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WO2016154998A1 - Dérivé de pyrazolopyrimidine, procédé de fabrication, composition pharmaceutique, et son utilisation - Google Patents

Dérivé de pyrazolopyrimidine, procédé de fabrication, composition pharmaceutique, et son utilisation Download PDF

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Publication number
WO2016154998A1
WO2016154998A1 PCT/CN2015/075819 CN2015075819W WO2016154998A1 WO 2016154998 A1 WO2016154998 A1 WO 2016154998A1 CN 2015075819 W CN2015075819 W CN 2015075819W WO 2016154998 A1 WO2016154998 A1 WO 2016154998A1
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Prior art keywords
substituted
group
unsubstituted
atom
groups
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Chinese (zh)
Inventor
洪健
许忻
乐小勇
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ARROMAX PHARMATECH Co Ltd
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ARROMAX PHARMATECH Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention particularly relates to pyrazolopyrimidine derivatives, methods of preparation, pharmaceutical compositions and uses.
  • Btk Bruton's tyrosine kinase
  • BCR cell surface B-cell receptor
  • Btk is a key regulator of B cell development, activation, signaling and survival (Kurosaki, Curr Op Imm, 2000, 276-281; Schaeffer and Schwartzberg, Curr Op Imm 2000, 282-288).
  • Btk plays a role in numerous other hematopoietic signaling pathways, such as Toll like receptor (TLR) and cytokine receptor-mediated TNF- ⁇ production in macrophages, in mast cells.
  • TLR Toll like receptor
  • Fc ⁇ RI Immunoglobulin E receptor
  • BTK targeting inhibitors have been used in tumor therapy, but their inhibitory activity and efficacy are not significant enough. Clinically, larger doses are needed. Common side effects include thrombocytopenia, diarrhea, neutropenia, anemia and Upper respiratory tract infections, etc., and there is still a need to further develop compounds with better activity or pharmacological properties as newer, improved or more efficient BTK receptor inhibitors, thus enabling a deeper understanding of these drugs and BTK targets. The relationship between proteins and their anti-tumor mechanism are of great significance for the clinical treatment of tumors.
  • the technical problem to be solved by the present invention is to provide a pyrazolopyrimidine derivative in order to overcome the defects in the prior art that Bruton's tyrosine kinase inhibitor has insufficient biological activity and efficacy, large dosage, and side effects. , preparation methods, pharmaceutical compositions and uses.
  • the pyrazolopyrimidine derivative of the present invention as shown in Formula I against Bruton's tyrosine The kinase (BTK) has good inhibitory activity, especially has good in vitro and in vivo inhibitory activity on the growth of tumor cells, and has a good market prospect.
  • the present invention provides a pyrazolopyrimidine derivative of the formula I, a stereoisomer, a solvate thereof, a pharmaceutically acceptable salt, an active metabolite or a prodrug,
  • L is O, S, or When L is O, S, or When Z is or When L is or When Z is or When L is or When Z is or Wherein X is a halogen atom (for example, a fluorine atom, a chlorine atom or a bromine atom), a cyano group, or R is a C 1 -C 4 alkyl group (the "C 1 -C 4 alkyl group" such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, preferably methyl);
  • halogen atom for example, a fluorine atom, a chlorine atom or a bromine atom
  • R is a C 1 -C 4 alkyl group (the "C 1 -C 4 alkyl group" such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, preferably
  • Ar is a substituted or unsubstituted aryl group (preferably "substituted or unsubstituted C 5 -C 10 aryl group"; the "substituted or unsubstituted C 5 -C 10 aryl group” is preferably substituted or unsubstituted Phenyl; said "substituted phenyl” may be phenyl substituted by one or more fluorine atoms, phenyl substituted by one or more methyl groups, phenyl substituted by one or more cyano groups a phenyl substituted by one or more trifluoromethyl groups, a phenyl group substituted by one or more methoxy groups, a phenyl group substituted by one or more vinyl groups, a benzene substituted by one or more ethynyl groups a phenyl group substituted by one or more phenyl groups; said "phenyl group substituted by one or more fluorine atom
  • a substituted or unsubstituted alkyl group (preferably a substituted or unsubstituted C 1 -C 4 alkyl group, and the "unsubstituted alkyl C 1 -C 4 alkyl group" is preferably a methyl group.
