(7.31g, 22.5mmol)
In the solution of THF (50mL).The reaction solution is warmed to room temperature, and is continuously stirred overnight.By resulting solution water
(200mL) dilutes, and is then extracted with ethyl acetate (3 × 80mL).The organic layer for merging is washed and through nothing with salt solution (100mL)
Aqueous sodium persulfate is dried.Solvent is removed under reduced pressure, and residue over silica gel column chromatography layer (ethyl acetate: n-hexane 4: 1) purifying is obtained
To white solid 1- { 4- [(2- Oxoquinolines -1 (2H)-yl) methyl] phenyl } guanidine 3.98g, content 99%, yield 90%.ESI-
MS：294.13[M+H]+。
Step 2：By in alchlor (1.97g, 15.0mmol), toluene (100ml) addition three-necked bottle, stir, Ran Houjia
Enter 1- { 4- [(2- Oxoquinolines -1 (2H)-yl) methyl] phenyl } guanidines (2.93g, 10.0mmol) and 1- (bromomethyl) -4- methyl
Piperazine (2.11g, 11.0mmol), is heated to backflow, reacts 10 hours.Reaction solution is poured into 300ml ice-dense after stopping reaction
In hydrochloric acid, extracted with ethyl acetate (3 × 80mL), organic phase is washed and through anhydrous slufuric acid with salt solution (100mL), water (100mL)
Sodium is dried, and solvent is removed under reduced pressure, and residue over silica gel column chromatography layer (formic acid: hexamethylene 1: 15) purifying obtains light yellow
Solid 1- { 4- [(4- { [4- methylpiperazine-1-yls] methyl } -2- Oxoquinolines -1 (2H)-yl) methyl] phenyl } guanidine 1.41g, contains
Amount 98%, yield 34%.
ESI-MS：405.23[M+H]+
Elementary analysis：Theoretical value/measured value, C (68.29/68.17), H (6.98/6.87), N (20.78/20.91), O
(3.96/4.05)
1H NMR (400MHz, DMSO-D6) δ 8.99 (s, 1H), 7.85 (s, 1H), 7.11-7.32 (m, 4H), 6.98 (s,
2H), 6.57-6.82 (m, 4H), 6.15 (s, 1H), 4.81 (s, 2H), 3.01 (s, 2H), 2.31-2.37 (m, 8H), 2.17 (s,
3H)。
Embodiment 2：1- { 6- [(4- { [2H-1,2,3- triazole -2- bases] methyl } -2- Oxoquinolines -1 (2H)-yl) methyl]
Pyridin-3-yl } guanidine (compound II)
According to the method for embodiment 1,1- [4- (chloromethyl) phenyl] is replaced with 1- [6- (chloromethyl) pyridin-3-yl] guanidine
Guanidine, with 1- (bromomethyl) -2H-1,2,3- triazoles replace 1- (bromomethyl) -4- methyl piperazines, obtain white solid 1- { 6- [(4-
{ [2H-1,2,3- triazole -2- bases] methyl } -2- Oxoquinolines -1 (2H)-yl) methyl] pyridin-3-yl } guanidine, two step gross production rates
27%.
ESI-MS：375.16[M+H]+
Elementary analysis：Theoretical value/measured value, C (60.95/60.78), H (4.85/4.77), N (29.93/30.04), O
(4.27/4.41)
1H NMR (400MHz, DMSO-D6) δ 8.97 (s, 1H), 7.82 (s, 1H), 7.73 (d, 2H), 7.14-7.47 (m,
7H), 6.98 (s, 2H), 6.25 (s, 1H), 4.80 (s, 2H), 4.41 (s, 2H).
