WO2003089410A1 - Derive de phenylalanine - Google Patents

Derive de phenylalanine Download PDF

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Publication number
WO2003089410A1
WO2003089410A1 PCT/JP2003/004970 JP0304970W WO03089410A1 WO 2003089410 A1 WO2003089410 A1 WO 2003089410A1 JP 0304970 W JP0304970 W JP 0304970W WO 03089410 A1 WO03089410 A1 WO 03089410A1
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substituted
unsubstituted
heterocyclic group
compound
lower alkyl
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PCT/JP2003/004970
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Japanese (ja)
Inventor
Yoshisuke Nakasato
Kiminori Ohta
Eri Arai
Osamu Saku
Hiroko Kusaka
Satoshi Nakanishi
Haruhiko Manabe
Akira Ogawa
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Kyowa Hakko Kogyo Co., Ltd.
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Priority to JP2003586131A priority Critical patent/JPWO2003089410A1/ja
Priority to AU2003235256A priority patent/AU2003235256A1/en
Publication of WO2003089410A1 publication Critical patent/WO2003089410A1/fr

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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
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    • 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
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a phenylalanine derivative or a pharmacologically acceptable salt thereof, which is useful as an ⁇ 4 integrin inhibitor.
  • Adhesion between cells and cells or extracellular matrices plays an important role in the migration and adhesion of leukocytes to sites of inflammation and the migration of stem cells during ontogeny. It is clear that a variety of adhesion molecules are involved in these processes, but in particular, one of the adhesion molecules, integrin, interacts with ligands expressed on cells, and [Adhesion Molecules In Health And Disease]; Paulon, LC (Adhesion Molecules In Health And Disease) ), Ischkouts
  • integrins include J31 integrins and hepatic dimers ( ⁇ 4] 31) LPAM-1 (lymphocyte Peyer's patch HEV adhesion molecule-1), which forms ⁇ $ VLA-4 (very late antigeN-4) and] S7 integrin and hete mouth dimer ( ⁇ 4
  • VLA-4 is expressed on lymphocytes, monocytes, eosinophils and mast cells, and is expressed on vascular endothelium.VCAM-1 (Vascular Cell Adhesion Molecule-1) and fibrous nectin are the ligands. is there.
  • LPAM-1 is also expressed on lymphocytes, monocytes, eosinophils, and basophils, and is present in VCAM-1 and fibronectin as well as in the intestinal mucosa, mesenteric lymph nodes, and Peyer's patch spleen.
  • MadCAM-1 micosal addressin cell adhesion molecule expressed in the high endothelial venule (layer) is its ligand.
  • Inflammatory encephalopathies such as multiple sclerosis (MS) and encephalomyelitis [Nature, 356, 63 (1992), Giannarole 'ob' et apermental ⁇ Medicine (J. Exp. Med. ), 177, 57 (1993)], asthma [Journal 'Ob' Expermental 'Medicin (J. Exp. Med.), 180, 795 (1994), Giannare-Ov-Klini J. Clin. Invest., Vol. 93, p. 776 (1994), J. Immunology, 150, 2407 (1993)], inflammatory bowel disease (including ulcerative colitis and Crohn's disease) [J.
  • a4-integrin inhibitors have been studied in a variety of inflammatory models using anti- ⁇ 4 antibodies that inhibit the interaction of a4-integrin with its ligand.
  • II experimental autoimmune encephalomyelitis
  • MS multiple sclerosis
  • asthma asthma [J. Allergy Clin. Immunol., 100 vol., 242 (1997), International Archives] , Allergy and Immunology (Int. Arch.
  • the purpose of the present invention is to provide various diseases which are useful as a 4 integrin inhibitor and which involve an adhesion mechanism mediated by 4 integrins (eg, multiple sclerosis, asthma, inflammatory bowel disease) , Rheumatoid arthritis, diabetes, tumor metastasis, arteriosclerosis, atopic dermatitis, nephritis, psoriasis, myocardial ischemia, cell rejection during organ transplantation, etc.)
  • An object of the present invention is to provide a lanine derivative or a pharmacologically acceptable salt thereof.
  • the present invention relates to the following (1) (11)
  • R 2 is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, Represents a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted alicyclic heterocyclic group,
  • R 2 is R 2A ⁇ wherein, R 2A has the same meaning as R 2 ,
  • R 13A is added to the definition of the R 12A, one NR 12A.
  • R 13Ae (wherein, R 12A. And R 13A.
  • R 12A and R 13A is as defined above) with a representative of, a substituted or unsubstituted 2-pyrrolyl or 4-substituted 4 Ichipi Perijiniru,
  • Position 1 in the ring structure (the position of the bond to the carbonyl adjacent to R 2 is position 1) is a nitrogen atom, and position 2 (the position of the bond to the carbonyl adjacent to R 2 is position 1) ) gar S0 2 - properly be substituted composed monocyclic 5-7 membered ring of the unsubstituted alicyclic heterocyclic group,
  • position 1 (the position of the bond to the carbonyl adjacent to R 2 is position 1) is NR 15 S0 2 R 16 (wherein, R 15 and R 16 are as defined above, respectively)
  • R 9b (wherein R 9b has the same meaning as described above)]
  • R 3 , R 4 , R 5 and R 6 are each R 3A , R 4A , R 5A and R 6A (where R 3A , R 4A , R 5A and ⁇ ⁇ R 6A are each R 3 , R 4 , R 5 and R 6
  • R 2A is a substituted or unsubstituted alicyclic heterocyclic group having one or two atoms selected from an oxygen atom and a sulfur atom
  • the phenylalanine derivative or the pharmacologically acceptable salt thereof according to the above (1).
