WO2005058326A1 - USE OF QUINAZOLINONE DERIVATIVES FOR THE INHIBITION OF TRANSIENT LOWER ESOPHAGEAL SPHINCTER RELAXATIONS (TLESRs) - Google Patents
USE OF QUINAZOLINONE DERIVATIVES FOR THE INHIBITION OF TRANSIENT LOWER ESOPHAGEAL SPHINCTER RELAXATIONS (TLESRs) Download PDFInfo
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- WO2005058326A1 WO2005058326A1 PCT/SE2004/001876 SE2004001876W WO2005058326A1 WO 2005058326 A1 WO2005058326 A1 WO 2005058326A1 SE 2004001876 W SE2004001876 W SE 2004001876W WO 2005058326 A1 WO2005058326 A1 WO 2005058326A1
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- Prior art keywords
- alkyl
- alkylene
- compound
- formula
- acceptable salt
- Prior art date
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- 210000000111 lower esophageal sphincter Anatomy 0.000 title claims abstract description 23
- 230000005764 inhibitory process Effects 0.000 title claims abstract description 16
- 230000001052 transient effect Effects 0.000 title claims abstract description 14
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical class C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 56
- 208000021302 gastroesophageal reflux disease Diseases 0.000 claims abstract description 18
- 206010067171 Regurgitation Diseases 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 31
- 239000001257 hydrogen Substances 0.000 claims description 30
- 230000002265 prevention Effects 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 230000003287 optical effect Effects 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 18
- 238000004519 manufacturing process Methods 0.000 claims description 18
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
- 125000001931 aliphatic group Chemical group 0.000 claims description 15
- 125000006413 ring segment Chemical group 0.000 claims description 15
- 150000002431 hydrogen Chemical class 0.000 claims description 14
- -1 d-C4alkoxy Chemical group 0.000 claims description 13
- 238000010992 reflux Methods 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 208000006673 asthma Diseases 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- PMBUDILHPXTDNY-UHFFFAOYSA-N ethyl 2-(2-hydroxyethylcarbamoyloxymethyl)-5,7-dimethyl-3-[2-(methylsulfamoyl)phenyl]-4-oxoquinazoline-6-carboxylate Chemical compound O=C1C2=C(C)C(C(=O)OCC)=C(C)C=C2N=C(COC(=O)NCCO)N1C1=CC=CC=C1S(=O)(=O)NC PMBUDILHPXTDNY-UHFFFAOYSA-N 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 239000011593 sulfur Substances 0.000 claims description 6
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims description 5
- 208000019693 Lung disease Diseases 0.000 claims description 5
- 206010016165 failure to thrive Diseases 0.000 claims description 5
- 201000008197 Laryngitis Diseases 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 201000009243 chronic laryngitis Diseases 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 3
- 230000037396 body weight Effects 0.000 claims description 3
- 125000002837 carbocyclic group Chemical group 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical group FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 3
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 8
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 2
- 125000005157 alkyl carboxy group Chemical group 0.000 claims 2
- UFXNCSRAJJJLJN-UHFFFAOYSA-N ethyl 2-(ethylcarbamoyloxymethyl)-5,7-dimethyl-3-[2-(methylsulfamoyl)phenyl]-4-oxoquinazoline-6-carboxylate Chemical compound CCNC(=O)OCC1=NC2=CC(C)=C(C(=O)OCC)C(C)=C2C(=O)N1C1=CC=CC=C1S(=O)(=O)NC UFXNCSRAJJJLJN-UHFFFAOYSA-N 0.000 claims 2
- 229920000159 gelatin Polymers 0.000 description 7
- 235000019322 gelatine Nutrition 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000001828 Gelatine Substances 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 210000002784 stomach Anatomy 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 210000003238 esophagus Anatomy 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 229920000945 Amylopectin Polymers 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 241000792859 Enema Species 0.000 description 2
- 241000167880 Hirundinidae Species 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000013681 dietary sucrose Nutrition 0.000 description 2
- 239000007920 enema Substances 0.000 description 2
- 229940095399 enema Drugs 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 230000027119 gastric acid secretion Effects 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 235000012054 meals Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 229960004793 sucrose Drugs 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- 102100033868 Cannabinoid receptor 1 Human genes 0.000 description 1
- 101710187010 Cannabinoid receptor 1 Proteins 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 239000004150 EU approved colour Substances 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 229910052787 antimony Inorganic materials 0.000 description 1
- WATWJIUSRGPENY-UHFFFAOYSA-N antimony atom Chemical compound [Sb] WATWJIUSRGPENY-UHFFFAOYSA-N 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 229940028435 intralipid Drugs 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 230000037023 motor activity Effects 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 238000001050 pharmacotherapy Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- WWABBFPTGJZEDN-UHFFFAOYSA-N quinazoline-6-carboxylic acid Chemical compound N1=CN=CC2=CC(C(=O)O)=CC=C21 WWABBFPTGJZEDN-UHFFFAOYSA-N 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 208000016752 upper digestive tract disease Diseases 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000013022 venting Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
Definitions
- the present invention relates to the use of certain compounds for the inhibition of transient lower esophageal sphincter relaxations.
