WO2017051761A1 - Nouveau promédicament - Google Patents

Nouveau promédicament Download PDF

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WO2017051761A1
WO2017051761A1 PCT/JP2016/077252 JP2016077252W WO2017051761A1 WO 2017051761 A1 WO2017051761 A1 WO 2017051761A1 JP 2016077252 W JP2016077252 W JP 2016077252W WO 2017051761 A1 WO2017051761 A1 WO 2017051761A1
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optionally substituted
mmol
prodrug
compound
added
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PCT/JP2016/077252
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Japanese (ja)
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芳男 ▲浜▼田
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芳男 ▲浜▼田
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/22—Y being a hydrogen or a carbon atom, e.g. benzoylguanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/80—Two oxygen atoms, e.g. hydantoin with hetero atoms or acyl radicals directly attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/50—Nitrogen atoms bound to hetero atoms
    • C07D277/52—Nitrogen atoms bound to hetero atoms to sulfur atoms, e.g. sulfonamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C07D453/04—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine
    • 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 a prodrug that spontaneously produces a useful compound under physiological conditions.
  • Non-Patent Documents 1 to 4 The present inventor has developed a prodrug that spontaneously generates a drug regardless of the action of an enzyme.
  • This prodrug is a compound obtained by isomerizing an amide into an ester in the molecule, and spontaneously produces a pharmaceutical compound by an ON intramolecular acyl group rearrangement reaction under physiological conditions.
  • the ritonavir prodrug prepared using this prodrugation technique was evaluated for the rate of formation of a pharmaceutical compound in a pH 7.4 phosphate buffer, and the half-life of the prodrug was 32 hours. Is not suitable for use (Non-patent Document 1).
  • Non-Patent Documents 1 to 4 require at least one modifiable hydroxyl group and amide on the drug side, and have limitations on the chemical structure.
  • ⁇ -secretase inhibitors that are Alzheimer's drugs, antiepileptic drugs such as phenytoin, sulfa drugs, and antipyretic analgesics.
  • antiepileptic drugs such as phenytoin, sulfa drugs
  • antipyretic analgesics since phenytoin is soluble only in a strong alkaline aqueous solvent, phenytoin injection is used as a strong alkaline aqueous solution having a pH of 12 and is highly irritating.
  • the ⁇ -secretase inhibitor has an action site in the brain, and it is necessary to increase log P in order to permeate the blood brain barrier. Further, many ⁇ -secretase inhibitors optimized for the hydrophobic pocket of ⁇ -secretase are hardly soluble. In order to improve the solubility or absorbability of these poorly soluble drugs and obtain high bioavailability, new prodrugs are required.
  • the problem to be solved by the present invention can be applied to many useful compounds, has higher solubility in aqueous solvents than useful compounds, and quickly produces useful compounds under neutral to weakly basic conditions. It is to provide a prodrug that can.
  • the present inventor binds a specific structure having a guanidyl group and an amide group or amino group to a useful compound, whereby the amino group or guanidyl group undergoes a nucleophilic reaction in the molecule to liberate a glycosylamidine derivative. It was thought that useful compounds were formed.
  • the present inventors have found that when the above structure is bonded to a useful compound and placed in an environment of pH 7.4, the useful compound is promptly produced within a half-life of 1 hour.
  • the present invention has been completed. That is, the present invention is as follows.
  • DXL [Wherein D represents D—X—H and represents a useful compound.
  • X represents NR 1 , O, S or Se.
  • R 1 is a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted aryl, a substituted Optionally substituted heteroaryl, optionally substituted heterocyclic group, optionally substituted alkanoyl, optionally substituted arylcarbonyl, optionally substituted alkylsulfonyl or optionally substituted aryl Represents a sulfonyl or binds to D to form a heterocycle with the nitrogen atom to which R 1 is bound.
  • L represents a group represented by the formula (a) or the formula (b).
  • A represents an optionally substituted C 1-3 alkylene.
