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EP0998293A1 - Cytokine related treatments of disease - Google Patents

Cytokine related treatments of disease

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Publication number
EP0998293A1
EP0998293A1 EP98903474A EP98903474A EP0998293A1 EP 0998293 A1 EP0998293 A1 EP 0998293A1 EP 98903474 A EP98903474 A EP 98903474A EP 98903474 A EP98903474 A EP 98903474A EP 0998293 A1 EP0998293 A1 EP 0998293A1
Authority
EP
European Patent Office
Prior art keywords
disease
compound
drug
patient
nucleoside
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98903474A
Other languages
German (de)
French (fr)
Other versions
EP0998293A4 (en
Inventor
Robert Tam
Guangyi Wang
Devron Averett
Kandasamy Ramasamy
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Valeant Research and Development
Original Assignee
ICN Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by ICN Pharmaceuticals Inc filed Critical ICN Pharmaceuticals Inc
Priority to EP02021843A priority Critical patent/EP1277759A1/en
Priority to EP03008818A priority patent/EP1329220A1/en
Priority to EP00118252A priority patent/EP1103559A1/en
Publication of EP0998293A1 publication Critical patent/EP0998293A1/en
Publication of EP0998293A4 publication Critical patent/EP0998293A4/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7115—Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine
    • 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
    • A61P1/16—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
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • 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
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/052—Imidazole radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/056—Triazole or tetrazole radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/24—Heterocyclic radicals containing oxygen or sulfur as ring hetero atom

