GB2071655A - N-imidazolyl derivatives of 1- chroman and process for their preparation - Google Patents

N-imidazolyl derivatives of 1- chroman and process for their preparation Download PDF

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GB2071655A
GB2071655A GB8106495A GB8106495A GB2071655A GB 2071655 A GB2071655 A GB 2071655A GB 8106495 A GB8106495 A GB 8106495A GB 8106495 A GB8106495 A GB 8106495A GB 2071655 A GB2071655 A GB 2071655A
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benzopyran
dihydro
imidazolyl
hydroxy
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Farmitalia Carlo Erba SRL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Abstract

Compounds of formula <IMAGE> wherein R is C1-C6 alkyl, n is 0, 1, 2 or 3, one of R1 and R2 is hydroxy and the other is hydrogen or C1-C6 alkyl or R1 and R2, taken together, form an oxo group; and each of X1, X2, X3 and X4 independently is hydrogen; halogen; hydroxy; NO2; CN; C1-C6 alkyl; C1-C6 alkyloxy; trihalo-C1-C6 alkyl; -SR% or -COOR%, R% being hydrogen or C1-C6 alkyl; <IMAGE> each or R_ and R> being hydrogen or C1 to C6 alkyl; or one of X1, X2, X3 and X4 is phenyl, phenylthio, phenoxy or benzyl, optionally substituted by various substituents; or two adjacent X1, X2, X3 and X4 groups, taken together, complete a fused saturated or unsaturated 6-membered carboxylic ring optionally substituted by various substituents; and pharmaceutically acceptable salts of these compounds. The compounds and salts are useful in the treatment of, for example, thrombosis.

Description

SPECIFICATION N-imidazolyl derivatives of 1-chroman and process for their preparation The present invention relates to new N-imidazolyl derivatives of 1-chroman, that is 2,3-dihydro-1- benzopyran, to a process for their preparation and to pharmaceutical compositions containing them.
The invention provides compounds having the following general formula (I)
wherein R is C1-C6 alkyl; n is 0,1,2 or 3 one of R, and R2 is hydroxy and the other is hydrogen or C1-6 alkyl, or R1 and R2, taken together, form an oxo group; each of X1, X2, X3 and X4, which may be the same or different , is hydrogen; halogen; hydroxy; -NO2;-CN;C1-C6 alkyl; C1-C6 alkoxy; trihalo-C1-C8 alkyl; -SR' or -COOR', R' being hydrogen or C1-C6 alkyl;
each of R" and R"', which may be the same or different, being hydrogen or C1-C6 alkyl, or one of X1,X2, X3 and X4 is phenyl, phenylthio, phenoxy or benzyl, the phenyl, phenylthio, phenoxy and benzyl groups being unsubstituted or substituted by halogen C1-C6 alkyl, C16 alkoxy, or -SR', wherein R' is as defined above, and the others are as defined above : or any two adjacent X1, X2, X3 and X4 groups, taken together. complete a saturated or unsaturated 6-membered carbocylic ring fused to the benzene ring shown in formula (I), the carbocylic ring being unsubstituted or substituted by one of more groups selected from halogen, C1-C6 alkyl, 1-6 haloalkyl, C1-C6 alkoxy or -SR', wherein R' is as defined above, and any groups X1 to X4 not participating in the completion of such a fused ring are as defined above, and the pharmaceutically acceptable salts thereof.
The present invention includes all the possible isomers of formula (I) and the mixtures, was well as the metabolites and the metabolic precursors of the compounds of formula (I). The compounds of formula (I) in which one of R1 and R2 is hydroxy may be in the cis- or in the trans-configuration: both the single cis and trans-isomers and their mixtures are included in the scope of the invention.
Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts, with inorganic, e.g. nitric, hydrochloric, hydrobromic, sulphuric, perchloric and phosphoric, acids, or organic, e.g. acetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic and salicylic acids, and salts with inorganic, e.g. alkali metal, especially sodium or potassium bases or alkaline-earth metal, especially calcium or magnesium bases, or with organic bases, e.g.
alkylamines, preferably triethylamine.
The alkyl, alkoxy and alkylthio groups may be branched or straight chain groups.
A halogen atom is preferably fluorine, chlorine or bromine, AC1-C6 alkyl group is preferably isopropyl or tert.butyl.
A C1-C6 alkoxy group is preferably methoxy or isopropoxy.
A C1-C6 alkylthio group is preferably methylthio or isopropylthio.
A trihalo-C1-C6-alkyl is preferably trihalomethyl and more preferably trifluoromethyl.
Any two of X1 to X4 can complete a saturated or unsaturated fused ring. The adjacent participating X1 to X4 groups can be X2 and X3, X1 and X2, X3 and X4 or both X1 and X2 and X3 and X4. Each pair of participating X1 to X4 groups has the formula
wherein each of the symbols Y1 to Y8, which may the same or different represents hydrogen, halogen, C16 alkyl, C16 haloalkyl. especially trifluoromethyl, C16 alkoxy or SR', R' being as defined above or Y6 and Y8 together and/or Y7 and Y8 together represent a carbon to carbon double bond and the remaining symbols Y1 to Y6 are as defined above. Preferably the pair of participating groups X1 to X4 complete a fused benzene ring unsubstituted or substituted as defined above, preferably by a halogen, preferably chlorine, atom.
Preferred compounds of the invention are the compounds of formula (I) wherein n is zero, one of R1 and R2 is hydrogen and the other is hydroxy, or R1 and R2, taken together, form an oxo group, and wherein X1,X2,X3and X4 are, independently, hydrogen, halogen, hydroxy, carboxy, trifluoromethyl, C1-C4 alkylthio, C1-C4 alkyl, C1-C4 alkoxy, carbamoyl or
wherein R" and R" are as defined above, or one of X1, X2, X3 and X4 is phenyl, phenylthio, phenoxy or benzyl, the phenyl, phenylthio phenoxy and benzyl groups being unsubstituted or substituted by halogen, C1-C4 alkyl, C1-C4 aikylthio or C1-C4 alkoxy, and the others are independently, hydrogen, halogen, C1-C4 alkyl, C1-C4 alkylthio or C1-C4 alkoxy, as well as the pharmaceutically acceptable salts thereof.
Examples of preferred compounds of the invention are the following: 1 ) 3~ 1 -imidazolyl)-2,3-dihydro-4H-1 -benzopyran-4-one; 2) 3-(1-imidazolyl)-2,3-dihydro-6-methyl-4H-1-benzopyran-4-one ; 3) 3-(1-imidazolyl)-2,3-dihydro-6-chloro-4H-1-benzopyran-4-one ; 4) 3-(1-imidazolyl)-2,3-dihydro-6-bromol-4H-1-benzopyran-4-one ; 5) 3-( 1 -imidazolyl)-2,3-di hydro-6-trifl uoromethyl-4H- 1 -benzopyran-4-one; 6) 3-(1 -imidazolyl)-2,3-dihydro-6-methoxy-4H-l -benzopyran-4-one; 7) 3-(1-imidazolyl)-2,3-dihydro-6-phenyl-4H-1-benzopyran-4-one ; 8) 3-(1-imidazolyl)-2,3-dihydro-6-phenoxy-4H-1-benzopyran-4-one ; 9) 3-(1-imidazolyl)-2,3-dihydro-7-chloro-4H-1-benzopyran-4-one ; 10) 3-(1-imidazolyl)-2,3-dihydro-7-phenyl-4H-1-benzopyran-4-one ; 11) 3-(1-imidazolyl)-2,3-dihydro-6.8-dichloro-4H-1-benzopyran-4-one ; 12) 3-(1 -imidazolyl)-2,3-dihydro-6,8-dibromo-4H- 1 -benzopyran-4-one 13) 3-(1-imidazolyl)-2,3-dihydro-5.7-dichloro-4H-1-benzopyran-4-one ; 14) 3-( 1 -im idazolyl)-2,3-dihydro-7-methoxy-4H- 1 -benzopyran-4-one.
1 5) 3-( 1 -imidazolyl)-2,3-di hydro-6-hydroxy-8-n-propyl-4H- 1 -benzopyran-4-one.
16) 3-(1-imidazolyl)-2,3-dihydro-7-isopropyloxy-4H-1-benzopyran-4-one.
17) 3-(1-imidazolyl)-2,3-dihydro-5,7-diisopropyl-6-hydroxy-4H-1-benzopyran-4-one 1 8) 3-( 1 -i midazolyl)-2,3-dihydro-7-hydroxy-4H-1 -benzopyran-4-one.
19) 3-(1-imidazolyl)-2,3-dihydro-6-bromo-7-hydroxy-4H-1-benzopyran-4-one.
20) 3-(1-imidazolyl)-2,3-dihydro-6,8-dibromo-7-hydroxy-4H-1-benzopyran-4-one.
21) 3-( 1 -imidazolyl)-2,3-dihydro-6-chloro-7-hydroxy-4H-1 -benzopyran-4-one.
22)3-( 1 -imidazolyl)-2,3-dihydro-6-tert. butyl-7-hydroxy-4H- 1 -benzopyran-4-one.
23) 3-(1-imidazolyl)-2,3-dihydro-6-isopropyl-7-hydroxy-4H-1-benzopyran-4-one.
24) 3-(1-imidazolyl)-2,3-dihydro-6-tert. butyl-7-hydroxy-8-isopropyl-4H-1-benzopyran-4-one.
25) 3-(1 -imidazolyl)-2,3-dihydro-6,8-diisopropyl-7-hydroxy-4H-1 -benzopyran-4-one.
26) 3-(1-imidazolyl)-2,3-dihydro-7-bromo-4H-1-benzopyran-4-one.
27) 3-(1 -i -imidazolyl)-2,3-dihydro-5,7-dibromo-6-hydroxy-4H-1 -benzopyran-4-one.
28) 3-(1 -imidazolyl)-2,3-dihydro-6-hydroxy-4H- 1 -benzopyran-4-one.
29) 3-(1 -imidazolyl )-2,3-di hydro-6-hydroxy-8-bromo-4H- 1 -benzopyran-4-one.
30) 3-(1-imidazolyl)-2,3-dihydro-6-hydroxy-8-chloro-4H-1-benzopyran-4-one.
31) 3-( 1 -imidazolyl)-2,3-dihydro-6-hydroxy-8-isopropyl-4H-1 -benzopyran-4-one.
32) 3-( 1 -imidazolyl)-2,3-dihydro-5,8-dibromo-6-hydroxy-4H- 1 -benzopyran-4-one.
33) 3-(1-imidazolyl)-2,3-dihydro-5,7-ditert. butyl-6-hydroxy-4H-1-benzopyran-4-one.
34) 3-( 1 -imidazolyl)-2,3-dihydro-5-hydroxy-6-tert.butyl-4H- 1 -benzopyran-4-one.
35) 3-(1-imidazolyl)-2,3-dihydro-6-tert. butyl-8-isopropyl-4H-1-benzopyran-4-one.
36) 3-(1-imidazolyl)-2,3-dihydro-6-methyl-8-bromo-4H-1-benzopyran-4-one.
37) 3-( 1 -imidazolyl)-2,3-di hydro-6-tert.butyl-7-hydroxy-8- bromo-4H- 1 -benzopyran-4-one.
38) 3-(1 -i -imidazolyl)-2,3-dihydro-6-amino-8-bromo-4H-1 -benzopyran-4-one.
