CN112778156A - Bishydrazide structure compound, preparation method and application thereof - Google Patents

Bishydrazide structure compound, preparation method and application thereof Download PDF

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CN112778156A
CN112778156A CN201911089415.XA CN201911089415A CN112778156A CN 112778156 A CN112778156 A CN 112778156A CN 201911089415 A CN201911089415 A CN 201911089415A CN 112778156 A CN112778156 A CN 112778156A
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hydrazine
carbonyl
carboxylic acid
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substituted
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CN112778156B (en
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蒋华良
沈晓燕
郑明月
侯辉
鲍维廉
刘小红
张素林
杨瑞瑞
吴小龙
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Fudan University
Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
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    • C07C243/30—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
    • C07C243/32—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
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    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/86—Hydrazides; Thio or imino analogues thereof
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    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Abstract

The invention provides a dihydrazide structure compound, a preparation method and application thereof. Specifically, the invention provides diacyl shown in formula IHydrazine structure compounds. The compound of the invention has the functions of enhancing the activity of intestinal stem cells, promoting the repair of intestinal epithelium and simultaneously reducing the expression of proinflammatory cytokines, thereby achieving the purpose of treating inflammatory intestinal diseases.

Description

Bishydrazide structure compound, preparation method and application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a dihydrazide structure compound, and a preparation method and application thereof.
Background
Inflammatory Bowel Disease (IBD) includes Ulcerative Colitis (UC) and Crohn's Disease (CD), characterized by recurrent episodes of inflammation of the digestive tract. In recent years, global incidence has seen a dramatic rise. The pathogenesis of IBD is not clear up to now and studies have shown to be associated with genetic, immunological, infectious and mental activities. Repeated attacks of disease can cause DNA damage and microsatellite instability of mucosal cells, leading to the development of colon cancer. It has been demonstrated that IBD patients are significantly more at risk of developing colon cancer than normal populations.
Of the inflammatory cytokines involved in the pathogenesis of IBD, members of the IL-12 family, particularly IL-23, are widely regarded as central factors in experimental models of enteritis and in the pathogenesis of human IBD. IL-23 activates CD4+ memory cells, CD8+ cells, NK cells and a few mononuclear macrophages/dendritic cells. By binding to the IL-23 receptor (IL-23R), secretion of IL-10, IL-17, INF-gamma, and the like is induced, thereby promoting the development of inflammation. Recent human genetic studies have established that IL-23R variation is associated with inflammatory responses in the small intestine (ileum CD) and large intestine (UC). IL-23 was found to maintain and expand Th17 cell function and to exacerbate the inflammatory response of the intestinal tract.
In recent years, the advent of biological therapies (such as anti-TNF therapy) has greatly improved the treatment of IBD. However, there are still a large number of patients with refractory ulcers or refractory epithelial isomerism, making "mucosal healing" difficult for these patients. Mucosal healing indicates that IBD patients have restored intestinal epithelial structure and function, while also revealing a long-term remission or low-risk prognosis of surgery. The importance of restoring the structure and function of the intestinal epithelium has been identified in the treatment of IBD at present; mucosal healing has also reached consensus among clinicians and researchers as a standard goal of treatment. However, suitable therapeutic means are not yet available. The use of immunosuppressive agents and anti-cytokines improves the recurrence rate of IBD patients, however, there is still a lack of drugs that can cure IBD.
Therefore, there is an urgent need in the art to find key molecules in the pathogenesis and/or disease progression of IBD and to develop new compounds that can be used to treat IBD.
Disclosure of Invention
The invention aims to provide a class of bishydrazide structural compounds which can be used for treating IBD.
In a first aspect of the invention, there is provided a compound of formula I, an optical isomer or cis-trans isomer thereof, a pharmaceutically acceptable salt, hydrate, solvate, prodrug or an active metabolite thereof,
Figure BDA0002266407890000021
wherein the content of the first and second substances,
Figure BDA0002266407890000023
represents a single bond or a double bondA key;
X1，X2，X3each independently selected from the group consisting of: c (R)1)2、NR1、CR1Or N;
and is
Figure BDA0002266407890000022
Is aromatic or non-aromatic;
g is selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, amino, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylamino, hydroxymethyl, C1-C6Haloalkyl, or-L1-M；
Q is selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, amino, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylamino, hydroxymethyl, C1-C6Haloalkyl, or-L1-M；
When G is located at X3In the above, Q may be located at X1Or X2The above step (1);
when Q is at X3In the above, G may be located at X1Or X2The above step (1);
R1independently selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, amino, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylamino, hydroxymethyl, or C1-C6A haloalkyl group;
L1independently selected from the group consisting of: -NHC (═ O) -, -OC (═ O) -, -NHS (═ O) -, -OS (═ O) -, -NHSO2-, -C (═ O) NH-, -C (═ O) O-, -S (═ O) NH-, -OS (═ O) O-, or-SO2NH-；
M is independently selected from the group consisting of: c1-C6Alkyl radical, C1-C6Alkoxy, substituted or unsubstituted C3-C20Cycloalkyl, substituted or unsubstituted 3-20 heteroCyclic radical, substituted or unsubstituted C6-C14Aryl, substituted or unsubstituted 6-14 membered heteroaryl; and-L1-M may optionally be further substituted by one or more halogens, 3-12 membered heterocyclyl or C3-12Cycloalkyl is substituted;
the substitution is selected from one or more of the following groups: halogen, nitro, cyano, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylamino radical, C2-C6Alkenyl radical, C2-C6Haloalkenyl, C3-C6Cycloalkenyl radical, C2-C6Alkynyl, C2-C6Halogenated alkynyl, C3-C6Cycloalkyl alkynyl, C6-C14Aryl, 5-14 membered heterocyclyl, and said aryl, heteroaryl may optionally be further substituted with one or more substituents selected from the group consisting of: halogen, nitro, cyano, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Haloalkoxy, C1-C6Alkoxy radical, C1-C6An alkylamino group;
a is independently selected from the group consisting of: substituted or unsubstituted C3-12Cycloalkyl, substituted or unsubstituted 3-20 membered heterocyclyl, substituted or unsubstituted C6-C14Aryl, substituted or unsubstituted 6-14 membered heteroaryl; wherein the substitution is selected from one or more of the group consisting of: halogen, hydroxy, amino, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Alkylamino, hydroxymethyl or C1-C6A haloalkyl group;
k is independently selected from the group consisting of: r2-C(＝O)NH-、R2-C(＝O)O-、-C(＝O)NH-R2、-C(＝O)O-R2，R2Independently selected from the group consisting of: hydrogen, C1-C6Alkyl radical, C6-C14Aryl, 6-14 membered heteroaryl.
In another preferred embodiment, the compound, its optical isomer or cis-trans isomer, pharmaceutically acceptable salt, hydrate, solvate, prodrug or active metabolite thereof has the structure shown in formula II
Figure BDA0002266407890000031
Wherein the content of the first and second substances,
X1，X2，X3each independently selected from: CR1Or N;
R1independently selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, amino, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylamino, hydroxymethyl, halomethyl or-L1-M；
L1Independently selected from the group consisting of: -NHC (═ O) -, -OC (═ O) -, -NHS (═ O) -, -OS (═ O) -, -NHSO2-, -C (═ O) NH-, -C (═ O) O-, -S (═ O) NH-, -OS (═ O) O-, or-SO2NH-；
M is independently selected from the group consisting of: c2-C4Alkyl radical, C1-C6Alkoxy, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted tetrahydronaphthyl, substituted or unsubstituted 6-20 membered fused heterocycle, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted 5-6 membered heteroaryl; said M may be further substituted by one or more halogens, 3-12 membered heterocyclic groups or C3-12Cycloalkyl substituted; and the substitution is selected from one or more of the following groups: halogen, nitro, cyano, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylamino radical, C2-C6Alkenyl radical, C2-C6Haloalkenyl, C3-C6Cycloalkenyl radical, C2-C6Alkynyl, C2-C6Haloalkynyl, C3-C6 cycloalkyl-C3-C6 alkynyl, phenyl,Or 5-14 membered heterocyclyl, and the phenyl, 5-14 membered heterocyclyl may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, nitro, cyano, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Haloalkoxy, C1-C6Alkoxy, or C1-C6An alkylamino group;
a is independently selected from the group consisting of: substituted or unsubstituted C3-12Cycloalkyl, substituted or unsubstituted C6-C14Aryl, or substituted or unsubstituted 6-14 membered heteroaryl; wherein the substitution is selected from one or more of the group consisting of: halogen, hydroxy, amino, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Alkylamino, hydroxymethyl or halomethyl;
k is independently selected from the group consisting of: -C (═ O) NH-R2、-C(＝O)O-R2，R2Independently selected from the group consisting of: hydrogen, C1-C6Alkyl radical, C6-C14Aryl or 6-14 membered heteroaryl.
