WO2017124934A1 - Dérivé de carboline contenant de la phosphine servant d'inhibiteur de bromodomaine - Google Patents

Dérivé de carboline contenant de la phosphine servant d'inhibiteur de bromodomaine Download PDF

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WO2017124934A1
WO2017124934A1 PCT/CN2017/070636 CN2017070636W WO2017124934A1 WO 2017124934 A1 WO2017124934 A1 WO 2017124934A1 CN 2017070636 W CN2017070636 W CN 2017070636W WO 2017124934 A1 WO2017124934 A1 WO 2017124934A1
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group
compound
phosphine
alkynyl
alkyl
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PCT/CN2017/070636
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English (en)
Chinese (zh)
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王能辉
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宁波文达医药科技有限公司
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the present invention relates to a phosphine-containing porphyrin derivative as a bromodomain inhibitor.
  • the genome of eukaryotes is highly organized within the nucleus.
  • the long chain of double-stranded DNA is entangled with a group of protein octamers (most commonly comprising two copies of histones H2A, H2B, H3 and H4) to form nucleosomes.
  • the basic unit is then further compressed by nucleosome aggregation and folding to form a highly agglomerated chromatin structure.
  • a range of different condensed states are possible, and the tightness of the structure changes during the cell cycle and is most tight during the cell division process.
  • Chromatin structure plays a key role in regulating gene transcription, and gene transcription cannot be efficiently produced by highly condensed chromatin.
  • the chromatin structure is controlled by a series of post-translational modifications to histones, particularly histones H3 and H4, and the modifications are most commonly within the histone tail, which extends beyond the core nucleosome structure. These modifications include acetylation, methylation, phosphorylation, ubiquitination, and SUMOylation. These epigenetic marks are written and erased by specific enzymes that will be tagged to specific residues within the tail of the histone, thus forming an epigenetic code, which is then interpreted by the cell to allow for the chromatin structure. Specific regulation and thus transcription.
  • Histone acetylation is most commonly associated with activation of gene transcription, as this modification relaxes the interaction of DNA and histone octamers by altering electrostatic properties.
  • specific proteins bind to acetylated lysine residues within histones to read epigenetic coding.
  • the bromodomains are small, distinct domains within a protein that are normally, but not exclusively, bound to acetylated lysine residues.
  • the Bet family domain-containing protein of the Bet family includes four proteins (BRD2, BRD3, BRD4 and BRD-t) containing a tandem Bromo domain domain, and the tandem Bromo domain domain can bind two The acetylated lysine residue is in close proximity, thereby increasing the specificity of the interaction. It has been reported that BRD2 and BRD3 bind to histones along actively transcribed genes and may be involved in promoting transcriptional elongation (Leroy et al., Mol. Cel.
  • Bromo domain domain inhibitors are BMS-986158 (BMS), MRK-8628 (Merck), BAY 1238097 (Bayer), INCB54329 (Incyte) and the like.
  • BMS-986158 BMS
  • MRK-8628 Merck
  • BAY 1238097 Bayer
  • INCB54329 IncB54329
  • a phosphine-containing porphyrin derivative a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein the phosphine-containing porphyrin-derived
  • the structure of the object is as shown in the following formula I:
  • R 1 , R 2 , R 3 and R 4 are each independently hydrogen, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 1 -8 alkoxy, C 1-8 alkoxycarbonyl, C 3-8 epoxyalkyl, aryl, heteroaryl, or 3- to 12-membered heterocyclic; or, adjacent R 1 , R 2 , R 3 , R 4 together with the carbon atom to which they are bonded form a 3- to 9-membered ring;
  • R 5 is selected from the group consisting of hydrogen, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 An alkoxycarbonyl group, an aryl group, a heteroaryl group, or a 3- to 12-membered heterocyclic group;
  • R 6 is selected from the group consisting of hydrogen, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 An alkoxycarbonyl group, an aryl group, a heteroaryl group, or a 3- to 12-membered heterocyclic group;
  • R 7 is selected from the group consisting of: hydrogen, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 An alkoxycarbonyl group, an aryl group, a heteroaryl group, or a 3- to 12-membered heterocyclic group;
  • R 8 is selected from the group consisting of: hydrogen, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 Alkoxycarbonyl;
  • R 9 is selected from the group consisting of: hydrogen, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 Alkoxycarbonyl;
  • each substitution refers to substitution with from 1 to 6 substituents, preferably from 1 to 3 substituents.