- a further aspect of the invention is directed to the use of certain compounds for the treatment of gastro-esophageal reflux disease, as well as for the treatment of regurgitation.
- the lower esophageal sphincter (LES) is prone to relaxing intermittently. As a consequence, fluid from the stomach can pass into the esophagus since the mechanical barrier is temporarily lost at such times, an event hereinafter referred to as "reflux".
- Gastro-esophageal reflux disease is the most prevalent upper gastrointestinal tract disease. Current pharmacotherapy aims at reducing gastric acid secretion, or at neutralizing acid in the esophagus. The major mechanism behind reflux has been considered to depend on a hypotonic lower esophageal sphincter. However, e.g. Holloway & Dent (1990) Gastroenterol. Clin. N. Amer. 19, pp. 517-535, has shown that most reflux episodes occur during transient lower esophageal sphincter relaxations (TLESRs), i.e. relaxations not triggered by swallows. It has also been shown that gastric acid secretion usually is normal in patients with GERD.
- TLESRs transient lower esophageal sphincter relaxations
- the object of the present invention was to find a new way for the inhibition of transient lower esophageal sphincter relaxations (TLESRs), thereby preventing reflux. More particularly the object of the invention was to find a new way of treating gastro-esophageal reflux disease (GERD), as well as a new way for the treatment of regurgitation in infants.
- GENERAL gastro-esophageal reflux disease
- the present invention is directed to the use of compounds of formula I
- R 1 , R 2 , R 3 , R 4 and R 5 independently are hydrogen; halogen; C ⁇ -C alkyl; C 2 - C 4 alkenyl; C 3 -C cycloalkyl; C 3 -C cycloalkylC 1 -C alkyl; C 1 -C alkoxyC 1 -C alkyl; Cj- C 4 alkylcarboxy; hydroxyC 1 -C 4 alkoxyC 1 -C 4 alkyl; hydroxy; hydroxyC !
- R 10 and R n independently are hydrogen, - alkyl; C 2 -C alkenyl; C 3 -C cycloalkyl; C 3 - C cycloalkylC ⁇ -C 4 alkyl; C 1 -C alkoxyC 1 -C 4 alkyl; C !
- R 10 and R n form together an aliphatic heterocyclic group having 5 to 10 ring atoms of which one, two or three are hetero atoms selected from nitrogen, oxygen and sulfur;
- R 12 and R 13 independently are hydrogen, C]-C 4 alkyl, C -C alkenyl, C 3 -C cycloalkyl, C 3 - C cy cloalky 1C i -C 4 alkyl, C i -C 4 alkoxyC i -C alkyl, hydroxy C ⁇ -C 4 alkoxy -C 4 alky 1, hydroxy - alkyl, dihydroxyC]-C 4 alkyl, C ⁇ -C 4 alkoxycarbonylC ⁇ -C 4 alkyl, Ci-
- R 1 is -SO 2 NHCH 3 ;
- R 4 is hydrogen, chloro
- R 5 is hydrogen or chloro
- R 5 is methyl, hydroxymethyl, -CH 2 -O-C(O)-N(R 12 )R 13 and -CH 2 -X-C(O)-R 14 ;
- R 7 and R 8 are methyl;
- R 9 is ethyl or propyl
- R 10 is 1-pyrrolidinyl, -CH 2 COOH, methyl or hydrogen;
- R 11 is methyl or hydrogen
- R 12 is methyl, ethyl, propyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 1- (hydroxymethyl)-2-hydroxyethyl, cyano, -CH 2 CH 2 -SO 2 CH 3 , -CH 2 CH 2 -S-CH 3 , -CH 2 CH 2 -
- R 13 is hydrogen or forms with R 12 a -CH 2 -CH 2 -CHOH-CH 2 -CH 2 - ring;
- R 14 is -NH-CH 3 , -NH-CH 2 CH 3 , -NH-CH 2 CH 2 CH 3 , 2-hydroxyethyl-NH-, 3- hydroxypropyl-NH-, 2,3-dihydroxypropyl-NH-, l-(hydroxymethyl)-2-hydroxyethyl-NH-, -
- the compounds of formula I above can be prepared as described in WO03/066603 Al. Consequently, the present invention is directed to the use of a compound of formula I for the manufacture of a medicament for the inhibition of transient lower esophageal sphincter relaxations (TLESRs).
- TLESRs transient lower esophageal sphincter relaxations
- a further aspect of the invention is the use of a compound of formula I for the manufacture of a medicament for the prevention of reflux.
