WO1986004583A1 - Composes de 4-substitue-6-aryl-pyrimidine - Google Patents

Composes de 4-substitue-6-aryl-pyrimidine Download PDF

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Publication number
WO1986004583A1
WO1986004583A1 PCT/US1986/000074 US8600074W WO8604583A1 WO 1986004583 A1 WO1986004583 A1 WO 1986004583A1 US 8600074 W US8600074 W US 8600074W WO 8604583 A1 WO8604583 A1 WO 8604583A1
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WO
WIPO (PCT)
Prior art keywords
phenyl
chloro
bromo
carbon atoms
aziridyl
Prior art date
Application number
PCT/US1986/000074
Other languages
English (en)
Inventor
Harvey I. Skulnick
Wendell Wierenga
Original Assignee
The Upjohn Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Upjohn Company filed Critical The Upjohn Company
Publication of WO1986004583A1 publication Critical patent/WO1986004583A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • 5-Fluorouracil is a well known and widely used antineoplastic agent.
  • Wierenga et al. disclose the use of 2-amino-6-aryl-5-substituted-4-pyrimidinols (pyrimidines) as interferon inducers, antiviral agents and for treatment of cancer in Belgium Patent No. 882,315 and Great Britain Patent No. 2,048,250.
  • aziridine-containing anticancer agents including triethylenemelamine, triethylenethiophosphoramide (thio-TEPA), aziridylbenzoquinone, mitomycins and 1-(2,3,5-tribenzoyl- ⁇ -1)-ribofuranosyl)-4-aziridil-2-pyrimidinone. See W.B. Pratt and R.W. Ruddon, The Anti-Cancer Drugs, Oxford Univ. Press, N.Y., 1979 and S.K. Carter, et al (ed.), Recent Results in Cancer Research, Springerverlag, Berlin, 1977 for a review. BRIEF DESCRIPTION OF THE INVENTION
  • This application relates to 4-substituted-5-substituted/unsubstituted-6-aryl-pyrimidine compounds represented by Formula I, wherein R 4 is chloro, bromo, aziridyl or 2-(1-aziridyl)ethylamino and R 5 and R 6 are as defined below, and the use thereof to treat an animal or human hosting a neoplastic disease.
  • R 4 is chloro, bromo, aziridyl or 2-(1-aziridyl)ethylamino
  • R 5 and R 6 are as defined below
  • Groups X, X 1 , X 2 , X 3 or X 4 is not hydrogen and is fluoro, chloro, bromo, iodo, alkyl of from 1 to 5 carbon atoms, inclusive, including isomeric forms, alkoxy of from 1 to 5 carbon atoms, inclusive, including isomeric forms, nitro or dialkylamino of from 1 to 3 carbon atoms, inclusive, including isomeric forms, and c) a disubstituted phenyl of Formula A wherein any two of X, X 1 , X 2 , X 3 and X 4 are not hydrogen and are the same or different and are fluoro, chloro, bromo, iodo, alkyl of frcm 1 to 5 carbon atoms, inclusive, including isomeric forms, alkoxy of from 1 to 5 carbon atoms, inclusive, including isomeric forms, nitro or dialkylamino of from 1 to 3 carbon atoms, inclusive, including isomeric forms,
  • the 6-aryl-pyrimidinol compounds are, however, tautomeric and can therefore also be drawn and/ or named as isocytosines (Formula IIB), for example 2-amino-5-bromo-6-phenyl-1-pyrimidinol can also be named as 5-bromo-6-phenyl-isocytosine.
  • the 6-aryl-pyrimidinol compounds of Formula II can be obtained by the methods disclosed in Belgium Patent No. 882,315 or Great Britain Patent No. 2,048,250.
  • the compounds of Formula III preferably where Z is chloro, is reacted with aziridine in the presence of an aprotic base, for example triethylamine, and carried out at 0° to 50°.
  • an aprotic base for example triethylamine
  • the compounds of Formula III are unsubstituted at the 5-position, the compounds of Formula IA or IB can be halogenated, if desired, by well known art methods. See, Preparation III or IV and Chart B. DEFINITIONS
  • THP refers to tetrahydropyranyl
  • - DMSO dimethylsulfoxide.
  • - Skellysolve B refers to an isomeric mixture of hexanes.
  • - DMA refers to dimethylacetamide
  • NBS N-bromosuccinimide
  • NCS refers to N-chlorosuccinimide
  • - TEA refers to triethylamine.
  • - Saline refers to an aqueous saturated sodium chloride solution.
  • - IR refers to infrared spectroscopy.
  • - CMR 13 C magnetic resonance spectroscopy
  • chemical shifts are reported in ppm ( ⁇ ) downfield from TMS.
  • - NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemical shifts are reported in ppm ( ⁇ ) downfield from tetramethylsilane.
  • MS mass spectrometry expressed as m/e or mass/change unit.
  • - Ether refers to diethyl ether.
  • - Alcohol refers to ethyl alcohol.
  • compositions, formulation, stability, patient acceptance and bioavailability refers to those properties and/or substances which are acceptable to the patient from a pharmacologicaltoxicological point of view and to the manufacturing pharmaceutical chemist from a physical-chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
  • the ratios of solvents used are volume/volume (v/v).
  • Example 2 4-(1-aziridyl)-6-phenyl-2-pyrimidinamine; 2-amino-4-(1-aziridyl)-6-phenylpyrimidine To 10.0 g (48.7 mM) of 4-chloro-6-phenyl-2-pyrimidinamine is added a solution of 10.25 ml of triethylamine (73 mM) in 50.0 ml of aziridine (965 mM).
  • the mixture is stirred t 20° for 2-4 hours and evaporated, under vacuum to dryness (the distillate is collected in a trap that is cooled with a dry-ice/acetone bath, and then carefully discarded).
  • the residue is dissolved in a minimum amount of methanol and poured into 1500 ml of ethyl acetate.
  • the solids are filtered and the organic solution evaporated to dryness under vacuum.
  • the residue is dissolved in 50.0 ml of ethyl acetate, placed on top of 500 g silica gel and eluted with ethyl acetate taking 50.0 ml fractions.
  • Example 3 4-(1-aziridyl)-5-bromo-6-phenyl-2-pyrimidinaraine; 2-amino-4-(1-aziridyl)-5-bromo-6-phenylpyrimidine
  • ID 50 and ID 90 refer to the concentration of compound needed to inhibit cell growth by 50 and 90 percent, respectively.
  • 4-(1-aziridyl)-6-phenyl-2-pyrimidinamine also demonstrated activity in vivo against P388 and L-1210 leukemias in mice but no in vivo activity in mice against B-16 melanoma.
  • the P-388 mouse leukemia test is described in detail in a publication by G.L. Neil, et al, Cancer Treatment Reports 63, 1971-1978 (1979). The results of in vivo testing using different dosage schedules is shown in Table II.
  • the compounds of the subject invention (Formula I) or the pharmacologically acceptable acid addition salts thereof when R 4 is chloro or bromo, in association with a pharmaceutical carrier can be used to treat animals or humans hosting a neoplastic disease, for example, acute a denocarcinoma of lung, neuroblastoma, small cell carcinoma of lung, breast carcinoma, lymphomas, leukemias, colon carcinoma, ovarian carcinoma, bladder carcinoma, and the like.
  • Suitable pharmacologically acceptable acid addition salts are, for example, the hydrochloride, sulfate, phosphate, nitrate, and the like. These salts can be used in the same manner as the base compounds.
  • dosage administered will be dependent upon the identity of the neoplastic disease, the type of host involved, its age, health, weight, kind of concurrent treatment, if any, frequency of treatment and therapeutic ratio.
  • dosage levels of the administered active ingredients can be: intravenously or interaperitoneally at 10 to about 100 mg/kg/day intraperitoneally or orally at 10 to about 1000 mg/kg/day.
  • dosage levels of the administered active ingredient can be: orally at 10 to about 1000 mg/kg/day, or preferably intravenously at 1 to about 100 mg/kg/day; the foregoing dose to be administered in one day.
  • the dose can be readrainistered at daily intervals for 3-10 days for a course of therapy. Courses of therapy can be repeated at intervals, for example, every 4 weeks.
  • an active ingredient can be present in the compositions of the present invention in a concentration of from about 0.1 to about 90 percent w/w of the composition; preferably about 1 to about 20 percent w/w of the composition; and for parenteral use in a concentration of from about 0.5 to about 50 percent w/v of the composition and preferably from about 5 to about 20 percent w/v.
  • compositions of the present invention are preferably presented for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile non-parenteral solutions or suspensions, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient.
