Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
  • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
  • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
  • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
  • C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
  • C07K1/1075—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of amino acids or peptide residues
• • 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 novel guanidine derivative and the like.
• arginine is known as a natural amino acid having a guanidine group, and it is known that the guanidine group in arginine plays an important role in the living body, for example, interaction with a cell membrane and intracellular translocation.
• arginine is a natural amino acid, it is easily decomposed by proteases and the like, and problems such as half-life in blood are likely to occur when it is used as a pharmaceutical product.
• 4-Guanidinophenylalanine (F4G) is known as an alternative to arginine (J. Med.
• An object of the present invention is to provide a guanidine derivative (particularly an amino acid compound having a 4-guanidino group), a method for producing the same, and an intermediate used for the production thereof, which have a low production cost and are less likely to cause a waste liquid problem.
• the first aspect is a compound represented by the following formula (I) (a novel guanidine compound), a tautomer thereof, an enantiomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. Regarding.
• -R 1- may have one or more substituents selected from group A C 1 ⁇ C 10 alkylene groups and may have one or more substituents selected from group A C 6-10 .
• An arylene group or a group represented by -R 11 -R 12- is indicated.
• Group A is a halogen atom, an amino group, a nitro group, a C 1-5 alkyl group, a C 1-3 alkoxy group, a C 1-3 alkyl thio group, and a C 1-3 halogenoalkyl group.
• -R 11- indicates a C 6-10 arylene group which may have one or more substituents selected from the group A.
• the group represented by ⁇ R12 ⁇ indicates a C1- C4 alkylene group which may have one or more substituents selected from the group A.
• R 2 and R 4 may be the same or different, indicating a protecting group or a hydrogen atom.
• R 3 indicates a hydrogen atom, Does R 5 represent a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitro group, a C 1-5 alkyl group, a C 1-3 alkoxy group, a C 1-3 alkyl thio group, or a C 1-3 halogenoalkyl group?
• R 5 together with -N-R 1- form a C 5-7 heterocyclic amine that may contain an asymmetric carbon atom at the ⁇ -position.
• R 6 and R 7 may be the same or different and represent a protecting group, a C 1-5 alkyl group or a hydrogen atom.
• R8 is an amino acid protective group, hydrogen atom, halogen atom, hydroxyl group, amino group, nitro group, C 1-5 alkyl group, C 1-3 alkoxy group, C 1-3 alkyl thio group, C 1-3 halogenoalkyl. Indicates a group or a group indicated by -OR 13- , indicating a group.
• the group represented by R 13- indicates an oxygen atom protecting group, a C 1-5 alkyl group, a C 1-3 alkoxy group, a C 1-3 alkyl thio group, or a C 1-3 halogenoalkyl group.
• -R 1- indicates a propylene group
• R 2 to and R 7 indicate a hydrogen atom
• R 8 indicates a hydroxyl group
• -R 1- indicates a group represented by -R 11 -R 12- .
• -R 11- indicates a 1,4-phenylene group
• -R 12- indicates a methylene group
• R 2 , R 4 , R 5 , R 6 , and R 7 are all hydrogen atoms. Excludes those in which R 8 indicates a hydroxyl group.
• the second aspect relates to a method for producing a peptide using the above-mentioned compound, its tautomer, its enantiomer, its pharmaceutically acceptable salt, or its pharmaceutically acceptable solvate.
• the third aspect is the compound represented by the formula (I), its tautomer thereof, which comprises a mixing step of mixing the compound represented by the following formula (II) and the compound represented by the following formula (III). It relates to a method for producing an enantiomer, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.
• R 22 , R 23 and R 24 are synonymous with R 2 , R 3 and R 4 , respectively.
• R 21 , R 25 , R 26 , and R 27 are synonymous with R 1 , R 5 , R 6 , and R 7 , respectively.
• R 28 indicates the group represented by -OR 33- .
• the group represented by R 33- indicates a protecting group for oxygen atoms