In another preferred embodiment, the compound, its optical isomer or cis-trans isomer, pharmaceutically acceptable salt, hydrate, solvate, prodrug or active metabolite thereof has the structure shown in the following formula III,
Figure BDA0002266407890000032
wherein G, Q, A, K is as defined above.
In another preferred embodiment, the compound, its optical isomer or cis-trans isomer, pharmaceutically acceptable salt, hydrate, solvate, prodrug or active metabolite thereof has the structure shown in formula IV,
Figure BDA0002266407890000041
wherein G, Q, A, K is as defined above.
In another preferred embodiment, the compound, its optical isomer or cis-trans isomer, pharmaceutically acceptable salt, hydrate, solvate, prodrug or active metabolite thereof has the structure shown in the following formula V,
Figure BDA0002266407890000042
wherein G, Q, A, K is as defined above.
In another preferred embodiment, the compound is selected from the following compounds:
2- (2- (4- (cyclopropanecarboxamido) benzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (4- (cyclopropanecarboxamido) benzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid methyl ester;
2- (2- (4- (3-methylbutanamido) benzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (4-acetamidobenzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (4-benzoylaminobenzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (4- (cyclohexanecarboxamido) benzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (4- (cyclopropylcarbamoyl) benzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (4-chlorobenzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (4-fluorobenzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (4- (trifluoromethoxy) benzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (4- (tert-butyl) benzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (4- (trifluoromethyl) benzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (4- (oxazol-5-yl) benzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (3-chlorobenzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (2-chlorobenzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (2, 4-dichlorobenzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (6-chloronicotinyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (6-bromonicotinyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (4- (cyclopropanecarboxamido) -3-fluorobenzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (4- (cyclopropanecarboxamido) -2-fluorobenzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (2-chloro-4- (cyclopropanecarboxamido) benzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (3-chloro-4- (cyclopropanecarboxamido) benzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (3- (cyclopropanecarboxamido) -4-fluorobenzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
3- (2- (4- (cyclopropanecarboxamido) benzoyl) hydrazine-1-carbonyl) bicyclo [2.2.1] hept-5-ene-2-carboxylic acid;
2- (2- (4- (cyclopropanecarboxamido) benzoyl) hydrazine-1-carbonyl) benzoic acid;
3- (2- (4- (cyclopropanecarboxamido) benzoyl) hydrazine-1-carbonyl) bicyclo [2.2.1] heptane-2-carboxylic acid;
2- (2- (4- (cyclopropanecarboxamido) benzoyl) hydrazine-1-carbonyl) cyclopropane-1-carboxylic acid;
4, 5-dibromo-2- (2- (4- (cyclopropanecarboxamido) benzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (4- (cyclopropanecarboxamido) benzoyl) hydrazine-1-carbonyl) -3, 6-difluorobenzoic acid;
2- (2- (4- (cyclopropanecarboxamido) benzoyl) hydrazine-1-carbonyl) -3, 6-difluorobenzoic acid;
2- (2- (4-fluorobenzoyl) hydrazine-1-carbonyl) benzoic acid;
3- (2- (4-fluorobenzoyl) hydrazine-1-carbonyl) bicyclo [2.2.1] heptane-2-carboxylic acid;
3- (2- (4-chlorobenzoyl) hydrazine-1-carbonyl) bicyclo [2.2.1] heptane-2-carboxylic acid;
3- (2- (3-chlorobenzoyl) hydrazine-1-carbonyl) bicyclo [2.2.1] heptane-2-carboxylic acid;
3- (2- (2-chlorobenzoyl) hydrazine-1-carbonyl) bicyclo [2.2.1] heptane-2-carboxylic acid;
3- (2- (2, 4-dichlorobenzoyl) hydrazine-1-carbonyl) bicyclo [2.2.1] heptane-2-carboxylic acid;
3- (2- (4- (cyclopropanecarboxamido) benzoyl) hydrazine-1-carbonyl) -2-naphthoic acid.
In a second aspect of the present invention, there is provided a process for preparing a compound of formula I, an optical isomer or a cis-trans isomer thereof, a pharmaceutically acceptable salt, a hydrate, a solvate, a prodrug or an active metabolite thereof as described in the first aspect, comprising the steps of:
Figure BDA0002266407890000051
in a first inert solvent, a2Reacting the compound with a compound b, optionally further reacting to obtain a compound I;
wherein, X1，X2，X3G, Q, A, K are as defined above.
In another preferred embodiment, the further reaction refers to the substitution with halogenated alkane, or the condensation reaction with alcohol or amine to prepare the compound I; the alcohol is C1-C6alkyl-OH, said amine being C1-C6alkyl-NH2Or C1-C6alkyl-N-C1-C6An alkyl group.
In another preferred embodiment, the first inert solvent is selected from: CH (CH)3CN, toluene, xylene, dichloromethane, DMF, or combinations thereof.
In another preferred embodiment, the salts are prepared by reacting a compound of formula I with the free base or acid with a chemically equivalent or excess of the acid (inorganic or organic) or base (inorganic or organic) in a suitable solvent or solvent composition.
In another preferred embodiment, the process for preparing a compound of formula I, its optical isomer or cis-trans isomer, pharmaceutically acceptable salt, hydrate, solvate, prodrug or active metabolite thereof, further comprises the steps of:
Figure BDA0002266407890000061
in a second inert solvent, compound a1With hydrazine hydrate to form the compound a2；
Wherein, X1，X2，X3G, Q are as defined above.
In another preferred embodiment, the second inert solvent is an alcohol, preferably C1-C6An alkyl alcohol, more preferably methanol or ethanol.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the first aspect, an optical isomer or a cis-trans isomer thereof, a pharmaceutically acceptable salt, hydrate, solvate, prodrug or active metabolite thereof; and a pharmaceutically acceptable carrier.
In a fourth aspect of the present invention, there is provided a use of the compound of the first aspect, its optical isomer or cis-trans isomer, pharmaceutically acceptable salt, hydrate, solvate, prodrug or active metabolite, or the pharmaceutical composition of the third aspect in preparing a medicament and a pharmaceutical composition for treating or preventing inflammatory bowel disease.
In another preferred embodiment, the inflammatory bowel disease comprises crohn's disease or Behcet's disease with intestinal lesions, ulcerative colitis, bleeding rectal ulcers and ileocolitis.
In another preferred embodiment, the treatment comprises: promoting mucosal healing, restoring intestinal epithelial structure, or a combination thereof.
In another preferred embodiment, the treatment comprises: promoting the activity of an intestinal stem cell, reducing the expression of a proinflammatory cytokine, or a combination thereof.
In a fifth aspect of the invention, there is provided a method of inhibiting IL-23 and up-regulating cyclinD1 in vitro, comprising the steps of: contacting a compound according to the first aspect of the invention, an optical isomer or a cis-trans isomer thereof, a pharmaceutically acceptable salt, hydrate, solvate, prodrug or active metabolite thereof, with a somatic cell (or tissue) to inhibit IL-23 and upregulate cyclinD 1.
In another preferred embodiment, said inhibiting IL-23 includes inhibiting the formation of IL-23miRNA and inhibiting the expression of IL-23 protein.
In another preferred example, the up-regulation of cyclinD1 comprises promotion of formation of cyclinD1 miRNA and promotion of expression of cyclinD1 protein.
In another preferred embodiment, the somatic cell is selected from the group consisting of: macrophages, intestinal cells (including intestinal stem cells, intestinal epithelial cells), or a combination thereof.
In another preferred embodiment, the somatic cell is from a rodent (e.g., mouse, rat), or primate (e.g., human).
In a fifth aspect of the present invention, there is provided a method of treating inflammatory bowel disease, comprising the steps of: administering to a subject in need thereof a compound, an optical isomer or a cis-trans isomer thereof, a pharmaceutically acceptable salt, a hydrate, a solvate, a prodrug or an active metabolite thereof according to the first aspect of the present invention, or a pharmaceutical composition according to the third aspect.
In another preferred embodiment, the inflammatory bowel disease comprises crohn's disease or Behcet's disease with intestinal lesions, ulcerative colitis, bleeding rectal ulcers and ileocolitis.
In another preferred embodiment, the subject is a mammal, preferably a human.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 shows Compound A1Therapeutic effect on mouse colitis model.
FIG. 2 shows Compound A1At both concentrations, the plasma levels of the orally administered mice varied.
FIG. 3 shows Compound A1Promoting growth of mouse-derived intestinal organoids.
