EP2723740A1 - Formes solides et sels de dérivés de tétrahydro-pyrido-pyrimidine - Google Patents

Formes solides et sels de dérivés de tétrahydro-pyrido-pyrimidine

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Publication number
EP2723740A1
EP2723740A1 EP12738616.7A EP12738616A EP2723740A1 EP 2723740 A1 EP2723740 A1 EP 2723740A1 EP 12738616 A EP12738616 A EP 12738616A EP 2723740 A1 EP2723740 A1 EP 2723740A1
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European Patent Office
Prior art keywords
tetrahydro
pyrido
pyrimidin
salt
methoxy
Prior art date
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EP12738616.7A
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German (de)
English (en)
Inventor
Paulo Antonio FERNANDES GOMES DOS SANTOS
Klemens HÖGENAUER
Gregory Hollingworth
Nicolas Soldermann
Frank Stowasser
Nicola Tufilli
Frédéric ZECRI
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Novartis AG
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Novartis AG
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Publication of EP2723740A1 publication Critical patent/EP2723740A1/fr
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention relates to novel solid forms and salts of tetrahydro-pyrido-pyrimidine derivatives, processes for their preparation and their use in pharmaceutical compositions.
  • PCT/EP201 1/061393 discloses ⁇ (S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8- tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl ⁇ -(tetrahydro-pyran-4-yl)-methanone and 1- ⁇ (S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3- d]pyrimidin-4-ylamino]-pyrrolidin-1-yl ⁇ -propan-1-one and methods of making these compounds.
  • PI3K-related diseases including but not limited to autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and COPD, transplant rejection, cancers eg of hematopoietic origin or solid tumors.
  • These compounds are also useful for treatment, either alone or in combination, with one or more other pharmacologically active compounds, includes methods of treating conditions, diseases or disorders in which one or more of the functions of B cells such as antibody production, antigen presentation, cytokine production or lymphoid organogenesis are abnormal or are undesirable including rheumatoid arthritis, pemphigus vulgaris, idiopathic thrombocytopenia purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjogren's syndrome, autoimmune hemolytic anemia, ANCA-associated vasculitides, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic autoimmune urticaria, allergy (atopic dermatitis, contact dermatitis, allergic rhinitis), goodpasture's syndrome, AMR (antibody-mediated transplant rejection), B cell-mediated hyperacute, acute and chronic transplant rejection and cancers of haematopoietic origin
  • the invention relates to crystalline anhydrous forms, crystalline solvate forms and/or salt forms including crystalline salt forms of ⁇ (S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8- tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl ⁇ -(tetrahydro-pyran-4-yl)-methanone or salt forms including crystalline salt forms of 1- ⁇ (S)-3-[6-(6-methoxy-5-trifluoromethyl- pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl ⁇ -propan-1 -on; pharmaceutical compositions and combinations including these forms.
  • the invention further relates to methods of using these forms, including their pharmaceutical compositions and combinations for the treatment of diseases mediated by the activity of the
  • Crystalline forms occur where the same composition of matter crystallizes in a different lattice arrangement resulting in different thermodynamic properties and stabilities specific to the particular crystalline form. Crystalline forms may also include different hydrates or solvates of the same compound. In deciding which form is preferable, the numerous properties of the forms are compared and the preferred form chosen based on the many physical property variables.
  • polymorphs whether any such polymorphs will be suitable for commercial use in a therapeutic composition, or which polymorphs will display such desirable properties.
  • Figure 1 discloses the X-ray Powder Diffraction Pattern of Example 1 citrate salt
  • Figure 2 discloses the X-ray Powder Diffraction Pattern of Example 1 fumarate salt
  • Figure 3 discloses the X-ray Powder Diffraction Pattern of Example 1 napadisylate salt
  • Figure 4 discloses the X-ray Powder Diffraction Pattern of Example 67 phosphate salt
  • Figure 5 discloses the X-ray Powder Diffraction Pattern of Example 67 HCI salt
  • Figure 6 discloses the X-ray Powder Diffraction Pattern of Example 67 hippurate salt
  • Figure 7 discloses the X-ray Powder Diffraction Pattern of Example 1 anhydrous form
  • Figure 8 discloses the X-ray Powder Diffraction Pattern of Example 1 trihydrate
  • Figure 9 discloses the X-ray Powder Diffraction Pattern of Example 67 anhydrous form DETAILED DESCRIPTION OF THE INVENTION
  • the invention relates to an anhydrous crystalline form of ⁇ (S)-3-[6-(6- methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1 - yl ⁇ -(tetrahydro-pyran-4-yl)-methanone.
  • the anhydrous crystalline form of ⁇ (S)-3-[6-(6-methoxy-5-methyl- pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1 -yl ⁇ -(tetrahydro- pyran-4-yl)-methanone is characterized by an X-Ray powder diffraction pattern comprising the following peaks given at degrees 2-Theta +/- 0.2 degrees: 7.5, 10.9, 1 1 .7, 14.3, 15.1 , 15.8, 16.7, 17.7, 18.9, 20.5, 21.8, 22.5, 23.3, 24.2, 24.6, 25.0, 25.6, 26.2, 27.0, 28.0, 29.1 , 32.8 and 34.6.
  • the invention relates to a trihydrate crystalline form of ⁇ (S)-3-[6-(6- methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1 - yl ⁇ -(tetrahydro-pyran-4-yl)-methanone.
  • the trihydrate crystalline form of ⁇ (S)-3-[6-(6-methoxy-5-methyl- pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1 -yl ⁇ -(tetrahydro- pyran-4-yl)-methanone is characterized by an X-Ray powder diffraction pattern comprising the following peaks given at degrees 2-Theta +/- 0.2 degrees: 6.6, 8.9, 13.3, 14.5, 15.0, 16.5, 17.5, 17.7, 18.2, 20.0, 21 .6, 22.6, 23.8, 24.4, 26.7, 27.5, 27.8, 29.2, 33.3, 33.9, 35.7 and 38.8.
  • the invention relates to a salt of ⁇ (S)-3-[6-(6-methoxy-5-methyl- pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1 -yl ⁇ -(tetrahydro- pyran-4-yl)-methanone, wherein the anion is selected from citrate, fumarate or napadisylate.
  • the invention relates to a salt of ⁇ (S)-3-[6-(6-methoxy-5-methyl- pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1 -yl ⁇ -(tetrahydro- pyran-4-yl)-methanone, wherein the anion is selected from citrate.
  • the invention relates to a citrate salt of ⁇ (S)-3-[6-(6-methoxy-5- methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl ⁇ - (tetrahydro-pyran-4-yl)-methanone, in form of a monohydrate.
  • the monohydrate citrate salt of ⁇ (S)-3-[6-(6-methoxy-5-methyl- pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1 -yl ⁇ -(tetrahydro- pyran-4-yl)-methanone is characterized by an X-Ray powder diffraction pattern comprising the following peaks given at degrees 2-Theta +/- 0.2 degrees: 5.7, 1 1.5, 12.1 , 14.3, 15.4, 17.2, 17.9, 19.3, 20.2, 20.7, 21.9, 23.3, 23.9, 25.5, 27.0, 27.7, 29.8 and 30.3.
  • the invention relates to a salt of ⁇ (S)-3-[6-(6-methoxy-5-methyl- pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1 -yl ⁇ -(tetrahydro- pyran-4-yl)-methanone, wherein the anion is selected from fumarate.
  • the invention relates to a fumarate salt of ⁇ (S)-3-[6-(6-methoxy-5- methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl ⁇ - (tetrahydro-pyran-4-yl)-methanone, in form of a monohydrate.
  • the monohydrate fumarate salt of ⁇ (S)-3-[6-(6-methoxy-5-methyl- pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1 -yl ⁇ -(tetrahydro- pyran-4-yl)-methanone is characterized by an X-Ray powder diffraction pattern comprising the following peaks given at degrees 2-Theta +/- 0.2 degrees: 6.0, 6.5, 9.8, 12.3, 13.1 , 15.6, 17.7, 19.1 , 19.7, 23.9, 24.7, 24.9, 25.2, 26.4 and 27.0.
