EP0395734A1 - 1-aminomethyl-1,2,3,4-tetrahydronaphthaline - Google Patents

1-aminomethyl-1,2,3,4-tetrahydronaphthaline

Info

Publication number
EP0395734A1
EP0395734A1 EP89902122A EP89902122A EP0395734A1 EP 0395734 A1 EP0395734 A1 EP 0395734A1 EP 89902122 A EP89902122 A EP 89902122A EP 89902122 A EP89902122 A EP 89902122A EP 0395734 A1 EP0395734 A1 EP 0395734A1
Authority
EP
European Patent Office
Prior art keywords
loweralkyl
hydrogen
phenyl
hydroxy
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP89902122A
Other languages
English (en)
French (fr)
Other versions
EP0395734A4 (en
Inventor
John Francis Debernardis
Robert Edward Zelle
Fatima Zehra Basha
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Laboratories
Original Assignee
Abbott Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of EP0395734A1 publication Critical patent/EP0395734A1/de
Publication of EP0395734A4 publication Critical patent/EP0395734A4/en
Pending legal-status Critical Current

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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07C211/30—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by two rings
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    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • This invention relates to alpha-2-adrenergic antagonists useful in the treatment of depression, metabolic disorders (e.g. obesity or diabetes), glaucoma, migraine and hypertension.
  • the adrenergic nervous system plays a major role in the innervation of heart, blood vessel and smooth muscle tissue.
  • Compounds capable of interacting with receptor sites within the adrenergic nervous system can initiate a variety of physiological responses, including vasoconstriction, vasodilation, and increased or decreased heart rate (chronotropic), contractility (inotropic) and metabolic activity.
  • various adrenergic compounds have been employed toaffect these and other physiological responses.
  • many adrenergic compounds do not possess significant selectivity to enable desirable interactions with adrenergic receptor sites. That is, these adrenergic compounds do not demonstrate a high degree of specificity for differing receptor types within the
  • adrenergic nervous system in order to obtain a desired physiological response separate from other possible, and perhaps less desirable, responses of the system.
  • alpha-adrenergic receptor Through inhibitory interaction with the alpha-adrenergic receptor in the peripheral nervous system, one can modulate the function of adrenergic neurons and hemodynamic equilibrium which is therapeutically useful in a multitude of cardiovascular indications such as hypertension, congestive heart failure, and a variety of vascular spastic conditions. Furthermore, the alpha-adrenergic antagonists are useful in certain neurological and psychiatric disorders such as depression.
  • the present invention includes compounds represented by the formula:
  • n 0 or 1 ;
  • R 1 , R 2 , R 3 , and R 4 are independently selected from hydrogen, hydroxy, amino, alkylamino, alkylsulfonylamino, loweralkyl, loweralkoxy, halo, and thioalkoxy; or R 1 , and R 2 or R 2 and R 3 taken together can form a methylenedioxy or ethylenedioxy bridge;
  • R 5 is loweralkyl
  • R 6 and R 8 are hydrogen
  • m is 0 , 1 or 2 and X is CH 2 , O , S or N-CH 3 ; or R 7 is
  • R 11 and R 12 are independently selected from hydrogen, halo, hydroxy, methoxy, thiomethoxy, amino and loweralkyl, or R 11 and R 12 taken together can form a methylenedioxy or ethylenedioxy bridge; or R 7 is
  • t is 0 or 1
  • R 9 is hydrogen or loweralkyl
  • R 10 is hydrogen, loweralkyl, phenyl, or substituted phenyl wherein the the phenyl ring is substituted with one, two or three substituents independently selected from loweralkyl, halo, hydroxy, loweralkoxy, amino and thioalkoxy; or
  • R 5 and R 9 taken together form a pyrrolidine ring and then R 6 , and R 8 are hydrogen and R 7 is
  • m 0, 1 or 2 and X is CPU, O, S or N-CH 3 ; or R 7 is
  • R 11 and R 12 are independently selected from hydrogen, halo, hydroxy, methoxy, thiomethoxy, amino and loweralkyl, or R 11 and R 12 taken together can form a methylenedioxy or ethylenedioxy bridge; or R 7 is
  • t is 0 or 1;
  • R 5 and R 9 taken together form a pyrrolidine ring and then R 6 is hydrogen and R 7 , and R 8 taken together form a phenyl, thienyl, furyl or substituted phenyl wherein the phenyl ring is substituted with one, two or three substituents independently selected from loweralkyl, halo, hydroxy, loweralkoxy, amino and thioalkoxy; or
  • R 5 and R 8 taken together form a pyrrolidine ring and then R 9 and R 6 are hydrogen and R 7 is phenyl, thienyl, furyl or substituted phenyl wherein the phenyl ring is substituted with one, two or three substituents independently selected from loweralkyl, halo, hydroxy, loweralkoxy, amino and thioalkoxy; or R 7 and R 9 are hydrogen and R 9 is benzyl, thienylmethyl, furylmethyl or substituted benzyl wherein the phenyl ring is substituted with one, two or three substituents independently selected from loweralkyl, halo, hydroxy, loweralkoxy, amino and thioalkoxy; or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention contain one or more asymmetric carbon atoms and it is to be understood that the invention includes both the racemic mixture as well as the optically active compounds.
  • the dashed lines mean that either a single or double bond may exist.
  • loweralkoxy refers to alkoxy groups containing 1 or 2 carbon atoms.
  • thioalkoxy refers to -SR" wherein R" is a loweralkyl residue.
  • loweralkyl means straight or branched chain saturated hydrocarbon radicals having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl. and iso-propyl.
  • alkylamino means -NHR 20 or -NR 20 R 21 wherein R 20 and R 21 are independently selected from loweralkyl.
  • alkylsulfonylamino means R 22 S(O) 2 N(R 23 )- wherein R 22 is loweralkyl and R 23 is hydrogen or loweralkyl.
  • substituted phenyl means a phenyl ring with one, two or three substituents independently selected from loweralkyl, halo, hydroxy, loweralkoxy, amino, and thioalkoxy.
  • substituted benzyl means a benzyl group wherein the phenyl ring is substituted with one, two or three substituents independently selected from halo, loweralkoxy, thioalkoxy, loweralkyl, amino and hydroxy.
  • halo or halogen means fluorine, iodine, bromine or chlorine.
  • pharmaceutically acceptable salts refers to the pharmaceutically acceptable, relatively nontoxic, inorganic or organic acid addition salts of the compounds of this invention. These salts can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the free base with a suitable organic or inorganic acid.
  • Representative salts include the hydrochloride, hydrobromide, sulfate, phosphate, nitrate, bisulfate, acetate, oxalate, valerate, oleate, palmitrate, methanesulfonate, stearate, laurate, borate, benzoate, lactate, phosphate, t ⁇ sylate, citrate, maleate, fumarate, succinate, tartrate, napsylate and the like. It will be apparent to those skilled in the art that, depending upon the number of available amino groups for salt formation, the salt of this invention can be per-N-salts.
  • the compounds of the present invention can be prepared as illustrated in Schemes 1-4.
  • the dihydro-1-cyanonaphthylene derivative is obtained either with trimethylsilyl cyanide or diethylcyanophosphonate. Reduction to the corresponding aminomethyl tetralin is accomplished with Raney-Nickel to afford compound 1. If desired, the 1-carboxylic acid derivative is obtained after reduction with sodium borohydride, followed by hydrolysis, affording 2.
  • the amine l can be alkylated using the appropriate carboxylic acid or ester, activated ester or acid halide derivatives thereof, followed by reduction of the resulting amide bond.
  • Acid halide derivatives include the acid chloride.
  • Esters include the methyl and ethyl esters.
  • Activated ester derivatives include activated esters commonly used by those skilled in the art for activating carboxylic acid groups for coupling with an amine to form an amide bond including, but not limited to, formic and acetic acid derived anhydrides, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, N-hydroxysuccinimide derived esters, N-hydroxyphthalimide derived esters, N-hydroxybenzotriazole derived esters, 4-nitrophenol derived esters, 2,4,5-trichlorophenol derived esters and the like.
  • compound 1 can be N-alkylated with ethyl formate, followed by diborane reduction of the amide, to give 3 or N-alkylated to the mono ethyl derivative with acetic anhydride, followed by diborane reduction, affording 4.
  • compound 2 upon coupling with DCC and the desired pyrrolidine derivative, affords 7 which upon reduction with diborane affords the desired pyrrolidine product 9.
  • Carboxylic acid derivatives such as those described above can also be used in this process.
  • the pyrrolidine product 12 may be prepared from 2 following formation of the acid chloride with oxalyl chloride and subsequent formation of the carboxamide 8.
  • N-alkylation of the pyrrolidine is accomplished with DCC coupling with a carboxylic acid derivative and diborane reduction to give 12.
  • Carboxylic acid derivatives such as those described above can also be used in this process.
  • the desired 3-substituted 1-tetralones can be synthesized from the appropriate 1,3-dithiane derivative, which is formed from the corresponding substituted benzaldehyde. Addition of the dithiane anion to various cinnamates or acrylates provides the homologated ester. Raney-nickel reduction and basic hydrolysis, followed by acidic cyclization, affords the desired 3-substituted 1-tetralones, which can be carried on as outlined in schemes 1-3.
