WO2007110704A2 - Macrolide compositions as therapeutic agent - Google Patents

Macrolide compositions as therapeutic agent Download PDF

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Publication number
WO2007110704A2
WO2007110704A2 PCT/IB2006/004213 IB2006004213W WO2007110704A2 WO 2007110704 A2 WO2007110704 A2 WO 2007110704A2 IB 2006004213 W IB2006004213 W IB 2006004213W WO 2007110704 A2 WO2007110704 A2 WO 2007110704A2
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WIPO (PCT)
Prior art keywords
compound according
substituted
ring
heteroaryl
alkyl
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PCT/IB2006/004213
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French (fr)
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WO2007110704A3 (en
Inventor
Bernard Mach
Peter Traxler
Krzysztof Masternak
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 WO2007110704A2 publication Critical patent/WO2007110704A2/en
Publication of WO2007110704A3 publication Critical patent/WO2007110704A3/en

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    • 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
    • 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
    • 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

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.
  • 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.
  • 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.
  • 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.
  • psoriasis chronic inflammatory diseases
  • atherosclerosis pulmonary embosuppression
  • 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 provides compositions 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 invention include a twelve-membered ring structure such as the twelve-membered ring shown below 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. 60/721,556, filed September 28, 2005.
  • the compounds of this related application have been modified at the Rn position of the macrolide ring.
  • the macrolide compounds of the invention include a twelve-membered ring. More particularly, the present invention includes a compound according to Formula (I):
  • R d is -NH 2 or azide.
  • R 7a and R 7b are each, independently -OC(O)NR]R 2 , -OC(O)OR 5 , -OC(O)R 6 , or hydrogen, or taken together R 7a and R- ⁇ form a carbonyl.
  • Ri and R 2 are the same as or different from each other and each is selected from: hydrogen;
  • n is 1 , 2, or 3.
  • x is 1, 2, or 3.
  • y is 0, 1, 2, or 3.
  • Ri + R 2 together with the nitrogen atom to which Ri and R 2 are connected form a 3, 4, 5, 6, 7, or 8-membered ring, wherein the ring is a non-aromatic heterocyclic ring, wherein any of the atoms in the ring may be substituted.
  • R 5 is C 2 , C3, 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 -amino; or methyl, each of which may be substituted.
  • R 6 is C 5 , C 6 , C 7 , or C 8 aryl; heteroaryl; C 2 , C 3 , C 4 , Cs 9 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 - amino; or -(CH 2 ) j -heteroaryl, 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 21 is methyl, C2-6 alkyl, or hydrogen.
  • Z is O. In another embodiment, Z is NH. In another embodiment, Z is S. In another embodiment, Z is absent such that the compound is represented by the formula (P):
  • R 21 is methyl.
  • R 2 i is hydrogen.
  • any one of R 7a or R ⁇ is -OC(O)NRiR 2 and the other is hydrogen.
  • R] and R 2 are the same as or different from each other and each is selected from hydrogen, C 2 -C 6 alkyl, C 2 -C 6 acyl, C 3 -C 6 alkenyl, unsaturated C 3 -C 8 acyl, C 5 -C 8 aryl, heteroaryl, Ci-C 6 alkylsulfonyl, benzenesulfonyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, methyl, -(CH 2 ) X -heteroaryl, -(CH 2 ) n - amino, and -(CH 2 )
  • n is 1, 2, or 3.
  • x is 1, 2, or 3.
  • y is 0, 1, 2, or 3.
  • Ri + R 2 together with the nitrogen atom to which Ri and R 2 are connected form a 3, 4, 5, 6, 7, or 8-membered ring, wherein the ring is a non-aromatic heterocyclic ring, wherein any of the atoms in the ring may be substituted.
  • Ri and R? are the same as or different from each other and each is selected from hydrogen, C2-C 6 alkyl, C 2 -CO acyl, methyl, -(CEk) n - amino, and -(CH 2 ) x -heteroaryl, each of which may be substituted.
  • R 1 and R 2 are the same as or different from each other and each is selected from hydrogen, C 3 -Cs cycloalkyl, C 3 -Cg alkenyl, unsaturated C 3 -Cs acyl, Cs-Cg aryl, heteroaryl, CrC 6 alkylsulfonyl, benzenesulfonyl, or C 3 -Cs cycloalkenyl, each of which may be substituted.
  • Ri + R 2 together with the nitrogen atom to which Ri and R 2 are connected form a 3, 4, 5, 6, 7, or 8-membered ring, wherein the ring is a non-aromatic heterocyclic ring, further 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.
  • the ring contains at least one heteroatom selected from O, N, or S.
  • the heterocyclic ring formed when Rj and R 2 are connected is selected from the group consisting of pyrrolidine, piperidine, azepane, and azocane, each of which may be substituted.
  • the heterocyclic ring formed when Ri and R 2 are connected contains at least two nitrogen atoms.
  • the heterocyclic ring formed when Ri and R 2 are connected is selected from piperazine or homopiperazine, each of which may be substituted.
  • the heterocyclic ring formed when Rj and R 2 are connected is piperazine.
  • piperazine is substituted on the nitrogen atom located at the four position of the ring.
  • piperazine is substituted with methyl, C 2 -Cg alkyl, C 3 -C 8 cycloalkyl, or heteroaryl.
  • piperazine is substituted with pyridine.
  • piperazine is substituted with methyl.
  • piperazine is substituted with cyclohexyl.
  • any one of Rj or R 2 is -(CH 2 ) x ⁇ heteroaryl, -(CH 2 ) y -heterocycle, or -(CH 2 ) n -amino and the other is hydrogen.
  • any one of Ri or R 2 is -(CH 2 ) x -heteroaryl and the other is hydrogen.
  • x is 1.
  • x is 2.
  • x is 3.
  • heteroaryl is pyridine.
  • any one of R] or R 2 is-(CH 2 ) y -heterocycle and the other is hydrogen.
  • y is 0.
  • y is 1.
  • y is 2.
  • y is 3.
  • heterocycle is piperidine, pyrrolidine, morpholine, or piperazine, each of which may be substituted.
  • heterocycle is pyrrolidine.
  • heterocycle is piperidine.
  • heterocycle is morpholine.
  • heterocycle is piperazine.
  • piperazine is substituted on the nitrogen at the four position on the ring.
  • piperazine is substituted with methyl.
  • any one of R] or R 2 is -(CH 2 ) n -amino and the other is hydrogen.
  • n is 1.
  • n is 2.
  • n is 3.
  • amino is -NH 2 , alkylamino, or dialkylamino.
  • amino is -NH 2 .
  • amino is dimethylamine.
  • any one of Ri or R 2 is Ci-Cz cycloalkyl and the other is hydrogen. In another embodiment, C 3 -Cs cycloalkyl is cyclohexyl. In one embodiment, each of Rj and R 2 is hydrogen. In another embodiment, each of Ri and R 2 is Ci -CO alkyl. In another embodiment, each of Ri and R 2 is methyl. In one embodiment, any one of R 7a or R 7 b is -OC(O)OR 5 and the other is hydrogen.
  • R5 is C 2 -C O alkyl, C3-C6 alkenyl, C5-C8 aryl, heteroaryl, benzyl, ⁇ (CH 2 ) s -heteroaryl, C 3 -C 8 cycloalkyl, C 3 -Cs cycloalkenyl, -(CH 2 ) u -heterocycle, or -(CH 2 ) t -amino, 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.
  • any one of R 7a or R 7 b is -OC(O)R 6 and the other is hydrogen.
  • R 6 is C 5 -C 8 aryl., heteroaryl, C 2 -Cg alkyl, -(CH 2 ) g -heterocycle, -(CH 2 ) J -Ca-Cs cycloalkyl, C 3 -Cs cycloalkyl, -(CH 2 ) h -amino, -(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 6 is C5-C 8 aryl, C 2 -C 6 alkyl, or methyl. In one embodiment, R 6 is phenyl. In another embodiment, R 6 is ethyl. In another embodiment, taken together R 7a and R 7b form a carbonyl.
  • the compound is selected from:
  • Another aspect of the present invention is a compound according to formula II:
  • R d is -NH 2 or azide.
  • R 3 is Ci-Ce allcyl, substituted Ci -CO alkyl, or silyl.
  • Silyl is R a R b R c Si-, wherein R a , R b , and R c are the same as or different from each other.
  • R a , R b , and R c represents methyl, ethyl, i-propyl, t-butyl, or phenyl.
  • R 6a is methyl, Ci -C O alkyl, substituted CpC 6 alkyl, or hydrogen.
  • R 7a and R 7b are each, independently -OC(O)NRiR 2 , -OC(O)OR 5 , -OC(O)R 6 , hydroxyl, or hydrogen, or taken together R 7a and R 7 ⁇ form a carbonyl.
  • Ri and R 2 are the same as or different from each other and each is selected from hydrogen;
  • Ri + R 2 together with the nitrogen atom to which they are connected form a
  • R 5 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; -(CEfeVamino; or methyl, each of which may be substituted.
  • s is 1, 2, or 3.
  • t is 1, 2, or 3.
  • R 6 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; -
  • g is 0, 1, 2, or 3.
  • h 1, 2, or 3.
  • Ri 7 is methyl, CrC 6 alkyl or substituted Ci-Ce alkyl, or silyl.
  • R21 is C 1 -Cg alkyl or substituted C]-Ce alkyl.
  • 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 carrier 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), Sj ⁇ gren'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.
  • Another embodiment includes a method of alleviating a symptom associated with an 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.
  • Another embodiment includes
  • autoimmune disease which is selected from systemic lupus erythematosus (SLE), systemic sclerosis (scleroderma), Sj ⁇ gren'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 enanriomerically 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 enanriomerically 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.
  • compositions of the invention include a compound that modulates and/or regulates an immune response.
  • This compound is 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. Often, macrolides are glycosylated.
  • the invention also includes ring-opened macrolides as represented by the structures below:
  • the macrolide compounds of the invention include a twelve-membered ring. More particularly, the present invention includes a compound according to Formula (I):
  • R d is -NH 2 or azide.
  • R 7a and R 7b are each, independently -OC(O)NR 1 R 2 , -OC(O)OR 5 , -OC(O)R 6 , or hydrogen, or taken together R 7a and R 7 ⁇ form a carbonyl.
  • Ri and R 2 are the same as or different from each other and each is selected from: hydrogen;
  • C3, C 4 , C5, C 6 , C 7 , or C 8 acyl C5, C 6 , C 7 , or Cg aryl; heteroaryl; C 1 , C 2 , C 3 , C 4 , C5, or C 6 alkylsulfonyl; benzenesulfonyl; C 3 , C 4 , C 5 , Ce 5 C 7 , or Cs cycloalkyl; C 3 , C 4 , C5, C 6 , C 7 , or Cg cycloalkenyl; methyl; -(CH 2 ) x -heteroaryl; -(CH 2 ) n -amino; and -(CH 2 ) y -heterocycle, each of which may be substituted.
  • n is 1, 2, or 3.
  • x is 1, 2, or 3.
  • y is O, 1, 2, or 3.
  • R 1 + R 2 together with the nitrogen atom to which Rj and R 2 are connected form a 3, 4, 5, 6, 7, or 8-membered ring, wherein the ring is a non-aromatic heterocyclic ring, wherein any of the atoms in the ring may be substituted.
  • R5 is C 2 , C 3 , C 4 , C 5 , or Ce alkyl; C3, C 4 , C5, or Ce 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 ) r amino; 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 6 is Cs, C(j, C 7 , or C 8 aryl; heteroaryl; C 2 , C 3 , C 4 , C 5 , or C 6 alkyl; -(CH 2 ) g -lieterocycle; - (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 - amino; or -(CH 2 ) j ⁇ heteroaryl, each of which may be substituted.
  • g is O, 1, 2, or 3.
  • h is 1, 2, or 3.
  • j is O, 1, 2, or 3.
  • i is O, 1, 2, or 3.
  • R 2 ] is methyl, C 2 -e alkyl,
  • Z is O. In another embodiment, Z is NH. In another embodiment, Z is S. In another embodiment, Z is absent such that the compound is represented by the formula (P):
  • R 2 i is methyl.
  • R 21 is hydrogen.
  • any one of R 7a or R 7 b is -OC(O)NRiR 2 and the other is hydrogen.
  • Ri and R 2 are the same as or different from each other and each is selected from hydrogen, Ci-Cn alkyl, C 2 -C 6 acyl, C 3 -C 6 alkenyl, unsaturated C 3 -C 8 acyl, C 5 -C 8 aryl, heteroaryl, Ci-C 6 alkylsulfonyl, benzenesulfonyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, methyl, -(CH 2 ) x -heteroaryl, -(CH 2 ) n - amino, and -(CH 2 ) y
  • n is 1, 2, or 3.
  • x is 1, 2, or 3.
  • y is 0, 1, 2, or 3.
  • Ri + R 2 together with the nitrogen atom to which Ri and R 2 are connected form a 3, 4, 5, 6, 7, or 8-membered ring, wherein the ring is a non-aromatic heterocyclic ring, wherein any of the atoms in the ring may be substituted.
  • Ri and R 2 are the same as or different from each other and each is selected from hydrogen, C 2 -C 6 alkyl, C 2 -C O acyl, methyl, -(CEb)y--heteiOcycle, -(CEk) n - amino, and -(CH 2 ) x -heteroaryl, each of which may be substituted.
  • Ri and R 2 are the same as or different from each other and each is selected from hydrogen, C 3 -C 8 cycloalkyl, C3-C 6 alkenyl, unsaturated Ci-Cg acyl, Cs-Cg aryl, heteroaryl, CrC 6 alkylsulfonyl, benzenesulfonyl, or C 3 -Cs cycloalkenyl, each of which may be substituted.
  • Ri + R 2 together with the nitrogen atom to which R] and R 2 are connected fo ⁇ n a 3, 4, 5, 6, 7, or 8-membered ring, wherein the ring is a non-aromatic heterocyclic ring, further 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.
  • the ring contains at least one heteroatom selected from O, N, or S.
  • the heterocyclic ring formed when Rj and R 2 are connected is selected from the group consisting of pyrrolidine, piperidine, azepane, and azocane, each of which may be substituted.
  • the heterocyclic ring fonned when Ri and R 2 are connected contains at least two nitrogen atoms.
  • the heterocyclic ring formed when Ri and R 2 are connected is selected from piperazine or homopiperazine, each of which may be substituted.
  • the heterocyclic ring formed when Rj and R 2 are connected is piperazine.
  • piperazine is substituted on the nitrogen atom located at the four position of the ring. In another embodiment, piperazine is substituted with methyl, C 2 -C 6 alkyl, C 3 -Cs cycloalkyl, or heteroaryl. In another embodiment, piperazine is substituted with pyridine. In another embodiment, piperazine is substituted with methyl. In another embodiment, piperazine is substituted with cyclohexyl.
  • any one of Ri Or R 2 is -(CH 2 ) x -heteroaryl, -(CH 2 ) y -heterocycle, or -(CH 2 ) n -amino and the other is hydrogen.
  • any one of Ri or R 2 is -(CH 2 ) x -heteroaryl and the other is hydrogen.
  • x is 1.
  • x is 2.
  • x is 3.
  • heteroaryl is pyridine.
  • any one of Ri or R 2 is-(CH 2 ) y -heterocycle and the other is hydrogen.
  • y is 0.
  • y is 1.
  • y is 2.
  • y is 3.
  • heterocycle is piperidine, pyrrolidine, morpholine, or piperazine, each of which may be substituted.
  • heterocycle is pyrrolidine.
  • heterocycle is piperidine.
  • heterocycle is morpholine.
  • heterocycle is piperazine.
  • piperazine is substituted on the nitrogen at the four position on the ring.
  • piperazine is substituted with methyl.
  • any one of Ri or R 2 is -(CH 2 ) n -amino and the other is hydrogen.
  • n is 1.
  • n is 2.
  • n is 3.
  • amino is -NH 2 , alkylamino, or dialkylamino.
  • amino is -NH 2 .
  • amino is dimethylamine.
  • any one of Ri or R 2 is C 3 -Cs cycloalkyl and the other is hydrogen. In another embodiment, C 3 -C 8 cycloalkyl is cyclohexyl. In one embodiment, each of Ri and R 2 is hydrogen. In another embodiment, each of Ri and R 2 is C]-C 6 alkyl. In another embodiment, each of Ri and R 2 is methyl. In one embodiment, any one of R 7a or R 7 b is -OC(O)ORs and the other is hydrogen.
  • Rs is C 2 -C O alkyl, C 3 -C 6 alkenyl, Cs-C 8 aryl, lieteroaryl, benzyl, -(CH 2 ) s -heteroaryl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, -(CH 2 ) u -heterocycle, or -(CH 2 ) r amino, 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.
  • any one of R 7a or R 7b is -OC(O)R 6 and the other is hydrogen.
  • R 6 is C 5 -C 8 aryl, heteroaryl, C 2 -C 6 alkyl, -(CH 2 ) g -heterocycle, -(CH 2 )j-C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl, -(CH 2 ) h -amino, -(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 6 is C 5 -C 8 aryl, C 2 -C 6 alkyl, or methyl. In one embodiment, R 6 is phenyl. In another embodiment, R 6 is ethyl. In another embodiment, taken together R 7a and R 7b form a carbonyl.
  • the compound is selected from:
  • Another aspect of the present invention is a compound according to formula II:
  • R d is -NH 2 or azide.
  • R 3 is Ci-C 6 alkyl, substituted Ci-C 6 alkyl, or silyl.
  • Silyl is R a R b R e Si-, wherein R a , R b , and R c are the same as or different from each other.
  • R a , R b , and R c represents methyl, ethyl, i-propyl, t-butyl, or phenyl.
  • R ⁇ a is methyl, Ci-C 6 alkyl, substituted Ci-C 6 alkyl, or hydrogen.
  • R 7a and R 7b are each, independently -OC(O)NRjR 2 , -OC(O)OR 5 , -OC(O)R 6 , hydroxyl, or hydrogen, or taken together R 7a and R 7b form a carbonyl.
