WO2007110705A2 - Compositions macrolides en tant qu'agents thérapeutiques - Google Patents

Compositions macrolides en tant qu'agents thérapeutiques Download PDF

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Publication number
WO2007110705A2
WO2007110705A2 PCT/IB2006/004214 IB2006004214W WO2007110705A2 WO 2007110705 A2 WO2007110705 A2 WO 2007110705A2 IB 2006004214 W IB2006004214 W IB 2006004214W WO 2007110705 A2 WO2007110705 A2 WO 2007110705A2
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Prior art keywords
compound according
compound
hydrogen
substituted
alkyl
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PCT/IB2006/004214
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English (en)
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WO2007110705A3 (fr
Inventor
Bernard Mach
Peter Traxler
Krzysztof Masternak
Antony David Buss
Stephen Robert Whitton
Mark Stuart Butler
Yogonathan Kanagasundaram
Horst Flotow
Guo Xuming
Mui Mui Sim
Chee Wee Phoon
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Novimmune Sa
Merlion Pharmaceuticals Pte Ltd.
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Publication of WO2007110705A2 publication Critical patent/WO2007110705A2/fr
Publication of WO2007110705A3 publication Critical patent/WO2007110705A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • This invention relates generally to methods of using compositions including a 12- membered ring macrolide compound as therapeutics in the treatment of immune-related disorders and cancer.
  • the immune system is highly complex and tightly regulated, with many alternative pathways capable of compensating deficiencies in other parts of the system.
  • diseases or undesirable conditions are, for example, autoimmune diseases, graft rejection after transplantation, allergy to innocuous antigens, psoriasis, chronic inflammatory diseases such as atherosclerosis, and inflammation in general. In these cases and others involving inappropriate or undesired immune response, there is a clinical need for immunosuppression.
  • cancers have thus far proved problematic. While “cancers” share many characteristics in common, each particular cancer has its own specific characteristics. Genetics and environmental factors have a complex interplay in severity and prognosis of treatment. Thus, treatment must be carefully tailored. Certain pharmaceutical treatments have proven useful for one form of cancer, but not others. Other treatments such as radiation, while partially useful for a range of cancers, do not typically result in a complete cure. Indeed, given the severity of many cancers and the mortality rate, a drug can be deemed successful if it improves quality of life, e.g., by delaying growth of tumors, or prolongs life— without actually curing the condition. Thus, in many circumstances, an individual is treated with a compound or combination of treatments that can eliminate 90-95% of the malignant cells, but the remaining cells can regrow and metastasize, ultimately resulting in death.
  • compositions that can be used in the treatment of immune-related diseases and/or disorders, as well as compositions that are useful in the treatment of cancers and other related disorders.
  • the present invention is directed to compounds and pharmaceutically acceptable salts thereof including a macrolide compound that inhibits MHC class II expression and that can be used as an immunosuppressive agent in the treatment prior to, during and/or after organ or tissue transplantation, as well as in the treatment of immune-related disorders and/or cancer and cancer-related disorders.
  • the macrolide compounds of the present invention include a twelve-membered ring structure such as the twelve-membered ring structure shown below in formula A for the macrolide compound N831 (A).
  • the compounds of the present invention have been modified at the R] 7 position of the macrolide ring.
  • This application is related to the application U.S.S.N. 60/721,513, filed September 28, 2005.
  • the compounds of this related application have been modified at the R 7 position of the macrolide ring.
  • the macrolide compounds of the invention include a twelve-membered ring. More particularly, the present invention includes compounds of Formula I:
  • R d is -NH 2 or azide.
  • R- 3 is hydrogen, silyl, C 1 -C 6 allcyl or substituted Ci-C 6 alkyl, or -C(O)R S .
  • Silyl is R a R b R c Si-, further wherein R a , R b , and R c are the same as or different from each other and each represents methyl, ethyl, i-propyl, t-butyl, or phenyl.
  • R 5 is methyl, -NH 2 , Ci-C 6 alkylamino, CrC 6 dialkylamino, or heterocycle, each of which may be substituted.
  • R 4 is hydrogen
  • R 5 and R 5a are each, independently, hydrogen or hydroxyl, or taken together form a carbonyl, or taken together, R 4 and any one of R 5 or Rs a form a double bond.
  • R 6 is hydrogen, hydroxyl, Ci-C 6 alkyl or substituted C 1 -C 6 alkyl.
  • R 7 is hydrogen or -C(O)R t .
  • R t is methyl, -NH 2 , Ci-C 6 alkylamino, Ci-C 6 dialkylamino, or heterocycle, each of which may be substituted.
  • R 16 and Ri 6a are the same or different from each other and each represents: methyl, hydrogen, or hydroxyl.
  • Rn is:
  • Ri 7a is hydrogen, or taken together Rn and Ri 7a form a carbonyl.
  • R 17b is -NR j R k , -OR 1n , or -R n .
  • R j and R k are the same as or different from eacli other and each represents: hydrogen; C 2 , C 3 , C 4 , C 5 , or C 6 alkyl; C 3 , C 4 , C 5 , or C 6 alkenyl; C 2 , C3, C 4 , C5, or C 6 acyl; unsaturated C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 acyl; C 5 , C 6 , C 7 , or C 8 aryl; heteroaryl; benzyl; Cj, C 2 , C 3 , C 4 , C 5 , or C 6 alkylsulfonyl; benzenesulfonyl; -(CH 2 ) x -
  • -NR j R k is bound together to represent a ring, wherein the ring is a non- aromatic heterocyclic ring containing at least one nitrogen atom, wherein any of the atoms in the ring may be substituted.
  • R m is C 2 , C 3 , C 4 , C 5 , or C 6 alkyl; C 3 , C 4 , C 5 , or C 6 alkenyl; C 5 , C 6 , C7, or Cg aryl; heteroaryl; , benzyl; -(CH 2 ) s -heteroaryl; C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl; C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkenyl; -(CH 2 ) u -heterocycle, -(CH 2 ) t -NH 2 , or methyl, each of which may be substituted, s is 1, 2, or 3. t is 1, 2, or 3. u is O, 1, 2, or 3.
  • R n is C 5 , C 6 , C 7 , or C 8 aryl; heteroaryl; C 2 , C 3 , C 4 , C 5 , or C 6 alkyl; -(CH 2 ) g -heterocycle; - (CH 2 )i-C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl; C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl; -(CH 2 ) h - NH 2 ; -(CH 2 ) j -heteroaryl; or methyl, each of which may be substituted.
  • g is O, I, 2, or 3.
  • h is 1, 2, or 3.
  • j is O, 1, 2, or 3.
  • i is 0, 1, 2, or 3.
  • R 18 is hydroxyl, halogen, or taken together any one of Rn or Ri 7a and R 18 are connected to form a 3, 4, 5, or 6-membered ring containing at least one oxygen atom.
  • Ri 9 is hydroxyl, halogen, or -C(O)R 11 , or taken together
  • Rj 8 and R 19 are connected to form a 3, 4, 5, or 6-membered ring containing at least one oxygen atom or taken together Ri 8 and Ri 9 form a double bond.
  • R 11 is methyl, aryloxy, -NH 2 , Ci-C 6 alkoxy, Ci-C 6 alkylamino, Ci-C 6 dialkylamino, or heterocycle, each of which may be substituted.
  • R 2 i and R 2 u are the same or different from each other and each represents: hydrogen, hydroxy, C 1 -C O alkyl, Ci-C 6 alkoxy, or -OC(O)R V , or taken together R 2] and R 2 i a form a carbonyl.
  • R v is methyl, aryloxy, -NH 2 , Ci-C 6 alkoxy, CrC 6 alkylamino, Ci-C 6 dialkylamino, or heterocycle, each which may be substituted.
  • R 22 is hydrogen or Ci-C 6 alkyl.
  • R 7 is -COR t , wherein R t is -NH 2 , CpC 6 alkylamino, or Ci-C 6 dialkylamino, then any one of R] 7 or Ri 7a is not hydroxyl when the other is hydrogen.
  • R t is -NH 2 , CpC 6 alkylamino, or Ci-C 6 dialkylamino
  • R 4 and any one of R 5 or R 5a form a double bond and any one of R 2I or R 2 ia is hydroxyl, then the other R 2 i or R 2 i a is not hydrogen.
  • R 4 , R5, and Rs 3 are each independently hydrogen and any one of R 2 i or R 2 i a is methoxy or hydroxyl, then the other R 2 I or R 2 i a is not hydrogen.
  • the present invention includes a method of treating an immune-related disorder comprising administering to a patient in need of such treatment a composition comprising a earlier and a non-toxic therapeutically effective amount of a macrolide compound of the present invention.
  • One aspect of the invention includes a method of treating an immune-related disorder which is an autoimmune disease selected from a connective tissue disease, a neuromuscular disease, an endocrine disease, a gastrointestinal disease, an autoimmune skin disease, a vasculitis syndrome, a hematologic autoimmune disease, and uveitis.
  • an immune-related disorder which is an autoimmune disease selected from a connective tissue disease, a neuromuscular disease, an endocrine disease, a gastrointestinal disease, an autoimmune skin disease, a vasculitis syndrome, a hematologic autoimmune disease, and uveitis.
  • the autoimmune disease is selected from systemic lupus erythematosus (SLE), systemic sclerosis (scleroderma), Sjogren's syndrome, multiple sclerosis (MS), myasthenis gravis, Guillain-Barre syndrome, Hashimoto's thyroiditis, Graves' disease, insulin-dependent (Type 1) diabetes, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and psoriatic arthritis.
  • SLE systemic lupus erythematosus
  • scleroderma systemic sclerosis
  • MS multiple sclerosis
  • myasthenis gravis Guillain-Barre syndrome
  • Hashimoto's thyroiditis Hashimoto's thyroiditis
  • Graves' disease insulin-dependent (Type 1) diabetes, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and psoriatic arthritis.
  • Another aspect of the invention includes a method of treating an immune-related disorder which is an inflammatory disorder selected from Alzheimer's disease, asthma, atopic allergy, allergy, bronchial asthma, diabetic retinopathy, atopic dermatitis (also called eczema), glomerulonephritis, graft vs. host disease, hemolytic anemias, sepsis, stroke, vasculitis, and ventilator induced lung injury.
  • an immune-related disorder which is an inflammatory disorder selected from Alzheimer's disease, asthma, atopic allergy, allergy, bronchial asthma, diabetic retinopathy, atopic dermatitis (also called eczema), glomerulonephritis, graft vs. host disease, hemolytic anemias, sepsis, stroke, vasculitis, and ventilator induced lung injury.
  • Another embodiment of the invention includes a method of alleviating a symptom associated with an immune-related disorder comprising administering to a patient in need of such treatment a composition comprising a carrier and a non-toxic, therapeutically effective amount of a macrolide compound of the present invention.
  • One embodiment includes a method of alleviating a symptom associated with an immune-related disorder which is an autoimmune disease selected from a connective tissue disease, a neuromuscular disease, an endocrine disease, a gastrointestinal disease, an autoimmune skin disease, a vasculitis syndrome, a hematologic autoimmune disease, and uveitis.
