TW200400826A - Combination of an acid secretion inhibiting agent and a reflux inhibitor for the treatment of GERD - Google Patents

Abstract

The present invention relates to a medicament comprising, separately or together, (i) at least one acid secretion inhibiting agent; and (ii) at least one reflux inhibitor. A further aspect of the invention relates to methods of treatment of gastro-esophageal reflux disease regurgitation, asthma, failure to thrive and lung disease.

Description

200400826 Rose, description of the invention: TECHNICAL FIELD The present invention relates to a combination of an acid secretion inhibitor and a reflux inhibition sword. Another aspect of the present invention relates to the prevention of gastroesophageal reflux disease. Prior art The lower esophageal sphincter (LES) tends to relax briefly. Therefore, the gastric fluid can enter the esophagus because the mechanical obstacle temporarily disappears, and this situation is hereinafter referred to as "backflow". Gastroesophageal reflux disease (GERD) is the most common upper gastrointestinal disease. The main mechanism of reflux is thought to be determined by the hypotonic lower esophageal sphincter. However, 'more detailed studies (eg, Holloway & Dent (1990) Gastroenterol. Clin. N. Amer. 19, ρρ · 517-535) have indicated that reflux events occur in the transient lower esophagus Sleeve relaxation (TLESR) is not caused by swallowing. It has been shown that gastric acid secretion is usually normal for patients with GERD. GERD is caused by reflux of gastric contents into the esophagus, which causes heartburn and other typical symptoms. In many cases, inflammation occurs in the distal esophagus (esophagitis). It has long been known that suppressing gastric acid secretion improves symptoms and esophagitis. However, some patients may have symptoms that persist despite adequate control of acid secretion. The return of other harmful factors is thought to be responsible for those symptoms. Most of the focus is on the importance of bile acids, and the development of severe GERD is related to the level of bile acid exposure in the esophagus. The combination of cisapride, omeprazole, and baclofen for the treatment of primary chronic gastritis has been described by Petroianu G. et al. In Clinical Therapeutics ( 1997), 19, ρ · 200400826 103 1-1038. The combination of ezepela, omegapezo, and gabapentin for the treatment of primary chronic gastritis has been described by Petrionian et al in Journal of Clinical Gastroenterology (2000), 20, pp_ 321-324 ° Invented SUMMARY The present invention provides a combination comprising (i) at least one acid secretion inhibitor; and (ii) at least one reflux inhibitor, separately or in combination. The present invention relates to a combination of an acid secretion inhibitor and a reflux inhibitor. Furthermore, the present invention relates to the preparation of a medicament using a combination of an acid secretion inhibitor and a reflux inhibitor, which is used for the treatment of gastroesophageal reflux disease, reflux, asthma, abnormal development, and lung diseases. Acid secretion inhibitor The term "acid secretion inhibitor" useful according to the present invention includes, inter alia, H2 blockers such as cimetidine, ranitine; and hydrogen ion pump inhibitors. An example of a hydrogen ion pump inhibitor that can be used in accordance with the present invention is p-methylidenemethylbenzoic acid benzoimide sigma, for example, omeprazole, esomeprazole, lansoprazole Lansoprazole pantoprazole, rabeprazole, or related substances, such as leminoprazole. Hydrogen ion pump inhibitors that can be used in accordance with the present invention can be reversible or irreversible. Reflux inhibitor

The term "reflux inhibitor" is defined herein as an agent used to prevent reflux of gastric contents. GABAb-receptor agonists are examples of reflux inhibitors. GABAb-receptor agonists have been shown to inhibit TLESR, which is disclosed in WO 98/11885 A1 ° 200400826. Examples of acid secretion inhibitors useful according to the present invention are compounds of formula I below

