Patent Application
20130245009
The present invention relates to new CGRP-antagonists of general formulae Ia and Ib
wherein R1, R2, R3, R4 and R5 are defined as mentioned below, the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates, the mixtures and the salts thereof as well as the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, pharmaceutical compositions containing these compounds, the use thereof and processes for the preparation thereof.
In the above general formulae Ia and Ib in a first embodiment
and
A second embodiment of the present invention comprises the compounds of the above general formulae Ia and Ib, wherein R3, R4 and R5 are defined as hereinbefore in the first embodiment and
and
A third embodiment of the present invention comprises the compounds of the above general formulae Ia and Ib, wherein R3, R4 and R5 are defined as hereinbefore in the first embodiment and
and
A fourth embodiment of the present invention comprises the compounds of the above general formulae Ia and Ib, wherein R3, R4 and R5 are defined as hereinbefore in the first embodiment and
and
the tautomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof as well as the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases.
A fifth embodiment of the present invention comprises the compounds of the above general formulae Ia and Ib, wherein R1, R2 and R5 are defined as hereinbefore in the first, second, third or fourth embodiment and
A sixth embodiment of the present invention comprises the compounds of the above general formulae Ia and Ib, wherein R1, R2 and R5 are defined as hereinbefore in the first, second, third or fourth embodiment and
A seventh embodiment of the present invention comprises the compounds of the above general formulae Ia and Ib, wherein R1, R2 and R5 are defined as hereinbefore in the first, second, third or fourth embodiment and
An eighth embodiment of the present invention comprises the compounds of the above general formulae Ia and Ib, wherein R1, R2 and R5 are defined as hereinbefore in the first, second, third or fourth embodiment and
or
the tautomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof as well as the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases.
A ninth embodiment of the present invention comprises the compounds of the above general formulae Ia and Ib, wherein R1, R2, R3 and R4 are defined as hereinbefore in the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment and
A tenth embodiment of the present invention comprises the compounds of general formulae Ia and Ib wherein
and
or
and
The following compounds are mentioned as examples of most particularly preferred compounds of the above general formulae Ia and Ib:
the enantiomers, the diastereomers, the hydrates, the mixtures thereof and the salts thereof as well as the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases.
The present specification of the invention is to be interpreted in accordance with the conventions and rules of chemical bonds.
The compounds included in this invention are those that are also chemically stable.
Unless otherwise stated, all the substituents are independent of one another. If for example there are a plurality of C1-4-alkyl groups as substituents in one group, in the case of three C1-4-alkyl substituents, independently of one another, one may represent methyl, one ethyl and one n-propyl.
Within the scope of this application, in the definition of possible substituents, these may also be represented in the form of a structural formula. If present, an asterisk (*) in the structural formula of the substituent is to be understood as being the linking point to the rest of the molecule. For example a phenyl group is shown as follows:
Moreover, the atom of the substituent that follows the linking point is understood as being the atom at position number 1.
The subject-matter of this invention also includes the compounds according to the invention, including the salts thereof, wherein one or more hydrogen atoms, for example one, two, three, four or five hydrogen atoms, are replaced by deuterium.
By the term “C1-3-alkyl” (including those which are a part of other groups) are meant branched and unbranched alkyl groups with 1 to 3 carbon atoms, by the term “C1-4-alkyl” are meant branched and unbranched alkyl groups with 1 to 4 carbon atoms and by the term “C1-6-alkyl” are meant branched and unbranched alkyl groups with 1 to 6 carbon atoms. Examples include: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, neopentyl or n-hexyl. The abbreviations may optionally also be used for the above-mentioned groups Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. Unless stated otherwise, the definitions propyl and butyl include all the possible isomeric forms of the groups in question. Thus, for example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl etc.
By the term “C1-6-alkylene” (including those which are a part of other groups) are meant branched and unbranched alkylene groups with 1 to 6 carbon atoms and by the term “C1-3-alkylene” are meant branched and unbranched alkylene groups with 1 to 3 carbon atoms. Examples include: methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene or hexylene. Unless stated otherwise, the definition propylene includes all the possible isomeric forms of the groups in question with the same number of carbons. Thus, for example, propyl also includes 1-methylethylene and butylene includes 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene. The definition for Co-alkylene denotes a bond.
By the term “C2-6-alkenyl” (including those which are a part of other groups) are meant branched and unbranched alkenyl groups with 2 to 6 carbon atoms and by the term “C2-4-alkenyl” are meant branched and unbranched alkenyl groups with 2 to 4 carbon atoms, provided that they comprise at least one double bond. Alkenyl groups with 2 to 4 carbon atoms are preferred. Examples include: ethenyl or vinyl, propenyl, butenyl, pentenyl, or hexenyl. Unless stated otherwise, the definitions propenyl, butenyl, pentenyl and hexenyl include all the possible isomeric forms of the groups in question. Thus, for example, propenyl includes 1-propenyl and 2-propenyl, butenyl includes 1-, 2- and 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl etc.
By the term “C2-6-alkynyl” (including those which are a part of other groups) are meant branched and unbranched alkynyl groups with 2 to 6 carbon atoms and by the term “C2-4-alkynyl” are meant branched and unbranched alkynyl groups with 2 to 4 carbon atoms, provided that they comprise at least one triple bond. Examples include: ethynyl, propynyl, butynyl, pentynyl, or hexynyl. Unless stated otherwise, the definitions propynyl, butynyl, pentynyl and hexynyl include all the possible isomeric forms of the groups in question. Thus, for example propynyl includes 1-propynyl and 2-propynyl, butynyl includes 1-, 2- and 3-butynyl, 1-methyl-1-propynyl, 1-methyl-2-propynyl etc.
By the term “C3-6-cycloalkyl” (including those which are a part of other groups) are meant cyclic alkyl groups with 3 to 6 carbon atoms and by the term “C5-6-cycloalkyl” are meant cyclic alkyl groups with 5 to 6 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Unless otherwise stated, the cyclic alkyl groups may be substituted by one or more groups selected from among methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.
