WO2017082759A1 - {3-[(7н-pyrrolo[2,3-d]pyrimidine-4-yle)-azolyle]azétidine-3-yle}-acétonitriles utilisés comme inhibiteurs de janus-kinases - Google Patents

{3-[(7н-pyrrolo[2,3-d]pyrimidine-4-yle)-azolyle]azétidine-3-yle}-acétonitriles utilisés comme inhibiteurs de janus-kinases Download PDF

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WO2017082759A1
WO2017082759A1 PCT/RU2015/000878 RU2015000878W WO2017082759A1 WO 2017082759 A1 WO2017082759 A1 WO 2017082759A1 RU 2015000878 W RU2015000878 W RU 2015000878W WO 2017082759 A1 WO2017082759 A1 WO 2017082759A1
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pyrrolo
pyrimidin
azetidin
pyrazol
compound
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PCT/RU2015/000878
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English (en)
Russian (ru)
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Алексей Евгеньевич РЕПИК
Александр Васильевич ИВАЩЕНКО
Василий Геннадьевич ИГНАТЬЕВ
Михаил Айратович ШАФЕЕВ
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Акционерное Общество "Р-Фарм" (Ао "Р-Фарм")
Алексей Евгеньевич РЕПИК
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Publication of WO2017082759A1 publication Critical patent/WO2017082759A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to ⁇ 3 - [(7H-pyrrolo [2,3- (1] pyrimidin-4-yl) -azolyl] azetidin-3-yl ⁇ -acetonitriles, as well as their compositions, methods of use and preparation. and their compositions are Janus kinase (JAK) inhibitors and can be used in the treatment of JAK associated diseases, including, for example, inflammatory and autoimmune disorders, as well as cancer.
  • JAK Janus kinase
  • JAKs play an important role in the cytokine-dependent regulation of proliferation and function of cells involved in the immune response.
  • JAKs are currently known: JAK1, JAK2, JA 3 (also known as white blood cell Janus kinase; JAKL; L-JAK) and TYK2 (also known as tyrosine kinase T).
  • Blocking signal transmission at the JAK level is promising for the development of methods for treating inflammatory diseases, autoimmune diseases, myeloproliferative and human cancers.
  • JAK inhibition is believed to have a therapeutic effect in patients suffering from immune disorders of the skin, such as psoriasis and skin sensitization.
  • Effective JAK inhibitors are of undoubted interest in the development of new drugs.
  • Some JA inhibitors, including pyrrolopyrimidines, are presented in WO 2009/1 14512. In this series of compounds, Baricitinib is the most advanced drug candidate.
  • Baricitinib showed fast (after 6 months of treatment) and sustained effectiveness in the treatment of rheumatoid arthritis in three phase III studies [NCT02340104, NCT02263911, NCT01710358. http: //www.medpagetoday.eom/MeetingCoverage/EULARy52084.http: //wvm.fiercepharma.com/pr ess-releases / lilly-and-incyte-announce-positive-top-line-results-phase-3-trial -baricitin].
  • JAK inhibitors are one of the main directions for the development of new, more effective drugs for the treatment of rheumatoid arthritis, cancer and other diseases.
  • the compounds and methods described herein are intended to meet these needs.
  • Alkyl means an aliphatic hydrocarbon linear or branched group with 1 to 12 carbon atoms in the chain. Branched means that the alkyl chain has one or more "lower alkyl” (C [-C 6 ) alkyl substituents.
  • Preferred alkyl groups are (C1- C6 ) alkyl, even more preferred (C1-C3) alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butl, tert-bug, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, cyclohexyl.
  • Alkyl may have substituents.
  • “Substituted alkyl” - substituted alkyl may have one or more, same or different substituents, including halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, heteroaryl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl alkylthio, heteroarylthio, aralkylthio, arylsulfonyl, alkylsulfonyl, heteroaralkyloxy or R k a R k +] a N-, where R k a and Rk + i a are independently “amino substituents”, the meanings of which are defined in this section, for example, a hydrogen atom, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, or Rk a and Rk + i
  • Amino group means an R] R 2 N- group, optionally substituted or unsubstituted, with the same substituents Ri and R 2 .
  • An amino group may have substituents.
