Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/08—Tripeptides
  • C07K5/0815—Tripeptides with the first amino acid being basic
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
  • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
  • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/08—Tripeptides
  • C07K5/0802—Tripeptides with the first amino acid being neutral
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/08—Tripeptides
  • C07K5/0802—Tripeptides with the first amino acid being neutral
  • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/08—Tripeptides
  • C07K5/0819—Tripeptides with the first amino acid being acidic
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/08—Tripeptides
  • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• the present invention relates to a phenethylamine derivative which exhibits motilin receptor antagonistic activity and is useful as a medicament.
• Motilin one of the gastrointestinal hormones, is a linear peptide composed of 22 amino acids and is well known to regulate gastrointestinal motility in mammals including humans. It has been reported that exogenous motilin induces gastric emptying in humans and dogs, causing contractions similar to fasting transmissible yields (HCI nterdigestive Migrating Contractions, IMC) (I toheta). 1., Scand. J. G astroentero 1., 11. 93-110 (1976); Peeterseta 1., G astroenterology 102, 97-101 (1992)). For this reason, erythromycin derivatives, motilin agonists, are being developed as gastrointestinal motility promoters (S atohetal., J. Pharmaco 1. Exp. Thera p., 271, 574). -579 (1994); L arteyetal, J. Med. Chem., 38, 1793—1798 (1995); Drug of Future, 19, 910—912 (1994)) o
• the motilin receptor was known to mainly exist in the duodenum, but recently it was also found to be present in the large intestine of the lower gastrointestinal tract (Wi 11 i ameta, Am. J. Phy siol., 262. G50-G55 (1992)), it has been shown that motilin may be involved not only in the upper gastrointestinal tract but also in the lower gastrointestinal tract.
• motilin receptor antagonists may be able to ameliorate conditions with elevated blood motilin, such as irritable bowel syndrome. Disclosure of the invention
• An object of the present invention is to provide a phenethylamine derivative which has a motilin receptor antagonistic effect and is useful as a medicine.
• the present inventors have conducted intensive studies for the purpose of developing a compound having an excellent motilin receptor gonist action.
• the phenethylamine derivative represented by the general formula (1) was converted into an excellent motilin receptor He found that he was a gonist, and completed the present invention based on this finding.
• the present invention relates to the general formula (1)
• A represents an amino acid residue or a ⁇ -substituted amino acid residue.
• one bond is formed with one NR 2 — to form an amide.
• Is R 6 —CO— a linear or branched alkyl group having 2 to 7 carbon atoms which may have a substituent, a straight-chain or branched alkyl group having 3 to 8 carbon atoms which may have a substituent. It represents a chain or branched alkenyl group, a linear or branched alkynyl group having 3 to 8 carbon atoms which may have a substituent.
• R 2 represents a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms which may have a substituent.
• R 3 represents one CO—R 7 , a linear or branched alkyl group having 1 to 5 carbon atoms which may have a substituent, or a carbon atom having 2 to 5 carbon atoms which may have a substituent.
• R 4 is a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkenyl group having 2 to 6 carbon atoms, a linear or branched alkenyl group having 2 to 6 carbon atoms, A branched alkynyl group, or a general formula (2)
• R 5 represents a hydrogen atom or one OR 8 .
• Re is a linear or branched alkyl group having 1 to 6 carbon atoms which may have a substituent, or a linear or branched alkyl group having 2 to 7 carbon atoms which may have a substituent.
• R 7 is a hydrogen atom, a linear or branched alkyl group having 1 to 5 carbon atoms which may have a substituent, a cycloalkyl group having 3 to 7 carbon atoms, —N (R 12 ) R 13, represents an OR 14.
• R 8 represents a hydrogen atom or a linear alkyl group having 1 to 4 carbon atoms.
• R 9 and R L 0 are the same or different and each have a hydrogen atom, a linear or branched alkyl group having 1 to 5 carbon atoms, which may have a substituent, and a substituent.
• Ru is a linear or branched alkyl group having 1 to 5 carbon atoms which may have a substituent, a linear or branched alkyl group having 2 to 6 carbon atoms which may have a substituent.
• a chained alkenyl group, a linear or branched alkynyl group having 2 to 6 carbon atoms which may have a substituent, a carbon atom which may be fused to a benzene ring or a heterocyclic ring having 3 to 6 carbon atoms Represents a cycloalkyl group or an aromatic ring having 6 to 12 carbon atoms which may have a substituent.
• R 12 and R 13 are the same or different and each represent a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or a cycloalkyl group having 3 to 7 carbon atoms.
• RM represents a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, or a cycloalkyl group having 3 to 7 carbon atoms.
• R 15 represents a hydrogen atom or a methyl group.
• R 16 and R 17 together represent a cycloalkyl group or a cycloalkenyl group having 3 to 7 carbon atoms.
• the present invention provides a drug containing the compound represented by the general formula (1) as an active ingredient. Further, the present invention provides a motilin receptor antagonist containing the above compound. Further, the present invention also provides a gastrointestinal motility inhibitor containing the above compound as an active ingredient. Furthermore, high motilin containing the above compound as an active ingredient Also provided is a therapeutic agent for bloodemia.
• the amino acid residue in A may be any known amino acid residue, and examples thereof include ⁇ -, ⁇ -, and ⁇ -amino acid residues.
• the ⁇ -substituted amino acid residue in A refers to a residue in which the hydrogen atom of the amino group at the ⁇ -position of the above amino acid residue is substituted.
• substituent in the ⁇ -substituted amino acid residue include a linear or branched alkyl group having 1 to 3 carbon atoms which may be substituted with a benzene ring or the like, and a methyl group is preferable. .
• Examples of the ⁇ -amino acid residue of the ⁇ -substituted amino acid residue in ⁇ include the amino acids described above, and include Val, Leu, Lele, Phe, Tyr, Trp, Phg, Chg g, Ch a, Ties Th i are preferred, and Val, Leu. I le, P he, Phg, Ch a are more preferred.
• the ⁇ -substituted amino acid residues in A include ⁇ -methyl valine ( ⁇ —Me—V a 1), N-methyl leucine (N—Me—L eu), N-methyl isoleucine (N-Me-I 1 e) ), N-methylphenylalanine (N-Me-Phe), N-methyltyrosine (N_Me-Tyr), N-methyltryptophan (N-Me-Trp), N-methylphenylglycine ( N-Me-Phg), N-methylcyclohexylglycine (N-Me-Chg), N-methylcyclohexylalanine (N-Me-Cha), N-methyl tert bite-isine (N-Me — T le), N—methyl-2—Chenylalanine (N—Me—Th i), N—Me—V ai, N—Me_L eu, N-Me-I 1 e, N
• the alkyl group of the linear or branched alkyl group having 1 to 6 carbon atoms which may have a substituent is a straight-chain or branched alkyl group having 1 to 5 carbon atoms.
• a chain or branched alkyl group is preferred, a straight-chain or branched alkyl group having 2 to 3 carbon atoms is more preferred, and an ethyl group is particularly preferred.
• R e - CO- of the R e carbon atoms, which may have a substituent
• alkenyl group of the linear or branched alkenyl group having 2 to 7 carbon atoms a linear or branched alkenyl group having 4 to 6 carbon atoms is preferable.
• R 6 of R 6 —CO— the alkynyl group of the linear or branched alkynyl group having 2 to 7 carbon atoms which may have a substituent has the number of carbon atoms 4-6 straight or branched alkynyl groups are preferred.
• R 6 —CO— in R 6 the number of carbon atoms which may be substituted;!
