`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`Intematlonal Bureau
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification 6 :
`
`(11) International Publication Number:
`
`W0 99/43707
`
`C07K 14/605, A61K 38/26
`
`(43) International Publication Date:
`
`2 September 1999 (02.09.99)
`
`(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, 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.
`
`(21) International Application Number:
`
`PCT/DK99/00085
`
`(22) International 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 A116,
`DK—2880 Bagsvaerd (DK).
`
`(72) Inventors: KNUDSEN, Liselotte, Bjerre; Valby Langgade
`49A, 1.
`tv., DK—2500 Valby (DK). HUUSFELDT, Per,
`Olaf; Applebys Plads 27,5. mf., DK—1411 Copenhagen K
`(DK). NIELSEN, Per, Franklin; Dalsn Park 59, DK—3500
`Vaerlnse (DK). MADSEN, Kjeld; Nyvestergardsvej 3,
`DK—3500 Vaarlese (DK).
`
`
`
`ring system, e.g. an imidazole.
`
`(54) Title: N—TERMINALLY MODIFIED GLP—l DERIVATIVES
`
`(57) Abstract
`
`The present invention relates to N—terminally modified derivatives of human glucagon—like peptide—1 (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—l derivatives have a lipophilic substituent attached to at least one
`amino acid residue and are substituted at the N—terminal end with a substituent comprising an optionally substituted 5— or 6—membered
`
`MYLAN INST. EXHIBIT 1034 PAGE 1
`
`MYLAN INST. EXHIBIT 1034 PAGE 1
`
`MYLAN INST. EXHIBIT 1034 PAGE 1
`
`MYLAN INST. EXHIBIT 1034 PAGE 1
`
`
`
`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.
`SI
`Slovenia
`SK
`Slovakia
`SN
`Senegal
`SZ
`Swaziland
`TD
`Chad
`TG
`Togo
`TJ
`Tajikistan
`TM
`Turkmenistan
`TR
`Turkey
`TT
`Trinidad and Tobago
`UA
`Ukraine
`UG
`Uganda
`US
`United States of America
`UZ
`Uzbekistan
`VN
`Viet Nam
`YU
`Yugoslavia
`ZW
`
`Zimbabwe
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`cote d‘Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`ES
`FI
`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
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People’s
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`R0
`RU
`SD
`SE
`SG
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`MYLAN INST. EXHIBIT 1034 PAGE 2
`
`MYLAN INST. EXHIBIT 1034 PAGE 2
`
`MYLAN INST. EXHIBIT 1034 PAGE 2
`
`MYLAN INST. EXHIBIT 1034 PAGE 2
`
`
`
`wo 99/43707
`
`PCT/DK99/00085
`
`- 1 -
`
`N-TERMINALLY MODIFIED GLP-1 DERIVATIVES
`
`FIELD OF THE INVENTION
`
`The present invention relates to novel derivatives of human glucagon-like peptide-1
`
`(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
`
`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
`
`comprises GLP-1(7-37) and functional derivatives thereof and to its use as an insulinotropic
`
`10
`
`15
`
`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
`
`7
`
`21
`
`22
`
`23
`
`His—Ala—Glu—Gly—Thr—Phe—Thr—Ser—Asp—Val—Ser—Ser—Tyr—Leu—Glu—Gly—Gln-
`
`25
`
`30
`
`35
`
`24
`
`25
`
`26
`
`27
`
`28
`
`29
`
`3O
`
`31
`
`32
`
`33
`
`34
`
`35
`
`36
`
`(I)
`
`Ala—Ala—Lys—Glu—Phe—Ile—Ala—Trp—Leu—Val—Lys—Gly—Arg—X
`
`wherein X is NH2 for GLP-1(7—36)amide and X is GIy-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.
`
`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 6.9. 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 Cs-C1o acyl group in attached to the
`
`lysine residue in position 34.
`
`SUBSTlTUTE SHEET (RULE 26)
`
`MYLAN INST. EXHIBIT 1034 PAGE 3
`
`MYLAN INST. EXHIBIT 1034 PAGE 3
`
`MYLAN INST. EXHIBIT 1034 PAGE 3
`
`MYLAN INST. EXHIBIT 1034 PAGE 3
`
`
`
`WO 99/43707
`
`PCT/DK99/00085
`
`_ 2 _
`
`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-B) 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 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 AIS), 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
`
`15
`
`formula ll
`
`A—HN-GLP-1(8—B)-X
`
`(ll)
`
`wherein
`
`R3
`
`R2 0
`
`o
`
`Ai53 Yx/lk or Y>gk or
`
`R1
`
`R3
`
`R2
`
`YXCHK
`
`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-(Iower alkyl), -OH, lower alkoxy having 1 to 6 carbon atoms,
`
`halogen, SOz-(lower alkyl) or CF3, said phenyl is optionally substituted with at least one group
`
`selected from NHZ, -OH, lower alkyl or lower alkoxy having 1-6 carbon atoms, halogen, 802-
`
`(Iower alkyl), NH-CO-(lower alkyl) or CF3, or R1 and R2 may together form a bond;
`
`25 Y is a five or six membered ring system selected from the group consisting of:
`
`MYLAN INST. EXHIBIT 1034 PAGE 4
`
`MYLAN INST. EXHIBIT 1034 PAGE 4
`
`MYLAN INST. EXHIBIT 1034 PAGE 4
`
`MYLAN INST. EXHIBIT 1034 PAGE 4
`
`
`
`WO 99/43707
`
`PCT/DK99/00085
`
`fizz:§<
`
`N
`
`/N\N/
`{a
`
`r;
`
`N
`
`N’S
`LZ/
`
`z’\\ZR Q
`
`\
`
`NI)!\N/
`\N=/
`
`H /
`
`N /
`CM!
