FR2823748A1 - New 1-(heterocyclyl-alkyl)-4-(phenyl or pyridyl)-tetrahydropyridines, are tumor necrosis factor-alpha synthesis inhibitors useful for treating autoimmune or inflammatory diseases or pain - Google Patents

Abstract

1-(Benzoheterocyclyl-alkyl)-4-(phenyl or pyridyl)-1,2,3,6-tetrahydropyridine derivatives (I) are new. Tetrahydropyridine derivatives of formula (I) and their N-oxides, salts and solvates are new. X = CH or N; R1 = H, halo or CF3; R2, R3 = H or Me; m, n = 0 or 1; A = nitrogen-containing benzo-group of formula (a) - (i); R4 - R6 = H or 1-4C alkyl; R7, R8 = H, halo, 1-4C alkyl or 1-4C alkoxy; dotted line = optional bond; provided that if X = CH, then group A (a) is not indol-4-yl. Independent claims are included for: (1) the preparation of (I); and (2) the use of compounds (I) without the proviso (or their N-oxides, salts or solvates) in the preparation of medicaments for use as analgesics and/or treatment of diseases associatd with immunological and inflammatory disorders.

Description

inflammatory phase.

  / iA R. [O] o The present invention relates to new tetrahydropyridylalkyl beuzodiazines, pharmaceutical compositions containing them and a process

for their preparation.

  US S, 118,691 and US 5,620,988 describe tetrahydropyridines, substituted by a quinolyl-3-alkyl radical, showing dopaminergic activity. It has now been found that certain phecyl- and pyridyl tetrahydropyridines, substituted by benzodiazines, have a powerful activity vis-à-vis the modulation of TNF-alpha (from English Tumor

Necrosis Factor).

  TNF-alpha is a cytoLine which has recently aroused interest as a mediator of immunity, inflammation, cell proliferation, fibrosis etc. This mediator is abundantly present in inflamed 1S synovial tissue and plays an important role in the pathogenesis of autoimmunity

  (Annu. Rep. Med. Chem., 1997, 32: 241-250).

  Thus, the present invention relates, according to one of its aspects, tetrahydropyridyl-alkyl-benzodiazines of formula (I): A R; [o] o 1 (I) in which X represents N or CH; R1 represents a hydrogen or halogen atom or a CF3 group; R2 and R3 independently represent a hydrogen atom or a methyl group; n isWhere l; A represents a 1,2-, 1,3-, 1,4- or 2,3-benzodiazine of formula (a) - (d): R5

R4 R4

(a) (b)

{: R5 N

  R4 (c) (d) o R4 and Rs each independently represent a hydrogen or halogen atom, a (C, -C,) alkyl or (C, -C4) alkoxy group;

  as well as their N-oxides and their salts or solvates.

  In the present description, the term "(C, -C4) alkyl" denotes a radical

  monovalent of a saturated straight or branched chain C, -C4 hydrocarbon and the term "(C-C4) alkoxy" denotes a monovalent radical of a saturated straight or branched chain saturated C, -C4 hydrocarbon linked by intermediary of an oxygen atom

  In the present description, the term "halogen" denotes a chosen atom

  among chlorine, bromine, iodine and fluorine.

  Preferred compounds are those where n is zero.

  Other preferred compounds are those where R2 and R3 are each H.

  Other preferred compounds are those where R. is a CF3 group.

  Other preferred compounds are those where X is CH and R. is in the position

2 or 3 of benzene.

  Other preferred compounds are those where X is CH and R. is a group CF3.

  Other preferred compounds are those where X is N and pyridine is substituted

in positions 2.6.

  Other preDerated compounds are those where R4 and R. each represent H or

a (C, -C4) alkyl group.

  Other claimed compounds are those where A is a 1,4-benzodiazine of

formula (c).

  The nuclei of formula (a) - (d) may in the present description be

  alternatively called either 1,2-, 1,3-, 1,4- and 2,3-benzodiazines or, respectively, cinnoline, quinazoline, quinoxaline and phthalazine. These benzodiazines can be attached to the rest of the molecule of formula (I) by

  any of the carbon atoms in positions 5, 6, 7 or 8.

