CN109896998B - 3, 4-dihydroisoquinoline sulfonamide compound and application thereof - Google Patents
3, 4-dihydroisoquinoline sulfonamide compound and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicine, and relates to a 3, 4-dihydroisoquinoline sulfonamide compound with a structural formula (I) or a structural formula (II) and application thereof,
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a 3, 4-dihydroisoquinoline sulfonamide compound and application thereof; more particularly, the compound can be used as a ROR gamma t agonist for preventing, treating or improving tumor immunity related diseases mediated by Th17 cells.
Background
The prior art discloses that retinoic acid receptor-Related Orphan Receptors (RORs) belong to a member of the ligand-dependent transcription factor nuclear receptor superfamily. ROR γ t is one of the major members of the RORs subfamily, is distributed mainly in the thymus, and is expressed in key cells in the immune system; ROR gamma t is an important transcription factor for regulating the development and the function of CD4 positive Th17 and CD8 positive Tc17 lymphocytes, and a key regulator for regulating the differentiation of Th17 cells and producing inflammatory cytokine interleukin 17(IL-17), and researches prove that Thl7 cells have a key pathogenic effect in infection, inflammation, autoimmune diseases and graft-versus-host diseases. Recent studies have found that Thl7 cells are also present in tumor microenvironment and have a certain relation with the occurrence of inflammation-related tumors, about 15% of tumor infiltrating lymphocytes express ROR γ t, and ROR γ t agonists can enhance the level of IL-17 and other cytokines secreted by lymphocytes, thereby improving the cytotoxicity of the lymphocytes; these agonists also improve survival of Th17 and Tc17 lymphocytes. At the same time, ROR γ T agonists are able to inhibit the production of regulatory T cells which suppress immune responses, and therefore agonists are able to push the balance of the immune response in the direction of activation. ROR γ T agonists are also capable of promoting expression of a range of Co-Stimulatory molecules (Co-Stimulatory molecules), such as CD226, CD27 and 4-1BB (CD137), and inhibiting expression of Co-Inhibitory molecules (Co-Inhibitory molecules) such as PD-1, TIGIT, TIM3, CD73 and LAG3, thereby promoting T cell activation. Studies have shown that oral ROR γ t agonists inhibit Tumor growth and prolong animal survival by an immune response in a variety of homologous Tumor Models (Syngeneic Tumor Models).
In 2011, both the subject group of Littman professor at New York university and the subject group of Burris professor at Scripps research institute published research related to ROR γ t small molecule inhibitors in Nature journal: the Littman group screened the library of compounds for cardiotonic digoxin as an inhibitor of ROR γ t; the Burris group discovered that the first non-steroidal small molecule SR1001 can be used as a dual ROR alpha and ROR gamma t inhibitor. The research on ROR γ t small molecule modulators was started later by various major pharmaceutical companies and research institutes, but most of them focused on the research on ROR γ t small molecule inhibitors. The company Lycera first reported the development of small molecule agonists of ROR γ t, and in 2017, the company Lycera declared the initiation of a phase 1/2a clinical trial to examine the efficacy of the developed ROR γ t agonist LYC-55716 in treating patients with advanced, recurrent, or refractory solid tumors. LYC-55716 has "dual action" on T lymphocytes, and can activate T lymphocytes and weaken immunosuppressive mechanism, thereby making T lymphocytes more powerful in anticancer function.
At present, ROR gamma t agonist has attracted attention in the anti-tumor aspect, and a great deal of research is seen in the industry, for example, the number of cells expressing IL-17A infiltrated in the tumor tissue of a hepatocellular carcinoma patient is inversely related to the survival rate of the patient; the lymphocyte infiltrated in the tumor tissue of the breast cancer patient expresses IL-17A to promote the proliferation of the cancer cells, and the like, and the IL-17 family provides good targets for tumor treatment in the future; therefore, ROR gamma t is considered as a new target for developing anti-tumor, anti-inflammatory and autoimmune disease drugs, and can be used as a new way for treating cancers and autoimmune inflammatory diseases.
Based on the current state of the prior art, the inventors of the present application intend to provide a 3, 4-dihydroisoquinoline sulfonamide compound and an application thereof; in particular to the application of the compound as a ROR gamma t agonist in preventing, treating or improving tumor immunity related diseases mediated by Th17 cells.
Disclosure of Invention
The invention aims to provide a 3, 4-dihydroisoquinoline sulfonamide compound based on the current state of the prior art.
It is still another object of the present invention to provide pharmaceutically acceptable salts, solvates, precursor compounds or polymorphs of the 3, 4-dihydroisoquinoline sulfonamide compounds.
The invention further aims to provide a preparation method of the 3, 4-dihydroisoquinoline sulfonamide compound.
In a fourth aspect of the present invention, a pharmaceutical composition is provided.
The fifth object of the present invention is to provide the use of the 3, 4-dihydroisoquinoline sulfonamide compound, a pharmaceutically acceptable salt, a solvate, a prodrug or a polymorph thereof for the preparation of a medicament.
