CN117486813A - N-disubstituted phenyl acrylamide compound, and pharmaceutical composition and application thereof - Google Patents

N-disubstituted phenyl acrylamide compound, and pharmaceutical composition and application thereof Download PDF

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CN117486813A
CN117486813A CN202311332299.6A CN202311332299A CN117486813A CN 117486813 A CN117486813 A CN 117486813A CN 202311332299 A CN202311332299 A CN 202311332299A CN 117486813 A CN117486813 A CN 117486813A
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alkyl
pharmaceutically acceptable
compound
cycloalkyl
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唐春雷
丁若洋
桂豫乐
范为正
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Jiangnan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D401/10—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 aromatic rings

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Abstract

The invention discloses an N-disubstituted phenyl acrylamide compound, a pharmaceutical composition and application thereof, belonging to the field of chemical medicine, in particular. The invention provides a compound with a structure shown in a general formula (I) or a salt thereof, which can selectively inhibit Janus kinase 3 (JAK 3) and has good in-vitro inhibition activity, thereby being used as a therapeutic agent for related diseases such as atopic dermatitis, rheumatoid arthritis, alopecia areata and the like.

Description

N-disubstituted phenyl acrylamide compound, and pharmaceutical composition and application thereof
Technical Field
The invention belongs to the field of chemical medicines, and particularly relates to an N-disubstituted phenyl acrylamide compound, a pharmaceutical composition thereof and application thereof.
Background
Atopic dermatitis (Atopic Dermatitis, AD), rheumatoid arthritis (Rheumatoid Arthritis, RA) and Alopecia Areata (AA) are three chronic diseases with immunopathological characteristics. These diseases have a high incidence worldwide, and have a serious influence on the quality of life of patients. Drug development for the treatment of these diseases has long been a concern in the medical and pharmaceutical industries.
Atopic dermatitis: atopic dermatitis is a common chronic skin condition that manifests as dry skin, itching and redness. The etiology is not completely clear, but is related to various factors such as genetic factors, environmental factors, and immune response abnormality. Currently, the primary means of treating atopic dermatitis include corticosteroids, antihistamines, immunosuppressants, biologies, and the like. However, these drugs may cause side effects during use, for example, long-term use of corticosteroids may cause skin atrophy, diabetes mellitus, etc.; antihistamines may trigger somnolence; immunosuppressants may increase the risk of infection.
Rheumatoid arthritis: rheumatoid arthritis is an immune-mediated chronic inflammatory disease, with arthritis, bone destruction and disability as the main manifestations. The etiology is not completely defined but involves genetic, environmental and immunological factors. The medicine for treating rheumatoid arthritis mainly comprises nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, disease course control antirheumatic drugs (DMARDs), biological agents and the like. However, these drugs may produce such effects as gastrointestinal irritation, liver and kidney damage, immunosuppression, etc. during use.
Alopecia areata: alopecia areata is a common autoimmune disease that manifests itself as local or systemic alopecia. The etiology is not completely defined, but is thought to be related to genetic, environmental, psychological stress, immune abnormalities and other factors. The medicine for treating alopecia areata mainly comprises corticosteroid, immunosuppressant, biological agent, topical medicine, etc. However, these drugs may also have side effects during use, such as corticosteroids which may lead to skin atrophy, hypertension, etc. complications; immunosuppressants may increase the risk of infection.
In view of the limitations of the existing medicines for treating diseases such as atopic dermatitis, rheumatoid arthritis, alopecia areata and the like, the development of safer and more effective treatment methods is urgently needed. The development of new therapeutic agents requires a deep understanding of the pathogenesis of these diseases in an effort to find new targets and drug design strategies.
The Janus kinase 3 (JAK) -mediated cytokine pathway plays an important role in the pathogenesis of atopic dermatitis, rheumatoid arthritis, alopecia areata, and the like. Based on these new findings, attempts have been made to design and screen therapeutic agents for specific targets. However, drug development against these targets still faces many challenges, such as selecting appropriate compounds, assessing the bioactivity and safety of the drug, solving bioavailability and pharmacokinetic problems of the drug, and the like.
