WO1998045267A1 - Aminopyridine derivatives for inflammatory and malignant diseases - Google Patents
Aminopyridine derivatives for inflammatory and malignant diseases Download PDFInfo
- Publication number
- WO1998045267A1 WO1998045267A1 PCT/GB1998/000998 GB9800998W WO9845267A1 WO 1998045267 A1 WO1998045267 A1 WO 1998045267A1 GB 9800998 W GB9800998 W GB 9800998W WO 9845267 A1 WO9845267 A1 WO 9845267A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- amino
- pyridine
- mercaptopropylamino
- ethyloxy
- naphthyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- 0 **C(CN)C1OC1=C Chemical compound **C(CN)C1OC1=C 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the immune response is essential for the defence of the body against invading pathogens.
- an inappropriate activation of the immune system has been implicated in the etiology of some serious disease states. These arc characterised by progressive tissue damage with inflammation and invasion of the lesion by leukocytes. Examples of such diseases include inflammatory bowel disease, psoriasis, asthma and rheumatoid arthritis. Current therapeutic regimens for these conditions are often inadequate, and new approaches are required.
- One aspect of the present invention is a series of compounds that inhibit the proliferation of T lymphocytes. Because T lymphocytes play a central role in the immune response it is reasonable to suppose that such compounds will prove to be of value in the treatment of immunoinflammatory conditions.
- Another property exhibited by the compounds of the present invention is the ability to inhibit the enzyme famesyl protein transferase (EC 2.5.1 p21 farnesyl transferase; FPTase). Inhibitors of this enzyme have shown promise as agents for the treatment of tumours, particularly those which express variants of the oncogenic protein ras that are constituitively active. Therefore a second use for the compounds of this invention is the treatment of neoplastic diseases.
- famesyl protein transferase EC 2.5.1 p21 farnesyl transferase
- FPTase farnesyl transferase
- the compounds of the invention are 3-aminopyridine derivatives of general formula
- n 0-4;
- n 1-2;
- R is optionally substituted phenyl, naphthyl or monocyclic or bicyclic heteroaryl with up to three heteroatoms selected from O, N and S in the ring(s);
- R , R and R are independently selected from H, lower alkyl, perfluoro-lower alkyl, optionally substituted phenyl and optionally substituted naphthyl;
- X is selected from -CH 2 -, -0-, -S-, -NH- and -NMe-;
- Y is -CR 3 R - where R 3 and R are independently selected from H and methyl, and when m is greater than 1 the repeating embodiments of Y can be identical or different.
- the compounds of general formula 1 have at least one stereogenic centre and so can exist as stereoisomers (enantiomers and diastereomers). These isomers, as single compounds or as mixtures, are included within the scope of this invention.
- the compounds also have at least one basic site and so can form salts with acids. These salts, and particularly those salts formed by pharmaceutically acceptable acids (including, but not limited to, acetic acid, citric acid, lactic acid, tartaric acid, hydrochloric acid, sulphuric acid, trifluoroacetic acid) are also included in the scope of the invention.
- Certain embodiments of general formula 1 also include acidic sites. These compounds can form salts with bases. Again, these salts (for example the sodium, potassium and ammonium salts) are included within the scope of the invention.
- R , R and R are all hydrogen.
- Particularly preferred embodiments of the invention are the following compounds, their stereoisomers and salts:
- the invention includes medicinal formulations in which a compound as described above is used as an active principal.
- Such formulations will have as other ingredients such materials as bulking and binding agents and preservatives as are well known in the art.
- the formulation may be a tablet, solution, suspension, cream, suppository or any other form appropriate for the administration of the active principal.
- the administration can be topical, by intravenous, subcutaneous or intramuscular injection, or via the oral, nasal, bucal, rectal or vaginal routes.
- the invention includes equally the use of these formulations for the treatment of a pathological condition in a human or other mammal, wherein the pathological condition is either an inflammatory or autoimmune disease such as (but not limited to) ulcerative colitis, Crohn's disease, allergic rhinitis, graft- vs-host disease, conjunctivitis, asthma, rheumatoid arthritis, osteoarthritis, ARDS, Behcet's disease, transplant rejection, uticaria, allergic dermatitis, allopecia areata, scleroderma, exanthem, eczema, dermatomyositis, acne, diabetes, systemic lupus erythematosis, Kawasaki's disease, multiple sclerosis, emphysema, cystic fibrosis, chronic bronchitis or psoriasis, or a proliferative disease such as cancer, for example colon, prostate or mammary carcinoma or leukaemia, or
- the amount of formulation (and hence the amount of active principal) will be chosen by the treating physician taking into account the age, weight and state of health of the patient as well as any other factors he considers to be relevant.
- the amount of active principal used will generally be between 0.1 mg and lOg per day in a single dose or in divided doses. Preferably the amount will be between lmg and lg.
- the compounds of the invention can be prepared by the following general methods.
- the compounds of the invention have a primary amine and a thiol functional group. These groups are likely to be reactive under the conditions used to elaborate the compounds and so need to be protected during the synthesis. Protecting groups for primary amines and thiols are well known in the literature.
- the final step(s) in the synthesis of a compound of formula 1 will be the simultaneous or sequential removal of the amine and thiol protecting groups.
- One convenient combination of protecting groups is the use of trityl (triphenylmethyl) to protect the thiol and BOC (tert- butyloxycarbonyl) to protect the amine.
- Both groups can be removed simultaneously by treating a compound of formula 2 with a strong acid, for example trifluoroacetic acid, in an appropriate solvent, for example dichloromethane, in the presence of a cation scavenger such as triethylsilane.
- a strong acid for example trifluoroacetic acid
- an appropriate solvent for example dichloromethane
- a cation scavenger such as triethylsilane.
- the compound of formula 2 is generally prepared from an aminopyridine of formula 3 and an aldehyde of formula 4. These components are combined in a suitable solvent (for example methanol containing 1-10% acetic acid) in the presence of a reducing agent such as sodium cyanoborohydride.
- a suitable solvent for example methanol containing 1-10% acetic acid
- a reducing agent such as sodium cyanoborohydride.
- the aminopyridine of formula 3 can be prepared from the corresponding nitropyridine of formula 5 by reduction.
- One convenient method for achieving this conversion is to stir a solution of the nitropyridine under an atmosphere of hydrogen in the presence of a palladium or platinum catalyst.
- Some combinations of R 1 , Y, m and X are incompatible with this protocol, and in these cases suitable reaction conditions might involve the use of zinc/acetic acid or sodium hydrosulphite.
- the nitropyridine of formula 5 can be prepared from a chloronitropyridine of formula 6 by reaction with a reagent of formula 7 in the presence of a base such as sodium hydride, potassium carbonate or potassium fluoride.
- a base such as sodium hydride, potassium carbonate or potassium fluoride.
- a nitropyridone of formula 8 (which can exist as the tautomeric hydroxypyridine) can be alkylated with a reagent of formula 9.
- the bromine atom can be replaced by the required phenyl group using the Suzuki coupling (phenylboronic acid in the presence of a palladium catalyst). This conversion is most conveniently performed after the elaboration of the R'Y m X group.
