WO2010096619A1 - Procédé, purification et cristallisation de 1-(4-{[4-(diméthylamino)pipéridin-1-yl]carbonyl}phényl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phényl]urée - Google Patents

Procédé, purification et cristallisation de 1-(4-{[4-(diméthylamino)pipéridin-1-yl]carbonyl}phényl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phényl]urée Download PDF

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WO2010096619A1
WO2010096619A1 PCT/US2010/024672 US2010024672W WO2010096619A1 WO 2010096619 A1 WO2010096619 A1 WO 2010096619A1 US 2010024672 W US2010024672 W US 2010024672W WO 2010096619 A1 WO2010096619 A1 WO 2010096619A1
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alkyl
group
amino
aryl
carbonyl
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Gulnaz Khafizova
John Richard Potoski
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Wyeth Llc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • PROCESS PURIFICATION AND CRYSTALLIZATION OF 1-(4- ⁇ [4- (DIMETHYLAMINO)PIPERIDIN-I-YL]CARBONYL)PHENYL)-S-[ ⁇ e- DIMORPHOLIN-4-YL-1,3,5-TRIAZIN-2-YL)PHENYL]UREA
  • the invention relates to an improved process for the preparation of 1-(4-(4- (dimethylamino)piperidine-1-carbonyl)phenyl-3-(4-(4,6-dimorpholino-1 ,3,5-triazine-2- yl)phenyl) urea as a final product in the manufacture of biologically active mTOR and PI3K inhibitors.
  • R 6 , R 7 , R 8 , R 9 are each independently selected from the group consisting of a hydrogen atom, and a Ci-C 6 alkyl optionally substituted with C 2 -C 6 alkenyl, C 4 - C 6 alkadienyl, C 2 -C 6 alkynyl or C 4 -C 6 alkadiynyl; or R 6 and R 9 and/or R 7 and R 8 independently are attached by a (CH 2 ) y or (CH 2 -X-CH 2 ) linking group wherein one hydrogen atom in the linking group may be replaced by an OH; y is 2 or 3; X is O, S(O) n , or NR 10 ; n is O, 1 or 2;
  • R 10 is selected from the group consisting of H, d-C 6 alkyl-, (Ci-C 6 alkyl)SO 2 -, (Ci-C 6 alkoxy)carbonyl-, (Ci-C 6 alkyl)amido-, and R 11 NHSO 2 -;
  • R 11 is selected from the group consisting of H, d-C 6 alkyl-, d-C 6 heterocyclyl, C 6 -Ci 4 aryl, and d-Cgheteroaryl; or either R 6 and R 8 or R 7 and R 9 are attached by (CH 2 ) Z or (CH 2 -X-CH 2 ) linking group; z is 1 , 2 or 3; or one of R 6 and R 7 or R 8 and R 9 , together with the carbon atoms to which they are attached form an optionally substituted 5-8 membered saturated or unsaturated ring containing O, 1 or 2 atoms independently selected from O, N and S;
  • R 3 is NHR 5 ;
  • R 5 is C 6 -C 14 aryl or d-Cgheteroaryl wherein the C 6 -C 14 aryl or d-Cgheteroaryl is optionally substituted with 1 or 2 moieties selected from the group consisting of: O 2 N-, H 2 NSO 2 -, HOOC-, (C r C 6 alkoxy)carbonyl-, (Ci-C 6 alkyl)amido-, CIi(C 1 - C 6 alkyl)amino-, R a R b NC(O)-, and Q-Z-;
  • R 4 is selected from the group consisting of:
  • Ci-C ⁇ heterocyclyl with the proviso that 3 membered Cr C 6 heterocyclyl is saturated and attached to the triazine moiety through a nitrogen atom, and the 5 membered Ci-C 6 heterocyclyl is saturated;
  • Z is CH 2 , O, S(O) n or NR 10 wherein a and b are each independently -CH 2 -, O, S, or NR -> 1'0 ⁇ , and z is 1-3;
  • R 12 and R 13 are each independently selected from H, d-C 8 alkyl, C 3 - C 8 alkenyl, and C 3 -C 8 alkynyl, the Ci-C 8 alkyl, C 3 -C 8 alkenyl, and C 3 -C 8 alkynyl optionally substituted from the group selected from NR 11 R 11 and Ci-C 6 heterocyclyl, provided that an NR 11 R 11 is not directly bonded to a carbon atom that is double- or triple- bonded to another carbon atom; or R 12 and R 13 taken together with the nitrogen atom to which they are attached form a 3 to 8 membered ring system optionally substituted with d-C 6 alkyl, which ring system is saturated or unsaturated and has, in addition to said nitrogen atom, 0 to 2 heteroatom ring members selected from O, S(O) n and NR 10 ; such as those disclosed in US Patent Application 12
  • mTOR-related disorders and PI3K-related disorders including, disorders with which abnormal cell growth is associated.
  • abnormal cell growth disorders are restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation, angiogenesis, immunological disorders, pancreatitis, kidney disease, cancer, etc.
  • the 3- ⁇ 4-(4,6- dimorpholino-1 ,3,5-triazine-2-yl)phenyl ⁇ urea compounds possess excellent cancer cell growth inhibiting effects and are effective in treating cancers, preferably all types of solid cancers and malignant lymphomas, and especially, leukemia, skin cancer, bladder cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, brain tumor, etc.
