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Patent Analysis of

Prodrug compounds and uses thereof

Updated Time 12 June 2019

Patent Registration Data

Publication Number

US10150788

Application Number

US16/005601

Application Date

11 June 2018

Publication Date

11 December 2018

Current Assignee

LIGAND PHARMACEUTICALS, INC.

Original Assignee (Applicant)

LIGAND PHARMACEUTICALS INC.

International Classification

A61K31/662,A61K31/663,A61K31/6615,A61K45/06,C07F9/6574

Cooperative Classification

C07F9/657181,A61K31/662,A61K31/663,A61K45/06,C07F9/65746

Inventor

ZHI, LIN

Patent Images

This patent contains figures and images illustrating the invention and its embodiment.

US10150788 Prodrug compounds 1 US10150788 Prodrug compounds 2 US10150788 Prodrug compounds 3
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Abstract

Provided herein are cyclic phosphorus-containing prodrug compounds, their preparation and their uses, such as treating diseases via modulating molecular targets in the liver.

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Claims

1. A compound of Formula I: wherein: R1 and R2 are independently selected from the group consisting of H, M, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted aryl, and an optionally substituted heteroaryl; M is a biological agent or part of a biological agent or a prodrug of a biological agent; X and X′ are independently O or NR3; Y is selected from the group consisting of a bond, O, S, NR4, Si(R4)2, and an optionally substituted C1-C6 alkyl; R3 is selected from the group consisting of H, a C1-C6 alkyl, and a C1-C6 heteroalkyl; R4 is selected from the group consisting of H, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; or a stereoisomer or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein M is a nucleoside antiviral or anticancer agent.

3. The compound of claim 1, wherein M is a lipid modulator.

4. The compound of claim 1, wherein M is a nuclear hormone receptor modulator.

5. The compound of claim 1, wherein M is at least one selected from the group consisting of: a HCV polymerase inhibitor, a reverse transcriptase inhibitor, a DNA synthesis inhibitor, an RNA synthesis inhibitor, and an antimetabolic agent.

6. The compound of claim 1, having the structure: or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

8. A method of treating a disease, disorder or condition in the liver of a subject comprising:

administering an effective amount of a compound of claim 1 to a subject in need thereof.

9. A method of treating a disease, disorder or condition by intervening in a molecular pathway or target in the liver in a subject comprising:

administering an effective amount of a compound of claim 1 to a subject in need thereof.

10. A method of treating a disease, disorder or condition in the liver or a disease, disorder or condition in which the physiological or pathogenic pathways involve the liver in a subject, comprising:

administering an effective amount of a compound of claim 1 to the subject.

11. The method of claim 8, wherein the disease, disorder or condition is selected from the group consisting of hepatitis, liver cancer, liver fibrosis, malaria, viral infection, parasitic infection, cancer, fatty liver, diabetes, hyperlipidemia, atherosclerosis, obesity, dyslipidemia, hyperglycemia and a hormonal condition.

12. The method of claim 8, further comprising administering an effective amount of an additional therapeutic agent to the subject in need thereof.

13. The method of claim 8, wherein the subject is a mammal.

14. The method of claim 8, wherein the subject is a human.

15. A method of intervening in a molecular pathway or modulating a target in a cell comprising contacting the cell with a compound of claim 1.

16. The method of claim 15, wherein the cell is in vivo.

17. The method of claim 15, wherein the cell is ex vivo.

18. The method of claim 15, wherein the cell is a hepatocyte.

19. The method of claim 15, wherein the cell is mammalian.

20. The method of claim 15, wherein the cell is human.

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Claim Tree

  • 1
    1. A compound of Formula I: wherein
    • : R1 and R2 are independently selected from the group consisting of
    • 2. The compound of claim 1, wherein
      • M is a nucleoside antiviral or anticancer agent.
    • 3. The compound of claim 1, wherein
      • M is a lipid modulator.
    • 4. The compound of claim 1, wherein
      • M is a nuclear hormone receptor modulator.
    • 5. The compound of claim 1, wherein
      • M is at least one selected from the group consisting of:
    • 6. The compound of claim 1, having
      • the structure: or a pharmaceutically acceptable salt thereof.
  • 7
    7. A pharmaceutical composition comprising
    • a compound of claim 1 and a pharmaceutically acceptable excipient.
  • 8
    8. A method of treating a disease, disorder or condition in the liver of a subject comprising:
    • administering an effective amount of a compound of claim 1 to a subject in need thereof.
    • 11. The method of claim 8, wherein
      • the disease, disorder or condition is selected from the group consisting of
    • 12. The method of claim 8, further comprising
      • administering an effective amount of an additional therapeutic agent to the subject in need thereof.
    • 13. The method of claim 8, wherein
      • the subject is a mammal.
    • 14. The method of claim 8, wherein
      • the subject is a human.
  • 9
    9. A method of treating a disease, disorder or condition by intervening in a molecular pathway or target in the liver in a subject comprising:
    • administering an effective amount of a compound of claim 1 to a subject in need thereof.
  • 10
    10. A method of treating a disease, disorder or condition in the liver or a disease, disorder or condition in which
    • the physiological or pathogenic pathways involve the liver in a subject, comprising:
  • 15
    15. A method of intervening in a molecular pathway or modulating a target in a cell comprising
    • contacting the cell with a compound of claim 1.
    • 16. The method of claim 15, wherein
      • the cell is in vivo.
    • 17. The method of claim 15, wherein
      • the cell is ex vivo.
    • 18. The method of claim 15, wherein
      • the cell is a hepatocyte.
    • 19. The method of claim 15, wherein
      • the cell is mammalian.
    • 20. The method of claim 15, wherein
      • the cell is human.
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Description

FIELD

Compositions and methods in the field of medicine and chemistry are disclosed. Some of the disclosed embodiments are directed to medicinal dual and triple phosphorus containing prodrug compounds, medicinal compositions, as well as processes for their preparation and methods of their use. Some embodiments include prodrug compounds of acid/alcohol derivatives such as phosphates, phosphonates, phosphonamidates, phosphoramidates, carboxylates, phenolates, and alkoxyl, their preparation and their uses. In some embodiments, such prodrug compounds are useful to selectively deliver the acid/alcohol derivatives to the liver.

