Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-07-02
2002-08-13
O'Sullivan, Peter (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C564S079000
Reexamination Certificate
active
06433016
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates generally to carbocyclic imidodisulfamide derivatives and more specifically to N,N
1
-bis[[tricyclo 3.3.1.1
3,7
]dec-1-yl]alkyl]-, N,N
1
-bis[[tricyclo[3.3.1.1
3,7
]dec-
2
-yl]alkyl]-, and N, N
1
-di(bicyclo[2.2.1]hept-2-yl)imidodisulfamide derivatives, as well as their alkali salts and N-monophosphates. The compounds of this invention possess broad antiviral activity, especially activity against orthopoxviruses.
Ali at al., J. Med. Chem. 25: 1235-1240 (1982) describe a series of N,N
1
-bis(arylcyclopropyl)imidodisulfamide derivatives having antiallergic activity. Appel and Helwerth, Chem. Ber. 101: 1743-1745 (1968) disclose a bis(cyclohexyl)imidodisulfamide derivative. Yamaguchi and Nakano [Japan. Patent 19,962 (1963)] disclose the ammonium salt of a bis(cyclohexyl)imidodisulfamide derivative.
SUMMARY OF THE INVENTION
In accordance with the invention, there are provided compounds of the formula:
[R—(CH
2
)
n
NHSO
2
]
2
NR
1
(I)
wherein n is 0, 1 or 2, R is a carbocyclic radical selected from the group consisting of adamantyl, norbornyl, cyclooctyl and cyclododecyl, and R
1
is hydrogen, alkali metal such as sodium, potassium, etc., ammonium cation, and monophosphate moiety.
The invention further provides a method for treating a warm blooded animal for viral infections, preferably but not limited to infections caused by orthopoxviruses (such as vaccinia virus, cowpox, smallpox, monkeypox, camelpox, etc.) which method comprises administering to such animal an effective amount of a compound of formula (I).
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the invention may be prepared by reacting an appropriate carbocyclic alkylamine derivative (1) with imidodisulfuryl chloride (2) in the presence of triethylamine (n and R are as defined above):
The following carbocyclic alkylamine intermediates (1) are commercially available: tricyclo[3.3.1.1
3,7
]decan-1-amine (1; R=1-adamantyl, n=0); [(tricyclo[3.3.1.1
3,7
]-dec-1-yl)methyl]amine (1; R=1-adamantylmethyl, n=1); tricyclo[3.3.1.1
3,7
]decan-2-amine (1;R=2-adamantyl, n=0); exo-bicyclo[2.2.1]heptan-2-amine (1; R=exo-2-norbornyl, n=0); and endo-bicyclo[2.2.1]heptan-2-amine (1; R=endo-2-norbornyl, n=0).
Tricyclo[3.3.1.1
3,7
]decan-1-ethanamine (1; R=1-adamantyl, n=2) may be prepared according to U.S. Pat. No. 3,534,036 of V. L. Narayanan and F. L. Weisenborn, the entire disclosure of which is incorporated herein by reference.
Tricyclo[3.3.1.1
3,7
]decan-2-ethanamide (1; R=2-adamantyl, n=2) and 2-(tricyclo[3.3.1.13,7]dec-2-ylidene)ethanamine (4)
were prepared according to the procedure of Mariani et al., I1 Farmaco, Ed. Sci. 31: 272 (1976) and Schenonone et al. I1 Farmaco, Ed. Sci. 27: 322 (1972).
Imidodisulfuryl chloride was prepared utilizing the procedure of Appel and Eisenhouer, Chem. Ber. 95: 1753 (1962).
The compounds of the invention may also be prepared as their ammonium salts (6) by reacting an appropriate carbocyclic alkylamine derivative (1) (n and R are defined as above) with the ammonium salt of imidodisulfuryl chloride (5) according to the procedures of Appel and Helwerth [Chem. Ber. 101: 1743-1745 (1968)] and Yamaguchi and Nakano [Japan. Patent 19,962 (1963)]:
In order to increase their solubility in water and saline, the compounds of the invention may also be prepared as their alkali salts (8) by reacting an appropriate carbocyclic imidodisulfamide derivative 3 (n and R are defined as above) with aqueous alkaline hydroxide solution such as but not limited to sodium hydroxide and potassium hydroxide:
In order to increase their solubility in water and saline, the compounds of the invention may also be prepared as their N-substituted monophosphate derivatives (10) according to the procedure of Zavlin and Efremov, Phosphorous Sulfur, 40: 247-251 (1991) by reacting an appropriate carbocyclic imidodisulfamide derivative 3 (n and R are defined as above) with a phosphorylating agent 9 (e.g., phosphoric anhydride, phosphorus trichloride, phosphorous pentoxide and phosphorous oxychloride):
By having increased solubility in water and saline, compounds of the formula 6, 8 and 10 may be easily administrated by oral, intranasal, and intraperitoneal routes to treat warm-blooded animals against infections caused by orthopoxviruses.
REFERENCES:
patent: 4292305 (1981-09-01), Ali et al.
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