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US 8,263,608 B2Granted
Melanocortin receptor-specific spiro-piperidine compounds
AssigneePalatin Technologies, Inc.
InventorsYi-Qun Shi, John H. Dodd, Elizabeth G. Rowley, Gary L. Olson, Axel Metzger
Life of this patent
Estimating the term…
Abstract
Melanocortin receptor-specific compounds of formula I below: wherein the variables are as defined in the specification, and enantiomers, diastereomers and pharmaceutically acceptable salts thereof. Compounds disclosed herein bind to one or more melanocortin receptors and may be an agonist, a partial agonist, an antagonist, an inverse agonist or an antagonist of an inverse agonist as to one or more melanocortin receptors, and may be employed for treatment of one or more melanocortin receptor-associated conditions or disorders.
Claims15
A compound of formula I:
- or an enantiomer, stereoisomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
- G1 and G2 independently represent CH2 or C(O);
- R1 represents
- H,
- Rx,
- X1—R5 or
- N(H)R6;
- R5 represents
- Rx,
- OR7a,
- N(R7b)R7c or
- a structural fragment of the formula
- R5b and R5c independently represent H or Rx,
- or R5b and R5c, together with the N-atom to which they are attached, represent HetA,
- or R5b represents H or alkyl and R5c represents X2—R8;
- X1 and X2 independently represent C(O) or S(O)2;
- R8 represents
- Rx,
- OR7a,
- N(R7b)R7c or
- a structural fragment of the formula
- R7a represents Rx;
- R7b and R7c independently represent H or Rx;
- E represents a direct bond or phenylene;
- R5a and R8a independently represent H or Rx;
- R8b and R8c independently represent H or Rx,
- or R8b and R8c, together with the N-atom to which they are attached, represent HetB;
- HetA and HetB independently represent a 5- or 6-membered fully saturated, partly unsaturated or wholly aromatic heterocyclic group containing a N-atom (the atom to which either R5b and R5c or R8b and R8c are attached) and optionally containing one to three further heteroatoms selected from N, O and/or S, which heterocyclic group is optionally fused to a benzene ring and is optionally substituted by one or more substituents selected from Rx, halo, OR9a, S(O)pR9b, CN, N3, NO2, ═O, B3—C(O)—B4—R9c, N(R9d)R9e and N(OH)R9f;
- R6 represents C(O)—X3—Rx;
- X3 represents O or NH;
- R2 represents
- C2-4 alkyl optionally substituted by an OH, phenyl (which latter group is optionally substituted by one or two halo groups), pyridinyl, triazolyl, piperidinyl or morpholinyl group,
- C5-6 cycloalkyl or
- a structural fragment of the formula
- R3 represents Rx;
- Rx represents, independently at each occurrence,
- alkyl, alkenyl, alkynyl, cycloalkyl (which latter four groups are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, Het1, halo, OR4a, S(O)nR4b, CN, N3, NO2, ═O, B1—C(O)—B2—R4c, N(H)—C(═NH)—NH2, N(R4d)R4e and N(OH)R4f),
- aryl or
- Het2;
- R4a to R4f and R9a to R9f independently represent H, alkyl, alkenyl, alkynyl, cycloalkyl (which latter four groups are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, Het3, halo, OH, alkoxy, NH2, N(H)alkyl and N(alkyl)2), aryl or Het4;
- each aryl independently represents a C6-14 carbocyclic aromatic group, which group may comprise one, two or three rings, at least one of which rings must be aromatic, and which aryl group is optionally substituted by one or more substituents selected from
- alkyl, alkenyl, alkynyl, cycloalkyl (which latter four groups are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, cycloalkyl, phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, alkyl and alkoxy), Het5, halo, OR10a, S(O)qR10b, CN, N3, NO2, ═O, B5—C(O)—B6—R10c, N(R10d)R10e and N(OH)R10f),
- phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, alkyl and alkoxy),
- Het6, halo, OR11a, S(O)fR11b, CN, N3, NO2, B7—C(O)—B8—R11c, N(R11d)R11e and N(OH)R11f;
- R10a to R10f and R11a to R11f independently represent
- H,
- alkyl, alkenyl, alkynyl, cycloalkyl (which latter four groups are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, cycloalkyl, phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, alkyl and alkoxy), halo, OH, alkoxy, NH2, N(H)alkyl and N(alkyl)2),
- phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, alkyl and alkoxy) or
- Het7;
- Het1 to Het7 independently represent 4- to 14-membered heterocyclic groups containing one or more heteroatoms selected from O, N and/or S, which heterocyclic groups may comprise one, two or three rings and may be substituted by one or more substituents selected from
- alkyl, alkenyl, alkynyl, cycloalkyl (which latter four groups are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, cycloalkyl, phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, alkyl and alkoxy), Heta, halo, OR12a, S(O)tR12b, CN, N3, NO2, ═O, B9—C(O)—B10—R12c, N(R12d)R12e and N(OH)R12f)
- phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, alkyl and alkoxy),
- Hetb, halo, OR13a, ═O, S(O)uR13b, CN, N3, NO2, B11—C(O)—B12—R13c, N(R13d)R13e and N(OH)R13f;
- R12a to R12f and R13a to R13f independently represent
- H,
- alkyl, alkenyl, alkynyl, cycloalkyl (which latter four groups are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, cycloalkyl, phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, alkyl and alkoxy), Hetc, halo, OH, alkoxy, NH2, N(H)alkyl and N(alkyl)2),
- phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, alkyl and alkoxy) or
- Hetd;
- B1 to B12 independently represent a direct bond, O, S or N(R14);
- n, p, q, r, t and u independently represent 0, 1 or 2;
- R14 represents H, alkyl, phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, alkyl and alkoxy), cycloalkyl (which latter group is optionally substituted by one or more substituents selected from OH, ═O, halo, alkyl and alkoxy) or Hete;
- Heta to Hete independently represent 5- or 6-membered heterocyclic groups containing one to four heteroatoms selected from O, N and/or S, which heterocyclic groups may be substituted by one or more substituents selected from halo, ═O and alkyl;
- and
- unless otherwise specified alkyl, alkenyl, alkynyl and cycloalkyl groups, as well as the alkyl part of alkoxy groups, may be substituted by one or more halo atoms.