  • R 2 is R 2B [wherein R 2B has the same meaning as R 2 above,
  • a medicament comprising the phenylalanine derivative or the pharmacologically acceptable salt thereof according to any one of the above (1) to (6) as an active ingredient.
  • An anti-inflammatory agent comprising, as an active ingredient, the phenylalanine derivative or the pharmacologically acceptable salt thereof according to any one of (1) to (6).
  • the lower alkyl includes, for example, a linear or branched alkyl having 1 to 10 carbon atoms, specifically, methyl, ethyl, propyl, isopropyl, pentinole, sec butynole, tert-butynole, pentynole. , Isopentinole, neopentyl, hexyl, heptyl, octyl, isooctinole, noel, decyl and the like.
  • Lower alkynyl includes, for example, linear or fenched C2 to C8 olenokininole, specifically ethininole, 1-propininole, butchur, pentinole, hexinole, heptinole. , Octininole, propanoreginole and the like.
  • R 3 Among R 3 , RR 5, and R 6 , two existing on the same carbon atom are combined with the carbon atom to form a saturated monocyclic hydrocarbon ring.
  • Ten specific examples include cycloprono, cyclohexane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononene, cyclodecane, and the like.
  • Examples of the cycloalkenyl include an unsaturated monocyclic hydrocarbon group having 3 to 8 carbon atoms, specifically, cyclopropyl, cyclobutenyl, cyclopentinole, cyclohexenol, and cyclohexyl. Examples include pteninole, cyclopentenole, cyclopentageninole, cyclohexeninole, and cycloheptagenil.
  • Halogen represents each atom of fluorine, chlorine, bromine and iodine.
  • the aryl moiety, aromatic heterocyclic group, alicyclic heterocyclic group, and halogen are the above-mentioned lower alkyl (i), cycloalkyl (iv), cycloalkenyl (v), aryl (vi), and aromatic heterocyclic group, respectively.
  • the substituents in the substituted lower alkoxy, the substituted lower alkylthio, the substituted lower alkynyl, the substituted alkynole and the substituted alkenyl are the same or different, for example, having 1 to 3 substituents.
  • the aryl portion, the aromatic heterocyclic group, the alicyclic heterocyclic group and the halogen are the above-mentioned lower alkyl (i), cycloalkyl (iv), cycloalkenyl (v), aryl (vl), and aromatic, respectively.
  • Have the same meaning as the group heterocyclic group (vii), the alicyclic heterocyclic group (viii) and the halogen (ix), and the two lower alkyl moieties of the di-lower alkylamino may be the same or different.
  • pyrrolidinyl piperidino, piperazinole, monoreholino, thiomonoreholino, homopiperidino, and homopiperazine.
  • -Tetrahydropyridinyl Tetrahydroquinolinyl, Tetrahydroisoquinolinyl and the like.
  • Examples of the substituent in the substituted amino include the same or different, substituted or unsubstituted lower alkyl, lower alkanol and the like.
  • the lower alkyl portion of the lower alkyl and the lower alkyl group shown here has the same meaning as the lower alkyl (i).
  • compound (I) the compound represented by the formula (I) is referred to as compound (I).
  • compound (I) the compound represented by the formula (I).
  • acid addition salts examples include inorganic salts such as hydrochloride, hydrobromide, nitrate, sulfate, and phosphate, benzenesulfonate, benzoate, quaterate, fumarate, and dalcone.
  • Organic salts such as acid, lactate, maleate, malate, oxalate, methanesulfonate and tartrate are listed.
  • the metal salt examples include an alkali metal salt such as a sodium salt and a potassium salt, an alkaline earth metal salt such as a magnesium salt and a calcium salt, an aluminum salt, and a zinc salt.
  • ammonium salt examples include ammonium and tetramethylammonium
  • organic amine addition salt examples include morpholine addition salt and piperidine addition salt, and the like.
  • examples thereof include glycine addition salts, phenylalanine addition salts, lysine addition salts, aspartic acid addition salts, and glutamic acid addition salts.
  • Compound (I) can be obtained, for example, by the following production method. Manufacturing method 1:
  • X is a halogen (the halogen of the halogen (a) as synonymous) or single 0S0 2 W ⁇ W is lower alkyl [said lower Al kill also properly unsubstituted substituted the lower alkyl (i) And the substituents in the substituted lower alkyl are the same or different and have 1 to 3 halogen atoms (the halogen is the same as the halogen (a)) and the like.
  • aryl has the same meaning as the aryl (vi), and the substituents in the substituted aryl are the same or different and have 1 to 3 halogen atoms (the Halogen has the same meaning as the above-mentioned halogen (a)), lower alkyl (the lower alkyl has the same meaning as the above-mentioned lower alkyl (i)), etc.], and P 1 represents a lower alkyl (the lower alkyl).