  • Active component drug substance, drug substance, drug-substance
  • drug substance drug substance, drug-substance
  • drug-substance means a physiologically active substance of synthetic or other (biotechnological, plant, animal, microbial and other) origin, having pharmacological activity and is the active principle of the pharmaceutical composition used for the manufacture and manufacture medicinal product (means).
  • Halogen means fluoro, chloro, bromo and iodo. Fluorine, chlorine and bromine are preferred.
  • Metal is a group of one carbon atom and one hydrogen atom CH.
  • Medical product - a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of tablets, capsules, injections, ointments and other formulations intended to restore, correct or alter physiological functions in humans and animals, as well as for treatment and disease prevention, diagnosis, anesthesia, contraception, cosmetology and more.
  • “Pharmaceutical composition” means a composition comprising an active component and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible fillers, solvents, diluents, carriers, auxiliary, dispensing and perceptive means, means of delivery, such as preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterial agents, fungicides, lubricants, regulators of prolonged delivery, the choice and ratio of which depends on the nature and method of administration and dosage.
  • suspending agents examples include ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, as well as mixtures of these substances. Protection against the action of microorganisms can be achieved using a variety of antibacterial and antifungal agents, for example, parabens, chlorobuganol, sorbic acid and the like.
  • the composition may also include isotonic agents, for example, sugars, sodium chloride and the like.
  • the prolonged action of the composition can be achieved using agents that slow down the absorption of the active principle, for example aluminum monostearate and gelatin.
  • suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, and also mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate).
  • excipients are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like.
  • grinders and distributors are starch, alginic acid and its salts, silicates.
  • lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol.
  • the pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form in the form of a mixture with traditional pharmaceutical carriers.
  • Suitable unit dosage forms include oral forms such as tablets, gelatine capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, topical, transdermal such as ointments and creams, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.
  • “Pharmaceutically acceptable salt” means the relatively non-toxic organic and inorganic salts of the acids and bases of the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of the compounds or prepared specially. In particular, base salts can be prepared on the basis of the purified free base of the claimed compound and a suitable organic or inorganic acid.
  • salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, dichloroacetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, c tartrates, mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like Selection, and Use.
  • Salts of the claimed acids can also be specially prepared by reacting the purified acid with a suitable base, metal and amine salts can be synthesized.
  • a suitable base metal and amine salts can be synthesized.
  • Suitable inorganic bases from which metal salts can be obtained are hydroxide, carbonate, sodium bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide.
  • amines and amino acids are selected that are sufficiently basic to form a stable salt and are suitable for medical use (in particular, they should have low toxicity).
  • Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris (hydroxymethyl) aminomethane and the like.
  • tetraalkylammonium hydroxides such as, for example, choline, can be used for salt formation. tetramethylammonium, tetraethylammonium and the like.
  • amino acids the main amino acids can be used - lysine, ornithine and arginine.
  • An object of the present invention is to provide novel JAK inhibitors for the treatment of rheumatoid arthritis, cancer and other diseases.
  • R la represents alkyl or cycloalkyl, preferably Ci-Csalkyl
  • X and Y represent a nitrogen atom; or X represents a nitrogen atom, and Y represents methine; or X represents methine, and Y represents a nitrogen atom;
  • R 1 represents S0 2 CH 2 CH 3 ;
  • X and Y represent a nitrogen atom, or X represents a methine, and Y represents a nitrogen atom.
  • the subject of the present invention is a new JAK inhibitor of the general formula
  • the present invention relates in particular to a JAK inhibitor selected from: ⁇ 1 - (2-hydroxy-ethanesulfonyl) -3- [4- (7H-pyrrolo [2,3-] pyrimidin-4-yl) -pyrazol-1 - sludge] - azetidin-3-yl ⁇ -acetonitrile (1.1);
  • compound means all stereoisomers, geometric isomers, tautomers, and isotopes of compounds of general formula 1. All compounds and pharmaceutically acceptable salts can be isolated together with other substances, such as water and solvents (eg, hydrates and solvates).
  • the compounds of the present invention may also include all isotopes of atoms present in the intermediate or final compounds.
  • Isotopes include atoms having the same atomic number but different mass numbers.
  • hydrogen isotopes include tritium and deuterium.
  • phrases “pharmaceutically acceptable” is used herein to mean compounds, materials, compositions and / or dosage forms that, within the limits of the medical evaluation error, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problem or complication, proportionate to a reasonable benefit / risk ratio.
