| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | September 27, 1988 |
| PATENT TITLE |
Glucuronic acid derivatives of opioid antagonists |
| PATENT ABSTRACT | Intestine-specific delivery of an opioid antagonist can be accomplished without substantial central nervous system effects by administering the antagonist orally in the form of the glucuronide derivative |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | March 26, 1988 |
| PATENT REFERENCES CITED |
Fujimoto et al., Chemical Abstracts, vol. 71, 1969, p. 130, No. 37250y. Fujimoto et al., Chemical Abstracts, vol. 72, 1970, p. 131, No. 98055f |
| PATENT CLAIMS |
1. A compound of formula: ##STR2## wherein R.sub.1 is =CH.sub.2 or =O and R.sub.2 is cyclopropylmethyl. 2. A compound according to claim 1, wherein R.sub.1 is =O and R.sub.2 is cyclopropylmethyl. 3. A composition for site-specific delivery of an opioid antagonist to the intestine of a subject without substantial systemic effects, comprising nalmefene-3.beta.-D-glucuronide or naltrexone-3.beta.-D-glucuronide in an amount sufficient to provide opioid antagonism to the intestine of the subject and a pharmaceutically acceptable carrier for oral administration. 4. A method for providing site specific opioid antagonism in the intestine of a subject without substantial systemic effects, comprising orally administering to said subject an amount of an opioid antagonist sufficient to provide opioid antagonism to the intestine of a subject in the form of a glucuronide derivative having the formula: ##STR3## wherein R.sub.1 is =O or =CH.sub.2 and R.sub.2 is allyl or cyclopropylmethyl. 5. The method of claim 4, wherein the glucuronide derivative is selected from nalmefene-3.beta.-D-glucuronide, naloxone-3.beta.-D-glucuronide and naltrexone-3.beta.-D-glucuronide. 6. The method of claim 5, wherein the glucuronide derivative is nalmefene-3.beta.-D-glucuronide. 7. A method of treating intestinal dysmotility in a subject suffering from an intestinal dysmotility, without substantial systemic effects, comprising orally administering to the subject an opioid antagonist in the form of a glucuronide derivative, having the formula: ##STR4## wherein R.sub.1 is =O or =CH.sub.2 and R.sub.2 is allyl or cyclopropylmethyl, the amount of said glucuronide derivative being sufficient to provide opioid antagonism in the intestine of the subject, the glucuronide derivative undergoing cleavage in the intestine of the subject to assume the aglycone form of the antagonist. 8. The method of claim 7, wherein the glucuronide derivative is selected from nalmefene-3.beta.-D-glucuronide, naloxone-3.beta.-D-glucuronide and naltrexone-3.beta.-D-glucuronide. 9. The method of claim 8, wherein the glucuronide derivative is nalmefene-3.beta.-D-glucuronide. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
-------------------------------------------------------------------------------- BACKGROUND OF THE INVENTION This invention relates to glucuronic acid derivatives of opioid antagonists, and more particularly to the therapeutic use of such compounds in the treatment of localized symptoms with a minimum of systemic effects. Opioid antagonists are a well-known class of drugs which can be used to prevent or promptly reverse the effects of morphine-like opioid agonists. See Goodman and Gilman's The Pharmacological Basis of Therapeutics, Sixth Edition, pp. 521-525. It is known that the opioid antagonist, naloxone, is converted by the human body to the glucuronide form, although no use for this form of naloxone has been found before the present invention. Of particular interest among the known opioid antagonists is nalmefene, which was first identified and claimed in U.S. Pat. No. 3,814,768 as 6-methylene-6-desoxy-N-cyclopropylmethyl-14-hydroxydihydronormorphine. The constipating effect of opioids is the oldest known effect of these drugs. Indeed constipation is the most troubling side effect when opioid drugs are employed to relieve pain. Patients who require opioid analgesics to relieve pain on a chronic basis e.g. cancer victims, suffer severe constipation. Such constipation is also common among opioid addicts, and may even be a problem for those being given opioids on a short term basis, such as patients undergoing surgery. Sudden withdrawal of opioid drugs following prolonged exposure provokes intestinal hypermotility and diarrhea results. This withdrawal phenomenon of hypermotility and diarrhea is also produced if an opioid antagonist is given after prolonged opioid administration. Thus the opioid can cause