EP0354234A1 - Nouvelles amines, leur utilisation et leur preparation - Google Patents

Nouvelles amines, leur utilisation et leur preparation

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Publication number
EP0354234A1
EP0354234A1 EP89901611A EP89901611A EP0354234A1 EP 0354234 A1 EP0354234 A1 EP 0354234A1 EP 89901611 A EP89901611 A EP 89901611A EP 89901611 A EP89901611 A EP 89901611A EP 0354234 A1 EP0354234 A1 EP 0354234A1
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EP
European Patent Office
Prior art keywords
hydroxy
methyl
hcl
yield
found
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
EP89901611A
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German (de)
English (en)
Inventor
Nils Ake Jönsson
Bengt Ake Sparf
Lembit Mikiver
Pinchas Moses
Lisbet Nilvebrant
Gunilla Glas
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Pfizer Health AB
Original Assignee
Kabi Pharmacia AB
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Application filed by Kabi Pharmacia AB filed Critical Kabi Pharmacia AB
Publication of EP0354234A1 publication Critical patent/EP0354234A1/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having 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
    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having 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 amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
    • C07C215/54—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having 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 amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • 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
    • C07C217/56—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 amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/62—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 amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the present invention relates to novel 3,3-diphenylpropylamino derivatives, to pharmaceutical compositions containing the same, and to the use of said derivatives for preparing drugs.
  • Swedish patent No. 215 499 discloses certain 3,3-diphenylpropylyamines having an advantageous effect on the heart and circulation. These pharmacologically active 3,3-diphenylpropylamines are secondary amines. Said Swedish patent also discloses certain chemical intermediates which are tertiary amines carrying aromatic substituents on the amine nitrogen. Neither the end products (secondary amines) nor the intermediates (tertiary amines) have any hydroxy or methoxy groups as substituents in the ortho positions of the phenyl rings, but only meta and para substituents are specifically disclosed.
  • this drug has anti-cholinergic properties, and is well resorbed in the body.
  • this drug has a very long biological half-life and it is a multi-effect drug also having other pharmacological properties such as Ca-antagonist, noradrenaline antagonist and anti-histamine properties as well as a pronounced effect on the heart.
  • US-A-3.446.901, GB-A-1.169.944 and GB-A-1.169.945 disclose certain 3,3-diphenylpropylamine derivatives and pharmaceutical compositions having antidepressant activity, i.a. N,N-dimethyl-3-(2-methoxy ⁇ henyl)-3-phenylpropylamine, which is considered to be the closest prior art as regards chemical structure (see also the comparative tests reported at the end of this specification).
  • DK-A-111.894 discloses a special process for preparing certain diphenylalkylamines having an effect on the heart and circulation. The specifically described compounds are primary or secondary amines, and none of them has any hydroxy or alkoxy substituent in ortho position of the phenyl rings.
  • the Invention provides novel 3,3-diphenylpropylamines of formula I
  • R 1 signifies hydrogen or methyl
  • R 2 , R 3 and R 4 independently signify hydrogen, methyl, methoxy, hydroxy, carbamoyl, sulphanoyl or halogen
  • X represents a tertiary amino group of formula II
  • the compounds of formula I can form salts with physiologically acceptable acids, organic and inorganic, and the invention comprises the free bases as well as the salts thereof.
  • acid addition salts include the hydrochloride, hydrobromide, hydrogen fumarate, and the like.
  • the novel compounds can be in the form of optical isomers, the invention comprises the racemic mixture as well as the individual enantiomers as such.
  • a preferred sub-class of compounds according to the invention comprises tertiary amines of formula I, wherein each of R 5 and R 6 independently signifies C 1- 8 -alkyl, especially C 1- 6 -alkyl, or adamantyl, R 5 and R 6 together comprising at least three, preferably at least four carbon atoms.
  • R 5 and R 6 may carry one or more hydroxy groups, and they may be joined to form a ring together with the amine nitrogen atom.
  • Presently preferred tertiary amino-groups X in formula I include the following groups a) - f ), each of which may carry one or more hydroxy groups.