- Still a further aspect of the invention is the use of a compound of formula I for the manufacture of a.medicament for the treatment of gastro-esophageal reflux disease (GERD).
- GFD gastro-esophageal reflux disease
- a further aspect of the invention is the use of a compound of formula I for the manufacture of a medicament for the treatment of regurgitation.
- Still a further aspect of the invention is the use of a compound of formula I for the manufacture of a medicament for the treatment or prevention of lung disease.
- Another aspect of the invention is the use of a compound of formula I for the manufacture of a medicament for the management of failure to thrive.
- Still a further aspect of the invention is the use of a compound of formula I for the manufacture of a medicament for the treatment or prevention of asthma, such as reflux-related asthma.
- Another aspect of the invention is the use of a compound of formula I for the manufacture of a medicament for the treatment or prevention of chronic laryngitis.
- a further aspect of the present invention is a method for the inhibition of transient lower esophageal sphincter relaxations (TLESRs), whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such inhibition.
- TLESRs transient lower esophageal sphincter relaxations
- Another aspect of the invention is a method for the prevention of reflux, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such prevention.
- Still a further aspect of the invention is a method for the treatment of gastro-esophageal reflux disease (GERD), whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such treatment.
- GFD gastro-esophageal reflux disease
- Yet another aspect of the invention is a method for the treatment of regurgitation, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such treatment.
- Still a further aspect of the invention is a method for the treatment or prevention of asthma, such as reflux-related asthma, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such treatment.
- Yet another aspect of the invention is a method for the treatment of chronic laryngitis, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such treatment.
- Still a further aspect of the invention is a method for the treatment or inhibition of lung disease, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such treatment.
- Still a further aspect of the invention is a method for the management of failure to thrive, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such treatment.
- TLESR transient lower esophageal sphincter relaxations
- GFD gastro-esophageal reflux disease
- the compounds of formula I are in accordance with the present invention suitably formulated into pharmaceutical formulations for oral administration. Also rectal, parenteral or any other route of administration may be contemplated to the skilled man in the art of formulations.
- the compounds of formula I are formulated with at least one pharmaceutically and pharmacologically acceptable carrier or adjuvant.
- the carrier may be in the form of a solid, semi-solid or liquid diluent.
- the compound of formula I to be formulated is mixed with solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
- solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
- disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
- Soft gelatine capsules may be prepared with capsules containing a mixture of the active compound or compounds of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules.
- Hard gelatine capsules may contain the active compound in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.
- Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the active substance(s) mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil, or other suitable vehicle for gelatine rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
- Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions, containing the active compound and the remainder of the formulation consisting of sugar or sugar alcohols, and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agent.
- Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
- Solutions for parenteral administration may be prepared as a solution of a compound of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients and/or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.
- the compound of formula I may be administered once or twice daily, depending on the severity of the patient's condition.
- a typical daily dose of the compound of formula I is from 0.1 - 100 mg per kg body weight of the subject to be treated, but this will depend on various factors such as the route of administration, the age and weight of the patient as well as of severity of the patient's condition.
- a multilumen sleeve/sidehole assembly (Dentsleeve, Sydney, South Australia) is introduced through the esophagostomy to measure gastric, lower esophageal sphincter (LES) and esophageal pressures.
- the assembly is perfused with water using a low-compliance manometric perfusion pump (Dentsleeve, Sydney, South Australia).
- An air-perfused tube is passed in the oral direction to measure swallows, and an antimony electrode monitored pH, 3 cm above the LES. All signals are amplified and acquired on a personal computer at 10 Hz.
- placebo (0.9% NaCl) or test compound is administered intravenously (i.v., 0.5 ml/kg) in a foreleg vein.
- a nutrient meal (10% peptone, 5% D-glucose, 5% Intralipid, pH 3.0) is infused into the stomach through the central lumen of the assembly at 100 ml/min to a final volume of 30 ml/kg.
- air is insufflated at a rate of 500 ml/min until a intragastric pressure of 10+1 mmHg is obtained.
- the pressure is then maintained at this level throughout the experiment using the infusion pump for further air infusion or for venting air from the stomach.
- the experimental time from start of nutrient infusion to end of air insufflation is 45 min. The procedure has been validated as a reliable means of triggering TLESRs.
- TLESRs is defined as a decrease in lower esophageal sphincter pressure (with reference to intragastric pressure) at a rate of >1 mmHg/s.
- the relaxation should not be preceded by a pharyngeal signal ⁇ 2s before its onset in which case the relaxation is classified as swallow- induced.
- the pressure difference between the LES and the stomach should be less than 2 m Hg, and the duration of the complete relaxation longer than 1 s.
- N number of dogs tested.
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Abstract
The present invention relates to the use of a compound of formula (I) for the inhibition of transient lower esophageal sphincter relaxations. A further aspect of the invention is directed to the use of a compound of formula I for the treatment of gastro-esophageal reflux disease, as well as for the treatment of regurgitation.