  • Example 1 1-Cyano-6-methoxy-3,4-dihydronaphthalene To a refluxing benzene solution (60ml) of 6-methoxy-1-tetralone was added trimethylsilyl cyanide (TMSCN) (67.5g) and a trace of AlCl 3 or Znl 2 . Refluxing was continued for 1 hr., then the solvent removed under vacuum. Isopropyl alcohol saturated with HCl(g) was added and the solution refluxed for 1 hr. Precipitation began to occur and the reaction was cooled, then evaporated to dryness. Water was added, followed by an ethyl acetate (EtOAc) extraction.
  • EtOAc ethyl acetate
  • Example 2 6-Methoxy-1-aminomethyl tetralin hydrochloride
  • the product (93g) from Example 1 was hydrogenated at room temperature with RaNi (184g) at 3 atm pressure in the presence of MeOH (900 ml) and N H 2 (100 ml).
  • the solvent was evaporated, H 2 O and KOH added, followed by extraction with ethyl acetate.
  • the organic layer was washed with brine, separated, dried (MgSO 4 ), filtered then isopropanol/HCl added.
  • the desired product precipitated, was filtered and dried (87.7g).
  • Example 3 1-((N-Methylamino)methyl)-6-methoxytetralin hydrochloride
  • Example 2 The product from Example 2 was converted to the free base (15g) then dissolved in toluene (40 ml). Ethyl formate (70ml) was added and the reaction refluxed for 2 hr. The solvent was evaporated giving an oil. This was dissolved in dry tetrahydrofuran (THF) (100 ml) and added dropwise to lithium aluminum hydride (3.23 g) in THF, with cooling. Upon complete addition, the reaction was refluxed for 2 1/2 hr. then stirred an additional 24 hr at room temperature, followed by an additional 3 hrs refluxing. The mixture was cooled in an ice bath, then quenched with H 2 O (3.3ml), 15% aq.
  • THF dry tetrahydrofuran
  • Example 4 The product from Example 4 (7.2g) was dissolved in dry THF (50ml) then a 1M solution of B H 3 in THF (65ml) was added dropwise. The reaction was refluxed for 3 hrs., cooled, treated with 6N HCI (50ml) added dropwise, and upon complete addition, refluxed for 2 hrs. The reaction was then allowed to stand overnight during which time a solid precipitated. This solid was filtered and dried giving 7.24g of the hydrochloride salt, m.p. 211-213°C. Anal.calcd. for C 19 H 26 ClNOS: C, 64.83; H, 7.46; N, 3.98; Found: C, 64.59; H, 7.40; N, 3.74.
  • Example 6 Using the product from Example 3 and utilizing the procedures described in Examples 4 and 5 substituting for the 2-thiopheneacetic acid the desired readily available carboxylic acid the following compounds were prepared:
  • Example 7 1-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-6-hydroxy tetralin hydrochloride
  • the product from Example 4 (2.35g of the HCI salt) was added to CH-C1- (150ml) and stirred at -78°C while BBr 3 (2.2ml) was added dropwise.
  • BBr 3 2.2ml
  • the reaction was allowed to warm to room temperature and stirred for 1 hr. After this period, the reaction was cooled to -78°C and quenched by the careful addition of MeOH.
  • the reaction was evaporated to dryness then dissolved in MeOH/CH 2 Cl 2 and brought to pH7 with NH.OH.
  • Example 8 1-((N-Methylamino)methyl-N-(2-(3-thienyl)ethyl))-6-hydroxy tetralin hydrochloride Using the compound from Example 6d with the procedure of Example 7 the desired compound was obtained m.p. 114-16°C. Anal. calcd. for C 28 H 24 ClNOS: C, 63.97; H, 7.17; N, 4.15. Found: C, 63.57; H, 7.22; N, 3.98.
  • Example 9 1-((N-Methylamino)methyl-N-(2-(p-fluoropheny1)ethyl))-6- hydroxy tetralin hydrobromide
  • the product from Example 6a (1.6g) was added to CH 2 Cl 2 (30ml) then cooled to -78°C.
  • BBr 3 1.5ml in 5 ml CH 2 Cl 2 was added dropwise, and the reaction was stirred 3 hrs. At the end of this period, MeOH (10ml) was carefully added and the solution was evaporated to dryness affording a brownish residue. This residue was dissolved in CH 3 CN and allowed to stand at room temperature overnight.
  • Example 10 1-((N-Methylamino)methyl-N-(2-(m-fluorophenyDethyl))-6- hydroxy tetralin hydrochloride
  • the product from Example 6b (.75g) was O-demethylated with BBr 3 (0.7ml) using the procedure of Example 9. However, after quenching the reaction with MeOH the solution was evaporated to dryness then methanolic HCI (20ml) was added. This was heated on a steam bath until the volume was reduced to ca. 2-3ml. The white solid was triturated with ethylacetate, filtered and dried giving the product, m.p. 154-55°C. Anal. calcd. for C 20 H 25 ClFNO: C, 68.65; H, 7.22; N, 4.00. Found: C, 68.32; H, 7.22; N, 3.70.
  • Example 11 1-((N-Methylamino)methyl-N-(2-phenylethyl))-6-hydroxy tetralin hydrobromide Using the product from Example 6c with the procedure of Example 9 afforded the product, m.p. 156-57°C. Anal. calcd. for C 20 H 26 BrNO: C, 63.82; H, 6.98; N, 3.72. Found: C, 63.56; H, 6.84; N, 3.46.
  • Example 12 1-((N-Methylamino)methyl-N-(2-(N-methyl-2-pyrrolyl)- ethyl))-6-methoxy tetralin fumarate
  • the desired compound m.p. 145-6°C
  • 2-thiopheneacetic acid was replaced with N-methyl-2-pyrrolyl acetic acid and then preparing the fumarate salt in place of the HCI salt.
  • Anal. calcd. for C 24 H 32 N 2 O 5 C, 67.24; H, 7.53; N, 6.54. Found: C, 66.89; H, 7.54; N, 6.26.
  • Example 14 5-Methoxy-1-aminomethyl-tetralin hydrochloride The product from Example 13 was hydrogenated using the procedure of Example 2 to give the desired product. Anal. calcd. for C 12 H 18 ClNO: C, 63.30; H, 7.91; N, 6.15. Found: C, 63.13; H, 8.15; N, 6.09.
  • Example 16 1-((N-Formylamino)methyl)-5-methoxytetralin
  • the product from Example 14 was converted to its free base (3.4g) and dissolved into toluene (30ml). Ethyl formate (5ml) was added and the reaction stirred at reflux for 5 hr. The solvent was removed to afford a solid. Recrystallization from Et 2 O/CH 2 Cl 2 afforded 3.07g of desired product.
  • Example 18 N-(5-Methoxy-1,2,3,4-tetrahydro-1-naphthyl)methyl- N-methyl-2-thienylacetamide
  • the product from Example 17 (1.04g), 1-hydroxybenzotriazole hydrate (1.51g) and 2-thiopheneacetic acid (720mg) in dry THF (30ml) at 0°C was treated with dicyclohexylcarbodiimide (1.16g). The reaction was warmed to room temperature and stirred for 18 hr. The mixture was filtered and concentrated. The residue was dissolved into EtOAc (60ml) washed with 5% aq. HCI (15ml), water (15ml), 10% aq. KOH (15ml), dried (MgSO 4 ) filtered and concentrated. Chromatography on SiO 2 afforded 1.58g of product as a viscous oil.
  • Example 19 1-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))- 5-methoxy tetralin methanesulfonate
  • the product from Example 18 (1.58g) in dry THF (10ml) was slowly added to a suspension of lithium aluminum hydride (366 mg) in dry THF (30ml) and the resulting mixture heated at reflux for 1hr.
  • the reaction was cooled and treated with water (370uL), 15% aq. KOH (370uL) and water (1.1mL). After 30 min, the mixture was filtered and the filtrate concentrated. Chromatography on SiO 2 afforded 1.02g of product as a viscous oil.
  • Example 21 1-((N-Methylamino)methyl-N-(2-(2-furyl)ethyl))-6-methoxy tetralin hydrochloride Reacting the product from Example 3 with 2-furylacetic acid using the procedures of example 18 gave the desired amide. The amide was reduced using the procedure of example 19 except the hydrochloride salt was prepared with ethereal HCI in place of methanesulfonic acid, affording the compound, m.p. 203-5°C. Anal. calcd. for C 19 H 26 ClNO 2 : C, 67.94; H, 7.80; N, 4.17. Found: C, 67.93; H, 7.90; N, 4.07.
  • Example 22 1-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl)) tetralin hydrochloride
  • the desired compound was prepared (m.p. 222-23°C) using the procedures described in Examples 1-5 but replacing 6-methoxy-1-tetralone with 1-tetralone.
  • Example 23 l-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-5,6- methylenedioxy tetralin hydrochloride
  • the desired compound was prepared (m.p. 248-49°C) using the procedures described in Examples 1-5 but replacing 6-methoxy-1-tetralone with 5,6-methylenedioxy-1-te-ralone.
