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WO1998048786A1 - AMINOTETRALINES SERVANT D'AGONISTES DE 5-HT¿1Dα? - Google Patents

AMINOTETRALINES SERVANT D'AGONISTES DE 5-HT¿1Dα? Download PDF

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WO1998048786A1
WO1998048786A1 PCT/US1998/008436 US9808436W WO9848786A1 WO 1998048786 A1 WO1998048786 A1 WO 1998048786A1 US 9808436 W US9808436 W US 9808436W WO 9848786 A1 WO9848786 A1 WO 9848786A1
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compound
alkyl
dimethylamino
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John Mehnert Schaus
Clint Duane Walker
Yao-Chang Xu
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Eli Lilly and Co
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Eli Lilly and Co
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Priority to US09/403,854 priority Critical patent/US6355674B1/en
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Priority to CA002288897A priority patent/CA2288897A1/fr
Priority to AU71635/98A priority patent/AU7163598A/en
Priority to EP98918773A priority patent/EP1052982A4/fr
Priority to JP54724398A priority patent/JP2001524112A/ja
Publication of WO1998048786A1 publication Critical patent/WO1998048786A1/fr
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    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
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    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
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    • A61P25/00—Drugs for disorders of the nervous system
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
    • C07C211/41—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
    • C07C211/42—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems with six-membered aromatic rings being part of the condensed ring systems
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    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
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    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
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    • 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 novel substituted aminotetralins useful as 5-HTID agonists.
  • 5-HT receptors have been identified in the central nervous system (CNS; brain and spinal cord) and in peripheral tissues including the gastrointestinal tract, lung, heart, blood vessels, and various other smooth muscle tissues.
  • 5-HT receptors there are multiples types of 5-HT receptors. These receptors have been classificed as 5-HT ⁇ _, 5-HT2 and 5-HT3 receptors, with the former being further divided into the sub- classes 5-HT ⁇ _ ⁇ , 5-HT 1B , 5-HT lc , 5-HT 1D , 5-HT 1E , and 5-HT 1F .
  • 5-HT ⁇ _ receptor class Within the 5-HT ⁇ _ receptor class, several subtypes have been distinguished on the basis of their pharmacological binding profiles, second messenger coupling and physiological roles.
  • One such subtype, the 5-HT 1D receptor was originally defined as a particular type of [ 3 H]5-HT binding site in the bovine caudate (Heuring and Peroutka, Neurosci.. 7:894 (1987)).
  • 5-HT ⁇ _rj receptors are encloded by two separate but closely related genes, designated 5- HT lD ⁇ and 5-H ⁇ lD ⁇ ' which are members of the GPRC superfamily. These receptors display highly conserved transmembrane homology (75%) and similar binding properties and second messenger coupling (inhibition of adenylate cyclase) . Leonhardt, S., et al., J L. Neurochem, 53:465-471 (1989) .
  • the 5-HT ⁇ _r j ⁇ receptor is a species homolog of the 5-HT ] _TJ receptor of bovine calif caudate and guinea- pig brain. Hartig, et al . , supra.
  • the 5-HT 1B and 5-HT 1D ⁇ receptors have recently been shown to be species homologues of the same receptor subtype. They display similarities in their pharmacology, second messenger coupling, and anatomical distribution.
  • the 5-HTi ⁇ subtype appears to be confined to rat, mouse, and opossum whereas 5-HT]_ ⁇ j ⁇ sites have been demonstrated in human, pig, guinea pig and calf. Adham, N. , et al., Mol . Pharmacol . , 41:1-7 (1992).
  • the rat 5-HT ⁇ _g receptor differs from its human counterpart at only 4% of its transmembrane amino acids, but its pharmacological binding properties are dramatically different from those of the human 5-H IDB receptor. Hartig, et al . , Trends Pharmacol . Sci. , 13:152-159 (1992) .
  • This invention provides a compound of formula I
  • R 1 and R 2 are each individually hydrogen or - (Ci-
  • R 3 is - (C2-C8)alkenyl, - (CH 2 ) q (C 3 -Cg) cycloalkyl ⁇
  • D is -CH - or oxygen
  • R 4 is hydrogen or -OH
  • This invention also provides a pharmaceutical formulation comprising a compound of formula I in association with one or more pharmaceutically acceptable diluents, carriers and excipients.