  • Alkyl is the same as lower alkyl (i) Represents at that)
  • m, n, RRR 3 , RR 5, RR 7 and R 8 each have the same meanings as defined above>
  • Mouth sen 2, 2, 1 bis (dipheninole phosphino) _ 1, 1 '—binaphthyl (BINAP), 2 — [di (tert-butyl) phosphino] bifeninole, 2 — to dicyclo Xinolephosphino biphenyl, 2-dicyclohexynolephosphino 2 '-(N, N-dimethylamino) biphenyl and the like can be used. Among them, 2- [di (tert-butyl) phosphino] is used. Biphenyl is preferred.
  • the compound (V) obtained in Step 1 can be used, for example, in Protective Groups in Organic Synthesis, third edition, Clean, ⁇ '.
  • Compound (I) can be obtained.
  • the solvent inert to the reaction may be any solvent that is inert to the reaction, and is not particularly limited. Examples thereof include tetrahydrofuran, dioxane, 1,2-dimethoxetane, benzene, tonolene, and the like. Xylene, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, methanol, ethanol, N-propanol, isopropyl alcohol and the like can be used alone or as a mixture thereof.
  • the aforementioned compound (V) can also be obtained, for example, by the following method.
  • Compound (VII) can be obtained by reacting compound (VI) with compound (IV) in the same manner as in Step 1.
  • any compound synthesized according to the method described in, for example, 098/53817, W099 / 36393 and the like can be used arbitrarily.
  • P 2 when P 2 is tert-butoxycarbonyl, it is treated with an acid in an inert solvent or without solvent, for example, with trifluoroacetic acid, hydrochloric acid, etc., and when P 2 is benzyl, etc. Is the amount of catalyst in the inert solvent W
  • the solvent inert to the reaction may be any solvent as long as it is inert to the reaction, and is not particularly limited. Examples thereof include dichloromethane, chloroform, tetrahydrofuran, toluene, ethyl acetate, and acetate. Tonitrile, tetrahydrofuran, dioxane, 1,2-dimethoxetane, benzene, tonolen, xylene, dimethinolehonolemamide, dimethinorea cetamide, N-methylpyrrolidone, methanol, ethanol , N-propanol, isopropyl alcohol and the like can be used alone or in combination.
  • condensing agent examples include hexylcarbodiimide, diisopropinorecanolevodiimide, N-ethynole N ′ — (3-dimethinoleaminopropyl) carbodiimid or its hydrochloride, and benzotriazole.
  • hexylcarbodiimide diisopropinorecanolevodiimide
  • benzotriazole 1 Innorate tris (dimethylamino) phosphonium hexafenole phosphide salt, diphenylphosphoryl azide, etc. are used. Among them, N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide or its Hydrochloride is preferred. This reaction is carried out in the presence of
  • N-hydroxysuccinic acid imide for example, N-hydroxysuccinic acid imide, 1-hydroxybenzotriazolone, 3-hydroxy-14-oxo-13,4-dihydro-1,2,3-benzotriazine, etc. are used. And 1-hydroxybenzotriazole is particularly preferred.
  • a corresponding reactive equivalent of carboxylic acid (IX) for example, acid chloride of carboxylic acid (IX), active ester or mixed acid anhydride is used in place of carboxylic acid (IX).
  • Compound (V) can also be obtained by reacting with compound (VIII) in a solvent inert to the reaction or in the absence of a solvent in the presence or absence of a base.
  • the solvent inert to the reaction may be any solvent as long as it is inert to the reaction, and is not particularly limited.
  • examples thereof include dichloromethane, chloroform, tetrahydrofuran, dioxane, tonoleene, ethyl acetate, and ethyl acetate.
  • Cetonitrinole, pyridine and the like are used, and among them, dichloromethane or tetrahydrofuran is preferable.
  • the base examples include organic bases such as triethylamine, pyridine, diisopropylethylamine, and dimethylaminopyridine, and bases supported on a solid phase such as diisopropylaminoaminomethylpolystyrene, polyvinylinolepyridine, and monorefolinomethylpolystyrene.
  • organic bases such as triethylamine, pyridine, diisopropylethylamine, and dimethylaminopyridine
  • bases supported on a solid phase such as diisopropylaminoaminomethylpolystyrene, polyvinylinolepyridine, and monorefolinomethylpolystyrene.
  • triethylamine or pyridine is preferable, and when the reaction is carried out by a parallel synthesis method (such as Combinatorial Real Chemistry), diisopropylaminomethylpolystyrene is preferable.
  • P 2a represents a lower alkyloxycarbonyl (the lower alkyl has the same meaning as the above lower alkyl (i)), a protecting group for an amino group such as benzyl, and m, n, RR 4 , R 5 , R 6 , R 7 , R 8 and P 1 are as defined above, respectively.
  • Compound (X) can be used, for example, by Protective Groups in Organic Synthesis, third edition, TW Greene, John-Willie-Ayer, Protective Groups in Organic Synthesis, third edition.
  • Compound (XI) was obtained by deprotecting the amino-protecting group described in John Wiley & Sons Inc. (1999), etc. Obtainable.
  • the solvent inert to the reaction is not particularly limited as long as it is inert to the reaction.
  • the solvent include, but are not limited to, dichloromethane, Holm, tetrahydrofuran, toluene, ethyl acetate, acetate nitrinole, tetrahydrofuran, dioxane, 1,2-dimethoxetane, benzene, tonolen, xylene, dimethinolehonolemamide, Dimethinoleacetamide, N-methylpyrrolidone, methanol, ethanol, N-propanol, isopropyl alcohol, etc. can be used alone or in combination.
