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US 2009/0156483 A1Published application
Analogs of Ghrelin
AssigneeIpsen Pharma S.A.S.
InventorsZheng Xin Dong, Michael DeWitt Culler, Yeelana Shen, Jeanne Mary Comstock
Life of this patent
Estimating the term…
Abstract
The invention comprises peptidyl analogs according to formulae (I) or (II) as depicted below: (R2R3)-A1-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13- A14-A15-A16-A17-A18-A19-A20-A21-A22-A23-A24-A25- A-26-A27-A28-R1 wherein the definitions of A1 to A28 and R1 to R3 are provided for in the specification for each of formulae (I) and (II), pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising an effective amount of a compound of formula (I), that possess agonist or antagonist ghrelin activity, along with therapeutic and non-therapeutic uses thereof.
Claims83
A compound according to formula (I):
- (R2R3)-A1-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-
- A14-A15-A16-A17-A18-A19-A20-A21-A22-A23-A24-A25A26-A27-
- A28-R1 (I)
- wherein:
- A1 is Gly, Acc, Aib, Ala or β-Ala or Acc;
- A2 is Ser, Aib, Ala, Acc, Abu, Act, Ava, Thr or Val;
- A3 is Ser, Asp(NH—R9), Asp(O—R8), Cys(S—R14), Dab(S(O)2—R11), Dap(S(O)2—R10), Glu(NH—R7), Glu(O—R6), Ser(C(O)—R4), Thr(C(O)—R5) or HN—CH((CH2)n—N(R12R13))—C(O);
- A4 is Phe, Acc, Aic, Cha, 2-Fua, 1-Nal, 2-Nal, 2-Pal, 3-Pal, 4-Pal, hPhe, (X1,X2,X3,X4,X5)Phe, Taz, 2-Thi, 3-Thi, Trp or Tyr;
- A5 is Leu, Abu, Acc, Aib, Ala, Cha, Ile, hLeu, Nle, Nva, Phe, Tle or Val;
- A6 is Ser, Abu, Acc, Act, Aib, Ala, Gly, Thr or Val;
- A7 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz or Tic;
- A8 is Glu, Acc, Aib, Arg, Asn, Asp, Dab, Dap, Gln, Lys, Orn or HN—CH((CH2)n—N(R12R13))—C(O);
- A9 is His, Apc, Aib, Acc, 2-Fua, 2-Pal, 3-Pal, 4-Pal, (X1,X2,X3,X4,X5—)Phe, Taz, 2-Thi or 3-Thi;
- A10 is Gln, Acc, Aib, Asn, Asp or Glu;
- A11 is Arg, Apc, hArg, Dab, Dap, Lys, Om or HN—CH((CH2)n—N(R12R13))—C(O);
- A12 is Val, Abu, Acc, Aib, Ala, Cha, Nva, Gly, Ile, Leu, Nle or Tle;
- A13 is Gln, Acc, Aib, Asn, Asp or Glu;
- A14 is Gln, Acc, Aib, Asn, Asp or Glu;
- A15 is Arg, hArg, Acc, Aib, Apc, Dab, Dap, Lys, Om, Asp(NH—R9), Asp(O—R8), Cys(S—R14), Cys(R15), hCys(S—R16), hCys(R17), Dab(S(O)2—R11), Dap(S(O)2—R10), Glu(NH—R7), Glu(O—R6), Ser(C(O)—R4), Thr(C(O)—R5) or HN—CH((CH2)n—N(R12R13))—C(O);
- A16 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, Asp(NH—R9), Asp(O—R8), Cys(S—R14), Cys(R15), hCys(S—R16), hCys(R17), Dab(S(O)2—R11), Dap(S(O)2—R10), Glu(NH—R7, Glu(O—R6), Ser(C(O)—R4), Thr(C(O)—R5), HN—CH((CH2)n—N(R12R13))—C(O) or deleted;