Wherein R1 represents a hydrogen 'hydroxy' lower-carbon alkyl, a lower alkoxy group or a halogen; R2 represents a hydrogen, a thiol group, a halogen or an oxy group; R · 3 represents a hydrogen or a lower alkyl group (as the case may be via a hydroxyl group) 'Mercapto, low-carbon alkoxy' substituted with low-carbon thioalkoxy or aryl); R4 represents hydrogen, lower-carbon alkyl (optionally substituted with aryl), or aryl; and pharmacologically Acceptable salts, vehicles and stereoisomers. Examples of such compounds are (3-amino-2-fluoropropyl) phosphinic acid, (2R)-(3-amino-2-fluoropropyl) / human phosphine '(2S)-(3-amine 2-fluoropropyl) phosphinic acid, (3-amino-2-fluoro-methylpropyl) phosphinic acid, (3-amino-2-oxopropyl) phosphinic acid, (s) _ (3_Amino-2-¾propyl) phosphinic acid, (R) _ (3_Amino_2_Aminopropyl) phosphinic acid and (3_Amino-1 -fluorochipropyl) Phosphinic acid. In the definition of formula I above, it should be understood that when & is an oxy group, the bond between K and carbon is a double bond. In the definition of the above formula I, it should be understood that "low-carbon," radicals are, for example, those groups and compounds having up to and including 7, particularly up to and including 4 carbon atoms. Also, the general term has the following Meaning: Lower alkyl is, for example, Ci_C4 alkyl, such as methyl, ethyl, n-propyl or n-butyl, and isopropyl or isobutyl, secondary butyl or tertiary butyl , But can also be C ^ c: 7 alkyl, for example: pentyl, hexyl or heptyl. 200400826 Low-carbon alkoxy is, for example, CrC4 alkoxy, for example: methoxy, ethoxy, n-propoxy Or n-butoxy, as well as isopropoxy or isobutoxy, secondary butoxy or tertiary butoxy 'but can also be Cs-C7 alkoxy, such as: methoxy, hexyloxy or Heptyloxy. The low-percent carbofluorenyloxy is, for example, 'Ci-C4thiofeoxy', for example: thiocarboxide, thioethoxy ', n-propoxy or n-thiobutoxy, and Thioisopropoxy or thioisobutoxy, secondary thiobutoxy or tertiary thiobutoxy, but can also be thiothiooxy, for example: thiopentyloxy, thiohexyloxy or thioheptyloxy I * prime is an example For example, halogens having at most 35 atoms, such as fluorine, chlorine or molybdenum. The compounds of formula I according to the invention are amphoteric in nature and can exist in the form of internal salts. They can also form acid addition salts and Salts with bases. This is especially a pharmaceutically acceptable acid plus AM and its pharmacologically acceptable bases to form salts. Suitable acids used to generate such salts include, for example, mineral acids , Such as · Hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid, or organic acids' such as: sulfonic acids and carboxylic acids. Salts with bases, such as salts, such as: 铷 七 乂 丝士 w to sodium or potassium Salts' or alkaline earth metal salts, such as: calcium or magnesium salts, and Ming salts, such as the salts of the ancient I and II with organic or organic amines. When there are-or more stereocenters, the compounds according to formula I can It exists as a stereoisomeric mixture, which is a non-mirromeric isomer and / or a racemic mixture. Rong α α „_ times exists as an early independent stereoisomer. That is, 1¾-like wells alone; 5 +. Or non-mirror isomers. Compounds can also exist in the form of a medicament, e.g. Further improvement of the inhibitors that can be used in the field, g, and cloud 4 according to the present invention-an example is a compound of the following formula 200400826 11

μ R

Where RS stands for hydrogen, hydroxy'lower alkyl'lower alkoxy or halogen; stands for meridian, thiol, halogen or oxy, ‘

R7 represents hydrogen or a lower alkyl group (optionally substituted by a hydroxy group, a thiol group which is a low-blocking aryloxy group or an arylthio group), and R8 represents a hydrogen and a lower alkyl group (which may be determined by the case) Aryl substituted) or aryl; R9 represents methyl, fluoromethyl, difluoromethyl or trifluoromethyl; and its pharmacologically acceptable salts, vehicles and stereoisomers. Examples of such compounds are (3-amino-2-fluoropropyl) (methyl) phosphinic acid '(2R)-(3-amino-2-fluoropropyl) (fluorenyl) phosphinic acid, (2S)-(3-amino-2-fluoropropyl) (methyl) phosphinic acid, (3-amino-2-fluoro-1-methylpropyl) (fluorenyl) phosphinic acid or Pharmacologically acceptable salts, vehicles and stereoisomers.

In the definition of the above formula II, it should be understood that when R6 is an oxy group, the bond between R6 and carbon is a double bond. Furthermore, 'in the definition of Formula II' above, it should be understood that "low-carbon," radicals are, for example, those groups and compounds that have the highest and include 7 ', in particular, the highest and include 4 carbon atoms. At the same time, the general The terms have the following meanings: Low-carbon: fluorene, for example, q-C4 fluorenyl, for example: methyl, ethyl, n-propyl or n-butyl, and isopropyl or isobutyl, secondary butyl or Tertiary butyl, but can also be C5_C7 alkyl, such as: pentyl, hexyl or heptyl. Lower alkoxy is, for example, C1-C4 alkoxy, such as: methoxy, ethoxy, -10- 200400826 n- Propoxy or n-butoxy, and isopropoxy or isobutoxy, secondary butoxy or secondary butoxy, but it can also be (^ -C7 oxo ', for example: pentyloxy, Hexyloxy or heptyloxy. Low thiothioalkoxy is, for example, Cl_C: 4 thioalkoxy, such as: thiomethoxy, thioethoxy 'n-thiopropoxy or n-thiobutoxy , As well as thioisopropoxy or λ · /, butoxy, --- thiobutoxy or tertiary thiobutoxy, but also c5_c7 thioalkoxy, for example: thiopentyloxy, thiohexyloxy Thioheptyl oxide Quotients are, for example, halogens having up to 35 atoms, such as benzine, bromine or bromine. ≪ The compound of formula π according to the invention is amphoteric in nature and can exist in the form of internal salts. It also It can form acid addition salts and salts with bases. Such salts are especially pharmacologically acceptable acid addition salts, and pharmacologically compatible with test bases. Suitable for generating such salts For example, 'mineral acids' such as: hydrochloric acid, hydrobromic acid, stone acid, or phosphoric acid, only green and bismuth are added to the green. Salts with a base are, for example, base 2 7' such as : Na or unsalt 'or soil test metal salt U or magnesium salt, this = salt' such as those with ammonium or organic amines. When there are-or more stereoisomeric mixtures in the molecule, The compound of formula 11 is a mixture thereof, or the existence of the non-image isomers and / or racemates of the image isomers and / or non-isomers exists, that is, the individual forms exist. This compound can also be further improved by using the median II = =, the available reflux inhibitor-an example is the following formula 2004 00826 its