Definitions

  • provisional application ser. no. 60/028586 filed April 23, 1997 (2) provisional application ser. no. 60/043,974 filed April 23, 1997, (3) provisional application ser. no. 60/055,487 filed August 12, 1997; and (4) provisional application 60/036,094 dated January 14, 1997.
  • the present invention relates to the field of nucleosides.
  • B lymphocytes B cells
  • T lymphocytes T cells
  • T cells are generally considered to fall into two subclasses, helper T cells and cytotoxic T cells.
  • Helper T cells activate other lymphocytes, including B cells and cytotoxic T cells, and macrophages, by releasing soluble protein mediators called cytokines which are involved in cell-mediated immunity.
  • lymphokines are a subset of cytokines.
  • Thl and Th2 Thl cells also known as Type 1 cells
  • LL-2 interleukin 2
  • TNF ⁇ tumor necrosis factor
  • IFN ⁇ interferon gamma
  • Type 2 cells produce interleukins, IL4, IL-5, LL-6, LL-9, LL-10 and LL-13, and are primarily involved in assisting humoral immune responses such as those seen in response to allergens, e.g. IgE and lgG4 antibody isotype switching (Mosmann, 1989, Annu Rev Immunol, 7: 145-173).
  • Thl and Th2 responses
  • Thl and Th2 lymphocytes are meant to include the entire range of effects resulting from induction of Thl and Th2 lymphocytes, respectively.
  • responses include variation in production of the corresponding cytokines through transcription, translation, secretion and possibly other mechanisms, increased proliferation of the corresponding lymphocytes, and other effects associated with increased production of cytokines, including motility effects.
  • nucleosides which are defined herein to include derivatives and analogs of native nucleosides
  • lymphocyte responses we have shown that either of Thl and Th2 responses can be selectively suppressed while the other is either induced or left relatively unaffected, and either of Thl or Th2 responses can be selectively induced while the other is either suppressed or left relatively unaffected.
  • nucleosides effective in selectively modulating Thl and Th2 responses relative to one another tend to have a bimodal effect.
  • nucleosides which tend to generally suppress or induce both Thl and Thl activity at a relatively higher dose, tend to selectively modulate Thl and Th2 relative to each other at relatively lower doses.
  • nucleosides and other compounds selectively modulate Thl and Th2 responses relative to each other are still unclear.
  • One possibility contemplated by the present inventors is that effective nucleosides alter the pool of guanosine triphosphate (GTP), which in turn affects the rate at which cytokines are produced.
  • GTP guanosine triphosphate
  • relatively large variations in available GTP are sufficient to affect concentrations of both Thl and Th2 cytokines, while relatively smaller variations in available GTP tend to affect concentrations of Thl and Th2 cytokines to different extents.
  • Tumor cells are characterized by high levels of inosine monophosphate dehydrogenase (IMP DH) activity, and it is known that LMP DH is the rate-limiting enzyme of GTP biosynthesis. Weber, G., IMP Dehydrogenase and GTP as Targets in Human Leukemia Treatment. Adv. Exp. Med. Biol. 309B:287-292 (1991).
  • Tiazofurin has been shown to selectively block IMP DH activity and deplete guanine nucleotide pools, which in turn forces various tumors into remission.
  • Typical initial doses of Tiazofurin are about 4,400 mg/m 2 , with consolidation doses of about 1100 to 3300 mg/m 2 . At these levels synthesis of both Thl and Th2 responses are greatly reduced, thereby essentially shutting down much of the immune system.
  • much smaller doses of Tiazofurin in the range of 1/10th to one-half that set forth above, would be sufficient to specifically suppress either a Thl response or a Th2 response without greatly reducing the other response.
  • Ribavirin is a potent, broad-spectrum antiviral agent, which has also been shown to inhibit IMP DH. Yamada, Y. et al., Action of the Active Metabolites of Tiazofurin and Ribavirin on Purified IMP Dehydrogenase. Biochem. 27:2193-2196 (1988). Ribavirin proceeds under a different mechanism than Tiazofurin in inhibiting IMP DH, however, acting on a different site on the enzyme molecule. Ribavirin is converted to its active metabolite, ribavirin-monophosphate (RMP), which inhibits the enzyme at the IMP-
  • RMP ribavirin-monophosphate
  • Ribavirin XMP site of IMP DH.
  • the affinity of Ribavirin' s active form to the enzyme is higher than that of the natural metabolite.
  • Ribavirin reduces IMP DH activity to such an extent that both Thl and Th2 responses are inhibited.
  • Ribavirin promotes a Thl response and suppresses a Th2 response.
  • Thl relative to Th2 can be useful in treating a wide variety of conditions and diseases, ranging from infections, infestations, tumors and hypersensitivities to autoimmune diseases.
  • autoimmune disease for example, is frequently limited to palliative measures, removal of toxic antibodies (as in myasthenia gravis), and administration of hazardous drugs including corticosteroids, chloroquine derivatives, and antimetabolic or antitumor drugs, and drugs such as cyclosporines which target immune system cells.
  • This application relates to the use of nucleosides in the relatively low dosage range to selectively modulate Thl and Th2 responses relative to each other in the treatment of disease.
  • administration of a nucleoside or other compound reduces the dosage at which a primary drug is administered.
  • an abnormality reflected in increased response in one group of cytokines is treated by administering a nucleoside or other compound which increases response in another group of cytokines.
  • a patient is prophylactically treated by administering a nucleoside or other compound which selectively reduces Thl activity without significantly reducing Th2 activity.
  • a nucleoside or other compound is administered to a patient at a dose which reduces the patient's GTP pool to a degree that selectively reduces one of the Thl or Th2 response without significantly reducing the other response.
  • Controlled release dosage forms are particularly contemplated to achieve that result.
  • nucleosides contemplated to be effective in this manner are D- and L- forms of: (a) bicyclic nucleosides corresponding to any of Formulas 1, 1-A through 1-F; and (b) monocyclic nucleosides nucleosides corresponding to any of Formulas 2 through 5.
  • anti-viral agents such as Ribavirin , acyclovir, and AZTTM
  • anti-fungal agents such as tolnaftate
  • anti-parasitics such as MintezolTM, NiclocideTM, VermoxTM
  • ⁇ and ⁇ indicate the specific stereochemical configuration of a substituent at an asymmetric carbon atom in a chemical structure as drawn.
  • abnormality refers to a condition associated with a disease.
  • Thl and/or Th2 responses resulting from an autoimmune disease are considered herein to be abnormalities of the corresponding cytokine(s) even though such cytokine responses may commonly result from the disease.
  • aryl refers to a monovalent unsaturated aromatic carbocyclic radical having a single ring (e.g., phenyl) or two condensed rings (e.g., naphthyl), which can optionally be substituted with hydroxyl, lower alky, chloro, and/or cyano.
  • the term "effective amount” refers to the amount of a compound of formula (I) which will restore immune function to normal levels, or increase immune function above normal levels in order to eliminate infection.
  • enantiomers refers to a pair of stereoisomers that are non-superimposable mirror images of each other. A mixture of a pair of enantiomers, in a 1 : 1 ratio, is a "racemic" mixture.
  • heterocycle refers to a monovalent saturated or unsaturated carbocyclic radical having at least one hetero atom, such as N, O or S, within the ring each available position of which can be optionally substituted, independently, with, e.g., hydroxy, oxo, amino, imino, lower alkyl, bromo, chloro and/or cyano. Included within this class of substituents are purines, pyrimidines.
  • immunomodulators refers to natural or synthetic products capable of modifying the normal or aberrant immune system through stimulation or suppression.
  • isomers refers to different compounds that have the same formula.
  • Steps are isomers that differ only in the way the atoms are arranged in space.
  • the term "L-configuration” is used throughout the present invention to describe the chemical configuration of the ribofuranosyl moiety of the compounds that is linked to the nucleobases.
  • the L-configuration of the sugar moiety of compounds of the present invention contrasts with the D-configuration of ribose sugar moieties of the naturally occurring nucleosides such as cytidine, adenosine, thymidine, guanosine and uridine.
  • lower alkyl refers to methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, I- butyl or n-hexyl. This term is further exemplified to a cyclic, branched or straight chain from one to six carbon atoms.
  • monocyclic refers to a monovalent saturated carbocyclic radical having at least one hetero atom, such as O, N, S, Se or P, within the ring, each available position of which can be optionally substituted, independently, with a sugar moiety or any other groups like bromo, chloro and/or cyano, so that the monocyclic ring system eventually aromatized [e.g., Thymidine; l-(2'-deoxy-?-D-erythro-pentofuranosyl)thymine].
  • hetero atom such as O, N, S, Se or P
  • nucleoside refers to a compound composed of any pentose or modified pentose moiety attached to a specific position of a heterocycle or to the natural position of a purine (9-position) or pyrimidine (1 -position) or to the equivalent position in an analog, including especiall both D- and L- forms of nitrogenous bicyclic and monocyclic heterocycles depicted in Figures 1, 1-A through 1-F, and 2 through 5 herein.
  • C-nucleosides is used throughout the specification to describe the linkage type that formed between the ribose sugar moiety and the heterocyclic base.
  • the linkage originates from the C-1 position of the ribose sugar moiety and joins the carbon of the heterocyclic base.
  • the linkage that forms in C-nucleosides are carbon to carbon type.
  • D-nucleosides refers to nucleoside compounds that have a D-ribose sugar moiety (e.g., Adenosine).
  • L-nucleosides refers to nucleoside compounds that have an L-ribose sugar moiety.
  • N-nucleosides is used throughout the specification to describe the linkage type that formed between the ribose sugar moiety and the heterocyclic base. In N-nucleosides, the linkage originates from the C-1 position of the ribose sugar moiety and joins the nitrogen of the heterocyclic base. The linkage that forms in N-nucleosides are carbon to nitrogen type.
  • nucleotide refers to a phosphate ester substituted on the 5 '-position of a nucleoside.
  • pharmaceutically acceptable salts refers to any salt derived from inorganic and organic acids or bases.
  • protecting group refers to a chemical group that is added to, oxygen or nitrogen atom to prevent its further reaction during the course of derivatization of other moieties in the molecule in which the oxygen or nitrogen is located. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis.
  • purine refers to nitrogenous bicyclic heterocycles depicted in Figures 1, 1- A through 1-F herein.
  • pyrimidine refers to nitrogenous monocyclic heterocycles depicted in Figures 2 through 5 herein.
  • tumor refers broadly to all manner of autonomous morbid growth of tissue which may or may not become malignant, including all manner of neoplasms and cancers.
  • treating or “treatment” of a disease refers to executing a protocol, which may include administering one or more drugs to a patient, in an effort to alleviate signs or symptoms of the disease.
  • treating or “treatment” do not require complete alleviation of signs or symptoms, do not require a cure, and specifically include protocols which have only marginal effect on the patient.
  • Contemplated combinations in one aspect of the present invention generally include a primary or "first" drug and another or “second” drug, and contemplated methods involve selecting and combining the first and second drugs in combination therapies.
  • a disease is identified which is known to produce an abnormality in at least one cytokine in a patient
  • the first drug is selected from among those compounds demonstrated to treat the disease at a monotherapeutic dosage
  • the second drug which may be a bimodal nucleoside modulator as herein described, is selected from among those compounds known to exacerbate the very abnormality produced by the disease when administered within a given dosage range.
  • the first drug is then administered at less than the monotherapeutic dosage and the second drug is administered in a dosage outside the dosage range which exacerbates the abnormality. Since the second drug has a bimodal activity with respect to at least some of the cytokines of interest, the combination is still effective to treat the disease, and administration of the second drug allows reduction in the administered dosage of the primary or first drug.
  • anti-viral agents such as interferon, including but not limited to interferon and ⁇ , Ribavirin , acyclovir, and AZTTM; anti-fungal agents such as tolnaftate, FungizoneTM, Lotrimin,TM Mycelex,TM, Nystatin and Amphoteracin; anti-parasitics such as MintezolTM, NiclocideTM, VermoxTM, and FlagylTM; bowel agents such as ImmodiumTM, LomotilTM and PhazymeTM; anti-tumor agents such as interferon and ⁇ , AdriamycinTM, CytoxanTM, ImuranTM, Methotrexate, MithracinTM, TiazofurinTM, TaxolTM; dermatologic agents such as AclovateTM, CyclocortTM, DenorexTM, FloroneTM, OxsoralenTM, coal tar
  • Especially preferred primary drugs are AZT, 3TC, 8-substituted guanosine analogs, 2',3'-dideoxynucleosides, interleukin II, interferons such as I B-interferons, tucaresol, levamisole, isoprinosine and cyclolignans.
  • Examples of secondary drugs contemplated to be effective in the invention are D- and L- forms of (a) bicyclic nucleosides corresponding to generic Formula 1 and 1-A through 1-F, and (b) monocyclic nucleosides nucleosides corresponding to Formulas 2 through 5.
  • Other nucleoside and non-nucleoside compounds effective in the invention are readily identified through screening of such compounds in vitro for effect on IL-2, TNF- ⁇ , LFN- ⁇ , LL-4 and LL-
  • Formula 1 compounds are purine nucleosides having the structure:
  • Rj, R 2 , R 3 , R 4 , R 5 , R 2 ' and R 3 ' are independently selected from the group consisting of H, OH, NH 2 , F, Cl, Br, I, N 3 , -CN, -OR', -NR' 2 , -SR', -NHNH 2 , -NHOH, CHO,
  • Zj, Z 2 are independently selected from N, C, CH;
  • alkyl alkenyl, alkylnyl, aryl, aralkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, substituted aralkyl, where the substituent is selected from H, -OH, NH 2 , F, Cl, Br, I, N 3 , -CN, -COOR", -CONR" 2 , -OR", -NR" 2 , -SR", -NHNH 2 , -NHOH, -N0 2 , and R', R" are H, alkyl, alkenyl, alkynyl, aryl, aralkyl, acetyl, acyl, sulfonyl;
  • X and Y are independently selected from the group consisting of H, OH, NH 2 , F, Cl, Br, I, N 3 , -S-NH 2 , -S(O)-NH 2 , -S(O2)-NH 2 , -CN, -COOR', -CONR' 2 , -OR, -NR' 2 , -SR', - NHNH 2 , -NHOH, alkyl, alkenyl, alkylnyl, aryl, aralkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, substituted aralkyl, where the substituent is selected from F, Cl, Br, I, N 3 , -CN, -OR", NO 2 , -NR" 2 , SR", -NHNH 2 , -NHOH, and R', R" are H, alkyl, alkenyl, alkynyl, aryl
  • Formula 1-A compounds are 8-substituted "-or ⁇ - L- or D- guanosine analogs having the structure:
  • X is selected from H, R, F, Cl, Br, I, N 3 , -CN, -OR, -SR, -NR , -NHNH 2 , - NHOH, -CHO, -CONH 2 , -COOR, and -L-A; where R is selected from alkyl, alkenyl, alkynyl, and aralkyl, acetyl, acyl, sulfonyl; L is a linker and selected from alkyl, alkenyl, alkynyl, and aralkyl; and A is selected from H, -OR', -SR, -NR' 2 , -NHNR' 2 , -CHO, -COOR', -CONR' 2 , where R' is selected from H, Me, Et, allyl, acetyl, -COCF3; Y is selected from H, R, F, Cl Br, I, N 3 , CN, OR,
  • Formula IB compounds are 7-substituted-8-oxo-"-or ⁇ - L-guanosine analogs having structure:
  • Formula 1-C compounds are 7-deaza-7,8-mono- or disubstituted "-or ⁇ - L- or D- guanosine analogs having the structure:
