WO2005074931A1 - Pharmaceutical combinations comprising (s) -pantoprazole - Google Patents

Pharmaceutical combinations comprising (s) -pantoprazole Download PDF

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Publication number
WO2005074931A1
WO2005074931A1 PCT/EP2005/050336 EP2005050336W WO2005074931A1 WO 2005074931 A1 WO2005074931 A1 WO 2005074931A1 EP 2005050336 W EP2005050336 W EP 2005050336W WO 2005074931 A1 WO2005074931 A1 WO 2005074931A1
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Prior art keywords
antagonists
agonists
pantoprazole
receptor
partial
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PCT/EP2005/050336
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French (fr)
Inventor
Reinhard Huber
Bernhard Kohl
Wolfgang Kromer
Wolfgang-Alexander Simon
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Altana Pharma Ag
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Publication of WO2005074931A1 publication Critical patent/WO2005074931A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole

Definitions

  • the invention relates to the combination of certain active compounds for therapeutic purposes.
  • the substances used in the combination according to the present invention are partly known active compounds, which modify gastrointestinal motility, or compounds, which reduce the incidence of transient lower oesophageal sphincter relaxation (TLOSR).
  • TLOSR transient lower oesophageal sphincter relaxation
  • the prior art discloses compounds, which modify gastrointestinal motility by different ways.
  • the international applications WO 02100823, WO 02100869, WO 02100870 and WO 02100871 disclose compounds, which reduce the incidence of transient lower oesophageal sphincter relaxation (TLOSR).
  • TLOSR transient lower oesophageal sphincter relaxation
  • Said international applications are incorporated by reference into the specification of the present invention in their entirety for all purposes.
  • the prior art teaches the usability of compounds, which modify gastrointestinal motility by any way, for therapy of miscellaneous gastrointestinal diseases.
  • the international application WO 0069438 discloses, inter alia, pharmaceutical compositions comprising NK-1 antagonists and proton pump inhibitors exemplified by omeprazole, lansoprazole, pantoprazole, leminoprazole and certain salts of the (-)-enantiomer of omeprazole, which are said to be useful in the prevention and treatment of diseases brought about by hyper secretion of gastric acid in the gut and/or relaxation of the lower oesophageal sphincter.
  • the international application WO 0185167 discloses pharmaceutical compositions comprising gas- trin/cholecystokinin receptor ligands and certain proton pump inhibitors exemplified inter alia by (RS)- rabeprazole, (RS)-omeprazole, lansoprazole, pantoprazole, (R)-omeprazole, (S)-omeprazole, perpra- zole, (R)-rabeprazole, (S)-rabeprazole, or the alkaline salts thereof, which are said to be useful to reduce hyperplasia, associated with administration of proton pump inhibitors.
  • the international application WO 0141748 discloses pharmaceutical combinations comprising 5-HT4 partial agonists or 5-HT4 antagonists and, inter alia, reversible proton pump inhibitors and their uses in treating gastrointestinal disorders.
  • (S)-pantoprazole and its salts which are described in greater detail below, are particularly useful and beneficial to be employed in functional and synergistic combination with compounds, which modify gastrointestinal motility, for precise therapy of gastrointestinal diseases, in particular of gastro-oesophageal reflux disease (GERD) or irritable bowel syndrome (IBS).
  • GFD gastro-oesophageal reflux disease
  • IBS irritable bowel syndrome
  • (S)-pantoprazole and/or its salts is understood to include:
  • Salts in the context of the invention means all pharmaceutically acceptable salts prepared by reacting (S)-pantoprazole [(-)-pantoprazole] with a suitable inorganic or organic base.
  • bases aluminium, sodium, potassium, lithium, magnesium, zinc or calcium salts. Particularly preferred is the magnesium salt.
  • (S)-pantoprazole and/or its salts are isolated in crystalline form, the crystals may contain variable amounts of solvent. Accordingly, according to the invention, the term "(S)-pantoprazole and/or its salts” also includes all solvates, in particular all hydrates, of (S)-pantoprazole and/or its salts.
  • a particularly preferred hydrate of (S)-pantoprazole and/or its salts is the (S)- pantoprazole-magnesium dihydrate.
  • substantially free in the context of the invention means that (S)-pantoprazole and/or its salts contains less than 10 % by weight of (R)-pantoprazole.
  • substantially free means that (S)- pantoprazole and/or its salts contains less than 5 % by weight of (R)-pantoprazole.
  • substantially free means that (S)-pantoprazole and/or its salts contains less than 1 % by weight of (R)-pantoprazole.
  • active agents from miscellaneous active agent classes come into question, such as, for example, the following which are differentiated by modes of action: - 5-HT-(partial-)agonists/antagonists (such as, e.g. 5-HT2-, 5-HT3- and 5-HT4-(partial-)agonists/an- tagonists, in particular 5-HT3-antagonists, 5-HT4-agonists, 5-HT4-partial-agonists or 5-HT4- antagonists) known to the person skilled in the art, such as, for example, those mentioned below in the lists 1a, 1b and/or 1c - without being restricted thereto - by means of their INNs or their research code acronyms:
  • List 1a comprises and discloses as exemplary 5-HT-(partial-)agonists/antagonists the following active agents:
  • exemplary 5-HT-(partial-)agonists/antagonists according to lists 1a, 1b and 1c in more particular worthy to be mentioned are MOSAPRIDE and TEGASEROD;
  • a special subgroup of the class of 5-HT-(partial-)agonists/antagonists comprises those 5- HT-(partial-)agonists/antagonists, which are not either 5-HT4-partial-agonists or 5-HT4-antagonists, and whereby a special subgroup of the class of 5-HT-(partial-)agonists/antagonists to be more emphasized comprises those 5-HT-(partial-)agonists/antagonists mentioned expressis verbis above in the lists 1a, 1b and/or 1c, which are not either 5-HT4-partial-agonists or 5-HT4-antagonists;
  • muscarinic antagonists e.g. muscarinic M3 antagonists
  • muscarinic M3 antagonists known to the person skilled in the art, such as, for example, those mentioned below in the lists 2a, 2b and/or 2c - without being restricted thereto
  • List 2a comprises and discloses as exemplary muscarinic antagonists the following active agents:
  • DARIFENACIN and ZAMIFENACIN; list 2b comprises and discloses as further exemplary muscarinic antagonists the following active agents:
  • List 3a comprises and discloses as exemplary kappa opioid receptor agonists the following active agents: FEDOTOZINE and ASIMADOLINE; and list 3b comprises and discloses as further exemplary kappa opioid receptor agonists the following active agents:
  • list 4a comprises and discloses as exemplary delta opioid receptor agonists the following active agents:
  • ALVIMOPAN and TRK-851 are ALVIMOPAN and TRK-851;
  • opioid receptor agonists/antagonists in particular opioid receptor agonists known to the person skilled in the art, such as, for example, those mentioned below in the list 5a - without being restricted thereto - by means of their INNs or their research code acronyms:
  • List 5a comprises and discloses as exemplary opioid receptor agonists/antagonists the following active agents:
  • dopamine D2 receptor antagonists in particular dopamine D2 receptor antagonists known to the person skilled in the art, such as, for example, those mentioned below in the lists 6a, 6b and/or 6c - without being restricted thereto - by means of their INNs or their research code acronyms:
  • List 6a comprises and discloses as exemplary dopamine receptor antagonists the following active agents:
  • TINE, RACLOPRIDE, SDZ-GLC-756, SLV-313 and TICALOPRIDE; and list 6c comprises and discloses as still further exemplary dopamine receptor antagonists the following active agents:
  • ITOPRIDE LEVOSULPIRIDE
  • METOCLOPRAMIDE NEMONAPRIDE
  • OLANZAPINE OLANZAPINE
  • ITOPRIDE LEVOSULPIRIDE
  • METOCLOPRAMIDE METOCLOPRAMIDE
  • TICALOPRIDE TICALOPRIDE
  • List 7a comprises and discloses as exemplary cholecystokinin A antagonists the following active agents:
  • List 7b comprises and discloses as further exemplary cholecystokinin A antagonists the following active agents: DEVAZEPIDE, DEXLOXIGLUMIDE, KSG-504, LINTITRIPT, LOXIGLUMIDE and PRANAZEPIDE;
  • alpha-2 adrenoceptor agonists known to the person skilled in the art, such as, for example, those mentioned below in the list 8a - without being restricted thereto - by means of their INNs or their research code acronyms:
  • List 8a comprises and discloses as exemplary alpha-2 adrenoceptor agonists the following active agents:
  • ADRAFINIL ADRAFINIL, APRACLONIDINE, BRIMONIDINE, BUDRALAZINE, CLONIDINE, DEXMEDE-
  • TOMIDINE DIMETOFRINE, LOFEXIDINE, MEDETOMIDINE, MOXONIDINE, MPV-295, RIL-
  • MENIDINE ROMIFIDINE, S-17089-1, TALIPEXOLE and TIAMENIDINE;
  • NMDA N-methyl-D-aspartate
  • List 9a comprises and discloses as exemplary N-methyl-D-aspartate (NMDA) receptor antagonists the following active agents: ACPC, APTIGANEL, BMY-14802, CGP-37849, CNS-5161, DELUCEMINE, DEXANABINOL, DIZO- CILPINE, EAA-090, ELIPRODIL, ERLOSAMIDE, FPL-12495, GACYCLIDINE, GAVESTINEL, IPE- NOXAZONE, LANICEMINE, LICOSTINEL, LIGUSTIZINE, MIDAFOTEL, NERAMEXANE, REMACE- MIDE, SELFOTEL, TRAXOPRODIL, UK-240255 and ZD-9379; and list 9b comprises and discloses as further exemplary N-methyl-D-aspartate (NMDA) receptor antagonists the following active agents:
  • list 10a comprises and discloses as exemplary non-N-methyl-D-aspartate glutamate receptor antagonists the following active agents: FG-9041, FG-9065 and RILUZOLE;
  • list 11a comprises and discloses as exemplary nitric oxide synthase inhibitors the following active agents:
  • CNI-1493, ENECADIN, GW-274150, HP-228, ONO-1714, PIMAGEDINE, TARGININE; and list 11b comprises and discloses as further exemplary nitric oxide synthase inhibitor the following active agent: TIRILAZAD;
  • motilin agonists known to the person skilled in the art, such as, for example, those mentioned below in the lists 12a - without being restricted thereto - by means of their INNs or their research code acronyms:
  • List 12a comprises and discloses as exemplary motilin agonists the following active agents: A-173508, ALEMCINAL, GM-652, GM-665, KC-11458, KW 5139, IDREMCINAL, MITEMCINAL and SK-896;
  • motilin agonists according to list 12a more worthy to be mentioned are ALEMCINAL, IDREMCINAL, MITEMCINAL and SK-896;
  • List 13a comprises and discloses as exemplary somatostatin agonists/antagonists the following active agents:
  • neurotensin partial
  • antagonists suitable neurotensin agonists
  • neurotensin agonists known to the person skilled in the art, such as, for example, those mentioned below in the lists 14a - without being restricted thereto - by means of their INNs or their research code acronyms:
  • List 14a comprises and discloses as exemplary neurotensin (partial) agonists/antagonists the following active agents:
  • VIP vasoactive intestinal peptide
  • List 15a comprises and discloses as an exemplary vasoactive intestinal peptide antagonist the following active agent: RO-25-1553;
  • SP substance P
  • List 16a comprises and discloses as exemplary substance P antagonists the following active agents: CGP-49823, EZLOPITANT and LANEPITANT;
  • NK-1, NK-2 or NK-3 antagonists known to the person skilled in the art, such as, for example, those NK-1 antagonists, which are disclosed in the international application WO 0069438 as useful to be employed in combination therapy, and/or in particular those neurokinin antagonists mentioned below in the list 17a - without being restricted thereto - by means of their INNs or their research code acronyms:
  • List 17a comprises and discloses as exemplary neurokinin antagonists the following active agents: ALTINICLINE, APREPITANT, CGP-49823, CP-122721, EZLOPITANT as selective NK-1 antagonist, NEPADUTANT as selective NK-2 antagonist, LANEPITANT, OSANETANT, S-19752, SAREDUTANT, TALNETANT and VOFOPITANT;
  • List 18a comprises and discloses as exemplary calcium channel blockers the following active agents: AZELNIDIPINE, BELFOSDIL, BISARAMIL, CD-832, CERM-11956, CLENTIAZEM, CRE-202, CRONIDIPINE, CV-159, DAURICINE, DHP-218, DIPERDIPINE, DIPROTEVERINE , DOPROPIDIL, DOTARIZINE, ELGODIPINE, EMOPAMIL, FANTOFARONE, FOSTEDIL, FPL-62129, FURNIDIPINE, HA-1004, IGANIDIPINE, IOS-11212, KT-362, LECONOTIDE, LEMILDIPINE, LIFARIZINE, LUBELU- ZOLE, MANOALIDE, MCN-5691 , MEPAMIL, MIOFLAZINE, MONATEPIL, NICTIAZEM, OLRADIP- INE, OXODIPINE, P-0285, PRANIDIPINE, RANOLAZINE,
  • List 19a comprises and discloses as exemplary potassium channel openers the following active agents:
  • list 19b comprises and discloses as further exemplary potassium channel openers the following active agents:
  • SSRIs serotonin reuptake inhibitors
  • List 20a comprises and discloses as exemplary selective serotonin reuptake inhibitors the following active agents:
  • List 21a comprises and discloses as exemplary corticotropin releasing factor antagonists the following active agent:
  • GABA-A receptor agonists of gamma-aminobutyric acid receptors of the A-typ (GABA-A receptor agonists) known to the person skilled in the art, such as, for example, those mentioned below in the list 22a - without being restricted thereto - by means of their INNs or their research code acronyms:
  • List 22a comprises and discloses as exemplary GABA-A receptor agonists the following active agents: GABOXADOL, GEDOCARNIL, ORG-25435, PAGOCLONE and RETIGABINE;
  • GABA-B receptor agonists/partial agonists of gamma-aminobutyric acid receptors of the B-typ (GABA-B receptor agonists/partial agonists) known to the person skilled in the art, such as, for example, those mentioned below in the list 23a, without being restricted thereto:
  • List 23a comprises and discloses as exemplary GABA-B receptor agonists the following active agents:
  • AZD-3355 BACLOFEN (in more detail ( ⁇ )-baclofen, S(-)-baclofen or R(+)-baclofen), GABAPENTIN,
  • GABA-B agonists are GABAPENTIN, BACLOFEN, PAZINACLONE and SL-65.1498;
  • the term "compounds, which modify gastrointestinal motility” also comprises in the meaning of the present invention active agents from the following active agent classes which are — in contrast to the above differentiation by modes of action - now differentiated by physiological effects:
  • List 24a comprises and discloses as exemplary gastroprokinetics the following active agents: *243740, A-124728, ALFA-604, CHIR-6028, CYCRIMINE, DOBUPRIDE, EM-536, FLUPERAMIDE, KW-5092, KW-5139, L-368935, L-369466, LOPERAMIDE, P-1380, R-137696, R-18936, RP-73870, SILDENAFIL, SKF-91606, SLV-305, SR-58339, SR-58375-A, SR-58611-A, SR-58878, T-1815,
  • TRIPERIDEN. YM-31636; list 24b comprises and discloses as further exemplary gastroprokinetics the following active agents:
  • ALEMCINAL DARIFENACIN, DOBUPRIDE, E-3620, EM-523, FEDOTOZINE, IDREMCINAL, KW-
  • LAST, TICALOPRIDE, Z-338, ZACOPRIDE; and list 24c comprises and discloses as still further exemplary gastroprokinetics the following active agents:
  • gastroprokinetics according to lists 24a, 24b and 24c more worthy to be mentioned are ALEMCINAL, CINITAPRIDE, DOBUPRIDE, FEDOTOZINE, KW-5092, KW-5139, ITOPRIDE, LIREXAPRIDE, MITEMCINAL, PRUCALOPRIDE, R-137696, RENZAPRIDE, SR-58611-A, T-1815, TEGASEROD, TICALOPRIDE and Z-338; and
  • gastroprokinetics according to lists 24a, 24b and 24c in particular worthy to be mentioned are CINITAPRIDE, ITOPRIDE and TEGASEROD;
  • List 25a comprises and discloses as exemplary antiemetics the following active agents: CINITAPRIDE, RENZAPRIDE and TICALOPRIDE; list 25b comprises and discloses as further exemplary antiemetics the following active agents: AD-8210, ADR-847, ADR-851, BRL-20627-A, BRL-24682, PA-6236, R-51430 and SL-90.0629; list 25c comprises and discloses as still further exemplary antiemetics the following active agents: ALTINICLINE, APREPITANT, BATANOPRIDE, CILANSETRON, DAZOPRIDE, DEXANABINOL, E- 3620, EXEPANOL, FABESETRON, INDISETRON, ITASETRON, LERISETRON, LINTOPRIDE, PA- LONOSETRON, RS-25259-197, VOFOPITANT and ZACOPRIDE; list 25d comprises and discloses as also still further exemplary antiemetics the following active agents: ACETYLLEUCINE
  • antiemetics are CINITAPRIDE, RENZAPRIDE, TICALOPRIDE and, especially, CISAPRIDE, CLEBOPRIDE, DIFENIDOL, E-3620, LEVOSULPIRIDE, LINTOPRIDE, METOCLOPRAMIDE, MOSAPRIDE and ZACOPRIDE;
  • CINITAPRIDE and, especially, CISAPRIDE, CLEBOPRIDE, DIFENIDOL, LEVOSULPIRIDE, METOCLOPRAMIDE and MOSAPRIDE;
  • List 26a comprises and discloses as exemplary antispasmodics the following active agents: CIMETROPIUM BROMIDE, BIPERIDEN, DENBUFYLLINE, ETAZOLATE, FETOXILATE, ICI-63197, MEBEVERINE, NITRAQUAZONE, ORG-30029, PINAVERIUM BROMIDE, PRIDINOL, PROCYCLI- DINE, ROLIPRAM, TIBENELAST, TRIHEXYPHENIDYL, TRIMEBUTINE, UK-84149 and ZARDAVER- INE;
  • antispasmodics according to list 26a in particular worthy to be mentioned are BIPERIDEN, PRIDINOL, PROCYCLIDINE, TRIHEXYPHENIDYL and, especially, MEBEVERINE.
  • the term "compounds, which modify gastrointestinal motility” comprises not only the active compounds or active agents per se but also pharmacologically acceptable derivatives such as, for example, pharmaceutically acceptable salts, solvates (in particular hydrates), solvates of the salts, polymorphs, tautomers, racemates, diastereoisomers or enantiomers of these compounds or agents.
