EP0948331A2 - Methode de traitement de la sclerose en plaques - Google Patents

Methode de traitement de la sclerose en plaques

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Publication number
EP0948331A2
EP0948331A2 EP97953042A EP97953042A EP0948331A2 EP 0948331 A2 EP0948331 A2 EP 0948331A2 EP 97953042 A EP97953042 A EP 97953042A EP 97953042 A EP97953042 A EP 97953042A EP 0948331 A2 EP0948331 A2 EP 0948331A2
Authority
EP
European Patent Office
Prior art keywords
amino
pyrimidinol
bromo
iodo
chloro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP97953042A
Other languages
German (de)
English (en)
Inventor
Stephen E. Buxser
Francis A. Fitzpatrick
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmacia and Upjohn Co
Original Assignee
Pharmacia and Upjohn Co
Upjohn Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmacia and Upjohn Co, Upjohn Co filed Critical Pharmacia and Upjohn Co
Publication of EP0948331A2 publication Critical patent/EP0948331A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings

Definitions

  • the present invention provides a new use of known compounds. More particularly the present invention provides a method of treating multiple sclerosis using a series of known pyrimidiols including bropirimine.
  • US Patent 4,619,933 claims a process of treating aplastic anemia with 2- amino-6-aryl-4-pyrimidinol compounds and discloses that alteration of the immunoregulatory system of the host animal and that administration of the active compounds increases antibody formation and be used to treat acquired or congenital hypogammaglobulinemia; activates macorphages and can be used to treat or prevent intracellular or extracellular parasitic infections, including bacterial and protozoal; increases hematopoietic stem cells in bone marrow and spleen and can be used to treat or prevent aplastic anemia; and decreases generation of allospecific killer cells and can be used to prevent rejection of organ and skin grafts.
  • US Patent 5,434,157 claims various 6-aryl pyrimidinol compounds and compositions thereof as well a method for treating viral infections and inducing interferon production.
  • this patent also discloses that the compounds have immunoregulatory activity; for example the compounds increased antibody formation and decreased delayed hypersensitivity and are useful in the treatment of parasitic diseases, organ transplants and skin graft rejections, and immune deficiencies including those caused as a side effect of therapy with cytotoxic agents and radiation.
  • 08/419,963 claims the process of treating susceptible forms of cancer with 2-amino-6-aryl-4-pyrimidinol compounds and discloses the alteration of the immunoregulatory system of the host animal and that administration of the active compounds increases antibody formation and be used to treat acquired or congenital hypogammaglobulinemia; increases natural killer cells and can be used to treat various forms of cancer; activates macorphages and can be used to treat or prevent intracellular and can be used to treat or prevent intracellular or extracellular parasitic infections, including bacterial and protozoal; increases hematopoietic stem cells in bone marrow and spleen and can be used to treat or prevent aplastic anemia; and decreases generation of allospecific killer cells and can be used to prevent rejection of organ and skin grafts.
  • Bropirimine (2-amino-5-bromo-6-phenyl-4(lH)-pyrimidinone; ABPP) which was selected from this group of 6-arylpyrimidinones for further development, is an orally active inducer of endogenous interferon, with established antiviral, immunostimulatory and antitumor activity. Regulatory approval from the United States Food and Drug Administration is being sought to market bropirimine tablets for the treatment of superficial bladder cancer (CIS).
  • CIS superficial bladder cancer
  • MMPIs matrix metalloproteinase inhibitors
  • MS multiple sclerosis
  • MMPIs matrix metalloproteinase inhibitors
  • lymphokines such as interferon-beta
  • Swanborg, R.H. Experimental Autoimmune Encephalomyelitis in Rodents as a Model for Human Demyelinating Disease. Clin. Immunol. Immunopath.
  • interferons dosing of the interferons is restricted to parenteral injections, which must be repeated regularly, and there are indications that the administration of the interferons is unpleasant enough to result in a relatively high dropout rate for patients who initially attempt to use this therapy. Furthermore, the efficacy reported is weak enough to warrant continuing the search for better therapy to treat the disease.
  • One concern associated with the direct use of interferons is the failure of the natural regulation systems to be able to control the concentrations of the cytokine. Since lymphokine/cytokine systems are usually tightly regulated, such a lack of internal control systems may result in side effects and less than optimal efficacy.