  • Ri and R 2 are the same as or different from each other and each is selected from hydrogen;
  • C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 acyl C5, C 6 , C 7 , or C 8 aryl; heteroaryl; C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkylsulfonyl; benzenesulfonyl; C 3 , C 4 , C5, C 6 , C 7 , or C 8 cycloalkyl; C 3 , C 4 , C5, C 6 , C 7 , or Cg cycloalkenyl; methyl; -(CH 2 ) x -heteroaryl; -(CH 2 ) n -amino; or -(CH 2 ) y -heterocycle, each of which may be substituted.
  • n is O, 1, 2, or 3.
  • x is 1, 2, or 3.
  • y is 0, 1, 2, or 3.
  • R] + R 2 together with the nitrogen atom to which they are connected form a 3, 4, 5, 6, 7, or 8-membered ring, wherein the ring is a non-aromatic heterocyclic ring, wherein any of the atoms in the ring may be substituted.
  • R 5 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 -amino; 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 6 is Cs, C 6 , C 7 , or Cg aryl; heteroaryl; C 2 , C 3 , C 4 , C 5 , or C 6 alkyl; ⁇ (CH 2 ) g -heterocycle; -
  • Rn is methyl, CpC 6 alkyl or substituted Ci-C 6 alkyl, or silyl.
  • R 21 is Ci-C 6 alkyl or substituted Ci-C 6 alkyl.
  • 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 unsaruration e.g.,
  • a straight chain or branched alkyl has six or fewer carbon atoms in its backbone ⁇ e.g., methyl, C]-Cg for straight chain, C 3 -C 6 for branched chain).
  • a straight chain or branched alkyl has four or fewer carbon atoms in its backbone.
  • alkyl also includes both "unsubstituted” and “substituted allcyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbon of the hydrocarbon backbone.
  • substituents 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, sulfliydryl, alkylthio, arylthio, thiocarboxylate,
  • Alkyl also includes the side chains of natural and unnatural amino acids.
  • the term "Ci-C 6 alkyl” includes alkyl groups with 1, 2, 3, 4, 5, or 6 carbon atoms.
  • the term “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 multicyciic 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, isoqumoline, ⁇ " napthridine, indole, benzofuran, purine, benzofuran, deazapureiue, 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, piperazine, pyrazole, pyiimidine, furan, isoxazole, imidazole[2,l,b]thiazole, triazole, pyrazine, benzothiophene, imidazole, or thiophene.
  • aryl heterocycles e.g., pyridine, piperazine, pyrazole, pyiimidine, 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, cycloalkyl, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cyano, -NH 2 , alkylamino, dialkylarnino, arylamino, diarylaraino, and alkylarylamino, acyiamino (includmg alkylcarbonylamino, ary
  • 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), allcyl 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 O 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 O includes alkenyl groups containing 2, 3, 4, 5, or 6 carbon atoms.
  • C 3 -Cg 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 flirther 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., Cr-Ca for straight chain, C 3 -C 6 for branched chain).
  • C 2 -C O 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, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfliydryl, alkylthio, arylthio, thiocarboxylate, sulf
  • 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 alkylarylamino, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamo
  • 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, sulfhydryl, alkylthio, arylthio, thiocarboxylate, s
  • halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluorornethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.
  • Ci-C 6 alkoxy includes alkoxy groups which include 1, 2, 3, 4, 5, or 6 carbon atoms.
  • amino includes -NH 2 , alkylamino, and dialkylamino. For example, dialkylamino includes dimethylarnine.
  • 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.
  • 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, alkylthiocarbonyl, alkoxyl, cyano, -NH 2 , alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfon
  • 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 o
  • 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. In a preferred embodiment, 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.
  • One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient.
  • the dosage will also depend on the route of administration. A variety of routes are contemplated, 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, sulfinate, 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. Ciystal 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.
  • Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemical ⁇ controlled synthesis. Furthermore, the structures and other compounds and moieties discussed in this application also include all tautomers thereof. Alkenes can include either the E- or Z-geometry, where appropriate.
  • Atopic isomers are a type of stereoisomer in which the atoms of two isomers are arranged differently in space.
  • Atopic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond.
  • Such atopic 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 atopic 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 “macro lide 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 I or II 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). These cells are capable of presenting antigen to lymphocyte T-helpers, which control the development of an immune response. Thus, the expression of MHC class II molecules is the important to antigen presentation. Only a limited number of specialized cell types express MHC class II constitutively, numerous other cells become MHC class II positive upon stimulation, e.g., by a cytokine such as, for example, interferon gamma (IFN- ⁇ ).
  • 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, including a cell proliferative disorder.
  • a cell proliferative disorder refers to conditions in which the unregulated and/or abno ⁇ nal growth of cells can lead to the development of an unwanted condition or disease, which can be cancerous or noncancerous, 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 tumor cancers, 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 tumor cancers such as lung, pancreas, stomach, rectum, kidney, breast, cervical/uterine, testicular, colon, ovarian, prostate, head and neck, espophageal, malignant melanom
  • 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 or II 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 or II, 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, dermatomyositis- juvenile, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyos
  • 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 seborrheoic eczema, adult seborrheoic 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), Enbrel (Etanercept) and Hurnira (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 rumor 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 rumor 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 agent 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 the 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.
  • 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, or 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 be 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.
  • Stiitable 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
  • Suitable antioxidants and stabilizers include sodium bisulfite, sodium metabisulfite, sodium thiosulf ⁇ te, thiourea and the like.
  • Suitable wetting and clarifying agents include polysorbate 80, polysorbate 20, poloxamer 282 and tyloxapol.
  • Suitable viscosity-increasing agents include dextran 40, dextran 70, gelatin, glycerin, hydroxyethylcellulose, hydroxmethylpropylcellulose, 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
  • a sweetening agent such as sucrose, lactose or saccharin may be added or a flavor
  • compositions may be present as coatings or to otherwise modify the physical form of the dosage unit.
  • 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 parafin.
  • 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.
  • sweetening agents for example, glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • Topical application “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.
  • compounds of the invention are incorporated into a topical preparation suitable for pharmaceutical applications.
  • creams, ointments, jellies, hydrogels, salves, sprays, foams, mousse, aerosols, emulsions, • . nanoemulsions, microemulsion, solutions or suspensions are employed. Topical applications may include mouthwashes and gargles.
  • 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 earner is a water miscible carrier composition that is substantially miscible in water.
  • Such water miscible topical earner 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 emulsif ⁇ er 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.
  • 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.
  • the term "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.
  • drug substances such antiinflammatory agents, antibiotics, topical anesthetics, antimycotics, keratolytics, etc.
  • skin protectants or conditioners such as humectants, ultraviolet radiation absorbers and the like, depending on the intended uses for the formulation.
  • 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, trichlorofluoromethaiie, 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 lace 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 used 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.
  • 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.
  • 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. Compounds of the invention are assayed similarly.
  • N831 (A) (1.53 g, 2.70 mmol, isolated from the actinomycete mutant strain T658) and pyridinium />-toluenesulfonate (PPTS) (55.6 mg, 0.27 mmol) in anhydrous CH 2 Cl 2 (80 mL) was added ethyl vinyl ether (26 mL, 0.27 mol). The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography
  • the crude product was purified by silica gel column chromatography (elution with ethyl acetate-hexane 1:1, then gradient elution with chloroform-methanol 20:1 to 7:1), followed by purification with preparative HPLC (gradient elution; 4 mL/min; MeCN/H 2 O + 0.1% HCOOH; 15:85 to 24:76 over 29 min, 24:76 to 100:0 over 1 min; X-Terra ® MS Cl 8 column, 10x150 mm) to give the GM243 as a colourless oil (2 mg, 15%).
  • GM243 silica gel column chromatography
  • ketone 9 (6.4 mg, 8.53 ⁇ mol) was added pyridinium/»-toluenesulfonate (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%).

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Abstract

The present invention provides macrolide compounds, and pharmaceutically acceptable salts thereof, that inhibit MHC class II expression and that can be used as immunosuppressive agents 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.

Description

MACROLEDE COMPOSITIONS AS THERAPEUTIC AGENT
Field of the Invention
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.
Background of the Invention
The immune system is highly complex and tightly regulated, with many alternative pathways capable of compensating deficiencies in other parts of the system. There are however occasions when the immune response becomes a cause of disease or other undesirable conditions if activated. Such 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. In addition, the treatment of cancer has 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.
Accordingly, there exists a need for 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. Summary of the Invention
The present invention provides compositions 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 invention include a twelve-membered ring structure such as the twelve-membered ring shown below for the macrolide compound N831 (A).
Figure imgf000003_0001
The compounds of the present invention have been modified at the R7 position of the macrolide ring. This application is related to the application U.S. S.N. 60/721,556, filed September 28, 2005. The compounds of this related application have been modified at the Rn position of the macrolide ring.
The macrolide compounds of the invention include a twelve-membered ring. More particularly, the present invention includes a compound according to Formula (I):
Figure imgf000003_0002
or a pharmaceutically acceptable salt or individual diastereomer thereof, wherein Z is O, NH, S, or absent, such that when Z is absent the compound is represented by the formula (I')-"
Figure imgf000004_0001
Rd is -NH2 or azide.
R7a and R7b are each, independently -OC(O)NR]R2, -OC(O)OR5, -OC(O)R6, or hydrogen, or taken together R7a and R-^ form a carbonyl. Ri and R2 are the same as or different from each other and each is selected from: hydrogen;
C2, C3, C4, C5, or Ce alkyl; C2, C3, C4, C5, or C6 acyl; C3, C4, C5, or C6 alkenyl; unsaturated
C3, C4, C5, C6, C7, or C8 acyl; C5, C6, C7, or C8 aryl; heteroaryl; C1, C2, C3, C4, C5, or C6 alkylsulfonyl; benzenesulfonyl; C3, C4, C5, C6, C7, or Cg cycloalkyl; C3, C4, C5, C6, C7, or C8 cycloalkenyl; methyl; -(CH2)x-heteroaryl; -(CH2)n-amino; and -(CH2)y-heterocycle, each of which may be substituted. n is 1 , 2, or 3. x is 1, 2, or 3. y is 0, 1, 2, or 3.
Alternatively, Ri + R2 together with the nitrogen atom to which Ri and R2 are connected form a 3, 4, 5, 6, 7, or 8-membered ring, wherein the ring is a non-aromatic heterocyclic ring, wherein any of the atoms in the ring may be substituted.
R5 is C2, C3, C4, C5, or C6 alkyl; C3, C4, C5, or C6 alkenyl; C5, C6, C7, or C8 aryl; heteroaryl; benzyl; -(CH2)s-heteroaryl; C3, C4, C5, C6, C7, or C8 cycloalkyl; C3, C4, C5, C6, C7, or C8 cycloalkenyl; -(CH2)u-heterocycle; -(CH2)t-amino; or methyl, each of which may be substituted. s is 1, 2, or 3. t is l, 2, or 3. u is 0, 1, 2, or 3. R6 is C5, C6, C7, or C8 aryl; heteroaryl; C2, C3, C4, Cs9 or C6 alkyl; -(CH2)g-heterocycle; - (CH2)I-C3, C4, C5, C6, C7, or C8 cycloalkyl; C3, C4, C5, C6, C7, or C8 cycloalkyl; -(CH2)h- amino; or -(CH2)j-heteroaryl, 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. R21 is methyl, C2-6 alkyl, or hydrogen.
In one embodiment, Z is O. In another embodiment, Z is NH. In another embodiment, Z is S. In another embodiment, Z is absent such that the compound is represented by the formula (P):
Figure imgf000005_0001
(I')-
In one embodiment, R21 is methyl. In another embodiment, R2i is hydrogen. In another embodiment, any one of R7a or R^ is -OC(O)NRiR2 and the other is hydrogen. In a further embodiment, where R7a or R7b is -OC(O)NRiR2 and the other is hydrogen, R] and R2 are the same as or different from each other and each is selected from hydrogen, C2-C6 alkyl, C2-C6 acyl, C3-C6 alkenyl, unsaturated C3-C8 acyl, C5-C8 aryl, heteroaryl, Ci-C6 alkylsulfonyl, benzenesulfonyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, methyl, -(CH2)X -heteroaryl, -(CH2)n- amino, and -(CH2)y-heterocycle, each of which may be substituted. In one embodiment, n is 1, 2, or 3. In another embodiment, x is 1, 2, or 3. In another embodiment, y is 0, 1, 2, or 3. In another embodiment, Ri + R2 together with the nitrogen atom to which Ri and R2 are connected form a 3, 4, 5, 6, 7, or 8-membered ring, wherein the ring is a non-aromatic heterocyclic ring, wherein any of the atoms in the ring may be substituted. In one embodiment, Ri and R? are the same as or different from each other and each is selected from hydrogen, C2-C6 alkyl, C2-CO acyl, methyl,
Figure imgf000006_0001
-(CEk)n- amino, and -(CH2)x-heteroaryl, each of which may be substituted. In another embodiment, R1 and R2 are the same as or different from each other and each is selected from hydrogen, C3-Cs cycloalkyl, C3-Cg alkenyl, unsaturated C3-Cs acyl, Cs-Cg aryl, heteroaryl, CrC6 alkylsulfonyl, benzenesulfonyl, or C3-Cs cycloalkenyl, each of which may be substituted. In another embodiment, Ri + R2 together with the nitrogen atom to which Ri and R2 are connected form a 3, 4, 5, 6, 7, or 8-membered ring, wherein the ring is a non-aromatic heterocyclic ring, further wherein any of the atoms in the ring may be substituted. In one embodiment, the ring is a 3-membered ring. In one embodiment, the ring is a 4-membered ring. In another embodiment, the ring is a 5-membered ring. In another embodiment, the ring is a 6-membered ring. In another embodiment, the ring is a 7-membered ring. In another embodiment, the ring is an 8-membered ring. In another embodiment, the ring contains at least one heteroatom selected from O, N, or S. In one embodiment, the heterocyclic ring formed when Rj and R2 are connected is selected from the group consisting of pyrrolidine, piperidine, azepane, and azocane, each of which may be substituted. In another embodiment, the heterocyclic ring formed when Ri and R2 are connected contains at least two nitrogen atoms. In another embodiment, the heterocyclic ring formed when Ri and R2 are connected is selected from piperazine or homopiperazine, each of which may be substituted. In another embodiment, the heterocyclic ring formed when Rj and R2 are connected is piperazine. In one embodiment, piperazine is substituted on the nitrogen atom located at the four position of the ring. In another embodiment, piperazine is substituted with methyl, C2-Cg alkyl, C3-C8 cycloalkyl, or heteroaryl. In another embodiment, piperazine is substituted with pyridine. In another embodiment, piperazine is substituted with methyl. In another embodiment, piperazine is substituted with cyclohexyl.
In one embodiment, any one of Rj or R2 is -(CH2)x~heteroaryl, -(CH2)y-heterocycle, or -(CH2)n-amino and the other is hydrogen. In another embodiment, any one of Ri or R2 is -(CH2)x-heteroaryl and the other is hydrogen. In one embodiment, x is 1. In another embodiment, x is 2. Ih another embodiment, x is 3. In a further embodiment, heteroaryl is pyridine.
In one embodiment, any one of R] or R2 is-(CH2)y-heterocycle and the other is hydrogen. In another embodiment, y is 0. In another embodiment, y is 1. In another embodiment, y is 2. In another embodiment, y is 3. In one embodiment, heterocycle is piperidine, pyrrolidine, morpholine, or piperazine, each of which may be substituted. In another embodiment, heterocycle is pyrrolidine. In another embodiment, heterocycle is piperidine. In another embodiment, heterocycle is morpholine. In another embodiment, heterocycle is piperazine. In one embodiment, piperazine is substituted on the nitrogen at the four position on the ring. In another embodiment, piperazine is substituted with methyl. In one embodiment, any one of R] or R2 is -(CH2)n-amino and the other is hydrogen. In one embodiment, n is 1. In another embodiment, n is 2. In another embodiment, n is 3. In one embodiment, amino is -NH2, alkylamino, or dialkylamino. In another embodiment, amino is -NH2. In another embodiment, amino is dimethylamine.
In one embodiment, any one of Ri or R2 is Ci-Cz cycloalkyl and the other is hydrogen. In another embodiment, C3-Cs cycloalkyl is cyclohexyl. In one embodiment, each of Rj and R2 is hydrogen. In another embodiment, each of Ri and R2 is Ci -CO alkyl. In another embodiment, each of Ri and R2 is methyl. In one embodiment, any one of R7a or R7b is -OC(O)OR5 and the other is hydrogen.
R5 is C2-CO alkyl, C3-C6 alkenyl, C5-C8 aryl, heteroaryl, benzyl, ~(CH2)s-heteroaryl, C3-C8 cycloalkyl, C3-Cs cycloalkenyl, -(CH2)u-heterocycle, or -(CH2)t-amino, each of which may be substituted. In one embodiment, s is 1, 2, or 3. In another embodiment, t is 1, 2, or 3. In another embodiment, u is 0, 1, 2, or 3. In one embodiment, any one of R7a or R7b is -OC(O)R6 and the other is hydrogen. R6 is C5-C8 aryl., heteroaryl, C2-Cg alkyl, -(CH2)g-heterocycle, -(CH2)J-Ca-Cs cycloalkyl, C3-Cs cycloalkyl, -(CH2)h-amino, -(CH2)j-heteroaryl, or methyl, each of which may be substituted. In one embodiment, g is 0, 1, 2, or 3. In one embodiment, h is 1, 2, or 3. In another embodiment, j is 0, 1, 2, or 3. In another embodiment, i is 0, 1, 2, or 3. In one embodiment, R6 is C5-C8 aryl, C2-C6 alkyl, or methyl. In one embodiment, R6 is phenyl. In another embodiment, R6 is ethyl. In another embodiment, taken together R7a and R7b form a carbonyl.
In one embodiment, the compound is selected from
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000010_0001
Another aspect of the present invention is a compound according to formula II:
Figure imgf000010_0002
(H) or pharmaceutically acceptable salt or individual diastereomer. Z is O, NH, S, or absent, such that when Z is absent the compound is represented by the formula (IF):
Figure imgf000010_0003
Rd is -NH2 or azide.