  According to the present invention, the compounds of formula (I) can exist as N-oxide derivatives. As indicated in the above formula, the compounds of formula (I) may in particular bear the N-oxide group on tetrahydropyridine or else on one or both of the nitrogen groups (a) - (d), or

  well all the nitrogen present can be simultaneously oxidized.

  The salts of the compounds of formula (I) according to the present invention also include the addition salts with pharmaceutically acceptable inorganic or organic acids such as the hydrochloride, the hydrobromide, the sulfate, the hydrogen sulfate, the dihydrogen phosphate, the citrate, maleate, tartrate, fumarate, gluconate, methanesulfonate, 2-naphthalenesulfonate, etc., as addition salts which allow proper separation or crystallization of the compounds of formula (I), such as picrate, oxalate or addition salts with optically active acids, for example camphosulfonic acids and mandelic acids or

substituted mandelics.

  The optically pure stereoisomers, as well as mixtures of isomers of the compounds of formula (I), due to the asymmetric carbon, when one of R2 and R3 is methyl and the other hydrogen, in any proportion, make

part of the present invention.

  The compounds of formula (I) can be prepared by a condensation reaction starting from a compound of formula (II): -HX Rl (II) in which X and R. are as defined above, with a compound of formula (III): LA

(III)

  in which R2, R3, n and A are as defined above and L is a leaving group, isolation of the compound of formula (I) and transformation

  optionally in one of its salts or solvates or in its N-oxide derivatives.

  The condensation reaction is normally carried out by mixing the starting compounds (II) and (III) in an inert organic solvent, according to the

conventional methods.

  By "inert organic solvent" is meant a solvent which does not interfere with the reaction. Such solvents are, for example, alcohols such as methanol,

  Ethanol, isopropanol or butanol.

  1 S As leaving group L we can for example use a chlorine atom or

  bromine or a mesyloxy group (CH3-SO2-O-).

  The reaction is carried out at a temperature between -10 ° C. and the reflux temperature of the reaction mixture, the reflux temperature being preferred. The reaction can be suitably carried out in the presence of a proton acceptor, for example an alkali carbonate or a tertiary amine such as

triethylamine.

  The reaction is normally over after a few hours, normally

  1 to 6 hours are sufficient to complete the condensation.

  The desired compound is isolated according to conventional techniques in the form of a free base or of a salt thereof. The free base can be transformed into one of its salts by simple salification in an organic solvent such as an alcohol, preferably ethanol or isopropanol, an ether such as 1,2-dimethoxyethane, ethyl acetate. , Acetone or a hydrocarbon such as hexane. The compound of formula (I) obtained is isolated according to the usual techniques and optionally transformed into one of its salts or solvates or into its N oxide derivatives. The starting compounds of formula (II) are known or else they can be

  prepared analogously to known compounds.

  The starting compounds of formula (III) are known or they can be prepared from the corresponding acids or esters, by reduction of the carboxylic group to alcohol group and substitution of OH by the desired group L according to conventional methods. Examples of such reactions are

  recorded in the experimental part.

  The compounds of formula (I) carrying an N-oxide group on the nitrogen atoms of the groups (a) - (d) can be prepared from the Nooxide derivatives

compounds of formula (III).

  The compounds of formula (I) carrying an N-oxide group on the nitrogen atom of tetrahydropyridine can be prepared by oxidation of the corresponding compounds of formula (I). In this case, the compound of formula (I) as obtained for example by the above synthesis, is subjected to an oxidation reaction according to conventional methods, for example to a reaction with m- acid. chloro-perbenzoic acid in a suitable and isolated solvent

  according to the usual techniques well known to those skilled in the art.

  The compounds of the invention have advantageous properties vis-à-vis

TNL-a inLibition.

  These properties were demonstrated using a test to measure the effect of molecules on the synthesis of TNF-o induced in Balb / c mice by lipopolysaccharide (LPS) from Escherichia Coli (055 B5 , Sigma, St Louis, Mo). The test products are administered orally to groups of 5 female Balb / c mice (Charles River, France) aged 7 to 8 weeks. One hour later, the LPS is administered intravenously (10 g / mouse). The blood of each animal is taken 1.5 hours after administration of the LPS. The samples are centrifuged, the plasma is recovered and frozen at -80 C. The

  TNF-a is measured using commercial kits (R&D, Abingdon, UK).

