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US 7,125,840 B2Granted
Substituted dipeptides as growth hormone secretagogues
AssigneeEli Lilly and Company
InventorsJeffrey Alan Dodge, Britta Evers, Louis Nickolaus Jungheim, Brian Stephen Muehl, Gerd Ruehter, Kenneth Jeff Thrasher
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Abstract
This invention relates to novel compounds which are useful in the modulation of endogenous growth hormone levels in a mammal. The invention further relates to novel intermediates for use in the synthesis of said compounds, as well as novel processes employed in these syntheses. Also included are methods of treating a mammal which include the administration of said compounds.
Claims44
A compound of the Formula I
- wherein:
- R1 is NHR10 or C1–C6alkylNHR10;
- R10 selected from the group consisting of hydrogen, C1–C6alkyl, C1–C6alkyl(OH), C1–C6alkylidenyl(OH)R11, and an amino protecting group;
- R11 is selected from the group consisting of C1–C6alkyl, C2–C6alkenyl, C1–C6alkyl(O)C1–C6alkyl, C(O)O—C1–C6alkyl, aryl, and C1–C6alkylaryl;
- R2 is selected from hydrogen, C1–C6alkyl, aryl, and C1–C6alkylaryl;
- R3 is selected from the group consisting of optionally substituted aryl, C1–C6alkylaryl, C1–C6alkyl(O)—C1–C6alkylaryl, C3–C8 cycloalkyl, (C1–C6 alkyl) C3–C8 cycloalkyl, indolyl, indolinyl, (C1–C6 alkyl) indolyl;
- R4 is hydrogen, C1–C6alkyl, aryl, C1–C6alkylaryl, C2–C6alkenyl;
- R5 is selected from hydrogen, C1–C6alkyl, aryl, and C1–C6alkylaryl;
- W is —CH2C6H4— or —(CH2)m, where m is a number selected from 1 to 4;
- R6 and R7 are independently selected from the group consisting of hydrogen, C1–C6alkyl, C2–C6alkenyl, or R6 and R7 together with the carbon atom to which they are attached may form a carbocyclic ring of up to 8 atoms which is optionally partly unsaturated;
- R8 is selected from the group consisting of hydrogen, C1–C6alkyl, aryl, and C1–C6alkylaryl;
- R9 is selected from the group consisting of hydrogen, C1–C6alkyl, C2–C6alkenyl, C2–C6alkynyl, C3–C8cycloalkyl, C3–C8cycloalkenyl, optionally substituted aryl, optionally substituted —O-aryl, optionally substituted —N-aryl, optionally substituted —S-aryl, -aryl-aryl(K1)(K2), —O-aryl-aryl(K1)(K2), —N-aryl-aryl(K1)(K2), —S-aryl-aryl(K1)(K2), —O—C1–C6alkyl, and C1–C6alkylaryl, wherein K1 is halo or —CF3 and K2 is hydrogen, halo or —CF3;
- and
- Q is —S(O)2— or —C(O)—;
- or a pharmaceutically acceptable salt thereof.