  • the solvent inert to the reaction is not particularly limited as long as it is inert to the reaction.
  • the solvent include, but are not limited to, dichloromethane, Form, tetrahydrofuran, dioxane, toluene, ethynole acetate, acetonitrile, pyridine and the like can be used alone or as a mixture thereof. Of these, dichloromethane or tetrahydrofuran is preferable.
  • the reaction is carried out at a temperature between 0 ° C and 100 ° C, preferably at a temperature between room temperature and 80 ° C, and is usually completed in 5 minutes to 48 hours.
  • Vl lb can be obtained by the method shown below.
  • the solvent inert to the reaction may be any solvent as long as it is inert to the reaction, and is not particularly limited. Examples thereof include water, methanol, ethanol, tetrahydrofuran, dioxane, and dimethinolefo. / Remamide, dimethylsulfoxide, N-methylbiperidone and the like can be used alone or as a mixture thereof.
  • the base is, for example, an inorganic base such as potassium carbonate or sodium hydride, an organic base such as triethylamine, pyridine, etc., a solid support such as diisopropylaminomethylpolystyrene, polyvinylinolepyridine, monorefolinomethylinopolystyrene, or the like.
  • Triethylamine or pyridine is preferred, and when the reaction is carried out by a parallel synthesis method (such as combinatorial chemistry), diisopropylaminomethylpolyethylene is preferred.
  • Styrene is preferred.
  • the reaction is carried out at a temperature between 0 ° C and 150 ° C, preferably at a temperature between room temperature and 80 ° C, and is usually completed in 5 minutes to 48 hours.
  • Compound (VIIc) is prepared by reacting compound (XI) obtained in Step 6 with a solvent inert to the reaction in an amount of 1 to 10 equivalents of R le X 2 e (where R le is as defined above). And X 2c has the same meaning as X described above) in the presence or absence of 1 to 15 equivalents of a base.
  • the solvent inert to the reaction may be any solvent as long as it is inert to the reaction, and is not particularly limited. Examples thereof include acetone, tetrahydrofuran, dioxane, dimethylformamide, and dimethylsulfonic acid. Oxide, N-methylbiperidone and the like can be used alone or in combination, and tetrahydrofuran is particularly preferred.
  • the base examples include solid bases such as inorganic carbonates such as potassium carbonate and sodium hydride, organic bases such as triethylamine and pyridin, and solid phases such as diisopropylaminomethylpolystyrene, polyvinylpyridine and monorefolinomethylpolystyrene.
  • solid bases such as inorganic carbonates such as potassium carbonate and sodium hydride
  • organic bases such as triethylamine and pyridin
  • solid phases such as diisopropylaminomethylpolystyrene, polyvinylpyridine and monorefolinomethylpolystyrene.
  • a supported base or the like is used, and potassium carbonate or sodium hydride is particularly preferable.
  • diisopropylaminomethylpolystyrene is used. Is preferred.
  • the reaction is carried out at a temperature between 0 ° C and 150 ° C, preferably at a temperature between room temperature and 80 ° C, and is usually completed in about 5 minutes to 48 hours.
  • Is a CH 2 R ld (wherein R ld represents a group obtained by removing one terminal CH 2 — from substituted or unsubstituted lower alkyl in the definition of R 1 above) Vld) can also be obtained by the following method.
  • the compound (Vl ld) is obtained by converting the compound (XI) obtained in the step 6 into a solvent inert to the reaction in the presence of 1 to 10 equivalents of a reducing agent, 1 to 3 equivalents of R ld CH0 (where R ld Has the same meaning as described above).
  • the solvent inert to the reaction may be any solvent as long as it is inert to the reaction, and is not particularly limited.
  • examples thereof include methanol, ethanol, dichloromethane, chlorophonolem, dichloroethane, tetrahydrofuran, dioxane, and Chinore Ethenore, Jii Sopropinore Ethenore, Ben Zen, tonolen, xylene, dimethylformamide and the like can be used alone or in combination.
  • methanol or tetrahydrofuran is preferable.
  • reducing agent for example, sodium triacetoxyborohydride, sodium borohydride, sodium cyanoborohydride or the like is used, and among others, sodium triacetoxyborohydride is used. Um is preferred.
  • the reaction is carried out at a temperature between 0 ° C and 100 ° C, preferably at a temperature between 0 ° C and 50 ° C, and is usually completed in about 5 minutes to 48 hours.
  • Compound (XIV) can be obtained by reacting compound (XI I) with 1-3 equivalents of (XI II) in a solvent inert to the reaction in the presence of 1-10 equivalents of a reducing agent. it can.
  • the solvent inert to the reaction may be any solvent as long as it is inert to the reaction, and is not particularly limited.
  • examples thereof include methanol, ethanol, dichloromethane, chlorophonolem, dichloroethane, tetrahydrofuran, dioxane, and geloxane. It is possible to use tyl ether, disopropinolate ether, benzene, toluene, xylene, dimethylformamide or the like singly or as a mixture thereof, and among them, methanol or tetrahydrofuran is preferable.
  • sodium triacetoxyborohydride sodium borohydride, sodium cyanoborohydride and the like are used, and among them, sodium triacetoxyborohydride is used. Pum is preferred.
