59528-86-8Relevant articles and documents
4-Aminoquinoline derivatives
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, (2008/06/13)
The disclosure describes new 4-aminoquinoline derivatives of general formula SPC1 And their acid addition salts, where X is a halogen atom or a trifluoromethyl group, Z is a hydrogen atom or a defined substituent, R is group of the formula Or where A in formula II is a chain of 1 to 5 methylene groups which may be substituted with alkyl, the ring in formula IIIa and IIIb is a piperidine or pyrrolidine ring that may be substituted with alkyl and R1, R2 and R3 represent hydrogen or certain defined substituents. The new 4-aminoquinoline derivatives show anti-hypertensive activity and, in some cases, show one or more of the following activities: anti-malarial activity, anti-inflammatory activity, anti-trichomonal activity and inhibition of blood platelet aggregation. The present invention concerns new 4-aminoquinoline derivatives, a process for their preparation and pharmaceutical compositions containing them. The invention also concerns new intermediates useful for the preparation of the 4-aminoquinoline derivatives. The invention provides new 4-aminoquinoline derivatives of the general formula SPC2 And their acid addition salts, where I. X is a halogen atom or a trifluoromethyl group; Ii. Z is a hydrogen atom or a halogen atom, a trifluoromethyl group, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a nitro group, an amino group or a mono- or di-alkyl substituted amino group, and Iii. R represents a group of the formula --NR3 --A--NR1 R2 (II) or SPC3 Wherein: A. in formula II, A represents a chain of 1 to 5 methylene groups, which may be substituted by one or more alkyl groups; B. in formula IIIa and IIIb the ring denotes a piperidine or pyrrolidine ring that may be substituted by one or more alkyl groups or by a divalent aliphatic chain substituting two different ring members of the piperidine or pyrrolidine ring; C. R1 represents a hydrogen atom, an alkyl group, an aralkyl group, an acyl group or an aryl group or, in formula II or IIIb, R1 and R2 may together form the diacyl residue of a dicarboxylic acid or R1 and R2 may together form a divalent radical such that R1 R2 NH is a secondary cyclic amine with 5 to 7 ring atoms; D. R2 is as defined above in connection with R1 or represents a hydrogen atom, an alkyl group, an aralkyl group or an acyl group; and E. R3 represents a hydrogen atom, a cycloalkyl group of 5 to 7 carbon atoms, an alkyl group, an aralkyl group, or an alkyl group substituted by a heterocyclic group, or an aliphatic chain joining the nitrogen atom member to another ring member of the ring in formula IIIa. The invention also provides a new class of compounds useful as intermediates for the preparation of compounds of formula I and their acid addition salts. These new compounds are benzenesulphonamides having the formula SPC4 and their acid addition salts, where R is as defined in connection with formula I, Z is as defined in connection with formula I or is a protected amino or hydroxyl group and Y is a hydrogen atom or a lower alkanoyl group. It will be apparent to those skilled in the art that the above definition of R includes moieties possessing an asymmetric carbon atom, especially for instance, in the cases where 1. A is linear chain of 1 to 15 methylene groups, the chain being monosubstituted by methyl or ethyl, or 2. R is of the formula V or VI SPC5 for example, in the cases where R denotes groups of the formula SPC6 where R1, R2 and R3 may be, for instance, hydrogen or lower alkyl. It is to be understood that general formulae I and IV are intended to encompass both enantiomers where the compound contains an asymmetric carbon atom and mixtures of the enantiomers, for instance, a racemic mixture of the enantiomers. General methods are recorded in the literature for the resolution of enantiomers. In the compounds of formula I, X preferably represents a halogen atom, for example, a chlorine or bromine atom, but may also represent a trifluoromethyl group. Illustrative meanings of Z in formulae I and IV include hydrogen, chlorine, bromine atoms and trifluoromethyl, lower alkyl or alkoxy (for example, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy and butoxy), hydroxyl, nitro, amino, methylamino, ethylamino, dimethylamino and diethylamino groups. Additionally in formula IV, Z may be protected amino or protected hydroxyl group, for example a group of the formula IX