HK1036981B - Imidazo pyridine derivatives which inhibit gastric acid secretion - Google Patents
Imidazo pyridine derivatives which inhibit gastric acid secretion Download PDFInfo
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- HK1036981B HK1036981B HK01107808.6A HK01107808A HK1036981B HK 1036981 B HK1036981 B HK 1036981B HK 01107808 A HK01107808 A HK 01107808A HK 1036981 B HK1036981 B HK 1036981B
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Description
Technical Field
The present invention relates to novel compounds and pharmaceutically acceptable salts thereof, which inhibit exogenously or endogenously stimulated gastric acid secretion and are therefore useful in the prevention and treatment of gastrointestinal inflammatory diseases. In another aspect, the invention relates to the use of a compound of the invention in therapy; processes for preparing these novel compounds; a pharmaceutical composition containing at least one compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient; and the use of the active compound in the manufacture of a medicament for the above-mentioned medical uses. The invention also relates to novel intermediates useful in the preparation of the novel compounds.
Background
Substituted imidazo [1, 2-a ] pyridines for the treatment of peptic ulcer disease are compounds known in the art, e.g. from EP-B-0033094 and US 4,450,164(schering corporation); from EP-B-0204285 and US 4,725,601(Fujisawa pharmaceutical Co.); and from J.J.Kaminski et al, journal of pharmaceutical chemistry (Vol.28, 876-892, 1985; Vol.30, 2031-2046, 1987; Vol.30, 2047-2051, 1987; Vol.32, 1686-1700, 1989 and Vol.34, 533-541, 1991).
About gastric acid pump (H)+，K+-atpase) see Sachs et al (1995) annu. rev. pharmacol. toxicol.35: 277-305.
Disclosure of Invention
It has surprisingly been found that compounds of formula I which are imidazopyridine derivatives wherein the phenyl moiety is substituted and wherein the imidazopyridine moiety is substituted with a carboxamide group in the 6-position are particularly effective as gastrointestinal H+，K+Inhibitors of ATPase and thus of gastric acid secretion. Formyl in the 6-positionThe amine groups can be chosen arbitrarily to provide compounds of formula I with molecular weights ≦ 600.
Thus, in one aspect the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof,
wherein
R1Is that
(a)H，
(b)CH3Or is or
(c)CH2OH；
R2Is that
(a)CH3Or is or
(b)CH2CH3；
R3Is that
(a)H，
(b)C1-C6An alkyl group, a carboxyl group,
(c) hydroxylated C1-C6Alkyl, or
(d) Halogen;
R4is that
(a)H，
(b)C1-C6An alkyl group, a carboxyl group,
(c) hydroxylated C1-C6Alkyl, or
(d) Halogen;
R5is that
(a) H, or
(b) Halogen; r6And R7Are independently selectable substituents that may be used,comprising C, H, N, O, S, Se, P and halogen atoms, which provides a compound of formula I having a molecular weight of 600 or less, with the proviso that R6And R7Cannot be H, C1-C6Alkyl, hydroxylated C1-C6Alkyl or C1-C6Alkoxy-substituted C1-C6Alkyl, and
x is
(a) NH, or
(b)O。
The term "C" as used herein1-C6Alkyl "means a straight or branched chain alkyl group having 1 to 6 carbon atoms. Said C is1-C6Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl and straight-and branched-chain pentyl and hexyl groups.
The term "halogen" includes fluorine, chlorine, bromine and iodine.
Substituent R6And R7The definitions are independently selected substituents containing C, H, N, O, S, Se, P or halogen atoms which provide compounds of formula I having a molecular weight of 600 or less, as will be readily understood by those skilled in the art.
Examples of substituents within the scope of this definition include, but are not limited to:
(a)H，
(b)C1-C6an alkyl group, a carboxyl group,
(c) hydroxylated C1-C6An alkyl group, a carboxyl group,
(d)C1-C6alkoxy-substituted C1-C6An alkyl group, a carboxyl group,
(e)C2-C6an alkenyl group which is a radical of an alkylene group,
(f)C2-C6an alkynyl group which is a substituent of a heterocyclic ring,
(g) halogenated C1-C6An alkyl group, a carboxyl group,
(h)C3-C8a cycloalkyl group,
(i) cycloalkyl-substituted C1-C6An alkyl group, a carboxyl group,
(j) aryl, wherein aryl represents phenyl, pyridyl, thienyl, imidazolyl, indolyl, naphthyl or furyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Alkoxy, CF3OH, nitro, amino, C1-C6alkyl-NH-, (C)1-C6Alkyl radical)2-N-or CN or NH2SO2，
(k)C1-C6Alkyl-substituted aryl, wherein aryl represents phenyl, pyridyl, thienyl, imidazolyl, indolyl, naphthyl or furyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Alkoxy, CF3OH, nitro, amino, C1-C6alkyl-NH-, (C)1-C6Alkyl radical)2-N-, CN or NH2SO2，
(l)R8-(C1-C6) Alkyl-, wherein R8Is NH2C＝O-、C1-C6alkyl-NHC ═ O —, (C)1-C6Alkyl radical)2NC＝O-、C1-C6alkyl-OOC-, NH2SO2-、C1-C6alkyl-SO2NH-、ArSO2NH-, cyano, C1-C6alkyl-CO-NH-, C1-C6alkyl-OOCNH-, C1-C6alkyl-O-, C7-C12alkyl-O-, C1-C6alkyl-SO-, C1-C6alkyl-S-, C1-C6alkyl-SO2-、C1-C6alkyl-C ═ O-, NH2-、C1-C6alkyl-NH-, (C)1-C6Alkyl radical)2N-、ArCONH-、Ar(C1-C6Alkyl) CONH, ArNHSO2-、(Ar)2-N-SO2-、C1-C6alkyl-NHSO2-、ArS-、ArSO-、ArSO2-、ArC＝O-、NH2CONH-、C1-C6alkyl-NHCONH-, (C)1-C6Alkyl radical)2-NCONH-、ArNHCONH-、Ar-O-、Ar-NH-、Ar(C1-C6Alkyl) N-, (C)1-C6Alkyl radical)2NSO2-, hydroxylated C1-C6alkyl-O-or morpholinyl; wherein Ar represents phenyl, pyridyl, thienyl, imidazolyl, indolyl, naphthyl or furyl, optionally substituted by one or more substituents selected from: halogen, C1-C6Alkyl radical, C1-C6Alkoxy, CF3OH, CN, nitro, amino, C1-C6alkyl-NH-or (C)1-C6Alkyl radical)2N-，
(m)C7-C12，
(n)OH、O-C1-C6Alkyl or O-hydroxylated C1-C6An alkyl group, a carboxyl group,
(o) wherein R is9And R10Each independently is H or C1-C6An alkyl group, a carboxyl group,
(p)R11-(C1-C6) alkyl-COO- (C)1-C6) Alkyl-, wherein R11Is HOOC, C1-C6alkyl-OOC-or aminocarbonyl having the formula:
wherein R is12、R13Are the same or different H or C1-C6Alkyl radical, R6And R7With the nitrogen atom to which they are attachedTogether, the substituents form a saturated or unsaturated ring (e.g. morpholine, piperazine, pyrrolidine, piperidine) optionally containing one or more additional heteroatoms, optionally substituted with one or more substituents selected from: halogen, C1-C6Alkyl radical, C1-C6Alkoxy, CF3OH, nitro, amino, C1-C6alkyl-NH-, (C)1-C6Alkyl radical)2-N-、CN、NH2SO2Phenyl, NH2CO-、C1-C6alkyl-CO-said ring may be fused to an aromatic ring (e.g. tetrahydroquinoline).
Pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers are within the scope of the invention. It is understood that all possible diastereomeric forms (pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers) are within the scope of the invention. Derivatives (e.g., prodrugs) of the compounds of formula I that have the biological function of the compounds of formula I are also included in the invention.
It will also be appreciated by those skilled in the art that, although derivatives of the compounds of formula I may not possess such pharmacological activity, they may be administered parenterally or orally and metabolized in vivo to form the compounds of the invention which are pharmacologically active. Thus, these derivatives may be referred to as "prodrugs". All prodrugs of compounds of formula I are included within the scope of the present invention.
Depending on the process conditions, the final product of formula I may be obtained in neutral or salt form. The free base and salts of these end products are within the scope of the invention.
The acid addition salts of the novel compounds can be converted into the free bases by methods known per se, with basic reagents such as bases or by ion exchange. The free base obtained may also form salts with organic or inorganic acids.
In the preparation of acid addition salts, it is preferred to use acids suitable for forming pharmaceutically acceptable salts. Examples of such acids are hydrohalic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, aliphatic, cycloaliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, for example formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, P-hydroxybenzoic acid, embonic acid (embonic), methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, halobenzenesulfonic acid, toluenesulfonic acid or naphthalenesulfonic acid.
Preferred compounds according to the invention are compounds of formula I, wherein R1Is CH3Or CH2OH；R2Is CH3Or CH2CH3；R3Is CH3Or CH2CH3；R4Is CH3Or CH2CH3；R5Is H, Br, Cl or F; r6And R7Independently is (provided that R is6And R7Cannot be H, C1-C6Alkyl, hydroxylated C1-C6Alkyl or C1-C6Alkoxy-substituted C1-C6Alkyl):
(a)H，
(b)C1-C6an alkyl group, a carboxyl group,
(c) hydroxylation of C1-C6An alkyl group, a carboxyl group,
(d)C1-C6alkoxy-substituted C1-C6An alkyl group, a carboxyl group,
(e)C2-C6an alkenyl group which is a radical of an alkylene group,
(f)C2-C6an alkynyl group which is a substituent of a heterocyclic ring,
(g) halogenated C1-C6An alkyl group, a carboxyl group,
(h)C3-C8a cycloalkyl group,
(i) cycloalkyl-substituted C1-C6An alkyl group, a carboxyl group,
(j) aryl, wherein aryl represents phenyl, pyridyl, thienyl, imidazolyl, indolyl, naphthyl or furylOptionally substituted with one or more substituents selected from: halogen, C1-C6Alkyl radical, C1-C6Alkoxy, CF3OH, nitro, amino, C1-C6alkyl-NH-, (C)1-C6Alkyl radical)2-N-or CN or NH2SO2，
(k)C1-C6Alkyl-substituted aryl, wherein aryl represents phenyl, pyridyl, thienyl, imidazolyl, indolyl, naphthyl or furyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Alkoxy, CF3OH, nitro, amino, C1-C6alkyl-NH-, (C)1-C6Alkyl radical)2-N-, CN or NH2SO2，
(l)R8-(C1-C6) Alkyl-, wherein R8Is NH2C＝O-、C1-C6alkyl-NHC ═ O —, (C)1-C6Alkyl radical)2NC＝O-、C1-C6alkyl-OOC-, NH2SO2-、C1-C6alkyl-SO2NH-、ArSO2NH-, cyano, C1-C6alkyl-CO-NH-, C1-C6alkyl-OOCNH-, C1-C6alkyl-O-, C7-C12alkyl-O-, C1-C6alkyl-SO-, C1-C6alkyl-S-, C1-C6alkyl-SO2-、C1-C6alkyl-C ═ O-, NH2-、C1-C6alkyl-NH-, (C)1-C6Alkyl radical)2N-、ArCONH-、Ar(C1-C6Alkyl) CONH, ArNHSO2-、(Ar)2-N-SO2-、C1-C6alkyl-NHSO2-、ArS-、ArSO-、ArSO2-、ArC＝O-、NH2CONH-、C1-C6alkyl-NHCONH-, (C)1-C6Alkyl radical)2-NCONH-、ArNHCONH-、(C1-C6Alkyl radical)2-N-SO2-、Ar-O-、Ar-NH-、Ar(C1-C6Alkyl) N-, (C)1-C6Alkyl radical)2NSO2-, hydroxylated C1-C6alkyl-O-or morpholinyl; wherein Ar represents phenyl, pyridyl, thienyl, imidazolyl, indolyl, naphthyl or furyl, optionally substituted by one or more substituents selected from: halogen, C1-C6Alkyl radical, C1-C6Alkoxy, CF3OH, CN, nitro, amino, C1-C6alkyl-NH- -or (C)1-C6Alkyl radical)2N-，
(m)C7-C12，
(n)OH、O-C1-C6Alkyl or O-hydroxylated C1-C6An alkyl group, a carboxyl group,
(o) wherein R is9And R10Each independently is H or C1-C6An alkyl group, a carboxyl group,
(p)R11-(C1-C6) alkyl-COO- (C)1-C6) Alkyl-, wherein R11Is HOOC-, C1-C6alkyl-OOC-or aminocarbonyl having the formula:
wherein R is12、R13Are the same or different H or C1-C6Alkyl radical, R6And R7Together with the nitrogen atom to which they are attached, form a saturated or unsaturated ring optionally containing one or more additional heteroatoms (e.g. morpholine, piperazine, pyrrolidine, piperidine), optionally substituted with one or more substituents selected from: halogen, C1-C6Alkyl radical, C1-C6Alkoxy, CF3OH, nitro groupAmino group, C1-C6alkyl-NH-, (C)1-C6Alkyl radical)2-N-、CN、NH2SO2Phenyl, NH2CO-、C1-C6alkyl-CO-said ring may be fused to an aromatic ring (e.g. tetrahydroquinoline).
More preferred compounds according to the invention are compounds of formula I, wherein R1Is CH3Or CH2OH；R2Is CH3；R3Is CH3Or CH2CH3；R4Is CH3Or CH2CH3；R5Is H, Br, Cl or F; r6And R7Independently is (provided that R is6And R7Cannot be H, C1-C6Alkyl, hydroxylated C1-C6Alkyl or C1-C6Alkoxy-substituted C1-C6Alkyl):
(a)H，
(b)C1-C6an alkyl group, a carboxyl group,
(c) hydroxylated C1-C6An alkyl group, a carboxyl group,
(d)C1-C6alkoxy-substituted C1-C6An alkyl group, a carboxyl group,
(e) halogenated C2-C6An alkyl group, a carboxyl group,
(f) aryl, wherein aryl represents phenyl, pyridyl, imidazolyl, indolyl or naphthyl, optionally substituted with one or more substituents selected from: halogen, C1-C6Alkyl radical, C1-C6Alkoxy, CF3、OH、C1-C6alkyl-NH-, (C)1-C6Alkyl radical)2-N-or CN, -or a salt thereof,
(g)C1-C6alkyl-substituted aryl, wherein aryl represents phenyl, pyridyl, imidazolyl, indolyl or naphthyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Alkoxy, CF3Or an OH group, or a mixture of OH,
(h)R8-(C1-C6) Alkyl-, wherein R8Is NH2C＝O-、C1-C6alkyl-NHC ═ O —, (C)1-C6-alkyl groups)2NC＝O-、C1-C6alkyl-OOC-, cyano, C1-C6alkyl-CO-NH-, C1-C6alkyl-OOCNH-, C1-C6alkyl-O-, C7-C12alkyl-O-, C1-C6alkyl-SO-, C1-C6alkyl-S-, C1-C6alkyl-C ═ O-, -ArCONH-, Ar (C)1-C6Alkyl) CONH, ArC ═ O-, NH2CONH-、C1-C6alkyl-NHCONH-, (C)1-C6Alkyl radical)2-NCONH-, arnchonh-, hydroxylated C1-C6alkyl-O-or morpholinyl; wherein Ar represents phenyl, pyridyl, imidazolyl, indolyl or naphthyl, optionally substituted with one or more substituents selected from: halogen, C1-C6Alkyl radical, C1-C6Alkoxy, CF3、OH、CN，
(i)C7-C12An alkyl group, a carboxyl group,
(j)OH，
(k)R11-(C1-C6) alkyl-COO- (C)1-C6) Alkyl-, wherein R11Is HOOC-or C1-C6An alkyl group-OOC, which is,
R6and R7Together with the nitrogen atom to which they are attached, form a saturated or unsaturated ring optionally containing one or more additional heteroatoms (e.g. morpholine, piperazine, pyrrolidine, piperidine), optionally substituted with one or more substituents selected from: halogen, C1-C6Alkyl radical, C1-C6Alkoxy, CF3OH, nitro, amino, CN, NH2SO2Phenyl, NH2CO-、C1-C6alkyl-CO-said ring may be fused to an aromatic ring (e.g. tetrahydroquinoline).
