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WO1999035140A1 - AMINES DE PYRIDINYLPYRIMIDINE AGISSANT COMME INHIBITEURS DE LA SYNTHESE DE L'IMMUNOGLOBULINE E (IgE) - Google Patents

AMINES DE PYRIDINYLPYRIMIDINE AGISSANT COMME INHIBITEURS DE LA SYNTHESE DE L'IMMUNOGLOBULINE E (IgE) Download PDF

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Publication number
WO1999035140A1
WO1999035140A1 PCT/EP1999/000060 EP9900060W WO9935140A1 WO 1999035140 A1 WO1999035140 A1 WO 1999035140A1 EP 9900060 W EP9900060 W EP 9900060W WO 9935140 A1 WO9935140 A1 WO 9935140A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
halogen
salt form
free form
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/EP1999/000060
Other languages
English (en)
Inventor
Volker Brinkmann
Peter Ettmayer
Christoph Heusser
Max WOISETSCHLÄGER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis Pharma GmbH Austria
Novartis AG
Original Assignee
Novartis Erfindungen Verwaltungs GmbH
Novartis AG
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
Priority claimed from GBGB9800522.6A external-priority patent/GB9800522D0/en
Priority claimed from GBGB9800520.0A external-priority patent/GB9800520D0/en
Application filed by Novartis Erfindungen Verwaltungs GmbH, Novartis AG filed Critical Novartis Erfindungen Verwaltungs GmbH
Priority to AU25161/99A priority Critical patent/AU2516199A/en
Publication of WO1999035140A1 publication Critical patent/WO1999035140A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention relates to pyridinylpyrimidine amines.
  • R is halogen, phenyl or alkyl
  • R 2 is hydrogen, halogen, alkyl, alkoxy or trifluoromethyl, in free form or salt form.
  • a compound of formula I may be present in free form as base or, where such forms exist, in salt form, particularly acid addition salt form.
  • a compound of formula I in free form may be converted into a salt form in conventional manner and vice- versa.
  • Halogen preferably is of atomic number 17 or 35, especially chlorine.
  • Phenyl preferably is unsubstituted or substituted by halogen, alkyl or alkoxy. When it is substituted, it preferably is mono- or disubstituted, preferably monosubstituted. Phenyl preferably is unsubstituted.
  • Alkyl and alkoxy preferably independently are of 1 to 4 carbon atoms, they especially are of 1 or 2, even more preferably of 1 carbon atom.
  • Ri and R 2 preferably are, independently, halogen, preferably chlorine, or alkyl, preferably methyl; more preferably, either Ri and R 2 are both independently halogen, preferably chlorine, or Ri and R 2 are both independently alkyl, preferably methyl.
  • Ri is chlorine, unsubstituted phenyl or alkyl of 1 or 2 carbon atoms
  • R 2 is hydrogen, chlorine, methyl, methoxy or trifluoromethyl, in free form or salt form.
  • Ri ' is halogen
  • R 2 ' is halogen, lower alkyl or trifluoromethyl, their preparation and their use as protein kinase inhibitors in the treatment of, in particular, tumor diseases and further conditions wherein protein kinases are involved, are described in
  • Ri' is halogen and R ' is halogen or lower alkyl.
  • Immunoglobulin E is critically involved in the pathogenesis and maintenance of allergic diseases such as atopic dermatitis, allergic asthma, allergic conjunctivitis and allergic rhinitis.
  • patients suffering from atopic dermatitis are mainly treated with local or systemic glucocorticoids, ultraviolet light or, in severe cases, with immunosuppressants such as cyclosporin.
  • Allergic asthma patients are mainly treated with glucocorticoids or theophylline. These compounds suffer from various side effects and are not achieving the goal of reversal of disease progression in addition to alleviation of symptoms.
  • FACS fluorescence-activated cell sorting
  • HaCat cell line originating from human adult skin keratinocytes propagated under low calcium conditions and elevated temperature
  • IgE immunoglobulin E
  • IL-4 interleukin-4
  • SRBC sheep red blood cells
