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WO2012115575A1 - Dérivés pour induire une différenciation ostéogénique - Google Patents

Dérivés pour induire une différenciation ostéogénique Download PDF

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Publication number
WO2012115575A1
WO2012115575A1 PCT/SE2012/050180 SE2012050180W WO2012115575A1 WO 2012115575 A1 WO2012115575 A1 WO 2012115575A1 SE 2012050180 W SE2012050180 W SE 2012050180W WO 2012115575 A1 WO2012115575 A1 WO 2012115575A1
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Prior art keywords
compound
group
independently
enhance
methyl
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Inventor
Cecilia Graneli
Camilla KARLSSON
Anders Lindahl
Peter Thomsen
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BIOMATCELL AB
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BIOMATCELL AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/54—Three nitrogen atoms
    • C07D251/70—Other substituted melamines
    • 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
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/54—Three nitrogen atoms
    • C07D251/56—Preparation of melamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to osteoinductive substances, compositions comprising the same and the use of said substances and compounds and compositions.
  • MSCs Mesenchymal stem cells
  • BMP bone morphogenic protein
  • Hh hedgehog
  • BMPs are members of the transforming growth factor beta (TGF- ⁇ ) superfamily and have many interaction partners in the osteogenic differentiation process. They bind to a cell surface complex consisting of bone morphogenic receptors type I and II I and II with subsequent activation of a SMAD or MAP kinase pathway resulting in upregulation of target genes such as runt-related transcription factor 2 (Runx2).
  • TGF- ⁇ transforming growth factor beta
  • Hh signalling is essential for many processes during development in vertebrates. It has also been shown that the activation of this signalling pathway can increase osteogenic differentiation of MSCs, both in vitro and in vivo.
  • Hh ligands sonic Hh (SHh), indian Hh (IHh) or desert Hh (DHh) binds the Patched (Ptc) / Smoothened (Smo) cell surface complex and thereby allows for the activation of transcription factors glioma-associated oncogene homologs (Gli) 1 , 2 or 3 and subsequent regulation of target genes.
  • purmorphamine This substance was described as an osteogenesis-inducing small molecule substance, on the basis of increased alkaline phosphatase (ALP) activity in C3H 10T 1 / 2 cells and increased Runx2 expression in various mouse cell lines (J Am Chem Soc, 124, (49): 14520- 14521). Purmorphamine has also been shown to induce increased ALP-activity in human MSCs (hMSCs). The mechanism by which purmorphamine induces osteogenic differentiation was revealed by micro array, where activation of the SHh signalling pathway was indicated by the up- or down-regulated expression of several of its target genes (Wu et al. Chem Biol 11 (9): 1229-38). Recently, Plaisant et al.
  • the object of the present invention is to present one or more of a compound that enhances the osteogenic differentiation of hMSCs and the bone matrix formation of hMSCs, osteoblastic progenitors and osteoblasts.
  • One aspect of the present invention relates to a compound according to formula 1
  • X is carbon or nitrogen
  • Ri, R2 and R3 are selected from the groups consisting of
  • R2 or R3 may form a penta or hexa cyclic group with said carbon comprising at least one nitrogen atom wherein at least one nitrogen is substituted with an alkyl, phenyl and/or a benzyl group;
  • R 4 to Re are independently a methyl, ethyl, propyl, butyl and pentyl group, for use in a medicament.
  • Another aspect relates to a compound according to formula 1
  • X is carbon or nitrogen
  • Ri, R and R3 are selected from the groups consisting of
  • R2 or R3 may form a penta or hexa cyclic group with said carbon comprising at least one nitrogen atom wherein at least one nitrogen is substituted with an alkyl, phenyl and/or a benzyl group; and R 4 to Re are independently a methyl, ethyl, propyl, butyl and pentyl group, for use in a medicament for treating bone, tooth and cartilage related diseases or damages.
  • Another aspect of the present invention relates to the use of the compound defined above to induce or enhance osteogenic differentiation of mesenchymal stem cells and to induce or enhance matrix production and mineralization of osteoblastic progenitor cells or osteoblasts.
  • Another aspect of the present invention relates to the use of the compound defined above to enhance bone growth.
  • Another aspect of the present invention relates to the use of the compound defined above to induce or enhance adipogenic differentiation.