  • This invention further provides a method of activating the 5-HT ⁇ D ⁇ receptor comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula II
  • R! and R 2 are each individually hydrogen or - (Ci-Cg) lkyl ;
  • R 3 ' is - (Ci-C ⁇ ) alkyl, - (CH 2 ) q (C 3 -C 8 ) cycloalkyl, - (C 2 -C ⁇ )alkenyl, - (C ⁇ -C8)alkan-l-ol-l-yl, - (CH 2 ) n 0 (CH2) pR 5 ' ,
  • R 4 is hydrogen or -OH
  • This invention also provides a method of alleviating the pathological effects of 5-HT ⁇ D ⁇ receptor- activated diseases which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound of formula II.
  • a still further aspect of the invention is a method of treating a mammal suffering from or susceptible to any condition activated by the 5HTiD ⁇ receptor of the type represented by dementia, Parkinson's disease, anxiety, migraine, appetite modulation, sexual dysfunction, irritative bladder symptoms of benign prostatic hyperplasia, urge incontinence and excessive bladder activity caused by bacterial cystitis, interstitial cystitis, radiation/chemotherapy- induced cystitis, outlet obstruction, neurogenic bladder, spinal cord injury, stroke and nocturnal enurisis which comprises administering to said mammal a therapeutically- effective amount of a compound of formula (II) .
  • (Ci-Cs) alkyl by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as methyl, ethyl, n- propyl , isopropyl, n-butyl, tertiary butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, neopentyl , heptyl , hexyl , octyl and the like.
  • the term " (Ci-Cs) alkyl encompasses " (Ci-Cg) alkyl".
  • halo means chloro, fluoro, bromo or iodo.
  • (Ci-C ⁇ ) alkoxy denotes a straight or branched alkyl chain having one to six carbon atoms attached to the remainder of the molecule by an oxygen atom.
  • Typical (Ci-Cg) alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, n-pentoxy, isopentoxy, neopentoxy and the like.
  • (C3-C8) cycloalkyl referes to a hydrocarbon ring having the stated number of carbon atoms.
  • Typical (C3-C8) cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl .
  • (C -Cs) alkenyl means a straight chain or branched monovalent hydrocarbon group attached to the tetralin ring at any point on the chain, having the stated number range of carbon atoms and one double bond on the carbon attached to the tetralin ring.
  • Typical groups include vinyl, prop-1-en-l-yl, isoprop- 1-en-l-yl, n-but-2 -en-2-yl , tertiary but-l-en-1- yl, isobut-1-en-l-yl, n-pent-1-en- 1-yl , isopent-1-en- 1- yl, pent-1-en-l-yl, hept-3-en-3-yl, hex-2-en-2-yl, oct-2- en-2-yl and the like.
  • (Ci-Cs) alkan-1-ol- 1-yl means a straight or branched chain monovalent hydrocarbon radical having the stated number of carbon atoms attached to the tetralin ring at the 1-position of the chain and, further, having an hydroxy group attached to the 1- position of the chain.
  • Such groups include methan-1-ol- 1-yl, ethan-1-ol-l-yl, n-propan-1-ol-l-yl, isopropan-ol- 1-yl, n-butan-1-ol-l-yl, tertiary butan-1-ol-l-yl, isobutan-1-ol-l-yl, sec-butan-1-ol-l-yl, n-pentan-l-ol-1- yl , isopentan-1-ol-l-yl, neopentan-1-ol-l-yl, heptan-1- ol-l-yl, hexan-1-ol-l-yl, octan-1-ol-l-yl and the like.
  • Useful compounds for practicing the present invention includes pharmaceutically acceptable acid addition salts of the compounds defined by the above formulae I and II. Since the compounds of formula I are amines, they are basic in nature and accordingly react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts.
  • Acids commonly employed to form such salts are inorganic acids, such as hydrocholoric acid, hydrobomic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids, such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • inorganic acids such as hydrocholoric acid, hydrobomic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
  • organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • Examples of such pharmaceutically acceptable salts thus are the sulfate, pyrosolfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogensphosphate, dihydrogenphosphate, metaphosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumariate, maleate, butyne-1, 4-dioate, hexyne- 1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, cit
  • Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid.