39)3-(1 -imidazolyl)-2,3-dihydro-6-dimethylamino-8-bromo-4H-1 -benzopyran-4-one.
40)3-(1 -imidazolyl)-2,3-dihydro-6-tert.butyl-4H-1 -benzopyran-4-one.
41) 3-(1-imidazolyl)-2,3-dihydro-6-carbamoyl-4H-1-benzopyran-4-one.
42) 3-(1 -i -imidazolyl)-2,3-dihydro-6-carboxy-4H-1 -benzopyran-4-one.
43) 3-(1-imidazolyl)-2,3-dihydro-6-carbamoyl-8-bromo-4H-1-benzopyran-4-one.
44) 3-(1-imidazolyl)-2,3-dihydro-6-carboxy-8-bromo-4H-1-benzopyran-4-one.
45) 3-(1-imidazolyl)-2,3-dihydro-6-carboxy-8-n-propyl-4H-1-benzopyran-4-one.
46) 3-(1-imidazolyl)-2,3-dihydro-6-carbamoyl-8-n-propyl-4-H-1-benzopyran-4-one.
47) 3-(1-imidazolyl)-2,3-dihydro-7-tert. butyl--4H-1-benzopyran-4-one.
48) 3-(1-imidazolyl)-2,3-dihydro-6,8-ditert. butyl-4H-1-benzopyran-4-one.
49) 3-(1-imidazolyl)-2,3-dihydro-6-hydroxy-7-tert. butyl-4H-1-benzopyran-4-one.
50) 3-(1 -i -imidazolyl)-2,3-dihydro-6-tert.butyl-8-bromo-4H- 1 -benzopyran-4-one.
51) 3-( 1 -imidazolyl)-2,3-dihydro-4H- 1 -benzopyran-4-ol.
52) 3-(1 -imidazolyl)-2,3-di hydro-6-chloro-4H-l -benzopyran-4-ol.
53) 3-(1 -imidazolyl)-2,3-dihydro-6-bromo-4H- 1 -benzopyran-4-ol.
54) 3-(1-imidazolyl)-2,3-dihydro-6-methoxy-4H-1-benzopyran-4-ol.
55) 3-( 1 -imidazolyl)-2,3-dihydro-6-phenyl-4H- 1 -benzopyran-4-ol.
56) 3-( 1 -imidazolyl)-2,3-dihydro-7-chloro-4H-1 -benzopyran-4-ol.
57) 3-(1 -imidazolyl)-2,3-dihydro-6,8-dichloro-4H- 1 -benzopyran-4-ol.
58) 3-( 1 -imidazolyl)-2,3-dihydro-6,8-dibromo-4H-1 -benzopyran-4-ol.
59) 3-( 1 -imidazolyl)-2,3-dihydro-6-tert.butyl-7-hydroxy-4H-1 -benzopyran-4-ol.
60) 3-(1 -imidazolyl)-2,3-dihydro-6-bromo-7-hydroxy-4H-1 -benzopyran-4-ol.
61) 3-( 1 -imidazolyl)-2,3-dihydro-6-tert.butyl-4H-1 -benzopyran-4-ol.
62) 3-( 1 -imidazolyl)-2,3-dihydro-6,8-dibromo-7-hydroxy-4H-1 -benzopyran-4-ol.
63) 3-( 1 -imidazolyl)-2,3-dihydro-6-hydroxy-8-bromo-4H-1 -benzopyran-4-ol.
64) 3-(1 -imidazolyl)-2,3-dihydro-7-methoxy-4H- 1 -benzopyran-4-ol.
as well as the pharmaceutically acceptable salts thereof. The 4-ols can be in the form of cis or trans isomers or mixtures thereof.
The structural formulae of the above-numbered compounds indicated according to their progressive number, are reported in the following Table.
TABLE
Compound X X2 X3 X4 R, 2 1 H H H H =O 2 H CH3 H H -0 3 H Cl H H =0 4 H Br H H = O 5 ---------------- H CF H H =0 6 H OCH3 H H =O 7 H C6H5 H H -O 8 H C6HsO H H = O 9 H H Cl H =0 10 H H C6H5 H -0 11 H Cl H Cl -O 12 H Br - H Br a O 13 Cl H Cl H =0 14 H H CH3O H EO 15 H OH H n-Pr -O CHM 16 H H CHO H -O CHK 17 i-Pr OH i-Pr H -;O 18 H H OH H -O 19 H Br OH H -O 20 H H Br OH Br = O TABLE (Continued)
Compound XI X2 X3 X4 R1 R2 21 H Cl OH H r0 22 H tert-Bu OH H -O 23 H i-Pr OH H 0 24 H tert-Bu OH i-Pr = o 25 H i-Pr OH i-Pr - O 26 H H Br H - O 27 Br OH Br H = O 28 H OH H H - O 29 ------- H OH H Bur = O 30 H OH H Cl -O 31 H OH H i-Pr =0 32 Br OH H Br - 0 33 tert-Bu OH tert-Bu H = o 34 OH tert-Bu H H -O 35 OH tert-Bu H i-Pr = O 36 H CH3 H Br -O 37 H tert-Bu OH Br > O 38 H NH2 H Br -O CHN 39 H N- 3/ N H Br -O CH2 40 H tert-Bu H H = 0 TABLE (Continued)
Compound Xl X2 X3 X, R, R2 41 H CONH2 H H =O 42 H COOH H H =O 43 H CONH2 H Br PO 44 H COOH H Br =O 45 H COOH H n-Pr =O 46 H CONH2 H n-Pr =O 47 H H tert-Bu H =O 48 H tert-Bu H tert-Bu - 0 49 H OH tert-Bu H =O 50 H tert-Bu H Br -O 51 H H H H H OH 52 H Cl H H H OH 53 H Br H H H OH 54 H OCH3 H H H OH 55 H C6H5 H H H OH 56 H H Cl H H OH 57 H Cl H Cl H OH 58 H Br H Br H OH 59 H tert-Bu OH H H OH 60 H Br OH H H OH 61 H tert-Bu H H H OH TABLE (Continued)
Compound X1 X2 X3 X4 R1 R2 62 H Br OH Br H OH 63 H OH H Br H OH 63 OCH2 H OH H Br H OH 64 H H R1 H H OH In the above table the abbreviations i-Pr and tert-Bu mean isopropyl and tert.butyl respectively. In all the above listed compounds n represents zero.
The compounds of formula (I) in which R1 and R2 together represent an oxo group can be prepared by a process comprising: a) reacting a compound of formula (II)
wherein X1,X2,X3a and X4 are as defined above and X5 is halogen or a reactive ester group, with a compound of formula (III)
wherein R and n are as defined above or a salt thereof, thus giving a compound of formula (I) wherein R1 and R2, taken together, form an oxo group and R, n, X1, X2, X3 and X4 are as defined above, or b) reacting a compound of formula (IV)
wherein X1, X2, X3, X4, Rand n are as defined above, with formaldehyde or a reactive derivative thereof, thus giving a compound of formula (I) wherein R1 and R2, taken together, form an oxo group and R, n, X,.
X2,X3 and X4 are as defined above.
The compounds cf formula (I) in which one of R1 and R2 is hydroxy and the other hydrogen can be prepared by reducing a compound of formula (V), i.e. a compound of formula (I) in which R1 and R2 together represent an oxo group,
wherein R, n X,, X2, X3 and X4 are as defined above, thus giving a compound of formula (I) wherein one of R1 and R2 is hydrogen and the other is hydroxy and R, n, Xt, X2, X3 and X4 are as defined above.
The compounds of the invention of formula (I) in which one of R, and R2 is hydroxy and the other C16 alkyl can be prepared by reacting a compound of formula (V) wherein R, n, X1, X2, X3 and X4 are as defined above with a compound of formula (Vi) R3-Z (Vl) wherein Z is Li or the group MgX, in which X is halogen, and R3 is C1-C6 alkyl, thus giving a compound of formula (I) wherein one of R, and R2 is hydroxy and the other is C1-C6 alkyl and R, n, X1, X2, X3 and X4 are as defined above.
Further, if desired, any of the above processes can include a step of converting a compound of formula (I) into another compound of formula (i), and/or removing a protective group, and/or, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof and/or, if desired, converting a salt into a free compound and/or, if desired, separating a mixture of isomers of formula (I) into the single isomers.
When in the compound of formula (II) X5 is a halogen atom, it is preferably chlorine or bromine and when it is a reactive ester group, it is preferably -O-tosyl or -O-mesyl. A salt of a compound of formula (Ill) is preferably an alkali metal, e.g. sodium or potassium salt or a silver salt.The reaction of a compound of formula (il) with a compound of formula (III) or a salt thereof is preferably carried out either (a) in the absence of solvent, at a temperature preferably ranging between the room temperature and 1 800C and for reaction times which may vary from some minutes to about 20 hours using, if necessary, an excess of the compound of formula (III) or a salt thereof, or (b) in the presence of a suitable solvent, preferably dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide, benzene, toluene, ethyl acetate, ethyl alcohol, dioxane or acetone, at a temperature preferably ranging between about OOC and the reflux temperature, for reaction times varying from some minutes to about 12 hours and using, if necessary, an excess of the compound with formuía (ííí) or a stoichiometric amount of a tertiary base, preferably triethylamine. The reaction of a compound of formula (IV) with formaldehyde or a reactive derivative thereof, which may be, for instance, trioxymethylene, may be performed by using aqueous or aqueous-lcoholic solutions of formaldehyde, paraformaldehyde, or trioxymethylene, in a suitable solvent, e.g. methyl or ethyl alcohol or acetic acid, at a temperature preferably ranging between about the room temperature and the reflux temperature for reaction times varying from few minutes to some hours.
The reduction of a compound of formula (V) may be, for example, performed (a) by treatment with an alkali metal boronhydride, e.g. Nabs4, in a suitable solvent, e.g. methyl or ethyl alcohol or a mixture of water and ethyl alcohol, or (b) by treatment with LiAIH4 in an anhydrous solvent, e.g. diethyl ether or tetrahydrofuran, at a temperature ranging, in both cases, preferably between OOC and the reflux temperature, for reaction times varying approximately from 1 to 6 hours.
Alternatively the reduction of a compound of formula (V) may be carried out by catalytic hydrogenation in the presence of a suitable catalyst, e.g. palladium, platinum, Pt0z, ruthenium or Raneynickel in a suitable solvent, preferably chosen from methyl alcohol, ethyl alcohol, acetic acid; cyclohexane, n-hexane, ethyl acetate, benzene or toluene and operating at a pressure ranging from atmospheric pressure to about 50 atmospheres and at a temperature ranging from about 200C to about 1000C.
When in the compounds of formula (V) one or more of X1 X2, X3 and X4 are reducible groups, e.g.
-NO2, -CN, --COOR' or
the reduction is preferably performed with an alkali metal boronhydride, preferably NaBH4, in order to avoid the simultaneous reduction of such reducible groups. When in the compound of formula (VI) Z is -MgX, in the Grignard reagent of formula R3MgX, X is preferably iodine or bromine.
The reaction of a compound of formula (V) with a compound of formula R3MgX may be performed in an anhydrous suitable solvent, preferably an ether, conveniently anhydrous diethyl ether, and at temperatures ranging from about OOC to the room temperature.
The reaction of a compound of formula (V) with a compound of formula (VI) wherein Z is Li, that is a lithiumalkyl of formula LiR3, wherein R3 is as defined above, may be carried out, for example, in a suitable anhydrous solvent, which may be, for instance, n-hexane or n-pentane, at a temperature ranging from about -6O0C to about 800 C, preferably at approximately -780C.
