The present invention relates to a process for preparing a compound of formula [I], or a pharmaceutically acceptable salt thereof, said process comprising the steps of: (i) forming a reaction mixture comprising a compound of formula [II] and a compound of formula [III]; (ii) heating said reaction mixture to a temperature of at least about 130° C. to form a compound of formula [I]; (iii) isolating said compound of formula [I] from the mixture and optionally recovering unreacted compound of formula [III]; and (iv) optionally converting said compound of formula [I] into salt form; wherein: R1 and R2 are each independently H, alkyl or haloalkyl; R3 and R4 are each independently H, alkyl, haloalkyl or aryl; R5 is alkyl, alkenyl, cycloalkyl or cycloalkyl-alkyl, each of which may be optionally substituted with one or more OH groups; R6 is selected from cyclopropylamino, cyclopropylmethylamino, cyclobutylamino, cyclobutylmethylamino and where one of X, Y and Z is N and the remainder are CR9; R7, R8 and each R9 are independently H, alkyl or haloalkyl, wherein at least one of R7, R8 and R9 is other than H. Further aspects of the invention relate to a process for preparing intermediates of formula [II], and other intermediates useful in the synthesis of compounds of formula [I].
The present invention relates to a process for preparing a compound of formula [I], or a pharmaceutically acceptable salt thereof, said process comprising the steps of: (i) forming a reaction mixture comprising a compound of formula [II] and a compound of formula [III]; (ii) heating said reaction mixture to a temperature of at least about 130° C. to form a compound of formula [I]; (iii) isolating said compound of formula [I] from the mixture and optionally recovering unreacted compound of formula [III]; and (iv) optionally converting said compound of formula [I] into salt form; wherein: R1 and R2 are each independently H, alkyl or haloalkyl; R3 and R4 are each independently H, alkyl, haloalkyl or aryl; R5 is alkyl, alkenyl, cycloalkyl or cycloalkyl-alkyl, each of which may be optionally substituted with one or more OH groups; R6 is selected from cyclopropylamino, cyclopropylmethylamino, cyclobutylamino, cyclobutylmethylamino and where one of X, Y and Z is N and the remainder are CR9; R7, R8 and each R9 are independently H, alkyl or haloalkyl, wherein at least one of R7, R8 and R9 is other than H. Further aspects of the invention relate to a process for preparing intermediates of formula [II], and other intermediates useful in the synthesis of compounds of formula [I].
05 - Pharmaceutical, veterinary and sanitary products
42 - Scientific, technological and industrial services, research and design
Goods & Services
Pharmaceutical products for the treatment of cancer; pharmaceutical preparations for the treatment of cancer; pharmaceutical substances and preparations for the treatment of cancer, hematological disorders; pharmaceutical substances and preparations for use in oncology, hematology; medical preparations for the treatment of cancer and hematological disorders; medical substances in the nature of pharmaceuticals for the treatment of oncological diseases and preparations for use in oncology; medicinal preparations for the treatment of cancer and hematological disorders; medical substances in the nature of pharmaceuticals for the treatment of cancer and hematological disorders; pharmaceutical preparations for human use for the treatment of cancer and hematological disorders Pharmaceutical development; pharmaceutical products development; development of pharmaceuticals for the treatment of cancer; development of products for the treatment of cancer; development of pharmaceuticals for the treatment of leukemia; development of pharmaceuticals for the treatment of hematological cancers; development of products for the treatment of leukemia; development of products for the treatment of hematological cancers
05 - Pharmaceutical, veterinary and sanitary products
42 - Scientific, technological and industrial services, research and design
Goods & Services
Pharmaceutical products for the treatment of cancer; pharmaceutical preparations for the treatment of cancer; pharmaceutical substances and preparations for the treatment of cancer, hematological disorders; pharmaceutical substances and preparations for use in oncology, hematology; medical preparations for the treatment of cancer and hematological disorders; medical substances in the nature of pharmaceuticals for the treatment of oncological diseases and preparations for use in oncology; medicinal preparations for the treatment of cancer and hematological disorders; medical substances in the nature of pharmaceuticals for the treatment of cancer and hematological disorders; pharmaceutical preparations for human use for the treatment of cancer and hematological disorders Research services and laboratory research services in the nature of pharmaceutical development, pharmaceutical products development, development of pharmaceuticals for the treatment of cancer, development of products for the treatment of cancer, development of pharmaceuticals for the treatment of leukemia, development of pharmaceuticals for the treatment of hematological cancers, development of products for the treatment of leukemia, and development of products for the treatment of hematological cancers
4.
PROCESS FOR THE PREPARATION OF A PYRIMIDINO-DIAZEPINE DERIVATIVE
In one aspect, the invention relates to a process for preparing a compound of formula (XII), wherein PG is a protecting group, or a compound of formula (XI), comprising the steps of: (i) treating a compound of formula XIII, wherein PG is a protecting group, with N-methylpiperazine to form a compound of formula XII, wherein said compound of formula XII is in the form of a mixture of cis and trans isomers; (ii) combining the mixture formed in step (i) with an organic solvent and heating the solvent mixture so formed; (iii) isolating the trans-isomer of the compound of formula XII from the solvent mixture formed in step (ii); and (iv) optionally treating said trans-isomer of the compound of formula XII with an acid to form a compound of formula XI; and isolating said compound of formula XI. Further aspects of the invention relate to processes for preparing pyrimido-diazepinone derivatives using the above process and intermediates.
In one aspect, the invention relates to a process for preparing a compound of formula (XII), wherein PG is a protecting group, or a compound of formula (XI), comprising the steps of: (i) treating a compound of formula XIII, wherein PG is a protecting group, with N-methylpiperazine to form a compound of formula XII, wherein said compound of formula XII is in the form of a mixture of cis and trans isomers; (ii) combining the mixture formed in step (i) with an organic solvent and heating the solvent mixture so formed; (iii) isolating the trans-isomer of the compound of formula XII from the solvent mixture formed in step (ii); and (iv) optionally treating said trans-isomer of the compound of formula XII with an acid to form a compound of formula XI; and isolating said compound of formula XI. Further aspects of the invention relate to processes for preparing pyrimido-diazepinone derivatives using the above process and intermediates.
The present invention relates to new crystalline forms of a pyrimido-diazepine derivative which exhibits excellent anti-tumour activity. The invention also relates to a pharmaceutical composition containing said crystalline forms as an active ingredient, and use thereof in the prevention or treatment of disease. The invention further relates to a process for preparing the crystalline forms.
