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WO1998045267A1 - Derives d'aminopyridine pour maladies inflammatoires et affections malignes - Google Patents

Derives d'aminopyridine pour maladies inflammatoires et affections malignes Download PDF

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Publication number
WO1998045267A1
WO1998045267A1 PCT/GB1998/000998 GB9800998W WO9845267A1 WO 1998045267 A1 WO1998045267 A1 WO 1998045267A1 GB 9800998 W GB9800998 W GB 9800998W WO 9845267 A1 WO9845267 A1 WO 9845267A1
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Prior art keywords
amino
pyridine
mercaptopropylamino
ethyloxy
naphthyl
Prior art date
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PCT/GB1998/000998
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English (en)
Inventor
David Michael Evans
Doreen Mary Ashworth
David Alan Kendrick
Graeme Semple
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Ferring BV
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Ferring BV
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Application filed by Ferring BV filed Critical Ferring BV
Priority to AU69272/98A priority Critical patent/AU6927298A/en
Publication of WO1998045267A1 publication Critical patent/WO1998045267A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the immune response is essential for the defence of the body against invading pathogens.
  • an inappropriate activation of the immune system has been implicated in the etiology of some serious disease states. These arc characterised by progressive tissue damage with inflammation and invasion of the lesion by leukocytes. Examples of such diseases include inflammatory bowel disease, psoriasis, asthma and rheumatoid arthritis. Current therapeutic regimens for these conditions are often inadequate, and new approaches are required.
  • One aspect of the present invention is a series of compounds that inhibit the proliferation of T lymphocytes. Because T lymphocytes play a central role in the immune response it is reasonable to suppose that such compounds will prove to be of value in the treatment of immunoinflammatory conditions.
  • Another property exhibited by the compounds of the present invention is the ability to inhibit the enzyme famesyl protein transferase (EC 2.5.1 p21 farnesyl transferase; FPTase). Inhibitors of this enzyme have shown promise as agents for the treatment of tumours, particularly those which express variants of the oncogenic protein ras that are constituitively active. Therefore a second use for the compounds of this invention is the treatment of neoplastic diseases.
  • famesyl protein transferase EC 2.5.1 p21 farnesyl transferase
  • FPTase farnesyl transferase
  • the compounds of the invention are 3-aminopyridine derivatives of general formula
  • n 0-4;
  • n 1-2;
  • R is optionally substituted phenyl, naphthyl or monocyclic or bicyclic heteroaryl with up to three heteroatoms selected from O, N and S in the ring(s);
  • R , R and R are independently selected from H, lower alkyl, perfluoro-lower alkyl, optionally substituted phenyl and optionally substituted naphthyl;
  • X is selected from -CH 2 -, -0-, -S-, -NH- and -NMe-;
  • Y is -CR 3 R - where R 3 and R are independently selected from H and methyl, and when m is greater than 1 the repeating embodiments of Y can be identical or different.
  • the compounds of general formula 1 have at least one stereogenic centre and so can exist as stereoisomers (enantiomers and diastereomers). These isomers, as single compounds or as mixtures, are included within the scope of this invention.
  • the compounds also have at least one basic site and so can form salts with acids. These salts, and particularly those salts formed by pharmaceutically acceptable acids (including, but not limited to, acetic acid, citric acid, lactic acid, tartaric acid, hydrochloric acid, sulphuric acid, trifluoroacetic acid) are also included in the scope of the invention.
  • Certain embodiments of general formula 1 also include acidic sites. These compounds can form salts with bases. Again, these salts (for example the sodium, potassium and ammonium salts) are included within the scope of the invention.
  • R , R and R are all hydrogen.
  • Particularly preferred embodiments of the invention are the following compounds, their stereoisomers and salts:
  • the invention includes medicinal formulations in which a compound as described above is used as an active principal.
  • Such formulations will have as other ingredients such materials as bulking and binding agents and preservatives as are well known in the art.
  • the formulation may be a tablet, solution, suspension, cream, suppository or any other form appropriate for the administration of the active principal.
  • the administration can be topical, by intravenous, subcutaneous or intramuscular injection, or via the oral, nasal, bucal, rectal or vaginal routes.
