MXPA97007673A - Ureido derivatives biologically active, effective in the treatment of multiple sclerosis - Google Patents
Ureido derivatives biologically active, effective in the treatment of multiple sclerosisInfo
- Publication number
- MXPA97007673A MXPA97007673A MXPA/A/1997/007673A MX9707673A MXPA97007673A MX PA97007673 A MXPA97007673 A MX PA97007673A MX 9707673 A MX9707673 A MX 9707673A MX PA97007673 A MXPA97007673 A MX PA97007673A
- Authority
- MX
- Mexico
- Prior art keywords
- methyl
- bis
- imino
- carbonyl
- carbonylimino
- Prior art date
Links
- 201000006417 multiple sclerosis Diseases 0.000 title claims abstract description 26
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 49
- 239000011780 sodium chloride Substances 0.000 claims abstract description 33
- 150000003839 salts Chemical class 0.000 claims abstract description 31
- 239000003814 drug Substances 0.000 claims abstract description 7
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- -1 carbonylimino Chemical group 0.000 claims description 178
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- FKORGLNGEASTQE-UHFFFAOYSA-N naphthalene-1,3-disulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC(S(O)(=O)=O)=C21 FKORGLNGEASTQE-UHFFFAOYSA-N 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 9
- FMHFHTQXVYDQRT-UHFFFAOYSA-N naphthalene-1,4,6-trisulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(S(O)(=O)=O)C2=CC(S(=O)(=O)O)=CC=C21 FMHFHTQXVYDQRT-UHFFFAOYSA-N 0.000 claims description 8
- HEWDOWUUTBCVJP-UHFFFAOYSA-N naphthalene-1,6-disulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 HEWDOWUUTBCVJP-UHFFFAOYSA-N 0.000 claims description 8
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 claims description 8
- XTEGVFVZDVNBPF-UHFFFAOYSA-N Armstrong's acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1S(O)(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-N 0.000 claims description 6
- NFWQRTJHAGRZDD-UHFFFAOYSA-L [Na+].[Na+].[O-]S(=O)(=O)c1ccc2ccccc2c1.[O-]S(=O)(=O)c1ccc2ccccc2c1 Chemical compound [Na+].[Na+].[O-]S(=O)(=O)c1ccc2ccccc2c1.[O-]S(=O)(=O)c1ccc2ccccc2c1 NFWQRTJHAGRZDD-UHFFFAOYSA-L 0.000 claims description 6
- ZPBSAMLXSQCSOX-UHFFFAOYSA-N naphthalene-1,3,6-trisulfonic acid Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=CC2=CC(S(=O)(=O)O)=CC=C21 ZPBSAMLXSQCSOX-UHFFFAOYSA-N 0.000 claims description 6
- FEWNRIKJXAQRJJ-UHFFFAOYSA-N naphthalene-1,3,7-trisulfonic acid Chemical compound C1=C(S(O)(=O)=O)C=C(S(O)(=O)=O)C2=CC(S(=O)(=O)O)=CC=C21 FEWNRIKJXAQRJJ-UHFFFAOYSA-N 0.000 claims description 6
- BBCBMZZXCBYNRL-UHFFFAOYSA-N naphthalene-1,6,7-trisulfonic acid Chemical compound C1=CC(S(O)(=O)=O)=C2C=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC2=C1 BBCBMZZXCBYNRL-UHFFFAOYSA-N 0.000 claims description 6
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 claims description 6
- NMYPVNCHTWFDNI-UHFFFAOYSA-L [Na+].[Na+].C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1.C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 Chemical compound [Na+].[Na+].C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1.C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 NMYPVNCHTWFDNI-UHFFFAOYSA-L 0.000 claims description 5
- FCLVESYQTSOUMH-UHFFFAOYSA-J [Na+].[Na+].[Na+].[Na+].[O-]S(=O)(=O)c1cccc2c(cccc12)S([O-])(=O)=O.[O-]S(=O)(=O)c1cccc2c(cccc12)S([O-])(=O)=O Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S(=O)(=O)c1cccc2c(cccc12)S([O-])(=O)=O.[O-]S(=O)(=O)c1cccc2c(cccc12)S([O-])(=O)=O FCLVESYQTSOUMH-UHFFFAOYSA-J 0.000 claims description 5
- INMHJULHWVWVFN-UHFFFAOYSA-N naphthalene-1,3,5-trisulfonic acid Chemical compound C1=CC=C(S(O)(=O)=O)C2=CC(S(=O)(=O)O)=CC(S(O)(=O)=O)=C21 INMHJULHWVWVFN-UHFFFAOYSA-N 0.000 claims description 5
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- HYFMZOAPNQAXHU-UHFFFAOYSA-N naphthalene-1,7-disulfonic acid Chemical compound C1=CC=C(S(O)(=O)=O)C2=CC(S(=O)(=O)O)=CC=C21 HYFMZOAPNQAXHU-UHFFFAOYSA-N 0.000 claims description 4
- FITZJYAVATZPMJ-UHFFFAOYSA-N naphthalene-2,6-disulfonic acid Chemical compound C1=C(S(O)(=O)=O)C=CC2=CC(S(=O)(=O)O)=CC=C21 FITZJYAVATZPMJ-UHFFFAOYSA-N 0.000 claims description 4
- VILFVXYKHXVYAB-UHFFFAOYSA-N naphthalene-2,7-disulfonic acid Chemical compound C1=CC(S(O)(=O)=O)=CC2=CC(S(=O)(=O)O)=CC=C21 VILFVXYKHXVYAB-UHFFFAOYSA-N 0.000 claims description 4
- 159000000001 potassium salts Chemical class 0.000 claims description 4
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- 102000003996 Interferon beta Human genes 0.000 claims description 3
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- 229960001388 Interferon-beta Drugs 0.000 claims description 3
- GCLGEJMYGQKIIW-UHFFFAOYSA-H Sodium hexametaphosphate Chemical compound [Na]OP1(=O)OP(=O)(O[Na])OP(=O)(O[Na])OP(=O)(O[Na])OP(=O)(O[Na])OP(=O)(O[Na])O1 GCLGEJMYGQKIIW-UHFFFAOYSA-H 0.000 claims description 3
- HYSBOMDYYIJYKS-UHFFFAOYSA-J [Na+].[Na+].[Na+].[Na+].[O-]S(=O)(=O)c1ccc2ccc(cc2c1)S([O-])(=O)=O.[O-]S(=O)(=O)c1ccc2ccc(cc2c1)S([O-])(=O)=O Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S(=O)(=O)c1ccc2ccc(cc2c1)S([O-])(=O)=O.[O-]S(=O)(=O)c1ccc2ccc(cc2c1)S([O-])(=O)=O HYSBOMDYYIJYKS-UHFFFAOYSA-J 0.000 claims description 3
- 150000003431 steroids Chemical class 0.000 claims description 3
- YKFJUBNDHOLBNN-UHFFFAOYSA-N naphthalene-2,3-disulfonic acid Chemical compound C1=CC=C2C=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC2=C1 YKFJUBNDHOLBNN-UHFFFAOYSA-N 0.000 claims description 2
- 239000002260 anti-inflammatory agent Substances 0.000 claims 2
- 229940121363 anti-inflammatory agents Drugs 0.000 claims 2
- 230000003247 decreasing Effects 0.000 claims 1
- 125000000542 sulfonic acid group Chemical group 0.000 abstract description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- 201000010099 disease Diseases 0.000 description 10
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
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- 241000124008 Mammalia Species 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
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- 238000001990 intravenous administration Methods 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- 210000001175 Cerebrospinal Fluid Anatomy 0.000 description 3
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- 235000010443 alginic acid Nutrition 0.000 description 2
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- 125000005843 halogen group Chemical group 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