  • R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, or an optionally substituted Good cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic group, optionally substituted alkanoyl, optionally substituted arylcarbonyl, substituted Represents an optionally substituted alkylsulfonyl or an optionally substituted arylsulfonyl.
  • the substituent in A and two adjacent R 2 to R 5 may be combined to form a ring.
  • L is a group represented by the formula (b)
  • X is NR 1 . ] Or a salt thereof.
  • the prodrug of the present invention can be applied to many useful compounds having an amino group, an imino group, a hydroxyl group, a thiol group, or a selenol group, and has a higher solubility in an aqueous solvent than a useful compound, and is neutral to weak. It is possible to produce useful compounds quickly under basic conditions.
  • FIG. 2 shows the results of HPLC analysis of the change over time of phenytoin from prodrug 1 of phenytoin in Example 1.
  • FIG. 9 shows the results of HPLC analysis of the change over time of 2-aminobenzimidazole from 2-aminobenzimidazole prodrug 1 in Example 5.
  • FIG. 2 is a fitting graph for Prodog 1 of phenytoin in Example 1.
  • Prodrug The present invention is represented by the formula: DXL (wherein D, X and L are as defined above). ] Or a salt thereof.
  • Examples of the “useful compound” represented by DXH include a useful compound having NR 1 H, OH, SH or SeH as XH.
  • Examples of useful compounds include pharmaceutical compounds, agricultural chemical compounds, test chemical compounds, research reagent compounds, and the like.
  • R 1 represents a partial structure of the above-mentioned useful compound and becomes a useful compound by becoming D—NR 1 —H.
  • R 1 is dependent on the structure of the useful compound as described above, and includes, for example, a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, Cycloalkyl which may be substituted, aryl which may be substituted, heteroaryl which may be substituted, heterocyclic group which may be substituted, alkanoyl which may be substituted, which may be substituted Represents arylcarbonyl, optionally substituted alkylsulfonyl or optionally substituted arylsulfonyl, or is bonded to D to form a heterocycle with the nitrogen atom to which R 1 is bonded.
  • heterocycle formed examples include a hydantoin ring, a uracil ring, a thymine ring, and a glutarimide ring contained in phenytoin described in Example 1.
  • L represents a group represented by the formula (a) or the formula (b).
  • A represents an optionally substituted C 1-3 alkylene.
  • R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, or an optionally substituted Good cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic group, optionally substituted alkanoyl, optionally substituted arylcarbonyl, substituted Represents an optionally substituted alkylsulfonyl or an optionally substituted arylsulfonyl.
  • the substituent in A and two adjacent R 2 to R 5 may be combined to form a ring.
  • L is a group represented by the formula (b)
  • X is NR 1 ].
  • the C 1-3 alkylene in the "optionally substituted C 1-3 alkylene" represented by A for example, methylene, ethylene, trimethylene and the like, in the next to the carbonyl of the C 1-3 alkylene
  • One carbon atom not present may be substituted with O, NH, S, Se or the like.
  • Examples of the substituent in the “optionally substituted C 1-3 alkylene” represented by A include, for example, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, Optionally substituted alkoxy, optionally substituted alkoxycarbonyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetero A cyclic group, an optionally substituted alkanoyl, an optionally substituted arylcarbonyl, an optionally substituted alkylsulfonyl, an optionally substituted arylsulfonyl, an optionally substituted amino, nitro, halogen, Cyano, hydroxyl group, carboxyl, etc., and these same or different ones or A plurality of substituents may be substituted.
  • Alkyl means linear or branched alkyl, such as C 1-6 alkyl, preferably C 1-4 alkyl. Specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2 -Dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
  • Alkenyl means linear or branched alkenyl containing one double bond, and includes, for example, C 2-6 alkenyl, preferably C 2-4 alkenyl. Specific examples include vinyl, propenyl, methylpropenyl, butenyl, methylbutenyl and the like.
