Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D473/00—Heterocyclic compounds containing purine ring systems
  • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
  • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
• • 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
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

• the invention relates to the use of purine derivatives for the manufacture of a medicament for the treatment of pathologies in which an imbalance between cell division and apoptosis is involved and more particularly in which excessive apoptosis is at the origin of the pathology .
• Pathologies in which an imbalance between cell division and apoptosis is involved are in particular chronic lymphocytic leukemia and renal diseases such as polycystic disease.
• Chronic lymphocytic leukemia, LLC is a heterogeneous group of diseases characterized by the accumulation of CD5 + monoclonal B cells in the blood, bone marrow and hematopoietic organs.
• this disease is a disease in which the monoclonal B cells do not undergo or have a low rate of natural apoptosis (cell death) and a low proportion of B cells involved in the cell cycle.
• this disease is a disease somewhat different from diseases in which there is an excessive proliferation, which has not stopped, monoclonal cells, in which the monoclonal cells are strongly involved in the cell cycle and, in which the resistance to apoptosis (cell death) is a phenomenon of secondary pathogenicity.
• CLL is commonly classified into separate categories including chronic lymphocytic leukemia of B lymphocytes and chronic lymphocytic leukemia of T-type lymphocytes.
• CLL is commonly referred to as B-cell chronic lymphocytic leukemia (CLBC).
• B-lineage chronic lymphocytic leukemia known as LLC-B
• LLC-B B-lineage chronic lymphocytic leukemia
• LLC-B B-lymphocyte disease responsible for the accumulation of lymphocyte morphological B lymphocytes, expressing membrane antigens characteristic of the disease, such as CD5 and CD23, in the body. blood, resulting in hyperlymphocytosis, in the bone marrow, leading to bone marrow failure, and in the lymph nodes, resulting in polydenopathy.
• LLC-B has been characterized as a single biological entity with variable scalability.
• the prognostic classification of Binet makes it possible to fix the evolutionary profile of the disease in three stages A, B and C.
• Biological parameters include lymphocyte doubling time of less than 6 months, elevated soluble CD23, or thymidine activity.
• kinase serum are considered to be of poor prognosis.
• the perfectly identified genetic parameters of poor prognosis are the non-mutated forms of the disease (IgG immunoglobulin heavy chain gene at 14q32), deletions of chromosomes 1 Iq, 17p or additional chromosomal abnormalities of 12q + type.
• Patients with B-CLL who express these biological traits have a short progression time: thus, 50% of the non-mutated patients evolved in 24 months; 50% of patients with 17p-, 1 Iq- or 12q + evolved at 15 months.
• Patients of stage A expressing these biological criteria of gravity, the patients of stage B and C must benefit from an active therapeutic attitude.
• B-CLL two therapeutic antibodies emerge: rituximab and alemtuzumab.
• rituximab the activity of rituximab is hampered by the low expression of the target, the CD20 antigen, on the B lymphocyte of LLC.
• Rituximab is developed in B-CLL in synergy with purine analogues and / or cyclophosphamide (a 59% overall response observed with the fludarabine- cyclophosphamide-rituximab in patients refractory to fludarabine, with only 5% complete response).
• alemtuzumab directed against an antigen expressed on leukocytes and leukemic B lymphocytes of CLL, with a great heterogeneity of the membrane density of the antigen, is handicapped by its high immunosuppressive activity and the significant incidence of reactivation of cytomegalic infections and opportunistic infections during or after treatment: the antibody has a strong immunosuppressive activity T.
• the hematological response to alemtuzumab is 33%, the antibody is capable of destroying clonal B cells in the blood and bone marrow, but is little operative in the lymph nodes. These points limit the use of the antibody in this indication.
• Anti-CD20 radioimmunotherapy coupled with yttrium-90 (Zevalin) induces a low percentage of remission in B-CLL and is responsible for extensive myelosuppression.
• US Patent 6812232 discloses purine analogs close to those of the invention for their activity of inhibiting cell proliferation. But in the LLC, excessive cell proliferation has stopped.
• the patent application WO2005 / 002584 proposes, in turn, to use Roscovitine, preferably in its absolute configuration (R) in the treatment of chronic lymphocytic leukemia, and more particularly of chronic lymphocytic leukemia of line B.
• Roscovitine is a purine having the following formula:
• Roscovitine derivatives have a much higher activity than Roscovitine in the treatment of pathologies in which an imbalance between cell division and apoptosis is involved and that they have also in some cases a better solubility than Roscovitine.