12 more elements
A process for preparing a compound of Formula I
- wherein:
- R1 is NHR10 or C1–C6alkylNHR10;
- R10 selected from the group consisting of hydrogen, C1–C6alkyl, C1–C6alkyl(OH), C1–C6alkylidenyl(OH)R11, and an amino protecting group;
- R11 is selected from the group consisting of C1–C6alkyl, C2–C6alkenyl, C1–C6alkyl(O)C1–C6alkyl, C(O)O—C1–C6alkyl, aryl, and C1–C6alkylaryl;
- R2 is selected from hydrogen, C1–C6alkyl, aryl, and C1–C6alkylaryl;
- R3 is selected from the group consisting of optionally substituted aryl, C1–C6alkylaryl, C1–C6alkyl(O)—C1–C6alkylaryl, C3–C8 cycloalkyl, (C1–C6 alkyl) C3–C8 cycloalkyl, indolyl, indolinyl, (C1–C6 alkyl) indolyl;
- R4 is hydrogen, C1–C6alkyl, aryl, C1–C6alkylaryl, C2–C6alkenyl;
- R5 is selected from hydrogen, C1–C6alkyl, aryl, and C1–C6alkylaryl;
- W is —CH2C6H4— or —(CH2)m, where m is a number selected from 1 to 4;
- R6 and R7 are independently selected from the group consisting of hydrogen, C1–C6alkyl, C2–C6alkenyl, or R6 and R7 together with the carbon atom to which they are attached may form a carbocyclic ring of up to 8 atoms which is optionally partly unsaturated;
- R8 is selected from the group consisting of hydrogen, C1–C6alkyl, aryl, and C1–C6alkylaryl;
- R9 is selected from the group consisting of hydrogen, C1–C6alkyl, C1–C6alkenyl, C2–C6alkynyl, C2–C6alkynyl, C3–C8cycloalkyl, C3–C8cycloalkenyl, optionally substituted aryl, optionally substituted —O-aryl, optionally substituted —N-aryl, optionally substituted —S-aryl, -aryl-aryl(K1)(K2), —O-aryl-aryl(K1)(K2), —N-aryl-aryl(K1)(K2), —S-aryl-aryl(K1)(K2), —O—C1–C6alkyl, and C1–C6alkylaryl, wherein K1 is halo or —CF3 and K2 is hydrogen, halo or —CF3;
- and
- Q is —S(O)2— or —C(O)—;
- comprising coupling a compound of Formula IX′
- with a compound of Formula XI′
13 more elements
A process for preparing a compound of Formula I
- wherein:
- R1 is NHR10 or C1–C6alkylNHR10;
- R10 selected from the group consisting of hydrogen, C1–C6alkyl, C1–C6alkyl(OH), C1–C6alkylidenyl(OH)R11, and an amino protecting group;
- R11 is selected from the group consisting of C1–C6alkyl, C2–C6alkenyl, C1–C6alkyl(O)C1–C6alkyl, C(O)O—C1–C6alkyl, aryl, and C1–C6alkylaryl;
- R2 is selected from hydrogen, C1–C6alkyl, aryl, and C1–C6alkylaryl;
- R3 is selected from the group consisting of optionally substituted aryl, C1–C6alkylaryl, C1–C6alkyl(O)—C1–C6alkylaryl, C3–C8 cycloalkyl, (C1–C6 alkyl) C3–C8 cycloalkyl, indolyl, indolinyl, (C1–C6 alkyl) indolyl;
- R4 is hydrogen, C1–C6alkyl, aryl, C1–C6alkylaryl, C2–C6alkenyl;
- R5 is selected from hydrogen, C1–C6alkyl, aryl, and C1–C6alkylaryl;
- W is —CH2C6H4— or —(CH2)m, where m is a number selected from 1 to 4;
- R6 and R7 are independently selected from the group consisting of hydrogen, C1–C6alkyl, C2–C6alkenyl, or R6 and R7 together with the carbon atom to which they are attached may form a carbocyclic ring of up to 8 atoms which is optionally partly unsaturated;
- R8 is selected from the group consisting of hydrogen, C1–C6alkyl, aryl, and C1–C6alkylaryl;
- R9 is selected from the group consisting of hydrogen, C1–C6alkyl, C2–C6alkenyl, —C2–C6alkynyl, C3–C8cycloalkyl, C3–C8cycloalkenyl, optionally substituted aryl, optionally substituted —O-aryl, optionally substituted —N-aryl, optionally substituted —S-aryl, -aryl-aryl(K1)(K2), —O-aryl-aryl(K1)(K2), —N-aryl-aryl(K1)(K2), —S-aryl-aryl(K1)(K2), —O—C1–C6alkyl, and C1–C6alkylaryl, wherein K1 is halo or —CF3 and K2 is hydrogen, halo or —CF3;
- and
- Q is —S(O)2— or —C(O)—;
- comprising deprotecting a group of the formula Ia′
- Ia′;
- wherein PG is an amino-protecting group.
14 more elements
Dependencies are inferred from the claim text.