- Example 1A To a degassed solution of the nitropyridine of Example 1A (3.47g, 1 1.8mmol) in EtOAc (20mL) and ethanol (lOOmL) was added 10% palladium-on-carbon (500mg). The mixture was stirred at room temperature under an atmosphere of hydrogen for 2h then filtered. The catalyst was washed with ethanol and the combined filtrates were evaporated in vacuo. The residue was dried by azeotropic evaporation with toluene and used without further purification; assume 100% yield.
- Example 2C To an ice-cold solution of the alcohol of Example 2C (8.97g, 47.0mmol) in dry dimethylformamide (120mL) was added sodium hydride (2.1g, 60% dispersion, 52.5mmol). The mixture was stirred at 0°C for 45min, then 2-chloro-3 -nitropyridine (6.8g, 42.9mmol) was added following the method of Example 1A. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 15:85); yield 9.25g (69%).
- Example 2E The aminopyridine of Example 2E (13.88mmol) was reacted with N-BOC-S- tritylcysteinal (7.9g, 17.7mmol) and sodium cyanoborohydride (2.1g, 33.9mmol) in methanol (90mL) and acetic acid (lOmL) following the method of Example lC.
- the product was purified by chromatography on silica (eluant EtOAc:pet. ether 10:90); yield 4.17g (42%).
- Example 2F The compound of Example 2F (4.15g, 5.81mmol) was deprotected following the method of Example ID.
- the product was purified by MPLC (gradient wate ⁇ acetonitrile 100:0 ⁇ 50:50; 0.1% TFA) and lyophilised; yield 1.63g (75%%).
- Example 3A The compound of Example 3A (2.0g, 9.93mmol) was suspended in dimethylformamide (40mL). Phenethyliodide (4.6g, 16.7mmol) and potassium fluoride (l .lg, 19.0mmol) were added and the mixture stirred at room temperature for 3 days. The mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgS0 4 and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 4:96); yield 1.753g (58%).
- Example 3C To a degassed solution of the nitropyridine of Example 3C (170mg, 0.43mmol) in ethanol (40mL) was added 10% palladium-on-carbon (50mg). The mixture was stirred at room temperature under an atmosphere of hydrogen for 30min then filtered. The catalyst was washed with ethanol and the combined filtrates were evaporated in vacuo. The residue was dried by azeotropic evaporation with toluene and used without further purification; assume 100% yield.
- Example 3D The aminopyridine of Example 3D (0.43mmol) was reacted with N-BOC-S- tritylcysteinal (320mg, 0.71mmol) and sodium cyanoborohydride (93mg, 1.5mmol) in methanol (18mL) and acetic acid (2mL) following the method of Example IC.
- the product was purified by chromatography on silica (eluant EtOAc:pet. ether 4:96); yield 132mg (39%).
- Example 3F 3-r2-Amino-3-mercaptopropylaminoV6-(naphthyl)-2-(2-phenylethyloxy ' )pyridine
- the compound of Example 3E (132mg,0.17mmol) was deprotected following the method of Example ID.
- the product was purified by MPLC (gradient water:acetonitrile 100:0 ⁇ 50:50; 0.1% TFA) and lyophilised; yield 48.9mg (67%).
- Example 4A To a degassed solution of the nitropyridine of Example 4A (143mg, 0.39mmol) in ethanol (40mL) was added 10% palladium-on-carbon (50mg). The mixture was stirred at room temperature under an atmosphere of hydrogen for 30min then filtered. The catalyst was washed with ethanol and the combined filtrates were evaporated in vacuo. The residue was dried by azeotropic evaporation with toluene and used without further purification; assume 100% yield.
- Example 4B The aminopyridine of Example 4B (0.39mmol) was reacted with N-BOC-S- tritylcysteinal (210mg, 0.47mmol) and sodium cyanoborohydride (45mg, 0.73mmol) in methanol (18mL) and acetic acid (2mL) following the method of Example IC.
- the product was purified by chromatography on silica (eluant EtOAc:pet. ether 4:96); yield 114mg (38%).
- Example 4D 3-(2-Amino-3-mercaptopropylaminoV6-phenoxy-2-,2-phenylethyloxy ' )pyridine
- the compound of Example 4C (1 13mg,0.15mmol) was deprotected following the method of Example ID.
- the product was purified by MPLC (gradient water:acetonitrile 100:0 ⁇ 50:50; 0.1% TFA) and lyophilised; yield 14.1mg (24%).
- Example 5C The aminopyridine of Example 5C (l l lmg, 0.49mmol) was reacted with N-BOC-S- tritylcysteinal (325mg, 0.73mmol) and sodium cyanoborohydride (86mg, 1.39mmol) in methanol (18mL) and acetic acid (2mL) following the method of Example I C.
- the product was purified by chromatography on silica (eluant EtOAc:pet. ether 10:90); yield 164mg (51%).
- Example 5D The compound of Example 5D (164mg,0.25mmol) was deprotected following the method of Example ID.
- the product was purified by MPLC (gradient wate ⁇ acetonitrile 100:0 ⁇ 50:50; 0.1% TFA) and lyophilised; yield 26.7mg (34%).
- the compounds of the invention are useful as inhibitors of the enzyme farnesyl protein transferase and as inhibitors of T-lymphocyte proliferation.
- Inhibitors of farnesyl protein transferase are known to show good efficacy in animal models of tumour growth and hence can be expected to be useful in the chemotherapy of human cancers.
- T-lymphocytes are key mediators of the immune response and are believed to play a central role in the etiology of many inflammatory diseases. Hence, inhibitors of T-lymphocyte proliferation are expected to show clinically useful anti- inflammatory activity.
- the utility of the compounds of the invention can be demonstrated using the assays described below.
- ASSAY 1 Farnesyl Protein Transferase Inhibition.
- ASSAY 2 Geranylgeranyl Protein Transferase I Inhibition.
- Geranylgeranyl Protein Transferase I was also determined using standard literature methods. Again, the IC 50 is the concentration of test compound required to reduce the amount of product formed by 50%. Selected compounds of the invention have IC 50 values as shown below in Table 2.
- ASSAY 3 T-Lymphocyte Proliferation Inhibition.
- Human T-lymphocytes are stimulated to proliferate with an anti-CD3 antibody in the presence of varying concentrations of the test compound. After 3 days [ HJfhymidine is added. The cells are incubated for a further 12 hours, then proliferation is quantified by counting the incorporation of radioactivity into the cellular fraction.
- the compounds of the invention inhibit proliferation at concentrations below 50 ⁇ M. Typical examples are shown below in Table 2.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
3-Aminopyridine derivatives of general formula (1), wherein m is 0-4; n is 1-2; R1 is optionally substituted monocyclic or bicyclic aryl or heteroaryl; R?2, R3 and R4¿ are independently selected from H, lower alkyl, perfluoro-lower alkyl, optionally substituted phenyl and optionally substituted naphthyl; X is selected from -CH¿2?-, -O-, -S-, -NH- and -NMe- and Y is -CR?5R6¿- where R?5 and R6¿ are independently selected from H and methyl, and when m is greater than 1 the repeating embodiments of Y can be identical or different, are new. The compounds 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
Aminopyridine Derivatives for 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 arc characterised by progressive tissue damage with inflammation and invasion of the lesion by leukocytes. Examples of such diseases include inflammatory bowel disease, psoriasis, asthma and rheumatoid arthritis. Current therapeutic regimens for these conditions are often inadequate, and new approaches are required. One aspect of the present invention is a series of compounds that inhibit the proliferation of T lymphocytes. Because T lymphocytes play a central role in the immune response it is reasonable to suppose that such compounds will prove to be of value in the treatment of immunoinflammatory conditions.