  • Toxicological problems associated with interferons include neurological problems, such as changes in electroencephalograms, sleep patterns and cognition, and a flu-like syndrome [Spiegel, R.J., The alpha interferons: Clinical overview. Seminars in Oncology 14: 1-12 (1987) and Rohatiner, A.Z.S., Prior, P.F., and Burton, A.C., Central nervous system toxicity of interferon. Br. J. Cancer 47: 419-422 (1983)]. Furthermore, the full benefit of the cytokine may not be realized because the exogenous interferon concentration is determined strictly by timing of the doses and the dose administered. The role of naturally occurring interferon in MS is not understood.
  • EAE Experimental autoimmune encephalomyelitis
  • EAE in mice is often accompanied by demyelination in addition to the perivascular mononuclear cell infiltrates in the CNS.
  • perivascular mononuclear cell infiltrates are readily observed in EAE, but the lesions are not usually accompanied by demyelination.
  • the use of the animal models has significantly contributed to our understanding of some of the cellular events critical for initiating the disease. For example, a transient form of EAE can be transmitted between animals by transferring appropriately selected CD4 + T lymphocytes. This indicates a key role for the CD4 + T cells.
  • results from the animal models have shown that particular amino acid sequences from MBP and proteolipid protein (PLP), which are the major protein constituents of myelin, may be key antigenic determinants in initiation and/or progression of EAE.
  • PBP proteolipid protein
  • the importance of the immunoreactivity to these proteins has subsequently been confirmed in patients with MS.
  • the genetics associated with susceptibility to disease and the biochemical consequences of gene expression may be studied in considerably greater detail using animal models than may be carried out in human populations, especially by making use of a number of inbred strains of mice.
  • the origin of the macrophage-like cells appears to be a combination of cells from the periphery and differentiated microglial cells [Huitinga, I., Ruuls, S.R., Jung, S., Van Rooijen, N., Hartung, H.-P., and Dijkstra, CD., Macrophages in T Cell Line-Mediated, Demyelinating, and Chronic Relapsing
  • Suppressor cells also appear to play an important role in progression and control of EAE [Sun, D., Qin, Y., Chluba, J., Epplen, J.T., and Wekerle, H., Suppression of Experimentally Induced Autoimmune Encephalomyelitis by Cytolytic T-T Cell Interactions. Nature 332: 843-845 (1988)], although the particular type of cell involved in the suppression activity is only beginning to emerge [Fabry, Z., Raine, C.S., and Hart, M.N., Nervous tissue as an immune compartment: the dialect of the immune response in the CNS. Immunol. Today 15: 218-224 (1994)].
  • This invention relates to the use of 6-aryl pyrimidine compounds for the treatment of multiple sclerosis (MS).
  • the present invention a method of treating multiple sclerosis (MS) comprising the systemic administration of an effective amount of a compound represented by the formula
  • Xg is equal to X, X 4 or X 5 wherein X 4 is fluoro, chloro, bromo or iodo, and X 5 is mono-, di or trihalomethyl, mono, di or trifluoroethyl, perfluoropropyl, and wherein X is alkyl of from 1 to 3 carbon atoms, inclusive, including isomeric forms, 2 propynyl and 2-propenyl, and X ⁇ is a member selected from the group consisting of
  • R, R ⁇ , R2, R3, R4 is not hydrogen and wherein R or R4 is alkyl of from 1 to 8 carbon atoms, inclusive, including isomeric forms, alkoxy of from 1 to 8 carbon atoms, inclusive, including isomeric forms, fluoro, chloro, bromo, iodo or nitro; R- ⁇ or Rg is fluoro, chloro, bromo, iodo, nitro; trifluoromethyl or alkoxy of from 1 to 8 carbon atoms, inclusive, including isomeric forms, alkoxyethyloxy wherein alkoxy is from 1 to 5 carbon atoms, inclusive, including isomeric forms, or
  • Rg and Rg are the same or different and are alkyl of from 1 to 8 carbon atoms, inclusive, including isomeric forms, benzyl, or taken together with -N> are a saturated cycloalkylamino group
  • n' is 3, 4, 5 or 6 or dialkyl substituted cycloalkylamino wherein each alkyl is from 1 to 3 carbon atoms, inclusive; including isomeric forms, and R2 is chloro, fluoro, bromo, iodo, or alkyl of from 1 to 3 carbon atoms, inclusive;
  • R, R ⁇ , R 2 , 3 and R 4 are not hydrogen and are the same or different and are fluoro, chloro, bromo, iodo, alkyl of from 1 to 8 carbon atoms, inclusive,including isomeric forms, alkoxy of from 1 to 8 carbon atoms, inclusive, including isomeric forms, nitro and trifluoromethyl;
  • R 7 is substituted in either ring and is hydrogen, alkyl of from 1 to 8 carbon atoms, inclusive, including isomeric forms, alkoxy of from 1 to 8 carbon atoms, inclusive, including isomeric forms, fluoro, chloro, iodo, bromo or nitro- provided that when Xg is X, X ⁇ is not ⁇ -napthyl; (f) 2-furyl,
  • Preferred compounds are: 2-amino-5-iodo-6-(3-bromophenyl)-4-pyrimidinol; 2-amino-5-bromo-6-(3-fluorophenyl)-4-pyrimidinol; 2-amino-5-bromo-6-(3-ethoxyethylphenyl)-4-pyrimidinol; 2-amino-5-bromo-6-(2-methoxyphenyl)-4-pyrimidinol; 2-amino-5-chloro-6-(2-methoxyphenyl)-4-pyrimidinol; 2-amino-5-iodo-6-(2-methoxyphenyl)-4-pyrimidinol;