Disclosure of Invention
Problems to be solved by the invention
In order to solve the technical problems, the inventor discovers a new N-disubstituted phenyl acrylamide compound which has good metabolic stability and excellent skin penetration property under the condition of ensuring pharmacodynamic performance.
The invention also provides a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt thereof.
Furthermore, the present invention provides the use of the above compound or a pharmaceutically acceptable salt thereof.
Solution for solving the problem
The invention provides the following scheme:
the present invention provides, first of all, a compound having the general formula (I) or a pharmaceutically acceptable salt thereof,
wherein:
R 1 selected from H, C1-6 alkyl;
x is CH 2 Or NH;
a is a saturated heterocyclic group or an aromatic hybrid group selected from the group consisting of: substituted or unsubstituted pyridyl, pyrimidinyl, Wherein the substituents on the pyridyl OR pyrimidinyl groups are selected from halogen, CN, OR c 、NO 2 、NH 2 C1-6 alkyl, C3-8 cycloalkyl;
R 2 selected from-SO 2 -R d 、-COR e ；
R a 、R b Each independently selected from H, C1-6 alkyl, C3-8 cycloalkyl;
R c selected from H, C1-6 alkyl, C3-8 cycloalkyl, acyl-COR c '；R c ' is C1-6 alkyl;
R d selected from C1-6 alkyl, C3-8 cycloalkyl;
R e selected from C1-6 alkyl, C3-8 cycloalkyl, C1-6 alkoxy, amino-NR e 'R e ”；R e '、R e "each independently selected from H, C1-6 alkyl, C3-8 cycloalkyl.
In one embodiment of the invention, a is further selected from:
wherein R is 3a Selected from C1-6 alkyl, C3-8 cycloalkyl; r is R 3b Selected from C1-6 alkyl, C3-8 cycloalkyl, C1-6 alkoxy, amino-NR 3b 'R 3b ”；R 3b '、R 3b "each independently selected from H, C1-6 alkyl, C3-8 cycloalkyl; r is R 3c 、R 3d 、R 3e Selected from H, OR 4 R4 is H, C1-6 alkyl, C3-8 cycloalkyl, acyl-COR 4 '；R 4 ' is C1-6 alkyl.
In one embodiment of the invention, the compound is selected from:
in one embodiment of the present invention, the pharmaceutically acceptable salt is an inorganic salt or an organic salt, and the inorganic salt includes hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, bisulfate, nitrate, phosphate, and acid phosphate; the organic salt is selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, p-toluenesulfonate, ascorbate.
In one embodiment of the invention, the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, sulfate, succinate or mesylate salts.
The invention also provides a pharmaceutical composition comprising a compound according to the above or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient, diluent or carrier.
The invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof in the preparation of a JAK inhibitor.
The invention also provides application of the compound or pharmaceutically acceptable salt thereof in preparing medicines for treating JAK mediated diseases including but not limited to atopic dermatitis, rheumatoid arthritis, alopecia areata, ulcerative colitis, crohn's disease, vitiligo, psoriasis, lymphoma, solid tumors and the like.
ADVANTAGEOUS EFFECTS OF INVENTION
The invention provides a compound of a general formula (I), which has remarkable pharmacodynamic performance and high metabolic stability in treating related diseases such as atopic dermatitis, rheumatoid arthritis, alopecia areata and the like. Furthermore, the compounds of the present invention or pharmaceutically acceptable salts thereof are useful for the preparation of medicaments for the treatment of these diseases. Surprisingly, these compounds also have excellent skin permeability and are particularly suitable for the preparation of medicaments for the treatment of atopic dermatitis, rheumatoid arthritis, alopecia areata, ulcerative colitis, crohn's disease, vitiligo, psoriasis, lymphomas, solid tumors and the like.
In certain embodiments, the compounds of the present invention are particularly useful in the manufacture of a medicament for the treatment of diseases associated with atopic dermatitis, rheumatoid arthritis, alopecia areata, and the like. The application can improve the curative effect of the medicine and reduce the damage of the medicine to normal tissues, thereby providing better treatment selection and life quality for patients.
