Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
  • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
  • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
  • C07J43/006—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton spiro-condensed
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
  • C07J71/0005—Oxygen-containing hetero ring
  • C07J71/0026—Oxygen-containing hetero ring cyclic ketals
  • C07J71/0031—Oxygen-containing hetero ring cyclic ketals at positions 16, 17
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
  • C07J71/0036—Nitrogen-containing hetero ring
  • C07J71/0042—Nitrogen only
  • C07J71/0052—Nitrogen only at position 16(17)
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
  • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
  • C07K7/60—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation occurring through the 4-amino group of 2,4-diamino-butanoic acid
  • C07K7/62—Polymyxins; Related peptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• novel bioactive compounds are provided herein.
• novel bioactive compounds possess therapeutic activities useful in therapy of inflammation-associated renal disorders, in particular, the chronic kidney disease (CKD) , systemic lupus erythematosus (SLE) , diabetic nephropathy, chronic glomerulonephritis, and acute kidney injury (AKI) .
• CKD chronic kidney disease
• SLE systemic lupus erythematosus
• AKI acute kidney injury
• Kidney diseases comprise a diverse class of serious renal disorders with a profound impact on human lives worldwide. Renal inflammation may result due to a variety of exogenous and endogenous factors, including exposure to nephrotoxic substances, surgical procedures (such as kidney transplantation) , chemotherapy (such as in a treatment of cancer, diabetes, or infection) , infections (such as urinary tract infections and pyelonephritis) , and certain chronic conditions.
• acute and chronic kidney diseases such as CKD are reported as reaching epidemic proportions globally (as reviewed, for example, by Levey et al. in Kidney Int., 2005, pp. 2089-2100; and by Stenvinkel in J. Intern. Med. 2010, 268, pp. 456-467) .
• CKD chronic kidney diseases
• SLE Systemic lupus erythematosus
• LN debilitating disorder lupus nephritis
• Such chemotherapy is commonly limited by serious adverse effects of these drugs.
• a bioactive agent targeting a kidney disease administered as an oral or intravenous drug is necessarily circulated in a blood stream of a mammal or a patient in need of such therapy before it could reach kidneys.
• Such undesired but unavoidable distribution of a bioactive molecule throughout various bodily compartments and into organs other than kidneys results in an off-target effect, typically manifested as an adverse event.
• a targeted renal drug delivery comprising a selective transport of a bioactive molecule into kidneys is preferred to conventional therapies that entail an exposure of other organs to a drug that may induce an adverse effect in non-kidney compartments.
• kidney tissues also referred to as renal vectors or molecular guiding systems
• peptide carrier structures were described in publications Molecular Therapy, 2007, pp. 1647-1654, Bioconjugate Chem. 2012, pp. 1200-1210, Bioconjugate Chemistry, 2016, pp. 1050-1057, and in the patent US 10, 413, 614.
• Other molecular guiding systems acting as renal vectors include macromolecules such as polyvinylpyrrolidone (Nat. Biotechnol. 2003, pp. 399-404) , chitosans (J. Drug Target, 2007, pp. 269–278) , glucosamines (J. Controlled Release, 2013, pp. 148–156) , and proteins (as described, for example, J. Med. Chem., 1992, pp. 1246-1259; and Int. J. Nanomedicine, 2017, pp. 5673–5686) .
• Separate category of agents for targeted therapy of kidney disorders comprises prodrugs that selectively release a bioactive drug structure by kidney-associated enzymes (see, for example, J. Controlled Release, 2013, pp. 148-156; and RSC Adv. 4, 2014, pp. 50828-50831) .
• CKD is recognized as a global public health issue. Over time, this chronic condition can progress towards the debilitating end-stage renal disease. Eventually, life-preserving options would be limited to time-consuming and costly renal dialysis and/or kidney transplantation. The dire situation is exacerbated by the absence or scarcity of the dialysis stations in many world regions. Therefore, there is an unmet medical need for CKD treatment capable of preventing the end-stage renal disease through improved therapy and disease management (as reviewed, for example, by Perico et al. in Kidney Int. 2005, 68, Suppl. 98, pp. S21-S24) .
• CKD is a complex disease associated with multiple contributing parameters. Among chief factors is inflammation, often resulting from an overexpression of pro-inflammation mediators such as endothelin-1, monocyte chemoattractant protein-1, normal T cell and osteopontin have been described (Perico et al. in Kidney Int. 2005, 68, Suppl. 98, pp. S21-S24) . Acute kidney injury (AKI) is another risk factor associated with CKD (as described, for example, by campbell et al. in J. Clin. Hypertension, 2015, 17, pp. 514–527) .
• AKI Acute kidney injury
• AKI may also manifest separately from CKD, resulting, for example, from an exposure to renal toxins such as a nephrotoxic pro-inflammatory substance.
• renal ischemia-reperfusion injury is a major etiology factor in AKI.
• renal inflammation plays a major role in the pathophysiology of ischemic AKI (as described, for example, by Bonventre and Zuk in Kidney Int. 2004, 66, pp. 480–485) .
• anti-inflammatory agents are used in therapy of CKD and AKI.
• anti-inflammatory therapy with corticosteroid dexamethasone was described by Moonen et al. in BMC Nephrology. 2018, 19: 343.
• a supporting anti-inflammatory therapy is often used during treatment of cancers: for example, to attenuate toxic effects of anticancer drugs (as described, for example, by Shih et al. in J. Pain Palliative Care Pharmacother. 2007, 21 pp. 69-76; and by Vogelzang et al. in J. Clin. Oncol. 2003, 21, pp. 2636-2644) , or to induce a beneficial immunomodulatory affect (see, for example, Cook et al. in Oncoimmunology, 2016, 5, e1066062) .
• This invention provides unique conjugates of certain anti-inflammatory agents with acyclic and cyclic peptides (cyclopeptides) suitable for a targeted therapy of various kidney diseases.
• the conjugation (a covalent bonding) of bioactive agents with peptidic is achieved through deliberate design of appropriate linking groups (linkers) and additional structural elements (such as connectivity-altering spacers) serving to maximize the targeted delivery and therapeutic bioactivity.
• Agents provided herein are particularly suitable for therapy of CKD, AKI, and other non-cancer renal disorders.
• novel compounds and composition useful for targeted therapy of inflammation-associated renal disorders are provided herein.
• kidney tissues and, in particular, kidney cells affected by an inflammation including an inflammation resulted from overexpression of innate pro-inflammation mediators, or an inflammation induced by a foreign nephrotoxic substance, or an inflammation caused by another therapeutic agents (such as a cytotoxic anticancer drug, or a nephrotoxic antibacterial agent) .
• This unique affinity of the composition herein to kidney tissues affected by renal disorders permits to achieve a selective delivery to and accumulation of such molecules at the site of the disease, with minimal or no accumulation of these therapeutic agents in other tissues unaffected by such medical condition.
• a selective and generally safer renal therapy is achieved, with significantly minimized adverse effect (s) on other normal organs of a mammal under therapy, as compared to current standard-of-care drugs used to treat inflammation-associated kidney diseases, such as steroids and NSAID agents.
• a therapeutic action of compounds herein is achieved by release of one or more of an anti-inflammatory element (s) (bioactive payloads and/or drugs) incorporated into such designer molecules.