  • solid or fluid unit dosage forms can be prepared.
  • Powders are prepared quite simply by comminuting the active ingredient to a suitably fine size and mixing with a similarly comminuted lactose or starch.
  • a sweetening agent or sugar is present as well as a flavoring gel.
  • Capsules are produced by preparing a powder mixture as hereinbefore described and filling into formed gelatin sheaths.
  • a lubricant such as talc, magnesium stearate, calcium stearate and the like is added to the powder mixture before the filling operation.
  • Soft gelatin capsules are prepared by machine encapsulation of a slurry of active ingredients with an acceptable vegetable oil, light liquid petrolatum or other inert oil or triglyceride. Tablets are made by preparing a powder mixture , granulating or slugging , adding a lubricant and pressing into tablets.
  • the powder mixture is prepared by mixing an active ingredient , suitably comminuted, with a diluent or base such as starch , lactose , kaolin , di calcium phosphate and the like .
  • the powder mixture can be granulated by wetting with a binder such as corn syrup , gelatin solution , methylcellulose solution or acacia mucilage and forcing through a screen .
  • the powder mixture can be slugged , i .e . , run through the tablet machine and the resulting imperfectly formed tablets broken into pieces (slugs) .
  • the slugs can be lubricated to prevent sticking to the tablet-forming dies by means of the addition of stearic acid , a stearic salt , talc or mineral oil. The lubricated mixture is then compressed into tablets .
  • the tablet can be provided with a protective coating consisting of a sealing coat or enteric coat of shellac , coating of sugar and methylcellulose and a polish coating of carnauba wax.
  • Fluid unit dosage forms for oral administration such as syrups , elixirs and suspensions can be prepared wherein each teaspoonful of composition contains a predetermined amount of active ingredient for administration.
  • the water-soluble forms can be dissolved in an aqueous vehicle together with sugar , flavoring agents and preservatives to form a syrup.
  • An elixir is prepared by using a hydroalcoholic vehicle with suitable sweeteners together with a flavoring agent.
  • Suspensions can be prepared of the insoluble forms with a suitable vehicle with the aid of a suspending agent such as acacia , tragacanth , methylcellulose and the like .
  • fluid unit dosage forms are prepared utilizing an active ingredient and a sterile vehicle , water being preferred.
  • the active ingredient depending on the form and concentration used , can be either suspended or dissolved in the vehicle.
  • the water-soluble active ingredient can be dissolved in water for injection and f ilter sterilized before f illing into a suitable vial or ampul e and seal ing .
  • adj uvants such as a local anesthetic , preservative and buffering agents can be dissolved in the vehicle .
  • Parenteral suspensions are prepared in substantially the same manner except that an active ingredient is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
  • the active ingredient can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active ingredient.
  • the active ingredients can also be admixed in animal feed.
  • the active ingredients can conveniently be prepared in the form of a food premix.
  • the food premix can comprise an active ingredient in admixture with an edible pharmaceutical diluent such as starch, oatmeal, flour, calcium carbonate, talc, dried fish meal and the like nontoxic, orally acceptable pharmaceutical diluents.
  • the prepared premix is then conveniently added to the regular feed.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predeterminedquantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical diluent, carrier or vehicle.
  • the specifications for the novel unit dosage forms of this invention are dictated by and are directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitation inherent in the art of compounding such an active material for therapeutic use in humans, as disclosed in this specification, these being features of the present invention.
