Classifications

• • 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
  • C07C215/52—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 two 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
  • A61P13/00—Drugs for disorders of the urinary system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/06—Anti-spasmodics
• • 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

Definitions

• the present invention relates to novel therapeutic compounds, pharmaceutical compositions containing the same, the compounds for use as medicaments, and use of the compounds for the manufacture of specific medicaments.
• the present invention also concerns a method of treatment involving administration of the compounds.
• novel compounds are useful as antimuscarinic agents.
• novel compounds are useful for the treatment or control of events mediated by acetylcholine, such as urinary disorders.
• U.S. Pat. No. 5,382,600 discloses (substituted) 3,3-diphenylpropylamines useful for treating urinary incontinence.
• it discloses 2-[(1R)-3-(diisopropylamino)-1-phenylpropyl)-4-methylphenol, also known as N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine, with the generic name of tolterodine, as being useful to treat urinary incontinence.
• Tolterodine is the compound of Example 22 of U.S. Pat. No. 5,382,600.
• tolterodine is prepared by the processes of International Publication W098/29402 (U.S. Pat. No. 5,922,914).
• U.S. Pat. No. 5,559,269 and U.S. Pat. No. 5,686,464 disclose hydroxytolterodine and related compounds as being useful to treat urinary incontinence. Hydroxytolterodine is also the major metabolite of tolterodine (Nilvebrant et al, 1997, Eur J Pharmacol, 327:195-207).
• WO 99/58478 discloses substituted 3,3-diphenylpropylamines for use as pharmaceutically active substances.
• the international patent application WO 98/43942 discloses therapeutically active diarylpropylamines, which have favorable anticholinergic properties, and which can be used for the treatment of disorders related to urinary incontinence.
• tolterodine is metabolized by various cytochrome P450 enzymes.
• the two main metabolic events are oxidation of the 5-methyl group, catalyzed by the CYP2D6 enzyme, and dealkylation of the nitrogen, catalyzed by the CYP3A enzyme.
• the present invention provides according to a first aspect a 3,3-diphenylpropylamine of the formula and any stereoisomers thereof;
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a therapeutically effective amount of a 3,3-diphenylpropylamine according to the invention, and a suitable pharmaceutical carrier therefor.
• the present invention also provides a 3,3-diphenylpropylamine according to the invention for use as a medicament.
• the present invention provides novel use of a 3,3-diphenylpropylamine according to the invention for the manufacture of a medicament for treating urinary disorders.
• the present invention also provides a method of treating urinary disorders in a mammal, including man, comprising administering to said mammal, in need of such a treatment, a therapeutically effective amount of a 3,3-diphenylpropylamine according to the invention.
• the present invention provides a 3,3-diphenylpropylamine of the formula and any stereoisomers thereof.
• the invention also provides physiologically acceptable acid addition salts thereof.
• R 1 may represent —H or —CH 3 .
• R 1 represents hydrogen.
• R 2 represents —CX 3 , —CR 2-1 X 2 , —CR 2-1 R 2-2 X, or —CR 2-1 R 2-2 H, wherein X represents halogen, and R 2-1 and R 2-2 independently represent —H or —(C 1 -C 4 alkyl), optionally substituted with halogen.
• R 2 must comprise at least one halogen.
• R 2 represents —CX 3 , —CR 2-1 X 2 or —CR 2-1 R 2-2 X.
• the R 2 group is situated opposite (para) to the OR 1 group in their common phenyl ring structure.
• R 2 represents —CX 3 .
• X represents fluorine.
• R 2 represents —CF 3 .
• the bond strength of the C—F bond, relative to that of a C—H bond can decrease or preclude metabolism by cytochrome P450 enzymes. This may be optimal for safety and lack of CYP2D6 metabolism.
• the —CF 3 group provides increased lipophilicity and, when —OR 1 represents —OH (i.e. R 1 represents hydrogen), provides inductive effects on the acidity of that —OH group, that may impart favorable conformational changes to the molecule.
