US20080039427A1 - Method and compositions for treating hematological malignancies - Google Patents
Method and compositions for treating hematological malignancies Download PDFInfo
- Publication number
- US20080039427A1 US20080039427A1 US11/803,822 US80382207A US2008039427A1 US 20080039427 A1 US20080039427 A1 US 20080039427A1 US 80382207 A US80382207 A US 80382207A US 2008039427 A1 US2008039427 A1 US 2008039427A1
- Authority
- US
- United States
- Prior art keywords
- compound
- tautomers
- solvates
- organic acid
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- ANSPEDQTHURSFQ-UHFFFAOYSA-N CCOC(=O)C(C)NP(=O)(COCCN1C=NC2=C(NC3CC3)N=C(N)N=C21)NC(C)C(=O)OCC Chemical compound CCOC(=O)C(C)NP(=O)(COCCN1C=NC2=C(NC3CC3)N=C(N)N=C21)NC(C)C(=O)OCC ANSPEDQTHURSFQ-UHFFFAOYSA-N 0.000 description 16
- AQYMMSMXWFYCJG-YQFADDPSSA-N CCOC(=O)[C@@H](C)N[PH](=O)COCCN1C=NC2=C(NC3CC3)N=C(N)N=C21.O=C(O)CCC(=O)O.[H] Chemical compound CCOC(=O)[C@@H](C)N[PH](=O)COCCN1C=NC2=C(NC3CC3)N=C(N)N=C21.O=C(O)CCC(=O)O.[H] AQYMMSMXWFYCJG-YQFADDPSSA-N 0.000 description 1
- VNEFYOIBWSIDSZ-UHFFFAOYSA-N CCOC(C(C)NC(C)(C)P(COCC[n]1c2nc(N)nc(NC3CC3)c2nc1)=O)=O Chemical compound CCOC(C(C)NC(C)(C)P(COCC[n]1c2nc(N)nc(NC3CC3)c2nc1)=O)=O VNEFYOIBWSIDSZ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Definitions
- cpr-PMEDAP N-6 cyclopropylPMEDAP
- cpr-PMEDAP N-6 cyclopropylPMEDAP
- WO 02/08241 discloses a method for screening methoxyphosphonate nucleotide analogue prodrugs that are useful for treating hematological malignancies with reduced toxicity.
- lymphomas malignant masses of lymphoid cells, primarily but not exclusively in lymph nodes
- leukemias neoplasm derived typically from lymphoid or myeloid cells and primarily affecting the bone marrow and peripheral blood.
- the lymphomas can be sub-divided into Hodgkin's Disease and Non-Hodgkin's lymphoma (NHL).
- NHL Hodgkin's Disease
- NHL Non-Hodgkin's lymphoma
- lymphoma aggressive lymphoma, indolent lymphoma
- histologically e.g. follicular lymphoma, mantle cell lymphoma
- follicular lymphoma mantle cell lymphoma
- B lymphocyte T lymphocyte
- leukemias and related malignancies include acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL).
- Other hematological malignancies include the plasma cell dyscrasias including multiple myeloma, and the myelodysplastic syndromes.
- Leukemias have lower patient numbers. However, there remains substantial unmet medical need, for example for the treatment of acute myelogenous leukemia (AML) and chronic lymphocytic leukemia (CLL), as illustrated by poor 5-year survival rates.
- AML acute myelogenous leukemia
- CLL chronic lymphocytic leukemia
- adenosine analogs fludarabine, cladribine, and clofarabine
- the purine analog, pentostatin (2′-deoxycoformycin), an inhibitor of adenosine deaminase has clinical activity against lymphoid malignancies.
- Nelarabine is a prodrug of the deoxyguanosine analogue ara-G, which is resistant to catabolism by purine nucleoside phosphorylase and has demonstrated activity against T-cell malignancies.
- cytarabine cytarabine (ara-C) has been evaluated; it is active in a number of hematologic malignancies and is one of the agents used in the treatment of acute myelogenous leukemia.
- WO 05/066189 discloses a compound having structure 1:
- This invention relates to compound 1. It also relates to the diastereomer thereof in which the bis amino acid substituted on the phosphorus atom is an L amino acid, as well as such diasteromer substantially free of D amino acid.
- one embodiment of the invention is an organic acid salt of compound 1 and/or its tautomers and solvates.
- Another embodiment of the invention is a composition
- a composition comprising (a) an organic acid salt of compound 1 and/or its tautomers and solvates and (b) a carbohydrate, whereby storage stability of the salt is enhanced.
- Another embodiment of the invention is a method for the treatment of a patient having a hematological malignancy comprising administering to the patient a therapeutically effective amount of the compound and/or its salts, tautomers and solvates.
- a further embodiment of the invention is a combination comprising the compound and/or its salts, tautomers and solvates in a container suitable for use in parenteral administration of the compound.
- a further embodiment of the invention is a method comprising preparing an organic acid salt of the compound and a carbohydrate in a sterile aqueous solution, and storing said solution for a period exceeding about 1 hour.