- A7 is Glu, Arg, Asn, Asp, Dab, Dap, Gln, Lys, Orn, Asp(NH—R9), Asp(O—R8), Cys(S—R14), Cys(R15), hCys(S—R16), hCys(R17), Dab(S(O)2—R11), Dap(S(O)2—R10), Glu(NH—R7), Glu(O—R6), Lys(biotinyl), Ser(C(O)—R4), Thr(C(O)—R5), HN—CH((CH2)n—N(R12R13))—C(O) or deleted;
- A18 is Ser, Abu, Acc, Act, Aib, Ala, Thr, Val, Asp(NH—R9), Asp(O—R8), Cys(S—R14), Cys(R15), hCys(S—R16), hCys(R17), Dab(S(O)2—R11), Dap(S(O)2—R10), Glu(NH—R7), Glu(O—R6), Ser(C(O)—R4), Thr(C(O)—R5), HN—CH((CH2)n—N(R12R13))—C(O) or deleted;
- A19 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, Asp(NH—R9), Asp(O—R8), Cys(S—R14), Cys(R15), hCys(S—R16), hCys(R17), Dab(S(O)2—R11), Dap(S(O)2—R10), Glu(NH—R7), Glu(O—R6), Ser(C(O)—R4), Thr(C(O)—R5), HN—CH((CH2)n—N(R12R13))—C(O) or deleted;
- A20 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, Asp(NH—R9), Asp(O—R8), Cys(S—R14), Cys(R15), hCys(S—R16), hCys(R17), Dab(S(O)2—R7), Dap(S(O)2—R10), Glu(NH—R7), Glu(O—R6), Ser(C(O)—R4), Thr(C(O)—R5), HN—CH((CH2)n—N(R12R13))—C(O) or deleted;
- A21 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic or deleted;
- A22 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic or deleted;
- A23 is Ala, Abu, Acc, Act, Aib, Apc, Gly, Nva, Val or deleted;
- A24 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, HN—CH((CH2)n—N(R12R13))—C(O) or deleted;
- A25 is Leu, Abu, Acc, Aib, Ala, Cha, Ile, hLeu, Nle, Nva, Phe, Tle, Val or deleted;
- A26 is Gln, Aib, Asn, Asp, Glu or deleted;
- A27 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic or deleted;
- A28 is Arg, Acc, Aib, Apc, hArg, Dab, Dap, Lys, Orn, HN—CH((CH2)n—N(R12R13))—C(O) or deleted;
- R1 is —OH, —NH2, —(C1-C30)alkoxy or NH—X6—CH2-Z0, wherein X6 is a (C1-C12)alkyl, (C2-C12)alkenyl and Z0 is —H, —OH, —CO2H or —C(O)—NH2;
- R2 and R3 is, independently for each occurrence thereof, selected from the group consisting of H, (C1-C30)alkyl, (C1-C30)heteroalkyl, (C1-C30)acyl, (C2-C30)alkenyl, (C2-C30)alkynyl, aryl(C1-C30)alkyl, aryl(C1-C30)acyl, substituted (C1-C30)alkyl, substituted (C1-C30)heteroalkyl, substituted (C2-C30)acyl, substituted (C2-C30)alkenyl, substituted aryl(C1-C30)alkyl and substituted aryl(C1-C30)acyl;
- R4, R5, R6, R7, R8, R9, R10, R11, R14, R15, R16 and R17 is, independently for each occurrence thereof, selected from the group consisting of (C1-C40)alkyl, (C2-C40)alkenyl, substituted (C1-C40) alkyl, substituted (C2-C40) alkenyl, alkylaryl, substituted alkylaryl, aryl and substituted aryl;