  • the invention includes equally the use of these formulations for the treatment of a pathological condition in a human or other mammal, wherein the pathological condition is either an inflammatory or autoimmune disease such as (but not limited to) ulcerative colitis, Crohn's disease, allergic rhinitis, graft- vs-host disease, conjunctivitis, asthma, rheumatoid arthritis, osteoarthritis, ARDS, Behcet's disease, transplant rejection, uticaria, allergic dermatitis, allopecia areata, scleroderma, exanthem, eczema, dermatomyositis, acne, diabetes, systemic lupus erythematosis, Kawasaki's disease, multiple sclerosis, emphysema, cystic fibrosis, chronic bronchitis or psoriasis, or a proliferative disease such as cancer, for example colon, prostate or mammary carcinoma or leukaemia, or
  • the amount of formulation (and hence the amount of active principal) will be chosen by the treating physician taking into account the age, weight and state of health of the patient as well as any other factors he considers to be relevant.
  • the amount of active principal used will generally be between 0.1 mg and lOg per day in a single dose or in divided doses. Preferably the amount will be between lmg and lg.
  • the compounds of the invention can be prepared by the following general methods.
  • the compounds of the invention have a primary amine and a thiol functional group. These groups are likely to be reactive under the conditions used to elaborate the compounds and so need to be protected during the synthesis. Protecting groups for primary amines and thiols are well known in the literature.
  • the final step(s) in the synthesis of a compound of formula 1 will be the simultaneous or sequential removal of the amine and thiol protecting groups.
  • One convenient combination of protecting groups is the use of trityl (triphenylmethyl) to protect the thiol and BOC (tert- butyloxycarbonyl) to protect the amine.
  • Both groups can be removed simultaneously by treating a compound of formula 2 with a strong acid, for example trifluoroacetic acid, in an appropriate solvent, for example dichloromethane, in the presence of a cation scavenger such as triethylsilane.
  • a strong acid for example trifluoroacetic acid
  • an appropriate solvent for example dichloromethane
  • a cation scavenger such as triethylsilane.
  • the compound of formula 2 is generally prepared from an aminopyridine of formula 3 and an aldehyde of formula 4. These components are combined in a suitable solvent (for example methanol containing 1-10% acetic acid) in the presence of a reducing agent such as sodium cyanoborohydride.
  • a suitable solvent for example methanol containing 1-10% acetic acid
  • a reducing agent such as sodium cyanoborohydride.
  • the aminopyridine of formula 3 can be prepared from the corresponding nitropyridine of formula 5 by reduction.
  • One convenient method for achieving this conversion is to stir a solution of the nitropyridine under an atmosphere of hydrogen in the presence of a palladium or platinum catalyst.
  • Some combinations of R 1 , Y, m and X are incompatible with this protocol, and in these cases suitable reaction conditions might involve the use of zinc/acetic acid or sodium hydrosulphite.
  • the nitropyridine of formula 5 can be prepared from a chloronitropyridine of formula 6 by reaction with a reagent of formula 7 in the presence of a base such as sodium hydride, potassium carbonate or potassium fluoride.
  • a base such as sodium hydride, potassium carbonate or potassium fluoride.
  • a nitropyridone of formula 8 (which can exist as the tautomeric hydroxypyridine) can be alkylated with a reagent of formula 9.
  • the bromine atom can be replaced by the required phenyl group using the Suzuki coupling (phenylboronic acid in the presence of a palladium catalyst). This conversion is most conveniently performed after the elaboration of the R'Y m X group.
  • Example 1A To a degassed solution of the nitropyridine of Example 1A (3.47g, 1 1.8mmol) in EtOAc (20mL) and ethanol (lOOmL) was added 10% palladium-on-carbon (500mg). The mixture was stirred at room temperature under an atmosphere of hydrogen for 2h then filtered. The catalyst was washed with ethanol and the combined filtrates were evaporated in vacuo. The residue was dried by azeotropic evaporation with toluene and used without further purification; assume 100% yield.
  • Example 2C To an ice-cold solution of the alcohol of Example 2C (8.97g, 47.0mmol) in dry dimethylformamide (120mL) was added sodium hydride (2.1g, 60% dispersion, 52.5mmol). The mixture was stirred at 0°C for 45min, then 2-chloro-3 -nitropyridine (6.8g, 42.9mmol) was added following the method of Example 1A. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 15:85); yield 9.25g (69%).
  • Example 2E The aminopyridine of Example 2E (13.88mmol) was reacted with N-BOC-S- tritylcysteinal (7.9g, 17.7mmol) and sodium cyanoborohydride (2.1g, 33.9mmol) in methanol (90mL) and acetic acid (lOmL) following the method of Example lC.
  • the product was purified by chromatography on silica (eluant EtOAc:pet. ether 10:90); yield 4.17g (42%).