  • the third chlorine atom in the triazine moiety was reacted with 4-aminoaryl boronic acid or 4- aminophenyl boronic acid pinacol ester in refluxing DME in the presence of catalytic amount of tetrakis(triphenylpnosphine)palladium(0)/aqueous Na 2 CO 3 .
  • the product was purified by SiO 2 column chromatography.
  • the aniline compound was further reacted with 4-carbomethoxy aniline and triphosgene to obtain the urea derivative.
  • ester group was subsequently hydrolyzed to carboxylic acid and coupled with N,N-dimethylpiperidin-4-amine in the presence of Hunig's base, HBTU (2-(1 H- benzotriazole-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) in a polar solvent such as NMP.
  • HBTU 2-(1 H- benzotriazole-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate
  • the synthesis described herein eliminates the need to use triphosgene to make the initial urea intermediate, eliminates the need to use the hard to remove solvent NMP, eliminates the need to purify the intermediates, shortens the reaction times, eliminates the use of expensive HBTU, and avoids the use of SiO 2 column chromatography for purification. This procedure also gives products of high yields with high purity (>99%) and crystals of one form.
  • the present invention provides a method of making compounds of formula
  • FIG. 1 is an X-ray powder diffraction (XRD) scan of the amorphous form of 1- (4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl-3-(4-(4,6-dimorpholino-1 ,3,5- triazine-2-yl)phenyl)urea.
  • XRD X-ray powder diffraction
  • FIG. 2 is an XRD scan of the crystalline form of 1-(4-(4- (dimethylamino)piperidine-1-carbonyl)phenyl-3-(4-(4,6-dimorpholino-1 ,3,5-triazine-2- yl)phenyl)urea.
  • the present invention provides a method of making compounds of formula VII:
  • R 6 , R 7 , R 8 , R 9 are each independently selected from the group consisting of a hydrogen atom, and a (VCealkyl optionally substituted with C 2 -C 6 alkenyl, C 4 - C 6 alkadienyl, C 2 -C 6 alkynyl or C 4 -C 6 alkadiynyl; or R 6 and R 9 and/or R 7 and R 8 independently are attached by a (CH 2 ) y or (CH 2 -X-CH 2 ) linking group wherein one hydrogen atom in the linking group may be replaced by an OH; y is 2 or 3;
  • X is O, S(O) n , or NR 10 ; n is O, 1 or 2;
  • R 10 is selected from the group consisting of H, d-C 6 alkyl-, (Ci-C 6 alkyl)SO 2 -, (Ci-C 6 alkoxy)carbonyl-, (Ci-C 6 alkyl)amido-, and R 11 NHSO 2 -;
  • R 11 is selected from the group consisting of H, d-C 6 alkyl-, d-C 6 heterocyclyl, C 6 -Ci 4 aryl, and d-Cgheteroaryl; or either R 6 and R 8 or R 7 and R 9 are attached by (CH 2 ) Z or (CH 2 -X-CH 2 ) linking group; z is 1 , 2 or 3; or one of R 6 and R 7 or R 8 and R 9 , together with the carbon atoms to which they are attached form an optionally substituted 5-8 membered saturated or unsaturated ring containing O, 1 or 2 atoms independently selected from O, N and S; wherein Ar 1 is C 6 -Ci 4 aryl or d-Cgheteroaryl; wherein any C 6 -d 4 aryl or C 1 - Cgheteroaryl is optionally substituted with 1 or 2 moieties selected from the group consisting of: a) d-C 6 alkyl- optionally substituted
  • R 3 is NHR 5 ;
  • R 5 is C 6 -C 14 aryl or d-Cgheteroaryl wherein the C 6 -C 14 aryl or d-Cgheteroaryl is optionally substituted with 1 or 2 moieties selected from the group consisting of: O 2 N-, H 2 NSO 2 -, HOOC-, (C r C 6 alkoxy)carbonyl-, (Ci-C 6 alkyl)amido-, CIi(C 1 - C 6 alkyl)amino-, R a R b NC(O)-, and Q-Z-;
  • R 4 is selected from the group consisting of:
  • Ci-C ⁇ heterocyclyl with the proviso that 3 membered Cr C 6 heterocyclyl is saturated and attached to the triazine moiety through a nitrogen atom, and the 5 membered Ci-C 6 heterocyclyl is saturated;
  • Z is CH 2 , O, S(O) n or NR 1 1 0
  • a and b are each in O, S, or NR , and z is 1-3;
  • R 12 and R 13 are each independently selected from H, d-C 8 alkyl, C 3 - C 8 alkenyl, and C 3 -C 8 alkynyl, the Ci-C 8 alkyl, C 3 -C 8 alkenyl, and C 3 -C 8 alkynyl optionally substituted from the group selected from NR 11 R 11 and Ci-C 6 heterocyclyl, provided that an NR 11 R 11 is not directly bonded to a carbon atom that is double- or triple- bonded to another carbon atom; or R 12 and R 13 taken together with the nitrogen atom to which they are attached form a 3 to 8 membered ring system optionally substituted with d-C 6 alkyl, which ring system is saturated or unsaturated and has, in addition to said nitrogen atom, 0 to 2 heteroatom ring members selected from O, S(O) n and NR 10 ; comprising reacting compound Vl:
  • the present invention provides a method of making compounds of formula VII further comprising, when R 5 is -C6-Ci 4 aryl-carbonyl(d- C 6 alkoxy) or -d-C 9 heteroaryl-carbonyl(d-dialkoxy), saponifing the ester of formula VIII:
  • the present invention provides a method of making compounds of formula VII further comprising condensing the acid of formula IX:
  • R 1 and/or R 4 are:
  • R 1 and/or R 4 are:
  • R 1 and/or R 4 are:
  • R 1 and/or R 4 are independently selected from the group consisting of:
  • -Ar 1 - is -C 6 -Ci 4 aryk
  • -Ar 1 - is -phenyl-.