R3 is Ci-Ce allcyl, substituted Ci -CO alkyl, or silyl.
Silyl is RaRbRcSi-, wherein Ra, Rb, and Rc are the same as or different from each other.
Each of Ra, Rb, and Rc represents methyl, ethyl, i-propyl, t-butyl, or phenyl. R6a is methyl, Ci -CO alkyl, substituted CpC6 alkyl, or hydrogen.
R7a and R7b are each, independently -OC(O)NRiR2, -OC(O)OR5, -OC(O)R6, hydroxyl, or hydrogen, or taken together R7a and R7^ form a carbonyl.
Ri and R2 are the same as or different from each other and each is selected from hydrogen;
C2, C3, C4, C5, or CO alkyl; C2, C3, C4, C5, or C6 acyl; C3, C4, C5, or C6 alkenyl; unsaturated C3, C4, C5, C6, C7, or C8 acyl; C5, C6, C7, or C8 aryl; heteroaryl; Ci, C2, C3, C4, C5, or C6 alkylsulfonyl; benzenesulfonyl; C3, C4, C5, C6, C7, or Cs cycloalkyl; C3, C4, C5, C6, C7, or Cg cycloalkenyl; methyl; -(CH2)x-heteroaryl; -(CHaVamino; or -(CH2)y-heterocycle, each of which may be substituted. n is O, I5 2, or 3. x is 1, 2, or 3. y is 0, 1, 2, or 3.
Alternatively, Ri + R2 together with the nitrogen atom to which they are connected form a
3, 4, 5, 6, 7, or 8-membered ring, wherein the ring is a non-aromatic heterocyclic ring, wherein any of the atoms in the ring may be substituted. R5 is C2, C3, C4, C5, or C6 alkyl; C3, C4, C5, or C6 alkenyl; C5, C6, C7, or C8 aryl; heteroaryl; benzyl; ~(CH2)s-heteroaryl; C3, C4, C5, C6, C7, or C8 cycloalkyl; C3, C4, C5, C6, C7, or C8 cycloalkenyl; -(CH2)u-heterocycle; -(CEfeVamino; 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.
R6 is C5, C6, C7, or C8 aryl; heteroaryl; C2, C3, C4, C5, or C6 alkyl; -(CH2)g-heterocycle; -
(CH2)rC3, C4, C5, C6, C7, or C8 cycloalkyl; C3, C4, C5, C6, C7, or C8 cycloalkyl; -(CH2)h- amino; -(CH2)j-heteroaryL each of which may be substituted. g is 0, 1, 2, or 3. h = 1, 2, or 3.
J = O, I, 2, or 3. i = 0, 1, 2, or 3. Ri7 is methyl, CrC6 alkyl or substituted Ci-Ce alkyl, or silyl. R21 is C1-Cg alkyl or substituted C]-Ce alkyl.
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 carrier 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. In another embodiment of the invention, the autoimmune disease is selected from systemic lupus erythematosus (SLE), systemic sclerosis (scleroderma), Sjδgren'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.
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.
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. 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), Sjδgren'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.
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.
In one embodiment, the macrolide used to treat an immune-related disorder is a racemic mixture of a macrolide compound of the present invention. In another embodiment, the macrolide used to treat an immune-related disorder is an enanriomerically pure form of a macrolide compound of the present invention.
In one embodiment, the macrolide used to treat an immune-related disorder is administered in combination with a second agent used to treat an immune-related disorder. In another embodiment, 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). In a further embodiment, 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.
In one embodiment, the macrolide is administered in combination with a second agent used to suppress an immune response associated with organ or tissue transplantation. In a further embodiment, 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. In another embodiment, the second agent is cyclosporin A, further wherein the cyclosporin A is cyclosporin microemulsion.
In another embodiment, the macrolide administered in combination with a second agent used to suppress an immune response is an enanriomerically pure form of a macrolide compound of the present invention. In another embodiment, 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. In another embodiment, the macrolide is administered in combination with a second agent used to inhibit tumor growth. The above description sets forth the present invention in order that the detailed description thereof that follows may be understood, and in order that the present contributions to the art may be better appreciated. Other objects and features of the present invention will become apparent from the following detailed description considered in conjunction with the examples.
Detailed Description of the Invention
The details of at least one embodiments of the invention are set forth in the accompanying description below. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the methods and materials of the present invention are now described. Other features, objects, and advantages of the invention will be apparent from the description. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the case of conflict, the present specification will control. 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 of a patient prior to, during and/or after organ or tissue transplantation.
The compositions of the invention include a compound that modulates and/or regulates an immune response. This compound is 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. Often, macrolides are glycosylated. The invention also includes ring-opened macrolides as represented by the structures below:
Figure imgf000015_0001
The macrolide compounds of the invention include a twelve-membered ring. More particularly, the present invention includes a compound according to Formula (I):
Figure imgf000015_0002
or a pharmaceutically acceptable salt or individual diastereomer thereof, wherein Z is O, NH, S, or absent, such that when Z is absent the compound is represented by the formula (I'):
Figure imgf000016_0001
Rd is -NH2 or azide. R7a and R7b are each, independently -OC(O)NR1 R2, -OC(O)OR5, -OC(O)R6, or hydrogen, or taken together R7a and R7^ form a carbonyl.
Ri and R2 are the same as or different from each other and each is selected from: hydrogen;
C2, C3, C4, C5, or Cβ alkyl; C2, C3, C4, C5, or CO acyl; C3, C4, C5, or C6 alkenyl; unsaturated
C3, C4, C5, C6, C7, or C8 acyl; C5, C6, C7, or Cg aryl; heteroaryl; C1, C2, C3, C4, C5, or C6 alkylsulfonyl; benzenesulfonyl; C3, C4, C5, Ce5 C7, or Cs cycloalkyl; C3, C4, C5, C6, C7, or Cg cycloalkenyl; methyl; -(CH2)x-heteroaryl; -(CH2)n-amino; and -(CH2)y-heterocycle, each of which may be substituted. n is 1, 2, or 3. x is 1, 2, or 3. y is O, 1, 2, or 3.
Alternatively, R1 + R2 together with the nitrogen atom to which Rj and R2 are connected form a 3, 4, 5, 6, 7, or 8-membered ring, wherein the ring is a non-aromatic heterocyclic ring, wherein any of the atoms in the ring may be substituted.
R5 is C2, C3, C4, C5, or Ce alkyl; C3, C4, C5, or Ce alkenyl; C5, C6, C7, or C8 aryl; heteroaryl; benzyl; -(CH2)s-heteroaryl; C3, C4, C5, C6, C7, or C8 cycloalkyl; C3, C4, C5, C6, C7, or C8 cycloalkenyl; -(CH2)u-heterocycle; -(CH2)ramino; 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. R6 is Cs, C(j, C7, or C8 aryl; heteroaryl; C2, C3, C4, C5, or C6 alkyl; -(CH2)g-lieterocycle; - (CH2)I-C3, C4, C5, C6, C7, or C8 cycloalkyl; C3, C4, C5, C6, C7, or C8 cycloalkyl; -(CH2)h- amino; or -(CH2)j~heteroaryl, each of which may be substituted. g is O, 1, 2, or 3. h is 1, 2, or 3. j is O, 1, 2, or 3. i is O, 1, 2, or 3. R2] is methyl, C2-e alkyl, or hydrogen.
In one embodiment, Z is O. In another embodiment, Z is NH. In another embodiment, Z is S. In another embodiment, Z is absent such that the compound is represented by the formula (P):
Figure imgf000017_0001
(H-
In one embodiment, R2i is methyl. In another embodiment, R21 is hydrogen. In another embodiment, any one of R7a or R7b is -OC(O)NRiR2 and the other is hydrogen. In a further embodiment, where R7a or R7b is -OC(O)NRiR2 and the other is hydrogen, Ri and R2 are the same as or different from each other and each is selected from hydrogen, Ci-Cn alkyl, C2-C6 acyl, C3-C6 alkenyl, unsaturated C3-C8 acyl, C5-C8 aryl, heteroaryl, Ci-C6 alkylsulfonyl, benzenesulfonyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, methyl, -(CH2)x-heteroaryl, -(CH2)n- amino, and -(CH2)y-heterocycle, each of which may be substituted. In one embodiment, n is 1, 2, or 3. In another embodiment, x is 1, 2, or 3. In another embodiment, y is 0, 1, 2, or 3. In another embodiment, Ri + R2 together with the nitrogen atom to which Ri and R2 are connected form a 3, 4, 5, 6, 7, or 8-membered ring, wherein the ring is a non-aromatic heterocyclic ring, wherein any of the atoms in the ring may be substituted. In one embodiment, Ri and R2 are the same as or different from each other and each is selected from hydrogen, C2-C6 alkyl, C2-CO acyl, methyl, -(CEb)y--heteiOcycle, -(CEk)n- amino, and -(CH2)x-heteroaryl, each of which may be substituted. In another embodiment, Ri and R2 are the same as or different from each other and each is selected from hydrogen, C3-C8 cycloalkyl, C3-C6 alkenyl, unsaturated Ci-Cg acyl, Cs-Cg aryl, heteroaryl, CrC6 alkylsulfonyl, benzenesulfonyl, or C3-Cs cycloalkenyl, each of which may be substituted. • In another embodiment, Ri + R2 together with the nitrogen atom to which R] and R2 are connected foπn a 3, 4, 5, 6, 7, or 8-membered ring, wherein the ring is a non-aromatic heterocyclic ring, further wherein any of the atoms in the ring may be substituted. In one embodiment, the ring is a 3-membered ring. In one embodiment, the ring is a 4-membered ring. In another embodiment, the ring is a 5-membered ring. In another embodiment, the ring is a 6-membered ring. In another embodiment, the ring is a 7-membered ring. In another embodiment, the ring is an 8-membered ring. In another embodiment, the ring contains at least one heteroatom selected from O, N, or S. In one embodiment, the heterocyclic ring formed when Rj and R2 are connected is selected from the group consisting of pyrrolidine, piperidine, azepane, and azocane, each of which may be substituted. In another embodiment, the heterocyclic ring fonned when Ri and R2 are connected contains at least two nitrogen atoms. In another embodiment, the heterocyclic ring formed when Ri and R2 are connected is selected from piperazine or homopiperazine, each of which may be substituted. In another embodiment, the heterocyclic ring formed when Rj and R2 are connected is piperazine. In one embodiment, piperazine is substituted on the nitrogen atom located at the four position of the ring. In another embodiment, piperazine is substituted with methyl, C2-C6 alkyl, C3-Cs cycloalkyl, or heteroaryl. In another embodiment, piperazine is substituted with pyridine. In another embodiment, piperazine is substituted with methyl. In another embodiment, piperazine is substituted with cyclohexyl.
In one embodiment, any one of Ri Or R2 is -(CH2)x-heteroaryl, -(CH2)y-heterocycle, or -(CH2)n-amino and the other is hydrogen. In another embodiment, any one of Ri or R2 is -(CH2)x-heteroaryl and the other is hydrogen. In one embodiment, x is 1. In another embodiment, x is 2. In another embodiment, x is 3. In a further embodiment, heteroaryl is pyridine.
In one embodiment, any one of Ri or R2 is-(CH2)y-heterocycle and the other is hydrogen. In another embodiment, y is 0. In another embodiment, y is 1. In another embodiment, y is 2. In another embodiment, y is 3. In one embodiment, heterocycle is piperidine, pyrrolidine, morpholine, or piperazine, each of which may be substituted. In another embodiment, heterocycle is pyrrolidine. In another embodiment, heterocycle is piperidine. In another embodiment, heterocycle is morpholine. In another embodiment, heterocycle is piperazine. In one embodiment, piperazine is substituted on the nitrogen at the four position on the ring. In another embodiment, piperazine is substituted with methyl. In one embodiment, any one of Ri or R2 is -(CH2)n-amino and the other is hydrogen. In one embodiment, n is 1. In another embodiment, n is 2. In another embodiment, n is 3. In one embodiment, amino is -NH2, alkylamino, or dialkylamino. In another embodiment, amino is -NH2. In another embodiment, amino is dimethylamine.
In one embodiment, any one of Ri or R2 is C3-Cs cycloalkyl and the other is hydrogen. In another embodiment, C3-C8 cycloalkyl is cyclohexyl. In one embodiment, each of Ri and R2 is hydrogen. In another embodiment, each of Ri and R2 is C]-C6 alkyl. In another embodiment, each of Ri and R2 is methyl. In one embodiment, any one of R7aor R7b is -OC(O)ORs and the other is hydrogen.
Rs is C2-CO alkyl, C3-C6 alkenyl, Cs-C8 aryl, lieteroaryl, benzyl, -(CH2)s-heteroaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, -(CH2)u-heterocycle, or -(CH2)ramino, each of which may be substituted. In one embodiment, s is 1, 2, or 3. In another embodiment, t is 1, 2, or 3. In another embodiment, u is 0, 1, 2, or 3. In one embodiment, any one of R7a or R7b is -OC(O)R6 and the other is hydrogen. R6 is C5-C8 aryl, heteroaryl, C2-C6 alkyl, -(CH2)g-heterocycle, -(CH2)j-C3-C8 cycloalkyl, C3-C8 cycloalkyl, -(CH2)h-amino, -(CH2)j-heteroaryl, or methyl, each of which may be substituted. In one embodiment, g is 0, 1, 2, or 3. In one embodiment, h is 1, 2, or 3. In another embodiment, j is 0, 1 , 2, or 3. In another embodiment, i is 0, 1, 2, or 3. In one embodiment, R6 is C5-C8 aryl, C2-C6 alkyl, or methyl. In one embodiment, R6 is phenyl. In another embodiment, R6 is ethyl. In another embodiment, taken together R7a and R7b form a carbonyl.
In one embodiment, the compound is selected from
Figure imgf000020_0001
Figure imgf000021_0001
20
Figure imgf000022_0001
Another aspect of the present invention is a compound according to formula II:
Figure imgf000022_0002
(H) or pharmaceutically acceptable salt or individual diastereomer. Z is O, NH, S, or absent, such that when Z is absent the compound is represented by the formula (IF):
Figure imgf000023_0001
(IF)
Rd is -NH2 or azide.
R3 is Ci-C6 alkyl, substituted Ci-C6 alkyl, or silyl. Silyl is RaRbReSi-, wherein Ra, Rb, and Rc are the same as or different from each other.
Each of Ra, Rb, and Rc represents methyl, ethyl, i-propyl, t-butyl, or phenyl.
Rόa is methyl, Ci-C6 alkyl, substituted Ci-C6 alkyl, or hydrogen.
R7a and R7b are each, independently -OC(O)NRjR2, -OC(O)OR5, -OC(O)R6, hydroxyl, or hydrogen, or taken together R7a and R7b form a carbonyl. Ri and R2 are the same as or different from each other and each is selected from hydrogen;
C2, C3, C4, C5, or C6 alkyl; C2, C3, C4, C5, or C6 acyl; C3, C4, C5, or C6 alkenyl; unsaturated
C3, C4, C5, C6, C7, or C8 acyl; C5, C6, C7, or C8 aryl; heteroaryl; C1, C2, C3, C4, C5, or C6 alkylsulfonyl; benzenesulfonyl; C3, C4, C5, C6, C7, or C8 cycloalkyl; C3, C4, C5, C6, C7, or Cg cycloalkenyl; methyl; -(CH2)x-heteroaryl; -(CH2)n-amino; or -(CH2)y-heterocycle, each of which may be substituted. n is O, 1, 2, or 3. x is 1, 2, or 3. y is 0, 1, 2, or 3.
Alternatively, R] + R2 together with the nitrogen atom to which they are connected form a 3, 4, 5, 6, 7, or 8-membered ring, wherein the ring is a non-aromatic heterocyclic ring, wherein any of the atoms in the ring may be substituted.
R5 is C2, C3, C4, C5, or C6 alkyl; C3, C4, C5, or C6 alkenyl; C5, C6, C7, or C8 aryl; heteroaryl; benzyl; -(CH2)s-heteroaryl; C3, C4, C5, C6, C7, or C8 cycloalkyl; C3, C4, C5, C6, C7, or C8 cycloalkenyl; -(CH2)u-heterocycle; -(CH2)t-amino; 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.
R6 is Cs, C6, C7, or Cg aryl; heteroaryl; C2, C3, C4, C5, or C6 alkyl; ~(CH2)g-heterocycle; -
(CHa)1-C3, C4, C5, C6, C7, or C8 cycloalkyl; C3, C4, C5, C6, C7, or C8 cycloalkyl; -(CH2)h- amino; -(CH2)j-heteroaryl, each of which may be substituted. g is 0, 1, 2, or 3. h = 1, 2, or 3.
J = O, 1, 2, or 3. i = 0, 1, 2, or 3.
Rn is methyl, CpC6 alkyl or substituted Ci-C6 alkyl, or silyl.
R21 is Ci-C6 alkyl or substituted Ci-C6 alkyl.
Some representative compounds of the invention are shown in Table 1. Table 1: Macrolide Compounds
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
For convenience, certain terms used in the specification, examples and appended claims are collected herein.
"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 unsaruration e.g.,
Figure imgf000028_0002
In certain embodiments, a straight chain or branched alkyl has six or fewer carbon atoms in its backbone {e.g., methyl, C]-Cg for straight chain, C3-C6 for branched chain). In another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms in its backbone. The term "alkyl" also includes both "unsubstituted" and "substituted allcyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbon of the hydrocarbon backbone. Such substituents 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, -NH2, alkylamino, dialkylamino, arylamino, diarlylamino, alkylarylamino, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfliydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, aminesulfoxide, sulfonamide, nitro, -CF3, halogen, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. "Alkyl" also includes the side chains of natural and unnatural amino acids. The term "Ci-C6 alkyl" includes alkyl groups with 1, 2, 3, 4, 5, or 6 carbon atoms. The term "C2-CO 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 multicyciic systems with at least one aromatic ring:" Examples of aryl groups include phenyl, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Furthermore, the term "aryl" includes multi-cyclic groups, e.g. , tricyclic, bicyclic, e.g. , naphthalene, benzoxazole, benzodioxazole, benzothizole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoqumoline, ~" napthridine, indole, benzofuran, purine, benzofuran, deazapureiue, or indolizine. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles", "heterocycles", "heterocyclyls", "heteroaryls" or "heteroaromatics" e.g., pyridine, piperazine, pyrazole, pyiimidine, 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, cycloalkyl, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cyano, -NH2, alkylamino, dialkylarnino, arylamino, diarylaraino, and alkylarylamino, acyiamino (includmg alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfliydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g. , tetralin, methylenedioxyphenyl) .
"Alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term "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), allcyl or alkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenyl groups. The term "alkenyl" further includes alkenyl groups, which include oxygen, nitrogen, or sulfur replacing one or more hydrocarbon backbone carbons. In certain embodiments, a straight chain or branched chain alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-CO for branched chain). Likewise, 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. The term "C2-CO" includes alkenyl groups containing 2, 3, 4, 5, or 6 carbon atoms. The term "C3-Cg" includes alkenyl groups containing 3, 4, 5, or 6 carbon atoms.
The teπn "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. Such 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, alkylsulfinyl, sulfonate, sulfamoyl, hydroxyl, nitro, trifluoromethyl, cyano, azido, phenyl, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. "Alkynyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, "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. The term "alkynyl" flirther includes alkynyl groups having oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more hydrocarbon backbone carbons. In certain embodiments, a straight chain or branched chain alkynyl group has six or fewer carbon atoms in its backbone (e.g., Cr-Ca for straight chain, C3-C6 for branched chain). The term "C2-CO alkynyl" includes alkynyl groups containing 2, 3, 4, 5, or 6 carbon atoms.
The term "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. Such 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, sulfliydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfϊnyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. "Acyl" includes compounds and moieties that contain the acyl radical (CH3CO-) 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, -NH2, alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfliydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfmyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. The term "alkoxycarbonyl" or "ester" includes compounds and moieties that contain an oxygen atom covalently linked to a carbonyl group (-OC(O)-). Examples of ester groups include -OC(O)CH3, -OC(O)CH2NH2.
The term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups (or alkoxyl radicals) include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of 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, -NH2, alkylamino, dialkylamino, aiylamino, diarylamino, and alkylarylamino, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, hydroxyl, nitiO, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluorornethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy. The term "Ci-C6 alkoxy" includes alkoxy groups which include 1, 2, 3, 4, 5, or 6 carbon atoms. The term "amino" includes -NH2, alkylamino, and dialkylamino. For example, dialkylamino includes dimethylarnine.
The term "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. Such 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, -NH2, alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaiyl, or an aromatic or heteroaromatic moiety. The term "C3-Cg cycloalkyl" includes cycloalkyl groups with 3, 4, 5, 6, 7, or 8 carbon atoms.
The terms "heterocycle," "'heterocyclyl," or "heterocyclic group" 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, alkylthiocarbonyl, alkoxyl, cyano, -NH2, alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonate, sulfamoyl, hydroxyl, nitro, trifluoromethyl, cyano, azido, heterocyclyl, or an aromatic or heteroaromatic moiety. 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, -CF3, or - CN, or the like.
The term "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, -NH2, alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfmyl, sulfonato, sulfamoyl, hydroxyl, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties.
The term "thiocarbonyl" or "thiocarboxy" includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.
The term "hydroxy" or "hydroxyl" includes groups with an -OH or -O".
The teπn "halogen" includes fluorine, bromine, chlorine, iodine, etc. The term "perhalogenated" generally refers to a moiety wherein all hydrogen atoms are replaced by halogen atoms.
The term "carbamoyl" includes compounds and moieties which include the following arrangement of atoms -NHC(O)O- or -OC(O)NH-.
The term "carbonate" includes compounds and moieties which include the following arrangement of atoms -OC(O)O-.
The term sulfonate includes compounds and moieties which contain the sulfate ion o
HO- -o-
° or a sulfone group. "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. In a preferred embodiment, 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. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, 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. In a preferred embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.
An "anionic group," as used herein, refers to a group that is negatively charged at physiological pH. Anionic groups include carboxylate, sulfate, sulfonate, sulfinate, 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. Classical and non-classical bioisosteres are known in the art (see, e.g., Silverman, R. B. The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc.: San Diego, Calif., 1992, pp.19-23). One example of an anionic group is a carboxylate.
The term "unstable 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). Examples of unstable functionalities include acetals and ketals. The terms "crystal polymorphs" or "polymorphs" refer to the existence of more than one crystal form for a compound, salt or solvate thereof. Ciystal polymorphs of the doxepin-analog compounds are prepared by crystallization under different conditions.
It will be noted that 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. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemical^ controlled synthesis. Furthermore, the structures and other compounds and moieties discussed in this application also include all tautomers thereof. Alkenes can include either the E- or Z-geometry, where appropriate.
Further, the structures and other compounds discussed in this application include all atopic isomers thereof. Atopic isomers are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atopic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atopic 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 atopic isomers in select cases. As used herein, the term "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). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.
As defined herein, the term "derivative", e.g., in the term "macro lide derivatives", refers to compounds that have a common core structure, and are substituted with various groups as described herein. For example, all of the compounds represented by formula are macrolide derivatives, and have one of formula I or II as a common core. The macrolide compositions of the invention are used as immunosuppression agents in organ or tissue transplantation. As used herein, "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. For example, 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). These cells are capable of presenting antigen to lymphocyte T-helpers, which control the development of an immune response. Thus, the expression of MHC class II molecules is the important to antigen presentation. Only a limited number of specialized cell types express MHC class II constitutively, numerous other cells become MHC class II positive upon stimulation, e.g., by a cytokine such as, for example, interferon gamma (IFN-γ).
These immunosuppressive macrolide compositions are administered to a subject prior to, during and/or after organ or tissue transplantation. For example, the macrolide compositions of the invention are used to treat or prevent rejection after organ or tissue transplantation.
In one embodiment, 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.
In addition, the macrolide compositions of the invention are used to treat or alleviate a symptom associated with cancer and cancer-related disorders, including a cell proliferative disorder. As used herein, the term "cell proliferative disorder" refers to conditions in which the unregulated and/or abnoπnal growth of cells can lead to the development of an unwanted condition or disease, which can be cancerous or noncancerous, for example a psoriatic condition. As used herein, the term "psoriatic condition" refers to disorders involving keratinocyte hyperproliferation, inflammatory cell infiltration, and cytokine alteration. In one embodiment, the cell proliferation disorder is cancer. As used herein, the term "cancer" includes solid tumor cancers, 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. In addition to psoriatic conditions, the types of 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. In one embodiment, proliferative diseases include dysplasias and disorders of the like. The compositions include a pharmaceutically acceptable carrier and a compound according to formula I or II or pharmaceutically acceptable salts or hydrates thereof.
The macrolide 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 or II, 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, dermatomyositis- juvenile, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, insulin-dependent diabetes mellitus, juvenile chronic arthritis (Still's disease), juvenile rheumatoid arthritis, Meniere's disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, Cyclospori anemia, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, Raynaud's phenomena, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma (progressive systemic sclerosis (PSS), also known as systemic sclerosis (SS)), Sjogren's syndrome, stiff- man syndrome, systemic lupus erythematosus, Takayasu arteritis, temporal arteritis/giant cell arteritis, ulcerative colitis, uveitis, vitiligo and Wegener's granulomatosis. Inflammatory disorders, include, for example, chronic and acute inflammatory disorders. Examples of 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 seborrheoic eczema, adult seborrheoic eczema, varicose eczema, and discoid eczema.
In one embodiment, 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), Enbrel (Etanercept) and Hurnira (Adalimumab). For example, in the treatment of rheumatoid arthritis, the macrolide compositions of the invention are co-administered with corticosteroids, methotrexate, cyclosporine A, statins, Remicade (Infliximab), Enbrel (Etanercept) and/or Humira (Adalimumab). In the treatment of uveitis, the macrolide compositions are administered in conjunction with, e.g., corticosteroids, methotrexate, cyclosporine A, cyclophosphamide and/or statins. Likewise, 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.
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. For example, 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.
As described above, 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. For example, 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 rumor 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 agent 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 the 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). In one embodiment, "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. In another embodiment, "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. For example, 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. Alternatively, for example, 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.) Where 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.
To evaluate whether a patient is benefiting from the administration of a macrolide, alone or in combination, one examines the patient's symptoms and/or immune response in a quantitative way, and compares the patient's symptoms and/or immune response before and after treatment with the macrolide compound. For example, a patient's symptom 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. In a successful treatment, 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. The term "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).
A variety of preparations 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. Among others, oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, intranasal, and intratracheal means can be used. The 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.
The preparation of pharmaceutical or pharmacological compositions will be known to those of skill in the art in light of the present disclosure. Typically, such 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.
For human administration, 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, or 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.
Upon formulation, 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. In this context, 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. For example, for parenteral administration, 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 be 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. In many cases, it will be preferable to include 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.
In some embodiments, compositions of the invention are formulated for 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. Typically, 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. Stiitable 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 metabisulfite, sodium thiosulfϊte, thiourea and the like. Suitable wetting and clarifying agents include polysorbate 80, polysorbate 20, poloxamer 282 and tyloxapol. Suitable viscosity-increasing agents include dextran 40, dextran 70, gelatin, glycerin, hydroxyethylcellulose, hydroxmethylpropylcellulose, 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) or similar oils, 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. Generally, 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. In the case of sterile powders for the preparation of sterile injectable solutions, 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.
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. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure.
The preparation of more, or highly, concentrated solutions for intramuscular injection is also contemplated. In this regard, the use of DMSO as solvent is preferred as this will result in extremely rapid penetration, delivering high concentrations of the active compound(s) or agent(s) to a small area.
Where the composition or combination therapy is given orally, it 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. The following list includes examples of 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. 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.
In certain defined embodiments, 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. For oral therapeutic administration, 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. 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 parafin. 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. For topical use, creams, ointments, jellies, hydrogels, salves, sprays, foams, mousse, aerosols, emulsions, •. nanoemulsions, microemulsion, solutions or suspensions are employed. Topical applications may include mouthwashes and gargles. In another embodiment, 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.
For topical administration, 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. Excipients include solvents, surfactants, emollients, preservatives, colorants, fragrances and the like. In one embodiment, the earner is a water miscible carrier composition that is substantially miscible in water. Such water miscible topical earner 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. The presence of an emulsifϊer 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. Thus, one function of an emulsifier is to provide a thickening or "bodying" to an emulsion. Typically, emulsifiers are molecules with non-polar parts and polar parts that are able to reside at the interface of two immiscible liquids. The term "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.
The 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, trichlorofluoromethaiie, 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. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. Preferably 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 lace 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.
Additional formulations 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. For suppositories, 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 used 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. In one embodiment, 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. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, 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. For example, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required. Pharmaceutical 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.
Although a therapeutically effective amount of a macrolide compound will vary according to the patient being treated, 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. In one embodiment, a dose contains between about 0.1 mg and 500 mg/kg per day of the compound. In another embodiment, 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. It will be understood, however, that 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. In some cases, where it may be necessary to use dosages outside of the stated ranges to treat a patient. Those cases will be apparent to the prescribing physician. Where it is necessary, a physician will also know how and when to interrupt, adjust or terminate treatment in conjunction with a response of a particular patient. The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims.
Examples Example 1: Cytotoxicity of Macrolide Compounds
The cytotoxicity of a number of the macrolide compounds of the invention and the reference compound, N831 (A), were 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 (IC50 values). The results of this evaluation are presented below in Table 2:
Table 2: MHCII Activity and Cytotoxicity of Macrolide Compounds
Figure imgf000051_0001
Figure imgf000052_0001
Example 3: In Vivo Studies with N831 (A)
N831(A) maximum tolerated close (MTD)
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 bodyweight, 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.
Nude mice bearing PC3 xenografts were placed into groups often animals each. 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 mm3 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. Compounds of the invention are assayed similarly.
Example 4: Synthesis of Macrolide Compounds
The compounds of this invention and related derivatives can be synthesized by methods known to one skilled in the art. Schemes 1-4, shown below, depict the synthesis of several macrolide compounds of the invention with various degrees of substitution. Characterization and detailed methods for synthesizing these compounds are described below. A representative synthesis of N831 (A) R7 carbamates derivatives is shown in Scheme 1. Scheme 1. General Procedure for the Syntheses of N831 (A) R7 Carbamates
Figure imgf000053_0001
ave overall yield 21%
To a solution of N831 (A) (1.53 g, 2.70 mmol, isolated from the actinomycete mutant strain T658) and pyridinium />-toluenesulfonate (PPTS) (55.6 mg, 0.27 mmol) in anhydrous CH2Cl2 (80 mL) was added ethyl vinyl ether (26 mL, 0.27 mol). The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography
(gradient elution with ethyl acetate-hexane 1:3 to 1:1) to give compound 1 as a colourless oil (1.82 g, 86%).
To a solution of compound 1 (1.65 g, 2.11 mmol) in methanol (60 mL) was added anhydrous K2CO3 (870 mg, 6.3 mmol). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (60 mL) and water (40 mL), and extracted with ethyl acetate (3 x 60 mL). The organic extracts were combined, dried with anhydrous MgSO4, filtered, and then concentrated under reduced pressure to afford compound 2 (1.49g, 98%).
To a solution of compound 2 (1.46 g, 1.97 mmol), 4-N,N-dimethylaminopyridine (DMAP) (72 mg, 0.59 mmol) and triethylamine (1.7 mL, 11.82 mmol) in anhydrous CH2Cl2 (40 mL) was added 4-iiitrophenylchloro formate (2.38 g, 11.82 mmol). The reaction mixture was stirred at room temperature until compound 2 was completely consumed. The reaction mixture was washed with saturated aqueous NaHCO3 (4 x 30 mL). The organic layer was dried with anhydrous MgSO4, filtered, and then concentrated under reduced pressure. To a solution of crude carbonate (0.2 mmol) in anhydrous THF (4 mL) was added the respective amine (0.5 mmol). The reaction mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (gradient elution with ethyl acetate-hexane, then chloroform- methanol) to give compound 3. Deprotection of compound 3 (0.1-0.2 mmol) was carried out in methanol (4 mL) and PPTS (20-25 mg). The reaction mixture was stirred at room temperature for 2 to 18 hours and then concentrated under reduced pressure. The residue was taken into CH2Cl2 (5 mL) and washed with saturated aqueous NaHCO3 (3 mL). The organic layer was dried with anhydrous MgSO4, filtered, and then concentrated under reduced pressure. The crude product was purified by preparative TLC (ethyl acetate-hexane or chloroform-methanol) to give the corresponding C7-carbamate analogue.
