DERIVATIVES OF GLP-1 ANALOGS
First Claim
Patent Images
1. A pharmaceutical composition comprising a GLP-1 derivative of formula I (SEQ ID No:
- 2);
wherein Xaa at position 8 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 9 is Glu, Asp, or Lys, Xaa at position 11 is Thr, Ala, Gly, Ser, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 14 is Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 16 is Val, Ala, Gly, Ser, Thr, Leu, Ile, Tyr, Glu, Asp, or Lys, Xaa at position 17 is Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 18 is Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 19 is Tyr, Phe, Trp, Glu, Asp, or Lys, Xaa at position 20 is Leu, Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 21 is Glu, Asp, or Lys, Xaa at position 22 is Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 23 is Gln, Asn, Arg, Glu, Asp, or Lys, Xaa at position 24 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Arg, Glu, Asp, or Lys, Xaa at position 25 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 26 is Lys, Arg, Gln, Glu, Asp, or His, Xaa at position 27 is Glu, Asp, or Lys, Xaa at position 30 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 31 is Trp, Phe, Tyr, Glu, Asp, or Lys, Xaa at position 32 is Leu, Gly, Ala, Ser, Thr, Ile, Val, Glu, Asp, or Lys, Xaa at position 33 is Val, Gly, Ala, Ser, Thr, Leu, Ile, Glu, Asp, or Lys, Xaa at position 34 is Lys, Arg, Glu, Asp, or His, Xaa at position 35 is Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 36 is Arg, Lys, Glu, Asp, or His, Xaa at position 37 is Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, or is deleted, Xaa at position 38 is Arg, Lys, Glu, Asp, or His, or is deleted, Xaa at position 39 is Arg, Lys, Glu, Asp, or His, or is deleted, Xaa at position 40 is Asp, Glu, or Lys, or is deleted, Xaa at position 41 is Phe, Trp, Tyr, Glu, Asp, or Lys, or is deleted, Xaa at position 42 is Pro, Lys, Glu, or Asp, or is deleted, Xaa at position 43 is Glu, Asp, or Lys, or is deleted, Xaa at position 44 is Glu, Asp, or Lys, or is deleted, and Xaa at position 45 is Val, Glu, Asp, or Lys, or is deleted, or (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that (i) when the amino acid at position 37, 38, 39, 40, 41, 42, 43 or 44 is deleted, then each amino acid downstream of the amino acid is also deleted, (ii) the derivative of the GLP-1 analog contains only one or two Lys, (iii) the ε
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17His-Xaa-Xaa-Gly-Xaa-Phe-Thr-Xaa-Asp-Xaa-Xaa- 18
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28Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Phe- 29
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38Ile-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa 39
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45Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa
-amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and (iv) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and
a surfactant.
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Abstract
The present invention relates to a pharmaceutical composition comprising a GLP-1 derivative having a lipophilic substituent; and a surfactant.
104 Citations
238 Claims
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1. A pharmaceutical composition comprising a GLP-1 derivative of formula I (SEQ ID No:
- 2);
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17His-Xaa-Xaa-Gly-Xaa-Phe-Thr-Xaa-Asp-Xaa-Xaa- 18
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28Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Phe- 29
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38Ile-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa 39
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45Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa wherein Xaa at position 8 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 9 is Glu, Asp, or Lys, Xaa at position 11 is Thr, Ala, Gly, Ser, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 14 is Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 16 is Val, Ala, Gly, Ser, Thr, Leu, Ile, Tyr, Glu, Asp, or Lys, Xaa at position 17 is Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 18 is Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 19 is Tyr, Phe, Trp, Glu, Asp, or Lys, Xaa at position 20 is Leu, Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 21 is Glu, Asp, or Lys, Xaa at position 22 is Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 23 is Gln, Asn, Arg, Glu, Asp, or Lys, Xaa at position 24 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Arg, Glu, Asp, or Lys, Xaa at position 25 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 26 is Lys, Arg, Gln, Glu, Asp, or His, Xaa at position 27 is Glu, Asp, or Lys, Xaa at position 30 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 31 is Trp, Phe, Tyr, Glu, Asp, or Lys, Xaa at position 32 is Leu, Gly, Ala, Ser, Thr, Ile, Val, Glu, Asp, or Lys, Xaa at position 33 is Val, Gly, Ala, Ser, Thr, Leu, Ile, Glu, Asp, or Lys, Xaa at position 34 is Lys, Arg, Glu, Asp, or His, Xaa at position 35 is Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 36 is Arg, Lys, Glu, Asp, or His, Xaa at position 37 is Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, or is deleted, Xaa at position 38 is Arg, Lys, Glu, Asp, or His, or is deleted, Xaa at position 39 is Arg, Lys, Glu, Asp, or His, or is deleted, Xaa at position 40 is Asp, Glu, or Lys, or is deleted, Xaa at position 41 is Phe, Trp, Tyr, Glu, Asp, or Lys, or is deleted, Xaa at position 42 is Pro, Lys, Glu, or Asp, or is deleted, Xaa at position 43 is Glu, Asp, or Lys, or is deleted, Xaa at position 44 is Glu, Asp, or Lys, or is deleted, and Xaa at position 45 is Val, Glu, Asp, or Lys, or is deleted, or (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that (i) when the amino acid at position 37, 38, 39, 40, 41, 42, 43 or 44 is deleted, then each amino acid downstream of the amino acid is also deleted, (ii) the derivative of the GLP-1 analog contains only one or two Lys, (iii) the ε
-amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and(iv) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and
a surfactant. - View Dependent Claims (28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118)
- 2);