Another property exhibited by the compounds of the present invention is the ability to inhibit the enzyme famesyl protein transferase (EC 2.5.1 p21 farnesyl transferase; FPTase). Inhibitors of this enzyme have shown promise as agents for the treatment of tumours, particularly those which express variants of the oncogenic protein ras that are constituitively active. Therefore a second use for the compounds of this invention is the treatment of neoplastic diseases.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the invention are 3-aminopyridine derivatives of general formula
m is 0-4;
n is 1-2;
R is optionally substituted phenyl, naphthyl or monocyclic or bicyclic heteroaryl with up to three heteroatoms selected from O, N and S in the ring(s);
R , R and R are independently selected from H, lower alkyl, perfluoro-lower alkyl, optionally substituted phenyl and optionally substituted naphthyl;
X is selected from -CH2-, -0-, -S-, -NH- and -NMe-;
Y is -CR3R - where R3 and R are independently selected from H and methyl, and when m is greater than 1 the repeating embodiments of Y can be identical or different.
The compounds of general formula 1 have at least one stereogenic centre and so can exist as stereoisomers (enantiomers and diastereomers). These isomers, as single compounds or as mixtures, are included within the scope of this invention. The compounds also have at least one basic site and so can form salts with acids. These salts, and particularly those salts formed by pharmaceutically acceptable acids (including, but not limited to, acetic acid, citric acid, lactic acid, tartaric acid, hydrochloric acid, sulphuric acid, trifluoroacetic acid) are also included in the scope of the invention. Certain embodiments of general formula 1 also include acidic sites. These compounds can form salts with bases. Again, these salts (for example the sodium, potassium and ammonium salts) are included within the scope of the invention.
Preferably R , R and R are all hydrogen.
Particularly preferred embodiments of the invention are the following compounds, their stereoisomers and salts:
3-(2-Amino-3-mercaptopropylamino)-2-(2-phenylethyloxy)pyridine (Compound 1 )
3-(2-Amino-3-mercaptopropylamino)-2-(3-phenylpropyloxy)pyridine (Compound 2)
3-(2-Amino-3-mercaptopropylamino)-2-phenoxypyridine (Compound 3)
3-(2-Amino-3-mercaptopropylamino)-2-(4-phenylbutyloxy)pyridine (Compound 4)
3-(2-Amino-3-mercaptopropylamino)-2-benzyloxypyridine (Compound 5)
3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-(2-phenylethyloxy)pyridine (Compound 6 )
3-(2-Amino-3-mercaptopropylamino)-2-(2-(l-naphthyl)ethyloxy)pyridine (Compound 7)
3-(2-Amino-3-mercaptopropylamino)-2-(2-(2-naphthyl)ethyloxy)pyridine (Compound 8)
3-(2-Amino-3-mercaptopropylamino)-2-(2-(2-thienyl)ethyloxy)pyridine (Compound 9)
3-(2-Amino-3-mercaptopropylamino)-2-(2-(3-thienyl)ethyloxy)pyridine (Compound 10)
3-(2-Amino-3-mercaptopropylamino)-2-(N-methyl-N-(2-phenylethyl)amino)pyridine (Compound 11 )
3-(2-Amino-3-mercaptopropylamino)-6-butyl-2-(2-phenylethyloxy)pyridine (Compound 12)
3-(2-Amino-3-mercaptopropylamino)-6-phenoxy-2-(2-phenylethyloxy)pyridine (Compound 13)
3-(2-Amino-3-mercaptopropylamino)-2-(N-benzyl-N-methyl)amino)pyridine (Compound 14)
3-(2-Amino-3-mercaptopropylamino)-6-(l-naphthyl)-2-(2-phenylethyloxy)pyridine (Compound 15)
3-(2-Amino-3-mercaptopropylamino)-2-(2-(2-pyridyl)ethyloxy)pyridine (Compound 16)
3-(2-Amino-3-mercaptopropylamino)-2-(2-(4-pyridyl)ethyloxy)pyridine (Compound 17)
3-(2-Amino-3-mercaptopropylamino)-2-(N-methyl-N-(l-naphthyl)methyl)amino)- pyridine (Compound 18)
3-(2-Amino-3-mercaptopropylamino)-2-benzylaminopyridine (Compound 19)
3-(2-Amino-3-mercaptopropylamino)-2-((17^)-l -phenylethylamino)pyridine (Compound 20)
3 -(2-Amino-3 -mercaptopropy lamino)-2-(( 1 S)- 1 -phenylethy lamino)pyridine (Compound 21)
3-(2-Amino-3-mercaptopropylamino)-2-(N-methyl-N-((l/-)-l-phenylethyl)amino)- pyridine (Compound 22)
3-(2-Amino-3-mercaptopropylamino)-2-(N-methyl-N-((lS)-l -phenylethyl)amino)- pyridine (Compound 23)
3-(2-Amino-3-mercaptopropylamino)-2-(2-(2,3-dichlorophenyl)ethyloxy)pyridine (Compound 24)
3-(3-Amino-4-mercaptobutylamino)-2-(2-(l-naphthyl)ethyloxy)pyridine (Compound 25)
3-(3-Amino-4-mercaptobutylamino)-2-(2-(2-thienyl)ethyloxy)pyridine (Compound 26)
3-(2-Amino-3-mercaptopropylamino)-2-(2-benzothienylmethyloxy)pyridine (Compound 27)
3-(2-Amino-3-mercaptopropylamino)-4-methyl-2-(2-(l-naphthyl)ethyloxy)pyridine (Compound 28)
3-(2-Amino-3-mercaptopropylamino)-2-(2-(l-naphthyl)ethyloxy)-5-trifluoiOmethyl- pyridine (Compound 29)
3-(2-Amino-3-mercaptopropylamino)-2-(2-(l-naphthyl)ethyloxy)-5-phenylpyridine (Compound 30)
3-(2-Amino-3-mercaptopropylamino)-2-(2-phenylethylamino)pyridine (Compound 31)
3-(3-Amino-4-mercaptobutylamino)-2-(2-(2,3-dichlorophenyl)ethyloxy)pyridine (Compound 32)
3-(2-Amino-3-mercaptopropylamino)-2-(2-(3-benzothienyl)ethyloxy)pyridine (Compound 33)
3-(3-Amino-4-mercaptobutylamino)-2-(2-(3-benzothienyl)ethyloxy)pyridine (Compound 34)
3-(2-Amino-3-mercaptopropylamino)-2-(l-methyl-2-phenylethyloxy)pyridine (Compound 35)
3-(2-Amino-3-mercaptopropylamino)-2-(2-phenylpropyloxy)pyridine (Compound 36)
3-(2-Amino-3-mercaptopropylamino)-2-(2-(2-benzothienyl)ethyloxy)pyridine (Compound 37)
3-(2-Amino-3-mercaptopropylamino)-2-(2-(3-chlorophenyl)ethyloxy)pyridine (Compound 38)
3-(2-Amino-3-mercaptopropylamino)-2-(2-(2-chlorophenyl)ethyloxy)pyridine (Compound 39)
3-(2-Amino-3-mercaptopropylamino)-2-(2-(2,3-dimethoxyphenyl)ethyloxy)pyridine (Compound 40)
3-(2-Amino-3-mercaptopropylamino)-2-(2-(2,3-dimethylphenyl)ethyloxy)pyridine (Compound 41)
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 compounds of the invention can be prepared by the following general methods.