In summary, the compounds of formula (I) according to the invention have the following advantages:
1. the traditional Chinese medicine composition has excellent pharmacodynamic performance and high metabolic stability in the aspect of treating related diseases such as atopic dermatitis, rheumatoid arthritis, alopecia areata and the like, and becomes a potential effective treatment scheme.
2. The compound disclosed by the invention can be widely applied to the preparation of medicines for treating atopic dermatitis, rheumatoid arthritis, alopecia areata, ulcerative colitis, crohn disease, vitiligo, psoriasis, lymphoma, solid tumors and the like due to excellent blood brain barrier permeability.
3. In certain embodiments, the compounds of the present invention are useful as medicaments for treating diseases associated with atopic dermatitis, rheumatoid arthritis, alopecia areata, etc., improving the efficacy of the medicaments, reducing damage to normal tissues, and providing better treatment options and quality of life for patients.
Therefore, the invention provides a novel and effective therapeutic agent with potential wide application prospect for treating related diseases such as atopic dermatitis, rheumatoid arthritis, alopecia areata and the like.
Detailed Description
The technical scheme of the present invention will be described in detail with reference to examples.
In the present invention C 1-6 Alkyl refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms, examples of which include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, t-butyl, and the like.
C 1-6 Alkoxy refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms connected by an oxygen bridge, examples of which include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, and the like.
C 3-6 Cycloalkyloxy means a monocyclic or polycyclic hydrocarbon group or the like having 3 to 6 ring carbon atoms connected by an oxygen bridge.
Indicating the attachment of substituents therefrom.
The term "disease" as used herein refers to any condition or disorder that impairs or interferes with the normal function of cells, organs or tissues.
The term "inhibitor" as used herein refers to a compound or agent that has the ability to inhibit a biological function of a targeted protein or polypeptide, for example by inhibiting the activity or expression of the protein or polypeptide.
The term "antineoplastic agent" as used herein refers to any agent useful in the treatment of neoplastic disorders.
The term "pharmaceutically acceptable" as used herein refers to those compositions which are, within the scope of sound medicine, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio. By "pharmaceutically acceptable salt" is meant any non-toxic salt that, upon administration to a recipient, is capable of providing a compound or prodrug of a compound of the invention, either directly or indirectly.
The term "effective amount" or "therapeutically effective amount" as used herein means an amount of a compound or pharmaceutical composition described herein sufficient to achieve the intended use, including, but not limited to, treatment of a disease. The therapeutically effective amount may vary depending on the intended use, such as in vitro or in vivo, the condition and severity of the disease, the age, weight, or mode of administration of the subject, and the like. The specific dosage will depend, for example, upon the particular compound chosen, the subject species and their age/existing health or risk of health, the route of administration, the severity of the disease, the administration in combination with other agents, the time of administration, the tissue to which it is administered, and the means of administration, etc.
In the present invention, "administering" or "administering" a compound to an individual refers to providing a compound of the present invention to an individual in need of treatment.
The compounds of the present invention may contain one or more asymmetric centers and thus appear as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of these compounds are expressly included in the present invention. The compounds of the invention may also exhibit multiple tautomeric forms, in which case the invention expressly includes all tautomeric forms of the compounds described herein. All such isomeric forms of such compounds are included in the present invention. All crystalline forms of the compounds described herein are expressly included in the present invention.
The invention provides a novel therapeutic agent for overcoming the defects of the existing medicaments for treating diseases such as atopic dermatitis, rheumatoid arthritis, alopecia areata and the like. The therapeutic agent can effectively regulate the immune response and inflammatory response of a patient by acting on specific targets, thereby achieving the purposes of relieving symptoms and delaying disease progression. Meanwhile, the therapeutic agent has lower toxicity and side effect, and can bring better treatment experience and life quality for patients.
In the research process of the invention, a plurality of cytokines and signal paths are studied in depth, and a novel compound is screened out through strict in vitro and in vivo experiments, and can regulate the immune response and inflammatory response of a patient by acting on key targets, thereby effectively improving the symptoms of diseases such as atopic dermatitis, rheumatoid arthritis, alopecia areata and the like. Meanwhile, the compound has lower toxicity and side effect in the treatment process, and provides safer and more effective treatment options for patients.
