WO2004050635A2 - Imidazol derivatives having affinity for alpha 2 receptors activity - Google Patents

Imidazol derivatives having affinity for alpha 2 receptors activity Download PDF

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Publication number
WO2004050635A2
WO2004050635A2 PCT/FI2003/000933 FI0300933W WO2004050635A2 WO 2004050635 A2 WO2004050635 A2 WO 2004050635A2 FI 0300933 W FI0300933 W FI 0300933W WO 2004050635 A2 WO2004050635 A2 WO 2004050635A2
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Prior art keywords
compound
unsubstituted
imidazol
ylmethyl
ium chloride
Prior art date
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PCT/FI2003/000933
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French (fr)
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WO2004050635A3 (en
Inventor
Tomi Järvinen
Riku Niemi
Juhani Huuskonen
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Orion Oyj
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Orion Oyj
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Priority to MXPA05005963A priority Critical patent/MXPA05005963A/en
Priority to SI200330300T priority patent/SI1572198T1/en
Priority to US10/537,622 priority patent/US7759496B2/en
Priority to AU2003302622A priority patent/AU2003302622B2/en
Priority to MEP-2008-864A priority patent/ME00521B/en
Priority to EP03812203A priority patent/EP1572198B1/en
Priority to HRP20050617AA priority patent/HRP20050617B1/en
Priority to DE60304741T priority patent/DE60304741T2/en
Priority to EA200500922A priority patent/EA008251B1/en
Priority to BR0317024-1A priority patent/BR0317024A/en
Priority to NZ540466A priority patent/NZ540466A/en
Application filed by Orion Oyj filed Critical Orion Oyj
Priority to CA2508335A priority patent/CA2508335C/en
Priority to YU20050428A priority patent/RS52571B/en
Priority to JP2004556387A priority patent/JP4667042B2/en
Publication of WO2004050635A2 publication Critical patent/WO2004050635A2/en
Publication of WO2004050635A3 publication Critical patent/WO2004050635A3/en
Priority to IL168882A priority patent/IL168882A/en
Anticipated expiration legal-status Critical
Priority to IS7911A priority patent/IS2282B/en
Priority to NO20053302A priority patent/NO330392B1/en
Priority to CY20061100913T priority patent/CY1105699T1/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
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    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms

Definitions

  • the present invention relates to novel bioreversible prodrugs of MPN-2426, which is an alpha 2 adrenergic agonist, and specifically to ester derivatives, to methods for preparing said prodrug forms, to pharmaceutical compositions containing such prodrug forms, and to methods for using the prodrug forms.
  • MPN-2426 [4-(6-hydroxyindan-l-ylmethyl)-lH-imidazol-l-ium chloride] is disclosed in US 6,313,311 Bl as an alpha agonist useful in the treatment of hypertension, glaucoma, migraine, diarrhea, ischemia, addiction to chemical substances, anxiety, e.g. preoperative anxiety, and different neurological, musculoskeletal, psychiatric and cognition disorders as well as a sedative and an analgesic agent, nasal decongestant, and as an adjunct to anaesthesia.
  • MPN-2426 provides a spatially restricted and effective antinociception with minor side effects.
  • Intraspinal, intrathecal or epidural administration of MPV-2426 is disclosed in WO 00/18400 Al.
  • the treatment of hypotension, shock, and cardiopulmonary resuscitation by administering MPV-2426 is disclosed in WO 01/30347 Al.
  • IOP intraocular pressure
  • Prodrugs are pharmacologically inactive derivatives of drug molecules that after chemical or enzymatic transformation release the active drug exerting the therapeutic action. Prodrugs are designed to overcome various pharmaceutical or biopharmaceutical problems associated with the parent drug. A prodrug with good permeation across biological membranes should exhibit optimum lipophilicity. In addition, a prodrug should be stable enough against chemical degradation and revert to the active parent drug via enzymatic hydrolysis in the body during or after absorption.
  • the present invention provides novel bioreversible ester prodrugs of MPV-2426 that are chemically stable in non-enzyme medium, have suitable lipophilicity (able to permeate through biological membranes) and readily hydrolyze to the parent drug in vivo.
  • the invention may also provide compounds for the manufacture of a medicament to be used in the treatment of hypertension, glaucoma, migraine, diarrhea, ischemia, addiction to chemical substances, hypotension, shock, cardiopulmonary resuscitation, micturition disorders, withdrawal syndromes, congestive heart failure, anxiety, e.g. preoperative anxiety, or different neurological, musculoskeletal, psychiatric or cognition disorders or as a sedative or an analgesic agent, nasal decongestant or as an adjunct to anaesthesia.