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Abstract
Use, in the preparation of a medicament for use in the treatment of multiple sclerosis, of a compound which is a ureido derivative of the formula (I) wherein each m and n are the same, as an integer from 1 to 3; and each of the R groups, in which they are the same, is a naphthyl group substituted by 1 to 3 sulfonic acid groups, or a pharmaceutically acceptable salt thereof.
Description
ROOT DERIVATIVES BIOLOGICALLY ACTIVE, EFFECTIVE IN THE TREATMENT OF MULTIPLE SCLEROSIS.
The present invention relates to the use of substituted pyrrole ureido derivatives in the treatment of multiple sclerosis in mammals, including humans. Multiple sclerosis is a disease that destroys the myelin of the central nervous system and usually begins between 15 and 45 years. Myelin is a fatty substance that forms a coating around certain nerve fibers and conducts nerve impulses at a rate that allows the muscles to be able to perform precise and delicate movements. The disease is characterized by the hardening of the coating substance. This produces the formation of plates of different sizes and in different places which interferes with the impulses normally driven by the coating. The course of the disease can vary greatly in individual patients. The first stages of the disease in general are characterized by a phase of relapse and decrease, later the disease follows a chronic progressive course. However, the
REP: 25731
Disease usually produces a progressive deterioration of the control of muscle function with a final paralysis in many cases. The precise cause of multiple sclerosis is unknown and may be the result of a complex interaction of a number of different factors. Consequently, there is a need from a therapeutic point of view to find drugs that are active in the treatment of acute relapse and the progression of multiple sclerosis and / or that may reduce the symptoms or causes of multiple sclerosis. PCT / EP94 / 00268 and PCT / EP94 / 00984 describe the use of a selected class of poly-4-amino-2-carbonyl-1-methyl pyrrole compounds, mentioned in Patent PCT / EP91 / 00014, to prevent and / or treat the expansive metastasis of tumors and their use in the treatment of lentivirus infection, respectively. The present invention establishes the use of a compound that is a ureido derivative of the formula (I)
where
each m and n, which are equal, is an integer from 1 to 3; each of the R groups, which are the same, is a naphthyl group substituted by 1 to 3 sulfonic groups, or a pharmaceutically acceptable salt thereof; in the development of a drug to be used in the treatment of multiple sclerosis. Accordingly, the present invention prescribes the aforementioned use, in which the medicament is used to treat relapse, in particular acute relapse, and the development of multiple sclerosis and to diminish the clinical symptoms and causes of multiple sclerosis. Likewise, the present invention also describes a method for treating a mammal, including a human being, suffering from multiple sclerosis, which consists of administering to said mammal an effective amount of a compound as defined above. The substituted naphthyl group is preferably a naphthyl 5-, 6-, 7- or 8- group, commonly a naphthyl 7- or 8- group. When the naphthyl group is substituted by three sulfonic acid groups, the sulphonic acid substituents are preferably in the 1-, 3- and 5- or 1-, 3- and 6- position. When substituted by 2 acid groups the sulphonic acid substituents are preferably in positions 1-, and 3-, 5-
and 3-, and 5- or 3- and 6-. When it is substituted by an acid group, the sulfonic acid substituent is preferably in the 1-, 3- or 5- position. Likewise, the invention also includes within its scope all possible isomers and stereomers and their mixtures, as well as the metabolites and metabolic precursors or the bio-precursors of the compounds mentioned above. In accordance with the aforementioned, the invention also includes within its scope the pharmaceutically acceptable salts of the ureido derivatives of the formula (I). Examples of pharmaceutically acceptable salts are those with inorganic bases, such as sodium, potassium, calcium and aluminum hydroxides, or with organic bases, such as Usin, arginine, N-methyl-glucamine, triethylamine, triethanolamine, dibenzylamine, methylbenzylamine, di- (2-ethyl-hexyl) -amine, piperidine, N-ethylpiperidine, N, N-diethylaminoethylamine, N-ethylmorpholine, β-phenethyl-amine, N-benzyl-β-phenethylamine, N-benzyl-N, N-diethylamine and other acceptable organic amines. Sodium and potassium salts are preferred by the invention. As mentioned above, the present invention also includes within its scope bio-
pharmaceutically acceptable precursors (also known as pro-drugs) of the aforementioned compounds, ie compounds having a formula different from formula (I) above but which, however, when administered to humans are converted directly or indirectly in vivo in a ureido derivative of formula (I). Preferred compounds are those in which m and n in formula (I) are 2 each and each of the R groups are as defined above. Examples of specific preferred compounds are: 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-1-ene (N-methyl-4,2-pyrrole) carbonylimino)) bis (acid 3, 5-naphthalenedisulfonic); 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (3,6-naphthalenedisulfonic acid); 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,3,5-naphthalenetrisulfonic acid); 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,3,6-naphthalenetrisulfonic acid);
7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,3-naphthalenedisulfonic acid); 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2,4-naphthalenedisulfonic acid); 8, 8 '- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2,4-naphthalenedisulfonic acid); 8,8'- (carbonyl-bis (imino-N-methyl 1,4-, 2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,3,5-naphthalenetrisulfonic acid); 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (5-naphthalenesulfonic acid); 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,3-naphthalenedisulfonic acid); 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (3,5-naphthalenedisulfonic acid); 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,5-naphthalenedisulfonic acid);