  • a first special aspect (a) of the term "compounds, which modify gastrointestinal motility” refers to those compounds, which modify gastrointestinal motility and/or reduce the incidence of transient lower oesophageal sphincter relaxation (TLOSR).
  • TLOSR transient lower oesophageal sphincter relaxation
  • NK-1 neurokinin-1
  • GABA-B receptor agonists/partial agonists are to be mentioned, in particular those specified above by reference or expressis verbis.
  • Exemplary compounds, which reduce the incidence of transient lower oesophageal sphincter relaxation (TLOSR), according to aspect a to be emphasized are 4-amino-3-(4-chlorophenyl)butanoic acid (baclofen), (3-aminopropyl)methylphosphinic acid, (3-amino-2- hydroxypropyl)methylphosphinic acid, (3-amino-2-(4-chlorophenyl)propyl)sulfinic acid, (3- aminopropyl)(difluoromethyl)phosphinic acid, (3-amino-2-oxo-propyl)methyl phosphinic acid, 4-amino- 3-(5-chlorothien-2-yl)butanoic acid and (3-aminopropyl)phosphonous acid.
  • a second special aspect (aspect b) of the term "compounds, which modify gastrointestinal motility” refers to those compounds, which modify gastrointestinal motility, and, which are particularly useful for therapy of irritable bowel syndrome (IBS), such as, for example, those compounds of the following active agent classes:
  • 5-HT-(partial-)agonists/antagonists such as, e.g. 5-HT3-antagonists, 5-HT4-agonists, 5-HT4-partial- agonists or 5-HT4-antagonists
  • cholecystokinin A antagonists muscarinic M3 antagonists, kappa opioid receptor agonists, motilin agonists (motilides), delta opioid receptor agonists, dopamine receptor antagonists, neurokinin antagonists (in particular NK-1, NK-2 or NK-3 antagonists), NMDA-receptor antagonists, alpha-2 adrenoceptor agonists or corticotropin releasing factor antagonists, whereby
  • 5-HT-(partial-)agonists/antagonists such as, e.g. 5-HT3-antagonists, 5-HT4-agonists, 5-HT4-partial- agonists or 5-HT4-antagonists
  • cholecystokinin A antagonists e.g. 5-HT3-antagonists, 5-HT4-agonists, 5-HT4-partial- agonists or 5-HT4-antagonists
  • cholecystokinin A antagonists e.g. 5-HT3-antagonists, 5-HT4-agonists, 5-HT4-partial- agonists or 5-HT4-antagonists
  • cholecystokinin A antagonists cholecystokinin A antagonists
  • muscarinic M3 antagonists kappa opioid receptor agonists
  • motilin agonists motilin agonists (motilides)
  • delta opioid receptor agonists and dopamine receptor antagonists are more worthy to be mentioned.
  • CLONIDINE (as exemplary alpha-2 adrenoceptor agonist), DIZOCILPINE (as exemplary NMDA- receptor antagonist), EZLOPITANT (as exemplary selective NK-1 antagonist), NEPADUTANT (as exemplary selective NK-2 antagonist), ANTALARMIN (as exemplary corticotropin releasing factor antagonist) and, in particular,
  • a third special aspect (aspect c) of the term "compounds, which modify gastrointestinal motility” refers to those compounds, which modify gastrointestinal motility. and, which are particularly useful for therapy of gastro-oesophageal reflux disease (GERD), such as, for example, compounds of the class of motilin agonists (motilides), of the class of 5-HT-(partial-)agonists/antagonists (such as, e.g.
  • 5-HT3-antagonists 5-HT4-agonists, 5-HT4-partial-agonists or 5-HT4- antagonists
  • 5-HT4-agonists of the class of GABA-B receptor agonists or active agents which reduce the incidence of transient lower oesophageal sphincter relaxation (TLOSR) are more worthy to be mentioned.
  • TLOSR transient lower oesophageal sphincter relaxation
  • PIBOSEROD PIBOSEROD
  • MITEMCINAL MITEMCINAL
  • TEGASEROD TEGASEROD
  • a fourth special aspect (aspect d) of the term "compounds, which modify gastrointestinal motility” refers to those compounds, which modify gastrointestinal motility, and, which are particularly useful antiemetics, such as, for example, compounds of the class of
  • 5-HT-(partial-)agonists/antagonists such as, e.g. 5-HT3-antagonists, 5-HT4-agonists, 5-HT4-partial- agonists or 5-HT4-antagonists
  • the class of dopamine receptor antagonists in particular dopamine D2 receptor antagonists
  • the class of NMDA receptor antagonists in particular NK-1, NK-2 or NK-3 antagonists
  • the class of neurokinin antagonists in particular NK-1, NK-2 or NK-3 antagonists.
  • a fifth special aspect (aspect e) of the term "compounds, which modify gastrointestinal motility” refers to those compounds, which modify gastrointestinal motility, and, which are particularly useful gastroprokinetics, such as, for example, compounds of the class of
  • 5-HT-(partial-)agonists/antagonists such as, e.g. 5-HT2-, 5-HT3- and 5-HT4-(partial-)agonists/an- tagonists
  • muscarinic antagonists such as, e.g. 5-HT2-, 5-HT3- and 5-HT4-(partial-)agonists/an- tagonists
  • muscarinic antagonists such as, e.g. 5-HT2-, 5-HT3- and 5-HT4-(partial-)agonists/an- tagonists
  • muscarinic antagonists such as, e.g. 5-HT2-, 5-HT3- and 5-HT4-(partial-)agonists/an- tagonists
  • dopamine receptor antagonists in particular dopamine D2 receptor antagonists
  • cholecystokinin A antagonists such as, e.g. 5-HT2-, 5-HT3- and 5-HT4-(partial-)agonists/an- tagonists
  • ALEMCINAL DOBUPRIDE, FEDOTOZINE, KW-5092, KW-5139, LIREXAPRIDE, PRUCALOPRIDE, R-137696, RENZAPRIDE, SR-58611-A, Z-338 and, in particular, MITEMCINAL, TICALOPRIDE, and, in more particular,
  • a sixth special aspect (aspect f) of the term "compounds, which modify gastrointestinal motility” refers to those compounds, which are selected from the class of 5-HT-(partial-)agonists/antagonists (such as, e.g. 5-HT2-, 5-HT3- and 5-HT4-(partial-)ago- nists/antagonists, in particular 5-HT3-antagonists, 5-HT4-agonists, 5-HT4-partial-agonists or 5-HT4- antagonists), from the class of muscarinic antagonists, from the class of kappa opioid receptor agonists, from the class of dopamine receptor antagonists (in particular dopamine D2 receptor antagonists), from the class of cholecystokinin A antagonists, from the class of motilin agonists (motilides) or from the class of GABA-B receptor agonists/partial agonists or from active agents which reduce the incidence of transient lower oesophageal sphincter relaxation (TLOSR).
  • a seventh special aspect (aspect g) of the term "compounds, which modify gastrointestinal motility” refers to those compounds, which are selected from the class of 5-HT-(partiaI-)agonists/antagonists.
  • a first sub aspect of the expression "5-HT-(partial-)agonists/antagonists" refers to 5-HT4-partial-agonists.
  • 5-HT4-partial-agonists include any compound which can partially activate 5-HT4 receptors (intrinsic activity less than that of serotonin, i. e. ⁇ 1. 00.
  • the intrinsic activity may be determined in the non-electrically or electrically stimulated guinea pig ileum or striatum assay, e. g. as disclosed in EP-A1-0 505 322, Br. J. Pharmacol., 115, 1387, 1995 or in the guinea pig distal colon test e. g. as disclosed in Br. J.
  • Exemplary 5- HT4- partial-agonists include (1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-butyl-4-piperidinyl]-1- propanone or (1 -(4-amino-5-chloro-2-methoxyphenyl)-3-[1 -(methylsulphonylamino)ethyl-4-piperidinyl]- 1-propanone or, in particular, those compounds disclosed in EP0505322, e.g. TEGASEROD.
  • 5-HT4-agonists include any compound which can activate 5-HT4-receptors under quiescent/resting conditions, such as, for example, CISAPRIDE, NOR- CISAPRIDE, RENZAPRIDE, ZACOPRIDE, MOSAPRIDE, PRUCALOPRIDE, SB 205149, SC 53116, SL-65.0155, E-3620, RS 67333, RS 67506, BIMU-1, BIMU-8 or (S)-RS 56532.
  • CISAPRIDE CISAPRIDE
  • NOR- CISAPRIDE NOR- CISAPRIDE
  • RENZAPRIDE RENZAPRIDE
  • ZACOPRIDE ZACOPRIDE
  • MOSAPRIDE PRUCALOPRIDE
  • SB 205149 SC 53116, SL-65.0155, E-3620, RS 67333, RS 67506, BIMU-1, BIMU-8 or (S)-RS 56532.
  • a third sub aspect of the expression "5-HT-(partial-)agonists/antagonists" refers to 5-HT3-antagonists.
  • 5-HT3 receptor antagonists include any compound which binds to the 5-HT3 receptor and antagonize the effect of 5-HT3-agonists, such as, for example CILANSETRON, ALOSETRON, RAMOSETRON, AZASETRON, ONDANSETRON, DO- LASETRON, RAMOSETRON, GRANISETRON, or TROPISETRON.
  • a fourth sub aspect of the expression "5-HT-(partial-)agonists/antagonists” refers to compounds which activates and/or binds to 5-HT receptors and which are not either 5-HT4-partial-agonists or 5-HT4-antagonists as defined herein.
  • Exemplary compounds according to this fourth sub aspect are those 5-HT-(partial-)agonists/antagonists, which are mentioned expressis verbis in this description, with the proviso that 5-HT4-partial-agonists and 5-HT4-antagonists are thereof disclaimed.
  • a fifth sub aspect of the expression "5-HT-(partial-)agonists/antagonists" refers to any compound which binds to the 5-HT4 receptor as defined by the IUPHAR (Pharmacological Reviews, Vol. 44, p. 157-213, 1994) and that do not activate the 5-HT4 receptor and antagonize the effects of serotonin.
  • a relevant test to determine whether or not a compound is a 5-HT4- antagonist is the Guinea-Pig distal colon test as described in Br. J. Pharm., p. 1593-1599 (1993) or in the test described in Arch. Pharmacol., Vol.343, p. 439-446 (1991 ).
  • Representative 5-HT4 antagonists include e. g.
  • a sixth sub aspect of the expression "5-HT-(partial-)agonists/antagonists" refers to compounds which show characteristics of 5-HT3 receptor antagonists and 5-HT4 receptor agonists or antagonists such as, for example, CISAPRIDE and NOR-CISAPRIDE; BIMU compounds, for example BIMU1 , BIMU8 and DAU 6215 (also known as ITASETRON) as disclosed in Dumuis A., et al., Naunyn Schmiedeber's Arch. Pharmacol., Vol. 343 (3), pp. 245-251 (1991); DAU- 6236 as disclosed in Rizzi, C. A. et al., J. Pharmacol. Exp. Ther., Vol.
  • BIMU compounds for example BIMU1 , BIMU8 and DAU 6215 (also known as ITASETRON) as disclosed in Dumuis A., et al., Naunyn Schmiedeber's Arch. Pharmacol., Vol. 343 (3),
  • a seventh sub aspect of the expression "5-HT-(partial-)agonists/antagonists" according to said special aspect g refers to compounds, which activates or binds to 5-HT receptors, and which are not 5-HT4- partial-agonists.
  • Exemplary compounds according to this seventh sub aspect are those 5-HT-(partial- )agonists/antagonists, which are mentioned expressis verbis herein, with the proviso that 5-HT4- partial-agonists are thereof disclaimed.
  • 5-HT-(partial-)agonists/antagonists refers to compounds, which activates or binds to 5-HT receptors, and which are not either selective 5-HT4-partial-agonists or selective 5-HT-anatgonists.
  • exemplary compounds according to this eighth sub aspect are those 5-HT-(partial-)agonists/antagonists, which are mentioned expressis verbis herein, with the proviso that selective 5-HT4-partial-agonists and selective 5-HT4-antagonists are thereof disclaimed.
  • selective means in this context a compound which does not substantially bind to or stimulate the 5-HT3 receptor subtype.
  • An eighth special aspect (aspect h) of the term "compounds, which modify gastrointestinal motility” refers to those compounds, which are selected from the class of GABA-A and, in particular, of the class of GABA-B receptor agonists/partial agonists.
  • a ninth special aspect (aspect i) of the term "compounds, which modify gastrointestinal motility” refers to those compounds, which are selected from a group consisting of muscarinic antagonists, kappa opioid receptor agonists, delta opioid receptor agonists, opioid receptor agonists, dopamine receptor antagonists, cholecystokinin A antagonists, alpha-2 adrenoceptor agonists, N-methyl-D-aspartate receptor antagonists, non-N-methyl-D-aspartate glutamate receptor antagonists, nitric oxide synthase inhibitors, motilin agonists, somatostatin agonists/antagonists, neurotensin agonists/antagonists, vasoactive intestinal peptide antagonists, substance P antagonists, neurokinin antagonists, calcium channel blockers, potassium channel openers, selective serotonin reuptake inhibitors, corticotropin releasing factor antagonists, GABA-A receptor agonists, GABA-B receptor agonists
  • a tenth special aspect (aspect j) of the term “compounds, which modify gastrointestinal motility” refers to those compounds, which are mentioned or specified expressis verbis or by reference in the description of this invention, and which are not 5-HT-(partial-)agonists/antagonists.
  • An eleventh special aspect (aspect k) of the term “compounds, which modify gastrointestinal motility” refers to those compounds, which are mentioned or specified expressis verbis or by reference in the description of this invention, and which are not 5-HT4-partial-agonists or 5-HT4-antagonists.
  • a twelfth special aspect (aspect I) of the term "compounds, which modify gastrointestinal motility” refers to those compounds, which are mentioned or specified expressis verbis or by reference in the description of this invention, and which show characteristics of 5-HT3-antagonists and 5-HT4-agonists or antagonists.
  • a thirteenth special aspect (aspect m) of the term "compounds, which modify gastrointestinal motility” refers to those compounds, which are mentioned or specified expressis verbis or by reference in the description of this invention, and which are 5-HT3-antagonists.
  • a first sub aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a first agent which is a 5-HT-(partial- )agonist/an-tagonist such as, for example, one of those mentioned above; and a second agent which is (S)-pantoprazole and/or its salts.
  • a second sub aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a first agent which is a 5-HT-(partial- )ago-nist/antagonist such as, for example, one of those disclosed generically or, in particular, specifically in the international application WO 0141748 as useful to be employed in combination with co- agents; and a second agent which is (S)-pantoprazole and/or its salts.
  • a third sub aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a first agent which is a 5-HT-(partial- )ago-nist/antagonist such as, for example, 3-(5-methoxy-1H-indol-3-yl-methylene)-N- pentylcarbazimidamide, which is also known as tegaserod, or a salt (e.g. the hydrogen maleate) or a tautomere thereof; and a second agent which is (S)-pantoprazole and/or its salts.
  • a first agent which is a 5-HT-(partial- )ago-nist/antagonist such as, for example, 3-(5-methoxy-1H-indol-3-yl-methylene)-N- pentylcarbazimidamide, which is also known as tegaserod, or a salt (e.g. the hydrogen maleate) or a tautomere thereof
  • active agents selected from the following active agent classes:
  • 5-HT-(partial-)agonists/antagonists such as, e.g. 5-HT2-, 5-HT3- and 5-HT4-(partial-)agonists/an- tagonists, in particular 5-HT3-antagonists, 5-HT4-agonists or 5-HT4-antagonists
  • muscarinic e.g. muscarinic M3 antagonists
  • opioid receptor agonists e.g.
  • dopamine receptor antagonists in particular dopamine D2 recep- tor antagonists
  • IBS irritable bowel syndrome
  • 5-HT-(partial-)agonists/antagonists such as, e.g. 5-HT3-antagonists, 5-HT4-agonists or 5-HT4- antagonists), cholecystokinin A antagonists, muscarinic M3 antagonists, kappa opioid receptor agonists, motilin agonists (motilides), delta opioid receptor agonists, dopamine receptor antagonists, neurokinin antagonists (in particular NK-1, NK-2 or NK-3 antagonists), NMDA-receptor antagonists, alpha- 2 adrenoceptor agonists or corticotropin releasing factor antagonists.
  • 5-HT3-antagonists such as, e.g. 5-HT3-antagonists, 5-HT4-agonists or 5-HT4- antagonists
  • cholecystokinin A antagonists such as, e.g. 5-HT3-antagonists, 5-HT4-agonists or 5-HT4- antagonists
  • cholecystokinin A antagonists
  • GFD gastro-oesophageal reflux disease
  • active agent classes motilin agonists (motilides), 5-HT-(partial-)agonists/antagonists (such as, e.g.
  • 5-HT3-antagonists 5-HT4-agonists or 5-HT4-antagonists
  • muscarinic antagonists opioid agonists/partial agonists
  • NMDA- receptor antagonists non-NMDA glutamate receptor antagonists
  • somatostatin agonists NO-synthase inhibitors
  • GABA in particular GABA-B
  • active agents which reduce the incidence of transient lower oesophageal sphincter relaxation (TLOSR).
  • exemplary compounds which modify gastrointestinal motility, to be emphasized within the meaning of the present invention in a special embodiment (embodiment a) include active agents for use in therapy of IBS or GERD, or for use as gastroprokinetics or antiemetics, such as, for example without being restricted thereto,
  • Exemplary compounds, which modify gastrointestinal motility, to be emphasized within the meaning of the present invention in a further special embodiment include active agents for use in therapy of IBS or GERD, such as, for example without being restricted thereto, ALOSETRON, ALVIMOPAN, CILANSETRON, DARIFENACIN, DEXLOXIGLUMIDE, E-3620, FABESETRON, LINTOPRIDE, LY-353433, MITEMCINAL, (S)-OXYBUTININ, PIBOSEROD, TEGASEROD, TICALOPRIDE or TRIMEBUTINE.
