WO1998018791A1 - Heterocyclic furan compounds, their preparation and use as aromatase inhibitors - Google Patents
Heterocyclic furan compounds, their preparation and use as aromatase inhibitors Download PDFInfo
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- WO1998018791A1 WO1998018791A1 PCT/EP1997/005854 EP9705854W WO9818791A1 WO 1998018791 A1 WO1998018791 A1 WO 1998018791A1 EP 9705854 W EP9705854 W EP 9705854W WO 9818791 A1 WO9818791 A1 WO 9818791A1
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- methyl
- pyrimidine
- triazole
- furan
- phenylfuran
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- 0 *c1c(*)[o]c(C(C2=CI=CC=C2)=O)c1 Chemical compound *c1c(*)[o]c(C(C2=CI=CC=C2)=O)c1 0.000 description 1
Classifications
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- 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
- C07D405/06—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 carbon chain containing only aliphatic carbon atoms
Definitions
- R and R 1 F which may be the same or different from one another, are chosen in the group consisting of: H, halogen, C ⁇ -alkyl, C ⁇ -alkoxy, aryl, alkylaryl, cycloalkyl, or R and R, taken together form a -CH 2 -(CH 2 ) n -CH 2 chain, where n is comprised between 1 and 4, or an aromatic ring condensed to the possibly substituted furan ring;
- R 2 and R 3 which may be the same or different from one another, are chosen in the group consisting of: H, halogen, C ⁇ -alkyl, C ⁇ -alkoxy, phenyl, phenyl alky ⁇ C,. 4 ), nitro, cyano, amino C ⁇ -acylamine, sulphamide group, N-substituted sulphamide group, or else a -CR 4 R 5 X group, where X is nitro, cyano, amino, C - acylamine, and R 4 and R 5 , which may be the same or different from one another, are chosen in the group consisting of: C ⁇ -alkyl; HET is chosen in the group consisting of: imidazole, triazole, pyrimidine, with the proviso that when R and R together form an aromatic ring condensed to the furan ring HET is not imidazole; A is H, OH, F, their pharmaceutically acceptable salts and pharmaceutical compositions containing them. State of the art
- oestrogens are hormones involved in the pathogenic cell changes associated with the growth of certain forms of cancer, the so-called hormone- dependant cancers, among which breast cancer, cancer of the ovary, uterus, pancreas, endometrium, as well as being associated with benign prostate hypertrophy.
- heterocyclic benzofurans are described as inhibitors of aromatase.
- the nitrogenated heterocycle is bound through a methylene to the benzene ring of the benzofuran in position 4 or 7.
- the present invention refers to products of general formula (I) as defined above, possessing specific anti-aromatase properties which are useful for the treatment and prevention of cancer of the breast, ovary, uterus, pancreas, and endometrium, as well as the treatment and prevention of benign prostate hypertrophy.
- heterocyclic furan derivatives claimed in the present application compared with the products described in the Italian patent application Ml 92 A 000850, present an unexpected and surprising activity in vivo by either intravenous or oral administration, associated with a prolonged action over time (even longer than 24 hours).
- the compounds according to the present invention contain an asymmetrical carbon atom, and the present invention thus refers to both the possible enantiomers, as also the respective mixtures, and in particular the racemic mixtures.
- the heterocycles containing nitrogen the following are preferred: imidazole, triazole, and pyrimidine. More in particular, amongst the aforementioned heterocycles, the following are preferred: 1 H-imidazole, 1 H-1 ,2,4,- triazole, 1 H1 ,3,4-triazole, and 5-pyrimidine.
- the pharmaceutically acceptable salts of the components of formula (I) are the salts obtained with both inorganic pharmaceutically acceptable acids (e.g., hydrochloric acid and sulphuric acid) and organic pharmaceutically acceptable acids (e.g., citric acid, tartaric acid, maleic acid, malic acid, succinic acid, methasulphonic acid and ethasulphonic acid).
- inorganic pharmaceutically acceptable acids e.g., hydrochloric acid and sulphuric acid
- organic pharmaceutically acceptable acids e.g., citric acid, tartaric acid, maleic acid, malic acid, succinic acid, methasulphonic acid and ethasulphonic acid.
- the compounds according to the invention may be prepared: a) by reaction of a compound having the formula (II)
- X is a leaving group (e.g., bromine, chlorine, iodine, mesylate, tosylate) with imidazole or triazole, possibly in the presence of added bases (for example, sodium or potassium hydride, n-butyl lithium, lithium diisopropylamide and the like, or with the appropriate C-metal derivatives of pyrimidine or pyridine, thus obtaining the compounds of formula (I), where HET is as defined above, A is hydrogen, and R, R 1 t R 2 , R 3 are as defined above; b) by reaction of a compound having the formula (III)
- a leaving group e.g., bromine, chlorine, iodine, mesylate, tosylate
- imidazole or triazole possibly in the presence of added bases (for example, sodium or potassium hydride, n-butyl lithium, lithium diisopropylamide and the like, or with the appropriate C-metal derivatives of pyrimidine or
- X is an appropriate leaving group with metal hydrides (e.g., NaH/ZnCI 2 , Zn(BH 4 ) 2 , NaBH 3 CN/ZnCI 2 ) or with fluorinating reagents, such as the metal fluorides n-Bu 4 NF, Li/FCI0 3 , thus obtaining all the compounds of formula (I), in which HET is as defined above, A is hydrogen or fluorine, and R, R 1 ( R 2 , R 3 are as defined above; 1Q
- the compounds of formula (Ilia) may be obtained from the corresponding compounds of formula (III) by transformation of the oxydrylic group in a suitable leaving group X, with known reagents and methods.
- the compounds of formula (I) of the present invention show a marked in vitro activity of inhibition of aromatase of the human placenta (TABLE 1 ).
- the in vitro activity test was carried out in accordance with E.A. Thompson and P.K. Siiteri, J.
- the compounds of the invention show, as has been said, an unexpected and surprising in vivo activity, following on either intravenous or oral administration, associated with a prolonged action over time (even longer than 24 hours), when compared with the products described in the above said patent application Ml 92 A 000850.
- the in vivo test on anti-aromatase activity in rats was conducted using the test described in Brodie et al., J. Steroid Biochem. 7, 787-793 (1976).
- the compounds of the invention also showed in vivo activity in the test for evaluating the reduction in weight of the uterus in puberal rats in which the uterine development was stimulated with androstenedione, as described in P. Plourde et al., Breast Cancer Research and Treatment, 30, 103 (1994) (TABLE 3).
- An analysis of the pharmacological data thus makes evident the unexpected advantages obtained using the compounds of the present invention, which may thus be utilized in all the situations where a reduction is required in oestrogen synthesis, in particular in the treatment of oestrogen-dependent tumours, such as pre- and post-menopause breast cancer, cancer of the ovary, endometrium and pancreas, and which thus represent a method of treatment of these forms of cancer.
- This method comprises the administration to the patient of a therapeutically effective quantity of a compound according to the invention or of a pharmaceutical composition containing it.
- the compounds according to the invention may be administered in various forms; for example, orally (tablets, capsules, sugar-coated or film-coated tablets, solutions or suspensions), by rectal route (suppositories, capsules), by parenteral route, by i.v. injection or by infusion. Dosage depends on the age, weight and conditions of the patient and on the administration route. For example, the dosage adopted for oral administration in adult patients may range from 1 to 500 mg, preferably from 10 to 400 mg, per dose, from once to 5 times a day.
- the invention also regards compositions comprising a compound according to the invention in association with a pharmaceutically acceptable excipient (either a vehicle or a diluent).
- the pharmaceutical compositions containing the compounds of the invention are prepared following conventional techniques and are administered in the forms that are most appropriate.
- Example 6 1-[(Benzofuran-2-yl)(4'-methyl phenyl)methyl]1 H-1 ,2,4 triazole
- 1 H-1 ,2,4 triazole (25.4 mmol.) and [(benzofuran-2-yl)(4'-methyl phenyl)methyl]chloride (8.5 mmol.)
- 2.7 g of crude product are obtained.
- By purification on silica gel using flash chromatography, eluting with CHCI 3 /CH 3 OH 99.5/0.5, 1.7 g of 1-[(benzofuran-2-yl)(4'-methyl phenyl)methyl]1 H-1 ,2,4 triazole are obtained.
- Example 7 1-[(Benzofuran-2-yl)(4'-methyl phenyl)methyl]1 H-1 ,3,4 triazole
- chloroform methanol 99.5 : 0.5 of the residue in the column of Example 6, 910 mg of 1-[(benzofuran-2-yl)(4'-methyl phenyl )methyl]1 H- 1 ,3,4 triazole are obtained.
- Example 9 1-[(Benzofuran-2-yl)[3',5'-di[2-(2-methyl propionitrile) phenyl]methyl]-1 H-1 ,3,4 triazole
- 45 mg of 1-[(benzofuran-2-yl)[3',5'-di[2-(2-methyl propionitrile)phenyl]methyl]-1 H-1 ,3,4 triazole are obtained.
- Example 11 1-[(Benzofuran-2-yl)(2',4'-difluorophenyl)methyl]1 H-1 ,3,4 triazole
- chloroform methanol 99 : 1 of the residue in the column of Example 3
- 1-[(benzofuran-2-yl)(2',4'-difluorophenyl)methyl]1 H-1 ,3,4 triazole is obtained.
Abstract
Described herein are furan compounds having formula (I), their preparation and their use as aromatase inhibitors.