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2. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising one or more of the following substitutions:
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(a) Ala at position 8 is substituted with Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, (b) Glu at position 9 is substituted with Asp or Lys, (c) Thr at position 11 is substituted with Ala, Gly, Ser, Leu, Ile, Val, Glu, Asp, or Lys, (d) Ser at position 14 is substituted with Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, or Lys, (e) Val at position 16 is substituted with Val, Ala, Gly, Ser, Thr, Leu, Ile, Tyr, Glu, Asp, or Lys, (f) Ser at position 17 is substituted with Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, or Lys, (g) Ser at position 18 is substituted with Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, or Lys, (h) Tyr at position 19 is substituted with Tyr, Phe, Trp, Glu, Asp, or Lys, (i) Leu at position 20 is substituted with Leu, Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, (j) Glu at position 21 is substituted with Glu, Asp, or Lys, (k) Gly at position 22 is substituted with Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, (l) Gln at position 23 is substituted with Gln, Asn, Arg, Glu, Asp, or Lys, (m) Ala at position 24 is substituted with Ala, Gly, Ser, Thr, Leu, Ile, Val, Arg, Glu, Asp, or Lys, (n) Ala at position 25 is substituted with Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, (o) Lys at position 26 is substituted with Arg, Gln, Glu, Asp, or His, (p) Glu at position 27 is substituted with Asp or Lys, (q) Ala at position 30 is substituted with Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, (r) Trp at position 31 is substituted with Phe, Tyr, Glu, Asp, or Lys, (s) Leu at position 32 is substituted with Gly, Ala, Ser, Thr, Ile, Val, Glu, Asp, or Lys, (t) Val at position 33 is substituted with Gly, Ala, Ser, Thr, Leu, Ile, Glu, Asp, or Lys, (u) Lys at position 34 is substituted with Arg, Glu, Asp, or His, (v) Gly at position 35 is substituted with Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, (w) Arg at position 36 is substituted with Lys, Glu, Asp, or His, (x) Gly at position 37 is substituted with Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, (y) Arg at position 38 is substituted with Lys, Glu, Asp, or His, and (z) Arg at position 39 is substituted with Lys, Glu, Asp, or His, or (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that (i) the derivative of the GLP-1 analog contains only one or two Lys, (ii) the ε
-amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and
a surfactant.
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3. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Ala at position 8 with Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that
(i) the derivative of the GLP-1 analog contains only one or two Lys, (ii) the ε - -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and
a surfactant.
- -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
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4. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Ser at position 18 with Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that
(i) the derivative of the GLP-1 analog contains only one or two Lys, (ii) the ε - -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and
a surfactant.
- -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
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5. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Tyr at position 19 with Phe, Trp, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that
(i) the derivative of the GLP-1 analog contains only one or two Lys, (ii) the ε - -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and
a surfactant.
- -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
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6. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Leu at position 20 with Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that
(i) the derivative of the GLP-1 analog contains only one or two Lys, (ii) the ε - -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and
a surfactant.
- -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
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7. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Glu at position 21 with Asp or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that
(i) the derivative of the GLP-1 analog contains only one or two Lys, (ii) the ε - -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and
a surfactant.
- -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
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8. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Gly at position 22 with Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that
(i) the derivative of the GLP-1 analog contains only one or two Lys, (ii) the ε - -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and
a surfactant.
- -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
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9. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Gln at position 23 with Asn, Arg, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that
(i) the derivative of the GLP-1 analog contains only one or two Lys, (ii) the ε - -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and
a surfactant.
- -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
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10. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Ala at position 24 with Gly, Ser, Thr, Leu, Ile, Val, Arg, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that
(i) the derivative of the GLP-1 analog contains only one or two Lys, (ii) the ε - -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and
a surfactant. - View Dependent Claims (25, 26, 27)
- -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
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11. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Ala at position 25 with Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that
(i) the derivative of the GLP-1 analog contains only one or two Lys, (ii) the ε - -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and
a surfactant.
