Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1997-12-31
2002-06-11
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S044000
Reexamination Certificate
active
06403602
ABSTRACT:
TECHNICAL FIELD
The present invention relates to 3-O-Acetylmorphine-6-sulfate compounds and their ester derivatives which are potent, centrally-acting morphine derivatives. The compounds are useful for the treatment of pain.
BACKGROUND ART
The opiate analgesic morphine, when administered to humans, is converted by the liver into three major metabolites, viz. morphine-3-O-glucuronide (M3G), morphine-6-O-glucuronide (M6G) and morphine-3-O-sulfate (M3S) [9,19]. M6G is found in the systemic circulation in concentrations exceeding those of morphine itself, after both parenteral [12,19] and oral administration [12,18]. M6G is a very potent &mgr;-receptor agonist [3] with a high affinity for both mu
1
and mu
2
receptors [1,14] and appears to cross the blood-brain barrier in spite of its high polarity compared to morphine [20].
Some morphine compounds are known in the art. For example, U.S. Pat. No. 5,219,861 to Kanematsu et al. relates to a novel morphine-6-thiol derivatives. Kanematsu discloses acetylthio-derivatives on the six position of morphine and esters on position three.
U.S. Pat. Nos. 4,496,570 to Bodor and 5,352,680 to Portoghese et al. relates to opiates with heterocyclic substituents bound to position six of the opiate ring. Both patents disclose thiol ring substituents on morphine.
U.S. Pat. No. 4,362,870 to Portoghese relates to a non-addictive analgesic opiate. Portoghese further discloses morphine-like opiates which have substituted isothiocyanate groups on position six and ester groups on position three of the opiate.
U.S. Pat. No. 5,258,512 to Heiman et al. relates to a method for a fluorescence polarization immunoassay procedure for determining the amount opiate alkaloids in fluids. The invention discloses, in FIG. 13-9, the use of a morphine-sulfonamide on position six.
Houdi et al.,
Pharmacol., Biochem
. &
Behavior
(March, 1996) disclosing morphine-6-sulfate esters and their analgesic character. This is the work of the present inventors.
Brown et al.,
J. Pharm. Sci
. 74:821-24 (August, 1985) relates to the analgesic potencies of several morphine analogues with covalent modifications at carbons 3 and 6. Specifically, morphine-6-sulfate is disclosed.
Choonara et al.,
J. Clin. Pharmacol
. 30:897-900 (December, 1990) describes the metabolism of morphine and the detection of morphine-3 and morphine-6-sulfate.
Oguri et al.,
Eur. J. Pharmacol
. 102:229-35 (July, 1984) relates to the dependency of nalorphine-6-sulfate conjugates.
Hirano et al.,
Chem. Pharm. Bull
. 39:2000-4 (August, 1991) relates to the synthesis and pharmacological activity of nalorphine-6-sulfate conjugates.
There is a need in the art for effective treatments for relieving pain in animals and humans. The present invention overcomes deficiencies in the prior art in providing new and effective treatments for pain, and other conditions whose symptoms are known to be alleviated with morphine compounds.
DISCLOSURE OF THE INVENTION
The present invention relates to morphine analogues, substituted with both a sulfate group at position six of the ring and an ester group at position three. The compounds are used as analgesics and for the treatment of pain.
More particularly the compounds selected from the group consisting of the following formulas I and II:
wherein X is selected from the group consisting of —OR2,
and
wherein R1 may be a straight or branched chain alkyl or alkenyl group having 1-5 carbon atoms;
wherein R2 is an alkyl having 1-3 carbon atoms, and
wherein R3 is H or n-alkyl or branched alkyl with 1-10 carbon atoms (preferably 4-8 carbon atoms), cycloalkyl, aralkyl, n-alkenyl or branched alkenyl with 1-10 carbon atoms, and n-alkynyl or branched alkynyl with 1-10 carbon atoms. R3 is preferably OCH
3
, OCOCH
3
, OCOCH
2
CH
3
, OCOCH(CH
3
)
2
, OCOCH(CH
3
)
3
and OCO-phenyl.
wherein X is selected from the group consisting of —OR2,
and
wherein R1 may be a straight or branched chain alkyl or alkenyl group having 1-5 carbon atoms;
wherein R2 is an alkyl having 1-3 carbon atoms, and
wherein R3 is H or n-alkyl or branched alkyl with 1-10 carbon atoms, cycloalkyl, aralkyl, n-alkenyl or branched alkenyl with 1-10 carbon atoms (preferably 4-8 carbon atoms), and n-alkynyl or branched alkynyl with 1-10 carbon atoms. R3 is preferably selected from the group consisting of OCH
3
, OCOCH
3
, OCOCH
2
CH
3
.
The above and other objects of the invention will become readily apparent to those of skill in the relevant art from the following detailed description and figures, wherein only the preferred embodiments of the invention are shown and described, simply by way of illustration of the best mode of carrying out the invention. As is readily recognized the invention is capable of modifications within the skill of the relevant art without departing from the spirit and scope of the invention.
REFERENCES:
patent: 4362870 (1982-12-01), Portoghese
patent: 4496570 (1985-01-01), Bodor
patent: 5219861 (1993-06-01), Kanematsu et al.
patent: 5258512 (1993-11-01), Heiman et al.
patent: 5629011 (1997-05-01), Illum
patent: 5739145 (1998-04-01), Nagase
Beilstein, abstract registry No. 73 97 281, 1995.*
Sankyo, Chem. Abstr. vol. 96 Entry 218088, 1982.*
Brock et al., Chem. Abstr. vol. 124 Entry 161029, 1996.*
Aceto et al. Chem. Abstr vol. 125 entry 104826, 1995.*
Jacobson Chem. Abstr vol. 125 Entry 185591, 1996.*
Woods et al. Chem. Abstr. vol. 125 Entry 185592, 1996.*
Aceto et al Chem Abstr vol. 125 Entry 185593, 1996.*
Houdi et al., “3-O-Acetylmorphine-60-Sulfate: A Potent, Centrally Acting Morphine Derivative”, Pharmacology Biochemistry and Behavior, vol. 53, No. 3, pp. 665-671, Mar. 1996.
Choonara et al., “Morphine Sulphation in Children”, citied in Journal of Clinical Pharmacology, Dec. 1990, pp. 897-900. (see Abstract).
Hirano et al., “Synthesis and Pharmacological Activity of Sulfate Conjugate at 6-Position of N-Substituted Normorphine Derivatives, cited in Chemical Pharmaceutical Bulletin”, Aug. 1991, vol. 39, No. 8, pp. 2000-4. (see Abstract).
Brown et al., “Analgesic Potencies of Morphine 3- and 6-Sulfates After Intracerabroventricular Administration in Mice: Relationship to Structural Characteristics Defined by Mass Spectrometry and Nuclear Magnetic Reseonance”, Journal of Pharmaceutical Science, vol. 74, No. 8, pp. 821-824, Aug. 1985.
Oguri et al., “Potentiation of Physical Dependence by Conjugation at the 6-Position of Nalorphine”, cited in European Journal of Pharmacology, Jul. 1984, vol. 102 No. 2, pp. 229-35. (see Abstract).
Butterfield D. Allen
Crooks Peter A.
Houdi Abdulghani A.
Kottayil Santosh G.
Coleman Brenda
The University of Kentucky Research Foundation
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