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IE51685B1 - 6-substituted 6h-dibenzo(b,d)pyran derivatives and process for their preparation - Google Patents

6-substituted 6h-dibenzo(b,d)pyran derivatives and process for their preparation

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Publication number
IE51685B1
IE51685B1 IE2456/81A IE245681A IE51685B1 IE 51685 B1 IE51685 B1 IE 51685B1 IE 2456/81 A IE2456/81 A IE 2456/81A IE 245681 A IE245681 A IE 245681A IE 51685 B1 IE51685 B1 IE 51685B1
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Prior art keywords
pyran
dibenzo
benzo
methyl
hydroxy
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IE2456/81A
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IE812456L (en
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Melloni Piero
Salvadori Paolo
Paolo Lovisolo Pier
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Erba Farmitalia
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Publication of IE812456L publication Critical patent/IE812456L/en
Publication of IE51685B1 publication Critical patent/IE51685B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

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Description

The present invention relates to new 6-substituted 6H-dibenzo 2b,d/pyran derivatives, to a process for their preparation and pharmaceutical and veterinary compositions containing them. The compounds of this invention have the general formula (I) wherein R represents a) cyano; b) a carboxy or esterified carboxy group; c) -N^^a , wherein each of R and R , being the a same or different, is hydrogen or unsubstituted C -C alkyl, o or R and R , taken together with the nitrogen atom to which a b they are linked, form a heterocyclic ring, optionally containing a further heteroatom chosen from oxygen, sulphur and nitrogen, and optionally substituted by C -C, alkyl or 1 6 -zR phenyl; d) -CON:^ c, wherein each of R and R , being the H R cd d. same or different, is hydrogen or C -C alkyl unsubstituted R 16 or substituted by -Ntf” a, wherein R and R are as defined a b above, or R and R , taken together with the nitrogen atom c d to which they are linked, form a heterocyclic ring, optionally containing a further heteroatom chosen from oxygen, nitrogen 2C and sulphur, and optionally substituted by C ,-C alkyl or 6 phenyl; e) a saturated or unsaturated 5- or 6- membered heterocyclic ring, bound to the alkyl group or to the benzopyrane system through a carbon-carbon linkage, and containing at least a nitrogen atom and, optionally, a further heteroatom chosen from oxygen, sulphur and nitrogen, phen which ring is unsubstituted or optionally substituted by C -C alkyl or / 15 Ft is hydrogen; hydroxy or amino; n is zero, 1, 2 or 3; R represents hydrogen; C.-C alkyl optionally substituted by 2 16 hydroxy or by a -OCO-C -C, alkyl group; or an optionally 1 O substituted phenyl group; each of R , R , R_ , R=, R„ and R„, which may be the same or 3 4 5 6 7 8 different,is selected from a”) hydrogen; halogen; halo-C -C. o alkyl; or C -C, alkyl optionally substituted by amino; b) amino; nitro; or -NHCONJ^” a, wherein R and R are as a b defined above; c) -OR., wherein R is hydrogen, C -C alkyl 9 9 16 or C —C alkenyl; and the pharmaceutically or veterinarily 2 6 acceptable salts thereof.
The invention also includes within its scope all the possible isomers, stereoisomers and optical isomers and their mixtures, and the metabolites and the metabolic precursors or bioprecursors of the compounds of formula (I).
The alkyl and alkenyl groups may be branched or straight chain groups.
A halogen atom is preferably fluorine, chlorine or bromine. •k A C —C alkyl group is preferably methyl, ethyl, propyl, 6 isopropyl, butyl, sec-butyl or tert-butyl, preferably methyl or ethyl.
A halo-C -C alkyl group is preferably a trihalo-C-C -alkyl 16 16 group, preferably trifluoromethyl.
A C-C alkenyl group is preferably vinyl or allyl, preferably 2 6 allyl.
When R and R and. or R and R , taken together with the a b cd nitrogen atom to which they are linked, form a heterocyclic ring, this may be for example an unsaturated, 5- or 6-membered hetero monocyclic ring, e.g. pyrrole, pyrazole, imidazole, dihydro pyridine, dihydropyrazine, 1,4-oxazine or 1,4-thiazine or a saturated, 5- or 6-membered heteromonocyclic ring, e.g. pyrro lidine, piperidine, piperazine, morpholine or thiomorpholine.
When n is other than zero, the group -(CH)- may be for example R Π a group chosen from -CH,-, -ψΗ-, -CH -fH-, -CH„-CH„-CH„-, -CH -CH-CH 2 I -ch2-,h -ch2-ch2-, -ch2-ch2-ch-; OH -CH-, -CH -CHOH . 2 OH preferably it is '”2 2 chosen from -CH -CH-CH -, -CH-CH . 2 2 1 2 OH When R is an esterified carboxy group it is preferably the group -COOR^q, wherein R^ is n _r wherein R. hydrogen, methyl or ethyl; is { N -R wnereln R is \_! ii 11 or R,n is C-C. alkyl 10 R1 6 optionally substituted by (a' ) -N^ a, wherein are as defined above, (b') R and R, a b (c’ -OC or (d' ) -NHCO—· 51685» When represents a substituted phenyl group, the phenyl ring may be substituted preferably by one or more fluorine, chlorine, hydroxy and methoxy.
The pharmaceutically and veterinarily acceptable salts of the compounds of formula (I) include those formed with an inorganic acid, e.g. hydrochloric acid or sulphuric acid, or with an organic acid, e.g. citric, tartaric , malic, maleic, mandelic, fumaric or methanesulphonic acid, or with an inorganic base e.g. sodium, potassium, calcium or aluminium hydroxide or an alkali metal or alkaline earth metal carbonate or bicarbonate, or with an organic base, typically an organic amine, e.g. lysine, triethylamine, procaine, dibenzylamine, N-benzyl-βphenethylamine, Ν,N'-dibenzyl-ethylenediamine, dehydroabietyl amine, N-ethyl-piperidine, diethanolamine, N-methyl-glucamine, or tris-hydroxymethyl-aminomethane .
Preferred compounds of the invention are compounds of formula (I) wherein: R is hydrogen, hydroxy or amino; R is a free carboxy group or an esterified carboxy group of formula -COOR'wherein R'1Ois (aIV) ci~c4 alkyl, unsubstituted or substituted by a group wherein R and R, are as defined above, or by a group -(0C0) -Py, a b Λ wherein X is zero or 1 and Py represents a pyridyl group, XV or (b ) an unsubstituted or methyl- or ethyl- substituted -xR pyperidyl group; or R^ is -N^^a, wherein R^ and are as -r b defined above, or -CONC c, wherein R and R, are as defined ^Rd C 13 above; Rr is hydrogen, methyl, hydroxymethyl or unsubstituted phenyl; each of R^ , R^ and R^ is, independently, hydrogen, chlorine, fluorine, trifluoromethyl, C^-C alkyl, nitro, amino or a group -0 R' wherein R'^ is hydrogen or C^-C^ alkyl; each of R , R and R is, independently, hydrogen, halogen, 7 8 R nitro, amino; -NHCON^'’ a, wherein R and R, are as defined ^Rb a b above; or a group -0 R'^, wherein R’^ is as defined above; n is zero, 1 or 2; and the pharmaceutically or veterinarily acceptable salts thereof.
Particularly preferred compounds of the invention are the compounds of formula (X) wherein: R is hydrogen , hydroxy or amino R^ is -COOH, -C00C9H5> -COOCH (CH3 ) % , -COO-^ \l-CH3 , -CON^ c, wherein d R and R are as defined above; cd R -COO(CH } -N< a or -Nil a, wherein p is 2 or 3 and R and 2 n ^R ^R, a ,. b , b R are as aerined above; b is hydrogen, -CH^, -CH^OH or unsubstituted phenyl; each of R , R and R is, independently, hydrogen, chlorine, 4 5 fluorine, methyl, hydroxy, c1_c4 alkoxy, amino or nitro; each of R , R and R is, independently, fluorine, chlorine, 7 8 bromine, hydrogen, hydroxy, alkoxy, nitro, amino or -NHCON<^ a , wherein R and R, are as defined above; Χ4Ϊ a b b n is zero, 1 or 2; and the pharmaceutically or veterinarily COO(CH i^-OCO-l^^JJ , -COOCH acceptable salts thereof.
Specific examples of compounds of the inyention are the following: 51686 6H, 6-cyano-dibenzo jb ,d] pyran; 6H, 6-cyano-l-methoxy-di.benzo jb,dj pyran; 6H,6-cyano-2-chloro-dibenzo [b,d] pyran; 6H.6-cyano-2-fluoro-dibenzo jb, d] pyran: 6H,6-cyano-2-nitro-dibenzo jb,dj pyran; 6H,6-cyano-2-methoxy-dibenzo jb,d] pyran; 5H,6-cyano-l,10-dimethoxy-dibenzojb,dj pyran; 6H,6-cyano-8.9,10-trimethoxy-dibenzo jb,dj pyran; 6H,6-cyano-6-methyl-dibenzo jb,d] pyran; 6H,6-cyano-6-methyl-2-chloro-dibenzo jb,d] pyran; 6H,6-cyano-6-methyl-2~fluoro-dibenzo jb.dj pyran; 6H,6-cyano-6-methyl-l,10-dimethoxy-dibenzo jb,d| pyran; 6H,6-cyano-6-methyl-8,9,10-trimethoxy-dibenzo jb, dl pyran; 6H,6-(l-piperazinyl)-dibenzo jb,djpyran; IS 6H,6-(1-plperazinyl)-2-chloro-dibenzo fb, djoyran; 6H,6-(l-piperazinyl)-2-fluoro-dibenzo jb,djpyran; 6H,6-(1-piperazinyl)-2-nitro-dibenzo jb,dj pyran; 6H,6-(1-piperazinyl)-2-methoxy-dibenzoIbid]pyran; 6H,6-(1-piperazinyl)-1,10-dimethoxy-dibenzo jb ,d] pyran; 6H, 6-( 1-piperazinyl )-8,9,10-trimethoxy-dibenzo jb , d] pyrar.; 6H,6-ethoxycarbonyl-dibenzo jb ,d]pyran; 6H,6-ethoxycarbonyl-l-methoxy-dibenzo jb, d] pyran; 6H,6-ethoxycarbonyl-2-hydroxy-dibenzo jb,dj pyran; 6H,6-ethoxycarbonyl -2-chl oro-di benzo/B ,(j7pyran; 6H,6-ethoxycarbonyl-6-methyl-2-chloro-dibenzojb,dj pyran; 6H, 6-ethoxycarbonyl-2-amino-dibenzo jb,d] pyran; 6H,6-ethoxycarbonyl-6-methyl-dibenzojb,dl pyran; 6H,6-ethoxycarbonylmethyl-dibenzo [b, djpyran; 6H,6-ethoxycarbonylmethyl-2-chloro-dibenzo [b,d] pyran; 6H, 6-ethoxycarbony lmethyl-2-f luoro-dibenzo [b , dj pyran ; 6H, 6-ethoxycarbonylmethyl-2-nitro-dibenzo [b,d| pyran; 6H,6-ethoxycarbonylmethyl-2-amino-dibenzojb, d] pyran; 6H,6-ethoxycarbonylmethyi-2-methoxy—dibenzojb,d] pyran; 6H,6-ethoxycarbonylmethyl-2-hydroxy-dibenzo |b,dJpyran; 6H,6-ethoxycarbonylmethyl-l,10-dimethoxy-dibenzo jb, d] pyran; 6H,6-ethoxycarbonylmethyl-8,9,10-trimethoxy-dibenzo[b,dj pyran; 6H,6-ethoxycarbonylmethyl-6-methyl-dibenzojb,dl pyran; 6H,6-ethoxycarbonylmethyl-6-methyl-2-chloro-dibenzo fe,djpyran; 6H,6-ethoxycarbonyImethyl-6-methyl-2-fluoro-dibenzojb,d_l pyran; 6H,6-ethoxycarbonylmethyl-6-methyl-2-nitro-dibenzo |b, dl pyran; 6H,6-ethoxycarbonylmethyl-6-methyl-2-amino-dibenzo Ib.d] pyran; 6H,6-ethoxycarbonylmethyl-6-methyl-2-methoxy-dibenzo ib.cfl pyran; 6H,6-ethoxycarbonylmethyl-6-methyl-2-hydroxy-dibenzo ’ll,d]pyran; 6H,6-(2-ethoxycarbonylethyl)-dibenzo[b,d| pyran; 6H,6-(2-ethoxycarbonylethyl)-2-chloro-dibenzo fe ,dl pyran; 6H,6-(2-ethoxycarbonylethyl)-2-fluoro-dibenzo fe.djpyran; 6H,6-(2-ethoxycarbonylethyl)-8,9,10-trimethoxy-dibenzo Lb , d] pyran; 6H,6-(2-ethoxycarbonylethyl)-6-methyl-dibenzo fe ,dj pyran; 6H,6-(2-dimethylaminoethoxy-carbonyl)-dibenzo jb,dj nyran; 6H, 6 -( 2-dimethylaminoethoxy-carbonyl)-2-chlorodibenzo[fe,dlpyran; 6H,6-f 2-dimethylaminoethoxy-carbonyl)-2-fluoro-dibenzo jb ,dj pyran; 6H,6-(2-dimethylaminoethoxy-carbonyl)-2-nitro-dibenzo[b,dj pyran; 6H,6-(2-dimethylaminoethoxy-carbonyl)-2-methoxy-dibenzo [b, d] pyran; 6H,6-(2-dimethylaminoethoxy-carbonyl)-2-hydroxy-dibenzo[b,djpyran; 6H,6-(2-dimethylaminoethoxy-carbonyl)-2-amino-dibenzojb,d]pyran; 6H,6-(2-dimethylaminoethoxy-carbonyl)-1,1O-dimethoxy-dibenzo Eb, dj pyran; 6H,6-(2-dimethylaminoethoxy-carbonyl)-8,9,10-trimethoxy-dibenzo Eb , dj pyran; 6H,6-(2-dimethylaminoethoxy-carbonyl)-6-methyl-dibenzojb,dj pyran; 6H,6-(2-dimethylaminoethoxy-carbonyl)-6-ethyl-dibenzojb,djpyran; 6H,6-(2-dimethylami no-ethoxy-carbonyl)-6-methy1-2-hydroxy-dibenzo Z&,d7pyran; 6H,6-(2-dimethylami no-ethoxy-carbony))-6-methy)-2-ami no-di benzo /b.d/pyran; 6H,6-(2-dimethylami noethoxy-carbony)methyl)-di benzo/b,d7pyran; 6H,6-(3-pyridylmethylenoxy-carbonylmethyl)-dibenzo/B,d7pyran; 6H ,6-(3-pyri dy1methylenoxy-carbony)methyl)-6-methyl-di benzo/b, d7pyran; 6H,6-carboxy-6-methyl-2-chloro-dibenzo ,dj pyran; 6H,6-carboxy-6-methyl-2-fluoro-dibenzojb,d]pyran; 6H,6-carboxy-6-methyl-2-nitro-dibenzo ±>,djpyran; 6H, 6-carboxy-6-methyl-2-methoxy-dibenzo j_b,dj pyran; 6H, 6-carboxy-6-methyl-2-trifluoromethyl-dibenzo jb, d_j pyran ; G85 6Η,6-carboxy-6-methy1-1,10-dimethoxy-dibenzo jb, djpyran; 6H, 6-carboxy-8,9,10-trimethoxy—dibenzo [b , dj pyran; 6H,6-carboxymethyl-dibenzo |b,djpyran; 6H,6-carboxymethyl-l-methoxy-dibenzo[b,d] pyran; 6H,6-carboxymethyl-2-chloro-dibenzo[b,dl pyran; 6H,6-carboxymethyl-2-fluoro-dibenzo jb,dj pyran; 6H,6-carboxymethyl-2-nitro-dibenzo [b,djpyran; 6H,6-carboxymethyl-2-methoxy-dibenzo[b,d]pyran; 6H,6-carboxymethyl-2-trifluoromethyl-dibenzo[b,d!pyran; 6H,6-carboxymethyl-8-chloro-dibenzojb,dj pyran; 6H,6-carboxymethyl-8-fluoro-dibenzo jb,djpyran; 6H,6-carboxymethyl-8-nitro-dibenzo jb,djpyran; 6H,6-carboxymethyl-8-methoxy-dibenzojb,djpyran; 6H,6-carboxymethyl-l,10-dimethoxy-dibenzo jb,djpyran; 6H,6-carboxymethyl-8,9,10-trimethoxy-dibenzojb,djpyran; 6H,6-carboxymethyl-5-methyl-dibenzo jb,dj pyran; 5H,6-(2-carboxyethyl)-dibenzo (b, dj pyran; 6H,6-(2-carboxy-ethyl)-2- chloro-dibenzo jb,djpyran; 6H,6-(2-carboxy-ethyl)-2-fluoro-dibenzo jb,djpyran; 6H,6-(2-carboxy-ethyl)-2-nitro-dibenzoLb,djpyran; 6H,6-(2-carboxy-ethyl)-2-methoxy-dibenzo jb ,dj pyran; 6H,6-(2-carboxy-ethyl)-1,10-dimethoxy-dibenzo Jb, dj pyran; 6H,6-(2-carboxy-ethyl)-8,9,10-trimethoxy-dibenzo[b,dj pyran; 6H,6-amino-methyl-dibenzo [b,dj pyran; 6H,6-amino-methyl-2-chloro-dibenzojb, d]pyran; 51685 * 6H,6-aminomethyl-2-fluoro-dibenzo(b,d]pyran; 6H, 6-aminomethyl-2-methoxy-dibenzo Gb, dj pyran; 6H, 6-aminomethyl-2-hydroxy-dibenzo (b,d_i pyran; 6H,6-aminomethyl-1,10-dimethoxy-dibenzo!b,dj pyran; 6H,6-aminomethyl-8,9,10-trimethoxy-dibenzo ib.djpyran; 6H,6-(2-methylamino-ethyl)-dibenzo ib,dj pyran; 6H, 6-( 3-methylamino-propyl)-dibenzo |b , djpyran; 6H, 6-(3-me thy lami no-propyl)-l-methoxy-dibenzo/b,d7pyran; 6H,6-(4-piperidinyl)-dibenzo jb,dj pyran; 6H,6-(l-hydroxy-2-tert-butylamino-ethyl)-dibenzo jb,djpyran: 6H,6-(l-hydroxy-2-tert-butylamino-ethyl)-2-chloro-dibenzo jb, dj pyran; 6H,6-(1-hydroxy-2-tert-butylamino-ethyl)-2-methoxy-dibenzo [b,dj pyran ; 6H,6-(l-hydroxy-2-tert-bu.tylamino-ethyl)-l,10-dimethoxydibenzo jb,dj pyran; 6H,6-(l-hydroxy-2-tert-butylamino-ethyl)-8,9,10-trimethoxvdibenzo jb,dj pyran, and the pharmaceutically or veterinarily acceptable salts thereof.
The compounds of the present invention may be prepared by a process comprising: a) reacting a compound of formula (II) wherein R is a halogen atom or a hydroxy group; R'^is hydrogen, unsubstituted C-C alkyl or an optionally substituted 1 6 phenyl group and and Rg are as defined above, with an alkali metal cyanide or with a C -C -alkyl1 6 . . silylcyanide or with an amine oi formula HN^ a, wherein R Rb a and R are as defined above, so obtaining a comDuund ol b formula (I), wherein n is zero; R is -CN or -N^ a, wherein 1 Rb R and R are as defined above; R is hydrogen, unsubstitufced a ** b 2 alkyl or an optionally substituted phenyl group; and r3, r R=’ RC’ 4 5 6 R and R are as defined above; or 7 8 b> reacting a compound of formula (III) YO (III) (-) wherein Y is an halogen atom; R' is hydrogen, unsubstituted C-C alkyl or an optionally substituted phenyl group and 1 6 R , R , R , R , R and R are as defined above, with an alkali 3 4 5 6 7 8 metal cyanide, so obtaining a compound of formula (I), wherein n is zero; R is hydrogen, unsubstituted C-C alkyl or an 2 16 optionally substituted phenyl group; is -CN and R^ , R , R^, R , R and R are as defined above; or 6 7 o c) reacting a compound of formula (II), wherein R is hydroxy; R' is hydrogen, unsubstituted C-C alkyl or an optionally g 16 substituted phenyl group; R_, R., R_, FL·, R_ and R. are as 3 4 5 6 7 8 defined above, with a Wittig reagent of formula (IV) (-) E-CH-(CH ) -R, (IV) I ni 1 R' wherein R is as defined above; n is zero, 1 or 2; E is (C H,),P1 1 6 5 3 or a (RgOlgH- group, where each of may be independently C —C alkyl or phenyl and R' is hydrogen or amino; so obtaining 1 6 a compound of formula (I), wherein n is 1, 2 or 3; R is hydrogen or amino, wherein when R is amino, it is never linked to the «( -carbon atom bound at the 6-position of the benzopyrane system; R is hydrogen, unsubstituted C-C alkyl or an optionally substituted 16 phenyl group; R , R , R , R_, R , R and R are as defined above: or 1 3 4 5 6 7 8 5168» d) cyclizing a compound of formula (V) wherein A is R , where R is as defined above, or a 11 protected carboxy group and n, R, R , R , R , R , R , R 2 3 4 5 6 / and R are as defined above and removing the protecting 8 group(s), when present, so obtaining a compound of formula (I), wherein n, R, 5 , R^, R^, R^, Rg, R , R and R„ are as defined above, or 6 7 8 e) cyclizing a compound of formula (VI) 1C 51685' wherein R' is hydrogen, unsubstituted C-C alkyl or 2 1 6 an optionally substituted phenyl group; R13 is as R^ defined above under a), b) or e), and n, R , R , R , 4 5 R , R and R are as defined above, so obtaining a 6 7 8 compound of formula (I), wherein R is hydrogen; and, if R is as defined above under a) or b1, R^ is a free carboxy group, or, if R^^ is as R defined above under e) also R^ is as defined above under e); R? is hydrogen, unsubstituted C^-C^ alkyl or an optionally substituted phenyl group; and n, R _, R_, R., R., R_, and ' 3 4 5 o < R are as defined above; and, if desired, converting a 8 compound of formula (I) into another compound of formula (I), and, or, if desired, salifying a compound of formula (I) or obtaining a free compound of formula (I) from a salt thereof and/or, if desired, resolving a mixture of isomers into the individual isomers.
When in the compounds having the formulae (II), (III), (IV), (V) and (VI! free amino, carboxy or hydroxy groups are present, the amino, carboxy and hydroxy groups may be protected, if necessary, in a conventional manner, before the reaction takes place .
Amine and carboxy protecting groups may be, for example, the protecting groups usually employed in the chemistry ot peptides. Examples of amino protecting groups are formyl, an optional halo-substituted aliphatic acyl, preferably chloroacetyl or dichloroacetyl, tert-butoxycarbonyl, p-nitrobenzyloxycarbonyl or trityl .
Examples of carboxy protecting groups are tert-butyl, benzhydryl, p-methoxybenzyl, p-nitrobenzyl, trityl, trialkylsilyl group, or a carboxy group may be protected in the form of a oxazolinyl group.
The hydroxy groups may be protected, for example, by a formyl, acetyl, chloroacetyl, dichloroacetyl, trifluoroacetyl, tetrahydropyranyl, trityl or silyl group, preferably trimethylsilyl or dimethyl-tert.butyl silyl.
The amino, carboxy and hydroxy protecting groups are then 10 removed at the end of the reaction, usually in a known manner.
For example, when the amino protecting group is the monochloroacetyl group, it may be removed by treatment with thiourea; the formyl and the trifluoroacetyl groups may be removed by treatment with potassium carbonate in aqueous methanol and the trityl group by treatment with formic or trifluoroacetic acid.
