Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-10
2002-10-15
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S314000, C546S167000, C546S165000, C546S178000, C546S272700, C546S275100, C546S341000
Reexamination Certificate
active
06465486
ABSTRACT:
The present invention relates to compounds which bind to the &agr;
2
-adrenoceptor. More particularly, the present invention relates to certain imidazo pyridines/quinolines which are &agr;
2
receptor modulators.
BACKGROUND OF THE INVENTION
&agr;
2
-adrenoceptor modulators are useful to treat a variety of conditions, including, hypertension, glaucoma, sexual dysfunction, depression, attention deficit hyperactivity disorder, Parkinsonism, the need for anesthesia, cardiac arrythmia and the need for analgesia. Particularly, &agr;
2
-adrenoceptor agonists are well known analgesics. &agr;
2
-adrenoceptor antagonists have potential as antidepressants in their own right or as adjunct therapies to traditional inhibitors of monoamine reuptake.
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.
U.S. Pat. No. 5,621,113 and U.S. Pat No. 5,750,720, Boyd and Rasmussen disclose certain substituted 2- and 3-thienyl methylimidazoles as effective analgesic agents.
Many potent and selective &agr;
2
antagonists, such as idazoxan, have been synthesized and evaluated in limited clinical trials as antidepressants.(
J. Med. Chem
. 1995, 38 (23), 4615.) Mirtazapine is a closely related analog of the established antidepressant mianserin. This compound has been shown to be an antagonist at &agr;
2
receptors and exhibits antidepressant activity in vivo. (
Exp. Opin. Invest. Drugs
1995, 4(10), 945). An agent with the dual profile of a 5 HT reuptake inhibitor and an &agr;
2
antagonist might serve to enhance synaptic concentrations of 5-HT relative to that achievable through 5-HT uptake inhibition alone and in turn produce a more effective antidepressant response. A novel series of compounds with such a profile was found to possess putative antidepressant effects in vivo (
J. Med. Chem
. 1997, 40 (7), 1049
; Bioorg. Med. Chem Lett
. 1995, 5, 2287
.; Drug. Dev. Res
. 1995, 35, 237
.; Drug. Dev. Res
. 1995, 35, 246.)
SUMMARY OF THE INVENTION
Briefly, there is provided by the present invention compounds which are &agr;
2
-adrenoceptor modulators of the formula:
where
n is 0, 1, 2;
X is independently selected from the group consisting of C
1-4
alkyl, bromine, chlorine, iodide, trifluoromethyl, C
1-4
alkoxy, —SO
2
NH
2
, nitro, and two adjacent X may be fused to form the moiety:
whereby a saturated, partially unsaturated or aromatic six-membered fused ring is formed;
Y is independently selected from the group consisting of hydrogen, hydroxy, C
1-4
alkyl, C
1-4
alkoxy, trifluoromethyl and phenyl; and
Z is independently selected from the group consisting of hydroxy, C
1-4
alkyl, bromine, chlorine, iodide, trifluoromethyl, C
1-4
alkoxy, —SO
2
NH
2
and nitro.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention are prepared by the methods shown in Schemes 1 to 5. In Scheme 1, heterocyclic carboxylic acid 1 is converted to its Weinreb amide 2 by published procedures (Weinreb and Nahm,
Tetrahedron Letters
, 1981, 22, 3815) which is then reacted with the Grignard reagent derived from N
1
-trityl-4-iodoimidazole (Turner and Lindell,
J. Org. Chem
. 1991, 56, 5739) to give the ketone intermediate 3. This ketone intermediate 3 could be deoxygenated by reaction with a reagent such as HI to give product 4. Alternatively, as depicted in Scheme 2, the intermediate ketone 3 could be reacted with an alkyl or aryllmagnesium halide (or other Grignard or lithium reagent) to give 5 which is then deoxygenated and deprotected to yield 6. Suitable means of deoxygenation/deprotection include 57% hydriodic acid, hydrogenation using Pd(OH)
2
as catalyst, triethylsilane/trifluoroacetic acid, borane/methylsulfide or NaBH
4
/trifluoroacetic acid.
In Scheme 3, heterocyclic aldehyde 7 reacts with the Grignard reagent derived from N
1
-trityl-4-iodoimidazole (Turner and Lindell,
J. Org. Chem
. 1991, 56, 5739) to yield the heterocyclic hydroxymethylimidazole intermediate 8. This intermediate is deoxygenated and deprotected in one step for example with refluxing HI or another suitable means such as described above to give product 9.
In the case where X is hydrogen, C
1-4
alkyl, C
1-4
alkoxy and trifluoromethyl, the appropriately substituted heterocyclic hydroxyimidazoles 5 or 8 may be produced and the substituent in question will stably endure the reactions of Scheme 2 and Scheme 3 to arrive at target products 6 and 9 respectively. In the case where X is chlorine, bromine, and nitro, the above described deoxygenation-deprotection steps could also be achieved using triethylsilane/trifluoroacetic acid, 57% hydriodic acid or other means such as borane/methylsulfide or NaBH
4
/trifluoroacetic acid.
In Scheme 4, heterocyclic carbinol 10 is converted to the bromide by reaction with a brominating agent such as CBr
4
/PPh
3
or PBr
3
. The bromide 11 reacts with PPh
3
to yield the triphenylphosphonium reagent 12 which undergoes Wittig reaction with N
1
-tritylimidazole-4-carboxaldehyde in the presence of a suitable base such as NaOMe/MeOH or LiHMDS. The requisite N
1
-tritylimidazole-4-carboxaldehyde is easily obtained by published procedures (Jetter et al,
Org. Prep. Proc. Intl
. 1996, 28, 709.). The products of the Wittig reaction 13 are deprotected with an acid such as hydrochloric acid, formic acid or trifluoroacetic acid and then reduced by hydrogenation with an appropriate catalyst to yield the target 14.
In Scheme 5, hydroxyquinoline 15 is converted to its triflate by reaction with a strong base such as NaH and an appropriate triflating agent such as N-phenyl trifluoromethanesulfonimide to give quinolyl triflate 16. The triflate 16 could be condensed in a Stille coupling reaction with a 4-(stannyl)imidazole reagent in the presence of Pd(0) to give 17, or condensed with the 4-imidazo Grignard reagent descri
Baxter Ellen W.
Boyd Robert E.
Carson John R.
Jetter Michele C.
Reitz Allen B.
Ortho-McNeil Pharmaceutical , Inc.
Robinson Binta
Rotman Alan L.
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