  • the compounds of the instant invention may have one stereocenter at the 2 -position, and possibly more stereocenters, depending on the R 3 substituent at the 8 -position, and may be isolated in optically active and racemic forms.
  • the optically active isomers of the racemates of invention are also considered within the scope of Formulae I and II.
  • Such optically active isomers may be prepared from their respective optically active precursors following the procedure described below, or by resolving the racemic mixtures. These resolutions can typically be carried out in the presence of a resolving agent, by chromatography or by repeated cyrstallization.
  • amino-protecting group is used herein as it is frequently used in synthetic organic chemistry, to refer to a group which will prevent an amino group from participating in a reaction carried out on some other functional group of the molecule, but which can be removed from the amine when it is desired to do so.
  • hydroxy protecting group refers to a removable group which will prevent a hydroxy group from participating in a reaction performed on the molecule.
  • amino protecting groups include benzyl and substituted benzyl such as 3,4-dimethoxybenzyl, o-nitrobenzyl, and triphenylmethyl; those of the formula -C00R where R includes such groups as methyl, ethyl, propyl, isopropyl, 2,2,2-trichloroethyl, 1-methyl -1-phenylethyl, isobutyl, t .
  • acyl groups and substituted acyl such as formyl, acetyl, chloroacetyl , dichloroacetyl , trichloroacetyl , trifluoroacetyl , benzoyl, and p-methoxybenzoyl; and other groups such as methanesulfonyl, p-toluenesulfonyl, p- bromobenzenesulfonyl, p-nitrophenylethyl, and p- toluenesulfonylaminocarbonyl .
  • a preferred amino-blocking group is t-butoxycarbonyl .
  • hydroxy protecting groups include ether and substituted ether forming groups such as methyl, methoxymethyl, t-butoxymethyl, 1-ethoxyethyl and benzyl; silyl ether forming groups such as trimethylsilyl, triethylsilyl and methyl - diisopropylsilyl; ester forming groups such as formate, acetate and trichloroacetate and carbonate groups, such as methyl, 2 , 2 , 2 -trichloroethylcarbonate and p- nitrophenyl carbonates .
  • urinary incontinence includes bacterial cystitis, interstitial cystitis, radiation/chemotherapy induced cystitis, outlet obstruction, neurogenic bladder, incontinence due to spinal cord injury and stroke, and nocturnal enurisis.
  • Preferred substituent groups of compounds of formulae I and II include the following:
  • R 1 and R 2 are each independently hydrogen
  • R 1 and R 2 are each independently - (Ci-Cg) alkyl;
  • R 3 is - (Ci-C ⁇ ) alkyl ;
  • R 3 is - (CH 2 ) n 0(CH 2 ) p R 5 ;
  • R 3 is - (C2-C8)alkenyl
  • R 3 1S substituted with one substituent selected from the group consisting of - (Ci-Cg) alkyl or - (C3 -Cs) cycloalkyl ;
  • a preferred genus of compounds include those compounds of formula I where :
  • R 1 and R 2 are each individually hydrogen or
  • R 3 is ' ; and m is 2 or 3.
  • Still another preferred group of compounds include those where A-B is >CR 4 CH 2 - and D is -CH 2 -.
  • the most preferred compound of the instant invention is 2-N,N-dimethylamino-8- (2 -methylcyclopent-1- yl) tetralin hydrochloride .
  • Further typical examples of compounds of formula I which are useful in the present invention include:
  • 2-N,N-dipro ⁇ yl-8- (2- (6- (3- propylphenyl ) hexyl) oxy) ethyltetralin; 2 - N-methyl - N- butylamino- 8 - ( 4 - ( 4 - bromophenyl) butyl) oxymethyltetralin;
  • R a or R D is H and the other is -
  • R a and R ⁇ taken together are with the carbon to whi ) alkyl
  • A-B is >CR 4 CH 2 -
  • D is -CH 2 - and R 4 is -OH; R c and R°- taken together with the carbon to CH ⁇ V ⁇
  • R e is - (Ci - Cs ) alkyl , or substituted
  • A-B is >CR 4 CH 2 -
  • D is -CH 2 -
  • R 4 is hydrogen
  • Compound (1) 8-bromo aminotetralin, is first treated with an organo- lithium reagent, preferably n- butyl lithium, to form the activated intermediate (la) .