  • the 3- to 9-membered ring optionally contains 1-2 additional heteroatoms selected from N, O or S.
  • the 3- to 9-membered ring is saturated or unsaturated.
  • R 1 and R 2 together with the carbon atom to which they are attached form a 3- to 9-membered ring, preferably a 5-membered ring or a 6-membered ring.
  • R 2 and R 3 together with the carbon atom to which they are attached form a 3- to 9-membered ring, preferably a 5-membered ring or a 6-membered ring.
  • R 4 is selected from the group consisting of hydrogen, halogen, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-5 alkoxy.
  • R 5 is selected from the group consisting of C 3-8 epoxyalkyl, aryl, and heteroaryl.
  • R 6 is selected from the group consisting of aryl, heteroaryl, and 3- to 12-membered heterocyclic.
  • the 3- to 12-membered heterocyclic group is saturated or unsaturated and contains 1, 2, or 3 heteroatoms selected from N, O or S.
  • R 7 is selected from the group consisting of hydrogen, halogen, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-5 straight chain and branched alkoxy base.
  • R 8 is selected from the group consisting of hydrogen, halogen, deuterated C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl.
  • R 8 is a deuterated methyl group.
  • R 9 is selected from the group consisting of hydrogen, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 Cycloalkyl, C 1-8 alkoxy, C 1-8 alkoxycarbonyl.
  • R 9 is a deuterated methyl group.
  • R 9 is selected from the group consisting of C 1-3 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 1-5 alkoxy .
  • the configuration of the chiral carbon atom in the compound of formula (I) is R or S.
  • the phosphine-containing porphyrin derivative is:
  • a pharmaceutical composition comprising: (i) an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof; and (ii) A pharmaceutically acceptable carrier.
  • a third aspect of the invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, according to the first aspect of the invention, for use in:
  • the disease is selected from the group consisting of cancer, neurological diseases, metabolic diseases, cardiovascular diseases, viral infections, inflammation, tissue fibrosis-related diseases, and autoimmune diseases.
  • the tumor is selected from the group consisting of: lung cancer, breast cancer, blood cancer, cervical cancer, ovarian cancer, intestinal cancer, pancreatic cancer, prostate cancer, liver cancer, brain tumor, skin cancer, and other solid tumors.
  • a method of inhibiting the activity of a Bromo domain comprising the steps An inhibitory effective amount of a compound of formula I according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or an inhibitory effective amount of a pharmaceutical composition according to the second aspect of the invention, administered to an inhibitory subject, .
  • a process for the preparation of a compound according to the first aspect of the invention which comprises the steps of:
  • the method further includes the steps of:
  • the method further includes the steps of:
  • the method further includes the steps of:
  • the method further includes the steps of:
  • the reactivity of Hal 1 in the step (5) is superior to that of Hal 2 .
  • L is a halogen group.
  • M is a boric acid or borate group.
  • the inventors of the present application have extensively and intensively studied for the first time to develop a novel phosphine-containing porphyrin derivative having the structure shown in Formula I for use as a Bromo domain domain inhibitor. On the basis of this, the present invention has been completed.
  • each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
  • alkyl refers to a straight (ie, unbranched) or branched alkyl group having from 1 to 8 carbon atoms, or a combination thereof.
  • the alkyl group can be saturated, monounsaturated or polyunsaturated, and can include divalent or multivalent radicals.
  • the alkyl group has a carbon number limitation (for example, C 1-10 )
  • the C 1-8 alkyl group may include 1 to 8 carbon atoms.
  • a linear or branched alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.
  • alkenyl when used alone or as part of another substituent, refers to a straight or branched, carbon chain having at least one carbon-carbon double bond.
  • the alkenyl group having one double bond may be represented by -C n H 2n-1
  • the alkenyl group having 2 double bonds may be represented by -C n H 2n-3 .
  • the alkenyl group has a carbon number limitation (for example, C 2-8 )
  • it means that the alkenyl group has 2 to 8 carbon atoms, for example, a linear or branched alkenyl group having 2 to 8 carbon atoms.
  • alkynyl when used alone or as part of another substituent, refers to an aliphatic hydrocarbon group having at least one carbon to carbon triple bond.
  • the alkynyl group can be straight or branched, or a combination thereof.
  • the alkynyl group has 2-12 (eg, 2-8, 2-6, or 2-4) carbon atoms.
