EP1237546A2 - Composes servant a traiter des maladies d'origine virale - Google Patents

Composes servant a traiter des maladies d'origine virale

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Publication number
EP1237546A2
EP1237546A2 EP00965517A EP00965517A EP1237546A2 EP 1237546 A2 EP1237546 A2 EP 1237546A2 EP 00965517 A EP00965517 A EP 00965517A EP 00965517 A EP00965517 A EP 00965517A EP 1237546 A2 EP1237546 A2 EP 1237546A2
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EP
European Patent Office
Prior art keywords
group
alkyl
inhibitor
interferon
formula
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EP00965517A
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German (de)
English (en)
Inventor
Yin Hwee Tan
John Stanford Driscoll
Sim Mui Mui
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Institute of Molecular and Cell Biology
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Institute of Molecular and Cell Biology
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Publication of EP1237546A2 publication Critical patent/EP1237546A2/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
    • C07D215/52—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4 with aryl radicals attached in position 2
    • 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
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • hepatitis C A major problem with the study of hepatitis C is a lack of in vitro cell-based and animal model systems. To date, there is no good replicative cell system to assay for activity against hepatitis C virus. The only animal model for hepatitis C is the chimpanzee. However, chronic hepatitis C infection is difficult to establish in chimpanzees. This fact further complicates the use of chimpanzees as an animal model system.
  • “Surrogate” virus/host cell systems were used to search for antiviral compounds which can be used as antiviral drugs to treat patients with acute and chronic hepatitis C in particular, and flavivirus, rhabdovirus and paramyxovirus infections in general.
  • Several families of compounds which are structural and biological analogues were selected for testing for their antiviral activities in human and monkey cells against three viruses of the Flaviviridae family (yellow fever, kunjin and dengue viruses), a virus of the Rhabdoviridae family (vesicular stomatitis virus; VSV) and a virus of the Paramyxoviridae family (respiratory syncytial virus;
  • Ribavirin was also tested.
  • the dihydroorotate dehydrogenase inhibitors were always more potent than, and indeed act synergistically in combination with, an interferon.
  • An inhibitor of dihydroorotate dehydrogenase can also be administered in combination therapy with an inhibitor of a second enzyme selected from inosine monophosphate dehydrogenase, guanosine monophosphate synthetase, cytidine triphosphate synthetase and S-adenosylhomocysteine hydrolase, optionally in further combination with an interferon, to provide a synergistic antiviral effect.
  • a second enzyme selected from inosine monophosphate dehydrogenase, guanosine monophosphate synthetase, cytidine triphosphate synthetase and S-adenosylhomocysteine hydrolase, optionally in further combination with an interferon, to provide a synergistic antiviral effect.
  • the present invention provides a method of treating a host infected with a virus of the Flaviviridae, Rhaboviridae or Paramyxoviridae family, which method comprises the step of administering to the host an inhibitor of dihydroorotate dehydrogenase.
  • the invention additionally provides:
  • a method for identifying an anti-flavivirus, anti-rhabdovirus or anti- paramyxovirus agent comprises testing a test compound for its ability to inhibit dihydroorotate dehydrogenase.
  • Dihydroorotate dehydrogenase (DHO-DH, DHOD, EC 1.3.3.1) is the fourth enzyme in the de novo pyrimidine biosynthetic pathway. Any inhibitor of this enzyme is used in the present invention.
  • a technique for identifying inhibitors of dihydroorotate dehydrogenase using a computer algorithm is described in Biochemical and Biophysical Research Communications 223. 654-659 (1996) and in Biochemical Pharmacology vol 49, No. 7, pp 947-954 (1995).
  • the technique involves the correlation of the biological activity of a given compound with the biological activity of known DHOD inhibitors such as dichloroallyl lawsone and Brequinar.
  • the COMPARE computer algorithm may be used for the correlation (see J. Natl. Cancer Inst. 81, 1088-1092, 1989).
  • Mouse liver dihydroorotate dehydrogenase An in vitro assay for inhibitors of mouse liver dihydroorotate dehydrogenase is described in J. Biol. Chem. 270, No. 38, pages 22467-22472 (1995).
  • Mouse liver dihydroorotate dehydrogenase may be prepared as described in Biochem. J. (1998), 336, 299-303 (1998).
  • Inhibitors of dihydroorotate dehydrogenase are described, for example, by Douglas G. Batt in Exp. Opin. Ther. Patents (1999) 9 (1), 41-54, the contents of which are incorporated herein by reference.
  • the invention provides a method ofor identifying an anti-flavivirus, anti-rhabdovirus or anti-paramyxovirus agent, which method comprises: (a) providing a test compound;
  • test compound has activity as an inhibitor of dihydroorotate dehydrogenase
  • test compound selecting the test compound as an anti-flavivirus, anti-rhabdovirus or anti-paramyxovirus agent if it is shown to have activity in step (b).
