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US5270302.Pdf |||||||||||||||||| USOO527O3O2A United States Patent (19) 11 Patent Number: 5,270,302 Shiosaki et al. 45) Date of Patent: Dec. 14, 1993 (54) DERIVATIVES OF TETRAPEPTIDESAS CCK Stewart et al., (Solid Phase Peptide Synthesis, 2nd Ed, AGONSTS 1984, Pierce Chemical Company, Rockford, Ill., pp. 27 75 Inventors: Kazumi Shiosaki; Alex M. Nadzan, and 28. both of Libertyville; Hana Kopecka, Martinez, et al., J. Med., Chen. 1985, 28:1874. Vernon Hills; Youe-Kong Shue, Yabe et al., Chen. Pharm. Bull., 1977, 25:2731. Vernon Hills; Mark W. Holladay, Kovacs et al., "Cholesystokinin Analogs Containing Vernon Hills; Chun W. Lin, Wood Non-Coded Amino Acids', Pept Synthesis, Structure Dale; Hugh N. Nellans, Mundelein, and Function, Proc. 9th Am. Pept. Symp., 1985, pp. all of Ill. 583-586, 73) Assignee: Abbott Laboratories, Abbott Park, Primary Examiner-Lester L. Lee II. Attorney, Agent, or Firm-Richard A. Elder; Steven R. 21 Appl. No.: 713,010 Crowley; Steven F. Weinstock (22 Filed: Jun. 17, 1991 57 ABSTRACT Selective and potent Type-A CCK receptor agonists of Related U.S. Application Data formula (I): 63 Continuation-in-part of Ser. No. 541,230, Jun. 20, 1990, abandoned, which is a continuation-in-part of Ser. No. X-Y-2-Q (I) 5,673, Dec. 18, 1989, which is a continuation-in-part of Ser. No. 287,955, Dec. 21, 1988, abandoned. or a pharmaceutically acceptable salt thereof, wherein, X is selected from 51) Int. Cl........................ A61K 37/02; CO7K 5/08; CO7K 5/10 4 5 4 S 52 U.S. C. ........................................ 514/18; 514/17; R. R R R H O 514/19, 530/330,530/331 Ri and N 58) Field of Search .................. 530/330, 331; 514/17, R2 514/18, 19 ( FR3 56) References Cited U.S. PATENT DOCUMENTS 2,932,635 4/1960 Amiard et al. ...................... 530/33 N 4,687,760 8/1987 Martinez et al. ...................... 514/18 H 4,808,701 2/1989 Darho et al. ........................ 530/317 4,818,748 4/1989 Bender et al. ......................... 54/17 Y is selected from FOREIGN PATENT DOCUMENTS O 0175617 3/1986 European Pat. Off. HN-R10 A. l NR13 2945239 5/1981 Fed. Rep. of Germany ........ 54/8 ( ( 45-10506 4/1970 Japan . N N 1063728 3/1967 United Kingdom . s and N 9 OTHER PUBLICATIONS R Rll R12 R Rii R2 Vanderhaeger et al., Neuronal Cholecystokinin, 1985 pp. 461-462, 593, 599. Z is Miyamoto et al.-Chem. Pharm. Bull, 1986, 34(2) pp. 694-7OO. (Abstract continued on next page.) 5,270,302 Page 2 the treatment of gastrointestinal disorders (including R17 gallbladder disorders), central nervous system disor ( N 6 ders, insulin-related disorders and pain, as well as in N / N R2 appetite regulation. N 16 U ; and Q is R23 R X R ( S R25 or pharmaceutically-acceptable salts thereof, useful in 10 Claims, 2 Drawing Sheets U.S. Patent Dec. 14, 1993 Sheet 1 of 2 5,270,302 9|G7QZO||68/%, (u) S3XVLN (ues+) NVW 5,270,302 1. 2 ety,” Robinson College, Cambridge, U.K., Sep. 7 and 8, DERVATIVES OF TETRAPEPTIDES AS CCK 1990). AGONSTS Two sub-types of the CCK receptor have been identi fied. Type-A CCK receptors, commonly referred to as CROSS REFERENCE TO RELATED 5 the "peripheral-type' receptor, are primarily found in APPLICATIONS the pancreas, gall bladder, ileum and on vagal afferent nerve fibers. Type-A CCK receptors bind CCK-8 with This is a continuation-in-part of copending U.S. pa high affinity but have low affinity for desulfated CCK-8 tent application Ser. No. 541,230, filed Jun. 20, 1990 and and CCK-4. The brain contains predominantly the now abandoned, which is a continuation-in-part of PCT 10 Type-B receptors that bind CCK-8, desulfated CCK-8 patent application Ser. No. PCT/US89/05673, filed and CCK-4 with high affinity. Type-A CCK receptors Dec. 18, 1989, which is a continuation-in-part of U.S. are found in the brain, although in low abundance (D. patent application Ser. No. 287,955, filed Dec. 21, 1988, R. Hill et al., Brain Res, 1988, 454:10-5; D. R. Hill et now abandoned. al., Neurosci Lett., 1988, 89:133-9; R. W. Barrett et al., TECHNICAL FIELD 15 Mol, Pharmacol, 1989, 36:285-90; and D. R. Hill et al., J. Neurosci, 1990, 10:1070-81), and play an important role The present invention relates to novel organic com there also (V. Dauge et al., Pharmacol Biochem Behay, pounds and compositions which mimic the effects of 1989, 34:157-63; J. Soar et al., Pharmacol. Biochem. cholecystokinin, to processes for preparing such com Behav, 1989, 33:637-40). Type-A receptor-selective pounds, to synthetic intermediates employed in these 20 CCK agonists are currently of particular interest as processes and to a method of treating gastrointestinal potential anorectic agents because of the ability of disorders (including gallbladder disorders), central ner CCK-8 and Type-A