WO2008059014A2 - Antituberculosis agents with alkylidene or alkyl side chain - Google Patents
Antituberculosis agents with alkylidene or alkyl side chain Download PDFInfo
- Publication number
- WO2008059014A2 WO2008059014A2 PCT/EP2007/062381 EP2007062381W WO2008059014A2 WO 2008059014 A2 WO2008059014 A2 WO 2008059014A2 EP 2007062381 W EP2007062381 W EP 2007062381W WO 2008059014 A2 WO2008059014 A2 WO 2008059014A2
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- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- compound according
- hydrogen
- substituted
- previous
- Prior art date
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- 125000000217 alkyl group Chemical group 0.000 title claims description 50
- 125000001118 alkylidene group Chemical group 0.000 title claims description 16
- 229940121383 antituberculosis agent Drugs 0.000 title abstract description 6
- 239000000814 tuberculostatic agent Substances 0.000 title abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 100
- -1 alkoxycarbonylacyl Chemical group 0.000 claims description 39
- 239000001257 hydrogen Substances 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- 239000003814 drug Substances 0.000 claims description 31
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 30
- 229940079593 drug Drugs 0.000 claims description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 21
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- 239000001301 oxygen Substances 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 201000008827 tuberculosis Diseases 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 15
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 13
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 6
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- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 5
- 125000005018 aryl alkenyl group Chemical group 0.000 claims description 5
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
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- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 3
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000001204 arachidyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
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- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
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- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
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- 229940002612 prodrug Drugs 0.000 claims description 2
- 239000000651 prodrug Substances 0.000 claims description 2
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- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001260 acyclic compounds Chemical class 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 125000000266 alpha-aminoacyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003926 antimycobacterial agent Substances 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 108010039311 arabinosyltransferase Proteins 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 239000000022 bacteriostatic agent Substances 0.000 description 1
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000001851 biosynthetic effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- LSRPARCOXAUYNP-UHFFFAOYSA-N cyclohexylidene(oxido)oxidanium Chemical compound [O-][O+]=C1CCCCC1 LSRPARCOXAUYNP-UHFFFAOYSA-N 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 150000002009 diols Chemical group 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- ZMMJGEGLRURXTF-UHFFFAOYSA-N ethidium bromide Chemical compound [Br-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 ZMMJGEGLRURXTF-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- PWJWNZBLKWYLPP-UHFFFAOYSA-N hexadecane-1,2-diamine Chemical compound CCCCCCCCCCCCCCC(N)CN PWJWNZBLKWYLPP-UHFFFAOYSA-N 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 230000003641 microbiacidal effect Effects 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 229940124561 microbicide Drugs 0.000 description 1
- 239000002855 microbicide agent Substances 0.000 description 1
- QSTYZGFNBXBPDG-UHFFFAOYSA-N n,n-diethyl-1-phenylmethoxyhexadecan-2-amine Chemical compound CCCCCCCCCCCCCCC(N(CC)CC)COCC1=CC=CC=C1 QSTYZGFNBXBPDG-UHFFFAOYSA-N 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- QJPTYDGYJHVVEW-UHFFFAOYSA-N tert-butyl n-(1-hydroxyhexadecan-2-yl)carbamate Chemical compound CCCCCCCCCCCCCCC(CO)NC(=O)OC(C)(C)C QJPTYDGYJHVVEW-UHFFFAOYSA-N 0.000 description 1
- HVCNMFURAJFOGO-UHFFFAOYSA-N tetradecylphosphanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCC[PH3+] HVCNMFURAJFOGO-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
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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
- A61K31/396—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having three-membered rings, e.g. aziridine
-
- 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
- A61K31/13—Amines
- A61K31/132—Amines having two or more amino groups, e.g. spermidine, putrescine
-
- 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
- A61K31/13—Amines
- A61K31/133—Amines having hydroxy groups, e.g. sphingosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
Definitions
- the present invention relates to a family of compounds of general formula I, for its use as antituberculosis agents.
- Tuberculosis is a latent infectious disease, mainly caused by the mycobacteria Mycobacterium tuberculosis (MTB). It is caught by airborne contact and causes more than 1.6 million deaths a year (OMS-TDR- 2002). It affects a third of the world's population with highest incidence in the planet's poorest areas (Africa: 35% of the population infected, America: 18%, Western Mediterranean: 29%, Europe: 15%, Southeast Asia: 44%, Western Pacific: 35%) and it was declared a world health emergency in 1993. Each year, 1 % of the world's population is infected.
- MTB mycobacteria Mycobacterium tuberculosis
- the main differential characteristic of the mycobacteria in comparison with other types of pathogenic microorganisms, is related to their spe- cial cell wall, of polyglycoside-polypeptide-polylipidic nature, which protects the bacterial cell from possible extreme environmental conditions and, particularly, against attack by drugs and other external physicochemical agents (cf. Brennan PJ et al. 1995. Annu. Rev. Biochem. vol. 64, pp. 29- 63).
- the therapeutic agents used in the treatment of tuberculosis are grouped in two categories called first and second line.
- the first group of drugs is constituted by: isoniazid, rifampicin, pyrazinamide, ethambutol (EMB) and streptomycin.
- EMB is a basically non-toxic bacteriostatic agent, but not too potent, whose structure (i), contains two units of ⁇ -aminoalcohol, in a pseudosymmetrical distribution and located at the ends of a central unit of 1 ,2-ethylenediamine (cf. Myers JP, 2005, Curr. Opin. Infect. Dis, vol. 18, pp. 133-40; Blumberg, HM, et al., 2003, Am. J. Respir. Crit. Care Med. Vol. 167, pp. 603).
- EMB affects the metabolism of nucleic acids and specifically inhibits the arabinosyl transferase of the mycobacteria, preventing or disturbing the formation of arabinogalactose and lipoarabinomannan, which are basic elements and form part of the dominant glycolipids in the MTB wrapping (cf. Forbes M, et al., 1965, J Bacterial, vol. 89, pp. 1299-1305; Killburn JO, et al., 1981 , Antimicrob. Agents Chemother, vol. 19, pp. 346- 48; Takayama K. et al.,1989, Antimicrob. Agents Chemother, vol. 33, pp. 1493-99).
- sphingosine (SPH, ii) is a natural component of phospholipids in the membrane of live organisms, being biosynthesized from serine and palmitic acid. It contains a long linear chain, with an olefinic un- saturation, an amine group and two hydroxyl functions. Activated by phosphorylation, it is incorporated in the sphingomielin, in the ceramides and in other series of second messengers, involved in various chemophysiological cell processes.
- Ceramides which have an important function in membrane stability, are related to another group of lipidic compounds present in the mycobacterial cell wall, the mycolic acids, a group of fatty acids with extraordinary long chains, between 60 and 90 carbon atoms, which contain hydroxyl functions, methyl branches and cyclopropane rings (cf. Barry CE, et al., 1998, Proa. Lipid Res., vol. 37, pp.143-79).
- TB is considered a disease of poverty.
- the first line agents the most accessible, developed more than 40 years ago, are not suitable for effectively treating resistant infections and the use of second line agents, in addition to being less accessible, do not have clear guarantees of efficacy.
- the present invention discloses cyclolipidic diamines and aminoal- cohols, of discrete molecular size and some of their derivatives and analogues, as well as acyclic, epodixic, aziridine and amino acid compounds of lipidic nature, synthesis intermediates, which have considerable in vitro activity against strains of MTB sensitive (S), polyresistant (PDR) and mul- tiresistant (MDR) to first line antituberculosis drugs. Additionally, some elements selected from those active in vitro, in the form described below, also have demonstrated their therapeutic usefulness, by in vivo assays on mice infected with S strains and strains resistant to all first line drugs (TDR).
- S MTB sensitive
- PDR polyresistant
- MDR mul- tiresistant
- a compound of general formula I is provided for its use as a drug, preferably as antituberculosis agent.
- the compound of general formula I is:
- R 1 is a radical, substituted or not substituted, linear or branched, which is selected from the group which consists of alkyl (C 4 -C2o), alkenyl (C 4 -C 2 O), alkylidene (C 4 -C 2 o), arylalkyl (Ar-Ci to Ar-Ci 2 ), arylalkenyl (Ar-C 3 to Ar-Ci 2 ) or arylalkyl idene (Ar-Ci to Ar-Ci 2 ).
- R 1 may be bound to any of the carbon atoms of the ring and in the particular case wherein m is zero, it is bound to carbon 1.
- R 2 , R 3 , R 4 and R 5 are the same or different and each one is selected independently from the group formed by hydrogen (H); alkyl (C1-C10) sub- stituted or not substituted; hydroxyalkyl (C1-C10) substituted or unsubsti- tuted; alkoxyalkyl (C 1 -C 10 ) substituted or not substituted; alkenyl (C 1 -C 10 ) substituted or not substituted; aryl, substituted or not substituted; arylalkyl (Ar-Ci to Ar-Ci2) substituted or unsubstituted, heteroaryl substituted or not substituted; heteroarylalkyl (Het-Ci to Het-Ci 2 ) substituted or unsubstituted; an acyl, alkoxycarbonylacyl, alkoxycarbonyl, hydroxyacyl or hydroxycar- bonylacyl group and any of their possible salts, organic and inorganic esters or amides.
- X and Y are the same or different and each one independently represents a Nitrogen (N) or Oxygen (O) atom, configuring aminoalcohol, diamine or diol structures and their derivatives.