hypomotility and constipation, and withdrawal can cause the opposite effect of hypermotility and diarrhea. Hypomotility and hypermotility are dysmotilities at the extreme ends of the spectrum of intestinal motility. If an opioid antagonist were administered throughout the period of opioid exposure, intestinal dysmotility at both ends of the spectrum could be forestalled. Attempts have been made to provide opioid antagonists that would relieve the constipating effect of exogenous opioids without antagonizing the analgesic effect. This is particularly important for chronic users or addicts since systemic antagonism can cause severe withdrawal symptoms mediated by the central nervous system. One class of compounds which has been investigated for this purpose are the quaternary ammonium derivatives of known narcotic antagonists (U.S. Pat. No. 4,176,187). The quaternary antagonists antagonize opioid induced intestinal hypomotility at lower doses than are required to antagonize opioid induced analgesia. The selective antagonism, i.e. more effective on intestinal hypomotility than on central nervous system analgesia, occurs because quaternary compounds are highly charged. The blood brain barrier impedes passage of highly charged drugs. Thus, the quaternary ammonium antagonists have more limited access to the opioid receptors in the central nervous system (CNS) that mediate analgesia than they do to the opioid receptors in the intestine that mediate hypomotility. It is doubtful however that the quaternary ammonium antagonists will provide a practical solution to the clinical problem of the constipating effects of opioid analgesics. It has been known since the work of Eddy in 1933 (J. Pharmacol. Exp. Therap., 1967, 157: 185-195) that "quaternarization" was a means of directing opioids away from the CNS and toward the intestine. Yet no clinically useful quaternary opioid antagonist is available to patients. The failure of such a drug to emerge in therapeutics is likely related to the toxic effects on the autonomic nervous system that are known to occur with quaternary ammonium drugs. In addition to relieving the constipating effects of exogenous opioids, the present invention is also directed to preventing endogenous opioids from exacerbating intestinal dysmotility of irritable bowel syndrome. In the last decade it's been discovered that the body produces its own opioids. The endogenous opioids are called endorphins and enkephalins. There is an abundance of endogenous opioids and opioid receptors in the intestinal tract. From the work of Kreek et al. (Lancet 1983 1: 262) it appears that such endogenous opioids contribute to intestinal dysmotility. Kreek et al. have shown that the opioid antagonist naloxone relieves constipation even though the patients have not been exposed to an exogenous opioid. Irritable bowel syndrome is a form of intestinal dysmotility well known to gastroenterologists. The syndrome is characterized by pain as well as alternating constipation and diarrhea. The endogenous opioids may exacerbate the syndrome. The hypomotility and constipation phase of the syndrome could be the result of an excessive endogenous opioid influence, while the hypermotility and diarrhea could result from an abrupt cessation of endogenous opioid activity. In irritable bowel syndrome we believe that there is an exaggerated cyclic effect of the endogenous opioids on the intestines. During the upphase of the cycle the intestines can be immobilized and become physically dependent upon the endogenous opioids. During the down phase of the cycle the intestines can go into withdrawal, and thus become hypermotile and produce diarrhea. Pain can result from both constipation and diarrhea. It appears then that a cycling auto-addiction and withdrawal is an important contributor to irritable bowel syndrome. Just as the continued presence of an opioid antagonist would prevent the addiction or physical dependence of the intestines to exogenous opioids, an antagonist should similarly prevent the exacerbating influence of cycling endogenous opioids on the intestine. SUMMARY OF THE INVENTION It is therefore an object of the present invention to provide an opioid antagonist which has a local therapeutic effect in the intestinal tract with a minimum of systemic effects, particularly central nervous system (CNS) effects. A further object of this invention is to provide chemical analogs of known opioid antagonists which have a local intestinal effect with little or no CNS effects. A still further object of this invention is to provide a method for treating intestinal dysmotility by administration of an opioid antagonist which has a minimum of CNS effects. In accordance with the above objects of this invention, glucuronic acid derivatives of opioid antagonists are provided for the treatment of intestinal dysmotility with a minimum of systemic effects. Nalmefene glucuronide has been found particularly useful for achieving the objects of this invention. DETAILED DESCRIPTION This invention uses the .beta.