PCT
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`INTERNATIONAL APPLICATION PUBLISHED UNDER TiiE PATENT COOPERATION TREATY (PCT)
`WO 99/43705
`
`(11) International Publication Number:
`
`(51) International Patent Classification 6 :
`C07K 14/605, A61K 38/26, A61P 3/04,
`3/10, 5/50
`
`Al
`
`(43) International Publication Date:
`
`2 September 1999 (02.09.99)
`
`(21) International Application Number:
`
`PCT/DK99/00081
`
`(22) International Filing Date:
`
`25 February 1999 (25.02.99)
`
`(30) Priority Data:
`0264198
`0509/98
`
`27 February 1998 (27.02.98)
`8 April 1998 (08.04.98)
`
`DK
`DK
`
`(71) Applicant: NOVO NORDISK A/S [DK/DK); Novo All~,
`DK-2880 Bagsvaerd (DK).
`
`(72) Inventors: KNUDSEN, Liselotte, Bjerre; Valby Langgade
`49A, I.
`tv., DK-2500 Valby (DK). HUUSFELDT, Per,
`Olaf; Applebys Plads 27,5. mf., DK-1411 Copenhagen K
`(DK).
`
`(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
`BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD,
`GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP,
`KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK,
`MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG,
`SI, SK, SL, TJ, TM, TR, TI, UA, UG, UZ, VN, YU, 'ZW,
`ARIPO patent (GH, GM, KE, LS, MW, SD, SL, SZ, UG,
`ZW), Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`TM), European patent (AT, BE, CH, CY, DE, DK, ES, FI,
`FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OAPI patent
`(BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE,
`SN, TD, TG).
`
`Published
`With international search report.
`
`(54) Title: N- TERMINALLY TRUNCATED GLP-1 DERIVATIVES
`
`(57) Abstract
`
`The present invention relates to N-terrninally truncated derivatives of human glucagon-like peptide-I (GLP-1) and analogues thereof
`having a protracted profile of action, as well as the use of such derivatives in pharmaceutical compositions for the treatment of obesity,
`insulin dependent or non-insulin dependent diabetes mellitus. The GLP- 1 derivatives have a lipophilic substituent attached to at least one
`amino acid residue.
`
`FRESENIUS EXHIBIT 1032
`Page 1 of 50
`
`

`

`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`cc
`CH
`Cl
`CM
`CN
`cu
`CZ
`D£
`DK
`EE
`
`Albania
`Annenia
`Austria
`Australia
`Awbaijan
`lloMia and Hcrugovina
`Barbados
`Belgium
`Burkina Paso
`Bulgaria
`Benin
`Brazil
`Belarus
`C11nada
`Central African Republic
`Congo
`Swittcd and
`C-'!e d'Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`ES
`Fl
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JI'
`KE
`KG
`KP
`
`KR
`KZ
`LC
`u
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`Unired Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`lraly
`Japan
`Kenya
`Kyrgyutan
`Democra1ic ~!e's
`Republic of Korea
`Republic of Korea
`Kazalcstnn
`Saint Lucia
`Uechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`Lesolho
`Lithuania
`Lu.embourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The fonner Yugoslav
`Republic of MACedooia
`Mali
`ML
`Mongolia
`MN
`MR
`Muritania
`MW Malawi
`Mexico
`MX
`Niger
`NE
`Netherlands
`NL
`NO
`Norway
`NZ
`New Zealand
`PL
`Poland
`PT
`Ponugal
`RO
`Romania
`Russian Federation
`RU
`so
`Sudan
`Sweden
`SE
`SG
`Singapore
`
`SI
`SK
`SN
`sz
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UC
`us
`uz
`VN
`YU
`zw
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turlonenisran
`Turkey
`Trinidad and Tobago
`U1cr&ine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`Yugoslavia
`Zimbabwe
`
`FRESENIUS EXHIBIT 1032
`Page 2 of 50
`
`

`

`WO99/43705
`
`PCT/DK99/0008 l
`
`- 1 -
`
`N-TERMINALL Y TRUNCATED GLP-1 DERIVATIVES
`
`FIELD OF THE INVENTION
`The present invention relates to novel derivatives of human glucagon-like peptide-1
`
`5
`
`(GLP-1) and fragments analogues thereof having a protracted profile of action and to the use of
`
`such derivatives in pharmaceutical compositions.
`
`BACKGROUND OF THE INVENTION
`GLP-1 (Glucacon-Like-Peptide-1) is an important gut hormone with regulatory function in
`
`10
`
`glucose metabolism and gastrointestinal secretion and metabolism. Human GLP-1 is a 37 amino
`acid residue peptide originating from preproglucagon which is synthesised i.a. in the L-cells in the
`distal ileum, in the pancreas and in the brain. Processing of preproglucagon to give GLP-1(7-
`
`36)amide, GLP-1 (7-37) and GLP-2 occurs mainly in the L-cells.
`WO 87/06941 (The General Hospital Corporation) disclose peptide fragments which
`
`15
`
`comprises GLP-1(7-37) and functional derivatives thereof and to its use as an insulinotropic
`
`agent.
`
`WO 90/11296 (The General Hospital Corporation) disclose peptide fragments which
`
`comprise GLP-1(7-36) and functional derivatives thereof and have an insulinotropic activity which
`
`exceeds the insulinotropic activity of GLP-1 ( 1-36) or GLP-1 ( 1-37) and to their use as
`
`20
`
`insulinotropic agents.
`The amino acid sequence of GLP-1 (7-36)amide and GLP-1 (7-37) is:
`8
`9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
`
`7
`
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val -Ser- Ser- Tyr- Leu- Gl u-Gl y-Gln-
`
`25
`
`24 25 26 27 28 29 30 31 32 33 34
`
`35 36
`
`(I )
`
`Ala-Ala-Lys-Glu-Phe- I le- Ala- Trp-Leu-Val- Lys - Gly- Arg- X
`
`wherein Xis NH2 for GLP-1(7-36)amide and Xis Gly-OH for GLP-1(7-37).
`WO 91 /11457 (Buckley et al.) discloses analogues ofthe active GLP-1 peptides 7-34, 7-
`
`35, 7-36, and 7-37.
`
`30
`
`WO 98/08871 discloses GLP-1 derivatives in which a lipophilic substituent is attached to
`
`at least one amino acid residue. The lipophilic substituents are in particular long-chain groups
`
`containing e.g. 12-24 carbon atoms.
`EP 0699686-A2 (Eli Lilly & Co.) discloses certain N-terminal truncated fragments of GLP-
`
`1 that are reported to be biologically active.
`
`SUBSTITUTE SHEET (RULE 28)
`
`FRESENIUS EXHIBIT 1032
`Page 3 of 50
`
`