  • the candidate test compounds may be tested for dihydroorotate dehydrogenase inhibitory activity by any known technique, such as those mentioned above.
  • dihydroorotate dehydrogenase inhibitors are preferred for use in the present invention. These are:
  • each A is independently selected from the group consisting of hydrogen, halogen, perhaloalkoxy, amino C,-C 8 alkyl, NO 2 , CN, SO 2 CH 3 , C,-C 8 alkyl, C,-C 8 alkoxy, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkenyl, aryl, aryloxy, C r C 6 perhaloalkyl and Y; or two adjacent groups A on ring b form, together with the phenyl ring to which they are attached, a naphthalene ring system; R is cyclohexyl, phenoxy or benzoxy, or a phenyl ring which is unsubstituted or substituted by a group A as defined above; or
  • R and an adjacent group A on ring b form, together with the phenyl ring to which they are attached, a naphthalene or phenanthrene ring system;
  • Y is selected from the group consisting of COOM, CONHR', SO 3 M and hydrogen;
  • M is selected from the group consisting of H, Li, Na, K and O.5 Ca;
  • R ' is C,-C, 0 alkyl;
  • Z is selected from the group consisting of hydrogen, NH 2 , OH, C r C 8 alkyl, C 3 -C 7 cycloalkyl, aryl and C,-C 6 perhaloalkyl, or
  • R' is hydrogen and R" is a thiophene ring or a group of formula (i 1 ) or (ii'):
  • R' and R" form, together with the carbon atoms (denoted “C") to which they are attached, a ring system of formula (iii') or (iv'):
  • R" ' is H or halogen and R iv is H or C, - C 6 alkoxy;
  • each A 1 is independently selected from the group consisting of hydrogen, C,-C 8 alkyl, C,-C 8 alkoxy, C 2 -C 8 alkenyl, C -C 8 alkynyl, C 3 -C 7 cycloalkyl, halogen, unsubstituted aryl, X-substituted aryl, NO 2 , CN, COOR, CONHR and NHR;
  • X is selected from the group consisting of halogen, NO 2 , C,-C 8 alkyl, aryl, fused aryl and COOR;
  • R is selected from the group consisting of hydrogen and C,-C 8 alkyl
  • B is selected from the group consisting of C,-C 8 alkyl, H, CF 3 and aryl which is unsubstituted or substituted by halogen, C,-C 8 alkoxy, C,-C 8 alkyl, NO 2 , aryl or fused aryl;
  • a 2 is selected from the group consisting of hydrogen, C,-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -
  • R 1 is selected from the group consisting of hydrogen,, C r C 8 alkyl and OH; X 1 is hydrogen or halogen; and
  • B 1 , Y 1 and Z 1 are each independently selected from hydrogen, OH, C,-C 8 alkyl, halogen, CN, NO 2 and CF 3 ;
  • each A 3 is independently selected from the group consisting of hydrogen, C,-C 8 alkyl, C,-C 10 alkoxy, halogen and N(R 2 ) 2 ;
  • X 2 is selected from the group consisting of O, S and NR 2 ;
  • R 2 is selected from the group consisting of hydrogen, C,-C 4 alkyl and aryl;
  • Y 2 is selected from the group consisting of COOM 1 and SO 3 M';
  • M 1 is selected from the group consisting of H, Li, Na, K and 0.5 Ca.
  • a halogen atom may be fluoro, chloro, bromo or iodo.
  • a C,-C 8 alkyl group is suitably a C,-C 4 alkyl group.
  • a C r C 4 alkyl group is typically methyl, ethyl, n- propyl, isopropyl or butyl.
  • a C 3 -C 7 cycloalkenyl group is typically cyclohexenyl.
  • a C 3 -C 7 cycloalkyl group is typically a cyclopentyl or cyclohexyl group.
  • a C r C 6 perhaloalkyl group may be a C,-C 4 perhaloalkyl group.
  • the halo atom may be chloro or fluoro.
  • a particularly suitable perhaloalkyl group is trifluoromethyl.
  • An aryl group is typically a phenyl.
  • a C 2 -C 8 alkenyl group is suitably a C 2 -C 4 alkenyl group.
  • a C 2 -C 8 alkynyl group is suitably a C 2 -C 4 alkynyl group.
  • Fused aryl is generally naphthyl.
  • a C r C 10 alkoxy group is preferably a C,-C 6 alkoxy group, for example a C,-C 4 alkoxy group such as methoxy or ethoxy.
  • Perhaloalkoxy is, for example, OCF 3 , OCCl 3 or OCBr 3 Preferably it is OCF 3 .
  • Aryloxy is, for example, phenoxy or benzyloxy.
  • Compounds of formula (I) in which Z is a bridging moiety as defined above may be prepared as described in US-A-4918077, US-A-5002954, WO9506640, US-A-5371225, EP-A-721942, JP10231289, Organ Biol. (1997) 4(2): 43-48 and 49-57, JP-6306079-A2 and 216 th ACS Meeting, Boston USA (1998) ORGN 132.
