USOO5990159A United States Patent (19) 11 Patent Number: 5,990,159 Meulemans et al. (45) Date of Patent: Nov. 23, 1999 54 USE OF 5HT4 RECEPTOR ANTAGONISTS WO FOR OVERCOMING GASTRONTESTINAL 94.00113A 1/1994 WIPO. EFFECTS OF SEROTONIN REUPTAKE WO INHIBITORS 9408998A 4/1994 WIPO. WO 75 Inventors: Ann Louise Gabrielle Meulemans, 9427987A 12/1994 WIPO. Mol; Jean-Paul René Marie WO André Bosmans, Rijkevorsel, both of 9504737A 2/1995 WIPO. Belgium 73 Assignee: Janssen Pharmaceutica, N.V., Beerse, OTHER PUBLICATIONS Belgium Chemical Abstracts, vol. 122, No. 15, Apr. 10, 1995, 21 Appl. No.: 09/117,974 Abstract No. 178309, A. Lucchelli et al.: “The interaction of 22 PCT Filed: Feb. 7, 1997 antidepressant drugs with central and peripherical enteric 5-HT3 and 5-HT4 receptors”. 86 PCT No.: PCT/EP97/00586 S371 Date: Aug. 11, 1998 Primary Examiner Raymond Henley, III S 102(e) Date: Aug. 11, 1998 Attorney, Agent, or Firm-Ellen Ciambrone Coletti 87 PCT Pub. No.: WO97/29739 57 ABSTRACT PCT Pub. Date: Aug. 21, 1997 The present invention concerns the use of receptor antago 30 Foreign Application Priority Data nists of the 5HT4 receptor for avoiding, alleviating, Sup Feb. 15, 1996 EP European Pat. Off. .............. 962OO38O pressing or overcoming the gastrointestinal Side-effects of Serotonin reuptake inhibitors. The present invention also 51 Int. CI. A61K 31/34; A61K 31/135 concerns pharmaceutical formulations comprising 5HT4 52 U.S. Cl. ............................................. 514/469; 514/651 receptor antagonists for alleviating, Suppressing or overcom 58 Field of Search ...................................... 514/469, 651 ing the gastrointestinal Side-effects of Serotonin reuptake inhibitors, as well as pharmaceutical compositions compris 56) References Cited ing 5HT4 receptor antagonists and Serotonin reuptake FOREIGN PATENT DOCUMENTS inhibitors. WO 92001.03A 1/1992 WIPO. 11 Claims, 8 Drawing Sheets U.S. Patent Nov. 23, 1999 Sheet 1 of 8 5,990,159 Uuuu6H Z| ||0 8 ?InsSºud 00|| OOZ 008 007 00C 009 ueÐUu‘W’E’SF U.S. Patent Nov. 23, 1999 Sheet 2 of 8 5,990,159 Uuuu6H |Z ||0 8 eunssºud 00|| 00Z 009 009 009 ueÐUu‘W’E’SF U.S. Patent Nov. 23, 1999 Sheet 3 of 8 5,990,159 Uuuu6H Juaan?!g Z| 8 ?unssºud 00|| 00Z 009 007 009 009 ueÐUu‘W’E’SF U.S. Patent Nov. 23, 1999 Sheet 4 of 8 5,990,159 J???e 00|| OOZ 007 009 ueÐUuF‘W’E’S U.S. Patent Nov. 23, 1999 Sheet 5 of 8 5,990,159 Uuuu6H eunssºud 00|| 00Z 007 009 ueÐUu‘W’E’SF U.S. Patent Nov. 23, 1999 Sheet 6 of 8 5,990,159 // 8 eunssºud 00Z 00€ 009 009 U.S. Patent Nov. 23, 1999 Sheet 7 of 8 5,990,159 ?unssºuduuuu)(6H 00|| OOZ 009 BÐUuu‘W’E’SF U.S. Patent Nov. 23, 1999 Sheet 8 of 8 5,990,159 aan?!Jg ?unsselduuuu)(6H ueÐUu‘W’E’SF 5,990,159 1 2 USE OF 5HT4 RECEPTOR ANTAGONSTS exerting a regulated tonic contraction (gastric tone), accom FOR OVERCOMING GASTRONTESTINAL plishes the reservoir function of the Stomach, namely gastric EFFECTS OF SEROTONN REUPTAKE accommodation and emptying. Impairment of adaptive INHIBITORS relaxation as a response to food intake may be the patho physiological basis of Some gastrointestinal disturbances or This application is the national Stage of application no. disorders associated with the use of SSRIs. PCT/EP97/00586, filed Feb. 7, 1997, which application Patients Suffering from dyspepsia after the intake of claims priority from EP 96.200.380.2, filed Feb. 15, 1996. SSRIs feel hungry but cannot finish a normal meal. This is The present invention concerns the use of antagonists of explained by this diminished Stomach compliance. Normally the 5HT4 receptor for avoiding, alleviating, Suppressing or when a Subject Starts eating, the Stomach will show an overcoming the gastrointestinal side-effects of (Selective) adaptive relaxation, i.e. the Stomach will relax to accept the Serotonin reuptake inhibitors. The present invention also food that is ingested. This adaptive relaxation is not possible concerns pharmaceutical formulations comprising 5HT4 when the Stomach compliance is hampered. receptor antagonists and Serotonin reuptake inhibitors for The problem to be solved is to provide a means for avoiding, alleviating, Suppressing or Overcoming the gas 15 avoiding, alleviating, Suppressing or overcoming the gas trointestinal Side-effects of Serotonin reuptake inhibitors. trointestinal disturbances which are associated with the Depression in its many variations has recently become intake of SSRIs, i.e. to normalize the compliance of the much more visible to the general public than it has previ Stomach by reducing the gastric tone to a normal level. ously been. It is now recognized as an extremely damaging Unexpectedly, we have found that 5HT4 receptor antago disorder, and one that afflicts a Surprisingly large fraction of nists can normalise the diminished Stomach compliance the population. Suicide is the most extreme Symptom of caused by the administration of SSRIs, thus avoiding, depression, but many people, not So drastically afflicted, live alleviating, Suppressing or overcoming the gastrointestinal in misery and partial or complete uselessness, which