Tic-containing opioid dipeptide derivatives useful as analgesics

Details Tic-containing opioid dipeptide derivatives useful as analgesics Tic-containing opioid dipeptide derivatives useful as analgesics

1998-04-01

2000-11-21

Russel, Jeffrey E.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

546146, A61K 3805, C07K 5065

Patent

active

061503355

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

This invention is related to a new use of opioid dipeptide derivatives with .delta. agonist properties, particularly as analgesic compounds.


BACKGROUND AND PRIOR ART

The results of recent studies indicated that opioid agonists that selectively act via .delta. receptors should have advantages over currently available opioid analgesics. In particular, potential advantages include the production of analgesia with J. Pharmacol. Exp. Ther. 246, 950-955 (1988)); (P. Y. Cheng et al., Eur. J. Pharmacol. 230, 85-88 (1993)); and J. Pharmacol. Exp. Ther. 229, 641-648 (1984).
Selective peptide .delta. agonists currently available include the enkephalin analogs H-Tyr-D-Thr-Gly-Phe-Leu-Thr-OH (DTLET; G. Gacel et al., J. Med. Chem. 31, 1891-1897 (1988)) and ##STR2## (DPDPE, H. I. Mosberg et al., Proc Natl. Acad. Sci. USA 80, 5871-5874 (1983) and the deltorphins (H-Tyr-D-Met-Phe-His-Leu-Met-Asp-NH.sub.2 (dermenkephalin)), H-Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH.sub.2 (deltorphin I) and H-Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH.sub.2 (deltorphin II); V. Erspamer et al., Proc. Natl. Acad. Sci. USA 86, 5188-5192 (1989)). However, these peptides are of relatively large molecular size (molecular weight>600) and for this reason their ability to cross the blood-brain barrier (BBB) is very limited.
Non-peptide .delta. agonists that have recently been developed include the racemic compound BW373U86 (K.-J. Chang et al., J. Pharmacol. Exp. Ther. 267, 852-857 (1993)) and its chemically modified enantiomer SNC80 (S.N. Calderon et al., J. Med. Chem. 37, 2125-2128 (1994)) as well as the compound TAN-67 (J. Kamei et al., Eur. J. Pharmacol. 276, 131-135 (1995)). However, BW 373U86 produced significant toxicity, manifested behaviorally as convulsions and barrel rolling, in mice (S. D. Comer et al., J. Pharmacol. Exp. Ther. 267, 888-895 (1993)), and TAN-67 showed no significant antinociceptive effect in the mouse tail flick test (J. Kamei et al., Eur. J. Pharmacol. 276, 131-135 (1995)). Therefore, there is still a need for the development of new potent .delta. opioid agonists of low molecular weight and high lipophilic character.
Peptides containing the N-terminal segment H-Tyr-Tic-Aaa (Tic=1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, Aaa=aromatic or aliphatic amino acid residue) that are very potent and highly selective .delta. opioid antagonists have recently been disclosed by P. W. Schiller et al., in FASEB J. 6(4), A1575 (1992), at the International Narcotics Research Conference (INRC) Meetings in Keystone, CO, Jun. 24-29 (1992) and in Skovde, Sweden, Jul. 10-15 (1993), at the 2nd Japan Symposium on Peptide Chemistry, Shizuoka, Japan, Nov. 9-13 (1992), at the 22nd European Peptide Symposium in Interlaken, Switzerland, Sept. 9-13 (1992), at the 14th American Peptide Symposium in Columbus, Ohio, Jun. 18-23 (1995), in Proc. Natl. Acad. Sci. USA 89, 11871-11875 (1992), and in J. Med. Chem. 36, 3182-3187 (1993).
Recently, it has been found that dipeptide derivatives of the type H-Tyr-Tic-NH--(CH.sub.2).sub.n --Ph (Ph=phenyl) also have .delta. antagonist properties, if n=1, 3 or 4. In the case of n=2, however, the compound (H-Tyr-Tic-NH-CH.sub.2 --CH.sub.2 --Ph) surprisingly turned out to be a full, but only moderately potent .delta. agonist, as reported by P. W. Schiller et al. at the 23rd European Peptide Symposium in Braga, Portugal, Sept. 4-10, 1994.
Thus, the object of the present invention was to find structurally modified analogs of H-Tyr-Tic-NH--CH.sub.2 --CH.sub.2 --Ph with improved .delta. agonist potency. Compounds of this type should have potential for therapeutic use as centrally acting analgesics because their low molecular weight and lipophilic character can be expected to facilitate crossing of the BBB.