- a further embodiment of the invention is a packaged composition
- a packaged composition comprising a sterile aqueous solution of a carbohydrate and an organic acid salt of the compound together with a disclosure (e.g. a patient insert) that the solution optionally is stored for a period of greater than about 1 hour.
- Suitable organic acids for preparing the salts of this invention typically are compounds containing at least one carboxyl group, including amino acids (naturally occurring or synthetic) such as glutamic acid and aspartic acid, and C 1-16 alkyl and C 6-16 aryl and C 4-16 heteroaryl carboxylic acids such as acetic, glycolic, lactic, pyruvic, malonic, glutaric, tartaric, citric, fumaric, succinic, malic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic and 2-phenoxybenzoic acids, together with any derivative (excluding esters where no carboxyl remains free) thereof having the same root (e.g., “acetoacetic acid”) which is disclosed in the table “Physical Constants of Organic Compounds” pp 3-12 to 3-523 Merck Index 74 th Ed. 1993. Dicarboxylic organic acids are of particular interest. It is within the scope of this invention to employ more than
- the molar ratio of organic acid to compound 1 is about 1:1.
- the ratio may be as great as 1 mole of compound 1 to the number of acid groups in the case of polyorganic acids, e.g., a 2:1 ratio of compound 1 to salt for a dicarboxylic acid salt.
- the proportion is variable, ranging down to 1:1 or less, depending upon the enrichment of the acid functionality and its degree of substitution with acidic functionalities.
- Suitable formulations of compound 1, whether for veterinary and for human use, optionally comprise one or more acceptable carriers.
- the carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the patient.
- Formulations optionally will contain excipients such as those set forth in the “Handbook of Pharmaceutical Excipients” (1986).
- Excipients optionally include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, mannitol or dextrose, buffers (e.g., citrate), alkali metal salts, glidants, bulking agents and other substances conventionally found in tablets, capsules, solutions or other compositions suited or intended for therapeutic use.
- the formulations will not contain conventional tabletting excipients since they usually are formulated for parenteral use.
- the formulations ideally will be sterile.
- parenteral preparations will be substantially isotonic.
- the pH of the formulations optionally ranges from about 5-10, ordinarily about 6-9, typically about 5-6.
- Parenteral (sterile aqueous) solutions of the organic acid salts of compound 1 optionally comprise a stabilizing amount of carbohydrate, typically a saccharide (mono, di or polysaccharides), glycoside or sugar alcohol (alditols).
- carbohydrate typically a saccharide (mono, di or polysaccharides), glycoside or sugar alcohol (alditols).
- Polysaccharides should be biodegradable upon parenteral injection or infusion and include dextrins and starches, typically 3-10 units.
- Representative carbohydrates include hexoses, aldoses, aldohexoses, aldotrioses (e.g. glyceraldehyde), aldotetroses (e.g. erythrose), aldopentoses (e.g. arabinose), ketoses, ketohexose (e.g.
- fructose fructose
- ketopentoses e.g. ribulose
- maltose sucrose, lactose, ribose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, idose, galactose and talose.
- carbohydrates conventionally used in parenteral formulations, e.g., mannitol or dextrose.
- the optical character of the carbohydrate is not critical, but it is desirable for the configuration to be such that the carbohydrate is biodegradable upon parenteral administration.
- 5% dextrose by weight of solution; pH about 4.2, unbuffered
- storage in buffered solutions at pH 2, 7 and 9 under the same conditions lead to substantial degradation of compound 1: About 100%, 18% and 76% by weight, respectively.
- the stabilizing amount of carbohydrate is variable and will depend upon the expected storage conditions and desired shelf life, buffer choice, pH, amount of compound 1, and other factors that will be appreciated by the artisan. Usually, about from 0.5% to 5% by weight of solution will be used. Typically the optimal amount of carbohydrate will be determined by routine experimentation, but the amount generally will not exceed (along with buffers, sodium chloride and the like) an amount that provides isotonicity to the solution. Hyperisotonic concentrates are acceptable, however, if it is expected to dilute the parenteral composition prior to or during infusion.
- the parenteral solution optionally is buffered (typically with citrate buffer) at about pH 4 to 6.
- carbohydrate stabilizes the salts of compound 1 in aqueous solution for storage (including administration time) of at least about 60 hours, up to 1 week, 1 month or 1 year, or any intermediate period, depending upon the factors noted above for the concentration of carbohydrate, e.g., the storage temperature and the like.
- the therapeutic compositions optionally are administered by parenteral routes (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) since these are the most convenient for treatment of malignancies.
- parenteral routes including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural.
- Intravenous infusions are generally the administration method of choice.
- the formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules, vials or flexible infusion bags.
- the containers optionally will be glass or rigid plastic, but typically will be semirigid or flexible containers fabricated from polyolefins (polyethylene) or plasticized polyvinylchloride.
- the container is typically single chambered.
- These containers have at least one integral sterile port to facilitate the sterile entry into the container of a device for accessing the contents (usually syringes or an intravenous set spike).
- the port provides sterile access for solubilizing solution (if required) and egress of parenteral solutions.
- An overpouch (usually polyolefin) is optionally provided for the container.
