USRE39667E1 - 3,3-Diphenylpropylamines, their use and preparation - Google Patents

3,3-Diphenylpropylamines, their use and preparation Download PDF

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USRE39667E1
USRE39667E1 US11/017,635 US1763593D USRE39667E US RE39667 E1 USRE39667 E1 US RE39667E1 US 1763593 D US1763593 D US 1763593D US RE39667 E USRE39667 E US RE39667E
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diphenylpropylamine
hydroxy
group
hydrogen
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Rolf A. Johansson
Pinchas Moses
Lisbeth Nilvebrant
Bengt A. Sparf
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Pfizer Health AB
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    • 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
    • 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

Definitions

  • the present invention relates to novel therapeutically active compounds, methods for their preparation, pharmaceutical compositions containing the novel compounds, and the use of the compounds for preparing drugs.
  • WO 89/06644 discloses 3,3-diphenylpropylamines having anticholinergic activity.
  • novel therapeutically active compounds have now been found, some of which are formed as metabolites in mammals when treated with the 3,3-diphenylpropylamines disclosed in the above-mentioned WO publication. These metabolites have at least as favourable anti-cholinergic properties as the parent compounds and can thus be used for the control of events mediated by acetylcholine, like urination.
  • WO 89 / 06644 discloses 3 , 3 -diphenylpropylamines of formula Ia wherein R 1a signifies hydrogen or methyl, R 2a , R 3a and R 4a independently signify hydrogen, methyl, methoxyl, hydroxy, carbamoyl, sulphanoyl or halogen, and Xa represents a tertiary amino group of formula wherein R 5a and R 6a signify non-aromatic hydrocarbol groups, which may be the same or different and which together contain at least three carbon atoms, preferably at least four carbon atoms, especially at least five carbon atoms, and where R 5a and R 6a may form a ring together with the amine nitrogen, said ring preferably having no other hetero atom than the amine nitrogen, and physiologically acceptable acid salts thereof.
  • novel compounds of the present invention are represented by the general formula I wherein R 1 signifies hydrogen or methyl, R 2 and R 3 independently signify hydrogen, methyl, methoxy, hydroxy, carbamoyl, sulphamoyl or halogen, and X represents a tertiary amino group of formula II wherein R 4 and R 5 signify non-aromatic hydrocarbyl groups, which may be the same or different and which together contain at least three carbon atoms, preferably at least four carbon atoms, especially at least five carbon atoms, and wherein R 4 and R 5 may form a ring together with the amine nitrogen, said ring preferably having no other heteroatom than the amine nitrogen.
  • 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 invention comprises the racemic mixture as well as the individual isomers as such.
  • R 2 is preferably hydrogen
  • R 3 is preferably hydrogen or hydroxy
  • R 2 is preferably in 3-, 4- or 5-position.
  • R 3 is preferably in 2-position with respect to the propylamine group.
  • the HOCH 2 -group is preferably in 5-position.
  • each of R 4 and R 5 independently signifies C 1-8 -alkyl, especially C 1-6 -alkyl, or adamantyl, R 4 and R 5 together comprising at least three, preferably at least four carbon atoms.
  • R 4 and R 5 may carry one or more hydroxy groups, and they may be joined to form a ring together with the amine nitrogen atom.
  • tertiary amino groups X in formula I include the following groups a)-h):
  • R 4 and R 5 are both isopropyl.
  • a presently preferred specific compound of formula I is N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropylamine.
  • the compounds of formula I may, in accordance with the present invention, be prepared by per se conventional methods, and especially by
  • the oxidation in process g) above may be performed chemically, electrochemically or enzymatically.
  • Chemical oxidation is advantageously performed using a metal salt or oxide like ceric ammonium nitrate, manganese oxides, chromium oxides, vanadinium oxides, cobalt acetate, aluminium oxide, bismuth molybdate or combinations thereof.
  • Chemical oxidation may also be effected by peracids, with or without a catalyst, or with halides.
  • Electrochemical oxidation may be conducted with or without a catalyst.
  • bacteria or yeast e.g. Candida Guilliermondi, Candida Tropicalis.
  • hydroxy protecting groups according to i) above can e.g. be done by treatment with hydrobromic acid, borontribromide or by catalytic hydrogenation.
  • the separation of mixtures of optical isomers, according to ii) above, into the individual enantiomers can e.g. be achieved by fractional crystallization of salts with chiral acids or by chromatographic separation on chiral columns.
