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WO2001005750A1 - COMPOSES DE p-TERPHENYLE A CHAINES LATERALES D'ACYLOXYMETHOXYCARBONYLE - Google Patents

COMPOSES DE p-TERPHENYLE A CHAINES LATERALES D'ACYLOXYMETHOXYCARBONYLE Download PDF

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Publication number
WO2001005750A1
WO2001005750A1 PCT/JP2000/004723 JP0004723W WO0105750A1 WO 2001005750 A1 WO2001005750 A1 WO 2001005750A1 JP 0004723 W JP0004723 W JP 0004723W WO 0105750 A1 WO0105750 A1 WO 0105750A1
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WIPO (PCT)
Prior art keywords
compound
substituent
lower alkyl
hydrogen
pharmaceutically acceptable
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PCT/JP2000/004723
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English (en)
Japanese (ja)
Inventor
Katsutoshi Aono
Teruhisa Ichihashi
Tatsuo Tsuri
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Shionogi & Co., Ltd.
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Priority to AU60157/00A priority Critical patent/AU6015700A/en
Publication of WO2001005750A1 publication Critical patent/WO2001005750A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to a novel compound useful as a prodrug, a medicament containing the same and a novel compound which is an active form thereof. More specifically, the present invention relates to a novel paraterphenyl compound having an acyloxymethoxycarbonyl side chain, an immunosuppressant and an antiallergic agent containing the same, and a novel paraterphenyl compound which is an active form thereof.
  • Prodrugs of pharmaceutically active substances are often studied for the purpose of improving physical properties such as crystallinity, stability and water solubility, improving bioavailability, and improving pharmacological action.
  • WO97 / 39999 and WO98 / 45508 disclose that paraterphenyl derivatives are effective as immunosuppressants and antiallergic agents.
  • W098704508 also mentions prodrugs, and specifically describes the conversion of hydroxy forms into prodrugs.
  • R 3 alkyl, carboxyalkyl, haloalkyl, carbamylalkyl, etc.
  • Table 5-5-039392 and Synthesis (December, 199 0, 1159-116) have R as intermediates for the synthesis of prodrugs.
  • 2 S COO CH 2 ⁇ C ⁇ Describes R 1 (compound A) and Cl COO CH s OC OR 1 (compound B).
  • compound B cannot be synthesized from compound A in which R 1 is hydroxyxethyl or acetylaminomethyl in the method described herein.
  • the compound having a paraterphenyl skeleton is a chemical “And” Pharmacy Utility Canole ”Bulittin (Chemical & Pharmaceutical 1 Bulletin, 24 (4), 6 13-6 2 0 (1 9 7 6)), The Journal of Antibiotics (32 (6), 55-9-564 (1977)) and Agricultural 'Norological ⁇ Chemistry (Agricultural Biological Chemistry, 49 (3), 867-868 (19985)), etc., but no mention of immunosuppressive and antiallergic effects It has not been. Disclosure of the invention
  • the present invention provides the following compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. [1] Equation (I)
  • R 1 is lower alkyl substituted by 1 or 2 nonionic and hydrophilic groups
  • R 2 R 3 ⁇ R 4 R 5 R 6 R 7 R 8 ⁇ R 9 ⁇ R 1 0 R 1 1 R 1 2 3 ⁇ 4 preliminary R 1 3 are each independently hydrogen, arsenate Dorokishi, halogen, carboxy, substituents
  • a lower alkyl which may have a substituent, a lower alkoxy which may have a substituent, a lower alkenyl which may have a substituent, a lower alkenyloxy which may have a substituent, and a substituent
  • a lower alkylthio optionally having a substituent, a lower alkoxycarbonyl optionally having a substituent, an acyloxy optionally having a substituent, a lower alkylsulfonyl optionally having a substituent, a substituent
  • Lower alkylsulfonyloxy optionally having a substituent, lower alkylsulfonyl optionally having a substituent, nitro, cyano, formyl, amino having an optional substitu
  • R A and R B are each independently hydrogen or lower alkyl
  • R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , R 12 and R 13 are each independently hydrogen, halogen or lower alkoxy.
  • R 1 is substituted with 1 or 2 groups selected from the group consisting of hydroxy, rubamoyl, lower alkyl rubamoyl, carbamoyloxy, lower alkyl rubamoyloxy, and acylamino which may be substituted with acylamino
  • R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , R 12 and R 13 are each independently hydrogen, halogen or lower alkoxy
  • R 6 is lower Alkyl, lower alkoxy or lower alkoxycarbonyl
  • R 8 is hydrogen, hydroxy or lower alkyl
  • R 9 is lower alkyl or lower alkoxy
  • R 1 R A and R B each have the same meaning as [1], and R 6 , R 7 , R 8 and R 9 are each independently chromium, hydroxy, lower alkyl, lower alkoxy or Is lower alkoxycarbonyl, one of R 12 and R 13 is hydrogen and the other is halogen)
  • R 1 is selected from the group consisting of hydroxy, rubamoyl, lower alkyl rubamoyl, carbamoyloxy, lower alkyl rubamoyloxy, acetylamino, acetylaminoenoylamino and acetylaminopropanoylamino.