  • Alkynyl means linear or branched alkynyl containing one triple bond, and includes, for example, C 2-6 alkynyl, preferably C 2-4 alkynyl. Specific examples include ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, pentynyl, hexynyl and the like.
  • Alkoxy means linear or branched alkoxy, and includes, for example, C 1-6 alkoxy, preferably C 1-4 alkoxy. Specifically, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, 1-ethylpropoxy, hexoxy, isohexoxy, 1,1-dimethylbutoxy, 2, Examples include 2-dimethylbutoxy, 3,3-dimethylbutoxy, 2-ethylbutoxy and the like.
  • Alkoxycarbonyl means linear or branched alkoxycarbonyl, such as C 1-6 alkoxycarbonyl, preferably C 1-4 alkoxycarbonyl. Specifically, methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, neopentylcarbonyl, 1-ethylpropylcarbonyl, Examples include hexylcarbonyl, isohexylcarbonyl, 1,1-dimethylbutylcarbonyl, 2,2-dimethylbutylcarbonyl, 3,3-dimethylbutylcarbonyl, 2-ethylbutylcarbonyl and the like.
  • Examples of the substituent in the optionally substituted alkyl, the optionally substituted alkenyl, the optionally substituted alkynyl, the optionally substituted alkoxy and the optionally substituted alkoxycarbonyl include alkoxy, alkoxycarbonyl , Cycloalkyl, aryl, heteroaryl, heterocyclic group, alkanoyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, amino, nitro, halogen, cyano, hydroxyl group, carboxyl, etc., and the same or different one or more The substituent may be substituted.
  • Cycloalkyl includes, for example, C 3-7 cycloalkyl, preferably C 5-6 cycloalkyl. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • aryl examples include C 6-10 aryl, and specific examples include phenyl, 1-naphthyl, 2-naphthyl and the like. Preferably, phenyl is used.
  • Heteroaryl includes, for example, monocyclic or bicyclic 5- to 10-membered heteroaryl containing 1 or 2 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Preferably, monocyclic 5- or 6-membered heteroaryl is used.
  • monocyclic heteroaryls such as pyrrolyl, pyridyl, thienyl, furyl, pyrimidinyl, pyranyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, and quinolyl, isoquinolyl, quinazolinyl, chromanyl, isochromanyl , Benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, dihydrobenzothiophenyl, indolyl, isoindolyl, quinoxalyl, benzothiazolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzoxazolyl, benzoxanyl, indolizinyl, thienopyridyl, dihydrothieno
  • heterocyclic group examples include a 4- to 7-membered heterocyclic group containing 1 or 2 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • specific examples include azetidinyl, pyrrolidinyl, piperidyl, azepanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperazinyl, morpholinyl, dioxolanyl, dioxanyl, etc. Can do.
  • Alkanoyl means linear or branched alkanoyl, for example, C 1-6 alkanol, preferably C 1-4 alkanol. Specific examples include formyl, acetyl, propanoyl, isopropanoyl, butanoyl, isobutanoyl, pentanoyl, isopentanoyl, neopentanoyl, hexanoyl, isohexanoyl and the like.
  • alkyl in the “alkylsulfonyl” examples include the aforementioned alkyl.
  • the aryl in the “arylcarbonyl” and “arylsulfonyl” includes the above aryl.
  • substituent in arylcarbonyl, optionally substituted alkylsulfonyl and optionally substituted arylsulfonyl include alkyl, alkenyl, alkynyl, alkoxy, alkoxycarbonyl, cycloalkyl, aryl, heteroaryl, heterocyclic group, alkanoyl , Arylcarbonyl, alkylsulfonyl, arylsulfonyl, amino, nitro, halogen, cyano, hydroxyl group, carboxyl and the like, and these one or different substituents may be substituted.
  • substituent in the optionally substituted amino examples include alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic group and the like, and one or more of these same or different substituents are substituted. You may do it.
  • Preferred examples include alkyl, and specific examples of substituted amino include dimethylamino and diethylamino.
