Nova Patents
IL260511A

Prodrugs of fumarates and their use in treating various diseases

Abstract

This record has no abstract on file.

IL260511A, drawing sheet 1
Sheet 1 of 21

Term

No projected expiry on record.

  1. Priority
  2. Filed
  3. Published
  4. Today

26 claims: 15 independent, 11 dependent

  1. 1
    CLAIMS 1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof:O XT [1 ^R1 r3 o (i). wherein: Ri is methyl;La is unsubstituted C2-C6 alkyl linker;R2 is H, C1-C6 alkyl, C6-C10 aryl, or C3-C10 carbocycle, wherein the alkyl, aryl, or carbocycle groups may be optionally independently substituted one or more times with C1-C3alkyl, OH, O(C1־C4 alkyl), SO2(C1-C6 alkyl), C02H, or CO2(C1-C6 alkyl);and R3 is C1-C6 alkyl, C6-C10 aryl, or C3-C10 carbocycle, wherein the alkyl, aryl, or carbocycle groups may be optionally independently substituted one or more times with C1־C3־alkyl, OH, O(C1-C4 alkyl), SO2(C1־C6 alkyl), C02H, or CO2(C1־C6 alkyl).
  2. 3
    The compound or pharmaceutically acceptable salt according to any of the preceding claims, wherein La is an unsubstituted C2 alkyl linker.
  3. 4
    The compound or pharmaceutically acceptable salt according to any one of the preceding claims, wherein R3 is C6-C10 aryl or C3-C10 carbocycle.
  4. 6
    A compound of Formula (la), or a pharmaceutically acceptable salt thereof:260511/2 wherein: Ri is unsubstituted C1-C6 alkyl;La is unsubstituted C1-C6 alkyl linker;and R2 is unsubstituted C1-C6 alkyl.
  5. 7
    A compound of Formula (lb):O wherein: A' is a pharmaceutically acceptable anion;Ri is unsubstituted methyl;La is unsubstituted C2 alkyl linker;R3’ is unsubstituted C1-C6 alkyl;and R2 and R3 are each, independently, unsubstituted C1-C6 alkyl.
  6. 8
    A compound of Formula (II), or a pharmaceutically acceptable salt thereof:260511/2 wherein: Ri is unsubstituted methyl;R4 is H, unsubstituted C1-C6 alkyl, or unsubstituted C6-C10 aryl;R5 is unsubstituted C1-C6 alkyl, unsubstituted C6-C10 aryl, or unsubstituted C3-C10 carbocycle;R6, R7, R8 and R9 are each, independently, H, or unsubstituted C!-C6 alkyl.
  7. 9
    A compound of Formula (III), or a pharmaceutically acceptable salt thereof:wherein: R! is unsubstituted methyl;Z is C or N;m is 0, 1, 2, or 3;tisO, 1,2,3,4, 5, 6, 7, 8, 9 or 10;260511/2 R6, R7, R8 and R9 are each, independently, H or unsubstituted C1-C6 alkyl;and each Rio is, independently, H, halogen, or unsubstituted C1-C6 alkyl;or, alternatively, two Rio’s attached to the same carbon atom, together with the carbon atom to which they are attached, form a carbonyl, or unsubstituted C3-C10 carbocycle;or, alternatively, two Rio’s attached to different atoms, together with the atoms to which they are attached, form an unsubstituted C3-C10 carbocycle.