  • the alkynyl group has a carbon number number (for example, C 2-8 alkynyl group), it means that the alkynyl group has 2 to 8 carbon atoms.
  • C 2-8 alkynyl group means having 2 to 8 A linear or branched alkynyl group of one carbon atom, such as ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or the like.
  • cycloalkyl refers to a monocyclic, bicyclic or tricyclic (including cyclo, bridged or spiro) ring system having a saturated or partially saturated.
  • the cycloalkyl group may have 3 to 12 (e.g., 3 to 10, or 5 to 10) carbon atoms.
  • a certain cycloalkyl group has a carbon number limitation (e.g., C 3-10 ), it means that the cycloalkyl group has 3 to 10 carbon atoms.
  • C 3-8 cycloalkyl refers to a saturated or partially saturated monocyclic or bicyclic alkyl group having from 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentane. A group, a cycloheptyl group, or the like.
  • alkoxy refers to an alkyl group (eg, -O-alkyl) attached through an oxygen atom, wherein alkyl is as defined above.
  • alkoxy groups are, for example but not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, Or a similar group.
  • the alkoxy group may be substituted by one or more substituents such as a halogen, an amino group, a cyano group, or a hydroxyl group.
  • the alkoxy group can be straight or branched. When the alkoxy group has a carbon number limitation (e.g., C 1-8 ), it means that the cycloalkyl group has 1 to 8 carbon atoms.
  • halogen when used alone or as part of another substituent, refers to F, Cl, Br, and I.
  • the alkoxy group may have 1 to 8 carbon atoms.
  • the alkoxycarbonyl group has a carbon number limitation (for example, C 1-8 ) it means that the alkyl moiety of the alkoxycarbonyl group has 1-8 carbon atoms, for example, a C 1-8 alkoxycarbonyl group.
  • aryl when used alone or as part of another substituent, refers to a monocyclic, bicyclic or fused ring aromatic hydrocarbon group.
  • the aryl group may be substituted or unsubstituted.
  • an aryl group has a carbon number limit (e.g., C 6-12 ), it means that the aryl group has 6 to 12 carbon atoms.
  • Examples of aryl groups are, for example but not limited to, phenyl, biphenyl, naphthyl, or the like (each of which may be optionally substituted).
  • the aryl group is preferably a C 6-12 aryl group.
  • heteroaryl when used alone or as part of another substituent, refers to a monocyclic, bicyclic or fused ring aromatic group having a particular number of ring carbon atoms (eg, C 4-10 has 4 to 10 ring-forming carbon atoms) and includes at least one same or different hetero atom selected from N, O or S.
  • the atoms on each ring can be arbitrarily substituted.
  • the heteroaryl group may be 5- to 15-membered, having 1 to 5 aromatic ring groups each independently selected from a hetero atom of N, O or S. Examples of heteroaryl groups are, for example but not limited to, pyridine, pyrimidine, pyrrole, oxazole, indole, furan, benzofuran, thiophene, or the like.
  • heterocyclyl refers to a saturated or partially saturated substituent of a monocyclic or fused ring having a particular number of ring-forming carbon atoms (eg, C). 3-11 has 3 to 11 ring-forming carbon atoms) and includes at least one same or different hetero atom selected from N, O or S.
  • the heterocyclic group may be a 3- to 15-membered heterocyclic group having 1 to 5 hetero atoms each independently selected from N, O or S.
  • heterocyclic group examples are, for example but not limited to, a nitrogen heterocyclic group, an oxaheterocyclic group, a thioheterocyclic group, a nitrogen oxyheterocyclyl group, a nitrogen thioheterocyclic group, an oxathioheterocyclic group, etc., more preferably The heterocyclic groups appearing in the various examples of the present application.
  • the heterocyclic group may be monocyclic, bicyclic or tricyclic (including a bicyclic ring, a bridged ring or a spiro ring).
  • a pharmaceutically acceptable salt of a compound of the invention refers to a salt that is suitable for contact with the tissue of a subject (eg, a human) without causing unpleasant side effects.
  • a pharmaceutically acceptable salt of a compound of the invention includes a salt (eg, a potassium salt, a sodium salt, a magnesium salt, a calcium salt) of a compound of the invention having an acidic group or is basic A salt of a compound of the invention (e.g., a sulfate, a hydrochloride, a phosphate, a nitrate, a carbonate).
  • substituted when with or without “optionally” means that one or more hydrogen atoms on a particular group are replaced by a particular substituent.
