Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Reexamination Certificate
2001-09-15
2004-12-07
Zucker, Paul A. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
C562S560000, C562S561000
Reexamination Certificate
active
06828456
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to 2-amino-2-alkyl-3 hexenoic and hexynoic acid derivatives and their use in therapy, in particular their use as nitric oxide synthase inhibitors.
RELATED ART
It has been known since the early 1980's that the vascular relaxation caused by acetylcholine is dependent on the vascular endothelium. The endothelium-derived relaxing factor (EDRF), now known to be nitric oxide (NO) is generated in the vascular endothelium by nitric oxide synthase (NOS). The activity of NO as a vasodilator has been known for well over 100 years. In addition, NO is the active species deriving from amylnitrite, glyceryltrinitrate and other nitrovasodilators. The identification of EDRF as NO has coincided with the discovery of a biochemical pathway by which NO is synthesized from the amino acid L-arginine by the enzyme NO synthase.
Nitric oxide is an endogenous stimulator of the soluble guanylate cyclase. In addition to endothelium-dependent relaxation, NO is involved in a number of biological actions including cytotoxicity of phagocytic cells and cell-to-cell communication in the central nervous system.
There are at least three types of NO synthase as follows:
(i) a constitutive, Ca
++
/calmodulin dependent enzyme, located in the endothelium, that releases NO in response to receptor or physical stimulation.
(ii) a constitutive, Ca
++
/calmodulin dependent enzyme, located in the brain, that releases NO in response to receptor or physical stimulation.
(iii) a Ca
++
independent enzyme which is induced after activation of vascular smooth muscle, macrophages, endothelial cells, and a number of other cells by endotoxin and cytokines. Once expressed, this inducible nitric oxide synthase (hereinafter “iNOS”) generates NO continuously for long periods.
The NO released by each of the two constitutive enzymes acts as a transduction mechanism underlying several physiological responses. The NO produced by the inducible enzyme is a cytotoxic molecule for tumor cells and invading microorganisms. It also appears that adverse effects of excess NO production, in particular pathological vasodilation and tissue damage, may result largely from the NO synthesized by iNOS.
There is a growing body of evidence that NO may be involved in the degeneration of cartilage which takes place as a result of certain conditions such as arthritis and it is also known that NO synthesis is increased in rheumatoid arthritis and in osteoarthritis.
Some of the NO synthase inhibitors proposed for therapeutic use are non-selective; they inhibit both the constitutive and the inducible NO synthases. Use of such a non-selective NO synthase inhibitor requires that great care be taken in order to avoid the potentially serious consequences of over-inhibition of the constitutive NO-synthase, such consequences including hypertension and possible thrombosis and tissue damage. In particular, in the case of the therapeutic use of L-NMMA (a non-selective NO synthase inhibitor) for the treatment of toxic shock it has been recommended that the patient must be subject to continuous blood pressure monitoring throughout the treatment. Thus, while non-selective NO synthase inhibitors have therapeutic utility provided that appropriate precautions are taken, NO synthase inhibitors which are selective in the sense that they inhibit the inducible NO synthase to a considerably greater extent than the constitutive isoforms of NO synthase would be of even greater therapeutic benefit and easier to use (S. Moncada and E. Higgs, FASEB J., 9, 1319-1330, 1995).
PCT International Publication No. WO 93/13055 and U.S. Pat. No. 5,132,453, the disclosure of which are hereby incorporated by reference in their entirety as if written herein, disclose compounds that inhibit nitric oxide synthesis and preferentially inhibit the inducible isoform of nitric oxide synthase.
PCT International Publication No. WO 95/25717 discloses certain amidino derivatives as being useful in inhibiting inducible nitric oxide synthase.
Various attempts have been made to improve the potency and selectivity of NOS inhibitors by adding one or more rigidifying elements to the inhibitor's structure. Publications by Y. Lee et al (
Bioorg. Med. Chem
. 7, 1097 (1999)) and R. J. Young et al (
Bioorg. Med. Chem. Lett
. 10, 597 (2000)) teach that imposing conformational rigidity with one or more carbon-carbon double bonds is not a favorable approach to impart selectivity for NOS inhibitors.