• the active payload (drug) may comprise a steroid structure, NSAID structure, or an immunomodulating structure. These are selected, for example, from bioactive structures with ability to inhibit or counter an inflammation (such as inflammation due to AKI or in a transplantation surgery, or that induced by cytokines) , or with alike ability to activate immunomodulating a therapeutic anti-inflammatory response.
• the compounds provided herein are comprised of a peptide, cyclopeptide, or another “target seeker” (ligand) structure with a high affinity (ability to bind) towards kidney cells, along with the active drug (s) substructure, within a single conjugate molecule.
• the active drug (s) (payloads) is (are) connected to a kidney-affinity structure via a framework of uniquely designed linker (s) and spacer (s) . This unique design allows for an efficient release of an active drug (payload) directly into kidney tissues, resulting in a therapeutic anti-inflammatory effect.
• said composition possesses anti-inflammatory property (ies) in a molecular form of an intact conjugate, without a release of an active drug payload (comprised within the structure) at the site of a kidney inflammation. Upon accumulation at the site of a kidney inflammation, such compound (s) exert an anti-inflammatory action directly.
• above conjugate breaks-down into generally non-toxic metabolites after exerting a desired bioactive effect.
• the anti-inflammatory effect is achieved (upon accumulation at the cancer site) through a combined effect of (i) direct anti-inflammatory effect of said compound (s) , and (ii) a release of an active payload drug comprised within the structure.
• either an intact conjugate and/or the agent released from said conjugate in kidneys exhibit a protective effect against nephrotoxic substances, such as cytotoxic anticancer drugs.
• certain compounds and compositions provided herein are devoid of significant antibiotic and/or other biological activity, and only exerts the desired anti-inflammatory effect on kidneys affected by a renal disorder.
• composition provided herein incorporates cyclopeptide moieties (structures) of chemical classes generally known to cause renal toxicity (such as polymyxins)
• the therapeutic compounds of this invention exhibit little or no renal toxicity at the therapeutic dosing levels required form treatment of inflammation-associated kidney disorders.
• this composition comprises a class of molecules capable of specifically releasing anti-inflammatory payloads (incorporated within their structures) as a result of metabolic cleavage by classes of enzymes either specific to or overexpressed (enriched) within the renal cells affected by an inflammation (such as cathepsin, glutaminase, glutathione transferase, and peptide deformylase or PDF, peptidases, reductases, and alike known enzymes) .
• certain compounds provided herein are degraded in vivo through a chemical cleavage, such as pH-dependent self-cleavage known for molecules bearing both a cleavable group (such as an ester, an amide, or a carbamate group) and a free nucleophilic group (such as amine, alcohol, or thiol group) .
• a chemical cleavage such as pH-dependent self-cleavage known for molecules bearing both a cleavable group (such as an ester, an amide, or a carbamate group) and a free nucleophilic group (such as amine, alcohol, or thiol group) .
• the nucleophilic group may be acylated by the ester group, resulting in the acyl group transfer onto the nucleophilic atom (such as nitrogen atom in amine group) .
• the free amine may activate an adjacent to the carbamate group amide functionality, inducing the carbamate reaction with the latter, to result in a conversion of the native amide into a bis-acylated imide group.
• the cleavage of a chemical designer linker takes place after initial enzymatic metabolism of an auxiliary enzyme-cleavable linker (e.g., peptide substructure, or alike) , to overall effect of the release of anti-inflammatory payload in kidney tissues.
• an auxiliary enzyme-cleavable linker e.g., peptide substructure, or alike
• R 1 is a residue attached to X 1 , formed by subtracting a single H atom from parent (precursor) structure R 1 H at any one of the following H-containing group independently selected from NH 2 , NH, OH, and SH; and wherein R 1 H is selected from a compound possessing an activity or capable of inducing an activity that modulates glucocorticoid receptor (GR) activity; and
• X 2 is either absent, or comprises an amino acid or a peptide residue consisting of 1 to 6 amino acids, selected from unsubstituted or substituted at any N atom of alpha-, beta-, or gamma-amino acids, Phe, Gly, Val, Lys, Cit, Ser, Ala, Glu, Gln, Asp, D-Phe, D-Val, D-Lys, D-Cit, D-Ser, D-Ala, D-Glu, D-Gln, and D-Asp; wherein the carbonyl terminal of the X 2 groups provided above is attached to X 1 , or R 1 (if X 1 is absent) ;
• R 3 is either absent, or selected from the group consisting of NH, N (C 1-6 alkylene) , and C 1- 6 alkylene;
• R 4 is either absent, or selected from the group consisting of arylene, heteroarylene, C (C 3- 10 cycloalkylene) 2 , C 3-10 cycloalkylene, heterocycloalkylene, and (OCH 2 CH 2 O) q ;
• R 5 is either absent, or C 1-6 alkylene
• R 6 is either absent, or selected from the group consisting of OC 1-6 alkylene and
• R 13 is either absent, or selected from the group consisting of C 1-12 alkylene, C 3- 10 cycloalkylene, C 3-10 cycloalkyleneC 1-6 alkylene, heterocycloalkylene, heteroarylene, and arylene; wherein R 13 is optionally substituted with one to four R 15 ;
• R 14 is independently selected from the group consisting of -C 0-3 alkylene-polyethyleneglycol, halo, OH, NH 2 , SH, CN, C 3-10 cycloalkyl, C 1-8 alkoxy, aryl, and heteroaryl;
• R 15 is independently selected from the group consisting of halo, OH, NH 2 , SH, C 3- 10 cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
• a 8 through A 11 are optional amino acid residues independently selected from the residue of unsubstituted or substituted at any N atom of alpha-, beta-, or gamma-amino acids, Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, L-homoserine, Thr, Trp, Tyr, Val, D-Ala, D-Arg, D-Asn, D-Asp, D-Cys, D-Glu, D-Gln, D-His, D-Ile, D-Leu, D-Lys, D-Met, D-Phe, D-Pro, D-Ser, D-homoserine, D-Thr, D-Trp, D-Tyr, D-Val, 3-aminoproline, 4-aminoproline, biphenylalanine (Bip) , D-Bip, 2, 3-di
• R a , R b and R c represent the side chain of an amino acid independently selected from serine, threonine, leucine, phenylalanine, norleucine, norvaline or t-butylglycine;
• integers h, i, j, and k are independently selected from 0, 1, and 2;
• integer q is selected from 1-10;
• integer x, y, z, and p are independently selected from 1 and 2.
• R a is CH 2 CH (CH 3 ) 2 or CH 2 Ph;
• integer f is 1 or 2.
• R a is CH 2 CH (CH 3 ) 2 or CH 2 Ph.