SPC7 In formulae II and IIIb R1 and R2 may be separate or may be joined together to form a divalent residue. The divalent residue is a diacyl residue of a dicarboxylic acid, for example, a group of the formula --CO--(CH2)n --CO-- where n is 2 or 3, or SPC8 or is such that R1 R2 NH is a secondary cyclic amine with 5 to 7 ring atoms, for instance, piperidine, pyrrolidine or morpholine. R1, when in formula IIIa or when separate from R2 in formula II or IIIb, represents a hydrogen atom, an alkyl group, an aralkyl group, an acyl group or an aryl group, R2, when separate from R1 in formulae II and IIIb, represents a hydrogen atom, an alkyl group, an aralkyl group or an acyl group. R3 in formulae II and IIIa represents a hydrogen atom, a cycloalkyl group of 5 to 7 carbon atoms, an alkyl group, an aralkyl group, or an aliphatic chain joining the nitrogen ring atom to another ring atom of the ring shown in formula IIIa. Illustrative examples of such groups that can be denoted by R1, R2 or R3 will now be described. Alkyl groups are desirably lower alkyl groups, for example, methyl, ethyl, n- or i-propyl and n-butyl. Aryl groups particularly comprehend phenyl or phenyl substituted by one or more substituents. As substituents for a phenyl group there may be employed lower alkyl (for example, methyl, ethyl, propyl or butyl), lower alkoxy (for example, methoxy, ethoxy, propoxy or butoxy), nitro, halogen, (preferably chlorine or bromine), hydroxy, trifluoromethyl or amino (including mono- or dialkylamino, for instance, dimethylamino). Aralkyl groups are arylsubstituted alkyl groups, where the alkyl group is desirably a lower alkyl group (e.g. methyl, ethyl, propyl or butyl) and its aryl substituent may be phenyl or substituted phenyl, in which the one or more substituents for phenyl are as mentioned above. Acyl groups particularly include the acyl groups of the formula -- CO.R5 where R5 represents alkyl or aryl. As specific acyl groups there may be mentioned, for example, acetyl, propionyl, butanoyl, hexanoyl, benzoyl and benzoyl substituted by one or more of the above mentioned substituents for phenyl. As cycloalkyl of 5 to 7 carbon atoms there may be mentioned cyclopentyl, cyclohexyl and cycloheptyl. As alkyl substituted by a heterocyclyl group there may be mentioned lower alkyl such as methyl, ethyl, propyl or butyl, substituted by thienyl (for instance 2-thienyl), furyl, pyrrolyl, imidazolyl, pyrazolyl (for instance 4-pyrazolyl), indolyl, pyridyl (for instance 2- or 4-pyridyl), quinolyl, thiazolyl (specifically 2-, 4- or 5-thiazolyl), isothiazolyl or oxazolyl. As examples of A in formula II there may be mentioned methylene, dimethylene, trimethyleme, tetramethylene and pentamethylene and their mono- or di-(lower alkyl) substitution products, for example, groups of the formulae EQU1 The piperidine of pyrrolidine ring shown in formulae IIIa and IIIb may be substituted with one or more alkyl groups, preferably lower alkyl groups, for example, methyl, ethyl, propyl or butyl. As examples of R containing a piperidine or pyrrolidine ring there may be mentioned groups of the formula: SPC9 where m is 0 or 1; R1, R2 and R3 are as defined above; and R6, R7, R8 and R9, which may be the same or different may be hydrogen or lower alkyl, for instance, methyl, ethyl, propyl or butyl. In formula IV the symbol Y denotes a hydrogen atom or a lower alkanoyl group, for example, acetyl, propionyl, butanoyl or hexanoyl. In formulae I and IV the -- SO3 R group is preferably at the para-position relative to the 7-substituted-4-quinolylamino group in formula I and the group Y--NH-- in the case of formula IV. Thus the preferred new compounds of the invention are those of the formulae Ia and IVa SPC10 The term "lower" as used herein in connection with such groups as "alkanoyl", "alkyl" or "alkoxy" denotes that the group contains up to 6 carbon atoms, preferably up to 4 carbon atoms. Examples of acid addition salts are those formed from inorganic and organic acids and in particular include sulphate, hydrochloride, hydrobromide, hydroiodide, nitrate, phosphate, sulphonate (such as the methanesulphonate and p-toluene-sulphonate), acetate, maleate, fumarate, tartrate, malonate, citrate and formate. The compounds of the formula I may be made by building the compound up by known reactions. In particular the sulphonamide linkage shown in formula I may be formed by sulphonylation of an appropriate amine, and an amino-benzene sulphonamide may be converted to the secondary