U.S. patent application number 15/613431 was filed with the patent office on 2017-11-23 for morphinan derivatives for the treatment of drug overdose.
The applicant listed for this patent is Alkermes Pharma Ireland Limited. Invention is credited to Fen-Ni Fu, Chengyun Guo, Bernard Silverman.
Application Number | 20170333422 15/613431 |
Document ID | / |
Family ID | 44082631 |
Filed Date | 2017-11-23 |
United States Patent
Application |
20170333422 |
Kind Code |
A1 |
Silverman; Bernard ; et
al. |
November 23, 2017 |
Morphinan Derivatives for the Treatment of Drug Overdose
Abstract
The instant application relates to morphinan derivatives of
Formula I with sustained effectiveness in treating drug toxicity
and overdose: ##STR00001##
Inventors: |
Silverman; Bernard;
(Needham, MA) ; Fu; Fen-Ni; (Northborough, MA)
; Guo; Chengyun; (McFarland, WI) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Alkermes Pharma Ireland Limited |
Dublin |
|
IE |
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|
Family ID: |
44082631 |
Appl. No.: |
15/613431 |
Filed: |
June 5, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14835176 |
Aug 25, 2015 |
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15613431 |
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12903462 |
Oct 13, 2010 |
9119848 |
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14835176 |
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61266881 |
Dec 4, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 221/22 20130101;
A61K 31/4748 20130101; A61K 31/4748 20130101; A61P 25/36 20180101;
C07D 221/28 20130101; A61P 25/30 20180101; A61K 31/485 20130101;
A61K 2300/00 20130101; A61K 31/485 20130101; A61K 2300/00
20130101 |
International
Class: |
A61K 31/4748 20060101
A61K031/4748; A61K 31/485 20060101 A61K031/485; C07D 221/22
20060101 C07D221/22; C07D 221/28 20060101 C07D221/28 |
Claims
1. A method of treating an opioid toxicity or overdose in a subject
in need thereof comprising administrating a first opioid receptor
antagonist followed by a compound of Formula I: ##STR00009## or a
pharmaceutically acceptable salt, ester or prodrug thereof wherein;
R.sub.1 is --(CH.sub.2).sub.n-c-C.sub.3H.sub.5,
--(CH.sub.2).sub.n-c-C.sub.4H.sub.7,
--(CH.sub.2).sub.n-c-C.sub.5H.sub.9,
--(CH.sub.2).sub.n--CH.dbd.CH.sub.2 or
--(CH.sub.2).sub.n--CH.dbd.C(CH.sub.3).sub.2 wherein n is
independently 0, 1, 2 or 3; R.sub.2 is --CONH.sub.2 or
--CSNH.sub.2; R.sub.3 and R.sub.4 are independently H, --OH or
together R.sub.3 and R.sub.4 form an --O-- or --S-- group; R.sub.5
is H or C.sub.1-C.sub.8 alkyl; and R.sub.6 and R.sub.7 are
independently H, --OH, OCH.sub.3 or together R.sub.6 and R.sub.7
form a .dbd.O or .dbd.CH.sub.2 group.
2. The method according to claim 1, wherein said first opioid
receptor antagonist is naloxone.
3. The method according to any one of claim 1, wherein said drug
toxicity or overdose is resulting from opioid administration to a
non-dependent patient.
4. The method according to claim 3, wherein said subject is an
opioid experienced non-dependent opioid user.
5. The method according to claim 2, wherein said administration of
compound of Formula I is preceded by said naloxone
administration.
6. The method according to claim 5, wherein said naloxone
administration reduces symptoms of overdose or toxicity prior to
administration of compounds of Formula I.
7. The method according to any one of claim 1, wherein said
compound of Formula I is administered in a daily dose of about 3 to
about 20 mg/day.
8. The method according to claim 7, wherein said daily dose is
about 10 mg/day.
9. The method according to claim 1, wherein administration of a
compound of Formula I reduces symptoms of opioid toxicity or
overdose over a period of at least about 15 to about 30
minutes.
