N-Acyl-polypeptides and processes for the production thereof
First Claim
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1. An N-acyl-polypeptide of formula I, ##STR18## where "Acyl" is(a) RI CO-- wherein RI is C1-20 alkyl, C3-20 alkenyl, C3-20 alkinyl, phenyl, naphthyl or C7-10 (phenylalkyl);
- (b) RII SO2 -- wherein RII is C1-10 alkyl, phenyl or C7-10 (phenylalkyl);
(c) RIII O--CO-- wherein RIII is C1-10 alkyl or C7-10 (phenylalkyl); and
##STR19## wherein RIV is hydrogen, C1-10 alkyl, phenyl or C7-10 (phenylalkyl) andRV is hydrogen or C1-10 alkyl,A is hydrogen or C1-3 alkyl,>
N--CH(Z)--CO-- is(a) an (L)- or (D)-phenylalanine residue optionally ring-substituted by halogen, NO2, NH2, OH, C1-3 alkyl and/or C1-3 alkoxy, or(b) the residue of a natural α
-amino acid in which Z is alkyl of 3 to 4 carbon atoms,B is --Phe-- optionally ring-substituted by halogen, NO2, NH2, OH, C1-3 alkyl and/or C1-3 alkoxy,C is --Trp-- or (D)-Trp- optionally α
-N-methylated and optionally benzene-ring-substituted by halogen, NO2, NH2, OH, C1-3 alkyl and/or C1-3 alkoxy,D is --Lys-- optionally α
-N-methylated and optionally ε
-N-C1-3 alkylated,E is --Thr-- or --(D)--Thr-- optionally α
-N-methylated,F is a group of formula --COOR1, --CH2 OR2, ##STR20## or ##STR21## wherein R1 is hydrogen or C1-3 alkyl,R2 is hydrogen or the residue of a physiologically acceptable, physiologically hydrolysable ester,R3 is hydrogen or methyl,R4 is --CH(R5)--X,R5 is hydrogen, --(CH2)2 --OH, --(CH2)3 --OH, --CH2 --OH, --CH(CH3)--OH or isobutyl, andX is a group of formula --COOR1, --CH2 OR2 or ##STR22## wherein R1 and R2 are as defined above,R6 is hydrogen or C1-3 alkyl andR7 is hydrogen, C1-3 alkyl, phenyl or C7-10 phenylalkyl,the group --CH(R5)--X having the (D)- or (L)-configuration, and Y1 and Y2 are each hydrogen or together represent a direct bond, whereby the residues in the 2- and 7-position each independently have the (L)- or (D)-configuration, and with the proviso that (L)- and/or (D)-cysteine residues are present at the 2- and 7-positions only, or a pharmaceutically acceptable salt or complex thereof.
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Abstract
N-Acyl-polypeptides comprising the basic sequence ##STR1## wherein "Acyl" is the acyl residue of an organic or inorganic acid; A is H or alkyl; >N--CH(Z)--CO-- and E are the residues of natural α-amino acids or corresponding (D)-amino acids; C is --Trp-- or --(D)Trp--; F is a terminal grouping; and Y1 and Y2 are each H or together are a direct bond; as well as their salt forms and complexes.
28 Citations
20 Claims
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1. An N-acyl-polypeptide of formula I, ##STR18## where "Acyl" is
(a) RI CO-- wherein RI is C1-20 alkyl, C3-20 alkenyl, C3-20 alkinyl, phenyl, naphthyl or C7-10 (phenylalkyl); -
(b) RII SO2 -- wherein RII is C1-10 alkyl, phenyl or C7-10 (phenylalkyl); (c) RIII O--CO-- wherein RIII is C1-10 alkyl or C7-10 (phenylalkyl); and
##STR19## wherein RIV is hydrogen, C1-10 alkyl, phenyl or C7-10 (phenylalkyl) andRV is hydrogen or C1-10 alkyl, A is hydrogen or C1-3 alkyl, >
N--CH(Z)--CO-- is(a) an (L)- or (D)-phenylalanine residue optionally ring-substituted by halogen, NO2, NH2, OH, C1-3 alkyl and/or C1-3 alkoxy, or (b) the residue of a natural α
-amino acid in which Z is alkyl of 3 to 4 carbon atoms,B is --Phe-- optionally ring-substituted by halogen, NO2, NH2, OH, C1-3 alkyl and/or C1-3 alkoxy, C is --Trp-- or (D)-Trp- optionally α
-N-methylated and optionally benzene-ring-substituted by halogen, NO2, NH2, OH, C1-3 alkyl and/or C1-3 alkoxy,D is --Lys-- optionally α
-N-methylated and optionally ε
-N-C1-3 alkylated,E is --Thr-- or --(D)--Thr-- optionally α
-N-methylated,F is a group of formula --COOR1, --CH2 OR2, ##STR20## or ##STR21## wherein R1 is hydrogen or C1-3 alkyl, R2 is hydrogen or the residue of a physiologically acceptable, physiologically hydrolysable ester, R3 is hydrogen or methyl, R4 is --CH(R5)--X, R5 is hydrogen, --(CH2)2 --OH, --(CH2)3 --OH, --CH2 --OH, --CH(CH3)--OH or isobutyl, and X is a group of formula --COOR1, --CH2 OR2 or ##STR22## wherein R1 and R2 are as defined above, R6 is hydrogen or C1-3 alkyl and R7 is hydrogen, C1-3 alkyl, phenyl or C7-10 phenylalkyl, the group --CH(R5)--X having the (D)- or (L)-configuration, and Y1 and Y2 are each hydrogen or together represent a direct bond, whereby the residues in the 2- and 7-position each independently have the (L)- or (D)-configuration, and with the proviso that (L)- and/or (D)-cysteine residues are present at the 2- and 7-positions only, or a pharmaceutically acceptable salt or complex thereof. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20)