In order to achieve the purpose, the invention adopts the technical scheme that:
the 3, 4-dihydroisoquinoline sulfonamide derivative is characterized in that the structural general formula of the derivative is as follows:
wherein:
X1、X2is C or N;
m, n and p are respectively and independently selected from 0, 1, 2,3 or 4; preferably, m is 0; n is selected from 0, 1, 2 or 3; p is selected from 1 or 4;
substituent R1Selected from the group consisting of H, (C1-C3) alkyl, halo (C1-C3) alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl, preferably methyl;
substituent R2Absent or in at least one of the 2,3,4,5,6 positions, being unsubstituted, mono-, di-or poly-substituted, the substituent R2One, two or more selected from the following groups: hydrogen and halogen-element, nitro group, hydroxyl group, carboxyl group, trifluoromethyl group, cyano group, substituted or unsubstituted amino group, phenyl group, substituted or unsubstituted (C1-C6) alkyl group, substituted or unsubstituted (C1-C6) alkoxy group, -CONH2、-CONHR3、-CON(R3)2、-COOR3、-COR3、-NHCOR3、-NHCOOR3Group, wherein R3Optionally selected from H, (C1-C6) alkyl, trifluoromethyl, phenyl; when R is2When di-or tri-substituted, the substituents may be the same or different;
Cy1selected from H, Ar1, Hetar1, or (C3-C7) cycloalkyl;
ar1 above represents a monocyclic aromatic hydrocarbon system or a bicyclic aromatic hydrocarbon system and a cyclic aromatic hydrocarbon saturated ring system having 6 to 10 carbon atoms, which system is unsubstituted or substituted by one or more identical or different substituents selected from: (C1-C6) alkyl, (C3-C7) cycloalkyl, (C1-C6) alkoxy, carbonyl, carboxyl, amino, -CONH2、-COOR4、-COR4、-NHCOR4、-NHCOOR4、-COH(CF3)2、-SONH2、-SOOR4、-SOR4、-NHSOR4、-NHSOOR4Substituted by groups; wherein R is4Optionally selected from H, (C1-C6) alkyl;
the above Hetar1 represents a saturated 4,5,6, 7, 8, 9 or 10 membered heterocyclic ring having 1, 2 or 3N and/or O and/or S atoms, which heterocyclic ring is unsubstituted or substituted by one or more identical or different substituents selected from the group consisting of: (C1-C6) alkyl, (C3-C7) cycloalkyl, (C1-C6) alkoxy, carbonyl, carboxyl, amino, -CONH2、-COOR4、-COR4、-NHCOR4、-NHCOOR4、-COH(CF3)2、-SONH2、-SOOR4、-SOR4、-NHSOR4、-NHSOOR4Substituted by groups; wherein R is4Optionally selected from H, (C1-C6) alkyl.
Preferably, said R is1Is methyl.
Preferably, the substituent R2At least one of the 2-, 3-, 4-, 5-, 6-positions is unsubstituted (i.e., isR2Is H), mono-, di-or polysubstituted, preferably unsubstituted, mono-or disubstituted, the substituent R2One, two or more selected from the following groups: hydrogen, fluorine, chlorine, trifluoromethyl, cyano, methyl, phenyl, trifluoromethoxy, tert-butyl, when R is2When disubstituted or polysubstituted, the substituents may be the same or different.
Preferably, X is1Optionally C or N.
Preferably, X is2Optionally C or N.
Preferably, the Cy is1Is optionally selected from: 4-acetyl-piperazin-1-yl, 4- (propionyl) -piperazin-1-yl, 4-cyclopropylformyl-piperazin-1-yl, 4-tert-butoxycarbonyl-piperazin-1-yl, 4-trimethylacetyl-piperazin-1-yl, 4-methanesulfonyl-piperazin-1-yl, 4-sulfamoyl-piperazin-1-yl, 4-ethanesulfonyl-piperazin-1-yl, morpholinyl, piperazinyl, 4-methoxycarbonyl-phenyl, 4-carboxy-phenyl, naphthyl, tetrahydronaphthyl, 3, 4-dihydro-1 (2H) -naphthalenonyl, piperidinyl, 4-methoxy-piperidin-1-yl, di-or tri-tert-butoxycarbonyl-piperazin-1-yl, 4-methanesulfonyl-piperazin-1-yl, 4-trimethylacetyl-piperazin-1-yl, 4-carboxy-phenyl, naphthyl, tetrahydronaphthyl, 3, 4-dihydro-1 (2H) -naphthalenonyl, piperidinyl, 4-methoxy-piperidin-1-yl, m-yl, or a-methyl-oxo-yl, 4-carboxy-piperidin-1-yl, 4- (acetylamino-methyl) -piperidin-1-yl.
More preferably, the Cy is1Is 4-acetyl-piperazin-1-yl.
Unless otherwise indicated, (C1-C6) alkoxy in the present invention is (C1-C6) straight or branched chain alkoxy, and means alkoxy containing 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy or octyloxy.
Unless otherwise indicated, (C1-C6) alkyl as used herein is (C1-C6) straight or branched chain alkyl, and refers to alkyl groups containing 1 to 6 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, or octyl.
As used herein, (C3-C7) cycloalkyl refers to cycloalkyl groups containing 3-7 carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, unless otherwise specified.
Unless otherwise indicated, the term halogen is a halogen substituent, including but not limited to fluorine, chlorine, bromine, or iodine.