• R 3 and R 4 may be the same or different.
• R 3 and R 4 independently represent —H, —OCH 3 , —OH, —CONH 2 , —SO 2 NH 2 , —F, —Cl, —Br, —I, —CF 3 , or —(C 1 -C 4 alkyl), optionally substituted with one or two —OH, —(C 1 -C 4 alkoxy), —COOH, or —CO—O—(C 1 -C 3 alkyl).
• R 3 and R 4 represents —H. In a particular embodiment, both R 3 and R 4 represent —H.
• R 5 and R 6 may be the same or different.
• R 5 and R 6 independently represent C 1 -C 6 alkyl, optionally substituted with hydroxyl, wherein R 5 and R 6 together contain at least three carbon atoms, and wherein R 5 and R 6 may form a ring together with the amine nitrogen.
• At least one of R 5 and R 6 represents C 1 -C 3 alkyl.
• the C 1 -C 3 alkyl is isopropyl.
• both R 5 and R 6 represent isopropyl.
• the carbon stereocenter is (R). In another embodiment of the 3,3-diphenylpropylamine according to the invention, the carbon stereocenter is (S). In yet another embodiment of the 3,3-diphenylpropylamine according to the invention, it is present in the form of a mixture of stereoisomers.
• Particular embodiments of the 3,3-diphenylpropylamines according to the invention comprise the group consisting of:
• the 3,3-diphenylpropylamine is N,N-diisopropyl-3-(2-hydroxy-5-trifluoromethylphenyl)-3-phenylpropanamine.
• this compound exhibits favorable binding properties with regard to muscarinic receptors m1-m4.
• N,N-diisopropyl-3-(2-hydroxy-5-trifluoromethylphenyl)-3-phenylpropanamine can avoid being metabolized by the CYP2D6 enzyme.
• This is advantageous since metabolism by this enzyme accounts for a substantial part of the intersubject variability in the pharmacokinetic properties of tolterodine.
• CYP2D6 is a polymorphic enzyme, with about 10% of the population being genetically “poor metabolizers”. Therefore, compounds according to the invention may be helpful in providing a medicament that avoids the costs and problems related to intersubject variability in pharmacokinetics.
• antimuscarinic agents refer to muscarinic receptor antagonists.
• known antimuscarinic agents include tolterodine, hydroxytolterodine, 2-(diisopropylamino)ethyl-1-phenyl-cyclopentanecarboxylate, propiverine, oxybutynin, trospium, darifenacin, solifenacin, temiverine, ipratropium, and tiotropium.
• the compounds of the invention are preferably administered as salts with a pharmaceutically acceptable acid.
• the preferred pharmaceutically acceptable salts, organic or inorganic include salts of the following acids: tartaric, hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, nitric, citric, methanesulfonic, CH 3 —(CH 2 ) n —COOH where n is 0 to 4, HOOC—(CH 2 ) n —COOH where n is 1 to 4, HOOC—CH ⁇ CH—COOH, and benzoic.
• a particularly preferred salt is tartrate.
• a pharmaceutical composition comprising a therapeutically effective amount of a 3,3-diphenylpropylamine according to the invention, and a suitable pharmaceutical carrier therefor.
• compositions for administration can be brought into suitable dosage forms, such as compositions for administration through the oral, rectal, transdermal, parenteral, nasal, or pulmonary route in accordance with accepted pharmaceutical procedures.
• suitable dosage forms such as compositions for administration through the oral, rectal, transdermal, parenteral, nasal, or pulmonary route in accordance with accepted pharmaceutical procedures.
• Such pharmaceutical compositions according to the invention comprise the compounds according to the invention 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 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.
• compositions may also contain other pharmaceutically active agents, and conventional additives such as stabilizers, wetting agents, emulsifiers, flavoring agents, buffers, binders, disintegrants, lubricants, glidants, antiadherents, propellants, and the like.