  • an autoimmune disease selected from a connective tissue disease, a neuromuscular disease, an endocrine disease, a gastrointestinal disease, an autoimmune skin disease, a vasculitis syndrome, a hematologic autoimmune disease, and uveitis.
  • Another embodiment includes a method of alleviating a symptom associated with an autoimmune disease which is selected from systemic lupus erythematosus (SLE), systemic sclerosis (scleroderma), Sjogren's syndrome, multiple sclerosis (MS), myasthenis gravis, Guillain-Barre syndrome, Hashimoto's thyroiditis, Graves' disease, insulin-dependent (Type 1) diabetes, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and psoriatic arthritis.
  • SLE systemic lupus erythematosus
  • scleroderma systemic sclerosis
  • MS multiple sclerosis
  • myasthenis gravis Guillain-Barre syndrome
  • Hashimoto's thyroiditis Graves' disease
  • Type 1 diabetes inflammatory bowel disease
  • Crohn's disease Crohn's disease
  • ulcerative colitis ulcerative colitis
  • Another embodiment includes a method of alleviating a symptom associated with an immune-related disorder which is an inflammatory disorder selected from Alzheimer's disease, asthma, atopic allergy, allergy, bronchial asthma, diabetic retinopathy, eczema, glomerulonephritis, graft vs. host disease, hemolytic anemias, sepsis, stroke, vasculitis, and ventilator induced lung injury.
  • an immune-related disorder which is an inflammatory disorder selected from Alzheimer's disease, asthma, atopic allergy, allergy, bronchial asthma, diabetic retinopathy, eczema, glomerulonephritis, graft vs. host disease, hemolytic anemias, sepsis, stroke, vasculitis, and ventilator induced lung injury.
  • the macrolide used to treat an immune-related disorder is a racemic mixture of a macrolide compound of the present invention.
  • the macrolide used to treat an immune-related disorder is an enantiomerically pure form of a macrolide compound of the present invention.
  • the macrolide used to treat an immune-related disorder is administered in combination with a second agent used to treat an immune-related disorder.
  • a second agent is in combination with the macrolide compound to treat an immune-related disorder.
  • the second agent is selected from methotrexate, cyclosporin A, tacrolimus, corticosteroids, statins, interferon beta, nonsteroidal antiinflammatory drugs (NSAIDs), and the disease-modifying anti-rheumatic drugs (DMARDs).
  • the second agent is cyclosporin A, further wherein the cyclosporin A is cyclosporin microemulsion.
  • Another aspect of the invention includes a method of suppressing an immune response associated with organ or tissue transplantation comprising administering to a patient in need of such treatment a composition comprising a carrier and a non-toxic, therapeutically effective amount of a macrolide compound of the present invention.
  • the macrolide is administered in combination with a second agent used to suppress an immune response associated with organ or tissue transplantation.
  • the second agent used to suppress an immune response associated with organ or tissue transplantation is selected from methotrexate, cyclosporin A, cyclosporin microemulsion, tacrolimus, corticosteroids and statins.
  • the second agent is cyclosporin A, further wherein the cyclosporin A is cyclosporin microemulsion.
  • the macrolide administered in combination with a second agent used to suppress an immune response is an enantiomerically pure form of a macrolide compound of the present invention.
  • the macrolide administered in combination with a second agent used to suppress an immune response is administered to said patient at a time selected from prior to said organ or tissue transplantation, during said organ or tissue transplantation, after said organ or tissue transplantation, and combinations thereof.
  • Another aspect of the invention includes a method of inhibiting tumor growth comprising administering to a patient in need of such treatment a composition comprising a carrier and a non-toxic therapeutically effective amount of a compound, wherein the compound is a macrolide compound of the present invention.
  • the macrolide is administered in combination with a second agent used to inhibit tumor growth.
  • the present invention provides compositions that are used in the treatment of cancer and cancer-related disorders, in the treatment of immune-related disorders, as well as in the treatment prior to, during and/or after organ or tissue transplantation.
  • compositions of the invention include a compound that modulates and/or regulates an immune response.
  • This invention includes a macrolide compound. Macrolides are a group of antibiotics, produced for example by various strains of Streptomyces, that have a complex macrocyclic structure. These macrocyclic compounds are formed by chain extension and cyclized into a large, typically 12-membered ring containing a nitrogen, oxygen, or sulfur atom. Often, macrolides are glycosylated. This invention also includes ring-opened macrolide compounds as represented by the structure below:
  • the present invention includes compounds of Formula I:
  • Z is O, NH, S, or absent, such that when Z is absent the compound is represented by formula (F)
  • R d is -NH 2 or azide.
  • R 3 is hydrogen, silyl, Ci-C 6 alkyl or substituted Ci-C 6 alkyl, or - C(O)R 8 .
  • Silyl is R a R b R°Si- and R a , R b , and R c are the same as or different from each other and each represents methyl, ethyl, i-propyl, t-butyl, or phenyl.
  • R 3 is methyl, -NH 2 , Ci-C 6 alkylamino, CpC 6 dialkylamino, or heterocycle, each of which may be substituted.
  • R 4 is hydrogen.
  • R 5 and R 5a are each, independently, hydrogen or hydroxyl, or taken together R 5 and R 5a form a carbonyl. In another aspect, taken together, R 4 and any one of R5 or Rs a form a double bond.
  • R 6 is hydrogen, hydroxyl, Ci-C 6 alkyl or substituted Cj-C 6 alkyl.
  • R 7 is hydrogen or -C(O)R t .
  • R t is methyl, -NH 2 , Ci-C 6 alkylamino, Ci-C 6 dialkylamino, or heterocycle, each of which may be substituted.
  • R] 6 and Ri 6a are the same or different from each other and each represents: methyl, hydrogen, or hydroxyl.
  • Rn is -OC(O)Ri 7 b, sulfonate or substituted sulfonate, hydroxyl, or silyloxy.
  • R] 7a is hydrogen or taken together Ri 7 and Ri 7a form a carbonyl.
  • R 17b is -NRjR k , -OR m , or -R n .
  • R j and R ⁇ are the same as or different from each other and each represents: hydrogen; C 2 , C 3 , C 4 , C 5 , or C 6 alkyl; C 3 , C 4 , C 5 , or C 6 alkenyl; C 2 , C 3 , C 4 , C 5 , or Cc acyl; unsaturated C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 acyl; C 5 , C 6 , C 7 , or C 8 aryl; heteroaryl; benzyl; C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkylsulfonyl; benzenesulfonyl; -(CH 2 ) x -heteroaryl; C 3 , C 4 , C 5 , Ce, C 7 , or C 8 cycloalkyl; C 3 , C 4 , C 5 , C 6 , C 7 ,
  • -NR j R k is bound together to represent a ring, wherein the ring is a non-aromatic heterocyclic ring containing at least one nitrogen atom. Any of the atoms in the ring may be substituted.
  • R 111 is C 2 , C 3 , C 4 , C 5 , or C 6 alkyl; C 3 , C 4 , C 5 , or C 6 alkenyl; C 5 , C 6 , C 7 , or C 8 aryl; heteroaryl; benzyl; -(CH 2 ) s -heteroaryl; C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl; C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkenyl; -(CH 2 ) u ⁇ heterocycle, -(CH 2 ) t -NH 2 , or methyl, each of which may be substituted.
  • s is 1, 2, or 3.
  • t is 1, 2, or 3.
  • u is 0, 1, 2, or 3.
  • R n is C 5 , C 6 , C 7 , or C 8 aryl; heteroaryl; C 2 , C 3 , C 4 , C 5 , or C 6 alkyl; -(CH 2 ) g - heterocycle; -(CHa) 1 -C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl; C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl; -(CH 2 ) h -NH 2 ; -(CH 2 ) j -heteroaryl; or methyl, each of which may be substituted.
  • g is 0, 1, 2, or 3.
  • h is 1, 2, or 3.
  • j is O, 1, 2, or 3.
  • i is 0, 1, 2, or 3.
  • Ri 8 is hydroxyl, halogen, or taken together any one of Ri 7 or Ri 7a and Ri 8 are connected to form a 3, 4, 5, or 6-membered ring containing at least one oxygen atom.
  • R 19 is hydroxyl, halogen, or -C(O)R 11 , or taken together Ri 8 and R19 are connected to form a 3, 4, 5, or 6-membered ring containing at least one oxygen atom.
  • R u is methyl, aryloxy, -NH 2 , Ci- C 6 alkoxy, Ci-Cg alkylamino, Ci-C 6 dialkylamino, or heterocycle, each of which may be substituted, or taken together Rig and R 19 form a double bond.
  • R 2I and R 2 la are the same or different from each other and each represents: hydrogen, hydroxy, C 1 -C 6 alkyl, Ci-C 6 alkoxy, or -OC(O)R V , or taken together R 2 i and R 2 i a form a carbonyl.
  • R v is methyl, aryloxy, -NH 2 , Ci-C 6 alkoxy, Ci-C 6 alkylamino, Ci-C 6 dialkylamino, or heterocycle, each which may be substituted.
  • R 22 is hydrogen or Ci-C 6 alkyl.
  • R 7 is -COR t , wherein R t is -NH 2 , Ci-C 6 alkylamino, or Ci-C 6 dialkylamino, then any one of Rn or Ri 7a is not hydroxyl when the other is hydrogen.
  • R t is -NH 2 , Ci-C 6 alkylamino, or Ci-C 6 dialkylamino
  • R 4 and any one of R 5 or R 5a form a double bond and any one of R 21 or R 2 i a is hydroxyl, then the other R 21 or R 2 j a is not hydrogen.
  • R 4 , R5, and R 5a are each independently hydrogen and any one of R 21 or R 2 i a is methoxy or hydroxyl, then the other R 2 i or R 2 i a is not hydrogen.
  • R 3 is hydrogen, silyl, Ci-C 6 alkyl or substituted Ci-C 6 alkyl, or -C(O)R 8 .
  • Silyl is R a R b R c Si-, and R a , R b , and R c are the same as or different from each other and each represents methyl, ethyl, i-propyl, t-butyl, or phenyl.
  • R s is methyl, -NH 2 , C 1 -C 6 alkylamino, Ci-C 6 dialkylamino, or heterocycle, each of which may be substituted.
  • R 6 is hydrogen, hydroxyl, Ci-C 6 alkyl or substituted Ci-C 6 alkyl.
  • R 7 is hydrogen or - C(O)R t .
  • Ri is methyl, -NH 2 , Ci-C 6 alkylamino, Ci-C 6 dialkylamino, or heterocycle, each of which may be substituted.
  • Ri 7b is -NR j R k , -OR m , or -R n .