By the term “C5-6-cycloalkenyl” (including those which are a part of other groups) are meant cyclic alkenyl groups with 5 or 6 carbon atoms, which contain an unsaturated bond. Examples include: cyclopentenyl or cyclohexenyl. Unless otherwise stated, the cyclic alkenyl groups may be substituted by one or more groups selected from among methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.
By the term “heterocyclyl” or “heterocyclic group” are meant, unless otherwise described in the definitions, stable 5-, 6- or 7-membered monocyclic or 8-, 9-, 10- or 11-membered bicyclic heterocyclic ring systems, which do not form an aromatic ring system in at least one ring and in addition to carbon atoms may carry one to four heteroatoms selected from among nitrogen, oxygen and sulphur. The two nitrogen atoms and also sulphur atoms may optionally be oxidised and nitrogen atoms may be quaternised. The heterocyclic ring may contain one or two carbonyl, thiocarbonyl or cyanoimino groups adjacent to a nitrogen atom. The heterocycles mentioned previously may be linked to the rest of the molecule via a carbon atom or a nitrogen atom.
Unless otherwise stated, the heterocycles may be substituted by one or more groups selected from among:
The following compounds are mentioned by way of example, but the invention is not restricted to them: azetidine, oxetane, thietane, thietane dioxide, tetrahydrofuran, dihydrofuran, dioxolane, imidazolidine, imidazoline, imidazolidinone, dihydroimidazolone, oxazoline, oxazolidine, oxazolidinone, pyrrolidinone, dihydropyrazole, pyrrolidine, pyrroline, morpholine, tetrahydropyridine, dihydropyran, tetrahydropyran, dioxane, piperazine, piperidine, piperazinone, piperidinone, pyran, thiomorpholine-5-oxide, thiomorpholine-5-dioxide, thiomorpholine, dihydroxazine, morpholinedione, morpholinethione, perhydrothiazinedioxide, {acute over (ε)}-caprolactam, oxazepanone, diazepanone, thiazepanone, perhydroazepine, dihydroquinazolinone, dihydroindole, dihydroisoindole, benzoxazolone, benzimidazolone, chromanone, tetrahydroquinoline, tetrahydrobenzoxazole, tetrahydrobenzisoxazole, tetrahydrobenzothiophene, tetrahydrothieno-pyridine, tetrahydrobenzofuran, tetrahydro-oxazolopyridine, tetrahydro-isoxazolopyridine.
The following heterocycles are preferred according to the invention:
By the term “aryl” (including those which are a part of other groups) are meant monocyclic aromatic ring systems with 6 carbon atoms or bicyclic aromatic ring systems with 10 carbon atoms. Examples include phenyl, 1-naphthyl or 2-naphthyl; the preferred aryl group is phenyl.
Unless otherwise stated, the aromatic groups may be substituted by one or more groups selected from among:
By the term “heteroaryl” are meant stable five- or six-membered heterocyclic aromatic groups or 8- to 10-membered bicyclic heteroaryl rings that may contain in each ring one, two or three heteroatoms, selected from among oxygen, sulphur and nitrogen, and additionally sufficient conjugated double bonds to form an aromatic system. Examples of five- or six-membered heterocyclic aromatic groups are as follows, but the invention is not restricted to these:
furan, pyrrole, thiophene, pyrazole, imidazole, oxazole, thiazole, isothiazole, isoxazole, oxadiazole, triazole, tetrazole, furazan, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, triazine.
The following five-membered heterocyclic aromatic groups are preferred according to the invention:
The following six-membered heterocyclic aromatic groups are preferred according to the invention:
Examples of 9- or 10-membered bicyclic heteroaryl rings are as follows, but the invention is not restricted to these:
indole, isoindole, indazole, indolizine, benzofuran, benzthiophene, benzimidazole, benzoxazole, benzothiazole, benzotriazole, benzisoxazole, benzisothiazole, quinoline, isoquinoline, cinnoline, phthalazine, quinoxaline, quinazoline, pyridopyrimidine, pyridopyrazine, pyridopyridazine, pyrimidopyrimidine, pteridine, purine, quinolizine, benzoxazolecarbonitrile, quinoline, isoquinoline, quinolizine, pteridine, purine, quinolizine, benzoxazole-carbonitrile.
The following bicyclic heteroaryl rings are preferred according to this invention:
Unless otherwise stated, the heteroaryls previously mentioned may be substituted by one or more groups selected from among:
Bicyclic heteroaryl rings may preferably be substituted in the phenyl group.
By the term “halogen” are meant fluorine, chlorine, bromine or iodine atoms.
Compounds of general Ia and Ib may have acid groups, mainly carboxyl groups, and/or basic groups such as e.g. amino functions. Compounds of general Ia and Ib may therefore be present as internal salts, as salts with pharmaceutically useable inorganic acids such as for example hydrobromic acid, phosphoric acid, nitric acid, hydrochloric acid, sulphuric acid, methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic acid or organic acids such as for example malic acid, succinic acid, acetic acid, fumaric acid, maleic acid, mandelic acid, lactic acid, tartaric acid, citric acid or as salts with pharmaceutically useable bases such as alkali or alkaline earth metal hydroxides, e.g. sodium hydroxide or potassium hydroxide, or carbonates, ammonia, zinc or ammonium hydroxides or organic amines such as e.g. diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, inter alia.
The compounds according to the invention may be present as racemates, provided that they have only one chiral element, but may also be obtained as pure enantiomers, i.e. in the (R) or (S) form.
However, the application also includes the individual diastereomeric pairs of antipodes or mixtures thereof, which are obtained if there is more than one chiral element in the compounds of general formulae Ia and Ib, as well as the individual optically active enantiomers of which the above-mentioned racemates are made up.