• a drug-linker intermediate compound represented by the following formula: R 1 -X 1 -X 2 -X 3 -OH, wherein:
• R 1 is a residue attached to X 1 , formed by subtracting a single H atom from parent (precursor) structure R 1 H at any one of the following H-containing group independently selected from NH 2 , NH, OH, and SH; and wherein R 1 H is selected from a compound possessing an activity or capable of inducing an activity that modulates glucocorticoid receptor (GR) activity; and
• X 2 is either absent, or comprises an amino acid or a peptide residue consisting of 1 to 6 amino acids, selected from unsubstituted or substituted at any N atom of alpha-, beta-, or gamma-amino acids, Phe, Gly, Val, Lys, Cit, Ser, Ala, Glu, Gln, Asp, D-Phe, D-Val, D-Lys, D-Cit, D-Ser, D-Ala, D-Glu, D-Gln, and D-Asp; wherein the carbonyl terminal of the X 2 groups provided above is attached to X 1 , or R 1 (if X 1 is absent) ;
• R 3 is either absent, or selected from the group consisting of NH, N (C 1-6 alkylene) , and C 1- 6 alkylene;
• R 4 is either absent, or selected from the group consisting of arylene, heteroarylene, C (C 3- 10 cycloalkylene) 2 , C 3-10 cycloalkylene, heterocycloalkylene, and (OCH 2 CH 2 O) q ;
• R 5 is either absent, or C 1-6 alkylene
• R 6 is either absent, or selected from the group consisting of OC 1-6 alkylene and
• R 13 is either absent, or selected from the group consisting of C 1-12 alkylene, C 3- 10 cycloalkylene, C 3-10 cycloalkyleneC 1-6 alkylene, heterocycloalkylene, heteroarylene, or arylene; wherein R 13 is optionally substituted with one to four R 15 ;
• R 14 is independently selected from the group consisting of -C 0-3 alkylene-polyethyleneglycol, halo, OH, NH 2 , SH, CN, C 3-10 cycloalkyl, C 1-8 alkoxy, aryl, and heteroaryl;
• R 15 is independently selected from the group consisting of halo, OH, NH 2 , SH, C 3- 10 cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
• integer q is selected from 1-10;
• integer p is selected from 1 and 2.
• linker represented by the following formula: -X 1 -X 2 -X 3 -
• a drug preferably the drug is dexamethasone or its variants
• a peptide preferably the peptide is PMBN, PMBH, or a variant thereof
• X 2 is either absent, or comprises an amino acid or a peptide residue consisting of 1 to 6 amino acids, selected from unsubstituted or substituted at any N atom of alpha-, beta-, or gamma-amino acids, Phe, Gly, Val, Lys, Cit, Ser, Ala, Glu, Gln, Asp, D-Phe, D-Val, D-Lys, D-Cit, D-Ser, D-Ala, D-Glu, D-Gln, and D-Asp; wherein the carbonyl terminal of the X 2 groups provided above is attached to X 1 ;
• R 3 is either absent, or selected from the group consisting of NH, N (C 1-6 alkylene) , and C 1- 6 alkylene;
• R 4 is either absent, or selected from the group consisting of arylene, heteroarylene, C (C 3- 10 cycloalkylene) 2 , C 3-10 cycloalkylene, heterocycloalkylene, and (OCH 2 CH 2 O) q ;
• R 5 is either absent, or C 1-6 alkylene
• R 6 is either absent, or selected from the group consisting of OC 1-6 alkylene and
• R 13 is either absent, or selected from the group consisting of C 1-12 alkylene, C 3- 10 cycloalkylene, C 3-10 cycloalkyleneC 1-6 alkylene, heterocycloalkylene, heteroarylene, or arylene; wherein R 13 is optionally substituted with one to four R 15 ;
• R 14 is independently selected from the group consisting of -C 0-3 alkylene-polyethyleneglycol, halo, OH, SH, CN, C 3-10 cycloalkyl, C 1-8 alkoxy, aryl, and heteroaryl;
• R 15 is independently selected from the group consisting of halo, OH, NH 2 , SH, C 3- 10 cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
• integer q is selected from 1-10;
• integers p is independently selected from 1 and 2.
• X 2 is either absent, or comprises an amino acid or a peptide residue selected from Gly-Phe-Gly-Gly, Gly-Phe-Gly, Cit-Val, Cit, Glu, Glu-Gly, Asp-Val-Glu-Asp, Ala-Ala-Gly, and Ala-Ala.
• X 2 is either absent, or comprises an amino acid or a peptide residue selected from Gly-Phe-Gly-Gly, Gly-Phe-Gly, Cit-Val, Cit, Glu, Ala-Ala-Gly, and Ala-Ala.
• R 2 is selected from the group consisting of substituted or unsubstituted C 1-6 alkylene, C 4-7 cycloalkylene, -heteroarylene-C 1-3 alkylene-, -C 1-3 alkylene-heteroarylene-C 1-3 alkylene-, -C 1-6 alkylene- (2, 5-dioxopyrrolidin-1, 3-diyl) -S-C 1-3 alkylene-CH (NH 2 ) -, -C 1-6 alkylene- (2, 5-dioxopyrrolidin-1, 3-diyl) -S-C 1-12 alkylene-, -C 1-6 alkylene- (2, 5-dioxopyrrolidin-1, 3-diyl) -S-C 3-6 cycloalkylene-, , -C 1-6 alkylene- (OCH 2 CH 2 O) q -C 1-6 alkylene-R 6 -S- R 13 -,
• -X 1 -X 2 -X 3 is independently selected from the structures below:
• -X 1 -X 2 -X 3 is independently selected from the structures below:
• R 1 H is represented by Formula II:
• E is independently selected from CH 2 and O;
• R 11 is -W-Y-Z-R 12 or -W-Y-Z-C 1-6 alkylene-R 12 ;
• R 7 is selected from the group consisting of -C 1-6 alkylene-NR i R j , -C 1-6 alkylene-OH, -C 1- 6 alkylene-halo, -S-C 1-6 alkylene-halo, -C 1-6 alkylene-T-W-Y-Z-R 12 , and -C 1-6 alkylene-T-W-Y-Z-C 1-6 alkylene-R 12 ;
• R 12 at each occurrence is independently selected from the group consisting of H, NR i R j , OH, and SH;
• W and Z at each occurrence are independently absent, or independently selected from the group consisting of alkylene, arylene, heteroarylene, cycloalkylene, and heterocycloalkylene, each of which can be substituted with 1 to 4 -CH i R j , F, Cl, Br, I, -C 0-6 alkylene-OH, or -C 0- 6 alkylene-NR i R j ;
• R i and R j at each occurrence are independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and wherein a line with a dotted line represents either a single bond or a double bond;
• n is an integer from 0-19.
• R 1 H is represented by Formula IIa, IIb, IIc or IId according to formula II:
• R 1 is derived from subtraction of a H from the primary alcohol CH 2 OH group, phenylene-OH group, or NH 2 group in the structure R 1 H.
• a compound of any of the formulas I, Ia, or Ib that exerts a therapeutic effect after administration into a mammal by releasing a bioactive agent (s) R 1 H.
• a compound of any of the formulas I, Ia, or Ib possessing anti-inflammatory activity, or a therapeutic effect for a kidney disease as determined by (i) alleviating or slowing kidney cytokines release such as TNF- ⁇ , IL-6, IL-12; (ii) reducing one or more biomarker (s) , optionally wherein the one or more biomarker (s) are selected from protein level (s) , blood urea nitrogen, and serum creatinine; or, (iii) improving a condition of a patient in need of therapy, or of a mammal in animal tests.
• a compound of any of the formulas I, Ia, or Ib possessing anti-inflammatory activity is a therapy for renal inflammation, inflammation diseases in kidney injury or dysfunction, or inflammation induced by a nephrotoxic substance, including a pharmaceutical nephrotoxic substance, such as anticancer, anti-diabetes, anti-infective, or another chemotherapeutic substance.
