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United States Patent (19) 11 Patent Number: 6,075,120 Cheronis Et Al

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United States Patent (19) 11 Patent Number: 6,075,120 Cheronis Et Al USOO6075120A United States Patent (19) 11 Patent Number: 6,075,120 Cheronis et al. (45) Date of Patent: Jun. 13, 2000 54 BRADYKININ ANTAGONIST Cheronis et al., “Bradykinin antagonists: Synthesis and in vitro Activity of Bissuccinimidoalkane Peptide Dimers' 75 Inventors: John C. Cheronis, Lakewood; James Recent Progress on Kinins, (1992) pp. 551-558. K. Blodgett, Broomfield; Val Smith Whalley et al., “Novel Peptide Heterodimers Withactions. At Goodfellow; Manoj Vinayak Marathe, BK2 And Either u Opioid, NK1 Or NK2 Receptors: In Vitro both of Westminster; Lyle W. Spruce, Studies, British Journal of Pharmacology, vol. 109, Suppl., Arvada; Eric T. Whalley, Golden, all 19P, Jul 1993. of Colo. Vaverk et al., Suyccinyl Bis-Bradykinins: Potent Agonists 73 Assignee: Cortech, Inc., Denver, Colo. with Exceptional Resistance to Enzymatic Degradation, Peptide: Struc. and Func., Proceedings of the 8th Amer. Pept. Symp., Pierce Chem. Co., Rockford, IL, pp. 381-384 21 Appl. No.: 08/440,338 1983. 22 Filed: May 12, 1995 Stewart et al., Bradykinin Chemistry: Agonists and Antago nist, Advances in Experimental Medicine and Biology, Ple Related U.S. Application Data num Press, NY, NY pp. 585–589 1983. 63 Continuation of application No. 08/296,185, Aug. 29, 1994, Calixto et al., “Nonpeptide Bradykinin Antagonist, Brady which is a continuation of application No. 07/974,000, Nov. kinin Antagonists: Basic and Clinical Research, Ronald 10, 1992, abandoned, which is a continuation-in-part of Burch (Ed.), Marcel Dekker Inc., NY, NY, pp. 97-129 1991. application No. 07/859,582, Mar. 27, 1992, abandoned, which is a continuation-in-part of application No. 07/677, Kodama et al., “Dimerization of neurokinin Aand B COOH 391, Apr. 1, 1991, abandoned. terminal heptapeptide fragments enhanced the Selectivity for tachykinin receptor Subtypes, European Journal of Pharma 51 Int. Cl." .............................. C07K 7/18: A61K 38/08 cology, 151, pp. 317-320 1988. 52 U.S. Cl. .......................... 530/314; 530/328; 530/402; 514/15; 514/2 Primary Examiner-Cecilia J. Tsang 58 Field of Search .................................. 514/15, 2, 803; Assistant Examiner Anish Gupta 530/314, 328, 345, 402 Attorney, Agent, or Firm-Cushman Darby & Cushman IP 56) References Cited Group of Pillsbury Madison & Sutro LLP 57 ABSTRACT U.S. PATENT DOCUMENTS 4,618,598 10/1986 Conn et al. ................................. 514/6 A bradykinin antagonist of the formula: 4,894,443 1/1990 Greenfield et al. ..................... 530/388 OTHER PUBLICATIONS (BKAn)(X)(Y) Carr, “The Effect of Anit-Inflammatory Drugs on Increased Vascular Permeability Induced by Chemical Mediators.” where BKAn is a bradykinin antagonist peptide, Y is a The Journal of Pathology, vol. 108 (1), (1972) pp. 1-14. pharmacore; and X is a bridging link chemically joining the Calixto et al., “Nonpeptide Bradykinin Antagonists”, (1991), BKAn and Y components. pp. 97-129 The Journal of Pathology, vol. 108 (1), pp. 1-14 (1972). 11 Claims, 9 Drawing Sheets U.S. Patent Jun. 13, 2000 Sheet 1 of 9 6,075,120 N-CH HO O R I. R = Nich, chsch-K) O O Y-(CH), N II. R = NH-CH-CH-S O O S-CP-0126) (CP-0477) III. R=NH CH IV. R = NH-CO-CH-NH-COO--CH, CH V. R = Nicoch, Nicoach, sci-( ) O O VI. R = NH-CO-CH-NH-CO-(CH)-S CO chaelNS-ICP-0126 O (CP-0488) VII. R = Nich),sch-K) F.G. 1A U.S. Patent Jun. 13, 2000 Sheet 2 of 9 6,075,120 O O VIII. R = NH-(CH)-S u-all-lO O -CP-0126 (CP-0494) O O DX. R = NH-(CH)-S 1-all-O *ClO S-CP-0347 (CP-0499) X. CP-0126-BMH = D-Arg-Arg-Pro-Hyp-Gly-Phe-Cys-D-Phe-Leu-Arg S a CN (CH2)6 N XL, CP-0347 - BMH is D-Arg-Arg-Pro-Hyp-Gly-Thi-Cys-D-Tic-Oic-Arg S N (CH2)6 N O O -K - FIG. 1 B U.S. Patent Jun. 13, 2000 Sheet 3 of 9 6,075,120 MDd 5upolueds oup uDeW U.S. Patent Jun. 13, 2000 Sheet 4 of 9 6,075,120 f S. S. S. 1. 