  • TNF- ⁇ tumor necrosis factor - ⁇
  • TPA O-tetradecanoylphorbol 13-acetate
  • Isotype specificity Inhibition of immunoglobulin synthesis induced in primary human B-lymphocytes stimulated by IL-4 with added anti-CD40 antibody:
  • Normal human B-lymphocytes are purified from tonsils by removing contaminating T-cells with SRBC-rosetting according to M.S. Weiner et al., Blood 42 (1973) 939.
  • the resulting B-cells are more than 95 % pure as judged by CD 19 expression in a FACS analysis.
  • Using 96- well round-bottomed microtiter plates (Costar) 5xl0 4 B-cells are set up in a final volume of 200 ⁇ l/well in IMDM.
  • the cells After pre-incubation with test compound for one hour the cells are cultured to induce IgE production for 9 days at 37°C in air supplied with 5 % CO 2 in the presence of 50 ng/ml of IL-4 and 500 ng/ml of anti-CD40 antibody.
  • the culture cell supernatants are collected and quantitated for IgE, IgG 1 and IgM by standard isotype specific sandwich ELISA.
  • the compounds of formula I in free form or salt form inhibit IgE production preferentially over IgG (IgGl) and IgM with 50 % inhibitory concentrations (IC 50 .values) of from about 0.5 nM to about 200 nM.
  • HMEC- 1 cells are incubated with increasing amounts of test compound overnight and subsequently stimulated with TNF- ⁇ for 16 hours to induce VCAM-1 expression. After fixation, VCAM- 1 positivity is quantitated using an immunohistochemical method. To evaluate anti-proliferative effects of test substances cell numbers are counted by Giemsa dye staining. b) HaCat cells are incubated for 3 days with increasing concentrations of test substance. Cell proliferation is measured using a sulforhodamine B - based colorimetric assay.
  • IL-2, IL-3, IL-4, IL-5, IL-10 and IFN- ⁇ are quantitated in the supernatants by ELISA.
  • Monocyte-derived dendritic cells are co-cultivated with superantigen- or specific allergen- stimulated autologous or allogeneic T-cells for 4 days with increasing concentrations of test compound. The stimulation of T-cell proliferation by antigen-presenting dendritic cells is determined by pulsing with 3 H-thymidine for the last 16 hours.
  • the compounds of formula I in free form or salt form inhibit constitutive proliferation of the above endothelial keratinocyte and T-lymphocyte cell lines with IC 50 values of from about 400 nM to more than 5000 nM, well above the concentrations needed to block IgE synthesis.
  • the compounds of formula I in free form or pharmaceutically acceptable salt form are therefore indicated for use as inhibitors of immunoglobulin synthesis, especially inhibitors of IgE synthesis, in the treatment of IgE-mediated diseases, particularly IgE-mediated allergic diseases, such as atopic dermatitis, particularly in children, urticaria, particularly acute urticaria, allergic asthma, allergic rhinitis, food allergies, allergic conjunctivitis, hayfever, bullous pemphigoid, industrial sensitization and chronic rejection of transplants.
  • IgE-mediated diseases particularly IgE-mediated allergic diseases, such as atopic dermatitis, particularly in children, urticaria, particularly acute urticaria, allergic asthma, allergic rhinitis, food allergies, allergic conjunctivitis, hayfever, bullous pemphigoid, industrial sensitization and chronic rejection of transplants.
  • the dosage to be used will vary, of course, depending e.g. on the particular compound employed, the mode of administration and the treatment desired. However, in general satisfactory results are obtained when the compounds are administered at a daily dosage of from about 1 mg/kg to about 30 mg/kg animal body weight, suitably given in divided doses two to four times daily. For most larger mammals the total daily dosage is from about 70 mg to about 2000 mg, conveniently administered, for example, in divided doses up to four times a day or in retard form.