`
`[NET CI U 0/
`
`wherein Z is N, O or S, 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;
`
`B is an integer in the range of 35-45; and
`
`X is —OH, —NH2, or a C1_E5 alkyl amide or C1_6 dialkyl amide group;
`
`or an analogue thereof;
`
`said GLP—‘I 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
`
`(I I)
`
`wherein
`
`R3
`
`R2 0
`
`Ais: Y“ or
`
`R1
`
`o
`
`Y>(U\
`
`R3
`
`R2
`
`or
`
`Y><CH2\
`
`R3 R2
`
`15
`
`wherein R‘, R2 and R3 are independently H, lower alkyl, optionally substituted phenyl, NHZ, NH-
`
`CO-(lower alkyl), -OH, lower alkoxy, halogen, SOz—(lower alkyl) or CF3, wherein said phenyl is
`
`optionally substituted with at least one group selected from NHZ, -OH, lower alkyl or lower alkoxy
`
`MYLAN INST. EXHIBIT 1034 PAGE 5
`
`MYLAN INST. EXHIBIT 1034 PAGE 5
`
`MYLAN INST. EXHIBIT 1034 PAGE 5
`
`MYLAN INST. EXHIBIT 1034 PAGE 5
`
`
`
`wo 99/43707
`
`PCT/DK99/00085
`
`- 4 -
`
`having 1-6 carbon atoms, halogen, SOZ-(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:
`
`H
`
`/
`
`QN
`
`N
`
`N
`
`H
`
`)\k /
`
`NNrJN
`
`N\ /
`
`fall
`
`/8
`
`NLR/
`
`N/
`’0
`N’0
`’N\
`7 l7 7 27
`
`\
`
`I,/
`
`N\
`
`N\
`
`[NI U 0
`
`N/
`
`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, 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
`
`X is —OH, -NH2, or a C1_6 alkyl amide or 01-5 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.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`A simple system is used to describe the GLP-1 derivatives of the present invention. For
`
`example, GlyB-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
`
`acid residue in position 8 (Ala) with Gly. Similarly, Lys3“(N‘-tetradecanoy|)-GLP-1(7-37)
`
`1O
`
`15
`
`20
`
`MYLAN INST. EXHIBIT 1034 PAGE 6
`
`MYLAN INST. EXHIBIT 1034 PAGE 6
`
`MYLAN INST. EXHIBIT 1034 PAGE 6
`
`MYLAN INST. EXHIBIT 1034 PAGE 6
`
`
`
`wo 99/43707
`
`5
`
`PCT/DK99/00085
`
`designates GLP-1(7-37) wherein the s-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 othenNise 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 othewvise 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
`
`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
`
`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-I derivatives of formula II, B is preferably 36, 37 or 38.
`
`In the GLP-I derivatives of formula II, up to fifteen, preferably up to ten amino acid
`
`residues may be exchanged with any a—amino acid residue, in particular with any oc-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 oc-amino acid residue which can be
`
`coded for by the genetic code.
`
`Preferred GLP-1 derivatives or analogues are those in which:
`
`B is 36, and the parent peptide comprises one or more amino acid substitutions selected from
`
`the group consisting of Arg”, Arg34 and Lys”;
`
`B is 37, and the parent peptide comprises one or more amino acid substitutions selected from
`
`the group consisting of Arg”, Arg“, Lys36 and Lys”; or
`
`B is 38, and the parent peptide comprises one or more amino acid substitutions selected from
`
`the group consisting of Arg”, Arg“, Lys36 and Lys”.
`
`In a further preferred embodiment, a parent peptide for a derivative of the invention is
`
`ArgQB-GLP-1(7-37); Arg34-GLP-1(7-37); Lys”—GLP-1(7-37);
`
`Argzs'MLysas-GLPJ (7-37); ArgZS-“LyssaGLP-1(7-38);
`
`ArgZS'MLysag-GLP-I (7-39); ArgZG'MLys‘O-GLP-‘I (7—40);
`
`10
`
`15
`
`20
`
`25
`
`30
`
`MYLAN INST. EXHIBIT 1034 PAGE 7
`
`MYLAN INST. EXHIBIT 1034 PAGE 7
`
`MYLAN INST. EXHIBIT 1034 PAGE 7
`
`MYLAN INST. EXHIBIT 1034 PAGE 7
`
`
`
`wo 99/43707
`
`6
`
`PCT/DK99/00085
`
`ArgZSLysae-GLP-1(7-37); Arg34Lys36-GLP-1 (7-37);
`
`ArgZGLysag-GLP—1(7-39); ArguLys40-GLP—1 (7-40);
`
`Argzs'MLys36'39—GLP—1(7-39); Ar925'34Ly336'4°-GLP—1 (7-40);
`
`GlyBArgze-GLP—1(7—37); GlyaArgu-GLP-1 (7-37);
`
`GlyBLysae—GLP—1 (7—37); GlyaArQZG'MLys35—GLP-1(7—37);
`
`GIyBArgze'uLysae—GLPJ (7-39); GIyBArgza'MLySm-G LP-1 (7-40);
`
`GlyaArgzsLysae-GLP-i (7-37); GlyBArguLysas-GLP-i (7-37);
`
`GIyBArgzeLys39-GLP—1(7-39); GlyaArgs‘Lys4o-GLP-1(7-40);
`
`GlyBArgzs'MLysae-w-GLP-1(7-39); or
`
`GlyBArgze‘MLy335'40-GLP-1 (7—40).