10. The method according to claim 9, wherein symptoms of opioid
toxicity or overdose are reduced for a period of at least one
hour.
11. The method according to claim 9, wherein symptoms of opioid
toxicity or overdose are reduced for a period of at least two
hours.
12. The method according to claim 9, wherein symptoms of opioid
toxicity or overdose are reduced for a period of at least three
hours.
13. The method according to claim 9, wherein symptoms of opioid
toxicity or overdose are reduced for a period of at least four
hours.
14. The method according to claim 9, wherein symptoms of opioid
toxicity or overdose are reduced for a period of at least eight
hours.
15. The method according to any one of claim 9, wherein said
administration comprises about 3 mg to about 20 mg of a compound of
Formula I.
16. The method according to any one of claim 9, wherein said
symptoms of overdose is selected from decreased respiratory rate,
decreased respiratory depth, apnea, comotosis, hypoxia, delirium
hypotension, bradycardia, decreased body temperature, urinary
retention and pupil miosis.
17. The method according to claim 2, wherein naloxone is
administered concurrently with a compound of Formula I.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 14/835,176, filed Aug. 25, 2015, which is a continuation of
U.S. application Ser. No. 12/903,462, filed Oct. 13, 2010, now U.S.
Pat. No. 9,119,848, issued Sep. 1, 2015, which claims the benefit
of U.S. Provisional Application No. 61/266,881, filed on Dec. 4,
2009. The entire teachings of the above applications are
incorporated herein by reference.
TECHNICAL FIELD
[0002] This invention relates to morphinan compounds useful for the
treatment of drug toxicity and overdose, in particular opioid
overdose.
BACKGROUND OF THE INVENTION
[0003] Opioids are a class of drugs that include both natural and
synthetic substances. The natural opioids (referred to as opiates)
include opium and morphine. Heroin, the most abused opioid, is
synthesized from opium. Other synthetic opioids, commonly
prescribed for pain, as cough suppressants, or as anti-diarrhea
agents, includes, codeine, oxycodone (OXYCONTIN.RTM.), meperidine
(DEMEROL.RTM.), fentanyl (SUBLIMAZE.RTM.), hydromorphone
(DILAUDID.RTM.), methadone and propoxyphene (DARVON.RTM.). Heroin
is usually injected, either intravenously or subcutaneously, but
can also be smoked or used intranasally. Other opioids are either
injected or taken orally.
[0004] Opioids, whether used in a clinical or non-clinical
environment, are highly addictive and can lead to varying degrees
of opioid toxicity. Some chronic opioid users known as "addicts"
continue abusing the opioid despite significant problems caused by
or made worse by the use of opioid. Typically, chronic users become
physically dependent on the opioid, as evidenced by tolerance
and/or withdrawal. Acute users experience opioid intoxication,
wherein the user uses a sufficient amount of an opioid to get a
"high". These acute users do not experience typical withdrawal
symptoms upon elimination of the opioid, however, may experience
overdose symptoms (e.g., opioid-induced coma) when too much of an
opioid is taken.
[0005] Traditionally there are several forms of opioid
detoxification programs targeting users with various degrees of
opioid tolerance. Typical treatment regimes allow for complete
elimination of the opioid from the user's body and prevent the user
from reestablishing a dependence on the opioid. Opioid receptor
antagonists are one form of treatment effective at reversing the
clinical features of opioid toxicity. Opioid receptor antagonist
functions by completely binding to the same receptors as the
opioid. The opioid receptor antagonist displaces the opioid while
having the added advantage of having no addictive potential because
of its inability to activate opioid receptors. This approach has
the promising effect of reducing the pharmacodynamic effects (e.g.
"high") of the opioid user at a very rapid rate while allowing for
the opioid agonist to be eliminated from the body. However, the
very rapid removal rate of the opioid may result in exaggerated
withdrawal symptoms for addicts with tolerance to the opioid.