The most preferred compounds according to the invention are:
2, 3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -6- (morpholinocarbonyl) -imidazo [1, 2-a ] pyridine
N- (4-ethoxyphenyl) -8- (2-ethyl-6-methylbenzylamino) -2, 3-dimethylimidazo [1, 2-a ] pyridine-6-carboxamide
N- [2- (dimethylamine) -2-oxoethyl ] -8- (2-ethyl-6-methylbenzylamino) -N, 2, 3-trimethylimidazo [1, 2-a ] pyridine-6-carboxamide
(8- (2-Ethyl-6-methylbenzylamino) -2, 3-dimethylimidazo [1, 2-a ] pyridin-yl) (4-methylpiperazinyl) methanone
1- ((8- (2-ethyl-6-methylbenzylamino) -2, 3-dimethylimidazo [1, 2-a ] pyridin-6-yl) carbonyl) -2-(s) -pyrrolidinecarboxamide
8- (2-Ethyl-6-methylbenzylamino) -N-hydroxy-2, 3-dimethylimidazo [1, 2-a ] pyridine-6-carboxamide
(2-Ethyl-6-methylbenzylamino) -N- (2- (2-hydroxyethoxy) ethyl) -2, 3-dimethylimidazo [1, 2-a ] pyridine-6-carboxamide
(8- (2-Ethyl-6-methylbenzylamino) -2, 3-dimethylimidazo [1, 2-a ] pyridin-6-yl) (3-hydroxy-1-pyrrolidinyl) methanone
N- (3, 4-dihydroxyphenethyl) -8- (2-ethyl-6-methylbenzylamino) -2, 3-dimethylimidazo [1, 2-a ] pyridine-6-carboxamide
8- (2-Ethyl-6-methylbenzylamino-3- (hydroxymethyl) -2-methyl-6- (morpholinocarbonyl) -imidazo [1, 2-a ] pyridine
N- ((8- (2-ethyl-6-methylbenzyl) amino) -2, 3-dimethylimidazo [1, 2-a ] pyridin-6-yl) carbonyl) guanidine
4- (2- (((8- (2-ethyl-6-methylbenzylamino) -2, 3-dimethylimidazo [1, 2-a ] pyridin-6-yl) carbonyl) amino) ethoxy) -4-oxobutanoic acid.
Preparation of
The invention also provides the following process for preparing compounds of formula I.
The process for the preparation of the compounds of the general formula I comprises the following steps:
a) a compound of formula II
Wherein R is1、R2、R3、R4、R5And X is as defined in formula I, can be hydrolyzed under standard conditions to give the corresponding carboxylic acid compound of formula III,
b) a compound of formula III wherein R1、R2、R3、R4、R5And X is as defined in formula I, with an amino compound of formula IV
Wherein R is6And R7As defined in formula I, in the presence of a coupling reagent to give the corresponding amide compound of formula I. The reaction can be carried out in an inert solvent under standard conditions.
The present invention also provides the following process for preparing intermediate compounds of formula II.
A process for preparing a compound of formula II, wherein X is NH, comprising the steps of:
(a) reacting a compound of the formula V
With amino compounds of the formula IV
Wherein R is6And R7Are both hydrogen, to give the corresponding amide of formula VI. The reaction can be carried out under standard conditions in an inert solvent,
b) the compound of formula VI can be reacted with ammonia to give a compound of formula VII
Wherein R is6And R7Are all hydrogen. The reaction can be carried out under standard conditions in an inert solvent.
c) The compound of formula VII may be reduced to the compound of formula VIII by using hydrogen and a catalyst such as Pd/c
Wherein R is6And R7Are all hydrogen. The reaction can be carried out under standard conditions in an inert solvent.
d) The compound of formula X, imidazo [1, 2-a ] pyridines, can be prepared by reacting a compound of formula VIII with a compound of formula IX
Wherein R is2Z is a leaving group, as defined in formula I, e.g. halogen, methanesulfonyl, toluenesulfonyl, R9Representative H, CH3Or ester groups such as COOCH3、COOC2H5And the like. The reaction can be carried out under standard conditions in an inert solvent such as acetone, acetonitrile, alcohols, dimethylformamide and the like, with or without a base,
e) a compound of formula X can be reacted with a compound of formula XI
Wherein R is3、R4And R5As defined in formula I, Y is a leaving group such as halogen, tosyl or mesyl to give a compound of formula XII
Wherein R is2、R3、R4And R5As defined in formula I, R6And R7Are all hydrogen, R9Is H, CH3Or ester groups such as COOCH3、COOC2H5And the like. The reaction is conveniently carried out in an inert solvent such as acetone, acetonitrile, dimethoxyethane, methanol, ethanol or dimethylformamide, with or without a base. The base is, for example, an alkali metal hydroxide such as sodium hydroxide and potassium hydroxide, an alkali metal carbonate such as potassium carbonate and sodium carbonate; or an organic amine such as triethylamine.
f) For example by using lithium borohydride in an inert solvent such as tetrahydrofuran orIn diethyl ether, reducing the compound of the formula XII, wherein R9Is an ester group to give a compound of the formula I, wherein R1Is CH2OH，R6And R7Are all hydrogen.
Medical use
In another aspect, the invention relates to the use of a compound of formula I in therapy, in particular for the treatment of gastrointestinal inflammatory diseases. The invention also provides the use of a compound of formula I in the manufacture of a medicament for inhibiting gastric acid secretion or for the treatment of gastrointestinal inflammatory diseases.
Accordingly, the compounds according to the present invention are useful for the prevention and treatment of gastrointestinal inflammatory diseases and gastric acid related diseases such as gastritis, gastric ulcer, duodenal ulcer, reflux esophagitis and zollinger-ellison syndrome in mammals including humans. In addition, the compounds are useful in the treatment of other gastrointestinal disorders requiring antisecretory action of the stomach, such as patients with gastrinomas and patients with acute upper gastrointestinal bleeding. The compounds are also useful for enhancing patients under care, as well as for preventing gastric acid aspiration and stress ulcer formation before and after surgery.
The daily dose of the active substance will generally vary over a wide range and will depend on a number of factors such as the individual requirements of each patient, the route of administration and the disease itself. In general, the oral and parenteral dosages will be in the range of 5 to 1000mg of active substance per day.
Pharmaceutical formulations
In a further aspect, the present invention relates to pharmaceutical compositions containing at least one compound of the present invention, or a pharmaceutically acceptable salt thereof, as an active ingredient.
The compounds of the invention are also used in formulations with other active ingredients, for example antibiotics such as amoxicillin.