- -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
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12. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Lys at position 26 with Arg, Gln, His, Glu, or Asp, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that
(i) the derivative of the GLP-1 analog contains only one or two Lys, (ii) the ε - -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and
a surfactant. - View Dependent Claims (13)
- -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
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14. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Glu at position 27 with Asp or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that
(i) the derivative of the GLP-1 analog contains only one or two Lys, (ii) the ε - -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and
a surfactant.
- -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
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15. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Ala at position 30 with Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that
(i) the derivative of the GLP-1 analog contains only one or two Lys, (ii) the ε - -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and
a surfactant.
- -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
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16. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Trp at position 31 with Phe, Tyr, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that
(i) the derivative of the GLP-1 analog contains only one or two Lys, (ii) the ε - -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and
a surfactant.
- -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
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17. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Leu at position 32 with Gly, Ala, Ser, Thr, Ile, Val, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that
(i) the derivative of the GLP-1 analog contains only one or two Lys, (ii) the ε - -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and
a surfactant.
- -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
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18. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Val at position 33 with Gly, Ala, Ser, Thr, Leu, Ile, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that
(i) the derivative of the GLP-1 analog contains only one or two Lys, (ii) the ε - -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and
a surfactant.
- -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
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19. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Lys at position 34 with Arg, Glu, or Asp, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that
(i) the derivative of the GLP-1 analog contains only one or two Lys, (ii) the ε - -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and
a surfactant. - View Dependent Claims (20)
- -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
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21. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Gly at position 35 with Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that
(i) the derivative of the GLP-1 analog contains only one or two Lys, (ii) the ε - -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and
a surfactant.
- -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
-
22. A pharmaceutical composition comprising a GLP-1derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Arg at position 36 with His, Lys, Glu, or Asp, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that
(i) the derivative of the GLP-1analog contains only one or two Lys, (ii) the ε - -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
(iii) the total number of different amino acids between the derivative of the GLP-1analog and the corresponding native form of GLP-1does not exceed six; and
a surfactant.
- -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
-
23. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Gly at position 37 with Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that
(i) the derivative of the GLP-1 analog contains only one or two Lys, (ii) the ε - -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and
a surfactant.
- -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
-
24. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Arg at position 38 with His, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that
(i) the derivative of the GLP-1 analog contains only one or two Lys, (ii) the ε - -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and
a surfactant.
- -amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and
- 119. A pharmaceutical composition comprising a GLP-1 derivative wherein at least one amino acid residue of the parent peptide has a lipophilic substituent attached with the proviso that if only one lipophilic substituent is present and this substituent is attached to the N-terminal or to the C-terminal amino acid residue of the parent peptide then this substituent is an alkyl group or a group which has an ω
-
128. A pharmaceutical composition comprising a derivative of GLP-1(7-C), wherein C is selected from the group comprising 38, 39, 40, 41, 42, 43, 44 and 45 which derivative has just one lipophilic substituent which is attached to the C-terminal amino acid residue;
- and a surfactant.
-
162. A pharmaceutical composition comprising a derivative of GLP-1(A-B) wherein A is an integer from 1 to 7 and B is an integer from 38 to 45 or an analogue thereof comprising one lipophilic substituent attached to the C-terminal amino acid residue and a second lipophilic substituent attached to one of the other amino acid residues;
- and a surfactant.
