WO1998045266A1 - 3-aminopyridine derivatives for treatment of inflammatory and malignant diseases - Google Patents

3-aminopyridine derivatives for treatment of inflammatory and malignant diseases Download PDF

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Publication number
WO1998045266A1
WO1998045266A1 PCT/GB1998/000997 GB9800997W WO9845266A1 WO 1998045266 A1 WO1998045266 A1 WO 1998045266A1 GB 9800997 W GB9800997 W GB 9800997W WO 9845266 A1 WO9845266 A1 WO 9845266A1
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Prior art keywords
amino
mercaptopropylamino
phenyl
pyridyloxy
propionamide
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PCT/GB1998/000997
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French (fr)
Inventor
Richard Jeremy Franklin
Doreen Mary Ashworth
David Michael Evans
Paul David Jenkins
David Alan Kendrick
Graeme Semple
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Ferring B.V.
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Priority to AU69271/98A priority Critical patent/AU6927198A/en
Publication of WO1998045266A1 publication Critical patent/WO1998045266A1/en

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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
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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 are characterised by progressive tissue damage with inflammation and invasion of the lesion by leukocytes. Examples of such diseases include inflammatory bowel disease, asthma, psoriasis and rheumatoid arthritis. Current therapeutic regimens for these conditions arc 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 farnesyl protein transferase (EC 2.5.1 p21 AS 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.
  • farnesyl protein transferase EC 2.5.1 p21 AS farnesyl transferase; FPTase
  • the compounds of this invention arc pyridine derivatives of general formula 1 :
  • W is a group of general formula 2 or general formula 3:
  • X is a covalent bond; -CH ; -0-; -NH-; -NMe-; or -S-
  • Y is -O-, -S- or -NR 3 -:
  • R is hydrogen; linear or branched lower alkyl (C, - C 8 ); lower cycloalkyl (C 3 - C 8 ); substituted or unsubstituted phenyl or naphthyl: or substituted or unsubstituted monocyclic or benzofused heteroaryl:
  • R is hydrogen; linear or branched lower alkyl (C, - C 4 ) or Ph(CH 2 ) m :
  • R is hydrogen or linear or branched lower alkyl (C, - C 4 ):
  • R and R 3 are independently hydrogen; linear or branched lower alkyl (C ⁇ - C 8 ); lower cycloalkyl (C 3 - C 8 ) which may be benzofused or substituted with COR ; substituted or unsubstituted phenyl or naphthyl, substituted or unsubstituted monocyclic or benzofused heteroaryl; COR 6 ; or R 4 and R 5 together with the nitrogen atom and the methylene groups to which they are attached form a saturated heterocycle of up to 8 atoms which may be benzofused or substituted with COR :
  • R 6 is OH; O-alkyl; NH 2 ; NH-alkyl; N(alkyl) 2 ; or NHSO 2 -alkyl (wherein alkyl includes linear or branched lower alkyl C ( - C 8 , lower cycloalkyl C 3 - C 8 and (cycloalkyl)alkyl C 4 - C 10 ); or R and R together are -O(CH 2 ) 2 - to form a ⁇ -lactone ring:
  • R is selected from linear or branched lower alkyl (C, - C 6 ) or (CH 2 ) C R 9 ; or R 7 and R together are -(CH 2 ) 2 O- to form a ⁇ -lactone ring:
  • R is hydrogen or methyl
  • R 9 is OH; OCH 3 ; SCH 3 ; SOMe; SO 2 Me; NHCOMe; optionally substituted phenyl; or COR 6 :
  • R , R , R and R are independently hydrogen or lower alkyl or phenyl:
  • a, b and c are integers in the range 0-4:
  • n 0, 1 or 2:
  • n 1, 2 or 3.
  • p 1 or 2.
  • 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.
  • a preferred embodiment of the invention is a compound of formula 1 in which R is an optionally substituted phenyl group, X is a covalent bond and Y is an oxygen atom, all the other groups being as defined above.
  • 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.
  • 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 neurofibromatosis.
  • a proliferative disease such as cancer, for example colon, prostate or mammary carcinoma or leukaemia, or neurofibromatosis.
  • 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 general formula 1 are prepared from a precursor (formula 4) in which the potentially reactive amino (NH 2 ) and mercapto (SH) groups are masked. Suitable masking groups are well known to practitioners of the art. Conveniently, the amino group is protected as its tert-butyl carbamate (BOC) derivative and the mercapto group is protected as its triphenylmethyl (trityl) thioether. In this case both protecting groups can be removed by treating the compound with a strong acid (for example trifluoroacetic acid) in a solvent such as dichloromethane in the presence of a cation scavenger such as triethylsilane.
  • a strong acid for example trifluoroacetic acid
  • a solvent such as dichloromethane
  • a cation scavenger such as triethylsilane.
  • the compound of formula 4 can be prepared by coupling an amine H-W with an acid of formula 5. This may be achieved by any of several well known methods for amide bond formation (for example, the use of a carbodiimide or a phosphorus reagent such as BOP).
  • W there will be functionality in W that is incompatible with this reaction.
  • W may include a carboxyhc acid functional group or a second amine. Either of these would lead to a mixture of products arising from competition between alternative reaction centres. In these cases it will be necessary to use an amine H-W' in which the competing functional group is modified. Such a modification will generally involve the use of a protecting group, and it will often be most convenient if the protecting group is cleaved under the same conditions as are used to effect the final deprotection (formula 4 — . formula 1). Occasionally it may be preferable to deprotect W' in a separate operation. The choice of protection strategy for W' will reflect these considerations.
  • the acid of formula 5 is generally prepared from a suitable ester (formula 6). Conveniently, this will be a lower alkyl ester such as the methyl or ethyl ester. In this case the acid is released by alkaline hydrolysis using, for example, lithium hydroxide in a mixed water/dioxan solvent system.
  • the ester of formula 6 can be prepared from an aminopyridine (formula 7) and an aldehyde (formula 8) using conditions known to effect such reductive aminations. Typically this will involve mixing the aminopyridine and the aldehyde in a solvent such as methanol containing 1-10% acetic acid, and subsequently treating the mixture with a reducing agent such as sodium cyanoborohydride.
  • a solvent such as methanol containing 1-10% acetic acid
  • the aminopyridine of formula 7 can be prepared from the corresponding nitropyridine (formula 9) by any of several well known protocols (for example, hydrogenation in the presence of a platinum or palladium catalyst, reaction with zinc in acetic acid, reaction with sodium hydrosulphite)
  • n 2
  • the nitropyridine of formula 9 can be prepared by two routes. In the first, the group
  • R -X is introduced into a chloropyridine of formula 13.
  • X is a heteroatom
  • the second component in the reaction is R , I - XH and the reaction requires a basic catalyst such as potassium fluoride or sodium carbonate.
  • a basic catalyst such as potassium fluoride or sodium carbonate.
  • X is CH 2 or a covalent bond then the reaction is best achieved by a Suzuki coupling. This involves the reaction of the chloropyridine with a boronic acid R'XB(0H) 2 (or a boronate ester) in the presence of a palladium catalyst.
  • the chloropyridine of formula 13 is obtained from 2,6-dichloro-3-nitropyridine and a fragment of formula 14. These react in the presence of a base such as sodium carbonate, sodium hydride or potassium tert-butoxide.
  • a base such as sodium carbonate, sodium hydride or potassium tert-butoxide.
  • the second route to the nitropyridine of formula 9 involves the alkylation of a pyridone of formula 15 (which can exist as the tautomeric hydroxypyridine).
  • the pyridone and the alkylating agent will, in most cases, be known in the literature. Otherwise they can be prepared by methods analogous to those described for similar compounds.
  • a variation of this pyridone route starts with a pyridonenitrile of formula 17.
  • the nitrile may be more accessible than the nitropyridine.
  • the nitrile can be hydrolysed to the corresponding acid (formula 18) in the presence of strong acids.
  • the acid is then subjected to a Curtius rearrangement using diphenylphosphoryl azide and benzyl alcohol to give a protected aminopyridine of formula 19.
  • the protected aminopyridine of formula 20 can be further elaborated by either of two routes which are analogous to those described above for the nitropyridine of formula 9.
  • the ester can be hydrolysed to the corresponding acid. This is then coupled to the amine corresponding to H-W or H-W'. The result is the pyridine of formula 21.
  • Example 1A The nitrile of Example 1A (17.6g, 90mmol) was suspended in acetic acid (170mL). 48% HBr (8mL) was added and the mixture was heated at reflux overnight. The resulting solution was cooled to room temperature, diluted with water (lOOmL), and basified to pH5 with 10% NaOH (ca. 600mL). The precipitate was collected, washed with 1M HCl and water, and dried over P 2 O 5 ; yield 13.7g (71%).
  • Example IB To a solution of the acid of Example IB (8.0g, 37.2mmol) in dioxan (200mL) was added triethylamine (6.2mL, 45mmol) and diphenylphosphoryl azide (8.8mL, 41mmol). The mixture was heated under reflux for 4h. Benzyl alcohol (7.7mL, 74mmol) was added and heating was continued overnight. The mixture was cooled to room temperature and concentrated in vacuo. The residue was washed with 1M HCl, satd. NaHCO 3 , water (twice) and ether (twice); yield 7.2g (60%).
  • Example 2A The pyridone of Example 2A (6.0g, 14.7mmol) was hydrogenated over palladium following the method of Example IE. The product was used without purification.
  • Example 2B The aminopyridine of Example 2B (14.7mmol) was reacted with N-BOC-S-trityl- cysteinal (7.9g, 17.7mmol) and sodium cyanoborohydride (1.1 lg, 17.7mmol) in methanol (lOOmL) and acetic acid (7.5mL) following the method of Example IF.
  • the product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 15:85); yield 7.91g (76%).
  • Example 2C The ester of Example 2C (7.9 lg, 1 1.2mmol) was hydrolysed with lithium hydroxide hydrate (1.09g, 26mmol) in dioxan (20mL) and water (20mL) following the method of Example 1 G.
  • the product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 40:60 then EtOAc:HOAc 99:1); yield 3.74g (72%).
  • Example 2D To an ice-cold solution of the acid of Example 2D (200mg, 0.29mmol) in dichloromethane (lOmL) were added methyl 3-(aminomethyl)benzoate hydrochloride (70mg, 0.35mmol), triethylamine (120 ⁇ L, 0.87mmol) and benzotriazol-l-yloxy-trz_- pyixolidinophosphonium hexafluorophosphate (180mg, 0.35mmol). The mixture was allowed to warm to room temperature and stirred for 6h, then concentrated in vacuo. The residue was partitioned between EtOAc and 0.3M KHSO 4 . The organic layer was washed with brine, dried over MgS0 4 and concentrated.
  • methyl 3-(aminomethyl)benzoate hydrochloride 70mg, 0.35mmol
  • triethylamine 120 ⁇ L, 0.87mmol
  • Example 2D The acid of Example 2D (130mg, 0.188mmol) was coupled to (S)-(-)- ⁇ - methylbenzylamine (27.4mg, 0.226mmol) following the method of Example 2F.
  • the product was purified by flash chromatography on silica (eluant EtOAc :pet. ether
  • Example 3A The compound of Example 3A (90mg, 0.113mmol) was deprotected following the method of Example 2G.
  • the product was purified by preparative HPLC (gradient wate ⁇ acetonitrile 90: 10 ⁇ 40:60; 0.1% TFA) and lyophilised; yield 31.5mg (61%).
  • MS: calc m/e 450.21 ; found [M+H] + 451
  • Example 2D The acid of Example 2D (130mg, 0.188mmol) was coupled to 2-methoxybenzylamine
  • Example 4A The compound of Example 4A (137mg, 0. 169mmol) was deprotected following the method of Example 2G.
  • the product was purified by preparative HPLC (gradient wate ⁇ acetonitrile 85: 15 ⁇ 50:50; 0.1% TFA) and lyophilised; yield 46.3mg (59%).
  • MS: calc m/e 466.20; found [M+H] + 467
  • Example IJ The product was purified by preparative HPLC (gradient wate ⁇ acetonitrile 80:20 ⁇ 20:80; 0.1% TFA) and lyophilised; yield 68.3mg(64%).
  • Example 6A The compound of Example 6A (93mg, 11.5mmol ) was deprotected following the method of Example 2G.
  • the product was purified by preparative HPLC (gradient water: acetonitrile 85: 15 ⁇ 40:60 0.1% TFA) and lyophilised; yield 28.8mg (75%).
  • Example 7A The acid of Example 7A (400mg, 0.792mmol) was coupled to 3-
  • Example 7D The compound of Example 7D (lOOmg, 0.13mmol ) was deprotected following the method of Example 2G.
  • the product was purified by preparative HPLC (gradient wate ⁇ acetonitrile 90: 10- 50:50; 0.1% TFA) and lyophilised; yield 40.1mg (73%).
  • Example 8A The compound of Example 8A (76mg, 0.093mmol ) was deprotected following the method of Example 2G.
  • the product was purified by preparative HPLC (gradient water: acetonitrile 90: 10 ⁇ 50:50; 0.1% TFA) and lyophilised; yield 39.8mg (92%).
