PCT
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`WO 99/43707
`
`(11) International Publication Number:
`
`(51) International Patent Classification 6 :
`C07K 14/605, A61K 38/26
`
`Al
`
`( 43) International Publication Date:
`
`2 September 1999 (02.09 .99)
`
`(21) International Application Number:
`
`PCT/DK99/00085
`
`(22) Interna tional Filing Date:
`
`25 February 1999 (25.02.99)
`
`(30) Priority Data:
`0268/98
`0263/98
`0508/98
`
`27 February 1998 (27.02.98)
`27 February 1998 (27.02.98)
`8 April 1998 (08.04.98)
`
`DK
`DK
`DK
`
`(71) Applicant: NOVO NORDISK A/S [DK/DK]; Novo Alie,
`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-141 I Copenhagen K
`(DK). NIELSEN, Per, Franklin; Dals0 Park 59, DK-3500
`Vrerl0se (DK). MADSEN, Kjeld; Nyvestergardsvej 3,
`D K- 3500 Vrerl0se (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, TT, 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, Fl,
`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 MODIFIED GLP-1 DERIVATIVES
`
`(57) Abstract
`
`The present invention relates to N-terrninally modified 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 and are substituted at the N-tenninal end with a substituent comprising an optionally substituted 5- or 6-membered
`ring system, e.g. an imidazole.
`
`FRESENIUS EXHIBIT 1034
`Page 1 of 63
`
`

`

`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
`CG
`CH
`Cl
`CM
`CN
`cu
`CZ
`DE
`DK
`EE
`
`Albania
`Atmenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Braz.ii
`Belarus
`Canada
`Central African Republic
`Congo
`Switwrland
`COte d'Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Gem1any
`Denman:
`ES!onia
`
`ES
`Fl
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hu11gary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People's
`Republic of Korea
`Republic of Korea
`Kaz.akstan
`Saint Lucia
`Liechtenstei.t,
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MO
`MG
`MK
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The fonner Yugoslav
`Republic of Macedonia
`ML
`Mali
`MN
`Mongolia
`MR
`Mauritania
`MW Malawi
`MX
`Mexioo
`Niger
`NE
`NL
`Netherlands
`NO
`Norway
`NZ
`New Zealand
`PL
`Poland
`Portugal
`PT
`RO
`Romania
`Russian Federation
`RU
`so
`Sudan
`SE
`Sweden
`Singapore
`SG
`
`SI
`SK
`SN
`sz
`TD
`TG
`TJ
`TM
`TR
`TI'
`UA
`UG
`us
`uz
`VN
`YU
`zw
`
`Slovenia
`Slovakia
`Senegal
`Swaz.iland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`Yugoslavia
`Zimbabwe
`
`FRESENIUS EXHIBIT 1034
`Page 2 of 63
`
`

`

`WO99/43707
`
`- 1 -
`
`PCT/DK99/00085
`
`N-TERMINALLY MODIFIED 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 and 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:
`9 10 11
`12 13 14 15 16 17 18 19 20 21
`8
`
`7
`
`22 23
`
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-
`
`25
`
`24 25 26 27 28
`
`29 30 31 32
`
`33 34
`
`35 36
`
`(I)
`
`Ala-Ala-Lys-Glu- Phe- Ile-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 of the 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 0708179-A2 (Eli Lilly & Co.) discloses GLP-1 analogues and derivatives that include
`an N-terminal imidazole group and optionally an unbranched C6-C10 acyl group in attached to the
`lysine residue in position 34.
`
`35
`
`SUBSTITUTE SHEET (RULE 26)
`
`FRESENIUS EXHIBIT 1034
`Page 3 of 63
`
`

`

`WO 99/43707
`
`- 2 -
`
`PCT/DK99/00085
`
`It is an object of the present invention to provide improved GLP-1 derivatives.
`
`SUMMARY OF THE INVENTION
`
`In its broadest aspect, the present invention relates to derivatives of GLP-1(7-8) and
`
`s 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 comprise a lipophilic
`
`substituent (optionally via a spacer) attached to at least one amino acid residue and the N-
`
`10 terminal amino acid, i.e., the histidine residue at position 7 is modified. The lipophilic substituent
`
`is in particular a long-chain group of the type described in WO 98/08871 (Novo Nordisk NS), and
`
`the N-terminal substituent comprises an optionally substituted 5- or 6-membered ring system,
`
`e.g. an imidazole.
`
`Accordingly, the invention relates to a GLP-1 derivative comprising a parent peptide of
`
`1 s formula II
`
`A-HN-GLP-1 (8-8)-X
`
`wherein R:y
`
`Ais:
`
`{II)
`
`or
`
`R1
`
`0
`
`y><"
`
`R3
`
`R2
`
`or
`
`y XCH2,
`R3 R2
`
`20 wherein R1. R2 and R3 are independently H, lower alkyl having 1 to 6 carbon atoms, optionally
`
`substituted phenyl, NH2, NH-CO-(lower alkyl), -OH, lower alkoxy having 1 to 6 carbon atoms,
`halogen, S02-(lower alkyl) or CF3, said phenyl is optionally substituted with at least one group
`selected from NH2, -OH, lower alkyl or lower alkoxy having 1-6 carbon atoms, halogen, S02-
`(lower alkyl), NH-CO-(lower alkyl) or CF3, or R1 and R2 may together form a bond;
`2s Y is a five or six membered ring system selected from the group consisting of:
`
`FRESENIUS EXHIBIT 1034
`Page 4 of 63
`
`