[0006] An opioid antagonist, naloxone (NARCAN.RTM.), is often
administered to reverse the effects of opioid intoxication or
overdose. The drawback to this treatment is that the duration of
action of some opioids may exceed that of a single naloxone
administration. The pharmacodynamic actions of naloxone last for a
briefer period than all but the most short acting opioids. Clarke,
S F J et al., Emergency Medicine Journal, 2005 (22) 612-616. Clarke
notes that, "although the elimination half life of naloxone is
similar to that of morphine (60-90 minutes) it is redistributed
away from the brain more rapidly. Consequently, the patients may
become renarcotised and suffer harm if they self discharge from
medical care early. Clinicians are clearly walking a tightrope
between precipitating AWS (acute withdrawal syndrome) and avoiding
renarcotisation." Clarke at 612. Therefore, continued surveillance
is needed which is often achieved by hospitalization. Furthermore,
in patients with renal and hepatic failures require large doses of
naloxone over long periods. Maintaining therapeutically effective
naloxone concentration is a challenge. Redfern, N., British Medical
Journal, 1983 (287) 751-752. As such, new therapeutics for the
treatment of drug overdose/toxicity that are effective for a longer
period is needed.
SUMMARY OF THE INVENTION
[0007] The present invention relates to the unexpected discovery
that certain carboxamide substituted morphinans are useful for the
treatment of drug overdose and symptoms of drug overdose, in
particular opioid overdose. The carboxamide substituted morphinans
are effective in treating drug overdose for longer periods in
comparison to naloxone, for example 24 to 48 hours. Another aspect
of the invention is the use of carboxamide substituted morphinans
in combination or in conjunction with naloxone for the treatment of
drug overdose, in particular opioid overdose. In yet another aspect
of the invention is the treatment of opioid overdose in opioid
experienced non-dependent patients.
[0008] The present invention relates to the treatment of drug
overdose by the administration of compounds of Formula I:
##STR00002## [0009] or a pharmaceutically acceptable salt, ester or
prodrug thereof, wherein; [0010] R.sub.1 is
--(CH.sub.2).sub.n-c-C.sub.3H.sub.5,
--(CH.sub.2).sub.n-c-C.sub.4H.sub.7,
--(CH.sub.2).sub.n-c-C.sub.5H.sub.9,
--(CH.sub.2).sub.n--CH.dbd.CH.sub.2 or
--(CH.sub.2).sub.n--CH.dbd.C(CH.sub.3).sub.2 wherein n is
independently 0, 1, 2 or 3; [0011] R.sub.2 is --CONH.sub.2 or
--CSNH.sub.2; [0012] R.sub.3 and R.sub.4 are independently H, --OH
or together R.sub.3 and R.sub.4 form an --O-- or --S-- group;
[0013] R.sub.5 is H or C.sub.1-C.sub.8 alkyl; and [0014] R.sub.6
and R.sub.7 are independently H, --OH, OCH.sub.3 or together
R.sub.6 and R.sub.7 form a .dbd.O or .dbd.CH.sub.2 group.
[0015] Compounds of the instant application are useful in the
treatment of drug overdose resulting from opioid drugs such as
codeine, heroin, hydromorphone, methadone, propoxyphene oxycodone,
oxymorphone, hydrocodone or and morphine.
DETAILED DESCRIPTION OF THE INVENTION
[0016] FIG. 1: Pupilometry measures on day 1.
[0017] FIG. 2: Pupilometry measures for days 1 to 7.
[0018] FIG. 3: Visual analog scale (VAS) score for "High" on day
1.
[0019] FIG. 4: VAS score for "High" for days 1-7.
[0020] FIG. 5: VAS score for "Good effect" on day 1.
[0021] FIG. 6: VAS score for "Good effect" for days 1-7.
[0022] The present invention relates to the use of carboxamide
substituted morphinans of Formula I for the treatment of drug
toxicity or overdose. The present invention relates to the
unexpected discovery that compounds of Formula I exhibit sustained
efficacy for treating patients suffering from drug toxicity or
overdose. The compounds of Formula I can be used as a single dose
or once daily dose for the treatment of opioid toxicity or
overdose.
