NZ619737B2 - Peripherally acting opioid compounds - Google Patents

Peripherally acting opioid compounds Download PDF

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NZ619737B2
NZ619737B2 NZ619737A NZ61973712A NZ619737B2 NZ 619737 B2 NZ619737 B2 NZ 619737B2 NZ 619737 A NZ619737 A NZ 619737A NZ 61973712 A NZ61973712 A NZ 61973712A NZ 619737 B2 NZ619737 B2 NZ 619737B2
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substituted
aryl
pain
compound
kza
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NZ619737A
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NZ619737A (en
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Derrick Arnelle
Laura Cook Blumberg
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Alkermes Inc
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Priority claimed from PCT/US2012/044928 external-priority patent/WO2013003720A1/en
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Publication of NZ619737B2 publication Critical patent/NZ619737B2/en

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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone

Abstract

Disclosed are morphinan derivatives of formulae I, II, III or IV wherein the substituents are as defined herein. Also disclosed are methods of synthesis of the compounds and their use as mu receptor agonists in the treatment of conditions including pain, arthritis, addiction, and side effects of other opiate medications. er opiate medications.

Description

' 1 ' 2012/044928 PERIPHERALLY ACTING OPIOID COMPOUNDS D APPLICATION This application claims the benefit ofUS. Provisional Application No. 61/502,721, filed on June 29, 2011. The entire teachings of the above ation are incorporated herein by reference.
TECHNICAL FIELD This ion relates to peripherally acting opioid nds useful as opioid or modulators.
BACKGROUND OF THE INVENTION Opiates have been the subject of intense research since the isolation of morphine in 1805, and thousands of compounds having opiate or opiate-like activity have been fied.
Many opioid receptor-interactive compounds including those used for producing analgesia (e.g., morphine) and those used for treating drug addiction (e. g., naltrexone) have been employed in human therapy. Almost all therapeutically useful opioids in the benzomorphan and morphinan classes have a phenolic hydroxyl group (OH) at a position which is numbered “8” in the numbering system used for 2,6-methanobenzazocines [e.g., cyclazocine and EKC (ethylketocyclazocine)] and which is numbered “3” in the numbering system used for morphinans (e.g., morphine). When the 3-hydroxyl group is replaced by a number of small, polar, neutral residues, such as carboxamide and thiocarboxamide groups, the adjacent 4- position may be substituted with a hydroxyl to produce compounds with high affinity for the opioid or. (Wentland M: WO 2009023567; WO 2010011619; US 6784187; US 6887998; US 8; US 7557119). Compounds that bind to such receptors are likely to be useful in the treatment of diseases modulated by opiate receptors for example, mediating analgesia, combating drug and opioid addiction, alcohol addiction, drug overdose, mental illness, compulsive or, bladder dysfunctions, neurogenic bladder, interstitial cystitis, urinary incontinence, premature ejaculation, inflammatory pain, peripherally mediated and neuropathic pain, cough, convulsions, lung edema, diarrhea, constipation, pruritus, cardiac disorders, cardioprotection, and cognitive, respiratory depression, irritable bowel syndrome ' 2 ' and gastro-intestinal disorders, immunomodulation, binge eating,anorexia, hyperalgesia, dyskinesia, anti-psychotic induced weight gain and as anti-tumor .
The potent ciceptive actions of classical opioids such as morphine are traditionally considered to be predominantly mediated centrally through an action at the supraspinal or spinal level. Antinociceptive effects have also been demonstrated to result after local application of opioids in the periphery, for example, in mouse writhing, and in rat models of inflammation or neuropathic pain. These effects have been attributed to opioid induced actions ed by peripheral opioid receptors. Neuroanatomical, molecular and electro-physiological studies have shown that such receptors are expressed on peripheral terminals of sensory neurons where they can modulate both afferent and efferent neuronal ons, resulting in antinociception. (Furst et. al. J Pharmacol Exp Ther. 2005 312(2), 609-18.). In addition, opioid receptors have been found on immune cells known to migrate into enteric tissues and the epithelial cells lining the gastrointestinal tract. As such, opioids interacting with peripheral opioid ors without crossing the blood-brain barrier might be used as potent analgesics and are devoid of lly mediated side effects are of interest in treating opioid ed diseases.
SUMMARY The invention s to compounds of Formula I, II, III, IV or a pharmaceutically acceptable ester or prodrug thereof: Formula I Formula II ' 3 ' Formula 111 Formula IV Wherein: uis 0, l or 2; tis 0, l, 2, 3, 4, 5, 6, or 7; X is S or O; is a pharmaceutically able counterion; R1 is selected from aliphatic, substituted aliphatic, aryl, tuted aryl, heterocyclyl or substituted heterocyclyl; Each R2, R3, R4, R6, R8, and R11 is independently selected from absent, hydrogen, n, - ORzo, -SR20, -NR20R21, -C(O)R20, -C(O)OR20, -C(O)NR20R21, -N(R20)C(O)R21, -CF3, -CN, - N02, -N35 acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio, tuted alkylthio, alkylsulfonyl, substituted alkylsulfonyl, aliphatic, substituted tic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl; or alternatively, two of R2, R3, R4, R8 and R11 together with the atoms they are attached to form one or two optionally substituted rings; atively R2 and R3 together with the carbon they are attached to form a C=X group or a vinyl group; alternatively, two R11 groups together with the carbon atom to which they are attached form a C=X or a vinyl group; wherein each R20 and R21 is independently selected from absent, hydrogen, halogen, - alkyl, substituted alkyl, aryl or substituted aryl; R5 is alkyl, substituted alkyl, aryl or tuted aryl; R7 is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; According to a first aspect of the present ion there is provided a compound of Formula I, II, III, IV or a pharmaceutically acceptable ester thereof: R1 R1 R3 N R3 N Y R2 R2 R4 R4 (R8)u (R8)u (R11)t (R11)t X O R6 X O R6 N R7 N R7 R10 R9 R9 R10 Formula I Formula II (10820492_1):CCG R1 R1 R3 N R3 N Y R2 R2 R4 R4 (R8)u (R8)u (R11)t (R11)t X X O N N R10 R9 R10 R9 Formula III Formula IV Wherein: u is 0, 1 or 2; t is 0, 1, 2, 3, 4, 5, 6, or 7; X is S or O; Y is a pharmaceutically acceptable counterion; R1 is selected from aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl; Each R2, R3, R4, R6, R8, and R11 is independently ed from hydrogen, halogen, -OR20, -SR20, -NR20R21, -C(O)R20, -C(O)OR20, -C(O)NR20R21, -N(R20)C(O)R21, -CF3, -CN, -NO2, -N3, acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio, tuted alkylthio, alkylsulfonyl, tuted alkylsulfonyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl; or alternatively, two of R2, R3, R4, R8 and R11 together with the atoms they are attached to form one or two ally substituted rings; alternatively R2 and R3 together with the carbon they are attached form a C=X group or a vinyl group; alternatively, two R11 groups together with the carbon atom to which they are attached form a C=X or a vinyl group; wherein each R20 and R21 is independently selected from hydrogen, halogen, -alkyl, substituted alkyl, aryl or tuted aryl; R5 is alkyl, substituted alkyl, aryl or substituted aryl; R7 is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; R9 is selected from hydrogen, aliphatic, substituted aliphatic, aryl, substituted aryl, cyclyl or substituted heterocyclyl; (11063323_1):KZA R10 is selected from Table A: Table A R101 N * p (R100)q R102 H (R100)q R103 R101 N * p OH R102 (R100)q R103 R101 N * p OMe R102 (R100)q (R103)s R101 NR104 * p O R102 (R100)q s R101 NR105 * p O NR104 R102 (R100)q R101 * p NR104 R102 (R103)s (11063323_1):KZA (R100)q O R101 * p NR104 R102 (R103)s (R100)q R101 NR104 * p O R102 N (R103)s Wherein s is 0, 1, 2, or 3; p is 0, 1, 2, 3, 4, 5, 6, or 7; q is 0, 1, 2, 3 or 4; Each R100, R101, R102, R103-,R104, and R105- is independently selected from hydrogen, halogen, -OR20, -SR20, -NR20R21, -C(O)R20, -C(O)OR20, -C(O)NR20R21, -N(R20)C(O)R21, -CF3, -CN, -NO2, -N3, acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, optionally substituted aliphatic, optionally substituted aryl, heterocyclyl or substituted heterocyclyl; Wherein the term “substituted” refers to the replacement of one or more hydrogen radicals in a given structure with the radical selected from halo, alkyl, l, alkynyl, aryl, cyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, arbonyl, minocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, arbonylalkyl, acyl, xycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl, heteroaryl and aliphatic. (11063323_1):KZA According to a second aspect of the present invention there is provided a compound of Formula V or VI, or a pharmaceutically acceptable ester thereof: R5 R1 R1 N Y (R11)t (R11)t O OH O OH HN R10 R10 Formula V a VI; Wherein: t is 0, 1, 2, 3, 4, 5, 6, or 7; Y is a pharmaceutically acceptable counterion; R1 is selected from aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl; Each R4 and R11 is independently selected from hydrogen, halogen, -OR20, -SR20, - NR20R21, -C(O)R20, R20, -C(O)NR20R21, -N(R20)C(O)R21, -CF3, -CN, -NO2, -N3, acyl, alkoxy, tuted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio, substituted hio, alkylsulfonyl, substituted ulfonyl, tic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl wherein each R20 and R21 is independently selected from hydrogen, halogen, alkyl, substituted alkyl, aryl or substituted aryl; R5 is alkyl, substituted alkyl, aryl or substituted aryl; Wherein R10 is selected from Table A: Table A R101 N * p (R100)q R102 H (R100)q R103 R101 N * p OH R102 (11063323_1):KZA q R103 R101 N * p OMe R102 (R100)q (R103)s R101 NR104 * p O R102 (R100)q (R103)s R101 NR105 * p O NR104 R102 (R100)q R101 * p NR104 R102 (R103)s (R100)q O R101 * p NR104 R102 (R103)s (R100)q R101 NR104 * p O R102 N (R103)s Wherein s is 0, 1, 2, or 3; p is 0, 1, 2, 3, 4, 5, 6, or 7; (11063323_1):KZA q is 0, 1, 2, 3 or 4; Each R100, R101, R102, R103-,R104, and R105- is independently ed from en, halogen, -OR20, -SR20, -NR20R21, -C(O)R20, -C(O)OR20, -C(O)NR20R21, -N(R20)C(O)R21, -CF3, -CN, -NO2, -N3, acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or tituted alkylsulfonyl, optionally substituted aliphatic, optionally substituted aryl, heterocyclyl or substituted heterocyclyl; Wherein the term “substituted” refers to the replacement of one or more hydrogen radicals in a given structure with the radical selected from halo, alkyl, l, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, xy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl, ylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl, heteroaryl and aliphatic.
According to a third aspect of the t ion there is provided a compound selected from Table C: TABLE C No Compound 1 N O O HN N (11063323_1):KZA 3 N O O HN NH 4 N O O HN N N O OH O HN NH 6 N O OH HN NH 7 N O OH O HN NH 8 N O O 323_1):KZA 9 N O O HN N N O O O 11 N O O HN NH 12 N O O 13 N O O O 323_1):KZA 14 N O O O N O O 16 N O O 17 N O O 323_1):KZA O O According to a fourth aspect of the present invention there is provided use of a compound according to the first, second or third aspect of the invention in the manufacture of a pharmaceutical composition for treating a disease or disorder by modulating the activity of an opioid or. ing to a fifth aspect of the present invention there is provided use of a compound according to the first or second aspect of the ion in the manufacture of a pharmaceutical composition for treating or preventing a side effect associated with an opioid. (11063323_1):KZA ' 5 ' stration (intraperitoneal) of Compound 4 blocked acetic acid induced writhing in a ependent manner in an acetic-acid induced writhing model of inflammatory pain.
DETAILED DESCRIPTION In one embodiment, the invention relates to a compound of Formula I, II, III, IV or a pharmaceutically acceptable ester or prodrug thereof: Formula III Formula IV Wherein: uis 0, l or 2; tis 0, l, 2, 3, 4, 5, 6, or 7; X is S or O; YG . . . is a pharmaceut1cally acceptable counterlon; R1 is selected from aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or tuted heterocyclyl; ' 6 ' Each R2, R3, R4, R6, R3, and R11 is independently selected from absent, hydrogen, halogen, - OR20, -SR20, -NR20R21, -C(O)R20, -C(O)OR20, -C(O)NR20R21, -N(R20)C(O)R21, -CF3, -CN, - N02, -N35 acyl, , substituted alkoxy, alkylamino, substituted alkylamino, lamino, substituted dialkylamino, hio, substituted alkylthio, alkylsulfonyl, substituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or tuted heterocyclyl; or alternatively, two of R2, R3, R4, R3 and R11 together with the atoms they are attached to form one or two optionally substituted rings; alternatively R2 and R3 together with the carbon they are attached to form a C=X group or a vinyl group; alternatively, two R11 groups together with the carbon atom to which they are attached form a C=X or a vinyl group; wherein each R20 and R21 is independently selected from absent, hydrogen, halogen, - alkyl, substituted alkyl, aryl or tuted aryl; R5 is alkyl, substituted alkyl, aryl or substituted aryl; R7 is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; R9 is selected from hydrogen, aliphatic, tuted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl; R10 is selected from —[C(R23)(R24)]m-R25; Wherein m is 0, l, 2, 3, 4, 5, 6, 7, or 8; Each R23 and R24 is independently selected from hydrogen, halogen, -OR20, -SR20, - NR20R21, -C(O)R20, -C(O)OR20, -C(O)NR20R21, )C(O)R21, -CF3, -CN, -NO2, - N3, acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio, substituted alkylthio, alkylsulfonyl, substituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl; and, R25 is heterocyclyl, substituted heterocyclyl, aryl substituted with heteroaryl or aryl substituted with heterocyclyl.