  • halogen examples include fluorine, chlorine, bromine, iodine and the like.
  • fluorine, chlorine, bromine, etc. are mentioned, More preferably, fluorine, chlorine, etc. are mentioned.
  • the “ring formed by combining the substituent in A and two adjacent R 2 to R 5 together” specifically includes the substituent in A and R 2 formed together.
  • a ring formed by combining the substituent in A and R 5 a ring formed by combining R 2 and R 3, and formed by combining R 3 and R 4 together.
  • a ring formed by combining R 3 and R 5 together examples include 5- or 6-membered heterocycles containing a nitrogen atom, and specific examples include heterocycles corresponding to the above-described heterocyclic groups containing a nitrogen atom.
  • a substance having affinity for a substituent, R 2 , R 3 , R 4 or R 5 in A such as a tissue, cell, protozoa, bacterium, virus, test object, test object, etc., that is a target of a useful compound
  • a tissue or the like that is a target of a useful compound examples include antibodies, sugar chains, peptides, glycolipids, and the like.
  • the prodrug of the present invention bound via a linker to a substance having affinity for the tissue or the like that is the target of the useful compound gathers in the vicinity of the target tissue or the like, and a useful compound is generated in the vicinity of the prodrug.
  • the concentration of useful compounds can be increased, and high therapeutic effects or test / test effects can be achieved while reducing side effects or side reactions.
  • Examples of the salt of the prodrug of the present invention include salts with commonly used acids.
  • it is a prodrug of a pharmaceutical compound
  • it is preferably a pharmaceutically acceptable salt, for example, an inorganic acid salt such as hydrochloride, sulfate, nitrate, hydrobromide, phosphate, and oxalic acid Salt, succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, acetate, trifluoro
  • organic acid salts such as acetate, trichloroacetate, propionate, and ascorbate.
  • the prodrug of the present invention can be produced, for example, as follows.
  • Prodrug production method having group of formula (a) [Wherein, D, X, A, R 2 , R 3 and R 4 are as defined above.
  • P X represents a protecting group for a nitrogen atom.
  • R 3 ′ has the same meaning as R 3 , but when R 3 is a hydrogen atom, it may be a protecting group for a nitrogen atom.
  • the protective group for the nitrogen atom represented by P X for example, TW Green, Protective Groups in Organic Synthesis, John Wiley & Sons, 1999, 3rd Ed.
  • P X for example, TW Green, Protective Groups in Organic Synthesis, John Wiley & Sons, 1999, 3rd Ed.
  • protecting groups can be carried out by the methods described in the same document.
  • Specific examples of the protecting group for amino group include tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc) and the like. Boc and the like are preferable because they can be deprotected under acidic conditions.
  • the condensation reaction between the useful compound and Compound Ia can be carried out using a condensing agent according to a conventional method, to produce Compound IIa.
  • the condensing agent include N, N-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- [3- (N, N-dimethylamino) propyl] carbodiimide (EDCI), O-benzotriazol-1-yl-N , N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU), carbonyldiimidazole (CDI), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) 4- Examples include methylmorpholinium chloride (DMTMM), 2- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU), and the like.
  • DCC N-dic
  • reaction solvent examples include solvents not involved in the reaction, such as N, N-dimethylformamide (DMF), dioxane, water, methanol, ethanol, tetrahydrofuran (THF), dichloromethane, dichloroethane, diethyl ether, chloroform, dimethoxyethane (DME), Ethyl acetate, toluene, acetonitrile, dimethyl sulfoxide (DMSO) or a mixed solvent thereof can be used.
  • DMF N, N-dimethylformamide
  • DME dimethoxyethane
  • DME dimethoxyethane
  • Ethyl acetate toluene
  • acetonitrile dimethyl sulfoxide
  • DMSO dimethyl sulfoxide
  • the reaction may proceed smoothly in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, or by reacting these bases as a solvent.