SUMMARY OF THE INVENTION
Compounds have now been found which have the advantage of being very efficacious in the human cartilage explant assay, a model for osteoarthritis.
The present invention teaches that a carbon-carbon double bond can be used as a rigidifying element, and the resulting compounds will have unexpected potency and selectivity for inhibition of inducible NOS.
The present disclosure teaches that a carbon-carbon double bond imparts a favorable interaction with inducible NOS, such that the resulting compounds have unexpected potency and selectivity for inhibition of inducible NOS over the constitutive isoforms.
Further, compounds of the present invention have the advantage of being very efficacious as iNOS inhibitors in the human cartilage explant assay, a model for osteoarthritis. At the same time the compounds of the present invention are surprisingly less able to penetrate certain non-target organs in test systems, especially in comparison to the compounds of WO 93/13055. This surprising differentiation in expected access between the target organ (cartilage) and other organs is an unexpected advantage for the compounds of the present invention.
In a broad aspect, compounds of the present invention are represented by:
or a pharmaceutically acceptable salt thereof, wherein:
R
1
is selected from the group consisting of hydrogen, halo, C
1
-C
5
alkyl and C
1
-C
5
alkyl substituted by alkoxy or one or more halo;
R
2
is selected from the group consisting of hydrogen, halo, C
1
-C
5
alkyl and C
1
-C
5
alkyl substituted by alkoxy or one or more halo;
R
3
is C
1
-C
5
alkyl or C
1
-C
5
alkyl substituted by alkoxy or one or more halo.
In an embodiment represented by Formula I, the invention relates to:
or a pharmaceutically acceptable salt thereof, wherein:
R
1
is selected from the group consisting of hydrogen, halo, C
1
-C
5
alkyl and C
1
-C
5
alkyl substituted by alkoxy or one or more halo;
R
2
is selected from the group consisting of hydrogen, halo, C
1
-C
5
alkyl and C
1
-C
5
alkyl substituted by alkoxy or one or more halo;
R
3
is C
1
-C
5
alkyl or C
1
-C
5
alkyl substituted by alkoxy or one or more halo.
In an embodiment represented by Formula II, the invention relates to:
or a pharmaceutically acceptable salt thereof, wherein:
R
3
is C
1
-C
5
alkyl, said C
1
-C
5
alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo.
In an embodiment represented by Formula III, the invention relates to:
or a pharmaceutically acceptable salt thereof, wherein:
R
1
is selected from the group consisting of hydrogen, halo, C
1
-C
5
alkyl and C
1
-C
5
alkyl substituted by alkoxy or one or more halo;
R
2
is selected from the group consisting of hydrogen, halo, C
1
-C
5
alkyl and C
1
-C
5
alkyl substituted by alkoxy or one or more halo;
R
3
is C
1
-C
5
alkyl or C
1
-C
5
alkyl substituted by alkoxy or one or more halo.
In an embodiment represented by Formula IV, the invention relates to:
or a pharmaceutically acceptable salt thereof, wherein:
R
3
is C
1
-C
5
alkyl or C
1
-C
5
alkyl substituted by alkoxy or one or more halo.
In an embodiment represented by Formula V, the invention relates to:
or a pharmaceutically acceptable salt thereof, wherein:
R
1
is selected from the group consisting of hydrogen, halo, C
1
-C
5
alkyl and C
1
-C
5
alkyl substituted by alkoxy or one or more halo;
R
2
is selected from the group consisting of hydrogen, halo, C
1
-C
5
alkyl and C
1
-C
5
alkyl substituted by alkoxy or one or more halo;
R
3
is C
1
-C
5
alkyl or C
1
-C
5
alkyl
Hansen, Jr. Donald W.
Webber Ronald Keith
Pharmacia Corporation
Polster, II Philip B.
Zucker Paul A.
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