-
163. A pharmaceutical composition comprising a GLP-1 derivative of formula II
A-GLP-1(19-B)-X -
(II)wherein A is a peptide having the amino acid residues of GLP-1(8-18) or a fragment thereof;
B is an integer in the range of 35-45; and
X is —
OH, —
NH2, or a C1-6 alkyl amide or C1-6 dialkyl amide group;
or an analogue thereof;
and wherein a lipophilic substituent (optionally via a spacer) is attached to at least one amino acid residue; and
a surfactant.- View Dependent Claims (164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223)
wherein Xaa at position 8 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, or is deleted, Xaa at position 9 is Glu, Asp, or Lys, or is deleted, Xaa at position 10 is Gly or is deleted, Xaa at position 11 is Thr, Ala, Gly, Ser, Leu, Ile, Val, Glu, Asp, or Lys, or is deleted, Xaa at position 12 is Phe or is deleted, Xaa at position 13 is Thr or is deleted, Xaa at position 14 is Ser, Ala, Gly, Thr, Leu, Be, Val, Glu, Asp, or Lys, or is deleted, Xaa at position 15 is Asp or is deleted, Xaa at position 16 is Val, Ala, Gly, Ser, Thr, Leu, Ile, Tyr, Glu , Asp, or Lys, or is deleted, Xaa at position 17 is Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, or Lys, or is deleted, Xaa at position 18 is Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 19 is Tyr, Phe, Trp, Glu, Asp, or Lys, Xaa at position 20 is Leu, Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 21 is Glu, Asp, or Lys, Xaa at position 22 is Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 23 is Gln, Asn, Arg, Glu, Asp, or Lys, Xaa at position 24 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Arg, Glu, Asp, or Lys, Xaa at position 25 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 26 is Lys, Arg, Gln, Glu, Asp, or His, Xaa at position 27 is Glu, Asp, or Lys, Xaa at position 30 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 31 is Trp, Phe, Tyr, Glu, Asp, or Lys, Xaa at position 32 is Leu, Gly, Ala, Ser, Thr, Ile, Val, Glu, Asp, or Lys, Xaa at position 33 is Val, Gly, Ala, Ser, Thr, Met, Leu, Ile, Glu, Asp, or Lys, Xaa at position 34 is Lys, Arg, Glu, Asp, or His, Xaa at position 35 is Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 36 is Arg, Lys, Glu, Asp, or His, Xaa at position 37 is Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, or is deleted, Xaa at position 38 is Arg, Lys, Glu, Asp, or His, or is deleted, Xaa at position 39 is Arg, Lys, Glu, Asp, or His, or is deleted, Xaa at position 40 is Asp, Glu, or Lys, or is deleted, Xaa at position 41 is Phe, Trp, Tyr, Glu, Asp, or Lys, or is deleted, Xaa at position 42 is Pro, Lys, Glu, or Asp, or is deleted, Xaa at position 43 is Glu, Asp, or Lys, or is deleted, Xaa at position 44 is Glu, Asp, or Lys, or is deleted, and Xaa at position 45 is Val, Glu, Asp, or Lys, or is deleted, or (a) a C-1-6-ester thereof, (b) an amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, wherein (i) when the amino acid at position 9, 10, 11, 12, 13, 14, 15, 16 or 17 is deleted, then each amino acid upstream of the amino acid is also deleted, (ii) when the amino acid at position 37, 38, 39, 40, 41, 42, 43 or 44 is deleted, then each amino acid downstream of the amino acid is also deleted, (iii) a lipophilic substituent is attached optionally via a spacer to one or more of (a) the amino group of the N-terminal amino acid, (b) the carboxy group of the C-terminal amino acid, (C) the ε
-amino group of Lys, and/or (d) the carboxy group which is part of the R group of Asp or Glu, and(iv) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 is one, two, three, four, five or six.
-
-
178. The pharmaceutical composition of
claim 175 or176 which is a derivative of a native form of GLP-1. -
179. The pharmaceutical composition of any of claims 175-177, wherein up to fifteen, preferably up to ten amino acid residues have been exchanged with any α
- -amino acid residue.
-
180. The pharmaceutical composition of any of claims 175-178, wherein up to fifteen, preferably up to ten amino acid residues have been exchanged with any a,-amino acid residue which can be coded for by the genetic code.
-
181. The pharmaceutical composition of any of claims 175-179, wherein up to six amino acid residues have been exchanged with any α
- -amino acid residue which can be coded for by the genetic code.
-
182. The pharmaceutical composition of any of claims 175-180, wherein:
-
B is 36, and the parent peptide comprises one or more amino acid substitutions selected from the group consisting of Arg26, Arg34 and Lys36;
B is 37, and the parent peptide comprises one or more amino acid substitutions selected from the group consisting of Arg26, Arg34, Lys36 and Lys37;
orB is 38, and the parent peptide comprises one or more amino acid substitutions selected from the group consisting of Arg26, Arg34, Lys36 and Lys38.