The carboxy protecting groups, for example, may be removed by mild acid hydrolysis or by catalytic hydrogenation, e.g. with Ed/C ac room pressure.
The hydroxy protecting groups, for instance, may be removed by mild reaction conditions, e.g. acid hydrolysis.
When in the compounds of formula (II) R is halogen, the halogen may be chlorine, bromine or iodine, preferably chlorine, and the reaction may be performed with an alkaline, e.g. sodium or potassium, cyanide, preferably potassium cyanide. When in the compounds of formula (II) R is hydroxy, 51685 > the reaction is preferably performed with a C-C. alkylsilyl 10 cyanide, preferably trimethylsilylcyanide, and in the presence of a suitable catalyst, for example, zm in an inert solvent, 2 such as benzene or toluene.
The reaction of a compound of formula (II) wherein R is halogen with an alkali metal cyanide may be carried cut in a suitable organic solvent, e.g. dimethylformamide, dimethyl acetamide, dioxane or, preferably, in an aqueous solvent, e.g. a mixture of dimethylformamide or dimethylacetamide and water, at temperatures ranging from about 0°C to the solvent reflux temperature, preferably at room temperature.
The compounds of formula (II) wherein R is hydroxy are, preferably, the starting materials for obtaining compounds of formula (I), wherein R. is -N^ a , wherein R and R are 1 ^Rb 3 ° as defined above, according to process a). The reaction of a compound of formula (II), wherein R is hydroxy with an amine of formula HNf^Ra , wherein R and R, are as defined X'Rb 3 b above, is preferably carried out in an excess of the amine or in a solvent, such as, dimethylacetamide, N-methylpyrro lidone, benzene, toluene or mixtures thereof, at temperatures ranging from about 50°C to about 150°C.
When in the compound of formula (1X1) Y is a halogen atom, the halogen may be bromine, iodine or chlorine, preferably chlorine.
The reaction of a compound of formula (III) with an alkali metal e.g. sodium or potassium, cyanide, preferably potassium 31685 an oxazolinyl group. In the latter case A N-<^13 preferably a group of formula I 13 o—(CH2)m the R groups is, independently, hydrogen cyanide, may be effected in an inert organic solvent, e.g. benzene, toluene, xylene, dioxane, preferably benzene, in the presence of a suitable catalyst, for example a crown ether, preferably a 18-crown-6-ether, at temperatures ranging from about 0°C to the solvent reflux temperature, preferably at room temperature.
The reaction of a compound of formula (II) with a compound of formula (IV) may be performed in an anhydrous organic solvent, for example diethyl ether, benzene, toluene, xylene orn-hexane, either under cooling or at temperatures ranging from about 0°C to the reflux temperature of the reaction mixture, preferably at room temperature.
When in the compound of formula (V) A is a projected carboxy group it is protected, for example, through one of the protecting groups indicated above, i.e. tert.butyl, benzhydryl, p-methoxybenzyl, p-nitrobenzyl, trityl, trialkylsilyl or as represents , , wherein each of or C^-C alkyl, preferably methyl and m is 1 or 2.
The cyclization oi' a compound of formula (V) may be carried out with a suitable cyclizing agent, for example CuCNO^).3Η^0/Cu .0 in aqueous or alcoholic, e.g· ethanolic, solvent, at temperatures ranging from about 0°C to about 50°C, preferably from 5°C to 30°C . 51685’ The subsequent removal of the protecting groups possibly present may be carried out by a conventional way, e.g. as reported above. In particular when in a compound of formula (V), A is a protected carboxy group of formula R wherein R and m are as defined above, the 1 o t)—(CH„) '2'm protecting group may be removed in the presence of a suitable acid, for example an inorganic acid, i.e. hydrochloric or sulphuric acid, or an organic acid, i.e. oxalic acid, in aqueous medium at temperatures ranging from the room temperature to the reflux temperature of the reacting mixture, for reaction times ranging from 1 to 12 hours, thus giving a compound of formula (I) wherein R^ is a free carboxy group.
The same process, when carried out using a C-C aliphatic 1 o alcohol as solvent, e.g. using a 5-7% solution of sulphuric acid in the appropriate C-C. aliphatic alcohol, leads to a O compound of formula (I) wherein R is a C2-C7 alkoxycarbonyl group. The cyclization of a compound of formula (VI) may be,for example, carried out by dissolving a compound of formula (VI) into an aqueous saturated solution of a halogenidric acid, preferably hydrobromic acid, and keeping the temperature of the reacting mixture comprised between about 60°C and the boiling point of the reacting mixture.
The optional conversion of a compound of formula (I) into another compound of formula (I) may be carried out by known methods and free amino, carboxy or hydroxy groups, when present, may be protected, if necessary, in a conventional way as reported above, before the reaction takes place and then removed at the end of the reaction in a known manner, as reported above. a') For example a compound of formula (I) wherein is cyano, R, R , R , R , R , R , R , R and n are as 2 3 4 5 6 7 8 defined above, may be converted into the corresponding compound of formula (I) wherein R^ is -COOH, in a conventional manner, for example by alkaline hydrolysis, e.g. with KOH or NaOH in a hydroalcoholic solution, preferably with KOH in aqueous ethanol solution, at temperatures ranging from about 30°C to the solvent reflux temperature, followed by acidification. b') A compound of formula (I) wherein R is a free carboxy group may be converted into a compound of formula (I) wherein R^ is the group -COOR^, wherein R is as defined above, by a conventional method, for example by reacting the alkali metal salt of the acid with an alkyl halide, in an inert solvent, such as, e.g. acetone, dioxane, dimethylformamide or hexamethylphosphorotriamide at a temperature ranging from about 0°C to about 100°C, or by reacting the acid with an alcohol of formula R -OH wherein R^^ is as defined above, in the presence of a suitable acid catalyst, e.g. HC1. Alternatively the esterification of a compound of formula (I) may be effected a) converting the compound of formula (I) wherein is a carboxy group into the corresponding halocarbonyl, preferably chlorocarbonyl, derivative, by reaction, e.g, with the desired acid halide, for example oxalyl chloride, thionyl chloride, PCI,, PC1_ a or POCl^, either in the absence of a solvent or in an inert organic solvent, e.g. benzene, toluene, xylene, dioxane, dichloroethane, methylene chloride, or tetrahy drofuran, at a temperature preferably from about 0°C to about 120°C; and then b) reacting the obtained halocarbonyl derivative with the suitable alcohol of formula R^-OH, wherein R is as defined above, in a solvent which may be the same alcohol or in an inert solvent, e.g. benzene, toluene, xylene, dioxane, dichloroethane, methylene chloride, or tetrahydrofuran, at a temperature preferably from about 0°C to about 60°C, preferably in the presence of a base, e.g. triethylamine. c') A compound of formula (I) wherein R is a carboxy group or an esterified carboxy group may be converted into a compound of formula (I), wherein Rj is -CON^ c , in which Rc and Rg are as Rd defined above, by conventional method, for example by reacting the acid, or a reactive derivative thereof, e.g. an acyl halide, preferably chloride or a mixed anhydride, or a C^-Cg aliphatic ester thereof ZRc with an amine of formula HN , wherein Rc and Rg are as 685 defined above, or a derivative thereof, e.g. an amine salt. The reaction may be performed either at room temperature or under cooling, preferably from about -50°C to about 40°C in a suitable solvent, e.g. acetone, dioxane, tetrahydrofuran, acetonitrile, methylene chloride, benzene, toluene, or in a mixture of water and a solvent miscible with water and, if necessary, in the presence of a base, e.g. sodium bicarbonate or potassium bicarbonate, or in the presence of an acid acceptor, e.g. propylene oxide. In particular when a free acid or a salt thereof is reacted with ammonia or the appropriate amine, the reaction is performed in the presence of a condensing agent, e.g. Ν,Ν'dicyclohexylcarbodiimide .
/Re d') A compound of formula (I) wherein R is a group -CONQ or a group -COOR , wherein R , R and R have the d 10 c d 10 meanings reported above, may be converted into a compound of formula (I) wherein R is -COOH by hydrolysis, e.g. basic hydrolysis, using for example, sodium or potassium hydroxide, in a solvent, such as, e.g., water or a lower aliphatic alcohol, and operating at a temperature ranging from the room temperature to about 150°C and then acidifying; or acid hydrolysis, for example, in a solvent, such as, water, or mixtures of aliphatic alcohol or dioxane with water, operating at a temperature ranging from the room temperature to the reflux temperature; the same reaction may be also carried out e.g. by treatment with a lithium halide, preferably lithium bromide in a suitable solvent, e.g. dimethylsulphoxide, hexamethylenphosphortriamide or dimethylformamide, preferably in dimethylformamide at a temperature higher than 50°C.
In particular a compound of formula <, I) wherein -COOR represents a t-butoxycarbonyl group may be converted into a compound of formula (I) wherein is a free carboxy group e.g. by treatment with trifluoroacetic acid either in the absence of solvents or in the presence of an inert organic solvent selected e.g. from the group consisting of benzene, toluene, dioxane at a temperature ranging from about 0°C to about 50°C or also by treatment e.g. with trimethylsilyliodide in an inert organic solvent, preferably tetrachloromethane, according to the procedure described in J. Am. Chem. Soc. 1977, 99, 968. e') A compound of formula (I), wherein R is a cyano group; R is as defined above and n is zero, 1 or 2, may be converted into another compound of formula (I), wherein is an amino group; n is 1 and R is hydrogen or n is 2 or 3, respectively, and R is as defined above, by reducing the cyano group in a conventional way, for example by one of the methods reported in Catalytic Hydrogenation in Organic Synthesis” by P.N. Rylander, Academic Press 1979, page 138. f' ) Alternatively, 1) a compound of formula (I), wherein R is a cyano group, R is as defined above, n is zero, or 2, may be converted into another compound of formula (I), wherein R^ is an amino group, n is 1 and R is hydrogen or n is 2 or 3 and R is as defined above; or 2) a compound of formula (I), wherein R^ is a group ft -CON£^ c , wherein R and R , are as R and R, , wherein cd a b d R and R, are as defined above, n is zero, 1 or 2 and a b R is as defined above, may be converted into another compound of formula (I), wherein R is a group a , 1 ^'Rb wherein R and R are as defined above, n is 1 and R is a b hydrogen or n is 2 or 3 and R is as defined above.
Both the cyano or the amide groups may be reduced through a suitable reducing agent, such as LiAlH^, BH^, sodium dimethoxy-ethoxy-aluminium hydride (RED-AL), in organic solvents, e.g. tetrahydrofuran, diethylether, diglyme , benzene, toluene and at reaction temperatures ranging from the room temperature to the solvents' reflux temperatures . g') A compound of formula (I), wherein R^ is an unsaturated heterocyclic ring as defined above under e), may be coverted into another compound of formula (I), wherein R is the respective saturated heterocyclic ring as defined above under e), by reduction through known methods, for example those reported in Catalytic Hydrogenation in Organic Synthesis” by P.N. Rylander. Academic Press 1979, page 213. 5168S h') A compound of formula (I), wherein R is -COOH or an esterified carboxy group, n is zero, 1 or 2 and R is hydrogen, may be converted into another compound of formula (I) , wherein R^ is -CN or -COOH, n is 1, 2 or 3 and R is hydroxy, that is, for example, a compound of formula (I), wherein the group -(CH) -R, is -CH -COOH, may be R n 1 2 transformed into another compound of formula (I I , wherein the same group is -CH2~CH0H-C00H. This conversion may be, for example, carried out by reducing the carboxygroup or the esterified carboxy group to an aldehyde group through conventional methods well known in literature, e.g. J.O.C. 1976, 41, 3512; Chem. Comm. 1974, 45; Chem.
Ber. 1970, 103, 2984; Chem. Comm. 1978, 354; and J. Chem.
Soc Jerkin Trans. I (1980), (1), 27; and converting the aldehyde derivatives so obtained first into the respective cyanohydrins, that is a compound of formula (X), wherein R^ is -CN and R is hydroxy, and then converting the latter into the respective hydroxy acid derivatives. Also these reactions may be carried out by following conventional methods well known in the art. i') A compound of formula (I), wherein R is a carboxy or esterified carboxy group, n is zero, 1 or 2 and R is hydrogen, may be converted into another compound of formula (I) wherein R. is -CONsf^c , wherein R and R 1 ^~R , o d d are as defined above, n is 1, 2 or 3 and R is hydroxy, that is, for example, a compound of formula (I), wherein the group-(is -CH^-COOH, may be transformed into another compound of formula (I), wherein the same group above .
This conversion may be,for example, carried out by 5 converting, through conventional methods, the hydroxy acids, obtained according to the preceding process'll'), into the respective amides. Some of the amides obtained according to this process may be used as starting compounds for the conversion described under f'), where amides are converted into amines. j') A compound of formula (I), wherein R^ is a carboxy or esterified carboxy group, n is zero, or 1 and R is hydrogen, may be converted into another compound of formula (I), wherein R^ is -NH^ , n is 2 or 3 and R is hydroxy, that is, for example, a compound of formula (I), wherein the group (fH) -R is -CHg-COOH, may be transformed into another compound of formula (I), wherein the same group is -CH -CH-CH -NH . This conversion may be, for 2 OH 2 2 example, carried out by converting, through known methods, the cyanohydrin intermediates, obtained according to the preceding interconversion process h'), into the respective amines. k') A compound of formula (I), wherein Rg is hydrogen, n is zero, R^ is as defined above under a), b), d) or e) and R, R , R, R, R and R are as defined above may be 4 5 6 7 8 converted into the corresponding compound of formula (I) wherein is methyl or ethyl optionally substituted by hydroxy, by following known methods. For example a compound of formula (I) wherein is hydrogen, may be transformed into a compound of formula (I) wherein R? is methyl or ethyl by reaction with methyl or ethyl halide, preferably iodide, in the presence of NaH or a similar strong base and in a suitable anhydrous solvent, i.e. dimethylformamide, dioxane, toluene, xylene or dimethylsulphoxide, preferably dimethylformamide. 1') Alternatively, a compound of formula (I), wherein R^ is hydrogen, n is zero, R^ is as defined above under a), b), d) or e) and R^, R , R , R , R and R are as defined above, may be transformed 4 5 6 7 8 into the corresponding compound of formula (X) wherein R^ is methyl or ethyl substituted by a hydroxy group by reaction, for example, with formaldehyde or with a cyclic or linear polymer thereof, e.g, trioxymethylene, or with acetaldehyde, in a suitable solvent, e.g. dimethylsulphoxide at a temperature ranging from approximately the room temperature to about 100°C, for reaction times from about 2 to 12 hours, and in the presence of a base, such as sodium methoxide or potassium tert.butoxide. m') A compound of formula (I), wherein n is zero, 1 or 2; R is hydrogen; R* is a carboxy group; and R9, Rg, R^, r Rg, R_, and R^ are as defined above may be converted into another compound of formula (I), wherein n is 1, 2 or 3, respectively; R is hydrogen; is a free or esterified carboxy group or , wherein R and R are as . c d defined above and R , R , R , R , R , R„ and R_ are 2 3 4 5 6/ 8 as defined above. Also this conversion may be carried out by following known methods, for example an Amdt-Eistert synthesis. n') A compound of formula (I), wherein one or more of R^, R , R , R , R and R are hydrogen may be converted 4 5 6 7 8 into the corresponding compound of formula (I), wherein one or more of R , R , R , R , R and R are halogen o 4 o 6 ί o by halogenation. In particular, for example, a compound of formula (I) wherein one or more of R„, R., R^, R_, R 4 5 6 7 and R are hydrogen may be transformed into a compound 8 cf formula (I) wherein one or more of R„, R„, R , R . 4 o 6 R and R are chlorine by reaction with a suitable 7 8 chlorinating agent, for instance with SO^Cl^ in an 15 inorganic solvent, e.g. CH2C12 Or CHC13’ or following other well known methods, for example those described in J.O.C., 1970, 35 , 719 or Synthesis 1979, 417. o') A compound of formula (I), wherein one or more of R^, R , R , R , R_ and R are hydrogen, may be transformed 4 5 6 7 8 into another compound of formula (1), wherein one or more of R , R , R , R , R and R is -NO by conventional 3 4 5 6 7 8 2 methods, for example by treatment with nitric acid in an appropriate solvent which may be, for instance, acetic acid, acetic anhydride or concentrated sulphuric acid, at temperatures ranging from the room temperature to about 70°C. p') A compound of formula (I) wherein one or more of R^, R ι R_, R , R_ and R„ is -NQ„ and the others are 4 5 6 7 8 2 hydrogen may be transformed into a compound of formula (I) wherein one or more of R . R,f R,, R,, R_ and R„ is -NH 3 4 5 6 7 8 2 and the others are hydrogen by conventional methods, for example by hydrogenation in the presence of a suitable catalyst, e.g. Pd/C or PtO^/C, and in a solvent such as, e.g., an aliphatic alcohol, acetic acid, tetrahydrofuran or dimethylformamide, or by treatment with SnCl^, as reported in J. Med. Chem. 1978, 21, 621 or by treatment with TiClg ir> a suitable solvent, e.g. benzene, water, ethyl acetate, or a mixture thereof, or by treatment with NaBH4 or KBH^ in the presence of metal catalysts as reported, e.g., in Tetr. Lett. 1969, 4555. Simultaneous reduction of other reducible groups possibly present can be avoided, if undesired, by using selective reaction conditions. q* ) A compound of formula (I), wherein one or more of R^, R , R= > R„ , R-, and Rn is an amino group may be transformed 4 5 6 ι 8 into another compound of formula (I), wherein one or more of R . R., R_, R,, R_ and RD is a hydroxy group by following known methods, for example by treatment with an alkali metal nitrite, i.e. NaNO^ and a mineral acid, e.g. HCl or HgSO^ at temperatures ranging from the room temperature to 70°C, preferably from the room temperature to 50°C. r1) A compound of formula (I) wherein R is C-C alkyl 2 16 substituted by hydroxy may be converted into the corresponding compound wherein R is C-C alkyl 2 16 substituted by a group -O-CO-C-C -alkyl by acylation, o e.g. by treatment with the appropriate acyl halide or the appropriate anhydride operating in a solvent such as, for instance, methylene chloride, chloroform or tetrahydro furan at a temperature varying from about -10°C to the room temperature. s') Vice-versa a compound of formula (Π wherein R is C -C 16 alkyl substituted by a group -O-CO-C-C -alkyl may be 1 6 converted into the corresponding compound wherein Rp is C —C alkyl substituted by hydroxy by hydrolysis, espe daily basic hydrolysis with hydroalcoholic solutions of NaOH or KOH at the reflux temperature of the used alcohol, t') A compound of formula (I), wherein one or more of R^, R^, R_, R^, R, and Rg is a Cj-Cg alkoxy group may be transformed into another compound of formula (I), wherein one or more of R,, R , R . R , R 3 4 5 6 7 and R is a hydroxy group by following known methods, for example, either by treatment with BBr^ in anhydrous CH^Cl^ or other suitable solvents at temperatures ranging from about -30°C to the room temperature, or by treatment with concentrated HBr in water at temperatures ranging from the room temperature to the reflux temperature.
Also the optional salification of a compound of formula (I) as well as the conversion of a salt into the free compounds and the separation of a mixture of isomers into the single isomers may be carried out by con30 51685' ventionai methods. For example the separation of optical isomers may be carried out by salification with an optically active base or acid and by subsequent fractional crystallization of the diastereoisomeric salts followed by recovering of the optically active isomeric acids or, respectively, bases.
The separation of a mixture of cis- and trans-geometric isomers may be carried out for example by fractional crystallization or by chromatography.
A compound of formula (II), wherein R_, R., R., R , R„ u 4 5 ο ι and R are as defined above, R' is hydrogen and R is 8 2 12 hydroxy may be obtained by reducing a compound of formula (VII) wherein R„ , R., R_, R_, R_ and R are as defined above, 4 5 0 7 8 following the known methods of the organic chemistry, for example by treatment with diisobutylaluminiumhydride (DIBAH), as reported in Synth.,1975, 10, 617, in Tetr. Lett., 1976, 3279; or with sodium dimethoxy-ethoxy-aluminium hydride (RED-AL), as reported in Synthesis, 1976, _8_, 526, or with LiAlH^, as reported in Helv. Chim. Acta, 1957, 40, 1034.
A compound of formula (II), wherein , R^, Rg, R^, R_, and R are as defined above, R’ is methyl, ethyl or an optionally o 2 substituted phenyl group and R is hydroxy, may be obtained by reacting a compound of formula (VII), wherein R^, R , Rg, R , R and R are as defined above with a compound of formula 6 7 8 C^-C3-alkyl-M or Ph-M, where Ph is an optionally substituted phenyl group and M is lithium or the radical-MgX, where X is halogen, preferably bromine, provided that an inverse addition is done and the temperature is kept low enough to avoid subsequent unwanted reactions.
A compound of formula (II) wherein R is halogen, may be obtained from a compound of formula (II) wherein R^2 is hydroxy, by treatment with an appropriate halogenating agent, for example by treatment with SOCl^ or PSr^ at temperatures ranging from 0 to 60°C, preferably at room 10 temperature.
Compounds of formula (III) are known or may be prepared by known methods, as reported in Chemical Comm. 1970, 850.
The compounds with formula (IV) in which E is (ΗθΟ,^Ρ—► (0)(R as defined above) are prepared by reacting a compound e of formula (VIII) Re°M R 0' (VIII) wherein R , n and R are as defined above e 1 1 and R’ is hydrogen or amino, with at least one molar equivalent of one of the following bases: an alkali metal or alkaline earth metal hydride like sodium, potassium, lithium or calcium hydride, an alkali metal or alkaline earth metal alkoxide, like sodium or potassium tert-butylate, an alkali metal or alkaline earth metal amide,like sodium amide, or an alkali metal or alkaline earth metal salt of a carboxamide, like N-sodiumacetamide and N-sodiumsuccinimide.
Compounds with formula (IV) in which E is (CgH ) P- are 51685* prepared by reacting a compound with formula (IX) Hal-CH -(CH) -R (IX) ι, η 1 R' 1 wherein n , R' and B1 are as defined above and Hal is halogen, with 1.1-1.3 molar equivalents of triphenylphosphine in an organic solvent like benzene, acetonitrile or diethyl ether and then treating the product phosphonium salt with an equivalent quantity of an inorganic base like NaOH, KOH, Na2CO3 or NaHCO3· A compound of formula (V) may be obtained by diazotizing 10 a compound of formula (X) wherein R, R , R , R , R , R , R , R , A and n are as defined above, by conventional manner, for example with NaN0o and HCl or H„SO , at temperatures ranging from about 0°C to about 10°C. 2 4 A compound of formula (VI) may be obtained by reacting a compound of formula (XI) wherein R , R. , R . R . R 3 4 5 6 7 with a compound of formula Ro and M are as defined above, o (XII) R.2X(cH2)n-Ri3 (xn) wherein Ft'2> n an^ R13 are as defined above.
The reaction between a compound of formula (XI) and a compound of formula (XII) may be carried out by following known methods for this kind of reaction, for example, in aprotic solvents, e.g. tetrahydrofuran or toluene, and at temperatures from about -78°C to the room temperature. Compounds of formula (VII) are known or may be prepared from known compounds by known methods.
Compounds of formula (VIII) are prepared using standard methods, for example those described by Corey et al. in J. Amer. Chem. Soc., 1968, 90, 3247 and 1966, 88, 5654.
Compounds with formula (IX) are also prepared following standard procedures.
Compounds of formula (X), wherein A is R , wherein is as defined above, are known or may be obtained by known methods. 51685 ‘ Compounds of formula (X) wherein A is a protected carboxy group, may be obtained by reacting a compound of formula (XIII) wherein R is a carboxy group or a reactive derivative thereof, R , R , R , R , R , R , R Rand n 2 3 4 0 0 t o are as defined above, with a suitable carboxy protecting agent.