Compound 1 (mixture of diastereomers)
Figure imgf000054_0001
1H NMR (500 MHz, CDCl3) £0.87 (3H, m), 0.88 (6H, m), 1.15 (9H, m), 1.19 (3H, m), 1.21 (3H, m), 1.30 (9H, m), 1.33 (IH, m), 1.42 (IH, m), 1.44 (IH, m), 1.48 (IH, m), 1.54 (IH, m)5 1.65 (IH, m), 1.70 (IH, m), 1.71 (3H, m), 2.09 (3H, m), 2.51 (2H, m), 2.55 (IH3 m), 2.56 (IH, m), 2.73-2.79 (2H, m), 3.04-3.15 (IH, m), 3.19 (IH, m), 3.41 (3H, s), 3.49-3.58 (6H, m), 3.74-3.87 (IH, m), 4.67-4.98 (3H, m), 4.94-5.00 (IH, m), 5.09 (IH, m), 5.63 (IH, m), 5.67 (IH, m), 5.73 (IH, m), 6.09 (IH, m), 6.25 (IH, m); (+)-HR-ESIMS m/z 805.5094 [M+Na]+ Compound 2 (mixture of diastereomers)
Figure imgf000055_0001
1H NMR (500 MHz, CDCl3) 50.87 (3H, m), 0.88 (6H, m), 1.13 (3H, m), 1.14-1.19 (9H, m), 1.16-1.33 (12H, m), 1.31 (IH, m), 1.40 (IH, m), 1.41 (2H, m), 1.42 (IH, m), 1.60 (IH, m), 1.63 (IH5 m), 1.71 (3H, m), 2.37, 2.53, 2.56 (2H, m), 2.50 (2H, m), 2.72, 2.77 (2H, m), 3.02, 3.13 (IH, m), 3.18 (IH, m), 3.39 (3H, s), 3.47-3.77 (6H, m), 3.58, 3.65 (IH, m), 3.68, 3.81 (IH, m), 4.13 (IH, m), 4.77-5.00 (3H, m), 4.93, 5.00 (IH, m), 5.39 (IH, m), 5.71 (2H, m), 6.08 (IH, br d, J= 8.9 Hz), 6.25 (IH, m); (+)-HR-ESIMS m/z 758.5317 [M+NH4]+
GMl 24
Figure imgf000055_0002
1H NMR (500 MHz, CDCl3) 50.86 (3H, d, J= 6.9 Hz), 0.87 (3H, d, J= 7.2 Hz), 0.88 (3H, t, J= 7.5 Hz), 1.13 (3H, d, J= 6.8 Hz), 1.24 (3H, s), 1.32 (IH, m), 1.34 (IH, m), 1.40 (IH, m), 1.46 (IH, m), 1.52 (IH, m), 1.63 (IH, m), 1.70 (IH, m), 1.72 (3H, s), 2.48 (IH, m), 2.51 (IH, m), 2.52 (IH, dd, J= 14.9, 2.7 Hz), 2.59 (IH, dd, J= 14.9, 3.5 Hz), 2.79 (IH, dd, J = 5.5, 2.2 Hz), 2.88 (IH5 dd, J= 8.2, 2.2 Hz), 3.16 (IH, ddd, J= 6.4, 6.4, 4.1 Hz), 3.27 (IH, dd, J= 6.7, 5.5 Hz), 3.38 (3H, s), 3.74 (IH, m), 4.93 (2H, s), 4.95 (IH, d, J= 9.6 Hz), 5.13 (IH, d, J= 10.7 Hz), 5.62 (IH, dd, J= 15.2, 9.7 Hz), 5.68 (IH, m), 5.70 (IH, m), 6.07 (IH, d, J = 10.8 Hz), 6.30 (IH, dd, J = 15.0, 10.8 Hz); 13C NMR (125 MHz, CDCl3) δ 11.0, 11.3, 12.7, 17.4, 17.5, 24.6, 25.5, 30.8, 36.4, 39.3, 39.8, 41.6, 43.1, 59.1, 60.4, 61.1, 70.1, 74.6, 75.7, 80.6, 83.6, 84.6, 126.7, 127.2, 131.9, 132.4, 138.2, 141.1, 156.9, 172.9; (+)-HR- ESIMS m/z 590.3226 [M+Na]+
GM128
Figure imgf000056_0001
1H NMR (500 MHz, CDCl3) 50.87 (3H, d, J= 6.9 Hz), 0.88 (3H, d, J= 6.5 Hz), 0.89 (3H, t, J= 7.5 Hz), 1.14 (3H, d, J= 6.8 Hz), 1.24 (3H, s), 1.30 (IH, m), 1.32 (IH, m), 1.40 (IH, m), 1.45 (IH, m), 1.52 (IH, m), 1.63 (IH, m), 1.69 (IH, m), 1.73 (3H, s), 2.48 (IH, m), 2.49 (IH, m), 2.52 (IH, dd, J= 15.0, 2.5 Hz), 2.62 (IH, dd, J= 15.0, 3.5 Hz), 2.80 (IH, dd, J = 5.4, 2.2 Hz), 2.90 (IH, dd, J= 8.2, 2.2 Hz), 3.17 (IH, ddd, J= 6.4, 6.4, 4.1 Hz), 3.28 (IH, dd, J= 6.7, 5.4 Hz), 3.39 (3H, s), 3.75 (IH, m), 4.38 (2H, d, J= 5.8 Hz), 4.99 (IH, d, J = 9.4 Hz), 5.14 (IH, d, J= 10.7 Hz), 5.45 (IH, br t, J= 6.8 Hz), 5.61 (IH, dd, J= 15.1, 9.9 Hz), 5.68 (IH, dd, J= 15.1, 9.4 Hz), 5.69 (IH, dd, J= 15.1, 8.6 Hz), 6.08 (IH, d, J= 10.8 Hz), 6.30 (IH, dd, J- 15.1, 10.9 Hz), 7.27 (IH, dd, J= 7.8, 7.8 Hz), 7.64 (IH, d, J = 7.8 Hz), 8.52 (2H, br m); 13C NMR (125 MHz, CDCl3) 511.0, 11.3, 12.7, 17.4, 17.5, 24.6, 25.5, 30.8, 36.4, 39.3, 39.8, 41.7, 43.1, 43.6, 59.1, 60.3, 61.0, 70.1, 74.6, 75.6, 80.8, 83.6, 84.6, 124.6, 126.8, 127.2, 132.0, 132.4, 135.2, 136.5, 138.3, 141.2, 149.7, 156.6, 173.0; (+)~HR- ESIMS m/z 659.3953 [M+H]+
GM164
Figure imgf000056_0002
1H NMR (500 MHz, CDCl3) 50.88 (3H, d, J= 6.1 Hz), 0.90 (3H, d, J= 7.0 Hz), 0.91 (3H, t, J= 7.6 Hz), 1.15 (3H, d, J= 6.8 Hz), 1.25 (3H, s), 1.32 (IH, m), 1.36 (IH, m), 1.41 (IH, m), 1.47 (IH, m), 1.55 (IH, m), 1.66 (IH, m), 1.70 (IH, m), 1.75 (3H, s), 2.06 (IH, br s), 2.50 (IH, m), 2.51 (IH, m), 2.55 (IH, dd, J= 14.9, 2.9 Hz), 2.62 (IH, dd, J= 14.9, 3.7 Hz), 2.82 (IH, dd, J= 5.2, 2.2 Hz), 2.91 (IH, dd, J= 8.3, 2.2 Hz), 2.94 (6H, s), 3.18 (IH, ddd, J = 6.4, 6.4, 4.1 Hz), 3.32 (IH, dd, J = 5.9, 5.2 Hz), 3.41 (3H, s), 3.53 (IH, br s), 3.76 (IH, ni), 5.00 (IH, d, J- 9.6 Hz), 5.15 (IH, d, J= 10.6 Hz), 5.61 (IH, dd, J= 15.2, 9.8 Hz), 5.69 (IH, m), 5.71 (IH, m), 6.10 (IH, d, J= 10.8 Hz), 6.32 (IH, dd, J= 15.0, 10.8 Hz); 13C NMR (125 MHz, CDCl3) 511.0, 11.3, 12.8, 17.48, 17.52, 24.7, 25.8, 27.9, 30.8, 36.2, 37.0, 37.7, 39.4, 39.9, 41.7, 43.2, 59.1, 60.3, 60.9, 70.2, 74.8, 75.6, 80.9, 83.6, 84.6, 127.2, 127.3, 131.9, 132.6, 138.1, 140.8, 156.4, 173.0; (÷)-HR-ESIMS m/z 618.3624 [M+Na]+
GM201
Figure imgf000057_0001
1H NMR (500 MHz, CDCl3) £0.89 (3H, d, J= 7.1 Hz), 0.90 (3H, d, J= 6.2 Hz), 0.91 (3H, t, J= 7.3 Hz), 1.16 (3H, d, J= 6.8 Hz), 1.27 (3H, s), 1.32 (IH, m), 1.37 (IH, m), 1.42 (IH, m), 1.47 (IH, m), 1.57 (IH, m), 1.66 (IH, m), 1.73 (IH, m), 1.75 (3H, s), 2.02 (2H, br s), 2.50 (IH, m), 2.51 (IH, m), 2.54 (IH, dd, J= 14.9, 2.8 Hz), 2.63 (IH, dd, J= 14.9, 3.7 Hz), 2.82 (IH, dd, J= 5.2, 2.3 Hz), 2.91 (IH, dd, J= 8.2, 2.3 Hz), 3.18 (IH, ddd, J= 6.4, 6.4, 4.0 Hz), 3.31 (IH, dd, J= 5.7, 5.2 Hz), 3.41 (3H, s), 3.59 (4H, m), 3.63 (4H, m), 3.78 (IH, m), 5.06 (IH, d, J = 9.6 Hz), 5.17 (IH, d, J = 10.7 Hz), 5.63 (IH, dd, J = 15.2, 9.8 Hz), 5.70 (IH, dd, J= 15.1, 8.7 Hz), 5.73 (IH5 dd, J= 15.2, 9.6 Hz), 6.10 (IH, d, J= 10.8 Hz), 6.33 (IH, dd, J= 15.1, 10.8 Hz), 6.69 (2H, m), 7.54 (IH, t, J= 8.2 Hz), 8.21 (IH, m); 13C NMR (125 MHz, CDCl3) δ 11.0, 11.3, 12.7, 17.5, 24.7, 25.8, 30.8, 36.4, 39.4, 39.9, 41.7, 43.2, 44.6, 46.2, 59.1, 60.3, 60.9, 70.2, 74.8, 75.6, 81.3, 83.6, 84.6, 108.5, 114.8, 127.0, 127.3, 132.0, 132.5, 138.2, 139.0, 141.1, 148.5, 155.4, 159.7, 173.0; (+)-HR-ESIMS m/z 714.4325 [M+H]+ GM202
Figure imgf000058_0001
1H NMR (500 MHz, CDCl3) 50.89 (3H, d, J= 7.3 Hz), 0.90 (3H, d, J= 6.2 Hz), 0.91 (3H, t, J= 7.3 Hz), 1.16 (3H, d, J= 6.8 Hz), 1.25 (3H, s), 1.31 (IH, m), 1.38 (IH, m), 1.42 (IH, m), 1.47 (IH, m), 1.55 (IH, m), 1.65 (IH, m), 1.72 (IH, m), 1.75 (3H, s), 2.38 (3H, s), 2.48 (4H, m), 2.50 (IH, m), 2.53 (IH, m), 2.55 (IH, dd, J= 14.9, 2.9 Hz), 2.63 (IH, dd, J= 14.9, 3.6 Hz), 2.82 (IH, dd, J= 5.2, 2.2 Hz), 2.91 (IH, dd, J = 8.2, 2.2 Hz), 3.19 (IH, ddd, J = 6.4, 6.4, 4.1 Hz), 3.32 (IH, dd, J = 6.5, 5.2 Hz), 3.42 (3H, s), 3.57 (4H, m), 3.77 (IH, m), 5.03 (IH, d, J = 9.6 Hz), 5.16 (IH, d, J = 10.7 Hz), 5.62 (IH, dd, J = 15.2, 9.7 Hz), 5.70 (IH, dd, J= 15.1, 8.7 Hz), 5.71 (IH, dd, J= 15.2, 9.6 Hz), 6.10 (IH, d, J= 10.8 Hz), 6.33 (IH, dd, J = 15.1, 10.8 Hz); 13C NMR (125 MHz, CDCl3) 5 11.0, 11.3, 12.8, 17.5, 24.7, 25.7, 30.9, 36.4, 39.4, 39.9, 41.7, 43.2, 44.6, 46.9, 55.6, 59.2, 60.3, 60.9, 70.2, 74.8, 75.5, 81.1, 83.6, 84.6, 127.0, 127.3, 132.0, 132.5, 138.2, 141.1, 155.3, 173.0; (+)-HR-ESIMS m/z 651.4288 [M+H]+
GM221
Figure imgf000058_0002
1H NMR (500 MHz, CDCl3) 50.86 (3H, d, J= 6.8 Hz), 0.88 (3H, d, J= 6.9 Hz), 0.89 (3H, t, J= 7.5 Hz), 1.11 (IH, m), 1.14 (3H, d, J= 6.8 Hz), 1.20 (2H, m), 1.22 (3H, s), 1.22 (2H, m), 1.36 (IH, m), 1.37 (IH, m), 1.40 (IH, m), 1.46 (IH, m), 1.55 (IH, m), 1.64 (IH, m), 1.65 (IH, m), 1.69 (IH, m), 1.73 (3H, s), 1.81 (2H, m), 1.84 (2H, m), 2.28 (IH, m), 2.47 (IH, m), 2.51 (IH, m), 2.53 (4H, m), 2.54 (IH, m), 2.60 (IH, dd, J= 14.8, 3.6 Hz), 2.79 (IH, dd, J= 5.4, 2.3 Hz), 2.89 (IH, dd, J= 8.2, 2.3 Hz), 3.16 (IH, ddd, J= 6.4, 6.4, 4.1 Hz), 3.28 (IH, dd, J= 6.8, 5.4 Hz), 3.39 (3H, s), 3.48 (4H, m), 3.73 (IH, m), 5.00 (IH, d, J= 9.6 Hz), 5.14 (IH, d, J= 10.7 Hz), 5.59 (IH, dd, J= 15.2, 9.8 Hz), 5.67 (IH, dd, J= 15.0, 9.2 Hz), 5.70 (IH, dd, J= 15.2, 9.6 Hz), 6.08 (IH, d, J= 10.8 Hz), 6.30 (IH, dd, J= 15.0, 10.8 Hz); 13C NMR (125 MHz, CDCl3) δ 11.0, 11.3, 12.8, 17.49, 17.52, 24.7, 25.7, 26.8, 27.2, 29.7, 30.8, 36.3, 39.3, 39.9, 41.7, 43.2, 45.3, 49.7, 59.1, 60.3, 60.9, 64.8, 70.2, 74.8, 75.6, 80.9, 83.6, 84.6, 127.1, 127.3, 131.9, 132.5, 138.2, 140.9, 155.3, 173.0; (+)-HR-ESIMS m/z 719.4818 [M+H]+
GM223
Figure imgf000059_0001
1H NMR (500 MHz, CDCl3) (50.89 (3H, d, J= 6.8 Hz), 0.89 (3H, d, J= 6.8 Hz), 0.91 (3H, t, J= 7.4 Hz), 1.16 (3H, d, J= 6.8 Hz), 1.25 (3H, s), 1.35 (IH, m), 1.35 (IH, m), 1.42 (IH, m), 1.47 (IH, m), 1.53 (IH, m), 1.66 (IH, m), 1.69 (2H, m), 1.70 (IH, m), 1.75 (3H, s), 2.26 (6H, s), 2.39 (2H, br t, J= 5.6 Hz), 2.48 (IH, m), 2.50 (IH, m), 2.54 (IH, dd, J= 14.9, 2.7 Hz), 2.62 (IH, dd, J= 14:9, 3.6 Hz), 2.82 (IH, dd, J= 5.2, 2.2 Hz), 2.91 (IH, dd, J= 8.2, 2.2 Hz), 3.18 (IH, ddd, J= 6.4, 6.4, 4.1 Hz), 3.29 (2H, m), 3.32 (IH, dd, J= 6.7, 5.2 Hz), 3.41 (3H, s), 3.76 (IH, m), 4.98 (IH, d, J= 9.6 Hz), 5.15 (IH, d, J= 10.7 Hz), 5.60 (IH, dd, J= 15.1, 9.7 Hz), 5.70 (IH, dd, J= 15.1, 9.6 Hz), 5.70 (IH, dd, J= 15.1, 8.7 Hz), 6.09 (IH, d, J= 10.8 Hz), 6.32 (IH, dd, J= 15.1, 10.8 Hz); 13C NMR (125 MHz, CDCl3) 511.0, 11.3, 12.7, 17.45, 17.53, 24.6, 25.6, 27.9, 30.8, 36.3, 39.3, 39.8, 41.0, 41.6, 43.2, 46.2, 58.6, 59.1, 60.3, 61.1, 70.2, 74.6, 75.7, 80.1, 83.6, 84.6, 127.19, 127.22, 131.9, 132.5, 138.2, 140.6, 156.6, 173.0; (+)-HR-ESIMS m/z 653.4325 [M+H]+
GM224
Figure imgf000059_0002
1H NMR (500 MHz, CDCl3) «50.88 (3H, d, J = 6.9 Hz), 0.89 (3H, d, J= 6.9 Hz), 0.90 (3H, t, J= 6.7 Hz), 1.15 (3H, d, J= 6.8 Hz), 1.25 (3H, s), 1.32 (IH, m), 1.34 (IH, m), 1.42 (IH, m), 1.48 (IH, m), 1.53 (IH, m), 1.65 (IH, m), 1.71 (IH, m), 1.74 (3H, s), 1.81 (4H, m), 2.49 (IH, m), 2.52 (IH, m), 2.56 (IH5 m), 2.59 (4H, m), 2.64 (IH, m), 2.65 (2H, m), 2.81 (IH, dd, J= 5.3, 1.9 Hz), 2.90 (IH, dd, J= 8.2, 1.9 Hz), 3.18 (IH, ddd, J= 6.3, 6.3, 4.1 Hz), 3.29 (IH, dd, J= 6.2, 5.3 Hz), 3.33 (2H, m), 3.41 (3H, s), 3.74 (IH, m), 4.99 (IH, d, J= 9.7 Hz), 5.15 (IH, d, J= 10.7 Hz), 5.51 (IH, br s), 5.59 (IH5 dd, J= 15.1, 9.8 Hz), 5.69 (IH, dd, J= 15.1, 9.7 Hz), 5.70 (IH, dd, J= 15.1, 8.4 Hz), 6.09 (IH, d, J= 10.8 Hz), 6.32 (IH, dd, J = 15.1, 10.8 Hz); 13C NMR (125 MHz, CDCl3) 510.9, 11.3, 12.7, 17.4, 17.6, 24.3, 24.6, 25.5, 30.7, 36.3, 39.3, 39.8, 40.3, 41.6, 43.1, 54.9, 56.1, 59.1, 60.4, 61.2, 70.2, 74.6, 75.8, 80.1, 83.6, 84.5, 127.2, 127.3, 131.9, 132.5, 138.2, 140.5, 156.5, 172.9; (+)-HR-ESIMS m/z 665.4340 [M+H]+
GM225
Figure imgf000060_0001