  • Example 9D Methyl 2- .3-(2-tert-butyloxycarbonylamino-3- triphenylmethylmercaptopropylamino)-6-(2-biphenylyl)-2-pyridyloxy ) acetate
  • the compound of Example 9C (0. ⁇ mmol) was reacted with N-BOC-S- tritylcysteinal(268mg, 0. ⁇ mmol) and sodium cyanoborohydride (76mg, 1.2mmol) as described in Example IF.
  • the product was purified by flash chromatography on silica (eluant EtOAc:pet ether 25:75) yield 310mg (67%).
  • Example 9E The acid of Example 9E (0.39mmol) was coupled to methionine methyl ester hydrochloride (lOOmg, 0.5mmol) following the method of Example 1H.
  • the product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 40:60); yield
  • Example 2G The product was purified by preparative HPLC (gradient wate ⁇ acetonitrile 80:20 ⁇ 20:80; 0.1% TFA) and lyophilised; yield 69mg (89%).
  • Example 10C Methyl- 2- ⁇ 3-(2-tgrt-butyloxycarbonylamino-3- triphenylmethylmercaptopropy laminoV ⁇ - phenoxy-2-pyridyloxy ⁇ acetate
  • N-BOC-S- tritylcysteinal 670mg, 1.49mm01
  • sodium cyanoborohydride l lOmg, 1.79mmol
  • the product was purified by flash chromatography on silica (eluant EtOAc:pet ether 20:80); yield 774mg (74%).
  • Example 10D The acid of Example 10D (l .O ⁇ mmol) was coupled to methionine methyl ester hydrochloride (199.7mg,1.27mmol) following the method of Example 1H.
  • the product was purified by flash chromatography on silica (eluant EtOAc ⁇ et. ether35:65); yield 581mg (65%).
  • Example 10E The ester of Example 10E (300mg, 0.358mmol) was hydrolysed with lithium hydroxide (23mg, 0.538mmol) as described in Example 5 A; assume 100% yield.
  • Example 10F The compound of Example 10F (0.358mmol ) was deprotected following the method of Example 2G.
  • the product was purified by preparative HPLC (gradient water: acetonitrile 80:20- ⁇ 20:80; 0.1% TFA) and lyophilised; yield 103mg (60%).
  • Example 1 IC N- ⁇ 3-Nitro-6-phenyl-2-pyridy ⁇ -D-alanine-N-(2-methoxybenzyl)amide
  • 2-methoxybenzylamine 262mg, 1.68mmol
  • the product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 30:70 - 50:50); yield 256mg (68%).
  • Example HE The compound of Example HE (0.54mmol) was reacted with N-BOC-S- tritylcysteinal(330mg, 0.68mmol) and sodium cyanoborohydride (l lOmg, 1.79mmol) as described in Example IF.
  • the product was purified by flash chromatography on silica (eluant EtOAc:pet ether 25:75); yield 190mg (42%).
  • 1 1 G N- ⁇ 3- ( 2-Amino-3-mercaptopropy lamino)-6-pheny 1-2-pyridy 1 ⁇ -D-alanine-N-(2- methoxybenzyDamide
  • Example 1 IF The compound of Example 1 IF (180mg, 0.215mmol) was deprotected following the method of Example 2G.
  • the product was purified by preparative HPLC (gradient wate ⁇ acetonitrile 80:20-> 20:80; 0.1% TFA) and lyophilised; yield 35.2mg (35%).
  • ASSAY 1 Farnesyl Protein Transferase 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 j0 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 [ H]thymidine 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. Table 2
  • stereochemical descriptors to identify the particular stereoisomers concerned.
  • stereoisomeric compounds of formula 1 in general all related stereoisomers exist and are obtainable and are included in the invention individually and severally and in any admixture.
  • compounds indicated in R- (or S-) form are available in the possible S- (or R-) and RS- forms and all possible such forms are included in the invention as isolated isomers and mixtures thereof, as expressed herein by recitation of the compound with no stereochemical descriptor.
  • N- ⁇ -2-[3-(2- amino-3 mercaptylpropylamino)-6-phenyl-2-pyridyloxy)propionyl ⁇ -phenylalanine indicates any of the 2R-, 2S- and 2RS- isomers (compounds 131 , 134 and 136) separately and in any mixture of two or all thereof, and similar considerations apply to the recitation without stereochemical descriptor (e.g. in the following claims) of any other stereoisomeric compound of the invention.
  • N- ⁇ 3-(2-aminomercaptopropylamino)-6-phenyl-2- pyridyl ⁇ -alanine-(N-benzyl) amide and the corresponding -(N-2-methoxybenzyl)amide are available as the L-isomers instead of the D-isomers (compounds 184 and 189) and as iso er mixtures, and these separate isomers and the mixtures are part of the invention.

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Abstract

3-Aminopyridine derivatives of formula (1), wherein W is a group of general formula (2) or general formula (3) are inhibitors of T-cell proliferation and protein farnesyl transferase. They are useful as pharmaceutical agents for the treatment of inflammatory and malignant diseases.

Description

3 -Aminopyridine Derivatives for Treatment of Inflammatory and Malignant Diseases
BACKGROUND
The immune response is essential for the defence of the body against invading pathogens. However, an inappropriate activation of the immune system has been implicated in the etiology of some serious disease states. These are characterised by progressive tissue damage with inflammation and invasion of the lesion by leukocytes. Examples of such diseases include inflammatory bowel disease, asthma, psoriasis and rheumatoid arthritis. Current therapeutic regimens for these conditions arc 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 farnesyl protein transferase (EC 2.5.1 p21 AS 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.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention arc pyridine derivatives of general formula 1 :
Figure imgf000003_0001
formula 1 in which:
W is a group of general formula 2 or general formula 3:
Figure imgf000004_0001
formula 2 formula
X is a covalent bond; -CH ; -0-; -NH-; -NMe-; or -S-
Y is -O-, -S- or -NR3-:
R is hydrogen; linear or branched lower alkyl (C, - C8); lower cycloalkyl (C3 - C8); substituted or unsubstituted phenyl or naphthyl: or substituted or unsubstituted monocyclic or benzofused heteroaryl:
R is hydrogen; linear or branched lower alkyl (C, - C4) or Ph(CH2)m:
R is hydrogen or linear or branched lower alkyl (C, - C4):
R and R3 are independently hydrogen; linear or branched lower alkyl (C{ - C8); lower cycloalkyl (C3 - C8) which may be benzofused or substituted with COR ; substituted or unsubstituted phenyl or naphthyl, substituted or unsubstituted monocyclic or benzofused heteroaryl; COR6; or R4 and R5 together with the nitrogen atom and the methylene groups to which they are attached form a saturated heterocycle of up to 8 atoms which may be benzofused or substituted with COR :
R6 is OH; O-alkyl; NH2; NH-alkyl; N(alkyl)2; or NHSO2-alkyl (wherein alkyl includes linear or branched lower alkyl C( - C8, lower cycloalkyl C3 - C8 and (cycloalkyl)alkyl C4 - C10); or R and R together are -O(CH2)2- to form a γ-lactone ring:
R is selected from linear or branched lower alkyl (C, - C6) or (CH2)CR9; or R7 and R together are -(CH2)2O- to form a γ-lactone ring:
R is hydrogen or methyl:
R9 is OH; OCH3; SCH3; SOMe; SO2Me; NHCOMe; optionally substituted phenyl; or COR6:
R , R , R and R are independently hydrogen or lower alkyl or phenyl:
a, b and c are integers in the range 0-4:
m is 0, 1 or 2:
n is 1, 2 or 3.
p is 1 or 2.
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.
A preferred embodiment of the invention is a compound of formula 1 in which R is an optionally substituted phenyl group, X is a covalent bond and Y is an oxygen atom, all the other groups being as defined above.
A most preferred embodiment of the invention is a compound selected from:
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- phenylpropyl)acetamide (Compound 1)
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-benzylacetamide (Compound 2)
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2-phenylethyl)- acetamide (Compound 3)
2- { 3 -(2-Amino-3 -mercaptopropy lamino)-6-pheny 1-2-pyridy loxy } -N-( 4 -phenylbuty 1)- acetamide (Compound 4)
2- { 3 -(2-Amino-3 -mercaptopropy lamino)-6-pheny 1-2 -pyridy loxy } -N-buty lacetamide (Compound 5)
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-phenylacetamide (Compound 6)
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-benzyl-N- methylacetamide (Compound 7) 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-methyl-N-(2- phenylethyl)acetamide (Compound 8)
2- { 3-(2-Amino-3 -mercaptopropylamino)-6-pheny 1-2-pyridyloxy } -N-( 1 - naphthylmethyl)acetamide (Compound 9)
2- { 3-(2-Amino-3 -mercaptopropylamino)-6-pheny 1-2-pyridyloxy } -N-(2- naphthylmethyl)acetamide (Compound 10)
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- pyridylmethyl)acetamide (Compound 1 1)
2- { 3 -(2- Amino-3-mercaptopropylamino)-6-pheny 1-2-pyridyloxy } -N-(3 - pyridylmethyl)acetamide (Compound 12)
N- { 3 -(2- Amino-3 -mercaptopropy lamino)-6-pheny 1-2-pyridy loxy acetyl } methionine (Compound 13)
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}methionine methyl ester (Compound 14)
N-{3-(2-A_nino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}- methioninesulphone (Compound 15)
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}- methioninesulphoxide (Compound 16)
N- { 3 -(2- Amino-3 -mercaptopropy lamino)-6-pheny 1-2-pyridyloxyacety 1 } - homophenylalanine (Compound 17) Nα-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}glutamine (Compound 18)
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}glutamic acid (Compound 19)
2- { 3-(2-Amino-3 -mercaptopropylamino)-6-pheny 1-2-pyridyloxyacetamido } pentanoic acid (Compound 20)
Nα- { 3 -(2-Amino-3 -mercaptopropy lamino)-6-phenyl-2-pyridyloxyacetyl } -Nω-methy 1- glutamine (Compound 21)
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}- methionineamide (Compound 22)
Nα-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}-Nω- methanesulphonylglutamine (Compound 23)
N- { 3 -(2-Amino-3 -mercaptopropylamino)-6-pheny 1-2-pyridyloxyacetyl } methionine methanesulphonimide (Compound 24)
N- { 3 -(2- Amino-3 -mercaptopropy lamino)-6-pheny 1-2-pyridy loxy acetyl } homoserine lactone (Compound 25)
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}phenylalanine (Compound 26)
N- { 3 -(2- Amino-3 -mercaptopropy lamino)-6-pheny 1-2-pyridy loxy acetyl } serine (Compound 27) N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}aspartic acid (Compound 28)
N- { 3 -(2-Amino-3-mercaptopropy lamino)-6-pheny 1-2-pyridy loxyacetyl } - homophenylalanineamide (Compound 29)
Nα-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}asparagine (Compound 30)
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}- homophenylalanine methyl ester (Compound 31)
N- { 3-(2-Amino-3 -mercaptopropy lamino)-6-phenyl-2-pyridyloxyacety 1 } - methioninesulphoxide methyl ester (Compound 32)
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}methionine- N-methylamide (Compound 33)
N -Acetyl-N -{3-(2-amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}- 2,3-diaminopropionic acid (Compound 34)
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}methionine- N,N-dimethylamide (Compound 35)
(2i?)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(4- phenylbutyl)propionamide (Compound 36)
(2i?)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-benzyl- propionamide (Compound 37) (2R)-2- { 3 -(2- Amino-3 -mercaptopropylamino)-6-pheny 1-2-pyridy loxy } -N-(3 ,4- dichlorobenzyl)propionamide (Compound 38)
(2R)-2- { 3 -(2-Amino-3-mercaptopropylamino)-6-pheny 1-2-pyridyloxy } -N-(2- thienylmethyl)propionamide (Compound 39)
(2__)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(4- methoxybenzyl)propionamide (Compound 40)
(2_.)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(4- methybenzyl)propionamide (Compound 41)
(2J?)-2- { 3 -(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy } -N-(4- chlorobenzyl)propionamide (Compound 42)
(2_.)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- methyloxycarbonylbenzyl)propionamide (Compound 43)
(2__)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(4- methyloxycarbonylbenzyl)propionamide (Compound 44)
(2__)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3-carboxy- benzyl)propionamide (Compound 45)
(2 _)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(4-carboxy- benzyl)propionamide (Compound 46)
(2_.)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(l- naphthylmethyl)propionamide (Compound 47) (2R)-2- { 3 -(2- Amino-3 -mercaptopropy lamino)-6-pheny 1-2-pyridyloxy } -N-(2- naphthylmethyl)propionamide (Compound 48)