  • R 5 is phenyl is substituted with C(O)NR a R b .
  • the saponification is done with an alkali metal hydroxide.
  • the alkali metal hydroxide is lithium hydroxide.
  • the amide formation is done with a carboxyl-activating agent.
  • the carboxyl activating agent is N, N'- carbonyldiimidazole or N-(3-dimethylaminopropyl)ethyl carbodiimide hydrochloride.
  • the compound made of formula VII has the structure:
  • the present invention provides the crystalline form of 1-(4- (4-(dimethylamino)piperidine-1-carbonyl)phenyl-3-(4-(4,6-dimorpholino-1 ,3,5-triazine- 2-yl)phenyl)urea.
  • the crystalline form has an X-ray diffraction pattern having one or more characteristic peaks expressed in degrees 2 ⁇ at 7.9, 9.2, 14.1 ,
  • the crystalline form has an X-ray diffraction pattern substantially the same as that shown in FIG. 2.
  • salts include but are not limited to, e.g., water-soluble and water-insoluble salts, such as the acetate, aluminum, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzathine (N 1 N'- dibenzylethylenediamine), benzenesulfonate, benzoate, bicarbonate, bismuth, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate (camphorsulfonate), carbonate, chloride, choline, citrate, clavulariate, diethanolamine, dihydrochloride, diphosphate, edetate, edisylate (camphorsulfonate), esylate (ethanesulfonate), ethylenediamine, fumarate, gluceptate (glucoheptonate), gluconate, glucuronate, glutamate, he
  • Polymorphism is the ability of any element or compound to crystallize in more than one distinct crystalline form. Physical properties including solubility, melting point, density, hardness, crystalline shape and stability can be quite different for different polymorphic forms of the same chemical compound.
  • Crystalline forms are characterized by scattering techniques, e.g., x-ray diffraction powder pattern, by spectroscopic methods, e.g., infra-red, 13 C nuclear magnetic resonance spectroscopy, and by thermal techniques, e.g., differential scanning calorimetry or differential thermal analysis.
  • the compound of this invention is best characterized by the X-ray powder diffraction pattern determined in accordance with procedures that are known in the art. For a discussion of these techniques see J. Haleblian, J. Pharm. Sci. 1975 64:1269-1288, and J. Haleblain and W. McCrone, J. Pharm. Sci. 1969 58:911-929.
  • Crystal forms of the invention can be further processed to modulate particle size.
  • the crystal forms of the invention can be milled to reduce average crystal size and/or to prepare a sample suitable for manipulation and formulation.
  • a diffraction angle (2 ⁇ ) in powder X-ray diffractometry may have an error in the range of ⁇ .0.2°. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ⁇ .0.2°. Accordingly, the present invention includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ⁇ .0.2°.
  • the phrase "having a diffraction peak at a diffraction angle (2 ⁇ ⁇ .0.2°) of 7.9°” means “having a diffraction peak at a diffraction angle (2 ⁇ ) of 7.7° to 8.1°.
  • the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peaks and the peak locations are characteristic for a specific polymorphic form. Alternatively, the term “about” means within an acceptable standard error of the mean, when considered by one of ordinary skill in the art.
  • the relative intensities of the XRD peaks can vary depending on the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed.
  • the term "substantially" in the context of XRD is meant to encompass that peak assignments can vary by plus or minus about 0.2. degree. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a Ni filter is used or not.
  • Some compounds within the present invention possess one or more chiral centers, and the present invention includes each separate enantiomer of such compounds as well as mixtures of the enantiomers. Where multiple chiral centers exist in compounds of the present invention, the invention includes each combination as well as mixtures thereof. All chiral, diastereomeric, and racemic forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Definitions
  • the number of carbon atoms present in a given group is designated “C x -C y ", where x and y are the lower and upper limits, respectively.
  • a group designated as “CrC 6 " contains from 1 to 6 carbon atoms.
  • the carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like.
  • Alkadienyl- refer to a straight or branched chain unsaturated hydrocarbon containing at least two double bonds.
  • Examples of a C 4 -C6alkadienyl- group include, but are not limited to, buta-1 ,3-dienyl, penta-1 ,3-dienyl, penta-1 ,4-dienyl, penta-2,4- dienyl, hexa-1 ,3-dienyl, hexa-1 ,4-dienyl, hexa-1 ,5-dienyl, hexa-2,4-dienyl, and hexa- 2,5-dienyl.
  • An alkadienyl- group can be unsubstituted or substituted with one or more of the following groups: halogen, H 2 N-, (Ci-C6alkyl)amino-, di(Ci-C6alkyl)amino- , (Ci-C 6 alkyl)C(O)N(Ci-C 3 alkyl)-, (C r C 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (Ci-C 6 alkyl)NHC(O)-, di(C r C 6 alkyl)NC(O)-, NC-, hydroxyl, Ci-C 6 alkoxy-, Ci-C 6 alkyl-, HO 2 C-, (Ci-C 6 alkoxy)carbonyl-, (C r C 6 alkyl)C(O)-, C 6 -Ci 4 aryl-, Ci-Cgheteroaryl-, and C 3
  • Alkadiynyl- refer to a straight or branched chain unsaturated hydrocarbon containing at least two triple bonds.