  • Compounds of formula (F) may be prepared using the same synthetic strategy as that described in US-A-4680299.
  • Preferred compounds of formula (I) are those in which: each A is independently selected from the group consisting of hydrogen, halogen (preferably F) amino C,-C 8 alkyl (preferably NH 2 (CH 2 )-), C,-C 8 alkyl (preferably CH 3 ) and C,-C 6 perhaloalkyl (preferably CF 3 );
  • Z is selected from the group consisting of hydrogen, C,-C 8 alkyl (preferably CH 3 ), NH 2 and OH, or
  • the substituent A in ring a is preferably OCF 3 , halogen (most preferably F) or NH 2 (CH 2 ) 2 -, preferably bonded at position 6 of the quinoline ring system.
  • the substituent A in ring b is preferably hydrogen.
  • Examples of compounds of formula (I) include those of formula (la):
  • each A is independently selected from the group consisting of hydrogen, halogen, amino C,.C 8 alkyl, NO 2 , CN, SO 2 CH 3 , C,-C 8 alkyl, C 3 -C 7 cycloalkyl, aryl, C,-C 6 perhaloalkyl and Y;
  • Y is selected from the group consisting of COOM, CONHR ' SO 3 M and hydrogen;
  • M is selected from the group consisting of H, Li, Na, K and O.5 Ca;
  • R' is C,-C,o alkyl
  • the substituent A in ring c of formula (la) is preferably hydrogen or ortho- halogen (most preferably ortho-F).
  • R 1 is H, a halogen or OCF 3 ;
  • R 2 is H or C,-C 6 alkyl
  • R 3 is H or OR 6 wherein R 6 is H or C,-C 6 alkyl; R 4 is H or C,-C 6 alkyl; or R 3 and R 4 form, together with phenyl ring b to which they are attached, a naphthalene ring; and
  • R 5 is cyclohexyl, phenoxy or benzoxy, or a phenyl ring which is unsubstituted or substituted by halogen; or R 4 and R 5 form, together with phenyl ring b to which they are attached, a phenanthrene ring.
  • Brequinar can be prepared as described in US-A-4680299 (Example 28).
  • M is selected from the group consisting of H, Li, Na, K and 0.5 Ca;
  • R 22 is H or C,-C 6 alkyl
  • R 33 is H or OR 6 wherein R 6 is H or C,-C 6 alkyl
  • R 44 is H or C,-C 6 alkyl
  • R 55 is phenyl, cyclohexyl, phenoxy or benzoxy.
  • Preferred examples of the compounds of formula (Ila) are: 2-(4-biphenylyl)-6-trifluoromethoxy-quinoline-4-carboxylic acid (compound I2K5); 2-(4-biphenylyl)-3-methyl-6-trifluoromethoxy-quinoline-4-carboxylic acid (compound I2K55);
  • (Ila) may be prepared by the synthetic route described in US-A-4680299 mentioned above. This involves the Pfitzinger reaction, whereby an appropriately substituted isatin is condensed with an appropriately substituted ketone (J. Org. Chem. 18, 1209,
  • the invention further provides a process for producing a compound of formula (Ila) as defined above, which process comprises a) condensing the trifluoromethoxy-substituted isatin compound of the following formula (IX):
  • R , R , R and R are as defined above for formula (Ila), in the presence of a base;
  • the base used in step (a) may be an inorganic base or an organic base.
  • Preferred bases include potassium hydroxide and sodium hydroxide.
  • the reaction is generally conducted in a solvent.
  • the solvent is preferably ethanol.
  • Preferred compounds of formula (I') have the following substitution patterns:
  • Preferred compounds of formula (III) are those in which: each A 1 is independently selected from the group consisting of hydrogen, halogen, C
  • B is selected from the group consisting of hydrogen, C,-C 8 alkyl, phenyl and benzyl, the said phenyl and benzyl being unsubstituted or substituted by halogen (preferably Cl or Br), C,-C 8 alkoxy (preferably C,-C 4 alkoxy such as OCH 3 ) or C,-C 8 alkyl (preferably C
  • the substituent is preferably at position 4 of the phenyl ring.
  • the group A 1 in ring a is preferably H.
  • the group A 1 in ring b is preferably H, or it is para-C,-C 8 alkoxy or para-halogen (preferably Cl or Br).
  • BNID l-(p-bromophenyl)-2-methyl-lH-naphth[2,3- d]imidazole-4,9-dione
  • the compounds of formula (III) may be prepared as described in J. Med.
  • BNID can be prepared as described in J. Med. Chem.