`

`WO99/43705
`
`PCT/DK99/00081
`
`- 2 -
`
`It is an object of the present invention to provide improved N-terminal truncated
`
`fragments of GLP-1.
`
`SUMMARY OF THE INVENTION
`In its broadest aspect, the present invention relates to derivatives of GLP-1 and
`
`5
`
`analogues thereof. The derivatives according to the invention have interesting pharmacological
`
`properties, including a protracted profile of action. The derivatives also are more metabolically
`
`and physically stable, and more soluble.
`
`The GLP-1 derivatives and analogues of the present invention are truncated at the N-
`
`10
`
`terminal end and comprise a lipophilic substituent (optionally via a spacer) attached to at least
`
`one amino acid residue. The lipophilic substituent is in particular a long-chain group of the type
`
`described in WO 98/08871 (Novo Nordisk A/S).
`
`In particular, the invention relates to an N-terminal truncated GLP-1 derivative comprising
`
`a parent peptide of formula II
`
`15
`
`20
`
`A -GLP-1 (19-B)-X
`
`(II)
`
`wherein
`A is a peptide comprising 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 is attached to at least one amino acid residue.
`
`25 DETAILED DESCRIPTION OF THE INVENTION
`A simple system is used to describe the GLP-1 derivatives of the present invention. For
`
`example, Gly8-GLP-1(7-37) designates a fragment which relates to GLP-1(1-37) by the deletion
`of the amino acid residues at positions 1 to 6 and the substitution of the naturally occurring
`
`amino acid residue in position 8 (Ala) with Gly. Similarly, Lys34(N"-tetradecanoyl)-GLP-1(7-37)
`
`30
`
`designates GLP-1 (7-37) wherein the &-amino group of the Lys residue in position 34 has been
`
`tetradecanoylated. Where a reference is made to C-terminally extended GLP-1 analogues, the
`
`amino acid residue in position 38 is Arg unless otherwise indicated, the amino acid residue in
`
`position 39 is also Arg unless otherwise indicated and the amino acid residue in position 40 is
`
`Asp unless otherwise indicated. Also, if a C-terminally extended analogue extends to position 41 ,
`
`FRESENIUS EXHIBIT 1032
`Page 4 of 50
`
`

`

`WO99/43705
`
`PCT/DK99/00081
`
`- 3 -
`
`42, 43, 44 or 45, the amino acid sequence of this extension is as in the corresponding sequence
`
`in human preproglucagon unless otherwise indicated.
`
`The present invention relates to derivatives of native GLP-1 and derivatives of GLP-1
`
`analogs. In a preferred embodiment, the derivatives are derivatives of native GLP-1 (8-45) or a
`
`s
`
`fragment thereof. In a more preferred embodiment, the derivatives are derivatives of native GLP-
`
`1 (8-36). In another more preferred embodiment, the derivatives are derivatives of native GLP-
`
`1 (8-37). In another more preferred embodiment, the derivatives are derivatives of native GLP-
`
`1(8-38).
`
`In a preferred embodiment of GLP-1 derivatives of the present invention, A is a peptide
`
`10
`
`selected from the group consisting of GLP-1(8-18), GLP-1(9-18), GLP-1(10-18), GLP-1(11-18),
`
`GLP-1(12-18), GLP-1(13-18), GLP-1(14-18), GLP-1(15-18), GLP-1(16-18), GLP-1(17-18) and
`
`GLP-1(18). Preferably, A is GLP-1(8-18), GLP-1(9-18), GLP-1(10-18), GLP-1(11-18) or GLP-
`
`1(12-18), and Bis 36, 37 or 38. Most preferably, A is GLP-1(8-18).
`
`In a preferred embodiment of GLP-1 derivatives of the present invention, Bis 35, 36, 37,
`
`15
`
`38, 39, 40, 41 , 42, 43 or 44. In a more preferred embodiment, B is 36. In another more preferred
`
`embodiment.Bis 37. In another more preferred embodiment, Bis 38.
`
`GLP-1 Analogs
`
`The present invention also relates to derivatives of analogs of GLP-1 . The term
`
`20
`
`·analogue" is defined herein as a peptide which relates to a parent peptide by the substitution of
`
`one or more amino acid residues of the parent peptide with other amino acid residue(s).
`
`In the GLP-1 derivatives of formula 11, up to fifteen, preferably up to ten amino acid
`
`residues may be exchanged with any a-amino acid residue, in particular with any a-amino acid
`
`residue which can be coded for by the genetic code. Preferred analogues are those in which up
`
`2s
`
`to six amino acid residues have been exchanged with any a-amino acid residue which can be
`
`coded for by the genetic code.
`
`Preferred GLP-1 derivatives or analogues are those in which:
`
`A is selected from the group consisting of GLP-1(8-18), GLP-1(9-18) and GLP-1(10-18);
`
`i)
`
`and
`
`30
`
`ii)
`
`B is 36, and the parent peptide comprises one or more amino acid substitutions selected
`
`from the group consisting of Arg26
`
`, Arg34 and Lys36
`
`;
`
`, Lys36 and Lys37
`
`; or
`
`35
`
`B is 37, and the parent peptide comprises one or more amino acid substitutions selected
`from the group consisting of Arg26, Arg34
`B is 38, and the parent peptide comprises one or more amino acid substitutions selected
`from the group consisting of Arg26, Arg34
`
`, Lys36 and Lys38
`
`•
`
`FRESENIUS EXHIBIT 1032
`Page 5 of 50
`
`