  • Bropirimine (2-amino-5-bromo-6-phenyl-4(lH)-pyrimidinone; ABPP) is particularly preferred and exists as an odorless white crystalline powder which melts with decomposition near 270 C.
  • Bropirimine exists in several crystal forms comprising two general classes. One form, the hydroscopic, can undergo transition to at least two other polymorphic crystal forms; the other is a nonhydroscopic form stable to polymorphic transition. At 100% relative humidity, the hydroscopic form of bropirimine gains about 6.3% water, which is equivalent to the amount of water required to form a monohydrate. The nonhydroscopic drug does not show similar behavior and is preferred.
  • 6-aryl pyrimidine compounds used in the present invention can be prepared by the general procedure(s) disclosed therein.
  • the hydroscopic crystal form of bropirimine can be synthesized by treating 2- amino-6-phenyl-4(3H)-pyrimidine with bromine in acetic acid. The material is filtered from the mixture and dissolved in aqueous base. The material is reprecipitated by neutralization with acetic acid, filtered, washed with water, and dried.
  • the non-hydroscopic crystal form of bropirimine can be obtained by heating an aqueous suspension of the hydroscopic crystal form above 70° C. The material is filtered, washed with water, and dried.
  • Part A A mixture of guanidine carbonate, (39.4 g) n-butyl alcohol, and ethyl benzoylacetate (60 g) is reacted at or above 90°C The reaction is monitored by HPLC until the reaction is judged to be complete. The mixture is cooled and then acetic acid is added to pH 5.8-8.0 to complete the crystallization. The slurry is cooled further (0-5°C) and then the slurry is filtered. The cake is washed with n- butyl alcohol, and then with water. The cake of 2-amino-6-phenyl-4(3H)-pyrimidine may or may not be dried.
  • Part B Liquid bromine (about 41.6 g) is added slowly to a slurry of 2-amino- 6-phenyl-4(3H)-pyrimidine (about 45.0 g on a dry basis) in acetic acid (273.7 ml) and water (273.0 ml) until the reaction is judged to be complete by HPLC. The reaction is quenched with the addition of 50% sodium hydroxide (36.2 g). The reaction mixture is heated to 75-90°C for 1 or more hours. The slurry is cooled and filtered. The cake is washed with water and dried to yield the nonhydroscopic crystal form of bropirimine.
  • the mode of administration of the compounds of Formula I can be by the means disclosed in US Patent 5,434,157, preferably orally.
  • the dosage administered will be dependent upon the condition of the patient, its age, health, weight, kind of concurrent treatment, if any, frequency of treatment, therapeutic ratio, and tolerance.
  • the timing of drug administration can be important in maintenance of activity in the treatment of multiple sclerosis.
  • dosage levels of the administered compounds of Formula I can be intravenous, 0.1 to about 50 mg/kg.; subcutaneous, 0.1 to about 150 mg./kg.; intramuscular, 0.1 to about 150 mg/kg.; and about 0.1 to about 400 mg/kg orally, preferably 15 to about 150 mg/kg of animal (body) weight.
  • the active ingredients to be employed in the treatment of MS can be easily prepared in unit dosage form with the employment of pharmaceutical materials as disclosed in US Patent 5,434,157.
  • the active ingredients are administered, in divided doses, of about 50 to about 1,000 mg kg/week of human body weight.
  • a preferred oral dosage regimen of the present invention is the administration of three grams per day (divided over a six hour period) for three consecutive days per week, e.g. one gram of the active ingredient (preferably presented in unit dosage form) every two hours for three doses on days 1, 2 and 3 of each week for about three to about twelve months, or longer.
  • An alternative preferred oral dosage regimen is the administration of three grams of the active ingredient (preferably presented in unit dosage form) per day (divided over a six hour period) every other day for up to about one year, or longer.
  • Bropirimine which is representative of the compounds of Formula I, has been evaluated in an EAE model (Procedure A) and representative results shown in Figures 1-3.
  • Figure 1 Effect of ABPP on EAE in mice. Mice were dosed with 250 milligrams per kilogram (mpk) on the days indicated by arrows. Two priming doses were administered on consecutive days, and only these doses were given intraperitoneally (i.p.) into mice. Subsequent doses, all were administered orally via a gavage tube followed at 3 or 4 day intervals to result in a twice-a-week dosing regimen. The mean scores for 40 mice in each group were statistically significantly less in ABPP treated mice beginning at day 11 and continued through day 29, that is 7 days after dosing was stopped during the first dosing interval. No significant decline in disease scores was detected during the second dosing interval.
  • mpk milligrams per kilogram
  • Figure 2 Effect of two different doses of ABPP on EAE in mice. All doses of ABPP were administered orally using a gavage tube. Two priming doses on days 7 and 8 were followed with doses given twice a week for a total of three weeks.