`

`WO 99/43707
`
`PCT/DK99/00085
`
`H
`
`N
`rr
`c.~-N
`N\o/
`
`N-
`
`~N-
`Nd
`
`N.,..N'N-
`~d
`
`,,oy
`NL~
`
`N
`
`u
`(NJ
`N
`0/ Ct
`
`H
`
`- 3 -
`
`H
`
`N
`er
`
`(Y sw
`
`H
`
`f'~N-
`Nd
`
`N
`
`0--
`0--
`
`,,Sy
`
`/i
`N~
`\\_N
`
`N
`s(y
`N-
`
`fN /
`
`0~
`
`fN /
`HN~
`
`z V
`
`wherein Z is N, 0 or S, 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,
`s CF3 and aryl;
`B is an integer in the range of 35-45; and
`
`X is - OH, - NH2, or a C1-6 alkyl amide or C,.6 dialkyl amide group;
`or an analogue thereof;
`
`said GLP-1 derivative or analogue comprising a lipophilic substituent attached to at least one
`
`10 amino acid residue thereof.
`
`In particular, the invention relates to GLP-1 derivatives of formula II
`
`A-HN-GLP-1 (8-B)-X
`
`(II)
`
`wherein
`
`A is:
`
`15
`
`or
`
`or
`
`wherein R1, R2 and R3 are independently H, lower alkyl, optionally substituted phenyl , NH2, NH(cid:173)
`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 or lower alkoxy
`
`FRESENIUS EXHIBIT 1034
`Page 5 of 63
`
`

`

`WO99/43707
`
`-4-
`
`PCT/DK99/00085
`
`having 1-6 carbon atoms, halogen, S02-(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:
`
`N
`
`H
`
`rr
`C.,N-
`N
`
`H
`N
`
`(?r
`('N-
`
`N='
`
`sy SW
`/Sy
`
`'°=N
`
`/i
`N~
`\\_N
`
`H
`
`N
`
`tY
`rN/
`
`o J
`
`z 0--
`
`er-
`N~N-
`~='
`/off Or
`(NJ er
`V
`0/ Ct
`rN/
`
`N~
`~-
`
`NL~
`
`N
`
`H
`
`N
`
`N b-
`
`HNJ
`
`5
`
`wherein Z is N, 0 or S, and said ring system is optionally substituted with one or more functional
`
`groups selected from the group consisting of NH2, N02, OH, lower alkyl, lower alkoxy, halogen,
`CF3 and aryl (i.e. , optionally substituted phenyl, as define above), provided that A is not histidine;
`B is an integer in the range of 35-45; and
`
`10
`
`Xis-OH, - NH2, or a C1.s 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.
`
`15
`
`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 peptide 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
`
`20 acid residue in position 8 (Ala) with Gly. Similarly, Lys34{Nc-tetradecanoyl)-GLP-1(7-37)
`
`FRESENIUS EXHIBIT 1034
`Page 6 of 63
`
`

`

`WO99/43707
`
`- 5 -
`
`PCT/DK99/00085
`
`designates GLP-1(7-37) wherein thee-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
`
`5 Asp unless otherwise indicated. Also, if a C-terminally extended analogue extends to position 41 ,
`
`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 GLP-1 (7-45) or a fragment
`
`10 thereof. In a more preferred embodiment, the derivatives are derivatives of native GLP-1 (7-36).
`
`In another more preferred embodiment, the derivatives are derivatives of native GLP-1(7-37). In
`
`another more preferred embodiment, the derivatives are derivatives of native GLP-1 (7-38).
`
`GLP-1 Analogs
`
`15
`
`The present invention also relates to derivatives of analogs of GLP-1 . The term
`
`"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 II, Bis preferably 36, 37 or 38.
`
`In the GLP-1 derivatives of formula II, up to fifteen, preferably up to ten amino acid
`
`20 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
`
`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:
`
`25 B is 36, and the parent peptide comprises one or more amino acid substitutions selected from
`the group consisting of Arg26
`, Arg34 and Lys36
`;
`
`8 is 37, and the parent peptide comprises one or more amino acid substitutions selected from
`the group consisting of Arg26
`, Arg34
`, Lys36 and Lys37
`; or
`
`B is 38, and the parent peptide comprises one or more amino acid substitutions selected from
`30 the group consisting of Arg26
`, Arg34
`, Lys36 and Lys38
`
`.
`
`In a further preferred embodiment, a parent peptide for a derivative of the invention is
`Arg26-GLP-1(7-37); Arg34-GLP-1 (7-37); Lys36-GLP-1 (7-37);
`34Lys36-GLP-1 (7-37); Arg26
`Arg26
`34Lys38GLP-1 (7-38);
`·
`•
`4Lys39-GLP-1 (7-39); Arg26
`Arg26
`34Lys40-GLP-1 (7-40);
`•
`
`•3
`
`FRESENIUS EXHIBIT 1034
`Page 7 of 63
`
`

`

`WO 99/43707
`
`-6-
`
`PCT/DK99/00085
`
`1 o Gly8 Arg26
`•
`
`Arg26Lys36-GLP-1 (7-37); Arg34Lys36-GLP-1 (7-37);
`Arg26Lys39-GLP-1 (7-39); Arg34Lys40-GLP-1 (7-40);
`
`Arg26·34Lys36•39-GLP-1 (7-39); Arg26·34Lys36
`40-GLP-1 (7-40);
`·
`Gly8 Arg26-GLP-1 (7-37); Gly8 Arg34-GLP-1 (7-37);
`5 Gly8Lys36-GLP-1 (7-37); Gly8 Arg26·34Lys36-GLP-1 (7-37);
`34Lys39-GLP-1 (7-39); Gly8Arg26·34Lys40-GLP-1 (7-40);
`Gly8Arg26
`•
`Gly8Arg26Lys36-GLP-1(7-37); Gly8Arg34Lys36-GLP-1(7-37);
`Gly8Arg26Lys39-GLP-1(7-39); Gly8Arg34Lys40-GLP-1(7-4O);
`34Lys36·39-GLP-1 (7-39); or
`Gly8Arg26
`•
`34Lys36·40 -GLP-1 (7-40).
`In a further preferred embodiment, a parent peptide for a derivative of the invention is:
`Arg26·34Lys38GLP-1 (7-38);
`Arg26·34Lys39GLP-1 (7-39);
`Arg26·34Lys40GLP-1 (7-40);
`15 Arg26·34Lys41GLP-1(7-41 );
`Arg26·34Lys42GLP-1 (7-42);
`Arg26·34Lys43GLP-1 (7-43);
`Arg26·34Lys44GLP-1 (7-44);
`Arg26·34Lys45GLP-1 (7-45);
`20 Arg26Lys38GLP-1 (7-38);
`Arg34Lys38GLP-1 (7-38);
`34Lys36·38GLP-1 (7 -38);
`Arg26
`•
`Arg26·34Lys38GLP-1 (7-38);
`Arg26Lys39GLP-1 (7-39);
`2s Arg34Lys39GLP-1 (7-39); or
`Arg26·34Lys36·39GLP-1 (7-39).
`In a further preferred embodiment, the present invention relates to a GLP-1 derivative
`wherein the parent peptide is selected from the group comprising Arg28-GLP-1(7-37), Arg34-GLP-
`1 (7-37), Lys36-GLP-1 (7-37), Arg26·34Lys36-GLP-1(7-37), Arg26Lys36-GLP-1 (7-37), Arg34Lys36-GLP-
`30 1(7-37), Gly8Arg26-GLP-1(7-37), Gly8Arg34-GLP-1(7-37), Gly8Lys36-GLP-1(7-37), Gly8Arg26·34Lys36-
`GLP-1 (7-37), Gly8 Arg26Lys36-GLP-1 (7-37) and Gly8 Arg34Lys36-GLP-1 (7-37).
`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(7-38),
`Arg26·34Lys38-GLP-1 (7-38), Arg26·34Lys36
`38-GLP-1 (7-38), Gly8Arg26Lys38-GLP-1 (7-38) and
`34Lys36·38-GLP-1 (7-38).
`35 Gly8Arg26
`•
`
`•
`
`FRESENIUS EXHIBIT 1034
`Page 8 of 63
`
`

