Pharmaceutical compositions and methods for their use

a technology of compositions and pharmaceuticals, applied in the field of pharmaceutical compositions, can solve the problems of not producing the desired physiological effect, requiring more frequent and higher doses of drugs, etc., and achieve the effect of increasing the bioavailability of mammal cells and increasing the bioavailability

Inactive Publication Date: 2004-11-11
AGOURON PHARMA INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

0016] In another aspect of the present invention are provided methods of increasing the bioavailability in a mammal of a first compound which is metabolized by cytochrome P450, comprising administering to said mammal said first compound and a cytochrome P450-inhibiting amount of a compound of formula (i), or a pharmaceutically acceptable salt or solvate thereof, wherein the cytochrome P450 is the 2D6 isoform.
0017] Also provided in the present invention are methods of increasing the bioavailability in a mammal of a first compound which is metabolized by cytochrome P450, wherein the first compound is selected from alprenolol, amiflamine, amitryptyline, aprindine, atomoxetine, bisoprolol, brofaromine, bufuralol, bunitrolol, bupronolol, captopril, chlorpheniramine, chlorpromazine, cilostazol, cinnarizine, citalopram, clomipramine, clozapine, codeine, cyclobenzprine, debrisoquine, desipramine, desmethylcitalopram, dexfenfluramine, dextromethorphan, dihydrocodine, dolasetron, donezepil, doxepin, encainide, ethylmorphine, fenfluramine, flecainide, flunarizine, fluvoxamine, fluoxetine, fluphenazine, guanoxan, haloperidol, hydrocodone, imipramine, indoramin, labetalol, lidocaine, loratidine, maprotiline, (R)-methadone, meperidine, methamphetamine, methoxyamphetamine, 5-methoxyindoleethylamine, methoxyphenamine, methylenedioxymethamphetamine, metoprolol, mexiletine, mianserin, minaprine, morphine, nefazodone, nelfinavir, norcodeine, nortryptyline, ondansetron, omeprazole, oxycodone, paclitaxel, paroxetine, perhexiline, perphenazine, phenformin, procodeine, promethazine, N-propylajmaline, propafenone, propanolol, retinoic acid, quinidine, risperidone, ritonavir, RU-486, sparteine, tamoxifen, testosterone, thioridazine, timolol, tolterodine, tomoxatene, tramadol, trazodone, trifluperidol, trimipramine, tropisetron, venlafaxine, vinblastine, and zuclopenthixol.

Problems solved by technology

The drug metabolites that result may, in some cases, be inactive in mammals and therefore may not produce a desired physiological effect.
With some drugs, this metabolism by CYP450 enzymes to produce inactive metabolites may be so extensive that the pharmacokinetics of the drug are unfavorable, thereby requiring more frequent and higher doses of the drug than are desirable to achieve a desired physiological effect.

Method used

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  • Pharmaceutical compositions and methods for their use
  • Pharmaceutical compositions and methods for their use
  • Pharmaceutical compositions and methods for their use

Examples

Experimental program
Comparison scheme
Effect test

example 2

6-Cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)--6-(2-(3-ethyl-4-hydroxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one

[0206] 21

[0207] The desired product was prepared analogously to example 1, substituting 6-Cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]-dihydro--pyran-2,4-dione. from Step 4 below, in place of 2-{4-[2-(2-cyclopentyl-4,-6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-2-methyl-propionitr-ile of that example. .sup.1H NMR (DMSO-d.sub.6): .delta. 0.96 (t, 3H, J=7.4 Hz), 1.30-1.58 (br m, 8H), 1.95 (m, 2H), 2.41 (m, 12H), 2.63 (d,1 H, J =17.5 Hz), 3.61 (d, 1H, J=15.8 Hz), 3.72 (d, 1H, J=15.8 Hz), 6.52 (d, 1H, J=8.1 Hz), 6.74 (m, 2H), 6.93 (s, 1H), 8.84 (s,1 H). Anal. Calcd. For C.sub.28H.sub.34N.sub.4O.sub.4.0.5 AcOH: C, 66.90; H, 6.97; N, 10.76. Found: C, 66.89; H, 6.97, N, 10.83.

Step 1: 4-Bromo-2-ethyl-phenol

[0208] 22

[0209] Sodium hydroxide (1.4 g, 35 mmol) and hydrazine monohydrate (2.04 mL, 42 mmol) were added to a solution of 5'...

example 3

1-(4-{2-[2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-y-lmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl-)-cyclopropanecarbonitrile

[0217] 26

[0218] The desired product was prepared analogously to example 1, substituting 1-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethy-l]-2-fluoro-phenyl}-cyclopropanecarbonitrile (0.24 g, 0.65 mmol) from Step 3 below, in place of 2-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2--yl)-ethyl]-2-fluoro-phenyl}-2-methyl-propionitrile of that example. Yield: 64 mg, 19%. .sup.1H NMR (CDCl.sub.3) .delta.: 1.25-1.30 (m, 2H), 1.42-1.68 (m, 10H), 1.88-1.93 (m, 2H), 2.30 (p, J=8.59 Hz, 1H), 2.44-2.73 (m, 10H), 4.05 (d, J=3.03 Hz, 2H), 6.76-6.84 (m, 3H), 7.09-7.22 (m, 1H).