• a compound of any of the formulas I, Ia, or Ib wherein when it is administered to a mammal, said compound exhibits preferential accumulation in kidneys, with a ratio for its molar concentration in kidneys compared to that in blood of between about 5 and 500.
• a compound of any of the formulas I, Ia, or Ib wherein when administered to a mammal, said compound exhibits preferential accumulation in kidneys, with a ratio for its molar concentration in kidneys compared to that in blood of at least about 20.
• a compound of any of the formulas I, Ia, or Ib wherein when administered to a mammal at a dosing (expressed in molar amount) equal to a standard therapeutic dosing (in molar amount) of an agent R 1 H, said compound exhibits about 1.5-to 15-fold higher loading (tissue concentration) and/or drug exposure (area-under-the-curve, AUC) of agent R 1 H in kidneys, as compared to the standard therapeutic dosing of free drug R 1 H.
• a compound of any of the formulas I, Ia, or Ib wherein when administered to a mammal at a dosing (expressed in molar amount) equal to a standard therapeutic dosing (in molar amount) of agent (s) R 1 H, exhibits about 1.5-to 15-fold higher efficacy, as compared to the standard therapeutic dosing of agent (s) R 1 H, with said therapeutic effect determined as a slowed, stopped, or reversed progression of inflammation (as determined per changes in cytokine release, and/or by using biochemical biomarkers for disease monitoring, or similar methods) .
• a compound of any of the formulas I, Ia, or Ib wherein wherein when administered to a mammal at a dosing (expressed in molar amount) equal to a standard therapeutic dosing (in molar amount) of agent (s) R 1 H, exhibits at least 2-fold higher efficacy, as compared to the standard therapeutic dosing of agent (s) R 1 H, with said therapeutic effect determined as a slowed, stopped, or reversed progression of inflammation or a kidney injury (as determined by levels of a cytokine release, and/or by using biochemical biomarkers for inflammation monitoring, or by radiography, or by magnetic resonance imaging, or alike) .
• a compound of any of the formulas I, Ia, or Ib wherein when administered to a mammal at a dosing (expressed in molar amount) equal to a standard therapeutic dosing (in molar amount) of an agent R 1 H, exhibits at least 2-fold reduced rate of adverse effects and/or off-target toxicity manifestation, as compared to the standard therapeutic dosing of R 1 H, as determined by medical observations of a mammal under therapy, a blood cells count, a tissue biopsy, and/or by analysis of biochemical biomarkers, or similar method.
• a compound of any of the formulas I, Ia, or Ib for therapy of a renal inflammation and wherein the inflammation is the chronic kidney disease (CKD) , systemic lupus erythematosus (SLE) , a nephritis, acute kidney injury (AKI) , or an inflammation in a kidney transplant surgery.
• CKD chronic kidney disease
• SLE systemic lupus erythematosus
• AKI acute kidney injury
• a compound of any of the formulas I, Ia, or Ib possessing an increased in vivo efficacy against an inflammation-associated kidney disease, when compared to a related (parent) anti-inflammatory, immunomodulating, or nephron-protective structure (compound) incorporated into said compound (s) , as determined by in vivo test (s) in animal model (s) of such kidney disorders, wherein said compound and a related free drug (conjugated within a compound provided herein) are dosed at identical molar dose.
• a pharmaceutical composition comprising a compound of formula I, Ia, or Ib, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier.
• a method for treating inflammation in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formulas I, Ia, or Ib, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or the pharmaceutical composition.
• a method for treating an inflammation-associated kidney disease in humans or other warm-blooded animals by administering to the subject in need a therapeutically effective amount of a compound of formulas I, Ia, or Ib, or a pharmaceutically acceptable salt, prodrug, solvate, or hydrate thereof, or the pharmaceutical composition.
• the renal inflammation is the chronic kidney disease (CKD) , systemic lupus erythematosus (SLE) , a nephritis, acute kidney injury (AKI) , diabetic nephropathy, chronic glomerulonephritis, or an inflammation in a kidney transplant surgery.
• CKD chronic kidney disease
• SLE systemic lupus erythematosus
• AKI acute kidney injury
• diabetic nephropathy chronic glomerulonephritis
• an inflammation in a kidney transplant surgery CKD
• SLE systemic lupus erythematosus
• AKI acute kidney injury
• diabetic nephropathy diabetic nephropathy
• chronic glomerulonephritis chronic glomerulonephritis
• E is independently selected from CH 2 and O;
• R 11 is -W-Y-Z-R 12 or -W-Y-Z-C 1-6 alkylene-R 12 ;
• R 7 is selected from the group consisting of -C 1-6 alkylene-NR i R j , -C 1-6 alkylene-OH, -C 1- 6 alkylene-halo, -S-C 1-6 alkylene-halo, -C 1-6 alkylene-T-W-Y-Z-R 12 , and -C 1-6 alkylene-T-W-Y-Z-C 1-6 alkylene-R 12 ;
• R 12 at each occurrence is independently selected from the group consisting of H, NR i R j , OH, and SH;
• W and Z at each occurrence are independently absent, or independently selected from the group consisting of alkylene, arylene, heteroarylene, cycloalkylene, and heterocycloalkylene, each of which can be substituted with 1 to 4 -CH i R j , F, Cl, Br, I, -C 0-6 alkylene-OH, or -C 0- 6 alkylene-NR i R j ;
• R i and R j at each occurrence are independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
• n is an integer from 0-19.
• R 8 and R 9 together form
• E is independently selected from CH 2 and O;
• R 11 is selected from -Z-NR i R j , -Z-OH, and -W-Y-Z-R 12
• R 7 is selected from the group consisting of -C 1-6 alkylene-OH, -C 1-6 alkylene-NH 2 , -C 1- 6 alkylene-T-W-Y-Z-R 12 , -C 1-6 alkylene-T-Z-NR i R j , and -C 1-6 alkylene-T-Z-OH;
• R 11 is selected from the group consisting of alkyl, R 7 is -C 1- 6 alkylene-T-heteroarylene-NR i R j ;
• R 11 is selected from the group consisting of -heteroarylene-NR i R j , -arylene-heteroarylene-NR i R j , -Z-OH, -W-Y-Z-SH, and -W-Y-Z-OH, R 7 is -C 1-6 alkylene-OH;
• G is CH
• R 11 is selected from the group consisting of -Z-NR i R j , -Z-OH, and -W-Y-Z-R 12
• R 7 is selected from the group consisting of -C 1-6 alkylene-T-W-Y-Z-R 12 , -C 1- 6 alkylene-T-Z-OH, -C 1-6 alkylene-T-Z-NR i R j , and -C 1-6 alkylene-NH 2 ;
• R 12 at each occurrence is independently selected from the group consisting of H, -NR i R j , -OH, and -SH;
• W is selected from the group consisting of arylene, heteroarylene, cycloalkylene, and heterocycloalkylene;
• Z at each occurrence is independently selected from the group consisting of arylene, heteroarylene, cycloalkylene, and heterocycloalkylene;
• Y is C 1-6 alkylene, O, or S;
• R 10 at each occurrence is independently selected from the group consisting of -OH, halo, alkyl, and arylalkyl;
• R i and R j at each occurrence are independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and wherein a line with a dotted line represents either a single bond or a double bond;
• n is an integer from 0-19.