  • X ⁇ and X 2 are independently selected from H, R, F, Cl, Br, I, N3, -CN, -OR, -SR, -NR 2 , -NHNH 2 , -NHOH, -CHO, -CONH 2 , -COOR, and -L-A; where R is selected from alkyl, alkenyl, alkynyl, and aralkyl, acetyl, acyl, sulfonyl; L is a linker and selected from alkyl, alkenyl, alkynyl, and aralkyl; and A is selected from H, -OR', -SR', -NR' 2 , -NHNR' 2 , -CHO, - COOR', -CONR' 2 , where R' is selected from H, Me, Et, allyl, acetyl, -COCF3;
  • Y is selected from H, R, F, Cl, Br, I, N3, -CN, -OR, -SR, -NR 2 , where R is selected from H, alkyl, alkenyl, alkynyl, and aralkyl, acetyl, acyl, sulfonyl;
  • Z is N or CH
  • Ri , R 2 , and R 3 are independently selected from H, -OH, -OAc, -OBz, -OP(O 2 )OH.
  • Formula 1-D compounds are 7-deaza-8-aza-7-substituted "-or ⁇ - L- or D- guanosine analogs having the structure:
  • X is selected from H, R, F, Cl, Br, I, N 3 , -CN, -OR, -SR, -NR 2 , -NHNH 2 , -NHOH, CHO, -CONH 2 , -COOR, and -L-A; where R is selected from alkyl, alkenyl, alkynyl, and aralkyl, acetyl, acyl, sulfonyl; L is a linker and selected from alkyl, alkenyl, alkynyl, and aralkyl; and A is selected from H, -OR, SR, -NR' 2 , -NHNR' 2 , -CHO, -COOR, -CONR' 2 , where R' is selected from H, Me, Et, allyl, acetyl, -COCF3;
  • Y is selected from H, R, F, Cl, Br, I, N 3 , -CN, -OR, -SR, -NR2, where R is selected from H, alkyl, alkenyl, alkynyl, and aralkyl, acetyl, acyl, sulfonyl;
  • Z is N or CH; Rl, R , and R3 are independently selected from H, -OH, -OAc, -OBz, -OP(O 2 )OH.
  • Formula 1-E compounds are thiazolo[4,5-d]pyrimidine "-or ⁇ - L- or D- nucleosides having the structure:
  • Y is selected from H, R, F, Cl, Br, I, N 3 , -CN, -OR, -SR, -NR 2 , where R is selected from H, alkyl, alkenyl, alkynyl, and aralkyl, acetyl, acyl, sulfonyl;
  • Z is N or CH
  • Ri , R , and R3 are independently selected from H, -OH, -OAc, -OBz, -OP(O 2 )OH.
  • Formula 1-F compounds are ⁇ -L- or D- purine nucleosides having the structure:
  • Formula 1-F X is selected from H, R, -SNH 2 , -S(O)NH 2 , -SO 2 NH 2 , F, Cl, Br, I, N 3 , -CN, -OR, SR, -NR 2 , where R is selected from H, alkyl, alkenyl, alkynyl, and aralkyl, acetyl, acyl, sulfonyl;
  • Y is selected from H, R, F, Cl, Br, I, N 3 , -CN, -OR, -SR, -NR 2 , where R is selected from H, alkyl, alkenyl, alkynyl, and aralkyl, acetyl, acyl, sulfonyl;
  • Z ⁇ , Z 2 and Z3 are independently selected from C, N, and CH;
  • Rl, R 2 , and R 3 are independently selected from H, -OH, -OAc, -OBz, -OP(O 2 )OH.
  • Formula 2 compounds have the structure:
  • A is independently selected from N or C;
  • B, C, E, F are independently selected from CH, CO, N, S, Se, O, NR 1 , CCONH CCH 3 , C-R 2 or P;
  • R 1 is independently H, lower alkyl, lower alkylamines, COCH 3 , lower alkyl alkenyl, lower alkyl vinyl or lower alkyl aryls.
  • X is independently O, S, CH 2 or NR, where R is COCH 3 , R, and R, are independently selected from H, CN, N 3 , CH 2 OH, lower alkyl and lower alkyl amines,
  • X is independently O, S, CH 2 and NR, where R is COCH 3 ;
  • R, and R 4 are independently selected from H, CN, N 3 , CH 2 OH, lower alkyl or lower alkyl amines;
  • R' is preferably carboxamide or CN and R" is hydrogen or halogens;
  • Formula 4 compounds have the structure:
  • A is independently selected from N or C;
  • B, C, E and F are independently selected from CH, CO, N, S, Se, O, NR 1 , CCONH 2 , CCH 3 , C-R 2 or P;
  • R 1 is independently H, lower alkyl, lower alkylamines, COCH 3 , lower alkyl alkenyl, lower alkyl vinyl or lower alkyl aryls.
  • X is independently O, S, CH 2 or NR; where R is COCH 3 ;
  • R, and R 4 are independently selected from H, CN, N 3 , CH 2 OH, lower alkyl or lower alkyl amines;
  • R 1 is preferably H, lower alkyl or allyl
  • Formula 5 compounds have the structure:
  • A is independently selected from N or C;
  • B, C, E, F are independently selected from CH, CO, N, S, Se, O, NR 1 , CCONH 2 , CCH 3 , C-R 2 or P;
  • R 1 is independently H, lower alkyl, lower alkylamines, COCH 3 , lower alkyl alkenyl, lower alkyl vinyl or lower alkyl aryls.
  • R 2 is independently H, OH, halogens, CN, N 3 ,
  • D is independently selected from CH, CO, N, S, Se, O, NR 1 , CCONH 2 , CCH 3 , C-R 2 , P or nothing;
  • R 1 is independently H, O, lower alkyl, lower alkylamines, COCH 3 , lower alkyl alkenyl, lower alkyl vinyl or lower alkyl aryls.
  • R 2 is independently H, OH, halogens, CN, N 3 .
  • NH 2 lower alkyl, lower alkylamines, lower alkyl alkenyl, lower alkyl vinyl, lower alkyl aryls or substituted heterocycles;
  • X is independently O, S, CH 2 or NR where R is COCH 3 ;
  • R, and R 4 are independently selected from H, CN, N 3 , CH 2 OH, lower alkyl and lower alkyl amines; and
  • an abnormality reflected in increased response in one group of cytokines is treated by administering a nucleoside or other compound which increases response in another group of cytokines
  • a nucleoside or other compound which increases response in another group of cytokines results in an abnormally elevated Th2 response
  • the abnormality is treated by administering Ribavirin at between 600 mg/day and 1,000 mg/day (for a typical adult), at which dose the Thl response is induced
  • the treatment is effective because Thl and Th2 have a teeter-totter type relationship in this instance, such that the Th2 response is suppressed
  • a patient is prophylactically treated by administering a nucleoside or other compound which selectively reduces Thl activity without significantly reducing Th2 activity
  • the prophylaxis can, for example, prepare the patient for organ or tissue transplant, or for anticipated contact with allergens
  • a nucleoside or other compound is administered to a patient at a dose which reduces the patient's GTP pool to a degree that selectively reduces one of the Thl or Th2 response without significantly reducing the other response. Controlled release dosage forms are particularly contemplated to achieve that result, especially formulations which maintain the dose of the compound in the serum within a desirable range.
  • a controlled release formulation may advantageously have an in vitro dissolution rate when measured by the USP Paddle Method at 100 rpm at 900 ml aqueous buffer (pH between 1.6 and 7.2) between about 15% and 40% by weight of the compound after 1 hour, between about 30% and about 50% by weight of the compound after 2 hours, about 50%) and 70% by weight of the compound after 4 hours, between about 60% and about 80% by weight of the compound after 6 hours
  • the claimed combinations will be used to treat a wide variety of conditions, and in fact any condition which responds positively to administration of one or more such combinations. Among other things it is specifically contemplated that such combinations may be used to treat an infection, an infestation, a tumor, a hypersensitivity or an autoimmune disease.
  • Infections contemplated to be treated with the compounds of the present invention include respiratory syncytial virus (RSV), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex type 1 and 2, herpes genitalis, herpes keratitis, herpes encephalitis, herpes zoster, human immunodeficiency virus (HIV), influenza A virus, hantann virus (hemorrhagic fever), human papilloma virus (HPV), measles and fungus. It is especially contemplated that combinations claimed herein will be useful in treating chronic viral and bacterial infections, including HIV, Tuberculosis, leprosy and so forth.
  • Infestations contemplated to be treated with the compounds of the present invention include intracellular protozoan infestations, as well as helminth and other parasitic infestations. Again, it is especially contemplated that combinations claimed herein will be useful in treating chronic infestations.
  • Tumors contemplated to be treated include those caused by a virus, and the effect may involve inhibiting the transformation of virus-infected cells to a neoplastic state, inhibiting the spread of viruses from transformed cells to other normal cells and/or arresting the growth of virus-transformed cells.
  • Hypersensitivities contemplated to be treated include all types of allergies, including IgE and IgG allergies, hyper IgE syndrome, and dermatic conditions such as atopic dermatitis. It is also contemplated that claimed combinations can be used to treat transplant rejection, (graft vs. host disease) and implant reactions.
  • Non-organ-specific autoimmune diseases include rheumatoid arthritis, gout and gouty arthritis, Systemic Lupus Erythematosus (SLE), Sjogren syndrome, scleroderma, polymyositis and dermomyositis, ankylosing spondylitis, and rheumatic fever.
  • SLE Systemic Lupus Erythematosus
  • Organ-specific autoimmune diseases are known for virtually every organ, including insulin-dependent diabetes, thyroid diseases (Graves disease and Hashimoto thyroiditis), Addison disease, and some kidney and lung diseases including allergy and asthma, multiple sclerosis, myasthenia gravis, uveitis, psoriasis, forms of hepatitis and cirrhosis, celiac disease, inflammatory bowel disease, and some types of male and female infertility.
  • Autoimmune processes may also be stimulated by viral infections including the HIV virus, may result from rejection of transplantation, and may accompany certain tumors, or be precipitated by exposure to some chemicals.
  • an abnormality reflected in increased response in one group of cytokines can be treated by administering a nucleoside which increases response in another group of cytokines.
  • a nucleoside which increases response in another group of cytokines.
  • allergies can be treated with Ribavirin, which increases Thl response at low dosages of about 500 mg/day to about 1,000 mg/day.
  • a patient is prophylactically treated by administering a compound which selectively reduces Thl activity without significantly reducing Th2 activity.
  • the prophylactic treatment may be to reduce expected undesirable effects from an upcoming event, such as an organ or tissue transplant, or to reduce symptoms from an expected pulmonary insult, as from the onset of increase in airborne pollen levels in Spring
  • compounds according to the present invention will be administered in any appropriate pharmaceutical formulation, and under any appropriate protocol
  • preferred monotherapeutic dosages and protocols for such drugs are set forth in the PDR, or are at least available from the manufacturer or distributor Preferred dosages and protocols for the "second" drugs, such as bi-modal nucleosides described herein, may best be established through experimentation with particular patients Such experimentation need not be extensive, and it is contemplated that "second" drugs comprising nucleosides as described herein will be administered at between about 100 mg/day and about 5,000 mg/day
  • a therapeutically effective amount will vary with the infection or condition to be treated, its severity, the treatment regimen to be employed, the pharmacokinetics of the agent used, as well as the patient (animal or human) treated
  • effective dosages may range from 1 mg/kg of body weight, or less, to 25 mg/kg of body weight or more
  • a therapeutically effective amount of the "second" drug is contemplated to range from slightly less than about 1 mg /kg to about 25 mg /kg of the patient, depending upon the compound used, the condition or infection treated and the route of administration
  • This dosage range generally produces effective blood level concentrations of active compound ranging from about 0 04 to about 100 micrograms/cc of blood in the patient It is contemplated, however, that appropriate patient-specific regimens will be developed by administering a small amount, and then increasing the amount until either the side effects become unduly adverse, or the intended effect is achieved.
  • Administration of compounds according to the present invention may take place orally, parenterally (including subcutaneous injections, intravenous, intramuscularly, by intraster al injection or infusion techniques), by inhalation spray, or rectally, topically and so forth, and in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • compounds according to the present invention can be formulated in admixture with a pharmaceutically acceptable carrier.
  • the compounds of the present invention can be administered orally as pharmacologically acceptable salts.
  • physiological saline solution e.g., buffered to a pH of about 7.2 to 7.5.
  • physiological saline solution e.g., buffered to a pH of about 7.2 to 7.5.
  • Conventional buffers such as phosphates, bicarbonates or citrates can be used for this purpose.
  • physiological saline solution e.g., buffered to a pH of about 7.2 to 7.5.
  • Conventional buffers such as phosphates, bicarbonates or citrates can be used for this purpose.
  • one of ordinary skill in the art may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the compositions of the present invention unstable or compromising their therapeutic activity.
  • the modification of the present compounds to render them more soluble in water or other vehicle may be easily accomplished by minor modifications (salt formulation, esterification, etc.) which are well within the ordinary skill in the art. It is also well within the ordinary skill of the art to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect in patients.
  • the pro-drug form of administered compounds especially including acylated (acetylated or other) derivatives, pyridine esters and various salt forms of the present compounds are preferred.
  • acylated (acetylated or other) derivatives, pyridine esters and various salt forms of the present compounds are preferred.
  • One of ordinary skill in the art will recognize how to readily modify the present compounds to pro-drug forms to facilitate delivery of active compounds to a target site within the host organism or patient.
  • One of ordinary skill in the art will also take advantage of favorable pharmacokinetic parameters of the pro-drug forms, where applicable, in delivering the present compounds to a targeted site within the host organism or patient to maximize the intended effect of the compound.
  • compounds included in combinations according to the present invention may be administered separately or together, and when administered separately this may occur in any order.
  • the amounts of the active ingredient(s) and pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • Administration routes of compounds according to the present invention may range from continuous (intravenous drip) to several oral administrations per day (for example, Q.I.D.) and may include oral, topical, parenteral, intramuscular, intravenous, sub-cutaneous, transdermal (which may include a penetration enhancement agent), buccal and suppository administration, among other routes of administration.
  • a therapeutically effective amount of a compound is preferably intimately admixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques to produce a dose.
  • a carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral.
  • any of the usual pharmaceutical media may be used.
  • suitable carriers and additives including water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used.
  • suitable carriers and additives including starches, sugar carrier, such as dextrose, mannitol, lactose and related carriers, diluents, granulating agents, lubricants, binders, disintegrating agents and the like may be used.
  • the tablets or capsules may be enteric-coated or sustained release by standard techniques.
  • the carrier will usually comprise sterile water or aqueous sodium chloride solution, though other ingredients including those which aid dispersion may be included.
  • sterile water is to be used and maintained as sterile, the compositions and carriers must also be sterilized.
  • injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the most preferred uses according to the present invention are those in which the active compounds are relatively less cytotoxic to the non-target host cells and relatively more active against the target.
  • L-nucleosides may have increased stability over D-nucleosides, which could lead to better pharmacokinetics. This result may attain because L-nucleosides may not be recognized by enzymes, and therefore may have longer half-lives.