  • active agents for use in therapy of IBS or GERD such as, for example without being restricted thereto, ALOSETRON, ALVIMOPAN, CILANSETRON, DARIFENACIN, DEXLOXIGLUMIDE, E-3620, FABESETRON, LINTOPRIDE, LY-353433, MITEMCINAL, (S)-OXYBUTININ, PIBOSEROD,
  • Exemplary compounds, which modify gastrointestinal motility, to be emphasized within the meaning of the present invention in a further special embodiment include suitably ALEMCINAL, ASIMADOLINE, BACLOFEN, BIPERIDEN, CILANSETRON, CINITAPRIDE, CISAPRIDE, CLEBOPRIDE, DARIFENACIN, DAZOPRIDE, DIFENIDOL, DOBUPRIDE, E-3620, EM-523, FABESETRON, FEDOTOZINE, GABAPENTIN, IDREMCINAL, ITOPRIDE, KW-5092, KW-5139, LEVOSULPIRIDE, LINTOPRIDE, LIREXAPRIDE, MEBEVERINE, METOCLOPRAMIDE, MITEMCINAL, MOSAPRIDE, NITRAQUAZONE, PAZINACLONE, PIBOSEROD, PRIDINOL, PROCYCLIDINE, PRUCALOPRIDE, PUMOSETRAG, R-137696, RENZAPRIDE, RICA
  • Exemplary compounds, which modify gastrointestinal motility, to be emphasized within the meaning of the present invention in a further special embodiment include suitably ALEMCINAL, ALVIMOPAN, CINITAPRIDE, DEXLOXIGLUMIDE, DOBUPRIDE, FEDOTOZINE, KW- 5092, KW-5139, ITOPRIDE, LIREXAPRIDE, MITEMCINAL, PIBOSEROD, PRUCALOPRIDE, R- 137696, RENZAPRIDE, SR-58611-A, T-1815, TEGASEROD, TICALOPRIDE and Z-338.
  • gastrointestinal diseases comprises diseases or disorders of the gastrointestinal tract known to the person skilled in the art.
  • gastrointestinal motility disorders disorders of gastric emptying, bowel disorders, oesophageal diseases, gastrointestinal inflammatory diseases (such as inflammatory bowel disease) and gastrointestinal diseases associated with inflammatory attendant phenomenon are to be emphasized.
  • gastro- oesophageal reflux disease GFD
  • IBS irritable bowel syndrome
  • this invention relates to the combined use of (S)-pantoprazole and/or its salts and compounds, which modify gastrointestinal motility, in the treatment of gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD) or irritable bowel syndrome (IBS).
  • GFD gastro-oesophageal reflux disease
  • IBS irritable bowel syndrome
  • An alternative aspect of the present invention relates to the combined use of (S)-pantoprazole and/or its salts and compounds, which modify gastrointestinal motility, in the improved treatment of altered gastrointestinal motility, sensitivity and/or secretion and/or abdominal disorders including both functional and organic diseases, such as, for example, in the treatment of chronic symptoms of dyspepsia and diseases associated herewith, such as, for example, GERD, duodenal ulcer or gastric ulcer and other diagnoses (e.g. functional/non-ulcerative dyspepsia, gallbladder or liver diseases).
  • a further aspect of the present invention relates to the combined use of (S)-pantoprazole and/or its salts and compounds, which modify gastrointestinal motility, to modulate and normalize gastrointestinal motility, sensitivity and/or secretion in therapy or prophylaxis.
  • a further aspect of the present invention relates to the combined use of (S)-pantoprazole and/or its salts and compounds, which modify gastrointestinal motility, to obtain a particularly enhanced treatment response for altered gastrointestinal motility, sensitivity and/or secretion and/or abdominal disorders, in particular in patients suffering from GERD, and/or to obtain a particularly enhanced reduction of gastrointestinal pain and other symptoms normally associated with disturbed/altered gastrointestinal motility, sensitivity and/or secretion.
  • a further aspect of the present invention is the use of (S)-pantoprazole and/or its salts and compounds, which modify gastrointestinal motility, in the manufacture of pharmaceutical compositions for the treatment of gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD) or irritable bowel syndrome (IBS).
  • GFD gastro-oesophageal reflux disease
  • IBS irritable bowel syndrome
  • a further aspect of the present invention is the simultaneous, separate or sequential co-administration of (S)-pantoprazole and/or its salts with one or more compounds, which modify gastrointestinal motility, to treat gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD) or irritable bowel syndrome (IBS).
  • GFD gastro-oesophageal reflux disease
  • IBS irritable bowel syndrome
  • a further aspect of the present invention is a method for treatment of gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD) or irritable bowel syndrome (IBS), comprising administering an effective amount of (S)-pantoprazole and/or its salts simultaneously, separately or sequentially with one or more compounds, which modify gastrointestinal motility, to a mammal, preferably a human, in need thereof.
  • GFD gastro-oesophageal reflux disease
  • IBS irritable bowel syndrome
  • a further aspect of the present invention is a method for treatment of gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD) or irritable bowel syndrome (IBS), comprising ad- ministering a pharmaceutical composition according to this invention to a mammal, preferably a human, in need thereof.
  • GFD gastro-oesophageal reflux disease
  • IBS irritable bowel syndrome
  • a further aspect of the present invention is a preferably orally applicable pharmaceutical composition for simultaneous administration comprising, in admixture, a first active ingredient, which is (S)- pantoprazole and/or its salts, and a second active ingredient, which is at least one compound, which modifies gastrointestinal motility, to treat gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD) or irritable bowel syndrome (IBS) in a mammal, preferably a human.
  • GUD gastro-oesophageal reflux disease
  • IBS irritable bowel syndrome
  • a further aspect of the present invention is a composition
  • a composition comprising a first active ingredient, which is (S)-pantoprazole and/or its salts, and a second active ingredient, which is at least one compound, which modifies gastrointestinal motility, for simultaneous, sequential or separate use in therapy in any order.
  • a further aspect of the present invention is a preferably orally applicable pharmaceutical composition in unit dosage comprising (S)-pantoprazole and/or its salts together with at least one compound, which modifies gastrointestinal motility, for use in therapy, e.g. to treat gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD) or irritable bowel syndrome (IBS) in a mammal.
  • GFD gastro-oesophageal reflux disease
  • IBS irritable bowel syndrome
  • a further aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising (S)-pantoprazole and/or its salts together with at least one compound, which modifies gastrointestinal motility, wherein the acid pump antagonist and the compound, which modifies gastrointestinal motility, are administered in a single dosage form, such that the acid pump antagonist and the compound, which modifies gastrointestinal motility, are physically separated from each other.
  • a further aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising, in admixture, a first active ingredient, which is (S)-pantoprazole and/or its salts, and a second active ingredient, which is at least one compound, which modifies gastrointestinal motility.
  • a further aspect of this invention is a pharmaceutical composition
  • a pharmaceutical composition comprising: (a) a pharmaceutically effective amount of (S)-pantoprazole and/or its salts, and (b) a pharmaceutically effective amount of at least one compound, which modifies gastrointestinal motility.
  • a further aspect of this invention is a pharmaceutical composition
  • a pharmaceutical composition comprising: (a) a pharmaceutically effective amount of (S)-pantoprazole and/or its salts, and (b) a pharmaceutically effective amount of at least one compound, which modifies gastrointestinal motility, wherein component (a) and component (b) are maintained in the same delivery vehicle.
  • a pharmaceutical composition comprising: (a) a pharmaceutically effective amount of (S)-pantoprazole and/or its salts, and (b) a pharmaceutically effective amount of at least one compound, which modifies gastrointestinal motility, wherein component (a) and component (b) are maintained in different delivery vehicles.
  • a further aspect of the present invention is a preferably orally applicable pharmaceutical formulation
  • a first active ingredient which is (S)-pantoprazole and/or its salts
  • a second active ingredient which is at least one compound, which modifies gastrointestinal motility
  • a pharmaceutically acceptable carrier diluent, adjuvant, auxiliary or excipient for use in therapy, e.g. to treat gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD) or irritable bowel syndrome (IBS) in a mammal, especially a human.
  • GUD gastro-oesophageal reflux disease
  • IBS irritable bowel syndrome
  • a further aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a first active ingredient, which is (S)-pantoprazole and/or its salts, a second active ingredient, which is at least one compound, which modifies gastrointestinal motility, and one or more pharmaceutically acceptable carriers, diluents, adjuvants, auxiliaries or excipients.
  • a further aspect of the present invention is a first pharmaceutical formulation comprising (S)- pantoprazole and/or its salts and a pharmaceutically acceptable carrier or diluent, and a second pharmaceutical formulation comprising a compound, which modifies gastrointestinal motility, and a pharmaceutically acceptable carrier or diluent.
  • a further aspect of the present invention is a combination comprising (S)-pantoprazole and/or its salts and at least one compound, which modifies gastrointestinal motility, for simultaneous, sequential or separate use in therapy, e.g. to treat gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD) or irritable bowel syndrome (IBS) in a mammal, especially a human.
  • GFD gastro-oesophageal reflux disease
  • IBS irritable bowel syndrome
  • a further special aspect of the present invention is a pharmaceutical product comprising, in combination, a first active ingredient, which is (S)-pantoprazole and/or its salts, and a second active ingredient, which is at least one compound, which modifies gastrointestinal motility. for simultaneous, sequential or separate use in therapy.
  • a further aspect of the present invention is a pharmaceutical product comprising, in combination, a preparation of a first active ingredient, which is (S)-pantoprazole and/or its salts, and a preparation of a second active ingredient, which is at least one compound, which modifies gastrointestinal motility, for simultaneous, sequential or separate use in therapy, e.g. to treat gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD) or irritable bowel syndrome (IBS) in a mammal, especially a human.
  • GUD gastro-oesophageal reflux disease
  • IBS irritable bowel syndrome
  • a further aspect of the present invention is a pharmaceutical preparation comprising a first active ingredient, which is (S)-pantoprazole and/or its salts, a second active ingredient, which is at least one compound, which modifies gastrointestinal motility, and one or more pharmaceutically acceptable carriers, diluents, adjuvants, auxiliaries or excipients.
  • a further aspect of the present invention is a commercial package comprising a first active ingredient, which is (S)-pantoprazole and/or its salts, and a second active ingredient, which is at least one compound, which modifies gastrointestinal motility, together with instructions for simultaneous, sequential or separate use in therapy.
  • a first active ingredient which is (S)-pantoprazole and/or its salts
  • a second active ingredient which is at least one compound, which modifies gastrointestinal motility
  • a further aspect of the present invention is a commercial package comprising (S)-pantoprazole and/or its salts as active ingredient together with instructions for simultaneous, sequential or separate use with a compound, which modifies gastrointestinal motility.
  • a further aspect of the present invention is a commercial package comprising at least one compound, which modifies gastrointestinal motility, as active ingredient(s) together with instructions for simultaneous, sequential or separate use with (S)-pantoprazole and/or its salts.
  • a further aspect of the present invention is a kit comprising at least one dosage unit of (S)- pantoprazole and/or its salts as well as at least one dosage unit of at least one compound, which modifies gastrointestinal motility, for simultaneous, sequential or separate use in therapy.
  • kit can be provided with instructions for use.
  • a further aspect of the present invention is a kit comprising a preparation of a first active ingredient, which is (S)-pantoprazole and/or its salts, a preparation of a second active ingredient, which is at least one compound, which modifies gastrointestinal motility, and instructions for simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
  • a preparation of a first active ingredient which is (S)-pantoprazole and/or its salts
  • a preparation of a second active ingredient which is at least one compound, which modifies gastrointestinal motility
  • a further aspect of the present invention is the use of a pharmaceutical composition, pharmaceutical product, formulation, preparation, combination, commercial package or kit according to the invention in the manufacture of a medicament for use in the treatment of gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD) or irritable bowel syndrome (IBS).
  • GUD gastro-oesophageal reflux disease
  • IBS irritable bowel syndrome
  • this invention relates to the combined use of (S)-pantoprazole and/or its salts and compounds, which reduce the incidence of transient lower oesophageal sphincter relaxation (TLOSR), in the treatment of gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD).
  • TLOSR transient lower oesophageal sphincter relaxation
  • GOD gastro-oesophageal reflux disease
  • a further special aspect of the present invention is the use of (S)-pantoprazole and/or its salts and compounds, which reduce the incidence of transient lower oesophageal sphincter relaxation (TLOSR), in the manufacture of pharmaceutical compositions for the treatment of gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD).
  • TLOSR transient lower oesophageal sphincter relaxation
  • a further special aspect of the present invention is the simultaneous, separate or sequential co- administration of (S)-pantoprazole and/or its salts with one or more compounds, which reduce the incidence of transient lower oesophageal sphincter relaxation (TLOSR), to treat gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD).
  • TLOSR transient lower oesophageal sphincter relaxation
  • GOD gastro-oesophageal reflux disease
  • a further special aspect of the present invention is a method for treatment of gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD), comprising administering an effective amount of (S)-pantoprazole and/or its salts simultaneously, separately or sequentially with one or more compounds, which reduce the incidence of transient lower oesophageal sphincter relaxation (TLOSR), to a mammal, preferably a human, in need thereof.
  • GFD gastro-oesophageal reflux disease
  • TLOSR transient lower oesophageal sphincter relaxation
  • a further special aspect of the present invention is a preferably orally applicable pharmaceutical composition for simultaneous administration comprising, in admixture, a first active ingredient, which is (S)-pantoprazole and/or its salts, and a second active ingredient, which is at least one compound, which reduces the incidence of transient lower oesophageal sphincter relaxation (TLOSR), to treat gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD) in a mammal, preferably a human.
  • TLOSR transient lower oesophageal sphincter relaxation
  • a further special aspect of the present invention is a composition
  • a composition comprising a first active ingredient, which is (S)-pantoprazole and/or its salts, and a second active ingredient, which is at least one compound, which reduces the incidence of transient lower oesophageal sphincter relaxation (TLOSR), for simultaneous, sequential or separate use in therapy in any order.
  • TLOSR transient lower oesophageal sphincter relaxation
  • a further special aspect of the present invention is a pharmaceutical product comprising, in combination, a first active ingredient, which is (S)-pantoprazole and/or its salts, and a second active ingredient, which is at least one compound, which reduces the incidence of transient lower oesophageal sphincter relaxation (TLOSR), for simultaneous, sequential or separate use in therapy.
  • a first active ingredient which is (S)-pantoprazole and/or its salts
  • TLOSR transient lower oesophageal sphincter relaxation
  • a further special aspect of the present invention is a commercial package comprising a first active ingredient, which is (S)-pantoprazole and/or its salts, and a second active ingredient, which is at least one compound, which reduces the incidence of transient lower oesophageal sphincter relaxation (TLOSR), together with instructions for simultaneous, sequential or separate use in therapy.
  • a first active ingredient which is (S)-pantoprazole and/or its salts
  • TLOSR transient lower oesophageal sphincter relaxation
  • a further special aspect of the present invention is a commercial package comprising (S)-pantoprazole and/or its salts as active ingredient together with instructions for simultaneous, sequential or separate use with a compound, which reduces the incidence of transient lower oesophageal sphincter relaxation (TLOSR).
  • a further special aspect of the present invention is a commercial package comprising at least one compound, which reduces the incidence of transient lower oesophageal sphincter relaxation (TLOSR), as active ingredient together with instructions for simultaneous, sequential or separate use with (S)- pantoprazole and/or its salts.
  • a further special aspect of the present invention is a kit comprising a preparation of a first active ingredient, which is (S)-pantoprazole and/or its salts, a preparation of a second active ingredient, which is at least one compound, which reduces the incidence of transient lower oesophageal sphincter relaxation (TLOSR), and instructions for simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
  • a preparation of a first active ingredient which is (S)-pantoprazole and/or its salts
  • a preparation of a second active ingredient which is at least one compound, which reduces the incidence of transient lower oesophageal sphincter relaxation (TLOSR)
  • TLOSR transient lower oesophageal sphincter relaxation
  • administering refers preferably to oral application.
  • parenteral e.g. intravenous
  • subcutaneous or rectal application can be also advantageous.
  • the dosage of the active compounds is in a customary order of magnitude comparable with the monodosage, whereby, due to the additive and/or super-additive synergism of the single effects, the relevant doses of the active compounds in the combined dosage can be reduced compared to norm, or whereby - while maintaining the customary doses of the single components - a su ⁇ risingly higher and prolonged effect is obtained.
  • TLOSR transient lower oesophageal sphincter relaxation
  • compositions according to this invention comprising a first active ingredient, which is an acid pump antagonist, and a second active ingredient, which is a 5-HT4- (partial-)agonist/antagonist (e.g. tegaserod or its salt), may be administered in a molar ratio having a range of from about 0.01 to 1000 for the acid pump antagonist to a range of from about 0.01 to about 2 for the 5-HT4-(partial-)agonist/antagonist.
  • the molar ratio for the acid pump antago- nist to the 5-HT4-(partial-)agonist/antagonist is about 1000:1 (acid pump antagonist to 5-HT4-(partial- )agonist/antagonist).
  • the molar ratio for the acid pump antagonist to the 5-HT4-(partial-)agonist/antagonist may be about 1000:1 , 500:1 , 200:1 , 100:1 , 20:1, 5:1, 1:1, 1 :5, 1 :20, 1:100.
  • the total daily dose range which comprises the above described molar ratio, may be administered in a range of from about 0.01 mg to about 1000 mg.
  • the daily dose range may be about 800 mg, 600 mg, 400 mg, 200 mg, 100 mg, 50 mg, 20 mg, 10 mg, 5 mg, 1 mg, 0.1 mg or 0.01 mg.
  • a daily dose range should be between about 0.5 mg to about 100 mg, while more suitably, a daily dose range should be between about 5 mg to about 75 mg.
  • the doses can be administered once daily or two times a day.
  • the therapy should be initiated at a lower dose and increased depending on patient's response, whereby the person skilled in the art knows how and when to interrupt, adjust or terminate therapy in conjunction with individual patient response.
  • the skilled person knows on the base of his/her expert knowledge that it may be necessary to use dosages outside these abovementioned ranges.
  • the active compounds are preferably employed in the form of tablets, coated tablets, capsules, suppositories, patches, emulsions, suspensions, gels or solutions, the active compound content advantageously being between 0.1 and 95%.
  • the person skilled in the art can develop, on the basis of his/her knowledge, by appropriate choice of the excipients and the auxiliaries different galenic forms precisely tailored to the active ingredient(s) (such as, for example, retard forms or gastric acid resistant forms).
  • 'medicament' or 'pharmaceutical composition shall be taken to refer to a composition comprising both the compounds, which modify gastrointestinal motility and (S)-pantoprazole and/or its salts in a fixed combination (fixed unit dosage form), or a medicament pack comprising the two active ingredients as discrete separate dosage forms.
  • the active ingredients are preferably packed into blister cards which are suited for improving compliance.
  • Each blister card preferably contains the medicaments to be taken on one day of treatment.
  • the medicaments can be disposed in different sections on the blister card according to the different ranges of times of day at which the medicaments are to be taken (for example morning and evening or morning, midday and evening).
  • the blister cavities for the medicaments to be taken together at a particular time of day are accommodated in the respective range of times of day.
  • the various times of day are, of course, also put on the blister in a clearly visible way. It is also possible, of course, for example to indicate a period in which the medicaments are to be taken, for example stating the times.
  • the daily sections may represent one line of the blister card, and the times of day are then identified in chronological sequence in this column.