  • the invention provides pharmaceutical compositions comprising as an active agent a compound of the invention.
  • the invention provides methods for the treatment of diseases or conditions, wherein alpha 2 agonists are indicated to be useful, said method comprising to a mammal in need of such treatment an effective amount of a compound of the invention.
  • Figure 1 shows the formation of MPV-2426 (D) upon hydrolysis of its pivaloyl ester ( ⁇ ) in 80 % human serum at 37 °C.
  • R represents unsubstituted or substituted lower alkyl, unsubstituted or substituted aryl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted lower alkylamino or a saturated five or six membered heterocyclic group contaimng one or two nitrogen atoms.
  • R represents unsubstituted or substituted lower alkyl or unsubstituted or substituted aryl, e.g. unsubstituted or substituted lower alkyl.
  • the compound is 4-[6-(2,2-dimethylpropanoyloxy)indan- 1 -ylmethyl] - lH-imidazol- 1 -ium chloride, 4-(6-acetoxyindan-l-ylmethyl)-lH-imidazol-l-ium chloride or 4-(6-butyryloxyindan-l -ylmethyl)- lH-imidazol-1 -ium chloride, h the definitions of R, the term "lower” denotes residues with a maximum of 10 carbon atoms, e.g. a maximum of 6 carbon atoms.
  • alkyl taken alone or in combination with terms such as “cycloalkyl” or “alkylamino” denotes straight or branched chain hydrocarbon residues.
  • aryl denotes a carbocyclic aromatic group, possibly a mono- or bicyclic group.
  • heteroaryl denotes a mono- or bicyclic aromatic group containing 1 to 3 heteroatoms being nitrogen and/or oxygen and/or sulfur, e.g. 1 or 2 heteroatoms being nitrogen and/or oxygen and/or sulfur.
  • substituted in connection with various residues refers to hydroxy, cyano, nitro, halogen, amino, lower alkylamino, di(lower alkyl)amino, lower alkoxy, aryl or trifluoromethyl substituents.
  • the substituted residues may contain 1 to 3 of said substituents, e.g. 1 or 2 of said substituents.
  • halogen denotes fluorine, chlorine, bromine or iodine, e.g. chlorine or bromine.
  • Compounds of formula I may provide adequate lipophilicity and stability against chemical hydrolysis and revert to the active parent drug via enzymatic hydrolysis.
  • the invention may provide compounds for the manufacture of a medicament to be used in the treatment of hypertension, glaucoma, migraine, diarrhea, ischemia, addiction to chemical substances, hypotension, shock, cardiopulmonary resuscitation, micturition disorders, withdrawal syndromes, congestive heart failure, anxiety, e.g. preoperative anxiety, or different neurological, musculoskeletal, psychiatric or cognition disorders or as a sedative or an analgesic agent, nasal decongestant or as an adjunct to anaesthesia, hi addition, the invention provides pharmaceutical compositions comprising as an active agent a compound of the invention. Furthermore, the invention provides methods for the treatment of diseases or conditions, wherein alpha agonists are indicated to be useful, said method comprising to a mammal in need of such treatment an effective amount of a compound of the invention.
  • the compounds of the invention can be prepared by a variety of synthetic routes analogously to or according to the methods known in the literature using suitable starting materials.
  • Hydroxyindan compound II or a pharmaceutically acceptable salt or hydrate thereof, is dissolved in a solvent, e.g. trifluoroacetic acid (TFA), and a carboxylic acid chloride is added.
  • a solvent e.g. trifluoroacetic acid (TFA)
  • TFA trifluoroacetic acid
  • the mixture is stirred, for example, at room temperature, for example, for 24 h.
  • the solvent is evaporated and product compound I is isolated from the reaction mixture in a conventional manner.
  • the compounds of the invention may be converted, if desired, into their pharmaceutically acceptable salts or hydrates using methods well known in the art.
  • the synthetic route described above is meant to illustrate the preparation of the compounds of the invention and the preparation is by no means limited thereto, i.e. there are also other possible synthetic methods which are within the general knowledge of a person skilled in the art.
  • a prodrug with good permeation across biological membranes should exhibit optimum lipophilicity (generally described as octanol-water partition coefficient, log P ap p).
  • a prodrug should be stable enough against chemical degradation and revert to the active parent drug via enzymatic hydrolysis in the body during or after absorption.
  • the lipophilicity was evaluated by determining apparent partition coefficients (log P ap p) between 1-octanol and phosphate buffer pH 5.0 or 7.4 at room temperature. Generally log P app value in the range of 2-3 is considered optimal for absorption and membrane penetration in general.
  • the buffer and 1-octanol phases were saturated before use by stirring vigorously for 24 h at room temperature.