Embodiment 3：1- 2- [(2- oxos -4- pyrrolidin-1-yl methyl) -7- (trifluoromethyl) quinoline -1 (2H)-yl)
Methyl] pyrimidine -5- bases } guanidine (compound III)
According to the method for embodiment 1,1- [4- (chloromethyl) phenyl] is replaced with 1- [2- (chloromethyl) pyrimidine -5- bases] guanidine
Guanidine, quinoline -1 (2H) -one is replaced with 7- (trifluoromethyl) quinoline -1 (2H) -one, and 1- (bromines are replaced with 1- (bromomethyl)-pyrrolidines
Methyl) -4- methyl piperazines, obtain white solid 1- { 2- [(2- oxos -4- { pyrrolidin-1-yl methyl } -7- (trifluoromethyl) quinolines
Quinoline -1 (2H)-yl) methyl] pyrimidine -5- bases } guanidine, two step gross production rates 24%.
ESI-MS：446.18[M+H]+
Elementary analysis：Theoretical value/measured value, C (56.62/56.46), H (4.98/4.87), F (12.80/12.92), N
(22.01/22.07), O (3.59/3.68)
1H NMR (400MHz, DMSO-D6) 68.96 (s, 1H), 8.33 (s, 2H), 8.06 (s, 1H), 7.87 (s, 1H),
7.29-7.31 (m, 2H), 6.95 (s, 2H), 6.42 (s, 1H), 4.24 (s, 2H), 3.01 (s, 2H), 2.51 (t, 4H), 1.61
(m, 4H).
Pharmacological examples Example：The colitis research of induction
By the SD male rats 50 of 200~220g of body weight, 5 groups, every group 10, i.e. negative control group, mould are randomly divided into
Type group and compound I, II, III group.Model group and compound I, II, III group rat applied the 2,4 of 1% in the 1-7 days epidermises,
Solution of the 6- TNBs (TNBS) in 100% ethanol, then gave 5 μ L/g body weight at the+7th day in rectum
Solution of the 2.5%TNBS solution in 50% ethanol.Negative control group rat only receives 50% ethanol of respective volume.Compound
Subcutaneous injection is given to rat nape daily respectively for I, II, III, and dosage is 5.0mg/kg.Observe all groups of injection part
The depilation of position and baldness situation.Measure animal body within every 24 hours in experimentation since disease induces the previous day (the -1st day)
Weight.
1. rat body weight situation of change
Measure the weight of animals within every 24 hours in experimentation since disease induces the previous day (the -1st day), record rat
Daily changes of weight situation, rat body weight coefficient represents that the rat body weight on the measurement same day starts the same day (the 0th day) relative to induction
The percentage of rat body weight.Result is shown in Table 1：
Influence (n=10) of the target compound of table 1 to Colitis rat body weight
Note：Compare with model group, * P ＜ 0.05, * * P ＜ 0.01
The result of above-mentioned table 1 shows that negative control group does not receive the colitis of TNBS inductions and only receives carrier, its body
Galassing is steady and without reduction；Model group receives the colitis of TNBS inductions and does not carry out drug-treated, and its body weight is reduced at least
About 20%, representing the colitis of TNBS inductions causes the untreated rat body weight with induced disorders significantly to mitigate.And with originally
Invention compound I, II or III treatment with TNBS induction colitis rat body weight in whole research process before this
Somewhat mitigate, be then back to again substantially close to normal, point out the compounds of this invention to have for the colitis that TNBS is induced pre-
Anti- and therapeutic action, therefore can be used in the treatment of inflammatory bowel disease.
2. rat colon length change and disease activity value are assessed
Colon lengths are one of labels of colitis, because colitis can cause the related fibre modification of inflammation, and then
So that colon lengths shorten., to assess fibrosis and shorten, colon lengths are by measurement from caecum far side for measurement colon lengths
Distance to rectum most end face is determined.By the severity of naked eyes record assessment rat inflammation, it is considered to outside body weight and whole body
See the change of (hair, activity).Colon lengths are measured immediately after opening abdomen, using the average colon lengths of negative control group as ginseng
Examine, be designated as 100, remaining group takes relative value.Record stool is apparent with the color of hemoproctia and colon, expansion and serous coat.