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Abstract

Nucleosides and other compounds to selectively modulate Th1 and Th2 responses relative to each other in the treatment of disease. In one aspect of the invention, administration of a nucleoside or other compound reduces the dosage at which a primary drug is administered. In another aspect of the invention, an abnormality reflected in increased response in one group of cytokines is treated by administering a nucleoside or other compound which increases response in another group of cytokines. In yet another aspect of the invention, a patient is prophylactically treated by administering a nucleoside or other compound which selectively reduces Th1 activity without significantly reducing Th2 activity. In yet another aspect of the invention, a nucleoside or other compound is administered to a patient at a dose which reduces the patient's GTP pool to a degree that selectively reduces one of the Th1 or Th2 response without significantly reducing the other response. Controlled release dosage forms are particularly contemplated to achieve that result.

Description

CYTOKINE RELATED TREATMENTS OF DISEASE
This application claims priority to (1) provisional application ser. no. 60/028586 filed April 23, 1997, (2) provisional application ser. no. 60/043,974 filed April 23, 1997, (3) provisional application ser. no. 60/055,487 filed August 12, 1997; and (4) provisional application 60/036,094 dated January 14, 1997.
FIELD OF THE INVENTION
The present invention relates to the field of nucleosides.
BACKGROUND OF THE INVENTION
Mammalian immune systems contain two major classes of lymphocytes: B lymphocytes (B cells), which originate in the bone marrow; and T lymphocytes (T cells) which originate in the thymus. B cells are largely responsible for humoral immunity (i.e., antibody production), while T cells are largely responsible for cell-mediated immunity.
T cells are generally considered to fall into two subclasses, helper T cells and cytotoxic T cells. Helper T cells activate other lymphocytes, including B cells and cytotoxic T cells, and macrophages, by releasing soluble protein mediators called cytokines which are involved in cell-mediated immunity. As used herein, lymphokines are a subset of cytokines.
Helper T cells are also generally considered to fall into two subclasses, Thl and Th2 Thl cells (also known as Type 1 cells) produce interleukin 2 (LL-2), tumor necrosis factor (TNFα) and interferon gamma (IFNγ), and are responsible primarily for cell-mediated immunity such as delayed type hypersensitivity and antiviral immunity. In contrast, Th2 cells
(also known as Type 2 cells) produce interleukins, IL4, IL-5, LL-6, LL-9, LL-10 and LL-13, and are primarily involved in assisting humoral immune responses such as those seen in response to allergens, e.g. IgE and lgG4 antibody isotype switching (Mosmann, 1989, Annu Rev Immunol, 7: 145-173).
As used herein, the terms Thl and Th2 "responses" are meant to include the entire range of effects resulting from induction of Thl and Th2 lymphocytes, respectively. Among other things, such responses include variation in production of the corresponding cytokines through transcription, translation, secretion and possibly other mechanisms, increased proliferation of the corresponding lymphocytes, and other effects associated with increased production of cytokines, including motility effects.
The priority applications, each of which is incorporated herein by reference, relate to aspects of our recent discoveries involving the effect of various nucleosides (which are defined herein to include derivatives and analogs of native nucleosides) on selectively modulating lymphocyte responses relative to each other. Among other things, we have shown that either of Thl and Th2 responses can be selectively suppressed while the other is either induced or left relatively unaffected, and either of Thl or Th2 responses can be selectively induced while the other is either suppressed or left relatively unaffected. We have also discovered the surprising fact that nucleosides effective in selectively modulating Thl and Th2 responses relative to one another tend to have a bimodal effect. Among other things, nucleosides which tend to generally suppress or induce both Thl and Thl activity at a relatively higher dose, tend to selectively modulate Thl and Th2 relative to each other at relatively lower doses.
The mechanisms by which nucleosides and other compounds selectively modulate Thl and Th2 responses relative to each other are still unclear. One possibility contemplated by the present inventors is that effective nucleosides alter the pool of guanosine triphosphate (GTP), which in turn affects the rate at which cytokines are produced. In this theory, relatively large variations in available GTP are sufficient to affect concentrations of both Thl and Th2 cytokines, while relatively smaller variations in available GTP tend to affect concentrations of Thl and Th2 cytokines to different extents.
The effects of 2-β-D-ribofuranosylthiazole-4-carboxamide (Tiazofurin), a synthetic C- nucleoside analogue, on GTP levels supports this view. Tumor cells are characterized by high levels of inosine monophosphate dehydrogenase (IMP DH) activity, and it is known that LMP DH is the rate-limiting enzyme of GTP biosynthesis. Weber, G., IMP Dehydrogenase and GTP as Targets in Human Leukemia Treatment. Adv. Exp. Med. Biol. 309B:287-292 (1991). Tiazofurin has been shown to selectively block IMP DH activity and deplete guanine nucleotide pools, which in turn forces various tumors into remission. Weber, G., Critical Issues in Chemotherapy with Tiazofurin. Adv. Enzyme Regul. 29:75-95 (1989). Typical initial doses of Tiazofurin are about 4,400 mg/m2, with consolidation doses of about 1100 to 3300 mg/m2. At these levels synthesis of both Thl and Th2 responses are greatly reduced, thereby essentially shutting down much of the immune system. In one aspect of the present invention it is contemplated that much smaller doses of Tiazofurin, in the range of 1/10th to one-half that set forth above, would be sufficient to specifically suppress either a Thl response or a Th2 response without greatly reducing the other response.
The effects of l-b-D-ribofuranosyl-l,2,4-triazole-3-carboxamide (Ribavirin) also supports the present theory. Ribavirin is a potent, broad-spectrum antiviral agent, which has also been shown to inhibit IMP DH. Yamada, Y. et al., Action of the Active Metabolites of Tiazofurin and Ribavirin on Purified IMP Dehydrogenase. Biochem. 27:2193-2196 (1988). Ribavirin proceeds under a different mechanism than Tiazofurin in inhibiting IMP DH, however, acting on a different site on the enzyme molecule. Ribavirin is converted to its active metabolite, ribavirin-monophosphate (RMP), which inhibits the enzyme at the IMP-
XMP site of IMP DH. As with Tiazofurin, the affinity of Ribavirin' s active form to the enzyme is higher than that of the natural metabolite. At relatively high doses, approximately 2200 mg/m2 or about 1200 - 1500 mg/day for an adult, Ribavirin reduces IMP DH activity to such an extent that both Thl and Th2 responses are inhibited. At relatively lower dosages of approximately 600 to 1000 mg/day, Ribavirin promotes a Thl response and suppresses a Th2 response.
Despite the existence of as-yet undefined mechanisms, we have discovered that enormous potential benefits can be derived from selective modulation of Thl and Th2 responses relative to each other. We have concluded, for example, that specific modulation of
Thl relative to Th2 can be useful in treating a wide variety of conditions and diseases, ranging from infections, infestations, tumors and hypersensitivities to autoimmune diseases.
These discoveries are especially significant because modern treatment strategies for many of the above-listed diseases have either limited effectiveness, significant side effects, or both. Treatment of autoimmune disease, for example, is frequently limited to palliative measures, removal of toxic antibodies (as in myasthenia gravis), and administration of hazardous drugs including corticosteroids, chloroquine derivatives, and antimetabolic or antitumor drugs, and drugs such as cyclosporines which target immune system cells.
SUMMARY OF THE INVENTION
This application relates to the use of nucleosides in the relatively low dosage range to selectively modulate Thl and Th2 responses relative to each other in the treatment of disease. In one aspect of the invention, administration of a nucleoside or other compound reduces the dosage at which a primary drug is administered. In another aspect of the invention, an abnormality reflected in increased response in one group of cytokines is treated by administering a nucleoside or other compound which increases response in another group of cytokines. In yet another aspect of the invention, a patient is prophylactically treated by administering a nucleoside or other compound which selectively reduces Thl activity without significantly reducing Th2 activity. In yet another aspect of the invention, a nucleoside or other compound is administered to a patient at a dose which reduces the patient's GTP pool to a degree that selectively reduces one of the Thl or Th2 response without significantly reducing the other response. Controlled release dosage forms are particularly contemplated to achieve that result.
Examples of nucleosides contemplated to be effective in this manner are D- and L- forms of: (a) bicyclic nucleosides corresponding to any of Formulas 1, 1-A through 1-F; and (b) monocyclic nucleosides nucleosides corresponding to any of Formulas 2 through 5.
Examples of primary drugs contemplated to be effective in this manner are anti-viral agents such as Ribavirin , acyclovir, and AZT™; anti-fungal agents such as tolnaftate,
Fungizone™, Lotrimin,™ Mycelex,™, Nystatin and Amphoteracin; anti-parasitics such as Mintezol™, Niclocide™, Vermox™, and Flagyl™; bowel agents such as Immodium™, Lomotil™ and Phazyme™; anti-tumor agents such as Adriamycin™, Cytoxan™, Imuran™, Methotrxate, Mithracin™, Tiazofurin™, Taxol™; dermatologic agents such as Aclovate™, Cyclocort™, Denorex™, Florone™, Oxsoralen™, coal tar and salicylic acid; migraine preparations such as ergotamine compounds; steroids and immunosuppresants not listed above, including cyclosporins, Diprosone™, hydrocortisone; Floron™, Lidex™, Topicort and Valisone; and metabolic agents such as insulin.
DETAILED DESCRIPTION Definitions
Where the following terms are used in this specification, they are used as defined below.
The terms "α" and "β" indicate the specific stereochemical configuration of a substituent at an asymmetric carbon atom in a chemical structure as drawn. The term "abnormality" refers to a condition associated with a disease. Thus, Thl and/or Th2 responses resulting from an autoimmune disease are considered herein to be abnormalities of the corresponding cytokine(s) even though such cytokine responses may commonly result from the disease.