  • the invention provides methods for preparing the compounds of formula I, especially the following methods: a) reacting a reactively esterif ied 3,3-diphenylpropanol of formula III
  • R 1 -R 4 are as defined above, and any hydroxy groups may be protected such as by methylation or benzylation, and wherein Y is a leaving group, preferably halogen or an alkyl or arylsulphonyloxy group, with an amine of formula IV
  • R 1 -R 4 and X are as defined above and any hydroxy groups may be protected, preferably using a complex metal hydride, c) N-methylating a secondary 3,3-diphenylpropylamine VI
  • R 1 -R 4 are as defined above and any hydroxy groups may be protected, and wherein Z has the same meaning as R 5 and R 6 with the exception of methyl, Z preferably being a hydrocarbyl group comprising at least three carbon atoms, the N-methylation preferably being carried out using formaldehyde or formic acid, or d) reducing a 3,3-diphenylpropylamine of formula VIla or Vllb
  • R 1 -R 4 and X are as defined above and any hydroxy groups may be protected
  • W signifies a hydroxy group or a halogen atom, preferably by means of catalytic hydrogenation, and i) when necessary splitting off hydroxy protecting groups in the compounds obtained, if desired after mono or di-halogenation of one or both of the phenyl rings, and/or ii) if desired converting obtained bases of formula I into salts thereof with physiologically acceptable acids, or vice versa, and/or iii) if desired separating an obtained mixture of optical isomers into the individual enantiomers, and/or iv) if desired methylating an ortho-hydroxy group in an obtained compound of formula I, wherein R 1 is hydrogen and/or R is hydroxy.
  • the above general methods can be carried out in a manner known per se and/or in accordance with the working examples described below, with due consideration of the desired amino groups and the substituents on the benzene rings.
  • hydroxy protecting groups according to i) above can e.g. be done by treatment with hydrobromic acid, borontribromide or by catalytic hydrogenation.
  • R 1 -R 4 are as defined above, and the corresponding protected compounds (e.g. comprising protected hydroxy groups), are useful as chemical intermediates for the preparation of e.g. the compounds of formula I, and they can be prepared by means of several different methods which are known per se, such as by addition of ethylene oxide (X) to a correspondingly substituted diphenylmethane (IX) in the presence of a suitable base such as sodium amide:
  • the compounds VIII can also be prepared by reduction of the corresponding 3,3-diphenylpropionic acids, preferably using complex metal hydrides.
  • the 3,3-diphenylpropanols VIII can conveniently be converted into the corresponding reactively esterified derivatives III in a manner known per se by displacing the hydroxy groups with e.g. a halogen atom or an alkyl or arylsulphonyloxy group.
  • the 3,3-diphenylamides of formula V used as starting materials in method b), can e.g. be prepared by reacting the above mentioned 3,3-diphenylpropionic acids with an appropriate amine.
  • the secondary amines used as starting materials in method c) can conveniently be prepared by reacting a primary amine H 2 N-Z (wherein Z is as defined above) with a corresponding reactively esterified 3,3-diphenyIpropanol in analogy with method a) above, or by reduction of the corresponding secondary 3,3-diphenylpropionamides in analogy with method b) above.
  • the secondary amines can also be prepared by reduction of unsaturated hydroxyamines XI
  • R 1 -R 4 ft and Z are as defined above, either in one step by catalytic hydrogenation, or by reduction to the corresponding saturated hydroxyamine, preferably using a complex metal hydride such as lithium aluminium hydride, followed by removal of the hydroxy group by catalytic reduction.
  • the hydroxy group may first be split off as water, followed by reduction of the formed unsaturated amine.
  • the unsaturated hydroxy amines XI can conveniently be prepared by the addition of a Schiff base of formula XII
  • R 1 -R 4 are as defined above, in the presence of a base, preferably a lithium organic base such as lithium diisopropylamide.
  • starting materials VIla, Vllb for process d) can be prepared by methods known per se, such as by addition of an organometallic compound XlVa or XIVb
  • the compounds of formula I in the form of free bases or salts with physiologically acceptable acids, can be brought into suitable galenic forms, such as compositions for oral use, for injection, or the like, in accordance with accepted pharmaceutical procedures.
  • suitable galenic forms such as compositions for oral use, for injection, or the like, in accordance with accepted pharmaceutical procedures.
  • Such pharmaceuti cal compositions according to the invention comprise the compounds of formula I in association with compatible pharmaceutically acceptable carrier materials, or diluents, as is well known in the art.
  • the carriers may be any inert material, organic or inorganic, suitable for enteral, percutaneous or parenteral administration such as: water, gelatin, gum arabicum, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide, and the like.
  • Such compositions may also contain other pharmaceutically active agents, and conventional additives such as stabilizers, wetting agents, emulsifiers,
  • compositions according to the invention can e.g. be made up in solid or liquid form for oral administration, such as tablets, capsules, powders, syrups, elixirs and the like, in the form of sterile solutions, suspensions or emulsions for parenteral administration, and the like.