1H NMR (500 MHz, CDCl3) 50.87 (3H, d, J= 6.9 Hz), 0.88 (3H, d, J= 6.6 Hz), 0.89 (3H, t, J= 7.5 Hz), 1.14 (3H, d, J= 6.8 Hz), 1.25 (3H, s), 1.32 (IH, m), 1.34 (IH, m), 1.41 (IH, m), 1.47 (IH, m), 1.53 (IH, m), 1.65 (IH, m), 1.71 (IH, m), 1.74 (3H, s), 2.48 (4H, m), 2.49 (IH, m), 2.50 (2H, m), 2.52 (IH, m), 2.54 (IH, dd, J= 14.9, 2.4 Hz), 2.61 (IH, dd, J= 14.9, 3.5 Hz), 2.80 (IH, dd, J= 5.3, 2.2 Hz), 2.90 (IH, dd, J= 8.2, 2.2 Hz), 3.17 (IH, ddd, J = 6.3, 6.3, 4.1 Hz), 3.28 (IH, m), 3.31 (2H, m), 3.40 (3H, s), 3.72 (4H, m), 3.76 (IH, m), 4.99 (IH, d, J = 9.7 Hz), 5.15 (IH, d, J= 10.7 Hz), 5.28 (IH, br s), 5.60 (IH, dd, J= 15.1, 9.8 Hz), 5.70 (IH, dd, J= 15.1, 9.7 Hz), 5.69 (IH, dd, J= 15.1, 8.6 Hz), 6.08 (IH, d, J = 10.8 Hz), 6.31 (IH, dd, J= 15.1, 10.8 Hz); 13C NMR (125 MHz, CDCl3) 510.9, 11.3, 12.7, 17.4, 17.5, 24.6, 25.5, 30.7, 36.4, 38.1, 39.3, 39.8, 41.6, 43.1, 54.3, 58.6, 59.0, 60.4, 61.1, 67.6, 70.1, 74.6, 75.7, 80.2, 83.6, 84.5, 127.0, 127.1, 131.9, 132.4, 138.2, 140.7, 156.4, 172.9; (+)-HR-ESIMS m/z 681.4324 [M+H]+ GM226
Figure imgf000061_0001
1H NMR (500 MHz, CDCl3) δ 0.87 (3H, d, J = 6.9 Hz), 0.89 (3H, d, J= 6.7 Hz), 0.90 (3H, t, J= 7.4 Hz), 1.15 (3H, d, J= 6.8 Hz), 1.25 (3H, s), 1.32 (IH, m), 1.34 (IH, m), 1.42 (IH, m), 1.46 (IH, m), 1.53 (IH, m), 1.65 (IH, m), 1.70 (IH, m), 1.74 (3H, s), 2.28 (6H, s) 2.47 (2H, m) 2.48 (IH, m), 2.50 (IH, m), 2.50 (IH, dd, J= 14.9, 2.6 Hz), 2.61 (IH, dd, J= 14.9, 3.6 Hz), 2.80 (IH, dd, J = 5.3, 2.3 Hz), 2.90 (IH, dd, J- 8.2, 2.3 Hz), 3.18 (IH, ddd, J = 6.4, 6.4, 4.1 Hz), 3.30 (3H, m), 3.40 (3H, s), 3.73 (IH, m), 4.98 (IH, d, J= 9.6 Hz), 5.15 (IH, d, J= 10.7 Hz), 5.4 (IH, br t, J= 5.4 Hz) 5.59 (IH, dd, J= 15.1, 9.8 Hz), 5.69 (IH, dd, J= 15.1, 9.6 Hz), 5.69 (IH, dd, J= 14.9, 8.8 Hz), 6.09 (IH, d, J= 10.8 Hz), 6.32 (IH, dd, J = 14.9, 10.8 Hz); 13C NMR (125 MHz, CDCl3) δ 11.0, 11.3, 12.8, 17.5, 17.6, 24.7, 25.6, 30.8, 36.3, 39.1, 39.3, 39.9, 41.7, 43.2, 46.0, 59.0, 59.1, 60.3, 61.0, 70.2, 74.6, 75.7, 80.2, 83.6, 84.6, 127.2, 127.3, 131.9, 132.6, 138.2, 140.6, 156.5, 173.0; (+)-HR-ESIMS m/z 639.4156 [M+H]+
GM227
Figure imgf000061_0002
1H NMR (500 MHz, CDCl3) £0.88 (3H, d, J= 6.8 Hz), 0.88 (3H, d, J = 6.8 Hz), 0.90 (3H, t, J= 7.4 Hz), 1.14 (3H, d, J= 6.8 Hz), 1.24 (3H, s), 1.32 (IH, m), 1.35 (IH, m), 1.42 (IH, m), 1.48 (3H, m), 1.53 (IH, m), 1.61 (4H, m) 1.65 (IH, m), 1.70 (IH, m), 1.74 (3H, s), 2.48 (4H, m), 2.50 (2H, m), 2.51 (IH, m), 2.53 (IH, m), 2.54 (IH, dd, J = 14.9, 2.7 Hz), 2.62 (IH, dd, J = 14.9, 3.7 Hz), 2.81 (IH, dd, J = 5.2, 2.3 Hz), 2.90 (IH, dd, J = 8.2, 2.3 Hz), 3.18 (IH, ddd, J= 6.4, 6.4, 4.1 Hz), 3.30 (3H, m), 3.40 (3H, s), 3.75 (IH, m), 4.98 (IH, d, J = 9.7 Hz), 5.14 (IH, d, J= 10.7 Hz), 5.42 (IH, br s), 5.58 (IH, dd, J= 15.1, 9.9 Hz), 5.68 (IH, dd, J= 15.0, 8.9 Hz), 5.69 (IH, dd, J= 15.1, 9.7 Hz), 6.08 (IH, d, J= 10.8 Hz), 6.29 (IH, dd, J= 15.0, 10.8 Hz); '3C NMR (125 MHz, CDCl3) δ 11.0, 11.3, 12.7, 17.48, 17.53, 24.7, 25.0, 25.6, 26.5, 30.8, 36.3, 38.4, 39.3, 39.9, 41.7, 43.2, 55.3, 58.6, 59.1, 60.3, 61.0, 70.2, 74.7, 75.6, 80.2, 83.6, 84.6, 127.3, 127.3, 131.9, 132.6, 138.1, 140.6, 156.5, 173.0; (+)-HR-ESIMS m/∑ 679.4654 [M+H]+ GM228
Figure imgf000062_0001
1H NMR (500 MHz, CDCl3) £0.85 (3H, d, J= 6.8 Hz), 0.86 (3H, d, J= 6.8 Hz), 0.88 (3H, t, J = '7.4 Hz), 1.15 (3H, d, J= 6.8 Hz), 1.25 (3H, s), 1.33 (IH, m), 1.36 (IH, m), 1.41 (IH, m), 1.47 (IH, m), 1.54 (IH, m), 1.64 (IH, m), 1.70 (2H, m), 1.74 (3H, s), 2.10 (IH, m), 2.48 (IH, m), 2.52 (IH, m), 2.54 (IH, dd, J= 14.9, 3.0 Hz), 2.58 (IH, dd, J= 14.9, 3.6 Hz), 2.80 (IH, dd, J= 5.4, 2.2 Hz), 2.88 (IH, dd, J= 8.2, 2.2 Hz), 3.12 (IH, m), 3.17 (IH, ddd, J = 6.4, 6.4, 4.3 Hz), 3.29 (IH, dd, J= 6.7, 5.4 Hz), 3.40 (3H, s), 3.44 (IH, m), 3.59 (IH, m), 3.62 (2H, m), 3.76 (IH, m), 4.97 (IH, d, J= 9.6 Hz), 5.13 (IH, d, J= 10.7 Hz), 5.63 (IH, dd, J= 15.1, 9.8 Hz), 5.69 (IH, dd, J= 15.1, 9.6 Hz), 5.69 (IH, dd, J= 15.0, 8.6 Hz), 6.08 (IH, d, J= 10.8 Hz), 6.30 (IH, dd, J= 15.0, 10.8 Hz); 13C NMR (125 MHz, CDCl3) £11.0, 11.3, 12.8, 17.4, 17.5, 24.7, 25.8, 30.8, 35.4, 36.2, 39.4, 39.8, 41.6, 43.2, 45.6, 52.2, 55.4, 59.1, 60.3, 61.0, 70.2, 74.7, 75.6, 80.7, 83.6, 84.6, 127.3, 127.3, 131.9, 132.5, 138.2, 140.8, 155.5, 173.0; (+)-HR-ESIMS m/z 637.3939 [M+H]+
GM229
Figure imgf000062_0002
1H NMR (500 MHz, CDCl3) £0.86 (3H, d, J= 6.9 Hz), 0.87 (3H, d, J= 6.6 Hz), 0.88 (3H, t, J= 7.4 Hz), 1.12 (3H, d, J= 6.8 Hz), 1.25 (3H, s), 1.34 (IH, m), 1.36 (IH, m), 1.43 (IH, m), 1.49 (IH, m), 1.54 (IH, m), 1.66 (IH, m), 1.71 (2H, m), 1.73 (IH, m), 1.76 (3H, s), 2.45 (2H, m), 2.47 (4H, m), 2.48 (IH, m), 2.53 (IH5 m), 2.54 (IH, dd, J = 14.9, 2.7 Hz), 2.62 (IH, dd, J= 14.9, 3.4 Hz), 2.81 (IH, dd, J = 5.4, 2.3 Hz), 2.91 (IH, dd, J = 8.2, 2.3 Hz), 3.18 (IH, ddd, J= 6.4, 6.4, 4.1 Hz), 3.28 (3H, m), 3.42 (3H, s), 3.74 (4H, m), 3.76 (IH, m), 4.98 (IH, d, J = 9.6 Hz), 5.14 (IH, d, J = 10.7 Hz), 5.61 (IH, dd, J = 15.1, 9.7 Hz), 5.68 (IH, dd, J= 15.1, 9.6 Hz), 5.69 (IH, br s), 5.70 (IH, dd, J= 15.0, 8.7 Hz), 6.10 (IH, d, J= 10.8 Hz), 6.31 (IH, dd, J= 15.0, 10.8 Hz); 13C NMR (125 MHz, CDCl3) 511.0, 11.3, 12.7, 17.47, 17.52, 24.6, 25.6, 26.8, 30.8, 36.3, 39.3, 39.8, 41.2, 41.7, 43.2, 54.6, 57.9, 59.1, 60.3, 61.0, 67.9, 70.2, 74.6, 75.6, 80.1, 83.6, 84.6, 127.1, 127.2, 131.9, 132.5, 138.2, 140.8, 156.5, 173.0; (+)-HR-ESIMS m/z 695.4387 [M+H]+
GM233
Figure imgf000063_0001
1H NMR (500 MHz, CDCl3) 50.87 (3H, d, J= 6.8 Hz), 0.89 (3H, d, J= 6.8 Hz), 0.90 (3H, t, J= 7.4 Hz), 1.13 (2H, m), 1.14 (3H, d, J= 6.8 Hz), 1.16 (2H, m), 1.24 (3H, s), 1.32 (IH, m), 1.34 (IH, m), 1.36 (IH, m), 1.41 (IH, m), 1.47 (IH, m), 1.52 (IH, m), 1.61 (2H, m), 1.64 (IH, m), 1.71 (IH, m), 1.72 (IH, m), 1.74 (3H, s), 1.94, (2H, m), 2.48 (IH, m), 2.51 (IH, m), 2.53 (IH, dd, J= 14.9, 2.8 Hz), 2.61 (IH, dd, J= 14.9, 3.6 Hz), 2.80 (IH, dd, J = 5.3, 2.2 Hz), 2.89 (IH, dd, J= 8.2, 2.2 Hz), 3.17 (IH, ddd, J= 6.4, 6.4, 4.1 Hz), 3.30 (IH, dd, J= 6.7, 5.3 Hz), 3.40 (3H, s), 3.47 (IH, m), 3.74 (IH, m), 4.96 (IH, d, J= 9.6 Hz), 5.14 (IH, d, J= 10.7 Hz), 5.61 (IH, dd, J = 15.1, 9.7 Hz), 5.67 (IH, dd, J= 15.1, 9.6 Hz), 5.69 (IH, dd, J= 15.1, 8.7 Hz), 6.08 (IH, d, J= 10.8 Hz), 6.31 (IH, dd, J= 15.1, 10.8 Hz); 13C NMR (125 MHz, CDCl3) 511.0, 11.3, 12.7, 17.46, 17.53, 24.7, 25.6, 25.7, 26.4, 30.8, 34.4, 36.3, 39.3, 39.8, 41.7, 43.2, 50.9, 59.1, 60.3, 61.0, 70.2, 74.7, 75.6, 79.9, 83.6, 84.6, 127.1, 127.3, 131.9, 132.5, 138.2, 140.8, 155.5, 173.0; (+)-HR-ESIMS m/z 672.4081 [M+Naf GM241
Figure imgf000064_0001
1H NMR (500 MHz, CDCl3) £0.87 (3H, d, J- 6.9 Hz), 0.88 (3H, d, J= 6.8 Hz), 0.90 (3H, t, J= 7.5 Hz), 1.14 (3H, d, J= 6.8 Hz), 1.24 (3H, s), 1.31 (IH, m), 1.33 (IH, m), 1.41 (IH, m), 1.45 (IH, m), 1.52 (IH, br t, J=12.3 Hz), 1.63 (IH, m), 1.70 (IH, m), 1.73 (3H, s), 2.29 (3H, s), 2.45 - 2.53 (13H, m), 2.60 (IH, dd, J = 14.9, 3.4 Hz), 2.80 (IH, dd, J = 5.3, 2.3 Hz), 2.89 (IH, dd, J= 8.2, 2.3 Hz), 3.17 (IH, ddd, J= 6.4, 6.3, 4.2 Hz), 3.28 (3H, m), 3.39 (3H, s), 3.75 (IH, m), 4.98 (IH, d, J= 9.6 Hz), 5.14 (IH, d, J= 10.6 Hz), 5.27 (IH, br t, J= 5.4 Hz), 5.59 (IH, dd, J = 15.1, 9.8 Hz), 5.69 (IH, dd, J = 15.0, 8.7 Hz), 5.71 (IH, dd, J ==15.1, 9.6 Hz), 6.08 (IH5 d, J= 10.8 Hz), 6.31 (IH, dd, J= 15.0, 10.8 Hz); 13C NMR (125 MHz, CDCl3) £ 10.9, 11.3, 12.7, 17.4, 17.5, 24.7, 25.6, 30.8, 36.4, 38.5, 39.3, 39.8, 41.7, 43.1, 46.9, 53.7, 55.8, 57.9, 59.0, 60.3, 61.0, 70.2, 74.7, 75.7, 80.2, 83.5, 84.5, 127.1, 127.2, 131.9, 132.5, 138.2, 140.7, 156.4, 172.9; (+)-HR-ESIMS m/z 694.3435 [M+H]+
GM245
Figure imgf000064_0002
1H NMR (500 MHz, CDCl3) £0.87 (3H, d, J= 6.8 Hz), 0.88 (3H, d, J= 6.8 Hz), 0.89 (3H, t, J= 7.4 Hz), 1.14 (3H, d, J= 6.8 Hz), 1.23 (3H, s), 1.29 (IH, m), 1.33 (IH, m), 1.40 (IH, m), 1.45 (IH, m), 1.51 (IH, m), 1.63 (IH, m), 1.67 (2H, m), 1.70 (IH, m), 1.74 (3H, s), 2.28 (3H, s), 2.44 (4H, m), 2.46 (4H, m), 2.47 (IH, m), 2.50 (3H, m), 2.52 (IH, dd, J= 14.9, 2.8 Hz), 2.59 (IH, dd, J= 14.9, 3.5 Hz), 2.80 (IH, dd, J= 5.2, 2.2 Hz), 2.88 (IH, dd, J= 8.2, 2.2 Hz), 3.17 (IH, ddd, J= 6.4, 6.4, 4.1 Hz), 3.25 (2H, m), 3.29 (IH, dd, J= 6.5, 5.2 Hz), 3.39 (3H, s), 3.74 (IH, m), 4.95 (IH, d, J= 9.6 Hz), 5.14 (IH, d, J= 10.7 Hz), 5.58 (IH, dd, J= 15.1, 9.7 Hz), 5.65 (IH, dd, J= 15.1, 9.6 Hz), 5.67 (IH, dd, J= 15.1, 8.7 Hz), 5.83 (IH, br s), 6.08 (IH, d, J= 10.8 Hz), 6.29 (IH, dd, J= 15.1, 10.8 Hz); 13C NMR (125 MHz, CDCl3) £11.0, 11.3, 12.8, 17.5, 17.5, 24.7, 25.7, 26.8, 30.8, 36.3, 39.3, 39.9, 41.2, 41.7, 43.2, 46.6, 53.5, 55.6, 57.3, 59.1, 60.3, 60.9, 70.2, 74.7, 75.6, 80.1, 83.6, 84.6, 127.2, 127.3, 132.0, 132.5, 138.2, 140.7, 156.5, 173.0. (+)-HR-ESIMS m/z 708.4686 [M+H]+
GM254
Figure imgf000065_0001
1H NMR (500 MHz, CDCl3) (50.86 (3H, d, J = 6.9 Hz), 0.87 (3H, d, J= 6.9 Hz), 0.89 (3H, t, J= 7.4 Hz), 1.14 (3H, d, J= 6.8 Hz), 1.23 (3H, s), 1.31 (IH, m), 1.33 (IH, m), 1.40 (IH, m), 1.46 (IH, m), 1.52 (IH, m), 1.63 (IH, m), 1.69 (IH, m), 1.73 (3H, s), 1.80 (2H, m), 1.87 (4H, br m) 2.48 (IH, m), 2.49 (IH, m), 2.52 (IH, dd, J= 14.9, 2.8 Hz), 2.60 (IH, dd, J = 14.9, 3.7 Hz), 2.70 (6H, m), 2.80 (IH, dd, J = 5.3, 2.3 Hz), 2.89 (IH, dd, J= 8.2, 2.3 Hz), 3.17 (IH, ddd, J= 6.4, 6.4, 4.1 Hz), 3.28 (3H, m), 3.40 (3H, s), 3.74 (IH, m), 4.95 (IH, d, J = 9.6 Hz), 5.14 (IH, d, J= 10.7 Hz), 5.58 (IH, dd, J= 15.1, 9.8 Hz), 5.68 (IH, dd, J= 15.0, 8.8 Hz), 5.69 (IH, dd, J= 15.1, 9.6 Hz), 5.90 (IH, br t, J = 5.4 Hz), 6.08 (IH, d, J= 10.8 Hz), 6.31 (IH, dd, J= 15.0, 10.8 Hz); 13C NMR (125 MHz, CDCl3) £ 11.0, 11.3, 12.8, 17.5, 17.5, 24.4, 24.7, 25.6, 28.6, 30.8, 36.3, 39.3, 39.9, 40.6, 41.7, 43.2, 54.9, 54.9, 59.1, 60.3, 60.9, 70.2, 74.6, 75.6, 80.1, 83.6, 84.6, 127.3, 127.3, 131.9, 132.6, 138.2, 140.6, 156.7, 173.0; (+)-HR-ESIMS m/z 679.4426 [M+H]+
GM256
Figure imgf000065_0002
1H NMR (500 MHz, CDCl3) £0.87 (3H, d, J= 6.9 Hz), 0.88 (3H, d, J= 7.0 Hz), 0.89 (3H, t, J= 7.4 Hz), 1.14 (3H, d, J= 6.8 Hz), 1.23 (3H, s), 1.30 (IH, m), 1.32 (IH, m), 1.40 (IH, m), 1.44 (IH, m), 1.51 (IH, m), 1.58 (2H, m), 1.64 (IH, m), 1.69 (IH, m), 1.73 (3H, s), 1.86 (4H, m), 1.92 (2H, m), 2.48 (IH, m), 2.49 (IH, m), 2.53 (IH, dd, J= 14.9, 2.9 Hz), 2.60 (IH, dd, J = 14.9, 3.7 Hz), 2.77 (6H, m), 2.80 (IH, dd, J = 5.3, 2.2 Hz), 2.89 (IH, dd, J = 8.2, 2.2 Hz), 3.17 (IH, ddd, J = 6.4, 6.4, 4.1 Hz), 3.29 (IH, m), 3.31 (2H, m), 3.40 (3H, s), 3.53 (IH, br s), 3.73 (IH, m), 4.93 (IH, d, J= 9.7 Hz), 5.13 (IH, d, J= 10.7 Hz), 5.56 (IH, dd, J= 15.1, 9.9 Hz), 5.68 (IH, dd, J= 15.1, 8.3 Hz), 5.70 (IH, dd, J= 15.1, 9.7 Hz), 6.07 (IH, d, J= 10.9 Hz), 6.31 (IH, dd, J= 15.1, 10.9 Hz), 6.36 (IH, br s); 13C NMR (125 MHz, CDCl3) δ 10.9, 11.3, 12.7, 17.48, 17.50, 23.9, 24.7, 24.9, 25.6, 25.7, 30.8, 36.2, 39.3, 39.8, 39.9, 41.6, 43.1, 54.8, 56.8, 59.1, 60.3, 61.0, 70.2, 74.5, 75.7, 80.2, 83.6, 84.6, 127.2, 127.4, 131.9, 132.5, 138.2, 140.3, 156.9, 173.0; (+)-HR-ESIMS m/z 693.4662 [M+H]+
A representative synthesis of N831 (A) R7 ester derivatives is shown in Scheme 2.