  • organo- lithium reagent preferably n- butyl lithium
  • the reaction is carried out in a suitable solvent, preferably tetrahydrofuran or diethylether, at a temperature of about -78°C and is substantially complete in 5 to 60 minutes.
  • the lithiated intermediate (la) is treated with an alkyl ketone or aldehyde or cyclic ketone of the formula R a C0R ⁇ , where one of R a or TR is hydrogen and the other is
  • R 4 is hydrogen, to form product (2) , where R 3 is
  • A-B is >CR CH 2 -
  • D is -CH -
  • R 4 is hydroxy.
  • the reaction is substantially complete in about 10 minutes to an hour.
  • step (b) for compounds where R 3 or R 3 ' is methyl, the lithiated intermediate (la) is treated with dimethylformamide instead a compound of formula R a COR b .
  • X is a halogen
  • R f is (CH 2 ) n O(CH 2 ) p R 5 , or (CH,)
  • R 4 is hydrogen
  • step (a) above the brominated aminotetralin (1) is first activated by treatment with an organo- lithium reagent, such as n-butyl lithium to form (la) .
  • organo- lithium reagent such as n-butyl lithium
  • (la) is then C-alkylated with an alkyl halide of the formula XR f where X is a halogen and R f is - (CH 2 ) n 0 (CH 2 ) p R 5 ,
  • the halide starting material XR ⁇ may be prepared by reacting an appropriately substituted alcohol, HO (CH 2 ) n 0 (CH 2 ) p R 5 or HO (CH 2 ) n O (CH 2 ) p R 5 ' with methoxymethyl chloride and a base, such as diisopropylethylamine or sodium or potassium carbonate in an organic solvent, such as methylene chloride or chloroform to form the methoxy intermediate .
  • a base such as diisopropylethylamine or sodium or potassium carbonate
  • an organic solvent such as methylene chloride or chloroform
  • alkyl halide starting material XR f
  • R ⁇ 3 is -(CH 2 ) p R 5 or -(CH 2 ) p R 5 '
  • An appropriately substituted phenol (6) is 0- alkylated with an alkyl halide of the formula X(CH 2 ) p R 5 or X(CH 2 ) p R 5 ' where X is preferably chlorine, in the presence of a base, such as potassium hydroxide or potassium carbonate and a catalyst such as potassium iodide, to form product (7) .
  • a base such as potassium hydroxide or potassium carbonate
  • a catalyst such as potassium iodide
  • Compounds of formula I may have one or two stereocenters; one at the 2- position of the tetralin ring and the other at the 8 -position. Racemates of
  • Starting material (8) is first treated with methoxymethyl amine and trimethyl aluminum, at temperatures of about -15°C. The terminal hydroxy is protected using, for example, butyldiphenylsilane to prepare intermediate (9) .
  • Intermediate (9) is then coupled with lithiated starting material (la) , preferably at temperatures of from about -78°C to 0°C, in a solvent such as tetrahydrofuran, to prepare (10) .
  • Stereospecific reduction of the carbonyl of (10) can be achieved by treatment with (-)DIP-Cl ( (- ) dimethylaminoisopropyl chloride) hydrochloride to produce the (R) enantiomer (11) .
  • the reaction is preferably conducted at temperatures of about -25°C and is substantially complete in 1 to 3 days.
  • Protection of the alpha hydroxy can be accomplished by treating (11) with a selective hydrox - protecting group, such as benzoylchloride, followed by removal of the silyl hydroxy-protecting group on the omega hydroxy, using, for example, tetrabutylammonium fluoride to prepare (12) .
  • a selective hydrox - protecting group such as benzoylchloride
  • Reduction of the omega hydroxy can then be readily accomplished using pyridinum chlorochromate to prepare (13) . Removal of the alpha hydroxy protecting group and cyclization of (13) can then be accomplished by treatment with a strong base, such as sodium hydroxide. Reduction of (15) is achieved using triethyl silane and trifluoroacetic acid to yield (16) .