  • Particular substituents are the substituents described above in the corresponding paragraphs, or the substituents which appear in the examples.
  • an optionally substituted group may have a substituent selected from a particular group at any substitutable position of the group, and the substituents may be the same or different at each position.
  • a cyclic substituent, such as a heterocycloalkyl group may be attached to another ring, such as a cycloalkyl group, to form a spirobicyclic ring system, for example, two rings having a common carbon atom.
  • substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the substituents are, for example but not limited to, hydrazine, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered Cyclo, aryl, heteroaryl, halogen, hydroxy, carboxy (-COOH), C 1-8 aldehyde, C 2-10 acyl, C 2-10 ester, amino.
  • the deuterated alkyl group may be fully deuterated, or partially deuterated or a mixture thereof.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention and a pharmaceutically acceptable inorganic and organic acid, wherein preferred inorganic acids include, but are not limited to, hydrochloric acid, hydrogen Bromic acid, phosphoric acid, nitric acid, sulfuric acid; preferred organic acids include, but are not limited to: formic acid, acetic acid, propionic acid, succinic acid, naphthalene disulfonic acid (1, 5), asiamic acid, oxalic acid, tartaric acid, lactic acid , salicylic acid, benzoic acid, valeric acid, diethyl acetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, Gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic
  • pharmaceutically acceptable solvate refers to a compound of the invention that forms a solvate with a pharmaceutically acceptable solvent, wherein the pharmaceutically acceptable solvent includes, but is not limited to, water , ethanol, methanol, isopropanol, tetrahydrofuran, dichloromethane.
  • pharmaceutically acceptable stereoisomer means that the chiral carbon atom to which the compound of the invention relates may be in the R configuration, in the S configuration, or a combination thereof.
  • the invention also provides a pharmaceutical composition having significant anti-tumor efficacy comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable salts Carrier.
  • the preparation is administered orally in the form of a tablet, a capsule, a granule, a powder or a syrup, or is administered orally in the form of an injection.
  • the pharmaceutical composition preferably contains, as an active ingredient, a compound of the formula I of the present invention or a pharmaceutically acceptable salt thereof in an amount of from 0.01% to 99% by weight, more preferably from 0.1% to 90% by weight of the active ingredient.
  • compositions can be prepared by conventional pharmaceutical methods.
  • useful pharmaceutical adjuvants include excipients (e.g., saccharide derivatives such as lactose, sucrose, glucose, mannitol, and sorbitol; starch derivatives such as corn starch, potato starch, dextrin, and carboxymethyl starch; Cellulose derivatives such as crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose; gum arabic; dextran; silicate derivatives such as magnesium metasilicate Aluminum; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate, etc., binders such as gelatin, polyvinylpyrrolidone and polyethylene glycol, disintegrants For example, cellulose derivatives such as sodium carboxymethylcellulose, polyvinylpyrrolidone, lubricants (such as talc, calcium stea
  • the dose of the compound of the present invention, a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition thereof varies depending on the age, sex, race, condition, and the like of the patient.
  • the compound of the present invention has an excellent inhibitory activity against a bromodomain, the compound of the present invention and various crystal forms thereof, a pharmaceutically acceptable inorganic or organic salt, hydrate or solvate,
  • a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the treatment, prevention, and alleviation of diseases associated with the activity or expression level of the Bromo domain.
  • the compounds of the present invention are useful for treating (but not limited to) various diseases such as lung cancer, bladder cancer, breast cancer, stomach cancer, liver cancer, salivary gland sarcoma, ovarian cancer, prostate cancer, cervical cancer, and epithelium.
  • T cell carcinoma multiple myeloma, pancreatic cancer, lymphoma, chronic myelogenous leukemia, lymphocytic leukemia, cutaneous T-cell lymphoma, etc.
  • T cell-mediated inflammation and autoimmune diseases such as rheumatoid arthritis, collagen II Arthritis, multiple sclerosis, systemic lupus erythematosus, psoriasis, juvenile diabetes, Sjogren's syndrome, thyroid disease, sarcoidosis, inflammatory bowel disease, celiac disease, etc.
  • autoimmune diseases such as rheumatoid arthritis, collagen II Arthritis, multiple sclerosis, systemic lupus erythematosus, psoriasis, juvenile diabetes, Sjogren's syndrome, thyroid disease, sarcoidosis, inflammatory bowel disease, celiac disease, etc.
