Ohmeda Pharmaceutical Products Division Inc.

Ramalinga Dharanipragada

Mark J Macielag

Mary S Marvin

James R Florance

Alphonse Galdes

Jung Kim-Dettelback

This invention pertains to cyclic polypeptides having gastrointestinal motor stimulating activity which may be represented by formula (1): ##STR1## including optically active isomeric forms and the pharmaceutically acceptable acid addition salts thereof, wherein groups A and D are linked to from a cyclic structure; and R.sub.1 is lower alkyl; R.sub.2 is hydrogen or lower alkyl; R.sub.3 is hydrogen or lower alkyl; R.sub.4 is phenyl or substituted phenyl, wherein the phenyl group may be substituted with one or more substituents selected from the group consisting of halogen, hydroxy, and lower alkoxy; R.sub.5 is --OH or --NH.sub.2 ; A is selected from the group consisting of L-glutamic acid, L-aspartic acid, L-lysine, L-ornithine, and L-2,4-diaminobutyric acid; B is L-alanine or L-glutamine; C is L-arginine or D-arginine; D is selected from the group consisting of L-lysine, L-ornithine, L-2,4-diaminobutyric acid, L-glutamic acid, and L-aspartic acid; E is a direct bond between group D and group R.sub.5 or is L-lysine or D-lysine; m is 0 or 1; the symbol * represents an asymmetric carbon atom which may be in the D or L configuration, with the proviso that: (a) when A is L-glutamic acid or L-aspartic acid, D is L-lysine, L-ornithine, or L-2,4-diaminobutyric acid; and (b) when A is L-lysine, L-ornithine, or L-2,4-diaminobutyric acid, D is L-glutamic acid or L-aspartic acid. This invention also pertains to methods for using the novel cyclic polypeptides.

Cyclic motilin-like polypeptides with gastrointestinal motor stimulating

This invention pertains to polypeptides having gastrointestinal motor inhibitory activity represented by the formula: ##STR1## including optically active isomeric forms and the pharmaceutically acceptable acid addition salts thereof wherein A is the L-stereoisomer of a lipophilic aliphatic or alicyclic amino acid; B is selected from the group consisting of L and D aromatic, heteroaromatic, lipophilic aliphatic, and alicyclic amino acids; D is the L-stereoisomer of a lipophilic aliphatic or alicyclic amino acid; E is the L-stereoisomer of an aromatic, 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 is L-glutamine, L-glutamic acid, or L-alanine; J is a direct bond between I and group --NH-- or is selected from the group consisting of Z, Z-Leu, Z-Leu-Gln, Z-Leu-Gln-Glu (SEQ ID NO:2), Z-Leu-Gln-Glu-Lys (SEQ ID NO:3), Zleu-Gln-Glu-Lys-Glu (SEQ ID NO:4), Z-Leu-Gln-Glu-Lys-Glu-Arg (SEQ ID NO:5), ZLeu-Gln-Glu-Lys-Glu-Arg-Asn (SEQ ID NO:6), Z-Leu-Gln-Glu-Lys-Glu-Arg-AsnLys (SEQ ID NO:7), and Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn-Lys-Gly (SEQ ID NO:8), 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; R.sub.1 and R.sub.2 are independently hydrogen or lower alkyl; R.sub.3 is selected from the group consisting of lower-alkyl, cycloalkyl, substituted and unsubstituted aryl, and heteroaryl, wherein the aryl group may be substituted with one or more substituents selected from the group consisting of halogen, hydroxy, and lower-alkoxy; R.sub.4 is selected from the group consisting of --CH.sub.2 CONH.sub.2, aminoalkyl groups containing from 1 to 3 carbon atoms, and guanidinoalkyl groups containing 2 or 3 carbon atoms; R.sub.5 is --COOH or --CONH.sub.2 ; and the symbol * represents an asymmetric carbon atom which may be in the D or L configuration, and each lower-alkyl group contains from 1 to 4 carbon atoms, with the proviso that R.sub.4 is --CH.sub.2 CONH.sub.2 only when J is Z-Leu or Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn-Lys-Gly (SEQ ID NO:8).

Motilin-like polypeptides that inhibit gastrointestinal motor activity

This invention pertains to polypeptides, other than motilin, having gastrointestinal motor stimulating activity and represented by the formula: ##STR1## wherein A and D are lipophilic aliphatic or alicyclic amino acids; B is L-proline or L-alanine; E is an aromatic, lipophilic aliphatic, or alicyclic amino acid; F is an aromatic or heteroaromatic amino acid; G is glycine or D-alanine; H is L-glutamic acid or L-glutamine; I is L-glutamine, L-glutamic acid, or L-alanine; J is a direct bond or is selected from, inter alia Z, Z-Leu, Z-Leu-Gln, Z-Leu-Gln-Glu (SEQ ID NO:2) or Z-Leu-Gln-Glu-Lys (SEQ ID NO:3), wherein Z is, inter alia, arginine, D-arginine, D-homoarginine, or D-lysine, and further wherein the amino acids represented by A, D, E and F are L-stereoisomers; R.sub.1 is lower-alkyl or allyl; R.sub.2 is hydrogen, lower-alkyl, propargyl, or allyl; R.sub.3 is hydrogen, lower-alkyl, and allyl; R.sub.4 is lower-alkyl, cycloalkyl, heteroaryl, unsubstituted aryl, and aryl substituted by halogen, hydroxy, or lower-alkoxy; R.sub.5 is --CH.sub.2 CONH.sub.2, aminoalkyl, or guanidinoalkyl; R.sub.6 is --COOH or --CONH.sub.2 ; and m is 0 or 1, and the asymmetric carbon represented by * may be D or L configuration, with certain specified provisos.

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Chatham, NJ, United States of America

Ramalinga Dharanipragada