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WO2023204629A1 - Procédé de production d'un composé activateur de cftr et intermédiaire utilisé à cet effet - Google Patents

Procédé de production d'un composé activateur de cftr et intermédiaire utilisé à cet effet Download PDF

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Publication number
WO2023204629A1
WO2023204629A1 PCT/KR2023/005378 KR2023005378W WO2023204629A1 WO 2023204629 A1 WO2023204629 A1 WO 2023204629A1 KR 2023005378 W KR2023005378 W KR 2023005378W WO 2023204629 A1 WO2023204629 A1 WO 2023204629A1
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Prior art keywords
formula
compound
acid
pyrazolo
dimethoxyphenyl
Prior art date
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PCT/KR2023/005378
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English (en)
Korean (ko)
Inventor
유근철
이건희
권재욱
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Ildong Pharmaceutical Co Ltd
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Ildong Pharmaceutical Co Ltd
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Publication of WO2023204629A1 publication Critical patent/WO2023204629A1/fr
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/04—Artificial tears; Irrigation solutions
    • 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

Definitions

  • the present invention relates to a method of preparing a compound that modulates the activity of cystic fibrosis transmembrane conductance regulator (CFTR) and to intermediates used therein. More specifically, it relates to a novel compound that increases the activity of CFTR. It relates to a process for preparing a compound and novel intermediates used in the process.
  • CFTR cystic fibrosis transmembrane conductance regulator
  • Cystic fibrosis transmembrane conductance regulator refers to a membrane protein and chloride ion (Cl - ) channel encoded by the CFTR gene. Activating CFTR present in the cell membrane can treat a number of diseases mediated by loss or deterioration of CFTR function, for example, dry eye syndrome by activating chlorine ion (Cl - ) channels to increase tear volume. Abnormal tear film that appears can be corrected.
  • the present inventors have completed the present invention by not only providing a method for producing a new compound capable of controlling CFTR activity, but also by devising a new method that is more suitable for mass production and can obtain the target compound with high purity and high efficiency. did.
  • One aspect is to provide a method for preparing a compound represented by Formula 1 or Formula 1a.
  • Another aspect is to provide an intermediate that can be used in the above manufacturing method.
  • Another aspect is to provide a compound represented by Formula 1 or Formula 1a according to the above production method.
  • Another aspect is to provide a use of a CFTR activator compound represented by Formula 1 or Formula 1a.
  • One aspect provides a method for preparing a compound represented by Formula 1 or Formula 1a.
  • Another aspect provides an intermediate that can be used in the above manufacturing method.
  • Another aspect provides a compound represented by Formula 1 or Formula 1a according to the above production method.
  • Another aspect provides the use of a CFTR activator compound represented by Formula 1 or Formula 1a.
  • the present invention appropriately suppresses the production of unnecessary by-products in each process and obtains intermediate compounds as solids, so the reproducibility of the manufacturing process is excellent, manufacturing management is easy, and even on a scale-up scale for large-scale production. Since the target compound can be manufactured with high purity, it can be effectively used in the commercial manufacture of pharmaceuticals.
  • One aspect provides a method for preparing a compound of Formula 1, comprising the step of preparing a compound of Formula 1 by benzoylating a compound of Formula 5 below or a pharmaceutically acceptable acid addition salt thereof.
  • R 1 is C 1-3 alkoxy
  • R 2 is C 1-4 alkyl or C 3-4 cycloalkyl, and when R 2 is C 1-4 alkyl, two adjacent R 2 are spiro-linked cyclopropyl or spiro-linked cyclobutyl. can be formed,
  • R 3 is C 1-3 alkyl or halogen
  • n is an integer from 0 to 2
  • n is an integer from 0 to 2
  • a is an integer from 0 to 5
  • R 1 is C 1-3 alkoxy
  • R 2 is C 1-4 alkyl or C 3-4 cycloalkyl, and when R 2 is C 1-4 alkyl, two adjacent R 2 are spiro-linked cyclopropyl or spiro-linked cyclobutyl. can be formed,
  • n is an integer from 0 to 2
  • n is an integer from 0 to 2.
