US3655737A - 1-(3-hydroxy-4-methyl-phenyl)-propylamine (-2) and the salts thereof - Google Patents

1-(3-hydroxy-4-methyl-phenyl)-propylamine (-2) and the salts thereof Download PDF

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Publication number
US3655737A
US3655737A US811662A US3655737DA US3655737A US 3655737 A US3655737 A US 3655737A US 811662 A US811662 A US 811662A US 3655737D A US3655737D A US 3655737DA US 3655737 A US3655737 A US 3655737A
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US
United States
Prior art keywords
compounds
compound
methyl
hydroxy
propylamine
Prior art date
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Expired - Lifetime
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US811662A
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English (en)
Inventor
Per Arvid Emil Carlsson
Hans Rudolf Corrodi
Sven Goran Hallhagen
Ulf Krister Junggren
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Hassle AB
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Hassle AB
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A47—FURNITURE; DOMESTIC ARTICLES OR APPLIANCES; COFFEE MILLS; SPICE MILLS; SUCTION CLEANERS IN GENERAL
    • A47L—DOMESTIC WASHING OR CLEANING; SUCTION CLEANERS IN GENERAL
    • A47L23/00—Cleaning footwear
    • A47L23/04—Hand implements for shoe-cleaning, with or without applicators for shoe polish
    • A47L23/05—Hand implements for shoe-cleaning, with or without applicators for shoe polish with applicators for shoe polish
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds

Definitions

  • R wherein R is a member of the group consisting of CH;,, C H and C3H7, and R in position 2, 4, 5 or 6 on the benzene nucleus, is a member of the group consisting of F, Cl, BI, CH3, C2H5 and Cal I7-
  • Prior art compounds are 3-hydroxy-4-methyl-norephedrine;
  • the prior art compound II has no antihypertensive and antidepressant elfects, since it does not penetrate into the brain and displace noradrenaline there.
  • the prior art compound III does penetrate the blood brain barrier, but shows a high sympathomimetic activity which leads to an increase in blood pressure.
  • the increase in blood pressure caused by this side effect overshadows the antihypertensive etfect which might be expected from the ability of the compound to act as a false transmitter in the noradrenergic neurons of the brain.
  • the compound III is more toxic than the compounds disclosed in this invention.
  • the compounds of the invention may be prepared by known methods such as (A) Replacing Z with H in a compound of the formula NH: CH2
  • Z is preferably a methyl group, and Z is preferably a benzyl group.
  • Z may be split oif by strong acids such as HBr, and Z may be split off by hydrogenolysis.
  • reaction way D is applicable only in those cases when the substituent R in the compound of the Formula I is -CH -C H or C3H7. Catalytical removal of araliphatic protecting groups is not applicable when the substituent R is F, C1 or Br.
  • R is CH -C H or -C H all the outlined reaction ways can be used, and catalytical removal of an araliphatic protecting group is possible.
  • the reduction of the compound of the Formula V is preferably carried out by catalytical hydrogenation.
  • the reduction of the compound of the Formula VI is preferably carried out by means of a complex metal hydride such as lithium aluminium hydride.
  • Starting materials for the processes described above may be prepared in any desired way. Some of the possible ways for preparation of starting materials used in the methods A, B, C and E above are outlined in the following reaction schemes, which also serve as further illustrations of the various methods of preparation as described above.
  • the substituents R R R used in the reaction formulas have the meanings given above, Z is hydrogen or the radical Z and Z is hydrogen or the radical Z
  • Starting materials for the reaction Way D may be prepared by methods well known per se.
  • the racernate obtained at the above reactions can be resolved into the enantiomers 'by converting the free base into a salt or an amide of an optically active acid such as tartaric acid or any other optically active acid capable of forming crystalline salts with the amine, and regeneration of the amine after the usual separation of the diastereomeric mixture thus obtained.
  • an optically active acid such as tartaric acid or any other optically active acid capable of forming crystalline salts with the amine
  • the compounds of the present invention may be used either as a purified isomer which is biologically active or in the form of the mixed isomeric product obtained as a natural consequence of the reaction sequences described above, or any other reaction sequence for the preparation of the compounds which results in a mixed isomeric product containing the biologically active isomer or isomers.
  • the new compounds according to the invention may be administered in the form of salts with physiologically acceptable acids.
  • Suitable acids which may be used are, for example, hydrochloric, hydrobromic, sulphuric, fumaric, citric, tartaric, maleic or succinic acid.
  • compositions comprising as active ingredient at least one of the compounds according to the invention in association with a pharmaceutical carrier.
  • Such compositions may be designed for oral, rectal or parenteral administration.
  • the active ingredient may be mixed with a solid, pulverized carrier, for example lactose, saccharose, sorbitol, mannitol, a starch such as potato starch, corn starch, maize starch or amylopectin, a cellulose derivative of gelatin, and also may include lubricants such as magnesium or calcium stearate or a C-arbowax or other polyethylene glycol waxes and compressed to form tablets or centres for drages.
  • a solid, pulverized carrier for example lactose, saccharose, sorbitol, mannitol, a starch such as potato starch, corn starch, maize starch or amylopectin, a cellulose derivative of gelatin, and also may include lubricants such as magnesium or calcium stearate or a C-arbowax or other polyethylene glycol waxes and compressed to form tablets or centres for drages.
  • the centres may be coated, for example with concentrated sugar solutions which may contain gum arabic, talc and/or titanium dioxide, or alternatively with a lacquer dissolved in easily volatile organic solvents or mixtures of organic solvents.
  • Dyestuffs can be added to these coatings.
  • soft gelatin capsules pearl-shaped closed capsules consisting of gelatin and, for example, glycerol, or similar closed capsules
  • the active substance may be admixed with a Carbowax.
  • Hard gelatin capsules may contain granulates of the active substance with solid, pulverized carriers such as lactose, saccharose, sorbitol, mannitol, starches (for example potato starch, corn starch or amylopectin), cellulose derivatives or gelatin, and may also include magnesium stearate or stearic acid.
  • Dosage units for rectal application may be in the form of suppositories comprising the active substance in admixture with a neutral fatty base, or gelatin rectal capsules comprising the active substance in admixture with a Carbowax or other polyethylene glycol waxes. Each dosage unit preferably contains 1 to 200 mg. of active ingredient.
  • Liquid preparations for oral application may be in the form of syrups, suspensions or emulsions, for example containing from about 0.1% to 20% by weight of active substance and also, if desired, such adj'uvants as stabilizing agents, suspending agents, dispersing agents, flavouring agents and/ or sweetening agents.
  • Liquid preparations for rectal administration may be in the form of aqueous solutions containing from about 0.1 to 2% by weight of active substance and also, if desired, stabilizing agents and/ or buffer substances.
  • the carrier may be a sterile, parenterally acceptable liquid e.g. pyrogenfree water or an aqueous solution of polyvinylpyrrolidone, or a parenterally acceptable oil, e.g. arachis oil, and optionally stabilizing agents and/or buffer substances. Dosage units of the solution may advantageously be enclosed in ampoules.
  • the compounds of the invention such as l-(m-hydroxy-p-methylphenyl)-butylamine (-2) and 1-(In-hydroxy)-p-methylphenyl-propylamine (-2), may be given in widely varying dosages from, for example, 20 mg./day to 1 g./ day, but dosage-s of 50500 mg./day will ordinarily be given, amounts between 100 and 300 mg./day being usually preferred.
  • dosages of about 5-100 mg./day, preferably about -50 mg./day may be used.
  • the amine was obtained upon alkalisation of the acidic solution and ether extraction. The product could be used without further purification in the subsequent step.
  • the compounds specified in Table 2 were prepared by the same method. R and R have the significance given above, and Z is used to designate the protecting group used.
  • EXAMPLE 10TABLETS Active substance g.), lactose g.), calcium citrate (50 g.), and starch (50 g.) are mixed together and granulated using a 10% aqueous gelatin solution.
  • the granules are passed through a ZO-mesh sieve, mixed with magnesium stearate (1.5 g.) and tale (5 g.), and then tabletted using a 9 mm. punch.
  • PHARMACOLOGICAL TESTS (I) Effect as releasers and displacers of noradrenaline in the mouse brain
  • mice male, NMRI, b.w. of 18-22 g.
  • the noradrenaline in the brains was determined fluorometrically according to Bertler, Carlsson and Rosengren, Acta. physiol. scand. 44, 273 (1958) 1, 2, 4 and 8 hours after the administration.
  • the values are given in percents of normal values (450 :9 ng./g.).
  • a compound according claim 1 in form of their optical antipodes, or a therapeutically acceptable salt thereof.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Yarns And Mechanical Finishing Of Yarns Or Ropes (AREA)
US811662A 1968-04-01 1969-03-28 1-(3-hydroxy-4-methyl-phenyl)-propylamine (-2) and the salts thereof Expired - Lifetime US3655737A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
SE04332/68A SE348725B (enrdf_load_stackoverflow) 1968-04-01 1968-04-01