In the present invention, the terms "multi-substituted" and "plural" mean three or more, and the same meanings are shown below.
In a preferred embodiment, the 3, 4-dihydroisoquinoline sulfonamide derivatives of the present invention are specifically as follows:
6- (4-acetylpiperazin-1-yl) -N-benzyl-N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide
6- (4-acetylpiperazin-1-yl) -N-phenethyl-N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide
6- (4-acetylpiperazin-1-yl) -N-phenylpropyl-N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide
6- (4-acetylpiperazin-1-yl) -N- (4-trifluoromethyl-benzyl) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide
6- (4-acetylpiperazin-1-yl) -N- (3-trifluoromethyl-benzyl) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide
6- (4-acetylpiperazin-1-yl) -N- (2-trifluoromethyl-benzyl) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide
6- (4-acetylpiperazin-1-yl) -N- (4-chloro-benzyl) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide
6- (4-acetylpiperazin-1-yl) -N- (2-chloro-benzyl) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide
6- (4-acetylpiperazin-1-yl) -N- (3-chloro-benzyl) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide
6- (4-acetylpiperazin-1-yl) -N- (3-methyl-benzyl) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide
6- (4-acetylpiperazin-1-yl) -N- (4-phenyl-benzyl) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide
6- (4-acetylpiperazin-1-yl) -N- (4-tert-butyl-benzyl) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide
6- (4-acetylpiperazin-1-yl) -N- (2-chloro-6-fluoro-benzyl) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide
6- (4-acetylpiperazin-1-yl) -N- (2-fluoro-benzyl) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide
6- (4-acetylpiperazin-1-yl) -N- (4-methyl-benzyl) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide
6- (4-acetylpiperazin-1-yl) -N- (2-methyl-benzyl) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide
6- (4-acetylpiperazin-1-yl) -N- (4-trifluoromethyl-pyrimidin-2-yl) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -sulfonamide
6- (4-acetylpiperazin-1-yl) -N- (3-fluoro-benzyl) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide
6- (4-acetylpiperazin-1-yl) -N- (4-fluoro-benzyl) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide
6- (4-acetylpiperazin-1-yl) -N- (2, 4-difluoro-benzyl) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide
6- (4-acetylpiperazin-1-yl) -N- (2,3,4,5, 6-pentafluoro-benzyl) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide
6- (4-acetylpiperazin-1-yl) -N- (2-pyridinyl-methyl) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide
6- (4-acetylpiperazin-1-yl) -N- (cyclopropyl-methyl) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide
6- (4-acetylpiperazin-1-yl) -N- (4-cyano-benzyl) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide
6- (4-acetylpiperazin-1-yl) -N- (cyclohexyl-methyl) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide
6- (4-acetylpiperazin-1-yl) -N- (2-pyrimidinyl-methyl) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -sulfonamide
6- (4-acetylpiperazin-1-yl) -N- (4-trifluoromethoxy-benzyl) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -sulfonamide
6- (4-acetylpiperazin-1-yl) -N- (4-methoxycarbonyl-benzyl) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -sulfonamide
6- (4-acetylpiperazin-1-yl) -N- (2-methoxy-benzyl) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide
6- (4-acetylpiperazin-1-yl) -N- (4-carboxy-benzyl) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -sulfonamide
In order to achieve the second object, the invention adopts the technical scheme that:
the pharmaceutically acceptable salt, solvate, precursor compound or polymorph of the 3, 4-dihydroisoquinoline sulfonamide derivative.
A pharmaceutically acceptable salt, solvate, prodrug or polymorph, wherein the pharmaceutically acceptable salt is an inorganic salt, an organic salt or an amino acid salt;
wherein the inorganic salt is: sodium salts, hydrochlorides, trifluoroacetates, sulfates, phosphates, diphosphates, hydrobromides or nitrates;
wherein the organic salt is: maleate, acetate, fumarate, tartrate, succinate, lactate, p-toluenesulfonate, salicylate, or oxalate;
wherein the amino acid salt is: arginine salt, ornithine salt, lysine salt, leucine salt, isoleucine salt, glycine salt, cystine salt, cysteine salt, caseinate, alanine salt, phenylalanine salt, histidine salt, serine salt, threonine salt, methionine salt, tryptophan salt, glutamate, aspartate salt, valine salt, methionine salt, proline salt, or hydroxyproline salt.
In order to achieve the third object, the invention adopts the technical scheme that:
the preparation method of the 3, 4-dihydroisoquinoline sulfonamide derivative is synthesized and prepared by the following steps:
preparation of intermediate b
Dissolving the raw material a, chlorosulfonyl isocyanate and tertiary butanol in dichloromethane, stirring at room temperature, and condensing to obtain an intermediate b.
Preparation of intermediate c
Intermediate b and R1Dissolving X (X is Cl, Br or I) in N, N-dimethylformamide, and refluxing and stirring to obtain an intermediate c.
Preparation of intermediate d
Intermediate c and Cy1Carrying out coupling reaction or substitution reaction to obtain an intermediate d.
Preparation of intermediate e
And (3) adding trifluoroacetic acid into the intermediate d to remove the tert-butyloxycarbonyl group of the intermediate d.