`

`WO99/43705
`
`PCT/DK99/00081
`
`-4-
`
`ln a further preferred embodiment, a parent peptide for a derivative of the invention is
`
`Arg26-GLP-1 (8-37); Arg34-GLP-1 (8-37); Lys36-GLP-1 (8-37);
`
`4Lys38GLP-1 (8-38);
`
`
`
`Arg26•34Lys36-GLP-1 (8-37); Arg26
`
`•3
`
`4Lys40-GLP-1 (8-40);
`
`•3
`
`4Lys39-GLP-1 (8-39); Arg26
`
`•3
`
`Arg26
`
`5 Arg26Lys36-GLP-1 (8-37); Arg34Lys36-GLP-1 (8-37);
`Arg26Lys39-GLP-1 (8-39); Arg34Lys40-GLP-1 (8-40);
`Arg26
`4Lys36
`39-GLP-1 (8-39); Arg26
`34Lys36
`40-GLP-1 (8-40);
`•
`•
`•
`
`•3
`
`Gly8Arg26-GLP-1 (8-37); Gly8Arg34-GLP-1 (8-37);
`
`Gly8Lys36-GLP-1 (8-37); Gly8Arg26
`34Lys36-GLP-1 (8-37);
`•
`
`10 Gly8Arg26
`34Lys39-GLP-1 (8-39); Gly8Arg26
`34Lys40-GLP-1 (8-40);
`•
`•
`
`Gly8Arg26Lys36-GLP-1(8-37); Gly8Arg34Lys36-GLP-1(8-37);
`
`Gly8Arg26Lys39-GLP-1(8-39); Gly8Arg34Lys40-GLP-1(8-40);
`
`4Lys38
`39-GLP-1(8-39); or
`•
`
`Gly8Arg26
`
`•3
`
`40-GLP-1 (8-40).
`Gly8Arg26
`34Lys36
`•
`•
`In a further preferred embodiment, a parent peptide for a derivative of the invention is:
`
`15
`
`34Lys38GLP-1 (8-38);
`Arg26
`•
`34Lys39GLP-1 (8-39);
`Arg26
`•
`Arg26
`34Lys40GLP-1 (8-40);
`·
`
`Arg26
`34Lys41GLP-1 (8-41 );
`·
`
`20 Arg26
`34Lys42GLP-1 (8-42);
`•
`
`Arg26
`34Lys43GLP-1 (8-43);
`•
`
`Arg26
`34Lys44GLP-1(8-44);
`•
`34Lys45GLP-1 (8-45);
`Arg26
`·
`
`Arg26Lys38GLP-1 (8-38);
`25 Arg34Lys38GLP-1 (8-38);
`
`8GLP-1 (8-38);
`
`Arg26
`34Lys36
`•
`
`•3
`
`Arg26·34Lys38GLP-1 (8-38);
`
`Arg26Lys39GLP-1 (8-39);
`
`Arg34Lys39GLP-1 (8-39); or
`
`30
`
`Arg26
`34Lys36
`39GLP-1 (8-39).
`•
`•
`
`In a further preferred embodiment, the present invention relates to a GLP-1 derivative
`wherein the parent peptide is selected from the group comprising Arg26-GLP-1(8-37), Arg34-GLP-
`1 (8-37), Lys36-GLP-1 (8-37), Arg26
`34Lys36-GLP-1 (8-37), Arg26Lys36-GLP-1 (8-37), Arg34Lys36-GLP-
`•
`4Lys36
`1 (8-37), Gly8Arg26-GLP-1 (8-37), Gly8Arg34-GLP-1 (8-37), Gly8Lys36-GLP-1 (8-37), Gly8Arg26
`-
`35 GLP-1(8-37), Gly8Arg26Lys36-GLP-1(8-37), and Gly8Arg34Lys36-GLP-1(8-37).
`
`•3
`
`FRESENIUS EXHIBIT 1032
`Page 6 of 50
`
`

`

`WO99/43705
`
`PCT/DK99/00081
`
`-S-
`
`in a further preferred embodiment, the present invention relates to a GLP-1 derivative
`wherein the parent peptide is selected from the group comprising Arg26Lys38-GLP-1(8-38),
`8-GLP-1 (8-38), Gly8Arg26Lys38-GLP-1 (8-38) and
`
`Arg26•34Lys38-GLP-1 (8-38), Arg26
`34Lys36
`•
`
`•3
`
`8-GLP-1(8-38).
`Gly8Arg28
`34Lys36
`•
`In a further preferred embodiment, the present invention relates to a GLP-1 derivative
`wherein the parent peptide is selected from the group comprising Arg26Lys39-GLP-1 (8-39),
`39-GLP-1 (8-39), Gly8Arg26Lys39-GLP-1 (8-39) and Gly8Arg26
`4Lys36
`39-GLP-1 (8-39).
`Arg26•34Lys36·
`•
`
`•3
`
`•3
`
`5
`
`In a further preferred embodiment, the present invention relates to a GLP-1 derivative
`wherein the parent peptide is selected from the group comprising Arg34Lys40-GLP-1 (8-40),
`40-GLP-1 (8-40).
`10 Arg28•34Lys36•40-GLP-1 (8-40), Gly8Arg34Lys40-GLP-1 (8-40) and Gly8Arg26
`34Lys36
`•
`•
`
`In a further preferred embodiment, the present invention relates to a GLP-1 derivative
`
`wherein the parent peptide is:
`4Lys36-GLP-1 (8-36); Arg26-GLP-1 (8-36)amide;
`Arg26-GLP-1 (8-36); Arg34-GLP-1 (8-36); Arg26
`34Lys36-GLP-1 (8-36)amide; Arg28-GLP-1 (8-37); Arg34-GLP-1 (8-37);
`Arg34-GLP-1 (8-36)amide; Arg26
`•
`34Lys36-GLP-1 (8-37); Arg26-GLP-1 (8-38); Arg34-GLP-1 (8-38);
`15 Arg26
`•
`
`•3
`
`4Lys38GLP-1 (8-38); Arg26-GLP-1 (8-39); Arg34-GLP-1 (8-39);
`
`Arg26
`
`•3
`
`Arg26
`
`34Lys39-GLP-1 (8-39); Gly8Arg26-GLP-1 (8-36);
`•
`
`Gly8Arg34-GLP-1 (8-36); Gly8Arg26·34Lys36-GLP-1 (8-36);
`Gly8 Arg26-GLP-1 (8-36)amide; Gly8 Arg34-GLP-1 (8-36)amide;
`20 Gly8Arg28·34Lys36-GLP-1 (8-36)amide; Gly8Arg26-GLP-1 (8-37);
`Gly8Arg34-GLP-1 (8-37); Gly8Arg26
`34Lys36-GLP-1 (8-37);
`•
`
`Gly8Arg26-GLP-1(8-38); Gly8Arg34-GLP-1(8-38);
`Gly8Arg26·34Lys38GLP-1 (8-38); Gly8Arg26-GLP-1 (8-39);
`34Lys39-GLP-1(8-39);
`Gly8Arg34-GLP-1(8-39); Gly8Arg26
`•
`25 Val8Arg26-GLP-1 (8-36); Val8Arg34-GLP-1(8-36);
`
`4Lys36-GLP-1 (8-36); Val8Arg26-GLP-1 (8-36)amide;
`
`Val8Arg26
`
`•3
`
`4Lys36-GLP-1 (8-36)amide;
`
`Val8Arg34-GLP-1 (8-36)amide; Val8 Arg26
`
`•3
`
`Val6Arg26-GLP-1 (8-37); Val8Arg34-GLP-1 (8-37);
`
`Vat8 Arg26·34Lys36-GLP-1 (8-37); Val8Arg26-GLP-1 (8-38);
`Val8Arg34-GLP-1 (8-38); Val8Arg26
`34Lys38GLP-1 (8-38);
`•
`Val8Arg26-GLP-1(8-39); Val8Arg34-GLP-1 (8-39);
`Val8Arg26
`Ser8Arg34-GLP-1 (8-36); Ser8Arg26
`34Lys36-GLP-1 (8-36);
`•
`
`34Lys39-GLP-1 (8-39); Ser8Arg26-GLP-1(8-36);
`·
`
`Ser8Arg26-GLP-1 (8-36)amide; Ser8Arg34-GLP-1 (8-36)amide;
`Ser8Arg28
`
`4Lys36-GLP-1 (8-36)amide; Ser8Arg26-GLP-1 (8-37);
`
`•3
`
`30
`
`35
`
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`