Detailed Description
The inventor has conducted extensive and intensive research and unexpectedly developed a class of bishydrazide structural compounds which can inhibit IL-23 and up-regulate cyclinD 1. The compound not only can inhibit the over-activated intestinal inflammatory reaction and immune response so as to obviously reduce the colon inflammation of IBD mice, but also can effectively promote the healing of intestinal mucosa and maintain the steady state, thereby being effectively and synergistically used for treating inflammatory intestinal diseases. The present invention has been completed based on this finding.
Term(s) for
The term "alkyl" refers to a straight or branched chain alkyl group containing 1 to 18 carbon atoms, especially 1 to 6 carbon atoms. Typical "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, isopentyl, heptyl, 4-dimethylpentyl, octyl, 2,2, 4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. Term "(C)1-C6) Alkyl "refers to straight or branched chain alkyl groups including from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl. "substituted alkyl" means an alkyl group which is substituted at one or more positions, especially 1 to 4 substituents, and may be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g. monohalogen substituents or polyhalo substituents, the latter being trifluoromethyl or containing Cl3Alkyl group of (a), nitrile group, nitro group, oxygen (e.g., ═ O), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, heterocycle, aromatic ring, ORa、SRa、S(＝O)Re、S(＝O)2Re、P(＝O)2Re、S(＝O)2ORe,P(＝O)2ORe、NRbRc、NRbS(＝O)2Re、NRbP(＝O)2Re、S(＝O)2NRbRc、P(＝O)2NRbRc、C(＝O)ORd、C(＝O)Ra、C(＝O)NRbRc、OC(＝O)Ra、OC(＝O)NRbRc、NRbC(＝O)ORe,NRdC(＝O)NRbRc、NRdS(＝O)2NRbRc、NRdP(＝O)2NRbRc、NRbC(＝O)RaOr NRbP(＝O)2ReWherein R is present thereinaMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, Rb、RcAnd RdMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or RbAnd RcTogether with the N atom may form a heterocyclic ring; reMay independently represent hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above-mentioned typical substituents such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring may be optionally substituted.
The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing 2 to 18 carbon atoms, at least one carbon-carbon double bond. Term "(C)2-C6) Alkenyl "means a straight-chain or branched group having 2 to 6 carbon atoms and at least one carbon-carbon double bond, such as vinyl, propenyl, 2-propenyl, (E) -2-butenyl, (Z) -2-butenyl, (E) -2-methyl-2-butenyl, (Z) -2-methyl-2-butenyl, 2, 3-dimethyl-2-butenyl, (Z) -2-pentenyl, (E) -1-pentenyl, (E) -2-pentenyl, (Z) -2-hexenyl, (E) -1-hexenyl, (Z) -1-hexenyl, (E) -2-hexenyl, (Z) -3-hexenyl, (E) -3-hexenyl, (E) -1, 3-hexadienyl, 4-methyl-3-pentenyl or norbornene. "substituted alkenyl" means that one or more positions in the alkenyl group are substituted, especially 1 to 4 substituents, which may be substituted at any position. Typically by takingGenerations include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g. monohalogen substituents or polyhalo substituents, the latter being trifluoromethyl or containing Cl3Alkyl group of (a), nitrile group, nitro group, oxygen (e.g., ═ O), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, heterocycle, aromatic ring, ORa、SRa、S(＝O)Re、S(＝O)2Re、P(＝O)2Re、S(＝O)2ORe,P(＝O)2ORe、NRbRc、NRbS(＝O)2Re、NRbP(＝O)2Re、S(＝O)2NRbRc、P(＝O)2NRbRc、C(＝O)ORd、C(＝O)Ra、C(＝O)NRbRc、OC(＝O)Ra、OC(＝O)NRbRc、NRbC(＝O)ORe,NRdC(＝O)NRbRc、NRdS(＝O)2NRbRc、NRdP(＝O)2NRbRc、NRbC(＝O)RaOr NRbP(＝O)2ReWherein R is present thereinaMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, Rb、RcAnd RdMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or RbAnd RcTogether with the N atom may form a heterocyclic ring; reMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above-mentioned typical substituents such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring may be optionally substituted.
The term "alkynyl" refers to a substituent containing from 2 to 18 carbon atoms, at least one carbon-carbon triple bond, of a straight or branched hydrocarbon group. Typical groups include ethynyl. Term "(C)2-C6) Alkynyl means a straight or branched chain radical containing from 2 to 6 carbon atoms and at least one carbon-carbon double bond, e.g. ethynyl1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl. "substituted alkynyl" means that one or more positions in the alkynyl group are substituted, especially 1 to 4 substituents, which may be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalo substituents, the latter such as trifluoromethyl or containing Cl3Alkyl group of (a), nitrile group, nitro group, oxygen (e.g., ═ O), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, heterocycle, aromatic ring, ORa、SRa、S(＝O)Re、S(＝O)2Re、P(＝O)2Re、S(＝O)2ORe,P(＝O)2ORe、NRbRc、NRbS(＝O)2Re、NRbP(＝O)2Re、S(＝O)2NRbRc、P(＝O)2NRbRc、C(＝O)ORd、C(＝O)Ra、C(＝O)NRbRc、OC(＝O)Ra、OC(＝O)NRbRc、NRbC(＝O)ORe,NRdC(＝O)NRbRc、NRdS(＝O)2NRbRc、NRdP(＝O)2NRbRc、NRbC(＝O)RaOr NRbP(＝O)2ReWherein R is present thereinaMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, Rb、RcAnd RdMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or RbAnd RcTogether with the N atom may form a heterocyclic ring; reMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. Typical substituents may be optionally substituted.
The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group comprising 1 to 4 rings, each ringContaining 3 to 8 carbon atoms, for example comprising 3 to 18 carbon atoms, in particular 3 to 14 carbon atoms, including without limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or norbornane. "substituted cycloalkyl" means that one or more positions in the cycloalkyl group are substituted, especially 1 to 4 substituents, which may be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g. monohalogen substituents or polyhalo substituents, the latter being trifluoromethyl or containing Cl3Alkyl group of (a), nitrile group, nitro group, oxygen (e.g., ═ O), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, heterocycle, aromatic ring, ORa、SRa、S(＝O)Re、S(＝O)2Re、P(＝O)2Re、S(＝O)2ORe,P(＝O)2ORe、NRbRc、NRbS(＝O)2Re、NRbP(＝O)2Re、S(＝O)2NRbRc、P(＝O)2NRbRc、C(＝O)ORd、C(＝O)Ra、C(＝O)NRbRc、OC(＝O)Ra、OC(＝O)NRbRc、NRbC(＝O)ORe,NRdC(＝O)NRbRc、NRdS(＝O)2NRbRc、NRdP(＝O)2NRbRc、NRbC(＝O)RaOr NRbP(＝O)2ReWherein R is present thereinaMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, Rb、RcAnd RdMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or RbAnd RcTogether with the N atom may form a heterocyclic ring; reMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above typical substituents may be optionally substituted. Typical substitutions also include spiro, bridged or fused ring substituents, especially spirocycloalkyl, and the like,Spirocyclic alkenyl, spirocyclic heterocycle (excluding heteroaryl rings), bridged cycloalkyl, bridged cycloalkenyl, bridged heterocycle (excluding heteroaryl rings), fused cyclic alkyl, fused cyclic alkenyl, fused cyclic heterocyclyl, or fused cyclic aromatic ring groups, which may be optionally substituted.
The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon compound group comprising 1 to 4 rings containing 3 to 8 carbon atoms in each ring, for example containing 3 to 18 carbon atoms, especially 3 to 14 carbon atoms. Typical cycloalkenyl groups are cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like. "substituted cycloalkenyl" means cycloalkyl substituted at one or more positions, especially 1 to 4 substituents, and can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g. monohalogen substituents or polyhalo substituents, the latter being trifluoromethyl or containing Cl3Alkyl group of (a), nitrile group, nitro group, oxygen (e.g., ═ O), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, heterocycle, aromatic ring, ORa、SRa、S(＝O)Re、S(＝O)2Re、P(＝O)2Re、S(＝O)2ORe,P(＝O)2ORe、NRbRc、NRbS(＝O)2Re、NRbP(＝O)2Re、S(＝O)2NRbRc、P(＝O)2NRbRc、C(＝O)ORd、C(＝O)Ra、C(＝O)NRbRc、OC(＝O)Ra、OC(＝O)NRbRc、NRbC(＝O)ORe,NRdC(＝O)NRbRc、NRdS(＝O)2NRbRc、NRdP(＝O)2NRbRc、NRbC(＝O)RaOr NRbP(＝O)2ReWherein R is present thereinaMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, Rb、RcAnd RdMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or RbAnd RcTogether with the N atom may form a heterocyclic ring; reMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above typical substituents may be optionally substituted. Typical substitutions also include bridged, spiro or fused ring substituents, especially spirocycloalkyl, spiroalkenyl, spiroheterocyclic (excluding heteroaromatic rings), fused ring alkyl, fused ring alkenyl, fused ring heterocyclic or fused ring aromatic ring groups, which may be optionally substituted.