  • a base such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, or by reacting these bases as a solvent.
  • carboxyl group of compound Ia can be activated to condense with useful compounds.
  • Derivatives with activated carboxyl groups include phenolic compounds such as p-nitrophenol, 1-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt), 7-aza-1-hydroxybenzotriazole (HOAt) Obtained by reacting an active ester obtained by reacting with an N-hydroxyamine compound such as monoalkyl ester carbonate, mixed acid anhydride obtained by reacting with an organic acid, diphenylphosphoryl chloride and N-methylmorpholine.
  • phosphoric acid-based mixed acid anhydrides acid azides obtained by sequentially reacting esters with hydrazine and alkyl nitrite, acid halides such as acid chlorides or acid fluorides, and target acid anhydrides.
  • the resulting compound IIa is in a conventional manner, it can be deprotected of the protecting group of the nitrogen atom represented by P X, to produce the compound IIIa.
  • Compound IVa can be produced by amidylating the obtained compound IIIa.
  • Amidylation can be carried out, for example, by reacting with N, N′-bis (tert-butoxycarbonyl) -1H-pyrazole-1-carboamidine and the like under basic conditions as described in the Examples.
  • the base include organic bases such as pyridine and N-methylmorpholine. Also, trifurylguanidine with protected nitrogen atoms (J. Org.
  • the resulting compound IVa in a conventional manner can be deprotected of the protecting group of the nitrogen atom represented by P X, to produce a prodrug having a group of the formula of interest (a).
  • the prodrug having the group of the formula (a) can be converted into a salt.
  • Amidylation of useful compounds can be carried out, for example, by reacting with 1H-pyrazole-1-carboamidine or a derivative thereof in the presence of a base (Bioorganic & Medicinal Chemistry, 11, 2709-2714 (2003)). Moreover, it can also be made to react like the manufacture of compound IVa from compound IIIa.
  • reaction between the obtained compound Ib and compound IIb can be carried out in the same manner as the reaction between the useful compound and compound Ia, to produce compound IIIb.
  • the resulting compound IIIb in a conventional manner can be deprotected of the protecting group of the nitrogen atom represented by P X, to produce a prodrug having a group of the formula object (b).
  • the prodrug having the group of the formula (b) can be converted into a salt.
  • a protecting group can be introduced as necessary and the protecting group can be deprotected later.
  • the protecting group include those described in T. W. Green, Protective Groups in Organic Synthesis, John Wiley & Sons, 1999, 3rd Ed. Protection and deprotection of the protecting group are described in the same document. It can be carried out in the manner described.
  • the prodrug of the present invention is stable in its salt form.
  • the prodrug having the group of the formula (a) has a nitrogen atom of the terminal guanidino group as shown below.
  • a nucleophilic attack is carried out on the carbon atom of the carbonyl group in the molecule to release the glycocymidine derivative (a) to produce a useful compound.
  • the nitrogen atom of the terminal amino group makes a nucleophilic attack on the carbon atom of the guanidino group in the molecule, and the glycosiamidine derivative (b) is released, Useful compounds are produced.
  • released glycocyamidine derivatives are present in a large amount in human muscle tissue as represented by creatinine (1-methylglycocyanidin), and safety is not a problem even if it is by-produced in vivo. I don't think so.
  • the glycocyanidine derivative (a) or (b) is a 5-membered ring when A is methylene, a 6-membered ring when A is ethylene, and a 7-membered ring when A is trimethylene. Every time it becomes a 7-membered ring, a 6-membered ring, or a 5-membered ring, the production of a glycocyanidine derivative is accelerated, and a useful compound is produced more quickly. Therefore, as shown in the examples described later, the chain length of A can be changed according to the desired production rate of useful compounds. In addition, as shown in the examples described later, the production rate of useful compounds can be similarly adjusted by changing the substituent of A and the substituents of R 2 to R 5 in the glycosylamidine derivative. For example, if an electron-withdrawing group is introduced as the group of R 2 to R 5 , the production rate of useful compounds can be reduced by about 10 times or more.