`
`In a further preferred embodiment, a parent peptide for a derivative of the invention is:
`
`ArgZG'MLySSBGLP-1 7—38);
`
`Argze'mLysagGLP-1 7-39);
`
`Argze'MLys4°GLP-1 7-40);
`
`Argze'MLys4‘GLP-1 7-41);
`
`( ( ( ( ( ( ( (
`
`Argze'34Ly342GLP-1 7-42);
`
`Argzs'MLys4sGLP-1 7—43);
`
`Argzs'MLys“GLP-1 7-44);
`
`Argzs'MLys4sGLP-1 7-45);
`
`10
`
`15
`
`20
`
`ArgzsLysaaGLP-1 (7-38);
`
`Arg34Lys38GLP—1 (7-38);
`
`Argze'“Lys36'35GLP-1 (7-38);
`
`Argze'MLySSBGLP-1 (7-38);
`
`ArgzsLys39GLP-1 (7-39);
`
`25
`
`ArguLysngLP-1(7-39); or
`
`ArgstLysse'agGLP-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 Argze—GLP—1(7-37), Arg34-GLP-
`
`1(7-37), Lys36-GLP-1(7-37), Argze'34Lys35-GLP-1(7-37), ArgzeLys36—GLP—1(7—37), Args4Lys36—GLP—
`
`1(7-37), GlyaArgze-GLP-1(7-37), GIyBArg“-GLP-1(7-37), GlyBLysas-GLP—1(7-37), GlyBArgze'MLysss-
`
`GLP-1(7-37), GlyBArgzeLys36-GLP-1(7-37) and GIySArguLysas-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 ArgzeLyse‘S-GLP-1(7-38),
`
`ArgZG'MLysas-GLPJ (7-38), ArgZB'MLy536'38-GLP-1(7-38), GlyaArgzeLysas-GLPJ (7-38) and
`
`GlyBArgzs‘“Lys36'38-GLP-1 (7-38).
`
`30
`
`35
`
`MYLAN INST. EXHIBIT 1034 PAGE 8
`
`MYLAN INST. EXHIBIT 1034 PAGE 8
`
`MYLAN INST. EXHIBIT 1034 PAGE 8
`
`MYLAN INST. EXHIBIT 1034 PAGE 8
`
`
`
`WO 99/43707
`
`PCT/DK99/00085
`
`- 7 _
`
`In a further preferred embodiment, the present invention relates to a GLP—1 derivative
`
`wherein the parent peptide is selected from the group comprising ArgzeLysag-GLP-1(7-39),
`
`ArgZG-“Lysaev39-GLP-1 (7-39), GlyBArgzsLysag-GLP-1(7-39) and GlyBArgze'MLysae'39-GLP-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 ArgS4Lys40—GLP-1(7-4O),
`
`Arg26'3‘Lys35'40-GLP-1(7-40), GlyaArg34Lys40-GLP-1(7-40) and GlyaArgze’MLysw'w-GLP-1(7-40).
`
`In a further preferred embodiment, the present invention relates to a GLP-1 derivative
`
`wherein the parent peptide is:
`
`Argze-GLP-1(7-36); ArgS4-GLP—1(7-36); Argze'uLySSB-GLPJ (7-36); Argze-GLP-1(7—36)amide;
`
`Arg34-GLP-1(7—36)amide; ArgZS'MLysse-GLP-1(7—36)amide; ArgZG-GLP-1(7-37); Arg“-GLP-1(7-37);
`
`ArgZS‘MLySSS-GLP-‘l (7-37); ArgZG-GLP—1 (7-38); Arg34-GLP-1(7-38);
`
`Arg26'34LysasGLP-1(7-38); Arng-GLP-1(7—39); Args“-G LP-1 (7-39);
`
`Argza'MLysg’g-GLP-l (7-39); GlySArgze-GLP-1 (7—36);
`
`Gly"Arg“—GLP—1(7-36); GlyaArgze'MLySSB-GLP—‘l (7-36);
`
`GlyaArgze-GLP-l (7-36)amide; GlyBArQM-GLP-1(7-36)amide;
`
`GlyBArgze'MLysas—GLP-l (7-36)amide; GlyBArgzs-GLP-1(7—37);
`
`GIyBArQM-GLP-l (7-37); GlyBArgze'MLysse-G LP-1 (7-37);
`
`GlyBArgze-GLP—1(7-38); GlyBArQM-GLP-l (7-38);
`
`GIyBArgze'“Lys33GLP-1 (7—38); GlyBArgze-GLP-‘l (7-39);
`
`GlyBArg‘M-GLP-l (7-39); GlyaArgze'MLysag-G LP-1 (7-39);
`
`ValBArgze-GLP-1(7—36); ValBArg34-GLP—1(7-36);
`
`ValBArgzs'MLysae—GLP-l (7-36); VaIBArgze-GLP-1 (7-36)amide;
`
`VaIBArg34-GLP-1(7-36)amide; ValaArgzs'MLys36-GLP-1 (7-36)amide;
`
`VaIBAr926-GLP-1 (7-37); VaIBArg34-GLP-1 (7-37);
`
`ValBArgze'MLys36-GLP-1(7—37); VaIBArgzs-GLP-l (7-38);
`
`ValBArg34-GLP-1(7-38); ValaArgze'“Ly335GLP-1(7-38);
`
`ValBArg26-GLP—1 (7-39); VaiBArgM-G LP-1 (7-39);
`
`ValBArgze'MLys39-GLP-1 (7-39); SerBArgzs-GLP-l (7—36);