The term "cycloalkylalkynyl" refers to cycloalkyl-substituted alkynyl groups including C3-C8 cycloalkyl-C ≡ C-Ra，RaMay independently represent none, hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, for example: cyclopropyl acetylene, cyclobutyl acetylene, cyclopentyl acetylene, cyclohexyl acetylene. Wherein, cycloalkyl may be substituted, and the substituents may be as in the term "cycloalkyl".
The term "aryl" refers to an aromatic cyclic hydrocarbon group having 1 to 5 rings, e.g. containing 6 to 18 carbon atoms, especially 6 to 14 carbon atoms. In particular monocyclic and bicyclic radicals, such as phenyl, biphenyl or naphthyl. Where the aromatic ring contains two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be linked by a single bond (e.g., biphenyl), or fused (e.g., naphthalene, anthracene, etc.). "substituted aryl" means that one or more positions in the aryl group are substituted, especially 1 to 3 substituents, which may be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g. monohalogen substituents or polyhalo substituents, the latter being trifluoromethyl or containing Cl3Alkyl group of (a), nitrile group, nitro group, oxygen (e.g., ═ O), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, heterocycle, aromatic ring, ORa、SRa、S(＝O)Re、S(＝O)2Re、P(＝O)2Re、S(＝O)2ORe,P(＝O)2ORe、NRbRc、NRbS(＝O)2Re、NRbP(＝O)2Re、S(＝O)2NRbRc、P(＝O)2NRbRc、C(＝O)ORd、C(＝O)Ra、C(＝O)NRbRc、OC(＝O)Ra、OC(＝O)NRbRc、NRbC(＝O)ORe,NRdC(＝O)NRbRc、NRdS(＝O)2NRbRc、NRdP(＝O)2NRbRc、NRbC(＝O)RaOr NRbP(＝O)2ReWherein R is present thereinaMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, Rb、RcAnd RdMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or RbAnd RcTogether with the N atom may form a heterocyclic ring; reMay independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above typical substituents may be optionally substituted. Typical substitutions also include fused ring substituents, especially fused ring alkyl, fused ring alkenyl, fused ring heterocyclyl or fused ring aromatic ring groups, which cycloalkyl, cycloalkenyl, heterocyclyl and heterocyclylaryl groups may be optionally substituted.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms (preferably 1 or 2), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur. The heteroaryl group is preferably a 5-to 10-membered ring, more preferably a 5-or 6-membered ring, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, purine, carbazole, indolyl, indazolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, isomerized quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl or naphthyridinyl, tetrazolyl, and the like. "heteroaryl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxy, and carboxylate.
The term "halogen" or "halo" refers to chlorine, bromine, fluorine, iodine.
"haloalkyl" means straight or branched chain haloalkyl, such as "C1-C6Haloalkyl "which means a straight or branched chain haloalkyl group having 1 to 6 carbon atoms containing one or more of the same or different halogen atoms, including without limitation-CH2Cl、-CHCl2、-CCl3、-CH2F、-CHF2、-CF3、-CH2Br、-CHBr2、-CBr3、CF3CH2、CCl3CH2、CBr3CH2。
The term "alkoxy" refers to a straight or branched chain alkoxy group, such as "C1-C6 alkoxy", which refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including without limitation methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like. C1-C4 alkoxy is preferred.
The term "haloalkoxy" refers to a halogen-substituted straight or branched chain alkoxy group, such as "C1-C6 haloalkoxy", which refers to a straight or branched chain haloalkoxy group having 1 to 6 carbon atoms, including without limitation chloromethoxy, chloroethoxy, chloropropoxy, chloroisopropoxy, chlorobutoxy, bromomethoxy, bromoethoxy, bromopropoxy, bromoisopropoxy, and bromobutoxy, and the like.
The term "alkylamino" refers to "an amino-substituted straight or branched chain alkyl group, such as" C1-C6 alkylamino ", which refers to an amino-substituted straight or branched chain alkyl group having 1 to 6 carbon atoms, including without limitation H2N-CH2-、H2N-CH2CH2-、H2N-CH2CH2CH2-、H2N-CH(CH3)CH2-and the like.
The term "haloalkenyl" refers to a substituent containing 2 to 18 carbon atoms with at least one carbon-carbon double bond. Term "(C)2-C6) Haloalkenyl "refers to a straight or branched chain radical containing from 2 to 6 carbon atoms, having at least one carbon-carbon double bond, and one or more identical or different halogen atoms, including-CH ═ CHCl, -CH ═ CCl2、-CH＝CHF、-CH＝CF2、-CH＝CHBr、-CH＝CBr2、-CH＝CH-CH2F、-CH＝CHCHF2、-CH＝CH-CF3、-CH＝CHCH2Br、-CH＝CHCHBr2、-CH＝CHCBr3And the like.
The term "haloalkynyl" refers to a substituent containing 2 to 18 carbon atoms with at least one carbon-carbon triple bond. Term "(C)2-C6) Haloalkynyl "refers to a straight or branched chain group containing 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and one or more of the same or different halogen atoms, including-C.ident.CCl, -C.ident.CF, -C.ident.CBr, -C.ident.C-CH2F、-C≡CCHF2、-C≡C-CF3、-C≡CCH2Br、-C≡CCHBr2、-C≡CCBr3And the like.
The term "carboxy" refers to-COOH.
The term "hydroxymethyl" refers to-CH2OH。
The term "condensation reaction" means that the carboxylic acid compound obtained in the present invention is reacted with an alcohol or an amine in the presence of a condensing agent; the condensing agent may be a conventional condensing agent well known in the art, for example: DMAP, EDCI, HOBT, HOAT, HATU, HBTU, etc.
Unless otherwise stated, it is assumed that any heteroatom that is not in a valence state has sufficient hydrogen to replenish its valence state.
The salts which the compounds of the invention may form are also within the scope of the invention. Unless otherwise indicated, the compounds of the present invention are understood to include salts thereof. The term "salt" as used herein refers to a salt formed from an inorganic or organic acid and a base in either an acidic or basic form. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolation or purification steps during manufacture. The compounds of the invention may form salts, for example, by reacting compound I with an amount of acid or base, e.g. an equivalent amount, and salting out in a medium, or lyophilizing in an aqueous solution.
As described herein, the compounds of the present invention can be substituted with any number of substituents or functional groups to extend their inclusion range. In general, the term "substituted", whether occurring before or after the term "optional", in the formula of the present invention including substituents, means that the hydrogen radical is replaced with a substituent of the indicated structure. When a plurality of the specified structures are substituted at a position with a plurality of the specified substituents, each position of the substituents may be the same or different. The term "substituted" as used herein includes all permissible substitutions of organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched, unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds.
In the present invention, the heteroatom nitrogen may have a hydrogen substituent or any permissible organic compound described hereinabove to supplement its valence state.
In the present specification, inflammatory bowel disease refers not only to strictly inflammatory bowel diseases such as crohn's disease and ulcerative colitis but also to inflammatory bowel diseases in a broad sense including intestinal lesions with Behcet's disease, bleeding rectal ulcers, ileocele, intestinal tuberculosis, ischemic enteritis, drug colitis, radiation enteritis, infectious enteritis, and the like.
Furthermore, the present invention is not intended to be limited in any way as to the permissible substitution of organic compounds. The present invention recognizes that the combination of substituents and variable groups is excellent in the treatment of diseases, such as infectious diseases or proliferative diseases, in the form of stable compounds. The term "stable" as used herein refers to compounds that are stable enough to maintain the structural integrity of the compound when tested for a sufficient period of time, and preferably are effective for a sufficient period of time, and are used herein for the purposes described above.
Metabolites of the compounds referred to herein and pharmaceutically acceptable salts thereof, as well as prodrugs that can be converted in vivo into the structures of the compounds referred to herein and pharmaceutically acceptable salts thereof, are also included within the scope of the present invention.
Active ingredient
As used herein, the terms "compound of the present invention," or "bishydrazide structural class compound of the present invention," are used interchangeably to refer to the compound of formula I. The term also includes compounds of formula I, optical isomers or cis-trans isomers thereof, pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or active metabolites thereof.
