WO1999040063A1 - Nouveaux derives de l'acide hydroxamique de type azapeptide - Google Patents

Nouveaux derives de l'acide hydroxamique de type azapeptide Download PDF

Info

Publication number
WO1999040063A1
WO1999040063A1 PCT/JP1999/000439 JP9900439W WO9940063A1 WO 1999040063 A1 WO1999040063 A1 WO 1999040063A1 JP 9900439 W JP9900439 W JP 9900439W WO 9940063 A1 WO9940063 A1 WO 9940063A1
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
alkyl
isobutyl
tert
nmr
Prior art date
Application number
PCT/JP1999/000439
Other languages
English (en)
Japanese (ja)
Inventor
Naoki Sugiyama
Tomohiro Yoshida
Shinji Takeda
Kazuhiro Maeda
Tomokazu Gotou
Tadahiro Takemoto
Original Assignee
Yoshitomi Pharmaceutical Industries, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yoshitomi Pharmaceutical Industries, Ltd. filed Critical Yoshitomi Pharmaceutical Industries, Ltd.
Priority to AU22983/99A priority Critical patent/AU2298399A/en
Publication of WO1999040063A1 publication Critical patent/WO1999040063A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
    • C07D233/78—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a novel azapeptide-type hydroxamic acid derivative or a pharmacologically acceptable salt thereof. More specifically, the present invention relates to an azapeptide-type hydroxamic acid derivative or a pharmacologically acceptable salt thereof, which is useful as a production inhibitor of tumor cell necrosis factor (TNFa: tumor necrosis factor ⁇ ). The present invention also relates to a novel intermediate compound useful for synthesizing the azapeptide-type hydroxamic acid derivative.
  • TNF ⁇ is known as a cytokine that is widely involved in the defense of the body during inflammation and the activation of the immune system, while its continuous and excessive production is represented by multiple organ failure (MOF). It is also known to cause and hate various diseases associated with organ damage.
  • MOFs can be used during multiple major invasions (post major surgery, severe trauma, burns, acute inflammation, severe infectious diseases, etc.) during the course of multiple lungs, heart, kidney, liver, central nervous system, blood coagulation, etc. It is understood as a dysfunction that appears simultaneously or continuously in vital organs. MOF is a prominent example of a refractory disease that has a poor prognosis in proportion to the number of dysfunctional organs and a very high mortality rate, but has not yet established a cure for it. .
  • MMP matrix metalloproteinase
  • the present invention has been made based on the background art as described above, and its object is to provide a novel azapeptide-type hydroxamic acid derivative useful as a TNF ⁇ production inhibitor or a pharmacologically acceptable derivative thereof. To provide salt.
  • Another object of the present invention is to provide a novel intermediate compound useful for the synthesis of the compound.
  • the present invention provides a compound represented by the formula (I):
  • X represents hydrogen or a protecting group for a hydroxyl group
  • R 1 represents hydrogen, a hydroxyl group, amino, mercapto, alkoxy, optionally substituted alkyl, alkenyl, optionally substituted aryl, or — ( CH 2 ) k — A
  • k is an integer of any one of 1 to 4, and A is (a) linked by an N atom, and (b) as a further hetero atom at a position not adjacent to the bonded N atom.
  • N- May contain at least one atom selected from N, 0 and S, (c) with respect to one or both C atoms adjacent to the bonded N atom, substituted by oxo, and (d) benzo May be fused or substituted for one or more other C atoms by lower alkyl or oxo, and for Z or another N atom may be substituted by lower alkyl or phenyl.
  • N- shows a representative] heterocyclic ring
  • R 2 represents hydrogen, an optionally ⁇ Li Ichiru be alkyl or substituted optionally substituted
  • R 3 is hydrogen, optionally substituted Alkyl, optionally substituted aryl, optionally substituted heteroaryl or R 11
  • R 11 represents hydrogen or an optionally substituted alkyl
  • Y represents —C ⁇ 2 R 12 , one C ⁇ NR 12 R 12 ′ or one COR 12
  • R 12 and R 12 ′ are the same or Each represents hydrogen, an optionally substituted alkyl or an optionally substituted aryl, wherein R 12 and R 12 ′ may be substituted together with an adjacent nitrogen atom.
  • M may represent 0 or 1
  • n represents an integer of 0 to 4
  • R 4 may be substituted Good alkyl, optionally substituted aryl, optionally substituted heteroaryl, one SO 2 R 12 , -CO- (CH 2 ) q _NR 12 R 12 '
  • ⁇ q represents 1 or 2
  • R 12 and R 12 ′ are as defined above ⁇
  • -CONH-Z-R 13 ⁇ Z represents alkylene having 2 to 4 carbon atoms
  • R 13 represents a hydroxyl group, amino or NR 12 R 12 '[R 12 and R 12 ' are as defined above]] or
  • R ", Y, m and ⁇ are the same as defined above), and R 3 and R 4 together with an adjacent nitrogen atom represent a heterocycle which may be substituted. May be formed], or a pharmaceutically acceptable salt thereof.
  • R 1 represents hydrogen, a hydroxyl group, amino, mercapto, alkoxy, optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted Good heteroarylthioalkyl, optionally substituted arylthioalkyl, optionally substituted phthalimidalkyl, alkenyl, optionally substituted aryl, or 1 (CH 2 ) k —A (k Is
  • A is any integer from 1 to 4, and A is i
  • R 8 and R 9 each represent hydrogen or together form another bond to form a double bond
  • R 1 ⁇ represents hydrogen, lower alkyl or phenyl
  • X ′ represents —C 0 —, — CH 2 —, —CH (R 19 ) one, one C (R 19 ) 2 one, — NH —, —N (R 19 ) one or one 0—
  • Y ′ is —0—,- NH— or —N (R 18 ) —
  • R 19 represents lower alkyl
  • R 2 represents hydrogen, alkyl which may be substituted
  • R 11 is hydrogen, alkyl optionally substituted, optionally substituted ⁇ reel alkyl represents an alkyl thio alkyl optionally substituted, Y one C 0 2 R 12, - C ONR 12 R 12 ′ or one C OR 12
  • R 12 and R 12 ′ may be the same or different and each is hydrogen, optionally substituted alkyl, optionally substituted arylalkyl, substituted Represents an optionally substituted heteroarylalkyl, an optionally substituted cycloalkyl or an optionally substituted aryl, wherein R 12 and R 12 ′ are substituted together with an adjacent nitrogen atom.
  • M represents 0 or 1
  • n represents an integer of 0 to 4
  • R 4 is a substituted or unsubstituted group.
  • Good kill may be replaced Arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted heteroaryl, - S0 2 R 12, -CO- (CH 2) q - NR 12 R 12 ' ⁇ q represents 1 or 2, R 12 and R 12' as defined above is ⁇ , -C ONH-ZR 13
  • ⁇ Z represents an alkylene having 2 to 4 carbon atoms
  • R 13 represents a hydroxyl group, amino or one NR 12 R 12 ′ [R 12 and R 12 ′ are as defined above] ⁇ or
  • the present invention also relates to the above-mentioned azapeptide hydroxamic acid derivative or a pharmacologically acceptable salt thereof.
  • the present invention provides a compound represented by the formula (I) wherein R 1 is a hydrogen atom or substituted. Salts that are acceptable the Azape peptide-type human Dorokisamu acid derivative or its pharmacology alkyl, in formula (I), the Azape peptide-type human R 2 is alkyl optionally substituted A droxamate derivative or a pharmacologically acceptable salt thereof, in the formula (I), wherein the azapeptide type hydroxamic acid derivative wherein R 2 is isobutyl or a pharmacologically acceptable salt thereof in the formula (I) , R 3 and the Azape peptide-type human Dorokisamu acid derivative or a pharmaceutically acceptable salt thereof wherein R 4 to form a hetero cycle to which may be connexion substitutions together with the adjacent nitrogen atom , in formula (I), also the Azape peptide type arsenate de Rokisamu acid derivative to form a 2-O Kiso quinazolinylmethoxy or
  • R 14 represents hydrogen, optionally substituted alkyl or optionally substituted aryl
  • Is a double bond represents CH 2
  • R 2 represents hydrogen, an optionally substituted alkyl or an optionally substituted aryl
  • R S represents hydrogen, an optionally substituted alkyl, Optionally substituted aryl, optionally substituted heteroaryl or
  • R 11 represents hydrogen or an optionally substituted alkyl
  • Y represents one C 0 2 R 12 , -CONR , 2 R 12 ′ or —COR 12 and R 12 ′ are the same or different.
  • Each represents hydrogen, an optionally substituted alkyl or an optionally substituted aryl, wherein R 12 and R 12 ′ are an optionally substituted heterocycle together with an adjacent nitrogen atom.
  • M represents 0 or 1
  • n represents an integer of 0 to 4
