CN106916104B - For treating the drug of colitis - Google Patents
For treating the drug of colitis Download PDFInfo
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- CN106916104B CN106916104B CN201710116082.XA CN201710116082A CN106916104B CN 106916104 B CN106916104 B CN 106916104B CN 201710116082 A CN201710116082 A CN 201710116082A CN 106916104 B CN106916104 B CN 106916104B
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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 for treating the drug of colitis, the qualone derivative indicated for general formula (1).The qualone derivative that general formula (1) of the present invention indicates can reduce the weight loss of the animal with colitis and the case where colon lengths 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 especially colitis.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and the invention discloses for treating colitis and other inflammatory bowel diseases especially
Clone disease, intestinal tuberculosis, ischemic colitis, the enterelcosis generated with behcet's disease.
Background technique
Colitis is the term for describing colitis, refers to that colitis venereal disease caused by a variety of causes becomes.It is main
Want clinical manifestation diarrhea, abdominal pain, abdominal distension and pus and blood stool, it is tenesmus, very then constipation, stool cannot be led in a few days；Often
It is out of strength etc. with syntexis, more recurrent exerbations.Most of patients is with the diseases such as abdominal distension, syntexis, out of strength, borborygmus, insomnia, dreaminess, cold.
There are the inducement of a variety of colitis, including infect, blood supply is weak and autoimmune response.There are many layers for colon wall.Have
It is wrapped in external and is responsible for the smooth muscle layer longitudinally squeezed that will not digest food along colon.Internal layer or mucous membrane contact simultaneously with fluid
Make water and electrolyte absorption to help to solidify excrement.Mucous layer is that position occurs for colitis, and bears colitis symptoms.
Nowadays inflammatory bowel disease such as colitis is controlled by the pharmaceutical composition used with stepped approach.Initially use anti-inflammatory agent
Object can add the drug for inhibiting immune system if its is unsuccessful.In most of several cases, it may be necessary to which operation is to remove
Remove all or part of colon and small intestine.Treatment to ischemic colitis be initially it is supportive, use intravenous fluid come
Keep intestines stable and prevents from being dehydrated.If do not restored to the enough blood supplies of intestines, may need to perform the operation to remove the portion for losing blood supply
Divide intestines.
The present invention provides a kind of drug and method that can be used for treating inflammatory bowel disease especially colitis, the present invention is also mentioned
Preparation method, and the pharmaceutical composition comprising it are supplied.
Summary of the invention
The present invention relates to the qualone derivative comprising being indicated using the following general formula (1) or its pharmaceutically acceptable salt as
The therapeutic agent for inflammatory bowel disease of effective component.
One aspect of the present invention provides a kind of qualone derivative or its pharmaceutically acceptable salt that general formula (1) indicates:
In formula (1),
A is each independently selected from: N or CR1；
R1、R2It is each independently selected from: hydrogen, halogen, alkyl, naphthenic base, halogenated alkyl, alkoxy, alkylthio group, alkoxy
Alkyl, alkyl sulphonyl, hydroxyl, amino, alkyl monosubstituted amino, dialkyl amido, carboxyl, cyano, nitro, alkyl monosubstituted amino formyl
Base and dialkyl carbamoyl；
R3、R4Can be identical or different, it is each independently selected from: hydrogen, halogen, alkyl or cycloalkyl or R3、R4It can be with
The carbon atom being connect with it is formed together naphthenic base；
Het indicates heterocycle, is optionally selected from halogen, alkyl, naphthenic base, halogenated alkyl, alkoxy, alkylthio group, alkane
Oxygroup alkyl, alkyl sulphonyl, hydroxyl, amino, alkyl monosubstituted amino, dialkyl amido, carboxyl, cyano, nitro, alkyl monosubstituted amino
Replaced the group of formoxyl and dialkyl carbamoyl；
N indicates 0,1 or 2；
M indicates 0,1,2,3 or 4.
As " alkyl " in the present invention, the carbon number that can enumerate straight-chain or branch's chain state is the alkyl of 1-6, such as first
Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, dissident
Base.Wherein, preferably carbon number be 1-4 alkyl.