Wherein the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or a base, which is suitable for use as a medicament. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is that formed by reacting a compound of the present invention with an acid. Suitable acids for forming the salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, and the like; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid and the like; and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid, etc. Another preferred class of salts are those of the compounds of the invention with bases, for example alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (e.g., lower alkanolammonium salts and other pharmaceutically acceptable amine salts), for example methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, triethanolamine salts, and amine salts formed from morpholine, piperazine, lysine, respectively.
The term "solvate" refers to a compound of the present invention coordinated to solvent molecules to form a complex in a specified ratio. "hydrate" refers to a complex formed by the coordination of a compound of the present invention with water.
In addition, the compound also comprises a prodrug of the bishydrazide structure shown in the formula I. The term "prodrug" includes a class of compounds which are biologically active or inactive in nature and which, when administered by an appropriate method, undergo a metabolic or chemical reaction in the body to convert the compound to formula I, or a salt or solution of a compound of formula I. The prodrugs include, but are not limited to, carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amide, carbamate, azo, phosphoramide, glucoside, ether, acetal forms of the compounds.
Preparation method
The process for the preparation of the compounds of formula I according to the invention is described in more detail below, but these particular processes do not limit the invention in any way. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains.
In general, in the preparative schemes, each reaction is generally carried out in an inert solvent at 0 ℃ or room temperature to reflux temperature (e.g., 0 ℃ to 160 ℃, preferably 0 ℃ to 120 ℃). The reaction time is usually 0.1 to 60 hours, preferably 0.5 to 48 hours.
The following general preparative routes may be used to synthesize the compounds of the present invention having the structure of formula I:
Figure BDA0002266407890000131
in a first inert solvent, compound a2Reacting with the compound b to obtain the compound I.
In the present invention, the compound a2 can be prepared by the following steps:
Figure BDA0002266407890000141
in the above reaction formulae, each group is as defined above.
Pharmaceutical compositions and methods of administration
Because the compound of the present invention has the effects of inhibiting IL-23 (for example, inhibiting IL-23mRNA) and up-regulating cyclinD1 (for example, increasing cyclinD1 mRNA), the compound of the present invention, its optical isomer or cis-trans isomer, pharmaceutically acceptable salt, hydrate, solvate, prodrug or active metabolite thereof, and the pharmaceutical composition containing the compound of the present invention as the main active ingredient can be used for treating, preventing and relieving IBD.
The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof in a safe and effective amount range and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 10-1000mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g. tween, etc.)
Figure BDA0002266407890000142
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 50 to 1000 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The main advantages of the invention include:
1. the dihydrazide structure compound provided by the invention has the effects of enhancing the activity of intestinal stem cells, promoting the repair of intestinal epithelium and simultaneously reducing the expression of proinflammatory cytokines, thereby achieving the purpose of treating Inflammatory Bowel Diseases (IBD).
2. The bishydrazide structural compound of the invention can inhibit IL-23mRNA and can up-regulate cyclinD1mRNA, thereby being capable of treating IBD synergistically and more efficiently.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, generally followed by conventional conditions, such as Sambrook et al, molecular cloning: the conditions described in the Laboratory Manual (New York: Cold Spring Harbor Laboratory Press,1989), or according to the manufacturer's recommendations. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
EXAMPLE 1 Compound A1The synthesis of (2):
Figure BDA0002266407890000161
the first step is as follows: after dissolving Compound 1(500mg) in DCM (10mL), the temperature was lowered to 0 ℃ and Compound 3(348mg) was added, and the mixture was slowly warmed to room temperature and kept at room temperature for reaction for 30 min. The reaction was quenched with water, extracted with ethyl acetate, concentrated under reduced pressure, and the residue was extracted with petroleum ether: ethyl acetate ═ 5: purification by column chromatography using 1 as eluent gave compound 2(610mg, 84% yield).1HNMR(400MHz,CDCl3):δ8.00(d,J＝8.8Hz,2H),7.60(d,J＝8.8Hz,2H),3.90(s,3H),1.53(m,1H),1.12(m,2H),0.88(m,2H)。
The second step is that: compound 2(400mg) was dissolved in CH3CH2OH (25mL), and hydrazine hydrate (5mL) was added to conduct a reaction at reflux for 4 h. After completion of the reaction, concentration under reduced pressure and washing of the solid with ice water, followed by recrystallization from ethanol gave compound 4(120mg, yield 40%).1HNMR(400MHz,CD3OD):δ7.74(d,J＝9.2Hz,2H),7.65(d,J＝9.2Hz,2H),1.89(s,3H),1.77(m,1H),1.28(s,2H),0.95(m,2H),0.87(m,2H)。
The third step: dissolve Compound 5(352mg) in CH3CN (15mL), heated to reflux, then Compound 4(500mg) was added and the reflux reaction was maintained for 3And 0 min. After the reaction is finished, obtaining a solid by suction filtration, then washing the solid by CH3CN, and drying for 2h in vacuum at 70 ℃ to obtain a compound A1(605mg, yield 71%).1H NMR(400MHz,DMSO-d6):δ10.45(s,1H),10.11(s,1H),9.64(s,1H),7.82(d,J＝6.0Hz,2H),7.66(d,J＝5.6Hz,2H),2.87(m,1H),2.12(m,1H),2.06(m,1H),1.97(m,1H),1.80(m,1H),1.72(m,1H),1.65(m,1H),1.57(m,1H),1.41(m,2H),1.29(m,1H),0.82(m,5H)；13CNMR(125MHz,DMSO-d6):δ175.37,173.35,172.54,165.38,142.71,128.84,127.26,118.56,42.33,40.72,28.23,25.60,24.51,22.83,15.15,7.84；LRMS(ESI):397.5(M+Na)+,372.7(M-H)-；HRMS(ESI):calcd for C19H22N3O5(M-H)-:372.1565,found:372.1561.
EXAMPLE 2 Compound A2Synthesis of (2)
Figure BDA0002266407890000171
Mixing the compound A1(100mg) and K2CO3(74mg) was dissolved in DMF (2mL) and CH was added dropwise with stirring3I, stirring was continued overnight. After the reaction was completed, the reaction was quenched with water, extracted with EA, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was extracted with petroleum ether: ethyl acetate ═ 5: purifying the 1-bit eluent by column chromatography to obtain a compound A2(90mg, yield 85%).1H NMR(400MHz,DMSO-d6):δ10.37(s,1H),7.57(d,J＝8.8Hz,1H),7.20(d,J＝8.8Hz,1H),3.12(s,3H),2.94(s,1H),1.75(m,1H),1.45(m,3H),1.19(m,2H),0.88(m,4H),0.79(d,J＝5.6Hz,4H).LRMS(ESI):387.0(M)+。
EXAMPLES 3-37 Compound A3-A37Synthesis of (2)
Compound A was synthesized by following the procedure of examples 1-2 by substituting the substrate of example 1 with the corresponding substrate3-A37。
The structures and the characterization results of the compounds A3-A37 are as follows:
TABLE A
Figure BDA0002266407890000172
Figure BDA0002266407890000181
Figure BDA0002266407890000191
Figure BDA0002266407890000201
Figure BDA0002266407890000211
Figure BDA0002266407890000221
Figure BDA0002266407890000231
Figure BDA0002266407890000241
Example 38 animal and cell experiments
First, experimental material
Cells and animals
HCT116 cells and raw264.7 cells were provided by the cell bank of the chinese academy of sciences; intestinal organoids were derived from intestinal crypt cultures isolated from Lgr5-EGFP mice; the Lgr5-EGFP mouse is given by Hua national institute of intense research, the genetic background is C57/BL6, and the Lgr5-EGFP mouse is bred in the SPF animal room of second floor of the center of experimental animals of the pharmaceutical institute of the Compound Dan university.
Primary reagent
Figure BDA0002266407890000242
Figure BDA0002266407890000251
Second, Experimental methods
A. Cell experiments
Screening the activity of the compound:
detection of IL-23 mRNA:
all test compounds were made up in DMSO to a concentration of 50mM in stock and stored at-20 ℃ in a refrigerator. Raw264.7 cells are inoculated in a 12-well plate, the cell density is about 70-80% after 24 hours, compounds with different dilution ratios are added, 20 mu l (namely 0.5 mu g/ml) of LPS is added into each well after 1 hour of medicine addition, and the culture plate is shaken gently and mixed evenly. Blank groups were not added. After 6 hours, the medium was discarded, washed 3 times with ice-cold PBS buffer, 1ml Trizol was added, and the mixture was allowed to stand for 10min, the lysate was collected, the supernatant was obtained by centrifugation, 1/5 volumes of chloroform were added, shaken 1min, and left to stand for 3min, and 12000g was centrifuged at 4 ℃. And (3) taking the supernatant, adding isopropanol with the same volume, uniformly mixing, standing for 10min, and centrifuging for 12000Xg for 10 min. Removing supernatant, washing precipitate with 70% ethanol, centrifuging at 7500g for 5min, drying precipitate, and adding 20 μ L DEPC water. And detecting the RNA concentration of the sample, adjusting the RNA concentration to 100-1000 ng/. mu.L, and detecting the change of the mRNA level of the IL-23 by using a commercially available reverse transcription kit and a SYBR-qPCR kit.