• substituent of a linear or branched alkenyl group having 2 to 6 carbon atoms, an optionally substituted linear or branched alkynyl group having 2 to 7 carbon atoms such as amino Group, methylamino group, ethylamino group, dimethylamino group, trimethylammonium group, hydroxyl group, carboxyl group, aminocarbonyl group, aminocarbonylamino group, pyridylthio group, methylthio group, phenyl group, 3-indolyl group, 4-hydroxyphenyl Group, 2-phenyl, 2-furyl, 3-imidazolyl, cyclohexyl, etc., amino, methylamino, phenyl, 3-india Ryl, 4-hydroxyphenyl, 2-phenyl,
• R 6 CO—, the number of carbon atoms which may be substituted in R 6
• Examples of the straight-chain or branched alkyl group having 1 to 6 include a straight-chain or branched-chain alkyl group having 2 or 3 carbon atoms and having one or more of the same or different substituents. Groups are preferred. Among them, 1-amino-2-phenylethyl, 1-1-methylamino-2-phenylethyl, 1-amino-2- (3-indolyl) ethyl, and 11-amino-2- (4-hydroxy) ) A phenylethyl group, a 1-amino-2- (2-phenyl) ethyl group, a 1-amino-2- (2-furyl) ethyl group, a 1-amino-2-cyclohexylethyl group, and a 2-phenylpropyl group are preferred, and a 1-aminopropyl group is preferred. A 2-phenylethyl group is particularly preferred.
• R 6 of R 6 —CO— in R 6 has the above substituent.
• a linear or branched alkenyl group having 4 to 6 carbon atoms is preferred.
• R 6 of R 6 —CO— the linear or branched alkynyl group having 2 to 7 carbon atoms which may have a substituent includes the carbon atom having the above substituent 4-6 straight or branched alkynyl groups are preferred.
• the heterocyclic benzene ring or a heterocyclic ring and cycloalkyl group fused with carbon atoms and optionally 3-7 for example, it is selected from 0, N or S Examples thereof include an aliphatic or aromatic 5- or 6-membered ring containing one or two hetero atoms, and specific examples include pyridine, pyrazine, furan, thiophene, pyrrole, and imidazole.
• the cycloalkyl group having 3 to 7 carbon atoms which may be condensed with a benzene ring or a heterocyclic ring is a cycloalkyl group having 3 to 7 carbon atoms which is condensed with a benzene ring.
• Alkyl groups are preferred, and among them, 1-benzocyclobutyl group is preferred.
• R 6 CO—, the number of carbon atoms which may be substituted in R 6
• aromatic ring of 6 to 12 aromatic rings examples include a benzene ring and a naphthalene ring.
• R 6 of R 6 —CO— as the substituent of the optionally substituted aromatic ring having 6 to 12 carbon atoms, a hydroxyl group, a methoxy group, a phenoxy group, a benzyloxy group, a tert group —Butoxy group, amino group, methylamino group, dimethylamino group, ethylamino group, carboxyl group, methoxycarbonyl group, and the like. Further, the aromatic ring may have one or more identical or different substituents as described above.
• the saturated or unsaturated heterocyclic heterocyclic ring having 3 to 12 carbon atoms which may have a substituent is, for example, from 0, N or S
• An aliphatic or aromatic 5- to 10-membered monocyclic or condensed ring containing one or two selected hetero atoms can be mentioned, for example, pyrrolidine, piperidine, piperazine, tetrahydrogen. Examples include isoquinoline, pyridine, pyrazine, furan, thiophene, pyrrol, imidazole, quinolin, indone, benzimidazole, and benzofuran.
• R 6 CO—, the number of carbon atoms which may be substituted in R 6
• Examples of the substituent for the saturated or unsaturated heterocyclic ring having 3 to 12 include a hydroxyl group, a methoxy group, a phenoxy group, a benzyloquine group, a tert-butyloquine group, an amino group, a methylamino group, a dimethylamino group, an ethylamino group, and a carboxyl group. And methoxycarbonyl groups.
• the heterocyclic ring may have one or more One or more of the substituents may have different substituents as described above.
• R 6 of R 6 —CO— as the saturated or unsaturated heterocyclic ring having 3 to 12 carbon atoms which may have a substituent, one or more identical or different above-mentioned substituents
• the above-mentioned heterocyclic ring which may have a group is mentioned.
• a linear or branched alkyl group having 1 to 4 carbon atoms is preferable, a linear alkyl group having 1 to 2 carbon atoms is more preferable, and a methyl group is preferable. Particularly preferred.
• the alkenyl group of the alkenyl group is preferably a straight-chain or branched alkenyl group having 3 to 6 carbon atoms.
• the alkynyl group in the alkynyl group is preferably a linear or branched alkynyl group having 3 to 6 carbon atoms.
• R 6 —C ⁇ C—R 6 , N (R 9 ) R 10 of R 9 and R 10 optionally having 1 to 5 carbon atoms, linear or branched Alkyl group, linear or branched alkenyl group having 2 to 6 carbon atoms which may have a substituent, linear chain having 2 to 6 carbon atoms which may have a substituent Or as a substituent of a branched alkynyl group, for example, an amino group, a hydroxyl group, a carboxyl group, an aminocarbonyl group, an aminocarbonylamino group, a pyridylthio group, a methylthio group, a phenyl group, and a 3-indolyl group , 4-hydroxyphenyl group, 2-phenyl group, 2-furyl group, 3-imidazolyl group, cyclohexyl group, and the like; amino group, phenyl group, 3-indolyl group, and 4-hydroxyphenyl group.
• alkyl group, alkenyl group and alkynyl group may have one or more same or different substituents as described above.
• a methyl group having the above substituents is preferable, and among them, a benzyl group, a 3-indolylmethyl group, a ⁇ -hydroxybenzyl group, a 2-thienylmethyl group, and a 2-furylmethyl group are preferable.
• a cyclohexylmethyl group is preferred, and a benzyl group is particularly preferred.
• the alkenyl group is preferably a linear or branched alkenyl group having 3 to 6 carbon atoms.
• R 9 and R 10 the optionally substituted straight-chain or branched alkynyl group having 2 to 6 carbon atoms may be a straight-chain or branched-chain alkynyl group having 3 to 6 carbon atoms. Alkynyl groups are preferred.
• a cycloalkyl group having 3 to 6 carbon atoms which may be condensed with a benzene ring or a heterocyclic ring in R 9 and R 10 of one N (R 9 ) R 10 in R 6 of R 6 —CO—
• the heterocyclic ring include an aliphatic or aromatic 5- or 6-membered ring containing one or two hetero atoms selected from 0, N or S, and specifically, pyridine, pyrazine, Furan, thiophene, pyrrole, imidazole, and the like.
• R 6 - in R 6 of CO- one N (R 9) in which R 9 and R 10 of R 10, a benzene ring or heterocyclic ring fused even if a good 3 to 6 carbon atoms consequent opening alkyl group Is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.
• alkyl group include a cycloalkyl group having 3 to 6 carbon atoms which may be condensed with a benzene ring or the above heterocyclic ring.
• N (R 9 ) R 10 at R 9 and R 10 examples of the aromatic ring having 6 to 12 carbon atoms which may have a substituent include a benzene ring and a naphthalene ring.
• the aromatic ring may have one or more identical or different substituents as described above.
• R 6 - CO- in R e of one N (R 9) R 9 and R 10 of R 10 has a definition as above, as an N (R 9) R 10 is Benjiruamino group, A benzylmethylamino group is preferred.
• R 6 - in C 0- of R 6, in the RH one Oru as alkyl Le group linear or branched alkyl group having 1 to 5 carbon atoms which may have a substituent A linear or branched alkyl group having 1 to 4 carbon atoms is preferable, a linear alkyl group having 1 to 2 carbon atoms is more preferable, and a methyl group is particularly preferable.
• R 6 in R 6 -CO- one of OR U of R TL, as an alkenyl group of straight or branched chain alkenyl group which may carbon atoms 2-6 may have a substituent Is preferably a linear or branched alkenyl group having 3 to 6 carbon atoms.
• R 6 of R 6 —CO— at RH of one ORH, an alkynyl group of a linear or branched alkynyl group having 2 to 6 carbon atoms which may have a substituent is A straight-chain or branched alkynyl group having 3 to 6 carbon atoms is preferred.
• R 6 - in R 6 of CO- have at [one OR u, straight-chain or branched alkyl group having 1 to 5 carbon atoms which may have a substituent, a substituent A straight-chain or branched alkenyl group having 2 to 6 carbon atoms which may be substituted; a straight-chain or branched alkynyl group having 2 to 6 carbon atoms which may have a substituent; Examples include, for example, an amino group, a hydroxyl group, a carboxyl group, Group, aminocarbonylamino group, pyridylthio group, methylthio group, phenyl group,
• 3-indolyl 4-hydroxyphenyl, 2-phenyl, 2-furyl, 3-imidazolyl, cyclohexyl, etc., amino, phenyl, 3-indolyl, 4- Hydroxyphenyl, 2-phenyl, 2-furyl, and cyclohexyl are preferred, and phenyl is more preferred.