• the compound is represented by Formula IIa, IIb, IIc or IId according to formula II:
• W is selected from the group consisting of
• Z at each occurrence is independently selected from the group consisting of:
• the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix C i-j indicates a moiety of the integer “i” to the integer “j” carbon atoms, inclusive.
• C 1-14 alkyl refers to alkyl of one to fourteen carbon atoms, inclusive.
• alkyl refers to both straight and branched saturated hydrocarbon groups. Reference to an individual radical such as “propyl” embraces only the straight chain radical, and a branched chain isomer such as “isopropyl” being specifically referred to. Unless specified otherwise “alkyl” contains 1-12 carbon atoms. In addition to any group specifically recited in any of the embodiments or claims, the alkyl group is optionally substituted with one, two, three, or four substituents selected from the group consisting of halo, hydroxy, cyano, C 1-12 alkyl, C 3- 7 cycloalkyl, aryl, biaryl, heterocyclic, or heteroaryl (Het) group.
• alkyl is unsubstituted.
• Alkyl groups distinguished as “alkyl” and “alkyl 1 " or “alkyl 2 " refer to independently selected alkyl groups that may be different from each other, or independently equal to each other. If the term "alkyl" is used more than once in the same group, then each "alkyl" is independent of another "alkyl” , at each appearance.
• Alk refers to alkyl, as defined herein.
• alkylene refers to a divalent alkyl group. Unless specified otherwise linear “alkylene” contains 1-12 carbon atoms. The alkylene group is optionally substituted as described for alkyl. In some embodiments, alkylene is unsubstituted. Alkylene groups distinguished as “alkylene” and “alkylene 1 " or “alkylene 2 " refer to independently selected alkylene groups that may be different from each other, or independently equal to each other. Wherein, C 0 alkylene represents absent.
• alkenyl refers to both straight and branched hydrocarbon groups containing at least one double bond, and in some embodiments 1, 2, or 3 double bonds. Unless specified otherwise “alkenyl” contains 2-12 carbon atoms. In addition to any group specifically recited in any of the embodiments or claims, the alkenyl is optionally substituted with one, two, or three substituents selected from the group consisting of halo, C 1-12 alkyl, C 3-7 cycloalkyl, aryl, biaryl, Het 1 .
• alkenylene refers to a divalent alkenyl group. Unless specified otherwise “alkenylene” contains 2-12 carbon atoms. The alkenylene group is optionally substituted as described for alkenyl. In some embodiments, the alkenylene group is unsubstituted.
• cycloalkyl or “carbocycle” refers to a saturated or partially unsaturated, monocyclic, fused bicyclic, bridged polycyclic, or spirocyclic ring assembly containing from 3 to 12, from 3 to 10, or from 3 to 7 ring atoms, or the number of atoms indicated.
• Monocyclic rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.
• Bicyclic and polycyclic rings include, for example, norbornane, decahydronaphthalene and adamantane.
• C3-C8 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and norbornane. These encompass fused structures.
• the term “fused” refers to two or more rings which have at least two atoms and one bond in common, such as in two cyclohexane rings sharing one carbon-carbon bond.
• the term “bridged polycyclic” refers to compounds wherein the cycloalkyl contains a linkage of one or more atoms connecting non-adjacent atoms.
• the term “spirocyclic” refers to two rings which have one atom in common and the two rings are not linked by a bridge.
• fused cycloalkyl groups are decahydronaphthalenyl, dodecahydro-1H-phenalenyl and tetradecahydroanthracenyl; examples of bridged cycloalkyl groups are bicyclo [1.1.1] pentyl, adamantanyl, and norbornanyl; and examples of spiro cycloalkyl groups include spiro [3.3] heptane and spiro [4.5] decane.
• cycloalkyl group is optionally substituted with one, two, or three substituents selected from the group consisting of halo, C 1-12 alkyl, C 3-7 cycloalkyl, aryl, and Het or heteroaryl. In some embodiments, cycloalkyl is unsubstituted.
• cycloalkylene refers to a cycloalkyl group, as defined above, linking at least two other groups, i.e., a divalent hydrocarbon radical.
• the two moieties linked to the cycloalkylene can be linked to the same atom or different atoms of the cycloalkylene.
• Cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and cyclooctylene.
• the cycloalkylene group is optionally substituted as described for cycloalkyl.
• the cycloalkylene is unsubstituted.
• the C 3-6 cycloalkylene group formed by any two of R 4 through R 10 is optionally substituted with one or two groups independently selected from C 1-6 alkyl and aryl.
• heterocycloalkyl refers to a cycloalkyl, as defined above, containing 1 to 5 heteroatoms such as N, O and S.
• the heteroatoms can also be oxidized, such as, but not limited to, -S (O) -and -S (O) 2 -.
• heterocycle includes, but is not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, morpholino, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, piperidinyl, indolinyl, quinuclidinyl and 1, 4-dioxa-8-aza-spiro [4.5] dec-8-yl.
• heterocycloalkylene refers to a heterocyclalkyl group, as defined above, linking at least two other groups.
• the two moieties linked to the heterocycloalkylene can be linked to the same atom or different atoms of the heterocycloalkylene.
• heteroalkyl means an alkyl or cycloalkyl group, as defined above, having a substituent containing a heteroatom selected from N, O, and S (O) n , where n is an integer from 0 to 2, where in some embodiments the substituent includes, hydroxy (OH) , C 1- 4 alkoxy, amino, thio (-SH) , and the like.
• heterocyclic substituent e.g., heteroalkyl can be 2- (4-morpholino) ethyl
• substituents include -NR a R b , -OR a , and -S (O) n R c , wherein each R a is independently hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic, or –C (O) R (where R is C 1-4 alkyl) ; each R b is independently hydrogen, C 1-4 alkyl, -SO 2 R (where R is C 1-4 alkyl or C 1-4 hydroxyalkyl) , -SO 2 NRR’ (where R and R’ are independently of each other hydrogen or C 1-4 alkyl) , or -CONR'R” (where R’ and R” are independently of each other hydrogen or C 1-4 alkyl) ; n is an integer from 0 to 2; and each R c is independently hydrogen, C 1- 4 alkyl, C 3-6 cycloalkyl, optionally substituted aryl, or NR
• heteroalkyl includes, but is not limited to 2-methoxyethyl (-CH 2 CH 2 OCH 3 ) , 2-hydroxyethyl (-CH 2 CH 2 OH) , hydroxymethyl (-CH 2 OH) , 2-aminoethyl (- CH 2 CH 2 NH 2 ) , 2-dimethylaminoethyl (-CH 2 CH 2 NHCH 3 ) , benzyloxymethyl, thiophen-2-ylthiomethyl, and the like.
• halo refers to fluoro (F) , chloro (Cl) , bromo (Br) , or iodo (I) .
• aryl refers to a monocyclic or fused bicyclic, tricyclic or greater, aromatic ring assembly containing 6 to 16 ring carbon atoms.
• aryl may be phenyl, benzyl or naphthyl, preferably phenyl.
• Aryl groups may include fused multicyclic ring assemblies wherein only one ring in the multicyclic ring assembly is aromatic.