A compound of formula (I) may be converted, if desired, into another compound of formula (I).
These optional conversions may be carried out by methods known in themselves.
Thus, for example, a compound of formula (I) wherein one or more of X1, X2, X3 and X4 is hydrogen may be converted into a compound of formula (I) wherein one or more of Xa, X2 X3 and X4 is a halogen atom, e.g. chlorine or bromine, by reaction with chlorine or bromine in the presence of a Friedel-Crafts catalyst, preferably AICI3, operating in a suitable solvent, e.g. CH2CI2.
A compound of formula (I) wherein one or more of Xr, X2 X3 and X4 is an esterified carboxy group may be converted into a compound of formula (I) wherein one or more of X1, X2, X3 and X4 is a free carboxy group, by hydrolysis in a solvent, such as water or a lower aliphatic alcohol, operating at a temperature ranging from the room temperature to about 1 500 C; the same reaction may be also performed by treatment with lithium bromide in dimethylformamide, at a temperature higher than 50"C.
A compound of formula (I), wherein one or more of X1, X2 X3 and X4 is --CONH,. may be converted into a compound of formula (I), where one or more of X,. X2 X3 and X4 is a free carboxy group, by hydrolysis, preferably by acid hydrolysis, in a suitable solvent, such as water, or by the Bouveault procedure, that is by treatment with NaNo2 and an aqueous strong inorganic acid, i.e. H2SO4, operating at temperatures ranging from the room temperature and 100 C.
A compound of formula (I) wherein one or more off1, X2, X3 and X4 is a free carboxy group may be converted into a compound of formula (I) wherein one or more of X1, X2 X3 and X4 is an esterified carboxy group, i.e. an alkoxycarbonyl group, by reaction, for example, of the alkali metal salt of the acid with a suitable alkyl halide, in an inert solvent, such as acetone, dioxane, dimethylformamide, hexamethylphosphorotriamide, at a temperature ranging from about 0 C to about 1000.
A compound of formula (I)' wherein one or more of X1,X2,X3 and XA is hydrogen may be converted into a compound of formula (I), where one or more of X,, X2, X3 and X4 is C1-C6 alkyl, by alkylation through a Friedel-Crafts reaction, followed by reaction with a C1-C8 alkylhalide, preferably chloride, bromide or iodide, or with a C1-C6 alcohol in a suitable solvent, e.g. nitrobenzene or CH2CI2, or CS2, the latter in the presence of appropriate amount of a Friedel-Crafts catalyst, such as AICI3, ZnCI2 or BF3, the latter in the presence of a strong mineral acid as HF, HCI04or, if desired, in concentrated H2S04 or in concentrated H3PO4 without additional solvent, at temperatures ranging from the room temperature to 1000C.
A compound of formula (I) wherein one or more of X1,X2 X3 and X4 is a C1-C6 alkoxy group may be converted into a compound of formula (I) wherein one or more of X1, X2 X3 and X4 is a hydroxy group by following conventional procedures well known in organic chemistry. For example by treatment with a strong mineral acid, i.e. HCI, HBr, HI, preferably HBr, at temperature ranging from 30 C to the reflux temperature, preferably at reflux temperature, or by treatment with a Lewis acid, for example AICI3 or BF3, in a suitable solvent i.e. CH2CI2 or nitrobenzene, at temperature ranging from the room temperature to 80"C.
Also the optional salification of a compound of formula (I) as well as the conversion of a salt into the free compound and the separation of a mixture of isomers into the single isomers may be carried out by conventional methods.
For example the separation of a mixture of geometric isomers, e.g. cis- and trans-isomers, may be carried out by factional crystallization from a suitable solvent or by chromatography; either column chromatography or high pressure liquid chromatography.
A compound of formula (II) in which X5 is a halogen atom may be obtained halogenating the corresponding compound of formula (VII)
wherein X1, X2 X3 and X are as defined above.
The halogenation of a compound of formula (VII) to give a compound of formula (II) is usually carried out with a stoichiometric amount of halogen, preferably bromine or chlorine, in a suitable solvent, e.g. diethyl ether, methylene chloride, CHCl3, CCl4, CS2 or acetic acid, at a temperature ranging from about 0 C to about 100 C, for reaction times ranging approximately between 3 and 12 hours.
Alternatively, the halogenation reaction of a compound of formula (VII) may be carried out by using a stoichiometric amount of sulphuryl chloride in a suitable solvent, e.g. methylene chloride, chloroform or benzene at temperatures ranging from the room to the reflux temperature, for reaction times ranging from 3 to 12 hours.
A compound of formula (II) wherein X5 is -O-tosyl or -O-mesyl may be obtained by reacting the corresponding alcohol, that is a compound of formula (II) wherein X6 is hydroxy [which is known or may be prepared by known methods], with p-toluenesulphonyl or methanesulphonyl halide, preferably the chloride.
The reaction is preferably carried out in an anhydrous inert solvent, e.g. acetone, at temperatures ranging from the room to the reflux temperature.
The compounds of formula (III) are known or may be obtained by known methods starting from known compounds.
A compound of formula (IV) may be obtained by reacting a compound of formula (VIII)
wherein X1, X2, X3, X4 and X5 are as defined above, with a compound of formula (III) or a salt thereof, preferably an alkali metal, e.g. sodium or potassium salt or a silver salt.
The reaction may be carried out using the same reaction conditions reported above for the reaction between a compound of formula (II) and a compound of formula (III).
The compound of formula (V) is a compound of formula (I) wherein R1 and R2, taken together, form an oxo group and may be obtained by the process (a) or (b) described above.
The compounds of formula (VI) are known compounds. Also the compounds of formula (VII) are known or'they may be prepared by known methods from known compounds. For instance, a compound of formula (VII) in which X1, X2 X3 and X4 are as defined above, may be obtained by cyclizing a compound of formula (IX)
wherein R6 is cyano, carboxy, (C1-C7 alkoxy) carbonyl or the group -COX6, wherein Xe is a halogen atom and X1, X2 X3 and X4 are as defined above.
The cyclization of a compound of formula (IX) in which R5 is cyano, carboxy or (C1-C7 alkoxy) carbonyl, may be carried out by treatment with a suitable cyclizing agent, e.g. phosphoric anhydride, polyphosphoric acid, chlorosulphonic acid or sulphuric acid, optionally in the presence of a suitable solvent, preferably chosen from benzene, toluene and xylene, at a temperature which may range from about 2O0C to about 1300 C. The cyclisation of a compound with formula (IX) wherein R5 is the group -COX6 and Xe is as -defined above, is preferably carried out by using AICI3 in the presence of a suitable solvent, e.g. carbon disulfide, methylene chloride or carbon tetrachloride, at temperatures ranging frorn about OOC to about 500C.
The compounds of formula (VIII) and (IX) are known or may be prepared by known methods, starting from known compounds. For example, a compound of formula (IX) in which Xt, X2 X3 and X4 are as defined above and R5 is cyano, carboxy or (C1-C7 alkoxy) carbonyl may be obtained by reacting a compound of formula (X)
wherein X1 X2 X3 and X4 are as defined above, or a reactive derivative thereof, with a compound of formula (Xl) X6-CH2-CH2-R'5 (Xl) wherein X6 is halogen, preferably chlorine or bromine, and R'5 is cyano, carboxy, or (C1-C7 alkoxy) carbonyl.
Alternatively, a compound of formula (IX) wherein R5 is a carboxy group, may be obtained by reacting a compound of formula (X), or a reactive thereof, with p-propionolactone; a compound of formula (IX) in which R6 is cyano, may be obtained by reacting a compound of formula (X) or a reactive thereof, with acrylonitrile; a compound of formula (IX) in which R5 is (C1-C7 alkoxy) carbonyl, may be obtained by reacting a compound of formula (X), or a reactive thereof, with the appropriate alkyl acrylate. A reactive derivative of a compound with formula (X) may be, for example, a salt, e.g. an alkali metal (sodium or potassium, for instance) salt. The compounds of formula (X) as well as the reactive derivatives thereof, are known compounds or may be obtained by known methods starting from known compounds.The reaction of a compound of formula (X) with a compound of formula (Xl) or with B- propionolactone, is preferably carried out by using a salt of the compound of formula (X), preferably an alkal metal e.g. sodium salt, in a suitable solvent, e.g. water or a mixture of water and ethyl alcohol, preferably at the reflux temperature.
The reaction of a compound of formula (X) with acrylonitrile or an alkyl acrylate is preferably carried out in the absence of solvents but in the presence of "Triton B" and at the reflux temperature.
"Triton" is a trade mark.
The compounds of formula (X) and (XI) are known or may be obtained by known methods.
When in the compounds having the formulae (I), (II), (IV), (V), (VII), (VIII), (IX) and (X) groups are present which need to be protected during the reactions reported above, e.g. amino, hydroxy, further carboxy groups, etc., such groups can be protected in a conventional way before the reaction takes place.
Examples of protecting groups are those usually employed in the synthesis of peptides, for example, to protect amino groups, acetyl, benzoyl, tert.butoxy-carbonyl, p-methoxy-benzyloxy-carbonyl, o-nitro-phenylsulphonyl, dichloroacetyl or tert.butyl-dimethylsilyl protective groups may be employed.
To protect hydroxy groups (a useful step e.g. when converting a compound of formula (VIII) into a compound of formula (IV) as reported above) acetyl, benzoyl or benzyloxy groups may be, for instance, employed. To protect the carboxy group, tert.butyl, benzhydryl and p-methoxy-benzyl groups may be employed. The protecting groups are then removed, at the end of the reaction, in a known manner, e.g.
by mild acid hydrolysis or by mild catalytic reduction, for example with Pd/C as catalyst at atmospheric pressure.
The compounds of the present invention possess an elevated lipid lowering and antiatherosclerotic activity. In particular the compounds of the invention are active in lowering cholesterol and triglycerides, in increasing the total serum HDL cholesterol, as well as in increasing the ratio between a-lipoprotein and ,B-lipoprotein total cholesterol. [As is known, drugs selectively increasing the HDL-cholesterol concentration in blood and/or the ratio between a and ss lipoprotein cholesterol are useful in prevention and therapy of atherosclerosis: Glueck C.J., Artery, 2,196(1976); Day C.E. in Frank-H-Clarke (Ed.) Annual Reports in Medicinal Chemistry, 13, 184, Chapter 20 Academic Press, N.Y. 1978].
The activity of the compounds of the invention was evaluated on groups of Icem: CER (SPF Caw) male rats either fed for six days with hypercholesterolaemic diet according to C.E. Day [Schurr P.E., Schultz H.R., Day C.E. (Eds.) Atherosclerosis and drug discovery - Plenum Pub. Corp., 217 (1976)] (Experiment No. 1) or fed standard diet [Altromin (Experiment No. 2). "Altromin" is a trade mark.] The compounds were suspended in "Methocel" (registered Trade Mark for methyl cellulose, a 0.5% suspension in water) and administered by stomach tube at the dose of 50 mg/kg for 4 days.
Groups of animals were treated with the suspending agent only (control groups).
The total serum cholesterol was determined with the method of Trinder P.J. [J. Clin. Pathol., 22, 246(1969)].
The serum triglycerides were determined with the method of Mendez J. [J. Clin. Chem., 21, 783, (1975)].
The total serum HDL Cholesterol was determined according to Demacker P.N.M. [Clin. Chem., 23, 1238(1977)].