The invention fiarther relates to a method of treating a disease or er by ting the activity of an opioid receptor(s) comprising the step of administering a compound of Formula I or II to a subject in need thereof.
In a preferred ment, the invention relates to a compound of Formula V, VI, or a pharmaceutically able ester or g thereof: ' 7 ' HN—R10 Formula V a VI The invention fiarther relates to a method of treating a disease or disorder mediated by opioid receptor comprising the step of administering a compound of Formula II or a pharmaceutically acceptable ester or prodrug f to a subject in need thereof.
In a more preferred embodiment, the invention relates to a compound of Formula I or II or a ceutically acceptable ester or prodrug thereof, wherein R10 is selected from Table A: TABLE A WO 03720 ' 8 ' (R100)q (R103)5 Whereinsis 0, 1,2, or 3; pisO,1,2,3,4,5,6,0r7; qisO,1,2,3,4,or5; ' 9 ' Each R100, R101, R102, R1035R104, and R105 is independently selected from en, halogen, - ORzo, -SR20, -NR20R21, -C(O)R20, -C(O)OR20, -C(O)NR20R21, -N(R20)C(O)R21, -CF3, -CN, - N02, -N35 acyl, , substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, ally substituted aliphatic, optionally substituted aryl, heterocyclyl or substituted heterocyclyl.
In a preferred embodiment, the invention relates to a compound or a pharmaceutically acceptable ester or g thereof, selected from Table B: TABLE B W0 03720 PCT/U82012/044928 W0 2013/003720 PCT/U82012/044928 N—R10 In a preferred embodiment, the invention relates to a nd selected from Table B, wherein R10 is selected from Table A. In a more preferred embodiment, the invention relates to a compound selected Table B, wherein R10 is ed from Table A and R9 is In a preferred embodiment, R1 is selected from —(CH2)a-c-C3H5, —(CH2)a-c-C4H7, — (CH2)a-c-C5H9, —(CH2)a-CH=CH2, -CH3, -CH2-CH2-phenyl or -(CH2)a-CH=C(CH3)2 n a is independently 0, l, 2 or 3.
In a preferred embodiment, the invention relates to a compound selected from Table C or a pharmaceutically acceptable ester or prodrug thereof: TABLE C Compound W0 03720 PCT/U82012/044928 W0 03720 PCT/U82012/044928 W0 03720 PCT/U82012/044928 ' 15 ' In a more preferred embodiment, the invention s a method of ng opioid or mediated disease or disorder comprising the step of administering a compound of Table C to a t in need thereof. In one embodiment, the invention relates to the treatment of pain comprising the administration of a compound of Formula I or II to a subject in need thereof. In one embodiment, the pain is selected from inflammatory pain, centrally mediated pain, peripherally mediated pain, visceral pain, structural related pain, cancer pain, soft tissue injury d pain, progressive disease related pain, neuropathic pain and acute pain from acute injury, acute pain from trauma, acute pain from surgery, chronic pain from headache, chronic pain from neuropathic conditions, chronic pain from post-stroke conditions and chronic pain from migraine. In one embodiment, the pain is associated with W0 2013/003720 PCT/U82012/044928 osteoarthritis, rheumatoid arthritis, algia, migraine, he, toothache, burn, sunburn, snake bite, spider bite, insect sting, neurogenic bladder, benign prostatic hypertrophy, interstitial cystitis, rhinitis, contact dermatitis/hypersensitiVity, itch, eczema, pharyngitis, mucositis, enteritis, cellulitis, gia, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, post-operative ileus, cholecystitis, postmastectomy pain syndrome, oral neuropathic pain, Charcot's pain, reflex sympathetic dystrophy, Guillain-Barre syndrome, meralgia paresthetica, buming- mouth syndrome, post-herpetic neuralgia, trigeminal neuralgia, cluster headache, migraine headache, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, optic neuritis, postfebrile neuritis, migrating neuritis, segmental neuritis, lt's neuritis, neuronitis, cervicobrachial gia, cranial neuralgia, geniculate neuralgia, glossopharyngial neuralgia, migrainous neuralgia, idiopathic neuralgia, intercostals neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatine neuralgia, supraorbital gia, Vidian neuralgia, inflammatory bowel e, irritable bowel syndrome, sinus headache, tension headache, labor, childbirth, menstrual cramps, and cancer.
In one embodiment, the invention relates to the treatment of pain associated with arthritis. In one embodiment, arthritis is selected from rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty tis, le arthritis, scapulohumeral periarthritis.
Compounds of the instant ation show good binding affinities to opiate ors.
Some of the compounds of the invention show agonist activity based on their ability to induced GTPyS binding at one or more of the opiate receptors (MOR, DOR, KOR or NOP).
As such, the compounds of the instant ation are useful in the treatment of diseases modulated by opioid or activation; for example: mediating analgesia, combating drug and opioid addiction, alcohol addiction, drug overdose, mental illness, bladder dysfunctions, neurogenic r, interstitial cystitis, urinary inence, premature ejaculation, inflammatory pain, neuropathic pain, cough, lung edema, diarrhea, us, cardiac disorders, cardioprotection, and cognitive, respiratory depression, ble bowel syndrome and gastro-intestinal disorders, immunomodulation, and anti-tumor agents.
The compounds of the present invention may be used in methods to treat diseases where ligand binding primarily to the u opioid receptor is desired. Compounds of interest may also bind to K and 5 receptors. The opioid receptors may be d in the d outside central nervous system in the periphery and located on nerve cells, immune cells, glial cells, ' 17 ' 2012/044928 or epithelial cells. If compounds are directly injected into the central nervous system (CNS) they would bind to opioid receptors there.
In one ment, the compounds are opioid receptor agonist. In another embodiment, the compounds are opioid antagonists preventing or treating a ion or disease caused by an opioid (either endogenous or exogenous). In another embodiment, compounds can function broadly in modulating opioid receptor activity having a combination of agonist and antagonist properties at the u, K, and 5 receptors. In yet another embodiment the compounds of the invention preferably do not substantially cross the blood-brain r.
The compounds of the present invention may be used in methods to antagonize opioid receptors, particularly where undesirable symptoms or conditions are side effects of stering exogenous opioids. Furthermore, the compounds of the ion may be used to treat patients having disease states that are ameliorated by binding to opioid receptors or in any treatment wherein ary suppression or modulation of the u opioid receptor signaling is desired.
Such symptoms, conditions or es include the complete or partial antagonism of opioid-induced sedation, confusion, respiratory depression, euphoria, dysphoria, hallucinations, pruritus (itching), increased biliary tone, increased biliary colic, and urinary retention, ileus, emesis, and addiction liability; prevention or treatment of opioid and e dependence; rapid opioid detoxification; treatment of alcoholism; treatment of alcoholic coma; detection of opioid use or abuse (pupil test); treatment of eating disorders; treatment of obesity; treatment of post-concussional syndrome; tive therapy in septic, lemic or endotoxin-induced shock; potentiation of opioid sia (especially at ultra-low doses); al or prevention of opioid nce and physical dependence (especially at ultra-low doses); prevention of sudden infant death syndrome;); treatment of dyskinesia,; treatment of metabolic diseases, ing Type I and 2 diabetes; treatment of the endocrine system (including increased release of luteinizing hormone, treatment of ility, increasing number of multiple births in animal husbandry, and male and female sexual behavior); treatment of the immune system and cancers associated with binding of the opioid receptors; treatment of anxiolysis; treatment of diuresis; treatment and regulation of blood pressure; treatment of us or impaired hearing; treatment of epilepsy; treatment of cachexia; treatment of general ive dysfunctions; and treatment of kleptomania.
The compounds of the present invention may also be used as cytostatic agents, as antimigraine agents, as immunomodulators, as immunosuppressives, as antiarthritic agents, W0 2013/003720 as antiallergic agents, as des, to treat diarrhea, as antischizophrenics, as uropathic agents, as ssives, as antiaddictive agents, as anti-smoking agents, to treat alcoholism, as hypotensive agents, to treat and/or prevent paralysis resulting from traumatic ischemia, general neuroprotection against ischemic trauma, as adjuncts to nerve growth factor treatment of hyperalgesia and nerve , as iuretics, as stimulants, as anti-convulsants, or to treat obesity. Additionally, the present compounds may be used in the treatment of Parkinson's disease as an adjunct to L-dopa for treatment dyskinesia associated with the L- dopa treatment.
In certain embodiments, the nds of the invention may be used in methods for preventing or treating gastrointestinal dysfunction, including, but not limited to, irritable bowel me, opioid-bowel dysfianction, colitis, post-operative and -induced emesis (nausea and vomiting), sed gastric ty and ng, inhibition of small and/or large intestinal sion, increased amplitude of non-propulsive segmental contractions, constriction of sphincter of Oddi, increased anal ter tone, impaired reflex relaxation with rectal distention, diminished gastric, biliary, pancreatic or intestinal secretions, increased absorption of water from bowel contents, gastro-esophageal reflux, gastroparesis, cramping, bloating, abdominal or epigastric pain and discomfort, constipation, and delayed absorption of orally administered medications or nutritive substances.
In one embodiment, the compositions of the invention may further comprise one or more compounds that may be designed to enhance the analgesic potency of the opioid and/or to reduce analgesic tolerance development. Such compounds e, for example, dextromethorphan or other NMDA antagonists (Mao, M. J. et al., Pain, 1996, 67, 361), L- 364,718 and other CCK antagonists (Dourish, C. T. et al., Eur. J. Pharmacol., 1988, 147, 469), NOS tors (Bhargava, H. N. et al., Neuropeptz’des, 1996, 30, 219), PKC inhibitors (Bilsky, E. J. et al., J. Pharmacol. Exp. Ther., 1996, 277, 484), and hin antagonists or antisera (Nichols, M. L. et al., Pain, 1997, 69, 317). The disclosures of each of the foregoing documents are hereby incorporated herein by reference, in their entireties.
In one embodiment, the compounds of the invention can be used in methods for preventing or treating post-operative or opioid-induced ileus. In another embodiment, the compounds of the invention can be used as an analgesics, anesthetics, ruritics, anti- diarrheal agents, anti-convulsants, anti-tussives, and/or anorexics.
W0 2013/003720 PCT/U82012/044928 Definitions Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.
The term “aliphatic group” or “aliphatic” refers to a omatic moiety that may be saturated (e.g. single bond) or contain one or more units of unsaturation, e.g., double and/or triple bonds. An aliphatic group may be straight chained, branched or cyclic, contain carbon, hydrogen or, optionally, one or more heteroatoms and may be substituted or unsubstituted.
In addition to aliphatic hydrocarbon groups, aliphatic groups include, for example, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example.
Such aliphatic groups may be r substituted. It is understood that aliphatic groups may include alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, and substituted or unsubstituted cycloalkyl groups as described herein.
The term “acyl” refers to a carbonyl substituted with en, alkyl, lly saturated or fully saturated cycloalkyl, partially saturated or fillly saturated cycle, aryl, or heteroaryl. For example, acyl includes groups such as ) alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, valeryl, caproyl, t-butylacetyl, etc.), (C3-C6)cycloalkylcarbonyl (e.g., cyclopropylcarbonyl, utylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), cyclic carbonyl (e.g., pyrrolidinylcarbonyl, pyrrolidonecarbonyl, piperidinylcarbonyl, piperazinylcarbonyl, tetrahydrofilranylcarbonyl, etc.), aroyl (e. g., benzoyl) and heteroaroyl (e. g., thiophenylcarbonyl, thiophenylcarbonyl, furanyl carbonyl, furanylcarbonyl, lH-pyrroylcarbonyl, lH-pyrroylcarbonyl, benzo[b]thiophenylcarbonyl, etc.). In addition, the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl group may be any one of the groups described in the respective definitions. When indicated as being nally substituted”, the acyl group may be tituted or optionally substituted with one or more substituents (typically, one to three substituents) independently selected from the group of substituents listed below in the definition for “substituted” or the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl group may be substituted as bed above in the preferred and more preferred list of substituents, respectively.