  • a known concentration of the compound in phosphate buffer was shaken with a suitable volume of 1-octanol to achieve equilibrium. After 1 h shaking, the phases were separated by centrifugation and the concentration of the compound in the buffer phase was determined by HPLC.
  • the log P app values of the compounds are given in Table 1.
  • the lipophilicity of the compounds was substantially higher than that of the parent drug. Increased lipophilicity may result in enhanced membrane permeation as well as in longer duration of action as a consequence of altered pharmacokinetic properties (longer retention in the body).
  • test compound initial concentrations were 0.1-0.4 mM
  • the solution was placed in a thermostated water bath at 37°C and aliquots were taken at suitable intervals and analyzed by HPLC to determine the degradation rate of the compound.
  • the pseudo-first-order half-life (t ⁇ /2 ) was calculated from the linear slopes of semi-logarithmic plots of remaining compound over time.
  • a prodrug should be enzymatically degraded to the parent drug. Therefore, the susceptibility of the compounds to serum esterases was evaluated.
  • Four volumes (e.g. 4 ml) of pre-heated human serum were added and the solutions were mixed in a water bath at 37°C (initial concentrations were 0.2-0.5 mM).
  • 300 ⁇ l aliquots were withdrawn and deproteinated with 600 ⁇ l of acetonitrile. After mixing and centrifugation, 600 ⁇ l of the supernatant was evaporated to dryness under a stream of air at 40°C. The residue was re-dissolved in 300 ⁇ l of the mobile phase and analyzed by HPLC.
  • the pseudo-first-order half-life (tj /2 ) was calculated from the linear slopes of semi-logarithmic plots of remaining compound over time. Also the formation of the parent drug was determined.
  • MPV-2426 released the parent drug, MPV-2426, quantitatively via enzymatic hydrolysis in 80% human serum (pH 7.4).
  • the formation of MPV-2426 upon hydrolysis of its pivaloyl ester in 80 % human serum at 37 °C is illustrated in Figure 1.
  • the IOP study was performed to prove that the present prodrugs are able to release the parent drug and are thereby pharmacologically active in vivo.
  • the IOP lowering effect of the prodrug was also compared to the effect of MPV-2426.
  • a rabbit was placed in a plastic restraining box located in a quiet room.
  • a single drop (25 ⁇ l) of the test solution was instilled unilaterally into its left eye on the upper corneoscleral limbus.
  • the upper eyelid was pulled slightly away from the globe.
  • IOP was measured using a BioRad (Cambridge, MA) Digilab Modular One Pneumatonometer. Before each measurement one or two drops of oxybuprocaine (0.06%) were applied to the cornea before tonometry to eliminate discomfort. The upper and lower eyelids were then gently retracted, and the applanation sensor was brought into contact with the center of the cornea. For each Table 3.
  • IOP Intraocular pressure
  • IOP intraocular pressure
  • the pivaloyl ester of MPV-2426 showed increased IOP lowering potency as compared to an equimolar dose of MPV-2426 (Table 3). Also a prolonged duration of action was observed with the pivaloyl ester of MPV-2426.

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Abstract

The present invention relates to novel prodrugs of MPV-2426, to methods for preparing said prodrug forms, to pharmaceutical compositions containing such prodrug forms, and to methods for using the prodrug forms. A compound of general formula (I), or pharmaceutically acceptable salts or hydrates thereof, wherein R represents unsubstituted or substituted lower alkyl, unsubstituted or substituted aryl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted lower alkylamino or asaturated five or six membered heterocyclic group containing Olle or two nitrogen atoms.

Description

NEW PHARMACEUTICAL COMPOUNDS
FIELD OF THE INVENTION
The present invention relates to novel bioreversible prodrugs of MPN-2426, which is an alpha2 adrenergic agonist, and specifically to ester derivatives, to methods for preparing said prodrug forms, to pharmaceutical compositions containing such prodrug forms, and to methods for using the prodrug forms.
BACKGROUND OF THE INVENTION
MPN-2426 [4-(6-hydroxyindan-l-ylmethyl)-lH-imidazol-l-ium chloride] is disclosed in US 6,313,311 Bl as an alpha agonist useful in the treatment of hypertension, glaucoma, migraine, diarrhea, ischemia, addiction to chemical substances, anxiety, e.g. preoperative anxiety, and different neurological, musculoskeletal, psychiatric and cognition disorders as well as a sedative and an analgesic agent, nasal decongestant, and as an adjunct to anaesthesia. MPN-2426 provides a spatially restricted and effective antinociception with minor side effects. Intraspinal, intrathecal or epidural administration of MPV-2426 is disclosed in WO 00/18400 Al. The treatment of hypotension, shock, and cardiopulmonary resuscitation by administering MPV-2426 is disclosed in WO 01/30347 Al.