  • Example 24 1-((N-Methylamino)methyl-N-(2-(m-methoxyphenyl)ethyl))- 5,6-dimethoxy tetralin hydrochloride The product was obtained (m.p. 160-61°C) using the procedures described in Examples 1-5 but replacing 6-methoxy-1-tetralone with 5,6-dimethoxy-1-tetralone, and using 3-methoxyphenylacetic acid, in place of 2-thiopheneacetic acid. Anal. calcd. for
  • Example 25 1-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))- 6,7-dimethoxy tetralin hydrochloride The product was obtained (m.p. 149-50°C) using the procedures described in Examples 1-5 but replacing 6-methoxy-1-tetralone with 6,7-dimethoxy-1-tetralone.
  • Example 26 1-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))- 6,8-dimethoxy tetralin hydrochloride The product was obtained (m.p. 210-12°C) using the procedures described in Examples 1-5 but replacing 6-methoxy-1-tetralone with 6,8-dimethoxy-1-tetralone.
  • Example 27 1-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))- 7-methoxy tetralin hydrochloride The product was obtained (m.p. 180-1°C) using the procedures described in Examples 1-5 but replacing
  • Example 28 1-((N-Methylamino)methyl-N-(2-phenylethyl))-7-methoxy tetralin hydrochloride
  • the product was prepared (m.p. 178-79°C) using the procedures described in Examples 1-5 but replacing 6-methoxy-1-tetralone with 7-methoxy-1-tetralone, and using phenylacetic acid, in place of 2-thiopheneacetic acid.
  • Example 29 5,6-Ethylenedioxy-1-tetralone 5,6-Dihydroxy-1-tetralone (6g) was heated at 125°C with 1,2 dichloroethane (7ml) and K 2 CO 3 (14g) in DMSO (70ml) under N 2 for 45 min. The reaction was quenched with ice water then extracted with Et 2 O. The aqueous layer was removed, then EtOAc added to the remaining organics. This solution was dried (MgSO 4 ) filtered and evaporated to give the desired product.
  • Example 30 1-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-5,6- ethylenedioxy tetralin hydrochloride
  • the product was prepared (m.p. 205-6°C) using the procedures described in Examples 1-5 but replacing 6-methoxy-1-tetralone with the product from Example 29, Anal. calcd. for C 20 H 25 ClNO 2 S: C, 63.39; H, 6.65; N, 3.70. Found: C, 62.96; H, 6.99; N, 3.66.
  • Example 31 6-Thiomethyl-1-tetralone 6-Hydroxy-1-tetralone (16.2g) prepared from 6-methoxy-1-tetralone and AlCl3, was dissolved in dry dimethylformamide (DMF)(50ml) and added dropwise to a suspension of 4g NaH (60% in mineral oil) and dry DMF (200 ml) over 30 min. Then, dimethylthiocarbamyl chloride (14.8g) was added and the reaction heated at 85°C for 4 hrs. The reaction was poured onto ice and extracted with CH 2 Cl 2 (150ml). The CH 2 Cl 2 layer was washed with 10% aq. NaOH, then saturated NaCl solution.
  • DMF dry dimethylformamide
  • Example 32 1-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-6- thiomethyl tetralin hydrochloride
  • the product was prepared (m.p. 206-7°C) using the procedures described in Examples 1-5 but replacing 6-methoxy-1-tetralone with the product of Example 31.
  • Example 33 1-((N-Methylamino)methyl-N-(2-(m-fluorophenyl)ethyl))-5,6- dimethoxy-8-methyl tetralin hydrochloride The product was obtained (m.p. 184-86°C) using the procedures described in Examples 1-5 but replacing 6-methoxy-1-tetralone with 5,6-dimethoxy-8-methyl-1-tetralone and using 3-fluorophenylacetic acid, in place of 2-thiopheneacetic acid. Anal. calcd. for
  • Example 34 1-((N-Methylamino)methyl-N-(2-(m-fluorophenyDethyl))-5,6- dihydroxy-8-methyl tetralin hydrobromide Using the product of Example 33 and the procedure of Example 9 the desired compound was obtained m.p. (129-30°C). Anal. calcd. for C 21 H 27 BrFNO 2.1 /2H 2 O: C, 58.20; H, 6.40; N, 3.23. Found: C, 58.45; H, 6.33; N, 3.02.
  • Example 35 1-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-5,6- dimethoxy-8-methyl tetralin hydrochloride The product was obtained (M 359) using the procedures described in Examples 1-5 but replacing 6-methoxy-1-tetralone with 5,6-dimethoxy-8-methyl-1-tetralone.
  • Example 36 1-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-5- methoxy-8-methyl tetralin hydrochloride The product was obtained (m.p. 205-7°C) using the procedures described in Examples 1-5 but replacing 6-methoxy-1-tetralone with 5-methoxy-8-methyl-1-tetralone.
  • Example 37 1-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-5- methoxy indane hydrochloride The product was obtained (m.p. 197-99°C) using the procedures described in Examples 1-5 but replacing 6-methoxy-1-tetralone with 5-methoxy-1-indanone.
  • Example 39 1-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-6- methoxy-7-methyl tetralin hydrochloride The product was obtained (m.p. 173-4°C) using the procedures described in Examples 1-5 but replacing 6-methoxy-1-tetralone with the product of Example 38.
  • Example 41 1-((N-Ethylamino)methyl-N-(2-(2-thienyl)ethyl))-6-methoxy tetralin hydrochloride Using the product of Example 40 and the procedures of Examples 4 and 5 gave the desired compound m.p. 184-85°C. Anal. calcd. for C 20 H 28 ClNOS: C, 65.64; H, 7.71; N, 3.83. Found: C, 65.48; H, 7.75; N, 3.79.
  • Example 42 1-((N-Ethylamino)methyl-N-(2-(m-fluorophenyDethyl))-6- methoxy tetralin hydrochloride Using the product of Example 40 and the procedure of Examples 4 and 5 replacing
  • Example 43 1-((N-Ethylamino)methyl-N-(2-(2-furyl)ethyl))-6-methoxy tetralin hydrochloride Using the product of Example 40 and the procedure of Examples 18 and 19, replacing
  • Example 44 1-((N-Ethylamino)methyl-N-(2-(3-thienyl)ethyl))-6-methoxy tetralin hydrochloride Using the product of Example 40 and the procedure of Examples 4 and 5 replacing 2-thiopheneacetic acid with 3-thiopheneacetic acid gave the compound, m.p. 159-60°C. Anal. calcd. for C 20 H 28 ClNOS.1/4 H 2 O: C, 64.84; H, 7.75; N, 3.78. Found: C, 64.93 ; H, 7.63; N, 3.77.
  • Example 46 6-Chloro-3,4 dihydronaphthalene-1-carbonitrile Using the procedure of Example 13 replacing 5-methoxy-1-tetralone with 6-chloro-1-tetralone afforded the desired product.
  • Example 47 6-Chloro-1-aminomethyl tetralin hydrochloride
  • Example 46 The product from Example 46 was catalytically reduced with Pt 2 O at 4 atms. pressure in EtOH and HCI, affording the desired product.
  • Example 49 1-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-6-chloro tetralin hydrochloride Using the product from Example 48 and the procedures of Examples 4 and 5 afforded the desired compound, m.p. 233-34°C. Anal. calcd. for
  • Example 50 1-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl)-6-fluorotetralin hydrochloride Using the procedures described in Example 13, then in Examples 46-48 replacing 6-chloro-1-tetralone with 6-fluoro-1-tetralone gave 1-(N-methylamino) methyl-6-fluoro tetralin hydrochloride. Using this product and following the procedures of Examples 4 and 5 gave the desired compound, m.p. 225-27°C. Anal. calcd. for C 18 H 23 ClFNS: C, 63.62; H, 6.77; N, 4.12. Found: C, 63.93; H, 7.05; N, 4.11.
  • Example 51 5-Bromo-1-tetralone To a benzene solution (60ml) of 4-(o-bromophenyl) butyric acid (5g) was added oxalyl chloride (3.6ml) and the reaction refluxed for 1 1/2 hrs. The solution was evaporated to dryness, the residue was dissolved in CH 2 Cl 2 (50ml) then cooled to 0°C, followed by the addition of AlCl 3 (3.1g). The mixture was stirred at 0°C warming to room temperature overnight. The reaction was poured onto ice, then extracted with CH 2 Cl 2 . The organic layer was separated, washed with 1N NaOH, then brine, separated, dried (MgSO 4 ), filtered and evaporated affording the desired product (4.26g)
  • Example 51 Using the product from Example 51 (10g) and the procedure of Example 1 gave 5-bromo-3,4 dihydronaphthalene-1-carbonitrile (8.5g). This was reduced to the desired product with NaBH 4 (8.5g) in ethanol (165 ml), under reflux conditions for 2 hrs.
  • Example 53 5-Bromo-1-aminomethyl tetralin hydrochloride
  • the product from Example 52 (5g) was reduced with diborane as in Example 5 and afforded the desired product after recrystallization from EtOH.
  • Example 54 1-((N-Methylamino)methyl)-5-bromo tetralin hydrochloride The product from Example 53 was reacted as in the procedure described in Example 3 and gave the desired compound, m.p. 224-226°C. Anal. calcd. for C 12 H 17 BrClN: C, 49.59; H, 5.90; H, 4.82. Found: C, 49.73; H, 5.97; N, 4.81.