To further optimize the pharmaceutical properties of the compounds, structural modifications were made to them, by synthesizing a number of derivatives, whose biological activity and pharmacokinetic properties were assessed in comparison. Finally, an optimized therapeutic agent is identified that has significantly improved bioavailability, stability and safety.
In animal models and clinical trials, the therapeutic agent shows remarkable curative effects, can effectively relieve symptoms of diseases such as atopic dermatitis, rheumatoid arthritis, alopecia areata and the like, delays disease progression, and has lower toxicity and side effects. Compared with the existing treatment methods, the therapeutic agent has higher curative effect and better safety, and brings better treatment experience and life quality for patients.
In summary, the present invention provides a novel therapeutic agent for treating atopic dermatitis, rheumatoid arthritis, alopecia areata and other related diseases. The therapeutic agent regulates the immune response and inflammatory response of the patient by acting on specific targets, thereby providing a safer and more effective therapeutic option for the patient. In the future, the therapeutic agent is expected to become an important breakthrough and a new therapeutic scheme in the field of treatment of diseases such as atopic dermatitis, rheumatoid arthritis, alopecia areata and the like.
< Compound or pharmaceutically acceptable salt thereof >
The present invention provides a novel N-disubstituted phenyl acrylamide compound or pharmaceutically acceptable salt thereof which inhibits JAK3 activity, selected from the following structures:
it will be appreciated that certain compounds of formula (I) or pharmaceutically acceptable salts thereof may be in the form of a solvent compound as well as in the form of a non-solvate, such as, for example, a hydrated form. It is to be understood that the present invention encompasses all such solvent compound forms possessing JAK3 inhibitory activity.
The synthesis of the compounds of the general formula (I) according to the invention can be carried out by the skilled worker in synthetic chemistry. All documents mentioned in the background of the present text are incorporated herein by reference in their entirety. The preparation method is described in detail in examples.
< pharmaceutical composition >
The invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the invention and a pharmaceutically acceptable carrier, excipient or diluent.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be formulated as solid formulations for oral administration, including, but not limited to, capsules, tablets, pills, powders, granules, and the like. In these solid dosage forms, the compounds of formula (I) according to the invention are mixed as active ingredient with at least one conventional inert excipient (or carrier), for example with sodium citrate or dicalcium phosphate. Or with the following components: (1) Fillers or solubilisers, for example starch, lactose, sucrose, glucose, mannitol, silicic acid and the like; (2) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, acacia, and the like; (3) humectants, for example, glycerin, etc.; (4) Disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, and the like; (5) a slow solvent such as paraffin wax or the like; (6) absorption accelerators such as quaternary ammonium compounds and the like; (7) Wetting agents such as cetyl alcohol and glycerol monostearate, and the like; (8) adsorbents such as kaolin and the like; (9) Lubricants, for example, talc, calcium stearate, solid polyethylene glycol, sodium lauryl sulfate, and the like, or mixtures thereof. Buffers may also be included in capsules, tablets, pills.
The solid dosage forms, such as tablets, dragees, capsules, pills and granules, may be provided with coatings and shell materials such as enteric coatings and other materials known in the art in the form of crystalline coatings or microencapsulations. They may contain opacifying agents and the release of the active ingredient in such a composition may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active ingredient may also be in the form of microcapsules with one or more of the above excipients, if desired.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be formulated into liquid dosage forms for oral administration, including, but not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, tinctures, and the like. In addition to the compounds of formula (I) or pharmaceutically acceptable salts thereof as active ingredients, liquid dosage forms may contain inert diluents commonly used in the art such as water and 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, olive, castor, sesame oils and the like or mixtures of these substances and the like. In addition to these inert diluents, the liquid dosage forms of the present invention can also include conventional adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents and the like.
Such suspending agents include, for example, ethoxylated stearyl alcohol, polyoxyethylene sorbitol, and sorbitan, microcrystalline cellulose, agar-agar, and the like, or mixtures of these.