  • R j and R k are the same as or different from each other and each represents: hydrogen; C 2 , C 3 , C 4 , C 5 , or C 6 alkyl; C 3 , C 4 , C 5 , or C 6 alkenyl; C 2 , C 3 , C 4 , C 5 , or C 6 acyl; unsaturated C 3 , C 4 , C 5 , C 6 , C 7 , or Cs acyl; C 5 , C 6 , C 7 , or C 8 aryl; heteroaryl; benzyl; Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkylsulfonyl; benzenesulfonyl; -(CH 2 ) x -heteroaryl; C 3 , C 4 , C 5 , C 6 , C 7 , or Cg cycloalkyl; C 3 , C 4 , C 5 , C 6 , C 7
  • -NR j R k is bound together to represent a ring, wherein the ring is a non-aromatic heterocyclic ring containing at least one nitrogen atom. Any of the atoms in the ring may be substituted.
  • R ra is C 2 , C 3 , C 4 , C 5 , or C 6 alkyl; C 3 , C 4 , C 5 , or C 6 alkenyl; C 5 , C 6 , C 7 , or C 8 aryl; heteroaryl; benzyl; ⁇ (CH 2 ) s -heteroaryl; C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl; C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkenyl; -(CH 2 ) u -heterocycle, -(CH 2 ) t -NH 2 , or methyl, each of which may be substituted.
  • s is 1, 2, or 3.
  • t is 1, 2, or 3.
  • u is 0, 1, 2, or 3.
  • R 11 is C 5 , C 6 , C 7 , or C 8 aryl; heteroaryl; C 2 , C 3 , C 4 , C 5 , or C 6 alkyl; -(CH 2 ) g - heterocycle; -(CH 2 VC 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl; C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl; -(CH 2 ) h -NH 2 ; -(CH 2 ) j -heteroaryl; or methyl, each of which may be substituted.
  • g is 0, 1, 2, or 3.
  • h is 1, 2, or 3.
  • j is 0, 1, 2, or 3.
  • i O, 1, 2, or 3.
  • Z is O.
  • Z is NH.
  • Z is S.
  • R 6 is hydrogen.
  • R 7 is -C(O)R t .
  • R t is methyl.
  • R t is -NH 2 , Ci-C 6 alkylamino, Ci-C 6 dialkylamino, or heterocycle.
  • R 3 is hydrogen.
  • R 6 is hydrogen, R 7 is -C(O)CH 3 , and R 3 is hydrogen.
  • R 3 is -C(O)R S and R s is Ci-C 6 alkyl. In one embodiment, R s is methyl. In another embodiment, R 7 is hydrogen.
  • R 17b is -NRjR k .
  • Rj and Rk are the same as or different from each other and each represents: hydrogen; C 2 -C 6 alkyl; C 3 -C 6 alkenyl; C 2- C 6 acyl; unsaturated C 3- Cs acyl; Cs-Cs aryl; heteroaryl; benzyl; Ci-C 6 alkylsulfonyl; benzenesulfonyl; or methyl, each of which may be substituted.
  • R 17 b is -NRjR k
  • Rj and R k are the same as or different from each other and each represents: -(CH 2 ) x heteroaryl; C 3 -C 8 cycloalkyl; C 3 -C 8 cycloalkenyl; heterocycle; -(CH 2 ) y -heterocycle; -(CH 2 ) T1 -NH 2 ; or hydrogen.
  • Ri 7b is -NR j R k
  • -NR j R k is bound together to represent a 3, 4, 5, 6, 7, or 8-membered ring
  • the ring is a non-aromatic heterocyclic ring containing at least one nitrogen atom, wherein any of the atoms in the ring may be substituted.
  • the ring is a 3-membered ring.
  • the ring is a 4- membered ring.
  • the ring is a 5-membered ring.
  • the ring is a 6-membered ring.
  • the ring is a 7- membered ring.
  • the ring is an 8-membered ring.
  • R 17b when R 17b is -NR j R k bound together to represent a 3, 4, 5, 6, 7, or 8-membered ring, the ring contains at least two nitrogen atoms.
  • R 17b when R 17b is bound together to represent a 3, 4, 5, 6, 7, or 8- membered ring, the ring is pyrrolidine, piperidine, azepane, tetrahydropyridine, tetrahydropyrimidine, morpholine, piperazine, homopiperazine, or azocane, each of which may be substituted.
  • the ring when R 1 ⁇ is -NRjR k bound together to represent a ring, the ring is pyrrolidine. In a further embodiment, pyrrolidine is substituted with hydroxyl or Ci-C 6 alkyl. In another embodiment, pyrrolidine is substituted with methylhydroxyl. In another embodiment, when Ri 7b is -NRjR k bound together to represent a ring, the ring is piperidine. In a further embodiment, the piperidine ring is substituted with hydroxyl or pyridine.
  • the ring is 1,2,3,6-tetrahydropyridine or 1,2,5,6-tetrahydropyi ⁇ dine.
  • the 1,2,3,6-tetrahydropyridine or 1,2,5,6-tetrahydropyridine ring is substituted with pyridine.
  • Ri 7b is -NR j R k bound together to represent a ring
  • the ring is 2,4,5,6-tetrahydropyrimidine.
  • the ring is morpholine.
  • the ring is piperazine.
  • the piperazine ring is not substituted.
  • the piperazine ring is substituted with one Of C 3 -C 8 cycloalkyl, Ci-C 6 alkyl, heteroaryl, -C(O)R 0 , Cs-C 8 aryl, or hydroxyl.
  • piperazine is substituted with pyridine, phenol, pyrimidine, phenyl, or cyclohexyl.
  • piperazine is substituted with -C(O)R C , wherein R c is Ci-C ⁇ alkyl.
  • R 0 is ethyl.
  • piperazine is substituted with Ci-Ce alkyl.
  • piperazine is substituted with methyl.
  • piperazine is substituted with ethyl.
  • ethyl is substituted with hydroxyl, -NH 2 , Ci-C ⁇ alkylamino, or Ci-C 6 dialkylamino.
  • R ⁇ b is -NR j R k bound together to represent a ring
  • the ring is azepane.
  • Ri 7 b is -NRjR k bound together to represent a ring
  • the ring is homopiperazine.
  • any one of R,- or R k is selected from - (CH 2 ) x -heteroaryl; C 3 -C 8 cycloalkyl; -(CH 2 ) y -heterocycle, or -(CH 2 ) n -NH 2 and the other R j or R k is selected from hydrogen or methyl.
  • the other of Rj or R k is hydrogen.
  • the other of Rj or R k is methyl.
  • any one of R j or R k is selected from - (CH 2 ) x -heteroaryl.
  • x is 1.
  • x is 2.
  • x is 3.
  • heteroaryl is pyridine.
  • any one of R j or R k is C 3 -C 8 cycloalkyl. In another embodiment, C 3 -C 8 cycloalkyl is cyclohexyl. In one embodiment, when R ⁇ b is -NRjR k , any one of Rj or Rk is -(CH 2 ) y -heterocycle and the other of R j or R k is hydrogen. In another embodiment, heterocycle is a 6-membered ring. In one embodiment, y is 0. In another embodiment, y is 1. In another embodiment, y is 2. In another embodiment, y is 3.
  • heterocycle is selected from pyrrolidine, piperidine, morpholine, pyridine, or piperazine, each of which may be substituted.
  • heterocycle is pyrrolidine.
  • heterocycle is pyridine.
  • heterocycle is piperidine.
  • heterocycle is morpholine.
  • heterocycle is piperazine.
  • piperazine is substituted with methyl.
  • any one of Rj or R k is -(CH 2 ) n -NH 2 .
  • the other of R j or R k is hydrogen.
  • the other of R j or R k is methyl.
  • n is 1.
  • n is 2.
  • n is 3.
  • -NH 2 is substituted to form a Ci-C 6 alkylamino.
  • -NH 2 is substituted to form a Ci- Cedialkylamino.
  • -NH 2 is substituted with methyl to form
  • R ⁇ b when R ⁇ b is -NR j R k , R j and Rk are both Ci-C 6 alkyl. In another embodiment, R j and R k are both methyl. In another embodiment, any one of R j or R k is methyl and the other is ethyl. In a further embodiment, ethyl is substituted with hydroxyl. In one embodiment, when R ⁇ b is -NR j R k, R j and R k are both hydrogen.
  • R ⁇ b is -NR j R k and R 7 is -O(C)R t .
  • R t is methyl, -NH 2 , C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, or heterocycle, each of which may be substituted.
  • R ⁇ b is -NR j R k and R 7 is -0(C)Rt and Rt is -NH 2 , Ci-C 6 alkylamino, Ci-C 6 dialkylamino, each of which may be substituted.
  • R j and R k are the same as or different from each other and each represents: hydrogen; C 2 , C 3 , C 4 , C 5 , or C 6 alkyl; C 3 , C 4 , C 5 , or C 6 alkenyl; C 2 , C 3 , C 4 , C 5 , or C 6 acyl; unsaturated C 3 , C 4 , C 5 , C 6 , C 7 , or Cs acyl; C 5 , C 6 , C 7 , or C 8 aryl; heterparyl; benzyl; C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkylsulfonyl; benzenesulfonyl; -(CH 2 ) x -heteroaryl; C 3 , C 4 , C 5 , C 6 ,
  • -NR j R k is bound together to represent a ring, wherein the ring is a non-aromatic heterocyclic ring containing at least one nitrogen atom. Any of the atoms in the heterocycle ring may be substituted.
  • Rj 7 b is -NRjRk and R 7 is -0(C)R t
  • any one of R j or R k is -(CH 2 ) y -heterocycle and the other is hydrogen.
  • y is 2 and heterocycle is morpholine.
  • Ri 7b is - NRjR k and R 7 is -0(C)Rt
  • R t is Ci-C 6 alkylamino.
  • Ci-C 6 alkylamino is ethylamine substituted with morpholine.
  • R ⁇ b is -OR m .
  • R n is C 2 -C 6 alkyl; C 3 -C 6 alkenyl; Cs-C 8 aryl; heteroaryl; benzyl; -(CH 2 ) s -heteroaryl; C 3 -C 8 cycloalkyl; C 3 -C 8 cycloalkenyl; -(CEbXrheterocycle, -(CH 2 X-NH 2 , or methyl, each of which may be substituted.
  • s is 1, 2, or 3.
  • t is 1, 2, or 3.
  • u is 0, 1, 2, or 3.
  • R m is C 2 -C 6 alkyl; C 3 -C 6 alkenyl; Cs-C 8 aryl; heteroaryl; or methyl, each of which may be substituted.
  • R m is -(CH 2 ) s -aryl; -(CH 2 ) s -heteroaryl; C 3 -C 8 cycloalkyl; C 3 -C 8 cycloalkenyl; - (CH 2 ) u -heterocycle; or -(CH ⁇ -ammo, each of which may be substituted.
  • R m is C 5 -C 8 aryl.
  • C 5 -C 8 aryl is phenyl.
  • phenyl is substituted with -NO 2 .
  • R ⁇ b is R n .
  • R n is C 5 -C 8 aryl; heteroaryl; C 2 -C 6 alkyl; -(CH 2 ) g -heterocycle; -(CH 2 )I-C 3 -C 8 cycloalkyl; C 3 -C 8 cycloalkyl; -(CH 2 ) h - NH 2 ; -(CH 2 ) j -heteroaryl; or methyl, each of which may be substituted.