- R12 and R13 is, independently for each occurrence thereof, selected from the group consisting of H, (C1-C40)alkyl, (C1-C40)acyl, (C1-C30)alkylsulfonyl, biotinyl and —C(NH)—NH2,
- X1, X2, X3, X4, and X5 is, independently for each occurrence thereof, selected from the group consisting of H, F, Cl, Br, I, (C1-10)alkyl, substituted (C1-10)alkyl, aryl, substituted aryl, OH, NH2, NO2 and CN;
- and
- n is, independently for each occurrence thereof, 1, 2, 3, 4 or 5;
- provided that:
- (I). if R2 is (C1-C30)acyl, aryl(—C1-C30)acyl, substituted (C2-C30)acyl, or substituted aryl(C1-C30)acyl, then R3 is H, (C1-C30)alkyl, (C1-C30)heteroalkyl, (C2-C30)alkenyl, aryl(C1-C30)alkyl, substituted (C1-C30)alkyl, substituted (C1-C30)heteroalkyl, substituted (C2-C30)alkenyl or substituted aryl(C1-C30)alkyl;
- (II). if R12 is (C1-C40)acyl, (C1-C30)alkylsulfonyl, biotinyl or —C(NH)—NH2, then R13 is H or (C1-C40)alkyl;
- (III). at least one of A15, A16, A17, A18, A19 or A20 must be selected from the group consisting of Asp(NH—R9), Asp(O—R8), Cys(S—R14), Cys(R15), hCys(S—R16), hCys(R17), Dab(S(O)2—R11), Dap(S(O)2—R10), Glu(NH—R7), Glu(O—R6), Ser(C(O)—R4), Thr(C(O)—R5) and HN—CH((CH2)n—N(R12R13))—C(O);
- and
- (IV). if any member of the group consisting of A15, A16, A17, A19 and A20 is HN—CH((CH2)n—N(R12R13))—C(O), then R12 must be biotinyl;
- or a pharmaceutically acceptable salt thereof.
43 more elements
A compound according to formula (II):
- (R2R3)-A1-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-
- A14-A15-A16-A17-A18-A19-A20-A21-A22-A23-A24-A25-A26-
- A27-A28-R1 (II)
- wherein:
- A1 is Gly, Acc, Aib, Ala, β-Ala or Gly(myristyl);
- A2 is Ser, Abu, Acc, Act, Aib, Ala, Thr or Val;
- A3 is Ser, Asp(NH—R9), Asp(O—R8), Cys(S—R14), Dab(S(O)2—R11), Dap(S(O)2—R10), Glu(NH—R7), Glu(O—R6), Ser(C(O)—R4), Thr(C(O)—R5) or HN—CH((CH2)n—N(R12R13))—C(O);
- A4 is Phe, Acc, Aic, Cha, 2-Fua, 1-Nal, 2-Nal, 2-Pal, 3-Pal, 4-Pal, hPhe, (X1,X2,X3,X4,X5)Phe, Taz, 2-Thi, 3-Thi, Trp or Tyr;
- A5 is Leu, Abu, Acc, Aib, Ala, Cha, Ile, hLeu, Nle, Nva, Phe, Tle or Val;
- A6 is Ser, Abu, Acc, Act, Aib, Ala, Gly, Thr or Val;
- A7 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz or Tic;
- A8 is Glu, Acc, Aib, Arg, Asn, Asp, Dab, Dap, Gln, Lys, Orn or HN—CH((CH2)n—N(R12R13))—C(O);
- A9 is His, Acc, Aib, Apc, 2-Fua, 2-Pal, 3-Pal, 4-Pal, (X1,X2,X3,X4,X5—)Phe, Taz, 2-Thi or 3-Thi;
- A10 is Gln, Acc, Aib, Asn, Asp or Glu;
- A11 is Arg, Apc, hArg, Dab, Dap, Lys, Orn or HN—CH((CH2)n—N(R12R13))—C(O);
- A12 is Val, Abu, Acc, Aib, Ala, Cha, Nva, Gly, Ile, Leu, Nle or Tle;
- A13 is Gln, Acc, Aib, Asn, Asp or Glu;
- A14 is Gln, Acc, Aib, Asn, Asp or Glu;