  • the compounds and compositions according to the invention can be used for treating cholin-mediated disorders such as urinary incontinence.
  • the dosage depends on several factors such as the potency of the selected specific compound, the mode of administration, the age and weight of the patient, the severity of the condition to be treated, and the like.
  • the daily dosage may, for example, be from about 0.05 mg to about & mg per kilo of body weight, administered in one or more doses, e.g. containing from about 0.05 to about 200 mg each.
  • IPA diisopropyl amine
  • TBA tert.butyl amine
  • Example 4b The fumaric acid salt had m.p. 147-148° (acetone).
  • the free base was obtained in 86% yield from the tosylate (XLVIII) of Example 41) and was converted to the fumaric acid salt in the usual way. M.p. 134-136° (acetone-IPE) or 163-164° (methanol).
  • Example 4d 2-amino-2-methylpropanol.
  • the solid product was crystallized from diisopropyl ether and melted at 103°C. It was used as start material in Example 7p).
  • This compound was similarly prepared from the tosylate (XXIX) of Example 4d) and 1-aminoadamantane. It was used as start material in Example 7q).
  • the hydrochloridesemihydrate was prepared in acetonitrile and melted at 225°C.
  • the free base was obtained in 84% yield from the tosylate (XXIX) of Example 4d).
  • the oxalic acid salt had m.p. 198° (acetone-ether).
  • the free base was obtained in 94% yield from the tosylate (XXXIV) of Example 4h).
  • the HCL-salt had m.p. 210° (acetone-ether).
  • Example 4i The HCl-salt had m.p. 196° (acetone-ethanol-ether).
  • Example 4e and tert. amylamine.
  • the HCl-salt had m.p. 188-189° (ethanolacetone).
  • the free base was obtained in 94% yield from the tosylate (XXXII) of Example 4f) and tert. amylamine.
  • the HCl-salt had m.p. 210° (ethanol-acetone).
  • the free base was obtained in 96% yield from the amine (L) of Example 6a).
  • the HCl-salt had m.p. 187-190° (acetone-ether).
  • Example 6k The HCl-salt had m.p. 170-171° (acetone-ether).
  • the free base was obtained in 96% yield from the amine (LIX) of Example 6j).
  • the HCl-salt had m.p. 180-190° and seems to be associated with 1/4 mol of water.
  • Example 9q The free amine was obtained as an oil which was converted to the hydrochloride and crystallized from 2-propanol. M.p. 250°C.
  • Example 9q The benzyloxy compound from Example 5o was hydrogenolysed as described in Example 9q).
  • the free base was converted to the hydrochloride semihydrate which was crystallized from acetone.
  • the compound melts with decomposition at about 150°C.
  • 3-(2-Methoxy-5-methylphenyl)-3-phenylpropionic acid (12.8 g, 0.05 mol) (3.D. Simpson & H. Stehphen, 3. Chem. Soc. 1956 1382) and thionyl chloride (50 ml) are heated on a water bath for 3 h. The excess of thionyl chloride is distilled off under reduced pressure. The remaining crude 3-(2-methoxy-5-methylphenyl)-3-phenylpropionyl chloride is dissolved in 50 ml of dichloromethane and added dropwise to a stirred solution of diisopropylamine (20.2 g, 0.20 mol) in 200 ml of dichloromethane at about 0o C.
  • Example 11 N-Methyl-N-tert.butyl-3-(5-chloro-2-hydroxyphenyl)-3-phenylpropylamine A solution of chlorine (7,1 g, 0,10 mol) in acetic acid (500 ml) is added dropwise to a stirred solution of N-methyl-N-tert.butyl-3-(2-hydroxyphenyl)-3-phenylpropylamine (29.7 g, 0.10 mol) in acetic acid (200 ml) with stirring. After 2 h the solvent is distilled off under reduced pressure and the crude hydrochloride left is recrystallized from 2-propanol. Melting point 260°C. b) N,N-Diisopropyl-3-(5-chloro-2-hydroxyphenyl)-3-phenylpropylamine is similarly prepared. The hydrochloride melts at 202-3°C.
  • (+)-N,N-Diisopropyl-3-(2-hydroxyphenyl)-3-phenylpropylamine is similarly prepared using D-(-)-tartaric acid.
  • the hydrogen-D-(-)tartrate has [ ⁇ ] D 20 + 10.0°.
  • the free amine has [ ⁇ ] D 20 + 5.6°, both measured as 5% solutions in methanol.