BACKGROUND

The following description of the background is provided to aid in understanding the invention, but is not admitted to be, or to describe, prior art to the invention.

Prodrugs are frequently used to improve certain properties of pharmacological agents for a preferred route of administration, including physicochemical, biopharmaceutical or pharmacokinetic properties. Certain prodrugs (also called soft drugs) are designed by tissue selective activation or deactivation to achieve therapeutic advantages (See J. Rautio, et al. Nature Reviews Drug Discovery 7: 255-270 (2008)).

Certain cyclic phosphate, phosphonate, phosphonamidate, and phosphoramidate prodrugs are disclosed in U.S. Pat. No. 6,312,662 and U.S. Pat. No. 7,205,404 and designed for liver-targeting of pharmacological agents. These prodrugs are activated by liver cytochrome P450 enzymes CYP3As that are predominantly expressed in the target tissue and designed to achieve the selective delivery of pharmacological agents to the liver. Since the prodrugs are not active outside the liver, the liver-targeting strategy reduces pharmacological or toxicological effects of a biologically active agent outside the targeting tissue. As a result, once used to treat liver diseases or to treat diseases via intervening in molecular pathways in the liver, the liver-targeting significantly improves patient benefit/risk ratio of a pharmacological agent (e.g. see M. D. Erion, et al. J Pharm Exp Ther 312:554-60 (2005)).

SUMMARY

Novel dual and triple phosphorus containing prodrug compounds of acid/alcohol derivatives such as phosphates, phosphonates, phosphonamidates, phosphoramidates, carboxylates, phenolates, and alkoxylates, their preparation and their uses are described. Some embodiments are related to novel prodrug compounds that do not generate a vinyl keto reactive intermediate in the activation process. Some embodiments are directed to the use of the prodrugs to enhance oral drug delivery. Some embodiments are directed to the use of the prodrugs to enhance efficiency to achieve higher triphosphate levels. Another aspect includes the use of prodrugs to treat diseases that benefit from enhanced drug distribution to the liver and like tissues and cells, including but not limited to hepatitis, cancer, liver fibrosis, fatty liver, malaria, other viral and parasitic infections, and metabolic, cardiovascular, and/or hormonal diseases where the liver is involved in the production and/or the homeostasis control of the biochemical end products, e.g. glucose, cholesterol, triglycerides, lipoproteins, apolipoproteins, and sex hormone-binding globulin (SHBG). Examples of such diseases include diabetes, hyperlipidemia, atherosclerosis, obesity and the like. In another aspect, prodrugs are used to prolong pharmacodynamic half-life of a drug. In some embodiments, the prodrug methodology can be used to achieve sustained delivery of the parent drug. In another aspect, prodrugs are used to increase the therapeutic index of the drug. In some embodiments, the prodrugs are useful in the delivery of diagnostic imaging agents to the liver. Some additional embodiments relate to a method of making prodrugs.

Some embodiments of the compounds, compositions, and methods provided herein include a compound of Formula I:

    • wherein:
    • R1 and R2 are independently selected from the group consisting of H, M, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
    • M is a biological agent or part of a biological agent or a prodrug of a biological agent;
    • X and X′ are independently O or NR3;
    • Y is selected from the group consisting of a bond, O, S, NR4, Si(R4)2, and an optionally substituted C1-C6 alkyl;
    • R3 is selected from the group consisting of H, a C1-C6 alkyl, and a C1-C6 heteroalkyl;
    • R4 is selected from the group consisting of H, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
    • or a stereoisomer or a pharmaceutically acceptable salt thereof.

Some embodiments of the compounds, compositions, and methods provided herein include a compound of Formula II:

    • wherein:
    • R1 is selected from the group consisting of H, M, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
    • R5 is selected from the group consisting of M, Cl, OH, NH2, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 alkyloxy, and an optionally substituted alkylamino;
    • M is a biological agent or part of a biological agent or a prodrug of a biological agent;
    • X and X′ are independently O or NW;
    • Y′ and Y″ are independently selected from the group consisting of O, S, an optionally substituted CH2, and NR3;
    • R3 is selected from the group consisting of H, a C1-C6 alkyl, and a C1-C6 heteroalkyl;
    • or a stereoisomer or a pharmaceutically acceptable salt thereof.

Some embodiments of the compounds, compositions, and methods provided herein include a compound of Formula III:

    • wherein:
    • R1 is selected from the group consisting of H, M, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
    • R6 is selected from the group consisting of Cl, OH, NH2, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 alkyloxy, an optionally substituted alkylamino, and —OP(O)(R7)2;
    • R7 is selected from the group consisting of OH, an optionally substituted C1-C6 alkyl, and an optionally substituted C1-C6 alkyloxy;
    • M is a biological agent or part of a biological agent or a prodrug of a biological agent;
    • X and X′ are independently O or NR3;
    • Y′ is selected from the group consisting of O, S, an optionally substituted CH2, and NR3;
    • R3 is selected from the group consisting of H, a C1-C6 alkyl, and a C1-C6 heteroalkyl;
    • or a stereoisomer or a pharmaceutically acceptable salt thereof.