  • the "substituted C 1 -C 4 alkyl group” is preferably a trifluoromethyl group, an alkoxy group (preferably a C 1 -C 4 alkoxy group, and the "C 1 -C 4 alkoxy group”" Preferably, methoxy), alkenyl (preferably C 2 -C 4 alkenyl, said "C 2 -C 4 alkenyl” is preferably vinyl), alkynyl (preferably C 2 -C 4 alkynyl,
  • the "C 2 -C 4 alkynyl group” is preferably an ethynyl group and an aryl group (preferably a C 5 - C 10 aryl group, and the "C 5 - C 10 aryl group” is preferably a phenyl group).
  • substituted as used in the "substituted or unsubstituted alkyl group" means substituted by one or more halogen atoms (for example, a fluorine atom, a chlorine atom or a bromine atom).
  • halogen atoms for example, a fluorine atom, a chlorine atom or a bromine atom.
  • Substituted alkyl group "preferably trifluoromethyl", when stored When a plurality of substituents, the substituents may be the same or different;
  • V is hydrogen or a fluorine atom
  • Y is a substituted or unsubstituted alkylene group (preferably a substituted or unsubstituted C 1 -C 6 alkylene group, and the "substituted or unsubstituted C 1 -C 6 alkylene group" is preferably substituted or not
  • the substituted methylene group, the "substituted methylene group” is preferably a pyrrolidinyl-substituted methylene group;
  • the "pyrrolidinyl-substituted methylene group” is, for example, or a cycloalkyl group (preferably a C 4 -C 7 cycloalkyl group, said "C 4 -C 7 cycloalkyl group” preferably a C 5 -C 6 cycloalkyl group; said "C 6 ring”
  • An alkyl group such as a cyclohexyl group or a heterocycloalkyl group (preferably a hetero atom having a
  • a cycloalkyl group (preferably, the hetero atom is a nitrogen atom, a C 4 -C 5 heterocycloalkyl group having 1-2 hetero atoms, and the "hetero atom is a nitrogen atom, and the number of hetero atoms is 1-2"
  • a C 4 -C 5 heterocycloalkyl group "pyrrolidinyl group", a C 1 -C 6 alkoxy group, a C 1 -C 6 alkylthio group or a C 1 -C 6 alkylamino group or Multiple replaced.
  • the L is preferably O, S, or Further preferred O, S and
  • the Ar is preferably a substituted or unsubstituted aryl group
  • the "substituted or unsubstituted aryl group” is preferably a "substituted or unsubstituted C 5 - C 10 aryl group”
  • the substituted or unsubstituted C 5 -C 10 aryl group” is preferably a substituted or unsubstituted phenyl group
  • the "substituted phenyl group” is preferably one or more selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, and three Fluoromethyl, cyano, methyl, methoxy, vinyl Ethynyl Substituted with a substituent of a phenyl group; "phenyl group substituted by one or more fluorine atoms", for example or "Phenyl substituted by one or more methyl groups” such as 4-methylphenyl; "phenyl group
  • the V is preferably hydrogen.
  • Y is preferably a substituted or unsubstituted alkylene group (preferably a substituted or unsubstituted C 1 -C 6 alkylene group, said "substituted or unsubstituted C 1 -C 6 sub-
  • the alkyl group is preferably a substituted or unsubstituted methylene group
  • the "substituted methylene group” is preferably a pyrrolidinyl-substituted methylene group
  • the "pyrrolidinyl-substituted methylene group” is, for example, or Or a heterocycloalkyl group (preferably a C 4 -C 7 heterocycloalkyl group having a hetero atom of oxygen, sulfur or nitrogen, 1-3 hetero atoms, said "hetero atom” being oxygen, sulfur or nitrogen a C 4 -C 7 heterocycloalkyl group having 1 to 3 atoms and a hetero atom is preferably a C 4 -C
  • X is preferably Cl, Br or CN
  • Y is preferably pyrrolidinyl or piperidinyl; said “pyrrolidinyl” is preferred or Said “piperidinyl” is preferred or ).
  • the pyrazolopyrimidine derivative of the formula I is preferably a compound of the formula I-A:
  • the pyrazolopyrimidine derivative represented by Formula I is further preferably one of the following compounds:
  • alkyl is a branched or straight-chain saturated aliphatic hydrocarbon group having the specified number of carbon atoms; as defined in "C 1 -C 10 alkyl” as being included in a straight chain or A group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in the branched structure.
  • C 1 -C 10 alkyl specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, ⁇ , etc.
  • alkoxy means a group formed by linking an alkyl group to an oxygen atom, that is, "RO-", and R is an alkyl group.