- m has values between 0 and 6, preferably between 0 and 4 and more preferably 0, 3 or 4. When m is 0, the bond between positions 1 and 2 is a single bond. When X is Oxygen R 3 does not exist and when Y is Oxygen R 5 does not exist.
- the relative geometric configuration of the substituents bound to the cyclic systems may be cis or trans.
- the trans form being preferable.
- the symbol "1 ⁇ includes both and each one of the absolute configu- rations R or S of the corresponding stereocentres.
- R 2 R 3 , R 4 or R 5
- R 3 , R 4 or R 5 is a polymethylene spacer, of size between 2 and 4 units, which bounds two symmetrical or non-symmetrical molecular moieties.
- the compounds with antituberculosis activity have values of m equal to 4; X is nitrogen, Y is oxygen, R 2 and R 4 are hydrogen, R 3 is an alkyl (C 3 -Ci 0 ) and R 1 is an alkyl (CiO-Ci 4 ) or an alkylidene (Ci O -Ci 4 ).
- the compounds with antituberculosis activity have values of m equal to 4, X is ni- trogen, Y is oxygen, R 2 and R 4 are hydrogen, R 3 is an alkyl (C 4 -C ⁇ ) and R 1 is an alkyl (Ci 2 -Ci 4 ).
- the compounds with antituberculosis activity have values of m equal to 4, X is nitrogen, Y is oxygen, R 2 and R 4 are hydrogen, R 3 is an alkyl (C 3 -C 6 ) and R 1 is an alky- lidene (C IO -C M ).
- the compounds with antituberculosis activity have values of m equal to 4; X is oxygen, Y is nitrogen, R 2 and R 4 are hydrogen, R 5 is an alkyl (C2-C6) and R 1 an alky- lidene (Ci 0 -Ci 6 ).
- the compounds with antituberculosis activity have values of m equal to 4, X and Y are nitrogen, R 2 and R 4 are hydrogen, R 3 and R 5 are alkyl (C2-C 6 ) and R 1 an al- kylidene (Ci 0 -Ci 6 ).
- m is zero and comprises the compounds of general formula Il which correspond to acyclic compounds; and in another particular embodiment X (or Y) is bound to carbons 1 and 2 represented in formula I and comprises the compounds of general formula III, which correspond to compounds with bicyclic structure.
- the compounds of formula III also serve as intermediates for the synthesis of compounds of formulas I and II.
- Some partial structural qualities of the therapeutic agent EMB and others of the natural biosynthetic aminodiol SPH have been incorporated on these structures in different suitable groupings, and mainly on carbocyc- Nc systems such as those previously described, to achieve active compounds against the mycobacteria MTB and clinically effective against resis- tant tuberculosis.
- the radical R 1 present in general formulas I, Il and III, is an alkyl, alkenyl or alkylidene group, of between 4 and 20 carbon atoms, preferably between 10 and 16 carbon atoms, more preferably between 10 and 14 carbon atoms; or an arylalkyl or arylalkylidene group of between Ar-Ci and Ar-Ci2, preferably from Ar-Ci to Ar-C 6 ; or an arylalkenyl group of between Ar-C3 to Ar-Ci2, preferably from Ar-C3 to Ar-C 6 .
- the grouping XR 2 R 3 (or YR 4 R 5 ), of general formulas I and II is a carboxyl group in the form of a free acid, salt, ester or free amide or N-substituted amide.
- the compounds of formula Il have the following radicals: X is nitrogen, R 1 is an alkyl (C12- Ci 6 ), R 2 is hydrogen, alkyl (CrC 6 ), benzyl, t-butoxycarbonyl, ethoxycarbon- ylmethyl, hydroxycarbonylpropionyl, hydroxycarbonylbutyryl or ethoxycar- bonylbutyryl, R 3 is hydrogen or alkyl (CrC 6 ), R 4 is hydrogen, alkyl (CrC 6 ), cycloalkyl (C 5 -C 6 ), ethoxycarbonylbutyryl or aryl, and R 5 is hydrogen or alkyl (CrC 6 ) or does not exist when Y is oxygen.
- R 1 is an alkyl (C12- Ci 6 )
- R 2 is hydrogen, alkyl (CrC 6 ), benzyl, t-butoxycarbonyl, ethoxycarbon- ylmethyl, hydroxycarbonylpro
- R 1 is an alkyl (C12- Ci 4 )
- R 2 is hydrogen, alkyl (CrC 4 ) or t- butoxycarbonyl
- R 3 is hydrogen or alkyl (CrC 4 )
- R 4 is hydrogen or aryl
- R 5 is hydrogen or alkyl (CrC 6 ) or does not exist when Y is oxygen
- the R 1 group is that selected from the decyl, lauryl, myristyl, palmityl, stearyl, arachidyl, oleil, decylidene, laurylidene, myristylidene, palmitylidene, stearylidene, arachylidene, oleilidene, benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylhexyl, phenyloctyl, cinnamyl, benzylidene, phen
- the radi- cals R 2 , R 3 , R 4 and R 5 are the same or different and each one is selected independently from elements of the group that comprises: hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, alkenyl groups, with sizes of Ci to Ci 0 and with preference from C 4 to C 6 for alkyl and alkenyl and from C2 to C 4 for hy- droxyalkyls and alkoxyalkyls.
- aryl groups preferably phenyl, arylalkyl and arylalkenyl, preferably from Ar-Ci to Ar-Ci2 and het- eroaryl and heteroarylalkyl, preferably from Het-Ci to Het-Ci2.
- acyl hydroxyacyl, alkoxyalkyl, alkoxycarbonyl, aminoacyl, hydroxy- carbonylacyl, and alkoxycarbonylacyl groups.
- each of the radicals R 2 , R 3 , R 4 and R 5 is selected independently from the group which comprises, ethyl, propyl, butyl, hexyl, decyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, cinnamyl, all of them may or may not be substituted, furyl, (for example 2-furyl and 2- furylethyl), thienyl (for example 2-thienyl and 2-thienylethyl), acethyl, hy- droxyacethyl, glycinyl, methoxycarbonyl, t-butoxycarbonyl, hemisuccinyl or hemiglutaryl.
- furyl for example 2-furyl and 2- furylethyl
- thienyl for example 2-thienyl and 2-thienylethyl
- X is nitrogen and is bound simultaneously to carbons 1 and 2
- m is 4
- R 2 is hydrogen, alkyl (C 3 -Ci 2 ) or arylalkyl (Ar-Ci to Ar-C 6 ) and R 1 is an alkyl or alkylidene group (Ci O -Ci 4 ). More preferably, X is nitrogen and R 3 is hydrogen.
- All the aforementioned compounds described may exist in the forms of steroisomers, epimers and enantiomers; so that the configuration of the substituents bound to the cyclic systems may be selected as cis or trans, with preference for the trans stereoisomers.
- the configuration of the ole- finic unsaturations may be selected as Y or Z, with preference for the Z stereoisomers.
- references in the present document to groups substituted in the compounds of the present invention relate to the moiety specified which may be substituted in one or more available positions by one or more suitable groups, for example, alkyl groups including those groups which have from 1 to approximately 12 carbon atoms or from 1 to approximately 6 carbon atoms and, more preferably, 1 - 3 carbon atoms; alkenyl groups including groups which have one or more unsaturated bonds and from 2 to approximately 12 carbon atoms or from 2 to approximately 6 carbon atoms; hydroxyl; acyl (Ci-C 6 ) such as acetyl or similar; alkoxycarbonylacyl; alkoxy- carbonyl; hydroxyacyl or hydroxycarbonylacyl.
- alkyl groups including those groups which have from 1 to approximately 12 carbon atoms or from 1 to approximately 6 carbon atoms and, more preferably, 1 - 3 carbon atoms
- alkenyl groups including groups which have one or more unsaturated bonds and from 2 to approximately 12 carbon atoms or from 2 to
- the authors of the present invention have prepared compounds of this type with therapeutic purpose, and have examples and results of the in vitro antimycobactehal evaluation, the in vivo antituberculosis evaluation and the synthetic preparation of the compounds considered in the present invention.
- the compounds of structure general I both as compounds with particular structures Il and III, are obtained with variable yield, by controlled chemical procedures and expressly configured to synthesize them, starting from common raw materials, by generally known transformations and, in most cases, already used according to the state of the art.
- the present invention also comprises the intermediate compounds of the synthesis, with its variants and derivatives.
- several groups of compounds of general formulas I and III were prepared by sequences of reactions which have been summarized in Schemes 1 , and several specific and representative examples of the compounds active against MTB are described and characterized chemically and biologically in later sections of this document:
- Reagents i: CH 3 (CH 2 )nCH2 + PPh3 BrVnBu U/THF/-78 0 C. //: R 1 R 2 NH/MeCN/LiCIO 4 /50- 6O 0 C.
- xi a) pTsNHNH 2 /MeOH; b) NaH/toluene/ ⁇ ; xii: AnCPBAZCH 2 CI 2 ZNaHCO 3 ; xiii: NH2(CH 2 )nNH 2 /LiCIO 4 / MeCN/ ⁇ .