  • R 4 represents an optionally substituted alkyl, substituted is optionally Ariru, heteroaryl optionally substituted one S0 2 R 12, - CO- ( CH 2) q -NR 1 R 12 '
  • ⁇ Q represents 1 or 2
  • R 12 and R 12 ′ have the same meanings as defined above.
  • -CONH-Z-R 13 Z represents an alkylene having 2 to 4 carbon atoms, R 13 represents a hydroxyl group, amino or NR 12 R 12 '[R 12 and R 12 ' are as defined above]] or
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an azapeptide-type hydroxamic acid derivative represented by the formula (I) or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable carrier, and a medicament thereof.
  • the alkoxy in R 1 and R 15 preferably has 1 to 6 carbon atoms and may be linear or branched.
  • the optionally substituted alkyl in R 1 and R 15 is alkyl, arylalkyl, heteroarylthioalkyl, arylthioalkyl, phthalimidalkyl, and one or more, preferably from 1 to 3 each. May be substituted by a number of substituents.
  • the alkyl preferably has 1 to 10 carbon atoms and may be linear or branched.
  • An arylalkyl is preferably an alkyl moiety having 1 to 6 carbon atoms, which may be straight-chain or branched, and an aryl moiety preferably having a biaryl fused with fuunyl, naphthyl, or ortho-fused.
  • Examples of the group of the formula include those having from 8 to 10 ring atoms and at least one ring being an aromatic ring (for example, indenyl).
  • Heteroarylthioalkyl means that the alkyl portion thereof is preferably a straight-chain or branched chain having 1 to 6 carbon atoms, and the heteroaryl portion is preferably a carbon atom and 1 to 4 hetero atoms.
  • heteroaryl group examples include pyrrolyl, pyrrolinyl, furyl, phenyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, 1,3,4-oxaziazolyl, 1,2,4- Oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, bilanyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2.4-triazinyl, 1,2,3-triazinyl, 1,3 , 5—Triazinyl, 1,2,5-year-old xiathiazinyl, 1,2,6-oxathiazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, tianaphthenyl, isothianaphth
  • heteroarylthioalkyl examples include 2-pyrrolylthiomethyl, 2-pyridylthiomethyl, 3-pyridylthiomethyl, 4-pyridylthiomethyl, 2-chernylthiomethyl, 2- (2-pyridyl) thioethyl And 2- (3-pyridyl) thioethyl, 2- (4-pyridyl) thioethyl, 3- (2-pyrrolyl) thiopropyl and the like.
  • the arylthioalkyl means that the alkyl portion thereof preferably has 1 to 6 carbon atoms and may be linear or branched, and the aryl portion is the same as described above. Specifically, phenylthiomethyl, 3-phenylthiopropyl, 1-naphthylthiomethyl, 2 Mono-naphthylthiomethyl, 2- (1-naphthyl) thioethyl, 2- (2-naphthyl) thioethyl, 3- (1-naphthyl) thiopropyl, 3- (2-naphthyl) thiol pill and the like.
  • the alkyl moiety of the phthalimidalkyl preferably has 1 to 6 carbon atoms and may be linear or branched. Specifically, phthalimidmethyl, 2-phthalimidethyl and the like can be mentioned.
  • the optionally substituted alkyl in R 1 and R 15 is, for example, amino, halogen (fluorine, chlorine, bromine, iodine), hydroxyl, nitro, cyano, trifluoromethyl, lower alkyl (however, alkyl or aryl)
  • the alkyl moiety of alkyl, heteroarylthioalkyl, arylthioalkyl, phthalimidalkyl is not substituted), alkoxy, alkylthio, formyl, acyloxy, oxo, phenyl, arylalkyl, carboxyl, hydroxysulfo.
  • N aminosulfonyl, hydroxysulfonyloxy, alkoxycarbonyl, alkamoyl, arylalkyloxy, alkylaminoalkoxy, etc., even if substituted with one or more, preferably 1 to 3 substituents.
  • Yo aminosulfonyl, hydroxysulfonyloxy, alkoxycarbonyl, alkamoyl, arylalkyloxy, alkylaminoalkoxy, etc.
  • alkoxy and arylalkyl are the same as above.
  • Lower alkyl means a straight or branched chain having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isoptyl, sec-butyl, tert-butyl, n-pentyl, Examples include isopentyl, neopentyl, n-hexyl and the like.
  • the alkyl moiety thereof preferably has 1 to 6 carbon atoms and may be linear or branched, and examples thereof include methylthio, ethylthio, n-propylthio, and isopropylthio.
  • the acyloxy is preferably a linear or branched one having 1 to 6 carbon atoms, and examples thereof include alkanoyloxy such as acetyloxy, propionyloxy, petyriloxy, valeryloxy, bivaloyoxy, and hexanoyloxy.
  • Alkoxycarbonyl is represented by one COOR a, and Ra represents lower alkyl (as above) or arylalkyl (as above).
  • the arylalkyl part in arylalkyloxy is the above aryl JP
  • Alkylaminoalkoxy includes N-alkylaminoalkoxy and N, N-dialkylaminoalkoxy, the alkyl part of which preferably has 1 to 6 carbon atoms and may be straight-chain or branched, and the alkoxy part is preferably May have 1 to 6 carbon atoms and may be linear or branched.
  • methylaminomethoxy dimethylaminomethoxy, ethylmethylaminomethoxy, 2-methylaminoethoxy, 2-dimethylaminoethoxy, 2-ethylmethylaminoethoxy, 3-methylaminopropoxy, 3-dimethylaminopropyl ⁇ -poxy And the like.
  • the alkenyl in R 1 and R 15 preferably has 2 to 6 carbon atoms and includes, for example, vinyl, aryl, 3-butenyl, 5-hexenyl and the like. ...
  • a in — (CH 2 ) k —A in R 1 and R 15 is an N-heterocycle linked by an N atom, and examples thereof include the following groups.
  • R 8 and R 3 each represent hydrogen or together form another bond to form a double bond
  • R 1Q represents hydrogen, lower alkyl or phenyl
  • X ′ represents — C 0-, One CH 2 -,-CH (R 19 )-, — C (R 13 ) 2 -,-NH-,-N (R 19 ) — or — 0—
  • Y and 1 are 0—, — ⁇ — Or —N (R 13 ) —
  • R ′ 9 represents lower alkyl.
  • lower alkyl is as defined above.
  • heterocyclic ring examples include, for example, 2-oxo-11-pyrrolidinyl, 110-oxoisoindolin-1-yl, 2-oxoindolin-111-yl, 2,5 —Dioxo-1-1-pyrrolidinyl, 1,2-dimethyl-1,3,5-dioxo-1,2,4-triazolidin-41-yl, 3-methyl-2,5-dioxo-1-1-imidazolidinyl, 3,4,4 1-trimethyl-1,2,5-doxoxo 1-imidazolidinyl, 2-methyl-1,3,5-dioxo1,2,4,1-oxadiazo-1-yl 4-yl, 3-methyl-2,4,5-trioxo- Examples thereof include 1-imidazolidinyl, 2,5-dioxo-l-phenyl-1-1-imidazolidinyl, and 2,6-dioxopiperidino.
  • the optionally substituted alkyl in R 2 , R 3 and R 4 is alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl.
  • Alkyl and arylalkyl are the same as the alkyl and arylalkyl in R 1 and R 15 , respectively.
  • the heteroarylalkyl means that the alkyl portion thereof may preferably be a straight-chain or branched chain having 1 to 6 carbon atoms, and the heteroaryl portion may be the same as the heteroaryl portion of the heteroarylthioalkyl in R 1 and R 13 .
  • the same is true.
  • the cycloalkyl preferably has 3 to 7 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • the cycloalkylalkyl means that the alkyl portion thereof preferably has 1 to 6 carbon atoms and may be straight-chain or branched, and the cycloalkyl portion is the same as described above. Specific examples include cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, 3-cyclopentylpropyl, cyclohexylmethyl, 2-cyclohexylethyl, cycloheptylmethyl and the like.
  • R 5 one:
  • the optionally substituted alkyl in R 3 and R 4 is the same as the optionally substituted alkyl in R 1 and R 1S , one or more, preferably 1 to 3 substituents May be substituted.
  • the optionally substituted alkyl for R 11 is alkyl, arylalkyl, or alkylthioalkyl.
  • Alkyl and arylalkyl are the same as the alkyl and arylalkyl in R 1 and R 15 , respectively.
  • Alkylthioalkyl means that the alkyl part thereof preferably has 1 to 6 carbon atoms and may be linear or branched. Specific examples include methylthiomethyl, ethylthioethyl, n-propylthiomethyl, 2-methylthioethyl, 3-methylthiopropyl and the like.
  • the optionally substituted alkyl in R 11 may be substituted by one or more, preferably 1 to 3 substituents similar to the optionally substituted alkyl in R 1 and R 15 .
  • the optionally substituted alkyl in R 12 , R 12 ′, R 14 and R 18 is alkyl, arylalkyl, heteroarylalkyl, cycloalkyl. These are each alkyl in R 1 and R 15, ⁇ reel alkyl, heteroalkyl ⁇ reel alkyl in R 2 and R 3, is the same as cycloalkyl. These may be substituted by one or more, preferably 1 to 3 substituents similar to the optionally substituted alkyl in R 1 and R 15 .
  • the optionally substituted aryl in R 1 , R z , R 3 , R 4 , R 14 , R 15 and R 16 is the same as the aryl moiety of the arylalkyl in R 1 and R 15 .
  • the aryl includes, for example, amino, halogen (fluorine, chlorine, bromine, iodine), hydroxyl, nitro, cyano, trifluoromethyl, lower alkyl (same as above), alkoxy (same as above), alkylthio (same as above) ), Formyl, acyloxy (as above), oxo, phenyl, arylalkyl (as above), carboxylic acid, hydroxysulfonyl, aminosulfonyl, hydroxysulfonyloxy, alkoxycarbonyl (as above), It may be substituted with one or more, preferably 1 to 3 substituents selected from alkavamoyl, arylalkyloxy (as described above), alkylaminoalkoxy (as described above) and the like.