Scheme 2 Procedure for the Syntheses of N831 (A) R7 Esters
Figure imgf000066_0001
To a solution of N831 (A) (26 mg, 0.05 mmol) in methanol (2 mL) was added anhydrous K2CO3 (19 mg, 0.14 mmol). The reaction was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (4 mL) and water (4 mL), and extracted with ethyl acetate (3 x 4 mL). The organic extracts were combined, dried with anhydrous MgSO4, filtered, and then concentrated under reduced pressure to afford the crude Nl 407. To a solution of N1407 (20 mg, 0.04 mmol), DMAP (2 mg, 0.02 mmol) and triethylamine (5.5 μL, 0.04 mmol) in anhydrous CH2Cl2 (3 mL) was added the respective acid chloride (0.03 - 0.04 mmol). The reaction mixture was stiiτed at room temperature for 1.5 hour. Additional acid chloride (0.02 mmol) was introduced. The mixture was stirred at room temperature for another 1.5 hour and then concentrated under reduced pressure. The crude product was purified by preparative TLC (chloroform-methanol) to give the corresponding C7-ester analogue. GM150
Figure imgf000067_0001
1H NMR (500 MHz, CDCl3) £0.89 (3H, d, J= 6.6 Hz), 0.90 (3H, d, J= 7.1 Hz)5 0.91 (3H, X, J = 7.4 Hz), 1.16 (3H, d, J = 6.8 Hz), 1.30 (3H, s), 1.41 (IH, m), 1.43 (IH, m), 1.44 (IH, m), 1.48 (IH, m), 1.64 (IH, m), 1.65 (IH, m), 1.76 (3H, s), 1.77 (IH, m), 2.50 (IH, m), 2.56 (IH, m), 2.58 (IH, dd, J= 14.9, 3.1 Hz), 2.66 (IH, dd, J= 14.9, 3.6 Hz), 2.82 (IH, dd, J = 5.2, 2.2 Hz), 2.91 (IH, dd, J = 8.2, 2.2 Hz), 3.18 (IH, ddd, J= 6.4, 6.4, 4.1 Hz), 3.33 (IH, dd, J= 6.0, 5.2 Hz), 3.41 (3H, s), 3.55 (IH, br d, J= 9.5 Hz), 3.79 (IH, br m), 5.20 (IH, d, J = 10.7 Hz), 5.37 (IH, d, J= 9.6 Hz), 5.71 (IH, dd, J= 15.1, 8.6 Hz), 5.72 (IH, dd, J= 15.1, 9.7 Hz), 5.81 (IH, dd, J= 15.1, 9.6 Hz), 6.11 (IH, d, J = 10.8 Hz), 6.32 (IH, dd, J= 15.1, 10.8 Hz), 7.47 (2H5 dd, J= 7.8, 7.6 Hz), 7.59 (IH, dd, J = 7.6, 1.2 Hz), 8.04 (2H, dd, J = 7.8, 1.2 Hz); 13C NMR (125 MHz, CDCl3) δ 11.0, 11.3, 12.8, 17.4, 17.5, 24.7, 25.8, 30.9, 36.3, 39.3, 39.9, 41.7, 43.2, 59.1, 60.3, 60.9, 70.2, 74.8, 75.6, 80.5, 83.6, 84.6, 126.6, 127.3, 129.5, 130.6, 131.2, 132.0, 132.5, 134.2, 138.2, 141.7, 166.2, 173.0; (+)-HR-ESIMS m/z 646.4011 [M+NH4f; (÷)-HR-ESIMS m/z 651.3553 [M+Na]+
GM151
Figure imgf000067_0002
1H NMR (500 MHz, CDCl3) £0.88 (3H, d, J= 6.9 Hz), 0.89 (3H, d, J= 6.5 Hz), 0.90 (3H, t, J= 7.4 Hz), 1.15 (3H, d, J= 6.8 Hz), 1.16 (IH, t, J= 7.6 Hz), 1.21 (3H, s), 1.30 (2H, m), 1.41 (IH, m), 1.43 (IH, m), 1.64 (IH, m), 1.71 (2H, m), 1.74 (3H, s), 2.03 (IH, br s), 2.36 (2H, qd, J= 7.5, 1.4 Hz), 2.48 (IH, m), 2.52 (IH, m), 2.54 (IH, dd, J= 14.9, 3.0 Hz), 2.62 (IH, dd, J= 14.9, 3.6 Hz), 2.81 (IH, dd, J= 5.2, 2.3 Hz), 2.90 (IH, dd, J = 8.2, 2.3 Hz), 3.17 (IH, ddd, J= 6.4, 6.4, 4.1 Hz), 3.30 (IH, br), 3.40 (3H, s), 3.53 (IH, br d, J= 10.7 Hz), 3.75 (IH, br m), 5.09 (IH, d, J= 9.2 Hz), 5.15 (IH, d, J= 10.6 Hz), 5.60 (IH, dd, J= 15.1, 9.2 Hz), 5.66 (IH, dd, J = 15.1, 9.2 Hz), 5.69 (IH, dd, J= 15.1, 8.8 Hz), 6.09 (IH, d, J = 10.9 Hz), 6.31 (IH, dd, J= 15.1, 10.9 Hz); 13C NMR (125 MHz, CDCl3) 510.1, 11.0, 11.3, 12.8, 17.4, 17.5, 24.7, 25.6, 28.8, 30.8, 36.2, 39.3, 39.9, 41.7, 43.2, 59.1, 60.3, 60.9, 70.2, 74.5, 75.6, 79.7, 83.6, 84.6, 126.6, 127.3, 132.0, 132.5, 138.2, 141.4, 173.0, 174.0; (+)-HR- ESIMS m/z 598.4019 [M+NH4]+; (+)-HR-ESIMS m/z 603.3551 [M+Na]+
A representative synthesis of N1523 R7 carbamates derivatives is shown in Scheme 3.
Scheme 3. Synthesis of N1523 R7 Carbamate Derivatives
Figure imgf000068_0001
GM243
15%
To a solution of N1523 (20 mg, 0.04 mmol, isolated from the actinomycete mutant strain T658) and pyridinium />-toluenesulfonate (4 mg, 0.02 mmol) in anhydrous CH2Cl2 (3 mL) was added ethyl vinyl ether (0.35 niL, 3.6 mmol). The reaction mixture was stirred at room temperature for 4 hours and then washed with saturated aqueous NaHCO3 (3 mL). The basic layer was extracted further with CH2Cl2 (3 x 3 mL). The organic extracts were combined, dried with anhydrous MgSO4, filtered, and then concentrated under reduced pressure to afford compound 4.
To a solution of compound 4 in methanol (3 mL) was added anhydrous K2CO3 (305 mg, 2.2 mmol) over a period of 2.5 hours. The reaction mixture was then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (5 mL) and water (5 mL), and extracted with ethyl acetate (2 x 5 mL). The organic extracts were combined, dried with anhydrous MgSO4, filtered, and then concentrated under reduced pressure to afford compound 5.
To a solution of compound 5, DMAP (3 mg, 0.03 mmol) and triethylamine (15 μL, 0.11 mmol) in anhydrous CH2Cl2 (2 mL) was added 4-nitrophenyl chloroformate (22 mg, 0.11 mmol). The reaction mixture was stirred at room temperature for 18 hours. Additional 4-nitrophenyl chloroformate (60 mg, 0.3 mmol) and triethylamine (45 μL, 0.32 mmol) were added. The mixture was stirred at room temperature for another 2 hours, and then washed with saturated aqueous NaHCO3 (3 x 5 mL). The organic layer was dried with anhydrous MgSO4, filtered, and then concentrated. To a solution of crude carbonate in anhydrous THF (2 mL) was added l-(2-aminoethyl) pyrrolidine (9 μL, 0.07 mmol) four times over a period of 2 hours. Tire reaction mixture was then concentrated under reduced pressure. The residue was taken into ethyl acetate (8 mL) and washed with saturated aqueous NaHCO3 (3 x 5 mL). The organic layer was dried with anhydrous MgSO4, filtered, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution with ethyl acetate-hexane 1 :1, then chloroform-methanol 20:1) to give compound 6 (19.4 mg, 58 %).
To a solution of compound 6 (19.4mg, 0.02 mmol) in methanol (2 mL) was added ρyridinium/ι-toluenesulfonate (5 mg). The reaction mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure. To the residue was added methanol (2 mL) and the reaction mixture was stirred at room temperature for 30 min. This step was repeated five times until all the protecting groups were removed. Finally, the residue was taken into CH2Cl2 (10 mL) and washed with saturated aqueous NaHCO3 (5 mL). The organic layer was dried with anhydrous MgSO4, filtered, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (elution with ethyl acetate-hexane 1:1, then gradient elution with chloroform-methanol 20:1 to 7:1), followed by purification with preparative HPLC (gradient elution; 4 mL/min; MeCN/H2O + 0.1% HCOOH; 15:85 to 24:76 over 29 min, 24:76 to 100:0 over 1 min; X-Terra® MS Cl 8 column, 10x150 mm) to give the GM243 as a colourless oil (2 mg, 15%). GM243
Figure imgf000070_0001
1H NMR (500 MHz, CDCl3) 50.89 (3H, d, J- 6.7 Hz), 0.93 (3H, d, J= 7.1 Hz), 0.97 (3H, t, J = 7.4 Hz), 1.15 (3H, d, J = 6.8 Hz), 1.24 (3H, s), 1.34 (IH, m), 1.37 (IH, m), 1.43 (IH, m), 1.51 (2H, m), 1.53 (IH, m), 1.70 (IH, m), 1.74 (3H, s), 1.82 (4H, m), 2.48 (IH, m), 2.52 (IH, m), 2.55 (IH, m), 2.60 (5H, m), 2.67 (2H, m), 2.87 (IH, dd, J= 5.2, 2.2 Hz), 2.93 (IH, dd, J = 7.7, 2.2 Hz), 3.29 (IH, dd, J= 6.9, 5.2 Hz), 3.33 (2H, m), 3.61 (IH, ddd, J = 6.5, 6.5, 3.6 Hz), 3.76 (IH, m), 4.98 (IH, d, J = 9.6 Hz)5 5.14 (IH, d, J = 10.6 Hz), 5.54 (IH, br s), 5.59 (IH, dd, J= 15.2, 9.8 Hz), 5.69 (2H, m), 6.09 (IH, d, J = 10.9 Hz), 6.32 (IH, dd, J= 15.0, 10.9 Hz); (+)-HR-ESIMS m/z 651.4070 [M+H]+
A representative synthesis of N831 (A) R7 ketone and epimeric R7 derivatives are shown in Scheme 4.
Scheme 4. Syntheses of N831 (A) R7 Ketone and Epimeric Derivatives
Figure imgf000071_0001
Et3N
Figure imgf000071_0002
To a solution of N831 (A) (131 mg, 0.23 mmol) in dry THF (10 mL) was added triethylamine (50 μL, 0.50 mmol) followed by DMAP (14.2 mg, 0.12 mmol). The mixture was then stirred at 0 0C for 15 min. TES-Cl (150 μL, 1.00 mmol) was introduced dropwise to the reaction mixture at 0 0C. After all starting material had reacted as indicated by TLC
(ethyl acetate-hexane 1:1), it was diluted with ethyl acetate, then washed successively with water and brine. The aqueous layer was extracted with CH2Cl2, and the combined organic layers dried (MgSO4), filtered and concentrated. The crude product was purified by flash column chromatography (ethyl acetate-hexane 1:1) to give compound 7 (112 mg, 61%). To a solution of 7 (108 mg, 0.14 mmol) in dry methanol (4 mL) was added K2CO3 (70 mg, 0.51 mmol). After all starting material had reacted as indicated by TLC (ethyl acetate-hexaπe 1 :1), the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate, washed with brine, and the organic layer dried (MgSO4), filtered and concentrated. The crude product 8 was used for the next step without further purification or characterization. To a cooled (0 0C) solution of crude product 8 (110 mg, 0.15 mmol) in dry CH2Cl2 (5 mL) was added Dess-Martin periodinane (120 mg, 0.28 mmol). The reaction mixture was then stirred at room temperature overnight. It was worked-up by washing successively with saturated aqueous NaHCO3 and brine, the organic layer dried (MgSO4), filtered and concentrated. The crude product was purified by flash column chromatography (ethyl acetate-hexanes 1:1) to give ketone 9 (11.7 mg, 11%).
To ketone 9 (6.4 mg, 8.53 μmol) was added pyridinium/»-toluenesulfonate (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%).
To a cooled (0 0C) solution of ketone 9 (11.7 mg, 0.02 mmol) in dry THF (2 mL) was added NaBH4 (5 mg, 0.13 mmol). It was then stirred at room temperature until all starting material had reacted as indicated by TLC (ethyl acetate-hexane 1:1). Ethanol was added to the reaction mixture, stirred, and then evaporated under reduced pressure. The residue was taken up in ethyl acetate, washed with brine and the organic layers dried (MgSO4), filtered and concentrated. The crude product was purified by preparative TLC (ethyl acetate-hexane 1: 1) to give alcohol 10 (8.2 mg, 70%). To a solution of alcohol 10 (8.2 mg, 0.0109 mmol) in dry CH2Cl2 (2 mL) was added triethylamine (30 μL, 0.30 mmol) and DMAP (4 mg, 0.03 mmol) followed by acetic anhydride (20 μL, 0.20 mmol) dropwise at room temperature. It was then stirred until all starting material had reacted as indicated by TLC (ethyl acetate-hexane 1 :1). The reaction mixture was worked up by washing with brine and the organic layer dried (MgSO4), filtered and concentrated. The crude product (12 mg) was then dissolved in methanol (1 mL) prior to the addition of pyridiniump- toluenesulfonate (20 mg, 0.08 mmol). It was stirred at room temperature until TLC
(chloroform-methanol 19:1) indicated that all starting material had reacted. The solvent was removed under reduced pressure and the residue purified by preparative TLC (chloroform- methanol 19:1) to give GM172 (3.8 mg, 61%). Compound 7 (R3, R!7-diTES protected N831 (A))
Figure imgf000073_0001
1H NMR (500 MHz, CDCl3) £0.61 (12H, m), 0.85 (3H, d, J= 6.8 Hz), 0.87 (3H, d, J= 7.4 Hz), 0.88 (3H, t, J = 7.3 Hz), 0.95 (18H, m), 1.07 (3H, d, J = 6.8 Hz), 1.19 (3H, s), 1.32 (IH, m), 1.34 (IH, m), 1.39 (IH, m), 1.42 (2H, m), 1.62 (IH, m), 1.66 (IH, m), 1.68 (3H, s), 2.08 (3H, s), 2.37 (2H, m), 2.45 (IH, dd, J= 13.8, 3.0 Hz), 2.46 (IH, m), 2.67 (IH, dd, J = 6.1, 2.0 Hz), 2.73 (IH, br d, J= 8.1 Hz), 3.10 (IH, dd, J= 6.8, 6.1 Hz), 3.20 (IH, m), 3.39 (3H, s), 3.83 (IH, m), 4.95 (IH, d, J= 10.7 Hz), 5.06 (IH, d, J= 8.6 Hz), 5.63 (2H, m), 5.67 (IH, dd, J= 15.0, 8.3 Hz), 6.06 (IH, d, J= 10.8 Hz), 6.21 (IH, dd, J= 15.0, 10.8 Hz); (+)- HR-ESIMS m/z 817.5201 [M+Naf
GM161
Figure imgf000073_0002
1H-NMR (500MHz, CDCl3) £0.88 (3H, d, J= 6.9 Hz), 0.90 (3H, t, J= 7.4 Hz), 0.96 (3H, d, J = 6.7 Hz), 1.10 (IH, m), 1.15 (3H, d, J= 6.8 Hz), 1.39 (3H, s), 1.42 (IH, m), 1.47 (IH, m), 1.57 (IH, m), 1.59 (IH, m), 1.68 (IH, m), 1.72 (IH, m), 1.77 (3H, s), 2.50 (IH, m), 2.55 (IH, dd, J= 15.0, 5.8 Hz), 2.62 (IH, m), 2.64 (IH, m), 2.82 (IH, dd, J= 5.0, 2.1 Hz), 2.91 (IH, dd, J= 8.2, 2.1 Hz), 3.19 (IH, m), 3.32 (IH, m), 3.41 (3H, s), 3.97 (IH5 m), 5.11 (IH, d, J= 10.4 Hz), 5.72 (IH, dd, J= 15.1, 8.6 Hz), 6.11 (IH, d, J= 10.8 Hz), 6.33 (IH, dd, J = 15.1, 10.8 Hz), 6.39 (IH, dd, J= 15.5, 10.0 Hz), 6.89 (IH, d, J= 15.5 Hz); (+)-HR-ESIMS
Figure imgf000073_0003
GM172
Figure imgf000074_0001
1H-NMR (500MHz, CDCl3) <50.89 (3H, d, J= 6.7 Hz), 0.90 (3H, t, J= 7.5 Hz), 0.90 (3H, d, J = 7.2 Hz), 1.15 (3H, d, J= 6.8 Hz), 1.26 (3H, s), 1.30 (2H, m), 1.41 (IH, m), 1.46 (IH, m), 1.61 (2H, m), 1.66 (IH, m), 1.75 (3H, s), 2.15 (3H3 s), 2.51 (IH, m), 2.56 (IH, m), 2.59 (IH, m), 2.60 (IH, m), 2.82 (IH, m), 2.90 (IH, m), 3.19 (IH, m), 3.3-1 (IH, dd, J= 6.1, 5.8 Hz), 3.41 (3H, s), 3.72 (IH, m), 5.13 (IH, d, J= 10.6 Hz), 5.21 (IH, m), 5.23 (IH, m), 5.69 (IH, dd, J = 15.0, 8.6 Hz), 5.86 (IH, d, J = 16.4 Hz), 6.11 (IH, d, J= 10.8 Hz), 6.33 (IH, dd, J= 15.0, 10.8 Hz); (+)-HR-ESIMS m/z 589.3382 [M+Naf
Other Embodiments
While the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

What is claimed is:
1. A compound according to Formula (I):
Figure imgf000075_0001
or a pharmaceutically acceptable salt or individual diastereomer thereof, wherein Z is O, NH, S, or absent, such that when Z is absent the compoimd is represented by the formula (P):
Figure imgf000075_0002
(T) wherein Rd is -NH2 or azide; R7a and R7b are each, independently:
Figure imgf000075_0003
(B) -OC(O)OR5,
(C) -OC(O)R6, or
(D) hydrogen, or taken together R7a and R7b fomi a carbonyl;
R] and R2 are the same as or different from each other and eachis selected from: hydrogen;
C2, C3, C4, C5, or Ce alkyl; C2, C3, C4, C5, or C6 acyl; C3, C4, C5, or C6 alkenyl; unsaturated
C3, C4, C5, C6, C7, or C8 acyl; C5, C6, C7, or C8 aryl; heteroaryl; C1, C2, C3, C4, C5, or C6 alkylsulfonyl; benzenesulfonyl; C3, C4, C5, C6, C7, or C8 cycloalkyl; C3, C4, C5, C6, C7, or Cg cycloalkenyl; methyl; -(CH2)x-heteroaryl; -(CH2)n-aπύno; and -(CH2)y-heterocycle, each of which may be substituted; n = 1, 2, or 3; x = 1, 2, or 3; y = 0, 1, 2, or 3; or
Ri + R2 together with the nitrogen atom to which R1 and R2 are connected form a 3, 4, 5, 6,
7, or 8-membered 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;
R5 is C2, C3, C4, C5, or C6 alkyl; C3, C4, C5, or C6 alkenyl; C5, C6, C7, or Cs aryl; heteroaryl; benzyl; -(CH2)s-heteroaryl; C3, C4, C5, C6, C7, or C8 cycloalkyl; C3, C4, C5, C6, C7, or C8 cycloalkenyl; -(CH2)u-heterocycle; -(CH2)t-amino; or methyl, each of which may be substituted; s = 1, 2, or 3; t = 1, 2, or 3; and u = 0, 1, 2, or 3;
R(5 is C5, Cβ, C7, or Cg aryl; heteroaryl; C2, C3, C4, C5, or C6 alkyl; -(CH2)g-heterocycle; -
(CH2)J-C3, C4, C5, C6, C7, or C8 cycloalkyl; C3, C4, C5, C6, C7, or C8 cycloalkyl; -(CH2)h- amino; or -(CH2)j-heteroaryl, each of which may be substituted; g = 0, 1, 2, or 3; h = 1, 2, or 3; j = 0, 1, 2, or 3; and i = 0, 1, 2, or 3; and
R21 is methyl, C2-6 alkyl, or hydrogen.
