Patent EA-001362-B1 (EA)
Title: Stable non-hydroscopic crystalline form of n-[n-n-(4-(piperidin-4-yl)butanoyl)-n-ethylglycyl] compounds
Inventor: CHRZAN ZOFIA J
IPC: C07K5/083
Filed: 1997-08-21
Abstract: 1. A compound which is N-(N-t-butoxycarbonyl-N-ethylglycyl)-(L)-aspartic acid β-benzyl ester. 2. A compound which is N-[N-[N-[4-[N-benzyloxycarbonylpipcrdin-4-yl]butanoyl]-N-ethylglycyl]-(L)-aspartyl] β-benzyl ester]-(L)-β-cyclohexylalanine amide. 3. A compound which is 4-(4-piperidin)butylidenylcarboxylic acid. 4. A compound which is N-[N-[N-[3-[N-benzyloxycarbonyl-4- piperidin]propylidenylcarbonyl]-N-ethylglycyl]-(L)-aspartyl β-benzyl ester]-(L)-β-cyclohexylalanine amide. 5. A compound which is non-hygroscopic crystalline N-[N-[N-(4-piperdin-4-yl)butanoyl)-N- ethylglycyl]-(l.)-aspartyll-(l.)-β-cyclohexylalanine amide or a pharmaceutically acceptable salt thereof. 6. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier. 7. A method for preparing non-hygroscopic crystalline N-[N-[N-(4-piperidin-4-yl)butanoyl)N-ethylglycyl]-(L)-aspartyl]-(L)-β-cyclohexylalanine amide comprising exposing hygroscopic crystalline N-[N-[N-(4-piperidin-4-yl)butanoyl)-N-ethylglycyl]-(L)-aspartyl]-(L)-β-cyclohexylalanine amide to relative humidities from about 40% t degree  100% and at about 200 degree C to about 80 degree C. 8. The method according to claim 7 wherein the exposing is at relative humidities from about 65% to about 80%. 9. The method according to claim 7 wherein the exposing is at about 40 degree C to about 800 degree C. 10. The method according to claim 7 wherein the exposing is effected under static conditions. 11. The method according to claim 7 wherein the exposing is effected under dynamic conditions. 12. A method for preparing a salt compound of formula   wherein B is alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, aryl, aralkyl, alkylaryl or alkylaralkyl; E<1> is H; E<2> is the α-carbon side chain of a naturally occuring α-amino acid, H, alkyl. cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, aryl. substituted aryl, aralkyl, substilued aralkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl or E<1> and E<2> taken together with the nitrogen and carbon atoms through which E<1> and E<2> are linked form a 4-, 5-, 6-, or 7-membered azacycloalkane ring; G is OR<1> or NR<1>R<2>; R<1> and R<2> are independently H, alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, aryl, aralkyl, alkylaryl or alkylaralkyl; p is 1 to 4; and P<1> is an acid protecting group, comprising coupling compounds of the formulae   wherein P<2> is an acid labile amine protecting group to form a first intermediary compound of formula   further coupling the first intermediary compound with a compound of formula   to form a second intermediary compound of formula   removing the P<2> protecting group from the second intermediary compound with trifluoroacetic acid to yield the salt compound. 13. The method of claim 12 wherein P<1> is a hydrogenation labile acid protecting group. 14. A compound of formula   wherein P<3> is an amine protecting group; B is alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, aryl, aralkyl, alkylaryl or alkylaralkyl; P<1> is an acid protecting group; E<1> is H; E<2> is the α-carbon side chain of a naturally occuring a-amino acid, H, alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, aryl, substituted aryl, alkyl. substitued aralkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl, or E<1> and F<2> taken together with the nitrogen and carbon atoms through which E<1> and E<2> are linked form a 4-, 5-, 6-, or 7-membered azacycloalkane ring; G is OR<1> or NR<1>R<2>; R<1> and R<2> arc independently H, alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, aryl, aralkyl, alkylaryl or alkylaralkyl; and p is 1-4. 15. A compound according to claim 14 wherein P<1> is a hydrogenation labile acid protecting group and P<3> is a hydrogenation labile amine protecting group. 16. A compound according to claim 15 wherein B is alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, aryl, aralkyl, alkylaryl or alkylaralkyl; E<1> is H; E<2> is H, alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, aryl, substituted aryl, aralkyl or substitued aralkyl; L is OR<1> or NR<1>R<2>; R<1> and R<2> are independently H, alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, alkylcycloal kylalkyl, aryl, aralkyl, alkylaryl or alkylaralkyl; and p is 1 or 2. 17. A compound according to claim 16 wherein B is alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl or alkylcycloalkylalkyl; and E<2> is H, alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl or alkylcycloalkylalkyl. 18. A compound according to claim 17 wherein B is alkyl; E<2> is alkyl, cycloalkyl or cycloalkylalkyl; R<1> and R<2> are independently H, alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl or alkylcycloalkylalkyl; and p is 1. 19. A compound according to claim 18 wherein P<3> is benzyloxycarbonyl; B is ethyl; P<1> is benzyl; E<2> is cyclohexylmethyl; and G is NH2. 20. A method of preparing a compound of formula   wherein P<3> is an amine protecting group; B is alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, aryl, aralkyl, alkylaryl or alkylaralkyl; P<1> is an acid protecting group; E<1> is H; E<2> is the α-carbon side chain of a naturally occuring a-amino acid, H, alkyl, cycloalkyl. cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, aryl, substituted aryl, aralkyl, substitued alkyl. heterocyclyl, substituted heteroeyelyl, heterocyclylalkyl, substituted heterocyclylalkyl or E<1> and E<2> taken together with the nitrogen and carbon atoms through which E<1> and E<2> are linked form a 4-, 5-, 6-, or 7-membered azacycloalkane ring; G is OR<1> or NR<1>R<2>; R<1> and R<2> are independently H, alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, aryl, aralkyl, alkylaryl or alkylaralkyl; and p is 1-4, comprising coupling a ((4-piperidin)butylidenylcarboxylic acid) compound of formula   with a tripeptide of formula   or an acid addition salt thereof. 21. The method of claim 20 wherein P<1> is a hydrogenation labile acid protecting group and P<3> is a hydrogenation labile amine protecting group. 22. A compound of formula   wherein P<3> is an amine protecting group. 23. A compound according to claim 22 wherein P<3> is a hydrogenation labile amine protecting group. 24. A compound according to claim 23 wherein P<3> is benzyloxycarbonyl.