- the formulation is present in the container as a solution or in dry form. If stored in a substantially anhydrous form, e.g., lyophilized, the formulation will require only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Solutions include tonicity establishing agents such as sodium chloride or a sugar such as mannitol or dextrose. An unexpected advantage of carbohydrate or sugar is an increase in stability of compound 1 salt in stored aqueous solutions.
- the containers are filled with sterile solution or are filled and then sterilized, e.g., by heat or chemical agents, in accord with known processes. In general, a sterile solution of the formulation is sterile-filled into a flexible container and thereafter optionally lyophilized. Suitable technology for producing the container products of this invention is found in Avis et al., Pharmaceutical Dosage Forms: Parenteral Medications vols. 1 and 3 (1984).
- the parenteral containers will contain a daily dose or unit daily sub-dose of compound 1 as described below, or an appropriate fraction thereof.
- any neoplasm including not only hematologic malignancies but also solid tumors of all kinds, e.g., head and neck, lung, kidney, liver, bone, brain and the like, particularly uterine and cervical cancer and dysplasia, melanoma, and cancers of the breast, colon, prostate, lung (small cell and non-small cell) and pancreas.
- the formulations of this invention are administered either as monotherapy or in combination with other agents for the treatment of hematological malignancies.
- the formulation of this invention optionally is administered to the patient at substantially the same time as other antineoplastic agent(s), or the agent(s) is combined with the formulation of this invention and then administered simultaneously to the patient.
- Typical antineoplastic agents useful with compound 1 include any of the therapeutics currently employed in the treatment of malignancies, including those used for hematologic malignancies that are mentioned in the background above.
- companion agents are administered (a) at substantially the same time but by different administration routes, (b) are combined with the formulation of this invention and administered concurrently, or (c) are administered during alternative periods (for instance during a resting period from treatment with compound 1).
- the formulation of this invention is therapeutically combined with another antineoplastic agent selected from a distinct class, e.g., a monoclonal antibody.
- Treatment of NHL typically includes cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab. If used in combination, Compound 1 is administered in a course of therapy together with, or as a replacement of, one or more of the foregoing agents. Compound 1 may also be administered in combination with rituximab. For the therapy of CLL, administer Compound 1 either as monotherapy or in combination with other agents, such as cyclophosphamide and/or rituximab.
- therapeutic agents suitable for use with compound 1 include etoposide, melphalan, nitrosurea, busulfan, platinum complexes, nonclassic alkylators such as procarbazine, antimetabolites such as folate, purines, adenosine analogues, pyrimidine analogues, vinca alkyloides, and the like.
- a human efficacious dose for compound 1 (corrected for surface area by the factor of 0.54) of between 0.54 mg/kg IV and 1.62 mg/kg IV or greater, administered as a single dose with repeat dosing at interims of approximately 1 to 14 days, generally weekly or every 2 weeks, typically weekly for 2 doses, depending upon the condition of the patient and tolerance to the infusion, among other factors. Since considerable variation should be expected in suitable doses because of the unique nature of individual cancers, the condition of the patient, patient tolerance and other matters known to the ordinary oncologist, the range of effective doses will be larger than the core experimental model.
- a dosage range of about from 0.5 to 5.4 mg/kg/day is expected to be suitable.
- a single dose is suitable, but multiple cycles of dosing are anticipated to be typical, with a resting period of about 10-30, usually 23, days between cycles, again depending upon the condition of the patient and tolerance to the therapeutic as will be apparent to the ordinary artisan.
- Table 1 shows anti-proliferation EC 50 of compound 1 and its metabolites, cpr-PMEDAP (9-(2-phosphonylmethoxyethyl)-N 6 -cyclopropyl-2,6-diaminopurine), PMEG (9-(2-phosphonylmethoxyethyl)guanine), and PMEDAP (9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine).
- a variety of compounds that are used for treatment of hematologic malignancies were also tested, including a DNA polymerase inhibitor (ara-C), DNA polymerase/ribonucleotide reductase inhibitors (cladribine, clofarabine, fludarabine, gemcitabine), an adenosine deaminase inhibitor (deoxycoformycin), a DNA methylation inhibitor (decitabine), a DNA alkylator (doxorubicin), and a mitosis inhibitor (vincristine).
- ara-C DNA polymerase inhibitor
- cladribine DNA polymerase/ribonucleotide reductase inhibitors
- cladribine clofarabine, fludarabine, gemcitabine
- an adenosine deaminase inhibitor deoxycoformycin
- decitabine DNA methylation inhibitor
- doxorubicin doxorubicin
- a mitosis inhibitor vincristine
- doxorubicin and vincristine are nucleoside analogs; ara-C, gemcitabine, and decitabine are cytosine analogs and the rest are adenosine analogs.
- cpr-PMEDAP and PMEG can be considered adenosine and guanosine analogs, respectively.