-D-glucuronic acid derivatives of opioid antagonists for colon specific drug delivery. These compounds are given by the following general formula: ##STR1## wherein R.sub.1 is either =O or =CH.sub.2, and R.sub.2 is allyl or cyclopropylmethyl. Three compounds of particular interest are nalmefene-3.beta.-D-glucuronide (R.sub.1 is =CH.sub.2 and R.sub.2 is cyclopropylmethyl), naloxone-3.beta.-D-glucuronide (R.sub.1 is =O and R.sub.2 is allyl) and naltrexone-3.beta.-D-glucuronide (R.sub.1 is =O and R.sub.2 is cyclopropylmethyl). In accordance with the present invention, it has been found that these glucuronide compounds have little or no opioid antagonistic effect unless they are enzymatically cleaved to yield the free antagonist. For example: Nalmefene-3.beta.-D-glucuronide+.beta.-glucuronidase.fwdarw.Nalmefene+glucu ronic acid .beta.-glucuronidase is a naturally occuring enzyme which is present in the bacterial flora of the lower intestinal tract, particularly in the colon. Therefore the compounds of this invention provide a means of specific delivery of an opioid antagnoist to the lower intestinal tract. Opioid antagonist activity in the body outside the intestine is avoided because glucuronic acid derivatives are poorly absorbed and rapidly eliminated in the urine. Further, the glucuronides do not encounter .beta.-glucuronidase outside the intestine. After liberation of the aglycone antagonist in the lower intestinal tract, small amounts of this aglycone antagonist could be absorbed into the portal circulation. However as the aglycone antagonist passes into the portal blood and through the liver it will be reconverted to its .beta.-D-glucuronide conjugate by hepatic glucuronyl transferase. Therefore no significant amount of active antagonist will reach the systemic circulation. An analysis of the blood and urine of rats treated with nalmefene orally showed that the concentration of nalmefene glucuronide is about 100 fold higher than is the concentration of free nalmefene. Thus nalmefene is almost totally biotransformed as a result of "first-pass" metabolism when administered orally. Such a high degree of biotransformation is common for this type of drug. However it was discovered that the relative concentrations of free nalmefene and nalmefene glucuronide in the feces of these animals were in marked contrast to the blood and urine. Whereas the ratio of nalmefene to nalmefene glucuronide in the blood and urine was about 1:100, in the feces the ratio was about 3:1. This suggests that some of the nalmefene glucuronide formed from nalmefene as a result of "first-pass" metabolism in the liver, was excreted via the bile into the intestine and subsequently hydrolysed by intestinal micro flora to yield free nalmefene. This observation led to developing opioid antagonist drugs with activity confined to the intestine. This intestinal specificity would provide for the following three therapeutic applications: (1) Preventing the unwanted constipation (side effect) caused by opioid analgesic drugs without interfering with the wanted analgesic effect. (2) Treating idiopathic constipation. (3) Treating irritable bowel syndrome. SYNTHESIS The compounds according to the present invention can be prepared by the reaction of opioid antagonists salts (for example lithium salts) with the appropriate bromosugar followed by alkaline hydrolysis of the protecting groups. These compounds can also be obtained by the Koenigs-Knorr reaction (R. L. Whistler and M. L. Wolfrom, "Methods in Carbohydrate Chemistry"; R. B. Conrow and S. Bernstein, J. Org. Chem. 1971, (36), 863 and literature cited therein) followed by alkaline hydrolysis. The present invention is described in more detail by way of the following non-limiting examples. Examples 1 and 2 are synthesis of precursor materials and are described in Bollenback, et al., J. Am. Chem. Soc. 1955, (77), 3310. |
| PATENT EXAMPLES | Available on request |
| PATENT PHOTOCOPY | Available on request |
|
Want more information ? Interested in the hidden information ? Click here and do your request. |