Process for the preparation of imidazole, triazole and tetrazole derivatives and their use as selective 5-HT-1 receptor agonists

Abstract: A class of substituted imidazole, triazole and tetrazole derivatives are selective agonists of 5-HT 1 -like receptors and are therefore useful in the treatment of clinical conditions, in particular migraine and associated disorders, for which a selective agonist of these receptors is indicated. wherein the broken circle represents two non-adjacent double bonds in any position in the five-membered ring; two, three or four of V,W,X,Y and Z represent nitrogen and the remainder represent carbon provided that, when two of V,W,X,Y and Z represent nitrogen and the remainer represent carbon, then the said nitrogen atoms are in non-adjacent positions within the five-membered ring; A 1 represents hydrogen, methyl, ethyl, benzyl or amino; A 2 represents a non-bonded electron pair when four of V,W,X,Y and Z represent notrogen and the other represents carbon; or, when two or three of V,W,X,Y and Z represent nitrogen and the remainder represent carbon, A 2 represents hydrogen, methyl, ethyl, benzyl or amino; E represents a bond or a straight or branched alkylene chain containing from 1 to 4 carbon atoms; F represents a group of formula U represents nitrogen or C-R 2 ; B represents oxygen, sulphur or N-R 3 ; R 1 represents -CH 2 .CHR 4 .NR 6 R 7 or a group of formula in which the broken line represents an optional chemical bond; and R 2 ,R 3 ,R 4 ,R 5 ,R 6 and R 7 independently represent hydrogen or C 1-6 alkyl.

Description: The present invention relates to processes for the preparation of N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine and its benzoate salt. These compounds act on 5-hydroxytryptamine (5-HT) receptors, being selective agonists of so-called "5-HT 1 -like" receptors. They are therefore useful in the treatment of clinical conditions for which a selective agonist of these receptors is indicated. 5-HT 1 -like receptor agonists which exhibit selective vasoconstrictor activity have recently been described as being of use in the treatment of migraine (see, for example, A. Doenicke et al ., The Lancet, 1988, Vol. 1, 1309-11). The compounds prepared by the processes of the present invention, being selective 5-HT 1 -like receptor agonists, are accordingly of particular use in the treatment of migraine and associated conditions, e.g. cluster headache, chronic paroxysmal hemicrania, headache associated with vascular disorders, tension headache and paediatric migraine. EP-A-0313397 describes a class of tryptamine derivatives substituted by a five-membered heteroaliphatic ring, which are stated to be specific to a particular type of "5-HT 1 -like" receptor and thus to be effective therapeutic agents for the treatment of clinical conditions, particularly migraine, requiring this activity. However, EP-A-0313397 neither discloses nor suggests the compounds prepared by the processes of the present invention. In one aspect the present invention provides a process for the preparation of N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine which comprises reacting 2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine with formaldehyde and sodium cyanoborohydride in the presence of glacial acetic acid and methanol, followed by the addition of K 2 CO 3 . In another aspect the present invention provides a process for the preparation of N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine which comprises reacting 1-(4-hydrazinophenyl)methyl-1,2,4-triazole with 4-N,N-dimethylaminobutanal dimethylacetal in the presence of 4% aqueous sulphuric acid, followed by basification with K 2 CO 3 and extraction with ethyl acetate. In a further process the present invention provides a process for the preparation of the benzoate salt of N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-lH-indol-3-yl]ethylamine which comprises treating a solution of N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-lH-indol-3-yl]ethylamine free base in ethanol/diethyl ether with a solution of benzoic acid in diethyl ether. The compounds prepared by the processes of the present invention can be incorporated into pharmaceutical compositions in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of the active ingredient. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient. The tablets or pills can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate. Suitable liquid forms for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin. In the treatment of migraine, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day. The following Examples illustrate the processes for the preparation of N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-lH-indol-3-yl]ethylamine and its benzoate salt. The ability of test compounds to bind to 5-HT 1 -like receptors was measured in membranes prepared from pig caudate using the procedure described in J. Neurosci ., 1987, 7 , 894. Binding was determined using 2 nM 5-hydroxytryptamine creatinine sulphate, 5-[1,2- 3 H(N)] as a radioligand. Cyanopindolol (100 nM) and mesulergine (100 nM) were included in the assay to block out 5-HT 1A and 5-HT 1C binding sites respectively. The concentration of the compounds prepared as described in the accompanying Examples required to displace 50% of the specific binding (IC 50 ) is below 1 µ M in each case. The activity of test compounds as agonists of the 5-HT 1 -like receptor was measured in terms of their ability to mediate contraction of the saphenous vein of New Zealand White rabbits, using the procedure described in Arch. Pharm ., 1990, 342 , 111. Agonist potencies were calculated as -log 10 EC 50 (pEC 50 ) values, from plots of percentage 5-HT (1 µ m) response against the concentration of the agonist. The compounds prepared as described in the accompanying Examples were found to possess pEC 50 values in this assay of not less than 5.0 in each case. EXAMPLE 1 N,N-Dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine. Oxalate Hemihydrate 1. 1-(4-Nitrophenyl)methyl-1,2,4-triazole 4-Nitrobenzylbromide (21.6g, 0.1mol) was added to a rapidly stirred suspension of 1,2,4-triazole sodium salt (9.1g, 0.1mol) in anhydrous DMF (100ml) and the mixture stirred at room temperature for 16h. Ethyl acetate (400ml) was added followed by water (250ml) and the layers separated. The organic phase was washed with water (3 x 250ml), dried (MgSO 4 ) and evaporated. The residue was chromatographed on silica gel eluting with ethyl acetate to give the title- product (10.6g, 52%); m.p. 98-100°C. δ (360MHz, CDCl 3 ) 5.47 (2H, s, CH2) 7.40 (2H, d, J = 9Hz, Ar-H), 8.02 (1H, s, Ar-H), 8.18 (1H, s, Ar-H), 8.23 (2H, d, J = 9Hz, Ar-H). 2. 1-(4-Aminophenyl)methyl-1,2,4-triazole. Hydrochloride A solution of 1-(4-nitrophenyl)methyl-1,2,4-triazole (10.0g, 49mmol) in ethanol (50ml), ethyl acetate (50ml), 5N HCl (10ml) and water (10ml) was hydrogenated over 10% Pd/C (1.0g) at 40 p.s.i., in a Parr apparatus, until an uptake of 188 p.s.i., had been observed (approx 10mins). The catalyst was removed by filtration through hyflo and the solvent removed under vacuum. The residue was azeotroped with ethanol (x2) to give the title- amine hydrochloride (10.6g, 100%). δ (360MHz, D 2 O) 5.53 (2H, s, CH 2 ), 7.37-7.48 (4H, m, Ar-H), 8.12 (1H, s, Ar-H), 8.66 (1H, s, Ar-H). 3.1-(4-Hydrazinophenyl)methyl-1,2,4-triazole A solution of sodium nitrite (3.28g, 48mmol) in water (20ml) was added to a solution of the preceding amine hydrochloride (10.0g, 48mmol), in concentrated HCl (40ml), at such a rate that the temperature did not exceed -10°C. After addition was complete the solution was stirred at 0°C for 0.25h and then added portionwise to a rapidly stirred solution of SnCl 2 .2H 2 O (40g) in concentrated HCl (40ml). The solution was warmed to room temperature and basified with 20% aqueous NaOH solution. The solution was extracted with ethyl acetate (3 x 250ml) and the combined extracts dried (MgSO 4 ) and filtered through hyflo. The solution was evaporated to dryness to give the desired hydrazine (5.0g, 56%) m.p. 109-112°C. δ (360MHz, D 6 -DMSO) 3.93 (2H, br s, NH 2 ), 5.20 (2H, s, CH 2 ), 6.73 (2H, d, J = 8Hz, Ar-H), 7.08 (2H, d, J = 8Hz, Ar-H), 7.92 (1H, s, Ar-H), 8.57 (1H, s, Ar-H). 4. 2-[5-(1,2,4-Triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine. 4-Chlorobutanal dimethylacetal (3.22g, 21.1mmol) was added to a stirred solution of the preceding hydrazine (5.0g, 26.4mmol) in ethanol/water (5:1, 180ml) and 5N HCl (4.5ml) and the solution refluxed for 4h. The solvents were removed under vacuum and the residue chromatographed on silica gel, eluting with CH 2 Cl 2 /EtOH/NH 3 (30:8:1) to give the desired tryptamine (2.4g, 38%). δ(360MHz, CDCl 3 ) 2.90 (2H, t, J = 7Hz, CH 2 ), 2.99 (2H, t, J = 7Hz, CH 2 ), 5.43 (2H, s, CH 2 ), 7.10 (1H, s, Ar-H), 7.11 (1H, d, J = 8Hz, Ar-H), 7.39 (1H, d, J = 8Hz, Ar-H), 7.57 (1H, s, Ar-H), 7.94 (1H, s, Ar-H), 8.08 (1H, s, Ar-H). 