Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-04-05
2001-11-06
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C514S397000
Reexamination Certificate
active
06313309
ABSTRACT:
The present invention relates to &agr;
2
-adrenoceptor agonists/antagonists. More particularly, the present invention relates to certain 4-thionaphthyl-1H-imidazoles and analogues which are &agr;
2
-adrenoceptor agonists having analgesic activity.
BACKGROUND OF THE INVENTION
&agr;
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. Particularly, &agr;
2
-adrenoceptor agonists are well known analgesics.
Clonidine is a centrally acting &agr;
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 &agr;
2
-adrenoceptors located on the presynaptic nerve terminal. This action is believed to occur in both the central (CNS) and peripheral (PNS) nervous systems. More recently, the role of &agr;
2
-adrenoceptor agonists as analgesic agents in humans and antinociceptive agents in animals has been demonstrated. Clonidine and other &agr;
2
-adrenoceptor agonists have been shown to produce analgesia through a non-opiate mechanism and, thus, without opiate liability. However, other behavioral and physiological effects were also produced, including sedation and cardiovascular effects.
Medetomidine, detomidine, and dexmedetomidine are &agr;
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.
U.S. Pat. No. 3,574,844, Gardocki et al., teach 4-[4(or 5)-imidazolylmethyl]-oxazoles as effective analgesics. The disclosed compounds are of the general formula:
compounds of this type are insufficiently active and suffer from unwanted side effects.
U.S. Pat. No. 4,913,207, Nagel et al., teach arylthiazolylimidazoles as effective analgesics. The disclosed compounds are of the general formula:
Compounds of this type are insufficiently active and suffer from unwanted side effects.
WO92/14453, Campbell et al., teach 4-[(aryl or heteroaryl)methyl]-imidazoles as effective analgesics. The disclosed compounds are of the general formula:
The disclosed compounds are insufficiently active and suffer from unwanted side effects.
Kokai No. 1-242571, Kihara et al., disclose a method to produce imidazole derivatives for use, among other uses, as antihypertensive agents.
A single mixture of compounds meeting the above formula was reportedly produced by the inventive method. This was a mixture of 4-(2-thienyl)-methylimidazole and 4-(3-thienyl)-methylimidazole represented by the following formula:
The disclosed compounds are insufficiently active and suffer from unwanted side effects.
JP-42001546 (1964) discloses a compound of the general formula:
as a useful pesticide.
EP 129478 (1984) discloses a compound of the formula:
as useful in the treatment of glaucoma.
SUMMARY OF THE INVENTION
Briefly, there is provided by the present invention compounds having improved analgesic activity of the formula:
X is independently selected from the group consisting of hydrogen, C
1-4
alkyly, bromine, chlorine, iodide, trifluoromethyl, C
1-4
alkoxy, —SO
2
NH
2
and nitro; with the stipulation that the six membered ring, except for the bond shared with thienyl, is fully saturated, has a single unsaturated bond in conjugation with the imidazole ring or has two unsaturated bonds.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention are prepared by the methods shown in Schemes 1 and 2. In Scheme 1, 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. Subsequently, 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. Alternatively, 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 Wolff-Kishner reduction provides the keto acid. This acid is then converted to the acid chloride and intramolecular acylation yields the thienyl ketones 2. Certain thienyl ketones 2 are readily available commercially.
In the case where X is hydrogen, C
1-4
alkyl, C
1-4
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. In the case where X is chlorine, bromine, and nitro, 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 compounds 10 which can then be deprotected to give products 1.
Alternatively, certain of the compounds of the invention could be prepared in a more direct manner involving the condensation of the Grignard reagent from compound 8 with ketones 9. In this manner, products 1a were obtained from 8 and 9. Ketones 9 may be produced from reaction of the Grignard reagent derived from the imidazole with an appropriately substituted thiophene aldehyde, followed by oxidation. Production of ketones 9 is generally described and specifically exemplified in U. S. Pat. 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:
TABLE I
The activity of compounds of the invention as analgesics may be demonstrated by the in vivo and in vitro assays as described below:
Alpha-2D Adrenergic Receptor Binding Assay
Male, Wistar rats (150-250 g, VAF, Charles River, Kingston, N.Y.) 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 Teflon™-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 HEP
Baxter Ellen W.
Boyd Robert E.
Jetter Michelle C.
McDonnell Mark
Reitz Allen B.
Harbour John
Higel Floyd D.
Ortho-McNeil Pharmaceutical , Inc.
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