Maximum naked-eye observation value gives 12 points, according to following：Due to rat increased weight at least 5% weekly, changes of weight is more than 5% note 0
Point, increase 0-5%=1, weight loss=2.Hair is normal (0) or dim (1)；Mouse active (0) is not liked (1).Greatly
Just normal (0), semifluid (1) or fluid (2).Hemoproctia gives 1 point.Colon color is normal (0) or rubescent (1)；Expansion is without (0)
Or significantly (1).Serous coat aspect normal (0) is thickened (1).Score is higher, shows that rat is ill more serious.Result is shown in following table
In 2：
Influence (n=10) of the target compound of table 2 to Colitis rat disease activity value
Note：Compare with model group, * P ＜ 0.05, * * P ＜ 0.01
The result of above-mentioned table 2 shows, compared with negative control group, the colon lengths of model group rats significantly shorten, and greatly
Mouse disease activity value is significantly raised；Compared with model group, compound I, II or III group can be substantially reduced the change of colon lengths
It is short, and disease activity value substantially reduces, and points out the compounds of this invention to have prevention and treatment work for the colitis that TNBS induce
With, therefore can be used in the treatment of inflammatory bowel disease.
Above-mentioned pharmacological testing shows that the compounds of this invention can reduce the weight loss and colon of the animal with colitis
The situation that length shortens, can reduce its disease activity value, show that the compounds of this invention has prevention and treatment for colitis
Effect, therefore can be used in the treatment of inflammatory bowel disease particularly colitis.
The preferred embodiment for the present invention is the foregoing described, so it is not limited to the present invention.Those skilled in the art couple
Embodiment disclosed herein can carry out improvement and the change without departing from scope and spirit.
Claims (10)
1. a kind of formula (1) represents qualone derivative or its pharmaceutically acceptable salt：
In formula (1),
A is each independently selected from：N or CR1；
R1、R2It is each independently selected from：Hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, alkylthio group, alkoxyalkyl,
Alkyl sulphonyl, hydroxyl, amino, alkyl monosubstituted amino, dialkyl amido, carboxyl, cyano group, nitro, alkyl monosubstituted amino formoxyl and
Dialkyl carbamoyl；
R3、R4Can be each independently selected from identical or different：Hydrogen, halogen, alkyl or cycloalkyl, or R3、R4Can with its institute
The carbon atom of connection forms cycloalkyl together；
Het represents heterocyclic radical, and it is optionally selected from halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, alkylthio group, alkoxy
Alkyl, alkyl sulphonyl, hydroxyl, amino, alkyl monosubstituted amino, dialkyl amido, carboxyl, cyano group, nitro, alkyl monosubstituted amino formyl
The group of base and dialkyl carbamoyl is replaced；
N represents 0,1 or 2；
M represents 0,1,2,3 or 4.
2. formula (1) according to claim 1 represents qualone derivative or its pharmaceutically acceptable salt, its feature
It is, R1、R2It is each independently selected from：Hydrogen, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, halo C1-C6 alkyl, C1-C6 alcoxyls
Base, C1-C6 alkylthio groups, C1-C6 alkoxy C 1-C6 alkyl, C1-C6 alkyl sulphonyls, hydroxyl, amino, list C1-C6 alkyl ammonia
Base, two C1-C6 alkyl aminos, carboxyl, cyano group, nitro, list C1-C6 alkyl-carbamoyls and two C1-C6 alkyl carbamoyls
Base.
3. formula (1) according to claim 1 represents qualone derivative or its pharmaceutically acceptable salt, its feature
It is, R3、R4Can be each independently selected from identical or different：Hydrogen, halogen, C1-C6 alkyl or C3-C8 cycloalkyl, or R3、
R4C3-C8 cycloalkyl is formed together with the carbon atom that can be connected with it.
4. formula (1) according to claim 1 represents qualone derivative or its pharmaceutically acceptable salt, its feature
It is that Het is represented：
(1) heteroatomic five or hexa-atomic aromatic ring yl with the 1-4 selected from nitrogen-atoms, oxygen atom and sulphur atom or they
Benzene fused rings, when described ring member nitrogen atoms are nitrogen-atoms or sulphur atom, described nitrogen-atoms, sulphur atom can form oxidation
Thing；
(2) can be containing 1-4 identical or different nitrogen-atoms, oxygen atom or sulphur atom as four to the octatomic ring of ring member nitrogen atoms
Saturation ring group or their benzene condense ring group, when described ring member nitrogen atoms are nitrogen-atoms or sulphur atom, described nitrogen-atoms, sulphur original
Son can form oxide.