• additives such as stabilizers, wetting agents, emulsifiers, flavoring agents, buffers, binders, disintegrants, lubricants, glidants, antiadherents, propellants, and the like.
• novel compounds according to the present invention can be administered in any suitable way.
• the compounds according to the invention can be made up in solid or liquid form, such as tablets, capsules, powders, syrups, elixirs and the like, aerosols, sterile solutions, suspensions or emulsions, and the like.
• ⁇ ективное ⁇ ество refers to a therapeutically effective amount for treating urinary disorders.
• therapy and “therapeutically” encompass all kinds of treatments, including prophylaxis.
• therapeutically effective means that it is effective for anti-cholinergic treatment.
• the dosage of the specific compound according to the invention 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 medication may be administered orally once or twice daily, or less frequently, or intermittently.
• the present invention also provides a 3,3-diphenylpropylamine according to the invention for use as a medicament.
• the present invention provides novel use of a 3,3-diphenylpropylamine according to the invention for the manufacture of a medicament for treating urinary disorders.
• the compounds of the invention have anti-cholinergic properties. Thus, they are useful for the treatment of acetylcholine-mediated disorders. In particular, they are useful for treating urinary disorders.
• Urinary disorders and symptoms thereof include some or all of the following: urgency, frequency, incontinence, urine leakage, enuresis, dysuria, hesitancy, and difficulty of emptying bladder.
• urinary disorders include urinary incontinence, caused by e.g. unstable or overactive urinary bladder.
• Overactive urinary bladder encompasses variants of urinary disorders, including overactive detrusor (detrusor instability, detrusor hyperreflexia) and sensory urgency, as well as symptoms of detrusor overactivity, e.g. urge incontinence, urgency, urinary frequency, and LUTS (Lower Urinary Tract Symptoms), including obstructive urinary symptoms, such as slow urination, dribbling at the end of urination, inability to urinate and/or the need to strain to urinate at an acceptable rate, or irritating symptoms such as frequency, dry overactive bladder, and/or urgency).
• overactive detrusor detrusor instability, detrusor hyperreflexia
• symptoms of detrusor overactivity e.g. urge incontinence, urgency, urinary frequency, and LUTS (Lower Urinary Tract Symptoms)
• obstructive urinary symptoms such as slow urination, dribbling at the end of uri
• Overactive bladder disorders also include nocturia and mixed incontinence. While overactive bladder is often associated with detrusor muscle instability, disorders of bladder function may also be due to neuropathy of the central nervous system (detrusor hyperreflexia), including spinal cord and brain lesions, such as multiple sclerosis and stroke. Overactive bladder symptoms may also result from, for example, male bladder outlet obstruction (usually due to prostatic hypertrophy), interstitial cystitis, local edema and irritation due to focal bladder cancer, radiation cystitis due to radiotherapy to the pelvis, and cystitis.
• male bladder outlet obstruction usually due to prostatic hypertrophy
• interstitial cystitis local edema and irritation due to focal bladder cancer
• radiation cystitis due to radiotherapy to the pelvis, and cystitis.
• the present invention also provides a method of treating urinary disorders in a mammal, including man, comprising administering to said mammal, in need of such a treatment, a therapeutically effective amount of a 3,3-diphenylpropylamine according to the invention.
• the compounds of the present invention are used to treat mammals, including man, cat, dog, and horse. It is preferred that the mammal is a human.
• the light orange solution was stirred under nitrogen for 1 h as the temperature increased from 5.5° C. to 17.5° C.
• the light orange solution was cooled again in an ice bath. 20% Aqueous NH 4 Cl (500 mL) was added dropwise at 7-11° C. over 13 min.
• the resulting mixture was extracted with ether (2000 mL).
• the ether extract was washed successively with water (1000 mL), 10% aqueous NaHCO 3 (1000 mL) and then saturated brine (1000 mL).