  • alkylthio means a group formed by linking an alkyl group to a sulfur atom, that is, "RS-", and R is an alkyl group.
  • alkylamino means an amino group in which one hydrogen in “NH 3 " is substituted with an alkyl group.
  • alkylene (including when used alone or in another group) means a branched and straight-chain subsaturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably 1 ⁇ 10 carbon atoms, more preferably 1-8 carbon atoms, such as methylene, ethylene, propylene, isopropylidene, n-butylene, tert-butyl, isobutylene, pentylene Base, hexylene group, heptylene group, octylene group, fluorenylene group, fluorenylene group, arylene (4,4-dimethylpentyl), sub (2,2,4-trimethylpentyl), sub Undecyl, dodecylene, and various isomers thereof.
  • cycloalkyl means an all-carbon monocyclic or polycyclic group, preferably 1 to 3 cyclic cycloalkyl groups formed by 3 to 20 carbons, more preferably 3 to 10 carbons. , for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl, cyclooctyl, cyclodecane or cyclododecyl.
  • heterocycloalkyl refers to one or more of 1 to 4 heteroatoms (such as nitrogen, oxygen and sulfur).
  • any heterocycloalkyl ring can be fused to a cycloalkyl, aryl, heteroaryl or heterocycloalkyl ring.
  • Heterocycloalkyl groups within the scope of this definition include, but are not limited to, oxazoline, oxocyclobutyl, pyranyl, tetrahydropyranyl, azetidinyl, 1,4-dioxyl, Hexahydropyrazine, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrofuranyl, dihydroimidazolyl, indanyl, dihydroisoxazole , dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrogen Tetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydr
  • alkenyl means a straight-chain, branched or cyclic non-aromatic hydrocarbon group containing a specified number of carbon atoms and at least one carbon-carbon double bond. Preferably there is one carbon-carbon double bond and up to four non-aromatic carbon-carbon double bonds may be present.
  • C 2 -C 12 alkenyl means an alkenyl group having 2 to 12 carbon atoms.
  • the “C 2 -C 4 alkenyl group” means an alkenyl group having 2 to 4 carbon atoms, and includes a vinyl group, a propenyl group, a 2-methyl-propenyl group, a 1-butenyl group, and a 2-butenyl group.
  • the linear, branched or cyclic moiety of the alkenyl group may contain a double bond.
  • alkynyl means a straight-chain, branched or cyclic hydrocarbon group containing a specified number of carbon atoms and at least one carbon-carbon triple bond. There may be up to three carbon-carbon triple bonds.
  • C 2 -C 12 alkynyl means an alkynyl group having 2 to 12 carbon atoms.
  • the "C 2 -C 4 alkynyl group” means an alkynyl group having 2 to 4 carbon atoms, and includes an ethynyl group, a propynyl group, a 1-butynyl group, a 2-butynyl group and the like.
  • aryl means any stable monocyclic or bicyclic carbon ring which may be up to 7 atoms in each ring, wherein at least one ring is an aromatic ring; examples of the above aryl unit include benzene Base, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthracenyl or acenaphthyl. It will be understood that in the case where the aryl substituent is a bicyclic substituent and one of the rings is a non-aromatic ring, the linkage is carried out through an aromatic ring.
  • heteroaryl means a stable monocyclic or bicyclic ring of up to 7 atoms in each ring, wherein at least one ring is an aromatic ring and contains from 1 to 4 selected from O, N, and Heteroatoms of S; heterocyclic aryl groups within the scope of this definition include, but are not limited to, acridinyl, oxazolyl, porphyrinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl , furyl, thienyl, benzothienyl, benzofuranyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, Pyrimidinyl, pyrrolyl, tetrahydroquinoline.
  • heterocyclic aryl is also understood to include any nitrogen-containing heteroaryl N-oxide derivative.
  • heterocyclic aryl substituent is a bicyclic substituent and one ring is a non-aromatic ring or does not contain a hetero atom, it is understood that the linking is carried out through an aromatic ring or through a hetero atom containing a ring, respectively.
  • halogen means fluorine, chlorine, bromine, iodine or hydrazine.
  • provided herein are methods of making pyrazolopyrimidine derivatives of Formula I and methods of use thereof.
  • the compounds described herein can be synthesized using the schemes synthesized below, and the target compounds can be synthesized by selecting appropriate starting materials using methods analogous to those described below.
  • the general methods of preparing the compounds disclosed herein can be derived from reactions known in the art, and the reactions can be modified to synthesize the target compound molecules by reagents and conditions deemed appropriate by those skilled in the art.
  • the following synthesis methods can be used as a basic guide.
  • reaction product can be worked up (isolated and purified) using conventional techniques including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. These products can be characterized using conventional analytical methods, including Physical constants and map data (m.p, HPLC, LC-MS, NMR, optical rotation, etc.).
  • the compounds described herein can be prepared as a single isomer using the synthetic methods described herein.
  • the present invention also provides a process for the preparation of the pyrazolopyrimidine derivative of the formula I, which comprises the following steps: coupling a compound II with an acid ZOH to obtain a pyrazole as shown in the formula I. a pyrimidine derivative;
  • the method for preparing a pyrazolopyrimidine derivative of the formula I further comprising the step of: deprotecting the compound III with an acid to obtain the compound II. ;
  • PG is a protecting group and may be Boc (tert-butoxycarbonyl), CBz (benzyloxycarbonyl) or Troc (trichloroethoxycarbonyl), preferably Boc. (tert-butoxycarbonyl).
  • the deprotection group can be subjected to conventional methods and conditions for such reactions in the art.
  • the method for producing a pyrazolopyrimidine derivative of the formula I further comprising the steps of: subjecting the compound IV to the compound V by a Suzuki coupling reaction under palladium catalysis to obtain the Compound III can be used;
  • R' and R" are each independently H or alkyl (for example, C 1 -C 4 alkyl, said "C 1 -C”
  • An alkyl group of 4 for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl; or R', R" and an oxygen atom or a boron atom therebetween form a ring Structure (for example or
  • the Suzuki coupling can employ conventional methods and conditions for such reactions in the art.
  • the method for producing a pyrazolopyrimidine derivative of the formula I further comprising the steps of: performing a Mitsunobu reaction of the compound VI with the compound V to obtain the compound IV;
  • Method 1 comprises the steps of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Compound VI-1) via (Mi) or (S)-N-Boc- Coupling of 3-hydroxypiperidine with (R) or (S)-N-Boc-3-hydroxypyrrole affords Boc protected intermediate compound IV-1. Then, the appropriately substituted phenylboronic acid is subjected to palladium metal-catalyzed cross-coupling under basic conditions to form an intermediate compound III-1. After deprotection with an acid, it is coupled with Z acid to complete the synthesis to obtain the target compound I-1.
  • Method 2 comprises the steps of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Compound VI-1) via Mitsunobu reaction with (R) or (S)-N-Boc-oxime Amino alcohol coupling gave Boc protected intermediate IV-2. Then, the appropriately substituted phenylboronic acid is subjected to palladium metal-catalyzed cross-coupling under basic conditions to form an intermediate III-2. After deprotection with an acid, it is coupled with Z acid to complete the synthesis to obtain the target compound I-2.
  • pyrazolopyrimidine derivatives of Formula I disclosed herein are obtained in good yield and purity using the synthetic methods described herein, as well as those known in the art.
  • Compounds prepared according to the methods disclosed herein are purified by conventional methods known in the art, such as filtration, recrystallization, chromatography, distillation, and combinations thereof.
  • the present invention also provides the use of any of the compounds of Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer, solvate, active metabolite, and prodrug thereof, for the preparation of a medicament, It can be administered alone or in combination with other therapeutic agents.
  • the medicament for use in the treatment and/or prevention of Bruton's tyrosine kinase (Btk) activity or for the benefit of Bruton's tyrosine kinase (Btk) activity in a mammal (including a human) A disease, condition, or condition that is inhibited.
  • the medicament may be administered alone or in combination with other therapeutic agents.
  • Combination drugs include, but are not limited to, doxorubicin, dactinomycin, bleomycin, vinblastine, cisplatin, acevicin; arubicin; apodazole hydrochloride; acronin; Aldileukin; hexamethylene melamine; ampomycin; aramid acetate; aziridine; ampicillin; anastrozole; acitretin; asparaginase; triamcinol; azacitidine Azatto; azamycin; bamastat; benzozide; bicalutamide; chlorinated hydrochloride; dimethyl sulfamate; diazepam; bleomycin sulfate; Buquina sodium; bromopyrimidine; busulfan; actinomycin C; carrazine; calamine; carbemide; carboplatin; carmustine; carbofuran hydrochloride; New; Westfinoco; chlorambucil; sir
  • the disease, disorder or condition which benefits from inhibition of Bruton's tyrosine kinase (Btk) activity includes, but is not limited to, cancer, inflammatory disease or disease state, immune disease or disease state, hyperplasia a disease or disease state and a degenerative disease or disease state.
  • the inflammatory disease or disease state, immune disease or disease state includes, but is not limited to, asthma, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), appendicitis, orbital inflammation, bronchioles Inflammation, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, lacrimal gland inflammation, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis , enterocolitis, epicondylitis, epididymitis, fasciitis, fibrinitis, gastritis, gastroenteritis, hepatitis, suppurative sweat gland inflammation, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, Nephritis, oophoritis, orchitis,
  • the autoimmune diseases include, but are not limited to, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, striata, juvenile arthritis, lupus, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Des thyroiditis, Graves' disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, strabismus syndrome, ankylosing spondylitis, Antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, abdominal disease, Goodpasch's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis , Lytle's syndrome, high arteritis, temporal arteritis, Warm-antibody autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, systemic
  • the xenon immune condition or disease including but not limited to graft versus host disease, transplantation, blood transfusion, allergic reaction, allergies (eg, for plant pollen, latex, drugs, food, insect toxins, animal hair, animal dander) , dust mites or sputum allergies), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis and atopic dermatitis.
  • the cancer includes, but is not limited to, head cancer, thyroid cancer, neck cancer, eye cancer, skin cancer, oral cancer, throat cancer, esophageal cancer, chest cancer, bone cancer, blood cancer, bone marrow cancer, lung cancer, Colon cancer, sigmoid colon cancer, rectal cancer, stomach cancer, prostate cancer, breast cancer, ovarian cancer, kidney cancer, liver cancer, pancreatic cancer, brain cancer, intestinal cancer, heart cancer, adrenal cancer, subcutaneous tissue cancer, lymph node cancer, pigmentoma, Malignant glioma, B cell proliferative disease.
  • the B cell proliferative diseases such as diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell pro-lymphocytic leukemia, lymphoplasmacytic lymphoma/Walden Stryst macroglobulinemia, spleen marginal lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, lymph node marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinum (thymus Large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt's lymphoma/leukemia or lymphomatoid granulomatosis.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an active compound and, optionally, one or more pharmaceutically acceptable carriers or excipients; said active compound being as described in Formula I
  • a pyrazolopyrimidine derivative a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate, an active metabolite, and a prodrug.
  • the invention also provides a disease, disorder or condition for treating and/or preventing a mammal and for inhibiting Bruton's tyrosine kinase activity or for treating inhibition of Bruton's tyrosine kinase activity
  • a method comprising the steps of: administering an effective amount of said pharmaceutical composition to a population in need thereof.
  • compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers including excipients and excipients which facilitate processing the active compound into a pharmaceutically acceptable formulation.
  • pharmaceutically acceptable carriers including excipients and excipients which facilitate processing the active compound into a pharmaceutically acceptable formulation.
  • the appropriate formulation will depend on the route of administration chosen. Any of the well-known techniques, carriers and excipients can be suitably employed and as understood in the art.
  • the pharmaceutical composition described in the present invention refers to a compound of any one of the compounds described herein and other chemical components such as a carrier, a stabilizer, an antioxidant, a disintegrant, a diluent, a dispersant, a filler, and a flavor. Mixtures of suspending agents, suspending agents, glidants, solubilizers, surfactants, wetting agents, thickening agents and/or excipients.
  • the pharmaceutical composition facilitates administration of the active compound to an organism.
  • Compositions A therapeutically effective amount of an active compound described herein is administered to a mammal having a disease, disorder or condition to be treated.
  • the mammal is a human.
  • the therapeutically effective amount can vary widely, depending on the severity of the disease, the age and relative health of the subject, the efficacy of the compound employed, and the like.
  • the active compound may be used alone or in combination with one or more therapeutic agents as a component of the mixture.
  • the pharmaceutical composition will comprise at least one of the pyrazolopyrimidine derivatives of the formula I described herein, in the form of the free acid or the free base, or as a pharmaceutically acceptable salt. Active ingredient. Additionally, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), and active metabolites of these same type of pyrazolopyrimidine derivatives of Formula I. . In some cases, a pyrazolopyrimidine derivative as shown in Formula I can exist as a tautomer. All tautomers are included within the scope of the compounds provided herein.
  • pyrazolopyrimidine derivatives of Formula I described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • solvated forms of the pyrazolopyrimidine derivatives as shown herein, as provided herein, are also considered to be disclosed herein.
  • compositions described herein can be administered to a subject by a variety of routes of administration including, but not limited to, oral, parenteral (eg, intravenous, subcutaneous, intramuscular), intranasal, buccal, Local, rectal or transdermal routes of administration.
  • routes of administration including, but not limited to, oral, parenteral (eg, intravenous, subcutaneous, intramuscular), intranasal, buccal, Local, rectal or transdermal routes of administration.
  • Dosage forms of the pharmaceutical compositions described herein include, but are not limited to, aqueous dispersions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, instant solutions.
  • compositions for oral administration can be obtained by mixing one or more solid excipients with one or more of the compounds described herein, optionally grinding the resulting mixture, if necessary, after adding suitable excipients
  • suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl Cellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; and the like, such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
  • a disintegrating agent such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate may be added.
  • compositions which can be used orally include push-in capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol.
  • the push-in capsules can contain the active ingredient in admixture in a filler such as lactose, a binder such as a starch and/or a lubricant such as talc or magnesium stearate, and optionally a stabilizer.
  • the active compound can be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin or liquid polyethylene glycol.
  • a stabilizer may be added. All formulations for oral administration should be in a form suitable for such administration.
  • the solid dosage forms disclosed herein can be in the form of tablets (including suspension tablets, instant tablets, Chew disintegrating tablets, fast disintegrating tablets, effervescent tablets or capsules), pills, powders (including aseptically packaged powders, non-essential powders or effervescent powders), capsules (including soft capsules or Hard capsules, such as capsules made from gelatin of animal origin or capsules or "dispersed capsules” made from plant-derived HPMC), solid dispersions, solid solutions, bioerodible formulations, controlled release formulations, pulsatile release dosage forms, Multiparticulate formulations, pellets, granules or aerosols.
  • the pharmaceutical formulation is in powder form.
  • the pharmaceutical formulation is in the form of a tablet, including but not limited to a fast dissolving tablet.
  • the pharmaceutical formulations described herein can be administered as a single capsule or as a multi-capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, or three, or four capsules or tablets.
  • the pharmaceutical composition will comprise a formulation of at least one of the compounds described herein as any one of the pyrazolopyrimidine derivatives of Formula I, suitable for intramuscular, subcutaneous or intravenous injection, and may include physiologically acceptable sterile water. Or a non-aqueous solution, dispersion, suspension or emulsion, and sterile powder injection for reconstituting a sterile injectable solution or dispersion.
  • aqueous and nonaqueous vehicles examples include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, cremophor, etc.), suitable mixtures thereof, vegetable oils (eg Olive oil) and organic esters for injection such as ethyl oleate.
  • Appropriate fluidity can be maintained, for example by the use of a coating such as lecithin; by the maintenance of the required particle size; and by the use of surfactants.
  • Formulations suitable for subcutaneous injection may also contain additives such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of microbial growth can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
  • An isotonic agent such as sugar, sodium chloride or the like may also be included as needed.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of delayed absorption agents such as aluminum monostearate and gelatin.
  • the present application also relates to various pharmaceutical compositions known in the pharmaceutical arts for use in intraocular, intranasal, and intra-oral delivery.
  • the pharmaceutical formulation comprises an aqueous ophthalmic solution of the active compound, which may be present in a water-soluble form such as an eye drop, or as a gellan gum or hydrogel; an ophthalmic ointment; an ophthalmic suspension, such as a microparticle, suspension. Small polymeric particles comprising a drug, a fat-soluble formulation, and microspheres; and an ophthalmic inserting agent in a liquid carrier medium.
  • these suitable pharmaceutical preparations are most often and preferably manufactured as sterile, isotonic and buffered preparations.
  • compositions also include drops and sprays which often mimic nasal secretions in a number of ways to ensure maintenance of normal ciliary action.
  • suitable formulations are most often and preferably isotonic, are lightly buffered to maintain a pH of 5.5 to 6.5, and most often and preferably include antimicrobial preservatives and appropriate drugs. stabilizer.
  • Pharmaceutical formulations for intra-oral delivery include suspensions and ointments for topical application in the ear. Common solvents for these otic preparations include glycerin and water. It can be administered to a mammal, such as a human, by oral, parenteral (intravenous, intramuscular, subcutaneous, etc.), pulmonary, topical, dermal, and the like.
  • the human dose of the compounds of the invention may range from about 0.1 mg to about 1000 mg.
  • the reagents and starting materials used in the present invention are commercially available.
  • room temperature means an ambient temperature of 10 ° C to 25 ° C.
  • the positive progress of the present invention is that the pyrazolopyrimidine derivative of the present invention has a good inhibitory effect on Bruton's tyrosine kinase and has good in vivo and in vitro inhibitory activity against tumor cell growth. Have a good market prospects.
  • Methyl (R)-glycidylate (1.0 g, 9.8 mmol) was dissolved in ethanol (8 ml) and H 2 O (1 ml), and KOH (0.66 g, 12 mmol). After stirring at room temperature for 2 hours, the material of the plate was completely reacted, and the solution was directly dried to give a pale yellow solid, which was directly used for the next step.
  • 4-fluoro-4-phenoxyphenylboronic acid can be obtained by using 4-bromo-2-fluoro-1-phenoxybenzene as a starting material.
  • L1210 murine lymphocyte leukemia cell line, DMEM + 10% FBS;
  • WSU-DLCL2 human B lymphoma cell line, RPMI1640 + 10% FBS;
  • K562 human chronic myeloid leukemia cell line, IMDM + 10% FBS;
  • HL-60 human promyelocytic leukemia cell line, IMDM + 20% FBS;
  • the cell concentration was adjusted to an appropriate concentration, and 96-well plates were seeded, and 100 ⁇ l of the cell suspension was inoculated per well.
  • the cells were incubated for 24 hours at 37 ° C in a 100% relative humidity, 5% CO 2 incubator.
  • the logarithmic growth phase cells were collected, counted, and the cells were resuspended in complete medium, and the cell concentration was adjusted to an appropriate concentration (determined according to the cell density optimization test results), and 96-well plates were seeded, and 100 ⁇ l of the cell suspension was added to each well. The cells were incubated for 24 hours at 37 ° C in a 100% relative humidity, 5% CO 2 incubator.
  • test compound was diluted with the medium to the corresponding concentration of action set, and the cells were added at 25 ⁇ l/well.
  • the final concentration of the compound was diluted from 10 ⁇ M to 0 ⁇ M in 4 fold gradients for a total of 10 concentration points.
  • the cells were incubated for 72 hours at 37 ° C in a 100% relative humidity, 5% CO 2 incubator.
  • the medium was aspirated, and the complete medium containing 10% CCK-8 was added and incubated in a 37 ° C incubator for 2-4 hours.
  • the absorbance at a wavelength of 450 nm was measured on a SpectraMax M5 Microplate Reader with gentle shaking, and the absorbance at 650 nm was used as a reference to calculate the inhibition rate.
  • tumor cell growth inhibition rate % [(Ac-As) / (Ac-Ab)] ⁇ 100%
  • the IC 50 curve was fitted and the IC 50 value was calculated using the software Graphpad Prism 5 and using the calculation formula log(inhibitor) vs.response.
  • Table 1 shows the growth inhibitory activity (IC 50 ) of some compounds on different tumor cells
  • the following experiment can be used to determine the inhibitory effect of the compounds of the invention on Bruton's tyrosine kinase (BTK) enzymatic activity.
  • the in vitro kinase assay was performed using Cisbio's HTRF kinEASE TK kit, and the procedure was followed by reference to the kit instructions, which examined the inhibitory effect of the test compound on BTK enzyme activity in vitro.
  • the specific steps are as follows:
  • the kinase reaction was initiated by adding 2 ⁇ L of ATP solution at the corresponding concentration of BTK enzyme to all wells.
  • the enzymatic reaction time of BTK was 25 minutes (see Table 1 for the corresponding ATP concentration and reaction time for enzyme screening).
  • the BTK test solution was prepared 5 minutes before the end of the kinase reaction. Streptavidin-XL665 and TK antibody europium cryptate (1:100) solutions were prepared using the detection buffer in the kit. The concentrations of the corresponding detection reagents for enzyme screening are shown in Table 1.
  • the plate was mixed and reacted at room temperature for 1 h, and the fluorescence signal (320 nm stimulation, 665 nm, 615 nm emission) was detected using an ENVISION (Perkinelmer) instrument. Inhibition was calculated for each well by total active aperture hole and a background signal, duplicate wells were averaged for each test compound simultaneously fitting the median inhibitory activity (IC 50) with specialized drawing software PRISM 5.0.
  • IC 50 median inhibitory activity
  • SCID Beige mice female, 5-6 weeks old, weighing 18g ⁇ 2g, purchased from Beijing Weitong Lihua Experimental Animal Co., Ltd., SPF-level environment.
  • WSU-DLCL2 cells Take WSU-DLCL2 cells in logarithmic growth phase, centrifuge at 1000 rpm for 5 min, resuspend in serum-free medium, and take 10 ⁇ L. The number of viable cells (cell survival rate > 90%) was counted by trypan blue staining, and the cell density was adjusted to 1 x 107 cells/0.2 mL.
  • Four 5-6 week old SCID mice were injected, and 1 ⁇ 107/side/0.2 mL of WSU-DLCL2 cells were injected under the left and right sacs under sterile conditions. Apparent subcutaneous tumor formation was observed in about two weeks.
  • the mice When the tumor grows to 300-500 mm3, the mice are euthanized, the tumor is exfoliated under sterile conditions, placed in 1640 medium, and cut into 1-2 mm3 tumor blocks (each subcutaneous tumor can be divided into 20-30 Tumor block). Tumors were inoculated into the right subcutaneous of 80 5-6 week old SCID mice using a 12 gauge trocar.
  • mice When tumors of tumor-bearing mice grew to a measurable size, mice were randomly divided into 8 groups according to the mean tumor volume balance principle using SPSS 17.0 software.
  • Compound Example 1 and Compound Example 2 were administered orally at 90, 30, 10 mg/kg per day; the positive control drug, ibrutinib, was administered orally at 30 mg/kg daily for a dose of 0.1 ml/10 g. .
  • the drug was administered once a day for 23 days, and the negative control group was given an equal amount of solvent (1% DMSO in physiological saline solution).
  • solvent 1% DMSO in physiological saline solution
  • RTV relative tumor volume

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Abstract

La présente invention concerne un dérivé de pyrazolopyrimidine, un procédé de fabrication, une composition pharmaceutique, et son utilisation. L'invention concerne également un dérivé de pyrazolopyrimidine représenté par la formule I, un stéréoisomère, un solvate, un sel pharmaceutiquement acceptable, un métabolite actif ou un de ses promédicaments. Le dérivé de pyrazolopyrimidine tel que représenté par la formule I dans la présente invention a une bonne activité inhibitrice par rapport à une tyrosine kinase de Bruton (Btk), et en particulier a une bonne activité inhibitrice in vitro et in vivo par rapport à la croissance de cellules tumorales. Ainsi, la présente invention a une bonne perspective d'application commerciale.
PCT/CN2015/075819 2015-04-03 2015-04-03 Dérivé de pyrazolopyrimidine, procédé de fabrication, composition pharmaceutique, et son utilisation Ceased WO2016154998A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110483521A (zh) * 2018-05-14 2019-11-22 杭州和正医药有限公司 一种可逆共价布鲁顿酪氨酸激酶抑制剂、药物组合物及其应用
WO2022081512A1 (fr) * 2020-10-12 2022-04-21 Synubi Pharmaceuticals Llc Compositions et méthodes de traitement de maladies neuro-inflammatoires avec des inhibiteurs de tyrosine kinase de bruton

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013191965A1 (fr) * 2012-06-18 2013-12-27 Principia Biopharma Inc. Pyrrolopyrimidines ou pyrazolopyrimidines covalentes réversibles utiles pour le traitement du cancer et de maladies auto-immunes
WO2014187319A1 (fr) * 2013-05-21 2014-11-27 Jiangsu Medolution Ltd Pyrazolopyrimidines substituées utiles comme inhibiteurs de kinases
WO2014188173A1 (fr) * 2013-05-20 2014-11-27 Redx Pharma Limited Dérivés pyrazolopyrimidine utiles comme inhibiteurs de la tyrosine kinase de bruton

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013191965A1 (fr) * 2012-06-18 2013-12-27 Principia Biopharma Inc. Pyrrolopyrimidines ou pyrazolopyrimidines covalentes réversibles utiles pour le traitement du cancer et de maladies auto-immunes
WO2014188173A1 (fr) * 2013-05-20 2014-11-27 Redx Pharma Limited Dérivés pyrazolopyrimidine utiles comme inhibiteurs de la tyrosine kinase de bruton
WO2014187319A1 (fr) * 2013-05-21 2014-11-27 Jiangsu Medolution Ltd Pyrazolopyrimidines substituées utiles comme inhibiteurs de kinases

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110483521A (zh) * 2018-05-14 2019-11-22 杭州和正医药有限公司 一种可逆共价布鲁顿酪氨酸激酶抑制剂、药物组合物及其应用
WO2022081512A1 (fr) * 2020-10-12 2022-04-21 Synubi Pharmaceuticals Llc Compositions et méthodes de traitement de maladies neuro-inflammatoires avec des inhibiteurs de tyrosine kinase de bruton

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