  • Example 2F The compound of Example 2F (4.15g, 5.81mmol) was deprotected following the method of Example ID.
  • the product was purified by MPLC (gradient wate ⁇ acetonitrile 100:0 ⁇ 50:50; 0.1% TFA) and lyophilised; yield 1.63g (75%%).
  • Example 3A The compound of Example 3A (2.0g, 9.93mmol) was suspended in dimethylformamide (40mL). Phenethyliodide (4.6g, 16.7mmol) and potassium fluoride (l .lg, 19.0mmol) were added and the mixture stirred at room temperature for 3 days. The mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgS0 4 and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 4:96); yield 1.753g (58%).
  • Example 3C To a degassed solution of the nitropyridine of Example 3C (170mg, 0.43mmol) in ethanol (40mL) was added 10% palladium-on-carbon (50mg). The mixture was stirred at room temperature under an atmosphere of hydrogen for 30min then filtered. The catalyst was washed with ethanol and the combined filtrates were evaporated in vacuo. The residue was dried by azeotropic evaporation with toluene and used without further purification; assume 100% yield.
  • Example 3D The aminopyridine of Example 3D (0.43mmol) was reacted with N-BOC-S- tritylcysteinal (320mg, 0.71mmol) and sodium cyanoborohydride (93mg, 1.5mmol) in methanol (18mL) and acetic acid (2mL) following the method of Example IC.
  • the product was purified by chromatography on silica (eluant EtOAc:pet. ether 4:96); yield 132mg (39%).
  • Example 3F 3-r2-Amino-3-mercaptopropylaminoV6-(naphthyl)-2-(2-phenylethyloxy ' )pyridine
  • the compound of Example 3E (132mg,0.17mmol) was deprotected following the method of Example ID.
  • the product was purified by MPLC (gradient water:acetonitrile 100:0 ⁇ 50:50; 0.1% TFA) and lyophilised; yield 48.9mg (67%).
  • Example 4A To a degassed solution of the nitropyridine of Example 4A (143mg, 0.39mmol) in ethanol (40mL) was added 10% palladium-on-carbon (50mg). The mixture was stirred at room temperature under an atmosphere of hydrogen for 30min then filtered. The catalyst was washed with ethanol and the combined filtrates were evaporated in vacuo. The residue was dried by azeotropic evaporation with toluene and used without further purification; assume 100% yield.
  • Example 4B The aminopyridine of Example 4B (0.39mmol) was reacted with N-BOC-S- tritylcysteinal (210mg, 0.47mmol) and sodium cyanoborohydride (45mg, 0.73mmol) in methanol (18mL) and acetic acid (2mL) following the method of Example IC.
  • the product was purified by chromatography on silica (eluant EtOAc:pet. ether 4:96); yield 114mg (38%).
  • Example 4D 3-(2-Amino-3-mercaptopropylaminoV6-phenoxy-2-,2-phenylethyloxy ' )pyridine
  • the compound of Example 4C (1 13mg,0.15mmol) was deprotected following the method of Example ID.
  • the product was purified by MPLC (gradient water:acetonitrile 100:0 ⁇ 50:50; 0.1% TFA) and lyophilised; yield 14.1mg (24%).
  • Example 5C The aminopyridine of Example 5C (l l lmg, 0.49mmol) was reacted with N-BOC-S- tritylcysteinal (325mg, 0.73mmol) and sodium cyanoborohydride (86mg, 1.39mmol) in methanol (18mL) and acetic acid (2mL) following the method of Example I C.
  • the product was purified by chromatography on silica (eluant EtOAc:pet. ether 10:90); yield 164mg (51%).
  • Example 5D The compound of Example 5D (164mg,0.25mmol) was deprotected following the method of Example ID.
  • the product was purified by MPLC (gradient wate ⁇ acetonitrile 100:0 ⁇ 50:50; 0.1% TFA) and lyophilised; yield 26.7mg (34%).
  • the compounds of the invention are useful as inhibitors of the enzyme farnesyl protein transferase and as inhibitors of T-lymphocyte proliferation.
  • Inhibitors of farnesyl protein transferase are known to show good efficacy in animal models of tumour growth and hence can be expected to be useful in the chemotherapy of human cancers.
  • T-lymphocytes are key mediators of the immune response and are believed to play a central role in the etiology of many inflammatory diseases. Hence, inhibitors of T-lymphocyte proliferation are expected to show clinically useful anti- inflammatory activity.
  • the utility of the compounds of the invention can be demonstrated using the assays described below.
  • ASSAY 1 Farnesyl Protein Transferase Inhibition.
  • ASSAY 2 Geranylgeranyl Protein Transferase I Inhibition.
  • Geranylgeranyl Protein Transferase I was also determined using standard literature methods. Again, the IC 50 is the concentration of test compound required to reduce the amount of product formed by 50%. Selected compounds of the invention have IC 50 values as shown below in Table 2.
  • ASSAY 3 T-Lymphocyte Proliferation Inhibition.
  • Human T-lymphocytes are stimulated to proliferate with an anti-CD3 antibody in the presence of varying concentrations of the test compound. After 3 days [ HJfhymidine is added. The cells are incubated for a further 12 hours, then proliferation is quantified by counting the incorporation of radioactivity into the cellular fraction.
  • the compounds of the invention inhibit proliferation at concentrations below 50 ⁇ M. Typical examples are shown below in Table 2.