The total ,B-lipoprotein cholesterol was determined by difference between total serum cholesterol and HDL cholesterol.
Statistical analysis in experiment No. 1 was performed by the Student's test for independent samples or by the Cochran's t test when the variances were not homogeneous at the F ratio test [Bliss C.I. -- Statistics in Biology, Vol. 1, page 213 - McGraw Hill Book Company, New York, 1967; Cochran W.G., Cox G.M. -- Experimental designs - J. Wiley 8 Sons Inc., New York, II ED. (1968) page 100].
For the experiment No. 2 the following statistical methods were applied: the variance analysis, Bartlett test [Properties of sufficiency and Statistical Tests -- Proc. of the Royal Soc. of London A 160 (1937) pages 268-282] to prove the variance homogeneity and the Dunnett test [Dunnett C.W. - J.
Amer. Stat. Ass., 50, 1096 (1955)]. Taking in account the ratio between a and ss lipoprotein cholesterol it was necessary to make the variances homogeneous by a transformation of the values ((.
In the animals treated with hypercholesterolaemic diet the tested compounds were found to decrease the total serum cholesterol, to increase the total serum HDL cholesterol and the ratio between a and p lipoprotein total cholesterol. The Table 1 reports the values of serum total cholesterol and total HDL cholesterol and ratio between a and ss lipoprotein total cholesterol from animals fed hypercholesterolaemic diet and treated with two compounds of the invention: 3-(1-imidazolyl)-2,3dihydro-6-chloro-4H-1 -benzopyran-4-one: compound A, and 3-(1 -imidazolyl)-2,3-dihydro-6-chloro- 4H-1-benzopyran-4-ol (trans isomer): compound B, in comparison with the values of the same variables in controls.
TABLE 1 (Experiment 1)
Total serum Serum HDL &alpha;/ss lipo cholesterol total cholesterol proteln Dose Animals mg/100 ml mg/100 ml cholesterol Treatment mg/kg/os number mean + S.E. Result mean + S.E. Result mean # S.E. Result Control * 10 386.1 # 39.6 17.8 # 1.1 0.0597 # 0.010 Compound A 50 10 133.2 # 10.1 *** 44.3 # 1.3 *** 0.548 # 0.052 *** Control * 5 447.8 # 14.3 19.0 # 0.8 0.0444 # 0.002 Compound B 50 5 184.4 # 19.7 *** 47.6 # 2.4 *** 0.3664 # 0.055 *** * "Methocel" (0.5 % in distilled water) : 5 ml/kg/os *** HS = highly significant (p < 0.01) In the animals fed standard '-Altromin' diet the tested compounds were found to decrease both the total serum cholesterol and the serum triglycerides and also to increase both the HDL cholesterol and the ratio between a and jB lipoprotein total cholesterol.
The Table 2 shows the values of total serum cholesterol, triglycerides, HDL cholesterol and of the ratio a and p lipoprotein total cholesterol in animals fed standard diet and treated with the same compounds cited in Table 1, in comparison with the values in control animals.
TABLE 2 (Experiment No. 2)
Total serum Serum Serum HDL &alpha;/ss lipo cholesterol trigiycerides total cholesterol proteln Dose Animals mg/100 ml mg/100 ml mg / 100 ml total cholesterol Treatment mg/kg/os number mean + S.E. Result mean + S.E. Result mean # S.E. Result mean # S.E. Result Control * 10 88.9 # 2.3 142.0 # 6.2 43.5 # 1.4 0.983 # 0.018 Compound A 50 10 73.4 # 3.0 *** 77.2 # 7.0 *** 52.3 # 2.5 *** 1.450 # 0.054 *** Compound B 50 10 72.4 # 2.3 *** 90.6 # 6.1 *** 50.3 # 1.7 *** 1.432 # 0.046 *** * "Methocel" 0.5 % in distilled water, 5 ml/kg/os ** S = significant (p < 0.05) *** HS = highly significant (p < 0.01) The compounds of the invention are also endowed with blood platelet-antiaggregating activity.
This activity was evaluated e.g. "in vitro" on the basis of the ability of the test compounds to inhibit the collagen-induced platelet aggregation in Guinea pig platelet rich plasma according to the method of Born [Born G.V.R. -- Nature, 1942, 927 (1962)j. The compounds of the invention were found to have a strong platelet aggregation inhibiting activity: for example, the compound 3-(1 -imidazolyl)-2,3-dihydro6-chloro-4H-1 -benzopyran-4-one. was found to inhibit wholly, at the final 25 mcg/ml concentration, the platelet aggregation induced by a 2 mcg/ml concentration of collagen.
In view of their elevated lipid lowering activity, of their action on HDL cholesterol and in view of their platelet antiaggregating activity, the compounds of the invention, in particular: 3-(1-imidazolyl)2,3-dihydro-6-chloro-4H-1 -benzopyran-4-one; 3-( 1 -imidazolyl)-2.3-dihydro-6-tert.butyl-7- 1-benzopyran-4-one and 3-( 1 -imidazolyl)-2,3-dihydro-6,8-dibromo-4H-1 -benzopyran-4-one, are useful in the treatment of dislipidaemies and of the atherosclerotic syndrome as well as in the prevention and treatment of syndromes caused by platelet aggregation disorders such as, for example, thrombosis.
The toxicity of the compounds of the invention was found to be quite negligibie and therefore the can be safely used in therapy. The evaluation of the toxicity (as orientative acute toxicity, i.e. LD50), was carried out, e.g., as follows: nine hours food deprived mice were treated orally with single administration of increasing doses, then housed and normally fed; the LD50 was assessed on the seventh day after the treatment.
For example, the LD50 of the compounds of the above Tables was about 800 mg/kg. Similar LD50 values have been found for the other compounds of the invention. The compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solution or suspensions, rectally, in the form of suppositories, parenterally, e.g.
intramuscularly, or by intravenous injection or infusion.
The dosage depends on the age, weight, conditions of the patient and administration route; for example the dosage adopted for oral administration to adult humans ranges from about 50 to about 200 mg pro dose, from 1 to 3 times daily, preferably from 50 to 100 mg pro dose 1-3 times a day.
The invention includes pharmaceutical compositions comprising a compound of the invention in association with a pharmaceutically acceptable excipient (which can be a carrier or diluent).
The pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form.
For example, the solid oral forms may contain, together with the active compound, diluents, e.g.
lactose, dextrose, saccharose, cellulose, corn starch and potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethyl cellulose, polyvinyl pyrrolidone, disaggregating agents, e.g. a starch, alginicacid, alginates, sodium starch glycolate; effervescing mixtures; dyestuffs; sweetners; wetting agents, such as, for instance, lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes.The liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions. The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol in particular a syrup to be administered to diabetic patients can contain as carriers only products not metabolizable to glucose, or metabolizable in very small amount to glucose, such as, for example sorbitol.
The suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
The suspensions or solutions for intramuscular injections may contain together with the active compound a pharmaceutically acceptable carrier, e.g. sterile isotonic water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride. The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.
The suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e.g. cocoa-butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
The l.R. spectrum of the compounds was measured in solid phase (KBr) or "Nujol" solution or in a solution of a suitable solvent such as CHCl3, using Perking-Elmer 1 25 spectrophotometer. The N.M.R.
spectrum was measured preferably in solution of dimethyl sulphoxide-d6 or of CDCl3, using a 90 M-hertz Bruker HFX apparatus. "Nujol" is a registered Trade Mark.
The Rf values were determined by thin layer chromatography on ready-to-use silica gel plates of 0.25-mm coating thickness. The following examples illustrate but do not limit the invention.
EXAMPLE 1 A solution of 3-bromo-7-methoxy-2,3-dihydro-4H-1 -benzopyran-4-one (79), imidazole (8g), and N,N-dimethylformamide (200 ml), was kept at 600C for 5 hours.
The solvent was evaporated under reduced pressure and the residue, taken up with CH2CI2 (100 ml), washed with H2O, was extracted with a solution of 8% HCI.
The acid solution, neutralized with NaHCO3, extracted with CH2CI2, dried and evaporated, gave 29 of 3-( 1 -imidazolyl)-2,3-dihydro-7-methoxy-4H- 1 -benzopyran-4-one.
m.p.= 151-1550C.
ELEMENTAL ANALYSIS: Found: C 62.99; H 4.87; N 11.28.
Calculated for C13H12N2O3 : C 63.93; H 4.95; N 11.47 T.L.C. = eluent CH2CI2 CH30H = 180:20 Rf = 0.33 N.M.R. (CDCl3) # p.p.m.
3.91 (3H s O-CH3)
By proceding analogously, the following compounds were prepared: 3-(1 -imidazolyl)-2,3-dihydro-7-isopropyloxy-4H-1 -benzopyran-4-one; m.p.=80-85 C ELEMENTAL ANALYSIS: Found: C 65.10; H 5.60; N 9.85 Calculated for C15H18N2O3 : C 66.16; H 5.92; N 10.28 T.L.C. = eluent CH2CI2: CH30H = 1809:20 Rf = 0.5 N.M.R. (CDCl3) # p.p.m.
1.38 (6H d CH3)
6.49-7.90 (6H m aromatics + imidazole) 3-(1 -imidazolyl)-2,3-dihydro-6-tert.butyl-7-hydroxy-4H-1 -benzopyran-4-one: m.p. = 243-2450C ELEMENTAL ANALYSIS: Found: C 66.88; H 6.21; N 9.52 Calculated for C16H18N203: C 67.11; H 6.33; N 9.78 T.L.C. = eluent CH2CI2: CH3OH =180:20 Rf = 0.4 N.M.R. (DMS0-d6) 8 p.p.m.
1.35 (9H s CH3)
3-(1-imidazolyl)-2,3-dihydro-6-tert. butyl-4H-1-benzopyran-4-one ; m.p.=99-100 C.
ELEMENTAL ANALYSIS: Found: C 70.58; H 6.64; N 10.26 Calculated for C16H10N2O3 : C 71.09 ; H 6.71 ; N 10.36 T.L.C. = eluent CHCI3: CH3OH = 180: 20 Rf = 0.31 N.M.R. (CDCl3) 8 p.p.m.
1.33 (9H s CH3)
3-( 1 -imidazolyl)-2,3-dihydro-7-tert. butyl-4H- 1 -benzopyran-4-one; ELEMENTAL ANALYSIS Found:C70.21;H6.61;N 10.28 Calculated for C16H,8N202: C 71.09; H 6.71; N 10.36 N.M.R. (CDCl3) # p.p.m.
1.33 (9H s CH3)
7.0-7.95 (6H m. aromatics+imidazole) 3-(1 -imidazolyl)-2,3-dihydro-6-hydroxy-7-tert.butyl-4H-1 -benzopyran-4-one; ELEMENTAL ANALYSIS Found: C 67.1; H 6.39; N 9.4 Calculated for C16H18N2O3 : H 6.33 ; N 9.78 I.R. (KBr) Stretching (O-H) : # 3440 cm- ; 3130 cm- Stretching (C-H) aliphatics: a 2960 cm-1; 2930 cm- Stretching (C=O): S 1670 cm- Stretching (C= O)+bending (O-H): S 1400 cm-1; 1240 cm- 3-( 1 -imidazolyl)-2,3-dihydro-4H-1 -benzopyran-4-one m.p; 1 56-1 580C (EtOH) Analysis of the elements: Found: C 67.21; H 4.73; N 12.94 Theoretical for C12H10N202:C 67.27; H 4.71-; N 13.08 T.L.C. eluent CHCl3 : MeOH = 170:30 Rf = 0.50 3-(1'-imidazolyl)-2,3-dihydro-6-methoxy-4H-1-benzopyran-4-one ; m.p. 1 50-1 520C (EtOH 70%); Analysis of the elements: found: C 63.69; H 4.95; N 11.27; theoretical for C13H12N203: C 63.9; H 4.95; N 11.47 T.L.C. Eluent: CHC1 3:MeOH= 1 80:20 R1=0.35 N.M.R.: (CDC13 # p.p.m.