The compounds of the invention have a primary amine and a thiol functional group. These groups are likely to be reactive under the conditions used to elaborate the compounds and so need to be protected during the synthesis. Protecting groups for primary amines and thiols are well known in the literature. The final step(s) in the synthesis of a compound of formula 1 will be the simultaneous or sequential removal of the amine and thiol protecting groups. One convenient combination of protecting groups is the use of trityl (triphenylmethyl) to protect the thiol and BOC (tert-
butyloxycarbonyl) to protect the amine. Both groups can be removed simultaneously by treating a compound of formula 2 with a strong acid, for example trifluoroacetic acid, in an appropriate solvent, for example dichloromethane, in the presence of a cation scavenger such as triethylsilane.
The compound of formula 2 is generally prepared from an aminopyridine of formula 3 and an aldehyde of formula 4. These components are combined in a suitable solvent (for example methanol containing 1-10% acetic acid) in the presence of a reducing agent such as sodium cyanoborohydride.
BOC = Me3COCO; Trt = Ph3C formula 4 formula 3 formula 2
The aminopyridine of formula 3 can be prepared from the corresponding nitropyridine of formula 5 by reduction. One convenient method for achieving this conversion is to stir a solution of the nitropyridine under an atmosphere of hydrogen in the presence of a palladium or platinum catalyst. Some combinations of R1, Y, m and X are
incompatible with this protocol, and in these cases suitable reaction conditions might involve the use of zinc/acetic acid or sodium hydrosulphite.
The aldehyde of formula 4 can be prepared from the corresponding alcohol by oxidation or from an appropriate carboxylic acid derivative by reduction. For the case where n=l the starting material for these reactions is protected cysteine.
One convenient method is to proceed via the N,0-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.
formula 4 (n=2)
The nitropyridine of formula 5 can be prepared from a chloronitropyridine of formula 6 by reaction with a reagent of formula 7 in the presence of a base such as sodium hydride, potassium carbonate or potassium fluoride.
An alternative stategy is possible when X = O and m > 0. In this case, a nitropyridone of formula 8 (which can exist as the tautomeric hydroxypyridine) can be alkylated with a reagent of formula 9. The alkylating agent can be an alcohol (LG = OH), in which case the reaction can be effected under the Mitsunobu conditions (Ph3P and Et02CN:NC02Et). Another possibility is that the alkylating agent can be a halide or sulphonate (e.g. LG = CI, Br, MeS020), in which case the reaction requires the presence of a base such as sodium hydride or potassium carbonate.
formula 8 formula 9 formula 5 (X = O)
Pyridines of formula 6, pyridones of formula 8 and reagents of formula 7 and 9 are well represented in the literature. It will frequently be possible to obtain any particular starting material commercially or by following an existing procedure. When the particular compound has not been described previously it may be accessible by an obvious adaptation of a published route to an analogous compound. For some combinations of R , R and R neither of these options will be available and it will be necessary to include one or more extra steps in the synthesis to introduce these groups. The chemistry of pyridine derivatives has been extensively studied, and the skilled practitioner will be able to find an appropriate method. For example, when
~\ 7 4
R = Ph (with R and R = H) the pyridone of formula 8 is not available but 5-bromo- 3-nitro-2-pyridone is. The bromine atom can be replaced by the required phenyl group using the Suzuki coupling (phenylboronic acid in the presence of a palladium catalyst). This conversion is most conveniently performed after the elaboration of the R'YmX group.
These general procedures are further illustrated in the following non-limiting examples.
EXAMPLE 1
3-(2-Amino-3-mercaptopropylaminoV2-r2-fl-naphthyπethyloxy^pyridine (Compound 1)
1A. 2-(2-π -Naphthyl)ethyloxy)-3-nitropyridine
To an ice-cold solution of 2-(l-naphthyl)ethanol (3.26g, 18.9mmol) in dry dimethylformamide (40mL) was added sodium hydride (831mg, 60% dispersion, 20.8mmol). The mixture was stirred at 0°C for 45min, then 2-chloro-3-nitropyridine (2.5g, 15.8mmol) was added and the mixture was allowed to warm to room temperature, stirred for 18h, and partitioned between EtOAc and water. The organic layer was washed with water (3 times) and brine, dried over MgS04, and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 15:85); yield 3.47g (75%).
IB. 3-Amino-2-.2-(l-naphthv0ethyloxy)pyridine
To a degassed solution of the nitropyridine of Example 1A (3.47g, 1 1.8mmol) in EtOAc (20mL) and ethanol (lOOmL) was added 10% palladium-on-carbon (500mg). The mixture was stirred at room temperature under an atmosphere of hydrogen for 2h then filtered. The catalyst was washed with ethanol and the combined filtrates were evaporated in vacuo. The residue was dried by azeotropic evaporation with toluene and used without further purification; assume 100% yield.
l C. 3-f2-t-?rt-Butyloxycarbonylamino-3-triphenylmethylmercaptopropylamino)-2-(2- ( 1 -naphthyl)ethyloxy)pyridine
To a solution of the aminopyridine of Example IB (1 1.8mmol) and N-BOC-S- tritylcysteinal (6.4g, 14.3mmol) in methanol (90mL) and acetic acid (lOmL) was
added sodium cyanoborohydride (1.4g, 22.6mmol). The mixture was stirred overnight at room temperature and then concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified by chromatography on silica (eluant EtOAc:pet. ether 10:90); yield 6.058g (74%).
I D. 3- 2-Amino-3-mercaptopropylaminoV2-.2-(l-naphthyl)ethyloxy)pyridine
To a solution of the compound of Example 1C (6.058g, 8.72mmol) in dichloromethane (50mL) was added trifluoroacetic acid (50mL) and then triethylsilane dropwise until the yellow colour was discharged. The mixture was stirred overnight at room temperature, then diluted with toluene (20mL) and concentrated in vacuo. The residue was dissolved in acetonitrile/water (1 : 1) and filtered to remove triphenylmethane. The filtrate was lyophilised. The residue was purified by MPLC (gradient water:acetonitrile 100:0 → 50:50; 0.1% TFA) and lyophilised; yield 2.282g (74%).
