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WO1999051593A1 - 4-thionaphtyl-1h-imidazoles ayant une activite recepteur alpha-2-adrenergique - Google Patents

4-thionaphtyl-1h-imidazoles ayant une activite recepteur alpha-2-adrenergique Download PDF

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Publication number
WO1999051593A1
WO1999051593A1 PCT/US1999/007238 US9907238W WO9951593A1 WO 1999051593 A1 WO1999051593 A1 WO 1999051593A1 US 9907238 W US9907238 W US 9907238W WO 9951593 A1 WO9951593 A1 WO 9951593A1
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WIPO (PCT)
Prior art keywords
compound
effective
group
mmol
added
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PCT/US1999/007238
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English (en)
Inventor
Ellen W. Baxter
Robert E. Boyd
Michelle C. Jetter
Mark Mcdonnell
Allen B. Reitz
Tina Morgan Ross
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Ortho-Mcneil Pharmaceutical, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Ortho-Mcneil Pharmaceutical, Inc. filed Critical Ortho-Mcneil Pharmaceutical, Inc.
Priority to AU33783/99A priority Critical patent/AU3378399A/en
Publication of WO1999051593A1 publication Critical patent/WO1999051593A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to ⁇ 2 -adrenoceptor agonists/antagonists. More particularly, the present invention relates to certain 4-thionaphthyl-lH-imidazoles and analogues which are ⁇ 2 -adrenoceptor agonists having analgesic activity.
  • ⁇ 2 -adrenoceptor agonists/antagonists are useful to treat a variety of conditions, including, hypertension, glaucoma, sexual dysfunction, depression, attention deficit hyperactivity disorder, the need for anesthesia, cardiac arrythmia and the need for analgesia.
  • ⁇ 2 -adrenoceptor agonists are well known analgesics.
  • Clonidine is a centrally acting ⁇ 2 -adrenoceptor agonist with wide clinical utility as an antihypertensive agent. Clonidine is believed to act by inhibiting the release of norepinephrine from sympathetic nerve terminals via a negative feedback mechanism involving ⁇ 2 -adrenoceptors located on the presynaptic nerve terminal.
  • Medetomidine, detomidine, and dexmedetomidine are 2 -adrenoceptor agonists.
  • Dexmedetomidine is used clinically in veterinary medicine as a sedatives/hypnotic for pre-anaesthesia. These compounds are hypotensive in animals and in humans, but the magnitude of this cardiovascular effect is relatively insignificant.
  • the disclosed compounds are insufficiently active and suffer from unwanted side effects.
  • Kihara et al. disclose a method to produce imidazole derivatives for use, among other uses, as antihypertensive agents.
  • Z is H or phenyl R is H, alkyl or halogen
  • X is S or O
  • the disclosed compounds are insufficiently active and suffer from unwanted side effects.
  • JP-42001546 (1964) discloses a compound of the general formula: N
  • EP 129478 (1984) discloses a compound of the formula:
  • X is independently selected from the group consisting of hydrogen, C M alkyl, bromine, chlorine, iodide, trifluoromethyl, C M alkoxy, -SO 2 NH 2 and nitro; with the stipulation that the six membered ring, except for the bond shared with thienyl, can be fully unsaturated, have a single unsaturated bond in conjugation with the imidazole ring or have two unsaturated bonds.
  • the compounds of the present invention are prepared by the methods shown in Schemes 1 and 2.
  • thienyl ketones 2 are condensed with a Grignard reagent derived from a protected 4-iodoimidazole to give 3, or converted to the corresponding vinyl triflate reagent 7.
  • Grignard addition product 3 is dehydrated to provide a site of unsaturation (viz. 4), which is followed by removal of the imidazole protecting group to give desired products 5, and then further reduced to afford products 6.
  • Grignard addition product 3 is hydrogenolyzed directly to reduce the benzylic hydroxyl and remove the protecting group (e.g. the trityl or Ph 3 C group) to give products 6.
  • Vinyl triflate 7 could be condensed in a Stille coupling reaction with a 4-(stannyl)imidazole in the presence of Pd(0) to give 4, or condensed with the 4-imidazo Grignard reagent described above in the presence of ZnCl 2 to also give 4.
  • the thienyl ketones 2 may be produced by methods well known to the art. In a first method, thienyl ketone 2 may be produced in three steps. In a first and second step, the appropriate thiophene acrylic acid, appropriately substituted with X, is reduced and the resulting acid converted to the acid chloride. Finally, intramolecular acylation produces the thienyl ketones 2. Alternatively, thiophene, appropriately substituted with X is acylated with ethyl succinyl chloride. Saponification of the ester, followed by
  • X is hydrogen, C 1-4 alkyl, C,. 4 alkoxy and trifluoromethyl
  • the appropriately substituted thienyl ketone 2 may be produced and the substituent in question will stably endure the reactions of Scheme 1 to arrive at target products 5 and 6.
  • product 6 may be obtained from product 5 by alternate reduction conditions such as borane/methylsulfide or triethylsilane/trifluoroacetic acid.
  • the fully aromatic analogues of products 5 and 6 may be produced by extension of Scheme 1 as shown in Scheme 1A.
  • Vinyl imidazoles 4 can be oxidized with DDQ to yield the fully aromatic componds 10 which can then be deprotected to give products 1.
  • ketones 9 may be produced from reaction of the Grignard reagent derived from the imidazole with an appopriately substituted thiophene aldehyde, followed by oxidation. Production of ketones 9 is generally described and specifically exemplified in U. S. Patent No. 5,621,113 to Boyd et al.
  • Preferred X are selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, bromine, chlorine, trifluoromethyl, methoxy, ethoxy, propoxy and nitro.
  • the most preferred X is methyl, bromine, methoxy and nitro.
  • the most preferred compounds of the instant invention are shown in Table I:
  • mice Male, Wistar rats (150-250 g, VAF, Charles River, Springfield, NY) are sacrificed by cervical dislocation and their brains removed and placed immediately in ice cold HEPES buffered sucrose.
  • the cortex is dissected out and homogenized in 20 volumes of HEPES sucrose in a TeflonTM-glass homogenizer.
  • the homogenate is centrifuged at 1000 g for 10 min, and the resulting supernatant centrifuged at 42,000 g for 10 min.
  • the resulting pellet is resuspended in 30 volumes of 3 mM potassium phosphate buffer, pH 7.5, preincubated at 25 °C for 30 min and recentrifuged.
  • the resulting pellet is resuspended as described above and used for the receptor binding assay.
  • Incubation is performed in test tubes containing phosphate buffer, 2.5 mM MgCl 2 , aliquots of the synaptic membrane fraction, the ligand 3 H-para-aminoclonidine and test drug at 25 °C for 20 min. The incubation is terminated by filtration of the tube contents through glass fiber filter sheets. Following washing of the sheets with 10 mM HEPES buffer, the adhering radioactivity is quantified by liquid scintillation spectrometry.
  • Binding of the test drug to the receptor is determined by comparing the amount of radiolabeled ligand bound in control tubes without drug to the amount of radiolabeled ligand bound in the presence of the drug.
  • Dose-response data are analyzed with LIGAND, a nonlinear curve fitting program designed specifically for the analysis of ligand binding data. This assay is described by Simmons, R. M. A., and Jones, D. J., Binding of [ 3 H-]prazosin and [ 3 H-]p-aminoclonidine to ⁇ -Adrenoceptors in Rat Spinal Cord, Brain Research 445:338-349, 1988.
  • the mouse acetylcholine bromide-induced abdominal constriction assay as described by Collier et al. in Brit. J. Pharmacol. Chem. Ther., 32: 295-310, 1968, with minor modifications was used to assess analgesic potency of the compounds herein.
  • the test drugs or appropriate vehicle were administered orally (p.o.) and 30 minutes later the animal received an intraperitoneal (i.p.) injection of 5.5 mg/kg acetylcholine bromide (Matheson, Coleman and Bell, East Rutherford, NJ).
  • mice were then placed in groups of three into glass bell jars and observed for a ten minute observation period for the occurrence of an abdominal constriction response (defined as a wave of constriction and elongation passing caudally along the abdominal wall, accompanied by a twisting of the trunk and followed by extension of the hind limbs).
  • the percent inhibition of this response to a nociceptive stimulus (equated to % analgesia) was calculated as follows:
  • the % Inhibition of response, i.e., % analgesia is equal to the difference between the number of control animals responding and the number of drug- treated animals responding times 100 divided by the number of control animals responding.
  • At least 15 animals were used for control and in each of the drug treated groups. At least three doses were used to determine each dose response curve and ED 50 (that dose which would produce 50% analgesia). The ED 50 values and their 95% fiducial limits were determined by a computer assisted probit analysis.
  • invention compounds of the present invention may be used to treat mild to moderately severe pain in warm-blooded animals, such as, humans by administration of an analgesically effective dose.
