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WO1998018763A1 - Derives de tetrahydroisoquinoline - Google Patents

Derives de tetrahydroisoquinoline Download PDF

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Publication number
WO1998018763A1
WO1998018763A1 PCT/JP1997/003804 JP9703804W WO9818763A1 WO 1998018763 A1 WO1998018763 A1 WO 1998018763A1 JP 9703804 W JP9703804 W JP 9703804W WO 9818763 A1 WO9818763 A1 WO 9818763A1
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Prior art keywords
group
amino
hydrogen atom
protected
carboxy
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Ceased
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PCT/JP1997/003804
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English (en)
Japanese (ja)
Inventor
Takahisa Sugita
Tetsuo Ohnuki
Masaki Yamada
Sumiko Tanaka
Nobuaki Nonaka
Yasuyuki Asai
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Mitsubishi Tanabe Pharma Corp
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Tanabe Seiyaku Co Ltd
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Priority to AU47218/97A priority Critical patent/AU4721897A/en
Publication of WO1998018763A1 publication Critical patent/WO1998018763A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • C07K5/06—Dipeptides
    • C07K5/06086—Dipeptides 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
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • 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
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C07K5/06156—Dipeptides with the first amino acid being heterocyclic and Trp-amino acid; Derivatives thereof
    • 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
    • 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 pharmaceutical composition
  • a pharmaceutical composition comprising a compound having a dipeptidyl peptidase IV inhibitory activity and having a tetrahydroisoquinoline skeleton as an active ingredient, a novel tetrahydroisoquinoline derivative, and a method for producing the same.
  • Deptidyl peptidase IV is a serine protease that specifically hydrolyzes X--Pr0 (X is any amino acid) from the free N-terminus of the polypeptide chain.
  • X is any amino acid
  • T cells In immune system cells, expression is induced by activation of T cells, and plays an important role in T cell activation and proliferation (Yoichi Pian 'Cyanal' Ob Immunorossi, Eu ropean Journa 1 of Immunology, 17, 1821-1826, 1987; Noological 'chemistry' Hoppe Issailer (Bi 0 10 gica 1
  • dipeptidyl peptidase IV inhibitors examples include triptides.
  • Certain diprotin A (L-isoleucyl-L-prolyl-L-isoleucine), diprotin B (L-valylol L-prolyl-L-mouth isine) and diprotin C (L-valyl-L-prolyl-1: L-isoleucine) (JP 59-Patent 25366), A 1 a- P r o- two Torobe emission zone I le hydroxyl ⁇ Min (journal O Bed 'Enzaimu-Inhihishiyon, jounal 0 t En z yme I nhibition), 2 vol. Pp.
  • the present invention provides a compound having excellent dipeptidyl peptidase IV inhibitory activity, and a pharmaceutical composition comprising the compound as an active ingredient.
  • the present inventors have been examining cultures of microorganisms mainly isolated from soil, and show that they exhibit dipeptidyl peptidase IV inhibitory activity in cultures of Aspergillus fungi. Compounds were found to be produced. These compounds were isolated and purified from the culture solution, and their physicochemical properties were examined to determine their chemical structures. As a result, they were found to be novel compounds.
  • the present inventors have found that inhibition of dipeptidyl peptidase IV can specifically suppress the activation of T cells, and immunological disorders involving activation of T cells such as rheumatoid arthritis
  • a series of compounds having a tetrahydroisoquinoline skeleton, including the aforementioned microbial-derived compounds may have an inhibitory effect on dipeptidyl peptidase IV. They have obtained new knowledge that they are effective in preventing and treating autoimmune diseases (arthritis, rheumatoid arthritis, etc.), and have completed the present invention based on the knowledge.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound having a dipeptidyl peptidase IV inhibitory activity and having a tetrahydroisoquinoline skeleton or a pharmaceutically acceptable salt thereof as an active ingredient. is there.
  • R 1 is (1) a group having a structure obtained by removing a hydroxy group of a lipoxy group from an amino acid in which an amino group may be protected or (2) a protecting group of an amino group
  • R 2 is (1) a hydroxyl group which may be protected, (2) a group having a structure in which one hydrogen atom of an amino group has been removed from an amino acid whose carboxy group may be protected, or (3) a primary or secondary group
  • R 3 is the same or different and represent a hydrogen atom, a hydroxyl group or a lower alkoxy group.
  • the present invention provides a novel tetrahydroisoquinoline derivative represented by or a pharmaceutically acceptable salt thereof, and a method for producing these compounds.
  • R 7 and R 8 represents a hydroxyl group and the other represents a hydrogen atom or a hydroxyl group
  • a pharmacologically acceptable salt thereof a compound in which R 7 and R 8 are a hydroxyl group is hereinafter referred to as TMC ⁇ (: ⁇ 28 and a compound in which R 7 is a hydroxyl group and R 8 is a hydrogen atom.
  • TMC-2C A compound in which R 7 is a hydrogen atom and R 8 is a hydroxyl group is referred to as TMC-2C hereinafter.
  • the present invention also provides a method for producing TMC-2A, TMC-2B and TMC-2C using microorganisms.
  • FIG. 1 shows the UV spectrum of TMC-2A.
  • FIG. 2 shows the UV spectrum of TMC-2B.
  • FIG. 3 shows the UV spectrum of TMC-2C.
  • FIG. 4 shows the IR spectrum of TMC-2A.
  • FIG. 5 shows the IR spectrum of TMC-2B.
  • Figure 6 shows the IR spectrum of TMC-2C.
  • FIG. 7 is the 1 H-NMR spectrum of TMC-2A.
  • FIG. 8 is a 1 H-NMR spectrum of TMC-2B.
  • Figure 9 is the 1 H-NMR spectrum of TMC-2C.
  • FIG. 10 is a 13 C-NMR spectrum of TMC-2A.
  • FIG. 11 shows the 13 C-NMR spectrum of TMC-2B.
  • FIG. 12 is a 13 C-NMR spectrum of TMC-2 C.