  • the optionally substituted aryl in R 12 and R 12 ′ is the same as the aryl moiety of the aryl alkyl in R 1 and R 15 , preferably phenyl, naphthyl, and more preferably phenyl. .
  • the aryl includes, for example, amino, halogen (fluorine, chlorine, bromine, iodine), hydroxyl, nitro, cyano, trifluoromethyl, lower alkyl (as above), alkoxy (as above), alkylthio (as above) , Formyl, acyloxy (as above), oxo, phenyl, arylalkyl (as above), carboxyl, hydroxysulfonyl, aminosulfonyl, hydroxysulfonyloxy, alkoxycarbonyl (as above) May be substituted with one or more, preferably 1 to 3 substituents selected from carbamoyl, arylalkyloxy (same as above), alkylaminoalkoxy (same as above) and the like.
  • the reels in R 12 and R 12 ′ are
  • R 17 represents hydrogen, lower alkyl (same as above) or arylalkyl (same as above), and R 18 and R 18 ′ may be the same or different.
  • R 18 and R ′ 8 ′ together with an adjacent nitrogen atom may form a substituted or unsubstituted heterocyclo, where r is Represents an integer of 1 to 6, s represents an integer of 0 to 6, and t represents an integer of 1 to 6], and may be substituted with a substituent selected from the group consisting of:
  • the optionally substituted heteroaryl in R 3 and R 4 is the same as the heteroaryl portion of the heteroarylthioalkyl in R 1 and R 15 .
  • the heteroaryl is at least one, preferably 1 to 3 of the same as the optionally substituted aryl in R 1 , R 2 , R 3 , R 4 , R ′′, R 15 and R ie. May be substituted by a number of substituents.
  • Is 'R 3 and R 4 are hetero-cycle to substituted to a connexion formed nitrogen atom and cord adjacent, and R 12 and R 12' is connexion formed such together with the adjacent nitrogen atom substituted
  • a heterocycle may have carbon and at least one nitrogen and contain at least one atom selected from nitrogen, oxygen and sulfur as a further heteroatom on the ring.
  • a 4- to 7-membered ring group which may be substituted by oxo, and a benzene ring or the like utilizing two adjacent carbon atoms constituting the heterocycle. May be condensed.
  • they are morpholino, piperazino and 2-oxoquinazolinyl.
  • 2-oxoquinazolinyl is a group represented by the following formula.
  • Rb represents hydrogen or a low-alkyl (as above)
  • the heterocycle is one or more, preferably one to three of the same as the optionally substituted aryl in R 1 , R 2 , R 3 , R 4 , R 14 , and R 16. May be substituted by the substituent.
  • 1 8 Oyobi 18 'terrorism cycle to optionally substituted to form together with the adjacent nitrogen atom are the same as heterocycle in the R 3 and R 4, for example, Azechijino (1 Azetidinyl), pyrrolidino (1-pyrrolidinyl), piperidino, piperazino (1-piperazinyl), morpholino, thiomorpholino, oxothiomorpholino, dioxothiomorpholino, 2-oxoquinazolinyl and the like. Preferably, they are morpholino and piperazino.
  • the heterocycle may be substituted by one or more, preferably 1 to 3 substituents selected from lower alkyl (as above), arylalkyl (as above) and the like.
  • R 12 in R 12 and R 4 in R 3 are the same rather good be different also, 'and in R 4 R 12' R 12 in R 3 may be be the same or different .
  • the alkylene having 2 to 4 carbon atoms in Z may be linear or branched, and includes, for example, ethylene, trimethylene, tetramethylene, propylene, 1.1-dimethylethylene and the like.
  • the hydroxyl-protecting group for X includes, for example, arylalkyl which may be substituted, aryl which may be substituted, heteroaryl which may be substituted, tetrahydrobiranyl and the like.
  • the arylalkyl which may be substituted is the same as the arylalkyl for R 1 and R 15 , and the one or more substituents which may be present are also the same.
  • the aryls that may be substituted are R 1 , R 2 , R 3, is R 4, R 1 4, R 1 S and R which may Ariru the same way be substituted in ie, it is the same one or more substituents which may be possessed.
  • the optionally substituted heteroaryl is the same as the optionally substituted heteroaryl in R 3 and R 4 , and the one or more substituents which may be present are also the same.
  • the azapeptide hydroxamic acid derivative represented by the formula (I) or a pharmacologically acceptable salt thereof may have an asymmetric carbon, and therefore can exist as an optically active form and a racemic form.
  • the body can be separated into each optically active body by a method known per se.
  • the azapeptide-type hydroxamic acid derivative or a pharmacologically feasible salt further has an additional asymmetric carbon, the compound exists as a diastereomer mixture or a single diastereomer. These can also be separated from each other by a method known per se.
  • the azapeptide-type hydroxamic acid derivative or a pharmaceutically acceptable salt thereof can exhibit polymorphism, and can exist as more than one tautomer. It can exist as a hydrate (eg, ketone solvate, hydrate, etc.).
  • the present invention includes any stereoisomers, optical isomers, polymorphs, tautomers, solvates, and any mixtures thereof as described above. Active, racemic and diastereomers are also included within the scope of the present invention.
  • Pharmacologically acceptable salts of the azapeptide-type hydroxamic acid derivatives include, for example, alkyl metal salts (eg, salts with lithium, sodium, potassium, etc.), alkaline earth metal salts (eg, calcium, Salts with magnesium, etc.), anolemminium salts, ammonium salts, salts with organic bases (eg, salts with triethylamine, morpholine, piperidine, triethanolamine, etc.) and the like.
  • alkyl metal salts eg, salts with lithium, sodium, potassium, etc.
  • alkaline earth metal salts eg, calcium, Salts with magnesium, etc.
  • anolemminium salts eg, ammonium salts
  • salts with organic bases eg, salts with triethylamine, morpholine, piperidine, triethanolamine, etc.
  • salts include, for example, inorganic acid addition salts (eg, salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), organic acid addition salts Salts (for example, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, cunic acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, Salts with succinic acid, mandelic acid, and linoleic acid); salts with amino acids (eg, salts with glutamic acid, aspartic acid, etc.);
  • inorganic acid addition salts eg, salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.
  • organic acid addition salts Salts for example,
  • R 1 in the formula (I) is hydrogen or an optionally substituted alkyl.
  • a method for producing the azapeptide-type hydroxamic acid derivative of the present invention or a pharmacologically acceptable salt thereof will be described below.
  • R 14 synonymous (where hydrogen is excluded) is, R 15 'has the same meaning as R 1, R 1, R 2 , R 3, R 4 and X are as defined above]
  • the azapeptide hydroxamic acid derivative of the present invention or a pharmacologically acceptable salt thereof is basically prepared by using carboxylic acid (III) as a raw material and hydrazine (IV).
  • the intermediate compound (II ') is prepared by the C-terminal activation method in peptide synthesis [for example, basics and experiments on peptide synthesis (see Maruzen Shoten, Izumiya et al., Pp. 91)], and the succinic acid derivative (I ⁇ via conversion to '), human mud Kishiruamin: ⁇ 2 (X can be prepared by reacting with the same meaning).
  • the carboxylic acid (III) used as a raw material is described in the literature (Japanese Patent Application Laid-Open No. 6-506445, Japanese Patent Application Laid-Open No. 4-352757, Japanese Patent Application Laid-Open No. 7-157470, Japanese Patent Application Compounds described in Japanese Unexamined Patent Publication No. 6-65196, WO 96/33968, WO 94-21625, etc.) or prepared by conventional methods based on these documents.
  • Hydrazine (IV) is also a compound described in the literature (Tetrahedron, 44, 5525 (1988). J. Chem. So, Perkin Trans 1, 1975. 1712, etc.), or a hydrazine (IV) is used based on these literatures. It is prepared by a technique.
  • Step 1 is a step of preparing an intermediate compound (II ') by reacting carboxylic acid (III) with hydrazine (IV).
  • the typical method is shown below.c Step 1-1) Method using mixed acid anhydride
  • the intermediate compound (II ') is obtained by reacting carboxylic acid (III) with isobutyl carbonate and then hydrazine (IV) in the presence of an amine base such as triethylamine or N-methylmorpholine.