  • g is 0, 1, 2, or 3.
  • h is 1, 2, or 3.
  • j is 0, 1, 2, or 3.
  • i is 0, 1, 2, or 3.
  • R n when R ⁇ b is R n , R n is C 5 -C 8 aryl or heteroaryl, each of which may be substituted. In one embodiment, R n is phenyl or pyridine.
  • R n when R ⁇ b is R n , R n is Ci-C 6 alkyl; -(CH 2 ) g -heterocycle; - (CH 2 ) J -C 3 -C 8 cycloalkyl; C 3 -C 8 cycloalkyl; -(CH 2 ) h -NH 2 ; or -(CH 2 ) j -heteroaryl, each of which may be substituted. In another embodiment, when R ⁇ b is R n , R n is selected from C 1 -C 6 alkyl, -(CH 2 ) n - NH 2 , or C 3 -C 8 cycloalkyl, each which may be substituted. In one embodiment, R n is methyl or cyclopropyl.
  • R ⁇ b is R n> R n is -(CH 2 ) n -NH 2 .
  • h is l.
  • Z is O, NH, or S.
  • R 3 is hydrogen, silyl, or -C(O)R 3 .
  • Silyl is R a R b R c Si-, and R a , R b , and R c are the same as or different from each other and each represents methyl, ethyl, i-propyl, t-butyl, or phenyl, R 3 is methyl, -NH 2 , alkylamino, dialkylamino, or heterocycle, each which may be substituted.
  • R 7 is hydrogen or -C(O)CH 3 .
  • Ri 6 and R 16a are the same or different from each other and each represents: methyl, hydrogen, or hydroxyl.
  • R 17 is hydroxyl, silyloxy; or taken together Ri 7 and Ri 7a form a carbonyl; or Ri 7a is hydrogen.
  • Ri 8 is hydroxyl or halogen, or taken together Ri 7 and R 18 are connected to form a 3, 4, 5, or 6-membered ring containing at least one oxygen atom.
  • Ri 9 is hydroxyl, halogen, or -C(O)R 11 ; or taken together Ri 8 and R 19 are connected to form a 3, 4, 5, or 6-membered ring containing at least one oxygen atom.
  • R u is methyl, aryloxy, -NH 2 , C 1 -Cn alkylamino, Ci-C 6 dialkylamino, or heterocycle, each of which may be substituted.
  • R 2I and R 2 i a are the same or different from each other and each represents: hydrogen, hydroxyl, Ci-C 6 alkyl, Ci-C 6 alkoxy, or -OC(O)R V , or taken together R 2 i and R 2 i a form a carbonyl.
  • R v is methyl, aryloxy, -NH 2 , Ci-C 6 alkylamino, Ci-C 6 dialkylamino, or heterocycle, each of which may be substituted.
  • R 22 is hydrogen or Ci-C 6 alkyl.
  • Z is O. In another embodiment, Z is NH. In another embodiment, Z is S.
  • R 3 is -C(O)CH 3 . In another embodiment, R 3 is hydrogen. In another embodiment R 3 is -C(O)R S . In one embodiment, R s is methyl, -NH 2 , alkylamino, dialkylamino, or heterocycle, each which may be substituted. In another embodiment, R s is dialkylamino. In another embodiment, R s is dimethylamine.
  • R 7 is -C(O)CH 3 .
  • R 7 is hydrogen.
  • Ri 8 is a halogen.
  • Rig is bromide, chloride, or iodide.
  • R 19 is halogen.
  • R 1 9 is bromide, chloride, or iodide.
  • Rig and R 19 are connected to form an epoxide ring.
  • R 19 is -C(O)R U .
  • R 11 is aryloxy, -NH 2 , Ci-C 6 alkylamino, Ci-C 6 dialkylamino, or heterocycle.
  • R 2 i is C 1 -
  • R 2 i is methoxy.
  • any one of R 2 i or R 2Ia is -OC(O)Rv and the other is hydrogen.
  • any one of R 2 i or R 2]a is -OC(O)Ry and the other is hydrogen, and R v is -NH 2 , Ci-C 6 alkylamino, Ci-C 6 dialkylamino, or heterocycle, each of which may be substituted.
  • R v is Ci-C 6 alkylamino.
  • R v is ethylamine.
  • ethylamine is substituted with pyrrolidine.
  • any one of Rj 7 or Ri 7a is hydroxyl and the other is hydrogen.
  • Ri 7 and Ri 8 are connected to form a 3, 4, 5, or 6-membered ring containing at least one oxygen atom.
  • R 17 and Ri 8 are connected to form a cyclic carbonate ring.
  • Rn and R] 8 are connected to form an epoxide ring.
  • R 19 is -C(O)R 11 .
  • R 14 is aryloxy, -NH 2 , alkylamino, dialkylamino, or heterocycle.
  • R 19 is hydroxyl.
  • Ri 7 and R] 8 are each hydroxyl. In another embodiment, Ri 7 and R] 9 are each hydroxyl. In another embodiment, taken together, Rj 7 and Ri 7a form a carbonyl. In another embodiment, taken together, R 2 i and R 2 i a form a carbonyl. In another embodiment, any one of R 2 i or R ⁇ a is methyl and the other is hydroxyl. In one embodiment, R 7 is -C(O)CH 3 , R 3 is hydrogen, and R 2 1 is methoxy.
  • R 22 is Ci-C 6 alkyl or hydrogen. In one embodiment, R 22 is hydrogen. In another embodiment, R 22 is Ci-C 6 alkyl. In a further embodiment, R 22 is methyl.
  • Ri 6 and Ri 6a are different. In one embodiment, Ri 6 and Ri 6a are Ci-C 6 alkyl and hydroxyl. In another embodiment, Ri 6 and Ri 6a are methyl and hydroxyl.
  • R 3 is hydrogen, Ci-C 6 alkyl or substituted Ci-C 6 allcyl.
  • R 4 is hydrogen.
  • R5 and R 5a are each independently hydrogen or hydroxyl, or taken together form a carbonyl, or taken together, R 4 and any one of R 5 or R 53 form a double bond.
  • R 6 is hydrogen, hydroxyl, Ci-C 6 alkyl or substituted Ci-C 6 alkyl. Taken together Ri 8 and Ri 9 form a double bond or are connected to form a 3, 4, 5, or 6-membered ring containing at least one oxygen atom.
  • R 2 i and R 2 i a are the same or different from each other and each represents: hydrogen, hydroxyl, or Ci-C 6 alkoxy, or taken together R 21 and R 2 u form a carbonyl.
  • Z is O. In another embodiment, Z is NH. In another embodiment, Z is S.
  • R 3 is hydrogen. In another embodiment, R 6 is hydroxyl. In another embodiment, R 6 is hydrogen. In another embodiment, R 3 is hydrogen and R 6 is hydroxyl.
  • Ris and R 19 are connected to form an epoxide ring.
  • any one of R 21 or R 2 i a is hydroxyl. In a further embodiment, the other of R 2 i or R 2 i a is hydrogen.
  • any one of R 5 or Rs a taken together with R 4 forms a double bond.
  • R 5 and R 5a form a carbonyl.
  • R] 8 and R 19 form a double bond.
  • any one of R 5 or Rs a and R 4 are each hydroxyl.
  • R5 and Rs a form a double bond and taken together R 2 ] and R 2 ] a form a carbonyl.
  • Alkyl includes saturated aliphatic groups, including straight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl), branched-chain alkyl groups (e.g., isopropyl, tert-butyl, isobutyl).
  • Alkyl further includes alkyl groups that have oxygen, nitrogen, or sulfur atoms replacing one or more hydrocarbon backbone carbon atoms.
  • Alkyl further includes alkyl groups that have unsaturation e.g.,
  • a straight chain or branched alkyl has six or fewer carbon atoms in its backbone ⁇ e.g., methyl, Ci-C 6 for straight chain, C 3 -C 6 for branched chain). In another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms in its backbone.
  • alkyl also includes both "un substituted” and “substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbon of the hydrocarbon backbone.
  • Such substitutents can include, for example, alkyl, alkenyl, alkynyl, hydroxyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, ester alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, cyano, -NH 2 , alkylamino, dialkylamino, arylamino, diarlylamino, alkylarylamino, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, tliiocarbox
  • C 2 -C O alkyl includes alkyl groups with 2, 3, 4, 5, or 6 carbon atoms.
  • Aryl includes groups with aromaticity, including 5, 6, 7, or 8-membered "unconjugated", or single-ring aromatic groups that may include from one to four heteroatoms, as well as “conjugated”, or multicyclic systems with at least one aromatic ring.
  • aryl groups include phenyl, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • aryl includes multi-cyclic groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothizole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, benzofuran, deazapureine, or indolizine.
  • multi-cyclic groups e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothizole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, benzofuran, deazapureine, or indolizine.
  • aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles", “heterocycles”, “heterocyclyls”, “heteroaryls” or “heteroaromatics” e.g., pyridine, pyrazole, pyrimidine, furan, isoxazole, imidazole[2,l,b]thiazole, triazole, pyrazine, benzothiophene, imidazole, or thiophene.
  • aryl heterocycles e.g., pyridine, pyrazole, pyrimidine, furan, isoxazole, imidazole[2,l,b]thiazole, triazole, pyrazine, benzothiophene, imidazole, or thiophene.
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, allcylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cyano, -NH 2 , alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl
  • alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
  • alkenyl includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), branched-chain alkenyl groups, cycloalkenyl (e.g., alicyclic) groups (e.g., cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenyl groups.
  • alkenyl further includes alkenyl groups, which include oxygen, nitrogen, or sulfur replacing one or more hydrocarbon backbone carbons.
  • a straight chain or branched chain alkenyl group has six or fewer carbon atoms in its backbone (e.g., C 2 -C 6 for straight chain, C 3 -C 6 for branched chain).
  • cycloalkenyl groups may have from three to eight carbon atoms in their ring structure, and more preferably have five or six carbons in the ring structure.
  • C 2 -C 6 includes alkenyl groups containing 2, 3, 4, 5, or 6 carbon atoms.
  • C 3 -C 6 includes alkenyl groups containing 3, 4, 5, or 6 carbon atoms.
  • alkenyl also includes both “unsubstituted alkenyls” and “substituted alkenyls”, the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more hydrocarbon backbone carbon atoms.
  • substituents can include, for example, alkyl groups, alkenyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,
  • Alkynyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
  • alkynyl includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), branched chain alkynyl groups, and cycloalkyl or cycloallcenyl substituted alkynyl groups.
  • alkynyl further includes alkynyl groups having oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more hydrocarbon backbone carbons.
  • a straight chain or branched chain alkynyl group has six or fewer carbon atoms in its backbone (e.g., C 2 -C 6 for straight chain, C 3 -C 6 for branched chain).
  • C 2 -C 6 alkynyl includes alkynyl groups containing 2, 3, 4, 5, or 6 carbon atoms.