Some embodiments of the compounds, compositions, and methods provided herein include a compound of Formula IV:

    • wherein:
    • R1 is selected from the group consisting of H, M, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
    • R8 and R9 are independently selected from the group consisting of M, Cl, OH, NH2, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 alkyloxy, and an optionally substituted alkylamino;
    • R10 is selected from the group consisting of Cl, OH, NH2, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 alkyloxy, and an optionally substituted alkylamino;
    • M is a biological agent or part of a biological agent or a prodrug of a biological agent;
    • X and X′ are independently O or NR3;
    • R3 is selected from the group consisting of H, a C1-C6 alkyl, and a C1-C6 heteroalkyl;
    • Y′ and Y″ are independently selected from the group consisting of O, S, an optionally substituted CH2, and NR3;
    • or a stereoisomer or a pharmaceutically acceptable salt thereof.

In some embodiments, M is a nucleoside antiviral or anticancer agent.

In some embodiments, M is a lipid modulator.

In some embodiments, M is a nuclear hormone receptor modulator.

Some embodiments of the compounds, compositions, and methods provided herein include a pharmaceutical composition comprising any of the compounds provided herein and a pharmaceutically acceptable excipient.

Some embodiments of the compounds, compositions, and methods provided herein include a method of treating a disease or condition in the liver in a subject comprising administering an effective amount of any of the compounds provided herein to a subject in need thereof.

Some embodiments of the compounds, compositions, and methods provided herein include a method of treating a disease or condition by intervening in a molecular pathway/target (e.g. a receptor or an enzyme or the like) in the liver in a subject comprising administering an effective amount of any of the compounds provided herein to a subject in need thereof.

Some embodiments also include administering an effective amount of additional therapeutic agent to the subject in need thereof.

In some embodiments, the subject is a mammal.

In some embodiments, the subject is a human.

Some embodiments of the compounds, compositions, and methods provided herein include the use of any one of the compounds provided herein for treating a disease in the liver or a disease or condition in which the physiological or pathogenic pathways involve the liver in a subject.

Some embodiments also include the use of any one of the compounds provided herein in combination with an additional therapeutic agent.

Some embodiments of the compounds, compositions, and methods provided herein include any one of the compositions provided herein for use in the preparation of a medicament for treating a disease or condition in the liver or a disease or condition in which the physiological or pathogenic pathways involve the liver.

DETAILED DESCRIPTION

The present embodiments are directed to compositions and methods related to novel cyclic dual and triple phosphorus containing prodrug compounds of biologically active acid/alcohol derivatives such as phosphates, phosphonates, phosphonamidates, phosphoramidates, carboxylates, phenolates, and alkoxylates, their preparation and their uses.

Example activation of some cyclic phosph(on)ate and phosphoramidate compounds are illustrated below:

In the above example, the cyclic prodrugs (X═O or N) are oxidized by Cyp3A in the liver and undergo a ring opening and β-elimination sequence to provide the active drugs and an aryl vinyl ketone (Intermediate). The latter is rapidly conjugated with glutathione (GSH) that exists in millimole levels in the liver to yield the conjugate by-product.

Certain oral available pharmaceutical agents have been described to have certain liver-targeted property (e.g. see X. J. Zhou, et al. 2009 EASL meeting poster #966). The liver-targeting effects of these agents are based on liver first-pass metabolism of an orally administered agent and the liver-targeting efficiency varies widely, depending upon the pharmacokinetic property of the agent, and are not as efficient as the Cyp3A activated prodrugs.

Nucleoside based pharmacological agents are given as a prodrug form either as a nucleoside or its derivative, or monophosphate or its derivative. The prodrug is activated in the cell to form biologically active nucleoside triphosphates by nucleoside kinases. The first phosphorylation of nucleoside to form nucleoside monophosphate is often a slower process and, as a result, the monophosphate based prodrugs are typically superior than the prodrug of non-phosphorylated nucleoside drugs.

Bisphosphonate cyclic acetal compounds have been used as prodrug for more efficient oral delivery of bisphosphonate drugs in treatment of osteoporosis and other calcium and phosphate related disorders (e.g., see US 2011/0098251).

Some examples of novel cyclic dual and triple phosphorus containing prodrug compounds and their stereoisomers and pharmaceutically acceptable salts are represented by Formula I, II, III, and IV:

wherein:

R1 and R2 are independently selected from the group consisting of H, M, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

R3 is selected from the group consisting of H, a C1-C6 alkyl, and a C1-C6 heteroalkyl;

R4 is selected from the group consisting of H, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

R5 is selected from the group consisting of M, Cl, OH, NH2, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 alkyloxy, and an optionally substituted alkylamino;

R6 is selected from the group consisting of Cl, OH, NH2, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 alkyloxy, an optionally substituted alkylamino, and —OP(O)(R7)2;

R7 is selected from the group consisting of OH, an optionally substituted C1-C6 alkyl, and an optionally substituted C1-C6 alkyloxy;

R8 and R9 are independently selected from the group consisting of M, Cl, OH, NH2, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 alkyloxy, and an optionally substituted alkylamino;

R10 is selected from the group consisting of Cl, OH, NH2, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 alkyloxy, and an optionally substituted alkylamino;

M is a biological agent or part of a biological agent or a prodrug of a biological agent;

X and X′ are independently O or NR3;

Y is selected from the group consisting of a bond, O, S, NR4, Si(R4)2, and an optionally substituted C1-C6 alkyl;

Y′ and Y″ are independently selected from the group consisting of O, S, an optionally substituted CH2, and NR3;

or a stereoisomer or a pharmaceutically acceptable salt thereof.