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

Abstract

L'invention concerne de nouveaux dérivés nouveaux de 3-aminopyridine de formule générale (1), dans laquelle la valeur de m est comprise entre 0 et 4; celle de n, entre 1 et 2; R1 représente un aryle ou un hétéroaryle monocyclique ou bicyclique éventuellement substitué; R?2, R3, et R4¿ sont indépendamment sélectionnés parmi H, alkyle inférieur, alkyle inférieur perfluoré, phényle éventuellement substitué et naphtyle éventuellement substitué; X est choisi parmi -CH¿2?-, -O-, -S-, -NH- et NMe- et Y représente -CR?5R6-, R5 et R6¿ étant indépendamment sélectionnés parmi H et méthyle, et lorsque la valeur de m est supérieure à 1, les significations répétées de Y peuvent être identiques ou différentes. Ces composés sont des inhibiteurs de la prolifération des lymphocytes T et de la protéine-farnésyl-transférase. Ils sont utiles en tant qu'agents pharmaceutiques dans le traitement de maladies inflammatoires et d'affections malignes.
PCT/GB1998/000998 1997-04-04 1998-04-03 Derives d'aminopyridine pour maladies inflammatoires et affections malignes Ceased WO1998045267A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU69272/98A AU6927298A (en) 1997-04-04 1998-04-03 Aminopyridine derivatives for inflammatory and malignant diseases

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9706922A GB2323841A (en) 1997-04-04 1997-04-04 Pyridine derivatives with anti-tumor and anti-inflammatory activity
GB9706922.3 1997-04-04

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7045519B2 (en) 1998-06-19 2006-05-16 Chiron Corporation Inhibitors of glycogen synthase kinase 3
US7417047B2 (en) 2005-06-30 2008-08-26 Wyeth Amino-5-(5-membered)hetero-arylimidazolone compounds and the use thereof for β-secretase modulation
US7423158B2 (en) 2005-09-26 2008-09-09 Wyeth Amino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone compounds for the inhibition of β-secretase
US7452885B2 (en) 2005-06-30 2008-11-18 Wyeth Amino-5-(6-membered)heteroarylimidazolone compounds and the use thereof for β-secretase modulation
US7456186B2 (en) 2004-06-16 2008-11-25 Wyeth Diphenylimidazopyrimidines as inhibitors of β-secretase
US7482349B2 (en) 2004-06-16 2009-01-27 Wyeth Amino-5,5-diphenylimidazolone derivatives for the inhibition of β-secretase
US7488832B2 (en) 2005-02-14 2009-02-10 Wyeth Azolylacylguanidines as β-secretase inhibitors
US7563796B2 (en) 2005-01-14 2009-07-21 Wyeth Diphenylimidazopyrimidines as inhibitors of β-secretase
US7582667B2 (en) 2006-02-24 2009-09-01 Wyeth Dihydrospiro[dibenzo[a,d][7]annulene-5,4′-imidazol] compounds for the inhibition of beta-secretase
US7700606B2 (en) 2006-08-17 2010-04-20 Wyeth Llc Imidazole amines as inhibitors of β-secretase
US7723368B2 (en) 2007-03-23 2010-05-25 Wyeth Llc Amino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone compounds for the inhibition of beta-secretase
US7732457B2 (en) 2005-02-01 2010-06-08 Wyeth Llc Amino-pyridines as inhibitors of β-secretase