(1) Reverse transcription to synthesize cDNA
According to the instructions of the reverse transcription kit, the following mixture was prepared in an RNase free centrifuge tube and gently pipetted and mixed. Incubate at 42 ℃ for 2 min. The reverse transcription reaction procedure is as follows, stage 1:25 ℃,5 min; stage 2, 42 ℃ for 30 min; stage 3, 85 ℃ and 5 min; stage 4, keeping at 4 ℃, and storing the product at-20 ℃ or directly using the product in RT-qPCR.
(2) RT-PCR amplification
The primer sequences involved in Real-Time PCR are as follows:
Figure BDA0002266407890000252
by using
Figure BDA0002266407890000262
Method for analyzing data and calculating
Figure BDA0002266407890000263
The value of (A) is the fold of the expression of the target gene in the experimental group relative to the control group.
Detection of CyclinD1 mRNA:
the colorectal cancer HCT116 cell strain is subjected to compound screening, and the culture medium is McCOY's 5A culture medium containing 10% FBS. Inoculating the cells into a 12-hole plate, and enabling the density of adherent cells to be 70% -80% on the next day. mu.L of stock solution (50mM) was added to 1ml of the medium to prepare 50. mu.M of the drug-containing medium (control group, 0.1% DMSO medium). Discarding the original culture medium, adding the medicated culture medium, and culturing at 37 deg.C for 6 hr. Discarding the culture medium, washing with ice-cold PBS buffer for 3 times, adding 1ml Trizol, standing for 10min, collecting lysate, centrifuging to obtain supernatant, adding 1/5 volume of chloroform, shaking for 1min, standing for 3min, and centrifuging at 4 deg.C for 12000 Xg. And (3) taking the supernatant, adding isopropanol with the same volume, uniformly mixing, standing for 10min, and centrifuging for 12000Xg for 10 min. Removing supernatant, washing precipitate with 70% ethanol, centrifuging at 7500Xg for 5min, drying precipitate, and adding 20 μ L DEPC water. And detecting the RNA concentration of the sample, adjusting the RNA concentration to 100-1000 ng/. mu.L, and detecting the mRNA level change of the cyclinD1 by using a commercially available reverse transcription kit and a SYBR-qPCR kit.
(1) Reverse transcription to synthesize cDNA
According to the instructions of the reverse transcription kit, the following mixture was prepared in an RNase free centrifuge tube and gently pipetted and mixed. Incubate at 42 ℃ for 2 min. The reverse transcription reaction procedure is as follows, stage 1:25 ℃,5 min; stage 2, 42 ℃ for 30 min; stage 3, 85 ℃ and 5 min; stage 4, keeping at 4 ℃, and storing the product at-20 ℃ or directly using the product in RT-qPCR.
(2) RT-PCR amplification
The primer sequences involved in Real-Time PCR are as follows:
Figure BDA0002266407890000261
the desired fragment of cDNA was amplified using a CFX100 fluorescent quantitative PCR instrument from Bio-Rad.
Collecting instrument data, using 2-△△CtMethod to analyze data, calculate 2-△△CtThe value of (A) is the fold of the expression of the target gene in the experimental group relative to the control group.
B. Animal experiments
Animal breeding and gene identification
Propagation of Lgr5-EGFP mice
Mouse genotype identification
Lgr5-EGFP mouse genotype identification
Gene identification sequence
Figure BDA0002266407890000271
PCR was carried out as follows:
Figure BDA0002266407890000272
the reaction program was set up as indicated.
1. Establishment of mouse acute IBD model and compound A1In vivo efficacy test
The experimental groups were set as a control group, a model group, and a mesalazine administration group, A110mg/kg administration group and Compound A1Five groups of 8 male C57/BL6 mice of 8 weeks of age per group, except for the control group, were given free drinking of 3% dextran sulfate sodium salt (DSS) water, reconstituted every other day and replaced for 7 days.
Compound A1Dissolving with DMSO to obtain mother solution, dissolving in ultrapure water to obtain 4% DMSO aqueous solutions with final concentrations of 1mg/ml and 2mg/ml, respectively, and dissolving mesalazine in DMSO0.5% CMC-Na is prepared into 50mg/ml suspension, the intragastric administration is started at the same time of the modeling, and the intragastric administration dosage is 10 mu L/g (corresponding to the administration dosage of 10mg/kg, 20mg/kg and 50mg/kg) for 10 days.
Mice weight changes were recorded daily and mice were sacrificed 10 days before sampling.
2. Determination of serum inflammatory factors
After 10 days of the administration, the mice were bled by taking an eye-ball, and after collecting whole blood, the blood was allowed to clot undisturbed at room temperature for 15 to 30 minutes. Serum was obtained by centrifugation at 1,000 Xg for 10min at 4 ℃ in a centrifuge. Serum samples were tested for IL-1 β and IL-23 serum levels using IL-1 β and IL-23ELISA kits available from Dake, Inc.
3. Colon length measurement in mice
After blood was taken from the above eyeballs, the mice were sacrificed and the entire colon was photographed and length-measured.
4. Detection of inflammatory factor mRNA levels in colonic tissue
Repeatedly washing colon tissue with PBS, scraping mucus, separating colon mucosa of mouse, adding Trizol for tissue homogenization, standing for 10min, centrifuging to obtain supernatant, adding chloroform of 1/5 volume, shaking for 1min, standing for 3min, and centrifuging at 4 deg.C for 12000 Xg. And (3) taking the supernatant, adding isopropanol with the same volume, uniformly mixing, standing for 10min, and centrifuging for 12000Xg for 10 min. Removing supernatant, washing precipitate with 70% ethanol, centrifuging at 7500Xg for 5min, drying precipitate, and adding appropriate amount of DEPC water. And detecting the RNA concentration of the sample, adjusting the RNA concentration to 100-1000 ng/. mu.L, and detecting the mRNA level of the corresponding inflammatory factor by using a commercially available reverse transcription kit and a SYBR-qPCR kit.
5.RT-qPCR
According to the instructions of the reverse transcription kit, the following operations are carried out:
prepare the following mixture in RNase free centrifuge tube, gently blow and mix with a pipette. Incubate at 42 ℃ for 2 min.
Figure BDA0002266407890000281
Preparation of reverse transcription reaction System (20. mu.L System)
Figure BDA0002266407890000282
The cDNA was obtained and the working solution system was prepared according to the following table:
Figure BDA0002266407890000291
qPCR primers for each inflammatory factor are shown in the table below
Figure BDA0002266407890000292
Collecting instrument data, analyzing the data by adopting a 2-delta Ct method, and calculating the numerical value of the 2-delta Ct, namely the multiple of the target gene expression of the experimental group relative to the control group.
6. Inflammatory infiltration and mucosal injury observations
The middle section of the mouse is taken to be about 0.5cm colon, fixed by paraformaldehyde at 4 ℃ for 16H, entrusted to Wuhan Severe Biopsies company for paraffin embedding, sliced and stained by hematoxylin-eosin (H & E).
7. Pharmacokinetic experiments
18 mice (C57) were male, weighing 18-22g, randomly divided into 6 groups of 3 mice each, and the test compounds were gavaged with fasting for 12h before the test, with free water, and with a uniform diet 2h after the administration. The experimental protocol is as follows:
Figure BDA0002266407890000293
mice were collected in retro-orbital venous plexus blood collection in heparin sodium treated EP tubes and plasma was centrifuged according to the time points in the table. Accurately sucking 15 μ L of plasma into an EP tube corresponding to the sample number, adding 300 μ L of methanol/acetonitrile equal volume mixed solution containing 50ng/mL tolbutamide (tolbutamide) as internal standard, vortexing for 1min, and separating at 12000rpm at room temperatureHeart for 10 min. And (3) uniformly mixing 35 mu L of supernatant with 65 mu L of acetonitrile/water equal-volume mixed solution, transferring the mixture into a 96-well plate, and performing LC-MS/MS analysis, wherein the sample injection volume is 2 mu L. Gradient separation was performed by ultra performance liquid chromatography (Waters corporation) and triple quadrupole mass spectrometry (API5000, SCIEX corporation) was performed using electrospray ion source under negative ion conditions using multiple reaction monitoring mode (MRM). Compound A1The linear range of the calibration curve is 1-3000 ng/mL.