- Reagents i: a) EtOOCCI/ ⁇ /-methylmorpholine/THF; b) NaBH 4 /MeOH. //: BnCI/NaH/DMF. ///: HCI (g)/THF. ⁇ V: EtBr/Et 3 N/DMF. v: nBuCI (or CICH 2 COOEt, succinic or glutaric anhydrides, or glutahc acid- monoethylester chloride)/Et 2 O/NEt 3 . W: H 2 /Pd-C/AcOH. Wi: a)
- Another aspect of the present invention comprises a pharmaceutical composition with any of the previously described antituberculosis agents or any of their mixtures, in addition to a pharmaceutically acceptable carrier.
- Fig. 1. Determination of mycobacterial colony forming units (CFU) in Balb/c mice, two months after having being infected with M. tuberculosis H37Rv and treated during two months with the compounds of this invention, with conventional drugs and with associations thereof.
- CFU mycobacterial colony forming units
- Fig. 2. Quantification of the percentage of pulmonary area affected by pneumonia in Balb/c tuberculosis-infected mice, after treatment during two months with the different compounds and associations.
- Fig.3. Comparative effects on the mycobacterial colony forming units (CFU) in mice lung, after two-months infection either with sensitive H37Rv or MDR strains of M. tuberculosis and treatment during one month with one compound of this invention.
- CFU mycobacterial colony forming units
- EXAMPLES 1c Representative preparation of some diamines from groups 1-18 and 1-19.
- EM 395.55 (M+, 2); 140.25 (100); 324,45 (25). Properties of 1-346012: Max IR: 3385, 2930, 2855, 1643, 1460, 1370, 1078, 725 cm “1 . EM: 395.55 (M + , 2); 198.25 (100); 324,45 (25); 337.55 (44)
- IK ll-5b and 11 -6 b 18.5 g of 11-1 were dissolved in 250 ml_ of THF and it was cooled to 10 0 C, successively 5.5 ml_ of /V-methylmorpholine were added and slowly 4.5 imL of CICOOEt, controlling the reaction t during 10 min. It was cooled to 0 0 C, 5.60 g of NaBH 4 and 747 ml_ of MeOH were added, drop by drop, it was maintained at 0° C for 15 min, then 10 min at a.t.
- NMR 1 H 0.89 t (6.9); 1.28 sa; 4.91 m; 4.91 sa ; 3.54 dd (11.6; 6.9),3.76 dd (11.6; 2.8); 3.18 m.
- NMR 13 C 14.1 (CH 3 ); 22.7; 25.8; 25.9; 26.1 ; 29.4; 29.7; 31.8; 33.6; 34.0; 35.3 (CH 2 I; 69.9 (CH-OR); 52.4 (CH 2 -N); 56.7 (CH-N).
- EXAMPLE 2a - IN VITRO ACTIVITY ASSAYS AGAINST STANDARD SENSITIVE STRAIN AND ANOTHER TDR STRAIN, RESISTANT TO ALL FIRST LINE ANTI-TB DRUGS
- Table 3 shows results of the in vitro evaluation of some compounds of this invention to mycobacterial strains isolated from different patients refractory to the anti-TB treatments, carried out with first line drugs.
- compounds 11-4 and ll-5b are very effective against mycobacteria with any resistance profile against conventional drugs; whilst not to such an extent, compound ll-9b is also quite effective.
- mice 6 to 8 weeks old are infected by intratracheal injection with 1x10 6 bacteria of the virulent strain of M. tuberculosis H37Rv.
- This experimental procedure generates progressive pulmonary tuberculosis, which takes place in two phases. The first, which corresponds to the first month of infection, produces chronic perivascular, peribronchial and interstitial inflammation, with the mycobacteria controlled by activated macro- phages and Th-1 lymphocytes. In the second phase, progressive pneumonia occurs with logarithmic increase in the number of live bacteria in the lung which cases death of them.
- mice 6 groups of 5 mice were infected and the treated was started two months post-infection.
- the first group were treated with ll-5b; the second group received the compound II-4, the third group was administered ll-5b plus hfampicin (10mg/kg), isoni- azid (10mg/kg) and pyrazinamide (30mg/kg); the fourth group were treated with the compound II-4 plus said drugs; the fifth group only received said drugs and the sixth group only received the carrier (saline solution).
- the administration was carried out by nasogastric probe, daily during two months, at the end of which all the animals were sacrificed and the lungs were extracted. One of the lungs from each mouse were used to determine the number of live bacteria, by the quantification of colony forming units, the other lung was used for the histological study; specifically the percentage of surface affected by pneumonia was determined by computerized imaging analysis. Results:
- Figure 1 shows the values of mycobacterial colony forming units (CFU) after treatment with compounds ll-5b (in figures UCI-14), and II-4 (in figures UCI-05), with conventional drugs (3F), with the combination of ll-5b with three drugs (14+3F), or the combination of II-4 with three drugs (05+3F).
- the bars correspond to the mean of 5 animals per each group.
- Ctr corresponds to the control group which did not receive treatment.
- mice that received the three conventional drugs decreased by 30 times.
- mice exclusively treated with ll-5b showed a pneumonic area simi- lar to that of the untreated controls.
- compound 1-40612 (UCI 107 in Fig. 3) alone was administered to Balb/c mice infected with the sensitive H37Rv or the CIBIN-99 (SIREP- resistant, Table 3) strains of M. tuberculosis.
- the results showing its anti- TB efficacy are shown in Figure 3.
- compound 1-40612 reduced the CFU to almost 15 %, in the case of H37Rv infection, and to less than 44 %, in that of the CIBIN-99 MDR strain.
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Abstract
Antituberculosis agents of the general formula (I) and their use for the manufacture of pharmaceutical compositions.
Description
ANTITUBERCULOSIS AGENTS
Description
The present invention relates to a family of compounds of general formula I, for its use as antituberculosis agents.
I
PRIOR ART
Tuberculosis (TB) is a latent infectious disease, mainly caused by the mycobacteria Mycobacterium tuberculosis (MTB). It is caught by airborne contact and causes more than 1.6 million deaths a year (OMS-TDR- 2002). It affects a third of the world's population with highest incidence in the planet's poorest areas (Africa: 35% of the population infected, America: 18%, Western Mediterranean: 29%, Europe: 15%, Southeast Asia: 44%, Western Pacific: 35%) and it was declared a world health emergency in 1993. Each year, 1 % of the world's population is infected. From that per- centage, between 5 and 10% effectively develop the infection; so that we can assume that, without a coordinated international effort to combat it, by 2020 one billion people will be infected and ill and the number of deaths that year will exceed 70 million, largely due to the appearance of mycobacteria strains that are resistant and multi-resistant to the available drugs and
also to the increase in its opportunistic nature in the case of simultaneous AIDS-TB co-infection (see website of World Health Organization WHO).
The main differential characteristic of the mycobacteria, in comparison with other types of pathogenic microorganisms, is related to their spe- cial cell wall, of polyglycoside-polypeptide-polylipidic nature, which protects the bacterial cell from possible extreme environmental conditions and, particularly, against attack by drugs and other external physicochemical agents (cf. Brennan PJ et al. 1995. Annu. Rev. Biochem. vol. 64, pp. 29- 63). The therapeutic agents used in the treatment of tuberculosis are grouped in two categories called first and second line.
The first group of drugs, those most accessible, is constituted by: isoniazid, rifampicin, pyrazinamide, ethambutol (EMB) and streptomycin. Within this group, EMB is a basically non-toxic bacteriostatic agent, but not too potent, whose structure (i), contains two units of β-aminoalcohol, in a pseudosymmetrical distribution and located at the ends of a central unit of 1 ,2-ethylenediamine (cf. Myers JP, 2005, Curr. Opin. Infect. Dis, vol. 18, pp. 133-40; Blumberg, HM, et al., 2003, Am. J. Respir. Crit. Care Med. Vol. 167, pp. 603).
From a mechanistic point of view, although it is not totally clarified, it is accepted that EMB affects the metabolism of nucleic acids and specifically inhibits the arabinosyl transferase of the mycobacteria, preventing or disturbing the formation of arabinogalactose and lipoarabinomannan, which are basic elements and form part of the dominant glycolipids in the MTB wrapping (cf. Forbes M, et al., 1965, J Bacterial, vol. 89, pp. 1299-1305; Killburn JO, et al., 1981 , Antimicrob. Agents Chemother, vol. 19, pp. 346-
48; Takayama K. et al.,1989, Antimicrob. Agents Chemother, vol. 33, pp. 1493-99).
Furthermore, sphingosine (SPH, ii) is a natural component of phospholipids in the membrane of live organisms, being biosynthesized from serine and palmitic acid. It contains a long linear chain, with an olefinic un- saturation, an amine group and two hydroxyl functions. Activated by phosphorylation, it is incorporated in the sphingomielin, in the ceramides and in other series of second messengers, involved in various chemophysiological cell processes. Ceramides, which have an important function in membrane stability, are related to another group of lipidic compounds present in the mycobacterial cell wall, the mycolic acids, a group of fatty acids with extraordinary long chains, between 60 and 90 carbon atoms, which contain hydroxyl functions, methyl branches and cyclopropane rings (cf. Barry CE, et al., 1998, Proa. Lipid Res., vol. 37, pp.143-79).
At present, TB is considered a disease of poverty. The first line agents, the most accessible, developed more than 40 years ago, are not suitable for effectively treating resistant infections and the use of second line agents, in addition to being less accessible, do not have clear guarantees of efficacy.