  • a pharmaceutical composition containing the compound according to any one of [1] to [9] or a pharmaceutically acceptable salt thereof or a solvate thereof, more specifically, an immunosuppressant or an antiallergic agent I will provide a.
  • an immunosuppressant or an antiallergic agent I will provide a.
  • R., R 7 , R 8 and R 9 are each independently hydroxy, lower alkyl, lower alkoxy or lower alkoxycarbonyl; R 12 and R 13 are each hydrogen; Is halogen
  • a pharmaceutically acceptable salt or solvate thereof present invention is characterized by administering a compound (I) or (II), immunosuppressive And a method for treating or preventing an allergic disease and suppressing the immune response, and using the compound (I) or (II) for producing a medicament for treating or preventing an allergic disease.
  • the present invention provides a pharmaceutical composition, an immunosuppressant or an antiallergic agent containing the compound (III) or a pharmaceutically acceptable salt thereof or a solvate thereof.
  • FIG. 1 is a graph comparing the concentration of (IV-1) in plasma when the compound (1-1) or its parent compound (IV-1) is administered.
  • FIG. 2 is a graph comparing the concentration of (IV-3) in plasma when the compound (1-61) or its parent compound (IV-3) is administered.
  • FIG. 3 is a graph comparing the concentration of (IV-4) in plasma when the compound (1-91) or its parent compound (IV-4) was administered.
  • lower alkyl refers to a straight or branched chain having 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 5 carbon atoms, and most preferably 1 to 3 carbon atoms.
  • branched alkyls such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n — Heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, n-decyl and the like. Most preferably, it is methyl.
  • alkyl having 1 to 5 carbon atoms includes linear or branched alkyl, and specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl Includes butyl, tert-butyl, n-pentyl, isopentyl and neopentyl.
  • alkyl having 1 to 3 carbon atoms includes linear or branched alkyl, and specifically includes methyl, ethyl, n-propyl and isopropyl.
  • substituent of the “lower alkyl optionally having substituent (s)” include halogen; hydroxy; lower alkoxy optionally substituted by lower alkoxy; acyl; acysiloxy; carboxy; lower alkoxycarbonyl; mercapto; Alkylthio; hydroxy, lower alkyl, or amino which may be substituted with an optionally substituted acyl; hydroxy, lower alkoxy, carboxy lower alkoxy, aryl lower alkoxy or 5- or 6-membered Substituted with a member heterocycle Imino which may be substituted; hydrazono optionally substituted with carbamoyl or lower alkoxycarbonyl; sorbamoyl optionally substituted with lower alkyl or amino; thiomo optionally substituted with lower alkyl Carbamoyl; cycloalkyl optionally substituted by lower alkyl or lower alkoxy; cycloalkenyl optionally substituted by lower alkyl; cyano;
  • Nonionic and hydrophilic group includes a group that does not dissociate into ions in a solution and has an effect of reducing the lipophilicity (hydrophobicity) of a lipophilic compound and imparting hydrophilicity.
  • the hydrophilic group is, for example, Journa 1 of Medicinal Chemistry, 1973, vol. 16, No. 11, 12 07-12 16 or Journal of Medicine C 20, vol. 20, No. 20, 300-304, a group having a negative constant ⁇ , preferably 7 ⁇ Includes 0.5 or less groups.
  • the hydrophobic substituent constant 7 ⁇ can be determined by the following equation.
  • Halogen includes fluorine, chlorine, bromine and iodine. Preferably they are fluorine and chlorine, most preferably fluorine.
  • lower alkyl moiety of “lower alkoxy” is the same as the above “lower alkyl”.
  • Substituents of "lower alkoxy optionally having substituent (s)" include halogen; hydroxy; lower alkoxy optionally substituted by acyloxy; acryl; acryloxy; carboxy; lower alkoxycarbonyl; lower alkylthio; Amino which may be substituted with lower alkyl; phenyl which may be substituted with lower alkyl or lower alkoxy; heterocycle; heterocyclic carbonyloxy. Preferably, it is unsubstituted lower alkoxy.
  • Lower alkylthio “lower alkoxycarbonyl”, “lower alkylsulfonyl”, “lower alkylsulfonyloxy”, “lower alkylsulfinyl”, “lower alkyl power rubamoyl”, “lower alkyl power rubamoyloxy j” and “lower alkyl
  • the lower alkyl part of “lower alkylenedioxy” is the same as the above “lower alkyl”.
  • lower alkenyl refers to straight or branched alkenyl having 2 to 1 carbon atoms, preferably 2 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms. Specifically, vinyl, propenyl, isopropenyl, butenyl, isobutenyl, butenyl, pentenyl, isopentenyl, pentagenenyl, hexenyl, isohexenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc. Includes one or more double bonds at any position.