  • Example 13 (continuation of Example 1) Preparation of 4-phenyl-3 -4-dihydrocoumarins g) 4-(2-Methoxyphenyl)6-methyl-3,4-dihydrocoumarin ( CVT )
  • Example 15 (continuation of Example 3) Preparation of 3,3-diphenylpropanols m) 3-(5-Chloro-2-methoxyphenyl)-3-(2-methoxyphenyl)propanol (CX) was obtained in 84% yield fran the ester CIX of Example 14m in the manner described for the propanol XVI of Example 3a), except that the reduction was carried out in toluene with a 10% molar excess of a 3.4 M toluenic solution of sodium bis(2-methoxyethoxy)aluminium hydride (SMEAH) instead of LiAlH 4 . M.p. 70-72° (IPE).
  • SMEAH sodium bis(2-methoxyethoxy)aluminium hydride
  • Example 16 (continuation of Example 4) Preparation of 3,3-diphenylpropyl-p-toluenesulphonates n) 3-(2-Methoxyphenyl)-3-(2-met_hoxy-5-methylphenyl)propyl-p-toluenesulphonate (CXII) was prepared in the same way as the tosylate XXVTI of Example 4a) in quantitative yield from the propanol CXI of Example 15n) using CH 2 Cl 2 as solvent instead of chloroform. M.p. 101° (ether/IPE). C 25 H 28 O 5 S (440.57) requires: C 68.16 H 6.41 S 7.28 Found: 68.3 6.51 7.20
  • N,N-Diisopropyl-3-(2-methoxyphenyl)-3-(2-_methoxy-5-methylphenyl)-propylamine was obtained in the same way in 49% crude yield from the tosylate CXV of Example 16n).
  • the product (oil) had a purity of 100% according to GC.
  • CXVT N-T(2-Benzyloxy-5-methyl)-3-phenyl]-2,2,5,5-tetramethylpyrrolidine
  • Example 18 (continuation of Exairple 6) Preparation of secondary 3,3-diphenylpropylamines p) N-tert.Butyl-3-(5-chioro-2-methoxyphenyl)-3-(2-methoxyphenyl)propylamine (CXVII) was prepared in quantitative yield from the tosylate CXIII of Example 16o) in the manner described for the amine L of Example 6a). The HCl-salt had m.p. >260°.
  • Example 19 (continuation of Example 7) Preparation of tertiary 3,3-diphenylpropylamines from secondary amines r) N-Methyl-N-tert.butyl-3-(5-chloro-2-methoxyphenyl)-3-(2-methoxyphenyl)propylamine (CXIX) was prepared in 89% yield fran the amine CXVTI of Example 18p) in the manner described for the amine LXI of Example 7a). The HCl-salt was prepared by treating an acetonic solution of the free base with conctrated hydrochloric acid. M.p. 130°. C 22 H 30 ClO 2 N.HCl.H 2 O (430.42) Requires: C 61.39 H 7.74 N 3.25 Cl 16.47 Found: 62.0 7.93 3.26 16.5
  • N-Methyl-N-tert.butyl-3-(2-methoxyphenyl)-3-(2-methoxy-5-methylphenyl)propylamine was prepared in a similar way in 98% yield from the amine CXVIII of Example 18q).
  • the free base (oil) had a purity of 96% by GC.
  • Example 20 (continuation of Example 9) Removal of O-protective groups af) N,N-Diisopropyl-3-(2-hydroxyphenyl)-3-(2-hydroxy-5-methylphenyl)- propylamine (CXXI)
  • CXXI N,N-Diisopropyl-3-(2-hydroxyphenyl)-3-(2-hydroxy-5-methylphenyl)- propylamine
  • CXXIV N-Methyl-N-tert.butyl-3-(5-chloro-2-hydroxyphenyl)-3-(2-hydroxyphenyl)propylamine
  • Example 21 (continuation of Example 10) Reduction of amides N,N-Diisopropyl-3-(2-methoxyphenyl)-3-phenylpropionamine N,N-Diisopropyl-3-(2-methoxyphenyl)-3-phenylpropionamide was obtained as o pale yellow oil in quantitative yield fr ⁇ n 3-(2-methoxyphenyl)-3-phenylpropionic acid in the manner described for the amide of Example 10a). This amide (27 g, 0.08 mol) in toluene (50 g) was added dropwise under r.t.
  • Na + -Krebs in which they were kept throughout the dissection procedure.