5. N.N-Dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine Oxalate Hemihydrate A solution of formaldehyde (37% w/w solution, 0.19g), in methanol (10ml), was added to a mixture of the preceding tryptamine (0.36g, 1.5mmol), NaCNBH 3 (0.225g, 3.6mmol) and glacial acetic acid (0.45g), in methanol (10ml). The mixture was stirred at room temperature for 2h before adding saturated K 2 CO 3 (50ml) and evaporating the methanol. The residue was extracted with ethyl acetate (3 x 100ml) and the combined extracts washed with brine (100ml), dried (K 2 CO 3 ), and evaporated. The crude product was chromatographed on silica gel eluting with CH 2 Cl 2 /EtOH/NH 3 (20:8:1) to give the free base of the title- compound (0.21g, 52%). The oxalate hemihydrate salt was prepared, m.p. 165-167°C (MeOH/Et 2 O); (Found: C, 55.53; H, 6.04; N, 18.59. C 15 H 19 N 5 .C 2 H 2 O 4 . 0.55H 2 O requires C, 55.29; H, 6.03; N, 18.96%); m/e 269 (M + ); δ (360MHz, D 2 O) 2.91 (6H, s, NMe 2 ), 3.22 (2H, t, J = 7Hz, CH 2 ), 3.47 (2H, t, J = 7Hz, CH 2 ), 5.52 (2H, s, CH 2 ), 7.21 (1H, dd, J = 1.6 and 8.4Hz, Ar-H), 7.36 (1H, s, Ar-H), 7.52 (1H, d, J = 8.4Hz, Ar-H), 7.65 (1H, s, Ar-H), 8.06 (1H, s, Ar-H), 8.56 (1H, s, Ar-H). EXAMPLE 2 N,N-Dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine. Succinate. Procedure B A solution of 1-(4-hydrazinophenyl)methyl-1,2,4-triazole dihydrochloride (2g, 7.6mmol, Example 1 step 3) and 4-N,N-dimethylaminobutanal dimethylacetal (1.8g, 11.2mmol) in 4% aqueous sulphuric acid (70ml) was heated at reflux for 2h. After the reaction mixture was cooled to room temperature, ethyl acetate (200ml) was added and the aqueous basified with K 2 CO 3 . The aqueous was separated and extracted further with ethyl acetate (2 x 150ml). The combined organics were dried (Na 2 SO 4 ) and evaporated, and the residue chromatographed on silica gel eluting with CH 2 Cl 2 /EtOH/NH 3 (30:8:1) to give the title -triazole (610mg, 30%). The succinate salt was prepared by addition of a solution of succinic acid (0.27g, 2.3mmol) in methanol (3ml) to a solution of the triazole (0.61g, 2.3mmol) in methanol (5ml). The solvent was removed under vacuum and the resultant product recrystallised from isopropylalcohol, mp 118-120°C; (Found: C, 58.76; H, 6.27; N, 17.79. C 15 H 19 N 3 .C 4 H 6 O 4 requires C, 58.90; H, 6.50; N, 18.08%). EXAMPLE 3 N,N-Dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine. Benzoate The benzoate salt of N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-lH-indol-3-yl]ethylamine was prepared by addition of a solution of benzoic acid in diethyl ether to a solution of the free base in ethanol/diethyl ether (1:4). The precipitated salt was recrystallised from ethanol, mp 178-180°C; (Found: C, 67.28; H, 6.55; N, 17.66. C 15 H 19 N 3 .C 6 H 5 CO 2 H requires C, 67.50; H, 6.44; N, 17.89%); 1 H NMR (360MHz, D 2 O) δ 2.92 (6H, s, NMe 2 ); 3.22 (2H, t, J = 7.3Hz, CH 2 ); 3.46 (2H, t, J = 7.3Hz, CH 2 ); 5.52 (2H, s, CH 2 ); 7.22 (1H, dd, J = 1.6 and 8.4Hz, Ar-H); 7.36 (1H, s, Ar-H); 7.44-7.58 (4H, m, Ar-H); 7.65 (1H, s, Ar-H); 7.87-7.91 (2H, m, Ar-H); 8.06 (1H, s, Ar-H); 8.54 (1H, s, Ar-H).

Claims: A process for the preparation of N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine which comprises reacting 2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine with formaldehyde and sodium cyanoborohydride in the presence of glacial acetic acid and methanol, followed by the addition of K 2 CO 3 . A process for the preparation of N,N,dimethyl,2,[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine which comprises reacting 1-(4-hydrazinophenyl)methyl-1,2,4-triazole with 4-N,N-dimethylaminobutanal dimethylacetal in the presence of 4% aqueous sulphuric acid, followed by basification with K 2 CO 3 and extraction with ethyl acetate. A process for the preparation of the benzoate salt of N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine which comprises treating a solution of N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine free base in ethanol/diethyl ether with a solution of benzoic acid in diethyl ether.

Inventors: BAKER RAYMOND, MATASSA VICTOR, STREET LESLIE J, BAKER, RAYMOND, MATASSA, VICTOR, STREET, LESLIE J.
Applicants: MERCK SHARP & DOHME, MERCK SHARP & DOHME LTD.
Application year: 1992
Main classification: C07D403
IPC codes: A61P25, A61K31, C07D521, C07D403, C07D417, C07D401, C07D405, C07D409, C07D413