• the above-mentioned alkyl group, alkenyl group and alkynyl group may have one or more same or different above-mentioned substituents.
• R 6 of R 6 —CO— in R 6 the straight-chain or branched alkyl group having 1 to 5 carbon atoms which may have a substituent in the RH of ORH is the above-mentioned substituent.
• Preferred is a methyl group having benzyl group, 3-benzyloxy group, p-hydroxybenzyl group, 2-phenylmethyl group, 2-furylmethyl group, and cyclohexylmethyl group. Particularly preferred.
• R 6 —CO— in R 6 in one RH of ORH, the straight-chain or branched alkenyl group having 2 to 6 carbon atoms which may have a substituent has carbon atoms
• a straight-chain or branched alkenyl group of 3 to 6 is preferred.
• R 6 - in R 6 of CO- one at RH of OR n, as linear or partial skill chain alkynyl group having 2 to 6 carbon atoms which may have a substituent, 3 carbon atoms Preferred are straight-chain or branched alkynyl groups of from 6 to 6.
• R 6 - in CO- of R 6, in one OR of R u as double heterocycle benzene ring or a heterocyclic ring condensed with even if good 3 to 6 carbon atoms a cycloalkyl group, for example, An aliphatic or aromatic 5- or 6-membered ring containing one or two heteroatoms selected from, 0, N or S, specifically, pyridine, pyrazine, furan, thiophene, pyrrole, imidazole , And the like.
• R 6 - in C 0- of R 6, in one ORM of R u, and a cycloalkyl group of benzene ring or a heterocyclic ring condensed with even if good 3 to 6 carbon atoms a cycloalkyl group Refers to cyclopropyl group, cyclobutyl group, cyclopentyl group, and hexyl group.
• R E - CO- in R E of, and in RH one Oru, benzene ring or a heterocyclic ring condensed with good even if L, a cycloalkyl group having 3 to 6 carbon atoms And a cycloalkyl group having 3 to 6 carbon atoms which may be condensed with a benzene ring or the above heterocyclic ring.
• R 6 - in R 6 of CO- in an OR of R u, the aromatic rings of the aromatic ring having 6 to 12 carbon atoms which may have a substituent, a benzene ring, Na Futaren ring like Can be
• the substituent of the optionally substituted aromatic ring having 6 to 12 carbon atoms in one OR of R 6 may be a hydroxyl group, a methoxy group, a phenoxy group, A benzyloxy group, a tert-butyloxy group, an amino group, a methylamino group, a dimethylamino group, an ethylamino group, a carboxyl group, a methoxycarbonyl group, and the like.
• the aromatic ring may have one or more identical or different substituents as described above.
• R 6 —CO— in R 6 in one RH at ORH, as the optionally substituted aromatic ring having 6 to 12 carbon atoms, one or more identical or different aromatic rings
• the optionally substituted aromatic ring having 6 to 12 carbon atoms one or more identical or different aromatic rings
• R 6 - in C 0- of R 6, has a definition as above for one Oru, An OR 8, Benjiruokishi group.
• R 6 - CO- of R 6 is a force having a definition as above, as R 6 is
• a 2-phenylpropyl group, a 1-benzocyclobutyl group, a benzylamino group and a benzyloxy group are preferred, and a 1-amino-2-phenylethyl group is particularly preferred.
• the alkyl group of the linear or branched alkyl group having 2 to 7 carbon atoms which may have a substituent includes a linear or branched alkyl group having 3 to 4 carbon atoms.
• a propyl group is particularly preferred.
• R 3 may have a substituent L, and the alkenyl group of the linear or branched alkenyl group having 3 to 8 carbon atoms may be a linear or branched alkenyl group having 4 to 8 carbon atoms. Alkenyl groups are preferred, and straight-chain or branched alkenyl groups having 5 to 7 carbon atoms are more preferred.
• R 3 which may have a substituent, may be a straight-chain or branched alkynyl group having 3 to 8 carbon atoms, wherein the alkynyl group is a straight-chain or branched-chain alkynyl group having 3 to 7 carbon atoms.
• An alkynyl group is preferable, and a linear or branched alkynyl group having 5 to 7 carbon atoms is more preferable.
• Examples of the substituent of a linear alkenyl group or a linear or branched alkynyl group having 3 to 8 carbon atoms which may have a substituent include an amino group, a methylamino group, an ethylamino group, and a dimethylamino group.
• alkyl group, alkenyl group and alkynyl group may have one or more same or different substituents described above.
• the linear or branched alkyl group having 2 to 7 carbon atoms which may have a substituent includes one or more of the same or different carbon atoms having the same or different substituents.
• Preferred are straight-chain or branched-chain alkyl groups of from 2 to 4, especially 2-amino-3-phenylpropyl, 2-amino-3- (3-indolyl) propyl, 2-amino-3- (4-hydroquin) Preferred are phenylpropyl, 2-amino-3- (2-phenyl) propyl, 2-amino-3- (2-furyl) propyl, 2-amino-3-cyclohexylpropyl and 3-phenylbutyl, and 2-amino-butyl.
• a 3-phenylpropyl group is particularly preferred.
• the linear or branched alkenyl group having 3 to 8 carbon atoms which may have a substituent in R t the linear or branched alkenyl group having 4 to 8 carbon atoms having the substituent may be used. Is preferably a branched alkenyl group.
• R t a substituted or unsubstituted straight-chain or branched alkynyl group having 2 to 7 carbon atoms may be the straight-chain or branched alkynyl group having 3 to 7 carbon atoms.
• a branched alkynyl group is preferable.
• phenylanilanyl group N—Me phenylanilanyl group, ⁇ — (3-indolyl) araninyl group, tyrosinol group, ⁇ - (2-Chenyl) araninoyl group, ⁇ - (2-furyl) araninoyl group, / 5-cyclohexylaraninyl group, 3-phenylbutyryl group, 1-benzocyclobutylcarbonyl Group, a benzylaminocarbonyl group, or a benzyloxycarbonyl group is preferable, and a phenylalaninyl group is particularly preferable (
• the alkyl group of a linear or branched alkyl group having 1 to 3 carbon atoms which may have a substituent in R 2 represents a methyl group, an ethyl group, a propyl group, an isopropyl group, A methyl group and an ethyl group are preferred, and a methyl group is more preferred.
• Examples of the substituent of the linear or branched alkyl group having 1 to 3 carbon atoms which may have a substituent in R 2 include a phenyl group, a hydroxyl group, an amino group, a carboxy group, and the like. Can be Further, the alkyl group may have one or more of the same or different substituents described above.
• a methyl group is preferable.
• R 2 has the above definition, but R 2 is preferably a hydrogen atom or a methyl group.
• one CO—R 7 in R 7 the optionally substituted straight-chain or branched alkyl group having 1 to 5 carbon atoms may be a straight-chain alkyl group having 1 to 3 carbon atoms. Or a branched alkyl group is preferred.
• one of CO—R 7 , R 7 may optionally have a substituent: a linear or branched alkyl group having from! 5 to 5; Hydrogen, an alkoxy group, etc., and halogen is preferable,
• R 3 one CO—R 7 of R 7, optionally substituted carbon atoms
• the linear or branched alkyl group having 1 to 5 include a linear or branched alkyl group having 1 to 3 carbon atoms and having one or more of the same substituents. Preferred are a fluoromethyl group and a chloromethyl group.
• R 3 the R? One CO- R 7, the cycloalkyl group having 3 to 7 carbon atoms, preferably a cycloalkyl group having 3 to 5 carbon atoms.
• R 3 one CO—R 7 in R 7 , one N (R 12 ) R 13 in R 12 and R 3 as a straight-chain or branched alkyl group having 1 to 4 carbon atoms, A linear alkyl group of 1-2 is preferred, and a methyl group is more preferred.
• R 3 one CO- in R 7 in R 7, at R 12 and 3 one N (R 12) R 13, the cycloalkyl group having 3 to 7 carbon atoms, a cycloalkyl group having 3 to 5 carbon atoms Is preferred.