`

`WO99/43705
`
`PCT/DK99/00081
`
`-6-
`
`Ser8Arg34-GLP-1 (8-37); Ser8Arg26•34Lys36-GLP-1 (8-37);
`
`Ser8Arg26-GLP-1 (8-38); Ser8Arg34-GLP-1 (8-38);
`Ser8Arg26
`34Lys38GLP-1 (8-38); Ser8Arg26-GLP-1 (8-39);
`•
`
`Ser8Arg34-Gl.:P-1 (8-39); Ser8 Arg26•34Lys39 -GLP-1 (8-39);
`s Thr8Arg26-GLP-1 (8-36); Thr8Arg34-GLP-1 (8-36);
`•34Lys36-GLP-1 (8-36); Thr8Arg26-GLP-1 (8-36)amide;
`Thr8Arg26
`Thr8Arg34-GLP-1 (8-36)amide; Thr8Arg26
`4Lys36-GLP-1 (8-36)amide;
`Thr8Arg26-GLP-1 (8-37); Thr8Arg34-GLP-1 (8-37);
`Thr8Arg26
`34Lys36-GLP-1(8-37); Thr8Arg26-GLP-1(8-38);
`•
`34Lys38GLP-1(8-38);
`Thr8Arg34-GLP-1 (8-38); Thr8Arg26
`•
`Thr8Arg26-GLP-1 (8-39); Thr8Arg34-GLP-1 (8-39);
`•34Lys36-GLP-1 (8-36);
`34Lys39-GLP-1 (8-39); Val8Glu35Arg26
`Thr8Arg26
`•
`4Lys37 GLP-1 (8-37);
`4Lys36-GLP-1 (8-36)amide; Val8Glu36Arg26
`Val8Glu35 Arg26
`34Lys39-GLP-1 (8-39); Val8Glu35Arg26
`Val8Glu37 Arg26•34Lys38GLP-1 (8-38); Val8Glu38Arg26
`•
`
`•3
`
`10
`
`4Lys36-GLP-
`
`•3
`
`•3
`
`•3
`
`4Lys37 GLP-1 (8-37);
`
`4Lys36-GLP-1 (8-36)amide; Val8Glu36Arg26
`
`•3
`
`•3
`
`1s
`
`1(8-36);
`Val8Glu35 Arg26
`
`4Lys36
`-
`
`4Lys36-GLP-1(8-36); Val8Asp35Arg26
`
`•3
`
`Val8Glu37 Arg26
`34Lys38GLP-1 (8-38);
`•
`Val8Glu38Arg26
`4Lys39-GLP-1(8-39); Val8Asp35Arg26
`
`•3
`
`•3
`
`GLP-1 (8-36)amide;
`
`4Lys39
`4Lys38GLP-1(8-38); Val8Asp38Arg26
`20 Val8Asp36Arg26
`34Lys37GLP-1(8-37); Val8Asp37Arg26
`·
`-
`4Lys36-GLP-1 (8-36); Val8Asp35Arg28
`34Lys36-GLP-1 (8-36)amide;
`GLP-1 (8-39); Val8Asp35Arg26
`•
`4Lys38GLP-1 (8-38); Val8Asp38 Arg26
`4Lys39
`34Lys37 GLP-1 (8-37); Val8Asp37 Arg26
`Val8Asp36Arg26
`•
`-
`
`•3
`
`•3
`
`•3
`
`•3
`
`•3
`
`GLP-1 (8-39);
`34Lys36-GLP-1 (8-36)amide;
`Ser8Glu35Arg26
`34Lys36-GLP-1 (8-36); Ser8Glu35Arg26
`•
`•
`
`2s
`
`Ser8Glu36 Arg26
`34Lys37 GLP-1 (8-37);
`•
`
`34Lys36
`34Lys39-GLP-1(8-39); Ser8Glu35Arg26
`4Lys38GLP-1(8-38); Ser8Glu38Arg26
`•
`•
`34Lys37 GLP-1 (8-37);
`4Lys36 -GLP-1 (8-36)amide; Ser8Glu36 Arg26
`34Lys36
`4Lys39-GLP-1 (8-39); Ser8 Asp35 Arg26
`•
`-
`34Lys37GLP-1 (8-37);
`4Lys36-GLP-1(8-36)amide; Ser8Asp36Arg26
`•
`34Lys38GLP-1(8-38); Ser8Asp38Arg26•34Lys39-GLP-1(8-39); Ser8Asp35Arg26
`34Lys36
`•
`-
`4Lys37GLP-1(8-37);
`4Lys36-GLP-1(8-36)amide; Ser8Asp36Arg26
`4Lys39-GLP-1 (8-39); Thr8Glu35Arg26
`4Lys36
`-
`•34Lys37GLP-1(8-37);
`34Lys36-GLP-1(8-36)amide; Thr8Glu36Arg26
`•
`34Lys36
`34Lys39-GLP-1 (8-39); Thr8Glu35Arg26
`Thr8Glu37 Arg26
`34Lys38GLP-1 (8-38); Thr8Glu38Arg26
`•
`•
`-
`•
`4Lys37GLP-1 (8-37);
`
`-
`
`·
`
`Ser8Glu37Arg26
`
`•3
`
`•3
`
`GLP-1 (8-36); Ser8Glu35Arg28
`
`4Lys38GLP-1 (8-38); Ser8Glu38 Arg26
`
`•3
`
`Ser8Glu37 Arg26
`
`•3
`
`•3
`
`GLP-1 (8-36); Ser8Asp35Arg26
`
`30
`
`
`Ser8Asp37Arg26
`•
`
`•3
`
`•3
`
`GLP-1(8-36); Ser8Asp35Arg26
`
`•3
`
`Ser8Asp37 Arg26
`34Lys38GLP-1 (8-38); Ser8Asp38Arg26
`•
`
`•3
`
`GLP-1 (8-36); Thr8Glu35Arg26
`
`35 GLP-1(8-36); Thr8Glu35Arg26
`34Lys36-GLP-1 (8-36)amide; Thr8Glu36Arg26
`•
`
`•3
`
`FRESENIUS EXHIBIT 1032
`Page 8 of 50
`
`