Preparation of Compounds I or II
Dissolving intermediate e and different halides (halide f) in N, N-dimethylformamide, adding K2CO3Stirring to obtain the compound I or II.
The halide f is:
Among them, the preparation method of pharmaceutically acceptable salts of 3, 4-dihydroisoquinoline sulfonamide derivatives can be prepared according to the conventional methods in the field, and the compounds of the present invention are usually isolated as such or obtained by reacting with inorganic salts, organic salts or amino acid salts under the conventional conditions in the form of pharmaceutically acceptable salts thereof.
In order to achieve the fourth object, the invention adopts the technical scheme that:
a pharmaceutical composition comprising a) any one of the 3, 4-dihydroisoquinoline sulfonamide derivatives described above, and/or a pharmaceutically acceptable salt, solvate, prodrug, or polymorph of any one of the 3, 4-dihydroisoquinoline sulfonamide derivatives described above, and b) a pharmaceutically acceptable carrier therefor.
The pharmaceutical composition may be a solid form or a liquid form of pharmaceutical formulation, and the dosage form of the pharmaceutical composition includes, but is not limited to, tablets, capsules, powders, granules, suspensions or injections.
In order to achieve the fifth object, the invention adopts the technical scheme that:
the 3, 4-dihydroisoquinoline sulfonamide derivative, and the pharmaceutically acceptable salt, solvate, prodrug, polymorph or pharmaceutical composition thereof are used for preparing medicines, and are generally applicable to agonizing ROR gamma t. Accordingly, in some embodiments, the present invention provides a method of agonizing retinoic acid-related orphan receptor gamma (ROR γ), and preventing or treating cancer, autoimmune diseases, metabolism, inflammation, and other diseases or disorders, comprising administering the provided compounds or compositions. More specifically, the compounds and compositions described herein act as modulators of ROR γ.
Diseases and conditions that can be treated according to the methods of the present invention include, but are not limited to, solid tumors and cancers, such as, multiple myeloma, malignant myeloma, colon cancer, ovarian cancer, prostate cancer, breast cancer, cervical cancer, bladder cancer, adenocarcinoma, adrenocortical carcinoma, B-cell lymphoma, lung cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, hodgkin's disease, or gastric cancer; inflammatory, metabolic, autoimmune diseases, such as: psoriasis, rheumatoid arthritis, multiple sclerosis, ulcerative colitis, asthma, lupus erythematosus, autoimmune hepatitis or type I and type II diabetes, diabetic complications, diabetic nephropathy, diabetic retinopathy, diabetic retinitis, diabetic microangiopathy, ophthalmological diseases, uveitis, atherosclerosis, psoriatic arthritis, atopic dermatitis, crohn's disease, ulcerative colitis, ankylosing spondylitis, nephritis, organ allograft rejection, fibrotic lung, cystic fibrosis, renal insufficiency, tuberculosis, chronic obstructive pulmonary disease, sarcoidosis, invasive staphylococcal skin suppuration, inflammation after cataract surgery, allergic rhinitis, allergic conjunctivitis, chronic urticaria, systemic lupus erythematosus, asthma, allergic asthma, steroid resistant asthma, allergic rhinitis, urticaria, Neutrophilic asthma, periodontal disease, periodontitis, gingivitis, gingival disease, diastolic myocardial disease, myocardial infarction, myocarditis, and chronic heart failure.
Furthermore, the invention also provides application of the 3, 4-dihydroisoquinoline sulfonamide derivative or the pharmaceutically acceptable salt, solvate, precursor compound or polymorph thereof in preparing a medicament for treating inflammatory diseases.
Furthermore, the invention also provides application of the 3, 4-dihydroisoquinoline sulfonamide derivative or the pharmaceutically acceptable salt, solvate, precursor compound or polymorph thereof in preparing a medicament for treating autoimmune diseases.
Furthermore, the invention also provides application of the 3, 4-dihydroisoquinoline sulfonamide derivative or the pharmaceutically acceptable salt, solvate, precursor compound or polymorph thereof in preparing a medicament for treating metabolic related diseases.
Preferably, the invention also provides the application of the 3, 4-dihydroisoquinoline sulfonamide derivative or the pharmaceutically acceptable salt, solvate, precursor compound or polymorph thereof in preparing a medicament for treating multiple myeloma, malignant myeloma, colon cancer, ovarian cancer, prostatic cancer, breast cancer, cervical cancer, bladder cancer, adenocarcinoma, adrenocortical cancer, B-cell lymphoma, lung cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's disease or gastric cancer.
Detailed Description
The present invention is further explained below with reference to specific examples, which are not intended to limit the present invention in any way. Experimental procedures in the following examples, in which specific conditions are not specified, are generally carried out under conventional conditions or conditions recommended by the manufacturer.
In the chemical compounds of the invention, when any variable (e.g. R)1、R2Etc.) occur more than one time in any constituent, then the definition of each occurrence is independent of the definition of each other occurrence. Also, the substituents are allowedAnd combinations of variables, provided that such combinations stabilize the compound. The line drawn from a substituent into the ring system indicates that the indicated bond can be attached to any ring atom that can be substituted. If the ring system is polycyclic, it means that such a bond is only attached to any suitable carbon atom of the adjacent ring. It is to be understood that substituents and substitution patterns on the compounds of the present invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by those skilled in the art and by the methods set forth below from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, so long as the structure is stable. The phrase "optionally substituted with one or more substituents" is considered equivalent to the phrase "optionally substituted with at least one substituent" and preferred embodiments in this case will have from 0 to 3 substituents.