Description
Use of quinazolinone derivatives for the inhibition of transient lower esophageal sphincter' relaxations (TLESRs)
Field of the invention The present invention relates to the use of certain compounds for the inhibition of transient lower esophageal sphincter relaxations. A further aspect of the invention is directed to the use of certain compounds for the treatment of gastro-esophageal reflux disease, as well as for the treatment of regurgitation.
Background of the invention
The lower esophageal sphincter (LES) is prone to relaxing intermittently. As a consequence, fluid from the stomach can pass into the esophagus since the mechanical barrier is temporarily lost at such times, an event hereinafter referred to as "reflux".
Gastro-esophageal reflux disease (GERD) is the most prevalent upper gastrointestinal tract disease. Current pharmacotherapy aims at reducing gastric acid secretion, or at neutralizing acid in the esophagus. The major mechanism behind reflux has been considered to depend on a hypotonic lower esophageal sphincter. However, e.g. Holloway & Dent (1990) Gastroenterol. Clin. N. Amer. 19, pp. 517-535, has shown that most reflux episodes occur during transient lower esophageal sphincter relaxations (TLESRs), i.e. relaxations not triggered by swallows. It has also been shown that gastric acid secretion usually is normal in patients with GERD.
The object of the present invention was to find a new way for the inhibition of transient lower esophageal sphincter relaxations (TLESRs), thereby preventing reflux. More particularly the object of the invention was to find a new way of treating gastro-esophageal reflux disease (GERD), as well as a new way for the treatment of regurgitation in infants.
Outline of the invention
The present invention is directed to the use of compounds of formula I
R10 and Rn independently are hydrogen, - alkyl; C2-C alkenyl; C3-C cycloalkyl; C3- C cycloalkylCι-C4alkyl; C1-C alkoxyC1-C4alkyl; C!-C4alkylcarboxy; hydroxyCi- C4alkoxyC!-C alkyl; hydroxy; hydroxy - alkyl; phenylCι-C alkyl which is optionally substituted by hydroxy, Cι-C4alkoxy, carboxy, C1-C4alkoxycarbonylC1-C4alkyl, C\- C4alkoxycarbonyl, cyano; or R10 and Rn form together an aliphatic heterocyclic group having 5 to 10 ring atoms of which one, two or three are hetero atoms selected from nitrogen, oxygen and sulfur;
R12 and R13 independently are hydrogen, C]-C4alkyl, C -C alkenyl, C3-C cycloalkyl, C3- C cy cloalky 1C i -C4alkyl, C i -C4alkoxyC i -C alkyl, hydroxy C ι -C4alkoxy -C4alky 1, hydroxy - alkyl, dihydroxyC]-C4alkyl, Cι-C4alkoxycarbonylCι-C4alkyl, Ci-
C4alkoxycarbonyl, cyano, -SO2R10, -SO2N(R10)Rn, -S-R10, -SOR10, -C C4-alkylene-
SO2R10, -C1-C4-alkylene-SOR10, C C4-alkylene-NH-SO2R10, -d-C4-alkylene- CON(R10)Rn, -CON(R10)Rn, -Cι-C4-alkylene-C(O)OR10, fluoroalkyl, or R12 and R13 form a substituted or unsubstituted aliphatic heterocyclic group having 5 to 10 ring atoms; R14 is H, d-C4alkyl-NH-, C2-C4alkenyl- H-, C3-C7cycloalkyl-NH-, C3-C7cycloalkyld- C4alkyl-NH-, C C4alkoxyCι-C4alkyl-NH-, hydroxyC1-C4alkoxyC1-C4alkyl-NH-, hydroxy C ι -C4alkyl-NH-, dihydroxy d -C alkyl-NH-, Ci -C alkoxycarbony 1-C ] -C4alkyl- NH-, C1-C4alkoxycarbonyl-NH-, -NH-d-C4-alkylene-CN, - H-SO2R10, -NH- SO2N(R10)Rπ, -NH-d-Q-alkylene-S-R10, -NH-SOR10, -NH-d-C4-alkylene-SO2R10, - NH-C1-C4-alkylene-SOR10, -NH-Cι-C4-alkylene-NH-SO2R10, - H-C1-C4-alkylene- CON(R10)R1 ', -NH-CON(R10)R1 ', - H-C1-C4-alkylene-C(O)OR10, -NH-fluoroalkyl, or a substituted or unsubstituted aliphatic heterocyclic group having 5 to 10 ring atoms; X is O or CH2; with the proviso that when R1 is either halogen, methyl, ethyl, methoxy, trifluoromethyl or hydrogen and R2, R3, R4 are either hydrogen, methyl or methoxy and R5 is hydrogen or methyl, R12 is neither hydrogen, C2-C4alkyl, C2-C4alkenyl, hydroxyd- Qalkyl, -d-C4-alkylene-SO2R10, nor -Cι-C4-alkylene-SOR10; or a pharmaceutically acceptable salt or an optical isomer thereof; for the manufacture of a medicament for the inhibition of transient lower esophageal sphincter relaxations (TLESRs).