  • the starting compounds of formula III and IX may be prepared as described in the preparation example described below.
  • the starting materials used in processes b) to e) and g) may be prepared as described in the afore-mentioned WO 89/06644 (the disclosure of which is incorporated by reference herein) with due consideration of the disclosure in the present preparation example.
  • 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, for nasal spray administration or the like, in accordance with accepted pharmaceutical procedures.
  • suitable galenic forms such as compositions for oral use, for injection, for nasal spray administration or the like, in accordance with accepted pharmaceutical procedures.
  • Such pharmaceutical compositions according to the invention comprise an effective amount of 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, flavouring agents, buffers, and the like.
  • 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 can, as mentioned above, be used for the same therapeutical indications as the compounds of the above-mentioned WO 89/06644, i.e. for the treatment of acetylcholine-mediated disorders, such as urinary incontinence.
  • the dosage of the specific compound will vary depending on its potency, the mode of administration, the age and weight of the patient and the severity of the condition to be treated.
  • the daily dosage may, for example, range from about 0.01 mg to about 4 mg per kilo of body weight, administered singly or multiply in doses e.g. from about 0,05 mg to about 200 mg each.
  • FIGURE shows bladder pressure inhibition curves for a compound of the present invention and a prior art compound, respectively.
  • N.M.R data were acquired on a Jeol JNM-EX 270 Fourier transform spectrometer. Spectra were recorded with tetramethylsilane (TMS) as internal standard at 30° C. Infrared spectra were recorded on a Perkin Elmer 599B instrument. Non-corrected melting points were obtained on a Koeffler apparatus. Gas chromatography was performed on a HP 5940 instrument with a 10 m HP-1 column and the oven heated in the linear temperature gradient mode.
  • 6-Bromo-4-phenyl-3,4-dihydro-coumarine (290 g, 0.96 mole) was dissolved in a mixture of methanol (1 L) and acetone (1 L). To the above solution were added potassium carbonate (160 g, 1.16 mole), ⁇ -chlorotoluene (140 g, 1.1 mole) and sodium iodide (30 g, 0.47 mole), and the mixture was stirred under reflux for 3 h. The solution was concentrated by distillation, and the residue treated with water and extracted with diethyl ether. The ethereal layer was washed with water, saturated sodium carbonate solution and water, successively. The organic layer was dried over sodium sulfate, filtered and then evaporated to give 420 g ( ⁇ 100%) of the title compound as a light yellow oil.
  • the mixture was refluxed for 1.5 h and then cooled in an acetone/dry-ice bath, whereupon powdered dry ice ( ⁇ 100 g) was added gently. Tetrahydrofuran was added when needed to prevent the mixture from solidification.
  • the reaction mixture was stirred for 0.5 h when ammonium chloride (200 mL, 20% w/w) was added. The mixture was stirred vigorously until two transparent phases were formed, and then filtered through a pad of Celatom. The aqueous layer was washed with diethyl ether and then acidified with hydrochloric acid to pH 1. The precipitated semicrystalline gum was washed with water, and then transferred to a round bottom flask.
  • the product was dried by co-evaporation with acetone, benzene, toluene, diisopropyl ether and methanol, successively.
  • the title compound (35.1 g, 77%) was isolated as friable shiny flakes and used without any further purification.
  • (+)-N,N-Diisopropyl-3-(2-benzyloxy-5-carboxyphenyl)-3-phenylpropylamine (34 g, 0.07 mole) was dissolved in methanol (300 mL) containing sulfuric acid (6 g) and refluxed for 6 h. The solution was then cooled and concentrated. To the mixture were added ice-water and a slight excess of saturated sodium carbonate solution. The mixture was then extracted with diethyl ether. The organic phase was washed with water, dried over sodium sulfate, filtered and evaporated, giving 30 g (93%) of crude ester. Recrystallisation from diisopropyl ether gave white crystals melting at 85°-86° C. The 1-H N.M.R. spectrum was in accordance with the above structure.
  • (+)-N,N-Diisopropyl-3-(2-benzyloxy-5-carbomethoxyphenyl)-3-phenylpropylamine (30 g, 0.065 mole) dissolved in diethyl ether (250 mL) was added dropwise under nitrogen to a suspension of lithium aluminiumhydride (1.9 g, 0.05 mole) in dry diethyl ether (150 mL). The mixture was stirred overnight at room temperature, and the excess hydride was decomposed by the addition of water ( ⁇ 5 g). The mixture was stirred for 10 min, when sodium sulfate (s) was added. After stirring for 20 minutes, the mixture was filtered and then evaporated to give 28.4 g of the title compound as a colourless oil.