[0023] Compounds of the instant application are useful in the
treatment of drug overdose resulting from opioid drugs such as
alfentanil, allylprodine, alphaprodine, anileridine,
benzylmorphine, bezitramide, buprenorphine, butorphanol,
clonitazene, codeine, desomorphine, dextromoramide, dezocine,
diampromide, diamorphone, dihydrocodeine, dihydromorphine,
dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl
butyrate, dipipanone, eptazocine, ethoheptazine,
ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine,
dihydroetorphine, fentanyl and derivatives, heroin, hydrocodone,
hydromorphone, hydroxypethidine, isomethadone, ketobemidone,
levorphanol, levophenacylmorphan, lofentanil, meperidine,
meptazinol, metazocine, methadone, metopon, morphine, myrophine,
narceine, nicomorphine, norlevorphanol, normethadone, nalorphine,
nalbuphene, normorphine, norpipanone, opium, oxycodone,
oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan,
phenazocine, phenoperidine, piminodine, piritramide, propheptazine,
promedol, properidine, propoxyphene, sufentanil, tilidine,
tramadol, mixtures of any of the foregoing.
[0024] The compounds of Formula I are particularly useful for the
treatment of subjects that are opioid experienced non-dependent
patients suffering from opioid toxicity or overdose. For example,
those patients who have used opioid drugs in the past and have not
developed tolerance or dependence to the opioid drugs can be
treated for opioid toxicity or overdose. The prolonged period of
effectiveness of compounds of Formula I is beneficial for
unmonitored treatment of opioid overdose or toxicity. For example,
the effectiveness from a single dose administration can last from
about 30 minute to over 48 hours. A time period for effectiveness
can be over 1 hour; preferably over 2 hours; preferably over 3
hours; preferably over 4 hours; more preferably over 8 hours; more
preferably over 24 hours and even more preferably over 48 hours. In
a preferred embodiment, the effectiveness of a single dose
administration can last between about 1 hour and about 96 hours. In
some embodiments, the effectiveness can last between about 24 hours
and about 96 hours. In some embodiments, the effectiveness can last
between about 24 hours and about 72 hours.
[0025] Compounds of the instant invention can be obtained by
conversion from the phenolic hydroxyl of benzomorphan to a
carboxamide moiety. Phenolic hydroxyls of benzomorphan and
morphinan derivatives can be chemically converted to carboxamides
by a simple, flexible and convenient route described in U.S. Pat.
Nos. 6,784,187, 7,262,298 and 7,057,035, and in U.S. Patent
Application Publication No. US 2007/0021457 A1, which are all
incorporated herein by reference.
[0026] In one aspect the invention relates to the treatment of drug
overdose by oral or intravenous or intramuscular administration of
compounds of Formula I:
##STR00003## [0027] or a pharmaceutically acceptable salt, ester or
prodrug thereof, wherein; [0028] R.sub.1 is
--(CH.sub.2).sub.n-c-C.sub.3H.sub.5,
--(CH.sub.2).sub.n-c-C.sub.4H.sub.7,
--(CH.sub.2).sub.n-c-C.sub.5H.sub.9,
--(CH.sub.2).sub.n--CH.dbd.CH.sub.2 or
--(CH.sub.2).sub.n--CH.dbd.C(CH.sub.3).sub.2 wherein n is
independently 0, 1, 2 or 3; [0029] R.sub.2 is --CONH.sub.2 or
--CSNH.sub.2; [0030] R.sub.3 and R.sub.4 are independently H, --OH
or together R.sub.3 and R.sub.4 form an --O-- or --S-- group;
[0031] R.sub.5 is H or C.sub.1-C.sub.8 alkyl; and [0032] R.sub.6
and R.sub.7 are independently H, --OH, OCH.sub.3 or together
R.sub.6 and R.sub.7 form a .dbd.O or .dbd.CH.sub.2 group.