  • an amine base such as triethylamine or N-methylmorpholine.
  • a non-aqueous solvent such as tetrahydrofuran (THF), ethyl acetate, N, N-dimethylformamide (DMF) is used, and the reaction can be performed at a low temperature of 15 to 15 ° C.
  • Step 1 2 Method using acid chloride
  • the acid chloride is once prepared by reacting the carboxylic acid (III) with oxalyl chloride or thionyl chloride.
  • the solvent methylene chloride or a hydrocarbon solvent such as benzene or toluene is used, and the reaction is performed at a low temperature of 15 to -5 or under heating.
  • the intermediate compound (I ⁇ ) can be obtained by reacting the obtained acid chloride with hydrazine (IV) in the presence of an amine base such as triethylamine or pyridine.
  • a non-aqueous solvent such as THF, ethyl acetate, DMF or the like, methylene chloride, or a hydrocarbon solvent such as benzene or toluene is used, and the reaction can be performed at a low temperature or under heating.
  • Step 1—3) Method using DC C—HOB t method (coupling method)
  • Bok Riechiruami down or Amin presence of a base such as N- methylmorpholine, carbo phosphate (III), Kishirukarubojii mi de dicyclohexyl the hydrazine (IV) and 1 over human Dorokishibenzu Bok Riazor (HO B t ⁇ H 2 0 )
  • a condensing agent such as DCC
  • a solvent a non-aqueous solvent such as THF, ethyl acetate, DMF, and pyridin is used.
  • Step 1-1 Method using active ester method
  • An active ester is once prepared by reacting a carboxylic acid (III) with a phenol derivative such as pentafluorophenol or N-hydroxysuccinic acid imide with a condensing agent such as DCC.
  • a solvent an organic solvent such as THF, methylene chloride, benzene, and toluene is used, and the reaction is performed at a temperature lower than room temperature.
  • the obtained activity It can be obtained by reacting the ester with hydrazine (IV) in the presence of an amine base such as triethylamine or N-methylmorpholine.
  • a non-aqueous solvent such as THF or DMF, methylene chloride, or a hydrocarbon solvent such as benzene or toluene is used, and the reaction can be performed at room temperature or lower.
  • Step 2 is a step of converting the intermediate compound (I ⁇ ) to a succinic acid derivative (II ′ ′).
  • the succinic acid derivative (II ′ ′) can be obtained by reacting the intermediate compound (II ′) with a hydrogen chloride solution or trifluoroacetic acid.
  • a hydrogen chloride solution or trifluoroacetic acid As the solvent, an ether-based solvent such as 1,4-dioxane or a hydrocarbon-based solvent such as methylene chloride or benzene or toluene is used, and the reaction can be carried out at a temperature lower than room temperature.
  • step 3 the succinic acid derivative (I I ') is protected or unprotected with tert-butyl, benzyl, tetrahydrohydranil (Chem. Pharm. Bull. Jpn. 23, 167. 1975) or the like.
  • Droxylamine a step of reacting with XONH 2 (X is as defined above).
  • the conditions in Step 1 can be applied.
  • the protecting group can be removed after the reaction under ordinary conditions for deprotection of a hydroxyl group.
  • R 3 ′ has the same meaning as R 3 (excluding hydrogen), and R 2 , R 4 , R 14 ′ and R 15 ′ have the same meanings as above.
  • Step 4 is a step of introducing a substituent R 3 ′ from an intermediate compound (Ia) [a compound of the intermediate compound (II ′) wherein R 3 is hydrogen] as a raw material. That is, the intermediate conjugated compound (II 'a) the substituent R 3 in the presence of a base' is reacted with an electrophilic agent or protection agent to be introduced agents, to obtain the intermediate compound (I gamma b) It is.
  • Electrophilic agents include commonly used alkylating agents, acid chlorides, carbamoyl chloride, (thio) isocyanate, sulfonyl chlorides, and protective reagents such as benzyloxycarbonyl chloride and di-t-butyl carbonate. Of electrophilic reagents are available. Amines are used as the base. As the solvent, an ether-based solvent such as THF and 1,4-dioxane, or a hydrocarbon-based solvent such as methylene chloride or benzene or toluene is used, and the reaction can be carried out at a temperature of from 15 to room temperature.
  • substituent R 4 can be introduced in the same manner as in Scheme II described above.
  • H a 1 is halogen
  • R 2 , R 3 , R 12 , R 12 ′, R 14 ′ and R 15 ′ are as defined above.
  • Step 5 for example, intermediate compounds prepared by the method of Step 4 (I gamma c) as a starting material, ⁇ Mi emissions: HNR l2 R 12 '(R 12 and R 12' as defined above) a nucleophilic agent
  • Step 5 is a step of introducing —COCH 2 NR 1Z R 12 (where R 12 and R 12 ′ are as defined above) as the substituent R 4 .
  • This reaction can be carried out without a solvent or in a methylene chloride or a hydrocarbon solvent such as benzene or toluene under heating from room temperature.
  • the compound in which the substituents R 3 and Z or R 4 are —CONR 12 R 12 ′ (where R 12 and R 12 ′ have the same meaning as described above) (Cho)
  • the compound can be prepared by deprotection, if necessary, following the reaction using isocyanate as an electrophile, or by the method shown in Scheme IV below.
  • R is —C0 2 R 12 (R 12 has the same meaning as described above, except for hydrogen), and R 2 , R 3 , R 12 , R 12 ′, and R 15 ′ have the same meanings as above.]
  • step 6 in the succinic acid derivative (I ⁇ ′a) [in the succinic acid derivative (II ′ ′), R 4 is —CO 2 R 12 (R 12 is as defined above, except for hydrogen) Compound] and an amine: HNR 12 R 12 ′ (R 12 and R 12 ′ are as defined above) to react with the succinic acid derivative (II′′b) [succinic acid derivative (I ′ ′) Wherein R 4 is —CONR 12 R 12 ′ (R 12 and R 12 ′ are as defined above).
  • the solvent used is an ether-based solvent such as THF, 1,4-dioxane, methylene chloride, or a hydrocarbon-based solvent such as benzene or toluene, or a protonic solvent such as an alcohol, and is carried out at room temperature or under heating. be able to.
  • ether-based solvent such as THF, 1,4-dioxane, methylene chloride, or a hydrocarbon-based solvent such as benzene or toluene, or a protonic solvent such as an alcohol
  • a succinic acid derivative (II ′) in which the substituent R 3 is —CONR 12 R 12 ′ (R 12 and R 12 ′ are as defined above) may be prepared in the same manner as in the above scheme IV. it can.
  • the desired substituent R 1 is introduced using a carboxylic acid (III) having the substituent. If this is the case, it can be carried out without any special steps by the method shown in Scheme I above, but it can also be carried out by the method shown in Scheme V below, for example.
  • R 1 ′ is arylthioalkyl
  • R 18 ′ has the same meaning as R 16 (excluding hydrogen :)
  • R 2 , R 3 , R 4 and R 14 ′ have the same meanings as above.
  • Step 7 is a step in which an intermediate compound (IVe) is obtained using carboxylic acid (V) as a raw material in the same manner as in step 1 of scheme I above.
  • the raw material rubonic acid (V) is a compound described in a literature (Japanese Patent Application Laid-Open No. 4-502008, etc.) or is prepared by a conventional method based on these literatures. Is what is done.
  • Process 8
  • Step 8 is a step of removing the substituents R 14 ′ and R 16 ′ in the intermediate compound (I ⁇ e) to obtain a succinic acid derivative (I ⁇ ′f).
  • the reaction can be carried out at normal pressure or under pressure by a usual catalytic hydrogenation reaction in the presence of a metal catalyst.
  • a metal catalyst palladium, platinum, etc. can be used.
  • an ether solvent such as 1,4-dioxane, a hydrocarbon solvent such as benzene or toluene, or a protic solvent such as alcohol is used. From under heating.
  • step 9 the succinic acid derivative (I ′ ′ f) obtained in step 8 is reacted with formaldehyde in the presence of a base to give a succinic acid derivative (II ′ ′ g) which is r-exomethylene carboxylic acid.
  • a base amines such as piperidine are used, and the reaction can be carried out in an alcoholic solvent, methylene chloride, or a hydrocarbon-based solvent such as benzene or toluene from room temperature under heating.
  • Step 10 is a step of decarboxylating the succinic acid derivative (I ⁇ , f) obtained in Step 8 to obtain a succinic acid derivative (I ⁇ ′h) which is a monocarboxylic acid.
  • a solvent methylene chloride or a hydrocarbon solvent such as benzene or toluene is used, and the reaction can be performed at room temperature or under heating.
  • step 11 the succinic acid derivative (II'g) obtained in step 9 is reacted with arylthiol as a nucleophile, so that the substituent Ri is an arylthioalkyl.