(2i?)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N- (cyclohexylmethyl)propionamide (Compound 49)
(2_?)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2-hydroxy- benzyl)propionamide (Compound 50)
(2_?)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- phenylethyl)propionamide (Compound 51)
(2R)-2-{ 3 -(2-Amino-3 -mercaptopropy lamino)-6-phenyl-2-pyridyloxy}propionamide (Compound 52)
(2R)-2- { 3 -(2- Amino-3 -mercaptopropy lamino)-6-pheny 1-2-pyridy loxy } -N-(( 1 S)- 1 - phenylethyl)propionamide (Compound 53)
(2i.)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-((l_-)-l- phenylethyl)propionamide (Compound 54)
(2_?)-2- { 3 -(2-Amino-3-mercaptopropylamino)-6-pheny 1-2-pyridyloxy } -N-(4- (benzyloxycarbonylamino)benzyl)propionamide (Compound 55)
(2__)-2- { 3 -(2- Amino-3 -mercaptopropylamino)-6-pheny 1-2-pyridy loxy } -N-(3 - chlorobenzy propionamide (Compound 56)
(2R)-2- { 3 -(2-Amino-3 -mercaptopropy lamino)-6-pheny 1-2-pyridyloxy } -N-(3 - pyridylmethyl)propionamide (Compound 57)
(2i.)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- pyridylmethyl)propionamide (Compound 58)
(2R)-2- { 3-(2-Amino-3 -mercaptopropylamino)-6-phenyl-2-pyridy loxy } -N-(4- pyridylmethyl)propionamide (Compound 59)
(2R)-2- { 3 -(2-Amino-3-mercaptopropy lamino)-6-phenyl-2-pyridyloxy } -N-(2- furylmethyl)propionamide (Compound 60)
(2i-)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- hydroxybenzyl)propionamide (Compound 61)
(2R)-2- { 3 -(2-Amino-3 -mercaptopropy lamino)-6-pheny 1-2-pyridyloxy } -N-(4- hydroxybenzyl)propionamide (Compound 62)
(2_ )-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- bromobenzyl)propionamide (Compound 63)
(2R)-2- { 3 -(2- Amino-3 -mercaptopropylamino)-6-pheny 1-2-pyridy loxy } -N-(3 - nitrobenzyl)propionamide (Compound 64)
(2__)-2- { 3 -(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy } -N-(4- (methyloxycarbonyl)cyclohexylmethyl)propionamide (Compound 65)
(2i?)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- methoxybenzyl)propionamide (Compound 66)
(2i?)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- methylbenzyl)propionamide (Compound 67)
(2i?)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- methylbenzyl)propionamide (Compound 68) (2_?)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- methoxybenzyl)propionamide (Compound 69)
(2R)-2-{ 3 -(2- Amino-3 -mercaptopropylamino)-6-phenyl-2-pyridyloxy } -N-(2- chlorobenzyl)propionamide (Compound 70)
(2R)-2- { 3 -(2-Amino-3 -mercaptopropylamino)-6-phenyl-2-pyridyloxy } -N-(3- (methanesulphony laminocarbony l)benzyl)propionamide (Compound 71 )
(2_.)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- carboxamidobenzyl)propionamide (Compound 72)
(2_.)-N-(3-Aminobenzyl)-2-{3-(2-amino-3-mercaptopropylamino)-6-phenyl-2- pyridyloxy}propionamide (Compound 73)
(2_?)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- phenylbenzyl)propionamide (Compound 74)
(2i?)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- trifluoromethylbenzyl)propionamide (Compound 75)
(2_-)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N- (diphenylmethyl)propionamide (Compound 76)
(2i-)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- methylaminocarbonylbenzyl)propionamide (Compound 77)
(2i-)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- dimethylaminocarbonylbenzyl)propionamide (Compound 78)
l l (2_?)-2- { 3 -(2- Amino-3 -mercaptopropy lamino)-6-pheny 1-2-pyridy loxy } -N-(2- phenylbenzyl)propionamide (Compound 79)
(2__)-2- { 3 -(2-Amino-3-mercaptopropylamino)-6-pheny 1-2-pyridyloxy } -N-(2- bromobenzyl)ρropionamide (Compound 80)
(2_?)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N,N-dibenzyl- propionamide (Compound 81)
(2i?)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(l-indanyl)- propionamide (Compound 82)
(2R)-2- { 3-(2-Amino-3 -mercaptopropylamino)-6-phenyl-2-pyridy loxy } -N-(2- nitrobenzyl)propionamide (Compound 83)
(2_?)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2,3- dimethoxybenzyl)propionamide (Compound 84)
(2__)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- ethoxybenzyl)propionamide (Compound 85)
(2__)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- acetamidobenzyl)propionamide (Compound 86)
(2_?)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- bis(methanesulphonyl)aminobenzyl)propionamide (Compound 87)
(2_.)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-isopropyl- propionamide (Compound 88) (2__)-2-{3-(2-Ammo-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- bromobenzyl)propionamide (Compound 89)
(2R)-2- { 3 -(2- Amino-3 -mercaptopropy lamino)-6-phenyl-2-pyridyloxy } -N-tert-buty 1- propionamide (Compound 90)
(2R)-2- { 3 -(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy } -N- cyclopentylpropionamide (Compound 91)
(2_?)-2- { 3 -(2-Amino-3 -mercaptopropy lamino)-6-phenyl-2-pyridyloxy } -N-cyclohexyl- propionamide (Compound 92)
(2i?)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-cyclobutyl- propionamide (Compound 93)
(2_.)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2,6- dichlorobenzyl)propionamide (Compound 94)
(2_?)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3-pentyl)- propionamide (Compound 95)
(2__)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3,5- dimethoxybenzyl)propionamide (Compound 96)
(2R)-2- { 3-(2-Amino-3 -mercaptopropy lamino)-6-pheny 1-2-pyridyloxy } -N-(4- fluorobenzyl)propionamide (Compound 97)
(2i?)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- methylbutyl)propionamide (Compound 98) (2i.)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2,5- dimethoxybenzyl)propionamide (Compound 99)
(2__)-2- { 3 -(2- Amino-3 -mercaptopropylamino)-6-phenyl-2-pyridyloxy } -N-(2- trifluoromethoxybenzy propionamide (Compound 100)
(2 ?)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2,6- dimethoxybenzyl)propionamide (Compound 101)
(2i?)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3-chloro- 4-fluorobenzyl)propionamide (Compound 102)
(2_!)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2-chloro- 4-fluorobenzyl)propionamide (Compound 103)
(27?)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- acetamidobenzyl)propionamide (Compound 104)
(2_?)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2-(2- methoxyphenyl)ethyl)propionamide (Compound 105)
(2R)-2- { 3 -(2-Amino-3 -mercaptopropy lamino)-6-pheny 1-2-pyridy loxy } -N-(2-( 1 - cyclohexenyl)ethyl)propionamide (Compound 106)
(2_?)-2- { 3 -(2- Amino-3 -mercaptopropy lamino)-6-pheny 1-2-pyridy loxy } -N-(2- cyclohexylethyl)propionamide (Compound 107)
(2R)-2- { 3 -(2-Amino-3 -mercaptopropy lamino)-6-phenyl-2-pyridy loxy } -N-(2- dimethylamino-6-fluorobenzyl)propionamide (Compound 108) (2_-)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- fluorobenzy propionamide (Compound 109)
(2R)-2- { 3 -(2-Amino-3 -mercaptopropy lamino)-6-pheny 1-2-pyridyloxy } -N-(2- methanesulfonylbenzyl)propionamide (Compound 110)
(2__)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(4- methanesulfonylbenzyl)propionamide (Compound 1 1 1)
(2R)-2-{ 3 -(2- Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy } -N-(2- methylthiobenzyl)propionamide (Compound 1 12)
(2_?)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- benzothienylmethyl)propionamide (Compound 113)
(2_.)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-methyl-N- (l-phenylethyl)propionamide (Compound 1 14)
(2i?)-2- { 3 -(2-Amino-3 -mercaptopropy lamino)-6-pheny 1-2-pyridyloxy } -N-(4- methanesulfιnylbenzyl)propionamide (Compound 115)
(2__)-2-{3-(2-A__ιino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-phenyl- propionamide (Compound 116)
(2 ?)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2-indanyl)- propionamide (Compound 117)
(2i?)-2- { 3 -(2- Amino-3 -mercaptopropy lamino)-6-pheny 1-2-pyridy loxy } -N- (cyclopentylmethyl)propionamide (Compound 118) (2__)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- methylphenyl)propionamide (Compound 1 19)
(2__)-2- { 3 -(2- Amino-3 -mercaptopropy lamino)-6-pheny 1-2-pyridy loxy } -N-(4- methylphenyl)propionamide (Compound 120)
(2 ?)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-methyl-N- (3-methylbenzyl)propionamide (Compound 121)
(2R)-2- { 3 -(2- Amino-3 -mercaptopropy lamino)-6-pheny 1-2-pyridyloxy } -N-methy 1-N- (2-methylbenzyl)propionamide (Compound 122)
(2_?)-2- { 3-(2-Amino-3 -mercaptopropylamino)-6-phenyl-2-pyridyloxy } -N-( 1 -(2- methylphenyl)ethyl)propionamide (Compound 123)
(2i?)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(l-(3- methylphenyl)ethyl)propionamide (Compound 124)
2- { (2i?)-2- { 3 -(2-Amino-3-mercaptopropylamino)-6-pheny 1-2-pyridyloxy } propiony 1 } - 1,2,3,4-tetrahydroisoquinoline (Compound 125)
(2i?)-2- { 3 -(2- Amino-3 -mercaptopropylamino)-6-pheny 1-2-pyridyloxy } -N-( 1 -indany 1)- N-methylpropionamide (Compound 126)
(2__)-2-{3-(2-Ammo-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- chlorobenzyl)-N-methylpropionamide (Compound 127)
(2_?)-2- { 3 -(2- Amino-3 -mercaptopropy lamino)-6-pheny 1-2-pyridyloxy } -N-(2 ,3 - dimethylbenzyl)propionamide (Compound 128) N-{(2 .)-2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)propionylj - methionine methyl ester (Compound 129)
N- { (2_ )-2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)propionyl } - methionine (Compound 130)
N-{(27.)-2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)propionyl}- phenylalanine (Compound 131)
N- { (2_.)-2-(3 -(2-Amino-3 -mercaptopropylamino)-6-pheny l-2-pyridyloxy)propiony 1 } - phenylalanine methyl ester (Compound 132)
N-{(2S)-2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)propionyl}- phenylalanine methyl ester (Compound 133)
N- { (2S)-2-(3 -(2-Amino-3 -mercaptopropy lamino)-6-phenyl-2-pyridyloxy)propionyl } - phenylalanine (Compound 134)
N-{(2i.S)-2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2- pyridyloxy)propionyl} phenylalanine methyl ester (Compound 135)
N- { (2RS)-2-(3 -(2- Amino-3 -mercaptopropy lamino)-6-pheny 1-2- pyridyloxy)propionyl} phenylalanine (Compound 136)
N-{(2_.)-2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-2- phenylacetyl} methionine (Compound 137)
N-{(2S)-2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-2- phenylacetyl} methionine (Compound 138) N-{(2Λ)-2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)butyryl}- methionine methyl ester (Compound 139)
N- { (2S)-2-(3-(2-Amino-3-mercaptopropylamino)-6-pheny l-2-pyridyloxy)butyryl } - methionine methyl ester (Compound 140)
N-{(2_ )-2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)butyryl}- methionine (Compound 141)
N- { (2S)-2-(3 -(2-Amino-3 -mercaptopropylamino)-6-pheny l-2-pyridyloxy)butyryl } - methionine (Compound 142)
N- { (2_?)-2-(3-(2-Amino-3 -mercaptopropylamino)-6-phenyl-2-pyridyloxy)hexanoy 1 } - methionine (Compound 143)
N-{(2S)-2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)hexanoyl}- methionine (Compound 144)
N- { (2R)-2-(3 -(2- Amino-3 -mercaptopropy lamino)-6-pheny l-2-pyridyloxy)hexanoy 1 } - methionine methyl ester (Compound 145)
N-{(2S)-2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)hexanoyl}- methionine methyl ester (Compound 146)
N-{(2__)-2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)pentanoyl}- methionine methyl ester (Compound 147)
N-{(2S)-2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)pentanoyl}- methionine methyl ester (Compound 148) N-{(2i.)-2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)pentanoyl}- methionine (Compound 149)
N- { (2S)-2-(3 -(2- Amino-3 -mercaptopropylamino)-6-phenyl-2-pyridyloxy)pentanoyl } - methionine (Compound 150)
N- { 3 -(2-Amino-3 -mercaptopropylamino)-6-(2-chlorophenyl)-2-pyridyloxyacetyl } - methionine (Compound 151)
N-{3-(2-Amino-3-mercaptopropylamino)-6-(3-trifluoromethylphenyl)-2- pyridyloxyacetyl} methionine (Compound 152)
N- { 3 -(2-Amino-3 -mercaptopropy lamino)-6-(3 -methoxypheny l)-2-pyridyloxyacety 1 } - methionine (Compound 153)
N-{3-(2-Amino-3-mercaptopropylamino)-6-(3-hydroxymethylphenyl)-2- pyridyloxyacetyl} methionine (Compound 154)
N- { 3 -(2- Amino-3 -mercaptopropy lamino)-6-(3 -acetamidophenyl)-2- pyridyloxyacetyl} methionine (Compound 155)
N- { 3 -(2- Amino-3 -mercaptopropy lamino)-6-(2-bipheny ly l)-2-pyridy loxyacetyl } - methionine (Compound 156)