999 S. () S555 O V uno up 33to 3 os S s X () 5 5 R&S C. 8 N:& 3 8 O3 N * fi: P 5 MZZ PPPPPP Ya388 YaYa YaYa YaYa YaYa YaYa YaYaYYY & i O O O O O v M) CN vo MDd 5upolueds eup uDeW U.S. Patent Jun. 13, 2000 Sheet S of 9 6,075,120 MDd 5upolueds eup uDeW U.S. Patent Jun. 13, 2000 Sheet 7 of 9 6,075,120 O 0 G-0 vus MDd Bupo queds eup uDeW U.S. Patent Jun. 13, 2000 Sheet 8 of 9 6,075,120 O O N vano MDd 5upolueds eup uDeW U.S. Patent Jun. 13, 2000 Sheet 9 of 9 6,075,120 1.00 0.8O (f) O.6OWe Ds 0.40 O.2O O.OO OOO O.5O 1.OO 150 2.OO 2.25 J.OO 3.50 x 101 MINUTES FIG. 5A O 1.OO M N v O 5 N.N. CN CN 0.80 - : N n 0.60 SS H O OO OO O CN D M 0.40 CN O O.20 R r o g O o, SN d & O.OO OOO O.50 1.OO 150 2.OO 2.25 3.OO 3.50 FIG. 5B x1OMINUTES 6,075,120 1 2 BRADYKININ ANTAGONST This is not intended to Suggest that the Single molecule will engage two receptorS or a receptor and an enzyme Simulta RELATED APPLICATION neously; only that the molecule is capable of interacting with This is a continuation of application Ser. No. 08/296,185, either one of two receptor types or with a single class of filed Aug. 29, 1994, which is an CON of 07/974,000, filed receptors and/or an enzyme. The overall pharmacological Nov. 10, 1992, now abandoned which is a CIP of 07/859,582 effect of administering Such a compound in an appropriate filed Mar. 27, 1992 now abandoned and which is a CIP of dose, however, is at least the Summation of the two types of 07/677,391 filed Apr. 1, 1991 now abandoned. activities. The compounds can be designed to remain intact The present invention relates to pharmaceutically effec or they can be designed to be dissociated into two Separate tive heterodimers comprising a bradykinin antagonist molecules each retaining its own identifiable activity. (BKAn) component covalently linked to another different The heterodimers of the invention can be structurally pharmacophore component. represented as follows: In the prior applications mentioned above, there are 15 described bradykinin antagonist dimers of the type: (Y)(X)(BKAn) where BKAn is a bradykinin antagonist peptide; X is a linking group and Y is a peptide or non-peptide pharma X(BKAn). cophore which is not a bradykinin antagonist and demon Strates activity towards a different receptor or enzyme than where BKAn represents abradykinin antagonist peptide and the BKAn component, preferably one related to pain or the X is a linking group which joins the two BKAn components inflammatory process. at points intermediate to their ends. The BKAn substituents The present heterodimers offer the possibility of provid may be the same or different. However, also described are certain heterodimers involving the linkage of a BKAn ing a wider Spectrum of treatment for pain and inflammation. peptide and another peptide of different receptor activity 25 It is a generally held opinion that in inflammatory States, through the linking group X, e.g. an NK or NK antagonist regardless of Severity, the likelihood that a Single agent or peptide or a mu-opioid receptor agonist peptide. Such het mediator is completely responsible for all of the clinical erodimers are particularly useful where there is a close manifestations of the Syndrome being addressed is extraor relationship between the activities of concern. Thus, it is dinarily Small. A corollary to this is that, given the role of known that in a number of pathophysiologically important bradykinin in inflammatory pathophysiology, any combina processes, there is an intimate interaction of inflammatory tion therapy used in the treatment of inflammatory disorders and neurogenic mediators. This occurs, for example, in both should include bradykinin antagonism as part of its overall pain Secondary to tissue trauma (accidental and post profile of action. Broad Spectrum and potent non-specific operative) as well as in asthma. In both situations, there is a 35 complex interplay of tissue and plasma derived mediators therapies (such as the use of Steroids in asthma) while (Such as kinins acting at BK receptors) and neuronally perhaps efficacious, carry with them the burdens of undes derived factors such as substance P (NK receptors) and ired and potentially Serious Side effects and toxicities. neurokinin A (NK receptors). There are also locally acting In many cases, two discrete mediators are known to act neuronal receptors of the mu-opiate class that when Stimu 40 Synergistically and to account for an overwhelming propor lated can inhibit the release of the neurogenic peptides tion of the clinically important manifestations of the disease regardless of type (Substances P, neurokinin A, neurokinin being treated. Such is the case, for example, with B, cholecystokinin, CGRP, etc.). Substance-Pacting at NK receptors and bradykinin acting at Given the interaction of these as well as other inflamma BK receptors in the contexts of asthma and post-traumatic tory and neurogenic mediators, no one agent is likely to be 45 or post-operative pain. Similarly, neutrophil elastase as one universally efficacious in ameliorating the Symptoms atten of the more important down Stream effectors of inflamma dant to the pathophysiology.
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