The terms "alkyl" and "alkylene" as used herein are intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, the definition of "C1-C6" in "C1-C6 alkyl" includes groups having 1, 2,3,4,5, or 6 carbon atoms in a straight or branched chain arrangement. For example, "C1-6 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, sec-butyl, t-butyl, hexyl. The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, methyl-cyclopropyl, 2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and the like.
The term "aryl" as used herein refers to all carbon monocyclic or fused ring polycyclic aromatic groups containing from 6 to 10 carbon atoms and having a conjugated pi-electron system, such as phenyl or naphthyl.
The term "heteroaryl" as used herein represents a stable monocyclic or bicyclic carbon ring of up to 6 atoms in each ring, wherein at least one ring is aromatic and contains 1-4 heteroatoms selected from O, N and S. Heteroaryl groups within the scope of this definition include, but are not limited to: imidazolyl, triazolyl, pyrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl. For the following definition of heteroaryl, "heteroaryl" is also understood to include any N-oxide derivative of a nitrogen-containing heteroaryl group. In the case where the heteroaryl substituent is bicyclic and contains one ring that is non-aromatic or contains no heteroatoms, it is understood that each is attached via an aromatic ring or via a heteroatom-containing ring.
The term "heterocycle" or "heterocyclyl" as used herein refers to a 5-or 6-membered aromatic or nonaromatic heterocycle containing 1 to 4 heteroatoms selected from O, N and S, and includes bicyclic groups. "Heterocyclyl" thus includes the above-mentioned heteroaryl groups, as well as the dihydro and tetrahydro analogues thereof. Further examples of "heterocyclyl" include, but are not limited to: imidazolyl, indazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinoxalinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, l, 4-dioxanyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl and tetrahydrothienyl, and N-oxides thereof. Attachment of the heterocyclic substituent may be through a carbon atom or through a heteroatom.
As understood by those skilled in the art, "halogen" as used herein is meant to include chlorine, fluorine, bromine and iodine.
Unless otherwise defined, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl substituents may be considered unsubstituted or substituted. For example, (C1-C4) alkyl may be substituted with one, two or three substituents selected from OH, halogen, alkoxy, dialkylamino or heterocyclyl, e.g., morpholinyl, piperidinyl, and the like.
The invention includes the free forms of the compounds of formula i, as well as pharmaceutically acceptable salts and stereoisomers thereof. Some specific exemplary compounds herein are protonated salts of amine-based compounds. The term "free form" refers to the amine compound in a non-salt form. Included pharmaceutically acceptable salts include not only the exemplary salts of the particular compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of the compounds of formula I. The free form of a particular salt of the compound may be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a dilute aqueous solution of a suitable base, such as a dilute aqueous NaOH solution, a dilute aqueous potassium carbonate solution, dilute aqueous ammonia, and a dilute aqueous sodium bicarbonate solution. The free forms differ somewhat in certain physical properties, such as solubility in polar solvents, from their respective salt forms, but for the purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.
Pharmaceutically acceptable salts of the invention can be synthesized from compounds of the invention containing a basic or acidic moiety by conventional chemical methods. In general, salts of basic compounds are prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric amount or excess of an inorganic or organic acid in the form of the desired salt in an appropriate solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with suitable inorganic or organic bases.
Thus, pharmaceutically acceptable salts of the compounds of the present invention include the conventional non-toxic salts of the compounds of the present invention formed by the reaction of a basic compound of the present invention and an inorganic or organic acid. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, as well as those prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, and the like.
If the compounds of the invention are acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic and organic bases, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
Since acidic moieties such as carboxyl groups deprotonated in a compound under physiological conditions may be anionic and such charge may then be balanced out by a protonated or alkylated basic moiety such as a quaternary nitrogen atom bearing a cation internally, it should be noted that the compounds of the present invention are potential internal salts or zwitterions.
The pharmaceutical compositions of the present invention may be in liquid, semi-liquid or solid form, formulated in a manner appropriate to the route of administration employed. The pharmaceutical composition of the present invention can be administered in the following manner: oral, parenteral, intraperitoneal, intravenous, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, liposomal, and the like.
Oral pharmaceutical compositions may be solid, gel or liquid. Examples of solid formulations include, but are not limited to, tablets, capsules, granules, and bulk powders. These formulations may optionally contain binders, diluents, disintegrants, lubricants, glidants, sweeteners, flavoring agents and the like. Examples of binders include, but are not limited to, microcrystalline cellulose, glucose solutions, acacia mucilage, gelatin solutions, sucrose and starch pastes; examples of lubricants include, but are not limited to, talc, starch, magnesium stearate, calcium stearate, stearic acid; examples of diluents include, but are not limited to, lactose, sucrose, starch, mannitol, dicalcium phosphate; examples of glidants include, but are not limited to, silicon dioxide; examples of disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, methylcellulose, agar, and carboxymethylcellulose.