Representative compounds according to Formula I include the
following:
##STR00004## ##STR00005## ##STR00006##
[0032] A more preferred compound is the maleate salt of Compound-1
having the formula:
##STR00007##
Definitions
[0033] 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.
[0034] The term "side effect" refers to adverse effects produced by
a drug, especially on a tissue or organ system. In the case of
opioids, the term "side effect" may refer to such conditions as,
for example, respiratory depression, acute sedation, constipation,
opioid-induced bowel dysfunction, nausea and/or vomiting.
[0035] The term "C.sub.1-C.sub.8 alkyl," as used herein, refer to
saturated, straight- or branched-chain hydrocarbon radicals
containing from one to six, or from one to eight carbon atoms,
respectively. Examples of C.sub.1-C.sub.6 alkyl radicals include,
but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl,
tert-butyl, neopentyl, n-hexyl radicals; and examples of
C.sub.1-C.sub.8 alkyl radicals include, but are not limited to,
methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl,
n-hexyl, heptyl, octyl radicals.
[0036] The compounds described herein contain one or more
asymmetric centers and thus give rise to enantiomers,
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 present 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 carried
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, Racemates, and Resolutions (John Wiley & Sons,
1981). When the compounds described herein contain olefinic double
bonds or other centers of geometric asymmetry, and unless specified
otherwise, it is intended that the compounds include both E and Z
geometric isomers. 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 designate 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.
[0037] The term "subject" as used herein refers to a mammal. A
subject therefore refers to, for example, 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 referred to herein
as a patient.
[0038] As used herein, and as would be understood by the person of
skill in the art, the recitation of "a compound," unless expressly
further limited, is intended to include salts, solvates, esters,
prodrugs and inclusion complexes of that compound.
[0039] As used herein, the term "pharmaceutically acceptable salt"
refers to those salts of the compounds formed by the process 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.
[0040] The term "opioid drugs" as described herein include, but is
not limited to the following drugs; alfentanil, allylprodine,
alphaprodine, anileridine, benzylmorphine, bezitramide,
buprenorphine, butorphanol, clonitazene, codeine, desomorphine,
dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine,
dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,
dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine,
ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine,
dihydroetorphine, fentanyl and derivatives, heroin, hydrocodone,
hydromorphone, hydroxypethidine, isomethadone, ketobemidone,
levorphanol, levophenacylmorphan, lofentanil, meperidine,
meptazinol, metazocine, methadone, metopon, morphine, myrophine,
narceine, nicomorphine, norlevorphanol, normethadone, nalorphine,
nalbuphene, normorphine, norpipanone, opium, oxycodone,
oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan,
phenazocine, phenoperidine, piminodine, piritramide, propheptazine,
promedol, properidine, propoxyphene, sufentanil, tilidine,
tramadol, mixtures of any of the foregoing.
[0041] The term "opioid toxicity" refers to the effects of opioid
drugs that are toxic to the subject, resulting in effects such as
moderate to severe ventilatory depression, hypoxia, loss of
consciousness, decreased respiratory rate, decreased respiratory
depth, apnea, hypoxia, delirium, hypotension, bradycardia,
decreased body temperature, urinary retention and pupil miosis. The
opioid toxicity can be assessed by performing a central nervous
system review by assessing for confusion, altered mental state,
excessive drowsiness, lethargy, stupor, slurred speech (new onset),
hypoventilation, shortness of breath, apnea, hypoxia, and/or
hypercarbia; and/or cardiac review by assessing for bradycardia,
hypotension, and/or shock.
[0042] The term "opioid experienced" refers to subjects that have
taken an opioid at least once prior to the instance for which
treatment is sought.
[0043] The term "non-dependent" refers to subjects that have taken
an opioid at least once without becoming dependent prior to the
instance for which treatment is sought.