  • Examples of a C 4 -C 6 alkadiynyl- group include, but are not limited to, buta-1 ,3-diynyl, penta-1 ,3-diynyl, penta-1 ,4-diynyl, penta-2,4- diynyl, hexa-1 ,3-diynyl, hexa-1 ,4-diynyl, hexa-1 ,5-diynyl, hexa-2,4-diynyl, and hexa- 2,5-diynyl.
  • An alkadiynyl- group can be unsubstituted or substituted with one or more of the following groups: halogen, H 2 N-, (d-C 6 alkyl)amino-, di(Ci-C 6 alkyl)amino-, (d- C 6 alkyl)C(O)N(Ci-C 3 alkyl)-, (Ci-C 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (d- C 6 alkyl)NHC(O)-, di(C r C 6 alkyl)NC(O)-, NC-, hydroxyl, d-C 6 alkoxy-, d-C 6 alkyl-, HO 2 C-, (Ci-C 6 alkoxy)carbonyl-, (C r C 6 alkyl)C(O)-, C 6 -Ci 4 aryl-, Ci-Cgheteroaryl-, and C 3
  • Alkoxy- refers to the group R-O- where R is an alkyl group, as defined below.
  • exemplary d-C 6 alkoxy- groups include but are not limited to methoxy, ethoxy, n-propoxy, 1-propoxy, n-butoxy and t-butoxy.
  • An alkoxy group can be unsubstituted or substituted with one or more of the following groups: halogen, hydroxyl, d-C 6 alkoxy-, H 2 N-, (d-C 6 alkyl)amino-, di(d-C 6 alkyl)amino-, (d- C 6 alkyl)C(O)N(Ci-C 3 alkyl)-, (Ci-CealkyOcarboxyamido-, HC(O)NH-, H 2 NC(O)-, (d- C 6 alkyl)NHC(O)-, di(Ci-C 6 alkyl)NC(O)-, NC-, d-C 6 alkoxy-, HO 2 C-, (d- C 6 alkoxy)carbonyl-, (d-C 6 alkyl)C(O)-, C 6 -Ci 4 aryl-, Ci-Cgheteroaryl-, C 3 -C 8 cycloalkyl-,
  • (Alkoxy)carbonyl-" and “-carbonyl(alkoxy)” both refer to the group alkyl-O- C(O)-.
  • Exemplary (d-C 6 alkoxy)carbonyl- groups include but are not limited to methoxy, ethoxy, n-propoxy, 1-propoxy, n-butoxy and t-butoxy.
  • An (alkoxy )carbonyl group can be unsubstituted or substituted with one or more of the following groups: halogen, hydroxyl, H 2 N-, (d-C 6 alkyl)amino-, di(d-C 6 alkyl)amino-, (d- C 6 alkyl)C(O)N(Ci-C 3 alkyl)-, (Ci-C 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (d- C 6 alkyl)NHC(O)-, di(d-C 6 alkyl)NC(O)-, NC-, d-C 6 alkoxy-, HO 2 C-, (d- C 6 alkoxy)carbonyl-, (d-C 6 alkyl)C(O)-, C 6 -Ci 4 aryl-, Ci-Cgheteroaryl-, C 3 -C 8 cycloalkyl-, Ci-C 6
  • Alkenyl- refer to a straight or branched chain unsaturated hydrocarbon containing at least one double bond.
  • Examples of a C 2 -C6alkenyl- group include, but are not limited to, ethylene, propylene, 1-butylene, 2-butylene, isobutylene, sec- butylene, 1-pentene, 2-pentene, isopentene, 1-hexene, 2-hexene, 3-hexene, and isohexene.
  • An alkenyl- group can be unsubstituted or substituted with one or more of the following groups: halogen, H 2 N-, (d-C 6 alkyl)amino-, di(d-C 6 alkyl)amino-, (d- C 6 alkyl)C(O)N(C r C 3 alkyl)-, (d-C 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (C 1 - C 6 alkyl)NHC(O)-, di(C r C 6 alkyl)NC(O)-, NC-, hydroxyl, C r C 6 alkoxy-, C r C 6 alkyl-, HO 2 C-, (Ci-C 6 alkoxy)carbonyl-, (C r C 6 alkyl)C(O)-, C 6 -C 14 aryl-, C r C 9 heteroaryl-, and C 3 -C 8 cyclo
  • Alkyl- refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms, for example, a Cr C
  • alkyl is a chain (straight or branched) having 1 to 6 (inclusive) carbon atoms in it.
  • Ci-C 6 alkyl- groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert- butyl, isopentyl, neopentyl, and isohexyl.