Description
HETEROCYCLIC FURAN COMPOUNDS, THEIR PREPARATION AND USE AS AROMATASE INHIBITORS DESCRIPTION Scope of the invention The present invention refers to compounds having the general formula (I):
in which R and R1 F which may be the same or different from one another, are chosen in the group consisting of: H, halogen, C^-alkyl, C^-alkoxy, aryl, alkylaryl, cycloalkyl, or R and R, taken together form a -CH2-(CH2)n-CH2 chain, where n is comprised between 1 and 4, or an aromatic ring condensed to the possibly substituted furan ring;
R2 and R3, which may be the same or different from one another, are chosen in the group consisting of: H, halogen, C^-alkyl, C^-alkoxy, phenyl, phenyl alky^C,. 4), nitro, cyano, amino C^-acylamine, sulphamide group, N-substituted sulphamide group, or else a -CR4R5X group, where X is nitro, cyano, amino, C - acylamine, and R4 and R5, which may be the same or different from one another, are chosen in the group consisting of: C^-alkyl; HET is chosen in the group consisting of: imidazole, triazole, pyrimidine, with the proviso that when R and R together form an aromatic ring condensed to the furan ring HET is not imidazole; A is H, OH, F, their pharmaceutically acceptable salts and pharmaceutical compositions containing them. State of the art
It is known that oestrogens are hormones involved in the pathogenic cell changes associated with the growth of certain forms of cancer, the so-called hormone- dependant cancers, among which breast cancer, cancer of the ovary, uterus, pancreas, endometrium, as well as being associated with benign prostate hypertrophy.
It has been shown that an effective inhibition of the biosynthesis of oestrogens, preferably if these result from compounds that are able to inhibit in a specific way the enzyme aromatase, which is responsible for aromatization of the A ring of androgens (and hence their endogenous conversion into oestrogens), has a useful clinical application in the control of the levels of circulating oestrogens and consequently in the treatment of oestrogen-dependent tumours (Siiteri, P.K. et al., J. Steroid Biochem., 1976, 7, 897; Kirschener, M.A. et al., Cancer research, 1982, 42s, 3281s). Non-steroid substances, for example aminoglutethimide (Ann. Sur. 1978, 187, 475; Lancet, 1978, 2, 646) and arimidex (J. Steroid Biochem. Molec. Bi ., Vol. 53, Nos. 1-6, 175-179, 1995).
In the Italian patent Ml 92 A 000850 , benzofuran-imidazoles are described that have an inhibiting effect on aromatase and 17,20-lyase.
In EP 445 073, heterocyclic benzofurans are described as inhibitors of aromatase. In these heterocyclic benzofurans the nitrogenated heterocycle is bound through a methylene to the benzene ring of the benzofuran in position 4 or 7. Detailed description of the invention
The present invention refers to products of general formula (I) as defined above, possessing specific anti-aromatase properties which are useful for the treatment and prevention of cancer of the breast, ovary, uterus, pancreas, and endometrium, as well as the treatment and prevention of benign prostate hypertrophy.
In particular, the heterocyclic furan derivatives claimed in the present application, compared with the products described in the Italian patent application Ml 92 A 000850, present an unexpected and surprising activity in vivo by either intravenous or oral administration, associated with a prolonged action over time (even longer than 24 hours).
As it is clear from formula (I) the compounds according to the present invention contain an asymmetrical carbon atom, and the present invention thus refers to both the possible enantiomers, as also the respective mixtures, and in particular the racemic mixtures. Amongst the heterocycles containing nitrogen, the following are preferred: imidazole, triazole, and pyrimidine. More in particular, amongst the
aforementioned heterocycles, the following are preferred: 1 H-imidazole, 1 H-1 ,2,4,- triazole, 1 H1 ,3,4-triazole, and 5-pyrimidine.
The pharmaceutically acceptable salts of the components of formula (I) are the salts obtained with both inorganic pharmaceutically acceptable acids (e.g., hydrochloric acid and sulphuric acid) and organic pharmaceutically acceptable acids (e.g., citric acid, tartaric acid, maleic acid, malic acid, succinic acid, methasulphonic acid and ethasulphonic acid).
Particular examples of compounds according to the present invention are:
1 ) 1 -[(Furan-2-yl) phenylmethyl]-1 H-imidazole
2) 1 -[(Furan-2-yl)(4'-methylphenyl)methyl]-1 H-imidazole
3) 1 -[(Furan-2-yl)(4'-fluorophenyl)methyl]-1 H-imidazole
4) 1 -[(Furan-2-yl)(4'-chlorophenyl)methyl]-1 H-imidazole
5) 1 -[(Furan-2-yl)(4'-cyanophenyl)methyl]-1 H-imidazole
6) 1 -[(Furan-2-yl)[3',5'-di[2-(2-methyl propionitrile) phenyl]methyl]-1 H-imidazole
7) 1 -[(Furan-2-yl)(2',4'-difluorophenyl)methyl]-1 H-imidazole
8) 1 -[(Furan-2-yl)(2',4'-dicyanophenyl)methyl]-1 H-imidazole
9) 1 -[(Furan-2-yl)(2'-fluoro-4'-cyanophenyl)methyl]-1 H-imidazole
10) 1 -[(5-Phenylfuran-2-yl)phenylmethyl]-1 H-imidazole
11) 1 -[(5-Phenylfuran-2-yl)(4'-methylphenyl)methyl]-1 H-imidazole
12) 1 -[(5-Phenylfuran-2-yl)(4'-fluorophenyl)methyl]-1 H-imidazole
13) 1 -[(5-Phenylfuran-2-yl)(4'-chlorophenyl)methyl]-1 H-imidazole
14) 1 -[(5-Phenylfuran-2-yl)(4'-cyanophenyl)methyl]-1 H-imidazole
15) 1-[(5-Phenylfuran-2-yl)[3',5'-di[2-(2-methyl propionitrile)phenyl)]methyl]-1 H- imidazole
16) 1 -[(5-Phenylfuran-2-yl)(2',4'-difluorophenyl)methyl]-1 H-imidazole
17) 1 -[(5-Phenylfuran-2-yl)(2',4'-dicyanophenyl)methyl]-1 H-imidazole
18) 1 -[(5-Phenylfuran-2-yl)(2'-fluoro-4'-cyanophenyl)methyl]-1 H-imidazole
19) 1 -[(Furan-2-yl)phenylmethyl]-1 H-1 ,2,4-triazole
20) 1 -[(Furan-2-yl)(4'-methylphenyl)methyl]-1 H-1 ,2,4-triazole
21 ) 1 -[(Furan-2-yl)(4'-fluorophenyl)methyl]-1 H-1 ,2,4-triazole
22) 1 -[(Furan-2-yl)(4'-chlorophenyl)methyl]-1 H-1 ,2,4-triazole
23) 1 -[(Furan-2-yl)(4'-cyanophenyl)methyl]-1 H-1 ,2,4-triazole
24) 1-[[(Furan-2-yl)[3',5'-di[2-(2-methyl propionitrile) phenyl]methyl]-1 H-1 ,2,4- triazole
25) 1 -[(Furan-2-yl)(2',4'-difluorophenyi methyl]-1 H-1 ,2,4-triazole 26) 1-[(Furan-2-yl)(2',4'-dicyanophenyl)methyl]-1 H-1 ,2,4-triazole
27) 1 -[(Furan-2-yl)(2'-fluoro-4'-cyanophenyl)methyl]-1 H-1 ,2,4-triazole
28) 1 -[(5-Phenylfuran-2-yl)phenylmethyl]-1 H-1 ,2,4-triazole
29) 1 -[(5-Phenylfuran-2-yl)(4'-methylphenyl)methyl]-1 H-1 ,2,4-triazole
30) 1 -[(5-Phenylfuran-2-yl)(4'-fluorophenyl)methyl]-1 H-1 ,2,4-triazole 31 ) 1-[(5-Phenylfuran-2-yl)(4'-chlorophenyl)methyl]-1 H-1 ,2,4-triazole
32) 1 -[(5-Phenylfuran-2-yl)(4'-cyanophenyl)methyl]-1 H-1 ,2,4-triazole
33) [1 -[(5-Phenylfuran-2-yl)[3',5'-di[2-(2-methyl propionitrile)phenyl]methyl]-1 H- 1 ,2,4-triazole
34) 1 -[(5-Phenylfuran-2-yl)2',4'-difluorophenyl)methyl]-1 H-1 ,2,4-triazole 35) 1-[(5-Phenylfuran-2-yl)2',4'-dicyanophenyl)methyl]-1 H-1 ,2,4-triazole
36) 1 -[(5-Phenylfuran-2-yl)2'-fluoro-4'-cyanophenyl)methyl]-1 H-1 ,2,4-triazole
37) 1 -[(Benzofuran-2-yl)phenylmethyl]-1 H-1 ,2,4-triazole
38) 1 -[(Benzofuran-2-yl)(4'-methylphenyl)methyl]-1 H-1 ,2,4-triazole
39) 1 -[(Benzofuran-2-yl)(4'-fluorophenyl)methyl]-1 H-1 ,2,4-triazole 40) 1 -[(Benzofuran-2-yl)(4'-chlorophenyl)methyl]-1 H-1 ,2,4-triazole
41 ) 1-[(Benzofuran-2-yl)(4'-cyanophenyl)methyl]-1 H-1 ,2,4-triazole
42) 1-[[(Benzofuran-2-yl)[3',5'-di[2-(2-methyl propionitrile) phenyl]methyl]-1 H- 1 ,2,4-triazole
43) 1 -[(Benzofuran-2-yl)(2',4'-difluorophenyl)methyl]-1 H-1 ,2,4-triazole 44) 1-[(Benzofuran-2-yl)(2',4'-dicyanophenyl)methyl]-1H-1 ,2,4-triazole