8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (3-naphthalenesulfonic acid); 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1-naphthalenesulfonic acid); 2,2'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) is (1,5-naphthalenedisulfonic acid); 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,6-naphthalenedisulfonic acid); 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2,6-naphthalenedisulfonic acid); 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,5-naphthalenedisulfonic acid); 7,7 '- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2,5-naphthalenedisulfonic acid); 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2,3-naphthalenedisulfonic acid);
8,8'- (carbonyl-bis (imino-N-methyl 1,4-, 2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,6-naphthalenedisulfonic acid); 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2,6-naphthalenedisulfonic acid); 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2,5-naphthalenedisulfonic acid); 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (3,6-naphthalenedisulfonic acid);
8,8'- (carbonyl-bis (imino-N-methyl-1,4-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2,3,5-naphthalenetrisulfonic acid); 8,8'- (carbonyl-bis (imino-N-methyl 1,4-, 2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,4,6-naphthalenetrisulfonic acid); 8,8'- (carbonyl-bis (imino-N-methyl 1,4-, 2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2,4,6-naphthalenetrisulfonic acid); 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1-naphthalenesulfonic acid);
7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) is (2-naphthalenesulfonic acid); 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) is (3-naphthalenesulfonic acid); 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (4-naphthalenesulfonic acid); 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,4,6-naphthalenetrisulfonic acid); 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,3,6-naphthalenetrisulfonic acid); 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2,4,6-naphthalenetrisulfonic acid); 7, 7 '- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2,3,5-naphthalenetrisulfonic acid); 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-yl)) bis (1,3-naphthalenedisulfonic acid);
7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (acid 1,3-naphthalenedisulfonic acid) and the pharmaceutically acceptable salts thereof, in particular the sodium and potassium salts.
Pharmacology It was found that the ureido derivatives of formula (I) and their pharmaceutically acceptable salts thereof, hereinafter referred to as "the compounds of the invention" or "the active agents", are active in the treatment of multiple sclerosis in mammals, including humans. Said therapeutic activity of the compounds of the invention can be proved, for example, in the fact that they were found to be active in inhibiting the development of experimental allergic encephalomyelitis (EAE) in rats and mice. As is known, EAE is a disease that destroys the myelin of the central nervous system used as an experimental model of multiple sclerosis. According to the experimental system, female SJL mice (8-10 mice / group) were immunized with 200 μg of a purified Myelin Basic Protein (MBP) emulsion in Freund Incomplete Adjuvant administered intracutaneously at the base of the tail. One day of immunization and 48 hours
the mice were then injected intraperitoneally with 400 μg of pertussis toxin. Each group received the representative compound of the invention PNU 153429 or saline intravenously once a week for three consecutive times. Every day the signs of the disease were evaluated from the beginning, day 10-12, to day 21 according to the following scheme of clinical results: 0- there is no clinical disease; 1- weakness in the tail; 2- paraparesis (incomplete paralysis of one or two of its hind limbs); 3- paraplegia (complete paralysis of one or two of its hind limbs); 4- paraplegia with weakness in the front limbs or paralysis; 5- dying or dead animals.
As can be seen in Figure 1, PNU 153429 a dose of 50 mg / kg. completely avoided the development of EAE. Likewise, a significant reduction in the signs of the disease was obtained when PNU 153429 was administered at a dose of 25 mg / kg, as indicated in figure 2.
References for Figure 1 and 2:
f - - = PNU 153429 50 mg / kg i. v. ? = PNU 153429 25 mg / kg i. v. "X = saline
The dose of a compound of the invention administered to patients suffering from multiple sclerosis varies with the precise nature of the condition treated and the one receiving the treatment. For the compounds of the formula (I), for example the compound 2, 2 '- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2 pyrrole) carbonylimino)) is ( 1, 5-naphthalenedisulfonic acid) tetrasodium salt, internal code PNU 153429 (FCE 27266), the therapeutically effective dose is between 0.1-10 g per dose for adult humans. The appropriate dose can be administered in the form of a single dose or a series of separate doses by intervals of days, weeks, or months. Therefore, the compounds of the invention can be administered to patients suffering from recurrent-decreasing, recurrent-progressive and chronic progressive multiple sclerosis. In general, the compounds of the invention will be administered to the patient in the form of a formulation
pharmaceutical Said formulations preferably include, in addition to the active agent, a physiologically acceptable catalyst and / or diluent. Typical routes of administration are parenteral injections, including intrathecal, transdermal, intravenous, intramuscular, subcutaneous, and intraperitoneal, intravenous infusion, or oral administration. According to a preferred embodiment of the invention, it is preferred to administer the active agents employed in said invention directly to the central nervous system. However, the existence of a blood brain barrier limits the free passage of many types of blood molecules to the cells of the central nervous system. During the active phase of inflammatory diseases, such as multiple sclerosis, a number of blood brain lines are produced and will allow the entry of compounds of the invention into the central nervous system. However, there are several techniques that physically cross the blood brain barrier or surround it in order to allow the passage of therapeutic agents. Examples of these techniques include intrathecal injections, surgical implants, and osmotic techniques.