10 represents hydrogen, methyl, fluoromethyl, difluoromethyl or trifluoromethyl; RU represents hydrogen, hydroxy, CVC7 alkyl, CrC7 alkyloxy, or oxine; R! 2 represents hydrogen 'Ci-C: 7 alkyl (optionally substituted by hydroxyl, thiol, (^-(^ alkoxy'q-C7thioalkoxy'aryl or heteroaryl)), aryl or heteroaryl; R13 represents Hydrogen, Ci-C: 7 fluorenyl (optionally substituted by aryl or heteroaryl), aryl or heteroaryl; and its pharmacologically acceptable salts, vehicles and stereoisomers. Basis An example of a compound of formula III is (3-amino _;! _ Fluoropropyl) (methyl) phosphinic acid, 3-[(4-chlorotoluene) amino] propyl (methyl) phosphinic acid, [ Hydroxyl (oxy) pentyl] propyl} amino) ethyl] benzoic acid. In the definition of formula III above, the "C7 alkyl group may be a linear, branched or cyclic alkyl group, and is, for example, a CrC4 alkyl group. Group, such as: methyl, ethyl, n-propyl or n-y, and isopropyl or isobutyl, secondary butyl or tertiary butyl, but also C5_C7 alkyl, for example: pentyl Base, hexyl or heptyl.

Ci-C7 alkoxy is, for example, Ci_c4 alkoxy, such as: methoxy, ethoxy,, propoxy or n-butoxy 'and isopropoxy or isobutoxy, secondary butoxy Or tertiary butoxy 'but can also be c5_c7 alkoxy, such as: pentyloxy, hexyloxy or heptyloxy. > Ci-f 7 pitoxy is, for example, oxoalkoxy, such as: thiomethoxy, 1 ethyl lactyl 'n-thiopropoxy or n-thiobutoxy, and thioisopropyl Oxygen or isobutyl g, -h ^ Tu-I, 'and rabbit butoxy or tertiary thiobutoxy, but can also be C5_c7 -12- 200400826 thioalkoxy, for example: thiopentoxy, thiohexyl Oxy or thioheptyloxy. The halogen used in formula III is any one of chlorine, a 'bromine or iodine. As used herein, the term aryl refers to aromatic compounds having 6_i 4 carbon atoms, which contain 5% early and polycyclic compounds, such as benzyl or derivatyl, as appropriate, through more than one substituent Take KC as the base, Cl can oxygen,

Cl-C7 thioalkenyloxy, fluorene's vial, thiol, carboxylic acid, carboxylic acid vinegar, ammonium carboxylate or nitrile. The term "heteroaryl" used in micro and catenary refers to an aromatic diaryl group having 5 to 14 carbon atoms: a single iridium and a multi-framed compound, in which one or more rings of the original e nitrogen or ^. Heterogeneous radicals may be substituted by more than one type of substituent, as described above, Cl-C7: feoxy, Cl_C ^ alkoxy, hydrogen, hydroxyl, erucic acid, carboxylic acid ester, carboxylic acid Amidine or nitrile. : The compound of formula m according to the invention is amphoteric in nature and can be 1®. Salt I exists. It can also generate acid addition salts and bases: La 1. The stomach, especially the pharmacologically acceptable acid addition salts, and the pharmacologically generated salts with the test base. Suitable acids used to generate this type of salt are as follows: 2 such as: Λ-chloric acid, E-acid, lyo-acid, or phosphoric acid, metal money and slaves. A salt having a base is, for example, a base and a di-salt: e.g., or a soil metal salt * dirty salt, which is prepared by a method. First, there are salts of ammonium or organic amines. These salts may exist in the form of mixed compounds of compound energies with multiple stereo centers according to formula m, that is, non-image isomers and / or racemic degrees, or as individual stereoisomers. The form exists, that is, the mirror isomer and / or non-mirror isomer of 200400826 alone, such as a hydrate. The compound can also be a vehicle. Compounds according to the invention IV Further useful examples of reflux 4 inhibitors are given by the formula