- T-cell mitogen phytohemagglutinin (PHA) or a B-cell mitogen pokeweed mitogen (PWM) two T-lymphoid cell lines derived from patients with acute lymphocytic leukemia (CEM and Molt-4), two myeloid cell lines derived from patients with acute myelogenous leukemia (KG-1 and HL-60), two B-lymphoid cell lines derived from Burkitt's lymphoma (Daudi and Raji), a B-lymphoid cell line from non-Hodgkin's lymphoma (RL), a T-lymphoid cell line from cutaneous T-lymphoma (PM-1), and a monocytic cell line from histiocytic lymphoma (U937).
- PHA phytohemagglutinin
- PWM B-cell mitogen pokeweed mitogen
- Compound 1 exhibited anti-proliferative activity in a variety of lymphoblasts and leukemia/lymphoma cell lines. Its EC 50 range was between 27 and 1043 nM, similar to those of clofarabine (25-418 nM) and ara-C (23-1820 nM), two nucleoside analogs commonly used for the treatment of hematologic malignancies. Among other nucleosides, gemcitabine was the most potent (3.4-18 nM) and deoxycoformycin was the least potent (>200,000 nM). Among all compounds, vincristine (0.6-5.3 nM) exhibited the highest potency. There was no significant difference in activity of compound 1 in human and canine cells.
- compound 1 may be effective in both T- and B-cell lymphomas.
- cpr-PMEDAP which is the hydrolyzed product of compound 1
- compound 1 was significantly less potent than compound 1, suggesting that the phosphoramidate prodrug enhanced entry of the drug into cells, and that the prodrug moiety was cleaved inside cells.
- PMEG the deaminated product of cpr-PMEDAP was significantly more potent than the dealkylated product PMEDAP, consistent with the hypothesis that the active molecule for anti-proliferative activity of compound 1 is PMEGpp.
- the PHA-lymphoblasts were generated by incubating peripheral blood mononuclear cells (PBMC) with the T-cell mitogen PHA, (1 ug/mL) for 3 days 5 followed by incubation with 10 U/mL interleukin-2 for 4 more days.
- the PWM-lymphoblasts were generated by incubating B-cells (purified from PBMC using CD19-conjugated magnetic beads) with PWM (20 ⁇ g/mL) for 7 days.
- Lymphoblasts (150,000 cells per microtiter well) and leukemia/lymphoma cell lines (30,000 cells per well) were incubated with 5-fold serial dilutions of compounds for 3 days.
- BrdU assay was performed as follows: Lymphoblasts were incubated with 5-fold serial dilutions of compounds in microtiter plates (150,000 cells per well) for 3 days. On Day 3, cells were labeled with 10 ⁇ M BrdU for 3 hrs and the amount of BrdU incorporated into cellular DNA was quantified by Enzyme-Linked Immunosorbent Assay (ELISA).
- ELISA Enzyme-Linked Immunosorbent Assay
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/803,822 US20080039427A1 (en) | 2006-05-16 | 2007-05-16 | Method and compositions for treating hematological malignancies |
US13/070,179 US8435969B2 (en) | 2006-05-16 | 2011-03-23 | Method and compositions for treating hematological malignancies |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US80098306P | 2006-05-16 | 2006-05-16 | |
US83180506P | 2006-07-18 | 2006-07-18 | |
US11/803,822 US20080039427A1 (en) | 2006-05-16 | 2007-05-16 | Method and compositions for treating hematological malignancies |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/070,179 Division US8435969B2 (en) | 2006-05-16 | 2011-03-23 | Method and compositions for treating hematological malignancies |
Publications (1)
Publication Number | Publication Date |
---|---|
US20080039427A1 true US20080039427A1 (en) | 2008-02-14 |
Family
ID=38578698
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/298,987 Abandoned US20090258840A1 (en) | 2006-05-16 | 2007-05-16 | Method and compositions for treating hematological malignancies |
US11/803,822 Abandoned US20080039427A1 (en) | 2006-05-16 | 2007-05-16 | Method and compositions for treating hematological malignancies |
US13/070,179 Active US8435969B2 (en) | 2006-05-16 | 2011-03-23 | Method and compositions for treating hematological malignancies |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/298,987 Abandoned US20090258840A1 (en) | 2006-05-16 | 2007-05-16 | Method and compositions for treating hematological malignancies |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/070,179 Active US8435969B2 (en) | 2006-05-16 | 2011-03-23 | Method and compositions for treating hematological malignancies |
Country Status (20)
Country | Link |
---|---|
US (3) | US20090258840A1 (de) |