  • Medicaments which must be taken together at a particular time of day are placed together at the appropriate time on the blister card, preferably a narrow distance apart, allowing them to be pushed out of the blister easily, and having the effect that removal of the dosage form from the blister is not forgotten.
  • the title compound can also be prepared from organic-aqueous solvent mixtures.
  • (-)-pantoprazole sodium, or (-)-pantoprazole together with one equivalent of aqueous, for example 2N, sodium hydroxide solution is dissolved in an organic solvent, for example warm acetone.
  • a magnesium salt for example magnesium chloride hexahydrate
  • water 0.5 to 0.55 equivalents of a magnesium salt (for example magnesium chloride hexahydrate), dissolved in water, are added drop by drop, and the mixture is cooled with stirring.
  • the precipitated solid is filtered off, washed with the solvent mixture in question and dried at 50°C under reduced pressure until the weight remains constant. This gives the title compound as a colourless to beige powder.

Abstract

The invention relates to the combination of (S)-pantoprazole and/or its salts and compounds, which modify gastrointestinal motility.

Description

PHARMACEUTICAL COMBINATIONS COMPRISING (S) -PANTOPRAZOLE
Field of application of the invention
The invention relates to the combination of certain active compounds for therapeutic purposes. The substances used in the combination according to the present invention are partly known active compounds, which modify gastrointestinal motility, or compounds, which reduce the incidence of transient lower oesophageal sphincter relaxation (TLOSR).
Known technical background
In U. S. Patent 5,888,535, according to the abstract of said patent "methods and compositions are disclosed utilizing optically pure (-)-pantoprazole for the treatment of ulcers in humans while substantially reducing the concomitant liability of adverse effects associated with the racemic mixture of pantoprazole." - In U. S. Patent 6,552,045 methods and compositions for the prevention, treatment, or management of gastrointestinal disorders or symptoms thereof are disclosed, employing two or more agents or compounds to provide a triple site action on 5-HT3 receptors, 5-HT4 receptors, and at least one of H2 receptors and proton pumps.
Further on, the prior art discloses compounds, which modify gastrointestinal motility by different ways. Thus, for example, the international applications WO 02100823, WO 02100869, WO 02100870 and WO 02100871 disclose compounds, which reduce the incidence of transient lower oesophageal sphincter relaxation (TLOSR). Said international applications are incorporated by reference into the specification of the present invention in their entirety for all purposes. Still further, the prior art teaches the usability of compounds, which modify gastrointestinal motility by any way, for therapy of miscellaneous gastrointestinal diseases. The international application WO 0069438 discloses, inter alia, pharmaceutical compositions comprising NK-1 antagonists and proton pump inhibitors exemplified by omeprazole, lansoprazole, pantoprazole, leminoprazole and certain salts of the (-)-enantiomer of omeprazole, which are said to be useful in the prevention and treatment of diseases brought about by hyper secretion of gastric acid in the gut and/or relaxation of the lower oesophageal sphincter. The international application WO 0185167 discloses pharmaceutical compositions comprising gas- trin/cholecystokinin receptor ligands and certain proton pump inhibitors exemplified inter alia by (RS)- rabeprazole, (RS)-omeprazole, lansoprazole, pantoprazole, (R)-omeprazole, (S)-omeprazole, perpra- zole, (R)-rabeprazole, (S)-rabeprazole, or the alkaline salts thereof, which are said to be useful to reduce hyperplasia, associated with administration of proton pump inhibitors. The international application WO 0141748 discloses pharmaceutical combinations comprising 5-HT4 partial agonists or 5-HT4 antagonists and, inter alia, reversible proton pump inhibitors and their uses in treating gastrointestinal disorders.
There is still a severe need in the art of having drug therapies of gastrointestinal diseases, advantageously of gastro-oesophageal reflux disease (GERD) or irritable bowel syndrome (IBS). Accordingly, there is a need to invent new combinations of active compounds that when used together show preferred therapeutic profiles and/or are more efficacious than when used alone.
Description of the invention
Surprisingly and unanticipatedly, it has now been found that (S)-pantoprazole and its salts, which are described in greater detail below, are particularly useful and beneficial to be employed in functional and synergistic combination with compounds, which modify gastrointestinal motility, for precise therapy of gastrointestinal diseases, in particular of gastro-oesophageal reflux disease (GERD) or irritable bowel syndrome (IBS).
Within the scope of this invention, "(S)-pantoprazole and/or its salts" is understood to include:
- (S)-pantoprazole and/or its salts [which is the same as (-)-pantoprazole and its salts]
- (S)-pantoprazole [(-)-pantoprazole]
- salts of (S)-pantoprazole [(-)-pantoprazole]
- (S)-pantoprazole [(-)-pantoprazole] and/or its salts being substantially free of (R)-pantoprazole [(+)- pantoprazole] and /or its salts
- (S)-pantoprazole [(-)-pantoprazole] being substantially free of (R)-pantoprazole [(+)-pantoprazo!e]
- salts of (S)-pantoprazole [(-)-pantoprazole] being substantially free of salts of (R)-pantoprazole [(+)- pantoprazole].
"Salts" in the context of the invention means all pharmaceutically acceptable salts prepared by reacting (S)-pantoprazole [(-)-pantoprazole] with a suitable inorganic or organic base. Examples of salts with bases which may be mentioned are aluminium, sodium, potassium, lithium, magnesium, zinc or calcium salts. Particularly preferred is the magnesium salt. If (S)-pantoprazole and/or its salts are isolated in crystalline form, the crystals may contain variable amounts of solvent. Accordingly, according to the invention, the term "(S)-pantoprazole and/or its salts" also includes all solvates, in particular all hydrates, of (S)-pantoprazole and/or its salts. An exemplary hydrate of (S)-pantoprazole and/or its salts, which may be mentioned, is (S)-pantoprazole-sodium sesquihydrate [= (S)-pantoprazole-sodium x 1.5 H20]. A particularly preferred hydrate of (S)-pantoprazole and/or its salts is the (S)- pantoprazole-magnesium dihydrate.
"Substantially free" in the context of the invention means that (S)-pantoprazole and/or its salts contains less than 10 % by weight of (R)-pantoprazole. Preferably, "substantially free" means that (S)- pantoprazole and/or its salts contains less than 5 % by weight of (R)-pantoprazole. In the most preferred embodiment, "substantially free" means that (S)-pantoprazole and/or its salts contains less than 1 % by weight of (R)-pantoprazole.
In terms of the present invention, as compounds, which modify gastrointestinal motility, active agents from miscellaneous active agent classes come into question, such as, for example, the following which are differentiated by modes of action: - 5-HT-(partial-)agonists/antagonists (such as, e.g. 5-HT2-, 5-HT3- and 5-HT4-(partial-)agonists/an- tagonists, in particular 5-HT3-antagonists, 5-HT4-agonists, 5-HT4-partial-agonists or 5-HT4- antagonists) known to the person skilled in the art, such as, for example, those mentioned below in the lists 1a, 1b and/or 1c - without being restricted thereto - by means of their INNs or their research code acronyms:
List 1a comprises and discloses as exemplary 5-HT-(partial-)agonists/antagonists the following active agents:
(+)-DU-124884, (S)-[125I]-TDP-1040, (S)-[125l]-TDP-960, (S)-[125l]-TDP-984, ADR-851 , AU-100, AU- 130, AU-224, AU-228, BIMU-1, BIMU-8, BRL-24682, CHF-17454, CILANSETRON, CP-2289, DAZO- PRIDE, E-3620, EM-523, FABESETRON, FCE-26778, FCE-27733, FCE-28159, FCE-28232, FCE- 28276, FCE-28277, FCE-28278, FCE-28307, FCE-28355, FCE-28356, FCE-28773A, FCE-28797A , FCE-29029A, FCE-29030A, FCE-29031A, FCE-29032A, FCE-29033A, FCE-29034A, KGA-0941, KDR-5169, KF-66854, LINTOPRIDE, LIREXAPRIDE, LY-297524, LY-297582, MOSAPRIDE, PA- 6236, PIBOSEROD, PRUCALOPRIDE, PUMOSETRAG, R-76186, RENZAPRIDE, RICASETRON, SB-205149, SB-205800, SB-207710, SC-49518, SC-50410, SC-52246, SC-52491, SC-53116, SC- 55822, SC-56184, SK-951 , SKF-103829, SKF-47029, SL-90.0629, TEGASEROD, TKS-159, TS-951, VB-20B7, Y-34959, Y-36912, YM-114, YM-47813, YM-47821 , YM-53389 and ZACOPRIDE; list 1b comprises and discloses as further exemplary 5-HT-(partial-)agonists/antagonists the following active agents:
1192U90, ABAPERIDONE, ADATANSERIN, ALNESPIRONE, ALNIDITAN, ALX-646CL, AMESER- GIDE, AR-A000002, ASENAPINE, BEMESETRON, BINOSPIRONE, BLONANSERIN, CERI- CLAMINE, CILANSETRON, CP-122288, DAZOPRIDE, DOTARIZINE, DU-125530, DULOXETINE, E- 2101, E-3620, E-6006, EBALZOTAN, ELZASONAN, EM-523, ENILOSPIRONE, EPLIVANSERIN, FABESETRON, FANANSERIN, FLESINOXAN, FLIBANSERIN, FLUPAROXAN, GEPIRONE, ILOP- ERIDONE, INDISETRON, IPSAPIRONE, IRINDALONE, IS-159, ITASETRON, LERISETRON, LE- SOPITRON, LINTOPRIDE, LIREXAPRIDE, LY-353433, LY-53857, MCI-225, MDL-72832, METREN- PERONE, MOXIFETIN, ORG-GC-94, OSEMOZOTAN, PALONOSETRON, PELANSERIN, PIBOSEROD, PRUCALOPRIDE, PUMOSETRAG, REC-15/3079, RENZAPRIDE, RICASETRON, RITAN- SERIN, ROBALZOTAN, ROXINDOLE, RS-25259-197, RU-24969, RUCALOPRIDE, S-15535, SB- 243213, SB-271046, SEGANSERIN, SERGOLEXOLE, SKF-38393, SL-65.0155, STACOFYLLINE, T- 82, U-93385, VILAZODONE, WAY-100289, XALIPRODEN, Y-36912, YM-114, YM-47813, ZACOPRIDE, ZALOSPIRONE and ZATOSETRON; and list 1c comprises and discloses as still further exemplary 5-HT-(partial-)agonists/antagonists the following active agents:
ALMOTRIPTAN, ALOSETRON, AMPEROZIDE, AZASETRON, BUSPIRONE, CARPIPRAMINE, DEPTROPINE, DIMETOTIAZINE, DOLASETRON, ELETRIPTAN, FLUOXETINE, FROVATRIPTAN, GRANISETRON, LISURIDE, METERGOLINE, MIANSERIN, MOSAPRIDE, NARATRIPTAN, NEFA- ZODONE, OLANZAPINE, ONDANSETRON, OXITRIPTAN, RAMOSETRON, RISPERIDONE, Rl- ZATRIPTAN, SARPOGRELATE, SERTRALINE, SUMATRIPTAN, TEGASEROD, TROPISETRON, URAPIDIL, ZIPRASIDONE and ZOLMITRIPTAN;
whereby exemplary 5-HT-(partial-)agonists/antagonists according to lists 1a, 1b and 1c more worthy to be mentioned are
CILANSETRON, DAZOPRIDE, E-3620, EM-523, FABESETRON, LINTOPRIDE, LIREXAPRIDE, MOSAPRIDE, PIBOSEROD, PRUCALOPRIDE, PUMOSETRAG, RENZAPRIDE, RICASETRON, TEGASEROD, Y-36912, YM-114, YM-47813 and ZACOPRIDE;
whereby exemplary 5-HT-(partial-)agonists/antagonists according to lists 1a, 1b and 1c in particular worthy to be mentioned are
E-3620, EM-523, LINTOPRIDE, LIREXAPRIDE, PRUCALOPRIDE, MOSAPRIDE, PUMOSETRAG, RENZAPRIDE, TEGASEROD and ZACOPRIDE;
and whereby exemplary 5-HT-(partial-)agonists/antagonists according to lists 1a, 1b and 1c in more particular worthy to be mentioned are MOSAPRIDE and TEGASEROD;
and whereby a special subgroup of the class of 5-HT-(partial-)agonists/antagonists comprises those 5- HT-(partial-)agonists/antagonists, which are not either 5-HT4-partial-agonists or 5-HT4-antagonists, and whereby a special subgroup of the class of 5-HT-(partial-)agonists/antagonists to be more emphasized comprises those 5-HT-(partial-)agonists/antagonists mentioned expressis verbis above in the lists 1a, 1b and/or 1c, which are not either 5-HT4-partial-agonists or 5-HT4-antagonists;
- muscarinic antagonists (e.g. muscarinic M3 antagonists) known to the person skilled in the art, such as, for example, those mentioned below in the lists 2a, 2b and/or 2c - without being restricted thereto
- by means of their INNs or their research code acronyms:
List 2a comprises and discloses as exemplary muscarinic antagonists the following active agents:
DARIFENACIN and ZAMIFENACIN; list 2b comprises and discloses as further exemplary muscarinic antagonists the following active agents:
(S)-OXYBUTININ, ALVAMELINE, DARENZEPINE, DARIFENACIN, E-6006, FESOTERODINE, KRP-
197, KW-5805, OTENZEPAD, REVATROPATE, RISPENZEPINE, SCH-211803, SILTENZEPINE,
SINTROPIUM BROMIDE, SOLIFENACIN, TELENZEPINE and VAMICAMIDE; and list 2c comprises and discloses as still further exemplary muscarinic antagonists the following active agents:
PIRENZEPINE, TIOTROPIUM BROMIDE and TOLTERODINE;
whereby an exemplary muscarinic antagonist according to lists 2a, 2b and/or 2c more worthy to be mentioned is DARIFENACIN;
- kappa opioid receptor agonists known to the person skilled in the art, such as, for example, those mentioned below in the lists 3a and/or 3b- without being restricted thereto - by means of their INNs or their research code acronyms: List 3a comprises and discloses as exemplary kappa opioid receptor agonists the following active agents: FEDOTOZINE and ASIMADOLINE; and list 3b comprises and discloses as further exemplary kappa opioid receptor agonists the following active agents:
ADL-10-0101, ADL-10-0116, APADOLINE, ASIMADOLINE, E-2078, ENADOLINE, FEDOTOZINE, IGMESINE, LAPPACONITINE, NALFURAFINE and SPIRADOLINE;
whereby exemplary kappa opioid receptor agonists according to lists 3a and/or 3b more worthy to be mentioned are
FEDOTOZINE and ASIMADOLINE;
- delta opioid receptor agonists known to the person skilled in the art, such as, for example, those mentioned below in the list 4a - without being restricted thereto - by means of their INNs or their research code acronyms: list 4a comprises and discloses as exemplary delta opioid receptor agonists the following active agents:
ALVIMOPAN and TRK-851;
- opioid receptor agonists/antagonists (in particular opioid receptor agonists) known to the person skilled in the art, such as, for example, those mentioned below in the list 5a - without being restricted thereto - by means of their INNs or their research code acronyms:
List 5a comprises and discloses as exemplary opioid receptor agonists/antagonists the following active agents:
LEF-553, DIMETHYLTHIAMBUTENE, LOPERAMIDE and REMIFENTANIL;
- dopamine receptor antagonists (in particular dopamine D2 receptor antagonists) known to the person skilled in the art, such as, for example, those mentioned below in the lists 6a, 6b and/or 6c - without being restricted thereto - by means of their INNs or their research code acronyms:
List 6a comprises and discloses as exemplary dopamine receptor antagonists the following active agents:
AD-8210, ITOPRIDE, LEVOSULPIRIDE, METOCLOPRAMIDE, MOSAPRIDE and TICALOPRIDE; list 6b comprises and discloses as further exemplary dopamine receptor antagonists the following active agents: 1192U90, ABAPERIDONE, BIFEPRUNOX, BLONANSERIN, DAB-452, ILOPERIDONE, MAZAPER-
TINE, RACLOPRIDE, SDZ-GLC-756, SLV-313 and TICALOPRIDE; and list 6c comprises and discloses as still further exemplary dopamine receptor antagonists the following active agents:
ITOPRIDE, LEVOSULPIRIDE, METOCLOPRAMIDE, NEMONAPRIDE, OLANZAPINE, RISPERIDO-
NE, SULPIRIDE and ZIPRASIDONE;
whereby dopamine receptor agonists according to lists 6a, 6b and/or 6c more worthy to be mentioned are
ITOPRIDE, LEVOSULPIRIDE, METOCLOPRAMIDE and TICALOPRIDE;
and whereby dopamine receptor agonists according to lists 6a, 6b and/or 6c in particular worthy to be mentioned are
ITOPRIDE, LEVOSULPIRIDE and METOCLOPRAMIDE;
- cholecystokinin A antagonists known to the person skilled in the art, such as, for example, those mentioned below in the lists 7a and/or 7b - without being restricted thereto - by means of their INNs or their research code acronyms:
List 7a comprises and discloses as exemplary cholecystokinin A antagonists the following active agents:
(-)-RP-73870, (S)-(+)-RP-72540, L-365031 and TARAZEPIDE; and
List 7b comprises and discloses as further exemplary cholecystokinin A antagonists the following active agents: DEVAZEPIDE, DEXLOXIGLUMIDE, KSG-504, LINTITRIPT, LOXIGLUMIDE and PRANAZEPIDE;
- alpha-2 adrenoceptor agonists known to the person skilled in the art, such as, for example, those mentioned below in the list 8a - without being restricted thereto - by means of their INNs or their research code acronyms:
List 8a comprises and discloses as exemplary alpha-2 adrenoceptor agonists the following active agents:
ADRAFINIL, APRACLONIDINE, BRIMONIDINE, BUDRALAZINE, CLONIDINE, DEXMEDE-