EXPLANATION OF THE INVENTION
The present invention discloses cyclolipidic diamines and aminoal- cohols, of discrete molecular size and some of their derivatives and analogues, as well as acyclic, epodixic, aziridine and amino acid compounds of
lipidic nature, synthesis intermediates, which have considerable in vitro activity against strains of MTB sensitive (S), polyresistant (PDR) and mul- tiresistant (MDR) to first line antituberculosis drugs. Additionally, some elements selected from those active in vitro, in the form described below, also have demonstrated their therapeutic usefulness, by in vivo assays on mice infected with S strains and strains resistant to all first line drugs (TDR).
The compounds of the present invention are useful against multire- sistant TB, with even greater efficacy than against the sensitive type. In accordance with an aspect of the present invention, a compound of general formula I is provided for its use as a drug, preferably as antituberculosis agent.
The compound of general formula I is:
R1 is a radical, substituted or not substituted, linear or branched, which is selected from the group which consists of alkyl (C4-C2o), alkenyl (C4-C2O), alkylidene (C4-C2o), arylalkyl (Ar-Ci to Ar-Ci2), arylalkenyl (Ar-C3 to Ar-Ci2) or arylalkyl idene (Ar-Ci to Ar-Ci2). R1 may be bound to any of the carbon atoms of the ring and in the particular case wherein m is zero, it is bound to carbon 1.
R2, R3, R4 and R5 are the same or different and each one is selected independently from the group formed by hydrogen (H); alkyl (C1-C10) sub-
stituted or not substituted; hydroxyalkyl (C1-C10) substituted or unsubsti- tuted; alkoxyalkyl (C1-C10) substituted or not substituted; alkenyl (C1-C10) substituted or not substituted; aryl, substituted or not substituted; arylalkyl (Ar-Ci to Ar-Ci2) substituted or unsubstituted, heteroaryl substituted or not substituted; heteroarylalkyl (Het-Ci to Het-Ci2) substituted or unsubstituted; an acyl, alkoxycarbonylacyl, alkoxycarbonyl, hydroxyacyl or hydroxycar- bonylacyl group and any of their possible salts, organic and inorganic esters or amides.
X and Y are the same or different and each one independently represents a Nitrogen (N) or Oxygen (O) atom, configuring aminoalcohol, diamine or diol structures and their derivatives. m has values between 0 and 6, preferably between 0 and 4 and more preferably 0, 3 or 4. When m is 0, the bond between positions 1 and 2 is a single bond. When X is Oxygen R3 does not exist and when Y is Oxygen R5 does not exist.
The relative geometric configuration of the substituents bound to the cyclic systems may be cis or trans. The trans form being preferable.
The symbol "1^ includes both and each one of the absolute configu- rations R or S of the corresponding stereocentres.
It also includes compounds wherein one of the substituents R2 (R3, R4 or R5) is a polymethylene spacer, of size between 2 and 4 units, which bounds two symmetrical or non-symmetrical molecular moieties.
In a preferred embodiment of the present invention, the compounds with antituberculosis activity have values of m equal to 4; X is nitrogen, Y is oxygen, R2 and R4 are hydrogen, R3 is an alkyl (C3-Ci0) and R1 is an alkyl (CiO-Ci4) or an alkylidene (CiO-Ci4).
In a more preferred embodiment of the present invention, the compounds with antituberculosis activity have values of m equal to 4, X is ni- trogen, Y is oxygen, R2 and R4 are hydrogen, R3 is an alkyl (C4-Cβ) and R1 is an alkyl (Ci2-Ci4).
In another embodiment of the present invention, the compounds with antituberculosis activity have values of m equal to 4, X is nitrogen, Y is oxygen, R2 and R4 are hydrogen, R3 is an alkyl (C3-C6) and R1 is an alky- lidene (CIO-CM). In a further embodiment of the present invention, the compounds with antituberculosis activity have values of m equal to 4; X is oxygen, Y is nitrogen, R2 and R4 are hydrogen, R5 is an alkyl (C2-C6) and R1 an alky- lidene (Ci0-Ci6).
In yet another embodiment of the present invention, the compounds with antituberculosis activity have values of m equal to 4, X and Y are nitrogen, R2 and R4 are hydrogen, R3 and R5 are alkyl (C2-C6) and R1 an al- kylidene (Ci0-Ci6).
In another more preferred embodiment of the present invention m is zero and comprises the compounds of general formula Il which correspond to acyclic compounds; and in another particular embodiment X (or Y) is bound to carbons 1 and 2 represented in formula I and comprises the compounds of general formula III, which correspond to compounds with bicyclic structure.
When X (or Y) is bound simultaneously to carbons 1 and 2 represented in formula I, the YR4R5 group (or respectively XR2R3) does not exist.
The compounds of formula III also serve as intermediates for the synthesis of compounds of formulas I and II. Some partial structural qualities of the therapeutic agent EMB and
others of the natural biosynthetic aminodiol SPH have been incorporated on these structures in different suitable groupings, and mainly on carbocyc- Nc systems such as those previously described, to achieve active compounds against the mycobacteria MTB and clinically effective against resis- tant tuberculosis.
In general terms, the radical R1, present in general formulas I, Il and III, is an alkyl, alkenyl or alkylidene group, of between 4 and 20 carbon atoms, preferably between 10 and 16 carbon atoms, more preferably between 10 and 14 carbon atoms; or an arylalkyl or arylalkylidene group of between Ar-Ci and Ar-Ci2, preferably from Ar-Ci to Ar-C6; or an arylalkenyl group of between Ar-C3 to Ar-Ci2, preferably from Ar-C3 to Ar-C6.
In a preferred embodiment of the present invention, the grouping XR2R3 (or YR4R5), of general formulas I and II, is a carboxyl group in the form of a free acid, salt, ester or free amide or N-substituted amide. In a preferred embodiment of the present invention, the compounds of formula Il have the following radicals: X is nitrogen, R1 is an alkyl (C12- Ci6), R2 is hydrogen, alkyl (CrC6), benzyl, t-butoxycarbonyl, ethoxycarbon- ylmethyl, hydroxycarbonylpropionyl, hydroxycarbonylbutyryl or ethoxycar- bonylbutyryl, R3 is hydrogen or alkyl (CrC6), R4 is hydrogen, alkyl (CrC6), cycloalkyl (C5-C6), ethoxycarbonylbutyryl or aryl, and R5 is hydrogen or alkyl (CrC6) or does not exist when Y is oxygen. More preferably X is nitrogen, R1 is an alkyl (C12- Ci4), R2 is hydrogen, alkyl (CrC4) or t- butoxycarbonyl, R3 is hydrogen or alkyl (CrC4), R4 is hydrogen or aryl and R5 is hydrogen or alkyl (CrC6) or does not exist when Y is oxygen In another preferred embodiment, the R1 group is that selected from the decyl, lauryl, myristyl, palmityl, stearyl, arachidyl, oleil, decylidene, laurylidene, myristylidene, palmitylidene, stearylidene, arachylidene, oleilidene, benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylhexyl, phenyloctyl, cinnamyl, benzylidene, phenethylidene, phenylpropylidene, phenylbutylidene, phenylhexylidene or phenyloctylidene.
In another preferred embodiment of the present invention, the radi-
cals R2, R3, R4 and R5 are the same or different and each one is selected independently from elements of the group that comprises: hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, alkenyl groups, with sizes of Ci to Ci0 and with preference from C4 to C6 for alkyl and alkenyl and from C2 to C4 for hy- droxyalkyls and alkoxyalkyls. It also comprises aryl groups, preferably phenyl, arylalkyl and arylalkenyl, preferably from Ar-Ci to Ar-Ci2 and het- eroaryl and heteroarylalkyl, preferably from Het-Ci to Het-Ci2. It also comprises acyl, hydroxyacyl, alkoxyalkyl, alkoxycarbonyl, aminoacyl, hydroxy- carbonylacyl, and alkoxycarbonylacyl groups. More preferably each of the radicals R2, R3, R4 and R5 is selected independently from the group which comprises, ethyl, propyl, butyl, hexyl, decyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, cinnamyl, all of them may or may not be substituted, furyl, (for example 2-furyl and 2- furylethyl), thienyl (for example 2-thienyl and 2-thienylethyl), acethyl, hy- droxyacethyl, glycinyl, methoxycarbonyl, t-butoxycarbonyl, hemisuccinyl or hemiglutaryl.
In a preferred embodiment of the present invention, the compounds of formula III, X is nitrogen and is bound simultaneously to carbons 1 and 2, m is 4, R2 is hydrogen, alkyl (C3-Ci2) or arylalkyl (Ar-Ci to Ar-C6) and R1 is an alkyl or alkylidene group (CiO-Ci4). More preferably, X is nitrogen and R3 is hydrogen.
All the aforementioned compounds described may exist in the forms of steroisomers, epimers and enantiomers; so that the configuration of the substituents bound to the cyclic systems may be selected as cis or trans, with preference for the trans stereoisomers. The configuration of the ole- finic unsaturations may be selected as Y or Z, with preference for the Z stereoisomers.
Within the different types and variations considered in this document, those represented by the following structures are even more prefer- able substances, due to their greater antimycobacterial potency (see table 1 in the examples):
Group I, Compounds with cyclohexane ring and alkylidene or alkyl side chain Ci0/i4:
Group II, Compounds with alkyl chain Cu:
II-4 ll-5b ll-8c ll-9a
Group III, Compounds with alkyl side chain Cu:
The references in the present document to groups substituted in the compounds of the present invention relate to the moiety specified which may be substituted in one or more available positions by one or more suitable groups, for example, alkyl groups including those groups which have from 1 to approximately 12 carbon atoms or from 1 to approximately 6 carbon atoms and, more preferably, 1 - 3 carbon atoms; alkenyl groups including groups which have one or more unsaturated bonds and from 2 to approximately 12 carbon atoms or from 2 to approximately 6 carbon atoms;
hydroxyl; acyl (Ci-C6) such as acetyl or similar; alkoxycarbonylacyl; alkoxy- carbonyl; hydroxyacyl or hydroxycarbonylacyl.