EP (1) | EP2020996B1 (de) |
JP (2) | JP5544165B2 (de) |
KR (1) | KR101424832B1 (de) |
CN (1) | CN101442994B (de) |
AT (1) | ATE534377T1 (de) |
AU (1) | AU2007254309B2 (de) |
BR (1) | BRPI0711646C1 (de) |
CA (1) | CA2652048C (de) |
CY (1) | CY1112377T1 (de) |
DK (1) | DK2020996T3 (de) |
EA (1) | EA016995B1 (de) |
ES (1) | ES2377467T3 (de) |
HK (1) | HK1127913A1 (de) |
MX (1) | MX2008014665A (de) |
NZ (1) | NZ572368A (de) |
PL (1) | PL2020996T3 (de) |
PT (1) | PT2020996E (de) |
SI (1) | SI2020996T1 (de) |
WO (1) | WO2007136650A2 (de) |
Cited By (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070027168A1 (en) * | 2005-07-30 | 2007-02-01 | Waldemar Pfrengle | 8-(3-amino-piperidin-1-yl)-xanthines, their preparation, and their use as pharmaceuticals |
US20080249089A1 (en) * | 2002-08-21 | 2008-10-09 | Boehringer Ingelheim Pharma Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US7820815B2 (en) | 2004-11-05 | 2010-10-26 | Boehringer Ingelheim International Gmbh | Process for the preparation of chiral 8-(-3-aminopiperidin-1-yl) xanthines |
US8232281B2 (en) | 2006-05-04 | 2012-07-31 | Boehringer Ingelheim International Gmbh | Uses of DPP-IV inhibitors |
US8513264B2 (en) | 2008-09-10 | 2013-08-20 | Boehringer Ingelheim International Gmbh | Combination therapy for the treatment of diabetes and related conditions |
US8697868B2 (en) | 2004-02-18 | 2014-04-15 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions |
US8846695B2 (en) | 2009-01-07 | 2014-09-30 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with inadequate glycemic control despite metformin therapy comprising a DPP-IV inhibitor |
US8853156B2 (en) | 2008-08-06 | 2014-10-07 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients inappropriate for metformin therapy |
US8865729B2 (en) | 2008-12-23 | 2014-10-21 | Boehringer Ingelheim International Gmbh | Salt forms of a xanthine compound |
US8883800B2 (en) | 2011-07-15 | 2014-11-11 | Boehringer Ingelheim International Gmbh | Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions |
US9034883B2 (en) | 2010-11-15 | 2015-05-19 | Boehringer Ingelheim International Gmbh | Vasoprotective and cardioprotective antidiabetic therapy |
US9149478B2 (en) | 2010-06-24 | 2015-10-06 | Boehringer Ingelheim International Gmbh | Diabetes therapy |
US9155705B2 (en) | 2008-04-03 | 2015-10-13 | Boehringer Ingelheim International Gmbh | DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation |
US9186392B2 (en) | 2010-05-05 | 2015-11-17 | Boehringer Ingelheim International Gmbh | Combination therapy |
US9266888B2 (en) | 2006-05-04 | 2016-02-23 | Boehringer Ingelheim International Gmbh | Polymorphs |
US9457029B2 (en) | 2009-11-27 | 2016-10-04 | Boehringer Ingelheim International Gmbh | Treatment of genotyped diabetic patients with DPP-IV inhibitors such as linagliptin |
US9486526B2 (en) | 2008-08-06 | 2016-11-08 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients inappropriate for metformin therapy |
US9526728B2 (en) | 2014-02-28 | 2016-12-27 | Boehringer Ingelheim International Gmbh | Medical use of a DPP-4 inhibitor |
US9526730B2 (en) | 2012-05-14 | 2016-12-27 | Boehringer Ingelheim International Gmbh | Use of a DPP-4 inhibitor in podocytes related disorders and/or nephrotic syndrome |
US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
US9713618B2 (en) | 2012-05-24 | 2017-07-25 | Boehringer Ingelheim International Gmbh | Method for modifying food intake and regulating food preference with a DPP-4 inhibitor |
US10155000B2 (en) | 2016-06-10 | 2018-12-18 | Boehringer Ingelheim International Gmbh | Medical use of pharmaceutical combination or composition |
US11033552B2 (en) | 2006-05-04 | 2021-06-15 | Boehringer Ingelheim International Gmbh | DPP IV inhibitor formulations |
US11911388B2 (en) | 2008-10-16 | 2024-02-27 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral or non-oral antidiabetic drug |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EA016995B1 (ru) * | 2006-05-16 | 2012-09-28 | Джилид Сайэнс, Инк. | Соль карбоновой кислоты фосфонамидного производного 2,6-диаминопурина, способы и средства для лечения новообразований и лечения злокачественных новообразований крови, набор, стерильный водный раствор и композиция |
TWI444384B (zh) | 2008-02-20 | 2014-07-11 | Gilead Sciences Inc | 核苷酸類似物及其在治療惡性腫瘤上的用途 |
CN103665043B (zh) | 2012-08-30 | 2017-11-10 | 江苏豪森药业集团有限公司 | 一种替诺福韦前药及其在医药上的应用 |