The pharmaceutical compositions of the present invention are administered parenterally, typically by injection, including subcutaneous, intramuscular, or intravenous injection. Injectables can be prepared in any conventional form, such as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or emulsions. Examples of pharmaceutically acceptable carriers that may be used in the injections of the present invention include, but are not limited to, aqueous carriers, non-aqueous carriers, antimicrobial agents, isotonic agents, buffers, antioxidants, suspending and dispersing agents, emulsifying agents, chelating agents, and other pharmaceutically acceptable materials. Examples of aqueous carriers include sodium chloride injection, ringer's injection, isotonic glucose injection, sterile water injection, dextrose and lactated ringer's injection; examples of non-aqueous carriers include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil; examples of antimicrobial agents include m-cresol, benzyl alcohol, chlorobutanol, benzalkonium chloride, and the like; examples of isotonic agents include sodium chloride and glucose; buffers include phosphates and citrates.
The pharmaceutical compositions of the present invention may also be prepared as sterile lyophilized powders for injection, which are prepared by dissolving the compound in a sodium phosphate buffer solution containing glucose or other suitable excipients, followed by sterile filtration of the solution under standard conditions known to those skilled in the art, followed by lyophilization to provide the desired formulation.
In addition to standard methods known in the literature or exemplified in experimental procedures, the compounds of the invention can be prepared using reactions as shown in the following schemes. The following illustrative schemes are therefore for illustrative purposes and are not limited to the compounds listed or any particular substituents. The number of substituents shown in the schemes does not necessarily correspond to the number used in the claims and for the sake of clarity a single substituent is shown attached to the compound allowing for multiple substituents under the definition of formula I or II above.
The invention is further described in the following examples, which are not intended to limit the scope of the invention.
EXAMPLE 16 preparation of (4-acetylpiperazine) -N-benzyl-N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide (Compound 1)
Step 1: preparation of tert-butyl ((6-bromo-3, 4-dihydroquinoline-2 (1H)) sulfonyl) carbamate (intermediate (b))
Chlorosulfonic acid isocyanate (0.75g, 5mmol) and tert-butanol (0.37g, 5mmol) were dissolved in dichloromethane (15ml) and stirred in ice bath for 0.5 hr. Then, 6-bromo-3, 4-dihydroisoquinoline (1.05g,5mmol) and triethylamine (1.5g,15mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 6 hr. After the reaction was completed, 15ml of water was added, and extraction was performed with dichloromethane (10ml × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by column chromatography (PE: EtOAc ═ 20:1) to obtain 1.6g of a white solid with a yield of 81%. To obtain intermediate (b);
step 2: preparation of N-tert-butyl-N-methyl- ((6-bromo-3, 4-dihydroquinoline-2 (1H)) sulfonyl) carbamate (intermediate (c))
Intermediate (b) (0.76g, 1.84mmol) and potassium carbonate (0.51g, 3.7mmol) were dissolved in DMF (15mL) and iodomethane (0.18mL, 2.8mmol) was added dropwise and refluxed at 110 ℃. The reaction was checked by TLC. After the reaction, the reaction mixture was cooled, 35ml of water was added, extraction was performed with ethyl acetate (30ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by column chromatography (PE: EtOAc ═ 20:1) to obtain 0.55g of a white solid with a yield of 70%. To obtain intermediate (c);
and step 3: preparation of 6- (4-acetylpiperazine) -N-tert-butoxycarbonyl-N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide (intermediate (d))
Intermediate (c) (1.82g, 4.8mmol), palladium acetate (52mg,0.24mmol), 2-dicyclohexylphosphine-2 ', 6' -dimethoxybiphenyl (240mg, 0.48mmol), cesium carbonate (2.32g, 7.2mmol) were dissolved in dioxane (25ml), 1-acetylpiperazine (0.92g, 7.2mmol) was added, nitrogen was used for protection, reflux stirring was carried out at 100 ℃ for 6hr, and the reaction was detected by TLC. After the reaction was completed, the temperature was decreased to room temperature, 15ml of water was added, extraction was performed with ethyl acetate (10ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by column chromatography (PE: EtOAc ═ 1:1) to obtain 1.5g of a white solid with a yield of 75%. To obtain an intermediate (d),1HNMR(400MHz,cdcl3)δ6.99(d,J＝8.4Hz,1H),6.81(s,1H),6.67(s,1H),4.44(s,2H),3.76(s,2H),3.60(t,J＝5.8Hz,4H),3.28(s,3H),3.21–2.98(m,4H),2.87(t,J＝5.6Hz,2H),2.11(d,J＝11.8Hz,3H),1.44(s,9H)。
and 4, step 4: preparation of 6- (4-acetylpiperazine) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide (intermediate (e))
Intermediate (d) (1.5g, 3.3mmol) was dissolved in dichloromethane, trifluoroacetic acid (3mL, 33mmol) was added thereto, the mixture was stirred at room temperature for 2hr, the reaction mixture was slowly added to crushed ice (40g), a saturated solution of sodium hydrogencarbonate was added dropwise thereto, the mixture was stirred until the PH became 8, extracted with ethyl acetate (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by distillation under reduced pressure, and subjected to column chromatography (PE: EtOAc ═ 1: 2) to obtain 0.7g of a yellow solid with a yield of 60%. To obtain an intermediate (e),1H NMR(400MHz,dmso)δ7.22(q,J＝4.7Hz,1H),7.00(t,J＝11.7Hz,1H),6.81(t,J＝9.1Hz,1H),6.73(s,1H),4.18(s,2H),3.55(d,J＝4.6Hz,4H),3.35(dd,J＝11.1,5.3Hz,2H),3.11(d,J＝4.5Hz,2H),3.07–2.99(m,2H),2.82(t,J＝5.5Hz,2H),2.50(s,2H),2.49(s,1H),2.03(s,3H).；
and 5: preparation of 6- (4-acetylpiperazine) -N-benzyl-N-methyl-3, 4-dihydroisoquinoline-2 (1H) -methanesulfonamide
Intermediate (e) (0.1g, 0.28mmol) and potassium carbonate (0.07g, 0.56mmol) were dissolved in DMF (5ml) and benzyl bromide (0.145mg, 0.85mmol) was added dropwise with stirring at room temperature. And detecting the reaction by TLC. After completion of the reaction, the reaction mixture was cooled, 15ml of water was added, extraction was performed with ethyl acetate (10 ml. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by column chromatography (PE: EtOAc ═ 1:1) to obtain 0.09g of a white solid in a yield of 72%. The final product (compound 1) was obtained.