Step 1: 1-(4-Bromo-2-fluoro-phenyl)-cyclopropanecarbonitrile

[0219] 27

[0220] To a slurry of sodium hydride (60% dispersion in mineral oil, 0.82 g, 20.6 mmol) in DMF (20 mL) cooled to 0.degree. C. was added a solution of (4-bromo-2-fluoro-...

example 4

2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimid-in-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-m-ethylpropanenitrile

[0225] 30

[0226] The title compound was prepared analogously to Example 1 where 6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde from step 2 below was substituted in place of 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyri-midine-2-carbaldehyde in the final step of that example. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 1.48-1.71 (m, 8H), 1.76 (s, 6H), 2.00 (m, 2H), 2.06 (s, 1H), 2.10 (s, 1H), 2.38 (m, 1H), 2.39 (s, 3H), 2.68 (m, 2H), 2.81(m, 1H), 4.09 (s, 2H), 6.86 (d, J=12.9 Hz, 1H), 6.92 (d, J=8.1 Hz, 1H), 7.84 (t, J=8.1 Hz, 1H), 8.63 (s, 1H), 8.70 (s, 1H). MS (ESI): 518.6(M+H.sup.+).

Step 1: Preparation of (6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)metha-nol

[0227] 31

[0228] To a solution of (3-amino-1H-1,2,4-triazol-5-yl)methanol (16.6 g, 87.6 mmol) in acetic acid was added 3-ethoxymethacrolein (10.0 g, 87.6 mmo...

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Abstract

The present invention relates to pharmaceutical compositions and to methods for their use in decreasing cytochrome P450 (CYP450) enzyme activity. The present invention also relates to methods of increasing the bioavailability of a compound in a mammal. Additionally, the present invention relates to methods of decreasing the metabolism of certain compounds in a mammal that are metabolized by the cytochrome P450 enzyme. Furthermore, the present invention relates to pharmaceutical compositions comprising at least one compound metabolized by at least one cytochrome P450 enzyme and a cytochrome P450 enzyme-inhibiting amount of a compound of formula (I).

Description

[0001] This application claims priority to U.S. Patent Application Nos. 60 / 449088, filed Feb. 21, 2003, 60 / 472355, filed May 20, 2003, and U.S. Ser. No. 10 / 718337, filed Nov. 19, 2003.[0002] The present invention relates to pharmaceutical compositions and to methods for their use in decreasing cytochrome P450 (CYP450) enzyme activity. The present invention also relates to methods of increasing the bioavailability of a compound in a mammal. Additionally, the present invention relates to methods of decreasing the metabolism of certain compounds in a mammal that are metabolized by the cytochrome P450 enzyme. Furthermore, the present invention relates to pharmaceutical compositions comprising at least one compound metabolized by at least one cytochrome P450 enzyme and a cytochrome P450 enzyme-inhibiting amount of a compound of formula (I).[0003] In mammals, the cytochrome P450 enzyme system comprises over 100 enzymes that modulate various physiological functions. In particular, the CYP4...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4025A61K31/452A61K31/496A61K31/519A61K31/5377A61K31/541A61P31/14C07D263/58C07D285/06C07D309/32C07D405/06C07D405/10C07D405/12C07D405/14C07D407/06C07D407/10C07D407/12C07D409/06C07D409/10C07D413/02C07D413/06C07D413/10C07D413/12C07D413/14C07D417/02C07D417/06C07D417/10C07D417/12C07D471/04C07D473/30C07D473/36C07D487/04C07D495/04C07D513/04
CPCC07D263/58C07D513/04C07D309/32C07D405/06C07D405/10C07D405/12C07D405/14C07D407/06C07D407/10C07D407/12C07D409/06C07D409/10C07D413/06C07D413/10C07D413/12C07D413/14C07D417/06C07D417/10C07D417/12C07D471/04C07D473/30C07D473/36C07D487/04C07D495/04C07D285/06A61P1/16A61P31/14A61P43/00
Inventor BORCHARDT, ALLEN J.DRAGOVICH, PETER SCOTTGONZALEZ, JAVIERLI, HUILINTON, MARIA ANGELICATATLOCK, JOHN HOWARD
Owner AGOURON PHARMA INC
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