CH616933A5 - Heterocyclic compounds substituted by acylamino groups and process for their preparation - Google Patents

Abstract

Process for the preparation of heteroaryl compounds of formula: <IMAGE> in which the heteroaryl ring Ar is a 5-atom ring containing, as single heteroatoms, two nitrogen atoms and another heteroatom which is sulphur or oxygen, by reaction of an acyl derivative of the Ar-NHCOR<2> type with a compound capable of introducing the group R<1>. The compounds obtained have an antiallergic activity.

Description

The present invention relates to a process for the preparation of heterocyclic chemical compounds, and in particular of new heteroaryl derivatives with 5 atoms, substituted by an acylamino group, useful for the chemical therapy of states of immediate hypersensitivity and / or which are useful as compounds intermediates in the preparation of these active compounds.

Compounds similar to those of the present invention have been previously described for example in "Bull. Soc. Chim. ”, 1219, (1967) and in Belgian Patent No. 736854 and British Patent No. 1333495. However, it should be noted that the descriptions of this type of compound either mention a utility completely different from that possessed by the compounds of the invention, either constitute publications of academic interest in which there is no particular utility.

The compounds obtained according to the process of the invention are useful for the chemical therapy of states of immediate hypersensitivity. They respond to the formula:

Ar-N-R1 (I)

COR2

in which Ar represents a heteroaryl ring with 5 atoms chosen from 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyle, 1,2,4-thiadiazolyle and 1,3,4-thiadiazolyle, this heteroaryl ring being optionally substituted by formyl, carboxyl, hydroxyl, C1_4 hydroxyalkyl, Cui alkyl, C3_10 cycloalkyle, C3_6 acyloxyalkyle, optionally substituted phenyl or halogen, the acylamino group —NR'COR2 being attached to a carbon atom of the heteroaryl ring, and where R1 is C11Q alkyl, C2_6 alkenyl, C2_6 alkynyl, C2.6 alkoxyalkyle, C2_6 carboxyalkyle, Qg haloalkyle, C3.10 cycloalkyle, C3_10 cycloalkyl-Qg alkyl, phenyl-Qg optionally substituted alkyl or phenyl-C2_6 alkenyl possibly substituted, and R2 represents Qg alkyl, CU6 haloalkyle, C2_6 alényle, C3 „io cycloalkyle, C3.10 cycloalkyl-Qg alkyl, phenyl optionally substituted, phenyl-Qg alkyl optionally substituted or phenyl-C2.6 alkenyl optionally substituted, provided that:

a) when Ar is 1,3,4-thiadiazolyl, R1 is C13 alkyl and R2 is C1_1 alkyl, C17 haloalkyl, C2_3 alkenyl or C3_6 cycloalkyle, said 1,3,4-thiadiazolyle group cannot be unsubstituted or substituted by Cj_3 alkyl or halogen;

b) when Ar is 1,3,4-thiadiazolyl substituted with a Ct_4 alkyl group and R2 is trichloromethyl, R1 cannot be C16 alkyl or C2.6 alkenyl;

c) when Ar is 1,3,4-thiadiazolyl substituted by methyl and R1 is p-bromophenyl, R2 cannot be methyl, and d) when Ar is 1,2,4-oxadiazolyl substituted by phenyl, R1 cannot be methyl or benzyl when R2 is methyl.

e) when Ar is 1,2,4-thiadiazolyl substituted by halogen and R1 is C15 alkyl, allyl, C5_7 cycloalkyl or phenyl-C14 alkyl, R2 cannot be methyl, ethyl or trichloromethyl;

f) when Ar is 1,2,4-thiadiazolyl substituted by isopropyl and R1 is C14 alkyl, allyl, C16 haloalkyl or C2_6 alkoxyalkyl, R2 cannot be C14 alkyl, allyl or C16 haloalkyl, and g) when Ar is 1, 3,4-thiadiazolyl substituted with methyl and R1 is allyl, R2 cannot be dichloromethyl.

The above exclusions are intended to eliminate known compounds.