  • the invention relates to a salt of ⁇ (S)-3-[6-(6-methoxy-5-methyl- pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1 -yl ⁇ -(tetrahydro- pyran-4-yl)-methanone, wherein the anion is selected from napadisylate.
  • the invention relates to a napadisylate salt of ⁇ (S)-3-[6-(6-methoxy-5- methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl ⁇ - (tetrahydro-pyran-4-yl)-methanone, in form of a monohydrate.
  • the monohydrate napadisylate salt of ⁇ (S)-3-[6-(6-methoxy-5-methyl- pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1 -yl ⁇ -(tetrahydro- pyran-4-yl)-methanone is characterized by an X-Ray powder diffraction pattern comprising the following peaks given at degrees 2-Theta +/- 0.2 degrees: 4.3, 8.5, 9.4, 12.2, 12.9, 13.5, 15.0, 15.6, 16.0, 17.7, 18.9, 19.3, 20.0, 20.8, 21.2, 22.0, 23.0, 24.5 and 26.5.
  • the invention relates to an anhydrous crystalline form of 1 - ⁇ (S)-3-[6- (6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4- ylamino]-pyrrolidin-1 -yl ⁇ -propan-1 -one
  • the anhydrous crystalline form of 1- ⁇ (S)-3-[6-(6-Methoxy-5- trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1- yl ⁇ -propan-1 -one is characterized by an X-Ray powder diffraction pattern comprising the following peaks given at degrees 2-Theta +/- 0.2 degrees: 7.9, 9.6, 1 1 .5, 13.4, 15.2, 15.9, 16.8, 17.6, 18.7,
  • the invention relates to a salt of 1- ⁇ (S)-3-[6-(6-Methoxy-5- trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1- yl ⁇ -propan-1 -one, wherein the anion is selected from phosphate, chloride or hippurate.
  • the invention relates to a salt of 1- ⁇ (S)-3-[6-(6-Methoxy-5- trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1- yl ⁇ -propan-1 -one, wherein the anion is selected from phosphate.
  • the invention relates to a phosphate salt of 1 - ⁇ (S)-3-[6-(6-Methoxy-5- trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1- yl ⁇ -propan-1 -one, in anhydrous form.
  • the anhydrous phosphate salt of 1 - ⁇ (S)-3-[6-(6-Methoxy-5- trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1- yl ⁇ -propan-1 -one is characterized by an X-Ray powder diffraction pattern comprising the following peaks given at degrees 2-Theta +/- 0.2 degrees: 5.2, 9.8, 10.3, 1 1.6, 14.9, 15.5, 15.9, 16.6, 19.5, 20.7, 21.5, 22.1 , 23.3, 25.8, 26.4, 27.2 and 28.2.
  • the invention relates to a salt of 1- ⁇ (S)-3-[6-(6-Methoxy-5- trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1- yl ⁇ -propan-1 -one, wherein the anion is selected from chloride.
  • the invention relates to a hydrochloride salt of 1- ⁇ (S)-3-[6-(6- Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]- pyrrolidin-1 -yl ⁇ -propan-1-one, in anhydrous form.
  • the anhydrous hydrochloride salt of 1 - ⁇ (S)-3-[6-(6-Methoxy-5- trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1- yl ⁇ -propan-1 -one is characterized by an X-Ray powder diffraction pattern comprising the following peaks given at degrees 2-Theta +/- 0.2 degrees: 5.6, 1 1 .0, 1 1 .3, 1 1 .8, 14.7, 17.1 , 18.7, 19.4, 22.0, 22.6, 23.1 , 23.7, 24.9 and 25.5.
  • the invention relates to a salt of 1- ⁇ (S)-3-[6-(6-Methoxy-5- trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1- yl ⁇ -propan-1 -one, wherein the anion is selected from hippurate.
  • the invention relates to a hippurate salt of 1 - ⁇ (S)-3-[6-(6-Methoxy-5- trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1- yl ⁇ -propan-1 -one, in anhydrous form.
  • the anhydrous hippurate salt of 1 - ⁇ (S)-3-[6-(6-Methoxy-5- trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1- yl ⁇ -propan-1 -one is characterized by an X-Ray powder diffraction pattern comprising the following peaks given at degrees 2-Theta +/- 0.2 degrees: 5.2, 7.5, 10.3, 10.9, 1 1 .8, 13.1 , 16.1 , 16.7, 17.7, 18.4, 21.2, 23.2, 24.2 and 26.2.
  • the term "form of the invention” refers to a crystalline anhydrous form, a crystalline solvate form or a salt form including a crystalline salt form of ⁇ (S)-3-[6-(6- methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1 - yl ⁇ -(tetrahydro-pyran-4-yl)-methanone or a salt form including a crystalline salt form of 1 - ⁇ (S)- 3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4- ylamino]-pyrrolidin-1 -yl ⁇ -propan-1 -on.
  • the term "combination" refers to either a fixed combination in one dosage unit form, or a kit of parts for the combined administration where a crystalline anhydrous form, a crystalline solvate form or a salt form including a crystalline salt form of ⁇ (S)-3-[6-(6- methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1 - yl ⁇ -(tetrahydro-pyran-4-yl)-methanone or a salt form including a crystalline salt form of 1 - ⁇ (S)- 3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4- ylamino]-pyrrolidin-1 -yl ⁇ -propan-1-
  • an other drug as explained below also referred to as “therapeutic agent” or “co-agent”
  • therapeutic agent or “co-agent”
  • co-agent may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect.
  • co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof, e.g. a patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • pharmaceutical combination as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g. a crystalline anhydrous form, a crystalline solvate form or a salt form including a crystalline salt form of ⁇ (S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8- tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl ⁇ -(tetrahydro-pyran-4-yl)-methanone or a salt form including a crystalline salt form of 1 - ⁇ (S)-3-[6-(6-methoxy-5-trifluoromethyl- pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl ⁇ -propan-1 -on and a combination partner, are both administered to a patient simultaneously in the form of a combination partner,
  • non-fixed combination means that the active ingredients, e.g. a crystalline anhydrous form, a crystalline solvate form or a salt form including a crystalline salt form of ⁇ (S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro- pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl ⁇ -(tetrahydro-pyran-4-yl)-methanone or a salt form including a crystalline salt form of 1 - ⁇ (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)- 5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1 -yl ⁇ -propan-1-on and a combination partner, are both administered to a patient as separate entities either simultaneously
  • polymorph refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms, and/or ions forming the crystal.
  • solvate refers to a crystalline form of a molecule, atom, and/or ions that further comprises molecules of a solvent or solvents incorporated into the crystalline lattice structure.
  • the solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered arrangement.
  • the solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules.
  • a solvate with a nonstoichiometric amount of solvent molecules may result from partial loss of solvent from the solvate.
  • Solvates may occur as dimers or oligomers comprising more than one molecule or Compound ABC within the crystalline lattice structure.
  • the invention relates to the use of a crystalline anhydrous form, a crystalline solvate form or a salt form including a crystalline salt form of ⁇ (S)-3-[6-(6-methoxy- 5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl ⁇ - (tetrahydro-pyran-4-yl)-methanone or a salt form including a crystalline salt form of 1 - ⁇ (S)-3- [6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4- ylamino]-pyrrolidin-1 -yl ⁇ -propan-1-on of the present invention as pharmaceutical.
  • the invention thus provides: - a crystalline anhydrous form, a crystalline
  • vasculitides cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic autoimmune urticaria, allergy (atopic dermatitis, contact dermatitis, allergic rhinitis), goodpasture's syndrome, AMR (antibody-mediated transplant rejection), B cell-mediated hyperacute, acute and chronic transplant rejection and cancers of haematopoietic origin including but not limited to multiple myeloma; ; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin lymphoma; lymphomas; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; and Walden stroem disease.
