9,10-DIAZATRICYCLO[4.2.1.1<2,5>]DECANE AND 9,10-DIAZATRICYCLO[3.3.1.1<2,6>]DECANE DERIVATIVES HAVING ANALGESIC ACTIVITY

Abstract: 9,10-Diazatricyclo[4.2.1.1<2,5>]decane and 9,10-diazatricyclo[3.3.1.1<2,6>]decane derivatives of formula (Ia) and (Ib) having analgesic activity, are herein disclosed.

Description: 9-10-DIAZATRICYCLOr4.2.1-l 2 ' 5 lDECANE AND 9.10-DIAZATRI- CYCLOΓ3.3.1. 2 ^ 6 1DECANE DERIVATIVES HAVING ANALGESIC ACTIVITY The present invention relates to 9 , 10-diazatri- cyclo[4.2.1. I 2 . 5 ]decane and 9 , lO-diazatricyclo- [3.3.1.1 2 -* 6]decane derivatives having analgesic activity. WO 95/23152 and WO 94/16698 disclose 3,8- diazabicyclo[3.2. Hoctane derivatives having central analgesic activity, wherein the two nitrogen atoms are respectively substituted with acyl groups and aryl or heteroaryl-acrylic groups. Said compounds proved to be particularly active as central analgesics and are characterized by satisfactory tolerability and poor or no induction of addiction and tolerance. Now it has been found that analogues of two novel tricyclic systems, characterized by two endoethylenic bridges on the piperazine ring, have an even higher analgesic activity. The compounds of the invention have the following general formulae: la lb in which R^ and R 2 are both hydrogen or are different from each other, and are selected from hydrogen; C^-Cg alkyl; acyl; an Ar group wherein Ar is optionally substituted phenyl, optionally substituted naphthyl, an heterocyclic group containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur having 5 to 7 ring atoms, optionally benzofused and optionally substituted at the benzene ring; a group of formula wherein Ar is as defined above. Examples of Ar groups can be represented by the following formulae -G" wherein X, Y and Z, which are the same or different, are selected from N, NH, S, O, =(CH) n or -(CH 2 ) n - wherein n = 0 - 2 and R is hydrogen or a substituent selected from halogen atoms, nitro, amino, methoxy, ethoxy, C^-Cg alkyla ino or C^-Cg acylamino groups. Preferably, ^ is a C 2 *-C 10 acyl group and R 2 is an Ar group or -CH 2 -CH=CH-Ar as defined above. A C -C.,Q acyl group is preferably acetyl, propionyl or butyryl, more preferably propionyl. R 2 is preferably a group of formula -CH 2 -CH=CH-Ar wherein Ar is phenyl or substituted phenyl, more preferably phenyl. The compounds of formulae I and lb can be prepared according to the following schemes: SCHEME 1 (1) Crandall J.K. et al. J.O.C., Voi.33, No. l, 423-425 (1968) SCHEME 2 Vila tO t o O SCHEME 3 H 2 , Pd/C R 2 -X EtOH lb' lb ✓ / In the schemes reported above, X is a reactive group suitable for the desired N-alkylation or N- acylation reaction, for example a halogen atom, a meεyl, tosyl, acyl chloride, anhydride group and the like. The process according to the invention comprises the reaction of 5 , 6-epoxycyclooctene III / easily obtainable from commercially available 1,5-cyclo- octadiene II, with benzyla ine in dichloro ethane, in the presence of ytterbium (III) trifluoromethanesul- fonate, to give aminoalcohol IV. The alcohol group is then transformed into the corresponding sulphate ester which is refluxed in concentrated sodium hydroxide to yield aziridine V. The latter is treated with sodium azide and ammonium chloride with heating in ethanol and water to yield amino-azide VI, which is transformed into the compounds Vila and Vllb by addition of bromine. The dibromo derivatives cannot be isolated as an intramolecular condensation occurs. The compounds Vila and Vllb are separated by chromatography according to conventional techniques. The compounds Vila and Vllb can then be converted into compounds of formula Villa or Vlllb, respectively, by treatment with triphenylphosphine in tetrahydrofuran and subsequent addition of water. Conventional N-alkylation or N-acylation reactions, in suitable sequence, allow then to prepare the desired compounds . The compounds of formula la and lb have affinity to opioid receptors, evaluated according to the method described by Wood et al., Neuropharmacology , 1981, 20 , 1219, which is up to 5-fold higher than that of the compounds described in WO 95/23152 and WO 94/16698. The compounds of the invention, optionally in the form of pharmaceutically acceptable salts, can conventionally be formulated in pharmaceutical compositions suitable for the oral, parenteral or rectal administration. The daily dosage will, of course, depend on a number of factors, but it will generally range from 1 g to 100 mg/day, optionally subdivided in more administrations. The following example shows the invention in greater detail. Example Trans-2-benzylamino-5-cycloocten-l-ol ( IV) To a stirred solution of 5 , 6-epoxycyclooctene III (10.0 g, 0.081 mol) in dry CH 2 C1 2 (100 ml) kept under nitrogen atmosphere, benzyla ine (10.35 g, 0.097 mol) and Ytterbium( III ) trifluσromethanesulfonate (4.96 g, 0.008 mol) were added and the mixture was stirred for 24hrs at room temperature. Extractive work-up of the reaction mixture with water and CH 2 Cl gave the title product as a white solid (yield 83%). .p.: 70-71°C, b.p:140°C/l mm Hg . 1 H NMR (CDC1 3 ): δ 7.59-7.56 ( , 2H, ArH ) , 7.38-7.35 (m, 3H, ArH), 5.64-5.44 (m, 2H, CH=CH), 5.42-5.00 (bs, D 2 0 exchangeable, OH) 4.07 (AB syst , 2H, J=12.57 Hz, PhCH 2 ) , 3.75-3.65 (m, 1H, CHOH ) , 3.00-3.15 (m, 1H, CHNH- ) , 2.35- 2.02 ( , 6H), 1.95-1.42 ( , 2H ) . Trans-2-benzylamino-5-cycloocten-l-ol sulphate ester To a suspension of compound IV (2.6 g, 0.011 mol) in anhydrous ether (50 ml) kept under vigorous stirring at 0-5°C, chlorosulfonic acid (1.6 g, 0.011 mol) was added dropwiεe. The reaction mixture became gummy and difficult to stir. However, after stirring overnight at room temperature, the white solid that separated was filtered and washed with ether, yielding 3.2 g (93%) of the sulphate ester, m.p 162-163°C. 1 H NMR (CDC1 3 ): δ 8.50-8.00 (bs D 2 0 exchangeable, 1H, + NH);7.50-7.30 (m, 5H, ArH); 5.70-5.50 (m, 1H, CH=CH); 5.50-5.30 ( , 1H, CH=CH); 4.70-4.50 ( , 1H, CHOSO3 " ); 4.40-4.00 (m, 2H, PhCH 2 ) ; 3.50-3.30 (1H, CHN); 2.60-1.70 (m, 8H). N-Benzyl-9-azabicyclo[6.1.0]-4-nonene (V) The sulphate ester (4 g, 0.017 mol) was dissolved in a 33% sodium hydroxide solution (40 ml) and the mixture was refluxed for 2hrs, cooled, saturated with potassium hydroxide and extracted with 3x50 ml ethyl acetate. The organic layers were collected, dried (Na SO^) and the solvent evaporated to give the desired compound isolated by silica gel flash chromatography , eluting with CH 2 C1 2 /Ethyl acetate 9:1 (yield 62%). B.p. :125°C/1 mm Hg. ^ ■ H NMR (CDCI3): δ 7.39-7.15 (m, 5H, ArH), 5.64-5.45 ( , 2H CH=CH), 3.55 (s, 2H, PhCH 2 ) , 2.50-2.25 (m, 2H, CHN) 2.20-1.90 (b , 6H) 1.61-1.45 (m, 2H). Trans-2-azido-l-benzylamino-5-cyclooctene A solution of compound V (10 g, 0.047 mol), sodium azide (12.2 g, 0.19 mol), and ammonium chloride (10.02 g, 0.19 mol) in ethanol (500 ml) and water (100 ml) was refluxed for 4 hrs. Ethanol was evaporated off and the aqueous mixture was extracted with 3x150 ml CH 2 C1 2 - The organic layers were collected, dried (Na SO,) and the solvent evaporated to give the desired compound which was isolated as an oil by silica gel flash chromatography, eluting with CH 2 C1 2 /Ethyl acetate 9:1 (yield 91%) . 1 H NMR (CDC1 3 ): δ 7.35-7.10 (5H, ArH), 5.60 (dq, 2H, J=5.5, CH=CH), 3.80 (AB syεt, 2H, J--.12.82, PhCH 2 ) , 3.67 (dt, 1H, J=8.8, CHN3); 3.00-2.75 ( , 1H , CHN); 2.60-2.30 (m, 2H); 2.25-2.00 (m,4H); 1.90-1.60 (m, 2H). 2-β-Bromo-5-azido-9-benzyl-9-azabicyclo[4.2.1. ]nonane (Vila) 2-β-Bromo-6-azido-9-benzyl-9-azabicyclo[3.3.1. ]nonane (Vllb) To a solution of trans-2-azido-l-benzylamino-5- cyclooctene (2 g, 7.8 mol) in cyclohexane (110 ml), stirred at 5°C in subdued light, was slowly added a solution of 10% bromine in cyclohexane, until a yellow colour persisted in the reaction mixture. The solid which separated was filtered (1.6 g), treated with 10% sodium hydroxide and the bases thus liberated were extracted with ether. The organic layer was dried on Na 2 SO and the solvent evaporated. Flash chromatography on silica gel eluting with petroleum ether 40-60/diethyl ether 98:2 gave first compound Vila as an oil (yield 23%), further elution gave compound Vllb as a white solid m.p. 75-76 β C (diethyl ether) (yield 19%). Vila: !H NMR (CDCI3): δ 7.45-7.20 (m, 5H, ArH); 4.12 (t, 1H, J=7.2, CHBr); 3.90-3.70 (m, 3H, PhCH 2 , CHN); 3.56 (q, 1H, J=4.8, CHN3); 3.40-3.20 (m, 1H, CHN); 2.40-2.10 (m, 3H); 2.10-1.70 (m, 3H ) ; 1.60-1.20 (m, 2H). Vllb: -J-H NMR (CDCI3): δ 7.45-7.20 (m, 5H, ArH); 4.50- 4.30 (m, 1H, CHBr); 4.20-3.90 (m, 3H, PhCH 2 , CHN3 ) ; 3.20-3.00 (m, 1H, CHN); 3.00-2.90 (m, 1H , CHN); 2.50- 2.00 (m, 5H); 2.00-1.60 (m,3H). 2-β-Bromo-5-iminophosphorane-9-benzyl-9-azabicyclo- [4.2.1. ]nonane To a stirred solution of Vila (0.4 g, 0.0012 mol) in dry tetrahydrofuran at room temperature, a εtoichiometric amount of triphenylphoεphine , dissolved in THF, was added dropwise, and the mixture was refluxed for 4 hrs, then cooled and added with HCl in diethyl ether. The resulting solid was filtered, treated with 20% NaHCθ3 and extracted with ethyl acetate. The organic layers were dried over Na 2 S0 4 and the solvent was evaporated off. Flash chromatography eluting with diethyl ether/6 M NH3 in methanol 95:5 gave the title compound in quantitative yields, m.p. 114-115°C. 9-Benzyl-9 , 10-diazatricyclo[ 4.2.1. I 2 ' 5 ]decane ( VII la ) A solution of the above compound (0.35 g, 0.6 mmol ) in THF (9 ml) and water (0.1 ml) was refluxed for 15 hrs. After cooling, HCl waε bubbled through the mixture, the reεulting εolid was decanted and separated from the liquid, the solvents and the excess HCl were removed by co-evaporation with ethanol. The title compound as hydrochloride was washed with diethyl ether and crystallised (MeOH/Et 2 0) to give an 85% yield, m.p. (as free base) 75-76°C. 1 H NMR (CDCI3): δ 7.50-7.10 ( , 5H, ArH); 3.50 (s, 2H, PhCH 2 ), 3.20-3.00 ( , 2H, CHN); 2.90-2.70 (m, 2H, CHN); 2.20-2.00 (m, 2H ) ; 1.90-1.70 (m, 4H ) ; 1.60-1.40 ( , 2H ) . 9-Benzyl-9,10-diazatricyclo[3.3.1.1 2 ' 6 ]decane (VIIlb) To a stirred solution of Vllb (10.3 g, 0.0031 mol) in anhydrous THF (30 ml) at room temperature, a εtoichio etr ic amount of triphenylphosphine dissolved in THF was added and the mixture refluxed for 7 hrs. After cooling, water (0.1 ml) was added and the mixture refluxed overnight. The reaction was quenched as described for compound Villa. Flash chromatography eluting with diethyl/ether/6M NH 3 in MeOH 95:7 gave the title compound (yield 56%). m.p. (as free base) 127- 128°C. 1 H NMR (CDC1 3 ): δ 7.50-7.10 (m, 5H, ArH); 3.90 (AB syst , 2H, J=13.7, PhCH 2 ), 3.20-3.00 (m, 2H, CHN); 2.80-2.60 (m,2H, CHN); 2.30-1.50 (m, 8H). 9,10-Diazatricyclo[4.2.1. I 2 ' 5 ]decane la 1 9,10-Diazatricyclo[3.3.1.1 2 < • 6 ]decane lb' Compounds Villa and Vlllb hydrochlorides (0.14 g, 0.57 mmol) were disεolved in ethanol (6 ml). To this solution 10% w/w palladium on carbon was added together with a few μl of 6N hydrochloric acid. The mixture was hydrogenated at room temperature overnight, the catalyst was filtered off and washed with hot 50% ethanol in water. The filtrate was evaporated in vacuo to give the title compounds as hydrochlorides as white solids in quantitative yields. la': m.p. 295°C ( Et0H/H 2 0/Et 2 0) lb': m.p. 300°C ( Et0H/H 2 0/Et 2 0 ) . 1 H NMR (DMSO): δ 8.80 (bs, D 2 0 exchang., 2H, +NH.HC1); 3.94 (app.s, 4H , CHN); 2.40-2.20 (m, 4H ) ; 2.20-2.00 (m,4H). 3.2HC1: m.p. 300°C dec ( Et0H/H 2 0/Et 2 0 ) . 1 H NMR (D 2 0): δ 4.04 ( app . d , 4H, CHN); 2.50-2.20 (m, 4H); 2.20-1.90 (m,4H). 9-Propionyl-9,10-diazatricyclo[4.2.1.l ' 5 ]decane la' ' 9-Propionyl-9,10-diazatricyclo[3.3.1.1 2 ' 6 ]decane lb 1 ' A solution of propionic anhydride (6.9 m ol) in CH 2 C1 2 (2 ml) was added in one portion to an ice cooled solution of the appropriate benzyl derivative Villa or VI I lb (0.45 g, 1.9 mmol) in CH 2 C1 2 (15 ml). The mixture was refluxed for lh, allowed to cool to room temperature, alkalinized with a 40% sodium hydroxide excess and stirred overnight. Extraction with dichloromethane and drying yielded 9-propionyl-10- benzyl-derivatives (100%) which were hydrogenated as described above to give the title