M.S.: calc m/e=353.16; found [M+H]+= 354
EXAMPLE 2
3-.2-Amino-3-mercaptopropylaminoV2-.2-.2.3-dichlorophenyl)ethyloxy)pyridine (Compound 24)
2A. 2'-Diazo-2.3-dichloroacetophenone
To an ice-cold solution of diazomethane (6g, 143mmol) in diethyl ether (500mL) was added a solution of 2,3-dichlorobenzoyl chloride (17.5g, 84mmol) in tetrahydrofuran (lOOmL). After stirring at 0°C for 4h, acetic acid was added to destroy excess
diazomethane and the reaction mixture was concentrated in vacuo. The residue was partitioned between EtOAc and water, and the organic layer was washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 15:85); yield 15.17g (83%).
2B. Methyl 2.3-dichlorophenylacetate
To a solution of the diazoketone of Example 2A (15.17g, 69.9mmol) in methanol (200mL) was slowly added a solution of silver benzoate (8.1g, 35.3mmol) in triethylamine (80mL). The mixture was stirred at room temperature for 90min then filtered and concentrated in vacuo. The residue was partitioned between EtOAc and water and the organic layer was washed with water and brine, dried over MgS04 and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 9: 1); yield 14.9g (97%).
2C. 2-,2.3-DichlorophenyOethanol
To an ice-cold solution of the ester of Example 2B (14. g, 68.0mmol) in toluene (200mL) was added diisobutylaluminium hydride (1.5M solution in toluene, 200mL, 300mmol). The mixture was stirred for 2h, then methanol (25mL) was added slowly and the resulting mixture was poured into a saturated solution of potassium sodium tartrate (300mL) and stirred for lh. The mixture was filtered. The residue was washed with EtOAc. The filtrate and washings were combined and the organic layer was separated, washed with water and brine, dried over MgS04 and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAcφet.e her 15:85); yield 8.97g (69%).
2D. 2-.2-(2.3-Dichlorophenyl)ethyloxyV3-nitropyridine
To an ice-cold solution of the alcohol of Example 2C (8.97g, 47.0mmol) in dry dimethylformamide (120mL) was added sodium hydride (2.1g, 60% dispersion, 52.5mmol). The mixture was stirred at 0°C for 45min, then 2-chloro-3 -nitropyridine (6.8g, 42.9mmol) was added following the method of Example 1A. The product was
purified by flash chromatography on silica (eluant EtOAc:pet. ether 15:85); yield 9.25g (69%).
2E. 3-Amino-2-(2-.2.3-dichlorophenyπethyloxy)pyridine
To a solution of the nitropyridine of Example 2D (4.34g, 13.88mmol) in tetrahydrofuran (150mL) and water (80mL) was added potassium carbonate (10.6g, 76.8mmol) and sodium hydrosulphite (12. Og, 69.0mmol). The mixture was stirred at room temperature overnight and diluted with EtOAc (200mL). The organic phase was separated, washed with water and brine, dried over MgS04 and concentrated in vacuo. The residue was used without further purification; assume 100% yield.
2F. 3-(2-/grt-Butyloxycarbonylamino-3-triphenylmethylmercaptopropylaminoV2-.2-
(2.3-dichlorophenyl)ethyloxy pyridine
The aminopyridine of Example 2E (13.88mmol) was reacted with N-BOC-S- tritylcysteinal (7.9g, 17.7mmol) and sodium cyanoborohydride (2.1g, 33.9mmol) in methanol (90mL) and acetic acid (lOmL) following the method of Example lC. The product was purified by chromatography on silica (eluant EtOAc:pet. ether 10:90); yield 4.17g (42%).
2G. 3-(2-Amino-3-mercaptopropylaminoV2-(,2-(2.3-dichlorophenyπethyloxy)- pyridine
The compound of Example 2F (4.15g, 5.81mmol) was deprotected following the method of Example ID. The product was purified by MPLC (gradient wateπacetonitrile 100:0 → 50:50; 0.1% TFA) and lyophilised; yield 1.63g (75%%).
M.S.: calc m/e-371.10; found [M+H]+= 372
EXAMPLE 3 3-(2-Amino-3-mercaptopropylamino)-6-(naphthyl)-2-(2-phenylethyIoxy)pyridine
(Compound 15)
3 A: 6-ChloiO-2-hydroxy-3-nitropyridine
Potassium tert-butoxide (21.0g, 0.186mol) was added to a solution of 2,6-dichloro-3- nitropyridine (18.0g, 0.093mol) in ter/-butanol (200mL). After stirring at 100υC for 4h water (20mL) was added and the solvent evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:methanol 100:0-^75:25); yield 13Ng (84%).
3B: 6-Chloro-3-nitro-2-(2-phenylethyloxy)pyridine
The compound of Example 3A (2.0g, 9.93mmol) was suspended in dimethylformamide (40mL). Phenethyliodide (4.6g, 16.7mmol) and potassium fluoride (l .lg, 19.0mmol) were added and the mixture stirred at room temperature for 3 days. The mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 4:96); yield 1.753g (58%).
3C: 6-(l -Naphthyl) -3-nitro-2-(2-phenylethyloxy)pyridine
To a solution of the compound of Example 3B (210mg, 0.69mmol) in tetrahydrofuran (20mL) was added tetrakis(triphenylphosphine)palladium(0) (80mg, 0.069mmol). After stirring at room temperature for 45min 1 -naphthaleneboronic acid (230mg,
1.37mmol) was added. After a further 2h at room temperature 2M Na2C03 (5mL) 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 MgS04 and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc.pet. ether 2:98); yield 170mg (62%).
3D: 3-Amino-6-(l-naphthyl)-2-(2-phenylethyloxy pyridine
To a degassed solution of the nitropyridine of Example 3C (170mg, 0.43mmol) in ethanol (40mL) was added 10% palladium-on-carbon (50mg). The mixture was stirred at room temperature under an atmosphere of hydrogen for 30min then filtered. The catalyst was washed with ethanol and the combined filtrates were evaporated in vacuo. The residue was dried by azeotropic evaporation with toluene and used without further purification; assume 100% yield.
3E: 3-(2-tert-Butyloxycarbonylamino-3-triphenylmethylmercaptopropylamino)-6-(l - naphthy0-2-(2-phenylethyloxy pyridine
The aminopyridine of Example 3D (0.43mmol) was reacted with N-BOC-S- tritylcysteinal (320mg, 0.71mmol) and sodium cyanoborohydride (93mg, 1.5mmol) in methanol (18mL) and acetic acid (2mL) following the method of Example IC. The product was purified by chromatography on silica (eluant EtOAc:pet. ether 4:96); yield 132mg (39%).
3F: 3-r2-Amino-3-mercaptopropylaminoV6-(naphthyl)-2-(2-phenylethyloxy')pyridine The compound of Example 3E (132mg,0.17mmol) was deprotected following the method of Example ID. The product was purified by MPLC (gradient water:acetonitrile 100:0 → 50:50; 0.1% TFA) and lyophilised; yield 48.9mg (67%). M.S.: calc m/e=429.19 found [M+H]+= 430
EXAMPLE 4
3-(2-Amino-3-mercaptopropylaminoV6-phenoxy-2-(2-pheny.ethyloxy)pyridine (Compound 13
4 A: 3-Nitro-6-phenoxy-2-(2-phenylethyloxy pyridine
To an ice-cold solution of phenol (82mg, 0.81mmol) in dimethylformamide (l OmL) was added sodium hydride (60% oil dispersion, 38mg, 0.95mmol). After 45min a solution of the compound of Example 3B (196mg, 0.64mmol) in dimethylformamide (5mL) was added. After stirring for 18h, water (lOmL) was added and the mixture extracted with EtOAc. The organic layer was washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc :pet.ether 4:96); yield 143mg (61%).