3.85 (3H,s,-O-CH3) 4.7 (2H, m, -OCH2CH < ) 5.04 (1H, m, -O-CH2-CH < ) 6.9-7.6 (6H, m, aromatics+ imidazole) 3-(1-imidazolyl)-2,3-dihydro-6-phenoxy-4H-1-benzopyran-4-one ; 3-( 1 -imidazolyl)-2,3-di hydro-6-hydroxy-8-n-propyl-4H- 1 -benzopyran-4-one; 3-(1 -imidazolyl)-2,3-dihydro-5,7-diisopropyl-6-hydroxy-4H- 1 -benzopyran-4-one; 3-(1 -imidazolyl)-2,3-dihydro-5,7-dibromo-6-hydroxy-4H-1 -benzopyran-4-one; 3-(1 -imidazolyl)-2,3-dihydro-6,8-ditert. butyl-4H- 1 -benzopyran-4-one; 3-(1 -imidazolyl)-2,3-dihydro-5-hydroxy-6-ter.butyl-4H- 1 -benzopyran-4-one; 3-( 1 -imidazolyl)-2,3-dihydro-5-hydroxy-6-tert. butyl-8-isopropyl-4H-1 -benzopyran-4-one; 3-(1 -imidazolyl)-2,3-dihydro-6-amino-8-bromo-4H-1 -benzopyran-4-one; 3-( 1 -imidazolyl)-2,3-dihydro-6-dimethylamino-8-bromo-4H-1 -benzopyran-4-one; 3-81 -imidazolyl)-2,3-dihydro-6-chloro-7-hydroxy-4H-1 -benzopyran-4-one; 3-(1-imidazolyl)-2,3-dihydro-6-isopropyl-7-hydroxy-4H-1-benzopyran-4-one ; 3-(1-imidazolyl)-2,3-dihydro-6-tert. butyl-7-hydroxy-8-isopropyl-4H-1-benzopyran-4-one ; 3-(1-imidazolyl)-2,3-dihydro-6,8-diisopropyl-7-hydroxy-4H-1-benzopyran-4-one ; 3-( 1 -imidazolyl)-2,3-dihydro-6-hydroxy-8-chloro-4H-1 -benzopyran-4-one; 3-( 1 -i m idazo lyl)-2,3-d ihydro-6-hydroxy-8-i sopropyl-4H- 1 -benzopyran-4-one; 3-(1-imidazolyl)-2,3-dihydro-5.7-ditert. butyl-6-hydroxy-4H-1-benzopyran-4-one.
EXAMPLE 2 A solution of 2-hydroxy-5-chloro-a-( 1 -imidazolyl)-acetophenone (2.4 g), paraformaldehyde (0.3 g) and acetic acid (45 ml) was refluxed for 30 minutes. The solvent was removed under reduced pressure, ethanol was added and the impurity traces were filtered off. The solvent was evaporated and the residue crystallized from MeOH:H20 (75:25) affording 3-(1 -imidazolyl)-2,3-dihydro-6-chloro-4H- 1 -benzopyran-4-one (2 g), m.p. 123-1 250C.
Analysis of the elements: found: C 57.62; H 3.57; N 11.17 theoretical for C12H9N2O2Cl : C 58.0 ; H 3.6 ; N 11.2 T.L.C.: eluent CHCI3:MeOH: NH40H 32%=150:50:2 R1=0.63 N.M.R. (CDCI3) a p.p.m.
4.6-5.1 (2H, m, -0-CK2-CH < ) 5.84 (1H, m, -O-CH2CH < ) 6.92-7.84 (6H, m, aromatics+ imidazole).
Analogously, the following compounds were prepared: 3-(1 -imidazolyl)-2,3-dihydro-7-chloro-4H-1 -benzopyran-4-one; Analysis of the elements: Found: C 57.12; H 3.48; N 11.15 Theoretical for C12H9N202CL:C 58.0; H 3.6; N 11.2 N.M.R. (CDCI3) p.p.m.
4.61--5.2 (2H m -O-CH2-CH < ) 5.86 (1H m -0-CH2CH < ) 6.92-7.84 (6H m aromatics + imidazole) 3-(1 -imidazolyl)-2,3-dihydro-6-methyl-4H-1 -benzopyran-4-one; m.p. 105-107 C Analysis of the elements: Found: C 67.72; H 5.23; N 11.98 Theoretical for C13H12N202:C 68.2; H 5.26; N 12.25 I.R. (Nujol) Stretching (C=O) : # 1690 cm- 3-(1 -imidazolyl)-2,3-dihydro-6-trifluoromethyl-4H- 1 -benzopyran-4-one; 3-(1 -imidazolyl)-2,3-dihydro-6-phenyl-4H-1 -benzopyran-4-one; 3-(1 -imidazolyl)-2,3-dihydro-7-phenyl-4H- 1 -benzopyran-4-one; 3-(1 -i -imidazolyl)-2,3-dihydro-6,8-dichloro-4H 1 -benzopyran-4-one; 3-(1 -imidazolyl)-2,3-dihydro-5,7-dichloro-4H- 1 -benzopyran-4-one; 3-( 1 -imidazolyl)-2,3-dihydro-6-carboxy-8-n-propyl-4H- 1 -benzopyran-4-one; 3-(1-imidazolyl)-2,3-dihydro-6-carbamoyl-8-n-propyl-4H-1-benzopyran-4-oen ; 3-(1 -imidazolyl)-2,3-dihydro-6-carbamoyl-4H-1 -benzopyran-4-one; 3-(1-imidazolyl)-2,3-dihydro-6-carboxy-4H-1-benzopyran-4-one ; 3-(1 -imidazolyl)-2,3-dihydro-7-bromo-4H-1 -benzopyran-4-one; The 2-hydroxy-5-chloro-a-(1-imidazolyl)-acetophenone used above was prepared as follows: A solution of 2-hydroxy-5-chloro-&alpha;-bromo-acetophenone (7 g). imidazole (6 g) and N,Ndimethyl for mamide (50 ml), was heated to 40 C for 2 hours. The solution was poured into ice-water.
the solid was filtered off and taken up with NaOH. The basic solution, washed with CHCI3, neutralized with HCI, extracted with CHCl3, dried and evaporated to dryness gave 6 g of the above product, m.p. 201-203 C (Ethanol).
Analysis of the elements: found: C 54.96; H 3.68; N 11.60; Cl 14.97; theoretical for: C11HgClN2O2: C 55.82; H 3.83; N 11.84; Cl 14.98.
EXAMPLE 3 A solution of 2-hydroxy-a:-L1-(2-methyl)-imidazoly]-acetophenone (2 g) paraformaldehyde (0.27 g) and acetic acid ( 1 5 ml) was refluxed for 5 hours. The solvent was removed under reduced pressure, methanol was added and the impurity traces were filtered off. Evaporation of the solvent gave 3-[1 -(2-methyl)-imidzoly]-2,3-dihydro-4H-1 -benzopyran-4-one (1.8 g) m.p. 180-1820C Analysis of the elements: found: C 67.56; H 5.15; N 12.02; theoretical for C13H'2N202: C 68.40; H 5.30; N 12.27.
T.L.C.: eluent: Et2O:MeOH:NH4OH 32% =190:10:0.5 R1=0.4.
Analogously, the following compounds were prepared: 3-[1 -(2-methyl)-imidazolyl]-2,3-di hydro-6-methoxy-4H- 1 -benzopyran-4-one, m.p. 190-1920C; Analysis of the elements: found: C 64.8; H 5.40; N 10.25; theoretical for C14H14N203: C 65.1; H 5.46; N 10.84 T.L.C. : eluent : CHCl3 : MeOH=170:30 R1=0.61.
Analogously. the following compounds were prepared : 3-[1-(2,5-dimethyl)-imidazolyl]-2,3-dihydro-4H-1-benzopyran-4-one ; 3-[1 -2-methyl)-imidazolyl]-2,3-dihydro-6-chloro-4H-1 -benzopyran-4-one; 3-[1-(2,5-dimethyl)-imidazolyl]-2,3-dihydro-6-chloro-4H-1-benzopyran-4-one ; The 2-hydroxy-&alpha;[1-(2-methyl)-imidazolyl]-acetophone used above was prepared as follows: A solution of 2-hydroxy-(Z-bromoacetophenone (7.6 g), 2-methyl-imidazole (1 1.4 g) and N,Ndimethylformamide (60 ml) was heated to 400C for 10 hours. The solution was poured into ice-water.
The solid was filtered off and taken up with NaOH. The basic solution was washed with CHCl3, neutralized with HCI and extracted with CHCl3: The extract, dried and evaporated to dryness gave 6.5 g of the above product, m.p. 1 55-1 600C (ethanol) EXAMPLE 4 NaBH4 (1 g) was added portionwise to a solution of 3-(1-imidazolyl)-2,3-dihydro-6-chloro-4H-1benzopyran-4-one (2.7 g) in MeOH (70 ml) at 5-1 00C. The mixture, stirred at room temperature for 2 hours, added with water (300 ml), extracted with CHCI3, dried and evaporated to dryness gave 3-(1imidazolyl)-2,3-dihydro-6-chloro-4H-1 -benzopyran-4-ol (cis and trans mixture; 1.9 g).The separation of the isomers was made by column chromatography of silica gel, eluent used: CHCI3: MeOH:NH4OH 32% = 170:30:1 At first a fraction was obtained consisting of cis-3-( 1 -imidazolyl)-2,3-dihydro-6-chloro-4H-1- benzopyran-4-ol (0.8 g) (Rf = 0.44), m.p. 1 53-1 600C.
Analysis of the elelments: found: C 56.78; H 4.44; N 10.86; Cl 13:85; theoretical for C12H11N2O2Cl : C 57.48 ; H 4.42 ; N 11.17; Cl 14.14 N.M.R. (Pyridine) 3 p.p.m.
4.40-4.90 (3H, m, (0-CH2-CH-N < )
Then a second fraction was obtained consisting of trans-3-(1-imidazolyl)-2,3-dihydro-6-chloro- 4H-1-benzopyran-4-ol (1.1 g; Rf= 0.39), m.p. 60-650C.
Analysis of the elements: found: C 56.70; H 4.53; N 10.79; C11 13.66; theoretical for C12H11N2O2Cl : C 57.48; H 4.42; N 11.17; C11 14.14 N.M.R. (pyridine) # p.p.m.
Analogously, the following compounds were prepared: 3-(1 -imidazolyl)-2,3-dihydro-4H-1 -benzopyran-4-ol, m.p. 126-1280C Analysis of the elements: found: C 66.67; H 5.73; N 12.8 theoretical for C12H12Nz02: C 66.6; H 5.59; N 12.9 T.L.C.: eluent CHCl3 : MeOH:NH4OH 32% = 150:50:2 R1=0.64 N.M.R (CDCI3) s p.p.m.
