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US 7,521,420 B2Granted
Macrocyclic antagonists of the motilin receptor
AssigneeTranzyme Pharma Inc.
InventorsGraeme L. Fraser, Éric Marsault, Mark Peterson, Hamid Hoveyda, Sylvie Beaubien, Kamel Benakli, Robert Dèziel
Life of this patent
Estimating the term…
Abstract
The present invention is directed to novel macrocyclic compounds of formula (I) and their pharmaceutically acceptable salts, hydrates or solvates: wherein R1, R2, R3, R4, R5, R6, n1, m, p Z1, Z2, and Z3 are as describe in the specification. The invention also relates to compounds of formula (I) which are antagonists of the motilin receptor and are useful in the treatment of disorders associated with this receptor and with or with motility dysfunction.
Claims12
A compound represented by the general formula (I):
- or pharmaceutically acceptable salts thereof wherein:
- Z1, Z2, and Z3 are independently NR10, wherein R10 is selected from the group consisting of hydrogen and lower alkyl;
- R1 is —(CH2)qR11, wherein q is 0, 1 or 2, and R11 is selected from the group consisting of:
- wherein A1, A2, A3, A4 and A5 are each optionally present and are independently selected from the group consisting of halogen, alkyl, substituted alkyl, trifluoromethyl, hydroxy, alkoxy and nitro;
- and;
- B1, B2, B3, B4, B5 and B7 are independently NR14a, S or O, wherein R14a is selected from the group consisting of hydrogen, alkyl, substituted alkyl, formyl, acyl, carboxyalkyl, carboxyaryl, amido, sulfonyl and sulfonamido;
- B6 and B8 are independently N or CH;
- R2 is hydrogen,
- R3 is selected from the group consisting of:
- —(CH2)sCH3, —CH(CH3)(CH2)tCH3, —(CH2)uCH(CH3)2, —C(CH3)3, and —(CH2)y—R21, wherein:
- s is 0, 1, 2 or 3;
- t is 1 or 2;
- u is 0 or 1;
- y is 0, 1 or 2;
- R21 is selected from the group consisting of:
- wherein z1 is 1, 2, 3 or 4;
- and
- E1 is optionally present and selected from the group consisting of hydroxy and alkoxy;
- R4 and R5 are each hydrogen;
- R6 is selected from the group consisting of hydrogen, —(CH2)aaCH3, —CH2SCH3—CH2CH2SCH3, —(CH2)bbCH(CH3)2, —CH(CH3)(CH2)ccCH3, —(CH2)dd—NR22R23, and —(CH2)eeR24, wherein
- aa is 0, 1, 2 or 3;
- bb is 0 or 1;
- cc is 1 or 2;
- dd is 1, 2, 3 or 4;
- ee is 0, 1 or 2;
- R22 and R23 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, formyl, acyl, amido, amidino, sulfonyl and sulfonamido;
- R24 is selected from the group consisting of hydroxy, alkoxy
- wherein E2 is optionally present and is selected from the group consisting of hydroxy and alkoxy;
- B9 and B10 are independently selected from the group consisting of NR14b, S and O, wherein R14b is selected from the group consisting of hydrogen, alkyl, substituted alkyl, formyl, acyl, carboxyalkyl, carboxyaryl, amido, sulfonyl and sulfonamido;
- B11 is selected from N and CH;
- and z2 is 1, 2, 3 or 4;
- and
- X is NR8, wherein R8 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, formyl, acyl, carboxyalkyl, carboxyaryl, amido, sulfonyl, sulfonamido and amidino;
- with the provisos that when Z1, Z2 and Z3 are all NH, R1 is:
- R2 is:
- then R3 is not:
- and when Z1, Z2 and Z3 are all NH, R1 is:
- R3 is:
- then R2 is not:
- and when Z1, Z2 and Z3 are all NH, R2 is:
- and R3 is:
- then R1 is not:
- wherein Rp is hydrogen or a protecting group;
- m, n1 and p are 0;
- and
- T is selected from the group consisting of:
- wherein
- U3 is CH2;
- L2 is CH or N;
- L5 is CH or N;
- L6 is CR52R53 or O;
- R46 is H or CH3;
- R54, R55, R56 and R57 are independently selected from the group consisting of hydrogen and lower alkyl;
- R58 is selected from the group consisting of halogen and amidino;
- and
- (X) is the site of a covalent bond to X in formula (I);
- and (Z3) is the site of a covalent bond to Z3 in formula (I).