Compounds of the invention exist in free or salt, e.g. acid addition salt form. The invention is to be understood as including the compounds of formula I in free as well as in acid addition salt form, e.g. as trifiuoroacetate or hydrochloride salt. Suitable pharmaceutically acceptable acid addition salts for pharmaceutical use in accordance with the invention include in particular the hydrochloride salt.
In formula I the following residues are examples, independently, collectively or in any combination or sub-combination:
(a) R1 is hydrogen, chloro, methyl, methoxy, -CH2C(O)OCH3, -CH2CH2C(O)OCH3, - C(O)N(CH3)2, -C(O)OCH3, cyano, -SO2-l-pyrrolidinyl, -SO2CH3, -SO2NHCH3, -
SO2N(CH3)2, -SO2N(CH3)CH2COOH, -S-CH3, -SOCH3 or R1 forms with R2 a -NH-CH2- CH2-CH2- or -CH=CH CH=CH- ring. In one embodiment, R1 is -SO2NHCH3; (b) R2 is hydrogen, chloro, methyl, tri-fluoromethyl, or forms with R1 a -NH-CH2-CH2- CH2-, CH=CH-CH=CH- ring or with R3 a -CH=CH-CH=CH- ring. (c) R3 is hydrogen, fluoro, methyl, or forms with R2 a -CH=CH-CH=CH- ring. In particular embodiments R3 is hydrogen or chloro;
(d) R4 is hydrogen, chloro;
(e) R5 is hydrogen or chloro;
(f) R5 is methyl, hydroxymethyl, -CH2-O-C(O)-N(R12)R13 and -CH2-X-C(O)-R14; (g) R7 and R8 are methyl;
(h) R9 is ethyl or propyl;
(i) R10 is 1-pyrrolidinyl, -CH2COOH, methyl or hydrogen;
(k) R11 is methyl or hydrogen;
(1) R12 is methyl, ethyl, propyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 1- (hydroxymethyl)-2-hydroxyethyl, cyano, -CH2CH2-SO2CH3, -CH2CH2-S-CH3, -CH2CH2-
NH-SO2CH3, -CH2C(O)OCH3, -CH2CONH2, 2,2,2-trifluoro-ethyl, or forms with R13 a -
CH2-CH2-CHOH-CH2-CH2- ring;
(m) R13 is hydrogen or forms with R12 a -CH2-CH2-CHOH-CH2-CH2- ring;
(n) R14 is -NH-CH3, -NH-CH2CH3, -NH-CH2CH2CH3, 2-hydroxyethyl-NH-, 3- hydroxypropyl-NH-, 2,3-dihydroxypropyl-NH-, l-(hydroxymethyl)-2-hydroxyethyl-NH-, -
NH-CH2CN, -NH-CH2CH2-SO2CH3, -NH-CH2CH2-S-CH3, -NH-CH2CH2-NH-SO2CH3, -
NH-CH2C(O)OCH3, -NH-CH2CONH2, 2,2,2-NH-trifluoro-ethyl,
(o) X is O.
The compounds of formula I above can be prepared as described in WO03/066603 Al.
Consequently, the present invention is directed to the use of a compound of formula I for the manufacture of a medicament for the inhibition of transient lower esophageal sphincter relaxations (TLESRs).
A further aspect of the invention is the use of a compound of formula I for the manufacture of a medicament for the prevention of reflux.
Still a further aspect of the invention is the use of a compound of formula I for the manufacture of a.medicament for the treatment of gastro-esophageal reflux disease (GERD).
Effective prevention of regurgitation would be an important way of preventing, as well as curing lung disease due to aspiration of regurgitated gastric contents, and for managing failure to thrive. Thus, a further aspect of the invention is the use of a compound of formula I for the manufacture of a medicament for the treatment of regurgitation.
Still a further aspect of the invention is the use of a compound of formula I for the manufacture of a medicament for the treatment or prevention of lung disease.
Another aspect of the invention is the use of a compound of formula I for the manufacture of a medicament for the management of failure to thrive.
Still a further aspect of the invention is the use of a compound of formula I for the manufacture of a medicament for the treatment or prevention of asthma, such as reflux- related asthma.
Another aspect of the invention is the use of a compound of formula I for the manufacture of a medicament for the treatment or prevention of chronic laryngitis.
A further aspect of the present invention is a method for the inhibition of transient lower esophageal sphincter relaxations (TLESRs), whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such inhibition.
Another aspect of the invention is a method for the prevention of reflux, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such prevention.
Still a further aspect of the invention is a method for the treatment of gastro-esophageal reflux disease (GERD), whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such treatment.