The present invention relates to a process for preparing a compound of formula [I], or a pharmaceutically acceptable salt thereof, said process comprising the steps of: (i) forming a reaction mixture comprising a compound of formula [II] and a compound of formula [III]; (ii) heating said reaction mixture to a temperature of at least about 130°C to form a compound of formula [I]; (iii) isolating said compound of formula [I] from the mixture and optionally recovering unreacted compound of formula [III]; and (iv) optionally converting said compound of formula [I] into salt form; wherein: R1and R2are each independently H, alkyl or haloalkyl; R3and R4are each independently H, alkyl, haloalkyl or aryl; R5is alkyl, alkenyl, cycloalkyl or cycloalkyl-alkyl, each of which may be optionally substituted with one or more OH groups; R6 is selected from cyclopropylamino, cyclopropylmethylamino, cyclobutylamino, cyclobutylmethylamino and where one of X, Y and Z is N and the remainder are CR9;R7, R8and each R9are independently H, alkyl or haloalkyl, wherein at least one of R7, R8and R9 is other than H. Further aspects of the invention relate to a process for preparing intermediates of formula [II], and other intermediates useful in the synthesis of compounds of formula [I].
C07D 473/34 - Nitrogen atom attached in position 6, e.g. adenine
C07D 473/16 - Heterocyclic compounds containing purine ring systems with oxygen, sulfur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
The present invention provides a method of treating acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in a subject, said method comprising administering to a subject a therapeutically effective amount of (i) sapacitabine, or a metabolite thereof; and (ii) venetoclax; in accordance with a dosing regimen comprising at least one treatment cycle, wherein said treatment cycle comprises: (a) (i) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, for 3 consecutive days per week, for 2 weeks, followed by a rest period of at least 1 week, or until treatment-related toxicities are resolved, whichever is longer; or (ii) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, for 5 consecutive days followed by a rest period of at least 2 weeks, or until treatment-related toxicities are resolved, whichever is longer; and (b) administering a therapeutically effective amount of venetoclax for about 7 to about 14 consecutive days, followed by a rest period of at least 1 week, or until treatment-related toxicities are resolved, whichever is longer.
A61K 31/635 - Compounds containing para-N-benzene- sulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonohydrazide having a heterocyclic ring, e.g. sulfadiazine
A61K 31/7068 - Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
A61P 35/02 - Antineoplastic agents specific for leukemia
8.
CRYSTALLINE FORMS OF PYRIMIDINO DIAZEPINE DERIVATIVE
The present invention relates to new crystalline forms of a pyrimido-diazepine derivative which exhibits excellent anti-tumour activity. The invention also relates to a pharmaceutical composition containing said crystalline forms as an active ingredient, and use thereof in the prevention or treatment of disease. The invention further relates to a process for preparing the crystalline forms.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
9.
PROCESS FOR THE PREPARATION OF A PYRIMIDINO-DIAZEPINE DERIVATIVE
In one aspect, the invention relates to a process for preparing a compound of formula (XII), wherein PG is a protecting group, or a compound of formula (XI), comprising the steps of: (i) treating a compound of formula XIII, wherein PG is a protecting group, with N- methylpiperazine to form a compound of formula XII, wherein said compound of formula XII is in the form of a mixture of cis and trans isomers; (ii) combining the mixture formed in step (i) with an organic solvent and heating the solvent mixture so formed; (iii) isolating the trans-isomer of the compound of formula XII from the solvent mixture formed in step (ii); and (iv) optionally treating said trans-isomer of the compound of formula XII with an acid to form a compound of formula XI; and isolating said compound of formula XI. Further aspects of the invention relate to processes for preparing pyrimido-diazepinone derivatives using the above process and intermediates.
C07D 295/073 - Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
9 is other than H. Further aspects of the invention relate to a highly diastereoselective process for the preparation of compounds of formula [III], a process for preparing intermediates of formula [II], and other intermediates useful in the synthesis of compounds of formula [I], and to a process for preparing the crystalline tartrate salt and free base of compounds of formula [I].
C07D 473/16 - Heterocyclic compounds containing purine ring systems with oxygen, sulfur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
C07D 473/40 - Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
A first aspect of the invention relates to a method of treating AML in a subject, wherein said subject: (I) has a white blood cell (WBC) count of less than about 10,000 cells/microliter and/or (II) has a cytogenetic risk classification according to the US Southwest Oncology Group (SWOG) that is not unfavourable, and/or (III) falls within a classification selected from antecedent myelodysplastic syndrome (MDS), antecedent myeloproliferative neoplasm (MPN), and antecedent myelodysplastic/myeloproliferative neoplasm (MDS/MPN); said method comprising administering to the subject a therapeutically effective amount of (i) sapacitabine, or a metabolite thereof; and (ii) decitabine; in accordance with a dosing regimen comprising at least one first treatment cycle and at least one second treatment cycle, wherein said first treatment cycle comprises administering a therapeutically effective amount of decitabine for 5 to 10 consecutive days followed by a rest period of from 3 to 5 weeks, or until treatment-related toxicities are resolved, whichever is longer; and wherein said second treatment cycle comprises administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, for 3 consecutive days per week, for 2 weeks followed by a rest period of from 2 to 4 weeks, or until treatment- related toxicities are resolved, whichever is longer.
A61K 31/706 - Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
A61K 31/7068 - Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
A61K 9/00 - Medicinal preparations characterised by special physical form
05 - Pharmaceutical, veterinary and sanitary products
Goods & Services
Pharmaceutical substances and preparations for the treatment
of cancer, haematological disorders; pharmaceutical
substances and preparations for use in oncology,
haematology; medical preparations, medical substances and
preparations; medicinal preparations, medical substances and
preparations for human use; reagents and substances for
medical purposes; reagents and substances for human medical
purposes.
05 - Pharmaceutical, veterinary and sanitary products
Goods & Services
Pharmaceutical substances and preparations for the treatment
of cancer, haematological disorders; pharmaceutical
substances and preparations for use in oncology,
haematology; medical preparations, medical substances and
preparations; medicinal preparations, medical substances and
preparations for human use; reagents and substances for
medical purposes; reagents and substances for human medical
purposes.