  • alkyl refers to a straight-chain or branched hydrocarbon residue that may be substituted or unsubstituted.
  • alkyl having 1 to 4 carbon atoms may include without limitation all possible isomers thereof, such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, and t-butyl.
  • alkoxy refers to a straight-chain or branched hydrocarbon residue, which may be substituted or unsubstituted, connected to oxygen.
  • alkoxy with 1 to 4 carbon atoms limits all possible isomers thereof, such as methoxy, ethoxy, propoxy, and butoxy, or isopropoxy, isobutoxy, and t-butoxy. Can be included without.
  • halogen refers to an element in group 17 of the periodic table as a chemical series.
  • halogens may include fluoro (F), chloro (Cl), bromo (Br), and iodine (I).
  • cycloalkyl refers to a saturated hydrocarbon ring having a ring carbon atom.
  • cycloalkyl having 3 to 6 carbon atoms may include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • spiro refers to two rings sharing one atom, and refers to the case where the two rings are not connected by a bridge.
  • spirocycloalkyl refers to a saturated carbocycle forming two rings, where both rings share only one carbon atom as part of the ring.
  • spirocycloalkyl having 3 to 4 carbon atoms may include spirocyclopropyl and spirocyclobutyl.
  • R 1 can be methoxy, ethoxy, propoxy, or isopropoxy. In one embodiment, R 1 can be methoxy.
  • R 2 can be methyl, ethyl, propyl, butyl, isopropyl, isobutyl, t-butyl, cyclopropyl, cyclobutyl, spirocyclopropyl, or spirocyclobutyl. In one embodiment, R 2 can be methyl, ethyl, propyl, isopropyl, cyclopropyl, or spirocyclopropyl.
  • R 3 can be methyl, ethyl, propyl, isopropyl, fluoro, chloro, bromo, or iodine. In one embodiment, R 3 can be methyl, fluoro, or chloro.
  • the compound of Formula 5 may be in the form of a free base or an acid addition salt.
  • the acid addition salt may be any pharmaceutically acceptable acid addition salt for the compound, and may be prepared by any suitable method available to those skilled in the art.
  • the compound When using the acid addition salt of Formula 5, the compound can be solidified, making it suitable for mass production, and has the advantage of being able to obtain the target compound in high purity without undergoing a purification process such as column chromatography. Therefore, the acid addition salt can be included in the present invention regardless of its type as long as it can solidify the compound of Formula 5 in free base form.
  • the acid addition salt of the compound of Formula 5 may be an acid addition salt formed by a free acid, and the free acid may be an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, or sulfuric acid;
  • Organic acids such as L-aspartic acid, L-glutamic acid, maleic acid, fumaric acid, oxalic acid, and 4-aminosalicylic acid;
  • Halogen acetic acids such as 2,2-dichloroacetic acid and trifluoroacetic acid; or organic sulfonic acids or derivatives thereof such as alkanesulfonic acids or derivatives thereof such as ethane-1,2-disulfonic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid; Naphthalenesulfonic acid or derivatives thereof such as naphthalene-1,5-disulfonic acid, naphthalene-2
  • the acid addition salt may be an inorganic acid salt such as hydrochloride, hydrobromide, hydroiodide, nitrate, phosphate, or sulfate;
  • Organic acid salts such as L-aspartate, L-glutamate, maleate, fumarate, oxalate, and 4-aminosalicylate;
  • Halogen acetate such as 2,2-dichloroacetate and trifluoroacetate; or organic sulfonates or derivatives thereof such as alkanesulfonates or derivatives thereof such as ethane-1,2-disulfonate, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate;
  • Naphthalenesulfonate or derivatives thereof such as naphthalene-1,5-disulfonate, naphthalene-2-sulfonate, di(tert-butyl)naphthalenedisulfonate, di(
  • the pharmaceutically acceptable acid addition salt of the compound of Formula 5 is any one of trifluoroacetate, fumarate, hydrochloride, hydrobromide, benzenesulfonate, camphorsulfonate, and 4-toluenesulfonate. It can be.