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6. A polypeptide according to claim 1 of the formula ##STR23## where "Acyl" is RI CO or RII SO2 ;
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RI is C1-15 alkyl, phenyl or C7-10 (phenylalkyl); RII is C1-10 alkyl or phenyl optionally substituted by C1-3 alkyl; A is hydrogen; >
N--CH(Z)--CO-- is --(D)--Phe or --(D)--Nle--;B is --Phe--; C is --(D)--Trp--; D is --Lys--; E is --Thr--; F is ##STR24## R3 is hydrogen;
R5 is --CH2 OH;
--CH(CH3)OH or isobutyl;X is --CH2 OR2 ; R2 is hydrogen and Y1 and Y2 together represent a direct bond; or a pharmaceutically acceptable salt or complex thereof.
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7. A compound according to claim 1 in which "Acyl" is RI CO-- wherein RI is C1-15 alkyl.
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8. A compound according to claim 1 in which >
- N--CH(Z)--CO-- is --(D)--Phe--.
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9. A compound according to claim 1 in which R5 is --CH2 OH or --CH(CH3)OH.
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10. The compound according to claim 1 which is ##STR25## pharmaceutically acceptable salt or complex thereof.
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11. A compound according to claim 1 of the formula ##STR26## in which Acyl is selected from the group consisting of CH3 CO, CH3 (CH2)4 CO--, CH3 (CH2)6 CO--, CH3 (CH2)7 CO--, CH3 (CH2)10 CO--, CH3 (CH2)12 CO-- and t.C4 H9 --CO-- or a pharmaceutically acceptable salt or complex thereof.
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12. A compound according to claim 1 of the formula ##STR27## in which Acyl is selected from the group consisting of ##STR28## C2 H5 NH--CO--, D(+)-Biotinyl and CH3 (CH2)9 SO2 -- or a pharmaceutically acceptable salt or complex thereof.
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13. The pharmaceutical composition according to claim 10 in which the N-Acyl-polypeptide is ##STR29##
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14. The method according to claim 11 in which the N-Acyl-polypeptide is ##STR30##
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15. The method according to claim 13 in which the N-Acyl-polypeptide is ##STR31##
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16. A pharmaceutical composition useful in inhibiting GH secretion and in treating gastrointestinal disorders comprising an effective amount of an N-acyl-polypeptide as defined in claim 1 or a pharmaceutically acceptable salt or complex thereof, together with a pharmaceutically acceptable diluent or carrier therefor.
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17. A method of treating disorders with an aetiology comprising or associated with excess GH-secretion, in a subject in need of such treatment, which method comprises administering to said subject an effective amount of an N-acyl-polypeptide as defined in claim 1 or of a pharmaceutically acceptable salt form or complex thereof.
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18. A method according to claim 17 for the treatment of diabetes mellitus, angiopathy or acromegaly.
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19. A method of treating gastro-intestinal disorders in a subject in need of such treatment, which method comprises administering to said subject an effective amount of an N-acyl-polypeptide as defined in claim 1 or of a pharmaceutically acceptable salt form or complex thereof.
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20. A method according to claim 19 for the treatment of gastric ulcer, gastro-intestinal bleeding or acute pancreatitis.
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Specification
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Current AssigneeFidelity Union BAN National Association Morristown New Jersey
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Original AssigneeSandoz Inc. (Novartis Ag)
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InventorsBauer, Wilfried, Pless, Janos
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Primary Examiner(s)Phillips, Delbert R.
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Application NumberUS06/353,900Time in Patent Office735 DaysField of Search260/112.5 S, 424/177US Class Current514/6.9CPC Class CodesA61K 38/00 Medicinal preparations cont...C07K 14/6555 at least 1 amino acid in D-...Y10S 930/26 Containing cys-cys disulfid...