• R 7 one CO- R 7, in one N (R 12) R 12 and 3 of R 13, examples of R 12 and R 13, same or different, also can properly hydrogen atom a methyl group preferable.
• R 3 one CO—R 7 of R 7 , one N (R 12 ) R 13 R 12 and Ri 3 have the above definitions, but one N (R 9 ) R 10 is amino And a methylamino group are preferred.
• R 3 one CO—R 7 in R 7 , one OR 14 in R 14 , the straight-chain or branched alkyl group having 1 to 6 carbon atoms is a straight-chain having 1 to 2 carbon atoms. Is preferably an alkyl group, more preferably a methyl group.
• the R 7 one CO- R 7, at R l4 one 0R l4, a cycloalkyl group having 3 to 7 carbon atoms are cyclopropyl group, cyclobutyl group, Shikurobe pentyl group, a cyclohexyl group
• the power of cycloheptyl is preferably cyclopropyl.
• R 7 one C0- R 7, R 14 one 0R 14 has a definition as above, as an OR 14, hydroxyl, main butoxy group are preferable.
• one CO—R 7 is defined as above.
• an amide group and an N-methylamide group are preferable.
• the alkyl group a linear or branched alkyl group having 1 to 3 carbon atoms is preferable, and a methyl group is particularly preferable.
• linear or branched alkenyl group having 2 to 5 carbon atoms which may have a substituent in R 3
• a linear or branched alkenyl group having 2 to 3 carbon atoms is preferable.
• linear or branched alkynyl group having 2 to 5 carbon atoms which may have a substituent in R 3
• a linear alkynyl group having 2 to 3 carbon atoms is preferable.
• substituents of a linear alkenyl group, a linear or branched alkynyl group having 2 to 5 carbon atoms, which may have a substituent include an amino group, an alkylamino group, a hydroxyl group, an alkoxy group, Examples thereof include a carboxyl group and a halogen, and an amino group is particularly preferred.
• the alkyl group, alkenyl group, and alkynyl group may have one or more identical or different substituents described above.
• a methyl group and an aminomethyl group are preferable.
• R 3 has the above definition, but R 3 is preferably an amide group, an N-methylamide group, a methyl group, or an aminomethyl group, and particularly preferably an amide group or a methyl group.
• linear or branched alkyl group having 1 to 6 carbon atoms in R 4 a linear or branched alkyl group having 2 to 5 carbon atoms is preferable, and a branched or branched alkyl group having 3 to 5 carbon atoms.
• a chain alkyl group is more preferred, and a tert-butyl group is particularly preferred.
• linear or branched alkenyl group having 2 to 6 carbon atoms for R 4 a linear or branched alkenyl group having 3 to 5 carbon atoms is preferable, and a branched chain alkenyl group having 3 to 5 carbon atoms is preferable.
• a chain alkenyl group is more preferred.
• straight-chain or branched alkynyl group having 2 to 6 carbon atoms in R 4 a straight-chain or branched alkynyl group having 3 to 5 carbon atoms is preferable, and a branched chain alkynyl group having 3 to 5 carbon atoms is preferable.
• a chain alkynyl group is more preferred.
• R 15 in R 4 in the general formula (2) a methyl group is preferable.
• a cycloalkyl group having 3 to 7 carbon atoms formed by R 16 and R 17 in R 4 in general formula (2) together a cycloalkyl group having 3 to 5 carbon atoms is preferable.
• the cycloalkenyl group having 3 to 7 carbon atoms formed by R 16 and R 17 in R 4 in the general formula (2) together is preferably a cycloalkenyl group having 4 to 6 carbon atoms.
• R 4 is preferably an isopropyl group, a tert-butyl group, a 1,1-dimethylpropyl group, a 1,1-dimethyl-2-propenyl group, and particularly preferably a tert-butyl group.
• linear alkyl group having 1 to 4 carbon atoms in R 12 of one OR 12 in R 5 a methyl group and an ethyl group are preferable, and a methyl group is more preferable.
• the R 5, hydroxyl, main Bok alkoxy group are preferable, a hydroxyl group is particularly preferred.
• Salt forming acids include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, tartaric acid, methanesulfonic acid, trifluorosulfonic acid Organic acids such as acetic acid can be mentioned.
• the compounds of the present invention have optical isomers, and each optical isomer and a mixture thereof are all included in the present invention.
• Is a derivative of an amino acid containing a dipeptide or a tripeptide can be performed by either a solid phase method or a liquid phase method.
• an automatic organic synthesizer can be used, but it can also be carried out manually.
• amino acids constituting the compounds of the present invention are commercially available and can be easily purchased. However, when they are not commercially available, generally well-known methods such as the Strecker method and the Bucherer method are used. It can be produced by a method such as acetamide oxalate ester method or a method of alkylating an amino-protected glycine ester.
• La Nin esters are, for example, commercially available, Oh Rui tyrosine ester (Ty r one OR 14 (wherein obtainable by esterifying tyrosine, R l4 is as defined above )),
• the substituent R 4 (where R 4 is the m-position) is obtained by the usual organic chemical method, for example, the Friedel-Crafts reaction in the presence of an acid catalyst such as a protonic acid or a Lewis acid.
• an acid catalyst such as a protonic acid or a Lewis acid.
• it represents the case of an alkyl group, an alkenyl group, or an alkynyl group, and can be produced by introducing the same c ) in this paragraph.
• the introduction of the substituent R 4 is not limited to this stage, but can be performed at any possible stage in the production.
• the p- human Dorokishi m- substituted phenyl ⁇ La Nin esters of ⁇ - Amino groups, after benzyl O Kin carbonyl protecting For example, by performing the O-alkylation, R 8 one OR 8 get those alkyl groups be able to. If R 5 is a hydrogen atom or an alkoxy group, then --alkylation is performed, and R 2 is an alkyl group Can be obtained.
• R 2 After protecting the hydroxyl group of R 5 with a substance that can be easily removed at a later stage, for example, a benzyl group, N-alkylation and deprotection allow R 2 to be an alkyl group and R 5 to be a hydroxyl group. Can be obtained.
• a substance that can be easily removed at a later stage for example, a benzyl group, N-alkylation and deprotection allow R 2 to be an alkyl group and R 5 to be a hydroxyl group. Can be obtained.
• the ⁇ -amino-protected substituted phenylalanine ester can be reacted directly with the amine HN (R 12 ) R 13 or after conversion to carboxylic acid By condensing with an amine HN (R 12 ) R 13 according to a conventional method, it can be converted to an ⁇ -amino group protected substituted phenylalanine amide.
• R 3 is a substituted alkyl group, a halogen-substituted alkyl group, a hydroxyalkyl group, an aminoalkyl group, an aldehyde or an alcohol obtained by reducing an ester of an ⁇ -amino group-protected substituted phenylalanine ester, It can be converted to a methyl group or the like.
• ⁇ -substituted amino acids are commercially available and readily available for purchase, but when they are not commercially available, generally well-known methods, such as the reaction of ⁇ -bromocarbonate units with primary amines (J. Med. Chem., 37. 2678 (1994)), or amino-protected amino acid or its ester is treated with a base and an alkylating agent to obtain a ⁇ ⁇ ⁇ ⁇ -alkylated product. can do.
• Amino group protection of amino acids ⁇ -amino group, A-Ala, and Abu are protected by fluorenylmethyloxycarbonyl (Fmoc) group, tert-butynecarbonyl (Boc) group, and benzylo group. It is more efficient to use a xycarbonyl (Z) group.
• Preferred examples of the amino-protecting group in the solid phase synthesis include, for example, an Fmoc group.
• Examples of the method for activating the carboxyl group include a method using benzotriazole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), a method using 0- (7-azabenzotriazole).
• BOP benzotriazole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate
• BOP a method using 0- (7-azabenzotriazole.