The authors of the present invention have prepared compounds of this type with therapeutic purpose, and have examples and results of the in vitro antimycobactehal evaluation, the in vivo antituberculosis evaluation and the synthetic preparation of the compounds considered in the present invention.
The compounds of structure general I, both as compounds with particular structures Il and III, are obtained with variable yield, by controlled chemical procedures and expressly configured to synthesize them, starting from common raw materials, by generally known transformations and, in most cases, already used according to the state of the art. The present invention also comprises the intermediate compounds of the synthesis, with its variants and derivatives. In accordance with another aspect of this invention, several groups of compounds of general formulas I and III, were prepared by sequences of reactions which have been summarized in Schemes 1 , and several specific and representative examples of the compounds active against MTB are described and characterized chemically and biologically in later sections of this document:
///: H2/Pd/C(10%)/ MeOH. iv: AcOH/EtOAc. v: DIAD/PPh3/MTBE. vi: MsCI/pyr. vii: R1R2NH/LiCIO4/MeCN/Δ. viii: AcOH, EtOAc, 0 0C; ix: NH4OH/MeOH. x: NaN3/DMF/Δ. xi: a) pTsNHNH2/MeOH; b) NaH/toluene/Δ; xii: AnCPBAZCH2CI2ZNaHCO3; xiii: NH2(CH2)nNH2/LiCIO4/ MeCN/Δ. (The implicit variations of m, n, R, R2, R3, R4 and R5 in schemes 1, determine that each structure corresponds, in general, to a set or subfamily of compounds).
Schemes 1. Preparation of some subfamilies of type I and III compounds.
Several groups of compounds of general formula Il were prepared by reaction sequences such as those summarized in Schemes 2, and several specific and representative examples of the compounds active against MTB are described and characterized chemically and biologically in later sections of this document:
MsCI/Et3N/CH2CI2; b) NaN3/DMF; Pd-C/HCCI3. viii: Succinic or glutaric anhydride/ CH2CI2
(It only represents derivatives which correspond to the particular case of a subfamily of compounds II, corresponding to general structure I, with m = n = 0 and R1= C14H29. ).
Schemes 2. Preparations of several groups of type Il compounds.
Specific examples of the preparations and evaluations of compounds with particular structure II, which have been active against MTB are described in more detail in later sections of this document. Among the compounds of formula II, according to prior research which we have already published, are some substances with antiparasitic activity (cf. Del Olmo E, et al. 2002, Bioorg Med Chem Lett, vol. 12 pp. 659-62), others inhibit phospolipase A2, others are capable of causing cell apoptosis by caspase induction (cf. Lucas R et al., 2000, Bioorg. Med. Chem. Lett., vol. 10, pp. 285; Lucas R, et al. 2003, Biochem. Pharmacol, vol. 65, pp.1539- 49) and others are effective as antiparasitic vaccination adjuvants (cf. Del Olmo E. et al., 2006, Bioorg. Med Chem. Lett. 16, 6091-95).
Separations of diasteroisomers and resolutions of enantiomers, based on reactions with amines or chiral acids have been performed. See schemes 3:
111-13 1-13 1-13"
Reagents:
/: (R)-1 -phenylethylamine/EtOAc. #7: AC2O/ pyr. Hi: (S)-
MPA/DCC,DMAP/CH2Cl2 acid. iv: KOH(5%)/MeOH . v: H2/Pd-C/ MeOH.
Schemes 3. Resolution and separation of some diasteroisomers and enantiomers
Another aspect of the present invention comprises a pharmaceutical composition with any of the previously described antituberculosis agents or any of their mixtures, in addition to a pharmaceutically acceptable carrier.
Throughout the description and the claims the word "comprises" and its variants does not attempt to exclude other technical characteristics, additives, components or steps. For persons skilled in the art, other objects, advantages and characteristics of the invention will be partly inferred from the description and partly from the practice of the invention. The following examples and drawings are provided by way of illustration and do not aim to be limitative of the present invention.
DESCRIPTION OF THE FIGURES
Fig. 1.- Determination of mycobacterial colony forming units (CFU) in Balb/c mice, two months after having being infected with M. tuberculosis H37Rv and treated during two months with the compounds of this invention, with conventional drugs and with associations thereof.
Fig. 2.- Quantification of the percentage of pulmonary area affected by pneumonia in Balb/c tuberculosis-infected mice, after treatment during two months with the different compounds and associations. Fig.3.- Comparative effects on the mycobacterial colony forming units (CFU) in mice lung, after two-months infection either with sensitive H37Rv or MDR strains of M. tuberculosis and treatment during one month with one compound of this invention.
DETAILED EXPLANATION OF EMBODIMENTS
Below, the invention will be illustrated by assays carried out by the inventors, which reveal the special characteristics of the preparations, the potency of the bactericide action on sensitive and resistant mycobacteria, cultured in vitro, and its antituberculosis efficacy in the treatment of infected animals.
EXAMPLE 1 : Preparation of some compounds.
EXAMPLES 1a: Sequential preparation representative of some compounds of groups I-4, I-5 and III.
To the ylide formed in 50ml of THF and in argon atmosphere, 5.75 g of tetradecylphosphonium bromide and 7.3 ml_ of 1.6 M nBuLi solution in 1.6 M in hexane, at -78 0C, were added by dropping a solution of 0.60 g of cyclohexanone oxide in 10 ml_ of THF. It was left until reaching a.t. during
6h. The reaction crude, led, by chromatography, to 1.3 g of 3- tetradecylidenecycloxene oxide, 111-312, oily. Max IR: 2950, 2850, 1710, 1431 , 1465 and 940 cm"1 EM: 292 (5), 123 (74), 110 (100), 82.00 (36).
100 mg of the epoxyolefin 111-312 was made to react with 69μl_ of hexylamine and 55 mg of LiCIO4 in 20 ml_ of dry MeCN. The crude was purified by chromatography, eluting with MTBE, producing 120 mg of the
(Z)-frans-2-hexylamino-3-tetradecylidencyclohexanel, 1-40612, as yellowish oil. IR (v maxj: 3450, 2925, 2852, 1630, 1467, 1080, 979 cm"1. EM: 393.45 (4), 210.20 (100). 180 mg of 1-40612, in 10 ml_ of MeOH, were maintained at a.t., stirring for 24 h, in H2 atmosphere with slight overpressure and in the presence of 24 mg of Pd/C (10 %). The crude in AcOEt was washed with NH4OH (10%, it was processed in ordinary form to produce 182 mg of 1 ,2- trans- 7,3-c/s-2-hexylamino-3-tetradecylcyclohexanel, 1-5012, as almost colourless oil. IR (v maxj: 3300, 2920, 2853 and 1460 cm"1. EM: 367.40 (38), 184.15 (100), 324.35 (21 ).
Nuclear Magnetic Resonance data of 1H and 13C of representative compounds in Table 1
EXAMPLES 1b: Representative preparation of some compounds from groups 1-11, 1-12 and 1-13
1.30 g of 1-40612, in Mitsunobu reaction conditions, were made to react for 16 h with 1.5 ml_ of DIAD, in the presence of 1.05 g of PPh3. When the reaction concluded it was filtered through celite, it was evapo- rated and purified by chromatography, producing 1.0 g of the aziridine III-
13612, as rather colourless oil. IR (v maxj:: 2930, 2855, 1459, 1372, 1104 cm"1. EM: 375.5 (15), 206.20 (100), 192.25 (41 ); 304.30 ( 26)
64 mg of aziridine 111-13612 was dissolved in 2 ml_ of AcOEt and 2 ml_ of glacial AcOH. After 40 min of reaction, 78 mg of a crude were pro- duced, which was resolved by chromatography, giving 53 mg of 1-1161512
and 10 mg of cis 1-1261512, both oily and slightly yellowish with very similar properties. Max IR: 1-1161512: 3370, 2925, 2854, 1738, 1460, 1360, 1238, 961 cm"1; 1-1261512: 3376, 2924, 2854, 1736, 1624, 1458 cm"1. EM (1-1161512): 375.40 (M+, 15) 206.10 (100). Several pTsOH crystals were added to 63 mg of the acethoxy- dehvative 1-1141512, in 10 ml_ of MeOH, it was maintained at reflux for 6h, it was evaporated, the crude was conveniently handled and, by chromatography, 8 mg of the methoxylated product 1-114112, colourless oil and 38 mg of the alcohol 1-114012, as yellowish oil were produced. Properties of 1-114112: IR (v maxj: 2950, 2854, 1610, 1463, 1222, 1070, 940 cm"1 ; EM: 379.35 (M+, 2); 348.35 (5); 112.05 (100)
Properties of 1-114012: Max IR: 3377, 2924, 2854, 1460, 1120, 1022 cm"1. EMAR: 366.3731 (M+H+); theor. 366.3730;
Nuclear Magnetic Resonance data of 1H and 13C of representative compounds in Table 1
EXAMPLES 1c: Representative preparation of some diamines from groups 1-18 and 1-19.