  • FIG. 13 is a diagram showing the inhibitory effect of cho1 ⁇ (:-28 on rat alkyldiamine-induced arthritis.
  • FIG. 14 is a diagram showing the inhibitory effects of TMC-2A and the compound of Example 13 on rat adjuvant-induced arthritis.
  • Examples of the pharmaceutical composition of the present invention include a pharmaceutical composition having a dipeptidyl peptidase IV inhibitory activity and having, as an active ingredient, a compound having a tetrahydroisoquinoline skeleton or a pharmaceutically acceptable salt thereof. Specifically, it has a diptidyl peptidase IV inhibitory activity, and has the formula:
  • a pharmacologically acceptable salt thereof as an active ingredient a pharmaceutical composition comprising a tetrahydridoisoquinoline derivative represented by the general formula [I] or a pharmaceutically acceptable salt thereof as an active ingredient can be mentioned.
  • the pharmaceutical composition of the present invention is useful as a dipeptidyl peptidase IV inhibitor, a prophylactic / therapeutic agent for autoimmune diseases, especially a prophylactic / therapeutic agent for arthritis, and a prophylactic / therapeutic agent for rheumatoid arthritis. .
  • Examples of the tetrahydroisoquinoline derivative of the present invention include a compound represented by the general formula [I].
  • the tetrahydroisoquinoline derivative [I] of the present invention or a pharmacologically acceptable salt thereof has excellent dipeptidyl peptidase IV inhibitory activity, and is therefore useful as a dipeptidyl peptidase IV inhibitor. Furthermore, the tetrahydroisoquinoline derivative [I] or a pharmacologically acceptable salt thereof has an excellent preventive / therapeutic action for autoimmune diseases, and is a prophylactic / therapeutic agent for autoimmune diseases, especially for the prevention / treatment of arthritis. It is useful as an agent for the prevention and treatment of rheumatoid arthritis.
  • R 1 is (1) aryloxycarbonyl group, aryl substituted lower alkoxycarbonyl group or lower alkoxycarbonyl group, and is an amino group.
  • R 2 is (1) a hydrogen atom of an amino group which may be substituted with an aryl group-substituted lower alkyl group, or (2) an amino acid whose carboxy group may be protected with a lower alkyl or an aryl group-substituted lower alkyl group.
  • R 5 and R 6 may be the same or different and include a hydrogen atom, a hydroxyl group or a lower alkoxy group.
  • R 1 is (1) a benzyloxycarbonyl group or a tert-butoxycarbonyl group whose amino atom group is protected, such as a retryptofil group, a lysyl group, a phenylalanyl group, or 2) benzyloxycarbonyl group or tert-butoxycarbonyl group, 1 ⁇ 2 ⁇ ) hydroxyl group optionally protected by benzyl group, (2) carboxy group protected by methyl group or benzyl group.
  • R 1 is (1) a benzyloxycarbonyl group or a tert-butoxycarbonyl group whose amino atom group is protected, such as a retryptofil group, a lysyl group, a phenylalanyl group, or 2) benzyloxycarbonyl group or tert-butoxycarbonyl group, 1 ⁇ 2 ⁇ ) hydroxyl group optionally protected by benzyl group, (2) carboxy group protected by methyl group or
  • R 1 is a tributophyl group
  • R 2 is (1) a hydroxyl group
  • R 2 is (1) alanine, norin, leucine, isoleucine, proline, phenyla.
  • One of the hydrogen atoms of the amino group is selected from the amino acids selected from lanin, tributofan, methionine, glycine, serine, threonine, cystine, glutamine, asparagine, tyrosine, lysine, arginine, histidine, aspartic acid and glutamic acid Examples include the group having the removed structure or (3) an amino group, and a compound in which R 3 , R 4 , R 5 and R 6 are hydrogen atoms.
  • R 1 is a tributyl group
  • 1 ⁇ 2 is (1) a hydroxyl group
  • R 3, R 4, R 5 and R 6 Compounds that are hydrogen atoms are mentioned.
  • a particularly preferable compound in terms of pharmacological effect is 2-L-tributophyl-1,2,3,4-tetrahydroisoquinolyl-13-carboxylic acid.
  • TMC-2A TMC-2B or TMC-2C
  • TMC-2A a compound represented by the general formula [II]:
  • amino acids include both L-form, D-form and mixtures thereof, and include, for example, alanine, norin, leucine, isoleucine, proline, phenyla Protein components such as lanine, tryptophan, methionine, glycine, serine, threonine, cystine, glutamine, asparagine, tyrosine, lysine, arginine, histidine, aspartic acid and glutamic acid ⁇ -amino acid, norleucine, ⁇ -aminobutyric acid, y-amino Aliphatic monoaminocarboxylic acids such as butyric acid, monoaminoisobutyric acid, ⁇ -rylanine, homoserine, trimethyl-serine, dibenzyl-serine, 0-potassium rubamyl-serine, and hydroxy-1-oxo-norvaline; Monoaminodicarboxylic acids such as aminoadipic
  • examples of the “group having a structure in which a hydroxy group of a carboxy atom group has been removed from an amino acid” in R 1 include, for example, alanine, norin, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, A group having a structure obtained by removing the hydroxy group of ⁇ -carboxy group from a monoamino acid such as glycine, serine, threonine, cysteine, glutamine, asparagine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamic acid, etc.
  • preferred examples include a tributophyl group, a lysyl group, and a phenylalanyl group, and particularly preferred examples include a tributophyl group.
  • the carboxy group in R 2 may be replaced with an amino acid which may be protected.
  • the group having a structure in which one hydrogen atom of the amino group has been removed include, but are not limited to, alanine, norin, leucine, isoleucine, proline, phenylalanine, triptophan, methionine, glycine, serine, threonine, and cysteine.
  • Glutamine asparagine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamic acid, isoleucine methyl ester, benzyl lucerin benzyl ester, and the formula:
  • a group having a structure in which one hydrogen atom of an ⁇ -amino group has been removed from an amino acid such as the amino acid represented by Of these, preferred are groups having a structure in which one hydrogen atom of the ⁇ -amino group of glutamine, serine, aspartic acid, glutamic acid, alanine, cysteine, arginine, methionine and asparagine has been removed, and more preferred examples are Is a group having a structure obtained by removing one hydrogen atom from the amino group of glutamine and serine.