- A15 is Arg, Acc, Aib, Apc, hArg, Dab, Dap, Lys, Om, Asp(NH—R9), Asp(O—R8), Cys(S—R14), Cys(R15), hCys(S—R16), hCys(R17), Dab(S(O)2—R11), Dap(S(O)2—R10), Glu(NH—R7, Glu(O—R6), Ser(C(O)—R4), Thr(C(O)—R5) or HN—CH((CH2)n—N(R12R13))—C(O);
- A16 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, Asp(NH—R9), Asp(O—R8), Cys(S—R14), Cys(R15), hCys(S—R16), hCys(R17), Dab(S(O)2—R11), Dap(S(O)2—R10), Glu(NH—R7, Glu(O—R6), Ser(C(O)—R4), Thr(C(O)—R5), HN—CH((CH2)n—N(R12R13))—C(O) or deleted;
- A17 is Glu, Arg, Asn, Asp, Dab, Dap, Gln, Lys, Orn, Asp(NH—R9), Asp(O—R8), Cys(S—R14), Cys(R15), hCys(S—R16), hCys(R17), Dab(S(O)2—R11), Dap(S(O)2—R10), Glu(NH—R7), Glu(O—R6), Lys(biotinyl), Lys(myristyl), Ser(C(O)—R4), Thr(C(O)—R5), HN—CH((CH2)n—N(R12R13))—C(O) or deleted;
- A18 is Ser, Abu, Acc, Act, Aib, Ala, Thr, Val, Asp(NH—R9), Asp(O—R8), Cys(S—R14), Cys(R15), hCys(S—R16), hCys(R17), Dab(S(O)2—R11), Dap(S(O)2—R10), Glu(NH—R7), Glu(O—R6), Ser(C(O)—R4), Thr(C(O)—R5), HN—CH((CH2)n—N(R12R13))—C(O) or deleted;
- A19 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, Asp(NH—R9), Asp(O—R8), Cys(S—R14), Cys(R15), hCys(S—R16), hCys(R17), Dab(S(O)2—R11), Dap(S(O)2—R10), Glu(NH—R7), Glu(O—R6), Ser(C(O)—R4), Thr(C(O)—R5), HN—CH((CH2)n—N(R12R13))—C(O) or deleted;
- A20 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, Asp(NH—R9), Asp(O—R8), Cys(S—R14), Cys(R15), hCys(S—R16), hCys(R17), Dab(S(O)2—R7), Dap(S(O)2—R10), Glu(NH—R7), Glu(O—R6), Ser(C(O)—R4), Thr(C(O)—R5), HN—CH((CH2)n—N(R12R13))—C(O) or deleted;
- A21 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic or deleted;
- A22 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic or deleted;
- A23 is Abu, Acc, Act, Aib, Ala, Apc, Gly, Nva, Val or deleted;
- A24 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, HN—CH((CH2)n—N(R12R13))—C(O) or deleted;
- A25 is Leu, Abu, Acc, Aib, Ala, Cha, Ile, hLeu, Nle, Nva, Phe, Tle, Val or deleted;
- A26 is Gln, Aib, Asn, Asp, Glu or deleted;
- A27 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic or deleted;
- A28 is Acc, Aib, Apc, Arg, hArg, Dab, Dap, Lys, Orn, HN—CH((CH2)n—N(R12R13))—C(O) or deleted;
- R1 is —OH, —NH2, —(C1-C30)alkoxy or NH—X6—CH2-Z0, wherein X6 is a (C1-C12)alkyl or (C2-C12)alkenyl and Z0 is —H, —OH, —CO2H or —C(O)—NH2;
- each of R2 and R3 is, independently for each occurrence thereof, selected from the group consisting of H, (C1-C30)alkyl, (C1-C30)heteroalkyl, (C1-C30)acyl, (C2-C30)alkenyl, (C2-C30)alkynyl, aryl(C1-C30)alkyl, aryl(C1-C30)acyl, substituted (C1-C30)alkyl, substituted (C1-C30)heteroalkyl, substituted (C2-C30)acyl, substituted (C2-C30)alkenyl, substituted aryl(C1-C30)alkyl, substituted (C2-C30)alkynyl and substituted aryl(C1-C30)acyl or may be deleted;