The term ” is ed to include both branched and straight chain, tuted or unsubstituted saturated aliphatic hydrocarbon radicals/groups having the specified number of carbons. Preferred alkyl groups comprise about 1 to about 24 carbon atoms 24”).
Other preferred alkyl groups comprise at about 1 to about 8 carbon atoms (“C1-C8”) such as W0 2013/003720 about 1 to about 6 carbon atoms (“C1-C6”), or such as about 1 to about 3 carbon atoms (“C1- C3”). Examples of C1-C6 alkyl radicals e, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert—butyl, n-pentyl, neopentyl and n-hexyl ls.
The term “alkenyl” refers to linear or branched radicals having at least one carbon- carbon double bond. Such radicals preferably contain from about two to about twenty-four carbon atoms (“Cg-C24”). Other preferred alkenyl radicals are “lower alkenyl” radicals having two to about ten carbon atoms (“Cg-Clo”) such as ethenyl, allyl, propenyl, l and 4-methylbutenyl. Preferred lower alkenyl radicals include 2 to about 6 carbon atoms (“C2- C6”). The terms “alkenyl”, and “lower alkenyl”, embrace radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.
The term “alkynyl” refers to linear or branched radicals having at least one carbon- carbon triple bond. Such radicals preferably contain from about two to about twenty-four carbon atoms 24”). Other preferred alkynyl radicals are “lower alkynyl” radicals having two to about ten carbon atoms such as propargyl, l-propynyl, 2-propynyl, l-butyne, 2-butynyl and ynyl. Preferred lower alkynyl radicals e 2 to about 6 carbon atoms (“C2-C6”).
The term “cycloalkyl” refers to saturated carbocyclic radicals having three to about twelve carbon atoms 12”). The ycloalkyl” embraces saturated carbocyclic radicals having three to about twelve carbon atoms. Examples of such ls include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term “cycloalkenyl” refers to partially unsaturated carbocyclic radicals having three to twelve carbon atoms. Cycloalkenyl radicals that are partially unsaturated carbocyclic radicals that contain two double bonds (that may or may not be conjugated) can be called “cycloalkyldienyl”. More preferred cycloalkenyl radicals are “lower cycloalkenyl” radicals having four to about eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.
The term “alkylene,” as used herein, refers to a divalent group derived from a straight chain or branched saturated hydrocarbon chain having the specified number of carbons atoms. Examples of ne groups e, but are not limited to, ethylene, ene, butylene, 3-methyl-pentylene, and 5-ethyl-hexylene.
The term “alkenylene,” as used herein, denotes a divalent group derived from a straight chain or branched hydrocarbon moiety containing the ed number of carbon atoms having at least one carbon-carbon double bond. Alkenylene groups include, but are W0 2013/003720 2012/044928 not limited to, for example, ethenylene, enylene, nylene, ylbuten-l- ylene, and the like.
The term “alkynylene,” as used herein, denotes a divalent group derived from a straight chain or branched hydrocarbon moiety ning the specified number of carbon atoms having at least one carbon-carbon triple bond. Representative alkynylene groups include, but are not limited to, for example, propynylene, l-butynylene, 2-methyl hexynylene, and the like.
The term “alkoxy” refers to linear or branched oxy-containing radicals each having alkyl portions of one to about twenty-four carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkoxy radicals are “lower alkoxy” radicals having one to about ten carbon atoms and more preferably having one to about eight carbon atoms.
Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy.
The term “alkoxyalkyl” refers to alkyl radicals having one or more alkoxy radicals ed to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals.
The term , alone or in combination, means an aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be filSGd. The term “aryl” embraces ic ls such as phenyl, naphthyl, tetrahydronaphthyl, indane furanyl, quinazolinyl, pyridyl and biphenyl.
The terms “heterocyclyl”, “heterocycle” “heterocyclic” or “heterocyclo” refer to saturated, partially unsaturated and rated heteroatom-containing ring-shaped radicals, which can also be called “heterocyclyl”, “heterocycloalkenyl” and "heteroaryl"correspondingly, where the heteroatoms may be selected from nitrogen, sulfur and . Examples of saturated heterocyclyl radicals include saturated 3 to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g. pyrrolidinyl, imidazolidinyl, piperidino, zinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and l to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to 6- membered heteromonocyclic group containing 1 to 2 sulfur atoms and l to 3 nitrogen atoms (e. g., thiazolidinyl, etc.). Examples of partially unsaturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Heterocyclyl radicals may include a pentavalent nitrogen, such as in tetrazolium and pyridinium radicals. The term “heterocycle” also embraces radicals where heterocyclyl radicals are fused with aryl or cycloalkyl ls. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like.
W0 03720 PCT/U82012/044928 The term “heteroaryl” refers to unsaturated aromatic heterocyclyl radicals. Examples of heteroaryl radicals include unsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, yl, pyrrolinyl, olyl, pyrazolyl, pyridyl, dyl, pyrazinyl, pyridazinyl, triazolyl (e. g., 4H-l,2,4-triazolyl, lH-l,2,3- triazolyl, 2H-l,2,3-triazolyl, etc.) olyl (e.g. lH-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensed heterocyclyl group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, riazolyl, tetrazolopyridazinyl (e.g., tetrazolo[l,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-membered monocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.; unsaturated 3- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and l to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., l,2,4-oxadiazolyl, l,3,4-oxadiazolyl, l,2,5-oxadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl, etc.); unsaturated 3 to 6-membered monocyclic group containing 1 to 2 sulfur atoms and l to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl (e.g., l,2,4- thiadiazolyl, l,3,4-thiadiazolyl, l,2,5-thiadiazolyl, etc.) etc.; unsaturated sed cyclyl group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e. g., benzothiazolyl, benzothiadiazolyl, etc.) and the like.
The term “heterocycloalkyl” refers to heterocyclo-substituted alkyl radicals. More preferred heterocycloalkyl radicals are "lower heterocycloalkyl" radicals haVing one to six carbon atoms in the heterocyclo radical.
The term “alkylthio” refers to radicals containing a linear or branched alkyl radical, of one to about ten carbon atoms attached to a divalent sulfur atom. red alkylthio radicals have alkyl radicals of one to about twenty-four carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkylthio radicals have alkyl radicals which are “lower alkylthio” radicals haVing one to about ten carbon atoms. Most preferred are alkylthio radicals haVing lower alkyl radicals of one to about eight carbon atoms. Examples of such lower alkylthio radicals include methylthio, ethylthio, propylthio, butylthio and hexylthio.
The terms “aralkyl” or “arylalkyl” refer to aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, nylmethyl, phenylethyl, and ylethyl.
The term “aryloxy” refers to aryl ls attached through an oxygen atom to other radicals.
W0 2013/003720 PCT/U82012/044928 The terms “aralkoxy” or “arylalkoxy” refer to aralkyl radicals attached through an oxygen atom to other radicals.
The term “aminoalkyl” refers to alkyl radicals substituted with amino radicals.
Preferred aminoalkyl radicals have alkyl ls having about one to about twenty-four carbon atoms or, preferably, one to about twelve carbon atoms. More red aminoalkyl radicals are “lower aminoalkyl” that have alkyl radicals having one to about ten carbon atoms. Most red are aminoalkyl radicals having lower alkyl radicals having one to eight carbon atoms. Examples of such ls include aminomethyl, aminoethyl, and the like.
The term “alkylamino” denotes amino groups which are substituted with one or two alkyl radicals. Preferred alkylamino radicals have alkyl radicals having about one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkylamino radicals are “lower mino” that have alkyl radicals having one to about ten carbon atoms. Most preferred are alkylamino radicals having lower alkyl radicals having one to about eight carbon atoms. Suitable lower alkylamino may be monosubstituted N- mino or disubstituted N, N—alkylamino, such as N—methylamino, N—ethylamino, N, N- dimethylamino, N,N-diethylamino or the like.
The term “substituted” refers to the replacement of one or more en radicals in a given structure with the radical of a specified substituent including, but not limited to: halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, carbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl, heteroaryl, heterocyclic, and aliphatic. It is understood that the substituent may be fiarther substituted.
For simplicity, chemical moieties that are defined and ed to throughout can be univalent chemical moieties (e. g., alkyl, aryl, etc.) or multivalent moieties under the appropriate structural circumstances clear to those skilled in the art. For example, an ” moiety can be referred to a monovalent radical (e.g. 2-), or in other instances, a bivalent linking moiety can be “alkyl, ” in which case those skilled in the art will tand the alkyl to be a divalent radical (e.g., H2-), which is equivalent to the term “alkylene.
” Similarly, in circumstances in which divalent moieties are required and are stated as being “alkoxy3, (6 3, (6 3, H , mino , aryloxy”, “alkylthio , aryl", “heteroaryl”, “heterocyclic”, “alkyl” W0 2013/003720 PCT/U82012/044928 “alkenyl”, “alkynyl”, “aliphatic”, or “cycloalkyl”, those skilled in the art will understand that the terms alkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, "aryl", “heteroaryl”, “heterocyclic”, “alkyl”, “alkenyl”, “alkynyl”, “aliphatic”, or “cycloalkyl” refer to the corresponding divalent moiety.
The terms “compound” “drug”, and “prodrug” as used herein all include pharmaceutically acceptable salts, co-crystals, solvates, hydrates, polymorphs, enantiomers, diastereoisomers, racemates and the like of the compounds, drugs and prodrugs having the formulas as set forth herein.
Substituents indicated as attached through variable points of attachments can be attached to any available position on the ring structure.
As used herein, the term “effective amount” with respect to the t method of treatment, refers to an amount of the subject compound which, when red as part of desired dose n, brings about management of the disease or disorder to clinically acceptable standards.
It will be apparent that in s embodiments of the ion, the substituted or unsubstituted alkyl, alkenyl, l, cycloalkyl, cycloalkenyl, cycloalkynyl, arylalkyl, heteroarylalkyl, and heterocycloalkyl are ed to be monovalent or divalent. Thus, alkylene, alkenylene, and alkynylene, cycloaklylene, cycloalkenylene, cycloalkynylene, kylene, hetoerarylalkylene and heterocycloalkylene groups are to be included in the above definitions, and are applicable to provide the as herein with proper y.
The terms “halo” and “halogen,” as used herein, refer to an atom selected from fluorine, chlorine, bromine and iodine.
The compounds described herein contain one or more asymmetric centers and thus give rise to omers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)— or (L)- for amino acids. The t invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers may be prepared from their respective optically active precursors by the procedures described herein, or by resolving the racemic mixtures. The resolution can be d out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques, which are known to those skilled in the art. Further details regarding resolutions can be found in Jacques, et al., Enantiomers tes and Resolutions (John Wiley & Sons, 1981). When the compounds described herein contain olef1nic double bonds or other centers of geometric try, and unless ed otherwise, it is intended that the compounds include both E and Z geometric ' 25 ' s. Likewise, all tautomeric forms are also intended to be included. The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to ate a particular configuration unless the text so states; thus a carbon- carbon double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion.
The term “subject” as used herein refers to a mammal. A subject therefore refers to, for e, dogs, cats, horses, cows, pigs, guinea pigs, and the like. Preferably the subject is a human. When the subject is a human, the subject may be ed to herein as a patient.
As used herein, the term “pharmaceutically acceptable salt” refers to those salts of the compounds formed by the s of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art.
Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and ation of the compounds of the invention, or separately by reacting the free base function with a le organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts e.g., salts of an amino group formed with inorganic acids such as hydrochloric acid, romic acid, phosphoric acid, sulfiaric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, te, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, lsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, , e, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, ate, persulfate, 3-phenylpropionate, ate, picrate, te, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
Representative alkali or alkaline earth metal salts include sodium, lithium, ium, m, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using W0 2013/003720 2012/044928 counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
The compounds of this invention may be modified by appending various fianctionalities via synthetic means ated herein to enhance selective biological properties. Such modifications include those which increase biological penetration into a given biological system (e. g., blood, lymphatic system, central nervous system), se oral availability, increase solubility to allow stration by ion, alter metabolism and alter rate of excretion.
Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term “stable”, as used herein, refers to compounds which possess stability ient to allow manufacture and which maintains the integrity of the compound for a sufficient period oftime to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).
The synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization. onally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. In on, the solvents, temperatures, reaction durations, etc., delineated herein are for purposes of illustration only and variation of the reaction conditions can produce the desired bridged macrocyclic products of the present invention. Synthetic chemistry ormations and protecting group methodologies ction and deprotection) useful in sizing the compounds bed herein include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in c Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995).