TOMIDINE, DIMETOFRINE, LOFEXIDINE, MEDETOMIDINE, MOXONIDINE, MPV-295, RIL-
MENIDINE, ROMIFIDINE, S-17089-1, TALIPEXOLE and TIAMENIDINE;
- N-methyl-D-aspartate (NMDA) receptor antagonists known to the person skilled in the art, such as, for example, those mentioned below in the lists 9a and/or 9b - without being restricted thereto - by means of their INNs or their research code acronyms:
List 9a comprises and discloses as exemplary N-methyl-D-aspartate (NMDA) receptor antagonists the following active agents: ACPC, APTIGANEL, BMY-14802, CGP-37849, CNS-5161, DELUCEMINE, DEXANABINOL, DIZO- CILPINE, EAA-090, ELIPRODIL, ERLOSAMIDE, FPL-12495, GACYCLIDINE, GAVESTINEL, IPE- NOXAZONE, LANICEMINE, LICOSTINEL, LIGUSTIZINE, MIDAFOTEL, NERAMEXANE, REMACE- MIDE, SELFOTEL, TRAXOPRODIL, UK-240255 and ZD-9379; and list 9b comprises and discloses as further exemplary N-methyl-D-aspartate (NMDA) receptor antagonists the following active agents:
ALIMEMAZINE, AMINOPROMAZINE, CHLORPROETHAZINE, DEXTROMETHORPHAN , FEL- BAMATE, GLYCINE, MECAMYLAMINE, MILNACIPRAN, PROMAZINE and SERATRODAST;
- non-N-methyl-D-aspartate glutamate receptor antagonists (non-NMDA glutamate receptor antagonists) known to the person skilled in the art, such as, for example, those mentioned below in the list 10a - without being restricted thereto - by means of their INNs or their research code acronyms: list 10a comprises and discloses as exemplary non-N-methyl-D-aspartate glutamate receptor antagonists the following active agents: FG-9041, FG-9065 and RILUZOLE;
- nitric oxide synthase (NO-synthase) inhibitors known to the person skilled in the art, such as, for example, those mentioned below in the lists 11a and/or 11b - without being restricted thereto - by means of their INNs or their research code acronyms: list 11a comprises and discloses as exemplary nitric oxide synthase inhibitors the following active agents:
CNI-1493, ENECADIN, GW-274150, HP-228, ONO-1714, PIMAGEDINE, TARGININE; and list 11b comprises and discloses as further exemplary nitric oxide synthase inhibitor the following active agent: TIRILAZAD;
- motilin agonists (motilides) known to the person skilled in the art, such as, for example, those mentioned below in the lists 12a - without being restricted thereto - by means of their INNs or their research code acronyms:
List 12a comprises and discloses as exemplary motilin agonists the following active agents: A-173508, ALEMCINAL, GM-652, GM-665, KC-11458, KW 5139, IDREMCINAL, MITEMCINAL and SK-896;
whereby motilin agonists according to list 12a more worthy to be mentioned are ALEMCINAL, IDREMCINAL, MITEMCINAL and SK-896;
- somatostatin agonists/antagonists known to the person skilled in the art, such as, for example, those mentioned below in the list 13a - without being restricted thereto - by means of their INNs or their research code acronyms: List 13a comprises and discloses as exemplary somatostatin agonists/antagonists the following active agents:
L-054852, OCTREOTIDE, VAPREOTIDE and LANREOTIDE;
- neurotensin (partial) agonists/antagonists (suitably neurotensin agonists) known to the person skilled in the art, such as, for example, those mentioned below in the lists 14a - without being restricted thereto - by means of their INNs or their research code acronyms:
List 14a comprises and discloses as exemplary neurotensin (partial) agonists/antagonists the following active agents:
SR-142948-A, REMINERTANT and, suitably, CONTULAKIN G, CITRULLIMYCINE A and NT69L;
- vasoactive intestinal peptide (VIP) antagonists known to the person skilled in the art, such as, for example, this mentioned below in the list 15a - without being restricted thereto - by means of its research code acronym:
List 15a comprises and discloses as an exemplary vasoactive intestinal peptide antagonist the following active agent: RO-25-1553;
- substance P (SP) antagonists known to the person skilled in the art, such as, for example, NK-1 antagonists and/or in particular those antagonists mentioned below in the list 16a - without being restricted thereto - by means of their INNs or their research code acronyms:
List 16a comprises and discloses as exemplary substance P antagonists the following active agents: CGP-49823, EZLOPITANT and LANEPITANT;
- neurokinin antagonists (in particular NK-1, NK-2 or NK-3 antagonists) known to the person skilled in the art, such as, for example, those NK-1 antagonists, which are disclosed in the international application WO 0069438 as useful to be employed in combination therapy, and/or in particular those neurokinin antagonists mentioned below in the list 17a - without being restricted thereto - by means of their INNs or their research code acronyms:
List 17a comprises and discloses as exemplary neurokinin antagonists the following active agents: ALTINICLINE, APREPITANT, CGP-49823, CP-122721, EZLOPITANT as selective NK-1 antagonist, NEPADUTANT as selective NK-2 antagonist, LANEPITANT, OSANETANT, S-19752, SAREDUTANT, TALNETANT and VOFOPITANT;
- calcium channel blockers known to the person skilled in the art, such as, for example, those mentioned below in the lists 18a and/or 18b - without being restricted thereto - by means of their INNs or their research code acronyms:
List 18a comprises and discloses as exemplary calcium channel blockers the following active agents: AZELNIDIPINE, BELFOSDIL, BISARAMIL, CD-832, CERM-11956, CLENTIAZEM, CRE-202, CRONIDIPINE, CV-159, DAURICINE, DHP-218, DIPERDIPINE, DIPROTEVERINE , DOPROPIDIL, DOTARIZINE, ELGODIPINE, EMOPAMIL, FANTOFARONE, FOSTEDIL, FPL-62129, FURNIDIPINE, HA-1004, IGANIDIPINE, IOS-11212, KT-362, LECONOTIDE, LEMILDIPINE, LIFARIZINE, LUBELU- ZOLE, MANOALIDE, MCN-5691 , MEPAMIL, MIOFLAZINE, MONATEPIL, NICTIAZEM, OLRADIP- INE, OXODIPINE, P-0285, PRANIDIPINE, RANOLAZINE, RIODIPINE, RONIPAMIL, S-312, SABE- LUZOLE, SB-237376, SEMOTIADIL, SL-87.0495, SQ-31765, TAMOLARIZINE, TIPROPIDIL, TROM- BODIPINE, VATANIDIPINE, YM-16151-4 and ZICONOTIDE; and list 18b comprises and discloses as further exemplary calcium channel blockers the following active agents:
AMLODIPINE, ARANIDIPINE, BARNIDIPINE, BENCYCLANE, BENIDIPINE, BEPRIDIL, BUFLOME- DIL, CAROVERINE, CILNIDIPINE, CINNARIZINE, DILTIAZEM, DROPRENILAMINE, EFONIDIPINE, FASUDIL, FELODIPINE, FENDILINE, FLUNARIZINE, GALLOPAMIL, ISRADIPINE, LACIDIPINE, LERCANIDIPINE, LIDOFLAZINE, LOMERIZINE, MANIDIPINE, NADOLOL, NICARDIPINE, NIFEDIP- INE, NILVADIPINE, NIMODIPINE, NISOLDIPINE, NITRENDIPINE, PERHEXILINE, PINDOLOL, TERODILINE and VERAPAMIL;
- potassium channel openers known to the person skilled in the art, such as, for example, those mentioned below in the lists 19a and/or 19b -without being restricted thereto - by means of their INNs or their research code acronyms:
List 19a comprises and discloses as exemplary potassium channel openers the following active agents:
ABT-598, APRIKALIM, BIMAKALIM, EMAKALIM, EMD-57283, FLINDOKALNER, KCO-912, KRN-
2391, LEMAKALIM, LEVCROMAKALIM, NN-414, NS-8, RETIGABINE, RP-49356, Y-27152, ZD-0947 and ZD-6169; and list 19b comprises and discloses as further exemplary potassium channel openers the following active agents:
LEVOSIMENDAN, NICORANDIL and PINACIDIL;
- selective serotonin reuptake inhibitors (SSRIs) known to the person skilled in the art, such as, for example, those mentioned below in the lists 20a and/or 20b - without being restricted thereto - by means of their INNs or their research code acronyms:
List 20a comprises and discloses as exemplary selective serotonin reuptake inhibitors the following active agents:
BROFAROMINE, BTS-74398, CERICLAMINE, CYANODOTHIEPIN, DELUCEMINE, DULOXETINE, LU-35-138, LUBAZODONE, MANIFAXINE and VILAZODONE; and list 20b comprises and discloses as further exemplary selective serotonin reuptake inhibitors the following active agents:
CITALOPRAM, ESCITALOPRAM, FLUOXETINE, FLUVOXAMINE, MILNACIPRAN, NEFAZODONE, PAROXETINE, SERTRALINE and VENLAFAXINE; - corticotropin releasing factor antagonists known to the person skilled in the art, such as, for example, this mentioned below in the list 21a - without being restricted thereto - by means of its INN:
List 21a comprises and discloses as exemplary corticotropin releasing factor antagonists the following active agent:
ANTALARMIN;
- agonists of gamma-aminobutyric acid receptors of the A-typ (GABA-A receptor agonists) known to the person skilled in the art, such as, for example, those mentioned below in the list 22a - without being restricted thereto - by means of their INNs or their research code acronyms:
List 22a comprises and discloses as exemplary GABA-A receptor agonists the following active agents: GABOXADOL, GEDOCARNIL, ORG-25435, PAGOCLONE and RETIGABINE;
- agonists/partial agonists of gamma-aminobutyric acid receptors of the B-typ (GABA-B receptor agonists/partial agonists) known to the person skilled in the art, such as, for example, those mentioned below in the list 23a, without being restricted thereto:
List 23a comprises and discloses as exemplary GABA-B receptor agonists the following active agents:
AZD-3355, BACLOFEN (in more detail (±)-baclofen, S(-)-baclofen or R(+)-baclofen), GABAPENTIN,
PAZINACLONE, CGP-29030A, CGP-44532, SL-65.1498 and SKF-97541; and those which are disclosed in WO 9811885, EP 0356128, EP 0181833, EP 0399949, EP 0463969,
FR 2,722,192 or in J. Med. Chem (1995), 38, 3297-3312 (such as, e.g. (S)-(3-amino-2- hydroxypropyl)methylphosphinic acid); and those which are named expressis verbis (e.g. as an example) or described and/or claimed generi- cally in WO 02100823, WO 02100869, WO 02100870 or WO 02100871 such as, for example,
4-amino-3-phenylbutanoic acid,
4-amino-3-hydroxybutanoic acid,
4-amino-3-(4-chlorophenyl)-3-hydroxyphenylbutanoic acid,
4-amino-3-(thien-2-yl)butanoicacid,
4-amino-3-(5-chlorothien-2-yl)butanoicacid,
4-amino-3-(5-bromothien-2-yl)butanoicacid,
4-amino-3-(5-methylthien-2-yl)butanoicacid,
4-amino-3-(2-imidazolyl)butanoic acid ,
4-guanidino-3-(4-chlorophenyi)butanoic acid,
3-amino-2-(4-chlorophenyl)-l -nitropropane,
(3-aminopropyl)phosphonous acid,
(4-aminobut-2-yl)phosphonous acid,
(3-amino-2-methylpropyl)phosphonous acid,
(3-aminobutyl)phosphonous acid,
(3-amino-2-(4-chlorophenyl)propyl)phosphonous acid,
(3-amino-2-(4-chlorophenyl)-2-hydroxypropyl)phosphonous acid,
(3-amino-2-(4-fluorophenyl)propyl)phosphonous acid, (3-amino-2-phenylpropyl)phosphonous acid,
(3-amino-2-hydroxypropyl)phosphonous acid,
(E)-(3-aminopropen-1 -yl)phosphonous acid,
(3-amino-2-cyclohexylpropyl)phosphonous acid,
(3-amino-2-benzylpropyl)phosphonous acid,
[3-amino-2-(4-methylphenyl)propyl]phosphonous acid,
[3-amino-2-(4-trifIuoromethylphenyl)propyl]phosphonousacid,
[3-amino-2-(4-methoxyphenyl)propyl]phosphonous acid,
[3-amino-2-(4-chlorophenyl)-2hydroxypropyl]phosphonousacid,
(3-aminopropyl)methylphosphinic acid,
(3-amino-2-hydroxypropyl)methylphosphinic acid,
(3-aminopropyl)(difluoromethyl)phosphinic acid,
(4-aminobut-2-yl)methylphosphinic acid,
(3-amino-1-hydroxypropyl)methylphosphinic acid,
(3-amino-2-hydroxypropyl)(difluoromethyl)phosphinic acid,
(E)-(3-aminopropen-1 -yl)methylphosphinic acid,
(3-amino-2-oxo-propyl)methyl phosphinic acid,
(3-aminopropyl)hydroxymethylphosphinic acid,
(5-aminopent-3-yl)methylphosphinic acid,
(4-amino-1 ,1 ,1 -trifluorobut-2-yl)methylphosphinic acid,
(3-amino-2-(4-chlorophenyl)propyl)sulfinic acid or
3-aminopropylsulfinic acid;
whereby exemplary GABA-B agonists according to list 23a more worthy to be mentioned are GABAPENTIN, BACLOFEN, PAZINACLONE and SL-65.1498;
and whereby exemplary GABA-B agonists according to list 23a in particular worthy to be mentioned are
GABAPENTIN and BACLOFEN.
In addition to the specification given above, the term "compounds, which modify gastrointestinal motility" also comprises in the meaning of the present invention active agents from the following active agent classes which are — in contrast to the above differentiation by modes of action - now differentiated by physiological effects:
- gastroprokinetics known to the person skilled in the art, such as, for example, those mentioned below in the list 24a and/or, advantageously, in the lists 24b and/or 24c - without being restricted thereto - by means of their INNs or their research code acronyms:
List 24a comprises and discloses as exemplary gastroprokinetics the following active agents: *243740, A-124728, ALFA-604, CHIR-6028, CYCRIMINE, DOBUPRIDE, EM-536, FLUPERAMIDE, KW-5092, KW-5139, L-368935, L-369466, LOPERAMIDE, P-1380, R-137696, R-18936, RP-73870, SILDENAFIL, SKF-91606, SLV-305, SR-58339, SR-58375-A, SR-58611-A, SR-58878, T-1815,
TRIPERIDEN. YM-31636; list 24b comprises and discloses as further exemplary gastroprokinetics the following active agents:
ALEMCINAL, DARIFENACIN, DOBUPRIDE, E-3620, EM-523, FEDOTOZINE, IDREMCINAL, KW-
5092, KW-5139, LINTOPRIDE, LIREXAPRIDE, MITEMCINAL, NITRAQUAZONE, PUMOSETRAG,
PRUCALOPRIDE, R-137696, RENZAPRIDE, ROLIPRAM, SK-896, SR-58611-A, T-1815, TIBENE-
LAST, TICALOPRIDE, Z-338, ZACOPRIDE; and list 24c comprises and discloses as still further exemplary gastroprokinetics the following active agents:
BIPERIDEN, BUDIPINE, CINITAPRIDE, FEDOTOZINE, ITOPRIDE, LOPERAMIDE, PROCYCLI-
DINE, SULTOPRIDE, TEGASEROD and TRIHEXYPHENIDYL;
whereby gastroprokinetics according to lists 24a, 24b and 24c more worthy to be mentioned are ALEMCINAL, CINITAPRIDE, DOBUPRIDE, FEDOTOZINE, KW-5092, KW-5139, ITOPRIDE, LIREXAPRIDE, MITEMCINAL, PRUCALOPRIDE, R-137696, RENZAPRIDE, SR-58611-A, T-1815, TEGASEROD, TICALOPRIDE and Z-338; and
whereby gastroprokinetics according to lists 24a, 24b and 24c in particular worthy to be mentioned are CINITAPRIDE, ITOPRIDE and TEGASEROD;
- antiemetics known to the person skilled in the art, such as, for example, those mentioned below in the lists 25a and/or, advantageously, in the lists 25b, 25c and/or 25d - without being restricted thereto
- by means of their INNs or their research code acronyms:
List 25a comprises and discloses as exemplary antiemetics the following active agents: CINITAPRIDE, RENZAPRIDE and TICALOPRIDE; list 25b comprises and discloses as further exemplary antiemetics the following active agents: AD-8210, ADR-847, ADR-851, BRL-20627-A, BRL-24682, PA-6236, R-51430 and SL-90.0629; list 25c comprises and discloses as still further exemplary antiemetics the following active agents: ALTINICLINE, APREPITANT, BATANOPRIDE, CILANSETRON, DAZOPRIDE, DEXANABINOL, E- 3620, EXEPANOL, FABESETRON, INDISETRON, ITASETRON, LERISETRON, LINTOPRIDE, PA- LONOSETRON, RS-25259-197, VOFOPITANT and ZACOPRIDE; list 25d comprises and discloses as also still further exemplary antiemetics the following active agents: ACETYLLEUCINE, ALIZAPRIDE, ALOSETRON, AZASETRON, BROMOPRIDE, CISAPRIDE, CLE- BOPRIDE, DIFENIDOL, DOMPERIDONE, DRONABINOL, GRANISETRON, LEVOSULPIRIDE, METOCLOPRAMIDE, MOSAPRIDE, ONDANSETRON, OXYPENDYL, RAMOSETRON, THIETH- YLPERAZINE, TIAPRIDE, TRIMETHOBENZAMIDE and TROPISETRON;
whereby antiemetics according to lists 25a, 25b, 25c and 25d more worthy to be mentioned are CINITAPRIDE, RENZAPRIDE, TICALOPRIDE and, especially, CISAPRIDE, CLEBOPRIDE, DIFENIDOL, E-3620, LEVOSULPIRIDE, LINTOPRIDE, METOCLOPRAMIDE, MOSAPRIDE and ZACOPRIDE;
and whereby antiemetics in particular worthy to be mentioned are CINITAPRIDE and, especially, CISAPRIDE, CLEBOPRIDE, DIFENIDOL, LEVOSULPIRIDE, METOCLOPRAMIDE and MOSAPRIDE;
- antispasmodics (for example anticholinergics or smooth muscle relaxants) known to the person skilled in the art, such as, for example, those mentioned below in the list 26a - without being restricted thereto - by means of their INNs or their research code acronyms: List 26a comprises and discloses as exemplary antispasmodics the following active agents: CIMETROPIUM BROMIDE, BIPERIDEN, DENBUFYLLINE, ETAZOLATE, FETOXILATE, ICI-63197, MEBEVERINE, NITRAQUAZONE, ORG-30029, PINAVERIUM BROMIDE, PRIDINOL, PROCYCLI- DINE, ROLIPRAM, TIBENELAST, TRIHEXYPHENIDYL, TRIMEBUTINE, UK-84149 and ZARDAVER- INE;
whereby antispasmodics according to list 26a more worthy to be mentioned are
BIPERIDEN, PRIDINOL, PROCYCLIDINE, NITRAQUAZONE, ROLIPRAM, TRIHEXYPHENIDYL,
TIBENELAST and, especially, MEBEVERINE;
and whereby antispasmodics according to list 26a in particular worthy to be mentioned are BIPERIDEN, PRIDINOL, PROCYCLIDINE, TRIHEXYPHENIDYL and, especially, MEBEVERINE.