134 mg of the hexylaziridine 111-13612 were mixed with 57 mg of BnNH2 and 58 mg of LiCIO4. The mixture was heated to 70 0C until disappearance of the azihdine (24 h). 140 mg of the diamine 1-186712 were produced from the crude, by chromatography and elution with MTBE, solid with m.p. = 115 0C . IR (v maxj: 3300, 3100, 2924, 2854, 1602, 1460, 1109, 972, 730, 700 cm"1. EMAR: 477.5169 (M+H+); theor. 477.5142 33 mg of the diamine 1-186712 were hydrogenated in the presence of 5 mg of Pd/C (10%), in MeOH during 15 h. 17 mg of the saturated diamine 1-190612 were produced by chromatography of the crude, oily. EMAR; 395.4371 (M+H+); theor. 395.4360.
Nuclear Magnetic Resonance of 1H and 13C of representative com- pounds in Table 1
EXAMPLES 1d: Representative preparation of some compounds of type III and some diamines from groups 1-18 and 1-19.
163 mg of P-TsNH2NH2 were added to 260 mg of the 4- tetradecylcyclohexanene 1-3012, dissolved in 10 ml_ of MeOH. The mixture was maintained at a.t. during 1 h and then cooled to crystallize 253 mg of hydrazone, which were used in the following stage. The previous hydra- zone dissolved in 10 ml_ of dry toluene was added to 34 mg of clean NaH. It was refluxed during 6 h, and finalized with two drops of water. The reaction crude was chromatographied producing 150 mg of the olefin 1-3112, colourless liquid. 82 mg of m-chloroperbenzoic acid dissolved in 2 ml_ of CH2CI2 were slowly added to 65 mg of this olefin and 70 mg of KHCO3 in 5 ml_ of CH2CI2, and it was left to react for 45 minutes at a.t. 3 ml_ of an aqueous solution of Na2S2O7 (5%) were added and the product was extracted, which chromatographied gave rise to 48 mg of the epoxide III- 3212, colourless oil. IR (v maxj: 2923, 2853, 1461 , 1257, 974, 794, 549 cm"1. EMAR; 295.3001 (M+H+), theor. 295.2995
42 mg of the epoxide 111-3212 were heated to reflux with 22 mg of hexylamine and 23 mg of LiCIO4 in 5 mL of dry MeCN. After 24 h the reaction was finalized and, by chromatography, 5 mg of 2-hexylamino-4- tetradecylcyclohexanel, 1-330612, and 6 mg of 2-hexylamino-5- tetradecylcyclohexanel 1-346012, were produced, both yellowish solids, from the crude. Properties of 1-330612: IR (v maxj: 3387, 2930, 2854, 1643, 1460, 1373, 1077, 724 cm"1. EM: 395.55 (M+, 2); 140.25 (100); 324,45 (25). Properties of 1-346012: Max IR: 3385, 2930, 2855, 1643, 1460, 1370, 1078, 725 cm"1. EM: 395.55 (M+, 2); 198.25 (100); 324,45 (25); 337.55 (44)
Nuclear Magnetic Resonance data of 1H and 13C of representative compounds in Table 1
EXAMPLES 1e.- Sequential preparation of compounds ll-2a, II-3,
IK ll-5b and 11 -6 b
18.5 g of 11-1 were dissolved in 250 ml_ of THF and it was cooled to 10 0C, successively 5.5 ml_ of /V-methylmorpholine were added and slowly 4.5 imL of CICOOEt, controlling the reaction t during 10 min. It was cooled to 0 0C, 5.60 g of NaBH4 and 747 ml_ of MeOH were added, drop by drop, it was maintained at 0° C for 15 min, then 10 min at a.t. It was extracted with AcOEt/H2O, dried with anhydrous Na2SO4, filtered and dried, chroma- tographied and 12.5 g of 2-(terf-butoxycarbonyl)aminohexadecanol, ll-2a, were produced, white solid with m.p. = 53 0C. IR with maximums at: 3350, 2917, 2850, 1687, 1536, 1366, 1251 and 1173 cm"1. EM (IQ) m/z: 380 (M+ + Na, 10); 358 (M+ + H+, 10); 302 (M+ - C4H7, 60); 258 (M+ -[Boc + 2H+], 58); 226 (M+ - [Boc + H2O], 22).
5.0 g of ll-2a, in 20 imL of DMF, were cooled to 0° C for 5 or 10 min, 335 mg of HNa were added and it was stirred at a.t. between 20 and 25 min. 1.6 ml_ of CIBn were added and it was maintained during 4 to 6 hours, controlling by TLC. It was dried and 5.7 g of reaction crude were obtained, which by chromatography led to 2.1 g of benzylether of 2-tert- butoxycarbonylaminohexadecanol, II-3, oil with characteristics: Max IR: 3354, 2918, 2849, 1686, 1530, 1370, 1350, 905, 715 cm"1. EM m/z: 448 (M+, 2); 348 (M+ -[Boc + H+], 20); 284 (M+ - Ci0Hi4O, 10); 226 (M+ -[Boc + C8H9O], 10); 154 [CnH22, 10); 91 (C7H7, 100).
70 mL of phenol 4M in CHCI3 and 22 mL of Me3SiCI 4M in CHCI3 were added to 3.0 g of II-3 and it was stirred and at a.t. during 3 min. Then 100 mL of 4M phenol were added to CHCI3 and 33 mL of Me3SiCI 4M in CHCI3 and it was stirred for 17 min. It was evaporated until dry and 2.36 g of reaction crude were produced; from which, by chromatography, 2.1 g (89%) of 2-aminohexadecanol benzylether (II-4), were produced, white solid with m.p. = 121 0C.
IR Spectrum (NaCI) with maximums at: 3064, 3029, 2923, 2852, 1650, 1658, 1496, 1402, 1363, 1101 , 1028 and 735 cm"1. EM m/z: 347 (M+, 2); 226 (M+ - C8H9O, 100); 91 (C7H7, 25).
To 200 mg of II-4 in 1.1 mL of DMF, were added 48 mg of NaHCO3,
0.1 imL of NEt3 and 1.45 ml_ of BrEt, maintaining stirring and at a.t. during 48 hours. It is extracted with AcOEt/H2O, dried with anhydrous Na2SO4, filtered and dried producing 158 mg (68%) of the 2- diethylaminohexadecanol benzylether (ll-5b), in form of yellowish oil. 10 mg of Pd/ C (10%) were added to 50 mg of ll-5b, in 2 imL of
MeOH and 0.5 ml_ of glacial AcOH, maintaining in hydrogen atmosphere with slight overpressure at 50° C during 2 h and 1 h at a.t.. 30 mg of a reaction crude were produced which, by chromatography, led to 20 mg of 2,2- diethylaminohexadecanol, ll-6b, solid with m.p. = 90 ° C. EM m/z: 312 (M+ - H.1 ); 284 (M+ -C2H5, 1 ); 254 (M+ - [C2H5 + H], 100); 88 (M+ - Ci6H32, 25); 58 (M+ -C2H4NO, 20).
Nuclear Magnetic Resonance data of 1H and 13C of representative compounds in Table 1
Nuclear Magnetic Resonance data of 1H and 13C of representative compounds in Table 1
EXAMPLES 1f: Preparation of compounds ll-7a, ll-7b, ll-8b, ll-9a, ll-9b and 11-10.
6 ml_ of TEA and 3 ml_ of MIC were added to 10.0 g of compound II- 2a, in 125 ml_ of CH2CI2 in small fractions, in cold and with stirring. It was maintained at 0° C during 30 min, followed by 30 min at a.t. The crude was repeatedly washed with aqueous solutions of 5% NaCI and of NaHCO3.
The organic phase was dried, filtered and evaporated producing 9.6 g of 2- terf-butoxycarbonylaminohexadecanol mesylate, which is directly used in the following stage. 4.0 g of NaN3 were added dissolved in DMF and with stirring, and it was heated to 50 - 60 ° C, for 6 h. It is evaporated, extracted with AcOEt/H2O, purified by chromatography, producing 4.24 g of 1-azido-
2-terf-butoxycarbonylaminohexadecane, with m.p. = 48 ° C, which is used in the following stage. The azide dissolved in 43 ml_ of THF, 850 mg of Pd/C, 1.26 g of NaBH4 were added, and dropping 100 imL of MeOH. It was stirred for 30 min, filtered, extracted with AcOEt/ water, the organic phase
is dried with anhydrous Na2SO4 anhydrous, filtered, dried and chroma- tographied giving rise to 2.6 g of 2-terf-butoxycarbonylamino- hexadecylamine, ll-7a, with m.p. = 56 0C. IR (v max): 3349, 2918, 2850, 1687, 1531 , 1469, 1365, 1349 and 1174 cm"1. EM m/z: 357 (M+ + H+, 12); 301 (M+ - C4H7, 45); 240 (M+ -[Boc + NH], 10).
2.6 ml_ of HCI (1 N) in Et2O were added to 50 mg of ll-7a in 2 ml_ of dry ether, and it was stirred, at a.t., until the formation of a precipitate, which is filtered and washed with Et2O, producing 36 mg of 1 ,2- hexadecylendiamine dihydrochlohde, ll-7b, white solid with m.p. = 88 0C. IR (v maxj:: 3750, 3620, 2953, 2851 , 1653, 1558, 1472 and 720 cm"1. EM m/z: 257 (M+ +H, 100); 240 (M+ - NH2, 31 ); 226 (M+ - CH4N, 35); 154 (CnH22, 70).