For clinical use, the compounds of the invention are formulated into pharmaceutical preparations for oral, rectal, parenteral or other mode of administration. The pharmaceutical formulations contain at least one compound of the present invention in combination with one or more pharmaceutically acceptable ingredients. The carrier may be in the form of a solid, semi-solid or liquid diluent or capsule. These pharmaceutical formulations are another object of the present invention. Generally the amount of active compound is from 0.1 to 95% by weight of the formulation, preferably from 0.1 to 20% by weight of the formulation for parenteral administration and from 0.1 to 50% by weight of the formulation for oral administration.
In preparing pharmaceutical formulations containing a compound of the invention in dosage unit form for oral administration, the selected compound may be mixed with solid, powdered ingredients such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin or with other suitable ingredients as well as 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 gelatin 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 gelatin capsules. Hard gelatin capsules may contain granules of the active compound. Hard gelatin capsules may also contain the active compound in admixture with solid powdered ingredients such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.
Dosage units for rectal administration may be prepared (i) in the form of suppositories containing the active substance in admixture with a neutral fatty base; (ii) gelatin rectal capsule form containing the active substance in admixture with vegetable oil, paraffin oil or other suitable vehicle for gelatin rectal capsules; (iii) a pre-made micro enema form; or (iv) a dry micro enema form which can be reconstituted in a suitable solvent prior to administration.
Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, for example solutions or suspensions containing from 0.1% to 20% by weight of the active ingredient and the remainder consisting of a mixture of sugar or sugar alcohol and ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, the liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agents. Liquid preparations for oral administration may also be formulated in dry powder form for reconstitution with a suitable solvent prior to administration.
Solutions for parenteral administration may be prepared as solutions of the compounds of the invention in a pharmaceutically acceptable solvent, preferably at a concentration of 0.1 to 10% by weight. The solution may also contain stabilizing and/or buffering ingredients and be dispensed in unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as dry preparations for reconstitution with a suitable solvent prior to use.
The compounds according to the invention can be used in formulations and simultaneously, separately or sequentially with other active ingredients or in combination, for example for the treatment or prophylaxis of diseases caused by infection with helicobacter pylori (helicobacter pylori) of the human gastric mucosa. Other active ingredients may be antibacterial agents, in particular:
beta-lactam antibiotics such as amoxicillin, ampicillin, cephalothin, cefaclor or cefixime;
macrolides such as erythromycin or clarithromycin;
tetracyclines such as tetracycline or doxycycline;
aminoglycosides such as gentamicin, kanamycin or amikacin;
quinolones such as norfloxacin, ciprofloxacin, or enoxacin;
others such as metronidazole, nitrofurantoin or chloramphenicol; or
Formulations containing bismuth salts such as bismuth subcitrate, bismuth subsalicylate, bismuth subcarbonate, bismuth subnitrate or bismuth subgallate.
The compounds according to the invention may be used simultaneously, together or in combination with antacids such as aluminium hydroxide, magnesium carbonate and magnesium hydroxide or alginic acid,Separately or sequentially, or with drugs inhibiting gastric acid secretion such as H2-receptor blockers (e.g. cimetidine, ranitidine), H+/K+-ATPase inhibitors (e.g. omeprazole, pantoprazole, lansoprazole or rabeprazole) are administered together or in combination simultaneously, separately or sequentially or together with gastrokinetic drugs (e.g. cisapride, mosapride) or in combination simultaneously, separately or sequentially.
Intermediates
Another aspect of the invention is a novel intermediate compound for use in the synthesis of the compounds according to the invention.
Accordingly, the present invention comprises:
(a) a compound of formula XVIII
Wherein R is1、R2、R3、R4、R5And X is as defined for formula I;
(b) a compound of formula VIII
Wherein R is2、R6And R7As defined in formula I, R9Is H, CH3Or ester groups such as COOCH3、COOC2H5Etc.;
(c) a compound of formula X
Wherein R is2、R3、R4、R5、R6And R7As defined in formula I, R9Is an ester group such as COOCH3、COOC2H5And the like.
Detailed Description
1. Preparation of the Compounds of the invention
Example 1.1
Synthesis of 2, 3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -6- (morpholinocarbonyl) -imidazo [1, 2-a ] pyridine
2, 3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -imidazo [1, 2-a ] pyridine-6-carboxylic acid (0.15g, 0.44mmol) and o-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) (0.14g, 0.44mmol) were added to dichloromethane (10 ml). Morpholine (0.12g, 1.4mmol) was added and the reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was loaded onto a column together with silica gel and purified by chromatography using ethyl acetate/dichloromethane (1: 1) as eluent to give 0.12g (66%) of the desired product.
1H-NMR(300MHz，CDCl3)：δ1.2(t，3H)，2.32(s，3H)，2.35(s，3H)，2.37(s，3H)，2.7(q，2H)，3.7(s，8H)，4.35(d，2H)，4.95(bs，1H)，6.15(s，1H)，7.0-7.2(m，3H)，7.4(s，1H)。
Example 1.2
Synthesis of N- (4-ethoxyphenyl) -8- (2-ethyl-6-methylbenzylamino) -2, 3-dimethylimidazo [1, 2-a ] pyridine-6-carboxamide
2, 3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -imidazo [1, 2-a ] pyridine-6-carboxylic acid (0.15g, 0.44mmol) and o-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) (0.14g, 0.44mmol) were added to dichloromethane (10 ml). 4-ethoxyaniline (0.19g, 1.4mmol) was added and the reaction mixture was stirred at room temperature for 72 hours. The solvent was evaporated under reduced pressure and the residue was loaded onto a column together with silica gel and purified by chromatography using dichloromethane: methanol (95: 5) as eluent. The residue is treated with a hot mixture of hexane: ethyl acetate (2: 1), the product is filtered off and dried to give 0.14g (74%) of the desired product as white crystals.
1H-NMR(300MHz，CDCl3)：δ1.2(t，3H)，1.4(s，3H，)，2.35(s，9H)，2.65(q，2H)，4.0(q，2H)，4.35(d，2H)，4.9(t，1H)，6.55(s，1H)，6.85(d，2H)，7.0-7.2(m，3H)，7.5(d，2H)，7.9(s，1H)，8.15(s，1H)。
Example 1.3
Synthesis of N- [2- (dimethylamine) -2-oxoethyl ] -8- (2-ethyl-6-methylbenzylamino) -N, 2, 3-trimethylimidazo [1, 2-a ] pyridine-6-carboxamide
2, 3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -imidazo [1, 2-a ] pyridine-6-carboxylic acid (0.13g, 0.38mmol) and o-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) (0.12g, 0.38mmol) were added to dichloromethane (10 ml). N, N-dimethyl-2-methylamino-acetamide (0.088g, 0.38mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography using dichloromethane: methanol (95: 5) as eluent to yield 80mg (48%) of the title product.
1H-NMR(500MHz，CDCl3)：δ1.2(t，3H)，2.3(s，6H)，2.35(s，3H)，2.65(q，2H)，2.75(s，6H)，2.95(s，3H)，3.15(s，2H)，4.35(bs，2H)，4.85(bs，1H)，6.25(s，1H)，7.0-7.2(m，3H)，7.45(s，1H)。
Example 1.4
Synthesis of (8- (2-ethyl-6-methylbenzylamino) -2, 3-dimethylimidazo [1, 2-a ] pyridin-yl) (4-methylpiperazinyl) methanone
2, 3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -imidazo [1, 2-a ] pyridine-6-carboxylic acid (0.5g, 1.48mmol) and o-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) (0.48g, 0.15mmol) were added to dichloromethane (20ml) and the mixture was stirred for 5 minutes. N-methylpiperazine (0.16g, 1.6mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane: methanol (9: 1) as eluent to yield 0.46g (74%) of the title compound.