`
`SerBArgM-GLP-l (7-36); SerBArgZB-“Lysas-GLP—1(7-36);
`
`SeraArgze-GLP—l (7-36)amide; SerBArQM-GLP-l (7-36)amide;
`
`SeraArgze'MLysse-GLP-l (7-36)amide; SeraArgze-GLP-1(7-37);
`
`SeraArgu—GLP-1(7-37); SerBArgze'MLysss—GLP-l (7-37);
`
`SerSArgza—GLP-1(7-38); SeraArgu-GLP-1 (7-38);
`
`SeraArgze'MLyssaGLP-l(7—38); SeraArgze-GLP-1(7-39);
`
`SerBArgm-GLP-l (7-39); SersArgze'MLysag-GLP-1(7-39);
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`MYLAN INST . EXHIBIT 1034 PAGE 9
`
`MYLAN INST. EXHIBIT 1034 PAGE 9
`
`MYLAN INST. EXHIBIT 1034 PAGE 9
`
`MYLAN INST. EXHIBIT 1034 PAGE 9
`
`
`
`WO 99/43707
`
`PCT/DK99/00085
`
`_ 3 _
`
`ThrBArgze-GLP-1 (7-36); ThrsArg34-GLP-1(7-36);
`
`ThraArgzs'“Lys36—GLP—1 (7—36); ThrBArgzs—GLP-1(7-36)amide;
`
`ThrBArQM-GLP-1 (7-36)amide; ThraArgzs'MLysas-GLPJ (7-36)amide;
`
`ThrBArgzs-GLP-1 (7-37); ThraArQM-GLP-1(7—37);
`
`ThrBArQZWLysaS-GLP-1(7-37); ThraArgZG-GLP-1 (7-38);
`
`ThrBArgu-GLP-‘I (7-38); ThrsArgze'MLyS38GLP-1 (7—38);
`
`ThrfiArgze-GLP-1 (7-39); ThrBArg34-GLP-1 (7-39);
`
`ThrBArgZWLysag-GLP-1(7-39); VaIBGIuBSArgMLysSG-GLP-1(7-36);
`
`ValaGluasArgze’MLysae-GLP-1 (7-36)amide; VaI8Glu35Argzs'34Ly537GLP-1(7-37);
`
`VaIBGlu37Argzs-34Lys38GLP—1(7—38); VaIBG|u33Argze'34Ly539—GLP—1(7—39); VaIBGlu35Ar925'34Lys38—GLP—
`
`1(7-36);
`
`VaIBG|u35Argzs'34Lysae-GLP-1(7—36)amide; ValaG|u36Argze-34Lyss7GLP-1(7-37);
`
`VaIBGlu37Argze'34LysasGLP-1 (7-38);
`
`VaIBGluaaArgze'MLysag-GLP—1(7—39); ValBAsp35Argzs'34Lys36-GLP-1(7-36); VaIBAsp35Argz‘5'34Lysae-
`
`GLP-1(7-36)amide;
`
`ValaAsp36Argze'34Lys37GLP-1(7-37); ValsAsp37Argz‘3'34Lys38GLP-1(7-38); VaIBAspSBArgze'MLysag-
`
`GLP-1(7-39); VaIBAsp35Argzs'34Lys36-GLP-1(7—36); ValaAsp35Argze'34Lysss-GLP-1(7-36)amide;
`
`VaISAspSBArgze'MLysyGLP-1(7—37); ValeAsp37Argzs'34Lys38GLP-1(7-38); VaISAsp38Argze'34Ly339-
`
`GLP-1(7-39); Ser8G|u35Argze'34Lysae-G LP-1 (7-36); SeFGlu35Argzs'MLy336-GLP-1 (7-36)amide;
`
`SersGluseArgze'MLysmGLP-1(7-37);
`
`Ser8G|u37Argze-34LysssGLP-1(7-38); SerBGIuasArgze'MLysag-GLP-1(7-39); SerBGluasArgzs'a‘Lys36—
`
`GLP-1(7-36); SerBGlu35Argzs'34Lys36-GLP-1 (7-36)amide; SerBGIu36Argzs'34Lys37GLP-1(7-37);
`
`SeraGlu37Argzs'34Lys38GLP-1(7-38); SereGlU38Ar926'34Lys39-GLP-1(7-39); SerBAsp35Argze'34Lys35-
`
`GLP-1(7-36); SersAsp35Argze'34Lys35—GLP—1(7-36)amide; SerBAspSGArgze'MLystLP—1 (7-37);
`
`SeraAsp37Arg26'34Lys33GLP—1(7-38); SerBAspmArgze'uLysag-GLP-1(7-39); SeraAsp35Argzs'34Ly336—
`
`GLP-1(7-36); SerBAspasArgze'MLyss6-GLP-1(7—36)amide; SergAsp35Argze’34Lys37GLP—1 (7—37);
`
`SerBAsp37Argzs'34LysaeGLP-1(7-38); SeraAspaaArgze'uLysw-GLP-1(7-39); Thr8G|u35Argze'34Ly535-
`
`GLP-1(7-36); ThraGlufiArgze'MLysae-GLP-1(7-36)amide; ThrBGluaeArgze'MLysyGLP-1 (7-37);
`
`ThraGlU37Ar926'34Ly538GLP-1(7-38); ThraGlu38Argz’5'34Ly539-GLP-1(7-39); ThrBGlussArgzs'MLysas-
`
`GLP-1(7-36); ThraGluasArgzs'MLysae-GLP-1(7-36)amide; ThrBGlusaArgze-“Lysa7GLP-1(7-37);
`
`ThrflGlu37Argzs'34LysaaGLP-1 (7-38); ThrBGlussArgze'MLysw-GLP-1(7-39);
`
`ThrfiAsp35Argza'34Lysae-GLP-1(7-36); Thr8ASp35Argze'34Ly536-GLP-1 (7—36)amide;
`