The term “hydroxy protecting group,” as used , refers to a labile chemical moiety which is known in the art to protect a hydroxy group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the hydroxy protecting group as described herein may be ively removed. Hydroxy protecting groups as known in the are described generally in T.H. Greene and P.G., S. M. Wuts, Protective Groups in Organic Synthesis, 3rd n, John Wiley & Sons, New York (1999). Examples of hydroxy protecting groups include benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4- bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert- ' 27 ' butoxycarbonyl, isopropoxycarbonyl, ylmethoxycarbonyl, 2,2,2- trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-furfi1ryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, acetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, l,l-dimethylpropenyl, ylbutenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl, triphenylmethyl (trityl), tetrahydrofuryl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2,2,2- triehloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, esulfonyl, paratoluenesulfonyl , trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like. Preferred hydroxy protecting groups for the present invention are acetyl (Ac or -C(O)CH3), benzoyl (Bz or - C(O)C6H5), and trimethylsilyl (TMS or-Si(CH3)3).
The term “amino protecting group,” as used herein, refers to a labile chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the amino protecting group as described herein may be selectively removed. Amino protecting groups as known in the are described generally in T.H. Greene and PG. M. Wuts, tive Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York . Examples of amino protecting groups include, but are not limited to, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and the like.
As used herein, the term “pharmaceutically acceptable ester” refers to esters of the compounds formed by the process of the present invention which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly ic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, tes and ethylsuccinates.
The term “pharmaceutically acceptable prodrugs” as used herein refers to those prodrugs of the compounds formed by the process of the t invention which are, within the scope of sound medical judgment, suitable for use in contact with the s of humans and lower animals with undue toxicity, tion, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present invention.
"Prodrug", as used herein means a compound, which is convertible in vivo by lic means (e.g. by hydrolysis) to afford any nd delineated by the ae of the instant W0 2013/003720 PCT/U82012/044928 ion. Various forms of prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of gs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8: 1-38(1992); Bundgaard, J. of ceutical Sciences, 77:285 et seq. ; Higuchi and Stella (eds.) gs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim Mayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).
The term “acyl” includes residues derived from acids, including but not limited to carboxylic acids, carbamic acids, carbonic acids, sulfonic acids, and phosphorous acids.
Examples include tic carbonyls, aromatic carbonyls, aliphatic sulfonyls, aromatic sulf1nyls, aliphatic sulf1nyls, aromatic phosphates and aliphatic phosphates. Examples of aliphatic carbonyls e, but are not limited to, acetyl, propionyl, 2-fluoroacetyl, butyryl, 2-hydroxy acetyl, and the like.
The term “aprotic solvent,” as used herein, refers to a solvent that is relatively inert to proton ty, i.e., not acting as a proton-donor. Examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated arbons, such as, for example, ene de, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N—methylpyrrolidinone, and ethers such as l ether, bis-methoxymethyl ether. Such solvents are well known to those skilled in the art, and individual solvents or mixtures thereof may be preferred for specific nds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of aprotic solvents may be found in organic try textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in the Technigues of Chemistry Series, John Wiley & Sons, NY, 1986.
The terms “protogenic organic solvent” or “protic solvent” as used herein, refer to a solvent that tends to e protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, nol, and the like. Such solvents are well known to those skilled in the art, and dual solvents or mixtures thereofmay be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred ature ranges, for example. Further W0 2013/003720 discussions of protogenic solvents may be found in organic chemistry textbooks or in lized monographs, for example: Organic Solvents Physical ties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in the Technigues of Chemistm , John Wiley & Sons, NY, 1986.
PHARMACEUTICAL COMPOSITIONS The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically able carriers. As used herein, the term “pharmaceutically acceptable carrier” means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered anth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl e; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; c acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic ible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing , coating agents, sweetening, flavoring and perfilming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. The pharmaceutical compositions of this invention can be administered to humans and other animals , ly, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, nts, or drops), buccally, or as an oral or nasal spray.
The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted oir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this ion may contain any tional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the ity of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, utaneous, intravenous, intramuscular, intraarticular, W0 2013/003720 PCT/U82012/044928 intraarterial, intrasynovial, intrastemal, intrathecal, intralesional and intracranial injection or infusion techniques.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active nds, the liquid dosage forms may contain inert ts commonly used in the art such as, for example, water or other solvents, lizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfilryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, fying and suspending agents, sweetening, flavoring, and perfuming agents.
Inj ectable preparations, for example, sterile able aqueous or oleaginous suspensions may be formulated ing to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile inj ectable on, suspension or on in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in tanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this e any bland fixed oil can be employed including tic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of inj es.
The inj ectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating izing agents in the form of sterile solid compositions which can be dissolved or dispersed in e water or other sterile inj ectable medium prior to use.
In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from the injection site. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then s upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Inj ectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers W0 2013/003720 such as ctide or polylactide-co-glycolide. Depending upon the ratio of drug to r and the nature of the particular polymer employed, the rate of drug release can be controlled.
Examples of other biodegradable polymers include poly(orthoesters) and nhydrides).
Depot inj ectable formulations are also prepared by ping the drug in liposomes or microemulsions which are compatible with body tissues.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient ature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Solid dosage forms for oral administration include es, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically able excipient or carrier such as sodium citrate or ium phosphate and/or: a) s or extenders such as starches, lactose, sucrose, glucose, mannitol, and c acid; b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) egrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution ing agents such as paraff1n; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as, for e, cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene s, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
In one embodiment, administration of the microparticles comprising iloprost or another pharmaceutical agent to be administered in addition to iloprost provides local or plasma concentrations sustained at approximately constant values over the intended period of e (e. g., up to 2 to 24 hours, to enable dosing once, twice, three times, four times or more than four times per day). The microparticle formulations may allow ts to take treatments less frequently, and to receive more prolonged and steadier relief.
Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and W0 2013/003720 PCT/U82012/044928 granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluents such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they e the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed . Examples of embedding compositions which can be used include polymeric substances and waxes.
Dosage forms for topical or transdermal administration of a compound of this invention include ointments, , creams, s, gels, powders, solutions, , inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
The ointments, pastes, creams and gels may contain, in addition to an active nd of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or es thereof. s and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these nces. Sprays can onally contain customary propellants such as chlorofluorohydrocarbons.
Transdermal s have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. tion enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate lling membrane or by dispersing the nd in a polymer matrix or gel.
The total daily dose of the compounds of this invention administered to a subject in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight. Single dose compositions may n such amounts or submultiples thereof to make up the daily dose. In general, W0 2013/003720 PCT/U82012/044928 treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 1 mg to about 200 mg of the compound(s) of this invention per day or per weekly or per bi-weekly in single or multiple doses.
Dosing schedules may be adjusted to provide the optimal therapeutic response. For example, administration can be one to three times daily for a time course of one day to several days, weeks, months, and even years, and may even be for the life of the patient.
Practically speaking, a unit dose of any given composition of the invention or active agent can be stered in a variety of dosing schedules, depending on the judgment of the clinician, needs of the patient, and so forth. The specific dosing schedule will be known by those of ry skill in the art or can be determined experimentally using routine methods.
Exemplary dosing schedules include, without limitation, administration five times a day, four times a day, three times a day, twice daily, once daily, every other day, three times , twice weekly, once weekly, twice monthly, once monthly, and so forth.
Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art.
EXAMPLES The compounds and processes of the t invention will be better understood in connection with the ing examples, which are intended as an illustration only and not to limit the scope of the ion. s changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications ing, without limitation, those relating to the chemical structures, substituents, derivatives, formulations and/or methods of the invention may be made without ing from the spirit of the invention and the scope of the appended claims.
Although the invention has been described with respect to various red embodiments, it is not intended to be limited thereto, but rather those skilled in the art will recognize that variations and modifications may be made therein which are within the spirit of the invention and the scope of the appended claims.
The morphinan nds according to the present invention may be synthesized employing methods , for example, in US. Pat. No. 5,250,542, US. Pat. No. 5,434,171, US. Pat. No. 081, and US. Pat. No. 5,270,328. The optically active and commercially available naltrexone that can be employed as starting material in the synthesis of some of the W0 2013/003720 PCT/U82012/044928 nds of the invention may be prepared by the general procedure taught in US. Pat. No. 3,332,950.
Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical ures, substituents, derivatives, formulations and/or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims.
SYNTHESIS OF HETEROCYCLIC BI-ARYLS Exam le 1: S s of ut l4-br0m0 heneth lcarbamate Na2CO3, BocHN Pd(PPh3)4 Me BocZO 300“” H20IMS, DCM Et3N OMe (BHO)2IAN *OMe 6M HCI aq IHAO Bromophenethylamine (50 g, 250 mmol) and triethylamine (105 mL, 750 mmol) were stirred in dichloromethane (DCM; 1.5 L), and cooled to 0°C. Boc anhydride (82 g, 375 mmol) was added and the reaction mixture stirred at room temperature overnight. The reaction mixture was washed with water (1 L), brine (500 mL), dried (MgSO4) and concentrated to give an orange oil. The crude residue was llized from hexane (250 mL) to give a white solid, utyl 4-bromophenethylcarbamate (39.85 g, 133 mmol, 53 %). ' 35 ' Exam le 2: S nthesis of tert—bu l4- 2 4-dimeth0x rimidin-S- y] )phenethylcarbamate Industrial methylated spirits (IMS; 15 mL) and water (5 mL) were degassed thoroughly. tert-butyl 4-bromophenethylcarbamate (1.08 g, 3.63 mmol), sodium carbonate (1.54 g, 14.52 mmol), palladium tetrakis (0.42 g, 0.36 mmol) and 2,4-dimethoxy pyrimidinylboronic acid (1.00 g, 5.44 mmol) were added and the reaction mixture heated to 90°C for 18 hours. No starting material was observed by LCMS. Water (100 ml) and ethyl acetate (300 ml) were added and the organic layer ted. The organic layer was washed with water (100 ml), dried (MgSO4) and concentrated to give a yellow oil. The crude residue was t to column chromatography (20 to 60 % ethyl acetate/hexane) to give a yellow oil, tert-butyl 4-(2,4-dimethoxypyrimidinyl) phenethylcarbamate, which crystallized on standing (1.18 g, 3.28 mmol, 91 %).
Example 3: Synthesis of 5- 4- 2-amin0eth l hen l rimidine-2 4 1H 3H -di0ne hydrochloride To tert-butyl 4-(2,4-dimethoxypyrimidinyl) phenethylcarbamate (0.5 g, 1.39 mmol) was added s hydrochloric acid (6 M, 15 mL) and the reaction e stirred at reflux for 4 hours. No starting material was observed by LCMS. The precipitate was filtered, washed with water (5 mL) and dried under reduced pressure (50 °C) to give a pale yellow solid, 5-(4-(2-aminoethyl) phenyl) pyrimidine-2,4(1H,3H)—dione hydrochloride (0.32 g, 1.35 mmol, 86 %).
, B00HN BOCHN\/\©\ IMS, H20 j:o \ N Br | OB‘CNQ I N C HCI/dioxane HCI |\N W0 2013/003720 PCT/U82012/044928 Example 4: Synthesis of utyl 40x0-1,6-dihydropyridin ylmhenethylcarbamate IMS (50 mL) and water (16 mL) were degassed thoroughly. tert-Butyl 4- bromophenethylcarbamate (3.52 g, 11.7 mmol), sodium carbonate (5.0 g, 46.9 mmol), palladium tetrakis (1.35 g, 1.2 mmol) and yl-1H-pyrazoleboronic acid pinacol ester (5.0 g, 17.6 mmol) were added and the reaction mixture heated to 90°C overnight. The reaction was partitioned between ethyl acetate (500 mL) and water (250 mL) and brine (250 mL), then dried (MgSO4). Filtration and removal of the solvent gave the crude e which was subject to column chromatography (50 % ethyl acetate/heptane) to give tert-butyl 4-(6- oxo-1,6-dihydropyridinyl) hylcarbamate (4.2 g, 11.1 mmol, 95 % yield).
Exam le 5: S nthesis of 2- 4- l-Benz l-1H- razol l hen l ethanamine hydrochloride To tert-butyl 4-(6-oxo-1,6-dihydropyridinyl) phenethylcarbamate (4.2 g, 11.1 mmol) was added HCl/dioxane (approximately 4 M, 100 mL). After 5 minutes, the reaction mixture had stopped stirring and a further 50mL HCl/dioxane was added. The on was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure giving 2-(4-(1-benzyl-1H-pyrazolyl)phenyl) ethanamine hydrochloride as a yellow solid (4.0 g, 11.1 mmol, 100 % yield).
Na2CO3, B00HN Pd(PPh3)4 BOCHN\/\©\ IMS, H20 Br I (HO)2 aB / N OMe N OMe 6M HCI aq N O H Exam le 6: S nthesis of tert-But l4— 6-0x0-1 6-dih dro y] )phenethylcarbamate IMS (600 mL) and water (250 mL) were degassed thoroughly. tert-Butyl 4- bromophenethylcarbamate (32.7 g, 109 mmol), sodium carbonate (46.2 g, 436 mmol), palladium tetrakis (12.6 g, 11.0 mmol) and 2-methoxypyridine boronoic acid (25.0 g, 163 mmol) were added and the reaction mixture heated to 90°C for 18 hours. The reaction was cooled to room temperature, filtered and the residue washed with IMS (100 mL) and ethyl acetate (1 L). The filtrate was washed with water (500 mL), dried (MgSO4) and concentrated to give a brown solid. The crude residue was subject to column chromatography (0 to 1.5 % MeOH in DCM) to give a white solid, utyl xo-1,6-dihydropyridinyl) hylcarbamate (20.95 g, 63.8 mmol, 58 % yield).