  • Another aspect of the present invention relates to an implant comprising the compound defined above.
  • Another aspect of the present invention relates to a drug delivery vehicle containing the compound defined above.
  • Another aspect of the present invention relates to a medicament comprising the compound.
  • Another aspect of the present invention relates to a method of treating a bone, tooth or cartilage defect or damage by applying the compound as defined above to said defect or damage.
  • Yet another aspect of the present invention relates to a pharmaceutical composition comprising the compound as defined above and a suitable excipient or adjuvant.
  • Yet another aspect relates to a compound as defined above for the treatment of mesenchymal stem cells to induce or enhance osteogenic differentiation. Yet another aspect relates to a compound as defined above for the treatment to enhance bone growth.
  • Yet another aspect relates to a compound as defined above for the treatment to induce or enhance adipogenic differentiation.
  • Yet another aspect relates to a compound as defined above for the treatment of osteoblastic progenitor cells or osteoblasts to enhance matrix production and mineralization .
  • A Mean ALP activity per cell in hMSCs cultured in osteogenic conditions for two weeks, without (ctrl) or with either purmorphamine or one of five different osteoinductive compunds.
  • Figure 4 Mean ALP activity per cell in hMSCs cultured in osteogenic conditions for two weeks, without (ctrl) or with either purmorphamine or one of five different osteoinductive compunds.
  • A Mean ALP activity per 10,000 cells in hMSCs cultured in osteogenic medium for two weeks
  • B Calcium content of the ECM of hMSCs cultured in osteogenic conditions for five weeks, without (ctrl) or with either purmorphamine or one of three different compunds.
  • Cl 0.5 ⁇
  • C2 l ⁇
  • C3 2 ⁇ .
  • the present invention relates to one or more compounds defined in formula 1
  • X is carbon or nitrogen
  • R2 or R3 may form a penta or a hexa cyclic group with said carbon comprising at least one nitrogen atom wherein at least one nitrogen is substituted with an alkyl, phenyl and/ or a benzyl group; and R 4 to Re are independently a methyl, ethyl, propyl, butyl and pentyl group.
  • These compounds have potential of being osteoinductive and are therefore of interest for use as a medicament, especially for the treatment of various bone, tooth and cartilage diseases and defects. Further, the compounds may also induce adipogenic differentiation.
  • the R 4 to Re-groups are methyl, ethyl, propyl, butyl or pentyl groups but preferably they are independently methyl, ethyl or propyl groups, more preferably methyl or ethyl groups and more preferably methyl groups.
  • each Ri, R 2 and R3 are independently selected from the group consisting of -CF3, -O-CF3, or hydrogen, or when X is a carbon Ri, R2 or R3 may form a penta or a hexa cyclic group with said carbon comprising at least one nitrogen atom wherein at least one nitrogen is substituted with an alkyl, phenyl and/ or a benzyl group; and
  • each R 4 to Re are independently an alkyl group preferably a methyl, ethyl, propyl, butyl or pentyl group.
  • Ri, R 2 or R3 are independently selected from the substituents I, II, IV, V, VI, VII, VIII and IX defined above.
  • X in formula 1 is a carbon Ri
  • R 2 or R3 may form a penta or a hexa cyclic group with said carbon comprising at least one nitrogen atom wherein at least one nitrogen is substituted with an alkyl, phenyl and/or a benzyl group.
  • at least one of Ri, R 2 and R3 is I.
  • each Ri, R 2 or R3 are independently selected from I, II, V, IX, XI, XII, XIII and XIV-CF3, -O-CF3, or hydrogen, or when X is a carbon Ri, R2 or R3 may form a penta or a hexa cyclic group with said carbon comprising at least one nitrogen atom wherein at least one nitrogen is substituted with an alkyl, phenyl and/ or a benzyl group; and
  • each R 4 to Re are independently an alkyl group preferably a methyl, ethyl, propyl, butyl or pentyl group.
  • R 2 or R3 may individually form a penta or a hexa cyclic group with said carbon comprising at least one nitrogen atom wherein at least one nitrogen is substituted with an alkyl, phenyl and/ or a benzyl group.
  • Ri to R3 forms said cyclic group.
  • this cyclic group is preferably a penta cyclic group.
  • these cyclic groups should preferably comprise two nitrogen atoms.