`

`WO99/43705
`
`PCT /D K99/0008 l
`
`- 7 -
`
`34Lys39-GLP-1 (8-39);
`34Lys38GLP-1 (8-38); Thr8Glu38Arg26
`Thr8Glu37 Arg26
`•
`•
`4Lys36-GLP-1 (8-36); Thr8Asp35Arg26
`34Lys36-GLP-1 (8-36)amide;
`•
`
`Thr8Asp35Arg26
`
`•3
`
`34Lys37GLP-1 (8-37);
`Thr8Asp36Arg26
`•
`4Lys39-GLP-1 (8-39); Thr8Asp35Arg26
`34Lys36
`34Lys38GLP-1 (8-38); Thr8Asp38Arg26
`Thr8Asp37 Arg26
`•
`•
`-
`34Lys37GLP-1 (8-37);
`34lys36-GLP-1 (8-36)amide; Thr8Asp36Arg26
`5 GLP-1 (8-36); Thr8Asp35Arg26
`·
`·
`4Lys38GLP-1 (8-38); Thr8Asp38Arg26
`34Lys39-GLP-1 (8-39);
`•
`4Lys36-GLP-1 (8-36); Gly8Glu35Arg26
`4Lys36-GLP-1 (8-36)amide;
`
`Thr8Asp37 Arg26
`
`•3
`
`•3
`
`Gly8Glu35 Arg26
`
`•3
`
`•3
`
`Gly8Glu36Arg26
`34Lys37 GLP-1 (8-37);
`•
`34Lys36
`34Lys39 -GLP-1 (8-39); Gly8Glu35 Arg26
`4Lys38GLP-1 (8-38); Gly8Glu38 Arg26
`-
`•
`·
`34Lys37GLP-1(8-37);
`34Lys36-GLP-1(8-36)amide; Gly8Glu36Arg26
`10 GLP-1(8-36); Gly8Glu35Arg26
`·
`•
`4Lys39-GLP-1 (8-39); Gly8Asp35Arg26
`34Lys36
`34Lys38GLP-1 (8-38); Gly8Glu38Arg26
`Gly8Glu37Arg26
`•
`•
`-
`34Lys37 GLP-1 (8-37);
`34Lys36-GLP-1 (8-36)amide; Gly8 Asp36Arg26
`GLP-1 (8-36); Gly8 Asp35Arg26
`•
`•
`4Lys39-GLP-1 (8-39); Gly8Asp35Arg26
`34Lys36
`Gly8Asp37 Arg26
`34Lys38GLP-1 (8-38); Gly8Asp38Arg26
`·
`•
`-
`34Lys37GLP-1 (8-37);
`GLP-1 (8-36); Gly8Asp35Arg26
`34Lys36-GLP-1 (8-36)amide; Gly8Asp36Arg26
`•
`•
`34Lys 18-GLP-1 (8-36);
`15 Gly8Asp37 Arg26
`34Lys38GLP-1 (8-38); Gly8Asp38Arg26
`34Lys39-GLP-1 (8-39); Arg26
`•
`•
`•
`34Lys 18-GLP-1 (8-36)amide; Arg26
`34Lys 18GLP-1 (8-37); Arg26
`34Lys 18GLP-1 (8-38);
`Arg26
`•
`·
`•
`34Lys 18-GLP-1 (8-36); Gly8Asp 19Arg26
`34Lys 18
`Gly8Asp 19Arg26
`4lys 18-GLP-1 (8-36); Gly8Asp17 Arg26
`•
`•
`34Lys 18-GLP-1 (8-36)amide; Gly8Asp19Arg26
`34Lys 18GLP-1 (8-37);
`GLP-1 (8-36)amide; Gly8Asp17 Arg26
`·
`•
`34Lys 16GLP-1 (8-38); Gly8Asp17Arg26
`34Lys 18GLP-1 (8-38);
`Gly8Asp19Arg26
`•
`•
`4Lys23-GLP-1 (8-36)amide; Arg26
`4Lys23GLP-1 (8-37);
`20 Arg26
`4Lys23-GLP-1 (8-36); Arg26
`34Lys23-GLP-1 (8-36);
`4Lys23GLP-1 (8-38); Gly8Asp24Arg26
`34Lys23-GLP-1 (8-36); Gly8Asp22Arg26
`Arg26
`•
`•
`Gly8 Asp24Arg26
`34Lys23-GLP-1 (8-36)amide; Gly8 Asp22Arg26
`34Lys23-GLP-1 (8-36)amide;
`•
`·
`34Lys23GLP-1 (8-38); Gly8Asp22Arg26
`Gly8Asp24Arg26
`34Lys23GLP-1 (8-37); Gly8Asp24Arg26
`•
`•
`
`•3
`
`Gly8Glu37 Arg26
`
`•3
`
`•3
`
`•3
`
`-
`
`•3
`
`4Lys23GLP-
`
`•3
`
`•3
`
`•3
`
`•3
`
`1 (8-38);
`Arg26
`34Lys27-GLP-1 (8-36); Arg26
`34Lys27-GLP-1 (8-36)amide; Arg26
`34Lys27GLP-1 (8-37);
`·
`•
`•
`Arg26
`4Lys27GLP-1 (8-38); Gly8Asp28Arg26
`4Lys27-GLP-1 (8-36); Gly8Asp26Arg26
`34Lys27-GLP-1 (8-36);
`·
`
`•3
`
`•3
`
`25
`
`4Lys27-GLP-1 (8-36)amide; Gly8Asp26Arg26
`34Lys27-GLP-1 (8-36)amide;
`Gly8Asp28Arg26
`•
`34Lys27GLP-1 (8-38); Gly8Asp26Arg26
`34Lys27GLP-
`34Lys27GLP-1 (8-37); Gly8Asp28Arg26
`Gly8Asp28Arg26
`•
`•
`•
`
`•3
`
`1 (8-38);
`30 Arg26
`34Lys 18-GLP-1 (8-36); Arg26
`4Lys 16GLP-1 (8-37);
`4Lys 18-GLP-1 (8-36)amide; Arg26
`•
`34Lys 18GLP-1 (8-38); Val8Asp19Arg26
`34Lys 16-GLP-1 (8-36);
`Arg26
`34Lys 16-GLP-1 (8-36); Val8Asp17Arg26
`•
`•
`•
`4Lys 18-GLP-1 (8-36)amide; Val8 Asp 17 Arg26
`Val6 Asp 19 Arg26
`4Lys 18-GLP-1 (8-36)amide;
`34Lys18GLP-1(8-38); Val8Asp17Arg26
`34Lys16GLP-
`Val8Asp19Arg26·34Lys18GLP-1(8-37); Val8Asp19Arg26
`•
`•
`
`•3
`
`•3
`
`•3
`
`•3
`
`1(8-38);
`
`FRESENIUS EXHIBIT 1032
`Page 9 of 50
`
`