  In this test, representative compounds of the invention were shown to be very

  active, inhibiting the synthesis of TNF-a even at very low doses.

  Thanks to this activity and their low toxicity, the compounds of formula (I) and its salts or solvates can well be used in the treatment of diseases

  related to immune and inflammatory disorders or as pain relievers.

  In particular, the compounds of formula (I) can be used to treat atherosclerosis, autoimmune diseases, diseases which affect the demyelination of neurons (such as multiple sclerosis), asthma, rheumatoid arthritis, fibrotic diseases , pulmonary idiopathic fibrosis, cystic fibrosis, glumerulonephritis, rheumatoid spondylitis, osteoarthritis, gout, bone and cartilage resorption, osteoporosis, Paget's disease, multiple myeloma, uveoretinitis, shock septic, sepsis, endotoxin shock, graft versus host reaction, transplant rejection, adult respiratory distress syndrome, silicosis, asbestosis, pulmonary sarcoidosis, CroUn disease, ulcerative colitis, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, systemic lupus erythematosus, hemodynamic shock, ischemic pathologies (infarction s myocardial, myocardial ischemia, coronary vasospasm, angina pectoris, heart failure, heart attack), post ischemic reperfusion attacks, malaria, mycobacterial infections, meningitis, leprosy, viral infections (HIV, cytomegalovirus, virus herpes), opportunistic AIDS-related infections, tuberculosis, psoriasis, atopic and contact dermatosis,

  diabetes, cachexia, cancer, radiation damage.

  The compounds of formula (I) and their salts and solvates pharmaceutically

  acceptable are preferably administered orally.

  In the pharmaceutical compositions of the present invention by the oral route, the active principle can be administered in unit administration forms, in admixture with conventional pharmaceutical carriers, to animals and humans for the treatment of the abovementioned conditions. Suitable unit dosage forms include, for example, possibly scored tablets, capsules,

  powders, granules and oral solutions or suspensions.

  When preparing a solid composition in the form of tablets, the main active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose or other suitable materials or they can be treated in such a way that they have prolonged or delayed activity and that they continuously release a

  predetermined amount of active ingredient.

  A preparation in capsules is obtained by mixing the active ingredient with

  a diluent and pouring the mixture obtained into soft or hard capsules.

  A preparation in the form of a syrup or elixir may contain the active ingredient together with a sweetener, preferably calorie-free, methylp arab in and p rop ylp arab in anti se ep tic form, as well as flavoring agent and appropriate color. Water dispersible powders or granules may contain the active ingredient in admixture with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or correctors taste The active ingredient can also be formulated in the form of microcapsules,

  possibly with one or more supports or additives.

  In the pharmaceutical compositions according to the present invention, the active principle can also be in the form of an inclusion complex in

  cyclodextrins, their ethers or their esters.

  The amount of active ingredient to be administered depends as always on the degree

  progress of the disease as well as the age and weight of the patient.

  Nevertheless, the unit doses generally comprise from 0.001 to 100 mg, better still from 0.01 to 50 mg, preferably from 0.1 to 20 mg of active principle,

advantageously from 0.5 to 10 mg.

  According to another of its aspects, the present invention relates to a combination comprising a compound of formula (I) or one of its pharmaceutically acceptable salts or solvates, and at least one compound chosen from immunosuppressive agents, such as interferon beta -lb; The adrenocorticotropic hormone; glucocortieoids such as prednisone or

  methylprednisolone; interleukin-1 inhibitors.

  More particularly, the invention relates to a combination comprising a compound of formula (I), or one of its pharmaceutically acceptable salts or solvates and at least one compound chosen from roquinimex (1,2-dihydro 4-hydroxy-N, 1-dimethyl-2-oxo-3-quinolinocarboxanilide), myloran (Autoimmune product containing bovine myelin), antegren (human monoclonal antibody from the companies Elan / Athena Neurosciences)

recombinant beta-lb interferon.