  • the half-life at 37 ° C. under neutral conditions of the prodrug of the present invention is usually from within 1 minute to within 1 hour, but by changing the structure of the glycocyanidine derivative as described above, Within a short time, or a long time of 1 hour or more.
  • the prodrug of the present invention when it is orally administered to a human or an animal, it enters the duodenum from the stomach to form a weakly basic environment. And can be absorbed from the intestinal tract. In addition, if the production rate of the pharmaceutical compound is slowed, it can be administered orally and absorbed as a prodrug from the intestinal tract, or administered into the blood by infusion or the like to slowly produce the pharmaceutical compound in the blood. You can also.
  • compositions The prodrugs of the invention relating to pharmaceutical compounds are stable in the form of their pharmaceutically acceptable salts. Therefore, a pharmaceutical composition containing a pharmaceutically acceptable salt of the prodrug of the present invention can be prepared, and this pharmaceutical composition can be stored for a long period of time.
  • the pharmaceutically acceptable salts of the prodrugs of the invention can be used as pharmaceutical compositions, for example, orally, systemically (eg, transdermally, intranasally, suppositories, etc.) or parenterally (eg, intramuscularly. , Intravenous, subcutaneous, etc.).
  • the preparation of the pharmaceutical composition can be the same as the original preparation of the pharmaceutical compound contained in the prodrug of the present invention, for example. Specifically, tablets, granules, fine granules, powders, capsules, pills, dry syrups, troches, drops, chewables, orally disintegrating agents, foaming agents, liquids, suspensions, elixirs And preparations such as aerosols.
  • the preparation of the above-mentioned pharmaceutical composition can be prepared by adding a pharmaceutically acceptable carrier to the pharmaceutically acceptable salt of the prodrug of the present invention.
  • the pharmaceutically acceptable carrier can be selected according to the dosage form of the pharmaceutical composition, the nature of the pharmaceutical compound contained in the prodrug of the present invention, the administration method, etc., for example, excipients, binders, Disintegrating agents, lubricants, fluidizing agents, stabilizers, antioxidants, coloring agents, sweetening agents, flavoring agents and the like can be added.
  • excipients include crystalline cellulose, powdered cellulose, lactose, sucrose, glucose, mannitol, erythritol, xylitol, trehalose, maltitol, lactitol, sorbitol, wheat starch, corn starch, potato starch, silicon dioxide, calcium sulfate, etc. Is mentioned.
  • binder examples include methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, low-substituted hydroxypropylcellulose, hypromellose, carmellose sodium, dextrin, partially pregelatinized starch, pullulan, gum arabic, guar gum, Examples include agar, gelatin, tragacanth, sodium alginate, povidone, polyvinyl alcohol, pectin and the like.
  • Examples of the disintegrant include carmellose, carmellose calcium, croscarmellose sodium, carboxymethyl ethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospovidone, hydroxypropyl starch, and the like.
  • Examples of the lubricant include stearic acid, calcium stearate, magnesium stearate, palmitic acid, talc, sodium stearyl fumarate, carnauba wax, hydrogenated vegetable oil, mineral oil and the like.
  • Examples of the fluidizing agent include hydrous silicon dioxide, light anhydrous silicic acid, titanium oxide and the like.
  • the dosage of the above pharmaceutical composition varies depending on the administration method, dosage form, production rate of the pharmaceutical compound, age, weight, and health condition of the administration target, but the original administration of the pharmaceutical compound contained in the prodrug of the present invention. Can be determined based on quantity.
  • the above-mentioned pharmaceutical composition can be administered to a human or animal, for example, once to several times a day, or once every few days.
  • the extract was dried over magnesium sulfate, concentrated, purified by silica gel column chromatography (hexane / ethyl acetate), and finally crystallized from n-hexane to obtain the desired product as a white powder.