  8. 10
    A compound of Formula (IV), or a pharmaceutically acceptable salt thereof:C XT fl ^R1r3 O (IV);wherein: Ri is unsubstituted methyl;La is unsubstituted C2-C6 alkyl linker;R2 and R3 are each, independently, H, unsubstituted acyl, NR14R15, C(S)Rn, C(S)SRn, C(S)NRnR12, C(S)NRhNR13R14, C(NR!3)NRhR12, unsubstituted C1-C6 alkyl, unsubstituted C6C10 aryl, or unsubstituted C3-C10 carbocycle;Rn and R12 are each, independently, H, unsubstituted C1-C6 alkyl or unsubstituted C6-C10 aryl;R13 is H or unsubstituted C1-C6 alkyl;and R14 and R15 are each, independently, H, unsubstituted acyl, or unsubstituted C1-C6 alkyl;wherein at least one of R2 and R3 is unsubstituted acyl, NR14R15, C(S)Rn, C(S)SRn, C(S)NR״R12, C(S)NRhNR13R14, or C(NR13)NRnR12.
  9. 13
    A compound of Formula (III), or a pharmaceutically acceptable salt thereof:wherein: R! is unsubstituted methyl;X is S or SO2;n is 1 or 2;w is 0, 1, 2, or 3;tisO, 1,2,3,4, 5, 6, 7, 8, 9 or 10;R6, R7, R8 and R9 are each H;and each Rio is, independently, H, halogen, or unsubstituted C1-C6 alkyl;or, alternatively, two Rio’s attached to the same carbon atom, together with the carbon atom to which they are attached, form a carbonyl.
  10. 16
    The compound or pharmaceutically acceptable salt according to any one of claims 13-15, wherein each R!o is, independently, H or halogen.
  11. 17
    The compound or pharmaceutically acceptable salt according to any one of claims 13-15, wherein two Rio’s attached to the same carbon atom, together with the carbon atom to which they are attached, form a carbonyl.
  12. 18
    A compound selected from the group consisting of:1 ho2c^ o HO2C^N^\oA^\^OMe 0 2 ο0' ״ Ο 3 1 ίι 1 0 6 1 י II 0 ר S^| 0 Ν ^^OMe 0 8 ס=ל Ο=( Ο CD 9 I ? Ο 10 °'׳ζ° Η Ο 260511/2 11 0%^ 0 1^Ν^χθΑ^χ^ΟΜθ 0 12 ? י x^N^^-A^^OMe 0 13 H י S A^^OMe 0 19 ? י ^Ν^/χθΑ^γΟΜβ O 20 > 0 ^Ν^^θΑ^γΟΜβ 0 25 0־ '—1 ° O 26 0) S o o^ l·) /^-°1 O—' 27 o^° o ^^^׳'׳o^׳^' o o 28 o ן^׳ס X-׳ \z N Χχ^ο'^'^γ0171׳® o 29 0I 11 χ׳^\χ N χχ׳ζ^κθ'ζ^Χ^χΝ<׳׳'θ “ ® O 260511/2 30 ο L ,A _OMe O jf >ך Ο Ο 31 ο ο ן^׳״ס k^N.^x^JL^s^OMe Ο 32 0 SZ׳׳ Q 0 33 0 ן^0 /Νχ Ο 34 (<γ ο k״z Ν * 0 35 0 0^ 2 γ^Α^γ0״' 39 ζ°Ύ° 0 0 40 0, /\ 0 Ύ־־Γ ην\^ν Τ °^ί 41 Η ״ ΎΝ'׳׳׳׳׳׳' 0 Ο 42 /γ° ο /״׳Χζ״ Ν 0 ο 260511/2 43 Ύ° ° Ο 44 0 0 0 45 Η Ν ΝΗ2 0 46 PhHN. ..S Ο Η Ν Ο 47 I U 1 ο ο 49 Λ—ζ \ ΖΙ \=Ο Ο=ς ο 5 ο 50 Ο® 0® ΖΙ ο S φ 51 Α Η U 11 ° Ιϊ Ο Ο 52 Α Η U ןן O ^׳-י^ >ך Ο ο 55 .0 Ο 0 260511/2 57 \ ζθ 0 0 58 H ץ γ' ο O 59 O ־^ך N xx^QZ^F^x^OMe 1 O 60 f/° 0 ^z׳ N Xz^o A^yOMe 0 61 CN //° ° ^Z׳N Xz^Q-'F^X^OMe OH 0 62 H O^N^O _ O N____׳^θζ-^χ^γΟΜβ o 64 o ך־־־/ HN\^Fz^X^z^\ ^x ^OMe Y ס S O 66 0ύ° 0 N N x^z^qz-^j^^ O 67 0ύ° 0H N γ׳ N Xz^0-׳^FjX^ 0 0 260511/2 68 / Ο \=° ° X Ο i-5 1 V Ζ- ζ 69 V ο \χΝ·^χ״׳χ >ך ^־־^ 0 '׳״χ >ך 0 1 70 Η ί? ^χχ^ Ν Ο 71 Η ״ Ν Xx׳׳\o׳^X^X״xOMe 1 Ο 72 ° χκ,Ν χχ^Λ-^Χ^Χχ׳ΟΜθ ζΧ ο 73 I U — Ν —’ ׳׳׳- 1 Ο 74 Η ״ χχ. Ν xx^0-''UX^i;\Y ο 75 0 Ο 76 0 Ζ/\Χ || π ° Ο ^^Νχ^χ^θχ^Χ^Χ^χΟΜβ Ο 77 Ο ο ^Ν'^^θ'Υ^^'^ΟΜβ Η S 78 ״ Η ״ A .OMe >ך ho ο ο 260511/2 OH 79 HO^ HO''^ OH 0 >x.OMe 80 0 vOMe 1 0 81 'N^ k^N o χ^χθΛ ^;;;i^x^OMe HO^ o 82 ^x.OMe O | 0 83 .N^ \.OMe O 84 i| *ך H ___N^ o ίχ,ΟΜβ O 85 7χ.Ν> ^x^OMe η2ν^ O [*****^ CN O 86 .N^ ζχ χ,ΟΜβ O 87 O^־ H xX ο ^X-OMe O 88 H ΓΧ.Ν, ο ^x^OMe h2nx^! 0 260511/2 89 ΊΡ1 η ? ~χ*\ x~. ,A HO Ο ך< Ο 90 Pi ״ ν χχ0^׳ Α^^χ^οΜβ 0 91 ^°Ίθί Η 1 ״ ___^«A^x^OMe η2ν ο ο 92 0 11 —S=O S ° \ χχ___. Ν ^χ^θ JU^X^ 0^'' Π 0 0 93 S^^l ο Ν χχ>\ο Αχ^χ^ΟΜβ Ο Ο 94 0 Ιχ^Ν^χ-χ ΑχίΧ .OMe >ן ^׳,׳^ 0 Xr S ο 95 oSs^ ο ^Xx׳ Ν ''X^o''^'''''^S'V''OMe 0 0 96 α> S ο \=ο ο^ b y—Ζ \ ^=W xW—' °δ 98 1 1 U Ν____Λθ A^x^OMe 0 260511/2 99 u ן 1 o 100 I u /\ 0 fl ' ' 0 101 ן V u χ N____Ko A^x^OMe 0 102 HO>^ N׳־^! O I_____. N ^/\q As^X^OMe O 103 H ? ζκ ζ^κ/^Α^ΖΚ/ΟΜε 106 N-nh 0 NL· N A^VzOMe Y ° Y s o 107 O ף=/ N A^\^OMe O 108 O ף=־/ N A^\^OMe O י 109 O ף==/ N A^yOMe O 110 0 ^==/ ®^01'׳ץך^^^׳ס^׳^ N ' O 111 /=& o N ^־/^Οχ^χ<^Χ||^ΟΜθ \===/ O 260511/2 112 /=N ^O' 0 s-OMe O .n=N 0 113 Z 1 x-OMe O o 114 91^ \.OMe °^nh2 0 115 ,n=N 0 ^,ΟΜβ O /=N o 116 <.ΟΜε O 117 HN^N^z o ix^OMe O O 118 N<zNs/ 0 S\.OMe o 119 Ι^,Ν___ x.OMe 120 |l J H 0 O H ΟγΝχ 0 121 J^NH 0 260511/2 122 Α Η ? 1X JU .OMe 11 Υ S Ο 123 Η ״ MeS.____ Ν____ Υ ° Υ S ο 124 Η Η ? /ΝγΝ^θΛ^θΜθ 0 0 125 Ο ο 11 Η Η 11 ζχΑ,,Ν . Ν .___zs. Χ^χ,ΟΜβ 11 ך Η Υ 0 Υ 1χ^ S 0 126 0 ף=/ ΗΝ^Ν. ^χχ JL xjX .OMe Γ 0 Π 0 0 127 0 Ν χζ^0־ζ^χ^^ 0 128 Η Ν Ν^^-χ >U^ix^OMe s—ζ ο ך< ο ° 129 Η Ν Oj>_zX^N^^׳x ΧχίΧ .OMe kJ 0 131 ο ^x~ ^?χ ^OMe ^ןך ο ο 132 ,0 f\ 0Ν ׳׳׳X ο 0 260511/2 or a pharmaceutically acceptable salt thereof;or a compound wherein A' is a pharmaceutically acceptable anion.
  13. 19
    A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt as defined in any one of claims 1-18, together with a pharmaceutically acceptable diluent or carrier.
  14. 23
    The compound, pharmaceutically acceptable salt, or pharmaceutical composition for use of any one of claims 20-22, wherein it is the pharmaceutically acceptable salt that is for said use.
  15. 24
    A pharmaceutical composition when used for the treatment of a neurological disease, wherein the pharmaceutical composition comprises a compound or a pharmaceutically 260511/2 acceptable salt as defined in any one of claims 1-18, together with a pharmaceutically acceptable diluent or carrier.
Independent claims15