`

`WO99/43705
`
`PCT/DK99/00081
`
`-8-
`
`34Lys23GLP-
`
`·
`
`•
`
`·
`
`•3
`
`•3
`
`Arg26·34Lys23-GLP-1 (8-36); Arg26·34Lys23-GLP-1 (8-36)amide; Arg26•34Lys23GLP-1 (8-37);
`
`Arg26•34Lys23GLP-1 (8-38}; Val8Asp24Arg28·34Lys23-GLP-1 (8-36); Val8Asp22Arg26·34Lys23-GLP-1 (8-36);
`·34Lys23-GLP-1(8-36)amide;
`Val8Asp24Arg26·34Lys23-GLP-1(8-36}amide; Val8Asp22Arg26
`
`Val8Asp24Arg26•34Lys23GLP-1 (8-37); VaI8Asp24Arg26·34Lys23GLP-1 (8-38); Val8Asp22Arg26
`1(8-38);
`34Lys27GLP-1 (8-37};
`4Lys27-GLP-1 (8-36); Arg26·34Lys27-GLP-1 (8-36)amide; Arg26
`Arg26
`34Lys27-GLP-1 (8-36};
`·34Lys27-GLP-1 (8-36}; Val8Asp26Arg26
`Arg26•34Lys27GLP-1 (8-38); Val8Asp28Arg26
`4Lys27 -GLP-1 (8-36)amide;
`Val8Asp28 Arg26·34Lys27 -GLP-1 (8-36)amide; Val8Asp26Arg26
`4Lys27GLP-1 (8-38); Val8Asp26Arg26·34Lys27GLP-
`Val8Asp28Arg26·34Lys27GLP-1 (8-37}; Val8Asp28Arg26
`1(8-38);
`
`Arg26·34Lys 18-GLP-1 (8-36); Arg26·34Lys 18-GLP-1 (8-36)amide; Arg28·34Lys 18GLP-1 (8-37};
`34Lys 18-GLP-1 (8-36); Ser8Asp17 Arg26·34Lys 18-GLP-1 (8-
`Arg26·34Lys 18GLP-1 (8-38); Ser8Asp19Arg26
`34Lys18-GLP-1(8-36)amide;
`34Lys18-GLP-1(8-36)amide; Ser8Asp17Arg26
`36); Ser8Asp19Arg26
`
`Ser8Asp 19Arg26•34Lys 18GLP-1 (8-37); Ser8Asp 19Arg26•34Lys 18GLP-1 (8-38);
`Ser8Asp17Arg26
`4Lys18GLP-1(8-38);
`34Lys23-GLP-1 (8-36)amide; Arg26·34Lys23GLP-1 (8-37);
`
`Arg26·34Lys23-GLP-1 (8-36); Arg26
`34Lys23-GLP-1 (8-
`Arg26•34Lys23GLP-1 (8-38); Ser8Asp24Arg26•34Lys23-GLP-1 (8-36); Ser8Asp22Arg26
`34Lys23-GLP-1 (8-36)amide;
`36); Ser8Asp24Arg26·34Lys23-GLP-1 (8-36)amide; Ser8Asp22Arg26
`
`Ser8Asp24Arg26•34Lys23GLP-1 (8-37); Ser8Asp24Arg26·34Lys23GLP-1 (8-38);
`
`Ser8 Asp22Arg26•34Lys23GLP-1 (8-38);
`·34Lys27 GLP-1 (8-37);
`Arg26·34Lys27 -GLP-1 (8-36); Arg26•34Lys27 -GLP-1 (8-36)amide; Arg26
`Arg26·34Lys27GLP-1 (8-38); Ser8Asp28Arg26·34Lys27-GLP-1 (8-36); Ser8Asp26Arg26·34Lys27-GLP-1 (8-
`36); Ser8Asp28Arg26·34Lys27 -GLP-1 (8-36)amide; Ser8Asp26Arg26·34Lys27-GLP-1 (8-36)amide;
`34Lys27GLP-1 (8-37); Ser8Asp28Arg26·34Lys27GLP-1 (8-38);
`Ser8Asp28Arg26
`Ser8Asp28Arg26
`34Lys27GLP-1 (8-38);
`34Lys 18GLP-1 (8-37);
`4Lys 18-GLP-1 (8-36); Arg26·34Lys 18-GLP-1 (8-36)amide; Arg26
`Arg26
`34Lys 18-GLP-1 (8-36);
`34Lys 18GLP-1 (8-38); Thr8Asp19Arg28·34Lys 18-GLP-1 (8-36); Thr8Asp 17 Arg26
`Arg26
`•
`Thr8Asp19Arg26•34Lys 18-GLP-1 (8-36)amide; Thr8Asp17 Arg26
`34Lys 18-GLP-1 (8-36)amide;
`34Lys 18GLP-1 (8-38); Thr8Asp17 Arg26
`Thr8Asp19Arg26
`34Lys 18GLP-1 (8-37); Thr8Asp 19Arg26
`1(8-38);
`Arg26·34Lys23-GLP-1 (8-36); Arg26·34Lys23-GLP-1 (8-36)amide; Arg26·34Lys23GLP-1 (8-37);
`
`4Lys23GLP-1 (8-38); Thr8Asp24Arg26•34Lys23-GLP-1 (8-36); Thr8Asp22Arg26
`34Lys23-GLP-1 (8-36);
`Arg26
`Thr8Asp24Arg26·34Lys23-GLP-1 (8-36)amide; Thr8 Asp22Arg26·34Lys23-GLP-1 (8-36)amide;
`
`Thr8Asp24Arg26·34Lys23GLP-1 (8-37); Thr8 Asp24Arg26•34Lys23GLP-1 (8-38); Thr8 Asp22Arg26
`1(8-38);
`
`•
`
`•
`
`•
`
`·
`
`·
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`34Lys 18GLP-
`
`·
`
`34Lys23GLP-
`
`·
`
`•3
`
`·
`
`•
`
`•
`
`•3
`
`•3
`
`•3
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`FRESENIUS EXHIBIT 1032
`Page 10 of 50
`
`