Alpha2 agonists are known to decrease intraocular pressure (IOP). The first report of the IOP lowering effects of these therapeutic agents was published in 1966 [Makabe, R. Dtsch. Med. Wochenschr., 91 (1966) 1686].
Prodrugs are pharmacologically inactive derivatives of drug molecules that after chemical or enzymatic transformation release the active drug exerting the therapeutic action. Prodrugs are designed to overcome various pharmaceutical or biopharmaceutical problems associated with the parent drug. A prodrug with good permeation across biological membranes should exhibit optimum lipophilicity. In addition, a prodrug should be stable enough against chemical degradation and revert to the active parent drug via enzymatic hydrolysis in the body during or after absorption.
SUMMARY OF THE INVENTION The present invention provides novel bioreversible ester prodrugs of MPV-2426 that are chemically stable in non-enzyme medium, have suitable lipophilicity (able to permeate through biological membranes) and readily hydrolyze to the parent drug in vivo.
The invention may also provide compounds for the manufacture of a medicament to be used in the treatment of hypertension, glaucoma, migraine, diarrhea, ischemia, addiction to chemical substances, hypotension, shock, cardiopulmonary resuscitation, micturition disorders, withdrawal syndromes, congestive heart failure, anxiety, e.g. preoperative anxiety, or different neurological, musculoskeletal, psychiatric or cognition disorders or as a sedative or an analgesic agent, nasal decongestant or as an adjunct to anaesthesia. In addition, the invention provides pharmaceutical compositions comprising as an active agent a compound of the invention. Furthermore, the invention provides methods for the treatment of diseases or conditions, wherein alpha2 agonists are indicated to be useful, said method comprising to a mammal in need of such treatment an effective amount of a compound of the invention.
Additional embodiments of the invention will be set forth in part in the description, which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The embodiments of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.
It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 shows the formation of MPV-2426 (D) upon hydrolysis of its pivaloyl ester (Δ) in 80 % human serum at 37 °C.
DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel bioreversible ester prodrugs of general formula I,
Figure imgf000004_0001
or pharmaceutically acceptable salts or hydrates thereof, wherein R represents unsubstituted or substituted lower alkyl, unsubstituted or substituted aryl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted lower alkylamino or a saturated five or six membered heterocyclic group contaimng one or two nitrogen atoms. For example, R represents unsubstituted or substituted lower alkyl or unsubstituted or substituted aryl, e.g. unsubstituted or substituted lower alkyl. Possibly, the compound is 4-[6-(2,2-dimethylpropanoyloxy)indan- 1 -ylmethyl] - lH-imidazol- 1 -ium chloride, 4-(6-acetoxyindan-l-ylmethyl)-lH-imidazol-l-ium chloride or 4-(6-butyryloxyindan-l -ylmethyl)- lH-imidazol-1 -ium chloride, h the definitions of R, the term "lower" denotes residues with a maximum of 10 carbon atoms, e.g. a maximum of 6 carbon atoms. The term "alkyl" taken alone or in combination with terms such as "cycloalkyl" or "alkylamino" denotes straight or branched chain hydrocarbon residues. The term "aryl" denotes a carbocyclic aromatic group, possibly a mono- or bicyclic group. The term "heteroaryl" denotes a mono- or bicyclic aromatic group containing 1 to 3 heteroatoms being nitrogen and/or oxygen and/or sulfur, e.g. 1 or 2 heteroatoms being nitrogen and/or oxygen and/or sulfur. The term "substituted" in connection with various residues refers to hydroxy, cyano, nitro, halogen, amino, lower alkylamino, di(lower alkyl)amino, lower alkoxy, aryl or trifluoromethyl substituents. The substituted residues may contain 1 to 3 of said substituents, e.g. 1 or 2 of said substituents. The term "halogen" denotes fluorine, chlorine, bromine or iodine, e.g. chlorine or bromine.
Compounds of formula I may provide adequate lipophilicity and stability against chemical hydrolysis and revert to the active parent drug via enzymatic hydrolysis. The invention may provide compounds for the manufacture of a medicament to be used in the treatment of hypertension, glaucoma, migraine, diarrhea, ischemia, addiction to chemical substances, hypotension, shock, cardiopulmonary resuscitation, micturition disorders, withdrawal syndromes, congestive heart failure, anxiety, e.g. preoperative anxiety, or different neurological, musculoskeletal, psychiatric or cognition disorders or as a sedative or an analgesic agent, nasal decongestant or as an adjunct to anaesthesia, hi addition, the invention provides pharmaceutical compositions comprising as an active agent a compound of the invention. Furthermore, the invention provides methods for the treatment of diseases or conditions, wherein alpha agonists are indicated to be useful, said method comprising to a mammal in need of such treatment an effective amount of a compound of the invention.