  • This is the step of obtaining a succinic acid derivative (I ⁇ ′ i).
  • This reaction can be carried out without a solvent or in a hydrocarbon solvent such as methylene chloride or benzene or toluene under heating from room temperature.
  • the azapeptide-type hydroxamic acid derivative of the present invention synthesized in this manner is appropriately subjected to known separation and purification means, for example, concentration, extraction, chromatography, reprecipitation, recrystallization, and the like. Can be collected at any purity.
  • a pharmacologically acceptable salt of the azapeptide hydroxamic acid derivative can be produced by a known method.
  • various isomers of the hydroxamic acid derivative can also be produced by a known method.
  • the azapeptide hydroxamic acid derivative of the present invention and a pharmacologically acceptable salt thereof exhibit excellent TNFa production inhibitory activity against mammals (eg, humans, dogs, cats, etc.). Have.
  • the azapeptide hydroxamic acid derivative and the pharmacologically acceptable salt thereof of the present invention are useful as a TNF production inhibitor.
  • TNF production inhibitor for example, sepsis, MOF, rheumatoid arthritis, Crohn's disease, cachexia, skeletal muscle It is useful for the prevention and treatment of diseases such as asthenia, systemic lupus erythematosus, asthma, type I diabetes, psoriasis, other autoimmune diseases and inflammatory diseases.
  • azapeptide-type hydroxamic acid derivative of the present invention and a pharmacologically acceptable salt thereof are used as pharmaceuticals, granules, tablets, capsules, injections, and the like can be prepared using a pharmacologically acceptable carrier and the like. It can be orally or parenterally administered as a pharmaceutical composition in the form of plasters, creams, aerosols and the like. An effective amount of the hydroxamic acid derivative and a pharmacologically acceptable salt thereof is added to the above preparation.
  • the dose of the azapeptide hydroxamic acid derivative and its pharmacologically acceptable salt varies depending on the administration route, the patient's condition, weight, age, etc. It can be set appropriately according to the purpose of administration. Usually, when given orally to adults,
  • ' ⁇ -NMR was measured at 300 or 500 MHz, and l 3 C-NMR was measured at 75 or 125 MHz.
  • ' ⁇ -NMR chemical shifts used tetramethylsilane as an internal standard, and the relative delta ( ⁇ ) values were expressed as paper millions ( ⁇ ⁇ m).
  • Coupling constants indicate trivial multiplicity in Hertz (Hz), s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m ( Multiplet), dd (double toe doublet), brs (broad singlet), brd (broad doublet) and so on.
  • the title compound was produced according to the method described in WO95 / 0631, JP-T-6-5066445.
  • the title compound was produced according to the methods described in JP-A-6-61596 and JP-A-7-157470.
  • the title compound was produced according to the methods described in JP-A-4-3525757 and JP-A-7-157470.
  • the compound was synthesized by a known method (J. Chem. Soc. Perkin Trans. 1.1975. 1712) using 2-naphthaldehyde (tert-butyloxycarbonyl) hydrazone obtained in (1) of Reference Example 7.
  • N- (tert-butyloxycarbonyl) 1 N 1-benzylhydrazine (3.46 g., 15.6 rel.)
  • N-dimethylformamide solution 150 ml was added to a solution of potassium carbonate (3.23 g., 23.4 ol.).
  • methyl bromoacetate (1.77 ml. 18.7 mmol) were added, and the mixture was stirred at room temperature for 2 days.
  • Example 11-12 To a methylene chloride solution (50 ml) of N- [ ⁇ '-(4-tert-butoxy-2R-isobutylsuccinyl) amino] morpholine (693 mg, 2.20 mmol) obtained in Example 4 was added ice Under cooling, hydrogen chloride gas was blown for 10 minutes, and the mixture was stirred for 1 hour. The solvent of the reaction mixture was distilled off under a stream of nitrogen, and the residue was dried under reduced pressure to obtain the title compound. The title compound was used crude in the next reaction (Example 11-12).
  • Example 4 was carried out using 4-tert-butoxy-2R-isobutylsuccinic acid obtained in Reference Example 1 and N-benzyl-N-methylaminocarbonylmethylhydrazine hydrochloride obtained in Reference Example 9. In the same manner as in the above, the title compound (yield: 56 ⁇ ⁇ ⁇ ! was obtained as a white solid.
  • a 10% palladium carbon catalyst 60 mg was added to an ethanol solution (60 ml) of bonylmethylhydrazine (577 mg, 1.01 mmol), and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. After filtering off the catalyst, toluene (10 ml) was added to the residue obtained by concentrating the filtrate under reduced pressure, and the mixture was heated under reflux for 20 minutes.
  • Example 11 Piperidine (0.26 ml. 26.5 mmol) was added to an ethanol solution of N- (4-hydroxy-2R-isobutyl-3-carboxysuccinyl) aza-fernilalanine N'-methylamide obtained in Example 1 and added at room temperature for 1 hour. After stirring for 5 minutes, a 37% aqueous solution of formalin (1.0 ml) was added, and the mixture was stirred at room temperature for 14 hours and then refluxed for 1 hour. The reaction solution was diluted with ethyl acetate, washed with 0.5 N hydrochloric acid and water, and the organic layer was back-extracted with a saturated aqueous potassium carbonate solution.
  • Example 12 N- (4-Hydroxy-2R-isobutyl-3-methylenesuccinyl) azafunerilanine N'-methylamide (0.87 g, 2.51 mmo 1) obtained in Example 12 was mixed with thiophenol (10 ml). Then, the mixture was heated and stirred at 60 ° C for 2 days in a sealed state. The reaction solution was poured into getyl ether (200 ml), and the precipitate was collected by filtration to give the title compound (0.42 g, yield 37) as a white solid.
  • Example 3 N- (4-tert-butoxy-2R-isobutylsuccinyl) aza (2-naphthyl) azalanyl-L-alanine benzyl ester obtained in Example 2 (323 mg, 0.55 tmol) in tetrahydrofuran (10 10% palladium on carbon catalyst (100 mg) was added to a mixed solution of methanol (10 ml) and methanol (10 ml), and the mixture was stirred under a hydrogen atmosphere at room temperature for 6 hours. After filtering off the catalyst, the filtrate was concentrated under reduced pressure to obtain the title compound. The product was subjected to the reaction of Example 34 as crude.
  • Example 3 Using N-benzyl-N '-(4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl) hydrazine hydrochloride obtained in Example 19 In the same manner as in 2, the title compound was obtained as a white powder (yield 62. However, methylamine hydrochloride was used instead of L-alanine benzyl ester hydrochloride.
  • Example 38 The compounds of Examples 38 to 40 below were prepared using the N-benzyl-N '-(4-tert-butoxy-1 2R-isobutyl-3 (R or S) -phthalimidmethyl) obtained in Example 19 Succinyl) hydrazine hydrochloride was used as a starting material to synthesize according to the method of Example 32.
  • Example 15 A method similar to that of Example 42 using N-CN '-(4-tert-butoxy-2R-isobutylsuccinyl) amino] -l-phenyl-2-alanine N' '-methylamide obtained in Example 15 This yielded the title compound as a pale yellow oil (yield 31 mg).
  • Example 19 N-benzyl-N '-(4-tert-butoxy-2R-isobutyl-13 (R or S) -phthalimidomethylsuccinyl) hydrazine hydrochloride (514 nig. 0.97 miDol) obtained in Example 9
  • pyridine 0.40 ml. 4.95 minol
  • 4-dimethylaminopyridine 120 mg. 0.98 mmol
  • p-methoxybenzenesulfonyl chloride 600 mg, 2.90 ⁇
  • Example 22 N- (4-tert-butoxy-2 R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) -N '-(2-pyridylmethyl) hydrazine obtained in Example 2 was treated with methyl isocyanate. The title compound (yield 54 ⁇ ) was obtained as a white solid by the reaction.
  • Example 23 N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimidmethylsuccinyl) -N '-(2-ditrobenzyl) obtained in Example 3 was added to hydrazine with methyl isocyanate. Was reacted to give the title compound (yield 61!) As a pale yellow solid.
  • ⁇ -NR (CDC1 3) dp , 300MHz: 7.98 (.. D J 7.1 Hz 1H).
  • Example 26 N '— (4-biphenylmethyl) -N- (4-tert-butoxy-1-2R-isobutyl-13 (R or S) -phthalimid-methylsuccinyl) -N- (4-biphenylmethyl) obtained in Example 6 Methyl isocyanate was added to hydrazine. The reaction gave the title compound as a white solid (yield 92%).
  • Example 19 Using N-benzyl-N, 1- (4-1-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl) hydrazine hydrochloride and 3-pyridylmethylamine obtained in Example 19 The title compound (yield: 49 mg;) was obtained as a white amorphous substance in the same manner as in Example 62.