45) 1 -[(Benzofuran-2-yl)(2'-fluoro-4'-cyanophenyl)methyl]-1 H-1 ,2,4-triazole
46) 1 -[(Furan-2-yl)phenyl methyl]-1 H-1 ,3,4-triazole
47) 1-[(Furan-2-yl)[4'-methylphenyl)methyl]-1 H-1 ,3,4-triazole
48) 1 -[(Furan-2-yl)[4'-fluorophenyl)methyl]-1 H-1 ,3,4-triazole 49) 1-[(Furan-2-yl)[4'-chlorophenyl)methyl]-1 H-1 ,3,4-triazole
50) 1 -[(Furan-2-yl)[4'-cyanophenyl)methyl]-1 H-1 ,3,4-triazole
51 ) 1-[[(Furan-2-yl)[3\5'-di[2-(2-methyl propionitrile)phenyl] methyl]-1 H-1 ,3,4- triazole
52 1-[(Furan-2-yl)(2',4'-difluorophenyl)methyl]-1 H-1 ,3,4-triazole 53 1-[(Furan-2-yl)(2',4'-dicyanophenyl)methyl]-1 H-1 ,3,4-triazole 54 1 -[(Furan-2-yl)(2'-fluoro-4'-cyanophenyl)methyi]-1 H-1 ,3,4-triazole 55 1 -[(5-Phenylfuran-2-yl)phenylmethyl]-1 H-1 ,3,4-triazole 56 1 -[(5-Phenylfuran-2-yl)(4'-methylphenyl)methyl]-1 H-1 ,3,4-triazole 57 1 -[(5-Phenylfuran-2-yl)(4'-fluorophenyl)methyl]-1 H-1 ,3,4-triazole 58 1 -[(5-Phenylfuran-2-yl)(4'-chlorophenyl)methyl]-1 H-1 ,3,4-triazole 59 1 -[(5-Phenylfuran-2-yl)(4'-cyanophenyl)methyl]-1 H-1 ,3,4-triazole 60 1 -[(5-Phenylfuran-2-yl)[3',5'-di[2-(2-methyl propionitrile)phenyl]methyl]-1 H- 1 ,3,4-triazole
61 1-[(5-Phenylfuran-2-yl)(2',4'-difluorophenyl)methyl]-1 H-1 ,3,4-triazole 62 1 -[(5-Phenylfuran-2-yl)(2',4'-dicyanophenyl)methyl]-1 H-1 ,3,4-triazole 63 1 -[(5-Phenylfuran-2-yl)(2'-fluoro-4'-cyanophenyl)methyl]-1 H-1 ,3,4-triazole 64 1-[(Benzofuran-2-yl)phenylmethyl]-1 H-1 ,3,4-triazole 65 1 -[(Benzofuran-2-yl)(4'-methylphenyl)methyl]-1 H-1 ,3,4-triazole 66 1-[(Benzofuran-2-yl)(4'-fluorophenyl)methyl]-1 H-1 ,3,4-triazole 67 1 -[(Benzofuran-2-yl)(4'-chlorophenyl)methyl]-1 H-1 ,3,4-triazole 68 1 -[(Benzofuran-2-yl)(4'-cyanophenyl)methyl]-1 H-1 ,3,4-triazole 69 1-[(Benzofuran-2-yl)[3',5'-di[2-(2-methyl propionitrile) phenyl]methyl]-1 H- 1 ,3,4-triazole
70 1 -[(Benzofuran-2-yl)(2',4'-difluorophenyl)methyl]-1 H-1 ,3,4-triazole 71 1 -[(Benzofuran-2-yl)(2',4'-dicyanophenyl)methyl]-1 H-1 ,3,4-triazole 72 1 -[(Benzofuran-2-yl)(2'-fluoro-4'-cyanophenyl)methyl]-1 H-1 ,3,4-triazole 73 5-[(Furan-2-yl)phenylmethyl]pyrimidine 74 5-[(Furan-2-yl)(4'-methylphenyl)methyl]pyrimidine 75 5-[(Furan-2-yl)(4'-fluorophenyl)methyl]pyrimidine 76 5-[(Furan-2-yl)(4'-chlorophenyl)methyl]pyrimidine 77 5-[(Furan-2-yl)(4'-cyanophenyl)methyl]pyrimidine
78) 5-[(Furan-2-yl)[3',5'-di[2-(2-methyl propionitrile)phenyl]
methyrjpyrimidine
5-[(Furan-2-yl)(2\4'-difluorophenyl)methyl]pyrimidine 5-[(Furan-2-yl)(2,,4'-dicyanophenyl)methyl]pyrimidine 5-[(Furan-2-yl)(2'-fluoro-4'-cyanophenyl)methyl]pyrimidine 5-[(5-Phenylfuran-2-yl)phenylmethyl]pyrimidine 5-[(5-Phenylfuran-2-yl)(4'-methylphenyl)methyl]pyrimidine 5-[(5-Phenylfuran-2-yl)(4'-fluorophenyl)methyl]pyrimidine 5-[(5-Phenylfuran-2-yl)(4'-chlorophenyl)methyl]pyrimidine 5-[(5-Phenylfuran-2-yl)(4'-cyanophenyl)methyl]pyrimidine 5-[(5-Phenylfuran-2-yl)[3',5'-di[2-(2-methylpropionitrile) phenyl)]methyl]pyrimidine
5-[(5-Phenylfuran-2-yl)(2',4'-difluorophenyl)methyl] pyrimidine 5-[(5-Phenylfuran-2-yl)(2',4'-dicyanophenyl)methyl] pyrimidine 5-[(5-Phenylfuran-2-yl)(2'-fluoro-4'-cyanophenyl)methyl] pyrimidine 5-[(Benzofuran-2-yl)phenylmethyl]pyrimidine 5-[(Benzofuran-2-yl)(4'-methylphenyl)methyl]pyrimidine 5-[(Benzofuran-2-yl)(4'-fluorophenyl)methyl]pyrimidine 5-[(Benzofuran-2-yl)(4'-chlorophenyl)methyl]pyrimidine 5-[(Benzofuran-2-yl)(4'-cyanophenyl)methyl]pyrimidine [5-[(Benzofuran-2-yl)[3',5'-di[2-(2-methylpropionitrile) phenyl]methyl]pyrimidine
5-[(Benzofuran-2-yl)(2',4'-difluorophenyl)methyl] pyrimidine 5-[(Benzofuran-2-yl)(2',4'-dicyanophenyl)methyl]pyrimidine 5-[(Benzofuran-2-yl)(2'-fluoro-4'-cyanophenyl)methyl] pyrimidine 100) 5-[(Furan-2-yl)phenyl hydroxymethyl]pyrimidine
101 ) 5-[(Furan-2-yl)(4'-methylphenyl)hydroxymethyl]pyrimidine
102) 5-[(Furan-2-yi)(4,-fluorophenyl)hydroxymethyl]pyrimidine
103) 5-[(Furan-2-yl)(4'-chlorophenyl)hydroxymethyl]pyrimidine
104) 5-[(Furan-2-yl)(4'-cyanophenyl)hydroxymethyl]pyrimidine 105) 5-[(Furan-2-yl)[3',5'-di[2-(2-methylpropionitrile) phenyl]hydroxymethyl]pyrimidine
106) 5-[(Furan-2-yl)(2',4'-difluorophenyl)hydroxymethyl] pyrimidine
107) 5-[(Furan-2-yl)(2',4'-dicyanophenyl)hydroxymethyl] pyrimidine
108) 5-[(Furan-2-yl)(2'-fluoro-4'-cyanophenyl)hydroxymethyl] pyrimidine
109) 5-[(5-Phenylfuran-2-yl)phenyl hydroxymethyl]pyrimidine 110) 5-[(5-Phenylfuran-2-yl)(4'-methylphenyl)hydroxymethyl] pyrimidine
111 ) 5-[(5-Phenylfuran-2-yl)(4'-fluorophenyl)hydroxymethyl] pyrimidine
112) 5-[(5-Phenylfuran-2-yl)(4'-chlorophenyl)hydroxymethyl] pyrimidine
113) 5-[(5-Phenylfuran-2-yl)(4'-cyanophenyl)hydroxymethyl] pyrimidine
114) 5-[(5-Phenylfuran-2-yl)[3\5'-di[2-(2-methyl propionitrile)]hydroxymethyl]pyrimidine
115) 5-[(5-Phenylfuran-2-yl)(2',4'-difluorophenyl) hydroxymethyl]pyrimidine
116) 5-[(5-Phenylfuran-2-yl)(2',4'-dicyanophenyl) hydroxymethyl]pyrimidine
117) 5-[(5-Phenylfuran-2-yl)(2'-fluoro-4'-cyanophenyl) hydroxymethyl]pyrimidine
118) 5-[(Benzofuran-2-yl)phenyl hydroxymethyljpyrimidine 119) 5-[(Benzofuran-2-yl)(4'-methylphenyl)hydroxymethyl] pyrimidine
120) 5-[(Benzofuran-2-yl)(4'-fluorophenyl)hydroxymethyl] pyrimidine
121 ) 5-[(Benzofuran-2-yl)(4'-chlorophenyl)hydroxymethyl] pyrimidine
122) 5-[(Benzofuran-2-yl)(4'-cyanophenyl)hydroxymethyl] pyrimidine
123) 5-[(Benzofuran-2-yl)[3',5'-di[2-(2-methyl propionitrile) phenyl]hydroxymethyl]pyrimidine
124) 5-[(Benzofuran-2-yl)(2',4'-difluorophenyl)hydroxymethyl] pyrimidine
125) 5-[(Benzofuran-2-yl)(2',4'-dicyanophenyl)hydroxymethyl] pyrimidine
126) 5-[(Benzofuran-2-yl)(2'-fluoro-4'-cyanophenyl) hydroxymethyljpyrimidine
127) 5-[(Furan-2-yl) phenyl fluoromethyl]pyrimidine 128) 5-[(Furan-2-yl)(4'-methylphenyl)fluoromethyl]pyrimidine
129) 5-[(Furan-2-yl)(4'-fluorophenyl)fluoromethyl]pyrimidine
130) 5-[(Furan-2-yl)(4'-chlorophenyl)fluoromethyl]pyrimidine
131 ) 5-[(Furan-2-yl)(4'-cyanophenyl)fluoromethyl]pyrimidine
132) 5-[(Furan-2-yl)[3',5'-di[2-(2-methylpropionitrile)phenyl] fluoromethyl]pyrimidine
133) 5-[(Furan-2-yl)(2',4'-difluorophenyl)fluoromethyl] pyrimidine
134) 5-[(Furan-2-yl)(2',4'-dicyanophenyl)fluoromethyl] pyrimidine
135) 5-[(Furan-2-yl)(2'-fluoro-4'-cyanophenyl)fluoromethyl] pyrimidine
136) 5-[(5-Phenylfuran-2-yl)phenyl fluoromethyl]pyrimidine
137) 5-[(5-Phenylfuran-2-yl)(4'-methylphenyl)fluoromethyl] pyrimidine 138) 5-[(5-Phenylfuran-2-yl)(4'-fluorophenyl)fluoromethyl] pyrimidine
139) 5-[(5-Phenylfuran-2-yl)(4'-chlorophenyl)fluoromethyl] pyrimidine
140) 5-[(5-Phenylfuran-2-yl)(4'-cyanophenyl)fluoromethyl] pyrimidine
141 ) 5-[(5-Phenylfuran-2-yl)[3',5'-di[2-(2-methyl propionitrile)phenyl)]fluoromethyl]pyrimidine 142) 5-[(5-Phenylfuran-2-yl)(2',4'-difluorophenyl) fluoromethyl]pyrimidine
143) 5-[(5-Phenylfuran-2-yl)(2',4'-dicyanophenyl)fluoromethyl] pyrimidine
144) 5-[(5-Phenylfuran-2-yl)(2'-fluoro-4'-cyanophenyl) fluoromethyl]pyrimidine
145) 5-[(Benzofuran-2-yl)phenyl fluoromethyl]pyrimidine
146) 5-[(Benzofuran-2-yl)(4'-methylphenyl)fluoromethyl] pyrimidine 147) 5-[(Benzofuran-2-yl)(4'-fluorophenyl)fluoromethyl] pyrimidine
148) 5-[(Benzofuran-2-yl)(4'-chlorophenyl)fluoromethyl] pyrimidine
149) 5-[(Benzofuran-2-yl)(4'-cyanophenyl)fluoromethyl] pyrimidine
150) 5-[(Benzofuran-2-yl)[3',5'-di[2-(2-methyl propionitrile)] fluoromethyl]pyrimidine
151 ) 5-[(Benzofuran-2-yl)(2',4'-difluorophenyl)fluoromethyl] pyrimidine 152) 5-[(Benzofuran-2-yl)(2',4'-dicyanophenyl)fluoromethyl] pyrimidine
153) 5-[(Benzofuran-2-yl)(2'-fluoro-4'-cyanophenyl) fluoromethyl]pyrimidine and their pharmaceutically acceptable salts.
