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
  • A61K31/66—Phosphorus compounds
  • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
• • 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
  • A61K31/66—Phosphorus compounds
  • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
• • 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
  • A61K31/66—Phosphorus compounds
  • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
  • A61P31/06—Antibacterial agents for tuberculosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/06—Phosphorus compounds without P—C bonds
  • C07F9/08—Esters of oxyacids of phosphorus
  • C07F9/09—Esters of phosphoric acids
  • C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
  • C07F9/32—Esters thereof
  • C07F9/3258—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
  • C07F9/3282—Esters with hydroxyaryl compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
  • C07F9/40—Esters thereof
  • C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
  • C07F9/4084—Esters with hydroxyaryl compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
  • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
  • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
  • C07F9/65842—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring
  • C07F9/65846—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring the phosphorus atom being part of a six-membered ring which may be condensed with another ring system

Definitions

• the present invention relates to new aromatic derivatives of oxyphosphorus acids that are active against mycobacteria including multiresistant strains.
• Tuberculosis is one of the world's most problematic infectious disease caused by strains of Mycobacterium tuberculosis that is spread by droplet infection. The disease has become a serious health problem worldwide. WHO classifies tuberculosis, after HIV, as the leading cause of global deaths caused by an infectious disease. In 2013, approximately 9.0 million people fell ill with TB and 1.5 million died due to the disease, 360 000 of whom were HIV- positive (Global tuberculosis report 2015).
• Alarming are primarily data on the growing number of multidrug-resistant form (MDR-TB) - resistant to isoniazid ( ⁇ ) and rifampicin and extensively resistant forms (XDR-TB) resistant additionally to any and at least one of three injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin).
• MDR-TB multidrug-resistant form
• XDR-TB rifampicin and extensively resistant forms
• Patients with XDR-TB are left with treatment options that are much less effective and often have worse treatment outcomes.
• XDR-TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system.
• Resistant TB treatment requires an extension of the period of 6-9 months to two years, a combination of high doses of anti-tuberculosis drugs of first and second line and hence enormous burden for the organism.
• Novel compounds based on substituted 2-(phenylcarbamoyl)phenyl phosphenite of general formula I show significant activity against Mycobacterium tuberculosis, atypical mycobacterial strains including pathogenic strains isolated from patients with a manifest form of infection.
• each R 1 , R 2 is independently H, halogen, or N0 2 ; each R 3 , R 4 is independently H, halogen, N0 2 , or CF 3 ; R 5 is H, halogen, or N0 2 ; R 6 is C 2 -Ci 6 alkyl, C 6 -C 18 aryl, C 6 -C 18 aryloxy, or C 6 - C 18 arylC 2 -C 16 alkyloxy; R 7 is Ce-Qgaryl, Q-Cigaryloxy, C 6 -Ci 8 arylC 2 -Ci 6 alkyloxy, or R 7 is missing; R 8 is H or single bond to phosphorus atom.
• R 6 is phenyl
• R 7 is missing and simultaneously R 8 is single bond to phosphorus atom
• at least one of the substituents R 1 , R 2 , R 3 , R 4 and R 5 is not hydrogen. From the point of view of the protection of new compounds it must be stressed that 2,3-diphenyl-3-hydrobenzo[e][l,3,2]oxazaphosphinin-4- one 2-oxide is not claimed.
• Another aspect of this invention is the use of the above mentioned compounds with the general formula I as antituberculotics and/or antimycobacterial drugs. Further aspect of this invention is a pharmaceutical composition containing compound of general formula I as the active ingredient.
• the prepared substituted salicylanilide was esterified with chlorides of appropriate oxyphosphorus acids according to Vinsova, J.; ozic J.; Kratky, M.; Stolafikova, J.; Mandikova, J.; Trejtnar, F.; Buchta, V. Salicylanilide diethyl phosphates: Synthesis, antimicrobial activity and cytotoxicity. Bioorg. Med Chem. 2014 22, 728-737 (Scheme 2).
• DIPEA N-ethyl-N,N-diisopropylamine
• DMAP 4-(diraethylamino)pyridine
• MeCN - acetonitrile
• R aryl, arylalkyl.
• aromatic esters of phosphorus-based acids are generally hydrolytically more stable than esters derived from aliphatic oxyphosphorus acids (Kirby, A. J.; Medeiros, .; Oliveira, P. S. M.; Orth, E.