`

`WO 99/43707
`
`- 7 -
`
`PCT /D K99/00085
`
`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(7-39),
`
`4Lys36
`
`39-GLP-1 (7-39).
`•
`
`•3
`
`Arg26
`34Lys36
`•
`
`39-GLP-1 (7-39), Gly8Arg26Lys39-GLP-1 (7-39) and Gly8Arg26
`·
`
`In a further preferred embodiment, the present invention relates to a GLP-1 derivative
`
`s wherein the parent peptide is selected from the group comprising Arg34Lys40-GLP-1(7-40),
`
`40-GLP-1 (7-40), Gly8Arg34Lys40-GLP-1 (7-40) and Gly8Arg26
`Arg26
`34Lys36
`34Lys36
`•
`•
`•
`
`40-GLP-1 (7-40).
`•
`
`In a further preferred embodiment, the present invention relates to a GLP-1 derivative
`
`wherein the parent peptide is:
`
`34Lys36-GLP-1 (7-36); Arg26-GLP-1 (7-36)amide;
`Arg26-GLP-1 (7-36); Arg34-GLP-1 (7-36); Arg26
`•
`
`10 Arg34-GLP-1 (7-36)amide; Arg26
`
`34Lys36-GLP-1 (7-36)amide; Arg26-GLP-1 (7-37); Arg34-GLP-1 (7-37);
`·
`
`Arg26
`34Lys36-GLP-1 (7-37); Arg26-GLP-1 (7-38); Arg34-GLP-1 (7-38);
`·
`
`Arg26
`34Lys38GLP-1 (7-38); Arg26-GLP-1 (7-39); Arg34-GLP-1 (7-39);
`·
`
`Arg26
`34Lys39-GLP-1 (7-39); Gly8Arg26-GLP-1 (7-36);
`·
`
`GlysArg34-GLP-1(7-36); Gly6Arg26
`34Lys36-GLP-1(7-36);
`•
`1s Gly8Arg26-GLP-1 (7-36)amide; GlysArg34-GLP-1 (7-36)amide;
`34Lys36-GLP-1(7-36)amide; Gly8Arg26-GLP-1(7-37);
`Gly6Arg26
`·
`
`4Lys36-GLP-1 (7-37);
`
`•3
`
`GlysArg34-GLP-1 (7-37); Gly6Arg26
`
`Gly8Arg26-GLP-1 (7-38); Gly8Arg34-GLP-1 (7-38);
`
`4Lys38GLP-1 (7-38); Gly8Arg26-GLP-1 (7-39);
`Gly8Arg26
`20 Gly8Arg34-GLP-1 (7-39); Gly6Arg26
`Val8Arg26-GLP-1 (7-36); Val8Arg34-GLP-1 (7-36);
`
`34Lys39-GLP-1 (7-39);
`•
`
`•3
`
`4Lys36 -GLP-1 (7-36); Vais Arg26 -GLP-1 (7-36)amide;
`
`•3
`
`Vais Arg26
`
`Vais Arg34-GLP-1 (7-36)amide; Vais Arg26
`34Lys36-GLP-1 (7-36)amide;
`•
`Val8Arg26-GLP-1 (7-37); Val8Arg34-GLP-1 (7-37);
`
`2s ValsArg26
`34Lys36-GLP-1 (7-37); Val8Arg26-GLP-1 (7-38);
`•
`
`Val8Arg34-GLP-1 (7-38); ValsArg26
`4Lys38GLP-1 (7-38);
`Val8Arg26-GLP-1 (7-39); Val8Arg34-GLP-1 (7-39);
`
`•3
`
`34Lys39-GLP-1 (7-39); Ser8Arg26-GLP-1 (7-36);
`ValsArg26
`•
`
`Ser8Arg34-GLP-1 (7-36); Ser8Arg26
`
`34Lys36-GLP-1 (7-36);
`·
`
`30 Ser8Arg26-GLP-1 (7-36)amide; Ser8Arg34-GLP-1 (7-36)amide;
`34Lys36-GLP-1 (7-36)amide; Ser8Arg26-GLP-1 (7-37);
`Ser8Arg26
`•
`
`Ser8Arg34-GLP-1 (7-37); Ser8Arg26
`34Lys36-GLP-1 (7-37);
`·
`
`Ser8Arg26-GLP-1 (7-38); Ser8Arg34-GLP-1 (7-38);
`
`Ser8Arg26
`34Lys38GLP-1 (7-38); Ser8Arg26-GLP-1 (7-39);
`·
`
`35 Ser8 Arg34 -GLP-1 (7 -39); Ser8 Arg26
`
`34L ys39 -G LP-1 (7 -39);
`•
`
`FRESENIUS EXHIBIT 1034
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`