[0044] 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 purification
of the compounds of the invention, or separately by reacting the
free base function with a suitable 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, hydrobromic acid,
phosphoric acid, sulfuric 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, butyrate,
camphorate, camphorsulfonate, carbonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, ethanedisulfonate, ethylenediaminetetraacetate
(edetate), formate, fumarate, glucoheptonate, glutamate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, hydroxynaphthoate,
isethionate, lactobionate, lactate, laurate, lauryl sulfate,
malate, maleate, malonate, mandelate, methanesulfonate, mucate,
2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate,
palmitate, pamoate, pantothenate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate,
polygalacturonate, propionate, salicylate, stearate, succinate,
sulfate, tannate, tartrate, teoclate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Representative alkali or alkaline earth metal salts include sodium,
lithium, potassium, calcium, magnesium, aluminum, zinc 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 alkanoic, 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, acrylates and ethylsuccinates.
Further pharmaceutically acceptable salts include, when
appropriate, nontoxic ammonium cations and carboxylate, sulfonate
and phosphonate anions attached to alkyl having from 1 to 20 carbon
atoms.
[0045] The term "monitored treatment" refers to treatment
administered in a clinic, hospital, doctor's office or in a setting
where a medical professional is present.
[0046] The term "pharmaceutically acceptable prodrugs" as used
herein refers to those prodrugs of the compounds formed by the
process 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 with undue toxicity,
irritation, 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 metabolic means (e.g.
by hydrolysis) to afford any compound delineated by the formulae of
the instant invention. Various forms of prodrugs are known in the
art, for example, as discussed in Bundgaard, (ed.), Design of
Prodrugs, 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 Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and
Stella (eds.) Prodrugs 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).
[0047] The compounds of this invention may be modified by appending
various functionalities via synthetic means delineated 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),
increase oral availability, increase solubility to allow
administration by injection, alter metabolism and alter rate of
excretion.
Pharmaceutical Compositions
[0048] 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 acceptable 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 tragacanth; 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 laurate; agar; buffering agents such as magnesium
hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;
isotonic saline; Ringer's solution; ethyl alcohol, and phosphate
buffer solutions, as well as other non-toxic compatible lubricants
such as sodium lauryl sulfate and magnesium stearate, as well as
coloring agents, releasing agents, coating agents, sweetening,
flavoring and perfuming agents, preservatives and antioxidants can
also be present in the composition, according to the judgment of
the formulator.
[0049] The pharmaceutical compositions of this invention may be
administered orally, parenterally, by inhalation spray, topically,
rectally, nasally, buccally, vaginally or via an implanted
reservoir, preferably by oral administration or administration by
injection. The pharmaceutical compositions of this invention may
contain any conventional 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 stability of the formulated
compound or its delivery form. The term parenteral as used herein
includes subcutaneous, intracutaneous, intravenous, intramuscular,
intraarticular, intraarterial, intrasynovial, intrasternal,
intrathecal, intralesional and intracranial injection or infusion
techniques.
[0050] In order to prolong the effect of a drug, it is often
desirable to slow the absorption of the drug from subcutaneous or
intramuscular injection. 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 depends
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. Injectable
depot forms can be made by forming microencapsule matrices of the
drug in biodegradable polymers such as polylactide-polyglycolide.
Depending upon the ratio of drug to polymer 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 poly(anhydrides).
[0051] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, microemulsions, solutions,
suspensions, syrups and elixirs. In addition to the active
compounds, the liquid dosage forms may contain inert diluents
commonly used in the art such as, for example, water or other
solvents, solubilizing 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,
tetrahydrofurfuryl 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, emulsifying and suspending agents, sweetening, flavoring,
and perfuming agents.
[0052] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or: a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar-agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, 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 glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
[0053] 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 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 diluent 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 release the active
ingredient(s) only, or preferentially, in a certain part of the
intestinal tract, optionally, in a delayed manner. Examples of
embedding compositions which can be used include polymeric
substances and waxes.
[0054] Preferred suitable daily oral dosages for the compounds of
the inventions described herein are on the order of about 1.5 mg to
about 20 mg. 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 administered 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 ordinary skill in the art or can
be determined experimentally using routine methods. Exemplary
dosing schedules include, without limitation, administration twice
daily, once daily, every other day, three times weekly, twice
weekly, once weekly, twice monthly, once monthly, and so forth.