`ThraASpaeArgze'MLyss7GLP—1 (7-37);
`
`ThrBAsp37Argzs'34Lys38GLP-1(7-38); ThrBAspaaArgzs-“Lysag-GLP—1(7-39); ThrBAspasArg26~34Lys3i
`
`GLP—1(7-36); ThrsAsp35Argz‘3'34Lys35—GLP—1 (7-36)amide; ThraASpaeArgzs‘MLysflGLP-1(7-37);
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`35
`
`MYLAN INST. EXHIBIT 1034 PAGE 10
`
`MYLAN INST. EXHIBIT 1034 PAGE 10
`
`MYLAN INST. EXHIBIT 1034 PAGE 10
`
`MYLAN INST. EXHIBIT 1034 PAGE 10
`
`
`
`WO 99/43707
`
`9
`
`PCT/DK99/00085
`
`ThrSAsp37Argzs'34Lys3BGLP-‘I (7—38); ThrBAsp38Argze'34Lyss9-GLP-1 (7-39);
`
`GIyBGlu35Ar926'34Lys36-GLP-1 (7-36); GIyBGlU35Argzs'34Lys36-GLP-1(7-36)amide;
`
`GIyBGluaeArgze'uLystLP-1(7—37);
`
`Gly3G|u37Argzs'34Lys38GLP-1(7-38); GIyBGlu38Argze'34Ly539-GLP-1(7-39); GIyBGlu35Argze'34Lysse-
`
`GLP-1 (7—36); GIyaG|u35Argzs'34Lys36-GLP—1(7-36)amide; GlyBG|u36Argza‘34Lysa7GLP-1 (7—37);
`
`GIy8G|u37Argza'34LysaaGLP-1(7-38); GIyBGIU38Argz‘3'34Lys39—GLP-1(7-39); GIyBAsp35Argz‘5'34Lysae-
`
`GLP-1 (7-36); GlyeAspfiArgze'MLysa‘S-GLP-1 (7-36)amide; GIyBAspssArgzs'uLysyGLP-1(7-37);
`
`GlyBAsp37Argze'34LysasGLP—1(7-38); GIySAspaeArgze'MLyssg-GLP-1(7-39); GIyBAsp35Argzs'34Lysse-
`
`GLP—1(7-36); GlyBAspasArgze'MLysw-GLP-1(7-36)amide; GlyeAspasArgze'MLysyG LP-1 (7-37);
`
`GlyaAsp37Argze'34Ly538GLP-1 (7-38); GlysAsp38Argzs'34Ly339-GLP-1(7—39); Argze'MLys1B—GLP-1 (7-36);
`
`Argze'MLys15-GLP-1(7-36)amide; ArgZG'MLys‘BGLP-1U-37); Argze'MLys‘aGLP-T (7-38);
`
`GIyBAsp19Argze'34Lys‘e-GLP—‘I (7-36); GlyBAsp‘7Arg26'34Lys1B-GLP-1(7-36); GlyaAsp19Argzs'34Lys‘8-
`
`GLP—1(7—36)amide; GIyBAsp‘7Arg26'34Lys‘8-GLP-1(7-36)amide; GlysAsp‘QArgze'MLys‘BGLP-1(7—37);
`
`GlyBAsp‘QArgze'MLys1SGLP-1(7-38); GlyaAsp‘7Argzs'34Lys‘BGLP-1 (7-38);
`
`ArgZWLysza-GLP-1(7-36); ArgzeMLySZ3-GLP-1 (7-36)amide; ArgZG'MLysszLP—1(7-37);
`
`Argze'a‘LysszLP-1(7-38); GIyBAsp24Argzs'34Ly523-GLP-1 (7-36); GlysAsp22Argz‘5'34LySZ3-G LP-1 (7—36);
`
`GlyaAsp24Argze’34Ly323-GLP-1(7-36)amide; GIy8Asp22Ar926'34Ly323-GLP-1 (7-36)amide;
`
`GlyaAsp24Argze'34Ly323GLP-1(7-37); GlyeAsp24Argze'34LysszLP-1(7-38); GlyBAspZZArgZS'MLyszaGLP-
`
`1(7-38);
`
`Argze'MLySZ7-GLP-1 (7—36); ArgZB'MLySZ7-GLP-1(7-36)amide; Argzs'34Ly527GLP-1 (7-37);
`
`Argze'MLy527GLP-1 (7—38); GIyBAspzaAr926'34Ly327-GLP-1 (7-36); GIySAspzeArgzs'MLysfl-G LP-1 (7-36);
`
`GIyBAspZBArgze'MLysfl—GLP—1(7-36)amide; GlyaAspzeArgze'MLysfl-GLP-1 (7-36)amide;
`
`GIyBAspzaArgZWLysWGLP—1(7-37); GIyBAspZBArgze'MLysflGLP-1(7-38); GIyBAspZGArgMLySNGLP-
`
`1(7-38);
`
`Argze'MLys‘B-GLP-1 (7-36); Arng-“Lys18—GLP-1(7-36)amide; Argzs'MLys1aGLP-1 (7—37);
`
`ArgZG'MLys‘BGLP-1U-38); VaIBAsp‘9Ar926'34Lys18-GLP-1(7-36); VaIaAsp‘7Argzs'34Lys13-GLP-1 (7—36);
`
`VaIBAsp‘QArgzs'MLysm-GLP-1(7-36)amide; VaIBAsp‘7Argze‘34Lys18-GLP-1(7-36)amide;
`
`ValaAsp‘QArgze'MLysmGLP-1(7-37); ValaAsp‘9Argze'34Lys1aGLP—1(7-38); ValaAsp‘7Argze'34Lys‘8GLP-
`1(7-38);
`’
`
`ArgZS'MLySZ3-GLP-1 (7-36); ArgZG'MLysn-GLPJ (7-36)amide; Argze'MLy323GLP-1 (7-37);
`
`Argze'MLyszaGLP-1U-38); ValaAsp24Argzs'34Ly523-GLP-1(7-36); ValaAspzzArgze'MLySZ3-GLP-1 (7-36);
`
`ValaAsp24Arggs'34Lyszs-GLP-1 (7-36)amide; VaIBAspZZArgze'MLysza—GLP-1(7-36)amide;