US11186599B2 (en) * | 2018-06-12 | 2021-11-30 | Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. | Phosphonamide ester compound, salt thereof, related crystal form thereof, preparation method therefor and use thereof |
CN112168829B (zh) * | 2020-09-24 | 2022-02-15 | 华南理工大学 | 抗病毒药物在制备治疗骨髓增生异常综合征药物中的应用及制得的骨髓增生异常综合征药物 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030229225A1 (en) * | 2002-05-13 | 2003-12-11 | Reddy K. Raja | Novel phosphonic acid based prodrugs of PMEA and its analogues |
US20050222090A1 (en) * | 2003-12-30 | 2005-10-06 | Gilead Sciences, Inc. | Anti-proliferative compounds, compositions, and methods of use thereof |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5795909A (en) * | 1996-05-22 | 1998-08-18 | Neuromedica, Inc. | DHA-pharmaceutical agent conjugates of taxanes |
JP4651264B2 (ja) | 2000-07-21 | 2011-03-16 | ギリアード サイエンシーズ, インコーポレイテッド | ホスホネートヌクレオチドアナログのプロドラッグならびにこれを選択および作製するための方法。 |
SI1360169T1 (sl) * | 2001-02-12 | 2007-12-31 | Wyeth Corp | Sukcinatna sol o-desmetil-venlafaksina |
IL161326A0 (en) * | 2001-11-29 | 2004-09-27 | Pfizer Prod Inc | Succinic acid salts of 5,8,14-triazatetracyclo'10.3.1.0<2,11>.0<4,9>-hexadeca-2 (11),3,5,7,9-pentaene and pharmaceutical compositions thereof |
CN1608062A (zh) * | 2001-12-12 | 2005-04-20 | 辉瑞产品公司 | E-2-甲氧基-n-(3-{4-[3-甲基-4-(6-甲基-吡啶-3-基氧基) -苯氨基]-喹唑啉-6基}-烯丙基)-乙酰胺的盐,其制备和抗癌用途 |
US7563748B2 (en) | 2003-06-23 | 2009-07-21 | Cognis Ip Management Gmbh | Alcohol alkoxylate carriers for pesticide active ingredients |
JP5043429B2 (ja) * | 2003-08-18 | 2012-10-10 | ハー・ルンドベック・アクチエゼルスカベット | トランス−4−((1r,3s)−6−クロロ−3−フェニルインダン−1−イル)−1,2,2−トリメチルピペラジンのコハク酸塩およびマロン酸塩、および薬剤としての使用方法 |
US20050239753A1 (en) | 2004-01-21 | 2005-10-27 | Gilead Sciences, Inc. | Methods of inhibition of MMTV-like viruses |
DE102005041860A1 (de) * | 2005-09-02 | 2007-03-08 | Schering Ag | Nanopartikulärer Einschluss- und Ladungskomplex für pharmazeutische Formulierungen |
BRPI0619962A2 (pt) * | 2005-12-16 | 2011-10-25 | Wyeth Corp | composições liofilizadas de um composto triazolopirimidina |
EA016995B1 (ru) * | 2006-05-16 | 2012-09-28 | Джилид Сайэнс, Инк. | Соль карбоновой кислоты фосфонамидного производного 2,6-диаминопурина, способы и средства для лечения новообразований и лечения злокачественных новообразований крови, набор, стерильный водный раствор и композиция |
-
2007
- 2007-05-16 EA EA200802333A patent/EA016995B1/ru unknown
- 2007-05-16 JP JP2009511052A patent/JP5544165B2/ja active Active
- 2007-05-16 CN CN200780017637XA patent/CN101442994B/zh active Active
- 2007-05-16 SI SI200730862T patent/SI2020996T1/sl unknown
- 2007-05-16 WO PCT/US2007/011726 patent/WO2007136650A2/en active Application Filing
- 2007-05-16 PT PT07794933T patent/PT2020996E/pt unknown
- 2007-05-16 AU AU2007254309A patent/AU2007254309B2/en active Active
- 2007-05-16 US US12/298,987 patent/US20090258840A1/en not_active Abandoned
- 2007-05-16 MX MX2008014665A patent/MX2008014665A/es active IP Right Grant
- 2007-05-16 US US11/803,822 patent/US20080039427A1/en not_active Abandoned
- 2007-05-16 CA CA2652048A patent/CA2652048C/en active Active
- 2007-05-16 EP EP07794933A patent/EP2020996B1/de active Active
- 2007-05-16 AT AT07794933T patent/ATE534377T1/de active
- 2007-05-16 BR BRPI0711646A patent/BRPI0711646C1/pt active IP Right Grant
- 2007-05-16 PL PL07794933T patent/PL2020996T3/pl unknown
- 2007-05-16 ES ES07794933T patent/ES2377467T3/es active Active
- 2007-05-16 KR KR1020087030561A patent/KR101424832B1/ko active IP Right Grant
- 2007-05-16 DK DK07794933.7T patent/DK2020996T3/da active
- 2007-05-16 NZ NZ572368A patent/NZ572368A/en unknown
-
2009
- 2009-08-10 HK HK09107295.8A patent/HK1127913A1/xx unknown
-
2011
- 2011-03-23 US US13/070,179 patent/US8435969B2/en active Active
-
2012
- 2012-02-16 CY CY20121100159T patent/CY1112377T1/el unknown
-
2013
- 2013-01-17 JP JP2013006055A patent/JP2013100324A/ja not_active Withdrawn
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030229225A1 (en) * | 2002-05-13 | 2003-12-11 | Reddy K. Raja | Novel phosphonic acid based prodrugs of PMEA and its analogues |
US20050222090A1 (en) * | 2003-12-30 | 2005-10-06 | Gilead Sciences, Inc. | Anti-proliferative compounds, compositions, and methods of use thereof |
Cited By (59)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8664232B2 (en) | 2002-08-21 | 2014-03-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US20080249089A1 (en) * | 2002-08-21 | 2008-10-09 | Boehringer Ingelheim Pharma Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US9321791B2 (en) | 2002-08-21 | 2016-04-26 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US9556175B2 (en) | 2002-08-21 | 2017-01-31 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and thier use as pharmaceutical compositions |