Exam le 7: S sthesis of 5- 4- 2-Amin0eth l hen l ridin-Z 1H -one h drochloride To tert-butyl 4-(6-oxo-1,6-dihydropyridinyl) phenethylcarbamate (10.25 g, 31.0 mmol) was added aqueous hydrochloric acid (6 M, 220 mL) and the reaction e stirred at reflux overnight. The reaction was cooled to room temperature and the precipitate was d, washed with water (5 mL) and dried under reduced pressure (50 °C). The acidic solution was concentrated under reduced pressure and the resultant solid ed with the filtered solid to give 2-aminoethyl) phenyl) pyridin-2(1H)-one hydrochloride (7.80 g, 31.0 mmol, 100 % yield).
SYNTHESIS OF OPIOIDS NHS/Pd(OAc)2 OH Xantphos/TEA AcOH/conc. HCI DMSO/CO ow“ 0 TfO o HCI . NH {‘0 O OW220 Compound-4 Compound-12 W0 2013/003720 Example 8 : Synthesis of nd 4 To a solution of the crude nd 12 (52 g) in acetic acid (1 L) at 90°C was added concentrated HCl (35 mL). To this was then added zinc powder (64g, 0.98 mol) over minutes and after complete addition a further portion of concentrated HCl (40 mL) was added over 5 minutes. To the reaction mixture was then added a second portion of zinc powder (64g, 0.98 mol) over 1 hour. After 30 minutes a third portion of zinc powder (32g, 0.49 mol) and the reaction heated a further 1 hour. The reaction was cooled to ~60°C and filtered and the zinc residue washed with warm acetic acid. The filtrate was concentrated under reduced pressure and the e d with concentrated ammonia (1 L) and 2- methyltetrahydrofuran (1 L) and waster (0.5 L). The mixture was stirred for 10 minutes and the liquids decanted from the brown gum. The gum was washed with water and all the liquid combined. The organic phase was separated, dried over MgSO4 and combined with the brown gum and concentrated under d pressure. The resulting residue was dissolved in dichloromethane/methanol (8:2) and columned on a short plug of silica eluting with dichloromethane/methanol (8:2) and then dichloromethane/methanol/triethylamine (16:3: 1).
The product containing fractions were evaporated and re-columned eluting with romethane/methanol (9: 1) and then dichloromethane/(16% NHg/methanol) (9:1). The product obtained from this was then fithher purified by prep. HPLC to give Compound 4;LC/MS 545 (M+H)+; NMR(DMSO-D6): 1.30-2.10 (6H, rn), .05 (11H, rn), 3.10-3.60 (2H, m), 4.04 (1H, bs), 4.58 (1H, s), 6.42 (1H, bs), 7.19 (2H, d), 7.40-7.60 (5H, rn), 10.45 (3H, bs).
Example 9: Synthesis of Compounds 13 and 14 / )3, Compound-13 Compound-14 W0 2013/003720 A solution of (5a)-N-[2-(4-bromophenyl)ethyl]hydroxymethyloxo-4,5- epoxymorphinancarboxamide (1.7 g, 3.3 mmol) in denatured ethanol (15mL) was degassed with argon for 20min and then N32C03 (1.4 g, 13.3 mmol), 2,4- dimethoxypyrimidinylboronic acid (0.92 g, 5.0 mmol), degassed water (5 mL) and Pd(PPh3)4 (0.38 g, 0.33 mmol) added. The reaction was sealed and heated in a microwave reactor at 120°C for 25 min. The reaction was concentrated to ~10 mL, diluted with dichloromethane (50 mL) and washed with water (40 mL). The organic phase was dried over MgSO4, filtered and evaporated. The residue was fiarther purified on silica eluting with dichloromethane to methanol/dichloromethane (1:9). The product containing fraction were re-purified on silica eluting with dichloromethane/ethyl acetate (9: 1) to dichloromethane/ethyl acetate/methanol (8:1:1) to give the Compound 13 (1.38 g, 73%) as a yellow oil.
To a e of Compound 13 (0.70 g, 1.2 mmol) and sodium iodide (1.33 g, 4.9 mmol) in anhydrous itrile (8 mL) was added chlorotrimethylsilane (0.63 mL, 4.9 mmol) and the reaction mixture stirred for 5h. The reaction mixture was diluted with 5% s sodium sulfite (5 mL) and water (10 mL) and then made basic with saturated aqueous sodium carbonate. This was ted with twice with dichloromethane (80 mL) and once with ethyl e (50 mL). The c layers were combined and evaporated to give a yellow solid. This was partially dissolved in 2M HCl and the insoluble material was filtered off with celite. The aqueous phase was made basic with saturated sodium carbonate and the resulting white solid filtered and dried under vacuum. This was then purified on silica eluting with dichloromethane/methanol (9: 1) to give Compound 14 (197mg). Compound 14 was dissolved in dichloromethane (5 mL) and 4M HCl in diethyl ether (40mL) added. The mixture was stirred for 2.5h and ated to give the de salt of Compound 14 ( (0.21g, 29%) as a white solid; LC/MS 543 (M+H)+; NMR(DMSO-D6): 1.40-1.57 (2H, m), 1.90-2.01 (1H, m), .20 (1H, m), 2.58-2.70 (1H, m), 2.75-2.92 (5H, m), 2.92-3.15 (3H, m), 3.30-3.65 (4H, m), 5.31 (1H, s), 6.79 (1H, s), 6.93 (1H, d), 7.26 (2H, d), 7.44 (2H, d), 7.55 (1H, d), 7.60-7.70 (2H, m), 9.36 (1H, bs), 11.10 (1H, bs), 11.20 (1H, bs).
W0 2013/003720 Example 10: Synthesis of Compound 10 N/ N/ N/ NHS/Pd(OAc)2 OH Xantphos/TEA AcOH/conc.HC| OH O Zn —> —> O\\\“ o O O TfO O HWO O OH O NH NH NH O 0 Compound 10 Compound 15 Oxymorphone triflate (3.0 g, 7.0 mmol) was stirred in degassed DMSO (40 mL). N- hydroxysuccinimide (1.60 g, 13.9 mmol) was added followed by triethylamine (1.94 mL, 13.9 mmol), palladium acetate (156 mg, 0.7 mmol) and xantphos (402 mg, 0.7 mmol). The reaction mixture was stirred at 70°C under an atmosphere of CO overnight. Further palladium acetate (1.04 g, 4.61 mmol) and xantphos (2.68 g, 4.63 mmol) were added and the reaction mixture heated 6 hours 70 °C under an atmosphere of CO. The mixture was allowed to return to room temperature before the addition of 4-(4-(2-amin0ethyl)phenyl)pyridin-2(1H)—0ne hydrochloride (2.0 g, 8.0 mmol) and ylamine (2 mL, 14.3 mmol). The reaction was stirred for 1 hour before removal of the DMSO under reduced pressure. The residue was subject to column chromatography (0 to 5 % MeOH (NH3) in DCM). The isolated e was found to still contain DMSO and was portioned between DCM (500 mL) and water (250 mL). The aqueous phase was extracted a further five times until the product was tely extracted. The c phases were ed and the solvent removed under reduced pressure giving (4R,4aS,7aR,12bS)-4a-hydroxymethyl0x0-N—(4-(2-0x0-1,2- dihydropyridinyl)phenethyl)-2,3 ,4,4a,5 ,6,7,7a-0ctahydr0-1H-4, 12-methan0benz0furo [3 ,2- e]isoquinolinecarboxamide (Compound-15; 1.2 g, 2.3 mmol, 33 % yield).
To a solution of the crude Compound-15 (52 g) in acetic acid (55 mL) was added zinc powder (3.03 g, 45.8 mmol) followed by concentrated ) (2 mL). The reaction was heated at 90 0C for 2 hours. The reaction mixture was allowed to cool to 60 oC and filtered.
The zinc residue was washed with r acetic acid (30 mL). The combined acetic acid solutions were trated under reduced pressure. The residue was basified with ammonium ide solution (28 %) and extracted with Me-THF (2 x 250 mL). The organic phase was dried (MgSO4), filtered, and the solvent removed under reduced pressure.
W0 03720 2012/044928 The crude product was subject to column chromatography (0 to 5 % MeOH (NH3) in DCM) followed by prep-HPLC to give nd 10 (4,14-dihydroxy-N- {2-[4-(2-hydroxypyridin- 4-yl)phenyl]ethyl}-l7-methyloxomorphinancarboxamide) (378 mg, 0.72 mmol, 31 % yield) as a white solid; LC/MS 528 (M+H)+; NMR(DMSO-D6): 5337_lH-3.jdf: 1.45 (1H, d), 1.58-2.10 (4H), 1.8 (3H, s), 2.19-2.38 (1H, m), 2.40-3.10 (10H, m), 3.78 (1H, d), 4.68 (1H, bs), 6.46 (1H, dd), 6.53 (1H, s), 6.61 (1H, d), 7.31 (2H, d), 7.39 (1H, d), 7.53 (1H, d), 7.60 (2H, d), 8.96 (1H, bs).
Example 11: Synthesis of Compound 7 OH OMe OMe NaH, MeI, DMF Conc. HCI, MeOH —> —> \\\“ 0 0 \“v od O““- BnO 0d 0 BnO HO o PhTfZO N/ NHS/Pd(OAc)2 N/ 0M6 Xantphos/TEA DMSO/CO H2N O OH NH O\\\ o o A616} TfO 0 NH no / ):o Compound 7 Compound 16 To an ice cold solution of (4a'S,7a'R)-9'-(benzyloxy)-3'-methyl-l',2',3',4',5',6'- hexahydro-4a'H-spiro[ l ,3-dioxolane-2,7'-[4, l 2]methano[ l ]benzofuro[3 ,2-e]isoquinolin]-4a'- 01 (10 g, 23 mmol) in DMF (100 mL) was added portionwise sodium hydride (4.6 g, 115 mmol). The mixture was stirred cold for 2 hours then methyl iodide (2.9 mL, 45.9 mmol) was added in one portion. The reaction was warmed to room temperature and stirred overnight.
The mixture was poured into water (500 mL) and extracted into DCM (2 x 500 mL). The organic layer was washed with water (3 x 300 mL) and brine (300 mL), dried (MgSO4), d and concentrated to give the crude t. The product was purified by silica W0 2013/003720 column chromatography (eluting 0-10 % ammonia/methanol in DCM) to give the product S,7aR,12bS)(benzyloxy)-4a-methoxymethyl-1,2,3 ,4,4a,5 ,6,7a- octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2'-[1,3]dioxolane] as a viscous yellow oil (7.3 g, 71 % yield).
To a solution of (4R,4aS,7aR,12bS)(benzyloxy)-4a-methoxymethyl- 1,2,3 ,4,4a,5 ,6,7a-octahydrospiro[4,12-methanobenzofuro[3 ,2-e]isoquinoline-7,2'- [1,3]dioxolane] (7.3 g, 16.2 mmol) in MeOH (75 mL) was added conc. HCl (50 mL). The mixture was refluxed for 5 hours then cooled with an ice bath. Concentrated a (25 %) was added until pH 8 was reached. The mixture was concentrated and the residues stirred with 10 % MeOH/DCM (1 L) overnight. The mixture was filtered and the liquors trated to give (4R,4aS,7aR,12bS)hydroxy-4a-methoxymethyl-2,3,4,4a,5,6- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)—oneas a dark red oil (5.3 g , quantitative yields).
A mixture of (4R,4aS,7aR,12bS)hydroxy-4a-methoxymethyl-2,3,4,4a,5,6- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one (5.1 g, 16.2 mmol), N- Phenylbis(trifluoromethanesulfonamide) (6 g, 16.7 mmol), triethylamine (6.8 mL, 48.5 mmol) and DCM (80 mL) was d at room temperature overnight. The mixture was concentrated under reduced pressure to give the crude product still containing ing reagent. This was dissolved in 4:1 e of ethyl e/hexane (200 mL) and washed with water (5 x 150 mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to give the product (4R,4aS,7aR,12bS)—4a-methoxymethyloxo- 2,3 ,4,4a,5 ,6,7,7a-octahydro-1H-4,12-methanobenzofi1ro[3 ,2-e]isoquinolinyl trifluoromethanesulfonate as a brown oil (5.9 g, 81 % yield). Compounds 7 and 16 were synthesized from the above intermediate in a similar procedure as in the synthesis of compounds 10 and 15.