OUTLINE OF THE INVENTION

It has now been found that analogs of the dipeptide derivative H-Tyr-Tic-NH--CH.sub.2 --CH.sub.2 --Ph, as defined by the following formula I below, have high potency as .delta. opioid agonists and retain good .delta. receptor selectivity.
The present invention is directed to th

REFERENCES:
Title page for European Journal of Biochemistry, vol. 241, No. 3, Nov. 1996.
Calderon, et al., "Probes for Narcotic Receptor Mediated Phenomena 19. Synthesis of (+)-4[(.alpha.R)-.alpha.-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-me thoxybenzyl]-N,N-diethylbenzamide (SNC 80): A Highly Selective, Nonpeptide .delta. Opioid Receptor Agonist," J. Med. Chem. 37:2125-2128 (1994).
Carpenter, et al., "Role of Hydrophobic Substituents in the Interaction of Opioid Tyr-Tic Depeptide Analogs with Dodecylphosphocholine Micelles," Eur. J. Biochem. 241:756-764 (1996).
Chang, et al., "A Novel, Potent and Selective Nonpeptidic Delta Opioid Receptor Agonist BW373U86," J. Pharmacol. Exper. Ther. 267:852-857 (1993).
Cheng, et al., "Opioid-Induced Stimulation of Fetal Respiratory Activity by [D-Ala.sup.2 ]deltorphin I," Eur. J. Pharmacol 230:85-88 (1993).
Comer, et al., "Convulsive Effects of Systemic Administration of the Delta Opioid Agonist BW373U86 in Mice," J. Pharmacol. Exper. Ther. 267:888-895 (1993).
Cowan, et al., "Direct Dependence Studies in Rats with Agents Selective for Different Types of Opioid Receptor," J. Pharmcacol. Exper. Ther. 246:950-955 (1988).
Erspamer, et al., "Deltorphins: A Family of Naturally Occurring Peptides with High Affinity and Selectivity for .delta. Opioid Binding Sites," Proc. Natl. Acad. Sci. USA 86:5188-5192 (1989).
Gacel, et al. "Development of Conformationally Constrained Linear Peptides Exhibiting a High Affinity and Pronounced Selectivity for .delta. Opioid Receptors," J. Med. Chem. 31:1891-1897 (1988).
Galligan, et al., "Cerebral Delta Opioid Receptors Mediate Analgesia But Not the Intestinal Motility Effects of Intracerebroventricularly Administered Opioids," J. Pharmacol Exper. Ther. 229:641-648 (1984).
Kamei, et al., "Antinociceptive Effects of the Selective Non-Peptidic .delta.-Opioid Receptor Agonist TAN-67 in Diabetic Mice," Eur. J. Pharmacol. 276:131-135 (1995).
Mosberg, et al., "Bis-Penicillamine Enkephalins Possess Highly Improved Specificity Toward .delta. Opioid Receptors," Proc. Natl. Acad. Sci. USA 80:5871-5874 (1983).
Schiller, et al., "Differential Stereochemical Requirements of .mu. vs. .delta. Opioid Receptors for Ligand Binding and Signal Transduction: Development of a Class of Potent and Highly .delta.-Selective Peptide Antagonists," Proc. Natl. Acad. Sci. USA 89:11871-11875 (1992).
Schiller, et al., "Antagonism As a Consequence of Side Chain Conformational Restriction: A New Class of Potent, .delta. Opioid Receptor-Selective Peptide Antagonists," Peptides 1992:647-648 (1992).
Schiller, et al., "The TIPP Opioid Peptide Family: Development of a New Class of Highly Potent .delta.-Receptor Antagonists with Extraordinary .delta.-Selectivity," Peptide Chemistry 1992:337-340 (1992).
Schiller, et al., "A New Class of Potent and Highly Selective .delta. Opioid Receptor Peptide Antagonists Without .mu. Antagonist Properties," Abstr. 3699, Faseb J. 6:A1575 (1992).
Schiller, et al., "Novel Highly Selective .delta. Opioid Receptor Antagonists Without .mu. Antagonist Properties," INRC Abstracts:144 (1992).
Schiller, et al., "TIPP[.psi.]: A Highly Potent and Stable Pseudopeptide .delta. Opioid Receptor Antagonist with Extraordinary .delta. Selectivity," J. Med. Chem. 36:3182-3187 (1993).
Schiller, et al., "TIPP Analogs: Highly Selective .delta. Opioid Antagonists with Subnanomolar Potency and First Known Compounds with Mixed .mu. Agonist/.delta. Antagonist Properties," Proc. 24th INRC:S63-S64 (1993).
Schiller, et al., "Novel Opioid Peptide Analogs with Mixed .mu. Agonist/.delta.Antagonist Properties," Peptides 1994:632-633 (1994).
Schiller, et al., "Structure-Agonist/Antagonist Activity Relationships of TIPP Analogs," Peptides: Chemistry, Structure and Biology:609-611 (1995).
International Search Report for PCT/SE97/02156(Dated Mar. 30, 1999).

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