`

`WO99/43705
`
`PCT/DK99/00081
`
`- 9 -
`
`4Lys27 GLP-1 (8-37);
`Arg26•34Lys27 -GLP-1 (8-36); Arg26•34Lys27 -GLP-1 (8-36)amide; Arg26
`
`34Lys27-GLP-1(8-36);
`4Lys27-GLP-1(8-36); Thr8Asp26Arg26
`Arg26•34Lys27GLP-1(8-38); Thr8Asp28Arg26
`•
`
`Thr8Asp28Arg26•34Lys27-GLP-1(8-36)amide; Thr8Asp26Arg26
`34Lys27-GLP-1(8-36)amide;
`•
`34Lys27GLP-1 (8-37); Thr8Asp28Arg26
`4Lys27GLP-1 (8-38); or
`Thr8Asp28Arg26
`•
`34Lys27GLP-1(8-38).
`Thr8Asp26Arg26
`·
`In a further preferred embodiment, the present invention relates to a GLP-1 derivative
`
`•3
`
`•3
`
`
`
`•3
`
`wherein the parent peptide is:
`Arg26Lys36-GLP-1 (8-36); Arg34Lys36-GLP-1 (8-36); Arg26Lys36-GLP-1 (8-37); Arg34Lys36-GLP-1 (8-
`37); Arg26Lys37-GLP-1 (8-37); Arg34Lys37-GLP-1(8-37); Arg26Lys39-GLP-1(8-39); Arg34Lys39-GLP-
`
`5
`
`10
`
`34Lys36
`39-GLP-1(8-39);
`1(8-39); Arg26
`·
`·
`Arg26Lys 18-GLP-1 (8-36); Arg34Lys 18-GLP-1 (8-36); Arg26Lys18GLP-1 (8-37); Arg34Lys 18GLP-1 (8-37);
`Arg26Lys18GLP-1 (8-38); Arg34Lys18GLP-1(8-38); Arg26Lys 18GLP-1 (8-39); Arg34Lys18GLP-1(8-39);
`Arg26Lys23-GLP-1 (8-36); Arg34Lys23-GLP-1 (8-36); Arg26Lys23GLP-1 (8-37); Arg34Lys23GLP-1 (8-37);
`Arg26Lys23GLP-1 (8-38); Arg34Lys23GLP-1 (8-38); Arg26Lys23GLP-1 (8-39); Arg34Lys23GLP-1 (8-39);
`15 Arg26Lys27-GLP-1 (8-36); Arg34Lys27-GLP-1 (8-36); Arg26Lys27GLP-1 (8-37); Arg34Lys27GLP-1 (8-37);
`Arg26Lys27GLP-1 (8-38); Arg34Lys27GLP-1 (8-38); Arg26Lys27GLP-1 (8-39); Arg34Lys27GLP-1 (8-39);
`37GLP-1 (8-37);
`4Lys 18
`34Lys 18
`34Lys 18GLP-1 (8-37); Arg26
`36-GLP-1 (8-36); Arg26
`Arg26
`•
`•
`·
`·
`Arg26
`
`34Lys 18•38GLP-1 (8-38); Arg26
`
`4Lys 18·39GLP-1 (8-39); Arg26
`4Lys23
`36-GLP-1 (8-36);
`•
`·
`7GLP-1 (8-37); Arg26
`34Lys23
`8GLP-1 (8-38);
`•
`34Lys27•36-GLP-1 (8-36); Arg26
`34Lys27GLP-1 (8-37);
`•
`34Lys27
`9GLP-1 (8-39);
`8GLP-1 (8-38); Arg26
`4Lys27
`Arg26
`34Lys27
`37GLP-1 (8-37); Arg26
`•
`·
`•
`Gly8GLP-1 (8-36); Gly8GLP-1 (8-37); Gly8GLP-1 (8-38); Gly8GLP-1 (8-39);
`Gly8Arg26Lys36-GLP-1(8-36); Gly8Arg34Lys36-GLP-1(8-36); Gly8Arg26Lys36-GLP-1(8-37);
`Gly8Arg34Lys36-GLP-1(8-37); Gly8Arg26Lys37-GLP-1(8-37); Gly8Arg34Lys37-GLP-1(8-37);
`39-GLP-1 (8-39);
`25 Gly8Arg26Lys39-GLP-1 (8-39); Gly8Arg34Lys39-GLP-1 (8-39); Gly8Arg26
`4Lys36
`·
`Gly8Arg26Lys18-GLP-1(8-36); Gly8Arg34Lys18-GLP-1(8-36); Gly8Arg26Lys18GLP-1(8-37);
`Gly8Arg34Lys18GLP-1(8-37); Gly8Arg26Lys18GLP-1(8-38); Gly8Arg34Lys18GLP-1 (8-38);
`Gly8Arg28Lys18GLP-1(8-39); Gly8Arg34Lys18GLP-1(8-39);
`Gly8Arg26Lys23-GLP-1 (8-36); Gly8Arg34Lys23-GLP-1 (8-36); Gty8Arg26Lys23GLP-1 (8-37);
`30 Gly8Arg34Lys23GLP-1 (8-37); Gly8Arg26Lys23GLP-1 (8-38); Gly8Arg34Lys23GLP-1 (8-38);
`
`•3
`
`•3
`
`•3
`
`•3
`
`•3
`
`•3
`
`•3
`
`
`Arg26
`
`•34Lys23GLP-1 (8-37); Arg26•34Lys23
`
`20
`
`
`Arg26•34Lys23
`39GLP-1 (8-39); Arg26
`•
`·
`
`
`
`•3
`
`•3
`
`Gly8Arg26Lys23GLP-1 (8-39); Gly8Arg34Lys23GLP-1 (8-39);
`Gly8Arg26Lys27-GLP-1 (8-36); Gly8Arg34Lys27-GLP-1 (8-36); Gly8Arg26Lys27GLP-1 (8-37);
`Gly8Arg34Lys27GLP-1(8-37); Gly8Arg26Lys27GLP-1(8-38); Gly8Arg34Lys27GLP-1(8-38);
`Gly8Arg26Lys27GLP-1 (8-39); Gly8Arg34Lys27GLP-1 (8-39);
`
`FRESENIUS EXHIBIT 1032
`Page 11 of 50
`
`