A preferred embodiment of the invention for the administration of the compounds of the invention is through intrathecal injection, that is, directly into the cerebrospinal fluid by puncturing the membranes surrounding the central nervous system. Usually, this puncture is done by lumbar puncture. The dose of agents can be maintained directly in the cerebrospinal fluid using pumps that are surgically implanted. Another preferred embodiment of the invention for the administration of the compounds thereof is by means of injection directly applied to the lumbar cerebrospinal fluid (intrathecally) or by means of intravenous injection. Suitable catalysts and diluents for liquid preparations include, but are not limited by, physiological saline, glucose, buffered saline, olive oil, ethyl oleate, glycols, e.g. Ex. Propylene glycol, and, if desired, a convenient amount of lidocaine hydrochloride. Solid oral forms, for example, tablets and capsules may contain, together with the active compound, diluents, for example, lactose, dextrose, sucrose, cellulose, corn starch and potato starch; lubricants, eg silica, talc, acid
stearic, magnesium or calcium stearate, and / or polyethylene glycol; binding agents, for example starches, gum arabic, gelatin, methylcellulose, carboxymethyl cellulose, polyvinylpyrrolidone; disintegration agents, for example starch, alginic acid, alginates, sodium starch glycolate; effervescent mixtures; colorants; sweeteners; wetting agents, for example, lecithin, polysorbate, lauryl sulfates; and in general, pharmacologically inactive and non-toxic substances used in pharmaceutical formulations. Said pharmaceutical preparations can be prepared in a known manner, for example, using mixing, granulating, tableting, sugar coating or film coating processes. The compounds of the invention can be employed in a method for treating multiple sclerosis comprising both separate administration and contemporaneous administration of a composition containing the compound of formula (I), or a pharmaceutically acceptable salt thereof, and a composition Pharmaceutical that contains another biologically active agent. The present invention also has as an object to establish products containing a compound of
the invention and another biologically active agent as a combined preparation to be used simultaneously, separately or sequentially in the treatment of multiple sclerosis. The other biologically active component can be another compound of formula (I) or steroids, for example hydrocortisomers such as methylprednisolone, anti-inflammatory or anti-immune drugs, such as methotrexate, azathioprine, cyclophosphamide or cyclosporin A, or interferon-β, or antibodies, such as anti-CD4 antibodies, or their respective mixtures. The compounds of the invention can be obtained according to Patent PCT / EP91 // 00014, for example by reacting a compound of the formula (II)
wherein n and R are as defined above, or a salt thereof, with a compound of the formula (III) X-CO-X (III) wherein each of the X groups, which may be the same or different, It is a good residual group, and if desired,
salifying a free compound of the formula (I) of a salt thereof. A salt of the compound of the formula (II) can be a salt with inorganic bases for example those mentioned above as pharmaceutically acceptable salts used in the invention. Sodium and potassium salts are preferred. Preferred examples of residual groups according to the meaning of X are halogen atoms, in particular chlorine, or other easily displaceable groups such as imidazolyl, p-nitrophenoxy, trichlorophenoxy or trichloromethyloxy. The reaction of a compound of formula (II), or a salt thereof, with a compound of formula (III) is an analogous process and can be carried out according to well-known methods; for example in accordance with the conditions described in organic chemistry for this type of reaction, ie for the synthesis of urea derivatives. Preferably, when in a compound of formula (III) x is a halogen atom, for example, chlorine, the reaction can be carried out at a molar ratio of the compound (II), or a salt thereof: the compound (III) between 1.1 and about 1.4. The reaction is preferably carried out in organic solvents such as dimethylsulfoxide, hexamethylphosphotriamine, dimethyl-
acetamide or, preferably dimethylformamide, or their aqueous mixtures, or in water / dioxane or water / toluene mixtures, in the presence of an organic base such as triethylamine or diisopropylethylamine, or an inorganic base such as sodium bicarbonate or sodium acetate. The reaction temperature can vary between about -10 ° C and about 50 ° C and the reaction time can be from about 1 to about 12 hours. The compounds of the invention prepared according to the detailed procedures can be purified by conventional methods such as through column chromatography on silica gel or alumina and / or by means of recrystallization from organic solvents such as aliphatic alcohols. minors or dimethylformamide. Similarly, the salification of a ureido derivative of the formula (I) can be carried out using methods known in the art, as well as the conversion of a salt of a ureido derivative of the formula (I) into a free product and the conversion of a ureido derivative of the formula (I) in a pharmaceutically acceptable salt thereof. The following examples illustrate the present invention.