  Other possible associations are those consisting of a compound of formula (I) or one of its pharmaceutically acceptable salts or solvates and a potassium channel blocker, such as for example fampridine (4 aminopyridine). According to another of its aspects, the invention relates to a method for the treatment of diseases linked to immune and inflammatory disorders as well as in the treatment of pain, in particular atherosclerosis, autoimmune diseases, diseases which cause demyelination of neurons (such as multiple sclerosis), asthma, fumaroid arthritis, fibrotic diseases, pulmonary idiopathic fibro, cystic fibro, glumerulonephritis, rheumatoid spondylitis, osteoarthritis, gout, resorption bone and cartilage, osteoporosis, Paget's disease, multiple mycloma, uveoretinitis, septic shock, sepsis, endotoxin shock, graft versus host reaction, transplant rejection, distress syndrome respiratory disease in adults, silicosis, asbestosis, pulmonary sarcoidosis, Crohn's disease, ulcerative colitis, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, systemic lupus erythematosus, hemodynamic shock, ischemic pathologies (myocardial infarction, myocardial ischemia, coronary vasospasm, angina pectoris, heart failure, heart attack), post ischemic reperfusion disease, malaria, mycobacterial infections, meningitis, lopre, viral infections (HIV, cytomegalovirus, herpes virus), opportunistic infections linked to AIDS, tuberculosis, psoriasis, atopic and contact dermatosis, diabetes, cachexia, cancer, radiation-related damage, comprising the administration of a compound of formula (I) or one of its pharmaceutically acceptable salts or solvates, alone or in combination with other active principles.

  The following examples illustrate the invention.

PREPARATION 1

  6- (2-Chloroethyl) -quinoxaline 190 mg (0.9 mmol) of ethyl (4-ammino-nitrophenyl) acetate (obtained as described in J. Med. Chem., 1997, 40 (7) are dissolved ) in 30 ml of methanol and 48 mg of 10% Pd / C are added thereto. It is hydrogenated at room temperature for 6 hours. The catalyst is filtered and the solvent is evaporated, obtaining 160 mg of oil. The product thus obtained is dissolved in 4 ml of methanol, 160 ml of 1,4-dioxane-2,3-diol is added thereto and the mixture is stirred for two hours at room temperature. The solvent is evaporated off and the residue is purified by flash chromatography on a column of silica gel, eluting with a cyclohexane / ethyl acetate mixture = 4/6, thus obtaining the ethyl ester of quinoxalin-6-yl acetic acid. The product thus obtained is dissolved in 3 ml of anhydrous diethyl ether under a stream of nitrogen. 55 mg (1.46 mmol) of LiAlH suspended in 2 ml of diethyl ether are added thereto. The mixture is stirred at room temperature for 3.5 hours, diluted with diethyl ether, poured into a water / ice mixture, the phases are separated and the organic phase is dried and the solvent is evaporated. 110 mg of crude product are obtained, which product is purified by column of silica gel, eluting with ethyl acetate. 31 mg of 6- (2-hydroxyethyl) quinoxaline are thus obtained which are dissolved in 0.5 ml of anhydrous methylene chloride under a stream of nitrogen. The solution is cooled to 0 ° C., 0.3 ml of SOCl2 is added thereto dropwise and the mixture is stirred for 1 hour for two hours at 0 ° C. and after overnight at room temperature. Methylene chloride and water are added, the solution is brought to basic pH by addition of NaHCO 3, extraction is carried out with methylene chloride and the two phases are separated. The organic phase is dried and the solvent is evaporated. We thus obtain

34 mg of the title product.

PREPARATION 2

  6- (2-Chloroethyl) -2,3-dimethylquinoxaline By operating as described in Preparation 1 but using 1,3

  butandione instead of 1,4-dioxane-2,3-diol, the title compound is obtained.

PREPARATION 3

  6- (2-Bromoethyl) -2,3-diethylquinoxaline Operating as described in Preparation 1 but using 3,4 hexandione instead of 1,4-dioxane2,3-diol and treating alcohol 6- ( 2 hydroxyethyl) -2,3diethylquinoxaline intermediate thus obtained with acid

  hydrobromic instead of SOCl2, the title compound is obtained.

EXAMPLE 1

  6- [2- [4- (3-triflMoro-methyl-phenyl) -1,2,3,6-tetrahydro-pyrid-1-yl] ethyl] quinoxaline and its dihydrochloride Dissolving 340 mg (1.78 mmol) of 6- (2chloroethyl) -quinoxaline of preparation 1 in 12 ml of isopropanol and 791 mg (3.56 mmol) of 4- (3-trifluoro-methyl-phenyl) -1,2,3,6tetrahydropyridine are added thereto . The mixture is changed at reflux for 4 hours and then stirred overnight at room temperature. The solvent is evaporated off under reduced pressure and the crude product is obtained which is purified by chromatography on a silica gel column, eluting with ethyl acetate. The title product is thus obtained. Its dihydrochloride salt is prepared by reaction with hydrochloric aid in isopropanol.