• a guanidine derivative (particularly an amino acid compound having a 4-guanidino group) can be obtained, which has a low production cost and is less likely to cause a waste liquid problem.
• the novel guanidine derivative of the present invention is a compound represented by the following formula (I), a mutant thereof, an enantiomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. With respect to the solvates to be made.
• -R 1- may have one or more substituents selected from group A C 1 ⁇ C 10 alkylene groups and may have one or more substituents selected from group A C 6-10 .
• An arylene group or a group represented by -R 11 -R 12- is shown.
• Group A is a halogen atom, an amino group, a nitro group, a C 1-5 alkyl group, a C 1-3 alkoxy group, a C 1-3 alkyl thio group, and a C 1-3 halogenoalkyl group.
• -R 11- indicates a C 6-10 arylene group which may have one or more substituents selected from the group A.
• the group represented by ⁇ R12 ⁇ indicates a C1- C4 alkylene group which may have one or more substituents selected from the group A.
• R 2 and R 4 may be the same or different and represent a protecting group or a hydrogen atom, and R 3 represents a hydrogen atom.
• R 5 represents a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitro group, a C 1-5 alkyl group, a C 1-3 alkoxy group, a C 1-3 alkyl thio group, or a C 1-3 halogenoalkyl group.
• R 5 may be combined with —N—R 1 ⁇ to form a C 5-7 heterocyclic amine that may contain an asymmetric carbon atom at the ⁇ -position.
• R 6 and R 7 may be the same or different and represent a protecting group, a C 1-5 alkyl group or a hydrogen atom.
• R 8 is a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitro group, a C 1-5 alkyl group, a C 1-3 alkoxy group, a C 1-3 alkyl thio group, a C 1-3 halogenoalkyl group or -O-.
• the group represented by R 13- is shown.
• R8 may be an amino acid protecting group.
• the group represented by R 13- indicates an oxygen atom protecting group, a C 1-5 alkyl group, a C 1-3 alkoxy group, a C 1-3 alkyl thio group, or a C 1-3 halogenoalkyl group.
• R 1- indicates the group indicated by -R 11 -R 12-
• R 11- indicates the 1,4-phenylene group
• -R 12- indicates the methylene group
• R 2 and R 4 , R 5 , R 6 and R 7 all represent a hydrogen atom and R 8 represents a hydroxyl group (F4G) are excluded from the guanidine derivative of the present invention.
• the tautomer means a tautomer of the compound represented by the formula (I).
• a tautomer means one in which the rate of isomerization in which isomers are converted to each other is high and both isomers can reach an equilibrium state in which they coexist.
• the enantiomer means the enantiomer of the compound represented by the formula (I). Enantiomer means that two molecules are in a chiral (mirror image) relationship and cannot be overlapped.
• the pharmaceutically acceptable salt means a pharmaceutically acceptable salt of the compound represented by the formula (I).
• pharmacologically acceptable salts include salts consisting of inorganic bases, ammonia, organic bases, inorganic acids, organic acids, basic amino acids, halogen ions, etc., and intramolecular salts.
• inorganic bases include alkali metals (Na, K, etc.) and alkaline earth metals (Ca, Mg, etc.).
• organic bases include trimethylamine, triethylamine, choline, procaine, ethanolamine, dicyclohexylamine, cyclohexylamine, cinconidine, pyridine, rutidin, triethylenediamine and the like.
• inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
• organic acids include p-toluenesulfonic acid, methanesulfonic acid, formic acid, trifluoroacetic acid, maleic acid and the like.
• basic amino acids include lysine, arginine, ornithine, histidine and the like.
• the pharmaceutically acceptable solvate means a pharmaceutically acceptable solvate of the compound represented by the formula (I).
• An example of a solvate is a hydrate.
• the compound of the present invention may absorb water existing in the atmosphere during storage and become a hydrate.
• the present invention includes such hydrates.
• the pharmaceutically acceptable solvate may be a solvate of a pharmaceutically acceptable salt of the compound represented by the formula (I).
• Preferred examples of the compound represented by the formula (I) are those in which -R 1- indicates a group represented by -R 11 -R 12- .
• -R 11- indicates a 1,3-phenylene group or a 1,4-phenylene group which may have one or more substituents selected from group A, and is a group represented by -R 12- .