  • the bladders were dissected free from adherent fat and connective tissue before they were cut open by an incision on each side from the base towards apex.
  • the mucosa was carefully removed with a pair of scissors.
  • Four strips, approximately 3-5 mm long were prepared by cutting in a parallel direction to the longitudinal muscle fibres, on each half of the bladder.
  • the bladder strips were immediately mounted vertically in 5 ml organ baths containing Na + -Krebs solution aerated with carbogene gas to maintain the pH at about 7.4.
  • the temperature, 37°C was thermostatically controlled by a Lauda MS3 thermostatic circulator.
  • the preparations were suspended between two hooks, one of which was connected to a Grass Instruments FTO3 force transducer.
  • the isomeric tension of the preparations was recorded by a Grass polygraph model 79D.
  • the resting tension was applied to approximately 5 mN.
  • the strips were allowed to stabilize for at least 45 minutes. During this period the resting tension was adjusted to 5 mN and the preparations were repeatedly washed.
  • the strips were incubated with the antagonist for 15 minutes before the next carbachol was added. If the antagonist produced more than 50% inhibition of the response to carbachol, a complete concentration-inhibition curve was also made. In the complete inhibition curves, the strips were then incubated for 60 minutes with a fixed concentration of the antagonist before the next addition of carbachol. The effect of the antagonists was calculated as per cent inhibition of the mean of the initial agonist-induced contractions. To generate concentration-inhibition curves the antagonists were studied in 6-8 concentrations and for each concentration a fresh preparation was used, i.e. the strips were only exposed to the antagonist once before they were discarded.
  • Buffer Na + -Krebs, modified by K.E. Andersson
  • the rat is killed by a blow on the neck and decapitated.
  • the abdomen is opened, the vein is dissected free from fat, cut open longitudinally and mounted in an organ bath. Changes in isometric tension is registered by a force displacement transducer, connected to an amplifier and a writing oscillograph. Noradrenaline - anta gonism on portal vein
  • the chosen doses give about 70% of maximal response.
  • the agonist is added to the bath at 10-minutes intervals. When reproducible contractions are obtained a fixed concentration of the test substance is added to the bath. After an incubation period of 10 minutes noradrenaline is added. The next concentration of the test substance is added when the original response of the agonist is obtained.
  • the antagonistic effect of the substance is calculated as per cent inhibition of the mean response by three preceding doses of the agonist.
  • Buffer Na + -Krebs, modified by K.E. Andersson
  • the guinea pig is killed by a blow on the neck and decapitated.
  • the abdomen is opened and about 2 cm of the ileum is cut off about 15 cm above the ileocaecal junction.
  • the piece of ileum is washed with buffer and mounted in an organ bath. Changes in isometric tension is recorded by a force displacement transducer, connected to an amplifier and a writing oscillograph. Dose: 5 ⁇ 10 -7 M of histamine.
  • the chosen dose of histamine gives about 70% of maximal response.
  • the agonist is added to the bath at 3-minutes intervals. When reproducible contractions are obtained a fixed concentration of the test substance is added to the bath. After an incubation period of 2-10 minutes a new contraction is induced by histamine. The next concentration of the test substance is added when the original response of the agonist is obtained.
  • mice The agonistic effect of the test substance is calculated as per cent inhibition of the mean response by three preceding doses of histamine. d) Acute toxicity in mice
  • the antagonists to be tested were dissolved in 0.9% NaCl. If they were not soluble in 0.9% NaCl they were dissolved in double distilled water. The solutions were prepraed on the day of the experiment. Procedure
  • mice 25 g were placed in a mouse holder.
  • the tested compounds were given as i.v. bolus doses in one of the four tail-veins, with a volume of 0.01 ml/g mouse.
  • Each substance concentration was given to a group of four mice. 4-5 different concentrations of the antagonists were made and tested.
  • the acute lethal dose (LD 1 1 ) was the lowest concentration of the anticholinergic drug where 4 mice of 4 tested died within 5 minutes after an i.v. bolus dose.
  • LD 50 -interval The LD 50 -interval was between the highest dose where 4 mice survived and the lowest dose where 4 mice died within 5 minutes after an i.v. bolus dose.
  • the animal is slightly anaestetized by ether and an infusion cannula is inserted into a tail vein. While still asleep the rat is placed in a simple device, made of a coarse, somewhat elastic net fixing the rat in a constant position. Electrodes are attached to the extremities and connected to an ECG-puise preamplifier and a Grass polygraph. By recording the ECG, the heart rate can then be determined. Before any substance is given the animal has regained consciousness and the heart rate has been constant for at least 15 minutes.