US8119648B2 (en) | 2002-08-21 | 2012-02-21 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US8178541B2 (en) | 2002-08-21 | 2012-05-15 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US10202383B2 (en) | 2002-08-21 | 2019-02-12 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US10023574B2 (en) | 2002-08-21 | 2018-07-17 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US9108964B2 (en) | 2002-08-21 | 2015-08-18 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US8697868B2 (en) | 2004-02-18 | 2014-04-15 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions |
US8541450B2 (en) | 2004-11-05 | 2013-09-24 | Boehringer Ingelheim International Gmbh | Process for the preparation of chiral 8-(3-aminopiperidin-1yl)-xanthines |
US9751855B2 (en) | 2004-11-05 | 2017-09-05 | Boehringer Ingelheim International Gmbh | Process for the preparation of chiral 8-(3-aminopiperidin-1-yl)-xanthines |
US9499546B2 (en) | 2004-11-05 | 2016-11-22 | Boehringer Ingelheim International Gmbh | Process for the preparation of chiral 8-(3-aminopiperidin-1-yl)-xanthines |
US7820815B2 (en) | 2004-11-05 | 2010-10-26 | Boehringer Ingelheim International Gmbh | Process for the preparation of chiral 8-(-3-aminopiperidin-1-yl) xanthines |
US8883805B2 (en) | 2004-11-05 | 2014-11-11 | Boehringer Ingelheim International Gmbh | Process for the preparation of chiral 8-(3-aminopiperidin-1-yl)-xanthines |
US8637530B2 (en) | 2005-07-30 | 2014-01-28 | Boehringer Ingelheim International Gmbh | 8-(3-amino-piperidin-1-yl)-xanthines, their preparation, and their use as pharmaceuticals |
US20070027168A1 (en) * | 2005-07-30 | 2007-02-01 | Waldemar Pfrengle | 8-(3-amino-piperidin-1-yl)-xanthines, their preparation, and their use as pharmaceuticals |
US8106060B2 (en) * | 2005-07-30 | 2012-01-31 | Boehringer Ingelheim International Gmbh | 8-(3-amino-piperidin-1-yl)-xanthines, their preparation, and their use as pharmaceuticals |
US9815837B2 (en) | 2006-05-04 | 2017-11-14 | Boehringer Ingelheim International Gmbh | Polymorphs |
US9266888B2 (en) | 2006-05-04 | 2016-02-23 | Boehringer Ingelheim International Gmbh | Polymorphs |
US11033552B2 (en) | 2006-05-04 | 2021-06-15 | Boehringer Ingelheim International Gmbh | DPP IV inhibitor formulations |
US8673927B2 (en) | 2006-05-04 | 2014-03-18 | Boehringer Ingelheim International Gmbh | Uses of DPP-IV inhibitors |
US11084819B2 (en) | 2006-05-04 | 2021-08-10 | Boehringer Ingelheim International Gmbh | Polymorphs |
US9173859B2 (en) | 2006-05-04 | 2015-11-03 | Boehringer Ingelheim International Gmbh | Uses of DPP IV inhibitors |
US10301313B2 (en) | 2006-05-04 | 2019-05-28 | Boehringer Ingelheim International Gmbh | Polymorphs |
US8232281B2 (en) | 2006-05-04 | 2012-07-31 | Boehringer Ingelheim International Gmbh | Uses of DPP-IV inhibitors |
US11291668B2 (en) | 2006-05-04 | 2022-04-05 | Boehringer Ingelheim International Gmbh | Uses of DPP IV inhibitors |
US11919903B2 (en) | 2006-05-04 | 2024-03-05 | Boehringer Ingelheim International Gmbh | Polymorphs |
US10080754B2 (en) | 2006-05-04 | 2018-09-25 | Boehringer Ingelheim International Gmbh | Uses of DPP IV inhibitors |
US9493462B2 (en) | 2006-05-04 | 2016-11-15 | Boehringer Ingelheim International Gmbh | Polymorphs |
US9415016B2 (en) | 2008-04-03 | 2016-08-16 | Boehringer Ingelheim International Gmbh | DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation |
US10022379B2 (en) | 2008-04-03 | 2018-07-17 | Boehringer Ingelheim International Gmbh | DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation |
US9155705B2 (en) | 2008-04-03 | 2015-10-13 | Boehringer Ingelheim International Gmbh | DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation |
US10973827B2 (en) | 2008-04-03 | 2021-04-13 | Boehringer Ingelheim International Gmbh | DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation |
US10034877B2 (en) | 2008-08-06 | 2018-07-31 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients inappropriate for metformin therapy |
US9486526B2 (en) | 2008-08-06 | 2016-11-08 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients inappropriate for metformin therapy |
US8853156B2 (en) | 2008-08-06 | 2014-10-07 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients inappropriate for metformin therapy |
US8513264B2 (en) | 2008-09-10 | 2013-08-20 | Boehringer Ingelheim International Gmbh | Combination therapy for the treatment of diabetes and related conditions |
US11911388B2 (en) | 2008-10-16 | 2024-02-27 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral or non-oral antidiabetic drug |
US8865729B2 (en) | 2008-12-23 | 2014-10-21 | Boehringer Ingelheim International Gmbh | Salt forms of a xanthine compound |
US9212183B2 (en) | 2008-12-23 | 2015-12-15 | Boehringer Ingelheim International Gmbh | Salt forms of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine |
US8846695B2 (en) | 2009-01-07 | 2014-09-30 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with inadequate glycemic control despite metformin therapy comprising a DPP-IV inhibitor |
US9457029B2 (en) | 2009-11-27 | 2016-10-04 | Boehringer Ingelheim International Gmbh | Treatment of genotyped diabetic patients with DPP-IV inhibitors such as linagliptin |
US10092571B2 (en) | 2009-11-27 | 2018-10-09 | Boehringer Ingelheim International Gmbh | Treatment of genotyped diabetic patients with DPP-IV inhibitors such as linagliptin |
US9186392B2 (en) | 2010-05-05 | 2015-11-17 | Boehringer Ingelheim International Gmbh | Combination therapy |
US10004747B2 (en) | 2010-05-05 | 2018-06-26 | Boehringer Ingelheim International Gmbh | Combination therapy |
US9603851B2 (en) | 2010-05-05 | 2017-03-28 | Boehringer Ingelheim International Gmbh | Combination therapy |
US9149478B2 (en) | 2010-06-24 | 2015-10-06 | Boehringer Ingelheim International Gmbh | Diabetes therapy |
US11911387B2 (en) | 2010-11-15 | 2024-02-27 | Boehringer Ingelheim International Gmbh | Vasoprotective and cardioprotective antidiabetic therapy |
US9034883B2 (en) | 2010-11-15 | 2015-05-19 | Boehringer Ingelheim International Gmbh | Vasoprotective and cardioprotective antidiabetic therapy |
US8883800B2 (en) | 2011-07-15 | 2014-11-11 | Boehringer Ingelheim International Gmbh | Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions |
US9199998B2 (en) | 2011-07-15 | 2015-12-01 | Boehringer Ingelheim Internatioal Gmbh | Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions |
US8962636B2 (en) | 2011-07-15 | 2015-02-24 | Boehringer Ingelheim International Gmbh | Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions |
US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
US10195203B2 (en) | 2012-05-14 | 2019-02-05 | Boehringr Ingelheim International GmbH | Use of a DPP-4 inhibitor in podocytes related disorders and/or nephrotic syndrome |
US9526730B2 (en) | 2012-05-14 | 2016-12-27 | Boehringer Ingelheim International Gmbh | Use of a DPP-4 inhibitor in podocytes related disorders and/or nephrotic syndrome |
US9713618B2 (en) | 2012-05-24 | 2017-07-25 | Boehringer Ingelheim International Gmbh | Method for modifying food intake and regulating food preference with a DPP-4 inhibitor |
US9526728B2 (en) | 2014-02-28 | 2016-12-27 | Boehringer Ingelheim International Gmbh | Medical use of a DPP-4 inhibitor |
US10155000B2 (en) | 2016-06-10 | 2018-12-18 | Boehringer Ingelheim International Gmbh | Medical use of pharmaceutical combination or composition |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8435969B2 (en) | Method and compositions for treating hematological malignancies | |
KR100568035B1 (ko) | B형 간염의 치료용 β-L-2'-데옥시-뉴클레오시드 | |
EP1358198B1 (de) | Neue acyclische nukleosidphosphonatderivate, deren salze und verfahren zu deren herstellung | |
US7795238B2 (en) | β-L-2′-deoxy-nucleosides for the treatment of hepatitis B | |
AU2012290089B2 (en) | Vitamin B6 derivatives of nucleotides, acyclonucleotides and acyclonucleoside phosphonates | |
JP2006182779A (ja) | ヌクレオチドアナログ | |
MXPA06013559A (es) | Tratamiento de linfoma de celula t usando 10-propargil-10-deazaaminopterina. | |
AU774720B2 (en) | Nucleosides with anti-hepatitis B virus activity | |
KR19990022752A (ko) | 포스포네이트 뉴클레오티드 유도체 | |
US20130266591A1 (en) | Use of tri-substituted glycerol compounds for the treatment of hematological malignancies | |
AU2007216721B2 (en) | Beta-L-2'-Deoxy Nucleosides for the Treatment of Hepatitis B |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: GILEAD SCIENCES, INC., CALIFORNIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:RAY, ADRIAN S.;TUMAS, DANIEL B.;REISER, HANS;AND OTHERS;REEL/FRAME:020017/0281;SIGNING DATES FROM 20071019 TO 20071024 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |