Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-10-08
2004-10-12
Morris, Patricia L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S311000
Reexamination Certificate
active
06803470
ABSTRACT:
The present invention relates to certain 2-amino-6-(2,4,5-substituted-phenyl)-pyridines, to pharmaceutical compositions containing them and to their use in the treatment and prevention of central nervous system and other disorders The compounds of this invention exhibit activity as nitric oxide synthase (NOS) inhibitors.
There are three known isoforms of NOS—an inducible form (I-NOS) and two constitutive forms referred to as, respectively, neuronal NOS (N-NOS) and endothelial NOS (E-NOS). Each of these enzymes carries out the conversion of arginine to citrulline while producing a molecule of nitric oxide (NO) in response to various stimuli. It is believed that excess nitric oxide (NO) production by NOS plays a role in the pathology of a number of disorders and conditions in mammals. For example, NO produced by I-NOS is thought to play a role in diseases that involve systemic hypotension such as toxic shock and therapy with certain cytokines. It has been shown that cancer patients treated with cytokines such as interleukin 1 (IL-1), interleukin 2 (IL-2) or tumor necrosis factor (TNF) suffer cytokine-induced shock and hypotension due to NO produced from macrophages, i.e., inducible NOS (I-NOS), see
Chemical
&
Engineering News
, December 20, p. 33, (1993). I-NOS inhibitors can reverse this. It is also believed that I-NOS plays a role in the pathology of diseases of the central nervous system such as ischemia. For example, inhibition of I-NOS has been shown to ameliorate cerebral ischemic damage in rats, see
Am. J. Physiol
., 268, p. R286 (1995)). Suppression of adjuvant induced arthritis by selective inhibition of I-NOS is reported in
Eur. J. Pharmacol
., 273, p. 15-24 (1995).
NO produced by N-NOS is thought to play a role in diseases such as cerebral ischemia, pain, and opiate tolerance. For example, inhibition of N-NOS decreases infarct volume after proximal middle cerebral artery occlusion in the rat, see
J. Cerebr. Blood Flow Metab
., 14, p. 924-929 (1994). N-NOS inhibition has also been shown to be effective in antinociception, as evidenced by activity in the late phase of the formalin-induced hindpaw licking and acetic acid-induced abdominal constriction assays, see
Br. J. Pharmacol
., 110, p. 219-224 (1993). Finally, opioid withdrawal in rodents has been reported to be reduced by N-NOS inhibition, see
Neuropsychopharmacol
., 13, p. 269-293 (1995).
Other NOS inhibitors and their utility as pharmaceutical agents in the treatment of central nervous system disorders and other disorders are referred to in the following references: U.S. patent application Ser. No. 09/325,480, filed Jun. 3, 1999, allowed Nov. 14, 2000, U.S. patent application Ser. No. 09/802,086, filed Mar. 8, 2001, and counterpart International Patent Application No. WO 98/24766, published Jun. 11, 1998; U.S. Pat. No. 6,235,747, issued May 22, 2001, U.S. patent application Ser. No. 09/826,132, filed Apr. 4, 2001, and counterpart International Patent Application No. WO 97/36871, published Oct. 9, 1997; U.S. patent application Ser. No. 09/740,385, filed Dec. 20, 2000, and counterpart International Patent Application No. WO 99/10339, published Mar. 4, 1999; U.S. patent application Ser. No. 09/381,887, filed Mar. 28, 2000, and counterpart International Patent Application No. WO 99/11620, published Mar. 11, 1999; U.S. patent application Ser. No. 09/127,158, filed Jul. 31, 1998, and counterpart International Patent Application No. WO 98/34919, published Aug. 13, 1998; and U.S. patent application Ser. No. 09/403,177, filed Oct. 18, 1999, and counterpart International Patent Application No. WO 99/62883, published Dec. 9, 1999.
SUMMARY OF THE INVENTION
The present invention relates to a compound, or pharmaceutically acceptable salt thereof, that is selected from the following compounds and their pharmaceutically acceptable salts:
(a) 6-[4-(N-methyl-3-azetidinoxy)-5-ethyl-2-methoxy-phenyl]-pyridin-2-ylamine, which has the following structure
(b) 6-[4-(N,N-dimethylaminomethyl)-5-ethyl-2-methoxy-phenyl]-pyridin-2-ylamine, which has the following structure
(c) 6-[4-(N-methylaminomethyl)-5-ethyl-2-methoxy-phenyl]-pyridin-2-ylamine, which has the following structure
(d) 6-[4-(3-azetidinoxy)-5-ethyl-2-methoxy-phenyl]-pyridin-2-ylamine, which has the following structure
In so far as the compounds of formulas I, II, III and IV of this invention contain basic groups, they can form acid addition salts with various inorganic and organic acids. The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formulas I, II, III and IV. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the base compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert to the free base compound by treatment with an alkaline reagent, and thereafter, convert the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bi-tartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate))salts.
The present invention also includes isotopically-labeled compounds that are identical to those recited in formulas I, II, III and IV, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen and oxygen, such as
2
H,
3
H,
13
C,
11
C,
14
C,
15
N,
18
O,
17
O, respectively. The compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of such compounds or of such prodrugs which contain the aforementioned isotopes and/or other isotopes are within the scope of this invention. Such compounds may be useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays. Certain isotopically-labeled compounds of the present invention, for example, those into which radioactive isotopes such as
3
H and
14
C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e.,
3
H, and carbon-14, i.e.,
14
C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,
2
H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically-labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes and discussion of the schemes and/or in the examples and preparations described herein, by substituting a readily available isotopically-labeled reagent for a nonisotopically-labeled reagent.
More specific embodiments of this invention relate to a compound of the formula I, which has the chemical name 6-[4-(N-methyl-3-azetidinoxy)-5-ethyl-2-methoxy-phenyl
Lowe, III John A.
Volkmann Robert A.
Konstas K. L.
Ling L. B.
Morris Patricia L.
Pfizer Inc
Richardson P. C.
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