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`
`PCT/DK99/00085
`
`- 8 -
`
`Thr8Arg26-GLP-1 (7-36); Thr8Arg34-GLP-1 (7-36);
`
`Thr8Arg26
`34Lys36-GLP-1(7-36); Thr8Arg26-GLP-1(7-36)amide;
`·
`
`Thr8Arg34-GLP-1 (7-36)amide; Thr8Arg26
`
`34Lys36-GLP-1 (7-36)amide;
`•
`
`Thr8Arg26-GLP-1 (7-37); Thr8Arg34-GLP-1 (7-37);
`
`5 Thr8Arg26
`34Lys36-GLP-1 (7-37); Thr8Arg26-GLP-1 (7-38);
`·
`
`Thr8Arg34-GLP-1 (7-38); Thr8Arg26
`
`34Lys38GLP-1 (7-38);
`•
`
`Thr8Arg26-GLP-1 (7-39); Thr8Arg34-GLP-1 (7-39);
`
`4Lys36-GLP-
`
`•3
`
`Thr8Arg26
`34Lys39-GLP-1 (7-39); Val8Glu35Arg26
`34Lys36-GLP-1 (7-36);
`·
`•
`Val8Glu35Arg26
`4Lys36-GLP-1 (7-36)amide; Val8Glu36Arg26
`34Lys37GLP-1 (7-37);
`•
`10 Val8Glu37 Arg26
`4Lys38GLP-1 (7-38); Val8Glu38Arg26
`34Lys39-GLP-1 (7-39); Val8Glu35Arg26
`•
`1 (7-36);
`
`•3
`
`•3
`
`34Lys37GLP-1 (7-37);
`·
`
`Val8Glu35Arg26
`34Lys36-GLP-1 (7-36)amide; Val8Glu36Arg28
`•
`Val8Glu37 Arg26
`4Lys38GLP-1 (7-38);
`
`•3
`
`Val8Glu38Arg26
`4Lys39-GLP-1 (7-39); Val8Asp35Arg26
`34Lys36-GLP-1 (7-36); Val8Asp35Arg26·34Lys36-
`•
`15 GLP-1(7-36)amide;
`
`•3
`
`4Lys38GLP-1 (7-38); Val8Asp38Arg26•34Lys39-
`
`34Lys37 GLP-1 (7-37); Val8Asp37 Arg26
`•
`
`•3
`
`Val8Asp36Arg26
`
`GLP-1 (7-39); Val8Asp35Arg26
`4Lys36-GLP-1 (7-36); Val8Asp35Arg26·34Lys36-GLP-1 (7-36)amide;
`Val8Asp36Arg28
`4Lys37GLP-1 (7-37); Val8Asp37 Arg26
`4Lys38GLP-1 (7-38); Val8Asp38Arg28
`34Lys39
`-
`•
`GLP-1 (7-39); Ser8Glu35Arg26
`34Lys36-GLP-1 (7-36); Ser8Glu35Arg26
`•
`20 Ser8Glu36Arg26
`4Lys37GLP-1 (7-37);
`
`•3
`
`•3
`
`•3
`
`•3
`
`4Lys36-GLP-1 (7-36)amide;
`
`•3
`
`4Lys38GLP-1 (7-38); Ser8Glu38 Arg26
`Ser8Glu37 Arg26
`4Lys39-GLP-1 (7-39); Ser8Glu35 Arg26•34Lys36 -
`GLP-1 (7-36); Ser8Glu35Arg26
`34Lys36-GLP-1 (7-36)amide; Ser8Glu36Arg26
`•
`Ser8Glu37 Arg26
`34Lys38GLP-1 (7-38); Ser8Glu38 Arg26
`34Lys39 -GLP-1 (7-39); Ser8 Asp35 Arg26·34Lys36-
`•
`•
`34Lys36-GLP-1 (7-36)amide; Ser8Asp36Arg26•34Lys37GLP-1 (7-37);
`GLP-1 (7-36); Ser8Asp35Arg26
`•
`34Lys38GLP-1 (7-38); Ser8 Asp38 Arg26
`25 Ser8 Asp37 Arg26
`34Lys39-GLP-1 (7-39); Ser8 Asp35 Arg26
`34Lys36 -
`·
`'
`•
`GLP-1 (7-36); Ser8Asp35Arg26
`34Lys36-GLP-1 (7-36)amide; Ser8Asp38Arg26•34Lys37GLP-1 (7-37);
`•
`Ser8 Asp37 Arg26
`34Lys38GLP-1 (7 -38); Ser8 Asp38 Arg26
`34Lys39 -GLP-1 (7-39); Thr8Glu35 Arg26•34Lys36 -
`·
`•
`GLP-1 (7-36); Thr8Glu35Arg26
`4Lys36-GLP-1 (7-36)amide; Thr8Glu36Arg26·34Lys37 GLP-1 (7-37);
`4Lys38GLP-1 (7-38); Thr8Glu38Arg26
`Thr8Glu37 Arg26
`34Lys39-GLP-1 (7-39); Thr8Glu35Arg26·34Lys36-
`·
`34Lys36-GLP-1 (7-36)amide; Thr8Glu36Arg26•34Lys37GLP-1 (7-37);
`30 GLP-1 (7-36); Thr8Glu35Arg26
`·
`Thr8Glu37 Arg26
`34Lys38GLP-1 (7-38); Thr8Glu38 Arg26
`34Lys39-GLP-1 (7-39);
`•
`•
`Thr8Asp35Arg26
`34Lys36-GLP-1 (7-36); Thr8Asp35Arg26
`34Lys36-GLP-1 (7-36)amide;
`·
`•
`Thr8Asp36Arg26
`34Lys37GLP-1 (7-37);
`·
`Thr8Asp37 Arg26
`
`4Lys37GLP-1 (7-37);
`
`•3
`
`•3
`
`•3
`
`•3
`
`•3
`
`4Lys38GLP-1 (7-38); Thr8Asp38Arg26
`34Lys39-GLP-1 (7-39); Thr8Asp35Arg26·34Lys36-
`·
`
`•3
`
`4Lys37GLP-1 (7-37);
`
`34Lys36-GLP-1 (7-36)amide; Thr8Asp36Arg26
`•
`
`•3
`
`35 GLP-1 (7-36); Thr8Asp35Arg26
`
`FRESENIUS EXHIBIT 1034
`Page 10 of 63
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`