  • X is carbon or nitrogen; each Ri, R 2 and R3 are independently selected from the group consisting of
  • Ri OCH(CF3) , -CF3, -O-CF3, or hydrogen, or when X is a carbon Ri, R2 or R3 may form a penta or hexa cyclic group with said carbon comprising at least one nitrogen atom wherein at least one nitrogen is substituted with an alkyl, phenyl and /or a benzyl group; and least one of Ri, R 2 or R3 is
  • each R 4 to Re are independently an alkyl group preferably a methyl, ethyl, propyl, butyl or pentyl group, or stereoisomers or pharmaceutically acceptable salts thereof; for use in a medicament for treating bone, tooth and cartilage related diseases or damages.
  • each R 4 to Re are independently an alkyl group preferably a methyl, ethyl, propyl, butyl or pentyl group, or stereoisomers or pharmaceutically acceptable salts thereof.
  • each R 4 to Re are independently an alkyl group preferably a methyl, ethyl, propyl, butyl or pentyl group, or stereoisomers or pharmaceutically acceptable salts thereof; for use as a medicament.
  • Each R 4 to Re could be arranged in para, ortho or meta position.
  • the substituents may both be arranged in ortho or both in meta position, or one in ortho and one in meta position, or one in para and one in meta position or one in para and one in ortho position.
  • one of the substituents should be in para position.
  • the compound is selected from
  • each R 4 to Re are independently an alkyl group preferably a methyl, ethyl, propyl, butyl or pentyl group; or stereoisomers or pharmaceutically acceptable salts thereof.
  • the compound is selected from the group consisting of compounds A, C, D, H, I and J,
  • each Ri, R 2 and R3 are independently selected from the group consisting of
  • R 2 or R3 may form a penta or hexa cyclic group with said carbon comprising at least one nitrogen atom wherein at least one nitrogen is substituted with an alkyl, phenyl and/or a benzyl group; and wherein at least one of Ri, R2 or R3 is
  • each R 4 to Re are independently a methyl, ethyl, propyl, butyl or pentyl group, or stereoisomers or pharmaceutically acceptable salts thereof.
  • the compound is selected from the group consisting of compounds C, D, H, I and J,
  • the compound is one of compounds C, D, H, I or J.
  • the compound is one of compounds A, D, H or J.
  • the compound is selected from D, H or J.
  • compound C is used to induce or enhance adipogenic differentiation.
  • compound C is used for the treatment to induce or enhance adipogenic differentiation.
  • compounds A, D, H or J are used for the treatment of mesenchymal stem cells to induce or enhance osteogenic differentiation, or for the treatment to enhance bone growth, or for the treatment of osteoblastic progenitor cells or osteoblasts to enhance matrix production and mineralization.
  • Table 1 is used for the treatment of mesenchymal stem cells to induce or enhance osteogenic differentiation, or for the treatment to enhance bone growth, or for the treatment of osteoblastic progenitor cells or osteoblasts to enhance matrix production and mineralization.
  • compositions and medicaments according to the present invention may in a certain embodiments comprise two or more compounds, for example three or four compounds.
  • the compound could be used as a medicament but also as a pharmaceutical composition and may then also comprise various excipients or adjuvants.
  • the compound is present in a pharmaceutical composition in a pharmaceutically active amount.
  • the medicament could be used to treat
  • osteoporosis osteogenesis imperfecta
  • Paget's disease of bone or to induce or enhance osteogenetic differentiation extra cellular matrix production and or mineralization .
  • composition according to the present invention is for enteral, topical or parenteral administration.
  • the composition could further comprise a suitable carrier or a capsule.
  • WO2004 / 0889286 describes compounds similar to the present compounds but none of the compounds described herein are explicitly mentioned and the purpose of the compounds of WO2004/ 0889286 are to treat or prevent disorders associated with abnormal or deregulated tyrosine kinase activity.
  • ALP activity is commonly used as a marker for osteogenic differentiation, and has previously been used in similar studies screening purmorphamine analogues in the C2C12 cell line.
  • the present study has, in addition to ALP assays, quantitatively evaluated the substances by the more clinically relevant capacity of inducing ECM mineralization as well as by the expression of several genes connected to
  • results of the present invention show that, purmorphamine and the derivatives abbreviated A, D, H and J all have osteoinductive effects on hMSCs generating ALP activity, expression of common osteogenic markers, and ultimately a more mineralised ECM than compared to the control.
