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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/16—Otologicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents

Definitions

• the present invention relates to novel azaindolylpiperidine compounds and pharmaceutically acceptable salts thereof. These compounds are antagonists of H-i histamine receptors and are thus useful for the treatment of bronchial asthma, allergic rhinitis, conjunctivitis, dermatitis, urticaria and other allergic diseases.
• R 4 and R 5 each independently represents a hydrogen or halogen atom, a hydroxy group, or a group selected from one of alkyl, alkoxy, alkenyl, alkynyl or phenyl, which is optionally substituted by one or more, for example, 1 , 2, 3 or 4, substituents selected from, halogen, hydroxy, oxo, alkoxy, alkylthio, acylamino, phenyl, alkoxycarbonyl, amino, monoalkylamino, dialkylamino and hydroxycarbonyl groups;
• X represents -O- or -NR 6 -;
• a hydrocarbon chain is a straight or branched non-cyclic sequence of carbon atoms covalently linked by single, double or triple bonds, and substituted by hydrogen atoms, for example straight or branched alkyl, alkenyl or alkynyl groups, moieties or chains. Typically, the hydrocarbon chains, contain from 1 to 10 carbon atoms.
• an alkyl, alkenyl or alkynyl group or moiety is a straight or branched group or moiety. Typically it is a CrC 10 group or moiety, for example a C ⁇ -C 6 group or moiety, preferably a C C 4 group or moiety. Examples include methyl, ethyl, i-propyl, n-propyl, n- butyl, t-butyl, allyl, 2-propenyl and 3-butynyl. Where a group contains two or more alkyl, alkenyl or alkynyl moieties, these moieties may be the same or different. When an alkyl, alkenyl or alkynyl chain, group or moiety carries 2 or more substituents, the substituents may be the same or different.
• an alkylene group or moiety is a divalent alkyl moiety typically having from 1 to 6, for example from 1 to 4, carbon atoms.
• Examples of C C 4 alkylene groups include methylene, ethylene, propylene and butylene groups.
• alkyl chains present in the alkoxy, alkylthio, monoalkylamino, dialkylamino, hydroxyalkoxy, alkylcarbonyl, alkoxycarbonyl, alkylcarbamoyl and alkylenedioxy groups are typically straight or branched alkyl chains containing from 1 to 6 carbon atoms.
• Oxadiazolyl, oxazolyl, pyridyl, pyrrolyl, imidazolyl, thiazolyl, thiadiazolyl, thienyl, furanyl, pyrazinyl and pyrimidinyl groups are preferred.
• the substituents may be the same or different.
• a heterocydyl group is typically a non-aromatic, saturated or unsaturated C 3 -C 10 carbocyclic ring in which one or more, for example 1 , 2, 3 or 4 of the carbon atoms are replaced by a heteroatom selected from N, O and S. Saturated heterocydyl groups are preferred. Examples of suitable heterocydyl groups include piperidinyl, piperazinyl, morpholinyl, 4,5-dihydro-oxazolyl, 3-aza-tetrahydrofuranyl, imidazolidinyl and pyrrolidinyl groups. Where a heterocydyl group carries 2 or more substituents, the substituents may be the same or different.
• each R T is independently selected from a hydrogen or halogen atom or an alkyl, or alkoxy group. More preferably, R T is hydrogen, chlorine, fluorine or methoxy and still more preferably R is hydrogen
• L T is an alkyl, oxyalkyl; aminoalkyl or thioalkyl group, for example methyl, ethyl, n-propyl, oxyethyl, oxypropyl, aminoethyl or thioethyl;
• L 2 is a single bond or an alkyl group, for example methyl or ethyl;
• L 3 is a single bond or an alkyl, oxyalkyl or alkoxyalkyl group, for example methyl, ethyl, n-propyl, isopropyl, butyl, oxyethyl, methoxyethyl or ethoxyethyl.
• W is preferably an aromatic monocyclic group which is optionally substituted by one or more, for example, 1 , 2, 3 or 4, substituents selected from halogen atoms, alkyl or alkoxy groups. More preferably W T is selected from a phenyl, furanyl or thienyl group, which is optionally substituted by one or more, for example 1 , 2, 3 or 4, substituents selected from halogen, alkyl or alkoxy, such as fluorine, chlorine, bromine, methyl or methoxy.
