CA1060438A - Pharmaceutical compositions - Google Patents
Pharmaceutical compositionsInfo
- Publication number
- CA1060438A CA1060438A CA225,873A CA225873A CA1060438A CA 1060438 A CA1060438 A CA 1060438A CA 225873 A CA225873 A CA 225873A CA 1060438 A CA1060438 A CA 1060438A
- Authority
- CA
- Canada
- Prior art keywords
- group
- hydrogen
- formula
- substituted
- lower alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/53—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
Abstract
A B S T R A C T
A pharmaceutical composition comprises a pharmaceutical carrier or diluent together with a compound of the formula:
(I) in which:
R1 is a hydrogen atom or a lower alkyl group;
R2 and R3 are the same or are different and each is is a hydrogen or halogen atom, a hydroxy group, or a lower alkoxy group, or R2 and R3 are attached to adjacent carbon atoms on the benzene nucleus A and together represent a carboxyclic ring fused to benzene nucleus A;
R4 is a hydrogen atom an alkyl or aralkyl group, or a substituted or unsubstituted aryl group, or R4 together with R3 forms a non-aromatic ring fused to benzene nucleus A which non-aromatic ring may itself have further rings fused thereto, R5 is a hydrogen atom, a lower alkyl group, a lower hydroxyalkyl group, or a carboxylic acid group;
R6 is a carbon-carbon or carbon-hydrogen bond, a methylene (-CH2-) group, a hydroxymethylene (-CHOH-) group, or a mercaptomeihylene (-CHSH) group;
and R7 is a hydrogen atom, an alkyl or substituted alkyl group, an aryl or substituted arly group, or a heterocyclic or substituted heterocyclic group.
A pharmaceutical composition comprises a pharmaceutical carrier or diluent together with a compound of the formula:
(I) in which:
R1 is a hydrogen atom or a lower alkyl group;
R2 and R3 are the same or are different and each is is a hydrogen or halogen atom, a hydroxy group, or a lower alkoxy group, or R2 and R3 are attached to adjacent carbon atoms on the benzene nucleus A and together represent a carboxyclic ring fused to benzene nucleus A;
R4 is a hydrogen atom an alkyl or aralkyl group, or a substituted or unsubstituted aryl group, or R4 together with R3 forms a non-aromatic ring fused to benzene nucleus A which non-aromatic ring may itself have further rings fused thereto, R5 is a hydrogen atom, a lower alkyl group, a lower hydroxyalkyl group, or a carboxylic acid group;
R6 is a carbon-carbon or carbon-hydrogen bond, a methylene (-CH2-) group, a hydroxymethylene (-CHOH-) group, or a mercaptomeihylene (-CHSH) group;
and R7 is a hydrogen atom, an alkyl or substituted alkyl group, an aryl or substituted arly group, or a heterocyclic or substituted heterocyclic group.
Description
This invention is concerned with improvements in and relating to pharmaceutical compositions containin~ certain Schiff bases (i.e. aldimines and ketimines).
It has now been found, in accorda~ce with the present invention, that certain Schiff bases, as hereinafter defined, possess interesting pharmacological properties in that they have general anti~ytotic and anti inflammatory activity, as evidenced, for example by in vitro and in vivo tests on calcified and fibrotic tissues.
, Accordingly the présent i~vention provides a pharmaceutical composition comprising a Schiff base of general formul& (I) as hereinafter defined in association with a pharmaceutical carrier or diluent.
~ he ~chiff bases used in the compositions of the invention ma~ be répresented by the general formula:-' ' \ oR1 ~ ~ R5 I A l (I) , \ C ~ - 1~6 R~ 14 17 : : .
~: ~. , '. '
It has now been found, in accorda~ce with the present invention, that certain Schiff bases, as hereinafter defined, possess interesting pharmacological properties in that they have general anti~ytotic and anti inflammatory activity, as evidenced, for example by in vitro and in vivo tests on calcified and fibrotic tissues.
, Accordingly the présent i~vention provides a pharmaceutical composition comprising a Schiff base of general formul& (I) as hereinafter defined in association with a pharmaceutical carrier or diluent.
~ he ~chiff bases used in the compositions of the invention ma~ be répresented by the general formula:-' ' \ oR1 ~ ~ R5 I A l (I) , \ C ~ - 1~6 R~ 14 17 : : .
~: ~. , '. '
2 -in which: 1 R is a hydrogen atom or a lower alkyl group;
R2 andR3 are the same or are different and each is a hydrogen or halogen atom, a hydroxy group, or a lower alkoxy group, or R2 and R3 are attached to adjacent carbon atoms on the benzene nucleus A
and together represent a carbocyclic ring fused to benzene nucleus A;
. ~4 i8 a hydrogen atom an alkyl or aralkyl group, or. :
a substituted or unsubstituted :
aryl group, or :
R4 together with R3 forms a non-aromatic ring fused to benze~e nucleus A which no~-~; aromatic ring may itself ha~e : further rings fused thereto;
R5 is a hydrogen atom, a lower alk~l group, a lower hydroxyaIkyl group, or a carbox~lic acid group;
R6 is a carbon-carbon or carbon-hydrogen bond, a methylene (-CH2-) group, a hydroxymethyle~e (-CHOH-) group, or a mercaptomethylene (-CHSH) group;
and .
~ 3 -R is a hydrogen atom, an alkyl or substituted alkyl group, an aryl or substituted aryl group, or a heterocyclic or substituted heterocyclic group.
' - The group R is preferably a hydrogen atom but may be a lower alkyl group, e.g. a methyl or ethyl group. When the group R2 and/or R3 is a lower alkoxy group it ma~, for example be a methox~ or ethoxy group and when it is a halogen atom may, for example, be a chlorine or bromine atom. Whe~ the groupæ
and R~ together form a ring fused to benzene nucleus A they ma~ form a saturated or unsaturated carbocyclic ring fused to nucleus A. Thus, for example, the groups R2 and R3 may together form a chain - CH-CH - CH=CH - fused to nucleus A.
; ~he group R4 whe~ an alkyl group may for example be a methyl or ethyl group. When group R4 is a substituted alkyl group it may, for example, be a~ araIkyl group such as a benzyl or phenethyl group. Alternatively group R4 may be an ar~l OEoup such as a phenyl group or may be such a group substituted with, for example, one or more hydroæy or lower alkox~ (e.g. methoxy or ethox~ groups.
~ he~group R5 may be a hydrogen atom (in which case the group _C~R5_ will represent a methylene group) or may be a lower alkyl (e.g. methyl) or hydroxyalkyl (e.g. hydro~ethyl) group.
:
When the group R6 is a hydroxymethylene or mercapto-methylene group the grouping:
\ ,N - CH
` f ~ HXlH
., , ~
~in which X is an oxygen or su~phur atom) may be cyclized to ~ :
give compounds of the formula:
\ ~R
R3 4 / ~ X CH
. R :
a~d formula (I) above is intended to cover such cyclization products.