In some embodiments, the cyclic dual or triple phosphorus containing prodrug compounds of Formula I, II, III, and IV are substrates of cytochrome p450 isozymes CYP3As, a family of monooxygenase enzymes. Known prodrugs of a different class (e.g. see M. D. Erion, et al. J Pharm Exp Ther 312:554-60 (2005)) are oxidized by CYP3A4 as the first activation step, but then generate an α,β-unsaturated carbonyl intermediate compound by a β-elimination reaction to complete the activation. Since certain α,β-unsaturated carbonyl compounds are toxic and/or have mutagenic activity, prodrugs activated by CYP3As without involvement of the β-elimination offer advantages in overall drug safety. In some embodiments, the novel prodrug compounds of Formula I, II, III, and IV do not generate a vinyl keto reactive intermediate in the activation process.

CYP3A4 is expressed in the liver at a level much higher than other tissues (DeWaziers et al. J Pharm Exp Ther 253:387 (1990)). Prodrug compounds of Formula I, II, III, and IV are predominantly activated via CYP3A4 in the liver. In some embodiments, the cyclic phosphorus prodrug compounds of Formula I, II, III, and IV have high efficiency in liver-targeting via selective delivery of biologically active agents to the liver. In some embodiments, the prodrugs are used to increase the therapeutic index of the drug, since the prodrug compounds of Formula I, II, III, and IV may not be active or may be less active outside the liver.

In some embodiments, the cyclic dual or triple phosphorus containing prodrug compounds of Formula II, III, and IV where M is a nucleoside or a nucleoside derivative are activated in the liver to directly generate a nucleoside diphosphate or triphosphate. In some embodiments, the cyclic phosphorus prodrug compounds of Formula II, III, and IV have higher efficiency in liver-targeting than that of nucleoside monophosphate prodrug compounds via selective delivery of higher orders of phosphates to the liver.

In some embodiments, the cyclic triple phosphorus containing prodrug compounds of Formula III and IV where M is a nucleoside or a nucleoside derivative are activated in the liver to directly generate a nucleoside triphosphate. In some embodiments, the cyclic phosphorus prodrug compounds of Formula III and IV have higher efficiency in liver-targeting than that of nucleoside monophosphate prodrug compounds via selective delivery of biologically active triphosphates to the liver.

In some embodiments, the cyclic triple phosphorus containing prodrug compounds of Formula II where M is a nucleoside or a nucleoside derivative are activated in the liver to directly generate a novel nucleoside cyclic triphosphate. In some embodiments, the novel cyclic triphosphates generated in the liver from prodrug compounds of Formula II may have unique biological and/or pharmacokinetic activities.

In some embodiments, the prodrug compounds of Formula I, II, III, and IV are used to treat diseases that benefit from enhanced drug distribution to the liver and like tissues and cells, including but not limited to diseases in the liver, such as hepatitis, liver cancer, liver fibrosis, fatty liver, malaria, other viral and parasitic infections, and metabolic, cardiovascular, and/or hormonal diseases where the liver is involved in the production and/or the homeostasis control of biochemical end products, e.g. glucose (e.g. diabetes); cholesterol, fatty acids, bile acids, triglycerides (e.g. hyperlipidemia, atherosclerosis and obesity), lipoproteins, apolipoproteins, and sex hormone-binding globulin (SHBG).

In some embodiments, the disclosed prodrugs are used to prolong pharmacodynamic half-life of the drug. In addition, the disclosed prodrug methodology can be used to achieve sustained delivery of the parent drug. In some embodiments, a method of making these prodrugs is described. In some embodiments, the prodrugs are also useful in the delivery of diagnostic imaging agents to the liver or other tissues.

Certain compounds of Formula I, II, III, and IV have asymmetric centers where the stereochemistry is unspecified, and the diastereomeric mixtures of these compounds are included, as well as the individual stereoisomers when referring to a compound of Formula I, II, III, and IV generally.

Some embodiments of the compounds, compositions and methods provided herein include a pharmaceutical composition comprising a compound provided herein and a pharmaceutically acceptable carrier.

Some embodiments also include administering an effective amount of a second or multiple therapeutic agents in combination with a compound provided herein to the subject in need thereof.

Some embodiments of the compounds, compositions and methods provided herein include a method of treating liver diseases such as hepatitis and liver cancer, comprising administering an effective amount of a compound provided herein where M is an antiviral or anticancer nucleoside such as a HCV polymerase inhibitor, a reverse transcriptase inhibitor, a DNA synthesis inhibitor, a RNA synthesis inhibitor, and/or an antimetabolic agent to a subject in need thereof.

Some embodiments of the compounds, compositions and methods provided herein include a method of treating dyslipidemia and fatty liver comprising administering an effective amount of a compound provided herein where M is a lipid modulator such as a HMG-CoA reductase inhibitor, a selective thyroid hormone receptor modulator, a peroxisome proliferator-activated receptor modulator, a fibrate, a DGAT inhibitor, a nicotinic acid, a bile acid, a folic acid and a fatty acid to a subject in need thereof.