  • a 2 is selected from the group consisting of hydrogen, C,-C 8 alkyl (preferably C,- C 4 alkyl such as CH 3 ) and halogen;
  • B is hydrogen or OH
  • X 1 is hydrogen; and Y 1 and Z 1 are each independently selected from the group consisting of hydrogen, halogen (preferably Cl) and C,-C 8 alkyl (preferably C,-C 4 alkyl such as CH 3 ).
  • dichloroallyl lawsone which has the formula (VI):
  • the compounds of formula (V) may be prepared as described in US-A- 3655699 or WO9106863, or by submitting compounds produced as described in these documents to routine synthetic modifications and interconversions which are well known in organic chemistry.
  • Dichloroallyl lawsone can be prepared as described in US-A-3655699.
  • Preferred compounds of formula (VII) are those in which each A 3 is hydrogen or C
  • each A 3 in formula (VII) is positioned meta to the linking group B 2 , and each Y 2 is positioned ortho to the linking group X 2 .
  • the interferon for use in the present invention may be an interferon ⁇ , such as interferon ⁇ 2 or ⁇ 8, or interferon ⁇ .
  • interferon includes fragments which have interferon activity and mutant forms of an interferon which retain interferon activity.
  • sequence of an interferon ⁇ or ⁇ may have been modified to enhance activity or stability as reported in US-A-5582824, US-A-5593667 or US- A-5594107.
  • the interferon may have been purified from natural sources or may be a recombinant interferon.
  • the species of interferon is generally the same as the host species to which the interferon is administered.
  • the invention is particularly applicable to the treatment of flavivirus infections in humans.
  • a human interferon such as human interferon ⁇ 2 or ⁇ 8 or human interferon ⁇ is used.
  • the interferon ⁇ 8, particularly the human interferon ⁇ 8, typically has a specific activity of more than 0.3xl0 9 , generally from 0.3xl0 9 to 3xl0 9 and preferably from 0.5x10 9 to 3x10 9 , IU per mg protein.
  • the human interferon ⁇ typically has a specific activity of from 4xl0 8 to 8xl0 8 , preferably from 4.8x10 8 to 6.4x10 8 , IU per mg protein.
  • Interferon ⁇ and interferon ⁇ specific activities are determined according to reference standards MRC 69/19 and Gb-23 -902-531 respectively. Specific activity is determined according to a modification of the method of Armstrong, Applied Microbiology 21, 723, 1971, in which 0.2 ⁇ g/ml of actinomycin D is included in the viral challenge and the viral induced cytopathic effect is read directly.
  • the interferon such as the interferon ⁇ 2 or ⁇ 8 or the interferon ⁇ is preferably obtainable by the methodology of WO 96/30531.
  • the interferon is thus obtainable by a process comprising culturing mammalian cells transfected with a nucleic acid vector comprising: (i) a coding sequence which encodes the interferon and which is operably linked to a promoter capable of directing expression of the coding sequence in mammalian cells in the presence of a heavy metal ion;
  • the transfected mammalian cells may be cells of a human or animal cell line.
  • the cells may be BHK, COS, Vero, human fibroblastoid such as CIO, HeLa, or human lymphoblastoid cells or cells of a human tumour cell line.
  • the cells are CHO cells, particularly wild-type CHO cells.
  • transfected cells will have all or part of such a vector integrated into their genomes. Such cells are preferred because they give stable expression of the coding sequence contained in the vector. Preferably, one or more copies of the entire vector will be integrated, with cells having multiple integrated copies of the vector, for example from 20 to 100 copies or more, being particularly preferred because these cells give a high stable level of expression of the coding sequence contained in the vector.
  • cells having less than complete sections of the vectors integrated into their genomes can be employed if they are functionally equivalent to cells having the entire vector integrated into their genomes, in the sense that the integrated sections of the vector enable the cell to express the coding sequence and to be selected for by the use of heavy metals.
  • cells exhibiting partial integration of a vector may be employed if the integrated element or elements include the coding sequence operably linked to its associated promoter and the metallothionein marker sequence operably linked to its associated promoter.
  • Any promoter capable of enhancing expression in a mammalian cell in the presence of a heavy metal ion such as Cd 2+ , Cu 2+ and Zn 2+ may be operably linked to the interferon coding sequence.
  • a suitable promoter is a metallothionein gene promoter.
  • the mouse metallothionein gene I (mMTl) promoter is preferred.
  • Suitable promoter/enhancer combinations for the coding sequence include the mMTl promoter flanked upstream with a mouse sarcoma virus (MSV) enhancer (MSV-mMTl) and a Rous sarcoma virus (RSV) enhancer upstream of a mouse mammary tumour virus (MMTV) promoter.
  • MSV mouse sarcoma virus
  • RSV Rous sarcoma virus
  • MMTV mouse mammary tumour virus
  • any promoter capable of enhancing expression in a mammalian cell in the presence of a heavy metal ion such as Cd 2+ , Cu 2+ and Zn 2+ may be operably linked to the metallothionein gene such as a human metallothionein gene.