The invention relates to the compounds in question, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of the tautomers as well as in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids.
So-called prodrugs of compounds of general formulae Ia and Ib are also encompassed by this invention. The term prodrug is used to denote any molecule that releases the active principle of general formula Ia and Ib in-vivo after administration to mammals. The prodrug may have little or no pharmacological activity per se, but releases the active principle of general formulae Ia and Ib in-vivo after administration and this has the activity described. Prodrugs for compounds of general formulae Ia and Ib may be prepared by modifying suitable functional groups in the compound of general formulae Ia and Ib, as known to the skilled man in this field. (H. Bundgaard (Editor), Design of Prodrugs. (1986), Elsevier)
This invention also includes those metabolites that are derived from the compounds of general formulae Ia and Ib. By metabolites are meant, in this context, compounds that are formed in-vivo from the compound of general formulae Ia and Ib after administration. Examples of metabolites include:
The invention also relates to a process for preparing the compounds of general formulae Ia and Ib
wherein R1, R2, R3, R4 and R5 are as hereinbefore defined.
Some methods of preparing the compounds of general formulae Ia and Ib according to the invention are illustrated in the following synthesis schemes and Examples.
The regioisomeric compounds of general formula Ib, wherein R1, R2, R3, R4 and R5 are as hereinbefore defined, may be prepared analogously to the methods described hereinafter.
In some cases the order of carrying out the reaction schemes may be varied in order to simplify the reactions or prevent unwanted by-products. The Examples that follow are provided to make the invention fully comprehensible. The Examples are intended to illustrate the invention and should in no way restrict it.
The compounds according to the invention may be prepared according to the schemes and specific examples provided or corresponding modifications thereof. Modifications to these reactions which are known to the skilled man but not described in detail here may also be implemented. The general methods of preparing the compounds according to the invention will become apparent to the skilled man from a study of the following schemes.
Starting compounds are commercially available or are prepared by processes which are described in the literature, known in the art or as described herein. Before the reaction is carried out corresponding functional groups in the compounds may be protected by conventional protective groups. These protective groups may be cleaved again at a suitable stage within the reaction sequence using methods familiar to the skilled man.
In the reactions described below, any reactive groups present such as hydroxy, carboxy, amino, alkylamino, amide or imino groups may be protected during the reaction by conventional protective groups that are cleaved again after the reaction.
For example
Other protective groups and their cleavage are described in T. W. Greene, P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Wiley, 1991 and 1999.
Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, or by ether splitting, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 100° C., preferably at temperatures between 10 and 50° C.
However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50° C., but preferably at ambient temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 1 to 5 bar.
A methoxybenzyl group may also be cleaved in the presence of an oxidising agent such as cerium(IV)ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile/water at temperatures of between 0 and 50° C., but preferably at ambient temperature.
A methoxy group is conveniently cleaved in the presence of boron tribromide in a solvent such as methylene chloride at temperatures between −35 and −25° C. Alternatively a methoxy group may also be cleaved using Brønsted acids with or without a solvent. Preferably pyridine hydrochloride is used at elevated temperatures without a solvent.
A 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisole.
A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxan or ether.
A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxan at temperatures between 20 and 50° C.
A methoxymethyl group may be cleaved in the presence of an acid such as concentrated hydrochloric acid in a solvent such as dimethoxyethane. Alternatively an acid such as trifluoroacetic acid may also be used without a solvent.
An N-(trimethylsilyl)ethoxymethyl group may be cleaved in the presence of TBAF and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone. Alternatively the SEM protective group may also be cleaved with an acid such as hydrogen chloride in an organic solvent such as dioxane or ethanol.
An allyloxycarbonyl group is cleaved by treating with a catalytic amount of tetrakis-(triphenylphosphine)-palladium(0), preferably in a solvent such as tetrahydrofuran and in the presence of an excess of a base such as morpholine at temperatures between 0 and 100° C., preferably at ambient temperature and under an inert gas, or by treating with a catalytic amount of tris-(triphenylphosphine)-rhodium(I)chloride in a solvent such as aqueous ethanol and optionally in the presence of a base such as 1,4-diazabicyclo-[2,2,2]octane at temperatures between 20 and 70° C.
The following methods of preparing the compounds of general formula Ia according to the invention wherein R1, R2, R3, R4 and R5 are as hereinbefore defined and their precursors have proved particularly suitable:
The preparation of a compound of general formula (1-4), wherein R1, R2, R3 and R4 are as hereinbefore defined and R5 denotes a hydrogen atom, is shown in Scheme 1. A compound of general formula (1-1), wherein Wand R2 are as hereinbefore defined, may be reacted with a compound of general formula (1-2), wherein R3 and R4 are as hereinbefore defined, LG denotes a leaving group and PG denotes a protective group. The leaving group LG may be halides, preferably chlorides and bromides, —SO2CH3, —OSO2CH3, —OSO2C6H4—CH3 or —S—CH3 (—S—CH3 requires further reaction with an organic peroxide in order to be able to be converted into the actual leaving group) etc., but the list is not restrictive. It is most particularly preferable to use chlorides. Protective groups PG for the hydroxy functionality are known to the skilled man or are described in the literature (T. W. Greene, P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Wiley, 1999). A methoxy protecting group is most particularly preferred.