  • Unit dosage forms comprise, for example, from about 17.5 mg to about 1000 mg of compound in admixture with at least one solid or liquid pharmaceutically acceptable carrier or diluent.
  • a compound of formula I in free form or pharmaceutically acceptable salt form may be administered in similar manner to known standards such as glucocorticoids and antihistaminics for use in such indications. It may be admixed with conventional chemotherapeutically acceptable carriers and diluents and, optionally, further excipients, and administered e.g. orally in such forms as tablets and capsules.
  • compositions may be administered topically in such conventional forms as aerosols, ointments or creams, parenterally or intravenously.
  • concentration of active substance will, of course vary depending e.g. on the compound employed, the treatment desired and the nature of the form. In general, however, satisfactory results are obtained in topical application forms at concentrations of from about 0.05 % to about 5 %, particularly from about 0.1 % to about 1 % by weight.
  • the invention thus comprises the use of a compound of formula I in free form or salt form in the preparation of a medicament for the therapy of IgE-mediated diseases.
  • compositions for use in the therapy of IgE-mediated diseases may be prepared by mixing a compound of formula I in free form or pharmaceutically acceptable salt form together with at least one pharmaceutically acceptable carrier or diluent.
  • the invention further includes a method of treatment of IgE-mediated diseases which comprises administering a therapeutically effective amount of a compound of formula I in free form or pharmaceutically acceptable salt form to a subject in need of such treatment.
  • a subject in need of such treatment may e.g. be a patient not suffering from, or not treated for, a tumor disease or further condition where protein kinases are involved, or not otherwise undergoing treatment for elevation of depressed immune responses associated with therapy.
  • the most preferred compounds of formula I in these indications are: a) N-(3-chlorophenyl)-N-[4-(2-chloropyridin-4-yI)pyrimidin-2-yl]amine (Compound A; of formula la; Example 1 in WO 95/9851); and b) N-(3-methylphenyl)-N-[4-(2-methylpyridin-4-yl)pyrimidin-2-yl]amine (Compound B; of formula lb hereunder; see Example 2).
  • the IC 50 in the above assay 1. is from about 0.5 nM to about 10 nM.
  • the following activity has for example be determined in the above assay 1.:
  • RJ is halogen of atomic number 17 or 35
  • R 2 " is hydrogen or alkoxy, or Ri " is phenyl or alkyl and
  • R 2 " is hydrogen, halogen, alkyl, alkoxy or trifluoromethyl, in free form or salt form.
  • the invention thus also concerns a compound of formula lb in free form or salt form.
  • R preferably is halogen of atomic number 17 or 35 or alkyl, preferably chlorine or methyl, especially methyl.
  • R 2 " preferably is halogen or alkyl, preferably halogen of atomic number 17 or 35, especially chlorine, or methyl; it especially is methyl. Even more preferably, R," and R 2 " are both methyl.
  • a preferred subgroup of compounds of formula lb is the compounds of formula lb wherein either R,” is chlorine and
  • R " is hydrogen or methoxy
  • Ri " is phenyl, methyl or ethyl
  • R " is hydrogen, chlorine, methyl, methoxy or trifluoromethyl, in free form or salt form.
  • R 2 " is other than hydrogen.
  • the remarkable cell type specificity of the compounds of formula lb is apparent e.g. from a collection of the IC 50 values obtained with the preferred compound of formula la and with the preferred compound of formula lb for inhibition of cell proliferation in various cell types and assays, and their comparison with the IC 50 values obtained for inhibition of IgE synthesis in human B-lymphocytes, as appears from the following Table: Comparison of
  • HMEC-2 cells (constitutive) 6350 2450
  • the compounds of formula lb possess beneficial pharmacogalenical properties, such as good solubility in various solvents.