• Aryl groups can be mono-, di-or tri-substituted by one, two or three radicals.
• aryl is naphthyl, phenyl or phenyl mono-or disubstituted by alkoxy, phenyl, halogen, alkyl or trifluoromethyl, especially phenyl or phenyl-mono-or disubstituted by alkoxy, halogen or trifluoromethyl, and in particular phenyl.
• Aryl groups distinguished as “aryl” and “aryl 1 " or “aryl 2 " refer to independently selected aryl groups that may be different from each other, or independently equal to each other. If the term “aryl” is used more than once in the same group, then each "aryl” is independent of another “aryl” , at each appearance.
• arylene refers to an aryl group, as defined above, linking at least two other groups.
• the two moieties linked to the arylene are linked to different atoms of the arylene.
• Arylene groups include, but are not limited to, phenylene.
• arylalkyl refers to an alkyl group substituted with an aryl group, each as defined herein, including where the aryl and alkyl are optionally substituted as described in their respective definitions.
• arylheteroaryl refers to an aryl group substituted with a heteroaryl group, each as defined herein, including where the aryl and heteroaryl are optionally substituted as described in their respective definitions.
• heteroarylaryl refers to a heteroaryl group substituted with an aryl group, each as defined herein, including where the aryl and heteroaryl are optionally substituted as described in their respective definitions.
• biasing refers to an aryl group as defined herein substituted with another aryl group as defined herein, including where the aryl groups are independently optionally substituted as described in the definition.
• biasing alkyl refers to an alkyl group substituted with an aryl group which is substituted with another aryl group, each as defined herein, including where each aryl independently and alkyl are optionally substituted as described in their respective definitions
• the heterocyclic ring is unsubstituted.
• the 4 to 7 or 5 to 7 membered ring formed by any two of R 4 through R 10 and/or formed by R 11 and R 12 and/or formed by R 4 and R 11 and/or formed by R 6 and R 12 is optionally substituted as described herein for heterocycle.
• the 5 to 7 membered ring formed by R 11 and R 12 and/or formed by R 4 and R 11 and/or formed by R 6 and R 12 is optionally substituted with one or two groups independently selected from C 1-6 alkyl and aryl.
• Het 1 at each occurrence is independently a C-linked 5-or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring.
• cycloalkyl in the context of the term cycloalkyl, cycloalkylene, and heterocycle refers to a partially unsaturated, but not aromatic ring.
• heterocylic rings include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, isoxazolinone, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1, 2, 3, 4-tetrahydro-is
• heteroaryl refers to a five- (5) or six- (6) membered C-or N-linked heterocyclic ring, optionally fused to a benzene or to another heterocyclic ring (wherein at least one of the heterocyclic rings is aromatic) .
• Heterocyclic ring fused to a benzene ring is also referred to as benzo-heterocyclic group.
• heteroaryl includes, but is not limited to, pyridine, thiophene, furan, pyrazole, indole, benzimidazole, quinoline, pyrimidine, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 4-oxo-2-imidazolyl, 2-imidazolyl, 4-imidazolyl, 3-isoxaz-olyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 4-oxo-2-oxazolyl, 5-oxazolyl, 1, 2, 3-oxathiazole, 1, 2, 3-oxadiazole, 1, 2, 4-oxadiazole, 1,
• heteroaryl is unsubstituted.
• Heteroaryl groups distinguished as “heteroaryl” and “heteroaryl 1 " or “heteroaryl 2 " refer to independently selected heteroaryl groups that may be different from each other, or independently equal to each other.
• heteroaryl is used more than once in the same group, then each "heteroaryl” is independent of another “heteroaryl” , at each appearance.
• heteroarylene is a divalent group based on the aforementioned heteroaryl.
• heteroarylalkyl refers to an alkyl group substituted with an heteroaryl group, each as defined herein.
• the term “mono-substituted” refers to a group having at least one substituent in said group, not counting the point of connection of this group to the main structure or general formula.
• the term “multiply-substituted” refers to a group having at least two substituents in said group, not counting the point of connection of this group to the main structure or general formula.
• carbon atom means the atom of element carbon optionally substituted with H, halo, NR a R b , C 1-12 alkyl, C 3-7 cycloalkyl, aryl, heteroaryl, or with a heterocyclic ring.
• Carbon atom comprises atoms with sp3, sp2, and sp electronic hybridization.
• aryl group optionally mono-or di-substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the aryl group is mono-or disubstituted with an alkyl group and situations where the aryl group is not substituted with the alkyl group.
• isomers Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers” . Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers” .
• stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers” .
• enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
• An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R-and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-) -isomers respectively) .
• a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture” .
• the compounds provided herein may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R) -or (S) -stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and Claims is intended to include all individual enantiomers and any mixtures, racemic, partially racemic, or otherwise, thereof.
• the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry” , 4th edition J. March, John Wiley and Sons, New York, 1992) .
• a hydrogen (H) , carbon (C) , or nitrogen (N) substitution for compounds of the formulas I-IV include a substitution with any isotope of the respective atom.
• a hydrogen (H) substitution includes a 1 H, 2 H (deuterium) , or 3 H (tritium) isotope substitution, as may be desired, for example, for a specific therapeutic or diagnostic therapy, or metabolic study application, or stability enhancement.
• a compound of this invention may incorporate a known in the art radioactive isotope or radioisotope, such as any number of 3 H, 15 O, 12 C, or 13 N isotopes, to afford a respective radiolabeled compound of formulas I-IV.
• a “pharmaceutically acceptable carrier” means a carrier that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use as well as human pharmaceutical use. “A pharmaceutically acceptable carrier” as used in the specification and Claims includes both one and more than one such carrier.
• a “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
• Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
• Treating” , “treatment” , or “therapy” of a disease includes:
• a “therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
• the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
• Leaving group has the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group capable of being displaced by a nucleophile and includes halogen, C 1-4 alkylsulfonyloxy, ester, or amino such as chloro, bromo, iodo, mesyloxy, tosyloxy, trifluorosulfonyloxy, methoxy, N, O-dimethylhydroxyl-amino, and the like.
• Prodrug means any compound which releases an active parent drug according to a compound provided herein in vivo when such prodrug is administered to a mammalian subject.
• Prodrugs of a compound of provided herein are prepared by modifying functional groups present in a compound provided herein in such a way that the modifications may be cleaved in vivo to release the parent compound.
• Prodrugs include compounds provided herein wherein a hydroxy, sulfhydryl, amido or amino group in the compound is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amido, amino, or sulfhydryl group, respectively.
• prodrugs include, but are not limited to esters (e.g., acetate, formate, benzoate, phosphate or phosphonate derivatives) , carbamates (e.g., N, N-dimethylaminocarbonyl) of hydroxy functional groups in compounds provided herein, and the like.
• Prodrugs of compounds provided herein may be used for particular therapeutic application, such as for pulmonary delivery of an aerosol containing a prodrug of such a compound, or to improve tolerance to same agent.
• a methanesulfonate prodrug form of polymyxin drug colistin (described, for example by Bergen et al. in Antimicrob. Agents Chemother. 2006, vol. 50, p. 1953) is used to reduce neurotoxic effects of colistin, and is used for aerosol administration of this drug.
• This and other known forms of prodrugs could be likewise used to further improve pharmaceutical properties of the compounds provided herein.