4B: 3-Amino-6-phenoxy-2-(2-phenylethyloxy)pyridine
To a degassed solution of the nitropyridine of Example 4A (143mg, 0.39mmol) in ethanol (40mL) was added 10% palladium-on-carbon (50mg). The mixture was stirred at room temperature under an atmosphere of hydrogen for 30min then filtered. The catalyst was washed with ethanol and the combined filtrates were evaporated in vacuo. The residue was dried by azeotropic evaporation with toluene and used without further purification; assume 100% yield.
4C: 3-(2-tgrt-Butyloxycarbonylamino-3-triphenylmethylmercaptopropylaminoV6- phenoxy-2-(2-phenylethyloxy)pyridine
The aminopyridine of Example 4B (0.39mmol) was reacted with N-BOC-S- tritylcysteinal (210mg, 0.47mmol) and sodium cyanoborohydride (45mg, 0.73mmol) in methanol (18mL) and acetic acid (2mL) following the method of Example IC.
The product was purified by chromatography on silica (eluant EtOAc:pet. ether 4:96); yield 114mg (38%).
4D: 3-(2-Amino-3-mercaptopropylaminoV6-phenoxy-2-,2-phenylethyloxy')pyridine The compound of Example 4C (1 13mg,0.15mmol) was deprotected following the method of Example ID. The product was purified by MPLC (gradient water:acetonitrile 100:0 → 50:50; 0.1% TFA) and lyophilised; yield 14.1mg (24%). M.S.: calc m/e=395.17 found [M+H]+= 396
EXAMPLE 5
3-(2-Amino-3-mercaptopropylamino -2-(N-methyl-N-((lRM-phenethy.)arnino)- pyridine (Compound 22)
5 A: 3-Nitro-2-r -((lR)-l -phenylethyπamino)pyridine
Potassium carbonate (1.6g, l l .όmmol) was added to a solution of 2-chloro-3- nitropyridine (1.5g, 9.46mmol) and (R)-(+)-l -phenylethylamine (1.4g, 1 l .όmmol). After stirring at 60ϋC for 18h the mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 5:95); yield 2.06g (90%).
5B: 2-(N-Methyl-N-((lR)-l-phenylethyl)amino)-3-nitro-pyridine
To an ice-cold solution of the compound of Example 5A (500mg, 2.05mmol) in dimethylformamide (25mL) was added sodium hydride (60% oil dispersion, 105mg,
2.63mmol). After 30min iodomethane (l .Og, 7.04mmol) was added and the mixture stirred at 60°C for 6h. The mixture was partitioned between EtOAc and water, the organic layer was washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 3:97); yield 441mg (87%).
5C: 3-Amino-2-(N-methyl-N-((1 R -l -phenylethvπamino)pyridine To a solution of the nitropyridine of Example 5B (200mg, 0.78mmol) in tetrahydrofuran (30mL) and water (lOmL) was added potassium carbonate (1.17g, 8.47mmol) and sodium hydrosulphite (1.3g, 7.47mmol). The mixture was stirred at room temperature overnight and diluted with EtOAc (lOOmL). The organic phase was separated, washed with water and brine, dried over MgS04 and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 10:90); yield l l lmg (63%).
5D: 3-(2-/grt-Butyloxycarbonylamino-3-triphenylmethylmercaptopropylaminoV2-rN- methyl-N-(( 1 RV 1 -pheny lethyDamino^pyridine
The aminopyridine of Example 5C (l l lmg, 0.49mmol) was reacted with N-BOC-S- tritylcysteinal (325mg, 0.73mmol) and sodium cyanoborohydride (86mg, 1.39mmol) in methanol (18mL) and acetic acid (2mL) following the method of Example I C. The product was purified by chromatography on silica (eluant EtOAc:pet. ether 10:90); yield 164mg (51%).
5E: 3-(2-Amino-3-mercaptopropylaminoV2-(N-methyl-N-((l R)-l -phenethyπamino')- pyridine
The compound of Example 5D (164mg,0.25mmol) was deprotected following the method of Example ID. The product was purified by MPLC (gradient wateπacetonitrile 100:0 → 50:50; 0.1% TFA) and lyophilised; yield 26.7mg (34%).
M. S. : calc m/e=316.17 found [M+H = 317
The compounds of the invention are useful as inhibitors of the enzyme farnesyl protein transferase and as inhibitors of T-lymphocyte proliferation. Inhibitors of farnesyl protein transferase are known to show good efficacy in animal models of tumour growth and hence can be expected to be useful in the chemotherapy of human cancers. T-lymphocytes are key mediators of the immune response and are believed to play a central role in the etiology of many inflammatory diseases. Hence, inhibitors of T-lymphocyte proliferation are expected to show clinically useful anti- inflammatory activity. The utility of the compounds of the invention can be demonstrated using the assays described below.
ASSAY 1 : Farnesyl Protein Transferase Inhibition.
Inhibition of Farnesyl Protein Transferase is determined using a Scintillation Proximity Assay (Amersham). A biotin-tagged peptide substrate and [ H]-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%. Typical examples are shown in Table 1.
Table 1
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 IC50 values as shown below in Table 2.
ASSAY 3: T-Lymphocyte Proliferation Inhibition.
Human T-lymphocytes are stimulated to proliferate with an anti-CD3 antibody in the presence of varying concentrations of the test compound. After 3 days [ HJfhymidine is added. The cells are incubated for a further 12 hours, then proliferation is
quantified by counting the incorporation of radioactivity into the cellular fraction. The compounds of the invention inhibit proliferation at concentrations below 50μιM. Typical examples are shown below in Table 2.
Table 2
Claims
1. A compound of general formula 1 , or a pharmaceutically acceptable salt thereof,
in which:
m is 0-4; n is 1-2;
R is optionally substituted phenyl, naphthyl or monocyclic or bicyclic heteroaryl with up to three heteroatoms selected from 0, N and S in the ring(s);
R2, R and R are independently selected from H, lower alkyl, perfluoro-lower alkyl, optionally substituted phenyl and optionally substituted naphthyl;
X is selected from -CH2-, -0-, -S-, -NH- and -NMe-;
Y is -CR^R - where RD and R are independently selected from H and methyl, and when m is greater than 1 the repeating embodiments of Y can be identical or different.