N- { 3-(2-Amino-3 -mercaptopropy lamino)-6-(4-biphenyly l)-2-pyridy loxyacetyl } - methionine (Compound 157)
N-{3-(2-Amino-3-mercaptopropylamino)-6-(3-methyloxycarbonylphenyl)-2- pyridy loxyacetyl} methionine (Compound 158) N-{3-(2-Amino-3-mercaptopropylamino)-6-(3-methyloxycarbonylphenyl)-2- pyridy loxyacetyl} methionine methyl ester (Compound 159)
N-{3-(2-Amino-3-mercaptopropylamino)-6-(3-carboxyphenyl)-2-pyridyloxyacetyl}- methionine (Compound 160)
N-{3-(2-Amino-3-mercaptopropylamino)-6-(2,4,6-trimethylphenyl)-2- pyridy loxy acetyl} methionine (Compound 161)
N-{3-(2-Amino-3-mercaptopropylamino)-6-(3-biphenylyl)-2-pyridyloxyacetyl}- methionine (Compound 162)
2- { 3-(2-Amino-3 -mercaptopropy lamino)-6-butyl-2-pyridy loxy } -N-(3 -phenylpropyl)- acetamide (Compound 163)
N-{3-(2-Amino-3-mercaptopropylamino)-6-(2-naphthyl)-2-pyridyloxyacetyl}- methionine (Compound 164)
N- { 3 -(2-Amino-3-mercaptopropylamino)-2-pyridyloxyacety 1 } methionine (Compound 165)
N- { 3 -(2- Amino-3 -mercaptopropy lamino)-6-(2-thieny l)-2-pyridy loxyacetyl } - methionine (Compound 166)
N-{3-(2-Amino-3-mercaptopropylamino)-6-(2-benzofuryl)-2-pyridyloxyacetyl}- methionine (Compound 167)
N- { 3 -(2- Amino-3 -mercaptopropy lamino)-6-buty 1-2-pyridy loxyacetyl } methionine (Compound 168) N-{ 3 -(2- Amino-3 -mercaptopropy lamino)-6-(l-naphthyl)-2-pyridy loxyacetyl }- methionine (Compound 169)
N-{3-(2-Amino-3-mercaptopropylamino)-6-(2-thienyl)-2-pyridyloxyacetyl}- methionine methyl ester (Compound 170)
N- { 3 -(2-Amino-3 -mercaptopropylamino)-6-( 1 -naphthy l)-2-pyridy loxyacetyl } - methionine methyl ester (Compound 171)
N-{3-(2-Amino-3-mercaptopropylamino)-6-butyl-2-pyridyloxyacetyl}methionine methyl ester (Compound 172)
N-{(2i?)-2-(3-(2-Amino-3-mercaptopropylamino)-6-butyl-2-pyridyloxy)propionyl}- methionine (Compound 173)
N- { (2S)-2-(3 -(2-Amino-3 -mercaptopropylamino)-6-buty l-2-pyridyloxy)propiony 1 } - methionine (Compound 174)
N-{(2_J)-2-(3-(2-Amino-3-mercaptopropylamino)-2-pyridyloxy)-3-phenylpropionyl}- methionine (Compound 175)
N-{(2S)-2-(3-(2-Amino-3-mercaptopropylamino)-2-pyridyloxy)-3-phenylpropionyl}- methionine (Compound 176)
N-{(2i?)-2-(3-(2-Amino-3-mercaptopropylamino)-2-pyridyloxy)-3-phenylpropionyl}- methionine methyl ester (Compound 177)
N- { (2S)-2-(3-(2-Amino-3 -mercaptopropylamino)-2-pyridyloxy)-3 -phenylpropionyl } - methionine methyl ester (Compound 178) N-{3-(2-Amino-3-mercaptopropylamino)-6-benzyl-2-pyridyloxyacetyl) methionine methyl ester (Compound 179)
N- { 3 -(2-Amino-3 -mercaptopropylamino)-6-benzyl-2-pyridy loxyacetyl } methionine (Compound 180)
N- { 3-(2-Amino-3-mercaptopropylamino)-6-phenoxy-2-pyridyloxyacetyl } methionine methyl ester (Compound 181)
N- { 3-(2- Amino-3 -mercaptopropylamino)-6-phenoxy-2-pyridyloxyacetyl } methionine (Compound 182)
N- { 3-(2-Amino-3 -mercaptopropy lamino)-6-pheny 1-2-pyridyl } alanine-(N- benzyl)amide (Compound 183)
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyl}-D-alanine-(N- benzyl)amide (Compound 184)
N- { 3-(2-Amino-3 -mercaptopropylamino)-6-pheny 1-2-pyridyl } -N-methylalanine-(N- benzyl)amide (Compound 185)
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyl}glycine-(N- benzyl)amide (Compound 186)
N-{3-(2-Amino-3-mercaptopropyiamino)-6-phenyl-2-pyridyl}-N-methylglycine-(N- benzyl)amide (Compound 187)
N- { 3-(2-Amino-3 -mercaptopropylamino)-6-phenyl-2-pyridyl } -N-methylalanine-(N- benzyl)amide (Compound 188)
99 N- { 3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyl } -D-alanine-(N-2- methoxybenzyl)amide (Compound 189)
N- { 3-(2-Amino-3 -mercaptopropylamino)-6-phenyl-2-pyridy 1 } alanine-(N- 1 - phenylethyl)amide (Compound 190)
(2_.S)-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridylthio}-N-benzyl- propionamide (Compound 191)
(2_.)-2-{3-(3-Amino-4-mercaptobutylamino)-6-phenyl-2-pyridyloxy}-N-(3- methyloxycarbonylbenzyl)propionamide (Compound 192)
(2i.)-2-{3-(3-Amino-4-mercaptobutylamino)-6-phenyl-2-pyridyloxy}-N-benzyl- propionamide (Compound 193)
(2__)-2- { 3 -(3 -Amino-4-mercaptobutylarnino)-6-phenyl-2-pyridyloxy } -N-(2- pyridylmethyl)propionamide (Compound 194)
(2_,)-2-{3-(3-A_nino-4-mercaptobutylamino)-6-phenyl-2-pyridyloxy}-N-(2- methylbenzy propionamide (Compound 195)
(2_?)-2-{3-(3-Amino-4-mercaptobutylamino)-6-phenyl-2-pyridyloxy}-N-(2- chlorobenzyl)propionamide (Compound 196)
(2__)-2-{3-(3-Amino-4-mercaptobutylamino)-6-phenyl-2-pyridyloxy}-N-(3- methyloxycarbonylbenzyl)-N-methylpropionamide (Compound 197)
N- { 3 -(3 - Amino-4-mercaptobuty lamino)-6-pheny 1-2-pyridy loxyacetyl } methionine methyl ester (Compound 198) N-{3-(3-Amino-4-mercaptobutylamino)-6-phenyl-2-pyridyloxyacetyl} methionine (Compound 199)
N-{3-(3-Amino-4-mercaptobutylamino)-6-phenyl-2-pyridyloxyacetyl}phenylalanine methyl ester (Compound 200)
N- { 3 -(3 -Amino-4-mercaptobuty lamino)-6-pheny 1-2-pyridy loxyacetyl } phenylalanine (Compound 201)
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 neurofibromatosis.
When used to treat these conditions 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 general methods for the synthesis of the compounds of the invention is outlined below. For simplicity, the structural formulae show the case where p=l . The analogues in which p=2 can be prepared in the same way but starting with the appropriate homocysteine derivative in place of cysteine.
The compounds of general formula 1 are prepared from a precursor (formula 4) in which the potentially reactive amino (NH2) and mercapto (SH) groups are masked. Suitable masking groups are well known to practitioners of the art. Conveniently, the amino group is protected as its tert-butyl carbamate (BOC) derivative and the mercapto group is protected as its triphenylmethyl (trityl) thioether. In this case both protecting groups can be removed by treating the compound with a strong acid (for example trifluoroacetic acid) in a solvent such as dichloromethane in the presence of a cation scavenger such as triethylsilane.
Figure imgf000027_0001
formula 4 formula 1
The compound of formula 4 can be prepared by coupling an amine H-W with an acid of formula 5. This may be achieved by any of several well known methods for amide bond formation (for example, the use of a carbodiimide or a phosphorus reagent such as BOP).
Figure imgf000028_0001
formula 5 formula 4 (where BOC = Me3COCO and Trt = Ph3C)
In some embodiments of the invention there will be functionality in W that is incompatible with this reaction. For example, W may include a carboxyhc acid functional group or a second amine. Either of these would lead to a mixture of products arising from competition between alternative reaction centres. In these cases it will be necessary to use an amine H-W' in which the competing functional group is modified. Such a modification will generally involve the use of a protecting group, and it will often be most convenient if the protecting group is cleaved under the same conditions as are used to effect the final deprotection (formula 4 — . formula 1). Occasionally it may be preferable to deprotect W' in a separate operation. The choice of protection strategy for W' will reflect these considerations.
The acid of formula 5 is generally prepared from a suitable ester (formula 6). Conveniently, this will be a lower alkyl ester such as the methyl or ethyl ester. In this case the acid is released by alkaline hydrolysis using, for example, lithium hydroxide in a mixed water/dioxan solvent system.
Figure imgf000028_0002
formula 6 formula 5 The ester of formula 6 can be prepared from an aminopyridine (formula 7) and an aldehyde (formula 8) using conditions known to effect such reductive aminations. Typically this will involve mixing the aminopyridine and the aldehyde in a solvent such as methanol containing 1-10% acetic acid, and subsequently treating the mixture with a reducing agent such as sodium cyanoborohydride.
Figure imgf000029_0001
The aminopyridine of formula 7 can be prepared from the corresponding nitropyridine (formula 9) by any of several well known protocols (for example, hydrogenation in the presence of a platinum or palladium catalyst, reaction with zinc in acetic acid, reaction with sodium hydrosulphite)
Figure imgf000029_0002
The aldehyde of formula 8 can be prepared from the corresponding alcohol by oxidation or from an appropriate carboxyhc acid derivative by reduction. For the case where n=l the starting material for these reactions is protected cysteine.
Figure imgf000030_0002
Figure imgf000030_0001
formula 8 (n=l)
One convenient method is to proceed via the N,O-dimethyl oxamate [Z = N(Me)OMe] which can be reduced to the aldehyde with lithium aluminium hydride. For the case where n=2 it is first necessary to homologate the cysteine. This can be achieved via a diazoketone intermediate.
Figure imgf000030_0003
formula 8 (n=2)
It is possible to reverse the order in which the substituents on the pyridine are elaborated. Starting from the nitropyridine of formula 9, hydrolysis to the corresponding acid (formula 10) and coupling with H-W (or H-W') using protocols analogous to those described above leads to the nitropyridine of formula 11.
Figure imgf000031_0001
The nitro group can then be reduced to give the aminopyridine (formula 12) which is then reacted with the aldehyde as described above to give the protected compound of formula 4.
Figure imgf000031_0002
formula 11 formula 12
Figure imgf000031_0003
formula 12 formula 8 formula 4
The nitropyridine of formula 9 can be prepared by two routes. In the first, the group
R -X is introduced into a chloropyridine of formula 13. When X is a heteroatom
(oxygen, nitrogen or sulphur) the second component in the reaction is R , I - XH and the reaction requires a basic catalyst such as potassium fluoride or sodium carbonate. When X is CH2 or a covalent bond then the reaction is best achieved by a Suzuki coupling. This involves the reaction of the chloropyridine with a boronic acid R'XB(0H)2 (or a boronate ester) in the presence of a palladium catalyst.
Figure imgf000032_0001
formula 13
Figure imgf000032_0002
The chloropyridine of formula 13 is obtained from 2,6-dichloro-3-nitropyridine and a fragment of formula 14. These react in the presence of a base such as sodium carbonate, sodium hydride or potassium tert-butoxide.
Figure imgf000032_0003
formula 14 formula 13
The second route to the nitropyridine of formula 9 involves the alkylation of a pyridone of formula 15 (which can exist as the tautomeric hydroxypyridine). This route is mainly of value when Y = O, although use of the analogous thiopyridone would lead to a product in which Y = S. The reaction can be performed under basic conditions, in which case the alkylating agent is a bromide, chloride or sulphonate (formula 16: LG = Br, CI, RSO3). The reaction can also be performed under neutral conditions using the Mitsunobu protocol (Ph3P, EtO2CN:NCO2Et) in which case the alkylating agent is an alcohol (LG = OH)
Figure imgf000033_0001
formula 15 formula 16 formula 9 (Y = O)
The pyridone and the alkylating agent will, in most cases, be known in the literature. Otherwise they can be prepared by methods analogous to those described for similar compounds.
A variation of this pyridone route starts with a pyridonenitrile of formula 17. For some combinations of R and X, the nitrile may be more accessible than the nitropyridine. The nitrile can be hydrolysed to the corresponding acid (formula 18) in the presence of strong acids. The acid is then subjected to a Curtius rearrangement using diphenylphosphoryl azide and benzyl alcohol to give a protected aminopyridine of formula 19.
Figure imgf000033_0002
formula 17 formula 18 formula 19
The use of benzyl alcohol in this reaction results in the amine being protected as its benzyl carbamate. When this is incompatible with the chemistry necessary for the further elaboration of this intermediate to the target compound a different alcohol may be used. The resulting carbamate will be chosen to have the appropriate compatibility with the conditions to be used and to require deprotection conditions which will be compatible with the functionality present when the amine is liberated. This pyridone can then be alkylated as described above with the fragment of formula 16 to give the pyridine of formula 20.