The reaction may be carried out in an inert solvent using an auxiliary base in a temperature range from 0° C. to the reflux temperature of the solvent. The reaction is carried out in a suitable inert solvent, such as tetrahydrofuran, toluene, xylene, dialkylformamide (particularly preferably dimethylformamide), cyclic amides (particularly preferably N-methylpyrrolidone), 1,4-dioxane, acetonitrile or in mixtures of solvents. Examples of suitable auxiliary bases are tertiary amines such as triethylamine or ethyldiisopropylamine, alkali metal carbonates such as potassium carbonate or sodium carbonate, sodium hydride (NaH) or lithium diisopropylamide (LDA). The inert solvent used must be compatible with the base used. Preferably the reaction is carried out in N-methylpyrrolidone, at temperatures between ambient temperature and the reflux temperature of the solvent in the presence of potassium carbonate as auxiliary base. Starting from a compound of general formula (1-3), wherein R1, R2, R3 and R4 are as hereinbefore defined and PG denotes a protective group, a compound of general formula (1-4), wherein R1, R2, Wand R4 are as hereinbefore defined and R5 denotes a hydrogen atom, may be obtained by ether cleavage as shown in Scheme 1. Ethers can be cleaved with Brønsted acids or Lewis acids. It is most preferable to react compounds of general formula (1-3) with pyridine hydrochloride without a solvent at elevated temperatures. Protective groups PG for the hydroxy functionality are known to the skilled man or are described in the literature (T. W. Greene, P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Wiley, 1999). A methoxy protecting group is most particularly preferred.
Compounds of general formula (2-3), wherein R3 and R4 are as hereinbefore defined, LG represents a leaving group and PG represents a protective group, may be synthesised analogously to Scheme 2. The leaving group LG may be halides, preferably chlorides and bromides, —SO2CH3, —OSO2CH3, —OSO2C6H4—CH3 or —S—CH3 (—S—CH3 requires further reaction with an organic peroxide in order to be able to be converted into the actual leaving group) etc., but the list is not restrictive. It is most particularly preferable to use chlorides. Protective groups PG for the hydroxy functionality are known to the skilled man or are described in the literature (T. W. Greene, P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Wiley, 1999). It is most preferable to protect the hydroxy functionality with a methoxy protecting group.
Carboxylic acids of general formula (2-1) wherein PG represents a protective group and LG denotes a leaving group, may be reacted with compounds of general formula (2-2), wherein R3 and R4 are as hereinbefore defined, using standard peptide coupling reagents and a base in an inert solvent to obtain amides of general formula (2-3) (cf e.g. Houben-Weyl, Methoden der Organischen Chemie, vol. 15/2). Inert solvents that may be used are dimethylformamide, N-methylpyrrolidone, dimethoxyethane, dichloromethane, acetonitrile or mixtures of solvents. The preferred solvent is dimethylformamide. Suitable bases are, in particular, amine bases such as e.g. triethylamine or diisopropylethylamine. Suitable coupling reagents may be for example 1H-benzotriazol-1-yl-oxy-tripyrrolidino-phosphonium-hexafluorophosphate (PyBOP), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), ethyl-(3-dimethylamino-propyl)-carbodiimide, O-(1H-benzo-triazol-1-yl)-N,N—N,N-tetramethyl-uronium hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP). The use of TBTU is particularly preferred. The activation of the carboxyl group may also be carried out using a corresponding acid anhydride or acid chloride. The reaction is generally carried out in a temperature range from −20° C. to the reflux temperature of the solvent at normal pressure. It is particularly preferable to use diisopropylethylamine as base and dimethylformamide as solvent.
The compounds of general formula (3-3), wherein R1, R2, R3 and R4 are as hereinbefore defined and R5 denotes a C1-6-alkyl group, may be synthesised analogously to Scheme 3.
A compound of general formula (3-1), wherein R1, R2, R3 and R4 are as hereinbefore defined and R5 denotes a hydrogen atom, may be reacted with a compound of general formula (3-2), wherein alkyl denotes a C1-6-alkyl group and LG denotes a leaving group. The leaving group LG used may be halides, preferably bromides and iodides, —OSO2CH3, —OSO2C6H4—CH3, etc., although this list is not restrictive. The use of iodides is most particularly preferred. The use of methyl iodides is most particularly preferred. The reaction may be carried out in an inert solvent using an auxiliary base in a temperature range from 0° C. to the reflux temperature of the solvent. Dimethylformamide, N-methylpyrrolidone, dimethylsulphoxide, acetonitrile or mixtures of solvents may be used as inert solvents. The preferred solvent is dimethylsulphoxide. Suitable auxiliary bases may be alkali metal carbonates such as potassium carbonate, sodium carbonate or caesium carbonate. The inert solvent used must be compatible with the base used. The use of caesium carbonate is particularly preferred.
In some cases the end product may be further derivatised, e.g. by manipulation of the substituents. These manipulations may be, inter alia, those which are generally known to the skilled man, such as oxidation, reduction, alkylation, acylation and hydrolysis, but need not be restricted to the above.
The new compounds of general formulae Ia and Ib according to the invention may contain one or more chiral centres. If for example there are two chiral centres present, the compounds may occur in the form of two diastereomeric pairs of antipodes. The invention includes the individual isomers as well as the mixtures thereof. The diastereomers may be separated on the basis of their different physico-chemical properties, e.g. by fractional crystallisation from suitable solvents, by high pressure liquid or column chromatography, using chiral or preferably non-chiral stationary phases.
Racemates covered by general formulae Ia and Ib may be separated for example by HPLC on suitable chiral stationary phases (e.g. Chiral AGP, Chiralpak AD). Racemates which contain a basic or acidic function can also be separated via the diastereomeric, optically active salts which are produced on reacting with an optically active acid, for example (+) or (−)-tartaric acid, (+) or (−)-diacetyl tartaric acid, (+) or (−)-monomethyl tartrate or (+) or (−)-camphorsulphonic acid, or an optically active base, for example with (R)-(+)-1-phenylethylamine, (S)-(−)-1-phenylethylamine or (S)-brucine.
According to a conventional method of separating isomers, the racemate of a compound of general formulae Ia and Ib is reacted with one of the abovementioned optically active acids or bases in equimolar amounts in a solvent and the resulting crystalline, diastereomeric, optically active salts thereof are separated using their different solubilities. This reaction may be carried out in any type of solvent provided that it is sufficiently different in terms of the solubility of the salts. Preferably, methanol, ethanol or mixtures thereof, for example in a ratio by volume of 50:50, are used. Then each of the optically active salts is dissolved in water, carefully neutralised with a base such as sodium-carbonate or potassium carbonate, or with a suitable acid, e.g. with dilute hydrochloric acid or aqueous methanesulphonic acid, and in this way the corresponding free compound is obtained in the (+) or (−) form.
