SIN-1A cyclodextrin inclusion complexes

Details SIN-1A cyclodextrin inclusion complexes SIN-1A cyclodextrin inclusion complexes

1996-04-16

1997-12-16

Kight, John

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

536 46, 536103, 514 46, 424464, 424499, 548125, A61K 31715, C08B 3018, C07D27102

Patent

active

056985355

DESCRIPTION:

BRIEF SUMMARY
The invention relates to physiologically active nitric oxide releasing agents, processes for preparation thereof, compositions containing as well as methods to use the same.
More particularly the invention relates to new SIN-1A inclusion complexes which are stable in their solid state and which are formed with cyclodextrins or with cyclodextrin derivatives and which are releasing nitric oxide at room temperature upon dissolving in water or aqueous systems and which optionally also contain ions as catalyst or stabilizer. The invention also relates to processes for their preparation, compositions containing the same and methods for their use.
The following abbreviations are used in this specification:


______________________________________ SIN-1 3-morpholino-sydnonimine SIN-1A N-morpholino-N-nitrosoaminoacetonitrile SIN-1C cyanomethylene-amino-morpholine CDPSI ionic soluble .beta.-cyclodextrin polymer DIMEB heptakis-2,6-di-O-methyl-.beta.-cyclodextrin EDRF endothelium- derived relaxing factor HP.beta.CD hydroxypropyl-.beta.-cyclodextrin 2,8 hydroxypropyl group per CD-unit (average) Molsidomin N-ethoxycarbonyl-3-morpholino-sydnonimine RAMEB randomly methylated-.beta.CD, .apprxeq. 12 methoxyl group per CD-unit (average) TRIMEB heptakis 2,3,6-tri-O-methyl-.beta.-cyclodextrin. ______________________________________ which is designated as nitric oxide, and an oxidized form (NO.sup.+) which is called nitrosonium ion. Nitric oxide (NO.cndot.) is implicated in numerous important bioregulatory processes.
The utility of a NO releasing donor depends on both the depth and duration of the mean arterial pressure lowering effect. Longer acting NO-donors are needed, which release the NO without metabolic transformation of the donors, i.e. which are not depending on the liver functions. Furthermore, a NO-donor should have some lipophilic character, to be able to cross cell-membranes to exert its action also in the targeted organs, tissues. Therefore relatively simple, inorganic compounds are not adequate for this purpose.
The product design may follow three different routes:
a. The NO-donor prodrugs contain the --NO-group, which is released either directly by a metabolic process or after removing by enzymatic hydrolysis of some protecting group. These processes are bound largely to the liver (e.g. Molsidomine).
The sydnonimine-type prodrugs (e.g. Molsidomine) depend on the liver to remove the protecting ethoxy-carbonyl-group from the molecule to produce first SIN-1 and then (in a second, pH dependent process catalysed by OH.sup.- ions) the very instable SIN-1A is formed which independently of the pH spontaneously decomposes with the release of NO.
b. Preparation of adducts or complexes of nitric oxide with various nucleophiles.
Generally the synthesis of the secondary amine NO complexes is as follows: The secondary amine e.g. anhydrous diethylamine is dissolved in anhydrous ether, oxygen is removed from the system by using aceton dry-ice bath and dry NO is bubbled through the ether solution at -78.degree. C. for 3 hours, preferably at high pressure (100 psi).
The half-life of the prior art diethylamine-nitric oxide adduct Et.sub.2 --N--NH--(ONa)--N.dbd.O (DEANO) amounts to about 2 minutes, while the nitric oxide addition product of polyamine-spermine (SPNO) has a half-life of 39 minutes.
c. The prodrug is stabilized by cyclodextrin inclusion-complex formation while NO is released spontaneously under physiological conditions. The known cyclodextrin complexed prodrug is stable in the solid state.
It is known, that SIN-1 is a stable compound in solid state, however, its open-chain tautomeric form SIN-1A is extremely unstable. It is highly difficult to isolate the yellow crystalline product in pure form and it can be stored only at -80.degree. C., under nitrogen. The SIN-1A form rapidly releases one mole NO in solid state through photolysis, and in aqueous solution even in darkness it is converted to cyanomethylene-amino-morpholine (SIN-1C).
SIN-1 is thus considered to be a prodrug and SIN-1C a b

REFERENCES:
patent: 5039705 (1991-08-01), Keefer et al.
patent: 5208233 (1993-05-01), Keefer et al.
patent: 5212204 (1993-05-01), Keefer et al.
patent: 5298496 (1994-03-01), Vikmon et al.
patent: 5366997 (1994-11-01), Keefer et al.
patent: 5389675 (1995-02-01), Christodoulou et al.
On the Mechanism of NO Release from Sydnonimines, Feelisch, M. et al. J. Cardiovascular Pharmacology 14(Suppl. 11)S13-S22 (1989).
Oxygen and Oxidation Promote the Release of Nitric Oxide from Sydnonomines, Bohn, H. et al., J. Cardiovascular Pharmacology 14(Suppl. 11) S6-S12 (1989).

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