Figure imgf000034_0001
formula 19 formula 16 formula 20
The protected aminopyridine of formula 20 can be further elaborated by either of two routes which are analogous to those described above for the nitropyridine of formula 9. The ester can be hydrolysed to the corresponding acid. This is then coupled to the amine corresponding to H-W or H-W'. The result is the pyridine of formula 21.
Figure imgf000034_0002
formula 20 formula 21
The amine function is then released. If, as illustrated, the amine is protected as its benzyl carbamate, the deprotection is conveniently performed by hydrogenolysis in the presence of a palladium or platinum catalyst. If a different alcohol was used in the Curtius rearrangement then the conditions for the deprotection will be chosen accordingly. The result is an amine of formula 12 (with Y = O) which can be taken on as described previously.
Figure imgf000035_0001
formula 21 formula 12 (Y = O)
The alternative route for the elaboration of the protected amine of formula 20 is to deprotect the amine prior to hydrolysis of the ester. This gives an amine of formula 7 (again with Y = O) which can be taken on as described above.
Figure imgf000035_0002
formula 20 formula 7 (Y = O)
These general methods are further illustrated in the following non-limiting examples.
EXAMPLE 1
N-{3-.2-Amino-3-mercaptopropylamino.-6-phenyl-2-pyridyloxyacetyl}- methionine methyl ester (Compound 14)
Figure imgf000036_0001
1A: 6-Phenyl-2-pyridone-3-carbonitrile
A solution of acetophenone (1 1.6mL, lOOmmol) and dimethylformamide dimethyl acetal (43.8mL, 330mmol) in acetonitrile was heated at reflux overnight, then cooled to room temperature and concentrated in vaciio. The residue was dissolved in dimethylformamide (160mL), cyanoacetamide (7.55g, 90mmol) and sodium methoxide (10.6g, 196mmol) were added, and the mixture was heated at 100°C for 5h, then allowed to stand at room temperature overnight. The solution was poured into water (500mL) and the mixture was acidified to pH2 with 1M HCl. The resulting precipitate was collected and dried over P2O5; yield 17.6g (100%).
IB: 6-Phenyl-2-pyridone-3-carboxylic acid
The nitrile of Example 1A (17.6g, 90mmol) was suspended in acetic acid (170mL). 48% HBr (8mL) was added and the mixture was heated at reflux overnight. The resulting solution was cooled to room temperature, diluted with water (lOOmL), and basified to pH5 with 10% NaOH (ca. 600mL). The precipitate was collected, washed with 1M HCl and water, and dried over P2O5; yield 13.7g (71%).
IC: 3-Benzyloxycarbonylamino-6-phenyl-2-pyridone
To a solution of the acid of Example IB (8.0g, 37.2mmol) in dioxan (200mL) was added triethylamine (6.2mL, 45mmol) and diphenylphosphoryl azide (8.8mL, 41mmol). The mixture was heated under reflux for 4h. Benzyl alcohol (7.7mL, 74mmol) was added and heating was continued overnight. The mixture was cooled to room temperature and concentrated in vacuo. The residue was washed with 1M HCl, satd. NaHCO3, water (twice) and ether (twice); yield 7.2g (60%).
ID: Methyl 2-{3-benzyloxycarbonylamino-6-phenyl-2-pyridyloxy}acetate To an ice-cold solution of the pyridone of Example IC (960mg, 3mmol) in dimethylformamide (lOmL) was added NaH (117mg, 80% dispersion, 3.9mmol). The mixture was allowed to warm to room temperature and stirred for 45min. Methyl bromoacetate (315μL, 3.3mmol) was added and stirring was continued overnight. The mixture was partitioned between EtOAc and 1M HCl, and the organic layer was washed with 5% KHCO3 and brine, then concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 25:75); yield 640mg (54%).
IE: Methyl 2-{3-amino-6-phenyl-2-pyridyloxy}acetate
To a degassed solution of the compound of Example ID (640mg, 1.63mmol) in methanol (50mL) was added 10% palladium-on-carbon (lOOmg). The mixture was stirred at room temperature under an atmosphere of hydrogen for 2h, then filtered. The catalyst was washed with methanol and the combined filtrates were concentrated in vacuo. The residue was dried by azeotropic evaporation with toluene and used without purification; assume 100% yield.
IF: Methyl 2-{3-(2-tert-butyloxycarbonylamino-3-triphenylmethylmercaptopropyO- 6-phenyl-2-pyridyloxy I acetate
To a solution of the aminopyridine of Example IE (1.63mmol) and N-BOC-S- tritylcysteinal (0.73g, 1.63mmol) in methanol (20mL) and acetic acid (0.2mL) was added sodium cyanoborohydride (113mg, 1.79mmol). The mixture was stirred overnight at room temperature and then concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 25:75); yield 893mg (79%). 1G: 2- .3-(2-tert-Butyloxycarbonylamino-3-triphenylmethylmercaptopropyl)-6- phenyl-2-pyridyloxy} acetic acid
To a solution of the ester of Example IF (893mg, 1.29mmol) in dioxan (lOmL) and water (lOmL) was added lithium hydroxide hydrate (60mg, 1.42mmol). The mixture was stirred overnight at room temperature then concentrated in vacuo. The residue was partitioned between dichloromethane and 0.5M KHSO4. The organic layer was washed with brine, dried over MgS04 and concentrated in vacuo; assume 100% yield.
1H: N-{3-(2-tgrt-Butyloxycarbonylamino-3-triphenylmethylmercaptopropyl)-6- phenyl-2-pyridyloxyacetyl} methionine methyl ester
To an ice-cold solution of the acid of Example 1G (half the total, 0.645mmol), methionine methyl ester hydrochloride (193mg, 0.968mmol), diisopropylethylamine (0.28mL, l .όlmmol) and 1 -hydroxybenzotriazole (150mg, l.lOmmol) in dichloromethane (40mL) was added WSCDI (198mg, 1.03mmol). The mixture was allowed to warm to room temperature and stirred for 3 days, then partitioned between EtOAc and water. The organic layer was washed with 1M KHSO4, satd. NaHCO3 and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica, (eluant EtOAc:pet.ether 30:70 then 40:60); yield 386mg (74%).
U N-{3-(2-Amino-3-mercaptopropyl)-6-phenyl-2-pyridyloxyacetyl}methionine methyl ester
To a solution of the ester of Example 1H (386mg, 0.476mmol) in dichloromethane (6mL) was added trifluoroacetic acid (3mL) and triethylsilane (0.38mL, 2.38mmol). The mixture was stirred overnight at room temperature, then diluted with toluene (2mL) and evaporated. The residue was purified by preparative HPLC (gradient water: acetonitrile 80:20 → 20:80; 0.1% TFA) and lyophilised; yield 155mg (68%) MS: calc m/e 478.17; found [M+H]+=479 EXAMPLE 2
.2R.-2-{3-(2-Amino-3-mercaptopropylaminoV6-phenyl-2-pyridyloxy.-N-(3- methyloxycarbonylbenzyl)propionamide (Compound 43.
Figure imgf000039_0001
2A: Methyl (2_?)-2-{3-benzyloxycarbonylamino-6-phenyl-2-pyridyloxy}propionate To an ice-cold stirred suspension of the pyridone of Example IC (16g, 50mmol) in dimethylformamide (lOOmL) was added sodium hydride (1.85g, 60% dispersion, 55mmol). The mixture was allowed to warm to room temperature and stirred for lh. Methyl (2S)-2-chloropropionate (6.74g, 55mmol) was added and the mixture was heated at 80°C for 4h then stirred at room temperature overnight and partitioned between EtOAc and 1M HCl. The organic layer was washed with 5% KHSO4, water (three times) and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 15:85); yield 6.0g (30%).
2B: Methyl (2i-V2-{3-amino-6-phenyl-2-pyridyloxy}propionate
The pyridone of Example 2A (6.0g, 14.7mmol) was hydrogenated over palladium following the method of Example IE. The product was used without purification.
2C: Methyl (2_.V2-(3-(2-tert-butyloxycarbonylamino-3- triphenylmethylmercaptopropylV6-phenyl-2-pyridyloxy}propionate
The aminopyridine of Example 2B (14.7mmol) was reacted with N-BOC-S-trityl- cysteinal (7.9g, 17.7mmol) and sodium cyanoborohydride (1.1 lg, 17.7mmol) in methanol (lOOmL) and acetic acid (7.5mL) following the method of Example IF. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 15:85); yield 7.91g (76%).
2D: (2_.V2-l3-(2-tgrt-Butyloxycarbonylamino-3-triphenylmethylmercaptopropylV6- phenyl-2-pyridyloxy}propionic acid
The ester of Example 2C (7.9 lg, 1 1.2mmol) was hydrolysed with lithium hydroxide hydrate (1.09g, 26mmol) in dioxan (20mL) and water (20mL) following the method of Example 1 G. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 40:60 then EtOAc:HOAc 99:1); yield 3.74g (72%).
2E: Methyl 3-(aminomethy0benzoate hydrochloride
3-Cyanobenzoic acid (lg, 6.8mmol) was dissolved in ethanol (50mL). The solution was acidified with 1M HCl (7mL) and hydrogenated over 10% palladium-on-carbon for 4h, then filtered and concentrated in vacuo. The residue was dissolved in methanol and cooled in ice. Thionyl chloride (1.8mL, 23.8mmol) was added dropwise, then the mixture was allowed to warm to room temperature and stirred overnight. The solution was concentrated to half its volume and diluted with ether (200mL). The resulting precipitate was collected and dried over P2O5; yield 1.21g (88%).
2F: (2_? _-2-{3-(2-tert-Butyloxycarbonylamino-3- triphenylmethylmercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- methyloxycarbonylbenzyDpropionamide
To an ice-cold solution of the acid of Example 2D (200mg, 0.29mmol) in dichloromethane (lOmL) were added methyl 3-(aminomethyl)benzoate hydrochloride (70mg, 0.35mmol), triethylamine (120μL, 0.87mmol) and benzotriazol-l-yloxy-trz_- pyixolidinophosphonium hexafluorophosphate (180mg, 0.35mmol). The mixture was allowed to warm to room temperature and stirred for 6h, then concentrated in vacuo. The residue was partitioned between EtOAc and 0.3M KHSO4. The organic layer was washed with brine, dried over MgS04 and concentrated. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 30:70 then 40:60); yield 155mg (64%). 2G: (2_ )-2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- methyloxycarbonylbenzyDpropionamide
To a solution of the compound of Example 2G (40mg, 0.048mmol) in dichloromethane (5mL) was added trifluoroacetic acid (5mL) and then triethylsilane was added dropwise until the yellow colour was discharged. The mixture was stirred at room temperature for 4h, diluted with toluene, and concentrated in vacuo. The residue was dissolved in acetonitrile/water and filtered to remove triphenylmethane.
The filtrate was lyophilised and the residue was purified by preparative HPLC
(gradient wateπacetonitrile 90:10 -. 50:50; 0.1% TFA) and lyophilised; yield 19.3mg
(81%)
MS: calc. m e 494.20; found [M+H]+ =495
EXAMPLE 3 (2RV2-{3-(2-Amino-3-mercaptopropylaminoV6-phenyl-2-pyridyloxyl-N-((lS.-l- phenylethyl.propionamide (Compound 53)
Figure imgf000041_0001
3 A: (2/?)-2-{3-(2-tert-Butyloxycarbonylamino-3- triphenylmethylmercaptopropy lamino )-6-pheny 1-2-pyridy loxy I -N-(( 1 S. - 1 - phenylethyπpropionamide
The acid of Example 2D (130mg, 0.188mmol) was coupled to (S)-(-)-α- methylbenzylamine (27.4mg, 0.226mmol) following the method of Example 2F. The product was purified by flash chromatography on silica (eluant EtOAc :pet. ether
30:70); yield 90mg (60%). 3B: (2/_ .-2-!3-(2-Amino-3-mercaptopropylaminoV6-phenyl-2-pyridyloxy}-N-((16.- 1 -phenylethyπpropionamide
The compound of Example 3A (90mg, 0.113mmol) was deprotected following the method of Example 2G. The product was purified by preparative HPLC (gradient wateπacetonitrile 90: 10 → 40:60; 0.1% TFA) and lyophilised; yield 31.5mg (61%). MS: calc m/e 450.21 ; found [M+H]+=451
EXAMPLE 4
(2RV2-(3-(2-Amino-3-mercaptopropylaminoV6-phenyl-2-pyridyloxyl-N-(2- methoxybenzyl.propionamide (Compound 69.
Figure imgf000042_0001
4A: (2R)-2-{3-(2-tgrt-Butyloxycarbonylamino-3- triphenylmethylmercaptopropylamino)-6-phenyl-2-pyridyloxyl-N-(2- methoxybenzyπpropionamide
The acid of Example 2D (130mg, 0.188mmol) was coupled to 2-methoxybenzylamine
(31mg, 0.226mmol) following the method of Example 2F. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 35:65); yield 137mg
(90%).