- each of R4, R5, R6, R7, R8, R9, R10, R11, R14, R15, R16 and R17 is, independently for each occurrence thereof, selected from the group consisting of (C1-C40)alkyl, (C2-C40)alkenyl, substituted (C1-C40) alkyl, substituted (C2-C40) alkenyl, alkylaryl, substituted alkylaryl, aryl and substituted aryl;
- each of R12 and R13 is, independently for each occurrence, selected from the group consisting of H, (C1-C40)alkyl, (C1-C40)heteroalkyl, (C1-C40)acyl, (C2-C40)alkenyl, (C2-C40)alkynyl, aryl(C1-C40)alkyl, aryl(C1-C40)acyl, substituted (C1-C40)alkyl, substituted (C1-C40)heteroalkyl, substituted (C1-C40)acyl, substituted (C2-C40)alkenyl, substituted (C2-C40)alkynyl, substituted aryl(C1-C40)alkyl, substituted aryl(C1-C40)acyl, (C1-C40)alkylsulfonyl, —C(NH)—NH2 and biotinyl;
- n is, independently for each occurrence thereof, 1, 2, 3, 4 or 5;
- each of X1, X2, X3, X4, and X5 is, independently for each occurrence thereof, selected from the group consisting of H, F, Cl, Br, I, (C1-10)alkyl, substituted (C1-C10)alkyl, aryl, substituted aryl, OH, NH2, NO2 and CN;
- provided that:
- (I) when R2 is (C1-C30)acyl, aryl(C1-C30)acyl, substituted (C2-C30)acyl, or substituted aryl(C1-C30)acyl, then R3 is H, (C1-C30)alkyl, (C1-C30)heteroalkyl, (C2-C30)alkenyl, aryl(C1-C30)alkyl, substituted (C1-C30)alkyl, substituted (C2-C30)heteroalkyl, substituted (C2-C30)alkenyl, substituted (C2-C30)alkynyl or substituted aryl(C1-C30)alkyl;
- (II) when R12 is (C1-C40)acyl, aryl(C1-C40)acyl, substituted (C1-C40)acyl, substituted aryl(C1-C40)acyl, (C1-C40)alkylsulfonyl, or —C(NH)—NH2, then R13 is H or (C1-C40)alkyl, (C1-C40)heteroalkyl, (C2-C40)alkenyl, (C2-C40)alkynyl, aryl(C1-C40)alkyl, substituted (C1-C40)alkyl, substituted (C1-C40)heteroalkyl, substituted (C2-C40)alkenyl, substituted (C2-C40)alkynyl, or substituted aryl(C1-C40)alkyl;
- (III) at least one of A15, A16, A17, A18, A19 or A20 of said ghrelin analog is selected from the group consisting of Asp(NH—R9), Asp(O—R8), Cys(S—R14), Cys(R15), hCys(S—R16), hCys(R17), Dab(S(O)2—R11), Dap(S(O)2—R10), Glu(NH—R7), Glu(O—R6), Ser(C(O)—R4), Thr(C(O)—R5) and HN—CH((CH2)n—N(R12R13))—C(O);
- and
- (IV) when any of the group consisting of A15, A16, A17, A19 and A20 is HN—CH((CH2)n—N(R12R13))—C(O), then R12 must be biotinyl;
- or a pharmaceutically acceptable salt thereof.
42 more elements
Dependencies are inferred from the claim text.