• R 5 , R 6 , R 7 and R 8 indicate the following groups.
• R5 indicates a hydrogen atom, a methyl group, or an ethyl group.
• R 6 indicates an Fmoc group (9-fluorenylmethyloxycarbonyl group).
• R 7 indicates a hydrogen atom.
• R 8 indicates a hydroxyl group or a group represented by -OR 13- .
• the group represented by R 13- indicates a protecting group, a methyl group, or an ethyl group of an oxygen atom.
• -R 1- indicates a C 3 -C 6 alkylene group.
• the one in which -R 1- indicates a C4 alkylene group is a preferable example.
• Preferred examples of the compound represented by the formula (I) are: -R 1- indicating a C4 alkylene group, R 2 indicating a protective group (eg Rbf-), R 3 indicating a hydrogen atom, and R. 4 indicates a protective group (for example, Sub-), R 5 indicates a methyl group, R 6 indicates an Fmoc group, R 7 indicates a hydrogen atom, and R 8 indicates a hydroxyl group (for example).
• -R 1- indicates a C 3 -C 6 alkylene group
• R 5 , R 6 , R 7 and R 8 indicate the following groups, which are preferable.
• R5 indicates a hydrogen atom, a methyl group, or an ethyl group.
• R 6 indicates an Fmoc group (9-fluorenylmethyloxycarbonyl group).
• R 7 indicates a hydrogen atom, a methyl group, or an ethyl group.
• R 8 indicates a hydroxyl group or a group represented by -OR 13- .
• the group represented by R 13- indicates a protecting group, a methyl group, or an ethyl group of an oxygen atom.
• a preferred example other than the above is a compound in which R 7 is a hydrogen atom and R 8 is a protective group (protective group of amino acid), C 1-5 alkyl group or hydrogen atom.
• R 7 is a hydrogen atom
• R 8 is a protective group (protective group of amino acid), C 1-5 alkyl group or hydrogen atom.
• Cmn means that the number of carbon atoms is any one of m to n.
• An alkyl group is a monovalent group generated by the loss of one atom of hydrogen from a linear or branched aliphatic hydrocarbon.
• Examples of C1-5 alkyl groups are methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, and neopentyl group.
• Examples of C1 - C4 alkyl groups are methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group and tert-butyl group.
• the alkoxy group is a monovalent group generated by the loss of a hydrogen atom from the hydroxyl group of a linear or branched alcohol.
• Examples of C1-3 alkoxy groups are methoxy group, ethoxy group, propoxy group, and isopropoxy group.
• An alkylthio group is a group in which oxygen of an alkoxy group is replaced with sulfur.
• Examples of C1-3 alkylthio groups are methylthio, ethylthio, propylthio, and isopropylthio groups.
• the halogenoalkyl group is a monovalent group in which one or more hydrogen atoms of the alkyl group are substituted with halogen atoms.
• C1-3 halogenoalkyl groups are trifluoromethyl group, trichloromethyl group, difluoromethyl group, dichloromethyl group, dibromomethyl group, fluoromethyl group, 2,2,2-trifluoroethyl group, 2,2. , 2-Trichloroethyl group, 2-bromoethyl group, 2-chloroethyl group, 2-fluoroethyl group, 2-iodoethyl group, 3-chloropropyl group, and 4-fluorobutyl group.
• An alkylene group is a divalent group generated by the loss of two hydrogen atoms from a linear or branched aliphatic hydrocarbon.
• Examples of C 1-10 alkylene groups are methylene group, methylmethylene group, ethylene group, propylene group, trimethylene group, 1-methylethylene group, tetramethylene group, 1-methyltrimethylene group, 2-methyltrimethylene group, 3-Methyltrimethylene group, 1-methylpropylene group, 1,1-dimethylethylene group, pentamethylene group, 1-methyltetramethylene group, 2-methyltetramethylene group, 3-methyltetramethylene group, 4-methyltetra Methylene group, 1,1-dimethyltrimethylene group, 2,2-dimethyltrimethylene group, 3,3-dimethyltrimethylene group, hexamethylene group, 1-methylpentamethylene group, 2-methylpentamethylene group, 3- Methylpentamethylene group, 4-methylpentamethylene group, 5-methylpentamethylene group, 1,1-di
• An arylene group is a divalent group formed by removing two hydrogen atoms bonded to a ring from an aromatic hydrocarbon.
• An example of a ring constituting the C 6-10 arylene group is a benzene ring or a naphthalene ring.
• halogen atoms are fluorine, chlorine, bromine, and iodine.