  • Example 19 Using N-benzyl-N '-(4-tert-butoxy-2R-isobutyl-13 (R or S) -phthalimidomethylsuccinyl) hydrazine hydrochloride and acetyl bromide obtained in Example 19 The title compound (89% in yield) was obtained as a white solid in the same manner as in Example 42.
  • N'-benzyl-N'-bromoacetyl-N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) hydrazine obtained in Example 6 (218 mg. 0.355 (mmol) (0.078 ml, 0.894 mmol) was added to a methylene chloride solution (10 ml) of the resulting solution, and the mixture was stirred at room temperature for 13 hours. Dilute hydrochloric acid (50 ml) was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (185 rag, yield 84 84) as a white solid.
  • Example 6 N'-benzyl-N'-bromoacetyl-N- (4-tert-butoxy-2R-isobutyl-1 (R or S) -phthalimidomethylsuccinyl) hydrazine and 4-benzyl obtained in 4
  • the title compound (97% in yield) was obtained as a white amorphous substance in the same manner as in Example 65 using piperazine.
  • N- (4-tert-butoxy-2R-isobutylsuccinyl) azaphenylalanyl obtained from Example 35; synthesized from L-alanine benzyl ester, which was used crude for the reaction of Example 108. Provided.
  • Example 42 N- (4-tert-butyn- 1 2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) obtained in Example 42 was synthesized from azafudinalanine benzyl ester to give the title compound as a white solid ( A yield of 95%) was obtained.
  • ⁇ -NR (Me0H-d4) ⁇ pm, 300MHz: 7.69 (s, 4H), 7.20-7.15 (m.7H), 6.93-6.46 (m, 3H), 5.02 (m, 2H). 2.95 (m, 1H) ), 2.38 (m, 1H),
  • Example 41 N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimidmethylsuccinyl) obtained in 1) was synthesized from azaphenylalanine N'-phenylamide, which was crude. It was subjected to 140 reactions.
  • Example 40 N- (4-tert-butoxy-1-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) obtained in Example 40 was synthesized from azafeniralara2luglycine benzyl ester to give a white solid. As a result, the title compound (yield 54) was obtained.
  • Example 4 4-benzyloxycarbonyl- ⁇ ⁇ ⁇ ⁇ ⁇ _ [ ⁇ '-(4-tert-butoxy-2R-isobutyl-13 (R or S) -phthalimidmethylsuccinyl) amino] -l-phenyl obtained in Example 4
  • the compound was synthesized from L-alanine N, '-methylamide and subjected to the reaction of Example 104 as crude.
  • Example 46 N- (4_tert-butoxy-2R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl) azaphynilalanine obtained in Example 46 was synthesized from N '-(-fluorophenyl) imide, The crude product was subjected to the reaction of Example 141.
  • Example 47 N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl) obtained in Example 47 Synthesized from azaphenylglycine N, -methylamide, crude The reaction of Example 1 16 was used.
  • Example 5 N- (4-tert-butoxy-2 R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) azahomophenylylalanine N'-methylamide obtained in 4 It was synthesized and subjected to the reaction of Example 124 as crude.
  • Example 55 N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) azahomopheniralanine N ′ obtained in Example 55 was synthesized from N′-phenylamide, and was used as crude in Example 12. It was subjected to the reaction of 5.
  • Example 9 N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) azahomopheniralanine N ′ obtained in Example 55 was synthesized from N′-phenylamide, and was used as crude in Example 12. It was subjected to the reaction of 5.
  • Example 56 Synthesis of N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl) other (3-phenylpropyl) glycine N'-methylamide obtained in 6 The crude product was subjected to the reaction of Example 126.
  • Example 9 1 N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl) other (3-phenylpropyl) glycine N'-methylamide obtained in 6 The crude product was subjected to the reaction of Example 126.
  • Example 9 1 N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl) other (3-phenylpropyl) glycine N'-methylamide obtained in 6 The crude product was subjected to the reaction of Example 126.
  • Example 9 1 N- (4-tert-butoxy-2R-isobut
  • Example 9 2 The compound was synthesized from N'-methyl amide and subjected to the reaction of Example 127 as crude.
  • Example 9 2 The compound was synthesized from N'-methyl amide and subjected to the reaction of Example 127 as crude.
  • Example 58 N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) azaneopentylglycine obtained in 8 Synthesis from N'-methylamide It was subjected to the reaction of Example 128 as it was.
  • Example 6 N- (4-tert-butoxy-2R-isobutyl-3 (R or S) -furimid-methylsuccinyl) azafinalalanine N '-[4- (4-methylbiperazino) phenyl obtained in 2 And subjected to the reaction of Example 144 as crude.
  • Example 6 From N— (4-tert-butoxy-2R—isobutyl-3 (R or S) —furimidomethylsuccinyl) azafuenylalanine N ′ — (3-pyridylmethyl) amide obtained in 3 It was synthesized and subjected to the reaction of Example 144 as crude.
  • Example 68 Using N- (4-hydroxy-2R-isobutylsuccinyl) aza (2-naphthyl) aranyl-L-alanine N′-benzylamide obtained in Example 68, a method similar to that of Example 100 was used. The title compound (70) was obtained as a white solid.
  • Example 7 Venzyloxycarbonyl obtained in Example 7 ⁇ — [ ⁇ '-(4-Hydroxy 2 R—Isoptyl-3 (R or S) —phthalimid-methylsuccinyl) amino] —Fenilalanine
  • the title compound (yield: 59 mg) was obtained as a white solid in the same manner as in Example 100, using N ′ ′-methylamide.
  • Example 70 The ⁇ - (4-hydroxy-2R-isobutylsuccinyl) azaleucyl-L-alanine benzyl ester (142 mg. 0.32 mmol) obtained in Example 70 was mixed with N, N-dimethylformamide (5 ml) and methylene chloride. (2 ml) in a mixed solvent, and 0-tetrahydropropyran-1-ylhydroxylamine (7500 mg. 0.64 mmol), BOP reagent (170 mg, 0.38 octol) and 4-methylmorpholine were dissolved in the mixture. (0.08 ml, 0.72 mmol) were sequentially added, and the mixture was stirred at room temperature for 1.5 hours.
  • Example 107 using ⁇ — [2R-isobutyl-41- ( ⁇ ′ -tetrahydropyran-1-2-yloxyamino) succinyl] azaphenyl-2-alanyl L-alanine benzyl ester obtained in Example 108 According to the method described above, the title compound (yield: 50 mg) was obtained as a white solid.
  • a methanol solution (2 ml) was added 10% palladium-carbon catalyst (7 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3.5 hours.
  • the catalyst in the reaction mixture was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (formaldehyde methanol: 50/1, 20/1) to give a light red solid.
  • the title compound (10 mg, yield 70 mg) was obtained.
  • Example 11 Using ⁇ — [ ⁇ ′ — [4- ( ⁇ ′ ′-I ⁇ C benzyloxyamino) -12R-isobutylsuccinyl] amino) morpholin obtained in Example 11 The title compound (yield: 61 mg) was obtained as a white solid in the same manner as in 1.
  • Example 7 8-benzyloxycarbonyl obtained in 8 ⁇ — [ ⁇ '— (4-hydroxy-1 2R-isobutylsuccinyl) amino] 1 L 1 phenylalanine ⁇ ' 1 methyl amide
  • the title compound was obtained as a white foamy substance (yield: 46 mg) in the same manner as in Example 110 using the above.
  • Example 11 ⁇ -CN ′ 1 [41- ( ⁇ ′ ′ — benzyloxyamino) —2R-isobutylsuccinyl] amino obtained in Example 14— ⁇ -benzyloxycarbonyl—L-phenylanilanin N
  • the title compound (yield: 68 mg) was obtained as a white solid in the same manner as in Example 11 using '' '-methylamide.
  • Example 10 Using 10- (4-hydroxy 2 R-isobutyl-3 (R or S) -phthalimidmethylsuccinyl) azaphenyl glycine N'-methyl amide obtained in Example 1, Example 10 By a method similar to that of 0, the title compound (yield 19) was obtained as a white solid.
  • Example 8 ⁇ — (4-hydroxy 2 R—isobutyl-3 (R or S) —phthalimidomethylsuccinyl) other (0—benzyl) tyrosine N ′ obtained in 2
  • the title compound was obtained as a white solid (yield 23) in the same manner as in Example 100 using monomethylamide.
  • Example 8 Using ⁇ ⁇ -(4-hydroxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl) aza (2-pyridyl) alanine ⁇ , -methylamide obtained in Example 3, By a method similar to that in Example 100, the title compound (yield: 32 mg) was obtained as a pale and color solid.
  • Example 8 Using ⁇ - (4-hydroxy-2 R-isobutyl-3 (R or S) -phthalimid-methylsuccinyl) other (2-nitrophenyl) aranan N'-methylamide obtained in Example 8, The title compound (yield: 52%) was obtained as a pale yellow solid in the same manner as in Example 100.
  • Example 11 ⁇ — [4- ( ⁇ '-hydroxyamino) -1-2 R-isobutyl-3 (R or S) —phthalimid-methylsuccinyl] other obtained in 19 (2-nitrophenyl) alanan N '' —Methyl amide, the same as in Example 11 By the method, the title compound was obtained as a pale and color solid (yield 10).