The compounds according to the invention may be prepared: a) by reaction of a compound having the formula (II)
in which the various substituents are as defined above, with a reducing agent (e.g., Li/NH3/NH4/CI, NaBH4/CF3COOH, AICI3/Pd-C,
or with a fluorinating agent (e.g., HF/KF, R2NSF3), thus obtaining the compounds of formula I, where HET is as defined above, A is hydrogen or else fluorine, and R, R1 ( R2, R3 are as defined above; c) by reaction of a compound having the formula (Ilia)
in which X is an appropriate leaving group with metal hydrides (e.g., NaH/ZnCI2, Zn(BH4)2, NaBH3CN/ZnCI2) or with fluorinating reagents, such as the metal fluorides n-Bu4NF, Li/FCI03, thus obtaining all the compounds of formula (I), in which HET is as defined above, A is hydrogen or fluorine, and R, R1 ( R2, R3 are as defined above;
1Q
d) by reaction of a compound of formula (I), where A is hydrogen with a fluorinating agent (e.g., N-fluoro dimethyl saccharin sultame, as described in EP 0490 816 A2), thus obtaining the corresponding compounds of Formula (I), where A is fluorine and HET is as defined above. The compounds of formula (II) may be prepared from the corresponding alcohols by transformation of the oxydrylic group in a suitable leaving group X, using known methods. The above alcohols may be prepared starting from the corresponding ketones, as described, for example, in EP - 257 171. The compounds of formula (III) may be obtained from the compounds of formula (IV)
by additioning the appropriate N-metal derivatives of imidazoles and triazoles.or the appropriate C-metal derivatives of pyrimidine and pyridine according to known methods (see, for example, CD. Jones et al., J. of Med. Chem. 33, 1990, 416-429 and EP 490 816). The compounds of formula (Ilia) may be obtained from the corresponding compounds of formula (III) by transformation of the oxydrylic group in a suitable leaving group X, with known reagents and methods.
In vitro and in vivo pharmacological activity
The compounds of formula (I) of the present invention show a marked in vitro activity of inhibition of aromatase of the human placenta (TABLE 1 ). The in vitro activity test was carried out in accordance with E.A. Thompson and P.K. Siiteri, J.
Biol. Chem., 249, 5364 (1974). The compounds of the invention show, as has been said, an unexpected and surprising in vivo activity, following on either intravenous or oral administration, associated with a prolonged action over time (even longer than 24 hours), when compared with the products described in the above said patent application Ml 92 A 000850.
The in vivo test on anti-aromatase activity in rats was conducted using the test described in Brodie et al., J. Steroid Biochem. 7, 787-793 (1976). When, for example, the compound of the invention 1-[(benzofuran-2-yl) (4'- cyanophenyl)methyl-1 H-1 ,2,4-triazole (41 ) was tested in accordance with the above said procedure, a significant decrease in oestrogen levels was found which was prolonged over time when compared with the corresponding imidazole derivative (TABLE 2).
The compounds of the invention also showed in vivo activity in the test for evaluating the reduction in weight of the uterus in puberal rats in which the uterine development was stimulated with androstenedione, as described in P. Plourde et al., Breast Cancer Research and Treatment, 30, 103 (1994) (TABLE 3). An analysis of the pharmacological data thus makes evident the unexpected advantages obtained using the compounds of the present invention, which may thus be utilized in all the situations where a reduction is required in oestrogen synthesis, in particular in the treatment of oestrogen-dependent tumours, such as pre- and post-menopause breast cancer, cancer of the ovary, endometrium and pancreas, and which thus represent a method of treatment of these forms of cancer. This method comprises the administration to the patient of a therapeutically effective quantity of a compound according to the invention or of a pharmaceutical composition containing it.
The compounds according to the invention may be administered in various forms; for example, orally (tablets, capsules, sugar-coated or film-coated tablets, solutions or suspensions), by rectal route (suppositories, capsules), by parenteral route, by i.v. injection or by infusion. Dosage depends on the age, weight and conditions of the patient and on the administration route. For example, the dosage adopted for oral administration in adult patients may range from 1 to 500 mg, preferably from 10 to 400 mg, per dose, from once to 5 times a day. The invention also regards compositions comprising a compound according to the invention in association with a pharmaceutically acceptable excipient (either a vehicle or a diluent).
The pharmaceutical compositions containing the compounds of the invention are prepared following conventional techniques and are administered in the forms that are most appropriate.
There following examples of preparation of the compounds of formula (I) are reported only to better illustrate the invention but do not have any limiting effect. Example 1
1-[(Benzofuran-2-yl)(4'-cyanophenyl)methyl]1 H-1 ,2,4 triazole To a suspension of 1 H-1 ,2,4 triazole (88.5 mmol.) in anhydrous dioxane (250 ml) at 400°C a solution of [(benzofuran-2-yl)(4'-cyanophenyl)methyl]chloride (29.5 mmol.) in anhydrous dioxane (100 ml) is added under stirring in nitrogen current. The resulting suspension is refluxed for one hour, and is then left at room temperature for 18 hours. The solvent is evaporated under reduced pressure and the residue is divided between water and chloroform. The organic extracts are pooled together and evaporated leaving a residue (9.8 g) which is separated by flash chromatography. By elution with chloroform, 6.2 g of 1-[(benzofuran-2-yl)(4'- cyanophenyl) methyl]1H-1 ,2,4 triazole are obtained. NMR (CDCI3) s 6.6 (s, 1 H), s 6.88 (s, 1 H), s 7.25-7.39 (m, 2H), s 7.38 (d, J = 8 Hz, 2H), s 7.46 (d, J = 7.7 Hz), s 7.56 (d, J = 7.7 Hz, 1 H), s 7.7 (d, J = 8 Hz, 2H), s 8.04 (s, 1 H), s 8.17 (s, 1 H). Using the same procedure and starting from appropriate substrates, the compounds 19-23, 28-32, and 37, as previously defined, were prepared. Example 2
1-[(Benzofuran-2-yl)(4'-cyanophenyl)methyl]1 H-1 ,3,4 triazole By further elution with chloroform : methanol 99 : 1 of the residue in the column of Example 1 , 0.8 g of 1-[(benzofuran-2-yl)(4'-cyanophenyl)methyl]1 H-1 ,3,4 triazole are obtained. NMR (CDCI3) s 6.65 (s, 1 H), s 6.71 (s, 1 H), s 7.25-7.40 (m, 2H), s 7.33 (d, J = 8.3 Hz, 2H), s 7.47 (d, J = 8 Hz, 1 H), s 7.57 (d, J = 8 Hz, 1 H), s 7.73 (d, J = 8.3 Hz), s 8.21 (s, 2H).