05 - Pharmaceutical, veterinary and sanitary products
Goods & Services
Pharmaceutical substances and preparations for the treatment of cancer, haematological disorders; pharmaceutical substances and preparations for use in oncology, haematology; medical preparations for the treatment of cancer and haematological disorders, medical substances in the nature of pharmaceuticals for the treatment of oncological diseases and preparations for use in oncology; medicinal preparations for the treatment of cancer and haematological disorders, medical substances in the nature of pharmaceuticals for the treatment of cancer and haematological disorders and preparations for human use for the treatment of cancer and haematological disorders; reagents and diagnostic substances for medical purposes; reagents and diagnostic substances for human medical purposes
05 - Pharmaceutical, veterinary and sanitary products
Goods & Services
Pharmaceutical substances and preparations for the treatment of cancer, haematological disorders; pharmaceutical substances and preparations for use in oncology, haematology; medical preparations for the treatment of cancer and haematological disorders, medical substances in the nature of pharmaceuticals for the treatment of oncological diseases and preparations for use in oncology; medicinal preparations for the treatment of cancer and haematological disorders, medical substances in the nature of pharmaceuticals for the treatment of cancer and haematological disorders and preparations for human use for the treatment of cancer and haematological disorders; reagents and diagnostic substances for medical purposes; reagents and diagnostic substances for human medical purposes
The present invention relates to a process for preparing a compound of formula [I], said process comprising the steps of: formula [II]+formula [III]−>formula [I] (i) forming a reaction mixture comprising (a) a compound of formula [II], (b) a compound of formula [III] and (c) 1,2-propanediol or polyethylene glycol, or a mixture thereof, and optionally (d) a base; (ii) heating said reaction mixture to a temperature of at least about 150°C to form a compound of formula [I]; (iii) isolating said compound of formula [I]; and (iv) optionally converting said compound of formula [I] into salt form; wherein: R1 and R2 are each independently H, alkyl or haloalkyl; R3 and R4 are each independently H, alkyl, haloalkyl or aryl; R5 is alkyl, alkenyl, cycloalkyl or cycloalkyl-alkyl, each of which may be optionally substituted with one or more OH groups; R6 is selected from cyclopropylamino, cyclopropylmethylamino, cyclobutylamino, cyclobutylmethylamino and formula (A) where one of X, Y and Z is N and the remainder are CR9; R7, R8 and each R9 are independently H, alkyl or haloalkyl, wherein at least one of R7, R8 and R9 is other than H. Further aspects of the invention relate to a highly diastereoselective process for the preparation of compounds of formula [III], a process for preparing intermediates of formula [II], and other intermediates useful in the synthesis of compounds of formula [I], and to a process for preparing the crystalline tartrate salt and free base of compounds of formula [I].
C07D 473/16 - Heterocyclic compounds containing purine ring systems with oxygen, sulfur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
A first aspect of the invention relates to a method of treating a proliferative disorder in a subject, said method comprising administering to the subject a therapeutically effective amount of (i) sapacitabine, or a metabolite thereof; and (ii) seliciclib; in accordance with a dosing regimen comprising at least one treatment cycle, wherein said treatment cycle comprises: (a) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on 3 to 5 consecutive days in a first period; and (b) administering a therapeutically effective amount of seliciclib on 2 to 4 consecutive days; (c) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, on 3 to 5 consecutive days in a second period; and (d) a rest period of at least about 10 days, or until treatment-related toxicities are resolved, whichever is longer. Further aspects of the invention relate to a kit of parts, and corresponding uses.
A61K 31/7068 - Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
The present invention relates to pyrimidine derivatives capable of inhibiting one or more protein kinases. Further aspects relate to pharmaceutical compositions comprising the pyrimidine derivatives and the use thereof in the treatment of proliferative disorders.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
C07D 519/00 - Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups or
C07D 453/02 - Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
A first aspect of the invention relates to a method of treating a proliferative disorder in a subject, said method comprising administering to the subject a therapeutically effective amount of (i) sapacitabine, or a metabolite thereof; and (ii) seliciclib; in accordance with a dosing regimen comprising at least one first treatment cycle and at least one second treatment cycle, wherein said first treatment cycle comprises: (a) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, for 3 to 5 consecutive days for 2 weeks, starting on day d, where d is the first day of treatment with sapacitabine, or the metabolite thereof, in said first treatment cycle; and (b) optionally administering a therapeutically effective amount of seliciclib for 3 to 5 consecutive days for 2 weeks, starting on day (d−1) relative to the administration of sapacitabine or the metabolite thereof, in said first treatment cycle; followed by a rest period of at least 2 weeks, or until treatment-related toxicities are resolved, whichever is longer; and wherein said second treatment cycle comprises: (a) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, for 3 to 5 consecutive days for 2 weeks, starting on day d, where d is the first day of treatment with sapacitabine, or the metabolite thereof, in said second treatment cycle; and (b) administering a therapeutically effective amount of seliciclib for 3 to 5 consecutive days for 2 weeks, starting on day (d−1) relative to the administration of sapacitabine or the metabolite thereof, in said second treatment cycle; followed by a rest period of at least 2 weeks, or until treatment-related toxicities are resolved, whichever is longer. Further aspects of the invention relate to a kit of parts, and corresponding uses.
A61K 31/7068 - Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
The present invention relates to new crystalline forms of a purine derivative which exhibits excellent anti-tumor activity. The invention also relates to a pharmaceutical composition containing said crystalline forms as an active ingredient, and use thereof in the prevention or treatment of disease. The invention further relates to a process for preparing the crystalline forms.
C07D 473/00 - Heterocyclic compounds containing purine ring systems
C07D 473/16 - Heterocyclic compounds containing purine ring systems with oxygen, sulfur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
G01F 1/115 - Measuring the volume flow or mass flow of fluid or fluent solid material wherein the fluid passes through a meter in a continuous flow by using mechanical effects using rotating vanes with axial admission with magnetic or electromagnetic coupling to the indicating device
G01P 3/48 - Devices characterised by the use of electric or magnetic means for measuring angular speed by measuring frequency of generated current or voltage
G01P 5/07 - Measuring speed of fluids, e.g. of air streamMeasuring speed of bodies relative to fluids, e.g. of ship, of aircraft by measuring forces exerted by the fluid on solid bodies, e.g. anemometer using rotation of vanes with electrical coupling to the indicating device
C07C 65/05 - Compounds having carboxyl groups bound to carbon atoms of six-membered aromatic rings and containing any of the groups OH, O-metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
C07C 303/32 - Preparation of esters or amides of sulfuric acidsPreparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
C07C 309/04 - Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
C07C 309/29 - Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
21.