The optional substituent on the heterocyclic ring is preferably chosen from CU4 alkyl, C3-8 cycloalkyl and phenyl. R1 substituents which are preferred are C1-6 alkyl, C3-6 alkenyl, C3-6 cycloalkyl and benzyl optionally substituted with halogen, C1-6 alkyl or C1-4 alkoxy. Preferred R2 substituents are C1-8 alkyl, C3-8 cycloalkyl, benzyl and phenyl optionally substituted by halogen or C1-4 alkoxy.

The expression C ^ alkyl in the present description relates to a straight or branched chain alkyl group containing from 1 to 6 carbon atoms such as methyl, ethyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, n -amyl, s-amyl, n-hexyl, 2-ethyl-butyl or 4-methylamyl.

5

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65

3

616,933

Similarly, the expression alkyl in the present description relates to a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, namely methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, s- butyl, t-butyl. C ^ hydroxyalkyle and C3.6 acyloxyalkyle mean the aforementioned alkyl groups substituted respectively by a hydroxyl or acyloxy group. C2.6 alkoxyalkyle and Cj.g haloalkyle mean CU6 alkyl groups mentioned above substituted by an alkoxy group or by one or more halogen atoms such as methoxyethyl, ethoxyethyl, ethoxybutyl, dibromomethyl, trifluoromethyl, 1-chloroethyl, 1,1-dichloroethyl , 1-iodo-butyl or pentafluoroethyl.

The expression C2.6 alkynyl used in the present description relates to an alicyclic hydrocarbon group comprising from 2 to 6 carbon atoms which also contains a group - C = C—. However, it should be noted that the group —C = C— cannot be directly adjacent to the nitrogen atom of the acylamino group.

C3-10 cycloalkyle signifies a saturated ring containing from 3 to 10 carbon atoms in the ring such as cyclopropyle, cyclo-butyle, cyclopentyle, cyclooctyle or adamantyle. C3.10 cycloalkyl-Q.g alkyl concerns the above-mentioned saturated rings attached to a C1-6 alkylene bridge.

The expression phenyl optionally substituted in the present description relates to a phenyl group which is unsubstituted or substituted by one or more groups which do not essentially modify the pharmacological activity of the compounds of formula (I) such as the halogen, trifluoromethyl, methyl, methoxy or nitro.

The expression C2.6 carboxyalkyl in the present description relates to a group C ^ s alkyl substituted by a carboxylic acid group. Examples of such groups are carboxymethyl, carboxyethyl, carboxypropyl and carboxybutyl.

The chemist will understand that heteroaryl rings with 5 atoms containing as only hetero atoms two nitrogen atoms and another hetero atom chosen from oxygen and sulfur comprise the ring systems 1,2,4- and 1,3,4-oxadiazolyle and 1,2,4- and 1,3,4-thiadiazolyle.

The compounds of the invention with these heterocyclic rings can be represented by the structural formulas:

(VII)

NR1C0R2

where R1 and R2 are as defined above and R is hydrogen or an optional substituent on the heteroaryl ring.

Particularly interesting compounds of formulas (I) to (VII) are those in which the heteroaryl group is substituted by a group Q.4 alkyl, in particular methyl, R1 is Qg alkyl, in particular C4.6 alkyl, C3_5 alkenyl or benzyl and R2 is C3_6 alkyl, C3_ "cycloalkyl or benzyl.

The invention relates to a process for the preparation of compounds of formula (I) as defined above, characterized in that it comprises the reaction of an acyl derivative of formula:

ArNHCOR2

(IX)

R

■ N

NOT

-0 "

NR COR

1 2 NR COR

1 2 NR COR

1 2 NR COR

1 2 NR COR

in which Ar is 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl and 1,3,4-oxadiazolyl, and R2 is as defined above with a compound capable of introducing the group R '.

The reaction of the compounds of formula (IX) can be carried out by dissolving the amide in a suitable inert anhydrous polar solvent such as dimethylformamide, by forming an alkali metal salt of this compound using an alkali metal hydride, preferably sodium hydride and by subsequent treatment of the salt with an alkylating agent of formula R'X1 where X1 is a reactive atom such as a halogen atom or a reactive group such as an alkyl sulfate group.