Abstract

L'invention concerne de nouveaux dérivés de l'acide hydroxamique de type azapeptide représentés par la formule (I) ou des sels pharmaceutiquement acceptables de ceux-ci et des compositions médicales contenant ces dérivés. Dans cette formule, X représente hydrogène ou un groupe protecteur hydroxyle; R1 représente hydrogène, hydroxy, amino, mercapto, alcoxy, alkyle, alcényle, aryle ou -(CH¿2?)k-A; R?2¿ représente hydrogène, alkyle ou aryle; R3 représente hydrogène, alkyle, aryle, hétéroaryle, ou -(CONH)¿m?-(CHR11)n-Y; et R?4¿ représente alkyle, aryle, hétéroaryle, -SO¿2R?12, -CO-(CH2)q-NR12R12', -CONH-Z-R13 ou -(CONH)¿m?-(CHR?11)¿n-y, ou R3 et R4 peuvent ensemble former un hétérocycle contenant de l'azote. Du fait qu'ils ont un effet inhibiteur sur la production de TNFα, ces composés sont utiles pour prévenir et traiter les maladies autoimmunes, les maladies inflammatoires, etc., par exemple, les maladies infectueuses, la défaillance polyviscérale (MOF), la polyarthrite rhumatoïde, la maladie de Crohn, la cachexie, l'adynamie sévère, le lupus érythémateux aigu disséminé, l'asthme, les diabètes de type I et le psoriasis.
PCT/JP1999/000439 1998-02-06 1999-02-03 Nouveaux derives de l'acide hydroxamique de type azapeptide WO1999040063A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU22983/99A AU2298399A (en) 1998-02-06 1999-02-03 Novel azapeptide type hydroxamic acid derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2566498 1998-02-06
JP10/25664 1998-02-06

Publications (1)