The compounds of the invention can be prepared by a variety of synthetic routes analogously to or according to the methods known in the literature using suitable starting materials.
In general, compounds of formula I, or pharmaceutically acceptable salts or hydrates thereof, can be prepared e.g. analogously to or according to scheme 1, wherein R is as defined above.
Scheme 1
Figure imgf000005_0001
Hydroxyindan compound II, or a pharmaceutically acceptable salt or hydrate thereof, is dissolved in a solvent, e.g. trifluoroacetic acid (TFA), and a carboxylic acid chloride is added. The mixture is stirred, for example, at room temperature, for example, for 24 h. The solvent is evaporated and product compound I is isolated from the reaction mixture in a conventional manner. The compounds of the invention may be converted, if desired, into their pharmaceutically acceptable salts or hydrates using methods well known in the art. The synthetic route described above is meant to illustrate the preparation of the compounds of the invention and the preparation is by no means limited thereto, i.e. there are also other possible synthetic methods which are within the general knowledge of a person skilled in the art.
Example 1
4-(6-Acetoxyindan-l-yImethyl)-l-H-imidazol-l-ium chloride
4-(6-hydroxy-indan-l -ylmethyl)- lH-imidazol-1 -ium chloride (100 mg, 0.399 mmol) was dissolved in 1 ml of trifluoroacetic acid (TFA) and acetic acid chloride (0.510 mmol) was added. The mixture was stirred at room temperature for 24 h. TFA was evaporated and the residue was dissolved in water and made basic with 2 M NΗ3 (aq.). The aqueous phase was extracted with dichloromethane (DCM). The combined extracts were dried (Na2SO4) and evaporated. The residue was dissolved in diethyl ether and the solution was saturated with dry HC1 gas. The precipitate was filtered and dried under vacuum. Yield 105 mg (82%) of a white hygroscopic solid. 1H NMR (CDCI3, TMS): δ 1.72 (m, 1H), 2.18-2.26 (m, 4H), 2.72-2.87 (m, 3H), 3.17 (dd, 1H), 3.56 (qui, 1H), 6.85 (m, 2H), 6.92 (s, 1H), 7.16 (d, 1H), 8.61 (s, 1H), 14.44 (s, 2H). 13C NMR (CDC13, TMS): 6 21.11, 29.60, 30.46, 31.68, 43.93, 115.72, 117.00, 120.29, 125.33, 132.32, 132.40, 141.37, 146.32, 149.39, 170.11. HPLC-MS (El): m/z = 257.2 ((M+H)+- CT). Anal. — Calc. for Cι5Hι6N2O2-HCl-0.2CH2Cl2: C 58.94, H 5.66, N 9.04. Found C 58.66, H 5.78, N 8.83.
Example 2
4-(6-ButyryIoxyindan-l-yImethyI)-lH-imidazol-l-ium chloride
4-(6-hydroxy-indan-l -ylmethyl)- lH-imidazol-1 -ium chloride (100 mg, 0.399 mmol) and butyric acid chloride (510 mmol) were reacted in TFA (1 ml) and purified as described in example 1. Yield 90 mg (77%) of a white hygroscopic solid. 1H NMR (CDC13, TMS): δ 1.02 (t, 3Η), 1.70-1.79 (m, 3H), 2.18-2.24 (m, 1H), 2.52 (t, 2H), 2.73-2.86 (m, 3H), 3.18 (dd, 1H), 3.53 (qui, 1H), 6.84 (dd, 1H), 6.87 (s, 1H), 6.92 (s, 1H), 8.66 (s, 1H), 11.28 (s (broad), 2H). 13C NMR (CDC13, TMS): δ 13.66, 18.45, 29.68, 30.52, 31.68, 36.24, 43.98, 115.79, 117.05, 120.36, 125.36, 132.32, 132.59, 141.32, 146.36, 149.51, 172.85. - HPLC-MS (El): m/z = 285.2 ((M+H)+ - CT). Anal. — Calc. for Cι7H20N2O2-HCl-0.2CH2Cl2: C 61.16, H 6.39, N 8.29. Found C 61.30, H 6.46, N 8.22.