The term "aryl" refers to a monovalent unsaturated aromatic carbocyclic radical having a single ring (e.g., phenyl) or two condensed rings (e.g., naphthyl), which can optionally be substituted with hydroxyl, lower alky, chloro, and/or cyano.
The term "effective amount" refers to the amount of a compound of formula (I) which will restore immune function to normal levels, or increase immune function above normal levels in order to eliminate infection. The term "enantiomers" refers to a pair of stereoisomers that are non-superimposable mirror images of each other. A mixture of a pair of enantiomers, in a 1 : 1 ratio, is a "racemic" mixture.
The term "heterocycle" refers to a monovalent saturated or unsaturated carbocyclic radical having at least one hetero atom, such as N, O or S, within the ring each available position of which can be optionally substituted, independently, with, e.g., hydroxy, oxo, amino, imino, lower alkyl, bromo, chloro and/or cyano. Included within this class of substituents are purines, pyrimidines.
The term "immunomodulators" refers to natural or synthetic products capable of modifying the normal or aberrant immune system through stimulation or suppression. The term "isomers" refers to different compounds that have the same formula.
"Stereoisomers" are isomers that differ only in the way the atoms are arranged in space. The term "L-configuration" is used throughout the present invention to describe the chemical configuration of the ribofuranosyl moiety of the compounds that is linked to the nucleobases. The L-configuration of the sugar moiety of compounds of the present invention contrasts with the D-configuration of ribose sugar moieties of the naturally occurring nucleosides such as cytidine, adenosine, thymidine, guanosine and uridine.
The term "lower alkyl" refers to methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, I- butyl or n-hexyl. This term is further exemplified to a cyclic, branched or straight chain from one to six carbon atoms.
The term "monocyclic" refers to a monovalent saturated carbocyclic radical having at least one hetero atom, such as O, N, S, Se or P, within the ring, each available position of which can be optionally substituted, independently, with a sugar moiety or any other groups like bromo, chloro and/or cyano, so that the monocyclic ring system eventually aromatized [e.g., Thymidine; l-(2'-deoxy-?-D-erythro-pentofuranosyl)thymine].
The term "nucleoside" refers to a compound composed of any pentose or modified pentose moiety attached to a specific position of a heterocycle or to the natural position of a purine (9-position) or pyrimidine (1 -position) or to the equivalent position in an analog, including especiall both D- and L- forms of nitrogenous bicyclic and monocyclic heterocycles depicted in Figures 1, 1-A through 1-F, and 2 through 5 herein.
The term "C-nucleosides" is used throughout the specification to describe the linkage type that formed between the ribose sugar moiety and the heterocyclic base. In C-nucleosides, the linkage originates from the C-1 position of the ribose sugar moiety and joins the carbon of the heterocyclic base. The linkage that forms in C-nucleosides are carbon to carbon type.
The term "D-nucleosides" refers to nucleoside compounds that have a D-ribose sugar moiety (e.g., Adenosine). The term "L-nucleosides" refers to nucleoside compounds that have an L-ribose sugar moiety.
The term "N-nucleosides" is used throughout the specification to describe the linkage type that formed between the ribose sugar moiety and the heterocyclic base. In N-nucleosides, the linkage originates from the C-1 position of the ribose sugar moiety and joins the nitrogen of the heterocyclic base. The linkage that forms in N-nucleosides are carbon to nitrogen type. The term "nucleotide" refers to a phosphate ester substituted on the 5 '-position of a nucleoside.
The term "pharmaceutically acceptable salts" refers to any salt derived from inorganic and organic acids or bases. The term "protecting group" refers to a chemical group that is added to, oxygen or nitrogen atom to prevent its further reaction during the course of derivatization of other moieties in the molecule in which the oxygen or nitrogen is located. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis.
The term "purine" refers to nitrogenous bicyclic heterocycles depicted in Figures 1, 1- A through 1-F herein.
The term "pyrimidine" refers to nitrogenous monocyclic heterocycles depicted in Figures 2 through 5 herein.
The term "tumor" refers broadly to all manner of autonomous morbid growth of tissue which may or may not become malignant, including all manner of neoplasms and cancers. The terms "treating" or "treatment" of a disease refers to executing a protocol, which may include administering one or more drugs to a patient, in an effort to alleviate signs or symptoms of the disease. Thus, "treating" or "treatment" do not require complete alleviation of signs or symptoms, do not require a cure, and specifically include protocols which have only marginal effect on the patient.
Combinations and Methods
Contemplated combinations in one aspect of the present invention generally include a primary or "first" drug and another or "second" drug, and contemplated methods involve selecting and combining the first and second drugs in combination therapies. In preferred embodiments a disease is identified which is known to produce an abnormality in at least one cytokine in a patient, the first drug is selected from among those compounds demonstrated to treat the disease at a monotherapeutic dosage, and the second drug, which may be a bimodal nucleoside modulator as herein described, is selected from among those compounds known to exacerbate the very abnormality produced by the disease when administered within a given dosage range. The first drug is then administered at less than the monotherapeutic dosage and the second drug is administered in a dosage outside the dosage range which exacerbates the abnormality. Since the second drug has a bimodal activity with respect to at least some of the cytokines of interest, the combination is still effective to treat the disease, and administration of the second drug allows reduction in the administered dosage of the primary or first drug.
Examples of primary drugs contemplated to be effective in combination with a modulator selected from Figures 1, 1-A through 1-F, and 2-5, are anti-viral agents such as interferon, including but not limited to interferon and γ, Ribavirin , acyclovir, and AZT™; anti-fungal agents such as tolnaftate, Fungizone™, Lotrimin,™ Mycelex,™, Nystatin and Amphoteracin; anti-parasitics such as Mintezol™, Niclocide™, Vermox™, and Flagyl™; bowel agents such as Immodium™, Lomotil™ and Phazyme™; anti-tumor agents such as interferon and γ, Adriamycin™, Cytoxan™, Imuran™, Methotrexate, Mithracin™, Tiazofurin™, Taxol™; dermatologic agents such as Aclovate™, Cyclocort™, Denorex™, Florone™, Oxsoralen™, coal tar and salicylic acid; migraine preparations such as ergotamine compounds; steroids and immunosuppresants not listed above, including cyclosporins, Diprosone™, hydrocortisone; Floron™, Lidex™, Topicort and Valisone; and metabolic agents such as insulin, and other drugs which may not nicely fit into the above categories, including cytokines such as LL2, IL4, IL6, LL8, EL10 and IL12. Especially preferred primary drugs are AZT, 3TC, 8-substituted guanosine analogs, 2',3'-dideoxynucleosides, interleukin II, interferons such as I B-interferons, tucaresol, levamisole, isoprinosine and cyclolignans.
Examples of secondary drugs contemplated to be effective in the invention are D- and L- forms of (a) bicyclic nucleosides corresponding to generic Formula 1 and 1-A through 1-F, and (b) monocyclic nucleosides nucleosides corresponding to Formulas 2 through 5. Other nucleoside and non-nucleoside compounds effective in the invention are readily identified through screening of such compounds in vitro for effect on IL-2, TNF-α, LFN-γ, LL-4 and LL-
5 as described in PCT/US97/00600. Formula 1 compounds are purine nucleosides having the structure:
Formula 1
wherein Rj, R2, R3, R4, R5, R2' and R3' are independently selected from the group consisting of H, OH, NH2, F, Cl, Br, I, N3, -CN, -OR', -NR'2, -SR', -NHNH2, -NHOH, CHO,
COOR', CONR'2, alkyl, alkenyl, alkylnyl, aryl, aralkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, substituted aralkyl, where the substituent is selected from F, Cl, Br, I, N3, -CN, -OR", NO2, -NR"2, SR", -NHNH2, -NHOH, COOR", CONR"2 and where R and R" are H, alkyl, alkenyl, alkynyl, aryl, aralkyl; W = O, S, CH2, Se;
Zj, Z2 are independently selected from N, C, CH;
Z3, Z4, Z5 are independently selected from the group consisting of -CR-, -NR-, -O-, -S- , -Se-, -C=O, -C=S, -S=O, -CR=CR-, -CR=N-, -N=N-, where R is selected from the group consisting of H, F, Cl, Br, I, N3, -CN, -OR', -NR'2, -SR1, -NHNH2, -NHOH, -NO2, CHO, COOR', CONH2, -C(O)-NH2, -C(S)-NH2, -C(NH)-NH2, -C(NOH)-NH2, =O, =NH, =NOH,
=NR, alkyl, alkenyl, alkylnyl, aryl, aralkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, substituted aralkyl, where the substituent is selected from H, -OH, NH2, F, Cl, Br, I, N3, -CN, -COOR", -CONR"2, -OR", -NR"2, -SR", -NHNH2, -NHOH, -N02, and R', R" are H, alkyl, alkenyl, alkynyl, aryl, aralkyl, acetyl, acyl, sulfonyl;
The Chemical bond between Z3 and Z4 or Z4 and Z5 is selected from C-C, C=C, C-N, C=N, N-N, N=N, C-S, N-S;
X and Y are independently selected from the group consisting of H, OH, NH2, F, Cl, Br, I, N3, -S-NH2, -S(O)-NH2, -S(O2)-NH2, -CN, -COOR', -CONR'2, -OR, -NR'2, -SR', - NHNH2, -NHOH, alkyl, alkenyl, alkylnyl, aryl, aralkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, substituted aralkyl, where the substituent is selected from F, Cl, Br, I, N3, -CN, -OR", NO2, -NR"2, SR", -NHNH2, -NHOH, and R', R" are H, alkyl, alkenyl, alkynyl, aryl, aralkyl.
Formula 1-A compounds are 8-substituted "-or β- L- or D- guanosine analogs having the structure:
Formula 1-A
wherein X is selected from H, R, F, Cl, Br, I, N3, -CN, -OR, -SR, -NR , -NHNH2, - NHOH, -CHO, -CONH2, -COOR, and -L-A; where R is selected from alkyl, alkenyl, alkynyl, and aralkyl, acetyl, acyl, sulfonyl; L is a linker and selected from alkyl, alkenyl, alkynyl, and aralkyl; and A is selected from H, -OR', -SR, -NR'2, -NHNR'2, -CHO, -COOR', -CONR'2, where R' is selected from H, Me, Et, allyl, acetyl, -COCF3; Y is selected from H, R, F, Cl Br, I, N3, CN, OR, SR, NR2, where R is selected from H, alkyl, alkenyl, alkynyl, and aralkyl, acetyl, acyl, sulfonyl; Z is N or CH; and Rl, R2, and R3 are independently selected from H, -OH, -OAc, -OBz, -OP(O2)OH.
Formula IB compounds are 7-substituted-8-oxo-"-or β- L-guanosine analogs having structure:
Formula 1-B
Formula 1-C compounds are 7-deaza-7,8-mono- or disubstituted "-or β- L- or D- guanosine analogs having the structure:
Formula 1-C wherein X\ and X2 are independently selected from H, R, F, Cl, Br, I, N3, -CN, -OR, -SR, -NR2, -NHNH2, -NHOH, -CHO, -CONH2, -COOR, and -L-A; where R is selected from alkyl, alkenyl, alkynyl, and aralkyl, acetyl, acyl, sulfonyl; L is a linker and selected from alkyl, alkenyl, alkynyl, and aralkyl; and A is selected from H, -OR', -SR', -NR'2, -NHNR'2, -CHO, - COOR', -CONR'2, where R' is selected from H, Me, Et, allyl, acetyl, -COCF3;