• n 0
• W 2 is preferably a cycloalkyl group, for example cyclopropyl, cyclobutyl or cyclopentyl, a phenyl group, or a 5- or 6-membered heterocydyl group, for example a tetrahydropyranyl, furanyl, thienyl, pyrrolyl, pyridinyl, oxetanyl or dioxanyl group. More preferably W 2 is selected from cyclopropyl, phenyl, pyridinyl, furanyl and thienyl.
• W 2 is optionally substituted by one or more, for example 1 , 2, 3 or 4, substituents selected from halogen, alkyl or alkoxy, such as fluorine, chlorine, bromine, methyl, ethyl or methoxy.
• R 4 and R 5 each independently represents a hydrogen or halogen atom, a C r C 4 alkyl group or a phenyl group, which is optionally substituted by one or more, for example 1 , 2, 3 or 4, substituents selected from halogen, alkyl or alkoxy, such as fluorine, chlorine, bromine, methyl, ethyl or methoxy. Most preferably R t and R 5 are both hydrogen.
• This reaction is preferably carried out in an organic solvent such as toluene, dicloromethane, dioxane or methyl isobutylketone at a temperature between 25°C and 140°C in the presence of a base such as an alkali metal carbonate or bicarbonate, triethylamine or diisopropilethylamine. Occasionally, the solvent used is dimethylformamide.
• an organic solvent such as toluene, dicloromethane, dioxane or methyl isobutylketone at a temperature between 25°C and 140°C in the presence of a base such as an alkali metal carbonate or bicarbonate, triethylamine or diisopropilethylamine.
• a base such as an alkali metal carbonate or bicarbonate, triethylamine or diisopropilethylamine.
• the solvent used is dimethylformamide.
• This reaction is preferably carried out in an inert solvent such as dimethylformamide, tetrahydrofuran or ethyl ether at a temperature between 0°C and 80°C in a presence of an inorganic base such as sodium hydride or sodium amide.
• an inert solvent such as dimethylformamide, tetrahydrofuran or ethyl ether at a temperature between 0°C and 80°C in a presence of an inorganic base such as sodium hydride or sodium amide.
• This compound was prepared following the procedure described in example 1 , part F, starting with 1.22 g (4.46 mmol) of 4-(1 H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1 -carboxylic acid ethyl ester and 6.3 ml (6.24 mmol) of a freshly prepared 1 M solution of 3- . bromomethylfuran in ethyl ether. The crude mixture was stirred at 60°C for 3 hours. After standard work-up, 1 g (63% of yield) of the expected product was isolated.
• This compound was prepared following the procedure described in example 1 , part G, starting with 1 g (2.83 mmol) of 4-(1 -furan-3-ylmethyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)- piperidine-1 -carboxylic acid ethyl ester. After standard work-up, 0.82 g (100% of yield) of the expected product were isolated.
• the mixture was refluxed for 18 hours and, after cooling, water was added, the organic layer separated, washed with water and brine.
• the solvent was distilled off.
• the crude material weighed 2.1 g and was purified by flash chromatography over silica gel affording 0.58 g (36% of yield) of the expected product.
• This reaction is preferably carried out in the presence of a base such as sodium or potassium hydroxide in an alcoholic solvent such as methanol, ethanol or isopropanol at a temperature between 60° and 150°C.
• Compound XVII is either hydrogenated using palladium or platinum oxide as catalyst in a solvent such as methanol or ethanol in acidic or neutral conditions at a pressure between 2 or 3 bar or reduced with an hydride such as sodium borohydride to give a compound of general formula XVIII wherein A, B, D, E, R t , R 5 and q are as defined above and Re is a tert-butyl group.
• the compound of general formula XVI wherein A, B, D, E, R t , R 5 and q are as defined above and Re is an ethyl group is either hydrogenated using palladium or platinum oxide as catalyst in a solvent such as methanol or ethanol in acidic or neutral conditions at a pressure between 2 or 3bar or reduced using an hydride such as sodium borohydride, to give a compound of general formula XIX wherein A, B, D, E, R t , R 5 and q are as defined before and Re is an. ethyl group.
• the compound of general formula XX is deprotected to give a compound of formula X, which is as previously defined in Scheme 1.