amine by introducing the 7-(halo or trifluoromethyl)-4-quinolyl group in known manner. The invention provides a method of making compounds of the formula I and their acid addition salts, wherein a compound of the formula RH, where R is as defined in connection with formula I, or, where necessary or desired, a corresponding compound with a protecting group, is sulphonylated to introduce the sulphonyl group of formula XIV SPC11 where X is defined in connection with formula I and Z is as defined in connection with formula IV. As sulphonating agent there may particularly be used a sulphonyl chloride of formula XV SPC12 where X is as defined above and Z is as defined in connection with formula IV. Alternatively, a compound of the formula XVI SPC13 (where R and Z are as defined in connection with formula IV is reacted with a compound of formula (XVII) SPC14 (where X is as defined above in connection with formula I and Q denotes a group or atom replaceable by nucleophilic attack by compound of formula XVI). Q is for example, an iodine atom, a bromine atom or a chloride atom or an organosulphonate group, for instance, p-toluenesulphonate. Where necessary or if desired, the process may also include removal of a protecting group, and if desired, conversion of a free base form of compound of formula I into an acid addition salt or conversion of an acid addition salt form of a compound of formula I into the corresponding free base form. Starting materials of formula RH and formulae XV are known compounds or, if new, are accessible by conventional methods. The sulphonylation method may be carried out by reacting the compound of formula XV with the compound of formula RH or a corresponding compound with a protecting group in chloroform in the presence of a saturated sodium carbonate solution. It will be apparent to those skilled in the art that certain unacylated compounds of formula RH may present more than one potentially reactive location for sulphonylation. Undesired sulphonylation may be avoided by chemical protection with removable blocking groups or other means. For example, the compounds of the formula SPC15 (wherein n is 0 or 1) may be sulphonylated at the ring nitrogen atom by using a starting material in which the NH2 function is protected with a blocking group which is removed after acylation. Compounds of formula I and their acid addition salts, in which, in formula IIIa, R3 denotes hydrogen, may be prepared by using, for example, a benzyl group as removable protecting group. Thus a starting compound of formula: SPC16 in which R3 is benzyl is sulphonylated and the protecting group is removed after sulphonylation by debenzylation. Debenzylation may be carried out using sodium in liquid ammonia or by catalytic hydrogenation under conditions such that the 7-halo- or 7-trifluoromethyl substituents on the quinolyl group is not removed. In addition, compounds of formula RH include compounds where a substituent on an aryl group or heterocyclyl group is susceptible to sulphonylation, e.g. a free hydroxyl or amino substituent. Such substituents may be protected with a removable blocking group which is cleaved off after sulphonylation. Sulphonylating derivatives for introducing the group of formula XIV include protection for a group Z sensitive to sulphonylation. For example, a final product in which Z is an amino function can be formed by using a sulphonylating derivative of the acid formula XX. SPC17 and, after sulphonylation, converting the phthalimido group to an NH2 group by reaction with hydrazine. The new compounds of the invention are comparatively stable to hydrolysis and therefore favour protecting groups that are readily hydrolysed off under acid or basic conditions. Compounds of the formula IV and their acid addition salts are accessible by a process wherein a compound formula RH where R is as defined in formula I, or a corresponding compound with a protecting group, is sulphonylated to introduce the sulphonyl group of formula: SPC18 where Y' is a lower alkanoyl group and Z is as defined above in connection with formula IV. The sulphonylating agent used is preferably the sulphonyl chloride of formula: SPC19 where Y' and Z are as defined in formula XXI. The corresponding sulphonylation product has the formula: SPC20 This product may be isolated as such or as an acid addition salt. This product may then be converted to the compound of formula XVI SPC21 by hydrolysis, preferably under alkaline conditions, to remove the lower alkanoyl