A class of novel aminotetralins is disclosed useful as 5-HT 1D&agr; agonists.

EXAMPLE 1 
 (R)-2-N,N-dimethylamino-8-methyltetralin hydrochloride 36 A. Preparation of (R)-2-N,N-dimethylamino-8-formyltetralin 
 Reaction under Nitrogen Atmosphere, using Flame Dried Glassware To 1.004 g of (&plus;)-(R)-2-N,N-dimethylamino-8-bromotetralin, dissolved in 15 mL of dry THF and chilled to −78° C. in a dry ice/acetone bath, was added 3.45 mL. (1.6 M) of n-BuLi, and the mixture was allowed to stir for one hour. Anhydrous dimethylformamide (0.46 mL) was then added via syringe. The reaction was allowed to slowly return to room temperature. Water was added and the mixture was extracted with ethyl acetate. The organic layers were dried over MgSO 4 and concentrated to leave a yellow oil that was purified by silica gel flash column chromatography using a solvent mixture (10% MeOH, 0.5% NH 4 OH in CH 2 C 1 2 ) to give 683 mg of (R)-2-N,N-dimethylamino-8-formyltetralin (85%), which was used for next step without further characterization. B. Preparation of (R)-2-N,N-dimethylamino-8-methyltetralin hydrochloride The compound of part A, above (660 mg) was dissolved in 8 mL of dry CH 2 Cl 2 and 9.3 mL of Et 3 SiH was added. To this vigorously stirring solution was bubbled BF 3 gas via syringe. The resulting solution oiled out to a yellow sludge and the solution cleared from yellow to a clear liquid. The reaction was allowed to stir overnight. After quenching with 20 mL of saturated NaHCO 3 and diluting with 50 mL of CH 2 Cl 2 ,the layers were separated and the organic layer was washed with brine. The organics were then dried over MgSO 4 , filtered, and evaporated to recover an oily yellow solid. The crude product was purified by silica gel flash column chromatography using a solvent mixture (6.5% MeOH, 0.5% NH 4 OH in CH 2 Cl 2 ). The HCl salt was made from this oily residue and recrystallized from hot EtOH and Et 2 O. 1 M.P.: 180-181° C. dec HRMS Calculated: 190.1596 Found: 190.157 
 EXAMPLE 2 
 (R)-2-N,N-dimethylamino-8-(cyclobut-1-en-1-yl)tetralin 37 A. Preparation of (R)-2-N,N-dimethylamino-8-(1′-hydroxy)cyclobutyltetralin hydrochloride 
 Reaction Under Nitrogen Atmosphere, using Flame Dried Glassware By substantially following the procedure in Example 1, part A, using 1.50 g of (&plus;)-(R)-2-N,N-dimethylamino-8-bromotetralin, 5.2 ml of n-BuLi (1.6M, 1.4 eq) and 0.75 mL of cyclobutanone (1.7 eq.), subtitled compound was prepared, 1.09 g (75%). B. Preparation of (R)-2-N,N-dimethylamino-8-(cyclobut-1-en-1-yl)tetralin hydrochloride Compound of part A above (1.09 g) was dissolved in 20 mL of dry CH 2 Cl 2 and chilled to 0° C. CF 3 COOH, 2.2 mL, was then added dropwise. The reaction stirred for 15 minutes at 0° C. before it was allowed to warm to room temperature over 2.3 hours. The reaction was quenched with 20 mL of NaOH (2N) and 80 mL of CH 2 C 12 . The organic phase was washed with water, dried over MgSO 4 , filtered, and evaporated to give 1.07 g of as a crude oil. Flash column purification over silica gel using a solvent mixture (6.5% MeOH, 0.5% NH 4 OH in CH 2 Cl 2 ) afforded 827 mg of (R)-2-N,N-dimethylamino-8-(cyclobut-1-enyl)tetralin. The HCl salt was made with 205 mg of the material. The salt was recrystallized from hot EtOH and (ether/hexane) to recover 159 mg of (R)-2-N,N-dimethylamino-8-(cyclobut-1-en-1-yl)tetralin hydrochloride. 2 M.P.: 196-197° C. dec Elemental Analysis: Calculated: C 72.85; H 8.41; N 5.31 Found C 72.59; H 8.37; N 5.43 
 EXAMPLE 3 
 (R)-2-N,N-dimethylamino-8-(prop-1-en-2-yl tetralin) hydrochloride 38 Title compound was prepared substantially according to the procedure of Example 2 using 1.50 g (5.9 mmol) of (&plus;)-(R)-2-N,N-dimethylamino-8-bromotetralin and 0.74 mL of acetone to give 682 mg of (R)-2-N,N-dimethylamino-8-(prop-1-en-2-yl-tetralin) as a free base which was converted to the HCl salt. 3 M.P.: 168-170° C. Elemental Analysis: Calculated: C 71.55; H 8.81; N 5.56 Found: C 71.66; H 8.95; N 5.57 
 EXAMPLE 4 
 (R)-2-N,N-dimethylamino-8-(cyclooct-1-en-1-yl)tetralin hydrochloride 39 Title compound was prepared substantially according to the procedure of Example 2 using 1.70 g (6.71 mmol) of (&plus;)-(R)-2-N,N-dimethylamino-8-bromotetralin and 1.5 mL of cyclooctanone to give 444 mg of (R)-2-N,N-dimethylamino-8-(cyclooct-1-en-1-yl)tetralin, and was recovered as the HCl salt. 4 M.P.: 174-176° C. Elemental Analysis Calculated: C 75.09; H 9.45; N 4.38 Found: C 75.06; H 9.21; N 4.48 
 EXAMPLE 5 
 (R)-2-N,N-dimethylamino-8-(pent-2-en-3-yl)tetralin hydrochloride 40 Title compound was prepared substantially according to the procedure of Example 2 using 953 mg (3.75 mmol) of (&plus;)-(R)-2-N,N-dimethylamino-8-bromotetralin and 0.68 mL of diethyl ketone to give 373 mg of (R)-2-N,N-dimethylamino-8-(pent-2-en-3-yl)tetralin hydrochloride. 5 M.P.: 158-160° C. Elemental Analysis: Calculated: C 72.96; H 9.37; N 5.01 Found: C 72.74; H 9.22; N 5.07 
 EXAMPLE 6 
 (R,S), (R,R)-2-N,N-dimethylamino-8-(3-methylcyclopent-1-en-1-yl)tetralin hydrochloride 41 Title compounds were prepared substantially according to the procedure of Example 2 using 602 mg (2.37 mmol) of (&plus;)-(R)-2-N,N-dimethylamino-8-bromotetralin and 4.03 mL of 3-methylcyclopentanone to give 229 mg of a mixture of two diasteromers of (R,S),(R,R)-2-N,N-dimethylamino-8-(3-methylcylopent-1-en-1-yl)tetralin hydrochloride which was isolated as the HCl salt. 6 M.P.: 160-162° C. Elemental Analysis: Calculated: C 73.82; H 9.13; N 5.01 Found: C 74.08; H 8.98; N 4.80 
 EXAMPLE 7 
 (R)-2-N,N-dimethylamino-8-cyclobutyltetralin hydrochloride 42 The compound of Example 2, 621 mg, was dissolved in 30 mL of MeOH along with 200 mg of Pd/C (5%) and 10 equivalents of ammonium formate. The mixture was stirred at reflux for 5 hours before allowing it to cool to room temperature. The resulting mixture was filtered over diatomaceous earth and the filter cake was rinsed with warm methanol. The filtrate was concentrated and redissolved in methylene chloride. The organic layer was washed with water (pH ˜11) and brine, and then dried over magnesium sulfate, filtered, and evaporated. The crude oil was made into its corresponding HCl salt and recrystallized from hot EtOH and (ether/hexanes) to recover 150 mg (R)-2-N,N-dimethylamino-8-cyclobutyltetralin hydrochloride. 7 M.P.: 155-156° C. Elemental Analysis Calculated: C 72.29; H 9.10; N 5.27 Found: C 72.50; H 9.15; N 5.57 
 EXAMPLE 8 
 (R,S), (R,R)-2-N,N-dimethylamino-8-(2-cyclopentylcyclopent-1-yl)tetralin hydrochloride 43 Title compound was prepared substantially according to the procedure of Examples 2 and 7 using 466 mg of (&plus;)-(R)-2-N,N-dimethylamino-8-bromotetralin and 0.616 mL of (R,S)-2-cyclopentyl cyclopeatanine. A mixture of two diastereomers (R,S),(R,R)-2-N,N-dimethylamino-8-(2-cyclopentylcyclopent-1-yl)tetralin, 108 mg, was isolated as the HCl salt. 8 M.P.: 172-174° C. Elemental Analysis Calculated: C 76.38; H 9.32; N 4.05 Found: C 76.13; H 9.59; N 3.97 
 EXAMPLE 9 
 (R,S), (R,R)-2-N,N-dimethylamino-8-(2-methylcyclopent-1-yl)tetralin hydrochloride 44 Title compound was prepared substantially according to the procedure of Examples 2 and 7 using 400 mg (1.57 mmol) of (&plus;)-(R)-2-N,N-dimethylamino-8-bromotetralin and 0.202 mL of 2-methylcyclopentanone to give 39 mg of a mixture of two diastereomers (R,S),(R,R)-2-N,N-dimethylamino-8-(2-methylcyclopent-1-yl)tetralin which was isolated as the HCl salt. 9 M.P.: 181-183° C. Elemental Analysis Calculated: C 73.57; H 9.60; N 4.77 Found: C 73.29; H 9.64; N 4.69 
 EXAMPLE 10 
 (R)-2-N,N-dimethylamino-8-cyclohexylmethyl tetralin hydrochloride 45 Title compound was prepared substantially according to the procedure of Examples 2 and 7 using 627 mg (2.47 mmol) of (&plus;)-(R)-2-N,N-dimethylamino-8-bromotetralin and 0.509 mL cyclohexanecarboxaldehyde to give (R)-2-N,N-dimethylamino-8-cyclohexylmethyltetralin, 356 mg of which was isolated as the HCl salt. 10 M.P.: 234-235° C. Elemental Analysis Calculated: C 74.12; H 9.82; N 4.55 Found: C 73.89; H 9.68; N 4.40 
 EXAMPLE 11 
 (R)-2-N,N-dimethylamino-8-cyclooctyltetralin hydrochloride 46 Title compound was prepared substantially according to the procedure of Example 7 using 303 mg (1.07 mmol) of (R)-2-N,N-dimethylamino-8-cyclooct-1-en-1-yl-tetralin hydrochloride. Title compound, 210 mg, was recovered as the HCl salt. 11 M.P.: 171-173° C. Elemental Analysis: Calculated: C 74.02; H 10.02; N 4.35 Found: C 74.40; H 9.97; N 4.55 
 EXAMPLE 15 
 (R)-2-N,N-dimethylamino-8-methoxyethoxymethyl tetralin hydrochloride 47 To a stirred solution of (&plus;)-(R)-2-N,N-dimethylamino-8-bromotetralin (1.67 mmol) in 9 mL of THF was added n-butyllithium (1.76 mmol) at −78° C. under nitrogen. After stirring for 45 minutes, methoxyethoxymethyl chloride (1.75 mmol) was added. The resulting mixture was stirred at −78° C. for 15 minutes and then gradually warmed to room temperature over a period of 1 hour. Ten ml of 5% NaHCO 3 solution was added. The mixture was extracted with CH 2 Cl 2 (15 mL×3). The combined organic layer was dried (Na 2 SO 4 ), filtered, and then concentrated. The crude residue was purified by flash chromatogrphy using a mixture of solvents (NH 4 OH, 0.5%; MeOH, 7%; in CH 2 Cl 2 ) to give 382.7 mg (87%) of title compound. MS (m/e): 263 (M &plus; ). HCl salt of the product has melting point of 147-148° C. 
 EXAMPLE 13 
 (R,S), (R,R)-2-N,N-dimethylamino-8-(tetrahydropyran-2-yl)tetralin hydrochloride 48 A. Preparation of 2-chlorotetrahydropyran The starting material of 2-chlorotetrahydropyran was synthesized by reported procedures (R. A. Earl, L. B. Townsend; Synthesis, 1972, 1140). Dihydropyran (300 mmol) and CH 2 Cl 2 (25 mL) were placed in a flask. HCl gas was bubbled through the precooled mixture (−78° C.) for 30 minutes. The mixture was then slowly warmed to room temperature. Distillation of the crude product (44° C./water aspirator) gave 20.4 g (56% purity) of 2-chlorotetrahydropyran. B. Preparation of (R,S)(R,R)-2-N,N-dimethylamino-8-(tetrahydropyran-2-yl)tetralin hydrochloride To a stirred solution of (&plus;)-(R)-2-N,N-dimethylamino-8-bromotetralin (1.10 mmol) in 5 mL of THF was added n-butyllithium (1.32 mmol) at −78° C. under nitrogen. After stirring for 45 minutes, 2-chlorotetrahydropyran (1.20 mmol) was added. The resulting mixture was stirred at −78° C. for 15 minutes and then gradually warmed to room temperature over a period of 1 hour. Ten mL of 5% NaHCO 3 solution was added. The mixture was extracted with CH 2 Cl 2 (15 mL×3). The combined organic layer was dried (Na 2 SO 4 ), filtered, and then concentrated. The crude residue was purified by flash chromatography using a mixture of solvent (NH 4 OH, 0.5%; MeOH, 7%; in CH 2 Cl 2 ) to give 116.4 mg (45%) of title compound a mixture of two diastereoisomers. HCl salts of the products were prepared. 12 MS (m/e) 296 (M &plus; ). Elemental Analysis: Calculated: C 69.02; H 8.86; N 4.73 Found: C 69.21; H 9.10; N 4.67 
 EXAMPLE 14 
 (R)-2-N,N-dimethylamino-8-(tetrahydrofuran-2-yl)tetralin hydrochloride 49 A. Preparation of 2-chlorotetrahydrofuran Subtitled product was prepared substantially according to the procedures reported in part A of Example 16. Thus, the reaction of dihydrofuran (400 mmol) and HCl gas in CH 2 Cl 2 gave 28.2 g (66%) of 2-chlorotetrahydrofuran. B. Preparation of (R)-2-N,N-dimethylamino-8-(tetrahydrofuran-2-yl)tetralin hydrochloride Using substantially the same procedure as in Example 13, part B, the reaction of (&plus;)-(R)-2-N,N-dimethylamino-8-bromotetralin (1.28 mmol) with n-butyllithium (1.54 mmol) and 2.-chlorotetrahydrofuran (1.53 mmol) in 5 mL of THF gave 175.1 mg (56%) of title compound as a mixture of the two diastereoisomers. HCl salts of the products were prepared. 13 MS (m/e): 246° (M &plus; ). Elemental Analysis: Calculated: C 68.19; H 8.58; N 4.97 Found: C 68.38; H 8.68; N 4.85 
 EXAMPLE 15 
 (R)-2-N,N-dimethylamino-8-(1′-hydroxycyclohexyl)tetralin hydrobromide 50 To a stirred solution of (&plus;)-(R)-2-N,N-dimethylamino-8-bromotetralin (4.17 mmol) in 15 mL of THF, was added n-butyllithium (1.6 M in hexanes, 5.76 mmol) at −78° C. under nitrogen. After stirring for 45 minutes, cyclohexanone (6.37 mmol) was added. The resulting mixture was stirred at −78° C. for 30 minutes and then gradually warmed to room temperature over a period of 30 minutes. The reaction mixture was quenched with 5% NaHCO 3 solution (25 mL), then extracted with CH 2 Cl 2 (20 mL×3). The combined organic layer was dried (Na 2 SO 4 ), filtered, and then concentrated. The crude residue was purified by flash chromatography using a mixture of NH 4 OH, MeOH, CH 2 Cl 2 (0.5%:9%:90.5%) to give 751.6 mg (66%) of title compound as an oil. MS (m/e): 256° (M &plus; -H 2 O). HBr salt of the product has melting point of 210-211° C. 
 EXAMPLE 16 
 (R)-2-N,N-dimethylamino-8-(1′-hydroxy cycloheptyl)tetralin hydrobromide 51 Following substantially the same procedure as described in Example 15, the reaction of (&plus;)-(R)-2-N,N-dimethylamino-8-bromotetralin (4.06 mmol) with n-butyllithium (5.66 mmol) and cycloheptanone (6.10 mmol) in 15 mL of THF gave 696.8 mg (60%) of title compound. MS (m/e): 270° (M &plus; -H 2 O) HBr salt of the products has melting point of 186-187° C. 
 EXAMPLE 17 
 (R)-2-N,N-dimethylamino-8-(cyclohex-1-en-1-yl)tetralin hydrochloride 52 A mixture of the compound of Example 15 (1.29 mmol) and trifluoroborane etherate (1.38 mmol) in 10 mL of CH 2 Cl 2 was stirred at room temperature for 5 minutes. NaOH solution (1N, 10 mL) was added. The product was extracted with CH 2 Cl 2 . The extract was dried, filtered, and concentrated. The crude residue was purified by flash chromatography using a mixture of NH 4 OH, MeOH, and CH 2 Cl 2 (0.5:10:120) to give 56% yield of title compound. The HCl salt of the product has melting point of 190-191° C. 
 Elemental Analysis 14 Calculated: C 74.08; H 8.98; N 4.80 Found: C 74.29; H 8.89; N 5.01 
 EXAMPLE 18 
 (R)-2-N,N-dimethylamino-8-(cyclohept-1-en-1-yl)tetralin hydrochloride 53 Using a substantially same procedure as described in Example 17, using (1.67 mmol) of the compound of Example 16, and trifluoroacetic acid (0.3 mL) in 8 mL of CH 2 Cl 2 gave 80% yield of title compound. HCl salt of the product has melting point of 160-161° C. 
 Elemental Analysis 15 Calculated: C 74.61; H 9.23; N 4.58 Found: C 74.85; H 9.25; N 4.78 
 EXAMPLE 19 
 (R)-2-N,N-dimethylamino-8-(cyclopent-1-en-1-yl) tetralin hydrochloride 54 A. Preparation of (R)-8-(1′-hydroxy)cyclopentyl-2-N,N-dimethylaminotetralin (R)-8-(1′-hydroxy)cyclopentyl-2-N,N-dimethylaminotetralin was prepared substantially according to the procedures described in Example 15 using (&plus;)-(R)-2-N,N-dimethyamino-8-bromotetralin (5.99 mmol) with n-butyllithium (8.32 mmol) and cyclopentanone (10.17 mmol) in 17 mL of THF to give 815.6 mg (53%) of subtitled product. B. Preparation of (R)-2-N,N-dimethylamino-8-(cyclopentyl-1-en-1-yl)tetralin hydrochloride Using a substantially same procedure as described in Example 17, (3.07 mmol) of the compound of part A, above, and trifluoroacetic acid (1.5 mL) in 20 mL of CH 2 Cl 2 gave 659.2 mg (80%) of title compound. HCL salt of the product has melting point of 184-185° C. 
 Elemental Analysis 16 Calculated: C 73.49; H 8.71; N 5.04 Found: C 73.27; H 8.51; N 5.27 
 EXAMPLE 20 
 (R)-2-N,N-dimethylamino-8-cyclopentyltetralin hydrochloride 55 To a stirred solution of the compound of Example 20 (0.41 mmol) and EtSiH (0.63 mmol) in 11 mL of CH 2 Cl 2 , was added trifluoroborane etherate (0.81 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. Saturated Na 2 CO 3 (15 mL) was added. The product was extracted with CH 2 Cl 2 . The extract was dried, filtered, and concentrated. The crude residue was purified by flash chromatography using a mixture of NH4OH, MeOH, CH 2 Cl 2 (0.5:5:95) to give 73.0 mg (73%) of title compound. HCl salt of the product has melting point of 158-159° C. MS (m/e): 244° (M&plus;H). 
 EXAMPLE 21 
 (R)-2-N,N-dimethylamino-8-cyclohexyltetralin hydrochloride 56 The compound of Example 17 (1.29 mmol) was hydrogenated (60 PSI H 2 ) in ethanol (25 mL) in the presence of catalyst Pd/C (5%, 80 mg) for 12 hours. The crude mixture was filtered and then evaporated. The residue was purified by flash chromatography using a mixture of NH 4 OH, methanol, and CH 2 Cl 2 (0.5:6:94) to give 243.2 mg (73%) of title product. HCl salt of the product has melting point of 213-214° C. 
 Elemental Analysis 17 Calculated: C 73.57; H 9.60; N 4.78 Found: C 73.49; H 9.57; N 4.96 
 EXAMPLE 22 
 (R)-2-N,N-dimethylamino-8-cycloheptyltetralin hydrochloride 57 The compound of Example 18 (1.08 mmol) was hydrogenated (60 PSI H 2 ) in ethanol (25 mL) in the presence of catalyst Pd/C (5%, 75 mg) for 12 hours. The crude mixture was filtered and then evaporated. The residue was purified by flash chromatography using a mixture of NH 4 OH, methanol, and CH 2 Cl 2 (0.5:6:94) to give 211.7 mg (73%) of title product. HCl salt of the product has melting point of 192-193° C. 
 Elemental Analysis 18 Calculated: C 74.12; H 9.82; N 4.55 Found: C 73.93; H 9.76; N 4.78 
 EXAMPLE 23 
 2-(R)-2′-(S)-N,N-dimethylamino-8-(tetrahydrofuran-2-yl)tetralin hydrochloride 58 A. Preparation of N-methyl-N-methoxy-4-t-butyldiphenylsilyloxybutylamide To a stirred solution of n-methyl-N-methoxyamine hydrochloride (107.12 mmol) in 100 mL of CH 2 Cl 2 , was added 2.0 M solution of AlMe 3 (62.5 mmol) at −15° C. under nitrogen. After the mixture was stirred for 40 minutes, &ggr;-butyrolactone (31.25 mmol) was added at −15° C. The resulting mixture was stirred at room temperature for 2.5 hours. HCl solution (1 N) was added dropwise until all the precipitate was dissolved. The mixture was extracted with CH 2 Cl 2 /MeOH (9:1; 50 mL×8). The combined organic layer was dried, filtered, and concentrated. Without further purification, the crude residue containing N-methyl-N-methoxy-4-hydroxybutylamide was treated with chloro-t-butyldiphenylsilane (34.6 mmol) and imidazole (38.19 mmol) in the presence of DMAP (1.23 mmol) and DMF (50 mL) at room temperature under nitrogen for 13 hours. Upon aqueous workup, the crude residue was purified by flash chromatography using a mixture of hexanes and ethyl acetate (4:1) to give subtitled product (7.98 g)-in 66% overall yield. B. Preparation of (&plus;)-(R)-2-N,N-dimethylaminotetralin-8-yl-(3′-t-butyldiphenylsilyloxy)propylketone To a stirred solution of (&plus;)-(R)-2-N,N-dimethylamino-8-bromotetralin (1.36 mmol) in 6 mL of THF was added n-butyllithium (1.6 M in hexanes, 1.6 mmol) at −78° C. under nitrogen. After stirred for 30 minutes, the compound of part A (1.43 mmol) in 4 mL of THF was added. The resulting mixture was stirred at −78° C. for 20 minutes and then at room temperature for 2 hours. After aqueous workup, the crude residue was purified by flash chromatography using a mixture of NH 4 OH, CH 2 Cl 2 and MeOH (0.5:6:94) to give subtitled product (170 mg) in 25% yield. C. Preparation of 2-(R)-1′-(S)-2-N,N-dimethylamino-8-(1′-hydroxy-3′-t-butyldiphenylsilyloxy)propyltetralin To a stirred solution of the compound of part B, above, (0.67 mmol) in 1.5 mL of THF was added (−)-DIP-Cl(0.81 mmol) at 25° C. After the mixture was stirred for 3 days, the solvent was removed by evaporation. The residue was purified by flash chromatography using a mixture of NH 4 OH, MeOH, and CH 2 Cl 2 (0.5:8:92) to give 107.6 mg (32%) of subtitled product. D. Preparation of 2-(R)-1′-(S)-2-N,N-dimethylamino-8-(1′-benzoyloxy-3′-t-butyldiphenylsilyloxy)propyl tetralin To a stirred solution of the compound of part C (0.64 mmol) in 6 mL of CH 2 Cl 2 were added 0.2 mL of pyridine and 0.1 mL of benzoyl chloride (0.86 mmol). The mixture was stirred at room temperature for 3 hours. Saturated Na 2 CO 3 (10 mL) was added. The product was extracted with CH 2 Cl 2 . The extract was dried, filtered, and concentrated. The residue was purified by flash chromatography using a mixture of NH 4 OH, MeOH, and CH 2 Cl 2 (0.5:8:92) to give subtitled product (0.64 mmol) (363.9 mg) in 94% yield. E. Preparation of 2-(R)-1′-(S)-2-N,N-dimethylamino-8-(1′-benzoyloxy-3′-hydroxy)propyltetralin To a stirred solution of the compound of part D (0.60 mmol) in 6 mL of THF was added tetrabutylammonium fluoride (1.20 mmol). The mixture was stirred at room temperature for 5 hours. After aqueous workup, the crude residue was purified by flash chromatography using a mixture of NH 4 OH, MeOH, and CH 2 Cl 2 (0.5:10:90) to give subtitled product (0.54 mmol) in 91% yield. F. Preparation of 2′-(R)-4-(S)-4-&lsqb;2′-N,N-dimethylaminotetralin&rsqb;-8′-yl-4-benzoyloxybutyraldehyde To a stirred solution of the compound of part E (0.207 mmol) in CH 2 Cl 2 (2 mL) was added pyridinium chlorochromate (0.414 mmol) at room temperature. The mixture was stirred for 45 minutes. NaOH solution (2N) was added to basify the mixture (pH&equals;12). The product was extracted with CH 2 Cl 2 . The extract was dried, filtered, and concentrated. Purification of the residue by flash chromatography using a mixture of NH 4 OH, MeOH, and CH 2 Cl 2 (0.5:8:92) gave subtitled product (21.8 mg) in 29% yield. G. Preparation of 2-(R)-2′-(S)-2-N,N-dimethylamino-8-(5′-hydroxytetrahydrofuran-2′-yl)tetralin To a stirred solution of the compound of part F (21.8 mg) in MeOH (3 mL) was added NaOH (1N, 3 mL). The mixture was stirred at room temperature for 50 minutes. The product was extracted with CH 2 Cl 2 (10 mL×3). The extract was dried, filtered, and concentrated to give 15.5 mg of subtitled product as a crude product. H. Preparation of 2-(R)-2′-(S)-N,N-dimethylamino-8-(tetrahydrofuran-2-yl)tetralin hydrochloride To a stirred solution of the compound of part G, above, (15.5 mg, 0.06 mmol) in 3 mL of CH 2 Cl 2 were added Et 3 SiH (0.2 mL) and trifluoroacetic acid (0.2 mL). The mixture was stirred at room temperature for 10 minutes. NaOH solution was added until the pH equaled 12-14. The product was extracted with CH 2 Cl 2 (10 mL×3). The combined organic layer was dried, filtered, and concentrated. The residue was purified by flash chromatography using a mixture of NH 4 OH, MeOH, and CH 2 Cl 2 (0.5:8:92) to give title product (8.2 mg) in 57% yield. MS (m/e): 246 (M&plus; H). HCl salt of the product has melting point of 186-188° C. 
 EXAMPLE 24 
 2-(R)-2′(R)-N,N-dimethylamino-8-(tetrahydrofuran-2-yl)tetralin hydrochloride 59 A. Preparation of 2-(R)-1′-(R)-2-N,N-dimethylamino-8-(1′-hydroxy-3′-t-butyldiphenylsilyloxy)propyltetralin To a stirred solution of (&plus;)-(R)-2-N,N-dimethylaminotetralin-8-yl-(3′-t-butyldiphenylsilyloxy)propylketone (0.47 mmol) (Example 30, Part B) and (S)-1,3,3-triphenyltetrahydro-1H, 3H-pyrrolo&lsqb;1,2-C&rsqb;&lsqb;1,3,2&rsqb;oxazaborole (0.09 mmol) in 6 mL of THF was added BH 3 solution in THF (0.50 mmol) at 0° C. under nitrogen. The mixture was stirred for 30 minutes. The solvent was evaporated and the residue was dissolved in ether (10 mL) and methanol (10 mL). Diethanolamine (2 mL) was added. The mixture was heated to reflux for 14 hours. NH 4 OH solution was added to basify the mixture. The product was extracted with CH 2 Cl 2 . The extract was dried, filtered, and concentrated. The residue was purified by flash chromatography using a mixture of NH 4 OH, MeOH, and CH 2 Cl 2 (0.5:6:94) to give 88.5 mg of subtitled product. B. Preparation of 2-(R)-1′-(R)-2-N,N-dimethylamino-8-(1′-benzoyloxy-3′-t-butyldiphenylsilyloxy)propyltetralin To a stirred solution of the compound of part A (0.568 mmol) in 8 mL of CH 2 Cl 2 were added 0.3 mL of pyridine and 0.1 mL of benzoyl chloride (0.86 mmol). The mixture was stirred at room temperature for 3 hours. Saturated Na 2 CO 3 (10 mL) was added. The product was extracted with CH 2 Cl 2. The extract was dried, filtered, and concentrated. The residue was purified by flash chromatography using a mixture of NH 4 OH, MeOH, and CH 2 Cl 2 (0.5:8:92) to give subtitled product (0.64 mmol) (308.0 mg) in 90% yield. C. Preparation of 2-(R)-1′-(R)-2-N,N-dimethylamino-8-(1′-benzoyloxy-3′-hydroxy)propyltetralin To a stirred solution of the compound of part B, above, (0.51 mmol) in 6 mL of THF was added tetrabutylammonium fluoride (1.02 mmol). The mixture was stirred at room temperature for 5 hours. After aqueous workup, the crude residue was purified by flash chromatography using a mixture of NH 4 OH, MeOH, and CH 2 Cl 2 (0.5:10:90) to give subtitled product (0.47 mmol) in 92% yield. D. Preparation of 2′-(R)-4-(R)-4-&lsqb;2′-N,N-dimethylaminotetralin&rsqb;-8′-yl-4-benzoyloxybutyraldehyde To a stirred solution of the compound of part C (0.466 mmol) in CH 2 Cl 2 (5 mL) was added pyridinium chlorochromate (0.932 mmol) at room temperature. The mixture was stirred for 45 minutes. NaOH solution (2N) was added to basify the mixture (pH&equals;12). The product was extracted with CH 2 Cl 2 . The extract was dried, filtered, and concentrated. Purification of the residue by flash chromatography using a mixture of NH 4 OH, MeOH, and CH 2 Cl 2 (0.5:8:92) gave subtitled product (61 mg). E. Preparation of 2-(R)-2′-(R)-2-N,N-dimethylamino-8-(5′-hydroxytetrahydrofuran-2′-yl)tetralin To a stirred solution of the compound of part D (61 mg) in MeOH (10 mL) was added NaOH (1N, 6 mL). The mixture was stirred at room temperature for 50 minutes. The product was extracted with CH 2 Cl 2 (15 mL×3). The extract was dried, filtered, and concentrated to give 35 mg of subtitled compound as a crude product. F. Preparation of 2-(R)-2′-(R)-N,N-dimethylamino-8-(tetrahydrofuran-2-yl)tetralin hydrochloride To a stirred solution of the compound of part E (35 mg) in 5 mL of CH 2 Cl 2 were added Et 3 SiH (0.3 mL) and trifluoroacetic acid (0.3 mL). The mixture was stirred at room temperature for 10 minutes. NaOH solution was added until pH&equals;12-14. The product was extracted with CH 2 Cl 2 (10 mL×3). The combined organic layer was dried, filtered, and concentrated. The residue was purified by flash chromatography using a mixture of NH 4 OH, MeOH, and CH 2 Cl 2 (0.5:8:92) to give title product (21.0 mg). MS (m/e): 245 (M &plus; ). HCl salt of the product has melting point of 195-197° C. 
 EXAMPLE 25 
 (R) -2-N,N-dimethylamino-8-(4-fluorophenyl)ethyloxymethyltetralin hydrochloride Following substantially the same procedure as described in Example 15, the reaction of (&plus;)-(R)-2-N,N-dimethylamino-8-bromotetralin (475 mg, 1.87 mm) with n-butyllithium (2.24 mmol) and 4-fluorophenethyl chloromethyl ether (389 mg, 2.06 mm) in 1 mL of THF gave 88.4 mg of the desired product. HCl salt of the product has melting point of 109-111° C. 
 Elemental Analysis 19 Calculated: C 69.31; H 7.48; N 3.85 Found: C 69.56; H 7.46; N 4.04 
 EXAMPLE 26 
 (R)-2-N,N-dimethylamino-8-(4-bromophenyl)ethyloxymethyl tetralin hydrochloride Following substantially similar procedure as described in Example 15, the reaction of (&plus;)-(R)-2-N,N-dimethylamino-8-bromotetralin (435 mg, 1.71 mmol) with n-butyllithium (2.05 mmol) and 4-bromophenethyl chloromethyl ether (512 mg, 1.88 mmol) in 12 mL of THF gave 201 mg of the desired product. HCl salt of the product has melting point of 114-115° C. 
 Elemental Analysis 20 Calculated: C 59.38; H 6.41; N 3.30 Found: C 59.12; H 6.21; N 3.28 
 EXAMPLE 27 
 (R)-2-N,N-dimethylamino-8-(4-methoxyphenyl)ethyloxymethyl tetralin hydrochloride Following substantially the same procedure as described in Example 15, the reaction of (&plus;)-(R)-2-N,N-dimethylamino-8-bromotetralin (395.7 mg, 1.557 mm) with n-butyllithium (1.07 ml) and 4-methoxyphenethyl chloromethyl ether (351 mg, 1.635 mm) in 1 mL of THF gave 117 mg of the desired product. HCl salt of the product has melting point of 131-132° C. 
 Elemental Analysis 21 Calculated: C 70.84; H 8.27; N 3.59 Found: C 70.81; H 8.37; N 3.59 The method of this invention is practiced by administering to a mammal a direct acting 5-HT 1D&agr; agonist or a pharmaceutically acceptable salt thereof. The phrase “direct acting 5-HT 1D&agr; agonist” as used in this specification and these claims means a non-endogenous chemical compound and includes: (1) synthetic chemical compounds (ligands) that mimic the action of serotonin on 5-HT 1D&agr; receptors by directly activating these receptors; and (2) partial agonists, which are synthetic chemical compounds (ligands) that mimic the action of serotonin on 5-HT 1D&agr; receptors by directly activating these receptors but produce a smaller maximal effect than do other ligands that act on the same receptor. These compounds may have activity at other receptors but must have some component of 5-HT 1D&agr; agonist activity. 
 Assay Experiments The ability of the compounds of this invention to bind to the 5-HT 1D&agr; receptor subtype was measured essentially as described in N. Adham, et al., Proceedings of the National Academy of Sciences ( USA ), 90, 408-412 (1993). Membrane Preparation: Membranes were prepared from transfected Ltk-cells which were grown to 100% confluency. The cells were washed twice with phosphate-buffered saline, scraped from the culture dishes into 5 mL of ice-cold phosphate-buffered saline, and centrifuged at 200×g for 5 minutes at 4° C. The pellet was resuspended in 2.5 mL of ice-cold Tris buffer (20 mM Tris HCl, pH&equals;7.4 at 23° C., 5 mM EDTA) and homogenized with a Wheaton tissue grinder. The lysate was subsequently centrifuged at 200×g for 5 minutes at 4° C. to pellet large fragments which were discarded. The supernatant was collected and centrifuged at 40,000×g for 20 minutes at 4° C. The pellet resulting from this centrifugation was washed once in ice-cold Tris wash buffer and resuspended in a final buffer containing 50 mM Tris HCl and 0.5 mM EDTA, pH&boxH;7.4 at 23° C. Membrane preparations were kept on ice and utilized within two hours for the radioligand binding assays. Protein concentrations were determined by the method of Bradford ( Anal. Biochem., 72, 248-254 (1976)). Radioligand Binding: &lsqb; 3 H-5-HT&rsqb; binding was performed using slight modifications of the 5-HT 1D assay conditions reported by Herrick-Davis and Titeler ( J. Neurochem., 50, 1624-1631 (1988)) with the omission of masking ligands. Radioligand binding studies were achieved at 37° C. in a total volume of 250 mL of buffer (50 mM Tris, 10 mM MgCl 2 , 0.2 mM EDTA, 10 mM pargyline, 0.1% ascorbate, pH&equals;7.4 at 37° C.) in 96 well microtiter plates. Saturation studies were conducted using &lsqb; 3 H&rsqb;5-HT at 12 different concentrations ranging from 0.5 nM to 100 nM. Displacement studies were performed using 4.5-5.5 nM &lsqb; 3 H&rsqb;5-HT. The binding profile of drugs in competition experiments was accomplished using 10-12 concentrations of compound. Incubation times were 30 minutes for both saturation and displacement studies based upon initial investigations which determined equilibrium binding conditions. Nonspecific binding was defined in the presence of 10 mM 5-HT. Binding was initiated by the addition of 50 mL membrane homogenates (10-20 &mgr;g). The reaction was terminated by rapid filtration through presoaked (0.5% poylethyleneimine) filters using 48R Cell Brandel Harvester (Gaithersburg, Md.). Subsequently, filters were washed for 5 seconds with ice cold buffer (50 mM Tris HCl, pH&equals;7.4 at 4° C.), dried and placed into vials containing 2.5 mL Readi-Safe (Beckman, Fullerton, Calif.) and radioactivity was measured using a Beckman LS 5000TA liquid scintillation counter. The efficiency of counting of &lsqb; 3 H&rsqb;5-HT averaged between 45-50%. Binding data was analyzed by computer-assisted nonlinear regression analysis (Accufit and Accucomp, Lunden Software, Chagrin Falls, Ohio). IC 50 values were converted to K i values using the Cheng-Prusoff equation ( Biochem. Pharmacol., 22, 3099-3108 (1973). All experiments were performed in triplicate. Representative compounds of the invention exhibited an Ki at the S-HT 1D&agr; receptor of at least 100 &mgr;mol. As was reported by R. L. Weinshank, et al., WO93/14201, the 5-HT 1D receptor is functionally coupled to a G-protein as measured by the ability of serotonin and serotonergic drugs to inhibit forskolin stimulated cAMP production in NIH3T3 cells transfected with the 5-HT 1D receptor. Adenylate cyclase activity was determined using standard techniques. A maximal effect is achieved by serotonin. An E max is determined by dividing the inhibition of a test compound by the maximal effect and determining a percent inhibition. (N. Adham, et al., supra,; R. L. Weinshank, et al., Proceedings of the National Academy of Sciences ( USA ), 89,3630-3634 (1992)), and the references cited therein. 
 Measurement of CAMP Formation Transfected NIH3T3 cells (estimated Bmax from one point competition studies&equals;488 fmol/mg of protein) were incubated in DMEM, 5 mM theophylline, 10 mM HEPES (4-&lsqb;2-hydroxyethyl&rsqb;-1-piperazineethanesulfonic acid) and 10 &mgr;M pargyline for 20 minutes at 37° C., 5% CO 2 . Drug dose-effect curves were then conducted by adding 6 different final concentrations of drug, followed immediately by the addition of forskolin (10 mM). Subsequently, the cells were incubated for an additional 10 minutes at 37° C., 5% CO 2 . The medium was aspirated and the reaction was stopped by the addition of 100 mM HCl. To demonstrate competitive antagonism, a dose-response curve for 5-HT was measured in parallel, using a fixed dose of methiothepin (0.32 mM). The plates were stored at 4° C. for 15 minutes and then centrifuged for 5 minutes at 500×g to pellet cellular debris, and the supernatant was aliquoted and stored at −20° C. before assessment of cAMP formation by radioimmunoassay (cAMP radioimmunoassay kit; Advanced Magnetics, Cambridge, Mass.). Radioactivity was quantified using a Packard COBRA Auto Gamma counter, equipped with data reduction software. Representative compounds were tested and found to be agonists at the 5-HT 1D&agr; receptor in the cAMP assay. 