-
-
183. The pharmaceutical composition of
claim 175 which is of formula III (SEQ ID NO:- 2)
7
8
9
10
11
12
13
14
15
16
17Xaa-Xaa-Xaa-Gly-Xaa-Phe-Thr-Xaa-Asp-Xaa-Xaa-
18
19
20
21
22
23
24
25
26
27
28Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Phe-
29
30
31
32
33
34
35
36
37
38Ile-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa
39
40
41
42
43
44
45Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa wherein Xaa at position 7 is A, Xaa at position 8 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 9 is Glu, Asp, or Lys, Xaa at position 11 is Thr, Ala, Gly, Ser, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 14 is Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 16 is Val, Ala, Gly, Ser, Thr, Leu, Ile, Tyr, Glu, Asp, or Lys, Xaa at position 17 is Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 18 is Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 19 is Tyr, Phe, Trp, Glu, Asp, or Lys, Xaa at position 20 is Leu, Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 21 is Glu, Asp, or Lys, Xaa at position 22 is Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 23 is Gln, Asn, Arg, Glu, Asp, or Lys, Xaa at position 24 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Arg, Glu, Asp, or Lys, Xaa at position 25 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 26 is Lys, Arg, Gln, Glu, Asp, or His, Xaa at position 27 is Glu, Asp, or Lys, Xaa at position 30 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 31 is Trp, Phe, Tyr, Glu, Asp, or Lys, Xaa at position 32 is Leu, Gly, Ala, Ser, Thr, Ile, Val, Glu, Asp, or Lys, Xaa at position 33 is Val, Gly, Ala, Ser, Thr, Met, Leu, Ile, Glu, Asp, or Lys, Xaa at position 34 is Lys, Arg, Glu, Asp, or His, Xaa at position 35 is Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, Xaa at position 36 is Arg, Lys, Glu, Asp, or His, Xaa at position 37 is Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, or is deleted, Xaa at position 38 is Arg, Lys, Glu, Asp, or His, or is deleted, Xaa at position 39 is Arg, Lys, Glu, Asp, or His, or is deleted, Xaa at position 40 is Asp, Glu, or Lys, or is deleted, Xaa at position 41 is Phe, Trp, Tyr, Glu, Asp, or Lys, or is deleted, Xaa at position 42 is Pro, Lys, Glu, or Asp, or is deleted, Xaa at position 43 is Glu, Asp, or Lys, or is deleted, Xaa at position 44 is Glu, Asp, or Lys, or is deleted, and Xaa at position 45 is Val, Glu, Asp, or Lys, or is deleted, or (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, wherein (i) when the amino acid at position 37, 38, 39, 40, 41, 42, 43 or 44 is deleted, then each amino acid downstream of the amino acid is also deleted, (ii) a lipophilic substituent is attached optionally via a spacer to one or more of (a) the carboxy group of the C-terminal amino acid, (b) the ε
-amino group of Lys, and/or (c) the carboxy group which is part of the R group of Asp or Glu, and(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 is one, two, three, four, five or six.
- 2)
-
184. The pharmaceutical composition of any of claims 175-183, wherein A is selected from
-
185. The pharnaceutical composition of any of claims 163-184 wherein the GLP-1 derivative contains three lipophilic substituents.
-
186. The pharnaceutical composition of any of claims 163-184 wherein the GLP-1 derivative contains two lipophilic substituents.
-
187. The pharnaceutical composition of any of claims 163-184 wherein the GLP-1 derivative contains one lipophilic substituent.
-
188. The pharnaceutical composition of any of claims 163-187, wherein a lipophilic substituent is attached to the amino group of the N-terminal amino acid residue of the parent GLP-1 peptide.
-
189. The pharnaceutical composition of any of claims 163-188, wherein a lipophilic substituent is attached to the carboxy group of the C-terminal amino acid residue of the parent GLP-1 peptide.
-
190. The pharnaceutical composition of any of claims 163-189, wherein a lipophilic substituent is attached to the carboxy group which is part of the R group of Asp or Glu of the parent GLP-1 peptide.
-
191. The pharnaceutical composition of any of claims 163-190, wherein a lipophilic substituent is attached to an ε
- -amino group of Lys of the parent GLP-1 peptide.
-
192. The pharmaceutical composition of any of claims 163-191, wherein the lipophilic substituent comprises from 4 to 40 carbon atoms, more preferably from 8 to 25 carbon atoms, most preferably 12 to 18 carbon atoms.
-
193. The pharmaceutical composition of any of claims 163-192, wherein a lipophilic substituent is attached to an amino acid residue in such a way that a carboxyl group of the lipophilic substituent forms an amide bond with the ε
- -amino group of Lys of the parent GLP-1 peptide.
-
194. The pharmaceutical composition of any of claims 163-193, wherein the lipophilic substituent is attached to the parent peptide by means of a spacer.
-
195. The pharmaceutical composition of
claim 194 , wherein the spacer is an unbranched alkane α- ,ω
-dicarboxylic acid group having from 1 to 7 methylene groups, preferably two methylene groups, which forms an amide bond with an amino group of the parent GLP-1 peptide and an amide bond with an amino group of the lipophilic substituent.
- ,ω
-
196. The pharmaceutical composition of
claim 194 , wherein the spacer is an amino acid residue except Cys or Met, or a dipeptide such as Gly-Lys. -
197. The pharmaceutical composition of
claim 196 , wherein the ε- -amino group of Lys forms an amide bond with a carboxylic group of the amino acid residue or dipeptide spacer, and an amino group of the amino acid residue or dipeptide spacer forms an amide bond with a carboxyl group of the lipophilic substituent.