(IV) R14 represents hydrogen, hydroxyl, CPC? Alkyl, Ci-C or oxy or halogen; is represents hydrogen, thiol, thiol, or halogen; represents chlorine or CVC7 alkyl (as appropriate) "Hydroxy, thiol, oxyCrC7 thioalkoxy, aryl or heteroaryl substituted for" aryl or heteroaryl ";

Rn represents hydrogen, crC7 alkyl (which may be substituted by aryl or heteroaryl as appropriate), aryl or heteroaryl; and pharmacologically acceptable salts, solvates and stereoisomers thereof. An example of a compound of formula IV according to the present invention is (3-amino-2-fluoropropyl) sulfenyl '(2S)-(3-amino-2-fluoropropyl) sulfinic acid, (2R)- (3-Aminofluoropropyl.) Hyaluronic acid '(2S)-(3-Amino-2-Epipropylpropyl) sulfinic acid, (2R) _ (3-Amino-2_hydroxypropyl) Sulfinic acid and (3-amino-2-oxopropyl) sulfinic acid. In the definition of the above formula IV, it should be understood that when Rls is an oxy group, the bond between Ris and carbon is a double bond. In the definition of the above formula IV, the C, -C7 alkyl group may be a straight-chain, paraxial + or 罅 or% -shaped alkyl group, and is, for example, a CVC4 alkyl group such as methyl, ethyl, n-inyl Or n-butyl ', and isopropyl or isobutyl, secondary butyl or trinytidine f, human J 丞, but can also be C5-C7 alkyl, such as: pentyl, hexyl or heptyl. • 14- 200400826