  • the compound of Formula 1 can be prepared by subjecting the compound of Formula 5 or a pharmaceutically acceptable acid addition salt thereof to a benzoylation reaction.
  • benzoylation or “benzoylation reaction” is a chemical reaction in which a benzoyl group is bonded to an organic compound.
  • the benzoylation may be performed by reacting the compound of Formula 5 or a pharmaceutically acceptable acid addition salt thereof with the compound of Formula 6 below.
  • R 3 is C 1-3 alkyl or halogen
  • R 4 is halogen, hydroxy, or ego
  • a is an integer from 0 to 5.
  • the compound of Formula 6 may be a compound of Formula 6a below.
  • R 4a is halogen, hydroxy, or am.
  • the reagent used in the benzoylation reaction of the compound of Formula 5 or a pharmaceutically acceptable acid addition salt thereof is benzoyl fluoride, benzoyl chloride, benzoyl bromide, benzoyl iodide, benzoic anhydride, benzoic acid, and any of these. It may be any one selected from the group consisting of combinations.
  • the reagent used in the benzoylation reaction may be benzoyl chloride, benzoic anhydride, or benzoic acid.
  • the benzoylation reaction of the compound of Formula 5 or a pharmaceutically acceptable acid addition salt thereof can be performed in the presence of a base.
  • the type of the base is not particularly limited as long as it does not inhibit the benzoylation reaction.
  • it may be performed in the presence of at least one base selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and any combinations thereof.
  • the benzoylation reaction of the compound of Formula 5 or a pharmaceutically acceptable acid addition salt thereof can be performed with the base in the presence of an amide coupling agent.
  • the amide coupling agent is propanephosphonic anhydride (T 3 P), thionyl chloride (SOCl 2 ), phosphorus trichloride (PCl- 3 ), phosphorus pentachloride (PCl- 5 ), phosphorus oxychloride (POCl 3 ), and pivalo chloride.
  • amide coupling agent used in the amidation reaction may be propanephosphonic acid anhydride (T 3 P).
  • the benzoylation reaction of the compound of Formula 5 or a pharmaceutically acceptable acid addition salt thereof is any one selected from benzoyl fluoride, benzoyl chloride, benzoyl bromide, benzoyl iodide, benzoic anhydride, benzoic acid, and combinations thereof. reagent; and
  • It may be performed in the presence of at least one base selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and any combination thereof.
  • the benzoylation reaction of the compound of Formula 5 or a pharmaceutically acceptable acid addition salt thereof is any one selected from benzoyl fluoride, benzoyl chloride, benzoyl bromide, benzoyl iodide, benzoic anhydride, benzoic acid, and combinations thereof. reagent;
  • At least one base selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and any combinations thereof;
  • T 3 P Propanephosphonic acid anhydride
  • SOCl 2 thionyl chloride
  • PCl- 3 phosphorus trichloride
  • PCl- 5 phosphorus pentachloride
  • POCl 3 phosphorus oxychloride
  • PivCl pivaloyl chloride
  • CDI 1,1'-carbonyldiimidazole
  • EDC 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride
  • EDC N,N,N,N'-tetramethyl- Performed in the presence of an amide coupling agent selected from the group consisting of O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), cyanuric chloride (TCT), and any combinations thereof. It can be.
  • the method may further include preparing a compound of Formula 5 or a pharmaceutically acceptable acid addition salt thereof by deprotecting the amine protecting group of the compound of Formula 4 below.