`

`WO 99/43707
`
`- 9 -
`
`PCT/DK99/00085
`
`34Lys39 -GLP-1 (7-39);
`4Lys38GLP-1 (7-38); Thr8 Asp38 Arg26
`•
`
`Thr8 Asp37 Arg26
`
`•3
`
`34Lys36-GLP-1 (7-36)amide;
`Gly8Glu35 Arg26
`34Lys36-GLP-1 (7-36); Gly8Glu35 Arg26
`•
`•
`
`Gly8Glu36Arg26
`34Lys37GLP-1(7-37);
`•
`
`Gly8Glu37 Arg26
`34Lys38GLP-1 (7-38); Gly8Glu38Arg26
`34Lys39-GLP-1 (7-39); Gly8Glu35Arg26
`34Lys36
`•
`-
`•
`•
`
`34Lys37 GLP-1 (7-37);
`·
`
`34Lys39-GLP-1 (7-39); Gly8Asp35Arg26·34Lys36
`-
`
`4Lys37GLP-1 (7-37);
`
`•3
`
`34Lys 18-GLP-1 (7-36);
`•
`
`4Lys 18GLP-1 (7-38);
`
`•3
`
`•3
`
`•3
`
`•3
`
`•3
`
`•3
`
`•3
`
`•3
`
`•3
`
`•3
`
`s GLP-1 (7-36); Gly8Glu35 Arg26
`34Lys36-GLP-1 (7-36)amide; Gly8Glu36 Arg26
`·
`Gly8Glu37 Arg26
`34Lys38GLP-1 (7-38); Gly8Glu38Arg26
`
`·
`•
`GLP-1 (7-36); Gly8Asp35Arg26
`34Lys36-GLP-1 (7-36)amide; Gly8Asp36Arg26
`•
`Gly8Asp37 Arg26
`34Lys38GLP-1 (7-38); Gly8Asp38Arg26
`34Lys39-GLP-1 (7-39); Gly8Asp35Arg26
`34Lys36
`·
`-
`·
`•
`4Lys36-GLP-1(7-36)amide; Gly8Asp36Arg26
`GLP-1 (7-36); Gly8Asp35Arg26
`34Lys37GLP-1(7-37);
`•
`1 o Gly8 Asp37 Arg26
`34Lys38GLP-1 (7-38); Gly8 Asp38 Arg26
`34Lys39 -GLP-1 (7-39); Arg26
`•
`•
`Arg26
`4Lys 18-GLP-1 (7-36)amide; Arg26
`34Lys 18GLP-1 (7-37); Arg26
`•
`Gly8Asp 19Arg26
`34Lys 18-GLP-1 (7-36); Gly8Asp17Arg26
`34Lys 18-GLP-1 (7-36); Gly8Asp19Arg26•34Lys 18-
`•
`•
`GLP-1 (7-36)amide; Gly8 Asp 17 Arg26
`34Lys 18-GLP-1 (7-36)amide; Gly8 Asp 19 Arg26
`34Lys 18GLP-1 (7 -37);
`•
`•
`Gly8 Asp 19 Arg26
`4Lys 18GLP-1 (7-38); Gly8 Asp 17 Arg26
`4Lys 18GLP-1 (7-38);
`34Lys23-GLP-1 (7-36)amide; Arg26•34Lys23GLP-1 (7-37);
`1s Arg26
`34Lys23-GLP-1 (7-36); Arg26
`•
`•
`34Lys23GLP-1 (7-38); Gly8Asp24Arg26
`Arg26
`34Lys23-GLP-1 (7-36); Gly8Asp22Arg26•34Lys23-GLP-1 (7-36);
`•
`•
`Gly8 Asp24Arg26
`4Lys23-GLP-1 (7 -36)amide; Gly8 Asp22Arg26
`34Lys23-GLP-1 (7-36)amide;
`•
`4Lys23GLP-1 (7-37); Gly8Asp24Arg26
`Gly8Asp24Arg26
`34Lys23GLP-1 (7-38); Gly8Asp22Arg26•34Lys23GLP-
`•
`1 (7-38);
`4Lys27-GLP-1 (7-36)amide; Arg26•34Lys27GLP-1 (7-37);
`34Lys27-GLP-1 (7-36); Arg26
`20 Arg26
`•
`34Lys27GLP-1 (7-38); Gly8 Asp28Arg26
`Arg26
`34Lys27-GLP-1 (7-36); Gly8Asp26Arg26•34Lys27-GLP-1 (7-36);
`·
`·
`Gly8Asp28Arg26
`34Lys27-GLP-1 (7-36)amide; Gly8Asp26Arg26
`•
`Gly8Asp28Arg26
`34Lys27GLP-1 (7-37); Gly8Asp28Arg26
`34Lys27GLP-1 (7-38); Gly8Asp26Arg26•34Lys27GLP-
`•
`•
`1 (7-38);
`34Lys 18-GLP-1 (7-36); Arg26•34Lys18-GLP-1 (7-36)amide; Arg26
`
`2s Arg26
`•
`34Lys 18GLP-1 (7-38); Val8Asp 19Arg26
`Arg26
`34Lys 18-GLP-1 (7-36); Val8Asp17 Arg26·34Lys 18-GLP-1 (7-36);
`•
`•
`Val8Asp 19Arg26
`34Lys 18-GLP-1 (7-36)amide; Val8Asp 17 Arg26
`34Lys 18-GLP-1 (7-36)amide;
`•
`•
`Val8Asp 19Arg26
`34Lys 18GLP-1 (7-37); Val8Asp 19Arg26
`4Lys 18GLP-1 (7-38); Val8Asp 17 Arg26·34Lys 18GLP-
`•
`1 (7-38);
`34Lys23-GLP-1 (7-36); Arg26
`30 Arg26
`34Lys23-GLP-1 (7-36)amide; Arg26
`34Lys23GLP-1 (7-37);
`·
`•
`•
`Arg26
`34Lys23GLP-1 (7 -38); Val8 Asp24Arg26
`4Lys23 -GLP-1 (7 -36); Val8 Asp22 Arg26·34Lys23 -G LP-1 (7 -36);
`•
`Val8Asp24Arg26
`34Lys23-GLP-1 (7-36)amide; Val8Asp22Arg26
`•
`Val8Asp24Arg26
`4Lys23GLP-1 (7-37); Val8Asp24Arg26
`34Lys23GLP-1 (7-38); Val8Asp22Arg26·34Lys23GLP-
`•
`1 (7-38);
`
`4Lys27-GLP-1 (7-36)amide;
`
`•3
`
`34Lys 18GLP-1 (7-37);
`•
`
`34Lys23-GLP-1 (7-36)amide;
`•
`
`•3
`
`FRESENIUS EXHIBIT 1034
`Page 11 of 63
`
`