  • the extract was dried over magnesium sulfate, concentrated, purified by silica gel column chromatography (hexane / ethyl acetate), and finally crystallized from n-hexane to obtain the desired product as a white powder.
  • Example 11 Production of useful compounds
  • the prodrugs of Examples 1 and 5 were dissolved in acetonitrile-methanol (1: 1 (v / v)) to a concentration of 0.1 mg / ml, and 5 ⁇ l of this solution was added to phosphorous having a pH of 7.4. It added to 500 microliters of acid buffer solutions (PBS solution), and incubated in a 37 degreeC thermostat. After a certain time, 200 ⁇ l of PBS solution was analyzed by HPLC. HPLC was performed using an ODS column and eluted with acetonitrile / 0.1% TFA (0-100%).
  • Example 12 Half-life of the prodrug The half-life of the prodrug was determined as follows. The prodrug concentration after incubation at 37 ° C. in a PBS solution at pH 7.4 for a certain time was measured. Based on the concentration, each plot was fitted, and the half-life t 1/2 of the prodrug was calculated using Formula (1).
  • ⁇ Calculation formula (1)> A t A MAX ⁇ (1-Exp ( ⁇ k ⁇ t)) [Wherein t represents the incubation time (minutes). k represents a rate constant.
  • a MAX represents the maximum concentration of useful compound (equal to the initial concentration of prodrug) (mg / ml).
  • a t represents the concentration (mg / ml) of the compounds useful in the time t].
  • FIG. 1 shows the half-life of the prodrug of each Example obtained from the fitting graph in PBS solution at pH 7.4.
  • the half-life of the prodrugs of Examples 1 to 10 was within 1 minute to within 1 hour, and useful compounds were rapidly formed.
  • the half-life was reduced to 1/10 or less by introducing a methyl group into the leaving group.
  • the half-life could be changed by using either the formula (a) or the formula (b) as the leaving group.
  • the half-life could be greatly changed depending on whether the leaving group was a 5-membered ring or a 6-membered ring.
  • the half-life can be adjusted to a desired time by changing the structure.
  • Example 13 The water-soluble useful compound of the prodrug and the prodrug of the present invention were dissolved in distilled water to prepare a saturated solution, and ultrasonic waves were irradiated for 15 minutes at a water temperature of 25 ° C. The solution was filtered through a membrane filter having a pore size of 25 ⁇ m, and 10 ⁇ l of this saturated solution was analyzed by HPLC, and the concentrations of useful compounds and prodrugs contained in the saturated solution were calculated. Table 2 shows the solubility (mg / ml) of each useful compound and each prodrug.
  • solubility in distilled water can be remarkably increased by using the prodrug of the present invention.
  • the absorbability of useful compounds can be improved.
  • the prodrug of the present invention can be applied to many useful compounds having an amino group, an imino group, a hydroxyl group, a thiol group, or a selenol group, and has a higher solubility in an aqueous solvent than a useful compound, and is neutral to weak. It is possible to produce useful compounds quickly under basic conditions.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Le promédicament ou un sel correspondant selon la présente invention est représenté par la formule : D-X-L. (Dans la formule, D représente un composé utile et devient D-X-H. X représente NR1, O, S ou Se. R1 représente un atome d'hydrogène, alkyle pouvant être substitué, alcényle pouvant être substitué, alcynyle pouvant être substitué, cycloalkyle pouvant être substitué, aryle pouvant être substitué, hétéroaryle pouvant être substitué, hétérocycle pouvant être substitué, alcanoyle pouvant être substitué, arylcarbonyle pouvant être substitué, alkylsulfonyle pouvant être substitué, ou arylsulfonyle pouvant être substitué, ou se lie à D et forme un hétérocycle avec un atome d'azote auquel R1 est lié. L représente un groupe représenté par la formule (a) ou la formule (b).)
PCT/JP2016/077252 2015-09-25 2016-09-15 Nouveau promédicament WO2017051761A1 (fr)

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