  • R 1 is C 1-3 alkoxy
  • R 2 is C 1-4 alkyl or C 3-4 cycloalkyl, and when R 2 is C 1-4 alkyl, two adjacent R 2 are spiro-linked cyclopropyl or spiro-linked cyclobutyl. can be formed,
  • n is an integer from 0 to 2
  • n is an integer from 0 to 2
  • Pr is t-butoxycarbonyl (Boc), triphenylmethyl (Trt), tetrahydropyranyl (THP), benzyloxycarbonyl (Cbz), benzyl (Bn), and fluorenylmethoxycarbonyl (Fmoc). It may be any one amine protecting group selected from among.
  • Pr may be another commercially available amine protecting group.
  • the amine protecting group of the compound of Formula 4 is 2,2-dichloroacetic acid, trifluoroacetic acid, 4-aminosalicylic acid, naphthalene-1,5-disulfonic acid, L-aspartic acid, L-glutamic acid, Maleic acid, oxalic acid, ethane-1,2-disulfonic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, (+)-1- (1S)-camphor-10-sulfonic acid, naphthalene-2-sulfonic acid, di(tert-butyl)naphthalenedisulfonic acid, di(tert-butyl)naphthalenesulfonic acid, 1-dodecanesulfonic acid, hydrochloric acid, hydrobromic acid, i
  • the metal catalyst may be selected from the group consisting of palladium, carbon, and combinations thereof, but is not limited thereto.
  • the non-nucleophilic base may be selected from the group consisting of piperidine, diisopropylethylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), and combinations thereof. , but is not limited to this.
  • the deprotection reaction of the amine protecting group Pr of Formula 4 can be controlled by varying the reagents used and reaction conditions depending on the type of protecting group Pr.
  • the deprotection reaction can be performed under acid conditions.
  • the type of the acid is not particularly limited as long as it can effectively remove the amine protecting group, for example, 2,2-dichloroacetic acid, L-aspartic acid, benzenesulfonic acid, camphorsulfonic acid, (+ )-1-(1S)-camphor-10-sulfonic acid, di(tert-butyl)naphthalenedisulfonic acid, di(tert-butyl)naphthalenesulfonic acid, 1-dodecanesulfonic acid, ethane-1,2-disulfonic acid, Ethanesulfonic acid, 2-hydroxyethanesulfonic acid, L-glutamic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, maleic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nitric acid, oxalic acid. , phosphoric acid,
  • the deprotection reaction can be performed under hydrogenation reaction conditions.
  • the hydrogenation reaction may be performed by reacting the compound of Formula 4 under a metal catalyst (palladium/carbon).
  • the deprotection reaction can be performed under non-nucleophilic base conditions.
  • the type of the non-nucleophilic base is not particularly limited as long as it can effectively remove the amine protecting group, for example, piperidine, diisopropylethylamine, 1,8-diazabicyclo[5, 4,0]undec-7-ene (DBU) and any combination thereof.
  • the pharmaceutically acceptable acid addition salt of the compound of Formula 5 is produced by evaporation without a post-treatment process after the deprotection reaction process of the compound of Formula 4, or by using another appropriate solvent.
  • the acid addition salt can be obtained by adding or precipitating it as an acid addition salt, or by a general method of preparing a free base salt known to those skilled in the art.
  • the deprotection reaction is carried out under acid conditions. Under these conditions, it can be obtained directly as an acid addition salt without a separate post-treatment process.
  • the free base can be obtained through evaporation and precipitation, or an acid addition salt can be obtained by adding a free acid to the free base after a post-treatment process.
  • Specific methods for performing the above-described evaporation, precipitation, acquisition of free base, addition of free acid, etc. can be performed according to conditions and methods commonly used in the art.
  • the amine protecting group of the compound of Formula 4 is t-butoxycarbonyl (Boc), and it can be deprotected with hydrochloric acid to form the hydrochloride salt of Formula 5.
  • the deprotection reaction can be performed under hydrogenation conditions, and the free base is formed through evaporation and precipitation.
  • An acid addition salt can be obtained by a general method of adding a free acid to a free base after a post-treatment process.