Where the group R4 is an alkyl group it may, for example, be a lower alkyl group such as a meth~l, ethyl or propyl group. Where the group R7 is a sub~tituted alkyl group it ma~ ~or example be a h~droxy alkyl or mercaptoalkyl group or may be an alk~l group interrupted by an o~ygen or suplhur atom. R7 may also be an aminoaIkyl group but in this case, fur to the method of preparation discussed below, the amino _. _.. _ ... ~ _ ,. ..... .. . . .
gro~p will generally be substituted to give a group of the formula:
- R'O R2 ~ R~
Purther when the group R7 is a substituted alkyI group it may be an aralkyl, substituted aralkyl, heterocyclic aIkyl or substituted heterocyclic alkyl group. ~he aryl moiety of the substituted or unsub~tituted aralkyl group may, for example, be a phenyl or substituted phe~yl group, e.g. an alkyl phenyl group, an alkoxy phenyl group, a halophenyl group a ~itrophenyl group, a h~droxy phenyl group or a cya~ophenyl group. ~hen the group r7 R' is a heterocyclic alkyl or substituted heterocyclic aIkyl group, the aryl graup, for example, be a pyridyl, imidazolyl, mdolyl or morpholyl group.
Whe~ R7 is a substituted or unsubstituted aryl or heterooyclic group it may, for èxample, be a group as discussed above for the aryl or heterocyclic moieties of the aralkyl or : . .
heterocyclic aIkyl groups.
he compounds of formula (I) i~ which R5 is a h hydrogen atom may be prepared from the corresponding OC- amino ~ ~ .
acids and carbonyl compound to give a carboxylated Schiff base which is subsequently decarboxylated. ~he reaction may be represented by the following equations:
, i 1060438 ~. .
, 1 ~ oR1 COOH
~ fo + H2N b - R6 _ R7 R R H
' ' V' ~ ':
R2 :
OR
~ C - R4 R ll COOH
. .
''' ~ -CO2 . ., \/
' R\
~2--R6 _ ~7 hie reaction is suitably carried out by mixing : the two reactant~ (in equimolecular preparation) and subsequently heating them together, as described in 7. Chem. ~oc. (C) 19~8, : ' ' ' ,; . .
1060438 `
pages 411 to ~15. It will be understood that where R7 is an aminoalkyl group formation of the Schiff base may take place at both amino groups.
Alternatively, the compounds of formula (I) may be prepared by reacting the appropriate carbonyl compound with the appropriate amine in accordance with the reaction scheme R2~ :
~ oR1 ~ oR1 R5 R ~ C0 + R ~ - C - R6_ R7 _ > ~ ==~- C_ R6 _ R7 In this case also, where R is an aminoalkyl group, it will be understood that formation of the Schiff base may take place at both amino groups. Additionall~ it is to be when R4 i~ a h~droxymeth~lene or understood that/mercaptome~hylene group, cyclization of the Schiff bass ma~ take place to produce an oxazolidine or thiazolidine as~discuseed above.
~ he reaction between the carbonyl compound and the amine will normally be carried out in the presence of an inert solvent and it has been found, in accordance with a further fea~ture of the inve~tion, that a particularly suitable solvent fQr the reaction is a lower alkanol, especially ethanol. ~hus, when employing a lower~alkanol as solvent it has been found ~;
that separation of the desired end product is particularly si~ple s~ ce the product precipitates out of the solvent and easily received thereupon by filtration, centrifugation or .
~ke prooess. Thé product so obtained is in a very pure state ' .
. , .. , .. ,~ .. , . ~ . ~ . -, . .. . . . ... . . ... . .
`
Such compounds are thosein which:-R2 and/or R3 is a halogen atom or R2 and/or R3 forms part of a ring fused to benzene nucleus A; -;
R5 is a lower alkyl or a hydroxy lower alkyl -group; or R comprises a pyridyl, substituted pyridyl, morpholino, substituted morpholino, alkaryl, alkoxyaryl, nitrophenyl, halophenyl or - cyanophenyl group.
,~ .
I ~he~following ~able I lists a number of Schiff .
ba~es of formula (I) which may be used in the composition of bhe i~vention. ~he symbol (*) mdicates that the compounds have ¦ been described in J. Chem. Soc. referencé referred to above.
he symbol (c) iidicates that the product cyclized to give the corresponding oxazolidine. ~he symbol (aa) indicates that the compound has been prepared by the carbonyl compound/amino acid route; the symbol (a) indicates that the compound has been prepared by the carbonyl compound/amine route.
'' ~ `~ ~ . ' . .
. ~ 9 ~
T A B L E 1.
Compounds of Formula (I) ~ompound R R~ R R4 R R6 R
____,_ . .-l~*)(aaj(a) H H H -CH3 H 6H5 :
2(*?(aa)(a) ., -C6H5
R2 andR3 are the same or are different and each is a hydrogen or halogen atom, a hydroxy group, or a lower alkoxy group, or R2 and R3 are attached to adjacent carbon atoms on the benzene nucleus A
and together represent a carbocyclic ring fused to benzene nucleus A;
. ~4 i8 a hydrogen atom an alkyl or aralkyl group, or. :
a substituted or unsubstituted :
aryl group, or :
R4 together with R3 forms a non-aromatic ring fused to benze~e nucleus A which no~-~; aromatic ring may itself ha~e : further rings fused thereto;
R5 is a hydrogen atom, a lower alk~l group, a lower hydroxyaIkyl group, or a carbox~lic acid group;
R6 is a carbon-carbon or carbon-hydrogen bond, a methylene (-CH2-) group, a hydroxymethyle~e (-CHOH-) group, or a mercaptomethylene (-CHSH) group;
and .
~ 3 -R is a hydrogen atom, an alkyl or substituted alkyl group, an aryl or substituted aryl group, or a heterocyclic or substituted heterocyclic group.
' - The group R is preferably a hydrogen atom but may be a lower alkyl group, e.g. a methyl or ethyl group. When the group R2 and/or R3 is a lower alkoxy group it ma~, for example be a methox~ or ethoxy group and when it is a halogen atom may, for example, be a chlorine or bromine atom. Whe~ the groupæ
and R~ together form a ring fused to benzene nucleus A they ma~ form a saturated or unsaturated carbocyclic ring fused to nucleus A. Thus, for example, the groups R2 and R3 may together form a chain - CH-CH - CH=CH - fused to nucleus A.
; ~he group R4 whe~ an alkyl group may for example be a methyl or ethyl group. When group R4 is a substituted alkyl group it may, for example, be a~ araIkyl group such as a benzyl or phenethyl group. Alternatively group R4 may be an ar~l OEoup such as a phenyl group or may be such a group substituted with, for example, one or more hydroæy or lower alkox~ (e.g. methoxy or ethox~ groups.