  • a method of modulating the activity of the PI3K enzymes, preferably the ⁇ 3 ⁇ isoform, in a subject comprising the step of administering to a subject a therapeutically effective amount of a crystalline anhydrous form, a crystalline solvate form or a salt form including a crystalline salt form of ⁇ (S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro- pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1 -yl ⁇ -(tetrahydro-pyran-4-yl)-methanone or a salt form including a crystalline salt form of 1 - ⁇ (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3- yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]
  • a method for the treatment of a disorder or disease mediated by the PI3K enzymes, preferably by the ⁇ 3 ⁇ isoform comprising the step of administering to a subject a therapeutically effective amount of a crystalline anhydrous form, a crystalline solvate form or a salt form including a crystalline salt form of ⁇ (S)-3-[6-(6-methoxy-5-methyl-pyridin-3- yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1 -yl ⁇ -(tetrahydro-pyran-4- yl)-methanone or a salt form including a crystalline salt form of 1 - ⁇ (S)-3-[6-(6-methoxy-5- trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamin
  • a method for inhibition of the PI3K enzymes, preferably the ⁇ 3 ⁇ isoform, in a cell comprising contacting said cell with an effective amound of a crystalline anhydrous form, a crystalline solvate form or a salt form including a crystalline salt form of ⁇ (S)-3-[6-(6- methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]- pyrrolidin-1-yl ⁇ -(tetrahydro-pyran-4-yl)-methanone or a salt form including a crystalline salt form of 1- ⁇ (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3- d]pyrimidin-4-ylamino]-pyrrolidin-1 -yl ⁇
  • the term "subject” refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human. As used herein, the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • the term “treat”, “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • “treat”, “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • “treat”, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • “treat”, “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • a subject is "in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • administration means providing a form of the invention to a subject in need of treatment.
  • Administration "in combination with” one or more further therapeutic agents includes simultaneous (concurrent) and consecutive administration in any order, and in any route of administration.
  • the invention relates to the treatment, either alone or in combination, with one or more other pharmacologically active compounds, of PI3K-related diseases including but not limited to autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and COPD, transplant rejection, cancers eg of hematopoietic origin or solid tumors.
  • PI3K-related diseases including but not limited to autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and COPD, transplant rejection, cancers eg of hematopoietic origin or solid tumors.
  • the invention also relates to the treatment, either alone or in combination, with one or more other pharmacologically active compounds, includes methods of treating conditions, diseases or disorders in which one or more of the functions of B cells such as antibody production, antigen presentation, cytokine production or lymphoid organogenesis are abnormal or are undesirable including rheumatoid arthritis, pemphigus vulgaris, idiopathic thrombocytopenia purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjogren's syndrome, autoimmune hemolytic anemia, ANCA-associated vasculitides, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic autoimmune urticaria, allergy (atopic dermatitis, contact dermatitis, allergic rhinitis), goodpasture's syndrome, AMR (antibody-mediated transplant rejection), B cell-mediated hyperacute, acute and chronic transplant rejection and cancers of haematopoietic
  • the invention includes methods of treating conditions, diseases or disorders in which one or more of the functions of neutrophils, such as superoxide release, stimulated exocytosis, or chemoatractic migration are abnormal or are undesirable including rheumatoid arthritis, sepsis, pulmonary or resporatory disorders such as asthma, inflammatory dermatoses such as psoriasis and others.
  • the invention includes methods of treating conditions, diseases or disorders in which one or more of the functions of basophil and mast cells such as chemoatractic migration or allergen- IgE-mediated degranulation are abnormal or are undesirable including allergic diseases (atopic dermatitis, contact dermatitis, allergic rhinitis) as well as other disorders such as COPD, asthma or emphysema.
  • the invention includes methods of treating conditions, diseases or disorders in which one or more of the functions of T cells such as cytokine production or cell-mediated cytotoxicity abnormal or are undesirable including rheumatoid arthritis, multiple sclerosis, acute or chronic rejection of cell tissue or organ grafts or cancers of haematopoietic origin.
  • the invention includes methods of treating neurodegenerative diseases,
  • cardiovascular diseases and platelet aggregation cardiovascular diseases and platelet aggregation.
  • the invention includes methods of treating skin diseases such as porphyria cutanea tarda, polymorphous light eruption, dermatomyositis, solar urticaria, oral lichen planus, panniculitis, scleroderma, urticarial vasculitis.
  • skin diseases such as porphyria cutanea tarda, polymorphous light eruption, dermatomyositis, solar urticaria, oral lichen planus, panniculitis, scleroderma, urticarial vasculitis.
  • the invention includes methods of treating chronic inflammatory diseases such as sarcoidosis, granuloma annulare.
  • the condition or disorder e.g. PI3K-mediated
  • the condition or disorder is selected from the group consisting of: polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, asthma, COPD, ARDS, Loffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia),
  • bronchopulmonary aspergillosis polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma, eosinophil-related disorders affecting the airways occasioned by drug-reaction, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, epidermolysis bullosa acquisita, autoimmune haematogical disorders (e.g. haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia), systemic lupus erythematosus,
  • endocrine opthalmopathy Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), interstitial lung fibrosis, psoriatic arthritis, glomerulonephritis, cardiovascular diseases, atherosclerosis, hypertension, deep venous thrombosis, stroke, myocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolytic diseases, acute arterial ischemia, peripheral thrombotic occlusions, and coronary artery disease, reperfusion injuries, retinopathy, such as diabetic retinopathy or hyperbaric oxygen-induced retinopathy, and conditions characterized by elevated intraocular pressure or secretion of ocular aqueous humor, such as glaucoma.
  • Grave's disease sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis,
  • the compounds of the present invention are useful in the treatment, prevention, or amelioration of autoimmune disease and of inflammatory conditions, in particular inflammatory conditions with an aetiology including an autoimmune component such as arthritis (for example rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans) and rheumatic diseases, including inflammatory conditions and rheumatic diseases involving bone loss, inflammatory pain, spondyloarhropathies including ankolsing spondylitis, Reiter syndrome, reactive arthritis, psoriatic arthritis, and enterophathics arthritis, hypersensitivity (including both airways hypersensitivity and dermal hypersensitivity) and allergies.
  • arthritis for example rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans
  • rheumatic diseases including inflammatory conditions and rheumatic diseases involving bone loss, inflammatory pain, spondyloarhropathies including ankolsing spondylitis, Reiter syndrome, reactive arthritis,
  • autoimmune haematological disorders including e.g. hemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopa-thic thrombocytopenia), acquired hemophilia A, cold agglutinin disease, cryoglobulinemia, thrombotic thrombocytopenic purpura, Sjogren's syndrome, systemic lupus erythematosus, inflammatory muscle disorders, polychondritis, sclerodoma, anti-neutrophil cytoplasmic antibody- associated vasculitis, IgM mediated neuropathy, opsoclonus myoclonus syndrome, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, pemphigus vulgaris, pemphigus foliacius, idio-pathic sprue
  • autoimmune haematological disorders including e.g. hemolytic
  • ulcerative colitis Crohn's disease and Irritable Bowel Syndrome
  • endocrine ophthalmopathy Graves' disease, sarcoidosis, multiple sclerosis, neuromyelitis optica, primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type I), uveitis (anterior, intermediate and posterior as well as panuveitis), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephro-tic syndrome or minimal change nephropathy), tumors, inflammatory disease of skin and cornea, myositis, loosening of bone implants, metabolic disorders, such as atherosclerosis, diabetes, and dislipidemia.