61 more elements
A compound of the formula:
- or an enantiomer, stereoisomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
- Ra represents, independently at each occurrence, CN, trifluoromethyl, methoxy, fluoro or chloro;
- Rb represents, independently at each occurrence, fluoro or chloro;
- a and b independently represent 0, 1 or 2;
- c represents, independently at each occurrence, 0 or 1;
- R2 represents
- alkyl, alkenyl, alkynyl, cycloalkyl (which latter four groups are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, Het1, halo, OR4a, S(O)nR4b, CN, N3, NO2, ═O, B1—C(O)—B2—R4c, N(H)—C(═NH)—NH2, N(R4d)R4e and N(OH)R4f),
- aryl or
- Het2;
- R4a to R4f independently represent H, alkyl, alkenyl, alkynyl, cycloalkyl (which latter four groups are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, Het3, halo, OH, alkoxy, NH2, N(H)alkyl and N(alkyl)2), aryl or Het4;
- each aryl independently represents a C6-14 carbocyclic aromatic group, which group may comprise one, two or three rings, at least one of which rings must be aromatic, and which aryl group is optionally substituted by one or more substituents selected from
- alkyl, alkenyl, alkynyl, cycloalkyl (which latter four groups are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, cycloalkyl, phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, alkyl and alkoxy) Het5, halo, OR10a, S(O)qR10b, CN, N3, NO2, ═O, B5—C(O)—B6—R10c, N(R10d)R10e and N(OH)R10f),
- phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, alkyl and alkoxy),
- Het6, halo, OR11a, S(O)rR11b, CN, N3, NO2, B7—C(O)—B8—R11c, N(R11d)R11e and N(OH)R11f;
- R10a to R10f and R11a to R11f independently represent
- H,
- alkyl, alkenyl, alkynyl, cycloalkyl (which latter four groups are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, cycloalkyl, phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, alkyl and alkoxy), halo, OH, alkoxy, NH2, N(H)alkyl and N(alkyl)2),
- phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, alkyl and alkoxy) or
- Het7;
- Het1 to Het7 independently represent 4- to 14-membered heterocyclic groups containing one or more heteroatoms selected from O, N and/or S, which heterocyclic groups may comprise one, two or three rings and may be substituted by one or more substituents selected from
- alkyl, alkenyl, alkynyl, cycloalkyl (which latter four groups are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, cycloalkyl, phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, alkyl and alkoxy), Heta, halo, OR12a, S(O)tR12b, CN, N3, NO2, ═O, B9—C(O)—B10—R12c, N(R12d)R12e and N(OH)R12f)
- phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, alkyl and alkoxy),
- Hetb, halo, OR13a, ═O, S(O)uR13b, CN, N3, NO2, B11—C(O)—B12—R13c, N(R13d)R13e and N(OH)R13f;
- R12a to R12f and R13a to R13f independently represent
- H,
- alkyl, alkenyl, alkynyl, cycloalkyl (which latter four groups are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, cycloalkyl, phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, alkyl and alkoxy), Hetc, halo, OH, alkoxy, NH2, N(H)alkyl and N(alkyl)2),
- phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, alkyl and alkoxy) or
- Hetd;
- B1 to B12 independently represent a direct bond, O, S or N(R14);
- n, p, q, r, t and u independently represent 0, 1 or 2;
- R14 represents H, alkyl, phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, alkyl and alkoxy), cycloalkyl (which latter group is optionally substituted by one or more substituents selected from OH, ═O, halo, alkyl and alkoxy) or Hete;
- Heta to Hete independently represent 5- or 6-membered heterocyclic groups containing one to four heteroatoms selected from O, N and/or S, which heterocyclic groups may be substituted by one or more substituents selected from halo, ═O and alkyl;
- R8 represents 1,2,3,4-tetrahydroisoquinolinyl;
- G2 represents CH2 or C(O);
- and
- unless otherwise specified alkyl, alkenyl, alkynyl and cycloalkyl groups, as well as the alkyl part of alkoxy groups, may be substituted by one or more halo atoms.
33 more elements
Dependencies are inferred from the claim text.