  • alkynyl also includes both “unsubstituted alkynyls” and “substituted alkynyls”, the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more hydrocarbon backbone carbon atoms.
  • substituents can include, for example, alkyl groups, alkenyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylamiiiocarbonyl, dialkylaminocarbonyl, allcylthiocarbonyl, alkoxyl, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sul
  • Acyl includes compounds and moieties that contain the acyl radical (CH 3 CO-) or a carbonyl group.
  • Substituted acyl includes acyl groups where one or more of the hydrogen atoms are replaced by for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, cyano, -NH 2 , alkylamino, dialkylamino, arylamino, diarylamino, and allcylarylamino, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbam
  • alkoxycarbonyl or "ester” includes compounds and moieties that contain an oxygen atom covalently linked to a carbonyl group (-OC(O)-).
  • ester groups include -OC(O)CH 3 , -OC(O)CH 2 NH 2 .
  • alkoxy or "alkoxyl” includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom.
  • alkoxy groups or alkoxyl radicals
  • alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups.
  • substituted alkoxy groups include halogenated alkoxy groups.
  • the alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, ester, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, cyano, -NH 2 , alkylamino, dialkylamino, aiylamino, diarylamino, and alkylarylamino, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, siilfhydryl, alkylthio, arylthio, thiocarboxylate, sul
  • halogen substituted allcoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.
  • C 1 -C 6 alkoxy includes alkoxy groups which include 1, 2, 3, 4, 5, or 6 carbon atoms.
  • cycloalkyl includes saturated acyclic groups (e.g., cyclopropyl, cyclopentyl, cyclohexyl, cyclohexyl, cycloheptyl, cyclooctyl). Cycloalkyls have from three to eight carbon atoms in their ring structure. In certain embodiments, cycloalkyls have five or six carbon atoms in the ring structure. Cycloalkyls includes both "unsubstituted cycloalkyls" and “substituted cycloalkyls", the latter of which refers to replacing a hydrogen on one or more of the carbons in the ring structure.
  • substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, ester, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, cyano, -NH 2 , alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulf
  • heterocycle include closed ring structures, e.g., 3, 4, 5, 6, 7, 8, 9, or 10-, or 4, 5, 6, or 7-membered rings, which include one or more heteroatoms.
  • Heteroatom includes atoms of any element other than carbon or hydrogen. Examples of heteroatoms include nitrogen, oxygen, or sulfur.
  • Heterocycle groups can be saturated or unsaturated and include pyrrolidine, pyrazine, pyrimidine, oxolane, 1,3-dioxolane, thiolane, tetrahydrofuran, tetrahydropyran, tetrahydropyridine, tetrahydropyrimidine, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, and sultones.
  • Heterocyclic groups such as pyrrole and furan can have aromatic character. They include fused ring structures such as quinoline and isoquinoline. Other examples of heterocyclic groups include pyridine and purine.
  • the heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl, alkoxycarbonyl, ester, aminocarbonyl, allcylthiocarbonyl, alkoxyl, cyano, -NH 2 , alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, im
  • Heterocyclic groups can also be substituted at one or more constituent atoms with, for example, a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkylthio, a lower alkylamino, a lower alkylcarboxyl, a nitro, a hydroxyl, -CF 3 , or - CN, or the like.
  • thioalkyl includes compounds or moieties which contain an alkyl group connected with a sulfur atom.
  • the thioalkyl groups can be substituted with groups such as alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, ester, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, cyano, -NH 2 , alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,
  • thiocarbonyl or "thiocarboxy” includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.
  • hydroxy or "hydroxyl” includes groups with an -OH or -O " .
  • halogen includes fluorine, bromine, chlorine, iodine, etc.
  • perhalogenated generally refers to a moiety wherein all hydrogen atoms are replaced by halogen atoms.
  • carbamoyl includes compounds and moieties which include the following arrangement of atoms -NHC(O)O- or -OC(O)NH-.
  • carbonate includes compounds and moieties which include the following arrangement of atoms -OC(O)O-.
  • sulfonate includes compounds and moieties which contain the sulfate ion
  • substituted sulfonate includes sulfonate groups where the hydrogen atom is replaced by for example, alkyl groups or aryl aryl groups. Examples of substituted sulfonate groups are methanesulfonate, trifluormethanesulfonate or p- toluenesulfonate .
  • a "pharmaceutically acceptable salt” or “salt” of one or more of the disclosed compounds is a product of the disclosed compound that contains an ionic bond, and is typically produced by reacting the disclosed compound with either an acid or a base, suitable for administering to a subject.
  • a "pharmaceutical composition” is a formulation containing one or more of the disclosed compounds in a form suitable for administration to a subject.
  • the pharmaceutical composition is in bulk or in unit dosage form.
  • the unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial.
  • the quantity of active ingredient (e.g., a formulation of the disclosed compound or salts thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved.
  • active ingredient e.g., a formulation of the disclosed compound or salts thereof
  • the dosage will also depend on the route of administration.
  • routes including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, and the like.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.
  • anionic group refers to a group that is negatively charged at physiological pH.
  • Anionic groups include carboxylate, sulfate, sulfonate, sulfmate, sulfamate, tetrazolyl, phosphate, phosphonate, phosphinate, or phosphorothioate or functional equivalents thereof.
  • "Functional equivalents" of anionic groups are intended to include bioisosteres, e.g., bioisosteres of a carboxylate group. Bioisosteres encompass both classical bioisosteric equivalents and non-classical bioisosteric equivalents.
  • stable functionality refers to a substitution pattern that contains a labile linkage, e.g., a functionality or bond that is susceptible to hydrolysis or cleavage under physiological conditions (e.g., aqueous solutions in the neutral pH range).
  • a labile linkage e.g., a functionality or bond that is susceptible to hydrolysis or cleavage under physiological conditions (e.g., aqueous solutions in the neutral pH range).
  • unstable functionalities include acetals and ketals.
  • crystal polymorphs or “polymorphs” refer to the existence of more than one crystal form for a compound, salt or solvate thereof. Crystal polymorphs of the doxepin-analog compounds are prepared by crystallization under different conditions.
  • the structure of some of the macrolide compounds of the invention includes asymmetric carbon atoms and thus are capable of existing as an enantiomer. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomeric and diastereomeric forms of a compound, including racemates or racemic mixtures) are included within the scope of the invention, unless indicated otherwise. In some cases, there may be advantages (i.e., the compound may have greater efficacy), to using a particular enantiomer when compared to the other enantiomer or the racemate or racemic mixture in the methods of the instant invention and such advantages can be readily determined by those skilled in the art.
  • Alkenes can include either the E- or Z-geometry, where appropriate.
  • Atropic isomers are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.
  • analog refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group).
  • an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.
  • the term “derivative”, e.g., in the term “macrolide derivatives”, refers to compounds that have a common core structure, and are substituted with various groups as described herein.
  • all of the compounds represented by formula are macrolide derivatives, and have one of formula 1, 1', II, III, or IV as a common core.
  • the macrolide compositions of the invention are used as immunosuppression agents in organ or tissue transplantation.
  • immunosuppression agent refers to an agent whose action on the immune system leads to the immediate or delayed reduction of the activity of at least one pathway involved in an immune response, whether this response is naturally occurring or artificially triggered, whether this response takes place as part of the innate immune system, the adaptive immune system, or both.
  • the macrolide compositions of the invention regulate the expression of Major Histocompatibility Complex (MHC) class II genes.
  • MHC class II molecules are directly involved in the activation of T lymphocytes and in the control of the immune response. MHC class II expression occurs on the surface of antigen-presenting cells (APCs).
  • APCs antigen-presenting cells
  • MHC class II molecules are capable of presenting antigen to lymphocyte T-helpers, which control the development of an immune response.
  • a cytokine such as, for example, interferon gamma (IFN- ⁇ ).
  • immunosuppressive macrolide compositions are administered to a subject prior to, during and/or after organ or tissue transplantation.
  • the macrolide compositions of the invention are used to treat or prevent rejection after organ or tissue transplantation.
  • these immunosuppressive macrolide compositions are administered in combination with any of a variety of known anti-inflammatory and/or immunosuppressive compounds.
  • Suitable anti-inflammatory and/or immunosuppressive compounds for use with the macrolide compounds of the invention include, but are not limited to, methotrexate, cyclosporine A (including, for example, cyclosporine microemulsion), tacrolimus, corticosteroids and statins.
  • the macrolide compositions of the invention are used to treat or alleviate a symptom associated with cancer and cancer-related disorders e.g. a cell proliferative disorder.
  • a cell proliferative disorder refers to conditions in which the unregulated and/or abnormal growth of cells can lead to the development of an unwanted condition or disease, which can be cancerous or non-cancerous, for example a psoriatic condition.
  • psoriatic condition refers to disorders involving keratinocyte hyperproliferation, inflammatory cell infiltration, and cytokine alteration.
  • the cell proliferation disorder is cancer.
  • cancer includes solid tumors, such as lung, pancreas, stomach, rectum, kidney, breast, cervical/uterine, testicular, colon, ovarian, prostate, head and neck, espophageal, malignant melanoma, non-melanoma skin cancers, as well as hematologic tumors and/or malignancies, such as childhood leukemia and lymphomas, multiple myeloma, Hodgkin's disease, lymphomas of lymphocytic and cutaneous origin, acute and chronic leukemia such as acute lymphoblastic, acute myelocytic or chronic myelocytic leukemia, plasma cell neoplasm, lymphoid neoplasm, non-malignant neoplasias, and cancers associated with AIDS.
  • solid tumors such as lung, pancreas, stomach, rectum, kidney, breast, cervical/uterine, testicular, colon, ovarian, prostate, head and neck, espophageal
  • proliferative diseases which may be treated using the compositions of the present invention are epidermic and dermoid cysts, lipomas, adenomas, capillary and cutaneous hemangiomas, lymphangiomas, nevi lesions, teratomas, nephromas, myofibromatosis, osteoplastic tumors, and other dysplastic masses and the like.
  • proliferative diseases include dysplasias and disorders of the like.
  • the compositions include a pharmaceutically acceptable carrier and a compound according to formula I, I', II, III, IV, or pharmaceutically acceptable salts or hydrates thereof.
  • compositions of the invention are also used to treat or alleviate a symptom associated with an immune-related disorder, such as, for example, an autoimmune disease or an inflammatory disorder.
  • the compositions include a pharmaceutically acceptable carrier and a compound according to formula I, I', II, III, IV, or pharmaceutically acceptable salts or hydrates thereof.
  • Autoimmune diseases include, for example, Acquired Immunodeficiency Syndrome (AIDS, which is a viral disease with an autoimmune component), alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune lymphoproliferative syndrome (ALPS), autoimmune thrombocytopenic purpura (ATP), Behcet's disease, cardiomyopathy, celiac sprue- dermatitis hepetiformis; chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy (CIPD), cicatricial pemphigoid, cold agglutinin disease, crest syndrome, Crohn's disease, Degos' disease, de ⁇ natomyositis- juvenile, discoid lupus, essential mixed cryoglobulinemia, fibr ⁇ myalgia-fibromyo
  • Inflammatory disorders include, for example, chronic and acute inflammatory disorders.