-
198. The pharmaceutical composition of any of claims 194-197, wherein the spacer is γ
- -L-glutamyl.
-
199. The pharmaceutical composition of any of claims 194-197, wherein the spacer is β
- -L-asparagyl.
-
200. The pharmaceutical composition of any of claims 194-197, wherein the spacer is β
- -alanyl.
-
201. The pharmaceutical composition of any of claims 194-197, wherein the spacer is glycyl.
-
202. The pharmaceutical composition of any of claims 194-197, wherein the spacer is α
- -(γ
-aminobutanoyl).
- -(γ
-
203. The pharmaceutical composition of any of claims 163-202, wherein the lipophilic substituent comprises a partially or completely hydrogenated cyclopentanophenathrene skeleton.
-
204. The pharmaceutical composition of any of claims 163-203, wherein the lipophilic substituent is a straight-chain or branched alkyl group.
-
205. The pharmaceutical composition of any of claims 163-204, wherein the lipophilic substituent is an acyl group of a straight-chain or branched fatty acid, preferably an acyl group of a straight-chain fatty acid.
-
206. The pharmaceutical composition of
claim 205 , wherein the acyl group is selected from the group comprising CH3(CH2)nCO—- , wherein n is 10 to 38, preferably CH3(CH2)10CO—
, CH3(CH2)12CO—
, CH3(CH2)14CO—
, CH3(CH2)16CO—
, CH3(CH2)18CO—
, CH3(CH2)20CO— and
CH3(CH2)22CO—
.
- , wherein n is 10 to 38, preferably CH3(CH2)10CO—
-
207. The pharmaceutical composition of
claim 205 , wherein the acyl group is tetradecanoyl. -
208. The pharmaceutical composition of
claim 205 , wherein the acyl group is hexadecanoyl. -
209. The pharmaceutical composition of any of claims 163-208 wherein the lipophilic substituent is an acyl group of a straight-chain or branched alkane α
- ,ω
-dicarboxylic acid.
- ,ω
-
210. The pharmaceutical composition of
claim 209 , wherein the acyl group is selected from the group comprising HOOC(CH2)mCO—- , wherein m is from 4 to 38, preferably from 4 to 24, more preferably selected from the group comprising HOOC(CH2)14CO—
, HOOC(CH2)16CO—
, HOOC(CH2)18CO—
, HOOC(CH2)20CO— and
HOOC(CH2)22CO—
.
- , wherein m is from 4 to 38, preferably from 4 to 24, more preferably selected from the group comprising HOOC(CH2)14CO—
-
211. The pharmaceutical composition of any of claims 163-210, wherein the lipophilic substituent with the attached spacer is a group of the formula CH3(CH2)pNH—
- CO(CH2)2CO—
, wherein p is an integer of from 8 to 33, preferably from 12 to 28.
- CO(CH2)2CO—
-
212. The pharmaceutical composition of any of claims 163-211, wherein the lipophilic substituent with the attached spacer is a group of the formula CH3(CH2)rCO—
- NHCH(COOH)(CH2)2CO—
, wherein r is an integer of from 10 to 24.
- NHCH(COOH)(CH2)2CO—
-
213. The pharmaceutical composition of any of claims 163-212, wherein the lipophilic substituent with the attached spacer is a group of the formula CH3(CH2)sCO—
- NHCH((CH2)2COOH)CO—
, wherein s is an integer of from 8 to 24.
- NHCH((CH2)2COOH)CO—
-
214. The pharmaceutical composition of any of claims 163-213, wherein the lipophilic substituent with the attached spacer is a group of the formula —
- NHCH(COOH)(C H2)4NH—
CO(CH2)uCH3, wherein u is an integer of from 8 to 18.
- NHCH(COOH)(C H2)4NH—
-
215. The pharmaceutical composition of any of claims 163-214, wherein the lipophilic substituent with the attached spacer is a group of the formula —
- NHCH(COOH)(CH2)4NH—
COCH((CH2)2COOH)NH—
CO(CH2)wCH3, wherein w is an integer of from 10 to 16.
- NHCH(COOH)(CH2)4NH—
-
216. The pharmaceutical composition of any of claims 163-215, wherein the lipophilic substituent with the attached spacer is a group of the formula —
- NHCH(COOH)(CH2)4NH—
CO(CH2)2CH(COOH)NH—
CO(CH2)xCH3, wherein x is an integer of from 10 to 16.