  • solubility in ethanol is 12J mg/ml for Compound B in free form, as compared with 0.64 mg/ml for Compound A in free form.
  • the invention also provides a process for the preparation of a compound of formula lb in free form or salt form, comprising
  • R 2 " is as defined above, with a reagent that introduces chlorine or bromine in the ortho position to the N-oxido group;
  • R,'" is phenyl or alkyl and R 2 " is as defined above, JO-
  • Me is Al, Zn or Mg; n is 1 to 3; m is O or l; X is halogen; and R,'" is as defined above;
  • Process variant a) can conveniently be performed by reacting a compound of formula II with phosphorous oxychloride or oxybromide, preferably in an inert solvent, e.g. acetonitrile, preferably at elevated temperature.
  • R, 1V preferably is chlorine.
  • Process variant b) can be performed according to known organometallic reactions. It preferably is effected in the presence of a suitable catalyst, such as a Ni- or Pd-catalyst. Conveniently an aprotic solvent such as tetrahydrofuran is used.
  • the reaction preferably is effected at room temperature or at elevated temperature.
  • the resultant compounds of formula lb can be recovered from the reaction mixture and isolated and purified in known manner.
  • the starting material of formula II may e.g. be prepared by reacting the compound of formula IV
  • R 2 is as defined above.
  • a compound to be used as a starting material is either known, or may be prepared in known manner or analogously to known methods from known compounds.
  • Example 1 N-(3-chlorophenyl)-N-r4-(2-methylpyridin-4-yl)pyrimidin-2-yllamine [process variant b)] Under argon, 952 mg of N-(3-chlorophenyl)-N-[4-(2-chloropyridin-4-yl)- pyrimidin-2-yl]amine (Compound A) and 18 mg of tetrakis-(triphenyl ⁇ hosphine) palladium are suspended in 10 ml of dry tetrahydrofuran. 2 ml of a 2M solution in heptane of trimethylaluminium are added and the reaction mixture is stirred at 67° for 2.5 hours.
  • Example 8 N-r4-(2-chloropyridin-4-yl)pyrimidin-2-vI1-N-(3-methoxyphenyl)amine [Process variant a)] A solution of 2.94 g N-(3-methoxyphenyl)-N-[4-(l-oxidopyridin-4-yl)- pyrimidin-2-yl]amine [formula II; see A) hereunder], 3.31 g of tetraethylammonium chloride and 0.809 ml of pyridine in 18 ml of acetonitrile is heated to reflux and carefully (vigorous boiling at the beginning) treated with 2.80 ml of phosphorous oxychloride.
  • the starting material of formula II may be prepared in the following manner:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne, pour le traitement de maladies à médiation IgE, dont le rejet chronique, l'utilisation, sous forme libre ou de sel, de composés représentés par la formule générale (I). Dans cette formule, R1 est halogène, phényle ou alkyle, R2 étant hydrogène, halogène, alkyle, alcoxy ou trifluorométhyle. Les composés représentés par la formule (I) sont en partie connus. L'invention concerne également un sous-groupe de ces derniers, lequel sous-groupe possède une spécificité remarquable par rapport à certains types de cellules. Ce sous-groupe rassemble en l'occurrence ceux des composés qui sont représentés par la formule (Ib). Dans cette formule, soit R1' est halogène avec un numéro atomique de 17 à 35 et R2' est hydrogène ou alcoxy, soit R1' est phényle ou alkyle et R2' est hydrogène, halogène, alkyle, alcoxy ou trifluorométhyle. Les composés représentés par la formule (Ib) peuvent être préparés, par exemple par chloration ou bromation au niveau d'une position adjacente à un groupe N-oxydo ou par mise en réaction du composé chloro ou bromo avec un composé organométallique.
PCT/EP1999/000060 1998-01-12 1999-01-08 AMINES DE PYRIDINYLPYRIMIDINE AGISSANT COMME INHIBITEURS DE LA SYNTHESE DE L'IMMUNOGLOBULINE E (IgE) Ceased WO1999035140A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU25161/99A AU2516199A (en) 1998-01-12 1999-01-08 Pyridinylpyrimidine amines as immunoglobuline e (ige) synthesis inhibitors