Some embodiments of the compounds, compositions and methods provided herein include a method of treating hyperglycemia comprising administering an effective amount of a compound provided herein where M is a glucose modulator such as peroxisome proliferator-activated receptor modulator, glucose biosynthesis inhibitor, and/or dipeptidyl peptidase 4 inhibitor to a subject in need thereof.

Some embodiments of the compounds, compositions and methods provided herein include a method of treating a hormonal condition comprising administering an effective amount of a compound provided herein where M is a nuclear hormone receptor modulator to a subject in need thereof.

In some embodiments, the subject is mammalian.

In some embodiments, the subject is human.

Some embodiments of the compounds, compositions and methods provided herein include a method of testing a compound in a cell comprising contacting the cell with the disclosed compounds.

Some embodiments of the compounds, compositions and methods provided herein include use of a compound provided herein in the treatment of a disease in the liver.

Some embodiments include the use of a compound provided herein in combination with additional therapeutic agent(s) for the treatment of a disease in the liver.

Some embodiments of the compounds, compositions and methods provided herein include use of a compound provided herein in the treatment of a disease or condition by intervening in a molecular pathway in the liver.

Some embodiments include the use of a compound provided herein in combination with additional therapeutic agent(s) for the treatment of a disease or condition by intervening in a molecular pathway in the liver.

Definitions

In accordance with the present disclosure and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise. It is to be understood that both the foregoing general description and the following detailed description are examples and explanatory only and are not restrictive of the subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. In this application, the use of “or” means “and/or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “includes,” and “included” is not limiting.

As used herein, ranges and amounts can be expressed as “about” a particular value or range. “About” also includes the exact amount. Hence “about 10%” means “about 10%” and also “10%.”

As used herein, “optional” or “optionally” means that the subsequently described event or circumstance does or does not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, an optionally substituted group means that the group is unsubstituted or is substituted.

As used herein, the singular forms “a,”“an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a composition comprising “a therapeutic agent” includes compositions with one or a plurality of therapeutic agents.

The term “alkyl” refers to saturated aliphatic groups including straight-chain, branched chain and cyclic groups, up to and including 10 carbon atoms. Suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, and cyclopropyl. The alkyl group may be optionally substituted with 1-3 substituents.

The term “optionally substituted” or “substituted” includes groups substituted by one to four substituents, independently selected from lower alkyl, lower aryl, lower aralkyl, lower cyclic alkyl, lower heterocycloalkyl, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkoxy, lower heteroaryl, lower heteroaryloxy, lower heteroarylalkyl, lower heteroaralkoxy, azido, amino, halogen, lower alkylthio, oxo, lower acylalkyl, lower carboxy esters, carboxyl, carboxamido, nitro, lower acyloxy, lower aminoalkyl, lower alkylaminoaryl, lower alkylaryl, lower alkylaminoalkyl, lower alkoxyaryl, lower arylamino, lower aralkylamino, lower alkylsulfonyl, lower carboxamidoalkylaryl, lower carboxamidoaryl, lower hydroxyalkyl, lower haloalkyl, lower alkylaminoalkylcarboxy, lower aminocarboxamidoalkyl, cyano, lower alkoxyalkyl, lower perhaloalkyl, and lower arylalkyloxyalkyl. “Substituted aryl” and “substituted heteroaryl” refers to aryl and heteroaryl groups substituted with 1-6 substituents. These substituents are selected from the group consisting of lower alkyl, lower alkoxy, lower perhaloalkyl, halogen, hydroxy, cyano, and amino.

The term “heteroalkyl” refer to alkyl groups containing at least one heteroatom, such as 1 to 3 heteroatoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen.

The term “heteroacyl” refer to —C(O)-heteroalkyl groups.

The term “acyloxy” refers to —OC(O)R where R is alkyl, or heteroalkyl.

The term “alkoxy” or “alkyloxy” refers to OR where R is alkyl, or heteroalkyl, all optionally substituted.

The term “carboxyl” refers to a C(O)OH.

The term “oxo” refers to an ═O group.

The term “oxo derivative” refers to ═NR where R is H, lower alkyl, lower alkoxyl, or lower alkylamino.

The term “amino” refers to NRR′ where R and R′ are each independently selected from hydrogen, alkyl, aryl, aralkyl and heterocycloalkyl, all except H are optionally substituted; and R and R′ can form a cyclic ring system.

The term “halogen” or “halo” refers to F, Cl, Br and I.

The term “haloalkyl” refer to alkyl groups containing at least one halogen, in a further aspect are 1 to 3 haloatoms. Suitable haloatoms include F, Cl, and Br.

The term “haloheteroalkyl” refer to alkyl groups containing at least one halogen and one heteroatom.

The term “haloacyl” refer to —C(O)-haloalkyl groups.

The term “haloheteroacyl” refer to —C(O)-haloheteroalkyl groups.

The term “alkenyl” refers to unsaturated groups which have 2 to 12 atoms and contain at least one carbon double bond and includes straight chain, branched chain and cyclic groups. Alkenyl groups may be optionally substituted. Suitable alkenyl groups include allyl.

The term “alkynyl” refers to unsaturated groups which have 2 to 12 atoms and contain at least one carbon triple bond and includes straight chain, branched chain and cyclic groups. Alkynyl groups may be optionally substituted. Suitable alkynyl groups include ethynyl.

The term “methylene” refers to ═CH2.