• protective groups are 10,11-dihydro-5H-dibenzo- [a, d] [7] anurene-5-yl group (Sub), diphenylmethyl group (Bzh), 4-methoxyphenylmethyl group (PMB).
• the guanidine derivative of the present invention has a guanidine group, and a peptide or protein can be synthesized by binding the guanidine group. Further, a peptide can be obtained by mixing and reacting the above-mentioned compounds and the like with amino acids.
• Thiourea compound A novel thiourea compound, which is an intermediate used for producing a guanidine derivative, is a compound represented by the following formula (II).
• R 22 and R 24 may be the same or different, indicating a protecting group or a hydrogen atom.
• protecting groups are Pbf, Pmc or Sub. Among these, those in which R 22 and R 24 are Pbf and Sub, respectively, are preferable.
• R 23 represents a hydrogen atom.
• R 2 and R 4 may be the same or different and represent a protecting group or a hydrogen atom. However, in Formulas 1-1, 1-3, and 1-4, R2 and R4 are preferably those showing a protecting group. Examples of R 2 and R 4 are Pbf and Sub, respectively. R 3 represents a hydrogen atom.
• X 1-1 represents an alkali metal (for example, Na, K) or an alkaline earth metal (the composition formula of X 1-1 SCN varies depending on the cation valence).
• the compound represented by the formula 1-1 is dissolved in an organic solvent (for example, N, N-dimethylformamide: DMF).
• the compound represented by the formula 1-2 is added to this solution, and the solution is stirred to obtain a solution containing the compound represented by the formula 1-3.
• the molar ratio of the compounds represented by the formulas 1-1 and 1-2 may be 1: 2 to 2: 1, may be 2: 3 to 3: 2, or 4: 5 to 5: 4. But it may be.
• the reaction temperature may be 10 ° C or higher and 60 ° C or lower, or 20 ° C or higher and 40 ° C or lower.
• the reaction time may be 10 minutes or more and 3 hours or less, or 20 minutes or more and 1 hour or less.
• a known catalyst may be added to the reaction system.
• the stirring speed may be adjusted as appropriate.
• the compound represented by the formula 1-4 is dissolved in an organic solvent (for example, DMF).
• a strong base eg, NaH
• the solution to which the strong base is added is stirred to obtain a reaction solution (for example, a suspension).
• the molar ratio of the compounds represented by the formulas 1-1 and 1-4 may be 1: 2 to 2: 1, may be 2: 3 to 3: 2, or 4: 5 to 5: 4. But it may be.
• the temperature of the solution when a strong base is added to the compound represented by the formula 1-4 is ⁇ 20 ° C. or higher and 10 ° C. or lower, and may be ⁇ 10 ° C. or higher and 5 ° C. or lower.
• the temperature of the solution at the time of stirring may be 10 ° C or higher and 60 ° C or lower, or 20 ° C or higher and 40 ° C or lower.
• the reaction time may be 5 minutes or more and 2 hours or less, or 10 minutes or more and 1 hour or less.
• a known catalyst may be added to the reaction system.
• the stirring speed may be adjusted as appropriate. In this way, a solution containing the compound represented by the formula 1-4 is obtained.
• a solution containing the compound represented by the formula 1-3 is added to the solution containing the compound represented by the formula 1-4, and the mixture is stirred to promote the reaction to obtain a solution containing the compound represented by the formula 1-5.
• the temperature of the solution at the time of stirring may be 10 ° C or higher and 60 ° C or lower, or 20 ° C or higher and 40 ° C or lower.
• the reaction time may be 10 minutes or more and 4 hours or less, or 30 minutes or more and 2 hours or less.
• the solution may be cooled and a strong acid (eg, hydrochloric acid) may be added.
• the compound represented by the formula 1-5 can be obtained by purifying or drying using a known purification / drying method.
• the guanidine derivative of the present invention can be produced by the following scheme. This step utilizes the fact that when the C-terminal of the side-chain amino acid is not protected, the protecting group by the silylating agent protects the unprotected C-terminal of the side-chain amino acid.
• R1 to R8 are synonymous with those described above.
• the compound represented by the formula 2-2 is mixed with an organic solvent (for example, tetrahydrofuran: THF), and if the C-terminal is not protected ( when R8 is a hydroxyl group), a silylating agent (for example, MSA) is added. And stir.