  • the substance is injected, i.v. in the infusion cannula and flushed with physiological saline.
  • ECG is recorded 0.25, 0.5, 1, 2, 3 and 5 minutes after completed injection and then every 5 minutes until the original heart rate is obtained.
  • the compound 1 according to the invention is mixed with ingredients 2, 3, 4 and 5 for about 10 minutes.
  • the magnesium stearate is then added, the resultant mixture being mixed for about 5 minutes and then compressed into tablet form with or without f ⁇ lmcoating.
  • Example B
  • the compound 1 according to the invention is mixed with ingredients 2 and 3 and then milled.
  • the resulting mixture is then mixed with ingredients 4 and 5 and then filled into capsules of appropriate size.

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Abstract

Nouvelles 3,3-diphénylpropylamines de formule (I) dans laquelle R1 représente hydrogène ou méthyle, R2, R3 et R4 représentent indépendamment hydrogène, méthyle, méthoxy, hydroxy, carbamoyle, sulfanoyle ou halogène. X représente un groupe amino tertiaire -NR5, R6, dans lequel R5 et R6 représentent des groupes d'hydrocarbyle non aromatiques pouvant être identiques ou différents, contenant ensemble au moins trois atomes de carbone et pouvant former un anneau avec l'azote de l'amine, leurs sels avec des acides physiologiquement acceptables et, lorsque les composés peuvent avoir la forme d'isomères optiques, le mélange racémique et les éniantomères individuels, leur utilisation comme produits pharmaceutiques, notamment comme agents anticholinergiques, leur utilisation pour préparer un médicament anticholinergique, des compositions pharmaceutiques contenant les nouvelles amines, et des procédés permettant leur préparation.
EP89901611A 1988-01-22 1989-01-20 Nouvelles amines, leur utilisation et leur preparation Pending EP0354234A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE8800207 1988-01-22
SE8800207A SE8800207D0 (sv) 1988-01-22 1988-01-22 Nya aminer, deras anvendning och framstellning

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EP0354234A1 true EP0354234A1 (fr) 1990-02-14

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EP89850017A Expired - Lifetime EP0325571B1 (fr) 1988-01-22 1989-01-20 Amines, leur utilisation et leur préparation

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JP (1) JP2664503B2 (fr)
AT (1) ATE65990T1 (fr)
AU (1) AU635493B2 (fr)
CA (1) CA1340223C (fr)
DE (2) DE68900180D1 (fr)
DK (1) DK172103B1 (fr)
ES (1) ES2029384T4 (fr)
FI (1) FI109900B (fr)
GR (1) GR3002854T3 (fr)
HK (1) HK64494A (fr)
HU (2) HU212729B (fr)
LU (1) LU90259I2 (fr)
NL (1) NL980020I2 (fr)
NO (2) NO173496C (fr)
SE (1) SE8800207D0 (fr)
WO (1) WO1989006644A1 (fr)

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SE8800207D0 (sv) 1988-01-22
DK172590A (da) 1990-07-19
GR3002854T3 (en) 1993-01-25
JP2664503B2 (ja) 1997-10-15
ES2029384T4 (es) 2011-05-30
DK172103B1 (da) 1997-10-27
FI109900B (fi) 2002-10-31
NO1998023I1 (no) 1998-10-20
CA1340223C (fr) 1998-12-15
DK172590D0 (da) 1990-07-19
ES2029384T3 (es) 1992-08-01
HU210603A9 (en) 1995-05-29
DE68900180D1 (de) 1991-09-12
HU212729B (en) 1996-10-28
NL980020I1 (nl) 1998-09-01
HUT58040A (en) 1992-01-28
NO173496B (no) 1993-09-13
JPH03503163A (ja) 1991-07-18
NO903085L (no) 1990-07-11
HU891069D0 (en) 1991-11-28
NL980020I2 (nl) 1999-02-01
FI903688A0 (fi) 1990-07-20
NO173496C (no) 1993-12-22
DE19875024I2 (de) 2002-09-26
EP0325571B1 (fr) 1991-08-07
AU2932989A (en) 1989-08-11
HK64494A (en) 1994-07-15
AU635493B2 (en) 1993-03-25
LU90259I2 (fr) 1998-09-16
NO903085D0 (no) 1990-07-11
WO1989006644A1 (fr) 1989-07-27
ATE65990T1 (de) 1991-08-15
EP0325571A1 (fr) 1989-07-26

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