• HATU 3-tetramethylperonium hexafluorophosphate
• DIC diisopropylcarpoimide
• WS CI N-ethyl N ' — 3-Dimethylaminopropylcarbodiimide
• DCC dicyclohexylcarbodiimide
• DPPA diphenylphosphoryl azide
• a method using hydroxybenzotriazole (HOBT) or N-hydroxysuccinimide (HONSu) in combination A mixed acid anhydride method using a luminate or the like, or an ⁇ -carboxyl group as an amino acid is a pen-fluorophenyl ester (OP f ⁇ ), an ⁇ -carboxyl group is a p-nitrophenyl ester ( ⁇ ) as an amino acid, There are a method using an ⁇ -carboxyl group as an amino acid using ⁇ -hydroxysuccinimide ester (0Su) and a method using each of these and ⁇ ⁇ ⁇ in combination.
• HOBT hydroxybenzotriazole
• HONSu N-hydroxysuccinimide
• bases such as triethylamine (TEA), diisopropylethylamine (DIEA), N-methylmorpholine (NMM), and 4-dimethylaminopyridine (DMAP) can be added.
• TAA triethylamine
• DIEA diisopropylethylamine
• NMM N-methylmorpholine
• DMAP 4-dimethylaminopyridine
• the compounds of the present invention can also be produced by applying the specific production methods described in the examples.
• amino acid residues and ⁇ -amino acid residues are in L-form unless otherwise specified.
• HPLC used was Hitachi L-6300, and the column used was Waters BONDAS PHERE 5 a C 18 300 A (300 ⁇ , 3.950 mm).
• the eluents are as follows: solution A: distilled water with 0.1% trifluoroacetic acid (TFA), solution B: linear gradient with 0.1% TFA acetonitrile (MeCN), solution B: 0-70%, 35 minutes, flow rate 1 m Performed for 1 min and detected at 280 nm (UV).
• Method b According to method a, linear gradient B solution: 0 to 60%, 30 minutes, flow rate 1 ml Zmin.
• Method c According to method a, linear gradient B solution: 20 to 60%, for 40 minutes at a flow rate of 1 m1 / in.
• Method d According to method a, the column used was Waters BONDAS PHERE 5 C18 10 OA (100 ⁇ , 3.9 x 150 mm).
• HPLC Waters 600E or Gisone 306, Column: YMC—Pac ODS (120 ⁇ , 250 ⁇ 20 mm l.D.).
• Mass spectrum (MS) was measured using EI-MS using Shimadzu G CMS-QP1000 or G CMS-QP 5050 A, and FAB-MS using JASCO 70-250 SEQ.
• NMR was measured by the following f method or g method.
• f method Measured using Bu rucher DX-500 (500 MHz).
• g method Measured using J EOL J NM-EX-270 (270 MHz).
• the resin used as the solid phase is a commercially available product, for example, a product of Nova Biochem.
• Method 1 1.5 to 2 equivalents of an acid component (eg, amino acid, ⁇ -substituted amino acid, carboxylic acid), 3 equivalents of ⁇ , 3 equivalents of ⁇ , and 0.1 mm of resin Using 1 ⁇ , N-dimethylformamide (DMF) of 31111 and 6 equivalents of NMM, shaking for 1.5 to 2 hours.
• an acid component eg, amino acid, ⁇ -substituted amino acid, carboxylic acid
• 3 equivalents of ⁇ 3 equivalents of ⁇ , and 0.1 mm of resin
• DMF N-dimethylformamide
• Method 2 Using 1.5 to 2 equivalents of the acid component, 3 equivalents of HATU, 3 ml of DMF for 0.1 mm of resin, and 6 equivalents of NMM for 1 How to shake for 5 to 2 hours.
• Method 3 Using 1.5 to 2 equivalents of acid component to resin, 3 equivalents of HOBT, 3 ml of DMF to 0.1 lmmo of resin, and 3.2 equivalents of DIC, shake for 2 hours how to.
• Method 4 Using 5 equivalents of acid component to resin, 0.1 equivalent of DMAP, 0.1 ml of resin, 3 ml of DMF to 1 lmmo, and 5 equivalents of DIC and shaking for 4 hours Law.
• Method 5 A method in which 2 equivalents of an active ester of an acid component (for example, P fp ester), 3 equivalents of HOBT, and 0.1 mmo 1 of resin are shaken for 2 hours with 0.1 ml of DMF.
• an active ester of an acid component for example, P fp ester
• 3 equivalents of HOBT for example, 3 equivalents of HOBT
• 0.1 mmo 1 of resin for example, 3 equivalents of HOBT, and 0.1 mmo 1 of resin are shaken for 2 hours with 0.1 ml of DMF.
• Method 6 Use 10 equivalents of substituted or unsubstituted bromoacetic acid, 0.1 ml of resin, 3 ml of DMF, and 13 equivalents of DIC, shake for 30 minutes, filter, and reacylate under the same conditions. After that, repeat washing with DMF, add 60 equivalents of amine dissolved in dimethyl sulfoxide (DMSO) and shake for 2 hours. Law.
• a resin to be used as a solid phase for example, Rink Amide Resin
• an appropriate solvent for example, DMF
• 20% piperidine ZDMF is added thereto and shaken. Wash repeatedly with DMF.
• the acid component is force-pulled by the first method.
• This operation is repeated by the number of acid components to be bound by using the force coupling method of the first to sixth methods.
• the order of deprotection and cleaving of the obtained resin can be appropriately changed or performed simultaneously.
• the clean-vaging process is completed by shaking in a 95% aqueous TFA solution at room temperature for 30 to 45 minutes. After the completion of the cleavage step, the resin is removed by filtration, and the filtrate is concentrated under reduced pressure and dried to obtain a crude phenylalanine derivative.
• the deprotection of an amino acid in solid phase synthesis can be specifically performed, for example, by the following method.
• Fmoc group when resin 0.025 to 0.1 mmo 1 is used, 0.1 mmo 1 of resin is mixed with 5 ml of 20% pyridine / DMF, shaken for 5 minutes, and filtered. After adding a new 5 m1 and shaking for 20 to 30 minutes, it can be removed by repeating filtration and DMF washing.
• 0.2 mmo 1 resin add 7 ml of 20% piperidine ZDMF and filter for 5 minutes. Then, add 7 ml and shake for 30-45 minutes, then remove by repeating filtration and DMF washing.
• the Boc, tBu, and Trt groups can be removed simultaneously with the cleaving in the cleaving process.
• Example 1 The same operation as in Example 1 (3) was performed using Fmoc-Tic-OH in place of Fmoc-Hyp-OH of Example 1, to obtain 34.4 mg of the TFA salt of the title compound.
• Example 1 The same operation as in Example 1 (3) was performed using Fmoc-Thz-OH in place of Fmoc-Hyp-OH of Example 1, to obtain 20.2 mg of the TFA salt of the title compound.
• Example 1 (3) The same operation as in Example 1 (3) was performed, except that Fmo c—2—AB z—OH was used instead of Fmo c—Hyp—OH in Example 1, to obtain 6.9 mg of the TFA salt of the title compound. .
• Example 1 The same operation as in Example 1 (3) was performed using Fmoc—Phg—OH instead of Fmoc—Hyp—OH in Example 1 (however, Fmoc—Phg—OH, Boc— Power coupling of P he—OH was performed by the first method.), 17.7 mg of the TFA salt of the title compound was obtained.
• Example 6 (2) The same operation as in Example 6 (2) was carried out except that Fmo c—Pro—OH ⁇ AcOEt was used instead of Fmo c—D—Hyp—OH in Example 6 (2). 27 mg of T?
• Example 6 (2) The same operation as in Example 6 (2) was performed using Fmo c—D—Pro—OH ⁇ AcOEt instead of Fmo c—D—Hyp—OH in Example 6 (2). Compound Yield 33.6 mg.
• Fmoc—Phg—OH of Example 5 Fmoc—Phe—OH was used as the resin, and Rin Amide Resin (0.47 mmo 1 / g) 2 13 mg (0. Immo 1 ) was carried out in the same manner as in Example 5 to obtain 20.5 mg of the TFA salt of the title compound.
• Fmoc-Va1OH instead of Fmoc-Phg-OH of Example 5 was used as a resin.
• Rink Amide Re sin (0.47 mmol / g) 213 mg (0. Immo1)
• the same operation as in Example 5 was performed using to obtain 28.4 mg of the TFA salt of the title compound.