  • inflammatory disorders include Alzheimer's disease, asthma, atopic allergy, allergy, atherosclerosis, bronchial asthma, atopic dermatitis (also called eczema), glomerulonephritis, graft vs. host disease, hemolytic anemias, osteoarthritis, sepsis, stroke, transplantation of tissue and organs, vasculitis, diabetic retinopathy and ventilator induced lung injury.
  • Atopic dermatitis is characterized by the distinctive phenomena of atopy and includes allergic contact dermatitis, irritant contact dermatitis, infantile seborrhoeic eczema, adult seborrhoeic eczema, varicose eczema, and discoid eczema.
  • the macrolide compositions used to treat an immune-related disorder are administered in combination with any of a variety of known anti-inflammatory and/or immunosuppressive compounds.
  • suitable known compounds include, but are not limited to methotrexate, cyclosporine A (including, for example, cyclosporine microemulsion), tacrolimus, corticosteroids, statins, interferon beta, Remicade (Infliximab), Eribrel (Etanercept) and Humira (Adalimumab).
  • the macrolide compositions of the invention are co-administered with corticosteroids, methotrexate, cyclosporine A, statins, Remicade (Infliximab), Enbrel (Etanercept) and/or Humira (Adalimumab).
  • the macrolide compositions are administered in conjunction with, e.g., corticosteroids, methotrexate, cyclosporine A, cyclophosphamide and/or statins.
  • patients afflicted with a disease such as Crohn's Disease or psoriasis are treated with a combination of a macrolide composition of the invention and Remicaid (Infliximab), and/or Humira (Adalimumab).
  • Patients with multiple sclerosis receive a combination of a macrolide composition of the invention in combination with, e.g., glatiramer acetate (Copaxone), interferon beta-la (Avonex), interferon beta-la (Rebif), interferon beta-lb (Betaseron or Betaferon), mitoxantrone (Novantrone), dexamethasone (Decadron), methylprednisolone (Depo- Medrol), prednisone (Deltasone) and/or statins.
  • glatiramer acetate Copaxone
  • interferon beta-la Avonex
  • interferon beta-la Rebif
  • interferon beta-lb Betaseron or Betaferon
  • mitoxantrone Novantrone
  • dexamethasone Decadron
  • methylprednisolone Depo- Medrol
  • prednisone Deltasone
  • the present invention also provides methods of treating or alleviating a symptom associated with an immune-related disorder or a symptom associated with rejection following organ transplantation.
  • the compositions of the invention are used to treat or alleviate a symptom of any of the autoimmune diseases and inflammatory disorders described herein.
  • Symptoms of an immune-related disorder include, for example, inflammation, fever, loss of appetite, weight loss, abdominal symptoms such as, for example, abdominal pain, diarrhea or constipation, joint pain or aches (arthralgia), fatigue, rash, anemia, extreme sensitivity to cold (Raynaud's phenomenon), muscle weakness, muscle fatigue, changes in skin or tissue tone, shortness of breath or other abnormal breathing patterns, chest pain or constriction of the chest muscles, abnormal heart rate (e.g., elevated or lowered), light sensitivity, blurry or otherwise abnormal vision, and reduced organ function.
  • the macrolide compositions of the invention are administered alone, or alternatively, in combination with another form of therapy, referred to herein as "combination therapy” (or “co-therapy”).
  • Co-therapy includes the administration of a macrolide composition of the invention and known therapy for a given immune-related disorder, or set of immune-related disorders.
  • a macrolide composition administered as an immunosuppressive agent in the treatment and/or prevention of rejection following organ transplantation is "co-administered" with one or more known immunosuppressive agents, such as, for example cyclosporine A, tacrolimus, and corticosteroids.
  • Macrolide compositions administered in the treatment of an autoimmune disease and/or inflammatory disorder is administered with any of a variety of known therapies.
  • Such therapies include, for example, known immunosuppressive agents such as COX2 inhibitors, corticosteroids, statins, cannabinoids (and derivatives thereof), interferon beta, aspirin and other anti-inflammatory agents, inhibitors of tumor necrosis factor, and inhibitors of interleukin 1.
  • known immunosuppressive agents such as COX2 inhibitors, corticosteroids, statins, cannabinoids (and derivatives thereof), interferon beta, aspirin and other anti-inflammatory agents, inhibitors of tumor necrosis factor, and inhibitors of interleukin 1.
  • the beneficial effect of the combination can include, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.
  • Combinations of the compound of the present invention and the other active agents may be administered together in a single combination or separately. Where separate administration is employed, the administration of one element may be prior to, concurrent with, or subsequent to the administration of other agents. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected).
  • “combination therapy” encompasses the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention.
  • “combination therapy” is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
  • Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents.
  • the therapeutic agents can be administered by the same route or by different routes.
  • a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally.
  • all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection.
  • the sequence in which the therapeutic agents are administered is not narrowly critical.
  • “Combination therapy” also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation treatment.)
  • the combination therapy further comprises a non- drug treatment
  • the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non- drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.
  • a patient's symptoms and/or immune response are determined by measuring a particular symptom, or set of symptoms, in a patient before and after treatment with a macrolide composition. For example, one measures and monitors symptoms such as fever, joint pain, muscle weakness using any of the standard measurement techniques known in the art.
  • the patient status has improved (i.e., the measurement number has decreased, or the time to sustained progression has increased).
  • a compound that is administered in a pharmaceutical composition is mixed with a suitable carrier or excipient such that a therapeutically effective amount is present in the composition.
  • a therapeutically effective amount refers to an amount of the compound that is necessary to achieve a desired endpoint (e.g., decreasing symptoms associated with an immune-related disorder).
  • compositions containing the macrolide compound can be used to formulate pharmaceutical compositions containing the macrolide compound, including solid, semi solid, liquid and gaseous forms.
  • Techniques for formulation and administration are found, for example, in "Remington: The Science and Practice of Pharmacy, Twentieth Edition," Lippincott Williams & Wilkins, Philadelphia, PA. Tablets, capsules, pills, powders, granules, dragees, gels, slurries, ointments, solutions suppositories, injections, inhalants and aerosols are examples of such formulations.
  • the formulations are administered in either a local or systemic manner or in a depot or sustained release fashion. Administration of the composition is performed in a variety of ways.
  • compositions and combination therapies of the invention are administered in combination with a variety of pharmaceutical excipients, including stabilizing agents, carriers and/or encapsulation formulations as described herein.
  • compositions of the present invention are prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid prior to injection; as tablets or other solids for oral administration; as time release capsules; or in any other form currently used, including topical administration e.g., creams, lotions, mouthwashes, inhalants and the like.
  • preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologies standards.
  • Administration of compounds alone or in combination therapies are, e.g., intraperitoneal, ICV, intralesional, intraperitoneal, intramuscular,intravenous or subcutaneous injection, infusion, implant, inhalation spray, vaginal, rectal, sublingual, aerosol, topical, nasal, oral, ocular or otic delivery.
  • the compounds can be administered on a regimen of 1 to 4 times per day.
  • a particularly convenient frequency for the administration of the compounds of the invention is once or twice a day.
  • therapeutics are administered in a manner compatible with the dosage formulation, and in such amount as is pharmacologically effective.
  • the formulations are easily administered in a variety of dosage forms, such as the injectable solutions described, but drug release capsules and the like can also be employed.
  • the quantity of active ingredient and volume of composition to be administered depends on the host animal to be treated. Precise amounts of active compound required for administration depend on the judgment of the practitioner and are peculiar to each individual.
  • a minimal volume of a composition required to disperse the active compounds is typically utilized. Suitable regimes for administration are also variable, but are typified by initially administering the compound and monitoring the results and then giving further controlled doses at further intervals.
  • a suitably buffered, and if necessary, isotonic aqueous solution is prepared and used for intravenous, intramuscular, subcutaneous or even intraperitoneal administration.
  • One dosage is dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermolysis fluid or injected at the proposed site of infusion, (see for example, "Remington: The Science and Practice of Pharmacy, Twentieth Edition," Lippincott Williams & Wilkins, Philadelphia, PA).
  • a carrier can he a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • compositions of the invention are formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, subcutaneous, intralesional, or even intraperitoneal routes.
  • parenteral administration e.g., formulated for injection via the intravenous, intramuscular, subcutaneous, intralesional, or even intraperitoneal routes.
  • the preparation of a composition that contains a compound or combination therapy of the invention, or an active component or ingredient will be known to those of skill in the art in light of the present disclosure.
  • such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for using to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified.
  • Suitable preservatives for use in solution include benzalkonium chloride, benzethonium chloride, chlorobutanol, thimerosal and the like.
  • Suitable buffers include boric acid, sodium and potassium bicarbonate, sodium and potassium borates, sodium and potassium carbonate, sodium acetate, sodium biphosphate and the like, in amounts sufficient to maintain the pH at between about pH 6 and pH 8, and preferably, between about pH 7 and pH 7.5.
  • Suitable tonicity agents are dextran 40, dextran 70, dextrose, glycerin, potassium chloride, propylene glycol, sodium chloride, and the like, such that the sodium chloride equivalent of the ophthalmic solution is in the range 0.9 plus or minus 0.2%.
  • Suitable antioxidants and stabilizers include sodium bisulfite, sodium metabisulflte, sodium thiosulf ⁇ te, thiourea and the like.
  • Suitable wetting and clarifying agents include polysorbate 80, polysorbate 20, poloxamer 282 and tyloxapol.
  • agents include dextran 40, dextran 70, gelatin, glycerin, hydroxyethylcellulose, hydroxniethylpropylcellulose, lanolin, methylcellulose, petrolatum, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose and the like.
  • the compounds of the invention can be formulated by dissolving, suspending or emulsifying in an aqueous or nonaqueous solvent.
  • Vegetable e.g., sesame oil, peanut oil
  • synthetic aliphatic acid glycerides e.g., synthetic aliphatic acid glycerides, esters of higher aliphatic acids and propylene glycol are examples of nonaqueous solvents.
  • Aqueous solutions such as Hank's solution, Ringer's solution or physiological saline buffer can also be used. In all cases the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • Solutions of active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • aqueous solutions For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure.
  • DMSO dimethyl methacrylate
  • composition or combination therapy can be formulated alone or together through combination with conventional, non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles that are well known in the art.
  • the carriers, adjuvants, and vehicles enable the compound to be formulated, for example, as a tablet, pill, troche, lozenge, hard or soft capsule, solution, aqueous or oily suspension, sustained release formulation, dispersible powder or granule, syrup, elixir, liquid or gel for oral ingestion by the patient.
  • Oral use formulations can be obtained in a variety of ways, including mixing the compound with a solid excipient, optionally grinding the resulting mixture, adding suitable auxiliaries and processing the granule mixture.