  • An alkyl- group can be unsubstituted or substituted with one or more of the following groups: halogen, H 2 N-, (d- C 6 alkyl)amino-, di(C r C 6 alkyl)amino-, (Ci-C 6 alkyl)C(O)N(Ci-C 3 alkyl)-, (C r C 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (Ci-C 6 alkyl)NHC(O)-, CIi(C 1 - C 6 alkyl)NC(O)-, NC-, hydroxyl, C r C 6 alkoxy-, d-C 6 alkyl-, HO 2 C-, (d- C 6 alkoxy)carbonyl-, (d-C 6 alkyl)C(O)-, C 6 -Ci 4 aryl-, d-Cgheteroaryl-, C 3 -C
  • (Alkyl)amido- refers to a -C(O)NH- group in which the nitrogen atom of said group is attached to a d-C 6 alkyl group, as defined above.
  • Representative examples of a (d-C 6 alkyl)amido- group include, but are not limited to, -C(O)NHCH 3 , - C(O)NHCH 2 CH 3 , -C(O)NHCH 2 CH 2 CH 3 , -C(O)NHCH 2 CH 2 CH 2 CH 3 , -C(O)NHCH 2 CH 2 CH 2 CH 3 ,
  • (Alkyl)amino- refers to an -NH group, the nitrogen atom of said group being attached to an alkyl group, as defined above.
  • Representative examples of an (Ci- C6alkyl)amino- group include, but are not limited to CH 3 NH-, CH 3 CH 2 NH-, CH 3 CH 2 CH 2 NH-, CH 3 CH 2 CH 2 CH 2 NH-, (CH 3 ) 2 CHNH-, (CH 3 ) 2 CHCH 2 NH-, CH 3 CH 2 CH(CH 3 )NH- and (CH 3 ) 3 CNH-.
  • An (alkyl)amino group can be unsubstituted or substituted with one or more of the following groups: halogen, H 2 N-, (d- C 6 alkyl)amino-, di(d-C 6 alkyl)amino-, (d-C 6 alkyl)C(O)N(d-C 3 alkyl)-, (C r C 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (d-C 6 alkyl)NHC(O)-, di(d- C 6 alkyl)NC(O)-, NC-, hydroxyl, d-C 6 alkoxy-, d-C 6 alkyl-, HO 2 C-, (d- C 6 alkoxy)carbonyl-, (d-C 6 alkyl)C(O)-, C 6 -d 4 aryl-, d-Cgheteroaryl-, C 3 -C 8 cycloal
  • Alkynyl- refers to a straight or branched chain unsaturated hydrocarbon containing at least one triple bond.
  • Examples of a C 2 -C 6 alkynyl- group include, but are not limited to, acetylene, propyne, 1-butyne, 2-butyne, isobutyne, sec-butyne, 1- pentyne, 2-pentyne, isopentyne, 1-hexyne, 2-hexyne, 3-hexyne, and isohexyne.
  • An alkynyl group can be unsubstituted or substituted with one or more of the following groups: halogen, H 2 N-, (d-C 6 alkyl)amino-, di(Ci-C 6 alkyl)amino-, (d- C 6 alkyl)C(O)N(Ci-C 3 alkyl)-, (d-C 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (d- C 6 alkyl)NHC(O)-, di(d-C 6 alkyl)NC(O)-, NC-, hydroxyl, d-C 6 alkoxy-, d-C 6 alkyl-, HO 2 C-, (Ci-C 6 alkoxy)carbonyl-, (C r C 6 alkyl)C(O)-, C 6 -Ci 4 aryl-, Ci-Cgheteroaryl-, and C 3 -C 8 cyclo
  • amorphous form denotes a material that lacks long-range order and as such does not show sharp X-ray peaks.
  • the XRD pattern of an amorphous material is characterized by one or more amorphous halos.
  • Aryl- refers to an aromatic hydrocarbon group.
  • Examples of a C ⁇ -C- H aryl- group include, but are not limited to, phenyl, 1-naphthyl, 2-naphthyl, 3-biphen-1-yl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenaphthenyl.
  • An aryl group can be unsubstituted or substituted with one or more of the following groups: d-C 6 alkyl-, halogen, haloalkyl-, hydroxyl, hydroxyl(d-C 6 alkyl)-, H 2 N-, amino(d-C 6 alkyl)-, di(d-C 6 alkyl)amino-, HO 2 C-, (C 1 -C 6 alkoxy)carbonyl-, (C 1 - C 6 alkyl)carboxyl-, di(C r C 6 alkyl)amido-, H 2 NC(O)-, (d-C 6 alkyl)amido-, or O 2 N-.
  • (Aryl)alkyl- refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been replaced with an aryl group as defined above.
  • Examples of (C6-C10aryl) alkyl- moieties include benzyl, benzhydryl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-naphthylmethyl, 2- naphthylmethyl and the like.
  • An (aryl)alkyl group can be unsubstituted or substituted with one or more of the following groups: halogen, H 2 N-, hydroxyl, (d-C 6 alkyl)amino- , di(Ci-C 6 alkyl)amino-, (d-C 6 alkyl)C(O)N(Ci-C 3 alkyl)-, (Ci-CealkyOcarboxyamido-, HC(O)NH-, H 2 NC(O)-, (C r C 6 alkyl)N HC(O)-, di(d-C 6 alkyl)NC(O)-, NC-, hydroxyl, d- C 6 alkoxy-, d-C 6 alkyl-, HO 2 C-, (d-C 6 alkoxy)carbonyl-, (d-C 6 alkyl)C(O)-, C 6 -d 4 aryl-, d-Cgheteroaryl-, C 3
  • Carboxyl-activating agent refers to a compound, molecule, or substance, capable of activating carboxylic acids with respect to nucleophilic attack.