  • “Lower alkynyl” includes straight-chain or branched alkynyl having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 3 to 6 carbon atoms, and specifically includes ethynyl. , Propynyl (such as 2-propynyl), butynyl (such as 2-butynyl), pentynyl, hexynyl, heptynyl, octynyl, noninyl, and decynyl. These have one or more triple bonds at arbitrary positions, and may further have a double bond.
  • acyl refers to a linear or branched alkylcarbonyl or alkenylcarbonyl having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and most preferably 1 to 4 carbon atoms. It includes cycloalkylcarbonyl having 4 to 9, preferably 4 to 7 carbon atoms and arylcarbonyl.
  • acetyl is preferred.
  • substituent of "optionally substituted aryl” is the same as the above-mentioned “optionally substituted lower alkoxy” substituent, and cycloalkylcarbonyl and arylcarbonyl are lower. It may have alkyl as a substituent.
  • acyl part of “Asiloxy” and “Acylamino” is the same as the above “Acyl”, and the “Asiloxy J optionally having substituent (s)” is the same as the above “Acyl optionally having substituent”. The same is true.
  • One or more arbitrary positions may be substituted with these substituents.
  • Cycloalkyl is a carbocyclic ring having 3 to 6 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • cycloalkyl optionally having substituent (s) is substituted with lower alkyl, halogen, hydroxy, ethoxy, lower alkoxycarbonyl, lower alkoxy, lower alkylenedioxy, lower alkoxy. And a 5- or 6-membered heterocyclic ring, and one or more arbitrary positions may be substituted.
  • Cycloalkenyl j includes those having one or more double bonds at any position in the above cycloalkyl ring, and specifically, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohetero Xenyl and cyclohexagenyl and the like.
  • the substituent of "cycloalkenyl optionally having substituent (s)” is the same as the substituent of "cycloalkyl” described above.
  • “Amino optionally having a substituent” includes substituted amino and unsubstituted amino, and the substituent is a lower alkyl optionally having a substituent [where the substituent is a lower alkoxy] , Cycloalkyl, optionally substituted amino (substituent is lower alkyl, phenyl, etc.), optionally substituted aryl (substituted is lower alkyl, lower alkoxy, carboxy) Lower alkenyl; lower alkynyl; cycloalkyl; lower alkyl, carboxy, acyl, lower alkoxycarbonyl, which may be substituted; lower alkyl; And lower alkylsulfonyl; lower alkylsulfonyl; and the like.
  • amino optionally having a substituent includes a substituted imino and an unsubstituted imino, and the substituent is the same as the above “amino optionally having a substituent”.
  • the “optionally substituted rubamoyl” includes lower alkyl, lower alkenyl, lower alkynyl and the like optionally substituted rubamoyl and the like.
  • “Sulfamoyl optionally having a substituent” includes sulfamoyl and the like which may be substituted with lower alkyl, lower alkenyl, lower alkynyl and the like.
  • aryl includes phenyl, naphthyl, anthryl, indenyl, phenanthryl and the like, and is preferably phenyl.
  • substituents examples include: halogen; hydroxy; lower alkyl optionally substituted with halogen or carboxy; halogen, aryl, heteroaryl or lower alkoxy substituted with halogen.
  • a halogen a hydroxy; a lower alkyl optionally substituted with a halogen; a lower alkoxy optionally substituted with an aryl or a lower alkoxy; a lower alkenyloxy; an acyloxy; a lower alkylthio; Alkyl, lower alkenyl, optionally substituted with halogen or lower alkylsulfonyl, amino or nitro; lower alkylsulfonyl; optionally substituted with lower alkylsulfonyl Xy; or arylsulfonyloxy.
  • aryl moiety of "arylsulfonyl” and “arylsulfonyloxy” is the same as the above “aryl", and phenyl is particularly preferable.
  • the substituent of "arylsulfonyl optionally having substituent (s)” is the same as the substituent of "aryl optionally having substituent (s)", and unsubstituted one is particularly preferable.
  • Heterocycle means a heteroatom arbitrarily selected from 0, S and N in the ring.
  • heterocyclic ring having one or more, and specifically, pyrrolyl, imidazolyl, virazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoxazolyl, oxazolyl, oxaziazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, and phenyl.
  • aromatic heterocycles such as indolyl, benzimidazolyl, ingzolyl, indridinyl, quinolyl, isoquinolyl, cinnolinyl, furazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, and benzisolone Xazozolyl, Benzoxazolyl, Xadiazolyl, Benzisothiazolyl, Benzthiazolyl, Benzthiadiazolyl, Condensed aromatic heterocycles such as P-benzofuryl and benzochenil, tetrahydrobiranil, dihydropyridyl, dihydropyridazyl, dihydrobirazil, ethyleneoxydinyl, dioxanyl, thiiranyl, oxathiolanyl, azetidinyl, thianil, pidinidinyl,
  • substituent of the "optionally substituted hetero ring” include halogen; hydroxy; lower alkyl optionally substituted by hydroxy or acyloxy; halogen, aryl, or 5- or 6-membered Lower alkoxy which may be substituted with a hetero ring; lower alkenyl; lower alkenyloxy; lower alkynyl; lower alkynyloxy; asiloxy; carboxy; lower alkoxycarbonyl; mercapto; lower alkylthio; lower alkenylthio; Monoalkyl or lower alkyl (substituted with cycloalkyl or a 5- or 6-membered heterocycle), lower-alkenyl, cycloalkyl or lower-alkylsulfonyl optionally substituted with halogen.