  • Another good example is the expression:
  • Examples of the “group having a structure in which one hydrogen atom on a nitrogen atom has been removed from a primary or secondary amine or ammonia” for R 2 include, for example, one group selected from lower alkyl or aryl-substituted lower alkyl or An amino group which may be substituted by two is exemplified. Of these, an amino group which may be substituted by one or two groups selected from a tert-butyl group and a benzyl group is preferred. More specific examples thereof include a tert-butylamino group, a benzylamino group, an amino group and the like, and a more preferred example is an amino group.
  • the target compound [I] of the present invention includes any one of the tetrahydroisoquinoline skeleton moiety having the R-configuration at the 3-position, the S-configuration, and a mixture thereof. Are preferred.
  • compound [I] further has an asymmetric carbon atom, any stereoisomer based on the asymmetric carbon atom or a mixture thereof is also included in the present invention.
  • the compound [I] which is the active ingredient of the present invention, can be prepared by a conventional method for peptide synthesis, for example, “peptide synthesis” (Synthetic Chemistry Series, published by Maruzen Co., Ltd., 1979) and “ Experiments ”(published by Maruzen Co., Ltd., 1985) or a method analogous thereto can be produced by either a liquid phase method or a solid phase method.
  • R 2 2 is (1) group or a (2-carboxy atomic group having one obtained by removing the structure of the hydrogen atom of Amino atomic group from amino acids which may optionally be protected) primary or secondary amine emissions or A group with a structure in which one hydrogen atom on a nitrogen atom has been removed from ammonia, R R3, R4, R5 and R6 have the same meaning as above)
  • R 1 is (1) a group having a structure in which at least an amino group protected by a s ′ protected amino acid is surrounded by a hydroxy group of a carboxy group or (2) a protecting group for an amino group , R 3 , R 4 , R 5 and R 6 have the same meaning as above)
  • R 2 1 is (1) group or (2) a primary or secondary Amin or ammonia with one obtained by removing the structure of the hydrogen atom of at least amino acids Karaa Mino atomic group carboxy atomic group is protected Represents a group having a structure obtained by removing one hydrogen atom on a nitrogen atom from
  • R 1 3 is a group having the structure Amino atomic group obtained by removing a hydroxy atomic group of a carboxy group of atoms from amino acids which may be substituted, R 2, R 3, R 4, R 5 ⁇ Pi R 6 Has the same meaning as above)
  • R 23 represents (1) a protected hydroxyl group, (2) a group having a structure in which at least one hydrogen atom of an amino group has been removed from an amino acid having at least a protected carboxy group, or (3) A group having a structure in which one hydrogen atom on a nitrogen atom has been removed from primary or secondary amine or ammonia, and R 3 , R 4 , R 5 and R 6 have the same meaning as described above.
  • R 1 2 denotes a group having a structure obtained by removing a hydroxy atomic carboxy atomic group of amino acids at least Amino atomic group is protected
  • R 12, R 23, R 3, R 4, R 5 and R 6 have the same meanings as described above, and, if desired, by removing the protecting group There is a monkey.
  • R 14 is a protecting group for amino group
  • R 31, R 41, R 51, and R 61 are the same or different and represent a hydrogen atom, a hydroxyl group, or a lower alkoxy group.
  • R 24 represents (1) a group having a structure in which at least one hydrogen atom of an amino group is removed from an amino acid in which at least a carboxy group is protected, or (2) a primary or secondary amine or ammonia Represents a group having a structure in which one hydrogen atom on a nitrogen atom has been removed
  • the compound represented by the general formula [XI] is condensed in a suitable solvent at a temperature of from 30 ° C. to room temperature using a suitable condensing agent.
  • R 1 5 represents a group having a structure obtained by removing a hydroxy atomic carboxy atomic group of amino acids at least amino atomic group is protected
  • R 4 include an aryl group-substituted lower alkoxycarbonyl group.
  • Preferred examples of 5 include a group having a structure in which a hydroxy atom group of an ⁇ -carboxy atom group is removed from an ⁇ -amino acid in which an amino group is protected by a lower alkoxycarbonyl group, and a preferred example of R 24 Is selected from a group having a structure in which one hydrogen atom of an a-amino group is removed from an ⁇ -amino acid in which a carboxy group is protected by a lower alkyl group, or a lower alkyl or aryl substituted lower alkyl.
  • the amino group which may be substituted with one or two groups include R 3 i, R 4 i, R 51 and R 6 i, which may be the same or different and include a hydrogen atom or a lower alkoxy group
  • R 25 represents a hydroxyl group having a protecting group
  • R 32, R 42, R 52 and R 62 are the same or different and represent a hydrogen atom, a hydroxyl group or a lower alkoxy group
  • R 16 represents a group having a structure in which at least the amino group is protected and the hydroxy group of the carboxy group is removed from the amino acid
  • R 16 include an ⁇ -amino acid having an amino group substituted by a lower alkoxycarbonyl group to a hydroxy of an ⁇ -carboxy atom group.
  • a group having a structure from which an atomic group has been removed is mentioned.
  • a preferred example of R 25 is a lower alkoxy group substituted with an aryl group.
  • a preferred example of R 32 , R 42 , R 52 and R 62 is hydrogen. Atoms.
  • R 16 R 32, R 42, R 52 and R 62 have the same meaning as described above, or a reactive derivative at the carboxy group thereof and a general formula [XIX]:
  • R 26 represents a group having a structure in which at least one hydrogen atom of an amino group has been removed from an amino acid in which at least a carboxy group is protected, or (2) a group having a primary or secondary amine or ammonia. Represents a group having a structure in which one hydrogen atom on a nitrogen atom has been removed
  • R 26, R 16, R 32, R 42, R 52 and R 62 have the same meanings as described above).