Example 3
4-[6-(2,2-Dimethylpropanoyloxy)indan-l-ylmethyl]-lH-imidazol-l-ium chloride
4-(6-hydroxy-indan-l -ylmethyl)- lH-imidazol-1 -ium chloride (100 mg, 0.399 mmol) and 2,2-dimethylpropionic acid chloride (510 mmol) were reacted in TFA (1 ml) and purified as described in example 1. Yield 74 mg (56%) of a white solid. M.p. 176- 177 °C. 1H NMR (CDC13, TMS): δ 1.33 (s, 9Η), 1.69-1.78 (m, 1H), 2.16-2.25 (m, 1H), 2.74-2.88 (m, 3H), 3.23 (dd, 1H), 3.57 (qui, 1H), 6.83 (dd, 1H), 6.89 (s, 1H), 6.93 (s, 1H), 7.16 (d, 1H), 8.85 (s, 1H), 14.38 (s , 1H), 14.47 (s, 1H). 13C NMR(CDC13, TMS): δ 27.17, 29.64, 30.55, 31.57, 39.07, 43.95, 115.69, 116.96, 120.24, 125.33, 132.12, 132.66, 141.20, 146.30, 149.30, 177.87. HPLC-MS (El): m/z = 297.7 (M+ - 2H+ - CT). Anal. —Calc. for Cι8H22N2O2-HCl: C 64.57, H 6.92, N 8.37. Found C 64.05, H 7.00, N 8.24.
EXPERIMENTS
A prodrug with good permeation across biological membranes should exhibit optimum lipophilicity (generally described as octanol-water partition coefficient, log Papp). addition a prodrug should be stable enough against chemical degradation and revert to the active parent drug via enzymatic hydrolysis in the body during or after absorption.
Experiment 1. Lipophilicity
The lipophilicity was evaluated by determining apparent partition coefficients (log Papp) between 1-octanol and phosphate buffer pH 5.0 or 7.4 at room temperature. Generally log Papp value in the range of 2-3 is considered optimal for absorption and membrane penetration in general. Method
The apparent partition coefficients (Papp) were evaluated from the distribution of the test compounds between 1-octanol and phosphate buffer (0.16 M, pH 5.0 or pH 7.4, μ = 0.5). The buffer and 1-octanol phases were saturated before use by stirring vigorously for 24 h at room temperature. A known concentration of the compound in phosphate buffer was shaken with a suitable volume of 1-octanol to achieve equilibrium. After 1 h shaking, the phases were separated by centrifugation and the concentration of the compound in the buffer phase was determined by HPLC.
Results
The log Papp values of the compounds are given in Table 1. The lipophilicity of the compounds was substantially higher than that of the parent drug. Increased lipophilicity may result in enhanced membrane permeation as well as in longer duration of action as a consequence of altered pharmacokinetic properties (longer retention in the body).
Experiment 2. Chemical stability
Method
An appropriate amount of the test compound (initial concentrations were 0.1-0.4 mM) was dissolved in pre-heated phosphate buffer (0.16 M, μ=0.5, pH 7.4 or pH 5.0). The solution was placed in a thermostated water bath at 37°C and aliquots were taken at suitable intervals and analyzed by HPLC to determine the degradation rate of the compound. The pseudo-first-order half-life (tι/2) was calculated from the linear slopes of semi-logarithmic plots of remaining compound over time.
Results
The degradation of the compounds in aqueous solution at pH 5.0 and 7.4 followed pseudo-first-order kinetics. The half-life (tι/2) for the degradation is shown in Table 2. The stability of the compounds was substantially higher at pH 5.0 than at Table 1. Apparent partition coefficients (log Papp, mean ± SD, n = 3) of MPV-2426 and its esters.
Compound log Papp at pH 5.0 log Papp at pH 7.4
MPV-2426 0.01 ± 0.02 1.87 ± 0.00
example 1 0.13 ± 0.00 2.05 + 0.01
example 2 1.25 ± 0.01 3.17 ± 0.02
example 3 1.75 + 0.01 3.59 ± 0.03
Experiment 3. Enzymatic hydrolysis
To exert the pharmacological effect in the body, a prodrug should be enzymatically degraded to the parent drug. Therefore, the susceptibility of the compounds to serum esterases was evaluated.
Method
An appropriate amount of the test compound was dissolved in one volume (e.g. 1 ml) of phosphate buffer (0.16 M, μ=0.5, pH 7.4) at 37°C. Four volumes (e.g. 4 ml) of pre-heated human serum were added and the solutions were mixed in a water bath at 37°C (initial concentrations were 0.2-0.5 mM). At suitable intervals, 300 μl aliquots were withdrawn and deproteinated with 600 μl of acetonitrile. After mixing and centrifugation, 600 μl of the supernatant was evaporated to dryness under a stream of air at 40°C. The residue was re-dissolved in 300 μl of the mobile phase and analyzed by HPLC. The pseudo-first-order half-life (tj/2) was calculated from the linear slopes of semi-logarithmic plots of remaining compound over time. Also the formation of the parent drug was determined.