  • the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts include, but are not limited to, salts of mineral or organic acids; alkaline or organic salts of acidic residues of compounds of formula 1, such as carboxylic or sulfonic acids.
  • Pharmaceutically acceptable salts of the present invention include the usual non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound that contains a basic or acidic group by conventional chemical methods.
  • such salts can be prepared by reacting the free acidic or basic forms of these compounds with a stoichiometric amount of the corresponding base or acid in water or in an organic solvent or in a mixture of the two.
  • Non-aqueous media are generally preferred, such as ether, ethyl acetate, ethanol, isopropanol, acetone or acetonitrile (ACN).
  • ACN acetonitrile
  • the compounds of the present invention can be prepared using known methods of organic synthesis and can be synthesized in accordance with any of the many possible synthetic routes.
  • the reaction for the preparation of the compounds of the invention can be carried out in suitable solvents, which can be easily selected by one skilled in the art of organic synthesis.
  • suitable solvents can essentially react with starting materials (reagents), intermediates at reaction temperatures, for example, the temperature of which can vary from the freezing point of the solvent to the boiling point of the solvent. This reaction can be carried out in one solvent or in a mixture of solvents.
  • suitable solvents for the particular reaction step may be selected by one skilled in the art.
  • the inhibitory activity and selectivity of the compounds of general formula 1 with respect to JAK are generally comparable to the activity and selectivity of Baricitinib, which is currently undergoing phase III clinical trials [NCT02340104; NCT0226391 1; NCT01710358; JD Clark, M.E. Flanagan, J.-B. Telliez. Discovery and Development of Janus Kinase (JAK) Inhibitors for Inflammatory Diseases. J. Med. Chem. 2014, 57, 5023-5038].
  • a process for preparing the compounds of the invention may include a protecting group and its removal.
  • the need for a protective group and its removal, and the selection of appropriate protective groups, can be easily determined by a person skilled in the art.
  • the chemistry of protecting groups can be found, for example, in T. W. Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., Wiley & Sons, Inc., New York ( 1999), which is incorporated herein by reference in its entirety.
  • the present invention relates to a method for producing a compound of general formula 1, which consists in processing a compound of formula 1a, resulting in the removal of the protective group R 2 (Scheme 1).
  • R 1 represents S0 2 (CH 2 ) n CH 2 OH, S0 2 (CH 2 ) n CH 2 F, S0 2 (CH 2 ) n CHF 2 , S0 2 (CH 2 ) n CF 3 , S0 2 (CH 2 ) n C0 2 R la , S0 2 (CH 2 ) n C0 2 H, CH 2 CH 2 S0 2 CH 3 , CH 2 CH 2 S0 3 H, CH 2 CH 2 S0 2 NH 2 ; n is 1 or 2;
  • R la represents alkyl or cycloalkyl, preferably C] -C 3 alkyl
  • X and Y represent a nitrogen atom; or X represents a nitrogen atom, and Y represents methine; or X represents methine, and Y represents a nitrogen atom;
  • R 1 represents S0 2 CH 2 CH 3 ;
  • X and Y represent a nitrogen atom, or X represents methine, and Y represents a nitrogen atom;
  • R denotes protective groups that include, but are not limited to, protective groups for amines presented in the book [Wuts and Greene, Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: New Jersey, 696-887, 2007] , which is incorporated into this description by reference in its entirety.
  • the protective group R 2 is stable under the conditions of removal of the protective groups R 3 and R 4 (scheme 1 and scheme 2).
  • the R 2 protecting group is a group that is not removed from 1N to 5N hydrochloric acid at room temperature, at a temperature of from about 10 ° C to 40 ° C, at a temperature of from about 15 ° C to 40 ° C, or at a temperature of 15 ° C to 30 ° C.