`

`WO 99/43707
`
`- 10 -
`
`PCT/DK99/00085
`
`•3
`
`Arg26
`
`•3
`
`34Lys27-GLP-1 (7-36)amide; Arg26
`4Lys27-GLP-1 (7-36); Arg26
`34Lys27 GLP-1 (7-37);
`•
`•
`34Lys27GLP-1 (7-38); Val8Asp28Arg26
`34Lys27-GLP-1 (7-36); Val8Asp26Arg26
`34Lys27-GLP-1 (7-36);
`Arg26
`·
`•
`•
`Val8Asp28Arg26
`34Lys27-GLP-1 (7-36)amide; Val8Asp26Arg26
`4Lys27-GLP-1 (7-36)amide;
`·
`Val8Asp28Arg26
`34Lys27GLP-1 (7-37); Val8Asp28Arg26
`34Lys27GLP-1 (7-38); Val8Asp26Arg26
`34Lys27GLP-
`•
`·
`•
`5 1(7-38);
`34Lys 18-GLP-1 (7 -36); Arg26
`34Lys 18-GLP-1 (7 -36)amide; Arg26
`Arg26
`34Lys 18GLP-1 (7 -37);
`•
`·
`·
`34Lys 18GLP-1 (7-38); Ser8Asp19Arg26
`34Lys 18-GLP-1 (7-36); Ser8Asp17Arg26
`Arg26
`34Lys 18-GLP-1 (7-
`•
`·
`·
`4Lys 18-GLP-1 (7-36)amide; Ser8Asp 17 Arg26
`36); Ser8Asp 19Arg26
`34Lys 18-GLP-1 (7-36)amide;
`•
`Ser8 Asp19Arg26
`34Lys 18GLP-1 (7-37); Ser8Asp19Arg26
`34Lys 18GLP-1 (7-38);
`•
`•
`34Lys18GLP-1 (7-38);
`10 Ser8Asp17Arg26
`·
`
`•3
`
`Arg26
`34Lys23-GLP-1 (7-36); Arg26
`34Lys23-GLP-1 (7-36)amide; Arg26
`34Lys23GLP-1 (7-37);
`•
`•
`•
`34Lys23GLP-1 (7-38); Ser8Asp24Arg26
`Arg26
`34Lys23-GLP-1 (7-36); Ser8Asp22Arg26•34Lys23-GLP-1 (7-
`•
`•
`36); Ser8Asp24Arg26
`34Lys23-GLP-1 (7-36)amide; Ser8Asp22Arg26
`34Lys23-GLP-1 (7-36)amide;
`•
`·
`Ser8 Asp24Arg26
`34Lys23GLP-1 (7-37); Ser8 Asp24Arg26
`34Lys23GLP-1 (7-38);
`•
`•
`15 Ser8Asp22Arg26
`34Lys23GLP-1(7-38);
`·
`34Lys27-GLP-1 (7-36); Arg26
`Arg26
`4Lys27 -GLP-1 (7-36)amide; Arg26
`34Lys27 GLP-1 (7-37);
`·
`·
`Arg26
`34Lys27GLP-1 (7-38); Ser8Asp28Arg26
`34Lys27-GLP-1 (7-36); Ser8Asp26Arg26•34Lys27-GLP-1 (7-
`·
`•
`36); Ser8Asp28Arg26
`34Lys27-GLP-1 (7-36)amide; Ser8Asp26Arg26
`•
`Ser8 Asp28 Arg26
`34Lys27 GLP-1 (7-37); Ser8 Asp28 Arg26
`34Lys27 GLP-1 (7-38);
`•
`•
`20 Ser8Asp26Arg26
`4Lys27GLP-1 (7-38);
`34Lys 18-GLP-1 (7-36); Arg26
`Arg26
`34Lys 18-GLP-1 (7-36)amide; Arg26
`34Lys 18GLP-1 (7-37);
`•
`·
`·
`4Lys 18GLP-1 (7-38); Thr8Asp19Arg26
`Arg26
`34Lys 18-GLP-1 (7-36); Thr8Asp17 Arg26•34Lys 18-GLP-1 (7-36);
`•
`Thr8Asp19Arg26
`34Lys 18-GLP-1 (7-36)amide; Thr8Asp 17 Arg26
`34Lys 18-GLP-1 (7-36)amide;
`·
`·
`Thr8 Asp 19 Arg26
`34Lys 18GLP-1 (7-37); Thr8 Asp 19 Arg26
`•
`25 1(7-38);
`4Lys23-GLP-1 (7-36); Arg26
`Arg26
`
`·
`4Lys23GLP-1 (7-38); Thr8Asp24Arg26
`Arg26
`34Lys23-GLP-1 (7-36); Thr8Asp22Arg26•34Lys23-GLP-1 (7-36);
`•
`Thr8 Asp24Arg26
`34Lys23 -GLP-1 (7 -36)amide; Thr8 Asp22Arg26
`·
`Thr8Asp24Arg26
`34Lys23GLP-1 (7-37); Thr8Asp24Arg26
`·
`3o 1(7-38);
`Arg26
`34Lys27-GLP-1 (7-36); Arg26
`4Lys27-GLP-1 (7-36)amide; Arg26
`34Lys27GLP-1 (7-37);
`•
`·
`Arg26
`4Lys27GLP-1 (7-38); Thr8Asp28Arg26
`34Lys27-GLP-1 (7-36); Thr8Asp26Arg26
`34Lys27-GLP-1 (7-36);
`·
`·
`Thr8Asp28Arg26
`34Lys27-GLP-1 (7-36)amide; Thr8Asp26Arg26
`34Lys27-GLP-1 (7-36)amide;
`•
`•
`Thr8Asp28Arg26
`34Lys27GLP-1 (7-37); Thr8Asp28Arg26
`4Lys27GLP-1 (7-38); or
`·
`35 Thr8Asp26Arg26
`34Lys27GLP-1 (7-38).
`·
`
`34Lys27-GLP-1 (7-36)amide;
`·
`
`•3
`
`•3
`
`4Lys 18GLP-1 (7-38); Thr8 Asp 17 Arg26·34Lys 18GLP-
`
`34Lys23-GLP-1 (7-36)amide; Arg26·34Lys23GLP-1 (7-37);
`
`4Lys23 -GLP-1 (7-36)amide;
`
`•3
`
`•3
`
`4Lys23GLP-1 (7-38); Thr8Asp22Arg26
`34Lys23GLP-
`•
`
`•3
`
`•3
`
`•3
`
`•3
`
`•3
`
`•3
`
`•3
`
`FRESENIUS EXHIBIT 1034
`Page 12 of 63
`
`