  • the carboxyl-activating agents are capable of activating carboxylic acids where the attacking nucleophile is an amine or alcohol, resulting in amide or ester formation.
  • Non-limiting examples of such carboxyl-activating agents include carbodiimide compounds (e.g. N,N'-dicyclohexylcarbodiimide (DCC), N, N'- diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC HCI), and the like).
  • Carbodiimide compounds may be either used alone or in combination with HOAt, HOBt, or HODhbt.
  • carboxyl-activating agents include alkyl chloroformate compounds (e.g. ethyl chloroformate, isobutyl chloroformate, and the like) that are generally used with a tertiary amine like triethyl amine, diethyl azodicarboxylate (DEAD) with triphenylphosphine (the Mitsunobu reaction), various chlorosilanes, chlorosulfonyl isocyanate, N,N'-carbonyldiimidazole (CDI), phosphonium reagents (e.g.
  • mixed carbon anhydrides e.g. EEDQ, NDQ, and the like
  • CIP CIP
  • BOP-CI BOP-CI
  • crystalline form means crystal structures in which a compound can crystallize in different crystal packing arrangements, all of which have the same molecular composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal shape, optical properties, electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate.
  • Cycloalkyl- refers to a monocyclic, non-aromatic, saturated hydrocarbon ring.
  • Representative examples of a C 3 -C 8 cycloalkyl- include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • a cycloalkyl can be unsubstituted or independently substituted with one or more of the following groups: halogen, H 2 N-, (d-C 6 alkyl)amino-, di(Ci-C 6 alkyl)amino-, (d- C 6 alkyl)C(O)N(Ci-C 3 alkyl)-, (d-C 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (d- C 6 alkyl)NHC(O)-, di(d-C 6 alkyl)NC(O)-, NC-, hydroxyl, d-C 6 alkoxy-, d-C 6 alkyl-, HO 2 C-, (Ci-C 6 alkoxy)carbonyl-, (C r C 6 alkyl)C(O)-, C 6 -Ci 4 aryl-, Ci-Cgheteroaryl-, or C 3 -C 8 cycl
  • "Di(alkyl)amino-" refers to a nitrogen atom attached to two alkyl groups, as defined above. Each alkyl group can be independently selected.
  • di(Ci-C 6 alkyl)amino- group examples include, but are not limited to, -N(CH 3 ) 2 , - N(CH 2 CH 3 )(CH 3 ), -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 2 CHs) 2 , -N(CH 2 CH 2 CH 2 CHs) 2 , - N(CH(CH 3 ) 2 ) 2 , -N(CH(CHS) 2 )(CH 3 ), -N(CH 2 CH(CH 3 ) 2 ) 2 , -NH(CH(CH 3 )CH 2 CH 3 ) 2 , - N(C(CH 3 )s) 2 , -N(C(CH 3 )s)(CH 3 ), and -N(CH 3 )(CH 2 CH 3 ).
  • the two alkyl groups on the nitrogen atom when taken together with the nitrogen to which they are attached, can form a 3- to 7- membered nitrogen containing heterocycle wherein up to two of the carbon atoms of the heterocycle can be replaced with -N(H)-, -N(d-C 6 alkyl)-, -N(C 3 - C ⁇ cycloalkyl)-, -N(C 6 -Ci 4 aryl)-, -N(Ci-C 9 heteroaryl)-, -N(amino(C r C 6 alkyl))-, -N(C 6 - Ci 4 arylamino)-, -O-, -S-, -S(O)-, or -S(O) 2 -.
  • Halo or halogen refers to fluorine, chlorine, bromine, or iodine.
  • ⁇ eteroaryl- refers to 5-10-membered mono and bicyclic aromatic groups containing at least one heteroatom, e.g. 1-4 heteroatoms, selected from oxygen, sulfur and nitrogen.
  • monocyclic d-Cgheteroaryl- radicals include, but are not limited to, oxazinyl, thiazinyl, diazinyl, triazinyl, thiadiazoyl, tetrazinyl, imidazolyl, tetrazolyl, isoxazolyl, furanyl, furazanyl, oxazolyl, thiazolyl, thiophenyl, pyrazolyl, triazolyl, pyrimidinyl, N-pyridyl, 2-pyridyl, 3-pyridyl and 4-pyridyl.
  • bicyclic d-Cgheteroaryl- radicals include but are not limited to, benzimidazolyl, indolyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indazolyl, quinolinyl, quinazolinyl, purinyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzodiazolyl, benzotriazolyl, isoindolyl, and indazolyl.
  • the contemplated heteroaryl- rings or ring systems have a minimum of 5 members.
  • C-iheteroaryl- radicals would include but are not limited to tetrazolyl
  • C 2 heteroaryl- radicals include but are not limited to triazolyl, thiadiazoyl, and tetrazinyl
  • Cgheteroaryl- radicals include but are not limited to quinolinyl and isoquinolinyl.
  • a heteroaryl group can be unsubstituted or substituted with one or more of the following groups: CrC ⁇ alkyl-, halogen, d-C 6 haloalkyl-, hydroxyl, Ci-C 6 hydroxylalkyl-, H 2 N-, amino(Ci-C 6 alkyl), di(Ci-C 6 alkyl)amino-, -COOH, (C r C 6 alkoxy)carbonyl-, (d-C 6 alkyl)carboxyl-, di(d- C 6 alkyl)amido-, H 2 NC(O)-, (d-C 6 alkyl)amido-, or O 2 N-.