4B: (2RV2-{3-(2-Amino-3-mercaptopropylaminoV6-phenyl-2-pyridyloxyl-N-(2- methoxybenzyDpropionamide
The compound of Example 4A (137mg, 0. 169mmol) was deprotected following the method of Example 2G. The product was purified by preparative HPLC (gradient wateπacetonitrile 85: 15 → 50:50; 0.1% TFA) and lyophilised; yield 46.3mg (59%). MS: calc m/e 466.20; found [M+H]+=467
EXAMPLE 5
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2- pyridyloxyacetyl} methionine (Compound 13.
Figure imgf000043_0001
5A N-{3-(2-tert-Butyloxycarbonylamino-3-triphenylmethylmercaptopropyl)-6- pheny 1-2-pyridyloxyacetyl } methionine
To a solution of the ester of Example 1H (190mg, 0.23mmol) in dioxan (lOmL) and water(lOmL) was added lithium hydroxide hydrate (15mg, 0.36mmol).The mixture was stirred for 1 hour at room temperature then concentrated in vacuo. The residue was partitioned between chloroform and 1 M citric acid. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo; assume 100% yield.
5B:N-{3-(2-Amino-3-mercaptopropylaminoV6-phenyl-2- pyridyloxyacetylj methionine
The compound of Example 5A (0.23mmol) was deprotected following the method of
Example IJ. The product was purified by preparative HPLC (gradient wateπacetonitrile 80:20^ 20:80; 0.1% TFA) and lyophilised; yield 68.3mg(64%).
MS: calc m/e 464.15; found [M+H]+=465 EXAMPLE 6
2-{3-(-Amino-3-mercaptopropylamino.-6-phenyl-2-pyridyloxy}-N-(4- phenylbutyD-acetamide (Compound 4)
Figure imgf000044_0001
6A: 2-{3-(2-tgrt-Butyloxycarbonylamino-3-triphenylmethylmercaptopropylamino)-6- phenyl-2-pyridyloxy}-N-(4-phenylbutyl)acetamide
To an ice-cold solution of the acid of Example 1G (39.6mg, 0.27mmol) and diisopropylethylamine (36mg, 0.36mmol) in dichloromethane (lOmL) was added bromo-tra-pyrrolidino-phosphonium hexafluorophosphate (151mg, 0.32mmol) and then 4-phenylbutylamine (52mg, 0.35mmol) The mixture was allowed to reach room temperature and stirred for 18h, then concentrated in vacuo. The residue was partitioned between EtOAc and 0.3M KHSO4. The organic layer was washed with brine, dried over MgSO and concentrated. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 35:65); yield 93mg(52%).
6B: 2-{3-(-Amino-3-mercaptopropylaminoV6-phenyl-2-pyridyloxy}-N-(4- phenylbutylVacetamide
The compound of Example 6A (93mg, 11.5mmol ) was deprotected following the method of Example 2G. The product was purified by preparative HPLC (gradient water: acetonitrile 85: 15^ 40:60 0.1% TFA) and lyophilised; yield 28.8mg (75%).
MS: calc m/e 464.22; found [M+H]+=465 EXAMPLE 7
2-{3-(2-Amino-3-mercaptopropylamino.-6-phenyl-2-pyridyloxy}-N- (3- pyridylmethyl.acetamide (Compound 12)
Figure imgf000045_0001
7A: 2-{3-Benzyloxycarbonylamino-6-phenyl-2-pyridyloxylacetic acid To a solution of the ester of Example ID (700mg, l .δmmol) in dioxan (20mL) was added 1M lithium hydroxide (3.6mL, 3.6mmol). After 2h at room temperature the mixture was concentrated in vacuo. The residue was partitioned between EtOAc and 1M citric acid. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo; yield 700mg (100%).
7B: 2-{3-Benzyloxycarbonylamino-6-phenyl-2-pyridyloxy}-N- (3- pyridylmethyDacetamide
The acid of Example 7A (400mg, 0.792mmol) was coupled to 3-
(aminomethyl)pyridine (102mg, 0.95mmol) following the method of Example 2F.
The product was purified by flash chromatography on silica (eluant EtOAc :pet. ether
90:10); yield 280mg (75%).
7C : 2- { 3-Amino-6-phenyl-2-pyridyloxy ) -N- (3 -pyridylmethyf)acetamide To a degassed solution of the compound of Example 7B (300mg, 0.64mmol) in methanol (50mL) and chloroform (5mL) was added palladium-on-carbon (lOOmg). The mixture was stirred at room temperature under an atmosphere of hydrogen for 6h, then filtered. The catalyst was washed with methanol and the combined filtrates were evaporated in vacuo; assume 100% yield. 7D: 2-{3-(2-tgrt-Butyloxycarbonylamino-3-triphenylmethylmercaptopropylamino)-6- phenyl-2-pyridyloxy}-N-(3-pyridylmethyl)acetamide
To a solution of the compound of Example 7C (0.64mmol) and N-BOC-S- tritylcysteinal (315mg, O Ommol) in methanol (20mL) and acetic acid (2mL) was added sodium cyanoborohydride (44mg, 0.70mmol). The mixture was stirred at room temperature for 18h and then concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc); yield 200mg (41%).
7E: 2-{3-(2-Amino-3-mercaptopropylaminoV6-phenyl-2-pyridyloχy . -N- (3- pyridylmethyl.acetamide
The compound of Example 7D (lOOmg, 0.13mmol ) was deprotected following the method of Example 2G. The product was purified by preparative HPLC (gradient wateπacetonitrile 90: 10- 50:50; 0.1% TFA) and lyophilised; yield 40.1mg (73%).
MS: calc m e 423.17; found [M+H]+=424
EXAMPLE 8
N-{3-(2-Amino-3-mercaptopropylamino.-6-phenyl-2-pyridyloxyacetyl}- methionine-N-rnethylamide (Compound 33.
Figure imgf000046_0001
8 A: N-{3-(2-tgrt-Butyloxycarbonylamino-3-triphenylmethylmercaptopropyπ-6- phenyl-2-pyridyloxyacety 1 } methionine-N-methy lamide
To an ice-cold solution of the acid of Example 5 A (1 lOmg, 0.136mmol), methyl lεamine hydrochloride (l lmg, O. lόmmol), diisopropylethylamine (160mg, O.lόmmol), and hydroxybenzotriazole (22mg, 0.163mmol) in dichloromethane (20mL) and dimethylformamide (2mL) was added WSCDI (32.6mg, 0.163mmol). The mixture was allowed to warm to room temperature and stirred for 18h, then partitioned between EtOAc and water. The organic layer was washed with 0.3M KHSO4, satd. NaHCO3 and brine, dried over MgSO4,and concentrated in vacuo. The residue was purified by flash chromatography on silica, (eluant EtOAc:pet ether 90:10); yield 76mg (68%).
8B: N-{3-(2-Amino-3-mercaptopropylaminoV6-phenyl-2- pyridy loxyacetyl } methionine-N-methy lamide
The compound of Example 8A (76mg, 0.093mmol ) was deprotected following the method of Example 2G. The product was purified by preparative HPLC (gradient water: acetonitrile 90: 10^ 50:50; 0.1% TFA) and lyophilised; yield 39.8mg (92%).
MS: calc m/e 477.19; found [M+H]+= 478.
EXAMPLE 9 N-{3-(2-Amino-3-mercaptopropylaminoV6-(2-biphenylyπ-2-pyridyloxyacetyl} methionine (Compound 156.
Figure imgf000047_0001
9A: Methyl 2-{6-chloro-3-nitro-2-pyridyloxy}acetate
To an ice-cold solution of methyl glycolate (5.7g, 65mmol) in dimethylformamide (lOOmL) was added sodium hydride (80% dispersion, 2.12g, 71mmol). The mixture was stirred for 30min. 2,6-Dichloro-3-nitropyridine (11.4g, 59mmol) was added and stirring continued overnight. Water (20mL) was added and the solvent evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet ether 20:80); yield 4.5g (31%).
9B: Methyl 2-{6-(2-biphenylyl)-3-nitro-2-pyridyloxy}acetate
To a solution of the ester of Example 9A (492mg, 2mmol) in tetrahydrofuran (lOmL) was added tetrakis(triphenylphosphine)palladium(0) (347mg, 0.3mmol). After stirring at room temperature for 45min 2-biphenylboronic acid (515mg, 2.6mmol) was added .After a further 2h at room temperature 2M Na2CO3 (lOmL) was added and the mixture stirred at reflux for 2h. The mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet ether 20:80); yield 440mg (60%).
9C: Methyl 2-{3-amino-6-(2-biphenylylV2-pyridyIoxy}acetate To a degassed solution of the compound of Example 9B (220mg, 0. όmmol) in methanol (20mL) and acetic acid (lmL) was added palladium-on-carbon (lOOmg). The mixture was stirred at room temperature under an atmosphere of hydrogen for 4h, then filtered. The catalyst was washed with methanol and the combined filtrates were evaporated in vacuo; assume 100% yield.
9D: Methyl 2- .3-(2-tert-butyloxycarbonylamino-3- triphenylmethylmercaptopropylamino)-6-(2-biphenylyl)-2-pyridyloxy ) acetate The compound of Example 9C (0. όmmol) was reacted with N-BOC-S- tritylcysteinal(268mg, 0. όmmol) and sodium cyanoborohydride (76mg, 1.2mmol) as described in Example IF. The product was purified by flash chromatography on silica (eluant EtOAc:pet ether 25:75) yield 310mg (67%).
9E: 2-{3-(2-tert-Butyloxycarbonylamino-3-triphenylmethylmercaptopropylaminoV6- (2- biphenylyl .-2-pyridyloxy} acetic acid
To a solution of the ester of Example 9D (300mg, 0.39mmol) in dioxan (20mL) was added IM lithium hydroxide (6mL, όmmol). After 2h at room temperature the mixture was concentrated in vacuo. The residue was partitioned between EtOAc and IM citric acid. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo; assume 100% yield.
9F: 2-{3-(2-tert-Butyloxycarbonylamino-3-triphenylmethylmercaptopropylamino)-6-
(2- biphenylyl .-2-pyridyloxyacetyl}methionine methyl ester
The acid of Example 9E (0.39mmol) was coupled to methionine methyl ester hydrochloride (lOOmg, 0.5mmol) following the method of Example 1H. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 40:60); yield
250mg (71%).
9G: 2-(3-(2-tert-Butyloxycarbonylamino-3-triphenylmethylmercaptopropylamino)-6- (2- biphenylyl )-2-pyridyloxyacety 1 } methionine
The ester of Example 9F (130mg, 0.144mmol) was hydrolysed with lithium hydroxide (9mg, 0.22mmol) as described in Example 5 A; assume 100% yield.
9H: N-{3-(2-Amino-3-mercaptopropylaminoV6-(2-biphenylyπ-2-pyridyloxyacetyll- methionine
The compound of Example 9G (0.144mmol) was deprotected following the method of
Example 2G. The product was purified by preparative HPLC (gradient wateπacetonitrile 80:20^20:80; 0.1% TFA) and lyophilised; yield 69mg (89%).
MS: calc m/e 540.19; found [M+H]+= 541
EXAMPLE 10
N-{3-.2-Amino-3-mercaptopropylamino.-6-phenoxy-2-pyridyloxyacetyl}- methionine (Compound 182.
Figure imgf000050_0001
10A: Methyl 2-{3-nitro-6-phenoxy-2-pyridyloxy . acetate
To an ice-cold solution of phenol (430mg, 4.59mmol) in dimethylformamide (30mL) was added sodium hydride (80% oil dispersion, 150mg, 5.01mmol). After 30min the compound of Example 9A (1.03g, 4.18mmol) was added. The mixture was allowed to attain room temperature and stirred overnight. Water (3mL) was added and the mixture concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 20:80); yield 920mg (72%).
10B: Methyl 2-(3-amino-6- phenoxy-2-pyridyloxy} acetate
To a degassed solution of the compound of Example 10A (908mg, 2.98mmol) in methanol (30mL) and EtOAc (15mL) was added palladium-on-carbon (lOOmg). The mixture was stirred at room temperature under an atmosphere of hydrogen for lh, then filtered. The catalyst was washed with methanol and the combined filtrates were evaporated in vacuo; assume 100% yield.
10C: Methyl- 2-{3-(2-tgrt-butyloxycarbonylamino-3- triphenylmethylmercaptopropy laminoVό- phenoxy-2-pyridyloxy } acetate The compound of Example 10B (2.98mmol) was reacted with N-BOC-S- tritylcysteinal (670mg, 1.49mm01) and sodium cyanoborohydride (l lOmg, 1.79mmol) as described in Example IF. The product was purified by flash chromatography on silica (eluant EtOAc:pet ether 20:80); yield 774mg (74%).
10D: 2-{3-(2-tgrt-Butyloxycarbonylamino-3-triphenylmethylmercaptopropylamino .- 6- phenoxy-2-pyridyloxy} acetic acid
To a solution of the ester of Example IOC (750mg, l.Oόmmol) in dioxan (20mL) was added IM lithium hydroxide (15mL, 1.5mmol). After 18h at room temperature the mixture was concentrated in vacuo. The residue was partitioned between EtOAc and IM citric acid. The organic layer was washed with brine, dried over MgS04 and concentrated in vacuo; assume 100% yield.