  • stereospecific reduction of the carbonyl of intermediate (11) can be accomplished using (S) -1, 3 , 3- triphenyltetrahydro-lH, 3H- pyrrolo [1,2-C] [13 , 2] oxazaborole and boron trihydride in step (d) Scheme IV above instead of DIP-C1.
  • the intermediates and final products may be isolated and purified by conventional techniques, for example by concentration of the solvents, followed by washing of the residue with water, then purification by conventional techniques such as chromatography or recrystallization.
  • the pharmaceutically acceptable acid addition salts are typically formed by reacting an aminotetralin of formula I with an equimolar or excess amount of acid, preferably hydrochloric acid.
  • the reactants are generally combined in a mutual solvent, such as diethyl ether or benzene, and the salt normally precipitates out of solution within about one hour to 10 days, and can be isolated by filtration.
  • a mutual solvent such as diethyl ether or benzene
  • NaHC ⁇ 3 is sodium bicarbonate
  • Na 2 S ⁇ 4 is sodium sulfate
  • HC1 is hydrochloric acid
  • MgS ⁇ 4 is magnesium sulfate
  • NaOH sodium hydroxide
  • THF is tetrahydrofuran
  • N-BuLi is n-butyllithium Et 3 SiH is triethylsilane
  • BF3 is borom trifluoride
  • Pd/C is palladium on carbon NH4OH is ammonium hydroxide
  • Al ⁇ 3 is trimethyl aluminum
  • Na 2 C ⁇ 3 sodium carbonate
  • the compound of part A, above (660 mg) was dissolved in 8 mL of dry CH 2 C1 2 and 9.3 mL of Et3SiH was added. To this vigorously stirring solution was bubbled BF3 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 NaHC ⁇ 3 and diluting with 50 mL of CH 2 C1 2 , the layers were separated and the organic layer was washed with brine. The organics were then dried over MgS ⁇ 4 , filtered, and evaporated to recover an oily yellow solid.
  • Example 2 Title compound was prepared substantially according to the procedure of Example 2 using 1.70g (6.71 mmol) of (+) - (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-l-yl) tetralin, and was recovered as the HC1 salt.
  • Example 2 Title compound was prepared substantially according to the procedure of Example 2 using 953mg (3.75 mmol) of (+) - (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.
  • Example 2 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.
  • Example 7 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-e -1-yl- tetralin hydrochloride. Title compound, 210 mg, was recovered as the HC1 salt.
  • HC1 salt of the product has melting point of 147-148°C.
  • HBr salt of the product has melting point of 210-211°C.
  • HBr salt of the products has melting point of 186-187°C.
  • the HCl salt of the product has melting point of 190-
  • HCl salt of the product has melting point of 160-161°C.
  • HCL salt of the product has melting point of 184-185°C.
  • Example 17 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 0H, methanol , and CH 2 C1 2 (0.5 : 6 : 94) to give 243.2 mg (73%) of title product.
  • Example 18 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 0H, methanol, and CH 2 C1 2 (0.5 : 6 : 94) to give 211.7 mg (73%) of title product.
  • 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.
  • 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.
  • (+) - (R) -2-N,N-dimethylaminotetralin- 8-yl- (3 ' - t-butyldiphenylsilyloxy)propylketone To a stirred solution of (+) - (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.
  • HCl salt of the product has melting point of 195-197°C.
  • the method of this invention is practiced by administering to a mammal a direct acting 5-HTiD ⁇ agonist or a pharmaceutically acceptable salt thereof.
  • direct acting 5-HT ⁇ D agonist means a non-endogenous chemical compound and includes: (1) synthetic chemical compounds (ligands) that mimic the action of serotonin on 5-HT ⁇ D 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 ⁇ D ⁇ 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 ⁇ D ⁇ agonist activity.
  • 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 x g for 5 minutes at 4°C.
  • Displacement studies were performed using 4.5-5.5 nM [ 3 H]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 ⁇ g) . The reaction was terminated by rapid filtration through presoaked (0.5% poylethyleneimine) filters using 48R Cell Brandel Harvester (Gaithersburg, MD) .