  • substances A and D stand out as the compounds that result in the highest degree of calcium and/ or phosphate deposition in the ECM after five weeks when osteogenic differentiation is induced without the addition of BMP-2.
  • the intermediate concentrations of substance D almost doubled the incorporation of calcium in the ECM compared to the control.
  • the present results of addition of recombinant BMP-2 strongly suggest that it is only the combination of purmorphamine which provide a positive synergistic effect on the induction or enhancement of the osteogenic differentiation process. This observation is interesting also from future in vivo and clinical perspectives.
  • Substances A, D and J are possible substitutes to purmorphamine e.g. in vivo without the expression and secretion of BMP-2 locally. Further, in a clinical situation, if the addition of a recombinant protein would be needed, an increased treatment cost would be likely.
  • the hypothesis is that the high ALP levels after two weeks of culture with purmorphamine and substance J (when no BMP-2 is added) are an indication of a more progressed i.e. faster differentiation process compared to the other substances. This in turn, makes the cells more susceptible for osteogenic stimulation by BMP-2 and the combination pushes the differentiation process further.
  • the method of predicting osteogenic differentiation by ALP activity is of much higher relevance when differentiation is induced and stimulated by recombinant BMP-2. This methodological finding indicate that the use of ALP activity assays as a tool for evaluating osteogenic differentiation should be used in combination with other quantitative methods of analysis.
  • the present invention shows the potential of the described compositions and compounds with regard to in vitro osteogenic differentiation of hMSC.
  • hMSC have been cultured in the presence of purmorphamine on titanium surfaces with positive osteogenic differentiation as a result (Beloti MM et al., Biomaterials 26(20):4245-8, 2005).
  • the observations open up the possibilities to explore the in vivo effects with purmorphamine or one of the derivatives in e.g. surface
  • the compounds according to the invention can be used in pharmaceutical compositions or alone as a medicament.
  • Said medicament can be used for treating various bone or tooth diseases.
  • the medicament could be administrated in any way known to a person skilled in the art, further the compound or composition could be loaded into a drug delivery vehicle.
  • the compound could be used to coat or soak an implant in order to enhance bone or tooth growth or to induce or enhance cell differentiation at the implant site.
  • a ceramic or polymeric implant be coated or soaked with the compound according to the invention.
  • the compound or composition When placed at the defect or damaged site the compound or composition will stimulate bone or tooth growth and thereby enhance the adherence to the surrounding tissue. This presents a strategy for treating a patient with a bone or tooth defect or damage by applying the compound or composition according to the present invention to said defect or damage.
  • Bone marrow from the iliac crest was obtained from a patient undergoing surgical spinal fusion at the Sahlgrenska University Hospital. From this biopsy, a
  • mononuclear cell population was isolated by density gradient centrifugation using Vacutainer CPT tubes (Becton, Dickinson and Company) prefilled with Ficoll (GE Healthcare Bio-Sciences AB) according to the manufacturer's instructions.
  • the mononuclear cell fraction was then seeded in primaria tissue culture flasks at a density of approximately 250,000 cells/cm 2 . After 24 hours the flask was rinsed with Dulbecco's modified Eagles medium-low glucose (DMEM-LG) (Thermo Fisher Scientific) and unattached cells were discarded.
  • DMEM-LG Dulbecco's modified Eagles medium-low glucose
  • the adherent cells were then expanded in DMEM-LG supplemented with 2mM L-glutamine (Invitrogen) , lx Penicillin-Streptomycin (Thermo Fisher Scientific), 10 ng/mL ⁇ -FGF (Invitrogen) and 10% fetal calf serum (FCS) (Sigma), and hMSCs were enriched through culture.
  • DMEM-LG 2mM L-glutamine
  • lx Penicillin-Streptomycin Thermo Fisher Scientific
  • 10 ng/mL ⁇ -FGF Invitrogen
  • FCS fetal calf serum
  • hMSCs from a fourteen-year-old female donor were used in this study.
  • the cells were characterised by flow cytometry prior to osteogenic differentiation.