  • R 2 is benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Tgos), 2- (trimethylsilyl) ethoxycarbonyl (Teoc), 2- (4-trifluoromethylphenylsulfonyl) ethoxycarbonyl (TSC), jure / i-butoxycarbonyl (BOC), 1-adamantyloxycarbonyl (Adoc), 2-adamantylcarbonyl (2-Adoc), 2,4-dimethyl -Z-yloxycarbonyl (Doc), cyclohexyloxycarbonyl (Special), L, L-dimethyl-2,2,2-trichloroethoxycarbonyl (TcBOC), vinyl, 2-chloroethyl, 2-phenylsulfonylethyl, allyl, benzyl, 2-nitrobenzyl, 4- nitrobenzyl, 4-diphenyl-pyridylmethyl
  • the R 2 protecting group may be removed by treatment with a fluoride ion (e.g., treatment with tetrabutylammonium fluoride), hydrochloric acid, or Lewis acid (e.g., lithium tetrafluoroborate).
  • a fluoride ion e.g., treatment with tetrabutylammonium fluoride
  • hydrochloric acid e.g., hydrochloric acid
  • Lewis acid e.g., lithium tetrafluoroborate
  • the treatment includes treatment with lithium tetrafluoroborate followed by treatment with ammonium hydroxide (for example, when R 2 is 2- (trimethylsilyl) ethoxymethyl)).
  • ammonium hydroxide for example, when R 2 is 2- (trimethylsilyl) ethoxymethyl
  • the resulting corresponding hydroxymethyl intermediate is then treated with an aqueous solution of ammonium hydroxide at room temperature to give a compound of general formula 1.
  • a compound of formula la can be prepared by reacting compound lb and a compound of formula R'-Z (Scheme 1).
  • Z in the compound R'-Z represents a leaving group.
  • the leaving group Z is a group well known in the art, for example, halogen.
  • a more preferred leaving group Z is chloro or fluoro.
  • the compound of formula lb can be obtained by removing the protective group R 3 from compound 1c (Scheme 1).
  • R protecting groups include, but are not limited to, amine protecting groups presented in the book [Wuts and Greene, Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: New Jersey, 696-887, 2007], which is included in the present description by reference in its entirety.
  • R 3 is a protecting group that can be selectively removed under conditions that do not displace
  • R is a protecting group that can be removed in acidic media at room temperature, at a temperature of from 15 ° C to 40 ° C, or at a temperature of from 15 ° C to about 30 ° C.
  • R is alkoxycarbonyl, for example, / wpew-butoxycarbonyl.
  • Suitable processing conditions do not displace the protecting group R 2 .
  • the treatment of the compound of formula 1c is carried out in acidic media at room temperature, at a temperature of from 15 ° C to 40 ° C, or at a temperature of from 15 ° C. to about 30 ° C.
  • treating the compound of formula 1c involves treating with hydrochloric acid in 1, 4-dioxane.
  • a compound of formula 1a is prepared by a process comprising reacting a compound of formula Id and a compound of formula 1e.
  • Michael addition reactions between the compound of formula Id and the compound of formula 1e can be carried out in the presence of a base (Michael catalyst).
  • a base Moichael catalyst
  • tetraalkyl ammonium halides, tetraalkyl ammonium hydroxides, guanidine, amidine, alkali metal hydroxide, alkali metal phosphate, tertiary amine, alkali metal carbonate, alkali metal bicarbonate, alkali metal hydrogen phosphate, phosphine or alkali metal salt are used as Michael catalyst carboxylic acid, etc.
  • 1,8-diazabicyclo (5.4.0) undec-7-ene is used as a Michael catalyst.
  • a stoichiometric or catalytic amount of base is used to facilitate the Michael addition reaction.
  • the reaction is carried out in an organic solvent, such as acetonitrile or dimethylacetamide, at room temperature for two to six hours.
  • a compound of formula If is prepared by a process comprising treating a compound of formula Id (Scheme 2).
  • R 4 represents a protective group.
  • the corresponding R 4 groups include, but are not limited to, the amine protecting groups presented in [Wuts and Greene, Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: New Jersey, 696- 887, 2007], which is incorporated herein by reference in its entirety.
  • R 4 represents a protective group that can be selectively removed under conditions that do not displace the protective group R 2 .
  • R 4 is a protecting group that can be removed with acid at room temperature, at a temperature of 15 ° C to 40 ° C, or at a temperature of 15 ° C to 30 ° C.
  • R 4 is 1- (ethoxy) ethyl, tri (C1-Calkyl) silyl (e.g., tetra-i-butyldimethylsilyl or triisopropylsilyl), p-methoxybenzyl (PMB), triphenylmethyl (Tg), diphenylmethyl, hydroxymethyl , methoxymethyl (MOM), diethoxymethyl, or mpew-butyldimethylsilyl.