- NHCH(COOH)(CH2)4NH—
-
217. The pharmaceutical composition of any of claims 163-216, wherein the lipophilic substituent with the attached spacer is a group of the formula —
- NHCH(COOH)(CH2)4NH—
CO(CH2)2CH(COOH)NH—
CO(CH2)yCH3, wherein y is zero or an integer of from 1 to 22.
- NHCH(COOH)(CH2)4NH—
-
218. The pharmaceutical composition of any of claims 163-217 which has insulinotropic activity, ability to decrease glucagon, ability to suppress gastric motility, ability to restore glucose competency to beta-cells, and/or ability to suppress appetite/reduce weight.
-
219. The pharmaceutical composition of
claim 218 , further comprising another antidiabetic agent. -
220. The pharmaceutical composition of
claim 219 , wherein the antidiabetic is an insulin, more preferably human insulin. -
221. The pharmaceutical composition of
claim 219 , wherein the antidiabetic agent is a hypoglycaemic agent. -
222. The pharmaceutical composition of
claim 218 , further comprising another antiobesity agent. -
223. The pharmaceutical composition of
claim 222 , wherein the antiobesity agent is selected from the group consisting of leptin, amphetamin, dexfenfluramine, sibutramine, orlistat, CART agonists, NPY antagonists, orexin antagonists, H3-antagonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β- 3 agonists, MSH agonists, CCK agonists, serotonin re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone releasing compounds, glucagon, TRH agonists, uncoupling protein 2 or 3 modulators, leptin agonists, DA agonists (Bromocriptin, Doprexin), lipase/amylase inhibitors, PPAR modulators, PXR modulators and TR β
agonists.
- 3 agonists, MSH agonists, CCK agonists, serotonin re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone releasing compounds, glucagon, TRH agonists, uncoupling protein 2 or 3 modulators, leptin agonists, DA agonists (Bromocriptin, Doprexin), lipase/amylase inhibitors, PPAR modulators, PXR modulators and TR β
-
176. A pharmaceutical composition comprising a GLP-1 derivative of formula II
A-HN-GLP-1(8-B)-X -
(II)wherein A is;
wherein R1, R2 and R3 are independently H, lower alkyl, optionally substituted phenyl, NH2, NH—
CO-(lower alkyl), —
OH, lower alkoxy, halogen, SO2-(lower alkyl) or CF3, wherein said phenyl is optionally substituted with at least one group selected from NH2, —
OH, lower alkyl, lower alkoxy, halogen, SO2-(lower alkyl), NH—
CO-(lower alkyl) or CF3, or R1 and R2 may together form a bond; and
Y is a five or six membered ring system selected from the group consisting of;
wherein Z is N, O or S, and said ring system is optionally substituted with one or more functional groups selected from the group consisting of NH2, NO2, OH, lower alkyl, lower alkoxy, halogen, CF3 and aryl, provided that A is not histidine;
B is an integer in the range of 35-45; and
X is —
OH, —
NH2, or a C1-6 alkyl amide or C1-6 dialkyl amide group;
or an analogue thereof;
wherein a lipophilic substituent (optionally via a spacer) is attached to at least one amino acid residue provided that when the lipophilic substituent is an acyl group and no spacer is present then the acyl group contains at least 12 carbon atoms; and
a surfactant.- View Dependent Claims (177)
-
-
224. The pharmaceutical composition of any one of the preceding composition claims wherein the surfactant is selected from a detergent, ethoxylated castor oil, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, such as 188 and 407, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene derivatives such as alkylated and alkoxylated derivatives (tweens, e.g. Tween-20), monoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives thereof, glycerol, cholic acid or derivatives thereof, lecithins, alcohols and phospholipids, glycerophospholipids (lecithins, kephalins, phosphatidyl serine), glyceroglycolipids (galactopyransoide), sphingophospholipids (sphingomyelin), and sphingoglycolipids (ceramides, gangliosides), DSS (docusate sodium, CAS registry no [577-11-7]), docusate calcium, CAS registry no [128-49-4]), docusate potassium, CAS registry no [7491-09-0]), SDS (sodium dodecyl sulfate or sodium lauryl sulfate), dipalmitoyl phosphatidic acid, sodium caprylate, bile acids and salts thereof and glycine or taurine conjugates, ursodeoxycholic acid, sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate, N-Hexadecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate, anionic (alkyl-aryl-sulphonates) monovalent surfactants, palmitoyl lysophosphatidyl-L-serine, lysophospholipids (e.g. 1-acyl-sn-glycero-3-phosphate esters of ethanolamine, choline, serine or threonine), alkyl, alkoxyl (alkyl ester), alkoxy (alkyl ether)-derivatives of lysophosphatidyl and phosphatidylcholines, e.g. lauroyl and myristoyl derivatives of lysophosphatidylcholine, dipalmitoylphosphatidylcholine, and modifications of the polar head group, that is cholines, ethanolamines, phosphatidic acid, serines, threonines, glycerol, inositol, and the postively charged DODAC, DOTMA, DCP, BISHOP, lysophosphatidylserine and lysophosphatidylthreonine, zwitterionic surfactants (e.g. N-alkyl-N,N-dimethylammonio-1-propanesulfonates, 3-cholamido-1-propyldimethylammonio-1-propanesulfonate, dodecylphosphocholine, myristoyl lysophosphatidylcholine, hen egg lysolecithin), cationic surfactants (quarternary ammonium bases) (e.g. cetyltrimethylammonium bromide, cetylpyridinium chloride), non-ionic surfactants, polyethyleneoxide/polypropyleneoxide block copolymers (Pluronics/Tetronics, Triton X-100, Dodecyl β