CCK-selective agonists to suppress vous systern disorders, insulin-related disorders and food intake in several animal species (Della-Fera et al., pain, or of regulating appetite with such compounds. Science, 1979, 206:471; K. E. Asin et al., Intl Conference BACKGROUND OF THE INVENTION 25 on Obesity, 1990, Abstract p. 40). Obesity is a major disorder affecting as much as one Cholecystokinin (CCK) is a polypeptide hormone third of the North American population. Several studies found in both the periphery and the brain that plays a have shown that such individuals are at increased risk in major role in gut function, in the digestive process and developing cardiovascular disease (hypertension and in the control of feeding behaviors. Relative to other 30 hypercholesterolemia), diabetes and several types of neuropeptides, high concentrations of CCK and CCK cancer. The effective treatment of obesity, however, receptors are found in the brain and CCK meets many remains a largely unachieved goal. Existing phamaco of the criteria for consideration as a neurotransmitter (J. therapeutic approaches to weight loss involve the use of F. Rehfeld, J. Neurochem, 1985, 448:1-8), suggesting amphetamine-based agents such as amphetamine, dieth important CNS functions for this peptide. CCK exists in 35 ylpropion, mazindol and fenfluramine which act di multiple biologically active forms (CCK-58, CCK-39, rectly on the CNS to lower food intake by modulating CCK-33, CCK-8 and CCK-4), with CCK-33, CCK-8 dopaminergic, adrenergic and/or serotonergic mecha and CCK-4 predominating in the periphery (J. Martinez nisms. Although weight loss can be achieved with such in Comprehensive Medicinal Chemistry, Vol. 3, J. C. agents, their use is restricted due to CNS side-effects, Emmett, ed, Pergamon Press, Oxford, England, 1990, p. 40 potential addiction liability and the production of toler 925) and the C-terminal octapeptide, CCK-8, predomi ance to their actions, with chronic administration lead nating in the brain, ing to potential depression, vestibular disturbances, CCK has a variety of regulatory roles in the periph hallucinations and addiction, as well as interference ery including gallbladder contraction and pancreatic with the actions other drugs such as MAO inhibitors enzyme secretion (V. Mutt in Gastrointestinal Hor 45 and antihypertensives. There is also a subpopulation of mones, G. B. J. Glass, ed, Raven Press, New York, 1980, obese patients that is refractory to present anorectic p. 169; J. A. Williams, Biomed. Res., 1982, 3:107), inhibi drug treatments. The medical need is high for an effec tion of gastric emptying and suppression of food intake. tive anorectic agent which overcomes the above disad CCK and its fragments are believed to play an impor vantages of existing therapies. Of particular need are tant role in appetite regulation and satiety (Della-Fera, 50 agents which act by alternative mechanisms to modu Science 1979, 206:471; Saito et al., Nature 1981, 289:599; late food intake and/or metabolism. and Smith, Eating and Its Disorders, A. J. Stunkard and Several references have disclosed CCK agonists or E. Stellar, eds., Raven Press, New York, 1984, p. 67) analogs of CCK-8. For example, U.S. Pat. No. and recently, patients with bulimia were shown to have 4,490,364, issued Dec. 25, 1984 to Rivier, discloses hep lower than normal CCK levels in their plasma (Geraci 55 tapeptide, octapeptide and nonapeptide analogs of oti et al., New England Journal of Medicine, 1988, CCK-8 as CCK agonists for stimulating gallbladder 319:683). An additional role for CCK in the periphery is contractions, arresting the secretion of gastric acid and to regulate the release of insulin. CCK has been shown treating convulsions. J. D. Rosamond in European Pa to increase the levels of insulin when administered to tent Application EP381,340, published Aug. 8, 1990, mammals (Rushakoff et al., J. Clin. Endocrinol. Metab. and in European Patent Application EP268,297, pub 1987, 65:395). lished May 25, 1988, discloses hepta- and octapeptides CCK in the brain has been suggested to have a role in with sulfate ester groups which are useful for treating schizophrenia (N.P.V. Nair et al, Prog. Brain Res., 1986, obesity. 65:237), memory and cognition (S. Itoh and H. Lal, C-terminal fragments of CCK have recently been Drug Dev. Res., 1990, 21:257), and CCK antagonists 65 reported to function as CCK receptor antagonists or have been suggested to be potentially useful in drug gastrin receptor antagonists (Jensen et al., Biochem. abuse therapy (B. Costall et al. in "Proceedings of the Biophys. Acta, 1983, 757:250; Spanarkel, J. Biol. Chem. Cambridge Symposia, The Neurological Basis of Anxi 1983, 258:6746).
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