`

`WO 99/43707
`
`PCT/DK99/00085
`
`- 11 -
`
`In a further preferred embodiment, the present invention relates to a GLP-1 derivative
`
`4Lys23·36-GLP-1 (7-36);
`
`•3
`
`•3
`
`6-GLP-1 (7-36); Arg26
`34Lys27GLP-1 (7-37);
`•
`
`•3
`
`wherein the parent peptide is:
`Arg26Lys36-GLP-1 (7 -36); Arg34Lys36-GLP-1 (7-36); Arg26Lys36-GLP-1 (7-37); Arg34Lys36-GLP-1 (7-
`37); Arg26Lys37-GLP-1 (7-37); Arg34Lys37-GLP-1 (7-37); Arg26Lys39-GLP-1 (7-39); Arg34Lys39-GLP-
`5 1(7-39); Arg26
`34Lys36
`39-GLP-1(7-39);
`·
`•
`Arg26Lys 18-GLP-1 (7-36); Arg34Lys18-GLP-1 (7-36); Arg26Lys18GLP-1 (7-37); Arg34Lys 18GLP-1 (7-37);
`Arg26Lys 18GLP-1 (7-38); Arg34Lys 18GLP-1 (7-38); Arg26Lys 18GLP-1 (7-39); Arg34Lys 18GLP-1 (7-39);
`Arg26Lys23-GLP-1 (7-36); Arg34Lys23-GLP-1 (7-36); Arg26Lys23GLP-1 (7-37); Arg34Lys23GLP-1 (7-37);
`Arg26Lys23GLP-1 (7-38); Arg34Lys23GLP-1 (7-38); Arg26Lys23GLP-1 (7-39); Arg34Lys23GLP-1 (7-39);
`10 Arg26Lys27-GLP-1 (7-36); Arg34Lys27-GLP-1 (7-36); Arg26Lys27GLP-1 (7-37); Arg34Lys27GLP-1 (7-37);
`Arg26Lys27GLP-1 (7-38); Arg34Lys27GLP-1 (7-38); Arg26Lys27GLP-1 (7-39); Arg34Lys27GLP-1 (7-39);
`Arg26
`34Lys 18
`36-GLP-1 (7-36); Arg26
`34Lys 18GLP-1 (7-37); Arg26
`34Lys 18
`37GLP-1 (7-37);
`•
`•
`•
`·
`•
`Arg26
`34Lys 18
`38GLP-1 (7-38); Arg26
`34Lys 18
`39GLP-1 (7-39); Arg26
`•
`·
`•
`·
`Arg26
`34Lys23GLP-1 (7-37); Arg26
`4Lys23
`37GLP-1 (7-37); Arg26
`34Lys23·38GLP-1 (7-38);
`•
`•
`•
`15 Arg26
`34Lys23
`39GLP-1 (7-39); Arg26
`34Lys27
`•
`•
`•
`Arg26
`34Lys27
`37GLP-1 (7-37); Arg26
`38GLP-1 (7-38); Arg26
`34Lys27
`34Lys27•39GLP-1 (7-39);
`
`•
`·
`•
`•
`•
`Gly8GLP-1 (7-36); Gly8GLP-1 (7-37); Gly8GLP-1 (7-38); Gly8GLP-1 (7-39);
`Gly8Arg26Lys36-GLP-1 (7-36); Gly8Arg34Lys36-GLP-1 (7-36); Gly8Arg26Lys36-GLP-1 (7-37);
`Gly8Arg34Lys36-GLP-1 (7-37); Gly8Arg26Lys37-GLP-1 (7-37); Gly8Arg34Lys37-GLP-1 (7-37);
`20 Gly8Arg26Lys39-GLP-1 (7-39); Gly8Arg34Lys39-GLP-1 (7-39); Gly8Arg26•34Lys36•39-GLP-1 (7-39);
`Gly8Arg26Lys 18-GLP-1 (7-36); Gly8Arg34Lys 18-GLP-1 (7-36); Gly8Arg26Lys 18GLP-1 (7-37);
`Gly8Arg34Lys 18GLP-1 (7-37); Gly8Arg26Lys 18GLP-1 (7-38); Gly8Arg34Lys 18GLP-1 (7-38);
`Gly8Arg26Lys 18GLP-1 (7-39); Gly8Arg34Lys 18GLP-1 (7-39);
`Gly8Arg26Lys23-GLP-1(7-36); Gly8Arg34Lys23-GLP-1(7-36); Gly8Arg26Lys23GLP-1 (7-37);
`25 Gly8Arg34Lys23GLP-1 (7-37); Gly8Arg26Lys23GLP-1 (7-38); Gly8Arg34Lys23GLP-1 (7-38);
`Gly8Arg26Lys23GLP-1(7-39); Gly8Arg34Lys23GLP-1(7-39);
`Gly8Arg26Lys27-GLP-1(7-36); Gly8Arg34Lys27-GLP-1(7-36); Gly8Arg26Lys27GLP-1(7-37);
`Gly8Arg34Lys27GLP-1 (7-37); Gly8Arg26Lys27GLP-1 (7-38); Gly8Arg34Lys27GLP-1 (7-38);
`Gly8Arg26Lys27GLP-1 (7-39); Gly8Arg34Lys27GLP-1 (7-39);
`30 Gly8Arg26
`34Lys 18
`6-GLP-1 (7-36); Gly8Arg26
`4Lys 18GLP-1 (7-37); Gly8Arg26·34Lys 18•37GLP-1 (7-37);
`•
`Gly8Arg26
`34Lys 18
`38GLP-1 (7-38); Gly8Arg26
`4Lys 18
`39GLP-1 (7-39); Gly8Arg26•34Lys23•36-GLP-1 (7-36);
`•
`•
`•
`Gly8Arg26
`34Lys23GLP-1 (7-37); Gly8Arg26
`34Lys23
`7GLP-1 (7-37); Gly8Arg26•34Lys23•38GLP-1 (7-38);
`•
`•
`Gly8Arg26
`34Lys23
`39GLP-1 (7-39); Gly8Arg26
`34Lys27
`36-GLP-1 (7-36); Gly8Arg26·34Lys27GLP-1 (7-37);
`•
`·
`•
`•
`Gly8Arg26
`34Lys27
`37GLP-1 (7-37); Gly8Arg26
`34Lys27
`38GLP-1 (7-38); Gly8Arg26·34Lys27•39GLP-1 (7-39);
`·
`•
`•
`·
`35 Val8GLP-1(7-36); Val8GLP-1(7-37); Val8GLP-1(7-38); Val8GLP-1(7-39)
`
`•3
`
`•3
`
`•3
`
`•3
`
`FRESENIUS EXHIBIT 1034
`Page 13 of 63
`
`