Y is selected from H, R, F, Cl, Br, I, N3, -CN, -OR, -SR, -NR2, where R is selected from H, alkyl, alkenyl, alkynyl, and aralkyl, acetyl, acyl, sulfonyl;
Z is N or CH;
Ri , R2, and R3 are independently selected from H, -OH, -OAc, -OBz, -OP(O2)OH.
Formula 1-D compounds are 7-deaza-8-aza-7-substituted "-or β- L- or D- guanosine analogs having the structure:
Formula 1-D
X is selected from H, R, F, Cl, Br, I, N3, -CN, -OR, -SR, -NR2, -NHNH2, -NHOH, CHO, -CONH2, -COOR, and -L-A; where R is selected from alkyl, alkenyl, alkynyl, and aralkyl, acetyl, acyl, sulfonyl; L is a linker and selected from alkyl, alkenyl, alkynyl, and aralkyl; and A is selected from H, -OR, SR, -NR'2, -NHNR'2, -CHO, -COOR, -CONR'2, where R' is selected from H, Me, Et, allyl, acetyl, -COCF3;
Y is selected from H, R, F, Cl, Br, I, N3, -CN, -OR, -SR, -NR2, where R is selected from H, alkyl, alkenyl, alkynyl, and aralkyl, acetyl, acyl, sulfonyl;
Z is N or CH; Rl, R , and R3 are independently selected from H, -OH, -OAc, -OBz, -OP(O2)OH.
Formula 1-E compounds are thiazolo[4,5-d]pyrimidine "-or β- L- or D- nucleosides having the structure:
Formula 1-E
X! = O, S, =NH, =NNH , =NHOH, =NR where R is selected from alkyl, alkyenyl, alkynyl, and aralkyl, acyl; X2 is S, O, or Se
Y is selected from H, R, F, Cl, Br, I, N3, -CN, -OR, -SR, -NR2, where R is selected from H, alkyl, alkenyl, alkynyl, and aralkyl, acetyl, acyl, sulfonyl;
Z is N or CH;
Ri , R , and R3 are independently selected from H, -OH, -OAc, -OBz, -OP(O2)OH. Formula 1-F compounds are β-L- or D- purine nucleosides having the structure:
Formula 1-F X is selected from H, R, -SNH2, -S(O)NH2, -SO2NH2, F, Cl, Br, I, N3, -CN, -OR, SR, -NR2, where R is selected from H, alkyl, alkenyl, alkynyl, and aralkyl, acetyl, acyl, sulfonyl;
Y is selected from H, R, F, Cl, Br, I, N3, -CN, -OR, -SR, -NR2, where R is selected from H, alkyl, alkenyl, alkynyl, and aralkyl, acetyl, acyl, sulfonyl;
Z\, Z2 and Z3 are independently selected from C, N, and CH;
Rl, R2, and R3 are independently selected from H, -OH, -OAc, -OBz, -OP(O2)OH.
Formula 2 compounds have the structure:
Formula 2
wherein:
A is independently selected from N or C;
B, C, E, F are independently selected from CH, CO, N, S, Se, O, NR1, CCONH CCH3, C-R2 or P; R1 is independently H, lower alkyl, lower alkylamines, COCH3, lower alkyl alkenyl, lower alkyl vinyl or lower alkyl aryls. R2 is independently H, OH, halogens, CN, N3, NH2, C(=O)NH2, C(=S)NH2, C(=NH)NH2.HC1, C(=NOH)NH2, C(=NH)OMe, lower alkyl, lower alkylamines, lower alkyl alkenyl, lower alkyl vinyl, lower alkyl aryls or substituted heterocycles; D is independently selected from CH, CO, N, S, Se, O, NR1, CCONH2, CCH3, C-R2, P or nothing, where R1 is independently H, O, lower alkyl, lower alkylamines, COCH3, lower alkyl alkenyl, lower alkyl vinyl or lower alkyl aryls, and R2 is independently H, OH, halogens, CN, N3, NH2, lower alkyl, lower alkylamines, lower alkyl alkenyl, lower alkyl vinyl, lower alkyl aryls or substituted heterocycles,
X is independently O, S, CH2 or NR, where R is COCH3, R, and R, are independently selected from H, CN, N3, CH2OH, lower alkyl and lower alkyl amines,
R2, R3, R5, Re, R7 and R8 are independently selected from H, OH, CN, N3, halogens, CH2OH, NH2, OCH3, NHCH3, ONHCH3, SCH3, SPh, alkenyl, lower alkyl, lower alkyl amines and substituted heterocycles, and R R2, R3, R4, R5, Rg, R7 and R8 are not all substituted at the same time, such that when R2 = R3 = H, then R7 and R8 are hydrogens or nothing, when Rb R4 or R5 are substituted, then R7 = R8 = H and R2 = R3 = OH, when R2 or R3 are substituted, then R7 and R8 are H or OH, when R7 or R8 are substituted, then R2 and R3 are H or OH, when R7 and R8 are hydroxyl, then R2 and R3 are not OH, when A = N, B = CO, C = N or NH, D = CO or C-NH2, E is CH or C-substituted, F = CH, X = O, S or CH2, then R2 will not be H, OH, CH3, halogens, N3, CN, SH, SPh, CH2OH, CH2OCH3, CH2SH, CH2F, CH2N3, aryl, aryloxy or heterocycles, when A = N, B = CO, C = N or NH, D = CO or C-NH2, E is CH, C-CH3 or halogen, F = CH, X = N-COCH3, then R2 will not be H or OH, when A = N, B - CH, C = CH or CH3, D = CH or C-CH3, E is CH, C- CH3 or C- CONH2, F = CH, X = O, or CH2, then R2 will not be H or OH, when A = N, B = N, CO or CH, C = CH, C-Cl or C-OCH3, D = CH or C-Ph, E is CH, C-Cl or C-Ph, F = N or CO, X = O, then R2 will not be H or OH, when A = N, B = CO or CS, C = N or NH, D = CO or C-NH2, E is CH or N, F = N or
CH, X = O, then R2 will not be H or OH, and when A = C, B = CH, C = NH, D = CO, CS or C-NH2, E is N or NH, F = CO or CH, X = O, then R2 will not be H or OH
Formula 3 compounds have the structure
Formula 3
wherein:
X is independently O, S, CH2 and NR, where R is COCH3;
R' and R" are independently selected from H, CN, C(=O)NH2, NH2, C(=S)NH2, C(=NH)NH2.HC1, C(=NOH)NH2, C(=NH)OMe, heterocycles, halogens, lower alkyl or lower alkyl aryl;
R, and R4 are independently selected from H, CN, N3, CH2OH, lower alkyl or lower alkyl amines; and
R2, R3, R5, Re, R7 and R8 are independently selected from H, OH, CN, N3, halogens, CH2OH, NH2, OCH3, NHCH3, ONHCH3, SCH3, SPh, alkenyl, lower alkyl, lower alkyl amines or substituted heterocycles; such that when R2 = R3 = H, then R7 and R8 are hydrogens or nothing.
In compounds of Formula 3, R' is preferably carboxamide or CN and R" is hydrogen or halogens; R, = R4 = R5 = R7 = R8 = H and R2 = R3 = OH, and preferably X is oxygen.
Formula 4 compounds have the structure:
Formula 4
wherein:
A is independently selected from N or C;
B, C, E and F are independently selected from CH, CO, N, S, Se, O, NR1, CCONH2, CCH3, C-R2 or P; R1 is independently H, lower alkyl, lower alkylamines, COCH3, lower alkyl alkenyl, lower alkyl vinyl or lower alkyl aryls. R2 is independently H, OH, halogens, CN, N3, NH2, C(=O)NH2, C(=S)NH2, C(=NH)NH2.HC1, C(=NOH)NH2, C(=NH)OMe, lower alkyl, lower alkylamines, lower alkyl alkenyl, lower alkyl vinyl, lower alkyl aryls or substituted heterocycles;
X is independently O, S, CH2 or NR; where R is COCH3;
R, and R4 are independently selected from H, CN, N3, CH2OH, lower alkyl or lower alkyl amines; and
R2, R3, R5, Rg, R7 and R8 are independently selected from H, OH, CN, N3, halogens, NH2, CH2OH, OCH3, NHCH3, ONHCH3, SCH3, SPh, alkenyl, allyl, lower alkyl, lower alkyl amines or substituted heterocycles; such that when R2 = R3 = H, then R7 and R8 are hydrogens or nothing; when A is carbon; B = E = N; C is N-Ph, then F is not CH; when A = N; C is CH; B = E = C-CH3, then F is not nitrogen; and when A is carbon, B = N; C = C-CONH2; E = CH; F = S, then X is not CH2.
In compounds of Formula 4, R1 is preferably H, lower alkyl or allyl; R2 is preferably H, OH, halogens, CN, N3, NH2, C(=O)NH2, C(=S)NH2, C(=NH)NH2.HC1, C(=NOH)NH2 or C(=NH)OMe; and when Rj = R4 = R5 = R7 = R8 = H, then preferably R2 = R3 = OH and preferably X is oxygen.
Formula 5 compounds have the structure:
Formula 5
wherein:
A is independently selected from N or C;
B, C, E, F are independently selected from CH, CO, N, S, Se, O, NR1, CCONH2, CCH3, C-R2 or P; R1 is independently H, lower alkyl, lower alkylamines, COCH3, lower alkyl alkenyl, lower alkyl vinyl or lower alkyl aryls. R2 is independently H, OH, halogens, CN, N3,
NH2, C(=O)NH2, C(=S)NH2, C(=NH)NH2.HC1, C(=NOH)NH2, C(=NH)OMe, lower alkyl, lower alkylamines, lower alkyl alkenyl, lower alkyl vinyl, lower alkyl aryls or substituted heterocycles;
D is independently selected from CH, CO, N, S, Se, O, NR1, CCONH2, CCH3, C-R2, P or nothing; R1 is independently H, O, lower alkyl, lower alkylamines, COCH3, lower alkyl alkenyl, lower alkyl vinyl or lower alkyl aryls. R2 is independently H, OH, halogens, CN, N3. NH2, lower alkyl, lower alkylamines, lower alkyl alkenyl, lower alkyl vinyl, lower alkyl aryls or substituted heterocycles;
X is independently O, S, CH2 or NR where R is COCH3; R, and R4 are independently selected from H, CN, N3, CH2OH, lower alkyl and lower alkyl amines; and R2, R3, R5, Re, R7 and R8 are independently selected from H, OH, CN, N3, halogens, CH2OH, NH2, OCH3, NHCH3, ONHCH3, SCH3, SPh, alkenyl, lower alkyl, lower alkyl amines and substituted heterocycles, such that when R2 = R3 = H, then R7 and R8 are hydrogens or nothing when A = N, B = CO, C = N or NH, D = CO or C-NH2, E is CH or C-substituted, F =
CH, X = O, S or CH2, then R2 will not be H, OH, CH3, halogens, N3, CN, SH, SPh, CH2OH, CH2OCH3, CH2SH, CH2F, CH2N3, aryl, aryloxy or heterocycles when A = N, B = CO, C = N or NH, D = CO or C-NH2, E is CH, C-CH3 or halogen, F = CH, X = N-COCH3, then R2 will not be H or OH, when A = N, B = CH, C = CH or CH3, D = CH or C-CH3, E is CH, C- CH3 or C-
CONH2, F = CH, X = O, or CH2, then R2 will not be H or OH, when A = N, B = N, CO or CH, C = CH, C-Cl or C-OCH3, D = CH or C-Ph, E is CH, C-Cl or C-Ph, F = N or CO, X = O, then R2 will not be H or OH, when A = N, B = CO or CS, C = N or NH, D = CO or C-NH2, E is CH or N, F = N or CH, X = O, then R2 will not be H or OH, and when A = C, B = CH, C = NH, D = CO, CS or C-NH2, E is N or NH, F = CO or CH, X = O, then R2 will not be H or OH
In another aspect of the invention, an abnormality reflected in increased response in one group of cytokines is treated by administering a nucleoside or other compound which increases response in another group of cytokines Thus, for example, a common rapid onset type of allergy results in an abnormally elevated Th2 response The abnormality is treated by administering Ribavirin at between 600 mg/day and 1,000 mg/day (for a typical adult), at which dose the Thl response is induced The treatment is effective because Thl and Th2 have a teeter-totter type relationship in this instance, such that the Th2 response is suppressed
In yet another aspect of the invention, a patient is prophylactically treated by administering a nucleoside or other compound which selectively reduces Thl activity without significantly reducing Th2 activity The prophylaxis can, for example, prepare the patient for organ or tissue transplant, or for anticipated contact with allergens In yet another aspect of the invention, a nucleoside or other compound is administered to a patient at a dose which reduces the patient's GTP pool to a degree that selectively reduces one of the Thl or Th2 response without significantly reducing the other response. Controlled release dosage forms are particularly contemplated to achieve that result, especially formulations which maintain the dose of the compound in the serum within a desirable range.
In the case of Ribavirin, for example, the serum level should be maintained between about 2 μM and about 5 μM. In terms of delivery rates, a controlled release formulation may advantageously have an in vitro dissolution rate when measured by the USP Paddle Method at 100 rpm at 900 ml aqueous buffer (pH between 1.6 and 7.2) between about 15% and 40% by weight of the compound after 1 hour, between about 30% and about 50% by weight of the compound after 2 hours, about 50%) and 70% by weight of the compound after 4 hours, between about 60% and about 80% by weight of the compound after 6 hours