Examples 2 to 29
Example 1 was repeated, with the difference that: different starting materials were used to prepare compounds 2-29. The method comprises the following specific steps:
beta-bromophenylethane, 1-bromo-3-phenylpropane, 4-trifluoromethyl bromobenzyl, 3-trifluoromethyl bromobenzyl, 2-trifluoromethyl bromobenzyl, 4-chloro bromobenzyl, 2-chloro bromobenzyl, 3-methyl bromobenzyl, 4-bromomethyl biphenyl, 4-tert-butyl bromobenzyl, 2-chloro-6-fluorobenzyl bromide, 2-fluoro bromobenzyl, 4-methyl bromobenzyl, 2-chloro-4- (trifluoromethyl) pyrimidine, 3-fluoro bromobenzyl, 4-fluoro bromobenzyl, 2, 4-difluoro bromobenzyl, 2,3,4,5, 6-pentafluorobromobenzyl, 2-bromomethylpyridine, bromomethylcyclopropane, 4-cyano bromobenzyl, bromomethylcyclohexane, 2- (chloromethyl) pyrimidine, 4-trifluoromethoxybenzyl bromide, 4-methoxycarbonylbromobenzyl bromide, 2-methoxybenzyl bromide were prepared with intermediate (e) and potassium carbonate, respectively, in the above examples, corresponding to compounds 2,3,4,5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, respectively.
Example 306 preparation of (4-acetylpiperazine) -N- (4-carboxy-benzyl) -N-methyl-3, 4-dihydroisoquinoline-2 (1H) -sulfonamide amide (Compound 30)
Example 28 was repeated, with the difference that: compound 28 is hydrolyzed to produce compound 30. The method comprises the following specific steps:
compound 28(0.5g) was dissolved in methanol and water (50:50, 10mL), NaOH (0.2g) was added, and reflux was carried out for 2h to finally obtain compound 30.
The chemical structure of the synthesized target product is shown in table 1. The nuclear magnetic hydrogen spectrum and mass spectrum system characterize the chemical structure of the target product, and the data are shown in Table 2.
TABLE 1 chemical Structure of the target product
TABLE 2 nuclear magnetic hydrogen spectrum and mass spectrum data of the target compound
Example 33:
pharmacological activity:
in vitro activity assay: the compound of the invention is verified to have the capability of stimulating the activity of ROR gamma t protein by a double Fluorescence Resonance Energy Transfer (FRET) method.
Test compounds were dissolved in dimethyl sulfoxide (DMSO) to prepare a 10.0mM stock solution and diluted to the desired concentration. The final concentration of DMSO in the reaction did not exceed 1% (v/v). By mixing GST-labeled ROR gamma Ligand Binding Domains (LBDs) in a buffer containing 25mM HEPES, 100mM NaCl, 5mM DTT and 0.01% BSA in the presence or absence of the desired concentration of the compound, incubation at 25 ℃ for 1 hour. After addition of Steroid Receptor activator-1(SRC-1), (676-700), biotin labeled and MAb AntiGST-Tb and Streptavidin-d2 to the reaction mixture and shaking for an additional 5 minutes, the reactions were incubated for an additional 1 hour at room temperature and the signals of 620, 665 read on a SpectraMax Paradigm microplate reader at 4 ℃ and the protein agonistic activity of the test compounds was calculated from the TR-FRET ratio of 620/665. IC was calculated from compound concentration activation curves by non-linear regression analysis using GraphPad Prism software50The value is obtained.
The prepared compounds were tested using the assay procedure described above and the resulting junctionsThe results are provided in table 3. Said compound is determined to have an IC of less than 5 μ M50Preferably IC50Compounds of less than 1. mu.M, more preferably IC50Less than 0.1. mu.M of compound.
IC50The values are set forth in Table 3, "NA" means not detected.