`
`ValaAsp24Argze'34LySZ3GLP-1(7-37); VaIBAsp24Argze'34Ly523GLP-1(7-38); ValaAspzzArgze'MLyszaGLP-
`
`1(7-38);
`
`1O
`
`15
`
`20
`
`25
`
`30
`
`MYLAN INST. EXHIBIT 1034 PAGE 11
`
`MYLAN INST. EXHIBIT 1034 PAGE 11
`
`MYLAN INST. EXHIBIT 1034 PAGE 11
`
`MYLAN INST. EXHIBIT 1034 PAGE 11
`
`
`
`wo 99/43707
`
`PCT/DK99/00085
`
`_ 1o _
`
`Argzs'MLySZ7-GLP-1(7—36); Argze'uLySZ7—GLP-1(7-36)amide; ArgZS'MLySZ7GLP-1U-37);
`
`ArgZG’MLySZ7GLP-1(7-38); ValaAspZBArgzs'MLysfl-GLP-1 (7-36); VaI8Asp26Argze'34LySZ7-GLP-1(7-36);
`
`VaIBAspZBArgze'MLysfl-GLP-1(7-36)amide; VaIBAspZSArgzs'“Lys”-GLP—1 (7-36)amide;
`
`ValaAspZBArgzs'MLysflGLP-1(7-37); ValBAspzsArgze'MLysflGLP-1(7—38); VaIBAspZSArgze'MLysflGLP-
`
`1(7-38);
`
`Argze'34Lys18-GLP-1 (7—36); Argze'MLySm-GLPJ (7-36)amide; Argze'MLyS1BGLP-1(7-37);
`
`Argze'uLys‘BGLP-1 (7-38); SerBAsp19Argzs'34Lys'8-GLP-1(7-36); SereAsp17Argze'34Lys18-GLP-1(7-
`
`36); SerBAsp‘gArgze'MLys‘a-GLP—1(7—36)amide; SerBAsp17Argze‘34Lys‘3-GLP-1(7-36)amide;
`
`SeraAsp‘gArgze'MLystLP-1 (7-37); SeraAsp‘gArgze'uLys‘eGLP-1(7-38);
`
`SerBAsp‘7Arg26'34Lys1BGLP-1 (7-38);
`
`ArgZS'MLysfi-GLPJ (7-36); Argze'34Ly823-GLP—1 (7-36)amide; Argzs'MLy323GLP-1(7-37);
`
`ArgZG'MLySZSGLP-1U-38); SeraAsp24Argzs'34LySZ3-GLP-1 (7-36); SersAspzzArgze'MLysza-GLP-1(7-
`
`36); SerBAsp24Ar926'34Lyszs-GLP-1(7-36)amide; SeraAspzzArgze-“Lysza-GLP—1(7-36)amide;
`
`SerBAsp24Argze'34Ly323G LP-1 (7—37); SerBAsp24Argzs'34Ly323GLP-1 (7-38);
`
`SeraAspzzArgze'MLyszaGLP-1 (7-38);
`
`Argze'MLy327-GLP-1(7-36); Argze'34Ly527-GLP-1 (7-36)amide; Argze'MLy527GLP-1(7-37);
`
`ArgZG'MLySZ7GLP-1 (7-38); SerBAszeArgzs'MLysfi-GLP-1 (7-36); SerBAsp26Argzs'34LySZ7—GLP-1(7-
`
`36); SerBAspzaArgze'MLysfl-GLP-1(7-36)amide; SerBAspzeArgze’uLysfl-GLP-1(7-36)amide;
`
`10
`
`15
`
`SersAspZBArgze'MLysflGLP-1 (7-37); SeraAspzsArgz6'34LySZ7GLP-1(7-38);
`
`20
`
`SeraAspzeArgze'“Ly327GLP-1 (7-38);
`
`ArgZS'MLysw-G LP-1 (7-36); ArgZS'MLys18—GLP-1 (7-36)amide; Argzs'MLys‘aGLP—1(7-37);
`
`Argze'“Lys‘°GLP-1 (7-38); ThrBAsp‘9Argze'34Lys‘8-GLP-1(7-36); Thr8ASp17Argze'34Lys‘B-GLP-1 (7—36);
`
`ThrBAsp‘gArgzs'MLys‘B-GLP-1(7-36)amide; ThrSAsp17Argze'34Lys‘8-GLP-1(7-36)amide;
`
`ThrBAsp‘gArgze'MLystLP-1(7-37); ThrBAsp‘9Argze'34Lys‘8GLP-1(7-38); ThrBAsp‘7Argze'34Lys18GLP-
`
`25
`
`1(7-38);
`
`Argzs'MLysza-GLP-1(7-36); Argze'MLySZB-GLPJ (7-36)amide; Argzs'MLy323GLP-1 (7-37);
`
`Argze'MLysz‘GLP-‘I (7-38); ThrBAsp24Argze'34Lysz3-GLP-1 (7-36); ThPAspZZArgze'MLysza-GLP-1 (7-36);
`
`ThrBAsp24Argze'34Ly323-GLP-1(7—36)amide; ThrBAspZZArgzs’MLysm-GLP-1 (7-36)amide;
`
`ThraAsp24Argzs'34LysszLP—1(7-37); ThrBAsp24Argzs'34LyszaGLP-1(7-38); ThrsAspzzArgze-“LySZSGLP-
`
`3O
`
`1(7-38);
`
`Argze'MLySZ7-GLP-1(7-36); Argze'MLySZ7—GLP-1(7-36)amide; Argze'MLySZ7GLP-1 (7-37);
`
`Argze'S‘Ly327GLP-1 (7-38); ThrBAspzaArgze'MLysn-GLP-1(7-36); ThrBAspzeArgze'uLysy—GLPJ (7-36);
`
`ThrBAspZBArgzs'MLysfl-GLP-1(7-36)amide; ThraAspzeArgzs'MLysfl-G LP-1 (7-36)amide;
`
`ThrBAspZBArgz‘s'MLysflGLP-1(7-37); ThrBAsp25Argzs-34Ly527GLP-1(7-38); or
`
`35
`
`Th rSAspzeArgzs'MLys27GLP-1 (7-38).