`

`WO99/43705
`
`PCT/DK99/00081
`
`-10 -
`
`7GLP-1 (8-37);
`4Lys 18
`4Lys 18GLP-1 (8-37); Gly8Arg26
`6-GLP-1 (8-36);
`34Lys23
`39GLP-1 (8-39); Gly8Arg26
`4Lys 18
`•
`•
`34Lys23
`38GLP-1 (8-38);
`34Lys23
`37GLP-1 (8-37); Gly8Arg26
`•
`•
`•
`•
`34Lys27GLP-1 (8-37);
`36-GLP-1 (8-36); Gly8Arg26
`9GLP-1 (8-39); Gly8Arg26
`34Lys27
`•
`•
`•
`38GLP-1 (8-38); Gly8Arg26
`34Lys27
`9GLP-1 (8-39);
`4Lys27
`5 Gly8Arg26
`34Lys27
`37GLP-1 (8-37); Gly8Arg26
`•
`·
`•
`•
`Val8GLP-1 (8-36); Val8GLP-1 (8-37); Val8GLP-1 (8-38); Val8GLP-1 (8-39)
`Val8Arg26Lys36-GLP-1(8-36); Val8Arg34Lys36-GLP-1(7-36); Val8Arg26Lys36-GLP-1(8-37);
`Val8Arg34Lys36-GLP-1 (8-37); Val8Arg26Lys37-GLP-1 (8-37); Val8Arg34Lys37-GLP-1 (8-37);
`34Lys36
`9-GLP-1 (8-39);
`Val8Arg26Lys39-GLP-1(8-39); Val8Arg34Lys39-GLP-1(8-39); Val8Arg26
`•
`
`•3
`
`Gly8 Arg26•34Lys 18
`
`•36-GLP-1 (8-36); Gly8Arg26
`
`Gly8Arg26
`34Lys 18
`38GLP-1 (8-38); Gly8Arg26
`•
`•
`
`•3
`
`Gly8Arg26•34Lys23GLP-1 (8-37); Gly8Arg26
`
`
`
`Gly8Arg26•34Lys23
`
`•3
`
`•3
`
`•3
`
`•3
`
`•3
`
`•3
`
`•3
`
`1 o Val8Arg26Lys 18-GLP-1 (8-36); Val8Arg34Lys 18-GLP-1 (8-36); Val8Arg26Lys 18GLP-1 (8-37);
`
`Val6Arg34Lys 18GLP-1 (8-37); Val8Arg26Lys 18GLP-1 (8-38); Val8Arg34Lys 18GLP-1 (8-38);
`
`Val8Arg26Lys 18GLP-1 (8-39); Val8Arg34Lys 18GLP-1 (8-39);
`Val8Arg26Lys23-GLP-1 (8-36); Val8Arg34Lys23-GLP-1 (8-36); Val8Arg26Lys23GLP-1 (8-37);
`
`Val8Arg34Lys23GLP-1 (8-37); Val8Arg26Lys23GLP-1 (8-38); Val8Arg34Lys23GLP-1 (8-38);
`
`Val8 Arg26Lys23GLP-1 (8-39); Val8Arg34Lys23GLP-1 (8-39);
`Val6Arg26Lys27-GLP-1 (8-36); Val6Arg34Lys27-GLP-1 (8-36); Val6Arg26Lys27GLP-1 (8-37);
`Val8Arg34Lys27GLP-1 (8-37); Val8Arg26Lys27GLP-1 (8-38); Val8Arg34Lys27GLP-1 (8-38);
`Val8Arg26Lys27GLP-1 (8-39); Val8Arg34Lys27GLP-1 (8-39);
`Val8Arg26
`4Lys18
`36-GLP-1 (8-36); Val8Arg26
`4Lys 18GLP-1 (8-37); Val8Arg26
`•
`
`•3
`
`•3
`
`4Lys23
`39GLP-1 (8-39); Val8Arg26
`34Lys27
`36-GLP-1 (8-36); Val8Arg26
`34Lys27GLP-1 (8-37);
`•
`•
`·
`•
`34Lys27
`39GLP-1 (8-39).
`·
`•
`
`Val8Arg26
`34Lys27
`37GLP-1 (8-37); Val8Arg26
`34Lys27
`38GLP-1 (8-38); or Val6Arg26
`·
`•
`•
`•
`
`In a most preferred embodiment, the present invention relates to derivatives of GLP-1
`analogues of formula 111:
`8
`9 10 11 12 13 14 15 16 17
`
`Xaa-Xaa-Xaa- Xaa-Xaa - Xaa - Xaa- Xaa- Xaa-Xaa-
`
`25 26 27 28
`18 19 20 21 22 23 24
`Xaa-Xaa - Xaa-Xaa - Xaa-Xaa- Xaa- Xaa- Xaa-Xaa- Phe-
`
`29 30 31
`
`32 33 34 35 36 37
`
`38
`
`I l e -Xaa- Xaa- Xaa-Xaa-Xaa-Xaa-Xaa- Xaa- Xaa
`
`35
`
`39 40 41
`
`42 43 44
`
`45
`
`7GLP-1 (8-37);
`4Lys 18
`34Lys23
`36-GLP-1 (8-36);
`9GLP-1 (8-39); Val8Arg26
`·
`•
`34Lys23
`8GLP-1 (8-38);
`34Lys23GLP-1 (8-37); Val8Arg26
`34Lys23
`37GLP-1 (8-37); Val8Arg26
`•
`•
`·
`·
`
`•3
`
`4Lys 18
`
`Val8Arg26
`34Lys 18
`38GLP-1 (8-38); Val8Arg26
`•
`•
`
`•3
`
`Val8Arg26
`
`Val8Arg26
`
`•3
`
`•3
`
`•3
`
`•3
`
`15
`
`20
`
`25
`
`30
`
`FRESENIUS EXHIBIT 1032
`Page 12 of 50
`
`

`

`WO99/43705
`
`PCT/DK99/00081
`
`- 11 -
`
`Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa
`
`(Ill)
`
`wherein
`Xaa at position 8 is Ala, Gly, Ser, Thr, Leu, lie, Val, Glu, Asp, or Lys, or is deleted,
`
`5
`
`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, lie, 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, Tor, Leu, lie, Val, Glu, Asp, or Lys, or is deleted,
`
`10
`
`Xaa at position 15 is Asp or is deleted,
`Xaa at position 16 is Val, Ala, Gly, Ser, Tor, Leu, lie, Tyr, Glu, Asp, or Lys, or is deleted,
`
`Xaa at position 17 is Ser, Ala, Gly, Thr, Leu, lie, Val, Glu, Asp, or Lys, or is deleted,
`
`Xaa at position 18 is Ser, Ala, Gly, Thr, Leu, lie, Val, Glu, Asp, or Lys,
`
`15
`
`Xaa at position 19 is Tyr, Phe, Trp, Glu, Asp, or Lys,
`
`Xaa at position 20 is Leu, Ala, Gly, Ser, Thr, Leu, lie, Val, Glu, Asp, or Lys,
`
`Xaa at position 21 is Glu, Asp, or Lys,
`
`Xaa at position 22 is Gly, Ala, Ser, Tor, Leu, lie, Val, Glu, Asp, or Lys,
`
`Xaa at position 23 is Gin, Asn, Arg, Glu, Asp, or Lys,
`
`20
`
`Xaa at position 24 is Ala, Gly, Ser, Thr, Leu, lie, Val, Arg, Glu, Asp, or Lys,
`
`Xaa at position 25 is Ala, Gly, Ser, Thr, Leu, lie, Val, Glu, Asp, or Lys,
`
`Xaa at position 26 is Lys, Arg, Gin, Glu, Asp, or His,
`
`Xaa at position 27 is Glu, Asp, or Lys,
`
`Xaa at position 30 is Ala, Gly, Ser, Thr, Leu, lie, Val, Glu, Asp, or Lys,
`
`2s
`
`Xaa at position 31 is Trp, Phe, Tyr, Glu, Asp, or Lys,
`
`Xaa at position 32 is Leu, Gly, Ala, Ser, Thr, lie, Val, Glu, Asp, or Lys,
`
`Xaa at position 33 is Val, Gly, Ala, Ser, Thr, Met, Leu, lie, Glu, Asp, or Lys,
`
`Xaa at position 34 is Lys, Arg, Glu, Asp, or His,
`
`Xaa at position 35 is Gly, Ala, Ser, Tor, Leu, lie, Val, Glu, Asp, or Lys,
`
`30
`
`Xaa at position 36 is Arg, Lys, Glu, Asp, or His,
`
`Xaa at position 37 is Gly, Ala, Ser, Thr, Leu, lie, 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,
`
`35
`
`Xaa at position 41 is Phe, Trp, Tyr, Glu, Asp, or Lys, or is deleted,
`
`FRESENIUS EXHIBIT 1032
`Page 13 of 50
`
`

`

`WO99/43705
`
`PCT/DK99/00081
`
`-12 -
`
`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
`
`s
`
`(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 d