C - Chemistry – Metallurgy – 07 – K
Patent
C - Chemistry, Metallurgy
07
K
C07K 7/08 (2006.01) C07K 7/02 (2006.01) C07K 7/06 (2006.01) C07K 14/63 (2006.01) A61K 38/00 (2006.01)
Patent
CA 2127330
This invention pertains to polypeptides having gastrointestinal motor stimulating activity represented by the formula: (see fig. I) wherein A is the L-stereoisomer of a lipophilic aliphatic or alicyclic amino acid; B is L-proline or L-alanine; D is the L-stereoisomer of a lipophilic aliphatic or alicyclic amino acid; E is the L-stereoisomer of an aromatic, lipophilic aliphatic, or alicyclic amino acid; F is the L-stereoisomer of an aromatic or heteroaromatic amino acid; G is glycine or D-alanine; H is L-glutamic acid or L-glutamine; I isL-glutamine, L-glutamic acid, or L-alanine; J is a direct bond or is selected from the group consisting of Z, Z-Leu, Z-Leu-Gln, Z-Leu-Gln-Glu, Z-Leu-Gln-Glu-Lys, Z-Leu-Gln-Glu-Lys-Glu, Z-Leu-Gln-Glu-Lys-Glu-Arg, Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn, Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn-Lys, and Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn-Lys-Gly, wherein Z is selected from the group consisting of arginine, D-arginine, D-homoarginine, D-lysine, D-ornithine, D-2,4-diaminobutyric acid, D-glutamine, D-asparagine, and D-alanine; R1 is lower-alkyl or allyl; R2 is selected from the group consisting of hydrogen, lower-alkyl, propargyl, and allyl; R3 is selected from the group consisting of hydrogen, lower-alkyl, and allyl; R4 is selected from the group consisting of lower-alkyl, cycloalkyl, substituted and unsubstituted aryl, and heteroaryl, wherein the aryl substituents are selected from the group consisting of halogen, hydroxy, and lower-alkoxy; R5 is selected from the group consisting of -CH2CONH2, aminoalkyl groups, and guanidinoalkyl groups; R6 is -COOH or -CONH2; and m is 0 or 1, with the proviso that (a) when m is 0, R2 and R3 are hydrogen, and J is a direct bond, the -NH-*CH(CH2R5)R6 group has the D-configuration; (b) R5 is -CH2CONH2 only when J is Z-Leu or Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn-Lys-Gly; (c) when m=0, R2 and R3 are hydrogen, and J is Z, Z-Leu, Z-Leu-Gln, Z-Leu-Gln-Glu, Z-Leu-Gln-Glu-Lys, Z-Leu-Gln-Glu-Lys-Glu, Z-Leu-Gln-Glu-Lys-Glu-Arg, Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn, Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn-Lys, and Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn-Lys-Gly, Z has the D configuration; and (d) the polypeptide is other than motilin.
L'invention porte sur des polypeptides stimulateurs du moteur gastro-intestinal, représentés par une formule (voir fig. I), où A le L-stéréoisomère d'un amino-acide alicyclique ou aliphatique, lipophile; B est la L-proline ou la L-alanine; D est le L-stéréoisomère d'un amino-acide alicyclique ou aliphatique, lipophile; E est le L-stéréoisomère d'un amino-acide aromatique, alicyclique ou aliphatique, lipophile; F est le L-stéréoisomère d'un amino-acide aromatique ou hétéroaromatique; G est la glycine ou la D-alanine; H est l'acide L-glutamique ou la L-glutamine; I est la L-glutamine, l'acide L-glutamique ou la L-alanine; J est une liaison directe ou est choisi parmi un groupe Z, Z-Leu, Z-Leu-Gln,Z-Leu-Gln-Glu, Z-Leu-Gln-Glu-Lys ou Z-Leu-Gln-Glu-Lys-Glu, Z-Leu-Gln-Glu-Lys-Glu-Arg, Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn, Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn-Lys, et Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn-Lys-Gly, où Z est choisi parmi un groupe arginine, D-arginine, D-homoarginine, D-lysine, D-ornithine, acide D-2,4-diaminobutyrique, D-glutamine, D-asparagine et D-alanine; R1 est un allyle ou un alkyle inf.; R2 est un hydrogène ou un groupe alkyle inf., propargyle ou allyle; R3 est choisi parmi un hydrogène, un allyle ou un alkyle inf.; R4 est choisi parmi un alkyle inf., un cycloalkyle, un aryle avec ou sans substitution et un hétéroaryle, les substituants sur l'aryle étant choisis parmi un halogène, un hydroxy et un alcoxy inf.; R5 est choisi parmi un groupe -CH2CONH2, aminoalkyle et guanidinoalkyle; R6 est -COOH ou -CONH2; m est 0 ou 1, à la condition que : a) lorsque m est 0, R2 et R3 chacun de l'hydrogène et J une liaison directe, le groupe -NH-*CH(CH2R5)R6 ait la configuration D; b) R5 soit -CH2CONH2 uniquement si J est Z-Leu ou Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn-Lys-Gly; c) lorsque m=0, R2 et R3 chacun de l'hydrogène et J un groupe Z, Z-Leu, Z-Leu-Gln, Z-Leu-Gln-Glu, Z-Leu-Gln-Glu-Lys, Z-Leu-Gln-Glu-Lys-Glu,Z-Leu-Gln-Glu-Lys-Glu-Arg, Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn, Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn-Lys et Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn-Lys-Gly, Z ait la configuration D; d) le polypeptide soit autre que la motiline.
Dharanipragada Ramalinga
Florance James R.
Galdes Alphonse
Macielag Mark J.
Marvin Mary S.
Baxter International Inc.
Gowling Lafleur Henderson Llp
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