  • the mean disease in mice treated with 400 milligrams per kilogram (mpk) ABPP was statistically significantly less than in mice treated with vehicle alone or with 100 mpk.
  • the mean disease was statistically highly significantly lower for the group treated with 400 mpk beginning on approximately day 15 and continuing through day 37, i.e. approximately 1 week after dosing was stopped.
  • the mean disease for mice treated with 100 mpk ABPP was statistically significantly less than in the vehicle-treated group only on days 16 and 17.
  • Each group began with 65 mice per group, and 5 mice were removed at three times during the course of the experiment for histological evaluation of the lower spinal cords. Additionally, 5 mice from each group were processed for histology on days 43 and 56.
  • FIG. 3 Dose response for ABPP.
  • Two priming doses of ABPP were given via gavage intubation on days 6 and 7 after injection of MBP to initiate EAE. Dosing was continued at 3 day intervals through day 25. The days that doses were administered to the mice are indicated by arrows just above the abscissa on the graph. Approximately equivalent and statistically significant suppression of disease was observed beginning on day 6 for all 3 doses of ABPP used. After day 16, the degree of disease suppression was greatest in mice treated with 400 mpk ABPP, and the mice treated with 400 mpk had significantly less disease than the mice treated with either 100 mpk or 200 mpk. However, it was difficult to distinguish between the degree of effect of the lower two doses.
  • mice (Jackson Laboratories, Bar Harbor, Maine) are injected intramuscularly in a rear flank on day 0 with 150 ⁇ g of purified guinea pig myelin basic protein (MBP) in complete Freund's adjuvant supplemented with 2.5 mg/ml M. tuberculosis.
  • MBP myelin basic protein
  • B. pertussis vaccine (Michigan Dept. of Health) is injected subcutaneously at the base of the tail.
  • a second dose of B. pertussis is injected two days later, on day 3.
  • the first signs of disease are usually observed in a few mice beginning at day 6-7 and the mean day of disease onset is approximately day 10.
  • the mice are scored approximately 6 times per week for changes in motor activity according to the following scale:
  • Dosing for the test compound is via a gavage tube inserted into the stomach of a mouse, unless indicated otherwise.
  • the volume administered is 0.5 ml.
  • the vehicle used with bropirimine (ABPP) contained 5.26 mg carboxymethylcellulose, 4.0 mg polysorbate 80 NF, 9.0 mg sodium chloride, and 9.18 mg benzylalcohol NF.
  • mice are perfused with formalin to fix tissues in situ.
  • Eight vertebrae, thoracic 10-13 and lumbar 1-4, are removed from the carcass, further fixed in formalin, decalcified using a 2 x 4 hr incubation in formic acid, carefully separated into individual vertebra and placed in cassettes for paraffin embedding, sectioning, and staining with hematoxylin and eosin (H&E).
  • H&E hematoxylin and eosin
  • Five, 5 ⁇ m thick spinal cord cross sections are cut, each 100 microns apart, from each of the 8 vertebrae for a total of 40 cross sections per mouse.
  • the cross sections are scored for the presence and degree of infiltration. For an individual mouse, the results are presented as the proportion of cross sections with leukocyte infiltration, regardless of the degree of infiltration, or as the sum of the histological scores for all 40 cross sections. Histology samples were scored according to the following scale: Score
  • Murine interferon determinations are performed using a modification of the method published previously [Stringfellow, D.A., Vanderberg, H.C, Weed, S.D., Interferon induction by 5-halo-6-phenyl pyrimidinones. J. Interferon Res. 1:1-14 (1980)].
  • L929 (ATCC) cells are used at 90% confluence in 24 well plates. Samples for interferon determination are diluted into DMEM (Gibco) tissue culture medium containing 10% fetal bovine sera and antibiotics. Dilutions of samples are then added to wells of L929 cells and the cells became 100% confluent overnight.
  • DMEM Gibco
  • VSV vesicular stomatitis virus
  • Virus is allowed to adsorb to cells for one hour, and the wells are overlaid with 0.9% agarose prepared in tissue culture medium containing 2% sera. Cell cultures are incubated for 40-44 hrs, and VSV plaques are counted after 3 hrs of staining with neutral red. Included in each interferon assay are samples of interferon standards obtained from the NIAID Repository, NIH. The standards included murine alpha interferon
  • Figure 4 Interferon concentrations in peripheral blood in vehicle- and ABPP treated mice. Blood samples were collected on the days indicated and assessed for interferon concentration. Results shown correspond to the experiment shown in Figure 2.
  • Figure 5. Interferon concentrations in peripheral blood in vehicle- and ABPP treated mice. Blood samples were collected on the days indicated and assessed for interferon concentration. Results shown correspond to the experiment shown in Figure 3.