  • R 4 is L- (ethoxy) ethyl.
  • R 4 protecting group from a compound of formula If can be achieved by methods known in the art for the removal of specific amine protecting groups presented in [Wuts and Greene, Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: New Jersey , 696-887, 2007], which is incorporated herein by reference in its entirety.
  • the compound of formula If is treated with an acid (e.g., hydrochloric acid or trifluoroacetic acid) at room temperature, at a temperature of 15 ° C to 40 ° C, or at a temperature of 15 ° C to 30 ° C.
  • a compound of formula 1 f is prepared using a process comprising reacting a compound of formula lg with a compound of formula lh (Scheme 2).
  • the Suzuki reaction can be carried out using a number of Pd (0) and Pd (II) catalysts under conditions known in the art (see, for example, a review by Miyaura and Suzuki, Chem. Rev. 1995, 95, 2457-2483, which is included in the description in its entirety).
  • a palladium catalyst from about 0.0010 to about 0.0015 equivalents of a palladium catalyst are used. In some embodiments, an approximately stoichiometric ratio of compounds of the formula log and lh is used, for example from about 1 to about 1.05, or from about 1 to about 1.35.
  • an organic solvent containing water is used for this synthesis step. The organic solvent used is 1,4-dioxane, 1-butanol, 1,2-dimethoxyethane (DME), 2-propanol, toluene or ethanol, or combinations thereof. In some embodiments, the organic solvent comprises a combination of 1-butanol and dimethyl ether.
  • the base is an inorganic base, and in some an organic base.
  • the base is an alkali metal carbonate or an alkali metal hydrogen carbonate.
  • the base is potassium carbonate (K 2 C0 3 ).
  • K 2 C0 3 potassium carbonate
  • two to five equivalents of a base (e.g., K 2 C0 3 ) or two to five equivalents of a base (e.g. NaHC0 3 ) are used.
  • the Suzuki reaction is carried out at a temperature of from about 80 ° C to 100 ° C. In some embodiments, the reaction is carried out for two to twelve hours.
  • Z in a compound of formula lg is chloro, bromo or iodo.
  • a compound of formula lg (Scheme 2) is prepared from a compound of formula P by the introduction of a protecting group R 2 as described above, preferably (trimethylsilyl) ethoxymethyl or ⁇ -pivaloyloxymethyl.
  • protective group R is carried out using known in the field of chemistry protective groups for amines [Wuts and Greene, Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: New Jersey, 696-887, 2007].
  • indole nitrogen is deprotonated with a base (e.g. sodium hydride) in an organic solvent (e.g.
  • a method for producing a compound of formula 1 includes the step of reacting a compound of formula lj with a compound of formula R'-Z; where Z represents a leaving group.
  • Z is halogen, including chlorine or fluorine.
  • reaction of a compound of formula lj with a compound of formula R —Z is carried out in the presence of a base, for example, a tertiary amine such as triethylamine, diisopropylethylamine, ⁇ -methylmorpholine and the like.
  • a base for example, a tertiary amine such as triethylamine, diisopropylethylamine, ⁇ -methylmorpholine and the like.
  • a compound of formula lj is prepared by removing the protecting group R 2 of a compound of formula lb (Scheme 1).
  • the above synthetic methods can be used to obtain any of the compounds described here or their combinations or any of the compounds described in the examples.
  • the present invention relates to any combination of separate methods for preparing a compound of general formula 1, a compound of formula 1 a, etc.
  • the present invention further relates to any of the intermediates described above or their salts.
  • a method for preparing salts of compounds of general formula 1 involves reacting a compound of formula 1a with hydrochloric acid, dichloroacetic acid, methanesulfonic acid, phosphoric acid, benzenesulfonic acid (PhS0 3 H), para-toluenesulfonic acid (i-CHzRpBOzN) or with 1,5-naphthalene disulfonic acid (1,5-NDSA) to form the corresponding salt.
  • Salts of a compound of general formula 1 can be prepared by treating a solution of the corresponding free base of formula 1a in an organic solvent such as ethanol (EtOH), an acid solution in an organic solvent such as ethanol at room temperature or at elevated temperature (for example, from 60 ° C to 70 ° C).