The (R) or (S) enantiomer alone or a mixture of two optically active diastereomeric compounds covered by general formulae Ia and Ib may also be obtained by performing the syntheses described above with a suitable reaction component in the (R) or (S) configuration.
The new compounds of general formulae Ia and Ib and the physiologically acceptable salts thereof have valuable pharmacological properties, based on their selective CGRP-antagonistic properties. The invention further relates to pharmaceutical compositions containing these compounds, their use and the preparation thereof.
The new compounds mentioned above and the physiologically acceptable salts thereof have CGRP-antagonistic properties and exhibit good affinities in CGRP receptor binding studies. The compounds display CGRP-antagonistic properties in the pharmacological test systems described hereinafter.
The following experiments were carried out to demonstrate the affinity of the above-mentioned compounds for human CGRP-receptors and their antagonistic properties:
A. Binding Studies with SK—N-MC Cells (Expressing the Human CGRP Receptor)
SK—N-MC membranes (˜20 μg protein) are incubated for 180 minutes at ambient temperature with 50 pM 125I-iodotyrosyl-Calcitonin-Gene-Related Peptide and increasing concentrations of the test substances in a total volume of 250 μl (assay buffer: 10 mM tris, 50 mM NaCl, 5 mM MgCl2, 1 mM EDTA, pH=7.4). The incubation is ended by rapid filtration through GF/B-glass fibre filters treated with polyethyleneimine (0.1%) using a cell harvester. The protein-bound radioactivity is measured using a gamma counter. Non-specific binding is defined as the bound radioactivity after the presence of 1 μM BIBN4096BS during incubation.
The concentration binding curves are analysed using computer-aided non-linear curve fitting.
The compounds mentioned hereinbefore show Ki values 50 μm in the test described.
SK—N-MC cells (˜1000 cells per well) are incubated for 30 minutes in the presence of increasing concentrations of CGRP and different concentrations of the test substance.
The cAMP contents of the samples are determined using an AlphaScreen cAMP assay kit (Perkin Elmer) and the pA2 values of antagonistically acting substances are determined graphically.
The compounds according to the invention exhibit CGRP-antagonistic properties in the in vitro test model described, in a dosage range between 10−12 and 10−4 M.
In view of their pharmacological properties the compounds according to the invention and the salts thereof with physiologically acceptable acids are thus suitable for the acute and prophylactic treatment of headaches, particularly migraine or cluster headaches and tension headaches. Moreover, the compounds according to the invention also have a positive effect on the following diseases: non-insulin-dependent diabetes mellitus (“NIDDM”), cardiovascular diseases, morphine tolerance, diarrhoea caused by clostridium toxin, skin diseases, particularly thermal and radiation-induced skin damage including sunburn, lichen, pruritis, pruritic toxidermies and severe itching, inflammatory diseases, e.g. inflammatory diseases of the joints (osteoarthritis, rheumatoid arthritis, neurogenic arthritis), generalised soft-tissue rheumatism (fibromyalgia), neurogenic inflammation of the oral mucosa, inflammatory lung diseases, allergic rhinitis, asthma, COPD, diseases accompanied by excessive vasodilatation and resultant reduced blood supply to the tissues, e.g. shock and sepsis, chronic pain, e.g. diabetic neuropathies, neuropathies induced by chemotherapy, HIV-induced neuropathies, postherpetic neuropathies, neuropathies induced by tissue trauma, trigeminal neuralgias, temporomandibular dysfunctions, CRPS (complex regional pain syndrome), back pain, and visceral complaints, such as e.g. irritable bowel syndrome (IBS) and inflammatory bowel syndrome. In addition, the compounds according to the invention have a general pain-relieving effect. The symptoms of menopausal hot flushes caused by vasodilatation and increased blood flow in oestrogen-deficient women and hormone-treated patients with prostate carcinoma and castrated men are favourably affected by the CGRP antagonists of the present application in a preventive and acute-therapeutic capacity, this therapeutic approach being distinguished from hormone replacement by the absence of side effects.
Preferably, the compounds according to the invention are suitable for the acute and prophylactic treatment of migraine and cluster headaches, for the treatment of irritable bowel syndrome (IBS) and for the preventive and acute-therapeutic treatment of hot flushes in oestrogen-deficient women.
The dosage required to achieve a corresponding effect is conveniently 0.0001 to 3 mg/kg of body weight, preferably 0.01 to 1 mg/kg of body weight, when administered intravenously or subcutaneously, and 0.01 to 10 mg/kg of body weight, preferably 0.1 to 10 mg/kg of body weight when administered orally, nasally or by inhalation, 1 to 3× a day in each case.
If the treatment with CGRP antagonists and/or CGRP release inhibitors is given as a supplement to conventional hormone replacement, it is advisable to reduce the doses specified above, in which case the dosage may be from ⅕ of the lower limits mentioned above up to 1/1 of the upper limits specified.
The invention further relates to the use of the compounds according to the invention as valuable adjuvants for the production and purification (by affinity chromatography) of antibodies as well as in RIA and ELISA assays, after suitable radioactive labelling, for example by tritiation of suitable precursors, for example by catalytic hydrogenation with tritium or replacing halogen atoms with tritium, and as a diagnostic or analytical adjuvant in neurotransmitter research.
Categories of active substance which may be used in combination include e.g. antiemetics, prokinetics, neuroleptics, antidepressants, neurokinin antagonists, anticonvulsants, histamine-H1-receptor antagonists, β-blockers, α-agonists and α-antagonists, ergot alkaloids, mild analgesics, non-steroidal antiphlogistics, corticosteroids, calcium antagonists, 5-HT1B/1D agonists or other anti-migraine agents which may be formulated together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, into conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, metered dose aerosols or suppositories.