• Heterocyclic 3-phenyl-3- hydrobenzo[e][l,3,2]oxazaphosphinin-4-one 2-oxides represent a new structural type of compounds having antimycobacterial activity.
• the prepared compounds corresponding to general formula I were evaluated in Regional Institute of Public Health, Ostrava (Department for Diagnostic of Mycobacteria, Partyzanske namesti 7, 702 00 Ostrava) in in vitro conditions in Sula's semisynthetic liquid medium (SEVAC, Moscow) and the niinimum inhibitory concentrations (MIC) were detennined.
• the antimycobacterial activity was tested against Czech National Collection strains Mycobacterium tuberculosis CNCTC (Czech National Collection of Type Cultures) 331/88 (H37R.V), CNCTC nontuberculous mycobacteria: Mycobacterium avium 330/88 and Mycobacterium kansasii 235/80 and a clinically isolated strain of M. kansasii 6509/96.
• the first-line anti-tuberculosis drug isoniazid ( ⁇ ) was used as a standard in each assay. The results are summarized in Table 1.
• MDR strains of M. tuberculosis multidrug-resistant strains
• Ostrava Department for Diagnostic of Mycobacteria, Partyzanske namesti 7, 702 00 Ostrava: 7357/1998, 9449/2007, 234/2005, Praha 1, Praha 4 and Praha 131.
• the resistance and susceptibility profiles of these strains to clinically used antituberculotic and antibiotic drugs are reported in Table 2. Isoniazid ( ⁇ ) was used as a standard in each assay.
• the subject matter of this invention comprises new structural types of salicylanilide derivatives with oxyphosphorus acids of general formula I, both esters and cyclic analogues, e.g., 3-phenyl-3-hydrobenzo[e][l,3,2]oxazaphosphinin-4-one 2-oxides, their antimycobacterial activity and a pharmaceutical preparation containing compound of the general formula I as the active ingredient.
• esters and cyclic analogues e.g., 3-phenyl-3-hydrobenzo[e][l,3,2]oxazaphosphinin-4-one 2-oxides, their antimycobacterial activity and a pharmaceutical preparation containing compound of the general formula I as the active ingredient.
• Compound 1 was prepared by reaction of salicylanilide (2-hydroxy-N-phenylbenzamide; 0.001 mol), which was suspended in 7 mL of dichloromethane, then triethylamine (Et 3 N, 0.0015 mol) was added in one portion, followed by diphenyl phosphoryl chloride (0.0015 mol) after 5 minutes of stirring at room temperature. The reaction was monitored on TLC until complete consumption of starting material. After 1 h, the reaction mixture was evaporated till dryness and the residue was suspended in ethyl acetate (EtOAc). The insoluble portion was filtered off and the filtrate was evaporated till dryness. The crystallization was performed from the EtO Ac hexane as well as the re-crystallization.
• Compound 5 was obtained using the above mentioned synthetic procedure (Example 1) from 5-chloro-N ⁇ -(3,4-dichlorophenyl)-2-hydroxybenzamide instead of 2-hydroxy-JV- phenylbenzamide .
• Compound 6 was obtained using the above mentioned synthetic procedure (Example 1) from 5-bromo-2-hydroxy-N-[4-(1xifluoromemyl)phenyl]ben2arnide instead of 2-hydroxy-JV- phenylbenzamide.
• Compound 13 was obtained using the above mentioned synthetic procedure (Example 1) from diphenylphosphinic chloride instead of diphenyl phosphoryl chloride. The crystallization and re-crystallization was performed from acetone instead of EtO Ac.
• Compound 14 was obtained using the above mentioned synthetic procedure (Example 1) from diphenylphosphinic chloride instead of diphenyl phosphoryl chloride and from 5-chloro-iV-(4- chlorophenyl)-2-hydroxybenzamide instead of 2-hydroxy-N-phenylbenzamide.
• the crystallization and re-crystallization was performed from acetone instead of EtOAc.
• Compound 15 was obtained using the above mentioned synthetic procedure (Example 1) from diphenylphosphinic chloride instead of diphenyl phosphoryl chloride and from N-(4- bromophenyl)-5-chloro-2-hydroxybenzamide instead of 2-hydroxy-N-phenylbenzamide.
• the crystallization and re-crystallization was performed from acetone instead of EtOAc.
• CisHigBrClNOsP Molecular weight 526.75. Yield: 98 %.
• Compound 16 was obtained using the above mentioned synthetic procedure (Example 1) from diphenylphosphinic chloride instead of diphenyl phosphoryl chloride and from 5-chloro-2- hy lroxy-N-[4-(trifluoromethyl)phenyl]benzamide instead of 2-hydroxy-N-phenylbenzamide.