Publication Number Publication Date
WO1999040063A1 true WO1999040063A1 (fr) 1999-08-12

Family

ID=12172072

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1999/000439 WO1999040063A1 (fr) 1998-02-06 1999-02-03 Nouveaux derives de l'acide hydroxamique de type azapeptide

Country Status (2)

Country Link
AU (1) AU2298399A (fr)
WO (1) WO1999040063A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000000465A1 (fr) * 1998-06-26 2000-01-06 F. Hoffmann-La Roche Ag Derives d'hydrazine
US6235787B1 (en) 1997-06-30 2001-05-22 Hoffmann-La Roche Inc. Hydrazine derivatives
US6265446B1 (en) 1998-11-27 2001-07-24 Hoffmann-La Roche Inc.. Hydrazine derivatives
US6281363B1 (en) 1998-12-11 2001-08-28 Hoffmann-La Roche Inc. Cyclic hydrazine derivatives
WO2006110516A1 (fr) * 2005-04-11 2006-10-19 Abbott Laboratories Antagonistes de l'acylhydrazide p2x7 et leurs utilisations

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04344641A (ja) * 1991-05-22 1992-12-01 Konica Corp 多層ハロゲン化銀カラー写真感光材料
JPH05194788A (ja) * 1991-06-27 1993-08-03 Fuji Photo Film Co Ltd セルロースエステルフィルム、ハロゲン化銀感光材料及び処理方法
JPH0625291A (ja) * 1992-03-05 1994-02-01 Behringwerke Ag グリコペプチド誘導体、それらの製造方法およびこれらの化合物を含有する薬剤
JPH08194279A (ja) * 1994-11-16 1996-07-30 Fuji Photo Film Co Ltd ハロゲン化銀写真感光材料
JPH08507536A (ja) * 1993-03-19 1996-08-13 ノボ ノルディスク アクティーゼルスカブ 〔１，２，４〕トリアゾロ〔４，３−ａ〕キノキサリン誘導体、それらの製造及び使用
JPH0940548A (ja) * 1995-07-28 1997-02-10 L'oreal Sa 皮膚科もしくは製薬用組成物及びその製法並びにその使用
JPH09512269A (ja) * 1994-04-26 1997-12-09 シンテックス（ユー・エス・エイ） インコーポレイテッド ベンゾシクロアルキルアゾールチオン誘導体
WO1999001428A1 (fr) * 1997-06-30 1999-01-14 F. Hoffmann-La Roche Ag Derives hydrazine

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04344641A (ja) * 1991-05-22 1992-12-01 Konica Corp 多層ハロゲン化銀カラー写真感光材料
JPH05194788A (ja) * 1991-06-27 1993-08-03 Fuji Photo Film Co Ltd セルロースエステルフィルム、ハロゲン化銀感光材料及び処理方法
JPH0625291A (ja) * 1992-03-05 1994-02-01 Behringwerke Ag グリコペプチド誘導体、それらの製造方法およびこれらの化合物を含有する薬剤
JPH08507536A (ja) * 1993-03-19 1996-08-13 ノボ ノルディスク アクティーゼルスカブ 〔１，２，４〕トリアゾロ〔４，３−ａ〕キノキサリン誘導体、それらの製造及び使用
JPH09512269A (ja) * 1994-04-26 1997-12-09 シンテックス（ユー・エス・エイ） インコーポレイテッド ベンゾシクロアルキルアゾールチオン誘導体
JPH08194279A (ja) * 1994-11-16 1996-07-30 Fuji Photo Film Co Ltd ハロゲン化銀写真感光材料
JPH0940548A (ja) * 1995-07-28 1997-02-10 L'oreal Sa 皮膚科もしくは製薬用組成物及びその製法並びにその使用
WO1999001428A1 (fr) * 1997-06-30 1999-01-14 F. Hoffmann-La Roche Ag Derives hydrazine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE STN CAPLUS 1 January 1900 (1900-01-01), XP002920387, Database accession no. 1983:557714 *
DATABASE STN CAPLUS 1 January 1900 (1900-01-01), XP002920388, Database accession no. 1978:6809 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6235787B1 (en) 1997-06-30 2001-05-22 Hoffmann-La Roche Inc. Hydrazine derivatives
WO2000000465A1 (fr) * 1998-06-26 2000-01-06 F. Hoffmann-La Roche Ag Derives d'hydrazine
US6239151B1 (en) 1998-06-26 2001-05-29 Hoffmann-La Roche Inc. Compounds as inhibitor of tumor necrosis factor alpha release
US6265446B1 (en) 1998-11-27 2001-07-24 Hoffmann-La Roche Inc.. Hydrazine derivatives
US6281363B1 (en) 1998-12-11 2001-08-28 Hoffmann-La Roche Inc. Cyclic hydrazine derivatives
WO2006110516A1 (fr) * 2005-04-11 2006-10-19 Abbott Laboratories Antagonistes de l'acylhydrazide p2x7 et leurs utilisations

Also Published As

Publication number Publication date
AU2298399A (en) 1999-08-23

Similar Documents

Publication Publication Date Title
JP2633085B2 (ja) アミド官能基を有するインドリン誘導体、それらの調製、およびそれらが内在する医薬組成物
JP6916795B2 (ja) Ｌｓｄ１阻害剤
RU2012556C1 (ru) Способ получения производных циклоалкилглутарамида или их фармацевтически приемлемых солей
AU711755B2 (en) N-(aroyl)glycine hydroxamic acid derivatives and related compounds
AU721325B2 (en) 1H-4(5)-substituted imidazole derivatives
EP1451163B1 (fr) Derives de 3-amido-1,2-benzoisoxazole et leur procede de preparation et d'utilisation
CA2844982A1 (fr) Antagonistes des recepteurs d'acide lysophosphatidique
JP3529381B2 (ja) エンドテリン変換酵素阻害剤
CZ298080B6 (cs) Inhibitory bunecné adheze, zpusob jejich prípravya farmaceutické prostredky s jejich obsahem
SK282529B6 (sk) Merkaptoalkanoylový a acylmerkaptoalkanoylový derivát oxazepínu, tiazínu a tiazepínu, spôsob jeho výroby, medziprodukt na jeho výrobu a farmaceutický prípravok, ktorý ho obsahuje
CA2941581A1 (fr) Nouveaux composes en tant qu'inhibiteurs de l'histone desacetylase 6 et compositions pharmaceutiques les comprenant
AU2008320718B2 (en) Indol-2-one derivatives disubstituted in the 3-position, preparation thereof and therapeutic use thereof
TW200808748A (en) Compounds and compositions as channel activating protease inhibitors
AU2018236290A1 (en) MK2 inhibitors, synthesis thereof, and intermediates thereto
AU2017326611A1 (en) YAP1 inhibitors that target the interaction of YAP1 with Oct4
WO2004014843A1 (fr) Composés amino substitués et utilisation de ces composés
JP2002506056A (ja) 酸化窒素シンターゼ阻害剤として有用であるハロゲン化アミジノアミノ酸誘導体
JPH10508847A (ja) 酸化窒素合成酵素インヒビターとして有用なアミノテトラゾール誘導体
JPH09512528A (ja) バソプレッシン拮抗物質としてのベンズアミド誘導体
WO2000023420A1 (fr) Derives d'amine aromatique, procede de preparation de ces derives et agents les contenant
TWI258469B (en) Aryl-substituted alicyclic compounds and pharmaceutical composition containing the same
JPH06504070A (ja) 新規メルカプトーアミド誘導体
JPH04230358A (ja) α−メルカプトアルキルアミンの新規なＮ−置換誘導体、それらの製造法及び中間体、それらの薬剤としての使用並びにそれらを含有する組成物
WO1999040063A1 (fr) Nouveaux derives de l'acide hydroxamique de type azapeptide
KR101571915B1 (ko) Ｈｄａｃ 저해제로서의 술포닐피롤의 신규 제조 방법

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

NENP Non-entry into the national phase

Ref country code: KR

122 Ep: pct application non-entry in european phase