• mamal refers to all mammals including humans, livestock, and companion animals.
• C 1-14 alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, octyl, nonyl, decyl, and isomeric forms thereof.
• C 2-12 alkenyl can be vinyl, propenyl, allyl, butenyl, and isomeric forms thereof (including cis and trans isomers) .
• C 3-7 cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and isomeric forms thereof.
• C 1-14 heteroalkyl can be hydroxymethyl, hydroxyethyl, 2- (N, N-dimethylamino) ethyl, 2- (4-morpholino) ethyl, and 2-methoxyethyl.
• halo can be fluoro (F) or chloro (Cl) .
• the parent (precursor) structure of R 1 in a compound of formula II is selected from the structures below.
• the parent (precursor) structure of R 1 in a compound of formula II is selected from the structures below.
• Some preferred compounds of formulas I are exemplified below, including any salt thereof, such as a hydrochloride, a sulfate, or another pharmaceutically acceptable salt.
• a compound of any one of formulas I, Ia, or Ib, or any embodiments therein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof is useful for therapy of an inflammation, wherein the inflammation is a renal inflammation, or inflammation diseases in a kidney injury or dysfunction, or an inflammation induced by a nephrotoxic substance, including a pharmaceutical nephrotoxic substance, such as anticancer, anti-diabetes, anti-infective, or another chemotherapeutic substance.
• a compound of any one of formulas I, Ia, or Ib, or any embodiments therein possesses an enhanced anti-inflammatory, immunomodulating, or nephro-protective effect when compared to a similar dose of a free agent or drug R 1 incorporated into said compound as determined by in vitro or in vivo test (s) for anti-inflammatory, immunomodulating, or nephro-protective activity.
• a compound of any one of formulas I, Ia, or Ib, or any embodiments therein and wherein when it is administered to a mammal at a dosing (expressed in molar amount) equal to a standard therapeutic dosing (in molar amount) of an agent R 1 , said compound exhibits about 1.5-to 15-fold higher loading (tissue concentration) and/or drug exposure (area-under-the-curve, AUC) of agent R 1 in kidneys, as compared to the standard therapeutic dosing of free drug R 1 .
• a compound provided herein may be used in a combination with an adjunct agent, to act synergistically and/or enhance therapeutic effects of said compound itself, or of an adjunct agent, or both.
• adjunct agents include other anticancer or immunomodulating agent (s) , such as a monoclonal antibody agent, or another anti-inflammatory agent (s) , or another anticancer or antibacterial agent, or humanized antibody such as pembrolizimab.
• a compound provided herein has modest or no anti-inflammatory activity in vitro, but exhibits high anti-inflammatory efficacy when administered to a mammal in need of such a therapy.
• a pharmaceutical composition comprising a therapeutically effective amount of a compound of a compound of formulaI, Ia, or Ib, or as defined in any of the embodiments described herein, and a pharmaceutically acceptable carrier.
• the compounds of this invention can be prepared in accordance with one or more of methods described, for example, in references below.
• General syntheses of certain related starting materials have been described in the literature.
• the preparation of Boc-protected polymyxin nonapeptide was described by O’Dowd et al. in Tetrahedron Lett. 2007, vol. 48, p. 2003.
• Additional protected polymyxin B nonapeptide and colistin nonapeptide derivatives can be prepared as described by Okimura et al. in Chem. Pharm. Bull. 2007, vol. 55, pp. 1724-1730.
• the general peptide acylation chemistry was described in the ref. Tetrahedron Lett. 2007, vol. 48, pp. 2003-2005.
• MS mass-spectroscopy data (m/z) for a positive ionization method.
• HPLC reverse-phase high-performance chromatography using commercial C18 phase columns.
• TCFH N, N, N′, N′-Tetramethylchloroformamidinium hexafluorophosphate.
• ACN MeCN
• DCC N, N’-dicyclohexylcarbodiimide.
• NMP N-methyl pyrrolidinone
• NsCl 4-nitrophenylsulfonyl chloride.
• PE hexanes or light petroleum ether.
• C18 chromatography reverse phase chromatography using a gradient of 0.1%TFA in water and acetonitrile (ACN) .
• PMBN (Boc) 4 same as PMBNBoc 4 : H-Thr-Dab (Boc) -cyclo [Dab-Dab (Boc) -D-Phe-Leu-
• PMBH (Boc) 3 same as PMBNBoc 3 : cyclo [Dab-Dab (Boc) -D-Phe-Leu-Dab (Boc) -Dab (Boc) -Thr] .
• Other reagent abbreviations are just as employed in common synthetic literature, including the American Chemical Society list of abbreviations, such as found, for example, in the Journal of Organic Chemistry; or in the Journal of Peptide Chemistry. Unless specified otherwise, all reagents were either from commercial sources, or made by conventional methods described in available literatures.
• the compounds provided herein exhibit potent activities against a variety of inflammation-associated kidney disorders, including CKD, AKI, post-surgery inflammation (such as in kidney transplantation surgery) , or an inflammation induced by anticancer or antibacterial therapy, or in treatment of diabetes, or due to an exposure to nephrotoxic substances. Therefore, these agents are useful for therapy of such renal diseases.
• In vitro activity of compounds provided herein may be assessed by testing procedures using standard bioassays used for evaluation of active entities (payloads) incorporated (conjugated) within the composition provided herein. Selection of specific assay (s) will be determined from a known or anticipated mode-of-action of the payload structure. For example, conjugates incorporating anti-inflammatory vanin-1 inhibitors may be tested in human vanin-1 enzymatic assay just as described in publication PCT WO 2020/114943.
• Preferential renal targeting validating the delivery of compounds provided herein into kidneys can be evaluated by pharmacokinetic (PK) tests, such as in a standard rodent PK test.
• PK data are generally used to establish the key parameters predictive of the therapy outcome.
• a drug concentration (C) at a given time point, drug concentration at the target tissue (s) (C Target ) , area under the curve (AUC) for a plot monitoring the change in the systemic drug concentration over time and other parameters are generally predictive of therapeutic efficacy.
• drug concentration at an organ affected by cancer is important for effective action of anticancer agents (as described, for example, by Zhang et al. in Drug Metabolism and Disposition. 2019, vol. 47, p. 1122) .
• LPS lipopolysaccharide
• the serum creatinine (CREA) was determined by a standard procedure using a biochemical analyzer. As clear from results shown in Table 2, the compounds of the present invention can significantly reduce the levels of serum creatinine induced by LPS. This indicates a beneficial reduction in the level of kidney inflammation (injury) induced by LPS toxins used in the model.
• the dexamethasone dose of 2.5 mg/kg (6.4 ⁇ mol/kg) was about 5x of active glucocorticoide within the Compounds of Example 15 (dosed at 2.5 mg/kg or 1.3 ⁇ mol/kg) , of Example 15 (2.5 mg/kg or 1.2 ⁇ mol/kg) and of Example 26 (2.5 mg/kg or 1.3 ⁇ mol/kg) .
• CREA data for dexamethasone (2.5 mg/kg) was 45.6 ⁇ 19.3, respectively.