  • EtOH ethanol
  • the salt obtained, if necessary, can be further purified by recrystallization or other well-known methods, for example, reprecipitation or washing.
  • the compounds of the present invention can modulate the activity of one or more JAKs.
  • modulate means the ability to increase or decrease the activity of one or more members of the JAK family. Accordingly, the compounds of the invention can be used in methods for modulating JAK activity by any one or more of the compounds of general formula 1 or compositions thereof.
  • compounds of general formula 1 may act as inhibitors of one or more JAKs.
  • compounds of general formula 1 can be used to modulate JAK activity in a patient who needs such modulation of the receptor by introducing a modulating amount of a compound of general formula 1.
  • An object of the present invention is a method for treating diseases or disorders in patients associated with JA by administering to a patient in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • a JAK-related disease can include any disease, disorder or condition directly or indirectly associated with expression or activity in a JAK, including overexpression and / or an abnormal level of activity.
  • a JAK concomitant disease can also include any disease, disorder or condition that can be prevented, ameliorated or cured by modulating JAK activity.
  • the subject of the present invention is a method for the treatment of JAK-associated autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, type I diabetes, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, myasthenia gravis, immunoglobulin nephropathy, and immunoglobulins, thyroid disease and the like.
  • the compounds of general formula 1 can be administered to a patient in the form of pharmaceutical compositions.
  • These compositions can be obtained by a method well known in the pharmaceutical field, and can be administered in various ways depending on whether local or systemic treatment is required and on the area to be treated.
  • the compositions may be in the form of tablets, pills, powders, lozenges, wafers, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
  • compositions may be formulated in unit dosage form, each dose containing from about 5 mg to about 1000 mg, usually from about 100 mg to about 500 mg, of the active ingredient.
  • unit dose refers to physically discrete units suitable as unit doses for humans and other mammals, each unit containing a predetermined amount of active material, calculated to produce the desired therapeutic effect, in combination with a suitable pharmaceutical excipient.
  • the active compound can be effective over a wide range of doses and is usually administered in a pharmaceutically effective amount. It should be understood, however, that the amount of actually taken compound will usually be determined by the attending physician in accordance with the condition of the patient to be treated.
  • Example 1 ⁇ 1 - (2-Hydroxy-ethanesulfonyl) -3- [4- (7H-pyrrolo [2,3- (1] pyrimidin-4-yl) pyrazol-1-yl] -azetidin-3-yl ⁇ -acetonitrile (1.1) was obtained in accordance with scheme 3.
  • the solution is degassed by passing an argon stream through the solution for 3 minutes, after which tetrakis (triphenylphosphine) palladium (0) (0.23 g, 1.4 mmol, 0.05 equiv) is added and the resulting reaction mixture was heated in a microwave system (120 ° C, 2 h).
  • a microwave system 120 ° C, 2 h.
  • Stage (b, c) 400 mg (0.78 mmol) of product 1.9 (1) were stirred for 2 hours in a mixture of 20 ml of methylene chloride and 10 ml of trifluoroacetic acid. Solvents were removed in vacuo. The residue 1.9 (2) was dissolved in 20 ml of methanol, a solution of 1 ml of 25% NH 4 OH in 2 ml of water was added. The mixture was stirred at room temperature overnight. The mixture was evaporated to dryness in vacuo, 70 ml of water was added to the residue and extracted with ethyl acetate (30 ml each three times). The combined organic extract was washed with brine, dried over Na 2 S0 4 and evaporated to dryness in vacuo.
  • Example 9 ⁇ 3- [4- (7H-Pyrrolo [2,3 ⁇ ] pyrimidin-4-yl) -pyrazol-1-yl] -1 - ethanesulfonyl-azetidin-3-yl ⁇ acetonitrile (1.10) was obtained in accordance with circuit 1 1.
  • Example 1 1. ⁇ 1- (3-Hydroxypropyl) -3- [4- (7H-pyrrolo [2,3 ⁇ ] pyrimidin-4-yl) -1H-pyrazol-1-yl] -azetidin-3-yl ⁇ acetonitrile trifluoroacetate (1.14 CF 3 C0 2 H) was prepared according to Scheme 13.