160 mg Of NaHCO3, 0.6 mL of TEA and 0.14 m L of BrEt were added to 307 mg of ll-7a dissolved in 1.8 mL of DMF, with stirring and at a.t, maintaining during 48. It was evaporated in a vacuum and extracted with
CHCI3/H2O and washed until pH neutral. The organic phase was dried, filtered and evaporated, producing 360 mg of Λ/,Λ/-diethyl-2-terf- butoxycarbonylamino-hexadecylamine, ll-8b, in oily form with IR (v max,):: 3358, 2964, 2853, 1704, 1495, 1389, 1365, 1245, 1174, 1062 and 775 cm" 1. EM m/z: 413 (M+ + H, 3); 357 (M+ - C4H7, 9); 298 (M+ - C5H8NO2, 1 ); 267 (M+ - [Boc + C2H6N], ); 226 (M+ - [Boc + C5Hi3N2], ); 86 (C5Hi2N, 60).
8.7 mL of phenol 4M CHCI3 and 2.9 mL of Me3SiCI 4M in CHCI3 were added to 360 mg of ll-8b and it was stirred at a.t. during 3 min. Then 13 mL of said phenol solution and 4 mL of Me3SiCI M were added and it was stirred for 17 minutes. It was evaporated until dry and 258 mg of reaction crude were added, which by chromatography led to 190 mg of 1 - diethylamino-2-hexadecylamine, ll-9b, yellow viscous oil with characteristics: IR (v maxJ:3410, 2922 2852, 1673, 1560, 1476 and 720 cm"1. EM m/z: 313 (M+ + H, 1 ); 296 (M+ - NH2, 1 ); 254 (M+ - C4Hi0, 1 ); 238 (M+ - C4Hi0N + 2H, 2); 226 (M+ - C5Hi3N, 10); 196 (Ci4H30, 1 ); 86 (C5Hi2N, 100);
72 (C4Hi0N, 80).
411 mg of 1 ,2-epoxyhexadecane and 0.2 ml_ of cyclohexylamine were maintained at reflux in 10 ml_ of MeOH during 2 h, followed by 23 h at a.t. The MeOH was evaporated and extracted with AcOEt/ HCI 2N(aq). 10% aqueous NaOH were added to the aqueous phase until slightly alkaline pH and it was extracted with AcOEt. The extract, conveniently handled, led to 330 mg of i-cyclohexylaminohexadecan-2-ol, 11-10; yellow solid, m.p. = 68 0C. IR (v maxj: 3382, 2918, 2850, 1455, 1215 and 1010 cm"1. EM m/z: 338 (M+ - H.1 ); 296 (M+ - C2H3O, 1 ); 266 (M+ - C7H13N, 1 ); 256 (M+ - C6Hn); 196 (Ci4H28, 1 ); 142 (C8Hi6ON, 5); 112 (M+ - Ci6H3iO, 100); 83 (C6H4, 5). NMR 1H: 0.89 t (6.9); 1.28 sa; 4.91 m; 4.91 sa ; 3.54 dd (11.6; 6.9),3.76 dd (11.6; 2.8); 3.18 m. NMR 13C: 14.1 (CH3); 22.7; 25.8; 25.9; 26.1 ; 29.4; 29.7; 31.8; 33.6; 34.0; 35.3 (CH2I; 69.9 (CH-OR); 52.4 (CH2-N); 56.7 (CH-N).
Table 1. NMR details of 1H and 13C of some representative compounds, active against MTB.
EXAMPLE 2.- RESULTS OF ANTIMYCOBACTERIAL ACTIVITY
EXAMPLE 2a.- IN VITRO ACTIVITY ASSAYS AGAINST STANDARD SENSITIVE STRAIN AND ANOTHER TDR STRAIN, RESISTANT TO ALL FIRST LINE ANTI-TB DRUGS
Various compounds of general formulas I and particular formulas Il and III, have considerable microbicide effects against Mycobacterium tuberculosis, both acting on sensitive strains (S) and multi-drug resistant strains (MDR), in comparison with the first line therapeutic agents. Protocol:
The in vitro evaluation was carried out in triplicate, according to the Alamar Blue microtechnique, following the protocol described by Jimenez-
Arellanes (Jimenez-Arellanes, A. et al. Phytother. Res. 2003, vol. 17 (8), pp. 903), on H37Rv strains (ATCC), Rockville, MD, USA; and CIBIN/UMF 15:99 (in Table CIBIN-99), resistant to all first line antituberculosis drugs, which was obtained from patients admitted to the Mexican Social Security hospital of Monterrey, NL, Mexico. Results of the evaluation:
The in vitro activity results found, according to said protocol, for different compounds of the invention, are illustrated in Table 2, which shows the values of Minimum Inhibitory Concentration (MIC, μM), in comparison with the clinical reference agent ethambutol (EMB).
Table 2. Antimycobacterial activity of representative compounds in Vitro against sensitive strain and TDR strain
MIC (μM) MIC (μM)
Compounds MTB MDR-TB Compounds MTB MDR-TB
H37Rv CIBIN-99 H37Rv CIBIN-99
GROUP I GROUP I
I-4093 336 336 1-114012 8.6 8.6
1-40113 283 283 1-1141512 123 61
I-4065 254 nd 1-1161512 >133 >133
I-4068 6.7 3.4 1-117112 >121 nd
I-4098 64 64 1-1241512 123 61
I-4078 36 36 1-186612 >105 Nd
I-40I8 78 39 1-184612 111 111
1-40610 8.6 nd 1-186412 7.0 14
1-40810 16.2 16.2 1-187612 >103 nd
1-40212 18.5 9.3 1-1871212 >110 55
1-40312 6.7 6.7 1-181012 >94 >94
1-40412 8.5 4.3 1-190612 15.8 nd
1-40612 5.9 5.9 1-360412 17.8 nd
1-401012 7.0 3.5
1-40912 17.9 nd GROUP Il
1-401112 8.0 8.0 ll-2a 84 84
1-40712 7.8 nd ll-2b 49 24
1-401212 68 nd II-4 3.6 3.6
1-401412 13.4 6.7 ll-5b 3.1 3.1
I -40420 52 13 ll-5e 72 72
I -40620 > 99 > 99 ll-5f 140 140
1-471212 112 nd M-5g 68 68
I-5008 98 49 ll-6a 23 11
1-50012 7.9 nd ll-7a 22 22
1-50412 4.3 4.3 ll-8b 133 133
1-50612 2.8 2.8 ll-δc 3.1 3.1
1-501012 27.7 13.8 ll-9a 4.0 8.0
1-601512 142 71 11-10 11.5 23
1-6161512 133 nd GROUP III
111-13412 144 144
EMB 7.2 58
111-13712 >131 66 nd: value not determined
It is appreciated in the Table, that a large number of compounds evaluated in this invention are more potent (MIC values less than 7.2 μM) than the clinical use agent EMB against the mycobacteria H37Rv, sensitive for the first line drugs and that an even greater number (values of MIC less than 58 μM), are so against the strain CIBIN-99, resistant to all first line drugs.
EXAMPLE 2b.- IN VITRO ASSAYS AGAINST 10 STRAINS OF
MTB WITH VARIOUS DEGREES OF RESISTANCE, PDR, MDR AND TDR.
Complementarily, Table 3 shows results of the in vitro evaluation of some compounds of this invention to mycobacterial strains isolated from different patients refractory to the anti-TB treatments, carried out with first line drugs. In the Table, it can be clearly seen that compounds 11-4 and ll-5b are very effective against mycobacteria with any resistance profile against conventional drugs; whilst not to such an extent, compound ll-9b is also quite effective.
Table 3. Activity of representative compounds of this invention against strains of MTB, with different profiles of poly- (one strain) and multiresistance (4 strains) and of resistance to all first line antituberculosis drugs (6 strains)
*S: streptomycin, I: isoniazid, R: rifampicin, E: EMB, P: pyrazinamide # R: resistant, S: sensitive
EXAMPLE 3.- IN VIVO ASSAYS ON ANIMALS INFECTED WITH PROGRESSIVE PULMONARY TUBERCULOSIS. Protocol:
Balb/c mice, 6 to 8 weeks old are infected by intratracheal injection with 1x106 bacteria of the virulent strain of M. tuberculosis H37Rv. This experimental procedure generates progressive pulmonary tuberculosis, which takes place in two phases. The first, which corresponds to the first month of infection, produces chronic perivascular, peribronchial and interstitial inflammation, with the mycobacteria controlled by activated macro- phages and Th-1 lymphocytes. In the second phase, progressive pneumonia occurs with logarithmic increase in the number of live bacteria in the lung which cases death of them. Assay:
6 groups of 5 mice were infected and the treated was started two months post-infection.
The first group were treated with ll-5b; the second group received the compound II-4, the third group was administered ll-5b plus hfampicin (10mg/kg), isoni- azid (10mg/kg) and pyrazinamide (30mg/kg); the fourth group were treated with the compound II-4 plus said drugs; the fifth group only received said drugs and the sixth group only received the carrier (saline solution). The administration was carried out by nasogastric probe, daily during two months, at the end of which all the animals were sacrificed and the lungs were extracted. One of the lungs from each mouse were used to determine the number of live bacteria, by the quantification of colony forming units, the other lung was used for the histological study; specifically the percentage of surface affected by pneumonia was determined by computerized imaging analysis. Results:
Shown in Fig. 1 and 2.