  • the marker sequence gene is a human metallothionein gene, such as the human metallothionein gene II A, which has its own promoter.
  • the second selectable marker sequence is a neo gene. More than one type of this gene exists in nature: any specific neo gene can be used in a vector of the invention.
  • One preferred neo gene is the E.coli neo gene.
  • the promoter for the neo gene is capable of directing expression of the gene in a mammalian cell.
  • Suitable promoters are the cytomegalovirus (CMV) early promoter, the SV40 promoter, the mouse mammary tumour virus promoter, the human elongation factor 1 ⁇ -P promoter (EF-l ⁇ -P), the SR ⁇ promoter and a metallothionein gene promoter such as mMTl .
  • CMV cytomegalovirus
  • the promoter may also be capable of expressing the neo gene in bacteria such as E.coli in which a vector may be constructed.
  • the interferon coding sequence (i) and the marker sequences (ii) and (iii) are thus each operably linked to a promoter capable of directing expression of the relevant sequence.
  • operably linked refers to a juxtaposition wherein the promoter and the coding/marker sequence are in a relationship permitting the coding/marker sequence to be expressed under the control of the promoter.
  • there may be elements such as 5' non-coding sequence between the promoter and coding/marker sequence.
  • sequences can be included in the construct if they enhance or do not impair the correct control of the coding/marker sequence by the promoter.
  • the vector may be a DNA or RNA vector, preferably a DNA vector.
  • the vector is a plasmid.
  • Each of the sequences (i) to (iii) will typically be associated with other elements that control their expression.
  • the following elements are generally present, usually in a 5' to 3' arrangement: a promoter for directing expression of the sequence and optionally a regulator of the promoter, a translational start codon, the coding/marker sequence, a polyadenylation signal and a transcriptional terminator.
  • the vector typically comprises one or more origins of replication, for example a bacterial origin of replication, such as the pBR322 origin, that allows replication in bacterial cells.
  • one or more eukaryotic origins of replication may be included in the vector so that replication is possible in, for example yeast cells and/or mammalian cells.
  • the vector may also comprise one or more introns or other non-coding sequences 3' or 5' to the coding sequence or to one or more of the marker sequences.
  • Such non-coding sequences may be derived from any organism, or may be synthetic in nature. Thus, they may have any sequence. Such sequences may be included if they enhance or do not impair correct expression of the coding sequence or marker sequences.
  • the transfected cells are typically cultured in the presence of a heavy metal ion selected from Cd 2+ , Cu 2+ and Zn 2+ , particularly in an amount which is not toxic to the cells. That can lead to higher expression of the desired interferon.
  • the concentration of the heavy metal ion in the culture medium is typically from 100 to 200 ⁇ M. Cells may therefore be cultured in the presence of from 100 to 200 ⁇ M of a heavy metal ion selected from Cd 2+ , Cu 2+ and Zn 2+ , for example from 130 to 170 ⁇ M of the heavy metal ion.
  • a useful concentration is about 150 ⁇ M, particularly when the heavy metal ion is Zn 2+ .
  • the interferon that is produced may be recovered by any suitable means and the method of recovery may vary depending on, for example, the type of cells employed and the culture conditions that have been used. Desirably, the interferon produced will be purified after recovery. Substantially pure interferon can thus be obtained.
  • the human ⁇ -interferon provided by WO 96/30531 has a high degree of sialylation. Like natural human ⁇ -interferon produced by primary diploid human fibroblasts, it is well glycosylated. However, it has a higher bioavailability than the natural ⁇ -interferon or recombinant ⁇ -interferon produced in E.coli (betaseron).
  • the higher bioavailability of the ⁇ -interferon can be characterised.
  • 1.5 x 10 6 IU of the interferon is injected subcutaneously into the back of a rabbit of about 2 kg: (a) ⁇ 128 IU/ml of the interferon is detectable in the serum of the rabbit after 1 hour, and/or (b) ⁇ 64 IU/ml of the interferon is detectable in the serum of the rabbit after 5 hours.
  • the maximum level of interferon is typically observed after 1 hour. According to (a), therefore, 128 to 256 IU/ml such as 140 to 190 IU/ml of the interferon may be detectable in the rabbit serum after 1 hour. After 5 hours according to (b), ⁇ 70 IU/ml such as ⁇ 80 IU/ml of the interferon may be detectable in the rabbit serum. Typically according to (b), an amount of interferon in the range of 64 to
  • 128 IU/ml such as 80 to 110 IU/ml can be detected.
  • the human interferon ⁇ can be characterised by its specific activity. It can have a specific activity from 4.8 x 10 8 to 6.4 x 10 8 IU per mg equivalent of bovine serum albumin protein, as noted above.
  • the specific activity may be from 5 x 10 8 to 6 x 10 8 , for example from 5.2 x 10 8 to 5.8 x 10 8 such as from 5.3 x 10 8 to 5.5 x 10 8 , IU per mg equivalent of bovine serum albumin protein.
  • the human interferon ⁇ may also be characterised by one or more of the following properties:
  • the interferon ⁇ typically has an apparent molecular weight of 26,300 as determined by 15% sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). 2.
  • SDS-PAGE sodium dodecyl sulphate-polyacrylamide gel electrophoresis
  • the half life of the interferon is typically in the range of from 12 to 15 min such as about 1314 min.
  • the bolus is injected into the rabbit ear vein and blood samples are withdrawn from the rabbit ear artery. Rabbit serum is assayed for the antiviral activity of the interferon according to the modification of the method of Armstrong ( 1971 ).
  • the antiviral activity of the interferon in a human hepatoblastoma cell line is at least equal to and, typically, about 1.5 times the activity of natural interferon ⁇ from primary diploid human fibroblast cells.
  • the interferon is also about 2.2 times more effective than betaseron in protecting Hep2 cells against a viral challenge.
  • Antiviral activity is again determined according to the modified method of Armstrong (1971). Actinomycin D was omitted in the antiviral determination in HepG2 cells.
  • the oligosaccharides associated with the interferon ⁇ of the invention may also characterise the interferon ⁇ .
  • the interferon ⁇ carries oligosaccharides which can be characterised by one or more of the following features: 1. Neutral (no acidic substituents): 5 to 15%, preferably about 10% or lower.
  • Acidic 95 to 85%, preferably about 90% or higher.
  • the total desialylated oligosaccharide pool is heterogeneous with at least six distinct structural components present in the pool.
  • MALDI-TOF Matrix- Assisted Laser Desorption Ionisation - Time of Flight
  • the carbohydrate moiety of the human interferon ⁇ of WO 96/30531 consists of bi-, tri- and tetra-antennary complex type N-linked oligosaccharides. These oligosaccharides contain repeating lactosamine(s). About 20 to 50%, for example 20 to 30%), 30 to 40% or 35 to 50%, of the oligosaccharides are bi-antennary oligosaccharides. About 30 to 65%, for example from 40 to 60% or 50 to 60%, of the oligosaccharides are tri-antennary oligosaccharides.
  • oligosaccharides About 2 to 15%, for example from 2 to 8%, 4 to 10% or 5 to 15%), of the oligosaccharides are tetra- antennary oligosaccharides. Percentages are calculated by weight of total analysable oligosaccharide content.
  • Inhibitors of the second enzyme Compounds which are inhibitors of inosine monophosphate dehydrogenase, guanosine monophosphate synthetase, cytidine triphosphate synthetase and S- adenosylhomocysteine hydrolase have been reported in WO 00/50064 (the contents of which are incorporated herein by reference) to have anti-viral activity against viruses of the Flaviviridae and Rhabdoviridae families. Examples of these compounds include 5-membered carbocyclic nucleosides and mycophenolic acid compounds such as those described below.
  • dihydroorotate dehydrogenase Some of these antiviral compounds have been tested as inhibitors of dihydroorotate dehydrogenase and found to be inactive. This indicates that (a) the replication of flaviviruses, rhabdoviruses and paramyxoviruses in cells involves more than the inhibition of dihydroorotate dehydrogenase, and (b) dihydroorotate dehydrogenase is only one of several nucleotide synthesis enzymes necessary for viral replication.
  • the 5-membered carbocyclic nucleoside may have the following formula (XI):
  • B is selected from the group consisting of purines, pyrimidines and five- or six-membered agylcones
  • R 2 and R 3 are independently selected from the group consisting of H, halogen, OH, O-acyl, O-aryl and O-silyl, and R, is as defined for R 2 and R 3 or is O-phosphate, or a pharmaceutically acceptable metabolite, metabolite derivative or salt thereof.
  • Preferred compounds of formula (XI) are those in which B denotes one of the following groups (i) to (viii):
  • R 25 is Cl or NH 2 and R 26 is H, CH 3 , CF 3 ⁇ F, Cl, Br or I.
  • the 5-membered carbocyclic nucleosides of formula (XI) are known compounds and may be synthesised by published procedures or by analogy with published procedures. For instance the synthesis of (-)-neplanocin A is described by Arita et al in J.Am. Chem. Soc. (1983), 105 (12), 4049-4055.
  • the mycophenolic acid compounds may have the following structure (XII):
  • R 4 is OR ft or -N(R 7 ) R 8 in which Rg, R 7 and R 8 are independently selected from the group consisting of hydrogen and C r C 6 alkyl, and R 5 is selected from the group consisting of hydrogen, phenyl and C,-C 6 alkyl unsubstituted or substituted by a five- or six-membered saturated or unsaturated heterocyclic ring.
  • Preferred compounds of formula (XII) include those in which ⁇ is hydroxy or NH 2 .
  • R 5 , Rg, R 7 and R 8 is a C,-C 6 alkyl group, preferably it is a C r C 4 alkyl group such as methyl or ethyl.