  • the deprotection reaction can be carried out under non-nucleophilic base conditions, and the free base can be obtained through evaporation or precipitation, or An acid addition salt can be obtained by a general method of adding a free acid to a free base after a post-treatment process.
  • the method may further include preparing the compound of Formula 4 through an amidation reaction between the compound of Formula 2 and the compound of Formula 3.
  • R 1 is C 1-3 alkoxy
  • n is an integer from 0 to 2
  • R 2 is C 1-4 alkyl or C 3-4 cycloalkyl, and when R 2 is C 1-4 alkyl, two adjacent R 2 are spiro-linked cyclopropyl or spiro-linked cyclobutyl. can be formed,
  • n is an integer from 0 to 2
  • Pr is t-butoxycarbonyl (Boc), triphenylmethyl (Trt), tetrahydropyranyl (THP), benzyloxycarbonyl (Cbz), benzyl (Bn), and fluorenylmethoxycarbonyl (Fmoc). It is any one amine protecting group selected from among.
  • amidation or “amidation reaction” is a chemical reaction in which the carboxyl group of a compound of Formula 2 and the amine group of a compound of Formula 3 are combined.
  • the amidation reaction between the compound of Formula 2 and the compound of Formula 3 may be performed in the presence of an amide coupling agent.
  • the amide coupling agent is thionyl chloride (SOCl 2 ), phosphorus trichloride (PCl- 3 ), phosphorus pentachloride (PCl- 5 ), phosphorus oxychloride (POCl 3 ), pivaloyl chloride (PivCl), and propanephosphonic acid anhydride ( T 3 P), 1,1'-carbonyldiimidazole (CDI), 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride (EDC), N,N,N,N '-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), cyanuric chloride (TCT), and any combination thereof.
  • SOCl 2 thionyl chloride
  • the amide coupling agent used in the amidation reaction is thionyl chloride (SOCl 2 ), pivaloyl chloride (PivCl), propanephosphonic acid anhydride (T 3 P), N,N,N,N'- It may be tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU).
  • the amidation reaction between the compound of Formula 2 and the compound of Formula 3 can be performed in the presence of a base.
  • the type of the base is not particularly limited as long as it does not inhibit the amide reaction, and for example, from the group consisting of triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and any combination thereof. It may be performed in the presence of at least one selected base.
  • the amidation reaction of the compound of Formula 2 and the compound of Formula 3 includes thionyl chloride (SOCl 2 ), phosphorus trichloride (PCl- 3 ), phosphorus pentachloride (PCl- 5 ), and phosphorus oxychloride (POCl 3 ), pivaloyl chloride (PivCl), propanephosphonic anhydride (T 3 P), 1,1'-carbonyldiimidazole (CDI), 1-ethyl-3-(3'-dimethylaminopropyl)-carboxylic acid Bodiimide hydrochloride (EDC), N,N,N,N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), cyanuric chloride (TCT) ) and at least one amide coupling agent selected from the group consisting of any combination thereof; and
  • At least one base selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and any combinations thereof.
  • the preparation method according to one embodiment is carried out under an appropriate solvent.
  • the solvent is an inorganic solvent or an organic solvent.
  • the organic solvents include, for example, alcohols (methanol, ethanol, propanol, isopropanol, ethylene glycol, etc.), ethers (diethyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), dioxane, etc.), ketones.
  • the inorganic solvent may be, for example, water, but is not limited thereto.
  • the production method may be performed in a non-polar organic solvent.
  • the non-polar organic solvent may be 2-methyltetrahydrofuran (MeTHF), dichloromethane (DCM), tetrahydrofuran (THF), or acetonitrile, but is not limited thereto.
  • the compound of Formula 1 may be any one compound selected from the group consisting of the compounds shown in Table 1 below.
  • Another aspect provides one or more compounds selected from the compounds of Formula 4, the compounds of Formula 5, and pharmaceutically acceptable acid addition salts of Formula 5 as intermediates for preparing the compound represented by Formula 1.