6.50-7.50 (7H, m, aromatics + imidazole) 3-( 1-imidazolyl)-2,3-dihydro-6-methoxy-4H- 1 -benzopyran-4-ol m.p. 171-173 C (EtOH) : Analysis of the elements: found: C 63.34; H 5.77; N 11.22; theoretical for C13H14N303: C 63.3; H 5.73; N 11.37; T.L.C. eluent: CHCI3: MeOH: HCOOH 99% = 160:70:30 R1=0.26 N.M.R. (DMSO) # p.p.m.
3.72 (3H, s, O-CH3)
6.76-6.95 (3H, m, aromatics) 6.94-7.16-7.64 (3H, imidazole) 3-[1-(2-methyl)-imidazolyl]-2,3-dihydro-6-methoxy-4H-1-benzopyran-4-ol ; m.p. 208-210 C Analysis of the elements: found: C 64.29; H 6.22; N 10.55; theoretical for C14H16N203: C 64.60; N 6.19; N 10.76 T.L.C.: eluent: CHCI3: MeOH = 170:30 R1=0.25 N.M.R. (DMSO) a p.p.m.
3.98 (3H, s, O-CH3
6.08 (1H, s, -OH) 6.88-7.20 (5H, m, aromatics + imidazole)
3-[1-(2p-methyl)-imidazolyl]-2,3-dihydro-4H-1-benzopyran-4-ol, m.p. 1 700C (dec.) Analysis of the elements: found C 66.92; H 6.20; N 11.73; theoretical for C13H14N202: C 67.8; H 6.12; N 12.1 T.L.C.: eluent: CHCI3 MeOH = 170:30 R1=0.27 3-(1-imidazolyl)-2,3-dihydro-7-methoxy-4H-1-benzopyran-il ; ELEMENTAL ANALYSIS Found: C 63.34; H 5.77; N 11.22; Theoretical for C13H14N303 C 63.3; H 5.73 ; N 11.37.
N.M.R. (DMSO) z p.p.m.
3.73 (3H s, OCH3) 4.15-5.1 (4H, m, C1'2-CH-CH < ) 6.70-7.65 (6H, m, aromatics + imidazole) 3-(1-imidazolyl)-2,3-dihydro-6-tert. butyl-7-hydroxy-4H-1-benzopytan-4-ol ; 3-(1-imidazolyl)-2,3-dihydro-6-bromo-7-hydroxy-4H-1-benzopytan-4-ol ; 3-(1-imidazolyl)-2,3-dihydro-6-tert. butyl-4H-1-benzopytan-4-ol ; 3-(1 -imidazolyl)-2,3-dihydro-6,8-dibromo-7-hydroxy-4H-1 -benzopyran-4-ol; 3-(1 -imidazolyl)-2,3-dihydro-6-hydroxy-8-bromo-4H- 1 -benzopyran-4-ol; 3-(1-imidazolyl)-2,3-dihydro-6-bromo-4H-1-benzopytan-4-ol ; 3-( 1 -imidazolyl)-2,3-dihydro-6-phenyl-4H- 1 -benzopyran-4-ol; 3-(1-imidazolyl)-2,3-dihydro-7-chloro-4H-1-benzopytan-4-ol ; 3-(1 -i -imidazolyl)-2,3-dihydro-6,8-dichloro-4H- 1 -benzopyran-4-ol; 3-(1 -imidazolyl)-2,3-dihydro-6,8-dibromo-4H-1 -benzopyran-4-ol; EXAMPLE 5 A solution of CH3l (0. 66 g) in anhydrous tetrahydrofurane (1 5 ml) was added to metallic anhydrous magnesium. A small crystal of iodine was added to the mixture, which was stirred at room temperature for one hour and then cooled in a cold water bath.
A solution of 3-( 1 -imidazolyl)-2,3-dihydro-6-chloro-4H-1 -benzopyran-4-one (0.5 g) in anhydrous tetrahydrofurane (20 ml) was added to the reaction mixture, which was refluxed moderately for 30 minutes and then for 1 hour on a water bath. The mixture was cooled, poured into a mixture of crushed ice and water (100 ml) and extracted with CHCI3 (100 ml). The organic layer, dried on anhydrous Na2SO4 and evaporated to dryness under vacuum, afforded 3-(1 -imidazolyl)-2,3-dihydro-4-methyl-6chloro-benzopyran-4-ol (0.3 g); Analysis of the elements: Found: C 58.1; H 4.66; N 10.40; Cl 13.00 Theoretical for C13H13CIN202: C 59.0; H 4.91; N 10.59; Cli 13.38 N.M.R. a p.p.m.
1.4 (3H s CH3) 4.20-4.80 (3H m O-CH2-Ch7.00-8.10 (6H m aromatics + imidazole) EXAMPLE 6 Br2 (1.7 g) was added dropwise to a solution of 3-(1-imidazolyl)-2,3-dihydro-4H-1-benzopyranone (1 9) and AICI3 (3.5 9) in 40 ml of CH2CI2. The solution was refluxed for 4 hours. Then water was added giving after acidifcation with HCI and filtration, 3-(1 -imidazolyl)-2,3-dihydro-6,8-dibromo-4H- - benzopyran-4-one hydrochloride (1 g), m.p. 2800C (dec.) Analysis of the elements: found C 34.88; H 2.19; N 6.73; Br 38.30; CI 8.50 theoretical for CH12H8Br2N202 HCC: C 35.28; H 2.22; H 6.86; Br 39.12; CI 8.68 T.L.C.: eluent: CHCI3: MeOH = 170:30 R1=0.45 N.M.R. (CF3COOD) # p.p.m.
7.70 (2H, s large -H-CH=CH-N-)
9.15 (1H, slarge. -N-CH-N-)
1.R. (KBr) : v (NH) 3160-3140 cm- ; 2800-2740-2620 cm- ; v (C-H) arom. 3070-3020 cm- ; v (C=) 1750 cm- ;
v (C=C) 1585-1566-1540 cm- L' (C=N) v (C-H) 1,2,3,5-substituted benzene ring group v (C-Br) 645 cm-t Analogously, the following compounds were prepared: 3-(1 -imidazolyl)-2,3-dihydro-6-bromo-4H- 1 -benzopyran-one hydrochloride; m.p. 260-265 C (dec.) Analysis of the elements: found: C 43.51; H 2.91; N 8.21; Br 23.96; CI 10.67; theoretical for C12H9BrN202.HCI: C 43.73; H 3.06: N 8.50; Br 24.24; CI 10.75; T.L.C. eluent: CHCI3:
CH3OH (180:20) Rf = 0.39 N.M.R. (CF3COOD) # p.p.m.
I.R. (KBr): v (NHç) 3100-2600 cm-' v(C=O) 1705 cm-
v (C=C) 1595-1565-1470 cm- v (C=N) v (C-O) ether. 1270 cm- V (C-Br) 645 cm-.
3-( 1 -imidazolyl)-2,3-dihyd ro-6-tert.butyl-8-bromo-4H- 1 -benzopyran-4-one, hydrochloride; ELEMENTAL ANALYSIS Found: C 49.1; H 4.57; N 7.15; Br 21.00 Calculated for C16H17BrN202.HCI: C 49.81; H 4.67; N 7.26; Br 20.75 N.M.R. (DMSO-d6) S p.p.m.
1.33 (9H, s, CH3)
7.71-7.90 (4H, m, aromatics + imidazole) 9.30 (1 H, s, large, -N-CH=N-) 3-(1-imidazolyl)-2,3-dihydro-6-methyl-8-bromo-4H-1-benzopyran-4-one hydrochloride ; m.p.=270-2 C (dec).
ELEMENTAL ANALYSIS Found: C 46.1; H 3.60; N 8.06; Br 22.80; CI 10.23 Calculated for C13H11N202Br.HCI: C 45.44; H 3.52; N 8.1 5 Br 23.25; Cl 10.32 T.L.C. = eluent CH3CI: CH30H = 1 80:2q Rf =0.4 N.M.R. (DMSO) a p.p.m.
2.34 (s 3H CH3)
3-(1-imidazolyl)-2,3-dihydro-5,8-dibromo-6-hydroxy-4H-1-benzopyran-one hydrochloride ; 3-( 1 -imidazolyl)-2,3-dihydro-6-carbamoyl-8-bromo-4H- 1 -benzopyran-4-one hydrochloride; 3-( 1 -i midazolyl)-2,3-dihydro-6-carboxy-8-bromo-4H- 1 -benzopyran-4-one hydrochloride; 3-(1 -imidazolyl)-2,3-dihydro-6-tertbutyl-7-hydroxy-8-bromo-4H- 1 -benzopyran-4-one hydrochloride; 3-( 1 -imidazolyl)-2,3-dihydro-6-bromo-7-hydroxy-4H- 1 -benzopyran-4-one hydrochloride; 3-(1 -imidazolyl)-2,3-dihydro-6,8-dibromo-7-hydroxy-4H- 1 -benzopyran-4-one hydrochloride; 3-(1-imidazolyl)-2,3-dihydro-6-hydroxy-8-bromo-4H-1-benzopyran-one hydrochloride ; EXAMPLE 7 3-( 1 -imidazolyl)-2,3-dihydro-7-methoxy-4H- 1 -benzopyran-one (1 g) was refluxed with 48% hydrobromic acid (60 ml) for 7 hours.
The solution was cooled in ice.
The solid was filtered off, washed with ice-water and dried, giving 3-(1 -imidazolyl)-2,3-dihydro 7-hydroxy-4H-1 -benzopyran-4-one hydrobromide; m.p. = 318 C (dec) ELEMENTAL ANALYSIS Found: C 46.10; H 3.48; N 8.92 Calculated for C12HlON203.HBr = C 46.32; H 3.56; N 9.00 T.L.C. = eluent CH2CI2: CH30H = 180:20 Rf= 0.2 N.M.R. (DMSO-D6) a p.p.m.
By proceeding analogously the following compound was obtained: 3-(1-imidazolyl)-2,3-dihydro-6-hydroxy-4H-1-benzopyran-4-one hydrobromide ; EXAMPLE 8 3-(1 -imidazolyl)-2,3-dihydro-7-bromo-4H- l-benzopyran-4-one was treated with a stoichiometric amount of hydrogen chloride, to give 3-(1-imidazolyl)-2,3-dihydro-7-bromo-4H-1-benzopyran-4-one hydrochloride; ELEMENTAL ANALYSIS Found: C 43.45; H 3.00; N 8.35; Br 24.10 Calculated for C12H9BrN2O2.HCI: C 43.73; H 3.06; N 8.50; Br 24.24 N.M.R. (CF3COOD) a p.p.m.
7.10-9.08 (6H m aromatics + imidazole) By proceeding similarly the hydrochloride derivatives of all the compounds, obtained in Examples 1 and 2, were obtained.
EXAMPLE 9 3-( 1 -imidazolyl)-2,3-dihydro-6-hydroxy-4H-1 -benzopyran-4-one hydrobromide treated with the stoichiometric amount of NaHCO3, gave 3-( 1 -imidazolyl)-2,3-dihydro-6-hydroxy-4H-1 -benzopyran-4- one; m.p. = 245-7 C (CH30H) Found: C 61.2; H 4.22; N 11.7; Calculated for C12HloN2o3 C 62.6; H 4.38; N 12.1.