Yet another aspect of the invention is a method for the treatment of regurgitation, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such treatment.
Still a further aspect of the invention is a method for the treatment or prevention of asthma, such as reflux-related asthma, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such treatment.
Yet another aspect of the invention is a method for the treatment of chronic laryngitis, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such treatment. Still a further aspect of the invention is a method for the treatment or inhibition of lung disease, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such treatment.
Still a further aspect of the invention is a method for the management of failure to thrive, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such treatment.
The wording "TLESR", transient lower esophageal sphincter relaxations, is herein defined in accordance with Mittal, R.K., Holloway, R.H., Penagini, R., Blackshaw, L.A., Dent, J., 1995; Transient lower esophageal sphincter relaxation. Gastroenterology 109, pp. 601-610.
The wording "reflux" is defined as fluid from the stomach being able to pass into the esophagus, since the mechanical barrier is temporarily lost at such times.
The wording "GERD", gastro-esophageal reflux disease, is defined in accordance with van Heerwarden, M.A., SmoutA.J.P.M., 2000; Diagnosis of reflux disease. Bailliere 's Clin. Gastroenterol. 14, pp. 759-774.
Pharmaceutical formulations
For clinical use, the compounds of formula I are in accordance with the present invention suitably formulated into pharmaceutical formulations for oral administration. Also rectal, parenteral or any other route of administration may be contemplated to the skilled man in the art of formulations. Thus, the compounds of formula I are formulated with at least one pharmaceutically and pharmacologically acceptable carrier or adjuvant. The carrier may be in the form of a solid, semi-solid or liquid diluent.
In the preparation of oral pharmaceutical formulations in accordance with the invention, the compound of formula I to be formulated is mixed with solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating
agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture is then processed into granules or compressed into tablets.
Soft gelatine capsules may be prepared with capsules containing a mixture of the active compound or compounds of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules. Hard gelatine capsules may contain the active compound in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.
Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the active substance(s) mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil, or other suitable vehicle for gelatine rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions, containing the active compound and the remainder of the formulation consisting of sugar or sugar alcohols, and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agent. Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
Solutions for parenteral administration may be prepared as a solution of a compound of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients and/or buffering ingredients and are dispensed into unit doses in the
form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.
In one aspect of the present invention, the compound of formula I may be administered once or twice daily, depending on the severity of the patient's condition.
A typical daily dose of the compound of formula I is from 0.1 - 100 mg per kg body weight of the subject to be treated, but this will depend on various factors such as the route of administration, the age and weight of the patient as well as of severity of the patient's condition.
Biological evaluation
Screening for compounds active against TLESR
Adult Labrador retrievers of both genders, trained to stand in a Pavlov sling, are used. Mucosa-to-skin esophagostomies are formed and the dogs are allowed to recover completely before any experiments are done.
Motility measurement
In brief, after fasting for approximately 17 h with free supply of water, a multilumen sleeve/sidehole assembly (Dentsleeve, Adelaide, South Australia) is introduced through the esophagostomy to measure gastric, lower esophageal sphincter (LES) and esophageal pressures. The assembly is perfused with water using a low-compliance manometric perfusion pump (Dentsleeve, Adelaide, South Australia). An air-perfused tube is passed in the oral direction to measure swallows, and an antimony electrode monitored pH, 3 cm above the LES. All signals are amplified and acquired on a personal computer at 10 Hz.
When a baseline measurement free from fasting gastric/LES phase III motor activity has been obtained, placebo (0.9% NaCl) or test compound is administered intravenously (i.v., 0.5 ml/kg) in a foreleg vein. Ten min after i.v. administration, a nutrient meal (10% peptone, 5% D-glucose, 5% Intralipid, pH 3.0) is infused into the stomach through the central lumen of the assembly at 100 ml/min to a final volume of 30 ml/kg. Immediately following the meal, air is insufflated at a rate of 500 ml/min until a intragastric pressure of 10+1 mmHg is obtained. The pressure is then maintained at this level throughout the experiment using the infusion pump for further air infusion or for venting air from the stomach. The experimental time from start of nutrient infusion to end of air insufflation is 45 min. The procedure has been validated as a reliable means of triggering TLESRs.
TLESRs is defined as a decrease in lower esophageal sphincter pressure (with reference to intragastric pressure) at a rate of >1 mmHg/s. The relaxation should not be preceded by a pharyngeal signal <2s before its onset in which case the relaxation is classified as swallow- induced. The pressure difference between the LES and the stomach should be less than 2 m Hg, and the duration of the complete relaxation longer than 1 s.
Inhibition of the number of TLESRs was calculated with regard to the five preceding control experiments for each dog, and the results as set out in Table 1 below were achieved.
The results shown below in Table 1 indicate that cannabinoid receptor 1 agonists are useful for the inhibition of TLESR, and thus for the treatment of GERD.