CrC? Alkoxy is for example Cr (: 4alkoxy, such as: methoxy, ethoxy, n-propoxy or n-butoxy, and isopropoxy or isobutoxy, secondary Butoxy or secondary butoxy, but can also be C5_c7 alkoxy, such as: pentyl 'hexyl or heptyloxy. Q-C7 thioalkoxy is, for example, Ci_CAt alkoxy, such as: Thiopenthoxy, thioethoxy, n-thiopropoxy or n-thiobutoxy, and thioisopropoxy or thioisobutoxy, secondary thiobutoxy or tertiary thiobutoxy However, it is also called CVC: I alkoxy, for example: thiopentyloxy, thiohexyloxy or thioheptyloxy. The halogen used in formula IV is any one of chlorine, fluorine 'bromine or iodine. The term aryl refers to an aromatic% with 6 to 14 carbon atoms, which includes monocyclic and polycyclic compounds, such as benzyl or theophyl, which may be substituted by more than one substituent, such as: alkyl , Oxy C1_C7 thioalkoxy, halogen, hydroxy, thiol, polyacid, carboxylic acid, ammonium carboxylic acid, or nitrile. As used herein, the term heteroaryl refers to a group having 5 to 14 carbon atoms. Aromatic 裒 which includes monocyclic and Polycyclic compounds in which one or more of the atoms are oxygen, nitrogen or selenium. Heteroaryl may optionally be substituted with more than one substituent such as Ci_C7 alkyl, eve: 7 alkoxy, CrC7 thioalkoxy A compound, a hydroxyl group, a thiol group, a carboxylic acid, a carboxylic acid ester, an ammonium carboxylic acid, or a nitrile. The compound of Formula 1V according to the present invention is amphoteric in nature and may exist in the form of an internal salt. It It can also generate acid addition salts and bases: this kind of salt is especially a pharmacologically acceptable acid addition salt, and a pharmacologically generated salt with a base. Suitable for generating such salts Acids such as' mine minerals' such as hydrogen acid, hydrogen acid 'sulfuric acid, or phosphoric acid, • 15-200400826 or organic acids such as ^ & Θ version and carboxylic acid. Salts with bases are, for example , Alkali metal salts, such as: sodium or potassium salts, or alkaline earth metal salts, such as: calcium or magnesium salts, and Shao salts, such as 仏 θ > A salts with ammonium or organic amines. It can be prepared by conventional methods. ^ When there is one or more stereocenters in A field knife, the compound according to formula IV = stereoisomeric mixture. The formula exists, that is, non-mirromeric isomers and / or elimination, or exists in the form of individual stereoisomers, that is, single: open: structure and / or non-mirromeric isomers. The compound can also be a vehicle Forms exist, such as hydrates. The combination of acid knife secretion clams and reflux inhibitors The combination according to the present invention can be "fixed combination, or" part eight wm combination, the type exists. Fei # / 刀 配件 件 件 组 " Part of the combination of component components "is determined. Eight anti-reflow inhibitors exist in a single unit 4 distribution sleeve component combination, the example is m 5 4, you λ 疋 a kind of medical music component, of which ⑴ Soil y — a kind of acid secretion ψ in the mixture, Example 4 \ () soil 乂 — a kind of reflux inhibitor. An example is the combination of ^ κ ^ I knife supporting elements, and another kind of medical music component. , Wherein, the agent; and (ii) to +, $ ,, 4 i (an acid secretion inhibition) to y-a reflux inhibitor are present in the mixture. "In early 7C" rather than in the #distribution set element combination "of the categorization-an acid secretion inhibitor; and (ii) at least-a kind of ^ & Strain α P preparations exist in one of the following (0 at least the second example is a combination, and "earthquake-an acid secretion inhibitor, and (to ,. Its kind of reflux inhibitor points 16- 200400826 Do not exist. "Some of the kit components, the components can be taken simultaneously, sequentially or separately, that is, separately or together. The molar ratio of the acid secretion inhibitor to the reflux inhibitor used according to the present invention is at k 1. In the range of 100 to 100: 1, for example, from J: 50 to 50 :! or 1.20 to 20: 1 or 1:10 to 10: 丨. Both drugs can be taken in the