A person of ordinary skill in the art knows that the abovementioned classification of the specific active agents in said active agent classes should not be regarded in a strict, sole or exclusive meaning. On the contrary, certain active agents can be allocated to more than one active agent class given above, in particular certain active agents can be allocated both to one or more of the abovementioned active agent classes differentiated by modes of action and to one or more of the abovementioned active agent classes differentiated by physiological effects.
Within the scope of this invention, the term "compounds, which modify gastrointestinal motility" comprises not only the active compounds or active agents per se but also pharmacologically acceptable derivatives such as, for example, pharmaceutically acceptable salts, solvates (in particular hydrates), solvates of the salts, polymorphs, tautomers, racemates, diastereoisomers or enantiomers of these compounds or agents.
In the meaning of the present invention, a first special aspect (aspect a) of the term "compounds, which modify gastrointestinal motility" refers to those compounds, which modify gastrointestinal motility and/or reduce the incidence of transient lower oesophageal sphincter relaxation (TLOSR). As ex- emplary compounds according to aspect a, neurokinin-1 (NK-1) antagonists and, particularly, GABA-B receptor agonists/partial agonists are to be mentioned, in particular those specified above by reference or expressis verbis. Exemplary compounds, which reduce the incidence of transient lower oesophageal sphincter relaxation (TLOSR), according to aspect a to be emphasized are 4-amino-3-(4-chlorophenyl)butanoic acid (baclofen), (3-aminopropyl)methylphosphinic acid, (3-amino-2- hydroxypropyl)methylphosphinic acid, (3-amino-2-(4-chlorophenyl)propyl)sulfinic acid, (3- aminopropyl)(difluoromethyl)phosphinic acid, (3-amino-2-oxo-propyl)methyl phosphinic acid, 4-amino- 3-(5-chlorothien-2-yl)butanoic acid and (3-aminopropyl)phosphonous acid.
A second special aspect (aspect b) of the term "compounds, which modify gastrointestinal motility" refers to those compounds, which modify gastrointestinal motility, and, which are particularly useful for therapy of irritable bowel syndrome (IBS), such as, for example, those compounds of the following active agent classes:
5-HT-(partial-)agonists/antagonists (such as, e.g. 5-HT3-antagonists, 5-HT4-agonists, 5-HT4-partial- agonists or 5-HT4-antagonists), cholecystokinin A antagonists, muscarinic M3 antagonists, kappa opioid receptor agonists, motilin agonists (motilides), delta opioid receptor agonists, dopamine receptor antagonists, neurokinin antagonists (in particular NK-1, NK-2 or NK-3 antagonists), NMDA-receptor antagonists, alpha-2 adrenoceptor agonists or corticotropin releasing factor antagonists, whereby
5-HT-(partial-)agonists/antagonists (such as, e.g. 5-HT3-antagonists, 5-HT4-agonists, 5-HT4-partial- agonists or 5-HT4-antagonists), cholecystokinin A antagonists, muscarinic M3 antagonists, kappa opioid receptor agonists, motilin agonists (motilides), delta opioid receptor agonists and dopamine receptor antagonists are more worthy to be mentioned.
As exemplary compounds according to said special aspect b are to be mentioned, without being restricted thereto,
CLONIDINE (as exemplary alpha-2 adrenoceptor agonist), DIZOCILPINE (as exemplary NMDA- receptor antagonist), EZLOPITANT (as exemplary selective NK-1 antagonist), NEPADUTANT (as exemplary selective NK-2 antagonist), ANTALARMIN (as exemplary corticotropin releasing factor antagonist) and, in particular,
CILANSETRON, DARIFENACIN, E-3620, FABESETRON, LINTOPRIDE, LY-353433, (S)- OXYBUTININ, TICALOPRIDE, ZAMIFENACIN and, in more particular, ALOSETRON, TRIMEBUTINE, TEGASEROD and, in most particular, ALVIMOPAN, DEXLOXIGLUMIDE and PIBOSEROD.
A third special aspect (aspect c) of the term "compounds, which modify gastrointestinal motility" refers to those compounds, which modify gastrointestinal motility. and, which are particularly useful for therapy of gastro-oesophageal reflux disease (GERD), such as, for example, compounds of the class of motilin agonists (motilides), of the class of 5-HT-(partial-)agonists/antagonists (such as, e.g. 5-HT3- antagonists, 5-HT4-agonists, 5-HT4-partial-agonists or 5-HT4-antagonists), of the class of muscarinic antagonists, of the class of opioid agonists/partial agonists, of the class of NMDA receptor antagonists, of the class of non-NMDA glutamate receptor antagonists, of the class of somatostatin agonists, of the class of NO-synthase inhibitors, of the class of GABA (in particular GABA-B) receptor agonists or active agents which reduce the incidence of transient lower oesophageal sphincter relaxation (TLOSR), whereby compounds of the class of motilin agonists (motilides), of the class of 5-HT-(partial-)agonists/an- tagonists (such as, e.g. 5-HT3-antagonists, 5-HT4-agonists, 5-HT4-partial-agonists or 5-HT4- antagonists), of the class of GABA-B receptor agonists or active agents which reduce the incidence of transient lower oesophageal sphincter relaxation (TLOSR) are more worthy to be mentioned.
As exemplary compounds according to said special aspect c are to be mentioned, without being restricted thereto,
PIBOSEROD, MITEMCINAL and, particularly, TEGASEROD.
A fourth special aspect (aspect d) of the term "compounds, which modify gastrointestinal motility" refers to those compounds, which modify gastrointestinal motility, and, which are particularly useful antiemetics, such as, for example, compounds of the class of
5-HT-(partial-)agonists/antagonists (such as, e.g. 5-HT3-antagonists, 5-HT4-agonists, 5-HT4-partial- agonists or 5-HT4-antagonists), of the class of dopamine receptor antagonists (in particular dopamine D2 receptor antagonists), of the class of NMDA receptor antagonists or of the class of neurokinin antagonists (in particular NK-1, NK-2 or NK-3 antagonists).
As exemplary compounds according to said special aspect d are to be mentioned, without being restricted thereto,
ALTINICLINE, APREPITANT, BATANOPRIDE, CILANSETRON, DAZOPRIDE, DEXANABINOL, E- 3620, EXEPANOL, FABESETRON, INDISETRON, ITASETRON, LERISETRON, LINTOPRIDE, PA- LONOSETRON, RS-25259-197, VOFOPITANT, ZACOPRIDE and, particularly, ALIZAPRIDE, ALOSETRON, AZASETRON, BROMOPRIDE, CISAPRIDE, CLEBOPRIDE, DIFENIDOL, DOMPERIDONE, GRANISETRON, LEVOSULPIRIDE, METOCLOPRAMIDE, MOSAPRIDE, ONDANSETRON, RAMOSETRON, TIAPRIDE and TROPISETRON.
A fifth special aspect (aspect e) of the term "compounds, which modify gastrointestinal motility" refers to those compounds, which modify gastrointestinal motility, and, which are particularly useful gastroprokinetics, such as, for example, compounds of the class of
5-HT-(partial-)agonists/antagonists (such as, e.g. 5-HT2-, 5-HT3- and 5-HT4-(partial-)agonists/an- tagonists), muscarinic antagonists, kappa opioid receptor agonists, dopamine receptor antagonists (in particular dopamine D2 receptor antagonists), cholecystokinin A antagonists, motilin agonists (motilides) or GABA-B receptor agonists/partial agonists. As exemplary compounds according to said special aspect e are to be mentioned, without being restricted thereto,
ALEMCINAL, DOBUPRIDE, FEDOTOZINE, KW-5092, KW-5139, LIREXAPRIDE, PRUCALOPRIDE, R-137696, RENZAPRIDE, SR-58611-A, Z-338 and, in particular, MITEMCINAL, TICALOPRIDE, and, in more particular,
CINITAPRIDE, ITOPRIDE and, in most particular, TEGASEROD.
A sixth special aspect (aspect f) of the term "compounds, which modify gastrointestinal motility" refers to those compounds, which are selected from the class of 5-HT-(partial-)agonists/antagonists (such as, e.g. 5-HT2-, 5-HT3- and 5-HT4-(partial-)ago- nists/antagonists, in particular 5-HT3-antagonists, 5-HT4-agonists, 5-HT4-partial-agonists or 5-HT4- antagonists), from the class of muscarinic antagonists, from the class of kappa opioid receptor agonists, from the class of dopamine receptor antagonists (in particular dopamine D2 receptor antagonists), from the class of cholecystokinin A antagonists, from the class of motilin agonists (motilides) or from the class of GABA-B receptor agonists/partial agonists or from active agents which reduce the incidence of transient lower oesophageal sphincter relaxation (TLOSR).
A seventh special aspect (aspect g) of the term "compounds, which modify gastrointestinal motility" refers to those compounds, which are selected from the class of 5-HT-(partiaI-)agonists/antagonists.
A first sub aspect of the expression "5-HT-(partial-)agonists/antagonists" according to said special aspect g refers to 5-HT4-partial-agonists. In this context, 5-HT4-partial-agonists include any compound which can partially activate 5-HT4 receptors (intrinsic activity less than that of serotonin, i. e. < 1. 00. The intrinsic activity may be determined in the non-electrically or electrically stimulated guinea pig ileum or striatum assay, e. g. as disclosed in EP-A1-0 505 322, Br. J. Pharmacol., 115, 1387, 1995 or in the guinea pig distal colon test e. g. as disclosed in Br. J. Pharm., 1593-1599, 1993). Exemplary 5- HT4- partial-agonists include (1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-butyl-4-piperidinyl]-1- propanone or (1 -(4-amino-5-chloro-2-methoxyphenyl)-3-[1 -(methylsulphonylamino)ethyl-4-piperidinyl]- 1-propanone or, in particular, those compounds disclosed in EP0505322, e.g. TEGASEROD.
A second sub aspect of the expression "5-HT-(partial-)agonists/antagonists" according to said special aspect g refers to 5-HT4-agonists. In this context, 5-HT4-agonists include any compound which can activate 5-HT4-receptors under quiescent/resting conditions, such as, for example, CISAPRIDE, NOR- CISAPRIDE, RENZAPRIDE, ZACOPRIDE, MOSAPRIDE, PRUCALOPRIDE, SB 205149, SC 53116, SL-65.0155, E-3620, RS 67333, RS 67506, BIMU-1, BIMU-8 or (S)-RS 56532. A third sub aspect of the expression "5-HT-(partial-)agonists/antagonists" according to said special aspect g refers to 5-HT3-antagonists. In this context, 5-HT3 receptor antagonists include any compound which binds to the 5-HT3 receptor and antagonize the effect of 5-HT3-agonists, such as, for example CILANSETRON, ALOSETRON, RAMOSETRON, AZASETRON, ONDANSETRON, DO- LASETRON, RAMOSETRON, GRANISETRON, or TROPISETRON.
A fourth sub aspect of the expression "5-HT-(partial-)agonists/antagonists" according to said special aspect g refers to compounds which activates and/or binds to 5-HT receptors and which are not either 5-HT4-partial-agonists or 5-HT4-antagonists as defined herein. Exemplary compounds according to this fourth sub aspect are those 5-HT-(partial-)agonists/antagonists, which are mentioned expressis verbis in this description, with the proviso that 5-HT4-partial-agonists and 5-HT4-antagonists are thereof disclaimed.
A fifth sub aspect of the expression "5-HT-(partial-)agonists/antagonists" according to said special aspect g refers to any compound which binds to the 5-HT4 receptor as defined by the IUPHAR (Pharmacological Reviews, Vol. 44, p. 157-213, 1994) and that do not activate the 5-HT4 receptor and antagonize the effects of serotonin. A relevant test to determine whether or not a compound is a 5-HT4- antagonist is the Guinea-Pig distal colon test as described in Br. J. Pharm., p. 1593-1599 (1993) or in the test described in Arch. Pharmacol., Vol.343, p. 439-446 (1991 ). Representative 5-HT4 antagonists include e. g. PIBOSEROD; A-85380; SB 204070 (Drugs Fut., 19 : 1109-1121, 1994); SB 207058 (Exp. Opin. Invest. Drugs, 3 (7): 767, 1994); SB 207710 (Drug Data Report, 15 (10): 949, 1993); SB 205800 (Drug Data Report, 15 (10): 949, 1993); SB 203186 (Br. J. Pharmacol., 110: 10231030, 1993); N 3389 (Eur. J. Pharmacol., 271 : 159, 1994); FK 1052 (J. Pharmacol. Exp. Ther., 265: 752, 1993); SC 56184 (R & D Focus, 2 (37) 10, 1993); SC 53606 (J. Pharmacol. Exp. Ther. 226: 1339, 1993); DAU 6285 (Br. J. Pharmacol., 105: 973, 1992); GR 125487 (Br. J. Pharmacol., 113 suppl. 119P & 120P, 1994); GR 113808 (Br. J. Pharmacol. 110: 1172, 1993); RS 23597 (Bioorg Med. Chem. Lett., 4 (20): 2477, 1994); RS 39604 (Br. J. Pharmacol., 115, 1087-1095, 1995); LY-353433 (EP 0732333, J. Pharmacol. Exp. Ther, 277 (1), 97-104, 1996); and R59595 (Eur. J. Pharmacol., 212, 51-59, 1992); whereby PIBOSEROD and LY-353433 are particularly emphasized.
A sixth sub aspect of the expression "5-HT-(partial-)agonists/antagonists" according to said special aspect g refers to compounds which show characteristics of 5-HT3 receptor antagonists and 5-HT4 receptor agonists or antagonists such as, for example, CISAPRIDE and NOR-CISAPRIDE; BIMU compounds, for example BIMU1 , BIMU8 and DAU 6215 (also known as ITASETRON) as disclosed in Dumuis A., et al., Naunyn Schmiedeber's Arch. Pharmacol., Vol. 343 (3), pp. 245-251 (1991); DAU- 6236 as disclosed in Rizzi, C. A. et al., J. Pharmacol. Exp. Ther., Vol. 261, pp. 412-419 (1992); and DAU-6258, Turconi M, et al., J. Med. Chem., Vol. 33 (8), pg. 2101-2108 (1990), SDZ 205557 which is a benzoic acid derivative (ester) Eglen R. M. et al., Proc. Br. Pharmacol. Soc, Vol. 149 (1992); RENZAPRIDE; ZACOPRIDE; SB 205149; SC 53116; RS 67333; RS 67506; or (S)-RS 56532, LINTOPRIDE. A seventh sub aspect of the expression "5-HT-(partial-)agonists/antagonists" according to said special aspect g refers to compounds, which activates or binds to 5-HT receptors, and which are not 5-HT4- partial-agonists. Exemplary compounds according to this seventh sub aspect are those 5-HT-(partial- )agonists/antagonists, which are mentioned expressis verbis herein, with the proviso that 5-HT4- partial-agonists are thereof disclaimed.
An eighth sub aspect of the expression "5-HT-(partial-)agonists/antagonists" according to said special aspect g refers to compounds, which activates or binds to 5-HT receptors, and which are not either selective 5-HT4-partial-agonists or selective 5-HT-anatgonists. Exemplary compounds according to this eighth sub aspect are those 5-HT-(partial-)agonists/antagonists, which are mentioned expressis verbis herein, with the proviso that selective 5-HT4-partial-agonists and selective 5-HT4-antagonists are thereof disclaimed. The term "selective" means in this context a compound which does not substantially bind to or stimulate the 5-HT3 receptor subtype.
An eighth special aspect (aspect h) of the term "compounds, which modify gastrointestinal motility" refers to those compounds, which are selected from the class of GABA-A and, in particular, of the class of GABA-B receptor agonists/partial agonists.
As exemplary compounds according to said special aspect h are to be mentioned, without being restricted thereto, those compounds mentioned or specified in the description of this invention.
A ninth special aspect (aspect i) of the term "compounds, which modify gastrointestinal motility" refers to those compounds, which are selected from a group consisting of muscarinic antagonists, kappa opioid receptor agonists, delta opioid receptor agonists, opioid receptor agonists, dopamine receptor antagonists, cholecystokinin A antagonists, alpha-2 adrenoceptor agonists, N-methyl-D-aspartate receptor antagonists, non-N-methyl-D-aspartate glutamate receptor antagonists, nitric oxide synthase inhibitors, motilin agonists, somatostatin agonists/antagonists, neurotensin agonists/antagonists, vasoactive intestinal peptide antagonists, substance P antagonists, neurokinin antagonists, calcium channel blockers, potassium channel openers, selective serotonin reuptake inhibitors, corticotropin releasing factor antagonists, GABA-A receptor agonists, GABA-B receptor agonists/partial agonists, gastroprokinetics, antiemetics and antispasmodics, and which are not 5-HT-(partial- )agonists/antagonists.
A tenth special aspect (aspect j) of the term "compounds, which modify gastrointestinal motility" refers to those compounds, which are mentioned or specified expressis verbis or by reference in the description of this invention, and which are not 5-HT-(partial-)agonists/antagonists. An eleventh special aspect (aspect k) of the term "compounds, which modify gastrointestinal motility" refers to those compounds, which are mentioned or specified expressis verbis or by reference in the description of this invention, and which are not 5-HT4-partial-agonists or 5-HT4-antagonists.
A twelfth special aspect (aspect I) of the term "compounds, which modify gastrointestinal motility" refers to those compounds, which are mentioned or specified expressis verbis or by reference in the description of this invention, and which show characteristics of 5-HT3-antagonists and 5-HT4-agonists or antagonists.
A thirteenth special aspect (aspect m) of the term "compounds, which modify gastrointestinal motility" refers to those compounds, which are mentioned or specified expressis verbis or by reference in the description of this invention, and which are 5-HT3-antagonists.
Special aspects of the term "compounds, which modify gastrointestinal motility" to be more worthy to be mentioned in the meaning of this invention are aspect a, aspect b, aspect c, aspect g and aspect h.
In the context of said aspect g more worthy to be mentioned, a first sub aspect of the present invention relates to a pharmaceutical composition comprising a first agent which is a 5-HT-(partial- )agonist/an-tagonist such as, for example, one of those mentioned above; and a second agent which is (S)-pantoprazole and/or its salts.
In further context of said aspect g more worthy to be mentioned, a second sub aspect of the present invention relates to a pharmaceutical composition comprising a first agent which is a 5-HT-(partial- )ago-nist/antagonist such as, for example, one of those disclosed generically or, in particular, specifically in the international application WO 0141748 as useful to be employed in combination with co- agents; and a second agent which is (S)-pantoprazole and/or its salts.
In still further context of said aspect g more worthy to be mentioned, a third sub aspect of the present invention relates to a pharmaceutical composition comprising a first agent which is a 5-HT-(partial- )ago-nist/antagonist such as, for example, 3-(5-methoxy-1H-indol-3-yl-methylene)-N- pentylcarbazimidamide, which is also known as tegaserod, or a salt (e.g. the hydrogen maleate) or a tautomere thereof; and a second agent which is (S)-pantoprazole and/or its salts.