  • the corresponding target compound can be prepared by removing according to the following.
  • R 16 is a ⁇ amino which is protected with an amino group by a lower alkoxycarbonyl group. From acid. Motogaa Gerare having a structure obtained by removing a hydroxy group of atoms one carboxy group of atoms, preferred examples of R 2 6 is carboxy sheet atomic in Ariru substituted lower alkyl groups are protected "alpha from single amino acid —A group having a structure in which one hydrogen atom of an amino group has been removed or an amino group, and examples of R 32, R 42, R 52 and R 62 include a hydrogen atom .
  • the protecting group for the carboxy group (carboxyl group) and the amino group (amino group) may be any group that does not participate in the condensation reaction and can be easily removed by a conventional method. It is usually used as a protecting group for amino acids in peptide synthesis. Can be used.
  • the protecting group for the carboxy atom group include a lower alkyl group and an aryl group-substituted lower alkyl group, and specifically, a methyl group, an ethyl group, a benzyl group, and the like. Among them, preferred is an aryl group-substituted lower alkyl group, such as a benzyl group.
  • Examples of the protecting group for the amino group include a substituted and unsubstituted lower alkoxycarbonyl group. Specific examples include a benzyloxycarbonyl group, a 4-methoxybenzyloxycarbonyl group, and a 9-fluorenyl. Examples include a methyloxycarbonyl group, a tert-butoxycarbonyl group, and a 2,2,2-trichloroethyloxycarbonyl group. Among them, preferred are an aryl group-substituted lower alkoxycarbonyl group and an unsubstituted lower alkoxycarbonyl group, for example, a benzyloxycarbonyl group and a tert-butoxycarbonyl group.
  • the protecting groups for the carboxy and amino groups can be easily removed by a known method, for example, a conventional method of peptide chemistry.
  • Examples of the reactive derivative at the carboxyl group of the amino acid include its active ester, such as succinimide ester and benzotriazole ester.
  • an ester activator 1,3-dicyclohexylcarbodiimide and the like are used.
  • Condensation reaction can also be performed with a combination of an ester activator and a condensing agent.
  • 1-hydroxybenzotriazole (monohydrate) and 1-ethyl-3- (3-dimethylaminopropyl) carboxydiimidide Hydrochloride, N-hydroxysuccinimide and 1,3-dicyclohexylcarpoimide can be used.
  • a combination of 1-hydroxybenzotriazole (monohydrate) and 1-ethyl-13- (3-dimethylaminopropyl) carboxydiimide hydrochloride is preferred.
  • Suitable solvents may be any inert solvents that do not participate in the condensation reaction, such as dimethylformamide, dimethylsulfoxide, dichloromethane, dichloroethane, chloroform, tetrahydrofuran, ethyl acetate and N-methylpyrrolidone. And dimethylformamide is preferred.
  • the functional group is protected in advance and then subjected to the condensation reaction according to a conventional method. Deprotection is preferred.
  • the target compound [I] of the present invention is subjected to condensation and deprotection of a carrier obtained by binding a desired starting amino acid to a resin and a corresponding starting amino acid derivative by using a commercially available automatic synthesizer.
  • the peptide may be purified by a means for separating the peptide, for example, extraction, distribution, reprecipitation, crystallization, recrystallization, various types of chromatography, high-performance chromatography, or the like.
  • any resin can be used as long as the target substance can be finally cut out in the form of an amide.
  • TMC-2A, TMC-2B or TMC-2C represented by the following formula, ie, TMC-2A, TMC-2B or TMC-2C, can also be obtained by culturing a mold belonging to the genus Aspergillus and isolating from the culture.
  • TMC-2A, TMC-2B and TMC-2C by a mold belonging to the genus Aspergillus will be described in more detail.
  • TMC-2A An example of a strain producing TMC-2A, TMC-2B and TMC-2C is A374 strain isolated from soil in Kochi City, Kochi Prefecture. The mycological properties of this strain are as follows.
  • Table 1 shows the growth of A374 strain in various media after culturing at 25 ° C for 7 days. The color tone was determined according to the JIS standard color table (Z 872 1). Table 1 Physicochemical properties of TMC-2A, 2B and 2C Property TMC-2A TMC-2B TMC-2C Shape White powder White powder White powder Melting point (° c) 166 168 166 168 175 175 181 Solubility Water , Soluble in methanol, soluble in methanol, soluble in methanol,
  • TMC-2A and TMC-2B were measured as aqueous solutions, and TMC-2C was measured as a methanol solution at 20 ° C.
  • Hyphae have smooth surfaces and partition walls.
  • Conidia 6.7-8.0 zmX 23-1 100 m
  • podocytes foot-cell; 6.7-8.7 ⁇ mX 37-57 m
  • a pin-shaped one-stage incisor pri marysteri gma ta; 2.3 to 3.3 mX 13 m
  • the conidium head is mainly cylindrical (50-100 mX16-200 m), but some conidium heads have a globular shape and a spherical shape (33-60 111 20-47 111). Is recognized.
  • the A374 strain belongs to the genus Aspergillus (Aspergii11us).
  • the As pergilluss p. A 374 strain was deposited on May 18, 1995 with the Institute of Biotechnology, Institute of Industrial Science and Technology, Ministry of International Trade and Industry (1-3 1-3 Higashi, Tsukuba, Ibaraki, Japan) under the accession number FERM. Deposited as P-14934, and then transferred to the Institute on September 1.9, 1997 as Accession No. FERM BP-6113.
  • TMC-2A, TMC-2B, and TMC-2C In order to produce TMC-2A, TMC-2B, and TMC-2C by the method of the present invention, a TMC-2A, TMC-2B and TMC-2C-producing bacterium belonging to the genus Aspergillus is contained as a nutrient source.
  • the medium is inoculated and grown aerobically. This results in a culture containing TMC-12A, TMC-2B and TMC-2C.
  • a carbon source and a nitrogen source that can be used as a nutrient source for microorganisms can be used.