• Example 6 (2) The same operation as in Example 6 (2) was performed using Fmo c—A la—OH ⁇ H 20 instead of Fmo c—D—Hyp—OH in Example 6 (2) (however, -. a coupling of a la- ⁇ ⁇ ⁇ 2 0, Fmo c- Ph e- OH is having conducted in the first method), to obtain a TF a salt 27. 8 mg of the title compound.
• Example 13 The same procedure as in Example 1 3 with Fmo c- L eu- OH instead of Fmo c- A la -OH ⁇ H 2 0
• Example 13 the TFA salt 3 1. 6 mg of the title compound Obtained.
• Example 6 Example 2 was repeated using Fmoc-Va1—OH instead of Fmoc—Phe—OH and Fmoc—Phg—OH instead of Fmoc—D—Hyp. 6 Perform the same operation as in (2) (however, coupling of Fmoc-Val-OH and Fmoc-Phg-OH was performed in the first method), and the TFA salt of the title compound was obtained. . 2 mg were obtained.
• Example 6 Example 2 was repeated using Fmo c—L eu—OH instead of Fmo c—P he—OH and Fmo c—P hg— ⁇ H instead of Fmo c—D—Hyp. 6 Perform the same operation as in (2) (however, the force coupling of Fmoc—Leu—OH and Fmoc—Phg—OH was performed in the first method), and the TFA salt of the title compound was obtained. 3 mg was obtained.
• Boc-Phe-OH was coupled by the second method. After completion of the reaction, filtration, DMF washing, and DCM washing were performed, and cleaving was performed with 3 ml of a 95% TFA aqueous solution. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 2 ml of DMF and purified by HP LC. The fractions were collectively concentrated and freeze-dried to obtain 21.9 mg (18A) and 12.9 mg (18B) of the TFA salt of the title compound, respectively.
• Rinnk Amide Re sin (0.47mmol / g) 213mg (0.lmmol) was put in the reaction vessel, the resin was swollen with DMF, and then Fmoc treated with piperidine. .
• Fmoc-Tyr (3-tBu) -OH was coupled by the first method. After filtration and DMF washing, Fmoc treatment was performed with piperidine. Next, coupling was performed using ⁇ -promophenylacetic acid and benzylamine according to the sixth method to construct a ⁇ -substituted amino acid residue.
• Example 5 The same operation as in Example 5 was performed using 274 mg (0.2 mmo 1) of Wag Resin (0.73 mmo 1 / g) as the resin of Example 5 (however, Fmo c-Ty r (3-t BU) —OH was subjected to force coupling according to Method 4.), to obtain 31.2 mg of the TFA salt of the title compound.
• Fmoc-Phg-OH In place of Fmoc-Phg-OH in Example 5, Fmoc-Tyr (tBu) -OH was used as a resin, and Rink Amide Resin (0.47 mmo1 / g) 107 mg (0 Perform the same operation as in Example 5 using .05mmo 1) (however, the reaction solution after clear bay treatment was concentrated under reduced pressure, the residue was dissolved in 3 ml of methanol, and then again under reduced pressure. Then, 15.8 mg of TFA salt of the title compound was obtained.
• Example 21 The same operation as in Example 21 was carried out using Fmoc-Hph-OH instead of Fmoc-Tyr (tBu) -OH of Example 21, to obtain 19.4 mg of the TFA salt of the title compound.
• Fmoc-Hph-OH instead of Fmoc-Tyr (tBu) -OH of Example 21, to obtain 19.4 mg of the TFA salt of the title compound.
• Example 21 Fmo c—Ty r (t Bu) —OH instead of Fmo c—Th i — The same operation as in Example 21 was carried out using OH to obtain 21.5 ′ mg of the TFA salt of the title compound.
• Example 21 The same operation as in Example 21 was performed using F moc—S—A 1 a—OH instead of Fmo c—Ty r (tBu) —0H of Example 21 to obtain the title compound TF A 29.4 mg of the salt were obtained.
• Example 21 The same operation as in Example 21 was performed using Fmoc-a-Abu-OH instead of Fmoc-Tyr (tBu) -OH of Example 21 to give the TFA salt of the title compound. 4 mg were obtained.
• Example 21 The same operation as in Example 21 was carried out, except that Fmoc—Tyr (tBu) -10H in Example 21 was replaced by Fmoc—Aib—OH, to give the TFA salt of the title compound 27. 2 mg were obtained.
• Example 21 The same operation as in Example 21 was performed using Fmo c—I 1 e -OP fp instead of Fmo c—Ty r (tBu) —0H in Example 21 (however, Fmo c—I 1 e — Coupling of OP fp was performed by Method 5.), 18.9 mg of the TFA salt of the title compound was obtained.
• Example 21 The same operation as in Example 21 was performed using Fmoc-Chg-OH instead of Fmoc-Tyr (tBu) -10H of Example 21.
• the crude product was further dissolved in DMSO and purified by HPLC, and the fractions were combined, concentrated, and lyophilized to obtain 10.1 mg of the TFA salt of the title compound.
• Example 21 The same operation as in Example 21 was performed using Fmo c—T 1 e —OH instead of Fmo c—Ty r (tBu) -OH in Example 21, to give 23.8 mg of the TFA salt of the title compound. Obtained.
• Example 21 Fmo c—Ty r (tBu) in Example 21 was replaced with Fmo c—A sp (OtBu) —OH, and the remaining solvent was Me CN instead of methyl alcohol. And the same operation as in Example 21 was carried out to obtain 30.2 mg of the TFA salt of the title compound.
• Example 21 Fmo c—Glu (0 tBu) -OH was used instead of Fmo c—Ty r (tBu) -OH, and Me CN was used instead of methanol for the remaining solvent. And using the same procedure as in Example 21 to obtain 28.2 mg of the TFA salt of the title compound.
• Example 21 Fmoc—Tyr (tBu) -10H was replaced with Fmoc—Aad (0tBu) -1OH, and the remaining solvent was MeCN instead of methanol. The same operation as in Example 21 was performed to obtain 31.8 mg of the TFA salt of the title compound.
• Example 21 The same operation as in Example 21 was performed using Fmoc-Asn-OH instead of Fmoc-Tyr (tBu) -OH of Example 21, to give 21.5 mg of the TFA salt of the title compound. Obtained.
• Example 21 The same operation as in Example 21 was performed using F moc—G 1 n-OP fp instead of Fmo c—Ty r (t Bu) 1 OH in Example 21) (provided that Fmo c—G 1 Power coupling of n-0 P fp was performed by the fifth method. ), 7.2 mg of TFA salt 2 "of the title compound.
• Example 21 The same operation as in Example 21 was performed using Fmoc—Cit—OH in place of Fmoc—Tyr (tBu) -OH of Example 21, to obtain 25.6 mg of the TFA salt of the title compound. I got
• Example 21 The same operation as in Example 21 was performed using F moc—D ab (B oc) -OH instead of Fmo c—Ty r (tBu) —0H in Example 21, to obtain a TFA salt of the title compound. 29. lmg was obtained.
• Example 21 The same procedure as in Example 21 was carried out, except that Fmo c—O rn (Bo c) —OH was used instead of Fmo c—Ty r (t Bu) -OH in Example 21), to give a TFA salt of the title compound. 7 mg were obtained.
• Example 21 The same operation as in Example 21 was carried out using Fmo c—Lys (Bo c) —OH in place of Fmo c—Ty r (t Bu) -OH in Example 21) to give the TFA salt of the title compound. 2 mg were obtained.
• Example 21 The same operation as in Example 21 was performed using Fmoc-Ser (tBu) —OH in place of Fmoc—Tyr (tBu) -OH in Example 21, to obtain the TFA salt of the title compound. .5 mg were obtained.
• Example 21 The same operation as in Example 21) was performed using Fmoc—Hse (Trt) —OH instead of Fmoc—Tyr (tBu) -10H in Example 21. After concentrating the crystal, the precipitate was reprecipitated with getyl ether to obtain 7.8 mg of the TFA salt of the title compound.
• Example 21 The same operation as in Example 21 was performed using F moc—T hr (t Bu) -OH instead of Fmo c—Tyr (t Bu) —0H in Example 21, to obtain the title compound TF A 24. lmg of the salt was obtained.
