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US 6,784,186 B1Granted
Therapeutic compounds
OwnerRoy W. Jackson, Kamani R. Subasinghe +1inventors
InventorsRoy W. Jackson, Kamani R. Subasinghe, Alan L. A. Boura
Life of this patent
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Abstract
This invention relates to novel structural analogues and derivatives of compounds with general analgesic or related pharmacological activity. In particular the invention relates to derivatives of opioid compounds, particularly morphine and related compounds, in which an opioid compound is linked via the nitrogen at position 17 to a spacer group, which in turn is linked to a charged group, or a pharmaceutically acceptable salt thereof. In particularly preferred embodiments the opioid compound is morphine, codeine, or buprenorphine.
Claims22
A compound having the formula:
- (YN)-(spacer)-(amidine or guanidine group) or
- wherein
- (YN) is an organic residue obtained by the removal of R, from an opioid of the formula YN—R, said opioid selected from the group consisting of morphine, codeine, heroin, ethylmorphine, O-carboxymethylmorphine, O-acetylmorphine, hydrocodone, hydromorphone, oxymorphone, oxycodone, dihydrocodcine, thebaine, metopon, ethorphine, acetorphine, diprenorphine (M5050), buprenorphine, phenomorphan, levorphanol, ethoheptazine, ketobemidone, dihydroetorphine and dihydroacetorphine R of YN—R is H, phenethyl, cyclopropylmethyl, or an alkyl of 1-6 carbon atoms;
- (spacer) is a group linking YN to an amidine or guanidine group, wherein YN and said amidine or guanidine group are separated by 1 to 6 carbon atoms;
- and
- (amidine or guanidine group) is a group of the formula
- in which
- R1 is H, alkyl or aryloxyalkyl, wherein the aryl group is optionally substituted by alkyl, alkoxy, halogen, or alkyl substituted by halogen, and alkyl, alkoxy and the alkyl moiety of aryloxy alkyl have 1 to 6 carbon atoms;
- R2 is H or an alkyl group having 1 to 6 carbon atoms;
- R3 is H, alkyl, hydroxy, amino, cyano or acyl, wherein alkyl and acyl have 1 to 6 carbon atoms;
- or
- R1 and R3 together complete a heterocyclic ring having two nitrogen atoms,
- or a pharmaceutically acceptable salt thereof,
- wherein said compound acts as an analgesic that has reduced sedative or addictive effect in comparison to any opioid of formula YN—R wherein YN of YN—R is identical to YN of said compound.
11 more elements
A method for the preparation of a compound of formula:
- wherein
- (YN) is an organic residue obtained by the removal of, R, from an opioid of the formula YN—R, said opioid selected from the group consisting of morphine, codeine, heroin, ethylmorphine, O-carboxymethylmorphine, O-acetylmorphine, hydrocodone, hydromorphone, oxymorphone, oxycodone, dihydrocodeine, thebaine, metopon, ethorphine, acetorphine, diprenorphine (M5050), buprenorphine, phenomorphan, levoiphanol, ethoheptazine, ketobemidone, dihydroetorphine and dihydroacetorphine R of YN—R is H, phenethyl, cyclopropylmethyl, or an alkyl of 1-6 carbon atoms;
- in which
- R1 is H, alkyl or aryloxyalkyl, wherein the aryl group is optionally substituted by alkyl, alkoxy, halogen, or alkyl substituted by halogen, and alkyl, alkoxy and the alkyl moiety of aryloxy alkyl have 1 to 6 carbon atoms;
- and
- n is an integer of 1 to 6;
- comprising the step of reacting a compound having the formula
- YN—(CH2)n—NH2
- or
- YN—H
- with a cyanamide of formula R1NHCN.
8 more elements
A method for the preparation of a compound of formula:
- wherein
- (YN) is an organic residue obtained by the removal of, R, from an opioid of the formula YN—R, said opioid selected from the group consisting of morphine, codeine, heroin, ethylmorphine, O-carboxymethylmorphine, O-acetylmorphine, hydrocodone, hydromorphone, oxymornbone, oxycodone, dihydrocodeine, thebaine, metopon, ethorphine, acetorphine, diprenorphine (M5050), buprenorphine, phenomorphan, levorphanol, ethoheptazine, ketobemidone, dihydroetorphine and dihydroacetorphine R of YN—R is H, phenethyl, cyclopropylmethyl, or an alkyl of 1-6 carbon atoms;
- in which
- R1 is H, alkyl or aryloxyalkyl, wherein the aryl group is optionally substituted by alkyl, alkoxy, halogen, or alkyl substituted by halogen, and alkyl, alkoxy and the alkyl moiety of aryloxy alkyl have 1 to 6 carbon atoms;
- R2 is H or an alkyl group having 1 to 6 carbon atoms;
- and
- n is an integer of 1 to 6;
- comprising the step of reacting a compound of formula
- YN—(CH2)n—CN
- or
- YN—CN
- with a metallated residue containing —NR1R2.
9 more elements
A method for the preparation of a compound of formula:
- wherein
- (YN) is an organic residue obtained by the removal of, R, from an opioid of the formula YN—R, said opioid selected from the group consisting of morphine, codeine, heroin, ethylmorphine, O-carboxymethylmorphine, O-acetylmorphine, hydrocodone, hydromorphone, oxymorphone, oxycodone, dihydrocodeine, thebaine, metopon, ethorphine, acetorphine, diprenorphine (M5050), buprenorphine, phenomorphan, levorphanol, ethoheptazine, ketobemidone, dihydroetorrhine and dihydroacetorphine R of YN—R is H, phenethyl, cyclopropylmethyl, or an alkyl of 1-6 carbon atoms;
- in which
- R1 is H, alkyl or aryloxyalkyl, wherein the aryl group is optionally substituted by alkyl, alkoxy, halogen, or alkyl substituted by halogen, and alkyl, alkoxy and the alkyl moiety of aryloxy alkyl have 1 to 6 carbon atoms;
- and
- n is an integer of 1 to 6;
- comprising the step of reacting a compound having the formula
- YN—(CH2)n—NH2
- or
- YN—H
- with a compound of formula (V)
- wherein R1 is as defined above, and
- L is a leaving group.
10 more elements
Dependencies are inferred from the claim text.