1H-NMR(500MHz，CDCl3)：δ1.22(t，3H)，2.34(s，3H)，2.36(s，3H)，2.38(s，3H)，2.47(bs，4H)，2.71(q，2H)，2.80(s，3H)，3.65(bs，4H)，4.36(d，2H)，4.94(t，1H)，6.19(s，1H)，7.04-7.18(m，3H)，7.42(s，1H)。
Example 1.5
Synthesis of 1- ((8- (2-ethyl-6-methylbenzylamino) -2, 3-dimethylimidazo [1, 2-a ] pyridin-6-yl) carbonyl) -2-(s) -pyrrolidinecarboxamide
2, 3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -imidazo [1, 2-a ] pyridine-6-carboxylic acid (0.15g, 0.44mmol), o-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) (0.14g, 0.45mmol) and triethylamine (0.05g, 0.5mmol) were added to dichloromethane (10ml) and the mixture was stirred for 10 minutes. (s) -prolinamide (0.016g, 0.45mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, the residue is purified by column chromatography on silica gel using dichloromethane: methanol (9: 1) as eluent and crystallized from diethyl ether to yield 0.07g (36%) of the title compound.
1H-NMR(500MHz，CDCl3)：δ1.21(t，3H)，2.1-2.2(m，4H)，2.33(s，3H)，2.35(s，3H)，2.37(s，3H)，2.70(q，2H)，3.65-3.75(m，2H)，4.36(d，2H)，4.80(bs，1H)，4.94(bs，1H)，5.88(s，1H)，6.33(s，1H)，6.98(s，1H)，7.04-7.19(m，3H)，7.54(s，1H)。
Example 1.6
Synthesis of 8- (2-ethyl-6-methylbenzylamino) -N-hydroxy-2, 3-dimethylimidazo [1, 2-a ] pyridine-6-carboxamide
2, 3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -imidazo [1, 2-a ] pyridine-6-carboxylic acid (0.15g, 0.45mmol), o-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) (0.14g, 0.45mmol), triethylamine (0.1g, 0.99mmol) and hydroxylamine hydrochloride (0.031g, 0.46mmol) in dimethylformamide (5 ml).
The title compound was prepared according to example 1.5 (yield: 0.016g, 10%).
1H-NMR(500MHz，CDCl3)：δ1.15(bs，3H)，2.25(bs，9H)，2.6(bs，2H)，4.25(bs，2H)，4.95(bs，1H)，6.45(bs，1H)，6.9-7.1(m，3H)，7.75(bs，1H)。
Example 1.7
Synthesis of (2-ethyl-6-methylbenzylamino) -N- (2- (2-hydroxyethoxy) ethyl) -2, 3-dimethylimidazo [1, 2-a ] pyridine-6-carboxamide
2, 3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -imidazo [1, 2-a ] pyridine-6-carboxylic acid (0.3g, 0.88mmol), o-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) (0.29g, 0.90mmol) and 2- (2-aminoethoxy) ethanol (0.2g, 1.9mmol) in dichloromethane (10 ml).
The title compound was prepared according to example 1.5 (yield: 0.24g, 80%).
1H-NMR(500MHz，CDCl3)：δ1.25(t，3H)，2.25(s，3H)，2.3(s，3H)，2.35(s，3H)，2.75(q，2H)，3.4-3.45(m，2H)，3.55-3.7(m，6H)，4.35(d，2H)，5.05(t，1H)，6.45(s，1H)，7.0-7.2(m，4H)，7.5(s，1H)。
Example 1.8
Synthesis of (8- (2-ethyl-6-methylbenzylamino) -2, 3-dimethylimidazo [1, 2-a ] pyridin-6-yl) (3-hydroxy-1-pyrrolidinyl) methanone
2, 3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -imidazo [1, 2-a ] pyridine-6-carboxylic acid (0.15g, 0.44mmol), o-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) (0.14g, 0.44mmol) and 3-pyrrolidinol (0.12g, 1.4mmol) in dichloromethane (10 ml).
The title compound was prepared according to example 1.4. Crystallization from ethyl acetate: hexane (2: 1) (yield: 0.24g, 80%).
1H-NMR(300MHz，CDCl3)：δ1.23(t，3H)，1.93(bs，2H)，2.33(s，3H)，2.34(s，3H)，2.41(s，3H)，2.70(q，2H)，3.51-3.89(m，4H)，4.35(d，2H)，4.38-4.55(m，1H)，5.04(bs，1H)，6.35(s，1H)，7.01-7.16(m，3H)，7.51(s，1H)。
Example 1.9
Synthesis of N- (3, 4-dihydroxyphenethyl) -8- (2-ethyl-6-methylbenzylamino) -2, 3-dimethylimidazo [1, 2-a ] pyridine-6-carboxamide
2, 3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -imidazo [1, 2-a ] pyridine-6-carboxylic acid (0.15g, 0.44mmol) and o-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) (0.14g, 0.45mmol) were added to dimethylformamide (10ml) and the mixture was stirred for 5 minutes. 3, 4-Dihydroxyphenylethylamine (0.27g, 1.4mmol) and triethylamine (0.28g, 1.4mmol) were added and the reaction mixture was stirred at room temperature for 72 hours. The solvent is evaporated under reduced pressure, the residue is purified by column chromatography on silica gel using dichloromethane: methanol (9: 1) as eluent and crystallized from acetonitrile to yield 0.059g (28%) of the title compound.
1H-NMR(400MHz，DMSO-d6)：δ1.15(t，1H)，2.22(s，3H)，2.33(s，3H)，2.37(s，3H)，2.65-2.74(m，4H)，3.41(q，2H)，4.37(d，2H)，4.85(t，1H)，6.48(dd，1H)，6.63-6.66(m，2H)，6.70(d，1H)，7.07-7.21(m，3H)8.04(d，1H)，8.49(t，1H)，8.63(s，1H)，8.75(s，1H)。
Example 1.10
Synthesis of 8- (2-ethyl-6-methylbenzylamino-3- (hydroxymethyl) -2-methyl-6- (morpholinocarbonyl) -imidazo [1, 2-a ] pyridine
8- (2-Ethyl-6-methylbenzylamino) -3-hydroxymethyl-2-methylimidazo [1, 2-a ] pyridine-6-carboxylic acid (0.012g, 0.034mmol), o-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU) (0.011g, 0.034mmol) and morpholine (0.009g, 0.1mmol) in dichloromethane (1 ml).
The title compound was prepared according to example 1.1 (yield: 0.008g, 56%).
1H-NMR(300MHz，DMSO-d6)：δ1.23(t，3H)，2.33(s，3H)，2.39(s，3H)，2.72(q，2H)，3.74(bs，8H)，4.37(d，2H)，4.85(s，2H)，5.02(t，1H)，6.27(d，1H)，7.06-7.22(m，3H)，7.75(d，1H)。
Example 1.86
Synthesis of N- ((8- (2-ethyl-6-methylbenzyl) amino) -2, 3-dimethylimidazo [1, 2-a ] pyridin-6-yl) carbonyl) guanidine
2, 3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -imidazo [1, 2-a ] pyridine-6-carboxylic acid (0.5g, 1.5mmol), diisopropylethylamine (0.57g, 1.5mmol) and guanidine carbonate (0.53g, 2.9mmol) were added to dimethylformamide (10 ml). o-benzotriazol-1-yl-N, N' -tetramethyluronium tetrafluoroborate (TBTU) (0.48g, 1.5mmol) was added and the reaction mixture was stirred at 50 ℃ for 3 hours. The solvent is evaporated under reduced pressure, the residue is purified by column chromatography on silica gel using dichloromethane: methanol (100: 15) as eluent and crystallized from diethyl ether to yield 0.12g (21%) of the title compound.
