US 9,040,552 B2 · Selective opioid compounds

Abstract

The present invention relates to compounds of Formula I or II, or pharmaceutically acceptable salts, esters, or prodrugs thereof: which relates to mophinan compounds useful as μ, δ and/or κ receptor opioid compounds and pharmaceuticals containing same that may be useful for mediating analgesia, combating drug addiction, alcohol addiction, drug overdose, mental illness, bladder dysfunctions, neurogenic bladder, interstitial cystitis, urinary incontinence, premature ejaculation, inflammatory pain, peripherally mediated and neuropathic pain, cough, lung edema, diarrhea, cardiac disorders, cardioprotection, depression, and cognitive, respiratory, diarrhea, irritable bowel syndrome and gastro-intestinal disorders, immunomodulation, and anti-tumor agents.

A method of treating a condition or disease associated with binding opioid receptors in a patient in need thereof, wherein the condition or disease is pain, gastrointestinal dysfunction, or ileus, comprising the step of:

administering to said patient a composition comprising an effective amount of a compound of Formula I or II:
or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein:
R1 is selected from the group consisting of:
hydrogen, halogen, ORa, SRa, S(O)Ra, SO2Ra, S(O)NRbRc, SO2NRbRc, NRb-Q-Rc, CN, (C═W)NRbRc, C(O)ORa, CH2ORa, CH2NRbRc, heteroaryl, and substituted heteroaryl;
Ra, Rb, Rc are each independently selected from:
(i) hydrogen;
(ii) aryl;
substituted aryl;
heteroaryl;
substituted heteroaryl;
(iii) heterocyclic or substituted heterocyclic;
and
(iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
—C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl;
—C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
alternatively, Rb and Rc are taken together to form a heterocyclic or substituted heterocyclic;
Q is absent or selected from (C═O), (SO2), (C═NH), (C═S), or (CONRa);
W is O, S, NORa or NRa;
R2 is independently selected from the group consisting of hydrogen, halogen, ORa, SRa, NRbRc;
alternatively, R1 and R2 are taken together to form a heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocylic;
R3 is independently selected from the group consisting of:
(v) hydrogen;
(vi) aryl;
substituted aryl;
heteroaryl;
substituted heteroaryl;
(vii) heterocyclic or substituted heterocyclic;
and
(viii) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 or more heteroatoms selected from O, S, or N;
substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 or more heteroatoms selected from O, S or N;
—C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl;
—C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
R4 is hydrogen, ORa, or NRb-Q1-Rc, where Q1 is absent or selected from (C═O) or (SO2);
R5 is selected from the group consisting of:
hydrogen, halogen, SRa, S(O)Ra, SO2Ra, S(O)NRbRc, SO2NRbRc, NRb-Q-Rc, CN, (C═W)NRbRc, C(O)ORa, CH2ORa, CH2NRbRc, heteroaryl, and substituted heteroaryl;
Y is hydrogen, lower akyl, or lower alkoxy;
V1 is C═O, C1-C6 alkylene or substituted alkylene;
V2 is absent, alkylene, substituted alkylene, or C═O;
V3 is absent;
V4 is absent;
n is 1, 2, 3 or 4;
wherein each repeating unit can be the same or different;
Z is hydrogen, (C═W)OH or C(O)NHOH;
alternatively,
can be selected from the group consisting of natural or unnatural amino acids;
and
denotes a carbon-carbon single or double bond.

45 more elements

Selective opioid compounds

Life of this patent

Selective opioid compounds

Life of this patent

Abstract

Claims14