The compounds of the present invention and pharmaceutically acceptable salts thereof may be formulated in dosage forms for parenteral injection, including, but not limited to, physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions and dispersions. Suitable carriers, diluents, solvents, excipients include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be formulated into dosage forms for topical administration, including, for example, ointments, powders, suppositories, drops, sprays, inhalants and the like. The compounds of the general formula (I) according to the invention or their pharmaceutically acceptable salts as active ingredients are mixed under sterile conditions with physiologically acceptable carriers and optionally with preservatives, buffers and, if appropriate, propellants.
The compound of formula (I) or a pharmaceutically acceptable salt thereof according to the invention will be administered to a mammal in a unit dose in the range of 0.01-2000mg/kg, in particular 2.5-1000mg/kg, in particular 5-500mg/kg, and this should provide an effective dose. However, the daily dose will necessarily vary depending on the host treated, the particular route of administration, and the severity of the condition being treated. Thus, the optimal dosage may be determined by the practitioner treating any particular patient.
< use >
The present invention provides the use of a compound of formula (I) as defined above, and pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment of a disease mediated by JAK3 in a mammal, particularly a human.
Types of diseases that may be susceptible to treatment affected by the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof include, but are not limited to: atopic dermatitis, rheumatoid arthritis, alopecia areata, ulcerative colitis, crohn's disease, vitiligo, psoriasis, lymphoma, and solid tumors.
The treatment of the diseases according to the invention, the compounds of formula (I) or pharmaceutically acceptable salts thereof, will be administered to a mammal, more particularly a human.
The JAK inhibitory activity treatment of the present invention may be used as a sole therapy or in addition to the compounds of the present invention, may be administered in combination with other pharmaceutically acceptable therapeutic agents, such combination therapy being accomplished by the simultaneous, sequential or separate use of the various components of the treatment. The individual components to be combined may be administered simultaneously or sequentially, in a single formulation or in different formulations. The combinations include not only combinations of one or more other active agents of the compounds of the present invention, but also combinations of two or more other active agents of the compounds of the present invention.
The following examples illustrate, but do not limit, the synthesis of compounds of formula (I). The temperatures are in degrees celsius. All the evaporation was carried out under reduced pressure, if not otherwise stated. Reagents were purchased from commercial suppliers and used without further purification, if not otherwise indicated. The structure of the end products, intermediates and starting materials is confirmed by standard analytical methods, such as elemental analysis, spectroscopic characterization, such as MS, NMR. The abbreviations used are those conventional in the art, and some of the intermediates are purchased from the company, forward biotechnology, inc.
Intermediate 1: 2-chloroquinoxaline (2)
2-chloroquinoxaline(2)
The steps are as follows: 2-Hydroxyquinoxaline (2.0 g,13.7 mmol) was suspended in 1, 2-dichloroethane (20 ml) at room temperature, two drops of DMF were added, followed by SOCl2 (5.0 g,42.0 mmol) and stirred at reflux for 6h. The reaction mixture was concentrated under reduced pressure, and petroleum ether (20 ml) was added with thionyl chloride 3 times. Petroleum ether is then added for dissolution, filtration and the filtrate is concentrated in vacuo to yield 2.0g of yellow solid with a yield of 88.7%. It was used in the next reaction without further purification. 1 HNMR(400MHz,DMSO-d 6 )δ:9.02(s,1H),8.15-8.18(m,1H),8.05-8.08(m,1H),7.90-7.97(m,2H)。
Intermediate 2: 3-hydroxymethyl-5-nitrobenzoic acid (4)
(3-(hydroxymethyl)-5-nitrophenyl)boronic acid(4)
The steps are as follows: 3-carboxy-5-nitrobenzoic acid (2.1 g,10.0 mmol) was dissolved in 40mL of THF, cooled to 0deg.C, isobutyl chloroformate (1.50 g,11.0 mmol) was added dropwise, stirred at 0deg.C for 1h, the solid was removed by filtration, 20mL of water was added to the filtrate, sodium borohydride (1.1 g,30.0 mmol) was added portionwise at 0deg.C, and stirred at room temperature for 2h. The reaction solution was adjusted to pH 3-4 by adding 1N diluted hydrochloric acid, extracted with ethyl acetate (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1.90g of a tan solid in 96.5% yield. It was used in the next reaction without further purification. ESI-MS (m/z): 198.0[ M+H ]] + 。
Intermediate 3: (3-nitro-5- (quinoxalin-2-yl) phenyl) methanol (5)
(3-nitro-5-(quinoxalin-2-yl)phenyl)methanol(5)
The steps are as follows: under nitrogen, 2 (2.2 g,13.4 mmol), 4 (2.6 g,13.4 mmol), sodium carbonate (5.7 g,53.6 mmol) and PdCl were combined 2 dppf (196 mg,0.02 eq) was added to 1, 4-dioxane (20 mL) and water (4 mL) and reacted at 80℃for 3h. After cooling the reaction to room temperature, pouring the reaction mixture into water (30 ml), pulping, filtering, washing with water and drying to obtain 3.4g of gray solid, wherein the yield is 90.2%. It was used in the next reaction without further purification.