1H-NMR(500MHz，CDCl3)：δ1.1(t，3H)，2.25(s，3H)，2.3(s，3H)，2.35(s，3H)，2.7(q，2H)，4.35(d，2H)，4.8(bs，1H)，6.9(s，1H)，7.05-7.2(m，3H)8.25(s，1H)。
Example 1.87
Synthesis of 4- (2- (((8- (2-ethyl-6-methylbenzylamino) -2, 3-dimethylimidazo [1, 2-a ] pyridin-6-yl) carbonyl) amino) ethoxy) -4-oxobutanoic acid
2, 3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -N-hydroxyethyl-imidazo [1, 2-a ] pyridine-6-carboxamide (250mg, 0.263mmo1) and succinic anhydride (100mg, 1.00mmo1) were added to 7ml of acetone. The mixture was refluxed for 48 hours. The precipitated product is filtered off and washed with acetone and diethyl ether to yield 288mg (91%) of the title compound.
1H-NMR(500MHz，DMSO)：δ1.16(t，3H)，2.24(s，3H)，2.35(s，3H)，2.39(s，3H)，2.48-2.58(m，4H)，2.70(q，2H)，3.54(q，2H)，4.19(t，2H)，4.39(d，2H)，4.90(t，1H)，6.72(s，1H)，7.09-7.22(m，3H)，8.08(s，1H)，8.59(t，1H)，12.25(s，1H)。
Examples 11-85 were prepared by parallel synthesis using the following method:
solution A: 0.149mmol of this was dissolved in 1ml of dimethylformamide
Solution b (tbtu): 0.297mmol was dissolved in 1ml of dimethylformamide
Solution C + D: amine (C) (0.297mmol in 1ml dimethylformamide) + TEA (D) (0.594mmol in 1ml dimethylamine).
To solution A (300. mu.l) was added solution B (150. mu.l) and solution C + D (150. mu.l). The reaction was stirred overnight at room temperature with shaking. The solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane/methanol (9/1) (600. mu.l) and filtered through a plug of silica gel (100mg), which was washed with dichloromethane/methanol (9/1) (0.5-1.0 ml). The filtrate was evaporated under reduced pressure to give the desired compound. (if desired, the compound can be purified by preparative HPLC).
Samples were analyzed by HPLC preparation and the compounds were identified by LC-mass spectrometry. All compounds prepared in examples 11-85 showed mass spectra confirming the proposed structure.
As the starting compound a in the reaction, the following compounds were used.
As the starting compound C in the reaction, the following amines were used.
Examples 11-85 were prepared according to scheme 1.
Primary or secondary amino nitrogen is the nitrogen involved in the reaction.
For example A1+ C5 → example 27
A1C 5 example 27
An + Cn → examples 11 to 85
| A1 | A2 | A3 | A4 | A5 | |
| C1 | Example 11 | Example 12 | Example 13 | Example 14 | Example 15 |
| C2 | Example 16 | Example 17 | Example 18 | Example 19 | Example 20 |
| C3 | - | - | - | - | Example 21 |
| C4 | Example 22 | Example 23 | Example 24 | Example 25 | Example 26 |
| C5 | Example 27 | Example 28 | Example 29 | Example 30 | Example 31 |
| C6 | Example 32 | Example 33 | Example 34 | Example 35 | Example 36 |
| C8 | Example 37 | Example 38 | Example 39 | Example 40 | EXAMPLE 41 |
| C9 | Example 42 | Example 43 | Example 44 | Example 45 | Example 46 |
| C10 | Example 47 | Example 48 | Example 49 | Example 50 | Example 51 |
| C11 | - | Example 52 | Example 53 | Example 54 | Example 55 |
| C12 | - | Example 56 | Example 57 | Example 58 | Example 59 |
| C13 | - | Example 60 | Example 61 | Example 62 | Example 63 |
| C14 | - | - | Example 64 | Example 65 | Example 66 |
| C15 | Example 67 | Example 68 | Example 69 | Example 70 | Example 71 |
| C16 | - | Example 72 | Example 73 | Example 74 | Example 75 |
| C17 | Example 76 | Example 77 | Example 78 | Example 79 | Example 80 |
| C18 | Example 81 | Example 82 | Example 83 | Example 84 | Example 85 |
2. Preparation of intermediates
Example 2.1
Synthesis of 8- (2-ethylbenzylamino) -2, 3-dimethylimidazo [1, 2-a ] pyridine-6-carboxylic acid
8- (2-ethylbenzylamino) -2, 3-dimethylimidazo [1, 2-a ] pyridine-6-carboxamide (1.0g, 0.0031mol) and sodium hydroxide (1.2g, 0.031mol) are dissolved in ethanol (95%) (30ml) and refluxed overnight. The solvent was evaporated under reduced pressure and water was added to the residue. The pH was adjusted to 7 by addition of concentrated HCl (2.6ml), and the precipitated solid was isolated by filtration, washed with water and dried to yield 1.0g (99%) of the title compound.
1H-NMR(300MHz，DMSO-d6)：δ1.2(t，3H)，2.25(s，3H)，2.35(s，3H)，2.7(q，2H)，4.45(d，2H)，6.3(s，1H)，6.45(t，1H)，7.05-7.25(m，4H)，7.95(s，1H)。
Example 2.2
Synthesis of 8- (2, 6-diethylbenzylamino) -2, 3-dimethylimidazo [1, 2-a ] pyridine-6-carboxylic acid
8- (2, 6-Diethylbenzylamino) -2, 3-dimethylimidazo [1, 2-a ] pyridine-6-carboxamide (1.5g, 0.0043mol) and sodium hydroxide (1.7g, 0.043mol) were dissolved in ethanol (95%) (30 ml).
The title compound was prepared according to example 1.4 (yield: 1.5g, 99%).
1H-NMR(400MHz，DMSO-d6)：δ1.14(t，6H)，2.22(s，3H)，2.37(s，3H)，2.67(q，4H)，4.37(d，2H)，4.89(t，1H)，6.68(s，1H)，7.11(d，2H)，7.23(t，1H)，8.09(s，1H)。
Example 2.3
Synthesis of 8- (2, 6-dimethyl-4-fluorobenzylamino) -2, 3-dimethylimidazo [1, 2-a ] pyridine-6-carboxylic acid
8- (2, 6-dimethyl-4-fluorobenzylamino) -2, 3-dimethylimidazo [1, 2-a ] pyridine-6-carboxamide mesylate (1.47g, 0.0034mol) and sodium hydroxide (1.7g, 0.034mol) were dissolved in ethanol (95%) (30 ml).
The title compound was prepared according to example 2.1 (yield: 1.1g, 95%).
1H-NMR(400MHz，DMSO-d6)：δ2.23(s，3H)，2.34(s，6H)，2.36(s，3H)，4.31(d，2H)，5.04(bs，1H)，6.70(s，1H)，6.90(d，2H)，8.02(s，1H)。
Example 2.4
Synthesis of 8- (2-isopropyl-6-methylbenzylamino) -2, 3-dimethylimidazo [1, 2-a ] pyridine-6-carboxylic acid
8- (2-isopropyl-6-methylbenzylamino) -2, 3-dimethylimidazo [1, 2-a ] pyridine-6-carboxamide mesylate (1.2g, 0.0027mol) and sodium hydroxide (1.1g, 0.027mol) were dissolved in ethanol (95%) (25 ml).
The title compound was prepared according to example 2.1 (yield: 1.1g, 95%).