  • suitable unit dosage forms in accord with this invention are tablets, capsules, troches, suppositories, powder packets, wafers, chachets, teaspoonfuls, tablespoonfuls, dropperfuls, ampules, vials, segregated multiples of any of the foregoing, and other forms as herein described.
  • Example I Hard-Gelatin Capsules One thousand two-piece gelatin capsules for oral use , each capsule containing 100 mg of 4-( 1-aziridyl)-6-phenyl-2-pyrimidinamine , are prepared from the following types and amounts of ingredients: 4-( 1-aziridyl )-6-phenyl-2-pyrimidinamine , 100 gm micronized
  • Magnesium stearate 2 gm The 4-( 1-aziridyl)-6-phenyl-2-pyrimidinamine , finely di vi ded by means of an air micronizer , is added to the other finely powdered ingredients , mixed thoroughly and then encapsulated in the usual manner .
  • the foregoing capsules are useful for treating lung cancer by the oral administration of one or two capsules one to four times a day . Using the procedure above , capsules are similarly prepared containing
  • Example II Soft Gelatin Capsules
  • One-piece soft gelatin capsules for oral use each containing 250 mg of 4-( 1-aziridyl )-6-phenyl-2-pyrimidinamine finely divided by means of an air raicronizer , are prepared by first suspending the compound in 0.5 ml of corn oil to render the material capsulatable and then capsulating in the above manner .
  • the foregoing capsules are useful for treating lung cancer by the oral administration of one or two capsules one to four times a day .
  • One thousand tablets each containing 500 mg of 4-( 1-aziridyl ) -6-phenyl-2-pyrimidinamine , are prepared from the following types and amounts of ingredients:
  • the foregoing tablets are useful for treating lung cancer by the oral administration of one or two tablets one to four times a day.
  • Lemon oil 2 gm Deionized water, q.s. 1,000 ml
  • citric acid, benzoic acid, sucrose, tragacanth and lemon oil are dispersed in sufficient water to make 850 ml of suspension.
  • the 4- (1-aziridyl)-6-phenyl-2-pyrimidinamine, finely divided by means of an air micronizer, is stirred into the syrup until uniformly distributed. Sufficient water is added to make 1,000 ml.
  • composition so prepared is useful for treating leukemia at a dose of one tablespoonful (15 ml) three times a day.
  • a sterile aqueous suspension for parenteral injection containing in one rag 300 mg of 4-(1-aziridyl)-6-phenyl-2-pyrimidinamine, is prepared from the following types and amounts of ingredients: 4-( 1-aziridyl )-6-phenyl-2-pyrimidinamine , micronized 300 gm
  • composition 30 prepared is useful for treating a denocarcinoma at a dose of one milliliter ( 1 M) three times a day.
  • Example VI Hard Gelatin Capsules One thousand two-piece hard gelatin capsules for oral use , each capsule containing 100 mg of 4-( 1-aziridyl)-6-phenyl-2-pyrimidinamine, are prepared from 100 gm of 4-( 1-aziridyl )-6-phenyl-2-pyrimidinamine .
  • the 4-( 1 -aziridyl)-6-phenyl-2-pyrimidinamine is f inely divided by means of an air micronizer and encapsulated in the usual manner .
  • capsules are useful for preventing or treating metastasis following mastectomy by the oral administration of one or two capsules one to four times a day. Using the procedure above , capsules are similarly prepared containing
  • the antibacterial spectrum of 4-( 1-azindinyl)-6-phenyl-2-pyrimidinamine was determined in an in vitro disk plate assay .
  • the assay procedure is as follows: A solution of 4- ( 1 -aziridinyl )-6 -phenyl-2-pyrimidinamine was prepared at 1 mg/ral in distilled water. Paper assay disks ( 1 /2 inch) were dripped into the solution and spotted on seeded agar trays . The zones were read after 18 hours incubation and are reported in Table III .
  • the NCI-designated criteria of significant activity for synthetic agents in these 3 systems are: for P388, 20% ILS; L1210 and B16, 25% ILS.
  • G Gray' s Medium ( Am. Type Culture Medium #855, AM. Type Culture