Families Citing this family (1)

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Publication number Priority date Publication date Assignee Title
US7271266B2 (en) 2002-03-28 2007-09-18 Merck & Co., Inc. Substituted 2,3-diphenyl pyridines

Citations (3)

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WO1995034535A1 (fr) * 1994-06-10 1995-12-21 Rhone-Poulenc Rorer S.A. Nouveaux inhibiteurs de farnesyl transferase, leur preparation et les compositions pharmaceutiques qui les contiennent
WO1996021456A1 (fr) * 1995-01-12 1996-07-18 University Of Pittsburgh Inhibiteurs des prenyle transferases
WO1996030014A1 (fr) * 1995-03-29 1996-10-03 Merck & Co., Inc. Inhibiteurs de farnesyl-proteine transferase

Family Cites Families (1)

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WO1995000497A1 (fr) * 1993-06-18 1995-01-05 Merck & Co., Inc. Inhibiteurs de farnesyle-proteine transferase

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
WO1995034535A1 (fr) * 1994-06-10 1995-12-21 Rhone-Poulenc Rorer S.A. Nouveaux inhibiteurs de farnesyl transferase, leur preparation et les compositions pharmaceutiques qui les contiennent
WO1996021456A1 (fr) * 1995-01-12 1996-07-18 University Of Pittsburgh Inhibiteurs des prenyle transferases
WO1996030014A1 (fr) * 1995-03-29 1996-10-03 Merck & Co., Inc. Inhibiteurs de farnesyl-proteine transferase

Non-Patent Citations (1)

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Title
QIAN Y ET AL: "DESIGN AND SYNTHESIS OF NON-PEPTIDE RAS CAAX MIMETICS AS POTENT FARNESYLTRANSFERASE INHIBITORS", JOURNAL OF MEDICINAL CHEMISTRY, vol. 39, 1996, pages 217 - 223, XP000198788 *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7425557B2 (en) 1998-06-19 2008-09-16 Novartis Vaccines And Diagnostics, Inc. Inhibitors of glycogen synthase kinase 3
US7045519B2 (en) 1998-06-19 2006-05-16 Chiron Corporation Inhibitors of glycogen synthase kinase 3
US7482349B2 (en) 2004-06-16 2009-01-27 Wyeth Amino-5,5-diphenylimidazolone derivatives for the inhibition of β-secretase
US7456186B2 (en) 2004-06-16 2008-11-25 Wyeth Diphenylimidazopyrimidines as inhibitors of β-secretase
US7700602B2 (en) 2004-06-16 2010-04-20 Wyeth Llc Amino-5,5-diphenylimidazolone derivatives for the inhibition of β-secretase
US7563796B2 (en) 2005-01-14 2009-07-21 Wyeth Diphenylimidazopyrimidines as inhibitors of β-secretase
US7732457B2 (en) 2005-02-01 2010-06-08 Wyeth Llc Amino-pyridines as inhibitors of β-secretase
US7488832B2 (en) 2005-02-14 2009-02-10 Wyeth Azolylacylguanidines as β-secretase inhibitors
US7452885B2 (en) 2005-06-30 2008-11-18 Wyeth Amino-5-(6-membered)heteroarylimidazolone compounds and the use thereof for β-secretase modulation
US7417047B2 (en) 2005-06-30 2008-08-26 Wyeth Amino-5-(5-membered)hetero-arylimidazolone compounds and the use thereof for β-secretase modulation
US7705030B2 (en) 2005-06-30 2010-04-27 Wyeth Llc Amino-5-(5-membered)hetero-arylimidazolone compounds and the use thereof for β-secretase modulation
US7423158B2 (en) 2005-09-26 2008-09-09 Wyeth Amino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone compounds for the inhibition of β-secretase
US7582667B2 (en) 2006-02-24 2009-09-01 Wyeth Dihydrospiro[dibenzo[a,d][7]annulene-5,4′-imidazol] compounds for the inhibition of beta-secretase
US7700606B2 (en) 2006-08-17 2010-04-20 Wyeth Llc Imidazole amines as inhibitors of β-secretase
US7723368B2 (en) 2007-03-23 2010-05-25 Wyeth Llc Amino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone compounds for the inhibition of beta-secretase

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Publication number Publication date
GB9706922D0 (en) 1997-05-21
GB2323841A (en) 1998-10-07
AU6927298A (en) 1998-10-30

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