  • excipients that can be used in an oral formulation: sugars such as lactose, sucrose, mannitol or sorbitol; cellulose preparations such as maize starch, wheat starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone (PVP), inert diluents, such as calcium carbonate, sodium carbonate, calcium phosphate or sodium phosphate; and lubricating agents, for example, stearic acid, or talc.
  • sugars such as lactose, sucrose, mannitol or sorbitol
  • cellulose preparations such as maize starch, wheat starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone (PVP), inert diluents, such as calcium carbonate, sodium
  • Oral formulations include such normally employed excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and the like.
  • the tablets may be uncoated or coated by known techniques to delay disintegration and adsorporption in the gastrointestinal tract and thereby provide a sustained action over a period of time.
  • oral pharmaceutical compositions will comprise an inert diluent or assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsule, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet.
  • the active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tables, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least 0.1% of active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 75% of the weight of the unit, or preferably between 25-60%.
  • the amount of active compounds in such therapeutically useful compositions is such that a suitable dosage will be obtained.
  • the tablets, troches, pills, capsules and the like may also contain the following: a binder, as gum tragacanth, acacia, cornstarch, or gelatin; excipients, such as dicalcium. phosphate; a disintegrating agent, such as corn starch, potato starch, alginic acid and the like; a lubricant, such as magnesium stearate; and a sweetening agent, such as sucrose, lactose or saccharin may be added or a flavoring agent, such as peppermint, oil of wintergreen, or cherry flavoring.
  • a binder as gum tragacanth, acacia, cornstarch, or gelatin
  • excipients such as dicalcium. phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • the dosage unit form When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both.
  • a syrup of elixir may contain the active compounds sucrose as a sweetening agent methyl and propylparabensas preservatives, a dye and flavoring, such as cherry or orange flavor.
  • Oily suspensions may be formulated for oral delivery by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraf ⁇ in.
  • the oily suspension may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents such as those set out above may be added to provide a palatable oral preparation.
  • the compositions may be preserved by the additiona of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension for oral deliverby the addition of water provide the active ingredient in a mixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Additional exicipents, for example, sweeting, flavoring and coloring agents may also be present.
  • the composition of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example, liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the compounds of the present invention can be delivered topically. 'Topical application”, “applied topically”, “topical administration”, and “administered topically”, are used interchangeably to mean the process of applying or spreading one or more compounds according to the present invention onto the surface of the skin or mucous membrane of a subject in need thereof. In one embodiment, compounds of the invention are incorporated into a topical preparation suitable for pharmaceutical applications.
  • the compound can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art. When the compound is administered by a patch, the dose administration will be continuous rather than intermittent throughout the dosage regimen.
  • the compound of the invention may be combined with other optional suitable ingredients such as estrogen, Vitamin A, C, and E, alpha-hydroxy of alpha-keto acids such as pyruvic, lactic or glycolic acids, lanolin, vaseline, aloe vera, methyl or propyl paraben, pigments and the like.
  • suitable topically acceptable carriers include water, petroleum jelly (vaseline), mineral oil, vegetable oil, animal oil, organic and inorganic waxes, such as microcrystalline, paraffin and ozocerite wax, natural polymers, such as xanthanes, gelatin, cellulose, collagen, starch, or gum arabic, synthetic polymers, such as discussed below, alcohols, polyols, and the like.
  • the carrier is a water miscible carrier composition that is substantially miscible in water.
  • water miscible topical carrier composition can include those made with one or more appropriate ingredients set forth above but can also include sustained or delayed release carrier, including water containing, water dispersable or water soluble compositions, such as liposomes, microsponges, microspheres or microcapsules, aqueous base ointments, water-in-oil or oil-in-water emulsions, gels or the like.
  • the compounds of the present invention can also be in the form of an emulsion for topical administration.
  • a stable emulsion is a mixture of two immiscible liquids, i.e. liquids that are not mutually soluble, but which can form a fluid in which very small droplets of one component are stably dispersed throught the other liquid, giving the mixture the appearance of a homogeneous fluid.
  • Emulsions can include particulate materials and materials which are solid or solid-like at room temperature, but which will liquify at higher temperatures used during formulation of the emulsion.
  • an emulsifier enhances the ability of one of the immiscible liquids to remain in a continuous form, while allowing the other immiscible liquid to remain in a dispersed droplet form.
  • one function of an emulsifier is to provide a thickening or "'bodying" to an emulsion.
  • emulsifiers are molecules with non-polar parts and polar parts that are able to reside at the interface of two immiscible liquids.
  • emulsion is used herein to identify oil-in-water (o/w) or water-in-oil (w/o) type dispersion formulations intended for applications to the skin, particularly lotions and creams providing cosmetic or therapeutic benefits.
  • the emulsions may contain any number of desired "active" ingredients, including skin colorants, drug substances (such antiinflammatory agents, antibiotics, topical anesthetics, antimycotics, keratolytics, etc.), skin protectants or conditioners, humectants, ultraviolet radiation absorbers and the like, depending on the intended uses for the formulation. Techniques for forming o/w and w/o emulsions are well known in the art.
  • compositions of the present invention can be delivered in an aerosol spray preparation from a pressurized pack, a nebulizer or from a dry powder inhaler.
  • Suitable propellants that can be used in a nebulizer include, for example, dichlorodifluoro-methane, trichlorofluoromethane, dichlorotetrafluoroethane and carbon dioxide.
  • the dosage can be determined by providing a valve to deliver a regulated amount of the compound in the case of a pressurized aerosol.
  • Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • compositions may contain suitable pharmaceutically acceptable excipients as set out above.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
  • compositions suitable for other modes of administration include suppositories. These compositions can be prepared by mixing the drug with a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melot in the rectum to release the drug.
  • a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melot in the rectum to release the drug.
  • traditional binders and carriers may include, for example, polyalkylene glycols or triglycerides; such suppositories may be formed from mixtures containing the active ingredient in the range of 0.5% to 10%, preferably l%-2%.
  • the subject treated by the methods of the invention is a mammal, more preferably a human.
  • the following properties or applications of these methods will essentially be described for humans although they may also be applied to non-human mammals, e.g., apes, monkeys, dogs, mice, rats, horses, cattle, sheep, cats, etc.
  • the invention therefore can also be tised in a veterinarian context.
  • a “pharmaceutically acceptable salt” or “salt” of the disclosed compound is a product of the disclosed compound that contains an ionic bond, and is typically produced by reacting the disclosed compound with either an acid or a base, suitable for administering to a subject.
  • a "pharmaceutical composition” is a formulation containing the disclosed compounds in a form suitable for administration to a subject.
  • the pharmaceutical composition is in bulk or in unit dosage form.
  • the unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial.
  • the quantity of active ingredient (e.g. , a formulation of the disclosed compound or salts thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved.
  • active ingredient e.g. , a formulation of the disclosed compound or salts thereof
  • the dosage will also depend on the route of administration.
  • routes including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, and the like.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.
  • compositions of the present invention contain a therapeutically effective amount of the macrolide compound.
  • the amount of the compound will depend on the patient being treated. The patient' s weight, severity of illness, manner of administration and judgment of the prescribing physician should be taken into account in deciding the proper amount. The determination of a therapeutically effective amount of a macrolide compound is well within the capabilities of one with skill in the art.
  • suitable doses will typically include between about 0.1 mg and 1000 mg of the compound per kg patient body weight per day which can be administered in single or multiple doses.
  • a dose contains between about 0.1 mg and 500 mg/kg per day of the compound.
  • a dose contains between about 0.1 mg and 250 mg/kg per day of the compound, from about 0.1 to 100 mg/kg per day.
  • a suitable dosage level can be from about 0.1 to 50 mg/kg per day. Within this range the dosage maybe from 0.1 to about 0.5, from about 0.5 to about 5, or from about 5 to about 50 mg/kg per day.
  • the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
  • the dosages outside of the stated ranges to treat a patient those cases will be apparent to the prescribing physician.
  • a physician will also know how and when to interrupt, adjust or terminate treatment in conjunction with a response of a particular patient.
  • cytotoxicity of each of the macrolide compounds of the invention was evaluated in the following cell types: HEPG2, ME67.8, HL60, PC3, Ovcar-3 and Colo205.
  • the cell lines were cultured according to the suppliers' protocols. For cytotoxicity measurements the cells were seeded in 96 or 384 well tissue culture treated microtitre plates overnight. Compounds were diluted in appropriate buffers and added to the cells the next day. Following a further 72 hour incubation, cell viability was determined using standard tetrazolium dyes (MTT and XTT from Sigma) or Cell Titer GIo (from Promega) according to the manufacturers' instructions and the absorbance or luminescence measured in a Tecan Ultra or PerkinElmer Microbeta microplate reader. Both methods gave very similar results (IC 50 values). The results of this evaluation are presented below in Table 2:
  • mice The maximum tolerated dose of N831 (A) in Harlan nude mice is 10 mg/kg as established by the amount of weight loss observed. In the course of this study no fatalities and no adverse reactions were reported. At the 5 and 10 mg/kg doses, the mice lost around 20% of their body weight, all of which they had regained by the next week. Tumour growth delay xenograft study in mice
  • N831 (A) was evaluated for efficacy in athymic nude mice bearing xenografts of human PC3 prostate carcinoma.
  • N831 (A) was administered daily intravenously for 5 days.
  • the dose levels of N831 (A) were 2.5, 5.0 and 10 mg/kg.
  • Response was assessed by tumor growth delay compared with untreated control using an endpoint of 1000 mm 3 tumor volume, and by numbers of tumor regressions. All dose levels of N831 (A) were highly effective in delaying tumor growth of PC3 prostate carcinoma with time to endpoint values of 59.5-60.0 days. The tumor growth delay was highly significant when compared to control. A dose-response was evident in the number of regressions.
  • the Actinomycete strain T658 was isolated from marine sediments collected in waters off Singapore. The strain has been identified as a member of the genus Streptomyces owing to the presence of aerial mycelia and long, straight or flexuous spore chains. Currently species level identification is not available.
  • Strain T658 was subcultured on ISP4 agar (Difco) for 7 - 15 days at 28 0 C. As T658 is a marine derived organism the media was supplemented with 4% sea salts (Sigma). The subculture was used to inoculate 250 niL Erlenmeyer flasks each containing 50 mL of seed medium composed of 1.5% glucose (Sigma), 1.5% glycerol solution (Merck), 1.5% soy peptone (Oxoid), 4% sea salts and 0.1% CaCO 3 (BDH). The pH of the medium was adjusted to 7 prior to sterilization (autoclave 121 0 C for 20 min).
  • the seed culture was incubated for 3 days at 28 0 C on a rotary shaker at 200 rpm.
  • SP-207 resin Mitsubishi Chemicals
  • the resin was removed from the fermentation broth using a combination of centrifugation (Sorvall RC-4), washing and decanting.
  • the fermentation broth was first transferred to centrifuge containers and using the "quick run” mode the centrifuge was operated for 30 seconds (around 1300 rpm was obtained). This allowed the SP-207 beads to settle but most of the biomass remained suspended in the supernatant and could be easily poured off. Following this process the beads were washed with water and the remaining biomass was removed by decanting.