  • Example 14 Determination of the inhibitory activity of compounds against JAK. Compounds were tested according to Life Technologi's standard Z "-Lyte screening protocol.) Test compounds are tested in 1% DMSO (final) in the well. 100 nl YuOx test compounds in 100% DMSO 2.4 ⁇ l of kinase buffer (50 mM HEPES, pH6.5, 0.01% BRIJ-35, 10 mM MgCl 2 , 1 mM EGTA, 0.02% NaN 3 ) was added under low volume NBS, black 384 -Nu plates (Corning Cat. # 4514).
  • kinase buffer 50 mM HEPES, pH6.5, 0.01% BRIJ-35, 10 mM MgCl 2 , 1 mM EGTA, 0.02% NaN 3
  • the degree of phosphorylation of the FRET peptide can be calculated from the emission ratio.
  • the emission factor will remain low if the Lada peptide is not phosphorylated (i.e., not kinase inhibition) and will be high if the Lada peptide is non-phosphorylated (i.e., kinase inhibition).
  • Co% average coumarin emission signal control 0% phosphorylation
  • Fioo% average fluorescein emission signal control 100% phosphorylation
  • the concentration curve of the kinase activity versus the concentration of the tested substances was constructed using the sigmoid model.
  • Example 15 Determination of thermodynamic solubility of the compounds of formula (1) and the prototype Baricitinib. 5 mg of the test compound was mixed with 1 ml of universal buffer (pION) with a pH of 2.0, 4.0 or 7.0 for 15 min at 25 ° C. Additional amounts of substances were added until the solution became cloudy. Vials with solution were incubated with stirring for 24 hours at 25 ° C to achieve equilibrium between solution and precipitate at saturation. After equilibration, 200 ⁇ l of the solution (in duplicate) was filtered through a 96-well filter plate (Millipore) to separate the precipitate.
  • pION universal buffer
  • the concentration of compounds in the filtrate was determined spectrophotometrically using a standard calibration curve.
  • the optical absorption spectrum of the substance was measured and a calibration curve was constructed at the selected wavelength (usually corresponding to the maximum absorption of the substance Xmax).
  • the concentration of the substance in the filtrate was calculated by the formula below:
  • Solubility (OD imax filtrate - OD imax blank) / Slope x 1.67 x Filtrate dilution,
  • ODx max filtrate is the optical density of the filtrate
  • Example 16 Obtaining a drug in the form of tablets. A mixture of 1600 mg of starch, 1600 mg of crushed lactose, 400 mg of talc and 1000 mg of an inhibitor of 1.16 CHC1 2 C0 2 N was pressed. The resulting bar was crushed into granules and sieved through a sieve, collecting granules with a size of 14-16 mesh. The granules obtained were tabletted into tablets of suitable forms weighing 500 mg each.
  • Example 17 Obtaining a drug in the form of capsules. Inhibitor 1.16 CHC1 2 C0 2 H was thoroughly mixed with lactose in a ratio of 2: 1. The resulting powdery mixture was packaged in 600 mg in gelatin capsules of the appropriate size.
  • Example 18. Obtaining a medicinal product in the form of compositions for intramuscular, intraperitoneal or subcutaneous injection. 500 mg of the inhibitor 1.16 ⁇ 1 2 ⁇ 0 2 ⁇ , 300 mg of chlorobuganol, 2 ml of propylene glycol and 100 ml of water for injection were mixed. The solution was filtered and placed in 1 ml ampoules, which were sealed.
  • the invention can be used in medicine and veterinary medicine.

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Abstract

Le but de la présente invention est de produire de nouveaux inhibiteurs de JAK pour le traitement d'arthrite rhumatoïde, du cancer et d'autres maladies. Cet objectif est atteint grâce à des {3-[(7Н-pyrrolo[2,3-D]pyrimidine-4-yle)-azolyle]azétidine-3-yle}-acétonitriles correspondant à la formule générale (1), ou leurs sels acceptables sur le plan pharmaceutique, où R1 représente SO2(CH2)nCH2OH, SO2(CH2)nCH2F, SO2(CH2)nCHF2, SO2(CH2)nCF3, SO2(CH2)nCO2R1a, SO2(CH2)nCO2H, CH2CH2SO2CH3, CH2CH2SO3H, CH2CH2SO2NH2; n=1 ou 2. R1a représente alkyle ou cycloalkyle, de préférence С1-С3alkyle; X et Y représentent un atome d'azote; ou X représente un atome d'azote et Y représente méthyne; ou X représente méthyne et Y représente un atome d'azote; ou R1 représente SO2CH2CH3; ou Y et Y représentent un atome d'azote, ou X représente méthyne et Y représente un atome d'azote.