`

`WO 99/43707
`
`- 12 -
`
`PCT/DK99/00085
`
`Val8Arg26Lys36-GLP-1 (7-36); Val8Arg34Lys36-GLP-1 (7-36); Val8Arg26Lys36-GLP-1 (7-37);
`Val8Arg34Lys36-GLP-1 (7-37); Val8Arg26Lys37-GLP-1 (7-37); Val8Arg34Lys37-GLP-1 (7-37);
`
`Val8Arg26Lys39-GLP-1 (7-39); Val8Arg34Lys39-GLP-1 (7-39); Val8Arg26
`34Lys36
`9-GLP-1 (7-39);
`•
`Val8Arg26Lys 18-GLP-1 (7-36); Val8Arg34Lys 18-GLP-1 (7-36); Val8Arg26Lys 18GLP-1 (7-37);
`
`•3
`
`5 VaI8Arg34Lys 18GLP-1 (7-37); Val8Arg26Lys 18GLP-1 (7-38); Val8Arg34Lys18GLP-1 (7-38);
`
`Val8Arg26Lys 18GLP-1 (7-39); Val8Arg34Lys 18GLP-1 (7-39);
`
`Val8Arg26Lys23-GLP-1 (7-36); Val8Arg34Lys23-GLP-1 (7-36); Val8Arg26Lys23GLP-1 (7-37);
`Val8Arg34Lys23GLP-1 (7-37); Val8Arg26Lys23GLP-1 (7-38); Val8Arg34Lys23GLP-1 (7-38);
`
`Val8 Arg26Lys23GLP-1 (7 -39); Val8 Arg34Lys23GLP-1 (7-39);
`10 Val8Arg26Lys27-GLP-1 (7-36); Val8Arg34Lys27-GLP-1 (7-36); Val8Arg26Lys27GLP-1 (7-37);
`Val8Arg34Lys27GLP-1 (7-37); Val8Arg26Lys27GLP-1 (7-38); Val8Arg34Lys27GLP-1 (7-38);
`Val8Arg26Lys27GLP-1 (7-39); Val8Arg34Lys27GLP-1 (7-39);
`34Lys 18
`Val8Arg26
`36-GLP-1 (7-36); Val8Arg26
`·
`·
`34Lys 18
`Val8Arg26
`38GLP-1 (7-38); Val8Arg26
`•
`•
`4Lys23GLP-1 (7-37); Val8Arg26
`15 VaI8Arg26
`
`4Lys 18
`
`37GLP-1 (7-37);
`•
`
`•3
`
`34Lys 18GLP-1 (7-37); Val8Arg26
`•
`
`4Lys 18
`39GLP-1 (7-39); Val8Arg26
`•
`
`34Lys23
`36-GLP-1 (7-36);
`·
`•
`
`•3
`
`34Lys23
`37GLP-1 (7-37); Val8Arg26
`34Lys23
`•
`•
`•
`
`38GLP-1 (7-38);
`•
`
`•3
`
`9GLP-1 (7-39); Val8Arg26
`34Lys27
`36-GLP-1 (7-36); Val8Arg26
`34Lys27GLP-1 (7-37);
`·
`•
`•
`37GLP-1 (7-37); Val8Arg26
`34Lys27
`38GLP-1 (7-38); or Val8Arg26
`·
`•
`•
`
`
`
`4Lys27•39GLP-1 (7-39).
`
`•3
`
`•3
`
`Val8Arg26
`34Lys23
`•
`34Lys27
`Val8Arg26
`•
`
`In a most preferred embodiment, the present invention relates to derivatives of GLP-1
`
`analogues of formula Ill:
`7
`8
`9 10 11
`
`20
`
`12 13 14 15 1 6 1 7
`
`Xaa - Xaa- Xaa - Gly-Xaa- Phe-Thr - Xaa- Asp-Xaa-Xa a -
`
`18 19 20 21 22 23 24
`
`25 26 27
`
`28
`
`Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa- Xaa- Xaa- Phe-
`
`25
`
`29 30 31
`
`32 33 34
`
`35 36 37 38
`
`Ile-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa- Xaa
`
`39
`
`40 41 42 43 44 45
`
`30
`
`Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa
`
`(Ill)
`
`wherein
`
`Xaa at position 7 is any of the groups A (as defined herein),
`
`Xaa at position 8 is Ala, Gly, Ser, Thr, Leu, lie, Val, Glu, Asp, or Lys,
`
`35
`
`Xaa at position 9 is Glu, Asp, or Lys,
`
`FRESENIUS EXHIBIT 1034
`Page 14 of 63
`
`

`

`WO99/43707
`
`- 13 -
`
`PCT/DK99/00085
`
`Xaa at position 11 is Thr, Ala, Gly, Ser, Leu, lie, Val, Glu, Asp, or Lys,
`
`Xaa at position 14 is Ser, Ala,