Uses
It is contemplated that the claimed combinations will be used to treat a wide variety of conditions, and in fact any condition which responds positively to administration of one or more such combinations. Among other things it is specifically contemplated that such combinations may be used to treat an infection, an infestation, a tumor, a hypersensitivity or an autoimmune disease.
Infections contemplated to be treated with the compounds of the present invention include respiratory syncytial virus (RSV), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex type 1 and 2, herpes genitalis, herpes keratitis, herpes encephalitis, herpes zoster, human immunodeficiency virus (HIV), influenza A virus, hantann virus (hemorrhagic fever), human papilloma virus (HPV), measles and fungus. It is especially contemplated that combinations claimed herein will be useful in treating chronic viral and bacterial infections, including HIV, Tuberculosis, leprosy and so forth.
Infestations contemplated to be treated with the compounds of the present invention include intracellular protozoan infestations, as well as helminth and other parasitic infestations. Again, it is especially contemplated that combinations claimed herein will be useful in treating chronic infestations. Tumors contemplated to be treated include those caused by a virus, and the effect may involve inhibiting the transformation of virus-infected cells to a neoplastic state, inhibiting the spread of viruses from transformed cells to other normal cells and/or arresting the growth of virus-transformed cells.
Hypersensitivities contemplated to be treated include all types of allergies, including IgE and IgG allergies, hyper IgE syndrome, and dermatic conditions such as atopic dermatitis. It is also contemplated that claimed combinations can be used to treat transplant rejection, (graft vs. host disease) and implant reactions.
Autoimmune diseases can be classified as either non-organ-specific or organ-specific. Non-organ-specific autoimmune diseases include rheumatoid arthritis, gout and gouty arthritis, Systemic Lupus Erythematosus (SLE), Sjogren syndrome, scleroderma, polymyositis and dermomyositis, ankylosing spondylitis, and rheumatic fever. Organ-specific autoimmune diseases are known for virtually every organ, including insulin-dependent diabetes, thyroid diseases (Graves disease and Hashimoto thyroiditis), Addison disease, and some kidney and lung diseases including allergy and asthma, multiple sclerosis, myasthenia gravis, uveitis, psoriasis, forms of hepatitis and cirrhosis, celiac disease, inflammatory bowel disease, and some types of male and female infertility. Autoimmune processes may also be stimulated by viral infections including the HIV virus, may result from rejection of transplantation, and may accompany certain tumors, or be precipitated by exposure to some chemicals.
It is also contemplated that an abnormality reflected in increased response in one group of cytokines can be treated by administering a nucleoside which increases response in another group of cytokines. Thus, for example, since common IgE allergies are associated with a predominantly Th2 response, allergies can be treated with Ribavirin, which increases Thl response at low dosages of about 500 mg/day to about 1,000 mg/day.
In yet another aspect of the invention, a patient is prophylactically treated by administering a compound which selectively reduces Thl activity without significantly reducing Th2 activity. The prophylactic treatment may be to reduce expected undesirable effects from an upcoming event, such as an organ or tissue transplant, or to reduce symptoms from an expected pulmonary insult, as from the onset of increase in airborne pollen levels in Spring
Synthesis
Synthesis of compounds according to Formulas 1, and 1-A through 1-F were set forth in co-pending PCT application PCT/US97/ 18387, which is incorporated herein as though set forth in full Synthesis of compounds according to Formulas 2 through 5 were set forth in co- pending PCT application PCT/US97/00600
Administration
It is contemplated that compounds according to the present invention will be administered in any appropriate pharmaceutical formulation, and under any appropriate protocol Where primary or "first" treatment drugs are employed as discussed above, preferred monotherapeutic dosages and protocols for such drugs are set forth in the PDR, or are at least available from the manufacturer or distributor Preferred dosages and protocols for the "second" drugs, such as bi-modal nucleosides described herein, may best be established through experimentation with particular patients Such experimentation need not be extensive, and it is contemplated that "second" drugs comprising nucleosides as described herein will be administered at between about 100 mg/day and about 5,000 mg/day
Of course, one of ordinary skill in the art will recognize that a therapeutically effective amount will vary with the infection or condition to be treated, its severity, the treatment regimen to be employed, the pharmacokinetics of the agent used, as well as the patient (animal or human) treated Thus, effective dosages may range from 1 mg/kg of body weight, or less, to 25 mg/kg of body weight or more In general a therapeutically effective amount of the "second" drug is contemplated to range from slightly less than about 1 mg /kg to about 25 mg /kg of the patient, depending upon the compound used, the condition or infection treated and the route of administration This dosage range generally produces effective blood level concentrations of active compound ranging from about 0 04 to about 100 micrograms/cc of blood in the patient It is contemplated, however, that appropriate patient-specific regimens will be developed by administering a small amount, and then increasing the amount until either the side effects become unduly adverse, or the intended effect is achieved.
Administration of compounds according to the present invention may take place orally, parenterally (including subcutaneous injections, intravenous, intramuscularly, by intraster al injection or infusion techniques), by inhalation spray, or rectally, topically and so forth, and in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
It is contemplated that compounds according to the present invention can be formulated in admixture with a pharmaceutically acceptable carrier. For example, the compounds of the present invention can be administered orally as pharmacologically acceptable salts. Because the compounds of the present invention are mostly water soluble, they can be administered intravenously in physiological saline solution (e.g., buffered to a pH of about 7.2 to 7.5). Conventional buffers such as phosphates, bicarbonates or citrates can be used for this purpose. Of course, one of ordinary skill in the art may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the compositions of the present invention unstable or compromising their therapeutic activity. In particular, the modification of the present compounds to render them more soluble in water or other vehicle, for example, may be easily accomplished by minor modifications (salt formulation, esterification, etc.) which are well within the ordinary skill in the art. It is also well within the ordinary skill of the art to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect in patients.
In certain pharmaceutical dosage forms, the pro-drug form of administered compounds, especially including acylated (acetylated or other) derivatives, pyridine esters and various salt forms of the present compounds are preferred. One of ordinary skill in the art will recognize how to readily modify the present compounds to pro-drug forms to facilitate delivery of active compounds to a target site within the host organism or patient. One of ordinary skill in the art will also take advantage of favorable pharmacokinetic parameters of the pro-drug forms, where applicable, in delivering the present compounds to a targeted site within the host organism or patient to maximize the intended effect of the compound.
In addition, compounds included in combinations according to the present invention may be administered separately or together, and when administered separately this may occur in any order. The amounts of the active ingredient(s) and pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
Administration routes of compounds according to the present invention may range from continuous (intravenous drip) to several oral administrations per day (for example, Q.I.D.) and may include oral, topical, parenteral, intramuscular, intravenous, sub-cutaneous, transdermal (which may include a penetration enhancement agent), buccal and suppository administration, among other routes of administration.
To prepare therapies according to the present invention, a therapeutically effective amount of a compound is preferably intimately admixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques to produce a dose. A carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral. In preparing pharmaceutical compositions in oral dosage form, any of the usual pharmaceutical media may be used. Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives including water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used. For solid oral preparations such as powders, tablets, capsules, and for solid preparations such as suppositories, suitable carriers and additives including starches, sugar carrier, such as dextrose, mannitol, lactose and related carriers, diluents, granulating agents, lubricants, binders, disintegrating agents and the like may be used. If desired, the tablets or capsules may be enteric-coated or sustained release by standard techniques.
For parenteral formulations, the carrier will usually comprise sterile water or aqueous sodium chloride solution, though other ingredients including those which aid dispersion may be included. Of course, where sterile water is to be used and maintained as sterile, the compositions and carriers must also be sterilized. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
It will also be appreciated that in general, the most preferred uses according to the present invention are those in which the active compounds are relatively less cytotoxic to the non-target host cells and relatively more active against the target. In this respect, it may also be advantageous that L-nucleosides may have increased stability over D-nucleosides, which could lead to better pharmacokinetics. This result may attain because L-nucleosides may not be recognized by enzymes, and therefore may have longer half-lives.
Thus, therapies have been disclosed which employ nucleosides and other compounds to selectively modulate Thl and Th2 responses relative to each other in the treatment of disease. While specific embodiments have been disclosed herein, the scope of the invention is not be limited except through interpretation of the appended claims.