same ratio. Acid secretion A suitable daily dose of the inhibitor is in the range of 10 to 400 mg daily, such as 10 or 20 or 50 or 100 or 200 mg daily. A suitable daily dose of reflux inhibitor The dosage is in the range of micrograms to 100 mg daily and per kilogram of body weight, such as 10 micrograms to 20 mg daily and per kilogram. Weight. "TLESRs are known to allow gastric juices to flow back to the esophagus. Administration of acid secretion inhibitors, such as chloride ion pump inhibitors, can control acid reflux, but there are aspects of the effect of bile reflux that are treated with a " lb inhibitor, For example, GABAB-receptor excitement prevents the bile regurgitation of the sap, but the effect on acid regurgitation is quite limited. Fortunately, the hydrogen ion pump inhibits zibu. Therefore, the combination of the two types of agents effectively controls And at the same time reduce the reflux of bile acids to the esophagus. ^ :: reflux inhibitors used in the "Shao distribution sleeve element, or" fixed combination, ": Example 疋 the above formula I, Ι, Ιπ, or ^ Any one, which is used in combination with any kind of acid secretion inhibitor. Σ Xin. Another aspect of the present invention is to use Gaba (γ-molyl butyric acid) or baclofen. ㈣ as a reflux inhibitor. Ben Aoyue < Another aspect is a method for the treatment of gastroesophageal reflux disease (GERD), in which the pharmacological μ + #t is an effective amount of an acid secretion agent and a reflux inhibitor, which are operatively or lesologically effective.之 相 人 #,, ', and 5 forks for those who need this kind of treatment. Acid Inhibitors and regurgitation inhibitors can be administered simultaneously, sequentially, or separately. The effective control of reflux is the prevention, suppression, and treatment of lung diseases caused by the inhalation of gastric contents caused by the inhalation of reflux. An important method to control abnormality caused by excessive loss of nutrients is eliminated. Therefore, the group of acid secretion inhibitors and reflux inhibitors of the present invention is used for reflux treatment. Acid secretion inhibitors and Back ..., it is administered with or separately. 丨 and mud return inhibitors are simultaneous and sequential. Another aspect of the present invention is for treatment. + W, Li Wanfa, in which pharmacology 2 :: effective agent ^ "The combination of an acid secretion inhibitor and a reflux inhibitor is happy to give to those in need of such treatment. '' Is the simultaneous, sequential or separate application. "Inhibitors and reflux inhibitors Another aspect of the present invention is the use of an acid secretion combination to produce a medicament, which is used in lung diseases: 2 :::: 卩3 Temples, sequential or separate administration: .Slave,, Ben: The other aspect of the method is for the treatment or prevention of lung diseases, in which pharmacologically or pharmacologically effective agents are exposed The combined administration of * j and the regurgitation agent and regurgitation inhibitor required for such treatment is simultaneous, sequential or separate administration. 鷇 secretion inhibition Another aspect of the present invention is the use of an acid secretion inhibitor, a combination, to manufacture a medicament, which It is used for the development of abnormal development * 1 reflux inhibitor and the reflux inhibitor is the same #, sequential or hanging: control. Acid secretion antisense knife surgery. Another aspect of the present invention is for controlling hair Lieutenant, pharmacologically or pharmacologically effective dose of acid content * "Wan Qu, its combination is administered to those who need such treatment: preparations and reflux inhibitors are administered simultaneously, sequentially or separately 'Secret inhibitors and another aspect of the present invention Using an acid secretion inhibiting and y back into -18-200400826 inhibitors are combined in manufacture of a medicament, which is based for the prevention of reflux. Reflux inhibitors and inhibitors of acid secretion is the simultaneous, sequential or separate administration.