EXAMPLE 1
Ethyl 2-[( { [(2-hydroxyethy l)amino] carbony 1 } oxy)methyl]-5 ,7-dimethyl-3 - { 2- [(methylamino)sulfonyl]phenyl}-4-oxo-3,4-dihydroquinazoline-6-carboxylate [CA Index Name: 6-quinazolinecarboxylic acid, 3,4-dihydro-2-[[[[(2- hydroxyethyl)amino]carbonyl]oxy]methyl]-5,7-dimethyl-3-[2-
[(methylamino)sulfonyl]phenyl]-4-oxo-ethyl ester and CAS registry number: 581106-09-4 or also called 2-(2-hydroxy-ethylcarbamoyloxymethyl)-5,7-dimethyl-3-(2- methylsulfamoyl-phenyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid ethyl ester] was prepared according to the procedure described in WO 03/066603 (Example 2). The above quinazoline, herein referred to as: 581106-09-4, was tested on adult Labrador retrievers of both genders in accordance with the model described above.
Table 1 - Barostat model
N= number of dogs tested.
Claims
1.
2. Use of a compound of formula I as defined in claim 1, wherein said compound is selected from 2-ethylcarbamoyloxymethyl-5,7-dimethyl-3-(2-methylsulfamoyl- phenyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid ethyl ester and 2-(2- hydroxy-ethylcarbamoyloxymethyl)-5,7-dimethyl-3-(2-methylsulfamoyl-phenyl)- 4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid ethyl ester; or a pharmaceutically acceptable salt or an optical isomer thereof; for the manufacture of a medicament for the inhibition of transient lower esophageal sphincter relaxations (TLESRs).
3. Use of a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for the treatment of gastro-esophageal reflux disease (GERD).
4. Use of a compound of formula I as defined in claim 1 , or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for the prevention of reflux.
5. Use of a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for the treatment of, or prevention of, regurgitation.
6. Use of a compound of formula I as defined in claim 1 , or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for the treatment of, or prevention of, asthma.
7. Use according to claim 6, wherein the asthma is reflux-related asthma.
8. Use of a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for the treatment of, or prevention of, chronic laryngitis.
9. Use of a compound of formula I as defined in claim 1 , or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for the treatment of, or prevention of, lung disease.
10. Use of a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for managing failure to thrive.
11. Use according to any one of the preceding claims, wherein the daily dose of the compound of formula I is from 0.1 - 100 mg per kg body weight of the subject to be treated.
12. A method for the inhibition of transient lower esophageal sphincter relaxations (TLESRs), whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I
R12 and R13 independently are hydrogen, C1-C4alkyl, C2-C4alkenyl, C3- C7cycloalkyl, C3-C7cycloalkyld-C4alkyl, C1-C alkoxyC1-C4alkyl, hydroxyCi-
C4alkoxyCι-C alkyl, hydroxyCι-C alkyl, dihydroxyC1-C4alkyl, d- C4alkoxycarbonylC1-C4alkyl, d- C4alkoxycarbonyl, cyano, -SO2R10, - SO2N(R10)Rn, -S-R10, -SOR10, -Cι-C4-alkylene-SO2R10, -d-C4-alkylene-SOR10, Cι-C4-alkylene-NH-SO2R10, -Cι-C4-alkylene-CON(R10)Rn, -CON(R10)Rn, -C C4-alkylene-C(O)OR10, fluoroalkyl, or R12 and R13 form a substituted or unsubstituted aliphatic heterocyclic group having 5 to 10 ring atoms; R14 is NH, Cι-C4alkyl-NH-, C2-C4alkenyl-NH-, C3-C7cycloalkyl-NH-, C3- C7cycloalkyld-C4alkyl-NH-, Cι-C4alkoxyCι-C4alkyl-NH-, hydroxyCi- C4alkoxyCι-C alkyl-NH-, hydroxyd-C4alkyl-NH-, dihydroxyC1-C4alkyl-NH-, d-C4alkoxycarbonyl-Cι-C4alkyl-NH-, d-C4alkoxycarbonyl-NH-, -NH-Cj-C4- alkylene-CN, -NH-SO2R10, -NH-SO2N(R10)Rπ, -NH-d-C4-alkylene-S-R10, -NH- SOR10, -NH-d-C4-alkylene-SO2R10, -NH-d-C4-alkylene-SOR10, -NH-d-C4- alkylene-NH-SO2R10, -NH-d-C4-alkylene-CON(R10)Rn, -NH-CON(R10)Rn, - NH-C]-C4-alkylene-C(O)OR10, -NH-fluoroalkyl, or a substituted or unsubstituted aliphatic heterocyclic group having 5 to 10 ring atoms;
X is O or CH2; with the proviso that when R1 is either halogen, methyl, ethyl, methoxy, trifluoromethyl or hydrogen and R2, R3, R4 are either hydrogen, methyl or methoxy and R5 is hydrogen or methyl, R12 is neither hydrogen, C2-C4alkyl, C2- C4alkenyl, hydroxyd-Qalkyl, -Cι-C4-alkylene-SO2R10, nor -d-C4-alkylene- SOR10; or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such inhibition.