By proceeding analogously the following compounds were obtained: 3-(1 -imidazolyl)-2,3-di hydro-6,8-dibromo-7-hydroxy-4H- 1 -benzopyran-one; ELEMENTAL ANALYSIS Found: C 36.6; H 2.10; N 7.8; Br 40.29 Calculated for C12H8Br2N203: C 37.14; H 2.07; N 7.21; Br 41.18 N.M.R. # p.p.m.
5.00 (2H m O-CU2-CH-) 5.95 (1H m O-CH2-CU-) 6.70-7.8 (4H m aromatic + imidazole) 3-(1-imidazolyl)-2,3-dihydro-6-hydroxy-8-bromo-4H-1-benzopyran-4-one ; ELEMENTAL ANALYSIS Found: C 46.12; H 2.85; N 8.95; Br 25.75 Calculated for Cl2HgN203Br: C 46.62; H 2.93; N 9.06; Br 25.85 N.M.R. ö p.p.m.
4.6-5.2 (2H m 0-CU2-CH-) 5.95 (1 H m O-CH2-CU) 6.80-7.85 (5H m aromatic + imidazole) 3-(1-imidazolyl)-2,3-dihydro-6,8-dibromo-4H-1-benzopyran-4-one ; 3-(1 -imidazolyl)-2,3-dihydro-6-bromo-4H-1 -benzopyran-4-one; 3-(1 -imidazolyl)-2,3-dihydro-6-tert. butyl-8-bromo-4H- 1 -benzopyran-4-one; 3-(1 -imidazolyl)-2,3-dihydro-6-methyl-8-bromo-4H-1 -benzopyran-4-one; 3-(1 -imidazolyl)-2,3-dihydro-5,8-dibromo-6-hydroxy-4H- 1 -benzopyran-4-one; 3-( 1 -imidazolyl)-2,3-dihydro-6-ca rba moyl-8-bromo-4H- 1 -benzopyra n-4-one; 3-(1 -imidazolyl)-2,3-dihydro-6-carboxy-8-bromo-4H- 1 -benzopyran-4-one; 3-(1-imidazolyl)-2,3-dihydro-6-tert. butyl-7-hydroxy-8-bromo-4H-1-benzopyran-4-one ;; 3-( 1 -imidazolyl)-2,3-dihydro-7-hydroxy-4H-1 -benzopyran-4-one; 3-(1-imidazolyl)-2,3-dihydro-7-hydroxy-4H-1-benzopyran-4-one.
FORMULATION EXAMPLES Formulation 1: Tablet Tablets, each weighing 300 mg and containing 100 mg of the active substance are manufactured as follows: Composition (for 10,000 tablets) 3-(1 -imidazolyl)-2,3-dihydro-6-tert.butyl 7-hydroxy-4H-1 -benzopyran-4-one 1000 g Lactose 1420 g Corn starch 474 g Talc powder 75 g Magnesium stearate 30 g 3-(1-imidazolyl)-2,3-dihydro-6-tert. butyl-7-hydroxy-4H-1 -benzopyran-4-one, lactose, and a half of the corn starch are mixed; the mixture is then forced through a sieve of 0.5 mm openings. Corn starch (18 g) is suspended in warm water (180 ml). The resulting paste is used to granulate the powder. The granules are dried, comminuted on a sieve of sieve size 1.4 mm, then the remaining quantity of starch, talc and magnesium stearate is added, carefully mixed, and processed into tablets using punches of 10 mm diameter.
Formulation 2: intramuscular injection An injectable pharmaceutical composition was manufactured by dissolving 50-100 mgof3-(1- imidazolyl)-2,3-dihydro-6-tert.butyl-7-hydroxy-4H-1 -benzopyran-4-one hydrochloride in sterile water or sterile aqueous normal saline solution (1-2 ml).
Formulation 3: Capsule with the usual methods of pharmaceutical technique, preparation was made of capsules having the following composition: 3-(1 -imidazolyl)-2,3-dihydro-6-tert.butyl 7-hydroxy-4H-1 -benzopyran-4-one 50 mg Lactose 298 mg Corn Starch 50 mg Magnesium stearate 2 mg Formulation 4: Suppository with the usual methods of pharmaceutical technique, preparation was made of suppositories having the following composition: 3-(1 -imidazolyl)-2,3-dihydro-6-tert.butyl 7-hydroxy-4H- 1 -benzopyran-4-one 0.05 g Lecithin 0.07 g Cacao butter 0.88g Formulation 5: Capsule with the usual methods of pharmaceutical technique, preparation was made of capsules having the following composition: 3-(1 -imidazolyl)-2,3-dihydro-6 chloro-4H- 1 -benzopyran-4-one 50 mg Lactose 298 mg Corn starch 50 mg Magnesium stearate 2 mg Formulation 6: Suppository with the usual methods of pharmaceutical technique, preparation was made of suppositories having the following composition: 3-(1 -imidazolyl)-2,3-dihydro-6,8 dibromo-4-H-l -benzopyran-4-one 0.05 g Lecithin 0.07 g Cacao butter 0.88 g

Claims (84)

1. Compounds having the general formula (I)
wherein R is C1-C6 alkyl; n is 0, 1, 2 or 3 one of R1 and R2 is hydroxy and the other is hydrogen or C1-C6, or R1 and R2, taken together, form an oxo group ; each of X1, X2, X3 and X4, which way be the same or different, is hydrogen ; halogen ; hydroxy ; -NO2 -CN; C1-C6 alkyl; C1-C6 alkoxy; trihalo-C1-C6 alkyl; -SR' or -COOR', R' being hydrogen or 1-C6 alkyl ;
each of R" and R", which may be the same or different, being hydrogen or C2-C5 alkyl; or one of X1, X2,X3, and X4 is phenyl, phenylthio, phenoxy or benzyl, the phenyl, phenylthio, phenoxy and benzyl groups being unsubstituted or substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, or -SR', wherein R' is as defined above, and the others are as defined above; or any two adjacent X1, X2, X3, and X4 groups, taken together, complete a saturated or unsaturated 6-membered carbocylic ring fused to the benzene ring shown in formula (I) the carboxyclic ring being unsubstituted or substituted by one or more groups selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or -SR', wherein R' is as defined above, and any groups X1 to X4 not participating in the completion of such a fused ring are as defined above, and the pharmaceutically acceptable salts thereof.
2. A compound according to claim 1 having formula (I) wherein n is zero, one of R1 and R2 is hydrogen and the other is hydroxy or R, and R2, taken together, form an oxo group, and wherein X1, X2, X3, and X4 are, independently, hydrogen, halogen, hydroxy, carboxy, trifluoromethyl, C1-C4 alkylthio, C1-C4 alkyl, C1-C4 alkoxy, carbamoyl or
wherein R" and R"' are as defined in claim 1, or one of X1, X2, X3, and X4 is phenyl, phenylthio, phenoxy or benzyl, the phenyl, phenylthio, phenoxy and benzyl groups being unsubstituted or substituted by halogen, C1-C4 alkyl, C1-C4 alkylthio or C1-C4 alkoxy, and the others are independently, hydrogen, halogen, C1-C4 alkyl, C1-C4 alkylthio or C1-C4 alkoxy, as well as the pharmaceutically acceptable salts thereof.
3. A compound according to claim 1 having the formula (I) wherein n is zero, one of R2 and R2 is hydroxy and the other is hydrogen, or R, and R2, taken together, form an oxo group and wherein X1, X2, X3, and X4 are, independently hydrogen, halogen, trifuoromethyl, C1-C4 alkylthio, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, carboxy, carbamoyl or
where R" and R"' are as defined in claim 1 and the pharmaceutically acceptable salts thereof.
4. 3-(1 -imidazolyl)-2,3-dihydro-4H-l -benzopyran-4-one;
5. 3-( 1 -imidazolyl)-2,3-dihydro-6-methyl-4H- t -benzopyran-4-one;
6.3-(1-imidazolyl)-2,3-dihydro-6-chloro-4H-1-benzopyran-4-one ;
7.3-(1-imidazolyl)-2,3-dihydro-6-bromo-4H-1-benzopyran-4-one ;
8.3-(1-imidazolyl)-2,3-dihydro-6-trifluoromethyl-4H-1-benzopyran-4-one ;
9.3-(1-imidazolyl)-2,3-dihydro-6-methoxy-4H-1-benzopyran-4-one ;
10.3-(1-imidazolyl)-2,3-dihydro-6-phenyl-4H-1-benzopyran-4-one ;
11.3-(1-imidazolyl)-2,3-dihydro-6-phenoxy-4H-1-benzopyran-4-one ;
12.3-(1-imidazolyl)-2,3-dihydro-6-chloro-4H-1-benzopyran-4-one ;
13.3-(1-imidazolyl)-2,3-dihydro-6-phenyl-4H-1-benzopyran-4-one ;
14.3-(1-imidazolyl)-2,3-dihydro-6,8-dichloro-4H-1-benzopyran-4-one ;
15. 3-(1 -imidazolyl)-2,3-dihydro-6,8-dibromo-4H-1 -benzopyran-4-one;;
1 6. 3-( 1 -imidazolyl)-2,3-dihyd ro-5,7-di chloro-4H- 1 -benzopyran-4-one;
1 7. 3-( 1 -imidazolyl)-2,3-dihydro-7-methoxy-4H- 1 -benzopyran-4-one.
1 8. 3-(1 -imidazolyl)-2,3dihydrn-6-hydroxy-8-n-propyl-4H-1 -benzopyran-4-one.
19.3-(1-imidazolyl)-2,3-dihydro-7-isopropyloxy-4H-1-benzopyran-4-one.
20.3-(1-imidazolyl)-2,3-dihydro-5,7-diisopropyl-6-hydroxy-4H-1-benzopyran-4-one.
21.3-(1 -imidazolyl)-2,3-dihydro-7-hydroxy-4H-1 -benzopyran-4-one.
22. 3-( 1 -imidazolyl)-2,3-dihydro-6-bromo-7-hydroxy-4H-1 -benzopyran-4-one.
23. 3-( 1 -imidazolyl)-2,3-dihydro-6,8-dibromo-7-hydroxy-4H-1 -benzopyran-4-one.
24. 3-( 1 -i midazolyl)-2,3-dihydro-6-ch loro-7-hydroxy-4H- 1 -benzopyran-4-one.
25.3-(1-imidazolyl)-2,3-dihydro-6-tert. butyl-7-hydroxy-4H-1-benzopyran-4-one.
26.3-(1-imidazolyí)-2,3-dihydro-6-;sopropyl-7-hydroxy-4H-1-benzopyran-4-one.
27.3-(1-imidazolyl)-2,3-dihydro-6-tert. btuyl-7-hydroxy-8-isopropyl-4H-1-benzopyran-4-one.
28. 3-( 1 -imidazolyl)-2,3-dihydro-6,8-diisopropyl-7-hydroxy-4H-1 -benzopyran-4-one.
29.3-(1-imidazolyl)-2,3-dihydro-7-bromo-4H-1-benzopyran-4-one.
30.3-(1-imidazolyl)-2,3-dihydro-5,7-dibromo-6-hydroxy-4H-1-benzopyran-4-one.
31.3-(1-imidazolyl)-2,3-dihydro-6-hydroxy-4H-1-benzopyran-4-one.
32. 3-( 1 -imidazolyl)-2,3-dihydro-6-hydroxy-8-bromo-4H- 1 -benzopyran-4-one.
33.3-(1-imidazolyl)-2,3-dihydro-6-hydroxy-8-chloro-4H-1-benzopyran-4-one.