  • (Heteroaryl)alkyl- refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been replaced with a heteroaryl- group as defined above.
  • Examples of (Ci-Cgheteroaryl)alkyl- moieties include 2- pyridylmethyl, 2-thiophenylethyl, 3-pyridylpropyl, 2-quinolinylmethyl, 2-indolylmethyl, and the like.
  • a (heteroaryl)alkyl group can be unsubstituted or substituted with one or more of the following groups: halogen, H 2 N-, hydroxyl, (d-C 6 alkyl)amino-, CIi(C 1 - C 6 alkyl)amino-, (C 1 -C 6 alkyl)C(O)N(C 1 -C 3 alkyl)-, (Ci-C 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (C r C 6 alkyl)N HC(O)-, di(d-C 6 alkyl)NC(O)-, NC-, hydroxyl, C 1 - C 6 alkoxy-, C r C 6 alkyl-, HO 2 C-, (C r C 6 alkoxy)carbonyl-, (d-C 6 alkyl)C(O)-, C 6 -Ci 4 aryl-, d-
  • ⁇ eterocycle or “heterocyclyl-” refers to 3-10-membered monocyclic, fused bicyclic, and bridged bicyclic groups containing at least one heteroatom, e.g. 1 to 4 heteroatoms, selected from oxygen, sulfur and nitrogen.
  • a heterocycle may be saturated or partially saturated.
  • Exemplary d-Cgheterocyclyl- groups include but are not limited to aziridine, oxirane, oxirene, thiirane, pyrroline, pyrrolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dithiolane, piperidine, 1 ,2,3,6-tetrahydropyridine-1-yl, tetrahydropyran, pyran, thiane, thiine, piperazine, oxazine, 5,6-dihydro-4H-1 ,3-oxazine, azetidine, 1 ,4-dioxane, hexahydroazepine, piperazine, morpholine, thiomorpholine, dihydrobenzimidazole, dihydrobenzofurane, dihydrobenzothiene, dihydrobenzoxazole, dihydroimidazole,
  • C 1 heterocyclyl- radicals would include but are not limited to oxaziranyl, diaziridinyl, and diazirinyl
  • C 2 heterocyclyl- radicals include but are not limited to aziridinyl, oxiranyl, and diazetidinyl
  • C 6 heterocyclyl- radicals include but are not limited to azepanyl, 3-azabicyclo[3.2.0]heptanyl, and 3-azabicyclo[3.1.0]hexanyl
  • Cgheterocyclyl- radicals include but are not limited to azecanyl, tetrahydroquinolinyl, and perhydroisoquinolinyl.
  • ⁇ eterocyclyl(alkyl)- refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been replaced with a heterocycle group as defined above.
  • heterocyclyl(Ci-C 6 alkyl)- moieties include 1- piperazinylethyl, 4-morpholinylpropyl, 6-piperazinylhexyl, and the like.
  • a heterocyclyl(alkyl) group can be unsubstituted or substituted with one or more of the following groups: halogen, H 2 N-, (d-C 6 alkyl)amino-, di(Ci-C 6 alkyl)amino-, (d- C 6 alkyl)C(O)N(Ci-C 3 alkyl)-, (Ci-C 6 alkyl)carboxyamido-, HC(O)NH-, H 2 NC(O)-, (d- C 6 alkyl)NHC(O)-, di(C r C 6 alkyl)NC(O)-, NC-, hydroxyl, C r C 6 alkoxy-, C r C 6 alkyl-, HO 2 C-, (Ci-C 6 alkoxy)carbonyl-, (d-C 6 alkyl)C(O)-, 4- to 7-membered monocyclic heterocycle, C 6 -Ci 4 aryl-, d-
  • substituent groups independently include hydroxyl, nitro, amino, imino, cyano, halo, thio, sulfonyl, aminocarbonyl, carbonylamino, carbonyl, oxo, guanidine, carboxyl, formyl, d-C 6 alkyl, perfluoroalkyl, alkyamino, dialkylamino, C 1 -C 6 BIkOXy, alkoxyalkyl, alkylcarbonyl, arylcarbonyl, alkylthio, C 6 -Ci 4 aryl, C 4 -C 9 heteroaryl, a heterocyclic ring, cycloalkyl, hydroxyalkyl, carboxyalkyl, halo
  • Substituent groups that have one or more available hydrogen atoms can in turn optionally bear further independently selected substituents, to a maximum of three levels of substitutions.
  • the term "optionally substituted d-C 6 alkyl” is intended to mean an d-C 6 alkyl group that can optionally have up to four of its hydrogen atoms replaced with substituent groups as defined above (i.e., a first level of substitution), wherein each of the substituent groups attached to the d-C 6 alkyl group can optionally have up to four of its hydrogen atoms replaced by substituent groups as defined above (i.e., a second level of substitution), and each of the substituent groups of the second level of substitution can optionally have up to four of its hydrogen atoms replaced by substituent groups as defined above (i.e., a third level of substitution).
  • impermissible substitution patterns e.g., methyl substituted with 5 fluoro groups.
  • impermissible substitution patterns are well known to the skilled artisan.
  • Scheme 1 outlines the synthesis of 1-(4-(4-(dimethylamino)piperidine-1- carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1 ,3,5-triazin-2-yl)phenyl)urea (9).