Using the same procedure and starting from appropriate substrates, the compounds 46-50, 55-59, 64, and 66, as previously defined, were prepared. Example 3
1-[(Benzofuran-2-yl)(4'-chlorophenyl)methyl]1 H-1 ,2,4 triazole
Following the procedure described in Example 1 , starting from 1 H-1 ,2,4 triazole (2.52 mmol.) and [(benzofuran-2-yl)(4'-chlorophenyl)methyl]chloride (0.839 mmol.), 280 mg of crude product are obtained. By purification on silica gel using flash chromatography, eluting with CHCI3/CH3OH 99.5/0.5, 169 mg are obtained of 1-[(benzofuran-2-yl)(4'-chlorophenyl)methyl]1 H-1 ,2,4 triazole: NMR (CDCI3) s 6.61 (s, 1 H), s 6.84 (s, 1 H), s 7.23-7.28 (m, 3H), s 7.34 (d, J = 8.1 Hz, 1 H), s 7.4 (d, J = 7.4 Hz, 2H), s 7.46 (d, J = 8.0 Hz, 1 H), s 7.55 (d, J = 8.2 Hz, 1 H), s 8.10 (s, 1 H), s 8.33 (s, 1 H). Example 4 1 -[(Benzofuran-2-yl)(4'-chlorophenyl)methyl]1 H-1 ,3,4 triazole
By further elution with chloroform : methanol 99.5 : 0.5 of the residue in the column of Example 3 and subsequent purification in HPLC preparation with Lichrospher RP-18 column (7 mm), using as eluent CH3CN/H20 + 0.1% TFA 1/1 , 91 mg are obtained of 1-[(benzofuran-2-yl)(4'-chlorophenyl)methyl]1H-1 ,3,4 triazole: NMR (CDCI3) s 6.59 (t, J = 0.8 Hz, 1 H), s 6.62 (s, 1 H), s 7.18 (dd, J = 8.5 Hz J = 0.8 Hz, 2H), s 7.27 (t, J = 7.4 Hz, 1 H), s 7.35 (t, J = 8.0 Hz, 1 H), s 7.41 (d, J = 8.5 Hz, 2H), s 7.46 (d, J = 8.1 Hz, 1 H), s 7.56 (d, J = 7.7 Hz, 1 H), s 8.19 (s, 2H). Example 5 1 -[(Benzofuran-2-yl)(4'-fluorophenyl)methyl]1 H-1 ,2,4 triazole
Employing the same procedure as that described in Example 1 , starting from 1 H- 1 ,2,4 triazole (12.4 mmol.) and [(benzofuran-2-yl)(4'-fluorophenyl)methyl]chloride (4.13 mmol.), 1.4 mg of crude product of reaction are obtained. By purification on silica gel using flash chromatography, eluting with n-hexane/ethyl acetate 7:3, 787 mg are obtained of 1-[(benzofuran-2-yl)(4'-chlorophenyl)methyl]1 H-1 ,2,4 triazole: NMR (CDCI3) s 6.58 (s, 1 H), s 6.83 (s, 1 H), s 7.11 (t, 8.5 Hz, 1 H), s 7.25-7.35 (m, 5H), s 7.46 (d, J = 8.1 , 1 H), s 7.55 (d, J = 8.1 , 1 H), s 8.04 (s, 1 H), s 8.17 (s, 1 H). Example 6 1-[(Benzofuran-2-yl)(4'-methyl phenyl)methyl]1 H-1 ,2,4 triazole Employing the same procedure as that described in Example 1 ,
starting from 1 H-1 ,2,4 triazole (25.4 mmol.) and [(benzofuran-2-yl)(4'-methyl phenyl)methyl]chloride (8.5 mmol.), 2.7 g of crude product are obtained. By purification on silica gel using flash chromatography, eluting with CHCI3/CH3OH 99.5/0.5, 1.7 g of 1-[(benzofuran-2-yl)(4'-methyl phenyl)methyl]1 H-1 ,2,4 triazole are obtained. NMR (CDCI3) s 2.41 (s, 3H), s 6.61 (s, 1 H), s 6.85 (s, 1 H), s 7.2 (bs, 5H), s 7.23 (t, J = 7.7, 1 H), s 7.30 (t, J = 7.9, 1 H), s 7.44 (d, J = 8.2, 1 H), s 7.52 (d, J = 7.6, 1 H). Example 7 1-[(Benzofuran-2-yl)(4'-methyl phenyl)methyl]1 H-1 ,3,4 triazole By further elution with chloroform : methanol 99.5 : 0.5 of the residue in the column of Example 6, 910 mg of 1-[(benzofuran-2-yl)(4'-methyl phenyl )methyl]1 H- 1 ,3,4 triazole are obtained. NMR (CDCI3) s 2.39 (s, 3H), s 6.57 (s, 1 H), s 6.67 (s, 1H), s 7.15 (d, J = 8.1 Hz, 2H), s 7.23-7.29 (m, 3H), s 7.34 (t, J = 15.4 Hz, 1H), s 7.46 (d, J = 8.1 Hz, 1 H), s 7.55 (d, J = 8.1 , 1 H), s 8.20 (s, 2H). Example 8
1-[(Benzofuran-2-yl)[3',5'-di[2-(2-methyl propionitrile) phenyl]methyl]-1 H-1 ,2,4 triazole
Employing the same procedure as that described in Example 1 , starting from 1H-
1 ,2,4 triazole (1.00 mmol.) and [(benzofuran-2-yl) [3',5'-di[2-(2-methyl propionitrile)phenyl]methyl] chloride (0.200 mmol.), 110 mg of crude product are obtained. By purification on silica gel using flash chromatography, eluting with n- hexane/ethyl acetate 1/1 , 20 mg are obtained of 1-[(benzofuran-2-yl)[3',5'-di[2-(2- methyl propionitrile)phenyl]methyl]-1 H-1 ,2,4 triazole: NMR (CDCI3) s 1.71 (s, 6H), s 1.72 (s, 6H), s 6.60 (s, 1H), s 6.85 (s, 1H), s 7.26 (t, J = 7.5 Hz, 1 H), s 7.34 (t, J = 7.3 Hz, 1 H), s 7.4 (d, J = 1.8 Hz, 2H), s 7.46 (d, J = 8.1 Hz, 1 H), s 7.56 (d, J = 7 Hz, 1 H), s 7.62 (t, J = 1.8 Hz, 1 H), s 8.04 (s, 1 H), s 8.18 (s, 1 H). Using the same procedure and starting from appropriate substrates the compounds 24 and 33, as previously defined, were prepared. Example 9 1-[(Benzofuran-2-yl)[3',5'-di[2-(2-methyl propionitrile) phenyl]methyl]-1 H-1 ,3,4 triazole
By further elution with ethyl acetate of the residue in the column of Example 8, 45 mg of 1-[(benzofuran-2-yl)[3',5'-di[2-(2-methyl propionitrile)phenyl]methyl]-1 H-1 ,3,4 triazole are obtained. NMR (CDCI3) s 1.99 (s, 12H), s 6.91 (s, 1 H), s 6.95 (s, 1 H), s 7.56 (t, J = 8.6 Hz, 1 H), s 7.64 (t, J = 7.2 Hz, 1 H), s 7.75 (d, J = 8.1 Hz, 1 H), s 7.85 (d, J = 7.2 Hz, 1 H), s 8.48 (s, 2H).
Using the same procedure and starting from appropriate substrates the compounds 51 and 60, as previously defined, were prepared.
Example 10
1-[(Benzofuran-2-yl)(2',4'-difluorophenyl)methyl]1 H-1 ,2,4 triazole Employing the same procedure as that described in Example 1 , starting from 1 H- 1 ,2,4 triazole (5.37 mmol.) and [(benzofuran-2-yl)(2',4'- difluorophenyl)methyl]chloride (1.79 mmol.), 0.333 g of 1-[(benzofuran-2-yl)(2',4'- difluorophenyl) methyl] 1 H-1 , 2, 4 triazole are obtained. NMR (CDCI3) s 6.6 (s, 1 H), s 6.87-6.97 (m, 2H), s 7.1 (s, 1 H), s 7.22-7.36 (m, 3H), s 7.46 (d, J = 8.1 , 1H), s 7.55 (d, J = 8.1 , 1 H), s 8.02 (s, 1 H), s 8.16 (s, 1 H).
Using the same procedure and starting from appropriate substrates the compounds 26, 27, 34-36, 44, and 45, as previously defined, were prepared. Example 11 1-[(Benzofuran-2-yl)(2',4'-difluorophenyl)methyl]1 H-1 ,3,4 triazole By further elution with chloroform : methanol 99 : 1 of the residue in the column of Example 3, 1-[(benzofuran-2-yl)(2',4'-difluorophenyl)methyl]1 H-1 ,3,4 triazole is obtained.
Using the same procedure and starting from appropriate substrates the compounds 52-54, 61-63, 71 , and 72, as previously defined, were prepared. Example 12
5-[(Benzofuran-2-yl)(4'-cyanophenyl)methyl]pyrimidine
To a solution of 5-[(benzofuran-2-yl)(4'-cyanophenyl) hydroxymethyl]pyrimidine (1.52 mmol.) in glacial acetic acid (5 ml) stannous chloride (3 mmol.) and concentrated hydrochloric acid (1.8 ml) are added. The resulting green solution is heated to 100°C for an hour, and then, at room temperature, H20 (10 ml) is added to precipitate the reduced product. The separated precipitate, washed with H20
and dried, is filtered on a silica gel column 70-230 mesh, eluted with chloroform to yield 0.307 g of 5-[(benzofuran-2-yl)(4'-cyanophenyl)methyl] pyrimidine: NMR (CDCI3) s 5.87 (s, 1 H), s 6.68 (s, 1 H), s 7.50 (t, J = 7.3 Hz, 1 H), s 7.57 (t, J = 7.3 Hz, 1 H), s 7.63 (d, J = 8 Hz, 2H), s 7.69 (d, J = 6.7 Hz, 1 H), s 7.78 (d, J = 6.7 Hz, 1 H), s 7.94 (d, J = 8 Hz, 2H), s 8.89 (s, 2H), s 9.45 (s, 1 H).