The term “methylene derivative” refers to ═CRR′ where R and R′ are each independently selected from an optionally substituted alkyl and an optionally substituted alkenyl.

The term “aminoalkyl” refers to the group NR2-alkyl where R is selected from H, alkyl, aryl, aralkyl, and heterocycloalkyl.

The terms “alkylamino” refers to the group alkyl-NH— or (alkyl)2-N—.

The term “amido” refers to the NR2 group next to an acyl or sulfonyl group as in NR2C(O)—, RC(O)NR2—, NR2S(═O)2— and RS(═O)2—NR2—, where R includes H, alkyl, aryl, aralkyl, and heterocycloalkyl.

The term “perhalo” refers to groups wherein every C—H bond has been replaced with a C-halo bond on an aliphatic or aryl group. Suitable perhaloalkyl groups include CF3 and CFCl2.

The term “aryl” refers to an aromatic group wherein each of the atoms forming the ring is a carbon atom. Aryl rings may be formed by five, six, seven, eight, nine, or more than nine carbon atoms. Aryl groups may be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, naphthalenyl, phenanthrenyl, anthracenyl, tetralinyl, fluorenyl, indenyl, and indanyl.

The term “heteroaryl” refers to an aromatic group wherein at least one atom forming the aromatic ring is a heteroatom. Heteroaryl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Heteroaryl groups may be optionally substituted. Examples of heteroaryl groups include, but are not limited to, aromatic C3-8 heterocyclic groups comprising one oxygen or sulfur atom or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom and up to two nitrogen atoms, and their substituted as well as benzo- and pyrido-fused derivatives, for example, connected via one of the ring-forming carbon atoms. In some embodiments, heteroaryl groups are optionally substituted with one or more substituents, independently selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, C1-6-alkoxy, C1-6-alkyl, C1-6-hydroxyalkyl, C1-6-aminoalkyl, C1-6-alkylamino, alkylsulfenyl, alkylsulfinyl, alkyl sulfonyl, sulfamoyl, or trifluoromethyl. Examples of heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline, and quinoxaline. In some embodiments, the substituents are halo, hydroxy, cyano, O—C1-6-alkyl, C1-6-alkyl, hydroxy-C1-6-alkyl, and amino-C1-6-alkyl.

The phrase “therapeutically effective amount” means an amount of a compound or a combination of compounds that partially or fully ameliorates, attenuates or eliminates one or more of the symptoms of a particular disease or condition or prevents, modifies, or delays the onset of one or more of the symptoms of a particular disease or condition. Such amount can be administered as a single dosage or can be administered according to a regimen, whereby it is effective. Repeated administration may be needed to achieve a desired result (e.g., treatment of the disease and/or condition).

The term “pharmaceutically acceptable salt” includes salts of compounds of Formula I, II, III and IV and their prodrugs derived from the combination of a compound of the present embodiments and an organic or inorganic acid or base. Suitable acids include acetic acid, adipic acid, benzenesulfonic acid, (+)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonic acid, citric acid, 1,2-ethanedisulfonic acid, dodecyl sulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, hippuric acid, hydrochloride hemiethanolic acid, HBr, HCl, HI, 2-hydroxyethanesulfonic acid, lactic acid, lactobionic acid, maleic acid, methanesulfonic acid, methylbromide acid, methyl sulfuric acid, 2-naphthalenesulfonic acid, nitric acid, oleic acid, 4,4′-methylenebis-[3-hydroxy-2-naphthalenecarboxylic acid], phosphoric acid, polygalacturonic acid, stearic acid, succinic acid, sulfuric acid, sulfosalicylic acid, tannic acid, tartaric acid, terphthalic acid, and p-toluenesulfonic acid.

Where the number of any given substituent is not specified (e.g., “haloalkyl”), there may be one or more substituents present. For example, “haloalkyl” can include one or more of the same or different halogens. For example, “haloalkyl” includes each of the substituents CF3, CHF2 and CH2F.

The term “patient” refers to an animal being treated including a mammal, such as a dog, a cat, a cow, a horse, a sheep, and a human. In some embodiments the patient is a mammal, either male or female. In some embodiments, the patient is a male or female human.

The term “prodrug” as used herein refers to any compound that when administered to a biological system generates a biologically active compound as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), and/or metabolic chemical reaction(s), or a combination of each. Standard prodrugs are formed using groups attached to functionality, e.g. HO—, HS—, HOOC—, HOOPR2—, associated with the drug, that cleave in vivo. Standard prodrugs include but are not limited to carboxylate esters where the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl as well as esters of hydroxyl, thiol and amines where the group attached is an acyl group, an alkoxycarbonyl, aminocarbonyl, phosphate or sulfate. The groups illustrated are examples, not exhaustive, and one skilled in the art could prepare other known varieties of prodrugs. Prodrugs must undergo some form of a chemical transformation to produce the compound that is biologically active or is a precursor of the biologically active compound. In some cases, the prodrug is biologically active, usually less than the drug itself, and serves to improve drug efficacy or safety through improved oral bioavailability, pharmacodynamic half-life, etc. Prodrug forms of compounds may be utilized, for example, to improve bioavailability, improve subject acceptability such as by masking or reducing unpleasant characteristics such as bitter taste or gastrointestinal irritability, alter solubility such as for intravenous use, provide for prolonged or sustained release or delivery, improve ease of formulation, or provide site specific delivery of the compound.