 Pharmaceutical Formulations of the Invention The therapeutic and prophylactic treatments provided by this invention are practiced by administering to a mammal in need thereof a dose of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, that is effective in activating the 5-HT 1D&agr; receptor. While it is possible to administer a compound employed in the methods of this invention directly without any formulation, the compounds are usually administered in the form of pharmaceutical formulation comprising a pharmaceutically acceptable excipient and at least one compound of the present invention. The compounds or formulations of the present invention may be administered by the oral and rectal routes, topically, parenterally, e.g., by injection and by continuous or discontinuous intra-arterial infusion, in the form of, for example, tablets, lozenges, sublingual tablets, sachets, cachets, elixirs, gels, suspensions, aerosols, ointments, for example, containing from 0.01 to 90% by weight of the active compound in a suitable base, soft and hard gelatin capsules, suppositories, injectable solutions and suspensions in physiologically acceptable media, and sterile packaged powders adsorbed onto a support material for making injectable solutions. Such formulations are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. See. e.g., REMINGTON'S PHARMACEUTICAL SCIENCES, (16th ed. 1980). In making the formulations employed in the present invention the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh. Some examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, tragacanth, gelatin, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. The compounds of this invention may be delivered transdermally using known transdermal delivery systems and excipients. Most preferably, a compound of this invention is admixed with permeation enhancers including, but not limited to, propylene glycol, polyethylene glycol monolaurate, and azacycloalkan-2-ones, and incorporated into a patch or similar delivery system. Additional excipients including gelling agents, emulsifiers, and buffers may be added to the transdermal formulation as desired. For topical administration, a compound of this invention ideally can be admixed with any variety of excipients in order to form a viscous liquid or cream-like preparation. For oral administration, a compound of this invention ideally can be admixed with carriers and diluents and molded into tablets or enclosed in gelatin capsules. In the case of tablets, a lubricant may be incorporated to prevent sticking and binding of the powdered ingredients in the dies and on the punch of the tableting machine. For such purpose there may be employed for instance aluminum, magnesium or calcium stearates, talc or mineral oil. Preferred pharmaceutical forms of the present invention include capsules, tablets and injectable solutions. Especially preferred are capsules and tablets. The therapeutic and prophylactic treatments provided by this invention are practiced by administering to a mammal in need thereof a dose of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof that is effective to alleviate the pathological effects of 5-HT 1D&agr; receptor-activated diseases. Advantageously for this purpose, formulations may be provided in unit dosage form, preferably each dosage unit containing from about 5 to about 500 mg (from about 5 to 50 mg in the case of parenteral or inhalation administration, and from about 25 to 500 mg in the case of oral or rectal administration) of a compound of Formula I. Dosages from about 0.5 to about 300 mg/kg per day, preferably 0.5 to 20 mg/kg, of active ingredient may be administered although it will, of course, readily be understood that the amount of the compound or compounds of Formula I actually to be administered will be determined by a physician, in the light of all the relevant circumstances including the condition to be treated, the choice of compound to be administered and the choice of route of administration and therefore the above preferred dosage range is not intended to limit the scope of the present invention in any way. The specific dose of a compound administered according to this invention to obtain therapeutic or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the route of administration the age, weight and response of the individual patient, the condition being treated and the severity of the patient's symptoms. In general, the compounds of the invention are most desirably administered at a concentration that will generally afford effective results without causing any serious side effects and can be administered either as a single unit dose, or if desired, the dosage may be divided into convenient subunits administered at suitable times throughout the day. The following formulation examples may employ as active compounds any of the compounds of this invention. The examples are illustrative only and are not intended to limit the scope of the invention in any way. 
 Formulation 1 Hard gelatin capsules are prepared using the following ingredients: 22 Quantity (mg/capsule) (R)-2-N-methyl-N-hexylamino-8- 250 cyclooctyltetralin Starch, dried 200 Magnesium stearate 10 Total 460 mg 
 Formulation 2 A tablet is prepared using the ingredients below: 23 Quantity (mg/tablet) (R)-2-N-isopentylamino-8-(1- 250 oxacyclopropyl) tetralin Cellulose, microcrystalline 400 Silicon dioxide, fumed 10 Stearic acid 5 Total 665 mg The components are blended and compressed to form tablets each weighing 665 mg. 
 Formulation 3 An aerosol solution is prepared containing the following components: 24 Weight (R)-2-N,N-di-t-butylamino-8- 0.25 isobutyltetralin Ethanol 25.75 Propellant 22 74.00 (Chlorodifluoromethane) Total 100.00 The active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to −30° C. and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container. 
 Formulation 4 Tablets, each containing 60 mg of active ingredient, are made as follows: 25 (R)-2-N-propylamino-8-hept-1-en-1yltetralin 60 mg Starch 45 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone (as 10% solution in 4 mg water) Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg Total 150 mg The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The aqueous solution containing polyvinylpyrrolidone is mixed with the resultant powder, and the mixture then is passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50° C. and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg. 
 Formulation 5 Capsules, each containing 80 mg of active ingredient, are made as follows: 26 (R)-2-N-methyl-N-propylamino-8-(4- 80 mg bromophenyl)butyloxymethyl tetralin Starch 59 mg Microcrystalline cellulose 59 mg Magnesium stearate 2 mg Total 200 mg The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities. 
 Formulation 6 Suppositories, each containing 225 mg of active ingredient, are made as follows: 27 (R)-2-N,N-dimethylamino-8-(3- 225 mg chlorophenyl)propyloxymethyltetralin Saturated fatty acid glycerides 2,000 mg Total 2,225 mg The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool. 
 Formulation 7 Suspensions, each containing 50 mg of active ingredient per 5 ml dose, are made as follows: 28 (R 50 mg (R)-2-N-ethyl-N-methylamino-8-(4- methylphenyl)butyloxytetralin Sodium carboxymethyl cellulose 50 mg Syrup 1.25 ml Benzoic acid solution 0.10 ml Flavor q.v. Color q.v. Purified water to total 5 ml The active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with a portion of the water and added, with stirring. Sufficient water is then added to produce the required volume. 
 Formulation 8 An intravenous formulation may be prepared as follows: 29 (R)-2-N,N-dipropyl-8-(3- 100 mg propylphenyl)hexyloxyethyltetralin hydrochloride Isotonic saline 1,000 ml The solution of the above ingredients generally is administered intravenously to a subject at a rate of 1 ml per minute.