Abstract

L'invention concerne une méthode de traitement de la sclérose en plaques par administration systémique à un humain présentant des symptômes de sclérose en plaques, d'un composé de 6-aryl pyrimidine ou d'un sel de ce dernier acceptable du point de vue pharmaceutique, associé à un excipient pharmaceutique.
EP97953042A 1996-12-12 1997-12-03 Methode de traitement de la sclerose en plaques Withdrawn EP0948331A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US3264896P 1996-12-12 1996-12-12
US32648P 1996-12-12
PCT/US1997/021402 WO1998025596A2 (fr) 1996-12-12 1997-12-03 Methode de traitement de la sclerose en plaques

Publications (1)

Publication Number Publication Date
EP0948331A2 true EP0948331A2 (fr) 1999-10-13

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Application Number Title Priority Date Filing Date
EP97953042A Withdrawn EP0948331A2 (fr) 1996-12-12 1997-12-03 Methode de traitement de la sclerose en plaques

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EP (1) EP0948331A2 (fr)
JP (1) JP2001505911A (fr)
AU (1) AU5687198A (fr)
CA (1) CA2269681A1 (fr)
WO (1) WO1998025596A2 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1144390A2 (fr) * 1999-01-22 2001-10-17 Amgen Inc., Inhibiteurs de kinase
US6495558B1 (en) 1999-01-22 2002-12-17 Amgen Inc. Kinase inhibitors
WO2001068613A1 (fr) * 2000-03-17 2001-09-20 Nissan Chemical Industries, Ltd. Dérivés pyrimidinone et herbicides

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3008693A1 (de) * 1979-03-19 1980-10-02 Upjohn Co 6-aryl-pyrimidinverbindungen
US5434157A (en) * 1979-03-19 1995-07-18 The Upjohn Company 6-aryl pyrimidine compounds and method for treating viral infections and inducing interferon production
JPH09504010A (ja) * 1993-10-20 1997-04-22 ジ・アップジョン・カンパニー 抗関節炎剤および抗炎症剤としてのピリミジノン

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9825596A3 *

Also Published As

Publication number Publication date
CA2269681A1 (fr) 1998-06-18
JP2001505911A (ja) 2001-05-08
AU5687198A (en) 1998-07-03
WO1998025596A2 (fr) 1998-06-18
WO1998025596A3 (fr) 1998-08-13

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