Dosing regimens for treatment of proliferative disorders comprising administration of sapacitabine
One aspect of the present invention relates to the use of sapacitabine, or a metabolite thereof, in the preparation of a medicament for treating a proliferative disorder, wherein the sapacitabine or metabolite thereof is administered in a dosing regimen comprising at least one treatment cycle, wherein said treatment cycle comprises administering a therapeutically effective amount of sapacitabine or metabolite thereof for about 2 to about 6 days per week, for 2 weeks out of 3 weeks. Another aspect of the invention relates to the use of sapacitabine, or a metabolite thereof, in the preparation of a medicament for treating cutaneous T-cell lymphoma (CTCL).
A61K 31/7068 - Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
A61K 31/513 - PyrimidinesHydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
22.
Combinations of sapacitabine or CNDAC with DNA methyltransferase inhibitors such as decitabine and procaine
A first aspect of the invention relates to a combination comprising a DNA methyltransferase inhibitor and 1-(2-C-cyano-2-dioxy-β-D-arabino-pentofuranosyl)-N4-palmitoyl cytosine, or a metabolite thereof. A second aspect of the invention relates to a pharmaceutical product comprising a DNA methyltransferase inhibitor and 1-(2-C-cyano-2-dioxy-β-D-arabino-pentofuranosyl)-N4-palmitoyl cytosine, or a metabolite thereof, as a combined preparation for simultaneous, sequential or separate use in therapy. A third aspect of the invention relates to a method of treating a proliferative disorder, said method comprising simultaneously, sequentially or separately administering a DNA methyltransferase inhibitor and 1-(2-C-cyano-2-dioxy-β-D-arabino-pentofuranosyl)-N4-palmitoyl cytosine, or a metabolite thereof, to a subject.
A01N 43/04 - Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atom with one hetero atom
A61K 31/405 - Indole-alkanecarboxylic acidsDerivatives thereof, e.g. tryptophan, indomethacin
A61K 31/245 - Amino benzoic acid types, e.g. procaine, novocaine
A61K 31/353 - 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
A61K 31/502 - PyridazinesHydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
A61K 31/706 - Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
A61K 31/7068 - Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
23.
Dosage regimen for sapacitabine and decitabine in combination for treating acute myeloid leukemia
A first aspect of the invention relates to a method of treating AML in a subject, said method comprising administering to a subject a therapeutically effective amount of (i) sapacitabine, or a metabolite thereof; and (ii) decitabine; in accordance with a dosing regimen comprising at least one first treatment cycle and at least one second treatment cycle, wherein said first treatment cycle comprises administering a therapeutically effective amount of decitabine for 5 to 10 consecutive days followed by a rest period of from 3 to 5 weeks, or until treatment-related toxicities are resolved, whichever is longer; and wherein said second treatment cycle comprises administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, for 3 consecutive days per week, for 2 weeks followed by a rest period of from 2 to 4 weeks, or until treatment-related toxicities are resolved, whichever is longer.
A61K 31/7068 - Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
A61K 31/706 - Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
24.
Pyrimidine derivatives as protein kinase inhibitors
8 are each independently H or alkyl. Further aspects relate to pharmaceutical compositions comprising said compounds and use therefore in the treatment of proliferative disorders and the like.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
C07D 519/00 - Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups or
C07D 453/02 - Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
A first aspect of the invention relates to a method of treating a proliferative disorder in a subject, said method comprising administering to the subject a therapeutically effective amount of (i) sapacitabine, or a metabolite thereof; and (ii) seliciclib; in accordance with a dosing regimen comprising at least one first treatment cycle and at least one second treatment cycle, wherein said first treatment cycle comprises: (a) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, for 3 to 5 consecutive days for 2 weeks, starting on day d, where d is the first day of treatment with sapacitabine, or the metabolite thereof, in said first treatment cycle; and (b) optionally administering a therapeutically effective amount of seliciclib for 3 to 5 consecutive days for 2 weeks, starting on day (d-1) relative to the administration of sapacitabine or the metabolite thereof, in said first treatment cycle; followed by a rest period of at least 2 weeks, or until treatment-related toxicities are resolved, whichever is longer; and wherein said second treatment cycle comprises: (a) administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, for 3 to 5 consecutive days for 2 weeks, starting on day d, where d is the first day of treatment with sapacitabine, or the metabolite thereof, in said second treatment cycle; and (b) administering a therapeutically effective amount of seliciclib for 3 to 5 consecutive days for 2 weeks, starting on day (d-1) relative to the administration of sapacitabine or the metabolite thereof, in said second treatment cycle; followed by a rest period of at least 2 weeks, or until treatment-related toxicities are resolved, whichever is longer. Further aspects of the invention relate to a kit of parts, and corresponding uses.
A61K 31/706 - Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
A61K 31/505 - PyrimidinesHydrogenated pyrimidines, e.g. trimethoprim
A first aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a proliferative disorder, wherein: X is NR7; R1 and R2 are each independently H, alkyl or cycloalkyl; R3 is a 6-membered heterocycloalkyi group selected from piperidinyl, piperazinyl, morpholinyl and tetrahydropyranyl, wherein said heterocycloalkyi group is optionally further substituted by one or more (CH2)nR19 groups; R4 and R4' are each independently H or alkyl; or R4 and R4' together form a spiro cycloalkyl group; Q is CH or N; R6 is OR8 or halogen; n is 1, 2 or 3; R19 is H, alkyl, aryl or a cycloalkyl group; R7 and R8 are each independently H or alkyl; and wherein said compound is administered in accordance with a dosing regimen which: (i) maintains a plasma concentration of from about 50 to about 500 nM for a period of up to about 16 hours; or (ii) maintains a plasma concentration of from about 0.5 μΜ to about 1 μΜ for a period of up to about 6 hours; or (iii) achieves a maximum plasma concentration (Cmax) of no more than about 500 nM within a period of about 6 hours; or (iv) achieves a maximum plasma concentration (Cmax) of no more than about 200 nM within a period of about 16 hours; or (v) achieves a maximum plasma concentration (Cmax) of about 0.5 μΜ to about 1 μΜ within about 6 hours. Further claims relate to a method of treatment based on this dosing regimen, and kits relating to the same.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
The present invention relates to new crystalline forms of a purine derivative which exhibits excellent anti-tumour activity. The invention also relates to a pharmaceutical composition containing said crystalline forms as an active ingredient, and use thereof in the prevention or treatment of disease. The invention further relates to a process for preparing the crystalline forms.