  • nephrotic syndrome e.g. including idiopathic ne
  • the compounds of the present invention are useful in the treatment of conditions or disorders selected from the group consisting of, primary cutaneous B-cell lymphoma, immunobullous disease, pemphigus vulgaris, pemphigus foliaceus,
  • epidermolysis bullosa acquisita, chronic graft versus host disease, dermatomyositis, systemic lupus erythematosus, vasculitis, small vessel vasculitis, hypocomplementemic urticarial vasculitis, antineutrophil cytoplasmic antibody-vasculitis, cryoglobulinemia,
  • Schnitzler syndrome Waldenstrom's macroglobulinemia, angioedema, vitiligo, systemic lupus erythematosus, idiopathic thrombocytopenic purpura, multiple sclerosis, cold agglutinin disease, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody— associated vasculitis, graft versus host disease, cryoglobulinemia and thrombotic thrombocytopenic.
  • the invention relates to a process or a method for the treatment of one of the disorders or diseases mentioned hereinabove, especially a disease which responds to the inhibition of the PI3K enzymes.
  • the invention relates to the use of a crystalline anhydrous form, a crystalline solvate form or a salt form including a crystalline salt form of ⁇ (S)-3-[6-(6-methoxy- 5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl ⁇ - (tetrahydro-pyran-4-yl)-methanone or a salt form including a crystalline salt form of 1 - ⁇ (S)-3- [6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4- ylamino]-pyrrolidin-1 -yl ⁇ -propan-1-on, as such or in the form of a pharmaceutical composition with at least one pharmaceutically acceptable carrier, for the therapeutic
  • the invention relates to the use of a crystalline anhydrous form, a crystalline solvate form or a salt form including a crystalline salt form of ⁇ (S)-3-[6-(6-methoxy- 5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl ⁇ -
  • the invention relates to pharmaceutical compositions comprising a crystalline anhydrous form, a crystalline solvate form or a salt form including a crystalline salt form of ⁇ (S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin- 4-yloxy]-pyrrolidin-1-yl ⁇ -(tetrahydro-pyran-4-yl)-methanone or a salt form including a crystalline salt form of 1 - ⁇ (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8- tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl ⁇ -propan-1 -on of the present invention.
  • the invention thus provides
  • a pharmaceutical composition comprising (i.e. containing or consisting of) a crystalline anhydrous form, a crystalline solvate form or a salt form including a crystalline salt form of ⁇ (S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4- yloxy]-pyrrolidin-1 -yl ⁇ -(tetrahydro-pyran-4-yl)-methanone or a salt form including a crystalline salt form of 1 - ⁇ (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8- tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl ⁇ -propan-1 -onas defined herein and one or more carriers / excipients
  • crystalline anhydrous form, a crystalline solvate form or a salt form including a crystalline salt form of ⁇ (S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3- d] pyrimidin-4-yloxy]-pyrrolidin-1 -yl ⁇ -(tetrahydro-pyran-4-yl)-methan or a salt form including a crystalline salt form of 1- ⁇ (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)- 5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1 -yl ⁇ -propan-1-onas defined herein, and one or more pharmaceutically acceptable carriers / excipients.
  • the term "pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a form of the present invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, etc.
  • the pharmaceutical compositions of the present invention can be made up in a solid form
  • compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.
  • the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with
  • diluents e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine
  • lubricants e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol
  • binders e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth,
  • disintegrants e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or
  • compositions for oral administration include an effective amount of a form of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable
  • Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.
  • Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 -75%, or contain about 1 -50%, of the active ingredient.
  • compositions for transdermal application include an effective amount of a form of the invention with a suitable carrier.
  • Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the form of the invention optionally with carriers, optionally a rate controlling barrier to deliver the form of the invention of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • compositions for topical application include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosol or the like.
  • topical delivery systems will in particular be appropriate for dermal application, e.g., for the treatment of skin cancer, e.g., for prophylactic use in sun creams, lotions, sprays and the like. They are thus particularly suited for use in topical, including cosmetic, formulations well-known in the art.
  • Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • a topical application may also pertain to an inhalation or to an intranasal application. They may be conveniently delivered in the form of a dry powder, either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids, from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant.
  • a dry powder either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids
  • the present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water may facilitate the degradation of certain compounds of the present invention.
  • Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained.
  • anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers,e. g., vials, blister packs, and strip packs.
  • compositions and dosage forms that comprise one or more agents that reduce the rate by which the form of the present invention as an active ingredient will decompose.
  • agents which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, etc.
  • physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or
  • immunoglobulins include hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEEN®, polyethylene glycol (PEG), and PLURONICS®.
  • hydrophilic polymers such as polyvinylpyrrolidone
  • amino acids such as glycine, glutamine, asparagine, arginine or lysine
  • monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins include chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium
  • Suitable excipients / carriers may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • Compressed gases may be used to disperse a compound of of the present invention in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
  • the dosage of the active ingredient depends upon the disease to be treated and upon the species, its age, weight, and individual condition, the individual pharmacokinetic data, and the mode of administration.
  • the amount of the form of the present invention in a formulation can vary within the full range employed by those skilled in the art.
  • the formulation will contain, on a weight percent (wt%) basis, from about 0.01-99.99 wt% of a form of the present invention based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
  • compositions comprising a crystalline anhydrous form, a crystalline solvate form or a salt form including a crystalline salt form of ⁇ (S)-3-[6-(6-methoxy-5-methyl-pyridin-3- yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1 -yl ⁇ -(tetrahydro-pyran-4-yl)- methanone or a salt form including a crystalline salt form of 1 - ⁇ (S)-3-[6-(6-methoxy-5- trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1- yl ⁇ -propan-1 -onas defined herein in association with at least one pharmaceutical acceptable carrier (such as excipient a and/or diluent)
  • the invention relates to a pharmaceutical composition for administration to a warm-blooded animal, especially humans or commercially useful mammals suffering from a disease which responds to an inhibition of the PI3K enzymes, comprising an effective quantity of a crystalline anhydrous form, a crystalline solvate form or a salt form including a crystalline salt form of ⁇ (S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)- 5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl ⁇ -(tetrahydro-pyran-4-yl)- methanone or a salt form including a crystalline salt form of 1 - ⁇ (S)-3-[6-(6-methoxy-5- trifluoromethyl-pyridin-3-yl)-5,6,7,8
  • the invention relates to a pharmaceutical composition for the prophylactic or especially therapeutic management of a disorder or disease selected from autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and COPD, transplant rejection, cancers eg of hematopoietic origin or solid tumors; of a warm-blooded animal, especially a human or a commercially useful mammal requiring such treatment.
  • a disorder or disease selected from autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and COPD, transplant rejection, cancers eg of hematopoietic origin or solid tumors; of a warm-blooded animal, especially a human or a commercially useful mammal requiring such treatment.
  • the invention relates to combinations comprising a crystalline anhydrous form, a crystalline solvate form or a salt form including a crystalline salt form of ⁇ (S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]- pyrrolidin-1 -yl ⁇ -(tetrahydro-pyran-4-yl)-methanone or a salt form including a crystalline salt form of 1- ⁇ (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3- d]pyrimidin-4-ylamino]-pyrrolidin-1-yl ⁇ -propan-1 -on and one or more additional active ingredients.
  • the invention thus provides
  • a combination in particular a pharmaceutical combination comprising a therapeutically effective amount of a crystalline anhydrous form, a crystalline solvate form or a salt form including a crystalline salt form of ⁇ (S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5, 6,7,8- tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1 -yl ⁇ -(tetrahydro-pyran-4-yl)- methanone or a salt form including a crystalline salt form of 1- ⁇ (S)-3-[6-(6-methoxy-5- trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin- 1-yl ⁇ -propan-1 -on and one or more therapeutically active agents, e.g. an
  • a combined pharmaceutical composition adapted for simultaneous or sequential administration, comprising a therapeutically effective amount of a crystalline anhydrous form, a crystalline solvate form or a salt form including a crystalline salt form of ⁇ (S)-3-[6- (6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]- pyrrolidin-1-yl ⁇ -(tetrahydro-pyran-4-yl)-methanone or a salt form including a crystalline salt form of 1- ⁇ (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3- d]pyrimidin-4-ylamino]-pyr
  • a combined pharmaceutical composition as defined herein (i) as pharmaceutical, (ii) for use in the treatment of a disease mediated by the PI3K enzymes, (iii) in a method of treatment of a disease mediated by the PI3K enzymes.
  • ком ⁇ онент there is meant either a fixed combination in one dosage unit form, or a kit of parts for the combined administration where a crystalline anhydrous form, a crystalline solvate form or a salt form including a crystalline salt form of ⁇ (S)-3-[6-(6-methoxy-5-methyl- pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1 -yl ⁇ -(tetrahydro- pyran-4-yl)-methanone or a salt form including a crystalline salt form of 1 - ⁇ (S)-3-[6-(6- methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]- pyrrolidin-1 -yl ⁇ -propan-1-on and
  • a therapeutically effective amount of a form of the present invention refers to an amount of the form of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
  • the term "a therapeutically effective amount” refers to the amount of the form of the present invention that, when administered to a subject, is effective to (1 ) at least partially alleviating, inhibiting, preventing and/or
  • a therapeutically effective amount refers to the amount of the form of the present invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting PI3K delta.
  • a crystalline anhydrous form, a crystalline solvate form or a salt form including a crystalline salt form of ⁇ (S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro- pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl ⁇ -(tetrahydro-pyran-4-yl)-methanone or a salt form including a crystalline salt form of 1 - ⁇ (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)- 5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl ⁇ -propan-1 -on may be administered as the sole active ingredient or in conjunction with, e.g.
  • the compounds of the present invention may be used in combination with a calcineurin inhibitor, e.g. cyclosporin A or FK 506; a mTOR inhibitor, e.g.
  • rapamycin 40-O-(2-hydroxyethyl)-rapamycin, CCI779, ABT578, AP23573, TAFA-93, biolimus-7 or biolimus-9; an ascomycin having immuno-suppressive properties, e.g. ABT- 281 , ASM981 , etc.; corticosteroids; cyclophosphamide; azathioprene; methotrexate;
  • leflunomide leflunomide
  • mizoribine mycophenolic acid or salt
  • mycophenolate mofetil 15- deoxyspergualine or an immunosuppressive homologue, analogue or derivative thereof
  • PKC inhibitor e.g. as disclosed in WO 02/38561 or WO 03/82859, e.g. the compound of Example 56 or 70
  • JAK3 kinase inhibitor e.g.
  • mono-citrate also called CP-690,550
  • CP-690,550 mono-citrate
  • immunosuppressive monoclonal antibodies e.g., monoclonal antibodies to leukocyte receptors, e.g., MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86 or their ligands
  • other immunomodulatory compounds e.g. a recombinant binding molecule having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, e.g.
  • CTLA4 an at least extracellular portion of CTLA4 or a mutant thereof joined to a non- CTLA4 protein sequence, e.g. CTLA4lg (for ex. designated ATCC 68629) or a mutant thereof, e.g. LEA29Y; adhesion molecule inhibitors, e.g. LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists or VLA-4 antagonists; or antihistamines; or antitussives, or a bronchodilatory agent; or an angiotensin receptor blockers; or an anti-infectious agent.
  • CTLA4lg for ex. designated ATCC 68629
  • adhesion molecule inhibitors e.g. LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists or VLA-4 antagonists
  • antihistamines or antitussives, or a bronchodilatory agent
  • an angiotensin receptor blockers or an anti-infectious agent.
  • dosages of the co-administered immunosuppressant, immunomodulatory, anti-inflammatory, chemotherapeutic or anti-infectious compound will of course vary depending on the type of co-drug employed, e.g. whether it is a steroid or a calcineurin inhibitor, on the specific drug employed, on the condition being treated and so forth.
  • a form of the present invention may also be used to advantage in combination with each other or in combination with other therapeutic agents, especially other antiproliferative agents.
  • antiproliferative agents include, but are not limited to, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active agents; alkylating agents; histone deacetylase inhibitors; compounds, which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors;
  • antineoplastic antimetabolites platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti- androgens; methionine aminopeptidase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; agents used in the treatment of hematologic malignancies; compounds which target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors; temozolomide (TEMODAL ® ); and leucovorin.
  • aromatase inhibitor relates to a compound which inhibits the estrogen production, i.e., the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively.
  • the term includes, but is not limited to, steroids, especially atamestane, exemestane and formestane; and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole and letrozole.
  • Exemestane can be administered, e.g., in the form as it is marketed, e.g., under the trademark AROMASIN.
  • Formestane can be administered, e.g., in the form as it is marketed, e.g., under the trademark LENTARON.
  • Fadrozole can be administered, e.g., in the form as it is marketed, e.g., under the trademark AFEMA.
  • Anastrozole can be administered, e.g., in the form as it is marketed, e.g., under the trademark ARIMIDEX.
  • Letrozole can be administered, e.g., in the form as it is marketed, e.g., under the trademark FEMARA or FEMAR.
  • Aminoglutethimide can be administered, e.g., in the form as it is marketed, e.g., under the trademark
  • a combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, e.g., breast tumors.
  • anti-estrogen as used herein, relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level.
  • the term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen can be
  • Raloxifene hydrochloride can be administered, e.g., in the form as it is marketed, e.g., under the trademark EVISTA.
  • Fulvestrant can be formulated as disclosed in U.S. Patent No.
  • 4,659,516 or it can be administered, e.g., in the form as it is marketed, e.g., under the trademark FASLODEX.
  • a combination of the invention comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, e.g., breast tumors.
  • anti-androgen relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (CASODEX), which can be formulated, e.g., as disclosed in U.S. Patent No. 4,636,505.
  • CASODEX bicalutamide
  • gonadorelin agonist includes, but is not limited to, abarelix, goserelin and goserelin acetate.
  • Goserelin is disclosed in U.S. Patent No. 4, 100,274 and can be administered, e.g., in the form as it is marketed, e.g., under the trademark ZOLADEX.
  • Abarelix can be formulated, e.g., as disclosed in U.S. Patent No. 5,843,901 .
  • topoisomerase I inhibitor includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148 (compound A1 in WO 99/17804).
  • Irinotecan can be administered, e.g., in the form as it is marketed, e.g., under the trademark CAMPTOSAR.
  • Topotecan can be administered, e.g., in the form as it is marketed, e.g., under the trademark HYCAMTIN.
  • topoisomerase II inhibitor includes, but is not limited to, the anthracyclines, such as doxorubicin, including liposomal formulation, e.g., CAELYX;
  • daunorubicin can be administered, e.g., in the form as it is marketed, e.g., under the trademark ETOPOPHOS.
  • Teniposide can be administered, e.g., in the form as it is marketed, e.g., under the trademark VM 26-BRISTOL.
  • Doxorubicin can be administered, e.g., in the form as it is marketed, e.g., under the trademark ADRIBLASTIN or ADRIAMYCIN.
  • Epirubicin can be administered, e.g., in the form as it is marketed, e.g., under the trademark FARMORUBICIN.
  • Idarubicin can be administered, e.g., in the form as it is marketed, e.g., under the trademark ZAVEDOS.
  • Mitoxantrone can be administered, e.g., in the form as it is marketed, e.g., under the trademark NOVANTRON.
  • microtubule active agent relates to microtubule stabilizing, microtubule destabilizing agents and microtublin polymerization inhibitors including, but not limited to, taxanes, e.g., paclitaxel and docetaxel; vinca alkaloids, e.g., vinblastine, especially vinblastine sulfate; vincristine, especially vincristine sulfate and vinorelbine; discodermolides; cochicine; and epothilones and derivatives thereof, e.g., epothilone B or D or derivatives thereof.
  • Paclitaxel may be administered, e.g., in the form as it is marketed, e.g., TAXOL.
  • Docetaxel can be administered, e.g., in the form as it is marketed, e.g., under the trademark TAXOTERE.
  • Vinblastine sulfate can be administered, e.g., in the form as it is marketed, e.g., under the trademark VINBLASTIN R.P.
  • Vincristine sulfate can be administered, e.g., in the form as it is marketed, e.g., under the trademark FARMISTIN.
  • Discodermolide can be obtained, e.g., as disclosed in U.S. Patent No. 5,010,099.
  • epothilone derivatives which are disclosed in WO 98/10121 , U.S. Patent No. 6, 194, 181 , WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO 00/31247. Especially preferred are epothilone A and/or B.
  • alkylating agent includes, but is not limited to,
  • cyclophosphamide ifosfamide, melphalan or nitrosourea (BCNU or Gliadel).
  • Cyclophosphamide can be administered, e.g., in the form as it is marketed, e.g., under the trademark CYCLOSTIN. Ifosfamide can be administered, e.g., in the form as it is marketed, e.g., under the trademark HOLOXAN.
  • histone deacetylase inhibitors or "HDAC inhibitors” relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes compounds disclosed in WO 02/22577, especially A/-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1 /-/- indol-3-yl)ethyl]-amino]methyl]phenyl]-2£-2-propenamide, A/-hydroxy-3-[4-[[[2-(2-methyl-1 /-/- indol-3-yl)-ethyl]-amino]methyl]phenyl]-2£-2-propenamide and pharmaceutically acceptable salts thereof. It further especially includes suberoylanilide hydroxamic acid (SAHA).
  • SAHA suberoylanilide hydroxamic acid
  • antimetabolite includes, but is not limited to, 5-fluorouracil or 5-FU; capecitabine; gemcitabine; DNA demethylating agents, such as 5-azacytidine and
  • decitabine can be administered, e.g., in the form as it is marketed, e.g., under the trademark XELODA.
  • Gemcitabine can be administered, e.g., in the form as it is marketed, e.g., under the trademark GEMZAR.
  • monoclonal antibody trastuzumab which can be administered, e.g., in the form as it is marketed, e.g., under the trademark HERCEPTIN.
  • platinum compound includes, but is not limited to, carboplatin, c/s-platin, cisplatinum and oxaliplatin.
  • Carboplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark CARBOPLAT.
  • Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark ELOXATIN.
  • compounds targeting/decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or further anti-angiogenic compounds includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, e.g.,
  • PDGFR platelet-derived growth factor-receptors
  • compounds which target, decrease or inhibit the activity of PDGFR especially compounds which inhibit the PDGF receptor, e.g., a A/-phenyl-2-pyrimidine-amine derivative, e.g., imatinib, SU101 , SU6668 and GFB-1 1 1 ;
  • FGFR fibroblast growth factor-receptors
  • IGF-IR insulin-like growth factor receptor I
  • compounds which target, decrease or inhibit the activity of IGF-IR especially compounds which inhibit the IGF-IR receptor, such as those compounds disclosed in WO 02/092599;
  • compounds targeting, decreasing or inhibiting the activity of the C-kit receptor tyrosine kinases - such as compounds which target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds which inhibit the c-Kit receptor, e.g., imatinib;
  • compounds targeting, decreasing or inhibiting the activity of members of the c-Abl family and their gene-fusion products e.g., BCR-Abl kinase, such as compounds which target decrease or inhibit the activity of c-Abl family members and their gene fusion products, e.g., a A/-phenyl-2-pyrimidine-amine derivative, e.g., imatinib,
  • examples of further compounds include, e.g., UCN-01 ; safingol; BAY 43-9006; Bryostatin 1 ; Perifosine; llmofosine; RO
  • k) compounds targeting, decreasing or inhibiting the activity of protein-tyrosine kinase inhibitors include imatinib mesylate (GLEEVEC) or tyrphostin.
  • a tyrphostin is preferably a low molecular weight (Mr ⁇ 1500) compound, or a pharmaceutically acceptable salt thereof, especially a compound selected from the benzylidenemalonitrile class or the S-arylbenzenemalonirile or bisubstrate quinoline class of compounds, more especially any compound selected from the group consisting of Tyrphostin A23/RG-50810, AG 99, Tyrphostin AG 213, Tyrphostin AG
  • compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases are especially compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, e.g., EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands, and are in particular those compounds, proteins or monoclonal antibodies generically and specifically disclosed in WO 97/02266, e.g., the compound of Example 39, or in EP 0 564 409; WO 99/03854; EP 0520722; EP 0 566 226; EP 0 787 722;
  • Further anti-angiogenic compounds include compounds having another mechanism for their activity, e.g., unrelated to protein or lipid kinase inhibition, e.g., thalidomide (THALOMID) and TNP-470.
  • TAALOMID thalidomide
  • TNP-470 TNP-470.
  • Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are, e.g., inhibitors of phosphatase 1 , phosphatase 2A, PTEN or CDC25, e.g., okadaic acid or a derivative thereof.
  • Compounds which induce cell differentiation processes are e.g. retinoic acid, ⁇ - ⁇ - or ⁇ -tocopherol or a- ⁇ - or ⁇ -tocotrienol.
  • cyclooxygenase inhibitor includes, but is not limited to, e.g., Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (CELEBREX), rofecoxib (VIOXX), etoricoxib, valdecoxib or a 5-alkyl-2-arylaminophenylacetic acid, e.g., 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid or lumiracoxib.
  • Cox-2 inhibitors such as celecoxib (CELEBREX), rofecoxib (VIOXX), etoricoxib, valdecoxib or a 5-alkyl-2-arylaminophenylacetic acid, e.g., 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid or lumiracoxib.
  • bisphosphonates includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid.
  • Etridonic acid can be administered, e.g., in the form as it is marketed, e.g., under the trademark DIDRONEL.
  • Clodronic acid can be administered, e.g., in the form as it is marketed, e.g., under the trademark BONEFOS.
  • Teiludronic acid can be administered, e.g., in the form as it is marketed, e.g., under the trademark SKELID.
  • Pamidronic acid can be administered, e.g., in the form as it is marketed, e.g., under the trademark AREDIATM.
  • “Alendronic acid” can be administered, e.g., in the form as it is marketed, e.g., under the trademark FOSAMAX.
  • “Ibandronic acid” can be administered, e.g., in the form as it is marketed, e.g., under the trademark BONDRANAT.
  • “Risedronic acid” can be administered, e.g., in the form as it is marketed, e.g., under the trademark ACTONEL.
  • “Zoledronic acid” can be administered, e.g., in the form as it is marketed, e.g., under the trademark ZOMETA.
  • the term “mTOR inhibitors” relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity, such as sirolimus
  • heparanase inhibitor refers to compounds which target, decrease or inhibit heparin sulphate degradation.
  • the term includes, but is not limited to, PI-88.
  • biological response modifier refers to a lymphokine or interferons, e.g., interferon ⁇ .
  • inhibitor of Ras oncogenic isoforms refers to compounds which target, decrease or inhibit the oncogenic activity of Ras, e.g., a "farnesyl transferase inhibitor”, e.g., L-744832, DK8G557 or R1 15777 (Zarnestra).
  • telomerase inhibitor refers to compounds which target, decrease or inhibit the activity of telomerase.
  • Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, e.g., telomestatin.
  • methionine aminopeptidase inhibitor refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase.
  • Compounds which target, decrease or inhibit the activity of methionine aminopeptidase are, e.g., bengamide or a derivative thereof.
  • proteasome inhibitor refers to compounds which target, decrease or inhibit the activity of the proteasome.
  • Compounds which target, decrease or inhibit the activity of the proteasome include, e.g., PS-341 and MLN 341 .
  • matrix metalloproteinase inhibitor or "MMP inhibitor”, as used herein, includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g., hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551 )
  • BMS-279251 BAY 12-9566, TAA21 1 , MMI270B or AAJ996.
  • agents used in the treatment of hematologic malignancies includes, but is not limited to, FMS-like tyrosine kinase inhibitors, e.g., compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1 -b-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors, e.g., compounds which target, decrease or inhibit anaplastic lymphoma kinase.
  • FMS-like tyrosine kinase inhibitors e.g., compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1 -b-D-arabinofuransylcytosine (ara-c) and bisulfan
  • ALK inhibitors e.g., compounds which target, decrease or inhibit anaplastic lymphoma
  • FMS-like tyrosine kinase receptors are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, e.g., PKC412, midostaurin, a staurosporine derivative, SU1 1248 and MLN518.
  • HSP90 inhibitors includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteasome pathway.
  • Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90, e.g., 17-allylamino, 17-demethoxygeldanamycin (17AAG), a geldanamycin derivative, other geldanamycin related compounds, radicicol and HDAC inhibitors.
  • antiproliferative antibodies includes, but is not limited to, trastuzumab (HerceptinTM), Trastuzumab-DM1 , erlotinib (TarcevaTM), bevacizumab
  • antibodies is meant, e.g., intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity.
  • AML acute myeloid leukemia
  • compounds of the present invention can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML.
  • compounds the present invention can be administered in combination with, e.g., farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16,
  • a form of the present invention may also be used to advantage in combination with known therapeutic processes, e.g., the administration of hormones or especially radiation.
  • a form of the present invention may in particular be used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.
  • combination there is meant either a fixed combination in one dosage unit form, or a kit of parts for the combined administration where a form of the present invention and a combination partner may be administered independently at the same time or separately within time intervals that especially allow that the combination partners show a cooperative, e.g., synergistic, effect or any combination thereof.
  • co-administration or
  • a single subject in need thereof e.g. a patient
  • administration of the selected combination partner to a single subject in need thereof (e.g. a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • pharmaceutical combination as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g. a form of the present inventionand a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g.
  • a form of the present invention and a combination partner are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • the compounds of the present invention are known or may be prepared analogously to methods known in the art or as described hereafter.
  • Microwave equipment used is a Biotage Initiator
  • LC method 1 (Rt The retention times (Rt) were obtained on a Agilent HPLC system with an Ascentis®Express column C18 30 x 2.1 mm, 2.7 ⁇ (Supelco) applying a gradient (H 2 O+0.05% formic acid+3.75 mM Ammonium acetate) / (CH 3 CN+0.04% formic acid) 90/10 to 5/95 over 3.7 min and 1 .2 mL/min as solvent flow and then 5/95 over 0.7 min with 1.4 mL/min as solvent flow and 40°C for the oven temperature. Detection method UV 220-400 nm - MS.
  • LC method 2 (Rt ( '): The retention times (Rt) were obtained on a Agilent HPLC system with an Ascentis®Express column C18 30 x 2.1 mm, 2.7 ⁇ (Supelco) applying a gradient (H 2 O+0.05% formic acid+3.75 mM Ammonium acetate) / (CH 3 CN+0.04% formic acid) 95/5 to 5/95 over 3.7 min and 1 .2 mL/min as solvent flow and then 5/95 over 0.7 min with 1 .4 mL/min as solvent flow and 40°C for the oven temperature.
  • Detection method UV 220-400 nm - MS.
  • LC method 4 (Rt (4) ): The retention times (Rt) were obtained on a Agilent HPLC system with an Ascentis®Express column C18 30 x 2.1 mm, 2.7 ⁇ (Supelco) applying a gradient (H 2 O+0.05% formic acid+3.75 mM Ammonium acetate) / (CH 3 CN+0.04% formic acid) 90/10 to 5/95 over 1 .7 min and 1 .2 mL/min as solvent flow and then 5/95 over 0.7 min with 1.4 mL/min as solvent flow and 40°C for the oven temperature. Detection method UV 220-400 nm - MS.
  • LC method 6 (Rt (6) ): The retention times (Rt) were obtained on a Agilent HPLC system with an Ascentis®Express column C18 30 x 2.1 mm, 2.7 ⁇ (Supelco) applying a gradient (H 2 0+TFA) / (CH 3 CN+0.04% TFA) 99/1 over 0.5 min and 1.2 mL/ min as solvent flow then 99/1 to 5/95 over 1.7 min and 1 .2 mL/min as solvent flow and then 5/95 over 0.7 min with 1.4 mL/min as solvent flow and 40°C for the oven temperature. Detection method UV 220-400 nm - MS.
  • LC method 7 (Rt (7) ): The retention times (Rt) were obtained on a Waters Agilent HPLC system with an Ascentis®Express column C18 30 x 2.1 mm, 2.7 ⁇ (Supelco) applying a gradient (H 2 O+0.05% TFA) / (CH 3 CN+0.04% TFA) 90/10 to 5/95 over 1.7 min and 1.2 mL/min as solvent flow and then 5/95 over 0.7 min with 1 .4 mL/min as solvent flow and 40°C for the oven temperature. Detection method UV 220-400 nm - MS.
  • Method A Column SunFire prep C18 OBD 5 ⁇ , 30 x 100mm from WATERS, with H 2 0 + 0.1 % TFA and Acetonitrile + 0.1 % TFA as mobile phase. Detection method UV 220-400 nm
  • Method B Column Atlantis prep T3 OBD 5 ⁇ , 30 x 150mm from WATERS, with H 2 0 + 0.1 % TFA and Acetonitrile + 0.1 % TFA as mobile phase. Detection method UV 220-400 nm
  • Method C Column XTerra RP18 OBD 5 ⁇ , 19 x 50mm from WATERS, with H 2 0 + 0.1 % TFA and Acetonitrile + 0.1 % TFA as mobile phase. Detection method UV 220-400 nm X-ray Powder Diffraction
  • the vial was flushed with a stream of argon for 15 sec and capped. The mixture was heated with stirring for 5h at 100°C. Allowed to cool and partitioned between EtOAc (100 mL) and water (20 mL) and filtered the biphasic mixture through a celite pad. The organic layer was separated, dried (MgS0 4 ) and concentrated in vacuo.
  • the flask was flushed with a stream of nitrogen for 15 sec and capped.
  • the mixture was heated with stirring for 4h under reflux.
  • the mixture was allowed to cool to rt and partitioned between EtOAc (100 mL) and water (20 mL).
  • the biphasic mixture was filtered the through a celite pad.
  • the reaction is preferably stirred at a temperature of approximately 80-120°C, preferably 120°C.
  • the reaction may preferably carry out under an inert gas such as nitrogen or argon, d) N-BOC deprotection is performed under customary BOC deprotection conditions using among the possible acid preferably trifluoro- acetic acid or HCI and suitable organic solvent such as CH 2 CI 2 or diethyl ether.
  • the reaction is preferably performed at room temperature, e)
  • Typical conditions comprise of 1.0 eq. of 6-benzyl-4- chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine, 1.0 eq. of (S)-3-amino-pyrrolidine-1 - carboxylic acid tert-butyl ester and 1 .5 eq. of triethylamine at 120°C for 48h.
  • Removal of the benzyl protecting group is performed using standard methodology as described in "Protecting groups in Organic Synthesis" by T.W. Greene and P. Wutz, 3 rd edition, 1999, John Wiley and Sons.
  • Typical conditions comprise of 1 .0 eq.t of (S)-3-(6-benzyl-5, 6,7,8- tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1 -carboxylic acid tert-butyl ester XIX, 1 .1 - 8.0 eq.
  • the reaction may preferably be carried out under an inert gas such as nitrogen or argon.
  • Typical conditions comprise of 1 eq. of (S)-3-(5, 6,7,8- tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1 -carboxylic acid tert-butyl ester XX, 1 - 1 .5 eq. of R2-X, 1.5-2.0 eq.
  • N-Boc deprotection is performed under customary Boc deprotection conditions with a suitable acid such as trifluoroactetic acid in a suitable solvent such as CH 2 CI 2 at room temperature.
  • Typical conditions comprise of 1 eq. of compound of general formula XII in excess trifluoroacetic acid in CH 2 CI 2 at room temperature for 1-3 h.
  • Example 1 ⁇ (S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3- d]pyrimidin-4-yloxy]-pyrrolidin-1 -yl ⁇ -(tetrahydro-pyran-4-yl)-methanone
  • reaction mixture was cooled to rt and partitioned between CH 2 CI 2 and water.
  • the organic layer was separated and washed with an addition portion of CH 2 CI 2 .
  • the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product which was purified by flash-chromatography on silica gel
  • pyrrolidine-1-carboxylic acid tert-butyl ester (2.05 g, 4.63 mmol) was dissolved in TFA / CH 2 CI 2 (1/2) and stirred at rt for 1 h. The reaction mixture was concentrated under vacuum, the residue was diluted with CH 2 CI 2 , the organic layer washed with NaOH 1 N then brine, dried over Na 2 S0 4 , filtered and evaporated to give 6-(6-methoxy-5-methyl-pyridin-3-yl)-4- ((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine.
  • Example 1 1 part of Example 1 (eg. 100 mg) was mixed with 5 parts of acetonitrile (0.5 ml. for each 100 mg of compound) with stirring. A solution was obtained by heating up to 40-60°C. The mixture was then allowed to slowly cooled down to RT. After further cooling overnight (5°C), precipitation was observed. In case no precipitation is not observed, the volume of ethanol can be reduce using a nitrogen stream and repeating the overnight cooling step. The mixture was centrifuged to remove the ethanol. The solid was dried under vacuum at 25°C and 70 mbar. A crystalline anhydrous form of Example 1 with a MP of 131 °C was obtained.
  • Example 1 Slurry of Example 1 in water e.g., 1 part of Example 1 in 10 parts of water, at RT produced a trihydrate form of Example 1.
  • the crystals were separated by centrifugation and dried at room environment.
  • Example 1 0.5 g of Example 1 (assay 91 .8%) were dissolved in 5 mL of methylethylketone and 0.25 mL of water and heated at 60°C. 213 mg of citric acid were added at 50°C and the mixture was allowed to cool down to RT within 30 min. Crystallization occurs at 45°C. The mixture was stirred for 16 h at RT. The crystals were collected by filtration. The filter cake was washed 3 times with 1 mL of methylethylketone and afterwards dried for 16 h at 50°C and ca. 10 mbar vacuum. Elementary analysis of the citrate salt showed a 1 :1 (monohydrate) form.
  • Example 1 (assay 91.8%) were dissolved in 15 mL of acetonitrile and 0.2 mL of water and heated at 76°C. 129 mg of fumaric acid were added at 60°C. The solution was allowed to cool down to RT within 30 min. The salt precipitated and the suspension was stirred for 16 h at RT. The crystals were collected by filtration. The filter cake was washed 3 times with 1 mL of acetonitrile and afterwards dried for 16 h at 50°C and ca. 10 mbar vacuum. Elementary analysis of the fumarate salt showed a 1 :1 (monohydrate) form.
  • Example 1 (assay 91.8%) were dissolved in 5 mL of ethanol absolute and 0.25 mL of water at 60°C. 250 mg of naphthalendisulfonic acid were added at 50°C and the mixture was allowed to cool down to RT within 30 min. Crystallization occurs at 40°C. The mixture was stirred for 16 h at RT. The crystals were collected by filtration. The filter cake was washed 3 times with 1 mL of ethanol and afterwards dried for 16 h at 50°C and ca. 10 mbar vacuum. Elementary analysis of the napadisylate salt showed a 2:1 (monohydrate) form.
  • Example 67 was prepared according the general procedure described in scheme 4
  • Example 67 1- ⁇ (S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro- pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1 -yl ⁇ -propan-1 -one
  • To a solution of (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro- pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 24) (13.4 g, 27.1 mmol) in CH 2 CI 2 (100 mL), was added TFA (41.8 mL) and the mixture stirred at rt for 1 h.
  • the aqueous phase was partitioned between 25% NaOH (aq) (200 g) and 2-Me-THF (200 mL), and the organic phase was collected and dried.
  • Triethylamine (16.32 mL, 1 17.48 mmol) was added into the organic phase followed by dropwise addition of propionyl chloride (6.0 g, 64.6 mmol) at 0 °C.
  • the resulting mixture was stirred at 0 °C for 1 h.
  • the reaction mixture was washed with water (1 10 mL) and the resulting organic phase was concentrated in vacuo to give a brown gum.
  • Example 67 (4.440 mol) were dissolved in 10 mL of acetonitrile and 0.5 mL of water at 75°C. The solution was allowed to cool down to rt within 30 min resulting in a suspension. The mixture was stirred for 16 h at rt. The crystals were collected by filtration. The filter cake was washed 2 times with 1 mL of acetonitrile and afterwards dried for 16 h at 24°C and ca. 10 mbar vacuum. Elementary analysis of the material showed a waterless form.
  • Example 67 (4.440 mol) were dissolved in 10 mL of acetonitrile and 0.5 mL of water at 75°C. 512 mg of ortho-phosphoric acid 85% (4.440 mol) were added at 70°C.
  • Example 67 (.440 mol) were dissolved in 20 mL of acetonitrile and 1 .0 mL of water at 70°C. 459 mg of hydrochloric acid 37% (4.440 mol) were added at 70°C. Crystallization occurs quickly at 70°C. The suspension was allowed to cool down to rt within 30 min and stirred for 16 h at rt. The crystals were collected by filtration. The filter cake was washed 3 times with 1 mL of acetonitrile and afterwards dried for 16 h at 24°C and ca. 10 mbar vacuum. Elementary analysis of the HCI salt showed a 1 :1 (waterless) form.
  • Example 67 (0.888 mmol) were dissolved in 8 mL of acetonitrile and 0.2 mL of water at 70°C. 167 mg of hippuric acid (0.888 mmol) were added at 70°C. The solution was allowed to cool down to rt within 30 min. Crystallization occurs at 40°C. The suspension was stirred for 16 h at rt. The crystals were collected by filtration. The filter cake was washed 3 times with 1 mL of acetonitrile and afterwards dried for 16 h at 50°C and ca. 10 mbar vacuum. Elementary analysis of the hippurate salt showed a 1 :1 (waterless) form.

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Abstract

Cette invention concerne des formes anhydres cristallines, des formes solvates cristallines et/ou des formes sels comprenant les formes sels cristallines de la {(S)-3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8- tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tétrahydro-pyran-4-yl)-méthanone ou les formes sels comprenant les formes sels cristallines de la 1-{(S)-3-[6-(6-méthoxy-5-trifluorométhyl- pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]- pyrrolidin-1-yl}-propan-1-one ; des compositions pharmaceutiques et des combinaisons contenant ces formes ainsi que des procédés d'utilisation desdites formes, y compris leurs compositions pharmaceutiques et combinaisons pour le traitement des maladies.
EP12738616.7A 2011-06-27 2012-06-25 Formes solides et sels de dérivés de tétrahydro-pyrido-pyrimidine Withdrawn EP2723740A1 (fr)

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CN104945367A (zh) * 2015-06-04 2015-09-30 聂超 一种苯甲醛丙二醇缩醛及其制备方法
PT3413894T (pt) * 2016-02-10 2020-06-16 Novartis Ag Uso de inibidores da atividade ou função do pi3k para o tratamento da síndrome de sjögren primária

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CN103608349A (zh) 2014-02-26
JP2014518256A (ja) 2014-07-28
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MX2013015001A (es) 2014-03-31
CA2840315A1 (fr) 2013-01-03
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KR20140025530A (ko) 2014-03-04

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