Different agents for introducing the group R ′ and reaction conditions other than those mentioned above can be used, the nature of these agents and these conditions being well known to practitioners.

The derivatives of formula (IX) can be obtained from corresponding amines of formula ArNH2 by conventional alkylation or acylation techniques. The co-haloacylamino derivative of formula (XII) can be obtained by reaction of the amine of formula ArNH2 with an appropriate o-haloacyl halide.

The amines of formula ArNH2 constitute either known compounds or can be prepared by modification of known synthetic methods.

The intermediate compounds of formula (IX), with the exception of

(II) case where:

a) Ar is 1,2,4-thiadiazolyl unsubstituted or substituted by C1.4

45 alkyl, C3.10 cycloalkyl or phenyl optionally substituted and

R2 is C1-4 alkyl or Q.4 haloalkyl;

b) Ar is 1,2,4-oxadiazolyl substituted with phenyl and R2 is

(III) Ci.8 alkyl, constitute new compounds.

The compounds of formula (I) appeared useful for the prophylactic and therapeutic treatment of immediate hypersensitivity disorders including asthma and to avoid the asthmatic state (status asthmaticus). The products have low toxicity.

The compounds of formula (I) or the preparations containing these 0 ^) compounds can be administered orally and rectally, topically, parenterally, for example by injection or by continuous or discontinuous intra-arterial infusion, and this, for example tablets, diamonds, sucking tablets, sachets, cachets, elixirs, suspensions, aerosols, ointments, for example containing from 1 to 10% by weight of the active compound in a suitable base, hard or soft gelatin capsules, suppositories, injection solutions and suspensions in physiologically acceptable media and packaged powders sterile adsorbed on a support material to make injection solutions. Advantageously, for this purpose, the compositions can be supplied in unit dosage form, each dosage unit (VI) preferably containing from 5 to 500 mg (from 5 to 50 mg in the case of parenteral administration, from 5 50 mg in the case of inhalation and 25 to 500 mg in the case of oral or rectal administration)

(V)

616933

4

of a compound of formula (I). Dosages of the order of 0.5 to 300 mg / kg / day, preferably 0.5 to 20 mg / kg of active ingredient can be administered, although it will be understood that the amount of the component (s) of formula ( I) which are effectively administered will be determined by the attending physician having regard to the particular circumstances, including the condition to be treated, the choice of the compound to be administered and the choice of the route of administration.

In the present description, the expression unit dosage form applies to a physically limited unit ^ containing an individual amount of the active component, generally in admixture with a pharmaceutical diluent for it or in another way, in association with a pharmaceutical carrier, the amount of the active component being such that one or more units are normally necessary for a single therapeutic administration or, in the case of units which can be divided, such as scored tablets, at least one part such as half or a quarter of a divisible unit is necessary for a single therapeutic administration.

The pharmaceutical compositions will normally contain at least one compound of formula (I) mixed with a support or diluted by a support or else enclosed or encapsulated in an ingestible support in the form of a capsule, a sachet, a cachet , paper or other container or in a disposable container such as an ampoule. The support or diluent can be a solid, semi-solid or liquid material which serves as a vehicle, excipient or medium for the substance with therapeutic activity.

Some examples of diluents or carriers which can be used in pharmaceutical compositions are the following: lactose, dextrose, sucrose, sorbital, mannitol, pro-pylene glycol, liquid paraffin, soft white paraffin, kaolin, fumed silicon dioxide, microcrystalline cellulose, calcium silicate, silica, polyvinylpyrrolidine, cetostearyl alcohol, starch, modified starches, acacia gum, calcium phosphate, cocoa butter , ethoxylated esters, theobromine oil, peanut oil, alginates, tragacanth, gelatin, BP syrup, methylcellulose, polyoxyethylene sorbitan mono-laurate, ethyl lactate, l propyl methyl benzoate, sorbitan trioleate, sorbitan sesquioleate and oleyl alcohol and propellants such as trichloromonofluoromethane, dichlorodifluoro-methane and dichlorotetrafluoroethane. In the case of tablets, a lubricant can be incorporated to prevent the powdered components from sticking to the mold and the punch of the pelletizer. For this purpose, it is possible to use, for example, aluminum, magnesium or calcium stearates, talc or mineral oil.