  • Di-substituted Amino optionally substituted by lower alkylsulfonyl; nitro; lower alkylsulfonyl; aryl; 5- or 6-membered heterocycle; oxo; and oxosides. It may have a substituent at any position.
  • compositions of “compound (1)”, “compound (II)” or “compound (III)” include, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, Salts of mineral acids such as hydrofluoric acid and hydrobromic acid; salts of organic acids such as formic acid, acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, and succinic acid; ammonium, trimethylammonium And salts of organic bases such as triethylammonium; salts of alkali metals such as sodium and potassium; salts of alkaline earth metals such as calcium and magnesium.
  • the present invention also includes solvates of the compound of the present invention, and one molecule of the compound may be coordinated with any number of appropriate organic solvents or water molecules. Preferably, it is a hydrate. Ma In addition, all stereoisomers of the compound (I) of the present invention (for example, atrob isomers) are included.
  • the compounds (I) and (II) of the present invention are prodrugs obtained by substituting the amino group of an amino-substituted terphenyl compound with an acyloxyalkoxycarbonyl group substituted with a nonionic and hydrophilic group. It has a great feature in that
  • the obtained compound when the amino group is simply substituted with, for example, acyl or alkoxycarbonyl, the obtained compound is stable and does not revert to the active form in vivo.
  • the amino group when the amino group is substituted with aminoacyl or carboxyl, the obtained compound has reduced lipophilicity, but does not revert to the active form in vivo.
  • the amino group when the amino group is substituted with an unsubstituted acyloxyalkoxycarbonyl, it has high lipophilicity and is hardly absorbed in the body.
  • Compounds in which the amino group has been substituted with an acyloxyalkoxycarbonyl substituted with an ionic hydrophilic group such as carboxy or dialkylamino have an effect of improving hydrophilicity, but the active substance in vivo Poor resilience to In addition, they all have problems such as low yield and no crystallization, so that they cannot be industrially practically used.
  • the present invention is characterized by a combination of an amino-substituted terphenyl compound and an acyloxyalkoxycarbonyl group substituted with a nonionic and hydrophilic group.
  • Compounds (I) and (II) are all prodrugs of compounds having an immunosuppressive action and / or an antiallergic action, and among them, the following compounds are particularly preferred.
  • R 1 is --OH, one C ONH 2, one C ONH CH 3 ,-CONH C 2 H 5 one OC ⁇ NH 2 ,-0 C 0 NH 2 One OC ONH CH 3 , One OC ONH C 2 H 5 , — NH C ⁇ CH 3 , One NH C ⁇ CH 2 NH C ⁇ CH 3 , NH CO CH (Me) NHC 0 CH 3, one NH COC 2 H 5 , — CS NH 2 , one (0 CH 2 CH 2 ) n OH, one CH 3 ,-(0 CH 2 CH 2) n 0 CH 3 one CO CH 3 , - C 0 C 2 H 5, one OC_ ⁇ CH 3, one O CO C 2 H 5, one NHOH, one NH C_ ⁇ _NH 2, one NH C SNH 2, -NH S 0 2 CH 3, one N (S 0 2 CH 3 ) 2 , ⁇ S 0 2 H 2, one SO CH 3 , -S 02 CH 3 one O CH 2 CONH 2 ,
  • R 1 Gahi Dorokishi force Rubamoiru, methylcarbamoyl, E Ji carbamoyl, force Rubamoiruokishi, methylcarbamoyl O carboxymethyl, E Ji carbamoyl O carboxymethyl, Asechiruamino, from the group consisting ⁇ cetyl amino eth noisy Rua Mino and ⁇ cetyl ⁇ Mino prop Noiruamino
  • R 1 is R 1 — 2
  • R 1 Gahi Dorokishi or forces have been Ru alkyl der having 1 to 3 carbon atoms substituted with Rubamoiru (hereinafter, R 1 is R 1 - and a 3) compound,
  • R 1 is selected from the group consisting of methyl carbamoyl, ethyl carbamoyloxy, methyl rubamoyloxy, methyl methyl carbamoyloxy and ethyl carbamoyloxy
  • a compound having 1 to 5 carbon atoms and substituted with 1 or 2 groups (hereinafter,! ⁇ ⁇ is! ⁇ 1 to 5)
  • R 2 , R 3 , R 4 and R 5 are each independently hydrogen, hydroxy, halogen, Carboxy, lower alkyl optionally having substituent (s), lower alkoxy optionally having substituent (s), lower alkoxycarbonyl optionally having substituent (s), acyloxy optionally having substituent (s) , formyl, have a good amino or substituted group which may have a substituent is also good force Rubamoiru (hereinafter, 1 2 to 1 5 1 2 R 5 - and 1) compounds,
  • R 2 , R 3 , R 4 and R 5 are each independently hydrogen, hydroxy, halogen, carboxy, lower alkyl optionally having substituent (s), lower alkoxy optionally having substituent (s)
  • a lower alkoxycarbonyl which may have a substituent, an amino which may have a substituent hereinafter, R 2 to R 5 are R 2 R 5 —2)