  • Example 57 1-((N-Propylamino)methyl)-6-methoxy tetralin hydrochloride
  • the product from Example 2 was reacted as in Example 15 but replacing acetic anhydride with propionic anhydride and gave the desired product.
  • Example 58 1-((N-Propylamino)methyl)-N-(2-(2-thienyl)ethyl))-6- meth ⁇ xy tetralin hydrochloride Using the product of Example 57 and the procedure of Examples 4 and 5 gave the compound (amorphous).
  • Example 59 1-((N-Methylamino)methyl)-N-(2-(2-thienyl)ethyl))-5- fluoro indane hydrochloride Using the procedures described in Example 13, and 46-48 but replacing the 6-methoxy-1-tetralone with 5-fluoro-1-indanone gave the product, m.p. 200-2°C. Anal. calcd. for C 17 H 21 ClFNS: C, 62.66; H, 6.50; N, 4.30. Found: C, 62.37; H, 6.45; N, 3.98.
  • Example 61 5-Methoxy-6-iodo-1-indanone
  • the product of Example 60 was added to methyl ethyl ketone (50ml), K 2 CO 3 (5g) and methyl iodide (5ml) then heated at reflux for 4 1/2 hrs.
  • the reaction was cooled, H-0 added, followed by an EtOAc extraction.
  • the organic layer was separated, washed with brine, dried (Na 2 SO 4 ), filtered and evaporated. Trituration of the residue afforded the desired compound after filtration, m.p. 129-30°C.
  • Example 63 1-((N-Propylamino)methyl)-5,6-dimethoxy tetralin hydrochloride Using the procedure of Example 57 but replacing 6-methoxy-1-tetralone with 5,6-dimethoxy-1-tetralone gave the desired product.
  • Example 64 1-((N-Propylamino)methyl-N-(2-(p-fluorophenyl)ethyl))- 5,6-dihydroxy tetralin hydrobromide Using the product of Example 63 and the procedures described in Examples 4 and 5 replacing the 2-thiopheneacetic acid with 4-fluorophenylacetic acid gave 1-( (N-propylamino)methyl-N- (2-(p-fluorophenyDethyl))-5,6-dimethoxy tetralin hydrochloride. This product was reacted as described in Example 9 to give the desired product, m.p. 212-14°C. Anal. calcd. for C 22 H 29 BrFNO 2 : C, 60.27; H, 6.68; N, 3.20. Found: C, 60.26; H, 6.58; N, 3.19.
  • Example 65 1-((N-Methylamino)methyl-N-(2-(m-nitrophenyl)ethyl))- tetralin hydrochloride Using the procedures described in Examples 1-5 but replacing 6-methoxy-1-tetralone with 1-tetralone and replacing 2-thiopheneacetic acid with 3-nitrophenylacetic acid gave the desired compound.
  • Example 66 1-((N-Methylamino)methyl-N-(2-(m-aminophenyl)ethyl))tetralin dihydrochloride
  • the product from Example 65 (3g) was catalytically reduced with 5% Pd/C at 3 atms. pressure in MeOH (95ml) and CHCl 3 (5ml) affording the desired amorphous dihydrochloride.
  • Example 67 1-((N-Methylamino)methyl-N-(2-(m-aminophenyl)ethyl))- 6-methoxytetralin dihydrochloride Using the product of Example 3 and the procedures of Example 4, 5 and 66 the product was obtained, after recrystallization from EtOAc/EtOH. Anal. calcd. for C 21 H 30 Cl 2 N 2 O.1/2 H 2 O: C, 62.05; H, 7.70; N, 6.89. Found: C, 62.15; H, 7.83; N, 6.51.
  • Example 68 1-((N-Methylamino)methyl-N-(2-(m-aminophenyl)ethyl))- 6-hydroxy tetralin dihydrobromide
  • BBr 3 1.ml
  • Example 69 1-((N-Methylamino)methyl-N-(2-(m-aminophenyl)ethyl))- 6-ethoxy tetralin dihydrochloride Using the procedures described in Examples 1-5 but replacing 6-methoxy-1-tetralone with 6-ethoxy-1-tetralone and replacing 2-thiopheneacetic acid with 3-nitrophenylacetic acid gave the nitro derivative which was reduced as in Example 66. The product was obtained as an amorphous solid. Anal. calcd. for C 22 H 32 Cl 2 N 2 0.1 1/2 H 2 O: C, 62.84; H, 7.93; N, 6.66. Found: C, 63.06; H, 7.82; N, 6.47.
  • Example 70 1-((N-Methylamino)methyl-N-(2-(m-fluorophenyDethyl))- tetralin hydrochloride Using the procedures described in Examples 1-5 but replacing 6-methoxy-1-tetralone with 1-tetralone and replacing 2-thiopheneacetic acid with m-fluorophenyl acetic acid gave the desired product, m.p. 198-99°C. Anal. calcd. for C 20 H 25 ClFNH: C, 71.94; H, 7.56; N, 4.20. Found: C, 72.33; H, 7.53; N, 3.86.
  • Example 71 1-((N-Ethylamino)methyl-N-(2-(2-furyl)ethyl))-5-methoxy tetralin methanesulfonate Using the product (free base) of Example 15 and the procedures described in Examples 18 and 19 but replacing 2-thiopheneacetic acid with 2-furylacetic acid gave the desired compound.
  • Example 72 1-((N-Ethylamino)methyl-N-(2-(m-fluorophenyl)ethyl))-5- methoxy tetralin hydrochloride Using the product (free base) of Example 15 and the procedures described in Examples 18 and 19 but replacing 2-thiopheneacetic acid with m-fluorophenyl acetic acid gave the desired compound, m.p. 177-78°C. Anal. calcd. for C 22 H 29 Cl 2 FNHO: C, 69.72; H, 7.73; N, 3.71. Found: C, 69.96; H, 7.96; N, 3.66.
  • Example 73 1-((N-Ethylamino)methyl-N-(2-(2-thienyl)ethyl))-5- methoxy tetralin hydrochloride Using the product (free base) of Example 15 and the procedures described in Examples 18 and 19 the desired compound was obtained, m.p. 149-151°C. Anal. calcd. for C 20 H 28 ClNOS: C, 65.64; H, 7.71; H, 3.83. Found: C, 65.86; H, 8.00, N, 3.84.
  • Example 74 6-Fluoro-1-aminomethyl-3,4-dihydronaphthalene hydrochloride 6-Fluorotetralone (8.2g), and TMSCN (13.4ml) in 15ml benzene containing a trace of AlCl 3 or Znl 2 was heated at 60-65oC for 6 1/2 hrs. The reaction was added to Et 2 O (50ml) then added dropwise to Et 2 O (350ml) containing lithium aluminum hydride (3.8g) under N 2 . Upon complete addition, the mixture was gently refluxed for 5 hrs followed by stirring at room temperature overnight. The reaction was quenched by the successive addition of EtOAc (12ml), H 2 O (4ml), 15% aq.
  • Example 75 6-Fluoro-1-aminomethyl-1,2,3,4-tetrahydronaphthalene hydrochloride
  • the product from Example 74 was reduced as in Example 2 but replacing the NH 3 with acetic acid and afforded the desired compound, m.p. 236-38°C.
  • Example 76 1-((N-Isopropylamino)methyl)-6-fluoro-tetralin hydrochloride
  • the product from Example 75 was added to a solution of acetone (25ml) and MeOH (25ml) then 95% sodium cyanoborohydride (1.32g) was added in portions.
  • the pH of the reaction was adjusted to ca. pH 5 after complete addition of the NaBH-CN.
  • the reaction was then stirred at room temperature for 8 hrs.
  • the reaction was evaporated to dryness, then dilute HCI and CH 2 Cl 2 (50ml) was added.
  • the aqueous layer was separated, basified then CH 2 Cl 2 added.
  • the organic layer was separated, dried (MgSO 4 ), filtered and evaporated.
  • the residue was taken up in Et 2 O (300 ml) then ethereal HCI added.
  • the resulting precipitate was filtered and recrystallized from EtOAc/MeOH giving the desired compound, m.p.
  • Example 77 1-((N-Isopropylamino)methyl-N-(2-(2-furyl)ethyl))-6- fluoro tetralin fumarate
  • the product (free base) of Example 76 was reacted as described in Examples 18 and 19 but replacing 2-thiopheneacetic acid with 2-furylacetic acid and gave the desired product after formation of the fumarate salt, m.p. 138-39°C.
  • Anal. calcd. for C 24 H 30 FNO 5 C, 66.80; H, 7.01; N, 3.25. Found: C, 66.36; H, 6.89; N, 3.20.
  • Example 78 1-((N-Isopropylamino)methyl)-5- fluoro tetralin hydrochloride Following the procedures described in Examples 74-76 but replacing 6-fluoro-1-tetralone with 5-fluoro-1-tetralone afforded the desired product.