Thus other active substances which may be used for the combinations mentioned above include for example the non-steroidal antiinflammatories aceclofenac, acemetacin, acetyl-salicylic acid, acetaminophen (paracetamol), azathioprine, diclofenac, diflunisal, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, leflunomide, lornoxicam, mefenamic acid, naproxen, phenylbutazone, piroxicam, sulphasalazine, zomepirac or the pharmaceutically acceptable salts thereof as well as meloxicam and other selective COX2-inhibitors, such as for example rofecoxib, valdecoxib, parecoxib, etoricoxib and celecoxib, as well as substances that inhibit earlier or later stages of prostaglandin synthesis or prostaglandin receptor antagonists such as e.g. EP2-receptor antagonists and IP-receptor antagonists.
It is also possible to use ergotamine, dihydroergotamine, metoclopramide, domperidone, diphenhydramine, cyclizine, promethazine, chlorpromazine, vigabatrin, timolol, isometheptene, pizotifen, botox, gabapentin, pregabalin, duloxetine, topiramate, riboflavin, montelukast, lisinopril, micardis, prochloroperazine, dexamethasone, flunarizine, dextropropoxyphene, meperidine, metoprolol, propranolol, nadolol, atenolol, clonidine, indoramin, carbamazepine, phenyloin, valproate, amitryptiline, imipramine, venlafaxine, lidocaine or diltiazem and other 5-HT1B/1D-agonists such as, for example, almotriptan, avitriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan.
Furthermore, CGRP antagonists with vanilloid receptor antagonists, such as e.g. VR-1 antagonists, glutamate receptor antagonists, such as e.g. MGIu5 receptor antagonists, mGlu1 receptor antagonists, iGlu5 receptor antagonists, AMPA receptor antagonists, purine receptor blockers, such as e.g. P2X3 antagonists, NO-synthase inhibitors, such as e.g. INOS inhibitors, calcium channel blockers, such as e.g. PQ-type blockers, N-type blockers, potassium channel openers, such as e.g. KCNQ channel openers, sodium channel blockers, such as e.g. PN3 channel blockers, NMDA receptor antagonists, acid-sensing ion channel antagonists, such as e.g. ASIC3 antagonists, bradykinin receptor antagonists such as e.g. B1 receptor antagonists, cannabinoid receptor agonists, such as e.g. CB2 agonists, CB1 agonists, somatostatin receptor agonists, such as e.g. Sst2 receptor agonists may be added.
The dosage of these active substances is expediently ⅕ of the lowest usually recommended dose to 1/1 of the normally recommended dose, i.e. for example 20 to 100 mg of sumatriptan.
The compounds prepared according to the invention may be administered either on their own or optionally in combination with other active substances for the treatment of migraine by intravenous, subcutaneous, intramuscular, intraarticular, intrarectal, intranasal route, by inhalation, topically, transdermally or orally, while aerosol formulations are particularly suitable for inhalation. The combinations may be administered either simultaneously or sequentially.
Suitable forms for administration are for example tablets, capsules, solutions, syrups, emulsions or inhalable powders or aerosols. The content of the pharmaceutically effective compound(s) in each case should be in the range from 0.1 to 90 wt. %, preferably 0.5 to 50 wt. % of the total composition, i.e. in amounts which are sufficient to achieve the dosage range specified hereinafter.
The preparations may be administered orally in the form of a tablet, as a powder, as a powder in a capsule (e.g. a hard gelatine capsule), as a solution or suspension. When administered by inhalation the active substance combination may be given as a powder, as an aqueous or aqueous-ethanolic solution or using a propellant gas formulation.
Preferably, therefore, pharmaceutical formulations are characterised by the content of one or more compounds of formulae Ia and Ib according to the preferred embodiments above.
It is particularly preferable if the compounds of formulae Ia and Ib are administered orally, and it is also particularly preferable if they are administered once or twice a day. Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.
Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
Syrups containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules. Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.
Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate).
For oral administration the tablets may, of course, contain, apart from the above-mentioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like. Moreover, lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.
It is also preferred if the compounds of general formulae Ia and Ib are administered by inhalation, particularly preferably if they are administered once or twice a day. For this purpose, the compounds of general formulae Ia and Ib have to be made available in forms suitable for inhalation. Inhalable preparations include inhalable powders, propellant-containing metered-dose aerosols or propellant-free inhalable solutions, which are optionally present in admixture with conventional physiologically acceptable excipients.
Within the scope of the present invention, the term propellant-free inhalable solutions also includes concentrates or sterile ready-to-use inhalable solutions. The preparations which may be used according to the invention are described in more detail in the next part of the specification.
As a rule IR, 1H-NMR and/or mass spectra have been obtained for the compounds prepared. Unless stated otherwise, Rf values are determined using ready-made TLC silica gel plates 60 F254 (E. Merck, Darmstadt, Item no. 1.05714) without chamber saturation.
The ratios given for the eluants relate to units by volume of the particular solvents. The units by volume given for NH3 relate to a concentrated solution of NH3 in water. Eluant systems used for TLC:
Unless stated otherwise, the acid, base and salt solutions used in working up the reaction solutions are aqueous systems of the specified concentrations. Silica gel made by Millipore (MATREX™, 35-70 μm) is used for chromatographic purifications. The HPLC data provided are measured under the parameters listed below and using the columns mentioned:
(column temperature: 30° C.; injection volume: 5 μL; detection at 254 nm)
In preparative HPLC purifications, the products are collected either under mass control or by UV detection. The fractions containing product are combined and freeze-dried. The following columns may be used for preparative HPLC separations:
The percentages given relate in each case to the total volume.