Unit dose preparations can contain a compound of Formula I in the
range of about 1.5 to about 30 mg. Preferably, a unit dose form can
contain about 1.5 to about 20 mg of a compound of Formula I, while
even more preferably a unit dose can have about 1.5 to about 10 mg
of a compound of Formula I.
[0055] Pharmaceutical kits useful in treating opioid overdose or
toxicity with compounds of Formula I of the invention, in one or
more sterile containers, are also within the ambit of the present
invention. Sterilization of the container may be carried out using
conventional sterilization methodology well known to those skilled
in the art. The sterile containers of materials may comprise
separate containers, or one or more multi-part containers, as
exemplified by the UNIVIAL.RTM. two-part container (available from
Abbott Labs, Chicago, Ill.), as desired. Such kits may further
include, if desired, one or more of various conventional
pharmaceutical kit components, such as for example, one or more
pharmaceutically acceptable carriers, additional vials for mixing
the components, etc., as will be readily apparent to those skilled
in the art. Instructions, either as inserts or as labels,
indicating quantities of the components to be administered,
guidelines for administration, and/or guidelines for mixing the
components, may also be included in the kit.
[0056] Unless otherwise defined, all technical and scientific terms
used herein are accorded the meaning commonly known to one with
ordinary skill in the art. All publications, patents, published
patent applications, and other references mentioned herein are
hereby incorporated by reference in their entirety.
Synthetic Methods
[0057] The compounds and processes of the present invention will be
better understood in connection with the following synthetic
schemes that illustrate the methods by which the compounds of the
invention may be prepared, which are intended as an illustration
only and not to limit the scope of the invention. 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
structures, 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.
[0058] The compounds of Formula I according to the present
invention may be synthesized employing methods taught, for example,
in U.S. Pat. No. 5,250,542, U.S. Pat. No. 5,434,171, U.S. Pat. No.
5,159,081, U.S. Pat. No. 4,176,186 U.S. Pat. No. 6,365,594, U.S.
Pat. No. 6,784,187 and U.S. Pat. No. 5,270,328, the disclosures of
which are hereby incorporated herein by reference in their
entireties. Synthetic methodology for indolylmorphinans is
described in Jones et al., Journal of Medicinal Chemistry, 1998,
41, 4911. Synthetic methodology for pyridomorphinans is described
in Ananthan et al., Bioorganic & Medicinal Chemistry Letters,
13, 2003, 529-532. The optically active and commercially available
Naltrexone was employed as starting material in the synthesis of
the present compounds may be prepared by the general procedure
taught in U.S. Pat. No. 3,332,950, the disclosure of which is
hereby incorporated herein by reference in its entireties.
Compounds 1a and 1b were synthesized from their corresponding
phenols using methodology described in the following references:
U.S. Pat. No. 6,784,187; Wentland et al. Bioorganic & Medicinal
Chemistry Letters, 2001, 11, 623; Wentland et al., Bioorganic &
Medicinal Chemistry Letters, 2001, 11, 1717, Wentland et al.,
Bioorganic & Medicinal Chemistry Letters, 2005, 15, 2107.
Examples
[0059] The compounds and processes of the present invention will be
better understood in connection with the following examples, which
are intended as an illustration only and not to limit the scope of
the invention. 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 structures, 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.
Example 1
[0060] A single-center, randomized, single-blind,
placebo-controlled study was conducted in 24 healthy,
non-dependent, opioid experienced subjects. Placebo (Quinine
solution (0.01% w/v)) was administered on Day 1. Compound-1 (10 or
20 mg) was administered on Day 2. Five remifentanyl (REMI) and 2
saline infusion challenges were administered on Day 1 and Day 2.
Daily REMI and saline challenges were administered on Days 3-9. At
each challenge repeated pharmacodynamic (PD) evaluations were
conducted up to 25 minutes post-infusion including pupil diameter.