  • This reaction can be carried out in the presence of molecular sieves, if necessary.
  • the reaction is carried out at a temperature between 0 ° C and 100 ° C, preferably at a temperature between 0 ° C and 50 ° C, and is usually completed in 5 minutes to 48 hours.
  • the compound (XII) for example, a compound synthesized according to the method described in W099 / 10312 or the like can be arbitrarily used.
  • the compound (XIII) for example, those synthesized according to the method described in Tetrahedron-Letters (Tetrahedron Lett.), Vol. 41, p. 6309 (2000) and the like can be used arbitrarily.
  • Compound (Va) can be obtained by treating compound (XIV) obtained in step 11 with 1 to 10 equivalents of a base in a solvent inert to the reaction.
  • the solvent inert to the reaction may be any solvent as long as it is inert to the reaction, and is not particularly limited. Examples thereof include acetone and tetrahydro. Furan, dioxane, dimethinolehonoremamide, dimethi / resluoxide,
  • N-methylbiperidone or the like can be used alone or as a mixture thereof, and among them, tetrahydrofuran is preferable.
  • lithium carbonate, triethylamine, pyridine, sodium hydride and the like are used, and among them, potassium carbonate or sodium hydride is preferable.
  • the reaction is carried out at a temperature between 0 ° C and 150 ° C, preferably at a temperature between room temperature and 80 ° C, and is usually completed in 5 minutes to 48 hours.
  • the compound (Vb) can be obtained by treating the compound (XVI) obtained in Step 13 in a solvent inert to the reaction in the presence of 1 to 10 equivalents of a base.
  • the solvent inert to the reaction may be any solvent that is inert to the reaction, and is not particularly limited.
  • examples include methanol, ethanol, tetrahydrofuran, dioxane, dimethinolephonolamide, Dimethinole sulfoxide, N-methylbiperidone, or the like can be used alone or in a mixture thereof, and among them, methanol or tetrahydrofuran is preferable.
  • potassium tert-butoxide sodium hydride, lithium diisopropylamide and the like are used, and among them, potassium tert-butoxide or sodium hydride is preferable.
  • the reaction is carried out at a temperature between 0 ° C and 150 ° C, preferably at a temperature between room temperature and 80 ° C, and is usually completed in 5 minutes to 48 hours.
  • P 1 may be removed to form carboxylic acid.
  • each functional group in the compound (1), the starting compound, and the intermediate compound and the conversion of the functional group contained in the substituent may be performed by a known method [eg, Comprehensive 'Organic Transformation].
  • LiR Compprehens ive Organic Transiormat ions, second edi ti on
  • RC Larock John's Wylie and And Sons, Inc. (1999)
  • the compound (I) having a desired functional group at a desired position can be obtained by appropriately combining the above methods and the like.
  • the isolation and purification of the products and intermediates in the above production method are performed by appropriately combining the methods used in ordinary organic synthesis, for example, filtration, extraction, washing, drying, concentration, crystallization, various types of chromatography, etc. It can be carried out.
  • purification methods commonly used in general parallel synthesis methods such as combinatorial chemistry
  • benzoyl-clad ride polymer bound poly (4-butylpyridine), polyamine, benzaldehyde depolymer binder
  • the purification can also be carried out by a purification method using a resin, such as a resin binder such as a lithium chloride polymer bound, for example, an ion exchange resin such as AG1-X80H-resin (manufactured by Biorad).
  • a resin such as a resin binder such as a lithium chloride polymer bound
  • an ion exchange resin such as AG1-X80H-resin (manufactured by Biorad).
  • the intermediate can be subjected to the next reaction without purification.
  • Some of the compounds (I) may have isomers such as positional isomers, geometric isomers or optical isomers, but all possible isomers including these, and mixtures of the isomers in any ratio Are also included in the compounds of the present invention.
  • the compound (I) may be purified as it is when the salt of the compound (I) is obtained, and when the compound (I) is obtained in a free form, the compound (I) May be dissolved or suspended in an appropriate solvent, and an acid or a base may be added to form a salt.
  • Compound (I) or a pharmacologically acceptable salt thereof may be present in the form of an adduct with water or various solvents (eg, ethanol, tetrahydrofuran, dioxane, etc.). Additives are also included in the compounds of the present invention.
  • Me represents methyl
  • Et represents ethynole
  • Ph represents phenyl
  • Ac represents acetyl
  • Test Example 1 VLA-4 / VCAM-1 binding inhibition (cell adhesion inhibition) test
  • the recombinant solubl e VCAM-1 (R & D System) was adjusted to a concentration of 0.25 g / mL with 50 mmol / L sodium phosphate buffer (PBS, pH 6.0). 50 ZL per well was dispensed into a well titer plate and left overnight at 4 ° C (immobilization of VCAM-1). After removing the supernatant from the solution in each of the dispensed wells and washing once with 100 L of PBS per well, the test drug solution diluted with RPMI-1640 medium (Sigma) was added at 90 ⁇ l / well. L was added.
  • Human cell line Jurkat (ATCC, TIB-152), which is known to express VLA-4, was cultured in RPMI-1640 medium (Sigma) at 2 x 10 7 eel 1 s / mL. The concentration was adjusted to 10 / zL per well. After attaching these cells for 1 hour at 37 ° C (adhering by VLA-4 / VCAM-1 binding), wash the plate with RPMI-1640 medium (Gibco, without phenolic red) and remove the plate. Cells were removed.