  • a carbon source and a nitrogen source that can be used as a nutrient source for microorganisms
  • a carbon source and a nitrogen source that can be used as a nutrient source for microorganisms
  • peptone, meat extract, corn 'steep' rice Nitrogen sources such as cottonseed flour, peanut flour, soy flour, yeast extract, NZ-amine, casein hydrolyzate, ammonium nitrate, ammonium sulfate, and starch, glycerin, sucrose, glucose, galactose, mannose, molasses
  • Carbon sources such as carbohydrates or fats
  • inorganic salts such as salt, calcium carbonate, phosphate, magnesium sulfate and the like can be added.
  • TMC-2A, TMC-2B and TMC-2C can be used as long as they are used by the producing bacteria and are useful for producing TMC-2A, TMC-2B and TMC-2C.
  • Liquid culture is preferred for culturing the above-mentioned bacteria producing TMC-2A, TMC-2B and TMC-2C.
  • the cultivation temperature can be used in a range in which the producing bacteria grow and produce a desired substance, and is usually 20 to 35 ° C.
  • the cultivation can be carried out by appropriately selecting from the above conditions depending on the properties of the producing bacteria to be used.
  • the desired TMC-2A, TMC-2B and TMC-2C are produced in culture. Isolation and purification of those products can be carried out by a method known per se, for example, ion exchange chromatography, partition chromatography, reverse phase chromatography, etc., as appropriate.
  • TMC-2A, TMC-2B and TMC-2C of the present invention are shown in Table 2 below.
  • the whole surface is velvet and double colored and the outside is
  • TMC-2A, TMC-2B and TMC-2C are shown in FIGS. 1 to 3 and 4 to 6, respectively.
  • the UV spectrum was analyzed for a 50 gZm1 methanol solution of each sample.
  • IR spectra were analyzed on potassium bromide tablets containing 1% (w / w) of each sample.
  • TMC-2A, TMC-2B and TMC-2C are shown in FIGS. 7 to 9 respectively.
  • TMC-2A and TMC-2B were measured in heavy water using TSP (sodium trimethylsilylpropylsulfonate) as an internal standard.
  • TMC-2C was measured in heavy methanol using TMS (tetramethylsilane) as an internal standard. The chemical shifts (ppm) are described below.
  • TMC- 2 A 7.55 (1H, d), 7.46 (1H, d), 7.34 (1H, s), 7.13 (1H, t), 7.07 (1H, t), 6.02 ( 1H, s), 4.82 (1H, d), 4.50 (1H, dd), 4.11 (1H, dd), 3.77 (1H, d), 3.73 (4H, m), 3.49 Up to 3.28 (5H, m), 3.19 (1H, dd), 2.35 (1H, dd), 1.68 (1H, ddd), 1.44 (1H, ddd), 1.14 (1H, dd), 0.7 1 (1 H, m)
  • TMC-2B 7.58 (1 H, dd), 7.52 (1 H, d), 7.38 (1 H, s), 7.22 (1 H, dd), 7.16 (1 H, dd), 6.09 (1H, s), 4.80 (1H, dd), 4.50 (1H, dd), 4.04 (1H, dd), 3.83 (1H, d), 3.77 (1H, m), 3.73 (3 H, s), 3.50 (1 H, dd), 3.43 (1 H, dd), 3.08 (2 H, d), 2.39 (1 H, dd), 1.64 (1 H, ddd), 1.20 (2 H, m), 0.63 (4 H, m)
  • TMC- 2.C 7.53 (1 H, d), 7.40 (1 H, d), 7.24 (1 H, s), 7.12 (1 H, dd), 7.07 (1 H, dd), 6.09 ( 1 H, s), 5.06 (1 H, d ), 4.23 (1H, dd), 4.22 (1H, dd), 3.73 (3H, s), 3.70 (1H, d), 3.60 (1H, dd), 3.36 (2H, dd) ), 3.12 (2 H, d), 2.37 (1 H, dd), 1.45 (2 H, dd), 1.29 (1 H, m), 0.58 (1 H, m), 0.50 ( 3 H, d)
  • TMC-2A, TMC-2B and TMC-2C are shown in FIGS. 10 to 12, respectively.
  • TMC-2A and TMC-2B were measured in heavy water using dioxane as an internal standard.
  • TMC-2C was measured in heavy methanol using TMS as an internal standard. The chemical shifts (ppm) are described below.
  • TMC-2A 181.4, 174.1, 173.7, 151.1, 148.6, 139.6, 137.1, 132.0, 129.2, 128.0, 125.2, 1 22.6, 1 20.7, 1 14.9, 1 13.6, 109.9, 109.1, 65.6, 63.5, 62.7, 59.3, 55.5, 54.8, 41.6, 41.4, 33.1, 32.2, 3 0.5
  • TMC-2B 182.0, 174.4, 174.2, 151.5, 149.1, 139.5, 137.7, 132.4, 129.6, 128.5, 125.7, 123. 1, 1 2 1.2, 1 15.4, 1 14.0, 1 10.4, 109.1, 67.6, 64.0, 59.7, 56.3, 55.2, 42.1, 37.7, 34.4, 33.4, 30.9, 20 . 1
  • TMC-2C 179.6, 171.9, 171.4, 150.8, 148.0, 138.1, 135.8, 130.0, 128.1, 125.6, 123.2, 120.6, 119.3, 112.7, 111.4, 108.2, 107.7, 68.6, 60.9, 58.2, 53.6, 53.5, 39.9, 36.9, 33.1, 31.7, 29.5, 15.5
  • Protons bonded to nitrogen and oxygen atoms were prepared by preparing acetylated form of D-(-28), and measuring the proton and carbon nuclear magnetic resonance spectra in the double-mouthed form. I confirmed.
  • TMC-2A, TMC-2B and TMC-2C had the structure of the aforementioned general formula [II]. No compound with this chemical structure has been reported so far, and TMC_2A, TMC-2B and TMC-2C are new substances.