In the absence of any more information regarding the configuration, it is unclear whether there are pure enantiomers involved or whether partial or even total racemisation has taken place.
The following abbreviations are used in the test descriptions:
0.965 g (3.00 mmol) TBTU was added at RT to 0.500 g (2.67 mmol) 2-chloro-6-methoxyisonicotinic acid, 0.366 g (2.67 mmol) 5-fluoroindoline and 0.421 mL (3.00 mmol) triethylamine in 10.0 mL DMF. The mixture was stirred for 2 h at RT and then purified by preparative HPLC. The fractions containing the product were combined and evaporated down i.vac.
Yield: 0.700 g (86% of theoretical)
ESI-MS: m/z=307/309 (M+H)+ (CI)
Rt(HPLC): 1.60 min (method C)
At 170° C. 3.0 g (20 mmol) 5-fluoroindolinone were stirred in 10 mL (98 mmol) acetic anhydride for 3 h. After cooling to RT the mixture was poured onto 200 mL ice water, the precipitated substance was suction filtered and washed with 100 mL water. The solid was recrystallised from water and ethanol. The precipitated product was suction filtered, washed with water and dried i. vac.
Yield: 2.4 g (63% of theory)
ESI-MS: m/z=192 (M+H)+
Rt(HPLC): 1.2 min (method C)
At 0° C. to 5° C., 1.14 g (26.0 mmol) sodium hydride (55% in mineral oil) was added batchwise to 2.40 g (12.4 mmol) 1-acetyl-5-fluoro-1,3-dihydroindol-2-one in 30 mL DMF under an argon atmosphere and the mixture was stirred for 1 h. Then 1.91 mL (31.0 mmol) methyl iodide were added dropwise and the mixture was stirred overnight at RT. The reaction mixture was poured onto water and the precipitated substance was suction filtered. The solid was washed with water and dried i. vac.
Yield: 2.1 g (76% of theory)
ESI-MS: m/z=222 (M+H)+
Rt(HPLC): 1.48 min (method C)
2.10 g (9.49 mmol) 1-acetyl-5-fluoro-3,3-dimethyl-1,3-dihydro-indol-2-one in 20 mL isopropanol were refluxed with 50 mL of a aqueous 6M HCl solution for 1 h. After cooling the isopropanol was eliminated i.vac. The residue was diluted with water and cooled with ice. The precipitated substance was suction filtered and washed with water. The solid was dried i. vac.
Yield: 1.40 g (82% of theory)
ESI-MS: m/z=180 (M+H)+
Rt(HPLC): 1.14 min (method C)
Under an argon atmosphere, a solution of 9.30 mL (9.30 mmol) of a 1M solution of lithium aluminium hydride in THF and 10 mL THF was slowly added dropwise to 1.40 g (7.81 mmol) 5-fluoro-3,3-dimethyl-1,3-dihydroindol-2-one in 50 mL THF. Then the reaction mixture was heated to 70° C. for 1 h. After cooling 2 mL water were added. The solution was dried on sodium sulphate and filtered off. The solvent was eliminated i.vac.
Yield: 1.30 g (quant)
ESI-MS: m/z=166 (M+H)+
Rt(HPLC): 0.75 min (method C)
This compound was obtained analogously to (2-chloro-6-methoxypyridin-4-yl)-(5-fluoro-2,3-dihydroindol-1-yl)-methanone from 0.500 g (2.67 mmol) 2-chloro-6-methoxyisonicotinic acid, 0.439 g (2.66 mmol) 5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole and 0.421 mL (3.00 mmol) triethylamine in 10.0 mL DMF.
Yield: 0.600 g (67% of theoretical)
ESI-MS: m/z=335/337 (M+H)+ (CI)
Rt(HPLC): 1.73 min (method C)
was prepared as described in International Patent Application WO 2003/104236.
Yield: 5.20 g (97% of theoretical)
ESI-MS: m/z=218 (M+H)+
Rt 0.08 (silica gel, DCM/MeOH/cyc/NH4OH=70:15:15:2)
General Working Method 1 (GWM 1) for Reacting 2-Chloro-6-Methoxypyridine Derivatives with amine derivatives:
1.0 eq of an amine is stirred with 1.0 eq of a 2-chloro-6-methoxypyridine derivative and 3.0 eq potassium carbonate in NMP (0.41 mmol amine/mL) at 130° C. After the reaction has ended and the reaction mixture has cooled to RT the precipitate formed is filtered off and purified by preparative HPLC. The fractions containing the product are combined and evaporated down i.vac.
The following compounds may be obtained using this GWM:
Under a nitrogen atmosphere a solution of 32.74 g (0.15 mol) BOC anhydride in 100 mL THF was added dropwise at RT to 17.36 g (0.14 mol) 6-chloro-pyridin-2-ylamine and 300 mL (0.30 mol) of a 1 molar sodium hexamethyldisilazide solution in THF in 200 mL THF. The reaction mixture was stirred overnight at RT and then evaporated down. The residue was stirred between EtOAc and 1 N aqueous hydrochloric acid solution. The organic phase was separated off and the aqueous phase was extracted again with EtOAc. The combined organic phases were washed with 300 mL saturated sodium hydrogen carbonate solution, dried and evaporated down. The residue was recrystallised from EtOH, the solid was suction filtered and dried overnight in the drying cupboard at 50° C.
