Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-16
2002-07-30
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S397000, C514S311000, C514S315000, C548S205000
Reexamination Certificate
active
06426356
ABSTRACT:
The present invention relates to compounds which bind to the &agr;
2
-adrenoceptor. More particularly, the present invention relates to certain imidazoethyl thiophenes/thiazoles or benzothiophenes and analogues which are &agr;
2
-adrenoceptor 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, 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 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 snd 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 a2 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
Z is CH or N; and
X is independently selected from the group consisting of hydrogen, C
1-4
alkyl, bromine, chlorine, iodide, trifluoromethyl, C
1-4
alkoxy and nitro.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention are prepared by the methods shown in Scheme 1. Scheme 1 is drawn to depict only thiophene, but the thiophene of this scheme could in each instance be replaced with the equivalent benzothiophene to produce the benzothiophene end product. In Scheme 1, an appropriately substituted thiophene aldehyde A1 is reduced with an appropriate reducing agent such as NaBH
4
in a solvent such as methanol to give the thiophene alcohol A2. This thiophene alcohol A2 is converted to the thiophene bromide A3 by reaction with CBr
4
/PPh
3
. This bromomethyl thiophene A3 is then reacted with PPh
3
in a solvent such as THF to yield the thiophene phosphonium salt A4. This phosphonium salt undergoes Wittig reaction with N
1
-trityl-imidazole-4-carboxaldehyde in the presence of an appropriate base such as sodium methoxide in methanol or lithium hexamethyldisilazide in THF. The resultant mixture of cis and trans isomers A5 are deprotected under acidic conditions such as with acidic methanol or trifluoroacetic acid in dichloromethane. The desired product is then obtained by catalytic reduction to yield the appropriately substituted imidazoethyl thiophenes A6.
Alternatively, the phosphonium salt of the thiophene A4 can be obtained by direct reaction of the appropriately substituted hydroxymethylthiophene A2 with triphenylphosphine hydrobromide in trichloromethane as illustrated in Scheme 2.
The thiazoles can be made according to the procedure of Scheme 1 from an equivalent thiazole phosphonium salt A4 to an equivalent imidazoethylthiazole A6. To obtain the equivalent thiazole phosphonium salt A4 the procedure disclosed by Williams and Brooks
Tetrahedron Letters
1996, 983 should be employed. In the case where R is hydrogen, C
1-4
alkyl, C
1-4
alkoxy and trifluoromethyl, the appropriately substituted thiophene alkenyl imidazole A5 may be produced and the substituent in question will stably endure the reactions of Scheme 1 or Scheme 2 to arrive at target products A6. In the case where R is chlorine, bromine and nitro, the saturated product A6 may be obtained from the unsaturated intermediate A5 by alternate reduction conditions such as borane/methylsulfide or triethylsilane/trifluoroacetic acid.
The compounds of the present invention may be used to treat a medical condition as named herein, such as, mild to moderate pain in warm-blooded animals, such as, humans by administration of an 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. In regard to the use of these &agr;
2
-adrenoceptor modulators to treat hypertension, glaucoma, sexual dysfunction, depression, attention deficit hyperactivity disorder, the need for anesthesia and cardiac arrythmia, a therapeutically effective dose can be determined by persons skilled in the art by use of established animal models. Pharmaceutical compositions of the invention comprise the formula (I) compounds as defined above, particularly in admixture with a pharmaceutically-acceptable carrier.
To prepare the pharmaceutical 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 pharmaceuti
Baxter Ellen W.
Jetter Michele C.
Gerstl Robert
Harbour John W.
Ortho-McNeil Pharmaceutical , Inc.
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