compounds as hydrochlorides (yield 96%). la' ' : m.p. 230°C lb' ' : m.p. 234°C 9-Propionyl-10-cinnamyl-9 , 10-diazatricyclo[4.2.1. I 2 ' 5 ]- decane la'" 9-Propionyl-10-cinnamyl-9,10-diazatricyclo[3.3.1.l 2 ' 6 ]- decane lb' ' ' A mixture of the suitable propionyl derivative la' ' or lb' ' (1.1 mmol), cinnamyl chloride (1.1 mmol), K 2 C0 3 (1.1 mmol) in acetone waε refluxed for 24 hrs. The inorganic salts were filtered off, the filtrate was evaporated and the residue purified by silica gel flash chromatography, eluting with petroleum ether 40-60/ethyl acetate. The title compounds were obtained in 85-95% yields . la' ' ' : m.p. 189-190°C lb' 1 ': m.p. 220-221°C. Operating analogously to the procedure described above, using the suitable derivatives of -chlo- rocinnamic, p-nitrocinnamic, 3-α-naphthyl-propionic acids, the following compounds were obtained: 9-propionyl-10-(m-chlorocinnamyl )-9 ,10-diazatricyclo- [4.2.1.1 2 ' 5 ]decane.HCl.H 2 0; m.p. = 90°C, 9-propionyl-10-(p-nitrocinnamyl )-9 , 10-diazatricyclo- [4.2.1.1 2 ' 5 ]decane free base m.p. = 132-133°C, 9-propionyl-10-( 3 ' α-naphthylpropenyl )-9 , 10-diazatricy- clo[4.2.1.1 2 ' 5 ]decane.HC1.2H 2 0; m.p. = 138-142°C, 9-propiony1-10- (p-nitrocinnamyl )-9,10-diazatricyclo- [3.3.1.1 2 ' 5 ]decane.HCl.l/2H 2 0; m.p. = 135°C.

Claims: CLAIMS 1 . Compounds of f ormula ( I ) : la lb wherein R., and R 2 are both hydrogen or are different from each other, and are εelected from hydrogen; C^-Cg alkyl; C 2 -C-, Q acyl; an Ar group wherein Ar iε optionally substituted phenyl, optionally εubεtituted naphthyl, an heterocyclic group containing 1 to 3 heteroato s selected from oxygen, nitrogen and sulphur having 5 to 7 ring atoms, optionally benzofused and optionally subεtituted at the benzene ring; a group of formula -CH 2 -CH=CH-Ar wherein Ar iε as defined above. 2. Compounds according to claim 1, wherein Ar groups are selected from -O wherein X, Y and Z, which are the same or different, are selected from N, NH , S, 0, = ( CH ) or ~(CH 2 )—- wherein n = 0 - 2 and R is hydrogen or a εubstituent selected from halogen atoms, nitro, amino, methoxy, ethoxy, c ι~ c 6 alkylamino or C^-Cg acylamino groups. 3. Compounds according to claim 1, wherein R iε a C 2 _C 10 ac Yl group and R 2 iε an Ar group or -CH 2 -CH=CH-Ar aε defined above. 4. Compoundε according to any one of clai ε 1-3 wherein the C 2 -C 0 acyl group iε acetyl, propionyl or butyryl . 5. Compoundε according to any one of claims 1-4 wherein R 2 is a group of formula -CH 2 -CH=CH-Ar wherein Ar is phenyl or εubεtituted phenyl. 6. Pharmaceutical compoεitionε containing a compound of claimε 1-5 as the active ingredient. 7. Uεe of the compoundε of claimε 1-5 for the preparation of a medicament having analgesic activity.

Inventors: CIGNARELLA GIORGIO, VIANELLO PAOLA, CIGNARELLA, GIORGIO, VIANELLO, PAOLA
Applicants: CIGNARELLA GIORGIO, NEUROSCIENZE S C A R L, VIANELLO PAOLA, CIGNARELLA, GIORGIO, NEUROSCIENZE S.C.A.R.L., VIANELLO, PAOLA
Application year: 1998
Main classification: C07D487
IPC codes: A61K31, A61P25, C07D471, C07D487