• substituent Re of compound XX is a tert-butyl group this is done by treatment with trifluoroacetic acid in dichloromethane at a temperature between 0 °C and room temperature.
• substituent Re of compound XX is an ethyl group it is deprotected by treatment with sodium or potassium hydroxide in a solvent such as ethanol, isopropanol or n-butanol at a temperature between 80°C and 180°C.
• This compound was prepared following the procedure described in example 4, part F, starting with 0.95 g (2 mmol) of 5-[4-(1 -furan-3-ylmethyl-1 H- ⁇ yrrolo[2,3-b]pyridin-3-yl)- piperidin-1-ylmethyl]-2-methoxy-benzoic acid ethyl ester. After standard work-up, 0.7 g of the crude acid were obtained which were washed with hot water, ethanol and ethyl ether affording 0.33 g (37% of yield) of the pure acid.
• This compound was prepared following the'procedure described in example 17, parts C and D, starting with 0.098 g (0.33 mmol) of 1-(5-chloro-thiophen-2-ylmethyl)-3-piperidin-4- yl-1 H-pyrrolo[2,3-b]pyridine.
• the crude mixture was purified by preparative HPLC triggered by MS.
• This compound was prepared following the procedure described in example 4, part F, starting with 2.8 g (5.35 mmol) of 5- ⁇ 4-[1 -(5-chloro-thiophen-2-ylmethyl)-1 H-pyrrolo[2,3- b]pyridin-3-yl]-piperidin-1-ylmethyl ⁇ -2-methoxy-benzoic acid ethyl ester. After standard work-up, 2 g (75% of yield) of the expected acid were obtained.
• This compound was prepared following the procedure described in example 4, part D, starting with 3.1 g (9.1 mmol) of 4-(1 -butyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1- carboxylic acid ethyl ester. After standard work-up, 2.23 g (95% yield) of 1 -butyl-3- piperidin-4-yl-1 H-pyrrolo[2,3-b]pyridine were obtained.
• Example 25 was prepared following the procedure described in example 4 (parts E and F) and example 26 was prepared following the procedure described in example 24 (parts E and F) starting with 0.059 g (0.23 mmol) of 1-butyl-3-piperidin-4-yl-1H-pyrrolo[2,3- bjpyridine.
• the crude mixtures were purified by preparative HPLC triggered by MS. ESI/MS and purity data corresponding to these compounds are shown in table 7.
• This compound was prepared following the procedure described in example 24, part C, starting with 2.8 g (10 mmol) of 4-(1 H-pyrrolo[2,3-bJpyridin-3-yl)-piperidine-1 -carboxylic acid ethyl ester and 1.7 ml (15 mmol) of 2-bromoethylethyl ether. After standard work-up and purification, 3.5 g of 4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidine-1- carboxylic acid ethyl ester were obtained.
• This compound was prepared following the procedure described in example 4, part E and F starting with 3.6 g (11 mmol) of 1-furan-2-ylmethyl-3-piperidin-4-yl-1 H-pyrrolo[2,3- bjpyridine and 4.0 g (16.5 mmol) of 2-(2-chloroethoxy)-4-methoxy-benzoic acid methyl ester. After standard purification the overall yield was 36% (1.93 g).
• This compound was prepared following the procedure described in example 24, part C, starting with 1.05 g (3.84 mmol) of 4-(1 H-pyrrolo[2,3-cJpyridin-3-yl)-piperidine-1 -carboxylic acid ethyl ester and 0.52 ml (4.61 mmol) of 2-bromoethylethyl ether. After standard work- up and purification, 0.83 g (63% yield) 4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-ylJ- piperidine-1 -carboxylic acid ethyl ester were obtained.
• This compound was prepared following the procedure described in example 24, part D, starting with 0.83 g (2.4 mmol) of 4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-ylJ- piperidine-1 -carboxylic acid ethyl ester. After standard work-up, 0.46 g (71% yield) of 1-(2- ethoxyethyl)-3-piperidin-4-yl-1 H-pyrrolo[2,3-c]pyridine were obtained.