TABLE 3 FRET Activity data for Compounds
| Compound (I) | IC50(μM) | Compound (I) | IC50(μM) |
| 1 | 0.514 | 16 | 0.220 |
| 2 | 2.170 | 17 | 6.108 |
| 3 | 0.529 | 18 | 0.544 |
| 4 | 1.914 | 19 | 0.950 |
| 5 | 0.352 | 20 | 0.130 |
| 6 | 0.094 | 21 | NA |
| 7 | NA | 22 | 12.040 |
| 8 | 0.098 | 23 | NA |
| 9 | 0.136 | 24 | NA |
| 10 | 0.212 | 25 | NA |
| 11 | NA | 26 | NA |
| 12 | NA | 27 | NA |
| 13 | 0.02 | 28 | NA |
| 14 | 0.344 | 29 | 0.388 |
| 15 | 0.385 | 30 | NA |
As can be seen from table 3, the compounds of the present invention have agonistic activity against ROR γ t, which lays a foundation for the development of highly effective, novel, and highly specific ROR γ t-mediated drugs for tumors and autoimmune diseases such as multiple myeloma, malignant myeloma, colon cancer, ovarian cancer, prostate cancer, breast cancer, cervical cancer, bladder cancer, adenocarcinoma, adrenocortical carcinoma, B-cell lymphoma, lung cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, hodgkin's disease, or gastric cancer, psoriasis, rheumatoid arthritis, multiple sclerosis, etc., and have a very good development value.
The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, many modifications and additions can be made without departing from the present invention, and these modifications and additions should also be regarded as the protection scope of the present invention.
Claims (9)
1. A3, 4-dihydroisoquinoline sulfonamide derivative is characterized in that the structural general formula of the derivative is a compound shown in formula I or formula II:
wherein:
X1is C or N;
X2is C or N;
n is optionally selected from 0, 1, 2 or 3, p is optionally selected from 1, 2,3 or 4;
substituent R1Selected from H, (C1-C3) alkyl, halo (C1-C3) alkyl;
substituent R2Absent or in at least one of the 2,3,4,5,6 positions, being unsubstituted, mono-, di-or poly-substituted, the substituent R2One, two or more selected from the following groups: hydrogen, halogen, carboxyl, trifluoromethyl, cyano, phenyl, unsubstituted (C1-C6) alkyl, unsubstituted (C1-C6) alkoxy, trifluoromethoxy, -COOR3Wherein R is3Optionally selected from H, (C1-C6) alkyl; when R2 is di-or tri-substituted, the substituents may be the same or different;
Cy1-(CH2)m-is 4-acetyl-piperazin-1-yl.
2. The 3, 4-dihydroisoquinoline sulfonamide derivative according to claim 1, wherein the substituent R is1Is methyl.
3. The 3, 4-dihydroisoquinoline sulfonamide derivative according to claim 1 or 2, wherein the substituent R is2In at least one of the 2-, 3-, 4-, 5-or 6-positions, is unsubstituted, monosubstituted, disubstituted or polysubstituted, the substituent R2One, two or more selected from the following groups: hydrogen, fluorine, chlorine, trifluoromethyl, cyano, methyl, methoxy, phenyl, trifluoromethoxy, tert-butyl, methoxycarbonyl, carboxy when R is2When disubstituted or polysubstituted, the substituents may be the same or different.
4. The 3, 4-dihydroisoquinoline sulfonamide derivative according to claim 1 or 2, wherein p is selected from 1 or 4.
5. A pharmaceutically acceptable salt of the 3, 4-dihydroisoquinoline sulfonamide derivative according to any one of claims 1 to 4.
6. The pharmaceutically acceptable salt according to claim 5, wherein the pharmaceutically acceptable salt is an inorganic salt, an organic salt or an amino acid salt;
wherein the inorganic salt is: a hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, or nitrate salt;
wherein the organic salt is: acetate, maleate, fumarate, tartrate, succinate, lactate, p-toluenesulfonate, salicylate, or oxalate;
wherein the amino acid salt is: arginine, ornithine, lysine, leucine, isoleucine, glycine, cystine, cysteine, caseinate, alanine, phenylalanine, histidine, serine, threonine, methionine, tryptophan, glutamate, aspartate, valine, methionine, proline, or hydroxyproline.
7. A pharmaceutical composition comprising a) one or more of the 3, 4-dihydroisoquinoline sulfonamide derivatives of any one of claims 1 to 4, the pharmaceutically acceptable salts of the 3, 4-dihydroisoquinoline sulfonamide derivatives of claim 5 or 6, and b) a pharmaceutically acceptable carrier therefor.
8. Use of the 3, 4-dihydroisoquinoline sulfonamide derivatives according to any one of claims 1 to 4 or the pharmaceutically acceptable salts of the 3, 4-dihydroisoquinoline sulfonamide derivatives according to claim 5 or 6 or the pharmaceutical composition according to claim 7 for the preparation of a medicament for: cancer or inflammation, autoimmune diseases, and metabolic-related diseases.
9. The use according to claim 8, wherein the disease is: at least one of multiple myeloma, malignant myeloma, colon cancer, ovarian cancer, prostate cancer, breast cancer, cervical cancer, bladder cancer, adenocarcinoma, adrenocortical cancer, B-cell lymphoma, lung cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, hodgkin's disease, or gastric cancer.
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