5. formula (1) according to claim 1 represents qualone derivative or its pharmaceutically acceptable salt, its feature
It is that Het is optionally selected from halogen, C1-C6 alkyl, C3-C8 cycloalkyl, halo C1-C6 alkyl, C1-C6 alkoxies, C1-C6
Alkylthio group, C1-C6 alkoxy C 1-C6 alkyl, C1-C6 alkyl sulphonyls, hydroxyl, amino, list C1-C6 alkyl aminos, two C1-C6
The group institute of alkyl amino, carboxyl, cyano group, nitro, list C1-C6 alkyl-carbamoyls and two C1-C6 alkyl-carbamoyls
Substitution.
6. formula (1) according to claim 1 represents qualone derivative or its pharmaceutically acceptable salt, its feature
It is that the qualone derivative that the formula (1) represents is selected from：
7. one kind prepares the qualone derivative of formula according to claim 1 (1) expression or its is pharmaceutically acceptable
The method of salt, the described method comprises the following steps：
Step one：
Wherein A, R1、R2, n, m as described in the appended claim 1, X represents halogen, preferably chlorine or bromine；
Condition：Cs2CO3, THF, room temperature；
Step 2：
Wherein A, R1、R2、R3、R4, Het, n, m as described in the appended claim 1, X represents halogen, preferably chlorine or bromine；
Condition：Lewis acid, toluene, backflow；The lewis acid is preferably alchlor, ferric trichloride, boron trifluoride, more excellent
Select alchlor；
And
Optional step three：
In case there is a need, the qualone derivative for representing the formula (1) experiences salt-forming steps to prepare its pharmacy
Upper acceptable salt.
8. a kind of pharmaceutical composition, it includes the quinoline that at least one formula (1) according to claim any one of 1-6 is represented
Quinoline ketone derivatives or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier.
9. formula (1) according to claim any one of 1-6 is represented qualone derivative or its is pharmaceutically acceptable
Application of the salt in medicine is prepared, the medicine is used to treat inflammatory bowel disease.
10. application according to claim 10, the inflammatory bowel disease is selected from colitis, clone disease, intestinal tuberculosis, ischemic
Colitis, the preferably enterelcosis produced with behcet's disease, colitis.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108191851A (en) * | 2017-12-25 | 2018-06-22 | 牡丹江医学院 | For treat the drug of colitis with and preparation method thereof |
| WO2022141362A1 (en) * | 2020-12-31 | 2022-07-07 | 兰州大学 | Application of quinazoline derivative in preparation of drug for preventing and/or treating gastrointestinal disease |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1774247A (en) * | 2003-02-14 | 2006-05-17 | 史密丝克莱恩比彻姆公司 | Novel compounds |
| WO2008006050A2 (en) * | 2006-07-07 | 2008-01-10 | Govek Steven P | Bicyclic heteroaryl inhibitors of pde4 |
| CN102686578A (en) * | 2009-08-19 | 2012-09-19 | 凯利普西斯公司 | Bicyclic heteroaryl inhibitors of PDE4 |
-
2017
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1774247A (en) * | 2003-02-14 | 2006-05-17 | 史密丝克莱恩比彻姆公司 | Novel compounds |
| WO2008006050A2 (en) * | 2006-07-07 | 2008-01-10 | Govek Steven P | Bicyclic heteroaryl inhibitors of pde4 |
| CN102686578A (en) * | 2009-08-19 | 2012-09-19 | 凯利普西斯公司 | Bicyclic heteroaryl inhibitors of PDE4 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108191851A (en) * | 2017-12-25 | 2018-06-22 | 牡丹江医学院 | For treat the drug of colitis with and preparation method thereof |
| WO2022141362A1 (en) * | 2020-12-31 | 2022-07-07 | 兰州大学 | Application of quinazoline derivative in preparation of drug for preventing and/or treating gastrointestinal disease |
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