Intermediate 4:2- (3- (chloromethyl) -5-nitrophenyl) quinoxaline (6)
2-(3-(chloromethyl)-5-nitrophenyl)quinoxaline(6)
Step 5 (3.2 g,11.4 mmol) was dispersed in DCE (40 mL), a catalytic amount of DMF was added, followed by thionyl chloride (4.1 g,34.1 mmol) and the reaction was heated to reflux for 4h. The solvent was removed by concentrating under reduced pressure and petroleum ether (40 ml x 3) was added with thionyl chloride 3 times to give 3.0g of grey solid in 87.8% yield. It was used in the next reaction without further purification. 1 HNMR(400MHz,DMSO-d 6 )δ:9.72(s,1H),9.00(s,1H),8.74(s,1H),8.37(s,1H),8.17-8.25(m,2H),7.89-7.97(m,2H),4.78(s,2H)。
Intermediate 5:2- (3- ((4- (methylsulfonyl) piperazin-1-yl) methyl) -5-nitrophenyl) quinoxaline (7)
2-(3-((4-(methylsulfonyl)piperazin-1-yl)methyl)-5-nitrophenyl)quinoxaline(7)
Step 6 (600 mg,2.0 mmol), N-methanesulfonylpiperazine (345 mg,2.1 mmol), potassium carbonate (336 mg,2.4 mmol) were suspended in acetonitrile (15 mL), a catalytic amount of potassium iodide was added, and heated under reflux overnight. After cooling to room temperature, the reaction solution was poured into water (20 mL), and the solid was filtered and dried to give 688mg of a yellow solid in 80.5% yield. It was used in the next reaction without further purification. .
Intermediate 6:3- ((4- (methylsulfonyl) piperazin-1-yl) methyl) -5- (quinoxalin-2-yl) aniline (8)
3-((4-(methylsulfonyl)piperazin-1-yl)methyl)-5-(quinoxalin-2-yl)aniline(8)
Step 7 (427 mg,1.0 mmol), reduced iron powder (279 mg,5.0 mmol), ammonium chloride (374 mg,7.0 eq) were suspended in a mixed solvent of ethanol (12 ml) and water (4 ml). Reflux heating for 2h, filtering while hot, washing filter cake with ethanol, concentrating the filtrate under reduced pressure, adding sodium hydroxide to adjust pH to 7-8, extracting with mixed solvent (20 ml) with volume ratio of dichloromethane to methanol of 10:1, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain yellow solid 350mg, and directly using in the next reaction without further purification in 88.0% yield.
Intermediate 7: 3-chloro-N- (3- ((4- (methylsulfonyl) piperazin-1-yl) methyl) -5- (quinoxalin-2-yl) phenyl) propanamide (9)
3-chloro-N-(3-((4-(methylsulfonyl)piperazin-1-yl)methyl)-5-(quinoxalin-2-yl)phenyl)propana mide(9)
Step 8 (298 mg,0.75 mmol) was suspended in THF (10 mL) and water (1 mL), cooled to 0deg.C, 3-chloropropionyl chloride (114 mg,0.9 mmol) in THF (2 mL) was slowly added dropwise, reacted at room temperature for 1h, suction filtered, washed with dichloromethane, and the filter cake was dried to give 301mg of yellow solid in 82.2% yield. The reaction mixture was used in the next reaction without further purification.