• Z is H or CH 3 , or one of its pharmaceutically acceptable salts, hydrates, esters or isomers, for the manufacture of a medicament for treating pathologies in which an imbalance between cell division and apoptosis is involved.
• the pathology is chronic lymphocytic leukemia.
• the pathology is chronic lymphocytic leukemia of lineage B.
• the pathology is a renal disease, and more particularly polykystosis.
• a preferred salt for use in the manufacture of a medicament for treating diseases in which an imbalance between cell division and apoptosis is involved is the oxalate salt of the compounds of formula I.
• Formula II Indeed, these compounds are 4 to 5 times more active in cell models of chronic lymphoid leukemia and polycystic kidney disease and 5 to 10 times more soluble in aqueous medium than their corresponding in which X is C, as it is will see below.
• the compounds of structure I-II exhibit an activity comparable to that of derivatives I-I but their solubility in aqueous medium is further increased.
• the at least one compound used for the manufacture of a medicament for treating these pathologies is the compound of formula I in which X is N, Y is CH 3 and Z is H.
• compound has an absolute configuration (R) and has the following formula Ia:
• the at least one compound has the absolute configuration (S).
• This compound has the following formula Ib:
• the at least one compound of formula Ia or Ib is in the form of its oxalate salt.
• the at least one compound used for the manufacture of a medicament for treating pathologies in which an imbalance between cell division and apoptosis is involved is the compound of formula I in which X is C, Y is CH 3 , and Z is H.
• This compound has the following formula Ic:
• This compound can be used both in its absolute configuration (S) or (R) and in the form of a mixture thereof.
• the at least one compound used is the compound of formula I in which X is N, Y is OH, and Z is H.
• This compound has the following formula Id:
• the compound Id can be obtained as described in Example 1 which follows.
• Reagents and conditions a: 4- (2-pyridyl) benzylamine), n-BuOH, 110 ° C; b: 2 bromopropane, K 2 CO 3 , DMSO; vs :
• Step 1 2-Chloro-6- [4- (2-pyridyl) phenylmethylamino] purine (HIa). To a solution of 2,6-dichloropurine (2.3 g, 10 mmol) in 20 mL of ⁇ -BUOH is added
• Step 3 2- (1,3-Dihydroxyprop-2-ylamino) -6- [4- (2-pyridyl) phenylmethylamino] -9-isopropylpurine).
• the at least one compound used is the compound of formula I wherein X is N, Y is CH 3 , and Z is CH 3 .
• This compound has the following formula:
• the at least one compound used is the oxalate salt of the compound of formula Ie.
• This compound has the following formula If:
• one of the nitrogens of purine may be involved in salt formation which corresponds to the association of a molecule of purine with the diacid.
• the at least one compound used is the compound of formula Ig:
• the at least one compound used is the compound of formula Ih below:
• one of the nitrogens of purine may be involved in salt formation which corresponds to the association of a molecule of purine with the diacid.
• the three isomers of tartaric acid can be used.
• This compound is 2- (1,3-dihydroxyprop-2-ylamino) -6- [4- (2-pyridyl) phenylmethylamino] -9-isopropylpurine tartrate (Ih).
• esters of the compounds of formula Ia, Id and Ig as well as the isomers of the compounds of formula Ic and Ig may also be advantageously used.
• the esters of the compounds of formula I are also part of the invention.
• esters of the compounds of formula I are acylated esters such as acetyl, nicotinyl esters and L-series or D-series amino acid esters.
• esters are formed from amino acids such as valine or leucine.
• the particularly preferred esters have the following formulas II-1 to II-4:
• esters are precursors (prodrugs) of the products of formula I.
• FIG. 1 shows the induction of cell death by the compound of formula Ia, and the oxalate salt of the compound of formula Ia in chronic lymphocytic leukemia cells, compared with the induction of cell death induced by the roscovitine
• FIG. 2 shows the induction of cell death by the compounds of formula Ie and If in chronic lymphocytic leukemia cells.
• Tamyon buffer A 10 mM MgCl 2 , 1 mM EGTA, 1 mM DTT, 25 mM Tris-HCl pH 7.5, 50 ⁇ g heparin / ml.
• buffer C 60 mM glycerophosphate, 15 mM p-nitrophenylphosphate, 25 mM MOPS (pH 7.2), 5 mM EGTA, 15 mM MgCl 2 , 1 mM DTT, 1 mM sodium vanadate, 1 mM phenylphosphate.