  • R 2 , R 3 , R 4 and R 5 are each independently hydrogen, hydroxy, halogen, carboxy, lower alkyl, lower alkoxy, lower alkoxycarbonyl or amino (hereinafter, R 2 to R 5 are R 2 R 5 — 3) compound,
  • R 2 , R 3 , R 4 and R 5 are each independently hydrogen, halogen or lower alkoxy (hereinafter, R 2 to R 0 are R 2 R 5 — 4);
  • R 2 , R 3 , R 4 and R 5 are all hydrogen (hereinafter, R 2 to R 5 are R 2 R 5 — 5);
  • R 6 is hydrogen, hydroxy, halogen, carboxy, lower alkyl optionally having substituent (s), lower alkoxy optionally having substituent (s), lower alkoxy optionally having substituent (s) A carbonyl, an optionally substituted acyloxy, formyl, an optionally substituted amino or an optionally substituted rubamoyl (hereinafter, R 6 is R 6 — 1 Compound),
  • R 6 is hydrogen, hydroxy, halogen, carboxy, lower alkyl optionally having substituent (s), lower alkoxy optionally having substituent (s), lower alkoxycarbonyl optionally having substituent (s) or have a substituent is also optionally Amino (hereinafter, R 6 is assumed to be R 6 one 2) compounds, R 6 is hydrogen, arsenate Dorokishi, halogen, carboxy, lower alkyl, lower alkoxy sheet, lower alkoxycarbonyl or Amino (hereinafter, R 6 is R 6 - 3 Der Rutosuru) compound,
  • R 6 is hydrogen, lower alkyl, lower alkoxy or lower alkoxycarbonyl (hereinafter, R 6 is R 6 — 4);
  • R 6 is lower alkyl, lower alkoxy or lower alkoxycarbonyl (hereinafter, R 6 is assumed to be R 6 one 5) compounds,
  • R 7 is hydrogen, arsenate Dorokishi, halogen, carboxy, alkyl lower but it may also have a substituent group, an optionally substituted lower alkoxy, optionally substituted lower alkoxy optionally having substituent A carbonyl, an optionally substituted acyloxy, formyl, an optionally substituted amino or an optionally substituted rubamoyl (hereinafter, R 7 is R 7 — 1 Compound),
  • R 7 is hydrogen, hydroxy, halogen, carboxy, lower alkyl optionally having substituent (s), lower alkoxy optionally having substituent (s), lower alkoxycarbonyl optionally having substituent (s) or A compound which is an amino which may have a substituent (hereinafter, R 7 is R 7 — 2),
  • R 7 is hydrogen, arsenate Dorokishi, halogen, carboxy, lower alkyl, lower alkoxy sheet, lower alkoxycarbonyl or Amino (hereinafter, R 7 is R 7 - 3 Der Rutosuru) compound,
  • R 7 is hydrogen, hydroxy, lower alkyl, lower alkoxy or lower alkoxycarbonyl (hereinafter, R? Is R? -4);
  • R 7 is hydrogen, hydroxy or lower alkyl
  • R 8 is hydrogen, hydroxy, halogen, carboxy, lower alkyl optionally having substituent (s), lower alkoxy optionally having substituent (s), lower alkoxy optionally having substituent (s) Carbonyl, an optionally substituted acyloxy, A formyl, an optionally substituted amino or an optionally substituted compound rubamoyl (hereinafter, R 8 is R 8 -1),
  • R 8 is hydrogen, arsenate Dorokishi, halogen, carboxy, lower alkyl which may have a substituent, a lower alkoxy which may have a substituent group, optionally substituted lower alkoxycarbonyl which may have a substituent or A compound which is an amino which may have a substituent (hereinafter, R 8 is R 8 — 2),
  • R 8 is hydrogen, arsenate Dorokishi, halogen, carboxy, lower alkyl, lower alkoxy sheet, lower alkoxycarbonyl or Amino (hereinafter, R 8 is R 8 - 3 Der Rutosuru) compound,
  • R 8 is hydrogen, hydroxy, lower alkyl, lower alkoxy or lower alkoxy carbonyl (hereinafter, R 8 is R 8 — 4);
  • R 8 is hydrogen, hydroxy or lower alkyl
  • R 9 is hydrogen, hydroxy, halogen, carboxy, lower alkyl optionally having substituent (s), lower alkoxy optionally having substituent (s), lower alkoxy optionally having substituent (s) A carbonyl, an optionally substituted acyloxy, formyl, an optionally substituted amino or an optionally substituted rubamoyl (hereinafter, R 9 is R 9 — 1 Compound),
  • R 9 is hydrogen, hydroxy, halogen, carboxy, lower alkyl optionally having substituent (s), lower alkoxy optionally having substituent (s), lower alkoxycarbonyl optionally having substituent (s) or A compound which is an amino which may have a substituent (hereinafter, R 9 is R 9 — 2),
  • R 9 is hydrogen, arsenate Dorokishi, halogen, carboxy, lower alkyl, lower alkoxy sheet, lower alkoxycarbonyl or Amino (hereinafter, R 9 is R 9 - 3 Der Rutosuru) compound,
  • R 9 is hydrogen, lower alkyl, lower alkoxy or lower alkoxycarbonyl A compound (hereinafter, R 9 is R 9 — 4),
  • R 9 is R 9 — 5
  • R 10 , R 11 , R 12 and R 13 are each independently hydrogen, hydroxy, halogen, carboxy, lower alkyl optionally having substituent (s), and substituent (s).