• Example 21 The same operation as in Example 21 was performed using Fmoc—Abu—OH instead of Fmoc—Tyr (tBu) —0H in Example 21, to give 19.6 mg of the TFA salt of the title compound. I got
• Example 21 The same operation as in Example 21 was performed using Fmoc-Nva-OH in place of Fmoc-Tyr (tBu) -10H in Example 21, to obtain 19.8 mg of the TFA salt of the title compound. I got
• Example 21 The same procedure as in Example 21 was carried out except that Fmoc-Met-OH was used instead of Fmoc-Tyr (tBu) -OH in Example 21, to obtain 24.3 mg of the TFA salt of the title compound.
• Fmoc-Met-OH was used instead of Fmoc-Tyr (tBu) -OH in Example 21, to obtain 24.3 mg of the TFA salt of the title compound.
• Example 21 The same operation as in Example 21 was carried out, except that Fmo c—His (Bo c) —OH was used instead of Fmo c—Ty r (t Bu) -OH in Example 21, to obtain a TFA salt of the title compound. 7 mg were obtained.
• Example 21 The same operation as in Example 21 was performed using Fmo c—T rp (B oc) -OH instead of Fmo c—Tyr (t Bu) -OH in Example 21, to give 14.5 mg of the TFA salt of the title compound. I got
• Example 21 The same operation as in Example 21 was performed using Fmo c—T iq —OH instead of Fmo c—Ty r (tBu) —OH of Example 21, to give 23.7 mg of the TFA salt of the title compound. Obtained.
• Example 49 The same operation as in Example 49 was performed using 1-benzocyclobutane carboxylic acid instead of 4-pyridylthioacetic acid in Example 49 (however, the force coupling of 1-benzocyclobutane carboxylic acid was performed by the third method). 23.8 mg of the title compound as a diastereomeric mixture.
• Example 52 The same operation as in Example 52 was performed using Fmoc-Phg-OH instead of Fmoc-Tyr (tBu) -OH in Example 52, to obtain 23.2 mg of the TFA salt of the title compound. Obtained.
• the same operation as in Example 52 was performed using 1110 (: -d-111-OH) to obtain 27.4 mg of the TFA salt of the title compound.
• Example 52 The same procedure as in Example 52 was carried out, except that Fmo c—Tyr (tBu) -OH of Example 52 was used instead of Fmo c—T rp (B oc) —OH, to obtain a TFA salt of the title compound. 9 mg were obtained.
• H is-Ph g— Ty r (3-t B u)-NH 2
• Example 52 The same operation as in Example 52 was performed using Fmo c—His (Bo c) —OH instead of Fmo c—Ty r (tBu) -OH in Example 52, to give the TFA salt of the title compound 14. 4 mg were obtained.
• Example 50 instead of 1-benzocyclobutanecarboxylic acid, (Sat) -13-phenylbutyric acid was used as a resin, and Rink Amide Resin (0.47 mm o 1 / g) The same operation as in Example 50 was performed using 107 mg (0.05 mmol). However, Fmoc-Phg-OH was coupled by the first method, and 3-phenylbutyric acid was coupled by the second method. 18. lmg of the title compound were obtained.
• Fmo c-2 4-di me thoxy-4 '-(carbo xy me t hy l oxy) -benz hy dryl am inelinkedto Am inomethy 1 Resin (0.55 mm o 1 / g) 45 mg ( After adding 0.025 mmo 1), the resin was swollen with DMF, and then subjected to Fmoc removal with piperidine. Then, Fmoc-Tyr (3-tBu) - ⁇ H was force-coupled by the first method. After filtration and DMF washing, Fmoc treatment was performed with piperidine. Next, Fmoc—Phg—OH was coupled by the third method. DMF washing, DCM washing, and methanol washing were performed, and then dried.
• the dried resin was transferred to an ACT-496 MOS (advanced ChemTech) reaction vessel.
• the resin was swollen with DMF, and then subjected to Fmoc removal with piperidine.
• a mixture of Fmo c — /? — A la—OH, HOBT, and DMF 0.5 ml (Fmo c-/ 3-A 1 a-OH 0.55 Ommo K HOBT 0.075 mmo 1), DIC / DMF 0. 25 ml (DIC 0.080 mmo 1) was added and shaken for 2 hours. After filtration and washing with DMF, re-use with piperidine Fmoc treatment was performed.
• Example 59 The same operation as in Example 59 was performed using Fmoc—Aib—OH in place of Fmoc—; 3—A1a-0H in Example 59, to obtain 15.3 mg of the TFA salt of the title compound.
• Fmoc—Aib—OH in place of Fmoc—; 3—A1a-0H in Example 59, to obtain 15.3 mg of the TFA salt of the title compound.
• Example 59 The same operation as in Example 59 was performed using Fmoc—I 1 e-OH in place of Fmoc—3—Ala—0H in Example 59, to give 15.4 mg of the TFA salt of the title compound.
• Example 63 The same operation as in Example 59 was carried out using Fmoc-Chg-OH in place of Fmoc- / 3-Ala-OH of Example 59, to obtain 12.2 mg of the TFA salt of the title compound.
• Example 63
• Example 59 The same operation as in Example 59 was performed using Fmoc-Cha-OH in place of Fmoc- / 3-Ala-3H in Example 59, to obtain 16.7 mg of the TFA salt of the title compound.
• Example 59 The same operation as in Example 59 was performed using Fmoc-Cha-OH in place of Fmoc- / 3-Ala-3H in Example 59, to obtain 16.7 mg of the TFA salt of the title compound.
• Example 59 The same operation as in Example 59 was carried out using Fmoc—T1e—OH in place of Fmoc—3—Ala—OH of Example 59, to give 14.9 mg of the TFA salt of the title compound.
• Example 59 The same operation as in Example 59 was performed using Fmoc-Asp (OtBu) -OPfp instead of Fmoc- / 3-Ala-OH of Example 59. However, DI CZDMF 0.25m1 was not added at the time of Fmo c -A s (O t Bu) — OP fp cutting. 18. lmg of the TFA salt of the title compound was obtained.
• Example 59 The same operation as in Example 59 was performed using Fmoc-Aad (0tBu) _OH instead of Fmoc- / 5-Ala-OH of Example 59, and the TFA salt of the title compound 16. 8 mg were obtained.
• Example 59 The same operation as in Example 59 was carried out using Fmoc—Asn—OH in place of 1110 (— ⁇ ⁇ 18 13-0H in Example 59, to obtain 17.2 mg of the TFA salt of the title compound. .
• Example 65 The same operation as in Example 65 was performed using F moc—G 1 n-OP fp instead of Fmo c—A sp (O t Bu) —OP fp of Example 65, to give the TFA salt of the title compound. 9 mg was obtained.
• Example 59 The same operation as in Example 59 was performed using Fmoc—Cit-OH in place of Fmoc— / S—Ala—OH of Example 59, to give 15.3 mg of the TFA salt of the title compound.
• Example 59 Instead of Fmo c — / 3 — Al 3 — 0 ⁇ 1 in Example 59? The same operation as in Example 59 was carried out using 1110 c -D ab (Bo c) OH to obtain 15.3 mg of the TFA salt of the title compound.
• Example 59 The same operation as in Example 59 was performed using F in oc—Lys (Bo c) —OH instead of Fmo c— / 3—A la—0H in Example 59, to give the TFA salt of the title compound. .8 mg were obtained.
• Example 59 The same operation as in Example 59 was performed using Fmoc—Ser (tBu) -OH instead of Fmoc— / 3—Ala— ⁇ H in Example 59, to give the TFA salt of the title compound. 4 mg were obtained.
• Example 59 The same operation as in Example 59 was carried out, except that Fmo c—Th r (tBu) —OH was used instead of Fmo c— / 3—A la—OH in Example 59, to obtain a TFA salt of the title compound. 5 mg were obtained.
• Example 59 The same operation as in Example 59 was carried out using Fmoc—Abu—OH instead of Fmoc— / S—Ala-0H in Example 59, to obtain 13.6 mg of the TFA salt of the title compound. .
• Example 59 The same operation as in Example 59 was carried out using Fmoc—Nva—OH in place of Fmoc—; 3-Ala-OH of Example 59, to obtain 13.9 mg of the TFA salt of the title compound.