The chromatographic conditions were as follows
A chromatographic column: waters Acquity C18 column (2.1 x 50mm,1.7 μm)
Column temperature: 45 deg.C
Mobile phase: MPA 0.1% formic acid in water
MPB acetonitrile/methanol with 0.1% formic acid (9/1, v/v)
Flow rate: 0.5mL/min
Gradient elution procedure:
Figure BDA0002266407890000301
the mass spectrum conditions were as follows
Compound Transition
A1 372.3>218.0
tolbutamide 269.2>169.8
8. Isolation and culture of colonic organoids
The colon of a mouse of 6 to 8 weeks old is cut out from the middle, washed clean with precooled PBS, the small intestine is divided into segments of 5-8 cm in length, mucus on the surface of the colon is scraped off with a glass slide, and the scraped colon is placed in a 50mL centrifuge tube and placed on ice. The centrifuge tubes were transferred to a safety cabinet, washed 3-4 times with PBS containing the double antibody, and the colon was transferred to 25ml of a 2mM solution of EDTA and digested in a freezer at 4 ℃ for 25 minutes. Transferring the digested colon into a 50ml centrifuge tube, adding 25ml PBS containing the double antibody, properly shaking the colon under 50 ℃, filtering the suspension by using a 70um cell filter sieve, transferring the colon into a new centrifuge tube containing 25ml PBS containing the double antibody, continuously shaking the colon under 50, filtering the suspension by using a 70um cell filter sieve, transferring the suspension after twice filtration into the same 50ml centrifuge tube, and centrifuging the suspension at the room temperature under 900rpm for 5 minutes. The supernatant was discarded, the pellet was resuspended in 2mL of Advanced-DMEM/F12, and the appropriate amount of suspension was counted. The number of crypts is preferably 5-10 per ul. An appropriate volume of the suspension was added to a 1.5ml centrifuge tube and centrifuged at 900rpm for 5 minutes at room temperature. The pellet was resuspended with matrigel pre-cooled on ice. The 96-well plates were pre-warmed in the incubator before 5ul of resuspension was plated per well. The inoculated plate is placed in an incubator for 10-15 minutes. 100ul of medium was added to each well, and then the medium was changed every 2-3 days.
The WNER medium consists of:
Figure BDA0002266407890000311
9. detecting the Effect of Compounds on organoid growth
According to the compound A1Preparing 50 μ M DMSO solution, adding organoid culture medium, taking pictures to observe morphology, sucking out culture medium on day 7, cooling on ice for 10min to melt matrigel, and collecting organoids by PBS centrifugation. mRNA is extracted according to the above operation to detect the expression of the stem cell-related gene.
10. Data analysis
The data are analyzed by using SPSS 13.0, the matching t test is adopted for comparison between two groups, the one-factor analysis of variance is adopted for comparison between multiple groups, and the difference of the test results is considered to be when P is less than 0.05. Data are expressed as mean ± standard deviation (mean ± SD). Histogram and line plot were made with GraphPad Prism 7.0 software.
Third, experimental results
1. Cell test compound activity table
TABLE B
Figure BDA0002266407890000321
The inhibition rate calculation formula is as follows:
Figure BDA0002266407890000331
as shown in table B, the experiments showed that most compounds of the present invention inhibited IL-23mRNA by more than 50% (better than or equivalent to mesalazine), and most compounds up-regulated cyclinD1mRNA, wherein 19 compounds were present in the compounds with up-regulation degree exceeding 1.5. In addition, there were 14 compounds with an inhibition rate of IL-23mRNA of more than 50% (mean) and an upregulation effect of cyclinD1mRNA of more than 1.5 (mean). In contrast, the positive control drug mesalazine only inhibited IL-23mRNA expression, and showed no up-regulation or even slight down-regulation of cyclinD1mRNA (mean 0.9).
2. Results of animal experiments
FIG. 1 shows Compound A1Therapeutic effect on mouse colitis model. Wherein A is C57 mice molded at DSS and administered orally simultaneously (10mg/kg and 20mg/kg of Compound A)1And mesalamine) during 50mg/kg (N ═ 5-7). B is a photograph of the colon of the mouse and a colon length statistic (N-5-7) of DSS molding for 7 days, 10 days after administration. C is the result of mRNA expression detection of IBD-associated protein in colon tissue of mice. D is the result of ELISA detection of the level of the mouse serum inflammatory factor. E is mouse colon specimen H&E staining results, showing crypt destruction and inflammatory infiltration in the colon. P<0.05，**P<0.01，***P<0.001。
The results show that Compound A1Can improve DSS-induced IBD mice intestinal mucosa destruction and inflammatory infiltration dose-dependently, promote the mice body weight recovery and colon length recovery, reduce the peripheral blood and intestinal TNF alpha, IL-1 beta and IL-23 levels and the mRNA expression level of the inflammatory cytokines in the intestinal tract, and improve the mRNA expression level of cyclin D1. The above data indicate Compound A1Has obvious improvement effect on the condition of the acute IBD of the mice.
FIG. 2 shows Compound A1The plasma levels of the mice varied within 24h after the oral route of administration at both concentrations of 3mg/kg and 20 mg/kg. The results show that mice are orally administered3mg/kg and 20mg/kg of Compound A1The peak concentration of the blood and the drug is respectively 175ng/mL and 700ng/mL, and the peak reaching time is about 1 hour; half-life of about 1.72 hours; the area under the curve was 410(h ng/mL) and 2363(h ng/mL), respectively, indicating a linear relationship between exposure and dose.
FIG. 3 shows Compound A1Promoting growth of mouse-derived intestinal organoids. Wherein A is the growth of mouse colon crypt isolates in Matrigel coated with WNER medium, Compound A1Was taken using a Zeiss 710 live cell imager at a concentration of 50 μ M, and the organoids were counted for size and budding rate and analyzed using Image J software (N ═ 5). B is after organoids were collected on day 7, RNA was extracted for intestinal stem cell marker gene detection (N ═ 5). P<0.05，**P<0.01，***P<0.001。
The results show that Compound A1Has obvious effect of promoting the growth of intestinal organoid of mouse.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Sequence listing
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gcacctcagg gaagagtctg 20
<210> 14
<211> 20
<212> DNA
<213> Artificial sequence (artificial sequence)
<400> 14
tcgctcaggg tcacaagaaa 20
<210> 15
<211> 21
<212> DNA
<213> Artificial sequence (artificial sequence)
<400> 15
catcagaggc aaggaggaaa a 21

Claims (10)

1. A compound shown as a formula I, an optical isomer or cis-trans isomer thereof, a pharmaceutically acceptable salt, a hydrate, a solvate, a prodrug or an active metabolite thereof,
Figure FDA0002266407880000011
wherein the content of the first and second substances,
Figure FDA0002266407880000012
represents a single bond or a double bond;
X1，X2，X3each independently selected from the group consisting of: c (R)1)2、NR1、CR1Or N;
and is
Figure FDA0002266407880000013
Is aromatic or non-aromatic;
g is selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, amino, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylamino, hydroxymethyl, C1-C6Haloalkyl, or-L1-M；
Q is selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, amino, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylamino, hydroxyMethyl, C1-C6Haloalkyl, or-L1-M；
When G is located at X3In the above, Q may be located at X1Or X2The above step (1);
when Q is at X3In the above, G may be located at X1Or X2The above step (1);
R1independently selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, amino, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylamino, hydroxymethyl, or C1-C6A haloalkyl group;
L1independently selected from the group consisting of: -NHC (═ O) -, -OC (═ O) -, -NHS (═ O) -, -OS (═ O) -, -NHSO2-, -C (═ O) NH-, -C (═ O) O-, -S (═ O) NH-, -OS (═ O) O-, or-SO2NH-；
M is independently selected from the group consisting of: c1-C6Alkyl radical, C1-C6Alkoxy, substituted or unsubstituted C3-C20Cycloalkyl, substituted or unsubstituted 3-20 heterocyclyl, substituted or unsubstituted C6-C14Aryl, substituted or unsubstituted 6-14 membered heteroaryl; and-L1-M may optionally be further substituted by one or more halogens, 3-12 membered heterocyclyl or C3-12Cycloalkyl is substituted;
the substitution is selected from one or more of the following groups: halogen, nitro, cyano, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylamino radical, C2-C6Alkenyl radical, C2-C6Haloalkenyl, C3-C6Cycloalkenyl radical, C2-C6Alkynyl, C2-C6Halogenated alkynyl, C3-C6Cycloalkyl alkynyl, C6-C14Aryl, 5-14 membered heterocyclyl, and said aryl, heteroaryl may optionally be further substituted with one or more substituents selected from the group consisting of: halogen, nitro, cyano, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Haloalkoxy, C1-C6Alkoxy radical, C1-C6An alkylamino group;
a is independently selected from the group consisting of: substituted or unsubstituted C3-12Cycloalkyl, substituted or unsubstituted 3-20 membered heterocyclyl, substituted or unsubstituted C6-C14Aryl, substituted or unsubstituted 6-14 membered heteroaryl; wherein the substitution is selected from one or more of the group consisting of: halogen, hydroxy, amino, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Alkylamino, hydroxymethyl or C1-C6A haloalkyl group;
k is independently selected from the group consisting of: r2-C(＝O)NH-、R2-C(＝O)O-、-C(＝O)NH-R2、-C(＝O)O-R2，R2Independently selected from the group consisting of: hydrogen, C1-C6Alkyl radical, C6-C14Aryl, 6-14 membered heteroaryl.