• the crystallization and re-crystallization was performed from acetone instead of EtOAc.
• Compound 17 was obtained using the above mentioned synthetic procedure (Example 1) from diphenylphosphinic chloride instead of diphenyl phosphoryl chloride and from 5-chloro-JV- (3 s 4-dichlorophenyl)-2-hydroxybenzarnide instead of 2-hydroxy-N-phenylbenzamide. The crystallization and re- crystallization was performed from acetone instead of EtOAc.
• Compound 18 was obtained using the above mentioned synthetic procedure (Example 1) from diphenylphosphinic chloride instead of diphenyl phosphoryl chloride and from 5-bromo-2- hydroxy-N-[4-(trifluoromethyl)phenyl]ben2amide instead of 2-hydroxy-N-phenylbenzamide.
• the crystallization and re-crystallization was performed from acetone instead of EtOAc.
• Compound 20 was obtained using the above mentioned synthetic procedure (Example 19) from 5-chloro-N-(4-chlorophenyl)-2-hydroxybenzamide instead of 2-hydroxy-N- phenylbenzamide.
• Compound 21 was obtained using the above mentioned synthetic procedure (Example 19) from N-(4-bromophenyl)-5-cWoro-2-hychoxybenzamide instead of 2-hydroxy-N- phenylbenzamide.
• the crystallization was performed from the EtOAc.
• the resulting crystals were washed with 2 x 5 mL of cold water and 2 x 5 mL of hexane and dried. If necessary, the re-crystallization was performed from EtOAc.
• Ci 9 H 14 N0 3 P Molecular weight 335.30. Yield: 77 %.
• Compound 24 was obtained using the above mentioned synthetic procedure (Example 22) from 5-cMoro-2-hydroxy-N-[4-(trifluoromethyl)phenyl]benzamide instead of 2-hydroxy-iV- phenylbenzamide .
• Compound 25 was obtained using the above mentioned synthetic procedure (Example 22) from 5-chloro-N-(3,4-dichlorophenyl)-2-hydroxybenzamide instead of 2-hydroxy-N- phenylbenzamide.
• Compound 27 was obtained from 5-crUoro-N-(3,5-diclilorophenyl)-2-hydroxybenzarnide (0.001 mol), which was suspended in 7 mL of dichloromethane and then triethylamine (0.004 mol) was added in one portion. After 5 minutes of vigorous stirring, phenylphosphonic dichloride (0.0013 mol) was added in one portion. The reaction mixture was stirred for 12 hours at room temperature, then it was evaporated till dryness and the residue was suspended in 20 mL of ethyl acetate.
• Example 28 7-Chloro-3-(3 -chlorophenyl)-2-ethyl-3 -hydrobenzo [e] [ 1 ,3 ,2]oxazaphosphinin-4-
• Compound 28 was obtained using the above mentioned synthetic procedure (Example 27) from 4-cMoro-N-(3-chlorophenyl)-2-hydroxybenzamide instead of 5-chloro-N-(3,5- dichlorophenyl)-2-hydroxybenzamide.
• Compound 29 was obtained using the above mentioned synthetic procedure (Example 27) from 5-chloro-2-hydroxy-N-(4-iodophenyl)benzamide instead of 5-chloro-N-(3,5- dichlorophenyl)-2-hydroxybenzamide and using phenyl phosphorodichloridate (phenyl dichlorophosphate) instead of phenylphosphonic dichloride.
• Ci 9 Hi 2 CliN0 4 P Molecular weight: 511.64. Yield: 71 %.
• MDR strains M. tuberculosis (MDR strains)
• IR ATR-Ge: 3316, 1681, 1600, 1 531, 1490, 1480, 1313, 1267, 1190, 1183, 1163, 1107, 1026, 1014, 981, 970, 950, 911, 824, 775, 766, 692.
• IR ATR-Ge: 3249, 1687, 1677, 1 600, 1590, 1538, 1487, 1317, 1287, 1191, 1181, 1157, 1007, 966, 938, 911, 81 8, 777, 766, 689.
• IR ATR-Ge: 3279, 1691, 1674, 603, 1534, 1481, 1411, 1320, 1285, 1261, 1183, 1163, 1139, 1115, 1067, 10K 5, 961, 910, 839, 832, 795, 772, 758, 689.