C07D 473/16 - Heterocyclic compounds containing purine ring systems with oxygen, sulfur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
G01P 5/07 - Measuring speed of fluids, e.g. of air streamMeasuring speed of bodies relative to fluids, e.g. of ship, of aircraft by measuring forces exerted by the fluid on solid bodies, e.g. anemometer using rotation of vanes with electrical coupling to the indicating device
C07C 65/05 - Compounds having carboxyl groups bound to carbon atoms of six-membered aromatic rings and containing any of the groups OH, O-metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
G01F 1/115 - Measuring the volume flow or mass flow of fluid or fluent solid material wherein the fluid passes through a meter in a continuous flow by using mechanical effects using rotating vanes with axial admission with magnetic or electromagnetic coupling to the indicating device
C07C 309/04 - Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
C07C 51/41 - Preparation of salts of carboxylic acids by conversion of the acids or their salts into salts with the same carboxylic acid part
C07C 309/29 - Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
C07C 59/245 - Saturated compounds having more than one carboxyl group containing hydroxy or O-metal groups
C07C 303/32 - Preparation of esters or amides of sulfuric acidsPreparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
G01P 3/48 - Devices characterised by the use of electric or magnetic means for measuring angular speed by measuring frequency of generated current or voltage
A first aspect of the invention relates to a method of treating AML in a subject, said method comprising administering to a subject a therapeutically effective amount of (i) sapacitabine, or a metabolite thereof; and (ii) decitabine; in accordance with a dosing regimen comprising at least one first treatment cycle and at least one second treatment cycle, wherein said first treatment cycle comprises administering a therapeutically effective amount of decitabine for 5 to 10 consecutive days followed by a rest period of from 3 to 5 weeks, or until treatment-related toxicities are resolved, whichever is longer; and wherein said second treatment cycle comprises administering a therapeutically effective amount of sapacitabine, or a metabolite thereof, for 3 consecutive days per week, for 2 weeks followed by a rest period of from 2 to 4 weeks, or until treatment- related toxicities are resolved, whichever is longer.
A61K 31/706 - Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
A61K 31/7068 - Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
A61P 35/02 - Antineoplastic agents specific for leukemia
29.
Preparation of intermediates useful in the synthesis of 2′-cyano-2′-deoxy-N4-palmi-toyl-1-β-D-arabinofuranosylcytosine
The present invention relates to new crystalline forms of a purine derivative which exhibits excellent anti-tumour activity. The invention also relates to a pharmaceutical composition containing said crystalline forms as an active ingredient, and use thereof in the prevention or treatment of disease. The invention further relates to a process for preparing the crystalline forms.
C07D 473/16 - Heterocyclic compounds containing purine ring systems with oxygen, sulfur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
8 are each independently H or alkyl. Further aspects relate to pharmaceutical compositions comprising said compounds and use therefore in the treatment of proliferative disorders and the like.
C07D 519/00 - Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups or
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
32.
Dosing regimens for treatment of proliferative disorders comprising administration of sapacitabine
One aspect of the present invention relates to the use of sapacitabine, or a metabolite thereof, in the preparation of a medicament for treating a proliferative disorder, wherein the sapacitabine or metabolite thereof is administered in a dosing regimen comprising at least one treatment cycle, wherein said treatment cycle comprises administering a therapeutically effective amount of sapacitabine or metabolite thereof for about 2 to about 6 days per week, for 2 weeks out of 3 weeks. Another aspect of the invention relates to the use of sapacitabine, or a metabolite thereof, in the preparation of a medicament for treating cutaneous T-cell lymphoma (CTCL).
Cancer Research Technology Limited (United Kingdom)
Inventor
Sheldrake, Peter William
Atrash, Butrus
Green, Simon
Mcdonald, Edward
Frame, Sheelagh
Abstract
The present invention relates to compounds of formula (I)
6 is selected from cyclopropylamino, cyclopropylmethylamino, cyclobutylamino, cyclobutylmethylamino and
9 is other than H.
A further aspect of the invention relates to pharmaceutical compositions comprising compounds of formula (I), and the use of said compounds in treating proliferative disorders, viral disorders, stroke, alopecia, CNS disorders, neurodegenerative disorders, or diabetes.
C07D 473/16 - Heterocyclic compounds containing purine ring systems with oxygen, sulfur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
34.
Combination comprising CNDAC (2′-cyano-2′-deoxy-N4-palmitoyl-1-beta-D-arabinofuranosyl-cytosine) and a cytotoxic agent
4-palmitoyl-1-β-D-arabinofuranosyl-cytosine, or a metabolite thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating cutaneous T-cell lymphoma (CTCL).
A01N 43/04 - Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atom with one hetero atom
A01N 43/42 - Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings condensed with carbocyclic rings
A01N 37/00 - Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
A01N 37/28 - Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing the group —CO—N, e.g. carboxylic acid amides or imidesThio-analogues thereof containing the group Thio-analogues thereof
3, alkyl and alkoxy, wherein said alkyl and alkoxy groups may be further substituted by one or more OH groups. Further aspects of the invention relate to pharmaceutical compositions comprising compounds of formula I, and the use of compounds of formula (I) in the preparation of a medicament for treating a variety of disorders, including proliferative disorders, viral disorders, stroke, etc.
A first aspect of the invention relates to a combination comprising a DNA methyltransferase inhibitor and 1-(2-C-cyano-2-dioxy-β-D-arabino-pentofuranosyl)-N4- palmitoyl cytosine, or a metabolite thereof. A second aspect of the invention relates to a pharmaceutical product comprising a DNA methyltransferase inhibitor and 1-(2-C-cyano-2-dioxy-β-D-arabino- pentofuranosyl)-N4-palmitoyl cytosine, or a metabolite thereof, as a combined preparation for simultaneous, sequential or separate use in therapy. A third aspect of the invention relates to a method of treating a proliferative disorder, said method comprising simultaneously, sequentially or separately administering a DNA methyltransferase inhibitor and 1-(2-C-cyano-2-dioxy-β-D-arabino- pentofuranosyl)-N4-palmitoyl cytosine, or a metabolite thereof, to a subject.
A61K 31/245 - Amino benzoic acid types, e.g. procaine, novocaine
A61K 31/353 - 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
A61K 31/502 - PyridazinesHydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
A61K 31/706 - Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
A61K 31/7068 - Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
The present invention relates to a process for preparing a compound of formula (682-6'), said process comprising the steps of: formula (682-4), (682-5), (682-6'): (i) converting a compound of formula (682-4) into a compound of formula (682-5); and (ii) converting said compound of formula (682-5) into a compound of formula (682- 6'). Further aspects of the invention relate to the use of the above process in the preparation of 2'-cyano-2'-deoxy-N4-palmitoyl-l-β-D-arabinofuranosylcytosine, a pyrimidine nucleoside which is therapeutically useful in the treatment and/or prevention of cancer.
A61K 31/7068 - Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
C07F 7/08 - Compounds having one or more C—Si linkages
The present invention relates to a process for preparing a compound of formula 682-4, said process comprising the steps of: (i) converting a compound of formula 682-1 into a compound of formula 682-2'; (ii) converting said compound of formula 682-2' into a compound of formula 682-3; and (iii) converting said compound of formula 682-3 into a compound of formula 682-4. Further aspects of the invention relate to the use of the above process in the preparation of 2'-cyano-2'-deoxy-N4 -palmitoyl-1-β-D-arabmofuranosylcytosine, a pyrimidine nucleoside which is therapeutically useful in the treatment and/or prevention of cancer.
A61K 31/7068 - Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
C07F 7/08 - Compounds having one or more C—Si linkages
The present invention relates to a compound of formula (VII)I, or a pharmaceutically acceptable salt or ester thereof, wherein: X is NR7; Y is O or N-(CH2)nR19; n is 1, 2 or 3; m is 1 or 2; R1 and R2 are each independently H, alkyl or cycloalkyl; R4 and R4' are each independently H or alkyl; or R4 and R4' together form a spiro cycloalkyl group; R19 is H, alkyl, aryl or a cycloalkyl group; R6 is OR8 or halogen; and R7 and R8 are each independently H or alkyl. Further aspects relate to pharmaceutical compositions comprising said compounds and use therefore in the treatment of proliferative disorders and the like.
C07D 519/00 - Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups or
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
41.
Crystalline pyrimidine nucleoside derivative suspensions in capsules
A01N 43/80 - Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms, as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
One aspect of the present invention relates to the use of sapacitabine, or a metabolite thereof, in the preparation of a medicament for treating a proliferative disorder, wherein the sapacitabine or metabolite thereof is administered in a dosing regimen comprising at least one treatment cycle, wherein said treatment cycle comprises administering a therapeutically effective amount of sapacitabine or metabolite thereof for about 2 to about 6 days per week, for 2 weeks out of 3 weeks. Another aspect of the invention relates to the use of sapacitabine, or a metabolite thereof, in the preparation of a medicament for treating cutaneous T-cell lymphoma (CTCL).
CANCER RESEARCH TECHNOLOGY LIMITED (United Kingdom)
Inventor
Sheldrake, Peter, William
Atrash, Butrus
Green, Simon
Mcdonald, Edward
Frame, Sheelagh
Abstract
The present invention relates to compounds of formula (I) wherein: R1 and R2 are each independently H, alkyl or haloalkyl; R3 and R4 are each independently H, alkyl, haloalkyl or aryl; R5 is alkyl or cycloalkyl or cycloalkyl-alkyl, each of which may be optionally substituted with one or more OH groups; R6 is selected from cyclopropylamino, cyclopropylmethylamino, cyclobutylamino, cyclobutylmethylamino and formula (a) where one of X, Y and Z is N and the remainder are CR9; R7, R8 and each R9 are independently H, alkyl or haloalkyl, wherein at least one of R7, R8 and each R9 is other than H. A further aspect of the invention relates to pharmaceutical compositions comprising compounds of formula (I), and the use of said compounds in treating proliferative disorders, viral disorders, stroke, alopecia, CNS disorders, neurodegenerative disorders, or diabetes.
C07D 473/16 - Heterocyclic compounds containing purine ring systems with oxygen, sulfur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
The present invention relates to combination comprising (i) an ErbB inhibitor; and (ii) a CDK inhibitor, or a pharmaceutically acceptable salt thereof, selected from: (a) roscovitine; (b) 3-{9-isopropyl-6-[(pyridin-3-ylmethyl)-amino]-9H-purin-2-ylamino}- 2-methyl-pentan-2-ol; (c) 3-{9-isopropyl-6-[(pyridm-3-ylmethyl)-amino]-9H-purin-2- ylamino}-pentan-2-ol; and (d) (2R,3S-3-(6-((4,6-dimethylpyridin-3-ylmethylamino)-9- isopropyl-9H-purin-2-ylamino)pentan-2-ol. Further aspects of the invention relate to pharmaceutical products and pharmaceutical compositions comprising combinations according to the invention, and methods of treatment using the same.
A61K 31/517 - PyrimidinesHydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
A61K 45/00 - Medicinal preparations containing active ingredients not provided for in groups
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
A first aspect of the invention relates to a combination comprising 2'-cyano-2'-deoxy- N4-palmitoyl-l-β-D-arabinofuranosyl-cytosine, or a metabolite thereof, or a pharmaceutically acceptable salt thereof, and a cytotoxic agent selected from: (a) a HDAC inhibitor; and (b) a topoisomerase inhibitor selected from etoposide, topotecan and SN-38, or a prodrug thereof. A second aspect relates to a pharmaceutical product comprising (i) 2'-cyano-2'-deoxy- N4-palmitoyl-l-β-D-arabinofuranosyl-cytosine, or a metabolite thereof, or a pharmaceutically acceptable salt thereof, and (ii) a cytotoxic agent selected from: (a) a HDAC inhibitor; and (b) a topoisomerase inhibitor selected from etoposide, topotecan and SN-38, or a prodrug thereof, as a combined preparation for simultaneous, sequential or separate use in therapy. A third aspect relates to a method of treating a proliferative disorder, said method comprising simultaneously, separately or sequentially administering to a subject 2'- cyano-2'-deoxy-N4-palmitoyl-1-β-D-arabinofuranosyl-cytosine, or a metabolite thereof, or a pharmaceutically acceptable salt thereof, and a cytotoxic agent selected from: (a) a HDAC inhibitor; and (b) a topoisomerase inhibitor selected from etoposide, topotecan and SN-38, or a prodrug thereof. A fourth aspect of the invention relates to the use of a subject 2'-cyano-2'-deoxy-N4- palmitoyl-1-β-D-arabinofuranosyl-cytosine, or a metabolite thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating cutaneous T-cell lymphoma (CTCL).
A61K 31/7068 - Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
A61K 31/7042 - Compounds having saccharide radicals and heterocyclic rings
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
A first aspect of the invention relates to a combination comprising (a) a cytotoxic drug selected from: (i) doxorubicin; (ii) SN-38, or a prodrug thereof; (iii) gemcitabine; and (b) a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: R1 is alkyl; R2 and R3 are each independently selected from H and alkyl; and R4 is a heteroalicyclic group optionally substituted by one or more substituents selected from alkyl, CO-alkyl and aralkyl. Further aspects of the invention relate to pharmaceutical products and therapeutic uses of said combination.
A61K 31/4745 - QuinolinesIsoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenanthrolines
A61K 31/495 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
A61K 31/506 - PyrimidinesHydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
A61K 31/5377 - 1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
A61K 31/704 - Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin, digitoxin
A61K 31/7068 - Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
A first aspect of the invention relates to a combination comprising (a) a cytotoxic drug selected from (i) cisplatin; and (ii) 5-FU, or a prodrug thereof; and (b) a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: R1 is alkyl; R2 and R3 are each independently selected from H and alkyl; and R4 is a heteroalicyclic group optionally substituted by one or more substituents selected from alkyl, CO-alkyl and aralkyl. Further aspects of the invention relate to pharmaceutical products comprising the combination of the invention, and methods of treating proliferative disorders using the same.
A first aspect of the invention relates to a combination comprising CNDAC, or a prodrug thereof, and a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: R1 is alkyl; R2 and R3 are each independently selected from H and alkyl; and R4 is a heteroalicyclic group optionally substituted by one or more substituents selected from alkyl, CO-alkyl and aralkyl. A second aspect of the invention relates to a pharmaceutical product comprising a compound of formula (I),, or a pharmaceutically acceptable salt thereof, and CNDAC, or a prodrug thereof, as a combined preparation for simultaneous, sequential or separate use in therapy. A third aspect of the invention relates to a method of treating a proliferative disorder, said method comprising simultaneously, sequentially or separately administering a compound of formula I, or a pharmaceutically acceptable salt thereof, and CNDAC, or a prodrug thereof, to a subject.
A61K 31/495 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
A61K 31/506 - PyrimidinesHydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
A61K 31/5377 - 1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
A61K 31/7068 - Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
The present invention relates to a process for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R2 is (a) where R3, R4, R7 and R8 are each independently selected from H, alkyl, aryl and aralkyl, said alkyl, aryl and aralkyl groups each being optionally substituted with one or more R12 groups, and wherein at least one of R3, R4, R7 and R8 is other than H; R5 is OH, O-alkyl, NH2, H, alkyl, aryl or aralkyl, said alkyl, aryl and aralkyl groups each being optionally substituted with one or more R12 groups; R6 is NR10R11, wherein R10 and R11 are each independently H or hydrocarbyl; R9 is hydrocarbyl; and each R12 is independently selected from OR13, halo, alkyl, COOR14, CONR15R16, SO2NR17R18, NO2, CN, NR19R20SR21 and CF3, where R13-21 are each independently H, alkyl or aryl; said process comprising the steps of (II) (III) (IV) (i) converting a compound of formula (II) to a compound of formula (III), wherein X is halo and R is aryl, alkyl, cycloalkyl, aralkyl, heteroaryl or alkyl-heteroaryl; (ii) converting said compound of formula (III) to a compound of formula (IV); and (iii) converting said compound of formula (IV) to a compound of formula (I).
C07D 473/16 - Heterocyclic compounds containing purine ring systems with oxygen, sulfur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
The present invention relates to pharmacodynamic markers for CDKIs including the candidate 2,6,9-tri-substituted purine known as seliciclib (roscovitine). The identity of these markers facilitates the convenient identification of seliciclib (roscovitine)-like activity both in vitro and in vivo.
The present invention relates to a pharmaceutical formulation which comprises (i) a capsule, and (ii) a core comprising crystalline 2'-cyano-2'-deoxy-N4-palmitoyl-l-&bgr;-D-arabinofuranosylcytosine and a liquid carrier.
A first aspect of the invention relates to a combination comprising roscovitine, or a pharmaceutically acceptable salt thereof, and a HDAC inhibitor selected from sodium butyrate, or a prodrug thereof, suberoylanilide hydroxamic acid (SAHA), sodium valproate and trichostatin A (TSA). A second aspect of the invention relates to a pharmaceutical product comprising roscovitine, or a pharmaceutically acceptable salt thereof, and a HDAC inhibitor selected from sodium butyrate, or a prodrug thereof, suberoylanilide hydroxamic acid (SAHA), sodium valproate and trichostatin A (TSA) as a combined preparation for simultaneous, sequential or separate use in therapy. A third aspect of the invention relates to a method for treating a proliferative disorder, said method comprising simultaneously, sequentially or separately administering roscovitine, or a pharmaceutically acceptable salt thereof, and a HDAC inhibitor selected from sodium butyrate, or a prodrug thereof, suberoylanilide hydroxamic acid (SAHA), sodium valproate and trichostatin A (TSA) to a subject.
A first aspect of the invention relates to a combination comprising 2'-cyano-2'-deoxy-N4-palmitoyl-l-beta-D-arabinofuranosyl-cytosine, or a metabolite thereof, or a pharmaceutically acceptable salt thereof, and a cytotoxic agent selected from (a) a vinca alkaloid; (b) a taxane; (c) a cytosine analogue; (d) an anthracycline; and (e) a platinum antineoplastic agent. A second aspect of the invention relates to a pharmaceutical product comprising the above combination as a combined preparation for simultaneous, sequential or separate use in therapy. A third aspect of the invention relates to a method for treating a proliferative disorder, said method comprising simultaneously, sequentially or separately administering the above combination.
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
A61K 31/7068 - Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
A first aspect of the invention relates to a combination comprising a HDAC inhibitor and a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, and a HDAC inhibitor. A second aspect of the invention relates to a pharmaceutical product comprising a HDAC inhibitor and a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, as a combined preparation for simultaneous, sequential or separate use in therapy. A third aspect of the invention relates to a method for treating a proliferative disorder, said method comprising simultaneously, sequentially or separately administering a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, and a HDAC inhibitor to a subject.
A61K 31/167 - Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen atom of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
05 - Pharmaceutical, veterinary and sanitary products
10 - Medical apparatus and instruments
42 - Scientific, technological and industrial services, research and design
Goods & Services
Chemical preparations for pharmaceutical and medical purposes; pharmaceutical preparations and substances. Medical and surgical apparatus and instruments; parts and fittings for all the aforesaid goods. Medical services; research services and laboratory research services; compilation of medical, pharmaceutical and scientific information, and provision thereof via electronic media, including the internet, and non-electronic media; leasing of access time to databases.
05 - Pharmaceutical, veterinary and sanitary products
42 - Scientific, technological and industrial services, research and design
Goods & Services
[ pharmaceutical preparations for the treatment of degenerative diseases ] [ medical services; ] laboratory research in the field of drug discovery, database development and drug candidate optimization; medical research [ ; compiling and providing medical information, pharmaceutical and scientific information; computer services, namely, providing databases featuring medical, pharmaceutical and scientific information ]
57.
PROCESS FOR THE PREPARATION OF PURINE DERIVATIVES EXHIBITING CDK INHIBITORY ACTIVITY
The present invention relates to a process for preparing a compound of formula [I], or a pharmaceutically acceptable salt thereof, said process comprising the steps of: (i) forming a reaction mixture comprising a compound of formula [II] and a compound of formula [III]; (ii) heating said reaction mixture to a temperature of at least about 130°C to form a compound of formula [I]; (iii) isolating said compound of formula [I] from the mixture and optionally recovering unreacted compound of formula [III]; and (iv) optionally converting said compound of formula [I] into salt form; wherein: R1 and R2 are each independently H, alkyl or haloalkyl; R3 and R4 are each independently H, alkyl, haloalkyl or aryl; R5 is alkyl, alkenyl, cycloalkyl or cycloalkyl-alkyl, each of which may be optionally substituted with one or more OH groups; R6 is selected from cyclopropylamino, cyclopropylmethylamino, cyclobutylamino, cyclobutylmethylamino and where one of X, Y and Z is N and the remainder are CR9; R7, R8 and each R9 are independently H, alkyl or haloalkyl, wherein at least one of R7, R8 and R9 is other than H. Further aspects of the invention relate to a process for preparing intermediates of formula [II], and other intermediates useful in the synthesis of compounds of formula [I].
The present invention relates to new crystalline forms of a pyrimido-diazepine derivative which exhibits excellent anti-tumour activity. The invention also relates to a pharmaceutical composition containing said crystalline forms as an active ingredient, and use thereof in the prevention or treatment of disease. The invention further relates to a process for preparing the crystalline forms.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
C07C 309/30 - Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
In one aspect, the invention relates to a process for preparing a compound of formula (XII), wherein PG is a protecting group, or a compound of formula (XI), comprising the steps of: (i) treating a compound of formula XIII, wherein PG is a protecting group, with N- methylpiperazine to form a compound of formula XII, wherein said compound of formula XII is in the form of a mixture of cis and trans isomers; (ii) combining the mixture formed in step (i) with an organic solvent and heating the solvent mixture so formed; (iii) isolating the trans-isomer of the compound of formula XII from the solvent mixture formed in step (ii); and (iv) optionally treating said trans-isomer of the compound of formula XII with an acid to form a compound of formula XI; and isolating said compound of formula XI. Further aspects of the invention relate to processes for preparing pyrimido-diazepinone derivatives using the above process and intermediates.
C07D 295/135 - Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
CANCER RESEARCH TECHNOLOGY LIMITED (United Kingdom)
Inventor
Sheldrake, Peter William
Atrash, Butrus
Green, Simon
Mcdonald, Edward
Frame, Sheelagh
Abstract
The present invention relates to compounds of formula (I) wherein: R1 and R2 are each independently H, alkyl or haloalkyl; R3 and R4 are each independently H, alkyl, haloalkyl or aryl; R5 is alkyl or cycloalkyl or cycloalkyl-alkyl, each of which may be optionally substituted with one or more OH groups; R6 is selected from cyclopropylamino, cyclopropylmethylamino, cyclobutylamino, cyclobutylmethylamino and formula (a) where one of X, Y and Z is N and the remainder are CR9; R7, R8 and each R9 are independently H, alkyl or haloalkyl, wherein at least one of R7, R8 and each R9 is other than H. A further aspect of the invention relates to pharmaceutical compositions comprising compounds of formula (I), and the use of said compounds in treating proliferative disorders, viral disorders, stroke, alopecia, CNS disorders, neurodegenerative disorders, or diabetes.
C07D 473/16 - Heterocyclic compounds containing purine ring systems with oxygen, sulfur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
61.
PYRIMIDINE DERIVATIVES AS PROTEIN KINASE INHIBITORS
The present invention relates to a compound of formula (VII)I, or a pharmaceutically acceptable salt or ester thereof wherein: X is NR7; Y is O or N-(CH2)n R19 ; n is 1, 2 or 3; m is 1 or 2; R1 and R2 are each independently H, alkyl or cycloalkyl; R4 and R4' are each independently H or alkyl; or R4 and R4' together form a spiro cycloalkyl group; R19 is H, alkyl, aryl or a cycloalkyl group; R6 is OR8 or halogen; and R7 and R8 are each independently H or alkyl. Further aspects relate to pharmaceutical compositions comprising said compounds and use therefore in the treatment of proliferative disorders and the like.
A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
C07D 519/00 - Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups or
The present invention relates to a process for preparing a compound of formula [I], said process comprising the steps of: formula [II]+formula [III]->formula [I] (i) forming a reaction mixture comprising (a) a compound of formula [II], (b) a compound of formula [III] and (c) 1,2-propanediol or polyethylene glycol, or a mixture thereof, and optionally (d) a base; (ii) heating said reaction mixture to a temperature of at least about 150°C to form a compound of formula [I]; (iii) isolating said compound of formula [I]; and (iv) optionally converting said compound of formula [I] into salt form; wherein: R1 and R2 are each independently H, alkyl or haloalkyl; R3 and R4 are each independently H, alkyl, haloalkyl or aryl; R5 is alkyl, alkenyl, cycloalkyl or cycloalkyl-alkyl, each of which may be optionally substituted with one or more OH groups; R6 is selected from cyclopropylamino, cyclopropylmethylamino, cyclobutylamino, cyclobutylmethylamino and formula (A) where one of X, Y and Z is N and the remainder are CR9; R7, R8 and each R9 are independently H, alkyl or haloalkyl, wherein at least one of R7, R8 and R9 is other than H. Further aspects of the invention relate to a highly diastereoselective process for the preparation of compounds of formula [III], a process for preparing intermediates of formula [II], and other intermediates useful in the synthesis of compounds of formula [I], and to a process for preparing the crystalline tartrate salt and free base of compounds of formula [I].
C07D 473/16 - Heterocyclic compounds containing purine ring systems with oxygen, sulfur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