  • a compound that is a compound that may have are R 10 R 13 — 1);
  • R 10 , R 11 , R 12 and R 13 each independently represent hydrogen, hydroxy, halogen, carboxy, lower alkyl which may have a substituent, or optionally substituted lower alkoxy, optionally substituted lower alkoxycarbonyl which may have a substituent group, is optionally Amino optionally having substituent (hereinafter, R 1 0 ⁇ R 1 3 is a R 1 0 R 1 3 one 2 Compound),
  • R 10 , R 11 , R 12 and R 13 are each independently hydrogen, hydroxy, halogen, carboxy, lower alkyl, lower alkoxy, lower alkoxycarbonyl or amino ( hereinafter, R 1 0 ⁇ R 1 3 is R 1 0 R 1 3 - and a 3) I spoon compound,
  • R 10 , R 11 R 12 and R 13 are each independently hydrogen, halogen or lower alkoxy (hereinafter, R 1 OR 13 is R 1 OR 13 — 4) Compound,
  • R 1 is ⁇ and R 1 1 is hydrogen, one of R 1 2 and R 1 3 is hydrogen, the other person is halogen (hereinafter, 1 1 0-1 1 3 1 1 0 11 1 3 - 5) compound,
  • R 1 0, R 1 1 and R 1 2 is hydrogen, R 1 3 is halogen (hereinafter, R 1 OR 1 3 is assumed to be R l 0 R 1 3 one 5) compounds, 8) a compound wherein R A and R B are each independently hydrogen or alkyl having 1 to 5 carbon atoms (hereinafter, R A and R B are R A R B — 1);
  • R A and R B are each independently hydrogen or alkyl having 1 to 3 carbon atoms (hereinafter, R A and R B are R A R B — 2);
  • R A and R B are R A RB-3;
  • R A is hydrogen or methyl
  • R B is hydrogen (hereinafter, R A and R B are R
  • a compound represented by the following formula (IV) (hereinafter referred to as compound (IV)) is produced by the method described in W09 7/39999 or W98 / 04 508, and It is subjected to a two-stage reaction represented by the following scheme. That is, the secondary amino group of the compound (IV) is subjected to a haloalkoxycarbonylation to give an intermediate compound represented by the following formula (V) (hereinafter, referred to as compound (V)), and then the compound (V) and an appropriate compound Compound (I) may be synthesized by reacting a carboxylic acid under appropriate conditions.
  • the method for synthesizing such an acyloxyalkyl rubbamate can be carried out according to a known method described in WO9618605 and the like.
  • compound (IV) and a monohaloalkyl chloroformate are combined with pyridine, triethylamine, tetrahydrofuran, 1,4-dioxane, ethyl acetate, or toluene in an inert solvent such as pyridine or triethyl acetate.
  • the reaction is carried out at 0 ° C to room temperature in the presence of a base such as ethylamine or N-methylmorpholine to quantitatively obtain compound (V).
  • the compound (V) is treated in a solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, or sulfolane with a salt of a carboxylic acid having the desired substituent R 1
  • the compound (I) can be obtained by reacting it with an alkaline metal salt, an alkaline earth metal salt, a silver salt, a mercury salt, etc.) at room temperature to under heating for several hours to several days.
  • the target compound can be similarly obtained by using a free carboxylic acid in the presence of a metal salt, a silver salt or the like. If this reaction is performed in the presence of KBr or NaI, C1 of compound (V) can be replaced with more reactive Br or I.
  • the compound (IV), which is a secondary amine, is a compound of the formula (4) described in US Pat. No. 4,760,057, which is a para-nitrophenyl acyloxyalkyl carbonate (p—N02 C 6 H 4 O CO 2
  • the group may be previously substituted with lower alkoxycarbonyl, lower alkenyloxycarbonyl, halogenoalkoxycarbonyl, aralkyloxycarbonyl or the like.
  • the protecting group may be removed beforehand at an appropriate stage.
  • Compound (I) which exhibits high oral absorption and is useful as a prodrug, is degraded in vivo and converted into the active compound (III) or (IV).
  • the compound (III) or (IV) produced in vivo suppresses the mitogen reaction and the neukine or cytokine reaction, and exhibits strong immunosuppressive and antiallergic effects.