Publications (1)

Publication Number Publication Date
US3655737A true US3655737A (en) 1972-04-11

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Family Applications (2)

Application Number Title Priority Date Filing Date
US811662A Expired - Lifetime US3655737A (en) 1968-04-01 1969-03-28 1-(3-hydroxy-4-methyl-phenyl)-propylamine (-2) and the salts thereof
US00171018A Expired - Lifetime US3758691A (en) 1968-04-01 1971-08-11 Illness new substituted hydroxyphenyl-alkylamines in the treatment of mental

Family Applications After (1)

Application Number Title Priority Date Filing Date
US00171018A Expired - Lifetime US3758691A (en) 1968-04-01 1971-08-11 Illness new substituted hydroxyphenyl-alkylamines in the treatment of mental

Country Status (12)

Country Link
US (2) US3655737A (enrdf_load_stackoverflow)
JP (1) JPS5013784B1 (enrdf_load_stackoverflow)
AT (5) AT289756B (enrdf_load_stackoverflow)
CH (4) CH546215A (enrdf_load_stackoverflow)
DE (1) DE1915230C3 (enrdf_load_stackoverflow)
DK (1) DK120709B (enrdf_load_stackoverflow)
FI (1) FI51342C (enrdf_load_stackoverflow)
FR (1) FR2005295A1 (enrdf_load_stackoverflow)
GB (1) GB1238777A (enrdf_load_stackoverflow)
NL (1) NL6905061A (enrdf_load_stackoverflow)
NO (1) NO122979B (enrdf_load_stackoverflow)
SE (1) SE348725B (enrdf_load_stackoverflow)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4034113A (en) * 1975-04-09 1977-07-05 Shulgin Alexander T Treatment of senile geriatric patients to restore performance
US4105695A (en) * 1975-12-11 1978-08-08 Bristol-Myers Company 2-Amino-1-(2,5-dimethoxyphenyl)-butanes

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FI790459A7 (fi) * 1978-02-21 1979-08-22 Sandoz Ag Nya fenyletylaminer foerfarande foer deras framstaellning och kompositioner innehaollande dem
US7022492B2 (en) 2003-12-15 2006-04-04 Dade Behring Inc. Ecstasy haptens and immunogens
US20050130243A1 (en) * 2003-12-15 2005-06-16 Zheng Yi F. Assay for entactogens
US6991911B2 (en) * 2003-12-15 2006-01-31 Dade Behring Inc. Assay for entactogens
US7037669B2 (en) * 2004-03-22 2006-05-02 Dade Behring Inc. Assays for amphetamine and methamphetamine using stereospecific reagents
US7115383B2 (en) * 2004-03-22 2006-10-03 Dade Behring Inc. Assays for amphetamine and methamphetamine

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4034113A (en) * 1975-04-09 1977-07-05 Shulgin Alexander T Treatment of senile geriatric patients to restore performance
US4105695A (en) * 1975-12-11 1978-08-08 Bristol-Myers Company 2-Amino-1-(2,5-dimethoxyphenyl)-butanes

Also Published As

Publication number Publication date
FI51342C (fi) 1976-12-10
CH546215A (de) 1974-02-28
NL6905061A (enrdf_load_stackoverflow) 1969-10-03
AT289756B (de) 1971-05-10
AT294039B (de) 1971-11-10
DE1915230C3 (de) 1978-10-26
GB1238777A (enrdf_load_stackoverflow) 1971-07-07
NO122979B (enrdf_load_stackoverflow) 1971-09-13
DE1915230B2 (de) 1978-02-23
CH553153A (de) 1974-08-30
CH516508A (de) 1971-12-15
FR2005295A1 (enrdf_load_stackoverflow) 1969-12-12
FI51342B (enrdf_load_stackoverflow) 1976-08-31
DE1915230A1 (de) 1970-02-05
US3758691A (en) 1973-09-11
DK120709B (da) 1971-07-05
SE348725B (enrdf_load_stackoverflow) 1972-09-11
CH546214A (de) 1974-02-28
AT292666B (de) 1971-09-10
AT292664B (de) 1971-09-10
AT292665B (de) 1971-09-10
JPS5013784B1 (enrdf_load_stackoverflow) 1975-05-22

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