The onset of blockade of remifentanil-induced miosis by Compound-1
was analyzed by comparing PD parameters of maximum pupil
constriction (MPC) and pupillometry area over the curve
(PAOC.sub.0-25 minutes) derived for each challenge infusion
time-point on Day 1 (placebo) vs. the corresponding time-points on
Day 2. (FIGS. 1 and 2).
[0061] Visual analog scales (VAS) scoring for "high" and "good
effects" etc., were assessed immediately following pupillometry
measurements. Each VAS test cycle lasted approximately 1 minute and
included questions associated with each VAS measure. Subjects rated
their current perceptions of their subjective state and of the
effects of the challenge infusion. (FIGS. 3-6).
[0062] The degree, onset, and duration of blockade were determined
by statistical comparison of pupil miosis and VAS score at each
challenge. REMI produced significant PD effects on Day 1
(p<0.001 vs saline). Compound-1 (10 and 20 mg) blocked pupil
miosis induced by REMI within 1 hour (hr) and 0.25 hr,
respectively. Blockade persisted for at least 24 hours (p=0.54 vs
saline). Blockade of subjective effects of "Drug Liking" persisted
for at least 48 hours (p=0.31 vs saline). Compound-1 concentrations
greater than 15 ng/mL were sufficient for full blockade. Partial
blockade of physiologic and subjective effects persisted through 4
days post-dose, even after more than 99% of Compound-1 had been
eliminated (tv2=7 hr).
[0063] The patent and scientific literature referred to herein
establishes the knowledge that is available to those with skill in
the art. All United States patents and published or unpublished
United States patent applications cited herein are incorporated by
reference. All published foreign patents and patent applications
cited herein are hereby incorporated by reference. All other
published references, documents, manuscripts and scientific
literature cited herein are hereby incorporated by reference.
[0064] Along with the patients set out above, one opioid dependent,
opioid experienced subject was given Compound-1 (10 mg) after REMI
challenge. The patient experienced severe drug withdrawal 2 minutes
post-dosing with 10 mg of Compound-1 on Day 2. Withdrawal symptoms
included nausea, chills, headache, diarrhea, back pain, muscle
cramps, and vomiting. These were assessed as a collective and
determined to be symptoms of opiate withdrawal. The subject was
discontinued from the study prior to receiving the 0.25 hour
remifentanil challenge infusion.
[0065] The results of the study, particularly the rapid onset and
extended effectiveness, in combination with the withdrawal symptoms
observed in the opioid dependent patient points to the usefulness
of Compound-1 for the treatment of opioid overdose and
toxicity.
Example 2
##STR00008##
[0066] To a jacketed reactor under an inert atmosphere, Compound-1
(80 g) was added. Methanol (250 mL) was added to the reactor,
followed by ethanol (250 mL). The contents of the reactor was
warmed to approximately 65.degree. C. An ethanolic solution of
malic acid (34.5 g of malic acid in 100 mL of ethanol) was added to
the reactor at 60-65.degree. C. After stirring at elevated
temperature the reactor content was slowly cooled to room
temperature. The solids were isolated by filtration, followed by
washing of the wet cake with several volumes of methanol:ethanol
(40:60) solution. The solids were dried in a vacuum oven until
constant weight was reached.
[0067] NMR (300 MHz, DMSO-d.sub.6): 14.37, 0.9H, s; 12.39, 1.3H,
br; 8.41, 1.2H, s; 7.93, 1.2H, s; 7.66, 1.1H, d; 6.65, 1.2H, d;
6.29-4.83, 1.6H, m, 4.04, 1.2H, m; 3.87, 1.2H, d; 3.48, 1.2H, d;
3.10, 2.1H, m; 2.90-2.73, 2.9H, m; 2.72-2.48, 4.5H, m; 2.37, 1.1H,
dd; 2.13, 2H, m; 1.96, 1.1H, m; 1.80, 1.9H, m; 1.59, 1H, d; 0.97,
1H, m; 0.57, 2H, m; 0.27, 2H, m.
[0068] While this invention has been particularly shown and
described with references to preferred embodiments thereof, 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.
* * * * *