• the ether layer was dried over MgSO 4 , filtered and concentrated on a rotary evaporator at 45° C. to give a light yellow oily solid; 160.65 g. GC showed a high boiling component along with some starting 4-trifluoromethylanisole and benzaldehyde. This oily solid was slurried in hexane (200 mL) and cooled in the refrigerator overnight.
• the slurry was suction filtered and the light yellow solid was crushed with a spatula.
• the cake was then washed with hexane (250 mL) to give a light yellow crystalline solid; 116.0 g. GC showed 86.5% product with some residual low boiling point components.
• the yellow filtrate was concentrated on a rotary evaporator at 35° C. to give a yellow viscous oil; 39.2 g. GC showed mostly low boiling point components with some residual product (17.7%).
• a 250 mL 3-neck flask was equipped with a Teflon-coated thermocouple, a distillation head and a 60 mL addition funnel.
• N,N-Diisopropyl bromoacetamide (67.9 g; 0.306 mol) was charged to the flask and heated with a heating mantle. After the solid melted, the brown oil was stirred magnetically and heated to 110° C. under a nitrogen atmosphere.
• Neat triethyl phosphite (57 mL; 0.332 mol, Aldrich) was added dropwise over a period of 30 min at 104-117° C., as bromoethane co-product was distilled off at 35-45° C. and collected in a 100 mL flask.
• the red amber oil was transferred to a 500 mL flask with some ether and stripped on a rotary evaporator at 45° C.; 88.3 g. This red amber oil was then stripped on a Kugelrohr at 75° C. and 0.15-0.4 torr for 1 h to remove the residual low boiling impurities and leave a red amber oil; 78.3 g. GC showed 94% product with negligible low boiling point components.
• 1 H-NMR was consistent with the desired product, showing two different isopropyl groups. 13 C-NMR was also consistent with the desired diethyl phosphonate. The yield was 91.6%.
• This foam was slurried in ether (5 mL), suction filtered and washed with ether to give a gold solid that became tacky almost immediately on the filter.
• This hygroscopic solid was dissolved in methanol (10 mL) and concentrated on a rotary evaporator at 25-50° C. to approximately 2 mL volume. Addition of ether ( ⁇ 5 mL) until turbid gave precipitation of a brown oil. The mixture was concentrated again to give a gold foam; 451.5 mg. This foam was broken up with a spatula and dried in a vacuum oven overnight at 45° C.
• Amount of brown-gold glass 436.4 mg. Insoluble in CDCl 3 .
• LC showed the desired amino-phenol with a M-1 ion at 378 m/z and tartaric acid with a M-1 ion at 149 m/z by electrospray in the negative ion mode.
• 1 H-NMR was consistent with the 1:1 tartrate salt with the appropriate downfield shifts of the various aliphatic proton signals.
• 13 C-NMR showed the two unique carbons of tartaric acid and all carbons of the phenolic amine except for missing two quaternary aromatic carbons and the trifluoromethyl carbon.
• Affinities of test compounds for muscarinic receptor subtypes M 1 -M 4 were determined. Competition radioligand binding experiments employed 11 drug concentrations run in duplicate. [ 3 H]N-methylscopolamine (NMS) was used as an antagonist radioligand, at the concentration equal to its equilibrium dissociation constant (K d ) for each receptor subtype. Nonspecific binding (90-95% of total) was defined with cold atropine added in excess (5 ⁇ M). Total binding was determined with phosphate buffered saline (PBS). Cloned human receptors permanently expressed in CHO cells were the source of all binding sites. Membranes were purchased from Receptor Biology division of Perkin Elmer-Life Sciences (Beltsville, Md.).
• SPA scintillation proximity assay
• Binding mixtures were made in flexible, 96-well, Wallac Micro-Beta plates by the addition of 11 ⁇ l of drug dilution, 11 ⁇ l of radioligand, and 178 ⁇ l of membrane/SPA bead suspension (100 mg of WGA-coated SPA beads, incubated with 5-15 ⁇ g protein/plate in 10 ml PBS for 30 min at room temperature, followed by low-speed centrifugation and resuspension in 2 ml PBS). After sealing and incubation at room temperature for 1 hour the plates were counted in a Wallac Micro-Beta scintillation counter.