`
`MYLAN INST. EXHIBIT 1034 PAGE 12
`
`MYLAN INST. EXHIBIT 1034 PAGE 12
`
`MYLAN INST. EXHIBIT 1034 PAGE 12
`
`MYLAN INST. EXHIBIT 1034 PAGE 12
`
`
`
`W0 99/43707
`
`PCT/DK99/00085
`
`_ 11 _
`
`In a further preferred embodiment, the present invention relates to a GLP-1 derivative
`
`wherein the parent peptide is:
`
`ArgZBLysse-G LP-1 (7-36); ArgmLysss-GLP-1 (7-36); ArgZGLys36-GLP-1(7-37); ArguLysas—GLPJ (7-
`
`37); ArgzeLysa7-GLP-1(7-37); ArguLysa7-GLP-1(7-37); ArgzeLys39-GLP-1(7-39); Arg34Lys39-GLP-
`
`1 (7—39); Argze,34Lysae.39_G LP-1 (7-39);
`
`ArgzsLys‘a-GLP-1 (7-36); ArguLys‘B-GLP-‘I (7-36); ArgzeLys18GLP-1 (7-37); Arg“Lys18GLP-1(7-37);
`
`ArgzeLys1aGLP-1(7-38); ArgmLys‘sGLP-‘i (7-38); ArgZGLys15GLP-1(7-39); ArgmLys‘BGLP-1(7-39);
`
`ArgzeLysza—G LP-1 (7-36); ArgMLys23-GLP-1 (7-33); ArgZGLySZSGLP-1(7-37); ArguLyszaGLP-1 (7-37);
`
`ArgZBLyszaGLP-1(7-38); Arg34LySZ3GLP-‘l (7-38); ArgZBLySZ3GLP-1(7-39); Arga4Ly523GLP-1 (7-39);
`
`ArgzeLy527-GLP-1 (7-36); Arg“Lys”-GLP-1(7-36); Ar926Lys27GLP-1 (7-37); Arg34Ly527GLP-1 (7-37);
`
`ArgzeLy327GLP-1(7-38); Arg“Lys27GLP-1 (7-38); ArgzeLy527GLP-1 (7-39); Arg34LySZ7GLP-1(7-39);
`
`Argze'MLys‘a'ae-GLP-1(7-36); ArgZS'MLys18GLP-1 (7-37); Argze'MLys‘3'37GLP-1(7-37);
`
`Argze'MLys‘a'asGLP—1 (7-38); Argzs'MLys‘8-39GLP-1(7-39); Argzs'MLysza'ss-GLP—1 (7-36);
`
`Argze'MLySZ3GLP-1 (7-37); Argza'MLysa'37GLP-1 (7-37); ArgZG'MLy523'38GLP—1(7-38);
`
`ArgZG'MLysmgG LP-1 (7-39); ArgZG'MLysfl'SS-GLPJ (7-36); Ar926~34Lys27GLP-1 (7-37);
`
`Argzs'MLy527'37GLP-1 (7-37); ArgZB'MLys27'3eGLP-1(7-38); Argzs'MLySZ7'39GLP-1 (7-39);
`
`GIyBGLP-1(7-36); GlyBGLP-1(7-37); GIyBGLP-1(7-38); GIyBGLP-1(7-39);
`
`GIyBArgzsLysss-GLP-1(7-36); GlyBArg34Ly335-GLP-1(7—36); GIyBArgZSLys3G-GLP-1 (7-37);
`
`GlysArguLysss—GLP-1(7-37); GlyBArgzsLysw-G LP-1 (7-37); GiyaArg34Ly537-GLP-1 (7-37);
`
`GiysArgzsLys39-GLP—1 (7-39); GlyBArguLyssg-GLP-1 (7-39); GIyBArgze'MLys36’39-GLP-1(7-39);
`
`GlyaArgzsLys‘B—GLP-1(7—36); GlyaArg34Ly518—GLP-1(7-36); GlyBArgzsLys‘BGLP-1(7-37);
`
`GlyaArguLys‘BGLP-1 (7—37); GIyBArgzsLys‘aG LP-1 (7-38); GlyaArgmLys‘eGLP-1(7-38);
`
`GlyBArgzeLys‘aGLP-1(7-39); GIy“Arg“Lys15GLP-1 (7-39);
`
`GIyBArgzsLysza-GLP-1(7-36); GIyBArg34Ly323-GLP-1 (7—36); GIyBArgZGLys23GLP-1(7-37);
`
`GlyaArgmLyssz LP-1 (7-37); GlyaArgzeLyszaGLP-1 (7-38); GIyBArQMLyszaGLP-1 (7-38);
`
`GIyBArgzsLySZ3GLP-1 (7-39); GinArgmLyssz LP-1 (7-39);
`
`GlyaArgzeLysfl-GLP-‘I (7—36); GlyBArguLySZ7—GLP-1 (7-36); GlyBArgzsLySZ7GLP-1(7-37);
`
`GlyaArg34Ly327GLP—1(7-37); GlyaArgzaLy327GLP-1 (7-38); GiyaArg34Ly527GLP-1(7-38);
`
`GlyaArgz‘SLysflG LP-1 (7-39); GlyBArQMLySZ7GLP-1 (7-39);
`
`GlysArgzs'MLys‘a'ae-GLP-1(7-36); GlyaArgza'S‘Lys‘SG LP-1 (7-37); GIyBArgzs'MLys18'37GLP-1 (7-37);
`
`GiyaArgze'“Lys18'33GLP-1(7-38); GlyaArgzs'MLys‘a'ngLP-1(7-39); GlysArgzs'MLysza'as-GLP-1 (7-36);
`
`GlysArgze'MLysBGLP-1(7-37); GlysArgze'MLy523'37GLP-1(7-37); GIyBArgzs'“Lysza'seGLP-1(7-38);
`
`GIyBArgZB'MLysza'ngLP-1(7-39); GlyaArgzs'MLySZ7'36-GLP-1 (7-36); GlyeArgzs'MLysmGLP-i (7-37);
`
`GiyaArgze-“Ly527'37GLP-1(7-37); GIyBArgZWLysmBGLP-1(7-38); GlyBArgze'MLy327'39GLP-1(7-39);
`
`ValaGLP-1(7-36); ValaGLP-1(7-37); ValBGLP-1(7-38); ValaGLP-1(7-39)
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`35
