Method for the treatment of Multiple Sclerosis

Use of a compound of formula I ##STR1## wherein PA1 R.sub.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.sub.1 can be a hydroxyl group; PA1 X is a group --(CH.sub.2).sub.n --R.sub.2, wherein R.sub.2 represents a nitrogen containing basic residue such as NH.sub.2, NHR.sub.4 or NR.sub.5 R.sub.6, wherein R.sub.4, R.sub.5 and R.sub.6 independently are lower alkyl or cycloalkyl and n is an integer of from 1 to 4 and R.sub.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, for preparing a drug for treatment of MS (multiple sclerosis).

The present invention relates to the use of a compound of the general
 formula I
 ##STR2##
 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.RTM. and Betaseron.RTM.) 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.RTM.) 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
 ##STR3##
 wherein
 R.sub.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.sub.1 can be a hydroxyl group;
 X is a group --(CH.sub.2).sub.n --R.sub.2, wherein R.sub.2 represents a
 nitrogen containing basic residue such as NH.sub.2, NHR.sub.4 or NR.sub.5
 R.sub.6, wherein R.sub.4, R.sub.5 and R.sub.6 independently are lower
 alkyl or cycloalkyl and n is an integer of from 1 to 4 and R.sub.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.sub.1 is preferably selected from hydrogen and lower alkyl groups,
 especially methyl. More preferably R.sub.1 is methyl in positions 2 and 3
 and hydrogen in the other positions.
 Suitable compounds are such compounds wherein R.sub.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
 ##STR4##

The EAE (experimental autoimmune encephalomyelitis) model is a generally
 accepted animal model for the acute MS symptoms ((1)Ruuls et al, J.
 Immunology, 1996, 157, 5721-5731; (2)van der Medide et al, J.
 Neuroimmunology, 1998, 84, 14-23; (3)Smith et al, Nature Medicine,2000, 6,
 1, 62-66). The model is based on Lewis rats that day 0 are induced by 20
 .mu.g myeline peptide (MBP 68-86) och 2 mg of Myobacterium tuberculosis.
 After one week severe CNS symptoms appear that are by double blind
 examination given a value--a clinical score. The higher value, the more
 severe effect. The scale is 0-5. After some 14 days there is a peak in
 symptoms followed by a decline back to the normal situation.
 The negative control has no treatment except the immunization (day 0) to
 induce the acute MS response. In FIG. 1 the results from the negative
 control, Interferon-beta and a compound used according to the present
 invention, 2,3-dimethyl(dimethylaminoethyl)-5H-indolo-(2,3-b)quinoxaline,
 (B-220) are shown. From the figure it can be seen that Interferon-beta has
 no reducing effect of the CNS symptoms The lower curve represents the
 tested substance used according to the present invention, which substance
 surprisingly and unexpectedly reduces the CNS symptoms with 2/3.
 In the test Interferon-beta was administered daily with 3.times.10.sup.5
 U/animal which is a medium dose (2). The tested substance(B-220), was
 administered daily with 6 mg/animal, a dose that can be increased since
 the margin to toxic effects is wide and most likely further reduce the
 symptoms. It is to be noted that the acute toxicity of the tested
 substance used according to the present invention is low, which is
 exemplified with the following:
 LD.sub.50, oral, rat; &gt;800 mg/kg bw
 LD.sub.50, intravenous, rat; &gt;100 mg/kg bw
 NOEL, intravenous, rat; 12.5 mg/kg bw
 NOEL, cutaneous, rabbit; 200 mg/kg bw
 (NOEL=No Observable Effect Level)
 The chronic toxicity has been tested up to 270 days on mice and the
 substance has not induced toxicity, on the contrary the substance has
 protected the animals for different health effects.
 In the well established EAE rat model for multiple sclerosis (MS) a
 compound used according to the present invention, B-220, was shown to
 down-regulate the clinical symptoms (clinical score) in a dose dependent
 manner. The results are shown in FIG. 2. At the highest dose, 12
 mg/animal, (lower curve) the onset is delayed approximate 4 days, the
 recovery starts approximate 3 days earlier and the total effect is
 dramatically lowered. A majority of the animals do not show any symptoms
 at all in this group. Symptom grading 1 is thus a very weak and mild
 effect while grading 3 is a severe paralysis. The intermediate curve
 illustrates a dose of 6 mg/animal and the onset is delayed approximate 2
 days, the recovery starts approximate 2 days earlier and the total effect
 is substantially lower as compared to the control, highest curve, where no
 B-220 is added.
 In FIG. 3 pre-treatment with B-220 before the onset of the disease is
 shown. The highest curve is illustrating the control without any added
 B-220 while the lower curve is after administration of B-220 of 6
 mg/animal. As seen from the Figure the pre-treatment results in a clear
 lowered and delayed MS effect. Administration of B-220 was from -7 to +7
 days in relation to the onset of disease (day 0).
 In FIG. 4 after-treatment with B-220 starting from day 7 from the time
 point when the disease was initiated (day 0) and throughout the experiment
 is shown wherein the highest curve is a control without any addition of
 B-220 and the lower curve is representing a dose of 6 mg/animal of B-220.
 As seen from the Figure the after-treatment with B-220 lowered the MS
 effect in the rats.
 The vertical lines in both FIG. 3 and FIG. 4 represent mean.+-.standard
 deviation.
 A suitable dosage range for humans is 1 to 50 mg/kg body weight.