Mp 239-241 C.

EXAMPLE 2

  6- [2- [4- (3-trifluoro-methyl-phenyl) -1,2,3,6-tetrahydro-pyrid-1 -yl] -ethyl] 2,3-dimethyl-quinoxaline and its dihydrochloride By operating as described in Example 1 but using the 6- (2 chloroethyl) -2,3 dimethylquinoxaline from Preparation 2, the

composed of the title.

Mp 209-212 C.

EXAMPLE 3

  6- [2- [4- (3-trifluoro-methyl-phenyl) -1,2,3,6-tetrahydro-pyrid-1-yl] -ethyl] 2,3-diethyl-quinoxaline and its dihydrochloride By operating as described in Example 1 but using the 6- (2 bromoethyl) -2,3-diethylquinoxaline from Preparation 3, the compound is obtained

of the title.

Mp 210-212 C.

Claims (14)

  1. Compound of formula (I): 5 A Rl [o] 0-1 (I) in which X represents N or CH; R. represents a hydrogen or halogen atom or a CF3 group; R2 and R3 independently represent a hydrogen atom or a methyl group; n is 0 or 1; A represents a 1,2-, 1,3-, 1,4- or 2,3benzodiazine of formula (a) - (d): 5R5 R4 R4 (a) (b) LI5 N R4 IN   R4 (c) (d) o R4 and R5 each independently represent a hydrogen or halogen atom, a (C, -C4) alkyl or (C, -C4) alkoxy group;   as well as their N-oxides and their salts or solvates.   2. Compound according to claim 1, where n is zero.   3. Compound according to claim 1, where R2 and R3 are each H.   4. Compound according to claim 1, where R. is a group CF3.   5. A compound according to claim 1, where X is CH and R is in the position 3 of benzene.   6. A compound according to claim 1, where X is CH and R. is in the position 2 of benzone.   7. A compound according to claim 1, where X is N and the pyridine is substituted in position 2.6.   8. A compound according to claim 1, where R4 and Rs each represent   independently a hydrogen atom or a (C, -C4) alkyl group.   9. A compound according to claim 1, where A is a 1,4-benzodiazine of formula (c).   10. Compound according to claims 1 to 9, in the form of its derivatives   N-oxide. 11. Compound according to claim 1, chosen from 6- [2- [4- (3- trifluoro methyl-phenyl) -1,2,3,6-tetrahydro-pyrid-1-yl] -ethyl] - quinoxaline, 6 [2- [4- (3-trifluoro-methyl-phenyl) - 1,2,3,6-tetrahydro-pyrid-1-yl] -ethyl] 2,3-dimethyl-quinoxaline, 6- [2 - [4- (3-trifluoromethyl-phenyl) -1,2,3,6 tetrahydro-pyrid-1-yl] -ethyl] -2,3-diethylquinoxaline, their derivatives N oxide, their salts and solvates.   12. Process for the preparation of the compounds of formula (I) which comprises reacting a compound of formula (II) NH R (II) in which X and R are as defined above, with a compound of formula ( III) R2 R3   L _A (III) in which R "R3, n and A are as defined above and L is a leaving group, isolation of the compound of formula (I) and its transformation   optionally in one of its salts or solvates or in its N-oxide derivatives.   13. Pharmaceutical composition containing as active ingredient a   compound of formula (I) according to claims from 1 to 11 or one of its salts   or pharmaceutically acceptable solvates.   14. Composition according to claim 13, characterized in that it contains   from 0.001 to 100 mg of active ingredient.   1S. Use of a compound of formula (I) according to claims 1 to 11   or a pharmaceutically acceptable salt or solvate thereof for the preparation of analgesic and / or medicinal products intended for the treatment of   diseases related to immune and inflammatory disorders.   16. Medicament containing as active ingredient a compound of formula   (I) according to claims 1 to 11 or one of its salts or solvates pharmaceutically acceptable.