W0 2013/003720 PCT/U82012/044928 Exam le 12: S s of Com ound 11 H 002H / \ / N/ N/ N +N ‘020\d OH OH OH OH —> —> —> o 0‘“ o 0 OH 0 0 0H 0 0 0H 0 NH NH NH NH N / NH Br Br /_\>_O /_ >20 N N 1 2 3 Compound 11 A mixture of (5a)-N-[2-(4-bromophenyl)ethyl]hydroxymethyloxo-4,5- epoxymorphinancarboxamide (1) (10 g, 19.6 mmol), denatured ethanol (300 mL), zinc powder (28 g, 0.43 mol) and ammonium chloride (34.5 g, 0.65 mol) was heated at reflux for 30min and then cooled to ~40°C. The on mixture was filtered through celite and washed with denatured ethanol (300 mL, 40°C). The volatiles were removed under vacuum and the e partitioned between dichloromethane (200mL) and 2% s ammonia (300 mL).
The aqueous phase was further extracted with dichloromethane (2x200mL) and the ed organics were dried over MgSO4 and evaporated. The residue was purified on silica eluting with dichloromethane/methanol (95 :5 to 9: 1) to give N-[2-(4-bromophenyl)ethyl]-4,14- dihydroxymethyloxomorphinancarboxamide (2) (7.95 g, 79%) as a brown solid.
To a degassed mixture of ethanol and water (4:1, 20 mL) was added 2- methoxypyrimidinylboronic acid (0.67 g, 4.4 mmol), N32C03 (1.24 g, 11.7 mmol) and N- [2-(4-bromophenyl)ethyl] -4, 14-dihydroxymethyloxomorphinancarboxamide (2) (1.5 g, 2.9 mmol). The reaction e was further degassed and then Pd(PPh3)4 (0.32 g, 0.3 mmol) added. The reaction mixture was heated in a microwave reactor at 120°C for 25min. and . The reaction mixture was diluted with ethyl acetate (50mL) and washed with 1:1 brine/water (3x35mL). The c phase was dried over MgSO4, filtered and evaporated.
The resulting residue was further purified on silica eluting with dichloromethane /methanol (9: 1) to give 4,14-dihydroxy-N- {2-[4-(2-methoxypyrimidinyl)phenyl]ethyl}methyl oxomorphinancarboxamide (3) (0.50g, 32%) as a yellow foam.
A mixture of 4,14-dihydroxy-N- {2-[4-(2-methoxypyrimidinyl)phenyl]ethyl} methyloxomorphinancarboxamide (3) (0.5 g, 0.9 mmol) and pyridine hydrochloride (5 mL) was heated at 150°C for 6h. The on mixture was cooled, basified with saturated aqueous sodium bicarbonate and extracted with dichloromethane (3x40 mL). The aqueous phase was filtered and the collected brown solid was combined with the organic washes and evaporated to s. The residue was purified on silica eluting with W0 2013/003720 romethane/methanol (9: 1) to dichloromethane/16% NH3 in methanol (9: 1) to give 4,14- dihydroxy- 1 7-methyloxo-N- {2- oxo-1 ,2-dihydropyrimidin-5 - yl)phenyl]ethyl}morphinancarboxamide (RDC6139) (0.15g) as a white solid. This was dissolved in dichloromethane/methanol (3: 1, 20 mL) and maleic acid (32 mg, 1eq) added.
The reaction mixture was stirred for 4h and then the volatiles removed under vacuum at 40°C.
The residue was freeze dried from water to give Compound 11 4,14-dihydroxymethyl oxo-N- {2-[4-(2-oxo-1 ,2-dihydropyrimidin-5 -yl)phenyl]ethyl}morphinancarboxamide e salt(0.17g, 98%) as a white solid; LC/MS 529 (M+H)+; NMR(D20): .21 (4H, m), 1.49-1.60 (1H, m), 1.65-1.90 (3H, m), 2.10-2.22 (1H, m), 2.29 -2.41 (1H, m), 2.50-2.72 (5H, m), 2.90-3.00 (1H, m), .40 (3H, m), 3.45-3.60 (2H, m), 6.04 (2H, s), 6.95-7.05 (4H, m), 7.26 (1H, m), 8.11 (2H, bs).
Example 13: Synthesis of Compound 5 N/ N/ N/ NHS/Pd(OAc)2 PhTfZO Xantphos/TEA DMSO/CO —’ fl 0‘“ 0““ 0““ HO o TfO 0 RES 0 o H NH Hydromorphone HCI WtoNHNH Compound 17 l AcOH/conc.HC| 0:: OH 20 / ):o Compound 5 NH A mixture of Hydromorphone HCl (100 g, 0.31 mol), N- Phenylbis(trifluoromethanesulfonamide) (114 g, 0.32 mol), diisopropylethylamine (215 mL, 1.24 mol) and DCM (2 L) was stirred at room temperature overnight. The mixture was ' 45 ' concentrated under reduced pressure to give the crude product still containing trifiating reagent. This was dissolved in 4:1 mixture of ethyl acetate/hexane (1 L) and washed with water (6 x 1 L). The organic layer was dried (MgSO4), filtered and trated under reduced re to give the product(4R,7aR,12bS)—3-methyloxo-2,3,4,4a,5,6,7,7a- octahydro-lH-4,12-methanobenzofuro[3,2-e]isoquinolinyl trifiuoromethanesulfonate as a white solid (120 g, 93 % yield) (4R,7aR,12bS)—3-methyloxo-2,3,4,4a,5,6,7,7a-octahydro- 1H-4,12-methanobenzofi1ro[3,2-e]isoquinolinyl trifiuoromethanesulfonate (5 g, 11.98 mmol) was stirred in degassed DMSO (80 mL). N—hydroxysuccinimide (2.76 g, 23.96 mmol) was added followed by triethylamine (3.3 mL, 23.96 mmol), palladium acetate (0.27 g, 1.2 mmol) and os (0.69 g, 1.2 mmol). The reaction mixture was stirred at 70 °C under an atmosphere of CO overnight. The e was allowed to return to room temperature before the addition of 2-aminoethyl)phenyl)pyrimidine-2,4(1H,3H)-dione hydrochloride (3.2 g, 11.98 mmol) and triethylamine (3.3 mL, 23.96 mmol). The reaction was stirred for 5 hours before removal of the DMSO under reduced pressure. The residue was stirred with DCM and filtered to give a brown solid, which was used as it was for the next step (4R,7aR, 12bS)—N— (4-(2,4-dioxo- 1 ,2,3 ,4-tetrahydropyrimidin-5 -yl)phenethyl)-3 -methyloxo-2,3 ,4,4a,5 ,6,7,7aoctahydro-1H-4 ,12-methanobenzofuro[3,2-e]isoquinolinecarboxamide (6 g, 79 % crude yield).
To a solution of the crude (4R,7aR,12bS)—N—(4-(2,4-dioxo-1,2,3,4- tetrahydropyrimidinyl)phenethyl)methyloxo-2,3 5 ,6,7,7a-octahydro-1H-4, 12- methanobenzofuro[3,2-e]isoquinolinecarboxamide (5 g) in acetic acid (200 mL) was added zinc powder (12.6 g, 190 mmol) followed by concentrated HCl(aq) (7.5 mL). The reaction was heated at 90 0C for 2.5 hours. Further zinc powder (47.6 g, 717 mmol) was added portionwise over 24 hours. After cooling to room temperature, the zinc salts were removed by filtration and washed with further acetic acid (80 mL). The combined acetic acid solutions were concentrated under reduced pressure. The residue was basified with ammonium hydroxide solution (28 %) and extracted with Me-THF (3 x 500 mL). The organic phase was dried (MgSO4), filtered, and the solvent removed under reduced pressure.
The crude product purified by prep-HPLC to give Compound 5 (4bS,9R)-N—(4-(2,4-dioxo- 1 ,2,3 ,4-tetrahydropyrimidin-5 -yl)phenethyl)hydroxy-1 yloxo-6,7, 8 ,8a,9,10- hexahydro-5H-9,4b-(epiminoethano)phenanthrenecarboxamide as a white solid (0.89 g, 18 % yield); LC/MS 529 (M+H)+; SO-D6): .50 (1H, m), 1.55-1.89 (4H, m), 1.98 (1H, d), 2.05-3.00 (7H, m), 3.20-3.60 (6H, m), 4.01 (1H, d), 6.61 (1H, d), 7.19 (2H,d), 7.45 (2H, d), 7.50-7.64 (4H, m), 8.90 (1H, bs), 11.20 (1H, bs), 13.86 (1H, bs).
W0 2013/003720 Example 14: Synthesis of Compound 2 —> —> KHco3 0‘“ DM F HO 0 \“' \\" HO O TfO O Noroxymorphone "'2N o NHS/Pd(OAc)2 HCI NH os/TEA Nto DMSO/CO W© W© OH AcOH/conc.HC| OH O\\“' OH o O o O NH NH NH NH / >20 / >20 O 0 Compound 2 Compound 18 A mixture ofNoroxymorphone (40.0 g, 139.2 mmol), potassium hydrogen carbonate (27.9 g, 278.7 mmol), and (2-bromoethyl)benzene (47.6 mL, 348.0 mmol) in DMF (750 mL) was heated at 70°C overnight. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (800 mL) and water (500 mL). The organic phase was dried (MgSO4), d and the solvent removed under reduced re. To the crude residue was stirred with a mixture of 2N HCl(aq) (500 mL) and ethyl acetate (500 mL). The resultant precipitate was ed by filtration, washed with water and dried (50 CC) giving (4R,4aS,7aR,12bS)-4a,9-dihydr0xy phenethyl-2,3,4,4a,5,6-hexahydr0-1H-4,12-methanobenzofur0[3,2-e]isoquinolin-7(7aH)-0ne hydrochloride (46.6 g, 109.0 mmol, 78 % yield).
To a suspension of (4R,4aS,7aR,12bS)—4a,9-dihydr0xyphenethyl-2,3,4,4a,5,6- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one hydrochloride (46.6 g, 109.0 mmol) in DCM (1 L) was added diisopropylethylamine (76 mL, 435.9 mmol) ed by N-phenylbis(trifluoromethanesulfonamide) (40.1 g, 112.2 mmol). The reaction was stirred at room temperature overnight. The solvent was d under reduced pressure and the ' 47 ' e dissolved in 4:1 ethyl acetate:hexane (500 mL total). The organic phase was washed with water (6 x 500 mL) and dried (MgSO4). Filtration and removal of the solvent under reduced pressure gave 4R,4aS,7aR,12bS)-4a-hydroxyoxophenethyl-2,3,4,4a,5,6,7,7a- octahydro- 1 H-4, 12-methanobenzofuro [3 ,2-e]isoquinolinyl trifluoromethanesulfonate (5 7.0 g, 109.0 mmol, 100 % yield) as an orange oil. 4R,4aS,7aR,12bS)-4a-hydroxyoxophenethyl-2,3,4,4a,5,6,7,7a-octahydro-1H- 4,12-methanobenzofi1ro[3,2-e]isoquinolinyl trifluoromethanesulfonate (6.26 g, 12.0 mmol) was stirred in ed DMSO (80 mL). N—hydroxysuccinimide (2.76 g, 24.0 mmol) was added followed by ylamine (3.34 mL, 24.0 mmol), ium acetate (269 mg, 1.2 mmol) and xantphos (693 mg, 1.2 mmol). The reaction e was stirred at 70 °C under an atmosphere of CO overnight. The mixture was allowed to return to room temperature before the addition of 5-(4-(2-aminoethyl)phenyl)pyrimidine-2,4(1H,3H)-dione hydrochloride (2.0g, 8.0 mmol) and triethylamine (1.7 mL, 12.0 mmol). The reaction was stirred for 3 hours before removal of the DMSO under d pressure. The residue was subject to column chromatography (0 to 3 % MeOH(NH3) in DCM). The organic phases were combined and the solvent removed under reduced pressure giving (5a)-N- {2-[4-(2,4-dioxo-1,2,3,4- tetrahydropyrimidinyl)phenyl]ethyl} - 14-hydroxyoxo-1 henylethyl)-4,5 - epoxymorphinancarboxamide (Compound-18; 4.7 g, 7.4 mmol, 62 % yield).
To a solution of N— {2-[4-(2,4-dioxo-1,2,3,4-tetrahydropyrimidinyl)phenyl]ethyl}- 14-hydroxyoxo(2-phenylethyl)-4,5-epoxymorphinancarboxamide (Compound-18) (4.7 g, 7.4 mmol) in acetic acid (200 mL) was added zinc powder (14.6 g, 223 mmol) followed by concentrated HCl(aq) (8 mL). The reaction was heated at 90 0C for 1 hour after which time filrther zinc powder (14.6 g) was added. The reaction was maintained at the same temperature for an additional 2 hours. The reaction mixture was allowed to cool and filtered.