  • VCAM-1 non-immobilized group The group in which Jurkat cells were overlaid without immobilizing VCAM-1 (VCAM-1 non-immobilized group) was used as the background.
  • concentration of the compound that inhibits cell adhesion by 50% was calculated as the 50% inhibitory concentration using the All Fit 205 formula of Excel Fit.
  • Cell adhesion inhibition rate (%)
  • Test example 2 LPAM-1 / VCAM-1 binding inhibition test
  • B cell line JY (ECACC, 94022533) was assayed at 2 x 10 7 cells / mL using Assay , And 10 L per well was dispensed. After allowing these cells to adhere at 37 ° C for 30 minutes, the plate was washed with RPMI-1640 medium (without phenol red) to remove non-adherent cells. Here 50 L of XTT solution per hole
  • the medicament of the present invention comprises, as an active ingredient, compound (I) and a pharmacologically acceptable salt thereof, and a substance selected from the group consisting of hydrates and solvates thereof.
  • compound (I) as an active ingredient may be administered alone as it is, but generally, compound (I) as an active ingredient and one or more pharmaceutical additives are added. It is desirable to administer in the form of a pharmaceutical composition containing
  • the pharmaceutical composition according to the present invention contains the compound (I) or a pharmaceutically acceptable salt thereof alone or as a mixture with any other active ingredient for treatment as an active ingredient.
  • these pharmaceutical compositions are prepared by mixing the active ingredient with one or more pharmacologically acceptable carriers and by any method well-known in the technical field of pharmaceuticals.
  • the medicament of the present invention may be used for mammals including humans. Applicable to animals.
  • the administration route of the medicament of the present invention is not particularly limited, and the most effective administration route for treatment or prevention can be appropriately selected from either oral or parenteral administration such as intravenous administration. .
  • liquid preparations suitable for oral administration includes, for example, water, sucrose, sorbitol, fructose and other sugars, polyethylene glycol, propylene glycol and other daricols, sesame oil, olive oil, soybean oil and other oils.
  • preservatives such as P-hydroxybenzoic acid esters, and flavoring additives such as flavors such as strawberry flavors and ⁇ permeants.
  • excipients such as lactose and mannite, disintegrants such as starch, lubricating agents such as magnesium stearate, binders such as polybutylanololecol, hydroxypropyl selenololose, lunar fatty acid esters, etc.
  • Surfactants, plasticizers such as glycerin and the like can be used.
  • preparations suitable for parenteral administration can be preferably prepared using an aqueous medium isotonic with human blood.
  • an injection is prepared by using an aqueous medium selected from a salt solution, a solution of budsugar, and a mixture of saline and a solution of pudose, and forming a solution, suspension or dispersion together with a suitable auxiliary according to a conventional method.
  • a preparation for parenteral administration for example, one or two selected from diluents, fragrances, preservatives, excipients, disintegrants, lubricants, binders, surfactants, plasticizers, etc.
  • the above pharmaceutical additives can be used.
  • the dose and frequency of administration of the medicament of the present invention are not particularly limited, and the kind of the above-mentioned substance as an active ingredient, the administration route, the purpose of treatment and Z or prevention, the age and weight of the patient, the nature and severity of symptoms, etc. It can be appropriately selected according to the various conditions. For example, it is preferable to administer 1 to 50 mgZ kg per adult in 3 to 4 divided doses. However, the dose and the number of administrations vary depending on the various conditions described above.
  • N- (3,5-dioctanol benzenesulfoninole) 1-L-prolinole_L-tyrosine tert-butyl obtained according to the method described in W099 / 06390 in the same manner as in Reference Example 1. Luster ester 'to give the title compound.
  • N- (tert-ptoxycarpinorenole) _ O— (tri-frenoleolofumetans-norefonyl) obtained according to the method described in W099 / 36393—L-tyrosin-methinole ester (5.0 g, 12 mraol) and 1 —Feninolepiperazine (2.3 g, 14 trnnol) is dissolved in tetrahydrofuran (50 mL), and cesium carbonate (5.3 g, 16 mmol), 2- [di (tert-butinole) phosphino] bifeninole (263 mg) , 0.88 ramol) and tris (dibenzylideneacetone) dipalladium (266 mg, 0.29 mmol) were added, and the mixture was stirred at 60 ° C for 3 hours.
  • N- (tert-butoxycarbonyl) -14- (4-pheninolepiperazine-11-yl) -1-L-phenylinolealanine methinoester obtained in step 1 (2.4 g, 5.5 mmol) was added to dichloromethane.
  • the residue was dissolved in methane (40 mL), and trif-noroacetic acid (15 mL) was added, followed by stirring at room temperature for 30 minutes.
  • the reaction solution was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate. This solution was added to a saturated aqueous solution of sodium bicarbonate, and after liquid separation, the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
  • the solvent was distilled off to obtain the title compound as colorless crystals in 99% (1.8 g, 5.4 mmol).
  • N— (tert-butoxycarbonyl) —O— (tri-frenoleolomethane tansolehoninole) _ L-tyrosine Methinoleestenole and benzinolepiperazine were converted to N— ( tert-Butoxyka noreponinole) -4- (4-benzinolepiperazine-1-1-inole) 1-L-pheniralanine methyl ester was obtained.