Effects observed:
Figure 1 shows the values of mycobacterial colony forming units (CFU) after treatment with compounds ll-5b (in figures UCI-14), and II-4 (in figures UCI-05), with conventional drugs (3F), with the combination of ll-5b with three drugs (14+3F), or the combination of II-4 with three drugs (05+3F). The bars correspond to the mean of 5 animals per each group. Ctr corresponds to the control group which did not receive treatment.
In comparison with the untreated control group, it is observed that: -The animals treated with compound ll-5b reduced 3 times the pulmonary baccilar load.
-Those treated with compound II-4 decreased 15 times.
-The mice that received the three conventional drugs decreased by 30 times.
-In the animals treated with ll-5b + 3 drugs, the efficacy of compound II-4 alone was almost equalled.
-The association of compound II-4 with the 3 drugs was by far the most effective treatment, as it decreased by 100 times the quantity of live mycobacteria in the lung.
These results correlate adequately with the histological study, per- formed after sacrificing the animals, after the assay, whose results were shown in Fig. 2, showing:
- that the animals treated with the 3 conventional drugs have a pneumonic area affected corresponding to 6% of the pulmonary surface.
- that the animals treated with the association ll-5b + 3 drugs have a lower pneumonic area, corresponding to 4% of the pulmonary surface.
- that the animals treated with the association II-4 + 3 drugs have an even lower pneumonic area, only corresponding to 2% of the pulmonary surface.
- The mice exclusively treated with ll-5b showed a pneumonic area simi- lar to that of the untreated controls.
- The animals treated exclusively with compound II-4 showed a 20% re-
duction in comparison with the controls.
Considering that the current treatment of TB is based on the use of three to five drugs, these observations showed the usefulness of the compounds set down in this invention; since compound 11-4, by itself and better associated to other drugs, and compound ll-5b in combined treatments, constitute new therapeutic tools to successfully combat tuberculosis. The association of 11-4 with conventional drugs substantially boosts its effect making it the best treatment.
EXAMPLE 4.- IN VIVO ASSAYS ON ANIMALS INFECTED WITH SENSITIVE AND MDR STRAINS OF MYCOBACTERIUM TUBERCULOSIS
Following the same protocol of infection and treatment as described in example 3, compound 1-40612 (UCI 107 in Fig. 3) alone was administered to Balb/c mice infected with the sensitive H37Rv or the CIBIN-99 (SIREP- resistant, Table 3) strains of M. tuberculosis. The results showing its anti- TB efficacy are shown in Figure 3. With respect to controls, after one month of treatment at the very low dosage of 7μg/mouse/day (0.32 mg/kg/day), compound 1-40612 reduced the CFU to almost 15 %, in the case of H37Rv infection, and to less than 44 %, in that of the CIBIN-99 MDR strain.
These results support that compound 1-40612 could be used, in association with established drugs, for treating efficiently, either sensitive to common anti-TB drugs or MDR tuberculosis.
Claims
1. Use of the compound of general formula I,
R5 I or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof, for the preparation of a composition for its use as a drug in the treatment of tuberculosis and/or resistant tuberculosis, where:
R1 is a radical substituted or unsubstituted, linear or branched, which is selected from the group which consists of alkyl (C4-C2o), alkenyl (C4-C2O), alkylidene (C4-C2o), arylalkyl (Ar-Ci to Ar-Ci2), arylalkenyl (Ar-C3 to Ar-Ci2) or arylalkyl idene (Ar-Ci to Ar-Ci2). It may be bound to any of the carbon atoms of the ring.
R2, R3, R4 and R5, are the same or different and each one is se- lected independently from the group formed by hydrogen (H); alkyl (C1-C10) substituted or unsubstituted; hydroxyalkyl (C1-C10) substituted or unsubstituted; alkoxyalkyl (C1-C10) substituted or unsubstituted; alkenyl (C1-C10) substituted or unsubstituted; aryl substituted or unsubstituted; arylalkyl (Ar- Ci to Ar-Ci2) substituted or unsubstituted, heteroaryl substituted or unsub- stituted; heteroarylalkyl (Het-Ci to Het-Ci2) substituted or unsubstituted; or an acyl, alkoxycarbonylacyl, alkoxycarbonyl, hydroxyacyl or hydroxycar- bonylacyl group and any of their salts, organic and inorganic esters or amides.
X and Y are the same or different and each one independently represents a Nitrogen (N) or Oxygen (O) atom. m has values between 0 and 6.
When X is bound to carbons 1 and 2 represented in formula I, Y, R4 and R5 do not exist. When Y is bound to carbons 1 and 2 represented in formula I, X, R2 and R3 do not exist. When X is Oxygen R3 does not exist and when Y is Oxygen R5 does not exist.
2. Use of the compound according to the previous claim wherein the radical R1 is selected from the group which consists of alkyl (Ci0-Ci6), al- kenyl (Ci0-Ci6) or alkylidene (Ci0-Ci6), arylalkyl (Ar-Ci to Ar-C6), arylalkenyl (Ar-C3 to Ar-C6) or arylalkylidene (Ar-Ci to Ar-C6).
3. Use of the compound according to the previous claim, wherein the radical R1 is selected from the group which consists of alkyl (Ci0-Ci4), or alkylidene (Ci0-Ci4).
4. Use of the compound according to any of the previous claims, wherein m is 4; X is nitrogen, Y is oxygen, R2 and R4 are hydrogen, R3 is an alkyl (C3-Ci0) and R1 is an alkyl (Ci0-Ci4) or an alkylidene (Ci0-Ci4).
5. Use of the compound according to the previous claim, wherein the radical R1 is an alkyl (Ci2-Ci4) and R3 is an alkyl (C4-C6)
6. Use of the compound according to claim 4, wherein the radical R1 is an alkylidene (Ci0-Ci4) and R3 is an alkyl (C3-C6)
7. Use of the compound according to either of claims 1 or 2, wherein m is 4; X is oxygen, Y is nitrogen, R2 and R4 are hydrogen, R5 is an alkyl (C2- C6) and R1 an alkylidene (Ci0-Ci6).
8. Use of the compound according to either of claims 1 or 2, wherein m is 4; X and Y are nitrogen, R2 and R4 are hydrogen, R3 and R5 are alkyl (C2-C6) and R1 an alkylidene (Ci0-Ci6).
9. Use of the compound according to claims 1 or 2, wherein m is 0 and positions 1 and 2 are bound by a single bond.
10. Use of the compound according to the previous claim, wherein X is nitrogen, R1 is an alkyl (Ci2-Ci6), R2 is hydrogen, alkyl (Ci-C6), cycloalkyl (C5-C6), benzyl, t-butoxycarbonyl, ethoxycarbonylmethyl, hydroxycarbonyl- propionyl, hydroxycarbonylbutyryl, ethoxyoxycarbonylbutyryl, R3 is hydrogen or alkyl (Ci-C6), R4 is hydrogen, alkyl (CrC6), ethoxyoxycarbonylbutyryl or aryl, and R5 is hydrogen or alkyl (Ci-C6) or does not exist when Y is oxygen.
11. Use of the compound according to the previous claim, wherein X is nitrogen, R1 is an alkyl (Ci2- Ci4), R2 is hydrogen, alkyl (CrC4) or t- butoxycarbonyl, R3 is hydrogen or alkyl (CrC4), R4 is hydrogen or aryl and R5 is hydrogen or alkyl (CrC6) or does not exist when Y is oxygen.
12. Use of the compound according to any of claims 9 to 11 , wherein Y is oxygen.
13. Use of the compound according to claim 9, wherein Y is nitrogen.
14. Use of the compound according to claims 1 or 2, wherein X is bound simultaneously to carbons 1 and 2 represented in formula (I).
15. Use of the compound according to the previous claim, wherein m is 4; R2 is hydrogen, alkyl (C3-Ci2) or arylalkyl (Ar-Ci to Ar-C6) and R1 is an alkyl or an alkylidene (Cio- Ci4).
16. Use of the compound according to the previous claim, wherein X is nitrogen and R3 is hydrogen.
17. Use of the compound according to any of the previous claims, wwhheerreeiinn XX RR22RR33 oorr YYRR44RR55 aarree aa ccaarboxyl group in the form of free acid, salt, ester or free N-substituted amide.
18. Use of the compound according to any of the previous claims, wherein the radical R1 is selected from the group which consists of decyl, lauryl, myristyl, palmityl, stearyl, arachidyl, oleil, decylidene, laurylidene, myristylidene, palmitylidene, stearylidene, arachylidene, oleilidene, benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylhexyl, phenyloctyl, cinnamyl, benzylidene, phenethylidene, phenylpropylidene, phenylbutylidene, phenylhexylidene or phenyloctylidene.
19. Use of the compound according to any of the previous claims wherein R2, R3, R4 and R5 are the same or different and each one is selected independently from the group formed by hydrogen, ethyl, propyl, butyl, hexyl, decyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, cin- namyl (substituted or not) furyl, thienyl, acethyl, hydroxyacethyl, glycinyl, hemisuccinyl or hemiglutaryl.
20. Use of a pharmaceutical composition for the treatment of tuberculosis or resistant tuberculosis, which also comprises one of the compounds of general formula I, isolated or associated to other drugs, in addition to a pharmaceutically acceptable carrier.
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