  • Whether a compound has an inhibitory effect on dipeptidyl peptidase IV is determined, for example, by determining whether the compound has L-Gly-L-Pro-p-nitroanilide by dipeptidyl peptidase IV. Judgment can be made based on whether or not the reaction that is hydrolyzed by L-Gly-L-Pro and p-nitroaline is inhibited.
  • the compounds of the present invention can be used for pharmaceutical use either in free form or in the form of a pharmaceutically acceptable salt.
  • pharmacologically acceptable salts may be any conventional non-toxic salts, for example, inorganic salts such as hydrochloride, hydrobromide, sulfate or phosphate, and formate. , Acetate, trifluoroacetate, oxalate, maleate, fumarate, tartrate, metasulfonate, organic salts such as benzenesulfonate or toluenesulfonate, sodium salt, potassium salt, etc.
  • alkaline earth metal salts such as calcium salts and the like, and salts with amino acids such as arginine salts, aspartate and glutamate.
  • target compound of the present invention and the pharmaceutically acceptable salts thereof should be construed as including any of inner salts, adducts, solvates or hydrates thereof, etc.
  • a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable salt thereof as an active ingredient
  • Additives for these drugs may be used as long as they do not impair the therapeutic effect of each drug and are harmless at the dose of the drug. Any conventional additives can be used. For example, stabilizers, buffers, flavoring agents, suspending agents, emulsifiers, fragrances, preservatives, solubilizing agents, excipients, coloring agents, binders, disintegrants, sweeteners, thickeners, wetting agents , A solvent and the like can be used.
  • the amount of the active ingredient in the pharmaceutical preparation may be an amount sufficient to produce the desired therapeutic effect.
  • oral or parenteral administration is 0.0 lmg Z kg to: LOO mg Z kg, preferably 1 mg Z kg to 3 O mg Z kg.
  • examples of the protecting group for the amino group (protecting group for the amino group) in the “amino acid in which the amino group may be protected” include, for example, an acyl group, an akanoyl group, an aroyl group, an aralkylcarbonyl group.
  • the amino acid having a protected carboxy group in the “amino acid whose carboxy group may be protected” is a compound in which the carboxy group of an amino acid is esterified (amino acid ester) or the carboxy atom of an amino acid. And the like. Examples of such compounds include amino acids in which the carboxy group is protected by lower alkyl, amino acids in which the carboxy group is protected by aryl-substituted lower alkyl, and di-lower alkylamines. And an amino acid having a protected carboxy atom group.
  • amino acid when it has a reactive residue other than the amino group and the carboxy group (for example, a hydroxyl group in serine), it may be used in the field of peptide synthesis depending on the type of the reactive residue. It may be protected by a commonly used protecting group (for example, a benzyl group for a hydroxyl group).
  • aryloxycarbonyl group examples include a phenoxycarbonyl group and a naphthyloxycarbonyl group.
  • aryl group-substituted lower alkoxycarbonyl group examples include a benzyloxycarbonyl group and a phenethyloxy group. Examples thereof include a carbonyl group and a naphthylmethyloxy group, and preferably include a benzyloxycarbonyl group.
  • the “lower alkoxycarbonyl group” includes a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, an n-butoxycarbonyl group, an isobutoxycarbonyl group, a tert-butoxycarbonyl group, sec - butoxide deer Lupo sulfonyl group, n- pentyl group, isopentyl group, sec - pentyl group, tert - pentyl group, n - hexyl group, a cyclohexyl group isohexyl, hexyl group and tert into sec- One hexylcarbonyl group and the like are preferable, and a tert-butoxycarbonyl group is preferable.
  • Examples of the “aryl substituted lower alkyl” include a benzyl group, a phenethyl group and a
  • aryl means phenyl, naphthyl and the like.
  • lower alkyl and lower alkoxy represent a branched or straight chain having 1 to 6 carbon atoms, and preferably a branched or straight chain having 1 to 4 carbon atoms.
  • Dipeptidyl peptidase IV enzyme (25 mU / m 1) solution 51, water 30 and 2 mM dimethyl sulfoxide solution 5 ⁇ l of test compound were mixed, pre-incubated for 10 minutes, then 71 OmM G 1 yNaOH (pH 8.7) buffer solution 10 mM 3 mM L-Gly-L-Pr0-p troanilide (G1y-Pr0-pNA; Sigma) 50 ⁇ l aqueous solution was added. The amount of ⁇ -nitroaniline produced is measured using a plate reader (THERMOmax; manufactured by Molecular Devices) to measure the increase in absorbance ( ⁇ D) at a wavelength of 405 nm to determine the activity of dipeptidyl peptidase IV enzyme.
  • THERMOmax plate reader
  • the inhibition rate (%) is determined by the following equation 1. However, 1 U of dipeptidyl peptidase IV enzyme activity is defined as the amount of enzyme that produces 1 mol of p-troalinerin per minute. The results are shown in Table 3. l-(AOD -AOD blank )
  • TMC-2A, TMC-2B and TMC-2C were purified from rat kidney, as well as rat spleen, human peripheral blood mononuclear cells and human colon cancer cell line C. ac 0 di peptidyl peptidase was prepared from 2 peptidase IV was also confirmed inhibited child and power s.
  • TMC-2A, TMC-2B and TMC-2C were examined. That is, the effects of TMC-2A, TMC-2B and TMC-2C on prolyl endopeptidase, subtilisin, trypsin, cathepsin C, leucine aminopeptidase and proline aminopeptidase at a concentration of 100 g / 1 were examined. did. As a result, TMC-2A and TMC-2B had no effect on all tested and tested peptidases. TMC-2C, on the other hand, showed weak inhibition of oral lendopeptidase and proline aminopeptidase, but not other peptidases. Therefore, TMC-2A, TMC-1B and TMC-2C were found to be highly specific inhibitors of dipeptidyl peptidase IV.
  • Arthritis was induced by administering 35 mg / kg of alkyldiamine to the ridge of F344 / Jc1 rats (five weeks old, female). Ding 1 ⁇ ⁇ ⁇ 28 is in saline It was dissolved and administered once daily subcutaneously to the back for 3 weeks from the day of alkyldiamine administration to the end of the test. The doses were 30, 10, 3, and 1 mgZkg.