In particular a compound of formula (X) in which A is the group wherein m and R are as V defined above, may be obtained by reacting a compound of formula (XIII) with a suitable amino alcohol, preferably 2-aminoethanol or 2-amino-2-methylpropanol, according to Can. J. Chem.,1970, 48, 983 and cyclizing the obtained amide, in the presence of SOC13 according to J. Org. Chem., 1975, 40, 1430.
Compounds of formula (XI) are known compounds or may be prepared according to known methods, for example as described in Chem. Ber., 1972, 105, 217. Also compounds of formula (XII) and (XIII) are known compounds as may be obtained through known methods from known compounds. 51885 The compounds of the present invention are active on the gastroenterical system, in particular they are endowed with anti-uIcerogenic, gastric anti-secretory and a very negligible anti-choIinergic activity and are therefore useful in therapy, for example in the prevention and treatment of peptic, e.g. duodenal, gastric and exophageal, ulcers and to inhibit gastric acid secretion.
The compounds of the invention are also useful for reducing the undesirable gastrointestinaI side-effects resulting from systemic administration of anti-inf Iammatory prostag Iandin synthetase inhibitors and may be, therefore, used for this purpose in association with them.
The anti-uIcerogenic activity of the compounds of the invention is shown, e.g., by the fact that they are active in the test of the inhibition of restraint ulcers in rats, according to the method of Bonfils et al., (Therapie, I960, J, 1096; Jap. J. Pharmac. 1945, 43, 5)· According to this method, the tested compounds were administered per os (p.o.) one hour before the immobϊIization.
Six Sprague-Dawley male rats (100-120 g) fasted 24 hours were used for the experiment: a square flexible small-mesh wire netting was used for the immobiIization and 4 hours after the immobilization the rats were sacrificed, their stomachs were removed and the lesions counted under a dissecting m i croscope, Table 1 shows, for example, the approximate ED^^ value of the anti-ulcerogenic activity in the rat obtained for two of the compounds of the invention after oral administration: TABLE 1 Compound Antiulcerogenic activity ED50 p‘°· FCE 20524 4.8 mg/kg FCE 20618 7.0 mg/kg As already stated above, the compounds of the invention own also gastric antisecretory activity, as shown e.g. by the fact that they proved to be active after intraduodenaI administration in inhibiting the gastric secretion in rats according to the method of H. Shay et al, (Gastroenter., 1945, &, 5).
According to this method the tested compounds were injected intraduodenaIly (i.d.) at the time of ligature.
Six Sprague-Dawley male rats (110-130 g) were used for each group. Twenty-four hours before the test, the rats were deprived of food but the water supply was maintained. On the day of the operation, the pylorus was ligated under light ether anaesthesia. Four hours after the ligature, the rats were sacrificed. The stomach secretion was collected and centrifugated at 3500 r.p.m. for 10 minutes and the volume, less sediment, was determined.
The amount of free hydrochloric acid in the gastric juice was determined by titration against 0.01 N sodium hydroxide, to an end point of pH 7. 1685 Table 2 shows, for· example, the approximate Εϋ^θ value of the antisecretory activity in the rat obtained for the compounds reported above in Table 1: TABLE 2 Compound Antisecretory activity »50’·-· FCE 20524 6 mg/kg FCE 2O6l8 1.5 mg/kg Considering that many anti-ulcer agents display, as does atropine, a remarkable but undesired anti-choIinengic activity, the compounds of the invention were also assessed for their antagonism against syndrome induced by oxotremorine in mice, according to the method described by Leszkovszky G.P. and Tardos L. (Europ. J. Pharmac. 1971, 15, 3l0). According to this method 5 male mice, 20-25 9 body weight, were used for each group.
Table 3 shows, for example, the approximate Εϋ^θ value of the anti-choIinergic activity obtained according to the above method for the compounds reported in Table 1 and 2.
TABLE 3 _ Compound Anticholinergic activity ED50 p.o. FCE 20524 > 100 mg/kg FCE 20618 >100 mg/kg As anti-uIcerogenic and ant!-secretory agents, the compounds of the invention are administered through usual routes, e.g. orally, parenterally or in the form of suppositories. Amount, from about 50 to about 200 mg pro dose, from 1 to 5 times daily for oral administration to adult humans are used.
Compound FCE 206l8 is, for example, preferably administered to adult humans orally at dosages from 100 to 150 mg pro dose, from 1 to 5 times daily.
The compounds of this invention possess also immunomoduI ating activity and in particular antiviral activity.
Their immunomoduI ating activity is, for example, proven by their capacity to modify the antibody response induced in mice by a suboptima, dose of sheep red blood cel Is (SRBC) injected by i ntraper i toneal route (i.p.).
Groups of ten female CD-I mice were injected i.p. with 2x10^ SRBC as antigen. The tested compounds were administered i.p. at two dosage levels: 50 and 5 mg/kg body weight, two hours before the administration of the antigen. A control group of mice received SRBC and saline instead of the compounds. Six days later the mice were killed and antibody titres against SRBC determined in their sera, according to Williams C.A.: Methods in Immunology and Immunochemistry, C.A. Williams and M.W. Chase, Eds. Academic Press, New York, Vol. II, page 152, 1977.
Augmentation of haemolytic antibody production was shown, 685 for example, by compounds FCE 20696 and FCE 21849.
These two compounds increased the antibody titers several Fold as compared to control group.
The antiviral activity of the compound of the invention was, for example, evaluated on influenza and herpes simplex viruses experimental infections in mice.
Groups of CD-I mice were infected intranasally with the strain APR S of influenza virus and other groups were infected intraperitoneally with the strain IRC of herpes simplex virus. The tested compounds were administered through various routes, e.g. intraperitoneally, subcutaneously, oral Iy.
The effect of the tested compounds, against the influenza virus, was evaluated on the basis of the number of lung lesions and, against the herpes infection, the parameter considered was the protection from mortality since, as is known, herpes simplex infection is lethal in mice.
The tested compounds was found to be effective in protecting the mice from both the viral infections. For example compound FCE 20696, when administered in a single dose either one or two days after the infection, showed remarkable pharmacological activity by reducing substantially the number of lung lesions in the influenza infection and protecting up to 455- of animals from death in the herpes simplex infection. 51685’ The compounds of formula (l) are therefore useful in the therapy of transplant reactions, for example transplants of kidneys, heabt, bone marrow, skin and endocrine glands. Other afedd ot pathology, in which the immunomoduI ating propertifes of these compounds are of therapeutic benefit: the therapy of neoplastic diseases, acute and chronic infections of both bacterial and viral origin, and of diseases characterized by an immunologic imbalance, like primary or acquired immunodeficiencies and autoimmune disorders. This last category includes rheumatoid arthritis, systemic lupus erythematosus, glomeruloneohritis, vasculitis and blood dyscrasias. The therapeutic regimen for the different clinical syndromes must be adapted to the type of pathology.
In transplantation and infectious diseases the time of onset and the clinical course are, as a rule, known; conversely, the onset of immunological disorders is unknown and their clinical course is generally long and complex. Hence the therapeutic dose must be determined for each single clinical case, taking into account also the fact that it depends also on the route of administration.
The oral route is employed, in general, for all conditions requiring such compounds. Preference is given to the parenteral route, e.g. intravenous injection or infusion, for the prevention of rejection and the treatment of acute infections. In the latter case also topical applications may be used.
For maintenance regimens the oral or parenteral, e.g. intramuscular or subcutaneous, route is preferred, For these purposes the compounds of the invention, for example, compound FCE 20096, can be administered orally at doses ranging e.g. from about 5 to about 100 mg/kg of body weight per day; for example a total of from about 0.35 9 to about 7.00 9 of the active compound for a subject of 70 kg of body weight can be administered in a 24 hour per i od.
Doses of active compounds ranging e.g.from about 5 to about 100 mg/kg of body weight can be used also for the parenteral administration. Of course, these dosage regimens may be adjusted to provide the optimal therapeutic response.
The compounds of the invention are also endowed with an elevated Iipid-Iowering and antΐ-atheroscI erotic activity. In particular they are active in lowering total serum cholesterol and triglycerides, in increasing the total serum HDL cholesterol .
As known, drugs selectively increasing the HDL-choIesteroI concentration in blood and/or the ratio between a and β lipoprotein cholesterol are useful in the prevention and therapy of atherosclerosis: Glueck C.J., Artery, 2,:196 (1976); Day C.E. in Frank-H-CIarke (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: l) on groups of IcemzCER (SPF Caw) male rats, fed for six days with hypercholesterolaemic diet according to C.E. Day: Shurr P.E., Shultz H.R., Day C.E. (Ed.) Atherosclerosis and drug discovery Plenum Pub. Corp., 217 (1976): Experiment 1; or 2) on groups of Iva-SIV (SPF) male rats fed standard *MS/K Altromin diet; Experiment 2.
The tested compounds were suspended i n MethoceI (methy I-ce I I u lose, a 0.5?= solution in water) and administered by stomach tube at the dose of 50 mg/kg for 4 days in both the experiments.
Groups of anima Is were treated with the suspending agent only (control groups).
The total serum cholesterol was determined with the method of Allain, Clin. Chem., 1974, 20, 470.
The serum trigIycerides were determined with the method of Mendez, J. Clin. Chem., 1975, 21,, 768.
The total serum HDL cholesterol was determined according to Demacker P.N.H., Clin. Chem., 1977, 23. 1238, The total β-lipoprotein cholesterol was determined by *MS/K Altromin is a trade mark difference between total serum cholesterol and HDL cholesterol. Statistical analysis in experiment 1 and 2 was performed by the Student fet test for independent samples or by the Cochran's test when the variances were not homogeneous at the F ratio test [Bliss C.I., Statistics in Biology, Vo 1.1, page 213 McGraw Hill Book Company, New York 1967; Cochran W.G., Cox G.H., Experimental designs - J. Willey and Sons Inc., New York, I I Ed. (1968), page 100].
Table 4 shows that, in the animals treated with hypercho I estero1θ laemic diet (Experiment l), the tested compounds, for example FCE 20881), were found to decrease the total serum cholesterol and to increase the total HDL cholesterol.
Table 5 shows that, in the animal fed standard MS/K Altromin diet (Experiment 2), the tested compounds (for example FCE 2088l), were found to decrease the total serum cholesterol, in particular Q-lipoprotein cholesterol and serum triglycerides.
TABLE 4 (Exper i merit N p to 00 P CM c P * w 4) in *3 P 3 =fi a λ to II p « to (Λ Ρ fi. a tota 1 1 0 P fi- —a UJ Ο to ε • oo in =: +> cn > 0) o +1 o, g to o +1 δ 3 — tH c Ol CM L 0\ to • 0 X o to co CO 7) 0 ε ε CM p Tt o\ tn P • ω a* co P p 3 sz c m to 11 to Q) to T3 P l a 3 P cn ε — 3 0 £. fi. «. UJ > to 0 ε a o 0) p ω in CM to — β) o o ΐ1 i1 i1 β — • Ρ o \ to Ch © 0 X m to in Tt l·- 0 ε ε Tt CM — £. as to ε P g C 3 < C in in to 0 © * © « 0 OJ ο ε in P T< c X ο X s 0 o P S- CM to P to c UJ fi. 0 O l·- o U- λ © _X Έ U-) £.
P rs J ϋ to p M c LO a o o V fl. to c to υ to c © to CM Ο -Ρ C ο L 4) Ο.
X ω tn 1x1 CQ < V) Η r—i Ό C -Ρ -Ρ • ο ω — X 43 3 CM CD 3 -Ρ W II •ρ <ν ω -ρ l α 03 4) -σ • σ\ •3- £. — 1x1 B 4) Η • co co υ ω r*4 i—i X ο +1 +1 + i ε - ο Γχ CO □ 03 —< C • • L Χ\ <ϋ 00 oo 0 £. C1 43 CM Ό ω +> ε ε CM t-4 -Ρ 0) κ O -Ρ Γχ C -Ρ ο) — Ό +> 3 CD 3 03 0) II x -Ρ 43 0 ω -ρ £_ a C ο — •Ρ 0 0 L — 1X1 u α> ε β co Ω. -Ρ ω 0 0) Ο t»4 o, 0. 0 ο -{-1 + 1 +1 C »—* tn — 0 ''χ 0 • • ! X Ο 0 Γχ o CUE ε CM CM -Ρ 0) T? +3 CO C -Ρ • 43 — 0+^3 CO ω □ 03 Λ II X Ρ 4) ϋ ω -ρ ί» CL ε — □ 0 L L — 1x1 ο si ε Γχ in 03 -Ρ ω * • +1 tH — 0 Ο +1 +1 (0 ·“ τ“4 C cO fx -ρ 0 \ σ » • 0 X C3 43 O tx η ο ε ε \O tn — ί- 0 4) ε .ο — ε o O C 3 < C i-4 0) 0 '-χ 03 43 -X X o 03 \ ο σ; tn ο ε +3 t*4 C X ϋ — co 0 o -μ L CM τ -P ϋ c UJ L 0 o Ρ- o u. ϋ) ο ^χ. σ -X ιη ε. ο •P σ 3 o Ό © 43 V ~— s~\ •n CL +> © X-^ 0) • o «Ρ U V c 0 c □ 0. ·» tp — tn •P c « c C3 o 0 ··- x-^ ϋ 0) — tp X 43 ·— — 0 c 0 o C3 r· •P 43 0) f zz tl li if. ω ω S 1 6 8 5* In view of their high I ipid-1owering activity, these new compounds are used in the therapy of hyper I ipidemia.
They may be administered in a variety of dosage forms, e.g. orally in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally, in the form of suppositories, parenterally, e.g. subcutaneously, intramuscularly or by intravenous injection or infusion.
The dosage of these compounds depends on the age, weight, conditions of the patient and administration route; for example, for the conpound FCE 2038l, the dosage adopted for oral administrati on in adult ranges from about 50 to about 200 mg pro dose, from 1 to 2 times daily, preferably from 100 to 200 mg pro dose once a day.
The toxicity of the compounds of the invention is negligible. Nine hours food deprived mice were treated orally with single administration of increasing doses, then housed and normally fed. The orientative acute toxicity (LD^^) was assessed on the seventh day after the treatment and, for example, the following data were obtained: >400 40θ <800 mg/kg >800 mg/kg >400 <800 mg/kg >800 mg/kg >800 mg/kg 400 <800 mg/kg FCE 20521 ·· LDso FCE 20524 = LD50 >400 FCE 2O6i8: LDS0 >400 FCE 20696 = LD50 >400 FCE 21849: LD50 >400 The above i nterna1 codes refi >S00 mg/kg < 800 mg/kg < 800 mg/kg 800 mg/kg < 800 mg/kg r to the following compounds: FCE 20770 = 6H,6-carboxy-6-methyl-2-chloro-dibenzo[b,djpyran; FCE 20493 = 6H,6-cyano-dibenzo[b,djpyran; FCE 20519 = 6H,6-cyano-6-methy1-dibenzo[b,djpyran; FCE 20562 = 6H,6-carboxy-6-methyl-dibenzo[b,djpyran; FCE 20518 = 6H,6-cyano-6-hydroxymethyl-dibenzo[b,djpyran; FCE 20561 = 6H,6-carboxy-6-hydroxymethyl-dibenzo[b,djpyran; FCE 20881 = 6H,6-carboxymethyl-dibenzo[b,djpyran; FCE 20521 = 6H,6-ethoxycarbonyl-dibenzo[b,djpyran; FCE 20524 = 6H,6-aminomethyl-dibenzo[b,djpyran; FCE 20618 = 6H,6-(1-piperaziny1)-dibenzo/E>,djpyran; FCE 20696 = 6H,6-(2-dimethyI aminoethoxycarbonyI)-drbenzofb,dj pyran; FCE 21849 = 6H,6-(2-diethyI aminoethoxycarbonyl)-dibenzo[b,dJ pyran.
The invention includes a pharmaceutical composition comprising a compound of the invention in association with a pharmaceuticaI Iy acceptable excipient (which can be a carrier or diluent).
The pharmaceutical compositions of the invention are 51685 ' 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, carboxymethyI cellulose, polyvinyl pyrrolidone, disaggregating agents, e.g. a starch, alginic acid, alginates, sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, 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, sorbitol.
The suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl a I coho I .
The suspensions or solutions for intramuscular injections may contain together with the active compound a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochI or i de.
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 pharmaceuticaIly acceptable carrier, e.g. cocoa-butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
Other pharmaceuticaI forms may be used for topical application, e.g. as creams, lotions or pastes for use in dermatological treatments. For these compositions the active ingredient may be mixed with conventional oleaginous or emulsifying excipients.
The following examples illustrate but do not limit the i nvent i on.
Example 1 62,6-hydroxy-dibenzo/b,d/pyran (10 g, 0.05 mol) was treated vith SOC12 (50 ml) for 20 hours at room temperature. The thionyl chloride was evaporated, the organic residue vas taken up vith toluene and then the mixture vas evaporated to drynes6. The crude residue vas taken up vith anhydrous dimethylformamide (50 ml), then a saturated aqueous solution of KCE (0,05 »o1) was added at 0eC. The temperature vas allowed to rise to the room temperature and the mixture vas maintained at this temperature for 20 hours,- The reaction mixture vas diluted with water and extracted vith ethyl acetate. The organic phase vas washed with water, dried over JTa^SO^ and evaporated to dryness to give a clear oil which solidified. Crystallization from methyl alcohol gave 5H,6-cyano-dibenzo/b,d/ pyrar. as white solid (4.2 g; 0.021 mol; yield 40 $); m.p. 98-iOO°C. 3y proceeding analogously the following compounds were obtained: 6H,6-cyano-6-methyl-dibenzo/b,d/pyran; m.p. 114-ll6°C 6H,6-cyano-6-ethyl-di benzo/b,d/pyran; 6H,6-cyano-6-phenyl-di benzo/ti,d/pyran; m.p. 120-123°C 6H,6-cyano-l-methoxy-d i benzo/b,d/pyran; 6H,6-cyano-2-chIoro-dibenzo/b,d/pyran; m.p. 12S-131°C 6H,6-cyano-2-fIuoro-dibenzo/b,d/pyran; m.p. ll8-121°C 6H,6-cyano-2-nitro-dibenzo/b,d/pyran; m.p. l85~196°C 6H,0-cyano-2-methoxy-dΪbenzo/b,d/pyran; m.p. 122-126°C 6H,0-cyano-2-trifluoromethyl-dibenzo/b,d/pyran; m.p. llO-113°C 6H,0-cyano-8-chIoro-dibenzo/b,d/pyran; m.p. 117-120°C 6H,6-cyano-8-fIuoro-dibenzo/b,d/pyran; m.p. 113-117°C 6H, 6-cyano-8-methoxy-dibenzo/b,d/pyran; m.p. 102-105°C 0H,6-cyano-l,10-dimethoxy-dibenzo/b,d/pyran; m.p. 102-105°C 6H,6~cyano-8,9,10-tri methoxy-di benzo/b,d/pyran; m.p. 114-U5°C 6H,6-cyano-6-methyI-1-methoxy-dibenzo/b,d/pyran; 6H,6-cyano-6-methyI-2-chIoro-dibenzo/b,d/pyran; m.p. 111-116°C 0H,6-cyano-6-methyI-2-fIuoro-dibenzo/b,d/pyran; m.p. 67-71°C 0H,6-cyano-6-methyI-2-n i tro-d i benzo/b,d/pyran; 0H,6-cyano-6-methyI-2-methoxy-dibenzo/b,d/pyran; m.p. 94-99°C 10 6H,6-cyano-6-methyI-2-trif1uoromethyl-di benzo/b,d/pyran; 6H,6-cyano-6-methyI-8-ch1oro-di benzo/b,d/pyran; 6H,6-cyano-6-methyI-δ-fIuoro-di benzo/b,d/pyran; 6H, 6-cyano-6-methy I -S-n i tro-d i benzo/b, ci/py ran; 6H,6-cyano-6-methyI-8-methoxy-d i benzo/b,d/pyran; 6H,6-cyano-6-methyl -1,10-dimethoxy-dibenzo/b,d/pyran, m.p. 115-118°C; 6H,6-cyano-6- methyl -8,9,10-trimethoxy-dibenzo/b,d/pyran, m.p. 1O8-111°C.
Example 2 62,i-hydroxy-dibenzo/i,ά/pyran (4 g; 0.02 mol) was dissolved in anhydrous benzene (50 si). Trimethylsilylcyanide (1.96 g; 0.02 mol) and a catalytic amount of 2nl„ were added to the solution, then the reaction mixture was stirred for 20 hours at room temperature. The solvent and excess of trimethylsilylcyanide were evaporated and the organic residue was taken up twice with toluene. The toluene was evaporated and the residue was separated by column chromatography using silica gel as support and chloroform as mobile phase to give 6H,6-cyano-dibenzo/b,d/pyran as white solid (2.5 g; 0,012 mol); m.p. 98“1OO°C.
By proceeding analogously the following compounds were obtained: 6H,6-cyano-6-methy1-di ben 2o/_b, d/pyran; 6H,6-cyano-6-ethy1-dibenzo/b,d/pyran; m.p . 114-116’C 15 6H,6-cyano-6-phenyl-dibenzo/b,d/pyran: m.p. 120-123’C 6H,O-cyano-l-methoxy-d i benzo/b,d/pyran; 6H,6-cyano-2-ch1oro-di benzo/b,d/pyran; m.p . 128-131°C 6H,6-cyano-2-f1uoro-di benzo/b,d/pyran; m.p, ll8-121°C 6H,6-cyano-2-n ίtro-d i benzo/b,d/pyran; m.p. 185-196°C 20 6H,6-cyano-2-methoxy-d i benzo/b,d/pyran; m.p, . 122-126°! 6H,6-cyano-2-trifluoromethyl-di benzo/b,d/pyran; m.p. 6H,6-cyano-8-ch1oro-di benzo/b,d/pyran; m.p. 117-120°C 6H,6-cyano-8-fIuoro-dibenzo^b,d/pyran; m.p. 113-117°C 6H,6-cyano-8-methoxy-dibenzo/b,d/pyran; m.p. 102-105°C 6H,6-cyano-l,10-dimethoxy-dibenzo^b,d/pyran; m.p. 1O2-1Q5°C 6H,6-cyano-8,9,10-trimethoxy-dibenzo/b,d/pyran; m.p. 114-115°C 6H,6-cyano-6-methyI-1-methoxy-dibenzo/b,d/pyran; 6H,6-cyano-6-methyl-2-chIoro-dibenzo/b,d/pyran; m.p. lll-ll6°C 6H,6-cyano-6-methyI-2-fIuoro-dibenzo/b,d/pyran; m.p. 67-71°C 6H,6-cyano-6-methyI-2-n itro-di benzo^b,d/pyran; 6H,6-cyano-6-methyI-2-methoxy-dibenzo/b,d/pyran; m.p. 94-99°C 6H,6-cyano-6-methyl-2-tr i fIuoromethyl-di benzo^b,d/pyran; 6H, 6-cyano-6-methyI-8-chIoro-d i ben zo^jb, d/pyran; 0H,6-cyano-6-methy1-8-fIuoro-di benzo/b,d/pyran; 0H,6-cyano-6-methyI-S-ni tro-d i benzo/^b, d/pyran; 6H,6-cyano-6-methyI-8-methoxy-di benzo^b,d/pyran; 0H,6-cyano-6-methy1-1,10-di methoxy-di benzo/b,d/pyran; m.p.115-118°C; 6H,6-cyano-6-methyl-8,9,10-tri methoxy-di benzo/b,d/pyran; m.p. 108-11Γ0.
Example 3 6H,6-hydroxy-dibenzo/b,d/pyran (4 g; 0.02 mol) was dissolved in anhydrous benzene and piperazine (35 9; 0.4 mol) dissolved 100 ml of anhydrous dimethylformamide was added all at once.