  • R 1 is C 1-3 alkoxy
  • R 2 is C 1-3 alkyl, C 3-4 cycloalkyl, or spirocyclopropyl
  • R 3 is C 1-3 alkyl or halogen
  • n is an integer from 0 to 2
  • n is an integer from 0 to 2
  • a is an integer from 0 to 5
  • Pr is t-butoxycarbonyl (Boc), triphenylmethyl (Trt), tetrahydropyranyl (THP), benzyloxycarbonyl (Cbz), benzyl (Bn), or fluorenylmethoxycarbonyl (Fmoc) It can be.
  • R 1 is C 1-3 alkoxy
  • R 2 is C 1-3 alkyl, C 3-4 cycloalkyl, or spirocyclopropyl
  • R 3 is methyl, fluoro, or chloro
  • n is an integer from 0 to 2
  • n is an integer from 0 to 2
  • a is an integer from 0 to 5
  • Pr may be t-butoxycarbonyl (Boc).
  • R 1 is methoxy
  • R 2 is methyl, ethyl, propyl, isopropyl, cyclopropyl, or spirocyclopropyl
  • R 3 is methyl, fluoro, or chloro
  • n is an integer from 0 to 2
  • n is an integer from 0 to 2
  • a is an integer from 0 to 5
  • Pr may be t-butoxycarbonyl (Boc).
  • R 1 is methoxy
  • R 2 is methyl, ethyl, propyl, isopropyl, cyclopropyl, or spirocyclopropyl
  • R 3 is methyl, fluoro, or chloro
  • n is an integer of 2
  • n 1 to 2
  • a is an integer from 0 to 5
  • Pr may be t-butoxycarbonyl (Boc).
  • R 1 is methoxy
  • R 2 is methyl
  • n 2
  • Pr may be t-butoxycarbonyl (Boc).
  • a method for preparing a compound of Formula 1a comprising the step of preparing a compound of Formula 1a by benzoylating a compound of Formula 5a or a pharmaceutically acceptable acid addition salt thereof.
  • the benzoylation may be performed by reacting the compound of Formula 5a or a pharmaceutically acceptable acid addition salt thereof with the compound of Formula 6a below.
  • R 4a is halogen, hydroxy, or am.
  • the pharmaceutically acceptable acid addition salt of Formula 5a may be any one compound selected from the following Formulas 5aa, 5ab, 5ac, 5ad, 5ae, 5af, and 5ag.
  • the pharmaceutically acceptable acid addition salt is any one selected from the group consisting of trifluoroacetate, fumarate, hydrochloride, hydrobromide, benzenesulfonate, camphorsulfonate, and 4-toluenesulfonate. It can be.
  • the pharmaceutically acceptable acid addition salt of Formula 5a is selected from the group consisting of compounds represented by the following formulas 5aa, 5ab, 5ac, 5ad, 5ae, 5af, and 5ag. It may be one or more types of compounds.
  • any one compound selected from Formula 4a, a compound of Formula 5a, or a pharmaceutically acceptable acid addition salt of Formula 5a is provided.
  • Another aspect provides a compound represented by Formula 1 or Formula 1a according to the above production method.
  • the compound represented by Formula 1 or Formula 1a may be provided as a pharmaceutically acceptable salt.
  • the compound represented by Formula 1 or Formula 1a may be provided as a CFTR-activating pharmaceutical composition containing its isomer, solvate, hydrate, polymorph, or pharmaceutically acceptable salt thereof.
  • Another aspect provides the use of the compound represented by Formula 1 or Formula 1a in regulating CFTR.
  • the manufacturing method according to one embodiment can be expressed as Scheme 1 below.
  • (HA) in Formula 5 indicates the presence or absence of an acid addition salt.
  • the compounds of Formulas 1 to 6 and their respective substituents R 1 , R 2 , R 3 , n, m, a, Pr The definition is the same as described above.
  • the manufacturing method may include the following steps.
  • Step 1 is a step of preparing a compound of Formula 4a through an amidation reaction between a compound of Formula 2a and a compound of Formula 3a.