The zinc residue was washed with further acetic acid (100 mL). The ed acetic acid solutions were concentrated under reduced pressure. The residue was basified with ammonium hydroxide solution (28 %) and the itated solid isolated by filtration. The precipitate was washed with water and dried overnight in a dessicator. The material was purified by prep-HPLC to give Compound 2 N- {2-[4-(2,4-Dioxo-1,2,3,4- tetrahydropyrimidinyl)phenyl] ethyl} -4, 14-dihydroxyoxo- 1 7-(2-phenylethyl)morphinan- 3-carboxamide (1.17 g, 1.85 mmol, 25 % yield) as a white solid; LC/MS 635 ; NMR(DMSO-D6): 5029_1H-3.jdf: 1.40-1.50 (1H, m), 1.60-1.70 (2H, m), 1.78-1.95 (3H, m), 2.50-2.58 (2H, m), .67 (3H, m), 2.68-2.77 (3H, m), 2.78-2.90 (4H, m), 2.91- W0 2013/003720 PCT/U82012/044928 3.20 (2H, m), 3.77 (1H, d), 4.30 (1H, s), 6.61 (1H, d), 7.10—7.32 (7H, m), 7.44 (2H, d), 7.54 (2H, d), 8.91 (1H, t), 11.07 (1H, bs), 11.20 (1H, bs), 13.94 (1H, bs).
Example 15: Determination of binding ies for mu: delta and kappa receptors Receptor Binding (in vitro Assay) The K (binding affinity) for u-, 5-, and K-receptors was determined with a previously bed method using a itive displacement assay (Neumeyer, 2003). Membrane protein from CHO (Chinese Hamster Ovarian) cells that stably expressed one type of the cloned human opioid receptor were incubated with 12 different concentrations of the compound in the presence of 0.25 nM [3H]DAMGO, 0.2 nM [3H]naltrindole or 1 nM [3H]U69,593 in a final volume of 1 mL of 50 mM Tris—HCl, pH 7.5 at 25 0 C. tion times of 60 min were used for [3H]DAMGO and [3H]U69,593. Because of a slower association of [3H]naltrindole with the receptor, a 3 h incubation was used with this igand. Samples incubated with [3H]naltrindole also contained 10 mM MgClz and 0.5 mM phenylmethylsulfonyl fluoride. Nonspecific binding was measured by ion of uM naloxone. The binding was terminated by filtering the samples through Schleicher & Schuell N0. 32 glass fiber filters using a l 48-well cell harvester. The filters were subsequently washed three times with 3 mL of cold 50 mM Tris—HCl, pH 7.5, and were counted in 2 mL Ecoscint A scintillation fluid. For [3H]naltrindole and [3H]U69,593 binding, the filters were soaked in 0.1% polyethylenimine for at least 60 min before use. IC50 values will be calculated by least s fit to a logarithm-probit analysis. Ki values of unlabelled compounds were calculated from the equation Ki = (IC50)/l + S where S = (concentration of radioligand)/(Kd of radioligand) (Cheng and Prusoff, 1973).
W0 03720 PCT/U82012/044928 Exam le 16: Functional Activi GTP SBindin The [3SS]GTPyS assay measures the fiJnctional properties of a compound by quantifying the level of G-protein activation following agonist g in studies using stably transfected cells, and is ered to be a measure of the efficacy of a compound.
Membranes from CHO (Chinese Hamster Ovary) cells that stably expressed the cloned human Mu opioid or were used in the ments. In a final volume of 0.5 mL, 12 different concentrations of each test compound were incubated with 7.5 ug of CHO cell membranes that stably expressed the human u opioid receptor. The assay buffer consisted of 50mM Tris-HCl, pH 7.4, 3 mM MgClz, 0.2 mM EGTA, 3 uM GDP, and 100 mM NaCl. The final concentration of [35$]GTPyS was 0.080 nM. Nonspecific binding was measured by inclusion of 10 uM GTPyS. Binding was initiated by the addition of the membranes. After an incubation of 60 min at 30°C, the samples were filtered through cher & Schuell No. 32 glass fiber filters. The filters were washed three times with cold 50 mM Tris-HCl, pH 7.5, and were counted in 2 mL of Ecoscint scintillation fluid. Data are the mean Emax and EC50 values :: S.E.M. For calculation of the Emax values, the basal [35S]GTPyS binding was set at 0%, and the 100% [35S]GTPyS binding level was set at the maximum binding achieved with DAMGO. Compounds in Table D show [35S]GTPyS binding EC50 values between 1.3 nM and 300 nM with Emax values between 70 % and 140 %.
Example 17: In vivo oral studies Groups of mice (n=5 per group; >60 days; 20-25 grams weight) were dosed with vehicle (0.9% sterile saline) or test compounds (10 mg/kg free base, SC) 30 minutes before the first observation period. The occurrence of Straub tail, piloerection, hyperlocomotion, hypolocomotion, circling of the cage, sedation, breathing abnormalities, diuresis, e activity and occurrences of death were recorded at 0.5, l, 2, 4, 6 and 24 hours ing dosing.
The data below shows peripheral restriction for a series of compounds. This is tested with our clinical observation assay where mice are injected with 10 mg/kg subcutaneously with drug and the behaviors are noted over 24 hours. At the 10 mg/kg SC dose both morphine (Compound-A) and nd-B show severe effects that reflect mu agonism in the brain, with observed ity in the Compound-B group. In the heteroaryl compounds tested the behavioral effects and mortality was not observed.
W0 2013/003720 The binding affinities of Compounds 1-11 are given in Table D Clinical ations g affinity In vitro after functional agonism for mg/kg u receptor subcutaneous in'ection K (Ki, 8 (K, Agonist? nm) nm) Multiple central 11 nervous system like effects: Straub tail, hyperlocomotion, circling Angioedema; Straub tail, hypolocomotion, mortality WO 03720 ' 51 ' ' 52 ' Exam le 18: CFA Induced Wei ht Bearin Deficits in Rats Animals were ated to the weight bearing test apparatus for 2 days prior to the start of the experiment. On Day 0, rats were tested in the weight bearing apparatus to measure ne weight bearing of untreated hind paws. Following baseline testing, animals were injected intra-plantar with Complete Freund’s Adjuvant (CFA). Using a syringe with a locking hub and 25G needle, rats were injected Via rear, left intra-plantar administration with 100 uL of 100% CFA (l l) while under light isofluorane anesthesia. No treatment was administered to the right, rear, contralateral paw. ' 53 ' The treatment with ne or Compound 4 (Intra-articular) was given after at the onset of arthritis in CFA treated rats (Day 1). Intra-plantar test-compound administration was done while the animal was under light (3%) isofluorane anesthesia using 0.3ml insulin syringe. The amount of anesthesia given to the animal during test compound administration was limited to a very short duration, so not to impede measurement of weight bearing at the 5 minute time point. On Day 1 (24 hrs post CFA), rats were tested in the weight g apparatus to measure CFA-induced changes in weight bearing. Following testing, animals were injected intra-plantar with test compound (morphine or Compound 4) in a total volume of SOul containing 3, 10 or 100ug doses. The inhibitory effect of ne on the analgesic effects of nd 4 and morphine (10ug/paw) was tested by concurrent intra-plantar administration of 75ug naloxone methiodide, a peripherally restricted opioid antagonist.
Following test nd administration, s were retested in the weight bearing apparatus at the following time points: 5, 15, 30, 60 and 120 s post-test compound stration. s were retested on Day 2 (post-CFA) if there is a significant change in CFA induced weight bearing at the 120 minute time point on Day 1.
The administration (intra-plantar) of Compound 4 produced a dose-dependent al of CFA-induced weight bearing deficits at 3, 10 and 30 ug/paw.The analgesic effects of Compound 4, was comparable to that seen with Morphine (FIGS. 1 and 2). The analgesic effects of Compound 4 or Morphine (lOug/paw) are icantly inhibited by concurrent plantar administration of 75ug naloxone methiodide, a peripherally restricted opioid antagonist. The blockade of analgesia by intraplantar naloxone methiodide administration is suggestive of peripheral sic effects of Compound 4 and morphine.
Example 19: Rat Hot Plate model of centrally mediated analgesia The potential antinociceptive properties of subcutaneous (SC) administration of Compound 4 were assessed at doses of 10, 30, and 100 mg/kg in the rat hot plate test of antinociception. Morphine (used as a reference compound) produced maximal (60 sec) antinociception when administered SC at 7.5 mg/kg (shown here, and in previous in-house experiments). ' 54 ' Rats were tested for a baseline hot plate response (latency time for a paw on a hot plate set to 525°C) immediately prior to dosing with Compound 4 or morphine (7.5 mg/kg) by SC injection. Rats were then tested on the hot plate 5, 30, 60, 120, 240 and 360 minutes later. The amount of time it took to lick one hind paw is measured and is considered the response latency. The mean and SEM of the responses latencies for each experimental group were calculated and a line depicting mean hot plate y vs. time was generated using GraphPad Prism. An increase in mean response latency above baseline ing test nd administration is tive of an antinociceptive effect. nd 4 was significantly less active than morphine in hot plate, with sub- maximal efficacy at the highest dose tested (100 mg/kg), suggesting significant peripheral restriction of nd 4 (.
Example 20: Formalin model of pain Nonfasted male Harlan rats were assigned to treatment group according to a randomized block study design to balance for test chamber and time of day, and day of test (if applicable). Each rat was administered either vehicle or test compound subcutaneously and then placed in their assigned test chamber and acclimated for 25-30 minutes with the chamber enclosure door left open. Data was not collected during this . Following the acclimation period, each rat was removed individually starting with chamber 1, and dosed 5% in subcutaneously into the right rear paw plantar surface (formalin was made from a 37% stock solution, d down to 5% with saline).
Data collection started when the first rat was replaced in r 1 and the chamber door was closed and latched ed l-minute acclimation screen on software). The number of events (also defined as “number of seconds”), defined as the number of l-second bins with a change in dynamic force that exceeded an empirically determined threshold value (a value of arbitrary load units, which corresponded visually with rats quietly breathing or sniffing), were totaled in 5-minute intervals. In control rats, the number of events first increases within minutes and then decreases during the subsequent 5 minutes (a ent phase) after formalin administration (Phase I, or Early Phase, of the formalin test), then increases again during the subsequent 35 minutes (Phase II, or Late Phase) of the formalin test. Formalin- induced movements detected by the system include licking and flinching of the affected paw as well as hopping and turning.
W0 2013/003720 PCT/U82012/044928 For constructing summaries for is of dose response curves or screens in the formalin test, the total number of events during the first 5 minutes after formalin administration was considered to be Phase I (Early Phase), and the total number of events for minutes ll to 35 after formalin was considered to be Phase II (Late Phase). Data were analyzed using 1-way ANOVA, and comparisons of drug treatment groups were compared with control groups using appropriate, statistician-guided tests — most ly Dunnett’s for dose response curves and a Student’s t—test for two-group (i.e. e vs. positive control) comparison — utilizing JMP statistical software (SAS Institute Inc, Cary, NC). Data was expressed as means i SEM. An ED50 was calculated utilizing GraphPad Prism software.
Subcutaneous administration of Compound 4 ed a ependent reversal of formalin-induced events. The antinociceptive (analgesic) effects of Compound 4 (ED50 3.62 mg/kg) were able to morphine (ED50 2.4 mg/kg). As shown in a 10 mg/kg dose of morphine completely mitigates both the early and late phase effects of formalin, suggesting both a centrally mediated (Early Phase) and peripherally ed (Late Phase) effect on antinociception (analgesia). There is a more robust effect of Compound 4 in the Late Phase effects than the Early Phase, ting a preferential, peripherally ed effect on peripheral inflammatory pain.
Example 21: Acetic-acid induced writhing model of inflammatory pain Intraperitoneal administration of morphine dose-dependently blocks writhing induced by the intraperitoneal administration of l% acetic acid in mice with an ED50 of 0.25 mg/kg. A dose response of the analgesic effects of eritoneal stration of nd 4 in the l% acetic acid induced writhing assay in mice was measured.
Groups of mice (n=lO per group) were dosed intraperitoneally with a vehicle control (0.9% saline), morphine or Compound 4, 30 minutes before testing followed by a dose of l% acetic acid 5 s before testing. The number of writhes was counted for 15 minutes (3 consecutive 5 minute time bins). In order for a movement to be considered a writhe, two or more of the following criteria were met: 0 A perceivable concave curvature of the spine (termed a pelvic tilt) — dorsal movement of the caudal spine region creating a concave shape when viewed from the side; movement of the hips to either the left or the right; or both. 0 A more severe concave spinal curvature was considered a vertical writhe. o Abdomen made an effort to lower to the ground. ' 56 ' o Hind legs, body, or both ed backwards and lengthened. 0 Tail flicked upward from base (does not typically occur separate from pelvic tilt). o In the event of a chain of multiple writhes, the end of a discrete writhe was determined when the mouse returned to “normal” posture before writhing once again. “Normal” posture ned as movements opposite to those listed above (e. g. convex curvature of the spine, legs not extended, abdomen not lowered, tail in a ht or relaxed position, etc).