Using the same procedure and starting from appropriate substrates the compounds 73-92, 94, and 96-99, as previously defined, were prepared. Example 13 5-[(Benzofuran-2-yl)(4'-cyanophenyl)hydroxymethyl]pyrimidine A solution of 5-bromopyridine (4.04 mmol.) and [(benzofuran-2-yl)(4'- cyanophenyl)methyl]ketone (4.04 mmol.) in THF (10 ml) is cooled to -95°C. To the resulting suspension is added, drop by drop, in one hour, a solution 1.6 M of n- BuLi in n-hexane (4.04 mmol.). After the reaction mixture has been brought to -20°C, a standard processing procedure yields a residue, which is purified by means of flash chromatography on silica gel eluted with chloroform : methanol 99 : 1. 0.590 g of 5-[(benzofuran-2-yl)(4'-cyanophenyl)hydroxymethyl] pyrimidine are obtained. NMR (CDCI3) s 3.6 (s, 1H), s 6.4 (s, 1 H), s 7.28 (t, J = 7.3 Hz, 1H), s 7.36 (t, J = 7.3 Hz, 1 H), s 7.45 (d, J = 7 Hz, 1H), s 7.55 (d, J = 7 Hz, 1 H), s 7.55 (d, J = 7.3 Hz, 1 H), s 7.71 (d, J = 7.3 Hz, 2H), s 8.75 (s, 2H), s 9.2 (s, 1 H). Using the same procedure and starting from appropriate substrates, the compounds 100, 119, 121 , and 123-126, as previously defined, were prepared. Example 14
5-[(Benzofuran-2-yl)(4'-fluorophenyl)methyl]pyrimidine Following the procedure described in Example 12, starting from 5-[(benzofuran-2- yl)(4'-fluorophenyl)-hydroxymethyl]pyrimidine (1.85 mmol.), after flash chromatography on silica gel, eluting with CHCI3/CH3OH 99/1 , 365 mg of 5- [(benzofuran-2-yl)(4'-fluorophenyl) methyl]pyrimidine are obtained. NMR (CDCI3) s 5.55 (s, 1 H), s 6.36 (s, 1 H), s 7.06 (t, J = 9.0, 2H), s 7.18-7.29 (m, 4H), s 7.41 (d, J = 7.8, 1 H), s 7.5 (d, J = 7.3, 1 H), s 8.61 (s, 2H), s 9.15 (s, 1 H). Example 15
5-[(Benzofuran-2-yl)(4'-fluorophenyl)hydoxymethyl]pyrimidine
Following the procedure described in Example 13, starting from 5-[(benzofuran-2- yl)(4'-fluorophenyl)- methyl] ketone (1.2 mmol), after flash chromatography on silica gel, eluting with CHCI3, 192 mg of 5-[(benzofuran-2-yl)(4'- fluorophenyl)hydroxymethyl]pyrimidine are obtained. NMR (CDCI3) s 3.7 (s, 1 H), s 6.39 (s, 1 H), s 7.08 (t, J = 8.6, 2H), s 7.24-7.36 (m, 4H), s 7.45 (d, J = 8.1 , 1 H), s 7.45 (d, J = 7.5, 1 H), s 8.77 (s, 2H), s 9.97 (s, 1 H).
TABLE 1 In vitro inhibition of human placental aromatase
Compound IC50 (nM)
1-[(benzofuran-2-yl)(4-cyanophenyl) 6 methy midazole
38 13
39 3.7
40 30
41 2.8
42 9.2
65 6
67 42.3
68 16
69 21
93 72
95 27
122 20.8 aminoglutethimide 2554 anastrozole 8
TABLE 2 % decrease in blood plasma oestrogen levels in female rats pre-treated with PMSG
Compound %(3h) %(24h)
1 -[(benzofuran-2-yl)(4-cyano- ii..vv.. 85 71 phenyl)methyl]imidazole p.o. inactive inactive
1 -[(benzofuran-2-yl)(4-cyano i.v. 97 99 phenyl)methyl]triazole (41 ) p.o. 74 82
TABLE 3
% weight reduction of uterus of puberal rats stimulated with androstenedione and treated with the product for 3 days (0.3 mg/kg per day)
Compound % reduction
Anastrozole 90.6
1 -[(benzofuran-2-yl)(4-cyano phenyl)methyl]triazole (41 ) 100
Claims
CLAIMS 1. Compounds having the general formula (I):
in which R and R,, which may be the same or different from one another, are chosen in the group consisting of: H, halogen, C^-alkyl, C^-alkoxy, aryl, alkylaryl, cycloalkyl, or R and R, taken together form a -CH2-(CH2)n-CH2 chain, where n is comprised between 1 and 4, or an aromatic ring condensed to the possibly substituted furan ring; R2 and R3, which may be the same or different from one another, are chosen in the group consisting of: H, halogen, C^-alkyl, C^-alkoxy, phenyl, phenyl alkyl^. 4), nitro, cyano, amino C^-acylamine, sulphamide group, N-substituted sulphamide group, or a -CR4R5X group, where X is nitro, cyano, amino, Λ - acylamine, and R4 and R5, which may be the same or different from one another, are chosen in the group consisting of: C^-alkyl; HET is imidazole, triazole, pyrimidine, with the proviso that HET is not imidazole when R and R together form an aromatic ring condensed to the furan ring; A is chosen in the group consisting of: H, OH, F and their pharmaceutically acceptable salts. 2. Compounds having the general formula (I) according to Claim 1 , in which the nitrogenated heterocycle is chosen in the group consisting of triazole and pyrimidine. 3. Compounds having the general formula (I) according to Claim 2, in which the nitrogenated heterocycle is chosen in the group consisting of 1 H-imidazole, 1 H- 1 ,2,4-triazole, 1 H-1 ,3,4-triazole, and 5-pyrimidine. 4. Compounds having the general formula (I) according to Claim 3, as indicated below: 1 -[(Furan-2-yl) phenylmethyl]-1 H-imidazole 1 -[(Furan-2-yl)(4'-methylphenyl)methyl]-1 H-imidazole 1 -[(Furan-2-yl)(4'-fluorophenyl)methyl]-1 H-imidazole
2Q
1 -[(Furan-2-yl)(4'-chlorophenyl)methyl]-1 H-imidazole
1-[(Furan-2-yl)(4'-cyanophenyl)methyl]-1 H-imidazole
1-[(Furan-2-yl)[3',5'-di[2-(2-methyl propionitrile)phenyl] methyl]-1 H-imidazole
1-[(Furan-2-yl)(2',4'-difluorophenyl)methyl]-1 H-imidazole
1-[(Furan-2-yl)(2',4'-dicyanophenyl)methyl]-1 H-imidazole
1 -[(Furan-2-yl)(2'-fluoro-4'-cyanophenyl)methyl]-1 H-imidazole
1 -[(5-Phenylfuran-2-yl)phenylmethyl]-1 H-imidazole
1-[(5-Phenylfuran-2-yl)(4'-methylphenyl)methyl]-1 H-imidazole
1 -[(5-Phenylfuran-2-yl)(4'-fluorophenyl)methyl]-1 H-imidazole
1 -[(5-Phenylfuran-2-yl)(4'-chlorophenyl)methyl]-1 H-imidazole
1 -[(5-Phenylfuran-2-yl)(4'-cyanophenyl)methyl]-1 H-imidazole
1-[(5-Phenylfuran-2-yl)[3',5'-di[2-(2-methyl propionitrile) phenyl)]methyl]-1 H- imidazole
1-[(5-Phenylfuran-2-yl)(2',4'-difluorophenyl)methyl]-1 H-imidazole
1-[(5-Phenylfuran-2-yl)(2',4'-dicyanophenyl)methyl]-1 H-imidazole
1-[(5-Phenylfuran-2-yl)(2'-fluoro-4'-cyanophenyl)methyl]-1 H-imidazole
1-[(Furan-2-yl)phenylmethyl]-1 H-1 ,2,4-triazole
1 -[(Furan-2-yl)(4'-methylphenyl)methyl]-1 H-1 ,2,4-triazole
1 -[(Furan-2-yl)(4'-fluorophenyl)methyl]-1 H-1 ,2,4-triazole
1-[(Furan-2-yl)(4'-chlorophenyl)methyl]-1 H-1 ,2,4-triazole
1-[(Furan-2-yl)(4'-cyanophenyl)methyl]-1 H-1 ,2,4-triazole
1-[[(Furan-2-yl)[3',5'-di[2-(2-methyl propionitrile) phenyl]methyl]-1 H-1 ,2,4-triazole
1-[(Furan-2-yl)(2',4'-difluorophenyl methyl]-1 H-1 ,2,4-triazole
1-[(Furan-2-yl)(2',4'-dicyanophenyl)methyl]-1 H-1 ,2,4-triazole
1 -[(Furan-2-yl)(2'-fluoro-4'-cyanophenyl)methyl]-1 H-1 ,2,4-triazole
1-[(5-Phenylfuran-2-yl)phenylmethyl]-1 H-1 ,2,4-triazole
1 -[(5-Phenylfuran-2-yl)(4'-methylphenyl)methyl]-1 H-1 ,2,4-triazole
1 -[(5-Phenylfuran-2-yl)(4'-fluorophenyl)methyl]-1 H-1 ,2,4-triazole
1 -[(5-Phenylfuran-2-yl)(4'-chlorophenyl)methyl]-1 H-1 ,2,4-triazole
1 -[(5-Phenylfuran-2-yl)(4'-cyanophenyl)methyl]-1 H-1 ,2,4-triazole
[1 -[(5-Phenylfuran-2-yl)[3',5'-di[2-(2-methyl propionitrile)phenyl]methyl]-1 H-1 ,2,4- triazole 1-[(5-Phenylfuran-2-yl)2',4'-difluorophenyl)methyl]-1 H-1 ,2,4-triazole 1 -[(5-Phenylfuran-2-yl)2',4'-dicyanophenyl)methyl]-1 H-1 ,2,4-triazole 1 -[(5-Phenylfuran-2-yl)2'-fluoro-4'-cyanophenyl)methyl]-1 H-1 ,2,4-triazole 1 -[(Benzofuran-2-yl)phenylmethyl]-1 H-1 ,2,4-triazole 1 -[(Benzofuran-2-yl)(4'-methylphenyl)methyl]-1 H-1 ,2,4-triazole 1 -[(Benzofuran-2-yl)(4'-fluorophenyl)methyl]-1 H-1 ,2,4-triazole 1 -[(Benzofuran-2-yl)(4'-chlorophenyl)methyl]-1 H-1 ,2,4-triazole 1 -[(Benzofuran-2-yl)(4'-cyanophenyl)methyl]-1 H-1 ,2,4-triazole 1-[[(Benzofuran-2-yl)[3',5'-di[2-(2-methyl propionitrile) phenyl]methyl]-1 H-1 ,2,4- triazole 1 -[(Benzofuran-2-yl)(2',4'-difluorophenyl)methyl]-1 H-1 ,2,4-triazole 1-[(Benzofuran-2-yl)(2',4'-dicyanophenyl)methyl]-1 H-1 ,2,4-triazole 1 -[(Benzofuran-2-yl)(2'-fluoro-4'-cyanophenyl)methyl]-1 H-1 ,2,4-triazole 1 -[(Furan-2-yl)phenyl methyl]-1 H-1 ,3,4-triazole 1 -[(Furan-2-yl)[4'-methylphenyl)methyl]-1 H-1 ,3,4-triazole 1 -[(Furan-2-yl)[4'-fluorophenyl)methyl]-1 H-1 ,3,4-triazole 1 -[(Furan-2-yl)[4'-chlorophenyl)methyl]-1 H-1 ,3,4-triazole 1 -[(Furan-2-yl)[4'-cyanophenyl)methyl]-1 H-1 ,3,4-triazole 1-[[(Furan-2-yl)[3',5'-di[2-(2-methyl propionitrile)phenyl] methyl]-1 H-1 ,3,4-triazole 1-[(Furan-2-yl)(2',4'-difluorophenyl)methyl]-1 H-1 ,3,4-triazole 1 -[(Furan-2-yl)(2',4'-dicyanophenyl)methyl]-1 H-1 ,3,4-triazole 1 -[(Furan-2-yl)(2'-fluoro-4'-cyanophenyl)methyl]-1 H-1 ,3,4-triazole 1 -[(5-Phenylfuran-2-yl)phenylmethyl]-1 H-1 ,3,4-triazole 1 -[(5-Phenylfuran-2-yl)(4'-methylphenyl)methyl]-1 H-1 ,3,4-triazole 1 -[(5-Phenylfuran-2-yl)(4'-fluorophenyl)methyl]-1 H-1 ,3,4-triazole 1 -[(5-Phenylfuran-2-yl)(4'-chlorophenyl)methyl]-1 H-1 ,3,4-triazole 1-[(5-Phenylfuran-2-yl)(4'-cyanophenyl)methyl]-1 H-1 ,3,4-triazole 1-[(5-Phenylfuran-2-yl)[3',5'-di[2-(2-methyl propionitrile) phenyl]methyl]-1 H-1 ,3,4- triazole
1-[(5-Phenylfuran-2-yl)(2',4'-difluorophenyl)methyl]-1 H-1 ,3,4-triazole 1-[(5-Phenylfuran-2-yl)(2',4'-dicyanophenyl)methyl]-1 H-1 ,3,4-triazole 1 -[(5-Phenylfuran-2-yl)(2'-fluoro-4'-cyanophenyl)methyl]-1 H-1 ,3,4-triazole 1 -[(Benzofuran-2-yl)phenylmethyl]-1 H-1 ,3,4-triazole 1 -[(Benzofuran-2-yl)(4'-methylphenyl)methyl]-1 H-1 ,3,4-triazole 1 -[(Benzofuran-2-yl)(4'-fluorophenyl)methyl]-1 H-1 ,3,4-triazole 1 -[(Benzofuran-2-yl)(4'-chlorophenyl)methyl]-1 H-1 ,3,4-triazole 1 -[(Benzofuran-2-yl)(4'-cyanophenyl)methyl]-1 H-1 ,3,4-triazole 1-[(Benzofuran-2-yl)[3',5'-di[2-(2-methyl propionitrile) phenyl]methyl]-1 H-1 ,3,4- triazole 1 -[(Benzofuran-2-yl)(2',4'-difluorophenyl)methyl]-1 H-1 ,3,4-triazole 1-[(Benzofuran-2-yl)(2',4'-dicyanophenyl)methyl]-1 H-1 ,3,4-triazole 1 -[(Benzofuran-2-yl)(2'-fluoro-4'-cyanophenyl)methyl]-1 H-1 ,3,4-triazole 5-[(Furan-2-yl)phenylmethyl]pyrimidine 5-[(Furan-2-yl)(4'-methylphenyl)methyl]pyrimidine 5-[(Furan-2-yl)(4'-fluorophenyl)methyl]pyrimidine 5-[(Furan-2-yl)(4'-chlorophenyl)methyl]pyrimidine 5-[(Furan-2-yl)(4'-cyanophenyl)methyl]pyrimidine 5-[(Furan-2-yl)[3',5'-di[2-(2-methyl propionitrile)phenyl] methyl]pyrimidine 5-[(Furan-2-yl)(2',4'-difluorophenyl)methyl]pyrimidine 5-[(Furan-2-yl)(2',4'-dicyanophenyl)methyl]pyrimidine 5-[(Furan-2-yl)(2'-fluoro-4'-cyanophenyl)methyl]pyrimidine 5-[(5-Phenylfuran-2-yl)phenylmethyl]pyrimidine 5-[(5-Phenylfuran-2-yl)(4'-methylphenyl)methyl]pyrimidine 5-[(5-Phenylfuran-2-yl)(4'-fluorophenyl)methyl]pyrimidine 5-[(5-Phenylfuran-2-yl)(4'-chlorophenyl)methyl]pyrimidine 5-[(5-Phenylfuran-2-yl)(4'-cyanophenyl)methyl]pyrimidine 5-[(5-Phenylfuran-2-yl)[3',5'-di[2-(2-methyl propionitrile) phenyl)]methyl]pyrimidine 5-[(5-Phenylfuran-2-yl)(2',4'-difluorophenyl)methyl] pyrimidine 5-[(5-Phenylfuran-2-yl)(2',4'-dicyanophenyl)methyl] pyrimidine
98 5-[(5-Phenylfuran-2-yl)(2'-fluoro-4'-cyanophenyl)methyl] pyrimidine
99 5-[(Benzofuran-2-yl)phenylmethyl]pyrimidine
100 5-[(Benzofuran-2-yl)(4'-methylphenyl)methyl]pyrimidine loi 5-[(Benzofuran-2-yl)(4'-fluorophenyl)methyl]pyrimidine
102 5-[(Benzofuran-2-yl)(4'-chlorophenyl)methyl]pyrimidine
103 5-[(Benzofuran-2-yl)(4'-cyanophenyl)methyl]pyrimidine
104 5-[(Benzofuran-2-yl)[3',5'-di[2-(2-methyl propionitrile) phenyl]methyl]pyrimidine
105 5-[(Benzofuran-2-yl)(2',4'-difluorophenyl)methyl] pyrimidine
106 5-[(Benzofuran-2-yl)(2',4'-dicyanophenyl)methyl]pyrimidine
107 5-[(Benzofuran-2-yl)(2'-fluoro-4'-cyanophenyl)methyl] pyrimidine
108 5-[(Furan-2-yl)phenyl hydroxymethyl]pyrimidine
109 5-[(Furan-2-yl)(4'-methylphenyl)hydroxymethyl]pyrimidine
110 5-[(Furan-2-yl)(4'-fluorophenyl)hydroxymethyl]pyrimidine
111 5-[(Furan-2-yl)(4'-chlorophenyl)hydroxymethyl]pyrimidine
112 5-[(Furan-2-yl)(4'-cyanophenyl)hydroxymethyl]pyrimidine
113 5-[(Furan-2-yl)[3',5'-di[2-(2-methyl propionitrile) phenyl]hydroxymethyl]pyrimidine
114 5-[(Furan-2-yl)(2',4'-difluorophenyl)hydroxymethyl] pyrimidine
115 5-[(Furan-2-yl)(2',4'-dicyanophenyl)hydroxymethyl] pyrimidine
116 5-[(Furan-2-yl)(2'-fluoro-4'-cyanophenyl)hydroxymethyl] pyrimidine in 5-[(5-Phenylfuran-2-yl)phenyl hydroxymethyl]pyrimidine
118 5-[(5-Phenylfuran-2-yl)(4'-methylphenyl)hydroxymethyl] pyrimidine
119 5-[(5-Phenylfuran-2-yl)(4'-fluorophenyl)hydroxymethyl] pyrimidine
120 5-[(5-Phenylfuran-2-yl)(4'-chlorophenyl)hydroxymethyl] pyrimidine
121 5-[(5-Phenylfuran-2-yl)(4'-cyanophenyl)hydroxymethyl] pyrimidine
122 5-[(5-Phenylfuran-2-yl)[3',5'-di[2-(2-methyl propionitrile)]hydroxymethyl]pyrimidine
123 5-[(5-Phenylfuran-2-yl)(2',4'-difluorophenyl) hydroxymethyl]pyrimidine
124 5-[(5-Phenylfuran-2-yl)(2,,4'-dicyanophenyl) hydroxymethyl]pyrimidine
125 5-[(5-Phenylfuran-2-yl)(2'-fluoro-4'-cyanophenyi) hydroxymethyl]pyrimidine
126 5-[(Benzofuran-2-yl)phenyl hydroxymethyl]pyrimidine
127 5-[(Benzofuran-2-yl)(4'-methylphenyl)hydroxymethyl] pyrimidine
128 5-[(Benzofuran-2-yl)(4'-fluorophenyl)hydroxymethyl] pyrimidine
129 5-[(Benzofuran-2-yl)(4'-chlorophenyl)hydroxymethyl] pyrimidine
130 5-[(Benzofuran-2-yl)(4'-cyanophenyl)hydroxymethyl] pyrimidine
131 5-[(Benzofuran-2-yl)[3',5'-di[2-(2-methylpropionitrile)
132 phenyl]hydroxymethyl]pyrimidine
133 5-[(Benzofuran-2-yl)(2',4'-difluorophenyl)hydroxymethyl] pyrimidine
134 5-[(Benzofuran-2-yl)(2',4'-dicyanophenyl)hydroxymethyl] pyrimidine
135 5-[(Benzofuran-2-yl)(2'-fluoro-4'-cyanophenyl) hydroxymethyl]pyrimidine
136 5-[(Furan-2-yl)phenyl fluoromethyl]pyrimidine
137 5-[(Furan-2-yl)(4'-methylphenyl)fluoromethyl]pyrimidine
138 5-[(Furan-2-yl)(4'-fluorophenyl)fluoromethyl]pyrimidine
139 5-[(Furan-2-yl)(4'-chlorophenyl)fluoromethyl]pyrimidine
140 5-[(Furan-2-yl)(4'-cyanophenyl)fluoromethyl]pyrimidine
141 5-[(Furan-2-yl)[3',5'-di[2-(2-methyl propionitrile)phenyl] fluoromethyl]pyrimidine
142 5-[(Furan-2-yl)(2',4'-difluorophenyl)fluoromethyl] pyrimidine
143 5-[(Furan-2-yl)(2',4'-dicyanophenyl)fluoromethyl] pyrimidine
144 5-[(Furan-2-yl)(2'-fluoro-4'-cyanophenyl)fluoromethyl] pyrimidine
145 5-[(5-Phenylfuran-2-yl)phenyl fluoromethyljpyrimidine
146 5-[(5-Phenylfuran-2-yl)(4'-methylphenyl)fluoromethyl] pyrimidine
147 5-[(5-Phenylfuran-2-yl)(4'-fluorophenyl)fluoromethyl] pyrimidine
148 5-[(5-Phenylfuran-2-yl)(4'-chlorophenyl)fluoromethyl] pyrimidine
149 5-[(5-Phenylfuran-2-yl)(4'-cyanophenyl)fluoromethyl] pyrimidine
150 5-[(5-Phenylfuran-2-yl)[3',5'-di[2-(2-methylpropionitrile)
151 phenyl)]fluoromethyl]pyrimidine
152 5-[(5-Phenylfuran-2-yl)(2',4'-difluorophenyl) fluoromethyl] pyrimidine