- -D-glucopyranoside) or polymeric surfactants (Tween-40, Tween-80, Brij-35). Other preferred surfactants include fusidic acid derivatives—
(e.g. sodium tauro-dihydrofusidate etc.), long-chain fatty acids and salts thereof C6-C12(eg. oleic acid and caprylic acid), acylcarnitines and derivatives, Nα
-acylated derivatives of lysine, arginine or histidine, or side-chain acylated derivatives of lysine or arginine, Nα
-acylated derivatives of dipeptides comprising any combination of lysine, arginine or histidine and a neutral or acidic amino acid, Nα
-acylated derivative of a tripeptide comprising any combination of a neutral amino acid and two charged amino acids, or the surfactant may be selected from the group of imidazoline derivatives.
- -D-glucopyranoside) or polymeric surfactants (Tween-40, Tween-80, Brij-35). Other preferred surfactants include fusidic acid derivatives—
- 225. The pharmaceutical composition of any one of the preceding composition claims further comprising an isotonic agent, preferably sodium chloride, mannitol and glycerol.
- 227. The pharmaceutical composition of any one of the preceding composition claims further comprising a preservative, preferably phenol, m-cresol, methyl p-hydroxybenzoate and benzyl alcohol.
-
229. The pharmaceutical composition of any one of the preceding composition claims further comprising a buffer, preferably sodium acetate and sodium phosphate.
-
230. The pharmaceutical composition of any one of the preceding composition claims further comprising zinc.
-
231. The pharmaceutical composition of any one of the preceding composition claims wherein said composition is suitable for administration by injection.
-
232. Use of a pharmaceutical composition of any one of the preceding composition claims which has a protracted profile of action relative to GLP-1(7-37).
-
233. Use of a pharmaceutical composition of any one of the preceding composition claims with a protracted profile of action for the treatment of non-insulin dependent diabetes mellitus.
-
234. Use of a pharmaceutical composition of any one of the preceding composition claims with a protracted profile of action for the treatment of insulin dependent diabetes mellitus.
-
235. Use of a pharmaceutical composition of any one of the preceding composition claims for treating insulin resistance.
-
236. Use of a pharmaceutical composition of any one of the preceding composition claims with a protracted profile of action for the treatment of obesity.
-
237. A method of treating insulin dependent or non-insulin dependent diabetes mellitus in a patient in need of such a treatment, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition of any one of the preceding composition claims together with a pharmaceutically acceptable carrier.
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238. A method of treating obesity in a patient in need of such a treatment, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition of any one of the preceding composition claims.
Specification
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Current AssigneeFreddy Zimmerdahl Pedersen, Helle Birk Olsen, Kjeld Madsen, Liselotte Bjerre Knudsen, Niels C. Kaarsholm, Per Franklin Nielsen, Per Olaf Huusfeldt, Soren Erik Bjorn
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Original AssigneeFreddy Zimmerdahl Pedersen, Helle Birk Olsen, Kjeld Madsen, Liselotte Bjerre Knudsen, Niels C. Kaarsholm, Per Franklin Nielsen, Per Olaf Huusfeldt, Soren Erik Bjorn
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InventorsMADSEN, KJELD, HUUSFELDT, PER OLAF, NIELSEN, PER FRANKLIN, KAARSHOLM, NIELS C., OLSEN, HELLE BIRK, BJORN, SOREN ERIK, PEDERSEN, FREDDY ZIMMERDAHL, KNUDSEN, LISELOTTE BJERRE
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current514/12
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CPC Class CodesA61K 2300/00 Mixtures or combinations of...A61K 38/26 GlucagonsA61K 38/28 InsulinsA61K 47/24 containing atoms other than...C07K 14/605 GlucagonsC11D 3/0063 Photo- activating compoundsC11D 3/168 Organometallic compounds or...