The term “stereoisomer” refers to the relative or absolute spatial relationship of the R group(s) attached to the stereogenic centers either carbon or phosphorus atoms, and refers to individual or any combination of the individual isomers such as a racemic mixture and a diastereomeric mixture. When a compound has two stereogenic centers, there are 4 potential stereoisomers. When a compound has three stereogenic centers, there are 8 potential stereoisomers.

The term “liver” refers to the liver organ.

The term “liver specificity” refers to the ratio:

    • [drug or a drug metabolite in liver tissue]/[drug
    • or a drug metabolite in blood or another tissue]

as measured in animals treated with the drug or a prodrug. The ratio can be determined by measuring tissue levels at a specific time or may represent an AUC (area under a curve) based on values measured at three or more time points.

The term “increased or enhanced liver specificity” refers to an increase in liver specificity ratio in animals treated with the prodrug relative to animals treated with the parent drug. Compounds disclosed in U.S. Pat. No. 8,063,025, U.S. Pat. No. 7,666,855, and PCT Pub. No. WO2009/073506, are designed for the liver-specific delivery of nucleosides for the treatment of HCV patients and take advantage of a cytochrome P450 enzyme that is mainly expressed in the liver.

The term “enhanced oral bioavailability” refers to an increase of at least about 50% of the absorption of the dose of the parent drug. In an additional aspect, the increase in oral bioavailability of the prodrug (compared to the parent drug) is at least about 100%, or a doubling of the absorption. Measurement of oral bioavailability usually refers to measurements of the prodrug, drug, or drug metabolite in blood, plasma, tissues, or urine following oral administration compared to measurements following parenteral administration.

The term “therapeutic index” refers to the ratio of the dose of a drug or prodrug that produces a therapeutically beneficial response relative to the dose that produces an undesired response such as death, an elevation of markers that are indicative of toxicity, and/or pharmacological side effects.

The term “sustained delivery” refers to an increase in the period in which there is a prolongation of therapeutically-effective drug levels due to the presence of the prodrug.

The terms “treating” or “treatment” of a disease includes inhibiting the disease (slowing or arresting or partially arresting its development), preventing the disease, providing relief from the symptoms or side effects of the disease (including palliative treatment), and/or relieving the disease (causing regression of the disease).

The terms “biological agent” refers to a compound that has biological activity or that has molecular properties that can be used for therapeutic or diagnosis purposes, such as a compound carrying a radioactive isotope or a heavy atom.

The terms “molecular pathway” refers to a series of molecular events in tissues such as a receptor modulating sequence, an enzyme modulating sequence, or a biosynthesis sequence that is involved in physiological or pathophysiological functions of a living animal.

Formulations

The disclosed compounds may be used alone or in combination with other treatments. These compounds, when used in combination with other agents, may be administered as a daily dose or an appropriate fraction of the daily dose (e.g., bid). The compounds may be administered after a course of treatment by another agent, during a course of therapy with another agent, administered as part of a therapeutic regimen, or may be administered prior to therapy by another agent in a treatment program.

Examples of pharmaceutically acceptable salts include acetate, adipate, besylate, bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, mesylate, methylbromide, methyl sulfate, napsylate, nitrate, oleate, palmoate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terphthalate, tosylate, and triethiodide.

Compositions containing the active ingredient may be in any form suitable for the intended method of administration. In some embodiments, the compounds of a method and/or composition described herein can be provided via oral administration, rectal administration, transmucosal administration, intestinal administration, enteral administration, topical administration, transdermal administration, intrathecal administration, intraventricular administration, intraperitoneal administration, intranasal administration, intraocular administration and/or parenteral administration.

When the compounds are administered via oral administration, for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient can be mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient can be mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain, for example, antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

In some embodiments unit dosage formulations contain a daily dose or unit, daily sub-dose, or an appropriate fraction thereof, of a drug. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs which have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those skilled in the art.

Synthesis of Compounds

The following procedures for the preparation of the cyclic prodrug compounds illustrate the general procedures used to prepare the prodrug compounds. Prodrugs can be introduced at different stages of synthesis of a drug. In some embodiments, they are made at a later stage, because of the general sensitivity of these groups to various reaction conditions. Optically pure prodrugs containing a single isomer at the phosphorus center can be made, for example, by separation of the diastereomers by a combination of column chromatography and/or crystallization, or by enantioselective synthesis of chiral activated phosph(on)ate intermediates.

Scheme I describes general strategies of synthesis of the bicyclic prodrug compounds of Formula I. Diphosphate compound 1 is condensed with an aldehyde of structure 2 in the presence of catalytic amount of acid to give a product of structure 3. The aldehyde compound of structure 2 is prepared from the corresponding carboxylic acid. Second condensation of compounds of structure 3 with the second aldehyde affords the final bicyclic compounds of structure 5. Alternative approaches take advantages of aldehyde equivalent compounds such as compounds 6 and 7 to provide products 3 and 5 under basic conditions.

Scheme II describes general strategies of synthesis of the bicyclic prodrug compounds of Formula II. Treatment of the bisphosphonate of structure 6 with phosphorus oxychloride yields cyclic phosphate chloride of structure 7 that is reacted with an alcohol derivative to introduce an R5 group to form the compound of structure 8. A condensation reaction between the compound of structure 8 and an aldehyde under acidic conditions provides a final bicyclic compound of structure 9. Alternatively, the bisphosphonate of structure 6 is condensed with an aldehyde to form a compound of structure 10 that is then treated with phosphorus oxychloride to give an intermediate of structure 11. Displacement of the chloride in a compound of structure 11 with an alcohol affords the final compound of structure 9.