2. A compound according to Claim 1 in which R", R and R are all hydrogen.
3. A compound of Claim 1 selected from:
3-(2-Amino-3-mercaptopropylamino)-2-(2-phenylethyloxy)pyridine
3-(2-Amino-3-mercaptopropylamino)-2-(3-phenylpropyloxy)pyridine
3-(2-Amino-3-mercaptopropylamino)-2-phenoxypyridine
3-(2-Amino-3-mercaptopropylamino)-2-(4-phenylbutyloxy)pyridine
3-(2-Amino-3-mercaptopropylamino)-2-benzyloxypyridine
3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-(2-phenylethyloxy)pyridine
3-(2-Amino-3-mercaptopropylamino)-2-(2-(l-naphthyl)ethyloxy)pyridine -(2-Amino-3-mercaptopropylamino)-2-(2-(2-naphthyl)ethyloxy)pyridine
-(2-Amino-3-mercaptopropylamino)-2-(2-(2-thienyl)ethyloxy)pyridine
-(2-Amino-3-mercaptopropylamino)-2-(2-(3-lhienyl)ethyloxy)pyridine
-(2-Amino-3-mercaptopropylamino)-2-(N-methyl-N-(2-phenylethyl)amino)pyridine
-(2-Amino-3-mercaptopropylamino)-6-butyl-2-(2-phenylethyloxy)pyridine
-(2-Amino-3-mercaptopropylamino)-6-phenoxy-2-(2-phenylethyloxy)pyridine
-(2-Amino-3-mercaptopropylamino)-2-(N-benzyl-N-methyl)amino)pyridine
-(2-Amino-3-mercaptopropylamino)-6-(l-naphthyl)-2-(2-phenylethyloxy)pyridine
3-(2-Amino-3-mercaptopropylamino)-2-(2-(2-pyridyl)ethyloxy)pyridine
3-(2-Amino-3-mercaptopropylamino)-2-(2-(4-pyridyl)ethyloxy)pyridine
3-(2-Amino-3-mercaptopropylamino)-2-(N-methyl-N-(l-naphthyl)methyl)amino)- pyridine
3-(2-Amino-3-mercaptopropylamino)-2-benzylaminopyridine
3-(2-Amino-3-mercaptopropylamino)-2-((17-)-l-phenylethylamino)pyridine
3-(2-Amino-3-mercaptopropylamino)-2-((lS)-l-phenylethylamino)pyridine 3-(2-Amino-3-mercaptopropylamino)-2-(N-methyl-N-((iy.)-l-phenylethyl)amino)- pyridine
3-(2-Amino-3-mercaptopiOpylamino)-2-(N-methyl-N-((lS)-l-phenylethyl)amino)- pyridine
3-(2-Amino-3-mercaptopropylamino)-2-(2-(2,3-dichloiOphenyl)ethyloxy)pyridine
3-(3-Amino-4-mercaptobutylamino)-2-(2-(l-naphthyl)ethyloxy)pyridine
3-(3-Amino-4-mercaptobutylamino)-2-(2-(2-thienyl)ethyloxy)pyridine
3-(2-Amino-3-mercaptopropylamino)-2-(2-benzothienylmethyloxy)pyridine
3-(2-Amino-3-mercaptopropylamino)-4-methyl-2-(2-(l-naphthyl)ethyloxy)pyridine
3-(2-Amino-3-mercaptopiOpylamino)-2-(2-(l-naphthyl)ethyloxy)-5-trifluoromethyl- pyridine
3-(2-Amino-3-mercaptopropylamino)-2-(2-(l-naphthyl)ethyloxy)-5-phenylpyridine
3-(2-Amino-3-mercaptopropylamino)-2-(2-phenylethylamino)pyridine
3-(3-Amino-4-mercaptobutylamino)-2-(2-(2,3-dichlorophenyl)ethyloxy)pyridine
3-(2-Amino-3-mercaptopiOpylamino)-2-(2-(3-benzothienyl)ethyloxy)pyridine
3-(3-Amino-4-mercaptobutylamino)-2-(2-(3-benzothienyl)ethyloxy)pyridine
3-(2-Amino-3-mercaptopropylamino)-2-(l-methyl-2-phenylethyloxy)pyridine -(2-Amino-3-mercaptopropylamino)-2-(2-phenylpropyloxy)pyridine
-(2-Amino-3-mercaptopropylamino)-2-(2-(2-benzothienyl)ethyloxy)pyridine
-(2-Amino-3-mercaptopropylamino)-2-(2-(3-chlorophenyl)ethyloxy)pyridine
-(2-Amino-3-mercaptopropylamino)-2-(2-(2-chlorophenyl)ethyloxy)pyridine
-(2-Amino-3-mercaptopropylamino)-2-(2-(2,3-dimethoxyphenyl)ethyloxy)pyridine
-(2-Amino-3-mercaptopropylamino)-2-(2-(2,3-dimethylphenyl)ethyloxy)pyridine
4. A medicinal formulation which includes as an active principal a compound according to any preceding claim.
5. A formulation according to claim 4 which is 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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU69272/98A AU6927298A (en) | 1997-04-04 | 1998-04-03 | Aminopyridine derivatives for inflammatory and malignant diseases |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9706922A GB2323841A (en) | 1997-04-04 | 1997-04-04 | Pyridine derivatives with anti-tumor and anti-inflammatory activity |
| GB9706922.3 | 1997-04-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1998045267A1 true WO1998045267A1 (en) | 1998-10-15 |
Family
ID=10810332
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB1998/000998 Ceased WO1998045267A1 (en) | 1997-04-04 | 1998-04-03 | Aminopyridine derivatives for inflammatory and malignant diseases |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU6927298A (en) |
| GB (1) | GB2323841A (en) |
| WO (1) | WO1998045267A1 (en) |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7045519B2 (en) | 1998-06-19 | 2006-05-16 | Chiron Corporation | Inhibitors of glycogen synthase kinase 3 |
| US7417047B2 (en) | 2005-06-30 | 2008-08-26 | Wyeth | Amino-5-(5-membered)hetero-arylimidazolone compounds and the use thereof for β-secretase modulation |
| US7423158B2 (en) | 2005-09-26 | 2008-09-09 | Wyeth | Amino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone compounds for the inhibition of β-secretase |
| US7452885B2 (en) | 2005-06-30 | 2008-11-18 | Wyeth | Amino-5-(6-membered)heteroarylimidazolone compounds and the use thereof for β-secretase modulation |
| US7456186B2 (en) | 2004-06-16 | 2008-11-25 | Wyeth | Diphenylimidazopyrimidines as inhibitors of β-secretase |
| US7482349B2 (en) | 2004-06-16 | 2009-01-27 | Wyeth | Amino-5,5-diphenylimidazolone derivatives for the inhibition of β-secretase |
| US7488832B2 (en) | 2005-02-14 | 2009-02-10 | Wyeth | Azolylacylguanidines as β-secretase inhibitors |
| US7563796B2 (en) | 2005-01-14 | 2009-07-21 | Wyeth | Diphenylimidazopyrimidines as inhibitors of β-secretase |
| US7582667B2 (en) | 2006-02-24 | 2009-09-01 | Wyeth | Dihydrospiro[dibenzo[a,d][7]annulene-5,4′-imidazol] compounds for the inhibition of beta-secretase |
| US7700606B2 (en) | 2006-08-17 | 2010-04-20 | Wyeth Llc | Imidazole amines as inhibitors of β-secretase |
| US7723368B2 (en) | 2007-03-23 | 2010-05-25 | Wyeth Llc | Amino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone compounds for the inhibition of beta-secretase |
| US7732457B2 (en) | 2005-02-01 | 2010-06-08 | Wyeth Llc | Amino-pyridines as inhibitors of β-secretase |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003082191A2 (en) | 2002-03-28 | 2003-10-09 | Merck & Co., Inc. | Substituted 2,3-diphenyl pyridines |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO1996030014A1 (en) * | 1995-03-29 | 1996-10-03 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0703905A1 (en) * | 1993-06-18 | 1996-04-03 | Merck & Co. Inc. | Inhibitors of farnesyl-protein transferase |