  • the compound (III) or (IV) has a very strong growth inhibitory effect on T and human cells, and an inhibitory effect on the production of antibodies such as IgE and IgG. Therefore, compound (I) can be administered as a medicament for immunosuppression or antiallergy in animals including humans.
  • Immunosuppressive or fanatic allergic drugs containing compound (I) can be used for rejection of organ or tissue transplantation and graft-versus-host reaction caused by bone marrow transplantation, as well as rheumatoid arthritis, systemic lupus erythematosus, asthma, inflammatory bowel disease , Ischemia / reperfusion injury, allergic rhinitis, allergic conjunctivitis, atopy, prurigo and It is useful for preventing or treating allergic diseases such as psoriasis and psoriasis.
  • the immunosuppressant and / or the antiallergic agent containing the compound (I) When administering the immunosuppressant and / or the antiallergic agent containing the compound (I), it can be administered either orally or parenterally. Oral administration may be carried out in a usual dosage form such as tablets, granules, powders, capsules, pills, solutions, syrups, buccals or sublinguals according to a conventional method.
  • a usual dosage form such as tablets, granules, powders, capsules, pills, solutions, syrups, buccals or sublinguals according to a conventional method.
  • parenteral administration any commonly used dosage form, such as injections such as intramuscular administration and intravenous administration, suppositories, transdermal absorbers, and inhalants, can be suitably administered. In particular, oral administration is preferred.
  • compound (I) is mixed with various pharmaceutical additives such as excipients, binders, wetting agents, disintegrants, lubricants, diluents, etc., which are suitable for the dosage form. can do.
  • the preparation may be prepared by sterilizing with an appropriate carrier.
  • the excipients include lactose, sucrose, glucose, starch, calcium carbonate or crystalline cellulose
  • the binders include methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, gelatin or polyvinylpyrrole.
  • Disintegrators such as lidon, carboxymethylcellulose, sodium carboxymethylcellulose, starch, sodium alginate, agar powder or sodium lauryl sulfate, etc.
  • lubricants include talc, magnesium stearate or macrogol.
  • solubilizers when preparing a liquid formulation or an emulsion or suspension injection, commonly used solubilizers, suspending agents, emulsifiers, stabilizers, preservatives, isotonic agents, etc. are appropriately added.
  • a flavoring agent In the case of oral administration, a flavoring agent, a fragrance and the like may be added.
  • the dose of the immunosuppressant and / or antiallergic agent containing the compound of the present invention is desirably set in consideration of the patient's age, body weight, type and degree of disease, administration route, and the like.
  • When administered usually 0.05 to 100 mg / kg / day And preferably in the range of 0.1 to 10 mg / kg / day.
  • parenteral administration it varies greatly depending on the administration route, but is usually in the range of 0.05 to 10 mg / kg / day, preferably in the range of 0.01 to 1 mg / kg / day. It may be administered once or several times a day.
  • Example 1 22 g (845 mmol) of 4-durene (compound 1) and 250 g (3-fluoro-4-benzylbenzyl borate) of 3-fluoro-4-benzylboronic acid were added to ethylene glycol dimethyle Dissolve in 2.9 L of 1 ter, then add 1.7 L of 2 N aqueous sodium hydroxide solution and 13.5 g of 10% palladium-carbon solution at 80 ° C under a nitrogen atmosphere. The mixture was stirred for 2 hours and 35 minutes. After cooling the reaction solution, the insolubles were filtered and washed with water and ethyl acetate.
  • Step 2 Synthesis of Compound 2 Magnesium (56.9 g, 2340 mmol) and iodine (544 mg) were stirred under a nitrogen atmosphere in tetrahydrofuran (2,84 mL), and the compound 1 1 657 g (2,340 mmol) of tetrahydrofuran (1) was added thereto. A 5 L solution was added dropwise over 1 hour and 13 minutes, and the mixture was heated so that the internal temperature was maintained at 44 to 52 ° C. After completion of the dropwise addition, the mixture was stirred in a water bath at 50 ° C for 2 hours, and then cooled to room temperature to prepare a Grignard reagent.
  • the crude product of the compound (21) obtained above was dissolved in THF (100 ml) -methanol (500 ml), and a 3N aqueous hydroxide solution (80 ml) was added under ice cooling. For 2 hours. After the precipitated crystals were collected by filtration, they were washed with water and methanol. The obtained crystals were purified by silica gel chromatography (hexane monoacetate 10: 1) and then crystallized from ethanol (250 ml) (IV-3) (31.3 g; yield: 80). %).
  • Example 2 The compound IV-1 (943 mg, 2 mmol) obtained in Example 1 was dissolved in anhydrous ether (40 mL), cooled with ice, and stirred under a nitrogen stream while stirring chloromethyl chloroformate (387 mg, 3 mmol) and tritylamine (420 L, 3 mmol) were sequentially added, and the mixture was separated from the ice bath and further stirred for 4 hours.