Scheme III describes general strategies of syntheses of the cyclic prodrug compounds of Formula III. Condensation of the bisphosphonic chloride of structure 12 and an aldehyde of structure 2 generates the intermediate of structure 13 that is then treated with an alcohol of H-M and an alcohol of H—R6 to yield final product of structure 14. Alternatively, phosphonic acid of structure 15 is treated with a phosphorus oxychloride derivative to provide an intermediate of structure 16 that is condensed with an aldehyde of structure 2 to afford the final product.

Scheme IV describes general strategies of synthesis of the cyclic prodrug compounds of Formula IV. A phosphonic acid chloride of structure 16 is prepared from phosphorus oxychloride and an alcohol and then phosphorylated to give the triphosphate derivative of structure 17 with pyrophosphate. Cyclization of the triphosphate derivative of structure 17 with an aldehyde of structure 2 provides the final product of structure 18. Alternatively, the cyclic intermediate of structure 20 is formed from the triphosphate derivative of structure 19 and an aldehyde and then is activated to the intermediate of structure 21. Treatment of the phosphorus chloride of structure 21 with an alcohol provides the final product of structure 18.

EXAMPLES

It will be understood that the following are examples and that the present embodiments are not limited to these examples. The sample compounds are prepared to demonstrate the synthetic methodologies as outlined below without attaching a biologically active agent.

Example 1

2,4-Dihydroxy-6-phenethyl-1,5,2,4-dioxadiphosphinane 2,4-dioxide (Compound 101)

Compound 101 was prepared according to the general procedure of Scheme I as a triethylamine salt from 3-phenylpropanal and methylenebis(phosphonate). Treatment of 3-phenylpropanal (1.34 g, 10 mmol) with excess neat zinc triflate at 0° C. in the presence of acetyl chloride (1.2 g, 15 mmol) for 2 hours provided 1-chloro-3-phenylpropyl acetate (1.7 g, 80% yield). The resulting acetate (128 mg, 0.6 mmol) was then treated with methylenebis(phosphonate) (53 mg, 0.3 mmol) in acetonitrile in the presence of DIPEA (392 mg, 3.0 mmol) at 45° C. overnight. The mixture was worked up by standard procedure and prep-HPLC with Et3NHCO3 as buffer provided Compound 101 as a triethylamine salt. [M+H]+ calcd for C10H14O6P2: 293.03; found: 293.05. 1H NMR (300 MHz, CD3OD) 7.28-7.06 (m, 5H), 5.67-5.57 (m, 1H), 3.17 (q, J=7.4, 6H), 2.76 (t, J=8.1, 2H), 2.38 (t, J=28, 2H), 2.07-1.92 (m, 2H), and 1.29 (t, J=7.4, 9H). 31P NMR (300 MHz, CD3OD) 14.883 (s).

Example 2

2,4-Dihydroxy-6-phenethyl-1,3,5,2,4-trioxadiphosphinane 2,4-dioxide (Compound 102)

Compound 102 was prepared as a triethylamine salt from 3-phenylpropanal and pyrophosphate in the same fashion as described in Example 1. [M+H]+ calcd for C9H12O7P2: 295.01; found: 295.15. 1H NMR (300 MHz, CD3OD) 7.30-7.12 (m, 5H), 5.33 (t, J=4.5, 1H), 3.19 (q, J=7.4, 6H), 2.75 (t, J=7.5, 2H), 2.08-1.95 (m, 2H), and 1.30 (t, J=7.4, 9H).

Example 3

2,4-Dihydroxy-6-phenyl-1,3,5,2,4-trioxadiphosphinane 2,4-dioxide (Compound 103) and 3,7-diphenyl-2,4,6,8,9-pentaoxa-1,5-diphosphabicyclo[3.3.1]nonane 1,5-dioxide (Compound 104)

Compounds 103 and 104 were prepared from benzaldehyde and methylenebis(phosphonate) in a same fashion as described in Example 1. Compound 103 was isolated as DIPEA double salt, [M−H] calcd for C8H10O6P2: 263.00; found: 263.00. 1H NMR (300 MHz, CD3OD) 7.62-7.58 (m, 2H), 7.41-7.30 (m, 3H), 6.65 (bs, 1H), 3.78-3.61 (m, 4H), 3.22-3.06 (m, 4H), 2.40-2.02 (m, 2H), and 1.40-1.20 (m, 30H). 31P NMR (300 MHz, CD3OD) 14.345 (s). Compound 104, [M+H]+ calcd for C15H14O6P2: 353.03; found: 353.

All numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claims in any application claiming priority to the present application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.

The above description discloses several methods and materials. This invention is susceptible to modifications in the methods and materials, as well as alterations in the fabrication methods and equipment. Such modifications will become apparent to those skilled in the art from a consideration of this disclosure or practice of the invention disclosed herein. Consequently, it is not intended that this invention be limited to the specific embodiments disclosed herein, but that it cover all modifications and alternatives coming within the true scope and spirit of the invention.

All references cited herein, including but not limited to published and unpublished applications, patents, and literature references, are incorporated herein by reference in their entirety and are hereby made a part of this specification. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material.

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Citation

Patents Cited in This Cited by
Title Current Assignee Application Date Publication Date
Insektizide und Nematozide SUMITOMO CHEMICAL CO LTD 12 June 1963 17 September 1970
Chlorethyl group-containing oxazaphosph- - orine derivatives SANDOZ AG 13 September 1967 30 June 1970
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