  • optical purity as assessed by H.P.L.C. was >99%.
  • Dissected tissues were homogenized in an ice-cold sodium-potassium phosphate buffer (50 mM, pH 7.4) containing 1 mM PMSF, using a Polytron PT-10 instrument (bladder, heart, parotid) and a Potter-Elvehjem Teflon homogenizer (cortex). All homogenates were finally diluted with the ice-cold phosphate/PMSF buffer to a final protein concentration of ⁇ 0.3 mg/ml and immediately used in the receptor binding assays. Protein was determined by the method of Lowry et al. (1951) 4 , using bovine serum albumin as the standard.
  • the muscarinic receptor affinities of the unlabelled compounds A to D identified above were derived from competition experiments in which the ability to inhibit the receptor specific binding of ( ⁇ ) 3 H-QNB (1-quinuclidinyl[phenyl-4- 3 H]benzilate, 32.9 Ci/mmole) was monitored as previously described 3,5 .
  • Each sample contained 10 ⁇ l of ( ⁇ ) 3 H-QNB (final concentration 2 nM), 10 ⁇ l solution of test compound and 1.0 ml tissue homogenate.
  • Triplicate samples were incubated under conditions of equilibrium, i.e., at 25° C. for 60 minutes (urinary bladder), 80 minutes (heart and cerebral cortex) or 210 minutes (parotid gland), respectively.
  • Non-specific binding was determined in the presence of 10 ⁇ M unlabelled atropine. Incubations were terminated by centrifugation 2 , and the radioactivity in the pellets was determined by liquid scintillation spectrometry 2 .
  • IC 50 -values concentration of unlabelled compound producing 50% inhibition of the receptor specific ( ⁇ ) 3 H-QNB binding
  • Affinities expressed as the dissociation constants K i , were calculated by correcting the IC 50 for the radioligand-induced parallel shift and differences in receptor concentration, using the method of Jacobs et al. (1975) 6 .
  • the binding parameters for ( ⁇ ) 3 H-QNB (K D and receptor densities) used in these calculations were determined in separate series of experiments 1-3 .
  • the K i values obtained for bladder, heart, parotid and cortex, respectively, are presented in Table 1 below.
  • Carbachol (carbamylcholine chloride) was used as the standard agonist.
  • carbachol carbachol was then generated by cumulative addition of carbachol to the organ-bath (i.e., stepwise increase of the agonist concentration until the maximal contractile response was reached), followed by washing out and a resting period of at least 15 min. before a fix concentration of the test compound (antagonist) was added to the organ-bath. After 60 min. of incubation with the antagonist, a second cumulative concentration-response curve to carbachol was generated.
  • Blood flow in the central mesenteric artery was measured by an ultrasound flow probe around the artery connected to a transonic blood flow meter and then to a Grass polygraph for registration of the flow.
  • compounds D and A as identified above
  • a polyethylene catheter was inserted into the femoral vein three-way stopcock to a syringe placed in an infusion pump (Sage instrument).
  • a catheter was inserted into the urinary bladder.
  • this catheter was connected to an open vessel, which was filled with 38° C. tempered physiological saline and placed above the animal.
  • the bladder relaxed, leading to a filling of the bladder with saline, under constant hydrostatic pressure.
  • the bladder catheter was connected to a pressure transducer, for registration of intravesical pressure. Blood pressure, heart rate, blood flow and bladder pressure were recorded simultaneously and continuously throughout the experiment. The animals were left for at least 45 minutes to achieve steady state in cardiovascular variables before starting the experiment.
  • Bladder pressure was measured at 8 minutes after the end of infusion of the test substance.
  • the surgical preparation was tested by intravenous injection of 0.25 ⁇ g/kg b.w. of noradrenalin and 0.5 ⁇ g/kg b.w. of acetylcholine.
  • the substance was administered at the doses 0.000 (physiological saline), 0.003, 0.010, 0.030 and 0.100 mg/kg, respectively, with infusion during 2 minutes and an infusion volume of 1 mL/kg. Every cat got all doses and was left to reestablish at least 45 minutes between the 0.003 and 0.010 mg/kg doses, and 60 minutes between the 0.030 and 0.100 mg/kg doses.
  • Intravenous administration of compound D caused an increase with 8, 17 and 21% of the blood flow in superior mesenterica artery at 0.003, 0.01, and 0.03 mg/kg, respectively. Again at the highest dose (0.3 mg/kg) a 10% increase in blood flow was observed.
  • Intravenous administration of compound D caused a decrease with 9% at the highest dose (0.3 mg/kg).
  • compound D of the present invention produced a dose-dependent inhibition of the acetylcholine-induced effect on the bladder which was about ten times more efficient than that of prior art compound A.