The mixture was refluxed for 3 days and then poured in ice water. The organic layer was separated and the aqueous phase was extracted with ethyl acetate. The solvent was evaporated to dryness in vacuo and the residue was separated on a silica gel column (mobile phase CHCI^ : MEOH: 32¾ NH^OH = 190 : 10 : l) to obtain 6H,6-(1-piperazinyI)-dibenzo/b,d/pyran as an oily substance which was converted into the hydrochloride in diethyl ether with the stoichiometric amount of 14¾ ethanolic solution of HCl (3 g; 50%); m.p. 240-243°C.
Analogously the following compounds were obtained: 6H,6-/1-(4-methyI-p iperazi nyl j/-di benzo/b,d/pyran; m.p. 118-121 °C; 6H,6-/1-(4-phenyI-piperazinylj/-di benzo/b,d/pyran; m.p. 148-150°C; 6H,6-d i i sopropylami no-di benzo/b,d/pyran; 6H,6-d itert. butyl ami no-d i benzo/b,d/pyran; 6H,6-(1-pi perazi nyl)-l-methoxy-di benzo/b, d/pyran; 6H,6-(l-piperazinyl )-2-chIoro-dibenzo/b,d/pyran; m.p. 178-181°C; 6H,6-(1-p ί perazi nyl)-2-fIuoro-d i benzo/b,d/pyran; 6H,6-(l-pi perazi nyl)-2-ni tro-di benzo/b, c[/pyran; 6H,6-(l-piperazi nyl)-2~methoxy-di benzo/b,d/pyran; 6H,6-(l-piperazinyl)-2-trif Iuoromethyl-di benzo/b,d/pyran; 6H,6-(l-pi perazi nyl)-8-chIoro-di benzo/b,d/pyran; 6H,6-(1-p i perazi nyI)—8—fIuoro-di benzo/b,//pyran; 6H,6-(l-piperazinyl)-8-methoxy-di benzo/b,d/pyran; 6H,6-(1-pi perazi nyl )-1,10-di methoxy-di benzo/b,d/pyran; 6H,6-(l-piperazinyl)-8,9,10-tr ί methoxy-d i benzo/b, d/pyran;m.p. 131 -134°C; 6H,6-(1-p i perazi nyI)-6-methyl-l-methoxy-dibenzo/b,d/pyran; 6H,6-(1-p iperazinyl)-6-methyI-2-chIoro-di benzo/b,d/pyran; 6H,6—(1—ρ ίperazi nyI)-6-methyI-2-fIuoro-di benzo/b,d/pyran; 0H,6-(1-piperazinyl)-6-methyI-2-nitro-dibenzo/b,d/pyran; 6H,6-(l-piperazinyl)-6-methyI-2-methoxy-d i benzo/b,d/pyran; 6H,6-(1-p i peraz i nyl)-6-methyI-2-tri fIuoromethy1-d i benzo/b,d/pyran; 0H, 6-(1-p i peraz inyl)-6-methyl-8-chIoro-di benzo/b,d/pyran; 6H,6-(1-p iperazi nyI)-6-methyl-8-fluoro —di benzo/b,d/pyran; 6H—6—(1-p i perazi nyl)-6-methyI-8-nitro-d i benzo/b,d/pyran; 6H,6-(1-p iperazinyl)-6-methyI-8-methoxy-dibenzo/b,d/pyran; 6H,6-(1-p i peraz inyl)-6-methyl-1,10-di methoxy-d i benzo/b,d/pyran; 6H, 6-(1-piperazi nyl )-6-methyI-8,9,10-tri methoxy—dibenzo /b,d/pyran; 51685» Evam-ple 4 Dibenzo/b,d/pyrilium perchlorate (28 gj 0.1 mol) vas suspended in anhydrous benzene(200 ol),then KCK (1 mol) and a catalytic anount of a l8-erown-6-ether were added. The mixture vas- stirred for 2 days at room temperature. The solid was filtered and the solvent vas evaporated to give an oil which solidified.
Crystallization from methyl alcohol gave 6H,6-oyano-dibenzo /b,d/ pyran as white solid (10 gj yield 48 ¢), m.p. 98-100*0.
By proceeding analogously the following compounds were obtained: )0 6H,6-cyano-6-methy I-dibenzo/b,d/pyran; m.p. 114-ll6°C 6H,6-cyano-6-ethyI-di benzo/b,d/pyran; 6H,6-cyano-6-phenyl-dibenzo/b,d/pyran: m.p. 120-123°C 6H,6-cyano-l-methoxy-d i benzo/b,d/pyran; 6H,6-cyano-2-chIoro-dibenzo/b,d/pyran; m.p. 128-131°C 6H,6-cyano-2-fIuoro-dibenzo/b,d/pyran; m.p. ll8-121°C 6H,6-cyano-2-nitro-dibenzo/b,d/pyran; m.p. l85-196°C 6H,6-cyano-2-methoxy-dibenzo/b,d/pyran; m.p. 122-126°C 6H,6-cyano-2-trifIuoromethyl-dibenzo/b,d/pyran; m.p. 110-113’C 6H,6-cyano-8-chIoro-dibenzo/b,d/pyran; m.p. 117-120°C 6H,6-cyano-8-fIuoro-di benzo/b,d/pyran; m.p. 113-117°C 6H,6-cyano-8-methoxy-dibenzo/b,d/pyran; m.p. 102-105°C 6H,6-cyano-l,10—dimethoxy-dibenzo/b,d/pyran; m.p. 102-l05°C 6H,6-cyano-8,9,10-trimethoxy-dibenzo/b,d/pyran; m.p. 114-H5°C 6H,6-cyano-6-methyI-1-methoxy-di benzo/b, d/pyran; 6H,6-cyano-6-methyl-2-chloro-dibenzo/b,d/pyran; m.p. 111-116°C 6H,6-cyano-6-methyI-2-fluoro-dibenzo/b,d/pyran; m.p. 07-71eC 6H,6-cyano-6-methyI-2-ni tro-d i benzo/b,d/pyran; 6H,6-cyano-6-methyI-2-methoxy-dibenzo/b,d/pyran; m.p. 94-99°C 6H,6-cyano-6-methyI-2-tr ifluoromethyl-d i benzo/b,d/pyran; 6H,6-cyano-6-methyI-8-chIoro-di benzo/b,d/pyran; 6H,6-cyano-6-methyI-8-fIuoro-di benzo/b,d/pyran; 0H,0-cyano-0-methyI-8-n i tro-d i benzo/b,d/pyran; 6H,6-cyano-6-methyI-8-methoxy-d i benzo/b,d/pyran; 6H, 6-cyano-6-methy I -1,10—d i methoxy-di benzo/b, cl/p yr an ;m.p. 115-118°C; 6H,6-cyano-6-methyI-8,9,10-tr i methoxy-di benzo/b, d/pyran; m.p. 108-111°C.
Example 5 X solution of 6H,6-hydroxy-dibenso/b,d7pyran (7.2 gj 0.036’mol.' and • 5 (19.3 g; 0.054 mol) of the yield from ethoxycarbonylmethyl-triphenyl-phosphonium bromide in 200 ml of benzene was refluxed for 3 days. The solvent was evaporated under reduced pressure ana tae residue taken up with diethyl ether. The solid was filtered out and the ether evaporated to dryness. The residue was separated on a silica-gel column (mobile phase CECly CgHgOH = 300:10)to give 7 g (72 ¢) of 6H,6-ethoxycarbonyl — methyl-dibenoo/b,d/pyran; m.p. 45-47°C.
By proceeding analogously the followinq compounds were obtained: 6H,6-ethoxycarbonyImethyl-6-methyl-dibenzo/b,d/pyran; m.p.56-59°C; 6H,6-ethoxycarbonylmethyl-6-ethyl-di benzo/b,d/pyran; 6H,6-ethoxycarbonylmethyl-6-phenyl-di benzo/b,d/pyran; m.p.71-73°C; 6H,6-ethoxycarbonylmethyl-1-methoxy-dί benzo/b,d/pyran; 6H,6-ethoxycarbonyl methyl-2-ch I oro-di benzo/b,d/pyran; m.p.61-64°C; όΗ,ό-ethoxycarbonylmethyI-2-fIuoro-di benzo/b,d/pyran; m.p. 49-523C; 6H,6-ethoxycarbonyl methy l-2-n i tro-d i benzo/b,d/pyran; m.p.75-78°C; 6H,6-ethoxycarbonyl methyl -2-methoxy-di benzo/b, 6H,6-ethoxycarbony ImethyI-2-tr ifluoromethyI-d ί benzo/b,d/pyran 6H,6-ethoxycarbonyImethyl-8-chloro-di benzo/b,d/pyran; 6H,6-ethoxycarbonylmethyI-8-fIuoro-di benzo/b,d/pyran; 6H,6-ethoxycarbonylmethyI-8-methoxy-di benzo/b,d/pyran; 6H,6-ethoxycarbonylmethyl-1,10-dimethoxy-di benzo/b,d/pyran;m.p.44-47°C; 6H,6-ethoxycarbonylmethyl-8,9/10-trimethoxy-di benzo/b,d/pyran; m.p. 58-61°C; 6H,6-ethoxycarbonyI methyl-6-methyI-1-methoxy-di benzo/b,d/pyran; 6H,6-ethoxycarbonylmethyI-6-methyI-2-chIoro-di benzo/b,d/pyran;nhp.67-70°C; 6H,6-ethoxycarbonyI methyl-6-methyI-2-fIuoro-di benzo/b,d/pyran; m.p.56-59°C; 6H, 6-ethoxycarbonyI methyl-6-methyI-2-nitro-di benzo/b,d/pyran; m.p.71-74°C; 6H, 6-ethoxycarbonyl methyI-6-methyI-2-methoxy-di benzo/b,d/pyran; m.p.53-57°C; 6H,6-ethoxycarbonylmethyl-6-methyI-2-tri f1uoromethyl-di benzo/b,d/pyran; 6H,6-ethoxycarbonylmethyl-6-methyI-8-chIoro-di benzo/b,^/pyran; 6H,6-ethoxycarbonyI methyl-6-methyI-8-fIuoro-di benzo/b,d/pyran; 6H,6-ethoxycarbonylmethyl-6-methyI-8-nitro-di benzo/b,d/pyran; 6H,6-ethoxycarbonylmethyl-6-methyl-8-methoxy-di benzo/b,d/pyran; 6H,6-ethoxycarbonylmethyl-6-methyI-1,10-di methoxy-di benzo/b,d/pyran; m.p. 49-52°C; 6H, 6-ethoxycarbonylmethyl-6-methyl-8,9,10-tr i methoxy-d i benzo15 /b,d/pyran; m.p.54-57°C.
Example 6 4ι5 g (0.02 mol) of c(-(2-araino-phenoxy)-phenylacetoniti’ile were dissolved in distilled water (60 ml). H^SO^ (18 ml; 0.08 mol) was added to the above solution at O’C and then NaNO^ (1·7 Bi 0.025 mol) dissolved in distilled water was added drop by drop. Ihe unreacted excess of NaNO^ was destroyed by adding a suitable amount of urea. Cu(N0^)2’3H20 (75 g; 0.31 mol) dissolved in distilled water (250 ml) and Cu^O (2.6 g; 0.018 mol) were added to the mixture under vigorous stirring and by keeping the temperature at O’C.
The crude obtained products was extracted with ethyl acetate, washed with water, dried on anhydrous Na^O^, decolarated and finally evaporated to dryness. The residue taken up with pentene:isopropyl ether» 9:1 gave 6H,6-cyano-dibenzo/b,^7pyran as a clear brown solid (2.5 ?; yield 60%; m.p. 98-100’C).
Analogously, the following compounds were obtained: 6H,6-cyano-l-methoxy-di benzo/b,d/pyran; 6H,6-cyano-2-chloro-dibenzo/b,d/pyran; m.p. 128-131°C 6H,6-cyano-2-fIuoro-dibenzo/b,d/pyran; m.p. 118-121°C 6H,6-cyano-2-nitro-dibenzo/b,d/pyran; m.p. 185-190°C 6H,6-cyano-2-methoxy-dibenzo/b,d/pyran; m.p, 122-126°C 6H,6-cyano-2-trifIuoromethyl-dibenzo/b,d/pyran; m.p. 110-113°C 6H,6-cyano-8-chIoro-dibenzo/b,d/pyran; m.p. 117-120°C 6H,6-cyano-8-fIuoro-dibenzo/b,d/pyran; m.p. 113-117°C 6H,6-cyano-8-methoxy-dibenzo/b,d/pyran; m.p. 102-105°C 6H,6-cyano-l,10-dimethoxy-dibenzo/b,d/pyran; m.p. 102-105°C 6H,6-cyano-8,9,10-trimethoxy-dibenzo/b,d/pyran; m.p. 114-115°C 6H, 6-ethoxycOr bohy I-ii i behzo/b,d/pyran; m.p. 43-45°C; 0H,6-ethoxycarbony I -1-mdthoxy-d i benzo/b,//pyran; OH, 6-ethoxycarbdn yl ^2-chi oro-d i benzo/b,//pyran; m.p,49-52°C; OH,6-etboxydarb0nyI-2-f Iuoro-d i benzo/b,d/pyran; 0H,ό-ethoxycarbonyI-2-n i tro-d i benzo/b,d/pyran; OH, ό-ethoxycarbonyI-2-methoxy-dibenzo/b,d/pyran; m.p. 39-42°C; OH,O-ethoxycarbonyI-2-tr i fIuoromethy1-di benzo/b,d/pyran; OH,ό-ethoxycarbonyI-8-chloro-di benzo/b,d/pyran; OH, ό-ethoxycarbonyI-8-fIuoro-d i benzo/b,d/pyran; 1ΰ 0H,ό-ethoxycarbonyI-8-methoxy-di benzo/b,d/pyran; OH,O-ethoxycarbonyI-1,10—dimethoxy-di benzo/b,d/pyran; OH, 6-ethoxycar bony I -8,9,10-tr i metoxy-d i benzo/b, d/pyran; m.p.61-63“C; όH,6-/2-(4)4/_di methyl-oxazoli nylj/-di benzo/b,d/pyran.
ExampIe 7 A solution of¢(-(4-pyridyI)-2-(2-methoxy-phenyI)-benzyl alcohol (17.7 g; 0.001 mol) in 120 ml of 48% HBr was refluxed for 3 hours. On cooling, yellow crystals of 6H,65 -(4-pyridyl )-di benzo/b, d/pyran hydrobromide separated, which was washed with icy water ( 11.2 g; yield 70%); m.p. 240°C (dec).
By proceeding analogously the following compounds were obta i ned: 6H,6-(3-pyri dyl )-di benzo/b, d/pyran;-HBr m.p. 207-211°C; OH,6-(2-pyr idyl )-di benzo/b,d/pyran;-HCI m.p. 153- 157°C; 6H,6-(2-pyrazinyl)-di benzo/b,//pyran. -aW-g -dibenzo/b,d7pyran 6H,6-(4,4-dimethyl)-oxazolin-2-yl/(4.2 g; Ο.Ο15 aol) disperded in 3H HCl (lOO ml) was refluxed for 10 min. The solvent was evaporated to dryness and the residue, taken up with a 20 % solution of NaOH in · CH^OH/HgO (1/1) (100 ml), was refluxed for 30 min. Methyl alcohol was evaporated and the residue, taken up with water, was acidified. The solid product was filtrated and washed with water, then dried under vacuum in oil-bath for 24 hours, thus giving 6H,6-carhoxy-dibenzo /b,d/pyran (3.2 gj yield 95 %), m.p. 184-186°C.
Exanple $ , 6H,6-(4,4-dimethyl)-oxazolin-2-yl-dibenzo/b,d/pyran (4.2 gj O.OI5 mol) was dissolved into 7 % ethanolic sulphuric aeid (120 ml) and refluxed for 15 hours. The solvent was evaporated off and the residue, taken up with diethyl ether, was washed with 10 % MaHCO^ solution and then with £5 water. The solvent was evaporated, the residue decoloured and the residual solvent evaporated off, thus giving 6H,6-ethoxyoarbonyl-dibenzo /b,d/pyran as an orange oil which solidifies by treatment with pentane under cooling. (3.4 gj yield 90 %)ι 685 ,xa, ,1a 10 . 6-cyano-6-methyl-2-chloro-dibenzo[b,djpyran (6.3 g; 0.025 mol) and. NaOH (6.3 g; 0.1o mol) were dissolved, in 80 $ C^H^OH (100 ml) and the solution refluxed for 16 hours. After evaporation of the solvent the residue was dissolved in water and the solution washed vith diethyl ether. The aqueous solution was then acidified with.
HCl and extracted with ethyl acetate. The 6H,6-carhoxy-6-methyl-2-chloro-eC. 3y proceeding analogously the following compounds, were-ebtained: 6H,6-carboxy-di benzo/b,d/pyran; m.p.184-186°C; 6H, 6-carboxy-6-methyl -di benzo/b,d/pyran; m.p. 147-151 °C; 6H, 6-carboxy-6-hydroxymethy I -di benzo/b,d/pyran; m.p.180-182°C; 6H, 6-carboxy—6-ethy I -d i benzo/b, d/pyran; m.p.157-158°C; 6H, 6-carboxy-6-pheny l -di benzo/b,d/pyran; m.p.161-163°C 6H,6-carboxy-1-methoxy-dibenzo/b,d/pyran; 6H, 6-carboxy-2-chl oro-di benzo/b,d/pyran; m.p.164-167°C; 6H,6-carboxy-2-f I uoro-di benzo/b,d/pyran; m.p.148-152°C; 6H, 6-carboxy-2-n i tro-d i benzo/b, d/pyran; m.p. 196-199°C; 6H,6-carboxy-2-methoxy-dibenzo/b,d/pyran; m.p. 137-140°C; 6H,6-carboxy-2-tr i fIuoromethyl-d i benzo/b,d/pyran; 6H,6-carboxy-8-chIoro-di benzo/b,d/pyran; 6H,6-carboxy-8-fIuoro-d i benzo/b,d/pyran; 6H,6-carboxy-8-methoxy-di benzo/b,d/pyran; 6H,6-carboxy-1,10-di methoxy-d i benzo/b,d/pyran; 6H, 6-carboxy-8,9,10-tr i methoxy-di benzo/b,d/pyran; m.p. 135-138°C; 6H,6-carboxy-6-methyI-1-methoxy-d i benzo/b,d/pyran; 6H,6-carboxy-6-methyl -2-f I uoro-di benzo/b,d/pyran; m.p.142-145°C; 6H,6-carboxy-6-methyl-2-nitro-di benzo/b,4/pynan; m.p. 187-190°C; 6H,6-carboxy-6-methyI -2-methoxy-di benzo/b,d/pyran; m.p.133-136°C; 6H,6-carboxy-6-methyI-2-tri fIuoromethyl-di benzo/b,d/pyran; 6H,6-carboxy-6-methyl-8-chIoro-di benzo/b,d/pyran; 6H,6-carboxy-6-methyl-8-fIuoro-d i benzo/b,d/pyran; 6H,'6-carboxy-6-methyl-8-ni tro-di benzo/b, d/pyran; 6H,6-carboxy-6-methyl-8-methoxy-di benzo/b,d/pyran; 6H, 6-carboxy-6-methy I -1,10-di methoxy-di benzo/b,d/pyran;m,p, 139-142°C; 6H,6-carboxy-6-methy I-8,9,10-triinethoxy—di benzo/b, d/pyran.,m.p. 149-152°C 6H,6-(carboxy-aminomethyl)-dibenzo/b,d7pyran; m.p. 128-145°C 6H,6-(carboxy-ami nomethy 1)-6-methyl-d i benzo/b,d/pyran; 6H,6-(ca rboxy-ami nomethyl)-1-methoxy-d i benzo/b, d/pyran; 6H,6-(carboxy-ami nomethyl)-2-chloro-di benzo/b,d7pyran; 6H,6-(carboxy-aminomethy1)-8-chloro-dibenzo/b,d7pyran; m.p. 137-152°C; 6H,6-(carboxy-ami nomethyl)-8-f1uoro-di benzo/b,d/pyran; 6H,6-(carboxy-aminomethyl )-8,9,10-trimethoxy-di benzo/b,d/pyran.
Example 11 A solution of 6H,6(cyano-hydroxy-methyl)-dibenzo/b,d/pyran (24 9; 0.1 mol) in 100 ml of dioxane and 200 ml of 37% HCl was refluxed for 3 days. The dioxane was distilled off; the solution was made basic through 35% NaOH and washed twice with diethyl ether. After acidification with 8% HCl, the precipitate was extracted with ethyl acetate.
The obtained organic solution was washed thoroughly with water, treated with charcoal, anhydrified on sodium sulfate and evaporated to dryness.
The residue was ground with a mixture of di isopropyl ether: pentene = 1:1 to obtain 6H,6-(carboxy-hydroxy-methyl)-dibenzo /b,d/pyran (l6.4 g; yield 64%) as a mixture of diasteroisomers approximately in the 1:1 ratio; m.p. 137-147°C. '5 By proceeding analogously the following compounds were obta i ned: 6H, 6-/car boxy—hydroxy-methy l)-6-methy l|-d i benzo/b, d/p yr an; m.p. 134-147°C; 6H, 6-(car boxy-hydroxy-methy lj-1-methoxy-d i benzo/b, d/pyran;m.p. 116-130°C; 6H, 6-(car boxy-hydroxy-methy lj-2-ch I oro-d i benzo/b, d/pyran; 2θ 6H, 6-(oar boxy-hydroxy-methy l)-2-f I uoro-d i benzo/b, cl/pyran; m.p. 119-135°C; 0H, 6-(:ar boxy—hydroxy-methyl)-2-n i tro-d i benzo/b, d/pyran; 6H, 6-(car boxy—hydroxy-met hy l)-2-methoxy-d i ben z o/b, d/p y r an; m.p. 120-140°C; 6H, 6-(car boxy-hydroxy-methy 1)-2-tr i f I uoromethyl -d i benzo/b, d/p ^3 0H, 6-(car boxy-hydroxy-methy l)-8-ch I oro-di benzo/b, d/pyran; 6H, 6-{carboxy—hydroxy- methyl)-8-f I uoro-d i benzo/b, cl/pyran; 6H, 6-{carboxy—hydroxy-methy l)-8-n i tro-di benzo/b, d/pyran; 6H, 6-(car boxy—hydroxy-methy 1)-8-methoxy-di benzo/b,d/pyran; 6H, 6-(car boxy-hydroxy-methy 1)-1, 10-d i methoxy-d i benz o/b,d/p‘yr 6H, 6-{carboxy-hydroxy-methyl)-8,9, 10-tr i methoxy-d i benzo/b, d/30 pyran, m.p. 131-147°C.
Example 12 6H,6-carboxy-6-methyl-2-chlorodibenzo[b,d]pyran (4.1 g: 0.015 mol) was dissolved in 100 ml of absolute ethanol and the solution was refluxed for 16 hours while gaseous HCl was bubbled in. The solvent was evaporated to dryness, the residue was redissolved in diethyl ether and the organic solution washed with N/lo NaOH and with water to neutrality. The 6H,6-ethoxycarbonyl-6-methyl-2-chlorodibenzo[b,d]pyran was obtained as a thick oil after evaporation of the ether and was solidified with pentane to give 4.3 g (95 %) of product as white crystals; m.p. 62-65°C.