  • the obtained compound was dissolved in methanol (150 mL) and heated under reflux for 1 hour.
  • the reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
  • the solvent was distilled off, and the title compound as colorless crystals was 78 ° /. (7.7 g, 21.2 mraol).
  • the methyl N-aryl-N-phenylaminoacetate (4.0 g, 19 mmol) obtained in Step 1 was dissolved in tetrahydrofuran (30 mL) and cooled to -78 ° C. The mixture was added to lithium hexamethyldisilazide (29% tetrahydrofuran solution, 55 m, 95 mmol) and stirred for 30 minutes. Thereafter, iodomethane (5.9 mL, 95 mmol) was added, and the mixture was stirred at 0 ° C for 30 minutes.
  • Methinole 2- (N-phenylene-N-phenylamino) -2-methinolepropionate (2.4 g, 10 mmol) obtained in Step 2 was added to 25 mL of tetrahydrofuran and 25 mL of water. After dissolving in a mixed solvent, the mixture was cooled to 0 ° C, and osmium tetroxide (25 mg, 0.10 mmol) was added thereto, followed by stirring. Sodium meta-periodate (4.36 g, 20 mmol) was added over 40 minutes, and the mixture was stirred at room temperature for 2 hours.
  • Example 3 7 N— (toluene-4-1-sulfol) _L—prolyl 4- (4-methylinolehomopirazine-1-1-inole) 1-L-pheninoleanine A method similar to that in Example 1 was used. The title compound was obtained from compound a obtained in Reference Example 1 and 1-methylhomopirazine.
  • Example 39 N— (3, 5 —Jik Mouth Mouth Benzenesulfonyl) One Loop Mouth Linolee 4-1 [4-1 (2-Cyano-Feninole) Piperazine-1 1-Innole] 1 L-Fenylalanine
  • Example 40 N-benzenesulfonyl L-prolyl-1 41- (3-oxo-1 4-pheninolepiperazine-1 1-inole) 1-L-phenylenoleanine
  • a reference example was prepared. The title compound was obtained from compound b obtained in 2 and 11-phenylbiperazin-1-one.
  • step 1-4-1 (4-pheninolepiperazine-1-isle) -L-pheninoleranine methinolle stenole (1.1 g, 2.1 mmol) was added to te Tora hydrofuran (20 mL) and methanol
  • Trifluoroacetic acid (0.25 mL, 3.24 mmol) and dichloromethane (0.25 ml) were added to the compound (Vile) obtained in Step 1, and the mixture was stirred at room temperature for 5 hours. After the solvent and trifluoroacetic acid were distilled off, a dioxane solution of hydrogen chloride (4 raol / L, 0.5 ml) was obtained.
  • R le has the same meaning as described above, and R 2e is a group selected from the groups described in Table 2 above.
  • the compound (Vllle) obtained in Step 2 was dissolved in tetrahydrofuran (0.50 mL), and a solution of R 2e -C0C1 (where R 2e has the same meaning as described above) in a crotchform solution (1.0 mol / mol) L, 0.075 mL, 0.075 mol) and diisopropynoleaminomethyl polystyrene (33 mg) were added, and the mixture was closed and stirred at room temperature for 12 hours. Polyamine (33 mg) and porcine (0.20 mL) were added to the reaction solution, and the mixture was tightly closed and stirred at room temperature. The resin in the reaction mixture was filtered off, and the solvent was distilled off.
  • Example 380 N- (4-force benzoylone 2, 6-cyclobenzene) —4— (4 methinoresolephinolepiperazine-1—y / le) —L—fe Ninorealanine
  • N_ [2,6-dichloro-4-1 (1,3— Dioxane-1- (benzoyl) benzoinole]-4-(4-dimethinoresnolehoninolepiperazine-11-inole) -1-L-phenyl-2-alanine methyl ester was obtained in 82% (254 mg, 0.403 mmol).
  • Step 1 The compound (254 mg, 0.403 mmol) obtained in Step 1 was dissolved in acetone (10 mL), 6 mol / L hydrochloric acid (5 mL) was added, and the mixture was stirred at room temperature for 4 hours. 4 mol / L sodium hydroxide aqueous solution is added for neutralization, and then a saturated sodium hydrogen carbonate aqueous solution and ethyl acetate are added. The organic layer is extracted twice, washed with saturated saline, and then dried. Dried over magnesium sulfate.
  • the compound (188 rag, 0.306 mmol) obtained in Step 2 was dissolved in methanol (5 raL), and hydroxylated water (52 mg, 0.918 mmol) and iodine (58 mg, 0.459 mmol) were added, and the mixture was added at room temperature. Stir for 2 hours. An aqueous solution of ammonium chloride and ethyl acetate were added, and the organic layer was extracted twice, washed with saturated saline, and dried over anhydrous magnesium sulfate.
  • N— (2,6—dichloro_4-metoxcanolepotinolebenzinole) -4-1 (4-dimethinole-sulfoninolepiperazine-1-1-inole) -fueninoreaen Methiorene stenole was obtained at 60 ⁇ / ⁇ (114 mg, 0.216 mmol).
  • Step 3 The compound obtained in Step 3 (7 ⁇ .7 mg, 0.119 mmol) was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and water (3 ml), and lithium hydroxide monohydrate (51.0 mg, 1.22 mmol) and stirred at room temperature for 5 hours.
