N-6 substituted-5′-(N-substituted...

Details N-6 substituted-5′-(N-substituted... N-6 substituted-5′-(N-substituted...

1999-01-21

2001-02-06

Geist, Gary (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S045000, C536S027220

Reissue Patent

active

RE037045

ABSTRACT:

2. Field of the Invention
The present invention is directed to certain N-6 and 5′-N substituted carboxamidoadenosine derivatives which have beneficial cardiovascular and antihypertensive activity in mammals, including humans and domestic animals. The present invention is also directed to a process for making said compounds.
3. Brief Description of the Prior Art
Adenosine has been known for a long time to possess certain cardiovascular activity and particularly coronary dilatory activity. In an effort to obtain adenosine analogs of greater potency, or longer duration of activity, or both, many analogs of this naturally occurring nucleoside have been synthesized and tested.
Moreover, numerous studies have been conducted in order to elucidate the biochemical mechanism of action of adenosine and its analogs, and several theories and hypotheses have been proposed regarding biochemical pathways and receptor sites.
For discussion of current theories regarding the foregoing, reference is made to the following articles and publications: Adenosine Receptors: Targets for Future Drugs, by John W. Daly, Journal of Medicinal Chemistry, 25, 197 (1982); Cardiovascular Effects of Nucleoside Analogs, by Herman H. Stein and Pitambar Somani, Annals New York Academy of Sciences, 255, 380 (1979); Coronary Dilatory Action of Adenosine Analogs: a Comparative Study, by G. Reberger, W. Schutz and O. Kraupp, Archives internationales de Pharmacodynamie et de Therapie 230, 140-149 (1977); Chapter 6 of the book titled: Regulatory Function of Adenosine, (pages 77-96), R. M. Berne, T. W. Rall and R. Rubio editors, Martinus Nijhoff publishers, The Hague/Boston/London; Ethyl Adenosine-5′-carboxylate: A Potent Vasoactive Agent in the Dog, by Herman H. Stein, Journal of Medicinal Chemistry, 16, 1306 (1973); Modification of the 5′ Position of Purine Nucleosides: 2. Synthesis and Some Cardiovascular Properties of Adenosine-5′-(N-substituted)carboxamides, by Raj N. Prasad et al., Journal of Medicinal Chemistry, 23, 313 (1980); and Modification of the 5′ Position of Purine Nucleosides: 1. Synthesis and Biological Properties of Alkyl Adenosine-5′-carboxylates by Raj N. Prasad et al., Journal of Medicinal Chemistry, 19, 1180 (1976).
In addition to the foregoing publications, German Offenlegungschrift Nos. 2133273, 2426682, 1795761, 1913818, 2007273, 2238923, 2060189, 2244328, 1814711, 2136624, South African Patent Application No. 677630 (filed on Dec. 20, 1967) and British Patent Specification No. 1,123,245 describe adenosine derivatives which have cardiovascular, coronary dilator or antilipolytic activities. Still more adenosine derivatives having beneficial cardiovascular activity are described in another application for U.S. Letters Patent of the present inventors, Ser. No. 601,435, filed on Apr. 18, 1984.
Still further, Published Japanese Patent Application Nos. 58-167599 and 58-167600 disclose adenosine 5′-carboxamide derivatives which have fibrinolysis accelerating activity. U.S. Pat. No. 4,029,334 discloses anti-hypertensive and anti-anginal adenosine 5′-carboxamide derivatives where the N
6
amino group is unsubstituted. U.S. Pat. No. 4,167,565 discloses adenosine 5′-carboxamide derivatives which have substituents both in the N
6
and 5′-carboxamido position, and which are useful as poisons for certain noxious animals, such as rodents and coyotes.
In the cardiovascular and anti-hypertensive field, however, the therapeutic utility of the natural nucleoside adenosine and many of its analogs is limited because the desired beneficial effect is often of relatively short duration.
More particularly, the short duration of the beneficial cardiovascular effects of adenosine and those of its analogs which have an unsubstituted hydroxyl group at C-5 of the ribofuranose moiety is usually attributed to rapid penetration into cells followed by enzymatic conversion into less active or impermeant metabolites. For example, adenosine deaminase converts adenosine into inosine, which is a weak cardiovascular agonist. Alternatively, phosphorylation, catalyzed by adenosine kinase, forms adenylic acid (5′-AMP). Ionization of the phosphate group under physiological conditions prevents the escape of 5′-AMP from the cells in which it is formed. Thus trapped, 5′-AMP cannot exert its cardiovascular actions, which are mediated by cell surface receptors, as is discussed below.
Some known adenosine analogs, however, cannot be phosphorylated in the 5′ position because the 5′ position is effectively blocked. 5′-N-Ethylcarboxamidoadenosine [NECA] (Compound 1 in General Formula 1) is an example of such an adenosine analog incapable of phosphorylation by adenosine kinase. Nevertheless, this compound binds potently to certain adenosine receptor sites and exhibits substantial cardiovascular activity. Other examples of known derivatives of adenosine-5′-carboxamide, (Compound 2) and of adenosine-5′-carboxylic acid (Compound 9) are shown below in General Formulae 1 and 2. Generally speaking, in these compounds, the 5′-carboxylate or 5′-carboxamide group of the uronic acid moiety is substituted with lower alkyl or lower acyl groups. Some of the adenosine-5′-carboxamide derivatives shown in General Formula 1 are disclosed in Chemical Abstracts Volume 100, 68652c and 68653d (1984) and in the corresponding Published Japanese Patent Application Nos. 58-167599 and 58-167600.
The biological activity of adenosine-5′-carboxamide derivatives, such as NECA, is thought to be due to the activation of adenylate cyclase through cell surface “R
a
” or “A
2
” receptors. Structure-activity studies show that the R
a
receptor recognizes the alkyl uronamide moiety of NECA and its congeners. A second type of cell surface adenosine receptor designated “R
i
” or “A
1
” inhibits the catalytic activity of adenylate cyclase. Adenosine analogs possessing certain N-6 alkyl or aralkyl substituents such as cyclohexyl or R-1-phenyl-2-propyl are selective agonists at R
i
receptors. Many mammalian and human cells contain both R
a
and R
i
receptors; examples of exceptions are fat cells which contain R
i
receptors only, and blood platelets and human placenta, in which R
a
receptors predominate.
Currently available agonists are only selective, not absolutely specific, for R
a
and R
i
receptors. Because the two types of receptors coexist in many organs, including brain and heart, even a selective agonist will activate both to a certain degree. A goal of pharmaceutical chemistry is the development of agonists which are as nearly specific as possible because unselectivity can be a source of side effects.
The prior art makes no prediction about receptor selectivity of adenosine analogs which contain, in the same molecule, the recognition groups which confer specificity for R
a
and R
i
receptors.
Many of the known adenosine derivatives, including the above-noted N-6 substituted and the 5′-carboxamide derivatives are less than satisfactory as cardiovascular or antihypertensive drugs for animal and human use. This is either because of low activity, short duration of the desired activity, undue toxicity or undesirable side effects. Undesirable side effects of cardiovascularly active adenosine analogs often include cardiac depression.
In light of the foregoing, the pharmaceutical industry is still striving to obtain adenosine analogs having high cardiovascular and hypotensive potency coupled with other optimal physiological characteristics, such as relatively long duration of the desired activity, low toxicity and minimal side effects. The compounds of the present invention constitute a step in this direction.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide adenosine analogs which have potent and prolonged cardiovascular activity in mammals and humans, coupled with relatively low toxicity and minimal side effects.
It is another object of the present invention to provide adenosine analogs which have potent or p

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