group Y'. The compound of formula XVI may be recovered as the free base or as an acid addition salt. The reaction of the primary amine XVI with the compound of formula XVII may be carried out at elevated temperature in the presence of a suitable acidic solvent for example phenol or dilute hydrochloric acid. The reaction products may be recovered from the reaction mixtures by standard isolation procedures. In certain cases it is expedient to incorporate a protecting group for amino in the compound of formula XVI to reduce or preclude undesired reaction of the compounds of formula XVII with a primary or secondary amino function in the group R. In such cases the protecting group is removed after the reaction with the compound of formula XVII. The compounds of formula I may be isolated in free base form or as an acid addition salt. Acid addition salts may be converted into the free base in conventional manner. The free base forms may be converted into acid addition salts in conventional manner, for instance, by adding ethereal hydrogen chloride to a solution of the free base where a hydrochloride salt is desired. The sulphonylating agents used for reaction with a compound of formula RH can be prepared in known manner from the corresponding sulphonic acid. The sulphonic acid may be prepared by reacting an aminobenzene -sulphonic acid of the formula: SPC22 where Z is as defined in connection with formula IV with a compound of formula XVII SPC23 where X is a halogen atom or a trifluoromethyl group and Q is a group or atom replaceable by nucleophilic attack by the compound of formula XXIV. Q is for example, an iodine, bromine or chlorine atom. The secondary amine reaction product may be isolated as such or in the form of one of its salts. It may be purified salt formation and liberating the acid from the salt. The sulphonic acid or its salt may be converted into sulphonylating derivatives of the acid in known manner. For example the sulphonyl chloride of formula XV may be formed by reacting the corresponding sulphonic acid with thionyl chloride in the presence of dimethylformamide as catalyst. Some of the compounds of formula I may also be prepared by another method using the amide of the general formula XXV SPC24 where X is as defined above and Z is as defined in respect of formula IV. The amide can be prepared by reaction of the sulphonyl chloride of formula XV with ammonium hydroxide solution and isolated from the reaction mixture. The invention also provides a process for the preparation of a compound having general formula I wherein R is a group of formula II or IIIa and their acid addition salts. The compounds wherein R is a group of formula II and R3 is a hydrogen atom and wherein R is a group of formula IIIa whilst R1 is a hydrogen atom can be obtained by alkylation of the amide of formula XXV in aqueous or alcoholic alkaline solution. By means of this alkylation the group --A--NR1 R2 or the group SPC25 is introduced. The alkylating agent used is preferably the halide of formula: where Hal stands for a halogen atom preferably chlorine, bromine or iodine. Alternatively the corresponding sulphonates or organosulphonates may be used as alkylating agents. The compounds of formula I where R has formula II and R3 is an alkyl group, an aralkyl group or an alkyl group substituted by a heterocyclic group may be prepared by two successive alkylations of the amide of formula XXV, each carried out in aqueous or alcoholic alkaline solution. In this case the alkylation carried out to introduce the group R3 is preferably the second of the two reactions. Thus, for example, compounds of formula I where R is a group of formula II may be prepared by the reaction sequence SPC27 where Qu is the 7-(halo or trifluoromethyl)-4-quinolyl residue. Similarly the compounds of formula I where R is a group of formula IIIa and R1 is an alkyl or aralkyl group may be prepared by two successive alkylations of the amide of formula XXV in aqueous or alcoholic alkaline solution. One such alkylation introduces the group SPC28 whilst the other introduces the group R1. The reaction medium used for the alkylation of the amide of formula XXV may be an aqueous solution of sodium or potassium hydroxide. Alternatively the alkaline solution may be prepared from a lower alkanol, for example ethanol. The products of the alkylation steps may be recovered as such or as the acid addition salts in accordance with conventional isolation procedures. The compounds of formula I and