~ he~group R5 may be a hydrogen atom (in which case the group _C~R5_ will represent a methylene group) or may be a lower alkyl (e.g. methyl) or hydroxyalkyl (e.g. hydro~ethyl) group.
:
When the group R6 is a hydroxymethylene or mercapto-methylene group the grouping:
\ ,N - CH
` f ~ HXlH
., , ~
~in which X is an oxygen or su~phur atom) may be cyclized to ~ :
give compounds of the formula:
\ ~R
R3 4 / ~ X CH
. R :
a~d formula (I) above is intended to cover such cyclization products.
Where the group R4 is an alkyl group it may, for example, be a lower alkyl group such as a meth~l, ethyl or propyl group. Where the group R7 is a sub~tituted alkyl group it ma~ ~or example be a h~droxy alkyl or mercaptoalkyl group or may be an alk~l group interrupted by an o~ygen or suplhur atom. R7 may also be an aminoaIkyl group but in this case, fur to the method of preparation discussed below, the amino _. _.. _ ... ~ _ ,. ..... .. . . .
gro~p will generally be substituted to give a group of the formula:
- R'O R2 ~ R~
Purther when the group R7 is a substituted alkyI group it may be an aralkyl, substituted aralkyl, heterocyclic aIkyl or substituted heterocyclic alkyl group. ~he aryl moiety of the substituted or unsub~tituted aralkyl group may, for example, be a phenyl or substituted phe~yl group, e.g. an alkyl phenyl group, an alkoxy phenyl group, a halophenyl group a ~itrophenyl group, a h~droxy phenyl group or a cya~ophenyl group. ~hen the group r7 R' is a heterocyclic alkyl or substituted heterocyclic aIkyl group, the aryl graup, for example, be a pyridyl, imidazolyl, mdolyl or morpholyl group.
Whe~ R7 is a substituted or unsubstituted aryl or heterooyclic group it may, for èxample, be a group as discussed above for the aryl or heterocyclic moieties of the aralkyl or : . .
heterocyclic aIkyl groups.
he compounds of formula (I) i~ which R5 is a h hydrogen atom may be prepared from the corresponding OC- amino ~ ~ .
acids and carbonyl compound to give a carboxylated Schiff base which is subsequently decarboxylated. ~he reaction may be represented by the following equations:
, i 1060438 ~. .
, 1 ~ oR1 COOH
~ fo + H2N b - R6 _ R7 R R H
' ' V' ~ ':
R2 :
OR
~ C - R4 R ll COOH
. .
''' ~ -CO2 . ., \/
' R\
~2--R6 _ ~7 hie reaction is suitably carried out by mixing : the two reactant~ (in equimolecular preparation) and subsequently heating them together, as described in 7. Chem. ~oc. (C) 19~8, : ' ' ' ,; . .
1060438 `
pages 411 to ~15. It will be understood that where R7 is an aminoalkyl group formation of the Schiff base may take place at both amino groups.
Alternatively, the compounds of formula (I) may be prepared by reacting the appropriate carbonyl compound with the appropriate amine in accordance with the reaction scheme R2~ :
~ oR1 ~ oR1 R5 R ~ C0 + R ~ - C - R6_ R7 _ > ~ ==~- C_ R6 _ R7 In this case also, where R is an aminoalkyl group, it will be understood that formation of the Schiff base may take place at both amino groups. Additionall~ it is to be when R4 i~ a h~droxymeth~lene or understood that/mercaptome~hylene group, cyclization of the Schiff bass ma~ take place to produce an oxazolidine or thiazolidine as~discuseed above.
~ he reaction between the carbonyl compound and the amine will normally be carried out in the presence of an inert solvent and it has been found, in accordance with a further fea~ture of the inve~tion, that a particularly suitable solvent fQr the reaction is a lower alkanol, especially ethanol. ~hus, when employing a lower~alkanol as solvent it has been found ~;
that separation of the desired end product is particularly si~ple s~ ce the product precipitates out of the solvent and easily received thereupon by filtration, centrifugation or .
~ke prooess. Thé product so obtained is in a very pure state ' .
. , .. , .. ,~ .. , . ~ . ~ . -, . .. . . . ... . . ... . .
`
Such compounds are thosein which:-R2 and/or R3 is a halogen atom or R2 and/or R3 forms part of a ring fused to benzene nucleus A; -;
R5 is a lower alkyl or a hydroxy lower alkyl -group; or R comprises a pyridyl, substituted pyridyl, morpholino, substituted morpholino, alkaryl, alkoxyaryl, nitrophenyl, halophenyl or - cyanophenyl group.
,~ .
I ~he~following ~able I lists a number of Schiff .
ba~es of formula (I) which may be used in the composition of bhe i~vention. ~he symbol (*) mdicates that the compounds have ¦ been described in J. Chem. Soc. referencé referred to above.
he symbol (c) iidicates that the product cyclized to give the corresponding oxazolidine. ~he symbol (aa) indicates that the compound has been prepared by the carbonyl compound/amino acid route; the symbol (a) indicates that the compound has been prepared by the carbonyl compound/amine route.
'' ~ `~ ~ . ' . .
. ~ 9 ~
T A B L E 1.
Compounds of Formula (I) ~ompound R R~ R R4 R R6 R
____,_ . .-l~*)(aaj(a) H H H -CH3 H 6H5 :
2(*?(aa)(a) ., -C6H5
3(*)(aa)(a) ll ll ll OH ll ll _ ~ , ~(*)(aa)(a) H -OH(4) -C6H5 ;(*)(aa)(a) H H -CH3 H -CH2 : (*)(aa)(a) ll .. ., >
~: ~
7(*)~aa)(a) H -OH(4) ll -C6H5 ll ll ll _ , 8~*)~aa)~a) -CH3 H ,lO~CH3 ,l .l .l : ~:3 :, 9~*)(aa)~a) H -C~H5 ~OH
OH
10(*)(aa)(a) , ll~*)(aa)~a) H H H OH H L~N
12~ aa~a) ., .. -CN3 ..
13~*)(aa)(a) ., = = ~H2)3CH3 ,. ..
14(*)(aa)(a) " ... ,l n ~H
~: ~
7(*)~aa)(a) H -OH(4) ll -C6H5 ll ll ll _ , 8~*)~aa)~a) -CH3 H ,lO~CH3 ,l .l .l : ~:3 :, 9~*)(aa)~a) H -C~H5 ~OH
OH
10(*)(aa)(a) , ll~*)(aa)~a) H H H OH H L~N
12~ aa~a) ., .. -CN3 ..
13~*)(aa)(a) ., = = ~H2)3CH3 ,. ..
14(*)(aa)(a) " ... ,l n ~H
4~3 . . ~ _ . .
lS(*)(aa)(a) _ ., -CH2SCH3 . - - . -- . , ,, ~ .