• the administration of active glucocorticoid receptor agonists in the novel conjugated forms of the compounds of Examples 3, 5 and 15 results in the kidney drug levels (measured as the concentrations in the kidney tissue) enhanced about 5-6 folds, as compared to dexamethasone kidney levels achieved through injection of dexamethasone as its (unconjugated) drug form. Since the drug levels at the site affected by a disease directly affect the therapeutic efficacy (in vivo activity) of a pharmaceutical agent, the data illustrated in Table 1 indicate the greatly enhanced therapeutic potential in vivo of the novel composition provided herein.
• the data illustrated in the Table 1 further indicate that a less frequent dosing of such agents is possible, as compared to a standard administration of dexamethasone. Based on these data, the compounds of Examples 3 and 5 may be dosed much less frequently, for example, once-daily, or once-weekly, etc. This advantage greatly benefits patients in need of such therapy. In addition, this useful feature provides significant pharmacoeconomic benefits due to minimized need in medical procedures at a hospital providing the treatment.
• In vivo activity of compounds provided herein may also be assessed by testing procedures such described, for example, for evaluation of anti-inflammatory and immunomodulating effect of corticosteroid agents by Chen et al. in Inflammopharmacology, 2018 26, pp. 1331–1338; or for testing in rodent models of nondiabetic and diabetic chronic nephropathies described by Perico et al. in Kidney International, 2005, vol. 68, Supplement 98, pp. S21–S24 and by Remuzzi et al. in Kidney International, 2002, vol. 62, pp. 885–894, as well as in additional testing methods in references cited therein.
• certain compounds provided herein when tested in rodent models of renal inflammation and of kidney disease with intravenous administration at a dosing (molar amount) equal to a standard therapeutic dosing (molar amount) of dexamethasone or another corticosteroid, or a non-steroidal anti-inflammatory agent (such as naproxene, or a vanin-1 inhibitor) , exhibit at 2-fold or higher efficacy, as compared to a standard therapeutic dosing of such an agent, with said therapeutic effect determined as a slowed, stopped, or reversed progression of a renal inflammation or a kidney disease (including, for example, a renal nephropathy or acute kidney injury induced by a chemical agent, or a cytotoxic pharmaceutical agent, such as chemotherapeutic anticancer drug, or in the transplantation surgery) .
• compounds provided herein exhibit little or no toxic against normal kidney cells, both in vitro (such as in human kidney cell HK-2 assay) and in a live mammal model, such as a rodent model.
• a safe profile of the compounds of the current invention may be further established in biomarker assays predictive of nephrotoxicity.
• biomarker assays predictive of nephrotoxicity.
• assays including NGAL assay
• certain compounds provided herein when administered to a mammal at a dosing (expressed in molar amount) equal to a standard therapeutic dosing (molar amount) of dexamethasone or another corticosteroid, or a non-steroidal anti-inflammatory agent (such as naproxene, or a vanin-1 inhibitor) , exhibits at least 2-fold reduced rate (frequency or incidence) of adverse effects and/or off-target toxicity manifestation (such as myelosuppression or bone marrow toxicity) , as compared to the standard therapeutic dosing of axitinib, brivanib, pazopanib, or sunitinib (for example, as determined by the platelet and/or other blood cells count for myelosuppression or bone marrow toxicity) .
• certain compounds of this invention exhibit high efficacy in therapy of inflammation-associated renal disorders, but do not suffer from excessive off-target toxicity limiting a standard therapy of such diseases.
• novel compounds and compositions provided herein potentially provide a long throught-after safer and effective targeted therapy for kidney diseases and renal injury, including CKD, AKI, and other renal injuries encountered in kidney transplantations.
• the compounds provided herein can be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
• compounds provided herein may be administered orally, parenterally, transdermally, topically, rectally, or intranasally, or by way of intra-tumoral administration directly into a cancerous tumor.
• the actual amount of a compound provided herein, i.e., the active ingredient will depend on a number of factors, such as the severity of the disease, i.e., the infection, to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors, all of which are within the purview of the attending clinician.
• the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
• the dosage of such compounds lies preferably within a range of circulating concentrations that include therapeutic efficacy with little or no toxicity.
• the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
• the therapeutically effective dose can be estimated initially from animal models.
• a dose may be formulated in animal models to achieve a circulating plasma concentration range which includes the IC 50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans.
• the compounds provided herein are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, parenteral, transdermal, topical, rectal, and intranasal.
• compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
• compositions which contain, as the active ingredient, one or more of the compounds provided herein above associated with pharmaceutically acceptable carriers.
• the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
• the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
• compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium) , ointments containing, for example, up to 10%by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
• compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.1 to about 2000 mg, more usually about 1 to about 900 mg, of the active ingredient.
• unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
• the compound provided herein above is employed at no more than about 20 weight percent of the pharmaceutical composition, more preferably no more than about 15 weight percent, with the balance being pharmaceutically inert carrier (s) .
• An active compound is effective over a wide dosage range and is generally administered in a pharmaceutically or therapeutically effective amount. It will be understood, however, that the amount of the compound actually administered can be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the severity of the bacterial infection being treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.
• compounds or pharmaceutical compositions thereof can be administered orally, topically, transdermally, and/or parenterally at a dosage to obtain and maintain a concentration, that is, an amount, or blood-level of active component in the animal undergoing treatment which will be antibacterially effective.
• a dosage that is, an amount, or blood-level of active component in the animal undergoing treatment which will be antibacterially effective.
• such antibacterially or therapeutically effective amount of dosage of active component i.e., an effective dosage
• an effective dosage will be in the range of about 0.1 mg/kg to about 250 mg/kg, more preferably about 1.0 mg/kg to about 50 mg/kg of body weight/day.
• the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
• a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
• the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
• This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
• the tablets or pills described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
• the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
• the two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
• enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
• liquid forms in which the novel compositions described herein may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as corn oil, cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
• liposomal formulations of compounds of this invention may be used, for example, to enhance therapeutic effect against certain infections, such as pneumonia or ling infections.
• Intra-tumoral administration of compounds provided herein employs solutions or gels thereof prepared in suitable aqueous solutions containing appropriate excipient additives, such as dextrose, polyethylene glycol, cremophore, cyclodextrin, and alike.
• excipient additives such as dextrose, polyethylene glycol, cremophore, cyclodextrin, and alike.
• 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 described supra.
• the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
• Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure-breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
• the compounds of the present invention may be co-administered with additional agents, including antioxidants, such as ascorbic acid, or megalin-receptor inhibitors generally known to attenuate adverse effects of polymyxin drugs.
• antioxidants such as ascorbic acid
• megalin-receptor inhibitors generally known to attenuate adverse effects of polymyxin drugs.
• the compounds described herein are suitable for use in a variety of drug delivery systems described above. Additionally, in order to enhance the in vivo serum half-life of the administered compound, the compounds may be encapsulated, introduced into the lumen of liposomes, prepared as a colloid, or other conventional techniques may be employed which provide an extended serum half-life of the compounds. A variety of methods are available for preparing liposomes, as described in, e.g., Szoka, et al., U.S. Patent Nos. 4,235,871, 4,501,728 and 4,837,028 each of which is incorporated herein by reference.
• the compounds described herein could be administered as nanomicells, or nanomaterials-encapsulated compositions, prepared as described, for example, by Taki et al. in Pharmaceut., 2012, vol. 3, p. 1092.
• the compounds administered to a patient are in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
• the pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 and 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

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