2. The compound according to claim 1, wherein Z = O.
3. The compound according to claim 1 , wherein Z = NH.
4. The compound according to claim 1, wherein Z = S.
5. The compound according to claim 1, wherein Z is absent such that the compound is represented by the formula (F):
Figure imgf000077_0001
6. The compound according to claim 1, wherein R2] is methyl.
7. The compound according to claim 1, wherein R21 is hydrogen.
8. The compound according to claim 1, wherein any one OfR7n or R7b is - OC(O)NRiR2 and the other of R7a or R7b is hydrogen, further wherein,
Ri and R2 are the same as or different from each other and each is selected from: hydrogen; C2-C6 alkyl; C2-C6 acyl; C3-Ce alkenyl; unsaturated C3-Cs acyl; Cs-Cs aryl; heteroaryl; Cj-C6 alkylsulfonyl; benzenesulfonyl; C3-C8 cycloalkyl; C3-C8 cycloalkenyl; methyl; -(CH2)X- heteroaryl; -(CH2)n-amino; and -(CH2)y-heterocycle, each of which may be substituted; n = 1, 2, or 3; x = 1, 2, or 3; y = 0, 1, 2, or 3; or
Ri + R2 together with the nitrogen atom to which Ri and R2 are connected form a 3, 4, 5, 6, 7, or 8-membered 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.
9. The compound according to claim 8, wherein Ri and R2 are the same as or different from each other and each is selected from hydrogen, C2-C6 alkyl, C2-C6 acyl, methyl, -(CH2)y-heterocycle, -(CH2),, -amino, and -(CH2)x-heteroaryl, each of which may be substituted.
16
10. The compound according to claim 8, wherein R1 and R2 are the same as or different from each other and each is selected from hydrogen, C3-C8 cycloalkyl, C3-C6 allcenyl, unsaturated C3-Cs acyl, Cs-C8 aryl, heteroaryl, Ci-C6 alkylsulfonyl, benzenesulfonyl, Or C3-Cs cycloalkenyl, each of which may be substituted.
11. The compound according to claim 8, wherein Ri + R2 together with the nitrogen atom to which Ri and R2 are connected form a 3, 4, 5, 6, 7, or 8-membered ring, wherein the ring is a non-aromatic heterocyclic ring, wherein any of the atoms in the ring may be substituted.
12. The compound according to claim 11, wherein the ring is a 4-membered ring.
13. The compound according to claim 11, wherein the ring is a 5-membered ring.
14. The compound according to claim 11, wherein the ring is a 6-membered ring.
15. The compound according to claim 11, wherein the ring is a 7-membered ring.
16. The compound according to claim 11, wherein the ring is an 8-membered ring.
17. The compound according to claim 11, wherein the ring contains at least one heteroatom selected from O, N, or S.
18. The compound according to claim 11, wherein the ring is selected from the group consisting of pyrrolidine, piperidine, azepane, and azocane, each of which maybe substituted.
19. The compound according to claim 11, wherein the ring contains at least two nitrogen atoms.
20. The compound according to claim 19, wherein the ring is selected from piperazine or homopiperazine, each of which may be substituted.
21. The compound according to claim 20, wherein the ring is piperazine.
22. The compound according to claim 21 , wherein piperzine is substituted on the nitrogen atom located at the four position of the ring.
23. The compound according to claim 21, wherein piperazine is substituted with methyl, C2-Q alkyl, C3-Cs cycloalkyl, or heteroaryl.
24. The compound according to claim 23, wherein piperazine is substituted with pyridine.
25. The compound according to claim 23, wherein piperazine is substituted witli methyl.
26. The compound according to claim 23, wherein piperazine is substituted with cyclohexyl.
27. The compound according to claim 8, wherein any one of Ri or R2 is ~(CH2)X- heteroaryl; -(CH2)y-heterocycle, or -(CH2)π-amino and the other is hydrogen.
28. The compound according to claim 27, wherein any one of Rj or R2 is -(CH2)X- heteroaryl and the other is hydrogen.
29. The compound according to claim 28, wherein x = 1.
30. The compound according to claim 28, wherein x = 2.
31. The compound according to claim 28, wherein x = 3.
32. The compound according to claim 28, wherein heteroaryl is pyridine.
33. The compound according to claim 27, wherein any one of Ri or R2 is-(CH2)y- heterocycle and the other is hydrogen.
34. The compound according to claim 33, wherein y = 0.
35. The compound according to claim 33, wherein y = 1.
36. The compound according to claim 33, wherein y = 2.
37. The compound according to claim 33, wherein y = 3.
38. The compound according to claim 33, wherein heterocycle is piperidine, pyrrolidine, morpholine, or piperazine, each of which may be substituted.
39. The compound according to claim 38, wherein lieterocycle is pyrrolidine.
40. The compound according to claim 38, wherein lieterocycle is piperidine.
41. The compound according to claim 38, wherein heterocycle is morpholine.
42. The compound according to claim 38, wherein heterocycle is piperazine.
43. The compound according to claim 42, wherein piperazine is substituted on the nitrogen at the four position on the ring.
44. The compound according to claim 42, wherein piperazine is substituted with methyl.
45. The compound according to claim 27, wherein any one of R] or R2 is -(CEk)n- amino and the other is hydrogen.
46. The compound according to claim 45, wherein n = 1.
47. The compound according to claim 45, wherein n = 2.
48. The compound according to claim 45, wherein n = 3.
49. The compound according to claim 45, wherein amino is -NH2, alkylamino, or dialkylamino.
50. The compound according to claim 50, wherein amino is -NH2.
51. The compound according to claim 50, wherein amino is dimethylamine.
52. The compound according to claim 8, wherein any one of R] or R2 is C3-C8 cycloalkyl and the other is hydrogen.
53. The compound according to claim 52, wherein C3-C8 cycloalkyl is cyclohexyl.
54. The compound according to claim 8, wherein each of Ri and R2 is hydrogen.
55. The compound according to claim 8, wherein each of Rj and R2 is Ci-Cβ alkyl
56. The compound according to claim 55, wherein each of Ri and R2 is methyl.
57. The compound according to claim 1, wherein any one of R71 or R?b is - OC(O)OR5 and the other is hydrogen, further wherein:
R5 is C2-Cg alkyl; Cj-Cc alkenyl; Cs-C8 aryl; lieteroaryl; benzyl; -(CH2)s-heteroaryl; C3-C8 cycloalkyl; C3-C8 cycloalkenyl; -(CH2)u-heterocycle; or ~(CH2)t-amino, each of which may be substituted; s = 1, 2, or 3; t = 1, 2, or 3; and u = 0, 1, 2, or 3.
58. The compound according to claim 1, wherein any one of R7a or R7b is -OC(O)RO and the other is hydrogen, further wherein:
R6 is C5-C8 aryl; heteroaryl; C2-C6 alkyl; -(CH2)g-heterocycle; -(CH2)J-C3-C8 cycloalkyl; C3- C8 cycloalkyl; -(CByh-amino; -(CH2)j-heteroaryl; or methyl, each of which may be substituted; g = 0, 1, 2, or 3; h = 1, 2, or 3; j = 0, 1, 2, or 3; and i = 0, 1, 2, or 3.
59. The compound according to claim 58, wherein R6 is Cs-C8 aryl; C2-C6 alkyl; or methyl.
60. The compound according to claim 59, wherein R6 is phenyl.
61. The compound according to claim 59, wherein Rβ is ethyl.
62. The compound according to claim 1 , wherein taken together R7a and R7b form a carbonyl.
63. The compound according to claim 1, wherein the compound is selected from
Figure imgf000082_0001
Figure imgf000083_0001
64. A compound according to Formula II:
Figure imgf000084_0001
(II) or pharmaceutically acceptable salt or individual diastereomer thereof, wherein Z is O, NH, S, or absent, such that when Z is absent the compound is represented by the formula (IF):
Figure imgf000084_0002
Wherein R^ is -NH2 or azide;
R3 is Ci-C6 alkyl, substituted Ci-C6 alkyl, or silyl; further wherein silyl is RaRbRcSi-, wherein Ra, Rb, and Rc are the same as or different from each other and each represents methyl, ethyl, i-propyl, t-butyl, or phenyl;
Rβa is methyl, Ci-C6 alkyl, substituted CrC6 alkyl, or hydrogen;
R7a and R^ are each, independently:
(A) -OC(O)NRiR2,
(B) -OC(O)OR5,
(C) -OC(O)R6,
(D) hydroxyl, or
(E) hydrogen, or taken together R7a and R7bform a carbonyl; Ri and R2 are the same as or different from each other and each is selected from: hydrogen;
C2, C3, C4, C5, or Cs alkyl; C2, C3, C4, C5, or C6acyl; C3, C4, C5, or C6 alkenyl; unsaturated
C3, C4, C5, C6, C7, or C8 acyl; C5, C6, C7, or C8 aryl; heteroaryl; Ci, C2, C3, C4, C5, or C6 alkylsulfonyl; benzenesulfonyl; C3, C4, C5, C6, C7, or C8 cycloalkyl; C3, C4, C5, C6, C7, or Cs cycloalkenyl; methyl; -(CH2)x-heteroaryl; -(CH2)π-amino; or -(CH2)y-heterocycle, each of which may be substituted; n = 0, 1, 2, or 3; x = I, 2, or 3; y = 0, 1, 2, or 3; or RJ + R2 together with the nitrogen atom to which R] and R2 are connected form a 3, 4, 5, 6,
7, or 8-membered ring, wherein the ring is a non-aromatic heterocyclic ring wherein any of the atoms in the ring may be substituted;
R5 is C2, C3, C4, C5, or C6 alkyl; C3, C4, C5, or Co alkenyl; C5, Cs, C7, or C8 aryl; heteroaryl; benzyl; -(CH2)s-heteroaryl; C3, C4, C5, C6, C7, or C8 cycloalkyl; C3, C4, C5, C6, C7, or C8 cycloalkenyl; -(CH2)u-heterocycle; -(CH2)t-ammo; or methyl, each of which may be substituted; s = 1, 2, or 3; t = 1, 2, or 3; and u = 0, I, 2, or 3; R6 is C5, C6, C7, or C8 aryl; heteroaryl; C2, C3, C4, C5, or C6 alkyl; -(CH2)g-heterocycle; -
(CH2)I-C3, C4, C5, C6, C7, or C8 cycloalkyl; C3, C4, C5, C6, C7, or C8 cycloalkyl; -(CH2X- amino; -(CH2)j-heteroaryl, each of which may be substituted; g = 0, 1, 2, or 3;
Ii = 1, 2, or 3; j = 0, 1, 2, or 3; and i = 0, 1, 2, or 3;
R] 7 is methyl, Ci-C6 alky] or substituted Ci-C6 alkyl, or silyl; and
R21 is Ci-C6 alkyl or substituted Ci-C6 alkyl.
65. A method of treating an immune-related disorder comprising administering to a patient in need of such treatment a composition comprising a earner and a non-toxic therapeutically effective amount of a macrolide compound, according to the formula I or II or a pharmaceutically acceptable salt or hydrate thereof.
66. The method of claim 65, wherein the immune-related disorder 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.
67. The method of claim 66, wherein 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.
68. The method of claim 65, wherein the immune-related disorder 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.
69. 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, according to formula I or II or a pharmaceutically acceptable salt or hydrate thereof.
70. The method of claim 69, wherein the immune-related disorder 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.
71. The method of claim 70, wherein 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.
72. The method of claim 69, wherein the immune-related disorder 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.
73. The method of claim 69, wherein the macrolide is a raceinic mixture of a macrolide compound according to formula I or II.
74. The method according to claim 65 or 69, wherein the macrolide is an enantiomerically pure form of a macrolide compound according to formula I or II.
75. The method according to claims 65 or 69, wherein the macrolide is administered in combination with a second agent used to treat an immune-related disorder.
76. The method according to claim 75, wherein the second agent used to treat an immune-related disorder selected from methotrexate, cyclosporin A, tacrolimus, corticosteroids, statins, interferon beta, nonsteroidal anti-inflammatory drugs (NSAIDs), and the disease-modifying anti-rheumatic drugs (DMARDs).
77. The method according to claim 76, wherein the second agent is cyclosporin A, further wherein the cyclosporin A is cyclosporin microemulsion.
78. 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, according to formula I or II or a pharmaceutically acceptable salt or hydrate thereof.
79. The method of claim 78, wherein the macrolide is administered in combination with a second agent used to suppress an immune response associated with organ or tissue transplantation.
80. The method of claim 79, wherein 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.
81. The method of claim 80, wherein the second agent is cyclosporin A, further wherein the cyclosporin A is cyclosporin microemulsion.
82. The method of claim 78, wherein the macrolide is an enantiomerically pure form of a macrolide compound according to formula I or II.
83. The method of claim 78, wherein the macrolide 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.
84. 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 macrolide compound, wherein the macrolide compound is a macrolide compound according to formula I or II or a pharmaceutically acceptable salt or hydrate thereof.
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WO2010062265A1 (en) * 2008-11-25 2010-06-03 Merlion Pharmaceuticals Pte Ltd Therapeutic macrolide compounds and their use
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Publication number Priority date Publication date Assignee Title
WO2010062265A1 (en) * 2008-11-25 2010-06-03 Merlion Pharmaceuticals Pte Ltd Therapeutic macrolide compounds and their use
WO2019199667A3 (en) * 2018-04-09 2019-11-21 Keaney Gregg F Pladienolide compounds and their use
CN113166091A (en) * 2018-04-09 2021-07-23 卫材R&D管理有限公司 Pladienolide compounds and uses thereof
RU2813597C2 (en) * 2018-04-09 2024-02-13 Эйсай Ар Энд Ди Менеджмент Ко., Лтд. Specific pladienolide compounds and methods of their use
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JP2021521176A (en) * 2018-04-12 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 Pradienolide derivatives as spliceosome targeting agents for cancer treatment
US11679107B2 (en) 2018-04-12 2023-06-20 Eisai R&D Management Co., Ltd. Certain aryl pladienolide compounds and methods of use

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