Example 1 8,8'- (carbonyl-bis (imino-N-methyl 1,4-, 2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (3,5-naphthalenedisulfonic acid) tetrasodium salt. To a solution of 8- (amino-N-methyl-4,2-pyrrolcarboxynyl (N-methyl-4,2-pyrrole) carbonylimino)) (3,5-naphthalenedisulfonic acid disodium salt hydrochloride (1256 mg, 2mmols) in water and dioxane (20 ml), IN NaOH and sodium acetate (328 mg, 4 mmol) were added as it was stirred, cooled to 5 ° C with an ice bath, then a solution of bis (trichloromethyl) carbonate (149 mg, 0.5 mmol) in dioxane (15 ml) as drops in one hour The mixture was stirred for 2 hours at room temperature The solvents were evaporated in vacuo and column chromatography was performed silica gel with methylene chloride; methanol; water (300: 200: 20) as elution liquid, providing 856 mg of the title compound: N.M.R. (DMSO-dβ): d 3.85 (6H, s) ), 6.83 (lH, d, j-1.8), 7.06 (lH, d, J = 1.8), 7.26 (lH, d, J = l.8), 7.38 (lH, d, J = 1.8), 7.50 (lH, d, J = l. lH, d, J = l.8), 7.72 (lH, dd, J = 1.7, J = 8.9), 7.72 (lH, dd, J = l.7, J = 8.9), 7.98 (lH, d, J = 1.8), 8.25 (lH, bs), 9.19 (lH, d, J-1.7) 9.91 (lH, bs); 10.03 (lH, bs) U.V. (H20) nm:? max (E1% 1CM): 310 (431); 231 (1027)
F.A.B.M.S. m / z: 1209, M + + H; 640; 618; 614; 592. Proceeding in the same manner, the following compounds can be prepared:7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (3,5-naphthalenedisulfonic acid) tetrasodium salt
N.M.R. (DMSO-de): d 3.85 (3H, s); 3.90 (3Hs); 6.81
(lH, d, J = 1.8); 6.90 (lH, d, J = l.8); 7.12 (lH, d, J = l.8), 7.32 (lH, d, J = 1.8); 7.70 (lH, dd, J = l .6, J = 8.6); 7.8 (lH, dd, J = 8.6); 8.11 (lH, d, J = 1.6); 8.15 (lH, bs); 8.58 (lH, d, J = l .7); 10.05 (lH, bs); 10.94 (lH, bs)
U.V. (H20) nm:? max (E1 * ^): 321 (416); 231 (721) F.A.B.M.S. M / Z: 1209, M ++ H; 1187, M + -Ne + H. 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4, 2-pyrrole) carbonylimino)) bis (3,6-naphthalenedisulfonic acid) tetrasodium salt
N.M.R. (DMSO-d6): d 3.85 (3H, s); 3.93 (3Hs); 6.81
(lH, d, J- = 1.8); 6.91 (lH, d, J = l .8); 7.08 (lH, d, J = l .8); 7.51 (lH, d, J = 1.8); 7.68 (lH, dd, J = l.6, J = 8.6), 7.8 (lH, d, J = 8.6);
8. 04 (1H, S); 8.12 (lH, bs); 8.23 (lH, s); 8.89 (lH, s); 10.02
(lH, bs); 10.98 (lH, bs) F .A. B. M. S. m / z: 1209, M + + H; 1187, M + -Ne + H. OR . V. (H20) nm:? max (E1% 1CM): 323, 4 (540); 227, 7 (732)
7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,3,5-naphthalenetrisulfonic acid) hexodic salt N.M.R. (DMSO-de): d 3.85 (3H, s); 3.89 (3Hs); 6.78
(lH, d, J = 1.8); 7.08 (lH, d, J = l .8); 7.08 (lH, d, J = l .8); 7.22 lH, d, J = 1.8); 7.35 (lH, d, J = l .8); 8.25 (lH, d, J = l .9); 8.30 UH, bs); 8.36 (lH, bs); 9.00 (lH, bs): 9.07 (lH, d, J = l .6); 9.82 (lH, bs); 10,20 (lH, bs)
U.V. (H20) nm:? max (E1% 1CM): 320 (374); 254 (444)
8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4, 2-pyrrole) carbonylimino)) bis (1,3,6-naphthalenetrisulfonic acid) hexasodium salt N.M.R. (DMSO-d6): d 3.84 (3H, s); 3.88 (3Hs); 6.81 (lH, d, J = 1.8); 7.07 (1H, d, J = l .8); 7.11 (lH, d, J = l .8); 7.42
(lH, d, J = 1.8); 7.87 (lH, d, J = l.9); 8.87 (lH, d, J = l.9); 8.06
(lH, d, J = 1.9); 8.12 (lH, bs); 8.33 (lH, d, J = l.9); 8.54
(lH, d, J = 1.9); 9.93 (lH, bs); 12.19 (lH, bs)
U.V. (H20) nm:? max (E1% 1CM): 320 (374); 254 (444)
7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,3-naphthalenedisulfonic acid) tetrapotasium salt I.R. (KBr) cm_1: 3450 (b); 1650; 1580; 1530; 1190; 1030;
N.M.R. (DMSO-de): d 3.84 (3H, s); 3.87 (3H, s); 6.80 (lH, d);
7. 05 (lH, d); 7.18 (lH, d); 7.33 (lH, d); 7.86 (2H, m) 8.00
(lH, d); 8.16 (lH, bs); 8.21 (lH, d); 8.95 (lH, bs); 9.86
(lH, bs); 10.21 (lH, bs) F.A.B. M.J. m / z: 1273, (M + + H); 1311 (M ++ K) U.V. (H20) nm :? max (E? cm): 316.8, (371); 248.95 (444) 7.7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4, 2-pyrrole) carbonylimino)) bis (2,4-naphthalenedisulfonic acid) tetrasodium salt
N.M.R. (DMSO-d6): d 3.85 (3H, s); 3.89 (3Hs); 6.81 (lH, d, J = 1.7); 7.06 (lH, d, J = l .7); 7.22 (lH, d, J = l .7); 7.33 (lH, d, J = 1.7); 7.33 (1H, d, J = l .7); 7.38 (1H, dd, J = 2.0, J = 9.5); 7.92 (lH, bs); 8.10 (lH, d, J = 1.7); 8.32 (lH, d, J = 2.0); 8.69 (lH, d, J = 9.4); 9.88 (lH, bs); 10.08 (lH, bs)
8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4, 2-pyrrole) carbonylimino)) bis (2,4-naphthalenedisulfonic acid) tetrasodium salt
N.M.R. '(DMSO-d6): d 3.85 (3H, s); 3.81 (lH, d, J = 1.7 Hz); 7.06 (lH, d, J = 1 + Hz); 7.25 (lH, d, J = 1.7 Hz); 7.34 (lH, d, J = 1.7 Hz); 7.4, 7.6 (2H, m); 8.14 (lH, bs); 8.25 (2H, s); 8.73 (lH, dd, J = 13 Hz, J = 8.3 Hz); 9.92 (lH, bs); .10.07 (lH, bs)
U.V. (H20) nm:? max (E1% 1CM): 307 (435); 231 (932)
F.A.B.M.S. m / z: 1231, (M + + Na); 1128, M + -S03.