  • the five- or six-membered saturated or unsaturated heterocyclic ring generally contains one, two or three N-atoms and optionally an O- and/or S-atom. Suitable such rings include pyridino, piperidino, pyrrolo, pyrrolidono and morpholino rings. A N-morpholino ring may thus be present.
  • Mycophenolic acid compounds suitable for use in the invention in combination with an inhibitor of dihydroorotate dehydrogenase include mycophenolic acid, mycophenolate mofetil which is the mo ⁇ holinoethyl ester of mycophenolic acid, and the individual mycophenolic acid derivatives described in US-A-5380879. The contents of US-A-5380879 are inco ⁇ orated herein by reference.
  • the dihydroorotate dehydrogenase inhibitors are used to treat flavivirus, rhabdovirus and paramyxovirus infections, particularly in humans.
  • the infection may be acute or chronic.
  • the flavivirus may be yellow fever virus, kunjin virus, West Nile virus, dengue virus, a hepatitis virus such as hepatitis C virus, or an encephalitis virus such as St. Louis encephalitis virus, Japanese encephalitis virus, Murray valley encephalitis virus and tick-borne encephalitis virus.
  • the rhabdovirus may be vesicular stomatis virus or rabies virus.
  • the paramyxovirus may be respiratory syncytial virus (RSV).
  • a therapeutically effective amount of an inhibitor of dihydroorotate dehydrogenase is administered to a subject to be treated.
  • the condition of the subject can thus be improved.
  • the infection may be cleared from the subject entirely.
  • the inhibitor can be administered in a variety of dosage forms, for example orally such as in the form of tablets, capsules, sugar- or film-coated tablets, liquid solutions or suspensions or parenterally, for example intramuscularly, intravenously or subcutaneously. It may therefore be given by injection or infusion.
  • the mode of administration and dosage regimen of the inhibitor depends on a variety of factors including the particular inhibitor concerned, the age, weight and condition of the patient and the nature of the viral infection.
  • the dosage adopted for each route of administration for humans for example adult humans, is 0.001 to 30 mg/kg, most commonly in the range of 0.01 to 5 mg/kg, body weight. Such a dosage may be given, for example, daily.
  • the dosage may be given orally or by bolus infusion, infusion over several hours and/or repeated administration.
  • An interferon may also be administered to the subject under treatment.
  • the inhibitor of dihydroorotate dehydrogenase and the interferon may be given simultaneously. Alternatively they may be given up to five days from each other, for example up to two days apart or up to one day apart or up to four hours apart.
  • the relative timing of the administration of the inhibitor and the interferon may be determined by monitoring their respective serum levels.
  • the interferon may be given before the inhibitor of dihydroorotate dehydrogenase, or vice versa.
  • the interferon may be administered in various ways such as orally, intravenously, intramuscularly, intraperitoneally, intranasally, intradermally, and subcutaneously.
  • the particular mode of administration and dosage regimen will be selected by the attending physician taking into account a number of factors including the age, weight and condition of the patient, the nature of the viral infection, the dihydroorotate dehydrogenase inhibitor with which it is being administered and, as required, the need to obtain a synergistic effect.
  • An inhibitor of a second enzyme selected from inosine monophosphate dehydrogenase, guanosine monophosphate synthetase, cytidine triphosphate synthetase and S-adenosylhomocysteine hydrolase may be administered to the subject under treatment in addition to the inhibitor of dihydroorotate dehydrogenase, either in addition to or instead of the interferon.
  • Suitable dosages and formulations of the inhibitor of the said second enzyme are described in WO 00/50064 mentioned above.
  • Separate formulations of the inhibitor of dihydroorotate dehydrogenase on the one hand and of the inhibitor of the said second enzyme and/or the interferon on the other hand will generally be given to a patient.
  • a single formulation containing each component can however be administered if the dihydroorotate dehydrogenase inhibitor and the inhibitor of the said second enzyme and/or the interferon are stable in each other's presence and do not otherwise interfere with each other.
  • compositions that contain the interferon as an active principal will normally be formulated with an appropriate pharmaceutically acceptable carrier or diluent depending upon the particular mode of administration being used.
  • parenteral formulations are usually injectable fluids that use pharmaceutically and physiologically acceptable fluids such as physiological saline, balanced salt solutions, or the like as a vehicle which may contain physiologically acceptable amounts of organic diluents such as DMSO.
  • Oral formulations may be solids, e.g. tablets or capsules, or liquid solutions or suspensions.
  • the inhibitor of dihydroorotate dehydrogenase and the interferon, or the inhibitor of dihydroorotate dehydrogenase and the inhibitor of the said second enzyme are typically administered in such amounts that a synergistic effect is obtained.
  • Lower doses of the two inhibitors and of interferon can be used, which results in a cost- saving and a reduction or elimination of side effects that might occur at higher doses.