• the molar ratio of the compound represented by the formula 2-2 to the silylating agent may be 1: 4 to 2: 1, may be 1: 3 to 1: 1, or may be 1: 2 to 1: 1. good.
• the temperature of the solvent at the time of stirring is 10 ° C. or higher and 90 ° C. or lower, and may be 20 ° C. or higher and 80 ° C. or lower.
• the stirring time may be 20 minutes or more and 3 hours or less, or 30 minutes or more and 2 hours or less.
• the condensing agent may be a known condensing agent, for example, dimethylaminopropyl ethylcarbodiimide hydrochloride (EDCI).
• EDCI dimethylaminopropyl ethylcarbodiimide hydrochloride
• the stirring time may be 10 minutes or more and 2 hours or less, or 20 minutes or more and 1 hour or less.
• an acid for example, citric acid
• the molar ratio of the compounds represented by the formulas 2-1 and 1-5 may be 1: 2 to 2: 1, may be 2: 3 to 3: 2, or 4: 5 to 5: 4. But it may be.
• a liquid containing the compound represented by the formula 2-3 can be obtained.
• the compound represented by the formula 2-3 can be obtained by performing an extraction treatment, a purification treatment, and a drying treatment from this liquid.
• the extraction treatment may include treatments such as salt formation and purification.
• the guanidine derivative of the present invention can be used for the following uses.
• the guanidine derivative (particularly salt) of the present invention is used as a protein denaturing agent because it easily forms hydrogen bonds.
• the guanidine derivative of the present invention is used as a strong base in organic synthesis.
• the guanidine derivative of the present invention has a guanidine group, and a peptide or protein can be synthesized by binding the guanidine group. Since the guanidine derivative or peptide of the present invention has the property of penetrating the cell membrane, it is also effective as a carrier of a drug delivery system.
• Fmoc as 9-fluorenylmethyloxycarbonyl or 9-fluorenylmethoxycarbonyl; Pbf as 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl; Pmc as 2,2,5,7,8-pentamethylchroman-6-sulfonyl; 10,11-dihydro-5H-dibenzo [A, D] [7] Annulene-5-yl as Sub; Bzh as Benz Hydrill; TBu as tertiary-butyl; Pmb as paramethoxybenzyl; THF as tetrahydrofuran; MSA as N-methyl-N-trimethylsilylacetamide; TEA as triethylamine; EDCI as dimethylaminopropyl ethylcarbodiimide hydrochloride; DMF as N, N-dimethylformamide; DCM as dichloromethane; TIS as triisopropyl
• F4G as 2-amino-3- (4-guanidinophenyl) propanoic acid
• F3G as 2-amino-3- (3-guanidinophenyl) propanoic acid
• Har as N6-carbamimidyl-L-lysine
• (3-guanidinopropyl) GpG as glycine
• A4pG as 2-amino-3- (1-carbamimidylpiperidin-4-yl) propanoic acid
• HarMe as N6-carbamimidyl-N6-methyl-L-lysine
• RMe as Nd-methyl-L-arginine
• A4pipG as 4-amino-1-carbamimidylpiperidin-4-carboxylic acid
• G4pipG as 2-amino-2- (1-carbamimidylpiperidin-4-yl) acetic acid
• Nar 2-amino-4-guanidinobutanoi
• the proton nuclear magnetic resonance (1HNMR) in the following synthesis example is JEM-ECP300 manufactured by JEOL Ltd., JNM-ECX300 manufactured by JEOL Ltd., or Bruker.
• the chemical shift was measured in heavy chloroform or heavy dimethylsulfoxide solvent using AscendTM500 manufactured by AscendTM500, and the chemical shift was shown by the ⁇ value (ppm) when tetramethylsilane was used as the internal standard (0.0 ppm).
• ppm ⁇ value
• High performance liquid chromatography / mass spectrometry is either ACQUITY UPLC H-Class / QDa manufactured by Waters, ACQUITY UPLC H-Class / SQD2 manufactured by Waters, or LC-20AD / Triple Tof 5600 manufactured by Shimadzu, unless otherwise specified. It was measured using a chromatograph.
• ESI + means a positive mode of electrospray ionization
• M + H means a proton adduct
• M + Na means a sodium adduct.
• ESI- is the negative mode of the electrospray ionization method
• MH is the proton deficient.
• the ratio of raw materials to products was calculated from the area ratio of peaks obtained by the following analytical conditions in high performance liquid chromatography / mass spectrometry, and the structure of the obtained compound was confirmed by 1H NMR and LC / MS.
• Potassium thiocyanate (10.2 g, 105 mmol) was added to 5-chloro-10,11-dihydro-5H-dibenzo- [a, d] [7] annulene (22.87 g, 100 mmol) dissolved in 200 mL of DMF, and the temperature at room temperature. The mixture was stirred for 30 minutes to obtain a reaction solution.