Compounds, which modify gastrointestinal motility, to be emphasized in the meaning of the present invention as particularly useful to be employed in combination with (S)-pantoprazole and/or its salts, are active agents selected from the following active agent classes:
5-HT-(partial-)agonists/antagonists (such as, e.g. 5-HT2-, 5-HT3- and 5-HT4-(partial-)agonists/an- tagonists, in particular 5-HT3-antagonists, 5-HT4-agonists or 5-HT4-antagonists), muscarinic (e.g. muscarinic M3) antagonists, opioid receptor agonists (e.g. delta opioid receptor agonists or, in particular, kappa opioid receptor agonists), dopamine receptor antagonists (in particular dopamine D2 recep- tor antagonists), cholecystokinin A antagonists, motilin agonists (motilides), NMDA-receptor antagonists, non-NMDA glutamate receptor antagonists, neurokinin antagonists (in particular NK-1 , NK-2 or NK-3 antagonists), alpha-2 adrenoceptor agonists, corticotropin releasing factor antagonists, somatostatin agonists, NO-synthase inhibitors, GABA (in particular GABA-B) receptor agonists/partial agonists or active agents which reduce the incidence of transient lower oesophageal sphincter relaxation (TLOSR), and/or gastroprokinetics, antiemetics or antispasmodics.
Compounds, which modify gastrointestinal motility, to be more emphasized in the meaning of the present invention as particularly useful to be employed in combination with (S)-pantoprazole and/or its salts, are active agents for use in therapy of irritable bowel syndrome (IBS) selected from the following active agent classes:
5-HT-(partial-)agonists/antagonists (such as, e.g. 5-HT3-antagonists, 5-HT4-agonists or 5-HT4- antagonists), cholecystokinin A antagonists, muscarinic M3 antagonists, kappa opioid receptor agonists, motilin agonists (motilides), delta opioid receptor agonists, dopamine receptor antagonists, neurokinin antagonists (in particular NK-1, NK-2 or NK-3 antagonists), NMDA-receptor antagonists, alpha- 2 adrenoceptor agonists or corticotropin releasing factor antagonists.
Further compounds, which modify gastrointestinal motility, to be more emphasized in the meaning of the present invention as particularly useful to be employed in combination with (S)-pantoprazole and/or its salts, are active agents for use in therapy of gastro-oesophageal reflux disease (GERD) selected from the following active agent classes: motilin agonists (motilides), 5-HT-(partial-)agonists/antagonists (such as, e.g. 5-HT3-antagonists, 5- HT4-agonists or 5-HT4-antagonists), muscarinic antagonists, opioid agonists/partial agonists, NMDA- receptor antagonists, non-NMDA glutamate receptor antagonists, somatostatin agonists, NO-synthase inhibitors, GABA (in particular GABA-B) receptor agonists or active agents which reduce the incidence of transient lower oesophageal sphincter relaxation (TLOSR).
In this connection, exemplary compounds, which modify gastrointestinal motility, to be emphasized within the meaning of the present invention in a special embodiment (embodiment a) include active agents for use in therapy of IBS or GERD, or for use as gastroprokinetics or antiemetics, such as, for example without being restricted thereto,
(S)-OXYBUTININ, ALEMCINAL, ALIZAPRIDE, ALOSETRON, ALTINICLINE, ALVIMOPAN, APREPI- TANT, AZASETRON, BATANOPRIDE, BROMOPRIDE, CILANSETRON, CINITAPRIDE, CISAPRIDE, CLEBOPRIDE, DARIFENACIN, DAZOPRIDE, DEXANABINOL, DEXLOXIGLUMIDE, DIFENIDOL, DOBUPRIDE, DOMPERIDONE, E-3620, EXEPANOL, FABESETRON, FEDOTOZIN, GRANISE- TRON, INDISETRON, ITASETRON, ITOPRIDE, KW-5092, KW-5139, LERISETRON, LEVOSULPIRIDE, LINTOPRIDE, LIREXAPRIDE, LY-353433, METOCLOPRAMIDE, MITEMCINAL, MOSAPRIDE, ONDANSETRON, PALONOSETRON, PIBOSEROD, PRUCALOPRIDE, R-137696, RAMOSETRON, RENZAPRIDE, RS-25259-197, SR-58611-A, TEGASEROD, TIAPRIDE, TICALOPRIDE, TRIMEBUTINE, TROPISETRON, VOFOPITANT, Z-338 or ZACOPRIDE. Exemplary compounds, which modify gastrointestinal motility, to be emphasized within the meaning of the present invention in a further special embodiment (embodiment b) include active agents for use in therapy of IBS or GERD, such as, for example without being restricted thereto, ALOSETRON, ALVIMOPAN, CILANSETRON, DARIFENACIN, DEXLOXIGLUMIDE, E-3620, FABESETRON, LINTOPRIDE, LY-353433, MITEMCINAL, (S)-OXYBUTININ, PIBOSEROD, TEGASEROD, TICALOPRIDE or TRIMEBUTINE.
Exemplary compounds, which modify gastrointestinal motility, to be emphasized within the meaning of the present invention in a further special embodiment (embodiment c) include suitably ALEMCINAL, ASIMADOLINE, BACLOFEN, BIPERIDEN, CILANSETRON, CINITAPRIDE, CISAPRIDE, CLEBOPRIDE, DARIFENACIN, DAZOPRIDE, DIFENIDOL, DOBUPRIDE, E-3620, EM-523, FABESETRON, FEDOTOZINE, GABAPENTIN, IDREMCINAL, ITOPRIDE, KW-5092, KW-5139, LEVOSULPIRIDE, LINTOPRIDE, LIREXAPRIDE, MEBEVERINE, METOCLOPRAMIDE, MITEMCINAL, MOSAPRIDE, NITRAQUAZONE, PAZINACLONE, PIBOSEROD, PRIDINOL, PROCYCLIDINE, PRUCALOPRIDE, PUMOSETRAG, R-137696, RENZAPRIDE, RICASETRON, ROLIPRAM, SK-896, SL-65.1498, SR-58611-A, T-1815, TEGASEROD, TIBENELAST, TICALOPRIDE, TRIHEXYPHENIDYL, Y-36912, YM-114, YM-47813, Z-338 and ZACOPRIDE.
Exemplary compounds, which modify gastrointestinal motility, to be emphasized within the meaning of the present invention in a further special embodiment (embodiment d) include suitably ALEMCINAL, ALVIMOPAN, CINITAPRIDE, DEXLOXIGLUMIDE, DOBUPRIDE, FEDOTOZINE, KW- 5092, KW-5139, ITOPRIDE, LIREXAPRIDE, MITEMCINAL, PIBOSEROD, PRUCALOPRIDE, R- 137696, RENZAPRIDE, SR-58611-A, T-1815, TEGASEROD, TICALOPRIDE and Z-338.
The expression "gastrointestinal diseases" comprises diseases or disorders of the gastrointestinal tract known to the person skilled in the art. In this context, gastrointestinal motility disorders, disorders of gastric emptying, bowel disorders, oesophageal diseases, gastrointestinal inflammatory diseases (such as inflammatory bowel disease) and gastrointestinal diseases associated with inflammatory attendant phenomenon are to be emphasized. Particularly emphasized are hereby the gastro- oesophageal reflux disease (GERD) and the irritable bowel syndrome (IBS).
It is habitual to the person skilled in the art to decide on the base of his/her expert knowledge and/or of relevant prior art what is the meaning of the terms "agonists", "antagonists" or "inhibitors" as used in their respective context in this invention. In a first aspect, this invention relates to the combined use of (S)-pantoprazole and/or its salts and compounds, which modify gastrointestinal motility, in the treatment of gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD) or irritable bowel syndrome (IBS).
An alternative aspect of the present invention relates to the combined use of (S)-pantoprazole and/or its salts and compounds, which modify gastrointestinal motility, in the improved treatment of altered gastrointestinal motility, sensitivity and/or secretion and/or abdominal disorders including both functional and organic diseases, such as, for example, in the treatment of chronic symptoms of dyspepsia and diseases associated herewith, such as, for example, GERD, duodenal ulcer or gastric ulcer and other diagnoses (e.g. functional/non-ulcerative dyspepsia, gallbladder or liver diseases).
A further aspect of the present invention relates to the combined use of (S)-pantoprazole and/or its salts and compounds, which modify gastrointestinal motility, to modulate and normalize gastrointestinal motility, sensitivity and/or secretion in therapy or prophylaxis.
A further aspect of the present invention relates to the combined use of (S)-pantoprazole and/or its salts and compounds, which modify gastrointestinal motility, to obtain a particularly enhanced treatment response for altered gastrointestinal motility, sensitivity and/or secretion and/or abdominal disorders, in particular in patients suffering from GERD, and/or to obtain a particularly enhanced reduction of gastrointestinal pain and other symptoms normally associated with disturbed/altered gastrointestinal motility, sensitivity and/or secretion.
A further aspect of the present invention is the use of (S)-pantoprazole and/or its salts and compounds, which modify gastrointestinal motility, in the manufacture of pharmaceutical compositions for the treatment of gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD) or irritable bowel syndrome (IBS).
A further aspect of the present invention is the simultaneous, separate or sequential co-administration of (S)-pantoprazole and/or its salts with one or more compounds, which modify gastrointestinal motility, to treat gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD) or irritable bowel syndrome (IBS).
A further aspect of the present invention is a method for treatment of gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD) or irritable bowel syndrome (IBS), comprising administering an effective amount of (S)-pantoprazole and/or its salts simultaneously, separately or sequentially with one or more compounds, which modify gastrointestinal motility, to a mammal, preferably a human, in need thereof.
A further aspect of the present invention is a method for treatment of gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD) or irritable bowel syndrome (IBS), comprising ad- ministering a pharmaceutical composition according to this invention to a mammal, preferably a human, in need thereof.
A further aspect of the present invention is a preferably orally applicable pharmaceutical composition for simultaneous administration comprising, in admixture, a first active ingredient, which is (S)- pantoprazole and/or its salts, and a second active ingredient, which is at least one compound, which modifies gastrointestinal motility, to treat gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD) or irritable bowel syndrome (IBS) in a mammal, preferably a human.
A further aspect of the present invention is a composition comprising a first active ingredient, which is (S)-pantoprazole and/or its salts, and a second active ingredient, which is at least one compound, which modifies gastrointestinal motility, for simultaneous, sequential or separate use in therapy in any order.
A further aspect of the present invention is a preferably orally applicable pharmaceutical composition in unit dosage comprising (S)-pantoprazole and/or its salts together with at least one compound, which modifies gastrointestinal motility, for use in therapy, e.g. to treat gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD) or irritable bowel syndrome (IBS) in a mammal.
A further aspect of the present invention is a pharmaceutical composition comprising (S)-pantoprazole and/or its salts together with at least one compound, which modifies gastrointestinal motility, wherein the acid pump antagonist and the compound, which modifies gastrointestinal motility, are administered in a single dosage form, such that the acid pump antagonist and the compound, which modifies gastrointestinal motility, are physically separated from each other.
A further aspect of the present invention is a pharmaceutical composition comprising, in admixture, a first active ingredient, which is (S)-pantoprazole and/or its salts, and a second active ingredient, which is at least one compound, which modifies gastrointestinal motility.
A further aspect of this invention is a pharmaceutical composition comprising: (a) a pharmaceutically effective amount of (S)-pantoprazole and/or its salts, and (b) a pharmaceutically effective amount of at least one compound, which modifies gastrointestinal motility.
A further aspect of this invention is a pharmaceutical composition comprising: (a) a pharmaceutically effective amount of (S)-pantoprazole and/or its salts, and (b) a pharmaceutically effective amount of at least one compound, which modifies gastrointestinal motility, wherein component (a) and component (b) are maintained in the same delivery vehicle. A further aspect of this invention is a pharmaceutical composition comprising: (a) a pharmaceutically effective amount of (S)-pantoprazole and/or its salts, and (b) a pharmaceutically effective amount of at least one compound, which modifies gastrointestinal motility, wherein component (a) and component (b) are maintained in different delivery vehicles.
A further aspect of the present invention is a preferably orally applicable pharmaceutical formulation comprising a first active ingredient, which is (S)-pantoprazole and/or its salts, a second active ingredient, which is at least one compound, which modifies gastrointestinal motility, and a pharmaceutically acceptable carrier, diluent, adjuvant, auxiliary or excipient for use in therapy, e.g. to treat gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD) or irritable bowel syndrome (IBS) in a mammal, especially a human.
A further aspect of the present invention is a pharmaceutical composition comprising a first active ingredient, which is (S)-pantoprazole and/or its salts, a second active ingredient, which is at least one compound, which modifies gastrointestinal motility, and one or more pharmaceutically acceptable carriers, diluents, adjuvants, auxiliaries or excipients.
A further aspect of the present invention is a first pharmaceutical formulation comprising (S)- pantoprazole and/or its salts and a pharmaceutically acceptable carrier or diluent, and a second pharmaceutical formulation comprising a compound, which modifies gastrointestinal motility, and a pharmaceutically acceptable carrier or diluent.
A further aspect of the present invention is a combination comprising (S)-pantoprazole and/or its salts and at least one compound, which modifies gastrointestinal motility, for simultaneous, sequential or separate use in therapy, e.g. to treat gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD) or irritable bowel syndrome (IBS) in a mammal, especially a human.
A further special aspect of the present invention is a pharmaceutical product comprising, in combination, a first active ingredient, which is (S)-pantoprazole and/or its salts, and a second active ingredient, which is at least one compound, which modifies gastrointestinal motility. for simultaneous, sequential or separate use in therapy.
A further aspect of the present invention is a pharmaceutical product comprising, in combination, a preparation of a first active ingredient, which is (S)-pantoprazole and/or its salts, and a preparation of a second active ingredient, which is at least one compound, which modifies gastrointestinal motility, for simultaneous, sequential or separate use in therapy, e.g. to treat gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD) or irritable bowel syndrome (IBS) in a mammal, especially a human. A further aspect of the present invention is a pharmaceutical preparation comprising a first active ingredient, which is (S)-pantoprazole and/or its salts, a second active ingredient, which is at least one compound, which modifies gastrointestinal motility, and one or more pharmaceutically acceptable carriers, diluents, adjuvants, auxiliaries or excipients.
A further aspect of the present invention is a commercial package comprising a first active ingredient, which is (S)-pantoprazole and/or its salts, and a second active ingredient, which is at least one compound, which modifies gastrointestinal motility, together with instructions for simultaneous, sequential or separate use in therapy.
A further aspect of the present invention is a commercial package comprising (S)-pantoprazole and/or its salts as active ingredient together with instructions for simultaneous, sequential or separate use with a compound, which modifies gastrointestinal motility.
A further aspect of the present invention is a commercial package comprising at least one compound, which modifies gastrointestinal motility, as active ingredient(s) together with instructions for simultaneous, sequential or separate use with (S)-pantoprazole and/or its salts.
A further aspect of the present invention is a kit comprising at least one dosage unit of (S)- pantoprazole and/or its salts as well as at least one dosage unit of at least one compound, which modifies gastrointestinal motility, for simultaneous, sequential or separate use in therapy. Optionally, abovementioned kit can be provided with instructions for use.
A further aspect of the present invention is a kit comprising a preparation of a first active ingredient, which is (S)-pantoprazole and/or its salts, a preparation of a second active ingredient, which is at least one compound, which modifies gastrointestinal motility, and instructions for simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
A further aspect of the present invention is the use of a pharmaceutical composition, pharmaceutical product, formulation, preparation, combination, commercial package or kit according to the invention in the manufacture of a medicament for use in the treatment of gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD) or irritable bowel syndrome (IBS).
In a special aspect, this invention relates to the combined use of (S)-pantoprazole and/or its salts and compounds, which reduce the incidence of transient lower oesophageal sphincter relaxation (TLOSR), in the treatment of gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD).
A further special aspect of the present invention is the use of (S)-pantoprazole and/or its salts and compounds, which reduce the incidence of transient lower oesophageal sphincter relaxation (TLOSR), in the manufacture of pharmaceutical compositions for the treatment of gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD).
A further special aspect of the present invention is the simultaneous, separate or sequential co- administration of (S)-pantoprazole and/or its salts with one or more compounds, which reduce the incidence of transient lower oesophageal sphincter relaxation (TLOSR), to treat gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD).
A further special aspect of the present invention is a method for treatment of gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD), comprising administering an effective amount of (S)-pantoprazole and/or its salts simultaneously, separately or sequentially with one or more compounds, which reduce the incidence of transient lower oesophageal sphincter relaxation (TLOSR), to a mammal, preferably a human, in need thereof.
A further special aspect of the present invention is a preferably orally applicable pharmaceutical composition for simultaneous administration comprising, in admixture, a first active ingredient, which is (S)-pantoprazole and/or its salts, and a second active ingredient, which is at least one compound, which reduces the incidence of transient lower oesophageal sphincter relaxation (TLOSR), to treat gastrointestinal diseases, in particular gastro-oesophageal reflux disease (GERD) in a mammal, preferably a human.
A further special aspect of the present invention is a composition comprising a first active ingredient, which is (S)-pantoprazole and/or its salts, and a second active ingredient, which is at least one compound, which reduces the incidence of transient lower oesophageal sphincter relaxation (TLOSR), for simultaneous, sequential or separate use in therapy in any order.
A further special aspect of the present invention is a pharmaceutical product comprising, in combination, a first active ingredient, which is (S)-pantoprazole and/or its salts, and a second active ingredient, which is at least one compound, which reduces the incidence of transient lower oesophageal sphincter relaxation (TLOSR), for simultaneous, sequential or separate use in therapy.
A further special aspect of the present invention is a commercial package comprising a first active ingredient, which is (S)-pantoprazole and/or its salts, and a second active ingredient, which is at least one compound, which reduces the incidence of transient lower oesophageal sphincter relaxation (TLOSR), together with instructions for simultaneous, sequential or separate use in therapy.
A further special aspect of the present invention is a commercial package comprising (S)-pantoprazole and/or its salts as active ingredient together with instructions for simultaneous, sequential or separate use with a compound, which reduces the incidence of transient lower oesophageal sphincter relaxation (TLOSR). A further special aspect of the present invention is a commercial package comprising at least one compound, which reduces the incidence of transient lower oesophageal sphincter relaxation (TLOSR), as active ingredient together with instructions for simultaneous, sequential or separate use with (S)- pantoprazole and/or its salts.