  • the solution was acidified by adding 1 mol / L hydrochloric acid, and ethyl acetate was added.
  • the organic layer was extracted twice and dried over anhydrous magnesium sulfate.
  • N_ (4,6,6-dichlorobenzoinole) -1,4- (4-dimethinole snorehoninolepiperazine-1-1, -inole) 1 L-phenylenolealanine is reduced by 67%. (49.6 mg, 0.0865 mmol) were obtained.
  • Example 3 92 3—Amino-N— (2,6-cyclobenzoyl) 1-4- (4 pheninolepiperazine-1 1-inole) 1-L-pheninolealanine Step 1
  • Example 3 86—N— (2,6-dichlorobenzene) obtained in step 1 of step 1—3—2 1—4—1 (4—1 feninolebiperazine—1—inole) 1 L Dissolve 1-phenylalanineethyl ester (3.00 g, 5.25 mmol) in a mixed solvent of concentrated hydrochloric acid (10 mL) and methanol (40 mL), and add zinc (3.00 g, 46.2 mmol) at room temperature for 1 hour. Stirred. Aqueous ammonia was added to the reaction solution, and the mixture was extracted with a porcelain form. The organic layer was dried over anhydrous magnesium sulfate.
  • Example 3 96 3-bromo-N- (2,6-cyclobenzoyl) 1-4- (4-pheninolebiperazine-1-1-inole) 1 L-phenylenolaene Step 1
  • Example 400 N- (2,6-Dichlorobenzoinole) -4- (4-Ninolebiperazine-1-1-inole) -3- (Pyro-1-inole-1-inole) 1-L-pheninoleanine
  • Example 40 3 N- (2,6-Dicyclobenzoyl) -1 3-Dimethylamino 1 4— (3,3—Dimethylyl 4—Feninolebiperazine-1 1) L—Feninorearaen
  • reaction solution was concentrated, ethyl acetate was added to the obtained residue, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off. Methanol (4 mL) and tetrahydrofuran (4 mL) were added to and dissolved in the obtained residue, and a 5% aqueous lithium hydroxide solution (4 mL) was added, followed by stirring at room temperature for 4 hours.
  • Example 404 was synthesized as Example 400 in the same manner as in Example 400. Done. Proton nuclear magnetic resonance spectrum data of the obtained compound was
  • Example 4 05 3-Chloro N— [2,6-Dichloro 4 -— (Tetrazo 1-5-inole) Benzoinole] —4 _ [4— (3,5-dichloropheninole) [Piperazine-1—inole] one L one phenylenalanine
  • Step 1 The compound (423 tng, 0.636 mmol) obtained in Step 1 was dissolved in methanol (5 ml), concentrated hydrochloric acid (1 ml) and zinc / copper powder (426 mg) were added, and the mixture was stirred at room temperature for 2 hours. Under ice-cooling, add sodium nitrite (65.6 rag,
  • Nobenzoinole) 1-4_ [4— (3,5-dichloropheninole) piperazine-11-inole] —L-fuyuanolerana ninnetinole ester was obtained in 29% (119 mg, 0.182 mmol).
  • the compound (127 mg, 0.182 mmol) obtained in Step 3 was dissolved in a mixed solvent of tetrahydrofuran (5 ml) and water (3 ml), and lithium hydroxide monohydrate (61.0 rag, 1.45 nrnol ) And stirred at room temperature for 7 hours. After concentrating the reaction solution, acetic acid was added to the obtained residue, and the generated crystals were collected by filtration to obtain the title compound at 81% (98.4 rag, 0.147 ramol).
  • Example 4 06 N— (2, 6-dichloro) Mouth benzoinole)-4-(3,3-Dimethinolee 2-oxo-41-pheninolepiperazine-1 1-yl) One L-pheninoleanine.
  • Example 406 In the same manner as in Example 406, from the compound synthesized according to the method of Reference Example 7, the compound 407 to 424 was obtained as Examples 407 to 424. Synthesized.
  • the proton nuclear magnetic resonance spectrum data of the obtained compound is shown in Table 8 below.
  • a tablet having the following composition is prepared by a conventional method.
  • the present invention is useful as a 4-integrin inhibitor, and various diseases involving an adhesion mechanism via a4-integrin (eg, multiple sclerosis, asthma, inflammatory bowel disease) Disease, rheumatoid arthritis, diabetes, tumor metastasis, arteriosclerosis, atopic dermatitis, nephritis, psoriasis, myocardial ischemia, cell rejection during organ transplantation, etc.
  • a phenylalanine derivative or a pharmaceutically acceptable one thereof is provided.

Abstract

L'invention concerne un dérivé de phénylalanine représenté par la formule (I) (dans laquelle m et n sont identiques ou différents et chacun est 1 ou 2; R2 représente un alkyle inférieur (non) substitué, etc.; R1 représente un alkyle inférieur (non) substitué, etc.; et R3, R4, R5 et R6 sont identiques ou différents et chacun est hydrogène, un alkyle inférieur (non) substitué, oxo, etc.), ou un sel acceptable d'un point de vue pharmaceutique du dérivé, utilisés en tant qu'inhibiteurs de l'intégrine α4.
PCT/JP2003/004970 2002-04-19 2003-04-18 Derive de phenylalanine WO2003089410A1 (fr)

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