PCT/RU2015/000878 2015-11-13 2015-12-14 {3-[(7н-pyrrolo[2,3-d]pyrimidine-4-yle)-azolyle]azétidine-3-yle}-acétonitriles utilisés comme inhibiteurs de janus-kinases WO2017082759A1 (fr)

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CN108976233A (zh) * 2017-06-02 2018-12-11 南京优科生物医药研究有限公司 巴瑞替尼的杂质及其制备、检测方法
WO2018223859A1 (fr) * 2017-06-07 2018-12-13 四川科伦博泰生物医药股份有限公司 Forme solide de derivé d'azétidine, son procédé de préparation et son utilisation
CN109651424A (zh) * 2017-10-11 2019-04-19 新发药业有限公司 一种7-保护基-4-(1-氢-吡唑-4-基)吡咯[2,3-d]嘧啶的简便合成方法
US10766900B2 (en) 2017-12-29 2020-09-08 Formosa Laboratories, Inc. Baricitinib intermediate, method for forming Baricitinib intermediate, and method for preparing Baricitinib or pharmaceutically acceptable salt thereof
CN115124537A (zh) * 2022-07-13 2022-09-30 山东大学 一种jak抑制剂巴瑞替尼的制备方法

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EP3360878B9 (fr) * 2015-12-11 2021-05-05 Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. Dérivé d'azétidine, son procédé de préparation et son utilisation
EP3533451B1 (fr) 2017-01-21 2022-07-27 Guangzhou Hanfang Pharmaceuticals Co., Ltd. Application de paeéniflorin-6'-o-benzène sulfonate en médecine pour le traitement du syndrome de sjögren
CN113508114B (zh) * 2019-02-27 2024-03-26 四川科伦博泰生物医药股份有限公司 以氮杂环丁烷衍生物为活性成分的口服药物组合物、其制备方法及用途

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CN108976233A (zh) * 2017-06-02 2018-12-11 南京优科生物医药研究有限公司 巴瑞替尼的杂质及其制备、检测方法
WO2018223859A1 (fr) * 2017-06-07 2018-12-13 四川科伦博泰生物医药股份有限公司 Forme solide de derivé d'azétidine, son procédé de préparation et son utilisation
CN110494435A (zh) * 2017-06-07 2019-11-22 四川科伦博泰生物医药股份有限公司 氮杂环丁烷衍生物的固体形式及其制备方法和用途
JP2020522462A (ja) * 2017-06-07 2020-07-30 シチュアン ケルン−バイオテック バイオファーマシューティカル カンパニー リミテッド アゼチジン誘導体の固体形態並びにその調製方法及びその使用
US11066403B2 (en) 2017-06-07 2021-07-20 Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. Solid form of azetidine derivative and preparation method therefor and use thereof
CN110494435B (zh) * 2017-06-07 2022-02-15 四川科伦博泰生物医药股份有限公司 氮杂环丁烷衍生物的固体形式及其制备方法和用途
JP7120505B2 (ja) 2017-06-07 2022-08-17 シチュアン ケルン－バイオテック バイオファーマシューティカル カンパニー リミテッド アゼチジン誘導体の固体形態並びにその調製方法及びその使用
CN109651424A (zh) * 2017-10-11 2019-04-19 新发药业有限公司 一种7-保护基-4-(1-氢-吡唑-4-基)吡咯[2,3-d]嘧啶的简便合成方法
CN109651424B (zh) * 2017-10-11 2021-01-22 新发药业有限公司 一种7-保护基-4-(1-氢-吡唑-4-基)吡咯[2,3-d]嘧啶的合成方法
US10766900B2 (en) 2017-12-29 2020-09-08 Formosa Laboratories, Inc. Baricitinib intermediate, method for forming Baricitinib intermediate, and method for preparing Baricitinib or pharmaceutically acceptable salt thereof
CN115124537A (zh) * 2022-07-13 2022-09-30 山东大学 一种jak抑制剂巴瑞替尼的制备方法

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