-
1997
- 1997-04-04 GB GB9706922A patent/GB2323841A/en not_active Withdrawn
-
1998
- 1998-04-03 AU AU69272/98A patent/AU6927298A/en not_active Abandoned
- 1998-04-03 WO PCT/GB1998/000998 patent/WO1998045267A1/en not_active Ceased
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO1996030014A1 (en) * | 1995-03-29 | 1996-10-03 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
Non-Patent Citations (1)
| Title |
|---|
| QIAN Y ET AL: "DESIGN AND SYNTHESIS OF NON-PEPTIDE RAS CAAX MIMETICS AS POTENT FARNESYLTRANSFERASE INHIBITORS", JOURNAL OF MEDICINAL CHEMISTRY, vol. 39, 1996, pages 217 - 223, XP000198788 * |
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7425557B2 (en) | 1998-06-19 | 2008-09-16 | Novartis Vaccines And Diagnostics, Inc. | Inhibitors of glycogen synthase kinase 3 |
| US7045519B2 (en) | 1998-06-19 | 2006-05-16 | Chiron Corporation | Inhibitors of glycogen synthase kinase 3 |
| US7482349B2 (en) | 2004-06-16 | 2009-01-27 | Wyeth | Amino-5,5-diphenylimidazolone derivatives for the inhibition of β-secretase |
| US7456186B2 (en) | 2004-06-16 | 2008-11-25 | Wyeth | Diphenylimidazopyrimidines as inhibitors of β-secretase |
| US7700602B2 (en) | 2004-06-16 | 2010-04-20 | Wyeth Llc | Amino-5,5-diphenylimidazolone derivatives for the inhibition of β-secretase |
| US7563796B2 (en) | 2005-01-14 | 2009-07-21 | Wyeth | Diphenylimidazopyrimidines as inhibitors of β-secretase |
| US7732457B2 (en) | 2005-02-01 | 2010-06-08 | Wyeth Llc | Amino-pyridines as inhibitors of β-secretase |
| US7488832B2 (en) | 2005-02-14 | 2009-02-10 | Wyeth | Azolylacylguanidines as β-secretase inhibitors |
| US7452885B2 (en) | 2005-06-30 | 2008-11-18 | Wyeth | Amino-5-(6-membered)heteroarylimidazolone compounds and the use thereof for β-secretase modulation |
| US7417047B2 (en) | 2005-06-30 | 2008-08-26 | Wyeth | Amino-5-(5-membered)hetero-arylimidazolone compounds and the use thereof for β-secretase modulation |
| US7705030B2 (en) | 2005-06-30 | 2010-04-27 | Wyeth Llc | Amino-5-(5-membered)hetero-arylimidazolone compounds and the use thereof for β-secretase modulation |
| US7423158B2 (en) | 2005-09-26 | 2008-09-09 | Wyeth | Amino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone compounds for the inhibition of β-secretase |
| US7582667B2 (en) | 2006-02-24 | 2009-09-01 | Wyeth | Dihydrospiro[dibenzo[a,d][7]annulene-5,4′-imidazol] compounds for the inhibition of beta-secretase |
| US7700606B2 (en) | 2006-08-17 | 2010-04-20 | Wyeth Llc | Imidazole amines as inhibitors of β-secretase |
| US7723368B2 (en) | 2007-03-23 | 2010-05-25 | Wyeth Llc | Amino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone compounds for the inhibition of beta-secretase |
Also Published As
| Publication number | Publication date |
|---|---|
| AU6927298A (en) | 1998-10-30 |
| GB2323841A (en) | 1998-10-07 |
| GB9706922D0 (en) | 1997-05-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2015226855B2 (en) | Human plasma kallikrein inhibitors | |
| WO1998045267A1 (en) | Aminopyridine derivatives for inflammatory and malignant diseases | |
| KR101907573B1 (en) | Asymmetric ureas and medical uses thereof | |
| EP1129074A2 (en) | Antrhranilic acid amides and the use thereof as medicaments | |
| CN106892924A (en) | Short-acting benzodiazepine * * derivatives, Its Preparation Method And Use | |
| AU2008294410A1 (en) | Compounds with anti-cancer activity | |
| KR20010013881A (en) | Novel N-substituted urea inhibitors of farnesyl-protein transferase | |
| NZ335810A (en) | 3-(2-azetidinyl-methoxy)-pyridine derivatives useful as analgesics and azetidinyl intermediates | |
| JP2003532725A (en) | Ortho-substituted anthranilamides and use of ortho-substituted anthranilamides as pharmaceutical agents | |
| US6624178B2 (en) | Compounds for the management of aging-related and diabetic vascular complications, process for their preparation and therapeutic uses thereof | |
| TW200404541A (en) | Pyridine derivatives | |
| CN113861215B (en) | Selective copper ion chelating agent, preparation method thereof and application thereof in colorectal cancer | |
| US4886822A (en) | Substituted anilide compounds which are useful in the treatment of arrhythmia | |
| US6387911B1 (en) | Pyrazinone thrombin inhibitors | |
| KR20240006641A (en) | Heteroaryl compounds as TYK2 inhibitors, compositions and uses thereof | |
| SK33099A3 (en) | Novel tricyclic piperidinyl compounds useful as inhibitors of farnesyl-protein transferase | |
| KR20010013822A (en) | Benzpyrido cycloheptane compounds useful for inhibition of farnesyl protein transferase | |
| KR850001226B1 (en) | Process for preparing imidazolylpyridine therapeutic agents | |
| JP7726591B2 (en) | Boronic Acid Compounds | |
| SK286686B6 (en) | Substituted imidazoles and thiazoles, pharmaceutical composition containing them and use thereof | |
| KR20010013826A (en) | Novel tricyclic sulfonamide inhibitors of farnesyl-protein transferase | |
| EP1318983B1 (en) | Substituted imidazoles as histamine h1 and h3 agonists or antagonists | |
| HK1015780A (en) | Pyridine derivatives with anti-tumor and anti-inflammatory activity | |
| CN107129465B (en) | Arylguanidine compound and preparation method and use thereof | |
| CN111320574A (en) | Aryl amide derivative and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A1 Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM GW HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG |
|
| DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
| NENP | Non-entry into the national phase |
Ref country code: JP Ref document number: 1998542496 Format of ref document f/p: F |
|
| 122 | Ep: pct application non-entry in european phase | ||
| NENP | Non-entry into the national phase |
Ref country code: CA |