• This compound was prepared following the procedure described in example 4, part E, starting with 0.46 g (1.7 mmol) of 1-(2-ethoxyethyl)-3-piperidin-4-yl-1H-pyrrolo[2,3- cjpyridine and 0.44 g (2.0 mmol) of 2-(2-chloroethoxy)-benzoic acid methyl ester . After standard work-up and purification, 0.2 g (21% yield) of 2-(2- ⁇ 4-[1-(2-ethoxyethyl)-1 H- pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1 -ylj-ethoxy)-benzoic acid methyl ester were obtained.
• This compound was prepared following the procedure described in example 24, part D, starting with 6.14 g (18.6 mmol) of 4-(1 -butyl-1 H-pyrrolo[2,3-cJpyridin-3-yl)-piperidine-1- carboxylic acid ethyl ester. After standard work-up, 5.45 g (100% yield) of 1-butyl-3- piperidin-4-yl-1H-pyrrolo[2,3-cJpyridine were obtained.
• Example 94-99 These compounds were prepared following the procedure described in example 89 starting with the corresponding starting materials. They were purified by preparative HPLC triggered by MS. ESI/MS and purity data are shown in table 21.
• mice Male Wistar rats (180-210 g) were treated orally with the test compound or vehicle. Either one, four, eight or 24 hours later the rats were lightly anaesthetized with ether and a cutaneous reaction was induced by two intradermal injections of 50 ⁇ l of histamine (100 ⁇ g/ml) onto the back, followed by a intravenous injection of 3 ml/kg of Evan's Blue (5 mg/ml), both dissolved in saline. Sixty minutes later, the rats were killed by cervical dislocation and the back skin dissected free. The diameter (in millimetres) of the papule was measured in two directions and the area was calculated. Results are given as the % of inhibition at a given dose compared with the vehicle treated group.
• the assay was performed essentially as described by Leysen et al (Drug Development Reasearch 1991, 22, 165-178) with the following modifications. Overnight starved male Swiss albino mice (21 ⁇ 2 g) were treated orally with different doses of the test compounds (10 ml/kg, p.o.) and 90 minutes later were killed. The whole brain was dissected out and homogenized in 10 ml of ice-cold 0.05 M Na7K * phosphate buffer (pH 7.4). A 1 ml aliquot of the homogenate was incubated, in triplicate, with 0.1 ml [ 3 H]-mepyramine (2 nM final concentration, 27 Ci/mmol, Amersham) during 40 minutes at 30°C.
• the concentration of [ 3 H]-mepyramine bound to the membranes was determined by immediate filtration of the homogenates under vacuum onto glass fibre filters (Whatman GF/B) followed by three rapid rinses with 5 ml of cold buffer containing 10 ⁇ M cold mepyramine. The radioactivity bound in the filters was determined by liquid scintillation spectrometry. The non-specific binding was determined by treating the animals with 30 mg/kg p.o. D-chlorpheniramine maleate. Mice treated with vehicle (methylcellulose 0.5% and tween 0.1%) were used to determine the total binding.
• results of this assay show that the compounds of the present invention display little or no penetration through the blood brain barrier.
• Blood pressure sensors were implanted just above the iliac bifurcation in the abdominal aorta of adult male spontaneously hypertensive rats (SHR). After recovery from anaesthesia, rats were housed individually in cages placed on radio-frequency receivers. Amoxycillin (15 mg/kg, i.m., after surgery) was administered to prevent infection. The rats were allowed to recover for at least 2 weeks after transmitter implantation. Arterial blood pressure and heart rate were recorded and analysed by Dataquest V system (Data Science, St. Paul, MN). The animals were kept on a 12:12 hours light-dark cycle during the entire recording period. After 18 hours of fasting with water "ad libitum", the animals received drugs orally and were then given food.
• SHR spontaneously hypertensive rats
• the compounds of the present invention have little or no effects on blood pressure and heart rate at doses from 3 to 30 mg/kg.
• the compounds of the present invention have reduced cardiovascular and central nervous system side effects. They can thus be advantageously used for the treatment of allergic disorders, for instance, bronchial asthma, rhinitis, conjunctivitis, dermatitis and urticaria.
• the invention thus provides a method for treating an allergic disorder comprising the step of administering to a subject in need of such treatment an effective amount of a compound of formula I.
• the invention also provides the use of the compounds of formula I in the manufacture of a medicament for the treatment of an allergic disorder, as well as pharmaceutical compositions comprising a compound of formula I. Some examples of suitable compositions are shown below.
• Example 101

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