Example 1: n- (3- ((4- (methylsulfonyl) piperazin-1-yl) methyl) -5- (quinoxalin-2-yl) phenyl) acrylamide (10)
N-(3-((4-(methylsulfonyl)piperazin-1-yl)methyl)-5-(quinoxalin-2-yl)phenyl)acrylamide(10)
Step d1-8 (244 mg,0.5 mmol) was suspended in acetonitrile (15 mL), triethylamine (152 mg,1.5 mmol) was added, and the mixture was reacted at 80℃for 8 hours. The reaction solution was concentrated in vacuo to remove acetonitrile, water (15 mL) and a mixed solvent (15 mL) having a volume ratio of dichloromethane to methanol of 10:1 were added, extracted, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give 148mg of a yellow solid powder in 65.6% yield. ESI-MS (m/z): 452.2[ M+H ]] + . 1 HNMR(400MHz,DMSO-d 6 )δ:10.50(s,1H),9.51(s,1H),8.53(s,1H),8.14-8.18(m,2H),7.97(s,2H),7.85-7.94(m,2H),6.52-6.58(q,1H),6.34-6.38(dd,1H),5.82-5.85(dd,1H),3.67(s,2H),3.17-3.20(m,4H),2.92(s,3H),2.56-2.59(m,4H).
Examples 2-5 (see Table 1) were synthesized in a similar manner to the basic operation of example 1, to give the desired products.
TABLE 1
Application example
Measurement 1: lance screening assay for JAK3 inhibitory Activity
A time-resolved fluorescence resonance energy transfer (TR-FRET) detection method based on europium labels is adopted, and the method is realized by adopting a polypeptide of fluorescent label (Ulight-labeled) and an anti-phosphoric acid antibody marked by europium chelate. When the protein substrate is phosphorylated by JAK, the phosphorylation site of the substrate will be recognized by europium-labeled anti-phospho antibodies. When the europium chelate is excited at 320nm or 340nm, energy is transferred to the Ulight fluorescent acceptor, causing it to be excited and emit fluorescence at 665nm, the intensity of the luminescence being proportional to the Ulight peptide phosphorylation level. And reading out the fluorescence value on an enzyme-labeled instrument, and further quantitatively calculating the inhibition rate of the JAK small molecule inhibitor on the JAK under the concentration of the inhibitor according to the specific fluorescence value, a DMSO control group and an enzyme-free control group. 40L of test compound solution diluted to 0.1mM (JAK 1, JAK2JAK3, TYK2, respectively) and 0.1mM &0.03mM of reference compound (tofacitinib) were taken into an Echo 384-well PP plate, and the dilution transfer of the compound was performed by Echo from Labcyte Co., 3-fold dilution, for a total of 8 dose points, of 100nL of compound per reaction well. The highest concentration of test compound in the kinase reaction solution was 1000M. The highest concentration of the reference compound (tofacitinib) in the kinase reaction was 1000nM. The reference compound (tofacitinib) was at most 500nM in the kinase reaction.
Measurement 2: enzymatic reaction
Compound test concentration was 500nM, single concentration, multiplex well monitoring.
(1) Each compound was formulated with 100% DMSO as a 50 μm solution of complex DMSO.
(2) Into 1x kinase buffer (50mM HEPES pH7.5,10mM MgCl) 2 2mM DTT,0.01% Tween-20,0.01%10% BSA) was added to the kinase to be tested to prepare a kinase solution having a kinase concentration of 1 nM. Each well was replaced by adding 10. Mu.L of kinase solution and 10. Mu.L of kinase buffer to the enzyme-free control well.
(3) A2 x substrate solution was prepared by adding Ulight substrate and ATP to 1x kinase buffer.
(4) mu.L of 2 Xsubstrate solution was added to each well of the assay plate, and the kinase reaction was started and incubated at 25℃for 30 minutes.
(5) A 2-fold detection solution was prepared in the antibody dilution buffer at the final concentration.
(6) Add 20. Mu.L of assay solution to each well of the assay plate and stop the reaction. Incubate at 25℃for 60 min.
Data analysis:
(1) The Lance signal values were obtained from the Envision microplate reader software.