  • the precipitate in the reaction solution was filtered off, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain compound V-1 (1.05 g).
  • Compound I — 7 (554 mg) was prepared in the same manner as in Example 3 from Compound I V-1 (564 mg, 1 mmol) and 2,2-bis (hydroxymethyl) propionic acid (670 mg, 5 mmol). , 86%).
  • the compounds (I-11), (I-61) and (I-91) of the present invention and the respective parent compounds (IV-1), (IV-3) and (IV-4) are placed in a mortar The mixture was ground and a 0.5% aqueous solution of methylcellulose was used as a vehicle to prepare an aqueous suspension having a concentration of 10 mg / ml.
  • Jc1 Each compound was orally administered to SD male rats (at 10 weeks of age) as a parent compound at a rate of 20 mg / kg. In advance 0.3 ml of blood was collected 0.5, 1, 2, 4, 6, 8, and 24 hours after administration from the force neurite inserted into the face vein. Blood was centrifuged to obtain plasma.
  • FIGS. 1 to 3 Changes in plasma concentration after oral administration are shown in FIGS. 1 to 3, and Cmax and AUC are shown in Table 13.
  • the compound of the present invention was not detected in the circulating plasma of the rats to which the compound of the present invention was administered, and only the parent compound was recognized. At this time, the plasma concentration of the parent compound showed a higher change in the plasma concentration than that of the parent compound administration rat, and C max and AU C were (I ⁇ 11) and (I ⁇ 61) respectively.
  • the parent compounds (IV-1) and (IV-3) increased about 2 times and (1-91) increased 4 to 5 times as compared to (IV-4).
  • Compound (I) exhibits high oral absorbability, its intermediate, and the active compound (IV) exhibits strong immunosuppressive and / or antiallergic effects. Therefore, the compounds of the present invention are very useful as immunosuppressants and / or antiallergic agents.

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Abstract

L'invention porte sur des composés de formule générale (I), leurs sels pharmacocompatibles et les solvates des deux, et sur des compositions de médicaments les contenant. Dans ladite formule: R1 est alkyle inférieur substitué par un groupe hydrophile non ionique; R?2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, et R13¿ sont chacun indépendamment H, alkyle inférieur facultativement substitué, alkoxycarbonyle inférieur facultativement substitué ou analogue; et R?A, et RB¿ sont chacun indépendamment H ou alkyle inférieur.
PCT/JP2000/004723 1999-07-19 2000-07-14 COMPOSES DE p-TERPHENYLE A CHAINES LATERALES D'ACYLOXYMETHOXYCARBONYLE WO2001005750A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003016259A3 (fr) * 2001-08-16 2003-09-12 Pharmacon Forschung & Beratung Gmbh Composes contenant des elements d'acide lactique, leur procede de preparation et leur utilisation comme principes actifs pharmaceutiques
US6818787B2 (en) 2001-06-11 2004-11-16 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US7186855B2 (en) 2001-06-11 2007-03-06 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US7232924B2 (en) 2001-06-11 2007-06-19 Xenoport, Inc. Methods for synthesis of acyloxyalkyl derivatives of GABA analogs
US8048917B2 (en) 2005-04-06 2011-11-01 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection

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Publication number Priority date Publication date Assignee Title
WO1996018605A1 (fr) * 1994-12-13 1996-06-20 Merck & Co., Inc. Acyloxyisopropylcarbamates precurseurs de medicaments amino
WO1998024508A1 (fr) * 1996-12-05 1998-06-11 Medtronic, Inc. Codage de taux d'intervalles de stimulation pour transmission externe de donnees

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996018605A1 (fr) * 1994-12-13 1996-06-20 Merck & Co., Inc. Acyloxyisopropylcarbamates precurseurs de medicaments amino
WO1998024508A1 (fr) * 1996-12-05 1998-06-11 Medtronic, Inc. Codage de taux d'intervalles de stimulation pour transmission externe de donnees

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6818787B2 (en) 2001-06-11 2004-11-16 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US6972341B2 (en) 2001-06-11 2005-12-06 Xeno Port, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US7186855B2 (en) 2001-06-11 2007-03-06 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US7232924B2 (en) 2001-06-11 2007-06-19 Xenoport, Inc. Methods for synthesis of acyloxyalkyl derivatives of GABA analogs
US7423169B2 (en) 2001-06-11 2008-09-09 Xenoport, Inc. Methods for synthesis of acyloxyalkyl derivatives of GABA analogs
US7790708B2 (en) 2001-06-11 2010-09-07 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US8168623B2 (en) 2001-06-11 2012-05-01 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US9238616B2 (en) 2001-06-11 2016-01-19 Xenoport, Inc. Prodrugs of gaba analogs, compositions and uses thereof
WO2003016259A3 (fr) * 2001-08-16 2003-09-12 Pharmacon Forschung & Beratung Gmbh Composes contenant des elements d'acide lactique, leur procede de preparation et leur utilisation comme principes actifs pharmaceutiques
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection
US8048917B2 (en) 2005-04-06 2011-11-01 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof

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