153 5-[(5-Phenylfuran-2-yl)(2',4'-dicyanophenyl)fluoromethyl] pyrimidine
154 5-[(5-Phenylfuran-2-yl)(2'-fluoro-4'-cyanophenyl) fluoromethyl]pyrimidine
155 5-[(Benzofuran-2-yl)phenyl fluoromethyl]pyrimidine
156 5-[(Benzofuran-2-yl)(4'-methylphenyl)fluoromethyl] pyrimidine
157 5-[(Benzofuran-2-yl)(4'-fluorophenyl)fluoromethyl] pyrimidine
158 5-[(Benzofuran-2-yl)(4'-chlorophenyl)fluoromethyl] pyrimidine
159 5-[(Benzofuran-2-yl)(4'-cyanophenyl)fluoromethyl] pyrimidine
160 5-[(Benzofuran-2-yl)[3',5'-di[2-(2-methyl propionitrile)] fluoromethyl]pyrimidine
161 5-[(Benzofuran-2-yl)(2',4'-difluorophenyl)fluoromethyl] pyrimidine
162 5-[(Benzofuran-2-yl)(2',4'-dicyanophenyl)fluoromethyl] pyrimidine
163 5-[(Benzofuran-2-yl)(2'-fluoro-4'-cyanophenyl)fluoromethyl] pyrimidine
164 and their pharmaceutically acceptable salts.
1 5. Use of the products of the general formula (I) according to Claim 1 for the
2 preparation of pharmaceutical compositions for the treatment and prevention of
3 cancer of the breast, ovary, uterus, pancreas, and endometrium, as well as for the
4 treatment and prevention of benign prostate hypertrophy.
1 6. Pharmaceutical compositions for use as aromatase inhibitors, containing as
2 active principle a compound according to Claim 1 .
1 7. Pharmaceutical compositions according to Claim 6 for the treatment of
2 hormone-dependent tumours and of benign prostate hypertrophy.
1 8. Compositions according to Claim 7, in which the hormone-dependent tumours
2 are: cancer of the breast, ovary, uterus, endometrium, and pancreas.
1 9. Method for the inhibition of aromatase enzymes comprising the administration
2 to patients of therapeutically active quantities of product according to Claim 1 or of
3 compositions according to Claim 6.
1 10. Method according to Claim 9 for the treatment of hormone-dependent
2 tumours.
1 1 1 . Method according to Claim 10 in which the hormone-dependent tumours are:
2 cancer of the breast, ovary, uterus, endometrium, and pancreas. l 12. Method according to Claim 9 for the treatment of benign prostate hypertrophy.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU49491/97A AU4949197A (en) | 1996-10-28 | 1997-10-23 | Heterocyclic furan compounds, their preparation and use as aromatase inhibitors |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITFI96A000253 | 1996-10-28 | ||
| ITFI960253 IT1286866B1 (en) | 1996-10-28 | 1996-10-28 | FURANO-HETEROCYCLIC COMPOUNDS, THEIR PREPARATION AND USE AS AROMATASE INHIBITORS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1998018791A1 true WO1998018791A1 (en) | 1998-05-07 |
Family
ID=11351840
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1997/005854 WO1998018791A1 (en) | 1996-10-28 | 1997-10-23 | Heterocyclic furan compounds, their preparation and use as aromatase inhibitors |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU4949197A (en) |
| IT (1) | IT1286866B1 (en) |
| WO (1) | WO1998018791A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004035568A1 (en) * | 2002-10-15 | 2004-04-29 | University College Cardiff Consultants Limited | Benzofuran derivatives, formulations and uses thereof |
| JP2008500983A (en) * | 2004-06-01 | 2008-01-17 | エフ．ホフマン−ラ ロシュ アーゲー | 3-Amino-1-arylpropylindoles as monoamine reuptake inhibitors |
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|---|---|---|---|---|
| EP0165783A1 (en) * | 1984-06-18 | 1985-12-27 | Eli Lilly And Company | Aromatase inhibiting N-substitued imidazole derivatives |
| EP0257171A1 (en) * | 1986-08-13 | 1988-03-02 | A. Menarini Industrie Farmaceutiche Riunite S.R.L. | (Benzofuran-2-yl)imidazoles having pharmaceutical activity, their salts and relevant production processes |
| EP0260744A2 (en) * | 1986-09-15 | 1988-03-23 | Janssen Pharmaceutica N.V. | (1H-imidazol-1-ylmethyl) substituted benzimidazole derivatives |
| EP0293978A2 (en) * | 1987-06-01 | 1988-12-07 | Janssen Pharmaceutica N.V. | (1H-azol-1-ylmethyl)substituted benzotriazole derivatives |
| EP0340153A1 (en) * | 1988-03-31 | 1989-11-02 | Schering Aktiengesellschaft | N-substituted imidazoles, process for their preparation and their use in medicaments |
| EP0408509A2 (en) * | 1989-07-14 | 1991-01-16 | Ciba-Geigy Ag | Substituted benzonitriles |
| EP0445073A1 (en) * | 1990-02-27 | 1991-09-04 | Ciba-Geigy Ag | Benzofurans |
| EP0490816A2 (en) * | 1990-12-12 | 1992-06-17 | Ciba-Geigy Ag | Fluoro-compounds |
| US5583128A (en) * | 1991-04-24 | 1996-12-10 | Ciba-Geigy Corporation | Contraception in female primates without affecting the menstrual cycle |
-
1996
- 1996-10-28 IT ITFI960253 patent/IT1286866B1/en active IP Right Grant
-
1997
- 1997-10-23 AU AU49491/97A patent/AU4949197A/en not_active Abandoned
- 1997-10-23 WO PCT/EP1997/005854 patent/WO1998018791A1/en active Application Filing
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| EP0165783A1 (en) * | 1984-06-18 | 1985-12-27 | Eli Lilly And Company | Aromatase inhibiting N-substitued imidazole derivatives |
| EP0257171A1 (en) * | 1986-08-13 | 1988-03-02 | A. Menarini Industrie Farmaceutiche Riunite S.R.L. | (Benzofuran-2-yl)imidazoles having pharmaceutical activity, their salts and relevant production processes |
| EP0260744A2 (en) * | 1986-09-15 | 1988-03-23 | Janssen Pharmaceutica N.V. | (1H-imidazol-1-ylmethyl) substituted benzimidazole derivatives |
| EP0293978A2 (en) * | 1987-06-01 | 1988-12-07 | Janssen Pharmaceutica N.V. | (1H-azol-1-ylmethyl)substituted benzotriazole derivatives |
| EP0340153A1 (en) * | 1988-03-31 | 1989-11-02 | Schering Aktiengesellschaft | N-substituted imidazoles, process for their preparation and their use in medicaments |
| EP0408509A2 (en) * | 1989-07-14 | 1991-01-16 | Ciba-Geigy Ag | Substituted benzonitriles |
| EP0445073A1 (en) * | 1990-02-27 | 1991-09-04 | Ciba-Geigy Ag | Benzofurans |
| EP0490816A2 (en) * | 1990-12-12 | 1992-06-17 | Ciba-Geigy Ag | Fluoro-compounds |
| US5583128A (en) * | 1991-04-24 | 1996-12-10 | Ciba-Geigy Corporation | Contraception in female primates without affecting the menstrual cycle |
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| AL-HAMROUNI,A.M. ET AL.: "1-[(Benzofuran-2yl-)phenylmethyl] imidazoles as inhibitors of 17.alpha. -hydroxylase: 17,20-lyase (P450 17): species and tissue differences", PHARM.SCI., vol. 3, no. 5/6, 1997, pages 259 - 263, XP002058014 * |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004035568A1 (en) * | 2002-10-15 | 2004-04-29 | University College Cardiff Consultants Limited | Benzofuran derivatives, formulations and uses thereof |
| JP2008500983A (en) * | 2004-06-01 | 2008-01-17 | エフ．ホフマン−ラ ロシュ アーゲー | 3-Amino-1-arylpropylindoles as monoamine reuptake inhibitors |
| JP4698671B2 (en) * | 2004-06-01 | 2011-06-08 | エフ．ホフマン−ラ ロシュ アーゲー | 3-Amino-1-arylpropylindoles as monoamine reuptake inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| ITFI960253A1 (en) | 1998-04-28 |
| AU4949197A (en) | 1998-05-22 |
| IT1286866B1 (en) | 1998-07-17 |
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