• Tolterodine tartrate (the R(+) enantiomer) and racemic N,N-diisopropyl-3-(2-hydroxy-5-trifluoromethylphenyl)-3-phenylpropanamine according to the invention and example 9 were tested.
• tolterodine As a competitive muscarinic antagonist, tolterodine is regarded as having low muscarinic receptor subtype selectivity, but a favorable ratio of activity at bladder receptors, relative to salivary gland receptors (Nilvebrant et al, Neurourol Urodyn 15: 310-311 (1996)).
• N,N-diisopropyl-3-(2-hydroxy-5-trifluoromethylphenyl)-3-phenylpropanamine is relatively less potent at the m3 receptor.
• Gillberg et al, Eur J Pharmacol 349(2-3): 285-292 (1998) have suggested that decreased potency at the m3 receptor may improve the ratio of desired effects at the bladder, relative to effects on the salivary glands that result in dry mouth.
• the compounds according to the invention may be helpful in exhibiting functional selectivity for antimuscarinic effects on urinary bladder over salivary glands in vivo, since a selectivity for muscarinic M3/m3 over M2/m2 receptors may result in a more pronounced effect on salivation than on bladder contraction.
• the 5-trifluoromethyl group is interchangeable to any of the corresponding groups in that position according to invention, including trihalomethyl and mono- or dihalomethyl, optionally substituted with C 1 -C 4 alkyl.
• the C 1 -C 4 alkyl is optionally substituted with halogen.
• [ 14 C]-labeled N,N-diisopropyl-3-(2-hydroxy-5-trifluoromethylphenyl)-3-phenylpropanamine is synthesized, following the general procedure of examples 1-9. Approximately 10 ⁇ M of the compound is incubated with microsomes containing P450 CYP2D6 enzyme (20 pmol) in 100 mM potassium phosphate buffer (pH 7.4) and 1 mM P-NADPH at 37° C. in a final volume of 250 ul for 20 min.
• the incubations are analyzed for the parent drug and its metabolites by HPLC using standard procedures.
• the amount of each metabolite is calculated from the resulting radiochromatogram.
• the retention times of formed metabolites are compared with the retention times of synthesized reference standards, and the identity of the formed metabolites is further confirmed by electrospray ionization mass spectrometry.
• the compound according to the invention is not readily hydroxylated at the 5-trifluoromethyl substituent.
• the 3,3-diphenylpropylamines according to the invention do not possess a high propensity for being oxidized by the P450 CYP2D6 enzyme. Oxidation of 3,3-diphenylpropylamines, such as tolterodine, is generally held to be an important factor in pharmacokinetic differences between poor and extensive metabolizers, resulting in intersubject pharmacokinetic variability.

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• 2004
  • 2004-04-15 WO PCT/IB2004/001333 patent/WO2004096751A1/en not_active Ceased
  • 2004-04-15 EP EP04727624A patent/EP1620389A1/en not_active Withdrawn
  • 2004-04-15 BR BRPI0409653-3A patent/BRPI0409653A/pt not_active IP Right Cessation
  • 2004-04-15 MX MXPA05011509A patent/MXPA05011509A/es not_active Application Discontinuation
  • 2004-04-15 JP JP2006506554A patent/JP2006524677A/ja not_active Withdrawn
  • 2004-04-15 CA CA002523226A patent/CA2523226A1/en not_active Abandoned
  • 2004-04-26 US US10/832,555 patent/US20050004223A1/en not_active Abandoned
• 2005
  • 2005-08-25 US US11/212,330 patent/US7119121B2/en not_active Expired - Fee Related
• 2006
  • 2006-08-24 US US11/466,814 patent/US7291648B2/en not_active Expired - Fee Related

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