  • Example 79 1-((N-Isopropylamino)methyl-N-(2-(2-furyl)ethyl))-5- fluoro tetralin methanesulfonate The product (free base) of Example 78 was treated as described in Examples 18 and 19 but replacing 2-thiopheneacetic acid with 2-furylacetic acid giving the desired compound,
  • Example 80 1-((N-Methylamino)methyl-N-(2-(1,4-benzodioxan)ethyl))- 6,8-dimethoxy tetralin hydrochloride Starting with 1-((N-methylamino)methyl)-6,8-dimethoxy tetralin and using the procedures described in examples 4 and 5 but replacing 2-thiopheneacetic acid with 1,4-benzodioxanacetic acid gave the desired product, m.p. 210-13oC. Anal. calcd. for
  • Example 81 1-((N-Methylamino)methyl-N-(3-phenylpropyl))-6- hydroxy tetralin hydrochloride Using the product from Example 6j and the procedure of Example 10 gave the desired compound, m.p. 120-122°C. Anal. calcd. for C 21 H 28 ClNO.1/2 H 2 O:
  • Example 82 1-((N-Methylamino)methyl-N-(2-(m-hydroxyphenyl)ethyl))-6- hydroxy tetralin hydrochloride Using the product from example 6k and the procedure described in Example 10 the desired compound was obtained as an amorphous solid. Anal. calcd. for C 20 H 26 ClNO 2 .2H 2 O: C, 62.57; H, 7.88; N, 3.65.
  • Example 83 1-((N-Methylamino)methyl-N-(2-(m-hydroxyphenyl)ethyl))-6- methoxy tetralin hydrochloride Using the product from Example 3 and the procedure of Example 4 replacing the 2-thiopheneacetic acid with m-acetoxyphenylacetic acid gave the corresponding amide. Using this amide and the procedure described in Example 5 afforded the desired compound as an amorphous solid. Anal. calcd. for
  • Example 84 1-((N-Methylamino)methyl-N-(2-(m-fluorophenyl)ethyl))-5,6- dimethoxy tetralin hydrochloride
  • the product was obtained (m.p. 200-201°C) using the procedures described in Examples 1-5 but replacing 6-methoxy-1-tetralone with 5,6-dimethoxy-1-tetralone and using 3-fluorophenylacetic acid in place of 2-thiopheneacetic acid, m.p. 200-201°C.
  • Anal. calcd. for C 22 H 29 FClNO 2 C, 67.08; H, 7.42; N, 3.56. Found: C, 66.69; H, 7.47; N, 3.47.
  • Example 85 1-((N-Methylamino)methyl-N-(2-(m-fluorophenyDethyl))-5,6- dihydroxy tetralin hydrochloride Using the product of Example 84 and the procedures described in Examples 9 and 10, the desired compound was obtained, m.p, 158-60°C. Anal. calcd. for
  • Example 86 1-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-5,6- dimethoxy tetralin hydrochloride Using the procedures described in Examples 1-5 but replacing 6-methoxy-1-tetralone with 5,6-dimethoxy-1-tetralone gave the product, m.p. 235-6°C. Anal. calcd. for C 20 H 28 ClNO 2 S: C, 62.89; H, 7.39; N, 3.67. Found: C, 62.88; H, 7.68; N, 3.67.
  • Example 87 1-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-5,6- dihydroxy tetralin hydrochloride Using the product of Example 86 and the procedures described in Examples 9 and 10 the desired product was afforded Anal. calcd. for
  • Example 88 1-((N-Methylamino)methyl-N-(2-phenethyl)) tetralin hydrochloride Using the procedures described in Examples 1-5 but replacing 6-methoxy-1-tetralone with 1-tetralone and replacing 2-thiopheneacetic acid with 2-phenylacetic acid gave the product, m.p. 207-208°C. Anal. calcd. for
  • Example 89 The product from Example 89 was catalytically reduced as in Example 66 but replacing 5% Pd/C with 20% Pd/C and gave the desired compound, m.p. 188-90°C.
  • Example 91 6-Methoxy-1,2,3,4-tetrahydro-1-naphthylene carboxylic acid
  • the reaction mixture was cooled to 0°C and acidified with cold concentrated hydrochloric acid.
  • the acidic solution was extracted with methylene chloride.
  • the organic layer was washed with brine, separated dried (MgSO 4 ), filtered, and evaporated to afford ca. 20g of an oily residue. Crystallization with ether/hexane afforded ca. 17.1g (83%) of a white crystalline solid, m.p. 81-82°C.
  • Example 92 N-Methoxy-N-methyl-6-methoxy-1,2,3,4-tetrahydro-1- naphthylene carboxamide
  • the product of Example 91 (15g) was dissolved in benzene (100ml) and oxalyl chloride (15ml) and refluxed 1 hr under N .
  • the solvent was evaporated and the residue azeotroped with benzene (2 ⁇ 40ml).
  • the resulting acid chloride (18.4g), and
  • N,O-dimethylhydroxyl amine hydrochloride was dissolved in ethanol-free chloroform (200ml) and the solution cooled to 0°C, then pyridine (13.4ml) was slowly added. The mixture was then stirred at room temperature for 1 h then evaporated to dryness. The residue was partitioned between brine and a 1:1 mixture of Et 2 O and CH 2 Cl 2 . The organic layer was separated, dried (MgSO 4 ), filtered, and evaporated affording the desired product as an oil (98% yield).
  • Example 92 The product from Example 92 (2.49g) was dissolved in dry THF (50ml) and cooled to 0°C Then, an excess (3-4 equiv.) of 2,2,5,5-tetramethyl-1-aza-2,5-disilacycl ⁇ pentane-1-propyl magnesium bromide was added and the reaction stirred at 0°C warming to room temperature overnight. The reaction was cooled to 0°C then 10% HCI in EtOH was slowly added, followed by stirring for 3 h at room temperature. The solvent was evaporated and the residue dissolved in methanol. The mixture was cooled to 0°C, then treated with an excess of NaBH 4 . and the mixture stirred at room temperature for 3 h.
  • Example 95 N-(2-(2-Furyl)ethyl)-2-(1,2,3,4-tetrahydro-6-methoxy-1- naphthyl)pyrrolidine difumarate
  • the product from Example 94 was reacted as described in Examples 18 and 19 but replacing 2-thiopheneacetic acid with 2-furylacetic acid and gave the desired product, m.p. 110-111°C.
  • Anal. calcd. for C 29 H 37 NO 10 C, 62.47; H, 6.33; N, 2.51. Found: C, 62.90; H, 6.39; N, 2.55.
  • Example 96 N-(2-(2-Thienyl)ethyl)-2-(1,2,3,4-tetrahydro-6-methoxy-1- naphthyl)pyrrolidine methanesulfonate The product from Example 94 was reacted as described in Examples 18 and 19 and afforded the desired product.
  • Example 98 1-(6-Methoxy-1-2,3,4-tetrahydro-1-naphthyl)-N-ethyl-1- amino ethane
  • the product of Example 93 (2g) was dissolved in anhydrous MeOH (20ml) and EtNH 2 (3ml) and the pH adjusted to ca. 8 with methanolic HCI.
  • Sodium cyanoborohydride (500mg) was added and an additional 2ml methanolic HCI dropwise.
  • the reaction was stirred under N 2 for 48h then 6N HCI added to pH ⁇ 2.
  • the methanol was removed under vacuum and the aqueous layer extracted with CH 2 Cl 2 (2 ⁇ 100 ml).
  • Example 99 1-(6-Methoxy-1,2,3,4-tetrahydro-1-naphthyl)-N-methyl-1- amino ethane Using the procedure described in Example 98 but replacing EtNH 2 with methylamine afforded the desired product in 59% yield.
  • Example 100 N-(2-Phenylethyl)-1-(6-methoxy-1,2,3,4-tetrahydro-1- naphthyl)-N-methyl-1-amino ethane hydrochloride Using the procedures described in Examples 4 and 5 but replacing the 2-thiopheneacetic acid with phenylacetic acid and the product from Example 99 gave the desired compound, m.p. 159-160°C. Anal. calcd. for C 22 H 30 ClNO: C, 73.23; H, 8.32; N. 3.88. Found: C, 73.28; H, 8.28; N. 3.86.
  • Example 101 N-(2-(Phenyl)ethyl)-1-(6-hydroxy-1,2,3,4-tetrahydro-1- naphthyl)-N-methyl-1-amino ethane hydrobromide Using the product from Example 100 and the procedure of Example 9 gave the desired product, m.p. 88-90°C. Anal. calcd. for C 21 H 28 BrNO: C, 64.62; H, 7.18; N, 3.59. Found: C, 64.50; H, 7.14; N, 3.54..
  • Example 102 N-(2-(2-Furyl)ethyl)-1-(6-methoxy-1,2,3,4-tetrahydro-1- naphthyl)-N-methyl-1-anmino ethane methanesulfonate Using the product from Example 99 and the procedures described in Examples 18 and 19 but replacing 2-thiopheneacetic acid with 2-furylacetic acid gave the desired product, (M+H) + 314.
  • Example 103 N-(2-(2-Thienyl)ethy!)-1-(6-methoxy-1,2,3,4-tetrahydro-1- naphthyl)-N-methyl-1-amino ethane hydrochloride Using the product from Example 99 and the procedures described in Examples 4 and 5 gave the desired product, m.p. 160-61°C. Anal. calcd. for C 20 H2 8 ClNOS: C, 65.66; H, 7.66; N, 3.83. Found: C,
  • Example 104 N-(2-(2-Furyl)ethyl)-1-(6-methoxy-1,2,3,4-tetrahydro-1- naphthyl)-N-ethyl-1-amino ethane hydrochloride Using the compound from Example 98 and the procedures described in Examples 18 and 19 but replacing 2-thiopheneacetic acid with 2-furylacetic acid gave the desired product, (M+H) + 328.