A further special aspect of the present invention is a kit comprising a preparation of a first active ingredient, which is (S)-pantoprazole and/or its salts, a preparation of a second active ingredient, which is at least one compound, which reduces the incidence of transient lower oesophageal sphincter relaxation (TLOSR), and instructions for simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
Within the meaning of this invention the terms "use", "administration", "co-administration" or "administering" refer preferably to oral application. However in some cases, parenteral (e.g. intravenous), subcutaneous or rectal application can be also advantageous.
The dosage of the active compounds is in a customary order of magnitude comparable with the monodosage, whereby, due to the additive and/or super-additive synergism of the single effects, the relevant doses of the active compounds in the combined dosage can be reduced compared to norm, or whereby - while maintaining the customary doses of the single components - a suφrisingly higher and prolonged effect is obtained.
In general, it has proven advantageous in human medicine to administer (S)-pantoprazole and/or its salts in the case of oral administration in a daily dose from approximately 10 to approximately 80, preferably 20 to 40 mg as calculated for the free acid (S)-pantoprazole. In the case of parenteral treatment, similar or [in particular in the case of intravenous administration of (S)-pantoprazole and/or its salts], as a rule, lower doses can be used.
The person skilled in the art is aware on the base of his expert knowledge of the total daily dosage of the compounds, which modify gastrointestinal motility, and of the compounds, which reduce the incidence of transient lower oesophageal sphincter relaxation (TLOSR), comprised in the abovementioned (pharmaceutical) compositions, pharmaceutical products, preparations, formulations, combinations, commercial packages or kits according to this invention. Said total daily dosage can vary within a wide range. Said
In this context, for more detailed example, compositions according to this invention comprising a first active ingredient, which is an acid pump antagonist, and a second active ingredient, which is a 5-HT4- (partial-)agonist/antagonist (e.g. tegaserod or its salt), may be administered in a molar ratio having a range of from about 0.01 to 1000 for the acid pump antagonist to a range of from about 0.01 to about 2 for the 5-HT4-(partial-)agonist/antagonist. As an example, the molar ratio for the acid pump antago- nist to the 5-HT4-(partial-)agonist/antagonist is about 1000:1 (acid pump antagonist to 5-HT4-(partial- )agonist/antagonist). As a more specific example, the molar ratio for the acid pump antagonist to the 5-HT4-(partial-)agonist/antagonist may be about 1000:1 , 500:1 , 200:1 , 100:1 , 20:1, 5:1, 1:1, 1 :5, 1 :20, 1:100. The total daily dose range, which comprises the above described molar ratio, may be administered in a range of from about 0.01 mg to about 1000 mg. The daily dose range may be about 800 mg, 600 mg, 400 mg, 200 mg, 100 mg, 50 mg, 20 mg, 10 mg, 5 mg, 1 mg, 0.1 mg or 0.01 mg. Suitably, a daily dose range should be between about 0.5 mg to about 100 mg, while more suitably, a daily dose range should be between about 5 mg to about 75 mg. The doses can be administered once daily or two times a day. In managing the patient, the therapy should be initiated at a lower dose and increased depending on patient's response, whereby the person skilled in the art knows how and when to interrupt, adjust or terminate therapy in conjunction with individual patient response. As it is customary per se to the person skilled in the art, the skilled person knows on the base of his/her expert knowledge that it may be necessary to use dosages outside these abovementioned ranges.
The person skilled in the art is familiar, on the basis of his/her knowledge, with carriers, diluents, adjuvants, auxiliaries or excipients which are suitable for the desired pharmaceutical formulations and/or preparations. Beside solvents, gel-forming agents, suppository bases, tablet auxiliaries and other active carriers, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavour corrigents, preservatives, solubilizers, colorants or, in particular, permeation promoters and com- plexing agents (e.g. cyclodextrines).
In medicines, the active compounds are preferably employed in the form of tablets, coated tablets, capsules, suppositories, patches, emulsions, suspensions, gels or solutions, the active compound content advantageously being between 0.1 and 95%. Thus, for example with regard to the desired mode and site of action, the person skilled in the art can develop, on the basis of his/her knowledge, by appropriate choice of the excipients and the auxiliaries different galenic forms precisely tailored to the active ingredient(s) (such as, for example, retard forms or gastric acid resistant forms).
It is to be understood that when used herein, 'medicament' or 'pharmaceutical composition' shall be taken to refer to a composition comprising both the compounds, which modify gastrointestinal motility and (S)-pantoprazole and/or its salts in a fixed combination (fixed unit dosage form), or a medicament pack comprising the two active ingredients as discrete separate dosage forms. In case of a medicament pack comprising the two active ingredients, the active ingredients are preferably packed into blister cards which are suited for improving compliance. Each blister card preferably contains the medicaments to be taken on one day of treatment. If the medicaments are to be taken at different times of day, the medicaments can be disposed in different sections on the blister card according to the different ranges of times of day at which the medicaments are to be taken (for example morning and evening or morning, midday and evening). The blister cavities for the medicaments to be taken together at a particular time of day are accommodated in the respective range of times of day. The various times of day are, of course, also put on the blister in a clearly visible way. It is also possible, of course, for example to indicate a period in which the medicaments are to be taken, for example stating the times. The daily sections may represent one line of the blister card, and the times of day are then identified in chronological sequence in this column.
Medicaments which must be taken together at a particular time of day are placed together at the appropriate time on the blister card, preferably a narrow distance apart, allowing them to be pushed out of the blister easily, and having the effect that removal of the dosage form from the blister is not forgotten.
Having described the invention in detail, the scope of the present invention is not limited only to those described characteristics. As will be apparent to persons skilled in the art, modifications, variations and adaptations to the above-described invention can be made on the base of the disclosure (e.g. the explicit, implicit or inherent disclosure) of the present invention without departing from the spirit and scope of this invention.
All patents and patent applications referred to herein are incorporated by reference into the specification of the present invention in their entirety for all purposes.
Examples
Magnesium (-)-bis{[5-(difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1H- benzimidazolide} dihydrate
At 20-25°C, 20.2 g (52.7 mmol) of (-)-pantoprazole {(-)-[5-(difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyri- dinyl)methylsulphinyl]-1H-benzimidazole} were suspended in 200 ml of purified water. A solution of (55.2 mmol) sodium hydroxide in 10 ml of water was added, and the mixture was stirred at 20-30°C for 30 min. With addition of a filter aid (1g Hyflo-Super-Cel), the turbid solution was filtered. 6.32 g (31.2 mmol) of magnesium dichloride hexahydrate in 150 ml of water were then added drop by drop with stirring over a period of 30 min. After a further 30 min., the precipitated solid was filtered off with su c- tion using a suction filter, stirred with water (2 x 50 ml) and again filtered off with suction. Drying under reduced pressure at 50-60°C gave, in a yield of 17.36 g (80%), a hydrate of magnesium (-)-bis{[5- (difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1 H-benzimidazolide} having a water content of 4.5-4.7 % as a colourless to beige powder (m. p. 158-161 °C, with decomposition).
Specific rotation: αD 20° = -114° (c = 0.5, measured in methanol)
For recrystallisation, 1.88 g of the hydrate were, at 55°C, dissolved in 6 ml of methanol, and 20 ml of water were added with stirring. A colourless to beige solid crystallized out. This gave the title compound of m. p. 160-163°C (with decomposition) having a water content of 4.3-4.4 %.
Alternatively, the title compound can also be prepared from organic-aqueous solvent mixtures. To this end, (-)-pantoprazole sodium, or (-)-pantoprazole together with one equivalent of aqueous, for example 2N, sodium hydroxide solution, is dissolved in an organic solvent, for example warm acetone. 0.5 to 0.55 equivalents of a magnesium salt (for example magnesium chloride hexahydrate), dissolved in water, are added drop by drop, and the mixture is cooled with stirring. The precipitated solid is filtered off, washed with the solvent mixture in question and dried at 50°C under reduced pressure until the weight remains constant. This gives the title compound as a colourless to beige powder.
Magnesium (-)-bis{[5-(difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1H- benzimidazolide} dihydrate
A. (-)-Pantoprazole-Na
36 g of (-)-pantoprazole were suspended in 180 ml of methyl isobutyl ketone (MIBK) and 18 ml of 2-propanol and heated to an internal temperature of 45°C. The suspension was stirred at this temperature for 15 min. At 50°C, 11 g of 30% (w/w) aqueous sodium hydroxide solution were slowly added drop by drop to this suspension. A clear to slightly turbid solution resulted. This solution was stirred for a bit longer and then filtered to give a clear solution.
The clear filtrate was slowly cooled to room temperature. Between 45°C and 30°C, crystallization, which could be accelerated by seeding with (-)-pantoprazole sodium, began. The resulting suspension was stirred at an internal temperature of < 20°C for another 2 h. The suspension was then filtered, and the crystals were washed with 40 ml of Ml BK.
Drying was carried out in a vacuum drying cabinet at < 50 mbar and 40-45°C. [It is also possible to dispense with drying and to use the moist product (having an MIBK content of 10-20 %) directly for step B]. The white-beige crystalline product obtained after drying was hygroscopic. The water content was from 2 to 12 %. The absoφtion and release of water were reversible. Yield: 34 g = 90 % of theory (based on anhydrous product). Specific rotation: α 20 = - 95 (c = 0.5, measured in methanol, sodium salt having a water content of 12%). m. p.: 145-165°C (decomposition, sodium salt having a water content of 2 %); 102-109°C (decomposition, sodium salt having a water content of 12 %).
B. (-)-Pantoprazolθ-Mg
30 g of (-)-pantoprazole sodium salt (calculated anhydrous substance) were suspended in 260 ml of water. The suspension was heated to 35-40°C and stirred at 35-40°C for another 10 min. This gave a clear solution. The clear solution was cooled to 22-27°C. 14.3 g of magnesium chloride hexahydrate were dissolved in 100 ml of water, and at room temperature and with stirring, the solution was slowly added dropwise to the (-)-pantoprazole sodium salt solution. The resulting suspension was then stirred at room temperature for another 4 h. The suspension was, under pressure, filtered through a Nutsche filter, and the product was, a little at a time, washed twice with 300 ml of water. Drying in a vacuum drying cabinet at < 50 mbar and 40-45°C gave 27.5 g (90 %) of the title compound of m. p. 160- 163°C. Water content 4.3-4.4 %; specific rotation: αD 0° = -129 (c= 0.5, measured in methanol).
Recrystallisation of (-)-pantoprazole-Mg
For recrystallisation, 6.0 g of the (-)-pantoprazole-Mg-dihydrate were, at 55°C, dissolved in 18 ml of methanol. After 15 min, 90 ml of water were added with stirring to the orange-brown-solution. A colourless to beige solid crystallised out. The resulting suspension was then stirred at 20-25°C for another 1 hour. The solid was filtered off, washed with 10 ml of water and dried under vacuum for 20 hours at 50°C. The yield for the title compound was 88 % (5.26 g) with the following data:
M.P.: 161-165°C (with decomposition)
Specific rotation: αD 20° = -130° (c = 0.5, measured in methanol)

Claims

Patent Claims
1. A pharmaceutical composition comprising a first active ingredient, which is
- (S)-pantoprazole and/or its salts, and a second active ingredient, which is
- a compound, which modifies gastrointestinal motility, selected from a group consisting of 5-HT- (partial-)agonists/antagonists, muscarinic antagonists, kappa opioid receptor agonists, delta opioid receptor agonists, opioid receptor agonists, dopamine receptor antagonists, cholecystokinin A antagonists, alpha-2 adrenoceptor agonists, N-methyl-D-aspartate receptor antagonists, non-N-methyl-D- aspartate glutamate receptor antagonists, nitric oxide synthase inhibitors, motilin agonists, somatostatin agonists/antagonists, neurotensin agonists/antagonists, vasoactive intestinal peptide antagonists, substance P antagonists, neurokinin antagonists, calcium channel blockers, potassium channel openers, selective serotonin reuptake inhibitors, corticotropin releasing factor antagonists, GABA-A receptor agonists, GABA-B receptor agonists/partial agonists, gastroprokinetics, antiemetics and antispasmodics, or a pharmacologically acceptable derivative thereof.
2. A pharmaceutical composition comprising a first active ingredient, which is
- (S)-pantoprazole magnesium, and a second active ingredient, which is
- a compound, which modifies gastrointestinal motility, selected from a group consisting of 5-HT- (partial-)agonists/antagonists, muscarinic antagonists, kappa opioid receptor agonists, delta opioid receptor agonists, opioid receptor agonists, dopamine receptor antagonists, cholecystokinin A antagonists, alpha-2 adrenoceptor agonists, N-methyl-D-aspartate receptor antagonists, non-N-methyl-D- aspartate glutamate receptor antagonists, nitric oxide synthase inhibitors, motilin agonists, somatostatin agonists/antagonists, neurotensin agonists/antagonists, vasoactive intestinal peptide antagonists, substance P antagonists, neurokinin antagonists, calcium channel blockers, potassium channel openers, selective serotonin reuptake inhibitors, corticotropin releasing factor antagonists, GABA-A receptor agonists, GABA-B receptor agonists/partial agonists, gastroprokinetics, antiemetics and antispasmodics, or a pharmacologically acceptable derivative thereof.
3. A pharmaceutical composition comprising a first active ingredient, which is
- (S)-pantoprazole magnesium dihydrate, and a second active ingredient, which is
- a compound, which modifies gastrointestinal motility, selected from a group consisting of 5-HT- (partial-)agonists/antagonists, muscarinic antagonists, kappa opioid receptor agonists, delta opioid receptor agonists, opioid receptor agonists, dopamine receptor antagonists, cholecystokinin A antagonists, alpha-2 adrenoceptor agonists, N-methyl-D-aspartate receptor antagonists, non-N-methyl-D- aspartate glutamate receptor antagonists, nitric oxide synthase inhibitors, motilin agonists, somatostatin agonists/antagonists, neurotensin agonists/antagonists, vasoactive intestinal peptide antago- nists, substance P antagonists, neurokinin antagonists, calcium channel blockers, potassium channel openers, selective serotonin reuptake inhibitors, corticotropin releasing factor antagonists, GABA-A receptor agonists, GABA-B receptor agonists/partial agonists, gastroprokinetics, antiemetics and antispasmodics, or a pharmacologically acceptable derivative thereof.
4. A pharmaceutical composition according to claim 1 or 2 or 3, wherein the second active ingredient is a compound, which modifies gastrointestinal motility, selected from a group consisting of (S)- OXYBUTININ, ALEMCINAL, ALIZAPRIDE, ALOSETRON, ALTINICLINE, ALVIMOPAN, APREP I- TANT, AZASETRON, BATANOPRIDE, BROMOPRIDE, CILANSETRON, CINITAPRIDE, CISAPRIDE, CLEBOPRIDE, DARIFENACIN, DAZOPRIDE, DEXANABINOL, DEXLOXIGLUMIDE, DIFENIDOL, DOBUPRIDE, DOMPERIDONE, E-3620, EXEPANOL, FABESETRON, FEDOTOZINE, GRANISE- TRON, INDISETRON, ITASETRON, ITOPRIDE, KW-5092, KW-5139, LERISETRON, LEVOSULPIRIDE, LINTOPRIDE, LIREXAPRIDE, LY-353433, METOCLOPRAMIDE, MITEMCINAL, MOSAPRIDE, ONDANSETRON, PALONOSETRON, PIBOSEROD, PRUCALOPRIDE, R-137696, RAMOSETRON, RENZAPRIDE, RS-25259-197, SR-58611-A, TEGASEROD, TIAPRIDE, TICALOPRIDE, TRIMEBUTINE, TROPISETRON, VOFOPITANT, Z-338 and ZACOPRIDE, or a pharmacologically acceptable derivative thereof.
5. A pharmaceutical composition according to claim 1 or 2 or 3, wherein the second active ingredient is a compound, which modifies gastrointestinal motility, selected from a group consisting of ALEMCINAL, ASIMADOLINE, BACLOFEN, BIPERIDEN, CILANSETRON, CINITAPRIDE, CISAPRIDE, CLEBOPRIDE, DARIFENACIN, DAZOPRIDE, DIFENIDOL, DOBUPRIDE, E-3620, EM-523, FABESETRON, FEDOTOZINE, GABAPENTIN, IDREMCINAL, ITOPRIDE, KW-5092, KW -5139, LEVOSULPIRIDE, LINTOPRIDE, LIREXAPRIDE, MEBEVERINE, METOCLOPRAMIDE, MITEMCINAL, MOSAPRIDE, NITRAQUAZONE, PAZINACLONE, PIBOSEROD, PRIDINOL, PROCYCLIDINE, PRUCALOPRIDE, PUMOSETRAG, R-137696, RENZAPRIDE, RICASETRON, ROLIPRAM, SK-896, SL- 65.1498, SR-58611-A, T-1815, TEGASEROD, TIBENELAST, TICALOPRIDE, TRIHEXYPHENIDYL, Y-36912, YM-114, YM-47813, Z-338 and ZACOPRIDE, or a pharmacologically acceptable derivative thereof.
6. Use of a pharmaceutical composition according to claim 1 or 2 or 3 or 4 or 5 in the treatment of gastrointestinal diseases.
7. Use of a pharmaceutical composition according to claim 1 or 2 or 3 or 4 or 5 in the treatment of gastro-oesophageal reflux disease (GERD) or irritable bowel syndrome (IBS).
8. A pharmaceutical preparation comprising the pharmaceutical composition according to claim 1 or 2 or 3 or 4 or 5 and one or more pharmaceutically acceptable carriers, diluents, adjuvants, auxiliaries or excipients.
9. A medicament comprising in separate dosage forms a pharmaceutical preparation comprising (S)- pantoprazole and/or its salts, and a pharmaceutical preparation comprising a compound, which modifies gastrointestinal motility, selected from a group consisting of 5-HT-(partial-)agonists/antagonists, muscarinic antagonists, kappa opioid receptor agonists, delta opioid receptor agonists, opioid receptor agonists, dopamine receptor antagonists, cholecystokinin A antagonists, alpha-2 adrenoceptor agonists, N-methyl-D-aspartate receptor antagonists, non-N-methyl-D-aspartate glutamate receptor antagonists, nitric oxide synthase inhibitors, motilin agonists, somatostatin agonists/antagonists, neurotensin agonists/antagonists, vasoactive intestinal peptide antagonists, substance P antagonists, neurokinin antagonists, calcium channel blockers, potassium channel openers, selective serotonin reuptake inhibitors, corticotropin releasing factor antagonists, GABA-A receptor agonists, GABA-B receptor agonists/partial agonists, gastroprokinetics, antiemetics and antispasmodics, or a pharmacologically acceptable derivative thereof.
10. A medicament according to claim 9, comprising the pharmaceutical preparations in blister cards and containing instructions for simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
PCT/EP2005/050336 2004-01-28 2005-01-27 Pharmaceutical combinations comprising (s) -pantoprazole WO2005074931A1 (en)

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