Results
The hydrolysis of the prodrugs in 80% human serum followed pseudo-first-order kinetics. The half-life (ty2) for the degradation is shown in Table 2. All the prodrugs Table 2. Rate of hydrolysis in phosphate buffer solutions (pH 5.0 and 7.4) and in 80% human serum (pH 7.4) at 37°C.
Compound tl/2 (d) tl/2 (d) tι 2 (min)
phosphate buffer phosphate buffer 80% human serum pH 5.0 pH 7.4 (pH 7.4)
example 1 23 1.1 0.18
example 2 49 2.5 0.20
example 3 310 31 30
of MPV-2426 released the parent drug, MPV-2426, quantitatively via enzymatic hydrolysis in 80% human serum (pH 7.4). The formation of MPV-2426 upon hydrolysis of its pivaloyl ester in 80 % human serum at 37 °C is illustrated in Figure 1.
Experiment 4. IOP study in rabbits
The IOP study was performed to prove that the present prodrugs are able to release the parent drug and are thereby pharmacologically active in vivo. The IOP lowering effect of the prodrug was also compared to the effect of MPV-2426.
Method
To perform the IOP test, a rabbit was placed in a plastic restraining box located in a quiet room. A single drop (25 μl) of the test solution was instilled unilaterally into its left eye on the upper corneoscleral limbus. During installation, the upper eyelid was pulled slightly away from the globe. IOP was measured using a BioRad (Cambridge, MA) Digilab Modular One Pneumatonometer. Before each measurement one or two drops of oxybuprocaine (0.06%) were applied to the cornea before tonometry to eliminate discomfort. The upper and lower eyelids were then gently retracted, and the applanation sensor was brought into contact with the center of the cornea. For each Table 3. Intraocular pressure (IOP) changes (mean mmHg ± SE, n = 5-6) at predetermined times (h) in the treated and untreated eyes of normotensive rabbits after unilateral administration of 25 μl of MPV-2426 or its pivaloyl ester (PIV) solutions in phosphate buffer pH 5.0.
Figure imgf000011_0001
equimolar to 2.5 μg of MPV-2426
* data significantly different from values for MPV-2426, at a 95% confidence level (ANOVA, Fisher's PLSD test) determination at least two readings were taken from each treated (ipsilateral) and untreated (contralateral) eye, and the mean of these readings was used. IOP of the rabbits was measured at 2, 1, and 0 h before and at 0.5, 1, 2, 3, 4 and 5 h after eyedrop administration. IOP at the time of eyedrop administration (0 h) was used as a baseline value. All studies were set up using a masked and randomized crossover design. At least 72 h washout time was allowed for each rabbit between each dosing.
Results
The change in intraocular pressure (IOP) after topical unilateral administration of three different doses (0.1 μg, 1.0 μg, and 2.5 μg) of the pivaloyl ester of MPV-2426 is shown in Table 3. The IOP lowering effect lasted from 1 h through the duration of the 5 h experiment. Less significant changes were observed in the untreated eyes.
The pivaloyl ester of MPV-2426 showed increased IOP lowering potency as compared to an equimolar dose of MPV-2426 (Table 3). Also a prolonged duration of action was observed with the pivaloyl ester of MPV-2426.

Claims

1. A compound of general formula I,
Figure imgf000013_0001
or pharmaceutically acceptable salts or hydrates thereof, wherein R represents unsubstituted or substituted lower alkyl, unsubstituted or substituted aryl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted lower alkylamino or a saturated five or six membered heterocyclic group containing one or two nitrogen atoms.
2. A compound according to claim 1, wherein R represents unsubstituted or substituted lower alkyl or unsubstituted or substituted aryl.
3. A compound according to claim 2, wherein R represents unsubstituted or substituted lower alkyl.
4. A compound according to claim 3, said compound being
4- [6-(2,2-dimethylpropanoyloxy)indan- 1 -ylmethyl] - IH-imidazol- 1 -ium chloride
5. A compound according to claim 3, said compound being 4-(6-acetoxyindan- 1 -ylmethyl)- IH-imidazol- 1 -ium chloride
6. A compound according to claim 3, said compound being 4-(6-butyryloxyindan- 1 -ylmethyl)- IH-imidazol- 1 -ium chloride
7. Use of a compound of formula I,
Figure imgf000013_0002
or pharmaceutically acceptable salts or hydrates thereof, wherein R is as defined in claim 1, for the manufacture of a medicament to be used in the treatment of hypertension, glaucoma, migraine, diarrhea, ischemia, addiction to chemical substances, hypotension, shock, cardiopulmonary resuscitation, micturition disorders, withdrawal syndromes, congestive heart failure, anxiety or different neurological, musculoskeletal, psychiatric or cognition disorders or as a sedative or an analgesic agent, nasal decongestant or as an adjunct to anaesthesia.
8. A use according to claim 7, wherein the compound is 4-[6-(2,2-dimethylpropanoyloxy)indan-l-ylmethyl]-lH-imidazol-l-ium chloride.
9. A pharmaceutical composition which comprises as an active agent a compound of formula I,
Figure imgf000014_0001
or pharmaceutically acceptable salts or hydrates thereof, wherein R is as defined in claim 1, and optionally a pharmaceutically acceptable excipient.
10. A pharmaceutical composition according to claim 9, wherein the compound is 4-[6-(2,2-dimethylpropanoyloxy)indan- 1 -ylmethyl] - IH-imidazol- 1 -ium chloride.
11. A method for the treatment of diseases or conditions, wherein alpha2 agonists are indicated to be useful, said method comprising administering to a mammal in need of such treatment an effective amount of a compound of formula I,
Figure imgf000014_0002
or pharmaceutically acceptable salts or hydrates thereof, wherein R is as defined in claim 1.
2. A method according to claim 11, wherein the compound is
4-[6-(2,2-dimethylpropanoyloxy)indan-l-ylmethyl]-lH-imidazol-l-ium chloride.
PCT/FI2003/000933 2002-12-05 2003-12-05 Imidazol derivatives having affinity for alpha 2 receptors activity Ceased WO2004050635A2 (en)

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WO2010042473A1 (en) 2008-10-07 2010-04-15 Schering Corporation Biaryl spiroaminooxazoline analogues as alpha2c adrenergic receptor modulators
US7700592B2 (en) 2005-08-25 2010-04-20 Schering Corporation α2C adrenoreceptor agonists
US7985748B2 (en) 2005-08-25 2011-07-26 Pharmacopeia Drug Discovery, Inc. ALPHA2C adrenoreceptor agonists
US8003624B2 (en) 2005-08-25 2011-08-23 Schering Corporation Functionally selective ALPHA2C adrenoreceptor agonists

Family Cites Families (10)

* Cited by examiner, † Cited by third party
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US4673679A (en) * 1986-05-14 1987-06-16 E. I. Du Pont De Nemours And Company Use of prodrugs of 3-hydroxymorphinans to prevent bitter taste upon buccal, nasal or sublingual administration
GB9425211D0 (en) * 1994-12-14 1995-02-15 Ucb Sa Substituted 1H-imidazoles
GB9520150D0 (en) * 1995-10-03 1995-12-06 Orion Yhtymae Oy New imidazole derivatives
JPH10195056A (en) * 1996-11-12 1998-07-28 Takeda Chem Ind Ltd Condensed benzene derivative, its production and agent
DE69923698T2 (en) * 1998-09-28 2006-01-12 Orion Corp. USE OF 3- (1H-IMIDAZOLE-4-YLMETHYL) -INDAN-5-OL FOR THE PREPARATION OF A MEDICAMENT FOR INTRASPINAL, INTRATHEAL AND EPIDURAL USE
ATE312606T1 (en) * 1999-10-29 2005-12-15 Orion Corp USE OF AN IMIDAZOLE DERIVATIVE TO TREAT OR PREVENT HYPOTENSION AND SHOCK
FI20000073A0 (en) * 2000-01-14 2000-01-14 Orion Yhtymae Oy New imidazole derivatives
US6388090B2 (en) * 2000-01-14 2002-05-14 Orion Corporation Imidazole derivatives
US7091232B2 (en) 2002-05-21 2006-08-15 Allergan, Inc. 4-(substituted cycloalkylmethyl) imidazole-2-thiones, 4-(substituted cycloalkenylmethyl) imidazole-2-thiones, 4-(substituted cycloalkylmethyl) imidazol-2-ones and 4-(substituted cycloalkenylmethyl) imidazol-2-ones and related compounds
US7439268B2 (en) * 2003-07-18 2008-10-21 Idexx Laboratories Compositions containing prodrugs of florfenicol and methods of use

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* Cited by examiner, † Cited by third party
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US7700592B2 (en) 2005-08-25 2010-04-20 Schering Corporation α2C adrenoreceptor agonists
US7985748B2 (en) 2005-08-25 2011-07-26 Pharmacopeia Drug Discovery, Inc. ALPHA2C adrenoreceptor agonists
US8003624B2 (en) 2005-08-25 2011-08-23 Schering Corporation Functionally selective ALPHA2C adrenoreceptor agonists
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