  • FIG. 13 shows how much the foot swelled at the end of the test in each test group (percentage of the foot swelled based on the volume of the foot before administration of alkyldiamine in each individual). The volume of the foot is measured by a foot volume measurement device.
  • FIG. 14 shows how much the foot swelled at the end of the test in each test group (percentage of the foot swelling based on the volume of the foot before administration of the heat-killed M. tuberculosis in each individual).
  • the volume of the foot is measured by a foot volume measurement device.
  • TMC-2A and the compound of Example 13 suppressed the onset and progression of adjuvant-induced arthritis in a dose-dependent manner.
  • the suppression was significantly suppressed as compared with the control group (group administered with physiological saline).
  • Bn- represents a benzyl group
  • Boc- represents a tert-butoxycarbonyl group
  • Z- represents a benzyloxycarbonyl group
  • Boc- in the table represents a tert-butoxycarbonyl group.
  • Example 7 4.0 g of the compound obtained in Example 7 was dissolved in 50 ml of a 4 M hydrochloric acid-dioxane solution, and the mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water, and lyophilized to give a pale red powder (3S) -2- (L-tributophyl) -1,2,3,4-tetrahydroisoquinoline-3 3.3 g of carboxylic acid 'hydrochloride were obtained. m. p .: 1 58 ° C (decomposition)
  • z- in the table represents a benzyloxycarbonyl group.
  • Example 7 The compound obtained in Example 7 and L-one-isocyanate'benzyl ester were treated in the same manner as in Example 19 to give N-
  • N—K3 S) —2— (N-tert-butyloxycarbonyl L-tryptofil) -1-1,2,3,4-tetrahydroisoquinoline-3-carbonyl-1—L-serine and (2) amofus N- 1 (3 S)-2- (N-tert-butyloxycarbonyl-L-tryptofil)-1,2,3,4-tetrahydroisoquinoline- 3-carbonyl-1-0-benzyl-L-serine Was.
  • Amorphous N-1 (3S) -2-L-tributofyl-1,2,3,4-tetrahydroisoquinoline-3-carbonyl 1-L-serine / hydrochloric acid treated in the same manner as in Example 13 Salt was obtained. .
  • Example 28 350 mg of the compound obtained in Example 28 was dissolved in 15 ml of methanol, a catalytic amount of palladium-carbon was added, and the solution was hydrogenated under a balloon pressure at room temperature for 3 hours. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crystalline residue. The crystalline residue was washed with isopropyl ether, and amorphous N-1 (3S) -2-L-tryptofil 5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline 1-3-carbonate L-leucine methyl ester 17 Omg was obtained.
  • Example 28 1.3 g of the compound obtained in Example 28 was dissolved in 30 ml of methanol, 3.8 ml of a 1 M aqueous solution of sodium hydroxide was added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure, the residue was washed with ether, neutralized with an aqueous solution of potassium hydrogen sulfate, and extracted with ethyl acetate. The extract was washed, dried and concentrated to obtain a crystalline residue.
  • Example 30 600 mg of the compound obtained in Example 30 was dissolved in 15 ml of methanol, and after adding a catalytic amount of palladium-carbon, the solution was hydrogenated at room temperature under balloon pressure for 3 hours. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crystalline residue. The crystalline residue was washed with isopropyl ether, and amorphous N—j (3S) —2-L-tributyryl-1,5,8-dimethoxy-1,1,2,3,4-tetrahydroisoquinoline-3 —Carbon ⁇ —L-leucine 345 mg was obtained.
  • Peptide synthesis was performed using the automated solid phase method peptide synthesizer P S SM-8 (manufactured by Shimadzu Corporation) according to the following procedure.
  • a carrier Fmoc-Amino in which the corresponding starting amino acid is bonded to a benzoxybenzyl alcohol type resin
  • Acid—Resin 100 mg, and benzotriazole-1-yloxystris (pyrrolidino) phosphonium hexafluorophosphate, 1-hydroxybenzotriazole, N-methyl Morpholine system as deprotection system 20% piperidine / N, N-dimethylformamide as condensed amino acid N- ⁇ -9-Fluorenylcarbonyl 1,2-, 3,4-tetrahydroisoquinolin-13-carboxylic acid and N-tert-butyloxycarbonyl L-tryptophan
  • the synthesis was performed using the equipped standard protocol.
  • the mixture was treated with 1 ml of trifluoroacetic acid: water: thioanisole: ethanedithiol (75: 10: 10: 5) for 3 hours, deprotected, and cleaved from the resin.
  • the reaction solution was filtered to remove the resin, and the filtrate was precipitated by adding anhydrous getyl ether, or concentrated to obtain the desired crude peptide.
  • Example 1 The compound obtained in Example 1 was treated in the same manner as in Example 13 except that trifluoroacetic acid was used instead of the hydrochloric acid-dioxane solution, to give amorphous (3S) -2-L-tributyrophil 1,2,3,3 4-Tetrahydroisoquinoline-3-carboxylic acid ⁇ benzylester ′ trifluoroacetate was obtained.
  • Example 5.3 1.6 g of the compound obtained in Example 5.3 was treated in the same manner as in Example 13 to give a pale red powdery (3S) -2- (L-tryptofile) -1-1,2,3,4-tetrahydrofuran. Droisokinori 1.3 g of 3-hydroxylpoxamide hydrochloride was obtained.
  • Example 53 The compound obtained in Example 53 was treated in the same manner as in Example 13 using trifluoroacetic acid instead of the hydrochloric acid-dioxane solution, to give a pale red powdery (3S) -2- (L-tribute file). There was obtained 1,1,2,3,4-tetrahydroisoquinoline-13-carboxamide 'trifluoroacetate.
  • the obtained culture was used as a seed culture.
  • One hundred ml of a seed culture solution was inoculated into 100 Erlenmeyer flasks containing 100 ml of a liquid medium having the above-mentioned composition, and cultured with shaking at 27 ° C for 5 days.