By proceeding analogously the following compounds were obtained: 6H,6-ethoxycarbonyI-di benzo/b,d/pyran; m.p. 43-45°C; 6H,6-ethoxycarbony I methy I -d i benzo/b, d/pyran; m.p.45-47’C; 6H,6-(2-ethoxycarbonyl ethyl )-di benzo/b,d/pyran; m.p.29-32°C; 6H,6-(3-ethoxycarbonyI propyl)-di benzo/b,d/pyran; 6H,6-ethoxycarbonyI-6-methyI-di benzo/b,d/pyran; N.M.R. (CC14)J1.03 (t, 3H,CH2CH3) 1.9 (S,3H,CH3) 3.95 (q, 2H,CH2) 6.75-7.7 (m,8H) 6H, 6-ethoxycarbony I methy I -6-methy I -di benzo/b, d/pyran; m.p.56-59°C; 6H,6-ethoxycarbony I methyl-6-hydroxymethyI-di benzo/b,d/pyran; 6H,6-(2-ethoxycarbonyI ethyl}6-methyI-di benzo/b,d/pyran; 6H,6-(3-ethoxycarbonyI propyl)-6-methyI-di benzo/b,d/pyran; 6H,6-(2-dimethyI ami noethoxy-carbonyl)-dibenzo/b,d/pyran;.HCl m.p.158y _ 6H,6-(2-<5i methyl ami noethoxy-carbonyl)-6-methyl-di benzo/b,d/pyran, •HCl m.p.165-167°C; 6H,6-(2-di methyl ami noethoxy-carbonyl}-6-ethyl-d i benzo/b,d/pyran; · HC1, m.p. 147-15O°C; 6H,6-(2-di methyl ami noethoxy-carbonyI)-6-propyI-di benzo/b,d/pyran; 6H,6-(2-di methyI ami noethoxy-carbonyl)-l-methoxy-dibenzo/b,d/pyran; · HC1, m.p.139-142°C; 6H,6-(2-di methyl ami noethoxy-carbonyl)-2-chIoro-di benzo/b,d/pyran;»HC1, m.p. 183-186°C; 6H,6-(2-di methyl ami noethoxy-carbonyl)-2-fIuoro-di benzo/b,d/pyran; •HCT.m.p. 163-166°C; · HC1,m.p.T87-190°C; 6H,6-(2-di methyl ami noethoxy-carbonyI)-2-n itro-di benzo/b, d/pyran;/ 6H,6-(2-dimethyl ami noethoxy-carbonyl)-2-methoxy-dibenzo/b,d/pyran; · HC1, m.p. 146-149°C; 6H,6-(2-d i methyI ami noethoxy-carbonyI)-2-tr i fIuoromethyl-d i benzo/b,d/pyran; OH,6-(2-di methyl aminoethoxy-carbonyl)-8-chIoro-dί benzo/b,d/pyran; «HC1, m.p. 174-177°C; 6K,6-(2-dimethyl ami noethoxy-carbonyl)—S—fIuoro-di benzo/b,d/pyran; · HC1 jp.p.178-181°C; 6H,6-(2-di methyI ami noethoxy-carbonyl)-8-nitro-di benzo/b,d/pyran77 6H,6-(2-d imethyl ami noethoxy-carbonyI)-8-methoxy-di benzo/b^d/pyran; 6H, 6-(2-d i methy I ami noethoxy-carbonyl )-1, 10-dimethoxy-dibenzo-/ b,d_7 pyran; •HCl.m.p. 147-150°C; 6H,6-(2-diethylaminoethoxy-carbonyl)-dibenzo/b,d7pyran; oil η θ = 1.5841; 51685* όΗ,6-(2-dimethyI ami noethoxy-carbonyl )-8,9,10-tri methoxy-dibenzo/b,d/pyran; - HCI, m.p. 162-165°C; ,HC1 m p ^g^og. 6H, 6-(2-di methyl ami noethoxy-carbonyl methyl)-di benzo/b,d/pyranTT 6H,6-(2-di methyl ami noethoxy-carbonyl ethyl)-di benzo/b,d/pyran; 6H,6-ethoxycarbonyI-l-methoxy-dibenzo/b,d/pyran; 6H,6-ethoxycarbonyI -2-chl oro-d i benzo/b,d/pyran; m.p.49-52°C; 6H,6-ethoxycarbonyl-2-fluoro-dibenzo/b,d/pyran; m.p. 43-46°C; 6H,6-ethoxycarbony I-2-n i tro-d i benzo/b,d/pyran; 6H,6-ethoxycarbonyl-2-methoxy-dibenzo/b,d/pyran; m.p. 39-42°C; 6H,6-ethoxycarbonyI-2-trif IuoromethyI-dibenzo/b,d/pyran; 6H,6-ethoxycarbony I-8-chloro-d i benzo/b,d/pyran; 6H,6-ethoxycarbonyl-8-fIuoro-di benzo/b,d/pyran; 6H,6-ethoxycarbonyI-8-n i tro-d i benzo/b,d/pyran; 6H,6-ethoxycarbony I-8-methoxy-d i benzo/b,d/pyran; 6H,6-ethoxycarbony I-1,10-di methoxy-di benzo/b,d/pyran; 6H,6-ethoxycarbonyl-8,9,10-trimethoxy-di benzo/b,d/pyran; m.p.61*63°C; 6H,6-ethoxycarbonyI-methyI-l-methoxy-di benzo/b,d/pyran,· 6H,6-ethoxycarbony I-methyI-2-chIoro-di benzo/b,d/pyran; m.p.61-64°C; 6H, 6-ethoxycar bony I -methyl -2-f I uoro-di benzo/b, d/pyran; m.p,49-52°C; 6H,6-ethoxycarbonyI-methyl-2-nitro-di benzo/b,d/pyran;m.p.75-78°C; 0H,6-ethoxycarbonyI-methyI-2-methoxy-di benzo/b, d/pyran; m.p. 39-42°C; 6H,6-ethoxycarbony I-methyl-2-tri fIuoromethyI-di benzo/b,d/pyran; 6H,6-ethoxycarbonyI-methyl-8-chloro-di benzo/b,d/pyran; 6H,6-ethoxycarbonyI-methyI-8-fIuoro-di benzo/b,d/pyran; 6H,6-ethoxycarbony I-methyl-8-n i tro-d i benzo/b,d/pyran; όΗ,6-ethoxycarbonyI-methyI-8-methoxy-d i benzo/b,d/pyran; — - m.p.44-47°C; 6H,6-(2-ethoxycarbonyI-ethyl)-l-methoxy-di benzo/b,d/pyran; 6H,6-(2-ethoxycarbonyI-ethyl)-2-chIoro-di benzo/b,d/pyran; m.p.63-66°C; 6H,6-(2-ethoxycarbonyl-ethyl)-2-fIuoro-di benzo/b,d/pyran; m.p.48-52°C; 6H,6-(2-ethoxycarbonyI-ethyl)-2-ni tro-di benzo/b,d/pyran; 6H,6-(2-ethoxycarbonyI-ethyl )-2-methoxy-di benzo/b,d/pyran; 6H, 6-(2-ethoxycarbonyI-ethyl)-2-tri fIuoromethyl-di benzo/b,d/pyran; 6H,6-(2-ethoxycarbonyI-ethyl)-8-chloro-dibenzo/b,d/pyran; 6H,6-(2-ethoxycarbonyI-ethyl ) —8—FIuoro-d i benzo/b,d/pyran; 6H,6-(2-ethoxycarbonyI-ethyl )-8-nitro-di benzo/b,d/pyran; όΗ,6-(2-ethoxycarbonyI-ethyl )-8-methoxy-di benzo/b,d/pyran; 6H,6-(2-ethoxycarbonyI-ethyl )-1,10-dimethoxy-di benzo/b,d/pyran; 6H,6-(2-ethoxycarbonyl-ethyl )-8,9,10-tri methoxy-di benzo/b,^/pyran; m.p. 62-65°C; 6H,6-(ethoxycarbonyl-hydroxy-methyl)-di benzo/b,d/pyran, 6.65-7.7 (m,8H); 5H,6-(ethoxycarbonyl-hydroxy-methyl)-6-methyl-dibenzo/b,d/pyran; 6H,6-(ethoxycarbonyl-hydroxy-methyl)-2-chloro-dibenzo/b,d/pyran; 6H ,6-(ethoxycarbonyl-hydroxy-methyl)-2ni tro-dibenzo/b,d/pyran; 6H,6-(ethoxycarbonyl -hydroxy-methyl )-2-methoxy-dibenzo/b,d/pyran; 6H,6-(ethoxycarbonyl-hydroxy-methy1)-2-hydroxy-di benzo/b,d/pyran; 6H,6-(ethoxycarbonyl-hydroxy-methyl )-8,9,1O-trimethoxy-dibenzo/b,d7pyran; 51685 ‘ Example 13 6H,6-carboxy-dibenzo/b,d/pyran (4 9i 0.0l8 mol) was suspended in thionyl chloride (40 ml; 0,55 mol) and kept at room temperature for 24 hours. The clear solution was taken up with toluene and the solvent was evaporated to dryness in vacuo. The crude residue was dissolved in 100 ml of diethyl ether and the obtained solution was added dropwise, at room temperature, to a solution of 2-dimethyl ami no-ethanol (53 ml; 0,053 mol) in 100 ml of diethyl ether. After half an hour the solution was washed with water and made anhydrous with sodium sulfate. The obtained 6H,6-(2-drmethylaminoethoxy-carbonyl )-dibenzo/b,d/pyran was precipitated as hydrochloride with 14% HCl alcoholic solution; (4.4 9! yield 75%); m.p. 158-l60°C.
By proceeding analogously the following compounds were obtai ned: 6H,6-ethoxycarbonyI-6-methyI-2-chIoro-dibenzo/b,d/pyran; m.p.62-65°C; 6H,6-ethoxycarbony1-dibenzo/b,d/pyran; m.p. 43-45°C; 6H,6-ethoxycarbonylmethyI-di benzo/b,^/pyran; m.p.45-47°C; 0H,6-(2-ethoxycarbonylethyl)-di benzo/b,d/pyran; m.p.29-32°C; 6H,6-(3-ethoxycarbonyI propyl)-di benzo/b,d/pyran; 6H,6-ethoxycarbony I-6-methyI-d i benzo/b,d/pyran; N.M.R. (CCI4)J 1.03 (t, 3H,CH2CH3) 1.9 (s,3H,CH3) 3.95 (q, 2H,CH2) .75-7.7 (m,8H) 6H,6-ethoxycarbonylmethyI-6-methyI-d i benzo/b,d/pyran; m.p.56-59°C; 6H,6-ethoxycarbonyImethyI-6-hydroxymethy I-di benzo/b,d7pyran; 6H,6-(2-ethoxycarbonyI ethyl/6-methyI-d i benzo/b,d/pyran; 6H,6-(3-ethoxycarbonylpropyl)-6-methyI-dibenzo/b,d/pyran; 6H,6-(2-dimethylaminoethoxy-carbonyl)-6-methyl-dibenzo/&, d/pyran, · HCl, m.p.165-167°C; 6H,6-(2-d i methyl ami noethoxy-carbonyI)-6-ethyI-dibenzo/b,d/pyran; · HCl, m;p. 147-150°C; 6H,6-(2-dimethyl ami noethoxy-carbonyl)-6-propyI-dibenzo/b,d/pyran; 6H,6-(2-dimethyl ami noethoxy-carbonyl )-1-methoxy-di benzo/b,d7pyran; · HCl, m.p.139-142’C; 6H,6-(2-d i methyl ami noethoxy-carbonyl)-2-chloro-di benzo/b,d/pyran;.HCl, m.p. 183-186°C; 6H,6-(2-di methyl ami noethoxy-carbonyl)-2-fIuoro-d i benzo/b,d/pyran; «HCl, m.p. 163-166°C; · HCl ,m.p. 187-189°C; 6H, 6-(2-d i methyl ami noethoxy-car bony I )-2-ni tro-d i benzo/b,d/pyran;/ 6H,6-(2-di methyl ami noethoxy-carbonyl)-2-methoxy-dibenzo/b,d/pyran; · HCl, m.p.146-149°C; 0H,6-(2-dimethyl ami noethoxy-carbonyl)-2-tr ifIuoromethy I -dibenzo/b,d/pyran; 6H,6-(2-dimethyl ami noethoxy-carbonyl)-8-chIoro-di benzo/b,d/pyran; . HCl, m.p. 174-177’C; 6H,6—(2—dimethyl ami noethoxy-carbonyl)-8-fIuoro-di benzo/b, d/pyran; · HCl jn.p. 178-181 °C; 0H,6-(2-di methyl ami noethoxy-carbonyl)-8-nίtro-dibenzo/b,d/pyran;/ 0H,6-(2-d i methyl ami noethoxy-carbonyI )-8-methoxy-di benzo/b,.d/pyran; 6H,6-(2-d i methyl ami noethoxy-carbonyl )-1,10-di methoxy-dibenzo / b,d_/ pyran; «HCl, m.p. 147-150°C; 6H,6-(2-diethylaminoethoxy-carbonyl)-dibenzo/b,d/pyran; oil η θ= 1.5841; 51585 * 6H,6-(2-dimethyl ami noethoxy-carbonyl )-8,9,10-tri methoxy-dibenzo/b,d/pyran; «HCI, m.p. 162-165°C; .jdjn.p. 136-139°C; 6H,6-(2-di methyl ami noethoxy-carbonyl methyl)-di benzo/b,d/pyran;7 6H,6-(2-dimethyl ami noethoxy-carbonyl ethyl)-di benzo/b,d/pyran; 6H,6-ethoxycarbonyI-1-methoxy-di benzo/b,d/pyran; 6H,6-ethoxycarbony I-2-chIoro-di benzo/b,d/pyran; m.p.49-52°C; 6H,6-ethoxycarbonyl~2-fIuoro-dibenzo/b,d/pyran; m.p. 43-46°C; 6H,6-ethoxycarbonyI-2-n i tro-d i benzo/b,d/pyran; 6H,6-ethoxycarbonyl-2-methoxy-dibenzo/b,c[/pyran; m.p. 39-42°C; 6H,6-ethoxycarbonyl-2-tri f Iuoromethyl-di benzo/b,d/pyran; 6H,6-ethoxycarbonyl-8-chIoro-di benzo/b,d/pyran; OH,6-ethoxycarbonyI-8-fIuoro-d i benzo/b,d/pyran; 0H,6-ethoxycarbonyI-8-n itro-di benzo/b,d/pyran; 6H,6-ethoxycarbonyl-8-methoxy-d i benzo/b,d/pyran; 6H,6-ethoxycarbonyl-1,10—dimethoxy-di benzo/b,d/pyran; 6H,6-ethoxycarbonyl-8,9,10-tr i methoxy-di benzo/b,d/pyran; m.p.61-63°C; 0H,6-ethoxycarbony1-methyl-1-methoxy-di benzo/b,d/pyran; 6H,6-ethoxycarbonyl-methyl-2-chIoro-di benzo/b,d/pyran; m.p. 61-64 °C; 6H,6-ethoxycarbonyl-methyl-2-fIuoro-di benzo/b,d/pyran;m.p.49-52°C; -6H,6-ethoxycarbony1-methyI-2-ni tro-di benzo/b,d/pyran;m.p.75-78°C; 6H,6-ethoxycarbonyI-methyI-2-methoxy-di benzo/b,d/pyran;m.p.39-42°C; 6H,6-ethoxycarbonyI-methyI-2-tr i fIuoromethyI-di benzo/b,d/pyran; 6H,6-ethoxycarbonyl-methyI-8-chIoro-di benzo/b,d/pyran; 6H,6-ethoxycarbonyI-methyI-8-fIuoro-di benzo/b,d/pyran; 6H,6-ethoxycarbonyl-methyl-8-ni tro-di benzo/b,d/pyran; 6H,6-ethoxycarbony1-methyI-8-methoxy-dibenzo/b,d/pyran; — — m.p.44-47°C; 6H,6-ethoxycarbonyI-methyl-1,10-di methoxy-di benzo/b,d/pyranjy 6H,6-ethoxycarbonyI-methyI-8,9,10-tri methoxy-di benzo/b,d/pyrarfr|^~^· 6H,6-(2-ethoxycarbonyI-ethyl)-l-methoxy-di benzo/b,d/pyran; 6H, 6-(2-ethoxycarbonyI-ethyl)-2-chIoro-di benzo/b,d/pyran; m.p.63-65°C; 6H,6-(2-ethoxycarbonyI-ethyl)-2-fIuoro-di benzo/b,d/pyran; m.p.48-52°C; 6H,6-(2-ethoxycarbonyl-ethyl)-2-nitro-dibenzo/b,d/pyran; 6H,6-(2-ethoxycarbonyI-ethyI)-2-methoxy-di benzo/b,d/pyran; όΗ,6-(2-ethoxycarbonyI-ethyl)-2-tri fIuoromethyl-di benzo/b,d/pyran; όΗ,6-(2-ethoxycarbonyI-ethyl )-8-chIoro-di benzo/b^d/pyran; 6H,6-(2-ethoxycarbonyl-ethyl)-8-fIuoro-dibenzo/b,d/pyran; 6H,6-(2-ethoxycarbony I-ethyl)-8-n i tro-d i benzo/b,d/pyran; 6H,6-(2-ethoxycarbonyI-ethyl )-8-methoxy-di benzo/b, d/pyran; όΗ,6-(2-ethoxycarbonyI-ethyl )-1,10-dimethoxy-di benzo/b,d/pyran; 6H,6-(2-ethoxycarbonyI-ethyI )-8,9,10-tr i methoxy-di benzo/b,d/pyran; m.p. 62-65°C; 6H,6-(ethoxycarbonyl-hydroxy-methyl)-dibenzo/6,47pyran, N.M.R. CC1 :<Γ 1 (t,3H,CH3). ,2.77 (bS,1H,OH), 3.95 (q,2H,CH2) 6.55-7.7 (m,8H); 6H,6-(ethoxyca rbonyl-hydroxy-methyl)-6-methyl-dibenzo/b,d/pyran; 6H,6-(ethoxycarbonyl-hydroxy-methyl)-2-chloro-di benzo/b,d/pyran; 6H,6-(ethoxycarbonyl-hydroxy-methyl)-2ni tro-di benzo/b,47pyran; 6H, 6-(ethoxycarbonyl —hydroxy-methyl)-2-methoxy-dibenzo/b,d7pyran; 6H,6-(ethoxycarbonyl-hydroxy-methyl)-2-hydroxy-dibenzo/b,d/pyran; 6H,6-(ethoxycarbonyl-hydroxy-methyl)-8,9,10-trimethoxy-dibenzo/&,d7pyran; 6H,6-(N-methyl-4-p ipen i dyIoxycarbonyI)-methyI-di benzo/b,d/pyran; 6H,6-(N-methyl-4-piperidyloxycarbonyI)-methyI-6-methyl -d i benzo/b,d/pyran; 6Hz6-(3-pyri dyI methylenoxycarbonyI)-methyI-di benzo/b,d/pyran; 6K,6-(3-Pyr idylmethyIenoxycarbonyI )-methyI-6-methyI-d i benzo/b,d/pyran; Example 14 A solution of 6H,6-ethoxycarbonyI-dibenzo/b,d/pyran; (5 g; 0.02 mol) in 100 ml of 32% NH^OH and 50 ml of methanol was stirred in a tight stoppered flask at room temperature for ten hours. The solid 6H,6-aminocarbonyl-dibenzo/b,d/pyran was f i Itered (2.9 g; yield 64%); m.p. 193-194°C.
By proceeding analogously the following compounds were obtai ned: 6H,6-( ter.butyl ami nocarbonyl-hydroxy-methyl)-dibenzo/b,d7pyran,m.p.??3-235°C; SH,6-(tert.butyl ami noca rbonyl-hydroxy-methyl)-6-methyl-dibenzo/b,d7pyran; , ' m.p.207-219°C SH,6-(tert.butyl aminocarbonyl-hydroxy-methyl)-2-chloro-dibenzo/b, dj pyran;z , . , m.p.238-246°C; 6H ,6-(tert,butyl ami nocarbonyl-hydroxy-methyl)-2-ni tro-di benzo/b,dy pyran; ~J~ , T jn.p.195-215°C 6H,6-(tert.butyl ami nocarbonyl-hydroxy-methyl)-2-methoxy-dibenzo/b, d/pyran; / . m.p.227-241°C 5H,6-(tert.butyl ami nocarbonyl-hydroxy-methyl)-2-hydroxy-dibenzo/b,d/pyran 77 6H,5-{tert.butyl ami nocarbonyl-hydroxy-methyl )-8,9,1O-trimethoxy-dibenzo/b,d/pyran. m.p. 226-242°C; 6H,6-ami nocarbonyl-1-methoxy-dibenzo/b,d/pyran; 6H,6-ami nocarbonyl-2-chIoro-di benzo/b,d/pyran; 6H,6-ami nocarbonyl-2-fIuoro-dibenzo/b,d/pyran; 6H,6-ami nocarbonyl-2-ni tro-di benzo/b,d/pyran; S168S 6H,6-ami nocarbonyl-2-methoxy-d i benzo/b,d/pyran; 6H,6-aminocarbonyl-2-trί fIuoromethy!-di benzo/b,d/pyran; 0H,6-ami nocarbonyl-8-chIoro-di benzo/b,d/pyran; 6H,6-aminocarbonyl-8-f Iuoro-di benzo/b,d/pyran; 6H,6-ami nocarbonyI-8-n i tro-d i benzo/b,d/pyran; 6H, '.-ami nocarbonyl -8-methoxy-d i benzo/b,d/pyran; 6H,6-ami nocarbonyl-1,10-d i methoxy-di benzo/b,d/pyran; 6H,6-ami nocarbonyI-8,9,10-tr i methoxy-d i benzo/b,d/pyran; 6H-6-aminocarbonyl-6-methyl -2-ch I oro-di benzo/b,d/pyran; m.p.167-170°C; 6H,6-aminocarbonyl-methyl-dibenzo/b,d/pyran; m.p. 148-150°C; 6H,6-methyl ami nocarbonyl -methyl-di benzo/b,^/pyran; m.p.130-131°C; 6H, 6-di methyl ami nocarbony I -methyl -di benzo/b, d/pyran; m.p.87-89°C; 6H, 6-p i perazi nocarbony I -methyl -d i benzo/b, d/pyran; · HCl ,m.p.224-229oC; 6H,6-(4-methyI-piperazi nocarbonyl-methyl)-di benzo/b,d/pyran; -HCI, m.p. 259-262°C 6H,6-(4-phenyI-piperaz i nocarbonyl-methyl)-di benzo/b, cl/pyr an , m.p. 182-186°C.
Example 15 To a solution of 1-methyl piperazine (15.6 ml; 0.14 mol) in 200 ml of diethyl ether 6H,6-chIorocarbonyl-dibenzo/b,d/pyran (6.8 g; 28 mol) was added dropwise. After 8 hours of stirring at room temperature, the mixture was washed with water and the organic solution evaporated to dryness.
The residue was treated twice with di isopropyl ether to give .5 9 (yield 6l.4%) of 6H,6-/(4-methyIpiperazino)-carbony//-di benzo/b,d/pyran, m.p. 122-124°C.