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9800520.0 1998-01-12
GBGB9800522.6A GB9800522D0 (en) 1998-01-12 1998-01-12 Organic compounds
GB9800522.6 1998-01-12
GBGB9800520.0A GB9800520D0 (en) 1998-01-12 1998-01-12 Organic compounds

Publications (1)

Publication Number Publication Date
WO1999035140A1 true WO1999035140A1 (fr) 1999-07-15

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PCT/EP1999/000060 Ceased WO1999035140A1 (fr) 1998-01-12 1999-01-08 AMINES DE PYRIDINYLPYRIMIDINE AGISSANT COMME INHIBITEURS DE LA SYNTHESE DE L'IMMUNOGLOBULINE E (IgE)

Country Status (5)

Country Link
AR (1) AR014288A1 (fr)
AU (1) AU2516199A (fr)
CO (1) CO4940461A1 (fr)
PE (1) PE20000174A1 (fr)
WO (1) WO1999035140A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2369359A (en) * 2000-10-20 2002-05-29 Syngenta Participations Ag N-Phenyl-4-(4-pyridyl)-2-pyrimidinamines
WO2003063871A1 (fr) * 2002-02-01 2003-08-07 Novartis Ag Amines phenylpyrimidine utilisees comme inhibiteurs d'ige
US6706703B2 (en) 2001-06-29 2004-03-16 Kowa Co., Ltd. Bis(5-aryl-2-pyridyl) derivatives
US6890940B2 (en) 2001-06-29 2005-05-10 Kowa Co., Ltd. Bis(2-aryl-5-pyridyl) derivatives
WO2010055114A1 (fr) * 2008-11-14 2010-05-20 Bayer Cropscience Sa Dérivés substitués de (pyridyl)-azinylamine au titre d'agents de protection de végétaux

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0137979A1 (fr) * 1983-09-01 1985-04-24 Boehringer Ingelheim Pharmaceuticals Inc. Acides diazine-éthénylphényloxamiques, leurs esters et sels
WO1995009853A1 (fr) * 1993-10-01 1995-04-13 Ciba-Geigy Ag Derives pyridine pharmacologiquement actifs ainsi que leurs procedes de preparation
WO1995009851A1 (fr) * 1993-10-01 1995-04-13 Ciba-Geigy Ag Derives de pyrimidineamine pharmacologiquement actifs ainsi que leurs procedes de preparation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0137979A1 (fr) * 1983-09-01 1985-04-24 Boehringer Ingelheim Pharmaceuticals Inc. Acides diazine-éthénylphényloxamiques, leurs esters et sels
WO1995009853A1 (fr) * 1993-10-01 1995-04-13 Ciba-Geigy Ag Derives pyridine pharmacologiquement actifs ainsi que leurs procedes de preparation
WO1995009851A1 (fr) * 1993-10-01 1995-04-13 Ciba-Geigy Ag Derives de pyrimidineamine pharmacologiquement actifs ainsi que leurs procedes de preparation

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2369359A (en) * 2000-10-20 2002-05-29 Syngenta Participations Ag N-Phenyl-4-(4-pyridyl)-2-pyrimidinamines
US6706703B2 (en) 2001-06-29 2004-03-16 Kowa Co., Ltd. Bis(5-aryl-2-pyridyl) derivatives
US6890940B2 (en) 2001-06-29 2005-05-10 Kowa Co., Ltd. Bis(2-aryl-5-pyridyl) derivatives
US7196101B2 (en) 2001-06-29 2007-03-27 Kowa Co., Ltd Bis(5-aryl-2-pyridyl) derivatives
WO2003063871A1 (fr) * 2002-02-01 2003-08-07 Novartis Ag Amines phenylpyrimidine utilisees comme inhibiteurs d'ige
US7759357B2 (en) 2002-02-01 2010-07-20 Novartis Ag Phenylpyrimidine amines as IgE inhibitors
WO2010055114A1 (fr) * 2008-11-14 2010-05-20 Bayer Cropscience Sa Dérivés substitués de (pyridyl)-azinylamine au titre d'agents de protection de végétaux
CN102216286A (zh) * 2008-11-14 2011-10-12 拜尔农科股份公司 作为植物保护剂的取代的(吡啶基)-嗪基胺衍生物

Also Published As

Publication number Publication date
AR014288A1 (es) 2001-02-07
AU2516199A (en) 1999-07-26
PE20000174A1 (es) 2000-03-17
CO4940461A1 (es) 2000-07-24

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