• Example 59? 0 €;-/ 3--8 1a-OH was replaced with Fmoc-Met-OH, and the same operation as in Example 59 was carried out to obtain 11.6 mg of the TFA salt of the title compound.
• Example 59 The same operation as in Example 59 was carried out using Fmoc—Pro—OH.AcOEt instead of Fmoc——Ala_OH of Example 59, to obtain 14.8 mg of the TFA salt of the title compound. I got
• Example 59 The same operation as in Example 59 was carried out, except that Fmoc—Hyp—OH was used instead of Fmoc— / 3—Ala—OH in Example 59, to give 11.2 mg of the TFA salt of the title compound.
• Example 59 The same operation as in Example 59 was carried out using Fmoc—Tic—OH in place of Fmoc——Ala—OH in Example 59, to obtain 16.1 mg of the TFA salt of the title compound.
• Example 59 The same operation as in Example 59 was carried out using Fmoc-Tiq-OH in place of Fmoc- / 3-Ala-OH of Example 59, to obtain 14.7 mg of the TFA salt of the title compound. .
• Example 59 The same operation as in Example 59 was carried out using Fmo c—2—Ab a—OH in Example 59 instead of Fmo c——A 1 a—OH to obtain 15.2 mg of the TFA salt of the title compound.
• Fmo c—2—Ab a—OH Fmo c——A 1 a—OH
• Example 59 The same operation as in Example 59 was performed using Fmoc-Hph-OH in place of Fmoc- / 3-Ala-OH of Example 59, to obtain 16. Omg of the TFA salt of the title compound. .
• Example 59 The same operation as in Example 59 was performed using ⁇ -methylhydrocinnamic acid instead of Fmo c— — A la— 0H of Example 59 (however, since the Fmo c removal treatment before cleaving was unnecessary, Not performed.), 15.2 mg of the title compound.
• Example 84 was replaced by sodium methylcinnamate instead of ⁇ -methylhydroxycinnamate. The same operation as described above was performed to obtain 16.4 mg of the title compound.
• Example 84 using 3-quinolinecarboxylic acid instead of ⁇ -methylhydrocinnamic acid of Example 84 Perform the same operation as described above to obtain 16.9 mg of the TF ⁇ salt of the title compound.
• Fmo c—D—Phg—OH in place of Fmo c—Ph g—OH of Example 5, and Fmo c—2, 4-dimethoxy-4 ′-(carbo xym et hy lo xy) — Benz hy dryl amine 1 ink edto A minome t hy l Re sin (0.55 mmo 1 / g) 182 mg (0.1 mmo 1) was used and the same operation as in Example 5 was performed.
• force coupling of Fmoc-D-Phg-OH and Boc-Phe-OH was performed by the third method. This gave 15.4 mg of the TFA salt of the title compound.
• the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
• the resulting residue was used as a solution of 5 ml of DMF, and 0.115 ml of NMM (1.66 mmol) and chloroform at 15 ° C. 0.159 ml (1.66 mmol) of ethyl carbonate was added, and the mixture was stirred for 20 minutes.
• the reaction solution was further stirred for 30 minutes while publishing ammonia gas and left at room temperature.
• the reaction solution was diluted with ethyl acetate, washed with water, and then washed with saturated saline.
• reaction solution was diluted with acetic acid Echiru, washed with saturated N a HC0 3 solution, washed with water, then with saturated brine.
• the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
• reaction solution was diluted with acetic acid E chill, washed with saturated N aHC0 3 solution, washed with water, then with saturated brine.
• the reaction solution was distilled off under reduced pressure, and the obtained residue was dissolved in methylene chloride, washed with water, and then washed with saturated saline.
• the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was converted into a methylene chloride 5 ml solution, and TFA acetic acid 3 ml was added.
• 0.183 ml (1.66 mmol) of NMM and 0.159 ml (1.66 mmol) of ethyl ethyl carbonate were added, and the mixture was stirred for 30 minutes.
• the reaction solution was stirred for 30 minutes while bubbling ammonia gas into the reaction solution, allowed to stand at room temperature, diluted with ethyl acetate, washed with water, and then washed with saturated saline.
• reaction solution was diluted with acetic acid Echiru, washed with saturated N a HC0 3 solution, washed with water, then with saturated brine.
• e—Ch a—Phe (3-tBu) —NH 2 192 mg (43%) was obtained.
• reaction solution was diluted with methylene chloride, washed with water, and then with saturated saline.
• the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography.
• Example 100 The same operation as in Example 100 was carried out, except that Fmoc-D-Phg-0H was used instead of 1110 c—Phg—OH of Example 100, to obtain 7.2 mg of the title compound.
• Example 101 N — ((S) —3—phenylbutyryl) —D—Ph g_Ty r (3—t Bu) -NH 2
• Fmoc—D—Phg—OH is used instead of Fmoc—Phg—OH in Example 101, to obtain 16.1 mg of the title compound.
• Boc—L—one (3-methyl-1-butenyl) glycineol N-Me-Val-Tyr (3-tBu) —NH 2 0.17 g of methylene chloride TFA lm 1 was added to the 2 ml solution, and the mixture was stirred at room temperature for 10 minutes.
• the residue obtained by evaporating the solvent under reduced pressure was diluted with methylene chloride, washed with saturated N aHC0 3 solution.
• N—Me—Va 1—Ty r (3- t Bu) —NH 2 13 lmg (93%) was obtained.
• the organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
• the obtained residue was made into a solution of 2 ml of dioxane-4 ml of water, and 4 ml of 10% hydrochloric acid-methanol was added thereto, followed by stirring at room temperature overnight. After that, the mixture was made alkaline with an aqueous 2N NaOH solution, extracted with methylene chloride, and 5 ml of dioxane and 1.5 g of ditertbutyldicarbonate were added to the aqueous layer.
• N-Boc-3-aminohydrocinnamic acid 0.27 g (l. 03mmol), real N—Me—Va 1—Ty r (3-tBu) —NH 2 obtained according to Example 89—0.24 g (0.687 mmol), and HOB T 0.23 g (1.72 mmo)
• 0.27 ml of DIC (1.72 mmo 1) was added under ice-cooling. After stirring for 1 day at room temperature, the reaction was diluted with acetic acid Echiru, saturated N a HC 0 3 solution, water, and saturated brine.
• N- (N—Bo c—3-aminohydrocinnamyl) N—Me—Val—Ty r (3-tBu) -NH 2 285mg was prepared as methylene chloride 2ml solution and TFA 1ml In addition, the mixture was stirred at room temperature for 15 minutes. The residue obtained by evaporating the solvent under reduced pressure was diluted with methylene chloride and washed with saturated NaHC_ ⁇ 3 aq.
• N— (2-benzoxycarbonylamino-1-3-phenylpropyl) -Ph g—Ty r (3-t Bu) -NH 2 40.Omg (0.0664mmo 1) in methanol lm 1 15. Omg of palladium on carbon was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel gel chromatography (developing solvent, chromate form: methanol: aqueous ammonia 10: 1: 0.1) to give N— (2— amino one 3- Fuwenirupu port pills) to give an Ph g-Ty r (3- t Bu) -NH 2 29. Omg (92%).
• N—Me—V a 1—Ty r (3— tBu) A solution of NH 2 10 Omg (0.287m 11 0 1) in 01 ⁇ 1 ml and triethylamine (0.006 ml) was added, and the mixture was stirred at room temperature for 2 hours.
• reaction solution was diluted with acetic acid Echiru, washed with saturated NaHCO 3 solution, washed with water, washed with saturated brine. After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate: n-hexane 2: 1) to give B 0 c — N—Feniru GlyN-Me-Val-Tyr (3-tBu) —NH 2 139 mg (83%) was obtained.
• Ty r (3- tBu) -OMe To a mixed solution of 2.00 g (7.97 mmol) of 1,4-dioxane 15 mi and water 15 ml, add 929 mg (8.76 mmo 1) of sodium carbonate under ice-cooling. ) And 1.91 g (8.75 mmo 1) of ditertbutyl dicarbonate were added and stirred for 2 hours. Under ice-cooling, saturated NH 4 C 1 water was added, and the mixture was extracted with black hole form and washed with saturated saline.

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