Claims

We claim:
1. A method of reducing an administered dosage of a first drug in the treatment of a disease which is known to produce an abnormality in at least one cytokine in a patient, comprising: identifying a monotherapeutic dosage of the first drug which is effective to treat the disease; identifying a second drug which is known to exacerbate the abnormality when administered within a dosage range; and administering a combination therapy comprising the first drug at less than the monotherapeutic dosage and the second drug outside the dosage range.
2. The method of claim 1 wherein the disease comprises a chronic disease.
3. The method of claim 1 wherein the disease comprises chronic viral disease.
4. The method of claim 1 wherein the disease comprises insulin dependent diabetes.
6. The method of claim 1 wherein the disease comprises allergy. 6. The method of claim 1 wherein the disease comprises atopic dermatitis.
7. The method of claim 1 wherein the disease comprises intracellular protozoan infection.
8. The method of claim 1 wherein the disease comprises hyper IgE syndrome.
9. The method of claim 1 wherein the disease comprises HIV.
10. The method of claim 1 wherein the disease comprises graft versus host disease. 11. The method of claim 1 wherein the disease comprises Systemic Lupus Erythematosus.
12. The method of claim 1 wherein the disease comprises a tumor.
13. The method of any of claims 1-12 wherein the abnormality comprises an abnormal increase in Thl activity.
14. The method of any of claims 1-12 wherein the abnormality comprises an abnormal decrease in Thl activity.
15. The method of any of claims 1-12 wherein the abnormality comprises an abnormal increase in Th2 activity.
16. The method of any of claims 1-12 wherein the abnormality comprises an abnormal decrease in Th2 activity. 17. The method of any of claims 1-12 wherein the second drug comprises a pharmaceutically acceptable form of a nucleoside.
18. The method of any of claims 1-12 wherein the second drug comprises a pharmaceutically acceptable form of a D-nucleoside.
19. The method of any of claims 1-12 wherein the second drug comprises a pharmaceutically acceptable form of an L-nucleoside. 20. The method of any of claims 1-12 wherein the second drug comprises a pharmaceutically acceptable form of Ribavirin.
21. The method of any of claims 1-12 wherein the second drug comprises a pharmaceutically acceptable form of an interferon.
22. The method of any of claims 1-12 wherein the second drug comprises a nucleoside according to at least one of Formulas 1, 1A, IB, 1C, ID, IE or IF.
22. The method of any of claims 1-12 wherein the second drug comprises a nucleoside according to at least one of Formulas 2, 3, 4 or 5.
23. A method of treating a disease in a patient, comprising: associating the disease with an increase in activity of a first lymphokine phenotype; associating administration of a pharmaceutical within a first dosage range with an increase in activity of a second cytokine phenotype; administering the pharmaceutical within the first dosage range to treat the disease.
24. The method of claim 23 wherein the disease comprises a chronic disease.
25. The method of claim 23 wherein the disease comprises chronic viral disease.
26. The method of claim 23 wherein the disease comprises insulin dependent diabetes mellitus. 27. The method of claim 23 wherein the disease comprises allergy.
28. The method of claim 23 wherein the disease comprises atopic dermatitis.
29. The method of claim 23 wherein the disease comprises intracellular protozoan infection.
30. The method of claim 23 wherein the disease comprises hyper IgE syndrome. 31. The method of claim 23 wherein the disease comprises HIV.
32. The method of claim 23 wherein the disease comprises graft versus host disease.
33. The method of claim 23 wherein the disease comprises Systemic Lupus Erythematosus.
34. The method of claim 23 wherein the disease comprises a tumor. 35. The method of any of claims 23 - 34 further comprising: associating decreased activity of the second cytokine phenotype with administration of the pharmaceutical within a second dosage range. 36. The method of claim 35 wherein the pharmaceutical comprises a pharmaceutically acceptable form of Ribavirin. 37. The method of claim 35 wherein the pharmaceutical comprises a pharmaceutically acceptable form of an interferon. 38. The method of any of claims 23 - 34 further comprising: identifying a therapeutic agent which is recognized as being effective by itself to treat the disease at a recommended dosage; and administering the therapeutic agent at less than recommended dosage in combination with the pharmaceutical.
39. The method of claim 38 wherein the therapeutic agent is selected from the list consisting of anti-viral agents, anti-fungal agents, bowel agents, anti-tumor agents, dermatologic agents, migraine preparations, steroids, immuno-suppresants and metabolic agents. 40. The method of claim 39 further comprising associating decreased activity of the second cytokine phenotype with administration of the pharmaceutical within a second dosage range. 41. The method of claim 38 wherein the pharmaceutical comprises a pharmaceutically acceptable form of Ribavirin or an Interferon. 42. The method of claim 38 further comprising associating decreased activity of the second cytokine phenotype with administration of the pharmaceutical within a second dosage range. 43. The method of any of claims 23 - 34 wherein the second drug comprises a nucleoside according to at least one of Formulas 1, 1A, IB, 1C, ID, IE or IF. 44. The method of any of claims 23 - 34 wherein the second drug comprises a nucleoside according to at least one of Formulas 2, 3, 4 or 5.
45. The method of claim 38 wherein the second drug comprises a nucleoside according to at least one of Formulas 1, 1A, IB, 1C, ID, IE or IF.
46. The method of claim 38 wherein the second drug comprises a nucleoside according to at least one of Formulas 2, 3, 4 or 5.
47. A method of prophylactically treating a patient comprising: providing a pharmaceutical which suppresses Thl activity in the patient when administered below a given dosage level; and administering the pharmaceutical to the patient below the given dosage level. 48. The method of claim 47 wherein the prophylaxis comprises a preparing the patient for an organ transplant.
49. The method of claim 47 wherein the prophylaxis comprises a preparing the patient for a tissue transplant.
50. The method of claim 47 wherein the prophylaxis comprises a preparing the patient for expected contact with allergens.
51. The method of any of claims 47 - 49 further comprises providing the pharmaceutical at a dosage which induces Th2 activity.
52. The method of any of claims 47 - 49 wherein the pharmaceutical comprises a nucleoside according to at least one of Formulas 1, 1A, IB, 1C, ID, IE or IF. 53. The method of any of claims 47 - 49 wherein the pharmaceutical comprises a nucleoside according to at least one of Formulas 2, 3, 4 or 5.
A method of treating a disease having an elevated or suppressed Thl or Thl response, comprising identifying a compound and a dosage range for the compound which reduces the patient's GTP pool to a degree that selectively reduces one of the Thl or Th2 response without significantly reducing the other response, and administering the nucleoside to the patient within the dosage range The method of claim 54 wherein the disease comprises a chronic disease The method of claim 54 wherein the disease comprises chronic viral disease The method of claim 54 wherein the disease comprises insulin dependent diabetes mellitus The method of claim 54 wherein the disease comprises allergy The method of claim 54 wherein the disease comprises atopic dermatitis The method of claim 54 wherein the disease comprises intracellular protozoan infection The method of claim 54 wherein the disease comprises hyper IgE syndrome The method of claim 54 wherein the disease comprises HIV The method of claim 54 wherein the disease comprises graft versus host disease The method of claim 54 wherein the disease comprises Systemic Lupus Erythematosus The method of claim 54 wherein the disease comprises a tumor The method of any of claims 54 - 65 wherein the compound comprises a nucleoside according to at least one of Formulas 1, 1A, IB, 1C, ID, IE or IF The method of any of claims 54 - 65 wherein the compound comprises a nucleoside according to at least one of Formulas 2, 3, 4 or 5
68. A controlled release preparation for oral administration including a compound effective to selectively modulate Thl and Th2 responses with respect to each other within a dosage range.
69. The controlled release compound of claim 68 wherein the compound comprises a nucleoside according to at least one of Formulas 1, 1A, IB, 1C, ID, IE or IF.
70. The controlled release preparation of claim 68 wherein the compound comprises a nucleoside according to at least one of Formulas 2, 3, 4 or 5.
71. The controlled release preparation of claim 68 wherein the compound comprises Ribavirin. 72. The controlled release preparation of claim 68 wherein the compound comprises an interferon. 73. The controlled release preparation according to any of claims 68 - 73 wherein the patient maintains a serum level of between about 2 μM and about 5 μM of the compound. 74. The controlled release preparation according to any of claims 68 - 73 wherein the preparation has an in vitro dissolution rate when measured by the USP Paddle Method at 100 rpm at 900 ml aqueous buffer (pH between 1.6 and 7.2) between about 15% and 40%) by weight of the compound after 1 hour, between about 30% and about 50% by weight of the compound after 2 hours, about 50%o and 70%> by weight of the compound after 4 hours, between about 60% and about 80%o by weight of the compound after 6 hours.
EP98903474A 1997-01-17 1998-01-13 Cytokine related treatments of disease Withdrawn EP0998293A4 (en)

Priority Applications (3)

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EP02021843A EP1277759A1 (en) 1997-01-17 1998-01-13 Cytokine related treatments of disease
EP03008818A EP1329220A1 (en) 1997-01-17 1998-01-13 Cytokine related treatments of disease
EP00118252A EP1103559A1 (en) 1997-01-17 1998-01-13 Autoimmune nucleosides

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US28586P 1996-10-16
US3609497P 1997-01-17 1997-01-17
US36094P 1997-01-17
US2858697P 1997-04-23 1997-04-23
US4397497P 1997-04-23 1997-04-23
US43974P 1997-04-23
US5548797P 1997-08-12 1997-08-12
US55487P 1997-08-12
PCT/US1998/000634 WO1998030223A1 (en) 1997-01-17 1998-01-13 Cytokine related treatments of disease

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EP00118252A Division EP1103559A1 (en) 1997-01-17 1998-01-13 Autoimmune nucleosides
EP02021843A Division EP1277759A1 (en) 1997-01-17 1998-01-13 Cytokine related treatments of disease

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MY164523A (en) 2000-05-23 2017-12-29 Univ Degli Studi Cagliari Methods and compositions for treating hepatitis c virus
CZ301182B6 (en) 2000-05-26 2009-12-02 Idenix (Cayman) Limited Use of nucleoside derivatives for preparation of pharmaceutical compositions for treating infections caused by flaviviruses and pestiviruses
US7022830B2 (en) 2000-08-17 2006-04-04 Tripep Ab Hepatitis C virus codon optimized non-structural NS3/4A fusion gene
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WO2009022236A2 (en) 2007-08-16 2009-02-19 Tripep Ab Immunogen platform
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YU61598A (en) 2003-02-28
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JP2002515892A (en) 2002-05-28
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PL336579A1 (en) 2000-07-03
EP0998293A4 (en) 2002-07-17
KR20000070167A (en) 2000-11-25

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