  • Example 106 1-(6-Methoxy-1,2,3,4-tetrahydro-1-naphthyl)-N-methyl-1- amino propane Using the product of Example 105 with the procedure described in Example 98 but replacing the ethylamine with methylamine gave the desired product.
  • Example 107 N-(2-(2-Furyl)ethyl)-1-(6-methoxy-1,2,3,4-tetrahydro-1- naphthyl)-N-methyl-1-amino propane hydrochloride Using the product from Example 106 and following the procedures described in Examples 18 and 19 but replacing 2-thiopheneacetic acid with 2-furylacetic acid gave the desired product.
  • Example 108 N-(2-(m-Fluorophenyl)ethyl)-1-(6-methoxy-1,2,3,4- tetrahydro-1-naphthyl)-N-methyl-1-amino propane hydrochloride Using the product of Example 106 and the procedures described in Examples 4 and 5 but replacing 2-thiopheneacetic acid with m-fluorophenylacetic acid gave the desired product.
  • Example 109 N-(2-(m-Fluorophenyl)ethyl)-1-(6-methoxy-1,2,3,4- tetrahydro-1-naphthyl)-N-methyl-1-amino propane hydrochloride Using the product of Example 106 and the procedures described in Examples 4 and 5 but replacing 2-thiopheneacetic acid with m-fluorophenylacetic acid gave the desired product.
  • Example 109 N-(2-(m-Fluorophenyl)ethyl)-1-
  • Example 110 N-(2-(m-Fluorophenyl)ethyl)-2-(1,2,3,4-tetrahydro-1- naphthyl-6-hydroxy) pyrrolidine hydrobromide Using the product from Example 97 and the procedure of Example 9 gave the desired product.
  • Example 111 1-(N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))- 5-hydroxy tetralin hydrochloride 1-(N-methylamino)methyl-5-trimethylsilyoxy tetralin was reacted as in Example 18 and gave the desired amide. This amide was then treated as in Example 5 and afforded the desired compound, m.p. 202-3°C (free base).
  • Example 112 6-Acetamido-3,4-dihydronaphthylene-1-carbonitrile Using the procedure of Example 1, but replacing 6-methoxy-1-tetralone with 6-acetamido-1-tetralone gave the desired product.
  • Example 113 6-Amino-(1,2,3,4-tetrahydro-1-naphthylene) carboxylic acid
  • the product from Example 112 was reduced with NaBH. in MeOH and DME then hydrolyzed to the carboxylic acid as described in Example 92.
  • Example 114 1-((N-Methylaminomethyl-N-(2-phenylethyl))-6- amino tetralin dihydrochloride Replacing 2-thiopheneacetic acid with the product from Example 113 and using the procedure of Example 18 with N-methylphenethyl amine gave the desired amide. This amide was reduced as in Example 19 and gave the desired product, m.p. 255-56°C. Anal. calcd. for
  • Example 115 1-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-5-iodo-6 -hydroxy tetralin hydrochloride
  • the product from Example 7 (free base) was iodinated with silver trifluoroacetate in CH 2 Cl 2 at 0°C, and afforded the desired compound.
  • Example 116 1-((N-Methylamino)methyl-N-(2-phenylethyl))-5- iodo-6-hydroxy tetralin hydrochloride
  • the product from Example 11 was iodinated with chloramine-T and sodium iodide then treated with methanolic HCI to give the product, m.p. 112-114°C.
  • Example 117 1-((N-Methylamino)methyl-N-(2-phenylethyl))-5- iodo-6-amino tetralin dihydrochloride
  • the product from Example 114 was reacted as described in the procedure of Example 116 and afforded the desired product.
  • Example 118 1-( (N-Methylamino)methyl-N-(3-(2-furyppropyl))- 6-methoxy tetralin hydrochloride
  • the product from Example 3 was reacted with 2-furylpropionic acid using the procedure of Example 18.
  • the resulting amide was reduced as described in Example 19 and afforded the desired compound, m.p. 140-41°C.
  • Anal. calcd. for C 20 H 28 ClNO 2 C, 66.33; H, 7.21; N, 4.55. Found: C, 66.27; H, 7.19; N, 4.53.
  • Example 119 1-((N-Methylamino)methyl-N-(2-(m-methylphenyl)ethyl))-5-methoxy indane hydrochloride Using the procedures described in Examples 1-5 but replacing 6-methoxy-1-tetralone with 5-methoxy-1-indanone and replacing 2-thiopheneacetic acid with m-methylphenyl acetic acid gave the desired compound, m.p. 183-84°C. Anal. calcd. for C 21 H 28 ClNO.H 2 O: C, 69.31; H, 8.31; N, 3.85. Found: C, 69.44; H, 7.93; N, 3.90.
  • Example 120 6-Methoxy-1-(3-phenylpyrrolidino-1-carbonyl) tetralin Using 3-phenylpyrrolidine and the procedure described in Example 4 but replacing 2-thiopheneacetic acid with the product of example 91 gave the desired amide.
  • Example 121 6-Methoxy-1-(3-phenylpyrrolidino-1-methyl) tetralin hydrochloride Reduction of the product of Example 120 using the procedure described in Example 17 gave the desired compound, m.p. 228-232°C. Anal. calcd. for C 22 H 28 ClNO: C, 73.83; H, 7.89; N, 3.91. Found: C, 73.68; H, 7.86; N, 3.91.
  • Example 92 Using the procedure of Example 92 but replacing the product of Example 91 with 2-thiopheneacetic acid gave a 90% yield of the desired carboxamide. This carboxamide was reacted as described in Example 94 and gave the desired product in 43% yield.
  • Example 122 The product of Example 122 was reacted as described in Example 4 but replacing 2-thiopheneacetic acid with the product of Example 91 gave the desired amide. This was reduced as described in Example 17 and afforded a foam, m.p. 85-89°C.
  • Example 124 5-Methoxy-3-phenyl-1-tetralone o-Anisaldehyde (20.5g) was treated with 1,3-propanedithiol (24 ml) in the presence of BF 3 etherate (4 ml) and CH 2 Cl 2 (300 ml). This dithiane derivative (4.7g) was reacted with n-BuLi (2.5 M hexane solution) (7.3 ml), methyl cinnamate (3.4g) and 1,3-dimethyl-2-imidazolidone (4.6 ml) affording the desired product (M+H) + 389. Desulfurization was accomplished with Raney Nickel and EtOH, followed by hydrolysis to the desired carboxylic acid. Cyclization to the desired 5-methoxy-3-phenyl-1-tetralone was accomplished by heating with polyphosphoric acid, (M+H) + 253.
  • Example 125 1-(N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))- 3-phenyl-5-methoxy tetralin hydrochloride
  • the product from Example 124 was reacted as described in Examples 1-5 and gave the desired product, (M+H) + 392.
  • Example 126 The product from Example 126 was treated as described in Examples 1-5 and afforded the desired product, m.p. 155-160°C. Anal. calcd. for
  • Example 129 1-((N-Methylamino)methyl-N-(2-(2-thieny)ethyl))- 5-chloro tetralin hydrochloride Using the procedures described in Examples 46-49 but replacing 6-chloro-1-tetralone with 5-chloro-1-tetralone afforded the desired product, m.p. 216-217°C. Anal. calcd. for C 18 H 23 Cl 2 NS: C, 60.67; H, 6.18; N, 3.93. Found: C, 60.67; H, 5.57; N, 3.95.
  • Example 130 6-Methoxy-3-methyl-1-tetralone The compound was prepared as described in Example 124 replacing methyl cinnamate with ethyl crotonate affording the desired product, (M+H) + 191.
  • Example 131 1-((N-Methy1amino)methyl-N-(2-(2-thienyl)ethyl))- 3-methyl-6-methoxy tetralin hydrochloride Using the procedures described in Examples 1-5 but replacing 6-methoxy-1-tetralone with the product of Example 130 gave the desired compound, (M+H) + 330.
  • Example 132 Dimethyl (2-thienyl)methylidene malonate A solution of 2-thiophene carboxaldehyde (20.0g), dimethyl malonate (22.1 ml), acetic acid (2.0 ml) and piperidine ( 0.7 ml) in 130 ml of benzene was heated at reflux under azeotropic conditions.
  • Example 133 3-Cyano-3-(2-thienyl) propionic acid To a mechanically stirred solution of 12.4 g of Example 132 in 135 ml of abs. EtOH was added in one portion a solution of KCN (3.9 g) in 7.0 ml of water, and the mixture heated to 70°C. After 20 hr at 70°C, the reaction mixture was cooled to 15°C, filtered, and concentrated in vacuo. The residue was taken up into Et 2 O (150 ml) and 10% aq. KOH (100 ml). The layers were separated and the aqueous phase reextracted with Et 2 O (100 ml).