  • Adenylate cyclase activity was determined using standard techniques. A maximal effect is achieved by serotonin. An Emx is determined by dividing the inhibition of a test compound by the maximal effect and determining a percent inhibition.
  • Drug dose-effect curves were then conducted by adding 6 different final concentrations of drug, followed immediately by the addition of forskolin (10 mM) .
  • 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 ⁇ D ⁇ receptor in the cAMP assay.
  • Pharmaceutical Formulations of the 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 ⁇ D ⁇ receptor.
  • 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
  • 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.
  • a carrier which can be in the form of a capsule, sachet, paper or other container.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a compound of this invention ideally can be admixed with carriers and diluents and molded into tablets or enclosed in gelatin capsules.
  • 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.
  • a lubricant 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-HTiD ⁇ receptor-activated diseases.
  • 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.
  • 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.
  • Hard gelatin capsules are prepared using the following ingredients:
  • the components are blended and compressed to form tablets each weighing 665 mg.
  • Formulation 3 An aerosol solution is prepared containing the following components:
  • 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:
  • 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:
  • 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 :
  • the solution of the above ingredients generally is administered intravenously to a subject at a rate of 1 ml per minute .

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Abstract

La présente invention concerne une classe d'aminotétralines convenant comme agonistes de 5-HT1Dα.
PCT/US1998/008436 1997-04-30 1998-04-27 AMINOTETRALINES SERVANT D'AGONISTES DE 5-HT¿1Dα? Ceased WO1998048786A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US09/403,854 US6355674B1 (en) 1997-04-30 1997-04-27 Aminotetralins as 5-HT1D α Agonists
CA002288897A CA2288897A1 (fr) 1997-04-30 1998-04-27 Aminotetralines servant d'agonistes de 5-ht1d.alpha.
AU71635/98A AU7163598A (en) 1997-04-30 1998-04-27 Aminotetralins as 5-ht1dalpha agonists
EP98918773A EP1052982A4 (fr) 1997-04-30 1998-04-27 AMINOTETRALINES SERVANT D'AGONISTES DE 5-HT 1D$g(a)?
JP54724398A JP2001524112A (ja) 1997-04-30 1998-04-27 ５−ＨＴ▲下１Ｄα▼アゴニストであるアミノテトラリン

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US84639997A 1997-04-30 1997-04-30
US08/846,399 1997-04-30

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KR102538430B1 (ko) 2022-10-17 2023-06-01 만승에너지 주식회사 탄화수소와 가스용 내연기관 연료절감과 배연가스 저감장치
KR20240116149A (ko) 2023-01-20 2024-07-29 정청식 연료 완전연소로 배출가스 저감과 잉여의 힘이 증가되는 내연기관용 촉매와 그의 제조방법

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5047422A (en) * 1986-12-22 1991-09-10 Bayer Aktiengesellschaft 8-substituted 2-aminotetralins
US5286753A (en) * 1990-08-15 1994-02-15 Eli Lilly And Company Ring-substituted 2-amino-1,2,3,4-tetra-hydronaphthalenes and pharmaceutical compositions thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL114760A (en) * 1991-02-08 1997-11-20 Lilly Co Eli Ring-substituted-2-amino-1,2,3,4-tetrahydronaphthalenes and 3-aminochromanes intermediates thereto

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5047422A (en) * 1986-12-22 1991-09-10 Bayer Aktiengesellschaft 8-substituted 2-aminotetralins
US5286753A (en) * 1990-08-15 1994-02-15 Eli Lilly And Company Ring-substituted 2-amino-1,2,3,4-tetra-hydronaphthalenes and pharmaceutical compositions thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LIU Y., ET AL.: "DERIVATES OF 2-(DIPROPYLAMINO)TETRALIN: EFFECT OF THE C8- SUBSTITUENT ON THE INTERACTION WITH 5-HT 1A RECEPTORS.", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 36., 1 January 1993 (1993-01-01), US, pages 4221 - 4229., XP002912020, ISSN: 0022-2623, DOI: 10.1021/jm00078a012 *
See also references of EP1052982A4 *

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AU7163598A (en) 1998-11-24

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