8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,3,5-naphthalenetrisulfonic acid) hexasodium salt. GO. (KBr) cm'1: 3440B, 1640, 1590, 1190, 1030
N.M.R. (DMSO-d6): d 3.80 (3H, s); 3.83 (3H, s); 6.80 (lH, d); 7.06 (2H, m); 7.40 (lH, d); 7.88 (lH, d); 7.99 (lH, d); 8.02 (lH, bs); 8.57 (lH, d); 9.3 (lH, d); 9.91 (lH, bs); 12.29 (lH, bs)
8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (5-naphthalenesulfonic acid) disodium saltN.M.R. (DMSO-d6): d 3.85 (6H, s); 6.84 (lH, d, J = l .8); 7.05 (lH, d, J = 1.8); 7.46-7.56 (3H, m); 7.92-8.00 (2H, m); 8.15 (lH, bs); 8.87 (lH, m); 9.89 (lH, bs); 10.03 (lH, bs)
U.V. (H¿0) nm:? max (E1% 1CM): 310 (531); 227 (1043) F.A.B.M.S. M / Z: 1005, (M ++ H); 1027, (M + -Na); 512
8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,3-naphthalenedisulfonic acid) tetrasodium salt N.M.R. (DMSO-de): d 3.84 (3H, s); 3.86 (3H, s); 6.81 (lH, d, J = 1.8); 7.08 (2H, bs); 7.41 (lH, d, J = l .8); 7.50
(lH, t, J = 7.0); 7.78 (1H, d, J = 7. O); 8.02 (1H, d, J = 7.0); 8.11 (2H, m); 8.53 (1H, d, J = 2.02); 9.93 (lH, bs); 12.21 (lH, bs)
U.V. (H20) nm:? max (E1% 1CM): 309.05 (403); 229.65 (735) F.A.B.M.S. m / z: 1209 M ++ H; 1231, M ++ Na; 1187, M + -Na + H; 1129;: 640; 618; 614; 592
2,2 '- (carbonyl-bis (imino-N-methyl 1,4-, 2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,5-naphthalenedisulfonic acid) tetrasodium salt N.M.R. (DMS0-d6): d 3.85 (3H, s); 3.91 (3Hs); 6.90
(lH, d, J = 1.8); 6.98 (lH, d, J = l .8); 7.09 (lH, d, J = l .8); 7.35 (lH, dd, J = 7, J = 8.8); 7.47 (lH, d, J = l.8); 7.9 (lH, d, J = 7); 9.15 (lH, bs); 8.67-8.82 (2H, dd, J = 9.6); 8.99 (lH, d, J = 8.8); 9.98 (lH, bs); 12.64 (lH, bs)
F.A.B.M.S. m / z: 1207 [M-H] ~; 1185, [M-23] "; 1105 (M-S03Na) ~.
U.V. (H20) nm:? max 298 (E1 \ CM) 522
8,8'- (c-arbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4, 2-pyrrole) carbonylimino)) bis (1,5-naphthalenedisulfonic acid) tetrasodium salt I.R. (KBr) crrf1: 3440 b, 1660, 1640, 1585, 1180, 1030
N.M.R. (DMS0-d6): d 3.84 (3H, s); 3.85 (3H, s); 6.80
(lH, d); 7.07 (2H, m); 7.41 (2H, m); 7.92 (2H, dd); 8.12 (1.12
(lH, s); 8.27 (lH, dd); 9.07 (lH, dd); 9.90 (lH, bs); 12.27 (lH, bs)
U.V. (H20) nm:? max (E1% 1CM): 316 (331); 229 (478)
F.A.B.M.S. m / z: 1209, M ++ 1; 1231, M ++ 23; 1128; M-80
8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (3-naphthalenesulfonic acid) disodium salt I.R. (KBr) cpf1: 3430 b, 1640, 1585, 1200, 1030
N.M.R. (DMSO-de): d 3.84 (6H, s); 6.86 (lH, d); 7.05 (lH, d);
7. 24 (lH, d); 7.35 (lH, d); 7.54 (2H, m); 7.70 (lH, dd); 7.90 (2H, m); 8.15 (lH, d); 8.15 (lH, d); 8.95 (lH, bs); 9.94
(lH, bs); 10.03 (lH, bs)
U.V. (H20) nm:? max (E1% 1CM): 304 (366); 226 (1002) F.A.B.M.S. m / z: 1005, M + + H; 1027, M + -2Na.
8,8'- (carbonyl-bis (imino-N-methyl-1,4-pyrrolcarbonylimino (N-methyl-4, 2-pyrrole) carbonylimino)) bis (3-naphthalenesulfonic acid) disodium salt I.R. (KBr) cpf1: 3430 b, 1640, 1585, 1200, 1030
N.M.R. (DMSO-de): d 3.84 (6H, s); 6.86 (lH, d); 7.05 (lH, d); 7.24 (lH, d); 7.35 (lH, d); 7.54 (2H, m); 7.70 (lH, dd); 7.90 (2H, m); 8.15 (lH, d); 8.15 (lH, d); 8.95 (lH, bs); 9.94 (lH, bs); 10.03 (lH, bs)
U .V. (H20) nm:? max (E1% 1CM): 304 (366); 226 (1002) F. A. B .M. S. m / z: 1005, M + + H; 1027, M ++ 2Na.