Yield: 29.20 g (95% of theoretical)
ESI-MS: m/z=228 (M+)
Rt(HPLC): 1.70 min (method C)
Under a nitrogen atmosphere 26 mL (173.39 mmol) N,N,N,N-tetramethylenethylene-diamine in 180 mL THF were cooled to −20° C. and within 10 min 70 mL (175 mmol) of a 2.5 molar butyllithium solution were added. After 30 minutes' stirring the reaction mixture was cooled to −78° C. and at this temperature 17.84 g (78.00 mmol) tert-butyl (6-chloro-pyridin-2-yl)-carbamate in 120 mL THF were added dropwise within 20 min. The reaction mixture was stirred for 2.5 h at −78° C. and then combined with 27.22 g (116.70 mmol) Z-piperidone in 60 mL THF within 10 min. After a further hour's stirring at −78° C. the reaction mixture was first of all heated to RT and then stirred for 18 h at 40° C. Then the reaction mixture was decomposed by the dropwise addition of 150 mL saturated sodium hydrogen carbonate solution. Then the reaction mixture was extracted several times extracted with DCM. The combined organic phases were washed with water, dried and evaporated down. The residue was triturated with PE/EtOAc 1/1, the precipitate formed was suction filtered, washed with PE/ETOAc 1/1 and dried.
Yield: 16.40 g (54% of theoretical)
ESI-MS: m/z=388 (M+H)+
Rt(HPLC): 1.57 min (method C)
16.40 g (0.04 mol) benzyl 7′-chloro-2′-oxo-1′,2′-dihydrospiro[piperidine-4,4′-pyrido[2,3d]-[1,3]oxazine]-1-carboxylate and 2.00 g palladium (Pd/C 10%) in 500 mL EtOH were hydrogenated for 6 h at RT in a hydrogen atmosphere. Then 1 g of palladium (Pd/C 10%) were additionally added and the mixture was hydrogenated for a further 3 h at RT in a hydrogen atmosphere. After filtration of the reaction mixture the solvent was eliminated in vacuo. The residue was triturated with EtOH, the precipitate formed was suction filtered, washed with EtOH and dried in the drying cupboard for 3 h at 50° C.
Yield: 5.40 g (50% of theoretical)
ESI-MS: m/z=220 (M+H)+
Rt(HPLC): 0.90 min (method C)
550 mg (2.93 mmol) 4-chloro-6-methoxy-pyridin-2-carboxylic acid, 411 mg (3.00 mmol) 5-fluoroindoline, 1.06 g (3.30 mmol) TBTU and 927 μL (6.60 mmol) triethylamine in 5.00 mL DMF were stirred for 3 h at RT. The reaction mixture was purified by HPLC. The product-containing fractions were combined and evaporated down using the rotary evaporator.
Yield: 450 mg (50% of theoretical)
ESI-MS: m/z=307/309 (M+H)+ (CI)
Rt(HPLC): 1.7 min (method C)
According to General Working Method 1 (GWM 1) 1.0 eq of an amine is reacted with 1.0 eq of a chloro-methoxypyridine derivative and 3.0 eq potassium carbonate in NMP (0.41 mmol amine/mL) at 130° C. After the reaction has ended and the reaction mixture has cooled to RT the precipitate formed is filtered off and purified by preparative HPLC. The product-containing fractions are combined and evaporated down i.vac.
General Working Method 2 (GWM 2) for Converting 6-Methoxypyridine Derivatives into the Corresponding Pyridones:
A well stirred mixture of 1.0 eq of a 6-methoxypyridine derivative and 20 eq pyridine hydrochloride is kept in a melt for 7 min using a hot air blower. After the reaction mixture has cooled it is taken up in DMF and purified by preparative HPLC. The fractions containing the product are combined and lyophilised.
The following pyridones may be obtained using this GWM:
General Working Method 3 (GWM3) for Converting Pyridones into the Corresponding N-Methyl-Pyridone:
1.0 eq of a pyridone is placed in DMSO at RT (0.22 mmol/mL). To this are added 2.45 eq of caesium carbonate and the mixture is stirred for 15 min. Then a solution of 1.0 eq methyl iodide in DMSO is added and the mixture is stirred for 2 h at RT. Another 0.5 eq methyl iodide are added and the mixture is stirred for a further 2 h at RT. The reaction mixture is purified by preparative HPLC. The fractions containing the product are combined and lyophilised.
The following N-methyl-pyridones may be obtained using this GWM:
The following Examples describe the preparation of pharmaceutical formulations that contain as active substance any desired compound of general formulae Ia and Ib:
1 capsule for powder inhalation contains:
The active ingredient is ground to the particle size required for inhaled substances. The ground active ingredient is homogeneously mixed with the lactose. The mixture is transferred into hard gelatine capsules.
1 puff contains:
The active ingredient and benzalkonium chloride are dissolved in water and transferred into Respimat® cartridges.
1 vial contains:
The active ingredient, sodium chloride and benzalkonium chloride are dissolved in water.
1 puff contains:
The micronised active ingredient is homogeneously suspended in the mixture of lecithin and propellant gas. The suspension is transferred into a pressurised container with a metering valve.
The active ingredient and the excipients are dissolved in water and transferred into a suitable container.
Glycofurol and glucose are dissolved in water for injections (Wfl); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with Wfl; transferred into ampoules under nitrogen gas.
Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate are dissolved in water for injections (Wfl); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with Wfl; transferred into ampoules.
Mannitol is dissolved in water for injections (Wfl); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with Wfl; transferred into vials; freeze-dried.
Polysorbate 80 and mannitol are dissolved in water for injections (Wfl); transferred into ampoules.
Active substance, lactose and corn starch are homogeneously mixed; granulated with an aqueous solution of Povidone; mixed with magnesium stearate; compressed in a tablet press; weight of tablet 200 mg.
Active substance, corn starch and silica are homogeneously mixed; mixed with magnesium stearate; the mixture is packed into size for 3 hard gelatine capsules in a capsule filling machine.
Hard fat is melted at about 38° C.; ground active substance is homogeneously dispersed in the molten hard fat; after cooling to about 35° C. it is poured into chilled moulds.
Mannitol is dissolved in water for injections (Wfl); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with Wfl; transferred into ampoules under nitrogen gas.
| Number | Date | Country | Kind |
|---|---|---|---|
| 07121355.7 | Nov 2007 | EP | regional |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 12743015 | Sep 2010 | US |
| Child | 13869388 | US |