10E: 2- .3-(2-tert-Butyloxycarbonylamino-3-triphenylmethylmercaptopropylamino)- 6- phenoxy-2-pyridy loxyacetyl I methionine methyl ester
The acid of Example 10D (l .Oόmmol) was coupled to methionine methyl ester hydrochloride (199.7mg,1.27mmol) following the method of Example 1H. The product was purified by flash chromatography on silica (eluant EtOAcφet. ether35:65); yield 581mg (65%).
10F: 2-l3-(2-tgrt-Butyloxycarbonylamino-3-triphenylmethylmercaptopropylaminoV 6- phenoxy -2-pyridyloxyacetyl} methionine
The ester of Example 10E (300mg, 0.358mmol) was hydrolysed with lithium hydroxide (23mg, 0.538mmol) as described in Example 5 A; assume 100% yield.
10G: N-(3-.2-Amino-3-mercaptopropylamino)-6- phenoxy -2-ρyridyloxyacetyl . - methionine
The compound of Example 10F (0.358mmol ) was deprotected following the method of Example 2G. The product was purified by preparative HPLC (gradient water: acetonitrile 80:20-^20:80; 0.1% TFA) and lyophilised; yield 103mg (60%).
MS: calc m/e 480.15; found [M+H]+= 481. EXAMPLE 11
N-{3-(2-Amino-3-mercaptopropylaminoV6-phenyl-2-pyridyP/-D-alanine-N-(2- methoxybenzyl. amide (Compound 189.
Figure imgf000052_0001
1 1 A: N-(6-Chloro-3-nitro-2-p y ridyll-D-alanine methyl ester
Potassium carbonate (3.4g, 25mmol) and diisopropylethylamine (2.5g, 2.5mmol) were added to a solution of 2,6-dichloro-3-nitropyridine (3.6g, 18. όmmol) and D-alanine methyl ester hydrochloride (2.9g, 20.8mmol) in tetrahydrofuran (60mL). The mixture was stirred at 60°C for 18h and partitioned between EtOAc and 0.3M KHSO4. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 10:90); yield 4.17g (86%).
1 IB: N- 13 -Nitro-6-phenyl-2-pyridyl} -D-alanine methyl ester
To a solution of the ester of Example 1 1A (4.07g, 15.7mmol) in tetrahydrofuran (150mL) was added tetrakis(triphenylphosphine)palladium(0) (2.7g, 2.3mmol). After stirring at room temperature for 45min phenylboronic acid (3.9g,32.2mmol) was added .After a further 3h at room temperature 2M Na2CO3 (40mL) was added and the mixture stirred at reflux for 2h. The mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet ether 20:80); yieldl3.4g (86%). 1 IC: N-{3-Nitro-6-phenyl-2-pyridyl} -D-alanine
To a solution of the ester of Example 1 IB (3.94g, 13.1mmol) in dioxan (120mL) was added IM lithium hydroxide (20mL, 20mmol). After 18h at room temperature the mixture was concentrated in vacuo. The residue was partitioned between EtOAc and IM citric acid. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo; yield 3.42g (91%).
I IP: N-{3-Nitro-6-phenyl-2-pyridyπ -D-alanine-N-(2-methoxybenzyl)amide The acid of Example 1 IC (268mg, 0.93mmol) was coupled to 2-methoxybenzylamine (262mg, 1.68mmol) following the method of Example 2F. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 30:70 - 50:50); yield 256mg (68%).
HE: N-{3-Amino-6-phenyl-2-pyridyl}-D-alanine-N-(2-methoxybenzyl)amide To a degassed solution of the compound of Example 1 1D (220mg, 0.54mmol) in methanol (30mL) and EtOAc (15mL) was added palladium-on-carbon (lOOmg). The mixture was stirred at room temperature under an atmosphere of hydrogen for 30min, then filtered. The catalyst was washed with methanol and the combined filtrates were evaporated in vacuo; assume 100% yield.
1 IF: N-{3-(2-tgrt-Butyloxycarbonylamino-3-triphenylmethylmercaptopropylaminoV 6- phenyl-2-pyridyl}-D-alanine-N-(2-methoxybenzyl)amide
The compound of Example HE (0.54mmol) was reacted with N-BOC-S- tritylcysteinal(330mg, 0.68mmol) and sodium cyanoborohydride (l lOmg, 1.79mmol) as described in Example IF. The product was purified by flash chromatography on silica (eluant EtOAc:pet ether 25:75); yield 190mg (42%). 1 1 G: N- { 3-(2-Amino-3-mercaptopropy lamino)-6-pheny 1-2-pyridy 1 } -D-alanine-N-(2- methoxybenzyDamide
The compound of Example 1 IF (180mg, 0.215mmol) was deprotected following the method of Example 2G. The product was purified by preparative HPLC (gradient wateπacetonitrile 80:20-> 20:80; 0.1% TFA) and lyophilised; yield 35.2mg (35%).
MS: calc m/e 465.22; found [M+H]+=466.
Further examples contained in Table 1 below were prepared using an adaptation of one of the above examples as depicted in the table, and by employing the appropriate starting materials.
ASSAY 1 : Farnesyl Protein Transferase Inhibition.
Inhibition of Farnesyl Protein Transferase is determined using a Scintillation Proximity Assay (Amersham). A biotin-tagged peptide substrate and [3H]-farnesyl pyrophosphate are incubated with recombinant human enzyme and varying concentrations of the test compound. After a fixed time the reaction is halted, streptavidin-coated scintillation beads are added, and the product formation is quantified in a scintillation counter. The IC50 is the concentration of test compound required to reduce the amount of product formed by 50%. The compounds of the invention have IC50 values below lOμM. Typical examples are shown in Table 1.
Table 1
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
__
Figure imgf000058_0001
ASSAY 2: Geranylgeranyl Protein Transferase I Inhibition.
Inhibition of the related enzyme Geranylgeranyl Protein Transferase I was also determined using standard literature methods. Again, the IC50 is the concentration of test compound required to reduce the amount of product formed by 50%. Selected compounds of the invention have ICj0 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 [ H]thymidine 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 50μM. Typical examples are shown below in Table 2. Table 2
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Some of the preferred compounds 1 et seq according to the invention are listed above with stereochemical descriptors to identify the particular stereoisomers concerned. In each such case, however, as with stereoisomeric compounds of formula 1 in general all related stereoisomers exist and are obtainable and are included in the invention individually and severally and in any admixture. Thus compounds indicated in R- (or S-) form are available in the possible S- (or R-) and RS- forms and all possible such forms are included in the invention as isolated isomers and mixtures thereof, as expressed herein by recitation of the compound with no stereochemical descriptor. Thus herein recitation of "N-{-2-[3-(2- amino-3 mercaptylpropylamino)-6-phenyl-2-pyridyloxy)propionyl}-phenylalanine" indicates any of the 2R-, 2S- and 2RS- isomers (compounds 131 , 134 and 136) separately and in any mixture of two or all thereof, and similar considerations apply to the recitation without stereochemical descriptor (e.g. in the following claims) of any other stereoisomeric compound of the invention. Thus N-{3-(2-aminomercaptopropylamino)-6-phenyl-2- pyridyl}-alanine-(N-benzyl) amide and the corresponding -(N-2-methoxybenzyl)amide are available as the L-isomers instead of the D-isomers (compounds 184 and 189) and as iso er mixtures, and these separate isomers and the mixtures are part of the invention.

Claims

1. A compound of general formula 1 , or a pharmaceutically acceptable salt,
Figure imgf000062_0001
formula 1
in which:
W is a group of general formula 2 or general formula 3:
Figure imgf000062_0002
formula 2 formula 3 X is a covalent bond; -CH2-; -0-; -NH-; -NMe-; or -S-
Y is -0-, -S- or -NR -:
R is hydrogen; linear or branched lower alkyl (C, - C8); lower cycloalkyl (C3 - C8); substituted or unsubstituted phenyl or naphthyl: or substituted or unsubstituted monocyclic or benzofused heteroaryl:
R2 is hydrogen; linear or branched lower alkyl (C, - C4) or Ph(CH2)n
R is hydrogen or linear or branched lower alkyl (C, - C4):
R and RD are independently hydrogen; linear or branched lower alkyl (C, - C8); lower cycloalkyl (C3 - C8) which may be benzofused or substituted with COR ; substituted or unsubstituted phenyl or naphthyl, substituted or unsubstituted monocyclic or benzofused heteroaryl; COR ; or R and R^ together with the nitrogen atom and the methylene groups to which they are attached form a saturated heterocycle of up to 8 atoms which may be benzofused or substituted with COR6:
R6 is OH; O-alkyl; NH2; NH-alkyl; N(alkyl),; or NHSO2-al yl (wherein alkyl includes linear or branched lower alkyl C, - C8, lower cycloalkyl C3 - C8 and (cycloalkyl)alkyl C - C[0); or R and R together are -0(CH2)2- to form a ╬│-lactone ring:
R is selected from linear or branched lower alkyl (C, - C6) or (CFI2)CR ; or R and R together are -(CH2)20- to form a ╬│-lactone ring:
R is hydrogen or methyl:
R9 is OH; OCH3; SCH3; SOMe; S02Me: NHCOMe; optionally substituted phenyl; or
CORb R10, R1 ', R1" and R1 are independently hydrogen or lower alkyl or phenyl:
a, b and c are integers in the range 0-4:
m is 0, 1 or 2:
n is 1,2 or 3:
p is 1 or 2
2. A compound of Claim 1 in which;
R1 is an optionally substituted phenyl group;
X is a covalent bond; and
Y is an oxygen atom, all the other groups being as defined above.