34.3-(1-imidazolyl)-2,3-dihydro-6-hydroxy-8-isopropyl-4H-1-benzopyran-4-one.
35. 3-( 1 -imidazolyl)-2,3-dihydro- 5,8-dibromo-6-hydroxy-4H- 1 -benzopyran-4-one.
36.3-(1-imidazolyl)-2,3-dihydro-5,7-ditert. butyl-6-hydroxy-4H-1-benzopyran-4-one.
37.3-(1-imidazolyl)-2,3-dihydro-5-hydroxy-6-tert. butyl-4H-1-benzopyran-4-one.
38. 3-( 1 -i midazolyl )-2,3-dihyd ro-5-hydroxy-6-tert.butyl-8-isopropyl-4H- 1 -benzopyran-4-one.
39. 3-( 1 -imidazolyl)-2,3-dihydro-6-methyl-8-bromo-4H-1 -benzopyran-4-one.
40.3-(1-imidazolyl)-2,3-dihydro-6-tert. butyl-7-hydroxy-8-bromo-4H-1-benzopyran-4-one.
41. 3-( 1 -imidazolyl)-2,3-dihydro-6-a mino-8-bro mo-4H- 1 -benzopyran-4-one.
42.3-(1-imidazolyl)-2,3-dihydro-6-dimethylamino-8-bromo-4H-1-benzopyran-4-one.
43. 3-( 1 -imidazolyl)-2,3-dihydro-6-tert.butyl-4H- 1 -benzopyran-4-one.
44. 3-( 1 -imidazolyl)-2,3-dihydro-6-carbamoyl-4H-1 -benzopyran-4-one.
45. 3-( 1 -imidazolyl)-2,3-dihydro-6-carboxy-4H- 1 -benzopyran-4-one.
46.3-(1-imidazolyl)-2,3-dihydro-6-carbamoyl-8-bromo-4H-1-benzopyran-4-one.
47.3-(1-imidazolyl)-2,3-dihydro-6-carboxy-8-bromo-4H-1-benzopyran-4-one.
48.3-(1-imidazolyl)-2,3-dihydro-6-carboxy-8-n-propyl-4H-1-benzopyran-4-one.
49. 3-( 1 -imidazolyl)-2,3-dihydro-6-carbamoyl-8-n-propyl-4H-1 -benzopyran-4-one.
50.3-(1-imidazolyl)-2,3-dihydro-6-tert. butyl-4H-1-benzopyran-4-one.
51.3-(1 -imidazolyl)-2,3-dihydro-6,8-ditert.butyl-4H- 1 -benzopyran-4-one.
52.3-(1-imidazolyl)-2,3-dihydro-6-hydroxy-7-tert. butyl-4H-1-benzopyran-4-one ;
53. 3-( 1 -imidazolyl)-2.3-dihydro-6-tert.butyl-8-bromo-4H- 1 -benzopyran-4-one.
54. A Dharmaceuticaliy acceptable salt of each of the compounds of claims 4 to 53.
55. A pharmaceutically acceptable salt of each of the compounds of claims 4 to 53, wherein said salt is the hydrochloride.
56. A pharmaceutically acceptable salt of each of the compounds of claims 4 to 53, wherein said salt is the hydrobromide.
57.3-(1-imidazolyl)-2,3-dihydro-6,8-dichloro-4H-1-benzopyran-4-ol ;
58.3-(1-imidazolyl)-2,3-dihydro-6,8-dibromo-4H-1-benzopyran-4-ol.
59. 3-( 1 -imidazolyl)-2,3-dihydro-6-tert.butyl-7-hydroxy-4H-1 -benzopyran-4-ol.
60. 3-( 1 -imidazolyl)-2,3-dihydro-6-bromo-7-hydroxy-4H-1 -benzopyran-4-ol.
61.3-(1 -i midazolyl)-2,3-dihydro-6-tert.butyl-4H-1 -benzopyran-4-ol.
62.3-(1-imidazolyl)-2,3-dihydro-6,8-dibromo-7-hydroxy-4H-1-benzopyran-4-ol.
63. 3-( 1 -imidazolyl)-2.3-dihydro-6-hydroxy-8-bromo-4H-1 -benzopyran-4-ol.
64. 3-(1 -imidazolyl)-2.3-dihydro-7-methoxy-4H-l -benzopyran4-ol.
65. 3-(1 -imidazolyl)-2,3-dihydro-4H-l -benzopyran-4-ol;
66. 3-( 1 -imidazolyl)-2,3-dihydro-6-chloro-4H-1 -benzopyran-4-ol;
67. 3-( 1-i midazolyl)-2,3-dihydro-6-bromo-4H- 1 -benzopyran-4-ol;
68. 3-(1 -imidazolyl)-2,3-dihydro-6-methoxy-4H-1 -benzopyran-4-ol;
69. 3-( 1 -imidazolyl)-2,3-dihydro-6-phenyl-4H-1 -benzopyran-4-ol;
70. 3-(1 -imidazolyl)-2,3-dihydro-7-chloro-4H-l -benzopyran-4-ol;
71. A compound according to any one of claim 57 to 70, where the compound is a cis or a trans isomer or a mixture thereof.
72. A pharmaceutically acceptable salt of each of the compounds of claims 57 to 71.
73. A process for the preparation of compounds as claimed in claim 1, in which R and R2 together represent an oxo group, comprising: a) reacting a compound of formula (II)
wherein X1,X2,X3, and X4 are as defined inc claim I and X5 is halogen or a reactive ester group, with a compound of formula (Ill)
wherein R and n are as defined in claim I, or a salt thereof, thus giving a compound of formula (I) wherein R1 and R2, taken together, form an oxo group and R, n, X1, X2, X3, and X4 are as defined in claim I, or b) reacting a compound of formula (IV)
wherein X1,X2, X3, and X4, R and n are as defined in claim 1, with formaldehyde or a reactive derivative thereof, thus giving a compound of formula (I) wherein R1 and R2, taken together, form an oxo group and R, n, X1, X2, X3 and X4 are as defined in claim I, and, if desired, converting a compound of formula (I) thus obtained into another compound of formula (I), and/or removing the protective groups, and/or, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof and/or, if desired, converting a salt into a free compound and/or, if desired, separating a mixture of isomers of formula (I) into the single isomers.
74. A process for the preparation of a compound claimed in claim 1 in which one of R1 and R2 is hydroxy and the other is hydrogen, the process comprising reducing a compound of formula (I) in which R1a nd R2 together represent an oxo group, and, if desired, converting a compound of formula (I) thus obtained into another compound of formula (I) and/or removing the protective groups and/or, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof and/or, if desired, converting a salt into a free compound and/or, if desired, separating a mixture of isomers of formula (I) into the single isomers.
75. A process for the preparation of a compound claimed in claim 1 in which one of R1 and R2 is hydroxy and the other is C1-C6 alkyl, the process comprising reacting a compound of formula (I) wherein R1 and R2 together represent an oxo group with a compound of formula (VI) R3-Z (VI) wherein Z is Li or the group -MgX, in which X is halogen, and R3is C1-C8 alkyl, thus giving a compound of formula (I) wherein one of R, and R2 is hydroxy and the other is C1-C6alkylandR, n, X,, X2, X3, and X4 are as defined in claim 1, and, if desired, converting a compound of formula (I) thus obtained into another compound of formula (I) and/or removing the protective groups and/or, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof and/or, if desired, converting a salt into a free compound and/or, if desired, separating a mixture of isomers of formula (I) into the single isomers.
76. A process according to claim 73 substantially as described in Example 1 or Example 1 and 6 or Example 1 and 7.
77. A process according to claim 73 substantially as described in Example 2 or 3.
78. A process according to claim 74 substantially as described in Example 4.
79. A process according to claim 75 substantially as described in Example 5.
80. Compounds according to claim 1 when prepared by a process claimed in any one of claims 73 to 79.
81. A pharmaceutical composition containing a compound or a salt thereof according to any one of claims 1 to 72 or claim 80 and a pharmaceutically acceptable carrier and/or or diluent.
82. A composition according to claim 81, substantaially as described in Formulation Examples 1 to 6.
83. Compounds or salts thereof according to any one of claims 1 to 72 or a composition according to claim 81 or 82 for use in a method of therapy on the human body.
84. A compound or a salt thereof or a composition according to claim 83 for use in administration to human patients to inhibit blood platelet aggregation, increase HDL-cholesterol concentration in blood and/or the ratio between a- and s-liporoptein chloesterol, or reduce cholesterol or triglyceride level in the blood.
GB8106495A 1980-03-04 1981-03-02 N-amidazolyl derivatives of1-chroman and process for their preparation Expired GB2071655B (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3324069A1 (en) * 1982-07-05 1984-01-26 Farmitalia Carlo Erba S.p.A., 20159 Milano N-IMIDAZOLYL DERIVATIVES OF BICYCLIC COMPOUNDS, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THEM
US4492707A (en) * 1981-07-23 1985-01-08 Farmitalia Carlo Erba S.P.A. N-Imidazolyl derivatives of 1,2,3,4-tetrahydro-naphthalene and indan
EP0363789A1 (en) * 1988-10-06 1990-04-18 FARMITALIA CARLO ERBA S.r.l. N-imidazolyl-and N-imidazolyl-methyl derivatives or substituted bicyclic compounds
EP0499444A1 (en) * 1991-02-11 1992-08-19 PHARMACIA S.p.A. N-imidazolyl derivatives of substituted alkoxyimino tetrahydronaphthalenes and chromans
US6503935B1 (en) 1998-08-07 2003-01-07 Abbott Laboratories Imidazoles and related compounds as α1A agonists

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4492707A (en) * 1981-07-23 1985-01-08 Farmitalia Carlo Erba S.P.A. N-Imidazolyl derivatives of 1,2,3,4-tetrahydro-naphthalene and indan
DE3324069A1 (en) * 1982-07-05 1984-01-26 Farmitalia Carlo Erba S.p.A., 20159 Milano N-IMIDAZOLYL DERIVATIVES OF BICYCLIC COMPOUNDS, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THEM
DE3324069C2 (en) * 1982-07-05 1994-08-25 Erba Carlo Spa N-imidazolyl derivatives of bicyclic compounds, processes for their preparation and pharmaceutical compositions containing them
EP0363789A1 (en) * 1988-10-06 1990-04-18 FARMITALIA CARLO ERBA S.r.l. N-imidazolyl-and N-imidazolyl-methyl derivatives or substituted bicyclic compounds
WO1990003970A1 (en) * 1988-10-06 1990-04-19 Farmitalia Carlo Erba S.R.L. N-imidazolyl- and n-imidazolylmethyl-derivatives of substituted bicyclic compounds
US5204364A (en) * 1988-10-06 1993-04-20 Farmitalia Carlo Erba, S.R.L. N-imidazolyl- and n-imidazolylmethyl-derivatives of substituted bicyclic compounds
EP0499444A1 (en) * 1991-02-11 1992-08-19 PHARMACIA S.p.A. N-imidazolyl derivatives of substituted alkoxyimino tetrahydronaphthalenes and chromans
US5246956A (en) * 1991-02-11 1993-09-21 Farmitalia Carlo Erba S.R.L. N-imidazolyl derivatives of substituted alkoxyimino tetrahydronaphthalenes and chromans having antithromboxane a2 activity
US6503935B1 (en) 1998-08-07 2003-01-07 Abbott Laboratories Imidazoles and related compounds as α1A agonists

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