  • the amidation reaction in step 1 may be performed by adding an amide coupling agent and a base in an appropriate solvent.
  • the amidation reaction can be performed by adding pivaloyl chloride (PivCl) and triethylamine (TEA) in a halogenated hydrocarbon solvent such as dichloromethane.
  • a halogenated hydrocarbon solvent such as dichloromethane.
  • the amidation reaction can be performed by adding propanephosphonic anhydride (T 3 P) and triethylamine (TEA) in an ether-based solvent such as 2-methyltetrahydrofuran (MeTHF).
  • T 3 P propanephosphonic anhydride
  • TAA triethylamine
  • MeTHF 2-methyltetrahydrofuran
  • step 2 is a step of preparing a compound of formula 5ac by deprotecting the amine protecting group of the compound of formula 4a.
  • the deprotection may be performed by adding an acid in an appropriate solvent.
  • the deprotection can be performed by adding hydrogen chloride (5-6N 2-propanol solution) under 2-propanol (IPA).
  • step 3 is a step of preparing a compound of formula 1a by benzoylating a compound of formula 5ac.
  • the benzoylation may be performed by adding a benzoylation reagent and a base in an appropriate solvent. In one embodiment, the benzoylation may be performed by additionally adding an amide coupling agent.
  • the benzoylation can be performed by addition of benzoyl chloride and triethylamine (TEA) in a halogenated hydrocarbon solvent such as dichloromethane.
  • a halogenated hydrocarbon solvent such as dichloromethane.
  • the benzoylation can be carried out by addition of benzoic acid, an amide coupling agent (such as propanephosphophane anhydride (T 3 P)), and TEA, in an etheric solvent such as 2-methyltetrahydrofuran (MeTHF).
  • an amide coupling agent such as propanephosphophane anhydride (T 3 P)
  • TEA TEA
  • EtC solvent such as 2-methyltetrahydrofuran (MeTHF).
  • intermediates prepared according to the method of the present invention e.g., a compound of Formula 4, a compound of Formula 5, or a pharmaceutically acceptable acid addition salt
  • a compound of Formula 4 e.g., a compound of Formula 4, a compound of Formula 5, or a pharmaceutically acceptable acid addition salt
  • the target compound e.g., a compound of Formula 1
  • the compound of Formula 1 can be produced on a scale that allows commercial manufacturing of pharmaceuticals. .
  • the manufacturing method according to one embodiment is as follows.
  • (HA) in Formula 5 indicates the presence or presence of an acid addition salt, and HA is selected from trifluoroacetic acid, fumaric acid, hydrochloric acid, hydrobromic acid, benzenesulfonic acid, camphorsulfonic acid, and 4-toluenesulfonic acid. It is one of those things.
  • the substituent R 4a is halogen, hydroxy, and It is one selected from among.
  • separation of the intermediate may be simpler because the intermediate is obtained in solid phase in steps 1 and 2, and impurities are well removed, so there is no need to perform column chromatography necessary for additional separation and purification. does not exist.
  • pharmaceutically acceptable acid addition salts of Formula 5a (Formula 5aa, Formula 5ab, Formula 5ac, Formula 5ad, Formula 5ae, Formula 5ad, Formula 5af, and Formula 5ag) are obtained, and Step 3 is performed to obtain the target compound.
  • the purity of Chemical Formula 1a can be improved from 99.6% to a maximum of 99.9%.
  • the term “about” means within 5% of a predetermined value or range, preferably within 1% to 2%.
  • “about 10%” means 9.5% to 10.5%, preferably 9.8% to 10.2%.
  • “about 100°C means 95°C to 105°C, preferably 98°C to 102°C.
  • terms such as “have,” “may have,” “includes,” or “may include” indicate the presence of the corresponding feature (e.g., numerical value, or component such as an ingredient). indicates, does not rule out the presence of additional features. For example, when one structure is shown, it is understood that all stereoisomeric and tautomeric forms are included, unless otherwise noted.