8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1-naphthalenesulfonic acid) disodium salt N.M.R. (DMSO-de): d 3.84 (3H, s); 3.85 (3H, s); 6.82 (lH, d J = 1.8); 7.06 (lH, d, J = 1.8); 7.09 (lH, d, J = 1.8); 7.39-7.54 (3H, m); 7.74 (lH, dd, J = 1.3, J = 1.3, J = 8.2); 7.93-8.02 (2H, m); 8.13 (lH, bs); 8.26 (lH, d); 8.95 (lH, dd, J = 1.5, J = 7.3); 9.93 (lH, bs); 10.20 (lH, bs) F.A.B.M.S. m / z: 1005, M + + H; 1027, M + + Na. U.V. (H20) nm:? max (E1% 1CM): 312 (490); 224 (831) 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,6-naphthalenedisulfonic acid) tetrasodium salt; 7.7'-. { carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2,6-naphthalenedisulfonic acid) tetrasodium salt; 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,5-naphthalenedisulfonic acid) tetrasodium salt; 7,7'- (carbonyl-bis (imino-N-methyl 1,4-, 2-pyrrolcarbonylimino (N-methyl-4, 2-pyrrole) carbonylimino)) bis (2,5-naphthalenedisulfonic acid) tetrasodium salt; 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2,3-naphthalenedisulfonic acid) tetrasodium salt;
8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4, 2-pyrrole) carbonylimino)) bis (1,6-naphthalenedisulfonic acid) tetrasodium salt; 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2,6-naphthalenedisulfonic acid) tetrasodium salt; 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2,5-naphthalenedisulfonic acid) tetrasodium salt; 8, 8 '- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4, 2-pyrrole) carbonylimino)) bis (3,6-naphthalenedisulfonic acid) tetrasodium salt; 8,8'- (carbonyl-bis (imino-N-methyl-1,4-pyrrolcarbonylimino (N-methyl-4, 2-pyrrole) carbonylimino)) bis (2,3-naphthalenetrisulfonic acid) hexasodium salt; 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,4-, 6-naphthalenetrisulfonic acid) hexasodium salt; 7,7'- (carbonyl-bis (imino-N-me-il-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1-naphthalenesulfonic acid) disodium salt; 1, 1 '- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2-naphthalenesulfonic acid) disodium salt; 7.7'- (carbonyl-bis (imino-N-methyl-4, 2-
pyrrolcarbonylimino (N-methyl-4, 2-pyrrole) carbonylimino)) bis (3-naphthalenesulfonic acid) disodium salt; 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (4-naphthalenesulfonic acid) disodium salt; 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,4-, 6-naphthalenetrisulfonic acid) hexosodium salt; 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,3,6-naphthalenetrisulfonic acid) hexosodium salt; 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2,4,6-naphthalenetrisulfonic acid) hexosodium salt; and 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2,3,5-naphthalenetrisulfonic acid) hexosodium salt;
Example 2 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (3,5-naphthalenedisulfonic acid) Chromatography is performed of a solution
8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino)
(N-methyl-4, 2-pyrrole) carbonylimino)) bis (3,5-naphthalenedisulfonic acid) tetrasodium salt (400 mg) in water (10 ml), on a column Amberlite IR-120 (H) (20 ml) , with water as the eluent liquid. The solution is evaporated by dryness in vacuo, obtaining 0.3 g of the title compound. By proceeding in the same manner, the following compounds can be obtained: 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino)) bis (1,3-naphthalenedisulfonic acid) tetra-potassium salt XH- NMR (200 MHz, DMSO): d 3.86 (S, 3h); 6.98, 7.15 (two-d, J = 1.9 Hz, 2H); 7.87 (m, 2H); 8.00 (d, J = 1.7 Hz, 1H); 8.17 (s, 1H); 8.22 (d, J = 1.7 Hz, lH); 8.90 (s, lH); 10.08 (s, lH) 7.7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4, 2-pyrrole) carbonylimino)) bis (acid, 3-naphthalenedisulfonic) salt tetrahydroxy 1H-NMR (200 MHz, DMSO): 3.84, 3.86, 3.88 (three-s, 9H), 6.80, (d, J = 1.7 Hz 1H); 7.05 (m, 2H); 7.20 (d, J = 1.6 Hz, 1H); 7.25 (d, J = 1.6 Hz, 1H); 7.34 (d, J = 1.6 Hz, 1H); 7.87 (m, 2H); 7.80 (d, J = 1.7 Hz, 1H); 8.95 (s, 1H); 9.85, 9.99, 10.23 (three-s, 3H).
Example 3 Intramuscular injection 40 mg / ml
An injectable pharmaceutical preparation can be made by dissolving 40 g 2,2 '- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4, 2-pyrrole) carbonylimino)) bis (acid, 4-pyrrolidone). -naphthalenedisulfonic) tetrapotassium salt in water for an injection (1000 ml) and hermetic ampoules of 1-10 ml.
It is noted that in relation to this date, the best method known by the Applicant to carry out the aforementioned invention, is that which is clear from the manufacture of the objects to which it refers. Having described the invention as above, it is claimed as property contained in the following
Claims (12)
1. Use of a compound that is a ureido derivative of the formula (I) characterized in that each m and n, which are equal, is an integer from 1 to 3; each of the R groups, which are the same, is a naphthyl group substituted by 1 to 3 sulfonic groups, or a pharmaceutically acceptable salt thereof; in the development of a medically to be used in the treatment of multiple sclerosis.