54 more elements
A compound represented by the general formula (I):
- or pharmaceutically acceptable salts thereof wherein:
- Z1, Z2, and Z3 are independently NR10, wherein R10 is selected from the group consisting of hydrogen and lower alkyl;
- R1 is —(CH2)qR11, wherein q is 0, 1 or 2, and R11 is selected from the group consisting of:
- wherein A1, A2 and A3 are each optionally present and are independently selected from the group consisting of halogen, alkyl, substituted alkyl, trifluoromethyl, hydroxy, alkoxy and nitro;
- B1, B2, B3, B4, B5 and B7 are independently NR14a, S or O, wherein R14a is selected from the group consisting of hydrogen, alkyl, substituted alkyl, formyl, acyl, carboxyalkyl, carboxyaryl, amido, sulfonyl and sulfonamido;
- B6 and B8 are independently N or CH;
- R2 is hydrogen;
- R3 is selected from the group consisting of:
- —(CH2)sCH3, —CH(CH3)(CH2)tCH3, —(CH2)uCH(CH3)2, —C(CH3)3, and —(CH2)y—R21, wherein:
- s is 0, 1, 2 or 3;
- t is lor 2;
- u is 0 or 1;
- y is 0, 1 or 2;
- R21 is selected from the group consisting of:
- wherein z1 is 1, 2, 3 or 4;
- and
- E1 is optionally present and selected from the group consisting of hydroxy and alkoxy;
- R4 and R5 are each hydrogen;
- R6 is each independently selected from the group consisting of hydrogen, —(CH2)aaCH3, —CH2SCH3, —CH2CH2SCH3, —(CH2)bbCH(CH3)2, —CH(CH3)(CH2)ccCH3, —(CH2)dd—NR22R23, and —(CH2)eeR24, wherein
- aa is 0, 1, 2 or 3;
- bb is 0 or 1;
- cc is 1 or 2;
- dd is 1, 2, 3 or 4;
- ee is 0, 1 or 2;
- R22 and R23 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, formyl, acyl, amido, amidino, sulfonyl and sulfonamido;
- R24 is selected from the group consisting of hydroxy, alkoxy
- wherein E2 is optionally present and is selected from the group consisting of hydroxy and alkoxy;
- B9 and B10 are independently selected from the group consisting of NR14b, S and O, wherein R14b is selected from the group consisting of hydrogen, alkyl, substituted alkyl, formyl, acyl, carboxyalkyl, carboxyaryl, amido, sulfonyl and sulfonamido;
- B11 is selected from the group consisting of N and CH;
- and Z2 is 1, 2, 3 or 4;
- and
- X is NR8, wherein R8 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, formyl, acyl, carboxyalkyl, carboxyaryl, amido, sulfonyl, sulfonamido and amidino;
- with the provisos that when Z1, Z2 and Z3 are all NH, R1 is:
- R2 is:
- then R3 is not:
- and when Z1, Z2 and Z3 are all NH, R1 is:
- R3 is:
- then R2 is not:
- and when Z1, Z2 and Z3 are all NH, R2 is:
- and R3 is:
- then R1 is not:
- wherein Rp is hydrogen or a protecting group;
- m, n, and p are 0;
- and
- T is selected from the group consisting of:
- wherein R30 and R31 are independently selected from the group consisting of hydrogen and methyl;
- and (X) is the site of a covalent bond to X in formula (I);
- and (Z3) is the site of a covalent bond to Z3 in formula (I).
45 more elements
Dependencies are inferred from the claim text.