  • the interferon will usually be formulated as a unit dosage form that contains from 10 4 to 10 9 , more usually 10 6 to 10 7 , IU per dose.
  • Typically from 3 x 10 6 to 36 xlO 6 IU of interferon is administered per day, particularly by injection such as intravenously or subcutaneously.
  • the dosage may be administered daily, for example for up to five or up to twenty weeks.
  • Test compounds were weighed and freshly dissolved in dimethyl sulfoxide (DMSO). Stock solutions of each chemical in DMSO were kept at 4° C or for longer storage at minus 80° C. The stock solutions were diluted in regular medium such that the concentrations of each chemical ranged down from 100 ⁇ M as they were serially diluted two times to nM concentrations.
  • DMSO dimethyl sulfoxide
  • Human liver (HuH7) cells, human primary fibroblasts (MRC5) and transformed monkey cells (Vero) cultured in 96 well microtitre plates were each grown to near confluency in regular medium. The media was removed and each well of cells was re-incubated with 0.1 ml. of regular medium containing 1 to 2% of fetal calf serum, different concentrations of each of the chemical compounds dissolved in regular medium and an amount of each of the viruses listed in Tables 1 and 2.
  • the controls consisted of cell controls (cells treated with chemical compounds but not with virus) as well as viral controls (cells treated only with virus but not with chemicals).
  • the results are shown in Tables 1 and 2.
  • the antiviral activity of a compound is indicated by its ED 50 value which is the concentration of test compound that confers a 50%) protection against a 100 TCID 50 challenge dose of yellow fever virus, dengue virus or kunjin virus or RSV, or against a challenge virus of vesicular stomatitis virus at an multiciplicity of infection (M.O.I.) of 2.0.
  • SI Selectivity index
  • Vero cells and HuH7 cells were grown to about 99% confluency in 96 microwells with minimum essential medium (MEM) containing 10% fetal calf serum. Growth medium was removed from the microwells and incubated with one of the 10 following:-
  • the experiment was done in quadruplicates or duplicates. After the addition of 25 interferon to the Vero cells in the microwells, lOO ⁇ l of a viral challenge consisting of 100 TCLD 50 yellow fever virus, kunjin virus, dengue virus or VSV was added immediately to each of the microwells. Different concentrations of test compound were included in the viral challenge as well. In the case where no test compound was used (i.e. the viral control), only lOO ⁇ l of the viral challenge was added to the wells in 30 100 ⁇ l of MEM containing 2.5 mg/ml human serum albumin. The test compound was Brequinar.

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Abstract

On peut traiter des infections par flavivirus, rhabdovirus et paramyxovirus par administration d'un inhibiteur de l'enzyme dihydroorotate déshydrogénase, tel que sel de sodium d'acide 6-fluoro-2-(2'-fluoro-1,1'-biphényle-4-yl)-3-méthyl-4-quinolinecarboxylique (Brequinar). On peut obtenir un effet synergique si on administre également un interféron tel qu'interféron α2, interféron α8 ou interféron β ou un inhibiteur d'un deuxième enzyme sélectionné dans inosine monophosphate déshydrogénase, guanosine monophosphate synthétase, cytidine triphosphate synthétase et S-adénosylhomocystéine hydrolase.
EP00965517A 1999-10-01 2000-09-29 Composes servant a traiter des maladies d'origine virale Withdrawn EP1237546A2 (fr)

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WO2004056797A1 (fr) 2002-12-23 2004-07-08 4Sc Ag Aromatic compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents
US7365094B2 (en) 2002-12-23 2008-04-29 4Sc Ag Compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents
WO2004056746A1 (fr) * 2002-12-23 2004-07-08 4Sc Ag Composes d'acide dicarboxylique de cycloalcene servant d'agents anti-inflammatoires, d'immunomodulation et anti-proliferation
US7247736B2 (en) 2002-12-23 2007-07-24 4Sc Ag Method of identifying inhibitors of DHODH
CL2004000985A1 (es) * 2003-05-16 2005-01-14 Wyeth Corp Compuestos derivados de fenilquinolinas; composicion farmaceutica, proceso de preparacion; y uso para tratar osteoporosis, enfermedad de paget, dano vascular, osteoartritis, cancer oseo, cancer ovarico, cancer prostatico, hipercolesterolemia, aterosc
CN1832755A (zh) * 2003-05-23 2006-09-13 佩斯特卡生物医疗实验室公司 使用干扰素治疗严重急性呼吸综合征及其他病毒感染
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TWI530286B (zh) * 2009-05-04 2016-04-21 帕納特斯製藥格斯有限公司 作為抑制病毒化合物之抗發炎劑
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EP3793562A4 (fr) * 2018-06-22 2021-07-07 Ohio State Innovation Foundation Procédés et compositions pour inhiber la dihydroorotate déshydrogénase
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