may disturbances caused by the administration of SSRIs. It also afflict their family. should be noted that the 5HT4 receptor antagonists do not as Depression is often associated with other diseases or 25 Such influence the Stomach compliance, they only Seem to conditions, or caused by Such other conditions. For example, antagonise the effect on the stomach caused by the SSRIs. it is associated with Parkinson's disease; with HIV infection; Hence, there is provided the use of a 5HT4 receptor with Alzheimer disease; and with abuse of anabolic Steroids. antagonist for the manufacture of a medicament to avoid, Depression may also be associated with abuse of any alleviate, SuppreSS or overcome the gastrointestinal distur Substance, or may be associated with behavioral problems bances caused by SSRIs. Also provided is a method of resulting from or occuring in combination with head avoiding, alleviating, Suppressing or overcoming the gas injuries, mental retardation or stroke (EP 0714663). trointestinal disturbances of SSRIs. During the last two decades, the treatment of depression The term "selective Serotonin reuptake inhibitors' as with antidepressants has moved from the treatment of hoS used herein refer to compounds that selectively inhibit the pitalised melancholic inpatients to the outpatient Setting. 35 (re-)uptake of Serotonin. Relevant tests to determine whether During the last few years, the majority of depressed patients, a compound is a Selective Serotonin reuptake inhibitor are including patients with moderate or mild depressive known in the art (for an overview see Life Sciences, 57, Symptoms, are now treated in primary care. Recent Studies 411–441,1995). have shown that mild depression is a Serious condition, The term “selective serotonin reuptake inhibitors” or representing Social and economical liability to the patient 40 “SSRIs' will both be used hereinunder. The terms refer to and a high cost to Society. Such patient clearly benefits from the compounds as Such or where appropriate to the phar therapy with antidepressants. One of the main contributing maceutically acceptable acid or base addition Salts thereof factors to this evolution in therapeutic practice has been the or, again where appropriate, to Stereochemically isomeric introduction of new antidepressants, among which the Selec forms thereof. tive serotonin reuptake inhibitors (SSRIs) are the most 45 The term “5HT4 receptor antagonist” refers to the com important and most widely prescribed. Although the SSRIs pounds as Such or where appropriate to the pharmaceutically are Said to have a lesser incidence of Side effects, Still the use acceptable acid or base addition Salt thereof or, again of SSRIs is hampered by a number of adverse effects. The appropriate, to Stereochemically isomeric forms thereof. adverse effects occurring most frequently during treatment The pharmaceutically acceptable acid addition Salts as with SSRIs are gastrointestinal disturbances, Such as, for 50 mentioned hereinabove are meant to comprise the therapeu example nausea, diarrhoea/loose Stools, constipation, with tically active non-toxic acid addition Salt forms which the an incidence of 6 to 37% (Drugs 43 (Suppl. 2), 1992). compounds are able to form. The compounds which have Nausea is the main adverse effect in terms of incidence. basic properties can be converted in their pharmaceutically These adverse effects, although mild to moderate in Severity, acceptable acid addition Salts by treating Said base form with shy some patients away from treatment with SSRIs. The 55 an appropriate acid. Appropriate acids comprise, for percentage of patients withdrawing because of nausea example, inorganic acids Such as hydrohalic acids, e.g. ranges from 3 to 8% of the patients. Moreover it has been hydrochloric or hydrobromic acid, Sulfuric, nitric, phospho frequently observed that after administration of SSRIs, ric and the like acids, or organic acids Such as, for example, patients Suffer from dyspepsia. acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, We discovered that the gastrointestinal disturbances 60 malonic, Succinic (i.e. butanedioic acid), maleic, fumaric, associated with the administration of SSRIs is mainly due to malic, tartaric, citric, methaneSulfonic, ethaneSulfonic, a diminished compliance of the Stomach. The “compliance benzeneSulfonic, p-toluenesulfonic, cyclamic, Salicylic, of the Stomach” can be expressed as the ratio of the Volume p-aminoSalicylic, pamoic and the like acids. of the Stomach over the pressure exerted by the Stomach The pharmaceutically acceptable addition Salts as men wall. The compliance of the Stomach relates to the gastric 65 tioned hereinabove are meant to comprise the therapeuti tone, which is the result of the tonic contraction of muscle cally active non-toxic base addition Salt forms which the fibers of the proximal Stomach. This proximal part, by compounds are able to form. Examples of Such base addition 5,990,159 3 4 Salt forms are, for example, the Sodium, potassium, calcium LY-353433 (Eli Lilly Co Ltd) (J.