(2) The ratio of Lance signal 665nm/Lance signal 615nm was calculated, and the value of the percent inhibition was calculated from the Lance signal ratio. And calculating data by using a formula.
(3) The data shows that in MS Excel, log of concentration was used as X-axis and percent inhibition was Y-axis, fitted to the dose-response curve using XLFit Excel plug-in 5.4.0.8 version. Thus, IC50 values of the compounds were obtained.
The experimental results of the examples of the present invention and the reference compound (tofacitinib) and the comparative compound are shown in table 1.
The structure of the comparative compounds is shown below:
IC for measuring the Activity of each Compound in Table 1 50 (nM) data
Compounds of formula (I) JAK3 IC 50 (nM)
Example 1 0.9
Example 2 1.0
Example 3 1.9
Example 4 5.2
Example 5 6.7
Tofacitinib (reference example) 1.2
Comparative compounds 70.9
From the kinase activity data of the compounds of examples 1 to 5, it is clear that the compounds of general formula (I) have higher JAK3 inhibitory activity, and thus the present invention has potential to be a therapeutic agent for JAK 3-related diseases.
The above examples are not intended to limit the scope of the invention nor the order of execution of the steps described. The present invention is obviously modified by a person skilled in the art in combination with the prior common general knowledge, and falls within the scope of protection defined by the claims of the present invention.

Claims (10)

1. A compound having the general formula (I) or a pharmaceutically acceptable salt thereof,
wherein:
R 1 selected from H, C1-6 alkyl;
x is CH 2 Or NH;
a is a saturated heterocyclic group or an aromatic hybrid group selected from the group consisting of: substituted or unsubstituted pyridyl, pyrimidinyl, Wherein the substituents on the pyridyl OR pyrimidinyl groups are selected from halogen, CN, OR c 、NO 2 、NH 2 C1-6 alkyl, C3-8 cycloalkyl;
R 2 selected from-SO 2 -R d 、-COR e ；
R a 、R b Each independently selected from H, C1-6 alkyl, C3-8 cycloalkyl;
R c selected from H, C1-6 alkyl, C3-8 cycloalkyl, acyl-COR c '；R c ' is C1-6 alkyl;
R d selected from C1-6 alkyl, C3-8 cycloalkyl;
R e selected from C1-6 alkyl, C3-8 cycloalkyl, C1-6 alkoxy, amino-NR e 'R e ”；R e '、R e "each independently selected from H, C1-6 alkyl, C3-8 cycloalkyl.
2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein a in formula (I) is selected from:
wherein R is 3a Selected from C1-6 alkyl, C3-8 cycloalkyl; r is R 3b Selected from C1-6 alkyl, C3-8 cycloalkyl, C1-6 alkoxy, amino-NR 3b 'R 3b ”；R 3b '、R 3b "each independently selected from H, C1-6 alkyl, C3-8 cycloalkyl; r is R 3c 、R 3d 、R 3e Selected from H, OR 4 R4 is H, C1-6 alkyl, C3-8 cycloalkyl, acyl-COR 4 '；R 4 ' is C1-6 alkyl.
3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
4. a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is an inorganic or organic salt; wherein the inorganic salt comprises hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, bisulfate, nitrate, phosphate and acid phosphate; the organic salt is selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, p-toluenesulfonate, ascorbate.
5. A pharmaceutical composition comprising a compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable pharmaceutical excipient.
6. The pharmaceutical composition according to claim 5, wherein the optionally pharmaceutically acceptable pharmaceutical excipients comprise excipients, diluents.
7. The pharmaceutical composition of claim 5, further comprising a pharmaceutically acceptable carrier.
8. Use of a compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, in the preparation of a JAK inhibitor.
9. Use of a compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a JAK mediated disease.
10. The use according to claim 9, wherein the disease is dermatitis, rheumatoid arthritis, alopecia areata, ulcerative colitis, crohn's disease, vitiligo, psoriasis, lymphoma, or solid tumors.
CN202311332299.6A 2023-10-16 2023-10-16 N-disubstituted phenyl acrylamide compound, and pharmaceutical composition and application thereof Pending CN117486813A (en)

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