Another aspect of the present invention is a method for preventing reflux, wherein a combination of a pharmacologically or leucosically effective dose of an acid secretion inhibitor and a reflux inhibitor is administered to a subject in need of such treatment. Acid secretion inhibitors and reflux inhibitors are administered simultaneously, sequentially, or separately. Another aspect of the present invention is the use of a combination of an acid secretion inhibitor and a reflux inhibitor to produce a medicament for use in the treatment of esophagitis. Acid secretion inhibitors and reflux inhibitors are administered simultaneously, sequentially, or separately.

The other aspect of the present invention is administered simultaneously or separately to the need of the combination of the present invention to produce a product that has nothing to do with reflux, either sequentially or separately. Effective agent This kind of asthma administration is followed by another agent or asthma. The other side has no secretion of reflux. The acidic facet is a method for preventing esophagitis, in which the group of acid secretion inhibitor and reflux inhibitor of the drug I is treated. Acid secretion inhibitors and reflux inhibition | prescribe. Facial use of acid secretion inhibitors and reflux inhibitors: it is used for the treatment of asthma, for example, the reflux-related secretion inhibitor and reflux inhibitor are simultaneously used for the treatment of asthma, such as with i related asthma, in which the combination of pharmacologically or pharmacologically more than 4 and cashback inhibitors is required to simultaneously and successively require this strange secretion inhibitor and reflux inhibitor ^

Another aspect of the present invention is the use of a bismuth secretion inhibitor and a combination thereof to produce a medicament, which is used to treat pharyngitis, such as inflammation of a chronic preparation. acid

-19- 200400826 Secretion inhibitors and reflux inhibitors are administered simultaneously, sequentially or separately. Another aspect of the invention is a method for treating laryngitis, such as chronic laryngitis, in which a combination of a pharmacologically or pharmacologically effective amount of an acid secretion inhibitor and a reflux inhibitor is administered to a subject in need of such treatment . Acid secretion inhibitors and reflux inhibitors are administered simultaneously, sequentially, or separately. Another aspect of the present invention is to use a combination of an acid secretion inhibitor and a reflux inhibitor to manufacture a medicament, which is used to inhibit TLESRs, such as asthma related to or not related to reflux. The acid secretion inhibitor and reflux inhibitor are Simultaneously, sequentially or separately. Another aspect of the present invention is a method for inhibiting TLESRs, wherein a combination of an acid secretion inhibitor and a reflux inhibitor in a pharmacologically or pharmacologically effective dose is administered to a subject in need of such treatment. Acid secretion inhibitors and reflux inhibitors are administered simultaneously, sequentially, or separately. For the purposes of the present invention, the term "agonist" should be understood to include a full agonist sword and a partial agonist, where it should be understood that a "partial agonist" is a compound that can partially, but not completely, activate the recipient . The term "TLESR", transient lower esophageal sphincter relaxation, is defined in this context in terms of Mittal, RK, Holloway, RH, Penagini, R., and Berleke ( Blackshaw), LA 'Dent, J., 1995; transient lower esophageal sphincter relaxation. Gastroenterology 109, pp. 601-610. The term "backflow" is defined as the ability of fluid from the stomach to enter the esophagus, as mechanical obstacles temporarily disappear. The term "GERD", gastroesophageal reflux disease, is defined according to van Heerwarden, M.A., Smout A Lp M, 2000. 〇; Diagnosis of reflux disease. Baillidre's Clin. Gastroemer 〇 14, 14, pp 759 774. The term "treatment" also includes "prevention" unless specifically stated to the contrary. The terms "therapeutic," and "therapeutic," should be understood accordingly. The application of the drug formulation to the 5s bed, the combination of the acid secretion inhibitor and reflux inhibitor according to the present invention is suitable to be formulated for use in Oral pharmaceutical formulations. At the same time, rectal, intravenous or any other application channel can also be carefully considered by those skilled in formulation. Therefore, the combination of acid secretion inhibitor and reflux inhibitor is at least one pharmacological or pharmacological An acceptable vehicle or adjuvant is formulated. The vehicle can be a solid, semi-solid or liquid diluent. The acid secretion inhibitor and reflux inhibitor are administered simultaneously, sequentially or separately. In oral preparation according to the present invention For pharmaceutical formulations, the combination of slave secretion inhibitor and reflux inhibitor to be formulated is mixed with the following: solid, powdery ingredients such as lactose, sucrose, glucosyl alcohol, mannitol, starch, branched starch 'cellulose Derivatives' gelatin, or other suitable ingredients, as well as dispersants and lubricants, such as magnesium stearate, calcium stearate, sodium stearyl fumarate, and polymer Ethylene glycol wax. The mixture is then processed into granules or compressed into lozenges. Soft gelatin capsules can be prepared as capsules containing a combination of acid secretion inhibitors and reflux inhibitors, and vegetable oils, fats, or other suitable for softening Gelatin capsules are mixed with a vehicle. Hard gelatin capsules can contain a combination of acid secretion inhibitors and reflux inhibitors in combination with the following: solid powdery ingredients such as lactose, sucrose, glucosyl alcohol, mannitol, glutinous potato starch, Corn starch, divided into 200,400,826 branches of starch, cellulose derivatives or gelatin. The dosage unit for rectal administration can be prepared into a tincture suppository type, which contains S active substance mixed with a neutral lipid matrix; (Π) gelatin rectal capsule type, It contains a combination of an acid secretion inhibitor and a reflux inhibitor in a mixture with vegetable oil, paraffin oil, or other suitable medium for gelatin rectal capsules, (U1) a microenema formulation that can be used interchangeably; or ( iv) The punishment of dried micro-enema preparations is to be used to recover the soil. It is formulated with an appropriate solvent to restore the original state before application. Use: Liquid for oral administration Can be prepared into a syrup or suspension type, * 2 liquid or suspension, which contains acid secretion inhibitors and reflux inhibitors' and other parts of the wither include sugars or sugar alcohols, and ethanol, glycerol Mixture with ethylene glycol. If necessary, this liquid substance can contain the colorant 'flavor enhancer' and methylmethyl cellulose or terminal disulfide; thickener. Liquids for oral administration can also be prepared as dry Powder and soil 2, which are formulated with an appropriate solvent to restore the original state before application. Ί, ΊΊ 药, "Guye can be prepared as an acid secretion inhibitor and reflux inhibitory cold / night, a music acceptable solvent Medium. The type or buffering ingredients of these solutions and the adjustments made from dried amber glass bottles are reconstituted 1: Zao Wu. Solutions for intravenous administration can also be prepared on the date of issue; Appropriate solvents are formulated to restore the original state. In terms of the group of people, the severity of the situation can be treated with acid secretion inhibitors and reflux inhibition swords. Through I Biological Research, the ratio of the weight of the blade to the weight of the wither is from 0.1% to 95%. ', Knife / must inhibitor (such as: hydrogen heterozygous oath, or female ▲ Fei ion' pu inhibitor) and reflux inhibitor -22-200400826 (such as: GABAb-receptor agonist) against acid and bile The effect of reflux was studied on free-moving dogs. The esophagus was sectioned surgically and the dog was allowed to wear a vest after recovery. Place the pH electrode and bile acid sensor (Bilitec) 3 cm above the lower esophageal sphincter. The positioning is determined by pressure. The data counter is placed in the pocket of the vest. Acid and bile reflux are measured under four conditions: 1) after treatment with placebo; 2) after treatment with acid secretion inhibitor; 3) after treatment with reflux inhibitor; and 4) after acid treatment After combination therapy with secretory inhibitor and reflux inhibitor. -twenty three -