The total number of writhes over the 15 minute test session was used for all data analysis. All data was transformed using GraphPad Prism to % change from daily vehicle control for is based on the number of writhes produced by the saline vehicle control * group (% change = # writhes in test group/ mean # of writhes in daily vehicle control group 100). An ED50 of the % change from daily vehicle control was calculated for morphine and compound 4 utilizing ad Prism software.
As shown in administration (intraperitoneal) of Compound 4 blocked acetic acid induced writhing in a dose-dependent manner with a calculated ED50 of 0.7 mg/kg.
While this invention has been ularly shown and described with references to preferred embodiments f, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims (27)

We Claim:
1. A compound of a I, II, III, IV or a pharmaceutically acceptable ester thereof: R1 R1 R3 N R3 N Y R2 R2 R4 R4 (R8)u (R8)u (R11)t (R11)t X O R6 X O R6 N R7 N R7 R10 R9 R9 R10 5 Formula I Formula II R1 R1 R3 N R3 N Y R2 R2 R4 R4 (R8)u (R8)u (R11)t (R11)t X X O N N R10 R9 R10 R9 Formula III Formula IV Wherein: u is 0, 1 or 2; 10 t is 0, 1, 2, 3, 4, 5, 6, or 7; X is S or O; Y is a pharmaceutically acceptable counterion; R1 is selected from aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl; 15 Each R2, R3, R4, R6, R8, and R11 is independently selected from en, halogen, -OR20, -SR20, -NR20R21, -C(O)R20, -C(O)OR20, -C(O)NR20R21, -N(R20)C(O)R21, -CF3, -CN, - NO2, -N3, acyl, alkoxy, substituted , alkylamino, tuted alkylamino, dialkylamino, substituted dialkylamino, alkylthio, substituted alkylthio, alkylsulfonyl, substituted alkylsulfonyl, aliphatic, tuted aliphatic, aryl, substituted aryl, (11063323_1):KZA cyclyl or substituted heterocyclyl; or alternatively, two of R2, R3, R4, R8 and R11 together with the atoms they are attached to form one or two optionally substituted rings; alternatively R2 and R3 together with the carbon they are attached form a C=X group or a vinyl group; alternatively, two R11 groups together with the carbon atom to which they are 5 attached form a C=X or a vinyl group; n each R20 and R21 is independently selected from hydrogen, halogen, alkyl, substituted alkyl, aryl or substituted aryl; R5 is alkyl, substituted alkyl, aryl or substituted aryl; R7 is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; 10 R9 is selected from hydrogen, tic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl; R10 is selected from Table A: Table A R101 N * p (R100)q R102 H q R103 R101 N * p O H R102 (R100)q R103 R101 N * p OMe R102 (R100)q (R103)s R101 NR104 * p O R102 (11063323_1):KZA (R100)q (R103)s R101 NR105 * p O NR104 R102 (R100)q R101 * p NR104 R102 (R103)s (R100)q O R101 * p NR10 4 R102 (R103)s R101 NR104 * p O R102 N (R103)s Wherein s is 0, 1, 2, or 3; p is 0, 1, 2, 3, 4, 5, 6, or 7; q is 0, 1, 2, 3, or 4; Each R100, R101, R102, R103, R104, and R105 is independently selected from en, 5 halogen, -OR20, -SR20, -NR20R21, -C(O)R20, -C(O)OR20, R20R21, -N(R20)C(O)R21, -CF3, -CN, -NO2, -N3, acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted (11063323_1):KZA alkylthio, substituted or unsubstituted alkylsulfonyl, optionally substituted aliphatic, optionally substituted aryl, heterocyclyl or substituted heterocyclyl; Wherein the term ituted” refers to the replacement of one or more hydrogen radicals in a given structure with the radical selected from halo, alkyl, l, alkynyl, 5 aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, mino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, 10 alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl, heteroaryl and aliphatic.
2. A compound of Formula V or VI, or a pharmaceutically able ester thereof: R5 R1 R1 N Y (R11)t (R11)t O OH O OH HN R10 R10 Formula V Formula VI; 15 Wherein: t is 0, 1, 2, 3, 4, 5, 6, or 7; Y is a pharmaceutically acceptable counterion; R1 is selected from tic, substituted tic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl; 20 Each R4 and R11 is independently selected from hydrogen, halogen, -OR20, -SR20, - NR20R21, -C(O)R20, -C(O)OR20, -C(O)NR20R21, -N(R20)C(O)R21, -CF3, -CN, -NO2, -N3, acyl, , substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio, substituted alkylthio, alkylsulfonyl, substituted alkylsulfonyl, tic, substituted aliphatic, aryl, tuted aryl, cyclyl or 25 substituted heterocyclyl (11063323_1):KZA wherein each R20 and R21 is independently selected from hydrogen, halogen, alkyl, substituted alkyl, aryl or substituted aryl; R5 is alkyl, substituted alkyl, aryl or substituted aryl; Wherein R10 is ed from Table A: 5 Table A R101 N * p (R100)q R102 H (R100)q R103 R101 N * p O H R102 (R100)q R103 R101 N * p OMe R102 (R100)q s R101 NR104 * p O R102 (R100)q (R103)s R101 NR105 * p O NR104 R102 (R100)q R101 * p NR104 R102 (R103)s (11063323_1):KZA q O R101 * p NR10 4 R102 (R103)s (R100)q R101 NR104 * p O R102 N (R103)s n s is 0, 1, 2, or 3; p is 0, 1, 2, 3, 4, 5, 6, or 7; q is 0, 1, 2, 3, or 4; Each R100, R101, R102, R103, R104, and R105 is independently selected from hydrogen, 5 halogen, -OR20, -SR20, -NR20R21, -C(O)R20, -C(O)OR20, -C(O)NR20R21, -N(R20)C(O)R21, -CF3, -CN, -NO2, -N3, acyl, alkoxy, substituted alkoxy, mino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, optionally substituted aliphatic, optionally substituted aryl, heterocyclyl or substituted heterocyclyl; 10 Wherein the term “substituted” refers to the replacement of one or more hydrogen radicals in a given structure with the l selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, minocarbonyl, arylaminocarbonyl, carbonyl, aryloxycarbonyl, haloalkyl, 15 amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, (11063323_1):KZA arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, yalkyl, carbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl, heteroaryl and aliphatic.
3. A compound according to claims 1 or claim 2, selected from Table B: 5 TABLE B No Compound No Compound
1. N 2. O OH O O OH N R10 O R9 N R10
3.
4. N N OH O OH O OH O N R10 N R10 R9 R9
5. N
6. O OH OH N R10 (11063323_1):KZA
7. N
8. N OH OH O OH O OH O N R10 N R10 R9 R9
9. N 10. N OH OH O OH O OH OH N R10 N R
10 R9 R9
11. N
12. N O OH OMe O OH OMe N R10 N R10 R9 R9
13. N
14. CO2Me O OH HN N R10 O 323_1):KZA
15. N 16. O OH NH2 N R10 wherein R10 is selected from Table A: R101 N * p (R100)q R102 H q R103 R101 N * p O H R102 (R100)q R103 R101 N * p OMe R102 (R100)q (R103)s R101 NR104 * p O R102 (R100)q (R103)s R101 NR105 * p O NR104 R102 (11063323_1):KZA (R100)q R101 * p NR104 R102 (R103)s (R100)q O R101 * p NR10 4 R102 (R103)s (R100)q R101 NR104 * p O R102 N (R103)s Wherein s is 0, 1, 2, or 3; p is 0, 1, 2, 3, 4, 5, 6, or 7; q is 0, 1, 2, 3, or 4 ; Each R100, R101, R102, R103, R104, and R105 is independently selected from hydrogen, 5 halogen, -OR20, -SR20, 21, -C(O)R20, -C(O)OR20, -C(O)NR20R21, -N(R20)C(O)R21, -CF3, -CN, -NO2, -N3, acyl, alkoxy, substituted alkoxy, mino, substituted alkylamino, dialkylamino, tuted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, optionally substituted aliphatic, optionally substituted aryl, cyclyl or substituted heterocyclyl. (11063323_1):KZA
4. A compound according to any one of the claims 1-3, wherein R9 is hydrogen.
5. A compound according to any one of claims 1-4 wherein R1 is selected from -(CH2)-a-c-C3H5,–(CH2)a-CH=CH2 CH3, -CH2-CH2-Phenyl or -(CH2)a-CH=C(CH3)2 wherein a is independently 0, 1, 2 or 3; wherein -c-C3H5 is cyclopropyl. 5 6. A nd according to any one of claims 1-5 wherein R2 is hydrogen.
7. A compound according to any one of claims 1-6 wherein R3 is hydrogen.
8. A compound according to any one of claims 1-7 wherein R8 is en.
9. A compound according to any one of claims 1-8, wherein X is .
10. A compound according to any one of claims 1-9, wherein R4 is hydrogen or 10 hydroxy.
11. A nd according to any one of claims 1-10, wherein R7 is hydrogen.
12. A compound selected from Table C: TABLE C No Compound 1 N O O HN N (11063323_1):KZA 3 N O O HN NH 4 N O O HN N 5 N O OH O HN NH 6 N O OH HN NH 323_1):KZA 7 N O OH O HN NH 8 N O O 9 N O O HN N 10 N O O O 11 N O O HN NH 323_1):KZA 12 N O O 13 N O O O 14 N O O O 15 N O O 323_1):KZA 16 N O O 17 N O O O O
13. The use of a compound according to any one of the ing claims in the manufacture of a pharmaceutical composition for the treatment of a disease or er by modulating the activity of an opioid receptor.
14. The use according to claim 13, wherein said compound is a mu receptor agonist. 5 15. The use according to claim 13, wherein said compound is a mu receptor antagonist. (11063323_1):KZA
16. The use according to claim 13, wherein said disease or disorder is pain.
17. The use according to claim 16, wherein said pain is selected from inflammatory pain, centrally mediated pain, peripherally mediated pain, visceral pain, structural related pain, cancer pain, soft tissue injury related pain, progressive disease related pain, 5 neuropathic pain and acute pain from acute injury, acute pain from trauma, acute pain from surgery, chronic pain from headache, c pain from neuropathic conditions, chronic pain from post-stroke conditions and chronic pain from migraine.
18. The use according to claim 16, wherein said pain is associated with rthritis, rheumatoid arthritis, fibromyalgia, migraine, headache, toothache, burn, 10 sunburn, snake bite, spider bite, insect sting, enic bladder, benign prostatic hypertrophy, interstitial cystitis, rhinitis, contact dermatitis/hypersensitivity, itch, , pharyngitis, mucositis, tis, cellulitis, causalgia, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, post-operative ileus, cholecystitis, postmastectomy pain syndrome, oral neuropathic pain, Charcot's pain, 15 reflex sympathetic phy, Guillain-Barre me, meralgia paresthetica, burningmouth syndrome, post-herpetic neuralgia, trigeminal neuralgia, cluster headache, migraine headache, peripheral neuropathy, bilateral peripheral neuropathy, ic neuropathy, optic neuritis, postfebrile neuritis, ing neuritis, segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate 20 gia, glossopharyngial neuralgia, migrainous neuralgia, thic neuralgia, intercostals neuralgia, mammary gia, Morton's gia, nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatine neuralgia, supraorbital neuralgia, vidian neuralgia, inflammatory bowel disease, irritable bowel me, sinus headache, n headache, labor, childbirth, menstrual cramps, and 25 cancer.
19. The use according to claim 16, wherein said pain is associated with arthritis.
20. The use according to claim 19, wherein said arthritis is selected from rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, juvenile arthritis and scapulohumeral periarthritis. (11063323_1):KZA
21. The use according to claim 14, wherein said disease or disorder is selected from drug addiction, opiate addiction, l addiction, nicotine addiction, cocaine addiction, post-operative ileus, pruritis, diarrhea, irritable bowel syndrome, gastrointestinal motility disorder, obesity, respiratory depression, convulsions, coughing and hyperalgesia. 5
22. The use according to claim 22, wherein said disease or disorder is gastrointestinal ction, or ileus.
23. The use according to any one of claims 15-22, wherein the compound does not substantially cross the blood-brain barrier.
24. The use of a compound according to any one of claims 1-12, in the manufacture 10 of pharmaceutical composition for ng or preventing a side effect associated with an opioid
25. The use according to claim 24, wherein the side effect is ed from the group consisting of constipation, opioid-induced bowel dysfunction, nausea, vomiting, and combinations thereof. 15
26. A compound according to any of claim 1-11 n R10 is selected from: p (R100)q (R100)q R103 p OH (R100)q R103 p OMe (R100)q R103 p O (11063323_1):KZA (R100)q R103 NR105 p O NR104 (R100)q NR104 (R103)s (R100)q O p NR104 (R103)s (R100)q NR104 p O (R103)s ; or a ceutically acceptable salt thereof.
27. A compound according to any of claim 1-11 wherein R10 is selected from: (11063323_1):KZA or a ceutically acceptable salt thereof.
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