  • the dosage range would be from about 10 to 3000 mg, in particular about 25 to 1000 mg or about 100 to 500 mg, of active ingredient 1 to 4 times per day for an average (70 kg) human although it is apparent that activity of individual compounds of the invention will vary as will the pain being treated.
  • compositions of the invention comprise the formula (I) compounds as defined above, particularly in admixture with a pharmaceutically- acceptable carrier.
  • compositions of this invention one or more compounds of the invention or salt thereof as the active ingredient, is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
  • a pharmaceutical carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
  • any of the usual pharmaceutical media may be employed.
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired,
  • 12 tablets may be sugar coated or enteric coated by standard techniques.
  • the carrier will usually comprise sterile water, though other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included.
  • injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above.
  • the pharmaceutically acceptable salts referred to above generally take a form in which the imidazolyl ring is protonated with an inorganic or organic acid.
  • organic or inorganic acids include hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benezenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p- toluenesulfonic, cyclohexanesulfamic, salicylic or saccharic.
  • the following Examples illustrate the invention:
  • reaction mixture was filtered through a plug of silica, rinsed with ethyl acetate (300 mL), extracted sequentially with NaHCO 3 (sat'd), H 2 O, brine, dried with MgSO 4 , filtered and the solvent evaporated in vacuo to yield an oily residue. Crystals were precipitated with methylene chloride/hexane (80:20) and collected by filtration to yield 4-(l,3-dimethyl-6,7-dihydrobenzo[c]thiophen-4-yl)-l-trityl-lH- imidazole (1.7 g, 70%).
  • 4-(l,3-dimethyl-6,7-dihydrobenzo[c]thiophen-4- yl)-l-tritylimidazole can be prepared by treating a solution of 4-iodo-l-tritylimidazole (1.4 g, 3.2 mmol, prepared as described by Turner and Lindel, J. Org. Chem. 1991, 56, 5739-5740) and methylene chloride (500 mL) at 0°C with ethyl magnesium bromide (1.5 mL, 4.5 mmol). The reaction was stirred 15 min and then warmed to room temperature for 15 min.
  • Cp-3 (free base) could be prepared from Cp-2 by the following procedure.
  • the reaction mixture was hydrogenated at 45 psig for 6 hrs.
  • the reaction mixture was filtered through Celite and the solvent was evaporated under reduced pressure to yield the product as a white powder.
  • This powder was dissolved in 50 mL of water and the solution was made basic with Na ⁇ O-,.
  • the aqueous solution was extracted with 2 X 20 mL of ethyl acetate.
  • the combined organic layers were washed with brine and dried over K 2 CO 3 .
  • the solvent was evaporated to yield the free base as a pale golden oil (0.72 g, 88%).
  • the reaction mixture was cooled and 50 mL of saturated NH 4 C1 was added.
  • the mixture was extracted with 2X100 mL of CH 2 C1 2 .
  • the combined organic layers were washed with brine (1X50 mL), dried over Na 2 SO 4 and evaporated under reduced pressure.
  • the residue was chromatographed on silica gel eluting with 70:30 hexane/ethyl acetate.
  • the product was obtained as a tan solid, 4-[4-(l- tritylimidazoyl)]-6,7-dihydrothianapthene (3.37 g, 78%).
  • Cp-5 was prepared by hydrogenation of Cp-4 in a manner analogous to the preparation of Cp-3 from Cp-2.
  • Cp-7 was prepared in a manner analogous to the preparation of Cp-2 or Cp-4.
  • Cp-6 was prepared by hydrogenation of Cp-7 in a manner analogous to the preparation of Cp-3 from Cp-2.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Les 4-thionaphtyl-1H-imidazoles de l'invention sont des agonistes/antagonistes du récepteur alpha-2-adrénergique. En tant qu'agonistes du récepteur delta-opioïde, ces composés sont des analgésiques efficaces. Selon qu'ils ont une activité agoniste ou antagoniste, ces composés peuvent également s'avérer utiles dans le traitement de l'hypertension, du glaucome, de la dysfonction sexuelle, de la dépression, de l'hyperactivité avec déficit de l'attention, d'affections nécessitant l'anesthésie, ou de l'arythmie cardiaque
PCT/US1999/007238 1998-04-02 1999-04-01 4-thionaphtyl-1h-imidazoles ayant une activite recepteur alpha-2-adrenergique WO1999051593A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU33783/99A AU3378399A (en) 1998-04-02 1999-04-01 4-thionaphthyl-1h-imidazoles with alpha-2-adrenergic activity