Analogously, the following compounds were obtained: 6H, 6-( ter. butyl ami nocarbonyl-hydroxy-methyl )-dibenzo/b,d7pyran,m.p.223-235°C; 6H,6-(tert.butyl ami nocarbonyl-hydroxy-methyl)-6-methyl-dibenzo/b,d/pyran; , . , m.p.22Zz/19eC; 6H,6-(tert. butyl ami noca rbony1-hydroxy-methyl)-2-chloro-dibenzo/b,d7pyran . ,- ,, m,p.238-246°C; 6H, 6-(tert, butyl ami nocarbonyl -hydroxy-methyl) -2-m tro-di benzo/b, d/pyran; ~J~ , A , jn.p.195-215°C; 6H,6-(tert. butyl ami nocarbonyl-hydroxy-methyl)-2-methoxy-dibenzo/b,d/pyranT/- ' . m.p.227-241°C 6H,6-(tert. butyl ami nocarbonyl-hydroxy-methyl)-2-hydroxy-dibenzo/b,d/pyran; / 6H,5-(tert.butylaminocarbonyl-hydroxy-methyl )-8,9,10-trimethoxy-dibenzoZb,d/pyran- m·?· 226-242°C; 6H,6-ami nocarbony I-1-methoxy-d i benzo/b, d/pyran; 6H,6-ami nocarbonyl-2-chIoro-di benzo/b,d/pyran; 6H,6-aminocarbonyI-2-fIuoro-di benzo/b,d/pyran; 6H,6-ami nocarbonyI-2-n i tro-d i benzo/b,d/pyran; 51688 6H, 6-aminocarbonyl-2-methoxy-di benzo/b,d/pyran; 6H,6-aminocarbonyl-2-tr ifIuoromethyI-di benzo/b,d/pyran; 6H,6-ami nocarbonyl-8-chIoro-di benzo/b,d/pyran; 6H,6-ami nocarbonyl-8-fIuoro-di benzo/b,d/pyran; 6H,6-aminocarbonyl-8-n i tro-di benzo/b,d/pyran; 6H,6-ami nocarbonyl -8-methoxy-di benzo/b,d/pyran; 6H,6-ami nocarbonyl-1,10-d i methoxy-di benzo/b,d/pyran; 6H,6-ami nocarbonyI-8,9,10-tri methoxy-di benzo/b,d/pyran; 6H-6-ami nocarbonyl-6-methyI-2-chIoro-d i benzo/b,d/pyran; m.p. 167-170°C; 0H,6-ami nocarbonyl-methy I-di benzo/b, cl/pyran; m.p. 148-150°C; 6H,6-methy!ami nocarbonyl-methyI-di benzo/b,d/pyran; m.p. 130-131 °C; 0H,6-di methyl ami nocarbonyl-methyI-di benzo/b,d/pyran; m.p.87-89°C; 6H, 6-p i per az i nocarbonyl -methy I -d i benzo/b, cl/pyran; HCl ,m.p. 224-229°C; 6H,6-(4-methy1-p iperazί nocarbonyl-methyl)-di benzo/b,d/pyran;-HCl, m.p. 259-262eC 6H,6-(4-phenyl-piperazinocarbonyl-methyl)-di benzo/b,d/pyran., m.p. 182-186°C.
S1685 Example 16 A solution of 6H, 6-ethoxycarhonyliBetbyU 0.011 mol) in 23 5« HC1 (30 ml) and. dioxane (15 mi) was refluxed for 10 hours.
After dilution with water, the mixture was extracted with ethyl acetate and the organic solvent was evaporated to dryness. The residue was solidified with diisopropyl ether to give 2 g (74 ¢) of 63,6carboxymethyl-dibenzo/o,/pyran; m.p. 110-111°C.
By proceeding analogously the following compounds were obtai ned: 6H, 6-carboxymethyI-1-methoxy-di benzo/b, d/pyran; m.p. 87-90°C; 6H , 6—car boxymethy I -2-ch I or o-d i benzo/b,d/pyran; m. p.140-144°C; 6H, 6-carboxymethy I -2-f I uoro-di benzo/b, ci/pyr an; m.p.128-131°C; 6H,6-carboxymethyI-2-n itro-d i benzo/b,d/pyran; 6H,6-carboxymethyI-2-methoxy-dibenzo/b,d/pyran; m.p. 92-95°C; 6H,6-carboxymethyI-2-tr i fIuoromethyl-d i benzo/b,d/pyran; m.p.84-87°C; 6H, 6-carboxymethy I -8-chI oro-d i benzo/b,d/pyran; m.p.131-134°C; 6H,6-carboxymethyl-8-fIuoro-di benzo/b,d/pyran; 6H, 6-carboxymethy I -8-n i tro-d i benzo/b, d/pyran; m.p.168-172°C; 6H, 6-carboxymethyl -8-methoxy-d i benzo/b, d/pyr an; m,p.85-88°C; 6H,6-carboxymethyI-1,10-dimethoxy-di benzo/b,d/pyran; m.p.116-119°C; 6H, 6-carboxymethy I -8,9,10-tri methoxy-di benzo/b,d/pyran; m.p.144-147°C; 6H,6-(2-carboxy-ethyl )-di benzo/b,d/pyran; m.p.104-107°C; 6H,6-(2-carboxy-ethyI)-l-methoxy-di benzo/b,d/pyran; 6H,6-(2-carboxy-ethyI )-2-ch I oro-d i benzo/b, d/pyran; m.p.152-155°C; 6H,6-(2-carboxy-ethyl)-2-f I uoro-di benzo/b, d/pyran; m.p. 132-135°C 6H,6-(2-carboxy-ethyl)-2-n itro-d i benzo/b,d/pyran; 6H, 6-(2-carboxy-ethyl )-2-methoxy-di benzo/b,d/pyran; m.p.91-94°C; 6H, 6-(2-carboxy-ethyI )-2-tr i f I uoromethyl-di benzo/b,d/pyran; m.p.79-82°C; 6H, 6-(2-carboxy-ethy I )-8-chl oro-di ben zo/b, d/pyran; m.p.158-161’C; 6H, 6-(2-carboxy-ethyl)-8-fIuoro-di benzo/b,d/pyran; 6H, 6-(2-carboxy-ethyI )-8-nitro-di benzo/b, d/pyran; m.p.163-166°C; 6H, 6-(2-car boxy-ethy I )-8-methoxy-d i benzo/b,d/pyran; m,p.90-93°C; 6H, 6-(2-car boxy-ethy I )-1, 10-di methoxy-di benzo/b, d/pyran; m.p. 101-104°C 6K,6-(2-carboxy-ethyI )-8,9,10-tr i methoxy-di benzo/b,d/pyran, m.p. 128-131°C. si ess - 82 Example 17 A solution of 6H,6-cyano-dibenzo/b,d/pyran (4 9,' 0.02 mol) in 100 ml of anhydrous diethyl ether was slowly added under stirring, at room temperature, to LiAlH^ ()5 g; 0.04 mol) in 70 ml of anhydrous diethyl ether.
After 20 hours the excess of LiAIwas decomposed with water and sodium hydroxide. The suspension was filtered, the solid thoroughly washed with diethyl ether and the solvent was evaporated to dryness. The residue was taken up with 8% HCI. The obtained solution was washed with diethyl ether and then made basic with 35% NaOH. The mixture was extracted with diethyl ether. The organic solution was washed with a saturated NaCl aqueous solution and anhydrified over sodium sulfate 6H,6-ami no-methyl -di benzo/b, d/5 pyran was precipitated as hydrochloride with 14% HCI alcoholic solution and crystallized from absolute ethanol: (3.5 g; yield 73%): m.p. 25O°C; By proceeding analogously the following compounds were obta i ned: OH, 6-ami nomethyl -1-methoxy-d i benzo/b,d/pyran; «HCl ,m.p.196-199°C; OH, 6—ami nomethyl -2-f I uoro-d i benzo/b, d/pyran; · HCl ,m.p.212-217°C; 6H, 6-ami nomethyl -2-methoxy-di benzo/b,d/pyran; -HCl ,m.p.215-218°C; 6H, 6-ami nomethyl -2-tr i f I uoromethyl -d i benzo/b, d/pyran; · HCl,m.p. 206-209 6H,6-ami nomethyl-8-fIuoro-di benzo/b,d/pyran; 6H.6-ami nomethyl-8-methoxy-di benzo/b,d/pyran; 6H,ό-aminomethyl-1,10-di methoxy-di benzo/b,d/pyran; «HCl ,m.p.206-209°C; OH, 6-am ι nomethyl-8,9,10-tri methoxy-di benzo/b, d/pyran; -HCl,m.p.222-224°C.
Example l8 To a solution of 6H,6-cyano-8,9,10-trimethoxy-dibenzo/b, d/pyran In 100 ml of tetrahydrofurane 100 ml of a molar solution of ΒΗ^ in tetrahydrofurane was slowly added at 10°C.
The reacting mixture was kept at room temperature overnight; ml of water and 1 ml of 37% HCI were added and the mixture was warmed at 45°C for 2 hours. The solvent was evaporated to dryness; the residue was taken up with 2N HCl and the obtained solution was extracted several times with diethyl ether. The aqueous solution was then made basic with 35% NaOH, extracted with diethyl ether and the ether solution anhydrified. 6H,6-aminomethyI-8,9,10-trimethoxy-dibenzo/b,d/pyran was precipitated as hydrochloride with a 14% HCI alcoholic solution; (l2.0g; yield 71%): m.p. 222224°C.
By proceeding analogously the following compounds were prepared: 6H, 6-ami nomethy I-di benzo/b, d/pyran; m.p. 250°C 6H, 6-ami nomethy I - l-methoxy-d i benzo/b, d/pyran; - HCl ,m.p.196-199°C; 6H, 6-ami nomethyl-2-ch I oro-d i benzo/b, d/pyran; -HCl,m.p.248-251 °C; OH, 0-ami nomethy I-2-f I uoro-di benzo/b, d/pyran; · HCl ,m.p.212-217°C; OH, 6-ami nomethyl-2-ni tro-di benzo/b,d/pyran; OH,0-ami nomethyl-2-methoxy-di benzo/b,d/pyran; «HCl ,m.p.215-218°C; OH, ό-ami nomethy I -2-tr i f I uoromethy I-di benzo/b, d/pyran; .HCI ,m. p. 206-209 JC; 6H,6-ami nomethyl-8-chIoro-d i benzo/b,d/pyran; 6H,6-ami nomethyI-8-fIuoro-d i benzo/b,d/pyran; 6H,6-ami nomethyI-8-ni tro-d i benzo/b,d/pyran; OH,6-ami nomethyl-8-methoxy-d i benzo/b,d/pyran; 6H, 6-ami nomethy I -1,10-d i methoxy-d i benzo/btd/pyran; HCI ,m.p. 206-209 °C.
ExampIe 19 To a solution of 6H,6-aminocarbonylmethyI-dibenzo/b,d/pyran (4.2 g; 0. Ol86 mol), in 100 ml of anhydrous tetrahydrofurane, 100 ml of a molar solution of BH, in tetrao hydrofurane was added dropwise. The mixture was refluxed for 2 hours. After a warm up similar to that of example 18, 0H,6-aminomethyl-dibenzo/b,d/pyran was obtained as hydrochloride, which improved by grinding it in acetone; (3.0 g; 65%): m.p. 250°C.
By proceeding analogously the following compounds were obta i ned: 0H, 6-ami nomethyl -1-methoxy-d i benzo/b, d/pyran; 'HCl ,m.p. 196-199°C; 0H, 6-ami nomethyl -2-ch I oro-di benzo/b,d/pyran; 'HCl,m.p.248-251 °C; 6H, 6-ami nomethyl -2-f I uoro-d i benzo/b,d/pyran; · HCl ,m.p.212-217°C 6H, 6-ami nomethyI-2-π itro-di benzo/b,,d/pyran; 6H, 6-ami nomethyl -2-methoxy-d i benzo/b, d/pyran; HCl Sm.p.215-218°C; 6H, 6-ami nomethyl -2-tr i f I uoromethy I-di benzo/b,d/pyran; -HCl ,m.p.206-209°Q 6H,6-ami nomethyl-8-chIoro-d i benzo/b,d/pyran; 6H, 6-aminomethyl-8-fIuoro-di benzo/b,d/pyran; 6H,6-aminomethyI-8-nitro-dibenzo/b,d/pyran; 0H,6-ami nomethyl-8-methoxy-di benzo/b, d/pyran; 6H, 6-ami nomethy I -1,10-di methoxy-d i benzo/b, d/pyran; · HCl ,m.p.206-209°C; 6H, 6-ami nomethyl -8,9, 10-tr i methoxy-di benzo/b,d/pyran; · HCl ,m.p.222-224°C; 6H, 6-(2-methyl ami no-ethyl )-di benzo/b,d/pyran; .HCl ,m.p. 181-182°C; 0H, 6-(3-methyl ami no-propyl )-di benzo/b,d/pyran; .HCl ,m.p. 143-146°C; 51685* όΗ,6-(3-methylami no-propyl)-l-methoxy-di benzo/b,d/pyran; 6H,6-(3-methylami no-propyl )-2-chIoro-di benzo/b,d/pyran; 6H,6-(3-methyI ami no-propyl)-2-71uoro-di benzo/b,d/pyran; 6H,6-(3-methylami no-propyl )-2-nitro-di benzo/b,d/pyran; 6H,6-(3-methylami no-propyl )-2-methoxy-di benzo/b,d/pyran; 6H,6-(3-methylamino-propyl)-2-tri fIuoromethyl-di benzo/b,d/pyran; 6H,6-(3-methylami no-propyl)-8-chIoro-di benzo/b,d/pyran; 0H,6-(3-methylami no-propyl)-8-7(uoro-di benzo/b,d/pyran; 6H,6-(3-methyI ami no-propyl)-8-nitro-d i benzo/b,d/pyran; 6H,6-(3-methylamino-propyl)-8-methoxy-dibenzo/b,d/pyran; 6H,6-(3-methylami no-propyl )-1,10-di methoxy-di benzo/b,d/pyran; 6H,6-(3-methylami no-propyl )-8,9,10-tri methoxy-di benzo/b, dj PyPan' _ _ m.p.101-l11°C; 6H,6-(l-hydroxy-2-tert.butyl ami no-ethyl)-di benzo/b,d/pyrari)1 / 6H,6-(l-hydroxy-2-tert.butyl ami no-ethyl )-1-methoxy-di benzo/b,d/pyran; ·Η01, m.p.174-186°C; 6H,6-(l-hydroxy-2-tert.butyl ami no-ethyl)~2-chloro-di benzo/b,d7pyran; .HCl,m.p. 183-201°C; 6H,6-(l-hydroxy-2-tert.butyl ami no-ethyI )-2-71uoro-di benzo/b,d/pyran; -HCl,m.p. 165-178°C; 6H,6-(l-hydroxy-2-tert.butyl ami no-ethyl)-2-n itro-di benzo/b,d/pyran; 6H,6-(l-hydroxy-2-tert.butyl ami no-ethyl )-2-methoxy-di benzo/b,d/pyran; - HCl, m.p.176-189°C; 6H,6-(l-hydroxy-2-tert. butyl amino-ethyl )-2-trif Iuoromethyl-d i benzo/b, d/pyran; «HCl,m.p. 181-194°C; 6H,6-(1-hydroxy-2-tert, butyl ami no-ethyI)-S-chIoro-di benzo/b,d/pyran; 6H,6-(l-hydroxy-2-tert.butyl ami no-ethyl)-8-fIuoro-di benzo/b,d/pyran; 6H,6-(l-hydroxy-2-tert. butyl ami no-ethyl )-8-nitro-di benzo/b,d/pyran; 6H,6-(l-hydroxy-2-tert. butyl ami no-ethyI )-8-methoxy-di benzo10 /b,d/pyran; 6H,6-(l-hydroxy-2-tert. butyl ami no-ethyl )-1,10-d i methoxy-d i benzo/b, cl/pyr an; · HCl ,m.p. 187-206°C; 6H,6-(l-hydroxy-2-tert.butyl ami no-ethyl )-8,9,10-tri methoxy-dibenzo/b,d/pyran; ·Η01, m.p.201-218°C.
Example 20 6H,6-(2-pyridyl )-dibenzo/b,d/pyran -(2.8 9; 0.011 mol) in 60 ml of acetic acid was reduced by hydrogen in a Parr apparatus at 4 Atm,at room temperature, using PtO? (0.5 9) as a catalyst. After four hours the reaction mixture was filtered and the solvent evaporated to dryness under vacuo. The residue was taken up with a saturated NaHCO^ aqueous solution and extracted with diethyl ether. The organic solution was washed with water, anhydrified and 6H,6-(2.10 -piperidinyl)-dibenzo/b,d/pyran was precipitated as hydrochloride with a small excess of 14% HCl alcoholic solution. The hydrochloride was taken up several times with absolute ethanol and each time the solvent was evaporated to dryness under vacuo. At the end the residue was taken up with diethyl ether and filtered: (2.5 9/ yield 76%); m.p. 130°cdec (mixture of diasteroisomers).
Analogously the following compounds were obtained: 6H,6-(3-piperidinyl )-dibenzo/b,d/pyran; -HCl, m.p. 165°C(dec); 6H, 6-( 4-p! per i d i ny I )-d i benzo/b,d/pyran; -HCl, m.p. 197-225 °C (dec); 6H,6-(2-piperazinyI)-dibenzo/b,d/pyran; Example 21 6H,6-carboxy-dibenzo/b,/pyran (46 g; 0.2 mol) was suspended in 300 ml of SOCI. and kept under stirring at room ft temperature for l6 hours. After careful elimination of the excess of SOCI., the crude acid chloride was dissolved in 300 ml of anhydrous diglyme To this solution a suspension of Lithium tri.ter.butoxyaluminohydride (53.5 g; 0.21 mol) in 3θ0 ml of diglyme was added dropwise, at a temperature of -60°C and under N„ and stirring. After the addition was £t over, the temperature was raised to -40eC and a solution of 53-5 9 °f ammonium sulfate in 85 ml of water was added. At -20°C diethyl ether and decalite were added to make the suspension easier to stirr. After half an hour of vigorous stirring the suspension was filtered and the cake washed with diethyl ether. The ether was evaporated out under vacuum by keeping the external temperature not higher than 30°C. Sodium metabisulfite (54 9i 0.258 mol) in 100 ml of 8($ ethanol was added to the obtained solution of aldehyde in diglyme and the whole was stirred for 16 hours. The mix20 ture was then cooled to room temperature and KCN (13.7 9J 0.21 mol) was added all at once. After 7 hours at reflux temperature, the solution was evaporated to dryness under vacuum. The residue was taken up with diethyl ether and the obtained solution was filtered and thoroughly washed with water. After anhydrification on sodium sulfate, the solvent was evaporated to dryness to obtain crude 6H,6-fcyano-hydroxy-methyl)-dibenzo/b,d/pyran: (32.5 9; yield 70% ), as an oily light brown syrup.
By proceeding analogously the following compounds were obtained: ____ _ 6H, 6-(:yano-hydroxy-methy l)-6-methy I -di benzo/b,d/pyran; 6H,6-fc:yano-hydroxy-methy IJ-l-methoxy-dibenzo/b,d/pyran; 6H, 6-^cyano-hydroxy-methy l)-2-ch I oro-di benzo/b,d/pyran; 6H,6-{cyano-hydroxy-methyl)-2-f I uoro-di benzo/b, d/pyr an; 0H, 6-(cyano-hydroxy«methyl)-2-n i tro-d i benzo/b, d/pyran; 6H, 6-fcyano-hydroxy.^methy l)-2-methoxy-di benzo/b, d/pyran; 6H, 6-{cyano-hydroxy«dnethy l}-2-hydroxy-di benzo/b, d/pyran; 0H, 6-(cyano-hydroxy-^nethyl}-2-tr i f 1 uoromethy! -di benzo/b, d/pyran; 6H, 6-(cyano-hydroxy_methy l)-8-ch I oro-di benzo/b,d/pyran; 6H, 6-^zyano-hydroxy—methy l}-8-f I uoro-di benzo/b, d/pyran; 0H, 6-(cyano-hydroxy‘-methy ij—8— n i tro-d i benzo/b, d/pyran; 0H, 6-{cyano-hydroxy-.methy lJ-8-methoxy-di benzo/b, d/pyran; 6H, 6-(cyano-hydroxy-methy 1)-1,10-d i methoxy-d i benzo/b, d/pyran; 6H, 6-{cyano-hydroxy~methy 1)-8,9, 10-tr i methoxy-di benzo/b, d/pyran.
Example 22 Oxalyl chloride (ll ml; 0.125 mol) was added dropwise to a solution of 6H,6-carboxymethyl-dibenzo/b,d/pyran (l5 g; 0.06 mol) in 300 ml of anhydrous benzene and 0.5 ml of anhydrous dimethylformamide. After 24 hours at room temperature the solution was evaporated to dryness and the residue was dissolved in 200 ml of diethyl ether. This solution was added, at 0-j-5°C , to an ethereal solution of diazomethane (ll g) and the whole was kept at room temperature for 16 hours. After a further two hours at 40°C, nitrogen was bubbled in to remove the excess diazomethane and the solution was evaporated to dryness. The residue was dissolved in 80 ml of dioxane and to the obtained solution a mixture consisting of AgjO (4-4 9! 0.019 mol), Na2S2°3'5H2° (10,5 97 0,042 mo1) and Na2C03'10H2° ^14 9; 0.049 mol) in 300 mi of distilled water was added at 60°C. The temperature was raised to 90°C- and maintained at this temperature for 24 hours. The reaction mixture was then poured in icy water, filtered and the aqueous solution extracted several times with diethyl ether. After acidification with 8% HCI the precipitate was extracted with ethyl acetate and the organic solution evaporated to dryness. The oily residue was taken up with di isopropyl ether to give 6H,6-(2-carboxy-ethyl)-dibenzo/b,d/pyran (8.3 g; yield 52%): m.p. 1O5-1O7°C. 51688 By proceeding analogou obtained: 6H,6-(2 -carboxy-ethy 6H,6-(2 -carboxy-ethy 6H,6-(2-carboxy-ethy 0H,6-(2-carboxy-ethy OH,6-(2-carboxy-ethy 6H,6-(2-carboxy-ethy 6H,6-(2-carboxy-ethy OH,6-(2-carboxy-ethy 6H,6-(2-carboxy-ethy 6H,6-(2-carboxy-ethy 6fi, 6-(2-carboxy-ethy 6H,6-(2-carboxy-ethy 6H,0-(2-carboxy-ethy t)H, 6-(2-carboxy-ethy 0H,6-(2-carboxy-ethy 6H,6-(2-carboxy-ethy OH,6-(2-carboxy-eth y OH,6-(2-carboxy-ethy 6H,6-(2-carboxy-ethy OH,6-(2-carboxy-ethy /b,d/pyran; 6H,6-(2-carboxy-ethy OH,6-(2-carboxy~ethy 6H,6-(2-carboxy-ethy I ) OH,6-(2-carboxy-ethyI ) 6H,6-(2-carboxy-ethyl) pyran; OH,0-(2-carboxy-ethyI) /b,d/pyran; sly the following compounds were 6-methyl-di benzo/b,d/pyran; 6-ethyl-di benzo/b,d/pyran; 6-phenyI-d i benzo/b, cl/p yr an; 1- methoxy-di benzo/b,d/pyran; 2- chl oro-di benzo/b,d/pyran; m.p.152-155°C; 2-fl uoro-di benzo/b,d/pyran; m.p.132-135°C; 2-nitro-di benzo/b,d/pyran; 2-methoxy-d i benzo/b,d/pyran; m.p.91 -94°C; ,- -7 m.P.79-82°C; -2-tr i fIuoromethyl-d i benzo/b,^/pyran77 8-ch I oro-di benzo/b, d/pyran; m.p. 158-161 °C; 8-fIuoro-di benzo/b,d/pyran; 8-methoxy-di benzo/b,_d/pyran; m.p.90-93°C; 1, 10-d i methoxy-di benzo/b, d/pyran; m.p. 101-104°C; 8,9,10-tri methoxy-di benzo/b, d/pyran’ 6-methyl-1-methoxy-d i benzo/b,d/pyran; 6-methyI-2-chloro-di benzo/b,d/pyran; 6-methyl-2-fluoro-di benzo/b,d/pyran; 6-methyI-2-nitro-di benzo/b,d/pyran; 6-methyl-2-methoxy-di benzo/b,d/pyran; 6-methyl-2-tr i fIuoromethyl-d i benzo)6-methyI-8-chIoro-d i benzo/b,d/pyran; 6-methyI-8-fIuoro-di benzo/b,d/pyran; -6-methyl-8-nitro-di benzo/b,d/pyran; -6-methyI-8-methoxy-di benzo/b,d/pyran; -6-methyl-l,10-dimethoxy-dibenzo/b,d/-6-methyI-8,9,10-tr i methoxy-d i benzo91 Example 23 To a stirred solution of 6H,6-cyano-dibanzo/b,/pyran (4.2 g; 0.02 mol) ' and CHjI (28.4 g; 0.2 mol) in 100 ml of dimethylformamide, 50 % NaH (1.5 g} 0.03 mol) was added in small portions. After tS hours at room temperature the mixture was poured into water and extracted with diethyl ether. The organic phase was washed with water and dried over Na^SO^. Evaporation of the solvent gave 6H,6-cyano-6methyl-dibenzo/b,/pyran as a white solid (3.1 g; 0’.014 mol; yield 70 %); m.p. 114-116“C.