• the kinase activities were assayed in buffer A or C at 30 ° C and a final concentration of ATP of 15 ⁇ M. Controls are carried out with appropriate dilutions of dimethylsulfoxide.
• CDK1 / cyclin B (native starfish M-phase oocytes) and CDK5 / p25 (human, recombinant) were prepared and assayed as described in Leclerc S. et al., J Biol Chem 2001; 276: 251-60. .).
• the assay is carried out with 1 mg histone H1 / ml, in the presence of 15 ⁇ M [ ⁇ - 33 P] ATP (3,000 Ci / mmol, 10 mCi / ml) in a final volume of 30 ⁇ l. After 30 min.
• CDK2 / cyclin A and CDK2 / cyclin E are assayed as CDK1.
• CDKWcyclin T human, recombinant, expressed as insect cells
• CDK1 / cyclin B a pRB fragment (AA773-928) (3.5 ⁇ g / assay) as substrate.
• GSK-3a / ⁇ (porcine brain, native, affinity purified) is assayed as CDK1 / cyclin B, but in buffer A and with a specific GSK-3 substrate (GS-1: YRRAA VPPSPSLSRHSSPHQSpEDEEE) (Bach S. and al., J Biol Chem 2005; 280: 31208-19).
• CK1 ⁇ / e (porcine brain, native, affinity purified) is assayed as CDK1 / cyclin B, but in buffer A and with a specific substrate, RRKHAAIGSpA YSITA (Reinhardt J. et al., Protein Expr & Purif 2007; : 101-9).
• DYRK1A human, recombinant, expressed in E. coli cells
• CDK1 / cyclin B CDK1 / cyclin B
• IC 50 mean inhibitory concentration values were calculated from the dose-response curves and are reported in ⁇ M in the following Table I:
• B2 lymphocytes are the lymphocytes involved in B2 chronic lymphocytic leukemia. Cell viability is determined by the reduction of 3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium (MTS).
• LDH lactate dehydrogenase
• solubility of the compounds of the invention wherein X is N are 5 to 10 times more soluble in water than those in which X is C.
• the compound of formula Ic wherein X is C, has a solubility in water of 0.5 ⁇ g / mL while the corresponding compound wherein X is N, that is, the compound of formula Ib, has a solubility in water of 3.3 ⁇ g / mL.
• the compounds of formula Ib to Ih are also objects of the invention.
• the esters of the compounds of formula I are also part of the invention.
• esters of the compounds of formula I are acylated esters such as acetyl, nicotinyl esters and L-series or D-series amino acid esters.
• Preferred esters are formed from amino acids such as valine or leucine.
• the particularly preferred esters have the following formulas II-1 to II-4:
• esters are precursors (prodrugs) of the products of formula I.
• the compounds of the invention are particularly effective for use in the manufacture of a medicament for treating chronic lymphocytic leukemia. They are also particularly suitable for administration in a method of treating patients with chronic lymphocytic leukemia.
• They are also particularly effective for use in the manufacture of a medicament for treating renal diseases, and in particular polycysticosis. In the same way, they are particularly suitable for administration in a method of treating patients with renal disease, and in particular polycystic disease.
• the compounds of the invention may be used in admixture with one another, of two or more, and also in combination with other compounds having therapeutic activity in the treatment of chronic lymphocytic leukemia or chronic lymphocytic leukemia.
• renal diseases such as polycystic disease, and / or in combination with any pharmaceutically acceptable excipient for the manufacture of a medicament and that such combinations and mixtures are also part of the invention.

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• 2007
  • 2007-09-12 FR FR0706390A patent/FR2920776B1/fr active Active
• 2008
  • 2008-09-12 KR KR1020107007886A patent/KR20100075908A/ko not_active Ceased
  • 2008-09-12 WO PCT/FR2008/001278 patent/WO2009068761A2/fr not_active Ceased
  • 2008-09-12 CN CN2008801067270A patent/CN101918000B/zh not_active Expired - Fee Related
  • 2008-09-12 MX MX2010002680A patent/MX2010002680A/es active IP Right Grant
  • 2008-09-12 BR BRPI0816810A patent/BRPI0816810A2/pt not_active IP Right Cessation
  • 2008-09-12 JP JP2010524542A patent/JP5485893B2/ja not_active Expired - Fee Related
  • 2008-09-12 CA CA2699590A patent/CA2699590A1/fr not_active Abandoned
  • 2008-09-12 ES ES08855583.4T patent/ES2444419T3/es active Active
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