As in the present invention " halogenated alkyl ", " alkoxy ", " alkylthio group ", " alkoxyalkyl ", " alkyl sulphonyl ",
The moieties of " alkyl monosubstituted amino ", " dialkyl amido ", " alkyl monosubstituted amino formoxyl " and " dialkyl carbamoyl ", can
To enumerate group identical with the alkyl.
As " naphthenic base " in the present invention, the naphthenic base that carbon number is 3-8, such as cyclopropyl, cyclobutyl, ring can be enumerated
Amyl, cyclohexyl, suberyl, cyclooctyl.Wherein, preferably carbon number be 5-7 naphthenic base.
As " halogen " in the present invention, such as fluorine, chlorine, bromine, iodine can be enumerated.
As " heterocycle " in the present invention, (1) or (2) below can be enumerated:
(1) have the 1-4 selected from nitrogen-atoms, oxygen atom and sulphur atom heteroatomic five or hexa-atomic aromatic ring yl or
Their benzene fused rings, when the ring member nitrogen atoms are nitrogen-atoms or sulphur atom, the nitrogen-atoms, sulphur atom can form oxygen
Compound.For example, 1- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 3- indyl, 2- furyl, 3- furyl, 3- benzene can be enumerated
And furyl, 2- thienyl, 3- thienyl, 3- benzothienyl, 2- thiazolyl, 5- thiazolyl, 2-[4-morpholinodithio base, 1- imidazoles
Base, 2- imidazole radicals, 4- imidazole radicals, 2- benzimidazolyl, 2H-1,2,3- triazole -2- bases, 1H-1,2,4- triazol-1-yls, 1H- tetra-
Azoles -5- base, 2H- tetrazolium -5- base, 2- pyridyl group, 3- pyridyl group, 4- pyridyl group, 3- pyrazolyl, 2- pyrimidine radicals, 4- pyrimidine radicals, 2-
Pyrazinyl, 1,3,5-triazines -2- base.
(2) four to eight yuan containing 1-4 identical or different nitrogen-atoms, oxygen atom or sulphur atoms as ring member nitrogen atoms
Ring filling ring group or their benzene condense ring group, when the ring member nitrogen atoms are nitrogen-atoms or sulphur atom, the nitrogen-atoms,
Sulphur atom can form oxide.For example, can enumerate 1- piperidyl, 1- piperazinyl, 4- methylpiperazine-1-yl, equal piperazinyl,
Morpholine -4- base, thiomorpholine -4- base, 1- pyrrolidinyl, 2- pyrrolidinyl, 2- tetrahydrofuran base.
In a preferred embodiment of the invention, R1、R2It is each independently selected from: hydrogen, halogen, C1-C6 alkyl, C3-
C8 naphthenic base, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio group, C1-C6 alkoxy C 1-C6 alkyl, C1-C6 alkyl
Sulfonyl, hydroxyl, amino, list C1-C6 alkyl amino, two C1-C6 alkyl aminos, carboxyl, cyano, nitro, list C1-C6 alkyl ammonia
Base formoxyl and two C1-C6 alkyl-carbamoyls.
In a preferred embodiment of the invention, R3、R4Can be identical or different, it is each independently selected from: hydrogen, halogen
Element, C1-C6 alkyl or C3-C8 naphthenic base or R3、R4The carbon atom that can be connect with it is formed together C3-C8 naphthenic base.
In a preferred embodiment of the invention, Het is indicated:
(1) have the 1-4 selected from nitrogen-atoms, oxygen atom and sulphur atom heteroatomic five or hexa-atomic aromatic ring yl or
Their benzene fused rings, when the ring member nitrogen atoms are nitrogen-atoms or sulphur atom, the nitrogen-atoms, sulphur atom can form oxygen
Compound；
(2) four to eight yuan containing 1-4 identical or different nitrogen-atoms, oxygen atom or sulphur atoms as ring member nitrogen atoms
Ring filling ring group or their benzene condense ring group, when the ring member nitrogen atoms are nitrogen-atoms or sulphur atom, the 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 by selected from halogen, C1-C6 alkyl, C3-C8 naphthenic base, halogenated
C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio group, C1-C6 alkoxy C 1-C6 alkyl, C1-C6 alkyl sulphonyl, hydroxyl,
Amino, list C1-C6 alkyl amino, two C1-C6 alkyl aminos, carboxyl, cyano, nitro, list C1-C6 alkyl-carbamoyl and two
Replaced the group of C1-C6 alkyl-carbamoyl.
Currently preferred compound is:
Another aspect of the present invention be related to it is a kind of prepare above-mentioned general formula (1) expression qualone derivative or its can pharmaceutically connect
The method for the salt received, the described method comprises the following steps:
Step 1:
Wherein A, R1、R2, n, m be as described above, X indicates 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 indicates halogen, preferably chlorine or bromine；
Condition: lewis acid, toluene, reflux；The lewis acid is preferably alchlor, ferric trichloride, boron trifluoride,
More preferable alchlor；
And
Optional step three:
In case there is a need, the qualone derivative experience salt-forming steps for indicating the general formula (1) are to prepare it
Pharmaceutically acceptable salt.
In a preferred embodiment of the invention, the present invention provides the medicine for the qualone derivative that general formula (1) indicates
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.
For the qualone derivative that general formula (1) of the present invention indicates there are geometric isomer (Z body and E body), each geometry is different
Structure body and their mixture are also included in the qualone derivative of general formula (1) expression.In addition, the quinoline that general formula (1) indicates
For ketone derivatives there is also having asymmetric carbon compound, each optical isomer and their racemic modification are also included within general formula
(1) in the qualone derivative indicated.Optical isomer can be made by the racemic modification obtained as described above using its alkalinity
With the acid (such as tartaric acid, dibenzoyl tartaric acid, mandelic acid, 10- camphorsulfonic acid) of optical activity, carried out by well known method
Optical resolution, or manufactured with the compound of previously prepared optical activity is raw material.
According to another aspect of the present invention, the present invention provides a kind of pharmaceutical compositions, and it includes at least one present invention
The qualone derivative or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier that the general formula (1) indicates.
Being used as in the qualone derivative or its pharmaceutically acceptable salt for indicating general formula of the present invention (1) includes people
When the therapeutic agent of mammal inside, the administration form of various pharmacy can be made according to therapeutic purposes, can specifically be made
The oral agents such as tablet, cladding tablet, pill, powder, granule, capsule, liquor, suspension, emulsion, injection, suppository etc.
Non-oral dose.Pharmaceutically acceptable carrier etc. can be used in these drug-delivery preparations, using commonly known usual in the field
Formulation method is formulation.For example, when being formed as tablet form, as carrier, can be used for example lactose, white sugar, glucose,
The excipient such as urea, starch, calcium carbonate, silicic acid, water, ethyl alcohol, propyl alcohol, simple syrup, Glucose Liquid, gelatin solution, carboxymethyl are fine
The adhesives such as element, methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone are tieed up, dry starch, calcium carbonate, gathers mosanom
The disintegrating agents such as ethylene oxide sorbitan fatty acid ester class, lactose, the disintegration inhibitors such as white sugar, stearic acid, fixed oil, quaternary ammonium salt
Equal sorbefacients, the moisturizer such as glycerol, starch, the adsorbents such as lactose, kaolin, colloidal magnesium, Talc, polyethylene glycol
Equal lubricants etc..When manufacturing oral liquid preparations, corrigent, buffer, stabilizer, flavoring agent etc. can be used, using logical
Chang Fangfa manufactures mixture for internal use, syrup, elixir etc..At this point, white sugar, citric acid, tartaric acid can be enumerated as corrigent
Deng；As buffer, sodium citrate etc. can be enumerated；As stabilizer, Arabic gum, gelatin etc. can be enumerated.It is infused in manufacture
When penetrating agent, preferably liquor, emulsion and suspension are sterilized, and isotonic with blood, when being configured to these forms, as dilution
Water, lactic acid aqueous solution, ethyl alcohol, propylene glycol etc. can be used for example in agent.It can also cooperate in above-mentioned each preparation as needed
Colorant, preservative agent, fragrance, flavouring agent, sweetener etc. or other pharmaceuticals.General formula contained in preparation of the invention (1) table
The amount of the qualone derivative shown 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 general formula (1) of the present invention indicates or its is pharmaceutically acceptable
Salt treatment inflammatory bowel disease in application comprising it is of the present invention to give a effective amount of at least one to individual in need
The qualone derivative or its pharmaceutically acceptable salt that general formula (1) indicates.
Another aspect of the present invention provides the qualone derivative that general formula (1) of the present invention indicates or its is pharmaceutically acceptable
Salt application in medicine preparation, the drug is for treating inflammatory bowel disease.
As inflammatory bowel disease of the invention, such as colitis, clone disease, intestinal tuberculosis, ischemic colitis, companion can be enumerated
The enterelcosis generated with behcet's disease, preferably medicable inflammatory bowel disease is colitis.
The qualone derivative that general formula (1) of the present invention indicates can reduce the weight loss of the animal with colitis
The case where shortening with colon lengths can reduce its disease activity value, show that the compounds of this invention has prevention for colitis
And therapeutic effect, therefore can be used in the treatment of inflammatory bowel disease especially colitis.
Specific embodiment
The present invention is described below in more detail to facilitate 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 mostly of the invention, and other methods for the preparation of the compounds of the present invention are considered as in model of the invention
Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention
It is completed by method of modifying, such as protection interference group appropriate, by utilizing other known reagent in addition to 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 suitable for the preparation of other compounds of the invention.
Embodiment 1:1- { 4- [(4- { [4- methylpiperazine-1-yl] methyl } -2- Oxoquinoline -1 (2H)-yl) methyl] benzene
Base } guanidine (compound I)
Step 1: at 0 DEG C, 1- [4- (chloromethyl) phenyl] guanidine (3.20g, 16.5mmol) is existed under an inert atmosphere
Quinoline -1 (2H) -one (6.75g, 15.0mmol) and Cs is added dropwise in solution in THF (50mL)2CO3(7.31g, 22.5mmol)
In the solution of THF (50mL).It is warmed to room temperature the reaction solution, and is continuously stirred overnight.By obtained solution water
(200mL) dilution, then with ethyl acetate (3 × 80mL) extraction.Combined organic layer is washed and with salt water (100mL) through nothing
Aqueous sodium persulfate is dry.Solvent is removed under reduced pressure, and residue is purified with silica gel column chromatography layer (ethyl acetate: n-hexane 4: 1), obtained
To white solid 1- { 4- [(2- Oxoquinoline -1 (2H)-yl) methyl] phenyl } guanidine 3.98g, content 99%, yield 90%.ESI-
MS:294.13 [M+H]+。
Step 2: by alchlor (1.97g, 15.0mmol), toluene (100ml) be added three-necked bottle in, stirring, then plus
Enter 1- { 4- [(2- Oxoquinoline -1 (2H)-yl) methyl] phenyl } guanidine (2.93g, 10.0mmol) and 1- (bromomethyl) -4- methyl
Piperazine (2.11g, 11.0mmol), is heated to flowing back, and reacts 10 hours.Stop reaction solution being poured into 300ml ice-after reaction dense
In hydrochloric acid, extracted with ethyl acetate (3 × 80mL), organic phase salt water (100mL), water (100mL) wash and through anhydrous slufuric acid
Sodium is dry, removes solvent under reduced pressure, and residue is purified with silica gel column chromatography layer (formic acid: hexamethylene 1: 15), obtained light yellow
Solid 1- { 4- [(4- { [4- methylpiperazine-1-yl] methyl } -2- Oxoquinoline -1 (2H)-yl) methyl] phenyl } guanidine 1.41g, contains
Amount 98%, yield 34%.
ESI-MS:405.23 [M+H]+
Elemental 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- Oxoquinoline -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 piperazine, obtain white solid 1- { 6- [(4-
{ [2H-1,2,3- triazole -2- bases] methyl } -2- Oxoquinoline -1 (2H)-yl) methyl] pyridin-3-yl } guanidine, two step gross production rates
27%.
ESI-MS:375.16 [M+H]+
Elemental 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- oxo -4- pyrrolidin-1-yl methyl) -7- (trifluoromethyl) quinoline -1 (2H)-yl)
Methyl] pyrimidine -5- base } guanidine (compound III)
According to the method for embodiment 1,1- [4- (chloromethyl) phenyl] is replaced with 1- [2- (chloromethyl) pyrimidine -5- base] guanidine
Guanidine replaces quinoline -1 (2H) -one with 7- (trifluoromethyl) quinoline -1 (2H) -one, replaces 1- (bromine with 1- (bromomethyl)-pyrrolidines
Methyl) -4- methyl piperazine, obtain white solid 1- { 2- [(2- oxo -4- { pyrrolidin-1-yl methyl } -7- (trifluoromethyl) quinoline
Quinoline -1 (2H)-yl) methyl] pyrimidine -5- base } guanidine, two step gross production rates 24%.
ESI-MS:446.18 [M+H]+
Elemental 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 SD male rat 50 of 200~220g of weight, 5 groups are randomly divided into, every group 10, i.e. negative control group, mould
Type group and compound I, II, III group.Model group and compound I, II, III group rat the 2,4 of epidermis application 1% in the 1-7 days,
Then solution of the 6- trinitrobenzene sulfonic acid (TNBS) in 100% ethyl alcohol gave 5 μ L/g weight at the+7th day in rectum
Solution of the 2.5%TNBS solution in 50% ethyl alcohol.Negative control group rat only receives 50% ethyl alcohol of respective volume.Compound
I, subcutaneous injection is given daily to rat nape, dosage 5.0mg/kg respectively by II, III.Observe all groups of injection part
The depilation and baldness situation of position.The every 24 hours measurement animal bodies during the experiment since disease induces the previous day (the -1st day)
Weight.
1. rat body weight situation of change
The previous day (the -1st day) is induced to start every 24 hours measurement the weight of animals during the experiment, record rat since disease
Daily changes of weight situation, rat body weight coefficient indicate 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.As a result it is shown in Table 1:
Influence (n=10) of 1 target compound of table to Colitis rat weight
Note: compared with model group, * P < 0.05, * * P < 0.01
Above-mentioned table 1 the results show that negative control group do not receive TNBS induction colitis and only receive carrier, body
Galassing is steady and does not reduce；Model group receives the colitis of TNBS induction and does not carry out drug-treated, and weight loss is at least
About 20%, indicate that the colitis of TNBS induction causes the untreated rat body weight with induction disease significantly to mitigate.And with originally
Invention compound I, II or III processing with TNBS induction colitis rat weight in entire research process before this
Slightly mitigate, is then back to again and prompts substantially close to normal the compounds of this invention that there is in advance the colitis that TNBS induce
Anti- and therapeutic effect, therefore can be used in the treatment of inflammatory bowel disease.
2. the variation of rat colon length and the assessment of disease activity value
Colon lengths are one of markers of colitis, since colitis will lead to the relevant fibre modification of inflammation, in turn
So that colon lengths shorten.Measurement colon lengths are to assess fibrosis and shorten, and colon lengths are by measuring from caecum far side
Distance to rectum most end face is determined.The severity of assessment rat inflammation is recorded by naked eyes, is considered outside weight and whole body
See the variation of (hair, activity).Colon lengths are measured immediately after opening abdomen, using the average colon lengths of negative control group as ginseng
It examines, is denoted as 100, remaining group takes relative value.The color of record stool and hemoproctia and colon, expansion and serous coat are apparent.
Maximum naked-eye observation value gives 12 points, according to following: since weight gain at least 5%, changes of weight are more than 5% note 0 to rat weekly
Point, increase 0-5%=1, weight loss=2.Hair is normal (0) or dimness (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 it is significant (1).Serous coat aspect normal (0) thickens (1).Score is higher, shows that rat illness is more serious.As a result it is shown in following table
In 2:
Influence (n=10) of 2 target compound of table to Colitis rat disease activity value
Note: compared with model group, * P < 0.05, * * P < 0.01
Above-mentioned table 2 the results show that compared with negative control group, the colon lengths of model group rats significantly shorten, and it is big
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 prompts the compounds of this invention to have the colitis that TNBS is induced and prevents and treats work
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 case where length shortens can reduce its disease activity value, show that the compounds of this invention has colitis and prevent and treat
Effect, therefore can be used in the treatment of inflammatory bowel disease especially colitis.
The foregoing describe the preferred embodiment for the present invention, and however, it is not to limit the invention.Those skilled in the art couple
Embodiment disclosed herein can carry out the improvements and changes without departing from scope and spirit.
Claims (12)
1. qualone derivative or its pharmaceutically acceptable salt that a kind of general formula (1) indicates:
In formula (1),
A is each independently selected from: CR1；
R1It is each independently selected from: hydrogen；
R2It is each independently selected from: hydrogen, C1-6 alkyl or halogenated C1-6 alkyl；
R3、R4Can be identical or different, it is each independently selected from: hydrogen or C1-6 alkyl；
Het is indicated: 4- methylpiperazine-1-yl；
Het is optionally replaced the group selected from halogen and C1-6 alkyl；
N indicates 0,1 or 2；
M indicates 0,1,2,3 or 4.
2. qualone derivative or its pharmaceutically acceptable salt that general formula (1) according to claim 1 indicates, feature
It is, R2It is each independently selected from: hydrogen or C1-C6 alkyl.
3. qualone derivative or its pharmaceutically acceptable salt that general formula (1) according to claim 1 indicates, feature
It is, R3、R4It is selected from: hydrogen.
4. qualone derivative or its pharmaceutically acceptable salt that general formula (1) according to claim 1 indicates, feature
It is, Het is optionally replaced the group selected from C1-C6 alkyl.
5. qualone derivative or its pharmaceutically acceptable salt that general formula (1) according to claim 1 indicates, feature
It is, the qualone derivative that the general formula (1) indicates is selected from:
6. a kind of qualone derivative for preparing general formula according to claim 1 (1) expression or its is pharmaceutically acceptable
The method of salt, the described method comprises the following steps:
Step 1:
Wherein A, R1、R2, n, m as described in the appended claim 1, X indicate halogen；
Condition: Cs2CO3, THF, room temperature；
Step 2:
Wherein A, R1、R2、R3、R4, Het, n, m as described in the appended claim 1, X indicate halogen；
Condition: lewis acid, toluene, reflux；
And
Optional step three:
In case there is a need, the qualone derivative experience salt-forming steps for indicating the general formula (1) are to prepare its pharmacy
Upper acceptable salt.
7. according to the method described in claim 6, it is characterized in that, X described in step 1 indicates chlorine or bromine；Described in step 2
X indicates that chlorine or bromine, the lewis acid are alchlor, ferric trichloride, boron trifluoride.
8. according to the method described in claim 6, it is characterized in that, lewis acid described in step 2 is alchlor.
9. a kind of pharmaceutical composition, it includes the quinolines that at least one general formula (1) according to claim 1-5 indicates
Quinoline ketone derivatives or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
10. qualone derivative that general formula (1) according to claim 1-5 indicates or its is pharmaceutically acceptable
The application of salt in medicine preparation, the drug is for treating inflammatory bowel disease.
11. application according to claim 10, the inflammatory bowel disease is selected from colitis, clone disease, intestinal tuberculosis, ischemic
Colitis, the enterelcosis generated with behcet's disease.
12. application according to claim 10, the inflammatory bowel disease is selected from colitis.
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| CN201710116082.XA CN106916104B (en) | 2017-02-28 | 2017-02-28 | For treating the drug of colitis |
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| CN201710116082.XA CN106916104B (en) | 2017-02-28 | 2017-02-28 | For treating the drug of colitis |
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| CN108191851B (en) * | 2017-12-25 | 2019-07-23 | 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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| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
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