  • Other neurological diseases metabolic diseases, cardiovascular diseases, viral infections, inflammation, diseases related to tissue fibrosis, and
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 1 to 200 mg of the compound of the invention per agent.
  • the "one dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually from 1 to 2000 mg, preferably from 5 to 500 mg.
  • the specific dose Factors such as the route of administration, the health of the patient, and the like should also be considered, which are within the skill of the skilled physician.
  • porphyrin derivatives according to the present invention can be prepared by various methods well known in the art of organic synthetic chemistry and those skilled in the art.
  • the compounds of the present invention can be synthesized using the methods described hereinafter, along with synthetic methods known in the art of organic chemistry or variations as understood by those skilled in the art.
  • the compounds of the present invention can be prepared from readily available starting materials using the following general methods and procedures. It will be understood that when typical or preferred process operating conditions (i.e., reaction temperatures, times, moles of reactants, solvents, pressures, etc.) are given, other process operating conditions may also be used unless otherwise indicated. The optimum reaction conditions may vary depending on the particular reactants or solvents employed, but such conditions can be determined by one of ordinary skill in the art by routinely preferred procedures.
  • the methods of the compounds of formula I of the present invention described herein can be monitored according to any suitable method known in the art. For example, nuclear magnetic resonance, mass spectrometry, HPLC, thin layer chromatography to monitor product formation.
  • the preparation of the compounds can involve the protection and deprotection of multiple chemical groups.
  • the need for protection and deprotection, as well as the selection of suitable protecting groups, can be readily determined by those skilled in the art, and the chemistry of the protecting groups is in Greene and Wuts, Protective Groups in Organic Synthesis, Third Edition, Wiley & Sons, 1999.
  • the synthetic route of the compounds according to the invention is as follows:
  • the compounds of the invention may be prepared using the reaction schemes and procedures described above, but are not limited to the reagents and solvents in the reaction conditions.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each as defined above.
  • Hal 1 and Hal 2 are halides, and the reactivity of Hal 1 is better than that of Hal 2 , and the reactivity of I (Hal 1 ) is better than that of Cl (Hal 2 ).
  • Hal 1 in X can be easily converted to a phosphine-containing compound IX.
  • brominated benzene can be reacted with dimethylphosphine oxide or triethyl phosphite by Suzuki reaction to give the corresponding phosphine-containing compound.
  • Hal 2 in IX can be easily converted to boric acid or borate compound VIII by the Suzuki reaction.
  • L is a leaving functional group, such as a halogen or OH, which can be converted to a trifluoromethanesulfonic acid leaving functional group.
  • the Suzuki reaction such as 2,5-dibromo-3-nitropyridine and XIII, gives the pyridine compound VI.
  • phosphine reagent such as 1,2-bis(diphenylphosphino)ethane
  • a phosphine reagent such as 1,2-bis(diphenylphosphino)ethane
  • the nitrogen in the porphyrin compound IV can be reacted with V under the reaction conditions of Mitsunobu to obtain the compound II.
  • II and intermediate compound I are subjected to a phosphine-containing porphyrin compound I under appropriate catalyst conditions.
  • the present invention provides a novel structure of a phosphine-containing porphyrin derivative
  • the compound provided by the present invention has a significant inhibitory effect on the Bromo region domain
  • the present invention provides a pharmaceutical composition for preventing or treating a disease associated with a Bromo domain domain.
  • reaction solution was poured into water and extracted with ethyl acetate.
  • the BRD4 activity assay was performed according to the TR-FRET method in the Cayman kit. Dilute 3x BRD TR-FRET Assay Buffer 1 to 1x BRD TR-FRET Assay Buffer with ultrapure water. Use 1x BRD TR-FRET Assay Buffer 100 Dilute Tb-labeled donor and dye-labeled acceptor. Add 5 ⁇ l of diluted Tb-labeled donor and dye-labeled acceptor to the sample well, negative control well and positive control well.
  • the configured 1x BRD TR-FRET Assay Buffer was prepared in 10% DMSO solution (the concentration of DMSO was too high to affect the reaction, the final concentration of DMSO was controlled to be 1%), and then the test compound was diluted with 10% DMSO solution.
  • the initial screening concentration of the compound was 1 ⁇ M and 100 nM.
  • the IC50 test starts at 10 ⁇ M or 100 ⁇ M, 3 times dilution, 8 or 10 concentration points.