By proceeding analogously the following compounds were obtained: 6Κ,6-cyano-6-methyI -1-methoxy-di benzo/b,/pyran; 6H, 6-cyano-6-methyl-2-ch I oro-d i benzo/b, d/pyran; m.p.112-115°C; 6H, 6-cyano-6-methy I-2-f I uoro-di benzo/b, d/pyran; m.p. 98-102°C; 6H,6-cyano-6-methy I-2-nitro-di benzo/b,d/pyran; 6H,6-cyano-6-methyI-2-methoxy-di benzo/b,d/pyran; 6H,6-cyano-6-methyI-2-tr i fIuoromethyl-d ί benzo/b,/pyran; 6H,6-cyano-6-methyI-8-chIoro-dibenzo/b,d/pyran; 6H,6-cyano-6-methyI-8-fIuoro-di benzo/b,d/pyran; 6H,6-cyano-6-methyI-8-n i tro-d i benzo/b,/pyran; 6H, 6-cyano-6-methy I -8-methoxy-di benzo/b,/pyran; 6H, 6-cyano-6-methyI-1,10-di methoxy-di benzo/b,/pyran; 6H, 6-cyano-6-methy 1-8,9,10-tr i methoxy-d i benzo/b,/pyran; m.p.121-124°C; 6K, 6-cyano-6-ethy I-d i benzo/b,/pyran; m.p. 75-77°C; 6H, 6-cyano-6-ethyI-1-methoxy-di benzo/b,/pyran; 6H,6-cyano-6-ethyI-2-chloro-di benzo/b,/pyran; Λ 51665 6H,6-cyano-6-ethyI-2-fIuoro-d i bertzo/b,d/pyran; 6H, 6-Cyano-6-ethy I -2-n itro-d'i bento/b,d/pyran; 6H, 6-Cyand-6-dthyl-2-(rteifhoxy-di benzo/b,d/pyran; 6H,6-cyano-0-fethyl-2-trIfluoromethyl-di benzo/b,d/pyran; 6H,6-cyano-6-ethyI-8-chIoro-d i benzo/b,d/pyran; 6H,, 6-cyano-6-ethy I -8-f I uoro-d i benzo/b, d/pyr an; 6H, 6-cyano-6-ethy1-8-n itro-d i benzo/b,d/pyran; 6H, 6-eyano-6-«tft>»i -8-methoxy-d i benzo/b, d/pyr an; 6H,6-cyano-6-ethyI-1,10-di methoxy-di benzo/b,d/pyran; 6H,6-cyano-6-ethyI-8,9,10-tr i methoxy-d i benzo/b,d/pyran.
Exanple 24 6H,6-cyano-dibenzo/b,d7pyran (31 g; 0.15 mol) and. paraformaldehyde (6 Si 0.2 mol) in 300 ml of dimethylsulphoxide was treated with a suspension of sodium methoxide (3.8 gj 0.07 mol) in dimethylsulph5 oxide (100 ml). The mixture waa stirred for 2 hours at room temperature, then poured into water and extracted with diethyl ether.
The organic phase was washed with water, dried over lia^SO^ and evaporated to dryness to give 6H,6-cyano-6-hydroxymethyl —d.ibenzo/b,i^ pyran as a white solid (26.7 g; 0.11 molj yield 75 $); ®.p· 1O6-1O8°C.
Id By proceeding analogously the following compounds were obtained: 6H,6-cyano-6-hydroxymethyI-1-methoxy-di benzo/b,d/pyran; 6H, 6-cy an o-6-hydr oxy methy I -2-ch I oro-d i benzo/b, d/pyran; m.p. 107-110°C; 6H,6-cyano-6-hydroxymethyI-2-fIuoro-d i benzo/b,d/pyran; 6H,6-cyano-6-hydroxymethyI-2-n i tro-d i benzo/b,d/pyran; 6H,6-cyano-6-hydroxymethyI-2-methoxy-dibenzo/b,d/pyran; 6H,6-cyano-6-hydroxymethyl-2-trifJ uoromethyl-di benzo/b, d/pyran; 6H,6-cyano-6-hydroxymethyI-8-chIoro-di benzo/b,d/pyran; 6H,6-cyano-6-hydroxymethyI-8-fIuoro-di benzo/b,d/pyran; 6H,6-cyano-6-hydroxymethyI-8-ni tro-di benzo/b,d/pyran; 6H,6-cyano-6-hydroxymethyI-8-methoxy-di benzo/b,d/pyran; 6H, 6-cyano-6-nydroxymethy1-1,10-di methoxy-di benzo/b,d/pyran; 6H,6-cyano-6-hydroxymethyl-8,9,10-tri methoxy-di benzo/b,d/pyran; m.p. 111-114°C. 51685» Example 25 A solution of 6H,6-cyano-6-methyl-dibenzo/b,d/pyran (11.3 9! 0.05 mol) and sulfuryl chloride (25 ml; 0.3 mol) in CHCI^ (120 ml) was kept on standing for 4 days at room temperature.
After thorough washing with N/10 NaOH solution and water to neutrality, the solvent was evaporated under reduced pressure and the residue treated with isopropyl ether. The solid was filtered to obtain 7.5 9 (60%) of 6H,6-cyano-6-methyl-2-chIoro-dibenzo/b,d/pyran; m.p. 110-112°C.
By proceeding analogously the following compounds were obtained: 6H,6-ethoxycarbonyImethyI-6-methyl-2-chIoro-d i benzo/b,d/pyran; 6H,6-(2-ethoxycarbonyI-ethyl )-6-methyI-2-chIoro-di benzo/b,d/pyran.
Example 26 6H,6-ethoxycarbonyl-2-nitro-dibenzo/b,d/pyran (4.25 9! 0.015 mol) was dissolved in 150 ml of ethanol and reduced in a Parr apparatus using 10% Pd/C as a catalyst, at room temperature and 2 Atm of pressure. After 3 hours the reaction was complete. The reaction mixture was filtered and the solvent evaporated to dryness. The oily residue was taken up with 100 ml of diethyl ether and the product was extracted with 8% HCl. The acid solution was made basic with 35% NaOH and extracted with diethyl ether.
After evaporation of the solvent 6H,6-ethoxycarbonyI-2-amino-dibenzo/b,d/pyran was obtained (3.0 g; yield 78%) hydrochloride, m.p. 215-220°C.
Analogously the following compounds were obtained: 6H, 6-ethoxycarbonyl methyl -2-ami no-di benzo/b,d/pyran; *HC1 ,m.p.187-191°C; m.o. 178-182°C; 6H, 6-ethoxycarbonyl methy I-6-methy I-2-ami no-d i benzo/D,d/pyran; I,/ 6H,6-(2-ethoxycarbonyI-ethyl)-2-ami no-di benzo/b,d/pyran; 6H,6-(2-ethoxycarbony I-ethyl )-6-methyI-2-ami no-di benzo/b,d/pyran; 6H,6-aminomethyl-2-amino-dibenzo/b,d/pyran; m.p. 280°C; 6H,6-(2-methylami no-ethyl )-2-ami no-di benzo/b,d/pyran; 6H, 6-(3-methyI ami no-propyl)-2-ami no-di benzo/b,d/pyran; » > . /Γ -rm.P.147-150°C; 6H,6-(2-d i methyl ami no-ethoxycarbonyl)-2-ami no-dibenzo/b,d/pyran; Λ2ΗΕ1, 6H,6-(2-di methyl ami no-ethoxycarbonyl)-64methyl-2-ami no-di benzo/b, cl/pyr an; 51685* 6H,6-(2-di methyl ami no-ethoxycarbonyI methyl)-2-ami no-dibenzo/b,d/pyran; «2HC1, m.p. 136-139°C; 6H,6-ethoxycarbonyI-8-amino-di benzo/b,d/pyran; 6H,6-ethoxycarbonylmethyl-8-ami no-di benzo/b,d/pyran; 6H,6-ethoxycarbonyImethyI-6-methyI-8-ami no-di benzo/b,d/pyran; 6H,6-(2-ethoxycarbonyl-ethyI )-8-ami no-di benzo/b,d/pyran; 6H,6-(2-ethoxycarbonyl-ethyl )-6-methyI-8-amino-di benzo/b,d/pyran; 6H,6-methyI ami no-8-ami no-di benzo/b,d/pyran; 6H,6-(2-methylami no-ethyl )-8-ami no-di benzo/b,d/pyran; 6H,6-(3-methyI ami no-propyl)-8-ami no-di benzo/b,d/pyran; 0H,6-(2-dimethyl ami no-ethoxycarbonyl )-8-ami no-di benzo/b,d/pyran; 6H,6-(2-d imethyl ami no-ethoxycarbonyI )-6-methyI-8-amino-d i benzo15 /b,d/pyran; 6H,6-(2-di methyl ami no-ethoxycarbonyl methyl )-8-ami no-di benzo/b,d/pyran.
Example 27 By keeping the temperature at -5°/O°C, NaNO2 (1.4 g; (0.02 mol) dissolved in distilled water (30 ml) was added drop by drop to a solution of 6H,6-cyano-25 aminodibenzo[b,djpyran (4.5 g; 0.02 mol) in 23% HCl (8.4 ml), under stirring. Then the temperature of the reaction mixture was allowed to rise to about 20°C.
The mixture, after stirring for 24 hours, was diluted with water, basified to pH 9-10 by adding NaOH and then washed with diethyl ether. The crude product was acidified, extracted with ethyl acetate, washed again, dried on anhydrous Na2S04, and decolorised. The solvent was evaporated to dryness thus giving 6H,6-cyano-2-hydroxy—dibenzo[b, djpyran as a whitish solid (3.6 g; 0.016 mol; yield 80%; m.p. 146-148°C).
By proceeding analogously the following compounds were obta i ned: 6H, 6-ethoxycarbonyI -2-hydroxy-di benzo/b,d/pyran; m.p.79-82°C; 6H, 6-ethoxycar bony I methyI-2-hydroxy-di benzo/b,d/pyran; m.p.75-79°C; 6H, 6-ethoxycarbony I met hyl-6-methy I -2-hydroxy-d i benzo/b, d/p^sA^^· C 6H,6-(2-ethoxycarboxy-ethyI)-2-hydroxy-dibenzo/b,d/pyran; 6H, 6- (2-ethoxy carbonyl -ethy I -6-methy I -2-hydroxy-d i benzo/b,d/pyran; 51688 6H,6-(2-dimethyl ami no-ethoxycarbonyl )-2-hydroxy-di benzo/b,d/pyran; HCl, m.p. 179-182°C; 6H,6-(2-di methyl ami no-ethoxycarbonyl)-6-methyl-2-hydroxy~ -dibenzo/b,d/pyran; «HCl, m.p. 168-171 °C; 6H,6-(2-di methyl ami no-ethoxycarbonyI methyl)-2-hydroxy-dibenzo/b,d/pyran; «HCl, m.p. 152-155°C; 6H,6-ethoxycarbonyI-8-hydroxy-d i benzo/b,d/p yran; 6H,6-ethoxycarbonyImethyI-8-hydroxy-di benzo/b,d/pyran; 6H,6-ethoxycarbonyI methyl-6-methyl-8-hydroxy-dibenzo/b,d/10 pyran; 6H,6-(2-ethoxycarbonyl-ethyl)-8-hydroxy-di benzo/b,d/pyran; 6H,6-(2-ethoxycarbonyI-ethyl )-6-methyl-8-hydroxy-di benzo/b,d/pyran; 6H,6-(2-d i methyl ami no-ethoxycarbonyI )-8-hydroxy-d ί benzo13 /E, d7pyran; 6H,6-(2-di methyI ami no-ethoxycarbonyl)-6-methyl-8-hydroxy-dibenzo/b,d/pyran; 6H,6-(2-dimethyl ami no-ethoxycarbonyl methyl)-8-hydroxy-di benzo/b,d/pyran.
ExampIe 28 To a solution of 6H, 6-ami nomethyl -2-methoxy-d i benzo/b,/pyran (2.4 g; 0.01 mol) in 5θ ml of anhydrous Ci^C^ a solution of BBr (5.6 g; 0.0225 mol) in 100 mi of anhy0 drous CH.CI„ was added dropwise, at a temperature of -20°C. z z After two hours the temperature was left to raise spontaneouly to 0°C and 150 ml of water were added cautiously.
After one hour under stirring the agueous layer was separated, washed with ethyl acetate and then saturated with sodium bicarbonate. The solution was extracted with ethyl acetate.
After anhydrification on sodium sulphate, 6H,6-aminomethyl -2-hydroxy-d i benzo/b,/pyran was obtained by eliminating the solvent under vacuo: (1.2 g; yield 53%): hydrochloride m.p.279*282°C; Analogously the following compounds were obtained: 6H,6-cyano-l-hydroxy-d i benzo/b,/pyran; 6H,6-ethoxycarbonyI-1-hydroxy-di benzo/b,/pyran; 6H, 6-ethoxycarbonyImethyI-1-hydroxy-di benzo/b,/pyran; 6H,6-ethoxycarbonyImethyI-6-methyI-1-hydroxy-d i benzo/b,/pyran; 6H,6-(2-ethoxycarbony I-ethyl )-1-hydroxy-di benzo/b,/pyran; 6H, 6-(2-ethoxycarbony I -ethyl )-6-methyl -1-hydroxy-di benzo/b,/pyran; 6Κ,6-(2-methylami πο-ethyl)-l-hydroxy-di benzo/b,/pyran; 6H,6-(3-methylami no-propyl)-l-hydroxy-di benzo/b,/pyran; 6H,6-(2-d i methyl ami no-ethoxycarbony I)-1-hydroxy-di benzo/b,/pyran; 100 6H,6—(2—dimethyl ami no-ethoxycarbonyl )-6-methyI-1-hydroxy-di benzo/b,d/pyran; 6H,6-(2-di methyl ami no-ethoxycarbonyl methyl)-l-hydroxy-di benzo/b,d/pyran; 6H,6-cyano-2-hydroxy-d i benzo/b,d/pyran; 6H,6-ethoxycarbonyI-2-hydroxy-di benzo/b,d/pyran; 6H,6-ethoxycarbonyImethyI-2-hydroxy-di benzo/b, d/pyran; 6H,6-ethoxycarbonylmethyI-6-methyI-2-hydroxy-d i benzo/b,d/pyran; 6H,6-(2-ethoxycarbonyI-ethyI)-2-hydroxy-di benzo/b,d/pyran; 6H,6-(2-ethoxycarbonyI-ethyl)-6-methyI-2-hydroxy-di benzo/b,d/pyran; 6H,6-(2-di methyl ami no-ethoxycarbony I )-2-hydroxy-dibenzo/b,d/pyran; 6H,6-(2-di methyI ami no-ethoxycarbonyI)-6-methyl-2-hydroxy-di benzo/b,d/pyran; 6H,6-(2-di methyl ami no-ethoxycarbonyl methyl )-2-hydroxy-di benzo/b,d/pyran; 6H,6-cyano-8-hydroxy-d i benzo/b,d/pyran; 6H,6-ethoxycarbonyI-8-hydroxy-di benzo/b,d/pyran; 6H,6-ethoxycarbonyImethyI-8-hydroxy-d i benzo/b,d/pyran; 6H,6-ethoxycarbonyI methyl-6-methyI-8-hydroxy-di benzo/b,d/pyran; 6H,6-(2-ethoxycarbonyI-ethyl )-8-hydroxy-di benzo/b,d/pyran; 6H,6-(2-ethoxycarbony1-ethyI)-6-methyI-8-hydroxy-di benzo/b,d/pyran; 101 6H,6-methylami no-8-hydroxy-d i benzo/b,d/pyran; 6H,6-(2-methylamino-ethyl)-8-hydroxy-di benzo/b,d/pyran; 6H,6-(3-methyI ami no-propyl)-8-hydroxy-di benzo/b,d/pyran; 6H,6-(2-dimethyl ami no-ethoxycarbonyl)-8-hydroxy-di benzo5 /b,d/pyran; 6H,6-(2-d i methyl ami no-ethoxycarbonyl )-6-methyI-8-hydroxy— -di benzo/b,d/pyran; 6H,6-(2-dimethyl ami no-ethoxycarbonyl methyl)-8-hydroxy-di benzo/b,d/pyran. 102 51685‘ Example 29 0H,6-carboxy-dibenzo/b,d/pyran (40 g; 0.2 mol) was suspended in 300 ml of S0Clo and kept under stirring at room z temperature for 16 hours. After careful elimination of the excess of SOC^/ the crude acid chloride was dissolved in 300 ml of anhydrous diqlyme To this solution a suspension of Lithium tri.ter.butoxyaluminohydride (53.5 g; 0.21 mol) in 300 ml of diglyme was added dropwise, at a temperature of -60°C and under apd stirring. After the addition was over, the temperature was raised to -40°C and a solution of 53·5 9 of ammonium sulfate in 85 ml of water was added.
At -20°C diethyl ether and decalite were added to make the suspension easier to stirr. After half an hour of vigorous stirring the suspension was filtered and the cake washed with diethyl ether. The ether was evaporated out under vacuum by keeping the external temperature not higher than 30°C.
A solution of ammonium chloride (13 g; 0.24 mol) in 30 ml of water was added under stirring to the obtained solution of the aldehyde in diglyme.
A solution of sodium cyanide (8.6 g; 0.22 mol) in 20 ml of water was added keeping the temperature below 15°C. After 16 hours at room temperature the solution was evaporated under vacuum. The residue was dissolved in 100 ml of methanol and saturated with ammonia gas at 0°C. The mixture was allowed to stand for 2 days in a stoppered flask. The residue was taken up with diethyl ether and the obtained solution was filtered and thoroughly washed with water. 103 After anhydrification on sodium sulfate, the solvent was evaporated to dryness. The crude product was treated with ethanolic hydrogen chloride and precipitated from diethyl ether to give 6H,6-(cyano-aminomethyl)-dibenzo/b,d7pyran hydrochloride (10.2 g; yield 21%) m.p. 96-109°C.
By proceeding analogously the following compounds were obtained: 6H,6-(cyano-ami nomethyl)-6-methyl-di benzo/b, d/pyran; 6H,6-(cyano-ami nomethyl)-1-methoxy-di benzo/b, d/pyran: 6H,6-(cyano-aminomethyl)-2-chloro-dibenzo/b,d/pyran;-HCl; m.p.102-120°C; 6H,6-(cyano-ami nomethyl)-2-f1uoro-di benzo/b,d/pyran; 6H,6-(cyano-ami nomethyl)-2-ni tro-di benzo/b,d/pyran;-HCl; m.p.87-111 °C; 6H,6-(cyano-ami nomethyl)-2-methoxy-di benzo/5,8Jpyran; 6H,6-(cyano-ami nomethyl)-2-hydroxy-di benzo/b, d/pyran; 6H,6-(cyano-ami nomethyl)-2-tri f1uoromethyl-di benzo/b,d/pyran; 6H,6-(cyano-aminomethy1)-8-chloro-dibenzo/b,d7pyran; 6H,6-(cyano-ami nomethyl)-8-f1uoro-di benzo/b,d7pyran; 6H,6-(cyano-ami nomethyl)-8-nitro-dibenzo/b, ijpyran; 6H,6-(cyano-ami nomethyl)-8-methoxy-di benzo/B,d/pyran; 6H,6-(cyano-ami nomethyl )-1,10-di methoxy-di benzo/b,d/pyran; 6H,6-(cyano-ami nomethy1)-8,9,10-trimethoxy-di benzo/b,d7py ran. 104 Eaanple 30 A solution of HaOH drops (0.8 g; 0.02 mol) in methyl alcohol (10 ml) was added to a solution of 6H,6-car'bory-6-methyl-2-ohloro-di'benao /b,d/pyran (5.5 Si 0.02 mol) in methyl alcohol (100 ml). The solvent was evaporated off and the residue taken up with 99 % ethyl alcohol.
The solvent was evaporated, the residue taken up with 99 % ethyl alcohol and the solvent evaporated again^thus giving 6H,6-earboxy-6methyl-2-chloro-dibendo/b,d/pyran sodium salt (5.9 gi 0.02 mol; yield 100 %)} m.p. >25O°C.
Analogously the following compounds were obtained: 6H,6-carboxymethyI-dibenzo/b,d/pyran sodium salt; 6H,6-carboxymethyl-6-methyl-dibenzo/b,d/pyran sodium salt; 6H,6-(2-carboxy-ethyl)-dibenzo/b,d/pyran sodium salt. 105 Example 31 In an anhydrous reaction apparatus, under nitrogen atmosphere, 6Hdibenzo/b,d/pyran-6-one (30 g; 0.15 mol) was dissolved in anhydrous toluene (100 ml). The mixture was cooled to -60eC and a 1.2M solu5 tion of diisobutylaluminium hydride (DIBAH) in toluene (150 ml) was added. The temperature was kept at -60°C for 2 hours then water (150 ml) and decalite (3 g) were added; the mixture was filtered and the residue vas washed with toluene. The organic layer was separated, washed with water, dried over anhydrous Na^SO^ and finally 1C evaporated to dryness to give a semisolid product, which was crystallized from n-hexane; 6H,6-hydroxy-dibenzo/b,d/pyran (21 g; 0.106 mol; yield 70 ¢) was obtained as white solid; m.p. 89~91eC.
By proceeding analogously the following compounds were obtained: 6H,6-hydroxy-l-methoxy-dibenzo/b,d/pyran; 6H,6-hydroxy-2-chIoro-di benzo/b,d/pyran; 6H,6-hydroxy-2-fIuoro-d ibenzo/b,d/pyran; 6H, 6-hydroxy-2-ni tro-di benzo/b,d/pyran; 6H,6-hydroxy-2-methoxy-d i benzo/b,d/pyran; 6H,6-hydroxy-2-tr i fIuoromethyI-d i benzo/b, d/pyran; 6H,6-hydroxy-8-chIoro-d i benzo/b,d/pyran; 6H,6-hydroxy-8-fIuoro-d i benzo/b,d/pyran; 6H,6-hydroxy-8-methoxy-di benzo/b,d/pyran; 6H,6-hydroxy-l,10-di methoxy-di benzo/b,d/pyran; 6H,6-hydroxy-8,9,10-tr i methoxy-d i benzo/b,d/pyran. 106 51685' Example 32 To a solution of 6H-dibenzo/b,d/pyran-6-one (30 g; 0.153 mol), in a mixture of 250 ml of anhydrous diethyl ether and 250 ml of anhydrous benzene, an ethanol solution of Grignard reagent prepared from bromobenzene (23 ml; 0.23 mol) was added dropwise at 0°C. The temperature was left to reach the room temperature and the solution was stirred for a further 2 hours. After washing with 1NHCl and with water to neutrality, evaporation under vacuo of the solvent gave 6H,6-hydroxy-6-phenyl-dibenzo/b,d/pyran (39.3 9: yield 94%) as a light yeiIow oil.
Br proceeding analogously the following compounds were obtai ned: 6H,6-hydroxy-6-phenyI-1-methoxy-di benzo/b,d/pyran; 6H,6-hydroxy-6-phenyI-2-chIoro-di benzo/b,d/pyran; 6H,6-hydroxy-6-phenyI-2-fIuoro-di benzo/b,d/pyran; 6H,6-hydroxy-6-phenyI-2-nitro-di benzo/b,d/pyran; 6H,6-hydroxy-6-phenyI-2-methoxy-di benzo/b,d/pyran; 6H,6-hydroxy-6-phenyI-2-tr ifluoromethyl-d i benzo/b,d/pyran; 6H,6-hydroxy-6-phenyI-8-chIoro-di benzo/b, d/pyran; 6H,6-hydroxy-6-phenyI-8-fIuoro-di benzo/b,d/pyran; 6H,6-hydroxy-6-phenyI-8-nitro-di benzo/b,d/pyran; 6H,6-hydroxy-6-phenyI-8-methoxy-d ί benzo/b,d/pyran; 6H,6-hydroxy-6-phenyl-I,10-di methoxy-di benzo/b,d/pyran; 6H,6-hydroxy-6-phenyI-8,9,10-trimethoxy-di benzo/b, d/pyran. 107 Formulation Examples Formulation 1: Tablet (50 mg) Tablets, each weighing 150 mg and containing 50 mg of the active substance are manufactured as follows: Composition (for 10,000 tablets) 6H,6-carboxy-6-methyl-2-chloro-dibenzo/“b,d7pyran 500 g' Lactose 71° S Corn starch 237.5 g Talc powder 37-5 g Magnesium stearate 15 g 6H,6-carboxy-6-methyl-2-chloro-dibenzo/“b,d/pyran, 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 1180 ml). The resulting paste is used to granulate the powder. The granules are dried, comminu ted on a sieve of sieve size 1.4 mm, then the remaining quanti ty of starch, talc and magnesium stearate is added, carefully mixed, and processed into tablets using punches of 8 mm diame ter.
Formulation 2: intramuscular injection An inj ectable pharmaceutical composition was manufactured by dissolving 150-500 mg of 6H,6-carboxy-6-methyl-2-chlorodibenzo/-b,d7pyran sodium salt in sterile water or sterile normal saline solution (1-2 ml).
Analogously, injectable pharmaceutical compositions containing the compounds previously described in the preceding examples 108 5168» were prepared.
Formulation 3: Capsules(50 mg) 6H,6-ethoxycarbonyl-6-raethyl-2-chloro-dibenzo/“b,d7pyran 50 Lactose 298 corn starch 50 Magnesium stearate 2 Total 400 mg Encapsulate in two-piece hard gelatin capsules. Formulation 4: Suppository (50 mg) g/g 6H,6-carboxy-6-methyl-2-chloro-dibenzo/“b,d7pyran 0.05 Lecithin 0,07 Cocoa·butter 0.88 Total 1.00 g Formulation 5: Cream mg/g 6H,6-carboxy-6-methyl-2-chloro-dibenzo/~b,d7pyran 50,0 White petrolatum 100.0 Cetylstearyl alcohol 72.0 Mineral oil 60.0 Polypropylene glycol 22-5 4-Chloro-m-cresol 1,0 Purified water to make 1,0 g Formulation 6: Ointment mg/g 6H ,6-carboxy-6-methyl-2-chloro-dibenzo/-b,d7pyran 50,0 Mineral oil 50,0 109 Propylene glycol Petrolatum, to make Formulation 7: Syrup 6H, 6-carboxy-6-methy1-2-chloro-dibenzo/-b,d7pyran 5 salt Gum tragacanth Me thyl -£-hydroxybenzoate Propyl £-hydroxybenzoate Polyoxymethylene sorbitan.monolaurate Glycerine 30 Be Saccharose Natural Flavour Purified water to make

Claims (12)

  1. CLAIMS 1) A compound of general formula (I) wherein 5 R represents a) cyano; b) a carboxy or esterified carboxy group; c) a , wherein each of R and R , being the % a same or different, is hydrogen or unsubstituted C -Cg alkyl, or R and R , taken together with the nitrogen atom to which a b they are linked, form a heterocyclic ring, optionally 10 containing a further heteroatom chosen from oxygen, sulphur and nitrogen, and optionally substituted by C |~ C 6 alkyl or phenyl; d) -CON^* R c, wherein each of R and R , being the R . cd Q same or different, is hydrogen or C ,-C alkyl unsubstituted 1 o or substituted bv -Nif' a, wherein R and R are as defined 15 “ % a b above, or R and R,, taken together with the nitrogen atom c d to which they are linked, form a heterocyclic ring, optionally containing a further heteroatom chosen from oxygen, nitrogen and sulphur, and optionally substituted by C^-C*. alkyl or 111 phenyl; e) a saturated or unsaturated 5- or 5- membered heterocyclic ring, bound to the alkyl group or to the benzopyrane system through a carbon-carbon linkage, and containing at least a nitrogen atom and, optionally, a 5 further heteroatom chosen from oxygen, sulphur and nitrogen, which ring is unsubstituted or optionally substituted by C^-C^alky! or R is hydrogen; hydroxy or amino; I n is zero, 1, 2 or 3; R 2 represents hydrogen; alkyl optionally substituted by 10 hydroxy or by a -OCO-C^-Cg alkyl group; or an optionally substituted phenyl group each of R , R.i R., R, , R, and R , which may be the same or 3 4 5 6 7 o different,is selected from a) hydrogen; halogen; halo-C^-Cg alkyl; or C -C alkyl optionally substituted by amino; 16 15 b) amino; nitro; or -NHCONC „a> wherein R and R are as ^R^ a, d defined above; c”) -0R g , wherein R g is hydrogen, alkyl or C -C alkenyl; and the pharmaceutically or veterinarily 2 6 acceptable salts thereof.
  2. 2. ) A compound of formula (I) according to claim 1 wherein: 20 R is hydrogen, hydroxy or amino; R^ is a free carboxy group or an esterified carboxy group of formula -COOR'^, wherein R ' 1Q is (a IV ) C^-C alkyl, p -.unsubstituted or substituted by a group wherein „ . ,claim 1 R a and R are as defined in/ , or by a group -(0C0) -Py, X 25 wherein X is zero or 1 and Py represents a pyridyl group; IV or (b ) an unsubstituted or methyl- or ethyl- substituted • · _,p piperidyl group; or R is -N c . .claim 1 jr R b a b defined in/ , or -CON'c, wherein R and R are as defined H d C d in claim 1; 112 5168S Rg is hydrogen, methyl, hydroxymethyl or unsubstituted phenyl; each of R^ , R^ and R,. is, independently, hydrogen, chlorine. fluorine, trifluoromethyl, c 1’ _c 4 alkyl, nitro, amino or a group -0 R' g wherein R' g is hydrogen or Cj-C alkyl; each of R , R and R is, independently, hydrogen, halogen, 6 θ p nitro, amino; -NHCONf'’ a, wherein R and R, are as defined . claim 1 R b . a , in/ ; or a group -0 R'θ, wherein R' g is as defined above; n is zero, 1 or 2; and the pharmaceutically or veterinarily acceptable salts thereof.
  3. 3. ) A compound of formula (I) according to claim 1 wherein; R is hydrogen , hydroxy or amino R 1 is -COOH, -COOCgH -COOCH(CH -COO o -CH 3’ -COOCHg-^ ; -CON^E^ c > wherein R and R , are as defined in claim 1; d c d R a, wherein p is 2 or 3 and R and ’ a -COO( CHg ) g-OCO-J^ -C00( CH ) -N 2 p ^ R b ^ R b R are as defined in claim 1; b Rg is hydrogen, -CHy -CHgOH or unsubstituted phenyl; each of R^, and R$ is, independently, hydrogen, chlorine, fluorine, methyl, hydroxy, c 1~ c 4 alkoxy, amino or nitro; each of R , R and R is, independently, fluorine, chlorine, 6 7 8 bromine, hydrogen, hydroxy, C-C alkoxy, nitro, amino or 1 4 J? wherein R and R, are as defined in Claim 1; a b -NHCON<^ R a n is zero, 1 or 2; and the pharmaceutically or veterinarily acceptable salts thereof. 113
  4. 4. ) A compound selected from the group consisting of: 6H, 6-cyano-dibenzo jb , d] pyran; 6H,6-cyano-l-methoxy-drbenzojb,d_l pyran; 6H, 6-cyano-2-chloro-dibenzojb, dj pyran; 6H,6-cyano-2-fluoro-dibenzo(b,dj pyran: 6H,6-cyano-2-nitro-dibenzojb,dj pyran; 6H,6-cyano-2-methoxy-dibenzo jb,dj pyran; 6H,6-cyano-l,10-dimethoxy-dibenzo jb,dj pyran; 6H, 6-cyano-8,9,10-trimethoxy-dibenzo jb,'dj pyran; 6H,6-cyano-6-methyl-dibenzo jb,djpyran; 6H,6-cyano-6-methyl-2-chloro-dibenzo (b,dj pyran; 6H,6-cyano-6-methyl-2-fluoro-dibenzo jb ,dj pyran; 6H,6-cyano-6-methyl-1,10-dimethoxy-dibenzo jb,d| pyran; 6H,6-cyano-6-methy1-8,9,10-trimethoxy-dibenzo jb,dj pyran; 6H, 6-(1-piperazinyl)-dibenzojb , dj pyran; 6H,6-(1-piperazinyl)-2-chloro-dibenzo (b, dj pyran; 6H,6-(1-piperazinyl)-2-fluoro-dibenzo jb,dj pyran; 6H, 6- (1-piperazinyl) -2-nitro-dibenzo jjd, d] pyran; 6H,6-(1-piperazinyl)-2-methoxy-dibenzo jb,dj pyran; 6H,6-(1-piperazinyl)-1,10-dimethoxy-dibenzo jb,dj pyran; 6H,6-(1-piperazinyl)-8,9,10-trimethoxy-dibenzo jb,dj pyran! 6H,6-ethoxycarbonyl-dibenzo jb.djpyran; 6H,6-ethoxycarbonyl-1-methoxy-dibenzojb,d]pyran; 6H,6-ethoxycarbonyl-2-hydroxy-dibenzo jb,djpyran; 6H, 6-ethoxycarbony1-2-chloro-dibenzo/b,d/pyran; 6H,6-ethoxycarbonyl-6-methy1-2-chloro-dibenzo jb,djpyran; 6H , 6-ethoxycarbonyl-2-amino-dibenzojb.djpyran; 114 6H,6-ethoxycarbonyl-6-methyl-dibenzo(b,d] pyran; 6H,6-ethoxycarbonylmethyl-dibenzo [b,d] pyran; 6H,6-ethoxycarbonylmethyl-2-chloro-dibenzoLb.dJ pyran; 6H,6-ethoxycarbonylmethyl-2-fluoro-dibenzo[b,djpyran; 5 6H, 6-ethoxycarbonylmethyl-2-nitro-dibenzo (b,djpyran; 6H,6-ethoxycarbonylmethyl-2-aniino-dibenzo fb,dj pyran; 6H,6-ethoxycarbonylmethyl-2-methoxydibenzo[b, 6H,6-ethoxycarbonylmethyl-2—hydroxy-dibenzo |b,dj pyran; 6H,6-ethoxycarbonylmethyl-l,10-dimethoxy-dibenzo[b, dj pyran; 10 6H,6-ethoxycarbonylmethyl-8,9,10-trimethoxy-dibenzofb, dj pyran; 6H,6-ethoxycarbonylmethyl-6-methyl-dibenzo[b,dj pyran; 6H,6-ethoxycarbonylmethyl-6-jnethyl-2-chloro-dibenzo Lb ,dj pyran; 6H,6-ethoxycarbonylmethyl-6-methyl-2-fluoro-dibenzo jb,dj pyran; 6H,6-ethoxycarbonylmethyl-6-methyl-2-nitro-dibenzo jb,dj pyran; 15 6H,6-ethoxycarbonylmethyl-6-methyl-2-amino-dibenzo |b,dj pyran; 6H,6-ethoxycarbonylmethyl-6-methyl-2-methoxy-dibenzo lb,dl pyran; 6H,6-ethoxycarbonylmethyl-6-methyl-2-hydroxy-dibenzojb,d] pyran; 6H,6-(2-ethoxycarbonylethyl)-dibenzo [b, dj pyran; 6H,6-(2-ethoxycarbonylethyl)-2-chloro-dibenzo Jb,d] pyran; 20 6H,6-(2-ethoxycarbonylethyl)-2-fluoro-dibenzo (to,djpyran; t- η 6H,6-(2-ethoxycarbonylethyl)-8,9,10-trimethoxy-dibenzo Lb,dj pyran; 6H,6-(2-ethoxycarbonylethyl)-6-methyl-dibenzo [b,dj pyran; 6H,6-(2-dimethylaminoethoxy-carbonyl)-dibenzo jb,dj pyran; 6H,6-(2-dimethylaminoethoxy-carbonyl)-2-chloro-dibenzo Jb, d]pyran; 2 5 6H,6-(2-dimethylaminoethoxy-carbonyl)-2-fluoro-dibenzo jb,dj pyran; 115 6H,6-(2-dimethylaminoethoxy-carbonyl)-2-nitro-dibenzo jb,djpyran; 6H,6-(2-dimethylaminoethoxy-carbonyl)-2-methoxy-dibenzo jb,dj pyran; 6H,6-(2-dimethylaminoethoxy-carbonyl)-2-hydroxy-dibenzo[b,djpyran; 6H,6-(2-dimethylaminoethoxy-carbonyl)-2-amino-dibenzo jb, djpyran; 5 6H,6-(2-dimethylaminoethoxy-carbonyl)-l,10-dimethoxy-dibenzo t> , dj pyran; 6H,6-(2-dimethylaminoethoxy-carbonyl)-8,9,10-trimethoxy-dibenzo [b . dj pyran; 6H,6-(2-dimethylaminoethoxy-carbonyl)-6-methyl-dibenzo jb ,dj pyran; 10 6H,6-(2-dimethylaminoethoxy-carbonyl)-6-ethyl-dibenzo [b ,d] pyran; 6H,6-(2-dimethylamino-ethoxy-carbonyl)-6-methyl-2-hydroxy-dibenzo /B,d7pyran; 6H,6-(2-dimethylami no-ethoxy-carbonyl)-6-methyl-2-amino-dibenzo /b,d/pyran; 15 6H,6-(2-dimethylaminoethoxy-carbonylmethyl)-dibenzo/b,d?pyran; 6H,6-(3-pyri dy1 methylenoxy-carbonyl methyl)-di benzo/B,d/pyran; s· 6H,6-(3-pyridylmethylenoxy-carbonylmethyl)-6-methyl-dibenzo/b,d7pyran; 6H,6-carboxy-6-methyl-2-chloro-dibenzo Lb > dj pyran; 6H, 6-carboxy-6-methyl-2-fluoro-dibenzo j_b , dj pyran; 20 6H,6-carboxy-6-methyl-2-nitro-dibenzo[b,djpyran; 6H,6-carboxy-6-methyl-2-methoxy-dibenzo[b,dj pyran; i~ “1 6H, 6-carboxy-6-methy1-2-trifluoromethyl-dibenzo j_b, dj pyran; 116 516 8 5 1 6H,6-carboxy-6-methyl-l,10-dimethoxy-dibenzo jb,d/pyran; 6H,6-carboxy-8,9,10-trimethoxy—dibenzo [b ,dj pyran; 6H,6-carboxymethyl-dibenzo jb,d] pyran; 6H,6-carboxymethyl-l-methoxy-dibenzo [b,d] pyran; 5 6H,6-carboxymethyl-2-chloro-dibenzo jb,dl pyran; 6H,6-carboxymethyl-2-fluoro-dibenzo [b,dl pyran; 6H,6-carboxymethyl-2-nitro-dibenzo |b,dj pyran; 6H,6-carboxymethyl-2-methoxy-dibenzo[b, d] pyran; 6H,6-carboxymethyl-2-trifluoromethyl-dibenzo[b,dlpyran; 10 6H,6-carboxymethyl-8-chloro-dibenzojb.dj pyran; 6H,6-carboxymethyl-8-fluoro-dibenzo [b,d]pyran; 6H,6-carboxymethyl-8-nitro-dibenzo jb.dl pyran; 6H,6-carboxymethyl-8-methoxy-dibenzojb ,d]pyran; 6H,6-carboxymethyl-l,10-dimethoxy-dibenzo[b,d] pyran; 15 6H,6-carboxymethyl-8,9,10-trimethoxy-dibenzo |b,dlpyran; 6H,6-carboxymethyl-6-methyl-dibenzo jb,djpyran; 6H,6-(2-carboxyethyl)-dibenzo jb,dj pyran; 6H,6-(2-carboxy-ethyl)-2- chloro-dibenzo jb,d) pyran; 6H, 6-(2-carboxy-ethyl)-2-fluoro-dibenzo jb, dl pyran; 20 6H,6-(2-carboxy-ethyl)-2-nitro-dibenzo ib,4l pyran; 6H,6-( 2-carboxy-ethyl)-2-methoxy-dibenzojb,djpyran; 6H,6-( 2-carboxy-ethyl)-1,10-dimethoxy-dibenzo jb,dj pyran; 6H,6-(2-carboxy-ethyl)-8,9,10-trimethoxy-dibenzo [b,di pyran; 6H,6-amino-methyl-dibenzo [b,d[pyran; 25 6H,6-amino-methyl-2-chloro-dibenzojb,d]pyran; Π7 6H, 6-ami nomethyl-2-f luoro-dibenzo jb , d_[ pyran; 6H, 6-ami.nomethyl-2-methoxy-dibenzo [b ,djpyran; 6H,6-aminomethyl-2-hydroxy-dibenzo|b , dj pyran; 6H,6-aminomethyl-l,10-dimethoxy-dibenzo (b, d] pyran; 5 6H,6-aminomethyl-8,9,10-trimethoxy-dibenzo lb,djpyran; 6H, 6-(2-methylamino-ethyl) -dibenzo Lb, dl pyran; 6H, 6-(3-methylamino-propyl)-dibenzo jb, d]pyran; 6H, 6-(3-methylamino-propyl)-1-methoxy-di benzo/b, d7pyran; 6H,6-(4-piperidinyl)-dibenzo [b, dj pyran; 10 6H,6—(l-hydroxy-2-tert-butylamino-ethyl)-dibenzojb.djpyran 6H,6-(l-hydroxy-2-tert-butylamino-ethyl)-2—chloro-dibenzo jb , dj pyran; 6H, 6-(1-hydroxy-2-1ert-butylamino-ethyl)-2-methoxy-dibenzo jb.djpyran; 15 6H,6-(1-hydroxy-2-tert-butylamino-ethyl)-1,10-dimethoxydibenzo jb , dj pyran ; 6H,6-(1-hydroxy-2-tert-butylamino-ethyl)-8,9,10-trimethoxy dibenzo jb,dj pyran, and the pharmaceutically or veterinarily acceptable salts thereof. 118
  5. 5. ) A process for the preparation of a compound as claimed in any one of claims 1 to 4, said process comprising: a) reacting a compound of formula (11) 5 wherein R is a halogen atom or a hydroxy group; R'^is hydrogen, unsubstituted C-C alkyl or an optionally substituted 1 6 phenyl group and R„, R^ , R = , R,, R_ and R are as defined in 3 4 5 6 7 o claim 1,with an alkali metal cyanide or with a C-C -alkylsilylcyanide or with an amine of formula HN£^ R a, wherein R^ 10 and R, are as defined in/ C ^ a j m s'o obtaining a b compound of 6 · formula (I), wherein n is zero; R is -CN or a, wherein τ * 1 1 R and R are as defined in/®' ; R o is hydrogen, unsubstituted a b 4 C -C alkyl or an optionally substituted phenyl group; and 1 6 R , R., R » R ι R_ and R are as defined in claim 1; or 3 4 5 6 7 8 15 b) reacting a compound of formula (III) 119 wherein Y is an halogen atom; R' is hydrogen, unsubstituted C —C alkyl or an optionally substituted phenyl group and 1 6 claim 1 R , R , R , R , R and R are as defined in/ , with an alkali 3 4 5 6 7 8 metal cyanide, so obtaining a compound of formula (I), wherein 5 n is zero; R is hydrogen, unsubstituted C-C alkyl or an 2 16 optionally substituted phenyl group; R^ is -CN and R„, R^, R_, R , R and R are as defined, in Claim 1; Or 6 7 o reacting a compound of formula (II), R 1 is hydrogen, unsubstituted C -C 3 16 substituted phenyl group; R , R , R , . . , 3 4 5 . ,claim 1 detinedin/ , with a Wittig reagent wherein R is hydroxy; alkyl or an optionally R , R and R are as 6 7 8 of formula ([V) (-) E-CH-(CH ( R' ) -R η 1 (IV) wherein r. · Qlaim ί R is as defined in/ n is zero, 1 or 2; E is (C H_) P1 1 6 5 3 ? or a (R^OjgP- group, where each of R may be independently C -C alkyl or phenyl and R 1 is hydrogen or amino; so obtaining 1 6 a compound of formula (I), wherein n is 1, 2 or 3; R is hydrogen or amino, wherein when R is amino, it is never linked to the ¢( -carbon atom bound at the 6-position of the benzopyrane system; Rg is hydrogen, unsubstituted C^-C^ alkyl or an optionally substituted phenyl group; R , R , R , R , R , R and R are as defined in claim 1? or 1 3 4 5 6 7 8 120 d) cyclizing a compound of formula (V) (V) wherein A is R , where R^ is as defined in claim 1, or a protected carboxy group and n, R, R , R , R , R , R , R ... 2 3 4 5 6 7 _ ,olarm 1 and R are as defined in/ and removing the protecting 8 group(s), when present, so obtaining a compound of formula (I), wherein n, R, s , R. R , R x , R , 1 2 3 4 5 R , R and R are as defined in claim 1, or 6 7 o e) cyclizing a compound of formula (VI) (VI) 121 i wherein R' is hydrogen, unsubstituted C-C alkyl or 2 16 an optionally substituted phenyl group; R is as R^ claim 1 defined in/ under a), b) or e), and n, Rg, R^, Rg, n) aim 1 R , R and R are as defined in/ , so obtaining a 6 7 8 compound of formula (I), wherein R is hydrogen? and, if R is as defined in/ ClaiB under a) or b), is a free carboxy group, or, if R is as R^ defined-in claim 1 claim 1 . under e) also R^ is as defined in/ under e); R^ is hydrogen, unsubstituted C 1 -C g alkyl or an optionally substituted phenyl group; and n, Rg, R^, Rg, Rg, R? and R are as defined in claim/and, if desired, converting a 8 compound of formula (I) into another compound of formula (I), and/or, if desired, salifying a compound of formula (I) or obtaining a free compound of formula (I) from a salt thereof and/or, if desired, resolving a mixture of isomers into the individual isomers.
  6. 6. ) A pharmaceutical composition containing a suitable carrier and/or diluent and, as an active principle, a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof. 20
  7. 7) A compound or a pharmaceutically acceptable salt thereof, according to claim 1, for use in a method of treatment of the human or animal body by surgery or therapy or a diagnosis practised on the human or animal body. 122
  8. 8. A compound or a pharmaceutically acceptable salt thereof, according to claim 1, or a pharmaceutical composition according to claim 6 for use in administration to human patients or animal to treat or prevent the formation of gastrointestinal ulcers, to 5 treat transplant reactions, autoimmune disorders, bacterial and viral infections, to lower total serum cholesterol and triglycerides and to increase the total serum HDL cholesterol.
  9. 9. A compound or salt thereof according to claim 1 hereinbefore specifically mentioned with the exception of the compounds and salts 10 claimed in Claim 4.
  10. 10. A process according to Claim 5 substantially as hereinbefore described with reference to any one of the Examples.
  11. 11. A composition according to Claim 6 substantially as hereinbefore described with reference to any one of the Formulation Examples. 15
  12. 12. A compound as defined in claim 1 whenever prepared by a process according to claim 5 or 10.
IE2456/81A 1980-10-20 1981-10-19 6-substituted 6h-dibenzo(b,d)pyran derivatives and process for their preparation IE51685B1 (en)

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