3. A compound of Claim 1 which is selected from:
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- phenylpropyl)acetamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-benzylacetamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2-phenylethyl)- acetamide 2- (3-(2-Amino-3-mercapt9propylamino)-6-phenyl-2-pyridyloxy}-N-(4-phenylbutyl)- acetamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-butylacetamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-phenylacetamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-benzyl-N- methylacetamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-methyl-N-(2- phenylethyl)acetamide
2- { 3-(2-Amino-3-mercaptopropylamino)-6-pheny 1-2-pyridy loxy } -N-( 1 - naphthylmethyl)acetamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- naphthylmethyl)acetamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- pyridylmethyl)acetamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- pyridylmethyl)acetamide
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyIoxyacetyl} methionine
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridy loxyacetyl} methionine methyl ester N-{3-(2~Amino-3-rnercaptopropylarnino)-6-phenyl-2-pyridyloxyacetyl}- methioninesulphone
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}- methioninesulphoxide
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}- homophenylalanine
N╬▒-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}glutamine
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridy loxyacetyl} lutamic acid
2- {3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetamido} pentanoic acid
Nα-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}-Nω-methyl- glutamine
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}- methionineamide
Nα-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}-Nω- methanesulphonylglutamine
N-{3-(2-Amino-3 -mercaptopropy lamino)-6-phenyl-2-pyridyloxyacetyl} methionine methanesulphonimide
N- { 3-(2-Amino-3 -π_ercaptopropylamino)-6-pheny 1-2-pyridy loxyacetyl } homoserine lactone N-{3-(2-Amino-3-mercaptopropyIamino)-6-phenyl-2-pyridyloxyacetyl} phenylalanine
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl} serine
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}aspartic acid
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}- homophenylalanineamide
N╬▒-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}asparagine
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}- homophenylalanine methyl ester
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}- methioninesulphoxide methyl ester
N- { 3 -(2-Amino-3-mercaptopropylamino)-6-pheny 1-2-pyridyloxyacety 1 } methionine- N-methylamide
N -Acetyl-N -{3-(2-amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}- 2,3-diaminopropionic acid
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}methionine- N,N-dimethylamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(4- phenylbutyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-benzyl- propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3,4- dichlorobenzyl)propionamide
ΓÇó2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- thienylmethyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(4- methoxybenzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(4- methybenzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(4- chlorobenzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- methyloxycarbonylbenzy propionamide
2-{3-(2-Amino-3-mercaptopropyIamino)-6-phenyl-2-pyridyloxy}-N-(4- methyloxycarbonylbenzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3-carboxy- benzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(4-carboxy- benzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(l- naphthylmethyl)propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- naphthylmethy propionamide
Γûá2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N- (cyclohexylmethyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2-hydroxy- benzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- phenylethyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-( 1 - phenylethyl)propionamide
2- { 3 -(2-Amino-3-mercaptopropy lamino)-6-pheny l-2-pyridyloxy } -N-( I - phenylethyPpropionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(4- (benzyloxycarbonylamino)benzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- chlorobenzy propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- pyridylmethyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxv . -N-(2- pyridylmethyOpropionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(4- pyridylrnethyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- furylmethyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyI-2-pyridyloxy}-N-(3- hydroxybenzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(4- hydroxybenzy propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- bromobenzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- nitrobenzyl)propionamide
2-{3-(2-A_nino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(4- (methyloxycarbonyl)cyclohexylmethyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- methoxybenzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- methylbenzyl)propionamide
2- {3-(2-Amino-3 -mercaptopropy lamino)-6-phenyl-2-pyridy loxy} -N-(2- methylbenzyl)propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- methoxybenzyPpropionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- chlorobenzyPpropionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- (methanesulphonylaminocarbonyl)benzyi)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- carboxamidobenzyl)propionamide
N-(3-Aminobenzyl)-2-{3-(2-amino-3 -mercaptopropy lamino)-6-pheny 1-2- pyridyloxy}propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- phenylbenzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- trifluoromethylbenzy propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N- (diphenylmethyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- methylaminocarbonylbenzy propionamide
2- {3 -(2- Amino-3 -mercaptopropy lamino)-6-phenyl-2-pyridy loxy} -N-(3- dimethylaminocarbonylbenzyl)propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- phenylbenzy propionamide
2- { 3 -(2-A_nino-3-mercaptopropy lamino)-6-pheny 1-2-pyridyloxy } -N-(2- bromobenzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N,N-dibenzyl- propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(l-indanyl)- propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- nitrobenzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2,3- dimethoxybenzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- ethoxybenzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- acetamidobenzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- bis(methanesulphonyl)aminobenzyI)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-isopropyl- propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- bromobenzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-tgrt-butyl- propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N- cyclopentylpropionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-cyclohexyl- propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-cyclobutyl- propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2,6- dichlorobenzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3-pentyl)- propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3,5- dimethoxybenzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(4- fluorobenzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- methylbutyl)propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2,5- dimethoxybenzy propionamide
2- { 3 -(2-Amino-3-mercaptopropylamino)-6-pheny 1-2-pyridyloxy } -N-(2- trifluoromethoxybenzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2,6- dimethoxybenzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3-chloro- 4-fluorobenzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2-chloro- 4-fluorobenzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- acetamidobenzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2-(2- methoxyphenyl)ethyl)propionamide
2- { 3 -(2- Amino-3 -mercaptopropy lamino)-6-phenyl-2-pyridy loxy } -N-(2-( 1 - cyclohexenyl)ethyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- cyclohexylethyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- dimethylamino-6-fluorobenzyl)propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- fluorobenzyl)propionamide
2- { 3 -(2-Amino-3 -mercaptopropy lamino)-6-pheny 1-2-pyridy loxy } -N-(2- methanesulfonylbenzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(4- methanesulfonylbenzyOpropionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- methylthiobenzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- benzothienylmethyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-methyl-N- ( 1 -phenylethyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(4- methanesulfinylbenzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-phenyl- propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2-indanyl)- propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N- (cyclopentylmethyl)propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3- methylpheny propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(4- methylphenyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-methyl-N- (3-methylbenzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-methyl-N- (2-methylbenzyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(l-(2- methylphenyl)ethyl)propionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(l-(3- methylphenyl)ethyl)propionamide
2-{ 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}propionyl}- 1 ,2,3 ,4-tetrahydroisoquinoline
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(l -indany 1)- N-methylpropionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- chlorobenzyl)-N-methylpropionamide
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2,3- dimethylbenzy propionamide N-{ 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)propionyl}- methionine methyl ester
N-{ 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)propionyl}- methionine
N-{ 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)propionyl}- phenylalanine
N-{ 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)propionyl}- phenylalanine methyl ester
N-{ 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)propionyl}- phenylalanine methyl ester
N-{ 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)propionyl}- phenylalanine
N-{ 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2- pyridyloxy)propionyl} phenylalanine methyl ester
N-{ 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2- pyridy loxy)propionyl } phenylalanine
N-{ 2-(3-(2-Amino-3-mercaptopropyiamino)-6-phenyl-2-pyridyloxy)-2- pheny lacety 1 } methionine
N-{ 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-2- phenylacetyl} methionine N-{ 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)butyryl}- methionine methyl ester
N-{ 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)butyryl}- methionine methyl ester
N-{ 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)butyryl}- methionine
N-{ 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)butyryl}- methionine
N-{ 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)hexanoyl}- methionine
N-{ 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)hexanoyl}- methionine
N-{ 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)hexanoyl}- methionine methyl ester
N-( 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)hexanoyl}- methionine methyl ester
N-{ 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)pentanoyl}- methionine methyl ester
N-{ 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)pentanoyl}- methionine methyl ester N-{ 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)pentanoyl}- methionine
N-{ 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)pentanoyl}- methionine
N-{3-(2-Amino-3-mercaptopropylamino)-6-(2-chlorophenyl)-2-pyridyloxyacetyl}- methionine
N-{3-(2-Amino-3-mercaptopropylamino)-6-(3-trifluoromethylphenyl)-2- pyridy loxyacetyl} methionine
N-{3-(2-Amino-3-mercaptopropylamino)-6-(3-methoxyphenyl)-2-pyridyloxyacetyl}- methionine
N-{3-(2-Amino-3-mercaptopropylamino)-6-(3-hydroxymethylphenyl)-2- pyridy loxyacetyl } methionine
N-{3-(2-Amino-3-mercaptopropylamino)-6-(3-acetamidophenyl)-2- pyridy loxyacetyl} methionine
N-{3-(2-Amino-3-mercaptopropylamino)-6-(2-biphenylyl)-2-pyridyloxyacetyl}- methionine
N-{3-(2-Amino-3-mercaptopropylamino)-6-(4-biphenylyl)-2-pyridyloxyacetyl}- methionine
N-{3-(2-Amino-3-mercaptopropylamino)-6-(3-methyloxycarbonylphenyl)-2- pyridyloxyacetyl} methionine N-{3-(2-Amino-3-mercaptopropylamino)-6-(3-methyloxycarbonylphenyl)-2- pyridy loxyacetyl} methionine methyl ester
N-{3-(2-Amino-3-mercaptopropylamino)-6-(3-carboxyphenyl)-2-pyridyloxyacetyl}- methionine
N-{3-(2-Amino-3-mercaptopropylamino)-6-(2,4,6-trimethylphenyl)-2- pyridy loxyacetyl} methionine
N-{3-(2-Amino-3-mercaptopropylamino)-6-(3-biphenylyl)-2-pyridyloxyacetyl}- methionine
2-{3-(2-Amino-3-mercaptopropylamino)-6-butyl-2-pyridyloxy}-N-(3-phenylpropyl)- acetamide
N-{3-(2-Amino-3-mercaptopropylamino)-6-(2-naphthyl)-2-pyridyloxyacetyl}- methionine
N-{3-(2-Amino-3-mercaptopropylamino)-2-pyridyloxyacetyl} methionine
N-{3-(2-Amino-3-mercaptopropylamino)-6-(2-thienyl)-2-pyridyloxyacetyl}- methionine
N-{3-(2-Amino-3-mercaptopropylamino)-6-(2-benzofuryl)-2-pyridyloxyacetyl}- methionine
N-{3-(2-Amino-3-mercaptopropylamino)-6-butyl-2-pyridyloxyacetyl} methionine
N-{3-(2-Amino-3-mercaptopropylamino)-6-(l-naphthyl)-2-pyridyloxyacetyl}- methionine N-{3-(2-Amino-3-mercaptopropylamino)-6-(2-thienyl)-2-pyridyloxyacetyl}- methionine methyl ester
N-{3-(2-Amino-3-mercaptopropylamino)-6-(l-naphthyl)-2-pyridyloxyacetyl}- methionine methyl ester
N-{3-(2-Amino-3-mercaptopropylamino)-6-butyi-2-pyridyloxyacetyl} methionine methyl ester
N-{ 2-(3-(2-Amino-3-mercaptopropylamino)-6-butyl-2-pyridyloxy)propionyl}- methionine
N-{ 2-(3-(2-Amino-3-mercaptopropylamino)-6-butyl-2-pyridyloxy)propionyl}- methionine
N-{ 2-(3-(2-Amino-3-mercaptopropylamino)-2-pyridyloxy)-3-phenylpropionyl}- methionine
N-{ 2-(3-(2-Amino-3-mercaptopropylamino)-2-pyridyloxy)-3-phenylpropionyl}- methionine
N-{ 2-(3-(2-Amino-3-mercaptopropylamino)-2-pyridyloxy)-3-phenylpropionyl}- methionine methyl ester
N-{ 2-(3-(2-Amino-3-mercaptopropylamino)-2-pyridyloxy)-3-phenylpropionyl}- methionine methyl ester
N-{3-(2-Amino-3-mercaptopropylamino)-6-benzyl-2-pyridyloxyacetyl} methionine methyl ester
N-{3-(2-Amino-3-mercaptopropylamino)-6-benzyl-2-pyridyloxyacetyl} methionine N- { 3-(2-Amino-3-mercaptopropy lamino)-6-phenoxy-2-pyridyloxyacetyl } methionine methyl ester
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenoxy-2-pyridyloxyacetyl}methionine
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyl}alanine-(N- benzyl)amide
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyl}- alanine-(N- benzyl)amide
N- { 3 -(2- Amino-3 -mercaptopropy lamino)-6-phenyl-2-pyridyl } -N-methy lalanine-(N- benzyl)amide
N- { 3 -(2- Amino-3 -mercaptopropy lamino)-6-pheny 1-2-pyridy 1 } glycine-(N- benzyl)amide
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyl}-N-methylglycine-(N- benzyl)amide
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyl}-N-methylalanine-(N- benzyl)amide
N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyl}- alanine-(N-2- methoxybenzyl)amide
N- { 3 -(2- Amino-3 -mercaptopropy lamino)-6-pheny 1-2-pyridy 1 } alanine-(N- 1 - phenylethyl)amide ΓÇó2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridylthio}-N-benzyl- propionamide
2-{3-(3-Amino-4-mercaptobutylamino)-6-phenyl-2-pyridyloxy}-N-(3- methyloxycarbonylbenzyl)propionamide
ΓÇó2-{3-(3-Amino-4-mercaptobutylamino)-6-phenyl-2-pyridyloxy}-N-benzyl- propionamide
Γûá2-{3-(3-Amino-4-mercaptobutylamino)-6-phenyl-2-pyridyloxy}-N-(2- pyridylmethyl)propionamide
2-{3-(3-Amino-4-mercaptobutylamino)-6-phenyl-2-pyridyloxy}-N-(2- methylbenzyl)propionamide
2-{3-(3-Amino-4-mercaptobutylamino)-6-phenyl-2-pyridyloxy}-N-(2- chlorobenzyPpropionamide
2-(3-(3-Amino-4-mercaptobutylamino)-6-phenyl-2-pyridyloxy}-N-(3- methyloxycarbonylbenzyl)-N-methylpropionamide
N- { 3 -(3 -Amino-4-mercaptobuty lamino)-6-pheny l-2-py ridy loxyacetyl } methionine methyl ester
N-{ 3 -(3-Amino-4-mercaptobutylamino)-6-phenyl-2-pyridyloxyacetyl} methionine
N-{3-(3-Amino-4-mercaptobutylamino)-6-phenyl-2-pyridyloxyacetyl} phenylalanine methyl ester
N-{3-(3-Amino-4-mercaptobutylamino)-6-phenyl-2-pyridyloxyacetyl} phenylalanine
4. A medicinal formulation which includes as an active principal a compound according to any preceding claim.
5. A formulation according to claim 4 for the treatment of an inflammatory or proliferative pathological condition.
6. The use of a medicinal formulation which includes as an active principal a compound according to any of claims 1 to 3 for the treatment of a human or other mammal.
7. A use according to claim 6 for the treatment of an inflammatory pathological condition in a human or other mammal.
8. A use according to claim 6 for the treatment of a proliferative pathological condition in a human or other mammal.
9. A method for the treatment of an inflammatory or proliferative pathological condition in a human or other mammalian patient which comprises administering to the patient an effective amount of a compound according to any of claims 1 to 3 or of a formulation according to claim 4.
PCT/GB1998/000997 1997-04-04 1998-04-03 3-aminopyridine derivatives for treatment of inflammatory and malignant diseases WO1998045266A1 (en)

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GB9706923.1 1997-04-04
GB9706923A GB2323842A (en) 1997-04-04 1997-04-04 Pyridine derivatives

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AU2003276201A1 (en) * 2002-11-11 2004-06-03 Bayer Healthcare Ag Phenyl or heteroaryl amino alkane derivatives as ip receptor antagonist

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WO1995034535A1 (en) * 1994-06-10 1995-12-21 Rhone-Poulenc Rorer S.A. Novel farnesyl transferase inhibitors, their preparation and pharmaceutical compositions containing same
WO1996021456A1 (en) * 1995-01-12 1996-07-18 University Of Pittsburgh Inhibitors of prenyl transferases
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WO1996021456A1 (en) * 1995-01-12 1996-07-18 University Of Pittsburgh Inhibitors of prenyl transferases
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Cited By (5)

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Publication number Priority date Publication date Assignee Title
WO2013178816A1 (en) * 2012-06-01 2013-12-05 Nogra Pharma Limited Heterocycles capable of modulating t-cell responses, and methods of using same
CN104619691A (en) * 2012-06-01 2015-05-13 诺格拉制药有限公司 Heterocycles capable of modulating T-cell responses, and methods of using same
CN104619691B (en) * 2012-06-01 2018-05-25 诺格拉制药有限公司 The heterocycle and its application method of T- cell responses can be adjusted
US10208017B2 (en) 2012-06-01 2019-02-19 Nogra Pharma Limited Heterocycles capable of modulating T-cell responses, and methods of using same
US10562883B2 (en) 2012-06-01 2020-02-18 Nogra Pharma Limited Heterocycles capable of modulating T-cell responses, and methods of using same

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GB2323842A (en) 1998-10-07
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