Compound R I R2 I R3 R4 l R5 R ¦ R
No. _ ¦1 ~*)(a)¦~ ¦ ¦ -CH ¦~ ¦ CH2( 2) ~ L 1~1 17(*)(aa)(a) ll .. ll ll ll .. -CH(CH3) _ .
18(*)(aa)(a) ..... .. .. ll ll _ ll _ .
l9(*)(aa)(a) ll .. .. OH ll ll ll . \~
_ _ (a) .l .. .. -C6H5 .................. -CH20H
21(*)(aa)(c) H H H -C6H5 H -CHOH- -CH -C H
.. _. ._ 22(*)(aa)(c) ., ll .. .. .. -CHOH- -CH3 23(*)(a) ,l .l n H n -CH2- H
24(*)(a) ll .. .- .. .. .. -CH3 _ _ ._ 25(*)(a) _ _ .. .. .. CH2 CH3 26(a) . - ~ -CH3 -CH20H -CHOH- ~ NO2 .
27(a) .. .. .. .. -CH3 ......... -C6H5 28(a) ., _ .. H -CH20H ....... _ _ _ 29(a) .. .. .. ll -CH3 ll -C6H5 _ _ .
30(a) SEE BELOW H _ 6 5 OMe .
31(a) H H H -CH3 H -CH2 ~ Me _. .. MeMe 32(a) ll ll ll ll ll _ ~ Me _ _ Me Me _ _ C po~ n~, 1~ ~ R3 ~ ~?5 1:`6 R - :
33 ~ ) __ H EI --CH3 H -CH2---CH2--N O
34 (a ) ~ __ " ,, ,. _ ~Cl 35 (a ) " " " " " _ O >
~0 _ __ . .
3 6 ( a ) ll ll ll ., ll _ ~ N~
_ .. ~ ..... _ 37 (a ) ( c ) ., .l .l ., ,. -CH2CH2- -SH
._ _ 38 (a) .ll ll H ll _ ~
. _ 3g (a) ll ll ,. ll ll -CH2- N
. . ~? ' 4 0 ( a ) ll ll - . ll ll ll ~OMe . _ ~
41 (a) ll .. . " ll ll ll -CH2-N -.
4 2 ( a ) H HBr ( 5 ) H H -CH 2 ~ ~,OMe ~OMe . ._ 4 3 ( a ) " " " " " 4~3 44 (a) \=J
45 (a) .. Cl ~3) Cl (5) ll ll -CH2- ,~OMe 4~OMe I I
4 6 ( a ) ll~CH--CH' H H _ 4~
~5,6) \~J _ Compound R R R R R5 R R .
l ._ 4 7 ~ a) ,. n n n ~1 ~ ~C 6H5 48 (a) H Cl (3) Cl (5) ..
4 9 t a ) ll ,. .
..
50 (a) ll ll ll ll ll ll ~ CN
._ ._ 51 t a ) H Br ( 5 ) H H- H _ ~
\=~N
lS(*)(aa)(a) _ ., -CH2SCH3 . - - . -- . , ,, ~ .
Compound R I R2 I R3 R4 l R5 R ¦ R
No. _ ¦1 ~*)(a)¦~ ¦ ¦ -CH ¦~ ¦ CH2( 2) ~ L 1~1 17(*)(aa)(a) ll .. ll ll ll .. -CH(CH3) _ .
18(*)(aa)(a) ..... .. .. ll ll _ ll _ .
l9(*)(aa)(a) ll .. .. OH ll ll ll . \~
_ _ (a) .l .. .. -C6H5 .................. -CH20H
21(*)(aa)(c) H H H -C6H5 H -CHOH- -CH -C H
.. _. ._ 22(*)(aa)(c) ., ll .. .. .. -CHOH- -CH3 23(*)(a) ,l .l n H n -CH2- H
24(*)(a) ll .. .- .. .. .. -CH3 _ _ ._ 25(*)(a) _ _ .. .. .. CH2 CH3 26(a) . - ~ -CH3 -CH20H -CHOH- ~ NO2 .
27(a) .. .. .. .. -CH3 ......... -C6H5 28(a) ., _ .. H -CH20H ....... _ _ _ 29(a) .. .. .. ll -CH3 ll -C6H5 _ _ .
30(a) SEE BELOW H _ 6 5 OMe .
31(a) H H H -CH3 H -CH2 ~ Me _. .. MeMe 32(a) ll ll ll ll ll _ ~ Me _ _ Me Me _ _ C po~ n~, 1~ ~ R3 ~ ~?5 1:`6 R - :
33 ~ ) __ H EI --CH3 H -CH2---CH2--N O
34 (a ) ~ __ " ,, ,. _ ~Cl 35 (a ) " " " " " _ O >
~0 _ __ . .
3 6 ( a ) ll ll ll ., ll _ ~ N~
_ .. ~ ..... _ 37 (a ) ( c ) ., .l .l ., ,. -CH2CH2- -SH
._ _ 38 (a) .ll ll H ll _ ~
. _ 3g (a) ll ll ,. ll ll -CH2- N
. . ~? ' 4 0 ( a ) ll ll - . ll ll ll ~OMe . _ ~
41 (a) ll .. . " ll ll ll -CH2-N -.
4 2 ( a ) H HBr ( 5 ) H H -CH 2 ~ ~,OMe ~OMe . ._ 4 3 ( a ) " " " " " 4~3 44 (a) \=J
45 (a) .. Cl ~3) Cl (5) ll ll -CH2- ,~OMe 4~OMe I I
4 6 ( a ) ll~CH--CH' H H _ 4~
~5,6) \~J _ Compound R R R R R5 R R .
l ._ 4 7 ~ a) ,. n n n ~1 ~ ~C 6H5 48 (a) H Cl (3) Cl (5) ..
4 9 t a ) ll ,. .
..
50 (a) ll ll ll ll ll ll ~ CN
._ ._ 51 t a ) H Br ( 5 ) H H- H _ ~
\=~N
5 2 ( a ) ll H
~ ~N . ~ ~
5 3 ( a ) _ _ _ CH3_ _ _ ~CN ~:
54 ~ a) ll Br ( 3 ) ll H ll ll ~ CN
5 5 ( a ) .l H n l ,l ,l ~3 CN
56 (a) ll Br (3) Br (5) H H H 6 5 57 (a) ., H H --CH3 -CH -- ~} CN
58 (a) ll OH (4) OH ~6) .. H -C6H5 Note to ~able I
Compound No~ 30 was prepared using tetracyline as carboxyl compound and the grouping ~/
has the structure:-OH OH O . -~:~0~ :~
HO CH3 ( 3)2 ' .
Where the carrier is a liquid the compositions of the invention may, for example, take the form of a ~olution or suspension or injection comprising the active ingredient (i. e. the Schiff base of formula(I) ), together with sterile, pyrogen-free water or an injectable oil, Alternatively, where the carrier iæ a liquid the composition of the invention may comprise the active ingredient together with a carrier liqùid and one or more pharmaceutical adjuvants such as preservatives, flavouring agents, buffering agents, colouring agents, thickening agents, sweetening agents or suspending agents, Thus, in this latter case, the pharmaceutical compositions of the inver~tion may take the form of syrups, elixirs, linctuse~ or may take the form of a solution or suspension of the active ingredient in a carrier liquid contained in a capsule, especially a soft gelatine capsule, In anothér form of pharmaceutical composition where the carrier is a liquid, the carrier is a pressurised, liquefied propellant (e. g. an halogenated propellant such as Freon 12 and/or Freon 11) and thewhole composition is contained in a pressurised container (i, e. forms a so-called "aerosol"packages~) and is adapted to be administered by inhalation.
Finally, where it is intended to adminster the active ingredient with a liquid carrier the compositions of the invention may take the form of a container containing the active ingredient or provided with a puncturable sealing membrane whereby a carrier liquid (especially water) may be introduced into the container by means of a hypodermic . ~ ~ .. . . .. .
~06~438 syl~inge to form a solution in the container whicl~ the latter is then taken up into the syringe for administration.
Where the pharmaceutical carrier is a solid, the compositions of the invention may comprise conventional solid dosnge units such as tablets, pills or dragees or may compl~isc the solid active ingredient cont~ined in a capsule or may further comprise the active ingredient suspended in a suppository base. In any event, in addition to the solid carrier the solid pharmaccutical compositions of the invention may also include pharmaceutical adjuvents as described above.
Thc compositions of the invention are conveniently put up in dosage unit form and, in this case, each dosa~e unit suit~bly contains from 250 to 3, 000 milligrams of active ingredient, preferably from 500 to 1, 000 milligrams of active ingredient.
As stated above the Schiff bases of formula (I) have a broadly antimyto~ic activity, and, in particular, appear to l~ave an anti-fibrol~lastic and antiinflammatory activity which particularly adapts them for the treatmcnt of certain diseases of which fibrosis is the main or an important part such as, for example, tumour of the bladder, lungs, rectum, liver and pancreas calcification of the bladder due to bilhartzeal fibrosls of the bladder; and coronary occlusions.
The compounds aiso possess anabolic activity, . , ~ he antimytotic activity of the compounds is generally potentiated by the simultaneous adminis-tration of hydrocortisone in small doses, e.g. about 10 mg.. Thus, the invention also provides a composition as defined above also containing hydrocortisone.
Schiff bases are relatively non-toxic and rats when administered at doses of 100g. and 200 mgs./kg. hodyweight respectively.
The toxicity and in vitro and ~n vivo activit~
of compound No. 1 has been investigated under the auspices of the Govérnment of Iraq. ~he in vivo (clinica~) trials were carried out at the Medical Centre, ~aghdad, Iraq.
Acute toxicitly in rats - Rats of the CFY strain, in the weight range 101 to 114g were starved overnight before treatment with compound No. 1.
Compound ~o. 1 was prepared as a 4~o suspension in corn oil and administered by oral intubation at a dosage volume in the full scale test of 40m1./k~. bodyweight. Rats treated with corn oil alone (40ml./kg.) served as controls.
During the observation p~riod of 14 days, a record was kept of all mortalities and signs of toxicity. All rats that died were examined microscopically in an attempt to identify the target organs, and those animals surviving terminally were similarl~ examined to detect possible residual damage.
~ he results of preliminary range finding tests Indicated that the median lethal oral dose (~D50), was greater than 16g./kg. bodyweight.
Dosing was then extended to larger groups of rats (five male and females) in order to confirm this.
., ' .~
Signs of reaction to treatment, observed shortl~
after dosIng included slight lethargy and piloerection. ~his wa~ later accompanied by diarrhoea in six rats.
Death o¢curred withi~ twent~ hours of dosing.
Autops~ revealed injécted blood vessels of the peritoneum and intestinal mesenteries.
'Recovery of survivors a~ judged by external appearance and behaviour, was apparently complete within four da~s of treatment. his observation was substantiated b~ normal bodgweight'increases of treated rats compared with controls.
.
Terminal autopsy findings were normal.
~ hus, it was found that the acute median lethal ,~ ~ ' oral dose (IDso) to rats of compound No. 1 was found to be , ' ~ ~reater tha~,16g./kg. bodyweight~ ,, :
~ - 18 -: . , , , . , . .. . .. , ,, . . . ~ . .. . .
~ffects of Com~ound No. 1 on collagen bios~nthesis in vitro In view of the anti-fibrotic activity of the compounds in vivo, the possibility that they may interfere with collagen biosynthesis was investigated in a test system in vitro.
Cartilage slices from the thyroid plate of pigs were incubated in a chemically defined medium enriched with ascorbate in the presence of [3H]-proline. ~he amount of newly-synthesised collagen was assessed by the incorporation of label into hydrQxyproline, an amino acid virtually restricted to collagen. In control incubations a large proportion (~ 50%~ of the total protein synthesised by the cartilage was collagen. I~clu~ion of compound No. 1 at lm M in the medium almost completely inhibited the incorporation of [3H]-proline into [3H]-hydroxgp~oline, but overall incorporation of label into protein was not affected up to 2h, but was inhibited by 90% after 16h. Addition of ~e++ at 4mM to cartilage slices p-~us the drug almost fully restored the rate of formation of [3H~-hydroxyproline to control values.
Clinical Trials Reports on clinical trials on compound No. 1 are given below.
. -- 19 --_al S.A. Male, 62, Calcification of bladder with haematuria and severe pain in back and legs. Case regarded as hopeless. Given 2 gm, daily for 60 days. Gain of `-appetite, disappearance of pain after 8 days, haematuria disappearance after 14 days, marked shrinkage of tumour after 60 days.
. Trial 2 K,A, Female, 50. Calcification of bladder with haematuria and pain in back and legs. Given 750 mg three times daily, Pain disappeared after 25 days.
Haematuria disappeared after 32 days. Shrinkage of tumour seen by X-ray after 4 months.
Trial3 , G.J. Male. Paraplegia and epileptic fits. Given 2 gm.
daily. Disappearance of epileptic fits after 4 days and improved appetite. Treatment with drug continued for 20 days when spasticity was completely gone, Trial 4 K. S. Female, 9. Tumour in upper maxilla including right eye and mouth cavity. Treated with 2 gm. daily, Pain gone after 8 days. Tumour began to decrease after 14 days. Tumour disappeared from mouth cavity after 30 days. Treatment ce~sed aMer 2 months.
Trial 5 A. S Male, 43, 4 year history of numbness in right leg and arm and progressive disability in use of left leg due to disperse cerebral atrophy, probably of vascular origin. Treatment in hospital with drugs for vasodilation and physiotherapy gave no improvement in condition. Treatrnent with drug, 2 gm, daily for 20 days gave increased appetite and lessened spasticity till after 20 days spasticity disappeared.
Trial 6 M. A. Male, 35, history of Pyrones disease with inability to engage in normal sexual intercourse.. Given 750 mg three times daily for two weeks. Thickening of penis disappeared and sexual activity returned to normal.
.
The following Example illustrates the preparation of a new compound in accordance with the invention.
Examples Schiff bases were prepared by reacting a carbonyl compound (as listed in Table 2 below) with an amine (as listed inTable 2 below).
The reaction was carried out by dissolving 10 mMole of each of the reactants in the minimum quantity of ethanol and subsequently adding the two solutions together. In these cases marked (h) the reaction was conducted with heating and the product was received by allowing the reaction mixture to cool whereupon the product precipitated and wa~ filtered off. In the other cases the reaction was conducted in the cold and the product precipitated on mixing the solutions.
.
r~T~T~
- - - ~
: : V : = ~ ~ " = C ~
--- --- l ~ ~ ~z ~ 3Z, ~ ~ ~ t, ., c, ~.~, ^3 il ~9 l P ~ a ~ , O
P _ ~ _ _ _ _ ...
~J7 ~ W ~ IJ O ~) N ~1 0~ tJ' ~ t~ :
_ (DZ t~
ll . _,_ _ _ __ ~ '-'-U~ I_ O O O~ ~D . O CO O CO N O o _ h~ ~D 2 m o _ O r _ ~ o ~ ~ P.
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_ _~ __ _ ~ ~ ~n ~ ~- . ~ ~ ~ ~ 00 ~n oo Z ro F~ ~ ~ ~ ~ ~ D
_~_ _~ , . i~ , i~ '~_ o . ~C ~
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Z ~ I O . ~ . . . . o . .
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h ~ ~1~1 ~ ~1 ~ ~ ~ æ t~ o- u~ ~
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. W U ~ U U U UU~ U~ U~ U~ U~ U~ . . -_ _ __ . ~ ~D ~r U ., o ~ co a~ ~ ~D 00 . o l ~ I~ ' ~D
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. _ ~ __ _- ._ _ _ ~
Z~
co a~ o ~ ~ ~ ~r ~ ~7 1~ o~
~r ~r ~ d' er ~r ~ ~r ~r oo . - . . - - . -.
nL.~ /, - - - - ~ ~ ~- -~ l~
rSl ~1 ,_1 ~1 ~-i _I _I ~ ~I ~ N ~I
~ , . _ ~ _ i ,. ,, ~: i " , . ~ . .. .
lOf~0438 ~ æ __ __ __ ____ O :~ U~ OD
~q ~ ~ __ ~ _ ~ U~ ~ In _ ul ~ u~ i~ r r r ~ _ _ ~ Z l l 1 l 1.. l l l l l :r: ~o ~ a~ r- ~D ` In _1 O
~ ~ ~ ~ U~ U~ ~ U~
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__, ._ ._ _ _ .._ .__ _ æ ~' .
~ ~ o _l c~ u~ ul u~ u~ ~ u~
~o~
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L
~ ~N . ~ ~
5 3 ( a ) _ _ _ CH3_ _ _ ~CN ~:
54 ~ a) ll Br ( 3 ) ll H ll ll ~ CN
5 5 ( a ) .l H n l ,l ,l ~3 CN
56 (a) ll Br (3) Br (5) H H H 6 5 57 (a) ., H H --CH3 -CH -- ~} CN
58 (a) ll OH (4) OH ~6) .. H -C6H5 Note to ~able I
Compound No~ 30 was prepared using tetracyline as carboxyl compound and the grouping ~/
has the structure:-OH OH O . -~:~0~ :~
HO CH3 ( 3)2 ' .
Where the carrier is a liquid the compositions of the invention may, for example, take the form of a ~olution or suspension or injection comprising the active ingredient (i. e. the Schiff base of formula(I) ), together with sterile, pyrogen-free water or an injectable oil, Alternatively, where the carrier iæ a liquid the composition of the invention may comprise the active ingredient together with a carrier liqùid and one or more pharmaceutical adjuvants such as preservatives, flavouring agents, buffering agents, colouring agents, thickening agents, sweetening agents or suspending agents, Thus, in this latter case, the pharmaceutical compositions of the inver~tion may take the form of syrups, elixirs, linctuse~ or may take the form of a solution or suspension of the active ingredient in a carrier liquid contained in a capsule, especially a soft gelatine capsule, In anothér form of pharmaceutical composition where the carrier is a liquid, the carrier is a pressurised, liquefied propellant (e. g. an halogenated propellant such as Freon 12 and/or Freon 11) and thewhole composition is contained in a pressurised container (i, e. forms a so-called "aerosol"packages~) and is adapted to be administered by inhalation.
Finally, where it is intended to adminster the active ingredient with a liquid carrier the compositions of the invention may take the form of a container containing the active ingredient or provided with a puncturable sealing membrane whereby a carrier liquid (especially water) may be introduced into the container by means of a hypodermic . ~ ~ .. . . .. .
~06~438 syl~inge to form a solution in the container whicl~ the latter is then taken up into the syringe for administration.
Where the pharmaceutical carrier is a solid, the compositions of the invention may comprise conventional solid dosnge units such as tablets, pills or dragees or may compl~isc the solid active ingredient cont~ined in a capsule or may further comprise the active ingredient suspended in a suppository base. In any event, in addition to the solid carrier the solid pharmaccutical compositions of the invention may also include pharmaceutical adjuvents as described above.
Thc compositions of the invention are conveniently put up in dosage unit form and, in this case, each dosa~e unit suit~bly contains from 250 to 3, 000 milligrams of active ingredient, preferably from 500 to 1, 000 milligrams of active ingredient.
As stated above the Schiff bases of formula (I) have a broadly antimyto~ic activity, and, in particular, appear to l~ave an anti-fibrol~lastic and antiinflammatory activity which particularly adapts them for the treatmcnt of certain diseases of which fibrosis is the main or an important part such as, for example, tumour of the bladder, lungs, rectum, liver and pancreas calcification of the bladder due to bilhartzeal fibrosls of the bladder; and coronary occlusions.
The compounds aiso possess anabolic activity, . , ~ he antimytotic activity of the compounds is generally potentiated by the simultaneous adminis-tration of hydrocortisone in small doses, e.g. about 10 mg.. Thus, the invention also provides a composition as defined above also containing hydrocortisone.
Schiff bases are relatively non-toxic and rats when administered at doses of 100g. and 200 mgs./kg. hodyweight respectively.
The toxicity and in vitro and ~n vivo activit~
of compound No. 1 has been investigated under the auspices of the Govérnment of Iraq. ~he in vivo (clinica~) trials were carried out at the Medical Centre, ~aghdad, Iraq.
Acute toxicitly in rats - Rats of the CFY strain, in the weight range 101 to 114g were starved overnight before treatment with compound No. 1.
Compound ~o. 1 was prepared as a 4~o suspension in corn oil and administered by oral intubation at a dosage volume in the full scale test of 40m1./k~. bodyweight. Rats treated with corn oil alone (40ml./kg.) served as controls.
During the observation p~riod of 14 days, a record was kept of all mortalities and signs of toxicity. All rats that died were examined microscopically in an attempt to identify the target organs, and those animals surviving terminally were similarl~ examined to detect possible residual damage.
~ he results of preliminary range finding tests Indicated that the median lethal oral dose (~D50), was greater than 16g./kg. bodyweight.
Dosing was then extended to larger groups of rats (five male and females) in order to confirm this.
., ' .~
Signs of reaction to treatment, observed shortl~
after dosIng included slight lethargy and piloerection. ~his wa~ later accompanied by diarrhoea in six rats.
Death o¢curred withi~ twent~ hours of dosing.
Autops~ revealed injécted blood vessels of the peritoneum and intestinal mesenteries.
'Recovery of survivors a~ judged by external appearance and behaviour, was apparently complete within four da~s of treatment. his observation was substantiated b~ normal bodgweight'increases of treated rats compared with controls.
.
Terminal autopsy findings were normal.
~ hus, it was found that the acute median lethal ,~ ~ ' oral dose (IDso) to rats of compound No. 1 was found to be , ' ~ ~reater tha~,16g./kg. bodyweight~ ,, :
~ - 18 -: . , , , . , . .. . .. , ,, . . . ~ . .. . .
~ffects of Com~ound No. 1 on collagen bios~nthesis in vitro In view of the anti-fibrotic activity of the compounds in vivo, the possibility that they may interfere with collagen biosynthesis was investigated in a test system in vitro.
Cartilage slices from the thyroid plate of pigs were incubated in a chemically defined medium enriched with ascorbate in the presence of [3H]-proline. ~he amount of newly-synthesised collagen was assessed by the incorporation of label into hydrQxyproline, an amino acid virtually restricted to collagen. In control incubations a large proportion (~ 50%~ of the total protein synthesised by the cartilage was collagen. I~clu~ion of compound No. 1 at lm M in the medium almost completely inhibited the incorporation of [3H]-proline into [3H]-hydroxgp~oline, but overall incorporation of label into protein was not affected up to 2h, but was inhibited by 90% after 16h. Addition of ~e++ at 4mM to cartilage slices p-~us the drug almost fully restored the rate of formation of [3H~-hydroxyproline to control values.
Clinical Trials Reports on clinical trials on compound No. 1 are given below.
. -- 19 --_al S.A. Male, 62, Calcification of bladder with haematuria and severe pain in back and legs. Case regarded as hopeless. Given 2 gm, daily for 60 days. Gain of `-appetite, disappearance of pain after 8 days, haematuria disappearance after 14 days, marked shrinkage of tumour after 60 days.
. Trial 2 K,A, Female, 50. Calcification of bladder with haematuria and pain in back and legs. Given 750 mg three times daily, Pain disappeared after 25 days.
Haematuria disappeared after 32 days. Shrinkage of tumour seen by X-ray after 4 months.
Trial3 , G.J. Male. Paraplegia and epileptic fits. Given 2 gm.
daily. Disappearance of epileptic fits after 4 days and improved appetite. Treatment with drug continued for 20 days when spasticity was completely gone, Trial 4 K. S. Female, 9. Tumour in upper maxilla including right eye and mouth cavity. Treated with 2 gm. daily, Pain gone after 8 days. Tumour began to decrease after 14 days. Tumour disappeared from mouth cavity after 30 days. Treatment ce~sed aMer 2 months.
Trial 5 A. S Male, 43, 4 year history of numbness in right leg and arm and progressive disability in use of left leg due to disperse cerebral atrophy, probably of vascular origin. Treatment in hospital with drugs for vasodilation and physiotherapy gave no improvement in condition. Treatrnent with drug, 2 gm, daily for 20 days gave increased appetite and lessened spasticity till after 20 days spasticity disappeared.
Trial 6 M. A. Male, 35, history of Pyrones disease with inability to engage in normal sexual intercourse.. Given 750 mg three times daily for two weeks. Thickening of penis disappeared and sexual activity returned to normal.
.
The following Example illustrates the preparation of a new compound in accordance with the invention.
Examples Schiff bases were prepared by reacting a carbonyl compound (as listed in Table 2 below) with an amine (as listed inTable 2 below).
The reaction was carried out by dissolving 10 mMole of each of the reactants in the minimum quantity of ethanol and subsequently adding the two solutions together. In these cases marked (h) the reaction was conducted with heating and the product was received by allowing the reaction mixture to cool whereupon the product precipitated and wa~ filtered off. In the other cases the reaction was conducted in the cold and the product precipitated on mixing the solutions.
.
r~T~T~
- - - ~
: : V : = ~ ~ " = C ~
--- --- l ~ ~ ~z ~ 3Z, ~ ~ ~ t, ., c, ~.~, ^3 il ~9 l P ~ a ~ , O
P _ ~ _ _ _ _ ...
~J7 ~ W ~ IJ O ~) N ~1 0~ tJ' ~ t~ :
_ (DZ t~
ll . _,_ _ _ __ ~ '-'-U~ I_ O O O~ ~D . O CO O CO N O o _ h~ ~D 2 m o _ O r _ ~ o ~ ~ P.
,1_ _1 _ 'l~o ~ co ~ i~ <~ o ~ 1- _ 1-: o~ c~ ~n ,~ , co . ~ o o) ~ . i~ ~I ~n ~ ~
_ _~ __ _ ~ ~ ~n ~ ~- . ~ ~ ~ ~ 00 ~n oo Z ro F~ ~ ~ ~ ~ ~ D
_~_ _~ , . i~ , i~ '~_ o . ~C ~
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H_ ~ 1~ ~ 1~ N u~ I-- r~ ~ 0 . . ~ . O~ ID 0~ ~ . ~ O
Z ~ I O . ~ . . . . o . .
__ ~ . ~ ~ . . ~ ~ . _ o~ ~r ~ ~ u~ U
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h ~ ~1~1 ~ ~1 ~ ~ ~ æ t~ o- u~ ~
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. W U ~ U U U UU~ U~ U~ U~ U~ U~ . . -_ _ __ . ~ ~D ~r U ., o ~ co a~ ~ ~D 00 . o l ~ I~ ' ~D
o oo U ~ ~ ~r ~ u~
_, ~ m co o~
. _ ~ __ _- ._ _ _ ~
Z~
co a~ o ~ ~ ~ ~r ~ ~7 1~ o~
~r ~r ~ d' er ~r ~ ~r ~r oo . - . . - - . -.
nL.~ /, - - - - ~ ~ ~- -~ l~
rSl ~1 ,_1 ~1 ~-i _I _I ~ ~I ~ N ~I
~ , . _ ~ _ i ,. ,, ~: i " , . ~ . .. .
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~ ~ ~ ~ U~ U~ ~ U~
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~ ~ o _l c~ u~ ul u~ u~ ~ u~
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L
Claims (3)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of the compound of the formula:
(I) in which R1 is hydrogen, R2 is hydrogen, halogen or hydroxy, R3 is hydrogen, halogen or hydroxy or R2 and R3 together with the nucleus A may be naphthalene, or together with the salicylic acid nucleus and R4 may be tetracycline, R4 is lower alkyl of hydrogen, R5 is hydrogen, lower alkyl or hydroxy lower alkyl, R6 is a single bond, lower alkylene, or hydroxy lower alkylene, R7 is phenyl, nitrophenyl, benzonitrile, halophenyl, N-lower alkyl-ene morpholino, 3,4-di-lower alkyl phenyl, pentaloweralkyl phenyl, 3,4-methylene dioxy phenyl or mercaptyl provided that when R1, R2, R3 and R5 are hydrogen, R6 is a single bond or methylene and R4 is methyl; R7 is other than phenyl which comprises (a) reacting a carbonyl compound of the formula in which R1, R2, R3 and R4 have the meanings defined above with an amine of the formula:
in which R5, R6 and R7 have the meanings defined above, in the presence of a lower alkanol as solvent or (b) reacting a carbonyl compound of the formula:
in which R1, R2, R3 and R4 have the meanings defined above with an amino acid of the formula:
in which R6 and R7 have the meanings defined above.
(I) in which R1 is hydrogen, R2 is hydrogen, halogen or hydroxy, R3 is hydrogen, halogen or hydroxy or R2 and R3 together with the nucleus A may be naphthalene, or together with the salicylic acid nucleus and R4 may be tetracycline, R4 is lower alkyl of hydrogen, R5 is hydrogen, lower alkyl or hydroxy lower alkyl, R6 is a single bond, lower alkylene, or hydroxy lower alkylene, R7 is phenyl, nitrophenyl, benzonitrile, halophenyl, N-lower alkyl-ene morpholino, 3,4-di-lower alkyl phenyl, pentaloweralkyl phenyl, 3,4-methylene dioxy phenyl or mercaptyl provided that when R1, R2, R3 and R5 are hydrogen, R6 is a single bond or methylene and R4 is methyl; R7 is other than phenyl which comprises (a) reacting a carbonyl compound of the formula in which R1, R2, R3 and R4 have the meanings defined above with an amine of the formula:
in which R5, R6 and R7 have the meanings defined above, in the presence of a lower alkanol as solvent or (b) reacting a carbonyl compound of the formula:
in which R1, R2, R3 and R4 have the meanings defined above with an amino acid of the formula:
in which R6 and R7 have the meanings defined above.
2. A process as claimed in claim 1 in which the lower alkanol is ethanol.
3. A compound of the formula:
(I) in which R1, R2, R3, R4, R5, R6 and R7 are as in claim 1 whenever prepared or produced by the process as claimed in claim 1 or 2 or an obvious chemical equivalent thereof.
(I) in which R1, R2, R3, R4, R5, R6 and R7 are as in claim 1 whenever prepared or produced by the process as claimed in claim 1 or 2 or an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1915774A GB1529564A (en) | 1974-05-01 | 1974-05-01 | Pharmaceutical compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1060438A true CA1060438A (en) | 1979-08-14 |
Family
ID=10124714
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA225,873A Expired CA1060438A (en) | 1974-05-01 | 1975-04-30 | Pharmaceutical compositions |
Country Status (11)
| Country | Link |
|---|---|
| JP (1) | JPS5112933A (en) |
| AU (1) | AU502579B2 (en) |
| BE (1) | BE828530A (en) |
| CA (1) | CA1060438A (en) |
| DE (1) | DE2519193A1 (en) |
| EG (1) | EG12028A (en) |
| ES (1) | ES437363A1 (en) |
| FR (1) | FR2282870A1 (en) |
| GB (1) | GB1529564A (en) |
| NL (1) | NL7505174A (en) |
| NZ (1) | NZ177384A (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2418222A2 (en) * | 1975-08-01 | 1979-09-21 | Synthelabo | Alpha-phenyl 2-hydroxy-benzylidene amino-alkanoic acid derivs. - and novel di:phenyl-ketone intermediates, useful as anticonvulsants for treating epilepsy |
| JPS52159599U (en) * | 1976-05-27 | 1977-12-03 | ||
| JPS5812993Y2 (en) * | 1978-07-19 | 1983-03-12 | 日本鋼管株式会社 | Suspended opening/closing scaffolding device |
| FR2475543A1 (en) * | 1980-02-12 | 1981-08-14 | Synthelabo | BENZYLIDENIC DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| FR2544308B1 (en) * | 1983-04-14 | 1985-06-14 | Synthelabo | SUBSTITUTED ETHINS, THEIR PREPARATION AND THEIR APPLICATION IN THERAPEUTICS |
| NO940195L (en) * | 1993-01-25 | 1994-07-26 | Norsk Hydro As | New connections |
-
1974
- 1974-05-01 GB GB1915774A patent/GB1529564A/en not_active Expired
-
1975
- 1975-04-26 EG EG25475A patent/EG12028A/en active
- 1975-04-29 BE BE155898A patent/BE828530A/en unknown
- 1975-04-30 ES ES437363A patent/ES437363A1/en not_active Expired
- 1975-04-30 DE DE19752519193 patent/DE2519193A1/en active Pending
- 1975-04-30 CA CA225,873A patent/CA1060438A/en not_active Expired
- 1975-04-30 FR FR7513529A patent/FR2282870A1/en active Granted
- 1975-05-01 JP JP5308975A patent/JPS5112933A/en active Pending
- 1975-05-01 AU AU80721/75A patent/AU502579B2/en not_active Expired
- 1975-05-01 NL NL7505174A patent/NL7505174A/en not_active Application Discontinuation
- 1975-05-01 NZ NZ17738475A patent/NZ177384A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NZ177384A (en) | 1978-03-06 |
| DE2519193A1 (en) | 1975-11-20 |
| BE828530A (en) | 1975-10-29 |
| EG12028A (en) | 1978-06-30 |
| FR2282870B1 (en) | 1978-11-10 |
| AU8072175A (en) | 1976-11-04 |
| AU502579B2 (en) | 1979-08-02 |
| ES437363A1 (en) | 1977-05-16 |
| JPS5112933A (en) | 1976-01-31 |
| NL7505174A (en) | 1975-11-04 |
| FR2282870A1 (en) | 1976-03-26 |
| GB1529564A (en) | 1978-10-25 |
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