Applications Claiming Priority (2)

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US8044098P 1998-04-02 1998-04-02
US60/080,440 1998-04-02

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WO1999051593A1 true WO1999051593A1 (fr) 1999-10-14

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8188126B2 (en) 2002-05-16 2012-05-29 Pierre Fabre Medicament Imidazolic compounds and use thereof as alpha-2 adrenergic receptors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0129478A2 (fr) * 1983-06-20 1984-12-27 Merck & Co. Inc. Dérivés de 2-sulfamoylbenzo(b)thiophène, leur préparation et composition pharmaceutique pour le traitement de l'hypertension intra-oculaire
EP0183492A1 (fr) * 1984-11-23 1986-06-04 Farmos-Yhtyma Oy Dérivés d'imidazole substitués, leur préparation et leur application
EP0382935A1 (fr) * 1989-02-15 1990-08-22 FARMITALIA CARLO ERBA S.r.l. 2-(1H-imidazol-4(5)-yl)-3,4-dihydro-2H-1-benzothiopyrane

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0129478A2 (fr) * 1983-06-20 1984-12-27 Merck & Co. Inc. Dérivés de 2-sulfamoylbenzo(b)thiophène, leur préparation et composition pharmaceutique pour le traitement de l'hypertension intra-oculaire
EP0183492A1 (fr) * 1984-11-23 1986-06-04 Farmos-Yhtyma Oy Dérivés d'imidazole substitués, leur préparation et leur application
EP0382935A1 (fr) * 1989-02-15 1990-08-22 FARMITALIA CARLO ERBA S.r.l. 2-(1H-imidazol-4(5)-yl)-3,4-dihydro-2H-1-benzothiopyrane

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZHANG ET AL.: "Medetomidine analogs as alpha-2 adrenergic ligands...", J.MED.CHEM, vol. 40, 1997, pages 3014 - 3024, XP002108693 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8188126B2 (en) 2002-05-16 2012-05-29 Pierre Fabre Medicament Imidazolic compounds and use thereof as alpha-2 adrenergic receptors

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