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  • Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US11/017,635 1992-11-06 1993-11-05 3,3-Diphenylpropylamines, their use and preparation Expired - Lifetime USRE39667E1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9203318A SE9203318D0 (sv) 1992-11-06 1992-11-06 Novel 3,3-diphenylpropylamines, their use and preparation
PCT/SE1993/000927 WO1994011337A1 (en) 1992-11-06 1993-11-05 Novel 3,3-diphenylpropylamines, their use and preparation

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US11/402,337 Expired - Lifetime USRE40851E1 (en) 1992-11-06 1993-11-05 3,3-diphenylpropylamines, their use and preparation
US11/017,635 Expired - Lifetime USRE39667E1 (en) 1992-11-06 1993-11-05 3,3-Diphenylpropylamines, their use and preparation
US08/432,113 Ceased US5559269A (en) 1992-11-06 1995-05-05 3,3-diphenylpropylamines, their use and preparation
US08/684,638 Expired - Lifetime US5686464A (en) 1992-11-06 1996-07-22 3,3-diphenylpropylamines, their use and preparation

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US08/432,113 Ceased US5559269A (en) 1992-11-06 1995-05-05 3,3-diphenylpropylamines, their use and preparation
US08/684,638 Expired - Lifetime US5686464A (en) 1992-11-06 1996-07-22 3,3-diphenylpropylamines, their use and preparation

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US (4) USRE40851E1 (no)
EP (1) EP0667852B1 (no)
JP (1) JP3343256B2 (no)
AT (1) ATE164828T1 (no)
AU (1) AU672458B2 (no)
CA (1) CA2148827C (no)
DE (1) DE69317898T2 (no)
DK (1) DK0667852T3 (no)
ES (1) ES2117155T3 (no)
FI (1) FI120256B (no)
HK (1) HK1006349A1 (no)
HU (1) HU224916B1 (no)
NO (1) NO305477B1 (no)
SE (1) SE9203318D0 (no)
WO (1) WO1994011337A1 (no)

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US5686464A (en) 1997-11-11
DE69317898D1 (de) 1998-05-14
HU224916B1 (en) 2006-04-28
JP3343256B2 (ja) 2002-11-11
HU9501329D0 (en) 1995-06-28
EP0667852B1 (en) 1998-04-08
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HUT72742A (en) 1996-05-28
SE9203318D0 (sv) 1992-11-06
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HK1006349A1 (en) 1999-02-19
ATE164828T1 (de) 1998-04-15
AU5438094A (en) 1994-06-08
NO951775L (no) 1995-05-05
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NO951775D0 (no) 1995-05-05
USRE40851E1 (en) 2009-07-14
DK0667852T3 (da) 1999-01-11
WO1994011337A1 (en) 1994-05-26
EP0667852A1 (en) 1995-08-23
FI952179A0 (fi) 1995-05-05
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US5559269A (en) 1996-09-24
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