  • hMSCs were stained using PE-conjugated CD 166, APC-conjugated CD105, FITC- conjugated CD34 and PE-Cy7-conjugated CD45 or the appropriate isotype controls (Bio Legend), and thereafter analysed on the FACS ARIA III (BD Bioscience). Osteogenic differentiation
  • Osteogenic differentiation was induced with osteogenic medium containing dexamethasone (10 ⁇ ), ascorbic acid (45 mM) and -glycerophosphate (20 mM). Cells in passage five were seeded at 5000 cells/cm 2 and then kept in osteogenic conditions for up to five weeks. The medium was prepared fresh every week and changed twice a week. The osteogenic medium was supplemented with
  • the LDH activity was subsequently determined in a coupled enzymatic reaction, during which nicotinamide adenine dinucleotide (NAD + ) is reduced to NADH.
  • NAD + nicotinamide adenine dinucleotide
  • the rate of NADH increase is proportional to the catalytic activity of LDH and can be measured photometrically at 340nm.
  • Real-time PCR was performed with cDNA equivalent to 2,5 ng RNA and the TaqMan Universal PCR master mixture with l x assay-on-demand mixes of primers and TaqMan MGB probes. All samples were analysed in duplicates and PCR was performed using the 7900HT real time PCR System (Applied Biosystems). The assays used in this study were: Runx2, Osteocalcin (OCN), Glil and 18s as an endogenous control. The relative quantification of the target gene expression was performed according to the standard curve protocol and calculated by the ⁇ -Ct method.
  • the calcium levels were measured using the ortho-cresolphthalein complexone (OCPC) method. Under alkaline conditions, this reagent forms a complex with calcium that can be detected at 600 nm. The absorbance is directly proportional to the calcium concentration. Further, the phosphate levels were measured by colometry of phospho-vanado-molybdic acid. This reagent form, under acidic conditions, a complex that can be detected at 340 nm and the absorbance is directly proportional to the phosphate concentration. The analyses described above were performed at the accredited laboratory at Sahlgrenska University Hospital.
  • LDH and ALP activity were measured after two weeks of osteogenic culture, and calcium and phosphate after five weeks with concentrations of 2.0 and 5.0 ⁇ of each substance.
  • the later marker of OCN had an expression pattern more in line with the
  • BMP-2 stimulated hMSCs treated with, D, J and purmorphamine was higher than the control condition.
  • Purmorphamine had the highest expression of SHh marker Gli 1 compared to all other conditions.
  • the synergistic effect of BMP-2 on Hh-activation was, however, only significant in combination with substances A, D and J.

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  • Chemical & Material Sciences (AREA)
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  • Organic Chemistry (AREA)
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  • Physical Education & Sports Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur un composé destiné à être utilisé en tant que médicament, en particulier pour le traitement de maladies et de lésions liées à un os, à une dent et à un cartilage. Le composé a montré qu'il pouvait induire et améliorer une différenciation ostéogénique. La présente invention porte en outre sur des implants comprenant ledit composé.
PCT/SE2012/050180 2011-02-21 2012-02-20 Dérivés pour induire une différenciation ostéogénique Ceased WO2012115575A1 (fr)

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SE1150143-4 2011-02-21
SE1150143 2011-02-21
US201161445122P 2011-02-22 2011-02-22
US61/445,122 2011-02-22

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Cited By (1)

* Cited by examiner, † Cited by third party
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US11066419B2 (en) 2016-12-30 2021-07-20 Frequency Therapeutics, Inc. 1H-pyrrole-2,5-dione compounds and methods of using same

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WO2000049018A1 (fr) * 1999-02-18 2000-08-24 Novartis Ag 2-amino-6-anilino-purines et leur utilisation comme medicaments
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Publication number Priority date Publication date Assignee Title
WO1999036410A1 (fr) * 1998-01-13 1999-07-22 Scriptgen Pharmaceuticals, Inc. Composes de triazine antiviraux
WO2000049018A1 (fr) * 1999-02-18 2000-08-24 Novartis Ag 2-amino-6-anilino-purines et leur utilisation comme medicaments
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Title
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ZHENG M. ET AL.: "Synthesis and antitumor evaluation of a novel series of triaminotriazine derivatives", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 4, no. 15, 2007, pages 1815. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11066419B2 (en) 2016-12-30 2021-07-20 Frequency Therapeutics, Inc. 1H-pyrrole-2,5-dione compounds and methods of using same

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