  • BRD TR-FRET Assay Buffer BRD4 (BD1+BD2) bromodomain protein was diluted to 6 ng/ ⁇ l (18 ng/well), and 3 ⁇ l of diluted BRD4 (BD1+BD2) bromodomain protein was added to all wells and mixed, and reacted at room temperature for 2 h, using ENVISION ( The fluorescence signal (320 nm stimulation, 665 nm, 615 nm emission) was detected by Perkinelmer instrument. The inhibition rate of each well was calculated from the positive control well and the negative control well. The average value of the duplicate wells was taken, and the analysis software PRISM 5.0 was used for each Compounds were tested for fit to half-inhibitory activity (IC50), Table 1.
  • the MDA-MB-231 cell line was ordered from the Shanghai Cell Resource Center of the Chinese Academy of Sciences. It was carried out according to the method in the CCK-8 kit. The logarithmic growth phase cells were collected, counted, and the cells were resuspended in complete medium to adjust the cell concentration to the appropriate level. Concentration (determined according to cell density optimization test results), inoculate 96-well plates, add 100 ⁇ l of cell suspension per well. Cells were incubated at 37 ° C, 100% relative humidity, 5% CO 2 incubator for 24 hours. The compound was diluted to the corresponding concentration of the solution, and the cells were added at 25 ⁇ l/well.
  • the final concentration of the compound was from 1 ⁇ M to 0 ⁇ M, and the gradient was diluted by 3 times for a total of 10 concentration points.
  • the cells were placed at 37 ° C, 100% relative humidity, 5 Incubate for 72 hours in a %CO 2 incubator. Add 1/10 volume of CCK-8 directly to the cell culture medium and incubate in a 37 ° C incubator for 2-4 hours. Gently shake and measure 450 nm on a SpectraMax M5 Microplate Reader. The absorbance at the wavelength was calculated by taking the absorbance at 650 nm as a reference, and the inhibition rate was calculated. The IC50 curve was fitted and the IC50 value was calculated using the software Graphpad Prism 5.
  • the H211 and H187 cell lines were ordered from the ATCC and assayed according to the instructions of the Alamar-Blue assay kit.
  • the drug was dissolved in DMSO to a 50 mM stock solution and stored in a freezer at -20 °C.
  • dilute the DMSO-diluted drug to a final concentration of 10X in cell culture medium.
  • the 96-well cell culture plate was taken out from the box, and 10 ⁇ l of a medium containing a series of different concentrations of the drug (10X final concentration) was added to the 96-well plate, and placed in a CO 2 incubator for 72 hours at 37 ° C for detection, and the calculated inhibition was performed.
  • the rate was calculated by using the GraphPad Prism 5.0 and MATILAB software using a nonlinear regression method to obtain a series of dose response curves from which the IC50 of the sample to be tested was obtained, Table 2.

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Abstract

L'invention concerne un dérivé de carboline contenant de la phosphine servant d'inhibiteur de bromodomaine, et un procédé et des médicaments pour lutter contre des maladies en intervenant au moyen d'une protéine à bromodomaine.
PCT/CN2017/070636 2016-01-20 2017-01-09 Dérivé de carboline contenant de la phosphine servant d'inhibiteur de bromodomaine WO2017124934A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015100282A1 (fr) * 2013-12-24 2015-07-02 Bristol-Myers Squibb Company Composés tricycliques comme agents anti-cancers
CN104860995A (zh) * 2014-02-24 2015-08-26 宁波文达医药科技有限公司 作为Bromodomain抑制剂的含磷吲哚衍生物
US20160176864A1 (en) * 2014-12-23 2016-06-23 Bristol-Myers Squibb Company Novel tricyclic compounds as anticancer agents
WO2016183115A1 (fr) * 2015-05-12 2016-11-17 Bristol-Myers Squibb Company Composés 5h-pyrido[3,2-b]indole en tant qu'agents anticancéreux

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015100282A1 (fr) * 2013-12-24 2015-07-02 Bristol-Myers Squibb Company Composés tricycliques comme agents anti-cancers
CN104860995A (zh) * 2014-02-24 2015-08-26 宁波文达医药科技有限公司 作为Bromodomain抑制剂的含磷吲哚衍生物
US20160176864A1 (en) * 2014-12-23 2016-06-23 Bristol-Myers Squibb Company Novel tricyclic compounds as anticancer agents
WO2016183115A1 (fr) * 2015-05-12 2016-11-17 Bristol-Myers Squibb Company Composés 5h-pyrido[3,2-b]indole en tant qu'agents anticancéreux

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