1H-NMR(300MHz，DMSO-d6)：δ1.69(d，6H)，2.74(s，3H)，2.85(s，3H)，2.89(s，3H)，3.73(m，1H)，4.90(d，2H)，5.48(t，1H)，7.19(s，1H)，7.55-7.61(m，1H)，7.70-7.76(m，2H)，8.60(s，1H)。
Example 2.5
Synthesis of 8- (2-ethyl-6-methylbenzylamino) -2, 3-dimethylimidazo [1, 2-a ] pyridine-6-carboxylic acid
8- (2-Ethyl-6-methylbenzylamino) -2, 3-dimethylimidazo [1, 2-a ] pyridine-6-carboxamide mesylate (11.0g, 0.025mol) and sodium hydroxide (7.0g, 0.17mol) were dissolved in ethanol (95%) (120ml) and refluxed for 20 hours. The solvent was evaporated under reduced pressure and water (150ml) was added to the residue. The pH was adjusted to 5 by addition of concentrated HCl and acetic acid, and the precipitated solid was isolated by filtration, washed with water and acetone and dried to yield 7.6g (88%) of the title compound.
1H-NMR(500MHz，DMSO-d6)：δ1.15(t，3H)，2.26(s，3H)，2.34(s，3H)，2.39(s，3H)，2.69(q，2H)，4.38(d，2H)，5.2(bs，1H)，6.73(s，1H)，7.07-7.2(m，3H)，8.12(s，1H)。
Example 2.6
Synthesis of 8- (2-ethyl-6-methylbenzylamino) -3-hydroxymethyl-2-methylimidazo [1, 2-a ] pyridine-6-carboxylic acid
8- (2-Ethyl-6-methylbenzylamino) -3-hydroxymethyl-2-methylimidazo [1, 2-a ] pyridine-6-carboxamide (0.02g, 0.057mmol) and sodium hydroxide (0.02g, 0.29mmol) were dissolved in ethanol (95%) (1ml) and refluxed for 20 hours. The solvent was evaporated under reduced pressure and water (1ml) was added to the residue. The pH was adjusted to 5 by addition of acetic acid, and the precipitated solid was isolated by filtration, washed with water and dried to yield 0.012g (60%) of the title compound.
1H-NMR(300MHz，DMSO-d6)：δ1.14(t，3H)，2.22(s，3H)，2.33(s，3H)，2.67(q，2H)，4.33(d，2H)，4.55(bs，1H)，4.67(s，2H)，6.83(s，1H)，7.06-7.24(m，3H)，8.15(s，1H)。
Biological assay
1. In vitro experiments
Inhibition of acid secretion in isolated rabbit gastric glands
The inhibition of isolated rabbit gastric gland secretion in vitro was determined as described in Berglndh et al (1976) Acta physiol. Scand.97, 401-414. H+，K+Determination of the ATPase Activity
At 37 ℃ in the presence of 2mM MgCl2Membrane vesicles (2.5-5. mu.g) were incubated for 15 minutes in 18mM pegs/Tris buffer (pH7.4) with 10mM KCl and 2mM ATP. The ATPase activity was estimated from the release of inorganic phosphate from ATP as described in LeBel et al (1978) anal. biochem.85, 86-89,
2. in vivo experiments
Inhibition of acid secretion in female rats
Female rats of strain Sprague-Dawley were used. A cannula fistula was inserted in the stomach (cavity) and upper duodenum of the rats for collecting gastric secretions and administering test substances, respectively. Before the start of the test, 14 days after the operation was a recovery period.
Animals were fasted but not deprived of water for 20 hours prior to secretion testing. The stomach was repeatedly lavaged with tap water (+37 ℃) through a gastric cannula, and 6ml of ringer-dextrose solution was given subcutaneously. Pentagastrin and carbachol (20 and 110nmol/kg. h, respectively) were subcutaneously infused over a period of 2.5-4 hours at 1.2 ml/hour to stimulate acid secretion, during which time gastric secretions were collected in 30 minute aliquots. The test substance or vehicle is administered 60 minutes after the start of stimulation (intravenous and intraduodenal administration, 1ml/kg) or 2 hours before the start of stimulation (oral administration, 5ml/kg, gastric intubation). The time interval between administration and stimulation can be extended in order to study duration of action. Gastric juice samples were titrated with 0.1M NaOH to a pH of 7.0 and acid production was calculated based on the volume and concentration of product titration.
Further calculations are based on the group mean response from 4-6 rats. In the case of administration during the stimulation period, the acid production in the period after administration of the test substance or vehicle was expressed as fractional responses (fractional responses), which was set to 1.0 in the last administration period of 30 minutes. Percent inhibition was calculated from the fractional responses elicited by test compound and vehicle. In the case of pre-stimulation dosing, percent inhibition is calculated directly from the acid production recorded after administration of test compound and vehicle.
Bioavailability in rats
Adult Sprague-Dawley strain rats were used. All rats were intubated on the left carotid artery under general anesthesia 1-3 days prior to the experiment. Rats used for intravenous experiments were also cannulated in the jugular vein (Popovic (1960) J.appl.physiol.15, 727-728). The cannula is externally arranged on the back of the neck.
After administration, blood samples (0.1-0.4g) were drawn from the carotid artery multiple times at intervals up to 5.5 hours. The blood sample was frozen until the test compound was analyzed.
Bioavailability was assessed by calculating the quotient between the area under the blood/plasma concentration curve (AUC) after (i.d.) or oral (p.o.) administration and (ii) intravenous (i.v.) administration, respectively, in rats or dogs.
The AUC of the area under the blood concentration versus time curve is determined by the log/linear trapezoidal rule and extrapolated to infinity by dividing the final measured blood concentration by the clearance rate constant in the final phase. The bioavailability (F%) of the system in the duodenum or after oral administration was calculated as follows: f (%) - (AUC (p.o. or i.d.)/AUC (i.v.) × 100.
Conscious inhibition and bioavailability of gastric acid secretion in dogs
Labrador retrievers or Harrier dogs of any sex were used. They are subjected to duodenal fistulation to administer the test compound or vehicle, and gastric fistulae or Heidenhaim-pouch are made to collect gastric secretions.
The animals were fasted for about 18 hours before the secretion test, but had free access to water. Histamine dihydrochloride (12ml/h) was infused at a dose that resulted in about 80% of the individual's maximal secretory response to stimulate gastric acid secretion for 6.5 hours, and gastric juice was continuously collected in 30 minute aliquots. The test substance or vehicle is administered orally, i.d. or i.v. at a volume of 0.5ml/kg body weight 1 or 1.5 hours after the start of histamine infusion. It should be noted that in the case of oral administration, the test compound was administered to the Heidenham-pouch of the stomach of dogs that secreted primarily acid.
The acidity of the gastric juice sample was determined by titration to pH 7.0 and the acid yield was calculated. Acid production during the collection period after administration of test substance or vehicle was expressed as a fractional response, setting the acid production to 1.0 during the previous dose period. Percent inhibition was calculated from the fractional responses elicited by test compound and vehicle.
After administration, blood samples were taken at intervals up to 4 hours for analysis of the concentration of test compound in plasma. Plasma was separated and frozen 30 minutes after collection and then analyzed. The bioavailability (F%) of the system after oral or i.d. administration in the rat model was calculated as described above.