2. Use according to claim 1, characterized in that, in formula (I), m and n are 2 each.
3. Use according to claim 1, characterized in that the compound is selected from: 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl 1,4-2-pyrrole ) carbonylimino)) bis (3,5-naphthalenedisulfonic acid); 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (3,6-naphthalenedisulfonic acid); 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,3,5-naphthalenetrisulfonic acid); 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,3,6-naphthalenetrisulfonic acid); 7, 7 '- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,3-naphthalenedisulfonic acid); 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2,4-naphthalenedisulfonic acid); 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl 1,4-, 2-pyrrole) carbonylimino)) bis (2,4-naphthalenedisulfonic acid); 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,3,5-naphthalenetrisulfonic acid); 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (5-naphthalenesulfonic acid); 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,3-naphthalenedisulfonic acid); 8,8'- (carbonyl-bis (imino-N-methyl 1,4-, 2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (3,5-naphthalenedisulfonic acid); 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,5-naphthalenedisulfonic acid); 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (3-naphthalenesulfonic acid); 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1-naphthalenesulfonic acid); 2,2'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) is (1,5-naphthalenedisulfonic acid); 7,7 '- (carbonyl-bis (imino-N-methyl 1,4-, 2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole), carbonylimino)) bis (1,6-naphthalenedisulfonic acid); 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2,6-naphthalenedisulfonic acid); 7,7'- (carbonyl-bis (imino-N-methyl-4 2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino) bis (1,5-naphthalenedisulfonic acid); (carbonyl-bis (imino-N-methyl-4 2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrol) carbonylimino) bis (2,5-naphthalenedisulfonic acid); 7,7'- (carbonyl-bis ( imino-N-methyl-4 2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino) bis (2,3-naphthalenedisulfonic acid); 8,8'- (carbonyl-bis (imino-N-methyl) -4-pyrrolcarbonyl-imino (N-methyl-4, 2-pyrrol) carbonylimino) bis (1,6-naphthalenedisulfonic acid); 8,8'- (carbonyl-bis (imino-N-methyl-4 2-pyrrolcarbonyl -imino (N-methyl-4, 2-pyrrol) carbonylimino) bis (2,6-naphthalenedisulfonic acid); 8,8'- (carbonyl-bis (imino-N-methyl-4 2-pyrrolcarbonyl-imino (N- methyl-4, 2-pyrrole) carbonylimino) bis (2,5-naphthalenedisulfonic acid); 8,8'- (carbonyl-bis (imino-N-methyl-4 2-pyrrolcarbonyl-imino (N-methyl-4, 2 -pyrrole) carbonylimino) bis (3,6-naphthalenedisulfonic acid); 8,8'- (carbonyl-bis (imino-N-methyl- 4-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino) bis (2,3,5-naphthalenetrisulfonic acid); 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,4,6-naphthalenetrisulfonic acid); 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2,4,6-naphthalenetrisulfonic acid); 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1-naphthalenesulfonic acid); 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2-naphthalenesulfonic acid); 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (3-naphthalenesulfonic acid); 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (4-naphthalenesulfonic acid); 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,4,6-naphthalenetrisulfonic acid); 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,3,6-naphthalenetrisulfonic acid); 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2,4,6-naphthalenetrisulfonic acid); 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) is (2,3,5-naphthalenetrisulfonic acid); 1, 1 '- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino)) is (1,3-naphthalenedisulfonic acid); 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) is (acid 1,3-naphthalenedisulfonic acid) and the pharmaceutically acceptable salts thereof
4. Use according to claim 1, wherein the compound is the sodium or potassium salt of a ureido derivative of the formula (I). Use according to claim 1, wherein the medicament is for the treatment of relapse and progression of multiple sclerosis, or for decreasing the clinical symptoms and causes of multiple sclerosis 6. Products containing a compound as defined in claim 1, characterized in that another biologically active agent is used as a combined preparation in a simultaneous, separate or sequential in the treatment of patients suffering from multiple sclerosis. 7. Products according to claim 6, characterized in that the biologically active agent is a compound as defined in claim 1, a steroid, an anti-inflammatory agent, an anti-immune agent, interferon-beta, an antibody or a mixture of two or more of them. 8. A method for treating a patient suffering from multiple sclerosis, characterized in that it consists of administering to the patient an effective amount of the compound as defined in claim 1. 9. A method for treating a patient suffering from multiple sclerosis, characterized in that consists of administering to the patient an effective amount of the compound 2,2'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonyl-imino (N-methyl-4,2-pyrrole) carbonylimino)) is (acid 1, 5-naphthalenedisulfonic) tetrasodium salt, or a pharmaceutically acceptable salt thereof. 10. A method for treating a patient suffering from multiple sclerosis, characterized in that it consists of administering to the patient an effective amount of the compound selected from: 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,6-naphthalenedisulfonic acid) tetrasodium salt; 7,7'- (carbonyl-bis (imino-N-methyl-1,4-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2,6-naphthalenedisulfonic acid) tetrasodium salt; 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,5-naphthalenedisulfonic acid) tetrasodium salt; 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2,5-naphthalenedisulfonic acid) tetrasodium salt; 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2,3-naphthalenedisulfonic acid) tetrasodium salt; 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,6-naphthalenedisulfonic acid) tetrasodium salt; 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2,6-naphthalenedisulfonic acid) tetrasodium salt; 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2,5-naphthalenedisulfonic acid) tetrasodium salt; 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (3,6-naphthalenedisulfonic acid) tetrasodium salt; 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2, 3, 5-naphthalenetrisulfonic acid) hexasodium salt; 8,8'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,4-, 6-naphthalenetrisulfonic acid) hexasodium salt; 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1-naphthalenesulfonic acid) disodium salt; 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2-naphthalenesulfonic acid) disodium salt; 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (3-naphthalenesulfonic acid) disodium salt; 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (4-naphthalenesulfonic acid) disodium salt; 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,4-, 6-naphthalenetrisulfonic acid) hexosodium salt; 7,7'- (carbonyl-bis (imino-N-methyl-4, 2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (1,3,6-naphthalenetrisulfonic acid) hexosodium salt; 7,7'- (carbonyl-bis (imino-N-methyl-4, 2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2,4,6-naphthalenetrisulfonic acid) hexosodium salt; and 7,7'- (carbonyl-bis (imino-N-methyl-4,2-pyrrolcarbonylimino (N-methyl-4,2-pyrrole) carbonylimino)) bis (2,3,5-naphthalenetrisulfonic acid); and the pharmaceutically acceptable salts thereof. 11. A method for treating a patient suffering from multiple sclerosis, characterized in that it consists of administering to the patient, either separately or substantially simultaneously, a compound as defined in claim 1 and another biologically active agent. 12. A method according to claim 9, characterized in that the other biologically active agent is a compound as defined in claim 1, a steroid, an anti-inflammatory agent, an anti-immune agent ,. interferon-Beta, an antibody or a mixture of two or more thereof.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9602721.4 | 1996-02-09 | ||
| GBGB9602721.4A GB9602721D0 (en) | 1996-02-09 | 1996-02-09 | Biologically active ureido derivatives useful in the treatment of multiple sclerosis |
| PCT/EP1997/000412 WO1997028796A1 (en) | 1996-02-09 | 1997-01-24 | Biologically active ureido derivatives useful in the treatment of multiple sclerosis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| MX9707673A MX9707673A (en) | 1997-11-29 |
| MXPA97007673A true MXPA97007673A (en) | 1998-07-03 |
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