  • the fermentation broth (48 L) was eluted through SP-207 resin and washed with MeOH.
  • the MeOH eluent was added with H 2 O (1:1) and partitioned 3 times with CH 2 Cl 2 .
  • the active CH 2 Cl 2 fraction (51 g) was chromatographed on Silica gel (700 g) with a CHCl 3 - MeOH gradient (100:0 ⁇ 5:1) to yield 10 fractions.
  • T658 was subjected to UV mutagenesis and antibiotic resistance to streptomycin to provide a mutant strain, which was found to produce some additional active compounds.
  • the mutant strain was cultured following the standard protocol to provide a fermentation broth (4 L), which was eluted through SP-207 and washed with MeOH. The MeOH eluent was added with H 2 O (1:1) and partitioned 3 times with CH 2 Cl 2 .
  • the active CH 2 Cl 2 fraction (2.5 g) was subjected to reverse phase preparative HPLC (gradient elution;18 mL/min; (acetonitrile + H 2 O (10:90 ⁇ 15:85 over 10 min, 15:85 ⁇ 20:80 over 10 min, 20:80 ⁇ 25:75 over 20 min, 25:75 ⁇ 30:70 over 20 min, 30:70 ⁇ 35:65 over 20 min, 35:65 ⁇ 40:60 over 20 min, 40:60 ⁇ 50:50 over 20 min); Waters NovaPak C-18 radial cartridge column, 40 x 100 mm) to give N831 (A) (80 mg, RT 87 min), Nl 512 (20 mg, RT 73 min), N1523 (65 mg, RT 70 min) and N1611 (6 mg, RT 77 min). N831 (A) (80 mg, RT 87 min), Nl 512 (20 mg, RT 73 min), N1523 (65 mg, RT 70 min) and N1611 (6
  • N831 (A) (202 mg, 0.36 mmol) in anhydrous 1,2-dirnethoxyethane ether (DME)-ether 1:1 (5 niL) at 0 0 C was added 48% HBr (100 ⁇ L, 0.6 mmol). The reaction mixture was stirred at 0 0 C for 1.5 hours. Additional 48% HBr (100 ⁇ L, 0.6 mmol) was introduced to the mixture twice over a period of 20 min. The excess HBr was neutralized by adding K 2 CO 3 and saturated aqueous NaHCO 3 (0.3 mL). The stirring was continued at 0 0 C for 5 min. The mixture was then warmed to room temperature, dried with anhydrous MgSO 4 and then filtered.
  • DME 1,2-dirnethoxyethane ether
  • N831 (A) (10.7 mg, 0.02 mmol), LiI (20.1 mg, 0.15 mmol) in dimethoxyethane ether (7 mL) was heated to 68 0 C and stirred under argon for 5 days. The solvent was evaporated and the residue partitioned between ethyl acetate and saturated aqueous Na 2 S 2 O 3 solution. The ethyl acetate extract was washed with water, dried with anhydrous MgSO 4 and evaporated under reduced pressure.
  • GM129 2.9 mg, 22%).
  • N831 (A) (960 mg, 1.7 mmol), DMAP (104 mg, 0.85 mmol) and triethylamine (0.236 mL, 1.7 mmol) in anhydrous THF (32 mL) was added chlorotriethylsilane (TES-Cl) (0.285 mL, 1.7 mmol).
  • TES-Cl chlorotriethylsilane
  • the reaction mixture was stirred at room temperature for 1 hour. Additional chlorotriethylsilane (0.029 mL, 0.17 mmol) and triethylamine (0.024 mL, 0.17 mmol) were introduced. The mixture was stirred at room temperature for another 30 min and then quenched with water (8 mL).
  • ketone 1 (5 mg, 7.37 ⁇ mol) in dry MeOH-CH 2 Cl 2 (1:1, 2 mL) was added pyridiniump-toluenesulfonate (3 mg, 0.0119 mmol). The solution was stirred at room temperature until all starting material had reacted as indicated by TLC (ethyl acetate-hexane 1:1). The solvents were then removed under reduced pressure and the crude product purified by flash column chromatography (ethyl acetate-hexane 3:1 then 4:1) to give GM144 (3 mg, 72%).
  • N831 (A) (20 mg, 0.04 mmol), DMAP (1 mg, 8.2 ⁇ mol) and a base (triethylamine or pryridine, 0.04 mmol) in anhydrous CH 2 Cl 2 (10 mL) was added the acylating reagent (0.04 mmol). The reaction mixture was stirred at room temperature for 30 min. Additional acylating reagent (0.04 mmol) and base (0.04 mmol) were added twice over a period of 1 hour. The mixture was concentrated and purified by preparative TLC (ethyl acetate-hexane 1:1) to give the C3, C17-diester and C17-monoester.
  • GM203 For GM203, the Fmoc protecting group was removed by stirring the acylated product in 20% piperidine in chloroform at room temperature for 1 hour. The solvents were removed under reduced pressure and the mixture purified by preparative TLC (chloroform- methanol 20:1). The deprotection yield for GM 203 was 41%.
  • GM120 (130 mg, 0.20 mmol) was dissolved in dry CH 2 Cl 2 (4 mL) prior to the addition of triethylamine (200 ⁇ L, 1.98 mmol). The reaction mixture was stirred at 50 0 C for 48 hours. The solvent was then removed under reduced pressure and the crude product purified by preparative TLC (cliloroform-methanol 99:1, then 49:1) to give GM179 (79.8 mg, 70%).
  • the crude product was purified first by silica gel column chromatography (gradient elution with 50% ethyl acetate-hexane to 12.5% ethyl acetate-hexane, then 2% chloroform-methanol to 5% chloroform-methanol) followed by preparative TLC (chloroform-methanol 20:1) to give the triethylsilyl-protected biscarbamate 12 (35 mg, 39%).
  • the crude product was purified by preparative HPLC (gradient elution; 18 mL/min; MeCN/H 2 O + 0.1% HCOOH; 20:80 to 25:75 over 20 min, 25:75 to 30:70 over 30 min, 30:70 to 35:65 over 40 min, 35:65 to 50:50 over 20 min, 50:50 to 60:40 over 10 min and 60:40 to 100:0 over 20 min; Waters NovaPak radial cartridge column, 40x100 mm) to give GM218 (72.9 mg, 13%), GM219 (152.4 mg, 28%) and azide 13 (95.3 mg, 19%).
  • GM218 (107 mg, 0.18 mmol) was dissolved in degassed THF (4 mL).
  • Degassed Millipore water 32 ⁇ L, 1.78 mmol was then added, followed by Me 3 P (l.M in THF; 900 ⁇ L, 0.90 mmol) under an argon atmosphere.
  • the reaction mixture was stirred at room temperature until all starting material had reacted as indicated by TLC (chloroform- methanol 4:1). It was then concentrated under reduced pressure and dried overnight under vacuum. The crude amine 14 was used without further purification or characterization.
  • ketone 18 (6.4 mg, 8.53 ⁇ mol) was added (8 mg, 0.03 mmol) in methanol (1 mL). The solution was stirred at room temperature until all starting material had reacted. The solvent was removed under reduced pressure and the crude product purified by preparative TLC (chloroform-methanol 25:1) to give GM161 (0.9 mg, 20%).
  • GM161 (4 mg, 7.66 ⁇ mol) in dry THF (1.2 mL) was added NaBH 4 (10 mg, 0.26 mmol) at room temperature. After all starting material had reacted as indicated by TLC (ethyl acetate-hexane 9:1), methanol was added. All solvents were then removed under reduced pressure, and the crude product purified by preparative TLC (ethyl acetate-hexane 9:1) to give GM169 (1.9 mg, 47%).

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Abstract

La présente invention concerne des composés macrolides, ainsi que des sels pharmaceutiquement acceptables de ceux-ci, qui inhibent l'expression de la MHC de classe II et qui peuvent être utilisés en tant qu'agents immunosuppresseurs dans le traitement avant, pendant et/ou après une greffe d'organe ou de tissus, ainsi que dans le traitement de troubles immunitaires et/ou du cancer et de troubles liés au cancer.
PCT/IB2006/004214 2005-09-28 2006-09-27 Compositions macrolides en tant qu'agents thérapeutiques WO2007110705A2 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008126918A1 (fr) * 2007-04-12 2008-10-23 Eisai R & D Management Co., Ltd. Dérivé de cyclomacrolactame à douze éléments
WO2010062265A1 (fr) * 2008-11-25 2010-06-03 Merlion Pharmaceuticals Pte Ltd Composés de macrolides thérapeutiques et utilisation de ceux-ci
WO2013148324A1 (fr) * 2012-03-26 2013-10-03 The Regents Of The University Of California Composés de polycétides anticancéreux
JP2021521124A (ja) * 2018-04-09 2021-08-26 エーザイ・アール・アンド・ディー・マネジメント株式会社 ある種のプラジエノライド化合物及び使用方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997016425A1 (fr) * 1995-10-30 1997-05-09 Merck & Co., Inc. Nouveaux inhibiteurs de la liaison de peptides avec des proteines de classe ii du complexe d'histocompatibilite majeur
EP1548121A1 (fr) * 2002-07-31 2005-06-29 Mercian Corporation Nouvelles substances actives sur le plan physiologique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997016425A1 (fr) * 1995-10-30 1997-05-09 Merck & Co., Inc. Nouveaux inhibiteurs de la liaison de peptides avec des proteines de classe ii du complexe d'histocompatibilite majeur
EP1548121A1 (fr) * 2002-07-31 2005-06-29 Mercian Corporation Nouvelles substances actives sur le plan physiologique

Non-Patent Citations (1)

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Title
SEKI-ASANO M ET AL: "ISOLATION AND CHARACTERIZATION OF A NEW 12-MEMBERED MACROLIDE FD-895" JOURNAL OF ANTIBIOTICS, JAPAN ANTIBIOTICS RESEARCH ASSOCIATION, TOKYO, JP, vol. 47, no. 12, December 1994 (1994-12), pages 1395-1401, XP002951021 ISSN: 0021-8820 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008126918A1 (fr) * 2007-04-12 2008-10-23 Eisai R & D Management Co., Ltd. Dérivé de cyclomacrolactame à douze éléments
WO2010062265A1 (fr) * 2008-11-25 2010-06-03 Merlion Pharmaceuticals Pte Ltd Composés de macrolides thérapeutiques et utilisation de ceux-ci
WO2013148324A1 (fr) * 2012-03-26 2013-10-03 The Regents Of The University Of California Composés de polycétides anticancéreux
JP2021521124A (ja) * 2018-04-09 2021-08-26 エーザイ・アール・アンド・ディー・マネジメント株式会社 ある種のプラジエノライド化合物及び使用方法
JP7335265B2 (ja) 2018-04-09 2023-08-29 エーザイ・アール・アンド・ディー・マネジメント株式会社 ある種のプラジエノライド化合物及び使用方法
US11926619B2 (en) 2018-04-09 2024-03-12 Eisai R & D Management Co., Ltd. Certain pladienolide compounds and methods of use

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