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention décrit la synthèse et l'utilisation antinéoplastique de composés 4-aziridyl-5-substitué/non substitué 6-aryl-pyrimidine de formule (IA) ainsi que des N'- AD2-(1-aziridyl)éthyl BD-6-aryl-2,4-pyrimidinediamines de formule (IB) et des 4-chloro ou bromo-5-substitué/non substitué-6-aryl-pyrimidines.
PCT/US1986/000074 1985-02-05 1986-01-23 Composes de 4-substitue-6-aryl-pyrimidine WO1986004583A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US69830985A 1985-02-05 1985-02-05
US698,309 1985-02-05

Publications (1)

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WO1986004583A1 true WO1986004583A1 (fr) 1986-08-14

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JP (1) JPS62501632A (fr)
WO (1) WO1986004583A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0233461A2 (fr) * 1986-01-13 1987-08-26 American Cyanamid Company 2-Pyrimidinamines substituées en 4,5 et 6
WO1997044326A1 (fr) * 1996-05-23 1997-11-27 F. Hoffmann-La Roche Ag Derives d'aryl pyrimidine
US5952331A (en) * 1996-05-23 1999-09-14 Syntex (Usa) Inc. Aryl pyrimidine derivatives
US5958934A (en) * 1996-05-23 1999-09-28 Syntex (U.S.A.) Inc. Aryl pyrimidine derivatives and uses thereof
WO2004020673A1 (fr) * 2002-08-28 2004-03-11 Millipore Corporation Composition de solution permettant de purifier un produit de reaction de sequençage
WO2007098835A1 (fr) * 2006-02-27 2007-09-07 Merck Patent Gmbh Dérivés de l'aminopyrymidine
CZ305457B6 (cs) * 2011-02-28 2015-09-30 Ústav organické chemie a biochemie, Akademie věd ČR v. v. i. Pyrimidinové sloučeniny inhibující tvorbu oxidu dusnatého a prostaglandinu E2, způsob výroby a použití
US9604937B2 (en) 2012-11-27 2017-03-28 Thomas Helledays Stiftelse For Medicinsk Forskning Pyrimidine-2,4-diamine derivatives for treatment of cancer
US10064869B2 (en) 2014-06-04 2018-09-04 Thomas Helledays Stiftelse For Medicinsk Forskning MTH1 inhibitors for treatment of inflammatory and autoimmune conditions
US10179790B2 (en) 2014-06-04 2019-01-15 Thomas Helledays Stiftelse For Medicinsk Forskning MTH1 inhibitors for treatment of cancer

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3412094A (en) * 1967-06-21 1968-11-19 Searle & Co 5-alkyl-2-amino-4-azido-6-phenylpyrimidines and congeners

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3412094A (en) * 1967-06-21 1968-11-19 Searle & Co 5-alkyl-2-amino-4-azido-6-phenylpyrimidines and congeners

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0233461A3 (en) * 1986-01-13 1988-05-25 American Cyanamid Company 4,5,6-substituted-2-pyrimidinamines
EP0233461A2 (fr) * 1986-01-13 1987-08-26 American Cyanamid Company 2-Pyrimidinamines substituées en 4,5 et 6
WO1997044326A1 (fr) * 1996-05-23 1997-11-27 F. Hoffmann-La Roche Ag Derives d'aryl pyrimidine
US5863924A (en) * 1996-05-23 1999-01-26 Syntex (U.S.A.) Inc. Aryl pyrimidine derivatives
US5952331A (en) * 1996-05-23 1999-09-14 Syntex (Usa) Inc. Aryl pyrimidine derivatives
US5958934A (en) * 1996-05-23 1999-09-28 Syntex (U.S.A.) Inc. Aryl pyrimidine derivatives and uses thereof
CN1109675C (zh) * 1996-05-23 2003-05-28 弗·哈夫曼-拉罗切有限公司 芳基嘧啶衍生物
US7759055B2 (en) 2002-08-28 2010-07-20 Millipore Corporation Compositions of solution for sequencing reaction clean-up
WO2004020673A1 (fr) * 2002-08-28 2004-03-11 Millipore Corporation Composition de solution permettant de purifier un produit de reaction de sequençage
WO2007098835A1 (fr) * 2006-02-27 2007-09-07 Merck Patent Gmbh Dérivés de l'aminopyrymidine
CZ305457B6 (cs) * 2011-02-28 2015-09-30 Ústav organické chemie a biochemie, Akademie věd ČR v. v. i. Pyrimidinové sloučeniny inhibující tvorbu oxidu dusnatého a prostaglandinu E2, způsob výroby a použití
US9604937B2 (en) 2012-11-27 2017-03-28 Thomas Helledays Stiftelse For Medicinsk Forskning Pyrimidine-2,4-diamine derivatives for treatment of cancer
US9944640B2 (en) 2012-11-27 2018-04-17 Thomas Helledays Stiftelse For Medicinsk Forskning Pyrimidine-2,4-diamine derivatives for treatment of cancer
US10174029B2 (en) 2012-11-27 2019-01-08 Thomas Helledays Stiftelse For Medicinsk Forskning Pyrimidine-2,4-diamine derivatives for treatment of cancer
US10064869B2 (en) 2014-06-04 2018-09-04 Thomas Helledays Stiftelse For Medicinsk Forskning MTH1 inhibitors for treatment of inflammatory and autoimmune conditions
US10179790B2 (en) 2014-06-04 2019-01-15 Thomas Helledays Stiftelse For Medicinsk Forskning MTH1 inhibitors for treatment of cancer
US10632125B2 (en) 2014-06-04 2020-04-28 Thomas Helledays Stiftelse For Medicinsk Forskning MTH1 inhibitors for treatment of inflammatory and autoimmune conditions

Also Published As

Publication number Publication date
JPS62501632A (ja) 1987-07-02
EP0210228A1 (fr) 1987-02-04

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