Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-02-16
2001-12-25
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06333327
ABSTRACT:
The present invention relates to the use of a compound of the general formula I
for preparing a drug for treatment of MS (multiple sclerosis).
MS is a chronic disease with its origin in the central nervous system (CNS) that often leads to severe consequences. MS can be mild with minor symptoms to severe paralysis and loss of vision. The diagnosis is most common between the ages of 20 to 40 and thereafter the disease continues the remaining life span. Sometimes MS develops rapidly, while in other cases the afflicted persons can live for many decades only with some disabilities.
MS is more frequent at northern latitudes. Depending on region in the western world the prevalence varies with 50-150 cases per 100,000. In the US only, some 250,000-350,000 have the MS diagnosis. Females have a double risk, compared to males, to develop MS.
It is generally accepted that the immune defense of a patient with MS attacks the CNS, while the exact mechanisms are unknown. Due to inflammation of the nerve isolation (myeline) there are dysfunctions and short-circuits of nerve fibers and thereby effects on the muscles controlled by these nerves.
The treatment of MS is focused on the reduction of symptoms. To cure or stop the MS disease is not possible with today's knowledge. Consequently there does not exist any drug to cure or delay onset of the disease. Treatments used are:
#Transplantation of bone marrow and treatment of cytostatics and lifelong administration of immunosupressive drugs. This method could work for some patients but it is very expensive and includes several risks for the patient. Administration of cytostatics is still considered to be controversial in treatment of MS since the effects are unclear and potential side- effects are severe.
#There are two drugs used with the aim to cure or delay the MS disease; Interferon-beta (trademarks Avonex® and Betaseron®) can reduce the symptoms among certain groups of patients and is therefore administered to most patients for ethical reasons. The effect is unclear for the population of MS patients and it is a very expensive treatment.
Glatiramer acetate (trademark Copaxone®) can for some patients reduce the frequence of attacks, but the side effects are substantial and there is a problem to distinguish the symptoms of the MS disease and side effects.
Today there does not exist an effective treatment for MS. The treatment is focused on reducing symptoms. Tests with transplantation and different drug treatments to cure the disease have so far not shown any solutions. It can work for some patients, although there are risks, side effects and very high costs involved. MS is a rather common disease that appears early in life. In addition it is a life long disease with severe symptoms. The demand for drugs that can protect the MS patients for the severe development of the disease is therefore of high priority.
According to the present invention it has surprisingly been found that a substituted indolo-quinoxaline of the following general formula I can be used for preparing a drug for treatment of MS.
The compound which according to the present invention is to be used for preparing a drug for treatment of MS is a compound of the following general formula I
wherein
R
1
represents hydrogen or one or several, preferably 1 to 4, similar or different substituents in the positions 1-4 and/or 7-10, selected from halogen, preferably Br, lower alkyl/alkoxy group having not more than 4 carbon atoms, trifluoromethyl group, trichloromethyl group; and in one of the positions 7-10 R
1
can be a hydroxyl group;
X is a group —(CH
2
)
n
—R
2
, wherein R
2
represents a nitrogen containing basic residue such as NH
2
, NHR
4
or NR
5
R
6
, wherein R
4
, R
5
and R
6
independently are lower alkyl or cycloalkyl and n is an integer of from 1 to 4 and R
3
represents hydrogen, lower alkyl/cycloalkyl group having not more than 4 carbon atoms, and the physiologically acceptable addition products of the compounds with acids and halogen adducts, preferably adducts with iodine, iodine monochloride or iodine monobromide.
R
1
is preferably selected from hydrogen and lower alkyl groups, especially methyl. More preferably R
1
is methyl in positions 2 and 3 and hydrogen in the other positions.
Suitable compounds are such compounds wherein R
1
is hydroxy in one of the positions 7-10, especially in position 9.
The compounds used according to the present invention and their preparation are described in EP patent 0238459 and U.S. Pat. No. 4,990,510 which are incorporated herein by reference.
A compound which has proven to be especially effective is the compound of the following formula II
REFERENCES:
patent: 4990510 (1991-02-01), Bergman et al.
Ruuls et al., “The length of Treatment Determines Whether IFN-&bgr; Prevents or Aggravates Experimental Autoimmune Encephalomyelitis in Lewis Rats”,The Journal of Immunology,(1996), vol. 157, pp. 5721-5731.
Van Der Meide et al., “Discontinuation of treatment with IFN-&bgr; leads to exacerbation of experimental autoimmune encephalomyelitis in Lewis rats. Rapid reversal of the antiproliferative activity of IFN-&bgr; and excessive expansion of autoreactive T cells as disease promoting mechanisms”,Journal of Neuroimmunology,(1998), vol. 84, pp. 14-23.
Smith et al., “Autoimmune encephalomyelitis ameliorated by AMPA antagonists”,Nature Medicine,(2000), vol. 6, No. 1, pp. 62-66.
Bergman Jan
Möller Lennart
Browdy and Neimark
Henley III Raymond
Leif J. I. Lundblad
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