Therapeutic compounds

Details Therapeutic compounds Therapeutic compounds

2000-11-20

2004-08-31

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S282000, C514S286000, C514S295000, C514S307000, C514S330000, C546S039000, C546S044000, C546S045000, C546S046000, C546S063000, C546S097000, C546S149000, C546S225000, C546S228000

Reexamination Certificate

active

06784186

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.
BACKGROUND OF THE INVENTION
A large range of therapeutic compounds is currently used in the treatment of conditions such as allergies, diarrhoea, migraine and other pain conditions, and in the treatment of congestive heart failure. These compounds include compounds with analgesic or related activities, such as anti-tussives, anti-depressants, local anaesthetics, anti-hypertensives, anti-asthmatics, anti-histamines, and anti-serotonins.
However, many of the therapeutic compounds of the types enumerated above have undesirable side-effects, such as the respiratory depression caused by opiates. In particular, many drugs which are useful for their action on the peripheral nervous system have undesirable effects in the central nervous system.
Thus opiates are the most powerful analgesics known, but their usefulness is greatly limited by their side-effects, including severe respiratory depression, and ability to induce addiction and physical dependence.
Despite intensive efforts to design analogues of morphine and related opioids which retain the analgesic activity but which do not have a deleterious effect on the central nervous system and the bowel, success has been limited. Structure-activity relationships have been extensively investigated, and a number of features have been widely accepted as essential. See for example “An Introduction to Pharmacology” by J. J. Lewis (E. & S. Livingston Ltd, 1964 Pages 401-407), and “Principles of Drug Action: The Basis of Pharmacology (Ed. W. B. Pratt and P. Taylor; Churchill Livingstone, 3
rd
edition, 1990, Pages 25-27). In particular, it is generally considered that to retain analgesic activity the group on the tertiary nitrogen should be small, and should preferably be methyl; larger substituents are likely to be opiate receptor antagonists rather than agonists. Thus replacement of the methyl group of morphine by an allyl or cyclopropylmethyl moiety produces an antagonist. Although there are some exceptions to this rule, such as N-amylnormorphine and N-hexylnormorphine, in general a large substituent will result in antagonist activity.
We have attempted to modify the ability of biologically-active compounds to cross the blood-brain barrier by incorporating a highly polar group into the molecular structure. Thus we have shown that derivatives of the 2N atom of mianserin comprising a guanidino group show H
1
and 5-hydroxytryptamine activity, but show no detectable activity in the central nervous system. In contrast, a compound in which the 2N atom of mianserin was substituted with a urea group still showed pronounced central nervous system activity (Jackson et al; Clin. Ex. Pharmacol. Physiol., 1992 19 17-23 and our U.S. Pat. No. 5,049,637).
Naltrexamine and oximorphamine have been modified by incorporation of groups which are zwitterionic at biological pH in order to restrict access to the central nervous system (Botros et al; J. Med. Chem., 1989 32 2068-2071, and Portoghese, U.S. Pat. No. 4,730,048). In U.S. Pat. No. 4,730,048 the zwitterionic group was added at C6. Some of these analogues were full agonists, and one was a strong antagonist.
A bis(t-butyldimethylsiloxy)-substituted compound in which a guanidino derivative was attached to the nitrogen via a 3 carbon spacer chain was found to show no opioid activity at &mgr;-receptors in isolated guinea-pig ileum (Jackson et al, 1992). This suggested that such compounds would not have the desired activity.
Therefore there is a need for therapeutic compounds which have less activity within the central nervous system, thus having fewer undesirable side-effects, whilst at the same time having greater specificity of action on peripheral physiological mechanism. We have found that several compounds with the general formula outlined below not only have reduced central side-effects; but retain activity at desired peripheral receptors. In particular, those compounds which show activities at opioid receptors retain broad analgesic activity, contrary to current orthodoxy which teaches that the analgesic effects of opioids are mediated from the CNS. Their selectivity for peripheral opioid receptors not only makes them useful in for the treatment of pain without sedative or addictive effects, but also may make them useful for treatment of AIDS and related immune deficiency diseases.
SUMMARY OF THE INVENTION
In its broadest aspect, the invention provides an opioid compound of general formula I
[opioid-N]-[spacer]-[charged group],  I
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.
For the purposes of this specification, the term “opioid compound” is to be taken to mean a compound structurally related to morphine. The opioid compound preferably, but not necessarily, has opioid agonist or antagonist activity at opioid receptors.
The spacer can be any spacer group of dimensions approximately equivalent to an alkyl chain of 1 to 6 carbon atoms, and may for example be a straight or branched alkyl, alkenyl or alkynyl chain of 1 to 6 carbon atoms, which may optionally be susbstituted. The spacer also comprises a cyclic alkyl, alkenyl, or alkynyl group. Preferably the spacer group is unsubstituted, and more preferably is of 2 to 3 carbons atoms. The charged group may be any group which has the ability to restrict access of the compound of formula I to the central nervous system, and is preferably an amidine or guanidine group.
According to one embodiment, the present invention provides an opioid compound of general formula (II)
in which
YN— represents an organic residue obtained by removal of the R group from an opioid compound of general formula
YN—R  (IIIa)
 wherein R is H, alkyl of 1 to 6 carbon atoms, or cyclopropylmethyl,
 or of the general formula
wherein R
4
is methyl or ethyl, and
Y1—NR
4
represents the corresponding organic residue;
Z is O, S or NR
3
;
R
1
is H
1
, 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;
R
2
is H or an alkyl group having 1 to 6 carbon atoms;
R
3
is H, alkyl, hydroxy, amino, cyano or acyl, wherein alkyl and acyl have 1 to 6 carbon atoms;
n is an integer of 1 to 6, and wherein
R
1
and R
3
may together complete an addition ring; then the grouping
 may become a heterocyclic moiety such as 2-imidazolyl or 2-imidazolinyl:
Preferably R is CH
3
.
Preferably n is 2 or 3.
Preferably Z is NH, and R
1
and R
2
are both H.
In order to indicate the trivalent N-atom more clearly, the structure of compounds of the formula (IIIa) may be written
The precursors of YN— and Y
1
NR
4
— respectively are selected from compounds which are structurally related to morphine.
Thus the precursor of YN— or Y
1
NR
4
— is preferably a compound selected from the group consisting of morphine, codeine, heroin, ethylmorphine, O-carboxymethylmorphine, O-acetylmorphine, hydrocodone, hydromorphone, oxymorphone, oxycodone, dihydrocodeine, thebaine, metopon, etorphine, acetorphine, ketobemidone, ethohe ptazine, diprenorphine (M5050), buprenorphine, phenomorphan, levorphanol, pentazocine, eptazocine and metazocine.
Preferably the precursor is morphine, codeine or buprenorphine.
In a preferred embodiment, the compound of general formula I is one of the following:
Typical examples of morphine-related compounds of the formula (IIIa) or (hIIc) are illustrated in Table 1. In each case the group R has been circled in order to clearly identify the residue YN— or Y
1
N
4
— as the remainder of the molecule.
The preferred precursors also include the unnamed compounds whose structures are shown in Table 1, with the nitrogen atom at position 17 indicated.

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