13. A method according to claim 12, wherein the compound of formula I is selected from 2-ethylcarbamoyloxymethyl-5,7-dimethyl-3-(2-methylsulfamoyl-phenyl)-4- oxo-3,4-dihydro-quinazoline-6-carboxylic acid ethyl ester and 2-(2-hydroxy- ethylcarbamoyloxymethyl)-5,7-dimethyl-3-(2-methylsulfamoyl-phenyl)-4-oxo- 3,4-dihydro-quinazoline-6-carboxylic acid ethyl ester; or a pharmaceutically acceptable salt or an optical isomer thereof.
14. A method for the treatment of gastro-esophageal reflux disease (GERD), whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I as defined in claim 12, or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such treatment.
15. A method for the prevention of reflux, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I as defined in claim 12, or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such prevention.
16. A method for the treatment of, or prevention of, regurgitation, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I as defined in claim 12, or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such treatment or prevention.
17. A method for the prevention of, or treatment of, lung disease, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I as defined in claim 12, or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such treatment or prevention.
18. A method for managing failure to thrive, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I as defined in claim 12, or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such management.
19. A method for treatment or prevention of asthma, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I as defined in claim 12, or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such treatment or prevention.
20. A method according to claim 19, wherein the asthma is reflux-related asthma.
21. A method for treatment or prevention of chronic laryngitis, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I as defined in claim 12, or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such treatment or prevention.
22. A method according to any one of claims 12-21, wherein the daily dose of the compound of formula I is from 0.1 - 100 mg per kg body weight of the subject to be treated.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE0303491A SE0303491D0 (en) | 2003-12-19 | 2003-12-19 | New use VI |
| SE0303491-5 | 2003-12-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2005058326A1 true WO2005058326A1 (en) | 2005-06-30 |
Family
ID=30768810
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/SE2004/001876 WO2005058326A1 (en) | 2003-12-19 | 2004-12-15 | USE OF QUINAZOLINONE DERIVATIVES FOR THE INHIBITION OF TRANSIENT LOWER ESOPHAGEAL SPHINCTER RELAXATIONS (TLESRs) |
Country Status (2)
| Country | Link |
|---|---|
| SE (1) | SE0303491D0 (en) |
| WO (1) | WO2005058326A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005123694A2 (en) * | 2004-06-17 | 2005-12-29 | Novartis Ag | Quinazolinone compounds for the treatment of cough |
| US8552015B2 (en) | 2002-02-06 | 2013-10-08 | Novartis Ag | Quinazolinone derivatives and their use as CB agonists |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0371731A2 (en) * | 1988-11-30 | 1990-06-06 | Smith Kline & French Laboratories Limited | Quinazolinone derivatives |
| US20020169159A1 (en) * | 2000-12-11 | 2002-11-14 | Tularik Inc. | CXCR3 antagonists |
| WO2003066603A1 (en) * | 2002-02-06 | 2003-08-14 | Novartis Ag | Quinazolinone derivatives and their use as cb agonists |
| WO2004041755A2 (en) * | 2002-11-04 | 2004-05-21 | Nps Pharmaceuticals, Inc. | Quinazolinone compounds as calcilytics |
-
2003
- 2003-12-19 SE SE0303491A patent/SE0303491D0/en unknown
-
2004
- 2004-12-15 WO PCT/SE2004/001876 patent/WO2005058326A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0371731A2 (en) * | 1988-11-30 | 1990-06-06 | Smith Kline & French Laboratories Limited | Quinazolinone derivatives |
| US20020169159A1 (en) * | 2000-12-11 | 2002-11-14 | Tularik Inc. | CXCR3 antagonists |
| WO2003066603A1 (en) * | 2002-02-06 | 2003-08-14 | Novartis Ag | Quinazolinone derivatives and their use as cb agonists |
| WO2004041755A2 (en) * | 2002-11-04 | 2004-05-21 | Nps Pharmaceuticals, Inc. | Quinazolinone compounds as calcilytics |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8552015B2 (en) | 2002-02-06 | 2013-10-08 | Novartis Ag | Quinazolinone derivatives and their use as CB agonists |
| WO2005123694A2 (en) * | 2004-06-17 | 2005-12-29 | Novartis Ag | Quinazolinone compounds for the treatment of cough |
| WO2005123694A3 (en) * | 2004-06-17 | 2006-04-13 | Novartis Ag | Quinazolinone compounds for the treatment of cough |
Also Published As
| Publication number | Publication date |
|---|---|
| SE0303491D0 (en) | 2003-12-19 |
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