• Sodium hydride (4.20 g, 105 mmol) in 2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonamide (26.9 g, 100 mmol) dissolved in 200 mL of DMF at 0 ° C. ) was added and stirred at room temperature for 15 minutes.
• Triethylamine (TEA; 0.17 g, 1.64 mmol), N-((10,11-dihydro-5H-dibenzo [a, d] [7] anuren-5-yl) carbamoti oil) obtained in Example 1- 2,2,4,6,7-Pentamethyl-2,3-dihydrobenzofuran-5-sulfonamide (0.78 g, 1.49 mmol), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.286) g, 1.49 mmol) was added, and the mixture was stirred for 60 minutes.
• the compound described above was obtained by synthesis and purification by a known method. The product was confirmed by 1H NMR. The obtained notation compound was deprotected by the same method as in (1). After 60 minutes deprotection treatment, Fmoc-F4G-OH; (S) -2-((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -3- (4-guanidinophenyl) propanoic acid The formation was confirmed by LC / MS (analysis condition A), but the peak of Fmoc-F4G-OH was hardly observed at 4.61% (LC / MS area) of the whole, and tBu was not deprotected.
• the compound described above was obtained by synthesis and purification by a known method. The product was confirmed by 1H NMR. The obtained notation compound was deprotected by the same method as in (1). After deprotecting for 60 minutes, Fmoc-F4G-Met; (S) -2-((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -3- (4-guanidinophenyl) methyl propanoate The formation of Fmoc-F4G-Met was confirmed by LC / MS (analysis condition A), but the peak of Fmoc-F4G-Met was hardly observed at 1.32% (LC / MS area), and the title compound that was not deprotected at all was found.
• N-Fmoc-L-lysine hydrochloride (1.00 g, 2.47 mmol) was suspended in 10 mL of THF, MSA (0.99 mL, 6.17 mmol) was added, and the mixture was stirred at room temperature for 30 minutes.
• N-((10,11-dihydro-5H-dibenzo [a, d] [7] anuren-5-yl) carbamoti oil) obtained in Example 1 was added to the reaction solution, -2,2,4,6, 7-Pentamethyl-2,3-dihydrobenzofuran-5 sulfonamide (1.29 g, 2.47 mmol), 3-(((ethylimino) methylene) amino) -N, N-dimethylpropan-1-amine hydrochloride (497 mg, 2.59) mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was stopped with a 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate.
• N-((10,11-dihydro-5H-dibenzo [a, d] [7] anuren-5-yl) carbamoti oil) obtained in Example 1 was added to the reaction solution, -2,2,4,6, 7-Pentamethyl-2,3-dihydrobenzofuran-5 sulfonamide (4.96 g, 9.52 mmol), 3-(((ethylimino) methylene) amino) -N, N-dimethylpropan-1-amine hydrochloride (1.92 g, 10.00 mmol) was added at room temperature and stirred at room temperature for 30 minutes. The reaction was stopped at room temperature with saturated aqueous citric acid solution, and the mixture was extracted with ethyl acetate.
• N-((10,11-dihydro-5H-dibenzo [a, d] [7] anuren-5-yl) carbamoti oil) obtained in Example 1 was added to the reaction solution, -2,2,4,6, 7-Pentamethyl-2,3-dihydrobenzofuran-5-sulfonamide (2.47 g, 4.75 mmol), 3-(((ethylimino) methylene) amino) -N, N-dimethylpropan-1-amine hydrochloride (959 mg, 5.00 mmol) was added, and the mixture was stirred at room temperature for 2 hours.
• the present invention relates to guanidine derivatives and the like, it can be used in the fields of chemistry, biochemistry, pharmaceuticals and polymer chemistry.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Analytical Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Biochemistry (AREA)
• Biophysics (AREA)
• General Health & Medical Sciences (AREA)
• Genetics & Genomics (AREA)
• Medicinal Chemistry (AREA)
• Molecular Biology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Priority Applications (4)

Applications Claiming Priority (2)

Publications (1)

Family

ID=82357978

Family Applications (1)

Country Status (4)

Families Citing this family (1)

Citations (3)

Family Cites Families (1)

• 2022
  • 2022-01-07 US US18/271,200 patent/US20240010627A1/en active Pending
  • 2022-01-07 JP JP2022574078A patent/JPWO2022149610A1/ja active Pending
  • 2022-01-07 WO PCT/JP2022/000356 patent/WO2022149610A1/ja not_active Ceased
  • 2022-01-07 EP EP22736778.6A patent/EP4276096A4/en active Pending
• 2025
  • 2025-11-11 JP JP2025191313A patent/JP2026027427A/ja active Pending

Patent Citations (3)

Non-Patent Citations (14)

Also Published As

Similar Documents

Legal Events