  • protecting group means that when covalently attached to a functional group, such as an amino or alcohol group, the functional group is prevented from undergoing an undesirable reaction, but the functional group can be regenerated (i.e., deprotected) after treatment with an appropriate reagent. It refers to the functional group that makes it possible.
  • reaction mixture was washed with 5 L of 1 M aqueous hydrochloric acid solution, 5 L of 1 M aqueous sodium hydroxide solution, and 2 L of 5% aqueous sodium chloride solution.
  • the organic layer was concentrated, isopropyl acetate was added, stirred overnight, and n -heptane was slowly added dropwise to the resulting solid.
  • the solid was stirred at room temperature for an additional 2 hours, filtered, and dried at 50°C to obtain 1409.3 g (yield 87.5%) of the title compound.
  • Example 12 (S) -(7-(3,4-dimethoxyphenyl)pyrazolo[1,5- a ]pyrimidin-2-yl)(3-methylpiperazin-1-yl)methanone 4 -Manufacture of toluenesulfonate (Formula 5ag)
  • the reaction mixture is washed with 1 M aqueous hydrochloric acid solution (5 L x 3), 5 L of 1 M aqueous sodium hydroxide solution, and 5 L of constant water.
  • the organic layer was concentrated, isopropyl acetate was added, and the resulting solid was stirred overnight, then cooled to 0 ⁇ 5 °C, stirred, filtered, and dried at 40 °C to obtain 854.3 g of the title compound (yield 69.0%, HPLC purity: 99.95 % [area %). ]) was obtained.

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Abstract

La présente invention concerne un procédé de production d'un composé activateur de CFTR et un intermédiaire utilisé à cet effet et, plus spécifiquement, un procédé de production d'un nouveau composé qui améliore l'activité de CFTR, et un nouvel intermédiaire utilisé dans le procédé.
PCT/KR2023/005378 2022-04-20 2023-04-20 Procédé de production d'un composé activateur de cftr et intermédiaire utilisé à cet effet Ceased WO2023204629A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001040231A1 (fr) * 1999-12-06 2001-06-07 Bristol-Myers Squibb Company Dihydropyrimidines heterocycliques utiles en tant qu'inhibiteurs des canaux potassium
WO2007130468A2 (fr) * 2006-05-01 2007-11-15 Cephalon, Inc. Pyridopyrazines et leurs dérivés utilisés en tant qu'inhibiteurs de alk et de c-met
WO2013087805A1 (fr) * 2011-12-14 2013-06-20 Boehringer Ingelheim International Gmbh Dérivés de pipérazine et leur utilisation à titre de modulateurs allostériques positifs des récepteurs mglur5
WO2018145080A1 (fr) * 2017-02-06 2018-08-09 Case Western Reserve University Compositions et procédés de modulation de l'activité de la déshydrogénase à chaîne courte
WO2021243421A1 (fr) * 2020-06-05 2021-12-09 Monash University Inhibiteurs doubles de kinase-bromodomaine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001040231A1 (fr) * 1999-12-06 2001-06-07 Bristol-Myers Squibb Company Dihydropyrimidines heterocycliques utiles en tant qu'inhibiteurs des canaux potassium
WO2007130468A2 (fr) * 2006-05-01 2007-11-15 Cephalon, Inc. Pyridopyrazines et leurs dérivés utilisés en tant qu'inhibiteurs de alk et de c-met
WO2013087805A1 (fr) * 2011-12-14 2013-06-20 Boehringer Ingelheim International Gmbh Dérivés de pipérazine et leur utilisation à titre de modulateurs allostériques positifs des récepteurs mglur5
WO2018145080A1 (fr) * 2017-02-06 2018-08-09 Case Western Reserve University Compositions et procédés de modulation de l'activité de la déshydrogénase à chaîne courte
WO2021243421A1 (fr) * 2020-06-05 2021-12-09 Monash University Inhibiteurs doubles de kinase-bromodomaine

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