Preferred dosage forms are capsules, tablets, suppositories, aerosols, injectables, creams and ointments.

R

Claims (4)

616,933 1. Process for the preparation of a heteroaryl compound of formula: T. Ar-N-R1 (I) COR2 in which Ar represents a heteroaryl ring with 5 atoms chosen from 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyle, 1,2,4-thiadiazolyle and 1,3,4-thiadiazolyle, this heteroaryl ring being optionally substituted by formyl, carboxyl, hydroxyl, C ^ hydroxyalkyl, C1.4 alkyl, C3.10 cycloalkyl, C3.6 acyloxyalkyl, optionally substituted phenyl or halogen, the acylamino group - NR1 COR2 being attached to a carbon atom of the heteroaryl ring , and where R1 is Q.jo alkyl, C2.6 alkenyl, C2.6 alkynyl, C2_6 alkoxy-alkyl, C2.6 carboxyalkyl, C ^ haloalkyle, C3.10 cycloalkyle, C3.10 cycloalkyl-C1.6 alkyl, phenyl -Ci.g optionally substituted alkyl or phenyl-C2_6 alkenyl optionally substituted and R2 represents Qg alkyl, Qg haloalkyl, C2.6 alkenyl, C3.10 cycloalkyle, C3.10 cycloalkyl-C1.6 alkyl, optionally substituted phenyl, phenyl-Cj .6 optionally substituted alkyl or phenyl-C2_6 optionally substituted alkenyl, provided that: a) when Ar is 1,3,4-thiadiazolyl, R1 is Cx.3 alkyl and R2 is Cj.7 alkyl, Q.? haloalkyl, C2-3 alkenyl or C3-3 cycloalkyl, said 1,3,4-thiadiazolyl group may not be unsubstituted or substituted by C1-3 alkyl or halogen; b) when Ar is 1,3,4-thiadiazolyl substituted by an alkyl group and R2 is trichloromethyl, R1 cannot be Cj_6 alkyl or C2_6 alkenyl; c) when Ar is 1,3,4-thiadiazolyl substituted by methyl and R1 is p-bromophenyl, R2 cannot be methyl; d) when Ar is 1,2,4-oxadiazolyl substituted with phenyl, R1 cannot be methyl or benzyl when R2 is methyl; e) when Ar is 1,2,4-thiadiazolyl substituted by halogen and R1 is C1.5 alkyl, allyl, C5.7 cycloalkyl or phenyl-C ^ -alkyl, R2 cannot be methyl, ethyl or trichloromethyl; f) when Ar is 1,2,4-thiadiazolyl substituted by isopropyl and R1 is Cj.4 alkyl, allyl, Cu6 haloalkyle or C2_6 alkoxyalkyle, R2 cannot be CU4. alkyl, allyl or CU6 haloalkyl, and g) when Ar is 1,3,4-thiadiazolyl substituted by methyl and R1 is allyl, R2 cannot be dichloromethyl, characterized in that it comprises the reaction of an acyl derivative of formula: ArNHCOR2 (IX) in which Ar is 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyle and 1,3,4-oxadiazolyle, and R2 is as defined above with a compound capable of introducing the group R '. 2. Method according to claim 1, characterized in that Ar is optionally substituted by a group chosen from Cw alkyl, C3.8 cycloalkyl and phenyl; R1 is C1.8 alkyl, C3_6 alkenyl, C3_g cycloalkyl or benzyl optionally substituted by halogen, C1.4 alkyl or Ct_4 alkoxy and R2 is C ^ g alkyl, C3_8 cycloalkyl, benzyl or phenyl optionally substituted by halogen or Q.4 alkoxy. 2 3. Method according to claim 1, characterized in that the heteroaryl ring Ar is substituted by an alkyl group; R1 is C1.6 alkyl, C3_5 alkenyl or benzyl and R2 is C3_6 alkyl, C3_e cycloalkyl or benzyl. 4. Method according to one of claims 1 to 3, characterized in that the heteroaryl ring is the 1,2,4-oxadiazolyl system.