Claims (12)
1. A compound of formula I or a pharmaceutically acceptable salt thereof,
wherein R is1Is H, CH3Or CH2OH；R2Is CH3Or CH2CH3；R3Is CH3Or CH2CH3；R4Is CH3Or CH2CH3；R5Is H or halogen; at R6And R7Cannot be H, C1-C6Alkyl, hydroxylated C1-C6Alkyl or C1-C6Alkoxy-substituted C1-C6Under the precondition of alkyl, R6And R7Each independently is:
(a)H，
(b)C1-C6an alkyl group, a carboxyl group,
(c) hydroxylated C1-C6An alkyl group, a carboxyl group,
(d)C1-C6alkoxy-substituted C1-C6An alkyl group, a carboxyl group,
(e) halogenated C1-C6An alkyl group, a carboxyl group,
(f) aryl, wherein aryl represents phenyl, or is selected from C1-C6Alkyl radical, C1-C6Alkoxy and (C)1-C6Alkyl radical)2Phenyl substituted with one or more substituents of-N-,
(g)C1-C6aryl substituted by alkyl, wherein aryl represents phenyl or imidazolyl, or by a group selected from C1-C6Phenyl or imidazolyl substituted with one or more substituents of alkoxy and OH,
(h)R8-(C1-C6) Alkyl-, wherein R8Is NH2C＝O-、C1-C6alkyl-NHC ═ O —, (C)1-C6-alkyl groups)2NC＝O-、C1-C6alkyl-OOC-, C1-C6alkyl-CO-NH-, C1-C6alkyl-OOCNH-, C1-C6alkyl-O-, C7-C12alkyl-O-, C1-C6alkyl-C ═ O-, -ArCONH-, Ar (C)1-C6Alkyl) CONH, ArC ═ O-, NH2CONH-、C1-C6alkyl-NHCONH-, (C)1-C6Alkyl radical)2-NCONH-, arnchonh-, hydroxylated C1-C6alkyl-O-or morpholinyl; wherein Ar represents phenyl, pyridyl or naphthyl,
(i)C7-C12an alkyl group, a carboxyl group,
(j)OH，
R6and R7Together with the nitrogen atom to which they are attached form a saturated or unsaturated ring with or without one or more additional heteroatoms, or from the group consisting of halogen, C1-C6Alkyl radical, C1-C6Alkoxy, CF3OH, phenyl, NH2CO-、C1-C6Saturated or unsaturated rings substituted with one or more substituents in the alkyl-CO-,
x is NH or O.
2. The compound according to claim 1, wherein the saturated or unsaturated ring is selected from morpholine, piperazine, pyrrolidine and piperidine.
3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, is:
2, 3-dimethyl-8- (2-ethyl-6-methylbenzylamino) -6- (morpholinocarbonyl) -imidazo [1, 2-a ] pyridine,
n- (4-ethoxyphenyl) -8- (2-ethyl-6-methylbenzylamino) -2, 3-dimethylimidazo [1, 2-a ] pyridine-6-carboxamide,
n- [2- (dimethylamine) -2-oxoethyl ] -8- (2-ethyl-6-methylbenzylamino) -N, 2, 3-trimethylimidazo [1, 2-a ] pyridine-6-carboxamide,
(8- (2-ethyl-6-methylbenzylamino) -2, 3-dimethylimidazo [1, 2-a ] pyridin-yl) (4-methylpiperazinyl) methanone,
1- ((8- (2-ethyl-6-methylbenzylamino) -2, 3-dimethylimidazo [1, 2-a ] pyridin-6-yl) carbonyl) -2-(s) -pyrrolidinecarboxamide,
8- (2-ethyl-6-methylbenzylamino) -N-hydroxy-2, 3-dimethylimidazo [1, 2-a ] pyridine-6-carboxamide,
(2-ethyl-6-methylbenzylamino) -N- (2- (2-hydroxyethoxy) ethyl) -2, 3-dimethylimidazo [1, 2-a ] pyridine-6-carboxamide,
(8- (2-ethyl-6-methylbenzylamino) -2, 3-dimethylimidazo [1, 2-a ] pyridin-6-yl) (3-hydroxy-1-pyrrolidinyl) methanone,
n- (3, 4-dihydroxyphenethyl) -8- (2-ethyl-6-methylbenzylamino) -2, 3-dimethylimidazo [1, 2-a ] pyridine-6-carboxamide,
8- (2-ethyl-6-methylbenzyl) amino-3- (hydroxymethyl) -2-methyl-6- (morpholinylcarbonyl) -imidazo [1, 2-a ] pyridine,
n- ((8- (2-ethyl-6-methylbenzyl) amino) -2, 3-dimethylimidazo [1, 2-a ] pyridin-6-yl) carbonyl) guanidine,
4- (2- (((8- (2-ethyl-6-methylbenzylamino) -2, 3-dimethylimidazo [1, 2-a ] pyridin-6-yl) carbonyl) amino) ethoxy) -4-oxobutanoic acid.
4. A compound according to claim 1 which is the hydrochloride or mesylate salt.
5. A process for preparing a compound of claim 1 comprising:
(a) hydrolysis of Compounds of formula II under Standard conditions
Wherein R is1、R2、R3、R4、R5And X is as defined in claim 1, to give the corresponding carboxylic acid compound of the formula III,
(b) reacting a compound of formula III with an amino compound of formula IV
Wherein R is6And R7The reaction is carried out in the presence of a coupling reagent in an inert solvent under standard conditions to give the corresponding amide compound as defined in claim 1.
6. A process for preparing a compound of claim 1, wherein X in said compound is NH and R1Is H or CH3The method comprises the following steps:
(a) reacting a compound of formula II
And general formula R10An alcohol compound of-OH, wherein R10Is alkyl, under standard conditions to give a compound of formula XI,
(b) reacting a compound of formula XI, wherein R10Is an alkyl group, is reacted with ammonia in an inert solvent under standard conditions to give the compound of formula XII,
(c) a compound of the formula XII, wherein R10Is alkyl, in an inert solvent, under standard conditions to afford a compound of formula XIII,
(d) reacting a compound of formula XIII, wherein R10Is alkyl, with a compound of the formula XIV
Wherein R is2As defined in claim 1, Z is a leaving group and R11Represents H or CH3In an inert solvent, in the presence or absence of a base to give a compound of formula XV,
(e) reacting a compound of formula XV wherein R10Is alkyl, R2As defined in claim 1 and R11Is H or CH3Is combined with formula IXArticle (A)
Wherein R is3、R4And R5As defined in claim 1, Y is a leaving group, in an inert solvent, in the presence or absence of a base, to give a compound of formula XVI,
(f) reacting a compound of formula XVI wherein R2、R3、R4And R5As defined in claim I, R10Is alkyl and R11Is H or CH3With compounds of the formula III
Wherein R is6And R7As defined in claim 1, under standard conditions to give a compound of formula 1, wherein R1Is H or CH3And X is NH.
7. A process for preparing a compound of claim 1 comprising:
(a) treating the compound of formula XVII with an acid or base under standard conditions
Wherein R is1、R2、R3、R4、R5And X is as defined in claim 1, R10Is alkyl to give a compound of formula XVIII,
(b) reacting a compound of formula XVIII wherein R1、R2、R3、R4、R5And X is as defined inAs defined in claim 1, with a compound of formula III
Wherein R is6And R7As defined in claim 1, in the presence of a coupling reagent in an inert solvent under standard conditions to give the compound of formula I.
8. Use of a compound according to claim 1 in the manufacture of a medicament for inhibiting gastric acid secretion.
9. Use of a compound of claim 1 in the manufacture of a medicament for the treatment of gastrointestinal inflammatory diseases.
10. The use of a compound according to claim 1 in the manufacture of a medicament for the treatment or prophylaxis of conditions caused by infection of helicobacter pylori of human gastric mucosa, wherein the salt is administered in combination with at least one antibacterial agent.
11. A compound of formula X
Wherein R is2、R3、R4、R5、R6And R7As defined in claim 1, and R9Is an ester group.
12. A compound of the formula
Wherein R is1、R2、R3、R4、R5And X is as defined in claim 1.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9801526A SE9801526D0 (en) | 1998-04-29 | 1998-04-29 | New compounds |
| SE9801526-6 | 1998-04-29 | ||
| PCT/SE1999/000662 WO1999055705A1 (en) | 1998-04-29 | 1999-04-23 | Imidazo pyridine derivatives which inhibit gastric acid secretion |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1036981A1 HK1036981A1 (en) | 2002-01-25 |
| HK1036981B true HK1036981B (en) | 2005-05-27 |
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