  • Scheme 2 outlines the synthesis of 1-(4-(4-(dimethylamino)piperidine-1- carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1 ,3,5-triazin-2-yl)phenyl)urea (9).
  • R 5 is (C 1 -C 6 alkoxy)carbonyl-C 6 -C 14 aryl- or (C 1 -C 6 alkoxy)carbonyl-C 1 -C 9 heteroaryl-
  • Scheme 2 outlines a synthesis of X, using a carboxyl-activating agent to effect condensation of acid IX with amine R a R b NH.
  • DIPEA or Hunig's Base is diisopropylethylamine
  • DME is 1 ,2- dimethoxyethane
  • HPLC high-pressure liquid chromatography
  • KF Karl Fischer a method used for water determination
  • LSI refers to largest single impurity
  • MeOH is methanol
  • MS mass spectrometry
  • mTOR is Mammalian Target of Rapamycin (a protein)
  • NMP is N-methylpyrrolidinone or 1-methyl-2-pyrrolidinone.
  • PI3K is phosphoinositide 3-kinase (an enzyme)
  • TFA is trifluoroacetic acid
  • THF is tetrahydrofuran.
  • Methyl 4-(3-(4-(4,6-dimorpholino-1 ,3,5- triazine-2-yl)ureido)benzoate was obtained as beige solids in 90 % yield (66 g, 0.12 mol); HPLC: 97 % product and 3 % of 4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl) aniline.

Abstract

L'invention porte sur un procédé de fabrication de composés de formule VII (voir formule), ou sur un sel pharmaceutiquement acceptable de ces composés, les variables des constituants étant telles que définies présentement.
PCT/US2010/024672 2009-02-23 2010-02-19 Procédé, purification et cristallisation de 1-(4-{[4-(diméthylamino)pipéridin-1-yl]carbonyl}phényl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phényl]urée WO2010096619A1 (fr)

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WO2013041652A1 (fr) 2011-09-21 2013-03-28 Cellzome Limited Urée substituée par un groupe morpholino ou dérivés carbamate comme inhibiteurs de mtor
WO2013050508A1 (fr) 2011-10-07 2013-04-11 Cellzome Limited Dérivés urée ou carbamate de pyrimidine bicyclique à substitution morpholino en tant qu'inhibiteurs de mtor
WO2016097949A1 (fr) 2014-12-17 2016-06-23 Pfizer Inc. Formulations d'un inhibiteur de pi3k/mtor pour administration intraveineuse
WO2019038657A1 (fr) 2017-08-25 2019-02-28 Pfizer Inc. Formulation pharmaceutique aqueuse comprenant de la 1-(4-{[4-(diméthylamino)pipéridin-1-yl]carbonyl}phényl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phényl]urée
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EP4126839A4 (fr) * 2020-03-27 2024-04-17 Dong A St Co Ltd Dérivés d'aminopyrimidine et leur utilisation en tant que modulateurs du récepteur d'hydrocarbure aryle

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102250065A (zh) * 2011-05-20 2011-11-23 浙江海正药业股份有限公司 取代的三嗪苯脲衍生物及其用途
WO2012159557A1 (fr) * 2011-05-20 2012-11-29 浙江海正药业股份有限公司 Dérivé substitué de triazine phénylurée et son utilisation contre des tumeurs
WO2013041652A1 (fr) 2011-09-21 2013-03-28 Cellzome Limited Urée substituée par un groupe morpholino ou dérivés carbamate comme inhibiteurs de mtor
WO2013050508A1 (fr) 2011-10-07 2013-04-11 Cellzome Limited Dérivés urée ou carbamate de pyrimidine bicyclique à substitution morpholino en tant qu'inhibiteurs de mtor
WO2016097949A1 (fr) 2014-12-17 2016-06-23 Pfizer Inc. Formulations d'un inhibiteur de pi3k/mtor pour administration intraveineuse
US10172942B2 (en) 2014-12-17 2019-01-08 Pfizer Inc. Formulations of a PI3K/mTor-inhibitor for intravenous administration
US10660959B2 (en) 2014-12-17 2020-05-26 Pfizer Inc. Formulations of a PI3K/mTOR-inhibitor for intravenous administration
WO2019038657A1 (fr) 2017-08-25 2019-02-28 Pfizer Inc. Formulation pharmaceutique aqueuse comprenant de la 1-(4-{[4-(diméthylamino)pipéridin-1-yl]carbonyl}phényl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phényl]urée
US11541058B2 (en) 2017-08-25 2023-01-03 Pfizer Inc. Pharmaceutical aqueous formulation comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea
WO2019234632A1 (fr) 2018-06-07 2019-12-12 Pfizer Inc. Formulation aqueuse comprenant de la 1-(4-{[4-(diméthylamino)pipéridin-1-yl]carbonyl}phényl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phényl]urée
EP4249069A2 (fr) 2018-06-07 2023-09-27 Pfizer Inc. Formulation aqueuse comprenant de la 1-(4-{[4-(diméthylamino)pipéridin-1-yl]carbonyl}phényl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phényl]urée
EP4126839A4 (fr) * 2020-03-27 2024-04-17 Dong A St Co Ltd Dérivés d'aminopyrimidine et leur utilisation en tant que modulateurs du récepteur d'hydrocarbure aryle

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