Claims (1)

Patent application scope: ^ Combinations' which respectively or in combination include at least 27 and at least-reflux inhibition. Inhibition •: Application: The combination of Item 丨 of Patent Fanyuan, this combination is a pharmaceutical group of eight "more advanced-containing pharmacologically or pharmaceutically acceptable 0 or diluent. More lack of mediator and / 3 = application The combination of item 2 of the patent domain, where the acid secretion inhibitor θ ~ a kind of hydrogen ion pump inhibitor. "疋 4. Shikou applied for the combination of item 1 or 2 of the patent domain by D, in which the reflux inhibitor Is a compound according to formula I (I) Where I represents hydrogen I represents hydrogen I represents hydrogen represents hydrogen Fluorine or oxygen; Or its pharmaceutically acceptable salts, mediates and 3 5. The combination of item 1 or 2 in the scope of the patent application, where k is 4 is a compound according to formula II below Η where Rs represents hydrogen or low alkyl; R6 represents fluoro; (II) 200400826 R7 represents hydrogen; R8 represents hydrogen; R9 represents methyl, fluorofluorenyl, difluoromethyl or trifluoromethyl, or pharmacologically Acceptable salts, vehicles and stereoisomers. 6. The combination according to item 1 or 2 of the patent application scope, wherein the reflux inhibitor is a compound according to formula III R10 represents hydrogen, methyl, fluoromethyl, difluoromethyl or trifluoromethyl; Rn represents hydrogen, hydroxyl, CVC7 alkyl, CVC7 alkoxy, or autogen; R12 represents fluorene, crc7 alkyl (as appropriate) Can be substituted by hydroxyl, thiol, crG7 alkoxy, CrC7 thioalkoxy, aryl or heteroaryl), aryl or heteroaryl;? Represents hydrogen, fluorenyl (optionally via aryl or Heteroaryl substitution), 1 group or heteroaryl group; or pharmacologically acceptable salts thereof, such as the compounds of the compounds of formula IV and stereoisomers according to the following formula IV in the scope of patent application 1 or 2. Cascade ’where the reflux inhibitor is the root , Ci-C7 alkoxy or halogen; halogen or fluorenyl; R14 represents hydrogen, hydroxyl, CrCji: group represents hydrogen, hydroxyl, thiol group, 200400826, 16 represents hydrogen or Cl-C7 alkyl (optionally by hydroxyl , Thiol, qc-_earth, Cl-C? Thioalkoxy, aryl or heteroaryl substituted), aryl or heteroJ7 represents hydrogen, Cl-C7 alkyl (optionally via aryl or heteroaryl Aryl substitution), aryl or heteroaryl; or pharmacologically acceptable salts, vehicles and stereoisomers. 8. A combination according to item 1 or 2 of the scope of patent application ', wherein the combination is a combination preparation which can be used for simultaneous, continuous or separate administration. 9 · Κ1) at least-acid secretion inhibitor and (ii) at least-reflux inhibitor in the system of transient lower esophageal sphincter relaxation (tlesRs) made by Up 0 0. 10 species (1) less soil-species acid secretion inhibition Agent and (ii) the use of at least one combination of regurgitation suppressing Jianwan and manufacturing a combination of gastroesophageal reflux disease (gerd). 11.-species (, 1) at least-acid secretion inhibitors and (⑴ at least-the use of reflux inhibitors in the manufacture of combinations to prevent reflux.) 12.-species ⑴ at least-acid secretion inhibitors and (π) at least The use of a reflux inhibitor in the manufacture of a combination for the treatment or prevention of reflux. 13 • -Species at least—an acid secretion inhibitor and (⑴the use of at least one reflux inhibitor in the manufacture of a combination for the treatment or prevention of asthma. H . Such as _ β-specific | a 13th <use, in which asthma is associated with reflux. 15. species (0 soil y-secretion inhibitors and at least one reflux inhibitor in combination for the treatment or prevention of lung diseases) 16. Use of a kind of at least-acid secretion inhibitor and (U) at least-reflow inhibitor in 200400826 to manufacture a combination to control abnormal development. 17. If any of the scope of application for patents is 9 to 16 Item, wherein the acid secretion inhibitor is a hydrogen ion pump inhibitor. 18. The use according to any one of claims 9 to 16, wherein the reflux inhibitor is a GABAb-receptor agonist. 19 . If any of the scope of patent application items 9 to 16 Way, reflux inhibitor which is a compound of formula I according to the H R2 Q R3 R wherein the center represents hydrogen; K · 2 represents nitrogen 'gas or oxygen, R3 represents hydrogen; R4 represents hydrogen; or pharmacologically acceptable salts, solvates and related stereoisomers. 20. The use as claimed in any one of claims 9 to 16, wherein the reflux inhibitor is a compound according to formula II Where R5 represents hydrogen or lower alkyl; R6 represents fluoro; R7 represents nitrogen; ^ • 8 represents nitrogen, 200400826 represents methyl, fluoromethyl, difluoromethyl or trifluoromethyl; or pharmacologically acceptable Salts, intermediates and related stereoisomers. 21. Use as claimed in any one of claims 9 to 6 wherein the reflux inhibitor is a compound according to formula III below Rio represents hydrogen'methyl, fluorofluorenyl, difluoromethyl or trifluoromethyl; Ru represents hydrogen'hydroxy 'Cl_C7 alkyl, c "C7 alkoxy, or halogen; R12 represents hydrogen, CVC7 alkyl (may be Optionally substituted with hydroxyl, thiol, CVC7 koxy 'Ci-C7 thioalkoxy' aryl or heteroaryl), aryl or heteroaryl; R! 3 represents hydrogen, CrC7 slave (optional Is substituted by aryl or heteroaryl), aryl or heteroaryl; or pharmacologically acceptable salts, solvates and related stereoisomers. 22 · As in the scope of patent application 9 to 16 Use according to any one of the preceding clauses, wherein the reflux inhibitor is a compound according to formula IV below Where Ru represents hydrogen, hydroxy, CVC7 alkyl, CrC7 alkoxy or halogen; Rb represents hydrogen, hydroxy 'thiol, halogen or oxy; Ri6 represents hydrogen or CrC7 alkyl (optionally by hydroxy, thiol) , 'Kioxy, CVC7 sulfur; 1: complete oxy, aryl or heteroaryl substituted), aryl group 200400826 aryl; r17 represents hydrogen, crc7 alkyl (optionally by aryl or heteroaryl) Substituted), aryl or heteroaryl; or pharmacologically acceptable salts, intermediates and related stereoisomers. 23.-A combination for the treatment of transient lower esophageal sphincter relaxation (TLESR) comprising a pharmacologically or pharmacologically effective dose of at least one acid secretion inhibitor and at least one reflux inhibitor. 24. A combination for the treatment of gastroesophageal reflux disease (GERD) comprising a pharmacologically or pharmacologically effective dose of at least one acid secretion inhibitor and at least one reflux inhibitor. 200400826 (1) Designated representative map: (1) The designated representative map in this case is: (). (II) Brief description of the element representative symbols in this representative diagram ... 捌, if there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention