CA1258455A - Coumarin derivatives, pharmaceutical compositions containing the same, and the use thereof in the treatment of cancer - Google Patents
Coumarin derivatives, pharmaceutical compositions containing the same, and the use thereof in the treatment of cancerInfo
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- CA1258455A CA1258455A CA000459548A CA459548A CA1258455A CA 1258455 A CA1258455 A CA 1258455A CA 000459548 A CA000459548 A CA 000459548A CA 459548 A CA459548 A CA 459548A CA 1258455 A CA1258455 A CA 1258455A
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Abstract
ABSTRACT OF THE DISCLOSURE
A compound is provided herein having the formula:
A compound is provided herein having the formula:
Description
iZS8455 The present invention relates to new basic coumarin derivatives, procedures for their preparation, and pharmaceutical compositions containing them.
Tbe compounds according to the invention correspond to the following ~eneral Formula (I):
R R
.Ri s I f R, ~, R
R20 ~ (I) R, wherein R1 is halogen, an unsubstituted hydrocarbyl group, or a hydrocarbyl group substituted wi-th hydroxyl, amino or carbonyl Oroups and which can be interrupted in the carbon atom chain by 0, S or N; wherein R2, R6 and R7, which may be the same or different, each represents hydrogen, an unsubstituted hydrocarbyl group, or a hydrocarbyl group substituted with hydroxyl, amino or carbonyl groups and can be interrupted in the carbon atom chain by 0, S or N~ or wherein R6 and R7 taken together may represent a hete70 group having one or more hetero atoms; wherein R3 and R4, which may be the samè-or different, each represents an unsub-stituted hydrocarbyl group. or a hydrocarbyl group substituted ~Z58455 - la -with hydroxyl, amino or carbonyl groups and can be interrupted in the carbon atom chain by 0, S or ~, or wherein R~ and R4 taken together may represent an alkylene group or a hetero group having one or more hetero atoms; and wherein Rs is hydrogen, an unsubstituted hydrocarbyl group or a hydrocarbyl group substituted with hydroxyl, amino or carbonyl groups and can be interrupted in the carbon atom chain by 0, S or N, halogen or a free or protected hydroxy group, or a pharmaceutically acceptable salt thereof.
These compounds have antiaggregating properties and some of them also display antitumoral and antimetastatic activity. ..
`',~,~1 12~;84SS
The compounds of the invention are prepared by procedures which are themselves already known, such as by reacting, using a Mannich reaction, the coumarin derivatives corresponding to formula (II):
1 ~ R1 (II~
with formic aldehyde and a secondary amine HN and if desired, by introducing an R2 hydrocarbyl group into a compound obtained having a free phenolic hydroxyl in the 7-position.
The present invention relates to new basic coumarin derivatives, and in particular the compounds corresponding to the general ~ormula (I):
R4~ R5 R4 N-CH2 ~ ~ R7 R20 / ~ \ O / ~0 (I) ~258455 in which R2, R5, R6 and ~7 each represent nonsubstituted or substituted hydrocarbyl groups which may be interrupted in the carbon atom chain by he~eroatoms, or hydrogen; ~1' R3 and R4 individually S and R3 and R4 jointly, represent unsubstituted or substituted hydrocarbyl groups which may be ~nterrupted in the carbon atom chain by heteroatoms, and Rl may also represent a haloyen and R5 may represent a halogen or a free or protected hydroxyl group, their salts, procedures for the preparation of such new compounds and their salts, pharmaceutical compositions containing the same and methods for the use of the compounds and their salts.
The compounds of the present invention are active lS in inhibiting platelet aggregation. They can therefore be used for experimental, diagnostic or therapeutic pLrposes in veterinary or human medicines and especially as an antithrombotic arug. One of the . groups of compounds of the presen~ invention also has an antitumoral and antimetastatic action and can be used to this end on animals for experimental purposes .and in medicine, for ins~ance, on patients with lung carcinoma.
iZ58~55 One of the objects of the present invention is to provide various preparation procedures for the new coumarin derivatives.
Another object of the present invention is to 5provide methods for thP use of the new coumarin compounds as therapeutic agents.
A further object of the invention is to provide pharmaceutical compositions which contain at least one of the new coumarin compounds as an active ingredient.
10These and other objects and advantages of the present invention will become apparent to those skilled in the art from a consideration of th~
following specification and claims.
The hydrocarbyl groups in formula (I) are 15aliphatic, araliphatic or alicyclic groups and R6 and R7 may also represent aromatic hydrocarbyl ~roups.
These groups can be unsubstituted or substituted, saturated or unsaturated and can be in~errupted in the carbon atom chain by heteroatoms such as oxygen, 20sulfur or nitrogen. Of the aliphatic groups thus defined, alkyl groups having preferahly l to 7 carbon atoms and especially from l to 4 carbon atoms should be noted. The unsaturated hydrocarbon groups may be alkenyl or polyunsaturated groups such as alkyldienyl, lZS8~5 alkyltrienyl and the like having from 1 to 7 carbon atoms, preferably from 1 to 4 carbon atoms. Among the unsaturated aliphatic groups, alkenyl groups having from 2 to 4 carbon atoms are particularly worthy of mention. All of these groups may for~ linear or branched chains. Of the ~licyclic groups as described above, the ones with a simple saturated ring should particularly be mentioned, that is, the cycloalkyl monocyclic ~roups and especially those with 3 to 7 carbon atoms in the ring, and more particularly from 5 to 7 carbon atoms in the ring. Alicyclic unsaturated groups having 3 to 7, preferably 5 to 7, carbon atoms in the ring may be used. These groups may have one or more double bonds in their cycle, such as the cycloalkenyl groups with a double bond.
Of the unsubstituted alkvl groups, the following preferred groups should be mentioned: methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.
Preferred unsubstituted alkenyl groups include vinyl, allyl, propenyl, isobutenyl, 2-butenyl and 2-pentenyl.
Exe~plary cycloal~yl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Suitable unsubstituted cycloalkenyl groups include cyclopentenyl and cyclohexenyl. The hyarocarbyl aliphatic ~roups, like the above-mentioned alkyl 12S8 ~55 groups, may however also be substituted by aromatic hydrocarbyl groups, especially for example by phenyl, which may in turr. be substituted by various ~unctions, for example from 1 ~o 3 halogen atoms tparticularly chlorine and/or bromine) or by alkyl groups having 1 to 4 carbon atoms such as methyl.
The alicyclic groups include the cycloalkyl and cycloalkenyl groups, such as those mentioned above, having from 3 to 7 and especi~lly bet~een 5 and 7 carbon atoms in the ring, substituted for example by 1 to 3 alkyl groups having for example from 1 to 7, and especially from 1 to 4, carbon atoms, such as methyl, ethyl, propyl and/or isopropyl. The aromatic hydrocarbon groups directly bound to the coumarin ring, such as the R6 and R7 groups, are generally phenyl groups which may be substituted for example by 1 to 3 functions, especially chlorine and/or bromine atoms or by alkyl groups having from 1 to 4 carbon atoms, particularly methyl groups.
The hydrocarbyl groups, and especially the aliphatic and alicyclic groups iike all those already mentioned, can be interrupted in the carbon atom chain by heteroatoms, especially by one heteroatom, as in particular by oxygen, sulfur or nitrogen and may be substituted by functions, preferably one or two, for ~.2S8455 example halogens, free or protected alcoholic functions, free or protected carbonyl groups, free or protected carboxylic groups or free or su~stituted amine groups.
S Halogens are especially represented by fluorine, chlorine and bromine. Among the protected alcoholic functions, etherified or esterified hydroxy groups should have special mention.
The etherifying groups may correspond to each of the above-mentioned hydrocarbyl groups, particularly alkyl groups having 1 to 7, preferabiy 1 to 4, carbon a~oms or cycloalkyl moieties having 3 to 7 carbon atoms in the ring, such as the following groups:
methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl and cyclohexyl. The esterified hydroxyl groups may be derived from organic or inorganic acids, for example from acids of the aliphatic, araliphatic, aromatic or alicyclic series, having from 1 to 15 carbon atoms, for example from lower aliphatic acids having from 1 to 7 carhon atoms, such as formic acid, acetic acid, propionic acid, the butyric acids, trimethylacetic acid, caproic acid, succinic acid, phenylacetic acid, benzoic acid, the trimethoxybenzoic acids and the chlorobenzoic acids. The ester groups may also be derived from organic sulfonic acids, especially from alkylsulfonic acids containing from 1 to 7 carbon ~Z5E3~55 atoms, such as methanesulfonic acid, or from arylsulfonic acids, such as those containing only one aromatic ring, such as para-toluenesulfonic acid.
Ester groups derived from inorganic acids include for example, sulfuric acid, the phosphoric acids and the hydracids, such as hydrochloric or hydrobro~.ic acid.
Among the protected carbonyl functions, the ketal groups should be mentioned, especially cyclic ketal groups, such as those derived from ethylene glycol or propylene glycol. Among the protected carboxylic functions, the esters and amides should especially be mentioned. The esterifying groups ma~ correspond to each of the above-mentioned hydrocarbyl groups, particularly alkyl groups having 1 to 7, preferably 1 to 4, carbon atoms, or cycloalkyl groups having 3 to 7 carbon atoms in the ring, such as methyl, ethyl, isopropyl, cyclopentyl and cyclohexyl.
The amide groups may be the free amido group -CON~2 or an amide substituted at the nitrogen atom, 'O such as the groups deriving from the amine groups exemplified below. The amine group can be ~ree or substituted by hydrocarbyl groups, the substituting groups being, for example, the above-mentioned ones, especially alkyl groups having 1 to 7, prererably 1 to 4, carbon atoms, such as methyl, ethyl or isopropyl, or cycloalkyl groups having 3 to 7, preferably from 5 to 7, carbon atoms in the ring thereof, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The amine groups may be derived from primary or secondary amines, that is, one or two of the hydrocarbyl substituent group~ may be present. Thus, for example, the amine group may be the -NH2 group or a methylamine, ethylamine, propylamine or dimethylamine groop.
These amine groups may in turn be substituted in their hydrocarbyl residues by othèr functional groups such as a free or pro~ected hydroxyl group, and the free or substituted amine group, such groups being preferably those just mentioned hereinabove. The above-mentioned functions may be found in any position in the chain of carbon atoms of the hydrocarbyl groups, such as in the alpha, beta or gamma position with respect to the coumarin ring. For example, an alkyl group such as Rl, R6 or R7 may especially be a -CO-R group, in which R is a hydrocarbyl group, unsubstituted for instance, such as an acyl group, 3 C2~5, CO-C3H7, etc. Specifically therefore:
- Rl may be a hydrocarbyl group as defined, or a halogenr such as fluorine, chlorine or bromine.
1~8455 ~ R2 may be a hydrogen atom or one of the hydrocarbyl groups previously defined.
- R3 and R~ may be, considered separately, one of the hydrocarbyl groups previously define~.
The groups R3 and R4 jointly may also represent a bivalent aliphatic hydrocarbyl sroup bound to nitrogen by ~wo valences s~arting from two different carbon atoms (alkylene groups). The alkylene tor alkylenic) groups usually have from 2 to 7 and especially from 2 to 5 carbon atoms and can contain double bonds and be a linear or branched chain. ExPmplary alkylene groups incluce ethylenic, trimethylenic, tetramethylenic,
Tbe compounds according to the invention correspond to the following ~eneral Formula (I):
R R
.Ri s I f R, ~, R
R20 ~ (I) R, wherein R1 is halogen, an unsubstituted hydrocarbyl group, or a hydrocarbyl group substituted wi-th hydroxyl, amino or carbonyl Oroups and which can be interrupted in the carbon atom chain by 0, S or N; wherein R2, R6 and R7, which may be the same or different, each represents hydrogen, an unsubstituted hydrocarbyl group, or a hydrocarbyl group substituted with hydroxyl, amino or carbonyl groups and can be interrupted in the carbon atom chain by 0, S or N~ or wherein R6 and R7 taken together may represent a hete70 group having one or more hetero atoms; wherein R3 and R4, which may be the samè-or different, each represents an unsub-stituted hydrocarbyl group. or a hydrocarbyl group substituted ~Z58455 - la -with hydroxyl, amino or carbonyl groups and can be interrupted in the carbon atom chain by 0, S or ~, or wherein R~ and R4 taken together may represent an alkylene group or a hetero group having one or more hetero atoms; and wherein Rs is hydrogen, an unsubstituted hydrocarbyl group or a hydrocarbyl group substituted with hydroxyl, amino or carbonyl groups and can be interrupted in the carbon atom chain by 0, S or N, halogen or a free or protected hydroxy group, or a pharmaceutically acceptable salt thereof.
These compounds have antiaggregating properties and some of them also display antitumoral and antimetastatic activity. ..
`',~,~1 12~;84SS
The compounds of the invention are prepared by procedures which are themselves already known, such as by reacting, using a Mannich reaction, the coumarin derivatives corresponding to formula (II):
1 ~ R1 (II~
with formic aldehyde and a secondary amine HN and if desired, by introducing an R2 hydrocarbyl group into a compound obtained having a free phenolic hydroxyl in the 7-position.
The present invention relates to new basic coumarin derivatives, and in particular the compounds corresponding to the general ~ormula (I):
R4~ R5 R4 N-CH2 ~ ~ R7 R20 / ~ \ O / ~0 (I) ~258455 in which R2, R5, R6 and ~7 each represent nonsubstituted or substituted hydrocarbyl groups which may be interrupted in the carbon atom chain by he~eroatoms, or hydrogen; ~1' R3 and R4 individually S and R3 and R4 jointly, represent unsubstituted or substituted hydrocarbyl groups which may be ~nterrupted in the carbon atom chain by heteroatoms, and Rl may also represent a haloyen and R5 may represent a halogen or a free or protected hydroxyl group, their salts, procedures for the preparation of such new compounds and their salts, pharmaceutical compositions containing the same and methods for the use of the compounds and their salts.
The compounds of the present invention are active lS in inhibiting platelet aggregation. They can therefore be used for experimental, diagnostic or therapeutic pLrposes in veterinary or human medicines and especially as an antithrombotic arug. One of the . groups of compounds of the presen~ invention also has an antitumoral and antimetastatic action and can be used to this end on animals for experimental purposes .and in medicine, for ins~ance, on patients with lung carcinoma.
iZ58~55 One of the objects of the present invention is to provide various preparation procedures for the new coumarin derivatives.
Another object of the present invention is to 5provide methods for thP use of the new coumarin compounds as therapeutic agents.
A further object of the invention is to provide pharmaceutical compositions which contain at least one of the new coumarin compounds as an active ingredient.
10These and other objects and advantages of the present invention will become apparent to those skilled in the art from a consideration of th~
following specification and claims.
The hydrocarbyl groups in formula (I) are 15aliphatic, araliphatic or alicyclic groups and R6 and R7 may also represent aromatic hydrocarbyl ~roups.
These groups can be unsubstituted or substituted, saturated or unsaturated and can be in~errupted in the carbon atom chain by heteroatoms such as oxygen, 20sulfur or nitrogen. Of the aliphatic groups thus defined, alkyl groups having preferahly l to 7 carbon atoms and especially from l to 4 carbon atoms should be noted. The unsaturated hydrocarbon groups may be alkenyl or polyunsaturated groups such as alkyldienyl, lZS8~5 alkyltrienyl and the like having from 1 to 7 carbon atoms, preferably from 1 to 4 carbon atoms. Among the unsaturated aliphatic groups, alkenyl groups having from 2 to 4 carbon atoms are particularly worthy of mention. All of these groups may for~ linear or branched chains. Of the ~licyclic groups as described above, the ones with a simple saturated ring should particularly be mentioned, that is, the cycloalkyl monocyclic ~roups and especially those with 3 to 7 carbon atoms in the ring, and more particularly from 5 to 7 carbon atoms in the ring. Alicyclic unsaturated groups having 3 to 7, preferably 5 to 7, carbon atoms in the ring may be used. These groups may have one or more double bonds in their cycle, such as the cycloalkenyl groups with a double bond.
Of the unsubstituted alkvl groups, the following preferred groups should be mentioned: methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.
Preferred unsubstituted alkenyl groups include vinyl, allyl, propenyl, isobutenyl, 2-butenyl and 2-pentenyl.
Exe~plary cycloal~yl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Suitable unsubstituted cycloalkenyl groups include cyclopentenyl and cyclohexenyl. The hyarocarbyl aliphatic ~roups, like the above-mentioned alkyl 12S8 ~55 groups, may however also be substituted by aromatic hydrocarbyl groups, especially for example by phenyl, which may in turr. be substituted by various ~unctions, for example from 1 ~o 3 halogen atoms tparticularly chlorine and/or bromine) or by alkyl groups having 1 to 4 carbon atoms such as methyl.
The alicyclic groups include the cycloalkyl and cycloalkenyl groups, such as those mentioned above, having from 3 to 7 and especi~lly bet~een 5 and 7 carbon atoms in the ring, substituted for example by 1 to 3 alkyl groups having for example from 1 to 7, and especially from 1 to 4, carbon atoms, such as methyl, ethyl, propyl and/or isopropyl. The aromatic hydrocarbon groups directly bound to the coumarin ring, such as the R6 and R7 groups, are generally phenyl groups which may be substituted for example by 1 to 3 functions, especially chlorine and/or bromine atoms or by alkyl groups having from 1 to 4 carbon atoms, particularly methyl groups.
The hydrocarbyl groups, and especially the aliphatic and alicyclic groups iike all those already mentioned, can be interrupted in the carbon atom chain by heteroatoms, especially by one heteroatom, as in particular by oxygen, sulfur or nitrogen and may be substituted by functions, preferably one or two, for ~.2S8455 example halogens, free or protected alcoholic functions, free or protected carbonyl groups, free or protected carboxylic groups or free or su~stituted amine groups.
S Halogens are especially represented by fluorine, chlorine and bromine. Among the protected alcoholic functions, etherified or esterified hydroxy groups should have special mention.
The etherifying groups may correspond to each of the above-mentioned hydrocarbyl groups, particularly alkyl groups having 1 to 7, preferabiy 1 to 4, carbon a~oms or cycloalkyl moieties having 3 to 7 carbon atoms in the ring, such as the following groups:
methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl and cyclohexyl. The esterified hydroxyl groups may be derived from organic or inorganic acids, for example from acids of the aliphatic, araliphatic, aromatic or alicyclic series, having from 1 to 15 carbon atoms, for example from lower aliphatic acids having from 1 to 7 carhon atoms, such as formic acid, acetic acid, propionic acid, the butyric acids, trimethylacetic acid, caproic acid, succinic acid, phenylacetic acid, benzoic acid, the trimethoxybenzoic acids and the chlorobenzoic acids. The ester groups may also be derived from organic sulfonic acids, especially from alkylsulfonic acids containing from 1 to 7 carbon ~Z5E3~55 atoms, such as methanesulfonic acid, or from arylsulfonic acids, such as those containing only one aromatic ring, such as para-toluenesulfonic acid.
Ester groups derived from inorganic acids include for example, sulfuric acid, the phosphoric acids and the hydracids, such as hydrochloric or hydrobro~.ic acid.
Among the protected carbonyl functions, the ketal groups should be mentioned, especially cyclic ketal groups, such as those derived from ethylene glycol or propylene glycol. Among the protected carboxylic functions, the esters and amides should especially be mentioned. The esterifying groups ma~ correspond to each of the above-mentioned hydrocarbyl groups, particularly alkyl groups having 1 to 7, preferably 1 to 4, carbon atoms, or cycloalkyl groups having 3 to 7 carbon atoms in the ring, such as methyl, ethyl, isopropyl, cyclopentyl and cyclohexyl.
The amide groups may be the free amido group -CON~2 or an amide substituted at the nitrogen atom, 'O such as the groups deriving from the amine groups exemplified below. The amine group can be ~ree or substituted by hydrocarbyl groups, the substituting groups being, for example, the above-mentioned ones, especially alkyl groups having 1 to 7, prererably 1 to 4, carbon atoms, such as methyl, ethyl or isopropyl, or cycloalkyl groups having 3 to 7, preferably from 5 to 7, carbon atoms in the ring thereof, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The amine groups may be derived from primary or secondary amines, that is, one or two of the hydrocarbyl substituent group~ may be present. Thus, for example, the amine group may be the -NH2 group or a methylamine, ethylamine, propylamine or dimethylamine groop.
These amine groups may in turn be substituted in their hydrocarbyl residues by othèr functional groups such as a free or pro~ected hydroxyl group, and the free or substituted amine group, such groups being preferably those just mentioned hereinabove. The above-mentioned functions may be found in any position in the chain of carbon atoms of the hydrocarbyl groups, such as in the alpha, beta or gamma position with respect to the coumarin ring. For example, an alkyl group such as Rl, R6 or R7 may especially be a -CO-R group, in which R is a hydrocarbyl group, unsubstituted for instance, such as an acyl group, 3 C2~5, CO-C3H7, etc. Specifically therefore:
- Rl may be a hydrocarbyl group as defined, or a halogenr such as fluorine, chlorine or bromine.
1~8455 ~ R2 may be a hydrogen atom or one of the hydrocarbyl groups previously defined.
- R3 and R~ may be, considered separately, one of the hydrocarbyl groups previously define~.
The groups R3 and R4 jointly may also represent a bivalent aliphatic hydrocarbyl sroup bound to nitrogen by ~wo valences s~arting from two different carbon atoms (alkylene groups). The alkylene tor alkylenic) groups usually have from 2 to 7 and especially from 2 to 5 carbon atoms and can contain double bonds and be a linear or branched chain. ExPmplary alkylene groups incluce ethylenic, trimethylenic, tetramethylenic,
2-methyltrime~hylenic, pentamethylenic, esamethylenic - and groups derived therefrom by substitution with one or more methyl or ethyl groups. These hydrocarbyl groups may or may not be substituted by functions, as in the previously mentioned case of the monovalent hydrocarbyl groups and/or they may be interrupted in the carbon atom chain by heteroatoms, such as oxygen, sulfur or nitrogen (-IH~ in particular. Whenever R3 and R4 jointly represent an alkylene group they form, with the nitrogen atom, heterocyclic monoazotate systems, that is, azacycloalkyl groups, and when the ~Zs~45~
alkylene group represented b~ R3 and R4 is interrupted by a heteroatom, hetero-azacycloalkyl groups are formed. Of the azacycloalkyl groups, the following are worthy of special mention: pyrrolidino, pi pe ri di no , 3 - hy dr o xy pi p eri G ino an d 4-hydroxypiperidino. Of the bivalent or polyvalent heteroatoms interrupting the carbon atom chain of the alkylenic group R3, R4 ~he following should especially be mentioned: oxygen, sulfur, nitrogen or the group which may be substituted by an aliphatic hydrocarbyl group, especially an alkyl group having 1 to 7, particularly 1 to 4, carbon atoms, such as methyl, ethyl or isopropyl, which in turn may be substituted by one or more, for instance from 1 to 3 free or protected hydroxyl groups like those already mentioned, and/or may be interrupted in the carbon atom chain thereof by heteroatoms like those already mentioned above.
Of the hetero azacycloalkyl groups, the following are worthy of special mention: the morpholino, thiomorpholino, piperazino, N-ethylpip~razino and N-hydroxyethylpiperazino rings.
~ 2SB455 The group R5 is a hydrogen atom or a halogen as previously described for Rl or one of the hydrocarbyl groups also as previously described or a free or protected hydroxyl group. A protected hydroxyl group means an etherified or esterified group as defined above. The etherifying groups are especially Cl-C7, preferably Cl-C4, alkyl groups such as methyl, ethyl or isopropyl, or cycloalkyl groups having 3 to 7, preferably 5 to 7, carbon atoms in the ring, such as the cyclopentyl and cyclohexyl groups.
The R6 and R7 moieties are both hydrogen atoms or one of the hydrocarbyl groups previously defined by Rl or one of the aromatic hydrocarbyl groups also described above.
Of the compounds of formula (I) according to the invention, preferred are those in which:
- Rl is a hydrocarbyl group having from l to 7 and preferably from l to 4 carbon atoms or a halogen.
- R2 is a hydrogen atom or a hydrocarbyl group having from l to 7 and preferably from l to 4 carbon atoms, possibly substituted by a free carboxylic group or a carboxylic group esterified with an alkyl having from l to 7 and preferably l to 4 carbon atoms.
~ZS8455 - R3 and R4 are both alkyl g~oups with from 1 to 7 and preferabiy with 1 to 4 carbon atoms and R3 and R4 jointly form an alkylene grou~ with from 2 to 7 carbon atoms which may be interrupted in the carbon atom chain by an atom of oxygen or sulfur or by an -NH- or -IR group in which R represents an alkyl having 1 to 7 and preferably 1 to 4 carbon atoms which may be substituted by one or more, for instance from 1 to 3 free or etherified hydroxyl groups derived from an aliphatic alcohol having from 1 to 7 and preferably from 1 to 4 carbon atoms or esterified with an organic aliphatic acid having from 1 to 7 carbon atoms.
- R5 is hydrogen or a free or esterified hydroxyl group with an aliphatic alcohol having 1 to 7 and lS preferably 1 to 4 carbon atoms.
- R6 and R7 are each and independently hvdrogen or an alkyl having 1 to 7 and preferably from 1 to 4 carbon atoms which may be interrupted in tne car~on atom chain by a nitrogen atom, or by a -NH- group, or by the -~R- group, in which R represents an alkyl with from 1 to 7 and preferably from 1 to 4 carbon atoms which may be substituted by ' to 3 free or etherified hydroxyl groups derived from an aliphatic alcohol having from 1 to 7 and preferably from 1 to 4 ~Zs8~s caxbon atoms or esterified with an aliphatic organic acid having from 1 to 7 carbon atoms. The hydroxyl groups may also be substituted with phenyl or phenylalkyl having from 1 to 7 and preferably from 1 to 4 carbon atoms in the aliphatic part and in which groups the phenyl may also be substituted by 1 to 3 methyl groups or by 1 to 3 chlorine or bromine atoms.
Of the products mentioned here, it is worth noting those in which Rl is an unsaturated hyd ocarbyl group, especially an alkenyl group having from 2 to 7 carbon atoms, such as the vinyl, allyl, 2-butenyl and isobutenyl groups and wherein R3 and R4 are hydrocarbyl groups~ especially alkyl groups having from 1 to 7, preferably 1 to 4, carbon atoms or R3 and R4 jointly with the nitrogen atom constitute a piperazinyl group which may be substituted in the N'-position by an alkyl group with 1 to 4 carbon atoms, which may be terminally substituted by a free hydroxyl, etherified by an alkyl with 1 to 4 carbon atoms or esterified with an aliphatic organic acid having from 1 to 7 carbon atoms. Alternatively, R3 and R4 jointly with the nitrogen atom represent the morpholino or thiomorpholino group or the pyrrolidino or piperidino groups which may be C-substituted by a 2, free or etherified hydroxyl group with an alkyl having ~ Z ~ ~ ~ 5 S
1 to 4 carbon atomr or esterifie~ with an organic aliphatic acid having 1 tO 7 carbon atoms.
Of the specific compounds according to the invention, the following are listed as examples:
4-me~hyl-6 dimethylaminomethyl-7-hydroxy-8-allylcou-marin';
4-methyl-6-(4-morpholinylmethyl)-7-hydroxy-8-allylcou-mar in;
4-methyl-6- ~4-(2-hydroxyethyl)-1-pipe~azinyl~methyl]--7-hydroxv-8-allylcoumarin;
Ethyl ester of the ~4-methyl-S-(4-morpholinylmethyl) -8-allvlcoumarin-7-yl]oxyacetic acid;
4-methyl-6-(4-morpholinylmethyl)-7-allyloxy-8-allyl-coumarln;
Ethyl ester of the 2-[4-methyl-6-(4-morpholinylmethyl) -8-allylcoumarin-7-yl]oxy-2-me~hylpropionic acid;
4-phenyl-6-(4-morpholinylmethyl)-7-hycroxy-8-allyl-coumarin;
1 ~ 5 ~5 ~
4-phenyl-6- ~[4-t2-hydroxyPthyl)~l-pipera2inyl]methyl]
-7-hydroxy-8-allylcoumarin;
4-phenyl-6-(4-morpholinylmethyl)-7-allyloxy-8-allyl-coumarin;
Ethyl ester of ~he ~4-phenyl-6-(4-morpholinylmethyl)-8 -allylcoumarin-7-yl]oxyacetic acid;
Ethyl ester of ~he 2-[4-phenyl-6-(4-morpholinylmethyl) -8-allylcoumarin-7-yl~oxy-2-methylpropionic acid;
4-methyl-6-(1-pyrrolidinylmethyl1-7-hydroxy-8-allyl-coumarin;
4-methyl-6-diethylaminomethyl-7-hydroxy-8-allylcou-marln;
4-methyl-6-(1-piperidinylmethyl)-7-hydroxy-8-allyl-coumzrir.;
4-methyl-6-~4-hydroxy-1-piperidinyl)methyl]-7-hydroxy-8-allylcoumarin;
iZSB455 4-methyl-6-[(3-hydroxy-1-piperidinyl)methyl]-7-hydroxy -8-allylcoumarin;
alkylene group represented b~ R3 and R4 is interrupted by a heteroatom, hetero-azacycloalkyl groups are formed. Of the azacycloalkyl groups, the following are worthy of special mention: pyrrolidino, pi pe ri di no , 3 - hy dr o xy pi p eri G ino an d 4-hydroxypiperidino. Of the bivalent or polyvalent heteroatoms interrupting the carbon atom chain of the alkylenic group R3, R4 ~he following should especially be mentioned: oxygen, sulfur, nitrogen or the group which may be substituted by an aliphatic hydrocarbyl group, especially an alkyl group having 1 to 7, particularly 1 to 4, carbon atoms, such as methyl, ethyl or isopropyl, which in turn may be substituted by one or more, for instance from 1 to 3 free or protected hydroxyl groups like those already mentioned, and/or may be interrupted in the carbon atom chain thereof by heteroatoms like those already mentioned above.
Of the hetero azacycloalkyl groups, the following are worthy of special mention: the morpholino, thiomorpholino, piperazino, N-ethylpip~razino and N-hydroxyethylpiperazino rings.
~ 2SB455 The group R5 is a hydrogen atom or a halogen as previously described for Rl or one of the hydrocarbyl groups also as previously described or a free or protected hydroxyl group. A protected hydroxyl group means an etherified or esterified group as defined above. The etherifying groups are especially Cl-C7, preferably Cl-C4, alkyl groups such as methyl, ethyl or isopropyl, or cycloalkyl groups having 3 to 7, preferably 5 to 7, carbon atoms in the ring, such as the cyclopentyl and cyclohexyl groups.
The R6 and R7 moieties are both hydrogen atoms or one of the hydrocarbyl groups previously defined by Rl or one of the aromatic hydrocarbyl groups also described above.
Of the compounds of formula (I) according to the invention, preferred are those in which:
- Rl is a hydrocarbyl group having from l to 7 and preferably from l to 4 carbon atoms or a halogen.
- R2 is a hydrogen atom or a hydrocarbyl group having from l to 7 and preferably from l to 4 carbon atoms, possibly substituted by a free carboxylic group or a carboxylic group esterified with an alkyl having from l to 7 and preferably l to 4 carbon atoms.
~ZS8455 - R3 and R4 are both alkyl g~oups with from 1 to 7 and preferabiy with 1 to 4 carbon atoms and R3 and R4 jointly form an alkylene grou~ with from 2 to 7 carbon atoms which may be interrupted in the carbon atom chain by an atom of oxygen or sulfur or by an -NH- or -IR group in which R represents an alkyl having 1 to 7 and preferably 1 to 4 carbon atoms which may be substituted by one or more, for instance from 1 to 3 free or etherified hydroxyl groups derived from an aliphatic alcohol having from 1 to 7 and preferably from 1 to 4 carbon atoms or esterified with an organic aliphatic acid having from 1 to 7 carbon atoms.
- R5 is hydrogen or a free or esterified hydroxyl group with an aliphatic alcohol having 1 to 7 and lS preferably 1 to 4 carbon atoms.
- R6 and R7 are each and independently hvdrogen or an alkyl having 1 to 7 and preferably from 1 to 4 carbon atoms which may be interrupted in tne car~on atom chain by a nitrogen atom, or by a -NH- group, or by the -~R- group, in which R represents an alkyl with from 1 to 7 and preferably from 1 to 4 carbon atoms which may be substituted by ' to 3 free or etherified hydroxyl groups derived from an aliphatic alcohol having from 1 to 7 and preferably from 1 to 4 ~Zs8~s caxbon atoms or esterified with an aliphatic organic acid having from 1 to 7 carbon atoms. The hydroxyl groups may also be substituted with phenyl or phenylalkyl having from 1 to 7 and preferably from 1 to 4 carbon atoms in the aliphatic part and in which groups the phenyl may also be substituted by 1 to 3 methyl groups or by 1 to 3 chlorine or bromine atoms.
Of the products mentioned here, it is worth noting those in which Rl is an unsaturated hyd ocarbyl group, especially an alkenyl group having from 2 to 7 carbon atoms, such as the vinyl, allyl, 2-butenyl and isobutenyl groups and wherein R3 and R4 are hydrocarbyl groups~ especially alkyl groups having from 1 to 7, preferably 1 to 4, carbon atoms or R3 and R4 jointly with the nitrogen atom constitute a piperazinyl group which may be substituted in the N'-position by an alkyl group with 1 to 4 carbon atoms, which may be terminally substituted by a free hydroxyl, etherified by an alkyl with 1 to 4 carbon atoms or esterified with an aliphatic organic acid having from 1 to 7 carbon atoms. Alternatively, R3 and R4 jointly with the nitrogen atom represent the morpholino or thiomorpholino group or the pyrrolidino or piperidino groups which may be C-substituted by a 2, free or etherified hydroxyl group with an alkyl having ~ Z ~ ~ ~ 5 S
1 to 4 carbon atomr or esterifie~ with an organic aliphatic acid having 1 tO 7 carbon atoms.
Of the specific compounds according to the invention, the following are listed as examples:
4-me~hyl-6 dimethylaminomethyl-7-hydroxy-8-allylcou-marin';
4-methyl-6-(4-morpholinylmethyl)-7-hydroxy-8-allylcou-mar in;
4-methyl-6- ~4-(2-hydroxyethyl)-1-pipe~azinyl~methyl]--7-hydroxv-8-allylcoumarin;
Ethyl ester of the ~4-methyl-S-(4-morpholinylmethyl) -8-allvlcoumarin-7-yl]oxyacetic acid;
4-methyl-6-(4-morpholinylmethyl)-7-allyloxy-8-allyl-coumarln;
Ethyl ester of the 2-[4-methyl-6-(4-morpholinylmethyl) -8-allylcoumarin-7-yl]oxy-2-me~hylpropionic acid;
4-phenyl-6-(4-morpholinylmethyl)-7-hycroxy-8-allyl-coumarin;
1 ~ 5 ~5 ~
4-phenyl-6- ~[4-t2-hydroxyPthyl)~l-pipera2inyl]methyl]
-7-hydroxy-8-allylcoumarin;
4-phenyl-6-(4-morpholinylmethyl)-7-allyloxy-8-allyl-coumarin;
Ethyl ester of ~he ~4-phenyl-6-(4-morpholinylmethyl)-8 -allylcoumarin-7-yl]oxyacetic acid;
Ethyl ester of ~he 2-[4-phenyl-6-(4-morpholinylmethyl) -8-allylcoumarin-7-yl~oxy-2-methylpropionic acid;
4-methyl-6-(1-pyrrolidinylmethyl1-7-hydroxy-8-allyl-coumarin;
4-methyl-6-diethylaminomethyl-7-hydroxy-8-allylcou-marln;
4-methyl-6-(1-piperidinylmethyl)-7-hydroxy-8-allyl-coumzrir.;
4-methyl-6-~4-hydroxy-1-piperidinyl)methyl]-7-hydroxy-8-allylcoumarin;
iZSB455 4-methyl-6-[(3-hydroxy-1-piperidinyl)methyl]-7-hydroxy -8-allylcoumarin;
3-12-diethylaminoethyl)-4 methyl-6-(4-morpholinyl-methyl)-7-hydroxy-8-chlorocoumarin;
S Ethyl ester of the 13-(2-diethylaminoethyl)-4-methyl-6 . -(4-morpholinylmethyl)-8-chlorocoumarin-7-yl]oxy-acetic acid ;
3-(2-diethylaminoethyl)-4-methyl-6-(4-morpholinyl-methyl)-7-allyloxy-8-chlorocoumarin;
Ethyl ester of the 2-13-(2-diethylaminoethyl)-4-methyl)-6-(4-morpholinylmethyl)-8-chlorocoumarin-7-yl]
oxy-2-methylpropionic acid ;
S Ethyl ester of the 13-(2-diethylaminoethyl)-4-methyl-6 . -(4-morpholinylmethyl)-8-chlorocoumarin-7-yl]oxy-acetic acid ;
3-(2-diethylaminoethyl)-4-methyl-6-(4-morpholinyl-methyl)-7-allyloxy-8-chlorocoumarin;
Ethyl ester of the 2-13-(2-diethylaminoethyl)-4-methyl)-6-(4-morpholinylmethyl)-8-chlorocoumarin-7-yl]
oxy-2-methylpropionic acid ;
4-methyl-6'(4-morpholi~ylmethyl)-7-hydroxy-8-chloro-coumarin;
4-methyl-6-diethylaminomethyl-7-hydroxy 8-chloro-` coumarin;
~ZS8~55 4-phenyl-6-(4-morpholinylmethyl)-7-hydroxy-8-chloro-coumarini 3-(2-diethylamino~thyl)-4-methy~-6-(4-morpholinyl-methyl) 7-methoxv-8-chlorocoumarin;
4-methyl-7-hydroxy-6-dimethylaminomethyl-7-hydroxy-8-chlorocoumarin;
4,8-dimethyl-6-dimethylaminomethyl-7-hydroxycoumarin;
4,8-dimethvl-6-(4-morpholinylmethyl)-7-hydroxycou-marin ; and 4-phenyl-6-dimethylaminomethyl-7-hydroxy~8-allylcou-marin.
The compound~ of formula (I) may be salified by known methods and these salts are also an object of the present invention. Of these salts, those obtained 1~ by adding acids are par~icularly important. These are obtained in a conventional manner by treatment with suitable acids. Therapeuticallv acceptable acids such ~Z5~55 as hydrochloric, hydrobromic, sulfuric, the phosphoric acids, methanesulfonic, malic, tartaric and succinic acid are suitably used. Nontherapeutic acids may however also be used, thus ob~aining salts which can S be u~ed for the puri~ica~ion of the products, such as picric acid and picrolonic acid. The compounds of formula (I) in which Rl represents hydrogen (identifiable as compounds of formula IA) may be transformed into metal salts or organic bases by salifying a phenolic group in the 7-position with these bases. These salts are also an object of the invention and may be used in place of the acid addition salts or free compounds for pharmaceutical or medical purposes. T~e alkali metal salts, for instance, the sodium-and potassium salts, as well as the ammonium salt are worthy of special mention.
The compounds of formula (I) and their salts are active in preventing platelet aggregation. For example, these compounds exhibit this activity ln Vit~Q at a concentration of between 10 /ml and 1000Y
/ml, as the following experiments show.
~C~
Aggregation is evaluated by an aggregometer ELVI
840 according to Born's method (Nature L2~, 927, 1962).
l~Sl~SS
New Zealand rabbits are anaesthetized with a mixture of Chloralose and Urethane (40 mg/kg ~ 500 mg/kg), the carotid is cannulated and 40 ml of blood is drawn and 3.8~ of sodium citrate is immediately S added. Two separate centrifugations are effected (at lO00 rpm and at 6000 rpm), thus obtainins PRP (protein rich plasma) and PPP (protein poor plasma); the first is diluted with the second in order to obtain a p}atelet concentration of 300,000 per mm3 ~the count is effected in a Buerker apparatus). The compounds with a platelet antiaggregating activity of the present invention are added at the desired concentrations and incubated for 30 minutes at 37C.
with the aggregating agents. Platelet aggregation is stimulated by adding ADP at a concentration of 20 ~g/ml.
The results are express~d as percentage of inhibition of platelet hyperaggregation induced by ADP
added to the PRP in a concentration of 20 ~g/ml. ~The - results reported in Table l refer to the tests effected with lO0 r/ml of the single compound. The various compounds represented by the numbers in the first column are identifiable by the numbers in the second column which refer to the examples described -~ below in this specification.
TABI.E 1 ~i~ Ac'cis~ity Compounds Inhibi~ion of platelet hyper-aggregation induced by ADP ( 20 llg/ml ) at a concentration of 100 Y/ml of the acti~e compound expressed in 19 (Ex.1) 40 (Ex.2) 19 26 (Ex.3) 23 27 (Ex.4) 32 28 (Ex.5) 54 29 (Ex.6) 19 44 (Ex.7) 20 49 (Ex.8) 25 (Ex.9) 25 51 (Ex.10) 37 52 (Ex.11) 22 58 (Ex.17) 1 25 62 (Ex.18) 23 67 (Ex.19) 18 68 (Ex.20) 41 69 (Exo21) 29 76 (Ex.22) ~ 27 102 (Ex.23) 12 105 (Ex~24) 28 117 (Ex.12) 44 ~ 121 (Ex.13~ 51 124 (Ex.14) 38 130 (Ex.26) 29 132 (Ex.25) 13 188 (Ex.27) lc ~:~ 200 (Ex.15) 21 201 (Ex.15) 32 ~2S8455 Various products of the invention corresponding to formula (I) such as 4-methyl-6-dimethylaminome~hyl-7-hydroxy-8-allylcoumarin and its salts, for example the hydrochloride (compound 19) and 4-methyl-6- ~[4-(2-hy-droxyethyl)-1-piperazinyl]methyl~-7-hydroxy-8-allyl-coumarin and its salts, such as the dihydrochloride (compound 26) also have an antitumoral and anti~leta~tatic acti~ity, as shown by pharmacological - experiments carried out ir. vivo on mice. This activity is to be se en for instance aft er administration o~ doses of between 0.2 mg/kg and 10 mg/kg by the oral route, as illustrated by the following experiments.
Experiment B
1 x 105 3LL carcinoma cells (Lewis lung carcinoma) are implanted by intramuscular injection in the paws of male mice of the C57Bl/6J strain, weishing about 20-22 g. This operation is effected as described in the litèrature (Poggi A. et al. Cancer Res. 37, 272-277, 1977). The growth of the tumor is observed until the 25th day a~ter transplant. On this day the animals are sacrificed and the primary tumor and lungs are removed in order to evaluate the grow.h of the primary - ~2 -~;2S~3455 tumor and the number of metastases. Pharmacological treatment by the oral route besins 2 days before transplant cf the tumor and continues until sacrifice.
The substances are dissolved in tap water and are changed every 24 hours.
In a separate experiment, the anticoagulating ~ctivity of the compounds is verified on the same strain of mice at the same doses used for antimetastatic activity evaluation.
10The effect on coagulation is measured by a thrombotest on capillary blood taken from the retroorbital cavity (Owren, P.A. et al. Lancet iL~
754-758, 1959).
Table 2 reports the results obtained with the two iScoumarin derivatives 19 and 26, previously mentioned in comparison to Warfarin, the well-known antitumor and antimetastatic compound, which is also a coumarin derivative. Warfarin's antimetastatic acti~ity is widely documented both experimentally (Zacharski, L.R.
et al. Cancer 44, 732-741, 1979 and Poggi, A. et al.
Lancet i 163-164, 1978; and clinically (Zacharski, L.R. et al. J. Am. MedO Assoc. ~, 331-835, 1981).
Indeed, Warfarin has an antimetastatic effect on 'Lewis lung carcinoma', syngeneic with mice of the ~5~4S5 C57Bl/6J strain, causing spontaneous metastasis in the lungs 2fter in~ramuscular implantation of tumoral cells. This effect is measured by the number of metastases (Zacharski, L.R. et al. Cancer ~, 732-741, 1979 and Poggi, A. et al. Lancet i 163-164, 1978).
Clinically speaking, treatment with Warfarin in association with classic methods such as chemotherapy and radiation, prolongs survival time in patients with lung carcinoma. ~owever, Warfarin in antitumor therapy has the disadvantage of having a strong anticoagulating activity, and it seems ~hat its antitumor action mechanism is mainly linked with this activity. (Donati, M.B. et al. Brit. J. Haematol~ a4, 173-182, 1980).
The anticoagulating effect measured by the "thrombotest", the antitumor effect measured by the decrease in weight of the primary tumor and .he antimetastatic effect shown as the number of metastases present in the lungs, are reported in Table 2. While the antitumor and ar.timetastatic effects of Wararin and the two new products according to the present invention are roughly equal, the strong anticoagulating effect is absent in the two new products of the invention. This is not only a ~2S~3~55 completely unexpected result, but also represents a very important advantage of the new coumarin derivatives of the invention in view of their use as antitumor and antimetas~atic agents.
- 25 _ r ~12S8455 n ~ .s O ~
.
o ;
o ~, c _ ~O O r~
+l +l +l +
_ a~ ~ O
~ ~- _~ ~
o ~ I I +l +l .. ~ ~ ~ ~
o n ~I
~, r~ ~ O O o C
C C~ .
:>
e ~o o V~ _l _~ ~
~ ~ _ ~
J
~6 -.~
~zs~ss The compounds which are the object of the present invention have low toxicity, as can be shown by acute toxicit~ studies by the oral route in two animal species:
ExpC~i~$; C
Acute toxic-ty in the ~at: groups of Sprague Dawley rats (male + female) are treated with graduated doses ranging from 0.125 g/k~ of body weight to lOg/kg of body weight of the above mentioned compounds in aqueous solution. The compounds are administered orally by intubation. Subse~uent death may be immediate or may occur at any time up to 14 days after treatment.
The lethal dos~ 50 (LDSo)r that is, the dose which causes the death of 50% of the animals, is evaluated by the method of Litchfield and ~ilcoxo~ (J.
Pharmacol. Ex. Ther. ~h, 99-113, 1949). The L~50 determined for the two compounds under examination shows low toxicity, as is seen in Table 3.
34~5 TAI~LE ~
Acute toxicitv in the rat of the examined compounds, administered bv the oral route ir. aqueous solution.
Compound 19 (Ex. 1) LD50 2 g/kg of body weight Compound 26 (Ex. 3) LD50 3.16 g/kg of body weight Experiment D
1(' Acute t~xicity in the _mouse: groups of Swiss mice (male + female) are treated with graduated doses ranging from 0.125 g/kg to 5 g/kg of body weight with compounds 19 and 26. The compounds are administered orally by intubation and dissolved in water.
Subsequent death may be immediate or may occur at any time up to 14 days after treatment. The lethal dose 50 (~Dso), that is, the dose which causes the death of 50~ of the animals, is evaluated by the method of Litchfield and Wilcoxon (J. Pharmacol. Exp.
Th~r. ~, 9a-113, 1949).
Table 4 shows that the compounds are more toxic in the mouse than in the rat. It is, however, a known ~ZS845s fact that different results are obtained from a toxicological point of view, according to the animal species considered.
T~BLE 4 Acute toxicity in the mouse of the compounds examined after administration by the oral route in aqueous solution.
Compound 19 (Ex. 1~ LDso 1.21 g/kg of body weight Compound 26 (Ex. 3) LDsO 1.95 g/kg of body weight The coumarin derivatives of formulas I and I~ and their salts, according to the present invention, may lS be used as platelet antiaggregation druss for therapeutic and/or prophylactic purposes. The dosages vary according to the conditions, age and sta~e of the patient. Generally, a daily dose by the oral route of about 20-500 mg for a mammal weishinq about 70 kg is advisable. The compounds of the invention with an antitumor and antimetastatic action may be used mainly for the treatment of tumors of various origin.
~2S84S5 The procedure for the preparation of the compounds of formula I according to the pressnt invention is as follows:
A. The coumarin derivatives corresponding to formula II:
~ ~ Rl (II) H~O
in which Rl, Rs, R6 and R7 have th~ same significance as for formula I, are subjected to a Mannich reaction with the secondary amine HNR3R4 in which R3 and R4 have the same significance as for compound I; or B. Expose to a Claisen or Fries reaction, a compound of formula III:
4 ~ C~2 ~ ~,R7 R10 0 ~ (III3 in which R3, R4 Rs, R6 and R7 have the same significance as for the compounds of formula I and R1 signifies a possibly substituted hydrocarbyl group, transferable in the 8-position;
or ~2S~34S5 C. by means of a Friedel-Crafts reaction, introduce a possibly substituted hydrocarbyl group R1 as defined for formula I or introduce a halogen atom Rl by halogenation as defined for formula I in a compound of formula IV:
`N-CH2 ~ R7 (IV) R20 ~ ~
in which R1, R3, R~, R5, R6 and R7 have the same significance as for the compounds of formula I, and R2 may also signify a hydroxyl protection group substitutable by hydrogen and R5 may represent a temporarily protected hydroxyl group; or D. convert the aldehyde group in the 6-position present in a compound of formula V:
H R5 lR6 O=C ~ R7 ~V) R20 ~\0 ~
~Z58455 in which R1, R2, Rs, R6 and R7 have the same significance as for the compounds of formula I, by reductive alkylation, in the R4R3N-CH2- group in which R3 and R4 have the same significance as for the compounds of formula I, and R2 may also signify a hydroxyl protection group substitutable by hydrogen and Rs may represent a te~porarily protected hydroxyl group; or E. convert a functionally modified hydroxyl group or reagent X
present in a compound of formula VIo .. . . .. .
:, R5 f~6 X-CH~R7 20 1 0 0 (VI) Rl in which R1, R2, Rs and R7 have the same significance as for the compounds of formula I, and R2 may also signify a hydroxyl protection group substitutable by hydrogen and R5 may represent a temporarily protected hydroxyl group, in the R4R3N- group in which R3 and R4 have the same significance as for the compounds of formula I; or :~258455 F. convert the -NHZ group into a compound of formula VII:
N-CH2 ~ ,R7 R20 ~ o J ~o (VII) in which Rl, R2r Rs, R6 and R7 have the same significance as for the compound of formula I and Z represents hydrogen or one of the R3 or R4 groups having the same significance as for formula I, and R2 may also signify a hydroxyl protection group substitutable by hydrogen and Rs may represent a temporarily protected hydroxyl group, in the ~NR3R4 group; or - G. condense by a Pechmann reaction a compound of formula VIII:
`,N-CHz~ , H
¦ ¦¦ . (VIII) R20 ~ H
Rl in which R1, R2, R3, R4 hav2 the same significance as for the compounds of formula I, and R2 may also signify 125~3~55 a hydroxyl protection group substitutable by hydrogen and Rsmay represent a temporarily protected hydroxyl group, with a compound of formula IX:
Rl6 C=O
I (IX) COOR
in which R6 and R7 have the same significance as for the compounds of formula I and R represents hydrogen or a hydrocarbyl group; or H. condense by a Perkin reaction a compound of formula X:
R~ R5 ~ . .
,N-CH2 ~C=O
R20/ ~ OH (X) in which Rl, R2, R3, R4, and Rs have the same significance as for the compounds of formula I, and R2 may also signify a hydroxyl protection group substitutable by hydrogen and Rs may represent a temporarily pr~tected hydroxyl group, with a compound of formula XI:
I (XI) COOR
. .
~2S~55 in which R7 has the same significance as for the compounds of formula I and R represents hydrogen or a hydrocarbyl group; and if desired, introduce a hydrocarbyl group R2 as defined for formula I into a S compound obtained by any one of the previous procedures which has a structure in which R2 represents hydrogen (compound of formula IA) and/or, either before or simultaneously with this introduction, free one or more functional groups from the corresponding functionally modified groups and/or functionally modify the free functional groups and/or interconvert the free functional groups between themselves and/or functionally modify and/or transform an obtained product of formula I or IA into one of its salts.
In the above mentioned ~rocedure A, the Mannich reaction can be conducted in the known manner. The formic aldehyde may be used as such or may be formed in situ, for example using agents which generate formaldehyde, such as the polymerized or condensed . aldehydes, for example paraformaldehyde or hexamethylenetetramine. All of the solvents recommended or described in the literature for the Mannich reaction may be used. The most suitable ~z~ss solvents are aliphatic alcohols, such as those with 1 to 5 carbon atoms, or aliphatic carboxyl~c acids, such as those with 2 to 4 carbon atoms. In particular, ethyl alcohol or acetic acid, either as such or containi~g water, is suitably employed The amine ~NR3R4 may be used in its free form, or as one of its sal~s, such as the hydrochloride or sulfate. The secondary amines particularly suitable for the preparation of the compounds (I) are dimethylamine, diethylamine, pyrrolidine, morpholine, piperidine, 3-hydroxypiperidine, 4-hydroxypiperidine, N ethylpiperazine and N-hydroxyethylpiperazine.
Condensation according to Mannich's method is generally effPcted at a temperature of between about 20 and 120C., and preferably be~ween about 50 and 90CO ~
In prQGedure B, the above mentioned Rl in the compounds of formula III may be for Pxample an unsaturated aliphatic hydrocarbyl group, particularly an alkenyl group, with a double bond in the beta- or gamma- position, such as an allylic qroup, which is ` transferred in the 8-position by applying a Claisen reaction, carried out by a method which is itself well known. For instance, the starting compound is heated ~ZSI 34s5 to a suitable temperature, such as between 130 and 230C. with or without a solvent. A tertiary aromatic base, such as dimethylaniline or diethylaniline, can be used as the solvent.
Rl may however also represent a substitut~d hydrocarbyl group, for instance an acyl group, such as an acetyl, propionylr butyryl group, etc. In this case, a Fries reaction is used for the transfer of the Rl group in the 8-position and is effected by the known method, for example in the presence of suitable catalysts, such as aluminum chloride in a solvent, which could be for instance carbon disulfide or carbon tetrachloride, at between room temperature and the boiling point of the solvent.
lS In the above mentioned procedure C, some compounds of formula I are obtained in which Rl may be a substituted or unsubstituted hydrocarbyl aliphatic, araliphatic or alicyclic group, introduced in the 8~position by applying a ~riedel-Crafts reaction by the known method.
For example, a suitable derivative containing the ` Rl group is heated and bound to a halogen or an oxyhydryl (haloid, alcohol) with compound IV at a suitable temperature, such as between 50 and 120C.
in the presence of a solvent and a catalyst.
~Z58~55 Hydrocarbons such as petroleum ether, carboxylic aliphatic acids such as acetic acid, haloids or organic sulfides such as carbon disulfide may be used as solvents, and Lewis acids, such as boron trifluoride, zinc chloride, aluminum chloride, ferric chloride or sulfuric acid are used as catalysts.
In pLQ~edure C, Rl may also represent a chlorine or bromine atom. In this case, a halogenation reaction is used for the introduction of the chlorine or bromine atom, by means of the known method for the halogenation of aromatic compounds. For instance, a compoun~ IV is treated with chlorine or bromine and with one of their derivatives in the presence of a solvent and possibly also a catalyst at a suitable temperature.
In the above mentioned pL~c~_~/ the reductive alkylation reaction may be effected in the known way.
Aldehyde V is made to react with the a~ine R4R3N~ in the presence of a suitable reducing agent. Leukart's reaction is usually used, in ~hich case the reducing agent is formic acid, formamide or methylformate. The reaction is carried out in a suitable solvent, such as the same reducing agent, at a temperaturP of between 30 and 100C. In the above mentioned ~LQ~dure D, ~;~58~S5 the conversion of a functionally modified hydroxyl group X in the group -NR3R4 ls obtained by reaction of the compound of formula VI with the amine NHR3R4 in a suitable solvent according to a known method. A
suitable basic compound may be added to the reaction mixtur~, for instance an inorganic base ~uch as sodium or potassium carbonate, or tertiary organic bases such as pyridine.
The most suitable solvents for the alkylation reaction are the aliphatic alcohols and aliphatic ketones with between 1 and 5 carbon atoms. A
functionally modified and reac~ive hydroxyl group is especially a hydroxyl group esterified with a hydracid such as hydrochloric, hydrobromic or hydriodic acid, and in this sense X represents chlorine, bromine or iodine, or an organic sulfonic acid such as an alkylsulfonic acid with between 1 and 7 carbon atoms, for example, methylsulfonic acid or ethylsulfonic acid or an arylsulfonic monocyclic acid such as p-toluenesulfonic or benzen~sulfonic acid.
In the above mentione~ E, one or both of the R3 and R4 groups, as defined for formula I and taken individually and not jointly/ are in~roduced into the -NH~ group of the compound of formula VII
2S where Z represents respectively one of the above mentioned groups or hydrogen, in order to ~Z58~5~
obtain the compound of formula I, for example by an alkylation or reductive alkylation reaction, according to known methods. The alkylation reaction may be carried out using as an alkylating agent a haloid of the R3-Y or R4-Y formula where Y signifies chlorine, bromine or iodine. When starting compounds with the -CH2-NH2 group in position 6 are used, it is possible to introduce two identical R3 or R4 groups using an excess of alkylating agent. With the correct dose of this agent it is possible to introduce just one of the R3 or R~ groups and the compounds thus obtained may be further alkylated, as described above, thus obtaining, if it should be desired, compounds with the two R3 and R4 groups which differ between themselves. The compounds of the two identical R3 and R4 groups may be advantageously obtained by reductive alkylation.
Aldehydes with the same number of carbon atoms and the same substitutions present in the R3 or R4 groups may be used as alkylating agents.
~258~5S
In the above mentioned ~rocedur~ G, the Pechmann reaction may be carried out in the known way. The phenolic compound corresponding to formula VIII is made to react with the carbonyl compound of formula IX
in which the R group corresponds to a hydrogen or an alkyl, preferably with between 1 and 4 carbon atoms.
The reaction is carried out using the usual condensing agents for the Pechmann reaction, such as sulfuric, hydrochloric and polyphosphoric acid, phosphorus oxychloride, aluminum chloride and zinc chloride.
The reaction is generally carried out at a temperature of between about 0 and 80C. In some cases it is advisable to use those solvents which are recommend~d or described in the literature for the Pechmann reaction.
In the above mentioned ~rocedure H, the Perkin's reaction may be carried out in the known way. The aldehyde compound of formula X is made to react with the compound of formula XI in which the R group corresponds to a hydrogen or alkyl~ pre~erably with between 1 and 4 carbon atoms. The reaction is carried out using condensing agents and the solvents recommended or described in the literature ~or the Perkin's reaction. The reaction is generally carried out at a temperature of between 50 and 110C
The optional introduction of a hydrocarbyl R2 group in compounds of formula I~ obtained according to any one of the above mentioned proc~dures may be effected by means of an etherifying reaction using an
4-methyl-6-diethylaminomethyl-7-hydroxy 8-chloro-` coumarin;
~ZS8~55 4-phenyl-6-(4-morpholinylmethyl)-7-hydroxy-8-chloro-coumarini 3-(2-diethylamino~thyl)-4-methy~-6-(4-morpholinyl-methyl) 7-methoxv-8-chlorocoumarin;
4-methyl-7-hydroxy-6-dimethylaminomethyl-7-hydroxy-8-chlorocoumarin;
4,8-dimethyl-6-dimethylaminomethyl-7-hydroxycoumarin;
4,8-dimethvl-6-(4-morpholinylmethyl)-7-hydroxycou-marin ; and 4-phenyl-6-dimethylaminomethyl-7-hydroxy~8-allylcou-marin.
The compound~ of formula (I) may be salified by known methods and these salts are also an object of the present invention. Of these salts, those obtained 1~ by adding acids are par~icularly important. These are obtained in a conventional manner by treatment with suitable acids. Therapeuticallv acceptable acids such ~Z5~55 as hydrochloric, hydrobromic, sulfuric, the phosphoric acids, methanesulfonic, malic, tartaric and succinic acid are suitably used. Nontherapeutic acids may however also be used, thus ob~aining salts which can S be u~ed for the puri~ica~ion of the products, such as picric acid and picrolonic acid. The compounds of formula (I) in which Rl represents hydrogen (identifiable as compounds of formula IA) may be transformed into metal salts or organic bases by salifying a phenolic group in the 7-position with these bases. These salts are also an object of the invention and may be used in place of the acid addition salts or free compounds for pharmaceutical or medical purposes. T~e alkali metal salts, for instance, the sodium-and potassium salts, as well as the ammonium salt are worthy of special mention.
The compounds of formula (I) and their salts are active in preventing platelet aggregation. For example, these compounds exhibit this activity ln Vit~Q at a concentration of between 10 /ml and 1000Y
/ml, as the following experiments show.
~C~
Aggregation is evaluated by an aggregometer ELVI
840 according to Born's method (Nature L2~, 927, 1962).
l~Sl~SS
New Zealand rabbits are anaesthetized with a mixture of Chloralose and Urethane (40 mg/kg ~ 500 mg/kg), the carotid is cannulated and 40 ml of blood is drawn and 3.8~ of sodium citrate is immediately S added. Two separate centrifugations are effected (at lO00 rpm and at 6000 rpm), thus obtainins PRP (protein rich plasma) and PPP (protein poor plasma); the first is diluted with the second in order to obtain a p}atelet concentration of 300,000 per mm3 ~the count is effected in a Buerker apparatus). The compounds with a platelet antiaggregating activity of the present invention are added at the desired concentrations and incubated for 30 minutes at 37C.
with the aggregating agents. Platelet aggregation is stimulated by adding ADP at a concentration of 20 ~g/ml.
The results are express~d as percentage of inhibition of platelet hyperaggregation induced by ADP
added to the PRP in a concentration of 20 ~g/ml. ~The - results reported in Table l refer to the tests effected with lO0 r/ml of the single compound. The various compounds represented by the numbers in the first column are identifiable by the numbers in the second column which refer to the examples described -~ below in this specification.
TABI.E 1 ~i~ Ac'cis~ity Compounds Inhibi~ion of platelet hyper-aggregation induced by ADP ( 20 llg/ml ) at a concentration of 100 Y/ml of the acti~e compound expressed in 19 (Ex.1) 40 (Ex.2) 19 26 (Ex.3) 23 27 (Ex.4) 32 28 (Ex.5) 54 29 (Ex.6) 19 44 (Ex.7) 20 49 (Ex.8) 25 (Ex.9) 25 51 (Ex.10) 37 52 (Ex.11) 22 58 (Ex.17) 1 25 62 (Ex.18) 23 67 (Ex.19) 18 68 (Ex.20) 41 69 (Exo21) 29 76 (Ex.22) ~ 27 102 (Ex.23) 12 105 (Ex~24) 28 117 (Ex.12) 44 ~ 121 (Ex.13~ 51 124 (Ex.14) 38 130 (Ex.26) 29 132 (Ex.25) 13 188 (Ex.27) lc ~:~ 200 (Ex.15) 21 201 (Ex.15) 32 ~2S8455 Various products of the invention corresponding to formula (I) such as 4-methyl-6-dimethylaminome~hyl-7-hydroxy-8-allylcoumarin and its salts, for example the hydrochloride (compound 19) and 4-methyl-6- ~[4-(2-hy-droxyethyl)-1-piperazinyl]methyl~-7-hydroxy-8-allyl-coumarin and its salts, such as the dihydrochloride (compound 26) also have an antitumoral and anti~leta~tatic acti~ity, as shown by pharmacological - experiments carried out ir. vivo on mice. This activity is to be se en for instance aft er administration o~ doses of between 0.2 mg/kg and 10 mg/kg by the oral route, as illustrated by the following experiments.
Experiment B
1 x 105 3LL carcinoma cells (Lewis lung carcinoma) are implanted by intramuscular injection in the paws of male mice of the C57Bl/6J strain, weishing about 20-22 g. This operation is effected as described in the litèrature (Poggi A. et al. Cancer Res. 37, 272-277, 1977). The growth of the tumor is observed until the 25th day a~ter transplant. On this day the animals are sacrificed and the primary tumor and lungs are removed in order to evaluate the grow.h of the primary - ~2 -~;2S~3455 tumor and the number of metastases. Pharmacological treatment by the oral route besins 2 days before transplant cf the tumor and continues until sacrifice.
The substances are dissolved in tap water and are changed every 24 hours.
In a separate experiment, the anticoagulating ~ctivity of the compounds is verified on the same strain of mice at the same doses used for antimetastatic activity evaluation.
10The effect on coagulation is measured by a thrombotest on capillary blood taken from the retroorbital cavity (Owren, P.A. et al. Lancet iL~
754-758, 1959).
Table 2 reports the results obtained with the two iScoumarin derivatives 19 and 26, previously mentioned in comparison to Warfarin, the well-known antitumor and antimetastatic compound, which is also a coumarin derivative. Warfarin's antimetastatic acti~ity is widely documented both experimentally (Zacharski, L.R.
et al. Cancer 44, 732-741, 1979 and Poggi, A. et al.
Lancet i 163-164, 1978; and clinically (Zacharski, L.R. et al. J. Am. MedO Assoc. ~, 331-835, 1981).
Indeed, Warfarin has an antimetastatic effect on 'Lewis lung carcinoma', syngeneic with mice of the ~5~4S5 C57Bl/6J strain, causing spontaneous metastasis in the lungs 2fter in~ramuscular implantation of tumoral cells. This effect is measured by the number of metastases (Zacharski, L.R. et al. Cancer ~, 732-741, 1979 and Poggi, A. et al. Lancet i 163-164, 1978).
Clinically speaking, treatment with Warfarin in association with classic methods such as chemotherapy and radiation, prolongs survival time in patients with lung carcinoma. ~owever, Warfarin in antitumor therapy has the disadvantage of having a strong anticoagulating activity, and it seems ~hat its antitumor action mechanism is mainly linked with this activity. (Donati, M.B. et al. Brit. J. Haematol~ a4, 173-182, 1980).
The anticoagulating effect measured by the "thrombotest", the antitumor effect measured by the decrease in weight of the primary tumor and .he antimetastatic effect shown as the number of metastases present in the lungs, are reported in Table 2. While the antitumor and ar.timetastatic effects of Wararin and the two new products according to the present invention are roughly equal, the strong anticoagulating effect is absent in the two new products of the invention. This is not only a ~2S~3~55 completely unexpected result, but also represents a very important advantage of the new coumarin derivatives of the invention in view of their use as antitumor and antimetas~atic agents.
- 25 _ r ~12S8455 n ~ .s O ~
.
o ;
o ~, c _ ~O O r~
+l +l +l +
_ a~ ~ O
~ ~- _~ ~
o ~ I I +l +l .. ~ ~ ~ ~
o n ~I
~, r~ ~ O O o C
C C~ .
:>
e ~o o V~ _l _~ ~
~ ~ _ ~
J
~6 -.~
~zs~ss The compounds which are the object of the present invention have low toxicity, as can be shown by acute toxicit~ studies by the oral route in two animal species:
ExpC~i~$; C
Acute toxic-ty in the ~at: groups of Sprague Dawley rats (male + female) are treated with graduated doses ranging from 0.125 g/k~ of body weight to lOg/kg of body weight of the above mentioned compounds in aqueous solution. The compounds are administered orally by intubation. Subse~uent death may be immediate or may occur at any time up to 14 days after treatment.
The lethal dos~ 50 (LDSo)r that is, the dose which causes the death of 50% of the animals, is evaluated by the method of Litchfield and ~ilcoxo~ (J.
Pharmacol. Ex. Ther. ~h, 99-113, 1949). The L~50 determined for the two compounds under examination shows low toxicity, as is seen in Table 3.
34~5 TAI~LE ~
Acute toxicitv in the rat of the examined compounds, administered bv the oral route ir. aqueous solution.
Compound 19 (Ex. 1) LD50 2 g/kg of body weight Compound 26 (Ex. 3) LD50 3.16 g/kg of body weight Experiment D
1(' Acute t~xicity in the _mouse: groups of Swiss mice (male + female) are treated with graduated doses ranging from 0.125 g/kg to 5 g/kg of body weight with compounds 19 and 26. The compounds are administered orally by intubation and dissolved in water.
Subsequent death may be immediate or may occur at any time up to 14 days after treatment. The lethal dose 50 (~Dso), that is, the dose which causes the death of 50~ of the animals, is evaluated by the method of Litchfield and Wilcoxon (J. Pharmacol. Exp.
Th~r. ~, 9a-113, 1949).
Table 4 shows that the compounds are more toxic in the mouse than in the rat. It is, however, a known ~ZS845s fact that different results are obtained from a toxicological point of view, according to the animal species considered.
T~BLE 4 Acute toxicity in the mouse of the compounds examined after administration by the oral route in aqueous solution.
Compound 19 (Ex. 1~ LDso 1.21 g/kg of body weight Compound 26 (Ex. 3) LDsO 1.95 g/kg of body weight The coumarin derivatives of formulas I and I~ and their salts, according to the present invention, may lS be used as platelet antiaggregation druss for therapeutic and/or prophylactic purposes. The dosages vary according to the conditions, age and sta~e of the patient. Generally, a daily dose by the oral route of about 20-500 mg for a mammal weishinq about 70 kg is advisable. The compounds of the invention with an antitumor and antimetastatic action may be used mainly for the treatment of tumors of various origin.
~2S84S5 The procedure for the preparation of the compounds of formula I according to the pressnt invention is as follows:
A. The coumarin derivatives corresponding to formula II:
~ ~ Rl (II) H~O
in which Rl, Rs, R6 and R7 have th~ same significance as for formula I, are subjected to a Mannich reaction with the secondary amine HNR3R4 in which R3 and R4 have the same significance as for compound I; or B. Expose to a Claisen or Fries reaction, a compound of formula III:
4 ~ C~2 ~ ~,R7 R10 0 ~ (III3 in which R3, R4 Rs, R6 and R7 have the same significance as for the compounds of formula I and R1 signifies a possibly substituted hydrocarbyl group, transferable in the 8-position;
or ~2S~34S5 C. by means of a Friedel-Crafts reaction, introduce a possibly substituted hydrocarbyl group R1 as defined for formula I or introduce a halogen atom Rl by halogenation as defined for formula I in a compound of formula IV:
`N-CH2 ~ R7 (IV) R20 ~ ~
in which R1, R3, R~, R5, R6 and R7 have the same significance as for the compounds of formula I, and R2 may also signify a hydroxyl protection group substitutable by hydrogen and R5 may represent a temporarily protected hydroxyl group; or D. convert the aldehyde group in the 6-position present in a compound of formula V:
H R5 lR6 O=C ~ R7 ~V) R20 ~\0 ~
~Z58455 in which R1, R2, Rs, R6 and R7 have the same significance as for the compounds of formula I, by reductive alkylation, in the R4R3N-CH2- group in which R3 and R4 have the same significance as for the compounds of formula I, and R2 may also signify a hydroxyl protection group substitutable by hydrogen and Rs may represent a te~porarily protected hydroxyl group; or E. convert a functionally modified hydroxyl group or reagent X
present in a compound of formula VIo .. . . .. .
:, R5 f~6 X-CH~R7 20 1 0 0 (VI) Rl in which R1, R2, Rs and R7 have the same significance as for the compounds of formula I, and R2 may also signify a hydroxyl protection group substitutable by hydrogen and R5 may represent a temporarily protected hydroxyl group, in the R4R3N- group in which R3 and R4 have the same significance as for the compounds of formula I; or :~258455 F. convert the -NHZ group into a compound of formula VII:
N-CH2 ~ ,R7 R20 ~ o J ~o (VII) in which Rl, R2r Rs, R6 and R7 have the same significance as for the compound of formula I and Z represents hydrogen or one of the R3 or R4 groups having the same significance as for formula I, and R2 may also signify a hydroxyl protection group substitutable by hydrogen and Rs may represent a temporarily protected hydroxyl group, in the ~NR3R4 group; or - G. condense by a Pechmann reaction a compound of formula VIII:
`,N-CHz~ , H
¦ ¦¦ . (VIII) R20 ~ H
Rl in which R1, R2, R3, R4 hav2 the same significance as for the compounds of formula I, and R2 may also signify 125~3~55 a hydroxyl protection group substitutable by hydrogen and Rsmay represent a temporarily protected hydroxyl group, with a compound of formula IX:
Rl6 C=O
I (IX) COOR
in which R6 and R7 have the same significance as for the compounds of formula I and R represents hydrogen or a hydrocarbyl group; or H. condense by a Perkin reaction a compound of formula X:
R~ R5 ~ . .
,N-CH2 ~C=O
R20/ ~ OH (X) in which Rl, R2, R3, R4, and Rs have the same significance as for the compounds of formula I, and R2 may also signify a hydroxyl protection group substitutable by hydrogen and Rs may represent a temporarily pr~tected hydroxyl group, with a compound of formula XI:
I (XI) COOR
. .
~2S~55 in which R7 has the same significance as for the compounds of formula I and R represents hydrogen or a hydrocarbyl group; and if desired, introduce a hydrocarbyl group R2 as defined for formula I into a S compound obtained by any one of the previous procedures which has a structure in which R2 represents hydrogen (compound of formula IA) and/or, either before or simultaneously with this introduction, free one or more functional groups from the corresponding functionally modified groups and/or functionally modify the free functional groups and/or interconvert the free functional groups between themselves and/or functionally modify and/or transform an obtained product of formula I or IA into one of its salts.
In the above mentioned ~rocedure A, the Mannich reaction can be conducted in the known manner. The formic aldehyde may be used as such or may be formed in situ, for example using agents which generate formaldehyde, such as the polymerized or condensed . aldehydes, for example paraformaldehyde or hexamethylenetetramine. All of the solvents recommended or described in the literature for the Mannich reaction may be used. The most suitable ~z~ss solvents are aliphatic alcohols, such as those with 1 to 5 carbon atoms, or aliphatic carboxyl~c acids, such as those with 2 to 4 carbon atoms. In particular, ethyl alcohol or acetic acid, either as such or containi~g water, is suitably employed The amine ~NR3R4 may be used in its free form, or as one of its sal~s, such as the hydrochloride or sulfate. The secondary amines particularly suitable for the preparation of the compounds (I) are dimethylamine, diethylamine, pyrrolidine, morpholine, piperidine, 3-hydroxypiperidine, 4-hydroxypiperidine, N ethylpiperazine and N-hydroxyethylpiperazine.
Condensation according to Mannich's method is generally effPcted at a temperature of between about 20 and 120C., and preferably be~ween about 50 and 90CO ~
In prQGedure B, the above mentioned Rl in the compounds of formula III may be for Pxample an unsaturated aliphatic hydrocarbyl group, particularly an alkenyl group, with a double bond in the beta- or gamma- position, such as an allylic qroup, which is ` transferred in the 8-position by applying a Claisen reaction, carried out by a method which is itself well known. For instance, the starting compound is heated ~ZSI 34s5 to a suitable temperature, such as between 130 and 230C. with or without a solvent. A tertiary aromatic base, such as dimethylaniline or diethylaniline, can be used as the solvent.
Rl may however also represent a substitut~d hydrocarbyl group, for instance an acyl group, such as an acetyl, propionylr butyryl group, etc. In this case, a Fries reaction is used for the transfer of the Rl group in the 8-position and is effected by the known method, for example in the presence of suitable catalysts, such as aluminum chloride in a solvent, which could be for instance carbon disulfide or carbon tetrachloride, at between room temperature and the boiling point of the solvent.
lS In the above mentioned procedure C, some compounds of formula I are obtained in which Rl may be a substituted or unsubstituted hydrocarbyl aliphatic, araliphatic or alicyclic group, introduced in the 8~position by applying a ~riedel-Crafts reaction by the known method.
For example, a suitable derivative containing the ` Rl group is heated and bound to a halogen or an oxyhydryl (haloid, alcohol) with compound IV at a suitable temperature, such as between 50 and 120C.
in the presence of a solvent and a catalyst.
~Z58~55 Hydrocarbons such as petroleum ether, carboxylic aliphatic acids such as acetic acid, haloids or organic sulfides such as carbon disulfide may be used as solvents, and Lewis acids, such as boron trifluoride, zinc chloride, aluminum chloride, ferric chloride or sulfuric acid are used as catalysts.
In pLQ~edure C, Rl may also represent a chlorine or bromine atom. In this case, a halogenation reaction is used for the introduction of the chlorine or bromine atom, by means of the known method for the halogenation of aromatic compounds. For instance, a compoun~ IV is treated with chlorine or bromine and with one of their derivatives in the presence of a solvent and possibly also a catalyst at a suitable temperature.
In the above mentioned pL~c~_~/ the reductive alkylation reaction may be effected in the known way.
Aldehyde V is made to react with the a~ine R4R3N~ in the presence of a suitable reducing agent. Leukart's reaction is usually used, in ~hich case the reducing agent is formic acid, formamide or methylformate. The reaction is carried out in a suitable solvent, such as the same reducing agent, at a temperaturP of between 30 and 100C. In the above mentioned ~LQ~dure D, ~;~58~S5 the conversion of a functionally modified hydroxyl group X in the group -NR3R4 ls obtained by reaction of the compound of formula VI with the amine NHR3R4 in a suitable solvent according to a known method. A
suitable basic compound may be added to the reaction mixtur~, for instance an inorganic base ~uch as sodium or potassium carbonate, or tertiary organic bases such as pyridine.
The most suitable solvents for the alkylation reaction are the aliphatic alcohols and aliphatic ketones with between 1 and 5 carbon atoms. A
functionally modified and reac~ive hydroxyl group is especially a hydroxyl group esterified with a hydracid such as hydrochloric, hydrobromic or hydriodic acid, and in this sense X represents chlorine, bromine or iodine, or an organic sulfonic acid such as an alkylsulfonic acid with between 1 and 7 carbon atoms, for example, methylsulfonic acid or ethylsulfonic acid or an arylsulfonic monocyclic acid such as p-toluenesulfonic or benzen~sulfonic acid.
In the above mentione~ E, one or both of the R3 and R4 groups, as defined for formula I and taken individually and not jointly/ are in~roduced into the -NH~ group of the compound of formula VII
2S where Z represents respectively one of the above mentioned groups or hydrogen, in order to ~Z58~5~
obtain the compound of formula I, for example by an alkylation or reductive alkylation reaction, according to known methods. The alkylation reaction may be carried out using as an alkylating agent a haloid of the R3-Y or R4-Y formula where Y signifies chlorine, bromine or iodine. When starting compounds with the -CH2-NH2 group in position 6 are used, it is possible to introduce two identical R3 or R4 groups using an excess of alkylating agent. With the correct dose of this agent it is possible to introduce just one of the R3 or R~ groups and the compounds thus obtained may be further alkylated, as described above, thus obtaining, if it should be desired, compounds with the two R3 and R4 groups which differ between themselves. The compounds of the two identical R3 and R4 groups may be advantageously obtained by reductive alkylation.
Aldehydes with the same number of carbon atoms and the same substitutions present in the R3 or R4 groups may be used as alkylating agents.
~258~5S
In the above mentioned ~rocedur~ G, the Pechmann reaction may be carried out in the known way. The phenolic compound corresponding to formula VIII is made to react with the carbonyl compound of formula IX
in which the R group corresponds to a hydrogen or an alkyl, preferably with between 1 and 4 carbon atoms.
The reaction is carried out using the usual condensing agents for the Pechmann reaction, such as sulfuric, hydrochloric and polyphosphoric acid, phosphorus oxychloride, aluminum chloride and zinc chloride.
The reaction is generally carried out at a temperature of between about 0 and 80C. In some cases it is advisable to use those solvents which are recommend~d or described in the literature for the Pechmann reaction.
In the above mentioned ~rocedure H, the Perkin's reaction may be carried out in the known way. The aldehyde compound of formula X is made to react with the compound of formula XI in which the R group corresponds to a hydrogen or alkyl~ pre~erably with between 1 and 4 carbon atoms. The reaction is carried out using condensing agents and the solvents recommended or described in the literature ~or the Perkin's reaction. The reaction is generally carried out at a temperature of between 50 and 110C
The optional introduction of a hydrocarbyl R2 group in compounds of formula I~ obtained according to any one of the above mentioned proc~dures may be effected by means of an etherifying reaction using an
- 5 etherifying agent derived from the R2 hydroxy alcohol.
These etherifying agents are for example R2X
alkylation agents, in which R2 signifies a hydrocarbyl group as already described for formula I and X
represents a group derived from the functional modiication of the hydroxyl, or more precisely, of an ester such as a hydracid ester ~and therefore a halogen) or of an inorganic acid such as sulfuric, sulfurous or silicic acid, or of organic sulfonic acids such as the sulfonic acids derived from lower aliphatic hydrocarbons with between 1 and 7 carbon atoms, for example methanesulfonic acid or sulfonic acids derived from aromatic hydrocarbons, especially monocyclic hydrocarbons, such a~ paratoluenesulfonic or ben~enesulfonic acid. X may there~ore generally represent a halogen atom, in particular chlorine, bromine or iodine or an alkyl or arylsulfonyloxy, such as the methyl or ethylsulfonyloxy or ben2ene or p-toluenesulfonyloxy group.
iZS8~SS
The above mentioned esterification reaction, represented by the following diagram, may be effected in the known manner. The compound R2X is made to react with the compounds of formula IA or possibly also with their phenolic salts in a suitable solvent.
-N-CH2 ~ ~ / R7 HO ~ ~ ~oR2 X R20 ~ \ O ~0 . .
I bis A suitable basic compound should be added to the reaction mixture, for instance, an inorganic base such as hydrates or the basic salts of alkali or alkaline earth metals, such as sodium or potassium carbonate, or tertiary organic bases such as pyridine, guinoline, collidine or Huenig's base.
The most suitable solvents for the previously described alkylation reaction are the aliphatic alcohols such as those with between 1 and 5 carbon atoms, aliphatic ketones or aprotic solvents; in particular acetone, methylethylketone, dimethysulfoxide and sulfolane may be employed.
l;~S1~4~5 In some of the preparation procedures for the compounds according to the invention, R2 may represent a pro~ection group of the hydroxyl substitutable by hydrogen, that is, a hydroxyl in the 7-position may be temporarily protected during the reactions of th~
respective procedures and finally liberated. This temporary protection of the hydroxyl group may take place by functional modification as described in the literature, especially by esterification or etherification. Of the esters, it is worth men~ioning those with aliphatic araliphatic or aromatic acids having between 1 and 15 carbon atoms such as those mentioned previously, and also acids which give easily saponifiable esters, for example, halogenated lower aliphatic acids, such as trichloro- or trifluoroacetic ; acid. These ester groups may then be saponified to give the hydroxyl group by well known methods such as alkaline or possibly acid hydrolysis. Of the ethers, those of tertiary lower aliphatic alcohols such as tert-butyl alcohol, which may be hydrolyzed under acid conditions, can be used. Ethers of aliphatic alcohols such as benzyl or nitrobenzyl alcohol may also be prepared and then separated by reduction in ~he known way. The same protection groups may also serve to protect, perhaps temporarily, an R5 hydroxyl group ~l2~89~55 which is then liberated in the same way. In an independently known way, moieties present in the hydrocarbyl substituents in the protected form can also be liberated, that is, functionally modified, where the protecting groups are easily eliminated.
Vice versa, free functions may, if suitable, be converted in~o their functional derivatives. The transformation of a functional, free or modified group into another functional group, an object of the general preparation procedure, may be effected according to methods described in the literature.
The compounds obtained according to the above mentioned procedures can be isolated from the reaction mixture in the known way, for example by extraction with organic solvents, such as aliphatic chlorinated hydrocarbides such as methylene chloride, chloroform, dichloroethane, or esters such as ethylacetate, butylacetate, etc.
Before isolating the reaction products, these may be converted into their salts, which may then be purified. From these salts it is possible to obtain the reaction products in the known manner, for instance by adding a base such as a hydrate of an alkali metal or an ammonium compound or with a suitable ion exchanger.
1;~5~/455 The starting compounds to be used in the above mentioned procedures are well ~nown, as are the methods by which they are prepared. For example, the compounds II used to prepare derivatives I and IA according to procedure A can be prepared from the resorcinol derivatives of the formula:
H ~ H
HO ~\OH`
where Rl and R5 have the significance given for formula I by condensation with betacarbonyl acid esters or from coumarin or coumarinic compounds free from any of the desired substituents in which these are introduced. The starting compounds for procedures B, C, D, E, F are generally obtained by methods which are the same as the above mentioned procedures G and H, while the starting products in these procedures may be obtained from resorcinols or fluoroglucines, possibly substituted or functionally modified by known reactions, such as by introduction of the -CH2-NR3R4 group by a Mannich reaction similar to that used for procedure A. If the resorcinic or coumarinic starting compounds contain carbonyl reactive functions, such as ketonic functions in particular, it is advisable or necessary to protect them before the various reactions such as the Mannich-type condensation reaction~
Protection of the carbonyl functions for example is effected by one of the known methods such as by action of an ethylene glycol under anhydrous conditions in the presence of acid catalysts. Once the Mannich condensation has been obtained, the carbonyl functions can be regenerated by hydrolysis in an acid aqueous solvent.
The coumarin derivatives of formula I ~and therefore also of formula IA) according to the present invention may be used as drugs in pharmaceutical preparations intended for administration to man or animals by intramuscular, subcutaneous or intradermic routes, by injection or intravenous infusion. These preparations may therefore be formulated as solutions of the active compounds or as freeze-dried powders of the active compounds to be mixed with one or more excipients or diluents which are acceptable from a pharmaceutical point of view, and suitable for the above mentioned means of administration and with an osmolarity compatible with physiological liquids.
~25845S
Furthermore, the therapeutic compounds of formula I (and therefore also formula IA) of the present invention may be in solid or semi-solid form and may be administered by the oral or rectal route, in the form of tablets, sugar-coated pills, gelatinous opercula, suppositories, soft gelatine capsules mixed with pharmaceutically acceptable excipient~ and suitable for this use, or in the form of creams/
ointments or sprays for local, such as topical, use.
The preparations accordins to the present invention generally contain between 0.01% and 10% by weight of the active component for the solutions, sprays, ointments and creams and between 1% and 100%, preferably between 5% and 50% by weight, of the active component for the preparations in solid form. The dosage to be administered depends on the prescription, the desired effect and the chosen route of administration.
The preparations presented in Examples 29 and 30 may be administered directly to animals or human patients by one of the routes described. Examples 29 and 30 show a few possible pharmaceutical compositions which can be prepared for the treatment of tumor pathologies or platelet hyperaggregation pathology.
12584$5 The pharmaceutical compositions shown in Example 29 are prepared using a double container made of glass.
The first contains the active substance in the form of a freeze-dried powder together with a pharmaceutically S acceptable excipient. The second container is filled with the desired quantity of solvent. Not until just before administration are the contents of the two flacons mixed and ~he active substance, in the form of a freeze-dried powder, is rapidly dissolved to produce an injectable solution. The pharmaceutical form preferred by the present invention is that which consists of a container holding the active substance as a freeze-dried powder, as the active substance has proved to be more stable in a dry, powdered form than in solution.
;! Example 30 shows pharmaceutical preparations to be used by the oral route in tumoral pathologies or in pathologies connected with platelet hyperaggregation.
The preparations may also be formulated in a gastro-resistant form.
The present invention also includes modifications of the above mentioned procedures, where the procedures are interrupted at a certain point, or where an intermediate compound is used to begin with, after which the subsequent stages are carried out, or ~258~55 where the starting products are formed in situ. The following examples amply illustrate the products, the preparation procedures and the pharmaceutical preparations of the present invention, but are not to be considered as limiting. Unless otherwise noted, the percentages therein and throughout the application are by weight and the temperatures are in degrees Centigrade.
Exam~le 1 4-methyl-6-dime~hylamin~2m ~}~ L~7-hydroxy-~-allylcu~
~Lil~hY9r9~hl~i9~. 30 g of 4-methyl-7-hydroxy-8-allylcoumarin are mixed with 350 ml of ethanol, 24.3 g of dimethylamine aqueous solution at 33~ and 5.5 g of paraformaldehyde. The mixture is refluxed for 48 hours, while being continuously agitated; the ethanol is then evaporated in vacuum. The residue is gathered with ethyl acetate and the oryanic solution is extracted with lN hydrochloric acid. The acid aqueous layer is alkalinized with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate extract is dried on anhydrous sodium sulfate and, after filtration, is concentrated to a small volume;
precipitation of the crystalline hydrochloride is achieved by adding gaseous hydrochloric acid. The precipitate is separated and crystallized from ethanol; when the crystals have bee~ filtered and dried, the hydrochloride of 4-methyl-6-dimethyl-aminomethyl-7-hydroxy-8-allylcoumarin is obtained. MP
216, ~f 0.46 [thin layer chromatography (silica) chloroform-methanol-acetic acid-water (25 ~ 15 + 4 +2)].
~ZS8455 Fx~mpl~ 2 4-methyl-6-(4-mo~ehnlinylm~thyll-7-hydroxy-~-allylco~mari n hydrochlQride. 32.4 9 of 4-methyl-7-hydroxy-8-allylcoumarin ar~
mixed ~ith 300 ml of ethanol, 13 9 of morpholine and 4.5 9 of paraformaldehyde. The mixture is heated to 60 for 48 hours, being continuously agitated in the meantime; the ethanol is then evaporated in vacuum. A saturated ~olution of sodium bicarbonate i8 added to the re~idue and the mixture is then extracted with methylene chloride. The organic ~olution is extracted 3 times with hydrochloric acid, lN, and the aqueous acid layer is ne~tralised with aqueous ammonium hydroxide at 32%; a suspension i~ thus formed which is then filtered. The precipitate is vacuum dried and then treated with ethyl acetate; precipitation of the crystalline hydrochloride is achieved by addition of gaseous hydrochloric acid. The precipitate is separated and then crystallised by ethanol; after filtration and drying of the crystal~, hydrochloride of 4-methyl-6-(4-morpholinylmethyl)-7-hydroxy-8-allylcoumarin is obtained.
MP 234, Rf 0.78 lthin layer chromatography (silica) chloroform-methanol-water-ammonium hydroxide 32% (130 ~ 25 2.~ ~ 0.5)].
~S8455 4-methyl -6¦LA- t 2-hydro~yethyl)-1-piperaziny ~ methy ~7-~ydroxy-8-~llylcoumarin dichlorhydrate. 21.6 9 of 4-methyl-7-hydroxy-8-allylcoumarin arP mixed with 250 ml of ethanol r 16 ~ 9 g of 1-(2-hydroxyethyl)piperazine and 1102 9 of formaldehyde aqueous solution at 35%. The mixture is heated to 70 for 48 hours, being continuously agitated meanwhile; the ethanol is then evaporated in vacuum. A saturated solution of sodium bicarbonate is added to the residue and the mixture is e~tracted with methylene chloride. The organic solution is extracted 3 times with hydrochloric acid, lN 7 an~ the acid aqueous layer is alkalized with bicarbonate of soda and extracted with toluene.
The toluenic solution is dried on anhydrous sodium sulfate, filtered and the solvent is then eliminated in vacuum. The residue is gathered with ethyl acetate and the formation of crystalline hydrochloride is achieved by adding gaseous hydrochloric acid. The precipitate is separated and crystallised with 95% ethanol; after filtration and drying of the crystals, dichlorhydrate of 4-methyl-6-[4-(2-hydroxyethyl-1-piperazinyl)-methyl]-7-hydroxy-8-allylcoumarin is obtained.
MP 201, Rf 0.52Lthin layer chromatography ~silica) chloroform-methanol-water-ammonium hydroxide 32% ~130 ~ 25 +
2.8 ~ 0.5)].
i258455 xA~pl~ 4 ~ thyl ester of th~ ac;d ~4-methyl-6-54-morpholinylmet~yl)-~-allylco~m~rin-7-yl~oxyacetic. 16 g of 4-methyl-6-(4-morpholinyl-methyl)-7-hydroxy-8-allylcoumarin are mixed with 300 ml of toluene and 1.25 9 of sodium hydride. The mixture is gradually heated to 60, being continuously agitated meanwhile; after thirty minutes heating the solvent is evaporated in vacuum. The residue i8 solubilised with 100 ml of dimethyl~ulfoxide and to this ~olution, kept at room temperature, 9.8 9 of ethyl chloroacetate are added; after twelve hours, 300 ml oE toluene are added and the organic nixture is washed with water. The toluenic solution is reduced to a small volume in vacuum and the formation of crystalline hydrochloride is achieved by adding gaseous hydrochloric acid. The precipitate is separated and then crystallized in ethanol; after filtering and drying the crystal~, hydrochloride of 4-methyl-6-t4-morpholinylmethyl)-7-(ethoxyl-carbonylmethoxy)-8-allylcoumarin is obtained.
MP 176, Rf 0.85 tthin layer chromatography (silica) chloroform-methanol-acetic acid-water (25 - 15 + 4 + 2)].
~xample 5 4-methyl-6-(4-morpholinyl~ethytl-7-allyloxy-8-aLlylcoumarin hydrochloriae. 16 g of 4-methyl-6-(4-morpholinylmethyl)-7-hydroxy-8-allylcoumarin are treated as in the case of Example 4 until precipitation of the hydrochloride. 6.1 g of allyl bromide are used in place of the ethyl chloroacetate. The precipitate is separated and crystallised in ethanol; after filtering and drying the crystals, hydrochloride of the 4-methyl-6-(4-morpholinyl-methyl)-7-allyloxy-8-allyl coumarin is obtained.
MP 203, Rf 0.76 [thin layer chromatography (~ilica) chloroform-methanol-water-ammonium hydro~ide 32%
~ 130 + 25 + 2.8 ~ 0.5)].
~x~m~le ~
~thel ester o the acid 2-~4-methyl-6-~4-morpholinylmethyl)-8-~ ~ ~ ~ . 9.5 g of4-methyl-6-54-morpholinylmethyl)-7-hydroxy-8-allylcoumarin are mixed with 300 ml of toluene and 0.8 g of sodium hydride. The mixture is gradually heated to 60, being ~onstantly agitated meanwhile; after 30 minutes heating, the solvent is evaporated in vacuum. The residue is solubilised with 100 ml of dimethylsulf-oxide and 5.9 9 of ethyl ~-bromoisobutyrate are added to the solution which is kept at a temperature of 60. After 48 hours, 300 ml of toluene are added and the organic mixture is washed with water. The toluenic solution is reduced to a small volume lZ58455 in vacuum and formation of crystalline hydrochloride is achieved by addition of gaseous hydrochloric acid. The precipitate is separated and crystallised with ethanol; after filtering and drying the crystals, hydrochloride of the ethyl ester of the 2-l4-methyl-6-~4-morpholinylmethyl)-8-allylcoumarin-7-ylloxy-2-methylpropionic acid is obtained.
MP 171, Rf 0.79 [thin layer chromatography (silica) chloroorm-methanol-water-ammonium hydroxide 32% (130 + 25 + 2.8 + 0.5~1.
~xampl~ 7 4-~h~ny1-6-(4-morph~linyl~ethyl)-7-hydr~xy-8-allylc~marin hydrochlorid~~ 20 g of 4-phenyl-7-hydroxy-8-allyl coumarin are mixed with 200 ml of 80% aqueous ethanol, 6.3 g of morpholine and 6.2 9 of 35% formaldehyde aqueo~s solution. The same procedure a~ in the case of Example 1 is used until precipitation of the hydrochloride. The precipitate is separated and cry-~tallised with ethanol; after filtering and drying the crystals, hydrochloride of 4-phenyl-6-~4-morpholinylmethyl~-7-hydroxy-8-allylcoumarin is obtained.
MP 208D, Rf 0.87 ~thin layer chromatography ~silica) chloroform-methanol-Nater-ammonium hydroxide 32% (13~ + 25 +
2.8 + 0.5)~.
~Z58~55 E~amD1 e ~
4-phen~t-6-~4-(2-hydroxyethyl)-1-piperazinylJmeth~1~-7-hy~ro~y-~-allylcoumarin dihyaLQchlQride. 15 g of 4 phenyl-7-hydroxy-8-allylcoumarin are mixed with 200 ml of ethanol, 7 9 o 1-(2-hydroxyethyl)piperazine and 4.6 g o 35% formaldehyde aqueous solution. The mixture is refluxed for 48 hour~, being kept in constant agitation meanwhile. The ethanol is then evaporated in vacuum. The residue is gathered with ethyl acetate and the organic -~olution is e~tracted with hydrochloric acid 1~. The aqueous acid layer is alkalinized with sodium bicarbonate; a suspension is formed which iY then filtered. The precipitate is vacuum dried and then treated with ethyl acetate; precipitation of the cry~talline hydrochloride is achieved by adaing gaseous hydrochloric acid. The precipitate is separated and crystallised with ethanol; ater filtering and drying the crystals, dihydro-chloride of 4-phenyl-6-[~4-(2-hydroxyethyl)-1-piperazinyll methyll-7-hydroxy-8-allylcoumarin is obtained.
MP 250", Rf 0.74 [thin layer chromatography (silica) chloroform-methanol-acetic acid- water ~25 + 15 ~ 4 + 2)1.
~5134SS
Example ~
~-phenv1-6-14-morDholinvlmethyl)- 7-ally1o~Y-8-Ally~coum~rin hydrochloride. 20 g of 4-phenyl-6-(4-morpholinylmethyl)-7-hydroxy-8-allylcoumarin are mixed with 300 ml of toluene and 1.35 g of sodium hydride. The mixture is gradually heated to 60, being constantly agitated in the meantime. After 30 minutes' heating, the solvent is evaporated in vacuum. The residue is solubilised with 100 ml of dimethylsulfoxide and ~.4 9 of allyl bromide; after 12 hours, 300 ml of toluene are added and the organic ~ixture is washed with water. The toluenic solution is extracted with hydrochloric acid, lN, and the aqueous solution is alkalini~ed with sodium carbonate ana then extracted with methylene chloride. The methylene chloride solution is dried on anhydrous sodium sulfate and the solvent is eliminated in vacuum after filtration. The residue is gathered with toluene and formation of crystalline hydrochloride is achieved by adding gaseous hydrochloric acid. The precipitate is gathered and then crystallised with ethanol; after filtering and drying the crystals, hydrochloride of 4-phenyl-6-~4-morpholinylmethy1)-7-allyloxy-8-allylcoumarin is obtained.
MP 208~, Rf 0,871thin layer chromatography ~silica) chloroform-methanol-water-ammonium hydroxide 32~ ~130 + 25 +
2.8 + 0.5)].
~2584S5 ~x~ple 10 Ethyl e~r o~ ~4-phenyl-6-(4-morpholir-yllnet~lyrl)-8-allylcoum~rin-7-ylJoxy ace~ic acid hydrQchloride~ 24 g of 4 phenyl-6-~4-morpholinylmethyl)-7-hydroxy-8-allylcoumarin are mixed with 300 ml of toluene and 1.6 9 of sodium hydride. The mixture is gradually heated to 60, being constantly agitated meanwhile; after 30 minutes' heating the solvent is evaporated in vacuum. The re~idue is solubilised with 100 ml of dimethyl-sulfoxide and 8 9 of ethyl chloroacetate are added to the ~olution, which is kept at a temperature of 60; after 24 hours, 300 ml of toluene are added and the organic mixture is washed with water. The toluenic solution is extracted with hydrochloric acid, lN, and the acid agueous solution is alkalinised with sodium bicarbonate. A suspension is thus formed which i8 then filtered. The precipitate is vacuum dried and then gathered with toluene; the precipitation of the crystalline hydrochloride is achieved by adding gaseous hydrochloric acid. The precipitate is separated and then crystallised with ethanol; after filtering and drying the crystals, the hydrochloride of the ethyl ester of 14-phenyl-6-~4-morpholinylmethyl)-8-allylcoumarin-7-yl]oxy acetic acid is obtained.
MP 108~, Rf 0.88 lthin layer chromatography ~silica) chloro~orm-methanol-water-ammonium hydroxide 32% ~130 - 25 +
2.8 + 0.5)].
~;~58455 F~ample 11 ~thyl e~ter ~f 2-E4-pheDyl-6-(~-mor~h~linvlmethv])-8-llylcoumarin-7-ylJo~y-2-met~ lpropionic acid hydrQchlQride. 20 9 of 4-phenyl-6-~4-morpholinylmethyl)-7-hydroxy-8-allylcoumarin are mixed with 300 ml of toluene and 1~35 9 of sodium hydride; the mixture is ~radually heated to 60, ~eing constantly agitated meanwhile. After thirty minute~' heating, the solvent is evaporated in vacuum. The residue is solubilized with 100 ml of dimethylsulfoxide and 11.7 g of ethyl ~-bromoisobutyrate are added to the solution, which is kept at a temperature of 60.
After 72 hours, 300 ml of toluene are added to the organic mixture, which is then washed with water. The toluenic solution is extracted with hydrochloric acid, lN, and the aqueous solution is alkalinized with sodium bicarbonate; a suspension is thus formed which is subsequently filtered, The precipitate is vacuum dried and then gathered with toluene; precipitation of the crystalline hydrochloride is achieved by adding gaseous hydro-chloric acid. The precipitate is separated and crystalli2ed with ethanolic solution by adding ethyl acetate; after filtering and drying the crystals, hydrochloride of the ethyl ester of 2-14-phenyl-6-(4-morpholinylmethyl)-B-allylcoumarin-7-yl]oxy-2-methylpropionic acid is obtained~
MP 191~, Rf 0.83[thin layer chromatography (silica) chloroform-methanol-water-ammonium hydroxide 32% (130 + 25 2.8 ~ 0.5)].
~Z58~55 Exam~le L2 4-m~thy~-6-(L-pyrrolidinyl~thvl)-7-hy~Ln~y-~-al lylcQu~ari n hyd~nchlQride. 25 9 of 4-methyl-7-hydroxy-8-allylcoumarin are mixed with 300 ml of absolute ethanol, 8.3 9 of pyrrolidine and 3.4 9 of paraformaldehyde. The procedure then is the same as in Example 1 until the precipitation of the hydrochloride. The precipitate is separated and then crystallized with ethanol;
after filtering and drying the crystals, hydrochloride vf the 4-methyl-6~ pyrrolidinylmethyl)-7-hydroxy-8-allylcoumarin is obtained.
MP 116~, Rf 0.621thin layer chromatography ~silica) chloroform-methanol-acetic acid-water (25 ~ 15 ~ 4 + 2).
E~m~
4-rnethy1 -6-di ethyIATn; nometl~yl-7-hydro~y~8--al Iyl comTIari n hydrQc~lQride. 25 g of 4-methyl-7-hydroxy-8-allylcoumarin are mixed with 350 ml of ethanol, 8.9 g of diethylamine and 3.9 g of paraformaldehyde. The mixture is refluxed for 60 hours, being kept in constant agitation meanwhile; the ethanol is then evaporated in vacuum~ The residue is gathered ~ith ethyl acetate and the organic solution is extracted with hydrochloric acid, lN.
The aqueous acid layer is alkalini~ed with sodium bicarbonate and then extracted with methylene chloride. The methylene chloride solution is dried on anhydrous sodium sulfate, filtered and then the solvent i~ eliminated in vacuum. The residue is gathered with ethyl acetate and the formation of crystalline hydrochloride is achieved by adding ga~eous hydrochloric acid. The precipitate is lZS84SS
separated and then crystallized with isopropanol; after filtering and drying the crystals, hydrochlorlde of 4-methyl-6-diethyl-aminomethyl-7-hydroxy-8-allylcoumarin is obtained.
MP 188, Rf 0.72 lthin layer chromatography ~silica~
chloroform-methanol-acetic acid-water (25 + 15 + 4 + 2)l.
~xaD&~
4-met~yl-6-(1-~iperiain~lmethyl)-7-~ ~{L~LLL~
b4slY~hllclds. 25 g of 4-methyl-7-hydroxy-8-allylcoumarin are mi~ed with 300 ml of ethanol, 9.9 of piperidine and 3.4 g of paraormaldehyde. The ~ixture is refluxed for 96 hours, being kept constantly agitated meanwhile. The ethanol is evaporated in vacuum, after which the procedure is the same as for Example 8 until precipitation of the hydrochloride. The precipitate is separated and then crystallized with ethanol, after filtering and drying the crystals, hydrochloride of 4-methyl-6~l-piperidinyl-methyl)-7-hydroxy-8-allylcoumarin is obtained.
MP 234, Rf 0.84 [thin layer chromatoa,raphy ~silica) chloroform-methanol-water-ammonium hydroxide 32% ~130 + 25 +
2.8 + 0.5)l.
:~L;2S8455 xample L~
4-me~hyt-~-C~-hydroxy-l-~i~eridi ~
allylco~marin hydrochlQride. 30 9 of 4-methyl-7-hydroxy-8-allylco~marin are mixed with 300 ml of ethanol, 14.1 9 of 4-hydroxypiperidine and 4.2 g of formaldehydeO The procedure is then the same as for Example 8 until precipitation of the hydrochloride. The precipitate is separated and then crystal-lized with ethanol; after filtering and drying the crystals, hydrochloride of the 4-methyl-6-l(4-hydroxy-1-piperidinyl)-methyl~-7-hydroxy-8-allylco~arin is obtained.
MP 252, Rf 0.55 lthin layer chromatography ~silica) chloroform-methanol-acetic acid-water ~25 + 15 ~ 4 ~ 2)].
~am~le 16 4-meth~L-6-~-hydrQxy-1-piperidi~yl~me~hyl~-7-hy~rnYy-8-30 9 of 4-methyl-7-hydroxy-8-allylcoumarin are mixed with 300 ml of ethanol, 14.1 9 of 3-hydroxypiperidine and 4.2 g of paraformaldehyde. The mixture is refluxed for 24 hours, being kept in constant agitation meanwhile. The ethanol is evaporated in vacuum and the procedure i5 then the same a~ for Example 13 until the formation of hydrochloride. The precipitate is separated and then crystallized ~rom ethanol ~olution by adding ethyl acetate; after filtering and drying the crystals, hydrochloride of 4-methyl-6-~ZS8455 , [(3-hydroxy-1-piperidinyl) methyl]-7-hydroxy-8-allylcoumarin i5 obtained.
MP 184-, Rf 0.46lthin layer chromatography ~silica) chloride of methylene-ethyl acetate-methanol (70 + 30 + 5)] is obtained.
3-(2-di~thylamin~ethyl)-4-m~thvl-~ -mQr~hQli~ylme~hyl~-7-hydroxy-8-chlQrQcn~maxin dih~drQchlQride. 6.19 g of 3-(2-diethylaminoethyl)-4-methyl-7-hydroxy-8-chloro-coumarin are mixed with 200 ml of ethanol, 3.5 9 of morpholine and 1.7 9 o aqueous solution of 35% formaldehyde. The mixture i~ refluxed for 24 hours, being kept in constant agitation meanwhile. The ethanol is then evaporated in vacuum and the residue is gathered with ethyl acetate; a suspension is thus ormed which is then filtered; the organic solution is extracted with hydrochloric acid, lN. The aqueous acid layer is alkalinized with sodium bicarbonate and then extracte~ with methylene chloride. The methylene chloride solution i~ dried on anhydrous sodium sulfate and, after filtration, the solvent i~ eliminated in vacuum. The residue is gathered with ethyl acetate and the formation o crystalline hydrochloride is achieved by adding gaseous hydro-chloric acid. The precipitate is separated and crystallized form 95% ethanol; after filtering and dryin~ the crystals, hydrochlor-ide of 3-~2-diethylaminoethyl~-4-methyl-6-(4-morpholinylmethyl)-7-hydroxy-8-chlorocoumarin is obtained.
MP 174, R 0.56 tthin layer chromato~ra~hy (silica) chloro-form-methanol-water-ammonium hydroxide 32% (130 + 25 + 2..8 + O.5)3.
lZ58455 Example 18 Ethyl ester of L3- (2-diethylaminoethyl)-4-methyl-6-~4-morphQIinylmethyL)-8-chloroco~marin-7-yl~o~yacetiG acid dihvdrochloride. 18 g of 3-(2-diethylaminoethyl)-4-morpholinylmethyl)-7-hydroxy-8-chlorocoumarin are mixed with 300 ml of acetone, 12.2 9 of potassium carbonate and 5O4 g of ethyl chloroacetate; the mixture is gradually brought to the boiling point, being kept in constant agitation meanwhile, and then refluxed for 24 hours. The solvent is then evaporated in vacuum.
The residue is gathered with 300 ml of toluene and the mixture is treated with water. The toluenic layer is separated and then extracted with hydrochloric acid, lN; the aqueous acid solution is alkanized with sodium bicarbonate; a suspension is thus formed which is then filtered. The precipitate i3 vacuum dried and then gathered with toluene; the formation of crystalline hydrochloride is achieved by addition of gaseous hydrochloric acid. The precipitate is separated and crystallized from ethanol; after filtering and drying the crystals, hydrochloride of the ethyl ester of 13-~2-diethylaminoethyl)-4-methyl-6-(4-morpholinyl-methyl)-8-chloroco~arin-7-yl]oxy acetic acid is obtained.
MP 182, Rf 0.621thin layer chromatography (silica)chloro-form-methanol-acetic acid-water (25 + 15 + 4 +2)].
~xam~le L~
3-(2-diet~ylaminQethyl)-4-methyl-6-(4-mQr~hol iny l~eth~ 7-alLylQxy-8-chlorQ~QI~marin hydrochlQrid 16 g of 3-~2-diethylaminoethyl)-4-methyl-6-(4-morpholinylmethyl)-7- hydroxy-8-chlorocoumarin are mixed with 300 ml of acetone, 10.8 g of potas~ium carbonate and 4.8 g of allylbromide. The procedure is then the same as for Example 18 until the precipitation of the hydrochloride. The precipitate is separated and crystallized ~rom ethanolic solution by adding ethyl ether; after filtering and drying the crystals, hydrochloride of 3-~2-diethyl-aminoethyl)-4-methyl-~-~4-morpholinylmethyl)-7-allyloxy-8-chloroco~marin is obtained.
MP 150, Rf 0.35tthin layer chromatography(silica)-chloroform-methanol-acetic acid-water (25 + 15 +4 + 2)] is obtained.
~25~3~5S
B~ample 20 Ethyl ester of 2-~3-(2-diethyl~minoethvLL-4-methyl~fi-~4-morphQl invlmethyl!-8-chlorocn~marin-7-yl~o~y-2-methyl-vropionic acid dihydrochloride. 16 9 of 3-(2-diethylaminoethyl)-4-methyl-6-(4--morpholinylmethyl)-7-hydroxy-8-chlorocoumarin are mixed with 300 ml of toluene and 1 g of sodium hydride; the mixture is gradually heated to a temperature of 60, being kept in constant agitation in the meantime; after thirty minutes' heating, the solvent is solubilized ~ith 100 ml of dimethyl-sulfoxide and 7.6 g of ethyl ~-bromoisobutyrate are added to the solution, which is kept at room temperature; after 48 hours, 300 ml of toluene are added and the organic mixture is washed with water. The toluenic solution is extracted with hydrochloric acidv lN and the acid aqueous solution, after being alkalinized with sodium carbonate, is extracted with methylene chloride. The methylene chloride solution is dried on anhydrous sodium sulfate, filtered and the solvent is then eliminated in vacuum. The residue i~ gathered with toluene and the formation of cry~talline hydrochloride is achieved by adding gaseous hydrochloric acid.
The precipitate is separated and crystallized from ethanol; after iltering and drying the crystals, dihydrochloride of the ethyl ester of 2-[3-(2-diethylaminoethyl)-4-methyl-6-(4-morpholinyl-methyl)-8-chlorocoumarin-7-ylloxy-2-methylpropionic acid is obtained.
MP 148~, Rf 0.51[thin layer chromatography ~silica) chloroform-methanol-acetic acid-water ~25 + 15 + 4 + 2)1.
~`
~Z58~55 E~am~le 21 4-methyl-6-(4-~orpholinylmethyl)-7-hydrnxy-8-chloroc~umarin hydrochlQride. 20 g of 4-methyl-7-hydroxy-8-chlorocoumarin are mixed with 300 ml of ethanol, 16.5 g of morpholine and 8 g of 35%
formaldehyde aqueou~ solution. The mixture is refluxed for 48 hours, being kept in constant agitation meanwhile, and after 12 hours, a suspension is obtained which is then filtered. The precipitate is dissolved in methylene chloride and the organic solution is extracted with aqueous solution of 10% acetic acidr the organic solution is then extracted (3 times) with hydrochloric acid lN. The aqueous hydrochloric layer is alkalinized with sodium bicarbonate; a suspension is thus formed which is then filtered. The precipitate is vacuum dried and then treated with ethyl acetate; the precipitation of the crystalline hydrochloride is achieved by adding gaseous hydrochloric acid.
The precipitate is then separated and crystallized from methanolO
After filtering and drying the crystals, hydrochloride of 4-methyl-6-~4-morpholinylmethyl~-7-hydroxy-8-chlorocoumarin is obtained.
MP 227, Rf 0.80lthin layer chromatography (silica) chloroform-methanol-acetic acid-water ~25 + 15 + 4 + 2)1 is obtained.
~L25~34ss xam~L~ ~2 4-me~hyl-~-diethylaminometh~l-7-hydroxy-8-chlQ~Qc~marin hydrochloride. 21 g of 4-methyl-7-hydroxy-8-chlorocoumarin are mixed with l80 ml of ethanol, 20 ml of ch7oroform, 9.5 g of diethylamine and ll.2 of 35% aqueous formaldehyde solution. The mixture is refluxed for 20 hours, being kept in constant agitation meanwhile; the ethanol and chloroorm are evaporated in vacuum. The residue is solubilized in a methylene chloride-ethyl acetate-methanol mixture ~7 + 3 +l) and the solution i3 used for a chromatographic separation on silica, el~ting with the same mixture of solvents. 4-methyl-6-diethylaminomethyl-7-hydroxy-8-chloroco~marin is thus obtained. It i8 then treated with ethyl acetate and then, by adding gaseou~ hydrochloric acid~
crystalline hydrochloride i~ formed. The precipitate is ~eparated and crystallized from ethyl acetate. After filtering and drying the crystals, hydrochloride of 4-methyl-6-diethylaminomethyl-7-hydroxy-8-chlorocoumarin is obtained.
MP 202, Rf 0.671thin layer chromatography (~ilica) chloroform-methanol-acetic acid-water ~25 + 15 + 4 +2)].
~,5~3~55 ~am~
4-p~enyl-6-~a-~orpholinylmethyl)-7-h~d~oxy-~-chloroco~ari~
hydrochlorid~. 20 g of 4-phenyl-7-hydroxy-8-chloro coumarin are mixed with 300 ml of ethanol, 12.1 g of morpholine and 4.2 g of paraformaldehyde. The mixture is refluxed for 96 hours, being constantly agitated in the meantime; it is brought to room temperature and after 12 hours a suspension i~ obtained which is then filtered. The precipitate is dissolved in hydrochloric acidr lN, and the re~ulting solution is e~tracted ~3 times~ with methylene chloride. Evaporation of the solvent produce~ a methylene chloride solution from which a chloride residue is obtained. The precipitate i~ crystallized from ethyl acetate;
after filtering and drying the crystals, hydrochloride of 4-phenyl-6-~4-morpholinylmethyl~-7-hydroxy-8-chlorocoumarin is obtained.
MP 225~, Rf 0.791thin layer chromatography lsilica) chloroform-methanol-water-ammonium hydroxide 32% ~130 ~ 25 +
2.8 ~ 0.5)].
.~
~258455 Ex~m~le 24 3-(2-dieth~laminoethyl)-4-methvl-6-(4-mo~holinYI~ethvl~-7-~ethoxy-8-chlorocoumaLin dihydrochloride. 24.5 g of 3-(2-diethylaminoethyl)-4-methyl-6-t4-morpholinylmethyl)-7-hydroxy-8-chlorocoumarin are mixed with 300 ml of toluene and 1.6 9 of sodium hydrate; the mixture is gradually heated to 60, being constantly agitated meanwhiles after 30 minutes' heating the solvent i-~ evaporated in vacuum. The residue is solubilized with 100 ml of dimethylsulfo~ide and 7.5 g of aimethyl sulfate are added to the solution, which i~ kept at a tem~erature of 80;
after 48 hours, 300 ml of toluene are added and the organic mixture is washed with water. The toluene solution is extracted with hydrochloric acid, lN, and the acid aqueous solution is alkalinized with ~odium bicarbonate; a suspension is thus formed which is then filtered. The precipitate is vacuum dried and gathered with toluene; crystalline hydrochloride is formed by the addition of gaseous hydrochloric acid. The precipitate is separated and crystallized from ethanol. After ~iltering and drying the crystals, dihydrochloride of 3-(2-diethylaminoethyl~-4-methyl-6-~4-morpholinylmethyl)--7-methoxy-8-chlorocoumarin i~
obtained.
MP 181, Rf 0.41[thin layer chromatography (silica) chloroform-methanol-acetic acid-water (25 -~ 15 + 4 ~ 2)].
~amDle 25 4-~ethyl-7-hydroxy-6-di~ethyla~innm~hyl-7-hydroxy-~-chlorocoumarin hydrochloride~ 30 g of 4-methyl-7-hydroxy-8-chlorocoumarin are mixed with 200 ml of ethanol, 38.2 g of 33%
dimethylamine aqueous solution and 8.5 g of paraformaldehyde.
The mixture is refluxed for 72 hours, being constantly agitated in the meantime. The ethanol i~ evaporated in vacuum. The procedure is then the same as for Example 3 until the precipitation of the hydrochloride. The precipitate is separated and crystallized from ethyl acetate; after filtering and drying the crystals, hydrochloride of 4-methyl-7-hydroxy-6-dimethyl-aminomethyl-7-hydroxy-8-chlorocoumarin is obtained.
MP 238D, Rf 0.2171thin layer chromatography ~silica) chloroform-methanol-acetic acid-water ~25 + 15 + 4 + 2~]~
~258455 Exam~le 26 4.8-dimethyl-~-dimethylaminome~hyl-7-hy~rQxyconmarin hydrQchlQride. 30 g of 4,8-dimethyl-7-hydroxycoumarin are mixed with 300 ml of ethanol, 50 ml of chloroform, 27.1 g o 33%
dimethylamine aqueous solution and 6 9 of paraformaldehyde. The mixture i~ refluxed for 48 hour~, being constantly agitated meanwhile. The ethanol and chloroform are evaporated in vacuum.
The procedure i~ then the ~ame a~ for Example 13 until the formation of hydrochloride. The precipitate i~ ~eparated and then crystallized from 95% ethanol; after filtering and drying the cry~tal~, hydrochloride of 4,~-dimethyl-6-dimethylamino-methyl-7-hydroxycoumarin i~ obtained.
MP 252~, Rf 0.77 [thin layer chromatography ~silica) chloroform-methanol-acetic acid-water (25 + 15 + 4 +2)].
,; ~
~5~455 - 74 ~
~xa~L~ 27 4.8-dimethyl-fi-( 4-m~rp~ulinylm~li yl)-7-h~drQxycoumari n hydrochlorid~ 30 9 of 4,8-dimethyl-7-hydroxycoumarin are mixed with 300 ml of 85% aqueous ethanol~ 13.8 9 of morpholine and 4.8 g of paraformaldehyde. The mixture is refluxed for 96 hours, being constantly agitated meanwhile; it is then brought to a temperature of 5 and after 12 hours, a suspension is obtained which is then filtered. The preGipitate i~ vacuum dried and then treated with ethyl acetate. Precipitation of the crystalline hydrochloride is achieved by adding gaseous hydrochloric acid.
The precipitate is separated and crystallized from ethanol.
After filtering and drying the crystals, hydrochloride of 4.8-dimethyl-6-(4-morpholinylmethyl)-7-hydroxy coumarin is obtained.
MP 238 Rf 0.84 lthin layer chromatography ~silica) chloroform-methanol-acetic acid-water (13D + 25 + 2.8 +0.5)].
~ZS~S5 E~mple 28 4-phen~1-6-dimethvlarlnsm~ih~1_7-hydroYy-8-aLlylcoumar~n hydrochlnri~. 18 9 of 4-phenyl-7-hydroxy-8-allyl coumarin are mixed with 250 ml of ethanol, 23.4 g of 18.5% dimethylamine aqueous solution and 5.6 g of 35% formaldehyde aqueous solution.
The mixture is refluxed for 60 hours, being constantly agitated meanwhile. The ethanol is evaporated in vacuum. The procedure i~ then the same as for Example 8 until the precipitation of the hydrochloride. The precipitate is separated and crystallized from 95~ ethanol. After filtering and drying the crystals, hydrochloride of 4-phenyl-6-dimethylaminomethyl-7-hydroxy-8-allylcoumarin is obtained.
MP 199, Rf 0.82 lthin layer chromatography ~silica) chloroform-methanol-acetic acid-water (25 + 15 + 4 +2)].
~2~8455 F.xample 29 - Examples of injectable pharmaceutical compositions ~the active compounds can ~e identified from Table 1 of the general description) Preparation No. 1 Preparation with antitumoral and antimetastatic activity in the form of an aqueous solution.
Composition: .
a. one freeze-dried flacon contains:
- compound 19 ~Ex~1) mg 10 - mannitol mg 10 b. one vial of ~olvent contains:
- ~odiu~ chloride mg 18 - apyrogenetic distilled water ml 2 Preparation No. 2 Preparation with platelet antiaggregating activity in the form of an aqueous ~olution.
a. one freeze-dried flacon contains:
- compound 121 ~Ex.13~ mg 30 - mannitol mg 30 b. one 5 ml vial of solYent contains:
- sodium chloride mg 45 - apyrogenetic distilled water ml 5 '.~., ~ZS~3~5~
Preparation ~o. 3 Preparation with an antitumoral and antimetastatic activity in the form of an aqueous solution.
Composition aO one freeze-dried vial contains:
- compound 26 ~Ex.3) mg 50 - mannitol . mg 30 b. one 3 ml vial of solvent contains:
- sodium chloride mg 27 - apyrogenetic distilled water ml 3 Preparation 4 Preparation with platelet antiaggregating activity in the form of an aqueous solution.
Composition a. one freeze-dried vial contains:
- compound 117 (Ex.12) mg 40 - mannitol mg 25 b. one 5 ml vial of solvent contains:
- sodium chloride mg 45 - apyrogenetic distilled water ml 5 ~L258455 - 78 - &~L~_~Q - Examples of pharmaceutical compositions by oral route ~The compounds can be identified from Table 1 of the general description) Preparation No. 1 Preparation with an antitumDral and platelet antiaggregating activity in tablet form.
Composition:
each tablet contains - compound 19 (Ex~ 1~ mg. 20 - microcrystalline cellulose mg. 150 - lactose mg. 20 - starch mg. 10 - magne~ium steara$e mg. 5 Preparation No. 2 Preparation with a platelet antiaggregating activity in the form of ~ugar-coated pill~.
Composition:
each pill contains:
- compouna 124 (Ex. 14) mg. 30 - carboxymethyl cellulose mg. 150 - starch mg. lS
- shellac mg. 10 - saccharose mg. 35 - colouring mg. 0~5 Preparation No. 3 Prepa_ation with an antitumoral and antimetastatic-activity in the form of gelatinou~ opercula.
Composition:
each gelatinous operculum contains:
- compound 26 (Ex. 3) mg. 40 - lactose mg. 100 - ga~trore~i~tant varnish mg. 5 Preparation ~o. 4 Preparation with a platelet antiaggregating activity in capsule form.
Composition each soft gelatine capsule contains:
- compound 28 (E~.5~ mg. 50 - vegetable oil mg. 200 - beeswax mg. 20 - gelatine mg. 150 - glycerine mg. 50 - colouring mg. 3
These etherifying agents are for example R2X
alkylation agents, in which R2 signifies a hydrocarbyl group as already described for formula I and X
represents a group derived from the functional modiication of the hydroxyl, or more precisely, of an ester such as a hydracid ester ~and therefore a halogen) or of an inorganic acid such as sulfuric, sulfurous or silicic acid, or of organic sulfonic acids such as the sulfonic acids derived from lower aliphatic hydrocarbons with between 1 and 7 carbon atoms, for example methanesulfonic acid or sulfonic acids derived from aromatic hydrocarbons, especially monocyclic hydrocarbons, such a~ paratoluenesulfonic or ben~enesulfonic acid. X may there~ore generally represent a halogen atom, in particular chlorine, bromine or iodine or an alkyl or arylsulfonyloxy, such as the methyl or ethylsulfonyloxy or ben2ene or p-toluenesulfonyloxy group.
iZS8~SS
The above mentioned esterification reaction, represented by the following diagram, may be effected in the known manner. The compound R2X is made to react with the compounds of formula IA or possibly also with their phenolic salts in a suitable solvent.
-N-CH2 ~ ~ / R7 HO ~ ~ ~oR2 X R20 ~ \ O ~0 . .
I bis A suitable basic compound should be added to the reaction mixture, for instance, an inorganic base such as hydrates or the basic salts of alkali or alkaline earth metals, such as sodium or potassium carbonate, or tertiary organic bases such as pyridine, guinoline, collidine or Huenig's base.
The most suitable solvents for the previously described alkylation reaction are the aliphatic alcohols such as those with between 1 and 5 carbon atoms, aliphatic ketones or aprotic solvents; in particular acetone, methylethylketone, dimethysulfoxide and sulfolane may be employed.
l;~S1~4~5 In some of the preparation procedures for the compounds according to the invention, R2 may represent a pro~ection group of the hydroxyl substitutable by hydrogen, that is, a hydroxyl in the 7-position may be temporarily protected during the reactions of th~
respective procedures and finally liberated. This temporary protection of the hydroxyl group may take place by functional modification as described in the literature, especially by esterification or etherification. Of the esters, it is worth men~ioning those with aliphatic araliphatic or aromatic acids having between 1 and 15 carbon atoms such as those mentioned previously, and also acids which give easily saponifiable esters, for example, halogenated lower aliphatic acids, such as trichloro- or trifluoroacetic ; acid. These ester groups may then be saponified to give the hydroxyl group by well known methods such as alkaline or possibly acid hydrolysis. Of the ethers, those of tertiary lower aliphatic alcohols such as tert-butyl alcohol, which may be hydrolyzed under acid conditions, can be used. Ethers of aliphatic alcohols such as benzyl or nitrobenzyl alcohol may also be prepared and then separated by reduction in ~he known way. The same protection groups may also serve to protect, perhaps temporarily, an R5 hydroxyl group ~l2~89~55 which is then liberated in the same way. In an independently known way, moieties present in the hydrocarbyl substituents in the protected form can also be liberated, that is, functionally modified, where the protecting groups are easily eliminated.
Vice versa, free functions may, if suitable, be converted in~o their functional derivatives. The transformation of a functional, free or modified group into another functional group, an object of the general preparation procedure, may be effected according to methods described in the literature.
The compounds obtained according to the above mentioned procedures can be isolated from the reaction mixture in the known way, for example by extraction with organic solvents, such as aliphatic chlorinated hydrocarbides such as methylene chloride, chloroform, dichloroethane, or esters such as ethylacetate, butylacetate, etc.
Before isolating the reaction products, these may be converted into their salts, which may then be purified. From these salts it is possible to obtain the reaction products in the known manner, for instance by adding a base such as a hydrate of an alkali metal or an ammonium compound or with a suitable ion exchanger.
1;~5~/455 The starting compounds to be used in the above mentioned procedures are well ~nown, as are the methods by which they are prepared. For example, the compounds II used to prepare derivatives I and IA according to procedure A can be prepared from the resorcinol derivatives of the formula:
H ~ H
HO ~\OH`
where Rl and R5 have the significance given for formula I by condensation with betacarbonyl acid esters or from coumarin or coumarinic compounds free from any of the desired substituents in which these are introduced. The starting compounds for procedures B, C, D, E, F are generally obtained by methods which are the same as the above mentioned procedures G and H, while the starting products in these procedures may be obtained from resorcinols or fluoroglucines, possibly substituted or functionally modified by known reactions, such as by introduction of the -CH2-NR3R4 group by a Mannich reaction similar to that used for procedure A. If the resorcinic or coumarinic starting compounds contain carbonyl reactive functions, such as ketonic functions in particular, it is advisable or necessary to protect them before the various reactions such as the Mannich-type condensation reaction~
Protection of the carbonyl functions for example is effected by one of the known methods such as by action of an ethylene glycol under anhydrous conditions in the presence of acid catalysts. Once the Mannich condensation has been obtained, the carbonyl functions can be regenerated by hydrolysis in an acid aqueous solvent.
The coumarin derivatives of formula I ~and therefore also of formula IA) according to the present invention may be used as drugs in pharmaceutical preparations intended for administration to man or animals by intramuscular, subcutaneous or intradermic routes, by injection or intravenous infusion. These preparations may therefore be formulated as solutions of the active compounds or as freeze-dried powders of the active compounds to be mixed with one or more excipients or diluents which are acceptable from a pharmaceutical point of view, and suitable for the above mentioned means of administration and with an osmolarity compatible with physiological liquids.
~25845S
Furthermore, the therapeutic compounds of formula I (and therefore also formula IA) of the present invention may be in solid or semi-solid form and may be administered by the oral or rectal route, in the form of tablets, sugar-coated pills, gelatinous opercula, suppositories, soft gelatine capsules mixed with pharmaceutically acceptable excipient~ and suitable for this use, or in the form of creams/
ointments or sprays for local, such as topical, use.
The preparations accordins to the present invention generally contain between 0.01% and 10% by weight of the active component for the solutions, sprays, ointments and creams and between 1% and 100%, preferably between 5% and 50% by weight, of the active component for the preparations in solid form. The dosage to be administered depends on the prescription, the desired effect and the chosen route of administration.
The preparations presented in Examples 29 and 30 may be administered directly to animals or human patients by one of the routes described. Examples 29 and 30 show a few possible pharmaceutical compositions which can be prepared for the treatment of tumor pathologies or platelet hyperaggregation pathology.
12584$5 The pharmaceutical compositions shown in Example 29 are prepared using a double container made of glass.
The first contains the active substance in the form of a freeze-dried powder together with a pharmaceutically S acceptable excipient. The second container is filled with the desired quantity of solvent. Not until just before administration are the contents of the two flacons mixed and ~he active substance, in the form of a freeze-dried powder, is rapidly dissolved to produce an injectable solution. The pharmaceutical form preferred by the present invention is that which consists of a container holding the active substance as a freeze-dried powder, as the active substance has proved to be more stable in a dry, powdered form than in solution.
;! Example 30 shows pharmaceutical preparations to be used by the oral route in tumoral pathologies or in pathologies connected with platelet hyperaggregation.
The preparations may also be formulated in a gastro-resistant form.
The present invention also includes modifications of the above mentioned procedures, where the procedures are interrupted at a certain point, or where an intermediate compound is used to begin with, after which the subsequent stages are carried out, or ~258~55 where the starting products are formed in situ. The following examples amply illustrate the products, the preparation procedures and the pharmaceutical preparations of the present invention, but are not to be considered as limiting. Unless otherwise noted, the percentages therein and throughout the application are by weight and the temperatures are in degrees Centigrade.
Exam~le 1 4-methyl-6-dime~hylamin~2m ~}~ L~7-hydroxy-~-allylcu~
~Lil~hY9r9~hl~i9~. 30 g of 4-methyl-7-hydroxy-8-allylcoumarin are mixed with 350 ml of ethanol, 24.3 g of dimethylamine aqueous solution at 33~ and 5.5 g of paraformaldehyde. The mixture is refluxed for 48 hours, while being continuously agitated; the ethanol is then evaporated in vacuum. The residue is gathered with ethyl acetate and the oryanic solution is extracted with lN hydrochloric acid. The acid aqueous layer is alkalinized with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate extract is dried on anhydrous sodium sulfate and, after filtration, is concentrated to a small volume;
precipitation of the crystalline hydrochloride is achieved by adding gaseous hydrochloric acid. The precipitate is separated and crystallized from ethanol; when the crystals have bee~ filtered and dried, the hydrochloride of 4-methyl-6-dimethyl-aminomethyl-7-hydroxy-8-allylcoumarin is obtained. MP
216, ~f 0.46 [thin layer chromatography (silica) chloroform-methanol-acetic acid-water (25 ~ 15 + 4 +2)].
~ZS8455 Fx~mpl~ 2 4-methyl-6-(4-mo~ehnlinylm~thyll-7-hydroxy-~-allylco~mari n hydrochlQride. 32.4 9 of 4-methyl-7-hydroxy-8-allylcoumarin ar~
mixed ~ith 300 ml of ethanol, 13 9 of morpholine and 4.5 9 of paraformaldehyde. The mixture is heated to 60 for 48 hours, being continuously agitated in the meantime; the ethanol is then evaporated in vacuum. A saturated ~olution of sodium bicarbonate i8 added to the re~idue and the mixture is then extracted with methylene chloride. The organic ~olution is extracted 3 times with hydrochloric acid, lN, and the aqueous acid layer is ne~tralised with aqueous ammonium hydroxide at 32%; a suspension i~ thus formed which is then filtered. The precipitate is vacuum dried and then treated with ethyl acetate; precipitation of the crystalline hydrochloride is achieved by addition of gaseous hydrochloric acid. The precipitate is separated and then crystallised by ethanol; after filtration and drying of the crystal~, hydrochloride of 4-methyl-6-(4-morpholinylmethyl)-7-hydroxy-8-allylcoumarin is obtained.
MP 234, Rf 0.78 lthin layer chromatography (silica) chloroform-methanol-water-ammonium hydroxide 32% (130 ~ 25 2.~ ~ 0.5)].
~S8455 4-methyl -6¦LA- t 2-hydro~yethyl)-1-piperaziny ~ methy ~7-~ydroxy-8-~llylcoumarin dichlorhydrate. 21.6 9 of 4-methyl-7-hydroxy-8-allylcoumarin arP mixed with 250 ml of ethanol r 16 ~ 9 g of 1-(2-hydroxyethyl)piperazine and 1102 9 of formaldehyde aqueous solution at 35%. The mixture is heated to 70 for 48 hours, being continuously agitated meanwhile; the ethanol is then evaporated in vacuum. A saturated solution of sodium bicarbonate is added to the residue and the mixture is e~tracted with methylene chloride. The organic solution is extracted 3 times with hydrochloric acid, lN 7 an~ the acid aqueous layer is alkalized with bicarbonate of soda and extracted with toluene.
The toluenic solution is dried on anhydrous sodium sulfate, filtered and the solvent is then eliminated in vacuum. The residue is gathered with ethyl acetate and the formation of crystalline hydrochloride is achieved by adding gaseous hydrochloric acid. The precipitate is separated and crystallised with 95% ethanol; after filtration and drying of the crystals, dichlorhydrate of 4-methyl-6-[4-(2-hydroxyethyl-1-piperazinyl)-methyl]-7-hydroxy-8-allylcoumarin is obtained.
MP 201, Rf 0.52Lthin layer chromatography ~silica) chloroform-methanol-water-ammonium hydroxide 32% ~130 ~ 25 +
2.8 ~ 0.5)].
i258455 xA~pl~ 4 ~ thyl ester of th~ ac;d ~4-methyl-6-54-morpholinylmet~yl)-~-allylco~m~rin-7-yl~oxyacetic. 16 g of 4-methyl-6-(4-morpholinyl-methyl)-7-hydroxy-8-allylcoumarin are mixed with 300 ml of toluene and 1.25 9 of sodium hydride. The mixture is gradually heated to 60, being continuously agitated meanwhile; after thirty minutes heating the solvent is evaporated in vacuum. The residue i8 solubilised with 100 ml of dimethyl~ulfoxide and to this ~olution, kept at room temperature, 9.8 9 of ethyl chloroacetate are added; after twelve hours, 300 ml oE toluene are added and the organic nixture is washed with water. The toluenic solution is reduced to a small volume in vacuum and the formation of crystalline hydrochloride is achieved by adding gaseous hydrochloric acid. The precipitate is separated and then crystallized in ethanol; after filtering and drying the crystal~, hydrochloride of 4-methyl-6-t4-morpholinylmethyl)-7-(ethoxyl-carbonylmethoxy)-8-allylcoumarin is obtained.
MP 176, Rf 0.85 tthin layer chromatography (silica) chloroform-methanol-acetic acid-water (25 - 15 + 4 + 2)].
~xample 5 4-methyl-6-(4-morpholinyl~ethytl-7-allyloxy-8-aLlylcoumarin hydrochloriae. 16 g of 4-methyl-6-(4-morpholinylmethyl)-7-hydroxy-8-allylcoumarin are treated as in the case of Example 4 until precipitation of the hydrochloride. 6.1 g of allyl bromide are used in place of the ethyl chloroacetate. The precipitate is separated and crystallised in ethanol; after filtering and drying the crystals, hydrochloride of the 4-methyl-6-(4-morpholinyl-methyl)-7-allyloxy-8-allyl coumarin is obtained.
MP 203, Rf 0.76 [thin layer chromatography (~ilica) chloroform-methanol-water-ammonium hydro~ide 32%
~ 130 + 25 + 2.8 ~ 0.5)].
~x~m~le ~
~thel ester o the acid 2-~4-methyl-6-~4-morpholinylmethyl)-8-~ ~ ~ ~ . 9.5 g of4-methyl-6-54-morpholinylmethyl)-7-hydroxy-8-allylcoumarin are mixed with 300 ml of toluene and 0.8 g of sodium hydride. The mixture is gradually heated to 60, being ~onstantly agitated meanwhile; after 30 minutes heating, the solvent is evaporated in vacuum. The residue is solubilised with 100 ml of dimethylsulf-oxide and 5.9 9 of ethyl ~-bromoisobutyrate are added to the solution which is kept at a temperature of 60. After 48 hours, 300 ml of toluene are added and the organic mixture is washed with water. The toluenic solution is reduced to a small volume lZ58455 in vacuum and formation of crystalline hydrochloride is achieved by addition of gaseous hydrochloric acid. The precipitate is separated and crystallised with ethanol; after filtering and drying the crystals, hydrochloride of the ethyl ester of the 2-l4-methyl-6-~4-morpholinylmethyl)-8-allylcoumarin-7-ylloxy-2-methylpropionic acid is obtained.
MP 171, Rf 0.79 [thin layer chromatography (silica) chloroorm-methanol-water-ammonium hydroxide 32% (130 + 25 + 2.8 + 0.5~1.
~xampl~ 7 4-~h~ny1-6-(4-morph~linyl~ethyl)-7-hydr~xy-8-allylc~marin hydrochlorid~~ 20 g of 4-phenyl-7-hydroxy-8-allyl coumarin are mixed with 200 ml of 80% aqueous ethanol, 6.3 g of morpholine and 6.2 9 of 35% formaldehyde aqueo~s solution. The same procedure a~ in the case of Example 1 is used until precipitation of the hydrochloride. The precipitate is separated and cry-~tallised with ethanol; after filtering and drying the crystals, hydrochloride of 4-phenyl-6-~4-morpholinylmethyl~-7-hydroxy-8-allylcoumarin is obtained.
MP 208D, Rf 0.87 ~thin layer chromatography ~silica) chloroform-methanol-Nater-ammonium hydroxide 32% (13~ + 25 +
2.8 + 0.5)~.
~Z58~55 E~amD1 e ~
4-phen~t-6-~4-(2-hydroxyethyl)-1-piperazinylJmeth~1~-7-hy~ro~y-~-allylcoumarin dihyaLQchlQride. 15 g of 4 phenyl-7-hydroxy-8-allylcoumarin are mixed with 200 ml of ethanol, 7 9 o 1-(2-hydroxyethyl)piperazine and 4.6 g o 35% formaldehyde aqueous solution. The mixture is refluxed for 48 hour~, being kept in constant agitation meanwhile. The ethanol is then evaporated in vacuum. The residue is gathered with ethyl acetate and the organic -~olution is e~tracted with hydrochloric acid 1~. The aqueous acid layer is alkalinized with sodium bicarbonate; a suspension is formed which iY then filtered. The precipitate is vacuum dried and then treated with ethyl acetate; precipitation of the cry~talline hydrochloride is achieved by adaing gaseous hydrochloric acid. The precipitate is separated and crystallised with ethanol; ater filtering and drying the crystals, dihydro-chloride of 4-phenyl-6-[~4-(2-hydroxyethyl)-1-piperazinyll methyll-7-hydroxy-8-allylcoumarin is obtained.
MP 250", Rf 0.74 [thin layer chromatography (silica) chloroform-methanol-acetic acid- water ~25 + 15 ~ 4 + 2)1.
~5134SS
Example ~
~-phenv1-6-14-morDholinvlmethyl)- 7-ally1o~Y-8-Ally~coum~rin hydrochloride. 20 g of 4-phenyl-6-(4-morpholinylmethyl)-7-hydroxy-8-allylcoumarin are mixed with 300 ml of toluene and 1.35 g of sodium hydride. The mixture is gradually heated to 60, being constantly agitated in the meantime. After 30 minutes' heating, the solvent is evaporated in vacuum. The residue is solubilised with 100 ml of dimethylsulfoxide and ~.4 9 of allyl bromide; after 12 hours, 300 ml of toluene are added and the organic ~ixture is washed with water. The toluenic solution is extracted with hydrochloric acid, lN, and the aqueous solution is alkalini~ed with sodium carbonate ana then extracted with methylene chloride. The methylene chloride solution is dried on anhydrous sodium sulfate and the solvent is eliminated in vacuum after filtration. The residue is gathered with toluene and formation of crystalline hydrochloride is achieved by adding gaseous hydrochloric acid. The precipitate is gathered and then crystallised with ethanol; after filtering and drying the crystals, hydrochloride of 4-phenyl-6-~4-morpholinylmethy1)-7-allyloxy-8-allylcoumarin is obtained.
MP 208~, Rf 0,871thin layer chromatography ~silica) chloroform-methanol-water-ammonium hydroxide 32~ ~130 + 25 +
2.8 + 0.5)].
~2584S5 ~x~ple 10 Ethyl e~r o~ ~4-phenyl-6-(4-morpholir-yllnet~lyrl)-8-allylcoum~rin-7-ylJoxy ace~ic acid hydrQchloride~ 24 g of 4 phenyl-6-~4-morpholinylmethyl)-7-hydroxy-8-allylcoumarin are mixed with 300 ml of toluene and 1.6 9 of sodium hydride. The mixture is gradually heated to 60, being constantly agitated meanwhile; after 30 minutes' heating the solvent is evaporated in vacuum. The re~idue is solubilised with 100 ml of dimethyl-sulfoxide and 8 9 of ethyl chloroacetate are added to the ~olution, which is kept at a temperature of 60; after 24 hours, 300 ml of toluene are added and the organic mixture is washed with water. The toluenic solution is extracted with hydrochloric acid, lN, and the acid agueous solution is alkalinised with sodium bicarbonate. A suspension is thus formed which i8 then filtered. The precipitate is vacuum dried and then gathered with toluene; the precipitation of the crystalline hydrochloride is achieved by adding gaseous hydrochloric acid. The precipitate is separated and then crystallised with ethanol; after filtering and drying the crystals, the hydrochloride of the ethyl ester of 14-phenyl-6-~4-morpholinylmethyl)-8-allylcoumarin-7-yl]oxy acetic acid is obtained.
MP 108~, Rf 0.88 lthin layer chromatography ~silica) chloro~orm-methanol-water-ammonium hydroxide 32% ~130 - 25 +
2.8 + 0.5)].
~;~58455 F~ample 11 ~thyl e~ter ~f 2-E4-pheDyl-6-(~-mor~h~linvlmethv])-8-llylcoumarin-7-ylJo~y-2-met~ lpropionic acid hydrQchlQride. 20 9 of 4-phenyl-6-~4-morpholinylmethyl)-7-hydroxy-8-allylcoumarin are mixed with 300 ml of toluene and 1~35 9 of sodium hydride; the mixture is ~radually heated to 60, ~eing constantly agitated meanwhile. After thirty minute~' heating, the solvent is evaporated in vacuum. The residue is solubilized with 100 ml of dimethylsulfoxide and 11.7 g of ethyl ~-bromoisobutyrate are added to the solution, which is kept at a temperature of 60.
After 72 hours, 300 ml of toluene are added to the organic mixture, which is then washed with water. The toluenic solution is extracted with hydrochloric acid, lN, and the aqueous solution is alkalinized with sodium bicarbonate; a suspension is thus formed which is subsequently filtered, The precipitate is vacuum dried and then gathered with toluene; precipitation of the crystalline hydrochloride is achieved by adding gaseous hydro-chloric acid. The precipitate is separated and crystalli2ed with ethanolic solution by adding ethyl acetate; after filtering and drying the crystals, hydrochloride of the ethyl ester of 2-14-phenyl-6-(4-morpholinylmethyl)-B-allylcoumarin-7-yl]oxy-2-methylpropionic acid is obtained~
MP 191~, Rf 0.83[thin layer chromatography (silica) chloroform-methanol-water-ammonium hydroxide 32% (130 + 25 2.8 ~ 0.5)].
~Z58~55 Exam~le L2 4-m~thy~-6-(L-pyrrolidinyl~thvl)-7-hy~Ln~y-~-al lylcQu~ari n hyd~nchlQride. 25 9 of 4-methyl-7-hydroxy-8-allylcoumarin are mixed with 300 ml of absolute ethanol, 8.3 9 of pyrrolidine and 3.4 9 of paraformaldehyde. The procedure then is the same as in Example 1 until the precipitation of the hydrochloride. The precipitate is separated and then crystallized with ethanol;
after filtering and drying the crystals, hydrochloride vf the 4-methyl-6~ pyrrolidinylmethyl)-7-hydroxy-8-allylcoumarin is obtained.
MP 116~, Rf 0.621thin layer chromatography ~silica) chloroform-methanol-acetic acid-water (25 ~ 15 ~ 4 + 2).
E~m~
4-rnethy1 -6-di ethyIATn; nometl~yl-7-hydro~y~8--al Iyl comTIari n hydrQc~lQride. 25 g of 4-methyl-7-hydroxy-8-allylcoumarin are mixed with 350 ml of ethanol, 8.9 g of diethylamine and 3.9 g of paraformaldehyde. The mixture is refluxed for 60 hours, being kept in constant agitation meanwhile; the ethanol is then evaporated in vacuum~ The residue is gathered ~ith ethyl acetate and the organic solution is extracted with hydrochloric acid, lN.
The aqueous acid layer is alkalini~ed with sodium bicarbonate and then extracted with methylene chloride. The methylene chloride solution is dried on anhydrous sodium sulfate, filtered and then the solvent i~ eliminated in vacuum. The residue is gathered with ethyl acetate and the formation of crystalline hydrochloride is achieved by adding ga~eous hydrochloric acid. The precipitate is lZS84SS
separated and then crystallized with isopropanol; after filtering and drying the crystals, hydrochlorlde of 4-methyl-6-diethyl-aminomethyl-7-hydroxy-8-allylcoumarin is obtained.
MP 188, Rf 0.72 lthin layer chromatography ~silica~
chloroform-methanol-acetic acid-water (25 + 15 + 4 + 2)l.
~xaD&~
4-met~yl-6-(1-~iperiain~lmethyl)-7-~ ~{L~LLL~
b4slY~hllclds. 25 g of 4-methyl-7-hydroxy-8-allylcoumarin are mi~ed with 300 ml of ethanol, 9.9 of piperidine and 3.4 g of paraormaldehyde. The ~ixture is refluxed for 96 hours, being kept constantly agitated meanwhile. The ethanol is evaporated in vacuum, after which the procedure is the same as for Example 8 until precipitation of the hydrochloride. The precipitate is separated and then crystallized with ethanol, after filtering and drying the crystals, hydrochloride of 4-methyl-6~l-piperidinyl-methyl)-7-hydroxy-8-allylcoumarin is obtained.
MP 234, Rf 0.84 [thin layer chromatoa,raphy ~silica) chloroform-methanol-water-ammonium hydroxide 32% ~130 + 25 +
2.8 + 0.5)l.
:~L;2S8455 xample L~
4-me~hyt-~-C~-hydroxy-l-~i~eridi ~
allylco~marin hydrochlQride. 30 9 of 4-methyl-7-hydroxy-8-allylco~marin are mixed with 300 ml of ethanol, 14.1 9 of 4-hydroxypiperidine and 4.2 g of formaldehydeO The procedure is then the same as for Example 8 until precipitation of the hydrochloride. The precipitate is separated and then crystal-lized with ethanol; after filtering and drying the crystals, hydrochloride of the 4-methyl-6-l(4-hydroxy-1-piperidinyl)-methyl~-7-hydroxy-8-allylco~arin is obtained.
MP 252, Rf 0.55 lthin layer chromatography ~silica) chloroform-methanol-acetic acid-water ~25 + 15 ~ 4 ~ 2)].
~am~le 16 4-meth~L-6-~-hydrQxy-1-piperidi~yl~me~hyl~-7-hy~rnYy-8-30 9 of 4-methyl-7-hydroxy-8-allylcoumarin are mixed with 300 ml of ethanol, 14.1 9 of 3-hydroxypiperidine and 4.2 g of paraformaldehyde. The mixture is refluxed for 24 hours, being kept in constant agitation meanwhile. The ethanol is evaporated in vacuum and the procedure i5 then the same a~ for Example 13 until the formation of hydrochloride. The precipitate is separated and then crystallized ~rom ethanol ~olution by adding ethyl acetate; after filtering and drying the crystals, hydrochloride of 4-methyl-6-~ZS8455 , [(3-hydroxy-1-piperidinyl) methyl]-7-hydroxy-8-allylcoumarin i5 obtained.
MP 184-, Rf 0.46lthin layer chromatography ~silica) chloride of methylene-ethyl acetate-methanol (70 + 30 + 5)] is obtained.
3-(2-di~thylamin~ethyl)-4-m~thvl-~ -mQr~hQli~ylme~hyl~-7-hydroxy-8-chlQrQcn~maxin dih~drQchlQride. 6.19 g of 3-(2-diethylaminoethyl)-4-methyl-7-hydroxy-8-chloro-coumarin are mixed with 200 ml of ethanol, 3.5 9 of morpholine and 1.7 9 o aqueous solution of 35% formaldehyde. The mixture i~ refluxed for 24 hours, being kept in constant agitation meanwhile. The ethanol is then evaporated in vacuum and the residue is gathered with ethyl acetate; a suspension is thus ormed which is then filtered; the organic solution is extracted with hydrochloric acid, lN. The aqueous acid layer is alkalinized with sodium bicarbonate and then extracte~ with methylene chloride. The methylene chloride solution i~ dried on anhydrous sodium sulfate and, after filtration, the solvent i~ eliminated in vacuum. The residue is gathered with ethyl acetate and the formation o crystalline hydrochloride is achieved by adding gaseous hydro-chloric acid. The precipitate is separated and crystallized form 95% ethanol; after filtering and dryin~ the crystals, hydrochlor-ide of 3-~2-diethylaminoethyl~-4-methyl-6-(4-morpholinylmethyl)-7-hydroxy-8-chlorocoumarin is obtained.
MP 174, R 0.56 tthin layer chromato~ra~hy (silica) chloro-form-methanol-water-ammonium hydroxide 32% (130 + 25 + 2..8 + O.5)3.
lZ58455 Example 18 Ethyl ester of L3- (2-diethylaminoethyl)-4-methyl-6-~4-morphQIinylmethyL)-8-chloroco~marin-7-yl~o~yacetiG acid dihvdrochloride. 18 g of 3-(2-diethylaminoethyl)-4-morpholinylmethyl)-7-hydroxy-8-chlorocoumarin are mixed with 300 ml of acetone, 12.2 9 of potassium carbonate and 5O4 g of ethyl chloroacetate; the mixture is gradually brought to the boiling point, being kept in constant agitation meanwhile, and then refluxed for 24 hours. The solvent is then evaporated in vacuum.
The residue is gathered with 300 ml of toluene and the mixture is treated with water. The toluenic layer is separated and then extracted with hydrochloric acid, lN; the aqueous acid solution is alkanized with sodium bicarbonate; a suspension is thus formed which is then filtered. The precipitate i3 vacuum dried and then gathered with toluene; the formation of crystalline hydrochloride is achieved by addition of gaseous hydrochloric acid. The precipitate is separated and crystallized from ethanol; after filtering and drying the crystals, hydrochloride of the ethyl ester of 13-~2-diethylaminoethyl)-4-methyl-6-(4-morpholinyl-methyl)-8-chloroco~arin-7-yl]oxy acetic acid is obtained.
MP 182, Rf 0.621thin layer chromatography (silica)chloro-form-methanol-acetic acid-water (25 + 15 + 4 +2)].
~xam~le L~
3-(2-diet~ylaminQethyl)-4-methyl-6-(4-mQr~hol iny l~eth~ 7-alLylQxy-8-chlorQ~QI~marin hydrochlQrid 16 g of 3-~2-diethylaminoethyl)-4-methyl-6-(4-morpholinylmethyl)-7- hydroxy-8-chlorocoumarin are mixed with 300 ml of acetone, 10.8 g of potas~ium carbonate and 4.8 g of allylbromide. The procedure is then the same as for Example 18 until the precipitation of the hydrochloride. The precipitate is separated and crystallized ~rom ethanolic solution by adding ethyl ether; after filtering and drying the crystals, hydrochloride of 3-~2-diethyl-aminoethyl)-4-methyl-~-~4-morpholinylmethyl)-7-allyloxy-8-chloroco~marin is obtained.
MP 150, Rf 0.35tthin layer chromatography(silica)-chloroform-methanol-acetic acid-water (25 + 15 +4 + 2)] is obtained.
~25~3~5S
B~ample 20 Ethyl ester of 2-~3-(2-diethyl~minoethvLL-4-methyl~fi-~4-morphQl invlmethyl!-8-chlorocn~marin-7-yl~o~y-2-methyl-vropionic acid dihydrochloride. 16 9 of 3-(2-diethylaminoethyl)-4-methyl-6-(4--morpholinylmethyl)-7-hydroxy-8-chlorocoumarin are mixed with 300 ml of toluene and 1 g of sodium hydride; the mixture is gradually heated to a temperature of 60, being kept in constant agitation in the meantime; after thirty minutes' heating, the solvent is solubilized ~ith 100 ml of dimethyl-sulfoxide and 7.6 g of ethyl ~-bromoisobutyrate are added to the solution, which is kept at room temperature; after 48 hours, 300 ml of toluene are added and the organic mixture is washed with water. The toluenic solution is extracted with hydrochloric acidv lN and the acid aqueous solution, after being alkalinized with sodium carbonate, is extracted with methylene chloride. The methylene chloride solution is dried on anhydrous sodium sulfate, filtered and the solvent is then eliminated in vacuum. The residue i~ gathered with toluene and the formation of cry~talline hydrochloride is achieved by adding gaseous hydrochloric acid.
The precipitate is separated and crystallized from ethanol; after iltering and drying the crystals, dihydrochloride of the ethyl ester of 2-[3-(2-diethylaminoethyl)-4-methyl-6-(4-morpholinyl-methyl)-8-chlorocoumarin-7-ylloxy-2-methylpropionic acid is obtained.
MP 148~, Rf 0.51[thin layer chromatography ~silica) chloroform-methanol-acetic acid-water ~25 + 15 + 4 + 2)1.
~`
~Z58~55 E~am~le 21 4-methyl-6-(4-~orpholinylmethyl)-7-hydrnxy-8-chloroc~umarin hydrochlQride. 20 g of 4-methyl-7-hydroxy-8-chlorocoumarin are mixed with 300 ml of ethanol, 16.5 g of morpholine and 8 g of 35%
formaldehyde aqueou~ solution. The mixture is refluxed for 48 hours, being kept in constant agitation meanwhile, and after 12 hours, a suspension is obtained which is then filtered. The precipitate is dissolved in methylene chloride and the organic solution is extracted with aqueous solution of 10% acetic acidr the organic solution is then extracted (3 times) with hydrochloric acid lN. The aqueous hydrochloric layer is alkalinized with sodium bicarbonate; a suspension is thus formed which is then filtered. The precipitate is vacuum dried and then treated with ethyl acetate; the precipitation of the crystalline hydrochloride is achieved by adding gaseous hydrochloric acid.
The precipitate is then separated and crystallized from methanolO
After filtering and drying the crystals, hydrochloride of 4-methyl-6-~4-morpholinylmethyl~-7-hydroxy-8-chlorocoumarin is obtained.
MP 227, Rf 0.80lthin layer chromatography (silica) chloroform-methanol-acetic acid-water ~25 + 15 + 4 + 2)1 is obtained.
~L25~34ss xam~L~ ~2 4-me~hyl-~-diethylaminometh~l-7-hydroxy-8-chlQ~Qc~marin hydrochloride. 21 g of 4-methyl-7-hydroxy-8-chlorocoumarin are mixed with l80 ml of ethanol, 20 ml of ch7oroform, 9.5 g of diethylamine and ll.2 of 35% aqueous formaldehyde solution. The mixture is refluxed for 20 hours, being kept in constant agitation meanwhile; the ethanol and chloroorm are evaporated in vacuum. The residue is solubilized in a methylene chloride-ethyl acetate-methanol mixture ~7 + 3 +l) and the solution i3 used for a chromatographic separation on silica, el~ting with the same mixture of solvents. 4-methyl-6-diethylaminomethyl-7-hydroxy-8-chloroco~marin is thus obtained. It i8 then treated with ethyl acetate and then, by adding gaseou~ hydrochloric acid~
crystalline hydrochloride i~ formed. The precipitate is ~eparated and crystallized from ethyl acetate. After filtering and drying the crystals, hydrochloride of 4-methyl-6-diethylaminomethyl-7-hydroxy-8-chlorocoumarin is obtained.
MP 202, Rf 0.671thin layer chromatography (~ilica) chloroform-methanol-acetic acid-water ~25 + 15 + 4 +2)].
~,5~3~55 ~am~
4-p~enyl-6-~a-~orpholinylmethyl)-7-h~d~oxy-~-chloroco~ari~
hydrochlorid~. 20 g of 4-phenyl-7-hydroxy-8-chloro coumarin are mixed with 300 ml of ethanol, 12.1 g of morpholine and 4.2 g of paraformaldehyde. The mixture is refluxed for 96 hours, being constantly agitated in the meantime; it is brought to room temperature and after 12 hours a suspension i~ obtained which is then filtered. The precipitate is dissolved in hydrochloric acidr lN, and the re~ulting solution is e~tracted ~3 times~ with methylene chloride. Evaporation of the solvent produce~ a methylene chloride solution from which a chloride residue is obtained. The precipitate i~ crystallized from ethyl acetate;
after filtering and drying the crystals, hydrochloride of 4-phenyl-6-~4-morpholinylmethyl~-7-hydroxy-8-chlorocoumarin is obtained.
MP 225~, Rf 0.791thin layer chromatography lsilica) chloroform-methanol-water-ammonium hydroxide 32% ~130 ~ 25 +
2.8 ~ 0.5)].
.~
~258455 Ex~m~le 24 3-(2-dieth~laminoethyl)-4-methvl-6-(4-mo~holinYI~ethvl~-7-~ethoxy-8-chlorocoumaLin dihydrochloride. 24.5 g of 3-(2-diethylaminoethyl)-4-methyl-6-t4-morpholinylmethyl)-7-hydroxy-8-chlorocoumarin are mixed with 300 ml of toluene and 1.6 9 of sodium hydrate; the mixture is gradually heated to 60, being constantly agitated meanwhiles after 30 minutes' heating the solvent i-~ evaporated in vacuum. The residue is solubilized with 100 ml of dimethylsulfo~ide and 7.5 g of aimethyl sulfate are added to the solution, which i~ kept at a tem~erature of 80;
after 48 hours, 300 ml of toluene are added and the organic mixture is washed with water. The toluene solution is extracted with hydrochloric acid, lN, and the acid aqueous solution is alkalinized with ~odium bicarbonate; a suspension is thus formed which is then filtered. The precipitate is vacuum dried and gathered with toluene; crystalline hydrochloride is formed by the addition of gaseous hydrochloric acid. The precipitate is separated and crystallized from ethanol. After ~iltering and drying the crystals, dihydrochloride of 3-(2-diethylaminoethyl~-4-methyl-6-~4-morpholinylmethyl)--7-methoxy-8-chlorocoumarin i~
obtained.
MP 181, Rf 0.41[thin layer chromatography (silica) chloroform-methanol-acetic acid-water (25 -~ 15 + 4 ~ 2)].
~amDle 25 4-~ethyl-7-hydroxy-6-di~ethyla~innm~hyl-7-hydroxy-~-chlorocoumarin hydrochloride~ 30 g of 4-methyl-7-hydroxy-8-chlorocoumarin are mixed with 200 ml of ethanol, 38.2 g of 33%
dimethylamine aqueous solution and 8.5 g of paraformaldehyde.
The mixture is refluxed for 72 hours, being constantly agitated in the meantime. The ethanol i~ evaporated in vacuum. The procedure is then the same as for Example 3 until the precipitation of the hydrochloride. The precipitate is separated and crystallized from ethyl acetate; after filtering and drying the crystals, hydrochloride of 4-methyl-7-hydroxy-6-dimethyl-aminomethyl-7-hydroxy-8-chlorocoumarin is obtained.
MP 238D, Rf 0.2171thin layer chromatography ~silica) chloroform-methanol-acetic acid-water ~25 + 15 + 4 + 2~]~
~258455 Exam~le 26 4.8-dimethyl-~-dimethylaminome~hyl-7-hy~rQxyconmarin hydrQchlQride. 30 g of 4,8-dimethyl-7-hydroxycoumarin are mixed with 300 ml of ethanol, 50 ml of chloroform, 27.1 g o 33%
dimethylamine aqueous solution and 6 9 of paraformaldehyde. The mixture i~ refluxed for 48 hour~, being constantly agitated meanwhile. The ethanol and chloroform are evaporated in vacuum.
The procedure i~ then the ~ame a~ for Example 13 until the formation of hydrochloride. The precipitate i~ ~eparated and then crystallized from 95% ethanol; after filtering and drying the cry~tal~, hydrochloride of 4,~-dimethyl-6-dimethylamino-methyl-7-hydroxycoumarin i~ obtained.
MP 252~, Rf 0.77 [thin layer chromatography ~silica) chloroform-methanol-acetic acid-water (25 + 15 + 4 +2)].
,; ~
~5~455 - 74 ~
~xa~L~ 27 4.8-dimethyl-fi-( 4-m~rp~ulinylm~li yl)-7-h~drQxycoumari n hydrochlorid~ 30 9 of 4,8-dimethyl-7-hydroxycoumarin are mixed with 300 ml of 85% aqueous ethanol~ 13.8 9 of morpholine and 4.8 g of paraformaldehyde. The mixture is refluxed for 96 hours, being constantly agitated meanwhile; it is then brought to a temperature of 5 and after 12 hours, a suspension is obtained which is then filtered. The preGipitate i~ vacuum dried and then treated with ethyl acetate. Precipitation of the crystalline hydrochloride is achieved by adding gaseous hydrochloric acid.
The precipitate is separated and crystallized from ethanol.
After filtering and drying the crystals, hydrochloride of 4.8-dimethyl-6-(4-morpholinylmethyl)-7-hydroxy coumarin is obtained.
MP 238 Rf 0.84 lthin layer chromatography ~silica) chloroform-methanol-acetic acid-water (13D + 25 + 2.8 +0.5)].
~ZS~S5 E~mple 28 4-phen~1-6-dimethvlarlnsm~ih~1_7-hydroYy-8-aLlylcoumar~n hydrochlnri~. 18 9 of 4-phenyl-7-hydroxy-8-allyl coumarin are mixed with 250 ml of ethanol, 23.4 g of 18.5% dimethylamine aqueous solution and 5.6 g of 35% formaldehyde aqueous solution.
The mixture is refluxed for 60 hours, being constantly agitated meanwhile. The ethanol is evaporated in vacuum. The procedure i~ then the same as for Example 8 until the precipitation of the hydrochloride. The precipitate is separated and crystallized from 95~ ethanol. After filtering and drying the crystals, hydrochloride of 4-phenyl-6-dimethylaminomethyl-7-hydroxy-8-allylcoumarin is obtained.
MP 199, Rf 0.82 lthin layer chromatography ~silica) chloroform-methanol-acetic acid-water (25 + 15 + 4 +2)].
~2~8455 F.xample 29 - Examples of injectable pharmaceutical compositions ~the active compounds can ~e identified from Table 1 of the general description) Preparation No. 1 Preparation with antitumoral and antimetastatic activity in the form of an aqueous solution.
Composition: .
a. one freeze-dried flacon contains:
- compound 19 ~Ex~1) mg 10 - mannitol mg 10 b. one vial of ~olvent contains:
- ~odiu~ chloride mg 18 - apyrogenetic distilled water ml 2 Preparation No. 2 Preparation with platelet antiaggregating activity in the form of an aqueous ~olution.
a. one freeze-dried flacon contains:
- compound 121 ~Ex.13~ mg 30 - mannitol mg 30 b. one 5 ml vial of solYent contains:
- sodium chloride mg 45 - apyrogenetic distilled water ml 5 '.~., ~ZS~3~5~
Preparation ~o. 3 Preparation with an antitumoral and antimetastatic activity in the form of an aqueous solution.
Composition aO one freeze-dried vial contains:
- compound 26 ~Ex.3) mg 50 - mannitol . mg 30 b. one 3 ml vial of solvent contains:
- sodium chloride mg 27 - apyrogenetic distilled water ml 3 Preparation 4 Preparation with platelet antiaggregating activity in the form of an aqueous solution.
Composition a. one freeze-dried vial contains:
- compound 117 (Ex.12) mg 40 - mannitol mg 25 b. one 5 ml vial of solvent contains:
- sodium chloride mg 45 - apyrogenetic distilled water ml 5 ~L258455 - 78 - &~L~_~Q - Examples of pharmaceutical compositions by oral route ~The compounds can be identified from Table 1 of the general description) Preparation No. 1 Preparation with an antitumDral and platelet antiaggregating activity in tablet form.
Composition:
each tablet contains - compound 19 (Ex~ 1~ mg. 20 - microcrystalline cellulose mg. 150 - lactose mg. 20 - starch mg. 10 - magne~ium steara$e mg. 5 Preparation No. 2 Preparation with a platelet antiaggregating activity in the form of ~ugar-coated pill~.
Composition:
each pill contains:
- compouna 124 (Ex. 14) mg. 30 - carboxymethyl cellulose mg. 150 - starch mg. lS
- shellac mg. 10 - saccharose mg. 35 - colouring mg. 0~5 Preparation No. 3 Prepa_ation with an antitumoral and antimetastatic-activity in the form of gelatinou~ opercula.
Composition:
each gelatinous operculum contains:
- compound 26 (Ex. 3) mg. 40 - lactose mg. 100 - ga~trore~i~tant varnish mg. 5 Preparation ~o. 4 Preparation with a platelet antiaggregating activity in capsule form.
Composition each soft gelatine capsule contains:
- compound 28 (E~.5~ mg. 50 - vegetable oil mg. 200 - beeswax mg. 20 - gelatine mg. 150 - glycerine mg. 50 - colouring mg. 3
Claims (110)
- Claim 1 - page 7 temporarily-protected hydroxyl group, with a compound of Formula XI:
(XI) wherein R7 has the same significance as in Formula I, and wherein R represents hydrogen, an unsubstituted hydrocarbyl group, or a hydrocarbyl group substituted with hydroxyl, amino or carbonyl groups and which can be interrupted in the carbon atom chain by O, S or N. - 2. A process for the preparation of a compound of Formula I
as defined in claim 1, which comprises subjecting a coumarin derivative of Formula II:
(II) wherein R1, R5, R6 and R7 are as defined above in Formula I, to a Mannich reaction with a secondary amine, HNR3R4, in which R3 and R4 are as defined above in Formula I. - 3. The process of claim 2 including the step of converting the compound of Formula I so-formed into a salt thereof.
- 4. A process for the preparation of a compound of Formula I
as defined in claim 1, which comprises subjecting, to a Claisen or Fries reaction, a compound of Formula III:
(III) wherein R3, R4, R5, R6 and R7 are as defined above in Formula I, and R1 represents an unsubstituted hydrocarbyl group, or a hydrocarbyl group substituted with hydroxyl, amino or carbonyl groups, and which can be interrupted in the carbon atom chain by O, S or N. - 5. The process of claim 4 including the step of converting the compound of Formula I so-formed into a salt thereof.
- 6. A process for the preparation of a compound of Formula I
as defined in claim 1, which comprises subjecting, to a Friedel-Crafts reaction, a compound of Formula IV:
(IV) to introduce said R1 group therein, wherein R1, R2, R3, R4, R;, R6 and R7 are as defined above in Formula (I). - 7. The process of claim 6 including the step of converting the compound of Formula I so-formed into a salt thereof.
- 8. A process for the preparation of a compound of Formula I
as defined in claim 1, which comprises converting, to a -CH2-NR3R4 group, by a reductive alkylation reaction, the aldehyde present in the 6-position of a compound of Formula V:
(V) wherein R1, R2, R3, R4, R5, R6 and R7 are as defined above in Formula I, wherein R2 may also signify a protective group for the hydroxyl, and wherein R5 may represent a protected hydroxyl group. - 9. A process as claimed in claim 8 including the step of converting the compound of Formula I so-formed into a salt thereof.
- 10. A process for the preparation of a compound of Formula I as defined in claim 1, which comprises converting, to a -NR3R4 group, a functionally-modified hydroxyl or reactive group X
present in a compound of Formula VI:
(VI) wherein R1, R2, R3, R4, R5, R6 and R7 are as defined above in the Formula I, and wherein R2 and R5 may also represent a protective group for the hydroxyl, - 11. The process of claim 10 including the step of converting the compound of Formula I so-formed into a salt thereof.
- 12. A process for the preparation of a compound of Formula I as defined in claim 1, which comprises converting, to a -NR3R4 group, the -NHZ group in a compound of Formula VII:
(VII) wherein R1, R2, R3, R4, R5, R6 and R7 are as defined above in the Formula I, Z represents hydrogen or one of the groups R3 or R4, and wherein R2 or R5 may also signify a protective group for the hydroxyl. - 13. The process of claim 12 including the step of converting the compound of Formula I so-formed into a salt thereof.
- 14. A process for the preparation of a compound of Formula I as defined in claim 1, which comprises condensing, by Pechmann reaction, a compound of Formula VIII:
(VIII) wherein R1, R2, R3, R4, and R5 are as defined above in Formula I, and wherein R2 and R5 may also signify a protective group for the hydroxyl, with a compound of Formula IX:
(IX) wherein R6 and R7 are as defined above in Formula I, and wherein R represents hydrogen or a hydrocarbon group. - 15. The process of claim 14 including the step of converting the compound of Formula I so-formed into a salt thereof.
- 16. The process for the preparation of a compound of Formula I, as defined in claim 1, which comprises condensing, by a Perkin reaction, a compound of Formula X:
(X) with a compound of Formula XI
(XI) wherein R7 is as defined above in Formula I, and wherein R
represents hydrogen, an unsubstituted hydrocarbyl group, or a hydrocarbyl group substituted with hydroxyl, amino or carbonyl groups and which can be interrupted in the carbon atom chain by O, S or N. - 17. The process of claim 16 including the step of converting the compound of Formula I so-formed into a salt thereof.
- 18. A process according to claim 2, wherein said Mannich reaction is carried out using paraformaldehyde in ethanol or acetic acid and an amine HNR3R4 in free form at a temperature of between 50°C and 90°C.
- 19. A process according to claim 2, wherein, when R2 represents hydrogen, R2 can be converted to a hydrocarbon group by subsequent alkylation using a compound of Formula R2X, wherein R2 is a hydrocarbon group as defined for Formula I, and wherein X
represents halogen or hydroxyl group esterified with an acid selected from the group consisting of sulfuric, sulfurous, and silicic acid, or with an aliphatic sulfonic acid having from 1 to 7 carbon atoms or with a monocyclic aromatic sulfonic acid. - 20. A process according to claim 19, wherein said alkylation reaction is carried out in an aprotic solvent in the presence of a basic compound.
- 21. A process according to claim 19, wherein said alkylation is carried out with an alkali metal salt of a compound of Formula I, wherein R2 is hydrogen, using dimethylsulfoxide as the solvent at room temperature.
22. A compound having Formula I:
I - Claim 22 - page 2 wherein R1 is halogen, an unsubstituted hydrocarbyl group, or a hydrocarbyl group substituted with hydroxyl, amino or carbonyl groups and which can be interrupted in the carbon atom chain by O, S or N; wherein R2, R6 and R7, which may be the same or different, each represents hydrogen, an unsubstituted hydrocarbyl group, or a hydrocarbyl group substituted with hydroxyl, amino or carbonyl groups and can be interrupted in the carbon atom chain by O, S or N, or R6 and R7 taken together may represent a hetero group having one or more hetero atoms; wherein R3 and R4, which may be the same or different, each represents an unsubstituted hydrocarbyl group, or a hydrocarbyl group substituted with hydroxyl, amino or carbonyl groups and can be interrupted in the carbon atom chain by O, S or N, or R3 and R4 taken together may represent an alkylene group or a hetero group having one or more hetero atoms; and wherein R5 is hydrogen, an unsubstituted hydrocarbyl group or a hydrocarbyl group substituted with hydroxyl, amino or carbonyl groups and can be interrupted in the carbon atom chain by O, S or N, halogen or a free or protected hydroxy group, or a pharmaceutically acceptable salt thereof.
- 23. A compound according to claim 22, wherein said hydrocarbyl groups are aliphatic, araliphatic or alicyclic.
- 24. A compound according to claim 22, wherein R6 and R7 are aromatic hydrocarbyl groups.
- 25. A compound according to claim 22, wherein said hydrocarbyl groups are aliphatic groups have from 1 to 7 carbon atoms.
- 26. A compound according to claim 25, wherein said aliphatic hydrocarbyl groups have from 1 to 4 carbon atoms.
- 27. A compound according to claim 22, wherein said hydrocarbyl groups are substituted alkyl or unsubstituted alkenyl.
- 28. A compound according to claim 22, wherein said hydrocarbyl groups are monocyclic unsubstituted groups having from 3 to 7 carbon atoms in the ring thereof.
- 29. A compound according to claim 28, wherein said monocyclic hydrocarbon groups have from 5 to 7 carbon atoms in the ring thereof.
- 30. A compound according to claim 28, wherein said monocyclic hydrocarbyl group is saturated.
- 31. A compound according to claim 28, wherein said monocyclic hydrocarbyl group has a double bond in the ring thereof.
- 32. A compound according to claim 27, wherein said alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.
- 33. A compound according to claim 27, wherein said alkenyl group is selected from the group consisting of vinyl, allyl, propenyl, isobutenyl, 2-butenyl and 2-pentenyl.
- 34. A compound according to claim 30, wherein said monocyclic hydrocarbyl group is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
- 35. A compound according to claim 31, wherein said monocyclic hydrocarbyl group is cyclohexenyl or cyclopentenyl.
- 36. A compound according to claim 22, wherein said hydrocarbyl groups are araliphatic with from 1 to 7 carbon atoms in the aliphatic part thereof and a phenyl group, said phenyl group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of alkyl groups having 1 to 4 carbon atoms, chlorine and bromine.
- 37. A compound according to claim 22, wherein said hydrocarbyl groups are monocyclic groups having from 3 to 7 carbon atoms in the ring thereof which are substituted by 1 to 3 alkyl groups each having 1 to 4 carbon atoms.
- 38. A compound according to claim 22, wherein said hetero groups have nitrogen, oxygen or sulfur in the ring thereof.
- 39. A compound according to claim 22, wherein said hydrocarbyl groups are substituted by 1 to 2 substituents selected from the group consisting of free or protected hydroxyl, carbonyl, carboxyl and amine groups and halogen atoms.
- 40. A compound according to claim 39, wherein said protected hydroxyl group is a hydroxyl group etherified with an alkyl residue having from 1 to 7 carbon atoms or a cycloalkyl residue with 3 to 7 carbon atoms in the ring, or is an hydroxyl group esterified with an aliphatic, araliphatic, aromatic or alicyclic organic acid having from 1 to 15 carbon atoms, or esterified with an alkylsulfonic acid having 1 to 7 carbon atoms, a monocyclic arylsulfonic acid, sulfuric acid, phosphoric acid or a hydracid.
- 41. A compound according to claim 39, wherein said protected carbonyl group is a cyclic ketalic group derived from ethylene glycol or propylene glycol, and wherein said protected carboxyl group is a carboxyl group esterified with an alkyl group having from 1 to 7 carbon atoms or with a cycloalkyl group having from 3 to 7 carbon atoms in the ring thereof.
- 42. A compound according to claim 22, wherein R3 and R4, taken together, represent an alkylene group having from 2 to 7 carbon atoms.
- 43. A compound according to claim 22, wherein R3 and R4, taken together, represent an azacycloalkyl group,
- 44. A compound according to claim 43, wherein said azacycloalkyl group is pyrrolidino, piperidino, 3-hydroxy-piperidino or 4-hydroxypiperidino.
- 45. A compound according to claim 22, wherein R3 and R4, taken together, is a member selected from the group consisting of morpholino, thiomorpholino, piperazino, N-ethylpiperazino and N-hydroxyethylpiperazino.
- 46. A compound according to claim 22, wherein R5 is hydrogen, chlorine, bromine or a hydroxyl group etherified by an alkyl having from 1 to 7 carbon atoms or by a cycloalkyl having from 3 to 7 carbon atoms in the ring thereof.
- 47. A compound according to claim 22, wherein R1 is a halogen or a hydrocarbyl group having 1 to 7 carbon atoms;
wherein R2 is hydrogen, an unsubstituted hydrocarbon group having from 1 to 7 carbon atoms or a hydrocarbonoyl group having from 1 to 7 carbon atoms substituted by a free carboxyl group or a carboxyl group esterified with an alkyl having 1 to 7 carbon atoms; wherein R3 and R4 each represents an alkyl group having 1 to 7 carbon atoms or R3 and R4, taken together, represent an alkylene group having 2 to 7 carbon atoms or a hetero group having an oxygen, sulfur or nitrogen hetero atom; wherein R5 is hydrogen, a free hydroxyl group or a hydroxyl group etherified with an aliphatic alcohol having 1 to 7 carbon atoms; and wherein R6 and R7 each represents hydrogen or an alkyl group having 1 to 7 carbon atoms or R6 and R7, taken together, represent a hetero ring having nitrogen as the hetero atom. - 48. A compound according to claim 47, wherein R1 is an alkenyl group having from 2 to 7 carbon atoms and R3 and R4 are alkyl groups having from 1 to 7 carbon atoms or R3 and R4, taken together, represent a piperazinyl, morpholino, thiomorpholino, pyrrolidino or piperidino group.
- 49. A compound according to claim 48, wherein R1 is vinyl, allyl, 2-butenyl or isobutenyl.
- 50. As a compound according to claim 22, 4-methyl-6-dimethylaminomethyl-7-hydroxy-8-allyl coumarin, or a pharmaceutically-acceptable salt thereof.
- 51. As a compound according to claim 22, 4-methyl-6-{[4-(2-hydroxyethyl)-1-piperazinyl]-methyl}-7-hydroxy-8-allylcoumarin, or a pharmaceutically-acceptable salt thereof.
- 52. As a compound of claim 22, 4-methyl-6-dimethyl-aminomethyl-7-hydroxy-8-allylcoumarin.
- 53. As a compound of claim 22, 4-methyl-6-(4-morpholinyl-methyl)-7-hydroxy-8-allylcoumarin.
- 54. As a compound of claim 22, 4-methyl-6-[[(4-(2-hydroxy-ethyl)-1-piperazinyl]methyl]-7-hydroxy-8-allylcoumarin.
- 55. As a compound of claim 22, the ethyl ester of [4-methyl-6-(4-morpholinylmethyl)-8-allylcoumarin-7-yl]oxyacetic acid.
- 56. As a compound of claim 22, 4-methyl-6-(4-morpholinyl-methyl)-7-allyloxy-8-allylcoumarin.
- 57. As a compound of claim 22, the ethyl ester of 2-[4-methyl-6-(4-morpholinylmethyl)-8-allylcoumarin-7-yl]oxy-2-methylpropionic acid.
- 58. As a compound of claim 22, 4-phenyl-6-(4-morpholinyl-methyl)-7-hydroxy-8-allylcoumarin.
- 59. As a compound of claim 22, 4-phenyl-6-[[(4-(2-hydroxyethyl)-1-piperazinyl]methyl]-7-hydroxy-8-allylcoumarin.
- 60. As a compound of claim 22, 4-phenyl-6-(4-morpholinyl-methyl)-7-allyloxy-8-allylcoumarin.
- 61. As a compound of ciaim 22, the ethyl ester of [4-phenyl-6-(4-morpholinylmethyl)-8-allylcoumarin-7-yl]oxyacetic acid.
- 62. As a compound of claim 22, the ethyl ester of 2-[4-phenyl-6-(4-morpholinylmethyl)-8-allylcoumarin-7-yl]oxy-2-methylpropionic acid.
- 63. As a compound of claim 22, 4-methyl-6-(1-pyrrolidinyl-methyl)-7-hydroxy-8-allylcoumarin.
- 64. As a compound of claim 22, 4-methyl-6-diethylamino-methyl-7-hydroxy-8-allylcoumarin.
- 65. As a compound of claim 22, 4-methyl-6-(1-piperidinyl-methyl)-7-hydroxy-8-allylcoumarin.
- 66. As a compound of claim 22, 4-methyl-6-[4-hydroxy-1-piperidinyl)methyl]-7-hydroxy-8-allylcoumarin.
- 67. As a compound of claim 22, 4-methyl-6-[(3-hydroxy-1-piperidinyl)methyl]-7-hydroxy-8-allylcoumarin.
- 68. As a compound of claim 22, 3-(2-diethylaminoethyl)-4-methyl-6-(4-morpholinylmethyl)-7-hydroxy-8-chlorocoumarin.
- 69. As a compound of claim 22, the ethyl ester of [3-(2-diethylaminoethyl)-4-methyl-6-(4-morpholinylmethyl)-8-chlorocoumarin-7-yl]oxyacetic acid.
- 70. As a compound of claim 22, 3-(2-diethylaminoethyl)-4-methyl-6-(4-morpholinylmethyl)-7-allyloxy-8-chlorocoumarin.
- 71. As a compound of claim 22, the ethyl ester of 2-[3-(2-dimethylaminoethyl)-4-methyl-6-(4-morpholinylmethyl)-8-chlorocoumarin-7-yl]oxy-2-methylpropionic acid.
- 72. As a compound of claim 22, 4-methyl-6-(4-morpholinyl-methyl)-7-hydroxy-8-chlorocoumarin.
- 73. As a compound of claim 22, 4-methyl-6-diethylamino-methyl-7-hydroxy-8-chlorocoumrain.
- 74. As a compound of claim 22, 4-phenyl-6-(4-morpholinyl-methyl)-7-hydroxy-8-chlorocoumarin.
- 75. As a compound of claim 22, 3-(2-diethylaminocthyl)-4-methyl-6-(4-morpholinylmethyl)-7-methoxy-8-chlorocoumarin.
- 76. As a compound of claim 22, 4-methyl-7-hydroxy-6-dimethylaminomethyl-7-hydroxy-8-chlorocoumarin.
- 77. As a compound of claim 22, 4,8-dimethyl-6-dimethyl-aminomethy1-7-hydroxycoumarin.
- 78. As a compound of claim 22, 4,8-dimethyl-6-(4-morpholinylmethyl)-7-hydroxycoumarin.
- 79. As a compound of claim 22, 4-phenyl-6-dimethyl-aminomethyl-7-hydroxy-8-allylcoumarin.
- 80. A pharmaceutical composition comprising an effective amount of a compound of Formula I
( I ) wherein R1 is halogen, an unsubstituted hydrocarbyl group, or a hydrocarbyl group substituted with hydroxyl, amino or carbonyl groups and which can be interrupted in the carbon atom chain by O, S or N; wherein R2, R6 and R7, which may be the same or different, each represents hydrogen, an unsubstituted hydrocarbyl group, or a hydrocarbyl group substituted with hydroxyl, amino or carbonyl groups and can be interrupted in the carbon atom chain by O, S or N, or R6 and R7 taken together may represent a hetero group having one or more hetero atoms; wherein R3 and R4, which may be the same or different, each represents an unsubstituted hydrocarbyl group, or a hydrocarbyl group substituted with hydroxyl, amino or carbonyl groups and can be interrupted in the carbon atom chain by O, S or N, or R3 and R4 taken together may represent an alkylene group or a hetero group having one or more hetero atoms; and wherein R5 is hydrogen, an unsubstituted hydrocarbyl group or a hydrocarbyl group substituted with hydroxyl, amino or carbonyl groups and can be interrupted in the carbon atom chain by O, S or N, halogen or a free or protected hydroxy group, or a pharmaceutically acceptable salt thereof; and a pharmaceutically-acceptable carrier. - 81. A pharmaceutical composition comprising an effective amount of 4-methyl-6-dimethylaminomethyl-7-hydroxy-8-allyl coumarin, or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable carrier.
- 82. A pharmaceutical composition comprising an effective amount of 4-methyl-6-{[4-(2-hydroxyethyl)-1-piperazinyl]-methyl}-7-hydroxy-8-allylcoumarin, or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable carrier.
- 83. A pharmaceutical composition comprising an effective amount of 4-methyl-6-dimethylaminomethyl-7-hydroxy-8-allylcoumarin, or a pharmaceutically-acceptable salt thereof and a pharmaceutically-acceptable carrier.
- 84. A pharmaceutical composition comprising an effective amount of 4-methyl-6-(4-morpholinylmethyl)-7-hydroxy-8-allylcoumarin, or a pharmaceutically-acceptable salt thereof and a pharmaceutically-acceptable carrier.
- 85. A pharmaceutical composition comprising an effective amount of 4-methyl-6-[[(4-(2-hydroxyethyl)-1-piperazinyl]methyl]-7-hydroxy-8-allylcoumarin, or a pharmaceutically-acceptable salt thereof and a pharmaceutically-acceptable carrier.
- 86. A pharmaceutical composition comprising an effective amount of the ethyl ester of [4-methyl-6-(4-morpholinylmethyl)-8-allylcoumarin-7-yl]oxyacetic acid, and a pharmaceutically-acceptable carrier.
- 87. A pharmaceutical composition comprising an effective amount of 4-methyl-6-(4-morpholinylmethyl)-7-allyloxy-8-allylcoumarin, or a pharmaceutically-acceptable salt thereof and a pharmaceutically-acceptable carrier.
- 88. A pharmaceutical composition comprising an effective amount of the ethyl ester of 2-[4-methyl-6-(-morpholinyl-methyl)-8-allylcoumarin-7-yl]oxy-2-methylpropionic acid, and a pharmaceutically-acceptable carrier.
- 89. A pharmaceutical composition comprising an effective amount of 4-phenyl-6-(4-morpholinylmethyl)-7-hydroxy-8-allylcoumarin, or a pharmaceutically-acceptable salt thereof and a pharmaceutically-acceptable carrier.
- 90. A pharmaceutical composition comprising an effective amount of 4-phenyl-6-[[(4-(2-hydroxyethyl)-1-piperazinyl]methyl]-7-hydroxy-8-allylcoumarin, or a pharmaceutically-acceptable salt thereof and a pharmaceutically-acceptable carrier.
- 91. A pharmaceutical composition comprising an effective amount of 4-phenyl-6-(4-morpholinylmethyl)-7-allyloxy-8-allylcoumarin, or a pharmaceutically-acceptable salt thereof and a pharmaceutically-acceptable carrier.
- 92. A pharmaceutical composition comprising an effective amount of the ethyl ester of [4-phenyl-6-(4-morpholinylmethyl)-8-allylcoumarin-7-yl]oxyacetic acid, and a pharmaceutically-acceptable carrier.
- 93. A pharmaceutical composition comprising an effective amount of the ethyl ester of 2-[4-phenyl-6-(4-morpholinyl-methyl)-8-allylcoumarin-7-yl]oxy-2-methylpropionic acid, and a pharmaceutically-acceptable carrier.
- 94. A pharmaceutical composition comprising an effective amount of 4-methyl-6-(1-pyrrolidinylmethyl)-7-hydroxy-8-allylcoumarin, or a pharmaceutically-acceptable salt thereof and a pharmaceutically-acceptable carrier.
- 95. A pharmaceutical composition comprising an effective amount of 4-methyl-6-diethylaminomethyl-7-hydroxy-8-allyl-coumarin. or a pharmaceutically-acceptable salt thereof and a pharmaceutically-acceptable carrier.
- 96. A pharmaceutical composition comprising an effective amount of 4-methyl-6-(1-piperidinylmethyl)-7-hydroxy-8-allylcoumarin, or a pharmaceutically-acceptable salt thereof and a pharmaceutically-acceptable carrier.
- 97. A pharmaceutical composition comprising an effective amount of 4-methyl-6-[4-hydroxy-1-piperidinyl)methyl]-7-hydroxy-8-allylcoumarin, or a pharmaceutically-acceptable salt thereof and a pharmaceutically-acceptable carrier.
- 98. A pharmaceutical composition comprising an effective amount of 4-methyl-6-[(3-hydroxy-1-piperidinyl)methyl]-7-hydroxy-8-allylcoumarin, or a pharmaceutically-acceptable salt thereof and a pharmaceutically-acceptable carrier.
- 99. A pharmaceutical composition comprising an effective amount of 3-(2-diethylaminoethyl)-4-methyl-6-(4-morpholinyl-methyl)-7-hydroxy-8-chlorocoumarin, or a pharmaceutically-acceptable salt thereof and a pharmaceutically-acceptable carrier.
- 100. A pharmaceutical composition comprising an effective amount of the ethyl ester of [3-(2-diethylaminoethyl)-4-methyl-6-(4-morpholinylmethyl)-8-chlorocoumarin-7-yl]oxyacetic acid, and a pharmaceutically-acceptable carrier.
- 101. A pharmaceutical composition comprising an effective amount of 3-(2-diethylaminoethyl)-4-methyl-6-(4-morpholinyl-methyl)-7-allyloxy-8-chlorocoumarin, or a pharmaceutically-acceptable salt thereof and a pharmaceutically-acceptable carrier.
- 102. A pharmaceutical composition comprising an effective amount of the ethyl ester of 2-[3-(2-dimethylaminoethyl)-4-methyl-6-(4-morpholinylmethyl)-8-chlorocoumarin-7-yl]oxy-2-methylpropionic acid, and a pharmaceutically-acceptable carrier.
- 103. A pharmaceutical composition comprising an effective amount of 4-methyl-6-(4-morpholinylmethyl)-7-hydroxy-8-chlorocoumarin, or a pharmaceutically-acceptable salt thereof and a pharmaceutically-acceptable carrier.
- 104. A pharmaceutical composition comprising an effective amount of 4-methyl-6-diethylaminomethyl-7-hydroxy-8-chlorocoumrain, or a pharmaceutically-acceptable salt thereof and a pharmaceutically-acceptable carrier.
- 105. A pharmaceutical composition comprising an effective amount of 4-phenyl-6-(4-morpholinylmethyl)-7-hydroxy-8-chlorocoumarin, or a pharmaceutically-acceptable salt thereof and a pharmaceutically-acceptable carrier.
- 106. A pharmaceutical composition comprising an effective amount of 3-(2-diethylaminoethyl)-4-methyl-6-(4-morpholinyl-methyl)-7-methoxy-8-chlorocoumarin. or a pharmaceutically-acceptable salt thereof and a pharmaceu-tically-acceptable carrier.
- 107. A pharmaceutical composition comprising an effective amount of 4-methyl-7-hydroxy-6-dimethylaminomethyl-7-hydroxy-8-chlorocoumarin, or a pharmaceutically-acceptable salt thereof and a pharmaceutically-acceptable carrier.
- 108. A pharmaceutical composition comprising an effective amount of 4,8-dimethyl-6-dimethylaminomethyl-7-hydroxycoumarin, or a pharmaceutically-acceptable salt thereof and a pharma-ceutically-acceptable carrier.
- 109. A pharmaceutical composition comprising an effective amount of 4,8-dimethyl-6-(4-morpholinylmethyl)-7-hydroxycoumarin, or a pharmaceutically-acceptable salt thereof and a pharmaceuti-cally-acceptable carrier.
- 110. A pharmaceutical composition comprising an effective amount of 4-phenyl-6-dimethylaminomethyl-7-hydroxy-8-allyl-coumarin, or a pharmaceutically-acceptable salt thereof and a pharmaceutically-acceptable carrier.
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of Formula I:
wherein R1 is halogen, an unsubstituted hydrocarbyl group, or a hydrocarbyl group substituted with hydroxyl, amino or carbonyl groups and which can be interrupted in the carbon atom chain by O, S or N; wherein R2, R6 and R7, which may be the same or different, each represents hydrogen, an unsubstituted hydrocarbyl group, or a hydrocarbyl group substituted with hydroxyl, amino or carbonyl groups and can be interrupted in the carbon atom chain by O, S or N, or R6 and R7 taken together may represent a hetero group having one or more hetero atoms; and wherein R3 and R4, which may be the same or different, each represents an unsub-stituted hydrocarbyl group, or a hydrocarbyl group substituted with hydroxyl, amino or carbonyl groups and can be interrupted in the carbon atom chain by O, S or N. or wherein R3 and R4 taken together may represent an alkylene group or a hetero group having one or more hetero atoms; and wherein R5 is hydrogen, an Claim 1 - page 2 unsubstituted hydrocarbyl group or a hydrocarbyl group substituted with hydroxyl, amino or carbonyl groups and can be interrupted in the carbon atom chain by O, S or N, halogen or a free or protected hydroxy group, or a pharmaceutically acceptable salt thereof, which process comprises one of the following reactions:
A. subjecting the coumarin derivatives corresponding to Formula II:
(II) wherein R1, R6, and R7 have the same significance as in Formula I, to a Mannich reaction with the secondary amine, HNR3R4, in which R3 and R4 have the same significance as in Formula I; or B. exposing, to a Claisen or Fries reaction, a compound of Formula III:
( III) Claim 1 - page 3 wherein R3, R4, R5, R6 and R7 have the same significance as in Formula I and wherein R1 signifies that the hydrocarbyl group is transferable in the 8-position; or C. introducing, by means of a Friedel-Crafts reaction, a hydrocarbyl group R1 as defined in Formula I or introducing, by halogenation, a halogen atom R1 as defined in Formula I into a compound of Formula IV:
(IV) wherein R1, R3, R4, R5, R6 and R7 have the same significance as in Formula I, wherein R2 may also signify a hydroxyl protection group substitutable by hydrogen and wherein R5 may represent a temporarily-protected hydroxyl group; or D. converting, by reductive alkylation to a R4R3N-CH2-group, the aldehyde group in the 6-position present in a compound of Formula V :
(V) Claim 1 - page 4 wherein R1, R2, R5, R6 and R7 have the same significance as in Formula I, where, in the R4R3N-CH2- group, wherein R3 and R4 have the same significance as in Formula I, wherein R2 may also signify a hydroxyl protection group substitutable by hydrogen and wherein R5 may represent a temporarily-protected hydroxyl group;
or E. converting, to a R4R3N- group, a functionally-modified hydroxyl group or reagent X present in a compound of Formula VI:
(VI) wherein R1, R2, R5, and R7 have the same significance as in Formula I, wherein R2 may also signify a hydroxyl protection group substitutable by hydrogen, wherein R5 may represent a temporarily-protected hydroxyl group, and where, in the R4R3N-group, R3 and R4 have the same significance as in Formula I; or F. converting, to a R3R4N- group, the -NHZ group of a compound of Formula VII:
Claim 1 - page 5 (VII) wherein R1, R2, R5, R6 and R7 have the same significance as in Formula I, wherein Z represents hydrogen or one of the R3 or R4 groups having the same significance as in Formula I, wherein R2 may also signify a hydroxyl protection group substitutable by hydrogen, wherein R5 may represent a temporarily-protected hydroxyl group, and where, in the -NR3R4 group, R3 and R4 have the same significance as in Formula I; or G. condensing, by a Pechmann reaction, a compound of Formula VIII:
( VIII) wherein R1, R2, R3, R4, and R5 have the same significance as in Claim 1 - page 6 Formula I, wherein R2 may also signify a hydroxyl protection group substitutable by hydrogen, and wherein R5 may represent a temporarily-protected hydroxyl group, with a compound of Formula IX:
(IX) wherein R6 and R7 have the same significance as in of Formula I
and wherein R represents hydrogen, an unsubstituted hydrocarbyl group, or a hydrocarbyl group substituted with hydroxyl, amino or carbonyl groups and which can be interrupted in the carbon atom chain by O, S or N; or H. condensing, by a Perkin reaction, a compound of Formula X:
( X ) wherein R1, R2, R3, R4, and R; have the same significance as in Formula I, wherein R2 may also signify a hydroxyl protection group substitutable by hydrogen, and wherein R5 may represent a
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000459548A CA1258455A (en) | 1984-07-24 | 1984-07-24 | Coumarin derivatives, pharmaceutical compositions containing the same, and the use thereof in the treatment of cancer |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000459548A CA1258455A (en) | 1984-07-24 | 1984-07-24 | Coumarin derivatives, pharmaceutical compositions containing the same, and the use thereof in the treatment of cancer |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1258455A true CA1258455A (en) | 1989-08-15 |
Family
ID=4128377
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000459548A Expired CA1258455A (en) | 1984-07-24 | 1984-07-24 | Coumarin derivatives, pharmaceutical compositions containing the same, and the use thereof in the treatment of cancer |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1258455A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114748476A (en) * | 2021-01-08 | 2022-07-15 | 江苏九基生物科技有限公司 | Application of coumarin derivative containing piperidine in preparation of antitumor drugs |
-
1984
- 1984-07-24 CA CA000459548A patent/CA1258455A/en not_active Expired
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114748476A (en) * | 2021-01-08 | 2022-07-15 | 江苏九基生物科技有限公司 | Application of coumarin derivative containing piperidine in preparation of antitumor drugs |
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