2. The compound of claim 1, an optical isomer or cis-trans isomer thereof, a pharmaceutically acceptable salt, a hydrate, a solvate, a prodrug or an active metabolite thereof having the structure shown in formula II below
Figure FDA0002266407880000021
Wherein the content of the first and second substances,
X1，X2，X3each independently selected from: CR1Or N;
R1independently selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, amino, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylamino, hydroxymethyl, halomethyl or-L1-M；
L1Independently selected from the group consisting of: -NHC (═ O) -, -OC (═ O) -, -NHS (═ O) -, -OS (═ O) -, -OO)-、-NHSO2-, -C (═ O) NH-, -C (═ O) O-, -S (═ O) NH-, -OS (═ O) O-, or-SO2NH-；
M is independently selected from the group consisting of: c2-C4Alkyl radical, C1-C6Alkoxy, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted tetrahydronaphthyl, substituted or unsubstituted 6-20 membered fused heterocycle, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted 5-6 membered heteroaryl; said M may be further substituted by one or more halogens, 3-12 membered heterocyclic groups or C3-12Cycloalkyl substituted; and the substitution is selected from one or more of the following groups: halogen, nitro, cyano, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkylamino radical, C2-C6Alkenyl radical, C2-C6Haloalkenyl, C3-C6Cycloalkenyl radical, C2-C6Alkynyl, C2-C6Haloalkynyl, C3-C6 cycloalkyl-C3-C6 alkynyl, phenyl, or 5-14 membered heterocyclyl, and the phenyl, 5-14 membered heterocyclyl may optionally be further substituted with one or more substituents selected from the group consisting of: halogen, nitro, cyano, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Haloalkoxy, C1-C6Alkoxy, or C1-C6An alkylamino group;
a is independently selected from the group consisting of: substituted or unsubstituted C3-12Cycloalkyl, substituted or unsubstituted C6-C14Aryl, or substituted or unsubstituted 6-14 membered heteroaryl; wherein the substitution is selected from one or more of the group consisting of: halogen, hydroxy, amino, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Alkylamino, hydroxymethyl or halomethyl;
k is independently selected from the group consisting of: -C (═ O) NH-R2、-C(＝O)O-R2，R2Independently selected from the group consisting of: hydrogen、C1-C6Alkyl radical, C6-C14Aryl or 6-14 membered heteroaryl.
3. The compound of claim 1, an optical isomer or cis-trans isomer thereof, a pharmaceutically acceptable salt, a hydrate, a solvate, a prodrug, or an active metabolite thereof, having the structure shown in formula III below,
Figure FDA0002266407880000031
wherein G, Q, A, K is as defined in claim 1.
4. The compound of claim 1, an optical isomer or cis-trans isomer thereof, a pharmaceutically acceptable salt, a hydrate, a solvate, a prodrug, or an active metabolite thereof, having the structure shown in formula IV below,
Figure FDA0002266407880000032
wherein G, Q, A, K is as defined in claim 1.
5. The compound of claim 1, an optical isomer or cis-trans isomer thereof, a pharmaceutically acceptable salt, a hydrate, a solvate, a prodrug, or an active metabolite thereof, having the structure shown in formula V below,
Figure FDA0002266407880000033
wherein G, Q, A, K is as defined in claim 1.
6. The compound, its optical isomer or cis-trans isomer, pharmaceutically acceptable salt, hydrate, solvate, prodrug or active metabolite thereof according to claim 1, which is selected from the group consisting of:
2- (2- (4- (cyclopropanecarboxamido) benzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (4- (cyclopropanecarboxamido) benzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid methyl ester;
2- (2- (4- (3-methylbutanamido) benzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (4-acetamidobenzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (4-benzoylaminobenzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (4- (cyclohexanecarboxamido) benzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (4- (cyclopropylcarbamoyl) benzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (4-chlorobenzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (4-fluorobenzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (4- (trifluoromethoxy) benzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (4- (tert-butyl) benzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (4- (trifluoromethyl) benzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (4- (oxazol-5-yl) benzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (3-chlorobenzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (2-chlorobenzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (2, 4-dichlorobenzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (6-chloronicotinyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (6-bromonicotinyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (4- (cyclopropanecarboxamido) -3-fluorobenzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (4- (cyclopropanecarboxamido) -2-fluorobenzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (2-chloro-4- (cyclopropanecarboxamido) benzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (3-chloro-4- (cyclopropanecarboxamido) benzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (3- (cyclopropanecarboxamido) -4-fluorobenzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
3- (2- (4- (cyclopropanecarboxamido) benzoyl) hydrazine-1-carbonyl) bicyclo [2.2.1] hept-5-ene-2-carboxylic acid;
2- (2- (4- (cyclopropanecarboxamido) benzoyl) hydrazine-1-carbonyl) benzoic acid;
3- (2- (4- (cyclopropanecarboxamido) benzoyl) hydrazine-1-carbonyl) bicyclo [2.2.1] heptane-2-carboxylic acid;
2- (2- (4- (cyclopropanecarboxamido) benzoyl) hydrazine-1-carbonyl) cyclopropane-1-carboxylic acid;
4, 5-dibromo-2- (2- (4- (cyclopropanecarboxamido) benzoyl) hydrazine-1-carbonyl) cyclohexane-1-carboxylic acid;
2- (2- (4- (cyclopropanecarboxamido) benzoyl) hydrazine-1-carbonyl) -3, 6-difluorobenzoic acid;
2- (2- (4- (cyclopropanecarboxamido) benzoyl) hydrazine-1-carbonyl) -3, 6-difluorobenzoic acid;
2- (2- (4-fluorobenzoyl) hydrazine-1-carbonyl) benzoic acid;
3- (2- (4-fluorobenzoyl) hydrazine-1-carbonyl) bicyclo [2.2.1] heptane-2-carboxylic acid;
3- (2- (4-chlorobenzoyl) hydrazine-1-carbonyl) bicyclo [2.2.1] heptane-2-carboxylic acid;
3- (2- (3-chlorobenzoyl) hydrazine-1-carbonyl) bicyclo [2.2.1] heptane-2-carboxylic acid;
3- (2- (2-chlorobenzoyl) hydrazine-1-carbonyl) bicyclo [2.2.1] heptane-2-carboxylic acid;
3- (2- (2, 4-dichlorobenzoyl) hydrazine-1-carbonyl) bicyclo [2.2.1] heptane-2-carboxylic acid;
3- (2- (4- (cyclopropanecarboxamido) benzoyl) hydrazine-1-carbonyl) -2-naphthoic acid.
7. A process for preparing a compound of formula I, an optical isomer or a cis-trans isomer thereof, a pharmaceutically acceptable salt, a hydrate, a solvate, a prodrug or an active metabolite thereof, comprising the steps of:
Figure FDA0002266407880000051
in a first inert solvent, a2Reacting the compound with a compound b, optionally further reacting to obtain a compound I;
wherein, X1，X2，X3G, Q, A, K are as defined in claim 1.
8. A pharmaceutical composition comprising a compound of any one of claims 1-6, an optical isomer or a cis-trans isomer, a pharmaceutically acceptable salt, a hydrate, a solvate, a prodrug, or an active metabolite thereof; and a pharmaceutically acceptable carrier.
9. Use of a compound according to any one of claims 1 to 6, an optical isomer or cis-trans isomer, a pharmaceutically acceptable salt, hydrate, solvate, prodrug or active metabolite thereof, or a pharmaceutical composition according to claim 8 for the manufacture of a medicament and a pharmaceutical composition for the treatment or prevention of inflammatory bowel disease.
10. A method of inhibiting IL-23 and up-regulating cyclinD1 in vitro comprising the steps of: contacting a compound of claim 1, an optical isomer or cis-trans isomer, a pharmaceutically acceptable salt, hydrate, solvate, prodrug or active metabolite thereof with a somatic cell, thereby inhibiting IL-23 and upregulating cyclinD 1.
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