• IR ATR-Ge: 3284, 1683, 1634, 1 591, 1540, 1488, 1412, 1323, 1286, 1263, 1192, 1163, 1114, 1066, 1025, 1101 , 966, 906, 846, 768, 755, 688.
• IR ATR-Ge
• IR ATR-Ge: 3260, 1674, 1591, 1 524, 1492, 1475, 1400, 1308, 1263, 1235, 1214, 1036, 1016, 981, 956, 939, 9 " L2, 879, 818, 778, 748, 738, 700.
• IR ATR-Ge: 3289, 1674, 1649, 1604, 1541, 1489, 1456, 1403, 1315, 1245, 1215, 1072, 1008, 956, 894, 825, 781, 737, 697.
• IR ATR-Ge: 3257, 1681, 1607, 1548, 1479, 1413, 1319, 1284, 1266, 1215, 1154, 1116, 1065, 1044, 1028, 1101, 976, 956, 911, 897, 843, 822, 738, 727, 695.
• IR ATR-Ge: 3247, 1676, 1608, 1 545, 1494, 1479, 1440, 1407, 1319, 1218, 1206, 1132, 1110, 1101, 958, 931, S ) 03, 822, 780, 751, 730, 691.
• IR ATR-Ge: 3247, 1677, 1607, 591, 1543, 1490, 1476, 1440, 1406, 1319, 1218, 1206, 1179, 1132, 1106, 1074, 1007, 958, 931, 903, 822, 779, 751, 731, 692.
• IR ATR-Ge: 1692, 1610, 1486, 1456, 1438, 1304, 1271, 1217, 1128, 1121, 930, 793, 780, 754, 747, 726, 695, 689.
• IR ATR-Ge: 1652, 1630, 1609, 1 553, 1491, 1419, 1322, 1288, 1221, 1175, 1140,1112,1101,1011,997, 936, ⁇ >04, 823, 754, 745, 721, 695, 657.
• IR ATR-Ge: 1652, 1603, 1538, 480, 1440, 1416, 1325, 1273, 1221, 1204, 1185, 1170, 1107, 1069, 1017, 992, 935, 901, 843, 823, 749, 726, 694.
• IR ATR-Ge: 1682, 1608, 1474, 1442, 1418, 1314, 1289, 1265, 1216, 1137, 1128, 1034, 937, 906, 827, 819, 766, 749, 731, 701, 691.
• IR ATR-Ge: 1684, 1604, 1471, 1 441, 1412, 1333, 1311, 1276, 1265, 1216, 1167, 1132, 1115, 1070, 1035, 1024 I, 934, 868, 824, 801, 749, 733, 692.
• IR ATR-Ge: 1683, 1608, 1473, 1417, 1284, 1262, 1243, 1217, 1129, 1090, 1034, 939, 907, 834, 819, 766, 750, 741, 728, 701, 677, 656.
• IR ATR-Ge: 1688, 1608, 1591, 1475, 1414, 1319, 1302, 1288, 1243, 1207, 1131, 1099, 1081, 1038, 999, 959, 883, 818, 789, 760, 747, 716, 689, 679.
• IR ATR-Ge: 1695, 1609, 1483, 1475, 1421, 1305, 1284, 1212, 1179, 1155, 1134, 1105, 1048, 1027, 946, 922, 910, 879, 831, 821, 805, 774, 711, 693, 664.
• Example 1 content of active substance 100 mg in a tablet
• Example 2 content of active substance 200 mg in a tablet Active ingredient of general formula I (24) 0.2
• Example 3 content of active substance 300 mg in a tablet Active ingredient of general formula I (4) 0.3
• Example 4 content of active substance 400 mg in a tablet
• Example 5 content of active substance 500 mg in a tablet
• Colloidal silicon dioxide 0.0025 The active ingredient is mixed homogeneously together with other individual excipients and the obtained powder mixture is compressed by a regular manner using a conventional tablet machine.
• Example 6 content of active substance 100 mg in a tablet
• Example 7 content of active substance 200 mg in a tablet
• Example 8 content of active substance 300 mg in a tablet
• Example 9 content of active substance 400 mg in a tablet Active ingredient of general formula I (24) 0.4
• Example 10 content of active substance 500 mg in a tablet
• the active agent is mixed gradually together with lactose and potato starch; the mixture is granulated with povidone. Then, the dried granulate is mixed with sodium carboxymethyl starch, magnesium stearate and talc, and the resulting blend is compressed in a tablet machine in the usual way.

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• 2014
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