their pharmaceutically acceptable acid addition salts are indicated for pharmacological usage and, in some cases, for use as intermediates for the preparation of other compounds of formula I. For instance, the compounds of formula I demonstrate anti-hypertensive activity and, in some cases, also demonstrate at least one of the following activities: anti-malarial activity, anti-inflammatory activity, anti-trichomonal activity and inhibition of blood platelet aggregation. For example, in addition to their anti-hypertensive activity, 4-(7-chloro-4-quinolyamino)-N-(1-ethyl-3-piperidyl)benzenesulphonamide shows anti-inflammatory activity, anti-trichomonal activity and inhibition of blood platelet aggregation and 4-dimethylamino-1-[4-(7-chloro-4-quinolyamino)-benzenesulphonyl]-piperdine shows anti-malarial and anti-trichomonal activity. The compounds are evaluated for their activity by testing in standard procedures. Some of the compounds of the invention may also be used as intermediates for the preparation of other compounds conforming with formula I. For example, compounds containing a phthalimido group as --NR1 R2 in formula II or IIb may be subjected to cleavage using hydrazizne to form a corresponding compound containing an amino group (--NH2) as --NR1 R 2 and compounds containing an amino group may be alkylated to form a corresponding compound with an alkyl-substituted amino groups. The invention also includes pharmaceutical compositions containing as active ingredients a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof, which may be micronised if desired. In addition to the active ingredient, said compositions also contain a non-toxic carrier. Any suitable carrier known in the art can be used to prepare the pharmaceutical compositions. In such a composition, the carrier may be a solid, liquid or mixture of a solid and a liquid. Solid form compositions include powders, tablets and capsules. A solid carrier can be one or more substances which may also act as flavoring agents, lubricants, solubilisers, suspending agents, binders, or tablet-disintegrating agents; it can also be an encapsulating material. In powders the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5 to 99, preferably 10-80% of the active ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, and cocoa butter. The term "composition" is intended to include the formulation of an active ingredient with encapsulating material as carrier to give a capsule in which the active ingredient (with or without other carriers) is surrounded by carrier, which is thus in association with it. Similarly cachets are included. Sterile liquid form compositions include sterile solutions, suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable sterile liquid carrier, such as sterile water, sterile organic solvent or a mixture of both. Preferably a liquid carrier is one suitable for parenteral injection. Where the active ingredient is sufficiently soluble it can be dissolved in normal saline as a carrier; if it is too insoluble for this it can be dissolved in a suitable organic solvent, for instance aqueous propylene glycol or polyethylene glycol solutions. Aqueous propylene glycol containing from 10 to 75% of the glycol by weight is generally suitable. In other instances compositions can be made by dispersing the finely-divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution, or in a suitable oil, for instance arachis oil. Liquid pharmaceutical compositions which are sterile or suspensions can be utilised by intramuscular, intraperitoneal or subcutaneous injection. In many instances a compound is orally active and can be administered orally either in liquid or solid composition form. Preferably the pharmaceutical composition is in unit dosage form. In such form, the composition is sub-divided in unit doses containing appropriate quantities of the active ingredient; the unit dosage form can be a packaged composition, the package containing specific quantities of compositions, for example packeted powders or vials or ampoules. The unit dosage form can be a capsule, cachet or tablet itself, or it can be the appropriate number of any of these in package form. The quantity of active ingredient in a unit dose of composition may be varied or adjusted from 5 mg. or less to 500 or more, according to the particular need and the activity of the active ingredient. The invention also includes the compounds in the absence of carrier where the compounds are in unit dosage form.