`
`MYLAN INST. EXHIBIT 1034 PAGE 13
`
`MYLAN INST. EXHIBIT 1034 PAGE 13
`
`MYLAN INST. EXHIBIT 1034 PAGE 13
`
`MYLAN INST. EXHIBIT 1034 PAGE 13
`
`
`
`WO 99/43707
`
`PCT/DK99/00085
`
`_ 12 _
`
`ValBArgzsLysse-GLP-l (7-36); VaIBArguLysa’e-GLP-l (7-36); VaIBArgzeLysae—G LP-1 (7—37);
`
`ValBArguLysss-G LP-1 (7-37); VaIBArgzeLys37-GLP-1(7—37); ValBArg34Lys37-GLP-1 (7-37);
`
`ValaArgzsLys39-GLP-1 (7-39); VaISArgMLys39-GLP-1 (7-39); VaIBArgze-“Lysaevw-GLP-1 (7-39);
`
`ValBArgzsLys18-GLP-1 (7-36); VaIBArg‘MLys‘B-GLPJ (7-36); ValBArgzeLys‘sGLP—l (7—37);
`
`ValBArg34Lys‘8GLP-1(7-37); ValBArgzsLystLP-l (7-38); VaIBArg3‘Lys‘BGLP-1(7-38);
`
`ValaArgzsLys‘aGLP-l (7-39); ValaArguLys‘aGLP—l (7-39);
`
`ValBArgzsLySZ3-GLP—1 (7-36); VaIBArQMLysx-GLP-l (7-36); VaIBArgzeLys23GLP-1 (7-37);
`
`VaIBArg34Ly523GLP-1(7-37); ValsArgzeLyszaGLP-1 (7-38); VaIBArguLysz‘GLP-‘l (7-38);
`
`VaIBArgzsLy323GLP-1 (7-39); ValBArg34Ly323GLP-1 (7-39);
`
`ValBArgzeLySZ7—GLP-1 (7-36); VaIBArg34Ly327-GLP—1 (7-36); ValBArgzsLysflGLP—‘l (7-37);
`
`ValaArg“Lys”GLP-1(7—37); ValaArgzeLy527GLP-1 (7-38); ValaArg34Ly527GLP-1(7-38);
`
`Val8ArgzeLy327GLP-1(7-39); ValaArg34Ly327GLP-1 (7-39);
`
`ValaArgzs'MLys‘B's’G—GLP-1 (7—36); VaIBArgZWLys1BGLP-1(7-37); VaIBArgzs'MLys18'37GLP-1 (7-37);
`
`ValBArgzs'MLys‘e'saG LP-1 (7-38); VaIBArgZS'MLys‘B'3QGLP-1(7-39); VaIBArgzs'MLysza'a’S-GLP-1 (7—36);
`
`ValBArgze'MLyszaGLP-l (7-37); ValsArgze'MLysza-“GLP—l (7-37); VaIBArgzs-“Ly523'38GLP-1 (7-38);
`
`VaIBArgMLysmG LP-1 (7-39); VaIBArg25'34Ly527'36-GLP—1 (7-36); ValsArgZG-“Lys27GLP-1 (7-37);
`
`ValBArgze'MLysflmG LP-1 (7-37); VaIBArgze'MLysmaGLP-l (7—38); or ValBArgze'MLy527'3gGLP-1(7-39).
`
`In a most preferred embodiment, the present invention relates to derivatives of GLP-1
`
`analogues of formula III:
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`Xaa—Xaa—Xaa—Gly—Xaa—Phe—Thr—Xaa—Asp—Xaa—Xaa—
`
`18
`
`19
`
`2O
`
`21
`
`22
`
`23
`
`24
`
`25
`
`26
`
`27
`
`28
`
`Xaa—Xaa—Xaa—Xaa—Xaa—Xaa—Xaa—Xaa—Xaa—Xaa—Phe—
`
`29
`
`3O
`
`31
`
`32
`
`33
`
`34
`
`35
`
`36
`
`37
`
`38
`
`I 1e—Xaa—Xaa—Xaa—Xaa—Xaa—Xaa-Xaa—Xaa-—Xaa
`
`39
`
`4O
`
`41
`
`42
`
`43
`
`44
`
`45
`
`Xaa—Xaa—Xaa—Xaa~Xaa-Xaa—Xaa
`
`(III)
`
`wherein
`
`Xaa at position 7 is any of the groups A (as defined herein),
`
`Xaa at position 8 is Ala, Gly, Ser, Thr, Leu, lle, Val, Glu, Asp, or Lys,
`
`Xaa at position 9 is Glu, Asp, or Lys,
`
`1O
`
`15
`
`20
`
`25
`
`30
`
`35
`
`MYLAN INST. EXHIBIT 1034 PAGE 14
`
`MYLAN INST. EXHIBIT 1034 PAGE 14
`
`MYLAN INST. EXHIBIT 1034 PAGE 14
`
`MYLAN INST. EXHIBIT 1034 PAGE 14
`
`
`
`wo 99/43707
`
`PCT/DK99/00085
`
`- 13 -
`
`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, lle, Val, Glu, Asp, or Lys,
`
`Xaa at position 16 is Val, Ala, Gly, Ser, Thr, Leu, lle, Tyr, Glu, Asp, or Lys,
`
`Xaa at position 17 is Ser, Ala, Gly, Thr, Leu, lle, Val, Glu, Asp, or Lys,
`
`Xaa at position 18 is Ser, Ala, Gly, Thr, Leu, lle, 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, lle, 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, lie, Val, Arg, Glu, Asp, or Lys,
`
`Xaa at position 25 is Ala, Gly, Ser, Thr, Leu, lle, Val, Glu, Asp, or Lys,
`
`Xaa at position 26 is Lys, Arg, Gln, Glu, Asp, or His,
`
`Xaa at p