  • Example 136 6-Methoxy-1-(3-(2-thienyl)pyrrolidino-1-methyl) tetralin hydrochloride Using the products of Examples 91 and 135 and the procedures described in Examples 4 and 17, the desired compound was afforded, 114-117°C dec. Anal. calcd. for C 20 H 26 ClNOS: C, 66.00; H, 7.20; N, 3.85. Found: C, 65.68; H, 7.14; N, 3.79.
  • Example 137 N-(2-(2-furyl)ethyl)-2-(1,2,3,4-tetrahydro-6- hydroxy-1-naphthyl1 pyrrolidine hydrobromide
  • the product of Example 95 was reacted as described in Example 9 and gave the desired compound.
  • Example 138 N-(2-(2-Furyl)ethyl)-2-(1,2,3,4-tetrahydro-6- methoxy-3-methyl-1-naphthyl) pyrrolidine hydrochloride
  • the product from Example 133 was reacted as described in Example 13 and then Examples 91 and 92. This product was treated as in Example 94 and then Examples 18 and 19, affording the desired compound.
  • Example 139 N-(2-(2-Furyl)ethyl)-2-(1,2,3,4-tetrahydro-6- hydroxy-3-methyl-1-naphthyl) pyrrolidine hydrobromide
  • the product of Example 138 was reacted as in Example 9 giving the compound.
  • Example 140 N-(2-(2-Furyl)ethyl)-2-(1,2,3,4-tetrahydro-6-methoxy-3-phenyl-1-naphthyl) pyrrolidine hydrochloride
  • Example 126 The product of Example 126 was reacted as described in Example 13 and then Examples 91 and 92. This product was used as described in Example 94, followed by Examples 18 and 19, giving the desired compound,
  • Example 141 1-((N-methylamino)methyl-N-(2-(2-furyl)ethyl))-6-methoxy -7-fluoro tetralin methanesulfonate Using the procedures described in Example 1 but replacing 6-methoxy-1-tetralone and Znl 2 with 6-methoxy-7-fluoro tetralone and LiCN afforded the 1-cyano derivative. Catalytic reduction with Pd/C at 4 atm. gave the corresponding 1-aminomehtyl tetrali derivative in 97% yield. Utilizing this product and the procedures in examples 16-19 gave the desired product, m.p. 115-116°C. Anal. calcd. for
  • Example 143 5,6-Methylenedioxy-1-(3-phenylpyrrolidino-1-methyl) tetralin methanesulfonate Using 3-phenylpyrrolidine and the procedures described in Examples 4 and 5 but replacing 2-thiopheneacetic acid with Example 142 afforded the desired compound, m.p. 123-124°C. Anal. calcd. for
  • Example 144 5,6-Methylenedioxy-1-(3-(2-thienyl)pyrrolidino-1-methyl) tetralin methanesulfonate Using Example 135 and the procedures described in Examples 4 and 5 but replacing 2-thiopheneacetic acid with Example 142 afforded the desired compound, m.p. 150-151°C. Anal. calcd. for
  • Example 145 1,2,3,4-Tetrahydro-5-methoxy-1-naphthylene carboxylic acid Using the procedure described in Example 142 but replacing 1-cyano-3,4-dihydro-5,6-methylenedioxynaphthylene with 1-cyano-3,4-dihydro-5-methoxynaphthylene provided the desired product, m.p. 101-102°C.
  • Example 146 5-Methoxy-1-(3-( 2-thienyl)pyrrolidino-1-methyl) tetralin hydrochloride Using Example 135 and the procedures described in Examples 4 and 5 but replacing 2-thiopheneacetic acid with Example 145 afforded the desired compound, m.p. >230°C. Anal calcd. for C 20 H 25 NOS.HCI: C. 66.00; H, 7.20; N, 3.85. Found: C, 65.87; H, 7.19; N, 3.83.
  • Example 147 6 -Fluoro-1,2,3,4-tetrahydro-1-naphthylene carboxylic acid Using the procedure described in Example 142 but replacing 1-cyano-3,4-dihydro-5,6-methylenedioxynaphthylene with 1-cyano-6-fluoro-3,4- dihydronaphthylene provided the desired product, m.p. 90-91°C.
  • Example 148 6-Fluoro-1-(3-phenylpyrrolidino-1-methyl) tetralin methanesulfonate Using 3-phenylpyrrolidine and the procedures described in Examples 4 and 5 but replacing 2-thiopheneacetic acid with Example 147 afforded the desired compound, m.p. 166-167°C. Anal. calcd. for
  • Example 149 6-Fluoro-1-(3-(2-thienyl)pyrrolidino-1-methyl) tetralin methanesulfonate Using Example 135 and the procedures described in Examples 4 and 5 but replacing 2-thiopheneacetic acid with Example 147 afforded the desired compound, m.p. 136-137°C. Anal. calcd. for C 19 H 24 FN.CH 3 SO 3 H: C. 58.37; H, 6.37; N. 3.40. Found: C, 58.22; H, 6.34; N, 3.35.
  • Example 150 2,3-Dihydro-4-methoxy-1-indene carboxylic acid Using the procedure described in Example 142 but replacing 1-cyano-3,4-dihydro-5,6-methylenedioxynaphthylene with 1-cyano-2,3-dihydro-5-methoxy-1-indene provided the desired product, m.p. 117-118°C.
  • Example 151 5-Methoxy-1-(3-(2-thienyl)pyrrolidino-1-methyl) indane hydrochloride Using Example 135 and the procedures described in Examples 4 and 5 but replacing 2-thiopheneacetic acid with Example 150 provided the desired compound, m.p. 202-204°C dec. Anal. calcd. for C 19 H 23 NOS.HCl: C, 65.22; H, 6.91; N, 4.00. Found: C, 65.04; H, 6.92; N, 3.93.
  • Example 152 5-Methoxy-1-(3-phenylpyrrolidino-1-methyl) indane hydrochloride Using 3-phenylpyrrolidine and the procedures described in Examples 4 and 5 but replacing 2-thiopheneacetic acid with Example 150 provided the desired compound, m.p. 126-130°C dec. Anal. calcd. for C 22 H 25 NO.CH 3 SO 3 H: C, 65.48; H, 7.24; N, 3.47. Found: C, 65.44; H, 7.31; N. 3.46.
  • Example 153 5-Methoxy-1-(3-(m-fluorophenyl)pyrrolidino-1-methyl) indane hydrochloride Using 3-(m-fluorophenyPpyrrolidine and the procedures described in Examples 4 and 5 but replacing 2-thiopheneacetic acid with Example 150 provided the desired compound, m.p. 205-207°C dec. Anal. calcd. for C 21 H 24 FNO.HCl: C, 69.70; H, 6.96; N, 3.87. Found: C, 69.54; H, 7.06; N, 3.83.
  • Example 154 6-Amino-1,2,3,4-tetrahydro-1-naphthylene carboxylic acid hydrochloride Using the procedure outlined in Example 1 but replacing 6-methoxy-1-tetralone with
  • 6-acetamido-1-tetralone afforded the desired unsaturated nitrile.
  • a suspension of the above nitrile (24 g) in 260 mL of a 1:1 mixture of ethanol and dimethoxyethyl ether was treated with small portions of sodium borohydride (15 g). After the addition was complete the reaction was heated at reflux for 20 hours. The reaction was cooled to room temperature, quenched by the dropwise addition of acetone and concentrated. The residue was taken up into saturated NH 4 Cl and CH 2 Cl 2 . The phases were separated and the aqueous phase reextracted with CH 2 Cl 2 . The organic extracts were combined, dried over magnesium sulfate, filtered and concentrated to provide the desired saturated nitrile.
  • Example 155 1-((6-amino-1,2,3,4-tetrahydro-1-naphthalenyl)carbonyp- 3-phenylpyrrolidine
  • a mixture of Example 154 (2.3 g) and thionyl chloride (50 ml) were heated at reflux for 45 minutes. The reaction was concentrated and the residue was co-concentrated with toluene (3 ⁇ 50 ml).
  • Example 156 6-Amino-1-(3-phenylpyrrolidino-1-methyl) tetralin dihydrochloride Using the procedure described in Example 19 but replacing Example 18 with Example 155 yielded the desired compound, m.p. >260°C. Anal. calcd. for C 21 H 26 N 2 .2HCl: C, 66.49; H, 7.44; N, 7.38. Found: C, 65.81; H, 7.41; N. 7.21.
  • Example 157 6-(N-methylamino)-1-(3-phenylpyrrolidino-1-methyl) tetralin dihydrochloride Using the procedure outlined in Example 3 but replacing Example 2 with Example 155 provided the desired compound, m.p. 231°C. Anal. calcd. for
  • Example 159 8-Fluoro-1,2,3,4-tetrahydro-5,6-methylenedioxy-2- naphthylene carboxylic acid Using the procedure in Example 1, but replacing 6-methoxy-1-tetralone with Example 158 afforded the unsaturated nitrile. This material was subjected to the reaction conditions described in Example 142 to provide the desired material.
  • Example 160 8-Fluoro-5,6-methylenedioxy-1-(3-phenylpyrrolidino-1- methyl) tetralin hydrochloride Using 3-phenylpyrrolidine and the procedures described in Example 4 and 5 but replacing 2-thiopheneacetic acid with Example 159 afforded the desired compound.