  • the elution was performed by first mixing 5 L of a mixed solution of dichloromethane: methanol: ethanol (10: 4: 4) and then mixing a mixed solution of dichloromethane: methanol: ethanol: water in the following order with a ratio of ⁇ 7j. That is, a mixture of dichloromethane: methanol: ethanol: water was mixed with a 10: 4: 4: 0.1 solution 5 L, a 10: 4: 4: 0.2 solution 5 L, and a 10: 4: 4: 0.5 solution, respectively. Elution was carried out with 10 L of a 0: 4: 4: 1 solution and finally with 10 L of a 10: 4: 4: 2 solution. Fractions showing dipeptidyl peptidase IV inhibitory activity were collected and concentrated under reduced pressure to obtain a crude substance.
  • This crude substance was subjected to chromatography using a reverse-phase silica gel column (ODS A60, manufactured by JMc Co., Ltd., 60 ⁇ 900 mm). Elution was performed with 20% acetonitrile-80% water. Each eluted fraction was analyzed by high performance liquid chromatography, fractions containing only TMC-2A were collected, concentrated under reduced pressure, and lyophilized.
  • the high performance liquid chromatography for analysis was performed using a YMC_Pack AM_301-3 (manufactured by Jemushi Corporation) 4.6 x 100 mm column with a linear gradient of 1096 to 35% from acetonitrile for 15 minutes (flow rate 1.2m 1 Zm in ). The detection was based on the absorbance at 210 nm and 254 nm. By the above operation, about 1.6 g of pure TMC-2A was obtained.
  • TMC-2B and TMC-2C Purification of TMC-2B and TMC-2C was performed as follows. Fractions containing TMC-2B and TMC-2C in the above reverse phase chromatography were collected and concentrated under reduced pressure. TMC-2B and TMC-2C were fractionated from the concentrate using silica gel chromatography (Co-gel C-300, Wako Pure Chemical Industries, Ltd., 22 ⁇ 500 mm). For elution, flow 500 ml of a mixture of dichloromethane: methanol: ethanol (10: 4: 4).
  • the mixed solution of dichloromethane: methanol: ethanol: water was 200 ml for a 10: 4: 4: 0.1 solution, 200 ml for a 10: 4: 4: 0.2 solution, and 200 ml for a 10: 4: 4: 0.5 solution.
  • 500 ml of a 10: 4: 4: 1 solution and 500 ml of a 10: 4: 4: 2 solution were successively dropped.
  • Fractions containing only TMC-2B or TMC-2C were concentrated to dryness, respectively. By the above operations, pure TMC-2B and TMC-2C were obtained in 5.4 mg and 2 lmg, respectively.
  • the tetrahydroisoquinoline derivative of the present invention selectively inhibits dipeptidyl peptidase IV at a low concentration, and prevents and treats autoimmune diseases (immune disorders and immunodeficiencies) such as arthritis and rheumatoid arthritis. Useful as an agent.

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Abstract

Compositions médicinales contenant en tant que principe actif des composés qui inhibent la dipeptidyl-peptidaseIV et possèdent le squelette tétrahydroisoquinoline, par exemple, des dérivés de tétrahydroisoquinoline de formule générale (I) dans laquelle R1 représente (1) un groupe ayant la structure d'un acide aminé à amino éventuellement substitué dont a été éliminé le groupe atomique hydroxy dans le groupe atomique carboxy, ou (2) un groupe amino protecteur; R2 représente (1) hydroxy éventuellement protégé, (2) un groupe ayant la structure d'un acide aminé avec un groupe atomique carboxy éventuellement protégé dont a été éliminé un atome d'hydrogène dans le groupe atomique amino ou (3) un groupe ayant la structure d'une amine primaire ou secondaire ou de l'ammoniac dont a été éliminé un atome d'hydrogène; et R?3, R4, R5 et R6¿ sont identiques ou différents, chacun représentant hydrogène, hydroxy ou alcoxy inférieur.
PCT/JP1997/003804 1996-10-25 1997-10-22 Derives de tetrahydroisoquinoline Ceased WO1998018763A1 (fr)

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US11253508B2 (en) 2017-04-03 2022-02-22 Coherus Biosciences, Inc. PPARy agonist for treatment of progressive supranuclear palsy
CN117510578A (zh) * 2023-11-17 2024-02-06 首都医科大学 TNF-ɑ抑制剂2-Asn-四氢异喹啉-3S-甲酰-AA、及制备和应用

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EP2036554A1 (fr) 2000-06-19 2009-03-18 SmithKline Beecham plc Combinaisons d'inhibiteurs de dipeptidylpeptidase iv et d'autres agents antidiabetiques pour traiter le diabete sucre
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WO2007072083A1 (fr) 2005-12-23 2007-06-28 Prosidion Limited Traitement du diabete de type 2 par combinaison d'un inhibiteur de dpiv a de la metformine ou de la thiazolidinedione
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WO2011005929A1 (fr) 2009-07-09 2011-01-13 Arena Pharmaceuticals, Inc. Dérivé de pipéridine et son utilisation pour le traitement du diabète et de l'obésité
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WO2012170702A1 (fr) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés à celui-ci
WO2013055910A1 (fr) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés
WO2014074668A1 (fr) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulateurs de gpr119 et traitement de troubles associés à ceux-ci
US10555929B2 (en) 2015-03-09 2020-02-11 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US10772865B2 (en) 2015-03-09 2020-09-15 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
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WO2018162722A1 (fr) 2017-03-09 2018-09-13 Deutsches Institut Für Ernährungsforschung Potsdam-Rehbrücke Inhibiteurs de dpp-4 à utiliser dans le traitement de fractures osseuses
US11253508B2 (en) 2017-04-03 2022-02-22 Coherus Biosciences, Inc. PPARy agonist for treatment of progressive supranuclear palsy
CN117510578A (zh) * 2023-11-17 2024-02-06 首都医科大学 TNF-ɑ抑制剂2-Asn-四氢异喹啉-3S-甲酰-AA、及制备和应用

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