  • Example 161 8-Fluoro-5,6-methylene ⁇ ioxy-1-(3-(m-fluorophenyl) pyrrolidino-1-methyl) tetralin hydrochloride Using 3-(m-fluorophenyPpyrrolidine and the procedures described in Example 4 and 5 but replacing 2-thiopheneacetic acid with Example 159 afforded the desired compound.
  • Example 162 8-Fluoro-5,6-methylenedioxy-1-(3-(2-thienyl)pyrrolidino- 1-methyl) tetralin hydrochloride Using Example 135 and the procedures described in Example 4 and 5 but replacing 2-thiopheneacetic acid with Example 159 afforded the desired compound.
  • Example 163 5.6-Methylenedioxy-1—(3—(m-fluorophenyl)pyrrolidino- 1-methyl) tetralin methanesulfonate Using 3-(m-fluorophenyppyrrolidine and the procedures described in Example 4 and 5 but replacing 2-thiopheneacetic acid with Example 142 afforded the desired compound, m.p. 177-179°C dec. Anal. calcd. for
  • Example 164 1-((N-Ethylamino)methyl-N-(2-(2-thienyl)ethyl))-5,6- methylenedioxy tetralin hydrochloride
  • the desired compound (m.p. 163-164°C) was prepared using the procedures outlined in examples 1, 2, 15, 4 and 5, but replacing 6-methoxy-1-tetralone with 5,6-methylenedioxy-1-tetralone. Anal. calcd. for
  • Example 165 1-((N-Ethylamino)methyl-N-(2-(m-fluorophenethyl)-5,6- methylenedioxy tetralin hydrochloride The desired compound (m.p. 131.5-132.5°C) was prepared using the procedures in Example 165, but replacing 2-thiopheneacetic acid with m-fluorophenylacetic acid. Anal calcd. for C 22 H 26 FN0 2 .HCI: C, 67.42; H, 6.94; N, 3.57. Found: C, 67.40; H, 6.98; N, 3.51.
  • Example 166 1-((N-Methylamino)methyl-N-(2-(m-fluorophenethyl))-5,6- methylenedioxy tetralin methanesulfonate Using the procedures in Example 23, but replacing 2-thiopheneacetic acid with m-fluoroacetic acid provided the desired product upon formation of the methanesulfonate salt, m.p. 144-147°C. Anal. calcd. for
  • Example 167 1-((N-Methylamino)methyl-N-(2-(m-fluorophenethyl))-5,6- ethylenedioxy tetralin methanesulfonate The product was prepared (m.p. 174.175°C) using the procedures in Example 30, but replacing 2-thiopheneacetic acid with m-fluorophenylacetic acid and formation of the methanesulfonate salt. Anal. calcd. for C 22 H 26 FNO 2 .CH 3 SO 3 H: C , 61.18; H.
  • Example 168 1-((N-Ethylamino)methyl-N-(2-(2-thienyl)ethyl))-5,6- ethylenedioxy tetralin hydrochloride Using the procedures outlined in Example 164, but replacing 5,6-methylenedioxy-1-tetralone with 5,6-ethylenedioxy-1-tetralone provided the desired product. Anal. calcd. for
  • Example 169 1,2,3,4-Tetrahydro-5,6-ethylenedioxy-1-naphthylene carboxylic acid Using the procedure in Example 142 but replacing 1-cyano-3,4-dihydro-5,6-methylenedioxy ⁇ naphthylene with 1-cyano-3,4-dihydro-5,6-ethylenedioxynaphthylene provided the desired material.
  • Example 170 5,6-Ethylenedioxy-1-(3-phenylpyrrolidino-1-methyl) tetralin hydrochloride Using 3-phenylpyrrolidine and the procedures described in Examples 4 and 5 but replacing 2-thiopheneacetic acid with Example 169 afforded the desired compound.
  • Example 171 5,6-Ethylenedioxy-1-(3-(m-fluorophenyl)pyrrolidino-1- methyl) tetralin hydrochloride Using 3-(m-fluorophenyl)pyrrolidine and the procedures described in Examples 4 and 5 but replacing 2-thiopheneacetic acid with Example 169 afforded the desired compound.
  • Example 172 5,6-Ethylenedioxy-1-(3-(2-thienyl)pyrrolidino-1-methyl) tetralin hydrochloride Using 3-(2-thienyl)pyrrolidine and the procedures described in Examples 4 and 5 but replacing 2-thiopheneacetic acid with Example 169 afforded the desired compound.
  • the compounds were assessed for alpha-adrenergic receptor subtype selectivity by use of radioligand binding techniques as described previously
  • the compounds of the invention can be administered in any effective pharmaceutically acceptable form to warm blooded animals, e.g., in oral, parenteral or infusable dosage forms, or as a buccal or nasal spray.
  • suitable parenteral routes of administration include, for example, intramuscular, intravenous, intraperitoneal or subcutaneous administration of the compounds.
  • compositions according to this invention for parenteral injection may comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, suspensions or emulsions.
  • suitable nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils, such as olive oil, and injectable organic esters such as ethyl oleate.
  • Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents.
  • compositions may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents into the compositions.They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or other sterile injectable medium, immediately before use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
  • Actual dosage levels of active ingredient in the compositions of the invention may be varied so as to obtain an amount of active ingredient effective to obtain a desired therapeutic response for a particular composition and method of administration.
  • the selected dosage level therefore depends upon the desired therapeutic effect, on the route of administration, on the desired duration of treatment and other factors.
  • dosage levels of about 0.1 to about 200, more preferably about 0.5 to about 150 and most preferably about 1 to about 125 mg of active ingredient per kg of body weight per day are administered orally to a mammalian patient suffering from depression.
  • the daily dose may be divided into multiple doses for administration, e.g., two to four separate doses per day.

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EP19890902122 1988-01-15 1989-01-13 1-aminomethyl-1,2,3,4-tetrahydronaphthalenes Pending EP0395734A4 (en)

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AU655898B2 (en) * 1989-05-31 1995-01-12 Abbott Laboratories Dopamine agonists
US4963568A (en) * 1989-05-31 1990-10-16 Abbott Laboratories Dopamine agonists
IE65511B1 (en) * 1989-12-29 1995-11-01 Sanofi Sa New phenylethanolaminomethyltetralins
FR2656607B1 (fr) * 1989-12-29 1994-03-11 Midy Spa Phenylethanolaminomethyltetralines.
US5068234A (en) * 1990-02-26 1991-11-26 Sterling Drug Inc. 3-arylcarbonyl-1-(c-attached-n-heteryl)-1h-indoles
FR2664592B1 (fr) * 1990-07-10 1994-09-02 Adir Nouveaux derives de la piperidine, de la tetrahydropyridine et de la pyrrolidine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent.
DK148292D0 (da) * 1992-12-09 1992-12-09 Lundbeck & Co As H Forbindelser
US5792767A (en) * 1995-01-27 1998-08-11 Abbott Laboratories Bicyclic substituted hexahydrobenz e! isoindole alpha-1 adrenergic antagonists
PE20020690A1 (es) * 2000-11-03 2002-08-23 Upjohn Co Metodo y tratamiento y prevencion de los dolores de cabeza de migranas
SE0201938D0 (sv) * 2002-06-20 2002-06-20 Astrazeneca Ab New process
BRPI0608353A2 (pt) 2005-02-17 2009-12-01 Wyeth Corp derivados de indol, benzotiofeno, benzofurano e indeno cicloalquilfundidos
EP3055296B1 (de) 2013-10-08 2018-11-28 Bayer CropScience Aktiengesellschaft N-hetaryl(thio)carbonyl-2-(benzocycloalken-1-yl)cyclamine und ihre verwendung als fungizide

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JPS535146A (en) * 1976-07-02 1978-01-18 Tanabe Seiyaku Co Ltd Indane derivatives and their preparation
FR2500823A1 (fr) * 1981-03-02 1982-09-03 Abbott Lab 1-aminoalkyl-1, 2, 3, 4-tetrahydroanphtalenes mono- ou disubstitues utiles notamment comme adrenergiques et medicaments les contenant
EP0281261A2 (de) * 1987-02-26 1988-09-07 H. Lundbeck A/S Indan-, Indolin-, Dihydrobenzofuran- und Dihydrobenzothiophen-3-aminomethyl-Derivate

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DE2137276A1 (de) * 1971-07-26 1973-02-08 Basf Ag N-substituierte 1-aminomethylindane
JPS535146A (en) * 1976-07-02 1978-01-18 Tanabe Seiyaku Co Ltd Indane derivatives and their preparation
FR2500823A1 (fr) * 1981-03-02 1982-09-03 Abbott Lab 1-aminoalkyl-1, 2, 3, 4-tetrahydroanphtalenes mono- ou disubstitues utiles notamment comme adrenergiques et medicaments les contenant
EP0281261A2 (de) * 1987-02-26 1988-09-07 H. Lundbeck A/S Indan-, Indolin-, Dihydrobenzofuran- und Dihydrobenzothiophen-3-aminomethyl-Derivate

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See also references of WO8906645A1 *

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ES2059570T3 (es) 1994-11-16
EP0325963B1 (de) 1993-09-22
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